archivio italiano di urologia e andrologia 2013; 85, 134 introduction molecular mechanisms responsible from varicocele induced testicular dysfunction and male infertility have not been completely unknown. recent years have witnessed a huge amount of scientific works devoted to the mechanism of varicocele associated male infertility and rapid progress in research on its cellular and molecular mechanisms, including apoptosis and oxidative stress of germ cells. here we evaluated internal spermatic vein and brachal vein ischemia modified albumin (ima) level in 40 adult male patients with varicocele. materials and methods after ethical comittee approval a total of 40 normal gonadotropic patients, aged between 23 and 37 years, attending a male infertility clinic because of prolonged (more than 1 years) subfertility were included in the study. all patients were evaluated by physical examination and scrotal color doppler ultrasonography. all had unilateral grade ii or iii primary varicocele but no testicular atrophy was diagnosed. on the right side, scrotal doppler ultrasonography and physical examination were normal in all cases. those with abnormal hormone analysis, testicular atrophy, genito-urinary tract infection, azoospermia were excluded. the mean sperm concentration was 9.9 ± 2.3 x 106 spermatozoa/ml, while the mean percentage of motile spermatozoa after 1 h was 38.1 ± 1.6%. the mean percentage of morphologically normal spermatozoa was 29.3 + 0.8%. original paper lack of significant difference between internal spermatic vein and brachial vein ischemia modified albumin levels in patients with varicocele yuksel aliyazicioglu 1, emin ozbek 2, levent ozcan 3, s. sami cakir 2, murat dursun 2 1 department of biochemistry school of medicine, karadeniz technical university, trabzon, turkey; 2 okmeydani research and education hospital, department of urology, istanbul, turkey; 3 sinop state hospital, department of urology, sinop-turkey. varicocele is the most common and surgically correctible cause of male infertility in men attending to infertility clinics. infertility affects 15% of all couples and male factor is the primary or contributing cause in 40% to 60% of cases. varicocele has been shown to cause male infertility in about 15% of infertile couples. molecular mechanisms responsible from varicocele induced testicular dysfunction and male infertility have not been completely unknown. recent years have witnessed a huge amount of scientific works devoted to the mechanism of varicocele associated male infertility and rapid progress in research on its cellular and molecular mechanisms, including apoptosis and oxidative stress of germ cells. here we evaluated internal spermatic vein and brachal vein ischemia modified albumin (ima) level in 40 adult male patients with varicocele. ima level was analyzed using albumin cobalt-binding test. spermatic vein and brachial vein ima levels were 0.381 ± 0.135 absu (absorbance units) and 0.385 ± 0.131 absu, respectively. there was no statistically significant difference between the two areas. ima levels in the internal spermatic vein of patients with varicocele should not be used as a marker of hypoxia. key words: infertility; ischemia modified albumin; oxidative stress; varicocele. submitted 30 october 2012; accepted 28 february 2013 no conflict of interest declared summary ozbek_lack_stesura seveso 18/04/13 12:03 pagina 34 35archivio italiano di urologia e andrologia 2013; 85, 1 lack of significant difference between internal spermatic vein and brachial vein ischemia modified albumin levels in patients with varicocele stroke and myocardial infarction and testicular torsion are associated with increased serum ima concentrations (5). taking into account the evident ischemia-related oxidative stress in varicocele we compared in spermatic and brachial veins of patients with varicocele the ima level as sensitive marker of ischemia and oxidative stress. despite the increased oxidative stress and ischemia related to varicocele, ima concentrations in spermatic veins were not significantly higher than brachial veins. this finding is difficult to explain, although it may be possibly explained by the presence of only relatively small ischemic areas and by the short transit time of ischemic blood within the dilated internal spermatic veins. as a result of our study we have to conclude that ima levels in the internal spermatic veins of varicocele patients should not be used as a marker of hypoxia. references 1. sun y, wang l, xu c, et al. ypoxia-induced apoptosis in the bilateral testes of rats with left-sided varicocele: a new way to think about the varicocele. j androl. 2010; 31:299-305. 2. ozbek e, turkoz y, gokdeniz r, et al. increased nitric oxide production in the spermatic vein of patients with varicocele. eur urol. 2000; 37:172-5. 3. chen ss, huang wj, chang ls, wei yh. 8-hydroxy-2’deoxyguanosine in leukocyte dna of spermatic vein as a biomarker of oxidative stress in patients with varicocele. j urol. 2004; 172:1418-21. 4. kutlu o, mentese a, turkmen s, et al. investigation of the possibility of using ischemia-modified albumin in testicular torsion: an experimental. fertil steril. 2011; 95:1333-7. 5. mastella ak, moresco rn, da silva db, et al. evaluation of ischemia-modified albumin in myocardial infarction and prostatic diseases. biomed pharmacother. 2009; 63:762-6. 6. bar-or d, lau e, winkler jv. a novel assay for cobalt-albumin binding and its potential as a marker for myocardial ischemia-a preliminary report. j emerg med. 2000; 19:311-315. whole blood samples (1.5 ml) were drawn using a 25gauge-needle during surgery for varicocele from a brachial vein and from the internal spermatic vein. the dilated spermatic vein was punctured immediately after exposing the spermatic cord and before any further manipulation. after obtaining blood samples in plain tubes contained separation gels, the samples was allowed to clot for 30 minutes and centrifuged before separating the serum. the samples were then immediately frozen and stored at -80°c for assays ima. ima level was analyzed using albumin cobalt-binding test (6). results spermatic vein and brachial vein ima concentrations were 0.381 ± 0.135 absu (absorbance units) and 0.385 ± 0.131 absu, respectively. there was no statistically different at comparison with mann whitney u test (p > 0.05). discussion in a study (1) using expression of the alpha subunit of hypoxia-inducible factor 1 (hif-1 alpha) as a marker of hypoxia, it was reported that left-sided experimental varicocele in the rat causes bilateral testicular hypoxia and germ cell apoptosis. role of nitric oxide (no) and reactive oxygene species in varicocele induced male infertility have also been extensively reported (2, 3). ischemia modified albumin (ima) is produced when hypoxic heart tissue induces modification of circulating albumin (4). therefore ima is proposed as a biomarker of ischemia and oxidative stress. modifications that alter the binding capacity of albumin for cobalt may arise during ischemia as a result of acidosis, reduced oxygen tension and generation of free radicals. several clinical conditions such as pulmonary embolism, mesenteric ischemia, peripheral arterial occlusion, deep venous thrombosis, correspondence yuksel aliyazicioglu, md department of biochemistry school of medicine-karadeniz technical university, trabzon, turkey emin ozbek, md (correspoinding author) department of urology okmeydani research and education hospital darul aceze caddesi, 34384, sisli, istanbul, turkey ozbekemin@hotmail.com levent ozcam, md department of urology sinop state hospital sinop, turkey s. sami cakir, md murat dursun, md department of urology okmeydani research and education hospital istanbul, turkey ozbek_lack_stesura seveso 18/04/13 12:03 pagina 35 introduction angiomyolipoma is a nodule composed of variable amounts of mature adipose tissue, smooth muscle, and thick-walled blood vessels derived from perivascular epithelioid cells usually arising in the renal cortex. its prevalence in the general population has been reported to be 0,3-3% overall in the female patients (1). in the multifocal form, it is usually associated to tuberous sclerosis (2). the average lesion size is from 2 mm to 20 cm maximum diameter. in most cases the angiomyolipoma is asymptomatic and is diagnosed incidentally with ultrasound, ct and mri done for other reasons. renal angiomyolipoma at times can be aggressive and may show extension into renal vein and inferior vena cava (3). we describe a paradigmatic case of a giant kidney angiomyolipoma, not associated with tuberous sclerosis, invading the pelvis and the renal vein. case report the lesion have been incidentally discovered in a 78 years old woman by ultrasound scan done for other reasons. total body ct scan and mri have been done showing large node (18 mm) in the mediastinus, a 8 cm large lesion of the upper pole of the left kidney with prevalence of fat tissue and solid areas invading the renal vein for 4 cm, some large nodes (1 cm) in the retroperitoneum and gallbladder stones (figure 1, 2). past medical history included breast reduction; hyatal hernia surgery; hypothiroidism; pulmu107archivio italiano di urologia e andrologia 2013; 85, 2 case report renal angiomyolipoma with renal vein invasion francesca di cristofano, federico petrucci, guglielmo zeccolini, genesio leo, calogero cicero, dario del biondo, antonio celia department of urology, san bassiano hospital, bassano del grappa (vi), italy. renal angiomyolipoma is a uncommon benign tumor, considered an hamartoma. the lesion, usually benign, can be single or multiple and well-circumscribed. in letterature only few cases of infiltrating angiomyolipomas have been described. the aim of the paper is to describe a paradigmatic case of a giant kidney angiomyolipoma, not associated with tuberous sclerosis, invading the pelvis and the renal vein. the lesion have been discovered incidentally during abdominal ultrasound for other pathology. owing to the extent of the lesion and the appreciable risk of bleeding, we opted for surgical treatment. key words: angiomyolipoma; kidney; renal vein invasion; radical nephrectomy. submitted 20 november 2012; accepted 31 december 2012 no conflict of interest declared summary nary infection during the last months. blood tests: hb 15 g/dl-1 leukocyte 8 x 103 µl-1, urea 44 mg/d-1, creatinine 0.9 mg/dl-1. the extension of the lesion, the risk of bleeding and the risk of renal carcinoma were carefully evaluated in order to decide the surgical treatment. the patient underwent laparoscopic left adrenal sparing radical nephrectomy. definitive histology: renal angiomyolipoma invading the renal vein with negative ilar nodes and normal left renal parenchima (figure 3, 4). no post-operative complications. the patient was discharged in the fifth postoperative day. at the first control, one month after the operation, the patient was asymptomatic, the abdominal ultrasound scan was normal and the blood tests were normal. figure 1. axial ct section showing extension of the lesion into the renal vein. di cristofano_stesura seveso 24/06/13 11:12 pagina 107 archivio italiano di urologia e andrologia 2013; 85, 2 f. di cristofano, f. petrucci, g. zeccolini, g. leo, c. cicero, d. del biondo, a. celia 108 plex cases (7). lesion larger than 4 cm may bleed, may cause flank pain and may be palpable (8). when the lesion is growing, when it is symptomatic or when the differential diagnosis is doubtful, surgical treatment is necessary: enucleoresection, embolization or radical nephrectomy (9). conclusions in most cases angiomyolipoma is asymptomatic and it is an incidental finding during ultrasound scan or ct scan done for other reasons. it may involve regional nodes, renal vein or inferior vena cava, that can suggest an aggressive evolution (10); anyway, these lesions are not considered metastasis. in case of benign lesion the treatment has to be conservative. radical surgery is requested in those rare cases where the angiomyolipoma is really large or involves the renal vein. references 1. wagner bj, wong-you-cheong jj, davis cj. adult renal hamartomas. radographics. 1997; 17:155-69. 2. benanni s, dahami z, dakir m, et al. bilateral renal angiomyolipoma associated with tuberous sclerosis: report of a case. ann urol. 2000; 34:278-282. 3. bakshi ss, vishal k, kalia v, gill js. aggressive renal angiomyolipoma extending into the renal vein and inferior vena cava an uncommon entity. br j radiol. 2011; 84:e166-e168. 4. inomoto c, umemura s, sasaki y, et al. renal cell carcinoma arising in a long pre-existing angiomyolipoma. pathol int. 2007; 57:162-6. 5. inci o, kaplan m, yalcin o, et al. renal angiomyolipoma with malignant transformation, simultaneous occurrence with malignity and other complex clinical situations. int urol nephrol. 2006; 38:417-26. 6. salerno s, lo casto a, sorrentino f, et al. bleeding renal angiomyolipomas. ct findings. radiol med. 2004; 107:229-33. 7. pozzi mucelli r, locatelli m. diagnostica per immagini dell’angiomiolipoma renale: quadri tipici e atipici. radiol med. 2002; 103:474-87. 8. steiner ms, goldman sm, fishman ek, marshall ff. the natural history of renal angiomyolipoma. j urol. 1993; 150:1782-1786. 9. yiu wc, chu sm, collins rj, et al. aggressive renal angiomyolipoma: radiological and pathological correlation. jhk coll radiol. 2002; 5:240-2. 10. wilson ss, clark pe, stein jp. angiomyoplipoma with vena caval extension. urology. 2002; 60:695-6. discussion renal angiomyolipoma is usually a benign lesion, it can be rarely associated to renal adenocarcinoma (4, 5) and to tuberous sclerosis. the histology shows mature adipose tissue, smooth muscle, and thick-walled blood vessels. the sporadic angiomyolipoma is monolateral and more frequent in the females. when associated to tuberous sclerosis, angiomyolipomas are multiple, bilateral and larger. the clinical interest in angiomyolipoma is in its rapid growth, the difficulty in distinguishing it from malignant lesions, the difficulty of establishing the diagnosis and correct treatment. the diagnosis is usually made by ultrasound scan that find a hyperecogenic omogeneus lesion in the renal cortex. the large lesions may have disomogeneus areas that make the diagnosis difficult; tc scan is usually mandatory in the large lesions: the diagnosis is based on the identification of fat inside the lesion (6). mri is useful only in some comcorrespondence francesca di cristofano, md (corresponding author) vico san lorenzo 6 terni, italy fdicristofano@gmail.com federico petrucci, md guglielmo zeccolini, md genesio leo, md calogero cicero, md dario del biondo, md antonio celia, md department of urology san bassiano hospital bassano del grappa (vi), italy figure 2. t2 weighted mri mass shows hyperintense signal with extension into renal vein. figure 3. renal angiomyolipoma: blood vessels with thickened walls mature adipose tissue and smooth muscle cells mixed. eex20 figure 4. renal angiomyolipoma: renal vein invasion. eex5 di cristofano_stesura seveso 24/06/13 11:12 pagina 108 archivio italiano di urologia e andrologia 2013; 85, 296 introduction rupture of an aneurysm of the retroperitoneal or pelvic vessels represents an extremely rare cause of macroscopic haematuria (1, 2). the diagnosis is difficult but should be considered whereas conditions as neoplasms, lithiasis or infections have been excluded and there is a history of retroperitoneal/pelvic surgical treatment. case report in the present report, we describe the case of a 65 yearsold-woman who underwent a diagnostic laparoscopy for a suspected ovarian cancer. the procedure consisted in a peritoneal washing, right oophorectomy and multiple biopsies of the right and left diaphragmatic dome of the peritoneum with an intraoperative diagnosis of peritoneal carcinomatosis. the histological examination confirmed the presence of an ovarian serous carcinoma. the patient underwent an operative laparoscopy with extrafascial radical isterectomy, left oophorectomy, pelvic peritonectomy and pelvic-lomboaortic lymphadenectomy. during the procedure the right ureter was accidencase report massive hematuria due to ruptured iatrogenic aortic pseudoaneurysm: a case report valerio vagnoni 1, caterina gaudiano 2, giovanni passaretti 1, riccardo schiavina 1, eugenio brunocilla 1, cristian vincenzo pultrone 1, marco borghesi 1, giuseppe martorana 1 1 department of urology, university of bologna, s. orsola-malpighi hospital, bologna, italy; 2 department of radiology, bologna, s. orsola-malpighi hospital, bologna, italy. we report an interesting case of massive haematuria secondary to a rupture of a pseudoaneurysm of the abdominal aorta below the renal vessels. a 65-year-old woman presented at our institution with a painful massive haematuria and anaemia. two months before, she undergone a pelvic surgery complicated by an accidental injury of the right ureter sutured with a end-to-end anastomosis. an abdominal computed tomography (ct) scan with intravenous contrast showed a right-sided hydronephrosis with clots in the lumen of the right pelvis with a massive retroperitoneal hematoma due to a rupture of a iatrogenic pseudoaneurysm of the abdominal aorta below the origin of the renal arteries. key words: haematuria; aortic pseudoaneurysm; pelvic surgery. submitted 25 october 2012; accepted 31 december 2012 no conflict of interest declared summary tally injured; therefore a laparotomic surgery has been required and an end-to-end ureteral anastomosis with placement of a renovesical “jj stent” was performed. the stent was removed after 45 days and after 65 days from surgery the patient presented at our institution with massive haematuria and severe anaemia (haemoglobin 7.6 g/dl, haematocrit 23%). bladder irrigation was initiated and cystoscopy showed a little clot from the right ureteric orifice in the absence of urothelial bladder lesions: a right ureteral catheter was inserted, some clots were removed from the right pelvis and a right retrograde pyelography showed the dehiscence of the uretheral anastomosis with a mild passage of contrast medium in the left retroperitoneum; thereafter, a second renovesical “jj stent” was inserted. an abdominal computed tomography (ct) scan was performed: we noted a right-sided hydronephrosis with clots in the lumen of the right pelvis and the presence of a massive hematoma between the abdominal aorta and the vena cava, ahead the ileo-psoas muscle in the left retroperitoneum (figure 1); after the administration of vagnoni_stesura seveso 24/06/13 11:07 pagina 96 97archivio italiano di urologia e andrologia 2013; 85, 2 hematuria after ruptured aortic pseudoaneurysm la due to the rupture of a iatrogenic pseudoaneurysm of the abdominal aorta was diagnosed and, after consulting the vascular surgeon, the patient underwent an urgent placement of aortic endoprothesis. afterwards, the hematuria was controlled. a further ct exam showed the correct positioning of the prosthesis and the patient was discharged with ureteral stent. discussion we described an extremely rare cause of macroscopic hematuria due to the rupture of a iatrogenic pseudoaneurysm of the abdominal aorta. the recent ureterouretero-anastomosis due to the accidental injury of the ureter was the obligatory condition in order to have an aorto-ureteric fistula after the rupture of the aneurysm. the iatrogenic injury of the aortic wall during the lymphadenectomy may explain the pseudoaneurysm. surgical treatment procedures like vascular reconstructive surgery or retroperitoneal/pelvic surgery for urogynecolocic or abdominal malignancies represent conditions with a potential risk for a hemorrhagic fistula from an artery into the urinary outflow tract; furthermore, previous radiation therapy or presence of aortic or iliac aneurysm may represent a potential risk conditions for the development of a fistula between an artery and the urinary tract; in the latter cases the pathophysiology is unclear but seems to be related to the inflammatory reaction around the aneurysm caused by surgery, radiation, malignancy, pulsatile trauma with the fixation and subsequent perforation of ureteral or bladder wall (1, 2). also the endourological treatment such as holmium laser endoureterothomy or acucise ballon endopielotomy for ureteropelvic junction obstruction may represent a rare cause of iatrogenic arterio-urinary fistula (3). in the present case, hematuria represented the sole symptom. however the passage of the clots in the renal pelvis and ureter could have been the cause of the abdominal pain. in literature is anecdotally reported that, in the absence of the intravenous contrast (arterial phase), we noted the presence of a breach of the right wall of the abdominal aorta, 4 cm below the origin of the renal arteries, with a large loculated pseudoaneurysm (axial diameters 37 x 22 mm) (figures 2-3) in the right retroperitoneum with a massive hematoma due to a recent rupture of the aneurysm. hematuria caused by an aorto-ureteral fistufigure 1. non-enhanced abdominal ct scan in the axial plane showing a right-sided hydronephrosis with clots in the lumen of the right pelvis. figure 2. contrast enhanced abdominal ct scan in arterial phase (mpr-reconstruction in oblique axial plane) showing the abdominal aortic pseudoaneurysm in the context of a massive retroperitoneal hematoma. note the metallic clip utilized during pre-aortic lymphadenectomy and the right ureteral stent (red arrow). figure 3. contrast enhanced abdominal ct scan in arterial phase (mip-reconstruction in oblique coronal plane) showing the pseudoaneurysm below the right renal artery in the context of a massive retroperitoneal hematoma. vagnoni_stesura seveso 24/06/13 11:07 pagina 97 archivio italiano di urologia e andrologia 2013; 85, 2 v. vagnoni, c. gaudiano, g. passaretti, r. schiavina, e. brunocilla, c.v. pultrone, m. borghesi, g. martorana 98 references 1. honma i, takagi y, shigyo m, et al. massive hematuria after cystoscopy in a patient with an internal iliac artery aneurysm. int j urol. 2002; 9:407-409. 2. bergqvist d, parsson h, sherif a. arterio-ureteral fistula a systematic review. eur j vasc endovasc surg. 2001; 22:191-196. 3. preminger gm, clayman rv, nakada sy, et al. a multicenter clinical trial investigating the use of a fluoroscopically controlled cutting balloon catheter for the management of ureteral and ureteropelvic junction obstruction. j urol. 1997; 157:1625-1629. 4. levi n, sonksen jr, iversen p, helgstrand u. rupture of an iliac artery pseudo-aneurysm into a ureter case report. eur j vasc endovasc surg. 1999; 17:264-265. a correct diagnosis of the arterio-ureteral fistula, a nephroureterectomy has often been performed, in emergency and life-threatening cases (2, 4); however, it is clear that the goal of the treatment is to solve the vascular lesion. open or endovascular procedures generally allow to stop the hematuria even if postoperative morbidity and mortality still remains high but less than thirty years ago. in conclusion, the present case report represents a rare cause of massive hematuria due to a double iatrogenic surgical injury of the aortic wall and the right ureter. after the initial rupture of the pseudoaneurysm (with subsequent spontaneous closing), a massive hemorrhage of the retroperitoneum and the dehiscence of a recent uretero-ureteral anastomosis caused a massive aortoureteral fistula that was promptly corrected by the placement of aortic endoprothesis. correspondence valerio vagnoni, md (corresponding author) vagno07@libero.it giovanni passaretti, md giovannipassaretti@hotmail.it riccardo schiavina, md rschiavina@yahoo.it eugenio brunocilla, md eugenio.brunocilla@unibo.it cristian vincenzo pultrone, md cristian28@libero.it marco borghesi, md mark.borghesi@gmail.com giuseppe martorana, md giuseppe.martorana@unibo.it department of urology, university of bologna, s. orsola-malpighi hospital, via p. palagi 9 40138, bologna, italy caterina gaudiano, md department of radiology, bologna, s. orsola-malpighi hospital, via p. palagi 9 40138, bologna, italy caterina.gaudiano@aosp.bo.it vagnoni_stesura seveso 24/06/13 11:07 pagina 98 stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 note on surgical technique operative efficiency. we hereby describing our novel technique of penile tourniquet application using a silicone penrose tube designed as a strap. this technique increases the operative efficiency and simplifies the application of a tourniquet for any type of penile surgery. technique this technique was designed by an experienced penile reconstructive surgeon who performed and tested various tourniquet techniques. our technique consists of the application of sterile penrose silicone tube drain (medline® ref.dynd50427, size: 45.72 cm x 0.64 cm). in this purpose, we utilize all penrose length (45.72 cm) without shortening the tube. first, we create the tourniquet part of the tube by using about 15 cm of the tube length as a loop. then, we create a small 0.8 cm through and through hole in the 15 cm point using a surgical mayo scissors. the extremity of the drain is then passed through this small window. we apply then the tourniquet loops around the base of the penis and secure the loop by pulling away both extremities to create the desired compression on the corporal bodies. the tourniquet will be self-retained, anti-slip through the silicone surface characteristics and the hole resistance. additional clamping may be beneficial to increase or to maintain the exerted pressure. lastly, releasing the tourniquet will be achieved by removing the clamp if present or simply by untightening both penrose tube extremities. this maneuver can be repeated several times during the surgery without removing the tourniquet from the base of the penis. the tension exerted through the tourniquet is adjustable according to the pressure desired. in our experience, no complications, failures nor difficulties were encountered, and the application of this novel technique is reproducible and easy to perform (figure 1). discussion to our knowledge, this is the first article describing this technique. there is a paucity of data regarding the various tourniquet types and safety use guidelines for penile surgery. gupta et al. (6), studied the different type of penile tourniquet with an author’s design of silicone strip tourniquet secured by tubectomy ring. introduction: penile compression using a tourniquet is common with several materials and designs that have been previously described. the objective of the tourniquet is to induce an artificial erection through corporal occlusion for intra-operative penile curvature assessment or to obtain a clear visible bloodless surgical field. objective: we sought to describe our novel step-by-step technique of applying penile tourniquet using silicone penrose drain tube designed as a strap by creating a small hole on the side of the tube to obtain a loop at the base of the penis conclusions: this novel technique is simple, effective and requires no additional materials nor special equipment, and facilitates the application and release of a tourniquet during penile surgery. key words: penis; penile surgery; tourniquet; penoplasty, surgical technique. submitted 21 january 2023; accepted 17 february 2023 introduction penile surgery is common in general and reconstructive urology. frequently, surgeons apply intra-operative penile compression called tourniquet – derived from the french verb ‘’to turn’’ – at the base of the penis to induce an artificial arterial erection to assess penile curvature. furthermore, tourniquet use allows a bloodless surgical field and an adequate hemostatic control in either emergency or elective settings. the aim of the tourniquet in penile surgery is to compress and constrict distal penile blood outflow by corporal body occlusion (1). routine use of a tourniquet is safe respecting occlusion time and the exerted pressure to avoid complications (2). there is no standardized penile tourniquet design nor specific material recommendation. several material types have been used (for example silicone, rubber, and latex) in numerous forms such as catheters, bands, rolled gloves and drains secured either by a simple knot tie or by a two-turn loop fashion by clamping in order to maintain the pressure inside both corpora cavernosa (3-5). in an attempt to respect the recommended occlusive compression time of less than 30-40 minutes 2, surgeons may require to release and to reapply the tourniquet several times during the surgery. in contrast, repeating tourniquet applications and releasing could decrease the intranovel penile compression technique of penile surgeries ‘’penile strap’’ abdulghani khogeer 1, 2, abdullah alzahrani 1, 3, ahmed ibrahim 1, melanie aubé-peterkin 1, serge carrier 1 1 department of surgery, division of urology, mcgill university health center, montreal qc, canada; 2 department of surgery, faculty of medicine, rabigh, king abdulaziz university, jeddah, saudi arabia; 3 department of urology, college of medicine, imam abdulrahman bin faisal university, dammam, saudi arabia. doi: 10.4081/aiua.2023.11201 summary archivio italiano di urologia e andrologia 2023; 95, 1 a. khogeer, a. alzahrani, a. ibrahim, m. aubé-peterkin, s. carrier in our center, we examined the application of silicone penrose drain tube designed intra-operatively as a selfgripped strap with or without additional securing clamp to maintain the pressure. furthermore, we found that this technique helps to maintain the tourniquet at the base of the penis all over the surgery in either released or tightened fashion. tightening or un-tightening the tourniquet is achieved by simply pulling or releasing both extremities respectively. this technique doesn’t require any additional materials or resources and require exclusively a silicone penrose tube and surgical mayo scissors to create the small window. penrose drain is widespread available and currently used by many urologists as a tourniquet in several forms. we modified the usage of silicone penrose for this indication by inventing this strap-like tourniquet design. the aim of our study is to describe an effective technical surgical step that could interest current and future reconstructive urologist that we perceive as simple and easy to perform. however, our study is limited by its descriptive non-comparative design with no intention to prove superiority among other tourniquet techniques in terms of either facility or functional outcomes. we found this technique is easy with similar satisfactory operative objectives in terms of bleeding control and corporal occlusion. in addition, the use of tourniquet is advantageous during penile curvature surgery in order to achieve best results notably in cases of solitary saline infusion or vasoactive agents injection failure. surgeon should consider that penile tourniquet could compromise precise assessment of penile curvature through penile geometrical alteration especially in the presence of penile deformities at the base of the penis (hour-glass deformity, indentations). however, this technical field needs further studies to assess and to compare different tourniquet designs and to evaluate the exerted local mechanical pressure effects on the penile tissues and vascularity (dorsal penile arteries) and glandular supply. our future suggestion is to create a penile tourniquet inspired by our design with either selflocked strap or buckle band (e.g., tongue/button and holes) with a pressure graduation measurement. conclusions this novel technique of penile tourniquet is effective, reproducible and easy to perform to achieve complete corporal bodies occlusion for various penile surgery. further studies are warranted to compare different tourniquet designs with penile mechanical pressure evaluation. references 1. klenerman l. the tourniquet in surgery. j bone joint surg br. 1962; 44-b:937-943. 2. parsons ba, kalejaiye o, mohammed m, persad ra. the penile tourniquet. asian j androl. 2013; 15:364-367. figure 1. step-by-step technique (a-f). measuring 15 cm from one extremity. marking the hole window at the 15 cm creating the hole using the mayo point. scissors. (a) (b) (c) passing the extremity of the tube applying pressure by pulling away both securing the loop by using a surgical through the hole created. extremities. clamp. (d) (e) (f) archivio italiano di urologia e andrologia 2023; 95, 1 penile strap for penile surgery 3. redman jf. tourniquet as hemostatic aid in repair of hypospadias. urology. 1986; 28:241. 4. barnett a, pearl rm. readily available, inexpensive finger tourniquet. plast reconstr surg. 1983; 71:134-135. 5. obaidullah, aslam m. ten-year review of hypospadias surgery from a single centre. br j plast surg. 2005; 58:780-789. 6. gupta dk, devendra s. a simple and safe penile tourniquet. indian j plast surg. 2015; 48:93-95. correspondence abdulghani khogeer, md dr-abdulghani@hotmail.com melanie aubé-peterkin, md melanie.aube-peterkin@mcgill.ca abdullah alzahrani, md abdullah.alzahrani2@mail.mcgill.ca ahmed ibrahim, md eldemerdash90@gmail.com department of surgery, division of urology, mcgill university health center, montreal qc, canada serge carrier, md, frcs (c), mmmgt, professor of urology (corresponding author) serge.carrier@mcgill.ca mcgill university health centre 1001 boul decarie, suite d05.5331, montreal, quebec h4a 3j1 conflict of interest: the authors declare no potential conflict of interest. introduction the lymphatic drainage of the testis follows the vessels around the spermatic vein until the retroperitoneal nodes between the lower thoracic and lumbar vertebrae. for this reason testicular cancer spreading usually involves the lymph nodes in the retroperitoneum as primary landing site. however, atypical lymphatic sites may be involved and a 2% incidence of inguinal metastases in testicular cancer has been reported (1-4). this atypical spreading has been related to history of previous surgery in the inguinal region or scrotum. a modified lymphatic drainage can be created by surgical violation during orchidopexy, relief of hydrocele or varicocelectomy (5-10). in 47archivio italiano di urologia e andrologia 2012; 84, 4 case report inguinal polypropylene plug: a cause of unusual testicular tumor pelvic metastasis marco grasso 1, salvatore blanco 1, angelica anna chiara grasso 2, luca nespoli 3 1 department of urology, azienda ospedaliera san gerardo, università degli studi di milano-bicocca, monza, italy; 2 department of urology, fondazione irccs ca’ granda ospedale maggiore policlinico, università degli studi di milano, milano, italy; 3 department of general surgery, azienda ospedaliera san gerardo, università degli studi di milano-bicocca, monza, italy. we report the case of a patient who had undergone polypropylene plug placement 3 years before and referred to our institution with testicular tumor. ct scan demonstrated an enlargement of pelvic lymph nodes on the tumor side while retroperitoneal nodes were normal. orchifunicolectomy was performed and histopathological examination showed a mixed germ cell tumor involving the tunica vaginalis, rete testis, epididymis and spermatic cord. after surgery the patient was addressed to adjuvant chemotherapy according to peb scheme. clinical re-staging showed a decrease of the pelvic bulk disease whereas retroperitoneal nodes were still normal and tumor markers were negative. left external, internal and common iliac lymphadenectomy as well as left modified template nervesparing retroperitoneal lymph node dissection was performed. intraoperatively the node bulk was firmly adherent to the external iliac artery and extended until the common iliac bifurcation. in the deeper part of this enlarged and firm lymphatic chain the polypropylene plug placed at the time of hernioplasty was found. behind the plug all retroperitoneal nodes appeared normal and resulted negative on histopathologic examination. the patient had an unusual metastatization, probably due to the plug. key words: testicular tumor; polypropylene plug; metastasis. submitted 2 november 2012; accepted 31 december 2012 no conflict of interest declared summary these cases direct lymphatic drainage to the inguinal nodes can be developed. we report a case of unusual lymphatic spreading of testicular cancer after previous hernioplasty in which a polypropylene plug was deeply placed into internal inguinal ring according to the the lichtenstein tensionfree mesh onlay repair (11). case report a 26 years old man was examined on march 2001 for left testicular mass which appeared as clinically malignant. he grasso_stesura seveso 18/04/13 12:06 pagina 47 archivio italiano di urologia e andrologia 2012; 84, 4 m. grasso, s. blanco, a.a.c. grasso, l. nespoli 48 lene plug placed at the time of hernioplasty was found (figure 3). behind the plug all retroperitoneal nodes appeared normal and resulted negative on histopathologic examination. external iliac and otturatory lymph nodes however showed large tissue necrosis and focal mature teratoma. after 3 years the patient underwent left inguinal lymphadenectomy for lymphnodes enlargement. hystopathologic examination showed no recurrent cancer. at the last follow-up the patient was healthy and free of disease, father of a child spontaneously conceived two years ago. discussion inguinal hernioplasty represents one of the most frequently performed surgical operations. the recent introduction of prosthetic mesh made bassini operation obsolete, with more space gained by the newly developed “tension -free” and “sutureless” surgical technique (12, 13) the study proposed by gandolfo showed the tissutal reaction consequent to the plug. at ultrasonography the mesh presented as a small hyperechoic layer. in some patients a seroma was present above the mesh. the seroma disappeared spontaneously between 30 and 90 days postoperatively and was probably related to the size of the hernia and the number of plugs (14). various studies analyzed the factors associated with postoperative complications and hernia recurrence (15). in about 2% of cases testicular cancer lymphatic metastatization is atypical and includes inguinal lymph nodes (1-4). this unusual lymphatic spreading may happen for a significant variation of an otherwise normal anatomical pattern. it has been clearly reported in literature that in almost all cases of atypical lymphatic metastatization patients had previously undergone scrotal or inguinal surgery (orchidopexy, relief of hydrocele, trans-scrotal biopsy or varicocelectomy) (5-10). however, lymphnode metastases in the inguinal region can be found in patients with no previous surgery, mostly in patients with germ cell tumours, and these are probably due to infiltration from metastases of the spermatic cord (9, 16). in our case of atypical node metastatization, the lymphathad undergone lichtenstein tension-free mesh onlay repair by a “plug” technique three years before. alpha-fetoprotein (normal range 0-15 iu) and beta-hcg (normal range 0-5 iu) were both raised to 9.9 iu and 15 iu, respectively. ct scan showed bulk disease of pelvic lymph nodes on the left side while retroperitoneal nodes were normal (figure 1). orchifunicolectomy was performed and histopathological examination showed a mixed germ cell tumor involving the tunica vaginalis, rete testis, epididymis and spermatic cord. after surgery the tumor markers were still raised. the patient was addressed to adjuvant chemotherapy according to peb scheme. clinical re-staging showed a decrease of pelvic bulk disease, retroperitoneal nodes still normal and negative tumor markers. left external, internal and common iliac lymphadenectomy as well as left modified template nerve-sparing retroperitoneal lymph node dissection was performed (figure 2). intraoperatively the node bulk was firmly adherent to external iliac artery and extended until the common iliac bifurcation. in the deeper part of this enlarged and firm lymphatic chain the polypropyfigure 1. ct scan showing bulk disease of pelvic lymph nodes on the left side. figure 2. retroperitoneal lymph node dissection. figure 3. polypropylene plug found in the deeper part of the enlarged and firm lymphatic chain. grasso_stesura seveso 18/04/13 12:06 pagina 48 49archivio italiano di urologia e andrologia 2012; 84, 4 inguinal polypropylene plug: a cause of unusual testicular tumor pelvic metastasis node metastases following a torek orchiopexy. urology. 1983; 21:300-1. 6. herr hw, silber i, martin dc. management of inguinal lymph nodes in patients with testicular tumors following orchiopexy, inguinal or scrotal operations. j urol. 1973; 110: 223-45. 7. klein fa, whitmore wf jr, sogani pc, et al. inguinal lymph node metastases from germ cell testicular tumors. j urol. 1984; 131:497-500. 8. nishimoto k, ono h, hirayama m, et al. inguinal lymph node metastasis from contralateral testicular origin. urology. 1993; 41:275-7. 9. stein m, steiner m, suprun h, robinson e. inguinal lymph node metastases from testicular tumor. j urol. 1985; 134:144-5. 10. wheeler js jr, babayan rk, hong wk, krane rj. inguinal node metastases from testicular tumors in patients with prior orchiopexy. j urol. 1983; 129:1245-7. 11. lichtenstein il, shore jm. simplified repair of femoral and recurrent inguinal hernias by a "plug" technic. am j surg. 1974; 128:439-44. 12. leardi s, navarra l, pietroletti r, et al.the use of prosthetic meshes in the surgical treatment of inguinal hernia: the costs and profits for the local health screening unit. minerva chir. 1998; 53:581-5. 13. nathan jd, pappas tn. inguinal hernia: an old condition with new solutions.ann surg. 2003; 238(6 suppl):s148-57. 14. gandolfo l, donati m, privitera a, et al. ultrasound tissue modifications after polypropylene prosthesis apposition in inguinal hernia. chir ital. 2007; 59:835-41. 15. richard d. matthews et al. factors associated with postoperative complications and hernia recurrence for patients undergoing inguinal hernia repair: a report from the va cooperative hernia study group. am j surg. 2007; 194:611-617. 16. daugaard g, karas v, sommer p. inguinal metastases from testicular cancer. bju int. 2006; 97:724-726. ic spreading was very unusual since it only involved nodes in the pelvic area. this can be explained by the alteration of normal lymphatic drainage pattern in the spermatic cord during inguinal hernioplasty as well as during tissue healing in the post-operative period. the polypropylene plug deeply placed in the internal inguinal ring might have played a role in the alteration of the normal lymphatic circulation in the spermatic cord. the blockage of normal lymphatic up-flow probably caused a chronic extravasation and created new lymphatic communications with the pelvic nodes. as a consequence, the bulk pushed the plug deeper, up to the common iliac bifurcation. the absence of involved nodes above confirms the lymphatic barrier effect caused by the plug. another point of discussion is the left inguinal node enlargement that occurred three years later. as above mentioned, the inguinal node involvement in cases of previously scrotal or inguinal surgery or in cases of locally advanced disease is well known. for this reason the patient underwent inguinal lymphectomy, without evidence of disease. the treatment of these rare cases is matter of debate. on one hand mianne does not consider ipsilateral node dissection necessary, owing to the efficacy of primary or secondary chemotherapy in non seminomatous testicular tumors, while for testicular seminoma, he suggests additional inguinoscrotal radiotherapy (2). on the other hand van ahlen considers as therapy of choice the adjiuvant chemotherapy and salvage lymphadenectomy in case of residual tumor, including peri-iliac lymphadenectomy (3). conclusion in the case reported we stress that a polypropylene plug located near iliac vessels could induce an important tissutal reaction and alter the lymphatic flow, with the consequent metastatic involvement of pelvic nodes preserving the common iliac and paraortic nodes. in this case the massive local diffusion of the disease could allow a simple diagnosis, but nowadays in many cases the lymph nodes involvement is only microscopic, therefore not clinically evaluable. on the other hand the use of propylene plug for hernioplasty is very frequent. we think that is mandatory to consider the opportunity of extending surgical or radiant approach to iliac and obturator region in patients suffering from testicular germ cell cancer if they had previously underwent hernioplasty with polypropylene plug. references 1. stein m, steiner m, suprun h, robinson e. inguinal lymph node metastases from testicular tumor. j urol. 1985; 134:144-53. 2. mianne dm, barnaud p, altobelli a, et al. inguinal lymphatic metastasis of cancer of the testis: staging and therapeutic approach. ann urol. 1991; 25:199-202. 3. van ahlen h, von stauffenberg, porst h, vahlensieck w. inguinal metastasis of stage i testicular tumors. urologe a. 1988; 27:275-8. 4. daugaard g, karas v, sommer p. inguinal metastases from testicular cancer. bju int. 2006; 97:724-6. 5. crawford ed, cain dr, black wc, borden ta. inguinal lymph correspondence marco grasso, md grasso.m@virgilio.it salvatore blanco, md sblanco_74@yahoo.it luca nespoli, md l.nespoli@hsgerardo.org azienda ospedaliera san gerardo, via pergolesi 33 20900 monza, italy angelica anna chiara grasso, md (corresponding author) fondazione irccs ca’ granda ospedale maggiore policlinico via della commenda 15 20100 milano, italy angelica_grasso@yahoo.it grasso_stesura seveso 18/04/13 12:06 pagina 49 stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 126 letter to editor submitted 14 march 2023; accepted 23 march 2023 to the editor, although postoperative pain associated with robot-assisted radical prostatectomy (rarp) is less than pain following the open technique, it remains a fundamental issue as it can be a significant source of discomfort for the patient and lengthen recovery times after surgery. the optimal management of pain after rarp is far from being fully elucidated and many factors have to be evaluated to choose the best analgesic approach (1). pain management in the postoperative period is classically achieved through the administration of intermittent or continuous intravenous drugs; opioids and non-steroidal anti-inflammatory drugs (nsaids) represent the cornerstones of this approach. these drugs have many potential adverse effects (aes). nsaids can affect renal and platelet function leading to kidney injury and significant bleeding, while opioids can be associated with delayed recovery of gut motility, urinary retention, dizziness, nausea, vomiting, and immunosuppression (2). spinal anesthesia is emerging as an alternative technique to control the postoperative pain or even to avoid general anesthesia not only in urological but also in cardiac, gynecological, and spine laparoscopic and robotic surgery (table 1) (3-6). it allows to reduce the drugs dosage and, consequently, their aes. however, several additional advantages can be identified. spinal anesthesia is performed before the induction of general anesthesia and its analgesic effect covers also the intraoperative period, so lower dosage of intraoperative opioids can be used along with lower minimum alveolar concentration of inhalational anesthetics, thus leading to an important reduction of postoperative nausea and vomiting along with a faster recovery of consciousness after general anesthesia; furthermore, the reduction of analgesic drugs during anesthesia can contribute to the hemodynamic stability. recently, some concerns have been raised about the immunosuppressive effect of opioids and, consequently, the potential risk of promoting metastatic spread of cancer cells; therefore, reducing opioid administration in the perioperative period is even more important (7). pikramenos et al. reported their experience in 60 men, underwent combined spinal/epidural anaesthesia during radical retropubic prostatectomy: they showed that combined spinal/epidural anaesthesia is a safe procedure to perform and is associated with less intraoperative blood loss and potentially reduced risks of postoperative complications (8). the role of spinal anesthesia should also be considered in the management of the bladder spasm and the discomfort due to urethral catheter which can impact on the patient satisfaction and on the ability to early recover autonomous walking, with possible dramatic consequences on the risk of thromboembolism and on the length of hospital stay (9). interestingly, several adjuvants can be added to the solution injected in the subarachnoid space thus increasing the ability to achieve the desired effects with very small amounts of drugs. ketamine, dexmedetomidine, midazolam, and clonidine are some examples of drugs which are commonly used with or without opioids to prolong and/or potentiate the effect of the local anesthetic. many combinations of these drugs for spinal anesthesia have so far been reported in literature and appropriate use of their different pharmacological properties can be employed to manage not only postoperative pain but also intraoperative analgesia, allowing rarp to be performed only with spinal anesthesia and light sedation. no study is currently available on the topic, however, as part of a clinical trial, we have begun performing the first cases of rarp under spinal anesthesia in our center, with encouraging preliminary results demonstrating the feasibility and potential of this novel technique. some authors have expressed concerns regarding the risk-benefit ratio of spinal anesthesia, as this technique can cause severe aes. an accidental puncture of an epidural blood or a spinal nerve can lead to permanent injuries such as motor and sensory loss of the lower limbs, loss of sphincters continence, and typical neuropathic symptoms. these complications are actually very rare; for example, the reported incidence of spinal hematoma is about 1:220,000 cases and a careful medical history along with appropriate management of anti-platelet and anticoagulant drugs can significantly reduce the risk (10). absolute contraindications to spinal anesthesia are patient refusal, injection site infection, increased intracranial pressure (except for pseudotumor cerebri), allergy to the drugs to be injected, and uncorrected hypovolemia (as spinal anesthesia role of spinal anesthesia in robot-assisted radical prostatectomy: gamble or opportunity? lorenzo spirito 1, annachiara marra 2, vincenzo mirone 3, celeste manfredi 1, ferdinando fusco 1, luigi napolitano 3, giuseppe servillo 2, nicola logrieco 2, pasquale buonanno 2 1 urology unit, department of woman, child and general and specialized surgery, university of campania "luigi vanvitelli", naples, italy; 2 department of neurosciences, reproductive and odontostomatological sciences, university of naples “federico ii”, naples, italy; 3 urology unit, department of neurosciences, reproductive sciences and odontostomatology, urology unit, university of naples "federico ii", naples. doi: 10.4081/aiua.2023.11311 archivio italiano di urologia e andrologia 2023; 95, 2 l. spirito, a. marra, v. mirone, c. manfredi, f. fusco, l. napolitano, g. servillo, n. logrieco, p. buonanno 127 causes vasodilation due to sympathetic block). relative contraindications are sepsis, coagulopathy, fixed cardiac output states, aortic stenosis (previously considered an absolute contraindication), indeterminate neurological disease, multiple sclerosis and other demyelinating diseases (as demyelinated nerves seem more susceptible to local anesthetic toxicity (11). in conclusion spinal anesthesia to perform rarp can be a gamble or an opportunity depending on the players who take part to the match: the appropriate assessment and selection of the patient, the correct management of the drugs affecting coagulation and platelet function, and the proper use of adjuvants in the solution to be injected are essential for a successful and safe spinal anesthesia. however, the role of spinal anesthesia in the context of rarp needs to be evaluated in randomized controlled trials with adequate sample size and follow-up. not only the impact on the postoperative pain but also on other sources of possible discomfort for the patient should be investigated. the feasibility and relative advantages and disadvantages of spinal anesthesia when used as a replacement for general anesthesia should be clarified with adequate comparative studies. moreover, future studies should compare the spinal anesthesia with novel techniques of regional analgesia such as erector spinae plane and transversus abdominis plane blocks, which are less invasive and consequently safer than the intrathecal administration of drugs. references 1. joshi gp, jaschinski t, bonnet f, kehlet h. prospect collaboration. optimal pain management for radical prostatectomy surgery: what is the evidence? bmc anesthesiol. 2015; 15:159. 2. koh jc, lee j, kim sy, et al. postoperative pain and intravenous patient-controlled analgesia-related adverse effects in young and elderly patients: a retrospective analysis of 10,575 patients. medicine (baltimore). 2015; 94:e2008. 3. gontero p, oderda m, calleris g, et al. awake da vinci robotic partial nephrectomy: first case report ever in a situation of need. urol case rep. 2022; 42:102008. 4. giampaolino p, della corte l, mercorio a, et al. laparoscopic gynecological surgery under minimally invasive anesthesia: a prospective cohort study. updates surg. 2022; 74:1755-1762. 5. dhawan r, daubenspeck d, wroblewski ke, et al. intrathecal morphine for analgesia in minimally invasive cardiac surgery: a randomized, placebo-controlled, double-blinded clinical trial. anesthesiology. 2021; 135:864-876. table 1. use of spinal anesthesia and analgesia in robotic and laparoscopic surgery (see supplementary material for references). article study design surgery groups duration of intervention outcomes beilstein cm et al, 2022 rct urological/rarp or open general anesthesia associated with: group sss: 282 min [240; 322] no differences in qor; radical prostatectomy subarachnoid analgesia (sss) group tas: 270 min [240; 300] no differences in postoperative pain transversus abdomnis plane block (tap) group sa: 274 min [240; 312] systemic lidocaine (sa) gontero p. et al, 2022 case report urologicalc/robotic partial continuous subarachnoid anesthesia 2h 45 min patient hemodinamically stable; nephrectomy no intraoperative desaturation; optimal postoperative analgesia dhawan r et al, 2021 rct cardiac/robotic totally endoscopic general anesthesia without (groups ga) group ga: 290 (238–346) min group sa showed less postoperative pain, coronary artery bypassor with subarachnoid analgesia (group sa) group sa: 315 (235–366) min less need for postoperative morphine, and less cough shim jw et al, 2021 rct urological/rarp general anesthesia with (group non-itmb) group non-itmb: 120 (108-143)) min group itmb less postoperative pain or without (group itmb) intrathecal group itmb: 120 (115-130 min and opioids consumption morphine and bupivacaine shim jw et al, 2020 prospective urological /ralp general anesthesia with: group iv-pca: 123 (109-145) min group itmb required less intraoperative observational group iv-pca: intravenous group rsb: 123 (100-141) min opioids and showed less postoperative patient-controlled analgesia group itmb: 123 (114-138) min pain with a lower postoperative group rsb: rectus sheath bupivacaine block consumption of opioids, better qor. group itmb: intrathecal morphine and bupivacaine bae j et al, 2017 rct urological/ralp general anesthesia with group itm: group itm: 171 ± 42 min group itm showed less postoperative pain intrathecal morphine+ intravenous group iv-pca: 164 ± 41 min and morphine consumption atient-controlled analgesia group iv-pca: only intravenous patient-controlled analgesia segal d et al, 2014 rct urogynecological/robotic general anesthesia without (group ga) group sa showed less postoperative pain, sacrocervicopexy or with subarachnoid anesthesia (sa) lower postoperative consumption of opioids, and a higher satisfaction of patients and nurses ross sb et al, 2013 rct general surgery/laparo-endoscopic general anesthesia (group ga) group ga: 65.2 ± 25.1 min group ea showed less postoperative pain single-site (less) cholecystectomy vs epidural anesthesia (group ea) group ea: 64.5 ± 21.5 min qor: quality of recovery; ralp: robot-assisted laparoscopic prostatectomy; rct: randomized control trial. archivio italiano di urologia e andrologia 2023; 95, 2 128 spinal anesthesia and robot-assisted radical prostatectomy 6. gao s, wei j, li w, et al. accuracy of robot-assisted percutaneous pedicle screw placement under regional anesthesia: a retrospective cohort study. pain res manag. 2021; 2021:6894001. 7. lee bm, singh ghotra v, karam ja, et al. regional anesthesia/analgesia and the risk of cancer recurrence and mortality after prostatectomy: a meta-analysis. pain manag. 2015; 5:387-95. 8. pikramenos k, zachou m, apostolatou e, et al. the effects of method of anaesthesia on the safety and effectiveness of radical retropubic prostatectomy. arch ital urol androl 2022; 94:396-400. 9. morgan ms, ozayar a, friedlander ji, et al. an assessment of patient comfort and morbidity after robot-assisted radical prostatectomy with suprapubic tube versus urethral catheter drainage. j endourol. 2016; 30:300-5. 10. moen v, dahlgren n, irestedt l. severe neurological complications after central neuraxial blockades in sweden 1990-1999. anesthesiology 2004; 101:950-9. 11. carpenter rl, caplan ra, brown dl, et al. incidence and risk factors for side effects of spinal anesthesia. anesthesiology 1992; 76:906-16. correspondence lorenzo spirito, md lorenzospirito@msn.com celeste manfredi, md manfredi.celeste@gmail.com ferdinando fusco, md ferdinando-fusco@libero.it urology unit, department of woman, child and general and specialized surgery, university of campania "luigi vanvitelli", naples annachiara marra, md dottmarraannachiara@gmail.com giuseppe servillo, md giuseppe.servillo@unina.it nicola logrieco, md nicola.logrieco@unina.it pasquale buonanno, md pasquale.buonanno@unina.it department of neurosciences, reproductive and odontostomatological sciences, university of naples “federico ii”, naples, italy vincenzo mirone, md mirone@unina.it luigi napolitano, md (corresponding author) dr.luiginapolitano@gmail.com department of neurosciences, reproductive sciences and odontostomatology university of naples “federico ii” via pansini 5, 80131 naples, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper patients and methods this is a retrospective study including patients with pathologically proven stage i seminoma, who presented to the national cancer institute, cairo university, during the period from 2005 to 2019. data was retrieved from the patients' medical records. the collected data included age, pathological subtype, post-operative stage, date and type of surgery, pre & post-operative tumor markers, details of adjuvant treatment, patterns of failure and patients' status at last follow up. all patients had inguinal orchiectomy followed by staging computed tomography (ct) of abdomen & pelvis to exclude nodal or distant disease and serum tumor marker assessments (alpha-fetoprotein and beta-hcg). patients who were kept under active surveillance, were followed every 3 months in the first 2 years. in each visit history and physical examination was performed, serum tumor markers levels (ldh, beta-hcg, alpha-fetoprotein) were obtained, and imaging was done every 6 months. in the third year of follow up, the interval of the visits was every 6 months and imaging and markers were ordered annually. in the following years of follow up, the interval was annually with no imaging unless clinically indicated. all patient were adherent to the follow up schedule. in patients who received adjuvant chemotherapy, one cycle of carboplatin (auc 7, based on the formula 7x [glomerular filtration rate (gfr, ml/min) +25 mg] was given to all patients except one patient who was given two cycles. patients were kept under follow up every 6 months in the first and second year then follow up was annually, with serum tumor markers (ldh, beta-hcg, alpha-fetoprotein) obtained at each visit and imaging if clinically indicated. in patients who received adjuvant radiation radiotherapy; the field of radiation was para-aortic lymph nodes field (paln). the field extended from t11/t12 superiorly till l5/s1 inferiorly using anterior-posterior-posterio-anterior (ap/pa) field arrangement or multiple (4) fields. clinical target volume (ctv) comprised the para-caval, pre-caval and inter aorto-caval nodes. the prescribed dose was (25.5gy/1.5gy/17 fraction) or (19.8gy/1.8gy/11 fraction). following the end of the course, follow up was every 6 months in the first and second year then kept annually. background: the mainstay for management of stage i seminoma is high inguinal orchiectomy with post-orchiectomy therapeutic options including active surveillance, chemotherapy or radiation therapy. objectives: to analyze different post-orchiectomy treatment modalities outcomes of stage i seminoma patients presented to nci, cairo university in the period from 2005-2019. patients and methods: a retrospective review of all patients' records with clinical stage i seminoma who presented to our institute in the period from 2005-2019 was done. adjuvant treatment details were extracted, and we compared overall survival (os) and disease free survival (dfs) for different modalities and changes in patterns of care over this period. results: thirty-five patients were identified with thirty three patients eligible for analysis. median age was 35 years (range, 19-52). fourteen patients were kept under active surveillance, eleven patients received adjuvant carboplatin and eight patients received adjuvant radiation to para-aortic chain. five-year os was 100% for all patients regardless post-operative approach. five-year dfs was 100% for patients who received adjuvant chemotherapy or radiotherapy versus 93% for patients who were kept under active surveillance (p = 0.03). conclusions: clinical stage i seminoma is a favorable disease entity with favorable disease related outcomes regardless postoperative approach. active surveillance is reasonable and safe given equal survival to active treatment. key words: seminoma; stage i; surveillance; radiotherapy; chemotherapy. submitted 18 december 2022; accepted 31 december 2022 introduction testicular cancers are rare tumors with an incidence of less than 1% of all male tumors (1). the standard management of testicular tumors starts with high inguinal orchiectomy followed by a stage and pathology dictated management (2). clinical stage i seminoma has a very favorable outcome after surgery (3). management options for stage i disease have evolved over the past decades from adjuvant radiation to para-aortic chain to chemotherapy with single agent carboplatin and finally moving to active surveillance with equal survival among all strategies (4). herein, we review our experience and changes in patterns of care over time. stage i seminoma: outcome of different treatment modalities and changes in patterns of care. a single institution experience manar mahmoud sayed 1, azza mohamad nasr 1, ibtesam mohamad saad eldin 2, yasser anwar abdelazim 1 1 department of radiation oncology, national cancer institute, cairo university, egypt; 2 department of clinical oncology, faculty of medicine, cairo university, egypt. doi: 10.4081/aiua.2023.11057 summary archivio italiano di urologia e andrologia 2023; 95, 1 m. mahmoud sayed, a. mohamad nasr, i. mohamad saad eldin, y. anwar abdelazim statistical methodology data management and analysis was performed using statistical package for social sciences (spss) vs. 25. numerical data were checked for normality and were statistically described as means (standard deviations) or medians (ranges) as appropriate. categorical data were described as numbers and percentages. survival analysis was done using kaplan-meier method with comparison between two or more survival curves using log rank test with bonferroni adjustment when necessary. all statistically significant factors on kaplan-meier analysis entered the multivariate cox regression analysis using forward likelihood-ratio (lr) method for variable selection. hazard ratios were computed for significant factors in the last step of cox-regression with 95% confidence interval estimates. all tests were 2 tailed and p-value < 0.05 was considered statistically significant. all the patients treated with different modalities were compared in terms of overall survival (os), disease-free survival (dfs), loco-regional control (lrc) and metastaticfree survival (mfs). os was calculated from the date of diagnosis to the date of death or last follow-up, disease free survival (dfs) was calculated from the date of surgery to the date of locoregional recurrence or metastasis whichever comes first. metastasis free survival (mfs) was calculated from the date of surgery to the date of metastasis. para-aortic nodal relapse was not considered as metastatic event but a loco-regional failure. time to loco-regional control (lrc) was calculated from the date of surgery to the date of loco-regional recurrence. results in the period from 2005 to 2019, thirty five patients with clinical stage i seminoma presented to national cancer institute, cairo university. thirty three patients were included in our analysis and two patients were excluded from survival analysis due to lost follow up. median age in our cohort was 35 years (range, 19-52). thirty two patients (91%) had classic subtype and three patients (9%) had spermatocytic subtype. patients' clinical and demographic characteristics are summarized in table 1. fourteen patients (42%) were kept under active surveillance, eight patients (24%) received adjuvant radiation therapy to para-aortic nodal chain and eleven patients (34%) received adjuvant carboplatin, with 10 patients receiving only 1 cycle and one patients receiving 2 cycles. patients' clinical and demographic data in each arm are summarized in table 2. five-year overall survival rate was 100% in the whole cohort and median overall survival was not reached. no overall survival difference was seen between patients who were subjected to active treatment and patients who were kept under active surveillance. in terms of disease-free survival, five year dfs rate was 100% for patients who received active treatment (whether chemotherapy or radiotherapy) versus 93% for patients who were kept under active surveillance (p = 0.03). among those who were kept under active surveillance, one patient developed para-aortic nodal recurrence after 4 years. he was managed by salvage chemotherapy (3 cycles bep) and he achieved complete response and was disease free till data cutoff. in terms of loco-regional control (lrc), five-year lrc was 100% for patients who received active treatment (chemotherapy or radiotherapy) versus 93% in patients who were kept under active surveillance (p = 0.03). we tested proposed factors that would affect disease local control (namely, rete testis invasion and tumor size), however, none of them had a significant difference in relation to lrc in univariate analysis. fifteen patients had rete-testis invasion versus 18 patients without invasion, with 5 year lrc of 80 versus 100 percent, respectively (p = 0.439). sixteen patients had tumor size > 4 cm versus seventeen patients with tumor size < 4 cm, with five year lrc 100 percent and 75 percent, respectively (p=0.317). in terms of metastasis-free survival (mfs), five-year mfs rate was 100% in all patients, regardless the modality used. there has been a change in the pattern of care in our study population over the studied years. in the period from 2005 till 2009 the majority of the patients were treated with adjuvant radiation therapy. in the period from 2010 till 2014 chemotherapy was the modality of choice, while in the recent years from 2015 till 2019 active surveillance was the treatment of choice (figure 1). table 1. demographic, clinical data and pathological subtypes in patients of stage i seminoma. n = 35 n (%) age (median 35, range 19-52) < 35 20 (57) > 35 15 (43) history of undescended testis yes 6 (17) no 29 (83) history of contralateral seminoma yes 1 (3) no 34 (97) pathological subtypes classic 32 (91) spermatocytic 3 (9) anaplastic 0 (0) table 2. characteristics of the patients in each modality. active surveillance chemotherapy radiotherapy (14) (11) (8) age < 35 11 4 5 > 35 3 7 3 history of undescended testis 2 3 1 history of contralateral seminoma 1 0 0 pathological subtype classic 14 9 7 spermatocytic 0 2 1 archivio italiano di urologia e andrologia 2023; 95, 1 management of clinical stage i seminoma discussion this retrospective study included 33 patients with stage i seminoma who presented to nci cairo university in the period from 2005 to 2019. several epidemiological and clinical factors were studied as well as treatment strategies potentially influencing disease-free survival (dfs) in addition to overall survival (os) and loco regional recurrence (lrr). in our study the median os was not reached, with 5 year overall survival 100% in stage i seminoma. this is consistent with many other data. for example, a five-year survival of 99.0% was reported in seer statistics published in the year 20165. in another large cohort study of ncdb involving 33,094 patients, a ten year survival rate of 95% was reported for patients who received active treatment and 93.4% for patients who were kept under active surveillance (4). in another series coming from a tertiary portuguese center addressing testicular cancer, the five year survival rate for seminoma patients' was 100 percent (6). the 5 year disease-free survival in patients received adjuvant radiotherapy to para-aortic chain or single agent carboplatin was 100 percent, which is consistent with the study conducted by oliver et al. comparing adjuvant 1 cycle carboplatin versus radiotherapy showing relapsefree survival rates at 5 years of 94.7 and 96 percent, respectively (7). the 5 year dfs and the 5-year loco-regional control in our study was 93% in arm of surveillance with complete cure of the relapse and 100% in both radiation and chemotherapy groups. in a study conducted by dieckmann et al., the use of one course of adjuvant carboplatin, surveillance and radiotherapy were compared to each other. the results showed a disease-specific survival of 100% irrespective of the post-operative approach. crude relapse rates were 8.2, 2.4, 5.0, and 1.5% for surveillance, radiotherapy, 1 cycle carboplatin, and 2 cycles carboplatin, respectively, after a median follow up of 30 months. in this study, all recurrences were salvageable leading to a disease-specific survival rate of 100 percent, with no statistical difference in the incidences of relapses among the four treatment arms (log-rank, p = 0.0573) (8). in this study, the proposed risk factors of local recurrence in stage i seminoma (namely, rete-testis invasion and tumor size > 4 cm) didn’t show any adverse impact on local control for patients. in comparison to literature, this might be a little bit different. a risk-adapted adjuvant management was adopted by the swedish and norwegian testicular cancer group based on their prospective trial involving almost 900 patients. the study population developed 69 relapses; with 29 relapses among patients who were managed by surveillance and 40 relapses in patients managed with adjuvant 1 cycle carboplatin. the invasion of the rete testis [hazard ratio (hr) 1.9, p = 0.011] and tumor diameter > 4 cm (hr 2.7, p < 0.001) were identified as risk factors for disease relapse. in patients without any of these factors, the relapse rate was 4.0% for patients in surveillance arm versus 2.2% in patients receiving adjuvant carboplatin. in patients with one or two risk factors, the relapse rate was 15.5% in patients managed by surveillance versus 9.3% in patients receiving adjuvant carboplatin (9). in another systematic review including nineteen studies addressing prognostic factors for disease relapse in clinical stage i seminoma patients' managed by surveillance (10), rete testis invasion was identified as a significant factor for relapse in only 4 out of 13 studies, while tumor size was a significant factor for relapse in 10 out of 14 studies. the authors' conclusion was that size of tumor is the most important prognostic factor for disease relapse, but the authors failed to define a clear cutoff value for tumor size and that rete-testis invasion was a minor risk factor for disease recurrence. however, the most recent version of nccn guidelines still recommends for active surveillance as the preferred option of management for patients with clinical stage i seminoma, regardless tumor size or rete-testis invasion, given the equal survival of surveillance versus active treatment, potential long term treatment toxicities especially with the expected long term survival of the patients and high salvage rates of any recurrences, provided that patients will commit to the surveillance protocol (11). this study also shows a change in our pattern of care with time from adjuvant radiation to para-aortic chain towards single agent carboplatin and active surveillance, given the change in the international guidelines. study limitations include the retrospective nature of the study with the inherent selection bias in this type of studies (reserving active treatment for fit and younger patients or those who cannot adhere to the follow up schedule), the heterogeneous groups of patients with imbalance between treatment arms and lack of qol assessment with each treatment modality. in summary, our study highlights and confirms the data stating that stage i seminoma can be treated by different adjuvant modalities (radiotherapy, carboplatin or active surveillance) with similar outcomes in terms of dfs, lrc and os. active surveillance remains an appealing treatment option given similar survival compared to active treatment and complete cure after salvage with chemotherapy in relapsing patients. figure 1. change in the patterns of care along time from 2005 till 2019. archivio italiano di urologia e andrologia 2023; 95, 1 m. mahmoud sayed, a. mohamad nasr, i. mohamad saad eldin, y. anwar abdelazim references 1. seer cancer statistics factsheets: testicular cancer. national cancer institute. bethesda, md. 2020. 2. jones rh, vasey pa. part i: testicular cancer--management of early disease. lancet oncol. 2003; 4:730-7. 3. mead gm, fossa sd, oliver rt, et al. randomized trials in 2466 patients with stage i seminoma: patterns of relapse and follow-up. j natl cancer inst. 2011; 103:241-9. 4. glaser sm, vargo ja, balasubramani gk, beriwal s. surveillance and radiation therapy for stage i seminoma-have we learned from the evidence? int j radiat oncol biol phys. 2016; 94:75-84. 5. seer cancer statistics factsheets: testicular cancer. national cancer institute. bethesda, md. 2016. 6. andré marques-pinto, ana inês gomes, joana febra, et al. specialist management of testicular cancer: report of the last 10 years at a portuguese tertiary referral academic centre. arch ital urol androl. 2021; 93:153-157. 7. oliver rt, mead gm, rustin gj, et al. randomized trial of carboplatin versus radiotherapy for stage i seminoma: mature results on relapse and contralateral testis cancer rates in mrc te19/eortc 30982 study (isrctn27163214). j clin oncol. 2011; 29:957-62. 8. dieckmann kp, dralle-filiz i, matthies c, et al. testicular seminoma clinical stage 1: treatment outcome on a routine care level. j cancer res clin oncol. 2016; 142:1599-607. 9. tandstad t, ståhl o, dahl o, et al. treatment of stage i seminoma, with one course of adjuvant carboplatin or surveillance, riskadapted recommendations implementing patient autonomy: a report from the swedish and norwegian testicular cancer group (swenoteca). ann oncol. 2016; 27:1299-304. 10. zengerling f, kunath f, jensen k, et al. prognostic factors for tumor recurrence in patients with clinical stage i seminoma undergoing surveillance-a systematic review. urol oncol. 2018; 36:448-458. 11. nccn clinical practice guidelines in oncology (nccn guidelines®) for testicular cancer v.2.2022. ©national comprehensive cancer network, inc. 2022. correspondence manar mahmoud sayed, md manar.mahmoud54@yahoo.com azza mohamad nasr, md nasrazza2@hotmail.com yasser anwar abdelazim, md (corresponding author) yasser.anwar@nci.cu.edu.eg department of radiation oncology, national cancer institute, cairo university, egypt kasr el ainy street, cairo, egypt, 11796 ibtesam mohamad saad eldin, md ibtessamsaad@yahoo.com department of clinical oncology, faculty of medicine, cairo university, egypt al kasr el ainy, old cairo, egypt conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 note on surgical technique without any short-term complications (mean follow-up 20 months), the sexual medicine society of north america (smsna) recommends that silicone injections and any penile augmentation procedure should be considered experimental surgery (3, 6). this is due to the lack of sufficient data to support the safety and efficacy of these procedures and the fact that several complications requiring surgical correction have been published in multiple case series and reports (3, 7). the severity and complexity of complications may range from silicone migration to the development of erectile dysfunction, penile deformity, infection, and late granulomatous reactions requiring surgical silicone excision (3, 8). partial excision without skin grafting has been described in the past with suboptimal esthetic results (9). since 1993, penile degloving, foreign body removal, circumferential excision of penile skin and resurfacing with a split-thickness skin graft (stsg) has been the most reproduced and successful option due to its technical ease and superiority compared to flaps (10). in this paper, we describe a yet unpublished surgical approach of partial skin excision and resurfacing with a stsg with good functional and cosmetic outcomes for treatment of post-silicone penile injection late complication for girth augmentation (figures 1, 2). methods surgical technique: partial degloving and resurfacing with stsg the patient is placed under general anesthesia in supine position. wide spectrum antibiotic prophylaxis is given (piperacillin-tazobactam). the patient needs to be prepped and draped in a sterile manner, including the antero-lateral (left or right) thigh for stsg harvest. a silk traction suture is placed at the penis glans (this traction will be kept after the procedure). penile physical examination is performed under general anesthesia to delineate the affected area that will have to be resected (figure 3). a partial circumcising incision at the base of the corona is performed from 3 to 9 o’clock, or more if the foreign material extends forward, and the incision is extended down the dorsal aspect of the penile shaft, surrounding all the affected area where foreign material can be palpated (figure 4). then, the siliconoma is carefully dissected off the buck’s fascia introduction: siliconoma represents an inflammatory tissue response to extravasated silicone. penile enhancing silicone injections have been described for over 50 years. most of the publications report complications including negative effects on penile appearance and function which require corrective procedures. penile circumferential skin and siliconoma excision with skin grafting has been described in multiple case reports and series as an effective and feasible option to remove the silicone and achieve good esthetic results. methods: we describe a simple and feasible single stage procedure removing the siliconoma with adjacent non-viable skin while preserving 50% of healthy penile skin and resurfacing the defect with a split-thickness skin graft to treat a long-term complication of penile silicone injection associated with recurrent infections and a chronic skin ulceration. conclusion: partial excision of the affected penile skin and siliconoma with defect resurfacing with a split-thickness skin graft is a feasible with good functional and cosmetic outcomes. key words: penis; siliconoma; penile silicone injection; penile reconstruction; penile enlargement. submitted 12 january 2023; accepted 30 january 2023 introduction the penis has long been considered an essential part of masculinity, and its size and girth have been related to virility, sexual performance and even power. various cultures around the world have historically described rituals and processes involving penile manipulations to increase size and girth (1). exposure to pornographic content may lead men to have distorted perceptions of the normal size and appearance of genitalia and consequently seek out esthetic procedures (2, 3). the average penile length and girth are 9 cm and 9-10 cm respectively in a flaccid state, and 14-16 cm and 12-13 cm respectively in an erect state (3). most men seeking out length and/or girth augmentation have normal penile parameters and may suffer from penile dysmorphophobia (3, 4). filler injections to increase penile girth date back to the early 1900s, when liquid paraffin and other mineral oils were used. these substances frequently caused severe adverse effects, including infection and risk of penile loss. eventually, liquid injectable silicone began to be used (3, 5). although there have been reports of satisfactory results alternative surgical management of penile siliconoma using partial degloving and resurfacing manuel belmonte chico goerne 1, abdulghani khogeer 1, 2, peter davison 3, serge carrier 1, melanie aubé-peterkin 1 1 department of urology, mcgill university health center, montreal, canada; 2 department of surgery, faculty of medicine, rabigh, king abdulaziz university, jeddah, saudi arabia; 3 department of plastic surgery, mcgill university health center, montreal, canada. doi: 10.4081/aiua.2023.11150 summary archivio italiano di urologia e andrologia 2023; 95, 1 m. belmonte chico goerne, a. khogeer, p. davison, s. carrier, m. aubé-peterkin dorsal nerves that could be coursed through the siliconoma and hard to be spared. the siliconoma and overlying abnormal skin must be completely excised up to the suprapubic area, or wherever its limit is located, and the affected segment must be removed (figure 7). the ventral penile skin is preserved as our technique is for cases where the dorsal aspect of the penis is affected while the ventral is intact, healthy, and vascularized. if dissection extents proximally to the proximal corporal bodies, it’s better to fix them to the suprapubic tissue with 3-0 pds or similar, to exteriorize the penile shaft and avoid loss of length, also, doing this fixation prevents a potential dead space, and subsequent seroma formation. after the removal of the foreign material and the corporal bodies fixation, the removed skin is templated and measured for skin graft. a distal 0.014 inch stsg is harvested from the previously prepped donor area (we suggest the thigh) using a dermatome, then, the graft is slightly fenestrated to prevent hematoma formation. the stsg is inset with plain gut sutures (preferably 4-0 chromic), and then adjusted accordingly to the penile defect, so the excess graft is tailored to fit the defect (figure 8). once the graft is fixed, a 16-fr urinary catheter is installed. there are plenty dressing options that can be used for these kinds of procedures; a good option is an adaptic™ dressing. a single layer of adaptic™ dressing can be applied, and then, a tailored black vacuum assisted closure (vac) sponge is placed over the stsg; the remainder of the vac dressing is applied in the usual fashion (figure 9). then, the penile traction has to be kept to prevent disadherence of the vac dressing. to do so, we sugfigure 1. ulceration extending through all layers of the skin and subcutaneous tissue, exposing buck’s fascia. figure 2. complete ulcer healing after two months of dressing. figure 3. palpable silicone on the dorsal aspect of the penile shaft extending to the suprapubic area. figure 7. complete excision of the siliconoma and overlying abnormal skin up to the suprapubic area. figure 8. split-thickness skin graft application on the dorsal penile defect and sutured by 4-0 chromic. figure 4. partial circumcising incision at the base of the corona from 3 to 9 o’clock extended down the dorsal aspect of the penile shaft. figures 5, 6. siliconoma dissection off the buck’s fascia and the dorsal neurovascular bundle. figure 9. single layer adaptic™ dressing and vacuum assisted closure sponge were placed over the graft. and the dorsal neurovascular bundle (figures 5, 6). at this point, we must be careful of damaging the branches of the archivio italiano di urologia e andrologia 2023; 95, 1 surgical management of penile siliconoma gest a protective outer sheath, which can be tailored with an empty 1000 cc saline plastic bottle or similar, and then create a small opening where the suture can be fixed in a manner the penis is kept straight (important to avoid excessive traction). finally, the graft harvest site is draped with xeroform™ and a dry dressing. after the surgery, the vac and urinary catheter were removed on post-operative day five, when usually the graft has taken; if necessary, they can be kept longer. once the patient is discharged, daily dressing changes and a silver nitrate dressing on the donor site are mandatory to secure an optimal healing (figure 10). subsequently, on post-operative day 12, the stsg has an excellent take (figure 11), and the donor site shows signs of a good healing. the postoperative pain is mild and usually triggered by erections. glans numbness might be reported in cases of aggressive neurovascular bundle dissection or when the foreign material was markedly adherent. after one month, the penis usually shows an excellent healing with an excellent esthetic outcomes, achieving patient’s satisfaction (figures 12, 13). after two months, the improving continues; typically, the painful erections and glans numbness subside (figure 14). discussion penile enhancement procedures continue to be offered despite multiple case reports and series published in current medical literature depicting potentially devastating complications ranging for erectile dysfunction to penile deformity and even penile loss (3, 7, 8). despite small case series describing «successful» short-term follow-up with penile fillers (3), there are no current formal society guidelines supporting the use of these procedures. furthermore, these experimental procedures lack standardization, and no prospective trials or studies on large cohorts currently demonstrate their safety and feasibility. the defects and complications resulting from enhancement procedures can be difficult to manage, and to do so, reconstructive penile surgery is needed, which of the existing techniques will be used vary depending on the extent of the imperfection, and the involvement of different structures. currently, two of the most used are the scrotal flap (dartos fascio-myo-cutaneous flap) and the circumferential penile skin excision with stsg resurfacing. the goal of any of these reconstructive surgery techniques is to retrieve penis functionality and aspect. the scrotal flaps provide high aesthetic results and postoperative satisfaction with high flap viability, and they can be used for the treatment of various urogenital defects, regardless of its severity (11). surgical methods of this technique range from single-sided scrotal axial flap for defect closure to a combination of multistage stacked flap methods; scrotal axial flaps always requires an intact donor site and they are often used for patients with defects due to penile enhancement injections (11). stsg is an easy and effective technique capable of covering large surfaces of skin loss, and at the same time provide excellent functional and aesthetic outcomes (12). to perform this technique, usually the penile skin is excised, extending to the scrotum if necessary, preserving dartos as much as possible, since it facilitates the graft mobility. after dissection is done, and the graft harvested, it is placed over the defect and tacked in with sutures (usually chromic), securing it at the base and the neo-ventral raphe that is created (for this a total penile degloving is needed) (12). in this paper, we describe a partial penile skin degloving and stsg resurfacing, which to our knowledge is the first manuscript in current medical english literature to do so, as circumferential penile skin excision with stsg resurfacing has only been described to date. despite good esthetic and erectile function results obtained with circumferential penile skin excision, it was hypothesized by the authors that a partial penile degloving limited to the affected area would decrease the morbidity of the procedure, the risk of figure 10. home discharge on day five with daily dressing changes and a silver nitrate dressing on the donor site. figure 11. postoperative day 12, excellent take of the graft. figure 12. excellent esthetic outcomes and healing at one month. figure 13. excellent esthetic outcomes and healing at one month.. figure 14. two months after the procedure. archivio italiano di urologia e andrologia 2023; 95, 1 m. belmonte chico goerne, a. khogeer, p. davison, s. carrier, m. aubé-peterkin vascular or nerve damage while preserving normal and well vascularized native penile tissue. a smaller defect also decreases the morbidity of the stsg harvest site. currently, one of the most described alternative options for penile and scrotal reconstruction either post silicone excision or trauma (iatrogenic, burns, animal bites, gunshots, self-mutilation, circumcision, etc.) is the scrotal flap technique (13, 14). this technique is mostly used in cases with extensive penile scarring, concurrent scrotal migration and when the use of stsg is not possible (13). finally, proper patient counseling prior to silicone excision and penile reconstruction is primordial to address all possible future functional or esthetic outcomes. patient should be informed about the risk of penile skin and glans hypoesthesia, erectile dysfunction, penile curvature, residual silicone materials and any graft related complications. conclusions injection of foreign materials such as silicone for penile enhancement may lead to devastating complications and this practice is not currently supported by formal society guidelines. partial excision of the affected penile skin and siliconoma with resurfacing of the defect with a stsg is a feasible reconstructive technique in select cases with areas of intact penile anatomy while limiting the potential morbidity of circumferential penile degloving and a large stsg donor site defect. references 1. francoeur r, perper t, scherzeer na. descriptive dictionary, and atlas of sexology. greenwood press, new york; 1991. 2. alter gj, salgado cj, chim h. aesthetic surgery of the male genitalia. semin plast surg. 2011; 25:189-195. 3. bizic mr, djordjevic ml. penile enhancement surgery: an overview. emj urology. 2016; 4:94-100. 4. vardi y, har-shai y, gil t, gruenwald i. a critical analysis of penile enhancement procedures for patients with normal penile size: surgical techniques, success, and complications [published correction appears in eur urol. 2009; 55:1002. harshai, yaron [corrected to har-shai, yaron]]. eur urol. 2008; 54:1042-1050. 5. oates j, sharp g. nonsurgical medical penile girth augmentation: experience-based recommendations. aesthet surg j. 2017; 37:10321038. 6. yacobi y, tsivian a, grinberg r, kessler o. short-term results of incremental penile girth enhancement using liquid injectable silicone: words of praise for a change. asian j androl. 2007; 9:408-413. 7. silberstein j, downs t, goldstein i. penile injection with silicone: case report and review of the literature. j sex med. 2008; 5:2231-2237. 8. lee t, choi hr, lee yt, lee yh. paraffinoma of the penis. yonsei med j. 1994; 35:344-348. 9. lighterman i. silicone granuloma of the penis. case reports. plast reconstr surg. 1976; 57:517-519. 10. cavalcanti ag, hazan a, favorito la. surgical reconstruction after liquid silicone injection for penile augmentation. plast reconstr surg. 2006; 117:1660-1661. 11. adamyan rt, kamalov aa, ehoyan mm, et al. scrotal tissues: the perfect material for urogenital reconstruction. plast reconstr surg glob open. 2020; 8:e2948. 12. alwaal a, mcaninch jw, harris cr, breyer bn. utilities of split-thickness skin grafting for male genital reconstruction. urology. 2015; 86:835-839. 13. asanad k, banapour p, asanad s, et al. scrotal flap reconstruction for treatment of erectile dysfunction following penile enhancement with liquid silicone. urol case rep. 2018;20:75-77. 14. moussa m, abou chakra m. scrotal dartos-fascio-myocutaneous flaps for penis reconstruction after iatrogenic skin shaft sub-amputation. j surg case rep. 2019; 2019:rjz206. correspondence manuel belmonte chico goerne, md manuel.belmontecg@gmail.com abdulghani khogeer, md dr-abdulghani@hotmail.com serge carrier, md serge.carrier@mcgill.ca melanie aube-peterkin, md (corresponding author) melanie.aube-peterkin@mcgill.ca department of urology, mcgill university health center 1001 boulevard decarie, suite d05.5331, montreal, quebec h4a 3j1 (canada) peter davison, md peter.davison@mcgill.ca department of plastic surgery, mcgill university health center, montreal (canada) conflict of interest: the authors declare no potential conflict of interest. introduction prostate cancer (pca) is one of the most common cancers in men, with about 700,000 patients diagnosed worldwide each year (1). this figure is closely related to the development of early pca detection programmes, which are based on an increased public awareness about this type of cancer, prostate-specific antigen screening efforts, and the improvement of systematic transrectal ultrasound (trus)-guided prostate biopsy (pbx) techniques. pbx has evolved from the digitally guided pbx technique, described by astraldi (2) in 1937, to the standard sextant 69archivio italiano di urologia e andrologia 2013; 85, 2 original paper the effectivity of periprostatic nerve blockade for the pain control during transrectal ultrasound guided prostate biopsy alper otunctemur 1, murat dursun 1, huseyin besiroglu 1, emre can polat 2, suleyman sami cakir 1, emin ozbek 1, tahir karadeniz 1 1 okmeydani training and research hospital, department of urology, istanbul, turkey; 2 balikligol state hospital, department of urology, sanliurfa, turkey. aim: transrectal ultrasound (trus) guided prostete biopsy is accepted as a standard procedure in the diagnosis of prostate cancer. many different protocoles are applied to reduce the pain during the process. in this study we aimed to the comparison of two procedure with intrarectal lidocaine gel and periprostatice nerve blockade respectively in addition to perianal intrarectal lidocaine gel on the pain control in prostate biopsy by trus. methods: 473 patients who underwent prostate biopsy guided trus between 2008-2012 were included in the study. 10-point linear visual analog pain scale(vas) was used to evaluate the pain during biopsy. the patients were divided into two groups according to anesthesia procedure. in group 1, there were 159 patients who had perianal-intrarectal lidocaine gel, in group 2 there were 314 patients who had periprostatic nerve blockade in addition to intrarectal lidocain gel. the pain about probe manipulation was aseesed by vas-1 and during the biopsy needle entries was evaluated by vas-2. results were compared with mann-whitney u and pearson chi-square test. results: mean vas-2 scores in group 1 and group 2 were 4.54 ± 1.02 and 2.06 ± 0.79 respectively. the pain score was determined significantly lower in the group 2 (p = 0.001). in both groups there was no significant difference in vas-1 scores, patient’s age, prostate volume, complication rate and psa level. conclusion: the combination of periprostatic nerve blockade and intrarectal lidocain gel provides a more meaningful pain relief compared to group of patients undergoing intrarectal lidocaine gel. key words: transrectal prostete biopsy; visual analog scale; lidocaine; periprostatic nerve blockade. submitted 7 february 2013; accepted 28 february 2013 no conflict of interest declared summary method, described by hodge et al. (3) in 1989. transrectal ultrasound guided prostete biopsy (trus-bx) is accepted as a standard procedure in the diagnosis of prostate cancer. having established that the prostate spesific antigen (psa) could be a useful marker for detection of prostatic cancer there has been a significant increase in the number of biopsies (4). however most of patients undergoing trus-bx have discomfort and % 20 of these patients experienced severe pain about the procedure (3, 5). altough trus-bx is a standard common procedure there otunctemur_stesura seveso 24/06/13 11:00 pagina 69 archivio italiano di urologia e andrologia 2013; 85, 2 a. otunctemur, m. dursun, h. besiroglu, e. can polat, s. sami cakir, e. ozbek, t. karadeniz 70 500 mg of ciprofloxacin starting two days before and at least five days after the procedure. bowel preparation was made with two fleet enema, one of them at previous night and the other one two hours before the procedure. after giving detailed information and obtaining consent form, the patients were taken to the table on the lateral decubit position. trus was performed using a 6.5-mhz transrectal probe. the prostate volume was calculated using both sagittal and transverse plans. ten point linear visual analog scale (vas) was used to determine the degree of the pain during transrectal ultrasound guided prostate biopsy. the pain arising from the probe input and manipulation (vas-1) and the pain caused by the needle while taking biopsies from prostate (vas-2) were assesed. all patients were observed for two hours for any complications such as rectal bleeding, hematuria, voiding difficulty and fever. differences in the age, psa levels, prostate volume, vas scores were compared between two different anestethic practice groups. the comparisons about age, prostate volume and pain scores between two groups were applied using mann-whitney u test. complication rates were examined with the pearson chi-square test. results the mean ages were not statisticially different between two groups: 65.2 ± 8.3 for group 1, 66.1 ± 7.7 for group 2. mean psa levels, prostate volumes and complication rates were similar and there was no statistically differences between the groups (table 1). a critical status did not develop with respect to complications. the mean psa levels were similar in group 1 (15.5 ± 23.1) and in group 2 (11.9 ± 13.6 ng/ml). the only statistically significant difference was determined in vas-2 score between two groups. mean pain score caused by the needle while taking biopsies from prostate (vas-2) was lower in group 2 than in group 1. mean vas-2 scores were 4.54 ± 1.02 in group 1 and 2.06 ± 0.79 in group 2, respectively. there was no meaningful difference between the two groups of vas-1 score which shows the pain about probe manipulation (table 2). is no certain protocol or guideline for the preparation of the patient and need for analgesia and the technique used for administration (3, 5). there are many different approaches to reduce the pain and enhance the patients adaptation to the procedure. there is no concensus about which method to use but the patient’s consciousness, prior history about anorectal diseases, pain threshold of the patient, biopsy experience, socio-cultural level are important factors for the decision. the use of periprostatic nerve blockade (ppnb) had been introduced as early as 1996 (6) for minimizing prostatic biopsy pain with lignocaine local anaesthesia. many studies evaluated and conclusively proved the benefit of ppnb (7-9). in this study, we evaulated the pain control in patients who have trus-bx for detection prostate cancer, using ppnb for anaesthesia. we compared the efficacy of periprostatic nerve blockage with intrarectal gel instillation and just perianal intrarectal gel instillation during trus-guided prostate biopsy. materials and methods 473 men who underwent ultrasound guided prostate biopsy from 2009 to 2012, were enrolled in this study. increased prostate speific antigen (psa), abnormal digital rectal examination findings and serum psa levels higher than 2.5 ng/ml were the inclusion criterias. the patients were divided into two groups: in group 1 (159 patients) biopsies were performed after administering perianal intrarectal lidocain gel and in group 2 (314 patients) periprostatic nerve blockade was performed in addition to perianal intrarectal lidocain gel. injections were delivered at the angle between the seminal vesicle and prostate on each side using 5 cc of 2% lidocain. exclusion criterias are as follows: bleeding diathesis and/or use of anticoagulant; anorectal diseases such as hemorrhoids, anal fissures, anal surgery; acute prostatitis; pelvic pain syndrome; history of lidocaine allergies; inability to rate a visual analog scale (vas). all patients receieved standard antibiotic prophylaxis with group 1 group 2 p value number of patients 159 314 age (years) 65.2 ± 8.3 66.1 ± 7.7 0.405 psa (ng/ml) 15.5 ± 23.1 11.9 ± 13.6 0.331 prostate volume (ml) 60.3 ± 24 65.3 ± 26.5 0.07 complication rate (n, %) 64, 40.3 72, 48.3 0.1969 table 1. data of the patients in group 1 and group 2. group 1 group 2 p value pain score (vas1) 2.19 ± 0.9 2.18 ± 0.9 0.904 pain score (vas2) 4.54 ± 1.02 2.06 ± 0.79 0.001 table 2. the statistical data of vas scores in the two groups. otunctemur_stesura seveso 24/06/13 11:00 pagina 70 71archivio italiano di urologia e andrologia 2013; 85, 2 the effectivity of periprostatic nerve blockade for the pain control during transrectal ultrasound guided prostate biopsy 4. wang mc, papsidero ld, kuriyama m. prostate antigen: a new potential marker for prostatic cancer. prostate. 1981; 2:89-96. 5. clements r, aideyan ou, griffiths gj, peeling wb. side effects and patient acceptability of transrectal biopsy of the prostate. clin radiol. 1993; 47:125-6. 6. nash pa, bruce je, indudhara r, shinohara k. transrectal ultrasound guided prostatic nevre blockade eases systemic needle biopsy of the prostate. j urol. 1996; 155:607-9. 7. soloway ms, obek c. periprostatic local anaesthesia before ultrasound guided prostate biopsy. j urol 2000; 163:172-3. 8. alavi as, soloway ms, vaidya a, et al. local anaesthesia for ultrasound guided prostate biopsy: a prospective trial comparing 2 methods. j urol. 2001; 166:1343-5. 9. pareek g, armenaskas na, fracchia ja. periprostatic nerve blockade for transrectal ultrasound guided biopsy of the prostate: a randomized, double-blind, placebo controlled study. j urol. 2001; 166:894-7. 10. irani j, fournier f, bon d, et al. patient tolerance of transrectal ultrasound-guided biopsy of the prostate. br j urol. 1997; 79:608-10. 11. crundwell mc, cooke pw, wallace dm. patients’ tolerance of transrectal ultrasound-guided prostatic biopsy: an audit of 104 cases. bju int. 1999; 83:792-5. 12. krishna ns, kumar pm, morrison l. patients’ tolerance of transrectal ultrasound-guided prostatic biopsy: an audit of 104 cases. bju int. 1999; 84:890. 13. jones js, ulchaker jc, nelson d, et al. periprostatic local anesthesia eliminates pain of office-based transrectal prostate biopsy. prostate cancer prostatic dis. 2003; 6:53-5. 14. skriapas k, konstandinidis c, samarinas m, et al. pain level and anal discomfort during transrectal ultrasound for guided prostate biopsy. does intrarectal administration of local anesthetic before periprostatic anesthesia makes any difference? minerva urol nefrol. 2009; 61:137-42. 15. lynn nn, collins gn, brown sc, o’reilly ph. periprostatic nerve block gives better analgesia for prostatic biopsy. bju int. 2002; 90:424-6. 16. leung sy, wong bb, cheung mc, et al. intrarectal administration of lidocaine gel versus plain lubricant gel for pain control during transrectal ultrasound-guided extensive 10-core prostate biopsy in hong kong chinese population: prospective double-blind randomised controlled trial. hong kong med j. 2006; 12:103-7. 17. shrimali p, bhandari y, kharbanda s, et al. transrectal ultrasound-guided prostatic biopsy: midazolam, the ideal analgesic. urol int. 2009; 83:333-6. 18. kim s, et al. effect of oral administration of acetaminophen and topical application of emla on pain during transrectal ultrasound-guided prostate biopsy. korean j urol. 2011; 52:452-6. 19. saad f, yoon bi, kim sj, et al. a prospective randomized trial comparing lidocaine and lubricating gel on pain level in patients undergoing transrectal ultrasound prostate biopsy. can j urol. 2002; 9:1592-4. 20. ozok hu, sagnak l, ates ma, et al. the efficiency of a sedative or analgesic supplement to periprostatic nerve blockage for pain control during transrectal ultrasound-guided prostate biopsy a prospective, randomized, controlled, double blind study. arch med sci. 2010; 6:787-92. 21. izol v, soyupak b, seydaoglu g, et al. three different techniques for administering analgesia during transrectal ultrasound-guided prostate biopsy: a comparative study. int braz j urol. 2012; 38:122-8. discussion ultrasound guided prostate biopsy is a standard method used to detect prostate cancer. pain during trus-bx is an important problem that is associated with the patient tolerance about procedure (5, 10-12). pain mainly depends on two factors: anal discomfort due to the probe insertion and manipulation of the probe and the insertion of the needle through prostate capsule. periprostatic nerve blockage was firstly defined by nash et al. in 1996 and it is a good choice to reduce the pain (6). in this study it was suggested to inject at the junction of the base of the prostate and seminal vesicles. these findings were similarly confirmed by pareek et al. (9). there are many studies demonstrating that periprostatic nerve blockade is better than plasebo (13-21). recently new methods are being tested in various studies. in a study with 430 patients, acetaminophen and emla cream with intravenous injection of tramadol were found safe, easy, and effective methods of controlling pain during the procedure (18). in some studies midazolam was considered to be a suitable anesthetic during prostate biopsy (17, 20, 21). the application of perianal intrarectal gel and cream provides a good pain relief caused by probe manipulation (14, 23, 24). in the other hand, there are some studies showing that lidocaine gel did not diminish the sensation of pain (16, 25, 26). lidocaine suppositories are found an easyto-use and cheap method of local analgesia, with acceptable results (27). in a study published in 2011 by skriapas et al., the use of topical lidocaine gel and glyceryl trinitrate ointment (gtn) as an adjunct to periprostatic anesthesia to reduce anal pain and discomfort due to probe insertion was found very effective and safe (28). in the other study lidocaine spray was found to provide significantly better pain control than cream and anaesthetic gel (29). furthermore there are some studies comparing different anesthetic substances for pain relief. in a study by olmez et al., tramadol and lornoxicam were used for pain reduction and tramadol was found to be more effective (30). hirsh et al. had similar findings about tramadol in their study (31). in our study, pain scores related to probe manipulation was similar between two groups but there was a very significant difference between the pain score caused by the needle used to take biopsy cores. it was shown that periprostatic nerve blockade is a very good choice for pain control and compliance of the patient to the procedure although it is not effective for anorectal discomfort caused by the probe. we recommend the use of perianal intrarectal lidocain gel and periprostatic nerve blockade combination in trus-guided prostate biopsises. this combination is effective, cheap, safe and easy to perform. references 1. parkin dm, bray f, ferlay j, pisani p. global cancer statistics, 2002. ca cancer j clin. 2005; 55:74-108. 2. astraldi a. diagnosis of cancer of the prostate: biopsy by rectal route. urol cutaneous rev. 1937; 41:421-422. 3. hodge kk, mcneal je, terris mk, stamey ta. random systematic versus directed ultrasound guided transrectal core biopsies of the prostate. j urol. 1989; 142:71-4. otunctemur_stesura seveso 24/06/13 11:00 pagina 71 archivio italiano di urologia e andrologia 2013; 85, 2 a. otunctemur, m. dursun, h. besiroglu, e. can polat, s. sami cakir, e. ozbek, t. karadeniz 72 22. song jh, doo sw, yang wj, et al. value and safety of midazolam anesthesia during transrectal ultrasound-guided prostate biopsy. korean j urol. 2011; 52:216-20. 23. alvarez-mugica m, gonzález alvarez rc, jalón monzón a, et al. tolerability and complications of ultrasound guided prostate biopsies with intrarectal lidocaine gel. arch esp urol. 2007; 60:237-44. 24. siddiqui ej, ali s, koneru s. the rectal administration of lignocaine gel and periprostatic lignocaine infiltration during transrectal ultrasound-guided prostate biopsy provides effective analgesia. ann r coll surg engl 2006; 88:218-21. 25. diaz perez ga, meza montoya l, morante deza c, et al. pain during transrectal ultrasound guided needle biopsy of the prostate: comparison of the use or not of lidocaine gel. actas urol esp. 2009; 33:134-7. 26. argüelles salido e, congregado ruiz cb, conde sánchez jm, et al. ultrasound guided transrectal prostatic biopsy and pain. prospective randomized study comparing lubricant gel, lidocaine gel, and anesthetic blockage of the neurovascular bundles with 1% lidocaine. arch esp urol. 2008; 61:579-90. 27. goluza e, hudolin t, kastelan z, et al. lidocaine suppository for transrectal ultrasound-guided biopsy of the prostate: a prospective, double-blind, randomized study. urol int. 2011; 86:315-9. 28. skriapas k, konstantinidis c, samarinas m, et al. comparison between lidocaine and glyceryl trinitrate ointment for perianalintrarectal local anesthesia before transrectal ultrasonographyguided prostate biopsy: a placebo-controlled trial. urology. 2011; 77:905-8. 29. dell'atti l, daniele c. lidocaine spray administration during transrectal ultrasound guided prostate biopsy modified the discomfort and pain of the procedure: results of a randomized clinical trial. arch ital urol androl. 2010; 82:125-7. 30. olmez g, kaya s, aflay u, sahin h. comparison of lornoxicam versus tramadol analgesia for transrectal prostate biopsy: a randomized prospective study. int urol nephrol. 2008; 40:341-4. 31. hirsh i, kaploun a, faris g, et al. tramadol improves patients’ tolerance of transrectal ultrasound-guided prostate biopsy. urology. 2007; 69:491-4. correspondence alper otunctemur, md murat dursun, md (corresponding author) mrt_drsn@hotmail.com huseyin besiroglu, md suleyman sami cakir, md emin ozbek, md tahir karadeniz, md okmeydani training and research hospital, department of urology 34384, darulaceze cad. no: 25 sisli, istanbul, turkey emre can polat, md balikligol state hospital, department of urology, sanliurfa, turkey otunctemur_stesura seveso 24/06/13 11:00 pagina 72 archivio italiano di urologia e andrologia 2013; 85, 278 introduction modern medicine uses increasingly innovative techniques that require more and more capabilities in order to be acquired. consequently an objective is try to make easier the surgical technique to better manage the surgical procedure and consequently the postoperative patient's course. technical training in any surgical procedure involves three elements: didactic learning, supervised hands-on training and unsupervised experienced. original paper resident training in urology: bipolar transurethral resection of the prostate a safe method in learning endoscopic surgical procedure alessandro del rosso, stefano masciovecchio, giuseppe paradiso galatioto, carlo vicentini university of l’aquila, department of health science, mazzini hospital, urology department, teramo, italy. introduction: modern medicine uses increasingly innovative techniques that require more and more capabilities for acquisition. in the urological department is increasing the presence of patients with lower urinary tract symptoms (luts) and transurethral resection of the prostate (turp) is the standard of care in their surgical treatment. we report our surgical experience and learning curve of using bipolar plasmakinetic devices in the training of urological residents to benign prostatic hyperplasia (bph) treatment. materials and methods: 80 patients with benign prostatic enlargement due to bph were enrolled in the study. turp has been performed by three urological residents and by an experienced urologist. patients were evaluated before and 6 months after the endoscopic bipolar plasmakinetic resection using the international prostate symptom score (ipss), maximum urinary flow rate (qmax), postvoid residual urine (pvr) and prostate specific antigen (psa). results: overall 60 procedures were performed, 18 plasmakinetic (pk)-turp procedures were completed by the three residents. in the other 42 cases the procedures were completed by the experienced urologist. in eight cases there was a capsular perforation and the experienced urologist replaced the resident to complete the resection. no complications have been reported in the procedures completed by the senior urologist. all complications caused by the residents were managed intraoperatively without changing the course of the procedure. statistical differences were observed regarding ipss, quality of life (qol), and pvr at 6-month follow-up when procedures completed by urological residents were compared to those completed by the senior urologist. conclusion: bipolar device represents appropriate tools to acquire endoscopic skills. it is safe and it can be used at the first experience of bph treatment by a resident who has not previously approached this endoscopic surgical procedure. key words: bph; resident; surgical skills; turp. submitted 5 october 2012; accepted 31 december 2012 no conflict of interest declared summary the current organization of university departments and the new standards require that the trainees may demonstrate at least the minimum standards of competence. this would be to ensure uniform standards of training and allow comparisons among different institutions (1). in the urological departments is increasing the affluence of patients with lower urinary tract symptoms (luts) and benign prostatic hyperplasia (bph) parallel to the del rosso_stesura seveso 24/06/13 11:27 pagina 78 79archivio italiano di urologia e andrologia 2013; 85, 2 resident training in urology: bipolar transurethral resection of the prostate a safe method in learning endoscopic surgical procedure gation. after the introduction of the resectoscope, the surgeon always provided to mark the ureteral orifices. the incision at 6 o’clock position was the first step of the endoscopic procedure with a cut extended from bladder neck to the veru montanum, deep to the surgical capsule. thereafter the incision at the 12 o’clock position was performed, involving a 180° rotation of the sheath being careful to the adequate depth and length of the incision. finally we proceeded to resection of the prostatic lateral lobes. at the end of the procedure a 20 ch 3-way catheter was inserted. postoperatively a continuous saline bladder irrigation was used until the efflux was sufficiently clear, with subsequent catheter removal and patient discharge when urine were clear. residents training prior to perform endoscopic procedures in the operating room, the urological residents were given didactic lessons on the surgical technique at an academic teaching hospital (3). following these lessons, the residents practiced the surgical device and, once the attending surgeon determined that the residents were able to perform the procedure safely, they performed a surgical endoscopic resection on the patient in the operating room, always with the senior urologist supervision. results baseline and immediate postoperative parameters are reported in table 1. all patients completed the sixmonths follow-up. overall 80 procedures performed, the three residents completed a mean of 6 pk-turp for each one, without any intervention of the experienced urologist, but only with his supervision. in the first 14 cases for each resident, the procedures were completed by the experienced urologist due to different reasons (loss of orientation, low speed of resection, bleeding, capsular perforation). out of all the endoscopic pkturp treatments, a capsular perforation was observed in increase of the age of patients. the impact on quality of life (qol) and health care cost justifies additional research about the use of therapeutic resources. transurethral resection of the prostate (turp) is the standard of care in surgical management of luts due to bladder outlet obstruction for prostate of 30-80 ml (2). different type of resectoscope are actually available, roughly divided in monopolar and bipolar devices. today is currently more widespread the use of the bipolar plasmakinetic (pk) turp that appears to offer many advantages compared to the monopolar resection. we report here our surgical experience and learning curve of using bipolar plasmakinetic devices in the training of urological residents for bph treatment. materials and methods patients from january 2009 to august 2011, a total of 80 patients with benign prostatic enlargement due to bph were enrolled in the study. all patients undergo pkturp. the study included all patients candidates for transurethral resection with a prostate volume at least of 80 ml, luts causing a ipss of 15 or greater, qol index of 2 or greater and qmax less than 15 ml/s. all patients were older than 50 years with symptomatic benign prostatic hyperplasia of at least 3-months duration of and who did not benefit of medical therapy with persistence or progression of urinary symptoms. exclusion criteria included patients with urinary tract infections and patients who reported a neurogenic bladder dysfunction, abnormal digital rectal examination (dre) findings or known prostate cancer, previous prostatic or urethral surgery or bladder stones. written informed consent has been obtained from all subjects. anticoagulant drugs have been discontinued at least 7 days before surgery. patients were evaluated before and 6 months after the endoscopic resection using the ipss bother score, the measurements of the qmax, pvr and psa. we reported the experience and technical progress in treating patients with the plasmakinetic bipolar endoscopic device and evaluated the difficulties in carrying out the surgical procedures, considering patients outcome in the immediate postoperative and after six-months follow-up. spss for windows (version 10.0.7) computer package was used for statistical analysis of the data. the wilcoxon test was used and p < 0.05 was considered as a level of statistical significance. surgical technique all the procedures were performed under spinal anesthesia, in lithotomic position and after a preoperative antibiotic prophylaxis. the endoscopic procedures were performed by three urological residents (20 procedures for each) and an experienced urologist (20 procedures). pk-turp has been performed using the gyrus plasmakinetic tissue management system (gyrus medical ltd., cardiff, uk) with a 27 ch continuous flow resectoscope and a u-shaped cutting loop. once connected, the generator was automatically set to 160 w for cutting and 80 w for coagulation. saline solution was used for irrimean range age (years) 66.3 51-78 total prostate volume (g) 51.6 32-68 transitional zone volume (g) 28.5 18-44 resection time (min) 55 26-105 resection weight (g) 31 22-40 preoperative psa (ng/ml) 3.45 0.8-6.3 preoperative mean qmax (ml/s) 7.2 2.6-12.4 preoperative mean pvr (ml) 160 50-280 catheterization time (day) 2.4 2-4 hospital stay (day) 3.2 3-5 hemoglobin decrease (g/dl) 1.7 0.7-2.7 blood transfusion none tur syndrome none table 1. baseline and immediate postoperative parameters of the patients. del rosso_stesura seveso 24/06/13 11:27 pagina 79 archivio italiano di urologia e andrologia 2013; 85, 2 a. del rosso, s. masciovecchio, g. paradiso galatioto, c. vicentini 80 all professionals (1). although didactic training methods can accelerate the evolution of procedural skills, they cannot substitute the other elements, considering the hands-on experience through which technical skills, including three-dimensional awareness and hand-eye coordination, develop (5, 6). currently, the most frequently used models are the synthetic organ models for ureterorenoscopy and transurethral resection of the prostate. however the use of these tools has a limited value due to the lack of bleeding and the unrealistic force feedback. furthermore local and national regulation in relation to the use of animal organs in the hospital and use of instruments in animal urinary tracts must be also considered. as a consequence the main way to gain experience remains the real contact with the patient and the surgical treatment of his pathology (7). currently bph is one of the most common disease that affect men beyond middle age and turp is the standard of care in the surgical management of luts due to bladder outlet obstruction. regarding this endoscopic procedure, significant technical improvements during the past 15 years have been introduced and the bipolar technology has become a safe and effective procedure in alternative to conventional monopolar turp (8). our training course allowed us to learn and approach the endoscopic surgical technique with the new endoscopic modern devices. our data showed that there is a greater ease of training with the bipolar instrument, also confirmed by the increasing number of resections that have been completed by the residents alone with onlly supervision of an expert. in addition, only minor complications occurred during the endoscopic procedures confirming the easier handling for the pk device. in fact the learning curve seems to confirm that already an approximate number of about 20 procedures resulted in a good capacity of surgical management. in fact the latest procedures of this series were substantially completed by the residents who could complete them autonomously, although under the supervision of an experienced urologist. a six-months follow-up, although still limited, seems adequate to confirm the success of the procedure even in cases in which the resident has completed the eight cases. in these cases, the experienced urologist replaced the resident in order to complete the resection (table 2). all the complications caused by the residents were managed intraoperatively without changing the course of the procedure. comparing endourological procedures carried out by the resident alone with those performed by the senior urologist, the latter showed no problems or complications of the resection. mean catheterization time was 2.4 days in the pk-turp and mean hospital stay was 3.2 days. no cases of tur syndrome have been observed. considering the immediate postoperative and 6 months follow-up, in all cases there was a normal course of the patient both in the time of catheterization that in hospitalization. after 6 months, comparing the three groups: 1) procedures not completed by the resident, 2) procedures completed alone with supervision and 3) procedures completed by the experienced urologist, qmax value was significantly different between group 1 and 3 (p < 0.05), no significant differences have been reported between the other two groups. no differences were observed regarding ipss, qol, pvr and preoperative and postoperative 6-months psa. moreover, we report significant differences (p < 0.05) in the resected weight between group 2 and group 3. discussion endourology is one of the most difficult techniques to learn. safe and effective performance of diagnostic and therapeutic endourological procedures requires longterm practical experience. training opportunities for residents and urologists are the way to increase their experience in the surgical approach (4). as just reported, the technical training in any procedure involves three elements: 1) didactic learning, 2) supervised hands-on training and 3) unsupervised experience. obviously the third parameter continues throughout the individual professional career, and so, the first two elements are basic for proper growth of a resident. nowadays, the standardization of education is increasingly important for the education of procedures not completed procedures completed procedures completed by residents alone by residents alone (with supervision) by experienced urologist group 1 group 2 group 3 no. of procedures 42/60 (70%) 18/60 (30%) 20/20 (100%) capsular perforation 3/60 (5%) 5/60 (8.3%) 0/20 (-) mean qmax, ml/s* 20.1 (15.3-26.2) 22.7 (17.4-32.6) 25.6 (19.5-34.2) mean ipss 2.8 (1-3) 3.1 (2-3) 2.8 (2-3) mean qol 2.3 (1-3) 2.4 (1-3) 2.2 (0-3) mean pvr, ml 15 (0-40) 20 (0 -50) 10 (0-30) mean psa, ng/ml 1.5 (0.4-2.3) 1.5 (0.9-2.1) 1.2 (0.6-1.7) mean resected weight (g)** 32 (27-38) 27 (22-36) 42 (28-48) table 2. perioperative, immediate complications and postoperative characteristics at 6-months follow-up of the different type of procedures and surgeon. * p < 0.05 group 1 vs group 3; ** p < 0.05 group 2 vs group 3. del rosso_stesura seveso 24/06/13 11:27 pagina 80 81archivio italiano di urologia e andrologia 2013; 85, 2 resident training in urology: bipolar transurethral resection of the prostate a safe method in learning endoscopic surgical procedure resection alone by himself, without needing any direct aid for proper management of the endoscopic procedure. clearly, results cannot be comparable to the surgical management obtained by an experienced urologist, because significant differences in terms of mean qmax and resected weight were observed between the procedures entirely performed by residents and those performed by an experienced urologist. these results suggests that the bipolar resector seems to be a good tool for training because it is easy to handle and speeds the learning process. conclusions in our experience, bipolar devices represent a very important and appropriate way to acquire the endoscopic skills. it is possible to use this endoscopic device by residents even at their first experience of bph treatment. references 1. le cq, lightner dj, vanderlei l, et al. the current role of medical simulation in american urological residency training programs: an assessment by program directors. j urol. 2007; 177:288-91. 2. yu x, elliott sp, wilt tj, et al. practice patterns in benign prostatic hyperplasia surgical therapy: the dramatic increase in minimally invasive technologies. j urol. 2008; 180:241-5. 3. alley jr, stucky cc, moncure m. teaching surgical residents dome-down laparoscopic cholecystectomy in an academic medical center. j soc laparoendoscopic surg. 2008; 12:368-371. 4. schreuder hw, oei g, maas m, et al. implementation of simulation in surgical practice: minimally invasive surgery has taken the lead: the dutch experience. med teacher. 2011; 33:105-15. 5. el-hakim a, elhilali mm. holmium laser enucleation of the prostate can be taught: the first learning experience. bju international. 2002; 90:863-869. 6. kössi j, luostarinen m. virtual reality laparoscopic simulator as an aid in surgical resident education: two years’ experience. scand j surg. 2009; 98:48-54. 7. rodríguez-sanjuán jc, palazuelos cm, fernández-díez mj. et al. assessment of resident training in laparoscopic surgery based on a digestive system anastomosis model in the laboratory. cir esp. 2010; 87:20-25. 8. rassweiller j, schlze m, stock c, et al. bipolar transurethral resection of the prostate-technical modifications and early clinical experience. minim invasive ther allied technol. 2007; 16:11-21. correspondence alessandro del rosso, md (corresponding author) delrossoa@tiscali.it stefano masciovecchio, md giuseppe paradiso galatioto, md carlo vicentini, md mazzini hospital, department of urology, italy square, teramo, italy del rosso_stesura seveso 24/06/13 11:27 pagina 81 stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 91 original paper sive techniques (laparoscopic, robotic prostatectomy) and endoscopic interventions. first resectoscope and the first transurethral resection of prostate (turp) procedure was introduced by maximilian stern in 1926 (4). with technological advances, turp became more and more popular and has been considered the reference technique for the surgical management of bph. despite the decline in the rate of turp for bph surgery due to development of various alternative techniques such as holmium laser enucleation of prostate (holep), turp is still the most frequently taught and performed surgical technique for bph (5). the internet's baby steps began to be taken in the 1960’s and accelerated in the 80’s (6). nowadays, 60% of the world’s population has access to internet (7). with portable electronic devices online resources have become an important part of education in general. videos are easily accessible, allow creating personal time and space for learning. by watching videos online, one can learn different techniques from various surgeons, interact with colleagues around the world, exchange ideas and improve skills. with fewer opportunities being found lately by trainees in the operating rooms due to work hour restrictions, high costs, patient safety measures (8), videos became a crucial learning method in surgical training. many surgical videos are avaliable online and advantages of these videos in surgical education have been shown in various studies (9, 10). youtube™ (google, llc) which was founded on 2005, is the second most popular website in the world with over 33 billion total visits in june 2022 (11) and the biggest source of videos on the internet. studies showed that youtube™ is the most widely used platform by both residents and surgeons for surgical education (12, 13). there is a great opportunity to learn about surgical techniques and improving skills with watching videos on youtube™. however, since there is lack of professional peer review and quality check of the videos on youtube™, surgical videos may be untrustworthy. in this study we aimed to evaluate the educational quality of turp videos on youtube™. materials and methods in this study we evaluated turp surgery videos which are avaliable for the public. therefore, no ethical approval is background: our aim was to evaluate the educational value of transurethral resection of prostate (turp) videos on youtube. methods: a comprehensive search was conducted for turp videos on youtube. based on the laparoscopic surgery video educational guidelines we created a checklist which includes 20 items for evaluation of the videos. ibm spss statistics was used for analysis. results: a total of 104 surgical videos were assessed. the mean view count was 15647.3 (21-324.522, sd 47556.4). video image quality found as low for 57.7% of videos. both staff (76%) and resident (75%) rated most of the videos low educational quality. no statistically significant difference was found between staff’s total points (mean 4.35 ± sd 2.9) and resident’s total points (mean 4.63 ± sd 3.3) (p: 0.761). positive correlation was found between view count and staff’s total points (r: 0.242 p < 0.05), resident’s total points (r: 0.340 p < 0.01). there was also positive correlation between number of likes and staff’s total points (r: 0.375 p < 0.01) and resident’s total points (r: 0.466 p < 0.01). conclusions: most turp surgical videos on youtube are low quality. higher educational quality videos with detailed explanation of the procedure are needed on this subject. we believe this study could be a guide for future high quality turp videos. key words: transurethral resection of prostate; benign prostatic hyperplasia; social media; video recording; data quality. submitted 11 april 2023; accepted 27 april 2023 introduction benign prostatic hyperplasia (bph) is a histologic diagnosis which is characterized by proliferation of smooth muscle and epithelial cells of the periurethral prostatic tissue. its prevalance increases with age reaching 90% by the ninth decade of life at autopsy studies (1). bph is the leading cause of male lower urinary tract symptoms (luts) (2). most men after 45 suffer at least one component of luts and symptoms are mostly mild (3). with aging global population and high prevelance of luts especially in elderly men, treatment of male luts will become even more important in the future. treatment options for bph related male luts are conservative treatment, pharmacotherapy and surgery. surgical management of bph can basically divided into three main groups; open prostatectomy, minimally invaanalysis of transurethral resection of prostate videos on youtube™: educational quality assessment yavuz karaca 1, emre burak sahinler 1, didar ilke karaca 2, orhun sinanoglu 1 1 department of urology, sancaktepe sehit prof. dr. ilhan varank research and training hospital, istanbul, turkey; 2 department of public health, marmara university school of medicine, istanbul, turkey. doi: 10.4081/aiua.2023.11404 summary archivio italiano di urologia e andrologia 2023; 95, 2 y. karaca, e. burak sahinler, d. ilke karaca, o. sinanoglu 92 required. a comprehensive search was performed in october 31, 2022 on youtube™ (https://www.youtube.com) using the search terms “tur prostate”, “tur prostatectomy”, “tur p”, “monopolar tur p”, “bipolar tur p” seperately. the videos were selected by the first author based on following criterias: traditional resection of the prostate must be performed either with monopolar or bipolar systems, live surgery recorded by endoscopic camera systems, videos made by professionals and videos in english language. videos including multiple surgeries, externally recorded videos, commercial videos, slide based presentation videos and animation videos and nonenglish videos were excluded from the study. 104 videos met these criterias and were included the study (figure 1). characteristics of the videos were view count, number of likes, days online, video length, region, video image quality (480p resolution: low, 720p resolution: medium, 1080p resolution: high). there are several reports assessing youtube™ videos from patient’s perspective, rating their understandibility and patient educational value (14, 15). in this report, we tried to evaluate turp videos on youtube™ as tools for surgical education. no guideline for assessing the educational value of turp videos were present. first author which is a junior staff urologist and the third author which is a senior staff urologist created a video quality checklist based on the checklist that was developed for the evaluation of laparoscopic surgery videos (16). the checklist included five major categories which were author’s information, case presentation, critical steps of the procedure, outcomes of the procedure, supplementary contents with a total of 20 items. each item represented one point (table 1). first author and second author which was a junior restable 1. the checklist for the evaluation of turp surgical videos' educational quality. items of checklist author’s information 1. author’s information 2. title of the video including the procedure 3. conflict of interest disclosure case presentation 4. patient privacy protection 5. patient characteristics 6. preoperative work-up 7. prostate volume critical steps of the procedure 8. introduction of the equipments 9. setting of cut and coagulation 10. anatomic demonstration 11. step by step explanation 12. explanation of the critical steps outcomes of the procedure 13. operating time 14. volume of resected specimen 15. length of hospitalization 16. intraoperative and postoperative complications 17. functional outcomes supplementary contents 18. educational tables and photos 19. audio commentary 20. video commentary figure 1. prisma diagram showing the selection of the videos. archivio italiano di urologia e andrologia 2023; 95, 2 93 quality evaluation of turp videos on youtube™ ident evaluated the videos and scored each video from 1 to 20. videos were divided into 4 educational quality groups according to their total score; low quality (0-5 points), medium quality (6-10 points), high quality (1116 points) and very high quality (16-20 points). with scoring videos separately by a staff surgeon and a resident we aimed to not only evaluate the educational quality of the videos but to determine if there is a difference between a resident’s and a surgeon’s evaluation. statistical analysis statistical analysis was performed with ibm spss software (version 26 for macos, ibm corporation, ny, usa). the characteristics of the videos were presented as mean, median, ranges, standard deviation (sd). the distribution of the variables was measured by kolmogorovsmirnov test. mann whitney u test was used for the comparison of two reviewers mean points. pearson’s correlation coefficient was used to evaluate the correlations between variables. p < 0.05 was considered statistically significant. results total of 104 videos were evaluated. the mean view count was 15647.3 (range 21-324.522, sd 47556.4). mean like count was 30.8 (range 0-285, sd 54.7). the median days avaliable online was 1856.5 (137-5943) (table 2). videos were sourced from asia (65.3%), europe (15.3%), unknown region (14.4%), usa (2.8%) and australia (1.9%). 73 (70.1%) videos were uploaded by private users, 15 (14.4%) videos by medical organizations and 16 (15.3%) videos by unknown users. video image quality was found as low for 60 (57.7%), medium for 25 (24%) and high for 19 (18.3%) videos. no statistically significant difference was found between staff’s total points (mean 4.35 ± sd 2.9) and resident’s total points (mean 4.63 ± sd 3.3) for the evaluation of the videos (p: 0,761) (table 3). no video received full points from the checklist. both staff urologist (79/104, 76%) and resident (78/104, 75%) rated most of the videos low educational quality. resident rated 8 (7.7%) videos high quality while staff urologist rated 5 (4.8%). only one video rated very high quality and it was by the staff urologist. the correlation test showed positive correlation between view count and number of likes (r: 0.787 p < 0.01), staff’s total points (r: 0.242 p < 0.05), resident’s total points (r:0.340 p < 0.01) and days online (r: 0.477 p < 0.01). there was also positive correlation between number of likes and staff’s total points (r: 0.375 p < 0.01) and resident’s total points (r: 0.466 p < 0.01). there was a positive correlation between staff’s total points and resident’s total points (r: 0.887 p < 0.01). negative correalation was found between days online and video lenght (r: 0.207 p < 0.05) and staff’ total points (r: 0.195 p < 0.05) (table 4). discussion in this study our purpose was to evaluate turp videos on youtube™ to estimate their educational value, define the pros and cons of the videos and try to set a standard for future high quality videos. to our knowledge, this is the first report to review the quality of turp videos on youtube™. in this report we demostrated that most of the turp videos on youtube™ have low educational quality. in the majority of videos; there was limited information regarding patient’s data. most videos consisted of edited or unedited footage of the surgery and did not include any explanation of the critical steps regarding the procedure. very few of the videos have mentioned outcomes of the procedure. additionally image quality were low in most videos. these major defects resulted in videos that were not suitable for educational purpose. there are several studies in the literature assessing surgery videos on youtube™. a study on videos about surgical treatment of luts/bph indicated low quality content in the vast majority of the videos (17). yang et al. evaluated 70 thulep videos on youtube™ and concluded that there is lack of high educational valued videos on this topic (18). a review of 32 mid urethral sling videos on youtube™ showed that none of the videos demonstrated the complete list of critical steps of the procedure (19). loeb et al. reported that overall information quality was moderate to poor in 67% of 150 bladder cancer videos on youtube™ and moderate to high misinformation was present in 21% of the videos (20). haslam et al. assessed 23 robotic pyeloplasty videos on youtube™ and found out that only 6 videos included all critical steps of the procedure (21). these studies along with our’s outlined that, although table 3. comparison of staff’s and residents' mean points. staff urologist’s points resident’s points p-value mean ± sd 4.35 ± 2.9 4.63 ± 3.3 0.761 median (min-max) 3 (2-16) 3 (2-15) table 2. characteristics of the videos. mean ± sd median (min-max) view count (n) 15647.3 ± 47556.4 894 (21-324522) video length (m) 864 ± 988.6 528 (77-6236) like (n) 30.8 ± 54.7 7 (0-285) days online (d) 1961.1 ± 1297.4 1856.5 (137-5943) number (n); minute (m); days (d). table 4. correlation analysis of between video features and scores. 1 2 3 4 5 6 1. view count 1 2. video lenght 0.150 1 3. like 0.787** 0.190 1 4. point 1 0.242* -0.072 0.375** 1 5. point 2 0.340** 0.004 0.466** 0.887** 1 6. days online 0.477** -0.207* 0.086 -0.195* -0.134 1 * correlation is significant at the 0.05 level (2-tailed). ** correlation is significant at the 0.01 level (2tailed). archivio italiano di urologia e andrologia 2023; 95, 2 y. karaca, e. burak sahinler, d. ilke karaca, o. sinanoglu 94 youtube™ has a wide variety of medical videos, there are great heterogeneity in their quality. great care must be taken when using youtube™ videos as a source of information, because most of the videos contain inaccurate and incomplete information about the procedures, which may prove to be harmful than educational, especially for inexperienced learners. videos from academic institutions tend to be more high quality than videos from single users (22). sources with rigorous review processes like official websites of urological associations (i.e. american urological association, european association of urology) or video sections of certain urology journals may be used for more credible information. our study has limitations. firstly, we evaluated videos on youtube™ solely hence more websites should be included for more comprehensive view of the quality of turp videos. but since youtube™ is the most popular source for surgical videos we believe these results have great value. secondly, the fact that one of the reviewer was a junior resident with little experience on turp could have introduced bias into the study. however no statistically significant difference was found between two reviewers evaluations thus this suggests that his inexperience did not have any effects on our findings and our findings are reliable. lastly we were obligated to create a checklist for evaluation of turp videos because no other study has addressed this subject before. more studies are needed to develop a standardizied and validated checklist. conclusions youtube™ lacks high educational quality videos of transurethral resection of the prostate. it is important to detect high quality videos and verify the information with multiple sources. we believe that this study can guide future high educational quality videos. references 1. berry sj, coffey ds, walsh pc, ewing ll. the development of human benign prostatic hyperplasia with age. j urol. 1984; 132:474-9. 2. parsons jk. benign prostatic hyperplasia and male lower urinary tract symptoms: epidemiology and risk factors. curr bladder dysfunct rep. 2010; 5:212-218. 3. mcvary kt. bph: epidemiology and comorbidities. am j manag care. 2006; 12(5 suppl):s122-8. 4. https://www.baus.org.uk/_userfiles/pages/files/museum/20%20%20turp.pdf 5. malaeb bs, yu x, mcbean am, elliott sp. national trends in surgical therapy for benign prostatic hyperplasia in the united states (2000-2008). urology. 2012; 79:1111-6. 6. https://www.britannica.com/story/who-invented-the-internet. 7. https://data.worldbank.org. 8. pugh cm, watson a, bell rh jr, et al. surgical education in the internet era. j surg res. 2009; 156:177-82. 9. friedl r, höppler h, ecard k, et al. development and prospective evaluation of a multimedia teaching course on aortic valve replacement. thorac cardiovasc surg. 2006; 54:1-9. 10. pape-koehler c, immenroth m, sauerland s, et al. multimediabased training on internet platforms improves surgical performance: a randomized controlled trial. surg endosc. 2013; 27:1737-47. 11. https://www.similarweb.com/top-websites/ 12. rapp ak, healy mg, charlton me, et al. youtube is the most frequently used educational video source for surgical preparation. j surg educ. 2016; 73:1072-1076. 13. mota p, carvalho n, carvalho-dias e, et al. video-based surgical learning: improving trainee education and preparation for surgery. j surg educ. 2018; 75:828-835. 14. shoemaker sj, wolf ms, brach c. development of the patient education materials assessment tool (pemat): a new measure of understandability and actionability for print and audiovisual patient information. patient educ couns. 2014; 96:395-403. 15. morra s, napolitano l, collà ruvolo c, et al. could youtube™ encourage men on prostate checks? a contemporary analysis. arch ital urol androl. 2022; 94:285-290. 16. celentano v, smart n, mcgrath j, et al. lap-vegas practice guidelines for reporting of educational videos in laparoscopic surgery: a joint trainers and trainees consensus statement. ann surg. 2018; 268:920-926. 17. betschart p, pratsinis m, müllhaupt g, et al. information on surgical treatment of benign prostatic hyperplasia on youtube is highly biased and misleading. bju int. 2020; 125:595-601. 18. yang k, meng y, zhang k. educational value of youtube surgical videos of thulium laser enucleation of the prostate (thulep): the quality assessment. transl androl urol. 2021; 10:2848-2856. 19. larouche m, geoffrion r, lazare d, et al. mid-urethral slings on youtube: quality information on the internet? int urogynecol j. 2016; 27:903-8. 20. loeb s, reines k, abu-salha y, et al. quality of bladder cancer information on youtube. eur urol. 2021; 79:56-59. 21. haslam re, seideman ca. educational value of youtube surgical videos of pediatric robot-assisted laparoscopic pyeloplasty: a qualitative assessment. j endourol. 2020; 34:1129-1133. 22. sahin y, paslanmaz f, ulus i, et al. quality and content analysis of female urethroplasty videos on youtube. low urin tract symptoms. 2023; 15:24-30. correspondence yavuz karaca, md mdyavuzkaraca@gmail.com emre burak sahinler, md emre.sahinler@yahoo.com orhun sinanoglu, md orhundr@hotmail.com department of urology, sancaktepe sehit prof. dr. ilhan varank research and training hospital, istanbul, turkey didar ilke karaca, md karacailke@yahoo.com department of public health, marmara university school of medicine, istanbul, turkey conflict of interest: the authors declare no potential conflict of interest. introduction the suprapubic cystostomy (spc) is a common urological procedure to drain the bladder in a wide variety of pathological processes. suprapubic catheter can be placed either through a punch trocar, after localization of the bladder by palpation, or by using other safer techniques like the application of the lowsley retractor, seldinger technique using peel away sheath introducer or image guidance using ultrasonography (usg) guidance. local anesthesia is usually enough in most cases of spc insertion except some special circumstances, like in patients with spinal cord injuries, in which general or regional anesthesia is indicated (1). additionally, in uncooperative or agitated patients, sedation might be necessary along with local anesthesia (2). although the spc is a safe procedure, it is not devoid of complications such as site bleeding, catheter blockade, malpositioning, dislodgment, or bowel injury. bowel perforation is the most dreaded complication of spc insertion with an incidence rate of 2.4 to 2.7% in two 101archivio italiano di urologia e andrologia 2013; 85, 2 case report iatrogenic direct rectal injury: an unusual complication during suprapubic cystostomy (spc) insertion and its laparoscopic management rakesh rajmohan, bernardo aguilar-davidov, theodoros tokas, jens rassweiler, ali serdar gözen department of urology, slk-kliniken, university of heidelberg, heilbronn, germany. suprapubic cystostomy (spc) is commonly used, instead of indwelling urethral catheterization, as indicated in many pathological conditions. although considered to be a safe procedure that can be easily performed in an outpatient basis several complications have been reported in international literature. bowel injury can be a serious complication with the small intestine affected in the majority of cases. we present a case of an accidental rectal injury by a suprapubic catheter misplacement, in a 76 year old demented patient with prostatic hyperplasia and chronic urinary retention. the injury was confirmed by cystography and injection of contrast meterial through the suprapubic catheter, and successfully treated laparoscopically by an extraperitoneal approach. the patient was discharged after 10 days without any complications. the above method, in experienced hands, can be an effective primary treatment option for such rare but devastating complications. the case and management is unique as, to our knowledge, as no similar cases have been presented. key words: suprapubic cystostomy (spc); ultrasonography (usg); benign prostatic hyperplasia (bph). submitted 11 february 2013; accepted 30 april 2013 no conflict of interest declared summary different series (3, 4), the most commonly affected part is the small bowel and several cases have been reported (5, 6). in contrast, only a single case of rectal injury has been reported in international literature (7). it is of utmost importance to recognize a bowel injury immediately, since primary repair represents the best therapeutic option (8, 9). laproscopic radical prostatectomy is a well established operative therapy for localized prostate cancer in the era of minimally invasive surgery. rectal injuries during laparoscopic radical prostatectomy can be managed successfully intraoperatively without requiring any conversion to open surgery (10, 11). we present a case of rectal injury during spc insertion, as well as its subsequent management by laparoscopy using an extra peritoneal approach. its presentation and successful management is unique as, to our knowledge, as no similar cases have been presented. rajmohan_stesura seveso 24/06/13 11:09 pagina 101 archivio italiano di urologia e andrologia 2013; 85, 2 r. rajmohan, b. aguilar-davidov, t. tokas, j. rassweiler, a. serdar gözen 102 pyrexia during the first two days. the parenteral antibiotic combination was administered for 7 days and the total parenteral nutrition for 5 days. the drain and rectal tube was removed on 3rd and 5th. postoperative day respectively. the patient was discharged on the 10th day. discussion supra pubic cystostomy using a punch trocar, with localization of the bladder by palpation, is a well established interventional procedure for urinary drainage. the technique is usually safe when done in a well distended bladder. it is never a safe method to do, in a non distended bladder, or when bladder cannot be distended adequately, to a minimum of 300 ml of urine (12). it may not be feasible to fill the bladder adequately in some cases of neurogenic bladder due to low capcity or incontinence. there are safer techniques described for complicated cases, like using the lowsley retractor (13), seldinger technique with a peel away sheath introducer (14) or image guidance using usg (15) or fluroscopy (16). abdominal wall adhesions can be found in up to 59% of patients with previous midline laparotomy scars (17). in such cases with history of previous abdominal surgery open spc insertion is a safer option (1). usg guidance is advisable for safety, even in cases with adequate bladder distention, since there is always a risk of deep peritoneal fold or adhesions, as seen in patients with previous abdominal surgery. in one study by levrant et al., it was noted that when the distance between the upper border of the pubic symphysis and the umbilicus is less than 19 cm, there is a high risk for bowel inter positioning at spc trocar site due to deep peritoneal folding (18). the seldinger technique using a peel away trocar under local anesthesia is a safe method when a minimal bladder distention of 300 ml is achieved and none of the aforementioned risk factors are present (19). another key factor for a safe spc insertion is an adequate anesthesia, so that the patient should be comfortable and stable during the procedure. although different methods like general anesthesia and regional anesthesia have been used for spc insertion, the most preferred choice is local anesthesia. a sedo-analgesia, a technique combining adequate local anaesthesia with sedation, is recommended, especase report a 76 year old patient with bph and chronic urinary retention was under chronic indwelling urethral catheter, since he was unsuitable for definite operative treatment due to co-morbidities like senile dementia, diabetic neuropathy, coxarthrosis, osteoporosis and poor general heath. an insertion of a spc was decided due to recurrent urinary tract infections and urethral discomfort. an elective spc insertion, under local anesthesia, using a 12 f catheter through a punch trocar was performed in an outpatient basis. after filling the bladder with 300 cc saline, a 12 fr catheter was introduced under local anesthesia through a punch trocar. no ultrasound guidance was used. due to senile dementia the patient was uncooperative and moving during the procedure. the spc did not function satisfactorily after placement and a feculent catheter discharge was noted. the patient was admitted to our department immediately thereafter. cystography was done after reintroducing the urethral catheter, which showed an intact bladder outline with spc outside the bladder. when contrast was injected through the spc, it filled the rectal lumen without signs of extravasation (figure 1). we decided to perform a primary repair of the rectum using our described five port laparoscopic extraperitoneal approach as in our extraperitoneal laparoscopic radical prostatectomy technique under general anesthesia (14). a preoperative broad-spectrum intravenous antibiotic combination consisting of ceftriaxone and metronidazole was administered. a cautious dissection, initially around the spc and then downwards, following the catheter towards the rectum, was performed. the cystography findings were confirmed intraoperatively, with the bladder wall being almost intact and the spc placed directly into rectum (figure 2). two stay sutures were placed on the rectal wall, after an adequate dissection, and the catheter was removed. the rectum was then closed in 3 layers, with interrupted 3/0 vicryl sutures followed by a running 3/0 v-loc suture, and tested for the absence of leakage. finally, a drain was left in place and a rectal tube was placed. the patient was kept on intensive care unit for 2 days and the postoperative course was uneventful apart from mild figure 1. figure 2. rajmohan_stesura seveso 24/06/13 11:09 pagina 102 103archivio italiano di urologia e andrologia 2013; 85, 2 iatrogenic direct rectal injury: an unusual complication during suprapubic cystostomy (spc) insertion and its laparoscopic management catheterisation: clinical outcome and satisfaction survey. spinal cord. 1998; 36:171-176. 5. noller kl, pratt jh, symmonds r. bowel perforation with suprapubic cystostomy. report of two cases. obstet gynecol. 1976; 48:675-695. 6. cundiff g, bent ae. suprapubic catheterization complicated by bowel perforation. int urogynecol j pelvic floor dysfunct. 1995; 6:110-113. 7. ahmed sj, mehta a, rimington p. delayed bowel perforation following suprapubic catheter insertion. bmc urol. 2004; 4:16-18. 8. bostick pj, johnson da, heard jf, et al. management of extraperitoneal rectal injuries. j natl med assoc. 1993; 85:460-463. 9. gümüs m, böyük a, kapan m, et al. unusual extraperitoneal rectal injuries: a retrospective study. eur j trauma emerg surg. 2012; 38:295-299. 10. rassweiler j, schulze m, teber d, et al. laparoscopic radical prostatectomy with the heilbronn technique: oncological results in the first 500 patients. j urol. 2005; 173:761-764. 11. guillonneau b, gupta r, el fettouh h, et al. laparoscopic management of rectal injury during laparoscopic radical prostatectomy. j urol. 2003; 169:1694-1696. 12. k. albrecht, oelke m, schultheiss d, tröger hd. the relevance of urinary bladder filling in suprapubic bladder catheterization. urologe. 2004; 43:178-183. 13. zeidman ej, chiang h, alarcon a, raz s. suprapubic cystostomy using lowsley retractor. urology. 1998; 32:54-55. 14. o’brien wm. percutaneous placement of a suprapubic tube with peel away sheath introducer. j urol. 1991; 145:1015-1016. 15. røhl l, rasmussen os. ultrasound-guided percutaneous suprapubic cystostomy. eur j ultrasound. 1997; 6:57-61. 16. lee mj, papanicolaou n, nocks bn, et al. fluoroscopically guided percutaneous suprapubic cystotomy for long-term bladder drainage: an alternative to surgical cystotomy. radiology. 1993; 188:787-789. 17. levrant sg, bieber ej, barnes rb. anterior abdominal wall adhesions after laparotomy or laparoscopy. j am assoc gynecol laparosc. 1997; 4:353-356. 18. cho kh, doo sw, yang wj, et al. suprapubic cystostomy: risk analysis of possible bowel interposition through the percutaneous tract by computed tomography. korean j urol. 2010; 51:709-712. 19. morey af, iverson aj, swan a, et al. bladder rupture after blunt trauma: guidelines for diagnostic imaging. j trauma. 2001; 51:683-686. 20. khan a, abrams p. suprapubic catheter insertion is an outpatient procedure: cost savings resultant on closing an audit loop. bju int. 2008; 103:640-644. cially in case of uncooperative or agitated patients to ensure patient safety during the procedure (2). when the patient is restless during a punch trocar spc insertion without image guidance and adequate sedation, the procedure is always complicated. in this case the patient moved during the trocar insertion which, most probably, resulted in an accidental placement of the spc to the rectum. it may have been avoidable if he was adequately sedated and stabilized. murphy’s law “if anything can go wrong, it will”, explains that complications like these can occur even in ideal conditions. those who are doing these procedures should be vigilant and aware of these potential complications. if any misplacement or iatrogenic injury is suspected, imaging modalities like usg, cystogram, catheterogram, or flexible cystoscopy may be useful. in doubtful cases computer tomography or mri can be performed (19). we have performed usg, cystogram, catheterogram to localize the spc. in case of an iatrogenic rectal injury, a primary repair with or without diversion is the treatment of choice. in extraperitoneal injuries a diversion colostomy is not usually necessary. open surgery has been the treatment of choice in such cases, presenting good results (8, 9). laparoscopic repair has proven to be effective in intraoperative rectal injuries during laparoscopic radical prostatectomy (lrp) (10, 11). since our department is a high volume laparoscopic center, where the extraperitoneal approach for lrp is routinely performed, we could manage this case laparoscopically. the extraperitoneal approach allowed an adequate primary repair of the rectal injury without intraperitoneal contamination. previous papers present good results using a double-layered closure of the rectal wall. in this case we have performed a 3 layer closure reinforced by a 3rd layer with a v-loc barbed suture, which resulted in an uneventful recovery. conclusion image guidance; adequate anesthesia and stabilization of the patient are key factors for a safe spc placement in complicated cases. in case of an iatrogenic rectal injury, early recognition is of utmost importance and primary repair without diversion is the treatment of choice. laparoscopic extraperitoneal surgery, in experienced hands, is an effective minimal invasive treatment option. references 1. harrison scw, lawrence wt, morley r, et al. british association of urological surgeons’ suprapubic catheter practice guidelines. bju int. 2010; 107:77-85. 2. birch br, anson k, gelister j, et al. the role of midazolam and flumazenil in urology. acta anaesthesiol scand suppl. 1990; 92:25-32. 3. ahluwalia rs, johal n, kouriefs c, et al. the surgical risk of suprapubic catheter insertion and long-term sequelae. ann r coll surg engl. 2006; 88:210-213. 4. sheriff mk, foley s, mcfarlane j, et al. long-term suprapubic correspondence rakesh rajmohan, md, ms, mch bernardo aguilar-davidov, md theodoros tokas, md jens rassweiler, md ali serdar gözen, md, febu (corresponding author) asgozen@yahoo.com department of urology, slk-kliniken heilbronn am gesundbrunnen 20-26 d-74078 heilbronn, germany rajmohan_stesura seveso 24/06/13 11:09 pagina 103 stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 18 original paper 179.000 people annually (1). this phenomenon reflects the development of advanced diagnostic imaging, which determines a greater detection rate. in a retrospective study involving 3001 consecutively registered asymptomatic adults, a renal mass of at least 1 cm occurred in nearly 15% of examinations (2). currently, there is an increased number of diagnoses of small renal masses (srm), which consists of cystic or solid lesion measuring < 4 cm on cross-sectional imaging and with features suspicious of a ct1a rcc (3). nowadays, several therapeutic options may be offered, in particular nephron-sparing surgery (nss) is preferable to radical nephrectomy for tumors up to ct1b stage due to the preservation of renal function (4, 5). furthermore, partial nephrectomy is associated with a decrease in cardiovascular events and overall mortality (6). cryoablation is a valid option in patients with several comorbidities and low life expectancy, due to minimum effect on renal function and low post-procedure complication rate, despite the high treatment failure rates (7). alternatively, active surveillance has demonstrated cancer-specific survival similar to primary intervention for patients with srm (8). the most appropriate treatment decision for the patient is based first on the patient's general condition (including comorbidities, renal function, and life expectancy) and the nature of the renal tumor. however, traditional diagnostic imaging provides data on mass characteristics, but it cannot determine whether the lesion is benign or malignant yet. there is evidence that dynamic magnetic resonance imaging may differentiate tumor subtypes (9), but tumor aggressiveness cannot be defined. for the latter, the details from ultrasound-guided renal mass biopsy (rmb) are crucial. this procedure plays a key role in approximately 60% of patients (10), guiding them toward the most appropriate therapy, whether medical or surgical. this study aimed to describe our experience with rmb, evaluating its safety and feasibility. materials and methods an institutional retrospective review was conducted with data analysis of 80 patients with suspected primary or secondary kidney tumors who underwent rmb between january 2012 and december 2020. twelve cases were introduction: ultrasound-guided renal masses biopsy (rmb) is a useful and underestimated tool to evaluate suspected renal tumors. this study aimed to assess the safety and feasibility of this technique. materials and methods: data of 80 patients with suspected primary or secondary kidney tumors who underwent rmb between january 2012 and december 2020 were included in this retrospective study. twelve patients were excluded due to incomplete data. biopsy outcomes were collected through our electronic medical records system and then compared with definitive pathology. results: rmb was performed in 68 cases. pathological examination reported 43 (63%) malignant cases, while rmb was negative in 15 (22%) samples. on the other hand, a benign lesion was present in 8 (12%) cases, and 2 (3%) biopsies were non diagnostic. one major and one minor post-procedure complication were reported among the patients. a total of 31 patients underwent renal surgery including 19 partial and 12 radical nephrectomies. out of them, 4 patients had a negative biopsy, but radiological imaging strongly suggested malignancy. the concordance between biopsy and definitive pathology occurred in 22 out of 31 (71%) cases, with a higher rate among the masses greater than 4 cm, 9/11 (82%) compared to smaller ones 13/20 (65%). pathologic examination of the 4 cases with negative biopsy showed 3 renal cell and a translocation renal cell carcinoma. conclusions: ultrasound-guided biopsy for renal masses is a safe and effective procedure. its ability to identify malignancy is evident, especially for primary renal tumors. however, low concordance between biopsy and definitive pathology in cases with negative biopsies, especially for tumors < 4 cm, does not reliably guarantee the absence of tumor and, therefore, strict follow-up or repeat biopsy may be indicated. key words: kidney tumors; renal masses biopsy; ultrasound; small renal mass; nephron-sparing surgery; active surveillance. submitted 26 december 2022; accepted 20 march 2023 introduction since the past few decades, the incidence of clear cell renal cell carcinoma has dramatically increased, and currently counts approximately 431.000 new cases per year worldwide (1). furthermore, it is the cause of death of over the use of renal biopsy in the kidney tumor management: a retrospective analysis of consecutive cases in a referral center andrea benedetto galosi 1, marco macchini 2, roberto candelari 2, virgilio de stefano 1, silvia stramucci 1, vanessa cammarata 1, omar al ayoubi 1, andrea cicconofri 1, carlo giulioni 1 1 department of urology, polytechnic university of marche, azienda ospedaliera universitaria della marche, ancona, italy; 2 interventional radiology, department of radiology, azienda ospedaliera universitaria della marche, ancona, italy. doi: 10.4081/aiua.2023.11115 summary archivio italiano di urologia e andrologia 2023; 95, 2 a.b. galosi, m. macchini, r. candelari, et al. 19 excluded due to the lack of complete data in the database. all patients had previously performed a contrastenhanced computed tomography (ct) scan of the abdomen, which allowed for tumor characteristics evaluation (figure 1a). renal biopsy was indicated in the following cases: patients with various comorbidities in whom surgery is planned, patients with imaging findings suggestive of unresectable renal cancer, suspected metastasis in the kidney, and indeterminate cystic renal mass. two experienced radiologists performed all the rmb guided by ultrasound machine logiq s8 xdclear (ge healthcare®, chalfont st giles, uk) after the analysis of contrast-enhanced ct imaging. specimens were obtained through an automated biopsy gun with an 18-gauge needle (figure 1b). one to four cores were collected per biopsy, giving an average of two. patients’ characteristics, including age, gender, body mass index (bmi), skin-to tumor distance and thickness of subcutaneous fat, were calculated through the radiology. moreover, several radiological tumor characteristics were evaluated, such as size, location, endophyticity, cortical location and cystic component. all data regarding post-procedure complications following primary intervention were reported and ranked according to clavien-dindo (cd) classification (11) as collected through our electronic medical records system. qualitative variables were described using absolute frequencies and percentages. quantitative variables were described using the median and interquartile ranges. ibm spss (v26) was used as statistical software. results the median age of the patients was 71 years (36-85), and the median bmi was 27.5, as shown in table 1. median core needle samples per biopsy were 2. tumor characteristics were reported in table 2. forty-four cases had an srm (< 4 cm), and 24 had masses ≥ 4 cm. rmb in our series was performed in 68 cases. the histological outcomes of all the biopsies are listed in table 3. the biopsy outcome was malignancy in 43 (63%) cases, and the renal cell carcinoma (rcc) was the most frequent tumor; 15 biopsies were negative, a benign lesion was present in 8 (12%) cases, and 2 (3%) biopsies were non diagnostic. two patients experienced complications after the biopsy procedure: 1 case of a subcapsular renal haematoma that table 1. patients and samples characteristics. no. (%) median (range) age, years 71 (36-85) gender male 49 (72%) female 19 (28%) patient bmi 27.5 (18.6-44.2) < 30 46 (68%) ≥ 30 22 (32%) core needle samples, n 2 (1-4) skin-to-tumor distance, cm 5.8 (15-120) < 7 cm 43 (63%) ≥ 7 cm 25 (37%) thickness of subcutaneous fat, cm 1.9 (2 -54) < 3 cm 50 (74%) ≥ 3 cm 18 (26%) figure 1. (a) an axial ct image of a left superior mesopolar renal mass. (b) an ultrasound image of the renal mass biopsy with the needle guide. table 2. tumor characteristics. no. (%) side left 25 (37) right 43 (63) tumor size < 4 cm 44 (65) ≥ 4 cm 24 (35) mass location mesorenal 22 (32) upper pole 26 (38) lower pole 18 (27) renal pedicle 2 (3) cortical location anterior cortex 18 (27) posterior cortex 32 (47) neither 18 (27) endophytic vs. exophytic completely endophytic 10 (15) < 50% exophytic 29 (43) ≥ 50% exophytic 29 (43) cystic vs. solid cystic component ≥ 50% 5 (7) cystic component < 50% 10 (15) no cystic component 53 (78) archivio italiano di urologia e andrologia 2023; 95, 2 20 safety and feasibility of us guided renal mass biopsy not required treatment (cd 1), and 1 case of renal bleeding, who required super-selective embolization (cd 3), occurred. table 4 reported the treatment offered to the patients. chemoor immunotherapy was proposed to the seven patients with locally advanced disease or primary tumor in another location. active surveillance was offered to the 8 cases of oncocytoma, while 3 cases of watchful waiting occurred. as shown in table 5, the overall concordance between rmb and definitive pathology was 22/31, with a higher rate for masses greater than 4 cm. ultrasound-guided biopsy demonstrated its reliability in diagnosing rcc, both for small and large masses. tumor subtype was confirmed by definitive pathology in 82% of cases (22/27). however, in two cases of unspecified carcinoma, after excision, one had a histological outcome of skeletal muscle metastases and the other urothelial cell carcinoma. four patients with negative biopsies underwent surgery because of highly suspicious lesions for tumor on radiological imaging. biopsies reported only necrosis in two of them and solid component of a cystic lesion in the other two. the final diagnosis was rcc in three patients and translocation renal cell carcinoma in one. in summary, the overall sensibility was 71%, with a higher value for masses greater than 4 cm than the smaller ones (82% vs 65%, respectively). furthermore, the positive predictive value was 96%. discussion according to eau guidelines, surgery is the first-line choice therapy for patients with a localized renal mass, preferring, whenever feasible, the nss to radical nephrectomy (12). nowadays, there is a trend toward a conservative approach for renal surgery also for increasingly challenging cases. in a multicenter study involving 410 patients with high complexity masses, partial nephrectomy showed satisfactory long-term oncological and functional outcomes despite an acceptable rate of perioperative complications (13, 14). however, 20-50% of the definitive pathologies of this surgery find benign tumors, which might be managed by active surveillance (15). on the other hand, a multidisciplinary strategy is necessary for metastatic diseases or locally advanced renal cancer, which provides a palliative cytoreductive nephrectomy and systemic treatments (12). moreover, micrornas were proposed as a non-invasive biomarker for various roles in rcc management, although no definitive conclusions emerged from the literature (16). therefore, a histological diagnosis is essential to guide the best therapeutic management. although ultrasound-guided biopsy may have other hints, as in glomerulonephritis, its more frequent use is in the field of oncology. rmb indication occurs in several cases, such as the diagnosis of tumor metastasis, unresectable renal cancer, indeterminate cystic or multiple renal mass, and in patients not fit for surgery (17). the biopsy was proposed for srm, although an inverse relationship was reported between tumor size and its risk of malignancy (18). ultrasound-guided biopsy showed good accuracy in defining the nature of the renal tumor. in our series, a concordance of tumor malignancy between biopsy and definitive pathology always table 4. therapeutic management. no. (%) < 4 cm ≥ 4 cm nephron sparing surgery (nss) rcc 9 (13) 8 1 others 10 (15) 7 3 radical nephrectomy rcc 8 (12) 2 6 others 4 (6) 3 1 active surveillance rcc 1 (1) 1 0 oncocytoma 8 (12) 6 2 others 2 (3) 2 0 oncologic treatment (chemo or immunoterapy) rcc 2 (3) 0 2 others 5 (7) 2 3 watchful waiting rcc 1 (1) 0 1 others 2 (3) 1 1 patients lost during follow-up 16 (24) 12 4 rcc 2 (3) 1 1 others 14 (21) 11 3 rcc: renal cell carcinoma. table 5. concordance between biopsy and definitive pathology. concordance with concordance with concordance with definitive pathology definitive pathology definitive pathology in all masses in masses < 4 cm in masses ≥ 4 cm overall, n (%) 22/31 (71) 13/20 (65) 9/11 (82) rcc, n (%) 22/23 (96) 13/14 (93) 9/9 (100) unspecified carcinoma, n (%) 0/3 (0) 0/2 (0) 0/1 (0) others, n (%) 0/1 (0) 0/1 (0) 0/0 (0) negative, n (%) 0/4 (0) 0/3 (0) 0/1 (0) rcc: renal cell carcinoma. table 3. histological outcomes of diagnostic biopsies. histological subtype at rmb no. (%) clear cell rcc 21 (29) papillary rcc 9 (13) oncocytoma 8 (12) unspecified carcinoma 3 (4) oncocytic rcc 2 (3) lymphoma 3 (4) urothelial carcinoma 1 (1) skeletal muscle cancer (metastasis) 1 (1) collecting (bellini) duct carcinoma 1 (1) translocation renal cell carcinoma 1 (1) lung cancer (metastasis) 1 (1) non diagnostic 2 (3) negative 15 (22) rmb: renal mass biopsy; rcc: renal cell carcinoma. archivio italiano di urologia e andrologia 2023; 95, 2 a.b. galosi, m. macchini, r. candelari, et al. 21 occurred. moreover, the concordance of rcc between rmb and definitive pathology was 96%. in a large metaanalysis involving 5228 patients, its sensitivity and specificity were 99.1% and 99.7%, respectively (19). furthermore, the authors showed a concordance rate between tumor histotype on biopsy and surgical specimen of 90.3%, while concordance rates of tumor grade ranged from 43% to 93%. the last data raises several doubts about biopsies, especially for smr. similarly, pierorazio et al. reported high percentages in terms of sensitivity and specificity, while the negative predictive value was 68.5% and non-diagnostic rates ranged from 0% to 22.6% for masses less than 4 cm (20). in the same way, in the present study, the concordance rate between biopsy and definitive pathology of all srm dropped up to 65%. the most critical aspect that emerged from our analysis is the specificity of rmb. indeed, there was low concordance between biopsy and definitive pathology for negative or unspecified carcinoma diagnoses in our results. abel et al. reported that when carrying out a biopsy of a metastatic lesion or primary tumor, as opposed to nephrectomy specimen examination, it is likely that only one subpopulation of cells is sampled, and prognostic information is based on only one subpopulation of cells (21). therefore, high false-negative rates raise concerns about the reliability of the procedure. however, rmb may be repeated on all patients with unspecified masses or non-diagnostic cases to increase the diagnostic rate (22). furthermore, renal biopsy is not without complications, due to the procedure invasiveness, especially bleeding, although they are considered rare events. according to lane et al., minor and major complications after rmb are, respectively, less than 5% and 1% (23). of these, the most common is undoubtedly bleeding, which often tends to present subclinically and requires transfusion in about 1.5% of cases (24). indeed, both post-procedure complications were related to haemorrhage in the present study. another frequent complication is the intrarenal arteriovenous fistulae occurred. according to rollino et al., the development of this clinical condition has an incidence of up to 5% when colour-coded doppler sonography is used (25). however, no case was reported in our analysis. the limitations of the present study are evident. first, it is a retrospective study and biases linked to its nature are predictable. second, the pathological specimens were not reviewed independently for the current study. moreover, a considerable number of subjects dropped out from our analysis: in fact our radiology department also accepts patients referred from other hospitals and, therefore, a loss of some of them in the follow-up is inevitable. at last, a relatively small sample size is involved in this analysis, not allowing to obtain definitive data. conclusions ultrasound-guided biopsy for renal masses demonstrated satisfactory ability to distinguish benign and malignant tumors. concordance between biopsy and definitive pathology was high for rcc, particularly for masses greater than 4 cm. however, the low concordance in the negative biopsies, especially for tumors < 4 cm, may require a second biopsy. in any case, the procedure proved to be safe and effective in referring patients to the most appropriate therapeutic management. considering the low prevalence of this procedure in routine clinical practice, its use is recommended whenever an indication occurs. references 1. global cancer observatory. international agency for research on cancer. world health organization. 2. o'connor sd, pickhardt pj, kim dh, et al. incidental finding of renal masses at unenhanced ct: prevalence and analysis of features for guiding management. ajr am j roentgenol. 2011; 197:139-45. 3. finelli a, ismaila n, bro b, et al. management of small renal masses: american society of clinical oncology clinical practice guideline. j clin oncol. 2017; 35:668-680. 4. dell'atti l, scarcella s, manno s, et al. approach for renal tumors with low nephrometry score through unclamped sutureless laparoscopic enucleation technique: functional and oncologic outcomes. clin genitourin cancer. 2018; 16:e1251-e1256. 5. giulioni c, di biase m, marconi a, et al. clampless laparoscopic tumor enucleation for exophytic masses greater than 4 cm: is renorrhaphy necessary? j laparoendosc adv surg tech a. 2022; 32:931-937. 6. huang wc, elkin eb, levey as, et al. partial nephrectomy versus radical nephrectomy in patients with small renal tumors--is there a difference in mortality and cardiovascular outcomes? j urol. 2009; 181:55-61. 7. zargar h, atwell td, cadeddu ja, et al. cryoablation for small renal masses: selection criteria, complications, and functional and oncologic results. eur urol. 2016; 69:116-28. 8. pierorazio pm, johnson mh, ball mw, et al. five-year analysis of a multi-institutional prospective clinical trial of delayed intervention and surveillance for small renal masses: the dissrm registry. eur urol. 2015; 68:408-15. 9. sun mr, ngo l, genega em, et al. renal cell carcinoma: dynamic contrast-enhanced mr imaging for differentiation of tumor subtypes--correlation with pathologic findings. radiology. 2009; 250:793-802. 10. maturen ke, nghiem hv, caoili em, et al. renal mass core biopsy: accuracy and impact on clinical management. ajr am j roentgenol. 2007; 188:563-70. 11. clavien pa, barkun j, de oliveira ml, et al. the clavien-dindo classification of surgical complications: five-year experience. ann surg. 2009; 250:187-196. 12. b. ljungberg (chair), l. albiges, j. bedke, et al. volpe guidelines on prostate cancer. edn. presented at the eau annual congress milan 2021. 978-94-92671-13-4. eau guidelines office, arnhem, netherlands. 13. sciorio c, prontera pp, scuzzarella s, et al. predictors of surgical outcomes of retroperitoneal laparoscopic partial nephrectomy. arch ital urol androl. 2020; 92:165. 14. mari a, tellini r, porpiglia f, et al. perioperative and mid-term oncological and functional outcomes after partial nephrectomy for complex (padua score ≥10) renal tumors: a prospective multicenter observational study (the record2 project). eur urol focus. 2021; 7:1371-1379. 15. russo p, uzzo rg, lowrance wt, et al. incidence of benign versus malignant renal tumors in selected studies. j. clin. oncol. 2012; 30, 92. archivio italiano di urologia e andrologia 2023; 95, 2 22 safety and feasibility of us guided renal mass biopsy 16. napolitano l, orecchia l, giulioni c, et al. the role of mirna in the management of localized and advanced renal masses, a narrative review of the literature. applied sciences. 2023; 13:275. 17. sahni va, silverman sg. biopsy of renal masses: when and why. cancer imaging. 2009; 6; 9:44-55. 18. frank i, blute ml, cheville jc, et al. solid renal tumors: an analysis of pathological features related to tumor size. j urol. 2003; 170:2217-20. 19. marconi l, dabestani s, lam tb, et al. systematic review and meta-analysis of diagnostic accuracy of percutaneous renal tumour biopsy. eur urol. 2016; 69:660-673. 20. pierorazio pm, johnson mh, patel hd, et al. management of renal masses and localized renal cancer: systematic review and meta-analysis. j urol. 2016; 196:989-99. 21. abel ej, carrasco a, culp sh, et al. limitations of preoperative biopsy in patients with metastatic renal cell carcinoma: comparison to surgical pathology in 405 cases. bju int. 2012; 110:1742-6. 22. lim a, o'neil b, heilbrun me, et al. the contemporary role of renal mass biopsy in the management of small renal tumors. front oncol. 2012; 2:106. 23. lane br, samplaski mk, herts br, et al. renal mass biopsy--a renaissance? j urol. 2008; 179:20-7. 24. tang s, li jh, lui sl, et al. free-hand, ultrasound-guided percutaneous renal biopsy: experience from a single operator. eur j radiol. 2002; 41:65-9. 25. rollino c, garofalo g, roccatello d, et al. colour-coded doppler sonography in monitoring native kidney biopsies. nephrol dial transplant 1994; 9:1260-3. correspondence andrea bendetto galosi, md andreabenedettogalosi@ospedaliriuniti.marche.it virgilio de stefano, md virgilio.destefano@gmail.com silvia stramucci, md silvia.stramucci@gmail.com vanessa cammarata vanessa.cammarata@gmail.com omar al ayoubi, md omar.alayoubi@gmail.com andrea cicconofri, md andrea.cicconofri@gmail.com carlo giulioni, md (corresponding author) carlo.giulioni9@gmail.com department of urology, polytechnic university of marche azienda ospedaliero universitaria delle marche 71 conca street, 60126 ancona (italy) marco macchini, md marco.macchini@ospedaliriuniti.marche.it roberto candelari, md roberto.candelari@ospedaliriuniti.marche.it interventional radiology, department of radiology, azienda ospedaliera universitaria della marche, ancona (italy) conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 108 original paper muscle training is the most recommended treatment method, especially for stage 1 stress urinary incontinence (4). thus, pelvic floor muscle training (pfmt) has been recognized as the first-line therapy for urinary incontinence (5). women with the symptom of stress and mixed urinary incontinence who had the treatment of pfmt showed improvement in their symptoms of ui (4). the rationale for doing pfmt is to maximize the urethral pressure and improve the voluntary contraction of the muscle by improving pelvic floor muscle strength (6). in malaysia, the prevalence of ui among women was 17.3% while for antenatal cases it was 34.3% during their third trimester (3). however, compared with turkey, the prevalence of ui among pregnant women was high, with almost 80% with stress urinary incontinence (7). a study among antenatal women in kelantan showed women had a low level of knowledge regarding pfmt with only 5.8% doing pfmt (8). the result showed that the women knew the information regarding pfmt (9). whereas another finding in selangor stated that 46.6% of pregnant women had a good attitude towards pfmt (10). there is no standardized measurement tool that can be used to discern the type, severity, or bother attributed to ui at one time. in government hospitals and clinics throughout malaysia, a variety of forms of ui screening were identified. presently, to identify all the symptoms, women had to complete multiple questionnaires in one setting, and the healthcare professionals then had to determine how to interpret and assimilate the results of these different measures. one of the instruments with high accuracy levels to discern the types of urinary incontinence is michigan incontinence symptom index (m-isi) (11). unlike other ui questionnaires, the m-isi covers different aspects of ui that were essential for women's care and research. it also has been proved that the threshold scores for the m-isi could be used to screen for clinically relevant urinary incontinence (11). this study provided a simple and comprehensive instrument to measure types, severity, and bother related to ui among childbearing women. the aims were to identify the knowledge, attitude, and practice towards pelvic floor muscle training, to measure the ui using a validated misi questionnaire, and to identify the association between the ui and pfmt among childbearing women. objectives: this study aims to identify knowledge, attitude, and practice of pelvic floor muscle training (pfmt) and to identify the prevalence of urinary incontinence. materials and methods: the method used was a cross-sectional study. self-administered knowledge, attitude, and practice questionnaires were distributed among childbearing women attending maternal & child health clinics in the east coast region of malaysia. results: the findings revealed that most respondents (n = 896) had good or moderate knowledge (80.1%) and attitudes (77.3%) regarding pfmt but most of them (87.2%) still lacked practice. however, there was no association between urinary incontinence and pfmt practice. on the contrary, married women showed a higher risk of urinary incontinence. conclusions: the practice of pelvic floor muscle training should be recommended and emphasized to childbearing women by healthcare professionals. key words: attitude; knowledge; pelvic floor muscle training; practice; urinary incontinence; m-isi. submitted 10 march 2023; accepted 18 march 2023 introduction urinary incontinence (ui) is one of the worldwide health problems but is not considered life-threatening (1). most of the victims did not share their problems and kept silent until they were interviewed by healthcare professionals. a study identified factors that affect help-seeking behavior: not accepting incontinence as a disease, shame, non-optimal health care system, negative support of essential others and reduced quality of life (2). the risk factors for ui include menopause, increased body mass index, straining hard during defecation, coffee consumption and depression (3). the management of ui was divided into two, which are conservative and non-conservative treatment. the nonconservative treatment is the medical or surgical treatment, whereas the conservative treatment is non-costly. one of the conservative treatments is, pelvic floor muscle training, or known as kegel’s exercise. in 1948, dr. kegel, who invented the kegel exercise, stated that the cure rate after training pelvic floor muscles for women with different types of incontinence was 84%. besides, pelvic floor knowledge, attitude and practice towards pelvic floor muscle training among childbearing women nur fairuz mohd fauzey 1, siti mariam muda 2, haliza hasan 2, zalina nusee 3, muzaitul akma mustapa kamal basha 2 1 kulliyyah of nursing, international islamic university malaysia, kuantan, malaysia; 2 department of special care nursing, kulliyyah of nursing, international islamic university malaysia, kuantan, malaysia; 3 department of obstetrics & gynecology, kulliyah of medicine, international islamic university malaysia, kuantan, malaysia. presented as conference papers at the 8th v-binc at fon universitas indonesia. doi: 10.4081/aiua.2023.11298 summary archivio italiano di urologia e andrologia 2023; 95, 2 nur fairuz mohd fauzey, siti mariam muda, haliza hasan, zalina nusee, muzaitul akma mustapa kamal basha 109 materials and methods the study used a quantitative research method with crosssectional design. it was conducted at five government maternal & child health clinics in the east coast region in malaysia (kelantan, terengganu, pahang). the populations were childbearing women who attended the maternal and child health clinic. the inclusion criteria were malaysian women, aged 18 to 45 years old, and able to read in malay. the exclusion criteria included menopausal women, a history of mental health problems, and diagnosed chronic illness. the study included 2 parts: the first part was the recruitment process, and the second was the administration of two sets of questionnaires, m-isi screening test and a survey on knowledge, attitude, and practice of pelvic floor muscle training. figure 1 shows the process of recruitment of participants in this study. the sample size was calculated using the open-source calculation openepi version 3 using the odds ratio (or) from a previous study (10). using a 20% non-response factor, it was decided to have a total of 1219 childbearing women involved in the study. all the data obtained from the study were recorded and statistically analysed using statistical package for social science software, version 26.0. basic details of the participants and urinary incontinence were analysed using descriptive statistics, including mean and standard deviation or median with interquartile range for non-normally distributed data. a chi-square test was used to identify the association between urinary incontinence and pelvic floor muscle training and logistic regression was done to identify the predictors of urinary incontinence among childbearing women. this study obtained approval from the research committee at international islamic university malaysia (iium) (irec 2021-008) and national medical research register (nmrr) (nmrr-19-4172-51098). all participants consented and were involved in this study on a voluntary basis. results a total of 896 participants answered all questions yielding a 74% completion rate, with the power of the study being 100%. age distribution is shown in table 1. there were 506 participants (58.0%) who were multigravida (usually 3-5 pregnancies), while 30% were primigravida who had first-time experience in pregnancy. the majority of the participant were malay (99.5%), and the highest educational level was diploma/degree holder (48.8%). more than half of the participants (52.6%) were housewives, and in terms of monthly income, the majority of the participants (78.2%) were categorized in the lower household income group (b40), earning less than rm4,850 per month. the number of women with ui using the m-isi questionnaire was 173, with an estimated prevalence of 19.3% (table 2). as reported in table 3, 43.0% of the respondents had good knowledge of pfmt. most of the childbearing women had a moderate attitude toward pfmt (55.9%) and poor practice toward pfmt (87.2%). as reported in table 3, 43.0% of the respondents had good knowledge of pfmt. most of the childbearing women had table 1. socio-demographic characteristics. characteristics frequency percentage (%) age (years) (n = 887) < 20 28 3.2 21-30 432 48.7* 31-40 361 40.7 > 41 66 7.4 marital status (n=883) single 23 2.6 married 850 96.3* widow 10 1.1 gravida (n = 873) nulligravida 14 1.6 primigravida 262 30.0 multigravida 506 58.0* grand multigravida 91 10.4 ethnicity (n = 885) malay 881 99.5* chinese 2 0.2 india 2 0.2 educational level (n = 864) primary school 17 2.0 secondary school 401 46.4 diploma/degree 422 48.8* master/phd 24 2.8 occupation (n = 854) housewife 449 52.6* self-employed 92 10.8 government sector 175 20.5 private sector 135 15.8 student 3 0.4 monthly income** (n = 832) b40 (bottom 40%) 651 78.2* m40 (middle 40%) 168 20.2 t20 (top 20%) 13 1.6 *the highest score in each item; **malaysian household income classification. table 2. the prevalence of urinary incontinence. urinary incontinence frequency percentage (%) yes 173 19.3 no 723 80.7 figure 1. the process of recruitment of participants. archivio italiano di urologia e andrologia 2023; 95, 2 110 pelvic floor muscle training among childbearing women a moderate attitude toward pfmt (55.9%) and the majority reported a poor practice of pfmt (87.2%). table 4 depicted that there was a significant association between the level of knowledge of pfmt and ui (p = 0.001); it also showed a significant association between the level of attitude toward pfmt and ui (p = 0.009) but no significant association between level of practice of pfmt and ui (p > 0.05). good knowledge of pfmt (adjusted or = 0.69; 95% ci 0.41-1.19) and moderate knowledge of pfmt (adjusted or = 0.70, 95% ci 0.43-1.14) were negative predictors of ui, meaning that women with good/moderate knowledge are less likely prone to ui compared to those with poor knowledge. however, other socio-demographic factors, such as being married women, showed to be statistically significant towards the risk to be ui (p = 0.040). discussion the prevalence of ui among childbearing women in this study, which included the east coast region of malaysia, was lower than the one reported in a previous study, which evaluated the rate of ui among women aged > 18 years (12). however, the prevalence may vary with the place, population, and questionnaire that have been used. the various definitions of incontinence, the use of different questionnaires, settings, procedures, and the validity of self-report data all contributed to the variation in epidemiological data about the prevalence rate of ui (5). this study found that most of the childbearing women had a good knowledge of pfmt, similar to the previous study conducted at one of the teaching hospitals in malaysia (13). however, the respondents demonstrated a moderate attitude towards pfmt, contrary to the findings previously observed among antenatal women in kelantan (14). the pregnant women felt that pfmt had positive effects on their health, such as improved incontinence, pelvic organ prolapse, quality of life and increased sexual satisfaction (15). there was a positive change in attitude score after attending antenatal class (16), and as a result, education was a critical factor in improving women’s attitudes and motivation towards pfmt. the finding from this study showed that married women had a significant association with ui. married women were more likely to have ui than single women because they tend to have an older age, which becomes a risk factor for ui (17). being married women, earlier age at marriage, high parity, and old age were associated with the increase in ui among women in lahore (18). women do not practice pfmt, possibly due to a lack of information or awareness about doing this exercise during antenatal or postnatal periods. this can be seen in another study in which 44% of them reported lack of knowledge about the exercise and 96% stated that there was no guidance from healthcare professionals during the postpartum period in promoting pfmt (19). conclusions this study revealed that, although overall knowledge and attitude towards pfmt were good, women did not practice the exercise regularly. thus, it is recommended to healthcare professionals to play an essential role by providing more information as well as raising awareness about pfmt. the best method to give the information effectively is during consultation sessions and the antenatal class. acknowledgments: we would like to thank all participants involved in this study for their help and support. funding: this study was supported by the fundamental research grant scheme for research acculturation of early career researchers (racer) under ministry of higher education malaysia. acknowledgement of financial support: this work was supported by fundamental research grant scheme for research acculturation of early career researchers (racer) under ministry of higher education malaysia. references 1. mohd yusoff d, awang s, kueh yc. urinary incontinence among pregnant women attending an antenatal clinic at a tertiary teaching hospital in north-east malaysia. j taibah univ med sci. 2019; 14:39. table 3. the level of knowledge, attitude and practice towards pelvic floor muscle training. level frequency percentage (%) knowledge towards pelvic floor muscle training good 385 43.0 moderate 332 37.1 poor 179 20.0 attitude towards pelvic floor muscle training good 192 21.4 moderate 501 55.9 poor 203 22.7 practice towards pelvic floor muscle training good 32 3.6 moderate 81 9.2 poor 772 87.2 table 4. association between level of knowledge, attitude, and practice towards pelvic floor muscle training with urinary incontinence. variable urinary incontinence χ2 p-value yes (n = 173) n (%) no (n = 723) n (%) knowledge good 61 (35.3) 324 (44.8) 14.195 0.001 moderate 60 (34.7) 272 (37.6) poor 52 (30.1) 127 (17.6) attitude good 30 (17.3) 162 (22.4) 9.368 0.009 moderate 89 (51.4) 412 (57.0) poor 54 (31.2) 149 (20.6) yes (n = 169) n (%) no (n = 716) n (%) practice good 1 (0.6) 31 (4.3) 5.851 0.054 moderate 18 (10.7) 63 (8.8) poor 150 (88.8) 622 (86.9) significant value, p-value < 0.05. archivio italiano di urologia e andrologia 2023; 95, 2 nur fairuz mohd fauzey, siti mariam muda, haliza hasan, zalina nusee, muzaitul akma mustapa kamal basha 111 2. fakari fr, hajian s, darvish s, alavi majd h. explaining factors affecting help-seeking behaviors in women with urinary incontinence: a qualitative study. bmc health serv res. 2021; 21:1-10. 3. kaur dhillon h. urinary incontinence amongst malaysian women in selangor: prevalence, types and risk factors. world j public health. 2019; 4:10. 4. ptak m, ciećwiez s, brodowska a, et al. the effect of pelvic floor muscles exercise on quality of life in women with stress urinary incontinence and its relationship with vaginal deliveries: a randomized trial. biomed res int. 2019; 2019:5321864. 5. abrams p, smith ap, cotterill n. the impact of urinary incontinence on health-related quality of life (hrqol) in a real-world population of women aged 45-60 years: results from a survey in france, germany, the uk and the usa. bju int. 2015; 115:143. 6. malhotra n, chahal a. the effectiveness of pelvic floor exercises on symptoms in females with stress urinary incontinence. biosci biotechnol res commun. 2018; 11:681. 7. özdemir k, şahin s, özerdoğan n, ünsal a. evaluation of urinary incontinence and quality of life in married women aged between 20 and 49 years (sakarya, turkey). turk j med sci. 2018; 48:100-9. 8. ahmed ibrahim w. assess levels of knowledge, attitude and practice of the married women about pelvic floor muscles exercise. int j sci res. 2015; 6:2319. 9. rosediani m, nik rosmawati nh, juliawati m, norwati d. knowledge, attitude and parctice towards pelvic floor muscle exercise among pregnant women attending antenatal clinic in universiti sains malaysia hospital, malaysia. int med j. 2012; 19:37. 10. jaffar a, mohd-sidik s, nien fc, et al. urinary incontinence and its association with pelvic floor muscle exercise among pregnant women attending a primary care clinic in selangor, malaysia. plos one. 2020; 15:e0236140. 11. suskind am, dunn rl, morgan dm, et al. a screening tool for clinically relevant urinary incontinence. neurourol urodyn. 2015; 34:332-5. 12. baykuş n, yenal k. prevalence of urinary incontinence in women aged 18 and over and affecting factors. j women aging. 2020; 32:578-90. 13. jarni mf, mohamad my, kamarudzaman n. knowledge, attitude, and practice (kap) towards pelvic floor muscle exercise among the female population attending the obstetrics and gynaecology clinic at sultan ahmad shah medical centre (sasmec@iium). international journal of allied health sciences. 2021; 5:2521-2529. 14. muhammad j, muhamad r, husain nrn, daud n. pelvic floor muscle exercise education and factors associated with implementation among antenatal women in hospital universiti sains malaysia. korean j fam med. 2019; 40:45. 15. temtanakitpaisan t, bunyavejchevin s, buppasiri p, chongsomchai c. knowledge, attitude, and practices (kap) survey towards pelvic floor muscle training (pfmt) among pregnant women. int j womens health. 2020; 12:295-9. 16. habib m, sohail i, nasir m, nasir f. awareness, knowledge and practices of pakistani women towards pelvic floor muscle exercises (pfmes) during pregnancy. j soc obstet gynaecol pak. 2020; 10:121. 17. al kiyumi mh, al belushi zi, jaju s, al mahrezi am. urinary incontinence among omani women prevalence, risk factors and impact on quality of life. sultan qaboos univ med j. 2020; 20:45. 18. jawad z, malik a, khan s. prevalence of urinary incontinence in women in lahore: severity, associated factors and impact on daily life. age. 2021; 15:5. 19. alharqi hm, albattawi ja. assessment of knowledge and attitude of women towards postpartum exercise. j nurs health sci. 2018; 7:16. correspondence nur fairuz mohd fauzey kulliyyah of nursing, international islamic university malaysia, kuantan, malaysia siti mariam muda (corresponding author) sitimariam@iium.edu.my haliza hasan muzaitul akma mustapa kamal basha department of special care nursing, kulliyyah of nursing, international islamic university malaysia, kuantan, 25200, malaysia zalina nusee department of obstetrics & gynecology, kulliyah of medicine, international islamic university malaysia, kuantan, malaysia conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper tectomy have long been considered the historical gold standard for bpo with prostate volume less and over 80 ml, respectively. despite the excellent long-term functional results of these procedures, new technologies are being developed to reduce the hospital stay, the catheterization time, the haemorrhagic risk and the complication rate. at present, 3 types of laser technologies [holmium, 180w lbo crystal green light xcelerated performance system (xps), thulium] are considered by treatment guidelines for medically-refractory luts at the same level as turp with comparable shortand mid-term results, but with less morbidity and invasiveness (1). nowadays data about long term results are emerging (2-4). at present, the focus about the different laser technologies is not on functional results. the real questions are about which laser has the best safety profile and which laser for which patients should be used. one of the arguments against the widespread use of the holmium laser in bpo treatment is due to the fact that only enucleation procedures can be performed, which are characterized by a long learning curve (5). differently, greenlight and thulium laser are more versatile allowing a change in surgical technique (pure enucleation versus standard or anatomical vaporization) during the same procedure without modifying the functional outcomes and the complication rates (6, 7). in this study, we analysed the different intra and perioperative events between patients undergoing thulium vs. greenlight procedure for benign prostatic obstruction in two centers. materials and methods in this study, we retrospectively reviewed 100 consecutive cases undergoing greenlight standard photoselective vaporization of the prostate (pvp) and 100 consecutive cases undergoing thulium vapoenucleation of the prostate (thuvep) or thulium laser enucleation of the prostate (thulep) at the beginning of the learning curve of two expert endoscopic surgeons. this study and all related procedures were performed in accordance with the declaration of helsinki. informed consent was obtained from all individual participants included in the study. objective: the major strengths of surgical treatment of benign prostatic hyperplasia with laser are reduced morbidity compared to endoscopic resection. no studies analysed the different risk of intra/peri-operative events between patients undergoing thulium and greenlight procedures. materials and methods: we retrospectively reviewed 100 consecutive cases undergoing greenlight vaporization and thulium procedures performed during the learning curve of two expert endoscopic surgeons. pre-operative data, intra and post-operative events at 90 days were analysed. results: patients on antiplatelet/anticoagulant therapy were predominant in the green group (p < 0.0001). rates of blood transfusion (p < 0.0038), use of resectoscope (p < 0.0086), and transient stress urinary incontinence were statistically higher in the thulium group. on the contrary conversions to turp (p < 0.023) were more frequent in greenlight patients. readmissions were more frequently necessary in greenlight group (24%) vs. thulium group (26.6%). the overall complication rate in greenlight and thulium groups were 31% and 53% respectively; clavien 3b complications were 13% in thulium patients versus 1% in greenlight patients. conclusions: greenlight and thulium treatments show similar safety profiles. randomized controlled trial are needed to better clarify the rate of major complications in thulium group, and the incidence of post-operative storage symptoms in these patients’ populations. key words: benign prostatic hyperplasia; complications; greenlight laser; learning curve; safety; thulium laser. submitted 19 december 2022; accepted 31 december 2022 introduction benign prostatic obstruction (bpo) due to benign prostatic hyperplasia (bph) is the most common disease causing lower urinary tract symptoms (luts) in men. up to 50% of men over the age of 50 report some degree of luts. medical therapies, apart from lifestyle modifications, are the first line choice. in case of medical combination therapies failure, surgical management is the solution. transurethral resection of the prostate (turp) and open prostasafety profile of treatment with greenlight versus thulium laser for benign prostatic hyperplasia davide campobasso 1, 2, antonio barbieri 2, tommaso bocchialini 2, gian luigi pozzoli 1, francesco dinale 2, francesco facchini 1, marco serafino grande 1, jean emmanuel kwe 1, 3, michelangelo larosa 1, giulio guarino 1, 3, davide mezzogori 4, elisa simonetti 1, francesco ziglioli 2, antonio frattini 1, umberto vittorio maestroni 2 1 department of urology, ospedale civile di guastalla and ospedale ercole franchini di montecchio emilia, guastalla, italy; 2 department of urology, university hospital of parma, italy; 3 urological residency school network, department of urology, university hospital of modena and reggio emilia, modena, italy; 4 department of engineering and architecture, university of parma, italy. doi: 10.4081/aiua.2023.11101 summary archivio italiano di urologia e andrologia 2023; 95, 1 d. campobasso, a. barbieri, t. bocchialini, et al. we considered only greenlight procedures performed by a single surgeon (af) at the urology department of ercole franchini hospital in montecchio emilia, ausl-irccs of reggio emilia, from 2014 to 2016, with the 180w lbo crystal green light xcelerated performance system (xps)tm (american medical system-ams, minnetonka, minnesota) and a 532 nm fiber (moxy tm fiber). instead, all the procedures with thulium were performed by an expert endoscopic surgeon (ab) at the urology department of the university hospital of parma, from 2015 to 2018, with the thulium laser (cyber tm 200 w, quanta system spa, varese, italy) and a 1000 micron, reusable, front-firing laser fiber. standard greenlight pvp and thuvep/thulep procedures were performed as previously described (4, 8). examined preand post-operative factors and intraand peri-operative data included age, american society of anesthesiology (asa) score, prostate volume evaluated with trans-rectal ultrasound (trus), use of antiplatelet and anticoagulant medications, history of catheterization or retention, conversion to turp, capsular perforation, use of the resectoscope for haemostasis and other intra-operatively recorded events, catheterization time and length of hospital stay. complications were classified according to clavien-dindo classification (9). complications and postoperative events, such as access to hospital for consultation/readmission, incontinence, and erectile dysfunction were collected and classified as early (within 30 post-operative days) or late (31-90 days). luts such as dysuria, urinary frequency or urgency, and urinary incontinence, of any degree and type (stress or urge incontinence), were considered as post-operative complications when they required additional medical examination or therapy and negatively impacted on patient's quality of life. application of bladder catheter and irrigation or re-intervention or medical examination for haematuria were also reported as a complication. all patients underwent an outpatient clinic evaluation at 1 and 3 months. in all cases, antiplatelet therapies (such as glycoprotein iib/iiia receptor inhibitors or adenosine diphosphate -adpinhibitors), and anticoagulant therapies were stopped before surgery and bridging was done based on medical history. conversely, cox inhibitors (aspirin) were not stopped before surgery. antibiotic and antithrombotic prophylaxis were administered to all patients according to local practice protocols. in all cases, at the end of surgery, a three-way bladder catheter was placed with continuous bladder irrigation for at least 12 hours. statistical analyses the anova test and chi-square tests were used for statistical analysis. a p < 0.05 was considered to assess statistical significance. values were presented as n (%) or mean ± sd. results a standard pvp was performed in all 100 patients in the greenlight group, on the contrary 20 patients underwent thuvep and 80 patients thulep in the thulium group. age, asa score, and prostate volume were similar between the two groups. all data are reported in table 1. patients on antiplatelet/anticoagulant therapy were predominant in the green group (p < 0.0001). a history of indwelling catheter history was more represented in the thulium group (p = 0.002). interestingly, considering intra-operative data, the use of resectoscope for haemostasis was more frequent in patients undergoing thulium procedures (p = 0.008), but patients in the greenlight group had a higher conversion rate to turp (5% versus 0%, p = 0.023). no statistical difference was found in capsular perforation rate between thulium and greenlight (p = 0.13), despite an incidence of 12% versus 4%, respectively. no major differences were observed between the two groups in the following post-operative data: hospital stay, catheterization time, early acute urinary retention (aur), erectile dysfunction, post-operative storage symptoms and de novo urgency. blood transfusion rate (p = 0.003) and stress urinary incontinence (sui) three months post-operatively (p = 0.002) were lower in greenlight group. in particular, none of the patients undergoing greenlight pvp needed blood transfusion against 8% in the thulium group. the overall complication rate in greenlight and thulium groups were 31% versus 53% respectively (p < 0.0001) (table 2). the majority of complications in thulium group were clavien grade ii (22%), whereas in the greenlight group they were grade i (25%). thirteen patients needed a second operation for complications in the thulium series (clavien 3b), 84.6% (11 pts) of these being endoscopic revision for haematuria. in 5 cases endoscopic revision for haematuria was performed during the same admission. one patient of greenlight series required open surgery for bladder perforation with extraperitoneal fluid collection. the patient came to our attention after one month for haematuria and blood clots retention, during endoscopic revision a bladder perforation was discovered. in our series, 25% of patients needed an unplanned outpatient’s evaluations after discharge in the greenlight table 1. characteristics of study population. greenlight thulium p value group group age (years) 70.81 ± 7.56 70.73 ± 7.88 0.9 asa score 2.33 2.09 0.1 prostate volume (ml) 50.25 ± 16.67 68.6 ± 35 0.49 indwelling catheter (%) 12% 29% 0.002 antiplatelet and anticoagulant medications (%) 59% antiplatelet 34% antiplatelet < 0.0001 9% anticoagulant 6% anticoagulant capsular perforation (%) 4% 12% 0.13 conversions to turp 5% 0% 0.023 hemostasis with resectoscope 9% 28% 0.008 hospital stay (days) 2.07 ± 0.6 2.82 ± 1.5 0.6 catheterization time (days) 1.98 ± 1.3 1.95 ± 1.4 0.88 blood transfusion (%) 0% 8% 0.003 early urinary retention – aur (%) 12% 8% 0.75 storage symptoms and de novo urgency (%) 27% (27 pts) 39% (39 pts) 0.07 at 1 months 88.8% (24/27) 38.4% (15/39) at 3 months 66.7% (15/27) 5.1% (2/39) sui at three months (%) 7% 18% 0.0029 erectile disfunction (%) 5% 8% 0.38 aur = acute urinary retention; sui = stress urinary incontinence. archivio italiano di urologia e andrologia 2023; 95, 1 safety of green and thulium laser in bph group with 24% (6 pts) readmissions (one patient for heart failure and one for pulmonary embolism one month post-operatively). similarly, in the thulium group 30% of patients needed re-evaluation with 26.6% (8 pts) readmission. haematuria, requiring endoscopic revision was the most common cause of readmission (75% 6 pts). complications divided by time of onset are reported in table 3. discussion in recent years, with the development of laser technologies, overcoming the well-known complications and morbidity rates, turp procedures have decreased (1, 10). the necessity to find less invasive procedures is linked to two aspects. the prevalence of bph increases with advancing age in a linear fashion, and obesity and metabolic syndrome are two risk factors for this condition. all these aspects are prevalent in western countries. nowadays procedures are required to guarantee good functional results, low complications rates, short hospitalization with fast return to normal activity and safety in high-risk patients or patients under anticoagulant or antiplatelet therapy. in the literature, several papers reported data about safety and good results of thulium and greenlight (1, 11, 16, 17). only two papers compared the results of thulium and greenlight for the treatment of bpo (17-19). in the first (17, 18), the authors compared 116 and 118 patients undergone thulium and 120w high-performance system (hps)™ lithium triborate (lbo) vaporization, respectively. the authors did not find statistically significant differences in term of complications, with readmission, transfusion, and re-operation rates of 2.6 vs 1.7%, 2.6% vs 0% and 1.7 vs 5.1%, respectively. no major details are available on these aspects. in the second paper (19), the authors analysed the results of thuvep performed in one center (158 pts) and standard greenlight pvp in 3 centers (93 pts), with no significant differences in term of complications, only hemoglobin drop was in favor of pvp. in the pvp group, 66.7% developed a complication versus the 15.2% of the thuvep group. on the contrary in our series the greenlight group developed an overall complication rate of 31% versus 55% in the thulium group. however, in the study by castellani and colleagues, clavien grade i was the most common complication grade in pvp and thuvep (95.1 versus 35.1%), in line with our experience (80.6% versus 32.7%). the authors reported a reoperation rate after 30 days of 8.6% and 7% in patients undergoing pvp and thuvep, respectively, but they did not specify the cause table 3. association between ppla score and risk factors for kidney stones or stone recurrence. group complications peri-operative early (30 days) late (31-90 days) greenlight 6 acute urinary retention 4 acute urinary retention 2 acute urinary retention 2 fever 1 endoscopic revision with bladder perforation and open conversion 3 urinary tract infection with signs of bacteremia 1 urinary tract infection without signs of bacteremia 1 pulmonary embolism 4 urinary tract infection without signs of bacteremia 2 hematuria without blood clot retention 4 hematuria without blood clot retention 1 heart failure thulium 5 acute urinary retention 3 acute urinary retention 1 endoscopic revision for bladder neck contracture 1 fever 2 fever 5 urinary tract infection with signs of bacteremia 9 urinary tract infection with signs of bacteremia 8 blood transfusion 4 urinary tract infection without signs of bacteremia 5 endoscopic revision for hematuria 6 endoscopic revision for hematuria 1 stenting for ureteral orifice damage 3 hematuria without blood clot retention table 2. overall complication rate. greenlight thulium complications according to clavien-dindo classification (%) clavien i 25% clavien i 18% 12 aur 8 aur 6 hematuria without blood clot retention 4 urinary tract infection without signs of bacteremia 5 urinary tract infection without signs of bacteremia 3 hematuria without blood clot retention 2 fever 3 fever clavien ii 5% clavien ii 22% 3 urinary tract infection with signs of bacteremia 14 urinary tract infection with signs of bacteremia 1 pulmonary embolism 8 blood transfusion 1 heart failure clavien iiib 1% clavien iiib 13% 1 endoscopic revision with bladder perforation and open conversion 11 endoscopic revision for hematuria 1 endoscopic revision for bladder neck contracture 1 stenting for ureteral orifice damage aur = acute urinary retention. archivio italiano di urologia e andrologia 2023; 95, 1 d. campobasso, a. barbieri, t. bocchialini, et al. of the second procedure (haematuria, urethral/bladder neck stenosis etc). unfortunately, the two papers did not focus on safety profile and complications. the authors did not specify how many surgeons and how experienced performed the procedures, the type of complications and the reasons for readmission and re-operation. our study is based on collection of cases of patients treated by two surgeons at the beginning of their learning curve in greenlight pvp and thuvap/thuvep procedures. in particular, in our thulium series, the 5 cases of re-operation for haematuria in the post-operative period occurred in the first 50 procedures, and in 4 cases a capsular perforation was reported during the first enucleation procedures. these patients had a prostate volume < 80 cc (means 56.6 cc) and they were not on anticoagulant or antiplatelet therapies. also, the case of stenting for superficial ureteral orifice lesion occurred during the first 50 procedures. in the remaining 6 cases of re-operation for haematuria described in the post-discharge period for thulium series, one occurred during the first 50 procedures, the other 5 cases were high-risk patients with asa score 3 and prostate volume > 80 cc (mean 109.8 cc) and/or with antiplatelet or anticoagulant therapies. definitely, the 60% of complications clavien grade iiib occurred in the first 50 procedures with thulium, and these issues must be considered when analysing our data. also, the 8% of transfusion rate, which directly correlates with the endoscopic revision rate in the first 50 procedures, must be correctly interpreted. moreover, despite the conversion to turp being more frequent in the greenlight group, all the cases happened in the first 20 procedures and our rate was in line with other series (3). an additional aspect to consider was the higher number of enucleation procedures in the thulium series (80% vs 0%). in fact, the higher resectoscope use in the thulium group is linked to the need for an optimal endoscopic vision before morcellation. also, the 12% of capsular perforation in thulium group is linked to the enucleation procedures. the re-admission rate at 3 months is comparable between thulium and greenlight group (8% and 6%, respectively), with a higher incidence of further urgent medical examination in the patient undergoing greenlight pvp (25% versus 16%). concerning the urinary symptoms, our data on storage symptoms and de novo urgency are in line with the literature and do not differ between the two groups (p = 0.07) (20, 21). however, some differences are present in the time necessary to resolve these symptoms (table 1). in the thulium group, only two patients described persistence of storage symptoms at 3 months versus 15% in the greenlight group. moreover, in our series patients undergone greenlight pvp needed one further medical evaluation for post-operative luts and storage symptoms more frequently than in the thulium group (16% versus 9%). on the contrary, the incidence of transient postoperative urinary stress incontinence is more frequent in the thulium group (18% vs 7%, p = 0.0029). these data are in line with a recent review of the literature regarding thulep procedures, which reported transient irritative symptoms and incontinence between 6.7% and 18.5% (21). furthermore, the risk of incontinence was higher in enucleation than in resection methods and correlates with the learning curve (4). moreover, our study reported the functional results at 3 months. several papers describe a reduction of stress incontinence at 12 months in thulep series (21). some limitations are present in our study, first of all its retrospective nature and the presence of enucleation procedures in the thulium group compared to pvp greenlight group (80% versus 0%). otherwise, the choice to consider the first 100 thulium procedures by a single surgeon, including his learning curve, and 100 consecutives standard grennlight pvp by a surgeon during his learning curve are strengths of this paper. with careful data analysis we found a higher risk of clavien grade iiib complications and blood transfusion in the peri-operative period in the first 50 procedures of thulep. no patients required blood transfusion in the following 50 thulium procedures, despite the prostate volume and the enucleation procedure had increased. in these sub-groups of patients, the risk of endoscopic revision for haematuria was higher in patients with prostate volume > 80 cc and under antiplatelet/anticoagulant therapies. in our real-life setting with thulium and greenlight lasers, both laser systems were documented to be equally safe for patients affected by bpo, also at the beginning of the learning curve. we could not find any significant difference in terms of complications after the first 50 procedures. future prospective randomized studies are needed to confirm this conclusion on both techniques. conclusions greenlight and thulium treatments show similar safety profiles. the higher rate of transient ius in thulium patients is linked to the use of enucleation technique in contrast to vaporization technique with greenlight. furthermore, the higher use of resectoscope for haemostasis during thulium enucleation is needed to perform a safety morcellation procedure. larger study population reflecting multicentred experience would be necessary to better clarify the rate of major complications in thulium group, and the grade and durability of post-operative storage symptoms in these patients’ populations. references 1. gravas s, cornu jn, gacci m, et al. eau guidelines on management of non-neurogenic male lower urinary tract symptoms (luts), incl. benign prostatic obstruction (bpo). edn. presented at the eau annual congress amsterdam 2020. isbn 97894-92671-07-3. eau guidelines office, arnhem, the netherlands. http://uroweb.org/guidelines/compilations-of-all-guidelines/ 2. fallara g, capogrosso p, schifano n, et al. ten-year follow-up results after holmium laser enucleation of the prostate. eur urol focus. 2021; 7:612-617. 3. campobasso d, marchioni m, de nunzio c, et al. predictors of reintervention after greenlight laser photoselective vaporization of the prostate: multicenter long/mid-term follow-up experience. miniinvasive surgery. 2021; 5:45. 4. castellani d, pirola gm, pacchetti a, et al. state of the art of thulium laser enucleation and vapoenucleation of the prostate: a systematic review. urology. 2020; 136:19-34. 5. enikeev d, morozov a, taratkin m, et al. systematic review of the archivio italiano di urologia e andrologia 2023; 95, 1 safety of green and thulium laser in bph endoscopic enucleation of the prostate learning curve. world j urol. 2021; 39:2427-2438. 6. naspro r, gomez sancha f, manica m, et al. from "gold standard" resection to reproducible "future standard" endoscopic enucleation of the prostate: what we know about anatomical enucleation. minerva urol nefrol. 2017; 69:446-458. 7. campobasso d, ferrari g, frattini a. greenlight laser: a laser for every prostate and every urologist. world j urol. 2022; 40:295-296. 8. cindolo l, ruggera l, destefanis p, et al. vaporize, anatomically vaporize or enucleate the prostate? the flexible use of the greenlight laser. int urol nephrol. 2017; 49:405-411. 9. mamoulakis c, efthimiou i, kazoulis s, et al. the modified clavien classification system: a standardized platform for reporting complications in transurethral resection of the prostate. world j urol. 2011; 29:205-210. 10. leonardo c, lombardo r, cindolo l, et al. what is the standard surgical approach to large volume bpe? systematic review of existing randomized clinical trials. minerva urol nefrol. 2020; 72:22-29. 11. castellani d, di rosa m, gasparri l, et al. thulium laser vapoenucleation of the prostate (thuvep) in men at high cardiovascular risk and on antithrombotic therapy: a singlecenter experience. j clin med. 2020; 9:917. 12. meskawi m, hueber pa, valdivieso r, et al. complications and functional outcomes of high-risk patient with cardiovascular disease on antithrombotic medication treated with the 532-nm-laser photovaporization greenlight xps-180 w for benign prostate hyperplasia. world j urol. 2019; 37:1671-1678. 13. campobasso d, marchioni m, altieri v, et al. greenlight photoselective vaporization of the prostate: one laser for different prostate sizes. j endourol. 2020; 34:54-62. 14. campobasso d, acampora a, de nunzio c, et al. post-operative acute urinary retention after greenlight laser. analysis of risk factors from a multicentric database. urol j. 2021; 18:693-698. 15. mattevi d, luciani l, spina r, et al. comparison of greenlight 180-w xps laser vaporization versus transurethral resection of the prostate: outcomes of a single regional center. arch ital urol androl. 2020; 92:169-172 16. castellucci r, marchioni m, fasolis g, et al. the safety and feasibility of the simultaneous use of 180-w greenlight laser for prostate vaporization during concomitant surgery. arch ital urol androl. 2020; 92:297-301 17. elmansy h, hodhod a, elshafei a, et al. comparative analysis of mosestm technology versus novel thulium fiber laser (tfl) for transurethral enucleation of the prostate: a single-institutional study. arch ital urol androl. 2022; 94:180-185. 18. palmero-martí jl, panach-navarrete j, valls-gonzález l, et al. comparative study between thulium laser (tm: yag) 150w and greenlight laser (lbo:nd-yag) 120w for the treatment of benign prostatic hyperpplasia: short-term efficacy and security. actas urol esp. 2017; 41:188-193. 19. castellani d, cindolo l, de nunzio c, et al. comparison between thulium laser vapoenucleation and greenlight laser photoselective vaporization of the prostate in real-life setting: propensity score analysis. urology. 2018; 121:147-152. 20. cindolo l, de nunzio c, greco f, et al. standard vs. anatomical 180-w greenlight laser photoselective vaporization of the prostate: a propensity score analysis. world j urol. 2018; 36:91-97. 21. kyriazis i, swiniarski pp, jutzi s, et al. transurethral anatomical enucleation of the prostate with tm:yag support (thulep): review of the literature on a novel surgical approach in the management of benign prostatic enlargement. world j urol. 2015; 33:525-30. correspondence davide campobasso, md (corresponding author) d.campobasso@virgilio.it gian luigi pozzoli, md pozzolig@ausl.re.it grancesco facchini, md facchinifrancesco@yahoo.it marco serafino grande, md marcogrande2@yahoo.it jean emmanuel kwe, md jeanemmanuelk@yahoo.fr michelangelo larosa, md larosam@ausl.re.it elisa simonetti, md elisasimonetti88@gmail.com antonio frattini, md antonio.frattini@ausl.re.it urology unit, civil hospital of guastalla, azienda usl-irccs di reggio emilia via donatori di sangue 1, guastalla 42016 (re) (italy) antonio barbieri, md barbio68@icloud.com tommaso bocchialini, md tommaso.bocchialini@libero.it francesco dinale, md ceciodinale@gmail.com giulio guarino, md giulio.guarino3@gmail.com francesco ziglioli, md ziglioli@hotmail.it vittorio maestroni, md umaestroni@ao.pr.it department of urology, university hospital of parma viale antonio gramsci, 14, 43126 parma (italy) davide mezzogori, md davide.mezzogori@unipr.it department of engineering and architecture, university of parma parco area delle scienze, 59, 43124 parma (italy) conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 74 original paper introduction sexual dysfunctions (sd) are a broad spectrum of conditions such as decreased sexual desire, ejaculatory disorders, erectile dysfunction, orgasmic changes, painful intercourse, and insufficient vaginal lubrication (1-3). they are very common worldwide and have a negative impact on male and female quality of life (qol) (4). the etiopathogenesis of sd is multifactorial and it can be related to age, comorbidities, psychological or emotional state, hormonal imbalance, couple difficulties, and medical therapies (5). several studies reported the frequent association between sd and rheumatic diseases (rd) (6, 7). although many hypotheses have been proposed to explain this association, the exact mechanism is not identified yet. in patients with rheumatoid arthritis (ra), sd ranged from 31% to 76% of all cases (8). pain and depression seem to be the principal factors involved in sd in rheumatoid arthritis (9). vaginal discomfort or pain during intercourse occur in women affected by sjogren syndrome, systemic lupus erythematosus, and systemic sclerosis (10, 11). depression, pain, and fatigue can affect the sexual function of patients with fibromyalgia (12), premature ejaculation, erectile dysfunction and global sexual dysfunction in patients with ra (13, 14). a multidisciplinary approach to rheumatic diseases is therefore often mandatory. consequently, rheumatologists should know and introduction: sexual dysfunctions (sd) are frequently encountered in patients with rheumatologic diseases. in this scenario, a multidisciplinary approach to rheumatologic diseases is often mandatory. the aim of this survey was to assess whether italian rheumatologists routinely explore sexual health of their patients, their knowledge on the topic, and the barriers to discussing sd in clinical practice. methods: a 32-items anonymous questionnaire was mailed to members of the italian society of rheumatology (rheumatologists and residents in rheumatology training) in february 2023. the questionnaire aimed to determine attitudes, knowledge, and practice patterns regarding the discussion of sd with rheumatologic patients. a descriptive analysis of responses was performed. results: a total of 162 responses were received. overall, 50.0% of respondents occasionally asked patients about sd related to their rheumatologic pathologies, while 37.1% never did so. respondents declared that patients occasionally (82.3%) or never (16.1%) reported sd related to rheumatologic diseases. the main barriers to discussing sexual health were lack of time during medical examination (46.6%), patients’ discomfort (44.8%), and lack of knowledge/experience (39.7%). overall, 41.9% and 33.9% of respondents respectively totally and partially agreed that rheumatologists should routinely investigate patients' sexual health. most of the respondents (79.0%) thought that discussing sexual health problems could help patients cope with their rheumatologic diseases. of all respondents, 74.2% felt the need to broaden their personal knowledge about sd. finally, 45.9% and 34.4% of respondents respectively partially and totally agreed that training courses for rheumatologists could be helpful in the management of sexual health in rheumatological patients. conclusions: sd was not routinely discussed in rheumatology practice, still remaining a neglected issue. the most frequent explanations for the lack of attention toward sd were lack of time, patients’ discomfort, and lack of knowledge/experience. sexual dysfunctions of rheumatological patients are a neglected issue: results from a national survey of italian society of rheumatology luigi napolitano 1, ilenia pantano 2, lorenzo romano 1, luigi cirillo 1, celeste manfredi 3, francesco mastrangelo 1, giovanni maria fusco 1, daniele mauro 2, lorenzo spirito 3, roberto la rocca 1, davide arcaniolo 3, corrado aniello franzese 4, carmine sciorio 5, marco romano 6, marco de sio 3, vincenzo mirone 1, francesco ciccia 2 1 department of neurosciences, reproductive sciences and odontostomatology, university of naples "federico ii", naples, italy; 2 department of precision medicine, university of campania "luigi vanvitelli", naples, italy; 3 unit of urology, department of woman, child and general and specialized surgery, university of campania "luigi vanvitelli", naples, italy; 4 asl napoli 3 sud, naples, italy; 5 urology unit, ospedale alessandro manzoni, lecco, italy; 6 department of precision medicine and hepatogastroenterology unit, aou university luigi vanvitelli, naples, italy. doi: 10.4081/aiua.2023.11337 summary most of the respondents expressed the possible usefulness of attending sd courses to improve knowledge about these conditions. key words: sexual dysfunction; rheumatology; barrier; rheumatological disorders. submitted 26 march 2023; accepted 30 march 2023 archivio italiano di urologia e andrologia 2023; 95, 2 l. napolitano, i. pantano, l. romano, et al. 75 explore the sexuality of their patients for proper management, including referral to the appropriate health professionals (15). despite this, sexual counseling in patients with rd is a neglected issue nowadays. most of the evidence shows that it is also a neglected problem in other specialist fields such as cardiology, neurology and gastroenterology. several reasons such as lack of knowledge/training, lack of time during visits, and embarrassment have been reported (16-20). to the best of our knowledge, there are no study evaluating how the rheumatologists discuss and manage their patients' sexual problems. the aim of this survey was to assess whether italian rheumatologists routinely explore sexual health of their patients, their knowledge on the topic, and the barriers to discussing sd in clinical practice. materials and methods the questionnaire a national cross-sectional anonymous online questionnaire was sent to all members (specialists and residents) of italian society of rheumatology (sir) in february 2023. the questionnaire was designed by two authors (i.p. and l.r.) and structured according with questionnaires used in other studies after a literature review (11,15). a full professor of rheumatology (f.c.) was interviewed to analyze the survey, which was adjusted according to his feedback and comments. the questionnaire was designed using google forms (google llc, mountain view, ca, usa). a brief letter explaining the objectives of the study was sent with the questionnaire. all respondents had to fully complete the questionnaire before submission, since all questions were flagged as mandatory. after submission, users could not review neither amend their answers. reminder e-mails were sent to non-responders 1 and 2 months after the initial mailing. no incentives were offered for participation in the survey. the questionnaire comprised 30 questions focusing on: demographic data of respondents; frequency of discussing sexual health with patients during visit; rheumatologist’s level of knowledge on sexual dysfunction; rheumatologist’s level of knowledge on phosphodiesterase type 5 inhibitors (pde5is); perceived barriers to address sexual issues; knowledge about referring patients with sd. some questions had only one possible answer, others gave the possibility of multiple answers. a part of questions had multiple selectable options, others had an open answer. the questionnaire was detailed in supplementary table 1. given the nature of the study, it was not necessary to obtain ethics committee approval. all respondents consented to the publication of the collected data. a descriptive analysis of the results of survey was performed. categorical variables were presented as frequencies and percentages, continuous variables were reported as means and ranges. no normality test or power analysis was performed. results demographic data of respondents a total of 162 responses were received. overall, 50.0% of respondents were female, 48.4% male, and 1 subject did not declare gender (1.6%). age was mainly between 30 and 40 years old (56.4%). most of the respondents were rheumatologists (77.4%), while a minority consisted of rheumatology residents (22.6%). regarding the workplace, 62.9% of respondents worked in university hospitals, 17.2% in non-university hospitals, and 12.9% were self-employed. work experience was reported > 10 years by 51.6% of respondents. frequency of discussing sexual health with patients during visit overall, 50.0% of respondents occasionally asked patients about sd related to their rheumatologic pathologies, while 37.1% never did so. on the other hand, respondents declared that patients occasionally (82.3%) or never (16.1%) reported sd related to rheumatologic diseases. subjects reporting sd were mainly men < 50 years old (40.3%), men < 40 years old (35.5%), men whose age was between 40-50 years old (30.6%), and women < 40 years old (30.6%). men mainly complained about erectile dysfunction (57.4%) and loss of libido (27.9%). women mainly complained about sexual pain (including dyspareunia, vaginismus, and noncoital pain disorder). fibromyalgia was the rheumatologic disease most associated with sd (58.3%), followed by systemic sclerosis and dermatomyositis (21.7%) and sjogren syndrome (11.7%). management of sd and perceived barriers to discussing sexual health overall, 41.9% and 33.9% of respondents respectively totally and partially agreed that rheumatologists should routinely investigate patients' sexual health. most of the respondents (79.0%) thought that discussing sexual health problems could help patients cope with their rheumatologic diseases. related to this, 37.1% and 22.6% of respondents respectively totally and partially disagreed that discussing sexual health was only the responsibility of andrologists and gynecologists. besides, 37.7% and 29.9% of respondents respectively occasionally and often suggested patients to undergo an andrological/gynecological evaluation for sexual health problems. the main barriers to discussing sexual health were lack of time during medical examination (46.6%), patients’ discomfort (44.8%), and lack of knowledge/experience (39.7%) (figure 1). rheumatologist knowledge about sd and sexually impacting drugs of all respondents, 74.2% felt the need to broaden their personal knowledge about sd. besides, 43.5% believed that medicine courses lack sufficient knowledge about sexual health. finally, 45.9% and 34.4% of respondents respectively partially and totally agreed that training courses for rheumatologists could be helpful in the management of sexual health in rheumatological patients. overall, 71.0% of respondents said they were aware that some rheumatologic drugs have the potential to cause sd. the drugs most associated with sd were antidepressants (82.8%) and immunosuppressors (24.1%). moreover, 61.3% of respondents reported that patients occasionally relate sd to rheumatologic therapy, but 71.0% of physicians did not change therapy when sd were reported. of all respondents, 78.7% always referred to specialists in archivio italiano di urologia e andrologia 2023; 95, 2 76 rheumatologists and sexual dysfunction case of patients who need pharmacological treatment for sd. besides, 41.9% and 33.9% respectively reported that patients never or rarely used pde5is autonomously. finally, 88.5% of respondents were aware of pde5is inhibitors side effects that most of them (75.4%) identified only with flushing and headache. discussion sd have been reported to be common in rheumatologic patients and several risk factors as well as pain, fatigue, stiffness, disability, psychological state, hormonal imbalance, or side effects of medications can contribute to these conditions. there is no doubt that sexuality impacts on the qol, and represents a fundamental part of medical history, with a great significance in the lives of patients with rd. the reasons for sd are multifactorial and comprise diseaserelated factors, physiological factors, and therapy. despite this, sd in rheumatologic settings remains a neglected issue. this study represents the first italian nationwide survey to investigate the attitude, knowledge, practice, and barriers among rheumatologists in discussing sd in patients with rheumatologic disorders. we reported a gap between rheumatologists' attitudes and their daily practices regarding sd. indeed, although rheumatologists agreed with the importance of discussing sexual issues with their patients, they did not address it in their clinical practice. these data corroborated findings of previous published studies: 87.1% of rheumatologists addressed sd in their patients and 16.1% of patients did not refer to sd. in our recent publication about sd and gastroenterological disease, we reported that 71% of gastroenterologists never or infrequently addressed sd in patients with gastrointestinal disorders, and only 4% of patients refer their sd to their own gastroenterologist (20). similar results were reported by nicolai et al. and van ek et al. in cardiology and nephrology practice respectively (16, 21), while sobecki et al., reported that 63% of obstetrician and gynecologists routinely assess patients’ sexual activities but only 40% investigate their sd (22). insufficient time during visits (46.6%), followed by patients’ embarrassment (44.8%), and lack of training, are the most important reasons that contributed to not assess sd in the daily practice. on the contrary other healthcare professionals as well as gastroenterologists, cardiologists, nephrologists, neurologists, and neurosurgeons reported that the most important reasons are lack of knowledge and training, insufficient time during the visits and embarrassment (19). despite these, 34.4% of rheumatologists are conscious that a specific training in sexual medicine could be useful in sd treatments. these findings confirmed the data reported by romano et al. among gastroenterologists. adequate and standardized training should be mandatory to help healthcare in management of sd, in fact nowadays the lack of education represents a widespread problem for several healthcare. fibromyalgia represents the most frequent rheumatologic disorder (58.3%) related to sd (20). collado-mateo at al. reported a prevalence of 76% of sexual problems among women with fibromyalgia compared to 15% in healthy controls, in particular among those aged 50 or over (23). it is associated with menopause, psychiatric comorbidities, and high degree of musculoskeletal pain (24). one of the most important therapies in rd consist of antidepressants, that are notoriously related to sd (2526). our responders reported that antidepressants represent the most common drugs related to sd (82.8%), followed by immunosuppressive medication (24.1%). due to this, sometimes a multidisciplinary approach in sd is necessary (26-29). to the best of our knowledge, this is the first study focused on the behavior and knowledge of rheumatologists regarding the sd of their patients. however, our results should be read and interpretated according to several limitations, mainly including the small sample size, the use of a non-validated questionnaire, and the inclusion of a limited sample of respondents by country and age. future research is therefore needed to confirm and further our findings on the topic. in conclusion, sd is not routinely discussed in rheumatology practice, still remaining a neglected issue. the most frequent explanations are lack of time, patients’ discomfort, and lack of knowledge/experience. however, sexual health remains an essential issue in the lives of patients with rd, which should always be addressed by rheumatologists in order to start a correct counseling and an adequate multidisciplinary management. specific training on sd could be one of the most important steps to improve the practice of rheumatologists in this regard. figure 1. perceived barriers to discussing sexual health by rheumatologists. archivio italiano di urologia e andrologia 2023; 95, 2 l. napolitano, i. pantano, l. romano, et al. 77 references 1. manfredi c, fortier é, 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of fibromyalgia on sexual function in women. j back musculoskelet rehabil. 2020; 33:355-361. 24. mutti gw, de quadros m, cremonez lp, et al. fibromyalgia and sexual performance: a cross-sectional study in 726 brazilian patients. rheumatol int. 2021; 41:1471-1477. 25. derubeis rj, hollon sd, amsterdam jd, et al. cognitive therapy vs medications in the treatment of moderate to severe depression. arch gen psychiatry. 2005; 62:409-16. 26. higgins a, nash m, lynch am. antidepressant-associated sexual dysfunction: impact, effects, and treatment. drug healthc patient saf. 2010; 2:141-50. 27. cirillo l, fusco gm, di bello f, et al. sexual dysfunction: time for a multidisciplinary approach? arch ital urol androl. 2023; 95:11236. 28. napolitano l, fusco gm, cirillo l, et al. erectile dysfunction and mobile phone applications: quality, content and adherence to european association guidelines on male sexual dysfunction. arch ital urol androl. 2022; 94:211-216. 29. romano l, granata l, fusco f, et al. sexual dysfunction in patients with chronic gastrointestinal and liver diseases: a neglected issue. sex med rev. 2022; 10:620-631. correspondence luigi napolitano, md dr.luiginapolitano@gmail.com lorenzo romano, md (corresponding author) loryromano@hotmail.it luigi cirillo, md cirilloluigi22@gmail.com francesco matrangelo, md f.mastrangelo91@gmail.com giovanni maria fusco, md giom.fusco@gmail.com roberto la rocca, md robertolarocca87@gmail.com vincenzo mirone, md mirone@unina.it department of neurosciences, reproductive sciences and odontostomatology, university of naples "federico ii", naples, italy ilenia pantano, md ileniapantano@gmail.com daniele mauro, mc dranielmar@gmail.com francesco ciccia, md francesco.ciccia@unicampanaia.it department of precision medicine, university of campania "luigi vanvitelli", naples, italy celeste manfredi, md manfredi.celeste@gmail.com lorenzo spirito, md lorenzospirito@msn.com davide arcaniolo, md davide.arcaniolo@gmail.com marco de sio, md marco.desio@unicampania.it unit of urology, department of woman, child and general and specialized surgery, university of campania "luigi vanvitelli", naples corrado aniello franzese, md corradofranzese@libero.it asl napoli 3 sud, naples, italy carmine sciorio, md carmine.sciorio@gmail.com urology unit, ospedale alessandro manzoni, lecco, italy marco romano, md marco.romano@unicampania.it department of precision medicine and hepatogastroenterology unit, aou university luigi vanvitelli, naples, italy conflict of interest: the authors declare no potential conflict of interest. introduction high grade prostatic intraepithelial neoplasia (hgpin) is a cytoarchitectural modification of the prostatic tissue, with pre-existing acini and ducts lined by cytologically atypical cells (1). it has long been considered the pre-neoplastic lesion of prostate cancer (pca) (1, 2) and is considered a risk factor for pca on subsequent biopsy (3-7). the prognostic value of hgpin in prostate biopsy cores however has been questioned and controversy has arisen on whether patients with a diagnosis of hgpin should 59archivio italiano di urologia e andrologia 2013; 85, 2 original paper widespread high grade prostatic intraepithelial neoplasia on biopsy predicts the risk of prostate cancer: a 12 months analysis after three consecutive prostate biopsies cosimo de nunzio 1, simone albisinni 1, antonio cicione 1, mauro gacci 2, costantino leonardo 1, francesco esperto 1, andrea tubaro 1 1 department of urology, ospedale sant’andrea, university “la sapienza”, rome, italy; 2 department of urology, ospedale careggi, university of florence, italy. purpose: to evaluate the risk of prostate cancer (pca) on a third prostate biopsy in a group of patients with two consecutive diagnoses of high grade intraepithelial neoplasia (hgpin). materials and methods: from november 2004 to december 2007, patients referred to our clinic with a psa ! 4 ng/ml or an abnormal digital rectal examination (dre) were scheduled for trans-rectal ultrasound (trus) guided 12-core prostate biopsy. patients with hgpin underwent a second prostate biopsy, and if the results of such procedure yielded a second diagnosis of hgpin, we proposed a third 12-core needle biopsy regardless of psa value. crude and adjusted logistic regressions were used to assess predictors of pca on the third biopsy. results: a total of 650 patients underwent 12 cores transrectal ultrasound prostatic biopsy in the study period. of 147 (22%) men with a diagnosis of hgpin, 117 underwent a second prostatic biopsy after six months and 43 a third biopsy after other six months. after the third biopsy, 19 patients (34%) still showed hgpin, 15 (35%) were diagnosed with pca and 9 (21%) presented with chronic prostatitis. widespread hgpin on a second biopsy was significantly associated with pca on further biopsy (!2 = 4.04, p = 0.04). moreover, the presence of widespread hgpin significantly predicted the risk of pca on crude and adjusted logistic regressions. conclusions: widespread hgpin on second biopsy is associated with the presence of pca on a third biopsy. nonetheless, the relationship between hgpin and pca remains complex and further studies are needed to confirm our findings. key words: prostate cancer; high grade prostatic intraepithelial neoplasia; biopsy; gleason score; widespread. submitted 5 november 2012; accepted 31 january 2013 no conflict of interest declared summary undergo further biopsies (2, 8, 9). widespread hgpin, defined as ! 4 biopsy cores involved with the intraepithelial lesion, has been found to be significantly associated with pca diagnosis on further biopsy by different investigators (6, 10-15), including our group (16). other predictors of pca on a subsequent biopsy in patients with isolated hgpin, such as age, an abnormal digital rectal examination (dre), an abnormal prostate volume, psa, psa ratio or psa density values have been examined, yet no de nunzio_stesura seveso 24/06/13 10:57 pagina 59 archivio italiano di urologia e andrologia 2013; 85, 2 c. de nunzio, s. albisinni, a. cicione, m. gacci, c. leonardo, francesco esperto, a. tubaro 60 consensus on their predictive role has been reached (5, 7, 14, 17). to date, the prognostic value of hgpin, clinical markers (age, digital rectal examination, psa, etc) and widespread hgpin in men after multiple diagnoses of isolated hgpin remains controversial, and little is available on long term follow-up of these patients. data confirming a positive association of widespread hgpin and pca diagnosis on repeat biopsy have already been published by our group (16). we now report the results after the third biopsy in men with two consecutive diagnoses of isolated hgpin. we explored the association of hgpin, widespread hgpin and clinical markers (age, digital rectal examination, psa, etc) and pca risk on a third biopsy, in order to elucidate the potential predictive role of hgpin on pca and further help to indentify the correct clinical management for patients with hgpin. materials and methods from november 2004 to december 2007, after receiving institutional review board approval, patients referred to our clinic with a psa ! 4 ng/ml or an abnormal digital rectal examination (dre) were scheduled for trans-rectal ultrasound (trus) guided 12-core prostate biopsy after informed consent was signed. in every patient diagnosed with hgpin, a second biopsy was proposed after 6 months regardless of psa values. finally, in patients with a second diagnosis of hgpin a third and final biopsy was proposed 6 months after the second procedure, for a total of 12 months follow-up. biopsy was performed as an outpatient procedure and the methodology has been throughout fully described in previously published peer-reviewed manuscripts (16, 18). all biopsies were performed following the same 12-core scheme. before each procedure, blood specimens were obtained and free and total psa were measured. prostate volume was calculated by trus. patients on finasteride or dutasteride and men who had undergone prostate surgery were excluded from the study. a single uro-pathologist performed the histological evaluation for all biopsy series. the histological/architectural threshold used to assign the various diagnoses was that proposed by the who (19, 20). in areas suspicious for asap or hgpin, immunohistochemical staining of sequential sections was used to confirm the eventual loss of basal cells using a mix of anti-p63 and 34"12 cytokeratin antibodies. as defined by netto and epstein, widespread hgpin was defined as 4 or more cores involved with hgpin (21). statistical analysis widespread hgpin on the second biopsy was examined as a categorical variable. the presence or absence of cancer on the third biopsy specimens defined our main categorical outcome variable. we performed chi-square test to evaluate the association between widespread hgpin on the second biopsy and the diagnosis of pca on the subsequent biopsy. crude and adjusted logistic regressions were used to evaluate the association of clinical and pathological predictors and the risk of pca on the third biopsy. however, given the small number of events in our model, we executed separate multivariate analyses for each predictor other than widespread hgpin: multivariate analyses constantly included the presence of widespread hgpin on the second biopsy (categorical) plus a second term as age, psa, trus volume, dre, psa ratio and psa density. due to non-parametrical distribution, psa values and derivates (psa ratio and density) were logarithmically transformed in the multivariate logistic regression tests. mann-whitney test was used to explore differences in age, prostate volume, psa concentration, psa ratio and psa density across our two outcome groups and between men with and without widespread hgpin at second biopsy. wilcoxon signed rank sum test was used to evaluate significant modifications of psa concentration, ratio and density between the second and third biopsy. statistical analysis was performed using stata 11 (statacorp, college station, tx). results during the study period 650 men underwent primary prostate biopsy. of these, 147 (22%) were diagnosed with hgpin. as 30 men refused further procedures, a second biopsy was performed in 117 men, six months later. data regarding the second biopsy have already been published (16). out of 117 re-biopsies, 75 (64%) yielded a second diagnosis of hgpin and to these men a third prostate biopsy was proposed, 6 months after the second biopsy. 22 of these patients refused to undergo the third biopsy and 10 underwent prostate surgery for bladder outlet obstruction; no cancer was found in any of the pathological specimens examined after surgery in these 10 patients. 43 men were therefore available for final analysis. patients characteristic are illustrated in table 1. after the third biopsy, 19 patients (44%) still showed hgpin, 15 (35%) were diagnosed with pca and 9 (21%) presented with chronic prostatitis. a flow chart (figure 1) clearly illustrates the results of the biopsies. the 10 men who underwent prostate resection for bladder outlet obstruction were all diagnosed with benign prostatic hypertrophy. median (iqr) age (yrs) 65 (61-70) prostate volume (ml) 56 (42-64) psa (ng/ml) 7.53 (5.87-10.8) psa ratio (%) 15 (12-22) psa density (ng/ml2) 0.14 (0.10-0.22) dre negative 37 (86%) positive 6 (14%) widespread hgpin at second biopsy (! 4 cores) 17/43 (40%) table 1. clinical characteristics of the cohort (43 patients). de nunzio_stesura seveso 24/06/13 10:57 pagina 60 of the 15 patients with pca, 9 had a low grade gleason 6 (3 + 3) adenocarcinoma, 4 men had a gleason 7 (3 + 4) tumor, while only one gleason 8 (4+4) and one gleason 9 (4 + 5) cancers were diagnosed. a single core was involved in 10 of the men with cancer, with a 15% median core cancer extension. of these, 7 were gleason 6 (3 + 3) and the remaining 3 were gleason 7 (3 + 4). two cores were positive for cancer in 4 patients with a median extension of 15%. in one patient, diagnosed with a gleason 8 (4 + 4), 4 cores were involved with cancer, for a maximum of 60% of their length. no significant difference in the distribution of age, psa, prostate volume, dre, psa ratio and psa density (at the time of third biopsy) was found across the two outcome groups (table 2). widespread hgpin on a second biopsy was significantly associated with pca on further biopsy (!2 = 4.04, p = 0.04) (table 2). moreover, the presence of widespread hgpin significantly predicted the risk of pca on crude logistic regression (or 3.75, 95%ci 1.00-14.02, p = 0.049). widespread hgpin remained a significant predictor of pca on all 61archivio italiano di urologia e andrologia 2013; 85, 2 widespread high grade prostatic intraepithelial neoplasia on biopsy predicts the risk of prostate cancer no cancer cancer p-value1 < 4 cores involved ! 4 cores involved p-value1 (widespread hgpin) number of patients 28 (65%) 15 (35%) ----26 (60%) 17 (40%) ----age (yrs) median (iqr) 66 (60-70) 65 (61-71) 0.86 66 (62-71) 64 (57-70) 0.30 prostate volume (ml) median (iqr) 58 (43-65) 51 (38-64) 0.31 57 (40-65) 51 (45-63) 0.80 dre negative 25 (89%) 12 (80%) 0.402 22 (85%) 15 (88%) 0.742 positive 3(11%) 3 (20%) 4 (15%) 2 (12%) psa (ng/ml) median (iqr) 6.86 (5.66-9.3) 8.84 (6.75-13.5) 0.14 7.8 (5.88-11.7) 6.86 (5.87-8.89) 0.39 psa ratio (%) median (iqr) 16 (12-24) 15 (10-19) 0.27 16 (12-25) 15 (12-20) 0.72 psa density (ng/ml2) median (iqr) 0.13 (0.10-0.21) 0.15 (0.1-0.26) 0.24 0.145 (0.10-0.23) 0.14 (0.10-0.18) 0.57 widespread hgpin 8/28 (29%) 9/15 (60%) 0.042 ----------prostate cancer ----------6/26 (23%) 9/17 (53%) 0.042 table 2. clinical and pathological differences across groups. figure 1. study design. 1 mann-whitney test. 2 !2 test. de nunzio_stesura seveso 24/06/13 10:57 pagina 61 archivio italiano di urologia e andrologia 2013; 85, 2 c. de nunzio, s. albisinni, a. cicione, m. gacci, c. leonardo, francesco esperto, a. tubaro 62 epstein as ! 4 cores involved with hgpin (21). this pathological entity has been positively associated with a significantly increased risk of pca in numerous studies (6, 7, 10-14, 16), ranging from 36% to 39%. to date only few studies (12, 14, 22-25) have explored the risk of cancer following multiple biopsies (> 2 procedures) diagnosing hgpin; moreover only two manuscripts have examined the cancer risk at third biopsy after diagnosing multiple cores involved with hgpin on a second prostate biopsy (12, 14). in this manuscript we addressed this issue by conducting a prospective trial with a minimum 12 month follow-up, during which men with two consecutive diagnoses of hgpin underwent a third prostate biopsy. widespread hgpin on the second biopsy was significantly associated with the risk of pca. no clinical parameter such as age, dre, prostate volume, psa, psa density or psa ratio was able to significantly predict cancer. if validated, these results strengthen the prognostic value of widespread hgpin, with impact on the need for further oncologic surveillance in patients with such diagnosis. we found a significant association between widespread hgpin on second biopsy and pca (!2 = 4.04, p = 0.04), and men with widespread hgpin had a 4-fold, significant increase in risk of detecting pca on subsequent biopsy compared to men with 3 or less cores involved with hgpin. the overall cancer risk on the third biopsy for men with widespread hgpin on second prostate biopsy was 53%, higher that the risk if widespread was present at the time of the first biopsy (36-39% risk). in line with these findings are the results reported by bishara et al, who found a 50% cancer risk if multiple cores (! 2) involved with hgpin had been found on second biopsy (12). abdel-khaled et al. reported a similar 58% risk in patients with multifocal hgpin (14). whether these results justify the need to perform an early re-biopsy (6 months) in patients with widespread hgpin at the second biopsy cannot be fully determined by our data. however we feel that repeat biopsy should be advised after diagnosing widespread hgpin on second biopsy, after adequately counseling patients on the risks and benefits of undergoing further prostate biopsies. moreover, we explored the prognostic value of other clinical and laboratory parameters on pca. all parameters measured, including age, prostate volume, dre, psa, psa ratio psa density were not significant predictors of pca on subsequent biopsy. most studies have yielded similar results (5, 26-29), in that there does not appear to be any clinical parameter that helps identify men who are more likely to have cancer on further biopsies. given these results, a finding of widespread hgpin, especially on second biopsy, may be crucial in planning patients’ future follow-up and should draw the urologist’s attention, as it appears to be a significant predictor of pca on further testing. of the neoplasms diagnosed on the third biopsy of our cohort, 9/15 (60%) were low-grade, gleason 6 (3 + 3), 7 of which showed a single core, 10-15% core involvement. thus, 7/15 (47%) of the tumors identified are probably clinically insignificant and of 43 biopsies only 6 men had pca with gleason score ! 7. it could be argued multivariate models (all p < 0.05). all clinical parameters evaluated, such as age, psa, dre, prostate volume and psa ratio were not significant predictors of cancer at the time of the third prostate biopsy (table 3). no significant differences in age, prostate volume, dre, psa, psa ratio and psa density were found between men with and without widespread hgpin (table 2). psa concentration was not significantly modified between the second and third biopsy (median [iqr]: 7.83 [5.3410.50] vs. 7.53 [5.87-10.80], p = 0.34). the presence or absence of widespread hgpin on the second biopsy did not significantly differ across patients with chronic prostatitis and patients with hgpin on third biopsy (p = 0.12). finally, of the 43 patients who underwent the full set of three biopsies, 12 had a diagnosis of widespread hgpin at the time of the first biopsy. of these, 9 (75%) were rediagnosed with widespread hgpin on the second biopsy, while the remaining 3 (25%) had focal hgpin at that time. cancer was found on third biopsy only in the first 9 patients (those with widespread lesions on both biopsies, in particular in 5 of these 9 men (56%), while none of the 3 patients with widespread hgpin only on the first biopsy had a diagnosis of pca on the third biopsy. discussion hgpin is a common pathological finding on prostate biopsy and has been associated with an increased risk of pca on subsequent biopsies (3-6, 9). initially this risk was estimated around 50% (4), however studies performed after 2000, in the era of extended prostate biopsy, have shown that this risk is approximately 23%, compared to a 19% risk of detecting cancer after a benign diagnosis (2). the impact of hgpin on the need for further biopsies has thus been redimensioned, and numerous studies have explored pathological features of hgpin in order to predict pca on subsequent biopsies (2, 21). in this context, the denomination of widespread or multifocal hgpin has arisen, defined by netto and or 95% ci p-value widespread hgpin 3.75 1.00-14.02 0.04 age 1 1.04 0.93-1.15 0.51 psa 1, 2 3.98 0.83-19.02 0.08 prostate volume 1 1.00 0.97-1.04 0.81 dre 1 2.53 0.39-16.19 0.98 psa ratio 1, 2 0.37 0.10-1.35 0.13 psa density 1, 2 2.89 0.84-9.94 0.09 table 3. multivariate logistic regressions: exploring the risk of prostate cancer on third biopsy. 1 due to the small number of events separate regressions were performed, adding each single term to the initial model with our main predictor variable (widespread hgpin) (see text). 2 psa, psa ratio and psa density were log-transformed due to non-parametrical distribution. de nunzio_stesura seveso 24/06/13 10:57 pagina 62 therefore that performing a third biopsy in men all with two diagnoses of hgpin it may not be legitimate, as too many biopsies should to be performed to find one clinically significant cancer. however, if we restrict the analysis to patients with widespread lesions on second biopsy (17 men of 43), 9 tumors were identified, of which 4 were gleason ! 7. as such, 17 men underwent prostate biopsy to uncover 4 clinically significant high-grade cancers: these results in four men being biopsied to find one clinically significant cancer (4:1). these results suggests that, if not all men with two hgpin biopsies should undergo further procedures, it may be appropriate to perform a repeat biopsy in men with widespread lesions on the second biopsy specimens, in order to uncover clinically significant prostate cancer. it is correct to point out some limitations of this study as the small sample size (n = 43). given the singularity of this group of patients, as it represents a second subset group of our initial study population, we believe that these results express the impact that widespread hgpin on pca. 10 patients who underwent prostate resection for bladder outlet obstruction were excluded from final analysis: given the different accuracy in pca detection of trus-guided prostate biopsy vs. histologic analysis of resected specimen during transurethral prostatic surgery, we feel that such exclusion is justified (30). the follow-up period was limited to 12 months, time elapsed between the first and third biopsy: such period of time may seem inappropriate to evaluate the evolution of hgpin on pca, but patients are still under evaluation and the results of biopsies performed at 24 months will be soon available. moreover, a significant number of patients failed to return for rebiopsy and unfortunately data on their follow-up was not available for analysis: however, if we consider these drop outs to be random, the results of this study should not have been significantly biased by such loss of data. this finding underlines the importance of patient follow-up after a diagnosis of hgpin (3). nevertheless, we must acknowledge that our study firstly confirmed in a homogeneous population that widespread hgpin is associated with a significant higher risk of pca even in patients with two previous biopsies. furthermore another peculiar characteristics of our group is that our patients underwent three prostate biopsies in 12 months time regardless of psa value, using the presence of hgpin a mandatory indication for prostate biopsy. the lower cancer detection rate on initial biopsy and the high incidence of multiple isolated hgpin areas may depend on our study population: our academic hospital operates under the italian national care system which does not support screening programs for pca. furthermore, our clinical facility opened in 2002, and we can assume that our patient population had limited access to pca centers and screening programs in the past. conclusions the results of our study suggest that hgpin and in particular widespread hgpin are associated with an increased risk of pca on a repeat biopsy in men with two previous diagnoses of hgpin. no clinical parameter evaluated such as age, psa, prostate volume, dre and psa derivates was able to significantly predict pca in this particular group of patients. further studies are needed to confirm these findings in other populations and to evaluate which possible biological factors related to widespread hgpin are responsible for the observed results. references 1. montironi r, mazzucchelli r, lopez-beltran a, et al. prostatic intraepithelial neoplasia: its morphological and molecular diagnosis and clinical significance bju int. 2011; 108:1394-401. 2. epstein ji, herawi m. prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care j urol. 2006; 175:820-34. 3. maatman tj, papp sr, carothers gget al. the critical role of patient follow-up after receiving a diagnosis of prostatic intraepithelial neoplasia prostate cancer prostatic dis. 2001; 4:63-66. 4. aboseif s, shinohara k, weidner n, et al. the significance of prostatic intra-epithelial neoplasia br j urol. 1995; 76:355-9. 5. borboroglu pg, sur rl, roberts jl, amling cl. repeat biopsy strategy in patients with atypical small acinar proliferation or high grade prostatic intraepithelial neoplasia on initial prostate needle biopsy j urol. 2001; 166:866-70. 6. merrimen jl, jones g, srigley jr. is high grade prostatic intraepithelial neoplasia still a risk factor for adenocarcinoma in the era of extended biopsy sampling? pathology. 2010; 42:325-9. 7. antonelli a, tardanico r, giovanessi l, et al. predicting prostate cancer at rebiopsies in patients with high-grade prostatic intraepithelial neoplasia: a study on 546 patients prostate cancer prostatic dis. 2011; 14:173-6. 8. chin ai, dave ds, rajfer j. is repeat biopsy for isolated highgrade prostatic intraepithelial neoplasia necessary? rev urol. 2007; 9:124-31. 9. godoy g, taneja ss. contemporary clinical management of isolated high-grade prostatic intraepithelial neoplasia prostate cancer prostatic dis. 2008; 11:20-31. 10. srigley jr, merrimen jl, jones g, jamal m. multifocal highgrade prostatic intraepithelial neoplasia is still a significant risk factor for adenocarcinoma can urol assoc j. 2010; 4:434. 11. lee mc, moussa as, yu c, et al. multifocal high grade prostatic intraepithelial neoplasia is a risk factor for subsequent prostate cancer j urol. 2010; 184:1958-62. 12. bishara t, ramnani dm, epstein ji. high-grade prostatic intraepithelial neoplasia on needle biopsy: risk of cancer on repeat biopsy related to number of involved cores and morphologic pattern am j surg pathol. 2004; 28:629-33. 13. merrimen jl, jones g, walker d, et al. multifocal high grade prostatic intraepithelial neoplasia is a significant risk factor for prostatic adenocarcinoma j urol. 2009; 182:485-90; discussion 490. 14. abdel-khalek m, el-baz m ibrahiem el h. predictors of prostate cancer on extended biopsy in patients with high-grade prostatic intraepithelial neoplasia: a multivariate analysis model bju int. 2004; 94:528-33. 15. akhavan a, keith jd, bastacky si, et al. the proportion of cores with high-grade prostatic intraepithelial neoplasia on extended-pattern needle biopsy is significantly associated with prostate cancer on site-directed repeat biopsy bju int. 2007; 99:765-9. 63archivio italiano di urologia e andrologia 2013; 85, 2 widespread high grade prostatic intraepithelial neoplasia on biopsy predicts the risk of prostate cancer de nunzio_stesura seveso 24/06/13 10:57 pagina 63 correspondence cosimo de nunzio, md, phd (corresponding author) cosimodenunzio@virgilio.it simone albisinni, md albisinni.simone@gmail.com antonio cicione, md acicione@libero.it costantino leonardo, md costantino.leonardo@gmail.com francesco esperto, md francescoesperto@gmail.com andrea tubaro, md department of urology, ospedale sant’andrea, università “la sapienza” via di grottarossa 1035 00198 roma, italy mauro gacci, md department of urology, ospedale careggi, università di firenze largo brambilla 3 50134 firenze, italy maurogacci@yahoo.it 64 c. de nunzio, s. albisinni, a. cicione, m. gacci, c. leonardo, francesco esperto, a. tubaro archivio italiano di urologia e andrologia 2013; 85, 2 16. de nunzio c, trucchi a, miano r, et al. the number of cores positive for high grade prostatic intraepithelial neoplasia on initial biopsy is associated with prostate cancer on second biopsy j urol. 2009; 181:1069-74; discussion 1074-5. 17. raviv g, janssen t, zlotta ar, et al. prostatic intraepithelial neoplasia: influence of clinical and pathological data on the detection of prostate cancer j urol. 1996; 156:1050-4; discussion 1054-5. 18. de nunzio c, freedland sj, miano r, et al. metabolic syndrome is associated with high grade gleason score when prostate cancer is diagnosed on biopsy. prostate. 2011; doi: 10.1002/pros.21364. [epub ahead of print]. 19. sakr wa d. m. a., montironi r, humphrey, et al. prostatic intraepithelial neoplasia in: who classification of tumours: pathology and genetics of tumours of the urinary system and male genital organs. edited by jn eble, g sauter, ji epstein and ia sesterhenn. lyon, france: iarc press. 2004; 193:198. 20. epstein ji hb, algaba f, humphrey pa, et al. acinar adenocarcinoma in: who classification of tumours: pathology and genetics of tumours of the urinary system and male genital organs. edited by jn eble, g sauter, ji epstein and ia sesterhenn. lyon, france: iarc press. 2004; 162-192. 21. netto gj, epstein ji. widespread high-grade prostatic intraepithelial neoplasia on prostatic needle biopsy: a significant likelihood of subsequently diagnosed adenocarcinoma am j surg pathol. 2006; 30:1184-8. 22. goeman l, joniau s, ponette d, et al. is low-grade prostatic intraepithelial neoplasia a risk factor for cancer? prostate cancer prostatic dis. 2003; 6:305-10. 23. gokden n, roehl ka, catalona wj, humphrey pa. high-grade prostatic intraepithelial neoplasia in needle biopsy as risk factor for detection of adenocarcinoma: current level of risk in screening population urology. 2005; 65:538-42. 24. moore ck, karikehalli s, nazeer t, et al. prognostic significance of high grade prostatic intraepithelial neoplasia and atypical small acinar proliferation in the contemporary era j urol. 2005; 173:70-2. 25. park s, shinohara k, grossfeld gd, carroll pr. prostate cancer detection in men with prior high grade prostatic intraepithelial neoplasia or atypical prostate biopsy j urol. 2001; 165:1409-14. 26. kamoi k, troncoso p, babaian rj. strategy for repeat biopsy in patients with high grade prostatic intraepithelial neoplasia j urol. 2000; 163:819-23. 27. postma r, roobol m, schroder fh,van der kwast t. h. lesions predictive for prostate cancer in a screened population: first and second screening round findings prostate. 2004; 61:260-6. 28. roscigno m, scattoni v, freschi m, et al. monofocal and plurifocal high-grade prostatic intraepithelial neoplasia on extended prostate biopsies: factors predicting cancer detection on extended repeat biopsy urology 2004; 63:1105-10. 29. langer je, rovner es, coleman bg, et al. strategy for repeat biopsy of patients with prostatic intraepithelial neoplasia detected by prostate needle biopsy j urol. 1996; 155:228-31. 30. jones js, follis hw, johnson jr. probability of finding t1a and t1b (incidental) prostate cancer during turp has decreased in the psa era prostate cancer prostatic dis. 2009; 12:57-60. de nunzio_stesura seveso 24/06/13 10:57 pagina 64 archivio italiano di urologia e andrologia 2013; 85, 286 introduction benign prostatic hyperplasia (bph) is a highly prevalent medical condition worldwide. the prevalence of lower urinary tract symptoms (luts) associated with bph among older and middle-aged men is significant and is original paper comparative randomized study on the efficaciousness of endoscopic bipolar prostate resection versus monopolar resection technique. 3 year follow-up roberto giulianelli, luca albanesi, francesco attisani, barbara cristina gentile, giorgio vincenti, francesco pisanti, teuta shestani, luca mavilla, david granata, manlio schettini division of urology nuova villa claudia clinic, rome, italy. objective: transurethral resection of the prostate (turp) is the current optimal therapy for the relief of bladder outflow obstruction, with subjective and objective success rate of 85 to 90%. aim of this study was to evaluate efficacy and safety of plasmakinetic energy (gyrus electro surgical system), which produces vaporization of tissue immersed in isotonic saline against standard monopolar transurethral resection of the prostate. methods: from january 2002 to april 2002, 160 consecutive patients, who had low urinary tract symptoms (luts) of benign prostatic hyperplasia (bph) were enrolled in this study. patients were randomised to undergo bipolar turp (80 patients) or monopolar turp (80 patients). preoperative work-up was assessed by administering ipss, iief-5 and qol questionnaires. all patients were submitted to uroflowmetry, transrectal ultrasound (trus), post-voidal residual urine measurement and psa determination. in the two groups, ipss, iief-5 and qol, uroflowmetry, trus, post-voidal residual urine measurement, psa determination and number of reoperations were evaluated at 1, 3, 6, 12, 18, 24, 30 and 36 months follow up, and then every year. furthermore, in both groups operative time, resected tissue weight and perioperative complications were analysed. total postoperative catheter time, total post-operative hospital stay, haemoglobin loss were also recorded in the two groups. results: comparative data on ipss symptom score, iief-5, qol, psa, peak urinary flow rate and post-void residual urine volume were similar in the two groups but showed a significant improvement respect to baseline values. the postoperative haemoglobin levels, postoperative catheterization time, hospital stay and 3-year overall surgical re-treatment-free rate were significantly better in the bipolar group. conclusions: bipolar turp has a comparable outcome to standard monopolar turp at short and medium term regard to subjective and objective outcome measurements. its impact on bladder outlet function is also similar to that of monopolar turp. improvement in ipss, qol index, iief-5, qmax and post-void residual urine volume were comparable in both group denoting similar efficacy of the techniques. key words: bipolar turp; monopolar turp; outcome; gyrus device. submitted 21 february 2013; accepted 30 april 2013 no conflict of interest declared summary growing alongside the increasing age of western populations. it has been calculated that approximately 30% of the male population in europe and the united states have a chance of undergoing to standard transurethral giulianelli ok_stesura seveso 24/06/13 11:05 pagina 86 87archivio italiano di urologia e andrologia 2013; 85, 2 comparative randomized study on the efficaciousness of endoscopic bipolar prostate resection versus monopolar resection technique resection of the prostate (turp) during their lifetimes (1). transurethral resection of the prostate (turp) is the current optimal therapy for the relief of bladder outflow obstruction, with subjective and objective success rate of 85 to 90% (2). besides these excellent success rate, bleeding, transurethral resection syndrome, urinary tract infection, retrograde ejaculation and incontinence are the complications associated with the procedure (3). these complications have been estimated to develop in approximately 15% of the patients (4) and they may sometimes be of clinical relevance (5). contemporary turp uses a monopolar electrocautery system in which the current passes through the patient’s body: from the active electrode, placed on the resectoscope, towards the return plate, normally placed on the patient’s leg. this has several disadvantages such as heating of deeper tissue, nervous or muscle stimulation and possible malfunction of cardiac pace-maker (6). resectoscopes using bipolar electrocautery offer an alternative with active and return electrode placed on the same axis on the resectoscope using high current locally but with limited negative effects at distance. another risk of standard monopolar turp is the absorption of hypoosmolar irrigation fluid causing the tur syndrome. as bipolar resectoscopes use isotonic saline solution for irrigation, the risk of tur syndrome is eliminated. the first bipolar device for endourological procedures was the gyrus device using the bipolar electrocautery to electrovaporize the prostate (7). aim of this study was to evaluate efficacy and safety of plasmakinetic energy (gyrus electro surgical system), which produces vaporisation of tissue immersed in isotonic saline versus standard monopolar transurethral resection of the prostate. materials and methods from january 2002 to april 2002, 160 consecutive patients, with a mean age of 63.34 ± 7.1 years, who had luts of bph were enrolled in this study. out of them, 80 patients with a mean age of 62.5 ± 6.9 years were randomised to undergo bipolar turp (gyrus group) and 80 with a mean age of 64.18 ± 7.2 years to monopolar turp (traditional group). all surgical procedures were performed by the same surgeon who was fully trained in bipolar and monopolar turp. preoperative work-up included administration of ipss, iief-5 and qol questionnaires. all patients were submitted to uroflowmetry, transurethral ultrasound (trus), post-voidal residual urine measurement and psa determination. the patients provides informed written consent and were randomized to the traditional or gyrus group with a schedule balanced in blocks of 4. all patients were operated on within 4 weeks of randomization. exclusion criteria were patients with documented or suspected prostate cancer, bladder calculus, neurogenic bladder, previous prostate surgery, renal impairment, associated hydronephrosis and urethral stricture. the instruments (12° storz 24.5 f resectoscope) and the operative technique were the same of monopolar and bipolar turp. in the traditional group the monopolar turp was performed by a gyrus acmi generator, with a standard tungsten wire loop using a cutting current of 80 w and coagulating current of 160 w. in this group standard turp was carried-out using irrigation with a mannitol-sorbitol solution. in the bipolar group, turp was carried out using a gyrus plasmakinetic generator and saline irrigation that allowed electric current to complete the circuit without passing through the patient. the gyrus plasmakinetic system is a bipolar coaxial system with the active and return electrodes located in the same axis, separated by a ceramic insulator. we performed bipolar turp with a cutting current of 120 w and coagulating current of 80 w. at the end of the operation a 20 fr. dufour catheter was inserted and the bladder was continuously irrigated depending on the amount of postoperative bleeding. all tissue retrieved from each patient was investigated histologically. all patients were operated in peridural anesthesia. perioperative and postoperative outcomes were evaluated. in both groups operative time, resected tissue weight and perioperative complications were analysed. total postoperative catheter time, total post-operative hospital stay, haemoglobin loss were also recorded in the two groups. in both groups, ipss, iief-5 and qol scores, uroflowmetry and trus measurements of post-voidal residual urine, psa determinations and number of reoperations were evaluated at 1, 3, 6, 12, 18, 24, 30 and 36 months. the results were analysed with the use of descriptive statistic and with paired t test and chi-square test to compare the continuous variables and categorical data. significant differences were considered at p < 0.05. baseline characteristics, perioperative data and postoperative interim analyses of ipss symptom scores, peak urinary flow rates and residual volumes in the two groups were compared using the 2-sided mann-whitney test. perioperative and postoperative adverse events were compared with the 2tailed chi-square test (exact fisher’s test). results of 160 men 80 each were randomised to monopolar and bipolar turp. the patient population and their preoperative characteristics are shown in table 1. there was no statistically significant difference in any parameter between the two groups. the perioperative data are shown in table 2 and the postoperative data are shown in table 3. the resection time and the weight of resected prostate tissue were not significantly different in the two groups. histological examination of the retrieved tissue revealed bph and varying degrees of prostatitis. incidental carcinoma of the prostate was found in 7 (4.37%) patients (6 pt1a and 1 pt1b): 5 in the monopolar group and 2 in the bipolar group respectively. table 3 shows comparative data of ipss, iief-5 and qol, psa, peak urinary flow rates and post-void residual urine volumes in the two groups at 1, 3, 6, 12, 24, 30 and 36 months. compared to baseline there was an highly significant improvement for each parameter at all intervals in each group (p < 0.0001). on the contrary there was no signifgiulianelli ok_stesura seveso 24/06/13 11:05 pagina 87 archivio italiano di urologia e andrologia 2013; 85, 2 r. giulianelli, l. albanesi, f. attisani, b.c. gentile, g. vincenti, f. pisanti, t. shestani, l. mavilla, d. granata, m. schettini 88 pvr decreased to 97 ml. (sd ± 57.6, p < 0.05). at 3, 6 and 12 months, mean pvr was 81 ml (sd ± 17.6, p < 0,05), 22.5 (sd ± 15.6, p < 0,001) and 10 ml (sd ± 10, p < 0.001), respectively. the ipss in the bipolar group fell from 22.3 (sd ± 3.2) to 12.8 (sd ± 1.2) at 1 month, 5.3 (sd ± 1.4) at 3 months and 5.0 (sd ± 1.2) at 6 months respectively. there was also a significant modification of the qol score (baseline 3.3), which was 2.3 (p < 0.01) at 1 month, 1.1 (p < 0.001) at 6 months, and 0.9 (p < 0.001) at 12 months (figure 2). those results were stable in the following months. the mean preoperative haemoglobin fell from 14.88 mg/dl (sd ± 0.71) and 14.52 mg/dl (sd ± 0.71) in the monopolar and bipolar group to postoperative values of 10.4 (sd ± 1.2) and 13.6 (sd ± 0.6) respectively. the postoperative haemoglobin levels were lower in monopolar than bipolar group, and in the monopolar group 3 patients required transfusions. postoperative bladder irrigation was always stopped on the first postoperative day. median postoperative catheterization time and hospital stay time were 1 and 2 days in the bipolar group an 2 and 3 days in the monopolar group. nine patients in monopolar group and none in bipolar group were unable to void after initial removal of the catheter; they need to have the catheter reinserted and were discharged 2 days later. four patients in monopolar group and one in bipolar group developed clot retention within 3 weeks from surgery and in the monopolar group other two patients developed haematuria within 1 week from turp, all required readmission for cystoscopy and continuous bladder irrigation. in the monopolar group there were two cases of clinically evident tur syndrome and none in bipolar group. two patients in the monopolar group and fifteen in the bipolar group had postoperative irritative symptoms, which required occasional anticholinergic therapy. urinary tract infections developed in two patients in monopolar group and were treated with appropriate antibiotics. one year after turp 154 patients (75 in the monopolar and 79 in the bipolar group) were assessed for urinary continence and number of retreaments. none patient icant difference between the 2 groups for peak flow rate, improvement in ipps, iief-5 and qol score, psa modification and post-void residual urine volume at all postoperative follow-up evaluations. correlations between baseline and change from baseline showed that in each group improvement was more pronounced in patients with more severe preoperative symptoms and micturition impairment. in the bipolar group the qmax increased from 8.9 ml/sec (sd ± 2.9) preoperatively to 19.7 ml/sec (sd ± 5) after 1 month (p < 0.01). at 3, 6 and 12 months, qmax increased to 24.3 ml/sec (sd ± 3.2, p < 0.01), 25.2 ml/sec (sd ± 1.2, p < 0.001) and 26.7 (sd ± 2.2, p < 0.001), respectively (figure 1). in the same group, post-void residual urine volume (pvr) fell down substantially from the preoperative levels. the baseline value was 243 (sd ± 241.6); after removal of the catheter, the mean preoperative data bipolar turp monopolar turp age (years) 62.5 ± 6.9 64.18 ± 7.2 psa (ng/ml) 2.2 ± 0.5 2.8 ± 1.0 prostate volume (ml) 47.8 ± 14.6 50 ± 9.8 ipss 22.3 ± 3.2 23.4 ± 1.8 qol 3.3 ± 2.1 3.0 ± 2.5 qmax (ml/sec) 8.9 ± 2.9 6.5 ± 4.8 pvr 243 ± 241.6 187 ± 195 iief-5 16 ± 3.6 17 ± 2.5 hb 14.88 ± 0.71 14.52 ± 0.71 table 1. perioperative data bipolar turp monopolar turp resection time (min) 58 ± 14.6 59 ± 18 resected prostate tissue (gr) 30.6 ± 8.6 29.5 ± 7.8 hb (gr/dl) 13.6 ± 0.6 10.4 ± 1.2 time to catheterization (h) 24 ± 12 48 ± 48 hospital stay (h) 48 ± 6 72 ± 48 table 2. postoperative data bipolar turp monopolar turp follow-up (months) 1 3 6 12 18 24 30 36 1 3 6 12 18 24 30 36 ipss 12.8 5.3 5.0 4.5 4.2 3.0 3.0 2.0 8.8 7.8 7.0 5.3 5.0 4.8 4.8 4.0 qol 2.3 1.7 1.1 0.9 0.6 0.5 0.5 0.5 1.8 1.7 1.7 1.5 1.3 1.0 1.0 1.0 qmax 19.7 24.3 25.2 26.7 25.2 23.2 22.8 23.0 21.0 23.7 23.0 23.5 24.0 23.4 20.0 20.0 pvr 97 81 22.5 10 10 0 0 0 75 45 15 10 10 0 0 0 psa 0.55 0.90 0.95 0.90 0.9 0.9 0.60 0.90 1.00 1.00 1.15 1.50 iief-5 21 23 23 24 24 24 24 24 20 21 22 22 24 24 24 24 table 3. giulianelli ok_stesura seveso 24/06/13 11:05 pagina 88 89archivio italiano di urologia e andrologia 2013; 85, 2 comparative randomized study on the efficaciousness of endoscopic bipolar prostate resection versus monopolar resection technique until it was gradually replaced by transurethral resection of the prostate (turp). although turp is still regarded as the gold standard in patient with bph, it is associated with significant morbidity rates. neal et al. (8) reported a 10% morbidity rate in patients submitted to turp to remove obstruction. in our experience, the tissue ablation with the bipolar device was found to have similar clinical outcome compared to the standard procedure using a monopolar device, but with a significantly reduced bleeding rate. furthermore coagulation areas are found to be smaller when the bipolar resectoscope is used, due to the locally limited energy field between the electrodes of the resectoscope in which high power levels are achieved. this high energy field effectively coagulates bleeding vessels at the surface of the resected tissue. deeper tissue layers are less affected indicating that no energy is wasted to them and distant negative effects, such as deep tissue heating, nervous or muscle stimulation and interfering with cardiac pace-maker, are reduced. the rate of tissue ablation of bipolar resection was comparable to that achieved by a standard resection loop. in the current study we report the durable effect of bipolar turp. in our study the improvement in micturition and symptom scores were immediate and ipss, peak urinary flow rates and post-void residual urine volume returned to normal within 1 month postoperatively in each group. in the first postoperative month ipss, qol and qmax were better in the monopolar group than in the bipolar, but in all subsequent postoperative follow-up examinations were comparable in the 2 groups. at 3 years postoperatively, in the bipolar group, qmax increased significantly and post-void residual urine volume and psa declined. at 3 year follow up, improvement was significantly maintained for ipss, iief-5 and qol in both monopolar and bipolar group in comparison to baseline parameters (figure 3-5), but without statistically significant difference between 2 groups. many advantages of bipolar turp compared with monopolar are related to the haemostatic properties of the first device. intraoperative blood loss and postoperative bleeding were significantly decreased in bipolar group. no patients treated with bipolar turp required blood transfusion in contrast to three in the monopolar group. few investigations have been done on the histopathological changes and the depth of coagulation after bipolar and monopolar turp. huang et al. (9) compared the coagulation depth and specimen changes of figure 1. 3 year qmax improvement in monopolar and bipolar group. compared to baseline there was an highly significant improvement at all intervals in each group (p < 0.0001). figure 2. kaplan-meier curves, 3 year overall surgical re-treatment-free rate. preop 1 3 6 12 18 24 30 36 mo mo mo mo mo mo mo mo 0 2 4 6 8 10 12 36 mo mo mo mo mo mo mo had incontinence, whereas in total 12 patients (7.79%), 10 (6.49 %) and 2 (1.29%) in the monopolar and in the bipolar group respectively, required to be treated endoscopicallty for bladder neck contracture after 6 to 11 months postoperatively. after 24 and 36 months no more patients were submitted to retreatment. according to kaplan-meier plot, the 3-year overall surgical re-treatment-free rate was 92.5% (figure 2). discussion benign prostatic hyperplasia (bph) is a chronic agerelated condition, affecting approximately 50% of men older than 50 years, 75% of men older than 70 years and 90% of men older than 80 years (7). for many years open prostatectomy had been the primary treatment option in patients with benign prostatic hyperplasia giulianelli ok_stesura seveso 24/06/13 11:05 pagina 89 archivio italiano di urologia e andrologia 2013; 85, 2 r. giulianelli, l. albanesi, f. attisani, b.c. gentile, g. vincenti, f. pisanti, t. shestani, l. mavilla, d. granata, m. schettini 90 the prostate after bipolar and monopolar transurethral resection of the prostate in a canine model. the results of this study showed that the pathologic changes in the prostate after bipolar and monopolar turp are similar, but coagulation areas of bipolar turp are deeper and become thinner early after the operation than those the monopolar turp. botto et al. (10) found no significant intraoperative bleeding in 42 treated patients and eaton et al. (11) found that no patient required blood transfusion and no patients showed electrolyte disturbances intraoperatively. as a consequence of decreased bleeding in bipolar group, postoperative bladder irrigation, catheter time and hospital stay were significantly shorter than after monopolar turp. borboroglu et al. (12) recently reported a 0.4% transfusion rate, an average hospital stay of 1.1 days and an average catheter time of 1.4 days after turp. passavanti et al. (13) observed in 20 patients submitted to plasmakinetic resection the possibility to quickly stop continuous irrigation and to early remove the catheter. initially, in our experience with bipolar resection operative time was longer compared to standard turp, which could be due to the learning curve period. in both groups postvoidal residual urine (pvr) significantly decreased after treatment. pvr has traditionally been considered as an important parameter in the evaluation of patients with clinically evident bph. several guidelines on the management of bph consider pvr as a recommended (14) or optional (15) test in the clinical evaluation of patient with bph. another advantage of bipolar versus monopolar electrocautery lays in the use of 0.9% sodium chloride solution for irrigation. therefore the risk of tur syndrome, resulting from the absorption of large amounts of irrigation fluid during prolonged procedures, is theoretically reduced (16). dunsmuir et al. (17) report about a randomized prospective study comparing bipolar electro vaporization of the prostate with the gyrus device to the conventional turp. after one year follow-up symptom scores, qol, flow rates and post-voidal residual volumes were similar. they reported that re-catheterization was higher (30% vs 5%) in the bipolar vaporization group although the rate of postoperative clot evacuation was higher in the conventional turp group. in the bipolar group the 3-year surgical figure 5. a 3 years iief-5 improvement in monopolar and bipolar group. figure 4. a 3 years qol improvement in monopolar and bipolar group. compared to baseline there was highly significant improvement in each parameter at all intervals in each group (p < 0,0001), while there was no significant difference between the 2 groups in qol rates at any time. figure 3. 3 year ipss improvement in monopolar and bipolar group. compared to baseline there was an highly significant improvement at all intervals in each group (p < 0.0001), while there was no significant difference between the 2 groups in ipss score at any time. preop 3 12 24 36 mo mo mo mo preop 3 12 24 36 mo mo mo mo preop 3 12 24 36 mo mo mo mo giulianelli ok_stesura seveso 24/06/13 11:05 pagina 90 91archivio italiano di urologia e andrologia 2013; 85, 2 comparative randomized study on the efficaciousness of endoscopic bipolar prostate resection versus monopolar resection technique correspondence roberto giulianelli, md roberto.giulianelli@virgilio.it luca albanesi, md lucalbanesi@hotmail.com stefano brunori, md barbara cristina gentile, md giorgio vincenti, md stefano nardoni, md francesco pisanti, md teuta shestani, md luca mavilla, md francesco attisani, md gabriella mirabile, md manlio schettini, md division of urology villa tiberia clinic, rome, italy re-treatment-free rate was lower than in the monopolar (2 vs 10 patients). varkarakis e al (18) reported on long-term morbidity in 577 patients with a minimum follow-up of 10 years. the total re-intervention rate was 6%, including 2.4% who required reoperation for bladder neck contracture, 1.9% for recurrent bph obstruction, and 1.7% for urethral stricture. the annual rate of reoperation after minimal turp is 2.5% and the reoperation rate at 8 year follow-up is 23% after minimal resection and 7% after turp (11). conclusion the main advantages of bipolar turp is the use of saline as irrigation fluid, that eliminates the risk of trans urethral resection syndrome (tur syndrome) and the return current, reducing the risk of burns and the stimulation of nerves. in addition, the improved coupling of cut and coagulation may lead to less blood loss. bipolar turp has a comparable outcome to standard monopolar turp at short and medium term in term of subjective and objective outcome measures. its impact on bladder outlet function is also similar to that of monopolar turp. improvement in ipss, qol index, iief-5, qmax and post-void residual urine volume were comparable in both group denoting similar efficacy of the devices. furthermore, intraoperative blood loss, postoperative bleeding, time to catheterization, hospital-stay and the 3-year surgical re-treatment-free rate were significantly decreased with the use of the bipolar tool. references 1. keoghane sr, lawrence kc, gray am, et al. a double-blind randomized controlled trial and economic evaluation of transurethral resection vs contact laser vaporization for benign prostatic enlargement: a 3-year follow-up. bju int. 2000; 85:74-8. 2. down jb, cochett atk, peters pc et al. transurethral prostatectomy: practice aspects of the dominant operations in american urology. j urol. 1989; 141:248 3. mebust wk, holtgrewe hl, cochett atk, et al. transurethral prostatectomy: immediate and post-operative complications. a cooperative study of 13 institutions evaluating 3,885 patients. j urol. 1989; 141:243. 4. hahn rg, nilsson a, farahmand by, et al. blood haemoglobin and the long term incidence of acute myocardal infarction after transurethral resection of the prostate. eur urol. 1997; 31:199. 5. uchida t, ohori m, soh s, et al. factors influencing morbidity in patients undergoing transurethral resection of the prostate. urology. 1999; 53:98. 6. kellow nh. pacemaker failure during transurethral resection of the prostate. anaestesia. 1993; 48:136-8. 7. cabelin ma, te ae, kaplan sa. benign prostatic hyperplasia: challenges for the new millennium. curr opin urol. 2000; 10:301. 8. neal de. the national prostatectomy audit. br j urol. 1997; 79:69. 9. huang x, wang x-h, qu l-j, et al. bipolar versus monopolar transurethral resection of the prostate: pathologic study in canines. urology. 2007; 70:180-184. 10. botto h, lebret t, barre p, et al. electrovaporization of the prostate with the gyrus device. j endourol. 2001; 15:313-6. 11. eaton ac, francis rn. the provision of transurethral prostatectomy on a day-case basis using bipolar plasma kinetic technology. bju. 2002; 89:453-7. 12. borboroglu pg, krane cj, ward jf, et al. immediate and postoperative complications of transurethral prostatectomy in the 1990’s. j urol. 1999; 162:1307. 13. passavanti g, pizzuti v, bragaglia a, et al. the use of bipolar plasmakinetic resectoscope in endoscopic resection of the prostate: our experience. urologia. 2007; 74:160-163. 14. abrams p, griffiths d, hofner k, et al. the urodynamic assessment of lower urinary tract symptoms. in chatelain c, denis l, foo kt, et al. (eds.). benign prostatic hyperplasia. proceedings of the 5th international consultation on benign prostatic hyperplasia. paris, june 25-28, 2000. paris: health pubblication, ltd, 2001; 227-281. 15. aua, practice giudelines committee: aua guideline on management of benign prostatic hyperplasia (2003). chapter 1: diagnosis and treatment recommendations. j urol. 2003; 170:530. 16. aagaard j, jonler m, fuglsig s, et al. total transurethral resection versus minimal transurethral resection of the prostate-a 10years follow-up study of urinary symptoms, uroflowmetry and residual volume. br j urol. 2006; 50:563-8. 17. dunsmuir wd, mcfarlane jp, tan a, et al. gyrus bipolar electrovaporization vs transurethral resection of the prostate: a randomised prospective single-bind trial with a 1 year. follow up. prostate cancer prostatic dis. 2003; 6:182-6 18. varkarakis j, bartsch g, horninger w. long term morbidity and mortality of transurethral prostatectomy: a 10-year follow-up. prostate. 2004; 58:248-51. giulianelli ok_stesura seveso 24/06/13 11:05 pagina 91 stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 51 original paper inflammation is involved in carcinogenesis (1, 2). in the field of prostate diseases, recent studies have shown that patients with chronic inflammation of the prostate are at greater risk of more severe voiding symptoms, acute urinary retention and prostate surgery (3, 4). the gold standard for the diagnosis of tissue inflammation is represented by histological examination of tissue specimen. a biopsy cannot always be performed for both ethical and procedural issues (5). for this reason, in recent years, several studies attempted to identify a serological marker of inflammation for the various neoplastic and benign urological pathologies (6). however, most of the markers used at preclinical and in vitro levels have poor diagnostic specificity, significant variability over time or high costs. in recent years, several authors have shown how some laboratory tests (complete blood count/cbc, albumin, fibrinogen, c-protein reactive/pcr and procalcitonin/pct), that are routinely performed in preparation for various urological surgeries, can play a role in identifying patients at greatest risk of complications and adverse outcomes after surgery (7). in particular, these markers can be considered as proxies of inflammation of the organism and are related to an increased risk of mortality in numerous diseases. the role of these inflammation markers in urology is still unclear today and the scientific evidence comes mainly from retrospective studies (8). there is currently no consensus on the pharmacological management of inflammatory prostatic diseases in a unique way. nonsteroidal anti-inflammatory drugs (nsaids) are typically prescribed together with antibiotics without clear evidence. the use of herbal remedies is very common, but the clinical evidence remains scarce (9). above all, it remains unclear whether the use of such preparations can affect the reduction of the inflammatory state inferred on blood chemistry tests. the primary purpose of this multicenter study is to describe the variation in subjective, objective and biochemical inflammatory indexes in men affected by chronic abacterial prostatitis, treated with herbal extracts, containing curcuma longa 500 mg, boswellia 300 mg, urtica dioica 240 mg, pinus pinaster 200 mg and glycine max 70 mg, for each administration, as described in the manufacturer’s instructions (naturneed, macerata, italy). introduction: inflammation is a highly prevalent finding in the prostate. men with inflammation have higher ipss score and increased prostate size. for men with prostatic inflammation, there is a significantly increased risk of developing acute urinary retention and the need of a surgical approach to the disease. some laboratory tests (i.e. fibrinogen, c-reactive protein), can play a role in identifying patients at greatest risk of complications and adverse outcomes after surgery. there have been several experiences exploring the role of nutraceutical approach to the prostate inflammation. aim of our study were to describe the variation in symptoms and inflammatory indexes in men affected by chronic abacterial prostatitis, treated with an herbal extract containing curcuma longa 500 mg, boswellia 300 mg, urtica dioica 240 mg, pinus pinaster 200 mg and glycine max 70 mg. materials and methods: a prospective multicenter study was conducted from february 2021 and march 2022. one hundred patients, with a diagnosis of chronic prostatitis were enrolled in a multicentric phase iii observational study. they were treated with the herbal extract, one capsule per day, for 60 days. no placebo arm was included. in each patient, inflammatory indexes, psa, prostate volume, iief-5, puf, uroflowmetry (qmax), ipss-qol, nih-cpps were registered and statistically compared at baseline and at the follow up visit. results: the variation obtained on the inflammation indexes showed a global improvement after treatment, including the psa reduction. we also recorded a significant improvement on ipss-qol, nih-cpps, puf and qmax scores. conclusions: the herbal extract considered in our study may represent a promising and safe therapeutic agent leading to a reduction of inflammation markers, and could be used in the treatment of prostatitis and benign prostatic hyperplasia. key words: nutraceuticals; inflammation; inflammatory indexes; psa. submitted 1 may 2023; accepted 11 may 2023 introduction in recent years many authors highlighted the central role of inflammation in the pathogenesis of urological diseases. in particular, in patients with some neoplastic diseases, it has been shown that the presence of locoregional chronic variation of inflammatory indexes in patients with chronic abacterial prostatitis treated with an herbal compound/extract luca cindolo 1, andrea fabiani 2, daniele vitelli 1, filippo cianci 1, lorenzo gatti 1, nicola ghidini 1, nikolas niek ntep 1, rosario calarco piazza 1, alessandra filosa 3, giovanni ferrari 1 1 cure group, hesperia hospital, modena, italy; 2 urology unit, surgical dpt, ast macerata, macerata hospital, macerata, italy; 3 pathological anatomy, politechnic university of marche region, ancona, italy. doi: 10.4081/aiua.2023.11441 summary archivio italiano di urologia e andrologia 2023; 95, 2 l. cindolo, a. fabiani, d. vitelli, et al. 52 materials and methods from february 2021 and march 2022, all 100 consecutive patients, with prostatitis-like symptoms (10) attending each one of participating urologic centers, were enrolled in a multicentric phase iii observational study. the patients were treated with an herbal extract, containing curcuma longa 500 mg, boswellia 300 mg, urtica dioica 240 mg, pinus pinaster 200 mg and glycine max 70 mg (prostaflog®), taking one capsule at bedtime every 24h for 60 days. no placebo arm was included. the demographic characteristics were studied using descriptive analysis tables and the calculation on the sample size has not been determined because the sample will be a "convenience sample". inclusion criteria were: age more than 18 years, diagnosis of diagnosis of chronic abacterial prostatitis, any prostatic volume, qmax between 11 and 25, post voiding volume < 50 ml. exclusion criteria were patient under 18 years old, history of neurological or psychiatric disorders which may impair evaluation of urinary symptoms, patients with urethral stricture or history of bladder or prostatic cancer or concomitant bladder stones, previous pelvic radiation therapy, inability to assess urinary symptoms, chronic opioid or opioid derivatives (for any reason) or cortisone therapy, alpha blockers or 5-alpha-reductase therapies, phosphodiesterase-5 inhibitors (pde5i) or nsaids assumption during the study period, intolerance/allergies to the ingredients of the herbal extracts. after the diagnosis of chronic prostatitis, all patients who met the inclusion criteria signed a written informed consent and underwent baseline questionnaires: international prostatic symptoms score-quality of life (ipss-qol), national institutes of health chronic prostatitis symptom index (nih-cpsi), pelvic pain and urgency/frequency (puf) patient symptom scale, international index of erectile function-5 (iief-5) (11, 14). a urological examination using the expressed prostatic secrete (eps) culture or seminal fluid culture and a prostatic transrectal ultrasound (trus) were performed. uroflowmetry, cbc, inflammation indices (erythrocyte sedimentation rate/esr; pcr; prothrombin time/pt; partial thromboplastin time/ptt; fibrinogen; psa) were tested. the first follow-up visit was scheduled at 2 months from starting therapy, with a urological and microbiological examination, questionnaire collection, transrectal ultrasound (trus), treatment benefit scale (tbs) questionnaire compilation (15). the softwares used for statistical analyses were excel 2019, statplus pro 7.6.5 (med calc to confirm). mean, standard deviation, median, differences were calculated for the quantitative variables interquartile. the scores obtained in the responses to the ipss, nih cpsi, puf and iief 5 questionnaires were assimilated to variables quantitative, but ipss and iief 5 were also evaluated based on the frequency distribution for expected score ranges, which is perhaps a more correct way of considering them, since there is a division into interpretation classes. for the qol questionnaire, the frequency distributions recorded in the baseline versus follow up visit were evaluated, for the 5 scheduled answers. for tbs, the distribution of frequencies recorded in each of the 4 responses was equally evaluated as provided in the questionnaire. for each quantitative variable examined, the normality of the distribution of data was preliminarily evaluated, using shapiro wilk's test. in case of confirmed h0 and of normal distribution, parametric tests were used in the evaluation of the statistical significance of the differences between the different variables at baseline and after follow up (anova within subjects). in case of data non-normally distributed, the evaluation of the differences between the variables (baseline vs follow-up) was performed using nonparametric tests (wilcoxon signed rank test). the differences between the frequency distributions were evaluated by pearson's chi-square test. results one hundred patients were included in the study. the main characteristics were: mean age 52.1 ± 12.0 yeras, mean body mass index 25.5 ± 2.8. essential systemic arterial hypertension, dyslipidemia and diabetes mellitus occurred in 37%, 37% and 13%, respectively. the changes in baseline vs follow up clinical and biochemical variables were reported in table 1 and 2. these changes between visit 1 and visit 2 were significant for prostate volume, qmax and for all the questionnaires but the iief score variation which showed was not significant (table 1). the tbs score revealed an interesting improvetable 1. the clinical variables at baseline visit and follow-up. baseline follow-up variable mean ± sd median mean ± sd median baseline vs follow-up (p) prostate volume (ml) 35.58 ± 15.98 33.50 33.82 ± 15.64 30.00 < 0.001 uroflowmetry qmax (ml/s) 17.74 ± 5.40 17.00 19.00 ± 5.41 18.00 < 0.001 ipss 15.94 ± 5.01 17.5 13.78 ± 4.89 14.00 < 0.001 qol 2.60 ± 0.89 3.00 2.16 ± 0.94 2.00 0.003 nih cpsi 17.34 ± 5.43 18.00 14.56 ± 5.83 14.00 < 0.001 puf 12.77 ± 4.36 15.00 10.74 ± 4.8 10.00 < 0.001 iief 5 18 ± 4 19 18 ± 4 19 0.909 table 2. variation of inflammation indices. baseline follow-up variable mean ± sd median mean ± sd median baseline vs follow-up (p) wbc (10^3/ml) 6.36 ± 1.76 6.17 6.02 ± 1.30 5.80 0.0039 lymphocyte count (10^3/ml) 2.08 ± 0.55 2.05 1.96 ± 0.53 1.95 < 0.001 neutrophil count (10^3/ml) 3.97 ± 1.25 3.86 3.64 ± 0.90 3.60 < 0.001 esr (mm/h) 7.76 ± 7.99 6.00 5.98 ± 5.40 5.00 < 0.001 crp 2.40 ± 2.92 0.80 2.22 ± 2.90 0.50 < 0.001 fibrinogen (mg/dl) 261.33 ± 57.28 246.00 250.56 ± 57.27 230.00 < 0.001 total serum psa (ng/ml) 3.57 ± 3.70 2.80 2.37 ± 1.73 2.20 < 0.001 archivio italiano di urologia e andrologia 2023; 95, 2 53 herbal compound/extract in chronic abacterial prostatitis ment of perceived clinical status. at follow up visit, the patients declared an improvement (great also) in 76% of cases. no changes were declared in 22% and a worsened situation only in 2% (figure 1). for the iief-5 questionnaire the differences are not significant both if we evaluate the scores or if we consider it a quantitative variable dividing the patients into categories based on the score intervals (figure 2a, b). the variation obtained on the biochemical inflammation indexes was reported in table 2, showing a global improvement of all parameters at follow-up visit, including a significant reduction in psa as proxy of inflammatory status. discussion inflammation is a highly prevalent finding in the prostate, both at histological and biochemical level. men with inflammation have higher ipss scores and increased prostate size, even if these differences appear to be imperceptibly small. for men with prostatic inflammation, there is a significantly increased risk of developing acute urinary retention and the need of a surgical approach to the disease (4). in recent years, several authors have shown how some laboratory tests (cbc, albumin, esr, fibrinogen, pcr) that are routinely performed in preparation for various urological surgeries can play a role in identifying patients at greatest risk of complications and adverse outcomes after surgery (6). the effects of systemic inflammatory conditions, most notably metabolic syndrome, and their role in lower urinary tract symptoms (luts) have also been examined. when the data are examined at a clinically relevant level, we must take into high consideration that inflammation is a common process in the prostate and that the clinically significant impact of ingland inflammation is variable and difficult to define. for a long time, we know that the location of inflammation is important and that there are subsets of inflammation that are more frequently associated with the development of urinary symptoms or the prostate growth (16). in recent years, there was several experiences exploring the role of nutraceutical approach to the prostate inflammation. in particular, cai and co-workers (17) evaluated the efficacy of a combination of soyabean extracts associated with curcuma longa, boswellia, pinus pinaster and urtica dioica (prostaflog®) in patients affected by cp/cpps, through the evaluation of interleukin-8 (il-8) plasma seminal levels. all patients diagnosed with cp/cpps, attending the same urologic center, were enrolled in this randomized, controlled phase iii study. participants were randomized to receive oral capsules of prostaflog® (two capsules at bedtime every 24 h) or ibuprofen 600 mg (1 tablet daily), lasting for a period of four weeks. nihcpsi and sf-36 questionnaires in association with urological evaluations with trus, meares-stamey test, and il-8 dosage in seminal plasma were performed at baseline and at 3 months follow-up. a total of 77 patients were enrolled [prostaflog® (n = 39); ibuprofen (n = 38)] in the study and followed for 3 months. in the prostaflog® series, 69.2% of patients showed a significant reduction in the nih-cpsi score, compared with 34.2% in the ibuprofen group (p < 0.0001). the mean il8 levels were significantly lower in the prostaflog® figure 1. treatment benefit scale (tbs) after therapy. figure 2a, b. no improvement of iief score after therapy. a. b. archivio italiano di urologia e andrologia 2023; 95, 2 l. cindolo, a. fabiani, d. vitelli, et al. 54 cohort compared with the ibuprofen series (p < 0.0001), while a significant reduction in the il-8 level between the enrollment and last follow-up evaluation was also observed in this group (p < 0.0001). additionally, a significant reduction in the volume of the seminal vesicles assessed by trus was also found in the prostaflog® series during the observational timeframe. the authors concluded that prostaflog® significantly improves the qol in patients affected by cp/cpps and provides a significant reduction in il-8 seminal levels as the overall seminal vesicles volume. in our present study, the same observation in terms of qol improvement was made (figure 3). especially in case of moderate qol alteration, patients declared a positive impact from therapy on symptoms. these data are confirmed at the follow up evaluation with tbs questionnaire. the 20% of population studied reported a great improvement after treatment. the rate moves to 76% considering improvement to any extent. the statistically significant amelioration recorded at the follow-up visit after two months of therapy in ipss, nih cpps and puf scores (figures 4a-b, 5, 6) confirms how the control of prostatic inflammation is correlated closely with a better perception of urinary symptoms characteristic of chronic prostatitis. the iief-5 scores registered before treatment did not improve. this finding could be related to the markedly multifactorial nature of the etiology of erectile dysfunction (ed). given the age of the patients figure 3. qol improvement after therapy. figure 4a, b. ipss global score improvement at follow up visit, but not in cases with severe basal symptoms. figure 5. nih-cpsi score improvement at follow up visit. a. b. archivio italiano di urologia e andrologia 2023; 95, 2 55 herbal compound/extract in chronic abacterial prostatitis enrolled and the presence of known risk factors for ed, such as systemic hypertension and diabetes mellitus, the lack of improvement after treatment is not surprising as the therapy is aimed at the management of the prostatic inflammatory process which is only one of the possible causative factors of ed. considering inflammation indicators, we preferred to investigate laboratory tests more accessible in daily clinical practice than seminal il-8 levels. the routinely determined markers of inflammation showed a statistically significative improvement between the first visit and the visit performed at the follow-up. this clearly depends on prostatic inflammation etiology and confirm the anti-inflammatory role of the nutraceutical product. the first experience with prostaflog® was by fabiani et al. (18). they described their real-life experience with this anti-inflammatory mixture on psa levels and, in a prospective mono-institutional study of 50 patients, admitted for a first psa raising, reported a lowered psa value in 80% of cases, with a mean of reduction of 2.94 ng/ml (0.26-16.2 ng/ml) in one month therapy (two pill per day). no differences were reported in term of prostate volume variation. they concluded that prostaflog® use was able to lower the value of psa, inviting to evaluate in appropriate studies the nutraceuticals products use in the treatment of prostatic pathology. in our present experience, we can confirm the lowering effect on psa value by the prostaflog® administration. after 60 days of treatment, with one pill per day, we observed, at followup visit, a mean psa levels of 2.74 ng/ml, starting from a 4.63 ng/ml mean value (figure 7). moreover, in our results, we reported a statistically significant reduction on prostate volume (38.01 ml vs 35.86 ml), presumably linked to the anti-inflammatory effect of prolonged administration (figure 8). from a functional point of view, we found a significant improvement on flow parameters (figure 9). the qmax registered at the enrollment visit was significantly increased after prostaflog® treatment. this is evidently the effect induced by the reduction of the static and dynamic factors which underlie the typical symptoms of bph (9). conclusions prostaflog® treatment employed in case of chronic prostatitis may significantly increase qol, providing a significant improvement of symptomatic scores. a critical reduction in psa level may be eventually take into account in clinical decision making. prostaflog® may represent a promising and safe therapeutic agent leading to a reduction of inflammation markers, able to interrupt the pathophysiological mechanism of benign prostatic hyperplasia. references 1. lloyd gl, marks jm, ricke wa. benign prostatic hyperplasia and lower urinary tract symptoms: what is the role and significance of inflammation? curr urol rep. 2019; 20:54. 2. vasavada sr, dobbs rw, kajdacsy-balla aa, et al. inflammation on prostate needle biopsy is associated with lower prostate cancer risk: a meta-analysis. j urol. 2018; 199:1174-1181. figure 7. decreased psa level from baseline after 2 months of treatment. figure 8. prostate volume decrease after therapy. figure 9. qmax improvement at follow up visit. figure 6. puf score improvement after therapy. archivio italiano di urologia e andrologia 2023; 95, 2 l. cindolo, a. fabiani, d. vitelli, et al. 56 3. de nunzio c, voglino o, cicione a, et al. ultrasound prostate parameters as predictors of successful trial without catheter after acute urinary retention in patients ongoing medical treatment for benign prostatic hyperplasia: a prospective multicenter study. minerva urol nephrol. 2021; 73:625-630. 4. gandaglia g, briganti a, gontero p, et al. the role of chronic prostatic inflammation in the pathogenesis and progression of benign prostatic hyperplasia (bph). bju int. 2013; 112:432-41. 5. vela-navarrete r, alcaraz a, rodríguez-antolín a, et al. efficacy and safety of a hexanic extract of serenoa repens (permixon®) for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia (luts/bph): systematic review and metaanalysis of randomised controlled trials and observational studies. bju int. 2018; 122:1049-1065. 6. wang q, zhu sr, huang xp, et al. prognostic value of systemic immune-inflammation index in patients with urinary system cancers: a meta-analysis. eur rev med pharmacol sci. 2021; 25:1302-1310. 7. alazawi w, pirmadjid n, lahiri r, bhattacharya s. inflammatory and immune responses to surgery and their clinical impact. ann surg. 2016; 264:73-80. 8. paulis g. inflammatory mechanisms and oxidative stress in prostatitis: the possible role of antioxidant therapy. res rep urol. 2018; 10:75-87. 9. cicero afg, allkanjari o, busetto gm, et al. nutraceutical treatment and prevention of benign prostatic hyperplasia and prostate cancer. arch ital urol androl. 2019; 91. 10. krieger jn, nyberg l jr, nickel jc. nih consensus definition and classification of prostatitis. jama. 1999 jul; 282:236-7. 11. hopland-nechita fv, andersen jr, beisland c. ipss "bother question" score predicts health-related quality of life better than total ipss score. world j urol. 2022; 40:765-772. 12. giubilei g, mondaini n, crisci a, et al. the italian version of the national institutes of health chronic prostatitis symptom index. eur urol. 2005; 47:805-11. 13. brewer me, white wm, klein fa, et al. validity of pelvic pain, urgency, and frequency questionnaire in patients with interstitial cystitis/painful bladder syndrome. urology. 2007; 70:646-9. 14. rosen rc, cappelleri jc, smith md, et al. development and evaluation of an abridged, 5-item version of the international index of erectile function (iief-5) as a diagnostic tool for erectile dysfunction. int j impot res. 199; 11:319-26. 15. viktrup l, hayes rp, wang p, shen w. construct validation of patient global impression of severity (pgi-s) and improvement (pgii) questionnaires in the treatment of men with lower urinary tract symptoms secondary to benign prostatic hyperplasia. bmc urol. 2012; 12:30. 16. kohnen pw, drach gw. patterns of inflammation in prostatic hyperplasia: a histologic and bacteriologic study. j urol. 1979; 121:755-60. 17. cai t, anceschi u, tamanini i, et al. soybean extracts (glycine max) with curcuma, boswellia, pinus and urtica are able to improve quality of life in patients affected by cp/cpps: is the proinflammatory cytokine il-8 level decreasing the physiopathological link? uro 2022; 2:40-48. https://doi.org/10.3390/ uro2010006 18. fabiani a, morosetti c, filosa a, et al. effect on prostatic specific antigen by a short time treatment with a curcuma extract: a real life experience and implications for prostate biopsy. arch ital urol androl. 2018; 90:107-111. correspondence luca cindolo, md, phd lucacindolo@virgilio.it daniele vitelli, md doc.vitelli@gmail.com filippo cianci, md filippocianci3p@hotmail.com lorenzo gatti, md dottor102@gmail.com nicola ghidini, md info@nicolaghidini.it nikolas niek ntep, md nicolas22it@yahoo.fr rosario calarco piazza, md iaiiopiazza@gmail.com giovanni ferrari, md giogioferrari@yahoo.it cure group, hesperia hospital, modena, italy andrea fabiani, md (corresponding author) andreadoc1@libero.it surgery dpt, section of urology asur marche area vasta 3, macerata hospital, italy via santa lucia, 2; 62100 macerata (italy) alessandra filosa, md phd alessandrafilosa@yahoo.it pathology unit, asur marche area vasta 5, ascoli piceno (italy) conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11533 1 original paper introduction although uncommon, primary sarcoma of the urinary bladder (sub) is an aggressive type of bladder cancer (bca), accounting for less than 1% of all bca. the most common risk factors for the development of this disease is smoking and previous exposure to radiotherapy (rt) and cyclophosphamide (1, 2). based on mesenchymal and epithelial components, sub can be classified as sarcomatoid carcinoma (sc) and carcinosarcoma (cs), both considered malignant biphasic tumors (mbt) by the world health organization having malignant epithelial and mesenchymal elements (3). more recently researchers have cast doubts on the significance of distinguishing between these two entities in both bladder and other solid malignancy as they consider these two histological subtypes as separate moments between epithelial (sarcomatoid carcinoma) and mesenchymal differentiation (carcinosarcoma) (4). usually, the epithelial element contains high-grade transitional-cell carcinoma with some epidermoid and/or glandular differentiation, while the heterologous element contains chondrosarcoma, malignant fibrous histiocytoma, osteosarcoma, leiomyosarcoma, fibrosarcoma, or rhabdomyosarcoma. both sc and cs cases are most common among older men, manifesting as fastgrowing, advanced-stage polypoid tumors (1-4). when the mesenchymal element lacks epithelial components, sub can be considered a true heterologous sarcoma (ts). usually, treatment of sub has been deduced from the management of urothelial carcinoma (uc) of the bladder. muscle-invasive uc of the bladder often results in distant metastasis after radical cystectomy, and therefore, neoadjuvant or adjuvant chemotherapy has been recommended as a part of a multimodal approach (5, 6). however, because of to the rarity of sub and the absence of randomized controlled trial in this setting, definitive conclusions about the optimal treatment option cannot be made. poor outcomes have been reported in patients with sub, whatever the treatment used. even after adjustpurpose or objective: primary sarcoma of the urinary bladder (sub) is a rare but aggressive form of bladder cancer (bca). available evidence on sub is limited to case reports and small series. the aim of the present multi-institutional study was to assess the clinical features, treatments, and outcomes of patients with sub. materials and methods: using a standardized database, 7 institutions retrospectively collected the demographics, risk factors, clinical presentation, treatment modalities and follow-up data on patients with sub between january 1994 and september 2021. the main inclusion criteria included bca with soft tissue tumor histology and sarcomatoid differentiation. results: fifty-three patients (38 men and 15 women) were identified. median follow-up was 18 months (range 1-263 months). median age at presentation was 69 years (range 16-89 years). twenty-six percent of patients had a prior history of pelvic radiotherapy (rt), and 37% were previous smokers. the main presenting symptoms at diagnosis were hematuria (52%), pelvic pain (27%), and both hematuria and pelvic pain (10%). american joint committee on cancer (ajcc) 8 th edition stage ii, iii and iv at diagnosis were 21%, 63% and 16%, respectively. treatment modalities included surgery alone (45%), surgery plus neoor adjuvant-chemotherapy (17%), surgery plus neoor adjuvant-rt (11%), rt with concurrent chemotherapy (4%), neo-adjuvant chemotherapy plus surgery plus adjuvant rt (2%) and palliative treatment (21%). rates of local and distant recurrences were 49% and 37%, respectively. five-year overall survival and progression-free survival (pfs) were 66.5% and 37.6%, respectively. no statistically significant differences in pfs between the treatment modalities were observed. conclusions: primary sub is a heterogeneous disease group, commonly presenting at advanced stages and exhibiting aggressive disease evolution. in contrast to urothelial carcinoma, the primary pattern of recurrence of sub is local, suggesting the need for multimodal approaches. continuous international collaborative efforts seem warranted to provide guidance on how to best tailor treatments based on sub-specific indices. key words: primary sarcoma of the urinary bladder (sub); bladder cancer. submitted 19 june 2023; accepted 1 july 2023 primary bladder sarcoma: a multi-institutional experience from the rare cancer network piero bettoli 1, 2, zhihuiamy liu 3, natalia jara 4, federico bakal 1, william wong 5, mario terlizzi 6, paul sargos 6, thomas zilli 7, juliette thariat 8, sebastian sole 4, 9, guillaume ploussard 10, sharad goyal 11, peter chung 3, alejandro berlin 3, claudio v. sole 4, 9 1 department of radiation oncology, fundación arturo lópez pérez, santiago, chile; 2 facultad de medicina, universidad de los andes, santiago, chile; 3 radiation medicine program, princess margaret cancer centre, university health network, university of toronto, toronto, on, canada; 4 department of radiation oncology, instituto de radiomedicina, santiago, chile; 5 department of radiation oncology, mayo clinic arizona, phoenix, usa; 6 department of radiation oncology, institute bergonie, bordeaux, france; 7 department of radiation oncology, geneva university hospital, geneva, switzerland; 8 department of radiation therapy, centre francoise baclese, caen, france; 9 facultad de medicina, universidad diego portales, santiago, chile; 10 department of urology, la croix du sud hospital, toulouse, france; 11 department of radiation oncology, george washington university hospital, washington dc, usa. doi: 10.4081/aiua.2023.11533 summary archivio italiano di urologia e andrologia 2023; 95(3):11533 p. bettoli, z. liu, n. jara, et al. 2 ing for tumor stage, overall survival (os) rates for sub vs high-grade, pure uc are 54% vs 77% at 1 year and 37% vs 47% at 5 years, respectively (4, 7). published data on sub only consist of case reports and limited case series. not much is understood of sub biology and behavior and its rarity does not permit to design specific treatment guidelines. thus, we intend to summarize the current multi-institutional knowledge of sub and present an overview of the epidemiology, clinical features, and management of this uncommon type of bca that can help clinicians to better tailor clinical decisions on this rare disease. methods data on sub from january 1994 to september 2021 from 7 institutions were retrospectively collected. international review board (irb) approval based on each country/institution was obtained for retrospective review of data. we only collected data from localized primary bladder tumors with soft tissue tumor histology, including sc, cs and ts. the data obtained included age, gender, country and institution, symptoms at the time of diagnosis, risk factors (smoking and rt exposure), tumor size, tumor location, margins and nodal status. sarcoma subtype, grade and specific immuno-histochemical markers of these tumors were noted. staging at the time of pathological diagnosis was based on the tnm (tumor, lymph node, metastasis) classification for genitourinary tumors. treatment modalities analyzed included cystectomy (radical, partial, other), rt (definitive, adjuvant, neo-adjuvant or palliative) and chemotherapy (neo-adjuvant, adjuvant, radio-sensitizer or palliative). overall survival (os), cancer-specific survival (css), disease-free survival (dfs), distant metastases (dm) and local control (lc) were calculated from diagnosis to the date of any specific event or the date of last follow-up in case an event did not occur. probabilities for os, css and dfs were determined by kaplan-meier estimates. local recurrence (lr) and dm were estimated using cumulative incidence function considering death as a competing risk. selective comparisons of survival curves were calculated by the log-rank test. multivariate models were not used because of the small number of patients and events. for statistical analyses the software program stata (version 13; college station, texas, usa) was used. results fifty-three patients were evaluated, 38 men (72%) and 15 women (28%), who had a median age at presentation of 69 years (range 16-89 years). twenty-six percent of patients had a prior history of pelvic rt; contrary to patients with transitional cell carcinoma, only 37% of patients had a history of tobacco use. symptoms at diagnosis were mainly hematuria (52%), pelvic pain (27%), and both hematuria and pelvic pain (10%). median tumor size was 4.5 cm (range 1.5-9.5 cm). extravesical spread (t3/t4) was the most common presentation of the primary tumor in 59% of cases. nodal metastases were identified in 35% of patients. ajcc 8th edition stage ii, iii and iv at diagnosis were 21%, 63% and 16%, respectively. the majority of tumors presented with high grade histology (88%). distribution of ts and mbt were 43% and 57%, respectively. leiomyosarcoma was the most common histology in the ts group (63%), followed by angiosarcoma (13%), pleomorphic undifferentiated sarcoma (10%), rhabdomyosarcoma (7%), chondrosarcoma of soft tissue (3%) and leiomyoma (3%). table 1 presents patient and tumor characteristics. seventy-three percent of patients underwent radical or partial cystectomy. specifically, treatment modalities included surgery alone (45%), surgery preceded or followed by either chemotherapy (17%) or radiotherapy (11%), definitive radiotherapy with concurrent chemotherapy (4%), neo-adjuvant chemotherapy plus surgery plus adjuvant radiotherapy (2%) and palliative treatment (21%). treatment modalities are outlined in table 2. table 1. patient and tumor characteristics. patients characteristics n (%) age mean 69 gender male 38 (72) female 15 (28) prior history of rt 14 (26) tobacco exposure 20 (37) symptoms hematuria 28 (52) pelvic pain 14 (27) both 5 (10) other 6 (11) tumor size (median) 4.5 cm (1.5 -9.5) t stage t1/t2 22 (41) t3/t4 31 (59) nodal metastases 19 (35) ajcc ii 11 (21) iii 33 (63) iv 9 (16) malignant biphasic tumors (mbt) 23 (43) true sarcoma (ts) 31 (57) leiomyosarcoma 19 (61) angiosarcoma 7 (22) pleomorphic undifferentiated sarcoma 2 (7) rhabdomyosarcoma 2 (7) chondrosarcoma 1 (3) table 2. treatment modalities. treatment modalities n (%) surgery alone 24 (45) surgery plus neo-adjuvant or adjuvant chemotherapy 9 (17) surgery plus neo-adjuvant or adjuvant radiotherapy 6 (11) definitive radiotherapy with concurrent chemotherapy 2 (4) neo-adjuvant chemotherapy plus surgery plus adjuvant radiotherapy 1 (2) palliative 11 (21) archivio italiano di urologia e andrologia 2023; 95(3):11533 3 primary bladder sarcoma median follow-up was 18 months (range 1-263 months). local recurrence (lr) occurred in 49% of patients and distant metastases (dm) were present in 37%. five-year os and pfs were 66.5% and 37.6%, respectively. kaplanmeier curves for os and pfs and the cumulative incidence for lr and dm are shown in figures 1, 2, 3 and 4 respectively. when outcomes in subgroups were examined, a more advanced tumor stage (t2 vs t3/t4) correlated to shorter pfs (median pfs for t2-category was not reached and for t3/t4 was 8.4 months; p = 0.059). prior history of pelvic radiotherapy also related to lower pfs (7 vs 31 months, p = 0.0018) and os (9 vs 43 months, p = 0.0007). we found no statistically significant differences in pfs between treatment modalities or between the presence vs absence of epithelial components (ts and mbt). discussion although the occurrence of rare cancers in the general public is a serious health issue as a whole, acquiring statistically-reliable clinical trial data is difficult due to the low number of patients with an individual rare cancer type within specific areas (8). since most available literature on rare cancers is published as single-institution case reports, it is arduous to draw prognostic implications from these data; furthermore the impact of local practices on treatment outcomes is amplified when dealing with rare diseases. patients with rare neoplasm show significantly poorer results than patients with more common malignancies; mean 5-year survival for the former is up to 20% lower than for the latter (9). this is the case with primary sub, a disease comprising less than 1% of all bca, which poses a challenge in the treatment of this uncommon histological variant. poor outcomes have been reported in patients with sub, whatever the treatment used. the five-year overall survival (os) rate of the present cohort is 66.5%, which exceeds the findings of previous studies where survival rates at five years were consistently below 50% (4, 10, 11). this difference in outcomes can be attributed, at least partially, to two key factors within the study. firstly, this cohort predominantly consisted of a younger population, with a median age at presentation of 69 years, which is lower than other reports (4). younger patients have generally been associated with better treatment tolerance, higher overall fitness levels, and potentially more favorable disease characteristics, all of which could contribute to improved survival rates. secondly, the analysis encompassed both malignant biphasic tumors (cs and sc) and true heterologous sarcomas (ts). by including both types of tumors, we accounted for the inherent biological diverfigure 1. os 5-year rate 66.5% (53.3-83) figure 2. pfs 5-year rate: 37.6% (25.8-54.7). figure 3. lr 5-year rate: 49% (34-64). figure 4. dm 5-year rate: 36.9% (21.4-52.4). archivio italiano di urologia e andrologia 2023; 95(3):11533 p. bettoli, z. liu, n. jara, et al. 4 sity, variable clinical behavior of both entities and perhaps different outcomes. twenty-six percent of the patients of the cohort have a previous history of pelvic radiation therapy (rt), observing inferior outcomes in this subgroup compared to those without prior rt (median os of 9 vs. 43 months, p = 0.0007). is well known that radiation-induced sarcomas pose treatment challenges as they arise in areas with complications from previous treatments, making surgical removal difficult. retrospective analyses have shown poor prognosis in these patients compared to sporadic soft-tissue sarcomas, with 5-year os rates ranging between 32% and 45% (12) which are in line with the findings of this study. continuing with subgroup analyses, patients with extravesical spread (t3/t4) exhibit notable decreases in progression-free survival (pfs) compare to those with less advanced tumors (median pfs for t2-category was not reached and for t3/t4 was 8.4 months). the reduced pfs observed in this particular subgroup of patients (t3/t4) can be attributed to the higher likelihood of developing distant metastases, but also because of the complex relationship between advanced tumor stage and critical anatomical structures, resulting in a potentially decreased effectiveness of local treatment. data from pelvic sarcomas exemplify this last phenomenon, with successful attainment of a microscopically margin-negative resection (r0) surgery achieved only in 70% of cases (13). contrary to uc, where distant recurrence is the primary pattern, this study reveals that rates of local and distant recurrences observed were 49% and 37%, respectively. these findings hold significant implications, particularly considering that approximately 60% of patients in this cohort exhibit extra-vesical spread (t3/t4). the high rates of local failures observed emphasize the critical need for optimizing local therapies, particularly within the latter sub-group. typically, the treatment approach for sub has been extrapolated from the management of uc of the bladder, where cystectomy and chemotherapy are considered fundamental in a multimodality approach (5, 6). retroperitoneal sarcomas (rps) exhibit a behavioral pattern that aligns more closely with the presents findings, showing a higher incidence of local recurrence, which remains the primary cause of mortality (14). within this context, local recurrence and metastatic disease occur in approximately 50-60% and 20% of cases, respectively (15), mirroring the failure pattern observed in this study. the importance of local control drives management of rps, with surgery been the mainstay of curative intent therapy (16). complete gross resection (r0 or r1) has been associated with improved disease-free survival (17). however, even with a histologically negative margin (r0), local recurrence can still occur (18). considering the high incidence of local recurrences following surgery, neoadjuvant radiotherapy has emerged as an attractive yet controversial option for rps (19, 20). despite the retrospective nature of this study, and therefore hampered by its intrinsic biases, the high local failure rates seen in this cohort prompts the hypothesis that neoadjuvant radiotherapy as part of a multi-disciplinary approach for sub may play an important role in reducing loco-regional failure rate and improving, at least to some extent, the survival of this patients, especially in higher tumor stages (t3/t4) where r0 surgery with wide margins is more difficult to obtain and were poorer outcomes we have observed. although the existing evidence is limited, our retrospective data can provide valuable insights into this uncommon neoplasm, enabling clinicians to make more informed clinical decisions tailored to this rare disease. conclusions primary sub is a heterogeneous disease group, commonly presenting at advanced stages and exhibiting aggressive disease evolution. in contrast to uc, the primary pattern of recurrence of sub is local, suggesting the need for multimodal approaches. continuous international collaborative efforts seem warranted to provide guidance on how to best tailor treatments based on sub-specific indices. references 1. lopez-beltran a, pacelli a, rothenberg hj. carcinosarcoma and sarcomatoid carcinoma of the bladder: clinicopathological study of 41 cases. j urol. 1998; 159:1497-1503. 2. mukhopadhyay s, shrimpton ae, jones la. carcinosarcoma of the urinary bladder following cyclophosphamide therapy: evidence for monoclonal origin and chromosome 9p allelic loss. arch pathol lab med. 2004; 128:e8-e11. 3. wick mr, swanson pe. carcinosarcomas: current perspectives and an historical review of nosological concepts. semin diagn pathol. 1993; 10:118. 4. wright jl, black pc, brown ga, et al. differences in survival among patients with sarcomatoid carcinoma, carcinosarcoma, and urothelial carcinoma of the bladder. j urol. 2007; 178:2302-2307. 5. eau (european association of urology). guidelines on muscleinvasive and metastatic bladder cancer. 2021 edition. available at: https://uroweb.org/guideline/bladder-cancer-muscle-invasive-andmetastatic/. 6. nccn (national comprehensive cancer network). bladder cancer. nccn clinical practice guidelines in oncology. available at: https://www.nccn.org/professionals/physician_gls/default.aspx#bladder. 7. lobo n, et al. what is the significance of variant histology in urothelial carcinoma? eur urol focus. 2020 jul 15; 6:653-663. 8. blay jy, coindre jm, ducimetière f, ray-coquard i. rare cancers: the value of research collaborations and consortia in rare cancers. lancet oncol. 2016; 17:e62. 9. desantis ce, kramer jl, jemal a. the burden of rare cancers in the united states. ca cancer j clin. 2017; 67:261-72. 10. zieschang h, koch r, wirth m, froehner m. leiomyosarcoma of the urinary bladder in adult patients: a systematic review of the literature and meta-analysis. urolint. 2019; 102:96-101. 11. li s. development and validation of a prognostic nomogram for predicting overall survival in patients with primary bladder sarcoma: a seer-based retrospective study. bmc urol. 2021; 21:162. 12. callesen lb, et al. radiation-induced sarcoma: a retrospective population-based study over 34 years in a single institution. clin oncol. 2021; 33:e232-e238. 13. lee js. management of pelvic sarcoma. eur j surg oncol. 2022; 48:2299-2307. archivio italiano di urologia e andrologia 2023; 95(3):11533 5 primary bladder sarcoma 14. brennan mf, antonescu cr, moraco n, singer s. lessons learned from the study of 10,000 patients with soft tissue sarcoma. ann surg. 2014; 260:416-21. 15. chouliaras k, senehi r, ethun cg, et al. recurrence patterns after resection of retroperitoneal sarcomas: an eight-institution study from the us sarcoma collaborative. j surg oncol. 2019; 120:340-7. 16. trans-atlantic rpswg. management of primary retroperitoneal sarcoma (rps) in the adult: a consensus approach from the transatlantic rps working group. ann surg oncol. 2015; 22:256-63. 17. singer s, antonescu cr, riedel e, brennan mf. histologic subtype and margin of resection predict pattern of recurrence and survival for retroperitoneal liposarcoma. ann surg. 2003; 238:358-70, discussion 370-351. 18. stojadinovic a, leung dh, hoos a, jaques dp, lewis jj, brennan mf. analysis of the prognostic significance of microscopic margins in 2,084 localized primary adult soft tissue sarcomas. ann surg. 2002; 235:424-34. 19. molina g, hull ma, chen yl, et al. preoperative radiation therapy combined with radical surgical resection is associated with a lower rate of local recurrence when treating unifocal, primary retroperitoneal liposarcoma. j surg oncol. 2016; 114:814-20. 20. bonvalot s, gronchi a, le pechoux c, et al. preoperative radiotherapy plus surgery versus surgery alone for patients with primary retroperitoneal sarcoma (eortc-62092: strass): a multicentre, open-label, randomised, phase 3 trial. lancet oncol 2020; 21:1366-77. conference presentation bettoli p, liu za, jara n, et al. primary bladder sarcoma: a multi-institutional experience from the rare cancer network presentation number: po-1219: european society for radiotherapy and oncology (estro) congress; july 31 9facultad de medicina, universidad diego portales, santiago, chile. august 04, 2020; vienna, austria. correspondence piero bettoli, md (corresponding author) piero.bettoli@falp.org postal address 7591067 federico bakal, md federico.bakal@falp.org fundación arturo lópez pérez, santiago, chile zhihuiamy liu, md zhihuiamy.liu@uhn.ca peter chung, md peter.chung@rmp.uhn.ca alejandro berlin, md alejandro.berlin@rmp.uhn.ca princess margaret hospital, radiation oncology, toronto, canada natalia jara, md njarao@gmail.com sebastian sole, md sebasole@gmail.com claudio sole, md claudio.solep@iram.cl clinica instituto de radiomedicina (iram), santiago, chile facultad de medicina, universidad diego portales, santiago, chile william wong, md wong.william@mayo.edu mayo clinic arizona, radiation oncology, phoenix, usa mario terlizzi, md terlizzimario@yahoo.fr paul sargos, md p.sargos@bordeaux.unicancer.fr institute bergonie, radiation oncology, bordeaux, france thomas zilli, md thomas.zilli@hcuge.ch hospitaux universiaires de geneve, radiation oncology, geneve, switzerland juliette thariat, md jthariat@gmail.com centre francoise baclese, radiation oncology, caen, france guilaume ploussard, md g.ploussard@gmail.com la croix du sud hospital, urology department, quint fonsergrives, france sharad goyal, md shgoyal@mfa.gwu.edu george washington university hospital, radiation oncology, washington dc, usa conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11494 1 original paper (1). in africa, circumcisions are often not carried out in hospital settings and are typically performed by lesstrained nurses and traditional practitioners. circumcision complications can range from minor to major, impacting patients' vital or functional prognosis. this study aimed to review clinical presentations and evaluate the management and outcomes of circumcision at souro sanou university teaching hospital in burkina faso. patients and methods this retrospective descriptive study examined all circumcision complications collected between january 1, 2014 and december 31, 2018, at the urology division in souro sanou university hospital. all patients admitted to the urology division with circumcision complications were included. variables considered included age, reason for visit, reason for circumcision, place of residence, admission delay, qualification of the practitioner who performed the circumcision, clinical presentation upon admission, medication, surgical revision technique, voiding quality, and aesthetic appearance of the penis for each subject included in this study. all patients or their parents or legal guardian when they are minor consent for the publication of chosen images to illustrate our clinical presentation. the study obtain the approval of the local ethical committee of the department of surgery of souro sanou university hospital registered under the number n°007/2018. results we documented a total of 23 circumcision complications, averaging 4.6 cases per year. the patients' mean age was 8.33 years ± 3.5 years, with a range spanning from 18 months to 65 years. among the 23 patients, 22 underwent circumcision without medical indication, while one case involved circumcision for medical reasons due to phimosis. we identified three cases of hemophilia and one case of hiv infection. most patients (60.87%) lived in rural areas and worked in agriculture, compared to 39.13% who resided in urban areas. nurses performed 52% of the circumcisions, while objective: to report the clinical presentation of circumcision complications encountered at our center and evaluate their management and outcomes. patients and methods: a retrospective and descriptive study was conducted at souro sanou university hospital between january 1, 2014, and december 31, 2018. all patients presenting with circumcision complications were included. parameters related to clinical aspects of circumcision complication, their management and outcomes were studied. results: during the study period, 23 cases of circumcision complications were reported. the average age of patients with circumcision complications was 8.3 years ± 3.5 years, with ages ranging from 18 months to 65 years old. circumcision was performed by nurses in 12 cases and traditional practitioners in 11 cases. observed complications included post-circumcision bleeding and hematoma (n = 8), leading to surgical exploration and hemostasis; total or partial amputation of the glans (n = 4), requiring regularization and meatoplasty; infectious complications (n = 3), managed with combined resuscitation, antibiotic administration, and penile debridement; penile urethra-cutaneous fistulas (n = 2), which were repaired; and stenosis of the external urethral meatus (n = 2), treated by meatoplasty. no deaths were reported. conclusions: circumcision complications presented various clinical manifestations, including hemorrhagic complications, glans amputation, infection, penile fistulas, and meatal stenosis. these complications were effectively managed from a functional perspective; however, aesthetic issues may persist. emphasis should be placed on preventing these complications by ensuring circumcisions are performed by appropriately trained medical professionals. key words: circumcision; complications; hemorrhage; amputation; prevention. submitted 30 may 2023; accepted 18 june 2023 introduction circumcision involves the partial or complete removal of the foreskin. it is not only a religious requirement for israelites, a custom for muslims, and a rite of passage into adulthood for many africans, but also a common surgical procedure used to treat various balanopreputial diseases complications of non-medical assisted circumcision in burkina faso. clinical presentation, management, and outcomes about 23 cases and literature review adama ouattara 1, abdoul-karim paré 1, delphine yé 1, ali sherazi 2, mohamed simporé 1, mickael rouamba 1, aristide f. kaboré 3, timothée kambou 1 1 urology division, souro sanou university teaching hospital, bobo-dioulasso, burkina faso; 2 department of medicine, dalhousie medicine new brunswick, saint john, new brunswick, canada; 3 urology division, yalgado ouedraogo university teaching hospital, ouagadougou, burkina faso. doi: 10.4081/aiua.2023.11494 summary archivio italiano di urologia e andrologia 2023; 95(3):11494 a. ouattara, a.-k. paré, d. yé, et al. 2 traditional practitioners conducted 48%. the average consultation delay was 12 ± 8.5 hours, with a range between 2 hours and 15 days. according to patients or their relatives, all circumcisions took place without anesthesia. however, we could not determine if the general rules of asepsis were adhered to when nurses performed the circumcision. consultation reasons included urine leakage through a urethrocutaneous fistula for two patients (n = 2), local hemorrhage with blood loss for patients with partial or complete glandular section or hematoma (n = 8), dysuria with urine retention for patients with external urethral stenosis or incomplete circumcision, and local signs of suppuration for patients. table 1 lists the main consultation reasons that prompted patients to seek emergency care. nurses employed the classic guillotine method for foreskin removal, a technique commonly used by various professionals. this method involves removing the foreskin by placing forceps over the glans and cutting it flat. techniques performed by traditional practitioners are not described. the study reported various types of complications, including hemorrhages (n = 8), penile amputations (n = 4), incomplete circumcisions (n = 3), external urethral stenosis (n = 3), urethrocutaneous fistulas (n = 2), and infections (n = 3). these complications are detailed in table 2. figures 1 through 7 illustrate the different complications observed in this study. all patients admitted due to complications underwent both medical and surgical management. this comprehensive approach included medical resuscitation, antibiotic administration, tetanus prevention and serotherapy, as well as surgical treatments tailored to the specific complication. among patients with bleeding complications (n = 8), seven required an isogroup isorhesus blood transfusion to address anemia with signs of hypovolemic shock and hemoglobin levels below 7 g/dl. additionally, three patients (n = 3) with hemorrhagic complications related to hemophilia necessitated collaborative management with hematologists. the various surgical management methods for circumcision complications are outlined in table 3. table 1. main reasons of consultation. reasons of consultation frequency (n) percentage (%) local bleeding 10 26.08 amputation of glans 4 17.39 dysuria 3 13.04 urinary leakage from fistula 3 13.04 tumefaction of the penis 3 13.04 local infection 2 8.69 acute urinary retention 2 8.69 figure 1. total amputation of the glans. figure 2. post-circumcision infection. figure 3. gangrene of external genitalia. table 2. circumcision complications reported. type of complication frequency (n) percentage (%) post-circumcision bleeding 6 26.08 total amputation of the glans 3 13.04 incomplete circumcision 3 13.04 external urethral stenosis 3 13.04 urethro-cutaneous fistula 2 8.69 gangrene of external genitalia 2 8.69 post-circumcision hematoma 2 8.69 necrosis of the glans 1 4.34 partial amputation of the glans 1 4.34 total 23 100 table 3. distribution of patients by type of surgery. type of surgery frequency (n) percentage (%) revision of circumcision with hemostasis 6 26.08 regularisation of the glans stump 4 13.04 revision of circumcision/posthectomy 3 13.04 meatoplasty 3 13.04 cure of penile fistula 2 8.69 gangrene of external genitalia 2 8.69 evacuation of penile hematoma 2 8.69 glanduloplasty 1 4.34 total 23 100 archivio italiano di urologia e andrologia 2023; 95(3):11494 3 complications of non-medical assisted circumcision in burkina faso. clinical presentation, management, and outcomes in general, the management of circumcision complications led to delayed healing for the three patients (n = 3) experiencing infectious complications. the four patients (n = 4) who underwent glans amputations exhibited functional sequelae and an unaesthetic appearance of the glans, although they maintained good voiding quality. psychological trauma was not assessed in this study, and no deaths were reported. figure 8 and figure 9 provide an example of re-circumcision following an incomplete procedure and the final appearance after the procedure's revision. discussion in 1997, bankolé et al. (1) reported 22 cases of traditional circumcision and excision sequelae in abidjan. sylla et al. (2) documented 63 cases of circumcision complications in dakar in 2003, while dieth et al. (3) recorded 35 cases of circumcision accidents in abidjan in 2008. kimassoum et al. (4) reported 28 cases of circumcision complications in chad in 2016. in the west, gross et al. (5) studied ritual circumcision complications in paris in 1986. many authors argue that circumcision reduces the risk of urinary tract infections in children, helps prevent penile cancer in adults, and plays a significant role in preventing sexually transmitted infections, including hiv (6, 7, 9, 11). in muslim and jewish communities, circumcision is practiced as a religious rite, while in others (particularly traditional ones), it is performed for sociocultural or initiation reasons, with fewer than 10% having a medical indication (6, 7, 3, 9). in our series, the mean age of patients was 8.33 years, with a range between 1 month and 65 years. sylla et al. (2) reported a mean age of 10.5 ± 6.7 years in their dakar figure 4. huge penile hematoma extended to perineum figure 5. incomplete circumcision. figure 6. urethro-cutaneous fistula with glans penis buria. figure 7. incomplete circumcision with phimosis. figure 8. revision of circumcision figure 9. final appearance of glans after revision. archivio italiano di urologia e andrologia 2023; 95(3):11494 a. ouattara, a.-k. paré, d. yé, et al. 4 series, while gross et al. (5) in paris published a mean age of under 16 months. this age variability can be attributed to the fact that in african countries, the age at which circumcision is performed depends on the sociocultural and ritual practices of the populations. in our work environment, circumcision is practiced in early childhood and represents a sacred act that confirms a child's male identity and anticipates flawless sexuality in adulthood. however, with the increasing influence of muslim culture, neonatal circumcision is becoming more popular. in our study, only complications requiring surgical management were referred to hospitals. this was the case for the 23 circumcision complications we collected over five years. in côte d'ivoire, dieth et al. (3) reported 35 circumcision complications over 14 years, while in senegal, sylla et al. (2) had already reported 63 complications over 11 years. numerous factors contribute to these complications, and they largely depend on the operator. in our cases, 47.82% of patients were circumcised by traditional practitioners. this can be attributed to the influence of tradition, poverty, insufficient and inaccessible healthcare structures, and low education levels. circumcision is primarily a surgical procedure performed by a doctor, requiring knowledge of contraindications, adherence to rigorous asepsis during the procedure, understanding of anatomy, and expertise in circumcision techniques. failing to meet these requirements can result in complications and does not guarantee safety in terms of infectious risks and iatrogenic injuries. in our study, 52.17% of patients had their circumcision performed by a nurse. this highlights the need for improved training, especially since studies (11) have shown that the prevalence of circumcision complications increases when the procedure is performed by untrained individuals. in burkina faso and many other sub-saharan african countries, there is a shortage of urologists. considering these observations, it may be worthwhile to explore proposals from authors like dieth et al. (2) and okeke et al. (12), which suggest integrating circumcision into medical student curricula and training nurses to perform the procedure with minimal risk. in africa, nurses are often the only healthcare workers available in remote rural areas. the average consultation time in our department was 11.89 days. kimassoum et al. (4) in chad reported an average consultation time of 896 days. this difference in average consultation time can be attributed to the higher representation of late complications in their series. in our series, hemorrhage was due to a hemostasis defect (n = 3) or a hemostasis disorder, specifically hemophilia (n = 3). hemorrhage is a common complication in countries where ritual circumcision is performed by nurses or traditional practitioners and often leads to early consultation due to parental concern. three of our patients were hemophiliacs, emphasizing the importance of performing a coagulation test before any circumcision. glans amputation, one of the most horrifying aspects of circumcision accidents, occurred in 13.04% (n = 3) of our patients. diabaté et al. (10) in senegal found similar results in 2016. in contrast, kimassoum et al. (4) in chad reported a significant number of amputation cases in their series (n = 10). this reflects the incompetence of the practitioner and is sometimes a direct consequence of poor child immobilization during foreskin removal, lack of general anesthesia, and inadequate knowledge of the procedure. in the cases we collected, patients were seen late (more than 12 hours after the accident), making reimplantation impossible due to microvascular anastomosis challenges and insufficient technical resources. in our series, treatment consisted of a meatoplasty with satisfactory results in terms of urination but poor aesthetic outcomes, leading to an unfavorable social prognosis in a context where respecting the body's integrity is sacred. we report one case of penile denudation in our study, with similar results found in the literature (4, 10). this injury occurs after excessive removal of penile skin due to exaggerated traction of the skin covering the glans. retraction of the proximal part leaves a completely exposed penile area. treatment involved debridement and a wet oily dressing for healing, although other authors opt for a skin graft. some studies rank infectious complications as the second most common issue after hemorrhage (2, 10). these complications result from inadequate asepsis and the presence of skin flora (8). locally, at the circumcision wound site, they cause delayed healing. although rare, we observed two cases of necrotizing cellulitis of the external genitalia and perineum. treatment for these cases required debridement, resuscitation with antibiotic therapy, and local care. urethrocutaneous penile fistulas were the most frequent complication in kimassoum et al. (4) series; however, in our study, we only recorded two cases. these fistulas are located in the balanopreputial groove where the urethra is more superficial, and adhesions increase its vulnerability. inadequate hemostasis of the frenulum artery can also lead to urethral injury and subsequent fistula formation. clinically, urine passes through the fistula during urination, negatively affecting body image. the urethrocutaneous splitting technique with separate suturing of the two planes was most commonly used in our series, yielding good results. stenosis of the external urethral meatus has a traumatic and/or infectious origin, with ligation of the frenulum artery implicated as well (8). the main symptom is dysuria, and rarely, urinary retention. it occurs at varying times after the healing process. a meatotomy is usually sufficient to remove the stenosis, but recurrences are frequent. unsightly, incomplete circumcision was noted in one of our patients. kimassoum et al. (4) reported six cases in their series. this issue highlights the importance of anatomical knowledge and mastery of the learning curve before performing circumcisions. in our series, this patient underwent laborious adhesion lysis to expose the glans up to the balanopreputial groove before proceeding with the circumcision. conclusions accidents resulting from ill-timed and imprudent circumcision practices can sometimes be serious enough that this surgical procedure should either be reserved for expert hands or, at the very least, supervised. the challenge now lies in raising public awareness and providing appropriate training for everyone involved in circumcision practice, from medical students to doctors and even nurses, who remain the most widely distributed healthcare personnel in remote areas of the country. archivio italiano di urologia e andrologia 2023; 95(3):11494 5 complications of non-medical assisted circumcision in burkina faso. clinical presentation, management, and outcomes references 1. bankole sanni r, coulibaly b, nandiolo r, et al. sequelae of traditional circumcision and excision. med afr noire. 1997; 44:239-41. 2. sylla c, diao b, diallo ab, et al. complications of circumcision. about 63 cases. prog urol. 2003; 13:266-72. 3. dieth ag, moh-elloh n, fiogbe m, et al. circumcision accidents in children in abidjan, ivory coast. bull soc path exo. 2008; 101:314-5. 4. kimassoum r, franklin ds, arya zat, mignagnal k. epidemiological, anatomoclinical and therapeutic characteristics of circumcision complications. uro'andro. 2016; 1:218-224. 5. gross ph, pages r, bourdelat d. complications of ritual circumcision. chir pediatr. 1986; 27:224-5. 6. ceylan k, burhan k, yılmaz y, et al. severe complications of circumcision: an analysis of 48 cases. j pediatr urol. 2007; 3:32-5. 7. chaim jb, livne pm, binyamini j, et al. complications of circumcision in israel: a one-year multicentre survey. isr med assoc j. 2005; 7:368-70. 8. krill aj, palmer ls, palmer js. complications of circumcision. sciworld j. 2011; 11:2458-68. 9. moses s, bailey rc, ronald ar. male circumcision: assessment ofhealth benefits and risks. sex transm infect. 1998; 74:368-73. 10. diabaté i, et al. management of complications of circumcision. sexologies. 2017; 3:169-175. 11. muula as, prozesky hw, mataya rh, ikechebelu ji. prevalence of complications of male circumcision in anglophone africa: a systematic review. bmc urol. 2007; 7:4. 12. okeke li, asinobi aa, ikuerowo os. epidemiology of complications of male circumcision in ibadan, nigeria. bmc urol. 2006; 6:21. correspondence adama ouattara, md (corresponding auhor) adamsouat1@hotmail.com urologist, associate professor of urology division of urology, souro sanou university teaching hospital bp: 676 bobo-dioulasso, burkina faso abdoul-karim paré boupare@yahoo.fr delphine yé delphineye73@gmail.com mohamed simporé mohamedsimpore25@hotmail.com mickael rouamba rouambami@yahoo.com timothée kambou tkambou@hotmail.com division of urology, souro sanou university teaching hospital, bobo-dioulasso, burkina faso ali sherazi, bmsc ali.sherazi@dal.ca department of medicine, dalhousie medicine new brunswick, saint john, new brunswick, canada aristide f. kaboré urology division, yalgado ouedraogo university teaching hospital, ouagadougou kaborefamd@icloud.com conflict of interest: the authors declare no potential conflict of interest. stesura seveso introduction the incidence of erectile dysfunction (ed) increases with age. it is reported that 35% of married men aged 60 years and older suffer from ed (1). from the prevalence rates reported in the massachusetts male aging study (mmas), between the ages of 40 and 70 years, the probability of complete ed increased from 5.1% to 15%, moderate dysfunction increased from 17% to 34%, and mild ed remained constant at about 17% (1). according to the study of the national health and social life survey (nhsls) the following prevalence rates for ed were reported (responses to questions regarding obtaining and maintaining erection): 7% for ages 18 to 29 years, 9% for ages 30 to 39,11% for ages 40 to 49, and 18% for 50 to 59 (1). obesity has become a worldwide public health problem, it may decrease life expectancy by 7 years at the age of 113archivio italiano di urologia e andrologia 2013; 85, 3 original paper caloric restriction increases internal iliac artery and penil nitric oxide synthase expression in rat: comparison of aged and adult rats emin ozbek 1, abdulmuttalip simsek 1, mustafa ozbek 2, adnan somay 3 1 okmeydani research and education hospital, department of urology, istanbul, turkey; 2 diskapi research and education hospital, department of endocrinology, ankara, turkey; 3 fatih sultan mehmet research and education hospital, department of pathology, istanbul, turkey. because of the positive corelation between healthy cardiovascular system and sexual life we aimed to evaluate the effect of caloric restriction (cr) on endothelial and neuronal nitric oxide synthase (enos, nnos) expression in cavernousal tissues and enos expression in the internal iliac artery in young and aged rats. young (3 mo, n = 7) and aged (24 mo, n = 7) male sprague-dawley rats were subjected to 40% cr and were allowed free access to water for 3 months. control rats (n = 14) fed ad libitum had free access to food and water at all times. on day 90, rats were sacrified and internal iliac arteries and penis were removed and parafinized, enos and nnos expression evaluated with immunohistochemistry. results were evaluated semiquantitatively. enos and nnos expression in cavernousal tissue in cr rats were more strong than in control group in both young and old rats. enos expression was also higher in the internal iliac arteries of cr rats than in control in young and old rats. as a result of our study we can say that there is a positive link between cr and neurotransmitter of erection in cavernousal tissues and internal iliac arteries. cr has beneficial effect to prevent sexual dysfunction in young and old animals and possible humans. key words: rat; caloric restriction; nitric oxide synthase; internal iliac artery; penis. submitted 27 february 2013; accepted 30 april 2013 no conflict of interest declared summary 40 years: excess bodyweight is now the sixth most important risk factor contributing to the overall burden of disease throught the world. overweight and obesity may increase the risk of ed by 30-90% as compared with normal subjects. moreover, women with the metabolic syndrome have an increased prevalence of sexual dysfunctions as compared with matched controls. lifestyle changes reducing body weight induces amelioration of both erectile and endothelial functions in obese men (2). patients with ed show a higher body mass index (bmi), waist circumference (wc), and insulin-resistance (ir) and lower levels of total testosterone (tt ) and bioavailable testosterone (bt). there is a negative correlation between erectile function and ir and abdominal obesity. the tt levels are lower in patients with increased bmi, doi: 10.4081/aiua.2013.3.113 archivio italiano di urologia e andrologia 2013; 85, 3 e. ozbek, a. simsek, m. ozbek, a. somay 114 wc and ir. negative correlation was shown only between bt and abdominal obesity (3). androgen deficiency together with endothelial dysfunction may be responsible from ed in obesity (4). in animal experiments penile endonhelial nitric oxide synthase (enos) and neuronal nitric oxide synthase (nnos) expression were found decreased in hypercholesterolemic cavernousal tissue due to decrease activity of amp-activated protein kinase (ampk), which increases the expression of neuronal (n) nos and endothelial (e) nos (5). in another experiment we shown that mild to moderate exercise increases penile enos and nnos expression as well as serum total testosterone levels in young and aged rats (6). modifiable lifestyle factors such as obesity, lack of exercise and smoking play a role in the development, progression or remission not only of erectile dysfunction (ed), but also in cardiovascular disease and the metabolic syndrome. one-third of obese men with ed can regain their sexual activity after 2 y of adopting health behaviors, mainly regular exercise and reducing weight. western societies actually spend a huge part of their health care costs on chronic disease treatment and interventions for risk factors. the adoption of healthy lifestyles can reduce the prevalence of obesity and the metabolic syndrome, and hopefully the burden of sexual dysfunction (7). mediterranean-style diets and a reduction in caloric intake have been found to improve erectile function in men with the aspects of the metabolic syndrome. in addition, both clinical and experimental studies have confirmed that combining the two interventions provides additional benefit to erectile function, likely via reduced metabolic disturbances (e.g., inflammatory markers, insulin resistance), decreased visceral adipose tissue, and improvement in vascular function (e.g., increased endothelial function) (8). mediterranean-style diet might be effective in ameliorating sexual function in women with metabolic syndrome. lifestyle changes, mainly focussing on regular physical activity and a healthy diet, are effective and safe ways to reduce cardiovascular diseases and premature mortality in all population groups; they may also prevent and treat sexual dysfunctions in both sexes (9). taking all of these background into account, the objective of the our work was to investigate the role of caloric restriction on enos as well as nnos and enos expression in the internal iliac artery and cavernousal tissue of young and aged rats, respectively. materials and methods animals and diet 3-month-old young and 24-month-old aged male spraque-dawley rats were divided into four experimental groups (n = 7 rats per group). control rats in each group were fed ad libitum with pelleted standard diet. another two groups were subjected to 40% caloric restriction for three months (10). rats were housed induvidually with free access to water in wirebottom cages and acclimated at 22ºc with a 12h light/dark cycle. caloric restricted rats were fed on a daily basis at the beginning of the dark cycle and the amount of food was weekly updated. all animal experiments were approved by the animal ethics committee. isolation of samples and immunohistochemical staining at the end of 3 months rats were sacrificed and the and internal iliac arteries and penises were quickly removed, washed with saline and parafinized. all procedures were performed under general anaesthesia with 50 mg⁄ kg ketamine hcl administered intraperitoneally. enos, nnos expression in all tissues was evaluated with immunohistochemistry using specific antibodies. for the immunohistochemical evaluation, specimens were processed for light microscopy and sections incubated at +4°c overnight and then de-waxed in xylene for 30 min. after rehydrating in a decreasing series of ethanol, sections were washed with distilled water and phosphate buffered saline (pbs) for 10 min. sections were then treated with 2% trypsin in 50 mm tris buffer (ph 7.5) at 37°c for 15 min and washed with pbs. sections were delineated with a dako pen (dako, glostrup, denmark) and incubated in a solution of 3% h2o2 for 15 min to inhibit endogenous peroxidase activity. then, sections were incubated with enos ab-1 (rb-9279-r7, neomarkers, labvision, fremont, ca, usa) and nnos (sc-648, santa cruz biotechnology inc., santa cruz, ca, usa) antibodies. the ultra-vision (labvision) horseradish peroxidase⁄3amino-9-ethylcarbazole staining protocol was used at this stage. sections prepared for each case were examined by light microscopy. positive and negative controls were conducted in parallel with nos stained sections. staining of sections with commercially available antibodies served as the positive control. negative controls included staining tissue sections with omission of the primary antibody. the sections were evaluated for diffuseness and staining. penile enos and nnos were evaluated according to the diffuseness and intensity of staining in penile cavernousal smooth muscle. according to the diffuseness of the staining, sections were graded as 0 = no staining; 1 = staining < 25%; 2 = staining 25-50%; 3 = staining 50-75%; 4 = staining > 75%. according to staining intensity, sections were graded as follows: 0 = no staining; 1 = weak but detectable staining; 2 = distinct; 3 = intense staining (11, 6). immunohistochemical values were obtained by adding the diffuseness and intensity scores. results enos expression in internal iliac artery: in control young and aged rat internal iliac arteries there was focal mild to moderate e nos expression, but diffuse in caloric restricted young and aged rats (figure 1a-d). enos and nnos expression in cavernousal tissue: enos, nnos expression were weak in the cavernousal tissues of control rats. in caloric restricted group enos, nnos expression were more evident than in control young and aged rats (figure 2a-h). 115archivio italiano di urologia e andrologia 2013; 85, 3 caloric restriction increases internal iliac artery and penil nitric oxide synthase expression in rat: comparison of aged and adult rats figure 1a-c. enos expression in internal iliac artery. a-b: young control group: focal mild internal iliac artery enos staining (ihc 400x). c-d: young caloric restriction group: diffuse internal iliac artery enos staining (ihc 400x). b: aged control group: focal mild penile enos staining (ihc 400x). d: aged caloric restriction group: diffuse penile enos staining (ihc 400x). f: aged control group: focal mild penile nnos staining (ihc 400x). h: aged caloric restriction group: diffuse penile nnos staining (ihc 400x). figure 2a-h. enos and nnos expression in cavernousal tissue. a: young control group: focal mild penile enos staining (ihc 400x). c: young caloric restriction group: diffuse penile enos staining (ihc 400x). e: young control group: focal mild penile nnos staining (ihc 400x). g: young caloric restriction group: diffuse penile nnos staining (ihc 400x). archivio italiano di urologia e andrologia 2013; 85, 3 e. ozbek, a. simsek, m. ozbek, a. somay 116 discussion erectile function is a multi system phenomenon involving vascular, neuronal and endocrin system. in this process nitric oxide (no) released from nerve endings and endothelial cells plays a key role. no is produced from l-arginine through an enzymatic reaction in which the enzyme nitric oxide synthase is involved. in the cavernousal tissue no stimulates guanilate cyclase enzyme present in the smooth muscle cells. guanylate cyclase induces the formation of cyclicguanosine monophosphate (gmpc) from guanosine triphosphate (gtp). phosphorilation of gmpc, results in cytoplasmic calcium release causing smooth muscle relaxation of the corpus cavernousum, with the subsequent penile tumescence (12, 13). the most common causes of ed are organic such as cardiovascular and endocrin diseases including obesity, type-2 diabetes mellitus (dm2) and metabolic syndrome.depression, hormonal changes and vascular or neurological damage after trauma or surgery are other factors aasociated with ed (3, 14). obesity causes insulin resistence and cardiovascular system diseases through disrupting in the signaling pathways required for nitric oxide production with subsequently endothelial dysfunction. nowadays obesity is a major health problem throught the world, especially in western countries. type 2 diabetes mellitus, hypertension, hyperlipidemia are comorbitidies associated with obesity that cause cardiovascular disease and endothelial dysfunction. these abnormalities are frequently clustered in the so called “metabolic syndrome”. obesity and metabolic syndrome may lead directly to endothelial dysfunction and subsequently erectile dysfunction (15). villalba et al. reported that endothelial relaxant responses were impaired in penile arteries of obese zucker rats (16). enhanced superoxide production and reduced basal no activity are the proposed underlying mechanism in this process. in human, obesity causes impaired indices of endothelial function and increases circulating concentrations of the proinflammatory cytokines interleukin-6 (il-6), interleukin-8 (il-8), interleukin-18 (il18), as well as c-reactive protein (crp) and no bioavailability (17). nos expression in highfat-fed obese rats has been found lower and restored by metformin (18). in our experiment we found e nos and n nos expression lower in hypercholesterolemic young and aged rats. caloric restiction restriction restores nos expression in both group. reduced caloric intake decreases arterial pressure in healthy induviduals and improeves endothelium vasodilatation in obese and overweight induviduals. in literature it is reported that caloric restriction promotes endotheliumdependent vascular relaxation by activating e nos activity in mice throught sirt1 (19). in our experiment we found that caloric restiction increases e nos expression in the internal iliac artery of rats. because penile arterial supply comes from internal iliac artery we can say that caloric restriction improves penile blood supply by increasing internal artery vasodilatation. in vitro experiments are required to demonstrate the effect of caloric restriction on the endothelial relaxant response of caloric restiction in the internal iliac artery. weight loss resulting from cr improves endotheliumdependent vascular relaxation in obese and overweight induviduals with hypertension (20, 21). in this experiment, authors show that sirt1 promotes endotheliumdependent vasodilation by targeting endothelial nitric oxide synthetase (enos) for deacetylation. sirt1 and enos co-localize and co-precipitate in endothelial cells, and sirt1 deacetylates enos, stimulating enos activity and increasing endothelial nitric oxide (no). these mechanisms may be effective in the internal ilac arteries and cavernousal endothelial cells. further studies are needed to confirm this suggestion. caloric restriction improves cardiovascular system through increase of systemic no release, increase of no bioavailability, upregulation of sirtuin-1 as well as reducing oxidative stress in animal models. recently, it is reported that 8 weeks 30% caloric restriction reverses vascular endothelial dysfunction in old mice by restoring no bioavailability, reducing oxidative stress (via reduced nadph oxidase-mediated superoxide production and stimulation of anti-oxidant enzyme activity) and upregulation of sirtuin-1 (22). in another study it was found that, cr reduce blood pressure by elevating no production and lowering ace activity in rats (23). shinmura et al. reported that prolonged (6 months) cr improves myocardial ischemic tolerance and restores the ischemic precontidioning effect in middle-aged rats through nitric oxide-dependent increase in nuclear sirt1 content (24). nisoli et al. report that caloric restriction for either 3 or 12 months induced endothelial nitric oxide synthase (enos) expression and 3',5'-cyclic guanosine monophosphate formation in various tissues of male mice. other authors stated that this was accompanied by mitochondrial biogenesis, with increased oxygen consumption, adenosine triphosphate production and enhanced expression of sirtuin 1 (25). in different experiments it was shown that cr increases aortic enos and no release as well as improves endotheliumdependent vasorelaxation to acetylcholine (26). in a clinical study caloric restriction improves endothelial-dependent vasodilation through an increased release of nitric oxide in obese hypertensive patients (27). as a conclusion, as it shown in literature, cr improves cardiovascular system by increasing no levels, no bioavailability as well as decreasing ros, proinflammatory and inflammatory cytokines. our study is the first to demonstrate the local effect of caloric restriction in the pathophysiology of ed at molecular level. further in vitro studies are needed to evaluate the contractionrelaxation responses of cavernousal and internal iliac artery strips in cr rats. in clinical practice we think that cr improves response to phosphodiesterase-5 inhibitors in aged and young subjects. further clinical studies are also needed to confirm this suggestion. references 1. wein aj, kavoussi lr, novick ac, et al. campbell-walsh urology, ninth edition, elsevier, philadelphia, vol. 1, p.738. 2. esposito k, giugliano f, ciotola m, et al. obesity and sexual dysfunction, male and female.int j impot res. 2008; 20:358-65. 3. knoblovits p, costanzo pr, rey valzacchi gj, et al. erectile dysfunction, obesity, insulin resistance, and their relationship with testosterone levels in eugonadal patients in an andrology clinic setting. j androl. 2010; 31:263-70. 4. traish am, feeley rj, guay a. mechanisms of obesity and related pathologies: androgen deficiency and endothelial dysfunction may be the link between obesity and erectile dysfunction. febs j. 2009; 276:5755-67. 5. kim yw, park sy, kim jy, et al. metformin restores the penile expression of nitric oxide synthase in high-fat-fed obese rats. j androl. 2007; 28:555-60. 6. ozbek e, tasci ai, ilbey yo, et al. the effect of regular exercise on penile nitric oxide synthase expression in rats. int j androl. 2010, 33:623-8. 7. esposito k, giugliano d. obesity, the metabolic syndrome, and sexual dysfunction. int j impot res. 2005; 17:391-8. 8. hannan jl, maio mt, komolova m, adams ma. beneficial impact of exercise and obesity interventions on erectile function and its risk factors. j sex med. 2009; 6(suppl 3):254-61. 9. esposito k, giugliano f, ciotola m, et al. obesity and sexual dysfunction, male and female. int j impot res. 2008; 20:358-65. 10. zanetti m, barazzoni r, vadori m, et al. lack of direct effect of moderate hyperleptinemia to improve endothelial function in lean rat aorta: role of calorie restriction. atherosclerosis. 2004; 175:253-9. 11. moochhala s, chhatwal vj, chan st, et al. nitric oxide synthase activity and expression in human colorectal cancer. carcinogenesis 1996; 17:1171-1174. 12. barouch la, harrison rw, skaf mw, et al. nitric oxide regulates the heart by spatial confinement of nitric oxide synthetase isoforms. nature. 2002; 214:337-339. 13. trussell jc, legro rs. erectile dysfunction: does insulin resistance play a part? fertil steril. 2007; 88:771-777. 14. costanzo p, knoblovits p, rey valzacchi g, et al. erectile dysfunction is associated with a high prevalence of obesity and metabolic syndrome. rev argent endocrinol metab. 2008; 45:142-148. 15. fonseca v, jawa a. endothelial and erectile dysfunction, diabetes mellitus, and the metabolic syndrome: common pathways and treatments? am j cardiol. 2005; 96(12b):13m-18m. 16. villalba n, martínez p, bríones am, et al. differential structural and functional changes in penile and coronary arteries from obese zucker rats. am j physiol heart circ physiol. 2009; 297:h696-707. 17. giugliano f, esposito k, di palo c, et al. erectile dysfunction associates with endothelial dysfunction and raised proinflammatory cytokine levels in obese men. j endocrinol invest. 2004; 27:665-9. 18. kim yw, park sy, kim jy, et al. metformin restores the penile expression of nitric oxide synthase in high-fat-fed obese rats. j androl. 2007; 28:555-60. 19. mattagajasingh i, kim cs, naqvi a, et al. sirt1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. proc natl acad sci usa. 2007; 104:14855-60. 20. raitakari m, ilvonen t, ahotupa m, et al. weight reduction with very-low-caloric diet and endothelial function in overweight adults: role of plasma glucose. arterioscler thromb vasc biol. 2004; 24:124-128. 21. sasaki s, higashi y, nakagawa k, et al. a low-calorie diet improves endothelium-dependent vasodilation in obese patients with essential hypertension. am j hypertens. 2002; 15:302-309. 22. rippe c, lesniewski l, connell m, et al. short-term calorie restriction reverses vascular endothelial dysfunction in old mice by increasing nitric oxide and reducing oxidative stress. aging cell. 2010; 9:304-12. 23. sharifi am, mohseni s, nekoparvar s, et al. effect of caloric restriction on nitric oxide production, ace activity, and blood pressure regulation in rats. acta physiol hung. 2008; 95:55-63. 24. shinmura k, tamaki k, bolli r. impact of 6-mo caloric restriction on myocardial ischemic tolerance: possible involvement of nitric oxide-dependent increase in nuclear sirt1. am j physiol heart circ physiol. 2008; 295:h2348-55. 25. nisoli e, tonello c, cardile a, et al. calorie restriction promotes mitochondrial biogenesis by inducing the expression of enos. science. 2005; 310:314-7. 26. zanetti m, barazzoni r, vadori m, et al. lack of direct effect of moderate hyperleptinemia to improve endothelial function in lean rat aorta: role of calorie restriction. atherosclerosis. 2004; 175:253-9. 27. sasaki s, higashi y, nakagawa k, et al. a low-calorie diet improves endothelium-dependent vasodilation in obese patients with essential hypertension. am j hypertens. 2002; 15:302-9. 117archivio italiano di urologia e andrologia 2013; 85, 3 caloric restriction increases internal iliac artery and penil nitric oxide synthase expression in rat: comparison of aged and adult rats correspondence emin ozbek, md (corresponding author) ozbekemin@hotmail.com abdulmuttalip simsek, md department of urology okmeydani research and education hospital darulaceze street, 34384, sisli, istanbul, turkey mustafa ozbek, md department of endocrinology diskapi research and education hospital ankara, turkey adnan somay, md department of pathology fatih sultan mehmet research and education hospital istanbul, turkey archivio italiano di urologia e andrologia 2013; 85, 114 introduction women are currently well informed and adequately counselled for both gynecological and sexually transmitted diseases. moreover womens’ perception of “body health” is original paper genital diseases awareness in young male students: is information necessary to protect them? nicola mondaini 1, mauro silvani 2, teo zenico 3, fabrizio gallo 4, franco rosso 4, tommaso cai 1, gianni ughi 5, pasquale scarano 6, vincenzo orlando 7, riccardo bartoletti 1 ! u.o. urology, s. maria annunziata hospital, university of florence, italy; " department of surgery, division of urology, degli infermi hospital, biella, italy; # u.o. urology, morgagni pierantoni hospital, forlì, italy; 4 department of surgery, division of urology, san paolo hospital, savona, italy; 5 u.o. urology, morgagni pierantoni, ferrara, italy; 6 u.o. urology, civile hospital, rimini, italy; 7 stabilimento chimico farmaceutico militare, florence, italy. introduction: few studies on the prevalence of male sexual diseases are currently available due to difficult application of observational studies or andrological disease prevention campaigns on large series of apparently healthy subjects. the medical check-up linked to compulsory military service represented in italy a valid tool for epidemiological and observational study for 18 year old boys from 1861 to 2004. the stopping of compulsory military service and its related medical check-up could have determined an important social impact in terms of a lower level of attention and care on male genital/sexual diseases. the aim of the present observational study was to check the prevalence of genital/sexual diseases among young male high-school students and promote an alternative campaign of information among young students. methods: a prospective observational analytical study on young male students was conducted by 6 urological centres. genital and sexually transmitted diseases were presented with slides to students in a general assembly. some students were then counselled and filled out a short questionnaire on their lifestyle. results: 12,535 students (10,432 males-83.6%) followed the presentation. and 4,897 males (46.7%) decided to be checked-up by the urologist and out of them 1554 (31.7%) presented relevant andrological diseases. five-hundred students completed the questionnaire concerning their lifestyle. many of them had not yet experienced condom use during sexual intercourse (27.8%). drug abuse was reported by 39.6% of subjects and alcohol consumption in 80.8% of them. conclusions: these data suggest the need for a national information campaign on male sexual disorders to promote sexual health. key words: sexual dysfunctions; klinefelter syndrome; sexually transmitted diseases; sexual health awareness; fertility; andrologic disease; genital diseases; young male students. submitted 27 august 2012; accepted 31 december 2012 no conflict of interest declared summary more accurate and diligent than in men (1). the excess of reporting minor physical morbidity and affective disorders is probably related to specific subjective behaviours but mondaini_stesura seveso 18/04/13 10:59 pagina 14 15archivio italiano di urologia e andrologia 2013; 85, 1 genital diseases awareness in young male students: is information necessary to protect them? the informed consent to participate in the study. the term “binge drinking” is the modern definition of drinking alcoholic beverages with the primary intention of becoming intoxicated by heavy consumption of alcohol over a short period of time. each male subject with evidence of andrological problems was counselled to receive subsequent adequate medical and/or surgical treatment. statistical analysis the prevalence of genital/sexual diseases was calculated as the proportion of young male high-school students with genital/sexual diseases over the specified period of study time. the differences between each parameter were evaluated by using t-test or chi-square test when appropriate. moreover, the mann-whitney test was also used to compare mean values of different parameters. statistical significance was achieved if p was < 0.05. all reported p values were two-sides. all statistical analyses were performed by using spss 11.0 for apple macintosh (spss, inc., chicago, illinois). results 12,535 students (10,432 males-83.6%) followed the presentation. the mean number of male subjects explored in relation with the total number of males (all ages) per area was about 3% (range 1-18,4%). the rate of participation was also related to both the number of schools explored per-area and the regional territory extent. 4,897 males (46.7%) decided to be checked-up by the urologist and 1554 (31.7%) of them presented relevant andrological diseases potentially related to a reduced rate of fertility (table 1). thus the prevalence of andrological diseases among young male students was 31.7% (25.28% if related x 100.000 subjects). the rate of male subjects asking for a medical consultation seemed to be strongly influenced and proportionally increased by the number of women present in the single class. when women exceeded 50% of the total students in the single class, about 90% of males accepted to be checked-up. in the class where the number of female students were less than 50%, only 37.9% of male students underwent further urological controls (p < 0.001; df = 2; f = 87.33). a wide range of andrological diseases such as varicocele, testis hypotrophy, mobile testis, epidydimal cyst, phimosis, short prepucial frenulum, hypospadia, congenital penile curvature, ambiguous genitalia, micro penis were collected (table 2). among these hypospadia and disorders of sex development (pseudo-hermaproditism) had already been fully diagnosed. no significant differences between the prevalence of diseases and geographical area were found (p = 0.12; df = 2; f = 7.2); the number of affected subjects enrolled in the study in different geographical areas ranged from 30.5 to 32.5% (mean 31.7%) of evaluated males. five-hundred students completed the questionnaire concerning their lifestyle. most them reported a continuous (35.2%) or occasional (37%) use of condom during sexual intercourse while 27.8% of them hadn’t yet experienced condom use. about 90% of condom users ascribed this practice to avoid undesired pregnancies in could be also related with confounding variables such as age, race, unemployment, marital status, income, social class and education (2). men are conversely oriented to underestimate their symptoms and maintain a more practical lifestyle (3). although systemic and hereditary diseases could be easily diagnosed by either the general practitioner or health care non-invasive diagnostic tools such as ultrasonography, new-born medical screening and genome analysis, genital and sexual disorders remained often undiscovered and untreated (4). few studies on the prevalence of male sexual diseases are currently available due to difficult application of observational studies or andrological diseases prevention campaigns on large series of apparently healthy subjects. the medical checkup linked to compulsory military service represented in italy a valid tool for epidemiological and observational study for 18 years old boys from 1861 to 2004. previous studies on a series of 80,000 young males evidenced a 40% prevalence of genital abnormalities (5). thus stopping compulsory military service and its related medical check-up could have determined an important social impact in terms of a lower level of attention and care on male genital/sexual diseases and couples’ infertility (6). the aim of the present observational study was to check the prevalence of genital/sexual diseases among young male high-school students and compare these data with those obtained by armed forces sanitary service during the compulsory military service period preliminary medical check-up (msmc) (5) and promote an alternative campaign of investigation among young students to reduce the risk of infertility and sexually transmitted diseases among future couples. materials and methods this is a prospective multi centre observational analytical cohort study on young male high-school students, specially those between 18 and 19 years old, organized under the aegis of the italian society of andrology (sia). urologists from six different urological centres throughout italy were involved in the study. high school head master assemblies were convened in each town to present the study project. each of them thus organized a special student assembly to introduce a slide presentation by the urologists showing the most frequent unrecognized andrological and sexually transmitted diseases. in particular, pictures from subjects with different clinical cases of varicocele, hydrocele, preputial phymosis, ambiguous genitalia, hypospadia, micropenis, penile congenital curvature were shown to the students presenting all possible complications overall related to infertility. women could participate in the assembly to obtain information on male genital diseases and exert a sort of counselling on male sexual partners inducing them to be evaluated by the urologist in a private consultation. all male students who were present at the assembly received the option of having a free clinical consultation either in a special room in the school the same morning or at the hospital thereafter. a smaller cohort of students who reported having had previous sexual intercourse, were then randomly selected to fill in an anonymous self-report questionnaire on the use of condoms, alcohol and drug abuse (appendix 1). all of them signed mondaini_stesura seveso 18/04/13 10:59 pagina 15 archivio italiano di urologia e andrologia 2013; 85, 1 n. mondaini, m. silvani, t. zenico, f. gallo, f. rosso, t. cai, g. ughi, p. scarano, v. orlando, r. bartoletti 16 their partners and 7.5% of them to avoid the risk of sexual infection transmission. drug abuse was reported by 198 out of 500 subjects (39.6%) with current use of cannabinoids in 66.6% of cases, cocain 6.6%, ecstasy mixed with cocain and cannabinoids 26.7%. alcohol consumption was documented in 404 out 500 subjects (80.8%) but 22.5% of them only reported repeated “binge-drinking” episodes. the term “specialist andrologist” was known only by 65 out of 500 subjects (13%) (table 3). discussion currently, there are a great variety of health care evaluation indicators in relation with different clinical disciplines such as radiology, cardiology, geriatrics, pediatrics and many others (7). andrology is a modern medical discipline that deals with male health, particularly relating to the problems of the male reproductive system and urological problems that are unique to men. it is the counterpart to gynaecology, which deals with medical table 1. distribution of check-ups in six different urological centres. table 2. the predominance of single diseases in 4897 male check ups. table 3. answers to an anonymous self-report questionnaire concerning student’s lifestyle. city residents: reale/total subjects male female male-visits andrological diseases florence 170.737/365.881 4434 3501 (78.9%) 933 (21.1%) 1545 (44.1%) 471 (30.5%) rimini 66.886/138.465 ferrara 62.590/133.980 forlì 56.661/117.550 3831 3831 (100%) 0 1302 (33.9%) 418 (32.1%) savona 28.868/61.916 300 230 (76.6%) 70 (23.4%) 100 (43.4%) 31 (31%) biella 21.508/46.128 3970 2920 (73.5%) 1050 (26.5%) 1950 (66.7%) 634 (32.5%) total 407.250/743.918 12.535 10.482 (83.6%) 2053 (16.4%) 4897 (46.7%) 1554 (31.7%) pathology cases % already diagnoses % varicocele 857 17.5 29 3.3 testis volume < 12 ml 61 1.2 0 0 mobile testis 202 4.1 0 0 epidymal cysts 57 1.1 0 0 hydrocele 24 0.5 5 20.8 phimosis 49 1 31 63.2 short preputial frenulum 160 3.2 14 8.7 hypospadias 16 0.3 16 100 congenital penile curvature 46 0.9 0 0 disorders of sex development 2 0.04 2 100 inguinal hernia 14 0.3 7 50 micropenis 5 0.1 0 0 gynecomastia 61 1.2 2 3.2 testicular cancer 0 0 0 0 total 1554 31.7% 106 6.8% use of condoms always 176/500 (36.2%) seldom 185/500 (37%) never used before 139/500 (27.8%) reason to avoid pregnancy in their partner 325/361 (90%) to avoid the risks of sexual infections 27/361 (7.5%) no answer 9/361 (2.5%) drugs abuse 198/500 (39.6%) cannabinoids 132/198 (66.6%) cocain 13/198 (6.6%) ecstasy+cannabinoids+cocain 53/198 (26.7%) alchool use 404/500 (80.8%) “binge-drinking” 91/404 (22.5%) awareness of the term “specialist andrologist” 65/500 (13%) mondaini_stesura seveso 18/04/13 10:59 pagina 16 17archivio italiano di urologia e andrologia 2013; 85, 1 genital diseases awareness in young male students: is information necessary to protect them? issues which are specific to the female reproductive system (8). females are usually well informed and documented about infertility and sexually related diseases while many males have an urgent need to be counselled for sexual dysfunctions often related to relational and subjective psychological problems (9). the term “andrologist” is currently known by 13% of counselled males compared to 4% of males checked up during msmc, although the number of men aware of their personal situation decreased from 10-20% found during msmc (5, 10) to 6.8% found in the present study. moreover previous studies demonstrated that andrological disorders were found in about 30% of youngsters: these data have been confirmed by the mean rate of 31.7% found in the present series independently from the geographical area investigated.the logical explanation of this phenomenon could be that a lot of students are adequately informed on medical glossaries but not on their body health awareness to avoid subsequent complications on fertility and couples’s sexual problems. hypospadia and disorders of sex development such as pseudo-hermaphroditism, have always already been diagnosed in all cases found in both military and school check-ups while less evident diseases such as penile congenital curvature and short prepucial fraenulum have been diagnosed just after a projection of slides session (11). about 1% of subjects showed a substantial reduction of testicular volume and all of them were counselled to check a second level visit to test the presence of complicated diseases such as klinefelter syndrome (ks) (karyotipe 47, xxy). the time of first diagnosis in patients with ks is essential to test germ cell degeneration due to the presence of additional chromosome x and planning an adequate sperm collection. in the past 10 years, our knowledge about fertility chances of patients with ks has changed considerably, especially when regarding the possibility of ivf icsi treatment (in vitro fertilisation, intra cytoplasmic sperm injection) with single testicular spermatozoon. when entering puberty testicular volume of ks patients increases for a short time with rising testosterone and inhibin b levels at the same time. these decrease, however, and fsh increases during puberty. this seems to indicate a critical point in time when spermatogenetic function of the testicles could still be present. thus, in early puberty there could possibly be a time slot when spermatozoa could be detected in the ejaculate or-if not-at least in the testicular tissue. these could be extracted by testicular sperm extraction, cryopreserved and used for intra cytoplasmic sperm injection therapy later on. in the literature, a total of 133 births of children from klinefelter fathers have been reported. this early specific procedure could lead to a better acceptance of their diagnosis and also offer the option of not being incurably infertile (12). the high number of male students who have accepted to be checked-up seemed to be strictly related and proportional to the number of female students in the same classroom. female students are known to have a good perception of their bodies, careful to protect themselves against disease of all sorts,for future sexual activities. this could have determined a sort of inspiration for their male classmates to join the study. thirty-five percent of evaluated subjects only reported a persistent use of condoms during sexual intercourses and only 7.5% of them used condoms to avoid infections. these data sound alarming in relation to the opportunity of avoiding sexually transmitted diseases such as infections from human immunodeficiency virus (hiv) and human papilloma virus (hpv). foresta et al. found hpv dna in 10% young adult sperm cells who already had unprotected intercourse and its presence was associated with reduced sperm motility (13). thus male infection could determine the spread of the disease related to different sexual partners. due to these reasons the practice of safer sex, promoted in a sex-positive way, is necessary and should be included in a campaign of information directed at young male students. it includes the appropriate use of condoms (14). this is not just to prevent hiv, hpv and stds, but also to prevent unwanted pregnancy, sti-related infertility, and cervical cancer (15). a multifaceted intervention program that provided information and skills, as well as counselling and services, appears to have positive influence on contraceptive practice and condom use among unmarried young females and males (16). moreover the use of drugs (40%) and alcohol (80%) documented in our study could determine significant consequences on the students’ health by reducing their sexual function and desire and representing the first cause of death among young people due to car accidents. thus a good schoolbased prevention program should include a campaign on substance abuse related diseases. caria reported the effect of a new school-based prevention program against substance abuse on 7,079 students aged 12-14 years from 143 schools in seven european countries. the results demonstrated a subsequent decreased risk of alcohol-related problems (17). moreover faggiano reported a persistent positive effect over 18 months for alcohol abuse and for cannabis use, but not for cigarette smoking on the same sample of 7,079 students (18). these data stressed the importance of information, since the check-up enforcement could be difficult and socially expensive. on the other hand, all these data suggest the need for national information campaigns by media and other communication strategies such as internet website browsers and social networks (19-20). the world wide web is increasingly used by researchers, health care providers, and common people to seek medical information and could be also used to promote several opportunities of online communication, enhanced selfestimation, relationship formation, friendship quality, and sexual self-exploration (21-22). conclusions medical information remains one of the most useful tools to promote health. about 30% of male young students have undiagnosed genital and sexual dysfunctions compared to women who normally have a clear and safe perception of their bodies. this implies the need of campaigns for information to promote sexual health and protect future couples’ fertility. mondaini_stesura seveso 18/04/13 10:59 pagina 17 archivio italiano di urologia e andrologia 2013; 85, 1 n. mondaini, m. silvani, t. zenico, f. gallo, f. rosso, t. cai, g. ughi, p. scarano, v. orlando, r. bartoletti 18 references 1. popay j, bartley m, owen c. gender inequalities in health: social position, affective disorders and minor physical morbidity. soc sci med. 1993; 36:21-32. 2. mendoza-sassi ra, béria ju. gender differences in self-reported morbidity: evidence from a population-based study in southern brazil. cad saude publica. 2007; 23:341-6. 3. lai ch. major depressive disorder: gender differences in symptoms, life quality, and sexual function. j clin psychopharmacol. 2011; 31:39-44. 4. herlihy as, gillam l, halliday jl, mclachan ri. postnatal screening for klinefelter syndrome: is there a rationale? acta paediatr. 2011; 100:923-33. 5. mondaini n, bonafe’ m, di loro f, et al. andrologic disease in a population of 18 years old young men during conscription screening: how many were a first diagnosis? minerva urol nefrol. 2000; 52:63. 6. mondaini n, giubilei g, rizzo m, carini m. whither the andrologic pathology of italian lads with the end of medical check up to conscripts. arch ital urol androl. 2005; 77:121. 7. sans-corrales m, pujol-ribera e, gené-badia j, pet al. family medicine attributes related to satisfaction, health and costs. fam pract. 2006; 23:308-16. 8. lenzi a, jannini ea.the andrologist from medicine of reproduction to sexual medicine: the italian experience. int j androl. 2005; 28(suppl 2):9-13. 9. adegunloye oa, ezeoke gg sexual dysfunction-a silent hurt: issues on treatment awareness. j sex med. 2011; 8:1322-9. 10. campodonico f, michelazzi a, capurro a, carmignani g. andrologic disease detected during army medical visit. arch ital urol androl. 2003; 75:205. 11. mondaini n, ponchietti r, bonafè m, et al. hypospadias: incidence and effects on psychosexual development as evaluated with the minnesota multiphasic personality inventory test in a sample of 11,649 young italian men. urol int. 2002; 68:81-5. 12. kliesch s, zitzmann m, behre hm. fertility in patients with klinefelter syndrome (47,xxy). urologe a. 2011; 50:26-32. 13. foresta c, garolla a, zuccarello d, et al. human papilloappendix 1 how old are you? ______ do you use a condom? � always � seldom � never used before why do you use a condom? � to avoid pregnancy in your partner � to avoid the risks of sexual infections � no answer do you use drugs? � yes � no if, yes, what kind od drugs? � cannabinoids � cocain � ecstasy � cannabinoids + cocain � cannabinoids + ecstasy � cocain + ecstasy � cannabinoids + cocain + ecstasy do you use alcohol? � yes � no what kind of alcohol? � wine � beer � spirits do yu indulge in binge drinking? � yes � no do you know the term “specialist andrologist”? � yes � no mondaini_stesura seveso 18/04/13 10:59 pagina 18 19archivio italiano di urologia e andrologia 2013; 85, 1 genital diseases awareness in young male students: is information necessary to protect them? mavirus found in sperm head of young adult males affects the progressive motility. fertil steril. 2010; 93:802-6. 14. sartorius ga, nieschlag e. paternal age and reproduction. hum reprod update. 2010; 16:65-79. 15. kigbu jh, nyango dd. a critical look on condoms. niger j med. 2009; 18:354-9. 16. lou ch, wang b, shen y, gao es. effects of a community-based sex education and reproductive health service program on contraceptive use of unmarried youths in shanghai. j adolesc health. 2004; 34:433-40. 17. caria mp, faggiano f, bellocco r, et al. effects of a school-based prevention program on european adolescents' patterns of alcohol use. j adolesc health. 2011; 48:182-8. 18. faggiano f, vigna-taglianti f, burkhart g, et al. eu-dap study group. the effectiveness of a school-based substance abuse prevention program: 18-month follow-up of the eu-dap cluster randomized controlled trial. drug alcohol depend. 2010; 108:56-64. 19. http://www.salute.gov.it/resources/static/focus/307/presentazione.pdf 20. gosselin p, poitras p. use of an internet "viral" marketing software platform in health promotion. j med internet res. 2008; 10:e47. 21. tian h, brimmer dj, lin jm, et al. web usage data as a means of evaluating public health messaging and outreach. j med internet res. 2009; 11:e52. 22. valkenburg pm, peter j. online communication among adolescents: an integrated model of its attraction, opportunities, and risks. j adolesc health. 2011; 48:121-7. correspondence nicola mondaini, md (corresponding author) mondatre@hotmail.com tommaso cai, md riccardo bartoletti, md u.o. urology, s. maria annunziata hospital, university of florence, firenze, italy mauro silvani, md department of surgery, division of urology, ospedali degli infermi, biella, italy teo zenico, md u.o. urology, morgagni pierantoni hospital, forlì, italy fabrizio gallo, md franco rosso, md department of surgery, division of urology, san paolo hospital, savona, italy gianni ughi, md pasquale scarano, md u.o. urology, civile hospital, rimini, italy vincenzo orlando, md stabilimento chimico farmaceutico militare, firenze, italy mondaini_stesura seveso 18/04/13 10:59 pagina 19 stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 120 review midshaft penis are the most commonly affected sites by pf (1, 4). clinically, the onset of pf is usually accompanied by a loud cracking sound, followed by penile localized swelling, bruises, pain, and immediate detumescence. many reviews report that the diagnosis of penis fractures can depend exclusively on clinical findings, based on patient history and physical examination (2, 5). multiple studies have reported that a wide diversity of investigations are useful in the diagnosis of pf as x-ray imaging, doppler ultrasound, retrograde urethrocystography (rgu), flexible cystoscopy, and magnetic resonance imaging (mri) (6-8). however, it is unnecessary to use radiological investigations in most cases where the history and the clinical examination are sufficient to confirm the diagnosis. the x-ray imaging may still be required in some cases, especially in patients with atypical clinical presentation (9). some authors consider the doppler ultrasound as the preferred radiological tool for investigating penile trauma cases given that it is a non-invasive and inexpensive procedure. on the other hand, mri is the most accurate test in diagnosing the pf as it shows high contrast resolution between tissues and identifies the pathological processes of soft tissues. studies also reported that it can be used in the evaluation of the urethral injury, although it is not commonly used because of its low cost-effectiveness and long execution time (10, 11). rug is the gold standard for urethra evaluation. the rug is easy to perform on trauma patients at the bedside: 20 to 30 ml of diluted watersoluble contrast is injected into the urethral meatus, before x-raying. a positive rug will show contrast outside the urethral serpentine cylinder. retrograde urethrograms are sensitive in detecting urethral injuries but can't pinpoint their location and are operator-dependent (12). previous reports demonstrated that urethral injuries are present in 1-38% of the pf cases. patients with an associated urethral injury can present with blood at the meatus, leading to hematuria and urinary retention (5, 13, 14). however, these findings are not specific as previous case reports indicated that some pf cases with associated urethral injuries had no suspected symptoms. thus, investigations, particularly urine analysis and retrograde urethrogram (rgu), are of paramount importance for identifications of associated urethral injuries (15). accurate identification of urethral injuries is critical before pf repair to avoid the risk of postoperative complications, including urethral stricture and urethrocutaneous fistula (16). however, due to the rarity of the disease, little literature has been published so purposes: penile fracture (pf) with associated urethral injury has been described as a rare condition yet a serious urological emergency. we conducted this systematic review to address the current literature concerning the etiology, presentations, intra-operative findings, site of injury, and complications of pf with associated urethral injury, materials and methods: the present systematic review was limited to human-based studies published in english language, and reporting clinical data on pf cases with associated urethral injuries. a comprehensive search of the literature was conducted on five electronic databases from their inception to may 2022: medline via pubmed, web of science, google scholar, scopus, and ebsco host. results: a total of 15 studies were included encompassing 1671 patients with pf. out of 1665 patients with pf retrieved from the case series studies, 65 patients had associated urethral injuries giving a point prevalence of 3.9%. the vast majority of the patients had blood on the meatus and hematuria suggestive of urethral injury (57/59; 96.6%). forty patients had partial urethral disruption and the rest of the patients had a complete rupture. all patients received primary urethroplasty as the main modality of treatment. the median hospital stay was two days and the median duration of transurethral catheterization was 21 days. five patients (8.5%) developed urethral stricture; other complications included penile curvature (6.7%), palpable fibrosis (6.7%), and erectile dysfunction (3.4%). conclusions: urethral injuries are uncommon, but serious findings, in patients with pf. primary urethroplasty appears to achieve satisfactory outcomes with a low incidence of short and long-term complications. key words: penile fracture; urethra; urethral injury; systematic review. submitted 12 december 2022; accepted 7 april 2023 introduction penile fracture (pf) with associated urethral injury has been described as a rare condition yet a serious urological emergency (1). pf is characterized by signification injury of corpus cavernosum anatomy due to profound trauma or manipulation of an erect penis; while traumas to the flaccid penis or the suspensor ligament are not usually considered as pf (2, 3). commonly, pf is caused by severe bending of the erect penis during sexual intercourse, masturbation, rolling over during sleep, and powerful methods of sexual arousal. to a lesser extent, pf can result from direct trauma or fall onto the erect penis. the basal and the presentation and outcomes of penile fracture with associated urethral injury: a systematic literature review salah e. shebl urology department, faculty of medicine for girls, al-azhar university, cairo, egypt. doi: 10.4081/aiua.2023.11082 summary archivio italiano di urologia e andrologia 2023; 95, 2 s.e. shebl 121 far concerning the presentation and outcomes of pf with associated pf. therefore, we conducted this systematic review to address the current literature concerning the etiology, presentations, intra-operative findings, site of injury, and complications of pf with associated urethral injury. materials and methods the present systematic review receives prospero id 342298 and adhered to the recommendations of the recent version of the cochrane collaboration handbook and the moose statement (17, 18). eligibility criteria and literature search the present systematic review was limited to human-based studies, published in the english language, and reporting clinical data on pf cases with associated urethral injuries. there were no limitations regarding the date of publication or study design. studies were excluded if they were review articles, duplicate datasets, or they had no separate data on patients with associated urethral injuries. besides, we excluded conference abstracts with no available full texts. a comprehensive literature search was conducted on five electronic databases from their inception to may 2022. these bibliographic databases were: medline via pubmed, web of science, google scholar, scopus, and ebsco host. various combinations of the following queries were utilized: penile, penis, fracture, injury, urethra. following the literature search, retrieved citations were imported to endnote x7 for duplicates removal. unique records were then screened through two stages: the first stage was a screening by titles and abstracts, while the second stage was an full-text evaluation of potentially eligible abstracts for final inclusion in the present systematic review. quality assessment the quality assessment of the included case reports and case series was conducted using murad's tool (19), which is specifically designed to evaluate the methodological quality of case reports and case series. this tool consists of eight criteria that cover four primary domains: selection, ascertainment, causality, and reporting. two independent reviewers conducted the quality assessment of the included studies, in case of any discrepancies figure 1. prisma flow diagram. archivio italiano di urologia e andrologia 2023; 95, 2 122 the presentation and outcomes of penile fracture with associated urethral injury between the reviewers, a consensus was reached through discussion or, if necessary, by involving a third reviewer. data extraction standardized data extraction was done using excel software for data retrieval and processing. the following data were extracted from each eligible study: year of publication, country, study design, number of patients with pf, number of cases with confirmed urethral injuries, cause of pf, presentation of urethral injury, location of the injury, intraoperative findings, need for supra-pubic cystostomy tube, treatment, complications, hospital stay, and duration of follow-up. results a total of 7242 records were retrieved from online search and 12 records were identified by manual searching. of them, 4201 records were screened after duplicates removal. after the initial screening, 55 full texts were retained for a full evaluation. out of them, 40 studies were excluded as they were narrative or systematic review (n = 8), animal models (n = 3), irrelevant (n = 16), simulation-based studies (n = 6), or they had no data on urethral injuries (n = 7). finally, 15 studies were included in the present systematic review (see prisma flow diagram; figure 1). general characteristics of the included studies and prevalence of urethral injuries six retrospective studies (20-25), two prospective study (26, 27), and seven case reports were included in the present systematic review (21, 28-34). two from india, two from egypt, two from the united states, and one from serbia, italy, slovenia, canada, china, peru, tunisia, brazil and uk each. the median time from injury to presentation was six hours (range 1-48.5 hours) and the median time of follow-up was 21 months (1-107 months). a total of 1671 patients with pf were retrieved from the included studies. out of them, 65 patients had associated urethral injuries giving a point prevalence of 3.9% (table 1). quality assessment of included studies the quality assessment of the included studies was conducted using murad's tool. in terms of selection, eight studies did not report that this was their whole experience on penile fracture or provide a clear selection process. regarding ascertainment, the majority of the studies (14 out of 15) adequately ascertained exposure and outcomes, while one study failed to do so. alternative causes that could explain the observation were clearly ruled out in 12 of the included studies. most studies (10 out of 15) adequately followed their patients, while five studies lacked sufficient follow-up period. reporting: the majority of the studies (11 out of 15) provided sufficient details to allow other investigators to replicate the research or practitioners to make inferences related to their own practice. however, four studies did not provide enough details in their reports. overall, the quality assessment revealed that most studies had adequately ascertained exposure and outcome, and provided sufficient reporting details. however, some studies did not meet all the causality criteria (supplementary table 1). presentation of the included cases among the 65 patients with associated urethral injuries, the most common cause of fracture was sexual intercourse (41/65; 69%), followed by masturbation (8/65; 13.5%) and rolling over (6/65; 10.1%). with regard to the classic presentation of pf, the most common presentations were hematoma (34/65; 57%) and penile swelling (33/65; 55.9%), followed by aubergine sign/egg-plant deformity (30/65; 50.8%) and crackling sound (29/65; 49.1%). the vast majority of the patients had blood on the meatus and hematuria suggestive of urethral injury (57/65; 87.6%). the most commonly affected location of the included patients was proximal shaft (21/65; 35.5%) followed by midshaft (19/65; 32.2%). the vast majority of the patients had unilateral corporal involvement (54.2%), mainly on the right side (30.5%). forty patients had partial urethral disruption and the rest of the patients table 1. general characteristics of the included studies. authors, year country study design median time from the time mean hospital total cases confirmed of injury to the time of follow-up stay of penile urethral presentation to the hospital (months) (days) fracture injury amit et al, 2013 (20) india retrospective case series na 34.3 2 34 8 kasaraneni et al, 2019 (27) india prospective observational 6 24 2 75 12 derouiche et al, 2007 (22) tunisia retrospective case series 10 18 14 312 10 raheem et al, 2014 (6) egypt retrospective case series 5.5 72.6 2.1 246 12 ibrahiem et al, 2010 (23) egypt retrospective case series 48.5 107 2.3 155 14 barros et al, 2018 (26) brazil prospective observational na na na 175 27 mercado-olivares et al, 2018 (34) peru case report 19 na na 281 1 ouanes et al, 2021 (24) tunisia retrospective case series 1 to 5 12 na 138 15 hughes et al, 2021 (33) uk case report na na na 1 1 boncher et al, 2010 (39) usa case report 8 48 na 1 1 tang et al, 2018 (25) usa retrospective case series 1.2 ± 1.03 21 (1-73) na 62 13 ge et al, 2021 (31) china case report na 12 na 1 1 garofalo et al, 2015 (30) italy case report 1 12 2 1 1 jagodic̆ et al, 2007 (29) slovenia case report 6 12 13 1 1 hoag et al, 2011 (28) canada case report 1 1 2 1 1 archivio italiano di urologia e andrologia 2023; 95, 2 s.e. shebl 123 had a complete rupture. two studies reported the utilization of rgu for the evaluation of pf and associated urethral injuries (tables 2 and 3). treatment and outcomes of the included cases all patients received primary urethroplasty as the main modality of treatment. besides, 15 patients needed a supra-pubic cystostomy tube. fifty-one patients received medications to prevent erection in the form of estradiol, diazepam, sildenafil, and amyl nitrite. the median hospital stay was two days and the median duration of transurethral catheterization was 21 days. five patients (8.5%) developed urethral stricture; other complications included penile curvature (6.7%), palpable fibrosis (6.7%), and erectile dysfunction (3.4%) (table 4). discussion urethral injuries can concurrently occur in patients with pf and a considerable proportion of these injuries are missed at initial diagnosis, despite being widely considered as a serious complication. if not discovered and managed early, associated urethral injuries can dramatically lead to short and long-term complications in patients with pf (2). however, due to the rarity of the disease, little literature has been published so far concerning the presentation and outcomes of pf with associated urethral injury. table 3. the distribution of intraoperative findings and location of injury among the included patients. authors, year intra operative findings location of injury partial complete proximal midshaft distal bilateral unilateral right left urethral urethral shaft shaft corporal corporal corporal corporal disruption disruption of penis of penis involvement involvement involvement involvement amit et al, 2013 (20) 7 1 6 na na 1 7 5 2 kasaraneni et al, 2019 (27) 11 1 6 2 4 1 11 4 6 derouiche et al, 2007 (22) 10 0 5 4 1 0 10 6 4 raheem et al, 2014 (6) 1 11 0 12 0 12 0 0 0 ibrahiem et al, 2010 (23) 11 3 na na na na na na na barros et al, 2018 (26) na na na na na na na na na mercado-olivares et al, 2018 (34) na na 0 0 1 0 1 1 0 ouanes et al, 2021 (24) na na 118 0 20 0 138 na na hughes et al, 2021 (33) na na 0 0 1 0 1 0 1 boncher et al, 2010 (39) na na 0 0 1 0 1 1 0 tang et al, 2018 (25) na na 23 18 21 na na na na ge et al, 2021 (31) 0 1 1 0 0 na na na na garofalo et al, 2015 (30) 0 1 1 0 0 0 1 1 0 jagodic̆ et al, 2007 (29) 0 1 1 0 0 na na na na hoag et al, 2011 (28) 0 1 1 0 0 1 0 0 0 table 2. the distribution of causes and presentations among the included patients. authors, year causes of penile fractures presentation of penile fracture sexual rolling blunt forced masturbation urethral hematoma crackling penile bladder aubergine retention intercourse over injury penile bleed or sound swelling palpable sign/egg-plant of urine pending eccymosis deformity amit et al, 2013 (20) 6 0 0 0 2 6 0 6 0 na 6 na kasaraneni et al, 2019 (27) 9 2 1 0 0 11 0 7 0 3 12 3 derouiche et al, 2007 (22) 0 4 0 0 6 10 0 10 0 2 10 2 raheem et al, 2014 (6) 11 0 0 1 0 12 12 0 12 0 0 3 ibrahiem et al, 2010 (23) 7 na na 0 na 13 14 na 14 0 0 na barros et al, 2018 (26) 69 0 0 5 16 na na na na na na na mercado-olivares et al, 2018 (34) 1 0 0 0 0 0 1 0 0 0 0 0 ouanes et al, 2021 (24) 47 na na 62 na na na na na na na na hughes et al, 2021 (33) 1 0 0 0 0 1 1 1 0 0 0 0 boncher et al, 2010 (39) 1 0 0 0 0 0 1 1 1 0 1 0 tang et al, 2018 (25) 41 0 0 19 2 12 44 34 62 0 0 0 ge et al, 2021 (31) 1 0 0 0 0 1 1 1 1 0 0 0 garofalo et al, 2015 (30) 1 0 1 0 0 1 1 1 1 0 0 0 jagodic̆ et al, 2007 (29) 1 0 0 0 0 1 1 1 1 1 0 1 hoag et al, 2011 (28) 1 0 1 0 0 1 1 0 1 0 0 0 archivio italiano di urologia e andrologia 2023; 95, 2 124 the presentation and outcomes of penile fracture with associated urethral injury therefore, we conducted this systematic review to address the current literature concerning the pf with associated urethral injury. our results highlighted that there are currently 65 published cases of pf with associated urethral injuries giving a point prevalence of 3.9%. such findings are in line with a large case-series of 312 pf cases from the middle east, in which ten cases had associated urethral injuries (22). other reports from the middle east reported similar findings (35). on the contrary, reports from europe and the united states demonstrated a much higher prevalence of associated urethral injuries, affecting up to onethird of pf cases (36-38). it is not clear why patients from the middle east had a lower prevalence of associated urethral injuries; however, it was reported that a large number of pf in the middle east is attributed to the widespread practice of “taghaandan”, which is a low-energy trauma with a low possibility of urethral injuries (35, 32). we also postulated that the low prevalence of associated urethral injuries can be attributed to a large number of pooled cases with pf from the middle east and the dependence on clinical examination, without further investigations, which might have led to under-detection of associated urethral injuries. as previously mentioned, the proximal and midshaft penis are the most commonly affected sites by pf; while sexual intercourse and masturbation account for the vast majority of pf (1, 4). these findings appear to apply also to patients with associated urethral injuries; in this review, we found that the most common cause of fracture was sexual intercourse, followed by masturbation and rolling over; while the majority of the cases had proximal and midshaft fractures. clinically, the presence of urethral injuries is suspected when there is blood at the meatus, with or without hematuria, on examination; besides, urine analysis and rgu can be useful for identifications of associated urethral injuries (15). however, as demonstrated by this systematic review, some pf cases may not exhibit specific symptoms for urethral injuries (see table 3). besides, urine analysis and rgu exhibited false-negative results in some case-series (15, 39). thus, a careful intraoperative inspection of the urethra is recommended in all cases with pf to avoid missed injuries. to our knowledge, there is no published systematic review that has attempted to explore the presentation and outcomes of pf cases with associated urethral injuries; nonetheless, we acknowledge the existence of several limitations in our review. all included studies suffered from substantial methodological flaws that can affect the quality and generalizability of our findings. the outcome measurements are subjective and postoperative erectile and voiding functions have not been assessed using validated tools. in conclusion, urethral injuries are uncommon, but serious findings, in patients with pf. the clinical presentation of patients with urethral injuries usually involves urethral bleeding and hematuria. the diagnosis of associated urethral injuries can be established by clinical examination with the limited role of imaging studies. thus, a careful intraoperative inspection of the urethra is recommended in all cases with pf in order to avoid missed injuries. primary urethroplasty appears to achieve satisfactory outcomes with a low incidence of short and longterm complications. nonetheless, the current published literature is still limited by the low number of published cases and low quality of published reports; thus, further studies are needed to characterize the presentation and outcomes of pf with association urethral injuries. acknowledgment the authors thank the study participants, trial staff, and investigators for their participation. references 1. mahapatra rs, kundu ak, pal dk. penile fracture: our experience in a tertiary care hospital. world j mens health. 2015; 33:95. table 4. the treatment and outcomes of injury among the included patients. authors, year treatment supra-pubic medication median duration hospital complications cystostomy to prevent of transurethral stay penile palpable erectile stricture uti tube erection catheterization (days) (days) curvature fibrosis dysfunction urethra amit et al, 2013 (20) primary urethroplasty not used estradiol 21 2 0 0 1 0 0 kasaraneni et al, 2019 (27) primary urethroplasty not used estradiol 21 2 1 0 0 1 2 derouiche et al, 2007 (22) primary urethroplasty used diazepam 13 14 0 0 0 0 0 raheem et al, 2014 (6) primary urethroplasty used in 5 patients sildenafil® 22.5 2.1 2 3 1 1 0 ibrahiem et al, 2010 (23) primary urethroplasty not used pge1 na 2.3 na 1 na 1 0 barros et al, 2018 (26) na na na na na na na na na na mercado-olivares et al, 2018 (34) primary urethroplasty na na na na 0 0 0 0 0 ouanes et al, 2021 (24) primary urethroplasty na na na na na na na na na hughes et al, 2021 (33) primary urethroplasty na na na na na na na na na boncher et al, 2010 (39) primary urethroplasty na diazepam 28 na 0 0 0 0 0 tang et al, 2018 (25) primary urethroplasty used amyl nitate na na 0 0 0 0 0 ge et al, 2021 (31) primary urethroplasty na na 12 na na na na na na garofalo et al, 2015 (30) primary urethroplasty used na na 2 1 0 0 1 0 jagodic̆ et al, 2007 (29) primary urethroplasty used diazepam 12 13 0 0 0 1 0 hoag et al, 2011 (28) primary urethroplasty used na 28 2 na na na na na archivio italiano di urologia e andrologia 2023; 95, 2 s.e. shebl 125 2. eke n. fracture of the penis. br j surg. 2002; 89:555-65. 3. el-sherif ae, dauleh m, allowneh n, vijayan p. management of fracture of the penis in qatar. br j urol. 1991; 68:622-5. 4. ateyah a, mostafa t, nasser ta, et al. penile fracture: surgical repair and late effects on erectile function. j sex med. 2008; 5:1496502. 5. zargooshi j. sexual function and tunica albuginea wound healing following penile fracture: an 18-year follow-up study of 352 patients from kermanshah, iran. j sex med. 2009; 6:1141-50. 6. raheem aa, el-tatawy h, eissa a, et al. urinary and sexual functions after surgical treatment of penile fracture concomitant with complete urethral disruption. arch ital urol androl. 2014; 86:15-9. 7. kamdar c, mooppan umm, kim h, gulmi fa. penile fracture: preoperative evaluation and surgical technique for optimal patient outcome. bju int. 2008; 102:1640-4. 8. saglam e, tarhan f, hamarat mb, et al. efficacy of magnetic resonance imaging for diagnosis of penile fracture: a controlled study. investig clin urol. 2017; 58:255-60. 9. pavan n, tezzot g, liguori g, et al. penile fracture: retrospective analysis of our case history with long-term assessment of the erectile and sexological outcome. arch ital urol androl. 2014; 86:359-70. 10. choi mh, kim b, ryu ja, et al. mr imaging of acute penile fracture. radiographics. 2000; 20:1397-405. 11. murray ks, gilbert m, ricci lr, et al. penile fracture and magnetic resonance imaging. int braz j urol. 2012; 38:287-8. 12. rosenstein di, alsikafi nf. diagnosis and classification of urethral injuries. urol clin north am. 2006; 33:73-85. 13. koifman l, cavalcanti ag, manes ch, et al. penile fracture experience in 56 cases. int braz j urol. 2003; 29:35-9. 14. mydlo jh. surgeon experience with penile fracture. j urol. 2001; 166:526-9. 15. gedik a, kayan d, yamis s, et al. the diagnosis and treatment of penile fracture: our 19-year experience. ulus travma acil cerrahi derg. 2011; 17:57-60. 16. shaeer o. methylene blue-guided repair of fractured penis. j sex med. 2006; 3:349-54. 17. higgins jpt, thomas j, chandler j, et al. cochrane handbook for systematic reviews of interventions. cochrane handbook for systematic reviews of interventions. 2019, pp 1-694. 18. stroup df, berlin ja, morton sc, et al. meta-analysis of observational studies in epidemiologya proposal for reporting. jama. 2000; 283:2008-12. 19. murad mh, sultan s, haffar s, bazerbachi f. methodological quality and synthesis of case series and case reports. bmj evid bas med. 2018; 23:60-3. 20. amit a, arun k, bharat b, et al. penile fracture and associated urethral injury: experience at a tertiary care hospital. j can urol assoc. 2013; 7:e168-70. 21. raheem aa, el-tatawy h, eissa a, et al. urinary and sexual functions after surgical treatment of penile fracture concomitant with complete urethral disruption. arch ital urol androl 2014; 86:15-9. 22. derouiche a, belhaj k, hentati h, et al. management of penile fractures complicated by urethral rupture. int j impot res. 2008; 20:111-4. 23. ibrahiem ehi, el-tholoth hs, mohsen t, et al. penile fracture: long-term outcome of immediate surgical intervention. urology. 2010; 75:108-11. 24. ouanes y, saadi mh, haj alouene h, et al. sexual function outcomes after surgical treatment of penile fracture. sex med. 2021; 9:100353. 25. tang z, yang l, wei q, et al. management and outcomes of penile fracture: a retrospective analysis of 62 cases with long-term assessment. asian j androl. 2018; 20:412. 26. barros r, silva mis, antonucci v, et al. primary urethral reconstruction results in penile fracture. ann r coll surg engl. 2018; 100:21-5. 27. kasaraneni p, mylarappa p, gowda rd, et al. penile fracture with urethral injury: our experience in a tertiary care hospital. arch ital urol androl 2019; 90:283-7. 28. hoag na, hennesse k, so a. penile fracture with bilateral corporeal rupture and complete urethral disruption: case report and literature review. can urol assoc j. 2011; 5:e23. 29. jagodic k, erklavec m, bizjak i, et al. a case of penile fracture with complete urethral disruption during sexual intercourse: a case report. j med case rep. 2007; 1:14. 30. garofalo m, bianchi l, gentile g, et al. sex-related penile fracture with complete urethral rupture: a case report and review of the literature. arch ital urol androl 2015; 87:260-1. 31. ge g, wang h, chen y, et al. complete urethral injury in the penile fracture: a case report and literature review. transl androl urol. 2021; 10:969. 32. boncher na, vricella gj, jankowski jt, et al. penile fracture with associated urethral rupture. case rep med. 2010; 2010:791948. 33. hughes s, elbaroni w, o’donoghue j, williams m. atypical presentation of a vertical penile fracture. bmj case reports cp. 2021; 14:e243353. 34. mercado-olivares f, antonio grandez-urbina j, farfan-daza g, et al. case report: double penile fracture. f1000research. 2018; 7. f1000res. 2018; 7:1828. 35. zargooshi j. penile fracture in kermanshah, iran: report of 172 cases. j urol. 2000; 164:364-6. 36. fergany af, angermeier kw, montague dk. review of cleveland clinic experience with penile fracture. urology. 1999; 54:352-5. 37. bitker mo, belin j, jardin a, chatelain c. “faux pas du coit” with associated rupture of corpora cavernosa and urethra. urology. 1988; 32:447-8. 38. agarwal mm, singh sk, sharma dk, et al. fracture of the penis: a radiological or clinical diagnosis? a case series and literature review. can j urol. 2009; 16:4568-75. 39. mydlo jh, hayyeri m, macchia rj. urethrography and cavernosography imaging in a small series of penile fractures: a comparison with surgical findings. urology. 1998; 51:616-9. correspondence salah e. shebl, md (corresponding author) salahshebl@yahoo.com salahshebl@azhar.edu.eg urology department, faculty of medicine for girls al-azhar university urology department, alzahraa university hospital, cairo, egypt conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 14 original paper better surgical accuracy. the lack of comparative studies between the different surgical approaches has not allowed for many years to establish which of open, laparoscopic or robotic surgery guarantees better oncological and functional long-term results. today, the most commonly used procedures in various urological centers are laparoscopic and robotic surgery because they are considered minimally invasive techniques but open radical prostatectomy (orp) remains well established and commonly performed in many parts of the world (1). recently alexander haese et al. in a comparative study of robot-assisted and open radical prostatectomy in 10 790 men conclude that: “both surgical approaches, performed in a high volume centre by the same surgeons, achieve excellent, comparable oncological and functional outcomes” (2). we present in this study our experience in traditional open radical prostatectomy surgery performed under spinal anesthesia. materials and methods for analysis in this study, we reviewed the clinical courses of 88 consecutive patients who underwent orp between 05/2016 and 06/2021 at our institution. preoperatively, after diagnostic assessment of prostate cancer with transrectal eco-guided biopsy, an abdominal computerized tomography and bone scintigraphy were performed for staging the disease. pathology results in all patients confirmed adenocarcinoma of the prostate gland. however, some patients with prostate cancer diagnosed elsewhere were also referred to our hospital for further definite treatment. preoperative investigations included a complete blood count, serum coagulation, electrolytes, creatinine, electrocardiogram, and chest x-ray. we have placed the indications for the surgical treatment following the european guidelines 2020, edition 2021. morbidity influenced the choice of the anesthetic regimen. patients with a history of myocardial infarction, previous cerebrovascular accident, transient ischemic attack from the study within a year preoperatively and extensive spinal surgery were considered cases of contraindication for regional anesthesia and the patients were excluded from the study. instead, we considered eligible for the study patients with previous prostate surgery or endoscopic prostate procedures subjected to subsequent open radical prostatectomy. each patient was informed in detail about objective: prostate cancer is one of the most widespread neoplasms affecting the male gender. the most commonly used procedures in various urological centers are laparoscopic and robotic surgery because they are considered minimally invasive techniques. we present our experience in traditional open radical prostatectomy performed under spinal anesthesia. materials and methods: we reviewed the clinical courses of 88 consecutive patients who underwent open radical prostatectomy performed under spinal anesthesia at our institution. results: median age: 67.7 years. median follow up duration: 48 months. median pre-operative psa: 15,9 ng/ml, median prostate weight: 44.5 gr, median surgical time: 96.5 minutes (range 55138). perioperative complications were recorded. the most frequent complication was anemia, 9 cases need blood transfusion after surgery. complications directly related to spinal anesthesia were not observed. most patients were discharged within 5 days from the procedure. after two weeks we observed a quick recovery of total continence in 90% of patients. after 6 months all patients were perfectly continent. erectile dysfunction after 6 months was reported by 48 patients. conclusions: the reasons why the gold standard of radical prostatectomy surgery has been considered general anesthesia are essentially two: the long duration of the surgical procedure and the associated significant blood loss. multiple evidences show that radical retropubic prostatectomy can be safely performed under spinal anaesthesia with various advantages. it is therefore no longer justified to consider general anesthesia as the gold standard for radical prostatectomy with an open technique. key words: prostate cancer; radical prostatectomy; spinal anesthesia. submitted 28 february 2023; accepted 20 march 2023 introduction prostate cancer is one of the most widespread neoplasms affecting the male gender all over the world with variable incidence in relation to the geographical area considered. the gold standard remains in most cases the radical surgical removal of the prostate and district lymph nodes. the anatomical characteristics of the surgical field have made radical prostatectomy the most performed surgical procedure in the world with robotic-assisted laparoscopic technique; this is due to the search for less invasiveness and effectiveness and safety of spinal anesthesia in patients undergoing open radical retropubic prostatectomy salvatore blanco 1, angelica grasso 2, endrit sulmina 3, marco grasso 1 1 department of urology, fondazione irccs san gerardo dei tintori, monza, italy; 2 department of urology, asst santi paolo e carlo, university of milan, milan, italy; 3 department of anesthesia and intensive care medicine, fondazione irccs san gerardo dei tintori, monza, italy. doi: 10.4081/aiua.2023.11281 summary archivio italiano di urologia e andrologia 2023; 95, 2 s. blanco, a. grasso, e. sulmina, m. grasso 15 the advantages and disadvantages of spinal anesthesia and the accompanying risk factors. we have not considered patients’ bmi, although adiposity could influence the outcomes of prostatectomy. we might evaluate this topic in a different work. spinal anesthesia method subarachnoid or spinal anesthesia is a central locoregional anesthesia technique in which the anesthetic, whether or not combined with opiates or alpha agonists, is injected into the subarachnoid space, into the cephalorachid fluid surrounding the spinal cord, reversibly inhibiting sensory and motor nerve conduction. to perform the spinal anesthesia, the patient is positioned seated with knees flexed to 90° and relaxed shoulders, chin touching the chest, trying to bend the lumbar vertebrae outwards, causing the intervertebral space to open allowing the needle to pass through. careful disinfection of the skin with alcoholic solution or iodopovidone is performed. a sterile drape with a central slit is placed and the intervertebral space is searched by palpating the spinous processes of the lumbar vertebrae, then local anesthesia of the skin and the inter spinous and yellow ligaments is applied. for radical prostatectomy the space usually chosen is l2-l3 where hyperbaric bupivacaine is injected at a dosage of 0.12-0.15 mg/kg for a total of 12-14 mg with the addition of an opiate, disufen 2-4 mcgr or morphine 100200 mcg, which prolongs both the duration of anesthesia and postoperative pain control. the drug is injected in a cephalic direction to achieve a level of anesthesia of at least t9-t10, sufficient to cover the skin metameres at the surgical incision site, sub umbilical-pubic. mild or deep sedation is combined for the duration of the operation with benzodiazepines or hypnotics while maintaining spontaneous breathing. the duration of spinal anesthesia is approximately 2-3 hours after which the motor and sensory blockade is slowly resumed, which is prolonged up to 4 hours with the addition of opioids. intraoperative monitoring is done with a 5-lead ecg, with non invasive blood pressure monitoring every 5' and measurement of peripheral saturation. it is useful to place 2 venous accesses of at least 18 g, to perform loading with 500-1000 ml crystalloid and to have blood available as it is an operation with important fluid shift. the side effects of this anesthesia are usually hypotension and bradycardia, easily reversible. time in surgery we defined time of surgery as the period between start of cut on the suprapubic skin and the end of agraffes skin affixing. to reduce variations in surgical skill and experience of the surgeon, all patients in this series of open radical prostatectomies with spinal anesthesia were operated by two surgeons. surgical procedure we describe the technique of open radical prostatectomy developed on the basis of a personal series of more than 1500 procedures. we perform a conventional median surgical incision starting under umbilicus with pelvic space exposure. we performed a bilateral pelvic lymphadenectomy in all patients independently of value gleason grade biopsies or prostate specific antigen (psa) level. the operation was carried out using some variants with respect to the original technique described by walsh (3). our approach results from surgical experience observations collected since 1995 with patients subjected to radical prostatectomy with bladder neck preservation (4) and also using our particular experience in radio guided radical prostatectomy with sentinel lymph node dissection (5). during detachment of the prostate from the bladder, an electro incision was made in the demarcation point between the bladder and the gland, which was highlighted by palpating the balloon of a foley catheter inflated to 10 cc and tautened. following an electro incision extended by about 270° (i.e. from one lateral peduncle to the other in order to spare the ventral area), detachment of the prostatic gland on an anatomic plane was carried out manually by the surgeon. at the end of this operation, urethral and periurethral muscle fibers sectioning were performed by means of scissors. during this stage, particular attention should be paid to the prevention of lesions of the prostatic capsule, or lacerations in the bladder wall, especially in the ventral area. having removed the prostate-vesicular block, bladder neck biopsies were carried out in all quadrants; the urethrovesical anastomosis was performed with the aid of a urethral protractor (6) with 6 single 3/0 monocryl suture. the catheter was removed on the 11th day without the need of any radiological check. patients were discharged usually in the fourth day after surgery. in this study, we focused on findings useful to evaluate if spinal anesthesia could be an efficient and suitable technique for this procedure. particularly we evaluated the abdominal and pelvic muscle relaxation throughout the procedure on a scale of 1 to 4, with 1 indicating poor muscle relaxation and 4 excellent muscle relaxation as already indicated in other experiences of the efficacy of spinal anesthesia on muscle relaxation throughout the operative period (7). we also want to underline the good control of pain in the first postoperative hours which allowed to avoid or reduce the use of opiate drugs. postoperative period postoperatively all patients were monitored in the post anesthesia care unit (pacu). post anesthetic management of the patient included periodic assessment and monitoring of function of the lower urinary tract (urine output, drainage and bleeding), of respiratory function, cardiovascular function, neuromuscular function, temperature, pain (especially the ability of the patient to communicate breakthrough pain or if the feelings of tension is present in the abdominalpubic area), mental status, nausea and vomiting, fluid assessment. postoperative pain management was easily controlled with oral analgesics (fans) since spinal anesthesia demonstrated excellent pain control for at least four to five hours after surgery. therefore, an early mobilization was still guaranteed. hospital stay in order to compare time of hospital stay, minimum and maximum values and median values were calculated. low-weight heparin was administered in the post-operative period (at the end of the hemorrhagic risk) every day of hospitalization, at midnight, and then at home for at least fifteen days. archivio italiano di urologia e andrologia 2023; 95, 2 16 spinal anesthesia for open radical retropubic prostatectomy overall functional follow up the follow-up of the patients monitored the degree of urinary continence achieved during the immediate postoperative period (two weeks after the operation), then at three months, six months and one year after the operation. the degree of continence was assessed during the immediate post-operative period by compilation of a previously validated questionnaire (7), in which patients were invited to annotate actual urine leaks, as well as the need for protective pads. in this study, we defined “dry or continent” patients who did not use pads or just used a safety pad in a day because many patients used a pad as a precautionary measure, despite their sufficient continence. those patients who were completely dry or only subject to a sporadic leakage of drops of urine due to micturition urgency, or on straining or coughing, were defined as continent. finally, we evaluated intraoperative and postoperatively early and late complications of open radical prostatectomy and spinal anesthesia. early complications were defined as those that developed within one month postoperatively, and late ones those observed at least 1 month after operation. results we retrospectively screened 88 patients undergoing open radical prostatectomy for clinically localized prostate cancer (pca). median age was 67.7 years (range from 46 to 81 years) and median follow up duration was 48 months (6 to 54 months). median pre-operative psa was 15.9 ng/ml (range 2.1-80), median prostate weight (as reported by pathologist) was 44.58 g (range 12-86). median preoperative hb was 14.3 mg/dl, at hospital discharge hb was 10.3 mg/dl, and 9 patients have been transfused. median surgical time (calculated by surgical incision until closure of the skin) was 96.5 minutes (range 55-138). clinical-pathological stage were recorded in table 1. the efficacy of spinal anesthesia on muscle relaxation throughout the operative period has been always judged adequate by the surgeon. in all cases the surgery lasted less than two hours and the use of spinal anesthesia was more than sufficient. perioperative complications (intrapostoperatively) were recorded. the most frequent complication was post-operative anemia which was observed in 9 cases out of 88 requiring blood transfusion during stay in hospital and always after surgery. other early complications observed were anastomotic leakage in 2 patients that required prolonged drainage for more than 2 weeks with consequent extension of hospital stay. surgical site infection was observed in 3 patients, in all cases the infections were superficial and did not need specific treatment, surgical drainage being not required in any case. early complications directly related to spinal anesthesia were never observed. late complications were only related to surgical procedure: anastomotic stricture with poor urinary stream (< 10 ml/sec in qmax by uroflowmetry) was observed in 5 patients, requiring an endoscopic incision; more than half of them occurred within 6 months after operation. no case of lymphocele that required specific therapy. anterior urethral stricture was observed in 2 patients. most patients were discharged within 5 days from the procedure (range 3-17). following an anamnestic assessment conducted two weeks after the operation, we observed a quick recovery of total continence in 90% of patients. at six months visit all patients were perfectly continent. erectile dysfunction after 6 months was reported by 48 patients (not considering in this work the pre-operative status, the comorbidities and the correct intake of post-operative pde5 inhibitors). patients’ satisfaction was high; most of them confirmed that they were very happy with this anesthesia. discussion open radical retropubic prostatectomy is an effective treatment for localized prostate cancer but adequate anesthesiologic management is mandatory. spinal anesthesia is a form of regional anesthesia, which indications include lower abdominal and perineal surgery as are many genitourinary surgeries. the use of spinal anesthesia during radical prostatectomy is not usually considered as it is judged not suitable for long-term surgery with significant blood loss (8). in fact, it is generally considered not advisable to employ spinal anesthesia for surgeries lasting for more than 2 hours. on the other hand, time required for the performance of the open radical prostatectomy procedure varies depending on surgeon skill and competence. the advantages of this anesthesia technique for this type of operation are: patient comfort/satisfaction, less sedation score, faster postoperative recovery flatus passing, and mobilization/ambulation and pain control in the first hours postoperatively (8). other advantages are less effective surgical time, less use of amines and fluids, shorter post-anesthesia care unit stay as well as less hospital stay (9) and good muscle relaxation comparable to general anesthesia (10). studies demonstrated that in spinal anesthesia blood loss is less than with general anesthesia (12) although others do not sustain this finding (11). patients with locoregional anesthesia had significantly decreased risk of cardiac arrhythmia, deep vein thrombosis, respiratory depression, intubation risk, atelectasis, pneumonia, ileus, and postoperative nausea and vomiting (4), may have reduced risk of delirium in elderly ages (14) and had better overall survival after radical prostatectomy (14). the disadvantages are the limited duration of anesthesia in case of prolonged interventions, difficulties in the management of hemodynamics in case of significant blood loss as well as the need of conversion to general anesthesia in urgent care with an awake patient. table 1. pt2: 42pts pt3: 46pts n1: 8pts r+: 51pts t2a:5pts, t2b:2pts, t2c:35pts t3a:33pts, t3b:11pts t2an0r0:4pts t3an0r0:9pts t2an0r1:1pt t3an0r1:19pts t2bn0r0:1pt t3an0r2:3pts t2bn0r1:1pt t3an1r1:3pts t2cn0r0:18pts t3bn0r0:3pts t2cn0r1:17pts t3bn0r1:4pts t3bn1r0:1pt t3bn1r1:4pts archivio italiano di urologia e andrologia 2023; 95, 2 s. blanco, a. grasso, e. sulmina, m. grasso 17 spinal anesthesia is not always successful for long surgical procedures and is often associated with undesirable complications (15, 16). in our study the surgery procedure time was brief (median time 95 minutes). advantages of spinal anesthesia were also confirmed in our experience: reduced risk of respiratory complications and quick restoration of bowel function. the combination of the surgeon's experience (17, 18) able to perform the procedures with very limited laparotomies, and the known advantages of spinal anesthesia in terms of better control of postoperative pain, longer control of detrusor contractility, and no impact on the mental state of the patient in addition to the reduction of blood loss and the incidence of thromboembolic events (4), allows, in our opinion, to consider this surgical procedure as a minimally invasive procedure. in fact, these patients, as for other minimally invasive techniques, are characterized by a smooth postoperative time and early discharge, within 4 to 5 days. finally, we consider this procedure to be further advantageous not only in terms of costs for the national health service, but above all in terms of reducing the risk of postoperative delirium and cognitive impairment, given the large number of patients, including elderly ones, who are operated on today. in our opinion, we are recently creating a confused concept of invasiveness that cannot be measured with the length of a cut but with other parameters such as duration of surgery, blood loss, postoperative pain, absence of cognitive disorders, etc. conclusions we want to strongly emphasize that in choosing the type of anesthesia to use, the comparison with the prostatic adenomectomy surgery is crucial. in fact, all over the world and after many evaluations published and validated about 40 years ago, if there are no specific contraindications, prostatic adenomectomy is performed under spinal anesthesia. the reasons why the gold standard of radical prostatectomy surgery has been considered general anesthesia are essentially two: the long duration of the surgical procedure and the associated significant blood loss. it is known that, with the standardization of the surgical technique in highvolume surgical centers like our, the two types of surgery can be equated for bleeding risk and duration. multiple evidences show that radical retropubic prostatectomy can be safely performed under spinal anesthesia with various advantages (19), therefore it is no longer justified to consider general anesthesia as the only gold standard for radical prostatectomy with an open technique. our experience with spinal surgery could, of course, not be transferred to laparoscopic or robotic-assisted surgery where general anesthesia is currently mandatory due to patient’s positioning. references 1. pereira r, joshi a, roberts m, et al. open retropubic radical prostatectomy. transl androl urol. 2020; 9:3025-3035. 2. haese a, knipper s, isbarn h, et al. a comparative study of robotassisted and open radical prostatectomy in 10 790 men treated by highly trained surgeons for both procedures. m. bju int. 2019; 123:1031-1040. 3. walsh pc, retik ab, vaughan ed. anatomic radical retropubic prostatectomy. in: campbell’s urology, 7th ed., philadelphia: w.b. saunders, co., 1998; vol.3, chapt. 86, pp.2565-2588. 4. grasso m, torelli f, lania c, blanco s. the role of bladder neck preservation during radical prostatectomy: clinical and urodynamic study. arch ital urol androl. 2012; 84:1-6. 5. grasso m, blanco s, grasso aac, et al. radio guided radical prostatectomy: evaluation of feasibility, safety and clinical outcomes. minerva urol nefrol. 2016; 68:3-8. 6. fröhlich g, wördehoff a. the urethral protractor. a new instrument for facilitating the anastomosis between urethra and bladder in radical prostatectomy and urethro-intestinal anastomoses following cystectomy. urologe a. 1990; 29:155-7. 7. donovan jl, abrams p, peterset tj. the ics-‘bph’ study: the psychometric validity and reliability of the ics male questionnaire. br j urol. 1996; 77: 554-563. 8. salonia a, crescenti a, suardi n. general versus spinal anesthesia in patients undergoing radical retropubic prostatectomy: results of a prospective, randomized study. urology. 2004; 64:95-100. 9. kofler o, prueckner s, weninger e. anesthesia for open radical retropubic prostatectomy: a comparison between combined spinal epidural anesthesia and combined general epidural anesthesia. prostate cancer. 2019; 2019:4921620. 10. bajwa sj, kulshrestha a. anaesthesia for laparoscopic surgery: general vs regional anaesthesia. j minim access surg. 2016; 12:4-9. 11. wong rp, carter hb, wolfsonet a, et al. use of spinal anesthesia does not reduce intraoperative blood loss. urology. 2007; 70:523-6. 12. pöpping dm, elia n, van aken hk. et al. impact of epidural analgesia on mortality and morbidity after surgery: systematic review and meta-analysis of randomized controlled trials. ann surg. 2014; 259:1056-67. 13. european geriatric medicine, 2013; vol. 4, pp. s17-s18. 14. lee bm, ghotra vs, karam ja, et al. regional anesthesia/analgesia and the risk of cancer recurrence and mortality after prostatectomy: a meta-analysis. pain manag. 2015; 5:387-395. 15. hartmann b, junger a, klasen j, et al. the incidence and risk factors for hypotension after spinal anesthesia induction: an analysis with automated data collection. anesth analg. 2002; 94:1521-9. 16. bromage pr. neurological complications of subarachnoid and epidural anaesthesia. acta anaesthesiol scand. 1997; 41:439-44. 17. begg cb, riedel er, bachet pb. et al. variations in morbidity after radical prostatectomy. n engl j med. 2002; 346:1138-44. 18. gershman b, meier sk, jeffery mm, et al. redefining and contextualizing the hospital volume-outcome relationship for robotassisted radical prostatectomy: implications for centralization of care. j urol. 2017; 198:92-99. 19. pikramenos k, zachou m, apostolatou e, et al. the effects of method of anaesthesia on the safety and effectiveness of radical retropubic prostatectomy. arch ital urol androl. 2022; 94:396-400. correspondence salvatore blanco, md sblanco_74@yahoo.it marco grasso, md grasso.m@virgilio.it department of urology, fondazione irccs san gerardo dei tintori, monza, italy angelica grasso, md angelicagrasso84@gmail.com department of urology, asst santi paolo e carlo, university of milan, italy endrit sulmina, md e.sulmina@asst-monza.it department of anesthesia and intensive care medicine, fondazione irccs san gerardo dei tintori, monza, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper men, bladder cancer accounts for 70.7 cases per 100,000, while women account for 16.3 cases per 100,000 and it accounts for 3.6 per cent of all cancer mortalities (4.9 per cent men and 1.8 per cent women). the main risk factors include age, gender (men are considered to be at higher risk), smoking, exposure to chemicals; certain drugs used in cancer treatment, such as cyclophosphamide; chronic bladder inflammation such as urinary infections or cystitis; family history (4). there are various types of treatment including open, laparoscopic, and robotic surgery, immunotherapy, chemotherapy, and radiotherapy (5). surgery is the primary treatment for bladder cancer. depending on the patient's clinical need, bladder cancer surgery may include removal of the tumour from the bladder wall by cystoscopy (tur-v) or removal of the entire bladder (radical cystectomy). patients undergoing radical cystectomy may be candidates for bladder and urinary tract reconstruction or urinary diversion surgery. patients undergoing radical cystectomy (rc) and ileal conduit must learn to manage an ostomy that requires daily care, manual skills and must cope with the psychosocial impacts that accompany urostomy placement. maintaining patients' good quality of life (qol) depends largely on the caregiver's preparation and management skills (6). in this regard, before and after surgery, nursing and medical staff teach the patient and caregivers how to manage the new physical condition (4). the caregiver's role is of crucial importance; they will be entrusted to follow their relative's assistance at home, throughout the complete clinical and rehabilitation process (7). unfortunately, many caregivers are not adequately prepared to cope with the physical and psychological changes of post-cystectomy life and this leads to worsen the patients' quality of life (8). the aim of this study is to examine caregivers' experiences and training needs after radical cystectomy with urinary diversion for the first three months following the patient's discharge. our study is the first of its kind in italy, and it focuses exclusively on the three-month period at home, following discharge. objective: to examine caregivers' experiences and training needs after radical cystectomy with urinary diversion for the first three months following the patient's discharge. methods: this study applied a phenomenological design approach through open-ended interviews and descriptive analysis. phenomenology applied to empirical research requires researchers to explore the empirical facts narrated by participants. this study followed the consolidated criteria for reporting qualitative research guidelines, a 32 – item checklist for interviews and focus groups. the study population included caregivers of bladder cancer patients, admitted to three italian hospitals. data were collected between march 2020 and march 2022. results: fifty-two caregivers of patients who underwent cystectomy with urinary diversion from three italian hospitals (41 males and 11 females) participated to the study. the data analysis converged in the identification of three themes – with sub-themes – that included various aspects of the caregiver’s lived experiences: 1) living with the burden of being indispensable, for the family member, 2) feeling abandoned by institutions, 3) tiredness and less willingness to look after the relative due to work burden. conclusions: our study demonstrates that the caregiver of a patient with bladder cancer and urostomy in the first three months of hospital discharge is very worried and stressed. despite the training program received in hospital, the caregiver does not recognize the newly acquired skills and has difficulty applying them. further study would be required. key words: bladder cancer; caregiver burden; quality of life; urostomy. submitted 20 november 2022; accepted 22 november 2022 introduction a bladder neoplasia is a malignant tumour that forms in the bladder wall (1). worldwide, it is the ninth most common tumour and the most frequent of the genitourinary tract (2), while it accounts for (3, 4) per cent of all malignancies (america cancer society). it also ranks fourth among all malignant tumours affecting men and eighth among those affecting women (3). according to the italian society cancer registry (airt) every year among management of the patient with urostomy: caregiver needs during the three months after discharge. a qualitative study tatiana bolgeo 1, federico ruta 2, denise gatti 1, francesca gambalunga 3, laura iacorossi 4, roberta di matteo 1, salvatore cotroneo 5, carmelo boccafoschi 6, antonio maconi 1 1 department of research and innovation azienda ospedaliera ss antonio e biagio e cesare arrigo, alessandria, italy; 2 general direction, asl bat (health agency), andria, italy; 3 department of biomedicine and prevention, university of rome “tor vergata”, rome, italy; 4 national cancer institute “regina elena”, rome, italy; 5 sc urology, azienda ospedaliera ss antonio e biagio e cesare arrigo, alessandria, italy; 6 city of alessandria clinic monza polyclinic, alessandria, italy. doi: 10.4081/aiua.2023.11024 summary archivio italiano di urologia e andrologia 2023; 95, 1 t. bolgeo, f. ruta, d. gatti, f. gambalunga, l. iacorossi, r. di matteo, s. cotroneo, c. boccafoschi, a. maconi material and methods design this study applied a phenomenological design approach through open-ended interviews and descriptive analysis (9, 10). according to mortari (10), phenomenology applied to empirical research requires researchers to explore the empirical facts narrated by participants. the research questions focused on caregivers' experiences while caring for a family member with bladder cancer, who underwent radical cystectomy surgery with urostomy, during the 3 months following discharge. the study followed the consolidated criteria for reporting qualitative research (coreq) guidelines, a 32 – item checklist for interviews and focus group (11). this research was approved by the ethical committee of ss antonio e biagio e cesare arrigo hospital, alessandria, italy and data collection took place between march 2020 and march 2022. participants this study employed targeted sampling. the study population included caregivers of bladder cancer patients, who underwent radical cystectomy surgery with the creation of an urostomy in three italian hospitals, willing to share their experiences after their family member's hospital discharge. a minimum of 10 caregivers from each hospital were invited to participate, and recruitment continued until data saturation. caregiver recruitment took place at the hospital during patient discharge to facilitate collection of the caregivers’ experience in the daily management of the disease during the three months following discharge. the inclusion criteria were knowledge of the italian and english language, as well as experience in home care giving. the physicians and nurses in charge and working in the hospital unit made the initial contact with caregivers at least 48 hrs. before researchers, to ensure that the potential participants had enough time to consider their involvement (12). caregivers also received a leaflet, outlining the study's principles and inviting their participation. we agreed on this approach, as it was felt that presence of the patient could jeopardise the participant’s willingness to be open about some of the more negative aspects of caregiving and thus impact on our aim of obtaining in-depth and richly diverse experiences from the caregivers. participants provided written informed consent prior to enrolment, and they provided written informed consent to have their anonymized data presented or published. data collection the study setting was represented by the following hospitals: aou policlinico bari, puglia; azienda ospedaliera alessandria, piedemont; clinica città di alessandria, piedmont. the data was collected through a semi-structured open-ended interview; according to this type of interview the caregivers were able to describe their experiences according to how and what they thought essential to share. the interviews were conducted by rf (male, phd msn, rn), tb (female, phd, msn, rn) and (cb male rn, msn). the interviews were in part face-to-face within the hospital and in part by telephone. each participant chose between the two methods according to their personal needs. for the caregivers who choose face-toface interviews, a room within the hospital facility was available to maintain the confidentiality and the serenity necessary to share their story. the interviews were audiorecorded and verbatim transcribed by the interviewer. a total of 52 interviews were conducted (the time ranged from 30 to 60 minutes) (table 1). data analysis all interviews were transcribed verbatim by nvivo 12 and subsequently reviewed by nurse research scientists tb (rn phd) and fr (rn, phd). interviews were analysed using colaizzi’s (1978) descriptive analysis framework revisited by mortari (2019), which included the following steps: (1) in-depth reading of the transcripts to gain a deeper understanding and meaning of what was being said, by three researchers (tb, fr, cb); (2) extraction of meaningful descriptions provided by participants (tb, fr); (3) re-formulation of meanings into sub-themes and themes (tb, fr); (4) construction of themes’ descriptions of empirical-phenomenological qualities (tb, fr); (5) sharing results with participants for verification (tb, fr); (6) integration of the results into a complete description, i.e. the definition of general statements to summarise the participants' lived experience. the qualitative research data analysis software nvivo (12) was used for data management. table 1. caregiver semi-structured interviews. did the healthcare staff regarding the postoperative management of your family member, provide useful explanations and advice? at discharge, did you have any doubts about the management of the necessary guardianship for your family member? has your life changed from before surgery? could you describe what your typical day is like now? have you ever thought about going to the accident and emergency unit (a&e) in case of difficulty? what are the major difficulties encountered in the three months following discharge? table 2. caregiver socio-demographic characteristics. characteristics caregivers n = 52 age range 27-73 gender male 41 female 11 educational level elementary 28 lower intermediate 15 upper intermediate 7 bachelor’s degree 2 occupation employed full time 26 employed part time 7 unemployed 3 retired 16 relationship with patient spouse 34 daughter 6 son 12 home same 42 different 10 archivio italiano di urologia e andrologia 2023; 95, 1 map-uro results fifty-two caregivers of patients who underwent cystectomy with urinary diversion in three italian hospitals (41 males and 11 females) participated in the study. their socio-demographic characteristics is shown in table 2. the data analysis converged in the identification of three themes – with sub-themes – that include various aspects of the caregiver’s experiences: 1) living with the burden of being indispensable, for the family member, 2) feeling abandoned by institutions, 3) tiredness and less willingness to look after the relative due to work. theme 1: living with the burden of being indispensable to the family member this theme describes the burden the caregiver experiences after discharge. returning home and managing the family member alone, causes insecurity and increases the burden of the caregivers and awareness of their own abilities and limits. disease management involves the development of skills that the caregiver did not previously possess. returning home after discharge involves taking full personal custody of the family member, increasing the burden of responsibility. replacing professional healthcare staff involves the fear of making mistakes and causing harm. two subthemes have been identified, a) "i am not a healthcare professional" and b) "i am afraid of making mistakes." sub-theme 1a: "i am not a healthcare professional" during hospitalization, the patient identified and named his caregiver, who participated in an educational training program that included several meetings with doctors and nurses to plan for possible difficulties to be faced while managing the stoma at home. the caregivers in hospital feel secure and are confident that they are capable of coping with the post-discharge process. at home, however, the situation does not reflect the same feelings: “the problem is that at home i don't have the opportunity to compare myself with someone who understands .... i'm alone” (c6cf), “i am not a nurse and i do not know what to do sometimes ..... i get anxious ... i am afraid of making mistakes” (c2rs) sub-theme 1b: "i am afraid of making mistakes" “in the hospital i felt protected and when i looked after my family member, i had no hesitation. i knew there was someone always ready in case of difficulty” (c9re); “even though i understand what i have to do, the emotional side stops me” (c4as); “it would be enough for me to look at the doctor's eyes and i would have the strength to go on” (c11et); “my family members look at me and monitor me; they think i can make mistakes at any moment” (c8ap). theme 2: feeling abandoned by institutions the second theme describes the condition of feeling abandoned and the stress that the carer feels after hospital discharge. the distancing from healthcare staff causes not only fear but also a sense of strong insecurity. loneliness decreases the awareness of one's own abilities and increases the possibility of making mistakes a subtheme was identified: "the network does not exist". sub-theme: “the network does not exist” at home, the caregiver starts an adaptive phase and tries to implement all the operational instructions they have learnt from the healthcare professionals. in most cases the caregiver changes their habits and moves into the home of the family member they are caring for to avoid leaving them alone. from the interviews it emerged that after a week or so the caregiver tries to contact the family doctor to discuss the hospital discharge letter and new treatments to be administered. "one must remember that the doctor .... if he answers..... does so at set times and first one has to talk to the secretary...... i hope i never get sick after 7 p.m. otherwise i will have to go to the accident and emergency unit" (c21nm); "you must go to the district....there, they will order you the supplies......but i need them now, so how will i manage? (c24op); "the general practitioner told me to be patient......it takes a few days ......then i try phoning the hospital but even there it' s like winning the lottery. the phone rings but nobody answers.... i try again until the switchboard tells me to hold...... again!!!!.......if i can't speak to anyone by tomorrow, i'll go to the hospital." (c26un); "my brother told me don't worry, i'll try to call or go in person and ask what we should do......" (c14lp), theme 3: tiredness and less willingness to look after the relative due to work this theme describes the caregiver's mood and work difficulties during the three months after discharge. they must cope with a new organisation, which in most cases means a lack of free time as they must take care of a family member, in need of assistance. such a situation can be a source of enormous stress for the caregivers, who, in addition to their work, must worry about an equally tiring and demanding subsidiary activity. two sub-themes are identified: a) tiredness and b) sense of responsibility. sub-theme 3a: tiredness the thought of being the only family member caring for the patient causes a sense of fatigue that in the long term impairs daily life. symptoms such as insomnia and asthenia arise, leading to irritability "i hardly sleep at night and i'm nervous during the day... i didn't think taking care of my mum was so demanding... i don't know if i can do it much longer!" (c31tm); "i no longer have time to do anything......my life is centred on my mother's needs and she calls me all the time.....i am tired!" (c36vl) sub-theme 3b: sense of responsibility "every morning i get up with the thought that i have to go to work... i pray that nothing happens at home otherwise how can i manage? i can't leave work and i don't know who to call...." (c2nm); "the problem is that m. doesn't need continuous care but if a tube comes out and i'm not there he gets scared and who knows what happens... it happened once, a few hours passed... and then we had to go to hospital" (c14un). discussion caregivers caring for family members with bladder cancer who have undergone cystectomy and urinary diversion carry a burden.1 many of them are not adequately prepared to cope with post-ostomy life, and they reported that these difficulties often led to a reduced quality of life for the family member as well (8, 13). our study conarchivio italiano di urologia e andrologia 2023; 95, 1 t. bolgeo, f. ruta, d. gatti, f. gambalunga, l. iacorossi, r. di matteo, s. cotroneo, c. boccafoschi, a. maconi ducted in italian hospitals on caregiver experiences, notes some similarities with other studies conducted in other countries. similar difficulties and problems are mentioned such as the need for communication, an increased network, burden and caregiver stress (1, 7). our study reinforces themes highlighted in other studies that cite the importance of good caregiver health education during the family member's hospitalization and identifies a weaker development of community-based services compared to the rest of europe (12). it also reinforces the concept about the sense of duty felt by caregivers and emphasizes the need to obtain some free time for relaxation and leisure to continue caregiving subsequently (8, 14). the originality and strength of this study is to investigate caregivers' difficulties in the first three months after discharge. there are no studies in literature investigating this context. the first months reveal all the doubts and critical issues of caregivers and are the ones most at risk of improper hospital admissions. it emerged from the study themes, that in addition to the training program, an active network and more effective communication with healthcare staff, even after discharge, are crucial. conclusions our study demonstrates that the caregiver of a patient with bladder cancer and urostomy in the first three months after hospital discharge is very worried and stressed. despite the training program received in hospital, the caregiver does not recognize the newly acquired skills and has difficulty applying them. the lack of an active network and effective communication causes insecurity and subsequent hospital re-admissions. there were no substantial differences within the three hospitals for study performance. however, this study has not analysed the different approaches among different informal caregivers and financial status. therefore, further study would be required. references 1. fitch mi, miller d, sharir s, mcandrew a. radical cystectomy for bladder cancer: a qualitative study of patient experiences and implications for practice. can oncol nurs j rev can nurs oncol. 2010; 20:177-187. 2. linee guida carcinoma della vescica. published online 2015. 3. jackson ss, marks ma, katki ha, et al. sex disparities in the incidence of 21 cancer types: quantification of the contribution of risk factors. cancer. 2022; 128:3531-3540. 4. murray ks, prunty m, henderson a, et al. functional status in patients requiring nursing home stay after radical cystectomy. urology. 2018; 121:39-43. 5. gulliford mc, petruckevitch a, burney pg. survival with bladder cancer, evaluation of delay in treatment, type of surgeon, and modality of treatment. bmj. 1991; 303:437-440. 6. masiero m, busacchio d, guiddi p, et al. quality of life and psycho-emotional wellbeing in bladder cancer patients and their caregivers: a comparative analysis between urostomy versus ileal orthotopic neobladder. ecancermedicalscience. 2021; 15:1163. 7. hockman l, bailey j, sanders j, et al. a qualitative assessment of patient satisfaction with radical cystectomy for bladder cancer at a single institution: how can we improve? res rep urol. 2020; 12:447-453. 8. northouse ll, katapodi mc, schafenacker am, weiss d. the impact of caregiving on the psychological well-being of family caregivers and cancer patients. semin oncol nurs. 2012; 28:236-245. 9. colaizzi. existential phenomenological alternatives. accessed august 18, 2022. https://scholar.google.com/scholar_lookup?title=existentialphenomenological+alternatives+for+psychology&author=p.f.+colaizzi &publication_year=1978& 10. mortari l. la fenomenologia empirica in: l.mortari, l. ghirotto. metodi per la ricerca educativa. carocci editore, 2019, pp.41-77 11. tong a, sainsbury p, craig j. consolidated criteria for reporting qualitative research (coreq): a 32-item checklist for interviews and focus groups. int j qual health care j int soc qual health care. 2007; 19:349-357. 12. bagnasco a, rosa f, dasso n, et al. caring for patients at home after acute exacerbation of chronic obstructive pulmonary disease: a phenomenological study of family caregivers’ experiences. j clin nurs. 2021; 30:2246-2257. 13. wulff-burchfield em, potts m, glavin k, mirza m. a qualitative evaluation of a nurse-led pre-operative stoma education program for bladder cancer patients. support care cancer off j multinatl assoc support care cancer. 2021; 29:5711-5719. 14. cianfrocca c, caponnetto v, donati d, et al. the opinions and feelings about their educational needs and role of familial caregivers of parkinson’s disease patients: a qualitative study. acta bio-medica atenei parm. 2020; 91:e2020002. correspondence tatiana bolgeo, rn phd tbolgeo@ospedale.al.it denise gatti, rn dgatti@ospedale.al.it roberta di matteo rn msn1, (corrsponding author) rdimatteo@ospedale.al.it antonio maconi, md amaconi@ospedale.al.it department of research and innovation azienda ospedaliera ss antonio e biagio e cesare arrigo via venezia 16, 15100 alessandria (italy) federico ruta, rn phd federico.ruta@aslbat.it general direction, asl bat (health agency), andria (italy) francesca gambalunga, rn phd francescagambalunga86@gmail.com department of biomedicine and prevention, university of rome “tor vergata”, rome (italy) laura iacorossi, rn phd laura.iacorossi@gmail.com national cancer institute “regina elena”, rome (italy) salvatore cotroneo, rn scotroneo@ospedale.al.it sc urology, azienda ospedaliera ss antonio e biagio e cesare arrigo, alessandria (italy) carmelo boccafoschi, md cboccafoshi@libero.al.it city of alessandria clinic monza polyclinic, alessandria (italy) conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2013; 85, 3118 introduction human follicle stimulating hormone (fsh) is a heterodimeric pituitary glycoprotein that regulates gonadal function in both male and female. in males, fsh stimulates sertoli cell proliferation and function. it shares with testosterone in the initiation and maintenance of spermatogenesis (1-3). several workers reported the positive outcome of fsh therapy on sperm quality and fertilizing capability (4-7), sperm production (5, 7-10), sperm fine construction (11, 12) and enhancement in conception rate after gamete micromanipulation (7, 13, 14). because of these obviously significant tasks on spermatogenesis, fsh has been original paper isolated low follicle stimulating hormone (fsh) in infertile males – a preliminary report nader salama 1, mohamed el-sawy 2 1 departments of urology and clinical pathology, 2 alexandria faculty of medicine, alexandria, egypt. objectives: high levels of follicle stimulating hormone (fsh) in infertile males received a significant attention and exploration. studies investigating the isolated deficiency of fsh in males are few, and its real prevalence is still unknown. therefore, the objectives of the current study was to report the prevalence of isolated low fsh in infertile males and highlight their demographics and standard sperm parameters. methods: records of 3335 infertile men were retrospectively checked. patients with isolated low fsh were retrieved. fsh levels were categorized into 3 groups based on the number of affected sperm parameter (s). study variables were also arranged into 2 groups in relation to smoking history. a control group was included to document the changes in sperm morphology. results: isolated low fsh (1.146 ± 0.219 miu/ml) was found in 29 (0.87%) patients. all patients showed at least one abnormal sperm parameter. the abnormal parameters were present in different combinations within the same patient but with no significant correlations with the fsh levels. the fsh levels got lower as the number of the affected sperm parameters increased although the decline was insignificant. the most frequent abnormal parameter presented was sperm morphology (86.2%). anomalous sperm morphology was highly and significantly demonstrated in the head; specifically in acrosome. abnormal sperm parameters were present in both smoking and nonsmoking groups but with no significant differences in between. conclusions: isolated low fsh among infertile males has a low prevalence. this may be associated with abnormality in semen parameters; particularly sperm morphology. these patients are suggested to be found as a primary entity. however, an additional work-up is highly recommended to validate this hypothesis.. key words: male infertility; low fsh; sperm parameters. submitted 15 april 2013; accepted 31 may 2013 no conflict of interest declared summary acknowledged as a regular laboratory test in the evaluation of the infertile male (2, 6). most reports dealing with fsh in males have focused on its high level associated with disorders of testicular structure and altered spermatogenesis, and how it can act as a predictor of retrieving sperms for subsequent in-vitro gamete micromanipulation (15, 16). in such situations, fsh altered level is often accompanied with changes in other requested hormones like testosterone and lh. on the contrary, studies investigating the isolated deficiency of fsh in males on clinical level are lacking. literature review shows mostly few case reports indicating such doi: 10.4081/aiua.2013.3.118 119archivio italiano di urologia e andrologia 2013; 85, 3 isolated low follicle stimulating hormone (fsh) in infertile males – a preliminary report unique deficiency in males (17-19). at best, isolated low fsh in men was cited at a glance on referring to a small study subgroup whose patients were extremely few, and only to reveal the beneficial effect of fsh therapy on these patients (20). infertile females were fortunate. their problems with isolated low fsh received better attention. there are several studies which reported this problem in females, and research was expedited to investigate polymorphism in fsh receptor (21) and fsh auto-antibodies (22, 23). therefore, the prevalence of isolated low fsh in infertile males have not yet been reported. this prompted us to assess this prevalence among egyptian infertile males, highlight their demographics and report the implication of the isolated low fsh on their standard semen parameters; with a special emphasis on sperm morphology. patients and methods study design this retrospective study was carried out at the departments of urology and clinical pathology, alexandria faculty of medicine, alexandria, egypt. evaluation of records of 3335 consecutive men consulting for delayed pregnancy, during the period between february 2004 to may 2012, was accomplished. patients with fsh value ≤ the lower limit of the normal range (1.5-12.4 miu/ml) given by our laboratory kits were recruited. the study was approved by the departmental review boards. inclusion criteria these criteria defined what we meant by isolated low fsh. so, male patients with low fsh but with normal levels of testosterone (t), luteinizing hormone (lh) and prolactin (prl) were enrolled in the study. the criteria included also absence of any clinically detectable varicocele, excess white blood cells (wbc) in semen, antibody-mediated sperm disorder or female factor. absence of varicocele was further confirmed by scrotal duplex scanning using 7.5 mhz probe (aloka,ssd-1700, dynaview ii, tokyo, japan). the presence of abnormally elevated wbc in semen (24, 25) was confirmed using peroxidase test (26). lack of sperm-associated antibody was indicated by mixed antiglobulin reaction (mar) which failed to demonstrate any antisperm antibodies in semen of these patients. hormonal assay blood samples were taken for hormonal assays in the morning at 9: 00-10: 00 o’clock in a heparinized syringe. serum fsh concentrations as well as other hormones (t, lh and prl) were measured using roche elycsys 4020 and cobas e411 automated electrochemiluminescence systems (roche diagnostics gmbh, mannheim, germany). the lower detection limit for fsh was 0.1 miu/ ml. fsh levels were confirmed by re-testing on 2 different occasions. the intra-assay and inter-assay coefficients of variation were < 10%. additional retrieved data after final recruitment of the study patients, additional data were retrieved from their files. these included socio-demographic features as age, occupation, body weight, alcohol intake and smoking habit. retrieved data also incorporated past, drug and family histories, duration of infertility, physical examination and semen analysis results. semen analysis at least, each patient had 3 previous semen reports when he was first seen in our university clinic. all these reports denoted abnormality in one or more of sperm parameters. then a recent semen analysis was accomplished in our facility using manual check up in 16 cases but computer assisted semen analysis (casa) in the subsequent 13 cases. the casa machine was sperm class analyser sca gii (barcelona, spain). the examination included assessment of semen volume, sperm concentration / ml, percentage total and active (scale a-b) motility of sperm and percentage normal sperm forms. the world health organization (who) sperm criteria were used to define normal or abnormal semen parameters using who 1992 handbook (24) for manual assessment and who 1999 handbook (25) for casa evaluation as the study patients were recruited along several years. for further study of the association between state of fsh in the current study and details of sperm morphology as assessed by casa for 13 patients (casa subgroup), a control group (n = 13) was included. statistics the raised data were analyzed using spss statistical software for windows release 20 (spss inc., chicago, usa) on a personal computer. the relationships between serum fsh and sperm parameters were quantified using the spearman rank correlation coefficient (r). fsh levels were categorized into 3 groups based on the number of affected sperm parameter (one, two or three) which included sperm count, total motility and morphology, and comparison between the resulting 3 groups was done using mann-whitney test. the sperm parameters were arranged into 2 groups (normal vs abnormal), and fsh of each resulting group was included. comparison between normal vs abnormal group per each sperm parameter was done using independent-samples t test. according to smoking history, patients’ data including fsh levels and sperm parameters were put into 2 groups (smoking vs nonsmoking). impact of smoking on these variables was also analyzed with independent-samples t test. the same test was also used to compare between the study patients and controls as regard detailed description of the sperm morphology. p-value < 0.05 was considered significant. results patients of 3335 checked files, 29 patients with isolated low fsh were recruited. this yielded a prevalence of 0.87% for this group of patients. at entry, the patients had age (30.55 yr ± 3.85), weight (76 kg ± 15.97) and fsh level (1.146 miu/ml ± 0.219). there was no significant correlation between patient fsh levels and ages (r = 0.1, archivio italiano di urologia e andrologia 2013; 85, 3 n. salama, m. el-sawy 120 p = 0.61). all patients had primary infertility with a duration (3 yr ± 2.8); except 3 who had secondary infertility with a duration (5.73 yr ± 4.94). all study patients were white collar employees. their partners were (16-29) yr old for the group of primary infertility and (21-37) yr old for the group of secondary infertility. fertility check up of the partners excluded female factor. past and family histories were irrelevant and the patients did not receive any prior hormonal treatment or medications which might affect testicular function. self-reported alcohol intake was nil. thirteen patients were smokers, another 13 were nonsmokers while no data were available for 3 patients. clinical examination showed no abnormalities. the 13 controls had comparable age ( 27.3 y ± 3.1 vs 30 y ± 2.8) to that of the casa-patients subgroup. they were clinically free and had normal fsh (4.9 miu/ml ± 1). their other hormones and lab data were normal. sperm parameters all the study patients presented normal semen volumes (2.87 ml ± 1.26). they showed abnormalities in their semen reports. these abnormalities involved one or more of the studied sperm parameter(s). the number of the patients presented with 2 combined abnormal parameters was higher than those of the patients who had either 1 or 3 abnormal parameters (table 1). the most frequently affected parameter was morphology (table 2). abnormal sperm morphology in the casa-patients subgroup this was seen involving the head, mid-piece and tail. the head was the part with the highest percentage of abnormalities (40% ± 4.4) compared with mid-piece (24.3% ± 6.5) or tail (29.3% ± 4.3). the most frequent head deformity was abnormal acrosome (49.2% ± 6.2). the controls showed significantly less anomalies in the sperm head (21.6% ± 5.2; p < 0.001) and acrosome (20.1% ± 3.5; p < 0.001). relation between fsh level and semen parameters the level of fsh declined as the number of affected sperm parameters increased. however, this decline in fsh level was not significant (table 1). it was of interest that the fsh levels were obviously lower in all the patients’ groups with abnormal sperm parameters compared to those levels of the patients’ groups with normal parameters (table 2). again, these differences in fsh levels were insignificant; except with total sperm motility. there were also no significant correlation between fsh level and semen volume (r = -0.27, p = 0.16) or any abnormally affected sperm parameter (table 3). no negative impact of smoking on the study variables no statistically significant differences were appreciated between the smoking and nonsmoking group in regard to any of the study variables (table 4). number of negative patient number fsh (mean ± sd) sperm parameter(s) (%) miu/ml 1 5 (17.2) 1.22 ± 0.29 2 14 (48.3) 1.17 ± 0.20 3 10 (34.5) 1.07 ± 0.20 sperm parameter normal levels abnormal levels p-value mean ± sd patient no. fsh mean ± sd patient no. fsh no. (%) (mean ± sd) (%) (mean ± sd) count (106/ml) 82.91 ± 40.46 11 (38) 1.16 ± 0.28 2.59 ± 3.3 18 (62) 1.14 ± 0.18 0.845 total motility (%) 54 ± 4.6 11 (38) 1.27 ± 0.13 23.42 ± 14.82 18 (62) 1.08 ± 0.23 0.011 active motility (%) 33.75 ± 7.44 8 (27.6) 1.17 ±0.14 6.76 ± 7.36 21 (72.4) 1.14 ± 0.25 0.683 morphology (%) who 1992 37.5 ± 9.6 4 (13.8) 1.18 ± 0.32 15.67 ± 6.73 12 (41.4) 1.15 ± 0.25 0.878 who 1999 6.39 ± 1.33 13 (44.8) 1.13 ± 0.18 25 (86.2) table 1. categorization of fsh levels in relation to the number of negative sperm parameter(s)*. table 2. normal and abnormal sperm parameters of the study patients and fsh levels (miu/ml) in each group*. p = 0.143 p = 0.515 p = 0.326 } } } * mann-whitney test * independent-samples ttest. 121archivio italiano di urologia e andrologia 2013; 85, 3 isolated low follicle stimulating hormone (fsh) in infertile males – a preliminary report discussion gonadotropin deficiency in men is rather uncommon. low fsh was reported previously; either in studies dealing with hypogonadotrophic hypogonadism (9, 27) or without any note about other reproductive hormones (28). so, such reported low fsh was not an isolated deficiency. recently, a study by efesoy et al. (20) included a subgroup of infertile men with a real isolated low fsh among its other subgroups while checking for response to fsh therapy. however, the sample was very small in number and just touched at a glance without detailed reporting of related demographical, clinical or laboratory findings. clinical studies investigating the isolated deficiency of fsh in males are lacking and mostly old case-reports (17-19, 29). enrollment of male patients to launch a study related to this isolated hormonal deficiency, either clinically or epidemiologically, is extremely difficult. therefore, the characteristic features of patients with this deficiency have not been well defined so far. in the present study out of 3335 infertile males, only 29 patients with isolated fsh deficiency were successfully recruited giving a prevalence of 0.87%. to the best of our knowledge, this is the first study documenting this prevalence of isolated low fsh in infertile males, and it included the largest number of infertile men with this deficiency so far in the literature. this rarity of selective fsh deficiency in males made some investigators to claim that existence of this deficiency as a primary entity is not clear (29). these investigators presented case reports for patients with remarkably low and sometimes undetectable levels of fsh. in the current study, we presented a complete and true degree of selective fsh deficiency, and we think that it could be found as a primary entity. three reasons may support our suggestion. first, the levels of fsh (1.146 ± 0.219 miu/ml) in our patients were obviously below the lower limit of normal laboratory range. this low level, a) was not due to spurious laboratory results as retesting fsh level confirmed the first result, and b) would remain low even on considering fsh periodicity which was documented in some studies to have an amplitude of 0.21 ± 0.03 miu/ml (30). the standardized chemiluminescence used in the present study was, therefore, suitable although it is less sensitive than other assays like delfia method (31). we wished also to test serum inhibin and anti-mullerian hormone levels which could have been used as a lab corollary to the low fsh but such testing was, unfortunately, not available in this country during the time when the study patients were first seen in the clinic, long years ago. second, we selected only the patients with really isolated low fsh. so, the potentially negative implications imposed by clinical or other reproductive hormonal disorders were excluded from the start. third, tobacco smoking, which was the only unavoidable factor in the current study, did not cause any further adverse effect on the already declined sperm parameters. however the declined parameters of the patients in the smoking group showed less drop than those of the non-smoking group patients. this current finding about lack of negative effect of tobacco smoking comes in line with other investigators who denied any effect of smoking on any sperm parameter (32) but it disagrees with others who reported negative implications on sperm parameters induced by smoking (33). this point may be criticized by some as the number of patients in the smoking group was 13 patients and might by relatively small to draw conclusion. however, recruitment of sufficient number of patients with isolated low fsh and also with negative history of smoking would be extremely difficult; if not impossible. we tried, in the present study, to exclude any factors with negative impact on sperm parameters as much as possible in order to demonstrate clearly the real relationship between isolated low fsh and sperm parameters. study point smoking group nonsmoking group pvalue fsh level (miu/ml) 1.12 ± 0.24 1.14 ± 0.19 0.758 semen volume (ml) 2.89 ± 0.83 2.59 ± 0.74 0.352 sperm count (106/ml) 43.61 ± 57.19 19.52 ± 32.7 0.2 sperm total motility (%) 36.15 ± 18.61 33.08 ± 20.67 0.694 sperm active motility (%) 14.77 ± 12.94 16.92 ± 15.75 0.707 sperm normal forms (%) who 1992 23.29 ± 9.34 18.33 ± 17.22 0.548 who 1999 6.67 ± 1.63 6.14 ± 1.07 0.52 table 4. fsh levels and sperm parameters in relation to smoking *. * independent-samples ttest. sperm parameter mean ± sd correlation with fsh count (106/ml) 33.06 ± 46.52 p = 0.66 r = 0.09 total motility (%) 33.97 ± 19.15 p = 0.19 r = 0.25 active motility (%) 14.21 ± 14.26 p = 0.77 r = 0.06 morphology (%) who 1992 21.13 ± 11.11 p = 0.89 r = 0.04 who 1999 6.39 ± 1.31 p = 0.24 r = 0.35 table 3. sperm parameters of the 29 study patients and correlation with fsh levels *. * spearman rank correlation coefficient. archivio italiano di urologia e andrologia 2013; 85, 3 n. salama, m. el-sawy 122 pathogenic alterations in the hypothalamus or the pituitary have been incriminated as possible reasons for the defect in fsh secretion. in the current study, lh was within normal levels in all patients. so, a discrepancy in the levels of both hormones happened although different studies pointed out that both hormones are released from the same pituitary cell type (34). a possible explanation could be attributed to a change in the nature of gnrh pulse frequency and/or amplitude with a consequent abnormal fsh secretion by the pituitary cells (35). in support for this suggestion, recent studies demonstrated the differential interpretation ability of the same gonadotropin to the different gnrh inputs which depends mainly on signal-regulated mechanisms (36) as well as epigenetic factors (37) in maintaining these energetic responses of the gonadotropin. other causes which may decrease the fsh level alone may be attributed to multifaceted mutations in the coding region of the fsh gene (21). in the current study, screening for fsh-β gene has not been done due to financial reasons. these shortcomings in the present study may not unveil the exact reasons involved in the isolated fsh decline in the study patients. the present study is just a preliminary report, and we are starting now to collect new patients with similar abnormality who will be thoroughly screened for possible etiology in a new study. in the present work, isolated low fsh was associated with low percentage motile sperm in the majority of the patients. this comes in line with efesoy et al. (20) and novero et al. (28) although the number of patients in both studies were very limited. maroulis et al. have also reported similar abnormalities in sperm motility in their case reporting for 2 patients (18). this drop in sperm motility may be explained on the basis of the alteration in sertoli cell function due to the decline in fsh level which is known to stimulate its structure and function (3). this modification in function is expected to affect the growth factors secreted by the sertoli cell (38) where many of these factors are known to promote sperm motility (39). recent studies have addressed the existence of specific receptors for many of these factors on the sperm membrane itself (40). this may be a probable reason why some patients of the current work were infertile although they had sufficient number of motile sperms which may deal with their problem of asthenospermia. the drop in sperm concentration in the majority (62%) of the study patients is well accredited to the crucial role of fsh in the induction, regulation and maintenance of the spermatogenesis (3). the present study revealed also increased percentage abnormal forms as governed by who criteria (24, 25) in all patients, except only 4. this ranked the abnormal sperm morphology as the most prevailing anomaly associated with isolated low fsh. we agree, therefore, with novero and his co-workers (28) who showed a decline in normal forms in one of their patients and a borderline state in the second. the present study showed also an interesting finding, that is related to the sperm head anomalies. these anomalies represented the most frequent abnormalities in sperm morphology. they involved, in particular, the sperm acrosome. this may agree indirectly with bartoov et al. (41) who showed that abnormal forms, from infertile men who were kept on fsh therapy, were associated with significant improvement in acrosome shape with drop in its agenesis to reach normal frequency. the present finding of increased percentage of acrosome anomalies agrees also with courtens and courot (42) who showed that morphogenesis of the acrosome and its expansion in hypophysectomized ram was modulated by fsh and testosterone. recently, the enhancing effect of recombinant fsh on sperm morphology was also addressed in many studies which reported a significant increase in the sperm normal morphology after treatment (4, 6-8, 11, 14, 43). some of these studies indicated clearly the drop in head and acrosomal aberrations with this treatment (4, 11). conclusion isolated low fsh in infertile men has a low prevalence. disturbance in one or more sperm parameter (s) is (are) usually existent although abnormal sperm morphology was almost always present. anomalous sperm head with abnormal acrosome were the most eminent morphological findings. therefore, the need to measure serum fsh concentration in the infertile male has been reconfirmed. although the number of reported male patients with isolated low fsh in the literature is extremely limited so far, nevertheless, we believe that infertile men with isolated low fsh may be found as a primary entity in male infertility. extension of this work to thoroughly screen these patients for possible etiologies is highly recommended to validate this hypothesis. notes a master table containing the retrieved data of this study is documented, certified and saved at the department of urology, alexandria faculty of medicine, alexandria, egypt. statement of authorship nader salama: conception and design of the study, collection, analysis and interpretation of data, and drafting the article with final approval of its completed form. mohamed el-sawy: collection and interpretation of the data, and drafting the article with final approval 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to fsh treatment in oligozoospermic men depends on fsh receptor gene polymorphisms. int j androl. 2011; 34:306. correspondence nader salama, md (corresponding author) department of urology alexandria faculty of medicine alexandria, egypt nadersalama58@yahoo.com mohamed el-sawy, md department of clinical pathology alexandria faculty of medicine alexandria, egypt elsawymohamed@gmail.com stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11361 1 original paper introduction worldwide, nephrolithiasis is one of the commonest urologic diseases. in the last decades, the prevalence of nephrolithiasis has changed, with prevalence ranges from 7% to 13%, 5% to 9%, and 1% to 5% in north america, europe, and asia, respectively (1). the wide prevalence ranges among countries reflect several multifactorial conditions including age, sex, race, climate, occupation, dietary habits, fluid intake, genetic and metabolic diseases (2). in asia, the prevalence and incidence of urolithiasis have increased in most of the countries specifically more in the south asian countries than in the north asian countries (5.5% to 11.6% compared to 2.6% to 7.2%, respectively) (3). this is because of the higher temperature and excessive sunshine exposure in the south countries than that in the north countries. saudi arabia is located in the west asian region and due to its high temperature and semiarid climate the prevalence of urinary tract stones was documented to be rising. during the period from 1989 through 2008, the prevalence rate of urolithiasis has been increased from 6.8% (4) to 19.1% (5). renal stone recurrence is a devastating health problem, which affects the patients’ health-related quality of life (6), as well as represents an extra economic burden for its management (7). in a prospective study, trinchieri et al. studied the stone recurrence rate and risk after a first stone episode and found that 27% of patients developed symptomatic stone recurrence at mean follow-up of 7.5 years. in addition, age at onset of the disease was significantly lower for patients with ≥ 2 recurrence than those who had only 1 or no recurrence (8). among asian countries, the reported recurrence rate of urolithiasis in the first year was about 6% to 17%, and at 5 years reaching up to 53%, while the lifetime risk of urinary stones recurrence is estimated to be 60% to 80% (9). in saudi arabia, abdel-halim et al. reported a recurrence rate of renal stone ranging from 38.6% to 53.2% (4). studies evaluating the risk factors of renal stone recurrence are not common. our study aimed to explore the demographic characteristics of primary renal stones forobjectives: we evaluated the baseline characteristics, and risk factors of renal stone recurrence among saudi arabian patients after successful primary stone treatment. materials and methods: in this cross-sectional comparative study, we reviewed the medical records of patients who presented consecutively with a first renal stone episode from 2015 to 2021 and were followed-up by mail questionnaire, telephone interviews, and/or outpatient clinic visit. we included patients who achieved stone-free status after primary treatment. patients were divided into two groups: group i (patients with first episode renal stone) and group ⅱ (patients who developed renal stone recurrence). the study outcomes were to compare the demographics of both groups and to evaluate the risk factors of renal stone recurrence after successful primary treatment. we used student’s t-test, mann whitney test or chi-square (𝝌2) to compare variables between groups. cox regression analyses were used to examine the predictors. results: we investigated 1260 participants (820 males and 440 females). of this number, 877 (69.6%) didn’t develop renal stone recurrence and 383 (30.4%) had recurrence. primary treatments were percutaneous nephrolithotomy (pcnl), retrograde intrarenal surgery (rirs), extracorporeal shock wave lithotripsy (eswl), surgery and medical treatment in 22.5%, 34.7%, 26.5%, 10.3%, and 6%, respectively. after primary treatment, 970 (77%) and 1011 (80.2%) of patients didn’t have either stone chemical analysis or metabolic work-up, respectively. multivariate logistic regression analysis revealed that male gender (or: 1.686; 95% ci, 1.216-2.337), hypertension (or: 2.342; 95% ci, 1.439-3.812), primary hyperparathyroidism (or: 2.806; 95% ci, 1.510-5.215), low fluid intake (or: 28.398; 95% ci, 18.158-44.403) and high daily protein intake (or: 10.058; 95% ci, 6.400-15.807) were predictors of renal stone recurrence. conclusions: male gender, hypertension, primary hyperparathyroidism, low fluid intake and high daily protein intake increase the risk of renal stone recurrence among saudi arabian patients. key words: renal stone; risk factors; recurrence; saudi arabia. submitted 5 april 2023; accepted 28 may 2023 evaluation of risk factors for recurrent renal stone formation among saudi arabian patients: comparison with first renal stone episode mohammed alshehri1, hind alsaeed2, malath alrowili 2, faisal alhoshan3, ali abdel raheem4, 5, ayman hagras5, 6 1 department of urology, king abdullah bin abdulaziz university hospital, princess nourah bint abdulrahman university, riyadh, saudi arabia; 2 princess nourah bint abdulrahman university, riyadh, saudi arabia; 3 prince sultan military hospital, taif, saudi arabia; 4 department of urology, king saud medical city, riyadh, saudi arabia; 5 department of urology, tanta university hospital, tanta, egypt; 6 division of urology, surgery department, sharurah armed forces hospital, sharurah, saudi arabia. doi: 10.4081/aiua.2023.11361 summary archivio italiano di urologia e andrologia 2023; 95(3):11361 m. alshehri, h. alsaeed, m. alrowili, f. alhoshan, a. abdel raheem, a. hagras 2 mer, as well as the risk factors of renal stone recurrence after successful primary treatment in saudi arabia. we believe that the results of this study may provide an insight into ways that can help us to prevent the recurrence of renal stones. materials and methods study design and ethical statement a prospective cross-sectional comparative study was carried out at four saudi arabia's tertiary centers in riyadh, taif and sharurah cities. the study was approved by the institutional review boards and ethical committee of princess nourah bint abdulrahman university and was performed in accordance with the ethical standards and the helsinki declaration (institutional review board “irb” registration number: h-01-r-059). all patients included in our study signed a written informed consent. we reviewed the medical records of patients who presented consecutively with a first renal stone episode from 2015 to 2021 at urology departments of the participating centers. from march 2020 through march 2021, patients were interviewed either during their follow-up visits in the clinic or by telephone interviews to fill out a questionnaire. a total of 1260 patients completed the questionnaires successfully. patients were divided into two groups: group i (patients with first episode renal stone) and group ii (patients who developed renal stone recurrence). inclusion and exclusion criteria patients aged ≥ 18 years old with history of successful primary renal stone treatments (i.e., medical or surgical) were included in the current study. we excluded patients with remaining stones after the initial stone episode, patient who had urinary tract malformation, urinary tract obstructive disease, history of pyeloplasty or ureteric reimplantation surgery, renal failure, chronic gastric diseases, and incomplete questionnaire data. patients' characteristics demographic and baseline patients' characteristics were retrieved from our database including age, gender, body mass index (bmi), medical comorbidities such as diabetes mellitus (dm), hypertension (htn), cardiac diseases…etc, city of residency, nationality, family history of urolithiasis, and history of recurrent urinary tract infection (uti). moreover, data regarding renal stone were gathered such as primary or recurrent renal stone, time to first recurrence, frequency of recurrence, previous treatment methods (either surgical or medical), chemical analysis of the stone, and routine metabolic work-up after successful primary treatment. follow-up all patients were followed-up after treatment at 6 weeks, 3 months then yearly until the last visit. routine postoperative imaging study included kidney-ureter-bladder (kub) x-ray, urinary ultrasound (uus), or computed tomography (ct) scan that were performed according to the surgeon preference and/or stone radiopacity. stonefree status was defined as non-obstructing residual stone fragments of ≤ 2 mm in size detected at 3 months postoperatively on postoperative imaging studies (10). recurrent renal stone was defined as new stone formation and/or stone growth during routine follow-up that was diagnosed radiologically (11). patients' lifestyle information regarding the level of physical activity per week and dietary habits were obtained through asking the patients to complete a previously published (12, 13) non-validated self-administered questionnaire including selected items (1 question for physical activity and 5 questions for dietary habit). questionnaires were disseminated among patients either in the clinic during follow up visits and/or through telephone calls. the commonest dietary habits that are associated with increased risk of stone formation and recurrence include; low fluid intake (< 1 liter/day), high salt diet (> 10 g/day), high protein intake (> 100 g/day), lowcalcium diet (≤ 400 mg/day), and high intake of oxalate containing foods (14). outcome measurement the primary outcome was to compare groups in order to evaluate the predictors of renal stone recurrence after successful primary treatment. the secondary outcome was to assess demographic characteristics of stone formers in saudi arabia. statistical analysis continuous variables were illustrated as mean ± standard deviation (sd) or median and interquartile range (iqr), whereas categorical variables were illustrated as frequency and percentages (%). to compare variables of group i and group ii, we used the student’s t-test, mann whitney test or chi-square (𝝌2) test to examine the statistical significance of normally distributed data, nonparametric data, or categorical data, respectively. a univariable and multivariable cox regression analyses were used to examine the predictors of renal stone recurrence. all tests were twosided and p value of less than 0.05 was considered statistically significant. all tests used the spss version 23 software (ibm spss statistics, ibm corp., armonk, ny, usa). results a total of 1260 participants (820 males and 440 females) with history of successful renal stone primary treatment completed the questionnaire and were included in our study. baseline patients’ clinical and demographic data are summarized in (table i). median patients’ age was 29 years (iqr: 23-41), and median bmi was 25.3 kg/m2 (iqr: 21.8-29). the incidence of htn was 10.2% and phpt was 5.8%. most of patients 811 (64.4%) are living in the central region of the country. previous primary treatments were pcnl, rirs, eswl, surgery and medical treatment in 283 patients (22.5%), 437 patients (34.7%), 334 patients (26.5%), 130 patients (10.3%), and 76 patients (6%), respectively. among the participants, 383 patients (30.4%) had recurrent renal stone and 877 patients (69.6%) didn’t develop recurrence after primary stone treatment. the median follow-up period from the onset of primary stone treatment was 32 archivio italiano di urologia e andrologia 2023; 95(3):11361 3 predictors of renal stone recurrence months (iqr: 24-41). the median time to first recurrence of renal stone was 29 months (iqr: 14-35). after successful primary treatment, 970 (77%) and 1011 (80.2%) of patients didn’t have either stone chemical analysis or metabolic work-up, respectively. the comparison of patients with primary and recurrent renal stones is showed in (table 2). no significant differtable 1. baseline characteristic of patients with renal stone in saudi arabia (n = 1260). age (yr): mean ± sd 32.5 ± 12.4 median (iqr) 29 (23-41) bmi (kg/m2): mean ± sd 25.9 ± 6.1 median (iqr) 25.3 (21.8-29) bmi classification, n (%) underweight (< 18.5) 82 (6.5%) normal (18.5-24.9) 525 (41.7%) overweight and obese (> 25) 653 (51.8%) gender, n (%) female 440 (34.9%) male 820 (65.1%) chronic diseases, n (%) htn 129 (10.2%) dm 98 (7.8%) asthma 106 (8.1%) hypercholesterolemia 101 (8%) phpt 73 (5.8%) gout 27 (2.1%) residency, n (%) central region 811 (64.4%) eastern region 225 (17.9%) western region 125 (9.9%) southern region 55 (4.4%) northern region 44 (3.5%) nationality, n (%) saudi 1191 (94.5%) other 69 (5.5%) physical activity, n (%) low (≤ 1 day/week) 504 (40%) moderate (2-4 days/week) 548 (43.5%) high (≥ 5 days/week) 208 (16.5%) recurrence of kidney stones, n (%) first time 877 (69.6%) recurrent ≥ 2 times 383 (30.4%) family history of renal stone, n (%) no 854 (67.8%) yes 406 (32.2%) history of uti, n (%) no 721 (57.2%) yes 539 (42.8%) dietary habits, n (%) high salt diet (> 2 gm/day) 256 (20.3%) low fluid intake (< 1 l/day) 459 (36.4%) high protein intake (≥ 3 times/week) 763 (60.6%) low calcium intake (≤ 400 mg/day) 205 (16.3%) high oxalate containing foods 158 (12.5%) stone chemical analysis, n (%) yes 290 (23%) no 251 (19.9%) nobody asked 719 (57.1%) stone type, n (%) calcium oxalate 120 (9.5%) calcium phosphate 44 (3.5%) cystine 54 (4.3%) struvite 72 (5.7%) unknown 970 (77%) metabolic workup, n (%) yes 249 (19.8%) no 294 (23.3%) nobody asked 717 (56.9%) previous treatment, n (%) pcnl 283 (22.5%) rirs 437 (34.7%) eswl 334 (26.5%) surgery 130 (10.3%) controlled diet + medical ttt 76 (6%) uus: ultrasound scan, ctu; computed tompgraphy; htn: hypertension; dm: diabetes mellitus; bmi: body mass index; phpt: primary hyperparathyroidism; uti: urinary tract infection; pcnl: percutaneous nephrostomy; rirs: retrograde intrarenal surgery; eswl: extracorporeal shockwave lithotripsy. table 2. comparing characteristic of patients with first time and recurrent renal stones. primary stone recurrent stone p-value variables (group i, n = 877) (group ii, n = 383) age (yr), mean ± sd 31.3 ± 12.1 35.1 ± 12.6 0.000 bmi (kg/m2), mean ± sd 25.9 ± 6.1 26.2 ± 6.3 0.421 bmi classification, n (%) underweight 56 (6.4%) 26 (6.8%) 0.492 normal 375 (42.8%) 150 (39.2%) overweight and obese 446 (50.9%) 207 (54%) gender, n (%) female 340 (38.8%) 100 (26.1%) 0.000 male 607 (61.2%) 283 (73.9%) hypertension (htn), n (%) 73 (8.3%) 56 (14.6%) 0.001 diabetes (dm), n (%) 63 (7.2%) 35 (9.1%) 0.253 asthma, n (%) 71 (8.1%) 35 (9.1%) 0.581 hypercholesterolemia, n (%) 62 (7.1%) 39 (10.2%) 0.071 hyperparathyroidism, n (%) 41 (4.7%) 32 (8.4%) 0.013 gout, n (%) 15 (1.7%) 12 (3.1%) 0.137 residency, n (%) central region 580 (66.1%) 231 (60.3%) 0.133 eastern region 156 (17.8%) 69 (18%) western region 82 (9.4%) 43 (11.2%) southern region 33 (3.8%) 22 (5.7%) northern region 26 (3%) 18 (4.7%) nationality, n (%) saudi 835 (95.2%) 356 (93%) 0.105 other 42 (4.8%) 27 (7%) physical activity, n (%) low 363 (41.4%) 141 (36.8%) 0.300 moderate 371 (42.3%) 177 (46.2%) high 143 (16.3%) 65 (17%) history of uti, n (%) no 479 (54.6%) 242 (63.2%) 0.005 yes 398 (45.4%) 141 (36.8%) family history, n (%) no 607 (69.2%) 247 (64.5%) 0.101 yes 270 (30.8%) 136 (35.5%) dietary habits, n (%) high salt diet (yes) 180 (20.5%) 76 (19.8%) 0.782 low fluid intake (yes) 191 (21.8%) 268 (70%) 0.000 high protein intake (yes) 507 (57.8%) 256 (66.8%) 003 low calcium intake (yes) 151 (17.2%) 54 (14.1%) 0.168 high oxalate intake (yes) 105 (12%) 53 (13.8%) 0.358 stone type, n (%) calcium oxalate 49 (5.6%) 71 (18.5%) 0.000 calcium phosphate 20 (2.3%) 24 (6.3%) cystine 24 (2.7%) 30 (7.8%) struvite 36 (4.1%) 36 (9.4%) unknown 748 (85.3%) 222 (58%) previous treatment, n (%) pcnl 203 (23.1%) 80 (20.9%) 0.654 rirs 307 (35%) 130 (33.9%) eswl 232 (26.5%) 102 (26.6%) surgery 84 (9.6%) 46 (12%) controlled diet + medical ttt 51 (5.8%) 25 (6.5%) uus: ultrasound scan, ctu; computed tompgraphy; htn: hypertension; dm: diabetes mellitus; bmi: body mass index; phpt: primary hyperparathyroidism; uti: urinary tract infection; pcnl: percutaneous nephrostomy; rirs: retrograde intrarenal surgery; eswl: extracorporeal shockwave lithotripsy. archivio italiano di urologia e andrologia 2023; 95(3):11361 m. alshehri, h. alsaeed, m. alrowili, f. alhoshan, a. abdel raheem, a. hagras 4 ence was found in most variables (p > 0.05). mean patients’ age was 35.1 ± 12.6 yr. in group i compared to 31.3 ± 12.1 yr. in group ii (p = 0.000). more male patients were present in group ii compared to group i (73.9% vs. 61.2%, p = 0.000, respectively). the rates of htn, phpt, low fluid intake, and high daily protein diet were significantly higher in group ii (14.6% vs. 8.3% in group i, p = 0.001), (8.4% vs. 4.7% in group i, p = 0.013), (70% vs. 21.8 % in group i, p = 0.000) and (66.8% vs. 57.8% in group i, p = 0.003), respectively. univariate logistic regression analysis showed that age, male patients, htn, phpt, history of uti, low fluid intake, and high daily protein intake were associated with increased risk of renal stones recurrence (p < 0.05). multivariate logistic regression analysis revealed that male patients (or: 1.686; 95% ci, 1.216-2.337), htn (or: 2.342; 95% ci, 1.439-3.812), phpt (or: 2.806; 95% ci, 1.510-5.215), low fluid intake (or: 28.398; 95% ci, 18.158-44.403) and high daily protein intake (or: 10.058; 95% ci, 6.400-15.807) were predictors of renal stone recurrence. discussion in this prospective study, the risk factors and baseline characteristics of renal stone formers, as well as the predictors of recurrent renal stone formations were investigated in saudi arabian. a total of 1260 patients (820 males and 440 females) were included in the analysis. the rate of kidney stone recurrence after successful primary stone treatment was 30.4% among the participants. the results demonstrated that male gender, htn, phpt, low oral fluid intake and high daily protein intake were potential risk factors for recurrent kidney stone formation. we believe that the result of our study may provide better insight into the prevention of kidney stones recurrence through proper control and management of its risk factors. renal stone recurrence is a common disease. patients with renal stones have an increase chance of forming another stone in the future. stones can recur as long as 10 years after the first episode (8). in our cohort, the overall renal stone recurrence rate was 30.4%. among them, 11.3% of patients had two-time recurrences, 9.8% had three-time recurrences, and 9.4% had four-time recurrences. our results are in accordance with previous study reporting the recurrence rate of nephrolithiasis recurrence of 38.6% to 53.2% in saudi arabia (4). in the present study, the median time of renal stone recurrence was 29 months (iqr: 14-35). generally, following the initial episode, nephrolithiasis carries a high recurrence rate of 3.4 per 100 person-years, 7.1 after the second episode, 12.1 after the third episode, and 17.6 after the fourth episode or higher (15). moreover, the natural cumulative recurrence stone rate was estimated to be 6 to 17%, 35%, and 52% at one year, five years, and ten years, respectively (15). our study showed that the recurrent kidney stone rate was found to be significantly higher in men (56.6%) than in women (44.4%). in addition, male gender was identified as a predictor for nephrolithiasis recurrence. this may be attributed to the hormonal differences between men and women. in women, estrogen stimulates the secretion of citric acid in urine and regulates the synthesis of 1,25-dihydroxy-vitamin d which are considered protective factors against nephrolithiasis. on the other hand, men’s androgen induces the urinary accumulation of uric acid, calcium, and oxalate which increase the risk of kidney stone formation (16, 17). of note, 10.2% of the cases in our study had htn and the odds of recurrent renal stone in htn cases was 2.34 compared with non-htn cases. sahng et al. found that the risk of renal stone formation was directly associated with the incidence of htn (18). interestingly, in a recent study 29.7% of patients with nephrolithiasis had htn (19). in a recent systematic review and meta-analysis, htn was found to be one of the risk factors for renal stone recurrence (20). it worth note that, the exact mechanism of renal stone formation in patients with htn remains unclear, and only few studies have examined it. table 3. univariate and multivariate analysis of predictors of recurrent renal stone ≥ 2 times in saudi patients. univariable analysis multivariable analysis variable or (95% ci) p-value or (95% ci) p-value age 1.025 (1.015-1.035) 0.000 bmi 1.008 (0.989-1.028) 0.421 bmi classification: underweight ref normal 0.862 (0.521-1.424) 0.561 overweight and obese 1.000 (0.610-1.637) 0.999 male patient 1.794 (1.401-2.298) 0.000 1.686 (1.216-2.337) 0.002 htn 1.886 (1.301-2.734) 0.001 2.342 (1.439-3.812) 0.001 dm 1.299 (0.844-2.001) 0.234 asthma 0.142 (0.747-1744) 0.540 hypercholesterolemia 1.490 (0.979-2.268) 0.063 phpt 1.859 (1.152-3.001) 0.011 2.806 (1.510-5.215) 0.001 gout 1.859 (0.862-4.010) 0.114 residency: central region ref eastern region 1.111 (0.805-1.532) 0.523 western region 1.738 (0.935-3.231) 0.081 southern region 1.647 (0.956-2.932) 0.072 northern region 1.317 (0.883-1.963) 0.177 saudi patient 0.663 (0.403-1.092) 0.107 physical activity: low ref moderate 1.228 (0.943-1.600) 0.127 high 1.170 (0.823-1.664) 0.381 history of uti 1.426 (1.114-1.825) 0.005 renal stone family history 1.238 (0.960-1.595) 0.099 dietary habits: high salt diet 0.959 (0.710-1.294) 0.782 low fluid intake 8.370 (6.383-10.976) 0.000 28.398 (18.158-44.403) 0.000 high protein intake 1.471 (1.144-1.892) 0.003 10.058 (6.400-15.807) 0.000 low calcium intake 0.789 (0.563-1.105) 0.168 high oxalate intake 1.181 (0.828-1.683) 0.358 previous treatment: pcnl ref rirs 1.075 (0.772-1.495) 0.670 eswl 1.116 (0.788-1.580) 0.538 surgery 1.390 (0.892-2.164) 0.145 diet + medical ttt 1.244 (0.722-2.143) 0.432 uus: ultrasound scan, ctu; computed tompgraphy; htn: hypertension; dm: diabetes mellitus; bmi: body mass index; phpt: primary hyperparathyroidism; uti: urinary tract infection; pcnl: percutaneous nephrostomy; rirs: retrograde intrarenal surgery; eswl: extracorporeal shockwave lithotripsy. archivio italiano di urologia e andrologia 2023; 95(3):11361 5 predictors of renal stone recurrence frequent changes in the levels of blood pressure have a direct effect on the urinary microbiomes, which may stimulate nephrolithiasis (21). dietary habits play an important role in the renal stone formation. excessive meat consumption and low fluid intake were considered as main risk factors for nephrolithiasis. our study showed that in patients with recurrent kidney stones high protein intake rate was significantly higher (66.8%) than in primary stone formers (57.8%), similarly low fluid intake was significantly higher (70% vs. 21.8%). high protein intake leads to acidification of urine, which stimulate the formation of calcium oxalate stone (22). xu et al. found that each 500 ml increase in water intake was significantly associated with a reduced risk of kidney stone formation (rr = 0.93; 95% ci: 0.87, 0.98; p < 0.01). additionally, daily water intake > 2000 ml decreases the risk of first kidney stone formation by at least 8% compared to 1500 ml (23). phpt is one of the listed risk factors for renal stone formation. it has been estimated that 20% of patients with phpt have nephrolithiasis, and approximately 5% of patients who presented with renal stones have phpt (24). our results are in agreement with the aforementioned results. notably, 73 patients (5.8%) have phpt in our cohort analysis. moreover, the rate of patients with recurrent renal stone and phpt was significantly higher (8.4%) than those without phpt (4.7%), in addition, the odds of recurrent renal stone in phpt patients was 2.8 compared with non-phtp patients. the current study has limitations and strengths. the strength points of our study are the following: a prospective study, large sample size (n = 1260), and extensive data gathering for the factors of interest related to stone formation and recurrence (e.g., age, sex, bmi, medical comorbidities, dietary habits, area of residency etc.). however, our study does not devoid of limitations, and the results have to be interpreted with caution. for instance, the short median follow-up period (32 months) may be not enough to estimate the actual rate of renal stone recurrence. non-recurrent stone formers in this study are “patients who formed a first stone” although they may develop stone recurrence after longer follow-up period. also, stone composition and metabolic work-up results are unknown in 77% and 80.2% of patients, respectively. excluding those patients was not possible to complete the analysis. on the other hand, these findings raise an important concern regarding urologists practice in saudi arabia where best clinical practice guidelines regarding metabolic work-up and stone chemical analysis are underutilized and need to be applied by our urologists extensively among stone former patients. conclusions our study revealed that male gender, hypertension, primary hyperparathyroidism, low fluid intake and high daily protein intake are factors potentially increasing the risk of renal stone recurrence among saudi arabian patients. being aware of these risk factors can provide proper guidance for the prevention of nephrolithiasis recurrence and its management. references 1. sorokin i, mamoulakis c, miyazawa k, et al. epidemiology of stone disease across the world. world j urol. 2017; 35:1301-1320. 2. romero v, akpinar h, assimos dg. kidney stones: a global picture of prevalence, incidence, and associated risk factors. rev urol. 2010; 12: 86-96. 3. zeng g, mai z, xia s, et al. prevalence of kidney stones in china: an ultrasonography based cross-sectional study. bju int. 2017; 120:109-116. 4. abdel-halim re, al-hadramy ms, hussein m, et al. the prevalence of urolithiasis in the western region of saudi arabia: a population study. in: walker vr, sutton ral, cameron ecb, pak cyc, robertson wg, editors. urolithiasis. boston, ma: springer; p. 1989; 711-712. 5. ahmad f, nada mo, farid ab, et al. epidemiology of urolithiasis with emphasis on ultrasound detection: a retrospective analysis of 5371 cases in saudi arabia. saudi j kidney dis transpl. 2015; 26:386-391. 6. raja a, hekmati z, joshi hb. how do urinary calculi influence health-related quality of life and patient treatment preference: a systematic review. j endourol. 2016; 30:727-43. 7. lotan y. economics and cost of care of stone disease. advances in chronic kidney disease. 2009; 16:5-10. 8. trinchieri a, ostini f, nespoli r, et al. a prospective study of recurrence rate and risk factors for recurrence after a first renal stone. j urol. 1999; 162:27-30. 9. liu y, chen y, liao b, et al. epidemiology of urolithiasis in asia. asian journal of urology. 2018; 5, 205-214. 10. ho hc, hughes t, pietropaolo a, et al. apnoea is not necessary for flexible ureteroscopy and lasertripsy of renal stones: a prospective study over 6 years. cent european j urol. 2020; 73:193-198. 11. matthew d’costa, vernon m. pais, and andrew d. rule. leave no stone unturned: defining recurrence in kidney stone formers. curr opin nephrol hypertens. 2019; 28: 148-153. 12. khalili p, jamali z, sadeghi t, et al. risk factors of kidney stone disease: a cross-sectional study in the southeast of iran. bmc urol. 2021; 21:141. 13. dai m, zhao a, liu a, et al. dietary factors and risk of kidney stone: a case-control study in southern china. j ren nutr. 2013;23:e21-8. 14. ferraro pm, bargagli m, trinchieri a, et al. risk of kidney stones: influence of dietary factors, dietary patterns, and vegetarian-vegan diets. nutrients. 2020; 12:779. 15. vaughan le, enders ft, lieske jc, et al. predictors of symptomatic kidney stone recurrence after the first and subsequent episodes. mayo clin proc. 2019; 94:202-10. 16. heller hj, sakhaee k, moe ow, et al. etiological role of estrogen status in renal stone formation. j urol. 2002; 168:1923-7. 23. 17. liang l, li l, tian j, et al. androgen receptor enhances kidney stone-caox crystal formation via modulation of oxalate biosynthesis & oxidative stress. mol endocrinol. 2014; 28:1291-303. 18. shang w, li y, ren y, et al. nephrolithiasis and risk of hypertension: a meta-analysis of observational studies. bmc nephrol. 2017; 18:1-6. 19. kalani l, rashidi n, mehranfard s, et al. epidemiology of the archivio italiano di urologia e andrologia 2023; 95(3):11361 m. alshehri, h. alsaeed, m. alrowili, f. alhoshan, a. abdel raheem, a. hagras 6 urinary stones: a 6-year retrospective study at dezful-iran. int j pharm phytopharmacol res. 2020; 10:79-85. 20. wang k, ge1 j, han w, et al. risk factors for kidney stone disease recurrence: a comprehensive meta-analysis. bmc urology. 2022; 22:62. 21. liu f, zhang n, jiang p, et al. characteristics of the urinary microbiome in kidney stone patients with hypertension. j transl med. 2020; 18:130. 22. nasir sj. the mineralogy and chemistry of urinary stones from the united arab emirates. qatar univ sci j. 1999; 18:189-202. 23. xu c, zhang c, wang xl, et al. self-fluid management in prevention of kidney stones: a prisma-compliant systematic review and dose-response meta-analysis of observational studies. medicine (baltimore). 2015; 94:1042. 24. parks j, coe f, favus m. hyperparathyroidism in nephrolithiasis. arch intern med. 1980; 140:1479-81. correspondence mohammed alshehri, md mohammedalshehri95@yahoo.com department of urology, king abdullah bin abdulaziz university hospital, princess nourah bint abdulrahman university, riyadh, saudi arabia hind alsaeed, md alsaeedhindx@gmail.com princess nourah bint abdulrahman university, riyadh, saudi arabia malath alrowili, md pc435000386@gmail.com princess nourah bint abdulrahman university, riyadh, saudi arabia faisal alhoshan, md fmialhoshan@gmail.com prince sultan military hospital, taif, saudi arabia ali abdel raheem, md, phd (corresponding author) aliraheem82@yahoo.com a-hassan@ksmc.med.sa urology consultant, urology department, king saud medical city, riyadh, saudi arabia lecturer of urology, urology department, tanta university hospital, tanta, egypt ayman hagras, md ahagras80@yahoo.com department of urology, faculty of medicine, tanta university, tanta, egypt division of urology, surgery department, sharurah armed forces hospital, sharurah, saudi arabia conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper mediated acute respiratory distress syndrome (2), but therapeutic options to improve semen parameters remain very limited (3, 4). multiple studies demonstrated impaired semen quality parameters in men after clinically present coronavirus disease 2019 (covid-19) covid-19 disease, strongly indicating potential effects of this novel rna-virus on male fertility (5-7). less is known about the recovery time of sperm quality deterioration after patients’ convalescence. considering current evidence it seems likely that multiple mechanisms are involved in the pathogenesis of male fertility disruptions after covid-19 disease, including oxidative stress triggered by sars-cov-2 induced inflammation, testicular immune response and direct viral replication in male reproductive tissues (8-10). as underlying cellular processes remain an under-researched issue, targeted interventions to counteract semen parameter decline in male covid-19 patients or support sperm quality recovery are lacking. however, excess oxidative stress in the testicular environment has been shown to drastically impair spermatogenesis (11, 12). although the ability of certain micronutrient supplements to improve semen parameters is well documented (13, 14), no previous study has investigated the effects of dietary supplements on sperm quality following viral infection such as covid-19 disease. a better understanding of how male fertility can be supported in men infected by sars-cov-2 is relevant for future disease management in men seeking reproductive care following covid-19 illness. it will also present an incentive for further research regarding potential interactions of sars-cov-2 with the male reproductive system. therefore, this study is designed to evaluate the effect, safety and efficacy of a standard micronutrient composition on all major semen variables and seminal oxidative stress markers in men after symptomatic covid-19 disease in comparison to a control group without dietary supplement intake. materials and methods participants and study design this prospective, comparative study included 40 male subjects between 20-50 years of age with symptomatic covid-19 infection confirmed by a positive sars-covobjective: this study aims to evaluate the safety and efficacy of a standard micronutrient preparation to improve semen parameters and seminal oxidative stress in adult male subjects after coronavirus disease 2019 (covid-19) disease. methods: for this prospective pilot study, 30 males aged 20-50 years who had recently recovered from a symptomatic sarscov-2 infection were recruited from june to october 2021 through a public call for participation. participants of the study group (n = 30) received two semen analyses according to who criteria at an interval of 12 weeks, during which they daily received a micronutrient preparation (l-carnitine, l-arginine, coenzyme q10, vitamin e, zinc, folic acid, glutathione and selenium). changes in major semen variables and seminal oxidative stress levels before and after therapy were analyzed and compared to a control group (n = 10) adhering to the same inclusion criteria, including subjects who recently recovered from symptomatic covid-19 disease without micronutrient supplementation within the 12 weeks between the two semen analyses. results: after 3 months of micronutrient supplementation the rate of normal semen analysis results in the study group increased significantly (p = 0.009) by 66.7%: from 50.0% before to 83.3% after therapy. there was a significant increase in progressive (p = 0.014) and overall motility (p = 0.05) as well as in the vitality (p = 0.0004) of semen cells after 12 weeks of micronutrient intake. in the control group there were no significant changes in any semen parameter or in the rate of normal semen analysis results over the 3-month observation period. in both groups, sperm density, morphology and oxidative stress did not improve significantly. conclusions: our data suggests that supplementation of certain micronutrients may be a safe way to support recovery of impaired semen parameters in male adults recovered from covid-19 disease. key words: micronutrients; semen analysis; covid-19; male fertility; antioxidants. submitted 15 january 2023; accepted 29 january 2023 introduction since the outbreak of the global coronavirus pandemic in early 2020, the severe acute respiratory syndrome coronavirus 2 (sars-cov-2) is estimated to have infected more than 650 million people worldwide by the end of 2022 (1). during the last decades a remarkable depletion of sperm quality is observed even without a sars-cov-2 recovery of sperm quality after covid‐19 disease in male adults under the influence of a micronutrient combination: a prospective study judith aschauer 1, 2, michaela sima 1, 2, martin imhof 1 1 karl landsteiner society, institute for cell-focused therapy, korneuburg, austria; 2 medical university of vienna, vienna, austria. doi: 10.4081/aiua.2023.11157 summary archivio italiano di urologia e andrologia 2023; 95, 1 j. aschauer, m. sima, m. imhof 2 pcr test of nasal or pharyngeal swabs not more than 12 weeks prior to first semen sample collection. symptoms had to include one or more of the following: fever, cough, sore throat, headache, nasal congestion, malaise, diarrhea, loss of smell or loss of taste. participants were excluded if reporting on a history of subfertility before covid-19-infection, varicocele, urogenital infections, known or suspected hypersensitivity to ingredients of the study compound, history of severe disease other than covid-19 expected to prevent compliance with the present protocol, and intake of other micronutrient or vitamin supplements within the last 4 weeks. the recruitment of the study group of 30 men was conducted from may 2021 to december 2021. to participate, men registered voluntarily in response to calls for participation published on social media channels, in local newspapers and on the official study website. after online registration, potential participants were contacted via a short phone call from one of the study nurses to check eligibility and schedule an appointment for official inclusion and first semen sample collection at a fertility clinic in vienna austria, if all study criteria were met. all subjects were informed to adhere to 2-5 days of sexual abstinence prior to semen sample collection. on the first appointment, written informed consent to participate in the study was obtained and a short questionnaire filled out by each patient, including information on previous biological children, weight and height, current medication, current or past urological conditions, smoking status and alcohol consumption habits. we chose to obtain these additional parameters considering elevated body mass index (bmi), tobacco and alcohol consumption as well as age are individual risk factors for male factor infertility and possible confounders influencing sperm quality parameters (15). severity of covid-19 disease was assessed and categorized as “mild” with mere symptoms like headache, sore throat and/or flu like symptoms without fever; “moderate” if fever over 37.5°c persisted over 3 days and “severe” if hospitalization was required for disease management. subsequent semen analysis was performed on the day of enrolment, including measurement of major semen parameters and seminal oxidative stress levels. another appointment to repeat these tests was scheduled at an interval of 12 weeks and subjects were instructed to adhere to daily intake of a standard micronutrient preparation provided to them in the clinic until follow-up visit. at the second visit, participants were questioned about any side effects or changes observed during the 12-week micronutrient supplementation before proceeding to repeat identical semen quality work-up. semen parameters and seminal oxidative stress before and after the 12 weeks of micronutrient supplementation were analyzed and compared to a control group of 10 men from our data base. all men included in this control group were subject to the same inclusion and exclusion criteria as the study group but did not receive micronutrient supplementation or other fertility-related treatments within the 12 weeks between their two semen analyses after recovering from symptomatic covid-19 disease. micronutrient preparation the micronutrient supplement used for this study is a clinically tested, standardized nutraceutical for male fertility enhancement (profertil® lenus pharma gmbh, vienna, austria). subjects from the study group were instructed to take two oral capsules of this preparation per day for 12 weeks. two capsules contain: l-carnitine (440 mg), l-arginine (250 mg), zinc (40 mg), vitamin e (120 mg), glutathione (80 mg), selenium (60 μg), coenzyme q10 (15 mg) and folic acid (800 μg). semen analysis semen samples were obtained by masturbation in a sterile container in a separate room next to the fertility clinics’ laboratory, which is certified for semen analysis according to world health organisation (who) criteria. after liquefaction in a heat chamber with 37°c, semen analysis according to who laboratory manual (16) was performed. evaluation included a classical semen analysis assessing volume, semen cell concentration, total semen count, progressive and total motility, normal morphology and vitality, as well as measurement of oxidative stress levels in seminal fluid. semen parameters were considered abnormal when being lower than the fifth percentile, as suggested by who criteria. therefore, normal semen analysis results required a concentration of more than 15 million sperms per milliliter, progressive motility of more than 30%, total motility in total of more than 42%, vitality of at least 54% and normal morphology of at least 4% (16, 17). seminal oxidative stress levels were assessed using the electrochemical mioxsys®, “the male infertility oxidative system” (mioxsys, englewood, co, usa). this rapid in vitro diagnostic device has shown a good sensitivity for detecting both oxidants (reactive oxygen species, ros) and antioxidants in a liquid sample based on measurement of the static oxidant reductant potential (sorp). sorp can be interpreted as direct marker for the level of oxidative stress (18). statistical analysis statistical analysis was performed using the statistical package for the social sciences version 29.0 (ibm spss, armonk, ny, usa). numerical parameters are presented as the mean plus/minus standard deviation (sd) and dichotomous categorical parameters as absolute and relative frequencies. student’s t-test was used to determine significance of changes of individual parameters before and after micronutrient supplementation for the study group, and before and after observational period for the control group. for the comparison of categorical data such as amount of normal semen analysis results the chi square test was applied. for all calculations, a p value < 0.05 was considered statistically significant. results in total, 46 men met all study inclusion criteria and received a first semen analysis in the fertility clinic. only 30 participants adhered to their follow-up appointment and daily intake of 2 capsules of the standard micronutrient preparation and could be included in the analysis. no serious adverse events or other adverse events were reported by any of the participants taking micronutrient supplements during the investigational period. archivio italiano di urologia e andrologia 2023; 95, 1 micronutriemts and sperm quality after covid-19 the mean age was 29.3 (± sd 6.1) years in the study group and 30.2 (± sd 3.7) years in the control group. body mass index (bmi) was also similar with 24.4 (± sd 3.5) kg/m2 in the group receiving micronutrient supplementation and 24.8 (± sd 3.5) kg/m2 in the group without dietary support. in the study group, 13% of men reported on regular smoking and 17% of them reported on already having biological children, with comparable results in the control group reporting a 20% rate for both parameters. the relative number of participants with alcohol consumption at least 1 time per week was almost 3 times higher in the group of men taking micronutrient, amounting to 57% in the study group and only 20% within the control group not receiving any fertility-related interventions. the distribution of severity of covid19 disease was similar in the two groups: mild, moderate and severe symptoms were reported in 67%, 9% and 1% within the study group, and 67%, 30% an 3.3% in the control group, respectively (table 1). after 3 months of micronutrient supplementation the number of subjects with normal semen analysis results in the study group increased significantly (p = 0.009) by 66.7%, from 50.0% before to 83.3% after supplement therapy. results were considered normal if all semen parameters were within who reference limits as described in the “methods” section. there was a significant increase in progressive (p = 0.014) and overall motility (p = 0.05) as well as in the vitality (p = 0.0004) of semen cells after 12 weeks of micronutrient in men recovered from covid-19 disease. in the control group there were no significant changes in any semen parameter or in the rate of normal semen analysis results over the interval of 12 weeks. the mean sperm density and total sperm count increased in both groups during the observational period, though not significantly. mean percentage of normal sperm morphology remained at similar levels with only minimal changes recorded in both groups. interestingly, sorp levels showed a decrease both in the study group of covid-19 recovered men receiving micronutrient supplementation and in the control group without treatment. though not being significant, this decrease was more evident in the study group with a mean decrease of 13.16 mv during the period of micronutrient treatment, while in the control group the mean decrease of oxidative stress levels assessed by sorp was only 0.02 mv (table 2). discussion the results of this study revealed significantly more normal semen analysis results and a significant increase in overall sperm motility, progressive motility and vitality after 3 months of micronutrient supplementation in men recently recovered from covid-19 disease. sperm density and oxidative stress levels also improved during the observation period, though not significantly. there were no significant changes in semen analysis results in the control group of participants after sars-cov-2 infection not receiving dietary supplements. despite trends of recovery of semen parameters after covid-19 disease in both groups, sperm quality improvement was more evident in the study group receiving dietary support. sars-cov-2 and the male reproductive system while global covid-19 herd immunity against certain strains of sars-cov-2 is rising, the possibility of new variants cannot be ruled out and infections will continue to occur (19, 20). at the same time the public is becomtable 1. basal patients characteristics and disease severity. study group control group age 1 [years] 29.3 (± 6.1) 30.2 (± 3.7) bmi 1 [kg/m2] 24.4 (± 3.5) 24.8 (± 3.5) smoking 2 regular 4 (13.3%) 2 (20.0%) alcoho 2 ≥ 1/week 17 (56.7%) 2 (20.0%) biological child(ren) 2 5 (16.7%) 2 (20.0%) covid-19 disease severity 3 mild 2 20 (66.7%) 6 (60.0%) moderate 2 9 (30.0%) 3 (30.0%) severe 2 1 (10%) 1 (3.3%) 1 mean (± standard deviation); 2 absolute frequency (± percentage); 3 mild: headache, sore throat, flu like symptoms without fever; moderate: fever over 37.5°c ≥ 3 days; severe: hospitalization required; bmi = body weight in kg (body height in cm)2. table 2. semen analysis results. mean before mean after δmeanbef→aft p-value study control study control study control study control volume (ml) 3.43 3.42 3.61 3.60 0.18 0.18 0.251 0.321 density (mio/ml) 88.94 63.39 89.25 68.55 0.31 5.16 0.493 0.341 sperm count (mio) 264.06 225.61 277.04 234.20 12.98 8.59 0.397 0.452 progressive (%) 35.87 47.50 43.13 49.70 7.27 2.20 0.014* 0.359 motility (%) 47.98 52.80 53.63 55.60 5.65 2.80 0.050* 0.291 vitality (%) 65.57 77.10 81.60 79.80 16.03 2.70 0.000* 0.336 morphology (%) 10.37 7.10 13.15 6.50 2.78 -0.60 0.087 0.254 sorp (mv) 43.46 24.47 30.30 24.31 -13.16 -0.16 0.132 0.423 n. sorp (mv*mio/ml) 1.31 0.63 0.76 0.55 -0.55 -0.07 0.183 0.261 normal semen analysis results 15 (50%) 7 (70%) 25 (83%) 7 (70%) 10 0 0.0003* sorp = static oxidation reduction potential; n. sorp = sorp normed to sperm concentration = orp (mv) sperm density (mioml); (δmeanbef→aft) = difference of means of semen parameters between number of patients with normal semen analysis results between first and second semen cell analysis; p-values of paired students-t-test for sperm parameters or χ2-test for semen analysis results; significant changes marked by *. archivio italiano di urologia e andrologia 2023; 95, 1 j. aschauer, m. sima, m. imhof ing more aware about potential effects of a coronavirus infection on male reproductive system. the impact of sars-cov-2 on male fertility parameters after infection continues to be intensely researched and has been confirmed by various studies (5). a systematic review and meta-analysis conducted in 2021 revealed that compared to non-infected individuals, men recently recovered from covid-19 had lesser semen volume, sperm concentration and motility, though not all parameters were significantly lower (6). another more recent meta-analysis confirmed these results, demonstrating a decline in certain parameters of sperm quality in men after coronavirus infection compared to healthy controls and to individual baseline parameters before viral infection (7). in line with these outcomes, a large percentage of participants of this study presented with at least one abnormal sperm quality parameter within 3 months since covid19 recovery. most men included in this analysis experienced merely mild symptoms during coronavirus illness. approximately one third reported moderate symptoms with fever, while only one person of each group required hospitalization due to severe symptoms. considering the high percentage of abnormal semen analysis results at time of enrolment, sars-cov-2 infection seems to affect sperm quality even if symptoms are mild. interestingly, a recent prospective cohort study found no correlation between the presence of fever or symptom severity with semen characteristics in men after covid-19 infection (21). this is worth mentioning as the majority of covid19 infections disease severity will be mild, particularly in previously healthy men under the age of 65 (22). while several publications have observed short-term effects of sars-cov-2 on male fertility, the infectioninduced longitudinal and long-term changes in the male reproductive function are less clear. data on semen quality over time in covid-19 patients provides somewhat conflicting results. for example, one analysis of men infected with sars-cov-2 suggested a recovery time of sperm parameters to baseline values prior to infection of about 3 months (21), while another investigation indicated it may take up to up to 6 months (23). more research will be necessary to confirm if and how fast semen quality recovers after covid-19, and to what extent recovery time may vary between patients. to explore therapeutic options that may support male fertility after coronavirus infection, it is important to understand why the male reproductive system might be especially vulnerable to sars-cov-2. various mechanisms for impaired semen quality after covid-19 are discussed. firstly, direct cytopathic effects of sars-cov-2 replication and dissemination in certain testicular cells may impair spermatogenesis during active viral disease (24). two cell structures of particular interest in this regard are the angiotensin converting enzyme 2 (ace2) receptor and activating transmembrane protease serine 2 (tmprss2), as only binding to ace2 and activating tmprss2 enables the coronavirus to enter host cells (25). it has yet to be determined which genital tissues can indeed act as viral reservoirs for sars-cov-2, even though expression of ace2 and tmprss2 was already discovered on several cells of the male reproductive organs, that are crucial for spermatogenesis (10, 24). the role of oxidative stress general immune response triggered by sars-cov-2 and subsequent inflammatory reactions marked by increased cytokine release leads to major oxidative stress (os) as discussed in covid-19 focused publications (8,26). os is described as a metabolic state with an imbalance between antioxidants and oxidants, namely free radicals or reactive oxygen species (ros). cytokine storms in other viral infections have been shown to impact male fertility due to increased leucocyte infiltration and subsequent production of ros in the male gonads (10, 27). while certain levels of ros are crucial for physiological cell processes, an excessive production within seminal fluid can quickly exceed the neutralizing capacities of intrinsic antioxidants and cause significant cell damage. elevated os in the testicular microenvironment can thus drastically impair spermatogenesis and semen parameters (11, 12). based on the limited evidence available, infection with sars-cov-2 may be associated with elevated os in the ejaculate (28). two recent investigations analyzing oxidative stress in semen samples of covid-19 patients found higher ros levels shortly after illness, compared to a later time point following viral infection (29, 30). similar results were obtained in this present study, as mean os levels in both groups were lower at the second semen analysis 3 month after first measurement directly following covid-19 disease. however, this decrease was more evident in the study group receiving micronutrient supplementation, suggesting that intake of certain micronutrients may support reduction of ros in the seminal fluid. os levels in the ejaculate of all participants were assessed by measuring the static oxidation-reduction potential (sorp), which allows for simultaneous evaluation of the balance between oxidative and reductive stress within a sample (11). most previous research focusing on os in the ejaculate of men after covid-19 infection determined oxidative and antioxidative markers separately (30, 31), not considering potential reductive stress within the ejaculate (32). however, information on the true redox state of seminal fluid might of particular interest to guide reproductive management. micronutrients for semen quality improvement there are currently no general recommendations on fertility management for men after testing positive for sarscov-2, to reduce potential sperm quality deterioration or support recovery. options to counteract impairment of semen parameters after recovery from covid-19 are lacking, though especially needed for infected men with a current desire to have children, who want to optimize their reproductive health. in general, therapies to improve sperm quality are scarce (33). research suggests that men who stick to healthy diets tend to have better semen parameters (34) and dietary supplements are frequently recommended to men struggling with infertility. two recent systematic reviews and meta-analyses of randomized controlled trials investigating the effect of nutritional supplementation on sperm quality parameters showed similar results. salas-huetos et al. found that additional dietary selenium, zinc, and co-enzyme q10 seem to significantly improve sperm concentration and motility, while carnitines supplements showed beneficial effects archivio italiano di urologia e andrologia 2023; 95, 1 micronutriemts and sperm quality after covid-19 only on motility (14). similarly, buhling et al. demonstrated that semen parameters of infertile men may be improved with supplementation of co-enzyme q10, zinc, folic acid, l-carnitine and acetyl-l-carnitine (13). however, both analyses showed notable heterogeneity regarding supplement composition, dosages and patient population. one internventional study by rafiee et al. revealed that oral supplementation with the antioxidant n-acetylcysteine (nac) may support recovery of impaired sperm quality in men following covid-19 disease. their findings showed that nac intake significantly improved semen motility, concentration and morphology to levels similar to before sars-cov-2 infection, while sperm quality parameters of a control group not receiving nac remained at lower levels (35). the micronutrient regimen used in this is study a prescription free nutraceutical, which has been available on the international market for many years and contains vitamin e, coenzyme q10, l-arginine, folic acid, selenium, l-carnitine, zinc and glutathione. previous clinical studies with this defined composition of micronutrients suggested that daily intake may improve semen parameters and reduce sperm dna-fragmentation index in different subfertile male patient populations (36-38). vitamin e, l-carnitine, glutathione and l-arginine are all known to exhibit antioxidant properties and can scavenger free radicals, which may protect spermatozoa against membrane and dna damage caused by excess ros in the seminal fluid. selenium also plays a role in shielding tissues or cells from excess os, as it acts an important co-factor for various antioxidant enzymes (39). likewise, coenzyme-q10 is part of the nonenzymatic antioxidant defence system of the body and also crucial for mitochondrial energy production and maturation of semen cells (40). lastly, zinc and folate are both key molecules involved in dna and protein synthesis in germ cells such as spermatozoa. they are essential for various stages of sperm cell development, functionality and fertilizing capability (41). considering the mechanisms of action of these micronutrients it seems likely that their antioxidant properties play an important role to support sperm quality recovery when supplemented in patients after covid-19 infection. limitations an apparent limitation of this study is the lack of information regarding sperm quality of participants prior to sarscov-2 infection. therefore, it was not possible to determine if complete recovery of semen parameters occurred within the investigational period. moreover, intervals between viral illness and first semen sample collection varied between participants. regarding the study group receiving dietary support, it is not possible to confirm the extent to which improvement of semen parameters was due to micronutrient supplementation, or to potential physiological recovery of testicular function following convalescence from covid-19. to partly compensate for this lack of information a control group of men recovered from sars-cov-2 infection without micronutrient supplementation was additionally analysed, though sperm quality baseline values of first semen analysis varied between study and control group. another limitation to the power of this pilot study is the relatively low number of study group participants, and an even lower sample size for the control group. moreover, there is no information on which sarscov-2 virus strains caused the respective infections, though only two strains, alpha and delta, were primarily coexisting in austria during the recruitment period (42). despite these limitations, strict inclusion criteria were applied to ensure more homogeneity within both groups. conclusions the results of this study suggest that supplementation of certain micronutrients in male adults after covid-19 disease may improve recovery of sperm quality parameters and seminal oxidative stress, compared to a control group without dietary support. despite tendencies towards sperm quality recovery in both groups, significant positive effects on certain semen parameters were only evident in the study group. even though 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[cited 2023 jan 5]. available from: https://covariants.org/per-country. correspondence judith aschauer, b.sc. judith.aschauer@hotmail.com michaela sima michaela@sima.eu martin imhof martin@imhof.at wiener ring 3-5, 2100 korneuburg, austria conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper genetic predisposition and environmental influence, as for dietary habits (3, 4). besides, it is known to be associated with a wide spectrum of comorbidities such as obesity (5), arterial hypertension (6), diabetes mellitus (7), metabolic syndrome (8) and increased likelihood of developing chronic kidney disease, especially in secondary forms of systemic diseases (9). it was also shown that patients with urolithiasis have an increased risk of cardiovascular events (10) and vascular calcifications (11), highlighting the systemic involvement of this condition. kidney stones develop attached to either randall’s plaques (sub-epithelial interstitial deposits of calcium phosphate on the renal papillae), or stone plugs (crystal deposits in the terminal collecting ducts) (12). both these can be seen on the papillary surfaces. what promotes plaque formation is not well understood. it has been suggested that idiopathic calcium oxalate stones normally develop on randall’s plaques and that secondary forms of stones are mainly formed from plugs (12). a better understanding of both etiology and pathogenesis of the different forms of nephrolithiasis is fundamental to prevent recurrences with a more personalized and causespecific medical treatment. the improved optical ureterorenoscopic inspection techniques may make the evaluation of renal papilla not only possible but hopefully able to produce a large amount of new data and evidence as to the pathogenesis of stones (13). recently, a renal papillary appearance scoring system was proposed, in order to better characterize and to standardize the visual inspection of renal papillae (ppla score) (14). although it could certainly be a useful tool for improving reproducibility in the description of pathological findings in different patients and centers, at this moment the potential implications of this score on kidney stone risk factors are not well understood. the aim of this study is therefore to investigate the association between the main risk factors for kidney stone recurrence and the endoscopic papillary evaluation score (ppla) in a cohort of patients with nephrolithiasis. the association between ppla and subsequent recurrence was also investigated. objectives: the aim of this study is to investigate the association between the urinary metabolic milieu and kidney stone recurrence with a validated papillary evaluation score (ppla). materials and methods: we prospectively enrolled 30 stone formers who underwent retrograde intrarenal surgery procedures. visual inspection of the accessible renal papillae was performed to calculate ppla score, based on the characterization of ductal plugging, surface pitting, loss of papillary contour and randall’s plaque extension. stone compositions, 24h urine collections and kidney stone events during follow-up were collected. relative supersaturation ratios (rss) for calcium oxalate (caox), brushite and uric acid were calculated using equil-2. ppla score > 3 was defined as high. results: median follow-up period was 11 months (5, 34). ppla score was inversely correlated with bmi (or 0.59, 95% ci 0.38, 0.91, p = 0.018), type 2 diabetes (or 0.04, 95% ci 0.003, 0.58, p = 0.018) and history of recurrent kidney stones (or 0.17, 95% ci 0.04, 0.75, p = 0.019). the associations between ppla score, diabetes and bmi were not confirmed after excluding patients with uric acid stones. higher ppla score was associated with lower odds of new kidney stone events during follow-up (or 0.15, 95% ci 0.02, 1.00, p = 0.05). no other significant correlations were found. conclusions: our results confirm the lack of efficacy of ppla score in phenotyping patients affected by kidney stone disease or in predicting the risk of stone recurrence. larger, long-term studies need to be performed to clarify the role of ppla on the risk of stone recurrence. key words: kidney stones; retrograde intrarenal surgery; stone recurrence; management; stone phenotype. submitted 19 july 2022; accepted 20 august 2022 introduction nephrolithiasis is a medical condition characterized by a high prevalence in the general population and high recurrence rates (1), causing an elevated annual expenditure reaching up to $10 billion in the united states (2). kidney stone disease pathogenesis is multifactorial, including determinants of renal papillary appearance in kidney stone formers: an in-depth examination matteo bargagli 1, 2, francesco pinto 3, rossella de leonardis 1, mauro ragonese 3, angelo totaro 3, salvatore recupero 4, matteo vittori 5, pierfrancesco bassi 1, 3, giovanni gambaro 6, pietro manuel ferraro 1, 2 1 dipartimento universitario di medicina e chirurgia traslazionale, università cattolica del sacro cuore, roma, italia; 2 u.o.s. terapia conservativa della malattia renale cronica, dipartimento di scienze mediche e chirurgiche, fondazione policlinico universitario a. gemelli irccs, roma, italia; 3 u.o.c. clinica urologica, fondazione policlinico universitario a. gemelli irccs, roma, italia; 4 u.o.c. urologia, ospedale fatebenefratelli, rome, italy; 5 department of urology, san carlo di nancy hospital, rome, italy; 6 renal unit, department of medicine, university-hospital of verona, verona, italy. doi: 10.4081/aiua.2023.10748 summary archivio italiano di urologia e andrologia 2023; 95, 1 m. bargagli, f. pinto, r. de leonardis, et al. materials and methods study population we prospectively enrolled all patients undergoing retrograde intrarenal surgery (rirs) procedures for kidney stones at the u.o.c. clinica urologica, fondazione policlinico universitario a. gemelli irccs from may 2018 to september 2019. all patients were stone-free after rirs procedure. additional inclusion criteria were age ≥ 18 years and signed informed consent. at study initiation, all patients were naïve for dietary advice and medical treatment for kidney stone recurrence. all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. the study was approved by the bioethics committee of the fondazione policlinico univer sitario a. gemelli irccs, università cattolica del sacro cuore, rome, italy (id n° 2349). informed consent was obtained from all individual participants included in the study. data collection and measurements patients included in this study performed a baseline visit after rirs procedure at the nephrology stone clinic, fondazione policlinico universitario a. gemelli irccs, rome, italy, followed by a 1-year telephonic interview for investigating incident kidney stone events. either a visible spontaneous passage of stone, evidence of kidney stones at any instrumental exam or new kidney stones removal procedure, were considered as a recurrence and the variable “overall recurrent kidney stone disease at the end of the study” was generated accordingly. for each patient, demographic and anthropometric information (sex, age, height, weight), clinical data regarding stone disease (history of symptomatic stone events, family history of kidney stones, solitary kidney), self-reported comorbidities (hypertension, diabetes, cardiovascular diseases, bone fractures), a physical examination and office blood pressure measurements were recorded. standardized urine analyses (urine ph, daily urinary excretion of calcium, phosphate, magnesium, sodium, potassium, creatinine, urea, citrate, uric acid and oxalate) were conducted. stones were routinely collected during rirs procedures, in order to obtain composition analysis, using fourier-transform infrared spectroscopy. the creatinine-based ckd-epi equation was used to obtain the estimated glomerular filtration rate (egfr). among the metabolic evaluation parameters, the main one is represented by supersaturation for calcium oxalate, calcium phosphate and uric acid, representing the propensity of urine to form those crystals. urine relative supersaturation ratios (rss) for calcium oxalate monohydrate, brushite and undissociated uric acid were calculated by the equil2 program (15). visual inspection of the accessible renal papillae during rirs procedures was performed in order to calculate a score of papillary appearance (ppla score). ppla score is based on the characterization of 4 ordinal variables (ductal plugging, surface pitting, loss of papillary contour and randall’s plaque extension), representing worsening pictures of renal involvement. ppla score is an ordinal variable and it ranges from a minimum of 0 to a maximum of 8, produced by the sum of 4 components; each sub-component is an ordinal variable with 3 levels (from 0 to 2). in this study, the modified version of ppla score was used, considering randall’s plaque extension as an ordinal numeric variable (table 1) (16). all the images were evaltable 1. ppla score system for renal papillae (16). score 0 1 2 ductal plugging 0 plaque deposits/ ≤ 5 plaque deposits/ > 5 plaque deposits/ dilated ducts dilated ducts dilated ducts surface pitting none ≤ 25% papillary surface > 25% papillary surface loss of contour none depressed flattened randall’s plaque extension low medium high table 2. baseline characteristics of the study cohort. characteristic participants (n = 30) males 19 (63) age, years 60.2 (12) sbp, mmhg 130 (10) dbp, mmhg 83 (5) body mass index, kg/m2 25.8 (4) egfr creatinine equation ckd-epi 2009, ml/min per 1.73 m2 84.2 (19) arterial hypertension 14 (47) diabetes 3 (10) cardiovascular disease 6 (20) bone fractures 2 (7) hyperparathyroidism 1 (3) positive family history for kidney stones 11 (37) history of recurrent kidney stones 10 (33) solitary kidney 1 (3) 1-year kidney stone recurrence 9 (30) ppla score subgroups (0-6) 0 1 (3) 1 1 (3) 2 7 (23) 3 4 (13) 4 5 (17) 5 9 (30) 6 3 (10) high ppla score (> 3) 17 (57) rss for calcium oxalate 35.52 (20.20, 64.31) rss for calcium phosphate 0.42 (0.23, 1.82) rss for uric acid 1.03 (0.77, 1.89) urine ph 5.5 (5.0, 6.0) urine calcium, mg/day 183 (122, 283) urine phosphate, mg/day 770 (600-988) urine uric acid, mg/day 450 (326, 552) urine citrate, mg/day 427.1 (177.35, 614.7) urine oxalate, mg/day 19.5 (15.0, 26.8) urine creatinine, g/day 1.2 (1.0, 1.7) urine sodium, meq/day 145.9 (138.3, 191.0) urine potassium, meq/day 59.4 (48.0, 78.0) urine magnesium, mg/day 100.0 (80.2, 120.0) urine volume, ml/day 2,000 (1,550, 2,400) hypercalciuria 6 (20) hyperoxaluria 2 (7) hypocitraturia 11 (37) calcium oxalate stones 17 (57) urate stones 3 (9) calcium phosphate stones 0 mixed calcium oxalate and urate stones 5 (17) mixed calcium oxalate and calcium phosphate stones 8 (26) archivio italiano di urologia e andrologia 2023; 95, 1 renal papillary appearance in stone formers uated one by one from 4 expert surgeons (> 50 flexible ureteroscopy for renal stones) and 5 junior surgeons (< 50 procedures performed). all the graders evaluated the videos of the papillae using the same video system and were allowed to review the video more than one time. moreover, the percentage of agreement for the single item was evaluated in the two subgroups of surgeons and among senior graders, to ensure inter-grader concordance. hypercalciuria was considered as urine calcium excretion > 250 mg/24h for women and 300 mg/24h for men, hyperuricosuria as urine uric acid excretion > 750 mg/24h for women and 800 mg/24h for men, hyperoxaluria as urine oxalate excretion > 45 mg/24h and hypocitraturia as urine citrate excretion < 320 mg/24h (17). statistical analysis continuous variables were reported as medians with 25th and 75th percentiles or means with standard deviation (sd) and categorical variables were reported as counts with percentages. ppla score > 3 was defined as high. the interobserver surgeon concordance among all 10 investigators and between the median values of the two subgroups (junior vs senior) was analysed by the kendall coefficient of concordance. ordinal logistic regression was used to analyse the association between stone risk factors (hypertension, diabetes, body mass index, cardiovascular disease, history of recurrent kidney stones, family history of kidney stones, rss for calcium oxalate, calcium phosphate and uric acid, urine ph, urinary excretions of calcium, oxalate, citrate, uric acid and urine volume) and ppla and its components (ductal plugging, surface pitting, loss of papillary contour, randall’s plaque extension). the analyses were repeated after modelling ppla as lower (≤ 3) and higher (> 3) using logistic regression models. the association between ppla and 1-year kidney stone recurrence was analysed with logistic regression models. statistical tests were two-sided and a p-value < 0.05 was considered statistically significant. statistical analyses were performed using the software stata version 16 (statacorp, college station, tx, usa). results a total of 30 stone formers were enrolled in this study. mean age was 60.2 (sd 12.4) years and most patients were males (n = 19, 63%). overall, 47% were hypertensive (n = 14), 10% were diabetic (n = 3), 20% presented cardiovascular comorbidities (n = 6). as regards kidney stone disease, 33% had a positive history of recurrence (n = 10) and 37% had a positive family history of stones (n = 11). stone composition analysis, available in 23 patients (69%), revealed that calcium oxalate stones were the most frequent (56.5%), followed by mixed calcium oxalate and calcium phosphate stones (26.1%) (table 2). overall, 20% of the study sample had hypercalciuria (n = 6), 37% hypocitraturia (n = 11) and 7% hyperoxaluria (n = 2). the most frequent total ppla score was 5 (n = 9, 30%) and 57% of patients had a ppla score > 3 (n = 17). concordance between surgeon groups in the evaluations of plugging, pitting, loss of papillary contour and randall’s plaque extension were 86%, 73%, 72% and 80%, respectively. among senior surgeons concordance was even higher with a percentage of 91%, 80%, 76% and 85% agreement. the kendal coefficient of concordance was 0.93 among senior surgeons and 0.88 comparing the two groups of senior and junior surgeons. ppla score was inversely correlated with bmi (odds ratio [or] 0.59, 95% confidence interval [ci] 0.38, 0.91, p = 0.018), type 2 diabetes mellitus (or 0.04, 95% ci 0.003, 0.58, p = 0.018) and history of recurrent kidney stones (or 0.17, 95% ci 0.04, 0.75, p = 0.019) (table 3). the associations between type 2 diabetes and bmi with ppla score were not confirmed after excluding patients with uric acid stones. among the ppla components, randall’s plaque table 3. association between ppla score and risk factors for kidney stones or stone recurrence. ppla score high ppla score (> 3) variable no odds ratio 95% ci p-value no odds ratio 95% ci p-value hypertension 30 0.42 0.11, 1.57 0.197 30 0.34 0.08, 1.52 0.159 diabetes 30 0.04 0.003, 0.58 0.018* 30 0.33 0.99, 1.09 0.069 body mass index, kg/m2 30 0.59 0.38, 0.91 0.018* 30 0.78 0.61, 0.99 0.039 cardiovascular disease 30 0.98 0.21, 4.68 0.979 30 0.71 0.12, 4.30 0.713 history of recurrent kidney stones 30 0.17 0.04, 0.75 0.019* 30 0.08 0.01, 0.53 0.009 positive family history for kidney stones 30 1.83 0.48, 6.98 0.379 30 1.58 0.34, 7.22 0.559 1-year kidney stone recurrence 27 0.81 0.48, 1.37 0.426 27 0.15 0.02, 1.00 0.050* overall recurrent kidney stone disease 30 0.10 0.02, 0.48 0.004* 30 0.03 0.01, 0.28 0.001* rss for caox 30 1.01 0.99, 1.03 0.529 30 1.00 0.95, 1.06 0.948 rss for brushite 20 0.94 0.64, 1.37 0.726 20 0.54 0.23, 1.26 0.153 rss for uric acid 7 0.97 0.65, 1.45 0.887 7 not estimatable urinary excretion of calcium, mg/day 29 1.001 1.00, 1.01 0.657 29 1.00 1.00, 1.01 0.294 urinary excretion of oxalate, mg/day 30 0.95 0.90, 1.01 0.098 30 0.97 0.91, 1.03 0.330 urinary excretion of citrate, mg/day 30 1.00 1.00, 1.01 0.493 30 1.00 1.00, 1.00 0.934 urinary excretion of uric acid, mg/day 7 1.00 0.99, 1.01 0.488 7 1.00 0.99, 1.01 0.815 urinary excretion of sodium, meq/day 28 0.98 0.96, 1.00 0.050* 28 0.97 0.93, 1.01 0.150 urinary volume, ml/day 30 0.81 0.19, 3.43 0.774 30 0.48 0.09, 2.53 0.385 urine ph 30 1.10 0.41, 2.93 0.853 30 1.84 0.53, 6.38 0.337 archivio italiano di urologia e andrologia 2023; 95, 1 m. bargagli, f. pinto, r. de leonardis, et al. extension was inversely associated with history of recurrent kidney stones (or 0.03, 95% ci 0.003, 0.23, p = 0.001) (table 4). no other significant correlations were found between ppla components and kidney stone risk factors. after a median follow-up period of 11 months (5, 34), 30% of patients reported a new symptomatic kidney stone event (n = 9). higher ppla score was directly associated with lower odds of new kidney stone events during follow-up (or 0.15, 95% ci 0.02, 1.00, p = 0.050) and reduced likelihood of overall recurrent kidney stone disease at the end of the study (or 0.03, 95% ci 0.01, 0.28, p = 0.001). discussion novel methods capable of predicting the risk of stone recurrence and to better understand stone phenotype aetiology based on intra-renal crystals deposition are missing. in addition, three different hypotheses regarding the pathophysiology of stone formation have been proposed. the first hypothesis is randall’s plaque formation, with deposition of calcium phosphate crystals in form of apatite inside interstitial parenchyma. the second regards free solute crystallization for urine stasis and the third implies renal tubules crystal deposition as the nucleation factor for stone formation (18). recently, endoscopic visualization of the accessible portion of renal papillae and collecting duct system were applied for differentiating these pathways, creating a promising additional tool for future evaluation of recurrent stone formers (14). afterwards, a score of papillary appearance was created to study the association between stone phenotypes, urinary solute excretions and the description and quantification of either randall’s plaque, bellini duct plugging, focal erosion of papillary surface (pitting) and loss of papillary contour extensions (16). it can be then hypothesized that ppla score and its subscores might be of help in differentiating patients with the same stone composition, urinary lithogenic risk profile or recurrence risk but with diverse papillary aspects, perhaps reflecting multiple concomitant pathogenesis of nephrolithiasis. for these reasons, the use of ppla score was recently recommended in all patients who undergo ureteroscopy (19). however, evidence on the association between ppla score, stone composition and urinary solute excretions is conflicting. in a previous study, kuo et al. analyzed 14 stone formers, firstly showing the association between higher urinary calcium excretion, urine ph and urine volume on randall’s plaque extension (20), whereas analyzing larger cohorts of stone formers, linnes et al. (21) and pless et al. (22) did not confirm this association. in addition, sabaté arroyo et al. showed both increased frequency of intratubular calcification and papillary crater in patients with calcium oxalate dihydrate and calcium phosphate stones and a correlation between higher urinary calcium excretion and low urinary citrate excretion with papillary crater and randall’s plaque extension, respectively (23). in the present study, hypercalciuria and hypocitraturia were the most frequent 24-h urine abnormalities, reflecting data of the most common urinary lithogenic risk profile in the general population (24, 25). although we did not report any significant association between ppla score or sub-scores and stone composition, rss for calcium oxalate, brushite and uric acid or urinary lithogenic risk profile, both diabetes and bmi were found to be inversely correlated to ppla score. however, after excluding patients with uric acid stones, the former correlations were not confirmed. the association between increased risk for incident kidney stones and obesity, bmi and diabetes has been known for a long time (26). both type 2 diabetes mellitus and obesity share similar pathogenesis table 4. association between each ppla sub-score (ductal plugging, surface pitting, loss of papillary contour, randall’s plaque extension) and risk factors for kidney stones or stone recurrence. ductal plugging surface pitting loss of papillary contour randall’s plaque extension variable no or (95% ci) p-value or (95% ci) p-value or (95% ci) p-value or (95% ci) p-value hypertension 30 0.27 (0.06, 1.17) 0.080 0.77 (0.18, 3.34) 0.728 0.53 (0.10, 2.74) 0.448 1.02 (0.23, 4.48) 0.980 diabetes 30 0.32 (0.32, 0.35) 0.294 0.17 (0.01, 2.15) 0.171 0.09 (0.01, 1.17) 0.065 0.00 (0.31, 3.43) 0.995 bmi 30 0.91 (0.76, 1.10) 0.328 0.83 (0.68, 1.02) 0.079 0.91 (0.74, 1.13) 0.393 0.86 (0.69, 1.07) 0.174 cardiovascular disease 30 1.12 (0.19, 6.59) 0.904 0.68 (0.12, 3.99) 0.670 0.88 (0.13, 6.12) 0.894 2.12 (0.30, 14.82) 0.447 history of recurrent kidney stones 30 0.32 (0.07, 1.41) 0.131 0.64 (0.13, 3.06) 0.575 0.33 (0.06, 1.88) 0.213 0.03 (0.00, 0.23) 0.001* familiarity for kidney stones 30 1.88 (0.44, 8.10) 0.395 2.40 (0.48, 11.93) 0.285 0.68 (0.13, 3.60) 0.648 1.27 (0.28, 5.87) 0.757 1-year kidney stone recurrence 27 0.37 (0.09, 1.41) 0.145 0.50 (0.11, 2.27) 0.369 2.25 (0.41, 12.38) 0.351 0.67 (0.14, 3.21) 0.619 overall recurrent kidney stone disease 30 0.13 (0.03, 0.65) 0.013* 0.21 (0.04, 1.07) 0.061 0.48 (0.92, 2.51) 0.385 0.10 (0.17, 0.62) 0.013* rss for caox 30 1.01 (0.98, 1.03) 0.618 1.00 (0.98, 1.03) 0.802 1.00 (0.97, 1.03) 0.870 1.03 (0.99, 1.06) 0.122 rss for brushite 20 0.97 (0.66, 1.43) 0.870 0.97 (0.71, 1.32) 0.829 0.81 (0.57, 1.15) 0.229 1.00 (0.71, 1.41) 0.990 rss for uric acid 5 2.95 (0.03, 317.29) 0.650 0.01 (0.00, 22.90) 0.235 1.30 (0.58, 2.90) 0.526 1.95 (0.31, 27.19) 0.675 urinary excretion of calcium, mg/day 29 1.01 (1.00, 1.01) 0.138 1.00 (1.00, 1.01) 0.683 1.00 (0.99, 1.00) 0.209 1.00 (1.00, 1.01) 0.641 urinary excretion of oxalate, mg/day 30 0.98 (0.93, 1.04) 0.559 0.95 (0.89, 1.02) 0.134 0.95 (0.89, 1.02) 0.157 0.99 (0.93, 1.06) 0.826 urinary excretion of citrate, mg/day 30 1.00 (1.00, 1.00) 0.797 1.00 (0.99, 1.00) 0.147 1.00 (0.99, 1.00) 0.187 1.00 (1.00, 1.01) 0.173 urinary excretion of uric acid, mg/day 7 1.00 (0.99, 1.01) 0.993 0.99 (0.98, 1.00) 0.138 1.00 (0.99, 1.01) 0.455 1.04 (0.97, 1.12) 0.284 urinary excretion of sodium, meq/day 28 0.98 (0.96, 1.01) 0.180 0.98 (0.96, 1.00) 0.102 0.98 (0.96, 1.00) 0.101 0.99 (0.97, 1.02) 0.530 urinary volume, ml/day 30 0.78 (0.179, 3.45) 0.748 1.49 (0.30, 7.53) 0.629 0.59 (0.10, 3.40) 0.551 0.56 (0.10, 2.99) 0.496 urine ph 30 1.62 (0.53, 4.93) 0.400 1.18 (0.37, 3.82) 0.777 0.26 (0.06, 1.06) 0.060 1.47 (0.46, 4.68) 0.512 archivio italiano di urologia e andrologia 2023; 95, 1 renal papillary appearance in stone formers (27), being part of the metabolic syndrome, which is tightly associated to insulin resistance (28). insulin resistance results in acidic urine ph and defective renal production of ammonia, increasing the likelihood of developing uric acid kidney stones (8). notably, with a correct urinary alkalization, it is possible to reduce or even dissolve previously formed uric acid stones, provided the absence of combined uric acid and calcium stone composition (29). thus, the association between higher bmi, type 2 diabetes and lower ppla score, may be driven by uric acid nephrolithiasis, since it was no longer significant after restriction to calcium stone formers. however, there were too few uric acid stone formers in our cohort to confirm these observations. in this study on a prospective cohort of 30 stone formers, the association between ppla score and the risk of 1-year kidney stone recurrence was investigated for the first time. we demonstrated an inverse association between high ppla score and the odds of stone recurrence after a median follow-up time of 11 months. patients enrolled in this study were naïve for dietary advice and medical treatment for kidney stone disease. after rirs procedure, they underwent a work-up and dietary/medical management based on the results of 24h urine collections as well as their medical history; hence this data might reflect a more intensive medical management in the subgroup of patients with more severe pathological findings at papillary visualization. limitations of this study are the small sample size and low number of uric acid stone formers. overall, this evidence confirms the validity of advanced instrumental exams as a supplementary tool in medical and surgical management of kidney stones (30). future, larger studies with a systematic assessment of stone recurrence are needed to confirm our findings. conclusions in conclusion, our results confirm the lack of efficacy of ppla score in phenotyping patients affected by kidney stone disease or in predicting the risk of stone recurrence. larger, long-term studies need to be 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matteo.bargagli@unicatt.it pietro manuel ferraro, md msc phd fera (corresponding author) pietromanuel.ferraro@unicatt.it u.o.s. terapia conservativa della malattia renale cronica, dipartimento di scienze mediche e chirurgiche, fondazione policlinico universitario a. gemelli irccs & dipartimento universitario di medicina e chirurgia traslazionale, università cattolica del sacro cuore, roma, italia largo agostino gemelli 8, 00168, roma (italy) francesco pinto, md francesco.pinto@unicatt.it mauro ragonese, md mauro.ragonese@unicatt.it angelo totaro, md angelo.totaro@policlinicogemelli.it pierfrancesco bassi, md pierfrancesco.bassi@unicatt.it u.o.c. clinica urologica, fondazione policlinico universitario a. gemelli irccs, roma (italy) rossella de leonardis, md rosselladeleonardis95@gmail.com dipartimento universitario di medicina e chirurgia traslazionale, università cattolica del sacro cuore, roma (italy) salvatore recupero, md salvatoremarcorecupero@gmail.com u.o.c. urologia, ospedale fatebenefratelli, rome (italy) matteo vittori, md mvittori@gvmnet.it department of urology, san carlo di nancy hospital, rome (italy) giovanni gambaro, md giovanni.gambaro@univr.it renal unit, department of medicine, university-hospital of verona, verona (italy) conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper introduction congenital penile curvature (cpc) is a genetically inherited condition characterized by the presence of penile curvature. this malformation, already present at birth, is evident during erection and manifests in the absence of a demonstrable organic penile pathology. the pathogenesis of cpc is unknown (1, 2). however, it has been proposed that cpc may be caused by local androgen insufficiency determined by fetal androgen deficiency. alternatively, local deficiency of 5-alpha reductase, capable of causing penile malformation, has been proposed (3, 4). an ultrastructural study of the tunica albuginea, performed on tissue samples belonging to the ‘lozenge’ removed during nesbit's corrective surgery at the level of the external curvature (the zone of the concave angle), demonstrated the presence in this area of disruption of the tunica albuginea, associated with a chaotic alignment of collagen fibers, able to interfere with the normal mechanical properties of the same albuginea (darewicz et al., 2001) (5). in the frame of the same study, the authors analyzed microscopically the tissue contralateral to the lesions, at the inner side of the curvature, on the side of the convex angle. normal extension of the fibroblasts and blood vessels was demonstrated. moreover, in the latter tissue collagen fibers were shown to be normal both in quantity and in quality and organization. the authors concluded that the diseased area which causes the curvature is located at the level of the tunica albuginea on the external side, i.e. at the level of the great curvature, whereas the "diseased" albuginea is more yielding and extensible, causing this side of the penis to curve towards the opposite side (5). the prevalence of congenital penile curvature is very low and ranges between 0.04 and 0.6% (6-8) of the total population. the incidence of the various types of curvature shows minor variations among different authors: ventral curvatures occur in about 50% of cases, lateral ones in about 25% of cases (20% left, 5% right), mixed ventral/lateral ones in about 20-23% of cases, whereas dorsal curvatures are found in about 5% of cases (6, 9, 10). the incidence of the different degrees of curvature varies between different studies. according to various – and sometimes diverging – opinions, curvatures between 30 and 60 degrees show incidences ranging between 44 and 74%, whereas curvatures above 60 degrees are found by objective: to investigate a possible relationship between a history of congenital penile curvature (cpc) and peyronie's disease (pd), and to characterize the psychological profile of patients suffering from pd, with or without concomitant cpc. methods: we included 519 patients with peyronie's disease (pd), of which 73 were found to have underlaying cpc. as a comparator population, we selected 2166 patients without pd, referring to our tertiary care clinic. in this population we detected 15 subjects with cpc. all patients completed the gad7 (generalized-anxiety-disorder 7 questions) and the phq-9 (patient-health-questionnaire 9 questions) questionnaires. results: the overall prevalence of cpc in pd-patients was 14.07%, compared to a prevalence of 0.69% in the non-pd control population (p < 0.00001). moderate-to-severe anxiety was found to be present in 89.4% of all pd-patients. significantly higher proportions of patients with cpc associated with pd showed severe anxiety, compared to patients with pd alone (57.5% vs. 36.7%, respectively, p = 0.0008). moderatesevere depression was found to be present in 57.8% of all pdpatients. significantly higher proportions of pd patients with a history of cpc showed severe depression, compared to patients with pd alone (13.6% vs. 3.36%, respectively, p < 0.0002). gad-7 median scores were significantly higher in patients with more severe penile curvatures (> 45°; p = 0.029). we did not detect a statistically significant difference between phq-9 median scores based on the severity of pd (p = 0.53). analysis of phq-9 and gad-7 median scores showed significantly worse depressive and anxious symptoms in younger patients (p < 0.001 and p = 0.0013, respectively). conclusions: the presence of congenital-penile-curvature may represent a risk factor for the subsequent onset of peyronie's disease. moderate/severe anxiety and moderate/severe depression were reported in a high fraction of cases. anxiety was significantly higher in patients with more severe penile-curvatures, and depression was present independently of the degree of penile curvature. depression and anxiety were found to be more severe in younger subjects. key words: congenital penile curvature; peyronie’s disease; risk factors. submitted 5 february 2023; accepted 17 february 2023 congenital penile curvature as a possible risk factor for the onset of peyronie's disease, and psychological consequences of penile curvature gianni paulis 1, andrea paulis 2, gianpaolo perletti 3 1 peyronie’s care center, department of uro-andrology, castelfidardo clinical analysis center, rome, italy; 2 neurosystem center for applied psychology and neuroscience, janet clinical centre, rome, italy; 3 department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy. doi: 10.4081/aiua.2023.11238 summary archivio italiano di urologia e andrologia 2023; 95, 1 g. paulis, a. paulis, g. perletti some in about 32% of cases. alterations of 90 degrees show incidences of about 25%, whereas curvatures below 30 degrees are found in about 40% of cases (6, 9, 10). cpc (also referred to by some authors as "penile chordee") is often associated with hypospadias, as only 4-10% of cases are not associated with this condition (11). corporoplasty is the surgical treatment indicated for cpc (1). the most frequently used corporoplasty techniques include the nesbit procedure and its modifications, albuginea plication techniques, or techniques exploiting the insertion of grafts, aimed at lengthening the penis (10, 12-17). peyronie’s disease (pd) is an acquired penile curvature consisting of a chronic inflammation of the tunica albuginea of penile corpora cavernosa (18). although a genetic origin of the disease has been demonstrated, there is not unanimous agreement on its pathogenesis. trauma appears to be the triggering cause of the onset of the disease, which finally results in deformation of the penis (curvature, hourglass shape, shortening, etc.). the condition is also associated with penile pain, erectile dysfunction and depression (19-22). the incidence of the disease ranges between 3.2% and 13% (23-25). the pathogenesis of pd occurs in two main phases. initially, an active inflammatory phase takes place, whereby the plaque is formed, subsequently progressing to fibrosis and possible calcification. this stage is characterized by pain and by the progressive worsening of the deformation. in the second stage (the stabilization phase), pain has disappeared, and the deformation has stabilized. during the first phase, conservative medical treatment is indicated, including oral antioxidants, vitamin e, non-steroidal anti-inflammatory drugs, penile injections with various drugs (verapamil, interferon-α2b, cortisone, pentoxifylline, collagenase, hyaluronic acid, etc.), and physical therapies (swt, iontophoresis, vacuum penile and traction devices) (26-28). the surgical treatment is indicated in the second phase of the disease, when the curvature is severe and/or when severe erectile dysfunction occurs. the surgical techniques for pd differ according to the specific clinical condition and consist of corporoplasty (simple or with use of grafts), with or without application of penile prostheses (29-31). psychological consequences of congenital or acquired penile curvature the presence of a deformation of the penis showing different degrees of severity can affect the psychological equilibrium and the psycho-social relationships of the patients, resulting in a negative impact on the quality of life (qol). it has been documented that depression may occur in 48% of cases of peyronie's disease, and in 65% of cases of congenital penile curvature (22, 32). patients with penile deviation may show erectile dysfunction caused by sexual performance anxiety. this may be associated with a loss of personal body image, with reduced self-esteem and with a lack of confidence in the ability to achieve a satisfactory sexual intercourse (32). in this respect, surgical treatments have been shown to drastically improve the psychological state and the qol of patients (2, 32, 33). it is established that a diagnosis of pd is associated with alterations of the psycho-social functioning of affected subjects, who may show an array of conditions linked to each other and able to reinforce each other, including depressive symptoms, social isolation, stigmatization and sexual difficulties (34, 35). considering that pd does not affect all males, but only a fraction of those who are genetically predisposed, it may be hypothesized that congenital penile curvature could represent a risk factor for males genetically predisposed to pd. according to this hypothesis, cpc would favor traumatic events of different degrees of severity during coitus (3638). in fact, repeated intercoital thrusts can cause microtraumas in the context of the tunica albuginea of the corpora cavernosa, thus giving rise to the events underlying the formation of the plaque: delamination of the tunica albuginea, micro-hematoma, accumulation of fibrin, recruitment of macrophages, lymphocytes, platelets and fibroblasts, production of pro-inflammatory cytokines, and production and accumulation of collagen (26, 39). the present study was aimed at studying the relationship between a history of congenital penile curvature and peyronie's disease. the psychological impact of pd, in the presence of absence of concomitant cpc, was also investigated in depth. patients and methods we performed a retrospective analysis of the clinical database of a single andrology clinic. from the database we extracted two separate cohorts of patients referring to a single urology/andrology clinic between january 2013 and december 2022. one cohort included patients diagnosed with peyronie's disease (pd). as a comparator population, we extracted a cohort of urological patients without pd. all data were obtained from the available patient records. this retrospective observational study was conducted in compliance with the principles contained in the declaration of helsinki (fortaleza, 2013) (40): all study subjects were contacted and gave their informed consent to the study. sensitive data have in any case been anonymized in respect of privacy according to legislative decree 10 august 2018, n. 101 adapted to the gdpr (official gazette of the italian republic, general series n.205, dated 04-09-2018). inclusion criteria for the study were an age between 18 and 75 and the completion of two validated psychometric tests: the generalized anxiety disorder 7 questions (gad-7) and the patient health questionnaire 9 questions (phq-9) (41, 42). a diagnosis of cpc was not an exclusion criterion for the present study. the specific inclusion criterion for the pd cohort was a documented diagnosis of peyronie's disease. the exclusion criteria for the comparator control cohort were a diagnosis of peyronie’s disease or erectile dysfunction (ed). the primary endpoint of the study was the association between a history of cpc and the occurrence of pd in a patient population referring to a single tertiary care andrology center. secondary endpoints were the impact of the degree of penile curvature or of the age on the psychological profile of patients showing pd and/or cpc, assessed with the gad-7 and phq-9 tests. archivio italiano di urologia e andrologia 2023; 95, 1 congenital penile curvature as a risk factor for the onset of peyronie's disease statistical analysis to investigate an association between pd and a history of cpc, we calculated the pearson's chi-squared test with yates' continuity correction. statistical analysis was performed on the ‘r’ software environment for statistical computing and graphics. we performed a post-hoc analysis of the statistical power achieved for the crude odds-ratio calculation using the g*power 3.1 software (43). we investigated by the mann-whitney-wilcoxon test the impact of the degree of the penile curve on the median scores of the gad-7 or phq-9 questionnaires in patients stratified in two groups (group a, curve between 0-45 degrees; group b, curve > 45 degrees). we analyzed by the mann-whitney-wilcoxon test the impact of the age of patients on the median scores of the gad-7 or phq-9 questionnaires in patients stratified in two groups (group a, age up to 40 years; group b, age > 40 years). the significance of differences between prevalences/proportions was analyzed by a z-test. statistical analysis was performed on the ‘r’ software environment for statistical computing and graphics. two-sided crude odds ratios and 95% confidence intervals (95% cis) were calculated using the ‘epitools’ package for ‘r’. all statistical analyses were two-tailed. a 5% threshold for an alpha error was used to define statistical significance (significant p-value < 0.05). results we extracted from our database 519 patients meeting the inclusion criteria for this study, consecutively diagnosed with peyronie's disease (pd) between january 2013 and december 2022. as a comparator population, we extracted 2166 patients without pd and/or ed and meeting our inclusion criteria, referring to our tertiary care clinic for urological diseases. characteristics of congenital penile curvature the characteristics of the of cpc detected in 88 patients with or without pd, the prevalence and the degree of the different types of penile curvature are presented in table 1. the curvature angle was found to vary between 5 and 45 degrees. of the 73 patients with cpc who subsequently developed pd, 32 (43.8%) reported significant penile trauma in the weeks/months preceding the onset of the disease. notably, patients with cpc of the lateral type remember their previous penile trauma more frequently. prevalence of cpc in pd vs. non-pd patients in the cohort of 519 patients diagnosed with pd, 73 had a documented history of cpc (14.07%), whereas in the comparator population (n = 2166) cpc was reported in 15 cases (0.69%). the chi-square value for the comparison between frequencies of cpc in the pd and control cohorts was 201.65 (p < 0.0001). the z ratio was 15.4 (p < 0.001). we generated a contingency table comparing the presence/absence of a history of cpc in patients diagnosed or not with pd. the resulting significant crude odds ratio for cpc was 23.23 (95% ci, 13.57 to 42.51, p < 0.0001). post-hoc analysis showed an achieved power equal to 0.99 for the magnitude of effect (odds ratio) and 95% ci shown above. psychological profile of patients with pd with or without cpc the prevalence of anxiety in pd patients with or without cpc was assessed with the gad-7 test. moderate to severe anxiety (gad-7 score > 9) was reported in 89.4% of total patients (table 2). significantly higher proportions of patients with cpc associated with pd showed severe anxiety, compared to patients with pd alone (57.5% vs. 36.7%, respectively, p = 0.0008). conversely, moderate anxiety was reported more frequently in patients with pd alone than in subjects with cpc associated with pd (52.2% vs 34.2%, respectively; p = 0.004). table 1. typology of congenital penile curves and their characteristics in cpc patients with or without pd. type of congenital number degrees of no. and (%) of cases with penile curvature of cases (%) penile curvature memory of previous penile trauma patients with pd lateral 48 (65.7) 5-40 20 (27.39) left side 35 (47.9) 5-30 13 (17.8) right side 13 (17.8) 5-40 7 (9.58) ventral 11 (15.06) 10-40 5 (6.8) ventral and left side 3 (4.1) 5-10 1 (1.3) dorsal 9 (12.3) 10-45 5 (6.8) dorsal and left side 2 (2.7) 5-10 1 (1.3) total 73 32 (43.8) patients without pd lateral 13 (86.6) 5-45 0 (control cohort) left side 10 (66.6) 10-30 0 right side 3 (20.0) 5-45 0 ventral 1 (6.6) 10 0 ventral and left side dorsal dorsal and left side 1 (6.6) 15 0 total 15 0 table 2. prevalence of anxiety in pd patients with or without cpc, assessed with the gad-7 test. gad-7 no. total no. cases with no. cases with z-ratio score range cases (%) pd and cpc (%) pd alone (%) (p) no anxiety 0 2 (0.38) 2 (2.7) 0 (0) not assessable minimal or mild anxiety 1-9 53 (10.2) 4 (5.4) 49 (10.9) -1.073 (0.28) moderate-severe anxiety 10-21 464 (89.4) 67 (91.7) 397 (85.5) 0.71 (0.47) moderate anxiety 10-14 258 (42.0) 25 (34.2) 233 (52.2) -2.85 (0.004) severe anxiety 15-21 206 (39.6) 42 (57.5) 164 (36.7) 3.36 (0.0008) total 519 73 446 archivio italiano di urologia e andrologia 2023; 95, 1 g. paulis, a. paulis, g. perletti the prevalence of depression in pd patients with or without cpc was assessed with the phq-9 test. moderate to severe depression (phq-9 score > 9) was reported in 57.8% of total patients (table 3). significantly higher proportions of pd patients with a history of cpc showed severe depression, compared to patients with pd alone (13.6% vs. 3.36%, respectively, p < 0.0002). the impact of the severity of the penile curvature on the profile of anxiety or depression of pd patients was further investigated by dividing pd patients (irrespectively of concomitant cpc) in two groups, using 45 degrees as a curve cutoff value (group a, ≤ 45 degrees; group b, > 45 degrees). gad-7 median scores were significantly higher in patients with more severe penile curvatures (p = 0.029, table 4). conversely, we did not detect a statistically significant difference between phq-9 median scores based on the severity of penile curvature (p = 0.53, table 4). these results indicate that in pd patients depression can manifest independently of the degree of penile curvature. in addition, we investigated the impact of age on the median scores of both the gad-7 and phq-9 questionnaires, by dividing pd patients (irrespectively of concomitant cpc) into two main age categories, using 40 years as cutoff value (group a, ≤ 40 years; group b, > 40 years). phq-9 median scores were significantly higher in younger patients (p < 0.001, table 5). despite identical median values of gad-7 scores, a significant intergroup difference was found with the mann-whitney-wilcoxon test (0.0013). most likely, and similarly to the phq-9 analysis, younger patients show a higher degree of anxiety, since gad-7 mean values were higher (16.21 ± 3.99) than the mean values assessed in older individuals (14.66 ± 4.66). these results indicate that younger pd patients may have a more pronounced anxious profile. discussion a large number of studies have demonstrated the existence of several risk factors that can increase the possibility of developing pd. these risk factors include penile trauma, smoking, diabetes mellitus, hypertension, dupuytren's disease, alcohol consumption, erectile dysfunction, obesity, dyslipidemia, psoriasis, psoriatic arthritis, and rheumatoid arthritis (44-49). to our knowledge, this is the first study investigating the association between pd and cpc. our results show that the overall prevalence of cpc in patients with pd was significantly higher (14.07%), compared to the prevalence in a non-pd control population (0.69%). these data suggest that the presence of congenital penile curvature (cpc) may represent a risk factor for the subsequent onset of peyronie's disease (pd). a search in the scientific literature retrieved a single article that approaches on the subject (50). in presenting the results of their study, the authors made no reference to cpc as a possible risk factor for pd. the study included a sample of 60 patients who had already undergone tunica albuginea plication surgery (50). the authors specified that 21 patients reported worsening over time of the original congenital curve. the authors also added that these patients were older (mean age 34 years) and showed signs of peyronie's disease (penile shortening, history of penile trauma, palpable penile plaque, etc). in our study we diagnosed various types of congenital penile curves, although, unlike other authors we detected more frequently lateral congenital curves instead of ventral congenital curves (6, 9, 10). our results revealed that severe or moderate anxiety was present in 89.4% of pd patients. although in the literature there is no precise data regarding the incidence of anxiety symptoms during pd, smith and co-workers reported that 81% of pd patients included in their study reported ‘emotional difficulties’ (51). we also found that severe anxiety is more prevalent in pd patients showing the concomitant presence of cpc, compared to pd alone (57.5 vs. 36.7, respectively). table 3. prevalence of depression in pd patients with or without cpc, assessed with the phq-9 test. phq-9 no. total no. cases with no. cases with z-ratio score range cases (%) pd and cpc (%) pd alone (%) (p) no depression 0 2 (0.38) 2 (2.7) 0 (0) not assessable minimal or mild depression 1-9 217 (41.8) 26 (35.6) 191 (42.8) -1.15 (0.24) moderate-severe depression 10-27 300 (57.8) 45 (61.6) 255 (57.1) 0.71 (0.47) moderate depression 10-14 186 (35.8) 25 (34.2) 161 (36.09) -0.31 (0.75) moderately severe depression 15-19 89 (17.1) 10 (13.6) 79 (17.7) -0.84 (0.39) severe depression 20-27 25 (4.8) 10 (13.6) 15 (3.36) 3.92 (< 0.0002) total 519 73 446 table 4. gad-7 and phq-9 median scores in patients stratified according to penile curvature angles. questionnaires group a (n = 449) group b (n = 70) p-value administered angle of penile curvature ≤ 45 degrees angle of penile curvature > 45 degrees (mann-whitney-wilcoxon) phq-9 10 (8) 12 (6) 0.53 median, iqr (mean ± sd) (10.68 ± 4.99) (11.14 ± 5.09) gad-7 14 (7) 14.5 (8) 0.029 median, iqr (mean ± sd) (14.89 ± 4.49) (15.94 ± 4.86) iqr: interquartile range; sd: standard deviation. table 5. gad-7 and phq-9 median scores in pd patients stratified by age. questionnaires group a (n = 126) group b (n = 393) p-value administered angle of penile curvature ≤ 40 degrees angle of penile curvature > 40 degrees (mann-whitney-wilcoxon) phq-9 12.6 10.8 < 0.0001 median, iqr (mean ± sd) (13 ± 5.04) (10.02 ± 4.78) gad-7 14.7 14.7 0.0013 median, iqr (mean ± sd) (16.21 ± 3.99) (14.66 ± 4.66) iqr: interquartile range; sd: standard deviation. archivio italiano di urologia e andrologia 2023; 95, 1 congenital penile curvature as a risk factor for the onset of peyronie's disease in a study about the chronology of depression and distress in men with peyronie's disease, nelson and coworkers demonstrated that 48% of patients show clinically meaningful depression, assessed with the center for epidemiologic studies depression scale (ces-d) (22). in our study moderate to severe depression was reported in a higher fraction of patients (57.8%). however, a direct comparison is hampered by the different psychometric scales used in the two studies. beside corroborating the available evidence, our study suggests that, if not investigated in patients with pd by means of specific questionnaires, depressive and anxious symptoms may generally be underestimated in terms of severity and prevalence. in addition to the data in the overall pd population, we have also found that severe depression was present in a significantly higher fraction of patients with pd and concomitant cpc (13.6%) compared to patients with pd alone (3.36%). in our study we have shown that patients with more pronounced penile curves (> 45 degrees) show a higher degree of anxiety. conversely, analysis of phq-9 median scores using the 45-degree cutoff showed that pd patients develop various degrees of depression independently of the degree of penile curvature. articles containing similar considerations are present in the literature (34, 52-54). furthermore, when we investigated a possible relationship between the scores of the gad-7 and phq-9 questionnaires and the age of patients (age cutoff, 40 years) we noticed that younger patients show more severe depressive and anxious profiles. since age and the degree of penile curvature are potential factors for the development of psychological difficulties, it is deemed necessary to refine the diagnostic profiling of pd patients; a deeper understanding of these aspects may lead to the improvement of therapy protocols and their outcomes. conclusions the presence of congenital penile curvature may represent a risk factor for the subsequent onset of peyronie's disease. although the present study presents the limitations of a retrospective analysis of a patient database, the magnitude of the effect size, its statistical significance and the achieved power support the relative robustness of our results. nevertheless, further studies are needed to confirm cpc as a risk factor for pd, and also to investigate in depth the psychological effects of penile curvature. patients with pd and cpc showed a significantly higher prevalence of more severe depression and anxiety. patients with more pronounced penile curves show a higher degree of anxiety, compared with subjects showing a less severe curvature. depression and anxiety appear to be age-related, as their severity was shown to be higher in younger subjects. in the uro-andrological clinical practice a multidisciplinary approach with the involvement of 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relationship problems in peyronie’s disease. j sex med. 2008; 5:21792184. 52. punjani n, nascimento b, salter c, et al. predictors of depression in men with peyronie's disease seeking evaluation. j sex med. 2021; 18:783-788. 53. levine la. the clinical and psychosocial impact of peyronie's disease. am j manag care. 2013; 19(4 suppl):s55-61. 54. rosen r, catania j, lue t, et al. impact of peyronie's disease on sexual and psychosocial functioning: qualitative findings in patients and controls. j sex med. 2008; 5:1977-1984. 55. taylor fl, levine la. peyronie's disease. urol clin north am. 2007; 34:517-534. 56. bella aj, perelman ma, brant wo, et al. peyronie's disease (cme). j sex med. 2007; 4:1527-1538. 57. jordan gh, carson cc, lipshultz li. minimally invasive treatment of peyronie's disease: evidence-based progress. bju int. 2014; 114:1624. 58. porst h, burri a; european society for sexual medicine (essm) educational committee. current strategies in the management of peyronie's disease (pd)-results of a survey of 401 sexual medicine experts across europe. j sex med. 2019; 16:901-908. 59. el-sakka ai. medical, non-invasive, and minimally invasive treatment for peyronie's disease: a systematic review. andrology. 2021; 9:511-528. correspondence gianni paulis, md (corresponding author) paulisg@libero.it peyronie’s care center, department of uro-andrology, castelfidardo clinical analysis center, rome, italy andrea paulis, md andrea.fx.94@gmail.com neurosystem center for applied psychology and neuroscience, janet clinical centre, rome, italy gianpaolo perletti, dr. biol. sci. m. clin. pharmacol. gianpaolo.perletti@uninsubria.it department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 39 original paper nomic significance. the social aspect is related to the long duration of the illness, the high recurrence rate (up to 50%), and its frequent urgent presentation, leading to sudden disability (1). the economic aspect is related to high personal and government costs for treatment, and loss of working activity. mortality from urolithiasis has recently increased (2, 3). the multifactorial process of stone formation leads to a wide variety of clinical presentations. one of the most common forms of urolithiasis is the formation of calcium oxalate stones (4). the increased concentration of salts in the urine, inflammation, the presence of papillary plaques and plugs in the collecting system of the kidney, and other factors contribute to the development of the disease (5). a complex of metaphylactic measures, such as lifestyle changes, hyperhydration, dietary modifications, correction of concomitant diseases and hormonal disorders, is considered extremely important to prevent relapses after surgical treatment. in addition, the prevention of postoperative recurrence depends on minimizing intraoperative trauma, reducing the risk of infectious complications, and avoiding residual fragments that can act as initial nucleus of stone formation (6). it is important to note that the recommendations for stone treatment have been changed in the context of the pandemic. the international endourological society has reached a consensus on several recommendations for urolithiasis treatment. thus, it was recommended to conduct remote counseling, avoid intubation methods of anesthesia, reduce indications for surgical treatment of asymptomatic concretions, etc. (7). currently, there are two most effective alternative methods for minimally invasive removal of kidney stones with a high level of stone-free rate (sfr) that are the retrograde nephrolithotripsy or retrograde intra-renal surgery (rirs) and the percutaneous nephrolithotomy (pcnl) using flexible optics (8, 9). these methods are superior to the alternative method, shock-wave lithotripsy, in terms of sfr and complications (10, 11). an effective combination of both methods is possible in complex cases (12, 13). both objectives. the study presents a comparative analysis of the mini-percutaneous nephrolithotripsy (mini-pcnl) and retrograde nephrolithotripsy (rirs) with a logistic analysis of outcomes and complications. material and methods. the prospective study included 50 patients diagnosed with urolithiasis from 2018 to 2021 in the urological hospitals in irkutsk. patients were divided into two groups: rirs (group i, n = 23) and mini-pcnl (group ii, n = 27). the comparison groups are statistically homogeneous. results. both procedures equally lead to high stone free rates (sfr > 1 mm, 91.3% vs 85.1%; p = 0.867; sfr > 2 mm, 95.6% vs 92.5%; p = 0.936). the intergroup analysis of the total operation time (and lithotripsy) demonstrated similar times (p > 0.05). postoperative complications of classes ii-iii (clavien-dindo) in the early and late postoperative period developed rarely and were comparable (p > 0.05). class i complications were predominant in the pcnl group (p = 0.007). some parameters demonstrated the superiority of rirs over pcnl: less pronounced pain syndrome (p = 0.002), less drainage time (p < 0.001), no postoperative hematuria (p = 0.002), shorter hospitalization and total treatment period (p < 0.001). conclusions. the study highlighted the positive effect of the oneday surgery principle on the risk of developing postoperative hematuria, urinary infection, or severe postoperative pain. rirs and mini-pcnl have similar effectiveness, but rirs meets the criteria of the enhanced recovery program more than pcnl. key words: fast track surgery; rirs; pcnl; mini-pcnl; enhanced recovery. submitted 4 november 2022; accepted 17 february 2023 introduction enhanced recovery is the conventional name of various protocols or programs for optimizing the perioperative period (for example, fast track surgery, enhanced recovery after surgery or eras) aimed at restoring health, working capacity, and improving the quality of treatment. urolithiasis is a widespread disease affecting up to 12% of the human population, with pronounced social and ecoenhanced recovery after retrograde intra-renal surgery (rirs) in comparison with mini-percutaneous nephrolithotomy (mini-pcnl) for renal stone treatment vladimir vorobev 1, vladimir beloborodov 1, temirlan hovalyg 1, igor seminskiy 2, andrey sherbatykh 3, igor shaderkin 4, mikhail firsov 5 1 department of general surgery, irkutsk state medical university, krasnogo vosstaniya str., 1, irkutsk, 664003, russian federation; 2 department of pathology, irkutsk state medical university, krasnogo vosstaniya str., 1, irkutsk, 664003, russian federation; 3 department of faculty surgery, irkutsk state medical university, krasnogo vosstaniya str., 1, irkutsk, 664003, russian federation; 4 e-health laboratory, i.m. sechenov first moscow state medical university, pirogovskaya str., 2, moscow, 119296, russian; federation; 5 department of urology, andrology and sexology, krasnoyarsk state medical university named after professor v.f. voino-yasenetsky, partizan zheleznyaka str., 1, krasnoyarsk, 660022, russian federation. doi: 10.4081/aiua.2023.10991 summary archivio italiano di urologia e andrologia 2023; 95, 2 v. vorobev, v. beloborodov, t. hovalyg, i. seminskiy, a. sherbatykh, i. shaderkin, m. firsov 40 methods lead to several postoperative complications, such as hematuria, fever, extravasation, pain. however, complications after rirs are less pronounced and less likely to require surgical treatment (14, 15). nevertheless, reducing the diameter of the working tool can reduce the severity of complications after pcnl and even surpass rirs (10). there is a small number of publications devoted to rirs (according to pubmed, 601 works on 02.02.2022 from 1988 to 2022), and only 48 comparative studies of rirs and pcnl (according to pubmed, 48 works on 02.02.2022 from 2008 to 2022). moreover, there are practically no comparative studies on optimization of the perioperative period to improve the treatment effectiveness and enhance recovery. the study presents a comparative analysis of the use of mini-percutaneous nephrolithotripsy (mini-pcnl) and retrograde nephrolithotripsy (rirs) with a logistic analysis of outcomes and complications. methods research design the local ethics committee of the irkutsk state medical university (ismu) of the ministry of health of the russian federation approved the clinical trial. it was a prospective, blind, randomized study in irkutsk urological hospitals. the study included an analysis of perioperative data and treatment outcomes in patients with urolithiasis who underwent one of the surgical methods established by the protocol from january 2018 to october 2021. surgical operations were performed using one of two endourological methods: mini-pcnl or rirs. all the features of the planned treatment methods were explained to the patient. inclusion criteria: – planned surgery for kidney stones; – indications for the operation meeting the criteria of the approved protocol; – operation was planned to use one of the methods approved in the study; – age over 18 years; – patient signed a voluntary informed consent to participate in the study. non-inclusion criteria: – no indication to treatment; – presence of concomitant diseases that significantly affect the general conditions of the patient (decompensated diabetes mellitus, heart failure, gross neurological deficits, etc.); – inability to comply with the protocol of the study. exclusion criteria: – deviation from the study protocol; – deviation from the criteria of the group. the inclusion of patients in the study was carried out prospectively and continuously, until reaching the minimum sample size (20 patients in each group) and then within the planned timeframe of the study. finally, there were 77 patients recruited to participate in the study, out of them 50 patients completed the study. all the included patients were randomized into two groups based on the approved study protocol. the groups were not artificially aligned. the first group was treated with rirs, the second group with mini-pcnl. deviations from the protocol of the 77 patients included in both groups in the study, 27 were excluded (17 due to deviation from the protocol, and 10 for personal reasons). the evaluation of the results (per-protocol) included 50 patients who meet all the criteria of the study. rirs group included 23 patients (group i) and mini-pcnl group included 27 patients (group ii). outcomes primary outcomes of the study were: absence of residual fragments in the postoperative period, not earlier than a month later; need for re-operation, migration of the stone into the ureter during surgery. secondary outcomes: postoperative examination data; renal colic; urohematomas; urine leakage; recurrence of stone formation. comparison of study groups table 1 presents the preoperative parameters of patients. the statistical analysis established the homogeneity of the two groups (p > 0.05) according to the initial status. diagnostic methods evaluation included clinical history (history of stone disease, concomitant diseases, etc.), physical examination, table 1. preoperative status. parameter group i group ii p (n = 23) (n = 27) age, years weight, kg height, cm bmi, units female, n (%) disease duration, days emergency intervention, n (%) re-stenting, n (%) leukocytosis, n (%) anemia, n (%) ischemic heart disease, n (%) hypertension, n (%) diabetes mellitus, n (%) prostate hyperplasia, n (%) urinary tract cancer, n (%) kidney cysts, n (%) chronic urinary infection, n (%) area of the largest concretion, mm2 hu density, units concretion > 20 mm, n (%) more than one concretion, n (%) calcium oxalates, n (%) 60 (51; 63) 88.2 ± 20.8 1.66 ± 0.1 31 (27; 37) 16 (69.5%) 15 (4; 36) 2 (8.6%) 0 (0%) 3 (13.0%) 1 (4.3%) 10 (43.4%) 14 (60.8%) 3 (13.0%) 6 (26.0%) 1 (4.3%) 4 (17.3%) 8 (34.7%) 135 (117;195) 948 (± 298) 5 (21.7%) 8 (34.7%) 15 (65.2%) 51 (39; 55) 81.1 ± 15.7 1.70 ± 0.08 28 (25; 30) 12 (44.4%) 13 (5; 26) 5 (18.5%) 2 (7.4%) 4 (14.8%) 2 (7.4%) 11 (40.7%) 11 (40.7%) 3 (11.1%) 1 (3.7%) 0 (0%) 1 (3.7%) 15 (55.5%) 120 (90;228) 909 (± 394) 8 (29.6%) 11 (40.7%) 19 (70.3%) 0.413 0.173 0.147 0.052 0.345 0.847 0.384 0.199 0.875 0.668 0.900 0.414 0.852 0.049 0.284 0.147 0.367 0.602 0.697 0.626 0.771 0.864 archivio italiano di urologia e andrologia 2023; 95, 2 41 the retrograde intra-renal surgery biochemistry, imaging (ultrasound, tomography, x-ray) and endoscopy. the analysis of the composition of the calculi was performed by spectroscopy in a specialized laboratory after surgery. multi-slice computer tomography (msct) examination helped to assess the urinary system status, including the density and size of concretions. the severity of postoperative pain syndrome was assessed according to the visual analog scale (vas) of pain. before removal of the urethral catheter, nephrostomy, and stent an ultrasound examination was performed to rule out possible uro-hematomas. no earlier than one month after the operation and no later than two months, there was the first control by msct to assess sfr. after the first follow up visit after surgery, patients regularly (once every six months) underwent the examinations established by the protocol of the study: consultation of the operating doctor, blood and urine tests, ultrasound msct. there were several criteria for evaluation of treatment effectiveness: sfr, no re-operation, no complications > class ii according to clavian-dindo. sfr was evaluated according to two criteria: fragments > 1 mm and fragments > 2 mm. the perioperative period was evaluated separately by assessing the length of hospital stay, the total period of disability, the functional status in the postoperative period (pain, temperature, etc.). the cost-effectiveness of treatment was not evaluated. surgical treatment during the study, a common protocol of enhanced recovery for patients with planned endourological intervention foe renal stones was followed in both groups. table 2 presents the protocol scheme. table 2. the enhanced recovery protocol for endourological surgery for kidney stones. preoperative – informing the patient about the disease, treatment options, and possible outcomes, indicating the average effectiveness, risks of complications, typical postoperative condition, timing of catheterization, hospitalization, possible methods of pre-rehabilitation, and further rehabilitation methods – one-day concept: the patient undergoes most of the preoperative examinations in one day, without the need for multiple re-preparation; the order of examinations and tests is optimized and sorted to achieve the desired outcome – rigorous evaluation of indications for surgical treatment: symptomatic concretions; chronic urinary infection; concretions > 15 mm; progressive size growth; obstructive disorders; recurrent course – assessment of the possibility of patient compliance with the protocol and its feasibility in the medical institution – preventive administration of antihistamines and antacids drugs – avoiding of preoperative sedation – pre-rehabilitation based on indications: age group; obesity; exhaustion; sarcopenia; impaired carbohydrate tolerance or diabetes mellitus – preoperative antibiotic therapy according to the indications: latent or obvious infection of the genitourinary system (according to the results of bacteriological research) – multidisciplinary examination of patients: urologist; anesthetist; general practitioner/cardiologist; radiologist; and other specialists as needed – ct/mri of the urinary system, with 3d modeling and contrast, including angiography – a rich carbohydrate and protein meal (if there are no contraindications) and 200 ml of liquid 2.5 hours before surgery – the last meal (if the operation is in the morning) at 10 p.m. the day before, if in the afternoon no later than 6 hours before the operation – antibiotic prophylaxis 60 minutes before surgery with 3rd generation cephalosporins with a negative result of a urine culture examination – no shaving of the surgical area – preparation of the intestine with laxatives or single micro-clysm – prevention of thromboembolic complications by compression of the lower extremities and administration of low-molecular-weight heparins – no cleansing enemas – avoiding of pre-stenting/pre-catheterization intraoperative – preferred method of anesthesia: regional anesthesia/multimodal anesthesia – heating of the patient during the operation with the control of normothermia – heating of infusion solutions and inhalation gases – rirs or mini-(micro)-pcnl using flexible endoscopes – using a small diameter access sheath (up to 12-14fr with rirs; up to 14fr with pcnl) – laser application in low power mode (up to 10w) – avoiding of popcorning. spraying of fragments > 1 mm with difficult extraction – avoiding of the ureteral access sheath for single concretions < 10 mm with rirs – avoiding of multi-access with pcnl – administration of tranexamic acid before puncturing during pcnl – avoiding of nephrostomy/stenting if possible – reduced fluid pressure in the kidney – adhesive bandage on the skin – intraoperative euvolemia – urethral catheters 12-14ch – sealed cosmetic skin suture without loose ends and knots on the skin, adhesive bandages with pcnl postoperative – early fluids intake (2–3 hours after surgery) and food (6 hours after surgery) – early activation (2–4 hours after surgery, after evaluation by an anesthesiologist and urologist) – physical therapy (breathing exercises, walking, and other exercises) – multimodal prevention of nausea and vomiting (metoclopramide+ondansetron) – early ultrasound control to exclude hematomas and urinomas in the first 3-6 hours after surgery – removal of the urethral catheter, nephrostomy, stent after ultrasound control no later than 3 (for pcnl) and 1 (after rirs) day after surgery, followed by re-evaluation – hemostatic drugs (tranexamic acid) in intraoperative or detected postoperative bleeding – continuation of prevention of thromboembolic complications by compression of the lower extremities and the use of low-molecular-weight heparins – multimodal analgesia for pain control (dexketoprofen + paracetomol) – use of alpha blockers – chewing gum on the first and second day after surgery – monitoring of blood and urine parameters on the first day after surgery – strict glycemic control in case of impaired carbohydrate tolerance and diabetes mellitus – a detailed discussion of the behavior of the patient and the rehabilitation plan before the discharge – detailed written instructions in the discharge documents – strict plan of control examinations in the postoperative period – strict postoperative hygiene of the genitals and postoperative wounds (with an adhesive bandage, the patient is recommended to take a hygienic shower daily from the first day without additional processing) – discharge from the hospital within 1-3 days after the operation with the outpatient observation or the recovery archivio italiano di urologia e andrologia 2023; 95, 2 v. vorobev, v. beloborodov, t. hovalyg, i. seminskiy, a. sherbatykh, i. shaderkin, m. firsov 42 the final surgical treatment method was chosen before the operation by randomization. the operating time was estimated from the beginning (including patient positioning) to the complete end of all the actions of the surgical team. a thulium laser with a power mode up to 10w was used for lithotripsy. after both procedures, pyeloureterography was done at the end of the operation to assess the need for kidney stenting/nephrostomy. the main types of operations were mini-perc pcnl with access sheath up to 14 fr (for multiple and large concretions) and use of flexible optics (to avoid multi-access and to search for possible residual fragments). puncture of renal cavities was done under emergency operations center (eoc) and ultrasound control, after preliminary route planning based on the msct angiography results. the patient could be in any position at the discretion of the surgeon, avoiding prone position. nephrostomy was maintained in most cases for a period of 1 to 3 days. tubeless procedure was preferred for single, uninfected stones, without ongoing hematuria. rirs was performed under eoc control; when ureteral access sheath was not placed, the surgeon inserted the endoscope into the ureter up to the kidney with a guidewire. in absence of signs of perforation or fragments migration, a ureteral catheter was maintained for up to 12 hours from the end of surgery whereas in other situations, a ureteral stent was placed. after the operation, all patients stayed in the intensive care unit for 2-3 hours. all patients received multimodal analgesia, prevention of thromboembolic complications (low molecular weight heparin), and protection from stress ulcers (proton pump blockers). on the first day after surgical treatment patients were assessed the pain level. statistical analysis the pre-operative data and the results of surgical treatment were analyzed using statistica software for windows version 10.0 (statsoft, inc, usa), spss statistics version 23.0 (ibm, usa), and stata version 16.0 (statacorp, usa). the significance level for all the methods was set at p ≤ 0.05 (except multiple logistic regression). data of the two groups (rirs vs mini-pcnl) were compared. results peri-and postoperative results in the peri-and postoperative periods, there were no cases of lethality, anesthesiologic complications or critical deterioration of the state of health due to concomitant diseases in both groups. all registered complications corresponded to classes i-iiib clavien-dindo following the recommendations of the european association of urology (16, 17). there was one iiib complication in the pcnl group associated with an increasing paranephric hematoma. the average surgery duration in groups i and ii were 67 ± 34 and 75 ± 21 minutes, respectively (p = 0.350). the time of direct lithotripsy and evacuation of fragments for i and ii was 41 ± 31 and 49 ± 20 minutes, respectively (p = 0.276). table 3 shows the postoperative status of patients. significant postoperative complications (clavien-dindo ≥ 3) rarely developed in both groups. there is a significant statistical difference in the level of mild and minor complications: in group ii, class i complications occurred with a higher frequency (p = 0.007). migration of concretions fragments was more frequent in group ii (p = 0.009), which was probably due to worse visualization caused by the development of intraoperative hematuria. in general, hemorrhagic complications in group ii are significantly more common. an objective examination in the late postoperative period established the groups' comparability (p > 0.05) and a significant difference in the risks of complications, postoperative status, and duration of treatment (p < 0.05). it should be noted that the development of complications of classes iiia-b was isolated. univariate logistic regression analysis of these complications revealed no relationship with perioperative parameters (p > 0.05). table 4 partially presents the data of the performed regression analysis of predictors of postoperative complications. a significant predictor of residual concretions was the duration of lithotripsy for more than one hour (hr 2.40; 95% ci -0.21; 5.02; p = 0.072). the remaining factors were not significant (p > 0.1). table 3. postoperative status of patients. parameter group i group ii p (n = 23) (n = 27) clavien-dindo complications, n (%): i class ii class iiia class iiib class migration of concretions fragments, n (%) paranephral hematoma > 100 ml, n (%) blood transfusion, n (%) postoperative hematuria up to 1 day, n (%) subfebrility 1st day after surgery, n (%) febrility 1st day after surgery, n (%) pyelonephritis after surgery, n (%) stenting (i)\nephrostomy (ii), n (%) timing of kidney catheterization\nephrostomy, days perforation, n (%) re-operation, n (%) vas more than 5 points on the first day after surgery, n (%) postoperative pain, points average duration of hospitalization, bed-day 1-day stay, n (%) total treatment period, days sfr > 1 mm, n (%) sfr > 2 mm, n (%) vas: visual analog scale; sfr: stone-free rate. 1 (4.3%) 1 (4.3%) 1 (4.3%) 0 0 0 0 0 0 0 0 10 (43.4) 1 (1; 1) 1 (4.3%) 0 0 4 (4; 4) 1 (1; 1) 13 (56.5%) 1 (1; 2) 21 (91.3%) 22 (95.6%) 13 (48.1%) 6 (22.2%) 1 (3.7%) 1 (3.7%) 9 (33.3%) 1 (3.7%) 2 (7.4%) 13 (48.1%) 4 (14.8%) 3 (11.1%) 1 (3.7%) 17 (62.9) 2(2; 4) 1 (3.7%) 2 (7.4%) 21 (77.7%) 6 (6; 7) 3 (2; 4) 0 10 (3; 14) 23 (85.1%) 25 (92.5%) 0.007 0.115 0.911 0.360 0.009 0.360 0.199 0.002 0.073 0.118 0.360 0.448 < 0.001 0.911 0.199 0.002 < 0.001 < 0.001 0.005 < 0.001 0.867 0.936 archivio italiano di urologia e andrologia 2023; 95, 2 43 the retrograde intra-renal surgery figure 1 shows a model with a very good predictive value (area under curve, auc = 0.88) presented as a roc curve. consequently, the long duration of the operation (lithotripsy) increases the probability of residual fragments by 2.4 times. baseline anemia (hr 3.13; 95% ci 0.02; 6.24; p = 0.048; auc = 0.72) and urinary tract perforation (hr 3.85; 95% ci 0.44; 7.25; p = 0.027; auc = 0.73) were reliable predictors of the need for reoperation with one-factor regression. it was not possible to build a reliable multivariate regression model. significant predictors of postoperative hematuria were male gender (hr 2.14; 95% ci -0.27; 4.56; p = 0.082), duration of lithotripsy more than an hour (hr 3.53; 95% ci -0.31; 7.38; p = 0.072), chronic pyelonephritis (hr 3.09; 95% ci -0.48; 6.67; p = 0.090) and severe postoperative pain vas > 5 points (hr 3.35; 95% ci 0.34; 6.35; p = 0.029). figure 2 shows a model with excellent predictive value (area under curve, auc = 0.93) presented as a roc curve. the remaining factors were not significant (p > 0.1). significant predictors of postoperative exacerbation of urinary infection were chronic hepatitis (hr 3.93; 95% ci 0.15; 7.72; p = 0.041), baseline bacteriuria (hr 2.64; 95% ci -0.40; 5.69; p = 0.089) and any migration of concretion intraoperatively (hr 2.86; 95% ci -0.48; 6.22; p = 0.094). figure 3 shows a model with excellent predictive value (area under curve, auc = 0.94) presented as a roc curve. figure 1. roc curve for multivariate logit regression of predictors of postoperative residual concretions. figure 2. roc curve for multivariate logit regression of postoperative hematuria predictors. figure 3. roc curve for multivariate logit regression of predictors of exacerbation of urinary infection. table 4. analysis of predictors of complications in the early and late postoperative period. complication predictor univariate analysis multivariate analysis χ 2 or (95% ci) p or (95% ci) p residual concretion. lithotripsy time > 60 minutes 14.61 3.61 (1.32; 5.89) 0.002 2.40 (–0.21; 5.02) 0.072 multivariate logit regression: intraoperative hematuria 3.62 1.61 (–0.05; 3.28) 0.057 χ 2 = 16.89; p = 0.0007 any concrement migration 6.67 2.31 (0.55; 4.07) 0.010 1.21 (–1.07; 3.50) 0.299 area > 500 m2 9.17 2.8 (0.97; 4.77) 0.003 1.69 (–0.61; 4.00) 0.150 reoperation. multivariate initial anemia 3.30 3.13 (0.02; 6.24) 0.048 logit regression: χ2 = –; p =– perforation 4.30 3.85 (0.44; 7.25) 0.027 coagulopathy 2.20 2.39 (–.055; 5.35) 0.112 postoperative pain syndrome, increasing experience of the surgeon 9.59 –0.72 (–1.21; –0.23) 0.004 –0.51 (–1.7; 0.69) > 5 points on the vas scale lithotripsy time is more than 30 minutes 8.24 1.79 (0.47; 3.11) 0.008 2.28 (0.26; 4.31) prescription of acute illness, day 9.44 0.68 (0.20; 1.16) 0.005 0.03 (–0.07; 0.15) multivariate logit regression: 1-day surgery 6.96 –1.66 (–2.95; –0.37) 0.011 3.51 (–1.27; 8.31) χ 2 = 34.38; p < 0.0001 preoperative waiting > 3 days 7.14 1.87 (0.39; 3.34) 0.013 1.73 (–1.74; 5.21) intraoperative hematuria 13.69 2.69 (1.02; 4.37) 0.002 1.78 (–0.88; 4.45) stenting 15.60 –2.74 (–4.38; –1.10) 0.001 –3.4 (–5.93; 0.87) any concrement migration 5.85 1.90 (0.21; 3.60) 0.028 1.48 (–1.71; 4.68) vas: visual analog scale. archivio italiano di urologia e andrologia 2023; 95, 2 v. vorobev, v. beloborodov, t. hovalyg, i. seminskiy, a. sherbatykh, i. shaderkin, m. firsov 44 significant predictors of postoperative pain syndrome were lithotripsy time of more than half an hour (hr 2.28; 95% ci 0.26; 4.41; p = 0.027). postoperative kidney stenting was a protective factor (hr -3.4; 95% ci -5.93; -0.87; p = 0.008). figure 4 shows a model with excellent predictive value (area under curve, auc = 0.92) presented as a roc curve. long-term results general results were reported according to the last observation. true relapse was considered only when newly identified concretions were observed in patients who were previously considered stone free with a 1 mm cut off (sfr > 1 mm). successful primary sfr > 1 mm was observed in 21 (91.3%) vs 23 (85.1%) (p = 0.867); false relapse in 2 (8.6%) vs 4 (14.8%) (p = 0.555); and true relapse in 2 (9.5%) vs 3 (13.0%) (p = 0.742) in group i and ii, respectively. the average clinical observation period was 251 days (95% ci 98-146 days) and maximum duration of follow up was 664 days. for group i, the average follow-up period was 218 days (95% ci 61-112 days) and maximum period of follow up was 440 days. for group ii, the average follow-up period was 279 days (95% ci of 108-189 days) and maximum period of follow up was 664 days. due to the absence of cases of lethality, survival analysis was not performed, the survival rate for both groups being 100%. there were no significant complications in the long-term postoperative period. in group i, kaplan-meyer's estimate of freedom from true stone recurrence was 95.6 ± 4.25% after the first six months (95% ci 72.9; 99.3%), 88.8 ± 7.6% (95% ci 60.9; 92.2%) after 9 months and 74.0 ± 14.9% (95% ci 32.5; 92.2%) after a year and a half. in group ii, freedom from true stone recurrence was 96.3 ± 3.6% (95% ci 76.4; 99.4%) after the first six months, 91.7 ± 5.6% (95% ci 70.4; 97.8%) after 9 months, and 84.9 ± 8.3% (95% ci 58.6; 95.1%) after a year and a half. the statistical uniformity of the likelihood ratio (likelihood-ratio test statistical of homogeneity) is comparable (p = 0.620; χ 2 = 0.24). the log-rank criterion did not reveal statistical differences (p = 0.582; χ2 = 0.30) in the frequency of relapse over the entire follow-up period, which is graphically expressed by the kaplan-meyer method in figure 5. table 5 presents the regression model of proportional cox risks describing the influence of various factors on the development of relapse. multivariate regression analysis of proportional cox risk (sample from p < 0.05) demonstrated the significance of postoperative fever (hr 23.45; 95% ci 2.14; 256.5; p = 0.010) and initial stone density > 600 hu (hr 0.04; 95% ci 0.004; 0.49; p = 0.010) in predicting possible recurrence of urolithiasis. the treatment results showed statistical equality for stone free rate (sfr), freedom from stone recurrence during the entire follow-up period, and rate of complications of classes ii-iii clavien-dindo (p > 0.05). meanwhile, a significant superiority of group i (rirs) was demonstrated for shorter duration of hospitalization and overall disability, and better objective condition in the early postoperative period. economic efficiency was not evaluated. consequently, rirs meets the criteria of the enhanced recovery program more than pcnl with a similar perioperative protocol. figure 4. roc curve for multivariate logit regression of predictors of moderate postoperative pain. figure 5. freedom from a true relapse of stone formation according to the kaplan-meyer method. table 5. regression model of urolithiasis recurrence. variable univariate cox analysis multivariate cox analysis, χ 2 = 12.66; p = 0.0018 valda χ2 hr (95% ci) p hr (95% ci) p febrility after surgery 3.59 6.77 (1.21; 37.9) 0.029 23.45 (2.14; 256.5) 0.010 concretion density > 600, hu 6.12 0.12 (0.022; 0.683) 0.016 0.04 (0.004; 0.49) 0.010 body mass index > 25 7.19 2.24 (0.88; 5.70) 0.090 – – duration of postoperative follow-up 4.99 0.88(0.785; 1.00) 0.056 – – archivio italiano di urologia e andrologia 2023; 95, 2 45 the retrograde intra-renal surgery limitations limitations of the study were the relatively small sample size, the average postoperative follow-up period less than two years, mixing of various surgical techniques within the framework of the protocol (pcnl, rirs). discussion in the presented study, the outcomes for sfr, i-iii class complications development, and surgery duration (lithotripsy) were similar to the data of other authors and meta-analyses of these data. the problem of a longer hospitalization and general treatment period and a more pronounced pain syndrome also corresponds to what reported in previous papers (18-21). a possible solution to align the results of the two procedures and improve compliance with the enhanced recovery program is the transition from mini-pcnl to micro-pcnl (22, 23). in general, analyzing the results of pcnl and rirs comparison presented by different authors, attention is drawn to the pronounced spread of sfr indicators, the lack of a clear definition of sfr by the size of the fragments, the lack of a clear definition of the operation duration and its pronounced spread. probably, such differences are due to different technical conditions, the experience of the surgical team, and other similar reasons. in general, our own experience demonstrates greater ease of implementation and convenience for rirs patients in comparison with mini-pncl. both treatment protocols are safe, effective, and accompanied by minimal risks of complications. they equally lead to high stone free rates (sfr > 1 mm, 91.3% vs 85.1%; p = 0.867; sfr > 2 mm, 95.6% vs 92.5%; p = 0.936). intergroup analysis of the total operation duration (and lithotripsy) demonstrated a similar duration in the two group (p > 0.05). postoperative complications (claviendindo) in the early and late periods developed rarely and were comparable (p > 0.05) although class i complications were predominant in the pcnl group (p = 0.007). some parameters demonstrated the superiority of rirs over pcnl: less pronounced pain syndrome (p = 0.002), less drainage time (p < 0.001), no postoperative hematuria (p = 0.002), lower average duration of hospitalization, and total time spent on treatment (p < 0.001). the analysis of predictors of the complication development based on the results of multivariate analysis showed that exceeding the lithotripsy time by more than one hour increases by 2.4 times (hr 2.40; 95% ci -0.21;5.02; p = 0.072) the risk of presence of residual fragments (sfr > 1 mm). this indicates the expedience of discussing a possible second stage of treatment in certain groups of patients. postoperative hematuria can be triggered by the following factors: male gender (hr 2.14; 95% ci -0.27; 4.56; p = 0.082), duration of lithotripsy more than an hour (hr 3.53; 95% ci -0.31; 7.38; p = 0.072), chronic pyelonephritis (hr 3.09; 95% ci -0.48; 6.67; p = 0.090) and severe postoperative pain (vas > 5 points) (hr 3.35; 95% ci 0.34; 6.35; p = 0.029). significant predictors of postoperative exacerbation of urinary infection are chronic hepatitis (hr 3.93; 95% ci 0.15; 7.72; p = 0.041), baseline bacteriuria (hr 2.64; 95% ci -0.40; 5.69; p = 0.089) and migration of concretions intraoperatively (hr 2.86; 95% ci -0.48; 6.22; p = 0.094). lithotripsy time of more than half an hour is a significant predictor of severe postoperative pain syndrome (hr 2.28; 95% ci 0.26; 4.41; p = 0.027) whereas a protective factor is postoperative kidney stenting (hr -3.4; 95% ci -5.93; -0.87; p = 0.008). special attention should be paid to the prognostic protective effect of the one-day surgery principle and the effect of improvement of the operating surgeon skills on the risk of complications such as postoperative hematuria, exacerbation of chronic urinary infection, severe postoperative pain syndrome (p < 0.05). both treatment protocols have a high safety profile without the risk of mortality or relapse. the log-rank criterion did not reveal statistically significant differences in the frequency of survival (p = 1), or relapse (p = 0.582). the advantages of the performed study are its prospective design, randomization, homogeneity of groups, mandatory strict protocol of the study, in-depth statistical analysis of outcomes, description of the algorithm of patient management with a detailed presentation of the materials and results of the study. conclusions the results of the study have high practical and scientific significance. the design of the study according to a strict protocol, compliance with the good clinical practice (gcp) criteria, a clear presentation of diagnostic, surgical, and statistical techniques, specific and objective parameters allowed us to obtain reliable results. the results led to important conclusions for the selection of treatments. rirs and mini-pcnl have similar effectiveness, but the path to recovery using retrograde surgery is somewhat simpler and shorter. rirs meets the criteria of the enhanced recovery program more than pcnl with a similar perioperative protocol. references 1. zeng j, wang s, zhong l, et al. a retrospective study of kidney stone recurrence in adults. j clin med res. 2019; 11:208-212. 2. lang j, narendrula a, el-zawahry a, et al. global trends in incidence and burden of urolithiasis from 1990 to 2019: an analysis of global burden of disease study data. eur urol open sci. 2022; 35:37-46. 3. hill aj, basourakos sp, lewicki p, et al. incidence of kidney stones in the united states: the continuous national health and nutrition examination survey. j urol. 2022; 207:851-856. 4. skolarikos a, straub m, knoll t, et al. metabolic evaluation and recurrence prevention for urinary stone patients: eau guidelines. eur urology. 2015; 67:750-763. 5. alhasan ka, shalaby ma, albanna as, et al. comparison of renal stones and nephrocalcinosis in children: findings from two tertiary centers in saudi arabia. front pediatr. 2021; 9:736308. 6. streltsova os, vlasov vv, grebenkin ev, et al. controlled fragmentation of urinary stones as a method of preventing inflammatory infections in the treatment of urolithiasis (experience in successful clinical use). sovrem tekhnologii med. 2021; 13:55-61. 7. scotland k, tailly t, chew bh, et al. consensus statement on uriarchivio italiano di urologia e andrologia 2023; 95, 2 v. vorobev, v. beloborodov, t. hovalyg, i. seminskiy, a. sherbatykh, i. shaderkin, m. firsov 46 nary stone treatment during a pandemic: a delphi process from the endourological society tower research initiative. j endourol. 2022; 36:335-344. 8. buyko ee, ivanov vv, kaidash oa, et al. hypolipidemic activity of the polysaccharide l-rhamnopyranosyl-6-o-methyl-galacturonan in combined administration with hmg-coa reductase and cholesterol absorption inhibitors. drug dev registr. 2022; 11:57-63. 9. zolotov sa, demina nb, ponomarev es, et al. study of the technological methods effect on dissolution of the x-ray amorphous efavirenz-mesoporous carrier system. drug dev registr. 2022; 11:84-89. 10. datta sn, chalokia rs, wing kw, et al. ultramini-percutaneous nephrolithotomy versus retrograde intrarenal surgery in the treatment of 10-30 mm calculi: a randomized controlled trial. urolithiasis. 2022; 50:361-367. 11. fayad mk, fahmy o, abulazayem km, salama nm. retrograde intrarenal surgery versus percutaneous nephrolithotomy for treatment of renal pelvic stone more than 2 centimeters: a prospective randomized controlled trial. urolithiasis. 2022; 50:113-117. 12. su b, hu w, xiao b, et al. needle-perc-assisted endoscopic surgery for patients with complex renal stones: technique and outcomes. urolithiasis. 2022; 50:349. 13. dossanov b, trofimchuk v, lozovoy v, et al. evaluating the results of long tubular bone distraction with an advanced rod monolateral external fixator for achondroplasia. sci rep. 2021; 11:14727. 14. shrestha a, gharti bb, adhikari b. perirenal extravasation after retrograde intrarenal surgery for renal stones: a prospective study. cureus. 2022; 14:e21283. 15. senel s, ozden c, aslan y, et al. can the stone scoring systems be used to predict infective complications after retrograde intrarenal surgery? med princ pract. 2022; 31:231-237. 16. mitropoulos d, artibani w, biyani cs, et al. validation of the clavien-dindo grading system in urology by the european association of urology guidelines ad hoc panel. eur urol focus. 2018; 4:608-613. 17. mitropoulos d, artibani w, graefen m, et al. reporting and grading of complications after urologic surgical procedures: an ad hoc eau guidelines panel assessment and recommendations. eur urol. 2012; 61:341-349. 18. dossanova a, lozovoy v, wood d, et al. reducing the risk of postoperative genital complications in male adolescents. int j environ sci educ. 2016; 11:5797-5807. 19. ghazala sg, saeed ahmed sm, mohammed aa. can mini pcnl achieve the same results as rirs? the initial single center experience. ann med surg (lond). 2021; 68:102632. 20. erkoc m, bozkurt m, danis e, can o. comparison of minipcnl and retrograde intrarenal surgery in the treatment of kidney stone over 50 years old patients. urologia. 2022; 89:575-579. 21. nogaeva uv, naumova aa, novinkov ag, et al. comparative study of rheological properties of gels and creams on different carrier bases. drug dev registr. 2022; 11:121-129. 22. jain m, manohar cs, nagabhushan m, keshavamurthy r. a comparative study of minimally invasive percutaneous nephrolithotomy and retrograde intrarenal surgery for solitary renal stone of 12 cm. urol ann. 2021; 13:226-231. 23. pillai sb, chawla a, de la rosette j, et al. super-mini percutaneous nephrolithotomy (smp) vs retrograde intrarenal surgery (rirs) in the management of renal calculi ≤ 2 cm: a propensity matched study. world j urol. 2021; 40:553-562. conflict of interest: the authors declare no potential conflict of interest. correspondence vladimir vorobev, md (corresponding author) vorobevr782192@rambler.ru vladimir beloborodov, md vbeloborodov391@rambler.ru temirlan hovalyg, md temirlan_hovalyg@rambler.ru department of general surgery, irkutsk state medical university, krasnogo vosstaniya str., 1, irkutsk, 664003, russian federation igor seminskiy, md department of pathology, irkutsk state medical university, krasnogo vosstaniya str., 1, irkutsk, 664003, russian federation seminskiy.igor@rambler.ru andrey sherbatykh, md andsherbatykh3@rambler.ru department of faculty surgery, irkutsk state medical university, krasnogo vosstaniya str., 1, irkutsk, 664003, russian federation igor shaderkin, md igshaderkin@rambler.ru e-health laboratory, i.m. sechenov first moscow state medical university, pirogovskaya str., 2, moscow, 119296, russian federation mikhail firsov, md m_firsov31@rambler.ru department of urology, andrology and sexology, krasnoyarsk state medical university named after professor v.f. voino-yasenetsky, partizan zheleznyaka str., 1, krasnoyarsk, 660022, russian federation archivio italiano di urologia e andrologia 2013; 85, 144 introduction abdominoscrotal hydrocele (ash) is a rare entity with unclear etiology. it extends into the abdominal cavity through the inguinal canal (1, 2). mostly observed in pediatric patients, ash is scarcely described in adult population with only a few cases associated with one sided hydronephrosis reported in the literature (3, 4). we present a case of ash with bilateral hydronephrosis. case presentation a 49-year-old male was admitted to our clinic with progressively increasing left scrotal swelling along a period of one year. during initial physical examination lower abdominal mass on the left and hydrocele of the left testis were observed (figure 1). hydrocele had simultaneous fluctuation with the lower abdominal swelling. in spite of clinical diagnosis based on physical findings and ultrasound imaging an urethral foley catheter was inserted to rule out the presence of urinary retention and associated hydronephrosis demonstrating an empty bladder. bilateral hydronephrosis occurred as a result of the compression of the bladder and the left ureter by the sac (figure 2, 3). surgery was scheduled by inguinal approach in order to perform an high ligation of the processus vaginalis with complete excision of the abdominal component of the case report abdominoscrotal hydrocele with bilateral hydronephrosis in an adult: case report bircan mutlu, yusuf ozlem ilbey, alper bitkin, ali i̇hsan taşçı bakırköy dr. sadi konuk training and research hospital, istanbul, turkey. abdominoscrotal hydrocele is a rare entity with unclear etiology which may be diagnosed with general examination and ultrasound imaging. during examination it may misinterpreted as acute urinary retention of the bladder (globe-like) especially if associated with hydronephrosis. it should be treated surgically. here we present a case of left abdominoscrotal hydrocele with accompanying left grade 2 and right grade 1 hydronephrosis. key words: hydrocele; hydronephrosis; ultrasound. submitted 10 january 2013; accepted 28 february 2013 no conflict of interest declared summary lesion. during the abdominal dissection of the sac we injured the peritoneum and it was repaired. we also mobilised the scrotal part of the sac in order to excise the figure 1. mutlu_stesura seveso 18/04/13 12:05 pagina 44 45archivio italiano di urologia e andrologia 2013; 85, 1 abdominoscrotal hydrocele with bilateral hydronephrosis in an adult: case report leg edema in pediatric patients (6, 7). in our case at initial diagnosis we have observed bilateral hydronephrosis. ash should be considered for the differential diagnosis of bilateral hydronephrosis. mostly, it is one sided but in the literature bilateral ash is also reported (8). paratesticular malignant mesothelioma associated with ash has also been reported in a 14-year-old boy (9). ultrasound, magnetic resonance imaging (mri) and computed tomography (ct) may be used for the diagnosis. during surgical treatment of ash, dilated inguinal ring due to large sac shoud be repaired and mesh method should be used to avoid secondary herniation. although open surgery is generally a preferred option, as we did, bouhadiba et al. reported laparoscopic excision of ash (10). figure 2. a: computed tomography images demonstrating right grade one and left grade two hydronephrosis. b: abdominal part of abdominoscrotal hydrocele. a. b. figure 3. a: compression of abdominoscrotal hydrocele on left side of the bladder. b: bladder h: hydrocele. b: inguinal and scrotal part of abdominoscrotal hydrocele. b: bladder h: hydrocele t: testicle. tunica vaginalis of the testis and suture the edges of the remaining tunica vaginalis posterior to the testis. mesh (lichtenstein) method was used for inguinal hernia repair. testis and cord were normal. the postoperative period was uneventful. discussion the etiology of ash is not clear but there is general consensus on the need of surgical treatment. according to a pubmed search there is only one case which authors successfully managed by conservative approach (5). ash is not a real benign condition, because it may be complicated with acute appendicitis, and it may lead to ureterohydronephrosis, testicular dismorphism and even a. b. mutlu_stesura seveso 18/04/13 12:05 pagina 45 archivio italiano di urologia e andrologia 2013; 85, 1 b. mutlu, y. ozlem ilbey, a. bitkin, a. i̇hsan taşçı 46 6. halilbasic a, hotic n, skokic f, et al. both-sided large abdominoscrotal hydrocele associated with testicles atrophy. med arh. 2011; 65:182-4. 7. faure a, bouali o, chaumoitre k, et al. abdominoscrotal hydrocele with leg edema in a 4-month-old boy. prog urol. 2009; 19:639-42. 8. arslan as, incesu l, yalin t, et al. bilateral abdominoscrotal hydrocele. abdom imaging. 1996; 21:177-178. 9. velasco al, ophoven j, priest jr, brennom ws. paratesticular malignant mesothelioma associated with abdominoscrotal hydrocele. j pediatr surg. 1988; 23:1065-7. 10. bouhadiba n, godbole p, marven s. laparoscopic excision of abdominoscrotal hydrocele. j laparoendosc adv surg tech a. 2007; 17:701-3. references 1. celayir ac, akyüz u, ciftlik h, et al. a critical observation about the pathogenesis of abdominoscrotal hydrocele. j pediatr surg. 2001; 36:1082-4. 2. kaplan m, atakan ih, aktoz t, inci o. giant unilateral abdominoscrotal hydrocele in an adult: case report.int urol nephrol. 2006; 38:667-70. 3. avolio l, chiari g, caputo ma, bragheri r. abdominoscrotal hydrocele in childhood: is it really a rare entity? urology. 2000; 56:1047-9. 4, singh d, aga p, goel a. giant unilateral hydrocele "en-bisac" with right hydronephrosis in an adult: a rare entity. indian j urol. 2011; 27:142-3. 5. upadhyay v, abubacker m, teele r. abdominoscrotal hydrocele-is there a place for conservative management? eur j pediatr surg. 2006; 16:282-4. correspondence bircan mutlu, md (corresponding author) tevfik saglam cad. no:11 zuhuratbaba, istanbul, turkey mutlubircan@yahoo.com yusuf ozlem ilbey, md ozlemyusufilbey@hotmail.com alper bitkin, md alperbitkin@gmail.com ali i̇hsan taşçı, md aliihsantasci@hotmail.com bakırköy dr.sadi konuk training and research hospital, istanbul, turkey mutlu_stesura seveso 18/04/13 12:05 pagina 46 stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 letter to editor sexual health impairment is one of the most important issues worldwide, with an increasing number of men and women affected. specifically in male sexual dysfunction (sd), several risk factors were established such as atherosclerosis, hypertension, diabetes mellitus, smoking or obesity. the co-presence of more than one of risk factors identifies a condition, defined as the metabolic syndrome (mets), related directly to the sd. however, not all the physicians involved in the mets management routinely discussed the sexual impairment, increasing the bothering feelings of patients. furthermore, the lack of knowledge, insufficient time, lack of attention, ambiguities about responsibility, insufficient training and experience, shared among physicians, regarding the communication and treatment of sexual dysfunction, are all reported factors involved in undervaluation of sd. the current paper represents a warning to the experts, with the aim of increasing the awareness of sd among clinicians and to promote the education, training and collaboration with sex therapists, through a multidisciplinary team, that can lead to a holistic approach in sd assessment and treatment. key words: erectile dysfunction; mets; libido; sexual health. submitted 3 february 2023; accepted 17 february 2023 to the editor, sexual dysfunction (sd) includes erectile dysfunction (ed) defined as the persistent inability to attain and/or maintain penile erection sufficient to permit satisfactory sexual performance, ejaculation disorders, orgasmic dysfunctions, and disorders of sexual interest/desire (1). sexual health is an important aspect of our patients' lives, with a high impact on patients and partners quality of life and sd represents one of the most important problems worldwide, affecting a growing number of men and women (2-8). several risk factors have been identified in male sexual dysfunction (msd) such as atherosclerosis, hypertension, hyperlipidemia, diabetes mellitus, smoking, obesity, sedentary lifestyle, chronic alcohol use, benign prostate hyperplasia (9). in most of patients diagnosed with sd there is a concomitant presence of more than one risk factor. the metabolic syndrome (mets) also known as syndrome x and insulin resistance syndrome, is the term that consists of a cluster of disease states abdominal obesity, atherogenic dyslipidemia, raised blood pressure, insulin resistance ± glucose intolerance, proinflammatory state, and prothrombotic state (10). mets may cause ed through multiple mechanisms. all components of mets are frequently found in the obese population. abdominal obesity promotes insulin resistance that is associated with hyperinsulinemia and hyperglycemia. furthermore, several diseases and medical or surgical treatments such as radical pelvic surgery can significantly affect sexual health (11). collaboration between different specialists can be useful in some patients with many risk factors as well as chronic disease and multiple drugs treatments when the conventional treatments are not effective alone. despite this, previous published studies reported that most specialists do not address sexual problems during routine visits. nicolai et al. reported that in a setting of patients with cardiovascular disease sexual dysfunction is not routinely discussed in the cardiology practice (12). msd in particular ed shares the same risk factors of coronary artery disease. in fact, several studies have suggested that chronic inflammation and circulating inflammatory markers affect systemic endothelial function. chronic inflammation may, therefore, represent a link between ed and cardiovascular diseases (cvd) (13). according to montorsi et al. in patients with coronary artery disease (cad), ed comes before cad in the majority by an average of 2 up to 3 years (14). ed onset and severity are associated with increased expression of markers of inflammation. markers and mediators such as c-reactive protein (crp), intercellular adhesion molecule 1, interleukin (il)-6, il-10, il-1b, and tumor necrosis factor alpha (tnf-a) were found to be expressed at higher levels in patients with ed (15). furthermore, several cardiovascular drugs as well as diuretics, and b-blockers may negatively affect sexual function (16). this lack of information is against several cardiological consensus which recommended to assess sd in patients with cardiovascular risk factors and disease. perez-garcia lf et al. in a systematic review of the literature reported that male patients with rheumatic diseases have higher rates of sd, which also sexual dysfunction: time for a multidisciplinary approach? luigi cirillo, giovanni maria fusco, francesco di bello, vincenzo morgera, gianluigi cacace, ernesto di mauro, francesco mastrangelo, lorenzo romano, francesco paolo calace, roberto la rocca, luigi napolitano department of neurosciences, reproductive sciences and odontostomatology, school of medicine, university of naples "federico ii", naples, italy. doi: 10.4081/aiua.2023.11236 summary archivio italiano di urologia e andrologia 2023; 95, 1 l. cirillo, g.m. fusco, f. di bello, et al. seems to occur at a younger age compared to healthy controls. most of these patients remain undiagnosed and uninformed about sd due to lack of specialists investigation (17). van ek et al. reported some findings in patients suffering from chronic kidney disease (ckd). in fact, dutch nephrologists do not discuss sexual function routinely with their patients, despite a high incidence of sd both in men and women (18). in fact, men suffering from ckd reported ed, reduced libido and difficulty in reaching an orgasm, while female patients reported impaired vaginal lubrication, loss of arousal and desire, dysmenorrhea, and difficulty in reaching an orgasm. in patients undergoing renal dialysis there is a higher rate of sd, around 65% for men and 70% for women respectively. in neurosurgical and gastroenterological setting there are similar results: korse et al. reported that 72% of dutch neurosurgery do not counsel patients about sexual dysfunction (19); romano et al. reported that italian gastroenterologist never/infrequently investigated sd with their patients and, similarly, most patients never discussed sd during the visit (20-22). our findings show that despite sexuality is an important aspect of holistic care, it is not addressed in the healthcare system. physician should therefore investigate medical and sexual history. given the personal and social implications of sexual dysfunction it is not an easy task. hence, expert-guided, validated and standardized sexual inventories, structured interviews and self-reported questionnaires (for example iief-5 for ed) can help both inexperienced and seasoned clinicians to address sexual health and related conditions. the lack of knowledge, insufficient time, lack of attention, ambiguities about responsibility, insufficient training and experience regarding the communication and treatment of sexual dysfunction, are the most reported factors involved in undervaluation of sd. to avoid this, first it is necessary: an appropriate knowledge of sd, education, training and collaboration with sex therapists. it could be useful to create appropriate courses, and partnership through a multidisciplinary team of healthcare, that can lead to a holistic approach in assessment and treatment. references 1. rew kt, heidelbaugh jj. erectile dysfunction. am fam physician 2016; 94:820-7. 2. flynn ke, lin l, bruner dw, et al. sexual satisfaction and the importance of sexual health to quality of life throughout the life course of u.s. adults. j sex med.2016; 13:1642-50. 3. napolitano l, fusco gm, cirillo l, et al. erectile dysfunction and mobile phone applications: quality, content and adherence to european association guidelines on male sexual dysfunction. arch ital urol androl 2022; 94:211-6. 4. napolitano l, cirillo l, fusco gm, et al. natural treatments for erectile dysfunction: a focus on mobile health applications. arch ital urol androl 2022; 94:373-4. 5. mirone v, napolitano l, d’emmanuele di villa bianca r, et al. a new original nutraceutical formulation ameliorates the effect of tadalafil on clinical score and cgmp accumulation. arch ital urol androl 2021; 93:221-6. 6. napolitano l, cirillo l, fusco gm, et al. premature ejaculation in the era of mobile health application: a current analysis and evaluation of adherence to eau guidelines. arch ital urol androl 2022; 94:328-33. 7. fusco gm, cirillo l, abate m, et al. male infertility, what mobile health applications «know»: quality analysis and adherence to european association of urology guidelines. arch ital urol androl 2022; 94:470-5. 8. di bello f, creta m, napolitano l, et al. male sexual dysfunction and infertility in spinal cord injury patients: state-of-the-art and future perspectives. j pers med. 2022; 12:873. 9. napolitano l, barone b, crocetto f, et al. the covid-19 pandemic: is it a wolf consuming fertility? int j fertil steril. 2020; 14:159-60. 10. dong jy, zhang yh, qin lq. erectile dysfunction and risk of cardiovascular disease: meta-analysis of prospective cohort studies. j am coll cardiol. 2011; 58:1378-85. 11. zippe c, nandipati k, agarwal a, raina r. sexual dysfunction after pelvic surgery. int j impot res. 2006; 18:1-18. 12. nicolai mpj, both s, liem ss, pelger rcm, et al. discussing sexual function in the cardiology practice. clin res cardiol 2013; 102:329-36. 13. vlachopoulos c, rokkas k, ioakeimidis n, stefanadis c. inflammation, metabolic syndrome, erectile dysfunction, and coronary artery disease: common links. eur urol. 2007; 52:1590-600. 14. montorsi p, ravagnani pm, galli s, et al. association between erectile dysfunction and coronary artery disease. role of coronary clinical presentation and extent of coronary vessels involvement: the cobra trial. eur heart j. 2006; 27:2632-9. 15. carneiro fs, webb rc, tostes rc. emerging role for tnf-a in erectile dysfunction. j sex med. 2010; 7:3823-34. 16. nicolai mpj, liem ss, both s, et al. a review of the positive and negative effects of cardiovascular drugs on sexual function: a proposed table for use in clinical practice. neth heart j 2014; 22:11-9. 17. perez-garcia lf, te winkel b, carrizales jp, et al. sexual function and reproduction can be impaired in men with rheumatic diseases: a systematic review. semin arthritis rheum. 2020; 50:557-73. 18. van ek gf, krouwel em, nicolai mp, et al. discussing sexual dysfunction with chronic kidney disease patients: practice patterns in the office of the nephrologist. j sex med. 2015; 12:2350-63. 19. korse ns, nicolai mpj, both s, et al. discussing sexual health in spinal care. eur spine j 2016; 25:766-73. archivio italiano di urologia e andrologia 2023; 95, 1 title sexual dysfunction 20. romano l, zagari rm, arcaniolo d, et al. sexual dysfunction in gastroenterological patients: do gastroenterologists care enough? a nationwide survey from the italian society of gastroenterology (sige). dig liver dis 2022; 54:1494-501. 21. romano l, granata l, fusco f, et al. sexual dysfunction in patients with chronic gastrointestinal and liver diseases: a neglected issue. sex med rev. 2022; 10:620-31. 22. romano l, pellegrino r, sciorio c, et al. erectile and sexual dysfunction in male and female patients with celiac disease: a cross-sectional observational study. andrology. 2022; 10:910-8. correspondence luigi cirillo, md cirilloluigi22@gmail.com giovanni maria fusco, md giom.fusco@gmail.com francesco di bello, md (corresponding author) fran.dibello12@gmail.com vincenzo morgera, md vincemorgera87@gmail.com gianluigi cacace, md cacace.gianlu@gmail.com ernesto di mauro, md ernesto.dimauro@unina.it francesco mastrangelo, md fmastrangelo91@gmail.com lorenzo romano, md lorenzo.romano@unina.it francesco paolo calace, md fra.calace@gmail.com roberto la rocca, md roberto.larocca@unina.it luigi napolitano, md luiginap89@gmail.com department of neurosciences, reproductive sciences and odontostomatology, school of medicine, university of naples "federico ii" via sergio pansini n°5, 80138 naples (italy) conflict of interest: the authors declare no potential conflict of interest. introduction eosinophilic cystitis is a rare inflammatory disease, that may affect adults and children. the aetiology and the treatment of this condition remains controversial. the pathological presentation of this disease is a eosinophilic infiltration, ranging from mild inflammation to bladder fibrosis. his clinical presentation includes lower urinary tract symptoms, thath can simulate an urinary tract infections. case report a 61-year-old man presented to the emergency room with a 1-week history of constant lower quadrant abdominal pain and lower urinary tract symptoms (1) characterized by increased daytime frequency, slow stream, nocturia, bladder and urethral pain increasing 99archivio italiano di urologia e andrologia 2013; 85, 2 case report a case of eosinophilic cystitis in patients with abdominal pain, dysuria, genital skin hyperemia and slight toxocariasis maria angela cerruto, carolina d’elia, walter artibani urology clinic, university of verona, italy. eosinophilic cystitis is a rare inflammatory disease with controversial aetiology and treatment. we report the case of a 61-year-old man presented with lower quadrant abdominal pain and lower urinary tract symptoms, non responsive to antibiotics and nonsteroidal antiinflammatory drugs. physical examination was substantially negative, such as laboratory parameters, microscopic, bacteriological and serological evaluations. cystoscopy revealed red areas involving the mucosa of the bladder and transurethral biopsies revealed infiltrating eosinophils. the patient was treated with corticosteroids and montelukast sodium with improving of the symptoms, and at 5 weeks postoperative pain score was reduced. after discontinuing corticosteroids dysuria recurred with the development of hyperemia at the genital skin; the specific enzyme-linked immunosorbent assay (elisa) to detect antibodies against several parasites was slightly positive for toxocara species. montelukast sodium was discontinued and corticosteroid therapy was started together with albendazole, with improving of patient’s symptoms and pain decreasing after one week. key words: eosinophilic cystitis; dysuria; genital skin hyperemia; toxocariasis. submitted 2 october 2012; accepted 31 december 2012 no conflict of interest declared summary with bladder filling and reducing during and after voiding, nonresponsive to antibiotics and nonsteroidal antiinflammatory drugs. the patient’s past medical history was notable for hypertension diagnosed 5 years earlier and well controlled with ramipril 5 mg daily. no history of allergy was obtained. he denied having any domestic pets, high-risk sexual behaviour, the use of tobacco, alcohol or illicit drugs, had no sick contacts and hat not travelled recently. he denied having any visual changes or respiratory symptoms, chest pain, nausea, vomiting, melena or hematochezia. he reported changes in bowel habits (an increasing stipsis). upon physical examination skin rash, upper quadrant abdominal tenderness or palpable liver, spleen or abdominal mass were all absent. only a slight tenderness to palpation in the lower abdominal quadrants, mainly in the suprapubic cerruto_cystitis_stesura seveso 24/06/13 11:08 pagina 99 archivio italiano di urologia e andrologia 2013; 85, 2 m.a. cerruto, c. d’elia, w. artibani 100 discussion the eosinophilic cystitis, although rare and mysterious, should be considered in adults with bowel and voiding symptoms associated to lower abdominal quadrant pain. its management is a challenge. and should be tailored to each patient. although leukotriene receptor antagonist (montelukast sodium) is useful in the treatment of eosinophilic cystitis in children, in adults this drug seems to be ineffective without corticosteroids (2). steroidal anti-inflammatory drugs have been reported also to improve symptoms related to allergic response to parasitic infection such as toxocariasis (3). in the present case a mild toxocara infection with antibody titres only midly elevated (4) might be responsible for bladder and genital skin allergic response to the parasite also in the absence of serum eosinophilia. conclusion the eosinophilic cystitis should be considered in adults with bowel and voiding symptoms associated to lower abdominal quadrant pain and its management should be tailored to each patient. in the present case a mild toxocara infection with only midly elevated antibodies might be responsible for bladder and genital skin allergic response to the parasite also in the absence of serum eosinophilia. references 1. abrams p, cardozo l, fall m, et al. the standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the international continence society. urology. 2003; 61:37-49. 2. sterret s, morton j, perry d, donovan j. eosinophilic cystitis: successful long-term treatment with montelukast sodium. urology. 2006; 67:423.e19-423.e21. 3. despommier d. toxocariasis: clinical aspects, epidemiology, medical ecology, and molecular aspects. clin microbiol rev. 2003; 16:265-272. 4. leone n, baronio m, todros l, et al. hepatic involvement in larva migrans of toxocara canis: report of a case with pathological and radiological findings. dig liver dis. 2006; 38:511-514. region, was noted. digital rectal examination revealed an indolent regular prostate. urethral and bladder pain level was evaluated by a visual analogue scale in which 0 corresponded to “no pain” and 10 to “the worst pain imaginable”. patient’s score was 10. pelvic floor muscle examination was normal and neurologic examination did not reveal focal deficits. there was no lower extremity edema and there was no cervical, axillary or inguinal lymphadenopathy. laboratory parameters were all normal (including psa serum levels). microscopic and bacteriological evaluation of urine and expressed prostatic secretion were negative as well as coproculture. serological studies for viral hepatitis, hiv and syphilis were negative. a ct scan of the patient’s abdomen showed only the presence of small retroperitoneal lymph nodes at the celiac tripod level and a unique 6 mm calcific sigmoidal diverticulum, confirmed by colonoscopy and unable to justify alone the abdominal pain. cystoscopy revealed red areas involving the mucosa of the posterior and the left bladder walls. the prostatic urethra and the trigone appeared normal as did both ureteral orifices. bladder capacity under anaesthesia was 380 ml. after bladder hydrodistension the development of glomerulations did not occur. transurethral biopsies revealed infiltrating eosinophils (figure 1). postoperative course was unremarkable. patient’s postoperative symptoms decreased within 3 weeks taking corticosteroids (25 mg prednisone once-a-day) for 5 weeks. at 4 weeks postoperative he was given montelukast sodium. at 5 weeks postoperative pain score was 3 and bowel function improved. after discontinuing corticosteroids dysuria recurred (pain score 8) and itching, burning and hyperemia at the genital skin occurred. these symptoms temporarily resolved only at rest in a laying down position. in order to exclude parasitic origin of this dermatitis a specific enzyme-linked immunosorbent assay (elisa) to detect antibodies against several parasites was slightly positive for toxocara species. montelukast sodium was discontinued and 1 mg betamethasone dipropionate once-a-day was started together with albendazole 400 mg by oral route 2 times per day with food for 5 days. patient’s symptoms improved and the pain score decreased up to 4 within 1 week. figure 1. histopathology from the bladder biopsy specimen demonstrating a nodular cystitis with abundant eosinophilic cells infiltration (hematoxylin-eosin stain). correspondence maria angela cerruto, md mariaangela.cerruto@univr.it carolina d’elia, md, febu (corresponding author) karolinedelia@gmail.com walter artibani, md walter.artibani@univr.it urology clinic, department of surgery university of verona & aoui, p.le l scuro 10 37134 verona, italy cerruto_cystitis_stesura seveso 24/06/13 11:08 pagina 100 stesura seveso introduction the aim of this study is to evaluate the effectiveness of tamsulosin in patients affected by low urinary tract symptoms (luts) and erectile dysfunction (ed), and also to compare this monotherapy with one combined with sildenafil, belonging to phosphodiesterase type 5 (pde-5) inhibitors drug class, which are the recommended first-line treatment for ed. type iii chronic prostatitis or chronic prostatitis/chronic pelvic pain syndrome (cp/cpps) is characterized by 109archivio italiano di urologia e andrologia 2013; 85, 3 original paper comparison of tamsulosin vs tamsulosin/sildenafil effectiveness in the treatment of erectile dysfunction in patients affected by type iii chronic prostatitis ubaldo cantoro, francesco catanzariti, vito lacetera, luigi quaresima, giovanni muzzonigro, massimo polito institute of urology, polytechnic university of marche, azienda o.u. ospedali riuniti, ancona, italy. aim: we evaluated the effectiveness of tamsulosin monotherapy versus tamsulosin plus sildenafil combination therapy on erectile dysfunction (ed) in young patients with type iii chronic prostatitis and ed by using symptom score scales. materials and methods: 44 male patients were divided into 2 groups: the first group (20 patients) was treated with tamsulosin 0,4 mg monotherapy and the second one (24 patients) was treated with tamsulosin 0,4 mg plus sildenafil 50 mg combination therapy. “international prostate symptom score” (ipss), “national institute of health chronic prostatitis symptom index” (nih-cpsi) and “international index of erectile function” (iief-5) were investigated in each group of patients, and scores calculated during the first medical examination. both groups were treated with tamsulosin once daily for 60 days, while sildenafil 50 mg was given on demand (at least 2 times per week) for 60 days. during the second medical examination ipss, nih-cpsi and iief-5 scores were analyzed once more. afterwards, the alterations of scores among medical examinations in each group and between both groups were statistically compared. results: the age average of the 44 cases included was 32.04 ± 3.15 years. both groups present a statistically significant decrease, between the first and the second medical examination, in ipss, nih-cpsi scores and statistically significant increase in iief-5 score. in addition, there is no statistically significant difference, in all scores, between mono and combination therapy. conclusions: tamsulosin monotherapy, as well as a combination therapy (tamsulosin plus sildenafil) has an improving effect on symptoms and on ed in patients with type iii prostatitis. in the near future alpha-blockers monotherapy could be used in the treatment of chronic prostatitis and ed cases instead of phosphodiesterase type 5 (pde-5) inhibitors combination therapy. key words: chronic prostatitis; erectile dysfunction; tamsulosin; sildenafil. submitted 8 april 2013; accepted 30 april 2013 no conflict of interest declared summary abdominal, pelvic, genital pain, obstructive or irritative luts and by the absence of urinary tract infection (1). many studies showed its association with painful premature ejaculation and with erectile dysfunction. cp/cpps occurs frequently in young patients and is one of the organic causes of erectile dysfunction (ed) in this age range. therefore, a common pathogenic mechanism for these two diseases is likely to exist (2). adult-old patients luts affected have two times higher doi: 10.4081/aiua.2013.3.109 archivio italiano di urologia e andrologia 2013; 85, 3 u. cantoro, f. catanzariti, v. lacetera, l. quaresima, m. giovanni, m. polito 110 risk to develop ed, since the prevalence of luts is of 72.2% in males affected also by ed and of 37.7% in males with no ed (3). literature data show that ed associates with the severity of luts but, although studies pointed out a correlation between cp/cpps and ed, they do not provide with any explication of pathogenic mechanisms (4). many pathogenic mechanism were investigated to find an explanation to ed in young patients affected by cp/cpps. any connection with hypogonadism neither other endocrine disorders were found, except for a study which, unlike controls, found higher levels of testosterone in patients with cp/cpps (5). another study found an association with hypogonadism, due to the fact that patients took opioids for long periods because of luts severity (6). vascular diseases and arterial insufficiency are well known causes of ed, even though they are uncommon in young patients (7). anyway, one study pointed out alterations in the peripheral arterial tone in patients with cp/cpps (8), due to a endothelial vascular dysfunction mediated by nitric oxide (9). moreover, the arterial flow can be compromised from the outside by spastic contractions of pelvic floor (10). it is known muscle relaxant therapies can have positive effects on ed (11). occlusive vessel disease is a condition which frequently occurs in old patients, also in presence of penile fibrosis. therefore, also this pathogenic mechanism is uncommon in young patients. although ed psychogenic cause was not adequately investigated in patients with cp/cpps, a relation may exist since often patients affected by painful syndromes also suffer from stress, anxiety and maladaptive responses to stressful events (“catastrophizing”) (12). materials and methods our study analyzed a number of 44 patients who were examined at our clinic because affected by type iii chronic prostatitis associated with erectile dysfunction since at least 6 months. all patients were sexually active. we excluded from the study all patients affected by infections of the urinary system, neoplasia, congenital disorders, previous surgeries, urolithiasis and hyperactive bladder. none of the included patients used pde-5 in the past. none of the examined patients presented side effects due to the use of alpha-blockers and pde-5. patients were examined through anamnesis, which is a clinical exam with neurological evaluation of the pelvic floor and rectal examination, uroflowmetry, suprapubic ultrasound evaluation of post-void residual, trans-rectal prostate ultrasound, total psa, microscopic and cultural exams of urine and semen and urethral secretion after prostate massage. the 44 patients were divided into 2 groups: the first group (20 patients) was treated with monotherapy, tamsulosin 0.4 mg, the second one (24 patients) was treated with a combination therapy, tamsulosin 0.4 mg plus sildenafil 50 mg. patients assignment to one group or the other was random. the average age of patients included in the study is 32.04 ± 3.15 years. none of patients was affected by bph; prostate volume range was between 15 and 25 ml. both uroflowmetry parameters and post-void residuals were not pathological. during the first medical examination, all patients were subjected to “international prostate symptom score” (ipss), “national institute of health chronic prostatitis symptom index” (nih-cpsi) and “international index of erectile function” (iief-5). both groups were treated with tamsulosin for 60 days; sildenafil 50 mg was taken when needed before a sexual intercourse (at least 2 times per week) and for 60 days by the second group. during the second medical examination, 60 days later, all patients were subjected again to ipss, nih-cpsi and iief-5. we considered mild patients’ symptoms with ipss score between 0-7 and nih-cpsi between 0-14; moderate respectively between 8-19 and 15-29 and severe between 20-35 and > 30. we considered mild patients’ erectile dysfunction with iief-5 score between 17-21, mildmoderate between 12-16, moderate between 8-11 and severe between 5-7. we statistically evaluated a potential difference in iief-5 scores according to the symptomatic severity of ipss and nih-cpsi and in the last two questionnaires scores according to iief-5 severity. therefore, we statistically evaluated the differences of questionnaires scores means between the two medical examinations in each group and between the two groups. for the statistic analysis we used graphpad prism 5 program. in addition to the descriptive statistic modes (mean, standard deviation), oneway anova, kruskalwallis, mann-whitney and student t test were used for a statistic evaluation. the results were analyzed with a significance level of p < 0.05. results table 1 shows the mean of questionnaires analyzed and the mean of patients’ figures. according to ipss questionnaire, 4 patients presented mild symptoms, 26 moderates and 14 severe; according to nih-cpsi questionnaire 6 patients presented mild symptoms, 29 moderates, 9 severe; according to iief-5 questionnaire 8 patients suffered from mild erectile dysfunction, 17 mild-moderate, 13 moderate, 6 severe. we confronted iief-5 score means of patients with mild, moderate and severe symptoms according to ipss and we did not notice any statistically difference: anova (p = 0,87) and kruskal-wallis (p = 0.92) (table 2). moreover, there is no statistically difference between ipss mean sd range age (year) 32.04 3.15 23-35 pv (ml) 17.20 2.56 15-25 qmax (ml/s) 21.24 3.45 17.8-28.3 pmr (ml) 27.18 8.78 0-42 ipss 13.52 1.49 8-24 ipss-qol 3.87 0.27 0-5 iief-5 12.41 0.66 5.21 nih-cpsi 17.51 1.92 5-28 table 1. general characteristics and mean symptom scores of the cases. score means of patients with mild, mild-moderate, moderate, severe erectile dysfunction: anova (p = 0,43) and kruskal-wallis (p = 0,61) (table 3). we did not notice any statistically difference even through the comparison of iief-5 scores according to nih-cpsi mild, moderate and severe symptoms: anova (p = 0,12), kruskal-wallis (p=0,25) (table 4); any difference also in nih-cpsi scores according to iief-5: anova (p = 0,18), kruskal-wllis (p = 0,26) (table 5). we noticed, inside each therapy group, a statistically relevant decrease, between the first medical examination and 60 days later, in ipss, ipss-qol and nih-cpsi score. we also pointed out a statistically relevant increase in iief-5 score (table 6 -7). we did not notice, in 60 days, a statistically relevant difference, between the two therapy groups, in all questionnaires score, iief-5 included (table 8). discussion chronic prostatitis/chronic pelvic pain syndrome (cp/cpps) is a syndrome characterized by pain (abdominal, pelvic, genital), obstructive and irritative luts in absence of infection (1), causing quality of life (qol) decrease (13). although it is known that type iii chronic prostate associates with erectile dysfunction, it is still less clear the etiophatogenesis implied in these two nosological entities. great part of clinical studies examine old patients with luts and ed, but also with concomitant bph and obstruction of urine flow. still few are studies which investigate the presence of ed in younger patients affected by type iii chronic prostatitis in absence of bph and obstruction. the most supported theory explaining the common pathogenic mechanism of luts and concomitant ed, independently from bph, points out there is a hyperactivity of autonomic nervous system and endothelial alterations due to the effects on nitric oxide – cyclic 111archivio italiano di urologia e andrologia 2013; 85, 3 comparison of tamsulosin vs tamsulosin/sildenafil effectiveness in the treatment of erectile dysfunction in patients affected by type iii chronic prostatitis visit 1 visit 2 p ipss 13.26 ± 0.92 8.23 ± 0.72 < 0.001 iief-5 12.54 ± 0.59 17.83 ± 1.46 < 0.001 nih-cpsi 17.87 ± 1.14 10.54 ± 1.35 < 0.001 ipss-qol 3.95 ± 0.22 2.02 ± 0.56 < 0.001 table 6. alterations in ipss, iief-5, nih-cpsi, ipss-qol between visit 1 and visit 2 in group 1 treated with tamsulosin 0,4 mg. visit 1 visit 2 p ipss 13.75 ± 1.84 8.07 ± 0.91 < 0.001 iief-5 12.31 ± 0.78 18.75 ± 1.24 < 0.001 nih-cpsi 17.47 ± 2.09 9.74 ± 1.98 < 0.001 ipss-qol 3.65 ± 0.41 1.82 ± 0.25 < 0.001 table 7. alterations in ipss, iief-5, nih-cpsi, ipss-qol between visit 1 and visit 2 in group 2 treated with tamsulosin 0,4 mg plus sildenafil 50 mg. group 1 group 2 p ipss 8.23 ± 0.72 8.07 ± 0.91 0.751 iief-5 17.83 ± 1.46 18.75 ± 1.24 0.835 nih-cpsi 10.54 ± 1.35 9.74 ± 1.98 0.486 ipss-qol 2.02 ± 0.56 1.82 ± 0.25 0.574 table 8. alterations in ipss, iief-5, nih-cpsi, ipss-qol between group 1 and group 2 after 60 days. mean iief-5 score all cases 12.41 ± 0.66 ipss mild 13.28 ± 0.89 anova p = 0.87 moderate 12.85 ± 0.39 kruskal-wallis p = 0.92 severe 12.13 ± 1.98 table 2. the effect of ipss level on mean iief-5 score. mean iief-5 score all cases 12.41 ± 0.66 nih-cpsi mild 14.28 ± 0.27 anova p = 0.12 moderate 12.05 ± 0.39 kruskal-wallis p = 0.25 severe 15.13 ± 1.16 table 4. the effect of nih-cpsi level on mean iief-5 score. mean ipss score all cases 13.52 ± 1.49 iief-5 mild 13.25 ± 1.17 anova p = 0.43 mild-moderate 14.48 ± 0.96 kruskal-wallis p = 0.61 moderate 14.81 ± 0.91 severe 12.84 ± 1.57 table 3. the effect of iief-5 level on mean ipss score. nih-cpsi score all cases 17.51 ± 1.92 iief-5 mild 22.92 ± 0.87 anova p = 0.18 mild-moderate 19.08 ± 0.56 kruskal-wallis p = 0.26 moderate 17.83 ± 0.74 severe 21.98 ± 1.19 table 5. the effect of iief-5 level on mean nih-cpsi score. archivio italiano di urologia e andrologia 2013; 85, 3 u. cantoro, f. catanzariti, v. lacetera, l. quaresima, m. giovanni, m. polito 112 monophosphate guanosine e alterations in rho-kinase pathway (14). some studies already evaluated the effectiveness of alpha-blockers in treating erectile dysfunction associated with luts (15-16), but it was not compared with pde5 inhibitors and, as stated above, the patients examined were old people with concomitant bph. in our study, after 60 days of therapy, each group showed statistically relevant improvements in questionnaires scores: ipss, ipss-qol, iief-5, nih-cpsi. in other words, tamsulosin, as well as the combination therapy of tamsulosin and sildenafil, improved both luts and ed. sixty days after the therapy, we did not stress out any statistically relevant difference in questionnaires scores between the two groups, despite a pde-5 inhibitors treatment in the second group. moreover, there is no correlation between luts severity (classified according to ipss and nih-cpsi), ed rate and vice versa. these results suggest tamsulosin may improve ed and chronic prostatitis symptoms, reducing the spasm of prostate smooth muscle, the associated inflammation and improving prostate and penis blood flow. anyway, our study has several limitations; it does not have a placebo control arm and it is circumscribed. we are also persuaded other studies are needed for evaluating monotherapy and combination therapy for a longer period than 60 days. moreover, patients’ randomization does not guarantee a complete randomness: patients’ assignment to one study group or the other was made through their alternated insertion in one of the two groups. conclusions luts severity in young patients suffering from type iii chronic prostatitis does not correlate with the severity of ed and vice versa. tamsulosin therapy for the treatment of young patients with type iii chronic prostatitis together with erectile dysfunction has the same effectiveness of the most expensive combination therapy (tamsulosin and sildenafil). we are persuaded in the future the cheaper therapy with alpha-blocker will be used in cp/cpps and ed affected patients. references 1. schaeffer aj, datta ns, fowler jej, et al. overview summary statement. diagnosis and management of chronic prostatitis/chronic pelvic pain syndrome (cp/cpps). urology. 2002; 60:1-4. 2. costabile ra, steers wd. how can we best characterize the relationship between erectile dysfunction and benign prostatic hyperplasia? j sex med. 226; 3:676-681. 3. carson cc. combination of phosphodiesterase-5 inhibitors and alpha-blockers in patients with benign prostatic hyperplasia: treatments of lower urinary tract symptoms, erectile dysfunction, or both? bju int. 2006; 97:39-43. 4. shiri r, ha¨kkinen jt, hakama m, et al. effect of lower urinary tract symptoms on the incidence of erectile dysfunction. j urol. 2005; 174:205-209. 5. dimitrakov j, joffe hv, soldin sj, et al. adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome. urology. 2008; 71:261-6. 6. daniell hw. hypogonadism in men consuming sustained-action oral opioids. j pain. 2002; 3:377-84. 7. gonen m, kalkan m, cenker a, et al. prevalence of premature ejaculation in turkish men with chronic pelvic pain syndrome. j androl. 2005; 26:601-3. 8. shoskes da, prots d, karns j, et al. greater endothelial dysfunction and arterial stiffness in men with chronic prostatitis/chronic pelvic pain syndrome-a possible link to cardiovascular disease. j urol. 2011; 186:907-10. 9. rubinshtein r, kuvin jt, soffler m, et al. assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. eur heart j. 2010; 31:1142-8. 10. shoskes da, berger r, elmi a, et al. muscle tenderness in men with chronic prostatitis/chronic pelvic pain syndrome: the chronic prostatitis cohort study. j urol. 2008; 179:556-60. 11. anderson ru, wise d, sawyer t, et al. sexual dysfunction in men with chronic prostatitis/chronic pelvic pain syndrome: improvement after trigger point release and paradoxical relaxation training. j urol. 2006; 176:1534-8. 12. nickel jc, tripp da, chuai s, et al. psychosocial variables affect the quality of life of men diagnosed with chronic prostatitis/chronic pelvic pain syndrome. bju int. 2008; 101:59-64. 13. mcnaughton collins m, pontari ma, o’leary mp, et al. quality of life is impaired in men with chronic prostatitis: the chronic prostatitis collaborative research network. j gen intern med. 2001; 16:656-62. 14. rosen rc, wei jt, althof se, et al. association of sexual dysfunction with lower urinary tract symptoms of bph and bph medical therapies: results from the bph registry. urology. 2009; 73:562-566. 15. kirby rs, andersen m, gratzke p, et al. a combined analysis of double-blind trials of the efficacy and tolerability of doxazosin-gastrointestinal therapeutic system, doxazosin standard and placebo in patients with benign prostatic hyperplasia. bju int. 2001; 87:192-200. 16. de rose af, carmignani g, corbu c, et al. observational multicentric trial performed with doxazosin: evaluation of sexual effects on patients with diagnosed benign prostatic hyperplasia. urol int. 2002; 68:95-98. correspondence ubaldo cantoro, md (corresponding author) resident in urology ubaldocantoro@tiscali.it francesco catanzariti, md resident in urology fracatanzariti@libero.it vito lacetera, md urologist, resident in urology vlacetera@gmail.com luigi quaresima, md resident in urology luigiquaresima@yahoo.it giovanni muzzonigro md professor of urology and chief institute of urology, resident in urology g.muzzonigro@univpm.it massimo polito, md urologist, resident in urology max_polito@virgilio.it institute of urology, a.o. ospedali riuniti via conca 71 i-60020 ancona, italy stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 129 letter to editor key words: erectile dysfunction; pde5i; recreational drug. submitted 2 april 2023; accepted 6 april 2023 to the editor, in 1998 sildenafil was approved by the food and drug administration as first line therapy for erectile dysfunction. since then, phosphodiesterase type 5 inhibitors (pde5i) represent the first-line treatment of erectile dysfunction (ed), improving physiological erectile function, sexual orgasmic function, psychological self-esteem, couples’ relationship, and quality of life (1). sildenafil represents the most used recreational drugs (2, 3). this could be due to its popularity/familiarity, the presence of more than 30 generic sildenafil and to the significantly lower costs compared to other pde5i as well as tadalafil (2). the population of pde5i users is different in terms of demographics, sexual behaviors, attitudes in general/sexual health, and demands for ed treatments (4). nowadays pde5i are very popular drugs and one of the most important problems is their recreational use (5). mostly young men bypassed health care prescriptions (hcp) and obtained these drugs through uncontrolled sources, on the internet market (6, 7). there are several risks related to recreational use of pde5i: a certain portion of drugs available on the internet are contaminated by counterfeits and unapproved generics (1, 8). alshahrani et al. reported that in saudi arabia population, the most important reason in using pde5i for recreational use is curiosity (38.5%) followed by enhancing self-confidence (25.6%), increasing erection duration (10.3%) and improving ejaculation problems (5.1%). all these people bought the pde5i from drug stores (73.9%), without a medical prescription (9). similar data were reported by attia et al. in egyptian males: in 58.35% of cases pde5i were used for pleasure, followed by increasing intercourse duration/frequency (15.6%). in 62% of cases egyptian males obtained them from friends, relatives, and colleagues (62%) or by themselves (25%) or from pharmacists (6.7%), and only 5.4% after medical consultation (1, 10). bechara et al. reported that 21.5% of healthy men between 18 and 30 years old used pde5i as a recreational drug, mostly associated with alcohol or other drugs as well as illicit drugs, and psychotropic medications. this could explain the high incidence of adverse events, mainly related to vasodilator effects (6, 11) with the use of the cannabis, an inhibitor of the cytochrome p450 3a4 hepatic microsomal isoenzyme that is involved into pde5i metabolism (12, 13). kimura et al. reported that 45.4% of japanese men bypassed hcp interaction to obtain pde5i, 23.4% of men obtained it from friends and 22.0% obtained it via the internet (8). korkes et al. reported a recreational use in 9% of young men, although they considered themselves with perfect erectile function. of these, 46.7% had used pde5i more than three times, and 71.4% had mixed them with alcohol (7). harte et al. reported the same effect in users and nonusers, with a lower erectile confidence and overall satisfaction in the first group (14). in this scenario it should be necessary to provide more education with the aim to decrease the number of pde5i users without prior hcp consultation (7, 15). further work on the risk or potential health problems in such conditions is encouraged to improving the information in the general population, creating a collaborative effort between pharmacists, health professionals, and policy makers is necessary to avoid selling medication without a medical prescription and to give adequate and scientific information regarding pde5i use and misuse. references 1. attia aa, abdel-hameed aks, amer maem, et al. study of the prevalence and patterns of phosphodiesterase type 5 inhibitor use among sexually active egyptian males: a national cross-sectional survey. andrologia. 2019; 51:e13364. 2. huang sa, lie jd. phosphodiesterase-5 (pde5) inhibitors in the management of erectile dysfunction. p t. 2013; 38:407-19. recreation use of phosphodiesterase type 5 inhibitors, the other side of erectile dysfunction giovanni maria fusco 1, luigi cirillo 1, francesco mastrangelo 1, francesco romano 1, ernesto di mauro 1, gianluigi cacace 1, gianluca spena 1, annamaria iannicelli 2, corrado aniello franzese 3, vincenzo mirone 1, roberto la rocca 1, luigi napolitano 1 1 department of neurosciences, reproductive sciences and odontostomatology, urology unit, university of naples "federico ii", naples, italy; 2 department of translational medical sciences, university of naples "federico ii", naples, italy; 3 asl napoli 3 sud, naples, italy. doi: 10.4081/aiua.2023.11350 archivio italiano di urologia e andrologia 2023; 95, 2 g.m. fusco, l. cirillo, f. mastrangelo, f. romano, et al. 130 3. atsbeha bw, kebede bt, birhanu bs, et al. the weekend drug; recreational use of sildenafil citrate and concomitant factors: a crosssectional study. front med (lausanne). 2021; 8:665247. 4. mulhall jp, hassan ta, rienow j. sexual habits of men with ed who take phosphodiesterase 5 inhibitors: a survey conducted in 7 countries. int j clin pract. 2018; 72:e13074. 5. cirillo l, fusco gm, di bello f, et al. sexual dysfunction: time for a multidisciplinary approach? arch ital urol androl. 2023; 95:11236. 6. bechara a, casabé a, de bonis w, et al. recreational use of phosphodiesterase type 5 inhibitors by healthy young men. j sex med. 2010; 7:3736-42. 7. korkes f, costa-matos a, gasperini r, et al. recreational use of pde5 inhibitors by young healthy men: recognizing this issue among medical students. j sex med. 2008; 5:2414-2418. 8. kimura m, shimura s, kobayashi h, et al. profiling characteristics of men who use phosphodiesterase type 5 inhibitors based on obtaining patterns: data from the nationwide japanese population. j sex med 2012; 9:1649-1658. 9. alshahrani s, ahmed af, gabr ah, al ansari a, el-feky m, elbadry ms. phosphodiesterase type 5 inhibitors: irrational use in saudi arabia. arab journal of urology. 2016; 14:94-100. 10. mirone v, napolitano l, d’emmanuele di villa bianca r, et al. a new original nutraceutical formulation ameliorates the effect of tadalafil on clinical score and cgmp accumulation. arch ital urol androl. 2021; 93:221-226. 11. ahmed af, alshahrani s, morgan a, et al. demographics and sexual characteristics of sex-enhancing medication users: study of a web-based cross-sectional sample of sexually active men. arab journal of urology. 2017; 15:366-371. 12. napolitano l, fusco gm, cirillo l, et al. erectile dysfunction and mobile phone applications: quality, content and adherence to european association guidelines on male sexual dysfunction. arch ital urol androl. 2022; 94:211-216. 13. schnetzler g, banks i, kirby m, et al. original research—ed pharmacotherapy: characteristics, behaviors, and attitudes of men bypassing the healthcare system when obtaining phosphodiesterase type 5 inhibitors. j sex med 2010; 7:1237-1246. 14. harte cb, meston cm. recreational use of erectile dysfunction medications and its adverse effects on erectile function in young healthy men: the mediating role of confidence in erectile ability. j sex med 2012; 9:1852-1859. 15. napolitano l, cirillo l, fusco gm, et al. natural treatments for erectile dysfunction: a focus on mobile health applications. arch ital urol androl. 2022; 94:373-374. correspondence giovanni maria fusco, md giom.fusco@gmail.com luigi cirillo, md cirilloluigi22@gmail.com francesco mastrangelo, md f.mastrangelo91@gmail.com francesco romano, md romanofrancesco92@libero.it gianluca spena, md spena.dr@gmail.com ernesto di mauro, md ernesto.dimauro@unina.it gianluigi cacace, md naples cacace.gianlu@gmail.com vincenzo mirone, md mirone@unina.it roberto la rocca, md robertolarocca87@gmail.com luigi napolitano, md dr.luiginapolitano@gmail.com department of neurosciences, reproductive sciences and odontostomatology, urology unit, university of naples "federico ii", naples, italy annamaria iannicelli, md annamaria.iannicelli@unina.it department of translational medical sciences, university of naples "federico ii", via pansini 5, 80131, naples, italy corrado aniello franzese, md corradofranzese@libero.it asl napoli 3 sud, naples, italy conflict of interest: the authors declare no potential conflict of interest. archivio italiano di urologia e andrologia 2013; 85, 2104 introduction surgical treatment of female stress urinary incontinence (sui) has become very popular after respectable success with minimal invasive surgeries. however synthetic materials used in slings has some problems through their biocompatibility. among the different types of mesh, it seems they induce an inflammatory response (1). although tension-free vaginal tape (tvt) has been routinely used to treat female sui with a high success rate, there are concerns regarding its operative safety in relation to bowel and major blood vessel injuries, bladder and urethral perforation, and postoperative voiding difficulties. also, urethrovaginal and vesicovaginal fistulas were seen as a result of vaginal erosion leaded by mesh reaction. we documented a case presented 6 years after tvt sling operation with vaginocutenous fistula (vcf) and inguinal abcess. this is the first report of long term vcf plus inguinal abcess after propylene monofilament sling placement. case report vaginocutaneous fistula and inguinal abcess presented 6 years after tension-free vaginal tape sling ali feyzullah şahin 1, yusuf özlem i̇lbey 2, nur şahin 3 1 assistant professor in urology department of urology, şifa university medicine school, i̇zmir, turkey; 2 associative professor in urology department of urology, şifa university medicine school, i̇zmir, turkey; 3 specialist in gynecology and obstetrics department of gynecology and obstetrics, şifa university medicine school, i̇zmir, turkey. surgical treatment of female stress urinary incontinence (sui) has become very popular after respectable success with minimal invasive surgeries. this is the first report of long term vaginocutaneous fistula (vcf) plus inguinal abcess after tension-free vaginal tape (tvt). a 67 year-old woman with vaginal discharge lasting more than 3 years complained with a painful swelling in the left inguinal area for the last three months. she had a medical history of tvt sling procedure for sui six years ago. she had no history of pelvic surgery, cancer treatment or pelvic irradiation before or after tvt sling. no urethrovaginal or vesicovaginal fistula was found in physical examination and cystocopy. mri showed a vaginocutenaous fistula and inguinal abcess. this case highlights the need for a high index of suspicion for vcf after tvt. key words: abcess; fistula; tension-free vaginal tape; tvt; vaginocutaneous. submitted 11 february 2013; accepted 30 april 2013 no conflict of interest declared summary case a 67 year-old woman was referred to our urology clinic with vaginal discharge lasting more than 3 years and sometimes accompanying vaginal bleeding. for the last three months, a painful swelling in the left inguinal area was added to symptoms. she had a medical history of tvt sling procedure for sui six years ago. she had no history of pelvic surgery, cancer treatment or pelvic irradiation before or after tvt sling. in the physical examination, painful and hyperemic subcutaneous solid mass was present in the left inguinal area with 3 x 4 cm size. in the vaginal examination, there were two solid mass with pedicle in size of 4 x 4 cm which was originated from vaginal wall on both paraurethral areas seems like as entrance of sling trocars. both in vaginal or cystoscopic examination there was no urethravaginal or vesicovaginal fistula. mri showed a fistula tract originating from vagina to subcutaneous tissue of left inguinal area and mesh materials of tvt (figure 1a-c). both masses in the paraurethral areas were excised through vaginal approach at lithotomy position under sahin_stesura seveso 24/06/13 11:10 pagina 104 105archivio italiano di urologia e andrologia 2013; 85, 2 vaginocutaneous fistula and inguinal abcess presented 6 years after tension-free vaginal tape sling discussion tension-free vaginal tape is largely performed in the surgical treatment of sui as a minimal invasive treatment. the tvt procedure has been shown to have a cure rate of 90% and a low risk of complications (2). although tvt is minimally invasive surgical procedure, the blind passage of sharp trocars containing risk of injuries. also mesh has a risk of some inflammatory events because of foreign body reaction. the risk factors associated with genitourinary fistula formation are the same factors that predispose mesh erosion and include a history of pelvic surgery, pelvic irradiation or history or presence of cancer or infection (2). but in our case there was no history of these risk factors. also, quite long period was present between the tvt sling procedure and presentation of complications. it may depend on the ignorance of patient or very late reaction of body to mesh. urethrovaginal fistula is seen often after complication of pelvic floor surgery that is iatrogenic in developing countries. since tvt was commonly performed, many reports with urethrovaginal fistulas after tvt were published (2, 3). but there is no report of vcf after tvt. maffiolini and asteria (4) reported a 64 year-old woman patient with vcf 3 years after trans-obturator tape (tot) sling. patient had pre-obturatory abcess surfaced at the prepubic space of tape entry. firstly mesh was removed after tape exposure was found on the left side of vaginal wall. two months later pre-obturatory abcess was drained. the patient was referred to authors after worsening of symptoms, and they detected a vcf. marques et al. (1) reported 54-year-old woman with perineal cellulitis after tot sling. they have detected subugeneral anaesthesia. then, patient was switched to supine position and left inguinal incision was done. granulation tissue and abcess in the subcutenous tissue was excised. the sling mesh was dissected and removed from the fistula tract. fistula tract was removed lastly (figure 2a, b). skin and subcutaneous tissue was closed. she was discharged after removing urethral catheter and vaginal tampon at the first post operative day. clinical examination 6 weeks after procedure showed a perfect healing and no sui. figure 1. mri images of vaginocutaneous fistula and abcess. figure 2. images of fistula tract and tvt mesh after excision. 1c: transver axis, left inguinal abcess. 1b: transver axis, bilateral mesh and left vcf. 1a: saggital axis of the vcf. a b b a c 2a: mesh and inguinal abcess. 2b: distal part of fistula tract. sahin_stesura seveso 24/06/13 11:10 pagina 105 archivio italiano di urologia e andrologia 2013; 85, 2 ali feyzullah şahin, yusuf özlem i̇lbey, nur şahin 106 are underreported. the management of these complications is including removal of all tape, infectious tissue and, fistula tract, and also adjuvant antibiotic therapy. references 1. marques al, aparício c, negrão l. perineal cellulitis as a late complication of trans-obturator sub-urethral tape, obtape. int urogynecol j pelvic floor dysfunct. 2007; 18:821-2. 2. lowman j, moore rd, miklos jr. tension-free vaginal tape sling with a porcine interposition graft in an irradiated patient with a past history of a urethrovaginal fistula and urethral mesh erosion: a case report. j reprod med. 2007; 52:560-2. 3. estevez jp, cosson m, boukerrou m. an uncommon case of urethrovaginal fistula resulting from tension-free vaginal tape. int urogynecol j. 2010; 21:889-91. 4. maffiolini m, asteria cr. a cutaneous-vaginal fistula and myositis of the obturator muscle following placement of a trans-obturator tape for stress incontinence. eur j obstet gynecol reprod biol. 2010; 149:225-6. 5. marsh f, rogerson l. groin abscess secondary to trans obturator tape erosion: case report and literature review. neurourol urodyn. 2007; 26:543-6. rethral erosion allowed to see the tape. they removed the tape and infectious tissue after beginning intravenous antibiotic therapy. marsh and rogerson (5) reported a 46-year-old woman with groin abcess after tot erosion. the symptoms started with vaginal discharge 8 weeks after tot sling. they removed the tape, infectious and necrotic tissue after beginning antibiotic therapy. but their case was not late presentation and seems as an infectious complication. the patient had uncontrolled diabetes which could lead immune deficiency in her medical history. estevez (3) reported different pathologic mechanisms might affect due to presentation terms of fistula. they stated that short-term fistulas are probably due to an unknown intra-operative urethral injury or to an excessive tensioning of the sling, whereas, long-term fistulas, diagnosed after several months, may have a different complex physiopathology. vaginocutaneous fistula is a recognized, but rare, complication of tvt. this case highlights the need for a high index of suspicion for vcf after tvt. vaginal examination to identify any vaginal erosion and fistula is crucial in the follow-up of slings. most complications after slings correspondence ali feyzullah şahin, md, febu şifa üniversitesi bornova uygulama ve araştırma hastanesi, sanayi cad. no: 7 35100 bornova, i̇zmir, turkey uroali@yahoo.com sahin_stesura seveso 24/06/13 11:10 pagina 106 archivio italiano di urologia e andrologia 2013; 85, 282 introduction percutaneous nephrolithotomy is the gold standard in treating kidney stones larger than 2 cm (1). the technique has been modified and customized by many endourologists since its introduction in 1976 by fernstrom and johanson. many various safe and effective changes in patient positioning for pcnl have been proposed over years, including reverse lithotomy position (2), prone split-leg position (3-4), lateral decubitus (5, 6), supine position (7), and galdakao-modified supine valdivia (gmsv) position (8). in recent years it has been observed a remarkable increase in performing pcnl in supine original paper split-leg percutaneous nephrolithotomy: a safe and versatile technique eugenio di grazia, pasquale la rosa u.o.c. urologia-arnas garibaldi, catania, italy. objectives: percutaneos nephrolithotomy (pcnl) is the gold standard for treatment of urinary stones larger than 2 cm and refractory to eswl. nowadays most debate about surgical technique is related to the positioning of patients. we report our experience on prone pcnl with split-leg variant (sl-pcnl) materials and methods: 30 consecutive patients underwent prone sl-pcnl. preoperative stone size was determined by measuring stones longest diameter on ct scan. in cases with multiple stones, stone size was determined by the sum of each stone diameter on ct scan. patients evaluated consisted of 20 females and 10 males and median age was 55 (20-72). the average bmi was 27 (24-35). 15 patients had multiple stones, 10 pyelocalicial, 10 pelvic larger than 2 cm, 2 in horseshoe kidneys and 3 staghorn stones. results: stone free rate was 87% after first look and 97% after second look. in 2 cases, we used a flexible ureteroscopy 7.5 fr (flex 2 storz) to treat a calculus in ureter or for a contemporary double access (endoscopic combined retrograde intrarenal surgery ecirs). in 28 cases we placed a 20 fr nephrostomy while in two cases procedure was tubeless. in 20 cases we placed a double-j catheter. in 2 cases we performed two tract and in 2 horseshoe kidneys access was close to spine. the average surgical time was about 90 minutes (range 30-120 minutes). hemoglobin drop was about 1.5 mg/dl (range 1-3 .4 mg/dl) and no major complications were reported. conclusions: in our experience pcnl in prone with spread-legs variant is a versatile technique and allows to match the advantages you have with same technique in supine, providing at the same time benefits in cases of anatomical abnormalities, challenging cases, or when multi-tract accesses are required. key words: pcnl; percutaneous nephrolithotomy; urinary stones; prone; supine. submitted 12 october 2012; accepted 31 december 2012 no conflict of interest declared summary decubitus, although others have remained faithful to prone technique because supine decubitus doesn't seem to provide great benefits for morbidity and effectiveness (9), otherwise the prone position provides a larger area for the percutaneous renal access, a wider space for instrument manipulation, and a presumed lower risk of splanchnic injury. recently we adopted a variant to our technique in prone position, by splitting legs allowing surgeons a dual approach through retrograde and anterograde paths whithout changing decubitus. aim of this study is to test safety, advantages and feasibility of this technique. di grazia_stesura seveso 24/06/13 11:03 pagina 82 83archivio italiano di urologia e andrologia 2013; 85, 2 split-leg percutaneous nephrolithotomy: a safe and versatile technique procedure after general anesthesia patient was placed in prone position with legs apart (figures 1-2). with a 15 f flexible cystoscope (stors) under fluoroscopic guidance (c-arm) a 5 f open-end ureteral catheter was positioned until renal pelvis for contrast dye injection during percutaneous access; in 2 cases, we used a flexible ureteroscopy 7.5 fr (flex 2 -storz) to treat a calculus in ureter or for a combined access endoscopic combined intrarenal surgery (ecirs). the percutaneous kidney access is performed by combined echo-radiological approach and tract is dilated with balloon to place a 24 f amplatz sheath (x force-bard). the litotripsy was accomplished by a 24 f rigid nefroscope or 15 f flexible nefroscope (storz) using ultrasound energy sources (storz), ballistic (ems) and laser (dornier). operative time was determined by estimating the time from the application of the ureteric catheter to the placement of the nephrostomy tube. at the end of procedure we usually place a 20 f nephrostomy or ureteral stent according to the degree of bleeding or of stone clearence. results all cases were punctured successfully. stone free rate was 87% after first look and 97% after second look (table 2). at the end of procedure in 28 cases we placed a 20 f nephrostomy while in two case the procedure was tubematerials and methods after a series of about 300 patients undergoing pcnl from 2002 to 2012, we evaluated 30 consecutive cases performed in prone decubitus with split-leg variant (slpcnl). preoperative evaluation included history, clinical examination and basic laboratory investigations. radiological investigations included pelvi-abdominal ultrasonography and computerized tomography (ct) for all patients. preoperative stone size was determined by measuring stones longest diameter on ct scan. in cases with multiple stones, stone size was determined by the sum of each stone diameter on ct scan. patients evaluated consisted of 20 females and 10 males and median age was 55 (20-72). the average bmi was about 27 (2435 bmi). 15 patients had multiple stones, 10 pyelocalicial, 10 pelvic larger than 2 cm, 2 in horseshoe kidneys and 3 staghorn stones (table 1). we practiced an antibiotic prophylaxis the evening before the procedure with a cephalosporin of iii generation in case of sterile urine culture. when culture was positive generally we started a targeted antibiotic therapy a week earlier. site 15 multiple 10 pyelocalicial 5 pyelic 3 staghorn; 2 horseshoe kidney associated ureteral stones 2 cases accesses 28 single accesses 2 double accesses 2 upper calix accesses in horseshoe kidney table 1. stone characteristics. figure 1. figure 2. success rate first look (87%) second look (97%) complications bleeding requiring transfusion in 1 (3,3%) persistent fever over 38,5 c° in 4 (13,3%) prolonged urinary leakege in 2 (6,6%) table 2. success rate and complications. di grazia_stesura seveso 24/06/13 11:03 pagina 83 archivio italiano di urologia e andrologia 2013; 85, 2 e. di grazia, p. la rosa 84 sitating extra nurses. after draping, we start the procedure in prone and upper urinary tract may be contemporary instrumented both in an antegrade and retrograde fashion by two surgeons. the main difference between prone and supine is the impossibility for surgeon using flexible scopes to access upper urinary tract in prone while both semirigid or flexible instruments can be used in the latter. another criticism over prone position rise up when obese patients or patients affected by respiratory diseases are concerned, or in cases where extensive controlateral or omolateral ureteral instrumentation is requested before or contemporary to percutaneous access. croes studies demonstrated no significant differences in complications between prone and supine when such patients are concerned (11). in our opinion further experience on using flexible ureteroscope in split-leg position may overwhelm these presumed obstacles in traditional prone position. if no gross disadvantages are reported between prone and supine, we assert benefits that prone decubitus can account for: easier way of perform mutiple tracts when is necessary, greater freedom of movement of instrumentation. in addition, upper-pole calyx calyceal puncture is quite challenging as upper pole is normally more medial and posterior and concealed deeply in the rib cage, when patient is positioned supine (12). prone position account for an easier access to horseshoe kidney as target calix is normally close to spine, rendering access in supine very challenging. this is a description of technique with no direct comparison with a homogeneous control population treated in others surgical positions, however the advantage we obtained by adopting this variant to the traditional prone position makes us to propose such technique as a useful option for percutaneous renal surgery. conclusions in our experience pcnl in prone with spread-legs variant is a versatile technique that allows to match the advantages you have with same technique in supine, providing at the same time benefits in cases of anatomical abnormalities, challenging cases, or when multi-tract accesses are required. references 1. fernstrom s, johansson b. percutaneous pyelolithotomy. a new extraction technique. scand j nephrol urol. 1976; 10:257-9. 2. lehman t, bagley dh. reverse lithotomy, modified prone position for simultaneous nephroscopic and ureteroscopicprocedures in women. urology. 1988; 32:529-31. 3. grasso m, nord r, bagley dh. prone split leg and flank roll positioning antegrade and retrograde: simultaneous access to the upper urinary tract. j endourol. 1993; 7:307. 4. scarpa rm, cossu fm, de lisa, et al. severe recurrent ureteral stricture: the combined use of an anterograde and retrograde approach in the prone split-leg position without x-rays. eur urol. 1997; 31:254-6 5. kerbl k, clayman rv, chandhoke ps, et al. percuta neous less. in 20 cases we placed a double-j catheter. the nephrostomy was retrieved when any bleeding ceased and when no residual fragments were demonstrated at post-surgery radiological assessment. in those cases with residual fragments we performed a second look with flexible nefroscope, small baskets and holmium laser lithotripsy accessing the same matured tract without amplatz sheath. when 20 f nephrostomy is withdraw the tract is large and mature enough to allow access of 15 f flexible nephroscope through the kidney without patient discomfort as performed in an outpatient procedure. in 2 cases we performed two tract to clear stones and in 2 horseshoe kidneys target calix was close to the spine. the average surgical time was about 90 minutes (range 30-120 minutes). the drop in hemoglobin was about 1.5 mg/dl (range 13.4). applying classification of clavien-dindo in 1 case (3.3%) we practiced a transfusion of a blood unit (grade ii). 4 patients (13.3%) had a persistent fever over 38.5° c for more than 2 days (grade ii). in 2 cases (6,6%) was necessary to reposition the stent for persistent urinay leakage (grade ii). no case of visceral perforation or other major complications were reported. discussion the slpcnl is a technique already presented in literature by grasso et al. with aim of facilitating both contemporary antegrade and retrograde approach to upper urinary tract. in their experience grasso et al. reported a 41% of cases where this position was useful for dual instrumentation (3). also scarpa et al. described this approach in solving a ureteral stenosis with combined antegrade and retrograde approach (4). many studies have now demonstrated equivalence of pcnl in supine and prone positions, however proponents of supine believe that it offers advantages over the prone: no repositioning, lack of patient handling, spontaneous gravitational fall of fragments, less time consuming because of not repositioning, greater comfort for surgeon, reduced x-ray exposure, low pyelic pressures, retro and antegrade access simultaneously (8-9-10). nevertheless as seen by our experience slpcnl provides as many benefits as supine. many endourologists performing pcnl in prone position place a ureteral catheter for injecting contrast dye in supine decubitus, then they reposition patient in prone to start their percutanous procedure. a real criticism can be that patient repositioning is timeconsuming and associated with patient discomfort, increases radiological hazard to urologist’s hands, and asks for several nurses to be present for intraoperative changes of decubitus in case of simultaneous retrograde instrumentation of ureter (implying evident risks related to pressure points and possible ocular, spinal, or peripheral nerve injuries). in our experience it should be correct to talk of “positioning” patient in prone position, rather than “repositioning”, as patient is gently rotated from a stretcher to operating bed without spending much time and necesdi grazia_stesura seveso 24/06/13 11:03 pagina 84 85archivio italiano di urologia e andrologia 2013; 85, 2 split-leg percutaneous nephrolithotomy: a safe and versatile technique stone removal with the patient in a flank position. j urol. 1994; 151:686-8. 6. gofrit on, shapiro a, donchin a, et al. lateral decubitusposition for percutaneous nephrolithotripsy in the morbidlyobese or kyphotic patient. j endourol. 2002; 16:383-386. 7. uria in valdivia jg, valle gerhold j, lopez ja, et al. technique and complications of percutaneous nephroscopy: experience with 557 patients in the supine position. j urol. 1998; 160:1975-8. 8. scoffone cm, cracco cm, cossu m, et al. endoscopic combined intrarenal surgery in galdakao-modified supine valdivia position: a new standard for percutaneous nephrolithotomy? eur urol. 2008; 54:1393-403. 9. valdivia jg, scarpa rm, duvdevani m, et al. croes pcnl study group. supine versus prone position during percutaneous nephrolithotomy: a report from the clinical research office of the endourological society percutaneous nephrolithotomy global study. j endourol. 2011; 25:1619-25. 10. autorino r, giannarini g. prone or supine: is this the question? eur urol. 2008; 54:1216-1218. 11. fuller a, razvi h, denstedt jd, et al. croes pcnl study group. the croes percutaneous nephrolithotomy global study: the influence of body mass index on outcome. j urol. 2012; 188:138-44. 12. de la rosette jj, tsakiris p, ferrandino mn, et al. beyond prone position in percutaneous nephrolithotomy: a comprehensive review. eur urol. 2008; 54:1262-9. correspondence eugenio di grazia, md (corresponding author) via galermo 171/c 95123 catania, italy eugeniodigrazia@hotmail.com la rosa pasquale, md via palermo 636 95100 catania, italy pasq.larosa@alice.it di grazia_stesura seveso 24/06/13 11:03 pagina 85 stesura seveso archivio italiano di urologia e andrologia 2013; 85, 3154 introduction prostatic abscess is uncommon and difficult to diagnose because initial clinical presentation may mimic several other diseases of the lower urinary tract. the incidence of prostatic abscess has markedly decreased because of the widespread use of antibiotics and the decreased incidence of gonococcal urethritis. in the forties, mortality ranged from 6% to 30%, and major microorganism involved was neisseria gonorrhea (1). more recent data suggests a mortality rate from 3% to 16% (2), enterobacteriacae being the most common agents. among these, escherichia coli has the highest prevalence, in about 70% of the cases (3). in this paper we report a case of prostatic abscess treated in our department and review the literature as far as the clinical presentation, diagnostic modalities and management is concerned. case report a 52-year-old male presented at the emergency department of our hospital with dysuria, high fever, chills, perineal pain and poor general condition. a few days before he visited a private urologist who diagnosed acute prostatitis with urine culture positive for e. coli. he received ciprofloxacin and although there was an improvement at the beginning, the symptoms recurred. he was a known diabetic patient. on physical examination, his blood pressure, pulse rate case report prostatic abscess: case report and review of the literature orestis porfyris, paraskevas kalomoiris urology department, general hospital of sparta, sparta, greece. we report a case of prostatic abscess in a 52 year old male with a history of diabetes mellitus. the abscess was treated successfully with surgical drainage by transurethral unroofing of the cavity of the abscess. the use of transrectal ultrasound is valuable in the diagnosis, treatment and follow up of the abscess, while drainage is usually necessary for the treatment, which can be done by transrectal, transperineal and transurethral route. key words: abscess; prostate; drainage. submitted 2 april 2013; accepted 31 may 2013 no conflict of interest declared summary and temperature were 130/80mmhg, 95 per minute and 39° c, respectively. at rectal examination, the prostate was tender and enlarged with a fluctuating area between the two lobes. urine and blood cultures were obtained prior to starting antibiotic therapy. transabdominal ultrasonography of the prostate showed a hypoechoic area. transrectal ultrasonography showed two hypoechoic areas, one in the right and one in the left lobe (figure 1). computed tomography scan revealed two hypodense, homogenous areas with size 3 x 3,5 cm, in the same region of the prostate (figure 2). the patient was treated with ciprofloxacin, amikacin and metronidazole intravenously. under ultrasonography guidance the abscess was drained transrectally. about 7 ml of pus were obtained and its culture showed klebsiella pneumoniae. the same agent was found in blood cultures as well. during follow up the same procedure was repeated due to incomplete emptying of the abscess cavities. finally it was decided that the patient should have a transurethral drainage of the abscess. the simultaneous use of transrectal ultrasound confirmed the complete drainage of the abscess. the postoperative recovery of the patient was normal and on the 6th day after the tur the patient was discharged. one month later, the patient was symptom free, the urine culture was negative and the transrectal ultrasound appeared normal (figure 3). doi: 10.4081/aiua.2013.3.154 155archivio italiano di urologia e andrologia 2013; 85, 3 prostatic abscess: case report and review of the literature discussion prostatic abscess is an infrequent condition in the modern antibiotic era with an incidence of 0.5% to 2.5% of diseases accompanying prostatic symptoms (4). it can occur in patients of any age (including neonates) but is mainly found in men in their 5th and 6th decade of life (2). predisposing factors for the development of prostatic abscess are diabetes mellitus, bladder outlet obstruction, indwelling catheter, biopsy of prostate, chronic renal failure, haemodialysis, chronic liver disease and hiv infection (5,6). as far as pathogenesis is concerned, it is the retrograde flow of contaminated urine during micturition into prostatic ducts that promotes the formation of microabscesses that coalesce and form prostatic abscesses (3). it is already mentioned that e. coli and enterobacteriacae are the most prevalent bacteria in prostatic abscess. nevertheless, as the number of immunocompromised patients increase, atypical pathogens may be found, like mycobacteria, fungi, anaerobes and in case of haematogenous spread from distant foci, staphylococcus aureus (7). clinical manifestation of the disease includes dysuria, urgency and frequency in 96% of the cases, fever in 30% to 72% of the cases, perineal pain in 20% of the cases and urinary retention in 1/3 of the cases (1, 2, 4). the most typical sign of prostatic abscess is a fluctuating area in the prostate palpated by digital examination, although this finding is observed in 16% to 88% of the patients (1,2). in case of improper treatment or delayed diagnosis possible complications are the spontaneous rupture of the abscess and fistula formation towards the urethra, bladder, perineum and rectum and also septicemia with mortality rate between 3% and 16% (4). figure 1. transrectal ultrasound showing prostatic abscess with two cavities. figure 3. transrectal ultrasound 1 month after transurethral resection. figure 2. ct scan depicting the prostatic abscess. archivio italiano di urologia e andrologia 2013; 85, 3 o. porfyris, p. kalomoiris 156 the diagnostic study of choice to assist the treatment and follow up of patients with prostatic abscess is transrectal ultrasonography. the most common finding is one or more hypoechogenic lesions, of different sizes, located in the transitional or central zone of the prostate and surrounded by a hyperechogenic halo, that can cause distortion of the anatomy of prostate gland (8). color and power doppler sonography show a high perilesional vascularity. differential diagnosis includes neoplasias, cystic lesions, granulomas and acute prostatitis. ct scan and mri scan usually add few information as far as diagnosis is concerned. they are useful at the estimation of the extent of the abscess in the periprostatic tissues, at the detection of gas in the fluid of abscess and when extensive types of procedures are being planned after patient diagnosis (8). the treatment consists of parenteral broad-spectrum antibiotic administration and abscess drainage. due to the rareness of the disease there are no specific guidelines for the treatment of prostatic abscess. the administration of antibiotic agents by itself is effective in limited cases, such as monofocal abscess less than 1 cm in diameter. usually surgical intervention is required, which can be done under ultrasound guidance by transrectal (9, 10) or transperineal route (11, 12). these procedures are easy to perform under local anaesthesia, have low morbidity and can be repeated in case of failure. the culture of pus that is aspirated is important because pathogens isolated are often different from those found in urine culture. this can result in modification of antibiotic treatment. several authors recommend the insertion of drainage tubes (e.g. nephrostomy tubes) in the abscess cavity for achieving better drainage (10, 12). when the abscess recurs or cannot be completely evacuated, transurethral unroofing is a more appropriate approach, leading to better drainage of the abscess cavity with early recovery of the patient (7, 9). although there is a theoretical danger of haematogenous spread of the pathogen during transurethral resection, the use of preoperative broad-spectrum antibiotics prevents the occurrence of septicemia. finally, in very few cases, open surgical drainage may be indicated mainly in those patients with extraprostatic involvement (7). conclusion prostatic abscess should be suspected in patients presenting with fever and persistent voiding symptoms despite proper antibiotic treatment, in diabetics and those with a disease that causes immunodeficiency. it is important to rapidly establish a definitive diagnosis because mortality rate remains high. surgical drainage is usually required, even with minimal invasive techniques, but the optimal therapeutic modality for each patient should be individualized, aiming to prompt control of symptoms and early recovery. references 1. weinberger m, cytron s, servadio c, et al. prostatic abscess in the antibiotic era. rev infect dis. 1988; 10:239-49. 2. granados ea, caffaratti j, farina l, hocsman h. prostatic abscess drainage: clinical-sonography correlation. urol int. 1992; 48:358-61. 3. meares em, jr. prostatic abscess. j urol. 1996; 129:1281-2. 4. granados ea, riley g, salvador j, vincente j. prostatic abscess: diagnosis and treatment. j urol. 1992; 148:80-2. 5. olivieira p, andrade ja, porto hc, et al. diagnosis and treatment of prostatic abscess. int braz j urol. 2003; 29:30-34. 6. trauzzi sj, kay cj, kaufman dg, lowe fc. management of prostatic abscess in patients with human immunodeficiency syndrome. urology. 1994; 43:629-33. 7. ludwig m, scroederprintzen i, schiefer hg, weidner w. diagnosis and therapeutic management of 18 patients with prostatic abscess. urology. 1999; 53:340-5. 8. barozzi l, pavlica p, menchi i, et al. prostatic abscess: diagnosis and treatment. ajr. 1998; 170:753-757. 9. collado a, palou j, garcia-penit j, et al. ultrasound-guided needle aspiration in prostatic abscess. urology. 1999; 53:548-52. 10. aravantinos e, kalogeras n, zygoulakis n, et al. ultrasound-guided transrectal placement of a drainage tube as therapeutic management of patients with prostatic abscess. j endourol. 2008; 22:1751-4. 11. bachor r, gottfried hw, hautmann r. minimal invasive therapy of prostatic abscess by transrectal ultrasound-guided perineal drainage. eur urol. 1995; 28:320-4. 12. basiri a, javaherforooshzadeh a. percutaneous drainage for treatment of prostate abscess. urol j. 2010; 7:278-80. correspondence orestis porfyris, md (corresponding author) orestisporfyris@yahoo.gr epia thourias 24009 kalamatan, greece paraskevas kalomoiris, md diy@hospspa.gr vrasidou 156 23100 sparta, greece stesura seveso archivio italiano di urologia e andrologia 2013; 85, 3130 introduction prostate cancer (pca) is the most frequent tumor diagnosed in elder men with about 1 million biopsies for year performed in the united states (1). in the last decade a greater rate of prostate biopsy side effects has been reported and serious complications incidence requiring hospital admission ranges from 1.2% (2) to 2.5% (1) secondary, in the most of the cases, to urinary tract infection (uti), fever or sepsis (in case of transrectal biopsy). among minor complications erectile dysfunction (ed) has been reported in a little percentage of patients and it has been ascribed to anxiety (3), local anesthesia and/or number of needle cores (4, 5) inducing a clinical impact on patient well-being and quality of life (6). in our study ed incidence following repeat transperineal saturation prostate biopsy (spbx) was prospectively evaluated. materials and methods from january 2011 to june 2012 295 patients of ages between 56 and 71 years (median 63 years) underwent original paper erectile function after repeat saturation prostate biopsy: our experience in 100 patients pietro pepe, francesco pietropaolo, giuseppe dibenedetto, francesco aragona urology unit, cannizzaro hospital, catania, italy. introduction: erectile dysfunction (ed) incidence following repeat saturation prostate biopsy (spbx) was evaluated. materials and methods: from january 2011 to june 2012 295 patients underwent repeat transperineal spbx (median 28 cores) under sedation. the indications for biopsy were: abnormal dre, psa > 10 ng/ml or included between 4.1-10 with free/total psa < 25%. all patients were prospectively evaluated with the 5-item version of the international index of erectile function (iief-5) at baseline and 1, 3 and 6 months from spbx. results: 100/200 men with benign histology and normal sexual activity completed the study; median iief-5 score before and after spbx was equal to 18.3 (baseline) vs 17.8 (1 month later) vs 18 (3 months later) vs 18.1 (6 months later) (p > 0.05); in detail, 1 month from biopsy 5 (5%) men referred a mild ed that disappeared at 3 and 6 months evaluation. conclusions: repeat transperineal spbx under sedation did not significantly worsened erectile function; the minimal risk of temporary post-biopsy ed could be previously discussed (not emphasised) with potent patients. key words: erectile dysfunction; saturation prostate biopsy; sexuality; prostate biopsy. submitted 27 february 2013; accepted 30 april 2013 no conflict of interest declared summary repeat spbx (median 28 cores; range: 26-31) for persistent suspicious of pca. the indications for biopsy were (7): abnormal digital rectal examination (dre), persistent elevated or increasing psa values, psa > 10 ng/ml, psa values between 4.1-10 with free/total psa < 25%. prostate biopsy was performed transperineally (8) using a tru-cut 18 gauge needle (bard; covington, ga), a ge logiq 500 pro ecograph (general electric; milwaukee, wi) supplied with a biplanar transrectal probe (5-6.5 mhz). the spbx included at least 12 cores in the posterior zone of each lobe (apex, middle zone and base of the gland) beginning parasagittally to reach the outer edges of the gland (lateral margins) plus 2-3 cores in the transition and anterior zone. the procedure was performed under sedation and antibiotic prophylaxis, respectively. among clinical complications incidence of ed was evaluated only in men with benign histology (normal parenchyma), on the contrary patients with cancer, asap or hgpin were not included to eliminate anxiety from the hypothetical cause of ed. all patients were prospectively evaluated doi: 10.4081/aiua.2013.3.130 131archivio italiano di urologia e andrologia 2013; 85, 3 erectile function after repeat saturation prostate biopsy: our experience in 100 patients with the 5-item version of the international index of erectile function (iief-5) (9) before and 1, 3 and 6 months from spbx. none of the patients used 5-phosphodiesterase inhibitors or prostaglandins to improve sexual activity. for statistical analysis the t student’ test was used; a p value < 0.05 was considered statistically significant. results histological specimen showed a pca in 90/295 (30.5%) cases, an hgpin in 4 (1.3%), an asap 1 (0.4%) and a normal parenchyma in 200 (67.8%), respectively; 100/200 (50%) men with a referred normal sexual activity characterized by a median baseline iief-5 score equal to 18.3 (range: 16-25) completed the study. clinical (comorbidities, drug therapy) and laboratory data collected before spbx are reported in table 1. among clinical complications none of the patients needed hospital admission and 10 (10%) underwent emergency clinic visit within 2 day (median; range: 1-3 days) from spbx in 7 cases (7%) for acute urinary retention, in 2 (2%) for gross hematuria and in 1 (1%) for urinary tract infection; moreover, hemospermia was the most frequent side effect recorded in 36 (36%) and 9 (9%) patients 3 and 6 months from the procedure, respectively. a significantly difference between ieef-5 score at baseline (18.3) and 1 (17.8), 3 (18) and 6 (18.1) months from spbx was not found (p > 0.05) (table 2); in detail, after 1 month 5 (5%) patients with a pre-biopsy normal sexual activity (iief > 22) referred a mild de that disappeared at 3 and 6 months evaluation (table 2). discussion a minimal risk of temporary ed following prostate biopsy has been correlated with the increasing number of needle cores, use of periprostatic nerve block, disease involving neurovascular bundles, anxiety and diagnosis of pca. although tuncel et al. (10) reported a male sexual dysfunction combined with negative effect on female sexual function exceeding six months from biopsy, most of the papers (5,10) agree that prostate biopsies could have a significantly impact on short-term (30 days) erectile function that disappears at medium-term (3-6 months). glaser et al (3) in a systematic review reported that prostate biopsy was associated with short-term exacerbation of urinary symptoms score, anxiety and ed without a distinct relationship to the periprostatic nerve block or the number of cores biopsied. zisman et al. (4) attributed to anxiety a ed rate in anticipation of biopsy in 7% of the cases evaluated; akbal et al. (5) in 88 patients cancer-free after spbx showed a risk of ed after 1 and 6 months clinical findings no (%) of patients median age (years) 61 (range: 56-71) psa 4.1-10 ng/ml 68 psa > 10 ng/ml 32 abnormal dre luts 67 qmax 11 (8-19) ipss (median) 11 (4-29) comorbidities: 18 diabetes mellitus 3 hypertension 10 gastritis 18 other 3 drug therapy (overall): 86 oral hypoglycemic 2 antihypertensive 10 antiplatelet agents 10 diuretic 3 proton pomp inhibitor 19 alfa-blockers 62 other 6 ieff-5 baseline 1 month 3 month 6 month p value (score: 5-25) pts (%) pts (%) pts (%) pts (%) absence of ed 45 (45%) 40 (40%) 43 (43%) 44 (44%) > 0.05* (22-25) (p = 0.477) (p = 0.777) (p = 0.888) mild ed 39 (39%) 40 (40%) 42 (42%) 40 (40%) > 0.05* (17-21) (p = 0.886) (p = 0.688) (p = 0.886) mild-moderate ed 16 (16%) 20 (20%) 15 (15%) 16 (16%) > 0.05* (12-16) (p = 0.464) (p = 0846) (p = 1) moderate ed (8-11) severe ed (5-7) table 1. clinical findings in 100 patients who underwent repeat saturation prostate biopsy. table 2. iief-5 (international index erectile function) in 100 patient before (baseline) and after (1, 3 and 6 months) repeat transperineal saturation prostate biopsy. dre: digital rectal examination; luts: lower urinary tract symptoms; ipss: international prostate symptoms score. ed: erectile dysfunction; *p value did not showed a statistically significant difference when baseline iief-5 was compared with postbiopsy iief-5 (1, 3 and 6 months from the procedure). archivio italiano di urologia e andrologia 2013; 85, 3 p. pepe, f. pietropaolo, g. dibenedetto, f. aragona 132 equal to 11.6% and 0%, respectively. although in the last years number of repeat biopsies and/or needle cores (spbx) has been supposed to temporary induce ed the literature data are conflicting. in fact, fujita et al. (11) in 231 patients enrolled in active surveillance (as) protocol for pca found a correlation between number of repeat biopsy (3 or more) and erectile function; on the contrary, hilton et al. (12) in 427 men on as showed that sexual activity was not associated with biopsy exposure. recently, klein et al. (13) in 198 patients submitted to 10 (155 cases) and 20 (53 cases) needle cores demonstrated that erectile function was transiently affected by prostate biopsy regardless of periprostatic nerve block and the number of cores. in our series, to our knowledge the first that evaluated patients submitted to repeat transperineal spbx under sedation, ed incidence did not significantly increased 1, 3 and 6 months from biopsy; only 5/100 (5%) men with a pre-biopsy normal sexual activity (ieef-5 > 22) referred at first month evaluation a mild ed (ieef-5 score between 17 and 21) that disappeared 3-6 months later. regarding our results some considerations should be done. firstly, the true sexual activity of the couple administering a sexual questionnaire to the partners was not investigated. secondly, we don’t know if the transperineal biopsy approach and/or the absence of local anesthesia had a clinical impact on our results. finally, in the absence a of control group we don’t know if the onset of de one month from spbx (5% of the cases) was really given by prostate biopsy. in conclusion, repeat transperineal spbx under sedation did not significantly worsened erectile function; the minimal risk of temporary post-biopsy ed could be previously discussed (not emphasised) with potent patients. references 1. pinkhasov gi, lin yk, palmerola r, et al complications following prostate needle biopsy requiring or emergency department visitsexperience from 1000 consecutive cases. bju int. 2012; 110:369-374. 2. pepe p, aragona f. morbidity following transperineal prostate biopsy in 3,000 patients submitted to 12 vs 18 vs more than 24 needle cores. urology. 2013; 81:1142-1146. 3. glaser ap, novakic k, helfand bt. the impact of prostate biopsy on urinary symptoms, erectile function, and anxiety. curr urol rep. 2012; 13:447-454. 4. zisman a, leibovici d, keinmann j, siegel yi, lindner a. the impact of prostate biopsy on patient well-being: a prospective study of pain, anxiety and erectile dysfunction. j urol. 2001; 165:445-454. 5. akbal c, turker p, tavukcu hh, et al. erectile function in prostate cancer-free patients who underwent prostate saturation biopsy. eur urol. 2008; 53:540-544. 6. palumbo f, bettocchi c, spilotros m, et al. a prospective study on patient’s erectile function following transrectal ultrasound guided prostate biopsy. arch ital urol androl. 2010; 82:265-268. 7. pepe p, aragona f. incidence of insignificant prostate cancer using free/total psa: results of a case-finding protocol on 14453 patients. prostate cancer prostatic dis. 2010; 13:316-319. 8. pepe p, aragona f. saturation prostate needle biopsy and prostate cancer detection at initial and repeat evaluation. urology. 2007; 70:1131-1135. 9. rosen rc, cappelleri jc, smith md, et al. development and evaluation of an abridged, 5-item version of the international index of erectile function (iief-5) as a diagnostic tool for erectile dysfunction. int j impot res. 1999; 11:319-326. 10. tuncel a, kirilmaz u, nalcacioglu v, et al. the impact of transrectal prostate needle biopsy on sexuality in men and their female partners. urology. 2008; 71:1128-1131. 11. fujita k, landis p, mcneil bk, pavlovich cp. serial prostate biopsies are associated with an increased risk of erectile dysfunction in men with prostate cancer on active surveillance. j urol. 2009; 182:2664-2669. 12. hilton jf, blaschko sd, whitson jm, et al. the impact of serial prostate biopsies on sexual function in men on active surveillance for prostate cancer. j urol. 2012; 188:1252-1258. 13. klein t, palisaar rj, holz a, et al. the impact of prostate biopsy and periprostatic nerve block on erectile and voiding function: a prospective study. j urol. 2010; 184:1447-1452. correspondence pietro pepe, md (corresponding author) piepepe@hotmail.com francesco pietropaolo, md giuseppe dibenedetto, md francesco aragona, md urology unit cannizzaro hospital, via messina 829 catania, italy archivio italiano di urologia e andrologia 2013; 85, 292 introduction radical prostatectomy (rp) is the most common treatment option for prostate cancer, with more than 80 000 rps annually in the usa (1). urinary incontinence (ui) is a common and costly complication in men after rp, often adversely affecting their quality of life (qol) (2). despite improvements in surgical techniques and a better understanding of pelvic anatomy, the reported stress urinary incontinence (sui) rates are between 5% and 48% (3). conservative treatment of the urinary leakage represents the first line management of ui after rp, but the value of the various conservative approaches to treat postprostatectomy ui after rp remains uncertain (4). the last cochrane systematic review on this topic found that there was conflicting information about the benefit of pelvic floor muscle training for either prevention or review continence and complications rates after male slings as primary surgery for post-prostatectomy incontinence: a systematic review maria angela cerruto, carolina d'elia, walter artibani department of surgery urology clinic, university of verona, italy. objectives: to analyze continence and complications rates after male slings as first line surgical treatment, in order to improve patient counseling for the management of sui postprostatectomy. method: a medline search using specified search terms was done on january 23, 2012. this research rendered 160 records. results: no controlled trial was available for analysis. the majority of papers dealing with outcome and complications came from a few centres. at a median follow-up of 15 months the pooled cure rates for all kinds of slings was 77.4; in the advance group the pooled cure rates was 72.5%; in the invance group it was 74.2% while in the remeex group it was 84.3%. conclusions: only a few number observational studies addressed review selection criteria. the pooled overall cure rates is high but there are no data concerning reliable preand postoperative prognostic factors affecting treatment failure and complications rates, thus it is not possible to have suitable criteria for a better patient selection. the statistically pooled results obtained should be interpreted with caution because of several limitations due to several study selection limitations: observational study design, few number of analysed studies, heterogeneity, lack of outcome definition and standardisation, between-study variability, high risk of bias. key words: sling; male incontinence; radical prostatectomy; continence; complications. submitted 17 july 2012; accepted 31 december 2012 no conflict of interest declared summary treatment of urine leakage after prostate surgery. more research of better quality is needed to assess conservative managements (4). when conservative treatments are unsuccessful after a reasonable period of time (e.g. 8-12 weeks), invasive therapies should be considered (5). according to the last international consultation on incontinence recommendations, for sui due to sphincter incompetence the recommended option is the artificial urinary sphincter (aus) (grade b); other options, such as a male sling, may be considered (grade c) (5). these low grades of recommendation can be explained by the fact that, although there are several options for surgical treatment of ui after prostatectomy, surprisingly only one randomised clinical trial was identified in the literature, comparing aus implantation and injectable treatcerruto_cont_stesura seveso 24/06/13 11:06 pagina 92 93archivio italiano di urologia e andrologia 2013; 85, 2 continence and complications rates after male slings as primary surgery for post-prostatectomy incontinence: a systematic review length of follow-up, time period of surgery, type of prostatectomy), sling types, outcomes (overall cure rates, complications rates). a single reviewer (mac) assessed risk of bias at the study level. the downs-black quality assessment tool (9) was used for nonrandomized studies; a score ! 17 of 31 was considered higher quality. few studies presented their original data in a format amenable to meta-analysis. articles that presented data as a median and range were converted to means according to hozo et al. (10). a single weight-adjusted mean or proportion for each variable or outcome was computed for each of the nonrandomized studies. to derive pooled estimates of proportions for the outcomes explored, random effects models were used. pooling was conducted using comprehensive meta analysis version 2.2.046 (englewood, nj). given that this review assessed measures of prevalence, publication bias was not evaluated. results and discussion from screening 160 records, 49 full-text articles were retrieved with only 5 articles included in the systematic review (figure 1). the 5 included articles involved 356 participants living in 8 countries with a median followup after sling implant of 15 months (interquartile range, 12-21) and sling surgeries conducted between 2002 and 2009. patients’ mean age at time of surgery was 68.06 (standard deviation, 1.37) years. study characteristics and quality are summarized in table 1 (11-15). ment with macroplastique (6). for other surgical procedures such as male slings, pro-act system, other bulking agents and stem-cell therapy, only non-randomised studies were identified (7), making impossible to answer questions about treatment comparison in terms of efficacy, safety, complications and long term results. despite the lack of information, when patients seek effective and durable treatment to achieve a continence status, it is necessary to adequately make aware them of continence rates and all possible complication of any proposed treatment as first line surgical option. the aim of this review was to analyze continence and complications rates after male slings as first line surgical treatment, in order to improve patient counseling for the management of sui postprostatectomy. methods the preferred reporting items for systematic reviews and meta-analyses (prisma) checklist was used to help guide this report (8). we conducted a pubmed database search through january 2012 for relevant prospective cohort studies and case series that met the following inclusion criteria: english language; adults with sui postprostatectomy who underwent male slings as first surgical option for continence recovery; studies carried out on ! 20 patients with a mean follow-up of ! 1 year;because the majority of papers dealing with outcome and complications came from a few centres, only the most recent publication(s) from each centre were included to avoid the same patients being presented several times. multiple free-text searches were performed including the following terms: suburethral slings, suburethral sling, transobturator tape, transobturator tapes, transobturator suburethral tape, trans-obturator tape, male sling, male slings, argus sling, advance sling, invance sling, remeex sling, urinary incontinence, urinary stress incontinence, post prostatectomy, post-prostatectomy, prostatectomy, prosta tectomies, suprapubic prostatectomies, suprapubic prosta tectomy, retropubic prostatectomies, retropubic prosta tectomy. in addition, other significant studies cited in the reference lists of the selected papers were considered. both authors independently reviewed all records by title and abstract followed by full-text articles for those meeting the screening criteria. both authors independently abstracted data on study details (authors, year of publication, journal, location, study design), patient characteristics (age, figure 1. preferred reporting items for systematic reviews and meta-analyses (prisma) flow diagram. source publication journal nation patient time period rp rate patient sling type mean risk year number of surger (%) mean age follow-up of bias grise p, et al. (11) 2011 urology france 103 2007-2009 94.8 69.4 i-stop toms 12 high cornu jn, et al. (12) 2011 bju int france 136 2007-2009 92 67.4 advance 21 high cornel eb, et al. (13) 2010 j urol the netherlands 35 2007-2008 80 68.5 advance 12 high gallagher bl, et al. (14) 2007 urology usa 31 2002-2005 94 66 invance 15 high sousa-escandon a, et al. (15) 2007 eur urol spain, italy, 51 2002-2005 84.3 69 remeex 32 high greece, germany, portugal table 1. characteristics of included observational studies. 160 records identified by medline search 49 records for full text screen 5 records included in the analysis 111 removed by title abstract/screen 6 removed by full text screen cerruto_cont_stesura seveso 24/06/13 11:06 pagina 93 archivio italiano di urologia e andrologia 2013; 85, 2 m.a. cerruto, c. d'elia, w. artibani 94 ment in continence, necessitating long-term clean intermittent catheterization. the average time to removal of the sling because of infection was 99 days (range 35 to 163). all these patients presented with pain and superficial infections. in the remeex case series (15) the mesh was removed in 1 case owing to urethral erosion and the varitensor in 2 cases owing to infection. there were five (9.8%) uneventful intraoperative bladder perforations at the postoperative period, and there were three mild perineal haematomas (5.9%). most patients felt perineal discomfort or pain, which was easily treated with oral medications. conclusion the male slings approved for use currently include a variety of types: bone anchored slings, adjustable slings, and transobturator slings. this review tried to systematically assessed the outcomes of male slings used as the first line treatment, after conservative therapy failure, for the treatment of post-prostatectomy sui. only a few number of the observational studies published in the literature addressed review selection criteria. the pooled overall cure rates is high but there are no data concerning reliable preand postoperative prognostic factors affecting treatment failure and complications rates, thus it is not possible to have suitable criteria for a better patient selection. the statistically pooled results obtained should be interpreted with caution because of several limitations due to several study selection limitations: observational study design, few number of analysed studies, heterogeneity, lack of outcome definition and standardisation, between-study variability, high risk of bias. in order to better select patients for male slings in the management of post-prostatectomy sui as first line treatment, it is mandatory to carried out both well designed randomized clinical trials and longitudinal cohort studies, using standardised protocols and outcome measures. references 1. united states agency for healthcare research and quality. healthcare cost and utilization project (usa). available at: http://hcupnet.ahrq.gov/. accessed january 2012. 2. haab f, beley s, cornu jn, et al. urinary and sexual disorders following localised prostate cancer management. bull cancer. 2010; 97:1537-49. 3. schröde a, abrams p, andersson ke, et al. guidelines on urinary incontinence. in arnheim ag, editor. eau guidelines. arnheim, the netherlands: european association of urology. 2010; p.11-28. 4. campbell se, glazener cm, hunter kf, et al. conservative management for postprostatectomy urinary incontinence. cochrane database syst rev. 2012; 1:cd001843. 5. abrams p, andersson ke, birder l, et al. fourth international consultation on incontinence recommendations of the international scientific committee: evaluation and treatment of urinary incontinence, pelvic organ prolapse, and fecal incontinence. neurourol urodyn. 2010; 29:213-240. 6. imamoglu ma, tuygun c, bakirtas h, et al. the comparison of artificial urinary sphincter implantation and endourethral macroplasthe types of slings considered were: the 4-arm i-stop toms transobturator male sling (cl medical) (11) (that is an adapted version of the 2-arm toms bulbar sling) (16); the advance sling (12, 13) (a retrourethral transobturator sling working by relocating the lax and descended supporting structures of the posterior urethra and sphincter region after prostate surgery into the former preprostatectomy position (17); the invance sling (american medical system) (14) (a nonadjustable sling system characterised by a silicon-coated polyester sling positioned under the bulbar urethra via a perineal incision to obtain a compression (18); the remeex system (15) (a readjustable sling positioned under the bulbar urethra (19). figure 2 pooled the continence rates achieved after the analysed sling procedures. at a median follow-up of 15 months the pooled cure rates for all kinds of slings was 77.4% (95% ci 66.0-85.8); in the advance group the pooled cure rates was 72.5 (95% ci 65.0-68.8); in the invance group it was 74.2% (95% ci 56.3-86.5) while in the remeex group it was 84.3% (95% ci 71.6-92). these statistically pooled results should be interpreted with caution because of several limitations due to several study selection limitations: study design, number of analysed studies, betweenstudy variability, high risk of bias. concerning overall complications rate it was impossible to obtain this information. grise et al. did not report complications, such as bladder perforation, intraoperative bleeding (> 200 ml), or nerve, bowel, or vascular injury, occurred during the implant of the i-stop toms male sling, except for wounding of the corpus cavernosum in 4% of patients (11). the authors reported a successful catheter removal 48 hours after surgery in 98.9% of patients. moreover, 97.3%-100% were free of urinary tract infection at the different follow-up visits, and 96.5%-100.0% of the patients had not experienced urinary tract infection in the month before the visits. immediately after the advance implant, cornu et al. (12) reported only two cases of dysuria, one case of perineal haematoma and two cases of perineal paresthesia. during follow-up 10% of 10% of patients had perineal pain and 14% of patients had mild dysuria, but none require surgical management. in the other case series (13) complications developed in 2 patients, including sling infection and postoperative urinary retention in 1 each. in the invance group (14) 4 patients (13%) underwent sling removal; two removals were because of infection (both of these patients had undergone previous radiotherapy), one because of pain, and one because of the lack of improvefigure 2. pooled analysis of reported overall cure rates. grise p, et al. (11), 2011 cornu jn, et al. (12), 2011 cornel eb, et al. (13), 2010 gallagher bl, et al. (14), 2007 sousa-escandon a, et al. (15), 2007 cerruto_cont_stesura seveso 24/06/13 11:06 pagina 94 95archivio italiano di urologia e andrologia 2013; 85, 2 continence and complications rates after male slings as primary surgery for post-prostatectomy incontinence: a systematic review tique injection for the treatment of postprostatectomy incontinence. eur urol. 2005; 47:209-13. 7. silva la, andriolo rb, atallah an, da silva em. surgery for stress urinary incontinence due to presumed sphincter deficiency after prostate surgery. cochrane database syst rev. 2011; (4):cd008306. 8. moher d, liberati a, tetzlaf j, et al. preferred reporting items for systematic reviews and meta-analyses: the prisma statement. bmj. 2009; 339:332-336. 9. downs sh, black n. the feasibility of creating checklist for assessment of the methodological quality both randomized and non-randomized studies of health care interventions. j epidemiol community health. 1998; 52:377-384. 10. hozo sp, djubegovic b, hozo i. estimating the mean and variance from median, range and the size of the sample. bmc med res methodol. 2005; 5:13. 11. grise p, vautherin r, njinou-ngninkeu b, et al. i-stop toms transobturator male sling, a minimally invasive treatment for post-prostatectomy incontinence: continence improvement and tolerability. urology. 2012; 79:458-63. 12. cornu jn, sèbe p, ciofu c, et al. mid-term evaluation of the transobturator male sling for post-prostatectomy incontinence: focus on prognostic factors. bju int. 2011; 108:236-40. 13. cornel eb, elzevier hw, putter h. can advance transobturator sling suspension cure male urinary postoperative stress incontinence? j urol. 2010; 183:1459-63. 14. gallagher bl, dwyer nt, gaynor-krupnick dm, et al. objective and quality-of-life outcomes with bone-anchored male bulbourethral sling. urology. 2007; 69:1090-4. 15. sousa-escandón a, cabrera j, mantovani f, et al. adjustable suburethral sling (male remeex system) in the treatment of male stress urinary incontinence: a multicentric european study. eur urol. 2007; 52:1473-9. 16. grise p, geraud m, lienhart j, et al. transobturator male sling toms for the treatment of stress post-prostatectomy incontinence, initial experience and results with one year’s experience. int braz j urol. 2009; 35:706-713. 17. rehder p, gozzi c. transobturator sling suspension for male urinary incontinence including post-radical prostatectomy. eur urol. 2007; 52:860-7. 18. fassi-fehri h, bader l, cherass a, et al. efficacy of the invancetm male sling in men with stress urinary incontinence. eur urol. 2007; 51:498-503. 19. sousa-escandon a, cabrera j, mantovani f, et al. externally readjustable sling for treatment of male stress urinary incontinence: points of technique and preliminary results. j endourol. 2004; 18:113-8. correspondence maria angela cerruto, md mariaangela.cerruto@univr.it carolina d’elia, md, febu (corresponding author) karolinedelia@gmail.com walter artibani, md walter.artibani@univr.it urology clinic, department of surgery university of verona & aoui, p.le l scuro 10 37134 verona, italy cerruto_cont_stesura seveso 24/06/13 11:06 pagina 95 65archivio italiano di urologia e andrologia 2013; 85, 2 introduction the low specificity of psa test in diagnosing prostate cancer (pca), especially for serum psa values < 10 ng/ml is due to spontaneous fluctuation (1), ejaculation, bph and acute or subclinical chronic prostatitis (cp). psa levels have been correlated with the extent and degree of inflammation (2, 3) and a short trial of antibiotics for a likely subclinical cp has some theoretical advantages in decreasing psa levels (34.6-56% of the cases) (4, 5) thus minimizing the number of biopsies for falsely elevated psa (20-30% of the cases) (6, 7). the difference between pre and post-treatment psa levels appears significant only in benign conditions (bph and prostatitis cases) while in histologically proven original paper does prolonged anti-inflammatory therapy reduce number of unnecessary repeat saturation prostate biopsy? giuseppe candiano, pietro pepe, francesco pietropaolo, francesco aragona urology unit cannizzaro hospital, catania, italy. introduction. the effect of a prolonged oral anti-inflammatory therapy on psa values in patients with persistent abnormal psa values after negative prostate biopsy (pbx) was evaluated. material and methods. from september 2011 to september 2012, 70 patients (median age 62 years), with persistent abnormal psa values after negative extended pbx, were given an herbal extract with anti-inflammatory activity for 3 months (lenidase®; 1 tablet daily constituted of baicalina, bromelina and escina). all patients were submitted to prostate biopsy for: abnormal dre; psa > 10 ng/ml, psa values between 4.1-10 or 2.6-4 ng/ml with free/total psa < 25% and < 20%, respectively. three months after the end of anti-inflammatory therapy all patients were revaluated; indication for repeat saturation biopsy (spbx) and detection rate for pca were compared with those previously recorded in our department using the same inclusions criteria for biopsy. results. oral administration of lenidase® was well tolerated and no side effects were observed; psa values decreased in 54 (77.8%) out 70 patients with a median psa reduction of 20.5% (from 8.8 to 7 ng/ml) and remained unchanged in 16 patients (22.2%); the repeat spbx rate resulted significantly lower (22.8% vs 35.5%; p < 0.05) showing a superimposable detection rate for pca (3 cases) in comparison with our previous data (18.7% vs 22%). conclusions. in our preliminary data a prolonged oral anti-inflammatory therapy reduced psa levels in patients with negative pbx and persistent suspicious for pca decreasing the indication to perform repeat spbx (about 30% of the cases). key words: prostate cancer; repeat saturation biopsy; prostatitis; psa; anti-inflammatory therapy. submitted 24 september 2012; accepted 31 december 2012 no conflict of interest declared summary cancer the difference seems unremarkable (8). at the same time, the administration of nonsteroidal antiinflammatory drugs (nsaids) or aspirin, blocking the cyclooxygenase (cox) activity (a strong mediator of inflammation), could have a potential role in decreasing psa values. however, the relationship between oral nsaids consumption, psa levels and pca risk is unknown (9). in this prospective study we evaluated, in patients with negative extended prostate biopsy and persistent abnormal psa values, the effect of a prolonged oral antiinflammatory therapy on psa values in order to reduce the number of unnecessary repeat biopsies. candiano_stesura seveso 24/06/13 10:59 pagina 65 archivio italiano di urologia e andrologia 2013; 85, 2 g. candiano, p. pepe, f. pietropaolo, f. aragona 66 ously recorded in our department using the same inclusions criteria for biopsy. finally, a p value < 0.05 was considered statistically significant. results oral administration of lenidase® was well tolerated and no side effects were observed. among 70 patients enrolled, psa values decreased after anti-inflammatory therapy in 54 (77.8%) with a median psa reduction of 20.5% (from 8.8 to 7 ng/ml) and remained unchanged in the remaining 16 patients (22.2%). clinical parameters and serum exams before and after lenidase® administration are listed in table 1. all 16 patients whose psa did not decrease after therapy underwent repeat spbx (6 had a psa included between 4-10 ng/ml and 10 greater than 10 ng/ml) and in 3 of them a cancer was found (all these men had one previous negative biopsy and a psa > 10 ng/ml). the incidence of repeat biopsy in the patients submitted to anti-inflammatory therapy resulted significantly lower in comparison with our previous data (22.8% vs 35.5%) (p < 0.05), respectively; on the contrary, the detection rate for pca was superimposable (18.7% vs 22%) at repeat spbx. ipss and qmax values were superimposable before and after anti-inflammatory therapy (p > 0.05) (table 1). discussion repeat prostate biopsy constitutes about 30% of all the procedures with an estimated detection rate for pca equal, in our experience, to 20% and 6% at second and third spbx (10), respectively; today, the main goal of any early diagnosis protocol should be to reduce the number of unnecessary spbx due to false positive psa levels. the intra-individual (physiological) variation of psa in men with benign prostate biopsy is equal to 9.5% (12); moreover, many common medications have an effect on serum psa levels: nsaids, thiazide diuretics and statins reduce psa levels from 6% to 26% and the combination of statins with thiazide diuretics could decrease psa levmaterial and methods from september 2011 to september 2012, 70 patients (median age 62 years; range: 49-72 years), with previous negative extended prostate biopsy and persistent abnormal psa values, were given an herbal extract with antiinflammatory activity (lenidase®, 1 tablet daily) for 3 months. all patients, 2 months before assuming the herbal extract, underwent prostate biopsy for: abnormal digital rectal examination (dre); psa > 10 ng/ml, psa values between 4.1-10 or 2.6-4 ng/ml with free/total psa < 25% and < 20%, respectively according to our early diagnosis protocol (10). the biopsy was performed by transperineal approach using a 18 g tru-cut needle guided by a 5-6.5 mhz biplanar transrectal probe (ge logiq 500 pro). in case of primary biopsy or repeat saturation biopsy (spbx) a median of 18 (range 16-21) and 28 cores (range 26-35) were taken, respectively. the biopsy protocol included a median of 9-12 cores in the posterior zone of each lobe (apex, med and base) plus 2-4 cores on the transition zone in case of spbx (11). the procedure was performed under sedation and antibiotic prophylaxis. all patients had negative dre and no-one was symptomatic for acute prostatitis. patients with previous hgpin or asap were not included; moreover, all patients signed an informed consent form. clinical parameters of the patients enrolled in the protocol are listed in table 1; 37 (52.8%), 18 (25.7%) and 15 (22.5%) men previously underwent one, two and three negative biopsies, respectively. fifty-eight (64.5%) patients assumed alpha-blockers; none were currently treated with nsaids, aspirin, thiazide diuretic, statins, and 5-alfa-reductase inhibitors. at the end of the 3months course of therapy and after additional 3 months of wash-out, all patients were revaluated with dre, total psa, psa f/t and routine blood test for liver and kidney function. international prostate symptoms score (ipss) and qmax before and after anti-inflammatory therapy were recorded. the patients with persistent suspicious for pca underwent spbx. the repeat spbx rate after anti-inflammatory therapy and detection rate for pca were compared with those previ70 patients baseline after therapy % of reduction p value median psa (ng/ml) 8.8 (range: 4.6-28) 7 (range: 2.9-23) 20.5 < 0.05 decreased psa levels 54 77.2 < 0.05 psa > 10 14 10 28.5 < 0.05 psa 4-10 54 40 26.0 < 0.05 psa < 4 0 20 28.5 < 0.05 ipss (range) 13 (4-26) 12 (5-24) > 0.05 low (0-7) 36 38 > 0.05 intermediate (8-19) 25 23 > 0.05 severe (20-37) 9 9 > 0.05 qmax 11 ml/sec 12 ml/sec > 0.05 urine test negative negative blood test normal normal table 1. clinical parameters at baseline and 6 months after anti-inflammatory therapy. candiano_stesura seveso 24/06/13 10:59 pagina 66 67archivio italiano di urologia e andrologia 2013; 85, 2 does prolonged anti-inflammatory therapy reduce number of unnecessary repeat saturation prostate biopsy? anti-inflammatory therapy reduced psa levels in selected patients (negative prostate biopsy and persistent elevated psa values) decreasing the indication to perform repeat spbx (about 30% of the cases). references 1. nixon rg, lilly jd, liedtke rj, batjer jd. variation of free and total psa levels: the effect on the percent free/total prostate antigen. arch pathol lab med. 1997; 121:385-91. 2. yaman o, gogus c, tulunay o, et al. increased psa in subclinical prostatitis: the role of aggressiveness and extension of inflammation. urol int. 2003; 71:160-164. 3. kandirali e, boran c, serin e. association of extent and aggressiveness of inflammation with serum psa levels and psa density in asymptomatic patients. urology. 2007; 70:743-747. 2. hochreiter ww. the issue of prostate cancer evaluation in men with elevated psa and chronic prostatitis. andrologia. 2008; 40:130-133. 3. stopiglia rm, ferreira u, silva mm, et al. psa decrease and prostate cancer diagnosis: antibiotic versus placebo. prospective randomized clinical trial. j urol. 2010; 183:940-944. 4. magri v, trinchieri a, montanari e, et al. reduction of psa values by combination pharmacological therapy in patients with chronic prostatitis: implications for prostate cancer detection. arch it urol androl. 2007; 79:84-92. 5. serretta v, catanese a, daricello g, et al. psa reduction (after antibiotics) permits to avoid or postpone prostate biopsy in selected patients. prostate cancer prostatic diseases. 2008; 11:148-152. 6. schaeffer aj, wu sc, tennenberg am, kahn jb. treatment of chronic bacterial prostatitis with levofloxacin and ciprofloxacin lowers serum psa. j urol. 2005; 174:161-164. 7. terrone c, poggio m, bollito e, et al. asymptomatic prostatitis: a frequent cause of raising psa. rec prog med. 2005; 96:365-369. 8. erol h, beder n, caliskan t, et al. can the effect of antibiotic therapy and anti-inflammatory therapy on serum psa levels discriminate between benign and malign prostatic pathologies? urol int. 2006; 76:20-26. 9. murad as, down l, davey smith g, et al. associations of aspirin, nonsteroidal-antiflammatory drug and paracetamol use with psadetected prostate cancer: findings from a large, population-based, casecontrol study (the protect study). int j cancer. 2011; 128:1442-48. 10. pepe p, aragona f. incidence of insignificant prostate cancer using free/total psa: results of a case-finding protocol on 14,453 patients. prostate cancer prostatic diseases. 2010; 13:316-319. 11. pepe p, aragona f. saturation prostate needle biopsy and prostate cancer detection at initial and repeat evaluation. urology. 2007; 70:1131-1135. 12. boddy jl, dev s, pike dj, malone pr. intra-individual variation of serum psa levels in men with benign prostate biopsies. bju int. 2004; 93:735-38. 13. nieder c, norum j, geinitz h. impact of common medications on serum total psa levels and risk group assignment in patients with prostate cancer. anticancer research. 2011; 31:1735-39. 14. steven l. chang, lauren c. harshman, and joseph c. presti jr: impact of common medications on serum total psa levels: analysis of the national health and nutrition examination survey j clin oncol. 2010; 28:3951-3957. 15. nieder c, norum j, geinitz h. impact of common medications els of 36% after 5 years of combined therapy (13-15). prostatitis is responsible for falsely elevated psa levels, but it remains unclear in which patients we can avoid repeat biopsy without underestimating the risk of cancer (16). singer et al. (17) in 1319 men aged > 40 years observed that psa levels were 24% lower among acetaminophen users compared with non drug takers. several systematic reviews have examined the relationship between nsaid/aspirin consumption and the risk of developing pca. mahmud et al. (18) in a meta-analysis found that aspirin use provided a 10% risk reduction for pca and a 30% risk reduction for advanced disease. harris et al. (19) and jacobs et al. (20) reported that daily nsaid use (including aspirin) was associated with a 39% and 20% risk reduction for pca, respectively. engelhardt and rjedl (21) reported in 20 patients, assuming a daily dose (60 mg) of an isoflavone extract for 1 year, a psa reduction of 33% combined with a significant increase in hepatic transaminases. all these studies agree that the reduction in psa levels due to anti-inflammatory therapy may reduce the number of men referred for prostate biopsy decreasing the number of men diagnosed with pca. however, a clear correlation between nsaids, serum psa and risk of missing a pca diagnosis is still unknown (16). in our study, we used as anti-inflammatory agent a mixture of herbal extract (lenidase®) which has a demonstrated antiedematous and anti-inflammatory activity. each tablet contains: baicalina (190 mg), a flavonoid from scutellaria baicalensis that inhibits 5-lipoxygenase (5-lox) and cox activities and leukotriene synthesis (22-24); bromelina (50 mg), extract from ananas comosus, that is an enzymatic anti-inflammatory agent and escina (30 mg), extract from aesculus hyppocastanum, that has an antiedemigenous effect and enhances corticosteroid receptors activity. a median psa reduction of about 20% was observed in 54/70 (77.2%) patients assuming lenidase®. in details, 15 (28.5%) men reached a psa value < 4 ng/ml and the repeat spbx rate resulted significantly lower in comparison with our previous data (22.8% vs 35.5%; p < 0.05) showing a superimposable detection rate for cancer (18.7% vs 22%). therefore, the significantly reduction of psa levels in comparison with physiological psa fluctuations (12) and the absence of reliable criteria to select patients at risk for pca seems to suggest a prolonged trial of anti-inflammatory therapy before taking any decision in patients with negative prostate biopsy and persistently elevated psa levels. our results deserve some considerations. firstly, the absence of a placebo control group; for our purpose, we used as a surrogate our previously recorded cases. secondly, it is unknown if psa reduction is uniquely secondary to the anti-inflammatory activity or is in some way influenced by anti-proliferative effects of baicalina (25); thirdly, pca incidence is available only in patients whose psa levels remained unchanged after anti-inflammatory trial (the risk of missing pca diagnosis in men with decreased psa is actually unknown). finally, a greater number of patients and a longer follow up are necessary to confirm our results. in conclusion, in our preliminary data a prolonged oral candiano_stesura seveso 24/06/13 10:59 pagina 67 archivio italiano di urologia e andrologia 2013; 85, 2 g. candiano, p. pepe, f. pietropaolo, f. aragona 68 on serum total psa levels and risk group assignment in patients with prostate cancer. anticancer res. 2011; 31:1735-39. 16. platz ea, rohrmann s, pearson jd, et al. nonsteroidal antiinflammatory drugs and risk of prostate cancer in the baltimore longitudinal study of aging. cancer epidemiol biomarkers prev. 2005; 14:390-396. 17. singer ea, palapattu gs, van wijngaarden e. psa levels in relation to consumption of nonsteroidal anti-inflammatory drugs and acetaminophen: results from the 2001-2002 national health and nutrition examination survey. cancer. 2008; 113:2053-7. 18. mahmud s, franco e, aprikian a. prostate cancer and use of nonsteroidal anti-inflammatory drugs: systematic review and metaanalysis. br j cancer. 2004; 90:93-99. 19. harris re, beebe-donk j, doss h, burr doss d. aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs in cancer prevention: a critical review of nonselective cox-2 blockade. oncol rep. 2005; 13:559-583. 20. jacobs ej, thun mj, bain eb, et al. a large cohort study of longterm daily use of adult-strength aspirin and cancer incidence. j natl cancer inst. 2007; 99:608-615. 21. engelhardt pf, rjedl cr. effects of one-year treatment with isoflavone extract from red clover on prostate, liver function, sexual function, and quality of life in men with elevated psa levels and negative prostate biopsy findings. urology. 2008; 71:185-90. 22. burnett bp, jia q, zhao y, levy rm. a medical extract of scutellaria baicalensis and acacia catechu acts as dual inhibitor of ciclooxygenase to reduce inflammation. journal of medical food. 2007; 442-451. 23. lixuan z, jingcheng d, wengin y, et al. baicalin attenuates inflammation by inhibiting nf-kappab activation in cigarette smoke induced inflammatory models. pulm pharmacol ther. 2010; 23:411-19. 24. li c, lin g, zuo z. pharmacological effects and pharmacokinetics properties of radix scutellariae and its bioactive flavones. biopharm drug dispos. 2011; 32:427-45. 25. marks ls, dipaola rs, nelson p, et al. herbal formulation for prostate cancer. urology. 2002; 60:369-75. correspondence giuseppe candiano, md pietro pepe, md (corresponding author) piepepe@hotmail.com francesco pietropaolo, md francesco aragona, md urology unit cannizzaro hospital, via messina 829 catania, italy candiano_stesura seveso 24/06/13 10:59 pagina 68 stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 letter to editor key words: bladder cancer, nmibc, laser, cystoscopy. submitted 18 january 2023; accepted 21 january 2023 to the editor, bladder cancer (bca) is the second most common cancer in urological clinical practice, after prostate adenocarcinoma. usually occurs in patients between 60 and 70 years old, three times more frequently in men than women (1, 2). about 75% of bladder cancer are pta or pt1 (3), even more frequently considering a population younger than 40 years old. early detection is of paramount importance since allows to find tumors when they are still superficial and therefore with a better prognosis. management of non muscle invasive bladder cancer (nmibc) accordingly to eau guidelines (4), is based on intravesical chemotherapy and endourological procedures (transurethral resection of bladder cancer), which requires operating theater, anesthesiologic assistance, scrub nurses and dedicated instruments (5, 6). trans urethral resection of the bladder tumor (turbt) is the gold standard in the treatment of nmibc accordingly to the literature and it is in fact a mature procedure with a standardized technique, but it is still facing some challenges and risks such as difficult control of cutting depth, stimulation of the obturator nerve, bladder perforation and iliac vascular injury (7). for these reasons, it is interesting to study how other technologies are growing and how we could use them in this so frequent and ubiquitarian disease management. in particular, recently there is a great interest in transurethral laser surgery and especially regarding its comparison to standard turbt. some studies showed similar results in both oncological and safeness terms (8-12). the en bloc laser techniques might allow a clearer cut of the tumor base, simplifying pathologist reading of the surgical samples (13). furthermore, bca has a 1and 5-year recurrence rates that can be very high, and several patients require additional turbt during follow-up (4, 14). one of the recent problems of healthcare organizations is to address the current shortage of operating theater resources, reducing costs, while guaranteeing the best possible treatment for the patients. from this point of view, the possibility to treat some carefully selected bca recurrences patients with on an outpatient basis would represent an important saving in both economic and organizational terms, reducing hospitalization and discomfort for the patient and his family. according to these pressing needs, we present our experience of an innovative outpatient laser treatment (“tula dual”) in a bca relapsed patient. we highlight the case of an 85 years-old woman in follow-up over the previous five years for nmibc (urothelial bladder cancer, pta lg). she was ineligible for standard turbt because of age and several comorbidities which led to an asa iv score. she was taking medical therapy for atrial fibrillation (anticoagulation therapy), hypertension and diabetes mellitus, added to recurring episodes of hematuria. during a follow up cystoscopy were endoscopically detected over 20 lesions highly suspected for bca recurrence. the lesions were pink, papillary and typically aspect of non-muscle invasive lesions. the most of these lesions were millimetric, three of these had a plant base of about one centimeter. a recent urinary cytology was negative for high grade bca while a kidney-ureters-bladder ultrasound didn’t show hydronephrosis or further suspicious findings. in this situation we should have organized an operating theater to perform a turb, suspending the anticoagulation therapy; but instead, considering the anamnesis and the clinical condition, we decided accordingly to the patient to perform the tula dual procedure. the tula dual is an endoscopic procedure, executed with a dual laser (diode laser technology 980-1470 wave length) in local anesthesia or even without it, in an ambulatory setting. it allows the contemporary vaporization and hemostasis of tissues. patients are summoned in ambulatory, where is administered a one-shoot antibiotic prophylaxis according to current guidelines for endoscopic operative procedures such as turbt (15). tula dual: trans urethral laser ablation of recurrent bladder tumors in outpatient setting rosario leonardi 1, francesco vecco 2, 3, gabriele iacona 1, alessandro calarco 4, guglielmo mantica 2, 3 1 musumeci gecas clinic, gravina di catania (ct), italy; 2 irccs ospedale policlinico san martino, genova, italy; 3 department of surgical and diagnostic integrated sciences (disc), university of genova, genova, italy; 4 department of urology, "cristo re" hospital, rome, italy. doi: 10.4081/aiua.2023.11171 archivio italiano di urologia e andrologia 2023; 95, 1 r. leonardi, f. vecco, g. iacona, a. calarco, g. mantica in women such as this patient, we perform a bladder intravesical instillation with saline solution (50 ml) plus one lidocaine 2% vial for 15 minutes; in men we add also lidocainebased gel left in the urethra. it is necessary to empty the bladder before the beginning of the procedure. the tula is performed using a flexible cystoscopy with a 320 micron fiber and the dual laser (figure 1). the power of laser, and, the use of a single wave lentgh or a mixed wave lentgh, is based on volume of lesion/s. we usually use the single wavelength of 1470 nm set at 3 watts of power for small lesions while, for bigger lesions, we prefer to mix the wavelength of 980nm set at 5 watts of power plus the wavelength 1470nm set at 3 watts of power. the above described patient underwent a 20 minutes procedure in the endoscopy room, no operative theatre, no general o spinal anesthesia, no bladder catheter after procedure or preoperative exams. she didn’t complain any pain or discomfort during the procedure and neither intraoperative nor postoperative complications occurred. the patient only reported a minimal hematuria which disappeared in the first postoperative day. no disease recurrences were detected at the 3-months cystoscopic follow-up. the tula dual is a brand-new procedure that might be indicated during follow-up of nmibc selected patients, or for radiotherapy-related cystitis. the category of patients who could benefit the most by this outpatient laser alternative to turbt are those who are not fit for conventional treatments under anesthesia because of multiple comorbidities or anticoagulant/antiaggregant drugs assumption. considering the high frequency of bladder cancer, having the possibility of following up patients, managing them, even the ones who are not eligible for endoscopic surgery, and simultaneously lowering costs is surely a great deal that this treatment offers. because of the non-necessity of operating room this technique is even more interesting, especially after covid pandemic that still cost everybody a great demand of theatres and delays (16). bladder cancer has been estimated as the most expensive cancer to health care systems. the average expense for patient is currently more than $100.000 and more than 70% of this is due to the cost of repeated turbts (17-18). these prices could be dramatically reduced if patients were managed in the office setting. in fact, office-based laser vaporization might allow to save more than 50% of the estimated cost. the fundamental factor to determine the suitability of office-based management of nmibc is the correct identification of eligible patients that should be those at lower risk of progression and at higher risk of intraand post-operative complications if undergone turbt. some authors already evaluated office-based procedures for the management of nmibc with retrospective data (19). donat et al. (20) described successful management of nmibc with no recurrence within 6 months. all tumors were smaller than 0.5 cm, with a negative urine cytology. the risk of progression in this group was approximately 8%. recently, pedersen et al. (21) evaluated in a prospective study the office-based photocoagulation of bladder tumor. they found the first procedure to be non-inferior of turbt in terms of progression rate and complications. the 98% of patients declared to prefer the photocoagulation. studies are needed in order to determine results of office-based procedures and in particular of tula dual, both in terms of relapse and progression compared to turbt. elderly patients such as our, with multiple morbidities are often not fit for conventional treatment under general anesthesia. tula dual offers a technique using flexible cystoscopy for the treatment of bladder tumor under local or even no anesthesia in outpatient settings. references 1. kirkali z, chan t, manoharan m, et al. bladder cancer: epidemiology, staging and grading, and diagnosis. urology. 2005; 66:4-34. 2. malinaric r, mantica g, balzarini f, et al. extraperitoneal cystectomy with ureterocutaneostomy derivation in fragile patients should it be performed more often? arch ital urol androl. 2022; 94:144-149. 3. maffezzini m, fontana v, pacchetti a, et al. age above 70 years and charlson comorbidity index higher than 3 are associated with reduced survival probabilities after radical cystectomy for bladder cancer. data from a contemporary series of 334 consecutive patients. arch ital urol androl. 2021; 93:15-20. 4. eau guidelines on non-muscle-invasive bladder cancer diagnosis uroweb. accessed september 14, 2022. https://uroweb.org/guidelines/non-muscle-invasive-bladder-cancer/chapter/diagnosis 5. malmström pu, sylvester rj, crawford de, et al. an individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin c versus bacillus calmette-guérin for non-muscle-invasive bladder cancer. eur urol. 2009; 56:247-256. figure 1. intraoperative pictures showing office-based laser management of nmibc. archivio italiano di urologia e andrologia 2023; 95, 1 laser technique for bladder cancer treatment 6. shelley md, kynaston h, court j, et al. a systematic review of intravesical bacillus calmette-guérin plus transurethral resection vs transurethral resection alone in ta and t1 bladder cancer. bju int. 2001; 88:209-216. 7. gregg jr, mccormick b, wang l, et al. short term complications from transurethral resection of bladder tumor. can j urol. 2016; 23:8198203. 8. chen j, zhao y, wang s, et al. green-light laser en bloc resection for primary non-muscle-invasive bladder tumor versus transurethral electroresection: a prospective, nonrandomized two-center trial with 36-month follow-up. lasers surg med. 2016; 48:859-865. 9. zhang xr, feng c, zhu wd, et al. two micrometer continuous-wave thulium laser treating primary non-muscle-invasive bladder cancer: is it feasible? a randomized prospective study. photomed laser surg. 2015; 33:517-523. 10. xu y, guan w, chen w, et al. comparing the treatment outcomes of potassium-titanyl-phosphate laser vaporization and transurethral electroresection for primary nonmuscle-invasive bladder cancer: a prospective, randomized study. lasers surg med. 2015; 47:306-311. 11. chen x, liao j, chen l, et al. en bloc transurethral resection with 2-micron continuous-wave laser for primary non-muscle-invasive bladder cancer: a randomized controlled trial. world j urol. 2015; 33:989-995. 12. yu j, zheng j. comparative efficacy and safety of transurethral laser surgery with holmium laser, ktp laser, 2-micron laser or thulium laser for the treatment of non-muscle invasive bladder carcinoma: a protocol of network meta-analysis. bmj open. 2021; 11:e055840 13. leonardi r, calarco a, falcone l, et al. endoscopic laser en bloc removal of bladder tumor. surgical radicality and improvement of the pathological diagnostic accuracy. arch ital urol androl. 2022; 94:134-137. 14. sawazaki h, arai y, ito y, et al. expression of l-type amino acid transporter 1 is a predictive biomarker of intravesical recurrence in patients with non-muscle invasive bladder cancer. res rep urol. 2021; 13:603-611. 15. eau guidelines 2022 on urological infections. edn. presented at the eau annual congress amsterdam, the netherlands 2022. isbn 97894-92671-16-5. 16. leonardi r, bellinzoni p, broglia l, et al. hospital care in departments defined as covid-free: a proposal for a safe hospitalization protecting healthcare professionals and patients not affected by covid-19. arch ital urol androl. 2020; 92:67-72. 17. botteman mf, pashos cl, redaelli a, et al. the health economics of bladder cancer: a comprehensive review of the published literature. pharmacoeconomics. 2003; 21:1315-30. 18. meeks jj, herr hw. office-based management of nonmuscle invasive bladder cancer. urol clin north am. 2013; 40:473-9. 19. o'neil bb, lowrance wt. office-based bladder tumor fulguration and surveillance: indications and techniques. urol clin north am. 2013; 40:175-82. 20. donat sm, north a, dalbagni g, herr hw. efficacy of office fulguration for recurrent low grade papillary bladder tumors less than 0.5 cm. j urol. 2004; 171:636-9. 21. pedersen gl, erikson ms, mogensen k, et al. outpatient photodynamic diagnosis-guided laser destruction of bladder tumors is as good as conventional inpatient photodynamic diagnosis-guided transurethral tumor resection in patients with recurrent intermediate-risk lowgrade ta bladder tumors. a prospective randomized noninferiority clinical trial. eur urol. 2022:s0302-2838(22)02564-7. correspondence rosario leonardi, md (corresponding author) leonardi.r@tiscali.it musumeci gecas clinic, v.le dell'autonomia, 57, 95030 gravina di catania (ct) (italy) francesco vecco, md francesco.vecco@gmail.com irccs ospedale policlinico san martino, genova (italy) gabriele iacona, md gabryiac@yahoo.it musumeci gecas clinic, gravina di catania (ct)(italy) alessandro calarco, md alecalarco@gmail.com department of urology, "cristo re" hospital, rome (italy) guglielmo mantica, md guglielmo.mantica@gmail.com irccs ospedale policlinico san martino, genova (italy) conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 95 original paper progression, intravesical bacillus calmette-guérin (bcg) is the gold standard adjuvant therapy (4). the use of intravesical instillation of bcg for high risk nmibc demonstrates a role for immunotherapy in uc. bcg, originally used as a vaccine against tuberculosis (tb), contains live-attenuated mycobacterium bovis (4). the specific mechanism of bcg in nmibc treatment continues to be studied, however, its role is attributed to both local immunological efforts and systemic immune responses (5). some work has suggested that bcg vaccination may be associated with a lower rate of bladder cancer incidence (6). despite this relationship, research on bcg immunization as a possible predictive factor in nmibc has been limited. in the present study, we evaluated the relationship between history of infantile bcg vaccination with the depth of invasion and the grade in patients with nmibc. methods data were retrospectively collected between 2017 and 2022. inclusion criteria included all patients with a new diagnosis of nmibc at the thunder bay regional health sciences centre (tbrhsc), for whom complete clinical, lab, and pathological data could be retrieved. data collected included the history of infantile bcg as well as the patients’ age, sex, comorbid status, cbc, vaccination, history of intravesical bcg instillation, pathological data, recurrence, and progression. vaccination status was correlated with these variables. institutional ethical approval was obtained from the tbrhsc research ethics board (rp741). correlations between continuous variables were done using student’s t-test. categorical variables were compared using fisher exact test. a p-value of < 0.05 was used to define significance. results a total of 188 patients met the inclusion criteria for our study. no patients were lost to follow up. the mean follow-up time was 26 ± 7 months. of the 188 individuals meeting the eligibility criteria, 113 individuals had received the infantile bcg immunization and 75 did not. objective: to evaluate the utility of infantile bcg vaccination history in predicting stage and grade of tumours in non-muscle invasive bladder cancer (nmibc). materials and methods: we retrospectively analyzed data from patients from a single center who were diagnosed with new nmibc and underwent transurethral resection of bladder tumour (turbt) between 2017 and 2022. we assessed bcg immunization status with various demographics and comorbidities, as well as tumour recurrence, progression, stage, and grade. results: a total of 188 patients met the inclusion criteria for our study. the mean age of patients at the time of diagnosis was significantly lower in those that had been immunized with bcg (71 ± 9) than those who had not (77 ± 10) (p < 0.0001). history of bcg immunization did not correlate with sex, history of diabetes mellitus (dm), prior history of intravesical bcg treatment, and tumour recurrence, progression, stage, and grade. conclusions: history of infantile bcg vaccination did not correlate with the depth of invasion and/or the grade in patients with non-muscle invasive bladder cancer. patients that received infantile bcg vaccination were significantly younger at the time of diagnosis of nmibc. key words: bcg; non-muscle invasive bladder cancer (nmibt); bladder cancer. submitted 11 april 2023; accepted 26 may 2023 introduction bladder cancer is the tenth most common malignancy worldwide, with increasing incidence, particularly in developed nations (1). approximately 80% of bladder cancers arise in individuals aged 65 or older with the mean age being 73 years old (2, 3). this is thought to reflect a disease process requiring many decades of development following exposure to risk factors, such as tobacco (2). urothelial carcinoma (uc) accounts for 90% of bladder cancers (4). at the time of presentation, approximately 70% of uc cases are non-muscle invasive (nmibc), while 30% are muscle invasive (mibc) (4). initial management of nmibc is transurethral resection of bladder tumor (turbt) (4). for those with nmibc who are deemed to be at high risk for history of infantile bcg immunization did not predict lamina propria invasion and/or high-grade in patients with non-muscle invasive bladder cancer anastasia macdonald 1, vahid mehrnoush 1, asmaa ismail 1, livio di matteo 2, ahmed zakaria 1, waleed shabana 1, ashraf shaban 1, mohammed bassuony 1, hazem elmansy 1, walid shahrour 1, owen prowse 1, ahmed kotb 1 1 northern ontario school of medicine, thunder bay, on, canada; 2 department of economics, lakehead university, thunder bay, on, canada. doi: 10.4081/aiua.2023.11380 summary archivio italiano di urologia e andrologia 2023; 95, 2 a. macdonald, v. mehrnoush, a. ismail, et al. 96 a statistically significant difference was identified between the age of individuals who had received the immunization and those who did not (p < 0.0001). the mean age at the time of diagnosis for those immunized was 71 ± 9 years, and 77 ± 10 in the non-immunized group. there was no statistically significant difference found between immunization status and other patient characteristics including sex, history of diabetes mellitus (dm), or history of intravesical bcg treatment. history of immunization did not correspond with tumour recurrence, progression, stage, or grade in this population. the results are summarized in table 1. discussion studies assessing the relationship between nmibc and bcg immunization have been limited. one scoping literature review identified a 35-37% lower age-standardized rate of bladder cancer incidence in individuals with bcg immunizations, suggesting an association between the two (6). we demonstrated that bcg immunization did not correlate with tumour characteristics in nmibc, including stage, grade, and risk stratification. this may be explained by the routes of administration and subsequent immune responses elicited. the anti-tumour activity of intravesical bcg therapy is attributed to non-specific immune mechanisms related to the direct interaction with urothelial cells, as well as a contribution of systemic immune response, though specific mechanisms have yet to be fully elucidated (7). bcg immunization is also associated with non-specific immune mechanisms that provide protection against tuberculosis, however, given the nature of vaccinations, this response is exclusively systemic (8). interestingly, this generalized immune response from immunization has been shown to confer protection against other respiratory infections through a mechanism referred to as trained immunity (ti) (8, 9). it was demonstrated that bcg immunotherapy in nmibc patients induced ti and provided protection against respiratory infections (9). this suggests that intravesical bcg therapy can produce similar systemic immune responses as the bcg vaccination. given that our data demonstrated that immunization status did not impact the tumour progression characteristics and risk stratification, this may suggest increased importance in the role of the local immune response in intravesical bcg in preventing the progression of nmibc. our findings may also be explained by the waning protection from immunization over time. while bladder cancer incidence increases in the elderly (10), individuals immunized with bcg are typically immunized as infants. it has been well documented that protection from this immunization against tb infections wanes over time (7). studies have identified that a positive purified protein derivative (ppd) skin test, an indication of bcg immunity, was associated with a better response to intravesical bcg therapy than those with a negative reaction (11, 12). niwa et al. (2017) demonstrated that the recurrence-free survival (rfs) in patients with a slightly positive or negative ppd skin test reaction was significantly diminished compared to the rfs in those with a strongly positive response. this may suggest that a reduced immune response from bcg immunization does not generate the same benefit in bcg treatment. given that the mean age of those vaccinated with bcg in our study was 71 years, and our study specifically looked at infantile bcg immunization, this may also explain why individuals with waning immunity from remote immunization did not influence tumour characteristics or risk stratification in patients with nmibc. in our study, the mean age of patients diagnosed with new nmibc was significantly lower in individuals who received the infantile bcg vaccination (71 ± 9) compared to those who did not (77 ± 10) (p < 0.0001). increased age is a risk factor for developing uc, largely attributed to a disease course that develops decades after exposure to risk factors (2). countries with the lowest incidence of bladder cancer are typically those found to be below average on the human development index (hdi), which may be attributable to less industrial chemical exposure and access to tobacco, major risk factors for uc (1). interestingly, such countries tend to have a higher incidence of tuberculosis and subsequently higher rates of infantile bcg immunization (13). this may imply that non-immunized individuals were likely raised in countries with low tb incidence, yet above-average hdi. such individuals would likely have had a higher risk of exposure to industrial chemicals and tobacco, leading to the slow development of bladder cancer and presentation at a later age. those immunized and likely raised in countries with less exposure to common risk factors may have developed uc earlier on due to other reasons, such as genetics, diets, or other lifestyle factors. older age at presentation has been shown to be a poor prognostic factor in nmibc (4). consequently, the older age of presentation with nmibc in non-immunized individuals poses a significant healthcare concern. the incidence of bladder cancer has been steadily increasing, particularly in developed countries (1). such countries do not tend to implement routine immunization against tb table 1. correlation of clinical and tumour data with history of infantile bcg immunization. no infantile bcg infantile bcg p value age (mean + sd) 77 + 10 71 + 9 0.0001 sex males 60 77 0.09 females 15 36 recurrence no 34 57 0.5 yes 41 56 progression no 72 108 1 yes 3 5 intravesical bcg no 44 68 0.9 yes 31 45 dm no 61 86 0.5 yes 14 27 stage ta 58 86 1 t1 17 27 grade low 54 81 1 high 21 32 sd: standard deviation. bcg: bacillus calmette–guérin. dm: diabetes mellitus. archivio italiano di urologia e andrologia 2023; 95, 2 97 infantile bcg vaccination in patients with nmibc given the low incidence. consequently, there is a growing population of non-immunized individuals presenting with nmibc and potentially at older ages. this may result in overall more complicated patients with poorer prognostics. further research in this area would be of utility given the growing aging population and potentially increased demands on healthcare systems. there are several limitations to our study. first, it is a retrospective study completed at a single center. therefore, selection bias was inevitable, and our study represents a relatively small sample size of patients. this study also limited by the relatively short follow up period (26 + 7 months) for assessing recurrence and progression. additionally, we did not account for the various demographic factors that may influence the risk factors for developing nmibc. conclusions infantile bcg immunization was not associated with higher risk stratification in patients with nmibt. the mean age of patients diagnosed with nmibc was significantly lower in patients who received the infantile bcg vaccination. references 1. bray f, ferlay j, soerjomataram i, et al. global cancer statistics 2018: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries ca cancer j clin. 2018; 68:394. 2. mushtaq j, thurairaja r, nair, r. bladder cancer surgery (oxf). 2019; 37:529. 3. siegel rl, miller kd, jemal a. cancer statistics, 2019 ca cancer j clin. 2019; 69:7. 4. saginala k, barsouk a, aluru js, et al. epidemiology of bladder cancer med sci. 2020; 8:15. 5. taniguchi k, koga s, nishikido m, et al. systemic immune response after intravesical instillation of bacille calmette-guérin (bcg) for superficial bladder cancer clin exp immunol. 1999; 115:131. 6. trigo s, gonzalez k, di matteo l, et al. bacillus calmette-guerin vaccine and bladder cancer incidence: scoping literature review and preliminary analysis arch ital urol. 2021; 93:1. 7. mukherjee n, julián e, torrelles jb, svatek rs. effects of mycobacterium bovis calmette et guérin (bcg) in oncotherapy: bladder cancer and beyond vaccine. 2021; 39:7332. 8.covián c, fernández-fierro a, retamal-díaz a, et al. bcginduced cross-protection and development of trained immunity: implication for vaccine design front immunol. 2019; 10:2806. 9. van puffelen j h, novakovic b, van emst l, et al. intravesical bcg in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infections j immunother cancer. 2023; 11:e005518. 10. martinez l, cords o, liu q, et al. infant bcg vaccination and risk of pulmonary and extrapulmonary tuberculosis throughout the life course: a systematic review and individual participant data metaanalysis lancet glob health. 2022: 10:e1307. 11. niwa n, kikuchi e, matsumoto k, et al. purified protein derivative skin test reactions are associated with clinical outcomes of patients with nonmuscle invasive bladder cancer treated with induction bacillus calmette-guérin therapy urol oncol. 2018; 36e15. 12. biot c, rentsch ca, gsponer jr, et al. preexisting bcg-specific t cells improve intravesical immunotherapy for bladder cancer sci transl med. 2012; 4:72. 13. centers for disease control and prevention. bcg vaccine fact sheet. 2016. retrieved from https://www.cdc.gov/tb/publications/ factsheets/prevention/bcg.htm correspondence anastasia macdonald, md anamacdonald@nosm.ca vahid mehrnoush, md vahidmehrnoush7@gmail.com asmaa ismail, md asmaaismail0782@gmail.com ahmed zakaria, md aszakaria81@yahoo.com waleed shabana, md waleed.shabana@gmail.com ashraf shaban, md ashraf.shaban@tbh.net mohammed bassuony, md mohammed.bassuony@tbh.net hazem elmansy, md hazem.elmansy@tbh.net walid shahrour, md walid.shahrour@tbh.net owen prowse, md owen.prowse@tbh.net ahmed kotb, md, phd, frcsc, frcs urol, febu (corresponding author) associate professor drahmedfali@gmail.com northern ontario school of medicine (nosm) and thunder bay regional health research institute (tbrhri) thunder bay, on, canada livio di matteo, md ldimatte@lakeheadu.ca department of economics, lakehead university, thunder bay, on conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 35 original paper introduction prostate cancer (pca) is the second most commonly diagnosed cancer in men, with approximately 1.1 million diagnoses worldwide each year, accounting for 15% of all cancers diagnosed (1). the incidence of pca increases with age, with over 25% of men over the age of 75 years being affected (1). low-risk pca (psa < 10 ng/ml, isup 1, t2a) can be managed through several different modalities, including the non-operative approach of “active surveillance”, which involves laboratory and clinical monitoring of tumor progression and active treatment if necessary (2). other active treatments, such as radiotherapy or surgery, are also options. intermediate/high-risk organconfined prostate cancers require active treatment, which may include surgery and/or radiotherapy (external beam or brachytherapy). approximately 40% of people with prostate cancer undergo radiotherapy as part of their treatment, which can serve various purposes such as curative intent, post-operative adjuvant, post-operative rescue intent, or palliative intent (3). conventional radiotherapy is delivered as external beam radiotherapy (ebrt), and conformal radiotherapy, including 3d conformal radiotherapy (3dcrt) and intensity-modulated radiotherapy (imrt), is commonly used in high-income countries. during treatment, despite recent advances in techniques and technologies that allow precise delivery of radiation on the focus organ, pelvic radiotherapy inevitably exposes the surrounding normal gastrointestinal tract to some degree of radiation, potentially causing rectal bleeding, ulcers or fistulas and increasing the risk of rectal cancer by 105% over the following decade (4). different strategies have been recently adopted and implemented to minimize these complications; one technique aims to fixate the prostate gland during radiation treatment via a rectal balloon to reduce the prostate motion and to make sure the dose delivered to the target volume is efficient., allowing a safer and smaller planning target volume margin as stated elsewhere (5, 6). by using a rectal balloon, the dose exposure to the posterior rectal wall is decreased as opposed to an increased dose to the anterior rectal wall. biodegradable balloon spacers are three-dimensional scaffolds that can be implanted between the prostate gland introduction: radiotherapy is a common treatment for prostate cancer, and can be administered in various ways, including 3d conformal radiotherapy (3dcrt), intensity-modulated radiotherapy (imrt) and hypo-fractionated radiation therapy. during treatment the gastrointestinal tract may be exposed to radiation and the rectal wall may be exposed to high doses of ionizing radiation, which can lead to rectal bleeding, ulcers or fistulas, and an increased risk of rectum cancer. various strategies to minimize these complications have been developed in the last decade; one of the most promising is to use a rectal balloon to fixate the prostate gland during treatment or to inject biodegradable spacers between the prostate and rectum to reduce the rectal dose of radiation. aim of our paper is to evaluate the safety and tolerability of spacers implantation. materials and methods: from january 2021 to june 2022 all patients with a diagnosis of prostate cancer with unfavorable/intermediate risk poor prognosis and programmed hypofractionated radiation therapy were enrolled. in all patients biodegradable balloons spacers were placed posteriorly to the prostate to increase the separation between prostate and rectum. the duration of the procedure, observation time, the appearance of early and late complications and their severity (according to charlson comorbidity index) and tolerability of the device were recorded at the time of positioning and after 10 days. results: 25 patients were enrolled in our study. two patients (8%) underwent acute urine retention resolved with catheterization and one patient (4%) developed a mild perineal hematoma that did not require any treatment. as regards late complications 1 patient (4%) developed hyperpyrexia (> 38°c) the day after the procedure requiring continuation of antibiotic regimen. at t1 visit we recorded no medium-high grade complications. as for the tolerability of the device, it was optimal with no perineal discomfort or alterations of bowel function. conclusions: biodegradable balloon spacers appears to be safe and well tolerated and its positioning does not present any technical difficulties or risks of major complications. key words: prostate cancer; spacer; radiotherapy; hypo-fractionated radiotherapy. submitted 14 january 2023; accepted 22 april 2023 safety and tolerability of biodegradable balloon spacers in patients undergoing radiotherapy for organ-confined prostate cancer luca topazio 1, federico narcisi 1, fabio tana 2, cosimo ciotta 2, vincenzo iossa 2, pasquale perna 2, francesco chiaramonti 2, federico romantini 1 1 asl teramo, u.o.c. di urologia, teramo, italy; 2 university of l'aquila, department of life, health and environmental sciences, l'aquila; u.o.c. di urologia, p.o. mazzini, teramo, italy. doi: 10.4081/aiua.2023.11156 summary archivio italiano di urologia e andrologia 2023; 95, 2 l. topazio, f. narcisi, f. tana, et al. 36 and rectum to protect the rectum from radiation during radiotherapy. they are commercially available in europe. a further clinically available technique reduces the rectal dose of radiations using the injection of materials such as hydrogel, hyaluronic acid gels, and collagen between the prostate and rectum, remarkably lessening late-rectum toxicity. spacers implantation is indeed a minimally invasive surgical procedure guided by transrectal ultra-sound that permit the positioning of biodegradable balloons that can be placed posteriorly to the prostate to increase the separation between prostate and rectum thus protecting the latter from radiations during rt sessions. it demands attendance of a trained physician, qualified to perform this kind of surgery. the procedure takes from 10 to 30 min and can be carried out under local or general anesthesia. as reported in the eau 2022 guidelines, “…a meta-analysis including one rct and six cohort studies using the hydrogel spacer demonstrated a 5-8% reduction in the rectal volume receiving high-dose radiation…” (7). spacers can be implanted in outpatient setting, using local, epidural, or general anesthesia. a recent study, evaluated the correlation between the use of prostate spacers and the incidence of erectile dysfunction in men with organ-confined prostate cance submitted to hypofractionated radiotherapy (8). the use of spacers allowed to keep pretreatment sexual potency in 62.5% of the cases (8). a biodegradable balloon spacer is a three-dimensional scaffold made of biocompatible material that is designed to be implanted between the prostate gland and the rectum, prior to the beginning of a radiotherapy program. it is biodegradable and it is actually commercialized in europe (figure 1). with the patient in the lithotomy position, and under transrectal ultrasonography (trus) guidance, an 18-gauge needle is inserted between denonvilliers’ fascia and the anterior rectal wall (figure 2). once the needle is in the correct position, saline water is injected to carry out hydro-dissection and to create a potential space between the prostate and rectum. implantation time is relatively short, with a mean overall procedure time of 16 minutes (7.8 min) from time of trus insertion to trus removal; moreover, the biodegradable gel takes an average of 6 to 12 months to absorb once injected in the patients’ regions of interest. reported complications of spacers positioning, although rare, are prostatic abscess, fistulae and sepsis. the aim of this study is to evaluate the safety and efficacy of biodegradable balloon spacer placement in prostate cancer patients who are candidates for radiation treatment. materials and methods this is a prospective observational study that enrolled patients with a diagnosis of prostate cancer (pca) who had unfavorable/intermediate risk (poor prognosis) and were receiving hypofractionated radiation therapy between january 2021 and june 2022. patients who had previously received pelvic irradiation for rectum morbidities were also included in the study, and no exclusion criteria were used in the patient selection phase. the timing of the procedure, related complications, and the tolerability of the device were evaluated at two time points: t0 (the day of spacer placement) and t1 (an ambulatory control visit at 10 days). the spacer (bioprotect® biodegradable spacer) was placed in an outpatient setting with the patient in a lithotomic position. cefazoline 1 gram was administered intravenously and local anesthesia was given to the perineal area and levator ani muscles with 2% mepivacaine. the procedure was performed using transrectal ultrasound with a biplanar probe. a cutaneous incision was made at the perineal level, 1 cm above the anus, and the dilator was inserted behind the prostate at the level of the denonvilliers’ fascia. hydrodissection was performed to create a well-defined plane from the prostate apex to the seminal vesicles. the device containing the balloon was then inserted and advanced to the level of the seminal vesicles, inflated with physiological solution (16-23 ml), and released. the correct positioning of the device was confirmed using transrectal ultrasound (trus). the patient was observed for any early complications during the post-procedural observation period before being dismissed. late complications and the tolerability of the device were evaluated at t1. the duration of the procedure (in minutes), observation time (in minutes), and the appearance and severity (according to the charlson comorbidity index) of early and late complications were figure 1. illustration of a biodegradable balloon spacer positioning. figure 2. illustration of the 18-gauge needle needed for the implantation of the spacer. archivio italiano di urologia e andrologia 2023; 95, 2 37 tolerability of biodegradable balloon spacers recorded. the tolerability of the device was evaluated using a scale from 0 to 10 for discomfort (0 = no discomfort, 10 = severe discomfort) and by assessing pelvic-perineal encumbrance and changes in bowel function. after the t1 visit, the patient was sent for radiotherapy. results from january 2021 to june 2022, 25 patients were enrolled. their baseline epidemiological data are shown in table 1. the procedure was performed in an outpatient setting following the protocol described in the previous section. the average time of the procedure was 18 minutes [10-25 min]. all patients were then discharged within two hours of the procedure (average post-op observation time: 90 minutes [45-110 min]), after the resumption of spontaneous micturition and the absence of early complications. two patients (8%) experienced acute urine retention that was resolved with catheterization, and one patient (4%) developed a mild perineal hematoma that did not require treatment. as for late complications, one patient (4%) developed fever (> 38°c) the day after the procedure, requiring continuation of the antibiotic regimen. at the t1 visit, no medium-high grade complication was recorded. the tolerability of the device was optimal, with an average score of 2 and a range of 04 on the previously described discomfort scale. no patients reported disturbances in defecation, changes in intestinal transit, or a sense of encumbrance in the pelvic-perineal area. results are listed in table 2. discussion prostate cancer (pca) is the second most common cancer among men worldwide, ranking first in developed countries. according to the world research fund international, there were over 1.4 million new diagnoses of pca in 2020 worldwide. the incidence and mortality of pca are correlated with age, with the average age of diagnosis being 66 years. there is a higher incidence of pca in africanamerican men compared to white men, with 158.3 new cases diagnosed per 100.000 men and double the mortality. while the lethality of pca is not as severe as other types of cancer, the number of yearly deaths due to pca is high due to its high incidence. pca diagnosis is based on standardized protocols that involve prostate specific antigen (psa) testing, digital rectal examination (dre), and the newly implemented multiparametric magnetic reonance imaging (mpmri) as an additional diagnostic tool before biopsy, allowing for the specific targeting of possible malignant lesions. there are various treatment options for organ-confined pca, ranging from active surveillance to active treatment with surgery or radiotherapy. radiotherapy (rt) can be performed in various settings, such as external beam rt (ebrt) and intensity-modulated rt (imrt). imrt delivers a precise beam of modulated intensity that delivers radiation with higher selectivity to prostatic tissue, minimizing exposure to proximal organs. an hypofractionated rt protocol uses a higher dose of radiation per session, reducing the number of necessary sessions. the major drawback of rt is the incidental irradiation of proximal anatomical areas, such as the rectum, which is mostly inevitable due to the anatomical relationship between the rectum and prostate. spacers provide a solution to this problem by inserting a device between the prostate and rectum, separating the target of the radiation beam from a contiguous organ. in addition, the procedure can be performed in an outpatient setting via a dayhospital regimen, resulting in reduced costs and minimal operative time (9). overall, the implantation of spacers has been shown to be safe and fast, with optimal tolerability of the device (10, 11). no severe complications were observed in the postprocedural time (t0), allowing the procedure to be performed in an outpatient setting and at t1 follow-up outpatient visit. mild complications related to the implantation procedure have been documented, but they are relatively uncommon. we recorded one episode of acute urinary retention (aur) in a patient with a voluminous enlarged prostate, a risk factor commonly associated with prostate biopsies. the incidence of urinary tract infections (utis) is comparable to that of transperineal prostate biopsies, so adherence to the most recent guidelines is recommended (12). even among the most unfavorable cases (patients who have already undergone radiation treatment and need another cycle of imrt), no complications ranging from mild to severe were reported, in contrast to what is suggested in the eau guidelines about this topic (fistulas, abscesses, sepsis). our overall experience is in line with the european consensus, as we did not encounter acute or delayed intermediate-severe complications, despite having modest table 1. baseline epidemiologic data. patients’ characteristics number of patients 25 pts age 68 yo (range 59-77) tumor stage ct1c: 10 pts ct2a: 8 pts ct2b: 7 pts ct2c: o pts (0%) psa level 14 ng/ml (8-27 ng/ml) isupp isupp 1: 4 pts isupp 2: 6 pts isupp 3: 15 (%) pts isupp 4: 0 (0%) pts isupp 5: 0 (0%) pts table 2. data obtained after the spacer placement. average duration of the procedure 18 minutes (10-25 minutes) average duration of observation 90 minutes (45-110 minutes) early complications acute urinary retention 2 pz (10%) hematoma 1 pz (5%) late complications fever 1 pz (5%) spacer tolerability score 2 (0-4) reported bowel symptoms 0 pz perineal bulk sensation 0 pz archivio italiano di urologia e andrologia 2023; 95, 2 l. topazio, f. narcisi, f. tana, et al. 38 previous experience with these types of devices and transperineal procedures. this highlights the low learning curve for this procedure. conclusions biodegradable balloon spacers appear to be safe and well tolerated and their positioning does not present any technical difficulties or risks of major complications. its usage can and must be discussed when dealing with patients diagnosed with prostate cancer and scheduled to undergo radiation therapy in order to increase the selectivity of such treatment by protecting the rectum via mechanical separation from the prostate. the device is designed to be left in place as it is biodegradable and does not require any additional maintenance or monitoring. there are several potential benefits to using a biodegradable balloon spacer in the treatment of prostate cancer. in addition to potentially improving the effectiveness of radiation therapy, it may also reduce the risk of side effects such as rectal bleeding and discomfort. it may also help to reduce the risk of long-term complications such as bowel and urinary incontinence. overall, the biodegradable balloon spacers are promising tools in the treatment of prostate cancer, offering the potential for improved outcomes and fewer side effects for patients. it is an important advancement in the field of cancer treatment and continues to be studied and refined in order to optimize its effectiveness and safety. nonetheless, further data must be gathered as more of these devices are effectively used in everyday clinical practice to improve our understanding of its efficacy in protecting the rectum from radiation beams and their effects on the quality of life of patients, thus requiring a longer follow-up. references 1. wang l, lu b, he m, et al. prostate cancer incidence and mortality: global status and temporal trends in 89 countries from 2000 to 2019. front public health. 2022; 10:811044. 2. eau guidelines. edn. presented at the eau annual congress amsterdam 2022. isbn 978-94-92671-16-5. 3. hummel s, simpson el, hemingway p, et al. intensity-modulated radiotherapy for the treatment of prostate cancer: a systematic review and economic evaluation. health technol assess. 2010; 14:1108, iii-iv. 4. nilsson s, norlén bj, widmark a. a systematic overview of radiation therapy effects in prostate cancer. acta oncol. 2004; 43:316-81. 5. navaratnam a, cumsky j, abdul-muhsin h, et al. assessment of polyethylene glycol hydrogel spacer and its effect on rectal radiation dose in prostate cancer patients receiving proton beam radiation therapy. adv radiat oncol. 2019; 5:92-100. 6. mok g, benz e, vallee jp, et al. optimization of radiation therapy techniques for prostate cancer with prostate-rectum spacers: a systematic review. int j radiat oncol biol phys. 2014; 90:278-88. 7. miller le, efstathiou ja, bhattacharyya sk, et al. association of the placement of a perirectal hydrogel spacer with the clinical outcomes of men receiving radiotherapy for prostate cancer: a systematic review and meta-analysis. jama netw open. 2020; 3:e208221. 8. pepe p, tamburo m, panella p, et al. erectile dysfunction following hydrogel injection and hypofractionated radiotherapy for prostate cancer: our experience in 56 cases. arch ital urol androl. 2022; 94:166-168. 9. fathy mm, hassan bz, el-gebaly rh, mokhtar mh. dosimetric evaluation study of imrt and vmat techniques for prostate cancer based on different multileaf collimator designs. radiat environ biophys 2023; 62:97-106. 10. thompson ab, hamstra da. rectal spacer usage with proton radiation therapy for prostate cancer. int j radiat oncol biol phys. 2020; 108:644-648. 11. sanei m, ghaffari h, ardekani ma, et al. effectiveness of rectal displacement devices during prostate external-beam radiation therapy: a review. j cancer res ther. 2021; 17:303-310. 12. pradere b, veeratterapillay r, dimitropoulos k, et al. nonantibiotic strategies for the prevention of infectious complications following prostate biopsy: a systematic review and meta-analysis. j urol. 2021; 205:653-663. correspondence luca topazio, md (corresponding author) luca.topazio@aslteramo.it federico narcisi, md federico.narcisi@aslteramo.it federico romantini, md federico.romantini@aslteramo.it asl teramo, u.o.c. di urologia (teramo), italy fabio tana, md fabiotana21@gmail.com cosimo ciotta, md ciottacosimo@live.it vincenzo iossa, md vincenzoiossa@msn.com pasquale perna, md pasquper@gmail.com francesco chiaramonti, md francesco.tr92@virgilio.it university of l'aquila (l'aquila), department of life, health and environmental sciences; u.o.c. di urologia, p.o. mazzini, (teramo), italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso introduction semen analysis is a crucial and irreplaceable tool for evaluating male infertility and precise thresholds are needed. since 1951, the scientific community recognized this concept and mcload et al. (1, 2) indicated the cut-off values for sperm counts (> 20 x 106 /ml, total sperm count > 100 x 106) for the first time, to distinguish fertility from subfertility. however the clinicians noted several times that some men with a sperm count below these ranges were able to conceive and this creat125archivio italiano di urologia e andrologia 2013; 85, 3 original paper comparison between who (world health organization) 2010 and who 1999 parameters for semen analysis – interpretation of 529 consecutive samples francesco catanzariti, ubaldo cantoro, vito lacetera, giovanni muzzonigro, massimo polito polytechnic university of marche, faculty of medicine, department of odontostomatologic and specialized clinical sciences, urology clinic, department of general and specialized surgery, university hospital, ancona, italy. objective: to quantify how many men with normal semen according to who (who world health organization) 1999 criteria, should be considered with abnormal semen according to 2010 criteria and vice versa; to study which parameter of volume, concentration, motility and morphology is the most responsible of this change. materials and methods: we studied, using who 1999 parameters, 529 consecutive semen samples from 427 men, collected in our department from january 2008 to december 2009, then we re-evaluated those results using who 2010 parameters; we also studied each parameter to understand how changed the classification from normal (defined normal by all parameters) to abnormal (defined abnormal by at least one parameter) using the two who criteria. results: 3 men (0.56%) were azoospermic. among the remaining 526 samples, 199 (37.83%) were considered normal and 246 (46.76%) abnormal both according to who 1999 and who 2010 criteria; we found that none of the samples classified normal according to the previous criteria was classified abnormal according the more recent criteria, while 82 (15.58%) evaluated as abnormal according 1999 criteria changed to normal according 2010 criteria. the concordance between 1999 and 2010 evaluation was 84.44%. conclusions: in this study we noted that the changes from who 1999 to who 2010 criteria did not modify the interpretation of semen quality, because comparing the two classifications we demonstrated that there is a substantial agreement, considering the three parameters (count, motility and morphology) all together, and also considering each single parameter. anyhow, almost 16% of the patients considered infertile according to the old criteria, should be evaluated normal by the new classification and they should not need any treatment for infertility. key words: who 2010 parameters; infertility; semen analysis. submitted 5 june 2013; accepted 30 june 2013 no conflict of interest declared summary ed an uncertainty in the clinical practice. in 1980 the world health organization (who) tried to clarify these doubts, by publishing the first (3) of 5 editions of guidelines for semen analysis. the weak point of that edition was that its criteria had never been prospectively validated by any study, because all the works present in the literature of the following years used either a case-control design, comparing fertile and subfertile couples, or a cohort design among the first pregnancy planners (4, 5). doi: 10.4081/aiua.2013.3.125 archivio italiano di urologia e andrologia 2013; 85, 3 f. catanzariti, u. cantoro, v. lacetera, g. muzzonigro, m. polito 126 the ultimate edition published in 2010 (6) used the concepts of “percentile” and “confidence intervals”, for the first time, allowing the clinicians to evaluate the individual semen analysis values in the context of measurement error and indicated reference values for semen parameters based on data from fertile men above the 5th percentile. furthermore, the results were generated in multiple laboratories using standardized procedures and based on real world data. however the last who guidelines for semen analysis radically changed the interpretation of semen analysis of the previous who 1999 (7) guidelines especially regarding the parameters of number (from 20 x 10^6/ml to 15 x 10^6/ml) and morphology (from 30% to 4%). this change mean that some of the patients, who were considered abnormal for the quality of their semen according to the old classification, would be considered normal, as a result of the new classification. our study tried to quantify this change and to understand the percentage of concordance between the two classifications in the assessment of a sample, considering all three parameters at the same time (sperm count, motility and morphology) and analyzing each parameter individually to understand which of them is most responsible for the shift from normospermia to dyspermia. materials and methods we studied 529 consecutive semen samples from 427 men collected in our department from january 2008 to december 2009. semen analysis was performed 2 or more times in 74 patients during this period. this group was composed of healthy men and men affected by different diseases (infertility, infections, varicocele, and other pathologies), semen analysis was performed after at least 3 days of sexual abstinence. semen samples were collected at the hospital by masturbation directly into a 120 ml sterile jar. semen samples were analyzed within 1 hour of ejaculation. after liquefaction, semen volume was measured in a graded syringe with 0.1-ml accuracy. sperm concentration was counted and motility assessed in a makler counting chamber at a magnification of x 200. all semen parameters were classified first, according to the 1999 who criteria, then retrospectively using who 2010 parameters; we also studied each parameter to understand how the results changed from normal (defined as all parameters normal) to abnormal (defined with at least one parameter abnormal) using the two criteria. results the mean age of participants was 30.26 (18-60). sperm characteristics are summarized in table 1. between the 529 samples, we detected 3 (0.56%) cases of azoospermia. in analysing the specimens using the old criteria (figure 1) we found 199 (37.62%) cases of normospermia, 140 (26.47%) cases of asthenozoospermia and 83 (15.69%) cases of oligoasthenozoospermia, while using who 2010 criteria (figure 2) we found slightly different rates of prevalence: 283 (53.50%) cases of normospermia, 105 (19.85%) cases of asthenozoospermia and 85 (16.07%) cases of oligoasthenozoospermia. when we considered only the number (figures 3, 4) we observed that 355 (67.49%) patients had a normal number according to both who 1999 and who 2010 criteria, 138 (26.24 %) patients were considered to have oligozoospermia by both classifications and 33 (6.27%) patients were considered to have a normal number according to who 2010 criteria and to have oligomean 5th-95th percentile age (y) 30.26 18-45 mediana 5th-95th percentile volume (ml) 3 1-6 concentration (10^6/ml) 40 0.28-163.60 total motility (%) 46 10-80 normal morphology (%) 52 20-73 table 1. characteristics of age and semen quality of the patients (n: 529 men). figure 1. number of patients in each category (who 1999). figure 2. number of patients in each category (who 2010) zoospermia according to the who 1999 classification. we found that some patients who had an abnormal number according to old criteria were not considered abnormal according the new one. therefore the concordance between the two classifications for number was 93.73%. considering only the parameter of motility (figures 5, 6) we found that 248 (47.15%) cases had normal motility both according to who 1999 and who 2010 criteria, 192 (36.50%) patients were considered to have asthenozoospermia according to both classifications and 86 (16.35%) patients were considered to have a low motility according to who 1999 parameters and to have a normal motility according to the new parameters. we found that some patients who had an abnormal motility by the old criteria were not considered abnormal according to the new one. the concordance according to the two criteria about motility was 83.65%. studying only morphology (figures 7, 8) we observed that 469 (89.16%) cases presented normal morphology according to both classifications, 2 (0.38%) cases had teratozoospermia according to both who 1999 and who 2010 classification and 55 (10.46%) patients were considered to have abnormal morphology according to the old classification and to have normal morphology according to the new one. we found that patients who had an abnormal morphology by the old criteria were not considered abnormal according to the new one. therefore the concordance between the two classifications of morphology was 89.54%. considering the three parameters together (figures 9, 10) 199 (37.83%) patients were considered normal according 127archivio italiano di urologia e andrologia 2013; 85, 3 comparison between who (world health organization) 2010 and who 1999 parameters for semen analysis figure 3. concordance between who 1999 and who 2010 about number. figure 4. concordance between who 1999 and who 2010 about number. legend nnnn: percentage of men with normal number according to both who 1999 criteria and who 2010 criteria. nno: percentage of men with normal number according to who 1999 criteria and oligozoospermia according to who 2010 criteria. onn: percentage of men with oligozoospermia according to who 1999 criteria and normal number according to who 2010 criteria. oo: percentage of men with oligozoospermia according to both who 1999 criteria and who 2010 criteria. figure 5. concordance between who 1999 and who 2010 about total motility. figure 6. concordance between who 1999 and who 2010 about total motility legend nmnn: percentage of men with normal motility according to both who 1999 criteria and who 2010 criteria. nma: percentage of men with normal motility according to who 1999 criteria and asthenozoospermia according to who 2010 criteria. anm: percentage of men with asthenozoospermia according to who 1999 criteria and normal motility according to who 2010 criteria. aa: percentage of men with asthenozoospermia according to both who 1999 criteria and who 2010 criteria. archivio italiano di urologia e andrologia 2013; 85, 3 f. catanzariti, u. cantoro, v. lacetera, g. muzzonigro, m. polito 128 to both who 1999 and who 2010 classification, 246 (46.77%) cases were considered abnormal according to both classifications and 82 (15.59%) cases were evaluated abnormal according to the 1999 parameters and normal according to those of 2010. we found that patients who had all three parameters abnormal by the old criteria were not considered abnormal according to the new one, so that the concordance between 1999 and 2010 interpretation was 84.44%. discussion in literature there are few studies that analyze the changes in the interpretation of semen analysis from who 1999 to who 2010 criteria. murray et al. (8) recently did a multi-institutional retrospective study involving 387 infertile men, with the aim to understand how many semen samples of patients who were classified as infertile by timeline and previous semen analysis criteria would change classifications to be in the normal fertile range based on the 2010 who lower reference limits. they observed that overall, 43 (11.1%) patients who had one or more abnormal parameters in the original analysis would be converted to having all parameters within normal parameters and the most important changes in the interpretation of the data were in motility and morphology. these results are similar to our (11.1% vs 15.59%) another recent study by zou et al. (9) indirectly analyzed this change of interpretation. in his work zou examined figure 7. concordance between who 1999 and who 2010 about morphology. figure 8. concordance between who 1999 and who 2010 about morphology. legend nmnm: percentage of men with normozoospermia according to both who 1999 criteria and who 2010 criteria. nmt: percentage of men with normozoospermia according towho 1999 criteria and teratozoospermia according to who 2010 criteria. tnm: percentage of men with teratozoospermia according to who 1999 criteria and normozoospermia according to who 2010 criteria. tt: percentage of men with teratozoospermia according to both who 1999 criteria and who 2010 criteria. figure 9. total concordance between who 1999 and who 2010. figure 10. total concordance between who 1999 and who 2010. legend ff: percentage of men considered fertile according to both who 1999 criteria and who 2010 criteria. fi: percentage of men considered fertile according to who 1999 criteria and infertile according to who 2010 criteria. if: percentage of men considered infertile according to who 1999 criteria and fertile according to who 2010 criteria. ii: percentage of men considered infertile according to both who 1999 criteria and who 2010 criteria. the determinants of semen quality in a large sample of military personnel from different geographical areas of the people's republic of china. among 1194 patients he found that 88.3% had at least one semen parameter below the normal values according to world health organization (who) recommendations (1999), and 62.5% according to who recommendations (2010). therefore, this study also demonstrated that the new classification created a little shift in the patients from infertile to fertile. metha et al. (10) instead, evaluated the improvement in semen parameters and serum testosterone (t) in their study, following varicocelectomy in those men considered abnormal according to the 1999 who criteria yet normal by the new 2010 criteria. they analysed 152 patients in total, that met the inclusion criteria (sperm concentration 15-20 million/ml, motility 40-50%, or morphology 4-14%): 111 patients (73%) underwent bilateral varicocelectomy, while 41 (27%) underwent a left side varicocelectomy. overall, sperm concentration and serum testosterone (t) improved following surgery. among men who met the inclusion criteria for sperm concentration, only sperm concentration was significantly increased (17.8 vs. 38.0 million/ml, p = 0.03). they concluded that microsurgical varicocelectomy in the subset of men considered to have normal semen parameters according to the 2010 who reference ranges, but abnormal according to the 1999 reference ranges lead to a significant improvement in serum t, sperm concentration, and, in some cases, sperm motility. metha and his colleagues underlined that even among patients considered normal for the new classification but abnormal for the old one, microsurgical varicocelectomy should be performed because of its improvement of fertility potential as well as t levels. our study evaluated if there were any changes in the evaluation of the semen quality according to who 1999 criteria and who 2010 criteria in order to understand if there are cases, which can change from abnormal to normal, and vice versa using the two classifications. we concluded that, considering each parameter by itself and all three parameters together, the concordance is very high. concordance was high according to the number parameter (93.73%) that was slightly changed, from 20 x 10^6/ml (who 1999) to 15 x 10^6/ml (who 2010), but also according to morphology parameter (89.54%) that was radically changed from 30% (who 1999) to 4% (who 2010). another interesting observation from our results is that there are not cases considered normal by the old classification that change to abnormal by the new one, while there are patients that resulted abnormal by the old criteria and normal according to new who 2010 parameters. this change is more consistent for motility (16.35%) than morphology (10.46%), as we expected. this implies that none of the patients that were previously considered normal changed to abnormal, according to the new classification, but some patients, about 15%, changed from abnormal to normal by the new classification. so thanks to the new criteria, the rate of patients that do not need any treatment for infertility is now reduced because they are no more considered infertile. acknowledgements the authors would like to thank all of the patients for their contribution to this study and all the urologists of the department of urology of the polytechnic university of marche in ancona, who contributed to this study, with their data collection and sharing. references 1. macleod j, gold rz. the male factor in fertility and infertility. ii. sperm counts in 1000 men of known fertility and in 1000 cases of infertile marriage. j urol. 1951; 66:436. 2. macleod j, gold rz. the male factor in fertility and infertility. vi. semen quality and other factors in relation to ease of conception. fertilsteril. 1953; 4:10. 3. world health organization.who laboratory manual for the examination of human semen and semen-cervical mucus interaction. singapore: press concern, 1980. 4. bonde jp, ernst e, jensen tk, et al. relation between semen quality and fertility: a population-based study of 430 first-pregnancy planners. lancet. 1998; 352:1172-7. 5. zinaman mj, brown cc, selevan sg, clegg ed. semen quality and human fertility: a prospective study with healthycouples. j androl. 2000; 21:145-53. 6. cooper tg, noonan e, von eckardstein s, et al. world health organization reference values for human semen characteristics. human reprod update. 2010; 16:231-45. 7. world health organization. who laboratory manual for the examination of human semen and sperm-cervical mucus interaction, 4th edn. cambridge: cambridge university press, 1999, 128 p. 8. murray ks, james a, mcgeady jb, et al. the effect of the new 2010 world health organization criteria for semen analyses on male infertility. fertilsteril. 2012; 98:1428-31. 9. zou z, hu h, song m, et al. semen quality analysis of military personnel from six geographical areas of the people's republic of china. fertilsteril. 2011; 95:2018-23. 10. mehta a, najari b, rosoff js, goldstein m. impact of the revised who semen analysis reference limits on selection criteria for microsurgical varicocelectomy. j urol. 2012; 187:4s. 129archivio italiano di urologia e andrologia 2013; 85, 3 comparison between who (world health organization) 2010 and who 1999 parameters for semen analysis correspondence francesco catanzariti, md (corresponding author) resident in urology fracatanzariti@libero.it ubaldo cantoro, md resident in urology ubaldocantoro@tiscali.it vito lacetera, md urologist vlacetera@gmail.com giovanni muzzonigro, md professor of urology, chief department of urology g.muzzonigro@univpm.it massimo polito, md urologist, chief department of uro-andrology max_polito@virgilio.it polytechnic university of marche, faculty of medicine department of odontostomatologic and specialized clinical sciences urology clinic, department of general and specialized surgery university hospital of ancona via conca 71 i-60020 ancona, italy stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 28 original paper factor for ubc. exposure to chemical compounds, particularly aromatic amines and polycyclic aromatic hydrocarbons, parasitic infection, along with genetic predisposition are also considerable risk factors (1, 4). approximately 25% of newly diagnosed ubc are invasive, requiring radical surgery or radiotherapy (1, 2, 5). unfortunately, the disease outcome is still poor despite systemic therapy (1). five-year overall survival (os) and disease-specific survival (dss) rates for ubc are 57.2% and 77.3%, respectively (2). early detection of ubc is important to improve patient’s outcome, since the treatment can be delivered aggresively. hypoxia inducible factor (hif)-1α is a regulatory protein produced in hypoxic microenvironment that consists of two subunits. its expression is found in several solid tumors including ubc, lung, breast, ovary, prostate, and kidney cancers. the binding of hif-1α with its receptor initiates cell proliferation, migration, and invasion in ubc (3, 6, 7). additionally, hif-1α is also closely related to angiogenesis (3, 7-9). in this study, we aimed to evaluate the association between hif-1α and stage and grade of ubc. our findings may provide insight regarding earlier diagnosis, prompt management, improved outcome, and possible therapeutic method for ubc. methods this was a case-control study conducted in januarydecember 2022 at haji adam malik hospital medan, indonesia. the inclusion criteria for case group was subject aged 18 years or older and diagnosed with ubc based on histopathological examination. beside diagnosing ubc, biopsy specimen from case group underwent hematoxylin and eosin staining to determine stage and grade of disease. all histopathological examinations were conducted at department of pathology of universitas sumatera utara. control group included healthy subjects who came to the hospital for general check-up or healthy hospital employers. exclusion criteria was previous history of introduction: we aim to evaluate the association between serum hypoxia inducible factor (hif)-1α level and stage and grade of urothelial bladder cancer (ubc). methods: a case-control study was conducted at haji adam malik hospital medan, indonesia. inclusion criteria for case group was subject aged 18 years or older and diagnosed with ubc based on histopathological examination. control group consisted of gender and age matched healthy subjects. serum hif-1α level was determined using elisa method. data was analyzed with chi square, mann whitney, and independent t tests. results: a total of 80 subjects were enrolled and divided into case and control groups equally. most subjects were males with mean age of 69.65 years for case group and 68.25 years for control group. most subjects had advanced primary tumor and lymph node stages. only 30% subjects had metastasized ubc. higher serum hif-1α level was observed in case group (p < 0.001). serum hif-1α level was strongly associated with metastasis stage (p < 0.001), followed by lymph node (p = 0.005) and primary tumor (p = 0. 013) stages. serum hif-1α level was not associated with grading (p = 0.134). conclusions: serum hif-1α level is associated with staging but not grading of ubc. key words: hif-1α; grade; stage; urothelial bladder cancer. submitted 5 march 2023; accepted 2 april 2023 introduction urothelial bladder cancer (ubc) is the 7th and the 17th most common cancer globally in men and women, respectively (1). this subtype is responsible for more than 90% bladder cancer cases (2, 3). annually, there are 110.500 men and 70.000 women diagnosed with new ubc cases worldwide. the disease is more frequent in developed countries (1). every year, 38.200 cases were diagnosed in european union and 17.000 subjects died due to ubc (1, 2). smoking is the most important risk the association between serum hypoxia inducible factor-1α level and urothelial bladder cancer: a preliminary study ginanda putra siregar 1, 2 *, ida parwati 3 *, bambang sasongko noegroho 4 *, ferry safridai 4 *, gerhard reinaldi situmorang 5, raden yohana 6, astrid feinisa khairani 7 1 doctoral study program, faculty of medicine, universitas padjadjaran, bandung, indonesia; 2 division of urology, department of surgery, faculty of medicine, universitas sumatera utara, medan, indonesia; 3 department of clinical pathology, faculty of medicine, universitas padjadjaran, bandung, indonesia; 4 department of urology, faculty of medicine, universitas padjadjaran, bandung, indonesia; 5 department of urology, faculty of medicine, universitas indonesia, jakarta, indonesia; 6 division of oncology, department of surgery, faculty of medicine, padjadjaran university, bandung, indonesia; 7 department of biomedical sciences, faculty of medicine, universitas padjadjaran, bandung, indonesia. * these authors contributed equally to this paper. doi: 10.4081/aiua.2023.11292 summary archivio italiano di urologia e andrologia 2023; 95, 2 g. putra siregar, ida parwati, b. sasongko noegroho, et al. 29 malignancy, bladder lesion due to methastasis from distant primary cancers, patients receiving systemic therapy for badder cancer, patients with diabetes mellitus, chronic kidney disease, and cerebrovascular disease. we did gender and age mathcing between the two groups. all subjects received explanation regarding this study and were asked to sign informed consent. subjects unwilling to participate in this study were excluded. serum sample was obtained from each subject in case group. evaluation of serum hif-1α level was conducted at research and esoteric laboratory jakarta, indonesia. we used hif-1α human elisa kit (thermo fisher scientific inc., waltham, usa) to determine serum hif-1α level in this study. data was analyzed using statistical package for social science (spss) software. categorical data was presented in frequency and percentage while numerical data was presented in median and range if it was not normally distributed. otherwise, it was presented in mean and standard deviation. chi square test was utilized to determine relationship between categorical variables while mann whitney and independent t tests were used to determine the relationship between categorical and numerical data. all statistical analyses were conducted at confidence interval of 95%. a p value of < 0.05 was considered significant. results a total of 80 subjects were enrolled in this study. all subjects were divided into the two groups equally. in case group mean age of subjects was 69.65 years and males subjects were prevalent. most subjects had advanced primary tumor and lymph node involvement. only 30% subjects in the case group had metastasized ubc. significantly higher serum hif-1α level was observed in case group compared to control group (table 1). from statistical analysis, we found that serum hif-1α level was strongly associated with metastatic ubc (p < 0.001), followed by ubc with lymph node involvement (p = 0.005) and primary tumor (p = 0. 013) stage. overall, serum hif-1α level was associated with ubc staging (p = 0.008) but not grading (p = 0.134) (table 2). discussion as most solid tumors grow, the need of oxygen for their metabolism is increased. this situation creates hypoxic condition (6, 10). hypoxic condition upregulates several proteins including hif-1α that it is important for adaptation of tumor, including ubc, in hypoxic condition. angiogenesis or neovascularization is the end point of this adaptation (3, 4, 6), hypoxia is also the culprit of treatment resistance in many cancers (8, 10) and hif-1α is one of the underlying etiologies (11-13). binding of hif-1α with its receptor in the nucleus promotes cell proliferation, migration, and invasion. overexpression of hif-1α is associated with progression and recurrence of ubc (4, 6). the expression of hif-1α in bladder cancer cells is also influenced by several other factors, such as elevated serum copper level and decreased serum zinc level (4). in ubc, hif-1α expression was higher compared to normal tissue (4, 8). the expression of hif-1α in patients with bladder cancer was in line with the expression of vascular endothelial growth factor (vegf) (r = 0.606). we know that vegf is important in neovascularization and growth of malignant tissue (4). this finding was confirmed by theodoropoulos et al. who found in their study that hif-1α was positively associated with histological grade of ubc. this association was mediated by vegf expression and microvessel density (mvd). patients with high hif-1α expression tended to have advanced disease and unfavorable outcome (8). badr et al. also reported similar findings showing that hif-1α expression is significantly higher in patients with bladder cancer despite its etiology. the level of urinary hif-1α was also able to discriminate between malignant and non-malignant tumor with sensitivity and specificity of 82.1% and 63.3%, respectively. in contrast with our results, this study failed to demonstrate significant relationship between hif-1α and ubc stage and grade (9). table 1. baseline characteristics of subjects. characteristics case control p (n = 40) (n = 40) mean age, years ± sd 69.65 ± 7.01 68.25 ± 7.74 0.400 a gender, n (%) male 30 (75%) 32 (80) 0.592 a female 10 (25%) 8 (20%) primary tumor stage (t), n (%) na na t1+t2 10 (25%) t3+t4 30 (75%) lymph node stage (n), n (%) na na n0 18 (45%) n1 22 (55%) metastasis stage (m), n (%) na na m0 28 (70%) m1 12 (30%) median hif-1α level, pg/ml (range) 345 (142-587) 123 (94-234) < 0.001 * b sd: standard deviation; a chi square test; b mann whitney test; * p < 0.05. table 2. association between serum hif-1α level and staging and grading of ubc. variables mean hif-1α levels, pg/ml ± sd p primary tumor stage (t) t3+t4 389 ± 126.66 0.013 * t1+t2 273.4 ± 103.89 lymph node stage (n) n1 410.45 ± 115.4 0.005 * n0 298.56 ± 123.42 metastasis stage (m) m1 477 ± 95.16 < 0.001 * m0 310 ± 110.34 staging 3+4 395.67 ± 124.11 0.008 * 1+2 273.4 ± 103.89 grading high grade 378 ± 131.42 0.134 low grade 306.4 ± 117.04 sd: standard deviation; * p < 0.05. archivio italiano di urologia e andrologia 2023; 95, 2 30 serum hypoxia inducible factor-1α level and urothelial bladder most patients with ubc expressed high hif-1α. tumor size, histological grade, tumor invasion, and recurrence of ubc were also associated with high hif-1α expression. in line with previous study, this effect was linked to vegf and mvd. disease free survival (dfs) of ubc was independently influenced by hif-1α (p = 0.011) (7). deniz, et al. supported these findings with their study. immunoreactivity of hif-1α was in concordance with stage and histologic grade of ubc. immunoreactivity of hif-1α was also related to vegf (p < 0.001) and mvd (p = 0.002) (14). another study by theodoropoulos, et al. in 2005 reported that hif1α expression is more common in high grade ubc. it was also positively correlated with increased proliferative activity, apoptotic rate, and mvd. however, they found no association between hif-1α alone and prognosis of ubc. the prognosis of ubc was associated with both hif-1α and mutation in p53 nuclear protein (5). a study conducted by fus, et al. reported a contradictive result. they found that the expression of hif-1α is significantly lower in high grade ubc. negative correlation was also reported between the expression of hif-1α and mvd (3). we found that serum level of hif-1α in case group is significantly higher compared to control group (p < 0.001). serum hif-1α was also higher in advanced ubc stage, including primary tumor, lymph node, and metastasis stage. higher serum hif-1α was also observed in advanced ubc grade but the difference was not statistically significant. there were several limitations in our study. we did not analyze risk factors for ubc other than gender and age. we also did not analyze variables that influence the level of serum hif-1α. the kit we used to determine serum hif1α level was also different which may have given different result. additional study, preferably a meta-analysis, is requested to determine the association between serum hif-1α level and progression of ubc. conclusions there was a significant association between serum hif1α level and staging of ubc. serum hif-1α level may aid in early diagnosis, prompt management, and improved outcome of patients with ubc. references 1. burger m, catto jwf, dalbagni g, et al. epidemiology and risk factors of urothelial bladder cancer. eur urol. 2013; 63:234-41. 2. martin jw, jefferson fa, huang m, et al. a california cancer registry analysis of urothelial and non-urothelial bladder cancer subtypes: epidemiology, treatment, and survival. clin genitourin cancer. 2020; 18:e330-6. 3. fus lp, pihowicz p, koperski l, et al. hif-1α expression is inversely associated with tumor stage, grade and microvessel density in urothelial bladder carcinoma. pol j pathol. 2018; 69:395-404. 4. mortada wi, awadalla a, khater s, et al. copper and zinc levels in plasma and cancerous tissues and their relation with expression of vegf and hif-1 in the pathogenesis of muscle invasive urothelial bladder cancer: a case-controlled clinical study. environ sci pollut res int. 2020; 27:15835-41. 5. theodoropoulos ve, lazaris ac, kastriotis i, et al. evaluation of hypoxia-inducible factor 1 alpha overexpression as a predictor of tumour recurrence and progression in superficial urothelial bladder carcinoma. bju int. 2005; 95:425-31. 6. xue m, li x, li z, chen w. urothelial carcinoma associated 1 is a hypoxia-inducible factor-1α-targeted long noncoding rna that enhances hypoxic bladder cancer cell proliferation, migration, and invasion. tumour biol. 2014; 35:6901-12. 7. chai c, chen w, hung w, et al. hypoxia-inducible factor-1alpha expression correlates with focal macrophage infiltration, angiogenesis and unfavourable prognosis in urothelial carcinoma. j clin pathol. 2008; 61:658-64. 8. theodoropoulos ve, lazaris ac, sofras f, et al. hypoxia-inducible factor 1 alpha expression correlates with angiogenesis and unfavorable prognosis in bladder cancer. eur urol. 2004; 46:200-8. 9. badr s, salem a, yuosif ah, et al. hypoxia inducible factor-1alpha and microvessel density as angiogenic factors in bilharzial and nonbirharzial bladder cancer. clin lab. 2013; 59:805-12. 10. darmadi d, ruslie rh. association between prothrombin induced by vitamin k absence-ii (pivka-ii) and barcelona clinic liver cancer (bclc) stage, tumor size, portal venous thrombosis in hepatocellular carcinoma patients. sains malays. 2021; 50:475-80. 11. shigeta k, hasegawa m, hishiki t, et al. idh2 stabilizes hif1α-induced metabolic reprogramming and promotes chemoresistance in urothelial cancer. embo j. 2023; 42:e110620. 12. darmadi d, ruslie rh, pakpahan c. vascular endothelial growth factor levels difference among hepatocellular cancer patients based on barcelona clinic liver cancer staging. open access maced j med sci. 2021; 9:797-800. 13. ruslie rh, darmadi d, siregar ga. vascular endothelial growth factor (vegf) and neopterin levels in children with steroid sensitive and steroid-resistant nephrotic syndrome. med arch. 2021; 75:133-7. 14. deniz h, karakok m, yagci f, guldur me. evaluation of relationship between hif-1α immunoreactivity and stage, grade, angiogenic profile and proliferative index in bladder urothelial carcinomas. int urol nephrol. 2010; 42:103-7. correspondence ginanda putra siregar, md (corresponding author) ginandasir@gmail.com doctoral study program, faculty of medicine, universitas padjadjaran, bandung, indonesia and division of urology, department of surgery, faculty of medicine, universitas sumatera utara, medan, indonesia ida parwati, md department of clinical pathology, faculty of medicine, universitas padjadjaran, bandung, indonesia bambang sasongko noegroho, md ferry safridai, md department of urology, faculty of medicine, universitas padjadjaran, bandung, indonesia gerhard reinaldi situmorang, md department of urology, faculty of medicine, universitas indonesia, jakarta, indonesia raden yohana, md division of oncology, department of surgery, faculty of medicine, padjadjaran university, bandung, indonesia astrid feinisa khairani, md department of biomedical sciences, faculty of medicine, universitas padjadjaran, bandung, indonesia conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 47 original paper urologist armamentarium is the ureteral access sheath (uas), to access the proximal collecting system. the use of uas has the proposed advantages of lowering the intrarenal pressure that probably decreases the complications related to infection, increasing irrigation flow and facilitating multiple reinsertions and withdrawals of the ureteroscope during surgery (4, 5). however, these benefits are associated with the cost of increased insertion forces and greater risk for ureteral wall injury, and possible failed insertion. proposed higher stone free rates with uas use and cost-effectiveness are too much debated (6-8). uas has multiple designs across multiple brands. although safety has been demonstrated, there have been few studies comparing designs of different companies in the hands of practicing urologists in vivo. we aimed to compare two commonly used uass regarding functional characteristics, safety profile and effectiveness of each. this information will help guide urologists in product selection when performing ureteroscopy. methods after institutional review board (irb) and ethical committee approval, patients with proximal ureteral or kidney stones requiring flexible ureterorenoscopy and uas placement in our tertiary center were enrolled in the prospective clinical trial after signing the informed consent. patients less than 18 years old or patients with ureteric stricture were excluded. patients were randomized to the use of boston scientific navigator hdtm (nhd) (group i) or of cook flexortm (cf) (group ii) uas. randomization was performed by investigator using closed envelope technique. the data of both cohorts were prospectively obtained and analyzed. traxer grading system for uas-related injuries was used for classification and comparison of intraoperative ureteric injuries (8). primary outcome was incidence of sheath related intraoperative complications while the difficulty of uas placement, length of procedure (lop), post-operative complications, patient-reported complaints/phone calls/emergency department (ed) visits, postoperative hydronephrosis were secondary outcomes. the two uas brands have a design of outer hydrophilic sheath and smooth-tapered inner coaxial dilator. the cf outer sheath is specialized with coil construction core. the inner dilator of nhd has a stiff body and a more flexobjective: we aimed to evaluate and compare the functional characteristics, safety profile and effectiveness of two commonly used ureteral access sheaths (uas) during flexible ureteroscopy. methods: after institutional review board approval, patients with proximal ureteral or kidney stones requiring flexible ureteroscopy and uas were prospectively randomized to group i or group ii according to the type of access sheath used. primary outcome was incidence of intraoperative complications. results: eighty-eight patients were enrolled in the study, 44 patients in each group. sheath size 12/14 fr was used in both cohorts. median (iqr) stone size was 10 mm (7-13.5) and 10.5 mm (7.37-14) in group i and ii respectively (p = 0.915). nineteen and twenty patients, in group i and ii respectively, were pre-stented. subjective resistance with insertion of the uas was observed in 9 and 11 patients in group i and ii respectively (p = 0.61) while failed insertion was encountered in one patient in group i. traxer grade 1 ureteral injury was noted in 5 and 6 patients in group i and ii respectively while grade 3 injury was seen in 1 patient for both cohorts (p = 0.338). there was less resistance for uas placement in pre-stented patients (p = 0.0202) but without significant difference in ureteric injury incidence (p = 0.175). emergency department visits were encountered in 7 (group i) and 5 patients (group ii) (p = 0.534). conclusions: the studied uass were comparable regarding safety and efficacy in the current study. pre-stented and dilated ureters had less resistance to insertion although this was not reflected on incidence of ureteric injury. key words: ureteroscopy; urolithiasis; ureteral access sheath; ureteral trauma. submitted 11 january 2023; accepted 22 january 2023 background ureterorenoscopy continues to be one of the most common procedures performed in urology practice, being a minimally invasive option for treatment of nephrolithiasis and ureterolithiasis. technological advances in both the size and flexibility of ureteroscopes have been integral to removing larger stones with a higher stone free rate. the continued advancement of the technology surrounding holmium: yag lasers, graspers, and baskets have continued to widen the application of ureteroscopy (1, 2). there are multiple instruments available on the market to aid in the performance of ureteroscopy (3). one tool in the comparison of commonly utilized ureteral access sheaths: a prospective randomized trial mohamed elsaqa 1,2, zain hyder 1, kim thai 1, katherine dowd 1, amr el mekresh 1, kristofer wagner 1, belur patel 1, patrick lowry 1, marawan m. el tayeb 1 1 baylor scott & white medical center, temple, tx usa; 2 alexandria university faculty of medicine, alexandria, egypt. doi: 10.4081/aiua.2023.11149 summary archivio italiano di urologia e andrologia 2023; 95, 2 mohamed elsaqa, zain hyder, kim thai, et al. 48 ible tip while cf inner dilator has a stiff tip tapered to 6 fr diameter. the nhd is available in 3 sizes of 11/13 fr, 12/14 fr, and 13/15 fr whereas cf is available in 12/14 and 14/16 in addition to smaller diameters of 9.5/11.5 and 10.7/12.5 fr. statistical analysis all statistical analysis was performed using the commercially available sas version 9.4 (statistical analysis software) (sas institute inc., cary, nc, usa). frequencies and percentages were used to describe categorical variables while medians and interquartile ranges (or means and standard deviations where appropriate) were used to describe continuous variables. a chi-square test or fisher’s exact test were used to test for comparison of categorical variables according to the expected cell counts while two-sample t-test (or wilcoxon rank-sum test when appropriate) was used for comparison of quantitative variables. the significance level was set at a p-value < 0.05. results between february 2017 and february 2020, 88 patients were prospectively enrolled in the study. forty-four patients were included in each group. sheath of 12/14 french was used in both cohorts. patients' demographics were comparable with no statistical significance between both cohorts except for higher rate of preoperative alpha blocker use in group ii. median (iqr) stone size was 10 (7-13.5) mm and 10.5 (7.37-14) in group i and ii respectively (p = 0.915). thirty-nine patients had ureteric stents previously inserted (pre-stented) at the time of flexible ureteroscopy, nineteen and twenty patients, in group i and ii respectively (table 1). median (iqr) operative time was 54 (41-78) and 51 (3672) minutes in group i and ii respectively (p = 0.302). subjective resistance with insertion of the uas was observed in 9 patients in group i vs. 11 patients in group ii (p = 0.61). there was one failure of insertion of the uas in group i. there was a statistically less resistance for placement of the uas noted in pre-stented patients’ cohort (p = 0.0202). it was also noted that patients with preoperative hydronephrosis had significantly less resistance to uas placement (p = 0.0493). there was no significant difference in resistance to insertion between patients who had preoperative alpha blocker use or not (p = 0.34). regarding sheath-related ureteric trauma, a total of 13 (16%) injuries were observed; 7 and 6 injuries in group i and ii respectively. out of 13 patients with ureteric injury, 8 patients were not previously stented (p = 0.175). taxer grade 1 ureteral injury was noted in 6 patients in the group i vs 5 patients in group ii. taxer grade 3 injury was seen in 1 patient for both cohorts (p = 0.338) (table 2). need for opioid analgesia and patients’ phone calls were comparable between both groups (p = 0.247, 0.669 respectively) return to the ed was encountered in 7 and 5 patients from group i and ii respectively (p = 0.534). the complains were mainly related to pain and hematuria. there was no association with sheath complication and return to ed. within follow up of 3 months, one patient in group 2 had persistent hydronephrosis although imaging has excluded occurrence of ureteric stricture. discussion the benefits of the uas in ureteroscopy and retrograde intrarenal surgery (rirs) are still controversial. de coninck et al., in their systemic review, showed that uas helps increasing flow of irrigation and decreasing intrarenal pressure but the impact of uass on stone-free rates, ureteroscope protection or damage, postoperative pain, risk of ureteral strictures, and cost-effectiveness are still controversial (4). in another recent review article, wong et al have concluded that no evidence exists for higher stone free rate with the use of uas but facilitates multiple and rapid passages of the ureteroscope during the procedure. according to wong et al, larger uas diameters > 12/14 fr were associated with lower intrarenal pressure and greater efficacy at the cost of increased forces during insertion, greater risk for ureteral wall injury, and lower insertion success rates (6). regarding the uas size choice, yoshida et al. have evaluattable 1. preoperative patient criteria in both groups. group i (n = 44) group ii (n = 44) p value age, years, mean (sd) 59.1 (2.3) 53.9 (2.5) 0.13 sex, n (%) male 21 (48%) 25 (57%) 0.393 female 23(52%) 19(43%) stone size, mm, median (iqr) 10 (7-13.5) 10.5 (7.37-14) 0.915 stone side, n (%) right 18 (40%) 14 (32%) 0.414 left 24 (54.5%) 27 (61.3%) bilateral 2 (4.5%) 3 (6.8%) alpha blocker use, n (%) 15 (34%) 28 (63%) 0.005 stone location, n (%) renal 41 45 0.305 upper ureter 7 13 mid ureter 0 1 lower ureter 2 3 hydronephrosis, n (%) 23 (52%) 30 (68%) 0.127 preop uti, n (%) 6 (13.6%) 12 (27.2%) 0.112 pre-stenting, n (%) 19 (43.1%) 20 (45.4%) 0.83 table 2. perioperative outcome data. group i (n = 44) group ii (n = 44) p value operative time, min, median (iqr) 54 (41-78) 51 (36.5-72.25) 0.302 anesthesia time, min, median (iqr) 100 (74.5-121.5) 104 (76.5-118.5) 0.779 resistance to introduction, n (%) 9 (20.4%) 11 (25%) 0.61 failed insertion, n (%) 1 (2.27%) 0 0.314 string on stent 23 (52%) 25 (56.8%) 0.66 op. sheath complication, n (%) 7 (15.9%) 6 (13.6%) 0.763 ureteral injury grade, n (%) garde 1 6 (13.6%) 5 (11.3%) 0.338 grade 2 0 0 grade 3 1 (2.27%) 1 (2.27%) need for opioid analgesia, n (%) 16 (36.3%) 11 (25%) 0.247 phone calls, n (%) 22 (50%) 20 (45.4%) 0.669 ed-return, n (%) 7 (15.9%) 5 (11.36%) 0.5344 po hydronephrosis, n (%) 0 1 (2.27%) 0.314 archivio italiano di urologia e andrologia 2023; 95, 2 49 ureteral access sheaths ed different uas ≤ 10/12 f regarding the intrapelvic pressure in an ex-vivo porcine kidneys. they showed that 9.5/11.5 f uas were associated with excessive intrapelvic pressure (10). sener et al have recommended sheath size 10/12 f as the first choice during flexible ureterorenoscopy for good irrigation and lower rate of ureter injury than 12/14 f uas (11). de et al. compared the physical characteristics of nhd, cf and other two new single-wire system uass in ex-vivo study. they reported that nhd is more slippery and more rigid with larger outer diameter while cf had shorter and stiffer tip and appeared less traumatic (more force was required for tip perforation) (12). in a similar ex-vivo study, patel et al also compared the physical and mechanical characteristics of nhd uas versus glidewaytm and pathwaytm uass supplied by terumo. they reported superiority for nhd regarding safety and ease of use (13). loftus et al have compared the same two investigated uas brands in a randomized clinical trial. in contrary of our study, all the patients included in their study were not pre-stented. loftus et al used different uas sizes and they crossed over patients who fail insertion of one uas type to the other. they reported overall sheath placement success rate of 87.8% with no difference between both types although nhd was subjectively easier to insert and was successful in 3 out of 7 (43%) patients who failed insertion of cf. they have reported some factors associated with high-grade (grade 2 or 3) ureteral injury as male gender, difficult subjective insertion, longer time of sheath insertion and high stone burden (14). in the current study, the insertion success rate was 98.8% with no significant difference between both groups. the two uass appeared comparable on many fronts, including ease of placement, ureteral injury rates, operative times, and return to ed rates. of note, our results showed less resistance to insertion was seen with preoperative hydronephrosis and ureteric stenting although no difference regarding ureteric injury. similarly, yuk et al. have reported that pre-stenting was associated with higher uas placement success although had no effect on overall operative outcomes (15). other studies have investigated the use of alpha blockers on uas force of placement. koo et al have reported that preoperative use of alpha blockers was associated with lower uas insertion force (16). however, contradictory results were reported by erturhan et al in another study (17). in our cohort, the preoperative usage of alpha blockers prior to uas placement was not associated with an easier subjective uas clinical placement. study by stern et al. demonstrated that high-grade injury due to uas placement has around a 1.8% stricture rate and this rate was similar to that reported without use of uas (8). aykant et al., in a prospective randomized study, have recently reported the rates of low-grade ureteral injury rate of 23.1% while high-grade injury rate was 8.9%. after 1-year, the ureteral stricture was 1.6%. they reported that use of 12/14 f uas was associated with higher risk of high-grade injuries although there was no difference in ureteral stricture formation compared to use of 9.5f/11.5 f sheath (18). there were only two high grade ureteral injuries noted in the current study. all ureteral injuries were treated with stent placement for 2-4 weeks. on follow up, only 1 patient had persistent hydronephrosis and no patients were noted to have ureteral stricture at follow up of 3 months. our study adds to growing literature that the nhd and cf have similar safety profiles and have a broad range of clinical application. limitations of the study include small study group and lack of stone-free rate assessment. further studies could be used to target stone size and determine the effect of sheath usage on stone clearance rates. conclusions the two commonly utilized ureteral access sheath brands are equally safe and effective for utilization during flexible ureteroscopy and retrograde intrarenal surgery. prestented and dilated ureters show less resistance to insertion although this was not associated with lower incidence of associated ureteric injury. informed consent: the study and informed consent were approved by baylor scott & white institutional review board (irb no: 18-4720). all patients have signed an informed consent prior to participation to the study. references 1. doizi s, traxer o. flexible ureteroscopy: technique, tips and tricks. urolithiasis. 2018; 46:47-58. 2. rodríguez-monsalve herrero m, doizi s, keller ex, et al. retrograde intrarenal surgery: an expanding role in treatment of urolithiasis. asian j urol. 2018; 5:264-273. 3. inoue t, okada s, hamamoto s, fujisawa m. retrograde intrarenal surgery: past, present, and future. investig clin urol. 2021; 62:121-135. 4. de coninck v, keller ex, rodríguez-monsalve m, et al. systematic review of ureteral access sheaths: facts and myths. bju int. 2018; 122:959-969. 5. auge bk, pietrow pk, lallas cd, et al. ureteral access sheath provides protection against elevated renal pressures during routine flexible ureteroscopic stone manipulation. j endourol. 2004; 18:33-6. 6. wong vk, aminoltejari k, almutairi k, et al. controversies associated with ureteral access sheath placement during ureteroscopy. investig clin urol. 2020; 61:455-463. 7. meier k, hiller s, dauw c, et al. understanding ureteral access sheath use within a statewide collaborative and its effect on surgical and clinical outcomes. j endourol. 2021; 35:1340-1347. 8. stern jm, yiee j, park s. safety and efficacy of ureteral access sheaths. j endourol. 2007; 21:119-23. 9. traxer o, thomas a. prospective evaluation and classification of ureteral wall injuries resulting from insertion of a ureteral access sheath during retrograde intrarenal surgery. j urol. 2013; 189:580-4. 10. yoshida t, inoue t, abe t, matsuda t. evaluation of intrapelvic pressure when using small-sized ureteral access sheaths of ≤ 10/12f in an ex vivo porcine kidney model. j endourol. 2018; 32:1142-1147. 11. sener te, cloutier j, villa l, et al. can we provide low intrarenal pressures with good irrigation flow by decreasing the size of ureteral access sheaths? j endourol. 2016; 30:49-55. archivio italiano di urologia e andrologia 2023; 95, 2 mohamed elsaqa, zain hyder, kim thai, et al. 50 12. de s, sarkissian c, torricelli fc, et al. new ureteral access sheaths: a double standard. urology. 2015; 85:757-63. 13. patel n, monga m. ureteral access sheaths: a comprehensive comparison of physical and mechanical properties. int braz j urol. 2018; 44:524-535. 14. loftus cj, ganesan v, traxer o, et al. ureteral wall injury with ureteral access sheaths: a randomized prospective trial. j endourol. 2020; 34:932-936. 15. yuk hd, park j, cho sy, et al. the effect of preoperative ureteral stenting in retrograde intrarenal surgery: a multicenter, propensity score-matched study. bmc urol. 2020; 20:147. 16. koo kc, yoon jh, park nc, et al. the impact of preoperative αadrenergic antagonists on ureteral access sheath insertion force and the upper limit of force required to avoid ureteral mucosal injury: a randomized controlled study. j urol. 2018; 199:1622-30. 17. erturhan s, bayrak ö, şen h, et al. can alpha blockers facilitate the placement of ureteral access sheaths in retrograde intrarenal surgery? turk j urol. 2019; 45:108-112. 18. aykanat c, balci m, senel c, et al. the impact of ureteral access sheath size on perioperative parameters and postoperative ureteral stricture in retrograde intrarenal surgery. j endourol. 2022; 36:1013-1017. correspondence mohamed elsaqa, md (corresponding author) mohamed.elsaqa@alexmed.edu.eg division of urology, department of surgery, baylor scott & white health, 2401 s. 31st street, temple, tx 76508 zain hyder, md zain.hyder@bswhealth.org kim thai, md kthai88@gmail.com katherine dowd, md katiedowd12@gmail.com amr el mekresh, md elsaqa2020@yahoo.com kristofer wagner, md kristofer.wagner@bswhealth.org belur patel, md belur.patel@bswhealth.org patrick lowry, md patrick.lowry@bswhealth.org marawan m. el tayeb, md marawan.eltayeb@bswhealth.org baylor scott & white medical center, temple, tx, usa conflict of interest: the authors declare no potential conflict of interest. archivio italiano di urologia e andrologia 2013; 85, 120 introduction pharmacological therapy taken by the male partners of subfertile couples could represent a pathogenic factor that may negatively influence seminal parameters. the potential negative effects could impact on spermatogenesis, thus affecting the sperm number and morphology, and also epididymal maturation, which could affect progressive sperm motility. in the literature, there are few studies regarding the relationship between the effects of long-term and shortterm drug therapies and seminal parameters; moreover, such studies usually consider only a single class of drugs (such as statins, antihypertensives, etc.). original paper impact of long-term and short-term therapies on seminal parameters jlenia elia, norina imbrogno, michele delfino, rossella mazzilli, vincenzo spinosa, fernando mazzilli department of clinical and molecular medicine, sant’andrea hospital, unit of andrology, university of rome “sapienza”, rome, italy. aim: the aim of this work was: i) to evaluate the prevalence of male partners of subfertile couples being treated with long/short term therapies for non andrological diseases; ii) to study their seminal profile for the possible effects of their treatments on spermatogenesis and/or epididymal maturation. methods: the study group was made up of 723 subjects, aged between 25 and 47 years. semen analysis was performed according to world health organization (who) guidelines (1999). the superimposed image analysis system (sias), which is based on the computerized superimposition of spermatozoa images, was used to assess sperm motility parameters. results: the prevalence of subjects taking pharmacological treatments was 22.7% (164/723). the prevalence was 3.7% (27/723) for the short-term group and 18.9% (137/723) for the long-term group. the subjects of each group were also subdivided into subgroups according to the treatments being received. regarding the seminal profile, we did not observe a significant difference between the long-term, short-term or the control group. however, regarding the subgroups, we found a significant decrease in sperm number and progressive motility percentage in the subjects receiving treatment with antihypertensive drugs compared with the other subgroups and the control group. conclusions: in the management of infertile couples, the potential negative impact on seminal parameters of any drugs being taken as long-term therapy should be considered. the pathogenic mechanism needs to be clarified. key words: male fertility; semen, long-term therapy; short-term therapy. submitted 3 october 2012; accepted 31 december 2012 no conflict of interest declared summary concerning long-term therapies, one of the first papers on the effects of drug treatment on seminal parameters concerned sulfasalazine, generally used for intestinal illness. toth et al. (1) and cosentino et al. (2) reported a reduction in progressive sperm motility and an increase in atypical forms. subsequently, there were other papers, which concerned antiepileptics, antiretrovirals, alpha-lytics and statins. in particular, chen et al. (3) showed the negative effects “in vitro” on sperm motility of carbamazepine, phenytoin, valproate and phenobarbital. these data were also confirmed in other studies (4-6). in addition, several studies (7-8) elia_stesura seveso 18/04/13 11:00 pagina 20 21archivio italiano di urologia e andrologia 2013; 85, 1 impact of long-term and short-term therapies on seminal parameters controlled incubator at 37°c within 60 min of ejaculation and then analyzed according to world health organi zation (who) guidelines 1999 (16). the superimposed image analysis system (sias) (delta sistemi, rome italy), which is based on computerized image superimposition, was used to asses sperm motility parameters (17, 18). sperm morphology was assessed using the bryanleishman stain technique and examined at a magnification of 1000x, with an olympus cx 31 light microscope, using a micrometric scale. all the subjects had at least 2 standard semen analyses and the mean of the results obtained was established for each seminal parameter; at least 200 spermatozoa were evaluated. the total subjects were then subdivided into two groups, based on the pharmacological therapies being taken: – long-term therapy group (more than 6 months); – short-term therapy group (more than 7 days and less than 15 days). statistical analysis results are expressed as percentages, mean values and standard deviations. the fisher exact test and the student t-test for independent samples were performed to compare the means of the two distributions. a p value < 0.05 was considered significant. results the prevalence of subjects who were taking pharmacological treatments was 22.7% (164/723). in particular, the prevalence was 3.7% (27/723) for the short-term therapy group and 18.9% (137/723) for the long-term therapy group. subsequently, the subjects of each group were further subdivided into subgroups, according to the treatment being taken. the remaining subjects that were not taking any pharmacological therapies (559/723; 77.3%) were employed as a control group. the short-term therapy group the subjects in short-term therapy were subdivided as follows: antibiotics 2.3% (17/723); antinflammatory 1.1% (8/723) and pde5-inhibitors 0.3% (2/723); (table 1). regarding the seminal profile, we did not observe any significant differences between the shortterm group and the control group; the same was true for the subgroups. the long-term therapy group the subjects in long-term therapy group were subdivided into the following subgroups (table 1): a) antipsysuggested an enhancement in semen quality parameters following the cessation of pharmacological therapies. other authors showed a reduction of progressive sperm motility caused by antiretroviral drugs (9), by statin treatment (10) and by tamsulosin (11), that affect also sperm number and atypical forms. regarding short-term therapies, there are very few reports in the literature: schlegel et al. (12) defined antibiotics (nitrofurans, sulfasalazine, minocycline) as “potential hazards to male fertility” owing to potentially dangerous effects on sperm concentration. other studies regard the possible interaction between pde5-inhibitors and semen parameters; however, there are conflicting data about their action. aversa et al. (13) observed that sildenafil did not change seminal parameters; on the other hand, pomara et al. (14) observed an increase of progressive sperm motility in subjects treated with sildenafil (50 mg), while the use of tadalafil (20 mg) produced a decrease in semen quality. finally, jarvi et al. (15) studied the possible effects of daily treatment for 6 weeks with vardenafil and tadalafil; in both cases, no changes were observed on seminal parameters. the aim of this work was: i) to evaluate the prevalence of male partners of subfertile couples being treated with long/short term therapies for non andrological diseases; ii) to study their seminal profile for the possible effects of their treatments on spermatogenesis and/or epididymal maturation. materials and methods subjects the clinical study was conducted according to the hospital ethics’ committee guidelines. the study group was made up of 723 subjects, aged between 25 and 47 years, who were referred to our andrology unit from december 2007 to december 2011 for various andrological examinations. a full medical history was taken afterthat the patients underwent a diagnostic and therapeutic program comprising: clinical and seminal examination and hormonal profile. all subjects with hormonal alterations, treated cryptorchidism, previous testicular trauma, seminal obstructions or genetic alterations were excluded from the study. semen analysis semen samples were collected by masturbation after a sexual abstinence period of 3-5 days. after liquefaction (for 15-30 min at 37°c), the semen samples were stored in a short -term therapy group long-term therapy group control group n. 27/723 (3.7%) n. 137/723 (18.9%) n. 559/723 antibiotics antipde-5 antipsycotic/ antihypertensive antihistamine gastrohormone miscellaneous combined no therapy inflammatory inhibitors antiepileptic protective n. 17 n. 8 n. 2 n. 29 n. 19 n. 18 n. 12 n. 8 n. 17 n. 34 n. 559 (2.4%) (1.1%) (0.3%) (4.0%) (2.6%) (2.5%) (1.7%) (1.1%) (2.3%) (4.7%) (77.3%) table 1. total subjects in pharmacological treatments (shortand long-term therapy groups) and control group. elia_stesura seveso 18/04/13 11:00 pagina 21 archivio italiano di urologia e andrologia 2013; 85, 1 j. elia, n. imbrogno, m. delfino, r. mazzilli, v. spinosa, f. mazzilli 22 on the other hand, regarding the subgroups, we found a significant decrease in sperm number and progressive motility percentage in subjects treated with antihypertensive drugs compared with the other long-term therapy subgroups (p < 0.05) (figure 2). chotic and antiepileptic drugs: 4.0% (29/723 cases); b) antihypertensive drugs: 2.6% (19/723 cases); c) antihistaminic drugs: 2.5% (18/723 cases); d) gastroprotective drugs 1.7% (12/723 cases); e) hormone 1.1% (8/723 cases); f) miscellaneous (antiretroviral, statins, oral antidiabetic drugs or anticoagulants, etc) 2.3% (17/723 cases); g) combined therapy (antihypertensive and gastroprotective drugs; antipsychotic and metabolic drugs; antihypertensive, anticoagulant and statin drugs): 4.7% (34/723 cases). regarding the seminal profile, we did not observe any significant differences between the long-term therapy group and the control group (figure 1). figure 1. semen parameters in long-term therapy group and in control group. boxes indicate 25th and 75th percentiles while the horizontal line within the box indicates the 50th percentile value (median). vertical lines give 10th and 90th percentile limits of the data, while single points indicate extreme values outside this range. figure 2. semen parameters in long-term therapy subgroups and control group. a) control group; b) antipsychotic/antiepileptic; c) antihypertensive; d) antihistamine; e) gastroprotective; f) hormone; g) miscellaneus; h) combined. * p < 0.05 vs control group. boxes indicate 25th and 75th percentiles while the horizontal line within the box indicates the 50th percentile value (median). vertical lines give 10th and 90th percentile limits of the data, while single points indicate extreme values outside this range. elia_stesura seveso 18/04/13 11:00 pagina 22 23archivio italiano di urologia e andrologia 2013; 85, 1 impact of long-term and short-term therapies on seminal parameters discussion in this study we considered the prevalence of male partners of subfertile couples under long-term and shortterm pharmacological treatments for non andrological diseases and the possible effects of such treatment on seminal parameters. regarding the first, the prevalence of pharmacological treatments identified was 22.7%, almost double that of hayashi’s data (19). it is a remarkable prevalence, especially in such a relatively young population. we differentiated in short-term treatment for the possible effects only on epididymal maturation and long-term for possible effects on the process of spermatogenesis and/or epididymal maturation. the prevalence found was 3.7% in the short-term group and mainly involved the use of antibiotics and antinflammatory medication and only minimally the use of pde5 inhibitors. in subjects taking long-term therapy, the prevalence observed was 18.9%; this concerned the use of various classes of drugs, including antipsychotic, antiepileptic, antihypertensive, antihistamine medications and also drugs associations. regarding the seminal profile, we did not observe any significant differences between the shortterm therapy group, or the subgroups, vs the control group. regarding antinflammatory medication, this is not surprising since they are commonly used for the treatment of genital tract inflammation. however, even antibiotics did not appear to have a negative impact on seminal parameters. the number of subjects taking pde5 inhibitors was too small to have a statistical significance. also the long-term group did not show any significant variations compared with the control group. on the other hand, the long-term subgroup treated with antihypertensive drugs (calcium channel blockers, beta blockers, angiotensin converting enzyme inhibitors) showed a significant decrease in sperm number and progressive motility percentage compared with the other long-term therapy subgroups and the control group. the possible pathogenic mechanism may be an alteration in local blood flow, also at the hemato-testicular barrier, which would produce a reduction of the nutrients needed in spermatogenesis, or perhaps direct damage to the epididymis, which would inhibit kinetic sperm properties and then motility. in conclusion, long-term drug therapy is a factor that should always be taken into consideration in the management of infertile couples, owing to the potential negative impact of such treatment on seminal parameters. the pathogenic mechanisms involved need to be clarified. references 1. toth a. reversible toxic effect of salicylazosulfapyridine on semen quality. fertil steril. 1979; 31:538-40. 2. cosentino mj, chey wy, takihara h, cockett at. the effects of sulfasalazine on human male fertility potential and seminal prostaglandins. j urol. 1984; 132:682-6. 3. chen ss, shen mr, chen tj, lai sl. effects of antiepileptic drugs on sperm motility of normal controls and epileptic patients with long-term therapy. epilepsia. 1992; 33:149-53. 4.taneja n, kucheria k, jain s, maheshwari mc. effect of phenytoin on semen. epilepsia. 1994; 35:136-40. 5. roste ls, tauboll e, haugen tb, et al. alterations in semen parameters in men with epilepsy treated with valproate or carbamazepine monotherapy. eur j neurol. 2003; 10:501-6. 6. isojarvi ji, lofgren e, juntunen ks, et al. effect of epilepsy and antiepileptic drugs on male reproductive health. neurology. 2004; 62:247-53. 7. yerby ms, mccoy gb. male infertility: possible association with valproate exposure. epilepsia. 1999; 40:520-1. 8. hayashi t, yoshinaga a, ohno r, et al. asthenozoospermia: possible association with long-term exposure to an anti-epileptic drug of carbamazepine. int j urol. 2005; 12:113-4. 9. van leeuwen e, wit fw, repping s, et al. effects of antiretroviral therapy on semen quality. aids. 2008; 22:637-42. 10. dobs as, schrott h, davidson mh, et al. effects of high-dose simvastatin on adrenal and gonadal steroidogenesis in men with hypercholesterolemia. metabolism. 2000; 49:1234-8. 11. hellstrom wj, sikka sc. effects of alfuzosin and tamsulosin on sperm parameters in healthy men: results of a short-term, randomized, double blind, placebo-controlled, crossover study. j androl. 2009; 30:469-74. 12.schlegel pn, chang ts, marshall ff. antibiotics: potential hazards to male fertility. fertil steril. 1991; 55:235-42. 13. aversa a, mazzilli f, rossi t, et al. effects of sildenafil (viagra) administration on seminal parameters and post-ejaculatory refractory time in normal males. hum reprod. 2000; 15:131-4. 14. pomara g, morelli g, canale d, et al. alterations in sperm motility after acute oral administration of sildenafil or tadalafil in young, infertile men. fertil steril. 2007; 88:860-5. 15. jarvi k, dula e, drehobl m, et al. daily vardenafil for 6 months has no detrimental effects on semen characteristics or reproductive hormones in men with normal baseline levels. j urol. 2008; 179:1060-5. 16. world health organization. laboratory manual for the examination of human semen and sperm-cervical mucus interaction. 4rd ed. new york: cambridge university press. 1999. 17. mazzilli f, rossi t, sabatini l, dondero f. superimposed image analysis system (sias) software: a new approach to sperm motility assessment. fertil steril. 1995; 64:653-6. 18. mazzilli f, rossi t, delfino m, nofroni i. application of the upgraded image superimposition system (sias) to the assessment of sperm kinematics. andrologia. 1999; 31:187-94. 19. hayashi t, miyata a, yamada t. the impact of commonly prescribed drugs on male fertility. hum fertil. 2008; 11:191-6. correspondence jlenia elia, md norina imbrogno, md michele delfino, md rossella mazzilli, md vincenzo spinosa, md sant’andrea hospital, unit of andrology, university of rome “sapienza” via di grottarossa 1035 00189 roma, italy fernando mazzilli, md (corresponding author) professor sant’andrea hospital, unit of andrology university of rome “sapienza”, via di grottarossa 1035 00189 roma, italy fernando.mazzilli@uniroma1.it elia_stesura seveso 18/04/13 11:00 pagina 23 introduction bladder cancer is the second most common tumour of the genito-urinary tract. in 2010, approximately 70,000 new cases of bladder cancer with almost 15,000 deaths were estimated in the usa alone (1). when the disease is first diagnosed it is non-muscle-invasive (nmibc) in 75-80% of cases while the remaining cases are muscle-invasive (mibc) (2). over 50% of nmibc recur, while 15-20% advance towards a muscle-invasive form. early diagnosis 73archivio italiano di urologia e andrologia 2013; 85, 2 original paper her-2 immunohistochemical expression as prognostic marker in high-grade t1 bladder cancer (t1g3) luca bongiovanni 1, vincenzo arena 2, fabio maria vecchio 2, marco racioppi 1, pierfrancesco bassi 1, francesco pierconti 2 1 department of urology, 2 department of pathology catholic university of the sacred heart, policlinico “agostino gemelli”, rome, italy objectives: to evaluate if the human epidermal growth factor receptor 2 (her-2) expression levels may be used as potential prognostic marker in high grade t1 bladder cancer (t1g3) methods: specimens from transurethral resection of bladder tumour (turbt) of 103 patients with high-grade t1 bladder cancer were collected. this pathologic database was reviewed. four-year follow-up data were matched with pathologic data. eighty-three patients entered the study. her-2 staining was performed. patients were grouped for her-2 status. statistical analysis included kaplan meier survival analysis and log-rank test. results: pathological review of turbt specimens confirmed high-grade t1 transitional cell bladder cancer in all patients. median follow-up was 12 months (mean 23,5; range 3-48). twenty-one patients (25.4%) present strong her-2 expression (3+), 28 (33.7%) moderate expression (2+), 26 (33.7%) weak staining (1+) and 8 (9.6%) negative expression (0). thirtyone patients of 83 (37.4%) had not evidence of disease, 41 (49.4%) recurred, 11 (13.2%) had a progression of disease. forty-one patients had high grade t1 recurrence. patients with her-2 status 0 did not showed progression of disease. patients with her-2 status 3+, undergoing cystectomy because progression of disease, had a pathological stage > pt2 and a nodal involvement. median disease-free survival (dfs) for all patients was 12 months (dfs probability (pdfs) = 49.3%; 95% ci, -11.1/+10.1). median dfs in her-2 groups was 8 (pdfs 37.5%; 95% ci,-28.8/+29.9), 24 (pdfs 46.1%; 95% ci,-19.5/+17.5), 20 (pdfs 46.4%; 95% ci,-18.8/+16.9) and 10 months (pdfs 47.6%; 95% ci,-21.9/+19.1) respectively in her-2 status 0,1+,2+,3+. log-rank test is not statistically significant (p = 0,39). conclusions: this study showed that her-2 expression does not represent a prognostic marker of recurrence/progression of disease in high-grade t1 bladder cancer. key words: her-2 expression; prognostic marker; bladder cancer; t1g3. submitted 13 september 2012; accepted 30 december 2012 no conflict of interest declared summary of bladder tumour improves the patient’s prognosis and reduces the number of cases where cystectomy is needed. high-grade t1 lesions of the bladder (t1g3) have a high propensity to recur and progress to muscle invasion and are associated with a significant risk of metastasis and death. long-term progression and death rates as high as 53% and 34%, respectively, have been reported (3). these bladder tumours are heterogeneous in nature and bongiovanni_stesura seveso 24/06/13 11:01 pagina 73 archivio italiano di urologia e andrologia 2013; 85, 2 l. bongiovanni, v. arena, f.m. vecchio, m. racioppi, p. bassi, f. pierconti 74 from 103 subjects (74 males and 29 females; average age 67,8 years, range 41-90) undergoing complete transurethral resection of the bladder tumour (turbt) at department of urology, catholic university of sacred hearth, rome-italy. in january 2010 we have performed a review on this pathologic database. our uropathologist (f.p.) reviewed bladder tumour resection specimens in order to confirm stage/grade of the bladder tumour. the 2002 tnm classification (updated to 2009 tnm classification) was used for pathological staging. the 2004 who/isup classification was used for pathological grading. then, 4-year follow-up data (clinic database) of all patients were matched with pathologic data. inclusion criteria of the study encompassed, namely: presence of highgrade t1 transitional cell bladder cancer (established by pathological examination of complete turbt specimens in whom muscularis propria was present and negative), all patients were first-diagnosed bladder cancer, all patients had complete 4-year follow-up clinical data. exclusion criteria encompassed bacillus-calmetteguèrin(bcg)-treated patients following turbt; incomplete follow-up data. ten patients were excluded because not first-diagnosed, 8 because lost at first follow-up, 2 because incomplete follow-up data. eighty-three patients (67 males and 16 females, average age 69,2 years, range 45-88) of 103 entered the study. thus, her-2 ihc analysis was performed. this study was carried out in accordance with the guidelines set out by the ethics committee and all subjects prior to participation were required to sign an informed consent form. follow-up data the follow-up assessment adopted for these patients includes 3-months cystoscopy and urinary cytology for the first 2 years, then every 6 months for the following 2 years. no second tur was done. approximately after 2 to 4 weeks following turbt, bcg intravesical therapy induction course was performed, followed by bcg maintenance therapy if there was not evidence of disease recurrence/progression. ihc analysis of her-2 four-micron-tissue sections, prepared from a formalinfixed and paraffin-embedded representative of the tumor sample, were used (one to two conventional slides of tumor when available). after deparaffinization, rehydration and antigen retrieval in citrate buffer (10 mmol, ph 6,1), tissue sections were stained for her2 (a0485 policlonal antibody; 1/1500, dako, glostrup, denmark). her2 positivity was assessed using the asco scoring system, evaluating only membranous staining (20). specimen of normal breast tissue were used for negative control and invasive ductal breast carcinoma served as positive controls. the level of her2 protein expression was assessed semiquantitatively by the intensity and percentage of staining and score on a scale of 0 to 3+. score of 0 and 1+ are categorized negative, 2+ as weakly positive, and 3+ as strongly positive. score 0 was defined as negative membrane staining in all neoplastic cells or thus difficult to treat. nevertheless, many of these tumours can be treated successfully with bladder preservation approaches. the dilemma facing the urologist is how best to treat these tumours in a timely manner so that the chances of bladder preservation and cancer control are maximised, while the risks of overtreatment with radical therapy are minimised (4). useful prognostic variables and various biological makers have been proposed to assess the prognosis of bladder cancer, but the efficacy of these variables is still inadequate to accurately predict its heterogeneous behaviour. new reliable molecular indicators are required yet. also, during the past few decades, numerous trials have been conducted to develop new treatment regimens for both nmibc and mibc, because there is an urgent need to identify new agents to prevent bladder cancer recurrence and progression. human epidermal growth factor receptor 2 (her-2) is a transmembrane tyrosine kinase receptor in the epidermal growth factor receptor family and it plays a fundamental role in cell growth, survival and migration. abnormal activation of her-2 has been proposed to lead to oncogenic transformation (5, 6). human epidermal growth factors are involved in oncogenesis through its action on several pathways leading to proliferation, angiogenesis, cell survival and metastatic potential. the role of her-2 has been most studied in breast cancer, in which constitutively active her-2 is overexpressed in 18-22% of cases, correlating with poor prognosis (5, 6). but the prognostic significance of her2 expression status in transitional cell carcinoma (tcc) of the bladder remains uncertain. numerous studies showed that higher her-2 expression levels are associated with poor prognosis (7-10). recently her-2 positivity was identified as an independent predictor of disease recurrence and disease specific survival in patients with tcc of the bladder after radical cystectomy (11). in contrast, other analysis showed only limited or no prognostic value of her-2 expression (12-17). using tissue microarray (tma) data of 184 patients with primary tcc of the bladder, kassouf et al. reported no significant correlation between her-2 expression status and clinical outcomes (16). similarly, another study reported no statistically significant difference in survival rates of 80 consecutive patients with mibc between cases positive and normal her-2 status (12). however, a positive her2 protein expression status could represents a potential prognostic factor in patients affected by tcc of the bladder, particularly in high-grade t1 lesions, and it could be used as a novel target for adjuvant therapy (18, 19). thus, the purpose of our work was to evaluate her-2 immunohistochemical (ihc) expression as prognostic marker of disease recurrence and/or progression in highgrade t1 bladder tumour (t1g3). methods patients selection, inclusion and exclusion criteria. from june 2005 to october 2006, specimens of highgrade t1 transitional cell bladder cancer were collected bongiovanni_stesura seveso 24/06/13 11:01 pagina 74 75archivio italiano di urologia e andrologia 2013; 85, 2 her-2 immunohistochemical expression as prognostic marker in high-grade t1 bladder cancer (t1g3) groups) and its matching with follow-up data (no evidence of disease (ned), recurrence (rec) and progression (prog) data). please note that 31 patients of 83 (37.4%) had not evidence of disease, 41 (49.4%) recurred, 11 (13.2%) had a progression of disease. thus, 41 patients had high-grade t1 recurrence, 8 patients of whom with an association of carcinoma in situ of the bladder (cis). eleven patients of 83 showed progression from nmibc to mibc, requiring cystectomy. her-2 status and its relative association with pathological examination of cystectomy specimens is reported in table 2. high-grade t1 lesions with her-2 status 0 did not showed progression of disease. interestingly, all patients with her-2 status 3+, undergoing cystectomy because progression of disease, had a pathological stage > pt2 and a nodal involvement. figure 2 and 3 shows the kaplan meier plots of dfs for all patients and dfs between the 4 patient groups of her-2 status. median dfs for all patients was 12 months (dfs probability (pdfs) = 49.3%; 95% ci, -11.1/+10.1). median dfs in her-2 groups was respectively: • her-2 status 0 = 8 months (pdfs 37.5%; 95% ci, -28.8/+29.9); • her-2 status 1+ = 24 months (pdfs 46.1%; 95% ci, -19.5/+17.5); when membrane staining was observed in <10% the tumor cells. score 1+ was defined as faint/ barely perceptible membrane staining in > 10% of the cells and the cells exhibit incomplete membrane staining. score 2+ was defined weak-to-moderate complete membrane staining detected in > 10% of tumor cells. score 3+ was defined a strong complete membrane staining in > 10% of tumor cells (figure 1). a cytoplasmic staining was considered non specific. outcome measures and statistical analysis after her-2 staining, patients were grouped for her-2 status in 4 groups. kaplan-meier survival analysis was performed to obtain survival values as disease-free survival (dfs) for all patients and dfs between 4 patient groups of her-2 status. the difference in survival rates was determined by logrank test. statistical significance (p) was set at 0.05. statistical tests were carried out using medcalc statistical software (medcalc software bvba, mariakerke belgium). results pathological review of bladder tumour specimens confirmed high-grade t1 transitional cell bladder cancer in all patients (average diameter of lesions 2 cm, range 13,5 cm). median follow-up was 12 months (mean 23,5; range 3-48) regarding the expression of her-2 protein, 21 patients (25.4%) present strong expression (her-2 score 3+), 28 (33.7%) moderate expression (her-2 score 2+), 26 (33.7%) weak staining (her-2 score 1+) and 8 (9.6%) negative expression (her-2 score 0). table 1 shows her-2 status of patients (grouped in 4 figure 1. membrane her-2 stain intensity. her-2 status n (%) ned (%) rec (%) prog (%) (0) 8 (9.6) 1 (3.2) 7 (17.2) 0 (0) (1+) 26 (31.3) 11 (35.5) 11 (26.8) 4 (36.4) (2+) 28 (33.7) 12 (38.7) 13 (31.7) 3 (27.2) (3+) 21 (25.4) 7 (22.6) 10 (24.3) 4 (36.4) total 83 (100) 31 (100) 41 (100) 11 (100) (37.4) (49.4) (13.2) table 1. her-2 status of patients (grouped in 4 groups) and its matching with follow-up data (no evidence of disease (ned), recurrence (rec) and progression (prog) data). her-2 status prog (%) pathological examination of cystectomy specimens (0) 0 (0) no cystectomy specimens (1+) 4 (36.4) 3 (pt2a pn0 pmx g3) 1 (pt3a pn1 pmx g3) (2+) 3 (27.2) 2 (pt2b pn0 pmx g3) 1 (pt3a pn1 pmx g3) (3+) 4 (36.4) 2 (pt3a pn1 pmx g3) 1 (pt3a pn2 pmx g3) 1 (pt4a pn2 pmx g3) total 11 (100) table 2. her-2 status and its association with pathological examination of cystectomy specimens. bongiovanni_stesura seveso 24/06/13 11:01 pagina 75 archivio italiano di urologia e andrologia 2013; 85, 2 l. bongiovanni, v. arena, f.m. vecchio, m. racioppi, p. bassi, f. pierconti 76 • her-2 status 2+ = 20 months (pfs 46.4%; 95% ci, -18.8/+16.9); • her-2 status 3+ = 10 months (pdfs 47.6%; 95% ci, -21.9/+19.1). log-rank test was not statistically significant (p = 0,39). discussion at each stage of bladder cancer, clinical management strategies are aimed at preventing disease recurrence/progression and the use of unnecessary and potentially lifealtering procedures. once the disease becomes muscle-invasive, the main goal of treatment is threefold: to maximize long-term survival, to prevent pelvic recurrence or metastases, and to provide a good quality of life (21). general guidelines exist for treatment of high-risk tcc of the bladder (22, 23). however, to predict exactly which patients will progress, and who could, therefore, require more aggressive therapy, needs an individualized approach, although assessment remains more an art than science (24). zhau et al. reported her2 amplification and overexpression in bladder cancer for the first time in 1990 (25). in contrast with its known importance in breast cancer, the significance of her2 expression and/or her-2 gene amplification in bladder cancer is controversial. it was found that her2 is overexpressed with a greater frequency in higher grades (40%) and stages (38%) than in lower grades (0%) and stages (8%)[8] and several studies confirmed that her-2 could have a role as prognostic factor in bladder cancer, correlating its overexpression with poor prognosis for patients (shorter median survival time, reduced complete response to chemoradiation therapy) (8, 10, 13, 26-29). recently bolenz et al. identify her-2 positivity as an independent predictor of disease recurrence and specific survival in patients tcc of the bladder after radical cystectomy (11). in literature other data seem to indicate limited or no prognostic value of her-2 expression (12, 14-17). in a large series of patients with primary tcc of the bladder, no significant correlation between her-2 expression status and clinical outcome it has been reported (15). moreover, no statistically significant difference in the survival rates of 80 consecutive patients with mibc has been observed (14). a recent study showed that, in a large series of transurethral resection and cystectomy (1005 cases), 5,1% of mibc had a her-2 gene amplification with complete concordance (100%) between ihc and fluorescence in situ hybridization (fish) analyses (30). these variations in results are due to the heterogeneity of studies with respect to kits and type of antibodies used for ihc analysis, protocols, stage of the disease studied (nonmuscle-invasive vs muscle-invasive), definition of her-2 positivity and the material studied (fresh/formalin fixed). thus, discordant results reported in the literature highlight a need for standardized laboratory methods. in our work we evaluate her-2 ihc expression as prognostic marker of disease recurrence and/or progression in high-grade t1 bladder tumour (t1g3) high grade t1 lesions with her-2 status 0 did not showed progression of disease. interestingly, all patients with her-2 status 3+, undergoing cystectomy because progression of disease, had a pathological stage > pt2 and a nodal involvement. no statistically significant association between her-2 ihc expression and recurrence/progression of disease it has been found. conclusions this study showed that her-2 expression does not represent a prognostic marker of recurrence/progression of disease in high-grade t1 bladder cancer. the numbers of this cohort are actually quite small and they could affect the significance of statistical analysis. further studies analyzing a large group of disease progression are needed. figure 3. kaplan meier plot of disease-free survival (%) for groups of her-2 status. figure 2. kaplan meier plot of disease-free survival (%). bongiovanni_stesura seveso 24/06/13 11:01 pagina 76 references 1. jemal a, siegel r, xu j, et al. cancer statistics, 2010. ca cancer j clin. 2010; 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25:118. 28. chakraverti a, winter k, wu cl, et al. expression of the epidermal growth factor receptor and her-2 are predictors of favorable outcome and reduced complete response rates, respectively, in patients with muscle-invading bladder cancers treated by concurrent radiation and cisplatin-based chemotherapy: a report from the radiation therapy oncology group. int j radiat oncol biol phys. 2005; 62:209. 29. underwood m, bartlett j, reeves j, et al. c-erbb-2 gene amplification: a molecular marker in recurrent bladder tumors? cancer res. 1995; 55:2422. 30. laé m, couturier j, oudard s, et al. assessing her2 gene amplification as a potential target for therapy in invasive urothelial bladder cancerwith a standardized methodology: result in 1005 patients. ann oncol. 2010; 21:815. 77archivio italiano di urologia e andrologia 2013; 85, 2 her-2 immunohistochemical expression as prognostic marker in high-grade t1 bladder cancer (t1g3) correspondence luca bongiovanni, md, phd (corresponding author) lucabongiov@yahoo.it vincenzo arena, md fabio maria vecchio, md marco racioppi, md pierfrancesco bassi, md francesco pierconti, md, phd department of pathology catholic university of the sacred heart, policlinico “agostino gemelli" l.go f. vito 1 00168 rome, italy bongiovanni_stesura seveso 24/06/13 11:01 pagina 77 stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 31 original paper ber of systematic needle cores and the best imaging procedure to use for omitting or postponing scheduled repeated biopsies; in this respect, multiparametric magnetic resonance imaging (mpmri) is strongly recommended in as follow up (4, 5). recently, prostate-specific membrane antigen (psma) inhibitors conjugated with the radionuclides 68gallium (68ga) and 18fluoride (18f) have been well-explored and successfully translated for the clinical diagnosis of pca (6, 7). moreover, tumour uptake, which represents psma expression (standardised uptake value “suvmax), resulted highly correlated with the gleason score of the primary prostatic tumour (9). however, a limited number of studies have focused on the primary prostatic lesion (8, 9). 68ga-psma positron emission tomography/computed tomography (pet/ct) has shown to be sensitive for the detection of primary prostatic lesions and regional lymphadenopathy (10, 11). recently, the use of 68ga-psma pet/ct combined with mpmri has been suggested to improve the accuracy to identify men suitable for active surveillance (12). the aim of this study is to prospectively evaluate the diagnostic accuracy of 68ga-psma pet/ct in the diagnosis of cspca (grade group ≥ 2) (13) in men enrolled in as protocol. materials and methods from may 2013 to december 2021 200 men aged between 52 and 74 (median age 63) with very low risk pca were enrolled in an as protocol study. after institutional review board and ethical committee approval were granted, informed consents were obtained from all participants included in the study. presence of the following criteria defined eligibility: life expectancy greater than 10 years, clinical stage t1c, psa below 10 ng/ml, psa density (psa-d) < 0.20, ≤ 2 unilateral positive biopsy cores, gleason score 6/international society of urologic pathology (isup) grade groups (gg) 1, maximum core percentage of cancer (gpc) ≤ 50% (3). all the patients underwent confirmatory biopsy 6-12 months later the pca diagnosis previous mpmri evaluation. during the follow up 48/200 (24%) men were upgraded and 10/200 (5%) men autonomously decided to leave the as protocol. after five introduction: to evaluate the accuracy of 68ga-prostate specific membrane antigen (psma) positron emission tomography/computed tomography (pet/ct) in the diagnosis of clinically significant prostate cancer (cspca: grade group ≥ 2) in men enrolled in active surveillance (as) protocol. materials and methods: from may 2013 to december 2021 200 men aged between 52 and 74 years (median age 63) with very low risk pca were enrolled in an as protocol study. during the follow up 48/200 (24%) men were upgraded and 10/200 (5%) decided to leave the as protocol. after five years from confirmatory biopsy (range: 48-60 months) 40/142 (28.2%) consecutive patients were submitted to mpmri and 68ga-psma pet/ct imaging examinations before scheduled repeated biopsy. all the mpmri (pi-rads ≥ 3) and 68ga-pet/tc standardized uptake value (suvmax) ≥ 5 index lesions underwent targeted cores (mpmri-tpbx and psma-tpbx) combined with transperineal saturation prostate biopsy (spbx: median 20 cores). results: multiparametric mri and 68ga-psma pet/ct showed 18/40 (45%) and 9/40 (22.5%) lesions suspicious for pca. in 3/40 (7.5%) men a cspca (gg2) was found; 68ga-psma-tpbx vs. mpmri-tpbx vs. spbx diagnosed 2/3 (66.6%) vs. 2/3 (66.6%) vs. 3/3 (100%) cspca, respectively. in detail, mpmri and 68ga-psma pet/tc demonstrated 16/40 (40%) vs. 7/40 (17.5%) false positive and 1 (33.3%) vs. 1 (33.3%) false negative results. conclusion: although 68psma pet/ct did not improve the detection for cspca of spbx (1 false negative result equal to 33.3% of the cases), at the same time, would have spared 31/40 (77.5%) scheduled biopsies showing a better diagnostic accuracy in comparison with mpmri (83.3% vs. 70.2%). key words: prostate cancer; 68ga-psma pet/ct; active surveillance; pca. submitted 18 march 2023; accepted 28 march 2023 introduction active surveillance (as) has become an alternative to radical treatment of low/very low risk prostate cancer (pca), reducing the risk of overtreatment and improving quality of life of the patients (1-3). however, the time of confirmatory biopsy has been established within one year from initial diagnosis (4) there are no data regarding the num68ga-psma pet/ct evaluation in men enrolled in prostate cancer active surveillance pietro pepe 1, ludovica pepe 1, marinella tamburo 2, giulia marletta 2, francesco savoca 1, michele pennisi 1, filippo fraggetta 3 1 urology unit, cannizzaro hospital, catania, italy; 2 radiotherapy unit, cannizzaro hospital, catania, italy; 3 pathology unit, cannizzaro hospital, catania, italy. doi: 10.4081/aiua.2023.11322 summary archivio italiano di urologia e andrologia 2023; 95, 2 p. pepe, l. pepe, m. tamburo, g. marletta, f. savoca, m. pennisi, f. fraggetta 32 years from confirmatory biopsy (range: 48-60 months), also in the presence of stable clinical parameters, the last 40/142 (28.2%) consecutive patients were submitted to mpmri and 68ga-pet/ct imaging examinations before scheduled repeated biopsy. all mpmri examinations were performed using a 1.5 or 3.0 tesla scanner, equipped with surface 16 channels phased-array coil placed around the pelvic area with the patient in the supine position; multi-planar turbo spinecho t2-weighted (t2w), axial diffusion weighted imaging (dwi) and axial dynamic contrast enhanced (dce) were performed for each patient. the mpmri lesions characterized by prostate imaging reporting and data system (pirads) version 2 (4) scores ≥ 3 were considered suspicious for cancer; two radiologists blinded to pre-imaging clinical parameters evaluated the mpmri data separately and independently; moreover, one urologist with more than 25 years of experience performed the biopsy procedure (4). pet/ct imaging was performed using a ct-integrated pet scanner (biograph 6; siemens, knoxville, tn, usa). 68gapsma was prepared with a fully automated radiopharmaceutical synthesis device based on a modular concept (eckert & ziegler eurotope, berlin, germany). 68ga-psma-11 was given to patients via an intravenous bolus (mean, 144 ± 12 mbq; range, 122-188 mbq), and the pet acquisition was started at a mean of 58 ± 12 min (range, 50-81 min) afterward. scans were acquired in 3-dimensional mode with an acquisition time of 3 min per bed position. emission data were corrected for randoms, dead time, scatter, and attenuation and were reconstructed iteratively using ordered-subsets expectation maximization (4 iterations, 8 subsets) followed by a postreconstruction smoothing gaussian filter (5 mm in full width at half maximum). for attenuation correction, a low dose unenhanced ct scan was performed from the skull base to the middle of the thigh. images were processed to obtain pet, ct, and pet-ct fusion sections in the axial, coronal, and sagittal planes with a thickness of approximately 0.5 ~ cm by two experienced nuclear medicine specialists, who were blinded to the clinical data. the location of focal uptake on 68ga-psma pet/tc (figure 1), three-dimensional size, and suvmax values were reported on a per-lesion basis with a sextant scheme (apex, midgland, and base, each split into left and right) (4). all the mpmri (pi-rads score ≥ 3) and 68gapet/tc index lesions (suvmax ≥ 5) (14) underwent cognitive targeted cores (mpmritpbx and psma-tpbx: four cores) combined with saturation prostate biopsy (spbx: median 20 cores; range 18-22). the procedure was performed transperineally using a tru-cut 18 gauge needle (bard; covington, ga, usa) under sedation and antibiotic prophylaxis (15). the prostate targeted cores were done using an hitachi 70 arietta ecograph, chiba, japan) supplied by a bi-planar trans-rectal probe (16) performing a free-hand cognitive approach. results the clinical parameters of the 40 men enrolled in active surveillance protocol are listed in table 1. multiparametric mri and 68ga-psma showed 18/40 (45%) and 9/40 (22.5%) lesions suspicious for pca those were submitted to targeted cores combined with spbx. in detail, mpmri pi-rads score resulted ≤ 2 vs. 3 vs. 4 in 22 (55%) vs. 15 (37.5%) vs. 3 (7.5%) men. the average intraprostatic suvmax and tumor dimension was 4.6 g/ml (range: 3.2-19.8) and 7.0 mm (range 4-12 mm), respectively; only 9/40 (22.5%) men had a suvmax ≥ 5 (range: 5.1-19.8), moreover, 68ga-psma pet/tc showed two suspicious areas in correspondence of iliac ala and spinal cord those resulted negative for metastases at targeted mri for bone evaluation. in 3/40 (7.5%) men a cspca (gg2) was found: both patients had a gpc equal to 20% with a number of positive cores equal to 3 and 4, respectively, moreover psa density was 0.15, 0.16 and 0.18, respectively. 68ga-psma-tpbx vs. mpmri-tpbx vs. spbx diagnosed 2/3 (66.6%) vs. 2/3 (66.6%) vs. 3/3 (100%) cspca, respectively. in detail, mpmri and 68ga-psma pet/tc table 1. clinical parameters of 40 men enrolled in active surveillance protocol submitted to scheduled biopsy. figure 1. 68ga-prostate-specific membrane antigen (psma) pet/ct: presence of high vs. low suspicious area of clinically significant prostate cancer in the right (a) vs. left lobe (b) of prostate gland (axial valuation) with a standardized uptake value (suvmax) equal to 88.8 vs. 6.5, respectively. a. b. clinical and biopsy findings gg1 40 patients median psa (range: 4.5-12.5 ng/ml) 4.8 median psa density (range: 0.10-0.20) 0.15 median gpc (range: 10-50%) 40% median number of positive cores 2 percentage of positive cores 98% mpmri 18 pi-rads score ≥ 3 (45%) 68ga-psma pet/ct 9 suspicious for pca (22.5%) gg: international society of urological pathology grade group; mpmri: multiparametric magnetic resonance imaging; psa: prostate specific antigen; gpc: greatest percentage of cancer; psma: prostate specific membrane antigen; pi-rads: prostate imaging reporting and data system; pet/tc: positron emission tomography/computed tomography. archivio italiano di urologia e andrologia 2023; 95, 2 33 68ga-psma pet/ct and active surveillance demonstrated 16/40 (40%) vs. 7/40 (17.5%) false positive and 1 (33.3%) vs. 1 (33.3%) false negative results; in detail, one patient had pi-rads score 2 and suvmax of 6.8 and the second patient had pi-rads score 3 and suvmax equal to 4.5 g/ml. in addition, mpmri and 68ga-psma pet/tc showed a diagnostic accuracy in the diagnosis of cspca equal to 70.2 and 83.3%, respectively. discussion the estimated risk-free treatment at 15 years in men enrolled in as with gg1 pca is equal to 58% (1). although mpmri is strongly recommended in the revaluation of men in as (2, 5, 6), still today, scheduled systematic repeated prostate biopsies are recommended to reduce the false negative rate for cspca of mpmri equal to 15-20% of the cases (16); at the same time, the number of cores performed at initial and repeat evaluation is directly correlated with a lower risk of reclassification (6) during the follow up allowing to postpone scheduled repeated prostate biopsy in favour of clinical findings (i.e., psa density, risk calculator) (17-19) and imaging revaluation (mpmri) (5, 6). in the last years, 68ga-psma-pet/ct has been suggested to improve the clinical staging of high-risk pca and disease recurrence (20, 21); at the same psma pet/ct has been proposed for the diagnosis of primary intraprostatic cancer (22, 23). the presence of focal uptake on psmapet/ct (suvmax) and the maximal dimensions of petavid lesions have been correlated with the presence of cspca (24, 25). there is a range of proposed cut-offs to detect cspca from suvmax 3.15 to up suvmax 9.1 (26, 27); the concordance between preoperative psma pet/tc evaluation (suvmax, dimension of the lesion) and definitive prostate specimen ranges from 81.2% (28) to 96% (29); moreover, psma pet/mri seems reduce false positive rate of pet/ct (about 8% of cases) (30). in our series, 68ga-psma-tpbx vs. mpmri-tpbx vs. spbx diagnosed 2/3 (66.6%) vs. 2/3 (66.6%) vs. 3/3 (100%) cspca, respectively. in detail, mpmri and 68ga-psma pet/tc demonstrated 16/40 (40%) vs. 7/40 (17.5%) false positive and 1 (33.3%) vs. 1 (33.3%) false negative results. in addition, mpmri and 68ga-psma pet/tc showed a diagnostic accuracy in in the diagnosis of cspca equal to 70.2 and 83.3%, respectively. in definitive, still today, diagnostic imaging should not replace scheduled prostate biopsy but is mandatory to detect targeted lesions suspicious for cspca; in addion, several biochemical parameters, such as germline evaluation or phi (prostate health index), could be helpful in decrease the ratio of scheduled biopsy. among our results some considerations should be made. first, the number of patients evaluated was low. secondly, the results should be evaluated in the entire prostate specimen and not in biopsy histology; a more detailed histological evaluation of patients who underwent biopsy upstaging would be of interest, for example by adding supplementary staining for psma on the biopsy samples. third, the low rate of reclassification (7.5% of the cases) could be explained because the patients previously underwent spbx plus mpmri evaluation before confirmatory biopsy. four, 68ga-psma pet/tc evaluation could be proposed in men with negative mpmri or in the presence of claustrophobia, severe obesity or cardiac pacemaker (13); moreover, a 68ga-psma pet/tc fusion platform would have increased the accuracy of targeted prostate biopsy. in conclusion, although 68psma pet/ct did not improve the detection for cspca of spbx (1 false negative result equal to 33.3% of the cases), at the same time, would have spared 31/40 (77.5%) scheduled biopsies showing a better diagnostic accuracy in comparison with mpmri (70.2% vs. 83.3%). references 1. carlsson s, benfante n, alvim r, et al. long-term outcomes of active surveillance for prostate cancer: the memorial sloan kettering cancer center experience. j urol 2020; 203:1122-1127. 2. briganti a, fossati n, catto jwf, et al. active surveillance for low-risk prostate cancer: the european association of urology position in 2018. eur urol 2018; 74:357-368. 3. pepe p, cimino s, garufi a, et al. confirmatory biopsy of men under active surveillance: extended versus saturation versus multiparametric magnetic resonance imaging/transrectal ultrasound fusion prostate biopsy. scand j urol 2017; 51:260-263. 4. pepe p, pepe l, pennisi m, fraggetta f. which prostate biopsy in men enrolled in active surveillance? experience in 110 men submitted to scheduled three-years transperineal saturation biopsy combined with fusion targeted cores. clin genitourin cancer 2021; 19:305-308. 5. pepe p, garufi a, priolo gd, et al. is it time to perform only mri targeted biopsy? our experience in 1032 men submitted to prostate biopsy. j urol 2018; 200:774-778. 6. caglic i, sushentsev n, gnanapragasam vj, et al. mri-derived precise scores for predicting pathologically-confirmed radiological progression in prostate cancer patients on active surveillance. eur radiol 2021; 31:2696-2705. 7. perera m, papa n, roberts m, et al. gallium-68 prostate-specific membrane antigen positron emission tomography in advanced prostate cancer-updated diagnostic utility, sensitivity, specificity, and distribution of prostate-specific membrane antigen-avid lesions: a systematic review and meta-analysis. eur urol 2020; 77:403-417. 8. privé bm, israël b, schilham mgm, et al. evaluating f-18psma-1007-pet in primary prostate cancer and comparing it to multi-parametric mri and histopathology. prostate cancer prostatic dis. 2021; 24:423-430. 9. uprimny c, kroiss as, decristoforo c, et al. 68ga-psma-11 pet/ ct in primary staging of prostate cancer: psa and gleason score predict the intensity of tracer accumulation in the primary tumour. eur j nucl mol imaging 2017; 44:941-949. 10. zhang q, zang sm, zhang ce, et al. comparison of 68gapsma11 pet-ct with mpmri for preoperative lymph node staging in patients with intermediate to high-risk prostate cancer. j transl med 2017; 15:230-38. 11. pepe p, pepe l, cosentino s, et al. detection rate of 68ga-psma pet/ct vs. mpmri targeted biopsy for clinically significant prostate cancer. anticancer research 2022; 42:3011-3015. 12. raveenthiran s, yaxley wj, franklin t, et al. findings in 1,123 men with preoperative 68ga-prostate-specific membrane antigen positron emission tomography/computerized tomography and multiparametric magnetic resonance imaging compared to totally embedded radical prostatectomy histopathology: implications for archivio italiano di urologia e andrologia 2023; 95, 2 p. pepe, l. pepe, m. tamburo, g. marletta, f. savoca, m. pennisi, f. fraggetta 34 the diagnosis and management of prostate cancer. j urol 2022; 207:573-580. 13. pepe p, pepe l, tamburo m, et al. targeted prostate biopsy: 68gapsma pet/ct vs. mpmri in the diagnosis of prostate cancer. arch ital urol androl 2022; 94:274-277. 14. pepe p, roscigno m, pepe l, et al. could 68ga-psma pet/ct evaluation reduce the number of scheduled prostate biopsy in men enrolled in active surveillance protocols? j clin med 2022; 16:3473. 15. pepe p, pennisi m, fraggetta f. how many cores should be obtained during saturation biopsy in the ra of multiparametric magnetic resonance? experience in 875 patients submitted to repeat prostate biopsy. urology 2020; 137:133-37. 16. pepe p, garufi a, priolo g, pennisi m. can mri/trus fusion targeted biopsy replace saturation prostate biopsy in the re-evaluation of men in active surveillance? world j urol 2016; 34:1249-53. 17. roscigno m, stabile a, lughezzani g, et al. the use of multiparametric magnetic resonance imaging for follow-up of patients included in active surveillance protocol. can psa density discriminate patients at different risk of reclassification? clin genitourin cancer. 2020; 18:e698-e704. 18. roscigno m, stabile a, lughezzani g, et al. multiparametric magnetic resonance imaging and clinical variables: which is the best combination to predict reclassification in active surveillance patients? prostate int 2020; 8:167-172. 19. pepe p, dibenedetto g, pepe l, pennisi m. multiparametric mri versus selectmdx accuracy in the diagnosis of clinically significant pca in men enrolled in active surveillance. in vivo 2020; 34:393396. 20. pepe p, pennisi m. should 68ga-psma pet/ct replace ct and bone scan in clinical staging of high-risk prostate cancer? anticancer res. 2022; 42:1495-1498. 21. kwan tn, spremo s, teh aym, et al. performance of ga-68 psma pet/ct for diagnosis and grading of local prostate cancer. prostate international 2021; 9:107-112. 22. ma l, zhang wc, ya-xin hao yx, hao yx. current state of prostate-specific membrane antigen pet/ct imaging-targeted biopsy techniques for detection of clinically significant prostate cancer j med imaging radiat oncol 2022; 66:776-780. 23. perera m, papa n, roberts m, et al. gallium-68 prostate-specific membrane antigen positron emission tomography in advanced prostate cancer-updated diagnostic utility, sensitivity, specificity, and distribution of prostate-specific membrane antigen-avid lesions: a systematic review and meta-analysis. eur urol 2020; 77:403-417. 24. demirci e, kabasakal l, sahin oe, et al. can suvmax values of ga-68-psma pet/ct scan predict the clinically significant prostate cancer? nucl med commun 2019; 40:86-91. 25. rüschoff jh, ferraro da, muehlematter uj, et al. what's behind 68ga-psma-11 uptake in primary prostate cancer pet? investigation of histopathological parameters and immunohistochemical psma expression patterns. eur j nucl med mol imaging 2021; 48:4042-4053. 26. franklin a, yaxley wj, raveenthiran s, et al. histological comparison between predictive value of preoperative 3-t multiparametric mri and 68ga-psma pet/ct scan for pathological outcomes at radical prostatectomy and pelvic lymph node dissection for prostate cancer. bju int 2021; 127:71-79. 27. liu y, yu h, liu j, et al. a pilot study of 18 f-dcfpyl pet/ct or pet/mri and ultrasound fusion targeted prostate biopsy for intra-prostatic pet-positive lesions. front oncol 2021; 11:612157. 28. kalapara aa, nzenza t, pan hyc, et al. detection and localisation of primary prostate cancer using 68 gallium prostate-specific membrane antigen positron emission tomography/computed tomography compared with multiparametric magnetic resonance imaging and radical prostatectomy specimen pathology. bju int 2020; 126:83-90. 29. xue al, kalapara aa, ballok ze, et al. 68ga-prostate-specific membrane antigen positron emission tomography maximum standardized uptake value as a predictor of gleason pattern 4 and pathological upgrading in intermediate-risk prostate cancer. j urol 2022: 207:341-349. 30. bhanji y, rowe sp, pavlovich cp. new imaging modalities to consider for men with prostate cancer on active surveillance. world j urol world j urol 2022; 40:51-59. correspondence pietro pepe, md (corresponding author) piepepe@hotmail.com ludovica pepe, md ludopepe97@gmail.com francesco savoca, md michele pennisi, md michepennisi2@virgilio.it urology unit, cannizzaro hospital via messina 829, catania, italy marinella tamburo, md marinellatamburo@virgilio.it giulia marletta, md marlettagiulia1@gmail.com radiotherapy unit, cannizzaro hospital, catania, italy filippo fraggetta, md filippofra@hotmail.com pathology unit, cannizzaro hospital, catania, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper established, yet the majority will not be diagnosed with urological cancer and the cause will be attributed to transient benign physiological conditions, including uti, ul or bpe. the extent of investigation and timing of this investigation in not well defined. taking in consideration the finitude of available resources, it would be important to prioritize the patients with more risk of suffering from urological cancer, to quickly diagnose, evaluate and treat. there are known risks factors to urological cancer, such as smoking history, exposure to occupational chemical and dyes or pelvic radiation, but there is no algorithm available that allow the physicians to estimate an approximate risk of bladder malignancy. with our study we intend to help physicians assessing the likelihood of urologic malignancy based in general clinic, laboratory, and image data. the aim of the study was to identify predictive factors of bladder cancer among patients presenting with hematuria. patients and methods patients eligible for this study were referred to urology appointment by the general practitioner (gp) or from de emergency department because of hematuria, between january 1, 2017 and december 31, 2019. patients otherwise asymptomatic who were referred due to incidental imaging findings suspicious of bladder cancer or upper tract urothelial carcinoma were excluded. all patients had cystoscopy and upper tract imaging. main outcome of interest was bladder cancer diagnosis, defined as presence of urothelial carcinoma in pathological study after transurethral bladder resection (turb) according to tnm whow tumor classification and european association of urology risk classification. variables such as demographics, imaging and clinical factors were evaluated (including age, gender, smoker status, anticoagulation or antiaggregating drug use, previous pelvic irradiation, number of hematuria episodes, presence of lower urinary tract symptoms (luts), urine culture positivity, back pain, history of urolithiasis, fever, ultrasound and cystoscopy results). the demographic and clinical features are shown in table 1. statistical analysis descriptive statistics were calculated for all patients introduction: the presence of blood in the urine should be promptly investigated to rule out urological malignancies, bladder cancer being the most frequent. given its frequency among general population and the lack of unlimited health resources in an era of cost-effectiveness, it is important to prioritize patients with higher risk of malignancy. objectives: to identify predictive factors of bladder cancer among patients presenting with hematuria. patients and methods: we retrospectively reviewed 296 cases referred to our department for hematuria. we evaluated different demographic, clinical and ultrasound features to uncover possible associations with diagnosis of bladder cancer in those patients, to estimate the individual risk of being diagnosed with bladder cancer during the investigation of hematuria. results: a total of 296 patients were studied for hematuria between january 1, 2017 and december 31, 2019, 23.6% of those having ultimately bladder cancer confirmed after transurethral resection. older age, male gender (or 2.727, p = 0.069), a history of smoking (or 3.84, p < 0.05), recurrent hematuria (or 3.396, p < 0.05) and positive ultrasound exam for bladder cancer (or 30.423, p < 0.05) were identified as predictors of bladder cancer in patients with hematuria. conclusions: this study suggests that it is possible to reliably estimate the risk of bladder cancer in patients with hematuria, using clinical and imaging data to help defining who should be investigated first and in whom the investigation could be postponed. key words: bladder cancer; hematuria; smoking; ultrasound; male gender. submitted 20 november 2022; accepted 22 november 2022 introduction hematuria is defined as presence of blood in urine. it can either be microscopic (only detected in urinalysis and with variable definition among regions) or macroscopic. hematuria is one of the most frequent causes of referral to emergency department or urology appointment. there are many etiologies, most being benign, like urinary tract infection (uti), benign prostatic enlargement (bpe) or urolithiasis (ul) but the existence of a subjacent urological cancer, most often bladder cancer, must be dismissed. the need to investigate almost all patients who present with macroscopic and microscopic hematuria is well predicting bladder cancer risk in patients with hematuria. a single-centre retrospective study roberto jarimba 1, 2, vasco quaresma 1, joão pedroso lima 1, 2, miguel eliseu 1, 2, edgar tavares da silva 1, 2, pedro moreira 1, arnaldo figueiredo 1, 2 1 urology and renal transplantation department, centro hospitalar e universitário de coimbra, coimbra, portugal; 2 faculty of medicine, university of coimbra, portugal. doi: 10.4081/aiua.2023.11026 summary archivio italiano di urologia e andrologia 2023; 95, 1 r. jarimba, v. quaresma, j. pedroso lima, m. eliseu, e. tavares da silva, p. moreira, a. figueiredo included in the present study. the crude association between each individual categorical covariate and bladder cancer diagnosis was accessed by chi-square and binary logistic regression. all analysis were conducted using ibm spss statistics version 26. all comparisons were made using 2-sided tests, with p < 0.05 considered statistically significant. results a total of 296 patients were studied for hematuria between january 1, 2017 and december 31, 2019. overall, 23.6% of those patients were diagnosed with bladder cancer after turb results. clinical and imaging predictors were found to be statistically significative. some are well known risk factors for bladder cancer: patients diagnosed with bladder cancer were older (73.74 vs 66.8 years, p < 0.05); men had roughly 2.5 times (or: 2.519, p < 0.05) more risk of being diagnosed with bladder cancer; patients ever exposed to tobacco had 3.8 times (or 3.852, p < 0.05) more risk of bladder cancer. the number of hematuria episodes and urine microbiology seem to have a predictive value for the diagnosis of bladder cancer, in univariate analysis. patients with multiple episodes of hematuria have a higher risk of being diagnosed with bladder cancer (or: 2.093, p < 0.05) vs patients with a single episode. an identification of bacteria in the urine microbiology was inversely correlated with bladder cancer diagnosis (or: 0.737, p < 0.05); a total of 29 patients had a positive urine culture, none of those were found to have bladder cancer. ultrasound evaluation had a sensitivity and specificity for bladder cancer of 71% and 87%, respectively. while there was a bladder cancer suspicion at ultrasound examination in 70% of the patients with subsequent diagnosis of bladder cancer, only 16% of patients diagnosed with bladder cancer had a normal ultrasound evaluation. those patients were older (or: 1.084, p = 0.011) and had more frequently a smoking history (or: 4.503, p = 0.048). the second most common finding in the ultrasound exam among patients diagnosed with bladder cancer was unilateral hydronephrosis, found in 6.6% of those patients. in the multivariate analysis, using a binary logistic regression, age, tobacco exposure, multiple episodes of hematuria and a positive ultrasound were found to be correlated with risk of bladder cancer. the calculated model showed an accuracy of 86.5%, with a sensitivity of 64.9% and a specificity of 93.1%. twelve (15.4%) out of 78 patients with suspected bladder cancer at cystoscopy had negative histology for bladder cancer after turb. among patients studied for microscopic hematuria (10.6% of the total), only 6% were diagnosed with bladder cancer. all patients with microscopic hematuria diagnosed with bladder cancer were male older than 40 years of age and had ultrasound positive for bladder. only 1.4% and 0.3% of the patients were diagnosed with upper tract urothelial carcinoma and renal cell carcinoma, respectively. among patients with a diagnosis other than bladder cancer, 25% had prostatic bleeding, 15.9% uti-related hematuria and 8.1% were diagnosed with urolithiasis. results are shown in table 2. table 1. demographic and clinical features of patients referred because of hematuria. total (n = 296) non-bc (n = 226) bc (n = 70) age (years) 68.45 ± 15.94 66.81 ± 15.92 73.74 ± 14.92 gender female 95 (32.1%) 84 (37.2%) 11 (15.7%) male 201 (67.9%) 142 (62.8%) 59 (84.3%) tobacco never user 225 (76%) 184 (81.8%) 41 (58.6%) ever user 48 (16.2%) 28 (12.4%) 20 (28.6%) not known 23 (7.8%) 14 (6.2%) 9 (12.9%) hematuria episodes > 1x 147 (49.7%) 103 (45.6%) 44 (62.9%) 1x 118 (39.9%) 98 (43.4%) 20 (28.6%) microscopic hematuria 31 (10.5%) 25 (11.1%) 6 (8.6%) urine culture negative 216 (73.2%) 161 (71.6%) 55 (78.6%) positive 29 (9.8%) 29 (12.9%) 0 (0%) not known 50 (16.9%) 35 (15.6%) 15 (21.4%) ultrasound normal 126 (42.9%) 115 (42.9%) 11 (15.9%) suspicious 76 (25.9%) 27 (12%) 49 (71%) urolithiasis 31 (10.5%) 28 (12.4%) 2 (4.3%) renal mass 12 (4.1%) 12 (5.3%) 0 bladder wall thickness 8 (2.7%) 8 (3.6%) 0 hydronephrosis 13 (4.4%) 9 (4%) 4 (5.8%) prostate enlargement 18 (61%) 18 (8%) 0 vesical blood clot 1 (1.7%) 1 (0.4%) 0 bladder stone 3 (1%) 3 (1.3%) 0 suspicion of utuc 1 (0.3%) 1 (0.4%) 0 anticoagulation/anti aggregation no 180 (60.8%) 135 (59.7%) 45 (64.3%) yes 116 (39.2%) 91 (40.3%) 25 (35.7%) pelvic radiation no 281 (95.3%) 215 (95.6%) 66 (94.3%) yes 14 (4.7%) 10 (4.4%) 4 (5.7%) uti suspicion no 224 (75.7%) 167 (73.9%) 57 (81.4%) yes 72 (24.3%) 59 (26.1%) 13 (18.6%) back pain no 249 (84.7%) 187 (83.1%) 62 (89.9%) yes 45 (15.3%) 38 (16.9%) 7 (10.1%) fever no 286 (96.6%) 216 (95.6%) 70 (100%) yes 10 (3.4%) 10 (4.4%) 0 previous luts no 183 (61.8%) 139 (61.5%) 44 (62.9%) yes 104 (35.1%) 79 (35%) 25 (35.7%) not known 9 (3%) 8 (3.5%) 1 (1.4%) urolithiasis history no 268 (90.5%) 201 (88.9%) 67 (95.7%) yes 28 (9.5%) 25 (11.1%) 3 (4.3%) cystoscopy normal 130 (43.9%) 130 (57.5%) 0 dubious 25 (8.4%) 21 (9.3%) 4 (5.7%) suspicious 78 (26.4%) 12 (5.3%) 78 (94.3%) prostate enlargement 50 (16.9%) 50 (22.1%) 0 bladder trabeculation 6 (2%) 6 (2.7%) 0 urethral stenosis 3 (1%) 3 (1.3%) 0 bladder stone 3 (1%) 3 (1.3%) 0 uti: urinary tract infection; luts: lower urinary tract symptoms. archivio italiano di urologia e andrologia 2023; 95, 1 bladder cancer and hematuria discussion our study, as others (1), highlights the need for investigating almost every patient presenting with hematuria. in our cohort, the overall probability of being diagnosed with bladder cancer throughout the investigation of hematuria was 23.6%. nice states that a signal or a symptom associated with ≥ 3% risk of cancer should prompt referral for diagnostic test (2) and many patients want that investigation be made for a symptom associated ≥ 1% risk of cancer (3). american urology association (aua) recommends that all patients with visible hematuria and patients with microscopic hematuria (≥ 3 red blood cells/high-power field), aged ≥ 35 years, should be investigated (4). in an era of relative lack of health resources when compared with demands, it is of the most importance to prioritize patients regarding diagnostic procedures (i.e. cystoscopy, ct scan). this way, patients with higher probability of bladder cancer can be prioritized to receive said tests, and patients with lower probability being safely postponed (but studied nonetheless). we were not able to define thresholds for strictly riskbased categories, but the data allow us to roughly estimate the risk of bladder cancer in a single patient. some predictors for bladder cancer were uncovered, as age, gender, tobacco exposure history, number of episodes of visible hematuria and ultrasound evaluation. older patients, male (or 2.843, p = 0.061), a history of smoking (or 3.852, p < 0.05), with recurrent hematuria (or 3.471, p < 0.05) and positive ultrasound exam for bladder cancer (or 31.663, p < 0.05) are at highest risk and should be investigated promptly. univariate analysis showed that negative urine culture was a risk factor for bladder cancer, but not in multivariate analysis. none of patients with a positive urine culture at the moment of hematuria had a subsequent diagnosis of bladder cancer. in our study, ultrasound had sensibility of 71% and specificity of 87% for bladder cancer. it can be a good screening test but cannot be an alternative to cystoscopy, because 16% of patients diagnosed with bladder cancer had a normal ultrasound evaluation. in patients investigated for non-visible hematuria the diagnostic rate of bladder cancer was 8.6% and all of them had a positive ultrasound. according to our results and in agreement with national board of health and welfare of sweden (5), it seems plausible that patients with nonvisible hematuria with a negative ultrasound evaluation are at low risk of bladder cancer and the investigation can be postponed. we uncovered some new clinical predictors for bladder cancer in patients with hematuria, like recurrent hematuria and a negative urine culture. our study has some limitations. it is a retrospective study with a relatively small number of patients that limits the statistically power of the analysis. urinary cytology was not included in co-variates, because, in our department most patients collect a bladder washing during cystoscopy procedure. the incidence of bladder cancer in our cohort is probably higher than its real incidence in overall patients with hematuria because it represents the detection rate in a secondary care setting. this study suggests that it is possible to reliably estimate the risk of bladder cancer in patients with hematuria, using clinical and imaging data to manage available healthcare resources without compromising the standard of care. references 1. tan ws, feber a, sarpong r, et al. who should be investigated for haematuria? results of a contemporary prospective observational study of 3556 patients. eur urol. 2018; 74:10-4. 2. national collaborating centre for cancer (uk). suspected cancer: recognition and referral. london: national institute for health and care excellence (nice); 2015 jun. 3. banks j, hollinghurst s, bigwood l, et al. preferences for cancer investigation: a vignette-based study of primary-care attendees. lancet oncol. 2014; 15:232-40. 4. davis r, jones js, barocas da, et al. american urological association. diagnosis, evaluation and follow-up of asymptomatic microhematuria (amh) in adults: aua guideline. j urol. 2012; 188 (6 suppl):2473-81. 5. malmström p-u. time to abandon testing for microscopic haematuria in adults? bmj. 2003; 326:813-5. table 2. univariate and multivariate analysis for predictors of bladder cancer in patients with hematuria. predictors of bladder cancer for 265 visible hematuria referrals univariate multivariate or ci or ci age (years) 1.047 * 1.012-1.080 gender (0 = f, 1 = m) 2.519 * 1.236-5.131 2.843 0.952-8.489 ever smoker 2.876 * 1.435-5.764 3.852 * 1.301-11.405 hematuria episodes (0 = 1, 1 = > 1x) 2.093 * 1.153-3.801 3.471 * 1.435-8.395 urine culture (0 = neg, 1 = pos) 0.737 * 0.677-0.802 0.496 0.698-2.100 ultrasound suspicion 24.425 * 11.483-51.955 31.633 * 12.867-77.772 test �2 d� p overall model evaluation r square nagelkerke 0.545 goodness-of-fit test hosmer & lemeshow 8.531 8 0.383 uf: female; m: male; neg: negative; pos: positive. * p < 0.05. correspondence roberto jarimba, md (corresponding author) robertojarimba@chuc.min-saude.pt vasco quaresma, md vpdquaresma@gmail.com miguel eliseu, md mgl.nobre@gmail.com joão pedroso lima, md joaopedrosolima@gmail.com edgar tavares da silva, md edsilva.elv@gmail.com pedro moreira, md pedronetomoreira@gmail.com arnaldo figueiredo, md, phd ajcfigueiredo@gmail.com serviço de urologia, centro hospitalar e universitário de coimbra rua professor mota pinto 3004-561, coimbra (portugal) conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper complication rates, whether it was magnified inguinal (miv) or subinguinal varicocelectomy (msv) (4, 5). the magnified subinguinal varicocelectomy might preserve more arteries and veins than the magnified inguinal varicocelectomy. however, it raises the operation's complexity and the risk of artery damage (6). it was observed that antegrade flow during magnified subinguinal varicocelectomy and pulsatile movement could help visualize the main spermatic artery; however, it can be difficult for various reasons, including differences in anatomic architecture and blood pressure that can be low to be able to detect pulsatile movement (7). although papaverine droplets are applied to enhance arterial pulsation, vigorous manipulation of the arteries during dissection might cause spasms, making it challenging to identify arterial pulsation (8). furthermore, arteries are often found near to or buried beneath complex venous branching, requiring the development of a technology that can adequately detect these small arteries. to our knowledge, only a few studies have used intraoperative vascular doppler ultrasound-assisted magnified subinguinal varicocelectomy (ivdu-msv), which enhanced accurate visualization and preservation of arteries and veins (7, 9). in this trial, we compared the fertility and postoperative outcomes of combining intraoperative doppler and hydrodissection, versus intraoperative doppler alone in infertile men with varicocele undergoing magnified subinguinal varicocelectomy. materials and methods the local ethics committee approved the protocol of the current trial of faculty of medicine for girls, al-azhar university (fmg-irb) met at faculty of medicine for girls, nasr city, cairo, egypt (study id 894). then, written informed consent was obtained from all participants. all procedures run in compliance with the standards of the declaration of helsinki (10). study design and patients we performed a non-randomized comparative trial that recruited consecutive infertile men with varicocele who were scheduled to undergo magnified subinguinal varicocelectomy at al-azhar university hospitals through the period from december 2018 to august 2021. men were considered eligible if aged more than 18 years old and had a confirmed history of primary infertility due to unilateral or bilateral primary varicocele. the diagnosis of methods: we performed a non-randomized comparative trial that recruited infertile men with varicocele who were scheduled to undergo msv. eligible patients were allocated by the investigators in a 1:1 ratio to receive intraoperative doppler (group i) or intraoperative doppler plus hydrodissection (group ii). results: sixty men were included in each group. the two study groups showed a comparable number of ligated veins on the right (4.22 ±1.57 versus 4.42 ± 1.65; p = 0.49) and left side (6.77 ± 2.14 versus 6.98 ± 2.29; p = 0.59). on the contrary, group ii showed a significantly higher number of preserved arteries on the right (2.42 ± 0.56 versus 1.47 ±0.5 in group i) and left side (2.6 ± 0.53 versus 1.63 ± 0.55 in group i), with p-value < 0.001. the sperm motility was significantly higher in group ii than in group i (21.25 ± 13.73 versus 13.85 ± 12.25, respectively; p = 0.002). in both groups, the sperm motility increased significantly at the end of follow-up compared to the preoperative period. the postoperative sperm mortality remained significantly higher in group ii than in group i (p = 0.008). conclusions: intraoperative doppler plus hydrodissection (d+ih-msv) has advantages in preserving more arteries and enhancing the motility of sperms. based on these findings, we strongly recommend d+ih-msv when treating infertile men with varicocele. key words: intraoperative doppler; hydrodissection; magnified subinguinal varicocelectomy; infertility; varicocele. submitted 13 november 2022; accepted 24 december 2022 introduction varicoceles is one of the main risk factors of male infertility, which is present in both primary and secondary infertility, with an estimated prevalence of 50% and 81%, respectively (1). varicocelectomy is the main procedure for treating varicoceles, resolving testicular pain, increasing spontaneous pregnancy rates, and improving semen parameters (2). successful varicocelectomy should maintain the vas deferens, spermatic arteries and lymphatics and interrupts the retrograde backflow through the pampiniform plexus of veins, which increases the spontaneous pregnancy rate. besides, varicocelectomy aims to preserve the perivasal veins for venous outflow (3). regarding improving spontaneous pregnancy, many studies have demonstrated that magnified varicocelectomy is the most effective procedure with undetectable intraoperative hydrodissection and doppler ultrasound during magnified varicocelectomy: a comparative study salah e. shebl 1, saadelddin ali 2, ahmed el gammal 1 1 urology department, faculty of medicine for girls, al-azhar university, cairo, egypt; 2 dermatology and andrology department, al-azhar university, cairo, egypt. doi: 10.4081/aiua.2023.11008 summary archivio italiano di urologia e andrologia 2023; 95, 1 s.e. shebl, s. ali, a. el gammal varicocele was based on the findings of a duplex scan of the scrotal region and classified according to sarteschi (1). we excluded patients with painful varicocele, recurrent cases, history of inguinal or scrotal surgery, the co-existence of hydrocele, and/or the presence of technical difficulties in performing selective ligation of veins or preservation of arteries due to excessive fat content in the cord or cord lipoma that prevent proper dissection or occurrence of injured vessels during dissecting and hematoma formation that cause indistinct visualization. cases that we failed to separate the spermatic artery from adjacent veins due to anatomic architecture were excluded as well. eligible patients were allocated according to the investigator’s decision in a 1:1 ratio to receive magnified intraoperative doppler alone (group i) or intraoperative doppler, and hydrodissection (group ii). study's procedures and follow-up all patients were assessed preoperatively and underwent preoperative semen analysis, which was performed after ≥ three days of abstinence. the semen analysis was performed using the world health organization (who) guidelines (12). the samples were collected through masturbation in a sterile container; only non-spermicidal lubricants were allowed. samples were kept at 20-37℃ until liquefaction. macroscopic examination was performed to assess the semen characteristics, followed by microscopic examination on a fixed cell counting chamber. in case of abnormal semen analysis, another sample was collected after one month for confirmation. the same surgeon performed all procedures. patients underwent spinal or general anesthesia according to the surgeon and anesthetist decision. then, a three-cm skin incision was conducted over the external inguinal ring transversely. this incision dissected the camper's and scarpa's fascias to reach the spermatic cord, which was situated over a penrose drain using a babcock forceps. an 8-15x microscope was employed to identify all dilated veins. these veins were tied by 4-0 or 5-0 vicryl sutures according to size of ligated veins and sparing the artery with assistance of doppler during the operation (group i). in group ii doppler and hydrodissection were employed to identify the pulsating arteries using saline injection introduced directly in the cord by syringe without needle (figures 1, 2). following the incision of spermatic fascia, the vas deferens and its vessels were examined and suited in the posterior fascial compartment to create a window between vas and vessels using the penrose drain or forceps. we made another window between the internal spermatic vessels and the external spermatic fascia and its structures. the saline injection was introduced again to this a window created to separate the vessels from each other (figure 3). the internal spermatic arteries were then freed from the surrounding veins and irrigated with diluted warm papaverine; the surrounding veins were ligated by 3-0 vicryl, sparing the internal spermatic artery and lymphatic vessels. we closed the fascia, subcutaneous tissue and the skin using 2-0 vicryl sutures and subcuticular 4-0 proline or 3-0 vicryl, respectively. the incision was infiltrated with 0.5% marcaine solution with epinephrine, and a dry sterile dressing was applied. study's outcomes the primary outcome of the present study was the impact of employing intraoperative doppler and hydrodissection on the number of ligated veins and preserved arteries among men undergoing msv. the secondary outcomes of this study included the incidence of postoperative complications and semen analysis findings. the patients were followed up every three months for one year after the operation. the postoperative semen analysis was performed six months after surgery. figure 1. technique of hydrodissection (direct injection of saline in the cord). figure 2. the spermatic cord after saline injection. figure 3. the cord after hydrodissection. archivio italiano di urologia e andrologia 2023; 95, 1 intraoperative hydrodissection and doppler ultrasound during magnified varicocelectomy statistical analysis retrieved data were summarized and processed with ibm spss statistical software (version 25). frequencies were used to describe varicocele grade and postoperative complications. on the other hand, age, semen analysis findings, number of ligated veins, number of preserved arteries, duration of surgery, and hospital stay were summarized, according to normality, into mean (± standard deviation [sd]) or median (range) values. the hypothesis of significant differences between the type of procedures and primary or secondary outcomes was challenged using the independent t-test or chi-square test for continuous and categorical data. within group comparison was done using paired t-test. p-value < 0.05 was regarded as statistically significant. results sixty men were included in each group. the mean age of the patients was comparable between the intraoperative doppler group (group i) and doppler plus intraoperative hydrodissection group (group ii) (29.52 ± 5.48 versus 29.42 ± 4.64, respectively; p = 0.91). on the right side, the most commonly encountered varicocele grade was ii (58.3% and 53.3% in group i and ii, respectively; p = 0.88). however, on the left side, grade iii was the most common subtype in group i (50% compared to 41.7% in group ii) (p = 0.081) (table 1). the operative time was significantly longer in group ii (65.62 ±15.1 minutes) than in group i (35.18 ± 11.6; p < 0.001). concerning the number of ligated veins, the two study groups showed a comparable number of ligated veins on the right (4.22 ± 1.57 versus 4.42 ± 1.65; p = 0.49) and left sides (6.77 ± 2.14 versus 6.98 ± 2.29; p = 0.59). on the contrary, group ii showed a significantly higher number of preserved arteries on the right (2.42 ± 0.56 versus 1.47 ± 0.5 in group i) and left sides (2.6 ± 0.53 versus 1.63 ± 0.55 in group i), with p-value < 0.001. two patients (3.3%) in group i showed recurrent varicocele and hydrocele respectively, compared to no patients in group ii (p = 0.24 for both). there were no cases of testicular atrophy in both groups (table 2). in addition, group i and ii showed statistically significant increases in the sperm count at the end of follow-up, compared to the preoperative period (from 9.88 ± 4.77 to 35.22 ± 36.22 and from 11.07 ± 5.04 to 29.73 ± 27.62, respectively; p = 0.014 and 0.009, respectively). however, there were no significant differences between the two groups concerning both pre and postoperative sperm count (p = 0.189 and 0.35). group i and ii showed statistically significant increases in the sperm normal morphology at the end of follow-up, compared to the preoperative period (p = 0.001), with no significant differences between both groups. preoperatively, the sperm motility was significantly higher in group ii than group i (21.25 ± 13.73 versus 13.85 ± 12.25, respectively; p = 0.002). this trend was consistent during the postoperative period (p = 0.008). in both groups, the sperm motility increased significantly at the end of follow-up compared to the preoperative period (table 3). discussion varicocele repair appears to improve seminal parameters and to aid infertile couples in achieving spontaneous conception, according to current evidence. this disease has been treated with various open surgical methods, including retroperitoneal, miv, and msv (13). based on the previous literature, there was no significant difference table 2. comparison of intra and postoperative characteristics of the study groups. parameters group p-value * d (= 60) d + ih (n = 60) operative time in minutes mean ± sd 35.18 ± 11.6 65.62 ± 15.1 < 0.001 ligated veins (right) mean ± sd 4.22 ± 1.57 4.42 ± 1.65 0.49 ligated veins (left) mean ± sd 6.77 ± 2.14 6.98 ± 2.29 0.59 preserved arteries (right) mean ± sd 1.47 ± 0.5 2.42 ± 0.56 < 0.001 preserved arteries (left) mean ± sd 1.63 ± 0.55 2.6 ± 0.53 < 0.001 hospital stay in days mean ± sd 1 1 n/a recurrent varicocele no. (%) 2 (3.3%) 0 0.24 atrophy no. (%) 0 0 n/a hydrocele no. (%) 2 (3.3%) 0 0.24 d: doppler; ih: intraoperative hydrodissection; sd: standard deviation. *chi-square test. table 3. changes in the semen analysis parameters in the study groups. parameters group p-value * d (= 60) d + ih (n = 60) count (million per milliliter) pre-operative 9.88 ± 4.77 11.07 ± 5.04 0.189 post-operative 35.22 ± 36.22 29.73 ± 27.62 0.35 p-value ** 0.014 0.009 morphology (%) pre-operative 17.25 ± 17.7 12.27 ± 9.93 0.06 post-operative 31.65 ± 24.27 26.55 ± 18.92 0.22 p-value 0.001 0.001 motility (%) pre-operative 13.85 ± 12.25 21.25 ± 13.73 0.002 post-operative 29.98 ± 9.57 35.18 ± 11.57 0.008 p-value < 0.001 0.004 d: doppler; ih: intraoperative hydrodissection; sd: standard deviation. * mann-whitney u test. ** wilcoxon signed-rank. table 1. comparison of preoperative characteristics of the study groups. parameters group p-value * d (= 60) d + ih (n = 60) age mean ± sd 29.52 ± 5.48 29.42 ± 4.64 0.91 grade (right) ** 0 4 (6.7%) 3 (5%) 0.88 l 18 (30%) 21 (35%) ll 35 (58.3%) 32 (5.3%) lll 3 (5%) 4 (6.7%) grade (left) 0 0 0 0.081 l 4 (6.7%) 4 (6.7%) ll 25 (41.7%) 31 (51.7%) lll 30 (50%) 25 (41.7%) d: doppler; ih: intraoperative hydrodissection; sd: standard deviation. * chi-square test. ** based on sarteschi (11). archivio italiano di urologia e andrologia 2023; 95, 1 s.e. shebl, s. ali, a. el gammal between these methods in terms of improving fertility; however, they have different recurrence rates and potential complications (14). in addition, hypoxia produced by artery damage during the surgery disrupts energy metabolism, leading to spermatogenesis injury (15). consequently, several attempts have been made to reduce complication and recurrence rates following the surgery, allowing for better preservation of the testicular artery and lymphatic arteries and reduced incidence of hydrocele (16, 17). furthermore, even without testicular atrophy, ligation of the testicular artery can compromise the seminiferous tubules; thus, a dissection approach that preserves the spermatic artery and all branches is preferable (9). this study introduced a new technique by making another window between the internal spermatic vessels and the external spermatic fascia and its structures, which allowed us to separate the vessels from each other after injecting the saline. the internal spermatic arteries were then freed from the surrounding veins and irrigated with diluted warm papaverine; the surrounding veins were ligated by 4-0 & 5-0 vicryl, sparing the internal spermatic artery and lymphatic vessels. by comparing the outcomes of the procedure in both groups, doppler (d) and doppler+hydrodissection (d+ih), our findings showed that the mean age of the patients was comparable between both groups. varicocele grade ii was the most common in the right side, while grade iii was the most common in the left side. the operative time was significantly longer in the d+ih group than in the d group (p < 0.001). there were no significant differences between both groups in terms of ligated veins, sperm count, sperm morphology; however, the d+ih group was associated with higher preserved arteries and sperm motility than the d alone (p < 0.001 and p = 0.008), respectively. guo et al. (7), conducted a randomized trial to compare between magnified subinguinal varicocelectomy and intraoperative vascular doppler ultrasound assissted (ivdu) magnified subinguinal varicocelectomy in infertile males with varicoceles. their findings showed that intraoperative vascular doppler ultrasound reduced the operative time by about 10 minutes compared with the classic magnified subinguinal varicocelectomy (p < 0.05), which differs from our findings. in addition, they observed that the number of preserved arteries and spermatic veins ligated was significantly higher in the intraoperative vascular doppler ultrasound group than in the classic microsurgical subinguinal varicocelectomy group (p < 0.05). these findings can be explained by the precise identification of small veins using ivdu. some reports showed that ivdu helps remove more veins that were adherent as a dense complex to arteries. shindel et al. (18), demonstrated that the total number of veins ligated was significantly and positively correlated with improvements in total sperm motility, indicating that ligating a larger number of veins should result in a more significant reduction in the reflux of warm blood and/or toxic substances, resulting in less insult to spermatogenesis. in terms of sperm motility and concentration, guo et al. demonstrated that ivdu-microsurgical subinguinal varicocelectomy was more efficient than the classic microsurgical subinguinal varicocelectomy (p < 0.05). a recent systematic review showed that microsurgical varicocelectomy significantly improves spermatogenesis as reflected by biomarkers of infertile men including semen parameters and sperm dna fragmentation (19). on the other hand, there was no significant difference between both groups in terms of preserved lymphatics and sperm morphology. these findings align with the findings of many meta-analyses, which indicated that varicocelectomy could considerably enhance seminal parameters. in the study conducted by cocuzza et al., they found that there was no significant difference between ivdu-msv and msv (p = 0.37). besides, the number of injured arteries and preserved lymphatics was comparable in both groups (p = 0.06 and p = 0.21), respectively. on the other hand, the number of arteries preserved, and veins ligated was significantly higher in the ivdu-msv group than in msv group (p < 0.01 and p = 0.02), respectively (9). hydrocele formation after varicocelectomy in adolescents has not been thoroughly studied. the frequency of postvaricocelectomy hydrocele varies significantly, with rates as high as 39% in individuals who had ligation at internal inguinal ring (20). a range of 3.1% to 13% has been observed in previous investigations, with more significant ligation causing more hydroceles (21). ih of the spermatic cord lymphatics during varicocelectomy, according to atteya et al. (22), is a simple method that permits precise separation of the spermatic cord veins from its lymphatics, lowering the risk of post-varicocelectomy hydrocele development. we acknowledge that this study has some limitations, including the relatively small size, single center-based, and short follow-up period; however, this is the first study that combined d with msv and compared its outcomes with the ivdu+ih-msv. the fact that preoperative motility in group ii was significantly higher than in group i is another limitation. conclusions in conclusion, our findings suggested that both d-msv and d+ihmsv are effective methods for improving spermatic parameters in patients with varicocele, with a natural conception rate of 41.7% 46.7%, respectively. in addition, d+ih-msv has advantages in preserving more arteries and enhancing the motility of sperms. based on these findings, we strongly recommend d+ihmsv when treating infertile men with varicocele. references 1. cocuzza m, cocuzza ma, bragais fm, agarwal a. the role of varicocele repair in the new era of assisted reproductive technology. clinics (sao paulo). 2008; 63:395-404. 2. dubin l, amelar rd. varicocelectomy: 986 cases in a twelve-year study. urology. 1977; 10:446-9. 3. shridharani a, lockwood g, sandlow j. varicocelectomy in the treatment of testicular pain: a review. curr opin urol. 2012; 22:499-506. 4. lundy sd, sabanegh es jr. varicocele management for infertility and pain: a systematic review. arab j urol. 2017; 16:157-170. 5. schlegel pn, goldstein m. anatomical approach to varicocelectomy. semin urol. 1992; 10:242-7. archivio italiano di urologia e andrologia 2023; 95, 1 intraoperative hydrodissection and doppler ultrasound during magnified varicocelectomy 6. chan pt, wright ej, goldstein m. incidence and postoperative outcomes of accidental ligation of the testicular artery during microsurgical varicocelectomy. j urol. 2005; 173:482-4. 7. guo l, sun w, shao g, et al. outcomes of microscopic subinguinal varicocelectomy with and without the assistance of doppler ultrasound: a randomized clinical trial. urology. 2015; 86:922-8. 8. tatem aj, brannigan re. the role of microsurgical varicocelectomy in treating male infertility. transl androl urol. 2017; 6:722-9. 9. cocuzza m, pagani r, coelho r, et al. the systematic use of intraoperative vascular doppler ultrasound during microsurgical subinguinal varicocelectomy improves precise identification and preservation of testicular blood supply. fertil steril. 2010; 93:2396-9. 10. world medical association. world medical association declaration of helsinki. ethical principles for medical research involving human subjects. bull world health organ. 2001; 79:373-4. 11. sarteschi m, paoli r, bianchini m, menchini fabris gf. lo studio del varicocele con eco-color-doppler. g ital ultrasonol 1993; 4:43-9. 12. world health organization. who laboratory manual for the examination and processing of human semen (sixth edition) 2021 available from: http://whqlibdoc.who.int/publications/2010/ 9789241547789_eng.pdf 13. marmar jl, agarwal a, prabakaran s, et al. reassessing the value of varicocelectomy as a treatment for male subfertility with a new meta-analysis. fertil steril. 2007; 88:639-48. 14. agarwal a, deepinder f, cocuzza m, et al. efficacy of varicocelectomy in improving semen parameters: new meta-analytical approach. urology. 2007; 70:532-8. 15. reyes jg, farias jg, henríquez-olavarrieta s, et al. the hypoxic testicle: physiology and pathophysiology. oxid med cell longev. 2012; 2012:929285. 16. marmar jl, debenedictis tj, praiss d. the management of varicoceles by microdissection of the spermatic cord at the external inguinal ring. fertil steril. 1985; 43:583-8. 17. goldstein m, gilbert br, dicker ap, et al. microsurgical inguinal varicocelectomy with delivery of the testis: an artery and lymphatic sparing technique. j urol. 1992; 148:1808-11. 18. shindel aw, yan y, naughton ck. does the number and size of veins ligated at left-sided microsurgical subinguinal varicocelectomy affect semen analysis outcomes? urology. 2007; 69:1176-80. 19. soetandar a, noegroho bs, siregar s, et al. microsurgical varicocelectomy effects on sperm dna fragmentation and sperm parameters in infertile male patients: a systematic review and meta-analysis of more recent evidence. arch ital urol androl. 2022; 94:360-5. 20. salama n, blgozah s. immediate development of post-varicocelectomy hydrocele: a case report and review of the literature. j med case rep. 2014; 8:70. 21. paduch da, niedzielski j. repair versus observation in adolescent varicocele: a prospective study. j urol. 1997; 158:1128-32. 22. atteya a, amer m, abdelhady a, al-azzizi h, et al. lymphatic vessel hydrodissection during varicocelectomy. urology. 2007; 70:165-7. acknowledgments the authors thank the study participants, trial staff, and investigators for their participation. correspondence salah e. shebl, md (corresponding author) salahshebl@yahoo.com ahmed el gammal, md aelgammal36@gmail.com urology department, faculty of medicine for girls al-azhar university, alzahraa university hospital, al-azhar university, abbasia, cairo, egypt saadelddin ali, md saad2004@yahoo.com dermatology and andrology department, al-azhar university, cairo, egypt conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper and bladder dysfunction (1). the impact and pathophysiology of diabetes on the urinary bladder could be multifactorial including the osmolarity diuresis effect, metabolic perturbation, microvascular damage, and diabetic neuropathy, consequently resulting in detrusor smooth muscle and urinary bladder urothelial dysfunction (2). historically, luts associated with dm were reported as a triad of symptoms; impaired bladder sensation, increased bladder capacity, and decreased detrusor contractility (3). however, more recently, dm was reported to cause a variety of luts, including detrusor overactivity (do), impaired detrusor contractility and urethral dysfunction (4-6). these symptoms culminate in diabetic cystopathy and asymptomatic bacteriuria, which is reported to be between 25% and 90% in the literature (3). despite the main focus of dm associated luts being referred to as diabetic cystopathy for many years, recent evidence has demonstrated the impact of diabetes on the lower urinary tract to be multifactorial (1, 2, 7). furthermore, the pathogenesis of luts in diabetic patients is under-investigated, remaining elusive. osmolarity diuresis effect, metabolic abnormalities, microvascular damage, and neuropathy of diabetes may result in dysfunctions of smooth muscle, urothelium, and neuronal components of the bladder (6, 8). previous studies have reported several urodynamic findings in diabetic patients (1, 8). however, there is a paucity in the literature addressing the urodynamic changes concerning the duration of dm. therefore, the study aimed to address the pattern of urodynamic findings in diabetic patients presenting with luts, comparing short and long-standing dm. patients and methods study design after obtaining ethical approval, a prospective study was conducted on patients who presented with luts symptoms and had a concurrent diagnosis of type 2 dm between february 2016 and may 2018. all subjects signed informed consent to participate in the study. patients with purpose: to address the pattern of urodynamic findings in diabetic patients with lower urinary tract symptoms (luts), comparing short-standing and long-standing type 2 diabetes mellitus (t2dm). methods: a prospective study was conducted on 50 patients presenting with luts and a concurrent diagnosis of t2dm, between february 2016 and may 2018. patients were classified and evaluated according to the duration of diabetes into two groups: short-standing dm (< 15 years, n = 31), and long-standing dm (≥ 15 years, n = 19) groups. the impact of luts and quality of life were assessed in female patients using iciqfluts and male patients using iciq-mluts. results: a total of 50 patients were included in the study. the mean duration of t2dm was 10 ± 0.7 years. the mean age was 56.3 ± 1.2 years, and the mean hba1c was 7.5 ± 1.2%. urodynamic evaluation detected significantly higher detrusor overactivity (do) and increased bladder sensation with the short-standing dm group (35.5 vs. 15.8%, p = 0.01 and 32.3 vs. 5.3%, p = 0.01, respectively). comparatively, weak, or absent detrusor contractility were more frequent in patients with longstanding dm (52% and 26% respectively p = 0.01). as expected, overflow incontinence and straining during voiding were significantly higher in the long-standing dm group (p = 0.04 and p = 0.03, respectively). surprisingly, there was no significant correlation between patients presenting with urgency in their voiding diary (subjective) and urodynamic detection of do (p = 0.07). conclusions: there are different patterns in urodynamic characterizations of t2dm. patients with short-standing dm present more commonly with storage symptoms and detrusor overactivity on urodynamics. contrastingly, patients with long-standing dm present more frequently with voiding symptoms and detrusor underactivity on urodynamics. thus, screening for an underactive bladder is advisable in patients with long-standing t2dm. key words: urodynamic study; diabetes mellitus; luts; urinary bladder; urinary incontinence; detrusor underactivity; detrusor overactivity. submitted 7 december 2022; accepted 6 january 2023 introduction diabetes mellitus (dm) is a prevalent major health condition associated with lower urinary tract symptoms (luts) evaluation of urodynamic pattern in short and long-standing diabetic patients haytham elsakka 1*, ahmed ibrahim 2*, abdulghani khogeer 2, 3, adel elatreisy 4, rawan elabbady 2, osama shalkamy 4, ayesha khan 1, iman sadri 2, ahmad alshammari 2, ahmad khalifa 2, serge carrier 2, melanie aube-peterkin 2 1 urology department, east lancashire hospitals nhs trust, balckburn, lancashire, uk; 2 department of surgery, division of urology, mcgill university health center, montreal qc, canada; 3 department of surgery, faculty of medicine, rabigh, king abdulaziz university, jeddah, saudi arabia; 4 urology department, faculty of medicine, al-azhar university, cairo, egypt. * contributed equally as co-first author. doi: 10.4081/aiua.2023.11072 summary archivio italiano di urologia e andrologia 2023; 95, 1 h. elsakka, a. ibrahim, a. khogeer, et al. previous pelvic surgery, coexisting neurologic disorders, or any other medical condition that interferes with bladder or sphincter function were excluded from the study. patients were classified and evaluated according to the duration of diabetes into short-standing: > 15 years (group i), and long-standing: ≥ 15 years (group ii). subjects’ evaluation all patients were subjected to entire medical history. the impact of luts and quality of life was assessed in female patients utilizing iciq-fluts (international consultation on incontinence modular questionnaire on female lower urinary tract symptoms) and in male patients using iciq-mluts (international consultation on incontinence modular questionnaire on male lower urinary tract symptoms). these questionnaires provide rigorous validity and reliability, both of which are frequently used worldwide (9, 10). patients underwent a clinical examination (including focused neurological examination), furthermore, all patients underwent routine laboratory investigations, which included: urine analysis, urine culture and sensitivity, hba1c, fasting and postprandial blood sugar, and serum creatinine. imaging studies (kub, abdominopelvic us), and urodynamic evaluation. the urodynamic machine used was the ellipse-4 andromeda (gmbh, wallbergstraße 5. d-82024 taufkirchen/potzham germany). statistical analysis statistical analysis was carried out using spss software package version 28.0. numerical values were presented as means and standard deviation (sd). categorical values were presented as frequency and percentages. comparison between different categorical variables was made using fisher’s exact test. additionally, a student's ttest was used to compare the means of the continuous variables among different groups. two-tailed p values less than 0.05 were considered statistically significant. results a total of 50 patients were included in the study: 40 women (80%) and 10 men (20%). the mean age was 56.28 ± 1.14 years (range 45 to 73 years), the mean hba1c was 7.5 ± 1.2%, and the mean fasting blood sugar (fbs) was 199.88 ± 9.24 mg%. the mean duration of dm was 10 ± 0.77 years (table 1). clinical presentation storage symptoms were the predominant class of luts reported by the participants. in particular, 88% described nocturia (44 subjects) followed by 86% noting daytime frequency (43 subjects), urgency 78% (39 subjects), urge incontinence 54% (27 subjects), and nocturnal enuresis 28% (14 subjects). comparatively, voiding luts were reported less frequently: 40% complained of straining during voiding, 38% reported a weak urine stream and 34% of an interrupted stream. overflow incontinence was the main complaint in 20% of the study cohort (table 1). voiding diary charts were reported as the mean of variable per patient as follows: mean diurnal voids/day was 7.78 ± 0.45 and mean nocturnal voids/night was 3.78 ± 0.29; mean of urgency episodes/day was 4.54 ± 0.48, and mean of urge incontinence episodes/day was 2.17 ± 0.51. finally, the mean voided volume/void was 268.47 ± 14.86 ml (table 1). urodynamic evaluation the free flowmetry of the cohort revealed that the mean voided volume was 235 ± 17.05 ml. the mean maximum flow rate was 15.21 ± 1.12 ml/s and the mean of postvoid residual (pvr) urine was 114.94 ± 22.76 ml. of note, 30% of participants had a pvr greater than 100 ml. bladder sensation was normal in 54% (26 patients), increased in 22% (11 patients), reduced in 12% (6 patients) and absent in 14% (7 patients). the mean first sensation volume (fsv) was 159 ± 10.88 ml. the mean first desire volume (fdv) was 255.97 ± 11.36 ml, and the mean strong desire volume (sdv) was 334.68 ± 11.56 ml (table 2). the mean value of bladder compliance was 81.70 ± 9.84 ml/cm h2o. the latter was normal in 88% (44 subjects), reduced in 10% (5 subjects), and increased in 2% (1 subject). the mean maximum cystometric capacity (mcc) was 383.56 ± 15.7 ml of which, was valid for 74% of subjects. the mcc could not be assessed in 26% (13 subjects) due to either absent sensation, urine leakage, or reduced sensation (table 2). of the subjects whom the mcc was successfully calculated, 58% had a normal mcc; it was reduced in 14% and increased in 2% of the study cohort. amongst the studied participants, 28% (14 subjects) had do. the do was phasic in 20% (10 subjects) and termitable 1. patients demographics, clinical presentation, questionnaires evaluation and voiding diary profile. variable value patients demographics: vmean age (se, range), year 56.28 ± 1.14 (45 to 73) male/female ratio, n (%) 10 (20%)/40 (80%) mean duration of dm (se, range), year 10 ± 0.77 (5 to 29) mean fbs (se, range), mg % 199.88 ± 9.24 (102 to 392) hba1c 7.5 ± 1.2 mean serum creatinine (se, range), mg % 1.09 ± .04 (0.5 to 1.5) clinical presentation: nocturia, n (%) 44 (88%) daytime frequency, n (%) 43(86%) urgency, n (%) 39 (78%) urgency incontinence, n (%) 27 (54%) nocturnal enuresis, n (%) 14 (28%) weak stream, n (%) 19 (38%) interrupted stream, n (%) 17 (34%) straining during voiding, n (%) 20 (40%) continuous drippling of urine, n (%) 10 (20%) questionnaires evaluation: iciq-fluts 28.5 ± 7 iciq-mluts 30.3 ± 5.8 voiding diary profile: diurnal voids/day (se, range) 7.78 + 0.45 (2 to 15) nocturnal voids/night (se, range) 3.78 + 0.29 (0 to 8) urgency episodes/day (se, range) 4.54 + 0.48 (0 to 14) urgency incontinence episodes/day (se, range) 2.17 + 0.51 (0 to 14) voided volume/void (se, range) 268.47 + 14.86 (90 to 500) archivio italiano di urologia e andrologia 2023; 95, 1 urodynamics of diabetic patients nal in 8% (4 subjects) with regards to do; the mean value of wave numbers was 3.64 ± 0.82 waves (range 1 to 12 waves), the mean duration was 45.85 ± 10.75 seconds (range 10 to 149 seconds), the mean amplitude was 41.4 ± 6.02 cm h2o, and the mean value of the first contraction volume (fcv) was 141 ± 26.63. the detrusor contractility was normal in 60 % (30 subjects), weak in 26% (13 subjects), and absent in 14 % (7 subjects) (table 2). with regards to the duration of dm, the cohort was classified into group i (short-standing dm, < 15 years) included 31 patients (62%), and group ii (long-standing dm, ≥ 15 years) included 19 patients (38%). the mean score of iciq-fluts was significantly lower in group i when compared with group ii (24.67 ± 5.4 vs. 34.25 ± 4.9; p < 0.001). likewise, the mean score of iciq-mluts was significantly lower for group i when compared with group ii (28.7 ± 5.9 vs. 34 ± 2.3; p = 0.048) (table 3). do and increased bladder sensation were more common in patients with short-standing dm (35.5% vs. 15.8%, p = 0.01) and (32.3 vs. 5.3%, p = 0.01), respectively. in contrast, weak or absent detrusor contractility was more frequent in patients with long-standing dm (52% and 26% respectively p = 0.01). as expected, overflow incontinence and straining during voiding were significantly higher in the long-standing dm group (p = 0.04 and p = 0.03), respectively (table 4). there was no significant correlation between patients presenting with urgency on voiding diary (subjective) and urodynamic detection of do (p = 0.07). discussion diabetic bladder dysfunction can present with a broad spectrum of luts (10). clinically, luts in diabetic patients range from storage symptoms to voiding symptoms. common storage luts experienced by diabetic patients include nocturia, increased daytime frequency, urgency, and urge incontinence. on the other hand, frequently experienced voiding luts in diabetic patients encompass weak flow of urine, interrupted stream, straining during voiding, and eventually urine retention or overflow incontinence. the pathology shows a diverse and progressive evolution from an overactive bladder to a table 3. comparison between the study groups regarding clinical presentation. luts evaluation short-standing dm long-standing dm p value n = 31 (%) n = 19 (%) day time frequency 28 (90.3%) 15 (78.9%) 0.4 nocturia 28 (90.3%) 16 (84.2) 0.66 urgency 26 (83.9%) 13 (68.4%) 0.29 urgency incontinence 18 (58.1%) 9 (47.4) 0.56 nocturnal enuresis 5 (16.1%) 9 (47.4) 0.25 weak stream 7 (22.6%) 12 (63.2) 0.07 interrupted stream 6 (19.4%) 11 (57.9%) 0.12 overflow incontinence 2 (6.5%) 8 (42.1%) 0.04 straining during voiding 7 (22.6%) 13 (68.4%) 0.03 iciq-fluts 24.67 ± 5.4 34.25 ± 4.9 < 0.001 iciq-mluts 28.7 ± 5.9 34 ± 2.3 0.048 table 4. comparison between the study groups regarding urodynamic findings. bladder sensation short-standing dm long-standing dm p value n (%) n=31 n=19 normal 17 (54.8%) 9 (47.4%) 0.01 increased 10 (32.3%) 1 (5.3%) reduced 1 (3.2%) 5 (26.3%) absent 3 (9.7%) 4 (21.4%) bladder compliance 0.1 normal 26 (83.8%) 9 (47.4%) increased 2 (6.4%) 8 (42.1%) reduced 3 (9.7%) 2 (10.5%) maximum cystometric capacity 0.42 normal 17 (54.8%) 12 (63.2 %) increased 1 (3.2%) 0 reduced 6 (19.4%) 1 (5.3%) cannot be assessed 7 (22.6%) 6 (31.6) parameters of detrusor overactivity 0.01 phasic 9 (29%) 1 (5.3) terminal 2 (6.5%) 2 (10.5%) with leak 6 (19.4%) 2 (10.5%) without leak 5 (16.1%) 1 (5.3%) detrusor contractility 0.01 normal 26 (83.9%) 4 (21.1%) weak 3 (9.7%) 10 (52.6%) absent 2 (6.5%) 5 (26.3%) flowmetry 0.12 non obstructed 28 (90.3%) 14 (73.7%) obstructed 1 (3.2%) 0 could not be assessed 2 (6.5%) 5 (26.3%) table 2. urodynamic evaluation of the study’ cohort. 1. free flowmetry: mean voided volume (se, range), ml 235 ± 17.05 ml. (12 to 468) mean maximum flow rate (se, range), ml/s 15.21 ± 1.12 ml/s. (1 to 40) mean amount of post voiding residual urine (se, range), ml 114.94 ± 22.76 ml. (0 to 500) 2. filling cystometry: a. bladder sensation: absent bladder sensation, n (%) 7 (14%) reduced, increased, normal bladder sensation, n (%) 6 (12%), 11(22%), 26(54%) mean first sensation volume (fsv) (se, range) ml 159 ± 10.88 (31 to 352) mean first desire volume (fdv) (se, range) ml 255.97 ± 11.36 (129 to 430) mean strong desire volume (sdv) (se, range) ml 334.68 ± 11.56 (206 to 474) b. bladder compliance: normal, reduced, increased bladder compliance, n (%) 35 (70%), 5 (10%), 10(20%) mean value of bladder compliance (se, range) ml/cm h2o 81.70 ± 9.84 (5.7 to 455) c. maximum cystometric capacity: normal, increased, reduced n (%) 29 (58%), 7(14%), 1(2%) mean maximum cystometric capacity (se, range) ml 383.56 ± 15.7 ml (225 to 657) d. parameters of detrusor overactivity: detrusor overactivity number (se, range) 3.46 ± 0.82 (1 to 12) detrusor overactivity duration (se, range) 45.85 ± 10.75 (10 to 149) detrusor overactivity amplitude (se, range) 41.4 ± 6.02 (7.4 to 75) first contraction volume (se, range) 141 ± 26.63 (31 to 347) e. parameters of leakage with detrusor overactivity: amount of leakage (se, range) 125.62 ± 28.19 (30-258) first leakage volume (se, range) 172.75 ± 32.78 (73-324) leak detrusor pressure (se, range) 56.34 ± 3.77 (43-75) f. pressure flow study: detrusor contractility: normal, weak, absent n (%) 30 (60%), 13 (26%), 7 (14%) g. flow obstructed, not obstructed, could not be assessed n (%) 1 (2%), 42 (84%), 7 (14%) archivio italiano di urologia e andrologia 2023; 95, 1 h. elsakka, a. ibrahim, a. khogeer, et al. poor non-contractile bladder. diabetic urinary symptoms manifest alongside the progression of diabetes. as such, we evaluated diabetic patients presenting with luts to specifically address the urodynamic pattern in such cohort over the course of the disease. therefore, the study was conducted to characterize the specific urodynamic findings associated with the diabetic population in both short and long disease duration. as previously reported, in the early course of diabetes, the main pathological factor is related to polyuria, causing detrusor muscle remodeling, hypertrophy and overactivity. over time, there is an accumulation of toxic metabolites and oxidative stress leading to a decline in detrusor smooth muscles contractility, and bladder urothelium and neuronal alteration. collectively, this results in significant bladder sensation degradation and altered filling response (12). several reports demonstrate both urodynamic do and poor bladder contractility could be present. among 182 diabetic patients with a mean follow-up period of 5 years, kaplan et al. found that do was the main urodynamic pattern (55%), while detrusor contractility was impaired among 23% of patients (13). furthermore, kebapci et al. found that decreased bladder sensation, weak bladder contractility, and increased bladder capacity with pvr < 100 ml were the most prominent urodynamic findings in diabetic patients (14). in their cohort, the duration of diabetes was less than nine years, and hba1c was less than 7%. additionally, yamaguchi et al. reported trends of increased residual urine in long-standing diabetic patients (duration > 10 years) despite not being statistically significant (15). similarly, malik et al. (16) conducted a prospective comparative study on 288 non-diabetic and 96 diabetic women. they detected delayed first sensation, higher cystometric capacity, and reduced detrusor pressure at maximum flow rate among the diabetic group. those findings were more remarkable in long-standing dm (> 10 years). a significant relation between dm and a non-contractile bladder was not identified in their study. in contrast, in the present report, we included diabetic patients with a longer duration and reported weak detrusor contractility in 26% and 14%, respectively. additionally, we detected a significant difference in detrusor contractility between long and short dm duration. 52% of patients had weak detrusor contractility and 26% had very weak detrusor contractility of long-standing t2dm, compared to 9% and 6 % in short-standing, respectively (p < 0.001). furthermore, shin et al. performed a retrospective review of a urodynamic study for 708 females who clinically presented with stress urinary incontinence, comparing the diabetic and non-diabetic groups. they found that qmax and bladder contractility index is significantly reduced among the diabetic group (17). the distinct finding of the present study recognises diabetes mellitus had a different impact on urinary bladder function; the pattern of dysfunction varies according to the duration of dm. storage symptoms were more common amongst short-standing dm patients compared to long-standing t2dm patients. in particular, nocturia (90.3 vs. 84.2%), daytime frequency (90.3 vs. 78.9%), urgency (83.9 vs. 68.4%), and urge incontinence (58.1 vs. 47.4%). in contrast, voiding symptoms were more frequent in long-standing dm, namely weak stream (63.2 vs. 22.6%), interrupted stream (57.9 vs. 19.4%), overflow incontinence (42.1 vs. 6.5%), and straining during voiding (68.4 vs. 22.6%). furthermore, the current study showed no significant correlation between urgency on voiding diary (subjective) and urodynamic detection of do. we reported do in 35.4% of patients who presented with storage luts. such finding might reinforce the pathogenesis theory of diabetic luts as multifactorial (2). in such cohort, storage luts could be explained by the presence of glycosuria and osmolarity diuresis effect prior to detection of do. conversely, previous studies reported significant urodynamic findings in patients with mild voiding luts, specifically in the late stages of diabetic luts (8, 18). they explain that with the insidious onset of diabetic luts, patients may overlook the symptoms. in addition, health care workers tend not to consider bladder dysfunction complications while screening asymptomatic diabetic patients; they pay more attention to neuropathy, nephropathy, and retinopathy (19). hence diabetic patients are liable to be diagnosed during the late stages of diabetic cystopathy. finally, the study is not without limitations. first, the mcc could not be assessed in 31% patients in the longstanding dm group due to absent bladder sensation. however, the filling was stopped after 600 ml to avoid post-procedural urine retention, which is considered high bladder capacity. likewise, the mcc could not be assessed in 22% of the short-standing dm group primarily due to urine leakage. therefore, the bladder filling was stopped earlier in those patients. second, the relatively small sample size of the present study. nevertheless, the present study is prospective with strict and explicit inclusion and exclusion criteria in an attempt to eliminate any confounding factors which might affect bladder function. additionally, the voiding diary provided a subjective evaluation that could not reflect the objective bladder dysfunction in the urodynamic study. thus, we believe it is crucial to create a newly validated screening test for patients with diabetic cytopathy. further prospective studies are still advisable. conclusions there are different patterns in the urodynamic characterization of type 2 diabetic patients. patients with shortstanding dm often present with storage symptoms and detrusor overactivity on urodynamics. comparatively, patients with long-standing dm present more frequently with voiding symptoms and detrusor underactivity on urodynamics. screening for an underactive bladder is advisable in patients with a long-standing dm. references 1. bansal r, agarwal mm, modi m, et al. urodynamic profile of diabetic patients with lower urinary tract symptoms: association of diabetic cystopathy with autonomic and peripheral neuropathy. urology. 2011; 77:699-705. 2. geerlings se, stolk rp, camps mj, et al. diabetes women asymptomatic bacteriuria utrecht study group. risk factors for symptomatic urinary tract infection in women with diabetes. diabetes care. 2000; 23:1737-41. archivio italiano di urologia e andrologia 2023; 95, 1 urodynamics of diabetic patients 3. lee wc, wu hp, tai ty, et al. effects of diabetes on female voiding behavior. j urol. 2004; 17:989-92. 4. yuan z, tang z, 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caremel r, de sèze m, et al. the impact of mellitus diabetes on the lower urinary tract: a review of neuro-urology committee of the french association of urology. prog urol. 2016; 26:245-53. 12. daneshgari f, moore c. diabetic uropathy. semin nephrol. 2006; 26:182-5. 13. kaplan sa, te ae, blaivas jg. urodynamic findings in patients with diabetic cystopathy. j urol. 1995; 153:342-4. 14. kebapci n, yenilmez a, efe b, et al. bladder dysfunction in type 2 diabetic patients. neurourol urodyn. 2007; 26:814-9. 15. yamaguchi c, sakakibara r, uchiyama t, et al. overactive bladder in diabetes: a peripheral or central mechanism? neurourol urodyn. 2007; 26:807-13. 16. malik rd, cohn ja, volsky j, et al. a modern comparison of urodynamic findings in diabetic versus nondiabetic women. female pelvic med reconstr surg. 2020; 26:44-50. 17. shin ys, on jw, kim mk. clinical significance of diabetes mellitus on detrusor functionality on stress urinary incontinent women without bladder outlet obstruction. int urogynecol j. 2016; 27:1557-61. 18. esteghamati a, rashidi a, nikfallah a, yousefizadeh a. the association between urodynamic findings and microvascular complications in patients with long-term type 2 diabetes but without voiding symptoms. diabetes res clin pract. 2007; 78:42-50. 19. hill sr, fayyad am, jones gr. diabetes mellitus and female lower urinary tract symptoms: a review. neurourol. urodyn. 2008; 27:362-7. correspondence haytham elsakka, md haythamurology@gmail.com ayesha khan, md ayesha.khan@elht.nhs.uk urology department, east lancashire hospitals nhs trust, balckburn, lancashire (uk) ahmed ibrahim, md, msc (corresponding author) ahmed.eldemerdash@muhc.mcgill.ca eldemerdash90@gmail.com clinical fellow at mcgill university health centre 1001 boulevard décarie, montreal, qc, canada abdulghani khogeer, md dr-abdulghani@hotmail.com department of surgery, faculty of medicine, rabigh, king abdulaziz university, jeddah (saudi arabia) adel elatreisy, md adel.elatreisy@azhar.edu.eg osama shalkamy, md dr_shalkamy@azhar.edu.eg urology department, faculty of medicine, al-azhar university, cairo (egypt) rawan elabbady, md rawanelabbady93@hotmail.com iman sadri, md iman.sadri@mail.mcgill.ca ahmad alshammari, md dr.shammar@gmail.com ahmad khalifa, md khalifa.urology@gmail.com serge carrier, md serge.carrier@mcgill.ca melanie aube-peterkin, md melanie.aube-peterkin@mcgill.ca department of surgery, division of urology, mcgill university health center, montreal qc (canada) conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper pathologies beyond its common use in the management of renal stones (1). furs can be used as a conservative treatment for urothelial tumors of the upper urinary tract (utuc) and can be used in the follow-up after radical treatment of utuc (2). however, the use of furs is not without drawbacks. significant complications, including urinary tract infection (uti) and ureteric trauma, are frequently reported (3). in one study, febrile uti was reported in 14.1% of patients submitted to flexible ureteroscopic lithotripsy (4). unfortunately, prevention of postoperative uti after furs remains a debatable issue. current practice lacks well-established clinical evidence based on randomized clinical studies and is mainly based on retrospective studies (5). to standardize the periprocedural systemic antimicrobial administration, the american urological association best practice policy statement was developed (6). however, real-world practice is widely variable, and observational studies show relatively low compliance with these recommendations (5-7). to guard against post procedural infection, the most common approach is single-dose antibiotic prophylaxis (8). on the other hand, some centers use more enhanced precautions, including centralized collection and examination of preoperative urine cultures, standardized antibiotic prophylaxis, and use of ureteral access sheath. even with these precautions, postoperative uti was encountered in 6.7% of patients (9). the present randomized study aimed to compare the rate of post-procedural uti in patients subjected to the standard antibiotic prophylaxis alone versus enhanced prophylactic measures. patients and methods a prospective randomized controlled study was conducted at the department of urology, armed forces hospital, alhada, ksa, from march 2018 to july 2022. the study protocol was approved by the local ethical committee of the institution, and informed written consent was obtained from all patients before enrollment. the study included all patients subjected to furs to manage ureterpurpose: to compare the rate of post-flexible ureteroscopy urinary tract infection (uti) in patients subjected to the standard antibiotic prophylaxis alone versus enhanced prophylactic measures. methods: a prospective randomized controlled study included 256 patients subjected to flexible ureteroscopy (furs) for ureteral or renal stones from march 2018 to july 2022. treatment groups included the standard antibiotic prophylaxis group (group 1, n=128) and the enhanced prophylaxis group (group 2, n=128). patients in group 1 were injected with intravenous fluoroquinolone one hour preoperatively, and oral antibiotics were used for 24 h postoperatively. patients in group 2 had urine culture ten days before the procedure; antibioticculture based was given for positive asymptomatic cases, while the procedure was deferred for active uti. results: the study groups were comparable regarding patient demographics, stone characteristics, operative time, and intraoperative complications. the overall hospitalization time was 1.68 ± 0.81 days. postoperative, and overall complications were significantly higher in group 1 (15.6% vs. 6.3%, p = 0.04 and 26.6% vs. 17.2%, p = 0.047), respectively. twenty patients (15.6 %) in the standard prophylaxis group were diagnosed with uti in comparison to 8 patients (6.3 %) in the enhanced prophylaxis group (p = 0.047). conclusions: urinary tract infection after furs could be reduced significantly by utilizing the suggested enhanced prophylactic approach. key words: antibiotic; prophylaxis; ureteroscopy; urinary tract infect. submitted 13 december 2022; accepted 22 january 2023 introduction flexible ureteroscopy (furs) has become one of the most reliable tools in upper urinary tract endourology. thanks to creative ancillary instruments such as graspers and baskets, effective energy sources, and digital and robotic enhancements, furs has expanded its diagnostic and therapeutic applications to many upper urinary tract randomized comparison of effect of standard antibiotic prophylaxis versus enhanced prophylactic measures on rate of urinary tract infection after flexible ureteroscopy el-sayed i. el-agamy 1, mohamed a. elhelaly 1, tamer a. abouelgreed 2, abdrabuh m. abdrabuh 3, mohamed f. elebiary 3, adel elatreisy 3, osama m. ghoneimy 3, basem a. fathi 3, mohamed zamra 4, khalid kutub 5 1 department of urology, faculty of medicine, al-azhar university, cairo, egypt & department of urology, armed forced hospital, alhada, ksa; 2 department of urology, faculty of medicine, al-azhar university, cairo, egypt & gulf medical university, uae; 3 department of urology, faculty of medicine, al-azhar university, cairo, egypt; 4 department of urology, alqasemi hospital, sharjah, uae; 5 department of urology, al aharq jospital, fujairah, uae. doi: 10.4081/aiua.2023.11084 summary archivio italiano di urologia e andrologia 2023; 95, 1 el-sayed i. el-agamy, mohamed a. elhelaly, tamer a. abouelgreed, et al. al or renal stones. exclusion criteria were symptomatic uti, use of rigid ureteroscope, and antegrade ureteroscopy. preoperatively, all patients were subjected to careful history taking, thorough clinical examination, and non-contrast computed tomography scan to evaluate the stone characteristics. patients were equally and randomly allocated into one of the two treatment groups, including the standard antibiotic prophylaxis group and the enhanced prophylaxis group. the sample size was calculated utilizing the g-power software program for statistical power 80% and type ii statistical error 20%. the total number of patients was 256, equally divided into the two groups (each group included 128 patients). patients in the standard antibiotic prophylaxis group were injected intravenously with fluoroquinolone one hour preoperatively, and oral antibiotics were used for 24 hours postoperatively. patients in the enhanced prophylaxis group had urine culture ten days before the procedure. patients with sterile cultures received standard antibiotic prophylaxis. in contrast, patients with polymicrobial preoperative urine culture (defined by a urine culture isolating at least three microorganisms, of which none is predominant) were treated with ceftriaxone from 48 hours before the procedure until one day after surgery. patients with positive urine culture were contacted to assess if they had symptoms of uti. in asymptomatic cases, according to the specific pathogens identified, a full course of antibiotics was started five days before surgery until 48 h after the intervention (figure 1). for those having a clinically significant infection, the intervention was deferred. in addition to the antibiotic prophylaxis, hydrophiliccoated ureteral access sheaths were systematically used in all cases. the primary outcome of the study was the occurrence of postoperative uti within 30 days from treatment. postoperative uti was defined as the occurrence of a temperature higher than 38 °c associated with pyuria figure 1. flow chart of the study population. archivio italiano di urologia e andrologia 2023; 95, 1 antibiotic prophylaxis for urinary tract infection after flexible ureteroscopy and/or bacteriuria without any other focal infectious sites. in a symptomatic patient, no routine urine culture was requested. statistical analysis data obtained from the present study were presented as number and percent or mean and standard deviation (sd). numerical data were compared using a t-test, while categorical data were compared using the chi-square test. logistic regression was used to identify predictors of outcome. all statistical operations were computed using spss 25 (ibm, usa), and a p-value less than 0.05 was considered statistically significant. results in total, 256 patients were included in the study; the mean age in years ± sd was 46.8 ± 12.9, the male to female ratio was 178/78, and all patients underwent furs for stone disease with laser lithotripsy. the mean stone number ± sd of the entire cohort was 2.5 ± 1, and the largest stone diameter was 2.1 ± 0.78. the stones were recurrent in 50% of patients and were associated with moderate hydronephrosis in 21.9% and mild hydronephrosis in 48.4%, whereas no hydronephrosis was associated in 29.7%. regarding the stone location, it was in the proximal ureter in 35.2%, in the kidney in 36.7%, and combined in 28.1%. pre-furs internal double j ureteric stents were placed in 26.5% of patients who presented with proximal ureteric obstructing stones and slight acute renal impairment, which was normalized after ureteric stenting. group 1 included patients subjected to the standard antibiotic prophylaxis protocol (n = 128). group 2 included patients subjected to the enhanced prophylaxis protocol (n = 128) who had sterile urine culture in 66 cases (51.6%), polymicrobial positive urine culture in 41 cases (32%), and isolated organism in 21 (16.4%). there were no significant differences between the study groups regarding patient demographics and stone characteristics, as illustrated in table 1. the overall hospitalization time was 1.68 ± 0.81 days, comparable between groups 1 and 2 with no significant difference (p = 0.35) (table 1). we reported an overall complication rate of 21.9% (56 cases). intraoperative complications were comparable between the study groups. conversely, postoperative, and overall total complications were significantly higher in group 1, as shown in table 2. all the reported complications were mccs grades i and ii that were managed conservatively. regarding post-furs urinary tract infection, 20 patients (15.6%) in the standard prophylaxis group were diagnosed with uti in comparison to 8 patients (6.3%) in the enhanced prophylaxis group with statistically significant difference (p = 0.047) (table 2). hospital readmission was mandatory in 10 cases (3.9%) for uti and urosepsis. in these cases we collected urine and blood samples for culture and started with empirical intravenous meropenem (1 gram every 8 hours). urine culture showed e. coli in 8 cases and klebsiella pneumonia in two, all sensitive to meropenem, and all patients were discharged after ten days of antibiotic course after confirmation of sterile urine. using binary logistic regression analysis, female gender [or (95% ci): 0.09 (0.018-0.46) and operative time [or (95%ci): 0.97 (0.94-0.99)] were significant predictors of postoperative uti at univariate analysis. however, only female sex remained significant at multivariate analysis [or (95% ci): 0.09 (0.017-0.49)] (table 3). table 1. comparison between the studied groups regarding the preoperative, operative, and postoperative data. parameters standard prophylaxis enhanced prophylaxis p value group 1 (n = 128) group 2 (n = 128 age (years) mean ± sd 47.4 ± 11.8 46.1 ± 14.3 0.67 male/female n 86/42 96/36 0.52 bmi (kg/m2) mean ± sd 30.4 ± 4.8 29.4 ± 4.2 0.42 associated morbidities n (%) hypertension 38 (29.9%) 34 (26.7%) 0.66 diabetes mellitus 62 (48.4%) 56 (43.8%) 0.45 previous stone operation n (%) 59 (45.3%) 70 (54.7%) 0.26 preoperative ureteral stent n (%) 36 (28.3%) 32 (25 %) 0.72 preoperative hydronephrosis n (%) none 36 (28.1%) 40 (31.3%) 0.52 mild 66 (51.6%) 58 (45.3%) moderate 22 (20.3%) 30 (23.4%) stone location n (%) kidney 44 (34.4%) 50 (39.1%) 0.7 ureter 50 (39.1%) 40 (31.2%) combined 34 (26.6%) 38 (29.7%) stones number mean ± sd 2.6 ± 1.1 2.4 ± 1 0.43 largest stone size (cm3) mean ± sd 2 ± 0.9 2.2 ± 0.7 0.31 operative time (min.) mean ± sd 117.4 ± 26.2 114.8 ± 22.7 0.63 hospitalization time, days 1.53 ± 0.7 1.63 ± 0.8 0.34 table 3. predictors of postoperative uti in the studied groups. univariate analysis multivariate analysis or 95% ci p value or 95% ci p value age 0.99 0.94-1.03 0.54 sex 0.09 0.018-0.46 0.004 0.09 0.017-0.49 0.005 diabetes 0.53 0.14-2.02 0.36 stone size 0.82 0.55-1.24 0.35 operative time 0.97 0.94-0.99 0.032 0.97 0.95-1.01 0.063 type of prophylaxis 0.22 0.044-1.09 0.063 0.19 0.033-1.14 0.069 table 2. complications rate among studied groups. parameters total group 1 group 2 p value (n = 256) (n = 128) (n = 128) overall complications 56 (21.9%) 34 (26.6%) 22 (17.2%) 0.04 intraoperative complications 28 (10.9%) 14 (10.9%) 14 (10.9%) 0.89 postoperative complications 28 (10.9%) 20 (15.6%) 8 (6.3%) 0.047 mccs grading of complications grade 1 ureteric mucosal injury 12 (4.7%) 6 (4.7%) 6 (4.7%) 0.98 hematuria 16 (6.3%) 10 (3.9%) 6 (4.7%) 0.34 grade 2 uti 28 (10.9%) 20 (15.6%) 8 (6.3%) 0.047 readmission (within 8 weeks) 10 (3.9%) 8 (6.3%) 2 (1.7%) 0.038 archivio italiano di urologia e andrologia 2023; 95, 1 el-sayed i. el-agamy, mohamed a. elhelaly, tamer a. abouelgreed, et al. discussion urinary tract infections after furs are commonly seen in clinical practice. even in the absence of microbial invasion, the surgical procedure elicits a significant systemic inflammatory response related to the procedure's duration and can predispose to infectious complications (10). the present prospective study assessed the value of standard antibiotic prophylaxis versus enhanced prophylaxis in preventing utis after furs. postoperative uti was diagnosed in twenty patients (15.6%) in the standard prophylaxis group versus eight patients (6.3%) in the enhanced prophylaxis group (p = 0.047). the beneficial effects of enhanced prophylaxis are attributed to additional measures included in the protocol, namely the preoperative culture and treatment of identified infections and use of coated ureteral access sheaths. the relation between positive preoperative culture and postoperative uti in patients submitted to furs was discussed by the study by senocak et al. (11). in their paper, positive preoperative urine culture with multidrug resistance isolates was recognized as an independent risk factor of postoperative uti. of note, none of our patients had such isolates. also, in the study of alezra et al. (12), positive day-1 culture was a significant predictor of severe uti. in addition, the study of auge et al. (13) highlighted the value of ureteral access sheath (uas) in the reduction of postoperative uti after furs. similar conclusions were reported by the randomized study of özkaya et al. (14). they noted that using uas in impacted mid-upper ureteral stones was related to fewer infectious complications. the uas reduces the irrigation pressures transmitted to the renal pelvis and parenchyma (13). moreover, appropriate uas selection is essential to optimize the renal blood flow during furs. adequate renal blood flow is critical to maintain local immune defensive mechanisms (15). in our study, logistic regression analysis identified the female sex as an independent risk factor of postoperative uti. this finding conforms with the study of baboudjian et al. (9). their study showed preoperative polymicrobial urine culture and increased operative time as predictors of postoperative uti. our conclusions are also supported by the recent metaanalysis of ma et al. (16). in contrast, the study of baseskioglu et al. (17) recognized preoperative infection history, comorbidity score, and residual fragments as significant predictors of uti after furs, while the relevant risk factors in the study of ozgor et al. (18) were longer operation time, presence of renal abnormality and age ≤ 40 years. conclusions urinary tract infection after flexible ureteroscopy and laser lithotripsy could be reduced significantly by utilizing the suggested enhanced prophylactic approach. the female sex factor is the only independent predicting factor for the occurrence of post-furs urinary tract infections. references 1. alenezi h and denstedt jd. flexible ureteroscopy: technological advancements, current indications and outcomes in the treatment of urolithiasis. asian j urol. 2015; 2:133-141. 2. cho sy. current status of flexible ureteroscopy in urology. korean j urol. 2015; 56:680-688. 3. osther pjs. risks of flexible ureterorenoscopy: pathophysiology and prevention. urolithiasis. 2018; 46:59-67. 4. kim jw, lee yj, chung jw, et al. clinical characteristics of postoperative febrile urinary tract infections after ureteroscopic lithotripsy. investig clin urol. 2018; 59:335-341. 5. greene dj, gill bc, hinck b, et al. american urological association antibiotic best practice statement and ureteroscopy: does antibiotic stewardship help? j endourol. 2018; 32:283-288. 6. wolf js jr, bennett cj, dmochowski rr, et al. best practice policy statement on urologic surgery antimicrobial prophylaxis [published correction appears in j urol. 2008; 180:2262-3]. j urol. 2008; 179:1379-1390. 7. bapir r, bhatti kh, eliwa a, et al. infectious complications of endourological treatment of kidney stones: a meta-analysis of randomized clinical trials. arch ital urol androl. 2022; 94:97-106. 8. pietropaolo a, bres niewada e, skolarikos a, et al. worldwide survey of flexible ureteroscopy practice: a survey from european association of urology sections of young academic urologists and uro-technology groups. cent european j urol. 2019; 72:393-397. 9. baboudjian m, gondran tellier b, abdallah r, et al. predictive risk factors of urinary tract infection following flexible ureteroscopy despite preoperative precautions to avoid infectious complications. world j urol. 2020; 38:1253-1259. 10. zhong w, leto g, wang l, et al. systemic inflammatory response syndrome after flexible ureteroscopic lithotripsy: a study of risk factors. j endourol. 2015; 29:25-28. 11. senocak c, ozcan c, sahin t, et al. risk factors of infectious complications after flexible uretero-renoscopy with laser lithotripsy. urol j. 2018; 15:158-163. 12. alezra e, lasselin j, forzini t, et al. prognostic factors for severe infection after flexible ureteroscopy: clinical interest of urine culture the day before surgery? prog urol. 2016; 26:65-71. 13. auge bk, pietrow pk, lallas cd, et al. ureteral access sheath provides protection against elevated renal pressures during routine flexible ureteroscopic stone manipulation. j endourol. 2004;18:3336. 14. özkaya f, sertkaya z, karabulut i, et al. the effect of using ureteral access sheath for treatment of impacted ureteral stones at mid-upper part with flexible ureterorenoscopy: a randomized prospective study. minerva urol nefrol. 2019;71:413-420. 15. sener te, tanidir y, bin hamri s, et al. effects of flexible ureteroscopy on renal blood flow: a prospective evaluation. scand j urol. 2018; 52:213-218. 16. ma yc, jian zy, yuan c, et al. risk factors of infectious complications after ureteroscopy: a systematic review and metaanalysis based on adjusted effect estimate. surg infect (larchmt). 2020; 21:811-822. archivio italiano di urologia e andrologia 2023; 95, 1 antibiotic prophylaxis for urinary tract infection after flexible ureteroscopy 17. baseskioglu b. the prevalence of urinary tract infection following flexible ureterenoscopy and the associated risk factors. urol j. 2019; 16:439-442. 18. ozgor f, sahan m, cubuk a, et al. factors affecting infectious complications following flexible ureterorenoscopy. urolithiasis. 2019; 47:481-486. correspondence el-sayed i. el-agamy, md abuamr1978@yahoo.com mohamed a. elhelaly, md elhelalymohammed@yahoo.com department of urology, faculty of medicine, al-azhar university, cairo, egypt & department of urology, armed forced hospital, alhada, ksa tamer a. abouelgreed, md (corresponding author) dr_tamer_ali@yahoo.com tamerali.8@azhar.edu.eg department of urology, faculty of medicine, al-azhar university, cairo, egypt. & gulf medical university, uae abdrabuh m. abdrabuh, md abdo197871@yahoo.com mohamed f. elebiary, md dr_elebiary@yahoo.com adel elatreisy, md dr_adelelatreisy@yahoo.com osama m. ghoneimy, md elgendyosama787@gmail.com basem a. fathi, md basemhara@gmail.com basemabdalla.8@azhar.edu.eg department of urology, faculty of medicine, al-azhar university, cairo, egypt mohamed zamra, md mohamedzomrah@gmail.com department of urology, alqasemi hospital, sharjah, uae khalid kutub, md abanis35@gmail.com department of urology, al sharq hospital, fujairah, uae conflict of interest: the authors declare no potential conflict of interest. stesura seveso introduction penile prosthesis implantation is the solution of choice in patients who have failed or present contraindication to the use of all conservative treatment for erectile dysfunction 133archivio italiano di urologia e andrologia 2013; 85, 3 original paper long term patient satisfaction and quality of life with ams700cx inflatable penile prosthesis antonio vitarelli 1, lucia divenuto 1, francesca fortunato 2, antonio falco 3, vincenzo pagliarulo 1, gabriele antonini 4, vincenzo gentile 4, alessandro sciarra 4, stefano salciccia 4, salvatore sansalone 5, maria rosaria di placido 4, giulio garaffa 6, arcangelo pagliarulo 1 1 “urologia ii universitaria”, department of emergency and transplant, section of urology and andrology, university hospital “azienda ospedaliera policlinico”, bari, italy; 2 department of medical sciences and occupational medicine, section of hygiene, university of foggia, italy; 3 epidemiologic observatory of puglia, italy; 4 department of urology, university “la sapeinza”, rome, italy; 5 department of urology, “tor vergata” university, rome, italy; 6 st. peter’s andrology and the urology centre, broomfield hospital, chelmsford, uk. objective: penile prosthesis implantation is the solution of choice in patients who have failed or present contraindication to the use of all conservative treatment for erectile dysfunction (ed). overall, satisfaction rates are high, with more than 80% of patients and partners fully satisfied with cosmetic and functional result of surgery. chronic postoperative pain, penile shortening, soft or hyposensitive glans, pencil like penis syndrome and difficulty to cycle the device represent the most common causes of patient’s dissatisfaction. satisfaction rates are better assessed with the use of validated questionnaires such as the international index of erectile function (iief) and the erectile dysfunction inventory of treatment satisfaction (edits) the aim of our study was to analyze the long-term mechanical reliability of the ams 700cx/cxm inflatable penile prosthesis and the patient’s satisfaction rate using iief and edits questionaire as standard reference. materials and methods: a retrospective case notes review of all patients who have undergone implantation of a three pieces inflatable penile prosthesis ams 700 cx and cxr between october 1997 and december 2010. overall, 80 patients have undergone implantation of 3 pieces inflatable penile prosthesis ams 700 cx inhibizone. patients have been administered the iief-5 and edits questionnaires in combination with a non validated 9 domain questionnaire that assesses penile rigidity, sensation, orgasmic function, frequency of intercourse, impact of surgery on the quality of life, satisfaction rate. results: overall 10 years survival estimate according to the kaplan meier method of ams 700 cx touch pump and ams 700 cx momentary squeeze pump are respectively 77.6% and 82.5%. the median postoperative iief5 and edits score were respectively 21.46 and 73.11, which show a high level of satisfaction. 59 patients (90.8%) were able to cycle the device and were engaging in penetrative sexual intercourse. conclusions: penile prosthesis implantation yields excellent results in terms of cosmetic and functional outcome and therefore has a significant impact on patients’ satisfaction, sex life and overall quality of life. overall, long term reliability has been significantly improved and complication rates are low in the hands of experienced surgeons. key words: penile prosthesis; erctile disfunction; impotence; questionnaires. submitted 28 may 2013; accepted 25 june 2013 no conflict of interest declared summary (ed). overall, 25-30% of patients with ed will fail to respond to phosphodiesterase type 5 inhibitors (pde5i) and will therefore be offered intracavernosal injection (ici) doi: 10.4081/aiua.2013.3.133 archivio italiano di urologia e andrologia 2013; 85, 3 vitarelli, divenuto, fortunato, falco, pagliarulo, antonini, gentile, sciarra, salciccia, sansalone, di placido, garaffa, pagliarulo 134 of prostaglandin e (pge). since ici is associated with a high rate of drop out, around 10-15% of patients with ed will be candidate for penile prosthesis implantation (1). although prosthetic surgery in virgin corpora is associated with higher satisfaction rates in patients and partners than pde5i, intra and postoperative complications are not uncommon and therefore the procedure should be carried out only by a large volume surgeon. inflatable device have been initially introduced by scott in 1973 (2) and now are available in a two and three pieces version. in general, inflatable penile prosthesis are associated with higher satisfaction rates among patients and partners than their semirigid counterpart as they allow girth expansion, thus preventing the risk of “pencil penis” syndrome, and can be deflated mimicking the flaccid penile state. the most widely used three pieces inflatable penile prostheses are produced by american medical systems (ams, minnetonka, minnesota usa) and coloplast (coloplast corporation, humlebaek, denmark). since their initial introduction in 1973, three pieces inflatable penile prosthesis have undergone significant improvement in order to increase their long-term mechanical reliability and reduce the risk of infections. a major breakthrough has been the introduction by ams of the ams 700 cx model, which was characterized by controlled expansion cylinders. this has led to a reduction of mechanical failure from 62% to 15% at 5 years due to the reduced risk of aneurysmal dilatation of the cylinders (3). at present ams is on the market with two varieties of three pieces inflatable penile prosthesis: the ams 700cx, and the ams 700cxr, which presents narrow base cylinders and is designed for implantation in severely fibrotic corpora, where dilatation is difficult. the coloplast counterparts are respectively the titan and the titan narrow base. another breakthrough has been the introduction by ams of controlled girth and length expansion cylinders, this prosthesis, initially introduced on the market under the name of ultrex, was associated with a high rate of erosion and mechanical failure and therefore has been improved and it is now available under the name of lgx (length and girth expansion) which allows a length expansion up to 4 cm and is associated with a 5 year survival of 94% in carefully selected patients (4). also the pump has been redesigned, to render cycling easier and to reduce the incidence of mechanical failure. in particular, the introduction of the lock out valve has reduced the incidence of spontaneous autoinflation of the device and the momentary squeeze pump (ms) has allowed an easier deflation of the device (5-8). another breakthrough in the ams implants has been the use of the parilene coating of the cylinders, which renders the implant more resistant to friction and therefore reduces the risk of wearing, and the impregnation of the rods with inhibizone, a combination of rifampicin and minocyclin, which has significantly reduced the risk of infection from 1,61% a 0,68% and from 2,41% a 1,36% respectively in virgin and revision implants (7-10). indication for penile prosthesis implantation is refractory erectile dysfunction, which fails to respond to medical treatment. also patients who have medical contraindications to the use of pde5i, ici and vacuum device are candidates for penile prosthesis implantation. the choice between an inflatable penile prosthesis depends on the patient’s choice, funding, previous abdominal and genital surgery, body habitus and hand dexterity (1). in general, poor hand dexterity and multiple abdominal surgeries are relative contraindications to the implantation of an inflatable penile prosthesis. larger penises and physically active patients are instead better served with a three pieces inflatable device. adequate preoperative counseling is paramount, as excessively high patients expectations will lead to lower postoperative satisfaction rates. in particular, patients must be warned that stretched penile length is a good indicator of the postoperative penile length and that the procedure is irreversible. although the reliability of the device has been significantly improved, mechanical failure rates at 5 years still vary between 10 and 20%. if the failure occurs in the early months, it not necessary to remove the entire device and the identification and exchange of the faulty component usually suffices. if the mechanical failure occurs after 2 years instead, it is advisable to exchange the entire device. mechanical failure can occur in all components of the prosthesis, from the tubings, to the connectors, the pump, the reservoir and the cylinders. penile prosthesis infection still represents the most fearful complication, occurs in 1% to 3% of patients and is more common in case of diabetes, compromised immunitary system, neurological condition, revision surgery and fibrosis. in case of infection the entire device has to be removed and patients can be offered immediate (mulcahy procedure) or delayed reimplantation. erosion, necrosis, purulent discharge and systemic infection are contraindications for immediate reimplantation. erosion of the device is uncommon and occurs in 3% to 6% of cases and it usually occurs at the navicular fussa or at the corona. overall, satisfaction rates are high, with more than 80% of patients and partners fully satisfied with cosmetic and functional result of surgery. chronic postoperative pain, penile shortening, soft or hyposensitive glans, pencil like penis syndrome and difficulty to cycle the device represent the most common causes of patient’s dissatisfaction (11). satisfaction rates are better assessed with the use of validated questionnaires such as the international index of erectile function (iief) and the erectile dysfunction inventory of treatment satisfaction (edits) (12-13). the aim of our study was to analyze the long-term mechanical reliability of the ams 700cx/cxm inflatable penile prosthesis and the patient’s satisfaction rate using iief and edits questionaire as standard reference. materials and methods a retrospective case notes review of all patients who have undergone implantation of a three pieces inflatable penile prosthesis ams 700 cx and cxr between october 1997 and december 2010. this study was conducted after approval of the protocol from our department institutional committee and informed consent was obtained from all patients. overall, 80 patients have undergone implantation of 3 pieces inflatable penile prosthesis ams 700 cx inhibizone; a tactile pump has been used in 42 patients and momentary sqeeze® pump in the remainder. the median age at the time of implantation was 56 years (range 40-77). the aetiology of ed was radical pelvic surgery in 32 patients (43.2%), vasculogenic in 25 (33.8%), peyronie’s disease in 12 (16.2%), spinal cord injury in 4 (5.4%) and fibrosis post low flow priapism in 1 (1.4%). diabetes mellitus was present in 24 patients (20%) and 6 had already undergone explantation of an infected penile prosthesis and presented with severe corporeal fibrosis. implantation of the device has been carried out through a penoscrotal approach in 50 patients (62.5%) and through an infrapubic one in the remainder. implantation has been difficult in 7 patients due to severe corporeal fibrosis and a second subcoronal incision has been necessary in 4 cases to allow adequate distal dilatation. patients have been administered the iief-5 and edits questionnaires in combination with a non validated 9 domain questionnaire that assesses penile rigidity, sensation, orgasmic function, frequency of intercourse, impact of surgery on the quality of life, satisfaction rate. patients were invited to give a score between 1 and 4 for each of the questions (1: excellent; 2: good; 3: moderate; 4: poor) as reported in table 1. postoperative penile length has also been recorded. statistical analysis statistical data analysis was done with the statistical software medcalc software demo for windows, version 9.3. the kaplan-meier method was used to analyze the survival of the ams 700cx/cxm inflatable penile prostheses also a student’s t-test was performed and a p value of < 0.05 was considered to indicate a significant difference. results after a median follow up of 68.7 months (range 6164), infection of the device has occurred in 2 patients (2.5%) and has required the removal of the device followed by delayed reimplantation at 6 months. mechanical failure of the device has occurred in 10 patients (12.5%) and was due to pump failure, cylinder rupture and fluid leak from the reservoir in respectively 5, 3 and 2 patients. all patients have been managed with complete exchange of the device. erosion through the corona/glans occurred in 3 patients, through the scrotal skin in 1 and through the urethra in 1, as shown in figure 1 and 2. all the components of the implants have been removed in all patients. overall, 65 patients have completed all the questionnaires. both iief-5 and edits questionnaire have shown a mean improvement of the sexual function and of quality of life. the median postoperative iief5 and edits score were respectively 21,46 and 73,11, which show a high level of satisfaction. 59 patients (90,8%) were able to cycle the device and were engaging in penetrative sexual intercourse. with regards to the impact of surgery on the quality of life, 58 patients (89,2%) were fully satisfied with the outcome of surgery, and 57 (57%) were globally satisfied. 55 patients (84,6%) would undergo surgery again and 57 would advise a friend to undergo the same treatment. although patients who reported good sensitivity during intercourse scored higher at the edits (74,6 ± 19,2; ci95%: 69,4-79,7) and the iief-5 (21,7 ± 5,2; ci95%: 20,2-23,2) questionnaires than patients who had poor sensation [edits (63,8 ± 16,3; ci95%: 51,4-76,4); iief5 (19,6 ± 4,3; ci95%: 16,2-22,9)], the difference was not statistically significant (p > 0.05). patients who reported an adequate rigidity during intercourse scored significantly higher at the edits (76,8 ± 15,8; ci95%: 72,5-81,2) and iief-5 (22,2 ± 4,7; ci95%: 20,9-23,5) questionnaires than patients with moderate rigidity [edits (54,7 ± 23,4; ci95%: 38,9-70,5); iief-5 (17,7 ± 7,0; ic95%: 12,9-22,5)]. the difference reached statistical significance. also patients who reported an excellent/good orgasm scored higher at the edits (76,5 ± 15,7; ci95%: 72,280,7) and iief-5 (22,5 ± 3,6; ci95%: 21,5-23,5) questionnaires than patients who had a moderate/poor orgasm [edits (54,5 ± 25,6; ci95%: 36,2-72,8); iief-5 (15,8 ± 9,3; ci95%: 9,1-22,5)] and the difference reached statistical significance the median length of the cylinders in patients who reported an improvement in the quality of sexual life was superior (19 ± 1,9; ci 95% 18,5-19,5) than the one of 135archivio italiano di urologia e andrologia 2013; 85, 3 long term patient satisfaction and quality of life with ams700cx inflatable penile prosthesis 1. are you using the device? 1 2 3 4 2. is the device easy to cycle? 1 2 3 4 3. did you notice an improvement in your sexual life? 1 2 3 4 4. are you satisfied? 1 2 3 4 5. would you advise a friend to undergo the same procedure? 1 2 3 4 6. would you undergo the same procedure? 1 2 3 4 7. do you have sensation during intercourse? 1 2 3 4 8. do you obtain adequate rigidity? 1 2 3 4 9. do you achieve an orgasm? 1 2 3 4 table 1. the domains of the non validated questionnaire. figure 1. erosion of one cylinder through the urethra. figure 2. erosion through the glans penis. archivio italiano di urologia e andrologia 2013; 85, 3 vitarelli, divenuto, fortunato, falco, pagliarulo, antonini, gentile, sciarra, salciccia, sansalone, di placido, garaffa, pagliarulo 136 patients who did not report an improvement in sexual life (17,3 ± 1,9; ci 95% 15,5-19,0). this difference was statistically significant (p = 0,0284). also the cylinders were statistically longer (19 ± 1,9; ic 95% 18,5-19,5) in patients who would advise a friend to undergo surgery than in patients who would not advise to undergo the procedure (17,2 ± 1,7; ic 95% 15,8-18,7) (p = 0,0151) and in patients who were globally satisfied (19 ± 1,9; ci 95% 18,5-19,5) than in patients who were dissatisfied (17 ± 1,7; ic 95% 15,4-18,6) (p = 0,0087). there is a progressive but not statistically significant increase in the iief-5 and edits score with increasing length of the cylinders. when considering the type of prosthesis implanted, the median edits and iief-5 score of patients with an ams 700cx ms [edits (74,9 ± 15,1; ci 95% 69,3-80,6); iief-5 (21,5 ± 5,0; ci 95% 19,6-23,4)] was higher than the one of patients who have undergone implantation of a ams 700cx tactile pump [edits (71,5 ± 22,0; ci 95% 63,9-70,1); iief-5 (21,3 ± 5,7; ci 95% 19,4-23,3)], but the difference did not reach statistical significance. edits and iief-5 scores were lower in patients who presented comorbidities [edits (72,4 ± 20,0; ci95%: 67,177,7); iief-5 (21,1 ± 5,7; ci 95% 19,6-22,7)] than in patients with no comorbidities [edits (78,1 ± 9,1; ci 95%: 70,5-85,8); iief-5 (23,4 ± 0,9; ci 95%: 22,6-24,1)], but the difference did not reach statistical significance. overall, patients who have experienced complications scored lower both at the edits and iief-5 questionnaires [edits (54,9 ± 30,1; ci 95%: 34,7-75,2); iief-5 (14,4 ± 10,1; ic 95%: 8,6-22,2)] than patients who had no complications [edits (75,3 ± 16,9; ic 95%: 70,879,7); iief-5 (22,3 ± 3,9; ic 95%: 21,2-23,3)]. the difference reached statistical significance. overall 10 years survival estimate according to the kaplan meier method of ams 700 cx touch pump and ams 700 cx momentary squeeze pump are respectively 77,6% (ic 95%: 58,0-88,8) and 82,5% (ic 95%: 63,092,2), as reported in table 2 and 3. discussion penile prosthesis implantation represents the only solution for patients with refractory erectile dysfunction. overall, mechanical reliability and overall patients’ satisfaction of 3 pieces inflatable penile prosthesis has progressively increased since the first description of a hydraulic device by scott et al. more than 30 years ago (2). in particular, 5 years survival can be as high as 92.1% with patients’ satisfaction rates of 85.6% and a prevalence of mechanical failure of 9.1% (1416). the main limitation of all these studies is that patients’ satisfaction was assessed subjectively by the surgeon and not with a validated questionnaire. mulhall et al. in 2003 has been the first to use validated questionnaires such as iieftable 2. kaplan meier overall survival estimate (%). years overall survival [95% conf. int.] following estimate (%) 0 100 . . 1 97,2 89,4 99,3 2 97,2 89,4 99,3 3 97,2 89,4 99,3 4 91,9 79,0 97,0 5 86,4 71,3 93,8 6 86,4 71,3 93,8 7 82,5 65,3 91,6 8 82,5 65,3 91,6 9 77,6 58,0 88,8 10 77,6 58,0 88,8 table 3. kaplan meier overall survival estimate (%) according to the type of implant. type years overall survival [95% of implant following estimate (%) conf. int.] ams 700 cx 1 100 tactile pump 3 100 5 88,8 72,8 95,6 10 79,7 59,2 90,7 ams 700 cx 1 94,3 79,0 98,5 momentary 3 94,3 79,0 98,5 squeeze pump 5 10 5 and edits to assess patients’ satisfaction 6 months postoperatively (10). the present series using validated questionnaires confirms a statistically significant correlation between mechanical complications, degree of rigidity and quality of the orgasm with patient’s satisfaction. interestingly, the quality of sensation did not affect iief-5 and edits scores in a statistically significant way. overall 87.7% of the patients in the present series were satisfied with the cosmetic and functional result of surgery, and these results are similar to the one previously reported in the literature (17, 18). also median prosthesis survival rate in the present series was 97.2% at 1 year, 91.9% at 4 years and 77.6% at 10 years, substantially similar to the data reported by dhar et al. (19). the strength of our results has been to have used a validated questionnaires to assess the functional results, compared with other previously similar experiences. some limits of our study must be underlined: first, this is a retrospective analysis and not a prospective and randomized study. second, the follow-up was not so longer (68.7 months) to better evaluate the satisfaction of patients in a long time from surgery, however it is similar to previous experience in this field. conclusions penile prosthesis implantation yields excellent results in terms of cosmetic and functional outcome and therefore has a significant impact on patients’ satisfaction, sex life and overall quality of life. overall, long term reliability has been significantly improved and complication rates are low in the hands of experienced surgeons. references 1. montague dk. penile prosthesis implantation in the era of medical treatment for erectile dysfunction. urol clin north am. 2011; 38:217-25. 2. scott fb, bradley we, timm gw. management of erectile impotence: use of implantable inflatable prosthesis. urology. 1973; 2:80. 3. nickas me, kessler r, kabalin jm. long term experience with controlled expansion cylinders in the ams 700 cx inflatable penile prosthesis and comparison with earlier version of the scott inflatable penile prosthesis. urology. 1994; 44:400. 4. milbank aj montague dk, angermeier kw, et al. mechanical failure of the american medical system ultrex inflatable penile prosthesis: before and after 1993 structural modification. j urol. 2002; 167:2502-6. 5. daitch ja, angermeier kw, lakin mm, et al. long term mechanical reliability of ams 700 series inflatable penile prostheses: comparison of cx/cxm and ultrex cylinders. j urol. 1997; 158:1400. 6. wilson sk, cleves ma, delk jr 2nd. comparison of mechanical reliability of original and enhanced mentor alpha i penile prosthesis. j urol. 1999; 162:715-8. 7. delk j, knoll ld, mc murray j, et al. early experience with the american medical system new tactile pump: results of a multicentre study. j sex med. 2005:266-71. 8. knoll ld, henry g, culkin d, et al. physician and patient satisfaction with the new ams700 momentary sqeeze inflatable penile prosthesis. j sex med. 2009; 6:1773-8. 9. carson cc efficacy of antibiotic impregnation of inflatable penile prosthesis in decreasing infection in original implants. j urol. 2004; 171:1611-1614. 10. carson ci. initial success with the ams 700 series inflatable penile prosthesis with inhibizione antibiotic surface treatment: a retrospective review of revision cases incidence and comparative results versus non-treated devices. j urol. 2004; 171:236. 11. mc laren rh, barret dm. patient and partner satisfaction with the ams 700 penile prosthesis. j urol. 1992; 147:62. 12. mulhall jp, ahmed a, branch j, parker m. serial assessment of efficacy and satisfaction profiles following penile prosthesis surgery. j urol. 2003; 169:1429-1433. 13. althof se, corty ew, levine sb, et al. edits: development of questionnaires for evaluating satisfaction with treatments for erectile dysfunction. urology. 1999; 53:793-9. 14. carson cc penile prosthesis implantation in the treatment of peyronie desease” int j imp res. 1998; 10:125. 15. choi deuk y, jin choi y, hwan kim j, ki choi h. mechanical reability of the ams 700 cmx inflatable penile prosthesis for the treatment of male erectile dysfunction. j urol. 2001; 165:822-4. 16. carson cc, mulcahy jj, govier fe. efficacy, safety and patient satisfaction outcome of the ams 700 cx inflatable penile prosthesis: result of a long term multicenter study. ams 700 cx study group. j urol. 2000; 164:376-80. 17. bhojwani ag, jain s, kockelbergh rc, terry tr. sexual satisfaction after penile prosthesis insertion for the treatment of erectile dysfunction. sex dysfunction. 1998; i:133-136. 18. goldstein i, jain l, kockelbergh rc, terry tr. safety and efficacy outcome of mentor alpha1 inflatable penile prosthesis implantation for impotence treatment. j urol 1997; 157:833-9. 19. dhar nb, angermeier kw, montague dk. long-term mechanical reliability of ams 700cx ™/cxm inflatable penile prosthesis. j urol. 2006; 176:2599-2601. 137archivio italiano di urologia e andrologia 2013; 85, 3 long term patient satisfaction and quality of life with ams700cx inflatable penile prosthesis correspondence antonio vitarelli, md antoniovitarelli@hotmail.com lucia divenuto, md ldivenuto@urologia.uniba.it vincenzo pagliarulo, md vpagliarulo@urologia.uniba.it arcangelo pagliarulo, md apagliarulo@urologia.uniba.it urologia ii universitaria, department of emergency and transplant, section of urology and andrology, university hospital, azienda ospedaliera policlinico, bari, italy francesca fortunato, md f.fortunato@unifg.it department of medical sciences and occupational medicine, section of hygiene, university of foggia, foggia, italy antonio falco, md a.falco@unifg.it epidemiologic observatory of puglia, foggia italy stefano salciccia, md (corresponding author) stefi_sal77@tiscali.it gabriele antonini, md gabrieleantoninimd@gmail.com vincenzo gentile, md vincenzo.gentile@uniroma1.it alessandro sciarra, md sciarrajr@hotmail.com maria rosaria di placido, md m.diplacido@uniroma1.it department of urology, university “la sapienza”, viale del policlinico 155 00161 roma, italy salvatore sansalone, md salvatore.sansalone@yahoo.it department of urology, tor vergata, university, rome, italy giulio garaffa, md giuliogaraffa@gmail.com st. peter’s andrology and the urology centre, broomfield hospital chelmsford (uk) stesura seveso introduction varicocele can affect all parameters of sperm characteristics, including sperm count, sperm motility, and morphology. different techniques have been suggested for varicocele treatment, both surgical and non-surgical. the surgical techniques include the open surgical (inguinal, subinguinal, retroperitoneal approach), laparoscopic and microsurgical varicocelectomies. the non-surgical are 143archivio italiano di urologia e andrologia 2013; 85, 3 original paper varicocele treatment: a 2-centers comparison between non microsurgical open correction, laparoscopic approach and retrograde percutaneous sclerotization on 463 cases giangiacomo ollandini 1, giovanni liguori 1, stanislav ziaran 2, tomá! málek 2, giorgio mazzon 1, bernardino de concilio 1, stefano bucci 1, sara benvenuto 1, emanuele belgrano 1, carlo trombetta 1 1 urologic unit, cattinara hospital, university of trieste, trieste, italy; 2 urology clinic, university hospital in bratislava, comenius university, bratislava, slovakia. objectives: to determine whether there are differences in sperm parameters improvement after different varicocele correction techniques. to determine the role of age in sperm parameters improvement. methods: 2 different european centers collected preand postoperative sperm parameters of patients undergoing varicocele correction. among 463 evaluated patients, 367 were included. patients were divided in procedure-related and age-related groups. ivanissevich inguinal open surgical procedure (os), lymphatic-sparing laparoscopic approach (lsl) and retrograde percutaneous transfemoral sclerotization (rps) were performed. as outcome measurements sperm count (millions/ml, sc) and percentage of mobile sperms were analyzed. univariate and multivariate regression between the defined groups; bivariate regression analysis between age and sperm count and motility. results: number of patients: os 78; lsl 85; rps 204. mean age 30.2 (sd 6.83); postoperative sc increased from 18.2 to 30.1 (ci 95% 27.3-32.9; p < 0,001); motility from 25.6 to 32.56% (30.9-34.2; p < 0.001). os: sc varied from 16.9 to 18.2 (p < 0.001); sperm motility from 29% to 33% (p < 0.001). lsl: sc from 15.5 to 17.2 (p < 0.001); motility from 27 to 31% (p < 0.001). rps: sc from 18.9 to 36.2 (p < 0.001); motility from 24% to 32% (p < 0.001). univariate and multivariate analysis confirmed the significant difference of sc variation in rps, compared to the other groups (p < 0.001). no significance between lsl and os (p = 0.826). no significant differences regarding motility (p = 0.8). conclusions: varicocele correction is confirmed useful in improving sperm parameters; sclerotization technique leads to a better sperm improvement compared to other studied procedures; improvement in seminal parameters is not affected by age of the patients treated. key words: andrology; infertility; sclerotization; spermatozoa; varicocele. submitted 18 july 2013; accepted 31 july 2013 no conflict of interest declared summary represented by the radiological-assisted techniques: embolization or sclerotherapy (1, 2). several studies related the outcome in terms of invasiveness and costs between the different techniques used (3, 4); however a comparison of the efficacy on sperm parameters improvement of open ligation, laparoscopic approach and sclerotization is still missing. doi: 10.4081/aiua.2013.3.143 archivio italiano di urologia e andrologia 2013; 85, 3 g. ollandini, g. liguori, s. ziaran, t. málek, g. mazzon, b. de concilio, s. bucci, s. benvenuto, e. belgrano, c. trombetta 144 the goal of our study was to compare the clinical outcomes in terms of sperm quality after varicocele correction using the three cited techniques. we also referred to patients’ age in order to analyze whether there are significant differences of postoperative sperm improvement related to age increment. material and methods two different centers collected data of patients undergoing varicocele treatment from 1986 to 2011. patients were complaining both from infertility or testicular pain. all patients underwent a complete history, physical examination in a warm room, hormonal assessment, semen analysis. each center treated the patients with a different technique: open ligation of the spermatic vein according to ivanissevich technique, laparoscopic approach or retrograde sclerotization of the spermatic vein. at least 3 months after surgery, semen analysis and physical examination have been performed: in fact al bakri et al. in 2012 demonstrated that there is no significant improvement in sperm parameters after 3 months from correction (6). on a total of 463 patients, 96 have been excluded according to the following criteria: persistence of varicocele, endocrinological abnormalities, history of undescended testis, bilateral varicocele, and abnormal right testis. mean age of patients was 30.2 yr (sd 6.83); median clinical grade was 2 (iqr 1); mean sperm concentration was 18.0 millions/ml (sd 14.7) and mean sperm motility was 25.6% (sd 17.51). surgical procedures: the operative procedures are widely described in the literature. in ivanissevich open surgery inguinal approach (under general anesthesia) the exposure of the internal spermatic vessels within the inguinal canal takes place through an incision of the external oblique aponeurosis (7). in laparoscopic ligation of spermatic veins (under general anesthesia) the patients underwent varicocelectomy by the lymphatic sparing technique. in this procedure the internal spermatic veins alone were divided. using a microsurgical technique both the artery and the lymphatics were preserved (8). patients underwent retrograde percutaneous sclerotization of their left spermatic vein, using the right transfemoral retrograde percutaneous approach. the femoral vein is entered below the inguinal ligament using the standard seldinger technique. renal phlebography is carried out by injection of contrast medium under valsalva maneuver. after superselective catheterization of the spermatic vein, a guidewire is introduced and act as a guide for a very distal catheterization, through continuous fluoroscopy. superselective angiography shows every possible collateral circle and the possible presence of multiple spermatic veins. sclerotization technique is performed by injecting a 2-4 ml of sodium tetradecyl sulfate 3% mousse. patients are required to perform a valsalva maneuver at least 10 seconds long during the injection. venography is then performed again: should there be bulky veins, the operation is repeated at a higher lumbar level. after this procedure, a control venography is performed to confirm the absence of renospermatic reflow (9, 10). it is known from the literature that up to 20% of patients have anatomical abnormalities of their veins, that could eventually make not possible the retrograde technique. when this happened, we performed anterograde sclerotization according to tauber technique during the same session (11). semen analysis specimens were obtained by masturbation after 3 to 5 days of abstinence. the specimens were valuated within 1 hour from collection for the following parameters: sperm concentration (millions/ml), percentage of sperms with a + b motility (a, speed linear motility; b, slow linear motility; c, motility in situ; d, no motility at all), percentage of morphologically typical sperms. the laboratories evaluated the parameters according to who criteria. statistical analysis statistical analyses were performed with spss 17.0 software package. description of population and parameters have been reported as mean values with standard deviation (sd) for continuous variables, and with median values with interquartile range (iqr) for non-continuous ones. the significances of differences between preoperative and postoperative values within groups have been valued with the paired student t-test, if appropriate, or with the wilcoxon signed rank test. means variations between two groups has been valuated with mannwhitney u test. anova univariate analysis of variance with lsd post-hoc evaluation has been carried out in order to compare mean values of more than two groups. manova multivariate analysis has been then performed between our data. the linear regression coefficients have been calculated in order to test the correlation between age and parameters. probability values < .05 were considered significant. results patients included in the study were a total of 367. among these, 78 underwent open surgical approach; 85 were treated by laparoscopy and 204 by sclerotization technique. persistence and minor complication rates are shown in table 1. no major complications occurred. complications in surgical ligation of spermatic vein were hydrocele, difficult wound healing and hematomas. complications among sclerotization techniques were mostly represented by persistent (more than 3 days) pain at the spermatic chord. due to the injection of sclerosing substance, though, self-recovery pain and an acceptable increase of volume and consistence of the chord was not considered as a complication. sperm concentration increased postoperatively in 73% of global cases; motility from 25.6 to 32.56% (p < 0.001). average postoperative sperm concentration increased to 30.1 millions/ml (sd 29.9; ci 95% 27.332.9; p < 0.001) and motility to 32.56% (sd 17.3; ci 95% 30.9-34.2; p < 0.001). patients have been divided into three groups, according to the procedure performed, and into 4 groups, according to their age. every difference within the groups obtained a significance p-value < 0.001. differences between the groups univariate anova regression analysis and multivariate manova have been performed in order to evaluate the differences between the groups and set their significance (table 2). post hoc evaluation of variances between procedure-related groups have been reported for sperm count. variation of sperm count has been demonstrated to be related to the procedure (figure 1), being significantly higher for patients treated by sclerotization procedure. age decades showed no significant differences in mean values of sperm count and sperm motility improvement (table 2). mean variation of sperm concentration showed also no significant differences between age-related groups (figure 2). the linear regression standardized coefficient between age and sperm motility for preoperative values is -0.09 (p = 0.048) and for postoperative values is -0.10 (p = 0.021). therefore there is no significant difference between the calculated coefficients (figure 3). discussion in our study we found: • as already known from the literature, varicocele correction is confirmed as useful in improving sperm parameters 145archivio italiano di urologia e andrologia 2013; 85, 3 varicocele treatment: a 2-centers comparison between non microsurgical open correction, laparoscopic approach and retrograde percutaneous sclerotization figure 1. mean variation of sperm concentration and motility between the three procedure-related groups. technique n excluded included complications other reasons recurrency (%) total open surgery 77 2 7 (9,1%) 9 68 7% laparoscopic 80 4 1 (1,3%) 5 75 0% sclerotization 366 57 25 (9,3%) 82 284 5% total 523 63 33 96 427 table 1. total number of treated and excluded and rate of overall post-operative complications. age (sd) sperm concentration (95% ci) motility (95% ci) pre post* pre post* procedure open surgery 32,1 (6,85) 16,9 (13,4-20) 18,2 (15,0-21,5) 29 (25,8-32) 33,1 (30,9-35,4) laparoscopy 26 (5,6) 15,5 (13,7-17,1) 17,2 (15,5-18,9) 27 (23,5-29,6) 31,2 (28,7-33,8) sclerotization 25,9 (5,2) 18,9 (17-20,1) 36,2 (32,8-40,7) 24 (21,3-29,9) 32,9 (30,3-35,6) p-value univariate 0,2 < 0,0001 0,25 0,21 multivariate 0.18 < 0,0001 0.18 0.15 age decades group 1 0-20 18,8 (13,7-23,9) 27,3 (25,7-38,8) 30,6 (26,1-35,2) 38,5 (33,9-43,0) group 2 21-30 17,8 (15,7-19,9) 29,5 (25,4-33,6) 26,3 (24,0-28,5) 33,8 (31,5-36,2) group 3 31-40 17,2 (15-19,4) 30,9 (26,2-35,5) 24,1 (21,2-27,0) 30,9 (28,1-33,7) group 4 > 41 22,5 (17,1-27,9) 36,4 (28,2-44,6) 23,2 (16,0-30,3) 30,2 (24,7-35,7) p-value univariate 0,85 0,32 0,08 0,004 multivariate 0.97 0.30 0.13 0.003 table 2. univariate anova and multivariate manova analysis of variance. *p-value < 0,001 for each of the parameters withing the groups. archivio italiano di urologia e andrologia 2013; 85, 3 g. ollandini, g. liguori, s. ziaran, t. málek, g. mazzon, b. de concilio, s. bucci, s. benvenuto, e. belgrano, c. trombetta 146 • sclerotization technique leads to a better sperm improvement compared to other studied procedures • improvement in seminal parameters is not affected by age of the patients treated. the usefulness of varicocele repair remains a highly debated topic. the 2009 updated cochrane review by evers and collins discussed the indication to varicocele treatment in infertile men, and according to their metaanalysis there was no clear evidence of indication in varicocele correction to improve fertility (12). this review, though, have been debated by a contrary opinion: the authors (ficarra et al.) analyzed the methodology of the study and concluded that it was weak and poorly significant, as they included patients with subclinical varicoceles and normal semen parameters (13). more recently a randomized, controlled trial by abdel-eguid et al. (14) concluded that there is a statistically significant improvement in semen quality after microsurgical correction of varicocele and a higher pregnancy rate, comparing the results with the control arm. therefore the main focus of our study was not to demonstrate the outcome in terms of fertility and pregnancy rate, but to compare the efficacy in sperm improvement between the different used techniques. in 1998 barbalias et al. carried out a randomized clinical trial comparing a total of 88 patients who underwent varicocele correction either by retroperitoneal, inguinal, subinguinal or percutaneous approach. they analyzed pre and postoperative sperm parameters concluding that microsurgical subinguinal technique had a greater performance (15). a newer study in 2010 confirmed that microsurgical approach obtains better results compared to the standard inguinal approach (16). however microsurgical treatment of varicocele needs a greater amount of time and instruments than the other techniques. several studies compared the open surgery technique to sclerotization procedure, with contradictory results (12, 13, 17, 18); though one of the main outcomes of those studies was the pregnancy rate, this parameter seems to be affected by too many confounding factors to be eligible as a main outcome. many other studies, moreover, focused on the costs of the treatments, and the time to recovery: operative costs are shown to be similar for all the studied procedures, but the time to recovery is significantly less for patients treated by sclerotization technique. therefore bechara et al. concluded that the radiologicalassisted procedure has a cost-benefit compared to surgical treatment (19). the rate of technical failure of sclerotization procedure is described to vary from 5% to 20%, due to the anatomical abnormalities, venospasm or technical difficulties (13, 17, 19). in our experience the intervention is converted during the same session to an anterograde sclerotization, according to tauber technique. this possibility permits to obtain a 100% rate of technical success. our data clearly show that the sclerotization technique leads to a better improvement of sperm concentration compared to laparoscopic and ivanissevich techniques. moreover, these appear to obtain a similar outcome both regarding sperm density improvement and sperm motility improvement. the hypothesis regarding the better results of sclerotization techniques are probably related to: • better anatomical view and complete repair of varicocele • complete manteinance of lymphatic vascularization • no arterial injuries. figure 2. variation of sperm concentration is not significantly different among patients from different age decades. figure 3. pre and postoperative percentage of motility among age groups: the negative trend remains constant. sclerotization differs from the surgical approaches because of the venography that is repeated during the whole procedure, in order to guide step by step the intervention. this allows to obtain a clear imaging of the venous vascularization, and to close selectively every single vessel that is implicated in varicocele formation. in fact it is commonly known, that 19% of patients with varicocele have an aberrant anatomical situation (20). this situation cannot be completely discovered by laparoscopic and surgical approach, and will be probably not treated completely, even if post operatively there is no sign of clinically detectable persistence. the pathogenetic factors involving poor sperm quality on varicocele patients, if not completely corrected, could in fact continue their damage of the testis, that have been showed in several studies (21, 22). moreover, the risk of injuries to the testicular arteries is significantly higher in patients undergoing surgical procedures than in patients undergoing sclerotization, due to the procedure itself (23), even if the role of artery injury in sperm parameter’s outcome is not certainly significant (23, 24). finally, the preservation of lymphatic vessels is assured with sclerotization technique, while in patients undergoing surgical procedures the lymphatic damage is most likely avoided (laparoscopy) or most probably occurs (ivanissevich). lymphatic vessels ligation is thought to induce a significant worsening of testicular function, due to testicular edema (8). we may assume these factors cooperate in obtaining a better result in sperm concentration improvement in patients undergoing sclerotization of their varicocele instead of the other procedures. though there is an evidence of correlation between patients’ age and sperm parameters worsening in some studies in the literature (26, 27), according to other recent studies the role of age in sperm quality improvement after varicocele correction is believed to be not significant (9, 25). in our study the only significant trend, at linear regression estimation, is the decrease of sperm motility in relation to patients’ age. this trend is not affected by the intervention, as it remains constant after correction of varicocele, and represents the normal decrement of motility due to patient’s age. conclusions varicocele treatment leads to improvement in seminal parameter examined in 73% of the cases. both surgical and non-surgical approaches are effective, as in each group postoperative values are significantly better than preoperative ones. sclerotization of varicocele showed a better improvement of the postoperative sperm concentration, and is a safe and easy procedure, and should be therefore offered as a routine first line treatment to patients affected by varicocele, where the indication for treatment occurs. finally, even patients more than 40 years old showed a significant improvement of their sperm count and motility, and could be offered the treatment as well. references 1. will ma, swain j, fode m, et al. the great debate: varicocele treatment and impact on fertility. fertil steril. 2011; 95: 841-52. 2. belgrano e, trombetta c, liguori g. scleroembolization techniques in the treatment of varicocele. ann urol. 1999; 33:203-9. 3. al-kandari am, shabaan h, ibrahim hm, et al. comparison of outcomes of different varicocelectomy techniques: open inguinal, laparoscopic, and subinguinal microscopic varicocelectomy: a randomized clinical trial. urology. 2007; 69:417-20. 4. shamsa a, mohammadi l, abolbashari m, et al. comparison of open and laparoscopic varicocelectomies in terms of operative time, sperm parameters, and complications. urol j. 2009; 6:170-5. 5. dubin l, amelar rd. varicocele size and results of varicocelectomy in selected subfertile men with varicocele. fertil steril. 1970; 21:606-9. 6. al bakri a, lo k, grober e, et al. time for improvement in semen parameters after varicocelectomy. j urol. 2012; 187:227-31. 7. ivanissevich o. left varicocele due to reflux; experience with 4,470 operative cases in forty-two years. j int coll surg. 1960; 34:742-55. 8. kocvara r, dvorácek j, sedlácek j, et al. lymphatic sparing laparoscopic varicocelectomy: a microsurgical repair. j urol. 2005; 173:1751-4. 9. liguori g, ollandini g, pomara g, et al. role of renospermatic basal reflow and age on semen quality improvement after sclerotization of varicocele. urology. 2010; 75:1074-8. 10. trombetta c, liguori g, bucci s, et al. percutaneous treatment of varicocele. urol int. 2003; 70:113-8. 11. tauber r, pfeiffer d. surgical atlas varicocele: antegrade scrotal sclerotherapy. bju int. 2006; 98:1333-44. 12. evers jh, collins j, clarke j. surgery or embolisation for varicoceles in subfertile men. cochrane database syst rev. 2009; (1):cd000479. 13. ficarra v, cerruto ma, liguori g, et al. treatment of varicocele in subfertile men: the cochrane review--a contrary opinion. eur urol. 2006; 49:258-63. 14. abdel-meguid ta, al-sayyad a, tayib a, farsi hm. does varicocele repair improve male infertility? an evidence-based perspective from a randomized, controlled trial. eur urol. 2011; 59:455-61. 15. barbalias ga, liatsikos en, nikiforidis g, siablis d. treatment of varicocele for male infertility: a comparative study evaluating currently used approaches. eur urol. 1998; 34:393-8. 16. abdel-maguid af, othman i. microsurgical and nonmagnified subinguinal varicocelectomy for infertile men: a comparative study. fertil steril. 2010; 94:2600-3. 17. nabi g, asterlings s, greene dr, marsh rl. percutaneous embolization of varicoceles: outcomes and correlation of semen improvement with pregnancy. urology. 2004; 63:359-63. 18. shlansky-goldberg rd, vanarsdalen kn, rutter cm, et al.percutaneous varicocele embolization versus surgical ligation for the treatment of infertility: changes in seminal parameters and pregnancy outcomes. j vasc interv radiol. 1997; 8:759-67. 19. bechara cf, weakley sm, kougias p, et al. percutaneous treatment of varicocele with microcoil embolization: comparison of treatment outcome with laparoscopic varicocelectomy. vascular. 2009; 17(suppl 3):s129-36. 20. marsman jw. the aberrantly fed varicocele: frequency, veno147archivio italiano di urologia e andrologia 2013; 85, 3 varicocele treatment: a 2-centers comparison between non microsurgical open correction, laparoscopic approach and retrograde percutaneous sclerotization archivio italiano di urologia e andrologia 2013; 85, 3 g. ollandini, g. liguori, s. ziaran, t. málek, g. mazzon, b. de concilio, s. bucci, s. benvenuto, e. belgrano, c. trombetta 148 graphic appearance, and results of transcatheter embolization. ajr am j roentgenol. 1995; 164:649-57. 21. gat y, zukerman z, chakraborty j, gornish m. varicocele, hypoxia and male infertility. fluid mechanics analysis of the impaired testicular venous drainage system. hum reprod. 2005; 20:2614-9. 22. smith r, kaune h, parodi d, et al. increased sperm dna damage in patients with varicocele: relationship with seminal oxidative stress. hum reprod. 2006; 21:986-93 23. cuda sp, musser je, belnap cm, thibault gp. incidence and clinical significance of arterial injury in varicocele repair. bju int. 2011; 107:1635-7. 24. yamamoto m, tsuji y, ohmura m, et al. comparison of arteryligating and artery-preserving varicocelectomy: effect on post-operative spermatogenesis. andrologia 1995; 27:37-40. 25. ishikawa t, fujisawa m. effect of age and grade on surgery for patients with varicocele. urology 2005; 65:768-72. 26. centola gm, eberly s. seasonal variations and age-related changes in human sperm count, motility, motion parameters, morphology, and white blood cell concentration. fertil steril. 1999; 72:803-8. 27. sobreiro bp, lucon am, pasqualotto ff, et al. semen analysis in fertile patients undergoing vasectomy: reference values and variations according to age, length of sexual abstinence, seasonality, smoking habits and caffeine intake. sao paulo med j. 2005; 123:161-6. correspondence giangiacomo ollandini, md (corresponding author) g.ollandini@gmail.com viale gabriele d’annunzio 63, 34138 trieste (italy) giovanni liguori, md giorgio mazzon, md bernardino de concilio, md stefano bucci, md sara benvenuto, md emanuele belgrano, md carlo trombetta, md urologic unit, cattinara hospital, university of trieste via di fiume 447 34149 trieste, italy stanislav ziaran, md tomá! málek, md urology clinic, university hospital in bratislava, comenius university, bratislava, slovakia archivio italiano di urologia e andrologia 2013; 85, 18 introduction varicocele is one of the major causes of infertility in men, present in between 15-20% of the general male population (1, 2). it’s predominant in adolescents but found in 41% infertile men and 80% of those with secondary infertility (2). this anatomical abnormality due to the dilation of the venous plexus which covers the testicles (pampiniform plexus) is probably one of the most common causes of oligoasthenozoospermia (1, 3). the pathogenetic mechanism through which varicocele causes testicular dysfunction and subsequent alterations in spermatogenesis, is, however, not completely understood. although various factors may be involved (venous stasis which leads to testicular hypoxia) the increasing of internal testicular temoriginal paper the study of spermatic dna fragmentation and sperm motility in infertile subjects giuseppina peluso 1, alessandro palmieri 2, pietro paolo cozza 1, giancarlo morrone 1, paolo verze 2, nicola longo 2, vincenzo mirone 2 1 u.o.s. of andrology and physiophatology of reproduction-a.o. of cosenza, italy; 2 urological clinic, university federico ii of naples, italy. introduction: although the pathophysiology of the testicular damage associated with varicocele remains unclear, sperm dna damage has been identified as a potential explanation for this cause of male infertility. the current study was designed to determine the extent of sperm nuclear dna damage in patients with varicocele, and to examine its relationship with parameters of seminal motility. materials and method: semen samples from 60 patients with clinical varicocele and 90 infertile men without varicocele were examined. varicocele sperm samples were classified as normal or pathological according to the 1999 world health organizzation guidelines. sperm dna damage was evalutated using the halosperm kit, an improved sperm chromatin dispersion (scd) test. results: the dna fragmentation index (dfi: percentage of sperm with denatured nuclei) values was significantly higher in patients with varicocele, either with normal or abnormal (dfi 25.8 ± 3.2 vs 17.4 ± 2.8 p < 0,01) semen profiles. in addition, an inverse correlation was found between spermatic motility and the degree of spermatic dna fragmentation in patients with clinical varicocele. conclusions: varicocele is associated with high levels of dna-damage in spermatozoa. in addition, in subjects with varicocele, abnormal spermatozoa motility is associated with higher levels of sperm dna fragmentation. dna fragmentation may therefore be an essential additional diagnostic test that should be recommended for patients with clinical varicocele. key words: spermatic dna fragmentation; oxidative stress; varicocele; male infertility. submitted 18 march 2013; accepted 30 march 2013 no conflict of interest declared summary perature is probably the most likely link between varicocele and infertility. in fact, elevated scrotal temperature caused by vascular defects can cause altered production of spermatogenetic cells by germinal epithelium (1, 3). in fact, induced varicocele in laboratory animals leads to elevated intratesticular temperature and sperm dysfunction with decreased sperm motility (1, 3). another link between varicocele and infertility may arise from impairment of the hypothalamic-gonadal axis or oxidative stress (os) (4, 5). in fact, studies evaluating the role of oxidative stress in male infertility have recently shown that os could be considered as an important cause of sperm dysfunction in varicocele infertile men (6-8), peluso_stesura seveso 18/04/13 10:57 pagina 8 9archivio italiano di urologia e andrologia 2013; 85, 1 the study of spermatic dna fragmentation and sperm motility in infertile subjects and attending to andrology service for infertility diagnosis and other andrological problems. once consensus had been granted to be involved in this study, patients were given a thorough andrological analysis according to the guidelines provided by who 2001 which included complete anamnesis, scrotal scan, scrotal doppler ultrasound, hormonal profile based on serum/blood levels basal gonadotrophines (fsh, lh and total blood testo sterone), urethral sample for common microbes, two spermiograms at a week’s interval with a minimum of three days since sexual activity. considering the results of these analysis, it was possible to identify 80 patients with varying degrees of clinical varicocele but predominantly unilateral. all patients with urinary tract infections, leucocytospermia, hypogonadism (testicular volume < 15 ml), a history of excess of cigarette, alcohol or drug use were excluded from the study. the control group consisted of 100 healthy males with normal genitalia and normal seminal parameters, as defined by the who 2001 guidelines. for each patient included in the study, the spermatozoon population was determined. in addition, sperm dna fragmentation was quantified using the sperm chromatin dispersion (scd) test (halosperm kit-indas labora tories, madrid spain) which allows to express the spermatic dna fragmentation as a percentage index (dfi: dna fragmentation index). on the basis of the usual seminologic criteria, 34 patients with varicocele showed isolated asthenospermia, whereas spermatic concentration and morphology have normal values. patients with severe dispermia in conjunction with abnormal standard semen parameters such as oligoasthenotheratozoospermia (oat) where 3%: in such case high levels of damaged sperm dna are usually observed, consequently they were excluded from this study. patients considered in this phase of the study were therefore characterized by asthenozoospermia with various degrees of motility, ranging from 5-45% of the progressive linear a+b motility, according to the cut-off of normal sperm motility established by who, where a+b is greater than or equal to 50% values. the degree of dna damage in spermatozoa of these patients with only altered motility parameter was then correlated with the a+b motility seminal parameter. analysis of sperm dna fragmentation spermatozoon dna fragmentation was quantified using halosperm (diasint-cga, florence-italy) which has been used in the well-developed sperm chromatin dispersion (scd) test (16, 17). the basis of the technology lies in the differential response offered by the nuclei of spermatozoa with fragmented dna compared to those with their dna intact. the controlled denaturation of the dna followed by the extraction of the nuclear proteins, gives rise to partially deproteinized nucleoids in which the dna loops expand, forming halos of chromatin dispersion. the nucleoid, which corresponds to the massively deproteinized nucleus of the spermatozoon, is composed of two parts: spermatozoon nucleus silhouette, called the “core”, positioned centrally, and a peripheral halo of chrowith negative impact on sperm plasma membranes which contain higher amounts of polyunsaturated fatty acids (pufa) which easily experience lipid peroxidation by ros (9, 10). it is a result of cascade of events including lipid peroxidation (lpo) of sperm plasma membrane that ultimately affect an axonemal protein phosphorylation and sperm immobilization (9-11). these spermatozoa would therefore not only be particularly susceptible to reactive oxygen species (ros) (12), with compromised membrane fluidity and integrity and greatly reduced motility (11-13). metanalysis studies support this hypothesis, demonstrating that infertile patients with varicocele have higher levels of ros when compared to other typologies of infertility and controls (14, 15). in addition, the seminal plasma of varicocele patients exhibited reduced total antioxidant capacity (tac) (7, 15-18). recently, various studies have also demonstrated that an elevated presence of dna fragmentation is present in the spermatozoon nuclei of infertile patients with clinical varicocele (19, 18). interestingly, dna damage are higher when compared to spermatozoon of patients suffering from other types of infertility; moreover the spermatozoon of infertile varicocele patients exhibit higher levels of ros, suggesting correlation between oxidative damage and dna fragmentation. studies using rat models have confirmed this, demonstrating that nitric oxide (no) released by endothelial cells of dilated spermatic veins and peroxynitrites generated from reaction with superoxide radicals cause intracellular oxidative damage (20-22), particularly regarding membrane lipid peroxidation, thus altering the integrity of chromatin in spermatozoon nuclei which may be a direct expression of such oxidative damage (17). in addition, sperms of varicocele patients exhibit elevated levels of 8-hydroxy-2 deoxyguanosine which are associated with a deficiency in the pro-oxidant defense system which would cause oxidative damage to the dna by modifying the base, dna strand breaks and chromatin cross linking, since spermatozoa have limited defense mechanisms against oxidative attack on their dna mainly due to its exclusive structural composition for the complex packaging arrangement of dna (18, 23, 24). other indications of increased ros in patients with varicocele are elevated quantities of cytoplasmic droplets in the young spermatozoa. the droplets are indicative of immature and functionally defective spermatozoon (25-27) and, containing high concentrations of cytoplasmic enzymes such as g6pdh and sod, are additional sources of ros (21, 26). together, these studies indicate a positive correlation between spermatozoon immaturity, elevated levels of ros and increase of concentration of mature spermatozoa with damaged dna in ejaculates of these patients (21, 25-27). therefore, in this study, dna fragmentation in spermatozoa of infertile individuals diagnosed with clinical varicocele was quantified with respect to infertile men and controls. in addition, the amount of dna fragmentation was correlated to sperm motility. materials and methods one hundred and fifty subjects analyzed in this study ranged in age between 20-50 with the median age of 35 peluso_stesura seveso 18/04/13 10:57 pagina 9 archivio italiano di urologia e andrologia 2013; 85, 1 g. peluso, a. palmieri, p.p. cozza, g. morrone, p. verze, n. longo, v. mirone 10 sperm cells with very small halos, without halos, and without halo-degraded contain fragmented dna. nucleoids that do not correspond to sperm cells were separately scored. statistical analysis all data were calculated as average + standard deviation on experiments which were repeated and analyzed statistically using the statistical program spss. the statistical tests used were student’s t for continuous values and c2 for parametric values. in addition, statistical correlation was used to test non-linear regression with evaluation of the correlation coefficient. results the concentration of nemasperms in varicocele patients included in the study, was significantly lower than that of controls (19.8 + 6.5 e 39.7 + 7.1 respectively: p < 0.01. motility (type a+b) considered was also significantly lower than that of controls (30.4 + 9.7 and 49.9 + 8.5 respectively: p < 0.01). in addition, the frequency of dna damage in nemasperms of infertile patients with varicocele (% dfi) was statistically higher comparised with infertile patients without varicocele (25.8 + 3.2 and 17.4 + 2.8 respectively: p < 0.01: figure 1). besides the dfi of patients with varicocele was higher compared to values in patients with varicocele and infertile patients for other causes. as a whole the values measured is reported in figure 1. subsequently the values were grouped together, for everyone of the two categories of patients, referred to threshold values, established equal to 15, 20, 25, 30, 35, and 45. these values referred to conditions in a range from normality to extreme pathological condition. therefore the average values of groups under each threshold value were calculated, and the comparison is showed in the figure 2. the average of these groups were evaluated for differences matin/dna dispersion. likewise, when dna fragmentation is present, the nucleoid do not exhibit a dispersion hallow or, if present, is negligible. the tail of the spermatozoon is visible and serves as an important morphological parameter to distinguish the nuclei of nemaspermic cells from others. an aliquot of each sperm sample was diluted in phosphate buffer solution (pbs) to a concentration of 5 million/ml; 25 μl of each sample was mixed and resuspended in fused agarose microgel, as provided by the kit. 20 μl of semen-agarose mix was pipetted onto an agarose precoated slide, provided in the kit, and covered with a 22-x 22-mm coverslip. the slide was placed on a cold plate in the refrigerator (4°c) for 5 minutes to allow the agarose to produce a microgel with the sperm cells trapped. the coverslip was gently removed and the slide immediately immersed horizontally in a denatured solution, previously prepared by mixing 80 μl of hcl from an eppendorf tube in the kit, with 10 ml of distilled water, and incubated for 7 minutes at room temperature before transfer to 10 ml of lysing solution and left to incubate for 25 minutes. after washing 5 minutes in a tray with abundant distilled water, the slides were dehydrated in increasing ethanol bath (70%-90%-100%) for 2 minutes each and air dried at room temperature. for the latter, the slides were horizontally covered with a mix of wright’s solution (merck, darmstadt, germany) and phosphate buffer solution (merck) (1:1) for 5 to 10 minutes, with continuous airflow. then the slides were briefly washed in tap water and allowed to dry. strong staining is preferred to easily visualize the periphery of the dispersed dna loop halos. a minimum of 500 spermatozoa for sample were scored under the 100x objective of the microscope. scoring criteria the categorization of the different halo sizes is performed using the minor diameter of the core from the own nucleoid as a reference to which the halo width is compared. five scd patterns were established (28): a) sperm cells with large halos: those whose halo width is similar or higher than the smallest diameter of the core. b) sperm cells with mediumsize halos: the halo size is between those with high and with very small halo. c) sperm cells with very small-size halo: the halo width is similar or smaller than one third of the minor diameter of the core. d) sperm cells without a halo. e) sperm cells without a halo-degraded: similar to point d), but weakly or irregularly stained. figure 1. comparison of dna fragmentation index (dfi) experimentally evaluated for infertile men affected from varicocele (dots) or other causes (linees). peluso_stesura seveso 18/04/13 10:57 pagina 10 11archivio italiano di urologia e andrologia 2013; 85, 1 the study of spermatic dna fragmentation and sperm motility in infertile subjects such as varicocele-dfi infertile-dfi. such differences were correlated to the dfi values of the two categories and revealed that such differences were always positive and higher for patients with varicocele (fi gure 3). therefore, the most significant data of our study came from the analysis of correlation between the dfi values calculated and progressive a+b motility values expressed in % and calculated in patients with varicocele associated with the condition of isolated asthenozoospermia. statistical analysis of the data found a semi-empirical correlation of 0.9982 between the index of percentage fragmentation (dfi) and percentage sperm motility according to the: eq.1: dfi = 49,48*exp (0,022*motility), as seen in figure 4. discussion while varicocele is one of the most common adrological pathologies in the general population, it is particularly common in infertile men (2). that varicocele negatively influences spermatic function is well documented (29, 30), although the exact underlying mechanisms are still not understood. in fact, infertility may be associated to a variety of spermatogenetic conditions ranging from normozoospermia to moderate oligoasthenoteratozoospermia (oat), to azoospermia (4, 5). recently, several authors have suggested that human patients with varicocele have a significantly higher dna fragmentation index (27). studies show that varicocele samples contain a higher proportion of spermatozoa with abnormal dna and immature chromatin than those from fertile men as well as infertile men without varicocele (31). a cause of this phenomena may be the increased production of ros in varicocele patients which is significantly higher in patients diagnosed with 2° and 3° degree varicocele in whom altered sperm motility is common in these patients (8, 32). an enhancement in os, both due to an increase in ros production and a decrease in the antioxidant capacity, has been reported in men with varicocele (16, 17, 33, 34). no and peroxynitrite, a potent oxidant ros, have been demonstrated to be produced in high concentrations in the dilated spermatic veins, so they could be main contributors to the high os level in varicocele (20, 22, 35). in addition no can improve sperm dna fragmentation that is associated with infertility in men with varicocele (36). besides the dilated veins, ros may be released in the seminiferous tubules by the cytoplasmic droplets retained in immature spermatozoa, which seem to be frequent in the sperm samples from infertile men with figure 2. comparison of dna fragmentation index (dfi) experimental evaluated from different groups of infertile men. for each group, the threshold value has been selected on the basis of different relevance of the pathology. figure 3. detailed comparison of the relevance of the varicocele on the dna fragmentation index (dfi) for infertile men. it’s evident that dfi% is higher for varicocele infertile men. peluso_stesura seveso 18/04/13 10:57 pagina 11 archivio italiano di urologia e andrologia 2013; 85, 1 g. peluso, a. palmieri, p.p. cozza, g. morrone, p. verze, n. longo, v. mirone 12 varicocele (37). immaturity is a consequence of defective spermiogenesis that could also lead to differences in disulfide crosslinking and in susceptibility toward dna fragmentation (38, 39). because all the varicocele samples in this study showed abnormal standard semen parameters, we compared them with those from idiopathic infertility, either normozoospermic patients and from patients with abnormal semen parameters, all attending the infertility clinic. significant differences were found between the 3 groups in the frequency of sperm cells with fragmented dna using the halosperm kit, particulary between the varicocele group and the infertile group, except those samples with more intense and combined abnormalities that could have more frequency of sperm cells with fragmented dna. results of our study, on the higher frequency of dna fragmentation presented in the sperm cells of infertile patients with varicocele compared to patients suffering from other typologies of infertility and the fertile controls, supporting the hypothesis which has been proposed by other authors. besides, a higher proportion was evidenced in our varicocele samples in relation to the fertile controls. in addition, we also found a high inverse correlation between low sperm motility and index of dna fragmentation in sperms of varicocele patients and patients manifesting isolated asthenozoospermia. these findings suggest that a common pathological mechanisms underlies this pathological condition. this mechanism may be the presence of ros or other types of agents which compromise the energetic metabolism of gametes (32, 40). these can react negatively upon sperm membranes, probably by disrupting the equilibrium between antioxidants and prooxidant. in addition, these can also act upon genomic integrity and chromatin structure of the spermatozoon, damaging sperm cell dna (36, 41). the fact that sperms of subjects with varicocele exhibit higher levels of dna damage with respect to sperms from other typologies of infertility, even when normal seminal parameters are attained, clearly demonstrate the importance of studying sperm dna fragmentation (29). this evaluation can be included as a routine test in the clinical management of patients with varicocele, followed by suggestions regarding the potential negative effects that the elevated presence of damaged dna may have on eventual future fertility (30). future research is needed to better understand the exact mechanism by which dna is damaged in the spermatozoon of varicocele patients so that treatment to repair 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14:2801-7. 17. barbieri er, hidalgo me, venegas a, et al. varicocele-associated decrease in antioxidant defenses. j androl. 1999; 20:713-7. 18. sakkas d, alvarez jg. sperm dna fragmentation: mechanisms of origin, impact on reproductive outcome, and analysis. fertil steril. 2010; 93:1027-36. 19. saleh ra, agarwal a, nelson dr, et al. increased sperm nuclear dna damage in normozoospermic infertile men: a prospective study. fertil steril. 2002; 78:313-8. 20. mitropoulos d, deliconstantinos g, zervas a, et al. nitric oxide synthase and xanthine oxidase activities in the spermatic vein of patients with varicocele: a potential role for nitric oxide and peroxynitrite in sperm dysfunction. j urol. 1996; 156:1952-1958. 21. molina j, castilla ja, castano jl, et al. chromatin status in human ejaculated spermatozoa from infertile patients and relationship to seminal parameters. hum reprod. 2001; 16:534-539. 22. romeo c, ientile r, impellizzeri p, et al. preliminary report on nitric oxide-mediated oxidative damage in adolescent varicocele. hum reprod. 2003; 18:26-9. 23. duru nk, morshedi m, oehninger s. effects of hydrogen peroxide on dna and plasma membrane integrity of human spermatozoa. fertil steril. 2000; 74:1200-7. 24. turner tt. the study of varicocele through the use of animal models. hum reprod update. 2001; 7:78-84. 25. evenson dp, jost lk, marshall d, et al. utility of the sperm chromatin structure assay as a diagnostic and prognostic tool in the human fertility clinic. hum reprod 1999; 14:1039-1049. 26. evenson dp, larson kl, jost lk. sperm chromatin structure assay: its clinical use for detecting sperm dna fragmentation in male infertility and comparisons with other techniques. j androl. 2002; 23:25-43. 27. irvine ds, twiggs jp, gordon el, et al. dna integrity in human spermatozoa: relationships with semen quality. j androl 2000; 21:33-44. 28. fernàndez jl, lourdes m, goyanes vj, et al. simple determination of sperm dna fragmentation with an improved sperm chromatin dispersion (scd) test. fertil steril. 2005; 84:833-842. 29. world health organization. the influence of varicocele on parameters of infertility in a large group of men presenting to infertility clinic. fertil steril. 1992; 57:1289-93. 30. villanueva-diaz ca, vega-hernandez ea, diaz-perez ma, et al. sperm dysfunction in subfertile patients with varicocele and marginal semen analysis. andrologia 1999; 31:263-7. 31. gonzález-marín c, gosálvez j, roy r. types, causes, detection and repair of dna fragmentation in animal and human sperm cells. int j mol sci. 2012; 13:14026-52. 32. armstrong js, rajasekaran m, chamulitrat w, et al. characterization of reactive oxygen species induced effects on human spermatozoa movement and energy metabolism. free rad biol med. 1999; 26:869-80. 33. naughton ck, nangia ak, agarwal a. varicocele and male infertility. hum reprod update. 2001; 7:473-81. 34. kamal k, phang d, willis j, jarvi k. biologic variability of sperm dann denaturation in infertile men. urology. 2001; 58:258-61. 35. turkyilmaz z, gulen s, sonmez k, et al. increased nitric oxide is accompanied by lipid oxidation in adolescent varicocele. int j androl. 2004; 27:183-187. 36. abbasi m, alizadeh r, abolhassani f, et al. effect of aminoguanidine in sperm dna fragmentation in varicocelized rats: role of nitric oxide. reprod sci. 2011; 18:545-50. 37. sakkas d, alvarez jg. sperm dna fragmentation: mechanisms of origin, impact on reproductive outcome, and analysis. fertil steril. 2010; 93:1027-36. 38. world health organization. who laboratory manual for the examination of human semen and semen-cervical mucus interaction. cambridge, united kingdom: cambridge university press; 1999. 39. zini a, defreitas g, freeman m, et al. varicocele is associated with abnormal retention of cytoplasmic droplets by human spermatozoa. fertil steril. 2000; 74:461-464. 40. aitken rj, krausz c. oxidative stress, dann damage and the y chromosome. reproduction 2001; 122:497-506. 41. hauser r, paz g, botchan a, et al. varicocele and male infertility: part ii. varicocele: effect on sperm function. hum reprod update 2001; 7:482-5. correspondence giuseppina peluso, md (corresponding author) via g. verdi 82/d 87036 rende (cs), italy pina.peluso@libero.it pietro paolo cozza, md giancarlo morrone, md u.o.s. of andrology and physiophatology of reproduction a.o. of cosenza, italy alessandro palmieri, md paolo verze, md nicola longo, md vincenzo mirone, md urological clinic, university federico ii of naples, italy peluso_stesura seveso 18/04/13 10:57 pagina 13 stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper introduction urinary system stone disease, which is an endemic health issue, at least in some regions of the world, can irreparably harm the kidneys if not treated promptly and appropriately. the most significant feature of this disease is its recurrent nature, which is caused by insufficient metabolic evaluation and a lack of appropriate medical care, especially in individuals in high-risk groups (1, 2). while endourologists have made significant advancements in the minimally invasive therapy of calculi, there has been little progress made in the pharmacological management of urolithiasis. allopurinol, potassium citrate, thiazide diuretics, and other medications have been utilized in medical therapy, with different degrees of claimed efficacy (3). the medical method has some efficacy in preventing recurrences, but there are other significant drawbacks, including some drug-related adverse effects and low patient compliance rates observed during extended therapy follow-up. additionally, existing medical therapy techniques may fail due to the agents' insufficient impact on all fundamental relevant pathologic mechanisms at the kidney level given the very complicated etiology of urinary stone formation, which depends on multiple pathologic phases and/or mechanisms. in other words, the fundamental constraint of medical treatment is the impact through only one established pathogenetic process (after the formation of stones). regarding this, despite the fact that certain models concentrate on the creation of novel medications that may have powerful effects on the various stages of stone formation (nucleation, supersaturation, and crystal growth) (47), such models constitute only a rough imitation of the events taking place in the organism (8). introduction: to analyze the dose-dependent preventive effect of a plant-based herbal product on the new crystal formation in a rat model. materials and methods: a total of 42 rats were divided into 7 groups and zinc discs were placed into the bladder of rats to provide a nidus for the development of new crystal formation: group 1: control, group 2: 0.75 percent ethylene glycol (eg); group 3: 0.75 percent eg plus 0.051 ml of the compound; group 4: 0.75 percent eg plus 0.179 ml of the compound; group 5: 0.75 percent eg plus 0.217 ml of the compound; group 6: 0.75 percent eg plus 0.255 ml of the compound; group 7 0.75 percent eg plus 0.332 of the compound). the analysis and comparison focused on the disc weights, changes in urinary oxalate and calcium levels, urinary ph, and the histopathologic evaluation of the inflammatory changes in the bladder after 14 days. results: according to the evaluation of discs placed in the bladders of the animals, animals receiving the herbal compound on a dose-dependent basis showed a limited increase in the disc weights values after 14 days, despite a considerable increase in animals receiving eg alone (p = 0.001). further evaluation of the increase in disc weights on a dose-dependent basis in different subgroups (from groups 3 to 7) demonstrated that the limitation of crystal deposition began to be more prominent as the dose of herbal compound increased. this effect was more evident particularly in comparisons between group 7 and others, according to lsd multiple comparison tests (p = 0.001). as anticipated, there has been no discernible change in the weight of the discs in the control group. although urinary calcium levels in animals of groups 2, 6, and 7 were significantly higher than the other groups, we were not able to demonstrate a close correlation between urinary oxalate levels and the increasing dose levels. even though mean urine ph levels were statistically considerably higher in group 3, there was no statistically significant correlation between the oxalate and calcium levels between all groups, and no association was seen with the administration of herbal agents. the transitional epithelium between the three groups of animals' bladder samples did not exhibit any appreciable difference according to pathological analysis. dose-dependant preventive effect of a herbal compound on crystal formation in rat model rasim güzel 1, i̇smet bilger erïhan 2, i̇sa özaydin 3, uğur aydin 3, murat bağcioğlu 4, ramazan kocaaslan 5, ümit yildirim 2, kemal sarica 6 1 kavacık medistate hospital, istanbul, turkey; 2 kafkas university, medical school, departments of urology, kars, turkey; 3 kafkas university, veterinary faculty, department of surgery, kars, turkey; 4 bahçeşehir university, medical school, departments of urology, istanbul, turkey; 5 konya training and research hospital, konya, turkey; 6 biruni university, medical school, department of urology, istanbul, turkey. doi: 10.4081/aiua.2023.11114 summary conclusions: in this animal model, the treatment of the compound was successful in lowering the amount of crystal deposition surrounding the zinc discs, most noticeably at a dosage of 0.332 ml, three times per day. key words: herbal compound; rat model; crystal formation. submitted 24 december 2022; accepted 29 january 2023 11114 guzel_stesura seveso 23/03/23 12:24 pagina 1 archivio italiano di urologia e andrologia 2023; 95, 1 r. güzel, i̇. bilger erïhan, i̇. özaydin, et al. some herbal medications have been effectively used and assessed in terms of their shortor long-term efficacy as well as adverse effects to address the aforementioned challenges in the medical treatment and/or prevention of stone disease (6, 8-15). we used a herbal substance in this work that has been shown to have anti-apoptotic, anti-inflammatory, diuretic, nephroprotective, antioxidant, antibacterial, and spasmolytic activities. in some experimental tests, this substance has been proven to be effective at reducing the formation of stones (16). although calcium and oxalate may play a part in stone formation together, the most important risk factor for calcium oxalate stone disease has been revealed to be the presence of "hyperoxaluria". this condition affects 6070% of people (17, 18). the most widely utilized agent to cause hyperoxaluria in animal models is ethylene glycol (eg), which has also been discovered to be the best agent for evaluating and analyzing an agent's efficacy when employed in such models (19). the formation of nidus for further crystal deposition and stone formation in animal models has been described using a variety of models, including the use of plastic discs, the insertion of suture material parts, the implantation of calcium and oxalate crystals, and the implantation of zinc discs into the bladders of the animals (17). zinc disc implantation inside the bladder of hyperoxaluria-induced rats has been a widely used technique so far among these models. while the majority of animals' final stone composition measured on the zinc disc was calcium oxalate, as shown in several of these investigations, magnesium-ammonium-phosphate crystals (stones) were also shown in some other, more limited, experiments (17-19). in the current work, we sought to assess the potential benefits of the herbal ingredient on the prevention of new urinary stone formation by restricting new crystal deposition on the "zinc discs" in a rat model. materials and methods herbal agent we employed a plant-based herbal supplement composed by a stable mix that included rosmarinic acid, boldin, polysaccharides, the flavonoid quercetin, flavonglicozides, and essential fatty acids. its nephroprotective, diuretic, anti-inflammatory, antioxidant, antimicrobial, and spasmolytic activities have been employed as the basis for resolutivo regium. in 250 ml bottles, the medication is offered in hydrolate form. the dose for adults is 7 ml administered three times per day. the herb sideritis angustifolia, the leaves of melissa officinalis, the flowers of opuntia ficus indica, the leaves of peumus boldus, the rhizomes of cynodon dactylon, and the entire plant of spergularia rubra are all included in the drug's composition. it also contains dried parts of the stem of enguisetum arvensis and an aqueous distillate of those parts, as well as flowers. study design the study protocol was accepted by the ethical committee of kafkas university training and research hospital (june 28, 2022, approval number: kau-haydek2022-120). 42 male sprague dawley rats weighing between 300 and 350 grams were involved and divided into 7 groups. the lighting setup was set up to resemble the natural cycle of day and night. all rats in all groups received the appropriate cages, access to food and water without restriction, and normal (physiological) room temperature. small zinc discs were surgically inserted into the rats' bladders while they were under anesthesia in the first phase of the trial. applications of ethylene glycol and herbal compounds were started daily on the second postoperative day. in an effort to determine the minimal dose necessary for the substance to effectively prevent the growth of stones, the drug has been administered in a dose-dependent manner. regarding the treatment regimen in these subgroups, rats in group 2 received water that had 0.75 percent eg added to it. for each rat in group 3, 0.75 percent eg plus 0.051 ml of the compound was administered three times per day. each rat in group 4, received 0.75 percent eg plus 0.179 ml compound three times per day. each rat in group 5 received 0.75 percent eg plus 0.217 ml compound three times per day. for each rat in group 6, 0.75 percent eg plus 0.255 ml compound was given three times daily. finally, 0.75 percent eg plus 0.332 compound ml was given in group 7. treatment was continued for two weeks. group 1 was the control group, which had the zinc disc, but no eg and no herbal compound. rats were sacrificed at the conclusion of the study, after 14 days of treatment with the aforementioned protocols, and urine samples from the harvested bladders were collected for the evaluation of urine ph as well as the urinary levels of calcium and oxalate. harvested bladders were sent for histopathological analysis after the zinc discs were removed. results of the urine test, histopathological findings, and zinc disc weight values were compared between each group. operative technique ketamine hcl (ketalar, eczacibasi inc., istanbul, turkey) and 10 mg/kg xylazine (rompun, bayer turk inc., istanbul, turkey) were administered intramuscularly to induce anesthesia after a 6-hour fast. we assessed the impairment of the reflex arc reaction to compressing the claws in order to determine the efficacy of anesthesia. the skin was then cleaned with the appropriate antiseptic solutions after the incision site had been shaved with a blunt razor blade (poviodine, istanbul-based dioagnokim inc.) sharp dissection was used to split the abdominal wall muscles after a 2 cm incision in the lower quadrants of the abdomen. after the urinary bladders were separated and exposed, a small incision was made to open the bladder lumen. preparation zinc discs weighing 70 ± 2 mg were then placed inside the bladder lumen, and the existing incisions were sealed with 4/0 absorbable polyglactin (vicryl, ethicon inc., somerville, nj, usa). after the bladder was returned to its original position, the skin and abdominal muscles were stitched together with 2/0 silk and 3/0 absorbable polyglactin (vicryl, ethicaon inc., somerville, nj, usa). the rats were left for recovery after the closed incisions had been cleaned. after 14 days, the rats in each group had their bladders opened using the same surgical procedure as above, and urine samples were taken for 11114 guzel_stesura seveso 23/03/23 12:24 pagina 2 archivio italiano di urologia e andrologia 2023; 95, 1 herbal compound on crystal formation in rat model both microbiological and biochemical analysis. the crystal-covered and coated zinc discs were removed for weighting and stone analysis. the rats' bladder walls were removed and sent to pathology. the urine samples were stored and transported at 4°c while the harvested bladders were fixed in 4% neutral formaldehyde, embedded in paraffin blocks, and cut into 4-6 μm sections, and stained with hematoxylin and eosin. after that, the rats were sacrificed. histopathological evaluation prior to paraffin embedding, 10% formalin was used for the fixation of the bladder tissues. after the procedure, blocks were cut 5-6 μm slices and stained with hematoxylin-eosin. a pathologist expert with animal models analyzed the slices. all samples were examined under the light-microscopy and vascular congestion, level of edema (none, mild, moderate, and severe), level of inflammation, the thickness of the epithelium (in millimeters), changes in the epithelium (dysplasia, calcification, fibrosis, mitosis), and epithelial cell layers were recorded. laboratory analysis urine calcium levels were assessed using the photometric o-cresolphthalein complex method (cobas c501 analyzerroche diagnostics, germany). urine oxalate levels were measured using a rat elisa kit (sunred, china; catalogue no: 201-11-5547). urine ph was assessed using strips for urinalysis (dirui, china; catalogue no: 231011501001). statistical analysis the normality of the distribution of continuous variables was tested by the shapiro-wilk test. one-way anova and lsd multiple comparison tests were applied to investigate the difference between groups in terms of numerical variables and kruskal wallis tests were used to compare non-normal data across groups. statistical analysis was performed with spss for windows version 24.0 and a p-value < 0.05 was accepted as statistically significant. results evaluation of our data obtained in seven groups of animals revealed the following findings: effects of the medication on crystal deposition evaluation of the weights of the zinc disks placed in the bladders of animals receiving eg in addition to normal diet and water in group 2 revealed a significant increase at the end of 14 days when compared with the baseline (group 1) values. (p = 0.001, lsd multiple comparisons) (table 1). on the contrary, however, very little increase in the weight of the disks in the control group (group 1) animals has been noted as expected with mean values of 97.83 ± 2.93 during this evaluation, compared to 70 mg. of the free zinc disc weight (table 1). evaluation of the weight of the disks in animals receiving herbal compounds during the study period (in addition to eg administration) demonstrated a reduced (not significant) increase in these values after a 14-day follow-up (p = 0.001, table 1). evaluation of the increase in disc weights on a dose-dependent basis in different subgroups (from groups 3 to 7) demonstrated that the limitation of crystal deposition began to be more prominent as the dose of herbal compound increased. this effect was more evident particularly in comparisons between group 7 and others, according to lsd multiple comparison tests (p = 0.001) (table 1). effects of herbal compound application on urine parameters the mean urinary oxalate levels within groups 2, 3 to 7 were similar (p = 0.018, table 1) with no statistically significant difference between the groups from 2 to 7. only in group 1, the oxalate levels were lower than in the others. the difference was particularly prominent between groups 1 and 2 (p = 0.001). urinary calcium levels in animals of groups 2, 6, and 7 were significantly higher than the other groups as shown in table 1. we were not able to demonstrate a close correlation between urinary oxalate levels and the increasing dose levels. comparative evaluation of the mean urinary ph levels (table 1) showed that although it was significantly higher in group 3 animals (p = 0.026) during the 14-day evaluation, this finding has been accepted to be an isolated finding with no attributed correlation with herbal agent administration. crystals accumulated on the zinc disks were analyzed at the end of the trial and data revealed them to be composed of calcium oxalate in 17 and magnesium ammonium phosphate in 25 rats. effects of the compound on bladder inflammation following the two weeks of the trial period, the bladders were harvested and evaluated with respect to the possible histopathologic alterations. despite a mild degree increase in vascular congestion and edema formation in the animals of groups 4, 5, and 7, pathological evaluation findings revealed no significant difference regarding the presence as well as the extent of edema formation, vascular table 1. evaluation of laboratory findings. parameters oxalate (ng/l) ph calcium (mg/dl) zinc disc weights (mg) groups mean ± sd mean ± sd mean ± sd mean ± sd 1 (n = 6) control group ** 1111.63 ± 223.41 8.47 ± 0.1 2.57 ± 0.26 97.83 ± 2.93 2 (n = 6) 1533.73 ± 137.15 8.33 ± 0.2 4.17 ± 0.4 161.17 ± 11.86 3 (n = 6) 1401.22 ± 197.88 8.65 ± 0.19 2.72 ± 0.29 124.83 ± 10.3 4 (n = 6) 1293.33 ± 81.96 8.5 ± 0.33 3.08 ± 0.21 107 ± 1.9 5 (n = 6) 1381.73 ± 261.7 8.17 ± 0.49 1.68 ± 0.21 101 ± 2 6 (n = 6) 1348.02 ± 104.73 8.22 ± 0.17 4.88 ± 0.53 101 ± 4.6 7 (n = 6) 1419.82 ± 208.79 8.1 ± 0.37 4.23 ± 0.42 79.17 ± 2.4 p value 0.018 * 0.026 * 0.001 * 0.001 * * p: significant at 0.05 level. ** group 1 (control) is the one that had the zinc disc, but no eg (ethylene glycole) and no herbal compound. 11114 guzel_stesura seveso 23/03/23 12:24 pagina 3 archivio italiano di urologia e andrologia 2023; 95, 1 r. güzel, i̇. bilger erïhan, i̇. özaydin, et al. congestion, and inflammatory cell infiltration between the groups. additionally, no significant alteration was found to note with respect to the pathological changes in transitional epithelium like calcification, mitosis, fibrosis, dysplasia, or a number of epithelial cell layers. discussion prevention of new stone formation particularly in the risk group cases is the most important aim of the medical management for urolithiasis. despite minimally invasive treatment of urinary calculi with endoscopic/ureteroscopic treatment alternatives has gained more importance with their safe and practical characteristics, highly limited advancements have been achieved in the prevention of urinary stones, regarding the agents used with this aim, currently, potassium citrate, allopurinol, thiazide diuretics, and tiopronin are the most commonly applied ones depending on urinary ph and the chemical composition of the stone(s) treated. however, in addition to the ongoing controversies regarding the efficiency and optimal treatment duration of agents, certain side effects resulting in the discontinuation of the drug administration constituted another important limitation in decreasing the patient compliance rates, particularly during long-term follow-up. based on these facts, physicians began to consider phytotherapeutic agents, in other words, herbal compounds as a valuable option for the effective medical management of urinary stones. regarding the underlying pathogenetic mechanisms of calcium oxalate stone formation, accumulated information has clearly demonstrated that hyperoxaluria is one of the most important and crucial factors in this cascade. for that reason, eg is the most commonly used agent to induce hyperoxaluria status and form calcium oxalate crystals in animal models (17). however, some drawbacks have been stated for the use of this model regarding its detrimental effects like metabolic acidosis, cellular injury, and necrosis in tubular epithelial cells which will compromise interpretation of the real effects of either high oxalate levels or the crystals formed as a result of its application (20). in an attempt to reduce the urinary excretion of stone-forming risk factors as well as to inhibit the accumulation of stone crystals, certain herbal medications have been used in animal studies with a certain level of efficacy. with this aim, some experimental studies have pointed out that such herbal compounds could serve as an encouraging, efficient, and also safe alternative due to the limited toxic side effects observed with their application (21). this also emphasizes that phytotherapy can be used as a complementary or direct approach to decrease the established side effects of the commonly used treatment alternatives. literature-derived data show that these herbal compounds may exhibit anti-oxidant, diuretic, vasodilator, spasmolytic, nephroprotective, antibacterial, and anti-inflammatory effects (22-24). to augment such valuable effects some extra active ingredients like essential oils, flavonoids, saponins, xanthine derivatives, and glycosides are also added to these structural units (16). a variety of herbal agents including rubus idaeus (25), phyllanthus niruri (11), herniaria hirsute (22), alisma orientalis (23), and costus spiralis roscoe (24) have been applied with their proven effects of antiurolithiatic activity. although the precise underlying mechanisms causing these preventive effects have yet to be identified, some researchers have shown that these substances have an impact on the levels of oxalate, calcium, and malondialdehyde in the urine of animals who have stones (25). rubus idaeus (european raspberry) on this aspect was found to prevent renal tubular damage by limiting the formation of hyperoxaluria and also the accumulation of calcium oxalate crystals with reduced malondialdehyde excretion in urine. a tropical plant named phyllanthus niruri is known to limit the development of calcium crystals without changing the urinary magnesium or citrate levels. herniara hirsute, a flowering plant, is probably acting by dissolving the residual crystals deposited in the kidney (22). this plant extract decreases caox crystal binding to the tubular epithelium, without making any important difference in the urinary ph, volume, or chemistry. (26). alisma orientalis is known to inhibit stone formation steps like crystal formation, aggregation, and growth (23). the findings of these studies suggest well that these compounds can be efficiently used to inhibit urinary stone development and stone episodes even if the exact pathophysiology is not fully known. in one of these models, a herbal agent was applied to prevent the ethylene glycol-dependant apoptosis and calcium oxalate crystal accumulation in tubular cells of the kidney and it was found to be enough effective in this aspect (16). however, the administration of the compound in this study did not alter the urinary calcium and oxalate levels indicating that the inhibitory effect on stone development is independent of the urinary concentrations of these ions. in other words, obtained results suggested that factors other than calcium and oxalate may also play a role in the pathogenesis of urolithiasis. on the other hand, in addition to the levels of urinary stone-forming risk factors (calcium, oxalate, uric acid), urinary ph levels are also very important in stone formation. some researchers suggested that urinary ph levels in animal models can be changed between the range of 5.0 to 9.0 depending on dietary alterations (27). related to this issue, measured ph levels in this study varied between 7.5 and 9.0 with slightly increased levels reported in group 3 (table 1). additionally, no significant change was found to note with respect to the ph changes in other groups. in this study, we used a phytotherapeutic compound that was produced from fractions of a few different plant extracts. of these ingredients, extracts of opuntia ficus indica (28), rosmarinus officinales (29), and cynodon dactylon (13) have been found to exhibit potent inhibition of urinary stone growth. we evaluated its potential inhibitory effects on crystal formation in the rat model in a dosedependant-based manner and our results revealed that although animals receiving eg showed a significant increase in crystal formation around the zinc disc placed, no or limited change was noted in animals receiving the compound. in other words application of this agent seemed to be protective enough against new crystal formation. the herbal compound application was more effective at a dosage of 0.332 ml, 3 times a day in reducing the extent of crystal deposition in this animal model. 11114 guzel_stesura seveso 23/03/23 12:24 pagina 4 archivio italiano di urologia e andrologia 2023; 95, 1 herbal compound on crystal formation in rat model although the exact mechanism of this litholytic effect is not clear, the excretion of oxalate and calcium seemed to have no role because no significant correlation was assessed. we believe that the potent antioxidant and antiinflammatory effects of this herbal medication, shown well in other studies, may be responsible for the limitation of crystal formation. lastly, pathological evaluation of the bladder tissue specimens revealed no significant difference regarding the presence of edema formation, vascular congestion, inflammatory cell infiltration, and pathological changes in transitional epithelium between the groups. in light of the published data so far in the literature and our current findings as well, we may claim that the abovementioned effects of the herbal medication could play a role also at the kidney level to limit the formation of crystals in the tubules. our study has certain limitations. first of all, the main disadvantage is gender singularity as the study was performed on male animals. regarding this issue, although relatively smaller-sized stones were formed in female rats than in the male ones in a study with a zinc disc model (19), the efficiency of the herbal treatments were found to be similar in both genders (24). on the other hand, spot urine samples were collected for analysis at the time of sacrification, instead of using a metabolic cage and collection of all excreted urine. however, human clinical studies have clearly shown that spot urine also may be useful enough for metabolic assessment (30). last but not least, after stone formation, a herbal compound application is used to prevent stone growth but not chemical dissolution. in conclusion, our current findings demonstrated evident crystal deposition on the surface of the zinc discs, due to the hyperoxaluria induced by ethylene glycol. the herbal compound administration was effective in reducing the extent of crystal deposition around the zinc discs and this effect was found to be the most prominent at a dosage of 0.332 ml, 3 times a day. although the probable mechanism of this litholytic effect is not clear, it was shown not to be related to the excretion of oxalate and calcium. the potent antioxidant, as well as anti-inflammatory effects of this herbal medication shown in other studies, may be responsible for the limitation of crystal formation. however, we believe that further studies are needed to outline the possible effects of the herbal compound on the limitation of new stone formation in humans. references 1. skolarikos a, straub m, knoll t et al. metabolic evaluation and recurrence prevention for urinary stone patients: eau guidelines. eur urol. 2015; 67:750-63. 2. dhondup t, kittanamongkolchai w, vaughan le et al. risk of esrd and mortality in kidney and bladder stone formers. am j kidney dis. 2018; 72:790-97. 3. zisman al. effectiveness of treatment modalities on kidney stone recurrence. clin j am soc nephrol. 2017; 12:1699-708. 4. mager r, neisius a. current concepts on the pathogenesis of urinary stones. urologe a. 2019; 58:1272-80. 5. shadman a, bastani b. kidney calculi: pathophysiology and as a systemic disorder. iran j kidney dis. 2017; 11:180-91. 6. huang hs, ma mc. high sodium-induced oxidative stress and poor anticrystallization defense aggravate calcium oxalate crystal formation in rat hyperoxaluric kidneys. plos one. 2015; 10. 7. naghii mr, jafari m, mofid m, et al. the efficacy of antioxidant therapy against oxidative stress and androgen rise in ethylene glycol induced nephrolithiasis in wistar rats. hum exp toxicol. 2015; 34:744-54. 8. monti e, trinchieri a, magri v, et al. herbal medicines for urinary stone treatment. a systematic review. arch ital urol androl. 2016; 88:38-46. 9. kasote dm, jagtap sd, thapa d, et al. herbal remedies for urinary stones used in india and china: a review. j ethnopharmacol. 2017; 203:55-68. 10. ardakani movaghati mr, yousefi m, saghebi sa, et al. efficacy of black seed (nigella sativa l.) on kidney stone dissolution: a randomized, double-blind, placebo-controlled, clinical trial. phytother res. 2019; 33:1404-12. 11. pucci nd, marchini gs, mazzucchi e, et al. effect of phyllanthus niruri on metabolic parameters of patients with kidney stone: a perspective for disease prevention. int braz j urol. 2018; 44:758-64. 12. yousefi ghale-salimi m, eidi m, et al. antiurolithiatic effect of the taraxasterol on ethylene glycol induced kidney calculi in male rats. urolithiasis. 2018; 46:419-28. 13. golshan a, hayatdavoudi p, hadjzadeh ma-r, et al. kidney stone formation and antioxidant effects of cynodon dactylon decoction in male wistar rats. avicenna j phytomed. 7:180-90. 14. bahmani m, baharvand-ahmadi b, tajeddini p, et al. identification of medicinal plants for the treatment of kidney and urinary stones. j renal inj prev. 2016; 5:129-33. 15. nishihata m, kohjimoto y, hara i. effect of kampo extracts on urinary stone formation: an experimental investigation. int j urol. 2013; 20:1032-36. 16. yuruk e, tuken m, sahin c, et al. the protective effects of an herbal agent tutukon on ethylene glycol and zinc disk induced urolithiasis model in a rat model. urolithiasis. 2016; 44:501-07. 17. joshi s, wang w, khan sr. transcriptional study of hyperoxaluria and calcium oxalate nephrolithiasis in male rats: inflammatory changes are mainly associated with crystal deposition. plos one. 2017; 12. 18. khan sr, hackett rl. urolithogenesis of mixed foreign body stones. j urol. 1987; 138:1321-28. 19. prasad k v, bharathi k, srinivasan kk. evaluation of ammannia baccifera linn. for antiurolithic activity in albino rats. indian j exp biol. 1994; 32:311-13. 20. amoroso l, cocumelli c, bruni g, et al. ethylene glycol toxicity: a retrospective pathological study in cats. vet ital. 2017; 53:251-54. 21. posadzki p, watson lk, ernst e. adverse effects of herbal medicines: an overview of systematic reviews. clin med (lond). 2013; 13:7-12. 22. ammor k, bousta d, jennan s, et al. phytochemical screening, polyphenols content, antioxidant power, and antibacterial activity of herniaria hirsuta from morocco. scientific world journal. 2018; 2018:7470384. 23. zhao zy, zhang q, li yf, et al. optimization of ultrasound extraction of alisma orientalis polysaccharides by response surface methodology and their antioxidant activities. carbohydr polym. 2015; 119:101-09. 24. araújo viel t, diogo domingos c, da silva monteiro ap, et al. 11114 guzel_stesura seveso 23/03/23 12:24 pagina 5 archivio italiano di urologia e andrologia 2023; 95, 1 r. güzel, i̇. bilger erïhan, i̇. özaydin, et al. evaluation of the antiurolithiatic activity of the extract of costus spiralis roscoe in rats. j ethnopharmacol. 1999; 66:193-98. 25. nirumand mc, hajialyani m, rahimi r, et al. dietary plants for the prevention and management of kidney stones: preclinical and clinical evidence and molecular mechanisms. int j mol sci. 2018; 19. 26. atmani f, farell g, lieske jc. extract from herniaria hirsuta coats calcium oxalate monohydrate crystals and blocks their adhesion to renal epithelial cells. j urol. 2004; 172:1510-14. 27. cohen sm. role of urinary physiology and chemistry in bladder carcinogenesis. food and chemical toxicology. 1995; 33:715-30. 28. partovi n, ebadzadeh mr, fatemi sj, khaksari m. effect of fruit extract on renal stone formation and kidney injury in rats. nat prod res. 2018; 32:1180-83. 29. naber kg. efficacy and safety of the phytotherapeutic drug canephron® n in prevention and treatment of urogenital and gestational disease: review of clinical experience in eastern europe and central asia. res rep urol. 2013; 5:39-46. 30. van huysduynen ejch, hulshof pjm, van lee l, et al. evaluation of using spot urine to replace 24 h urine sodium and potassium excretions. public health nutr. 2014; 17:2505-11. correspondence rasim güzel, md (corresponding author) rasimguzel@hotmail.com medistate kavacık hospital, department of urology, istanbul (turkey) i̇smet bilger erïhan, md, assistant professor drbilger@yahoo.com ümit yildirim, md, assistant professor dr.umityildirim87@gmail.com kafkas university, medical faculty, department of urology, 36000, kars (turkey) i̇sa özaydin, professor aras_isa@hotmail.com iozaydin@kafkas.edu.tr uğur aydin, assistant professor uguraydin076@hotmail.com kafkas university, veterinary faculty, department of surgery, 36000, kars (turkey) murat bağcioğlu, md, associate professor dr.muratbagcioglu@gmail.com bahçeşehir university, medical faculty, department of urology, 34100, istanbul (turkey) ramazan kocaaslan, md, associate professor ramizkoca@gmail.com konya training and research hospital, konya (turkey) kemal sarica, md, professor saricakemal@gmail.com biruni university, medical school, department of urology, istanbul (turkey) conflict of interest: the authors declare no potential conflict of interest. 11114 guzel_stesura seveso 23/03/23 12:24 pagina 6 introduction the pelvic floor is a complex multifunctional structure made of both muscular and tendineus components. in fact, in addition to providing support to the pelvic organs, the pelvic floor muscles active the peripheral mechanisms of urinary and fecal continence and the evacuation facilitators (1). so, pelvic floor has an important role in the control of bowel and bladder functions. besides this, recently it is emerging the importance of pelvic floor muscles (pfm) on male and female sexual function. in the male, in particular, have been highlighted the ways in which contractions/relaxation of pfm are involved in the mechanisms of erection (2) and ejaculation (3). on this basis, it was postulated that some changes in erectile and ejaculatory function may be secondary to anatomical and functional perineal muscles alterations. finally, and most recently, it has been shown that some algic phenomena evoking symptoms due to an inflammatory prostato-vesicular process, can be supported by functional alteration of the pfm (4). the symptoms of dysfunction of pelvic floor muscles 1archivio italiano di urologia e andrologia 2013; 85, 1 review pelvic floor and sexual male dysfunction antonella pischedda 1, ferdinando fusco 2, andrea curreli 1, giovanni grimaldi 2, furio pirozzi farina 1 1 azienda ospedaliera universitaria di sassari, italy; 2 azienda ospedaliera universitaria federico ii di napoli, italy. the pelvic floor is a complex multifunctional structure that corresponds to the genito-urinary-anal area and consists of muscle and connective tissue. it supports the urinary, fecal, sexual and reproductive functions and pelvic statics. the symptoms caused by pelvic floor dysfunction often affect the quality of life of those who are afflicted, worsening significantly more aspects of daily life. in fact, in addition to providing support to the pelvic organs, the deep floor muscles support urinary continence and intestinal emptying whereas the superficial floor muscles are involved in the mechanism of erection and ejaculation. so, conditions of muscle hypotonia or hypertonicity may affect the efficiency of the pelvic floor, altering both the functionality of the deep and superficial floor muscles. in this evolution of knowledge it is possible imagine how the rehabilitation techniques of pelvic floor muscles, if altered and able to support a voiding or evacuative or sexual dysfunction, may have a role in improving the health and the quality of life. key words: pelvic floor; physical therapy; sexual dysfunction; pelvic floor dysfunction. submitted 18 march 2013; accepted 30 march 2013 no conflict of interest declared summary were divided into 5 groups by ics (table 1). in this evolution of knowledge it is possible to imagine how the rehabilitation techniques of pfm, if altered and able to support a voiding or evacuative or sexual dysfunction, may have a role in improving the health and the quality of life (6). nevertheless, it would seem that the approach to pelvic floor disease related dysfunction is still performed only from a restricted medical group and stenting to become well established in urologists’ routine clinical practice. this article will get closer to the uro-andrologist intriguing possibilities offered by a better understanding of the correlation between pelvic floor dysfunction and male sexual dysfunction. anatomy and physiology of the pelvic muscles of male the differences between male and female urogenital anatomy, also mark some anatomical and functional difpirozzi ok_stesura seveso 18/04/13 10:56 pagina 1 archivio italiano di urologia e andrologia 2013; 85, 1 a. pischedda, f. fusco, a. curreli, g. grimaldi, f. pirozzi farina 2 ferences of the muscle-tendon complex that forms the pelvic floor. that said, in both sexes the pelvic floor muscles are equal and symmetrical and form the pelvic diaphragm that covers the pelvic cavity from the front portion to the rear. the diaphragm supports the bladder and the rectum and is on two levels: the deep and superficial one (1) (figures 1-2). the deep muscles of the plan can be represented in two layers: the outer layer, represented by pubo-coccygeal muscle, ileum-coccygeal and ischium-coccygeal, the inner layer is represented by the pubo-rectalis muscle. the muscles pubo-coccygeal (pc), pubo-rectalis and ischio-coccygeal form a functional unit known as the levator ani muscle (lam). the pelvic diaphragm is completed, posteriorly, by ilio-coccygeal and ischio-coccygeal muscles. the superficial floor musculature is made up of the bulbo-cavernous, ischio-cavernous, external sphincter and superficial transverse perineal muscle (figure 3). this muscle floor plays an important role in erectile function, ejaculation and in the anal sphincter mechanism. the activity of the pc muscle expresses the overall functionality of the lam which is a good measure of definition of the pelvic floor muscles activity as a functional whole. for this reason, through the pc functional study, it is possible implement a reliable diagnostic and therapeutic approach to disorders of the pfm. the pfm is constituted, for approximately two thirds, by table 1. symptoms of pelvic floor muscles dysfunction. 1.1. low urinary tract syntoms • urinary incontinence • frequency/urgency • poor or intermittent stream initiated or supported by muscular effort • hesitancy • terminal dribbling • incomplete voiding 1.2. bowel syntoms • obstructed defecation • constipation • fecal incontinence • rectal/anal prolapse 1.3. vaginal syntoms • pelvic organ prolapse 1.4. sexual function • in women: dyspareunia • in the male: erectile dysfunction and ejaculatory disorders • both: orgasmic dysfunction 1.5. pain • pelvic pain • cronic pelvic pain syndrome (cpps) figure 1. pelvic diaphragm of male inferior view. pirozzi ok_stesura seveso 18/04/13 10:56 pagina 2 3archivio italiano di urologia e andrologia 2013; 85, 1 pelvic floor and sexual male dysfunction figure 2. pelvic diaphragm of male – inferior view – viscera removed. figure 3 perineum and external genitalia of male – deep dissection. pirozzi ok_stesura seveso 18/04/13 10:56 pagina 3 archivio italiano di urologia e andrologia 2013; 85, 1 a. pischedda, f. fusco, a. curreli, g. grimaldi, f. pirozzi farina 4 slow twitch fibers (type 1) and for about one third of fast-twitch fibers (type 2) (7). slow twitch fibers are stably in a tonic contraction and this muscle tone allows the pfm to support the pelvic organs (7). the sphincteric muscles, including the periurethral, consists of fibers of type 1 and 2 since it must fulfill a dual function: increasing the urethral endurance during the period of raised intra-abdominal pressure (fiber type 1) and the voluntary control of sphincters (fiber type 2) (8). schemes of use of the pelvic floor muscles pfm usage patterns are acquired in childhood and scheduled in cerebral mechanism. afferent stimuli generated by the voiding and sexual apparatus determine a central processing aimed the most appropriate response model of the pfm (10). in this way, in the course of its growth, people gradually learn to “hold” urination, feces and intestinal gas, but also to modulate the relaxation and contraction of the pelvic muscles to handle in the best way the ejaculation. these capabilities are in part related to adequate corticalization of the pfm and, overall, to the efficiency of muscle tone. so, conditions of muscle hypotonia or hypertonicity may affect the efficiency of the pelvic floor, altering both the functionality of the deep and superficial floor muscles. while the alterations of the deep floor muscles may determine effects on urinary continence and intestinal emptying, the alterations of the superficial floor muscles may affect the quality of the erection and ejaculation . in fact it is only under conditions of optimal tonicity that these muscles perform compressive action necessary to avoid the outflow of blood from the crura (m.ischio-cavernous) (1) and the periurethral glans along the spongiosa (m. bulbo-cavernous). with regard to erectile function, grace dorey (2000) conducted a review of the literature showed that the efficiency of the pfm is higher in powerful men than those affected by erectile dysfunction (ed) (11). the hypertonicity of the pelvic floor muscles in cases in which the pfm is chronically incorrectly used, for example when the subject takes the habit of delaying urination or defecation voluntarily by contracting the pelvic musculature, you can establish special patterns chronic pelvic floor summarized under the term “hypertonic” (1). other dysfunctional patterns are those resulting from unsuitable activation in voiding phase of perineal muscles. in these cases, the muscle groups most frequently involved are the abdominal muscles, the diaphragm, the adductors and gluteal muscles (12). when this happens, frequently are established perineal muscular synergies that can be of either agonist or antagonist kind (13). in the agonists synergies, in conjunction with the levator ani contraction, it determines the activation of the adductor muscles and buttocks; in antagonistic synergies, levator ani simultaneously activates the abdominal muscles and the diaphragm (13). the causes of dyssynergia can be congenital or acquired (10). as a congenital cause, has been suggested a poor perineal region corticalization (10). among the acquired causes, first of all, behavioral causes. then, reduced pelvic floor muscles efficiency and the psychological cause (10). in case of activation of the abdominal press, it is established a hypertonic reflection of the pfm that expresses a condition of antagonist muscolar synergism (4). over the time, incongruous patterns of emptying and a state of chronic contraction of the pfm will also involve the anorectal system and ischiocavernous and bulbo-cavernous muscles (4). in more severe cases, the antagonist synergy may increase up to become a dyssynergia. this happens when patient, rather than activate the levator ani muscle, only contracts the abdominal muscles, taking a particular pattern called “inversion of perineal control” (12). in addition, since superficial floor muscles form a functional whole with deep floor ones, the hypertonicity of the pfm and the dyssynergia may come to represent a correlation factor between functional urological alterations and some types of sexual dysfunction (1). in this way it can be caused, or aggravate, premature ejaculation. as regards erectile function, ischio-cavernosa muscle hypertonicity, however it is to determine, may support a reduction of volume expansion capacity of the roots of the corpora cavernosa with consequent reduction of the maximum rigidity. the hypotonia of the muscles of the pelvic floor the condition of hypotonia of the pfm is less frequent in men than in women, in which pregnancy and vaginal delivery (especially in multiparous), obesity, aging and, more discussed, menopausal characteristic hormonal changes (14) are also risk factors of dysfunction (15). although the condition of the pfm hypotonia may have a neurogenic, (1) malformative (16) and iatrogenic postsurgical cause (1). in the male tissue aging-associated changes are the most common cause of muscular hypotonia. this assertion is supported by the finding that the efficiency of the pfm decreases with aging and aging self correlates with an increase of ed (11). this is because with aging, the number of muscle fibers reduces and collagen undergoes both qualitative and quantitative changes, involving muscle bulboand ischio-cavernous hypotonia, and consequently changes in the cavernous veno-occlusive mechanism and post-void dribbling. (17) in support of this, strasser et al. (1997), in a study on human rabdomiosphincter, found a positive correlation between age progression and quantitative decrease of striated muscle fibers so that, in this muscle, fibers are represented as follows: 79% in childhood and 35% at 85 years (18). finally, although in the literature there is still not accordance, it would appear that both the pfm hypotonus and the hypertonicity can support a premature ejaculation, in these cases secondary to reduced efficiency of perineal contraction/decontraction mechanisms having a role in the control of the ejaculatory reflex (1). the clinical evaluation of pelvic floor the pfm correct functionality is linked to its normal morphological development and the integrity of its neuro-vascular component. subject to these assumptions, muscle assessment must define the tone, strength, endurance and fatigue of the pfm. after verifying the pirozzi ok_stesura seveso 18/04/13 10:56 pagina 4 absence of dysfunctional pattern of activation of the pfm, these assessments can be performed manually, introducing a flexed finger hooked in the anal canal or by kinesiological electromyography (emg). with these methods it is possible to detect the fasic strength and various tonic expressions of the strength of the pubo-coccygeal muscle (pc test). emg offers the advantage of measuring the actual muscle activity in microvolts, although the high cost of the equipment makes the technique not common (1). it should be noted, however, that the instrument by which is performed the kynesiological emg is advantageously used also as electromyographic biofeedback, in order to implement a physical therapy aimed at helping patients to optimize their muscles activity (20). the digital rectal evaluation is used to assess the symmetry and balance of muscles that can be explored with this method, differentiating muscle able to close (puborectalis and external anal sphincter) and muscles able to lift (pubococcygeus and ilealcoccygeus) (1). in the male, intra-anal palpation is therefore considered an appropriate sensitive method to assess the strength and tone of the pelvic floor muscles (1). physical therapy of sexual dysfunction secondary to the pelvic floor muscle dysfunction physical therapy of sexual dysfunction secondary to pelvic floor alteration, still lacks of unique and validated benchmark. however, physiotherapeutic treatment will have to be modulated, qualitatively and quantitatively, as a function of the objectives that were set in agreement with the patient and the results obtained progressively. academically, physical therapy is divided in two stages: the educational and rehabilitative in the strict sense. the educational stage is a preparation for the rehabilitation phase. it must provide, in a clear and simple information about the anatomy and physiology of the pelvic floor. the rehabilitation phase has the aim of improving the dysfunctional phenomenology reported by the patient. it is structured according to a treatment plan tailored to suit the type of detected pelvic dysfunction. the main objectives of physical therapy are raise awareness and proprioception of the muscles; discrimination and improve muscle relaxation; normalize muscle tone (25). to pursue these objectives, physiotherapy may use tools such as the electromyographic biofeedback, functional electrical stimulation and pelvic-perineal physiotherapy (25). of all the physiotherapy treatments, biofeedback is only reported in controlled studies (25). electromyographic biofeedback the electromyographic biofeedback is an equipment capable of providing information on the activity of a muscle district, so the patient can re-act and change it (12). takes place via a rectal emg probe associated with surface electrodes. using digital electronic interface connected to a computer, a video with a simplified graphic expresses, real time, electromyographic activity detected (12). in this way the patient highlights, and is able to influence muscular activity escaped from his cortical control mechanisms, or knowingly to put to work the muscle under examination in order to improve the phase and/or the endurance, implementing a kind of “competition” with the machine (12). functional electrical stimulation (fes) the electrical stimulation can be applied directly to the muscle or indirectly, through the stimulation of the n.pudendal fibers (12). usually is performed using indirect stimulation that through the n.peripheral depolarisation generates a nerve impulse that causes muscle contraction (12). administered therapeutically, these contractions help to increase muscle strength using the same mechanisms of exercise therapy. these result in two effects: the facilitation of voluntary movement of the treated muscle group and the improvement of neuromotor control (12). for these reasons, we talk about functional electrical stimulation (fes) for rehabilitation (12). contraindications to the sef are: the perineal complete denervation, the vu reflux, the cardiac pacemaker and urinary infections (12). it is used a biphasic current, 10 to 50hz. ! 50ma x 0.2msec. pelvic-perineal physiotherapy (pelvic floor muscle training or pfmt) the pfmt is the first therapeutic approach to be implemented in the home, after the patient has performed an adequate training learning (26). a good treatment schedule is applyng 1 hour treatment starting from 2 times per week and up to 4 months, then customizing the sessions in function of the results obtained progressively (27). pelvic floor rehabilitation therapy in male sexual dysfunction erectile dysfunction the pelvic floor muscle is involved in the increased intra-cavernous pressure. in fact, as reported above, the activity of the ischiocavernosus muscle facilitates erection while the contraction of the bulbocavernosus muscle slows the venous drainage from the corpora cavernosa, exerting pressure on the deep dorsal vein of the penis (1). this implies that, in case of hypotonia of the pfm can be established erectile dysfunction with venoocclusive mechanism. this can benefit significantly from the physical rehabilitation therapy of the pelvic floor, which aims to increase strength and muscle tone and improve the fatiguability (17, 28). by contrast, in the case of hypertonia of the superficial pelvic floor, and in particular of the cavernosa muscles, the possible reduction of the maximum stiffness that may occur due to a reduction of the expansion volume capacity of the corpora cavernosa roots, can benefit from appropriate therapy with electromyographic biofeedback associated with functional electrical stimulation (1). premature ejaculation clinical trials were conducted in which the ep was treated with different rehabilitation therapy of the pelvic floor (3, 29). pear & g, nicastro a (1996) published that 61% of their patients with pe, reported greater ability to control 5archivio italiano di urologia e andrologia 2013; 85, 1 pelvic floor and sexual male dysfunction pirozzi ok_stesura seveso 18/04/13 10:56 pagina 5 archivio italiano di urologia e andrologia 2013; 85, 1 a. pischedda, f. fusco, a. curreli, g. grimaldi, f. pirozzi farina 6 the ejaculatory reflex after 15-20 sessions of rehabilitation therapy of the pelvic floor (29). the rehabilitation protocol adopted by these authors included the pelvic-perineal physiotherapy, electrical stimulation and intra-anal electromyographic biofeedback with anal probe (29). actual mechanism that would improve the control over the ejaculatory reflex is not clearly evident. a better management of the pelvic floor may increases awareness of this poorly corticalized area, thus improving its sense of control. according to authoritative authors, during sexual activity, pleasure felt is amplified in both partners, from genital answers provided by the levator contraction (30). in particular, in women, the contractions would be supported by a production of myotonic m. pubo-coccygeal contraction that discharge during orgasm (31). the proposed mechanism for which the active control of the musculature of the pelvic floor may delay its beginning, can be related to the inhibition of the reflex ejaculation by means of an intentional relaxation of the muscles bulbocavernosus and ischiocavernosus during arousal (1). this is a clever technique that can be learned well by using biofeedback. sexual problems post-surgery another potential of pelvic floor rehabilitation therapy, is the treatment of some cases of erectile dysfunction (ed) and/or urinary incontinence (ui) that may occur, sometimes as a complication of surgery for radical prostatectomy. voiding and sexual iatrogenic post-surgical dysfunction, may also occur in other types of pelvic-perineal surgery in both men and women. the exact incidence of sexual dysfunction resulting from surgical pelvic-perineal procedures is not exactly known. there are, in fact, few randomized controlled trials comparing different surgical techniques in voiding function of relapses and, above all, the sexual ones (32). it is true that the ui and ed secondary to prostatectomy and pelvic-perineal surgery, can benefit from rehabilitation therapy of the pelvic floor muscles and, in particular, the use of electromyographic biofeedbeck (33, 34). these results would seem to provide additional capabilities to physical therapy rehabilitation. this provided that it is left over a sufficient amount of muscle tissue on which to operate with such therapeutic methods. chronic pelvic pain the male chronic pelvic pain syndrome (cpps) is frequently associated with sexual dysfunction. these, when present, can be expressed in various manifestation: de, ep, painful erection or, finally, painful orgasm. in a study conducted on 66 patients with turkish cpps, ep had 51 (77.3%), and 10 (15.2%) had ep associated with ed (35). chronic prostatitis-chronic pelvic pain syndrome (cpcpps), has traditionally been associated with infectious causes or inflammation of the accessory glands, especially the prostate. in many cases, however, is difficult to document the inflammation pathogenesis. many causes can simulate cp-cpps symptoms such as musculoskeletal pain, dysfunction of the pelvic floor muscles, myofascial syndrome or functional somatic syndromes (36). a study of dc hetrick (2006) comparing the pelvic floor muscles electromyography of patients with chronic pelvic pain with those of normal subjects, reported that men with pelvic pain show a tapered unstable pelvic muscles than those of normal controls (37). the same study concluded that the electromyography of the pelvic floor muscles, can be a valuable screening tool to identify patients with cp-cpps who may benefit from a treatment aimed at correcting the dysfunction of the pelvic floor muscles, if this was present (37) as evidence of this, it was verified that the treatment of pelvic floor muscles with electromyographic biofeedback is an effective therapeutic method when applied to men with cp-cpps (38, 39). conclusions sexual dysfunction is usually given by more than one factor, and certain components, biological, psychosocial and relational may contribute to dysfunction in men and women. among the many factors involved in sexual dysfunction, pelvic floor seems to have an important role. in conclusion, the treatment of male chronic pelvic pain should also considers physiotherapy techniques that include physical therapy, therapeutic exercises, electrical stimulation and bfb. in this review of the literature on the effectiveness of each technique in the treatment of sexual dysfunction in men and women is revealed that treating pelvic dysfunction may improve sexual health and quality of life. further randomized controlled trials are needed to validate the success of physical therapy. references 1. rosenbaum ty. pelvic floor involvement in male and female sexual dysfunction and the role of pelvic floor rehabilitation in treatment: a literature review. j sex med. 2007; 4:4-13. 2. dorey g, 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il bilancio muscolare perineale. in: di benedetto p (ed.). riabilitazione uro-ginecologica. torino, minerva medica. 1995; 63-70. 14. sayer t, smith t. pelvic floor biopsy in: b. schüssler, j. laycock, pa. norton, sl. stanton (eds.) pelvic floor re-education (3nd edn). springer-verlag. london, 2000; 98-101. 15. gilpin sa, gosling ja, smith arb, warrell dw. the pathogenesis of genitourinary prolapse and stress incontinence of urine. a histological and histochemical study. br j obstet gynaecol. 1989; 96:15-23. 16. debus-thiede g. magnetic resonance imaging (mri) of pelvic floor. in b. schüssler, j. laycock, p norton and s. stanton (eds). pelvic floor re-education. principles and practice. (3nd edn). london, springer-verlag. 2000; 78-82. 17. van kampen m, de weerdt w, claes h, et al. treatment of erectile dysfunction by perineal exercise, electromyographic biofeedback, and electrical stimulation. phys ther. 2003; 83:536-43. 18. strasser h, steinlechner m, bartsch g. morphometric analysis of the rhabdosphincter of the male urethra. j urol. 1997; 157(suppl 4):177-180. 19. wang c, swerdloff rs, iranmanesh a, et al. transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. j clin endocrinol metab. 2000; 85:2839-2853. 20. o'donnel pd, doyle r. biofeedback therapy technique for treatment of urinary incontinence. urology. 1991; 37:432-436. 21. laycock j. clinical evaluation of the pelvic floor. in b. schüssler, j. laycock, p norton and s. stanton (eds). pelvic floor re-education. principles and practice (3nd edn). springer-verlag. london, 2000; 42-48. 22. wilmore j, costill d. physiology of sport and exercise. (2nd edn). human kinetics, champaign; illinois, 1999. 23. mansoor a, jacquetin b, ohana m. evaluation des facteurs de l’incontinence urinaire féminine et indications thérapeutiques. ann. urol. 1993; 27:292-305. 24. vodusek d. electrophysiology. in: b. schüssler, j. laycock, p norton and s. stanton (eds). pelvic floor re-education. principles and practice (3nd edn). springer-verlag. london, 2000: 83-97. 25. rosenbaum ty. physiotherapy treatment of sexual pain disorders. j sex marital ther. 2005; 31:329-340. 26. p. abrams, s. khouri, a. wein. incontinence. 1st international consultation on incontinence. paris:health publication limited, 1999. 27. cornel eb, van haarst ep, schaarsberg rw, geels j. the effect of biofeedback physical therapy in men with chronic pelvic pain syndrome type iii. eur urol. 2005; 47:607-611. 28. claes h, baert l. pelvic floor exercise versus surgery in the treatment of impotence. br j urol.1993; 71:52-7. 29. la pera g, nicastro a. a new treatment for premature ejaculation: the rehabilitation of the pelvic floor. j sex marital ther. 1996; 22:22-6. 30. shafik a. the role of the levator ani muscle in evacuation, sexual performance, and pelvic floor disorders. int urogynecol j pelvic floor dysfunct. 2000; 11:361-76. 31. komisaruk br, whipple b. physiological and percentual correlates of orgasm produced by genital or non-genital stimulation. in: p. kothari (ed) the proceedings of the first international conference on orgasm. parthenon press, england, 1991. 32. achtari c, dwyer p. sexual function and pelvic floor disorders. best prac res clin obstet gynaecol. 2005; 19:993-1008. 33. lewis rw, fugl-meyer ks, bosch r, et al. epidemiology/risk factors of sexual dysfunction. j sex med. 2004; 1:35-39. 34. lue tf, giuliano f, montorsi f, et al. summary of the recommendations on sexual dysfunctions in men. j sex med. 2004; 1:6-23. 35. gonen m, kalkan m, cenker a, ozkardes h. prevalence of premature ejaculation in turkish men with chronic pelvic pain syndrome. j androl. 2005; 26:601-3. 36. potts jm. chronic pelvic pain syndrome: a non prostatocentric perspective. world j urol. 2003; 21:54-6. epub 2003. review. 37. hetrick dc, glazer h, liu yw, et al. pelvic floor electromyography in men with chronic pelvic pain syndrome: a case control study. neurourol urodyn. 2006; 25:46-9. 38. cornel eb, van haarst ep, schaarsberg rw, geels j. the effect of biofeedback physical therapy in men with chronic pelvic pain syndrome type iii. eur urol. 2005; 47:607-11. 39. yezq, cai d, du lan rzgh, et al. biofeedback therapy for chronic pelvic pain syndrome. asian j androl. 2003; 5:155-8. 7archivio italiano di urologia e andrologia 2013; 85, 1 pelvic floor and sexual male dysfunction correspondence ferdinando fusco, md (corresponding author) azienda ospedaliera universitaria federico ii di napoli ferdinando-fusco@libero.it antonella pischedda, md andrea curreli, md furio pirozzi farina, md pirozzi@uniss.it azienda ospedaliera universitaria viale s. pietro 43 07100 sassari, italy giovanni grimaldi, md azienda ospedaliera universitaria federico ii napoli, italy pirozzi ok_stesura seveso 18/04/13 10:56 pagina 7 stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11450 1 original paper and is usually caused by an aerobic bacterial invasion (1). the bacterial species' combined invasive and toxic activities produce endarteritis obliterans, cutaneous and subcutaneous artery thrombosis, local tissue necrosis and gangrene, and subsequently life-threatening adverse events such as multiple organ system failures, septic shock, and death if left untreated (1, 2). despite the advancement of medical knowledge towards fg’s pathobiology, diagnosis, and management, the mortality rate remains high, with some reported rates of approximately 50% (3). fg is a predominantly male illness and is commonly observed in men aged 40 to 50, with a reported annual incidence of 1.6 cases per 100.000 men. diabetes mellitus (dm), older age, liver cirrhosis, vascular disease, cancer, chronic alcoholism, overweight, paraplegia, and renal impairment are all thought to be associated with higher mortality rates; however, up to 30% to 50% of fg cases present with no identifiable risk fact (4). there are numerous scoring methods for predicting fg mortality, such as the acute physiology and chronic health evaluation (apache) ii scoring system, which is an extensively used tool for predicting mortality outcomes, charlson comorbidity index (cci), and fournier's gangrene severity index (fgsi) which are well-defined disease-specific metric (5, 6). however, those scorings still had limitations and some factors are not included such as length of hospital stay, which is related to hospitalization costs and treatment approaches (4). in low-income countries, such as yemen, there is limited information available about the extent of fg mortality rate, and its predisposing factors (7). here, we studied the characteristics and clinical course of patients diagnosed with fg at our institution over a period of 12 years. our primary objective was to discern the prognostic factors intricately linked to this debilitating disease. by furnishing essential data, we aspire to enhance the foundation for future investigations and therapeutic interventions. such endeavors hold immense potential to empower healthcare practitioners in promptly identifying fg and initiating timely and efficacious care for afflicted individuals. background: fournier’s gangrene (fg) is a destructive necrotizing infection with a generally poor prognosis. this study aims to share our experience in handling fg patients in a resource-limited setting and identify prognostic factors for fg mortality. methods: a retrospective study of thirty-six patients diagnosed with fg and treated at our teaching hospital between jun 2010 to oct 2022 was conducted. laboratory and nonlaboratory data and patients' outcomes were gathered. a univariate analysis was computed for identifying prognostic factors for fg mortality. result: the main age was 68.30 ± 5.61years and most (69.4%) were older than 65 years. the overall survival was 63.9% and the mortality rate was 36.1%. univariate analysis showed that advanced age (p = 0.02), delayed in hospital presentation (p = 0.024), involvement of larger area (p = 0.001), a history of diabetes mellitus (p < 0.006), end-stage renal disease (p = 0.018), heart failure (p = 0.005), cerebrovascular accident (p = 0.003), liver cirrhosis (p = 0.001), presence of multiple comorbidities (p = 0.001), septic conditions at admission (p = 0.048), need for mechanical ventilation (p = 0.001), hypoalbuminemia (p < 0.001), and elevated blood urea nitrogen (p = 0.002) were found to be risk factors for mortality in patients with fg. conclusions: fournier’s gangrene is a fulminant condition with a high mortality rate, especially in resource-limited settings. in this study, the mortality rate was 36.1%. advanced age, delayed in hospital presentation, involvement of larger area, a history of diabetes mellitus, end-stage renal disease, heart failure, cerebrovascular accident, liver cirrhosis, presence of multiple comorbidities, septic conditions at admission, need for mechanical ventilation, hypoalbuminemia, and elevated blood urea nitrogen were associated with fg mortality. key words: fournier's gangrene; mortality; prognostic factors; outcome. submitted 5 may 2023; accepted 8 june 2023 introduction fournier's gangrene (fg) is a poly-microbial necrotizing infection that spread drastically to involve the genital, perianal area, or perineal deep tissue causing rapid tissue prognostic determinants and treatment outcomes of fournier’s gangrene treatment in a resource-limited setting: a retrospective study saif ghabisha 1, faisal ahmed 2*, saleh al-wageeh 1, mohamed badheeb 3, qasem alyhari 1, abdulfattah altam 4, afaf alsharif 5 1 department of general surgery, school of medicine, ibb university of medical sciences, ibb, yemen; 2 department of urology, school of medicine, ibb university of medical sciences, ibb, yemen; 3 department of internal medicine, yale new haven health, bridgeport hospital, bridgeport, usa; 4 department of general surgery, school of medicine, 21 september university, sana'a, yemen; 5 department of gynaecology, school of medicine, jeblah university for medical and health sciences, ibb, yemen. doi: 10.4081/aiua.2023.11450 summary archivio italiano di urologia e andrologia 2023; 95(3):11450 saif ghabisha, faisal ahmed, saleh al-wageeh, mohamed badheeb, qasem alyhari, abdulfattah altam, afaf alsharif 2 materials and methods study design between jun 2010 to oct 2022, this retrospective study was conducted at ibb university-affiliated hospitals and included 36 consecutive patients diagnosed with fg and treated by the same surgeon (professor s. ghabisha). the ethics research committees of ibb university provided their approval for the study (id: ibbuni.ac.yem.2023.55, on 03.03.2023), which adhered to the ethical principles outlined in the declaration of helsinki. inclusion criteria patients diagnosed with fg and treated at ibb universityaffiliated hospitals (al-nasar hospital) were included in the study. the presence of fever (> 38°c), erythema and swelling in the perianal or scrotal region, purulent-malodorous discharge, and the detection of fluctuation or crepitation at the wound site were used to make the diagnosis of fg (8). exclusion criteria patients treated at other hospitals and those with scrotal, periurethral, or perianal abscesses with no fascial or soft tissue extension were excluded. surgical procedure and postoperative care all participants received immediate aggressive debridement under general or spinal anesthesia to remove necrotic tissue until healthy tissue was observed. in addition, cystostomy catheters were placed, limiting the contact of the urethra with urine. empiric intravenous antibiotic therapy, including crystalline penicillin (4miu iv every 6 hours), ceftriaxone (1 g every 12 hours), and metronidazole (500 mg every 12 hours), was administered until culture results were obtained and in cases of sepsis, imipenem and vancomycin were used. dressings were changed three times daily with sterile gauze soaked in a solution of povidone-iodine, 0.2% nitrofurazone ointment, and 250 mg rifampicin ampoule and hyperbaric oxygen was done in cases needing multiple debridements (9). a fecal diversion (colostomy) was performed in cases where the perirectal and anal regions were affected, while an orchiectomy was performed in testicular involvement cases (5). patients were transferred to the plastic and reconstructive surgery clinic once their general health status and wound cleanliness had improved. data collection patient demographic characteristics, including age, time to hospital admission, comorbidities, albumin level, number of surgical debridements, need for mechanical ventilation, need for colostomy diversion or orchiectomy, length of hospital stay, and mortality were extracted from the patient's medical records. mortality refers to all-cause mortality and any cause of fg-related death during the initial admission or follow-up. to assess the fg extension, we used a modified body surface area nomogram commonly used for estimating the extension of burn injuries. this involved assigning a value of 1% for penile, scrotal, and perineal involvement, and 2.5% for ischiorectal fossa involvement (5, 8). the comorbidities were heart failure, end-stage renal disease (esrd), liver cirrhosis, history of anorectal surgery, and old cerebrovascular accident (cva), which were also evaluated as several comorbidities (presence of one versus more than one of comorbidities) (10). the number of surgical debridements was defined as the number of times a patient entered the operating room (10). the albumin level was dived into two categories (equal or more than 3 g/dl and less than 3 g/dl). variables and measures the outcome variable was fg mortality expressed as a binary variable: alive and dead. independent variables included age (≤ 65 years and more than 65 years), cva (yes and no), heart disease (yes and no), liver cirrhosis (yes and no), esrd (yes and no), the number of debridement (≤ 2 times and ≥ times), comorbidity number (one and more than one), need for a colostomy (yes and no), need for orchiectomy (yes and no), mean hospital stays, etiological subtypes (genitourinary infection versus nongenitourinary infections), septic condition (yes and no), comorbidity number (< two comorbidities and ≥ two comorbidities), mean total affected body surface area (≤ than 3% and more than 3%), blood urea nitrogen figure 1. a. fournier’s gangrene involved the scrotum. b. fournier’s gangrene involved the penis, scrotum, and ischiorectal fossa. c. fournier’s gangrene involved both the penis and scrotum with a purulent discharger. archivio italiano di urologia e andrologia 2023; 95(3):11450 3 fournier's gangrene outcome (bun) (more than 50 mg/dl and less), albumin level (≤ 3 g/dl and more than 3 g/dl), need for mechanical ventilation (yes and no), time to hospital presentation (≤ 7 days and more than 7 days), and dm (yes and no). study outcome the mortality rate and the independent predictors of fg mortality. statistical analysis the study utilized both quantitative and qualitative, for which means and standard deviations were used to present quantitative data, while frequencies and percentages were reported for qualitative variables. the normality of the data was confirmed using the smirnov-kolmogorov test. to determine the independent risk variables related to fg mortality, univariate analysis was done. effect sizes in the model were expressed using odds ratios and confidence intervals at 59%. the statistical significance level was set at p < 0.05. the ibm spss version 22 software (ibm corp., armonk, new york) was used for statistical analysis. result baseline clinical characteristics the mean age was 68.30 ± 5.61 years and most of patients (69.4%) were aged more than 65 years. the main time to hospital presentations was 7.47 ± 4.10 days and 15 (41.7%) patients presented after 7 days from starting symptoms. most of them (25, 69.4%) were in septic conditions. history of dm, heart failure, esrd, cva, anorectal surgery, and liver cirrhosis was present in 20 (55.6%), 11(30.6%), 8 (22.2%), 5(13.9%), 6 (16.7%), 6 (16.7%), respectively. additionally, 14 (38.9%) had more than one comorbid number. the source of infection was a genitourinary infection in 15 (41.7%) patients, perianal infection in 6 (16.7%) patients, and an unknown source in 15 (41.7%) patients. the mean calculated total affected body surface area was 3.59 ± 1.47 (%) and was more than 3% in (19, 52.8%) patients. the serum albumin level was less than 3 g/dl in 14 (38.9%) patients. most of the patients (72.2%) more than one surgical debridement. colostomy and orchiectomy were done on 6 (16.7%) and 3 (8.3%) patients respectively. the mean hospital stay was 57.00 ± 4.01 days and 15 (41.7%) patients need mechanical ventilation. within a median follow-up time of 14.0 months (range 2-30 months), 23(63.9%) of patients survived and the total mortality rate was 36.1%. table 1 summarizes the baseline clinical characteristics of the research cohort. mortality predictors in patients with fournier’s gangrene the association of independent variables with the dependent variable was investigated using univariate, analysis. univariate analysis showed that advanced age (p = 0.02), delayed in hospital presentation (p = 0.024), involvement of larger area (p = 0.001) (table 2), a history of dm (p < 0.006), esrd (p = 0.018), heart failure (p = 0.005), cva (p = 0.003), liver cirrhosis (p = 0.001), presence of multiple comorbidities (p = 0.001), septic conditions at admission (p = 0.048), (p = 0.018), need for mechanical ventilation (p = 0.001), hypoalbuminemia (p < 0.001), and elevated blood urea nitrogen (p = 0.002) were found to be risk factors for mortable 1. demographic characteristics of patients. variable subgroup n (%) age (year) mean ± sd 68.30 ± 5.61 < 65 years 11 (30.6) ≥ 65 years 25 (69.4) time to hospital admission (days) mean ± sd 7.47 ± 4.10 (2-20) ≤ 7 days 21 (58.3) > 7 days 15 (41.7) source of infection urinary tract infection 15 (41.7) perianal or perirectal infection 6 (16.7) unknown 15 (41.7) septic condition 25 (69.4) predisposing factors diabetes mellitus 20 (55.6) heart failure 11 (30.6) renal failure 8 (22.2) cerebrovascular accident 5 (13.9) liver cirrhosis 6 (16.7) anorectal surgery 6 (16.7) comorbid number one 22 (61.1) ≥ two 14 (38.9) total affected body surface area (%) mean ± sd 3.59 ± 1.47 ≤ 3% 17 (47.2) > 3% 19 (52.8) number of debridement mean ± sd 2.27 ± 1.13 (1-5) one 10 (27.8) ≥ two 26 (72.2) needs for colostomy 6 (16.7) needs for orchiectomy 3 (8.3) need for mechanical ventilation 15 (41.7) blood urea nitrogen (mg/dl) ≥ 50 18 (50) albumin level (mg/dl) < 3 14 (38.9) hospital stay (day) mean ± sd 7.00 ± 4.01 outcome survivors 23 (63.9) non-survivors 13 (36.1) table 2. comparison between survivors and survivors for quantitative variables. variable outcome mean difference (95 % ci) t & z p-value * survivors n = 23 died n = 13 mean (sd) mean (sd) age (year) 66.69 (5.19) 71.15 (5.35) -4.45(-8.15 to -0.75) -2.44 0.020 number of debridements 2.21(1.12) 2.38(1.19) -0.16(-0.97 to 0.64) -0.42 0.678 time to hospital presentation (days) 6.91 (4.83) 8.46(2.14) -1.54(-4.43 to 1.33) -1.09 0.024 total bsa (%) 3.00(1.47) 4.65(0.65) -1.65(-2.53 to -0.77) -3.81 0.001 hospital stay (days) 7.08 (3.42) 6.84(5.04) 0.24(-2.63 to 3.11) 0.170 0.361 bsa: body surface area. * p-values of < 0.05 were considered significant. archivio italiano di urologia e andrologia 2023; 95(3):11450 saif ghabisha, faisal ahmed, saleh al-wageeh, mohamed badheeb, qasem alyhari, abdulfattah altam, afaf alsharif 4 tality in patients with fg (table 3). the relative risk of ssi occurrence was also higher among patients with genitourinary infection; however, it was not statistically significant in univariate analysis (p = 0.075). discussion in this study, we evaluated the predictive factor for mortality in fg patients who were treated in resource-limited settings. the survival rate was 63.9% and the mortality rate was 36.1%. univariate analysis showed that advanced age, delayed in hospital presentation, involvement of larger area, a history of dm, esrd, heart failure, cva, liver cirrhosis, presence of multiple comorbidities, septic conditions at admission, need for mechanical ventilation, hypoalbuminemia, and elevated blood urea nitrogen were found to be risk factors for mortality in patients with fg. fg is a polymicrobial illness that resulted typically from facultative aerobic and anaerobic bacterial growth. the rapid proliferation is linked to decreased cellular immunity of fg’s patients and the synergistic release of toxins (11). the mortality associated with the disease is high and has been reported from 6% to as high as 76% (12). in this study, the total mortality rate was 36.1%. this is in agreement with other studies in most developing countries. for example, sabzi et al. study in iran reported a mortality rate of 37.5% (12). in our study, genitourinary infection was the most common cause of fg and one-third of cases had an unknown etiology. our result was similar to tahmaz et al.'s study, which reported that 33% of fg cases were due to genitourinary infections (13). nevertheless, no identifiable cause was observed in one-quarter of the patients in the el-qushayri et al. study (14). the factors that predict fg mortality are, for the most part, debatable. because many studies are retrospective and included a small number of patients. for that, solid criteria are still missing and statistical analysis is still limited. there is a discrepancy in the literature regarding several independent prognostic factors in patients with fg. for example, some studies have shown that younger age was associated with improved survival (8, 15, 16). while other studies have not found a significant difference in disease onset between various age groups (17, 18). in our study group, advanced age was noticed among non-surviving patients and was a risk factor for fg mortality in univariate analysis. in line with earlier research, the majority of our patient population had dm as the most common comorbidity. this pathology in our study was a predictive factor for mortality in univariate analysis (19, 20). according to previous researchers, the incidence of dm was found in between 50% and 70% of fg patients (19, 21). dm has been identified as a risk factor for fg and has been linked to a more progressive and poorer outcome due to reduced phagocytic and intracellular bactericidal activity and neutrophil dysfunction (19). certain conditions such as alcohol consumption, immunocompromised status, malignancy, heart failure, hepatic disease, and esrd were reported to be associated with fg mortality (8, 13, 22). similarly, in our study, those factors were associated with fg mortality and were statistically significant in univariate analysis. additionally, 38.9% of our patients had at least one of the following conditions: esrd, cardiac insufficiency, cva, and liver cirrhosis; these conditions were highly represented among nonsurvivors patients. in roghmann et al. table 3. comparison between survivors and non-survivors for categorical variables. variable sub total (n = 36) outcome univariate analysis variable n (%) survivors n (%) died n (%) or (95 % ci) p-value * age (year) < 65 11 (30.6) 9 (81.8) 2 (18.2) 0.28 (0.05 to 1.58) 0.151 ≥ 65 25 (69.4) 14 (56.0) 11 (44.0) reference group diabetes mellitus yes 20 (55.6) 8 (40.0) 12 (60.0) 22.50 (2.46 to 205.7) 0.006 no 16 (44.4) 15 (93.8) 1 (6.3) reference group number of debridements ≤ 1 10 (27.8) 6 (60.0) 4 (40.0) 1.25 (0.28 to 5.65) 0.763 > 2 26 (72.2) 17 (65.4) 9 (34.6) reference group time to the presentation (day) ≤ 7 21 (58.3) 16 (76.2) 5 (23.8) 0.27 (0.06 to 1.14) 0.075 > 7 15 (41.7) 7 (46.7) 8 (53.3) reference group comorbidity number ≤ 1 22 (61.1) 19 (86.4) 3 (13.6) 0.06 (0.01 to 0.33) 0.001 > 1 14 (38.9) 4 (28.6) 10 (71.4) reference group need colostomy yes 6 (16.7) 4 (66.7) 2 (33.3) 0.86 (0.13 to 5.50) 0.877 no 30 (83.3) 19 (63.3) 11 (36.7) reference group need orchiectomy yes 8 (8.3) 2 (66.7) 1 (33.3) 0.87 (0.07 to 10.69) 0.917 no 33 (91.7) 21 (63.6) 12 (36.4) reference group septic condition yes 25 (69.4) 13 (52.0) 10 (90.9) 9.23 (1.02 to 83.33) 0.048 no 11 (30.6) 1 (9.1) reference group cva yes 0 (0.0) 0 (0.0) 5 (100.0) 0.003 no 0 (0.0) 23 (74.2) 8 (25.8) reference group liver cirrhosis yes 0 (0.0) 6 (100.0) 0.001 no 23 (76.7) 7 (23.3) reference group history of heart failure yes 11 (30.6) 3 (27.3) 8 (72.7) 10.66 (2.04 to 55.51) 0.005 no 25 (69.4) 20 (80.0) 5 (20.0) reference group esrd yes 8 (22.2) 2 (25.0) 6 (75.0) 9.00 (1.46 to 55.24) 0.018 no 28 (77.8) 21 (75.0) 7 (25.0) reference group history of anal surgery yes 6 (16.7) 4 (66.7) 2 (33.3) 0.86 (0.13 to 5.50) 0.877 no 30 (83.3) 19 (63.3) 11 (36.7) reference group mechanical ventilation yes 15 (41.7) 4 (26.7) 11 (73.3) 26.12 (4.09 to 166.0) 0.001 no 21 (58.3) 19 (90.5) 2 (9.5) reference group etiology non-gu 21 (58.3) 16 (76.2) 5 (23.8) 0.27 (0.06 to 1.14) 0.075 gu 15 (41.7) 7 (46.7) 8 (53.3) reference group bun (mg/dl) < 50 18 (50.0) 17 (94.4) 1 (5.6) 0.03 (0.003 to 0.27) 0.002 ≥ 50 18 (50.0) 6 (33.3) 12 (66.7) reference group albumin (g/dl) < 3 22 (61.1) 2 (14.3) 12 (85.7) 126.0 (10.31 to 1539) < 0.001 ≥ 3 14 (38.9) 21 (95.5) 1 (4.5) reference group bsa: body surface area; bun: blood urea nitrogen; ci: confidence interval; cva: cerebrovascular accident; esrd. end-stage renal disease; gu: genitourinary; or: odds ratio. * p-values of < 0.05 were considered significant. archivio italiano di urologia e andrologia 2023; 95(3):11450 5 fournier's gangrene outcome study, history of dm, esrd, cardiac insufficiency, cva, liver cirrhosis, and comorbidity were outcome predictors and authors suggested that the presence of multiple comorbidities might predict poorer outcomes (23). in our study, the presence of multiple comorbidities was associated with fg mortality in univariate analysis. the duration between symptom onset and treatment initiation has been reported as a significant predictor of outcomes for patients with fg (19, 24). however, these findings are not universally agreed upon. for instance, a study by sallami et al. reported no significant difference in time to admission between survivors and non-survivors (20). in our study, we found that a longer time to hospital admission was significantly associated with fg mortality (p = 0.024). other reports mentioned higher mortality among fg patients with delayed hospital admission (19, 24). these inconsistencies may be attributed to variations in study settings, patient demographics, hospital accessibility, income, and educational levels. in our study, the delayed patient presentation may be attributed to the limited access to healthcare facilities. specifically, the residence of our cohort was located at a considerably far distance from the specalized health centers, from the study area, which likely contributed to the delay in seeking medical attention. various laboratory abnormalities have been evaluated to predict fg mortality, including white blood cell (wbc) count, blood urea nitrogen (bun), serum creatinine, albumin, calcium, and sodium (12, 23). however, there is a discrepancy in the literature regarding several independent laboratory prognostic factors in patients with fg. sabzi sarvestani et al. reported a significant correlation between those factors and fg mortality (12). these findings were also endorsed by yeniyol et al., who showed elevated wbc, bun, creatinine, alkaline phosphatase (alp), and lactate dehydrogenase levels, and lower hematocrit, metabolic acidosis, hyponatremia, hypokalemia, in addition to decreased total protein, and albumin levels in non survivors compared to survivors (17). reduced sodium levels, along with lower serum albumin and total protein levels, can signify both a catabolic state and a poor response to therapy, which were seen among these patients with a worse prognosis and higher mortality rates. these factors are directly correlated with poor outcomes (20). laor et al. found a higher level of calcium, albumin, and cholesterol, and lower levels of bun and alp at admission of surviving patients compared to nonsurvivors (25). another retrospective study, reported that bun > 50 mg/dl was significantly associated with a higher mortality (26). it should be noted that various confounding factors or effect modifiers (e.g., severe dehydration, sepsis, and shock) that were not controlled in the study may have influenced these findings. our univariate analysis showed that albumin levels lower than 3 g/dl and bun > 50 mg/dl were associated with overall increased mortality. nevertheless, the generalizability of these findings is limited by the small and heterogeneous nature of our cohort. the reported indications for orchidectomy in fg patients were preexisting epididymorchitis, gangrenous testis damage, or scrotal abscess (21). although testicular involvement appears to be uncommon in fg, a modest incidence rate was reported by sallami et al. as seven patients, of 40 included, underwent orchidectomy for gangrenous testis damage; in addition to four patients needed subcutaneous testicular repositioning (20). in our study, three patients underwent orchidectomy as a sequala of testicular gangrenous necrosis. a colostomy is sometimes needed to decrease fecal contamination, especially in the presence of infective sphincteric destruction or rectal perforation (20, 27). in our study, six patients underwent colostomy diversion due to the extensively involved perianal area. this study found a significant difference in the average extent of body surface area affected by necrotizing tissue between patients who survived and those who did not (3.0 ± 1.5 vs. 4.7 ± 0.7 respectively). the number of surgical debridements, on the other hand, did not have a significant impact on patient outcomes, which is in line with the findings of yeniyol et al. (17). however, the result reported by spirnak et al. differs from these findings, as they showed a higher mortality rate among patients who underwent more frequent debridements due to more extensive disease (28). generally, prompt surgical intervention (aggressive and often repeat debridement), broad-spectrum antibiotics, and appropriate resuscitation are crucial in these patients (29). as expected, patients with large involved body surface areas usually died during the hospital course, and the chance of undergoing multiple debridements subsequently decreased in this group. a similar report has been mentioned by sabzi sarvestani et al. (12). postoperative mechanical ventilation has been demonstrated as a powerful factor in fg mortality. in benjelloun et al. and yanar et al. studies, the need for mechanical ventilation is a predictive factor for fg mortality (30, 31). our findings are consistent with those previously reported in the literature and the need for mechanical ventilation was an independent predictor of mortality (30, 31). this study has several limitations. firstly, the retrospective design and the small sample size were potential sources of bias that might limit the generalizability of our findings. secondly, due to the nature of the study, some relevant factors, such as blood gas analysis data, apache ii scoring system, cci, and fgsi, were not included in our analysis. future studies with more sample sizes and prospective designs are recommended to strengthen the validity and generalizability of our findings. conclusions fg represents a critical medical condition with notable morbidity and mortality rates. in this study, advanced age, delayed in hospital presentation, involvement of larger area, a history of dm, esrd, heart failure, cva, liver cirrhosis, presence of multiple comorbidities, septic conditions at admission, need for mechanical ventilation, hypoalbuminemia, and elevated blood urea nitrogen were associated with fg mortality. acknowledgments the authors would like to thank the general manager of al-thora general hospital and al-nassar hospital, ibb, yemen, dr. abdulghani ghabisha, for editorial assistance. archivio italiano di urologia e andrologia 2023; 95(3):11450 saif ghabisha, faisal ahmed, saleh al-wageeh, mohamed badheeb, qasem alyhari, abdulfattah altam, afaf alsharif 6 references 1. boughanmi f, ennaceur f, korbi i, et al. fournier's gangrene: its management remains a challenge. pan afr med j. 2021; 38:23. 2. thwaini a, khan a, malik a, et al. fournier's gangrene and its emergency management. postgrad med j. 2006; 82:516-519. 3. tuncel a, aydin o, tekdogan u, et al. fournier's gangrene: three years of experience with 20 patients and validity of the fournier's gangrene severity index score. eur urol. 2006; 50:838-843. 4. zhang kf, shi cx, chen sy, et al. progress in multidisciplinary treatment of fournier's gangrene. infect drug resist. 2022; 15:6869-6880. 5. hong ks, yi hj, lee ra, et al. prognostic factors and treatment outcomes for patients with fournier's gangrene: a retrospective study. int wound j. 2017; 14:1352-1358. 6. noegroho bs, adi k, mustafa a, et al. the role of quick sepsisrelated organ failure assessment score as simple scoring system to predict fournier gangrene mortality and the correlation with fournier's gangrene severity index: analysis of 69 patients. asian j urol. 2023; 10:201-207. 7. al-kohlany k, baker k, ahmed f, et al. treatment outcome of fournier's gangrene and its associated factors: a retrospective study. arch ital urol androl. 2023:11318. 8. doluoglu ö g, karagöz ma, kılınç mf, et al. overview of different scoring systems in fournier's gangrene and assessment of prognostic factors. turk j urol. 2016; 42:190-196. 9. feres o, feitosa mr, ribeiro da rocha jj, et al. hyperbaric oxygen therapy decreases mortality due to fournier's gangrene: a retrospective comparative study. med gas res. 2021; 11:18-23. 10. griebling tl. re: prognostic factors of fournier's gangrene in the elderly: experiences of a medical center in southern taiwan. j urol. 2017; 197:709. 11. huang cs. fournier's gangrene. n engl j med. 2017; 376:1158. 12. sabzi sarvestani a, zamiri m, sabouri m. prognostic factors for fournier's gangrene; a 10-year experience in southeastern iran. bull emerg trauma. 2013; 1:116-122. 13. tahmaz l, erdemir f, kibar y, et al. fournier's gangrene: report of thirty-three cases and a review of the literature. int j urol. 2006; 13:960-967. 14. el-qushayri ae, khalaf km, dahy a, et al. fournier's gangrene mortality: a 17-year systematic review and meta-analysis. int j infect dis. 2020; 92:218-225. 15. tuncel a, keten t, aslan y, et al. comparison of different scoring systems for outcome prediction in patients with fournier's gangrene: experience with 50 patients. scand j urol. 2014; 48:393-399. 16. martinschek a, evers b, lampl l, et al. prognostic aspects, survival rate, and predisposing risk factors in patients with fournier's gangrene and necrotizing soft tissue infections: evaluation of clinical outcome of 55 patients. urol int. 2012; 89:173-179. 17. yeniyol co, suelozgen t, arslan m, et al. fournier's gangrene: experience with 25 patients and use of fournier's gangrene severity index score. urology. 2004; 64:218-222. 18. wetterauer c, ebbing j, halla a, et al. a contemporary case series of fournier's gangrene at a swiss tertiary care center-can scoring systems accurately predict mortality and morbidity? world j emerg surg. 2018; 13:25. 19. chalya pl, igenge jz, mabula jb, et al. fournier's gangrene at a tertiary health facility in northwestern tanzania: a single centre experiences with 84 patients. bmc res notes. 2015; 8:481. 20. sallami s, maalla r, gammoudi a, et al. fournier's gangrene : what are the prognostic factors? our experience with 40 patients. tunis med. 2012; 90:708-714. 21. dahm p, roland fh, vaslef sn, et al. outcome analysis in patients with primary necrotizing fasciitis of the male genitalia. urology. 2000; 56:31-35. 22. lewis gd, majeed m, olang ca, et al. fournier's gangrene diagnosis and treatment: a systematic review. cureus. 2021; 13:e18948. 23. roghmann f, von bodman c, löppenberg b, et al. is there a need for the fournier's gangrene severity index? comparison of scoring systems for outcome prediction in patients with fournier's gangrene. bju int. 2012; 110:1359-1365. 24. villanueva-sáenz e, martínez hernández-magro p, valdés ovalle m, et al. experience in management of fournier's gangrene. tech coloproctol. 2002; 6:5-10. 25. laor e, palmer ls, tolia bm, et al. outcome prediction in patients with fournier's gangrene. j urol. 1995; 154:89-92. 26. clayton md, fowler je, jr., sharifi r, et al. causes, presentation and survival of fifty-seven patients with necrotizing fasciitis of the male genitalia. surg gynecol obstet. 1990; 170:49-55. 27. sarofim m, di re a, descallar j, et al. relationship between diversional stoma and mortality rate in fournier's gangrene: a systematic review and meta-analysis. langenbecks arch surg. 2021; 406:2581-2590. 28. spirnak jp, resnick mi, hampel n, et al. fournier's gangrene: report of 20 patients. j urol. 1984; 131:289-291. 29. auerbach j, bornstein k, ramzy m, et al. fournier gangrene in the emergency department: diagnostic dilemmas, treatments and current perspectives. open access emerg med. 2020; 12:353-364. 30. benjelloun el b, souiki t, yakla n, et al. fournier's gangrene: our experience with 50 patients and analysis of factors affecting mortality. world j emerg surg. 2013; 8:13. 31. yanar h, taviloglu k, ertekin c, et al. fournier's gangrene: risk factors and strategies for management. world j surg. 2006; 30:1750-1754. correspondence saif ghabisha, md saifalighabisha@yahoo.com saleh al-wageeh, md alwajihsa78@gmail.com department of general surgery, school of medicine, ibb university of medical sciences, ibb, yemen faisal ahmed, md (corresponding author) fmaaa2006@yahoo.com urology research center, al-thora general hospital, department of urology, school of medicine, ibb university of medical sciences, ibb, yemen mohamed badheeb, md badheeb2009@gmail.com internal medicine office, yale new haven/bridgeport hospital, ct (usa) qasem alyhari, md qalyhary@hotmail.com department of general surgery, school of medicine, ibb university of medical sciences, ibb, yemen urology office, althora general hospital, alodine street, ibb (yemen) abdulfattah altam, md dral_tam@yahoo.com urology office, school of medicine, 21 september university, sana'a (yemen) afaf alsharif, md afafmussa2018@gmail.com department of gynaecology, school of medicine, jeblah university for medical and health sciences, ibb, yemen gynaecology office, jeblah hospital, jeblah, ibb (yemen) conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 review introduction the term chronic prostatitis (cp) refers to a group of syndromes of various etiology characterized by subacute and persistent prostatic inflammation although a large proportion of patients with prostatic inflammation don’t have any symptoms (category iv, asymptomatic inflammatory prostatitis). the remaining patients, affected by category ii chronic bacterial prostatitis (cbp) or by category iii chronic prostatitis/chronic pelvic pain syndrome (cp/cpps) may experience pelvic pain, including suprapubic pain, pain in the penis, testicles or perineum, pain during sexual intercourse or during ejaculation, dysuria (painful urination), nocturia and/or urinary urgency. the duration and severity of pain and discomfort varies among patients. chronic pain may be accompanied by several voiding disturbances mainly urgency and nocturia sexual dysfunction as well (1). however pelvic pain is the most prominent symptom (as compared with patients with bph and those with erectile dysfunction (2). stress and a spectrum of various psychological problems are commonly found in cp patients, but it is not yet clear whether, a priori, psychological dysfunctions are the cause of these pain syndromes, or whether these pain conditions are themselves causing psychological disturbances (3). moreover, the exact incidence of individual psychological problems remains unspecified. in this article we present the current perspective on the impact of psychological problems in chronic prostatitis syndromes and we discuss the implications thereof from a clinical perspective. introduction/aim: a spectrum of psychological problems is commonly found in cp/cpps patients, though it is not yet clear whether, a priori, psychological dysfunctions are the cause of these pain syndromes, or whether these pain conditions are themselves causing psychological disturbances. in this article we present the current perspective on the impact of psychological problems in chronic prostatitis syndromes and we discuss the implications thereof from a clinical perspective. materials and methods: a database and a manual search were conducted in the medline database of the national library of medicine, embase, and other libraries using the key words “prostatitis syndromes”, “chronic bacterial prostatitis”, “chronic pelvic pain”, in various combinations with the terms “psychological issues”, “depression” “anxiety”, “stress”, “unhappiness”, “cognitive status” and “personality”. two independent reviewers performed data extraction. we included clinical studies with available information on chronic prostatitis and related psychological conditions. we considered full-text written papers. we excluded reviews and case reports. in order to reduce the risk of bias we analyzed only studies including patients with confirmed cbp or cp/cpps. bibliographic information in the selected publications was checked for relevant records not included in the initial search. results: database search allowed us to retrieve 638 studies to which we added to 16 additional studies retrieved by handsearching. after screening, 34 relevant papers were identified for thorough review. most studies included patients with chronic pelvic pain and prostatitis-like symptoms, whereas a smaller number of studies included patients with methodologically confirmed cp/cpps including studies with a microbiologically confirmed diagnosis of cbp. the psychosocial factors examined in the selected studies include pain, catastrophizing, stress, personality factors and social aspects. comorbid psychiatric disorders evidenced in the studies included depression, anxiety and trauma-related disorders, somatization disorders, and substance abuse. some studies investigated the association of pain with each individual psychological disturbance, while others examined the impact of pain in association with the overall quality of life. sample size, study design and diagnostic measures varied among studies. conclusions: despite limitations and variations in sample size, study design and diagnostic measures in all included studies, a relation between chronic prostatitis and psychological problems chronic prostatitis and related psychological problems. which came first: the chicken or the egg? a systematic review konstantinos stamatiou 1, margherita trinchieri 2, martina trinchieri 3, gianpaolo perletti 4, vittorio magri 5 1 department of urology, tzaneio hospital, pireus, greece; 2 psichiatry unit, asst rhodense, g. salvini hospital, garbagnate, milano, italy; 3 società italiana di psicoanalisi della relazione sipre, milano, italy; 4 department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy; 5 urology unit, asst fatebenefratelli sacco, milano, italy. doi: 10.4081/aiua.2023.11300 summary is a consistent finding. the existing evidence does not permit to definitely conclude whether psychological problems are a risk factor for cp/cpps or whether they represent an array of symptoms that are associated with the exacerbation of this disease. key words: prostatitis syndromes; chronic bacterial prostatitis; chronic pelvic pain; psychological issues: depression; anxiety; stress; unhappiness; cognitive status; personality. submitted 21 january 2023; accepted 25 february 2023 archivio italiano di urologia e andrologia 2023; 95, 1 k. stamatiou, m. trinchieri, m. trinchieri, g. perletti, v. magri materials and methods a database and a manual search were conducted in the medline database of the national library of medicine, embase, and other libraries using the key words “prostatitis syndromes”, “chronic bacterial prostatitis”, “chronic pelvic pain”, “males” in various combinations with the terms “psychological issues”, “depression” “anxiety”, “stress”, “unhappiness”, “cognitive status”, “personality”. two independent reviewers performed data extraction by using identical extraction tables. the search was carried out in accordance with preferred reporting items for systematic reviews and meta-analyses (prisma) methodology (4) and were extended from first records up to 15th december 2022. titles were screened and any duplicates removed before abstracts and finally full-text articles were assessed for relevance (figure 1). reference lists were also checked. relevant studies were evaluated by all authors and included in the narrative data synthesis. we included clinical studies with available information on chronic prostatitis and related psychological problems. we considered full-text written papers. we excluded reviews and case reports. in order to reduce the risk of bias we analyzed only studies including patients with confirmed cbp or cp/cpps. bibliographic information in the selected publications was checked for relevant records not included in the initial search. the methodological quality of included studies was assessed independently by 2 authors. case-control and cohort were evaluated using the newcastle-ottawa scale (nos) as bias assessment tool (5). results the initial search of the databases retrieved 668 studies. title/abstract screening led to select 60 papers after exclusion of 618 papers that were judged as not directly relevant to the research question. out of these 60 papers, 19 duplicates were removed. sixteen additional studies were retrieved by handsearching. review of the abstracts led to exclusion of 23 papers due to several reasons (review papers, papers reporting the same series described in other selected papers, congress reports/abstracts with limited information). finally, 34 relevant papers were identified for systematic review (6-39). specifically, 15 records reported case series, 13 were casecontrol studies and 6 were cross-sectional cohort studies. according to the quality assessment of newcastle-ottawa scale, 11 studies out 19 were characterized by high quality with scores ranging between 7 and 9 (supplementary materials). data synthesis most studies included patients with chronic pelvic pain and prostatitis-like symptoms, whereas a smaller number of studies included patients with methodologically confirmed cp/cpps including studies with a microbiologically confirmed diagnosis of cbp. the psychosocial factors examined in the selected studies include pain, catastrophizing, stress, personality factors and social aspects. comorbid psychiatric disorders evidenced in the studies included depression, anxiety and trauma-related disorders, somatization disorders, and substance abuse. some studies investigated the association of pain with each individual psychological disturbance, while others examined the impact of pain in association with the overall quality of life. sample size, study design and diagnostic measures varied among studies. several studies showed that this disease has a significant negative impact on mental and physical quality of life domains (6-9). men with cp/cpps have significantly more disturbances in their psychological profile compared to both healthy control patients (10-12) and patients with chronic pain of different etiology (13). in cp/cpps patients, pain has an impact in different domains of life (viz., sexual relationships) compared with patients with chronic pain of different etiology (viz., work and professional activity) (13). aubin and coworkers, compared self-report questionnaires measuring demographic, pain, and sexual function of men with cp/cpps with those of men without any pain condition. according to their findings, patients affected by cp/cpps differed from controls in the domains of sexual desire, frequency of sexual intercourse, and in the quality of erectile and orgasm functions (14). erectile dysfunction and decreased libido were reported by 43% and 24% of men with cp/cpps, respectively (15). one key difference between the populations investigated was the presence of depression and anxiety. smith et al. compared (a) the sexual and relationship functioning of 38 male patients with cp/cpps with those of their female partners, and (b) the sexual and relationship functioning of both cp/cpps men and their partners with the same items assessed in 37 control couples. compared to control males, men with cp/cpps reported significantly more sexual dysfunction and symptoms of depression. furthermore, the symptoms of depression mediated the relationship between some aspects of sexual function and male participant status as a patient or control (16). therefore, in cp/cpps subjects, the frequency of sexual activity decreased with increasing depression, the orgasm function decreased with increasing depression, and the quality of erectile function decreased with increasing pain symptoms. in addition, overall sexual satisfaction decreased with increasing pain symptoms (14). thus, from these data it appears that the psychological profile of patients can deteriorate in function of the kind and severity of symptoms of cp/cpps. the severity of erectile dysfunction also correlates significantly with anxiety. moreover, both depression and anxiety are closely correlated with chronic pain and urinary symptoms and contribute to the recurrence, refractoriness, and outcome of the disease (17, 18). the incidences of depression and anxiety in patients with cp/cpps are estimated to be approximately 20-50% and 40-60%, respectively. besides depression and anxiety, a variety of somatic and psychological conditions were detected among cp/cpps patients, including disturbances of several personality traits, mental distress, psychological stress, somatization, obsessive-compulsive disorder and interpersonal sensitivity (12, 19). a large population-based cross-sectional survey demonstrated a significantly high occurrence of mental distress archivio italiano di urologia e andrologia 2023; 95, 1 chronic prostatitis and related psychological problems and psychological stress related to cp/cpps in finnish men: suicidal thinking and fear of undetected prostate cancer or of having a sexually transmitted disease was reported by 17% of partients (15). psychological stress has a major impact on the sexuality of cp/cpps patients. in fact, the frequency of sexual activity decreased with increasing depression, arousal/erectile function decreased with increasing pain symptoms and orgasm function decreased with increasing depression. moreover, sexual satisfaction decreased with increasing pain symptoms, stress appraisal, and decreasing belief of a relationship between emotions and pain (14). male participants of the mapp study (national institute of diabetes and digestive and kidney diseases of the national institutes of health, usa) had a significant rate of non-urological associated somatic syndrome (31%) associated with longstanding disease, more severe urological symptoms and higher rates of depression and anxiety (20). a chinese study compared the demographics, character, leukocyte counts in eps, disease course, nih chronic prostatitis syndrome index (nih-cpsi), self-rating anxiety scale (sas) and self-rating depression scale (sds) of 291 cp/cpps patients and 100 normal controls, in order to establish the psychological factors related with cp/cpps. all patients were treated with the same protocol and followed-up for 6 weeks. according to this study, the rate of introversion was significantly higher while that of extroversion was significantly lower in the cp/cpps group compared to the control group. univariate and multivariate analyses with cox regression revealed that anxiety, depression and disease course were the definite factors that negatively affected the prognosis of cp/cpps, while other factors such as age, nih-cpsi, character and leukocyte counts in eps had no influence (12). a korean study investigated the association of personality traits with the baseline clinical characteristics and treatment outcomes of patients with cp/cpps. according to this study, although extraversion, agreeableness, and conscientiousness can influence the clinical characteristics of patients with cp/cpps, they do not affect the overall symptoms or the treatment response in those patients. in contrast, neuroticism is associated with a significantly poorer treatment response and with higher levels of depression and somatization (21). a small study conducted in the usa measured the perceived stress, pain intensity, and pain-related disability 1, 3, 6, and 12 months after a health care visit resulting in a new diagnosis of nonbacterial prostatitis/pelvic pain. according to this study, greater perceived stress during the 6 months after the health care visit was associated with greater pain intensity and disability at 12 months (22). another chinese study compared anxiety, depression, erectile function and the scores of the nih-cpsi among refractory cpps patients who had never received any psychotherapy and non-refractory cpps patients. no significant differences were observed in the chronic prostatitis symptom scores between the two groups, while anxiety and depression scores were significantly higher and that on erectile function was significantly lower in the refractory than in the non-refractory cpps patient group (23). a study based on the taiwan longitudinal health insurance database, compared 8,088 subjects with cp/cpps with 24,264 randomly matched controls and found that cp/cpps is consistently and significantly associated with prior anxiety disorder in all age groups. in particular, subjects aged 40-59 years had the highest rates of prior anxiety disorder among cases compared to controls (24). these results reflected those of a previous study which found that men who experienced severe stress were 1.2 and 1.5 times more likely to report prostatitis than those whose lives were relatively stress-free (25). similarly, a cross-sectional study from estonia revealed a familial predisposition to cp/cpps that may be associated also with susceptibility to respiratory tract infections (26). discussion chronic prostatitis is a relatively common male chronic pain condition. it is characterized by recurrent symptomatic episodes, or flare-ups. between flare-ups, some patients are asymptomatic, while others complain of mild symptoms. patients usually have a long history of persistent symptoms. it isn’t clear what causes chronic pain in cp/cpps, and the etiology of this disease is still uncertain. various theories have been hypothesized, such as autoimmunity, persistent inflammatory statuses, neuroinflammation oxidative stress, pathogen and host-specific factors, pelvic floor tension myalgia, and differences in systemic pressure sensitivity (40-42). in addition, there is evidence that cp/cpps patients show alterations of the hypothalamic-pituitary adrenal axis function in response to acute stress (9). moreover, it has been suggested that stress is a potent factor in the development of cp/cpps; for this reason the term “stress prostatitis” was proposed as an appropriate label for this condition (43). currently, psychological factors are considered to play an important role in cp/cpps and the possible association between personality disorders and chronic pelvic pain development has garnered increasing attention. for example, the validated upoint diagnostic-therapeutic algorithm, in its original or modified version (i.e. upoints, including a sexual function domain), acknowledges the importance of psychological factors in cp/cpps and includes a domain specifically focusing on the psychosocial functioning of patients (44, 45). in the upoint/upoints system, items such as a history of clinical depression, ongoing antidepressant therapy, a history of abuse, maladaptive coping mechanisms (for example, catastrophizing), anxiety, or a high score of a depression scale such as hads qualifies a patient as having a positive psychosocial phenotype. stress can have a significant impact on cp/cpps, as it can worsen the symptoms and significantly affect the emotional state of patients by causing extreme overwhelming or distress (36). on the other hand, it was shown that the development of stress in cp/cpps is time-dependent and is associated with subsequent pain and disability (23, 25). the severity of stress has been reported to depend on individual perception or subjective interpretation of causative factors rather than on the contents or frequency of factors causing stress (37). in a such a case, pain and disability are causative factors of stress while stress is a potent factor in the prolongation and perpetuation of the symptoms. in fact, psychological stress can lead to the archivio italiano di urologia e andrologia 2023; 95, 1 k. stamatiou, m. trinchieri, m. trinchieri, g. perletti, v. magri worsening of symptoms, and particularly to pain and discomfort during sexual intercourse, thus making patients more anxious and irritated. in turn, these negative emotions can worsen cp/cpps, thus triggering a vicious circle (14). as a consequence, the quality of life of men with cp/cpps can decrease to levels comparable to patients with severe illnesses (38, 39). existing data suggest that the experience and perception of pain is complex, and is maintained by educational, psychosocial, and behavioral variables (46). for this reason, the rate of introversion is significantly higher than that of extroversion in cp/cpps patients (21), and this evidence may also explain the association of cp/cpps with lower educational levels, poor emotional health and a lack of social support (44). therefore, several patients are more prone to develop persisting diseases, especially in the presence of exaggerated media-reported information, describing chronic prostatitis as a very serious condition. in addition, because of the lack of correct understanding about this disease, many patients can feel anxious and worried, fearing that the sexual function and fertility will be affected by cp/cpps. other patients may fear of having undetected prostate cancer or of having a sexually transmitted disease (15). in certain patients, persistent urinary symptoms may lead to weak masculine identity disorder (47). given that depression and anxiety are closely correlated with chronic pain, urinary symptoms, sexual dysfunction and weak masculine identity (14, 37), it could be assumed that, in addition to stress perception, psychological problems, personality traits, educational and behavioral variables can be considered as factors causing or deteriorating symptoms in patients with cp/cpps. this hypothesis explains the high incidence of anxiety and depression in treatment–resistant chronic bacterial prostatitis (24). given the familial predisposition to cp/cpps, the high incidence of cp/cpps among men who experience severe stress and the fact that cpps is consistently and significantly associated with prior anxiety disorders (24, 26), several researchers suggested cp/cpps patients to be psychologically seriously ill. in fact, studies on quality-of-life outcomes suggest that psychiatric disorders strongly coexist with cp/cpps (48). however, in a study by de la rosette and coworkers, it was shown that differences in scores of personality inventory (nvm), symptom checklist (slc-90), and depression inventory (idd) between cp/cpps patients and controls were not of a great magnitude, and in any case of lesser extent compared with differences in scores from psychiatric patients (10). in addition, fishbain et al. showed that some trait tests and inventories may not be pain state-independent, and therefore may interpret post-pain development personality profiles as being indicative of the true pre-pain personality structure (49). conclusions despite limitations and variations in sample size, study design and diagnostic measures shown by the studies included in this review, the relation between chronic prostatitis and different psychological conditions is a consistent finding. the existing evidence does not permit to definitely conclude whether psychological problems are a risk factor of cp/cpps or whether they represent a complex of symptoms that characterize the exacerbation of this disease. however, it seems logical that patients living with chronic (persistent or long-term) physical conditions such as cbp and cp/cpps are more likely to experience poor mental health, characterized by impaired emotional, psychological, and social well-being. in turn, individuals whose mental well-being is affected are at a higher risk of developing such physical conditions. references 1. stamatiou k, samara e, lacroix rn, et al. one, no one and one hundred thousand: patterns of chronic prostatic inflammation and infection. exp ther med. 2021; 22:966. 2. collins 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syndrome. j urol. 2009; 182:2319. 12. li hc, wang zl, li hl, et al. correlation of the prognosis of chronic prostatitis/chronic pelvic pain syndrome with psychological and other factors: a cox regression analysis. zhonghua nan ke xue. 2008; 14:723-7. 13. egan kj, krieger jn. psychological problems in chronic prostatitis patients with pain. clin j pain. 1994; 10:218-26. 14. aubin s, berger re, heiman jr, ciol ma. the association archivio italiano di urologia e andrologia 2023; 95, 1 chronic prostatitis and related psychological problems between sexual function, pain, and psychological adaptation of men diagnosed with chronic pelvic pain syndrome type iii. j sex med. 2008; 5:657-67. 15. mehik a, hellström p, sarpola a, et al. fears, sexual disturbances and personality features in men with prostatitis: a populationbased cross-sectional study in finland. bju int. 2001; 88:35-8. 16. smith kb, pukall cf, tripp da, nickel jc. sexual and relationship functioning in men with chronic prostatitis/chronic pelvic pain syndrome and their partners. arch sex behav. 2007; 36:301-11. 17. wu lx, liang cz, hao zy, et al. epidemiological study of chronic prostatitis patients with depression symptoms. zhonghua nan ke xue. 2006; 12:583. 18. ku jh, jeon ys, kim me, et al. psychological problems in young men with chronic prostatitis-like symptoms. scand j urol nephrol. 2002; 36:296-301. 19. mo mq, long ll, xie wl, et al. sexual dysfunctions and psychological disorders associated with type iiia chronic prostatitis: a clinical survey in china. int urol nephrol. 2014; 46:2255-61. 20. krieger jn, stephens aj, landis jr, et al. mapp research network. relationship between chronic nonurological associated somatic syndromes and symptom severity in urological chronic pelvic pain syndromes: baseline evaluation of the mapp study. j urol. 2015; 193:1254. 21. koh js, ko hj, wang sm, et al. the association of personality trait on treatment outcomes in patients with chronic prostatitis/chronic pelvic pain syndrome: an exploratory study. j psychosom res. 2014; 76:127-33. 22. ullrich pm, turner ja, ciol m, berger r. stress is associated with subsequent pain and disability among men with nonbacterial prostatitis/pelvic pain. ann behav med. 2005; 30:112-8. 23. zeng hq, zhang ch, lu gc. psychological factors and erectile function in men with refractory chronic prostatitis. zhonghua nan ke xue. 2008; 14:728-30. 24. chung sd, lin hc. association between chronic prostatitis/chronic pelvic pain syndrome and anxiety disorder: a population-based study. plos one. 2013; 8:e64630. 25. collins mm, meigs jb, barry mj, et al. prevalence and correlates of prostatitis in the health professionals follow-up study cohort. j urol. 2002; 167:1363-66. 26. mändar r, korrovits p, rahu k, et al. dramatically deteriorated quality of life in men with prostatitis-like symptoms. andrology. 2020; 8:101-109. 27. gao j, zhang x. a cross-sectional study of symptoms, sexual dysfunction and psychological burden in chinese men with chronic prostatitis/chronic pelvic pain syndrome. bju international. 2019; 123:4. 28. clemens jq, brown so, calhoun ea. mental health diagnoses in patients with interstitial cystitis/painful bladder syndrome and chronic prostatitis/chronic pelvic pain syndrome: a case/control study. j urol. 2008; 180:1378-82. 29. tripp da, nickel jc, shoskes d, koljuskov a. a 2-year followup of quality of life, pain, and psychosocial factors in patients with chronic prostatitis/chronic pelvic pain syndrome and their spouses. world j urol. 2013; 31:733-9. 30. zhang gx, bai wj, xu t, wang xf. a preliminary evaluation of the psychometric profiles in chinese men with chronic prostatitis/chronic pelvic pain syndrome. chin med j (engl). 2011; 124:514-8. 31. drannik gn, gorpynchenko ii, nurimanov k, et al. relationships among depression and levels of cytokines and testosterone in patients with chronic abacterial prostatitis. journal of allergy and clinical immunology 2017; 139:ab209. 32. naliboff bd, stephens aj, lai hh, et al. mapp research network. clinical and psychosocial predictors of urological chronic pelvic pain symptom change in 1 year: a prospective study from the mapp research network. j urol. 2017; 198:848-857. 33. rodríguez lv, stephens aj, clemens jq, et al. mapp research network. symptom duration in patients with urologic chronic pelvic pain syndrome is not associated with pain severity, nonurologic syndromes and mental health symptoms: a multidisciplinary approach to the study of chronic pelvic pain network study. urology. 2019; 124:14-22. 34. tripp da, nickel jc, wang y, et al. national institutes of health-chronic prostatitis collaborative research network (nihcpcrn) study group. catastrophizing and pain-contingent rest predict patient adjustment in men with chronic prostatitis/chronic pelvic pain syndrome. j pain. 2006; 7:697-708. 35. wang x, cui s, gong zy, et al. the effects of chronic prostatitis/chronic pelvic pain syndromes on mental and sexual function. chinese journal of andrology 2013; 27:41-44. 36. wallner lp, clemens jq, sarma av. prevalence of and risk factors for prostatitis in african american men: the flint men’s health study. prostate. 2009; 69:24-32. 37. ahn sg, kim sh, chung ki, et al. depression, anxiety, stress perception, and coping strategies in korean military patients with chronic prostatitis/chronic pelvic pain syndrome. korean j urol. 2012; 53:643-648. 38. mcnaughton collins m, pontari ma, o'leary mp, et al. chronic prostatitis collaborative research network. quality of life is impaired in men with chronic prostatitis: the chronic prostatitis collaborative research network. j gen intern med. 2001; 16:65662. 39. wenninger k, heiman jr, rothman i, et al. sickness impact of chronic nonbacterial prostatitis and its correlates. j urol. 1996; 155:965-8. 40. rudick cn, berry re, johnson jr, et al. uropathogenic escherichia coli induces chronic pelvic pain. infect immun 2011; 79:628-35. 41. davis sn, maykut ca, binik ym, et al. tenderness as measured by pressure pain thresholds extends beyond the pelvis in chronic pelvic pain syndrome in men. j sex med 2011; 8:232-9. 42. paulis g. inflammatory mechanisms and oxidative stress in prostatitis: the possible role of antioxidant therapy. res rep urol. 2018; 10:75-87. 43. miller hc. stress prostatitis. urology 1988; 32:507-510. 44. magri v, wagenlehner f, perletti g, et al. use of the upoint chronic prostatitis/chronic pelvic pain syndrome classification in european patient cohorts: sexual function domain improves correlations. j urol. 2010; 184:2339-2345. 45. shoskes da, nickel jc, rackley rr, pontari ma. clinical phenotyping in chronic prostatitis/chronic pelvic pain syndrome and interstitial cystitis: a management strategy for urologic chronic pelvic pain syndromes. prostate cancer prostatic dis. 2009; 12:177-183. 46. lian f, shah a, mueller b, welliver c. psychological perspectives in the patient with chronic orchialgia. review transl androl urol. 2017; 6(suppl 1):s14-s19. archivio italiano di urologia e andrologia 2023; 95, 1 k. stamatiou, m. trinchieri, m. trinchieri, g. perletti, v. magri 47. dunphy c, laor l, te a, et al. relationship between depression and lower urinary tract symptoms secondary to benign prostatic hyperplasia. rev urol. 2015; 17:51-7. 48. ku jh, kim sw, paick js. quality of life and psychological factors in chronic prostatitis/chronic pelvic pain syndrome. urology. 2005; 66:693-701. 49. fishbain da, cole b, cutler rb, et al. chronic pain and the measurement of personality: do states influence traits? pain med. 2006; 7:509-29. correspondence konstantinos stamatiou, md stamatiouk@gmail.com department of urology, tzaneio hospital 2 salepoula str., 18536 piraeus, greece margherita trinchieri, md margherita.trinchieri@gmail.com psichiatry unit, asst rhodense, g. salvini hospital, garbagnate, milano, italy martina trinchieri, md martinatrinchieri90@gmail.com società italiana di psicoanalisi della relazione sipre, milano, italy gianpaolo perletti, dr. biol. sci. m. clin. pharmacol. gianpaolo.perletti@uninsubria.it department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy vittorio magri, md vittorio.magri@asst-fbf-sacco.it urology unit, asst fatebenefratelli sacco, milano, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso introduction the bacterial adhesiveness to the bladder walls is important virulence factor in the pathogenesis of urinary tract infections. the development of a biofilm that prevents bacterial adhesion plays an important role in prophylaxis of recurrent urinary tract infections (utir). aim of this study is to evaluate the efficacy of a phytotherapic which includes solidago, orthosiphon and birch extract (cistimev®) in association with the antibiotic prophylaxis in female patients affected by (utir) materials and methods all the female patients affected by utir who referred to our urogynaecological unit between september 2010 and 197archivio italiano di urologia e andrologia 2013; 85, 4 original paper role of phytotherapy associated with antibiotic prophylaxis in female patients with recurrent urinary tract infections emanuela frumenzio, daniele maglia, eleonora salvini, silvia giovannozzi, manuel di biase, vittorio bini, elisabetta costantini clinica urologica e andrologica di perugia, università degli studi di perugia, italy objective: aim of this study is to evaluate the efficacy of a phytotherapic which includes solidago, orthosiphon and birch extract (cistimev®) in association with antibiotic prophylaxis in female patients affected by recurrent urinary tract infections (utir). materials and methods: patients affected by utir older than 18 years started a 3-months antibiotic prophylaxis (prulifloxacin 600 mg, 1 cps/week or phosphomicyn 1 cachet/week) according to antibiogram after urine culture. the patients were divided in 2 groups: group a: antibiotic prophylaxis plus phytotherapy (1 cps/die for 3 months) and group b: antibiotic prophylaxis alone. results: 164 consecutive patients were studied: 107 were included in group a (mean age 59 ± 17.3 years) and 57 (mean age 61 ± 15.7) in group b. during the treatment period the relapse frequencies between the two groups were not significantly different (p = 0.854): 12/107 (11.21%) patients interrupted the treatment for utir in group a and 6/57 (10.52%) in group b. in the long term follow-up the relapse uti risk was significant different in the two groups with a relapse risk 2.5 greater in group b than in group a (p < 0.0001). conclusion: our study demonstrated that in female patients affected by recurrent uti, the association between antibiotic prophylaxis and of a phytotherapic which includes solidago, orthosiphon and birch extract reduced the number of uti in the 12 months following the end of prophylaxis and obtained a longer relapsing time, greatly improving the quality of life of the patients. key words: recurrent urinary infection; phytotherapy; antibiotc prophylaxis. submitted 28 february 2013; accepted 30 april 2013 no conflict of interest declared summary january 2012 were included in a retrospective study comparing antibiotic prophylaxis alone or combined with solidago, birch e ortosiphon (cistimev®). utir was defined as at least three episodes of uncomplicated infection documented by urine culture (eau guidelines) (1). paatients affected by utir older than 18 years started a 3-months antibiotic prophylaxis (prulifloxacin 600 mg, 1 cps/week or phosphomicyn 1 cachet /week) according to antibiogram after urine culture. the patients were divided in 2 groups: group a: antibiotic prophylaxis plus phytotherapy (1 cps/die for 3 months) and group b: antibiotic prophylaxis alone. exclusion criteria were patients with less than three doi: 10.4081/aiua.2013.4.197 archivio italiano di urologia e andrologia 2013; 85, 4 e. frumenzio, d. maglia, e. salvini, s. giovannozzi, m. di biase, v. bini, e. costantini 198 uncomplicated utis in the previous year; significant (> 50 ml) residual urine; pregnancy; intolerance or allergy to drug compounds, pelvic organ prolapse more than stage ii (pop-q quantification). all patients were assessed by history, clinical examination, urine culture, uroflowmetry parameters and postvoid residual volume evaluation. the patients in both groups were followed-up with urine analysis and urine culture during the treatment every month and after the end of therapy at 3, 6 and 12 months. primary outcome was the efficacy in preventing infection recurrences during the treatments and the evaluation of uti relapse risk in the year after the end of therapy in both groups. statistical analysis: chi2 test was used for comparisons of categorical variables; kaplan-meier estimation with logrank test was applied to compare the relapse-free survival time in both groups. results 164 consecutive patients were studied: 107 were included in group a (mean age 59 ± 17.3 years) and 57 (mean age 61 ± 15.7) in group b. both groups were equivalent: there were no statistically significant difference, as regards the type of antibiotic chosen (prulifloxacin or phospho micyn), menopausal status, sexual activity, urinary incontinence and residual urine (table 1). no patients reported side effects in both groups. during the treatment the relapse frequencies between the two groups were not significantly different (p = 0.854): 12/107 (11.21%) patients interrupted the treatment for utir in group a and 6/57 (10.52%) in group b. in the long term follow-up the relapse uti risk was significant different in the two groups with a relapse risk 2.5 greater in group b than in group a (p < 0.0001). the survival curves (figure 1) demonstrated that 25% of patients that underwent the antibiotic prophylaxis plus phytotherapy had no recurrence at 1 year, while all the patients in group b had at least one recurrence within 1 year. it is also evident that the time to recurrence is always longer in group a, in fact the mean survival time was 10.4 months in group a and 3.6 months in group b (log-rank test p < 0.0001) discussion a major problem today in public health economy is the increase in multi-resistant micro-organisms in patients with recurrent cystitis. new therapeutic and behavioural strategies are needed to prevent recurrences. using drugs based on natural substances which are free of side effects may have a place in the armentarium for these very hard to treat patients. figure 1. kaplan-meier survival analysis. table 1. group a group b p antibiotic prophylaxis 55/107(51.4%) pts 52/107(48.6%) pts 29/57(50.9%) pts 28/57 (49.1%) pts prulifloxacin phosphomicyn prulifloxacin phosphomicyn < 0.540 sexual activity 62/107(57.9%) pts 45(42.1%) pts 30/57 (52.6%) pts 27/57 (47.4%) pts sexual activity no sexual activity sexual activity no sexual activity <0.312 menopause 72/107(67.3%) pts 35/107 (32.7%) pts 44/57(77.2%) pts 13/57 (22.8%) pts menopause no menopause menopause no menopause < 0.125 incontinence 56/107(52.3%) pts 51/107 (47.7%) pts 36/57 (63.2%) pts 21/57 (36.8%) pts incontinence no incontinence incontinence no incontinence < 0.122 survival plot (pl estimates) antibiotic prophylaxis has been reported to prevent recurrent episodes for as long as it is continued, with uti usually recurring as soon as it is suspended (2). when antibiotics are combined with drugs that inhibit bacterial adhesion it appears that the dose can be reduced and recurrences are not as frequent. the present study demonstrates that long-term results are better with a drop in the number of recurrences after prophylaxis was suspended. conclusions our study demonstrated that in female patients affected by recurrent uti, the association between antibiotic prophylaxis and cistimev® reduced the number of uti in the 12 months following the end of prophylaxis and obtained a longer relapsing time, greatly improving the quality of life of the patients. references 1. naber kg, bergman b, bishop mc, at all. eau guidelines for the management of urinary and male genital tract infections. urinary tract infection (uti) working group of the health care office (hco) of the european association of urology (eau); urinary tract infection (uti) working group of the health care office (hco) of the european association of urology (eau). eur urol. 2001; 40:576-88. 2. costantini e, salvini e, lazzeri m, et al. prulifloxacin vs phosphomycin: prophylaxis in patients with recurrent uti. preliminary results of a randomized multi-centre study. eur urol 2011; (suppl 10):480. 199archivio italiano di urologia e andrologia 2013; 85, 4 role of phytotherapy associated with antibiotic prophylaxis in female patients with recurrent urinary tract infections correspondence emanuela frumenzio, md (corresponding author) emanuela.frumenzio@virgilio.it daniele maglia, md eleonora salvini, md silvia giovannozzi, md manuel di biase, md vittorio bini, md elisabetta costantini, md clinica urologica e andrologica di perugia, università degli studi di perugia, perugia, italy stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 61 original paper inflammatory features common to two pathologies: pd and cp in both diseases, there is a chronic inflammatory process in which pro-inflammatory cytokines and oxygen and nitrogen reactive species (ros/rns) play an important role (6-10). furthermore, there are studies in the literature that have confirmed the therapeutic efficacy of the use of antioxidant substances in both diseases (10-15). we also know that pro-inflammatory cytokines, tumor necrosis factor (tnf), and interleukin 1 and 6 (il-1 and il-6) are present at high levels in the inflammatory process of pd and chronic prostatitis (cp) (6, 7). in both diseases, as well as in other chronic inflammatory diseases, the circulating levels of cytokines are increased; therefore, these can act systemically in other organs, including the nervous system (16-19). it has been ascertained that pro-inflammatory cytokines can determine various effects at this level and particularly by reducing serotonin levels. this mechanism, as is known, is also strongly involved in the development of depression. pro-inflammatory cytokines are also capable of causing an additional pro-depression effect as they cause changes in glucocorticoid function via the hypothalamicpituitary-adrenal axis (20). cytokines are also capable of having effects on the amygdala and hippocampus, which are areas widely involved in stress and anxiety (21, 22). thanks to this knowledge from the literature, we can better understand the causes of anxious-depressive symptoms in patients with pd and cp. pro-inflammatory cytokines are also involved in neurogenic inflammation causing pelvic pain in patients with prostatitis/chronic pelvic pain syndrome (cpps) (22). pelvic pain in cp is therefore the consequence of neurogenic inflammation in the nervous system (central and peripheral). an important signaling molecule implicated in neurogenic inflammation is nerve growth factor neurotrophin (ngf). neurotrophins are proteins that determine the survival, development, and function of neurons. ngf is a signaling molecule that is produced in the case of neuronal suffering, which in our case is caused by inflammation. ngf appears to be induced by il-10, a cytokine that possesses anti-inflammatory activity by inhibiting the synthesis of pro-inflammatory cytokines (23-25). several studies have demonstrated that ngf together with some cytokines (il-6 and il-10) that regulate inflammaobjective: this study aims to investigate a possible relationship between chronic prostatitis (cp) and peyronie's disease (pd) and to characterize the psychological profile of patients suffering from pd, with or without concomitant cp. methods: we included 539 patients with pd, of which 200 were found to have underlying cp. as a comparator population, we selected 2201 patients without pd, referring to our tertiary care clinic. in this population, we detected 384 subjects with cp. all 539 pd patients underwent photographic documentation of the penile deformation, and dynamic penile eco-color doppler with plaque and volume measurements and answered the following questionnaires: the generalized anxiety disorder-7, the patient health questionnaire-9, the visual analog scale for penile pain measurements, the international index of erectile function (iief), and the nih-chronic prostatitis symptom index. results: the overall prevalence of chronic prostatitis in pd patients was 37.1% compared to a prevalence of 17.4% in the non-pd control population (or = 2.79 and p < 0.0001). the severity of cp symptom total scores (nih-cpsi) correlated significantly with the severity of erectile dysfunction (p < 0.0001). significant anxiety was present in 89.2% of pd patients and it is more prevalent in pd patients with cp than in pd patients without cp (93.0% vs. 87.0%, respectively; p = 0.0434). significant depression was detected in 57.1% of pd patients and it is more prevalent in pd patients with cp than in pd patients without cp (64.0% vs. 53.09%, respectively; p = 0.0173). conclusion: chronic prostatitis (cp) and peyronie's disease (pd) are frequently associated. our results demonstrate the strong impact of chronic prostatitis on the mental status of pd patients. anxiety and depression were significantly more pronounced in pd patients with cp than in pd patients without cp. key words: chronic prostatitis; peyronie’s disease; risk factors. submitted 12 april 2023; accepted 11 may 2023 introduction prostatitis is a pathological condition that is often observed in patients with peyronie's disease (pd). this clinical association is often present in specialist outpatient practice and is also described in the literature (15). with this study, we set out to ascertain whether there are common factors between the two pathologies that could justify this relationship. chronic prostatitis as possible risk factor for peyronie's disease: psychological, sexual and prostatitis-like symptoms in patients with pd gianni paulis 1, andrea paulis 2 1 peyronie’s care center, department of uro-andrology, castelfidardo clinical analysis center, rome, italy; 2 neurosystem center for applied psychology and neuroscience, janet clinical centre, rome, italy. doi: 10.4081/aiua.2023.11406 summary archivio italiano di urologia e andrologia 2023; 95, 2 g. paulis, a. paulis 62 tion can play a role in the pain of patients with cpps; furthermore, ngf directly correlates with pain severity (2325). we also know that il-10 is a known inducer of ngf and a suppressor of il-6 and il-8 expression (23, 25). the association of increased levels of ngf in other inflammatory states (inflammatory bowel disease and arthritis) has also been demonstrated (25). although no studies exist in the literature, it is likely that ngf also plays a role in pd and associated erectile dysfunction, since some studies demonstrate a protective role of this neurotrophin on erectile function (26-28). kalisch et al., in one of their studies, demonstrated that the ngf neurotrophin increases nos activity expression (in all three of its isoforms: nnos, enos, and inos) and nitric oxide (no) production, the principal mediator of penile erection (29). in an experimental study on diabetic rats, the induction of igc (anti-ngf) was detected with related erectile dysfunction caused by a decrease in the tissue level of ngf (neutralizing effect of anti-ngf) (26). it is in fact known that in patients with diabetes mellitus, the incidence of erectile dysfunction is significantly higher than in the general male population. in another experimental study on diabetic rats with erectile dysfunction, the presence of high concentrations of ngf was found in the penis, and the authors hypothesized that the significant presence of ngf, in the presence of erectile nerves that are severely damaged by diabetes, would not be sufficient to compensate for the reproductive needs of nerve fibers (27). another study found elevated concentrations of ngf in urine in patients with type 2 diabetes mellitus and associated erectile dysfunction (28). considering that several pro-inflammatory biological factors and other signaling molecules are present in cp, it may be hypothesized that cp could represent a risk factor for pd. the present study aimed at studying the relationship between a history of cp and pd. the psychological impact of pd, in the presence or absence of concomitant cp, was also investigated in depth. psychological consequences of pd and cp the penile deformation present in patients with pd inevitably determines a significant impact on the psychic sphere of these patients, their quality of life (qol), and their psycho-social relationships. in fact, these patients show depressive symptoms in about 48% of cases (30). in these patients, bowing can frequently lead to a loss of personal body image, lower self-esteem, and a lower ability to achieve satisfactory sexual intercourse; furthermore, sexual performance anxiety with secondary psychogenic erectile dysfunction is often present (31). other possible consequences are as follows: the tendency to lose confidence in their sexual abilities; decreased sex drive or even sexual aversion; concern about further sexual trauma; and curtailing or canceling appointments with prospective sexual partners (32-34). although there is no specific incidence of anxiety symptoms in pd in the literature, some studies report the presence of "emotional difficulties" and "distress" in about 80-81% of cases (34, 35). in our recent study, we found that moderate-to-severe anxiety was present in 89.4% of pd patients (36). chronic prostatitis such as pd is characterized by a strong component of frustration with related anxious-depressive symptoms (21). depression and catastrophizing about pain are often present; in this regard, some authors believe that depression and catastrophism represent a strong factor in the development, prolongation, and perpetuation of prostatic symptoms and, particularly, chronic pelvic pain (37, 38). patients who have more pain tend to amplify it and have more catastrophic thoughts, resulting in a poorer physical qol and a tendency towards depression (39). in their recent study, bai et al. found a higher incidence of depression, anxiety, somatization disorder, and obsessive-compulsive behavior in patients with ed associated with cp/cpps (40). the literature is quite scarce regarding the incidence of anxiety and depression in patients with cp/cpss; however, in the few studies analyzed, the incidence of anxiety symptoms in patients with cp/cpps was found in about 60-90% of cases (41, 42), while with respect to the incidence of depressive symptoms, these were found to be present in approximately 27-90% of cases in patients with cp/cpps (42-44). this study aims to investigate a possible relationship between cp and pd and to characterize the psychological profile of patients suffering from pd, with or without concomitant cp. in the supplementary materials we published an "addendum"" as a deeper insight into the two diseases cp and pd. patients and methods study design we performed a retrospective analysis of the clinical database of a single andrology clinic. from the database, we considered two separate cohorts of patients observed between january 2013 and january 2023. in this study, one cohort included 539 patients diagnosed with pd. as a comparator population, we considered a cohort of 2201 urological patients referred to our clinic for any disease but not pd. among our cohorts of patients, we identified patients with a diagnosis of long-standing cp (cp, category ii chronic bacterial prostatitis or category iii chronic prostatitis/chronic pelvic pain syndrome, nih criteria). all data were obtained from patient records. this retrospective observational study was conducted in compliance with the principles contained in the declaration of helsinki ; all study subjects were contacted and provided informed consent for the study. sensitive data were anonymized to warrant patients’ privacy according to legislative decree 10 august 2018, n. 101, published in the official gazette of the italian republic, general series, issue 205, 09/04/2018. inclusion criteria the inclusion criteria for both groups were as follows: age between 18 and 75 years and availability of data that report the results of thorough clinical history examination (comprising all diseases, including prostatitis). the diagnosis of pd was made as follows: performing penile palpation for all pd patients and by a (i) photoarchivio italiano di urologia e andrologia 2023; 95, 2 63 chronic prostatitis as possible risk factor for peyronie's disease graphic documentation of the penile deformation (according to kelâmi) with a goniometric measurement of the angulation and evaluation with respect to the possible presence of the multiplanarity of the curvature (29) and a (ii) dynamic penile eco-color doppler ultrasound with plaque measurements and volume calculation (in the three dimensions) using an ellipsoid formula (volume = 0.524 x width x length x thickness) (45, 46). exclusion criteria the exclusion criteria were as follows: – for both groups, pd patients and non-pd patients an age under 18 years and over 75 years; – for the comparison control cohort (2201 non-pd patients) a diagnosis of pd, without excluding all other associated diseases including a possible erectile dysfunction. clinical data patients with pd were asked to complete of the following questionnaires: (i) the visual analog scale (vas) for penile pain measurement, (ii) the international index of erectile function (iief), (iii) the nih-chronic prostatitis symptom index (nih-cpsi), (iv) the generalized anxiety disorder-7 (gad-7, focusing on anxiety), and (v) the patient health questionnaire-9 (phq-9, focusing on depression) (4751). the vas score range varies from 0 (no pain) to 10 (most intolerable pain) (48). the iief score interpretation is as follows: severe ed = from 0 to 10; moderate ed = from 11 to 16; mild-tomoderate ed = from 17 to 21; mild ed = from 22 to 25; no ed, from 26 to 30 (49). the gad-7 score interpretation is as follows: minimal anxiety = 0-4; mild anxiety = 5-9; moderate anxiety = 1014; and severe anxiety = 15-21 (50). we considered the presence of significant anxiety when gad-7 score > 9. the phq-9 score interpretation is as follows: minimal depression = 0-4; mild depression = 5-9; moderate depression = 10-14; moderately severe depression = 1519; and severe depression = 20-27 (51). we considered significant depression when phq-9 score > 9. nih-cpsi is assessed in 3 domains with the following severity levels: pain (from 0 to 21), urinary symptoms (from 0 to 10), and impact on qol (from 0 to 12) (47). chronic prostatitis was diagnosed in patients with prostatitis-like symptoms according to the following examinations: clinical history, thorough physical examination, including the digital rectal exam, prostate ultrasound, and microbiological assessment (preand post-massage urine and sperm cultures). study endpoints the primary endpoint of the study was the association between a diagnosis of cp and the occurrence of pd in a patient population referring to a single tertiary care andrology center. the secondary endpoints are as follows: – the impact of prostatitis on the psychological status of patients and, particularly, on anxiety, which was assessed with the gad-7 test, and depression which was assessed with the phq-9 test; – the impact of prostatitis on the presence and severity of erectile dysfunction; – the impact of prostatitis on the presence and severity of penile pain; – the impact of prostatitis on the severity of penile curvature; – the impact of prostatitis on the pd plaque volume; – the impact of prostatitis on the multiplanarity of penile curvature; – the impact of prostatitis on plaque multifocality; – the impact of prostatitis on plaque calcification. statistical analysis the central tendency and dispersion data for continuous or interval variables were expressed as means and standard deviations (sds) or medians and interquartile ranges (iqrs), respectively. intergroup unpaired comparisons for continuous or interval variables were performed using a 2-tailed t-test (heteroscedastic) or a 2-tailed mann–whitney–wilcoxon (rank-sum) test, respectively. differences between proportions in unpaired groups were analyzed by both a z-test and pearson’s chi-square test. correlations between questionnaire scores were analyzed by non-parametric tests (spearman’s rho and kendall’s tau). analyses were performed in the “r” environment for statistical computing. we planned a post hoc analysis of the statistical power achieved for the crude odds ratio calculation using the g*power 3.1 software (52). a 5% threshold for the alpha error was used to define statistical significance (significant p-value < 0.05). results a table (supplementary materials) summarizes the clinical characteristics of the two groups (pd patients and non-pd control population) and the relative statistical study. cases and controls did not differ in age, and most associated pathologies. however, for some associated diseases such as diabetes mellitus, erectile dysfunction, hypertension, benign prostatic hyperplasia (bph), and cp, there was a statistically significant difference between the two groups. prevalence of cp in pd patients from our general patient database, we extracted a cohort of 539 pd patients, with a mean age of 49.68 years (± 12.16 sd), that met our inclusion criteria. within this cohort, 200 patients (37.1%) were diagnosed with cp. the median total score of the nih-cpsi test in this cohort was 9 (iqr = 10). the cohort of urological patients without pd meeting our inclusion criteria consisted of 2201 subjects, with a mean age of 50.53 years (± 12.04 sd), of which 384 (17.4%) were diagnosed with cp. the statistical comparison between the mean age of the two patient cohorts (unpaired t test) was not significant (p value = 0.1088). the difference between the proportions of cp patients in the two cohorts is statistically significant (p < 0.0002, two-tailed z-test: p < 0.0001 and two-tailed chi-square test; chi-square = 98.6). we generated a contingency archivio italiano di urologia e andrologia 2023; 95, 2 g. paulis, a. paulis 64 table comparing the presence/absence of a history of prostatitis in patients diagnosed or not with pd. the resulting significant crude odds ratio (or) for prostatitis was 2.79 (95% ci, 2.27 to 3.43, p < 0.0001) (see table 1). the post hoc analysis showed an achieved power equal to 0.99 for the magnitude of effect (odds ratio) and 95% ci. assessment of prostatitis symptoms (nih-cpsi test) in pd patients with or without pc median nih-cpsi scores were significantly higher in pd patients with cp (n = 200) (median nih-cpsi = 9, iqr = 10) compared to pd patients without cp (n = 339) (median nih-cpsi = 2, iqr=2; p = < 0.0001, two-tailed mann-whitney-wilcoxon test). psychological profiling of pd patients with or without cp all included pd patients completed the generalized anxiety disorder-7 questionnaire. median anxiety scores of gad-7 in patients with or without cp were identical and not significantly different at the statistical level (cp = 14, iqr = 7; no-cp = 14, iqr = 7, p = 0.21, two-tailed mann-whitney-wilcoxon test). however, the severity of total cp symptom scores assessed with the nih-cpsi test correlated positively and significantly with gad-7 anxiety scores (spearman’s rho, 0.21, p = 0.0031; kendall’s tau, 0.163, p = 0.018). phq-9 depression scores were significantly higher in cp patients (median = 14; iqr = 4) compared to patients without cp (median = 12.5; iqr = 4, p = 0.0017, twotailed mann-whitney-wilcoxon test). however, the severity of total cp symptom scores assessed with the nih-cpsi test did not significantly correlate with phq-9 depression scores (spearman’s rho, 0.072, p = 0.309; kendall’s tau, 0.054, p = 0.28). table 2 summarizes data of gad-7, phq-9, nih-cpsi, and iief in pd patients with and without prostatitis. erectile dysfunction in pd patients with or without cp we evaluated the median scores of the iief test in pd patients with erectile dysfunction with or without prostatitis. in these patients, erectile dysfunction developed concomitantly with pd. median iief scores were not significantly different in pd patients with (median iief = 23, iqr = 4.5) or without cp (median iief = 23, iqr = 5; p = 0.98, two-tailed mannwhitney-wilcoxon test). however, the severity of total cp symptom scores assessed with the nih-cpsi test correlated significantly and inversely with iief scores (spearman’s rho, -0.9, p < 0.0001; kendall’s tau, -0.77, p < 0.0001). penile pain assessments in pd patients with or without cp we evaluated the median vas scores in pd patients with penile pain with or without prostatitis. median vas scores were not significantly different in patients with (median vas = 2, iqr = 5) or without cp (median vas = 1, iqr = 4; p = 0.784, two-tailed mannwhitney-wilcoxon test) (see table 2). severity of the penile curve and fibrotic plaque in pd patients with or without cp patients with prostatitis showed a less pronounced penile curve (29 ± 34 degrees) compared with patients without cp (34 ± 21 degrees, p = 0.0066, two-tailed t-test). no significant differences were found between the mean volumes of fibrotic plaques in pd patients with (809.6 ± 563.9 mm^3) or without cp (mean = 908.4 ± 618.6 mm^3; p = 0.063, twotailed t-test). characteristics of pd in patients with or without cp table 3 summarizes the findings relative to plaque calcification and plurifocal lesions and relative to curve complexity (multiplanar curve deformity). no significant differences were found in any of the considered findings between patients with or without cp. psychological profile (anxiety and depression) of pd patients the results showing the psychological profile (anxiety and depression) of pd table 1. prevalence of cp in pd patients compared to the non-pd control population. cohort of patients with non-pd control statistical analysis peyronie's disease (pd) population odds ratio (or) p value chronic prostatitis (cp) 200 384 no chronic prostatitis (cp) 339 1817 total 539 2201 prevalence of cp (%) 37.1 17.4 or = 2.79 p < 0.0001 table 2. summary of data of gad-7, phq-9, nih-cpsi, iief and vas in pd patients with and without chronic prostatitis. questionnaire score pd patients with prostatitis (cp) pd patients without prostatitis (cp) mann-whitney test (n cases = 200) (n cases = 339) median score median score p value nih-cpsi 9 2 < 0.0001 iief 23 23 0.98 gad-7 14 14 0.21 phq-9 14 12.5 0.0017 vas 2 1 0.784 nih-cpsi = national institutes of health chronic prostatitis symptom index is assessed in 3 domains with the following severity levels: pain (from 0 to 21), urinary symptoms (from 0 to 10), and impact on quality of life (qol) (from 0 to 12) (47). iief = international index of erectile function (iief) questionnaire, score range = 0-30. interpretation: severe erectile dyisfunction (ed) = from 0 to 10; moderate ed = from 11 to 16; mild-to-moderate ed = from 17 to 21; mild ed = from 22 to 25; no ed, from 26 to 30 (49). gad-7 = generalized anxiety disorder-7 questionnaire, score range = 0-21. interpretation: 0-4, minimal anxiety; 5-9, mild anxiety; 10-14, moderate anxiety; 15-21, severe anxiety. “significant anxiety” (moderate-to-severe anxiety) when gad-7 score > 9 (50). phq-9 = patient health questionnaire-9, score range = 0-27. interpretation: 1-4, minimal depression; 5-9, mild depression; 10-14, moderate depression; 15-19, moderately severe depression; 20-27, severe depression. “significant depression” (moderate to severe depression) when phq-9 score > 9 (51). vas = visual analog scale questionnaire for pain measurement. score range = 0-10. interpretation: 1-5, mild–moderate pain; 6-7, severe pain; 8-10, very severe pain (48). archivio italiano di urologia e andrologia 2023; 95, 2 65 chronic prostatitis as possible risk factor for peyronie's disease patients are illustrated in table 4. notably, “significant anxiety” is more prevalent in pd patients showing the concomitant presence of cp compared to patients with pd alone (93.0% vs. 89.2%, respectively). we also found that severe anxiety is more prevalent in pd patients showing the concomitant presence of cp compared to patients with pd alone (43.5% vs. 39.3%, respectively) (see table 5). it should be also noted that “significant depression” is more prevalent in pd patients showing the concomitant presence of cp compared to patients with pd alone (64.0% vs. 57.1%, respectively). we also found that severe depression is more prevalent in pd patients showing the concomitant presence of cp compared to patients with pd alone (6.5% vs. 4.6%, respectively) (see table 5). discussion the scientific literature is rich in studies that have demonstrated the presence of numerous risk factors able to favor the onset of pd. these studies include the following risk factors: penile trauma, erectile dysfunction, congenital penile curvature, dupuytren's disease, diabetes mellitus, dyslipidemia, obesity, hypertension, smoking, alcohol consumption, rheumatoid arthritis, psoriasis, and psoriatic arthritis (36, 53-58). this is the first study that specifically investigates the association between pd and cp. our results show that the overall prevalence of cp in patients with pd was significantly higher (37.1%) compared to the prevalence in a non-pd control population (17.4%). our data suggest that cp and pd are frequently associated. another study on this topic identified pd as a risk factor for prostatitis (3). in our study, median iief scores were not significantly different in pd patients with or without cp although the severity of cp symptom total scores (nih-cpsi) correlated significantly with the severity of erectile dysfunction (p < 0.0001). some studies published in the literature have already argued or demonstrated the correlation between prostatic symptoms and erectile dysfunction (59-65). in our study, median vas scores were not significantly different in pd patients with or without cp. furthermore, the presence of cp in patients with pd does not affect the following: severity of penile curvature, complexity of penile curvature (multiplanarity), penile plaque volume, plaque plurifocality, and plaque calcification presence. in their study, smith and colleagues reported that 81% of pd patients suffered from "emotional difficulties" (35). our results revealed that “significant anxiety” was present in 89.2% of pd patients. furthermore, our study found that “significant anxiety” is more prevalent in pd patients showing the concomitant table 3. summary of findings related to plaque calcification and multifocal lesions and curve complexity (multiplanar curve deformity). prostatitis (n = 200) no prostatitis (n = 339) p, fisher’s exact test p, pearson’s chi-square no. of patients with a complex (multiplanar) curve 62 (31%) 105 (31%) 0.99 0.99 number of patients with multifocal plaque 46 (23%) 58 (17%) 0.11 0.094 number of patients with calcifications 61 (30.5%) 81 (24%) 0.105 0.092 table 4. psychological profile of 539 patients with peyronie’s disease. psychological questionnaire mental state n. cases prevalence (%) mean test score gad-7 minimal anxiety 6 1.1 2.5 mild anxiety 52 9.6 6.7 moderate anxiety 269 49.9 13.06 severe anxiety 212 39.3 19.7 “significant anxiety” 481 89.2 15.9 total 539 14.9 phq-9 minimal depression 62 11.5 3.3 mild depression 169 31.3 7.08 moderate depression 194 35.9 12.1 moderately severe depression 89 16.5 16.6 severe depression 25 4.6 21.64 “significant depression” 308 57.1 14.19 total 539 10.7 gad-7 = generalized anxiety disorder-7 questionnaire, score range = 0-21. interpretation: 0-4, minimal anxiety; 5-9, mild anxiety; 10-14, moderate anxiety; 15-21, severe anxiety. “significant anxiety” (moderate-to-severe anxiety) when gad-7 score > 9 (50). phq-9 = patient health questionnaire-9, score range = 0-27. interpretation: 1-4, minimal depression; 5-9, mild depression; 10-14, moderate depression; 15-19, moderately severe depression; 20-27, severe depression. “significant depression” (moderate to severe depression) when phq-9 score > 9 (51). table 5. psychological profile of pd patients with or without chronic prostatitis (pc). psychological mental state pd patients with cp pd patients without cp statistical analysis questionnaire n. cases out 200 cases n. cases out 339 cases p-value (χ2 test ) prevalence (%) prevalence (%) gad-7 “significant anxiety” 186 (93.0) 295 (87.0) 0.0434 severe anxiety 87 (43.5) 125 (36.8) 0.1526 phq-9 “significant depression” 128 (64.0) 180 (53.09) 0.0173 severe depression 13 (6.5) 25 (7.3) 0.8344 cp = chronic prostatitis. gad-7 = generalized anxiety disorder-7 questionnaire, score range = 0-21. interpretation: 0-4, minimal anxiety; 5-9, mild anxiety; 10-14, moderate anxiety; 15-21, severe anxiety. “significant anxiety” (moderate-to-severe anxiety) when gad-7 score > 9 (50). phq-9 = patient health questionnaire-9, score range = 0-27. interpretation: 1-4, minimal depression; 5-9, mild depression; 10-14, moderate depression; 15-19, moderately severe depression; 20-27, severe depression. “significant depression” (moderate to severe depression) when phq-9 score > 9 (51). archivio italiano di urologia e andrologia 2023; 95, 2 g. paulis, a. paulis 66 presence of cp compared to pd alone (93% vs. 89.2%, respectively). we also found that severe anxiety is more prevalent in pd patients showing the concomitant presence of cp compared to pd alone (43.5% vs. 39.3%, respectively). our findings show that prostatitis symptomatology affects pd patients' anxiety status; in fact, the severity of total cp symptom scores, assessed with the nih-cpsi test, correlates positively and significantly with gad-7 anxiety scores (p < 0.05). these results demonstrate the strong impact of cp on the anxiety state of pd patients. nelson and coworkers, in their study about depression in men with pd, demonstrated that 48% of patients show clinically meaningful depression (30). in our study “significant depression” was reported in a higher fraction of patients (57.1%). furthermore, our study found that “significant depression” is more prevalent in pd patients showing the concomitant presence of cp compared to pd alone (64.0% vs. 57.1%, respectively). we also found that severe depression is more prevalent in pd patients showing the concomitant presence of cp compared to pd alone (6.5% vs. 4.6%, respectively). overall, our results demonstrate the strong impact of pd and cp on the mental status of patients. conclusions chronic prostatitis (cp) and pd are frequently associated. although the present study has the limitations of a retrospective analysis performed on a patient database, the size of the odds ratio (= 2.79), and its statistical significance (p < 0.0001) support the relative certitude of our results. patients with pd and cp showed a significantly higher prevalence of more severe depression and anxiety. in urological and andrological clinical practice, the involvement of psychologists is desirable in order to provide the patient with psychological support treatment and to mitigate the psychological impact of these two physically and psychologically devastating diseases (pd and cp). our study suggests that patients with pd and/or cp should always be studied by administering specific psychological questionnaires because depressive and anxious symptoms may be unknown or at least underestimated in terms of severity and prevalence. further studies are needed not only to confirm cp as a risk factor for pd but also to further 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shoskes da. the challenge of erectile dysfunction in the man with chronic prostatitis/chronic pelvic pain syndrome. curr urol rep. 2012; 13:263-267. 63. zhang z, li z, yu q, et al. the prevalence of and risk factors for prostatitis-like symptoms and its relation to erectile dysfunction in chinese men. andrology. 2015; 3:1119-1124. 64. zhang y, zheng t, tu x, et al. erectile dysfunction in chronic prostatitis/chronic pelvic pain syndrome: outcomes from a multicenter study and risk factor analysis in a single center. plos one. 2016; 11:e0153054. 65. magri v, boltri m, cai t, et al. multidisciplinary approach to prostatitis. arch ital urol androl. 2019; 90:227-248. correspondence gianni paulis, md (corresponding author) paulisg@libero.it peyronie’s care center, department of uro-andrology, castelfidardo clinical analysis center, rome, italy andrea paulis, md andrea.fx.94@gmail.com neurosystem center for applied psychology and neuroscience, janet clinical centre, rome, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper death, contributing to their excess mortality in comparison to the general population (2). therefore, until recently, any form of active neoplasia was regarded as a contraindication to renal transplantation, and a waiting period between cancer treatment and transplantation was mandatory. the decision on the waiting period for transplantation in patients with a history of treated cancer is mainly based on the cincinnati transplant tumor registry (3), with times varying from two to at least five years, depending on the type of tumor. however, this study published more than twenty years ago has several drawbacks that may not reflect the actual epidemiology of current diagnosed cancers: treatment and staging were not defined, and many diagnostic, therapeutic and prognostic tools have improved over these last years. therefore, nowadays, there is not enough evidence to support a fixed waiting period before transplantation. besides, there is growing recent evidence suggesting that the increased risk of cancer by immunosuppression is restricted to particular subtypes, while others may not be affected. cancers at highest risk are viral-induced cancers such as lymphomas and kaposi sarcoma, and those caused by impaired immune surveillance or via direct dna damage by anti-rejection drugs such as skin and lip cancers (4). although renal cell carcinoma (rcc) of native kidneys is one of the most common tumors in renal transplant recipients, accounting for 8% of malignancies in this population (5), it has been shown that its incidence is lower during transplantation than during graft nonfunctioning periods without immunosuppression (6). a typical feature of esrd is a higher incidence of rcc, where it can be up to ten times higher than the general population, being found in 4% of dialyzed or renal transplant patients (7). the main risk factor for rcc is acquired cystic kidney disease (ackd), which increases with duration of dialysis (8), and seems to regress after successful transplantation. thus, a longer waiting period for transplantation may paradoxically increase the risk of this kidney dysfunction-related cancer. since the outcomes of rcc after kidney transplantation and its prognosis under immunosuppressive regimens remain poorly understood with conflicting evidence, we aimed to evaluate clinical and pathological characteristics of rcc of native kidneys in esrd patients, and to compare the risk of recurrence and survival according to their dialysis or transplantation status at the time of diagnosis. introduction: kidney transplantation requires immunosuppression, traditionally regarded as a risk factor for progression in all malignancies. based on the cincinnati registry, a waiting period before transplantation is therefore mandatory. however, recent evidence suggests this increased risk is restricted to particular tumors, whereas others like renal cell carcinoma (rcc) are not negatively affected. we aimed to compare oncological outcomes of rcc in native kidneys of end-stage renal disease (esrd) patients, according to their transplantation or dialysis status. material and methods: retrospective analysis of all esrd patients diagnosed with rcc between 2010 and 2020 in our center. recurrence-free survival (rfs) and overall survival (os) were estimated with kaplan-meier curves. multivariable cox regression model was used to evaluate their association with kidney transplantation. results: clinical and pathological characteristics were similar between groups. kidney transplant recipients had similar risk of recurrence (hazard ratio [hr] 0.40, 95% confidence interval [ci) 0.04-4.46, p = 0.458) and overall survival (hr 0.34, 95%ci 0.07-1.77, p = 0.202) as dialyzed patients. on multivariable cox regression model, presence or absence of transplantation was not significantly associated with rfs (p = 0.479) or os (p = 0.236). time on dialysis was the only independent predictor of worse survival (hr 1.86, 95%ci 1.18-2.93, p = 0.008). conclusions: most rcc in native kidneys of esrd patients are low-grade, low-stage and exhibit favourable pathological and outcome features. immunosuppression does not seem to have an impact on oncological outcomes, but an increased time on dialysis seems to be associated with worse overall survival. therefore, waiting time for transplantation for these tumors could be reduced. key words: kidney transplantation; immunosuppression; dialysis; renal cell carcinoma; recurrence; overall survival; waiting period. submitted 6 february 2023; accepted 17 february 2023 introduction renal transplantation is the most successful treatment for end-stage renal disease (esrd) owing to its superior survival and quality of life compared to other replacement therapies (1). however, it requires immunosuppression, traditionally being regarded as a risk factor for increased tumor incidence and progression. the increased incidence of cancer in this population is a significant cause of renal cell carcinoma in native kidneys before transplantation when will we stop waiting? jorge correia, bernardo teixeira, gonçalo mendes, avelino fraga, miguel silva-ramos department of urology, centro hospitalar universitário do porto, portugal. doi: 10.4081/aiua.2023.11240 summary archivio italiano di urologia e andrologia 2023; 95, 1 j. correia, b. teixeira, g. mendes, a. fraga, m. silva-ramos materials and methods study design and patient selection in this observational retrospective, single-center, cohort study, we evaluated data on all consecutive patients with esrd diagnosed with rcc of native kidneys and submitted to radical nephrectomy between 2010 and 2020. overall, 40 rcc cases were identified in this population based on post-operative histopathological staging. they were subsequently stratified according to their kidney transplantation or dialysis status at the time of diagnosis, and clinical, pathological and oncological outcomes were compared between groups. we excluded from analysis patients diagnosed with rcc while on dialysis who later received a renal transplant, and patients with regional or distant metastatic disease. renal transplant patients diagnosed with rcc, with later graft failure leading to resuming of dialysis were included in the kidney transplant cohort. perioperative and socio-demographic data, clinical and histopathological characteristics and survival outcomes were extracted from medical records. pre-operative staging and surgical technique all patents were evaluated preoperatively with computed tomography (ct) of the abdomen, pelvis and chest to confirm localized disease, and with biochemical blood work with creatinine. all patients were treated with radical nephrectomy, performed by either an open approach through flank incision or laparoscopic approach by standard transperitoneal four-trocar technique, based on patient and surgeon preference. lymph node dissection was not performed in any patient, since there was no nodal involvement suspected based on preoperative imaging or intraoperatively enlarged nodes. all kidney transplant patients were on standard immunosuppressive regimen, and no modification to this scheme due to oncological concerns was made at the time of rcc diagnosis or during follow-up. pathological evaluation all surgical specimens were processed according to standard pathological procedures. all lesions were confirmed to be malignant renal cell carcinomas. tumors were staged according to the 7th edition of the american joint committee on cancer tnm classification (9) and the histological subtype was assigned according to the 2016 world health organization (who) classification of kidney tumors (10). tumors were graded according to the international society of urological pathology grading classification (11). tumor multifocality was defined as the presence of two or more synchronous lesions in the same kidney, pathologically confirmed to be rcc. tumor bilaterality was defined as the presence of synchronous lesions in both kidneys at the time of diagnosis. follow-up patients were followed every 6 months during the first year after surgery, yearly until 3 years, and once every 2 years thereafter. follow-up consisted of medical history and appropriate physical examination, routine blood work and imaging re-evaluation. oncological outcomes comprised recurrence-free survival (rfs) and overall survival (os). both survival outcomes were evaluated from the date of surgery to time of event or, when lost to follow-up, the last documented outpatient visit with his physician. recurrences were treated with surgical excision, and patients continued on regular follow-up. statistical analysis categorical variables are presented as frequencies and percentages, and continuous variables as means and standard deviations, or medians and interquartile ranges (iqr) for variables with skewed distributions. normal distribution was checked using shapiro-wilk test or skewness and kurtosis. univariate logistic regression was used to investigate the association between baseline patient and pathological characteristics and the transplantation or dialysis status. continuous variables were compared with the use of paired student’s t-test or mann-whitney test for variables with normal and skewed distribution, respectively. categorical variables were compared with the use of table 1. ppla score system for renal papillae (16). kidney transplant dialysis p value (n = 22) (n = 18) demographic characteristics age (years) 57.7 ± 11.0 57.7 ± 11.0 0.999 sex, n (%) male 19 (86%) 18 (100%) 0.238 female 3 (14%) 0 (0%) asa score, n (%) ≤ 3 21 (95%) 8 (44%) < 0.001 > 3 1 (5%) 10 (56%) bmi (kg/m2) 25.0 ± 3.38 25.9 ± 3.04 0.387 time on dialysis before diagnosis (months) (iqr) 38.5 (13-60) 28.0 (11-42) 0.430 time on immunosuppression (months) (iqr) 136.5 (66-182) gfr (ml/min/1.73 m2), n (%) < 15 1 (5%) 18 (100%) < 0.001 15-30 4 (18%) > 30 17 (77%) clinical and pathological characteristics size (mm) 29.27 ± 16.78 38.11 ± 21.14 0.148 t stage, n (%) pt1a 18 (82%) 11 (61%) 0.184 pt1b 3 (14%) 5 (28%) pt2a 1 (4%) 0 (0%) pt2b 0 (0%) 0 (0%) pt3a 0 (0%) 2 (11%) histological subtype, n (%) clear cell 12 (55%) 8 (44%) 0.714 papillary (type 1 and 2) 6 (27%) 8 (44%) clear cell papillary 2 (9%) 1 (6%) other 2 (9%) 1 (6%) isup grade, n (%) grade 1-2 21 (95%) 11 (61%) 0.014 grade 3-4 1 (5%) 7 (39%) tumor multifocality, n (%) 3 (14%) 4 (22%) 0.680 tumor bilaterality, n (%) 1 (5%) 1 (6%) 0.884 asa = american society of anesthesiologists; bmi = body mass index; gfr = glomerular filtration rate; iqr = interquartile range; isup = international society of urological pathology. archivio italiano di urologia e andrologia 2023; 95, 1 renal cell carcinoma and transplantation teristics were homogeneous between populations. most of the patients had pt1a disease (82% transplant vs 61% dialysis, p = 0.184), with median tumor size 3-4 cm. the most frequent histological subtype was clear cell (cc) rcc, closely followed by papillary (prcc) which was slightly more frequent in the dialysis group, albeit without statistically significant difference (p = 0.714). 3 (7.5%) patients presented with clear cell papillary rcc (ccprcc). dialyzed patients were more likely to have higher grade disease (5% kidney transplant vs 39% dialysis, p = 0.014). overall, 7 (18%) and 2 (5%) patients presented with tumor multifocality and bilaterality respectively, similarly distributed between groups. over a median follow-up of 41 months (iqr 22-71), 3 recurrences occurred: 1 in kidney transplants (from ccrcc) and 2 in dialyzed patients (1 ccrcc, 1 prcc). all the 3 recurrences occurred in the contralateral kidney with the same histological subtype, and neither any of these recurrent patients nor from the remaining overall cohort later progressed to regional node or distant metastatic disease. figure 1 shows the probability of freedom from recurrence following nephrectomy according to kidney transplant or dialysis status. median time to recurrence was not reached in any group (nr, 95% confidence interval (ci) not evaluable (ne) ne), with 5-year rfs of 96% (95%ci 91-99) and 89% (95%ci 79-98) for kidney transplant and dialyzed patients, respectively (log-rank p = 0.443). kidney transplant patients did not show an increased risk of recurrence [hazard ratio (hr) 0.40, 95%ci 0.04-4.46, p = 0.458]. on multivariable cox figure 1. kaplan-meier estimates of recurrence-free survival (a) and overall survival (b) following radical nephrectomy, comparing kidney transplant (kidney tx) and dialysis patients. fisher’s exact test or the chi-square test, as appropriate. kaplan-meier survival curves were calculated for each group of esrd patients and log-rank (mantel-cox) test calculated for difference or equivalence between treatment groups, censoring patients without the event at their date of last follow-up. a multivariate cox proportional hazards regression model was fit with time to recurrence and time to death of any cause as the dependent variables, and clinical and pathological characteristics as the independent variables, to identify independent prognostic factors of rfs and os. all reported p values are two-sided, with a p value less than 0.05 indicating statistical significance. statistical analyses were performed using the statistical package for the social sciences (spss®), version 24.0 (ibm corp., armonk, ny, usa). results demographic and pathological characteristics of the cohort stratified by kidney transplant or dialysis status at the time of diagnosis are shown in table 1. kidney transplant recipients and dialysis accounted for 22 (55%) and 18 (45%) patients, respectively. mean age at the time of diagnosis was 58 years old, and the majority of patients in both groups were male (93% overall). demographic characteristics were similar between groups, except for a lower asa score being more common in the kidney transplant cohort (asa score ≤ 3, 95% kidney transplant vs 44% dialysis, p < 0.001). median time on dialysis until diagnosis was similar (p = 0.430). pathological characarchivio italiano di urologia e andrologia 2023; 95, 1 j. correia, b. teixeira, g. mendes, a. fraga, m. silva-ramos regression analysis (table 2), adjusting for clinical and pathological confounders, presence or absence of kidney transplant (and consequently immunosuppression) was not significantly associated with rfs (hr 0.42, 95%ci 0.04-4.65, p = 0.479). likewise, the time on immunosuppression was not an independent predictor of rfs (hr 0.98, 95%ci 0.95-1.02, p = 0.322). there were 7 deaths during follow-up, 2 in kidney transplant and 5 in dialysis patients. no cancer-related deaths were seen. most deaths were related to cardiovascular disease (71% overall; 100% kidney transplant and 60% dialysis). median time to death was not reached in any group (hr 0.34, 95%ci 0.07-1.77, p = 0.202). 5-year os was 91% (95%ci 78-99) for kidney transplant recipients and 72% (95%ci 59-85%) for dialyzed patients (log-rank p = 0.181). on multivariable analysis, neither the presence or absence of transplantation (hr 0.04, 95%ci 0.01-7.78, p = 0.236) nor the time on immunosuppression (hr 1.00, 95%ci 0.98-1.02, p = 0.862) were significantly associated with os. the only independent predictor of worse survival was time on dialysis (hr 1.86, 95%ci 1.18-2.93, p = 0.008). discussion considering that malignancy is a major cause of death after transplantation, a systematic screening for the presence of any active/latent cancer or a past history of cancer is mandatory when evaluating candidates for renal transplantation (12). however, previous history of malignancy and the role of immunosuppression as a causative risk factor for recurrence is still controversial, particular in certain subtypes of malignancy such as rcc, making it difficult to decide if the patient is suitable for transplantation and, if so, how long should the waiting period be. few studies have focused on the oncological outcomes of native kidneys rcc in esrd patients, all retrospective and most of them noncomparative, providing conflicting results. farrugia et al. (2) have shown that previous history of neoplasia was an independent risk factor for post-transplant death from malignancy. in a large swedish cohort of more than 10000 solid organ transplant recipients, brattström et al. (13) have found a 30% increased mortality risk for patients with a previous history of neoplasia. nevertheless, this risk was mainly driven by recipients of nonkidney transplants: mortality was increased by 20% in kidney recipients and by 80% among other organs recipients. besides, after stratification by waiting time between cancer treatment and transplantation, there was no association of increased mortality in kidney recipients, irrespective of waiting period. a two-fold increased risk of cancer-specific death was seen in transplant patients with a history of previous cancer other than kidney compared to rcc, regardless of waiting time. on the contrary, viecelli et al. (14), using data from the australian and new zealand dialysis and transplant registry, reported no significant association of previous cancer history with cancer-specific survival (css) or os in kidney transplant recipients. similarly, a recent nationwide norwegian study found that kidney recipients with a history of neoplasia had a similar os and graft survival as recipients without such cancer, and although cancer mortality was increased, particularly during the first 5 years, a short waiting period was not associated with all-cause or recurrent cancer mortality (15). in line with the most recent evidence, in our cohort, kidney transplant patients did not have an inferior rfs or os compared to dialyzed patients. moreover, on multivariable cox regression model, the presence or absence of transplant (and consequently immunosuppression) was not significantly associated with the risk of recurrence or increased mortality. in fact, the only independent predictor of an inferior survival was time on dialysis (hr 1.86, p = 0.008), which means that the common policy of a 2year waiting period before transplantation would translate into a 3-4-fold increased risk of death. cardiovascular disease remains a major cause of death in dialyzed patients (16) and since most esrd patients are elderly, it is possible that a longer waiting period will eventually lead to death, not due to cancer recurrence, but due to the burden of dialysis (17). reducing unnecessary lengthy waiting times could improve the care of these patients, optimizing timely transplantation. in accordance with our results, several studies have shown the safety of transplantation and immunosuppression in patients with a history of native kidney rcc. in a multicentric study from 24 centres conducted by the french urological association, gigante et al. (18) compared oncological outcomes of rcc in 213 transplanted and 90 dialyzed patients and reported higher 5-year rfs and css in the transplanted population. on multivariable analysis, presence of kidney transplant was not associated with css, with only t stage remaining an independent predictor of inferior survival. similarly, in a single-centre study comparing outcomes of native kidneys rcc in renal transplant recipients with a population with rcc without transplant, klatte et al. (19) showed that the presence of transplant did not affect css and os, and that most rcc were low-stage, low-grade with a favourable table 2. multivariable cox regression model predicting rfs and os after radical nephrectomy. rfs os hazard ratio 95% ci p value hazard ratio 95% ci p value kidney transplant, yes vs no 0.42 0.04-4.65 0.479 0.04 0.01-7.78 0.236 age, years 0.92 0.82-1.02 0.098 1.04 0.94-1.15 0.464 asa score, > 3 vs ≤ 3 5.39 0.49-59.87 0.170 0.31 0.01-8.18 0.487 time on dialysis, years 1.05 0.61-1.82 0.855 1.86 1.18-2.93 0.008 time on immunosuppression, months 0.98 0.95-1.02 0.322 1.00 0.98-1.02 0.862 histological subtype, non-clear cell vs clear cell 0.605 0.06-6.70 0.682 0.62 0.08-5.06 0.658 t stage, ≥ t1b vs t1a 5.78 0.52-63.78 0.152 0.50 0.01-44.35 0.762 isup grade, g3-4 vs g1-2 2.03 0.18-22.58 0.564 0.55 0.02-14.55 0.718 size, mm 1.03 0.98-1.08 0.276 1.00 0.92-1.08 0.945 asa = american society of anesthesiologists; ci = confidence interval; isup = international society of urological pathology; os = overall survival; rfs = recurrence-free survival. p values < 0.05 are shown in bold type. archivio italiano di urologia e andrologia 2023; 95, 1 renal cell carcinoma and transplantation outcome. tnm stage and grade were the only predictors of worse survival. a recent systematic review aimed to compare oncological outcomes of urological cancer in patients who subsequently received a kidney transplant or remained on dialysis (20). for rcc of native kidneys, rfs, css and os were similar between groups, with most of recurrences occurring in the contralateral kidney without impact on survival. the main prognostic factors for recurrence were stage, grade and histological subtype, with the authors concluding that immunosuppression didn’t modify the natural history of rcc. in our cohort, no metastasis (apart from recurrences in the contralateral kidney) or cancer-related deaths occurred, precluding any conclusion about these oncological outcomes. this contrasts with most of previous studies and could be related to the fact that only patients with localized disease with more favourable prognosis were included. however, in our opinion, a reduction or even elimination of waiting period would only be feasible in these lowstage cancers, making assumptions more reliable. for high-risk rcc, we believe that a waiting period according to the cincinnati registry is still adequate due to the considerable risks of recurrence and progression. several studies have highlighted the distinctive clinical and pathological features of rcc in esrd comparing to sporadic rcc (19, 21, 22). in line with these reports, we have also found that rcc occurred mainly in young male patients, were generally small and had low stage and grade, with a high incidence of multifocality and bilaterality. we found a higher incidence of papillary subtype compared to the general population and a substantial prevalence of ccprcc. ccprcc is a new but rare entity, first listed in the who 2016 renal tumor classification, that has an indolent course with no cases of metastasis reported to date (23). although also occurring in nonesrd patients, it is speculated that its prevalence is increased in dialyzed patients. although rcc of native kidneys of esrd patients seem to exhibit more favourable pathological and outcome features, the exact reason for its less aggressive behaviour still has to be determined. possible reasons for this better prognosis include a specific molecular pathway related to ackd not yet identified, or an earlier diagnosis due to more frequent imaging than the general population. there are no high-level evidence-based recommendations regarding screening for rcc in esrd patients, and no prospective studies on the cost-effectiveness of this approach. due to the higher incidence of rcc in this population and the fact that this risk increases with duration of dialysis, several authors have advocated regular screening in pretransplant and post-renal transplant recipients (19, 20, 24). in line with these studies, we also believe that regular screening of native kidneys should be part of pretransplant evaluation in order to diagnose rcc at lower stage and grade, allowing the feasibility of a shorter waiting period for renal transplantation. we acknowledge several limitations in our study. first, in line with previous reports, we recognize that our study is limited by its observational design and that the results should be interpreted within the limits of retrospective data. although it is unlikely that randomised controlled trials will be conducted in this setting due to ethical and logistical difficulties, well-designed prospective cohort studies are needed to confirm the safety of a reduced waiting period. second, this was a single-center study with a small sample size, which only included patients with localized disease. however, in order to evaluate the safety of reducing the waiting period for transplantation, we felt that it would be more appropriate to exclude patients with regional nodal or distant metastasis, as these are high-risk patients for recurrence or progressive disease even in the absence of immunosuppression, making comparisons more homogeneous and reliable. nevertheless, it precluded any conclusion on the effect of immunosuppression in pn+ and/or m+ patients. third, the low number of events in our cohort may have hampered our survival estimates and precluded further analysis on css. on the other hand, this low number reflects the favourable prognosis that most of these indolent tumors have. conclusions our study shows that most rccs in native kidneys of renal transplant and dialyzed patients are incidental lowgrade and low-stage cancers. these tumors exhibit many favourable clinical, pathological and outcomes features. kidney transplant recipients with rcc do not have increased risk of recurrence or death compared to dialyzed patients. immunosuppression doesn’t seem to have an impact on oncological outcomes, but an increased time on dialysis seems to be associated with worse overall survival. therefore, waiting time for transplantation for these tumors could be reduced. well-designed prospective studies are needed to confirm our findings. references 1. wolfe ra, ashby vb, milford el, et al. comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. n engl j med. 1999; 341:1725-1730. 2. farrugia d, mahboob s, cheshire j, et al. malignancy-related mortality following kidney transplantation is common. kidney int. 2014; 85:1395-1403. 3. penn i. evaluation of transplant candidates with pre-existing malignancies. ann transplant. 1997; 2:14-17. 4. piselli p, serraino d, segoloni gp, et al. risk of de novo cancers after transplantation: results from a cohort of 7217 kidney transplant recipients, italy 1997-2009. eur j cancer. 2013; 49:336-344. 5. kliem v, kolditz m, behrend m, et al. risk of renal cell carcinoma after kidney transplantation. clin transplant. 1997; 11:255258. 6. yanik el, clarke ca, snyder jj, pfeiffer rm, engels ea. variation in cancer incidence among patients with esrd during kidney function and nonfunction intervals. j am soc nephrol. 2016; 27:1495-1504. 7. moudouni sm, lakmichi a, tligui m, et al. renal cell carcinoma of native kidney in renal transplant recipients. bju int. 2006; 98:298-302. 8. choyke pl. acquired cystic kidney disease. eur radiol. 2000; 10:1716-1721. archivio italiano di urologia e andrologia 2023; 95, 1 j. correia, b. teixeira, g. mendes, a. fraga, m. silva-ramos 9. edge sb, compton cc. the american joint committee on cancer: the 7th edition of the ajcc cancer staging manual and the future of tnm. ann surg oncol. 2010; 17:1471-1474. 10. moch h, cubilla al, humphrey pa, et al. the 2016 who classification of tumours of the urinary system and male genital organs-part a: renal, penile, and testicular tumours. eur urol. 2016; 70:93-105. 11. delahunt b, cheville jc, martignoni g, et al. the international society of urological pathology (isup) grading system for renal cell carcinoma and other prognostic parameters. am j surg pathol. 2013; 37:1490-1504. 12. kälble t, lucan m, nicita g, sells r, burgos revilla fj, wiesel m. eau guidelines on renal transplantation. eur urol. 2005; 47:156-166. 13. brattström c, granath f, edgren g, et al. overall and causespecific mortality in transplant recipients with a pretransplantation cancer history. transplantation. 2013; 96:297-305. 14. viecelli ak, lim wh, macaskill p, et al. cancer-specific and allcause mortality in kidney transplant recipients with and without previous cancer. transplantation. 2015; 99:2586-2592. 15. dahle do, grotmol t, leivestad t, et al. association between pretransplant cancer and survival in kidney transplant recipients. transplantation. 2017; 101:2599-2605. 16. johansen kl, chertow gm, foley rn, et al. us renal data system 2020 annual data report: epidemiology of kidney disease in the united states. am j kidney dis. 2021; 77(4 suppl 1):a7-a8. 17. au eh, chapman jr, craig jc, et al. overall and site-specific cancer mortality in patients on dialysis and after kidney transplant. j am soc nephrol. 2019; 30:471-480. 18. gigante m, neuzillet y, patard jj, et al. renal cell carcinoma (rcc) arising in native kidneys of dialyzed and transplant patients: are they different entities? bju int. 2012; 110:e570-573. 19. klatte t, seitz c, waldert m, et al. features and outcomes of renal cell carcinoma of native kidneys in renal transplant recipients. bju int. 2010; 105:1260-1265. 20. boissier r, hevia v, bruins hm, et al. the risk of tumour recurrence in patients undergoing renal transplantation for endstage renal disease after previous treatment for a urological cancer: a systematic review. eur urol. 2018; 73:94-108. 21. breda a, lucarelli g, rodriguez-faba o, et al. clinical and pathological outcomes of renal cell carcinoma (rcc) in native kidneys of patients with end-stage renal disease: a long-term comparative retrospective study with rcc diagnosed in the general population. world j urol. 2015; 33:1-7. 22. tsuzuki t, iwata h, murase y, et al. renal tumors in end-stage renal disease: a comprehensive review. int j urol. 2018; 25:780786. 23. chen wj, pan cc, shen sh, et al. clear cell papillary renal cell carcinoma an indolent subtype of renal tumor. j chin med assoc. 2018; 81:878-883. 24. denton md, magee cc, ovuworie c, et al. prevalence of renal cell carcinoma in patients with esrd pre-transplantation: a pathologic analysis. kidney int. 2002; 61:2201-2209. correspondence jorge correia md (corresponding author) jorgericardocorreia@gmail.com bernardo teixeira, md bernardolat@gmail.com gonçalo mendes, md goncalo.grilomendes@gmail.com avelino fraga, md avfraga@gmail.com miguel silva-ramos, md miguelsilvaramos@gmail.com department of urology, centro hospitalar universitário do porto largo do prof. abel salazar, 4099-001 porto, portugal conflict of interest: the authors declare no potential conflict of interest. stesura seveso introduction renal cell carcinoma (rcc) has a very well known angiotropism, with up to 10% of tumors presenting neoplastic tumoral thrombosis (1). surgical treatment of this pathology is one of the most challenging procedures in urology, requiring optimal surgical skills and collaboration of many other specialists, like radiologist, heart-surgeon, general surgeon and oncologist (2-4). nowadays, most of urologic treatments can be offered in mini-invasive way (5), but the challenges of this procedure are still to be faced by open surgery (6). the aim of this paper is to review the 10 year experience of our institution in the sur175archivio italiano di urologia e andrologia 2013; 85, 4 original paper renal cell carcinoma with venous neoplastic thrombosis: a ten years review giacomo maria pirola, giovanni saredi, giuseppe damiano, alberto mario marconi urology unit, ospedale di circolo e fondazione macchi, varese, italy. purpose: to review the 10-year experience of our urological unit in the surgical management of renal cell carcinoma (rcc) with neoplastic tumor thrombosis focusing on postoperative survival. materials and methods: we underwent a retrospective analysis of the patients treated for this pathology during the last decade 2002-2012, stratifying them by tumor thrombus level and histological subtype. kaplan-meyer curves were used to assess survival. results: overall, 67 patients underwent surgery for rcc with neoplastic tumoral thrombosis in the period under review. 60 were clear cell rcc, 4 were urothelial papillary tumors of the renal pelvis and 3 were rare histotypes, as a nefroblastoma, a spinocellular tumor of the renal pelvis and an unclassifiable renal carcinoma. thrombus level was i in 40 cases, ii in 17, iii in 2 and iv in 8 patients. we report the main postoperative complications and our survival data, with mean follow up of 36 months. tumor stage is the most important variable in predicting survival. patients with n0m0 disease had 70% survival at 36 months, instead of 20% for those with primitive metastatic tumor. conclusion: our survival results fit with the main reports in literature and our surgical management was completely in keeping with international guidelines. we did not observe relevany post-operative complications, except of hemorrhagic ones that occurred in 6 patients (9% of total) and were always successfully managed. eighteen patients (26.87% of total) underwent caval filter positioning, without evidence of complications during its positioning or removal. life expectancy was particularly low for the cases of rcc without clear cell histotype (7 cases in our series, 10.4% of total) that always was less than one year from surgery. key words: renal cell carcinoma; neoplastic tumor thrombus; neves e zincke criteria; surgery; survival curves. submitted 11 february 2013; accepted 15 july 2013 no conflict of interest declared summary gical management of renal cell carcinoma with neoplastic tumor thrombus focusing on postoperative survival. materials and methods in the period between 2002 and 2012, we observed 67 cases of kidney tumor with neoplastic thrombosi. we stratified patients according clinical presentation, pathological staging and therapeutic approach applied and compared with tumor thrombus level using the chi-square test. kaplan-meyer method was used to estimate cancer-specific survival. doi: 10.4081/aiua.2013.4.175 pirola okkkkkk_stesura seveso 18/12/13 10:35 pagina 175 archivio italiano di urologia e andrologia 2013; 85, 4 g.m. pirola, g. saredi, g. damiano, a.m. marconi 176 we registered the main clinical perioperative variables to evaluate possible different outcomes related to thrombus extension, according to neves and zincke classification (7). in collaboration with the oncology division of our institution, we extracted survival data of patients that attended our hospital for follow up, unfortunately only about 50% of the total surgical series. results at the time of diagnosis, mean patients age was 71.5 years (range 3-91) with a median of 72 years, 39 patients (58.2%) were males and 28 (41.8%) were females. the tumor interested the right kidney in 39 cases (58.2%) and left in 28 (41.8%). the mean diameter of the neoplastic primitive mass was 9.4 cm, diameter ranged from a minimum of 3 cm to complete involvement of the whole organ with masses of up to 20 cm. there were 40 (59.7%) cases of level i thrombus, 17 (25.37%) with level ii, 2 (2.98%) with level iii and 8 (11.94%) with supra-diaphragmatic and intra-cardiac tumor thrombus (level iv). neoplastic thrombosis level was assessed according to neves and zincke criteria (7) (figure 1, table 1). at the time of diagnosis, most of our patients presented with definite symptoms, like local flank pain, hematuria and growth of systemic inflammatory parameters (creactive protein crp, erytrocite sedimentation rate esr and leucocytes). otherwise, 25% was totally asymptomatic, according to most of renal carcinomas behavior. ecog performance status was 0 in 43% of the patients, 1 in 45% and 2 in 12% of them, and surgical indication was always integrated with an accurate anesthesiologycal evaluation. mean hospitalization was 16.8 days (range 7-52 days), mostly due to surgical treatment and to peri-operative surgical or medical complications. all patients underwent clinical staging with ultra-sound (us), computed tomography (ct) and renal dynamic scintigraphy. a caval filter was placed in only 18 cases (26.87%) to prevent pulmonary embolism during surgery, because there is not a clear indication for this procedure and the risk of thrombus detachment during caval mobilization is very low. patients that positioned caval filter underwent computed tomography angiography (cta), which documented tumoral thrombosis and its extension into inferior vena cava (ivc). cavography was performed before and after filter implantation (8). the procedure had 100% feasibility. a right internal jugular vein puncture was performed after local anesthesia, and tumour thrombus level was determined by ivc phlebography. after the filter delivery sheath was placed in the suprarenal ivc, the filter was deployed according to the manufacturer’s guidelines. there was no evidence of perior post-procedural complications. all suprarenal ivc filters were removed from 30 to 60 days after surgery, except in three cases, where the filter was too near to neoplastic thrombus and it was necessary to remove it intraoperatively. surgical aim was always the debulking of the whole tumoral mass with the associated neoplastic thrombus (9).this was not possible only in one case, where the infiltration of caval wall was extended and we had to stop the procedure. the other two cases with caval wall thrombus level i ii iii iv operative time 158 175 215 289 (min.) (90-275) (135-275) (195-250) (240-390) blood supplement 0,8 1,6 2 4,6 (u rbc) (0-4) (0-6) (1-3) (3-8) hospitalization 14,4 19,3 20,5 22,6 (days) (7-30) (8-35) (20-21) (15-52) caval filter applied 5 9 2 2 (12,5%) (52,9%) (100%) (25%) peri-operative complications 13 7 1 3 table 1. surgical data and hospitalization data in our series of patients (varese, 2012). figure 1. percentage of neoplastic thrombosis level in our series of patients (varese, 2012). figure 2. surgical access stratified by level of neoplastic thrombosis (varese, 2012). pirola okkkkkk_stesura seveso 18/12/13 10:35 pagina 176 infiltration were treated with partial caval resection and apposition of a protesic biological patch. of the 67 patients considered in our series, 20 (30%) had preoperatively a metastatic illness, most of them interesting lung (30%, 6), adrenal glands (25%, 5), liver (20%, 4) and others brain, bone and pancreas (figure 2). level iv thrombosis (8 cases in our series, 12% of total), was always managed with cardiopulmonary bypass (cpb) and hypothermic circulatory arrest to achieve control on atrial region, in collaboration with a heart surgeon (10). we did not have neither perioperative deaths nor reinterventions, and the list of early complications is presented in the following chart (table 2). at pathological evaluation, 60 cases were renal clear cell carcinomas (90% of total), 4 were urothelial papillary neoplasms of renal pelvis (6.67% of total), one was a nefroblastoma (1,5% of total), one a squamous cell carcinoma of the renal pelvis and one an unclassifiable renal tumor. in the 60 clear cell rcc, 27 (45%) were t3a with thrombus limited to the first 2 cm of vena cava or within the renal vein, 21 (35%) were t3b, extended into the ivc, 7 (12%) were t3c, extended over the diaphragm, and 5 (8%) were t4 extended beyond gerota fascia, with a thrombus that involved renal vein in three cases, vena cava in one and supra-diaphragmatic region in another one. we did not perform extended lymphadenectomy, according to european association of urology (eau) guidelines, removing only big size or palpable nodes in six cases (9% of total). fuhrman grade was g2 in 37 cases (61.6%) and g3 in 23 (38.4%) (table 3). the 35 patients in our follow-up are divided in 24 with level i tumor thrombus, 6 with level ii, 2 with level iii and 3 with level iv neoplastic thrombosis. we present our survival data. among those 35 patients, 23 (65.7%) developed metastasis or local neoplastic recurrence, in 21 cases very soon, during the first year after surgery. the metastatic site was mainly pulmonary or hepatic (tables 4, 5). 177archivio italiano di urologia e andrologia 2013; 85, 4 renal cell carcinoma with venous neoplastic thrombosis: a ten years review postoperative complication patients number/% hemorrhage/hematoma 6/9 partial trombectomy 4/6 cvc infection 3/5 anesthesiologycal 2/3 lipothymia 2/3 hypertensive crisis 2/3 pnx 2/3 caval filter replacement 2/3 pulmonary emboli 2/3 arithmyas (fa-fv) 2/3 intestinal anastomosis leakage 2/3 allergic reactions 1/1,5 pneumonitis 1/1,5 paralytic ileus 1/1,5 table 2. post-surgical complications observed in our patients within the first month (varese, 2012). primitive tumor extension number of patients n0m0 n+m0 n0m+ n+m+ p patients with follow-up data t3a 27 21 2 3 1 15 t3b 21 15 6 < 0,01 15 t3c 7 3 1 3 3 t4 5 1 2 2 2 tot. 60 40 3 14 3 35 table 3. post-surgical complications observed in our patients within the first month (varese, 2012). thrombus level number of patients mean survival (months) median survival (months) survival range (months) deaths i 24 24,54 22 5-60 6 (25%) ii 6 25,1 21 14-44 2 (33,3%) iii 2 42 42 36-48 0 iv 3 23,66 24 12-35 2 (66,6%) table 4. patients stratification by tumoral thrombosis level and survival data (varese, 2012). pathologist stadiation number of patients mean survival (months) median survival (months) survival range (months) deaths n0m0 25 28,44 27 5-60 4 (16%) n+m0 1 12 12 12 1 (100%) n0m+ 8 19,75 15 5-35 4 (50%) n+m+ 1 6 6 6 1 (100%) table 5. patients stratification by tumor extension and survival data (varese, 2012. pirola okkkkkk_stesura seveso 18/12/13 10:35 pagina 177 archivio italiano di urologia e andrologia 2013; 85, 4 g.m. pirola, g. saredi, g. damiano, a.m. marconi 178 as we can see, tumor thrombus level is not so relevant in predicting survival and life expectancy is more stratified if patients are divided by pathologist stadiation (11). the four cases of urothelial neoplasms of renal pelvis were 3 with level i tumoral thrombosis and 1 with level ii; all of them had aggressive histological subtype, g3 fuhrman’s grade. they underwent uretero-nephrectomy with cystoscopy to exclude bladder invasion and associated trombectomy. all these cases had metastatic invasion, mainly in adrenals, lung and local lymph nodes. their mean survival was 14.25 months (range 11-18) and they had adjuvant chemotherapy with paclitaxel. they unusually represent about 6% of our series, because only few cases of transitional cell carcinoma with neoplastic tumoral thrombosis are presented in literature (12, 13). it is evident that these tumors have a high malignancy, with poor life expectancy for the patient. the three cases with rare histological type (nephroblastoma, spinocellular tumor of the renal pelvis and unclassifiable neoplasm) were all aggressive tumors, with level i tumor thrombus, and their survival was less than one year. despite poor prognosis, surgery was made for palliation, and patients achieved symptoms relief, mainly from hematuria that troubled most of them. discussion for the 60 cases of clear cell rcc the most significant prognostic factors are local tumor extension and fuhrman’s grading. on the contrary thrombus extension is more important for surgical planning than for predicting survival. these inferences are clearly valuable in the kaplanmeyer comparison of survival curves of the group without and with metastatic disease at pathological evaluation (figure 3). according to most of literature, radical surgery is the best option to adopt. cytoreductive aim is also useful for patients with metastatic disease, to achieve better answer to adjuvant immunotherapy on residual neoplastic foci after debulking. surgery is even important to give palliation to neoplastic symptoms, like local flank pain or hematuria, that occur with progressive neoplastic enlargement. survival at 36 months is clearly better for patients without metastatic disease (about 70%), but surgery offers a better life expectance also for advanced tumors (20% survival at 36 months). conclusions this work confirmed that rcc with neoplastic thrombosis is still a relevant health problem, with up to 10% of occurrence out of all patients with renal tumor. surgical treatment is clearly the first option for this pathology, and neoplastic thrombosis does not decline patients survival as an independent prognostic factor, but has to be evaluated together with tumor extension and performance status of the patient. the only difference is related to the surgical technique, more complex if tumoral thrombosis is spread to the whole ivc or even to right atrium, with the need of cpb. caval filter implantation is feasible and can be used to make safer the surgical procedure if thrombosis rises up into sub-diaphragmatic ivc with no complications in our series during its positioning or removal. in spite of all, surgery is effective both in oncological or palliative aim, and mainly safe with the absence of early post-operative deaths or re-operations. our experience in this field is in keeping with international guidelines, both in term of surgical approach and oncological follow-up. a different conclusion has to be made for the seven cases of uncommon renal tumor histotypes (four urothelial tumors of renal pelvis, one nefroblastoma, one spinocellular tumor of the renal pelvis and one unclassifiable renal carcinoma, accounting for 10.4% of our series), where the presence of neoplastic thrombosis was always linked to poor survival (about one year). figure 3. kaplan-meyer survival curves; group 1 (continue line) are n0m0 patients, group 2 (dotted line) are patients with metastatic disease (varese, 2012). time is expressed in months pirola okkkkkk_stesura seveso 18/12/13 10:35 pagina 178 references 1. boorjian sa, sengupta s, blute ml renal cell carcinoma: vena caval involvement bju int. 2007; 99:1239-1244. 2. ljungberg b, stenling r, osterdahl b, et al. vein invasion in renal cell carcinoma: impact on metastatic behavior and survival. j urol. 1995; 154:1681-1684. 3. zisman a, wieder ja, pantuck aj, et al. renal cell carcinoma with tumor thrombus extension: biology role of nephrectomy and response to immunotherapy. j urol. 2003; 169:909-916. 4. castelli p, caronno r, piffaretti g, et al. surgical treatment of malignant involvement of the inferior vena cava. int semin surg oncol. 2006; 16:3-19. 5. wotkowicz c, libertino ja, sorcini a, mourtzinos a. management of renal cell carcinoma with vena cava and atrial thrombus: minimal access vs median sternotomy with circulatory arrest. bju int. 2006; 98:289-97. 6. blute ml, leibovich bc, lohse cm, et al. the mayo clinic experience with surgical management, complications and outcome for patients with renal cell carcinoma and venous tumor thrombus. bju int. 2004; 94:33-41. 7. neves rj, zincke h. surgical treatment of renal cancer with vena cava extension. br j urol. 1987; 59:390 8. carrafiello g, mangini m, fontana f, et al. suprarenal inferior vena cava filter implantation. radiol med. 2012; 117:1190-8. 9. flanigan rc, mickisch g, sylvester r, et al. citoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. j urol. 2004; 171:1071-6. 10. belgrano e, trombetta c, siracusano s, et al. surgical treatment of renal cell carcinoma (rcc) with vena cava tumor thrombus. eur urol suppl. 2006; 5:610-618. 11. skinner dg, pritchett tr, lieskovsky g, et al. vena caval involvement by renal cell carcinoma. surgical resection provides meaningful long-term survival. ann surg. 1989; 210:387-92. 12. prando a, prando p, prando d. urothelial cancer of the renal pelvicaliceal system: unusual imaging manifestations. radiographics. 2010; 30:1553-66. 13. miyazato m, yonou h, sugaya k, koyama y, et al. transitional cell carcinoma of the renal pelvis forming tumor thrombus in the vena cava. int j urol. 2001; 8:575-7. 179archivio italiano di urologia e andrologia 2013; 85, 4 renal cell carcinoma with venous neoplastic thrombosis: a ten years review correspondence giacomo maria pirola, md (corresponding author) gmo.pirola@gmail.com giovanni saredi, md giovannisaredi@yahoo.it giuseppe damiano, md mediciurologia@ospedalivarese.net alberto mario marconi, md albertomario.marconi@ospedale.varese.it division of urology, ospedale di circolo e fondazione macchi, viale borri 57, 21100 varese, italy pirola okkkkkk_stesura seveso 18/12/13 10:35 pagina 179 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 120 original paper testicular microlithiasis and dyspermia: is there any correlation? francesco catanzariti, ubaldo cantoro, vito lacetera, giovanni muzzonigro, massimo polito polytechnic university of marche, faculty of medicine, department of odontostomatologic and specialized clinical sciences, urology clinic, department of general and specialized surgery, university hospital, ancona, italy. background: testicular microlithiasis (mt) is an uncommon sonographic finding (prevalence in the literature: 0.7 to 6%). several studies have highlighted its possible correlation with an increased risk of testicular cancer, but few studies have investigated its possible link with dyspermia. objectives: the aim of our study was to investigate in our series the number of patients with microlithiasis, diagnosed by ultrasound, and compare the quality of their sperm with that of patients in a control group with normal testicular ultrasound exam. materials and methods: we performed 277 consecutive testicular ultrasound examinations from january 2012 to july 2012. among all these, we selected 86 patients that showed no pathological elements at echography and 11 patients affected by mt, to one or both testicles. each patient was also submitted to a short-term semen analysis using the who2010 parameters for sperm evaluation. results: among 11 patients with mt, 7 (63.63%) were dyspermic and 4 (36.36%) were normospermic. among the 86 patients with normal testicular ultrasound 51 (59.3%) were dyspermic, 4 (4.65%) were azoospermic, while the remaining 31 (36.05%) were normospermic. comparing the results of the two groups we obtained an odds ratio of 0.99 (95% ci: 0.27 to 3.64, p: 0.98). conclusions: this study, although preliminary, with a low number of partecipants, shows that sperm quality is not affected by the presence of testicular microlithiasis, because the results of spermiograms are almost comparable between the two groups. key words: testicular microlithiasis; infertility; testicular ultrasound. submitted 1 september 2013; accepted 31 december 2013 summary introduction testicular microlithiasis (mt) is a quite rare ultrasound evidence, with a low prevalence, from 0.7 to 6%, as described in literature (1-3), although with the evolution of ultrasound machines, which allow the identification no conflict of interest declared. of structures of diameter less than one millimeter, the prevalence of mt has been increasing. the mt is characterized by the presence of hyperechoic spots of diameter between 1 and 3 mm, which don’t have posterior shadow cone, within testicular parenchima. microlithiasis can be classified as “classic” or “limited” depending on the presence of more or less than 5 hyperechoic spots per ultrasound section (figure 1). several studies in literature have shown a correlation between mt and some pathological conditions, such as testicular cancer, cryptorchidism, varicocele, testicular torsion, epididymitis, orchitis, klinefelter's syndrome, male pseudohermaphroditism, neurofibromatosis and hiv infection (4). some papers studied the association between microlithiasis and testicular cancer (4) and showed that the mt can predispose to the development of a carcinoma in situ (cis) or a germ cell tumors (tgct) of the testis. other authors have also noted that there could be a correlation between mt and intratubular germ cell neoplasia of unclassified type (itgcnu) (5) and that testicular microlithiasis might be part of a complex disease, the testicular dysgenesis syndrome (tds), comprising in addition to the testicular microlithiasis also other features such as infertility, testicular atrophy, cryptorchidism, tgct and other abnormalities of sexual development (6). in literature there are other studies, less numerous and with conflicting results, which analyze the association between infertility and testicular microlithiasis. some studies support the theory that there would be a higher prevalence of testicular microlithiasis among infertile patients (7), compared to fertile men. this evidence should be more frequent in the classical forms than in limited mt and the pathogenetic mechanism underlying this correlation has been described by some authors as the result of reduced inflow of arterial blood caused by microlithiasis (8). other authors instead believe that not statistically significant correlation exists between mt and infertility (9) and exclude that there is a greater number of antisperm antibodies in patients with testicular microlithiasis (10), which could be the cause of infertility in men affected by mt. doi: 10.4081/aiua.2014.1.20 catanzariti_stesura seveso 26/03/14 10:14 pagina 20 21archivio italiano di urologia e andrologia 2014; 86, 1 testicular microlithiasis and dyspermia: is there any correlation? objectives the aim of our work was to study the incidence of microlithiasis in our series, but above all to analyze how this ultrasound evidence can affect sperm quality of patients with this testicular desease, compared to patients normal at testicular ultrasound. materials and methods from january 2012 to july 2012, we performed 277 consecutive testicular ultrasound at our urology clinic. the testicular ultrasound examinations were performed by three different operators, all with good experience in the field of ultrasound, with the same new generation of machine, using a 7.5 mhz linear probe. during the examination particular attention has been placed on detection of hyperechoic areas compatible with testicular mt, distinguishing the limited forms (less than 5 hyperechoic areas for ultrasound section of diameter between 1 and 3 mm without shadow rear) from the classical ones (at least 5 hyperechoic areas for ultrasound section of diameter between 1 and 3 mm without shadow cone rear). among all the examinations, we selected those patients with testicular ultrasound without no alterations of didymus and epididymis (control group) and those with the presence of classical mt at ultrasound (study group). patients with limited mt were eliminated from the study. each patient of both groups was then subjected to a semen analysis that was performed in a short time (within 30 days) from the ultrasonographic examination. the semen analysis was conducted after at least 3 days of sexual abstinence. the semen samples were collected in the hospital asking patients to deposit its seed directly in sterile 120 ml containers. the samples were analyzed within 1 hour from ejaculation. after liquefaction, semen volume was measured by a syringe with an accuracy of 0.1 ml. the sperm concentration and motility was then evaluated by optical microscope through makler chamber with a magnification of x 200. we used who 2010 parameters for the sperm evaluation. results among the 277 testicular ultrasound examinations, we selected 11 (3.97%) patients with classical mt and 86 (31.05%) patients with normal testis at ultrasound investigation (figure 2), while we eliminated from the study the remaining 180 patients who resulted affected by other testicular diseases (varicocele, cysts, inflammation, etc.) at echography. spermiograms among patients with classical mt showed 7 cases (63.63%) of dyspermia, defined as the presence of at least one of the three parameters (concentration, motility and forms) under reference values according to the who 2010 classification. the remaining 4 patients (36.36%) of the study group instead resulted with normal semen analysis. among the patients belonging to the control group we found dyspermia in 51 (59.3%), azoospermia in 4 (4.65%) and normospermia in 31 (36.05%) cases (figure 3). figure 1. a. classic microlithiasis. figure 2. results in 277 consecutive testicular ultrasounds. figure 3. results of spermiograms in patients affected by mt and normal at echography. b. limited microlithiasis. 70 60 50 40 30 20 10 0 mt 36.36 36.05 59.3 4.65 63.63 0 normal % normospermia dyspermia azoospermia classic microlithiasis normal other catanzariti_stesura seveso 26/03/14 10:14 pagina 21 archivio italiano di urologia e andrologia 2014; 86, 1 f. catanzariti, u. cantoro, v. lacetera, g. muzzonigro, m. polito 22 by comparing the results of the two groups and calculating the odds ratio, we discovered a value of 0.99 (95% ci: 0.27 to 3.64, p: 0.98), so that the percentage distribution of dyspermia in the two groups resulted substantially comparable between the two groups and thus the testicular microlithiasis does not seem to determine the presence of dyspermia. conclusions our study showed that the testicular microlithiasis is an ultrasound fairly rare evidence, indeed, the prevalence in our series has remained around 4%, similar to that described in the literature. moreover, we have shown that the testicular microlithiasis not lead to changes in sperm quality, therefore results of spermiograms of patients with normal testes at ultrasound study were similar to those of the mt group. however, our study has several limitations: testicular ultrasound exams as well as semen analysis were performed by different operators so that results may have been affected by the interoperator variability. another important limitation is the low number of patients in the study group, justified by the fact that mt is an unusual disease so that it is difficult to perform a study with a high number of patients. further evaluation with a larger study population and greater standardization for both ultrasound of the testis and sperm evaluation would be necessary to demonstrate our thesis and to reach statistically significant conclusions about the correlation between mt and dyspermia, although our work is one of the few in the literature who analyzed this connection. references 1. yee ws, kim ys, kim sj, et al. testicular microlithiasis: prevalence and clinical significance in a population referred for scrotal ultrasonography. korean j urol. 2011; 52:172-7. 2. dutra ra, perez-bóscollo ac, melo ec, cruvinel jc clinical importance and prevalence of testicular microlithiasis in pediatric patients. acta cir bras. 2011; 26:387-90. 3. peterson ac, bauman jm, light de, et al. the prevalence of testicular microlithiasis in an asymptomatic population of men 18 to 35 years old. j urol 2001; 166:2061-2064. 4. van casteren nj, looijenga lh, dohle gr. testicular microlitiasis and carcinoma in situoverview and proposed clinical guideline. int j androl. 2009; 32:279-287. 5. tan ib, ang kk, ching bc, et al. testicular microlithiasis predicts concurrent testicular germ cell tumors and intratubular germ cell neoplasia of unclassified type in adults: a meta-analysis and systematic review. cancer. 2010; 116:4520-32. 6. tan mh, eng c. testicular microlithiasis: recent advances in understanding and management. medscape. nat rev urol. 2011; 8:153-63. 7. wang py, shen my. testicular microlithiasis: ultrasonic diagnosis and correlation with male infertility. zhonghua nan ke xue. 2009; 15:158-60. 8. deng ch, liu gh, lü jy, et al. testicular microlithiasis influences seminal profile and testicular blood flow in infertile men. zhonghua nan ke xue. 2008; 14:606-9. 9. yee ws, kim ys, kim sj, et al. testicular microlithiasis: prevalence and clinical significance in a population referred for scrotal ultrasonography. korean j urol. 2011; 52:172-7. 10. jiang h, zhu wj. testicular microlithiasis is not a risk factor for the production of antisperm antibody in infertile males. andrologia. 2013; 45:305-9. correspondence francesco catanzariti, md (corresponding author) fracatanzariti@libero.it resident in urology ubaldo cantoro, md ubaldocantoro@tiscali.it resident in urology vito lacetera, md vlacetera@gmail.com urologist giovanni muzzonigro, md g.muzzonigro@univpm.it professor of urology, chief department of urology massimo polito, md max_polito@virgilio.it urologist, chief department of uro-andrology polytechnic university of marche, faculty of medicine, department of odontostomatologic and specialized clinical sciences, urology clinic, department of general and specialized surgery, university hospital, via conca 71 i-60020 ancona, italy catanzariti_stesura seveso 26/03/14 10:14 pagina 22 stesura seveso archivio italiano di urologia e andrologia 2013; 85, 4164 introduction prostate cancer (pca) represents the second major cause of cancer death in men (1). radical prostatectomy (rp) and radiotherapy (rt) are well-established primary therapeutic options for management of localized pca, although cancer recurrence still remains a significant concern for patients. in fact, about 27-53% of patients original paper potential usefulness of ctc detection in follow up of prostate cancer patients. a preliminary report obtained by using adnagene platform giuseppe albino 1, 2, francesca vendittelli 1, carmela paolillo 1, cecilia zuppi 1, ettore capoluongo 1 1 laboratory of molecular diagnostics, institute of biochemistry and clinical biochemistry, catholic university, rome, italy; 2 unit of urology, ospedale di andria, asl bat, italy. objective: prostate cancer (pca) represents one of the most important medical problems for males, being the second major cause of cancer death. routinely, pca patients are followed up with both periodic evaluation of serum psa levels and imaging. recently, alternative laboratory methods were proposed for pca patients’ monitoring, with contrasting results. aim of the present study was to evaluate the usefulness of a new commercially ce-ivd kit for detection of prostate circulating tumour cells. our intention was to verify the adnagene platform usefulness to identify patients with disease progression, whatever treatment ongoing, in order to modify the therapeutic process even before treatment failure is evident with imaging methods. materials and methods: twenty-one patients were enrolled and subdivided into three groups: n = 10 high risk tumor pca patients; n = 6 low risk pca patients; n = 5 sbjects without any signs of pca. adnatest prostate cancer kit was used for enrichment and molecular characterization of prostate circulating tumour cells. results: healthy subjects (with bph) and patients without metastases resulted as negative, while 3 out of 10 high risk pca patients were positive at least for one molecular marker like psa, while only two showed positivity for psma mrna. our results indicate that the test specificity is 100% and the sensitivity is 100%; of course the sample is too small to give it statistical validity. in detail we verified that only the “not responder” patients resulted positive for adnatest. conclusions: the present preliminary report provides evidence that isolation and detection of circulating tumour cells (ctcs) is feasible and it may be useful in the follow-up of patients with advanced prostate cancer. if the results of this preliminary study would be confirmed by a large prospective cohort study, it could be demonstrated that this test is a rapid diagnostic method, based on the analysis of a blood sample and useful to the clinician to decide when to change therapy for patients resistant to castration or able to confirm that, at that time, the therapy is effective. key words: prostate cancer; circulating prostate tumor cells; adnatest. submitted 12 july 2013; accepted 31 july 2013 no conflict of interest declared summary undergoing rt or rp will develop local or at distance metastases within 10 years from initial treatment and 1635% of pca patients will receive second-line treatment within 5 years of initial therapy (2, 3). routinely, pca patients are followed up with periodic evaluation of serum prostate-specific antigen (psa) levels and imaging doi: 10.4081/aiua.2013.4.164 165archivio italiano di urologia e andrologia 2013; 85, 4 potential usefulness of ctc detection in follow up of prostate cancer patients. a preliminary report obtained by using adnagene platform (tc, rmn, bone scintigraphy, 18-f choline pet) (4), although undetectable serum psa does not necessarily indicate the absence of any potential metastatic risk. in this way, the release of tumor cells into bloodstream could represent a peculiar sign of cancer aggressiveness both before and after therapy (5, 6): therefore, circulating tumour cells (ctcs) detection could provide precious informations to the clinician regarding disease status. in this context, due to the lack of additional markers able to early detect pca relapse, use of reliable test for prostate ctcs detection could provide novel opportunities for alternative therapeutic approaches (7, 8). recent studies employed rt-pcr methods for detection of prostate-specific mrnas in whole blood without any pre-selection of ctcs (9, 10). prostate-specific mrnas are considered as surrogate markers of ctc presence, although with conflicting results (11, 12). however, recent studies on individuals with prostate cancer at advanced stages, performed using the cellsearch platform (13-15), found that high ctc counts correlated with poor prognosis (13-18). ctc detection rates are really variable among studies, ranging from 54% to 62%, mainly depending on the characteristics of the patients studied (19-20). some methods for ctc characterization in pca patients are in developing or under clinical laboratory evaluation (20, 21). a recent ce-ivd method, namely adnatest prostate cancer select plus adnatest prostate cancer detect (adnagen ag, langenhagen, germany), has been commercialized for laboratory ctcs detection through multiple amplification for pca-associated transcripts (reviewed as possible useful markers for monitoring of pca patients) (22-24). in the present work, we evaluated adnagene method for discriminating pca patients at risk for metastasis from those with remission or stable disease, in order to establish if this method may be predictive or not of disease recurrence, with any ongoing therapy. we describe preliminary data that might suggest the use of this method for management of pca patients and support the clinical utility of the assay here described. materials and methods patients selection and blood sampling (more details reported in supplemental files) we selected 21 patients who were subdivided into three groups (table 1), according to d’amico (25) classification: n = 10 pca patients belonging to group i (conventionally defined as prognostic grouping stage iv), because of the high risk tumor class (gleason score (gs) = 8-10 or tnm > t2b n0 m0 or psa > 20); n = 6 pca patients included into group ii (conventionally defined as prognostic grouping stage i), who were defined as at low risk tumor class (gs = 2-6 and tnm = t1-t2a and psa < 10); n = 5 patients with benign prostate hypertrophy, without any clinical and biochemical signs of pca, used as negative controls (defined as group iii; (psa < 2 and negative digital rectal exploration or trus). group iii cases were well known patients, with psa < 2 for at least 5 years, taken from the database of our “stone center”. group ii and group iii were assayed as negative control groups. pca patients belonging to intermediate risk class (gs = 7 and tnm = 2b-t2c) were excluded. the intermediate-risk patients were excluded due to their intermediate characteristics, concerning the risk of progression and recurrence of the disease. the design of the study aims to verify, without any doubt, that patients with localized disease or without prostatic cancer may never have circulating tumor cells detectable by this method (group ii and group iii). for logical reasoning, the only patients who might have ctcs are those belonging at high risk group (group i). in the design of the “case-control” study, the group to be studied is the “group i”. groups ii and iii are control groups. we felt it was a waste of resources the introduction of a further control group consisted of intermediate risk patients. overall pca patients (groups i and ii) were treated with single or combined therapy: radical prostatectomy, external beam radiotherapy, total androgen blockade; two patients of group i started chemotherapy, because of their castration resistance. in order to reduce the biases due to the selection during the enrolment, we choose consecutively only patients who received a diagnosis of pca within previous 36 ± 4 months, while the period of observation was 12 month from first blood sample collection for testing adnatest prostate cancer kit. in fact, for each patient enrolled we collected both 7 ml of whole blood using specific preservative tubes for ctcs capture (adnagen, langenhagen, germany) and 3.5 ml of vacutainer tubes for psa measurement at diagnosis (psa time = 0). additional psa assays were done during the follow up period study (2 per year). therapeutic information and clinical characteristics of patients were collected by a trained urologist (table i). all subjects enrolled in this preliminary investigation gave their informed consent. all procedures were made following the helsinki criteria for research studies. adnatest prostate cancer select/detect blood (5 ml) samples were taken using adnacollect blood collection tubes (adnagen, langenhagen, germany) and immediately processed not later than 24 hours after blood withdrawal, since it has been reported the possible lack of stability of cancer cell transcripts (26). the immunomagnetic enrichment of ctcs was performed by using adnatest prostate cancer select and total mrna/bead mixture was retro-transcribed by sensiscript reverse transcriptase (qiagen, valencia, ca, usa) according to the manufacturer’s instructions. analysis of tumor-associated mrnas, a multiplex pcr was carried out using adnatest prostate cancer detect according to the manufacturer’s instructions. the primer mixture consisted of amplified three tumour markers (psma, psa, egfr) and one housekeeping gene (actin). evaluations of cdna run were carried out using experion 1k analysis dna chip (bio-rad hercules, ca) and 4 % agarose gel. results for the correct interpretation of adnagene test results, actin amplicons must be present in all patient’s runs (internal pcr control): actin signal represents, in fact, the positive control for cell separation, reverse transcriparchivio italiano di urologia e andrologia 2013; 85, 4 g. albino, f. vendittelli, c. paolillo, c. zuppi, e. capoluongo 166 tion and multiplex pcr. adnatest was considered positive for ctc presence if a pcr fragment of at least one tumor-associated transcript was clearly detectable and visible (peak concentration ! 10 ng/µl was fixed as the cut-off). peaks outside the above described criteria were defined as inconclusive. all assays run on our samples passed the quality control criteria. results are briefly summarized in table 1. as expected, all healthy individuals, control group iii bph patients, as well as those belonging to group ii (who presented with disease properly controlled by therapy) resulted as negative for adnatest. contrastingly, among patients belonging to group i (staging class iv), adnatest identified as positive only those who were no more responsive to firstor second-line therapy, while as negative those responsive to firstor second-line chemotherapy, although being escaped by hormone therapy. three out of ten pca group i patients resulted as positive for at least one tumor-associated marker like psa, while only two showed positivity also for psma mrna. it is important to underline that the group i patient (listed as number 2 in table 1), who was negative for adnatest during the first-line of chemotherapy, became positive for psa marker five months later (as shown in the comparison between figures 1a and1b). surprisingly, egfr mrna resulted always negative in our patients: in order to establish if the negative results were dependent on limits of adna-kit, we spiked mrna extracted from prostate cancer slices positive at immunehistochemical analysis, and we found a perfect amplification of egfr target (data not shown). our results indicate that specificity of test is 100% and sensitivity was 100% (table 2). in detail, individuals with bph (group iii) and those defined as “stage i” (group ii) resulted as negative, while all patients belonging to group i (defined as stage iv) and responsive to therapy did not show any positivity for adnatest markers, while all “not responder” patients resulted positive for adnatest. the number of patients is too small to apply the tests of analysis of variance. furthermore, figure 1a is representative of a group of patients’ amplicons analyzed with experion instrumentation. clinical characteristics and main results of adnatest are synthetically reported below for each patient. details of clinical features of 15 pca patients studied patient n. 1: showed a psa relapse perhaps only for the infiltration of the bladder neck, but the bone and lymph node metastases were not metabolically active at scintigraphy examination: this test did not indicate the need of radiotherapy on the primitive mass; patient n. 2: was resistant to hormonal treatment. he initially responded to the first level chemotherapy, but subsequently his clinical conditions worsened. the adnatest prognostic patients psa t0 grouping (stage) gs tnm therapy current psa adna markers group ia 1 332 iv 5+5 n+m+ enantone + casodex 1,68 neg 2 12 iv 5+4 n+m+ eligard + casodex + rt + cht 0,98 neg/psa* 3 136 iv 4+4 t4 n+ m0 casodex 50 + rt 0,49 neg 4 15 iv 3+5 n+ gonapeptyl + casodex rt 52 psa/psma 5 5,73 iv 4+4 pt4 rt 0,01 neg 6 7,05 iv 5+3 pt3b m+ eligard + rt 15 psa 7 128 iv 4+5 n+ m+ eligard + casodex + taxotere 68,5 psa/psma 12 9.8 iv 4+4 m+ casodex + enantone + zometa 9,29 neg 13 12 iv 4+4 t4 rt casodex suspension 0,206 neg 14 8.9 iv 3+5 pt3b n+ rrp r1 (margins +) 0,03 neg group iib 8 6,95 i 3+3 n0 m0 rrp 0,04 neg 9 9,24 i 3+2 n0 m0 eligard 0,04 neg 10 5,64 i 3+3 n0 m0 decapeptyl + casodex + rt 0,00 neg 11 9,83 i 3+3 n0 m0 rt 4,01 neg 15 4.32 i 3+3 n0 m0 rrp 4,32 neg 21 7.13 i 3+3 n0 m0 casodex 0,04 neg group iii 16 bph 0,174 neg 17 bph 1,52 neg 18 bph 0,267 neg 19 bph 0,94 neg 20 bph 1,94 neg table 1. therapeutic informations and pathological characteristics of pca and control patients, following the tnm classification (uicc, 2009). tnm = cancer staging system; gs = gleason score (all gs are “biopsy gs” because they were not submitted to rrp; only pts 8-14-15 have “rp-gs”); adna markers: psa, psma, egfr; bph = benign prostate hypertrophy. all 15 healthy normal controls resulted as negative for the three adna markers. a) group i patients belong to stage iv of pca disease, as reported in tnm classification of malignant tumors. uicc international union against cancer. 7th edn, 2009 (ref. 39). b) as reported in the text, group ii patients includes low-risk progression pca individuals, as indicated in the reference (25). *patient n. 2 was firstly negative at the adnagene test, but five month later (following the disease progression) resulted as positive. 167archivio italiano di urologia e andrologia 2013; 85, 4 potential usefulness of ctc detection in follow up of prostate cancer patients. a preliminary report obtained by using adnagene platform has confirmed the disease status; under strict radiological follow up, at distance metastases became evident three months later the molecular test resulted positive. patient n. 3: the test confirmed the efficacy of enlarged radiotherapy; patient n. 4: after lymphadenectomy, positive obturator lymph nodes were found at the extemporary frozen histological section: therefore radical prostatectomy was not performed but enlarged radiotherapy and total androgen blockade were administered. since patient has become refractory to total androgen blockade, an “anti-androgen withdrawal” was started; patient n. 5: adnatest confirmed the efficacy of adjuvant postoperative rt; patient n. 6: he is currently under chemotherapy treatment because of the resistance also to second-line hormonal therapy patient n. 7: he is no longer responsive to chemotherapy since he showing constant disease progression; patient n. 12: despite a psa increase was registered, disease progression is not yet evident. since adnatest negative, a strict monitoring of psa and ctcs overtime has been planned. patient n. 13: adnatest confirmed the good compliance associated to anti-androgen therapy suspension after radiotherapy; patient n. 14: adnatest supported the efficacy of adjuvant radiotherapy after surgery; patient n. 16: (group ii). adnatest, performed before surgery, confirmed the preoperative staging (definitive histological examination: pt2b r0 n0). we underline that patients who responded to the therapies listed in table 2 were always negative for adna markers, while the non-responder resulted as positive for both serum psa increases and prostate ctc markers. discussion several reports showed that circulating tumor cell counts correlate with prognosis in patients with advanced breast, prostate and colorectal cancers, treated by conventional and/or hormonal therapy, suggesting the use of ctcs in the clinical management of cancer patients (18, 27, 28). furthermore, for prognostic and predictive purposes, ctcs detection, when coupled to molecular characterisation of specific cell transcripts or biomarkers, could provide important clinical information in terms of monitoring of efficacy or resistance to targeted therapy: in this way, ctcs represent an accurate laboratory clinical tool for predicting patient’s outcome also in prostate cancer and providing significant advantages in the view of personalised medicine (29). over the past few years, different approaches for enrichment of ctcs in blood have been developed (5, 30-33), associated or not to molecular approaches and/or to immunological characterization, respectively (34-35). the present preliminary study was aimed to assess the usefulness of adnatest prostate cancer for detection of ctcs in two groups of pca patients (with low and high risk) as compared to non pca individuals, in order to establish if the molecular result given by this assay could be helpful for the clinical and drug management of pca patients. this test is, in fact, able to detect some prostate or cancer-specific markers such as psa, psma and egfr (23, 24). in our study we found that adnatest: a) identified patients with disease progression or with biochemical relapse; b) confirmed the clinical staging of patient n.1, who showed biologically aggressive disease (gs 10) and biochemical tumor progression in spite of total androgen blockade or combined androgen blockade; c) likewise, in patient n. 2, molecular test agreed firstly with the efficacy of chemotherapy, due to the blood negativity for adnatest during the first line of cht, while only five months later adnatest resulted as positive, anticipating the results of radiological examination (the latter indicating at distance metastases only after three months from the evidence of a positive test for ctcs); d) adnatest was an useful predictive indicator for patient n.12, who was no more responsive to chemical castration so that anti-androgen therapy was currently discontinued. patients enrolled in the present study are now under stringent follow-up, since they group i patients psa t0 gs tnm therapy current psa adna markers responders 1 332 5+5 n+m+ enantone + casodex 1,68 neg 2* 12 5+4 n+m+ eligard + casodex + rt + cht 0,98 neg 3 136 4+4 t4 n+ m0 casodex 50 + rt 0,49 neg 5 5,73 4+4 pt4 rt 0,01 neg 12 9.8 4+4 m+ casodex + enantone + zometa 9,29 neg 13 12 4+4 t3a rt casodex suspension 0,206 neg 14 8.9 3+5 pt3b n+ rrp r1 (margins +) 0,03 neg not responders 4 15 3+5 n+ gonapeptyl + casodex rt 52 psa/psma 6 7,05 5+3 pt3b m+ eligard + rt 15 psa 7 128 4+5 n+ m+ eligard + casodex + taxotere 68,5 psa/psma responder patient became not-responder 2* 12 5+4 n+m+ eligard + casodex + rt + cht 6,81 pos* table 2. patient stratification based on response to single or combined therapies. archivio italiano di urologia e andrologia 2013; 85, 4 g. albino, f. vendittelli, c. paolillo, c. zuppi, e. capoluongo 168 are followed by psa assays overtime (every four months), and ct scan every six months, in order to plan other ctc tests for monitoring of disease progression. regarding the molecular typing performed after enrichment, the use of multiplex adnagen pcr may improve the detection of at least one marker potentially associated to circulating prostate tumor cells and possibly associated to poor prognosis. although mrna-psa is not unanimously considered as a better independent prognostic factor as compared to serum psa detection (36), a limit of this test is that tumor-associated proteins, like psa, are also expressed in normal cells. nevertheless, in our test, when the suggested cut-off of 10 ng/ml was used, no false-positive results, particularly in bph patients, were found. furthermore, several studies suggested the use of psma, alone or combined to psa-mrna, to increase assay specificity in pca patients (36), psma being over-expressed in advanced or in castration resistant pca (37) and preferentially expressed in anaplastic cells, hormone-refractory cells and bone metastases (38). conclusions in our opinion, molecular analysis of ctcs through psma mrna detection could provide important information for clinicians in terms of prediction of disease recurrence, before imaging findings. this finding demonstrates the potential role of ctcs in the follow up of the prostatic cancer; it can be obtained in a routine practice setting, by a simple blood sampling. we underline that although the present study did not compare the efficiency of adnatest with that of other platforms (in particular the cellsearch system), we can assume that our test may be considered as reliable: in fact, in this regard, andreopoulou e et al have recently reported the concordance between these two methods (40). finally, our results should be confirmed on larger cohorts of patients also considering that this type of test should be performed in laboratories with high expertise personnel in strict relationships with clinical departments. references 1. heidenreich a, bolla m, joniau s, et al. guidelines on prostate cancer eur urol. 2011; 59:61-71 and 59:572-83. 2. taplin me, bubley gj, shuster td, et al. mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. n engl j med. 1995; 332:1393-8. 3. chi kn, bjartell a, dearnaley d, et al. castration-resistant prostate cancer: from new pathophysiology to new treatment targets. eur urol. 2009, 56:594-605. 4. kruck s, gakis g, stenzl a. circulating and disseminated tumor cells in the management of advanced prostate cancer. adv urol. 2012;135281. epub 2011 aug 21. 5. paterlini-brechot p, benali nl. circulating tumor cells (ctc) detection: clinical impact and future directions. cancer lett. 2007; 253:180-204. 6. pantel k, brakenhoff rh, brandt b. detection, clinical relevance and specific biological properties of disseminating tumour cells. nat rev cancer. 2008; 8:329-40. 7. allard wj, matera j, miller mc, et al. tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with non-malignant diseases. clin cancer res. 2004; 10:6897-904. 8. jost m, day jr, slaughter r, et al. molecular assays for the detection of prostate tumor derived nucleic acids in peripheral blood. mol cancer. 2010; 2:174. figure 1a-b. amplification results obtained on a group of pca patients. adnatest results on some of patient samples analyzed with the experion instrument (biorad). dna size standards (ladder) and the pcr positive control are shown in the first and in the last lanes. the positive control generates fragments of following sizes: psma: 449 bp, psa: 357 bp, egfr: 163 bp, actin: 111 bp. patients 4 and 7, are positive for psa and psma targets. patient 6 is positive only for psa mrna. the remaining lanes are negative for any tumour associated-markers and show only the actin band as internal control. adnatest result of patient n. 2 on 4% agarose gel after five months from first-line of cht administered. ladder 1 2 3 4 6 7 10 11 + 2 ladder + 1a 1b 1500 850 700 500 400 300 200 150 100 50 15 169archivio italiano di urologia e andrologia 2013; 85, 4 potential usefulness of ctc detection in follow up of prostate cancer patients. a preliminary report obtained by using adnagene platform 9. moreno jg, croce cm, fischer r, et al. detection of hematogenous micrometastasis in patients with prostate cancer. cancer res. 1992; 52:6110-12. 10. katz ae, olsson ca, raffo aj, et al. molecular staging of prostate cancer with the use of an enhanced reverse transcriptasepcr assay. urology. 1994; 43:765-75. 11. sokoloff mh, tso cl, kaboo r, et al. quantitative polymerase chain reaction does not improve preoperative prostate cancer staging: a clinicopathological molecular analysis of 121 patients. j urol 1996; 156:1560-66. 12. thiounn n, saporta f, flam ta, et al. positive prostate-specific antigen circulating cells detected by reverse transcriptase-polymerase chain reaction does not imply the presence of prostatic micrometastases. urology. 1997; 50:245-50. 13. smalla ac, gonga y, oh wk, et al. the emerging role of circulating tumor cell detection in genitourinary cancer. j urol. 2012; 188:21-6. 14. nagrath s, sequist lv, maheswaran s, et al. isolation of rare circulating tumour cells in cancer patients by microchip technology. nature. 2007; 450:1235-9. 15. ellis wj, pfitzenmaier j, colli j, et al. detection and isolation of prostate cancer cells from peripheral blood and bone marrow. urology. 2003; 61:277-81. 16. moreno jg, miller mc, gross s, et al. circulating tumor cells predict survival in patients with metastatic prostate cancer. urology. 2005; 65:713-18. 17. danila dc, heller g, gignac ga, et al. circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer. clin cancer res. 2007; 13:7053-58. 18. de bono js, scher hi, montgomery rb, et al. circulating tumor cells predict survival benefit from treatment in metastatic castration resistant prostate cancer. clin cancer res. 2008; 14:6302-09. 19. scher hi, jia x, de bono js, et al. circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: a reanalysis of immc38 trial data. lancet oncol. 2009; 10:233-9. 20. stott sl, lee rj, nagrath s, et al. isolation and characterization of circulating tumor cells from patients with localized and metastatic prostate cancer. sci transl med. 2010; 2:25ra23. 21. rosenberg r, gertler r, friederichs j, et al. comparison of two density gradient centrifugation systems for the enrichment of disseminated tumor cells in blood. cytometry. 2002;49:150-58. 22. todenhöfer t, hennenlotter j, feyerabend s, et al. preliminary experience on the use of the adnatest® system for detection of circulating tumor cells in prostate cancer patients. anticancer res. 2012; 32:3507-13. 23. reynolds ma. molecular alterations in prostate cancer. cancer lett. 2008; 271:13-24. 24. bickers b, aukim-hastie c. new molecular biomarkers for the prognosis and management of prostate cancer--the post psa era. anticancer res. 2009; 29:3289-98. 25. d’amico av, whittington r, broderick ga. biochemical outcome after radical prostatectomy, external beam radiation therapy or interstitial radiation therapy for clinically localized prostate cancer. jama. 1998; 280:969-74. 26. benoy ih, elst h, van dam p, et al. detection of circulating tumour cells in blood by quantitative real-time rt-pcr: effect of pre-analytical time. clin chem lab med. 2006; 44:1082-7. 27. cohen sj, punt c j, iannotti n, et al. relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. j clin oncol. 2008; 26:3213-21. 28. torino f, bonmassar e, bonmassar l, et al. circulating tumor cells in colorectal cancer patients. treat rev. 2013 jan 30. doi:pii: s0305-7372(13)00002-9. 10.1016/j.ctrv.2012.12.007. 29. farace f, massard c, vimond n, et al. a direct comparison of cellsearch and iset for circulating tumour-cell detection in patients with metastatic carcinomas. british journal of cancer. 2011; 105:847-53. 30. alix-panabieres c, riethdorf s, pantel k. circulating tumor cells and bone marrow micrometastasis clin. cancer res 2008; 14:5013-21. 31. allan al, vantyghem sa, tuck ab, et al. detection and quantification of circulating tumor cells in mouse models of human breast cancer using immunomagnetic enrichment and multiparameter flow cytometry. cytometry. 2005; 65:4-14. 32. wiedswang g, borgen e, schirmer c, et al. comparison of the clinical significance of occult tumor cells in blood and bone marrow in breast cancer. int j cancer. 2006; 118:2013-19. 33. wong ns, kahn hj, zhang l, et al. prognostic significance of circulating tumour cells enumerated after filtration enrichment in early and metastatic breast cancer patients. breast cancer res treat. 2006; 99:63-9. 34. stathopoulou a, vlachonikolis i, mavroudis d, et al. molecular detection of cytokeratin-19-positive cells in the peripheral blood of patients with operable breast cancer: evaluation of their prognostic significance. j clin oncol. 2002; 20:3404-12. 35. benoy ih, elst h, van der auwera i, et al. real-time rt–pcr correlates with immunocytochemistry for the detection of disseminated epithelial cells in bone marrow aspirates of patients with breast cancer. br j cancer. 2004; 91:1813-20. 36. doyen j, alix-panabièresd c, hofmanb p, et al. circulating tumor cells in prostate cancer: a potential surrogate marker of survival. crit rev oncol hematol. 2012; 81:241-56. 37. perner s, hofer kr, shah rb, et al. prostate-specific membrane antigen expression as a predictor of prostate cancer progression. hum pathol. 2007; 38:696-701. 38. israeli rs, powell ct, corr jg, et al. expression of the prostatespecific membrane antigen. cancer res. 1994; 54:1807-11. 39. sobin lh, gospodariwicz m, wittekind c. tnm classification of malignant tumors. uicc international union against cancer. 7th edn. wiley-blackwell. 2009; pp. 243-248. 40. andreopoulou e, yang ly, rangel km, et al. comparison of assay methods for detection of circulating tumor cells in metastatic breast cancer: adnagen adnatest breastcancer select/detect™ versus veridex cellsearch™ system. int j cancer. 2012; 130:1590-7. correspondence giuseppe albino, md (corresponding author) urology unit ospedale di andria asl bat ospedale “l. bonomo”, andria, italy peppealbino@hotmail.com francesca vendittelli, md carmela paolillo, md cecilia zuppi, md ettore capoluongo, md laboratory of molecular diagnostics, institute of biochemistry and clinical biochemistry, catholic university, largo a. gemelli 8 00168 rome, italy stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 98 original paper cases. the number of breast cancer sufferers increases annually (1), and there were an estimated 2.261.419 new cases worldwide in 2020 (2). in indonesia, there is a high incidence of breast cancer in bali province. based on data reported by hospital in denpasar about patient visits for breast cancer ts from august to november 2020, out of a total of 1380 patient visits, 285 were cancer patients. breast cancer greatly affects a woman's life, and a recent study noted the importance of carrying out follow-up health checks, addressing post-treatment concerns, and improving the wellbeing and quality of life of cancer survivors (3). a high level of unmet needs in cancer survivors is associated with a poor quality of life. this condition can be attributed to the low attendance to care, which is rarely accepted by cancer survivors in indonesia. to remedy the situation, healthcare professionals, especially nurses, should be trained to identify various problems and unmet needs experienced by breast cancer survivors so they can provide holistic nursing care (medical, psychological, social, spiritual, and cultural) for cancer survivors (4). another study suggested that of all cancer care today, breast cancer patients represent the largest patient group with high supportive care needs (5). accordingly, it is important to strive to better understanding breast cancer survivors’ unmet needs, which should be explored in-depth. to do so, we must explore the experiences of breast cancer survivors, especially the balinese breast cancer survivors. materials and methods the research design used in this study was an interpretative phenomenological qualitative research design to examine the unmet needs of breast cancer survivors following cancer therapy. participants in this study were selected using a purposive sampling method. the sample in this study were breast cancer survivors who had experiences related to unmet needs according to inclusion criteria set by the researcher. the inclusion criteria in this study were: i) female breast cancer survivors from various age groups, both young adults and elderly adults; ii) breast cancer survivors who wish to discuss unmet needs. the number of subjects included in this qualitative descriptive study was of 14 participants. data was collected through in-depth interviews with all participants. objective: to explore: 1) the unmet needs of breast cancer patients; 2) the sexual needs experienced by breast cancer survivors; 3) the experiences of cancer patients at the time of relapse, including the biopsychosocial-spiritual aspects of their experiences. materials and methods: interpretative phenomenological qualitative research by conducting direct in-depth interviews with participants who met the inclusion criteria. sample analyzed were breast cancer survivors who had experiences related to unmet needs (14 participants) or sexual problems (12 participants); adult cancer patients who experienced recurrences (10 participants). results: themes identified for breast cancer patients with unmet needs were i) overcoming health problems in breast cancer survivors; ii) need to access the best health services; iii) women’s unmet information needs concerning cancer treatment. for breast cancer survivors: i) information is needed to overcome sexual problems, ii) family support is needed to get sexual information, and iii) health care facilities need to provide sexual information. for patients experiencing recurrences: i) the reaction that occurs when receiving bad news; ii) efforts made during a relapse, iii) self-concept during a relapse. conclusions: health-related problems of breast cancer survivors, such as fatigue and fear of cancer recurrence, can lead them to have trouble with social relationships, question their spirituality, and struggle with sex and sexuality. oncology nurses and other professionals need to be aware of the unmet needs of breast cancer survivors, especially in relation to resolving the sexuality issues of cancer survivors. understanding of the experiences of patients with relapse of different types of cancer should be improved. key words: cancer patients; cancer recurrence; cancer therapy; relapse; resilience; breast cancer; unmet needs; sexuality; survivors. submitted 10 march 2023; accepted 18 march 2023 breast cancer survivors' unmet needs following chemotherapy * (ida ayu made ari santi tisnasari, tuti nuraini, yati afiyanti) introduction breast cancer is the most common malignancy in women worldwide, accounting for almost one in four cancer psychological and sexual problems of cancer survivors ida ayu made ari santi tisnasari 1, tuti nuraini 2, yati afiyanti 3, rudi rudi 4, riri maria 5 1 faculty of nursing, universitas indonesia, depok, indonesia; 2 department of basic science and fundamental nursing, faculty of nursing universitas indonesia, depok, indonesia; 3 department of maternity nursing, faculty of nursing universitas indonesia, depok, indonesia 4 master of nursing program, faculty of nursing universitas indonesia, depok, indonesia; 5 department of medical surgical nursing, faculty of nursing universitas indonesia, depok, indonesia. presented as conference papers at the 8th v-binc at fon universitas indonesia. doi: 10.4081/aiua.2023.11473 summary archivio italiano di urologia e andrologia 2023; 95, 2 ida ayu made ari santi tisnasari, tuti nuraini, yati afiyanti, rudi rudi, riri maria 99 this research was conducted in march-june 2022. the study was conducted at the hospital in bali province, indonesia. this study used the researcher himself as the research instrument. the researcher collected the data by himself without a research assistant or co-researcher. the data analysis process in this study was carried out based on the research protocol, regarding the thematic approach to analysis, namely identifying, analyzing, and reporting patterns (themes) of the data (6). results theme 1: overcoming health problems in breast cancer survivors. theme 2: need to access the best health services. theme 3: unmet information needs about cancer treatment. (details are available in supplementary materials) discussion several themes were obtained from the data analysis. the three main themes were: i) overcoming health problems in breast cancer survivors; ii) need to access the best health services; iii) unmet information needs about cancer treatment. each of those themes were below discussed in more detail in comparison of the existing literature. overcoming health problems in breast cancer survivors the first theme that emerged through this work was the challenge that women must face as a result of the health problems they experience as breast cancer survivors. such challenges can be physical, psychological, social, spiritual, and sexual. physical problems reported included memory loss and stiff joints, although the most common physical problem reported by participants was fatigue. breast cancer survivors reported a lower quality of life than other women even years after completing their treatment due to experiencing disturbing and long-lasting side effects, including cancer-related fatigue, which can affect breast cancer survivors for many years after their treatment is completed (5). another physical challenge experienced by the participants was memory loss. there are various research results on how memory decline or cognitive impairment can occur in breast cancer survivors. a study reported that memory loss in breast cancer survivors can be more severe in patients undergoing chemotherapy as a side effect of treatment (6). another study similarly concluded that memory decline in breast cancer survivors could occur for years with significantly impact on the quality of life (7). memory loss due to side effects of cancer treatment is known generally as “chemo fog” or “chemo brain” or in medical terms as cancer-related cognitive impairment. it can be exacerbated by hormonal treatment, commonly taken after breast cancer therapy (8). it is recommended that nurses are trained to provide interventions to overcome memory loss problems, such as teaching mindfulness-based stress-reduction exercises (9). a further physical challenge experienced by participants was stiffness in their hands. according to research among breast cancer survivors in africa, stiffness in the hands is widely experienced, along with pain (10). another study described side effects caused by cancer treatment including problems in the hands and shoulders and muscle strength in breast cancer survivors (11). these effects can reduce the quality of life of survivors by creating barriers to carrying out daily activities, such as dressing, combing their hair, working, shopping, exercising, etc. accordingly, nurses should provide interventions to help women reduce the stiffness in their hands, such as by teaching them arm and shoulder muscle exercises (12). a further physical health-related challenge breast cancer survivors often face is changes in their appearance, such as weight loss. according to research, cancer therapy causes weight fluctuations, as well as changes in skin and nail color (13). breast cancer survivors often feel embarrassed, lose their confidence, and have body image problems due to their changed appearance. to provide support, various nursing interventions may be directed toward increasing the confidence of women with breast cancer and survivors to breast cancer, such as running beauty care activities, holding discussions with cancer survivors, or offering cognitive behavioral therapy to women with body image problems (12). another challenge experienced by breast cancer survivors after chemotherapy was psychological, largely constituted by fear of recurrence. the fear was greatest when the participants felt unwell, when going to the hospital for restaging, or when they heard of others with a diagnosis or metastasis (14). they explained that after receiving cancer treatment, the transition to the life of a breast cancer survivor brings a series of challenges, the most important being the worry that remission will not last and they will one day need to resume treatment. this worry causes women to stress and affects their quality of life. commonly, after chemotherapy, breast cancer survivors also experience social challenges due to their increased sensitivity, which prompts them to limit how much they socialize. the participants in this study stated that they assumed other people did not fully understand the situation they were facing, which implies that they were now quickly irritated and easily angered because of the chemotherapeutic drugs they had taken. this, of course, affected the participants’ relationships with the people around them. they notably socialize less than they had in the past and had feelings of being unproductive. such an outcome is in accordance with the results of other research that showed that the treatment of subjects with cancer also impacts on the people closest to them (14). all participants in this study also faced spiritual challenges, such as questioning their faith or wanting to end their life because they felt alone, despairing, like they had failed to achieve their life goals, or overcome family problems. other participants stated they were disappointed with the hand they had been dealt or felt as if all they ever got out of life were problems. this was different from the research finding who suggested that individuals tend to turn to spirituality to overcome cancer (15). greater overall spirituality was associated with fewer depressive symptoms and a better quality of life in individuals living with cancer or other illnesses. the researchers noted that for latinx breast cancer survivors, in particular, religion and spirituality are essential for overcoming cancer. although a cancer diagnosis increases feelings of vulnerability in latinx breast cancer survivors, the cancer event strengthens their spirituality. archivio italiano di urologia e andrologia 2023; 95, 2 100 problems of cancer survivors spirituality is a helpful source of coping for latinx cancer patients during both the treatment phase and the ensuing long-term survivor phase. the benefits of spirituality include a feeling of satisfaction, a sense of peace or harmony with life, and the comfort of feeling accompanied by a spiritual presence. the different findings in this study may have resulted due to factors that affected the participants’ spirituality, for instance, economic factors or life events that caused the participants to fall into despair and feel disappointed with this turn in their lives. to prevent that from happening, nurses should lead spiritual-based interventions such as preparing a spiritual care program that is tailored to a patient’s beliefs, supporting their spiritual well-being both as a patient and later as a breast cancer survivor (16). some of the participants in this study also faced challenges around sex and their sexuality, namely relationship problems with their husbands in married breast cancer survivors, or self-acceptance problems with potential sexual partners for unmarried breast cancer survivors (17). cancer treatment can cause reduced vaginal lubrication, impaired sexual desire and arousal, pain during sexual activity, and the stigmatization of a woman as "cancer contagious". such effects are hugely significant and detrimental to a women’s sense of fulfillment since sex and sexuality are basic elements of human life, regardless of whether or not someone has a long-term sexual partner. the need to access the best health services the second key theme that emerged from this research was a need to access the best health services, with accurate cancer-detection tools and friendly nurses. participants explained the importance of having a pet scanner and bone-scanning equipment available at the nearest hospital so that cancer survivors who wish to use these facilities do not need to travel outside the area to obtain accurate staging results. such tools are valuable for preventing errors when detecting cancer metastases in breast cancer survivors according to research showing that bone-scanning tools are very useful for detecting the incidence of bone metastases at an early stage (18). an article previously highlighted the importance of the introduction of accurate cancer-detection tools in regional hospitals so that survivors do not have to travel far for examinations, especially those concerning the incidence of metastases, and we support that request (19). in addition, we must note the importance of nurses adopting a caring attitude for patients and cancer survivors. care for each survivor must be specific, based on their history of treatment. survivorship services are usually offered in indonesia to every patient who completes cancer treatment seeing as each therapy has shortand long-term impacts that affect the quality of life of cancer survivors (20). to improve the current offering, nurses must be trained to help cancer survivors overcome health-related challenges such as fatigue, cognitive disorders, depression, and issues around sex. oncology nurses should understand the stages of breast cancer care so they can better understand survivors and adopt a caring attitude to meet the needs of breast cancer survivors. unmet information needs about cancer treatment a final theme identified in this study was the participants’ unmet needs regarding cancer care information, such as information on the treatment stages, how to cope with the side effects of the therapy, the latest treatment information, and signposting to information technology resources to accompany their cancer care. in the research conducted among breast cancer survivors in south korea, their greatest unmet need was in the domain of information, comprising a need for information about examinations and treatment, symptoms that need to be referred to the hospital, and how to see a doctor quickly and easily when needed (21). paired with the results of this study, these findings should provide valuable resources for those developing new interventions in the nursing field. it is vital that health information technology is made soon applied to make it easier for breast cancer survivors to obtain the information they need regarding their cancer care. conclusions the research results from this qualitative study exploring health problems and unmet needs in breast cancer survivors after chemotherapy lead us to highlight three key takeaways: i) breast cancer survivors must overcome various challenges associated with health problems; ii) they are highly motivated to access the best health services; iii) these survivors have unmet information needs about cancer treatment. a key consideration is how survivors’ health-related challenges, such as fatigue, fear of cancer recurrence, issues with social and romantic relationships, and spiritual distress, can create barriers to these women attending appointments for restaging. to increase their life expectancy and the survival rate after cancer treatment in indonesia, oncology nurses and other healthcare professionals must strive to understand better the challenges breath cancer survivors face, and accordingly, adapt their nursing practice to meet survivors’ needs better. special information to discuss sexuality problems: a balinese breast cancer survivor's unmet need ** (ida ayu made ari santi, yati afiyanti, tuti nuraini) introduction breast cancer is the most common malignancy in women worldwide, accounting for almost one in four cases of cancer. the number of breast cancer sufferers is increasing every year (1). it was estimated that in 2020, there were 2.261.419 new cases of breast cancer worldwide (22). in indonesia, bali is one of the provinces with the highest incidence of breast cancer. based on data from sanglah hospital denpasar, of a total of 1.380 patient visits to sanglah hospital between august and november 2020, 285 visits were made by cancer patients. the experience of breast cancer greatly affects a woman's life. recent studies confirm the importance of carrying out regular health checks, addressing post-treatment concerns, and improving the well-being and quality of life (qol) of cancer survivors (3). the development of technology and public awareness of the importance of early detection of breast cancer has led to an increase in the survival rate of breast cancer patients (23). an increased survival rate should be accompanied by archivio italiano di urologia e andrologia 2023; 95, 2 ida ayu made ari santi tisnasari, tuti nuraini, yati afiyanti, rudi rudi, riri maria 101 an increased qol. however, in many breast cancer survivors, sexual problems affect their qol. sexual health concerns have been reported in 50% of cancer survivors, and the situation, if not addressed, is likely to worsen (24). sexual issues can be complex. problems that are often reported include pain during intercourse, difficulty achieving orgasm, and psychological struggles, such as impaired body image, accompanied by reduced feelings of femininity and sexual attractiveness, which cause the partner to be less interested. feelings of femininity and attractiveness generally improved only after 10 months to three years after surgery. sexual attractiveness and feeling comfortable during sexual intimacy are major problems in the first one to two years after breast surgery (23). in indonesian society, which includes that of bali, a woman’s sexuality is not considered a basic need when she is first diagnosed with breast cancer. the situation can cause her husband (or life partner) to look for other ways to fulfill his sexual needs. this can lead to complex problems if not resolved, and a better solution needs to be discussed from the beginning. balinese women want to display perfect breasts as they symbolize their beauty and sexual attractiveness. when they develop breast cancer, many problems follow, especially for their spouses. balinese women are required to perform many tasks, including satisfying their spouses sexually. however, there are many things a woman cannot do when she has had breast cancer. information about sexual needs is still a taboo topic, even though these needs are very present to balinese women. in this study, the problem of sexual needs is explored, especially the information needed by cancer survivors to enable them to overcome their sexual issues. materials and methods research design the design used in this study was interpretative phenomenological qualitative research, designed to explore the sexual needs of breast cancer survivors following their cancer therapy. sample and sampling the participants in this study were selected using the purposive sampling method. the sample was composed by breast cancer survivors who had experienced sexual needs. the inclusion criteria were: i) female breast cancer survivors of various ages; ii) breast cancer survivors who finished their primary treatment. the sample for this qualitative descriptive study comprised 12 participants. data collection data were collected through in-depth interviews. this research was conducted between march and august 2022. the study was conducted at the oncology polyclinic of sanglah hospital denpasar. the researcher collected the data by interviewing all the participants without any research assistant, so that, in this study, the researcher was the research instrument. data analysis the data analysis process in this study was based on braun and clarke’s (2006) description of the thematic analysis approach, which involves identifying, analyzing, and reporting patterns (themes) of the data. in the first phase the researcher begins to record or transcribe data in written form. then, the researcher read the results of the transcript repeatedly to find out and record emerging ideas for the next coding process. the second phase is to generate the initial coding. the third phase is developing a theme: in this phase, all the collected and coded research data are analyzed into a larger theme. the fourth phase is reviewing the requested theme: in this phase, several themes can be grouped together if they are too different. the fifth phase is defining and naming the theme: here, the researcher determines the essence of each generated theme and then refines the resulting theme for analysis. the sixth phase is reporting: this phase begins when the researcher has fully defined and analyzed a theme and writes a report on the research results obtained (6). rigor the validity of the data in this study included the aspects of credibility, transferability, and confirmability. the researcher confirmed and clarified various items that have been expressed by participants. the researcher also observed participants during the interview process. the researcher confirmed data by reflecting on research results in comparison with related papers, consulting expert researchers, and confirming information with participants. the researcher also presented the results of the verbatim transcript in the research report so that the reader could assess the accuracy of the way the researcher transferred the research results to the readers and other researchers. ethical principles this study had the potential to cause psychological discomfort or psychological fatigue in participants. therefore, the researcher applied the principles of beneficence, respect for human dignity, and confidentiality. this meant that the identity of the participants was not included, or only the initial code on the informed consent form was included. this research design was approved by the ethics committee of sanglah hospital denpasar. results 1.information is needed to overcome sexual problems 2. family support is needed to get information on sexuality 3. healthcare facilities need to provide sexual information (details are available in supplementary materials) discussion sexuality is a normal part of life. therefore, as there has been a substantial increase in the number of breast cancer survivors, it is critical to address their qol after treatment (23). the survival rate for women with breast cancer is increasing. treatment regimens are accompanied by a range of physical, psychological, existential, and social concerns (23). balinese breast cancer survivors have different issues from others in relation to meeting sexual needs since they have a distinctive culture. nevertheless, the fulfillment of their sexual needs remains an important part of their lives. archivio italiano di urologia e andrologia 2023; 95, 2 102 problems of cancer survivors based on the results of the data analysis, three main themes emerged: i) the need for information to overcome sexual problems and meet the partner’s sexual needs; ii) the need for support from the extended family to meet the need for information about sexuality; iii) the need for health care practitioners to provide information on sexuality. information needed to overcome sexual problems informant 1 explained her need for information on sexuality. the informants discussed the problems experienced in fulfilling their own and their husband’s sexual needs, such as pain during intercourse. the informants were told that there is a gel that can help reduce pain during intercourse. interventions using technology to increase relational intimacy and a sexual enhancement intervention for couples experiencing sexual difficulties following breast cancer have been shown to be acceptable, with a high level of satisfaction (25). informant 2 explained that she didn't care that her husband was cheating on her because she was more focused on her own health treatment. however, she was still annoyed with her husband and demanded him to end the affair and stay away from her. she was successful in her demands because her caste level in bali was higher than her husband's. informant 2 felt that her partner was no longer interested in her. she no longer wanted to serve her partner. this would have a complex impact on the integrity of the family. this couple needed counseling and information about their sexuality so that their qol problems would not become even more complex. the husbands of women with breast cancer need support to improve their sexual and marital relationships. education and counseling about sexual activity during treatment for breast cancer should be incorporated into healthcare programs (26). family support is needed to get information on sexuality balinese women lack support and advice from their families in relation to their sexual needs. therefore, healthcare providers play an essential role. these women do not have the support they need. they believe that sexuality is a shameful issue, and they are reluctant to ask questions about it. healthcare professionals need to talk about the possibility of sexual problems arising due to the changes in women’s bodies caused by cancer and its treatments. these women need to be encouraged to talk about these problems, with due consideration for their religious and cultural positions (27). healthcare facilities need to provide sexual information informants 3 and 11 stated that they were ashamed to discuss their sexual needs. indonesian society considers it taboo to discuss sexuality, even though it is a normal basic need that must be met. the attitudes of healthcare providers and survivors concerning what constitutes helpful and unhelpful communication behaviors when discussing sexual health concerns were misaligned in nuanced and significant ways (24). providers should make an effort to find ways to communicate effectively with survivors. informant 4 felt that the nurses and healthcare workers did not care about whether the sexual needs of survivors were met. therefore, health workers need sufficient information to help survivors. zhang et al. explained that there is a significant gap between the providers’ perceptions and the patients’ needs regarding discussions on sexual health. more effort should be made to promote the communication needed regarding sexual health (28). a study showed that there is a need for healthcare providers to discuss sexual health after breast cancer with all their patients, as it is a concern that both single and partnered breast cancer survivors have to face after treatment (29). research implications and limitations breast cancer survivors have unmet needs for information, including information about their sexual needs. cancer nursing services should be equipped to provide this information. the results of this study can provide an overview for nurses and other healthcare workers regarding the unmet needs of breast cancer survivors, especially the information needed about sexuality. this would enable nurses and other healthcare professionals to improve the quality of the healthcare services they provide by offering supportive care services that are in alignment with the needs of breast cancer survivors, thereby achieving a more holistic quality of service. in addition, the findings of this study raise the hope that there will be consultation on the problems experienced by cancer patients and survivors, which will trigger awareness of the importance of specialist oncology nurses being present in cancer care structures. furthermore, it is recommended that more comprehensive nursing care should be provided by healthcare providers to assist cancer survivors in meeting their needs. this would result in an increased life expectancy or survival rate for cancer survivors in indonesia. recommendations for further research are that the unmet needs of cancer survivor couples be investigated so that new concepts relating to supportive care can emerge. the researcher realized that there were limitations and shortcomings in this study, namely that the participants felt embarrassed to express complaints relating to the services they received at the hospital. conclusions sexuality is still a basic need of breast cancer survivors. inaccurate information or poor communication can affect the fulfillment of survivors’ sexual needs, which will have a negative impact on their qol. therefore, oncology nurses and other professionals need to understand the problems of breast cancer survivors, especially those in bali, so that they can enable them to fulfill their sexual needs. life experiences of indonesian cancer patients with cancer recurrences: interpretative phenomenology *** (rudi rudi, yati afiyanti, riri maria) introduction a patient is considered to have had a cancer recurrence when the same type of cancer cells as when first diagnosed are found either in the same or a different place archivio italiano di urologia e andrologia 2023; 95, 2 ida ayu made ari santi tisnasari, tuti nuraini, yati afiyanti, rudi rudi, riri maria 103 after at least 1 year from receiving primary treatment (30). there is no time limit for determining whether the cancer is recurrent or developing, but most clinicians consider it as a recurrence if it reappears after one year of no signs or symptoms (30). each type of cancer has a recurrence rate that varies according to the stage, histology, genetic factors, patientrelated factors, and treatment. it is believed that many recurrence rates do not take into account the latest cancer treatment options, especially when new cancer therapies are being used for certain types of cancer. therefore, recurrence rate estimates can vary between individuals and include both high and low recurrence rates. some cancers have low recurrence rates if treatment occurs at an early stage. for example, patients with breast cancer who receive an initial treatment with receptor therapy followed by maintenance therapy have a recurrence rate of 5% to 9% (31). for cancer patients, the world health organization has created evaluation criteria for classifying clinical recurrence and remission in solid tumors called the response evaluation criteria in solid tumors, which consists of several definitions including complete response, partial remission, progressive disease, and stable disease (32). the definitions are used to assess the extent of the response obtained by cancer patients who have received different modalities of treatment such as chemotherapy, radiation, and surgery. when a patient has a cancer recurrence, several problems can arise. for example, in a phenomenological study conducted by finlayson et al., on ovarian cancer patients who consider recurrence as a chronic disease, the patients were unable to make treatment decisions and had longlasting emotional distress (33). according to shao et al., other issues, such as a poor financial situation, can make an impact on the quality of life (qol) of patients with cancer recurrence (34). good coping strategies are needed to overcome the problems arising after that a patient is informed to have had a cancer recurrence. in ovarian cancer recurrence, the coping strategies used have been based more on emotions and personal beliefs (35). there are no definitive data on cancer recurrence in indonesia regarding new cases and cancer deaths. however, cancer recurrence is a significant health issue for cancer patients who experienced this problem after treatment. in addition, data regarding the varied experiences of cancer survivors in indonesia who have had recurrences are also scarce. therefore, data regarding the experiences of cancer patients who experience recurrences should be the subject of in-depth study in order to make able oncology nurses and other health care professionals to understand the problems and needs of these patients and to develop interventions to solve them. materials and methods participants a total of 13 patients treated and followed at dharmais cancer hospital who had experienced a recurrence were recruited and included according to the following inclusion criteria: i) male or female adult cancer patient who had experienced a recurrence after at least 2 months from the declared relapse; ii) could communicate well. three patients were not interviewed for the following reasons: one patient was afraid of trauma when talking about the recurrence, one patient had a worsening condition and had to be admitted to the emergency room, and one patient could not be contacted again after being confirmed. in total only 10 patients participated in the study. data collection rd (first author) conducted data collection from march 2022 to may 2022. data were collected via in-depth direct interviews with seven patients (one patient was recruited at the dharmais hospital as an outpatient, two patients were recruited through home visits, and the rest were inpatients), and three patients were interviewed by telephone. the researcher and each patient agreed on location and methods of interview. with the consent of the participants, interviews were recorded for 60 to 75 minutes. interview guidelines are shown in table 1. thematic analysis the data analysis process was performed according to six steps (6). rd and ya did the data transcription separately. then, after obtaining the transcript, they read it repeatedly and recorded or marked keywords for the coding process. the researchers used the nvivo 12 application with serial number nvp12-lu001-ed03o-25004-lobi. this application was used to perform the initial coding of each interview transcript. the initial coding activity was carried out by rd with ya. the two authors then compiled the themes; namely, all the research data that had been coded and collected was analyzed to determine larger themes. the next stage was to review the generated themes and group them into sub-themes. this process was carried out by peer debriefing. in the fifth stage, the themes were defined and named to determine the essence of each generated theme, and then these themes were refined. the final stage determined the final themes of the results of this study. results theme 1: the reaction when information about recurrence or when bad news were received. theme 2: the efforts made during a recurrence. theme 3: the patient’s self-concept during a recurrence. (details are available in supplementary materials) discussion reaction when information of recurrence was received or when bad news was received a recurrence can be detected by the onset of symptoms like those of early cancer. these symptoms reappear at table 1. interview guidelines. no question 1 what did you experience when you had a recurrence? 2 what efforts have you made to overcome the recurrence of cancer? 3 what are the things that affect your resilience when experiencing a recurrence? archivio italiano di urologia e andrologia 2023; 95, 2 104 problems of cancer survivors least one year after an initial diagnosis of cancer (36). some participants in this study expressed psychological reactions when experiencing a recurrence, such as shock, sadness, disappointment, and shame. the participants who expressed disappointment felt that they had taken care of themselves as best as they could, so why did other people who did not take such good care of themselves not experience a recurrence? those participants felt that god was mistreating them. these experiences of the participants are similar to those conveyed in the research conducted by thornton et al., who mentioned that one of the themes found in their research was an emotion with a sub-theme of anger caused by feelings of envy because the patients felt that they had done everything correctly according to the doctors’ instructions (37). this is also as stated by economou et al., who indicated that patients who received bad news felt anger and sadness early during a recurrence (38). psychological responses to bad news can affect the qol of patients. for example, the results of the research by kugimoto et al., showed that psychological responses to stress that can affect qol occur in cancer patients from news about terminal conditions, disease names, and recurrences (39). bad news must be delivered by professional health personnel, such as nurses, who must pay attention to the room's condition, time, and atmosphere so that the patient does not become emotionally stressed (40). the efforts made during a recurrence some participants chose alternative treatments such as cupping or hypnotherapy before taking conventional medical treatments when they were declared to be recurrent. some of them had used herbal treatment before the recurrence, such as drinking soursop leaves, which are believed to cure cancer. when interviewed, participants said they received information on the benefits of herbal medicines from the internet. the recurrences experienced by the participants made them stop taking soursop leaf herbal medicine as they then considered it useless. the impressions regarding treatments and herbal medicines that participants conveyed were in line with the results of a previous study that found that an average of 51% of cancer patients used alternative and complementary therapies to improve their health and treat the complications from cancer or treatments (41). a qualitative study conducted by abu sharour, on patients with colorectal cancer in jordan found that participants sought complementary treatments when experiencing a recurrence (42). it takes the participation of health workers, especially nurses, to convey that there are alternative and complementary therapies that are safe and recommended for patients with cancer. one of the participants in this study had difficulty urinating and drank a decoction of kumis kucing leaves as suggested by a friend. after drinking the decoction of kumis kucing leaves, the participant could urinate but continued to go to the hospital because the participant considered the kumis kucing treatment only temporary. research by madyastuti et al. stated that the kumis kucing plant (orthosiphon aristatus blume) that is easily found in indonesia has flavonoid ingredients with diuretic activity (43). the conventional medical therapies received by the 10 participants consisted of surgery, chemotherapy, and radiation, with no other therapies besides these were found. previous studies have suggested that the available cancer treatments apart from surgery, chemotherapy, and radiation also include immunotherapy, hormone therapy, bone marrow transplantation, and targeted drug therapy that are conventionally administered metastatic breast cancer treatment (44). as stated by birmingham children’s hospital, patients need to be prepared physically and mentally for chemotherapy, surgery, and radiation treatments (45). chemotherapy is a serious medical procedure, and it must be ensured that the patient is otherwise in good health. mental preparation creating self-efficacy has been shown to reduce emotional stress, such as in patients who are about to undergo surgery (46). participants who received general oral chemotherapy experienced a weight loss because of the effects of chemotherapy can cause nausea, vomiting, and diarrhea. after chemotherapy, the participants experienced difficulties eating and persistent diarrhea until they were given drugs to stop the diarrhea (47).after mastectomy patients are at risk for lymphedema, which is soft tissue swelling due to the accumulation of protein-rich fluid in the extracellular space, with swelling usually in the arm or hand on the side of the body that was operated on (48). swelling in the hands after surgery was also experienced by one of the participants, who received an explanation from a medical rehabilitation doctor that this condition can occur as a side effect. some participants maintained the recommended diet by consuming foods that contain protein, such as fish, meat, tofu, and tempeh, and not eating satay. in another study, it was stated that one of the causes of the occurrence and recurrence of cancer is foods that contain carcinogens, such as salted fish (30). in addition to maintaining the diet, the participants also revealed the efforts they made in maintaining a healthy lifestyle, such as exercise, routine checks, self-checking their breasts, and not smoking. cancer patients are recommended to continue physical activity because routine physical activity can prevent cancer recurrence (30). this opinion is in accordance with research conducted by rock et al., which recommended that to prevent cancer, adults should perform a physical activity of a moderate-to-heavy intensity, depending on physical condition. not smoking is also part of maintaining a healthy lifestyle because cigarettes have tobacco as primary ingredient that is an agent that causes cancer. getting closer to god when suffering from illness is another part of the efforts made for healing by asking for his help. in this study, the participants revealed the efforts that they made to get closer to god through better prayer and worship. for someone who has been able to maintain their life despite experiencing a cancer recurrence, the next stage is then personal growth. at the individual post-traumatic growth stage, the result is an increase in spiritual well-being. self-concept during a recurrence this study explored various factors that can affect survival at the time of a recurrence. in this study, it was found that some participants expressed the reasons that they believed could enable them to survive their recurrences. namely archivio italiano di urologia e andrologia 2023; 95, 2 ida ayu made ari santi tisnasari, tuti nuraini, yati afiyanti, rudi rudi, riri maria 105 they believed that they could recover, by having a strong motivation to recover and enthusiasm for undergoing treatment, obtaining support when undergoing treatment, and eating food appropriate for treating a recurrence. the participants who said that they believed that they were sure to recover demonstrated their optimism, while those participants who said they had the motivation to recover demonstrated their hope. the support for undergoing treatments can come from family or from sources other than family; in this study, it came from husbands, wives, children, parents, and neighbors. patients who experience a relapse need to be given support and hope from everyone, especially their closest family members who act as caregivers while the patients are undergoing treatment. thus, support from families (parents or children) is very important for cancer patients and those who experience a recurrence. for example, if the cancer patient is a father, they especially need support from their children. optimism, hope, and support are part of the direct path to fostering the survival of someone who has just undergone a stressful event, such as receiving news of a cancer recurrence, while how one interprets a recurrence can be an indirect pathway to building resilience. if the meaning is positive, then survival can be achieved, but if the meaning is negative, it will be a warning that makes the patient uncomfortable. achieving resilience requires evaluation. if the evaluation results are positive, they will produce optimism, hope, and will ultimately have survival. the results found in this study can be used as a basic data source for education, nurses, and hospitals to provide nursing care to cancer patients who experience recurrence. hospitals need to prepare a special room for patients who will be given bad information such as news of recurrence so that patients can convey all their feelings after hearing this information. from this research data, oncology nursing specialists can also provide information about fact-based complementary therapies so that they can be used by patients who experience relapse. cancer patients need to involve the palliative team from the start so that when cancer patients experience a relapse, their self-concept and quality of life are good. for future researchers, the results of this study can provide the latest information about cancer recurrence, so that it becomes data to quantitatively measure the problems and needs of cancer patients when they experience a recurrence. the researcher realizes that there are limitations and deficiencies in this study, namely the setting of the place used when collecting data in the hospital, that was not s dedicated room because of limited space. conclusions when patients receive information that they are experiencing a recurrence, psychological reactions, such as shock, sadness, and disappointment, occur. many efforts have been made by patients to cope with recurrences, namely through non-medical activities, medical activities, lifestyle changes, and getting closer to god. this study also found a variety of factors that can influence patients when experiencing a recurrence, such as having the confidence to recover, strong motivation to recover, enthusiasm for undergoing treatment, support in undergoing treatment, and understanding of relapse. this study can help increase our understanding of the experiences of patients with different types of cancer during a recurrence phase. acknowledgments: we are grateful to universitas indonesia for supporting our research. acknowledgement of financial support: * the study “breast cancer survivors' unmet needs following chemotherapy” was supported by the universitas indonesia under grant puti 2022 (publication international indexed 2022) no: nkb-99/un2. rst/hkp.05.00/2022. ** the study “special information to discuss sexuality problems: a balinese breast cancer survivor's unmet need” was supported by tesis magister grant from the minister of national research and technology, culture, and education, republic of indonesia no. nkb-903/un2.rst/hkp.05.00/2022. *** the study “life experiences of indonesian cancer patients with cancer recurrences: interpretative phenomenology” was supported by the universitas indonesia under grant puti 2022 (publication international indexed 2022) no: nkb101/un2. rst/hkp.05.00/2022.. references 1. lee jw, lee j, lee mh, et al. unmet needs and quality of life of caregivers of korean breast cancer survivors: a cross-sectional study. ann surg treat res 2021; 101:69-78. 2. 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cancer survivors. breast 2021; 56:103-9. 8. ng t, dorajoo sr, cheung yt, et al. distinct and heterogeneous trajectories of self-perceived cognitive impairment among asian breast cancer survivors. psychooncology 2018; 27:1185-92. 9. bellens a, roelant e, sabbe b, et al. a video-game based cognitive training for breast cancer survivors with cognitive impairment: a prospective randomized pilot trial. breast 2020; 53:23-32. 10. lambert m, ouimet la, wan c, et al. cancer-related cognitive impairment in breast cancer survivors: an examination of conceptual and statistical cognitive domains using principal component analysis. oncol rev 2018; 12:90-7. 11. boucheron p, anele a, zietsman a, et al. self-reported arm and shoulder problems in breast cancer survivors in sub-saharan africa: the african breast cancer-disparities in outcomes cohort study. breast cancer res 2021; 23:109. archivio italiano di urologia e andrologia 2023; 95, 2 106 problems of cancer survivors 12. bruce j, williamson e, lait c, et al. randomised controlled trial of exercise to prevent shoulder problems in women undergoing breast cancer treatment: study protocol for the prevention of shoulder problems trial (uk prosper). bmj open 2018; 8.e019078. 13. esteban-simón a, díez-fernández dm, artés-rodríguez e, et al. absolute and relative handgrip strength as indicators of self-reported physical function and quality of life in breast cancer survivors: the efican study. cancers (basel) 2021; 13:5292. 14. kang d, choi ek, kim ir, et al. distress and body image due to altered appearance in posttreatment and active treatment of breast cancer patients and in general population controls. palliat support care 2018; 16:137-45. 15. morales-sánchez l, luque-ribelles v, gil-olarte p, et al. enhancing self-esteem and body image of breast cancer women through interventions: a systematic review. int j environ res public health 2021; 18:1-20. 16. soriano ec, perndorfer c, otto ak, et al. does sharing good news buffer fear of bad news? a daily diary study of fear of cancer recurrence in couples approaching the first mammogram post-diagnosis. psychooncology 2021; 18:1640. 17. garduño-ortega o, morales-cruz j, hunter-hernández m, et al. spiritual well-being, depression, and quality of life among latina breast cancer survivors. j relig health 2021; 60:1895-907. 18. khezri e, bagheri-saveh mi, kalhor mm, et al. nursing care based on the support-based spiritual care model increases hope among women with breast cancer in iran. support care cancer 2022; 30:423-9. 19. kowalczyk r, nowosielski k, cedrych i, et al. factors affecting sexual function and body image of early-stage breast cancer survivors in poland: a short-term observation. clin breast cancer 2019; 19:e30-9. 20. james j, teo m, ramachandran v, et al. looking for metastasis in early breast cancer: does bone scan help? a retrospective review. clin breast cancer 2021; 21:e18-21 21. high b, bohnenkamp s, mulligan s. what you need to know about caring for breast cancer survivors. medsurg nurs 2019; 28:189-93 22. ferlay j, ervik m, lam f, et al. international agency for research on cancer 2020. glob cancer obs cancer today 2020; 419:1-2 23. almeida ng de, knobf tm, oliveira mr de, et al. a pilot intervention study to improve sexuality outcomes in breast cancer survivors. asia pac j oncol nurs 2020; 7:161-6. 24. rose m, garcia d, fisher cl, et al. communication about sexual health with breast cancer survivors : variation among patient and provider perspectives. patient educ couns 2016; 99:1814-20. 25. cullen k, fergus k. acceptability of an online relational intimacy and sexual enhancement (irise) intervention after breast cancer. j marital fam ther 2021; 47:515-32. 26. maleki m, mardani a, ghafourifard m, vaismoradi m. changes and challenges in sexual life experienced by the husbands of women with breast cancer: a qualitative study. bmc womens health 2022; 22:1-12. 27. mofrad sa, nasiri a, rad ghm, shandiz fh. spousal sexual life issues after gynecological cancer: a qualitative study. support care cancer 2021; 29:3857-64. 28. zhang x, sherman l, foster m. patients’ and providers’ perspectives on sexual health discussion in the united states: a scoping review. patient educ couns 2020; 103:2205-13. 29. tat s, doan t, yoo gj, levine eg. qualitative exploration of sexual health among diverse breast cancer survivors. j cancer educ 2018; 33:477-84. 30. american cancer society. can i do anything to prevent cancer recurrence? available from: https://www.cancer.org/content/dam/ crc/pdf/public/8423.00.pdf. 2016; 1-5. 31. colleoni m, sun z, price kn, et al. annual hazard rates of recurrence for breast cancer during 24 years of follow-up: results from the international breast cancer study group trials i to v. j clin oncol 2016; 34:927-35. 32. widhiarta pr, mahendra inb, dwi aryana, mb, megaputra ig. faktor-faktor klinikopatologi kekambuhan kanker serviks stadium iiia2 pasca histerektomi radikal di rsup sanglah periode 20192020. intisari sains medis 2021; 12:196-200. 33. finlayson cs, fu mr, squires a, et al. the experience of being aware of disease status in women with recurrent ovarian cancer: a phenomenological study. j palliat med 2019; 22:377-84. 34. shao z, zhu t, zhang p, et al. association of financial status and the quality of life in chinese women with recurrent ovarian cancer. health qual life outcomes 2017; 15:1-8. 35. lee y, praveena k, woo y, ng c. coping strategies among malaysian women with recurrent ovarian cancer: a qualitative study. asia-pacific j oncol nurs 2021; 8:40-5 36. society ac. what is cancer recurrence? am cancer soc [internet]. available from: https://www.cancer.org/treatment/survivorship-during-and-after-treatment/understandingrecurrence/what-is-cancer-recurrence.html. 2016; 1-4. 37. thornton lm, levin ao, dorfman cs, et al. emotions and social relationships for breast and gynecologic patients: a qualitative study of coping with recurrence. psychooncology 2014; 23:382-9. 38. economou d, walshe c, brearley sg. exploring the experience of recurrence with advanced cancer for people who perceived themselves to be cancer free: a grounded theory study. support care cancer 2021; 29:3885-94. 39. kugimoto t, katsuki r, kosugi t, et al. significance of psychological stress response and health-related quality of life in spouses of cancer patients when given bad news. asia-pacific j oncol nurs 2017; 4:147-54. 40. matthews t, baken d, ross k, et al. the experiences of patients and their family members when receiving bad news about cancer: a qualitative meta-synthesis. psychooncology 2019; 28:2286-94. 41. keene mr, heslop im, sabesan ss, glass bd. complementary and alternative medicine use in cancer: a systematic review. complement ther clin pract [internet]. 2019; 35:33-47. 42. abu sharour l. lived experience of jordanian colorectal cancer patients with recurrence: an interpretative phenomenological analysis. psychol heal med [internet]. 2019; 00:1-9. 43. madyastuti r, ietje wientarsih, setyo widodo, erni h purwaningsih, eva harlina. aktivitas diuretik dan analisa mineral urin perlakuan ekstrak tanaman kumis kucing (orthosiphon stamineus benth) pada tikus jantan. acta vet indones 2020; 8:16-23. 44. al-mahmood s, sapiezynski j, garbuzenko ob, minko t. metastatic and triple-negative breast cancer: challenges and treatment options. drug deliv transl res 2018; 8:1483-507. 45. birmingham children’s hospital. guidelines for the administration of chemotherapy for malignant disease. nhs found trust [internet]. available from: https://www.england.nhs.uk/midseast/wp-content/uploads/sites/7/2018/04/guidelines-administrationchemotherapy-for-malignant-disease-v2-1-0.pdf. 2015; 1–17. archivio italiano di urologia e andrologia 2023; 95, 2 ida ayu made ari santi tisnasari, tuti nuraini, yati afiyanti, rudi rudi, riri maria 107 46. marinelli v, danzi op, mazzi ma, et al. prepare: preoperative anxiety reduction. one-year feasibility rct on a brief psychological intervention for pancreatic cancer patients prior to major surgery. front psychol 2020; 11:1-14. 47. amjad mt, chidharla a, kasi a. cancer chemotherapy. in treasure island (fl) 2022. 48. wanchai a, armer jm, stewart br, lasinski bb. breast cancerrelated lymphedema: a literature review for clinical practice. int j nurs sci [internet]. 2016; 3:202-7. 49. rock cl, thomson ca, sullivan kr, et al. american cancer society nutrition and physical activity guideline for cancer survivors. ca cancer j clin. 2022; 72:230-262. correspondence ida ayu made ari santi tisnasari faculty of nursing, universitas indonesia, depok, indonesia tuti nuraini (corresponding author) tutinfik@ui.ac.id department of basic science and fundamental nursing, faculty of nursing, universitas indonesia, depok, 16424, west java, indonesia yati afiyanti (corresponding author) yatikris@ui.ac.id department of maternity nursing, faculty of nursing, universitas indonesia, depok, 16424, west java, indonesia rudi rudi master of nursing program, faculty of nursing universitas indonesia, depok, indonesia riri maria department of medical surgical nursing, faculty of nursing universitas indonesia, depok, indonesia conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2013; 85, 4210 introduction wunderlich’s syndrome is a clinical condition defined as a spontaneous renal bleeding of non traumatic origin, contained within the gerota’s fascia. in 1700, bonet was the first one who described this condition, while c.r.a. wunderlich was the first to make a clinical de scription in 1856 (1). coenen used the term wunderlich’s syndrome for the first time in 1910 (2). various authors find as underlying causes: nephritis, tu mours, vascular diseases, cysts rupture (3-7). classically it presents with acute flank pain, tender palpable mass and clinical hemodynamic deterioration. these symptoms are defined as the lenk’s classic triad (8). we present three cases of spontaneous renal bleeding. case 1 a 72 years old man presented to the emergency department with severe generalized abdominal pain. he described a 3-hour history of acutely worsening abdominal and left lumbar pain and vomiting. neither urinary symptoms nor history of trauma. he had a previous medical history positive for hypertension, dyslipidaemia and hyperuricemia. clinically he had hypertension (160/100 case report wunderlich’s syndrome: three cases of acute spontaneous renal bleeding, conservately treated andrea guttilla, alessandro crestani, francesco cattaneo, fabio zattoni, claudio valotto, massimo iafrate, fabrizio dal moro, filiberto zattoni urology clinic, department of surgical, oncological and gastroenterological sciences, university of padua, italy. wunderlich’s syndrome is a clinical condition defined as a spontaneous renal bleeding of non traumatic origin, contained within the gerota’s fascia. wunderlich’s syndrome is rare. spontaneous bleeding of kidney tumors, either benign or malignant, represents the more common causes. classically it presents with acute flank pain, tender palpable mass and clinical hemodynamic deterioration. these symptoms are defined as the lenk’s classic triad. we present three cases of spontaneous renal bleeding. key words: kidney; spontaneous bleeding; angiography; kidney tumours. submitted 21 december 2012; accepted 31 march 2013 no conflict of interest declared summary mmhg), tachycardia, a voluminous lumbar tumefaction and haematoma (figure 1). haemoglobin was 7.1 g/dl. a computed to mography (ct) was performed, showing a figure 1. case 1: voluminous lumbar tumefaction and haematoma. doi: 10.4081/aiua.2013.4.210 211archivio italiano di urologia e andrologia 2013; 85, 4 wunderlich’s syndrome: three cases of acute spontaneous renal bleeding, conservately treated large (16 cm) left perinephric haema toma with an active bleeding in the sub capsular and perirenal space. normal controlateral kidney (figure 2). the patient’s haemoglobin levels continued to decrease, and he was transfused with 4 units of blood. the patient underwent emergency em bolization (figu re 3) of a 3-cm avascular area in the left kidney at the middle third (possible sub capsular lesion) with an active bleeding from a thin arterial capsular branch of the lower renal pole. then, he was admitted to the in tensive care unit (icu) for close observation and strict bed-rest. his haemoglobin level stabilized, and he was treated conservatively. he was discharged from the urology department after 30 days. ct scans before leaving the hospital and the one made after 90 days showed significant reduction of the perirenal haema toma (figures 4, 5). one year after the patient is fine. the haematoma is completely disappeared (figures 6, 7). he still has problems of blood pressure that he is controlling with different drugs. case 2 a 75 years old woman presented to the emergency department with severe left lumbar pain. neither urinary symptoms nor history of trauma. she had a previous medical history positive for ischemic heart disease, atrial fibrillation in therapy with anticoagulants, hypertension, cronic kidney failure with an atrophic right kidney. clinically he had hypotension (110/70 mmhg), tachycardia, haemoglobin 7 g/dl, serum creatinine 300 mmol/l. the patient’s haemoglobin levels continued to decrease, and she was transfused with 5 units of blood. the patient underwent a ct scan that showed an important lumbar haematoma (figure 8). the patient underwent emergency renal arteriography that described: stenosis of the left renal artery, with no parenchymal vascularisation. the left artery was embolized with kidney exclusion. then, she was admitted to the icu for close observation and strict bed-rest. the haemoglobin levels during the staying in the icu figure 2. case 1: computed tomography (ct) showing a large (16 cm) left perinephric haematoma with an active bleeding in the sub capsular and perirenal space. figure 3. case 1: emergency embolization of a 3-cm avascular area in the left kidney at the middle third (possible sub capsular lesion) with an active bleeding from a thin arterial capsular branch of the lower renal pole. figures 4-5. case 1: ct scans at dismissal and after 90 days showed significant reduction of the perirenal haematoma. archivio italiano di urologia e andrologia 2013; 85, 4 a. guttilla, a. crestani, f. cattaneo, f. zattoni, c. valotto, m. iafrate, f. dal moro, f. zattoni 212 started to rise up. she was discharged from the urology department after 12 days with haemoglobin value of 10.3 mg/dl. the patient was lost at follow-up. case 3 a 57 years old man presented to the emergency department with acute right lumbar pain. neither urinary symptoms nor history of trauma. he had a previous medical history positive for hypertension. clinically he had normal blood pressure (140/80 mmhg). haemoglobin was 12.1 g/dl. a ct was performed, showing a large (10 cm) right perinephric haematoma with no evidence of active bleeding and a 6 cm sub capsular mass. normal contralateral kidney. we decided to treat him conservately and to treat the mass surgically after the acute problem was resolved. he was discharged from the urology department after 12 days. ct scan before leaving the hospital showed significant reduction of the perirenal haematoma and confirmed the presence of a solid area. one month after, the patient underwent open right partial nephrectomy. the pathological report showed a type 2 papillary rc, fuhrman grade 3, pt1anx. discussion wunderlich’s syndrome is a rare syndrome, with about 300 cases described in the literature. the most common causes of these spontaneous haemorrhages are represented by neoplasm (61%) (9). as benign lesion, angiomyolipoma (31.5%) is the most common, while renal cell carcinoma is the most common malignant one (10, 11). some authors have also described some other different causes as vasculitis, arteriovenous fistulas, rupture of renal artery aneurism rupture and nephritis (12). the imaging studies, for patient with suspicious of a spontaneous renal bleeding, are ct scan or angiography (9, 10). ct scan can give the opportunity to know the entity of the haematoma and the presence of an active bleeding. selective angiography with embolization is often useful in the acute phase of the haemorrhage in order to control bleeding, contribute to diagnosis and reduce the need for surgery. the management is dictated by the clinical condition of the patient and by the underlying aetiology. sometimes subjects with unstable haemodynamic condition can require an emergency nephrectomy especially if the cause of the bleeding is clear (i.e. renal cancer). in other cases, as the one described above, a conservative treatment to preserve renal function can be the best choice. also in kidney bleeding following a trauma, many authors recommend a conservative treatment if major complications, as other abdominal injuries, are not present (13, 14). eventually, if the imaging done during the follow-up shows a clear diagnosis a nephrectomy must be perfigures 6-7. case 1: ct scan after 1 year showing that haematomais completely disappeared. figure 8. case 2: ct scan showing an important lumbar haematoma. 213archivio italiano di urologia e andrologia 2013; 85, 4 wunderlich’s syndrome: three cases of acute spontaneous renal bleeding, conservately treated formed. the follow-up, after patient discharge, should be done with ct scans to monitor the haematoma reduction and with measurements of blood pressure to exclude page syndrome (15, 16). conclusion wunderlich’s syndrome is rare. spontaneous bleeding of kidney tumours, either benign or malignant, represents the more common cause. ct scan and angiography are the preferred diagnostic tools. the treatment must be tailored for single cases. conservative treatment with a periodic follow-up is often a feasible approach. references 1. wunderlich cra. handbuch der pathologie und therapie. 2nd ed. stuttgart, ebner & seubert, 1856. 2. bilesio ae, campodonico a, molina r. síndrome périrrenal espontaneo (síndrome de wunderlich). rev urol. 1962; 2:17. 3. hao lw, lin cm, tsai sh. spontaneous hemorrhagic angiomyolipoma present with massive hematuria leading to urgent nephrectomy. am j emerg med. 2008; 26:249 e3-5. 4. pummer k, lammer j, wandschneider g, primus g. renal cell carcinoma presenting as spontaneous retroperitoneal haemorrhage. int urol nephrol. 1990; 22:307-11. 5. mcdougal ws, kursh ed, persky l. spontaneous rupture of kidney with perirenal hematoma. j urol. 1975; 114:181-184. 6. cinman ac, farrer j, kaufman jj. spontaneous perinephric hemorrhage in 65-year old man. j urol. 1985; 133:829-832. 7. belville js, morgentaler a, loughlin kr, tumeh ss. spontaneous perinephric and subcapsular renal hemorrhage: evaluation with ct, us, and angiography. radiology. 1989; 172:733-738. 8. flageat j, vicens jl, cosnard g, foster d, metges pj. hématome périrrénal reévelateur d'une périartérite nouse. j radiol. 1986; 67:419-422. 9. zhang jq, fielding jr, zou kh. etiology of spontaneous perirenal hemorrhage: a meta-analysis. j urol. 2002; 167:1593-6. 10. sebastia mc, perez-molina mo, alvarez-castells a, et al. ct evaluation of underlying cause in spontaneous subcapsular and perirenal hemorrhage. eur radiol. 1997; 7:686-90. 11. oon sf, murphy m, connolly ss. wunderlich syndrome as the first manifestation of renal cell carcinoma. j urol 2010; 7:129-32. 12. albi g, del campo l, tagarro d. wünderlich's syndrome: causes, diagnosis and radiological management. clin radiol. 2002; 57:840-5. 13. moudouni sm, patard jj, manunta a, et al. a conservative approach to major blunt renal lacerations with urinary extravasation and devitalized renal segments. bju int. 2001; 87:290-4. 14. husmann da, gilling pj, perry mo, et al. major renal laceration with a devitalized fragment following blunt abdominal trauma: a comparison between nonoperative (expectant) versus surgical management. j urol. 1993; 150:1774-7. 15. wein aj, kavoussi lr campbell-walsh urology 9th edition, saunders/elsevier, 2007, p.170. 16. monstrey sj, beerthuizen gl, vanderwerken c, et al. renal trauma and hypertension. j trauma. 1989; 29:65-6. correspondence andrea guttilla, md (corresponding author) andrea.guttilla@gmail.com alessandro crestani, md alessandro.crest@gmail.com francesco cattaneo, md i.francescocattaneo@gmail.com fabio zattoni, md fabiozattoni@gmail.com claudio valotto, md claudio.valotto@sanita.padova.it massimo iafrate, md massimo.iafrate@unipd.it fabrizio dal moro, md fabrizio.dalmor@gmail.com filiberto zattoni, md filiberto.zattoni@unipd.it urology clinic, department of surgical, oncological and gastroenterological sciences, university of padua, via giustiniani, 2 35100 padua, italy stesura seveso archivio italiano di urologia e andrologia 2013; 85, 4184 introduction lower urinary tract symptoms due to benign prostatic hyperplasia (bph/luts) and benign prostatic enlargement are very common diseases in men older than 40 years (1). male sexual dysfunction are, also, very common original paper an improvement in sexual function is related to better quality of life, regardless of urinary function improvement: results from the idiprost® gold study tommaso cai 1, giuseppe morgia 2, giuseppe carrieri 3, carlo terrone 4, ciro imbimbo 5, paolo verze 5, vincenzo mirone 5, idiprost® gold study group * 1 department of urology, santa chiara regional hospital, trento, italy; 2 department of urology and department of hygiene and public health, university of catania, catania, italy; 3 department of urology and renal transplantation, university of foggia, foggia, italy; 4 division of urology, aso maggiore della carità university hospital, university of eastern piedmont, novara, italy; 5 department of urology, university federico ii of naples, italy. objective. the relationship between lower urinary tract symptoms (luts) and erectile dysfunction (ed) has recently received increased attention. the aim of this study was to evaluate the efficacy of the alfa-5® association of serenoa repens, pinus massoniana bark extract (pmbe) and crocus sativus (idiprost® gold) in improvement of patient’s quality of life, when compared with serenoa repens alone. materials and methods. all patients with clinical and instrumental diagnosis of luts due to benign prostatic hyperplasia (bph) and ed, attending 5 italians urological institutions from may to december 2012 were enrolled in this prospective, multicentre, phase 3 study. participants were assigned to receive oral capsules of idiprost® gold (one capsule q24 h) or serenoa repens 320 mg (one capsule q24h) for 3 months. clinical and instrumental analyses were carried out at the enrolment and at the end of therapy. ipss, iief-5 and sf-36 questionnaires have been used. the main outcome measure was the improvement of quality of life at the end of the whole study period. results. 129 (mean age 45-71 ± 4.36) men were randomly allocated to idiprost® gold (n = 83) or serenoa repens (n = 46). the baseline questionnaire mean scores were 17.1 ± 6.4, 14.9 ± 3.7, 96.3 ± 1.2 for ipss, iief-5 and sf-36, respectively. at the follow-up examination, statistically significant differences have been reported in terms of ipss (11.9 vs 13.8; p < 0.001), iief-5 and sf-36 mean scores (19.3 vs 16.1; 99.7 vs 96.3; p < 0.003; p < 0.001). moreover, statistically significant differences were then reported between the two visits, in terms of ipss, iief-5 and sf-36 scores (p < 0.003; p < 0.001; p < 0.001), only in the idiprost® gold group. conclusions. in conclusions, we found that idiprost® gold significantly improve the quality of life of patients affected by luts due to bph and ed, specifically in terms of sexual function, highlighting that a better sexual quality of life is correlated with an higher overall quality of life regardless of the urinary function. key words: bph; luts; erectile dysfunction; serenoa repens; crocus sativus; quality of life. submitted 27 july 2013; accepted 5 october 2013 no conflict of interest declared summary in this population; in the european male ageing study of 3,369 community-dwelling men aged 40-79 years, moderate or severe erectile dysfunction (ed) was reported by 6% of men in their forties, rising to 64% of men aged over doi: 10.4081/aiua.2013.4.184 cai_stesura seveso 18/12/13 10:43 pagina 184 185archivio italiano di urologia e andrologia 2013; 85, 4 sexual function improvement and quality of life 70 years (2). moreover, in the multinational survey of the ageing male (msam-7) the overall prevalence of luts was 90%, while the overall prevalence of ed was 49%, highlighting that rate of ed was significantly dependent on age and correlated highly with the severity of luts (3). both bph⁄ luts and sexual dysfunction have a substantial negative impact on a man’s quality of life and are considered a serious socio-economic problem (4). the current therapies for bph/luts are associated with bothering sexual side effects, however, differing in rate and characteristics between different classes of medications, different medications within the same classes, and different combinations of drugs (5). for these reasons, pde5-is are introduced in the italian pharmacopeia as an effective and treatment for luts associated with ed. even if pde5-is are effective either alone or in combination with !-blockers in men with bph/luts, some adverse events, such as headache, dyspepsia, and back pain, are commonly reported (5). furthermore, future studies are needed to evaluate the long-term safety and efficacy outcomes and the overall cost-effectiveness analysis of this treatment (5). on the basis of the evidences, the use of phytotherapy in treating lower urinary tract symptoms and benign prostatic hyperplasia has been popular in europe for many years with promising results. in the last years, the attention has been focused on the both luts/bph and ed treatment, due to the patient’s request to improve his sexual and urinary quality of life. recently, the alfa-5® association of serenoa repens, pinus massoniana bark extract (pmbe) and crocus sativus, named idiprost® gold, has been produced in order to improve the micturition parameters and sexual function in patients affected by luts/bph and ed. the effects on micturition parameters are due to the effects of serenoa repens, as well known, and the effect on sexual function has due to pmbe and crocus sativus. we aimed to evaluate the efficacy of the alfa-5® association serenoa repens, pmbe and crocus sativus (idiprost® gold) in improvement of patient’s quality of life, when compared with serenoa repens alone. materials and methods study design all patients with clinical and instrumental diagnosis of luts due to bph and ed, attending 5 italians urological institutions from may to december 2012 were enrolled in this prospective, multicentre, phase 3 study. all patients underwent clinical and instrumental examinations and ipss, iief-5 and sf-36 questionnaires. after enrolment, all patients were assigned to receive oral capsules of idiprost® gold (one capsule q24h) or serenoa repens 320 mg (one capsule q24h) for 3 months. the main outcome measure was the improvement of quality of life at the end of the whole study period, evaluated by questionnaires results. inclusion and exclusion criteria patients were eligible for inclusion if they had to meet all of the following criteria: age of 50 years or older; to be sexually active; maximal urinary flow rate (cmax) of less than 15 ml/s; post-residual voided volume less than 100 cc; an international prostate symptom score (ipss) of 8 or greater and an ipss-quality of life (qol) score of 2 or greater; prostate specific antigen (psa) less than 4 ng/ml, or higher if negative prostate biopsy; an international index of erectile function (iief-5) score less than 21; to be untreated for luts/bph; testosterone level more than 3 ng/dl. we excluded all patients affected by major concomitant diseases such as diabetes, liver, and/or renal failure; had known anatomical abnormalities or malignancy of the urinary tract, bladder, or upper tract stones, diverticula, foreign bodies, prostatitis, active urinary tract infection, chronic retention or had polycystic kidney disease. moreover, we excluded all patients with urethral stenosis interfering with the evaluation of voiding function; patients with a history of transurethral resections of the prostate (turp), laser therapy, or thermotherapy. similarly, all patients who tested positive for sexually transmitted diseases such as chlamydia trachomatis, ureaplasma urealyticum or neisseria gonorrhoeae were excluded. moreover, all patients with allergy to one or more compounds of idiprost® gold were also excluded. all patients treated with pde5-is were excluded too. study and treatment schedule on arrival at each centre, all eligible individuals signed written informed consent and underwent a baseline questionnaire, urological examination with anamnestic interview and uroflowmetry (cmax) with evaluation of post voided residual volume (pvr), in accordance with the procedure described in eau guidelines (6). psa value has been previously evaluated. all patients who met the inclusion criteria were assigned to groups according to a 1:1 randomization (figure 1). group a: idiprost® gold (one capsule q24h). group b: serenoa repens 320 mg (one capsule q24h). all patients underwent treatment for 3 months. all patients were contacted by telephone on day 30 of the therapy to ensure correct timing and dose treatment. each subject was scheduled for follow-up examination at 3 months from starting therapy, with a urological visit, uroflowmetry with evaluation of pvr and questionnaires to be filled in. no placebo arm was included. the possible biases caused by the lack of placebo arm were considered in the results analysis. the main outcome measure was the improvement of quality of life at the end of the whole study period, in terms of changes in ipss, ipss-qol, cmax, pvr, sf-36 and the iief-5 from baseline to the evaluation point, that is, 3 months. clinical failure was defined as the persistence of symptoms after the treatment, or the suspension of therapy for significant reported adverse effects. in addition, spontaneously reported adverse events, or those noted by the investigator, were recorded during the whole study period. the study was conducted in line with good clinical practice guidelines, with the ethical principles laid down in the latest version of the declaration of helsinki. questionnaires and urological examinations the validated italian versions of the international prostatic symptom score (ipss) (7), international index of erectile function (iief-5) (8) and sf-36 (9) were administered to each patient. cai_stesura seveso 18/12/13 10:43 pagina 185 archivio italiano di urologia e andrologia 2013; 85, 4 t. cai, g. morgia, g. carrieri, c. terrone, c. imbimbo, p. verze, v. mirone, idiprost® gold study group 186 the questionnaire was offered to the patient on arrival at each centre. all questionnaires were also used in determining clinical therapy efficacy. composition and characterisation of the extracts used all patients assigned to group a were orally administered idiprost® gold once daily. idiprost® gold each capsule (950 mg) contains the alfa-5® association consists of serenoa repens 320 mg, crocus sativus 100 mg, pinus massoniana 120 mg. all compound analyses were carried out according to fiamegoset et al. (10). all patients assigned to group b were orally administered serenoa repens 320 mg. statistical analysis in order to analyse the homogeneity of the two groups, the baseline characteristics were compared using the t test and wilcoxon-mann-whitney test for continuous variables and by the chi-square test for categorical variables. the sample size was calculated prospectively under the following conditions: difference between the groups = 10%, alpha error level = 0.05 two-sided, statistical power = 80% and anticipated effect size (cohen’s d = 0.5). the calculation yielded 2 ! 64 individuals per group. analysis of variance (anova) was used for comparing means. bonferroni adjustment test was also used at the second stage of the analysis of variance. the effect size between the means (cohen's d) was also calculated. the differences between the groups regarding semen parameters were obtained using chi-square or fisher’s exact tests. statistical significance was achieved when p was < 0.05. all reported p-values were two-sided. statistical analyses were performed using spss 11.0 for apple-macintosh (spss, inc., chicago, illinois). results from a total population of 146 patients with luts/bph and ed, 132 patients were eventually enrolled and randomised. out of the 14 patients excluded from the study, 10 had refused to be enrolled and 4 were lost at the follow-up. finally, 132 were allocated (figure 2). anamnestic and clinical data at enrolment are described in table 1. no statistically significant differences between the groups were found. from 132 enrolled patients, 85 were allocated to idiprost® gold and 46 to serenoa repens 320 mg. compliance to treatment schedule and adverse effects in group a 83 patients (97.6%) were analysed after 2 were lost at follow up. in group b 46 patients (97.8%) were analysed after 1 was lost at follow up (figure 2). accordingly, compliance to this study protocol was satisfactory. the idiprost® gold formulation was well tolerated in all patients analysed and there were no significant drug-related side effects. in group a, 1 out of 83 patients (1.2%) had mild adverse effects that did not require treatment suspension. also in group b, 1 out of 46 patients (2.1%) reported mild adverse effects. clinical and laboratory results at follow up at the follow-up examination (3 months after treatment), statistically significant differences have been reported between the two groups in terms of ipss (11.9 vs 13.8; df = 127; t = 10.3; p < 0.001), iief-5 and sf-36 mean scores (19.3 vs 16.1; 99.7 vs 96.3; df = 127; t = 17.4; p < 0.003; df = 127; t = 18.4; p < 0.001). moreover, statistically significant differences were then reported between the two visits, in terms of iief-5 and sf-36 scores (p < 0.001; p < 0.001), in the idiprost® gold group. very few aes have been reported in the both groups without any significant difference. figure 1. the figure shows the study design. cai_stesura seveso 18/12/13 10:43 pagina 186 187archivio italiano di urologia e andrologia 2013; 85, 4 sexual function improvement and quality of life the table 2 shows all questionnaires results between the two groups at the enrolment and at the follow-up visit. discussion luts due to bph and sexual dysfunction are very common in men and the association between luts/bph and ed is very intriguing. moreover, some epidemiological studies demonstrated that the association between luts/bph and sexual dysfunction in ageing men is independent of the effects of age, other comorbidities and lifestyle factors (11). on the other hand, there is an increasing needed for drugs able to improve the patient’s quality of life without adverse side effects. in the present study we evaluate the efficacy of idiprost® gold in improvement of patient’s quality of life. we found some important findings: 1) the efficacy of idiprost® gold in improve urinary and sexual function in patients affected by luts/bph and ed, when compared with serenoa repens alone; 2) the improvement in sexual quality of life is linked with an higher overall quality of life regardless of the urinary function; 3) very few adverse side effects have been found in the idiprost® gold group. the efficacy of idiprost® gold in the management of urinary and sexual function is due to the association between serenoa repens, pmbe and crocus sativus. even if the efficacy of serenoa repens appears to be a useful option for improving lower urinary tract symptoms (12), the association with pmbe and crocus sativus is able to improve the efficacy of serenoa repens due to: a) antioxidant effect, free radical scavenging activities and vasoprotective effect due to oligomeric proanthocyanidin complexes (opc) of pinus massoniana bark extract (pmbe) (13-14), b) increasing of nitric oxide activity by antioxidant effect of pmbe, c) apoptosis inducing properties of pmbe (15), d) promotion of the diffusion of oxygen in tissues due to crocus sativus effect (16) and e) the aphrodisiac properties of crocus sativus (17). recently, hosseinzadeh et al. demonstrated in an animal model study the aphrodisiac activity of crocus sativus aqueous extract and its constituent crocin (18). moreover, they demonstrated that crocetin, a constituent of saffron, significantly restored the endo thelium-de pen dent relaxation of the thoracic aorta in hypercholesterolemic rabbit, which might be explained by its action to increase the vessel enos activity, leading to elevation of no production (18). figure 2. the figure shows the study flow-chart. cai_stesura seveso 18/12/13 10:43 pagina 187 archivio italiano di urologia e andrologia 2013; 85, 4 t. cai, g. morgia, g. carrieri, c. terrone, c. imbimbo, p. verze, v. mirone, idiprost® gold study group 188 the same authors highlighted that as crocin (the crocetin digentiobiosyl-ester) converts to crocetin, it is possible that this component acts in a way similar to pde-5 inhibitors such as sildenafil (18). furthermore, crocus sativus seems to have affinity to bind benzodiazepine receptors (19) and exhibited antidepressant activity that it might inhibit the reuptake of serotonin (20). moreover, shamsa et al. in a clinical trial found that after the ten days of taking saffron there was a statistically significant improvement in tip rigidity and tip tumescence as well as base rigidity and base tumescence, highlighting that crocus sativus showed a positive effect on sexual function with increased number and duration of erectile events seen in patients with ed even only after taking it for ten days (21). these are the pharmacological basis justifying the effectiveness of idiprost® gold. another aspect to discuss is the fact that we have found that an improvement in sexual quality of life is linked with a higher overall quality of life regardless of the urinary function. it could be due to the fact that the impact of sexual dysfunction on pa tients’ quality of life is higher than luts, as demonstrated by several authors (3, 22.) finally, the present study shows few limitations to take into account; firstly, the lacks of placebo arm. however, we planned this study without a placebo arm due to the fact that we think that is not ethical to not treat patients with luts/bph and ed. moreover, the short follow-up period that not allows to evaluate the possible adverse side effect at long time. idiprost®gold mean (sd or %) serenoa repens 320 mg mean (sd or %) patients (n°) 83 46 background information • age 58.9 (± 3.56) 59.1 (± 3.68) • marital status married 53 (63.8) 30 (65.3) unmarried 20 (24.0) 11 (23.9) divorced 10 (12.2) 5 (10.8) • educational qualification primary school 30 (36.2%) 18 (39.1%) high school 29 (35.0%) 15 (32.7%) university 24 (28.8%) 13 (28.2%) • smooking yes 28 (33.8) 16 (34.7) no 55 (66.2) 30 (65.3) • comorbidity charlson index 1.9 (± 0.8) 2.0 (± 0.9) • bmi (body mass index) 26.9 (± 1.3) 27.1 (± 1.1) baseline clinical data • psa total (ng/ml) 2.02 (± 1.45) 2.08 (± 1.59) • pvr (ml) 29.9 (± 28.8) 32.8 (± 29.9) • uroflowmetry data qmax (ml/sec) 11.7 (± 2.2) 11.9 (± 2.1) • prostate volume (ml) 43.9 (± 21.1) 41.4 (± 17.2) • ipss 17.1 (± 5.9) 16.9 (± 5.8) • iief-5 14.9 (± 3.5) 15.1 (± 3.7) • sf-36 96.4 (± 1.1) 96.9 (± 1.2) table 1. clinical, instrumental and laboratory patient’s data. idiprost®gold serenoa repens 320 mg mean (sd) mean (sd) ipss v1 17.1 (± 5.9) 16.9 (± 5.8) v2 11.9 (± 1.1) 13.8 (± 1.3) iief-5 v1 14.9 (± 3.5) 15.1 (± 3.7) v2 19.3 (± 1.0) 16.1 (±1.2) sf-36 v1 96.4 (± 1.1) 96.9 (± 1.2) v2 99.7 (± 1.2) 96.3 (± 2.3) table 2. questionnaires results at the enrolment and at the follow-up visit. the table shows the anamnestic, clinical and instrumental data from all patients at the enrolment time. n° = number; sd or % = standard deviation or percentage; pvr = post-residual voided volume; ipss = international prostate symptom score; iief-5 = international index of erectile function; sf-36 = short form-36. the table shows all questionnaires results between the two groups at the enrolment and at the follow-up visit. v1 = visit 1 (time 0); v2 = visit 2 (after 3 months). sd = standard deviation; ipss= international prostate symptom score; iief-5 = international index of erectile function; sf-36 = short form-36 cai_stesura seveso 18/12/13 10:43 pagina 188 189archivio italiano di urologia e andrologia 2013; 85, 4 sexual function improvement and quality of life conclusion in conclusions, we found that idiprost® gold significantly improve the quality of life of patients affected by luts due to bph and ed, specifically in terms of sexual function, highlighting that a better sexual quality of life is correlated with an higher overall quality of life regardless of the urinary function. references 1. girman cj, jacobsen sj, guess ha, et al. natural history of prostatism: relationship among symptoms, prostate volume and peak urinary flow rate. j urol. 1995; 153:1510-5. 2. corona g, lee dm, forti g, et al. age-related changes in general and sexual health in middle aged and older men: results from the european male ageing study (emas). j sex med. 2010; 7:1362-80. 3. rosen r, altwein j, boyle p, et al. lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (msam-7). eur urol. 2003; 44:637-49. 4. robertson c, link cl, onel e, et al. the impact of lower urinary tract symptoms and comorbidities on quality of life: the bach and urepik studies. bju int. 2007; 99:347-54. 5. gacci m, corona g, salvi m, et al. a systematic review and metaanalysis on the use of phosphodiesterase 5 inhibitors alone or in combination with !-blockers for lower urinary tract symptoms due to benign prostatic hyperplasia. eur urol. 2012; 61:994-1003. 6. madersbacher s, alivizatos g, nordling j, et al. eau 2004 guidelines on assessment, therapy and follow-up of men with lower urinary tract symptoms suggestive of benign prostatic obstruction (bph guidelines). eur urol. 2004; 46:547-54. 7. badia x, garcia-losa m, dal-re r. ten-language translation and harmonization of the international prostate symptom score: developing a methodology for multinational clinical trials. eur urol 1997; 31:129-40. 8. rosen rc, riley a, wagner g, et al. the international index of erectile function (iief): a multidimensional scale for assessment of erectile dysfunction. urology. 1997; 49:822-30. 9. apolone g, mosconi p. the italian sf-36 health survey: translation, validation and norming. j clin epidemiol. 1998; 51:1025-36. 10. fiamegos yc, nanos cg, vervoort j, stalikas cd. analytical procedure for the in-vial derivatization-extraction of phenolic acids and flavonoids in methanolic and aqueous plant extracts followed by gas chromatography with mass-selective detection. j chromatogr. a 2004; 1041:11-8. 11. mirone v, sessa a, giuliano f, et al. current benign prostatic hyperplasia treatment: impact on sexual function and management of related sexual adverse events. int j clin pract. 2011; 65:1005-13. 12. wilt tj, ishani a, rutks i, macdonald r. phytotherapy for benign prostatic hyperplasia. public health nutr. 2000; 3:459-72. 13. cui yy, xie h, qi kb, et al. effects of pinus massoniana bark extract on cell proliferation and apoptosis of human hepatoma bel7402 cells. world j gastroenterol. 2005; 11:5277-82. 14. neuwirt h, arias mc, puhr m, et al. oligomeric proanthocyanidin complexes (opc) exert anti-proliferative and pro-apoptotic effects on prostate cancer cells. prostate. 2008; 68:1647-54. 15. ma h, liu b, feng d, et al. pinus massoniana bark extract selectively induces apoptosis in human hepatoma cells, possibly through caspase-dependent pathways. int j mol med. 2010; 25:751-9. 16. rìos jl, recio mc, giner rm, manez s. an update review of saffron and its active constituents. phytother res. 1996; 10:189-193. 17. madan cl, kapur bm, gupta us. saffron. econ bot. 1966; 20:377. 18. hosseinzadeh h, ziaee t, sadeghi a. the effect of saffron, crocus sativus stigma, extract and its constituents, safranal and crocin on sexual behaviors in normal male rats. phytomedicine. 2008; 15:491-5. 19. hosseinzadeh h, sadeghnia hr. protective effect of safranal on pentylenetetrazol-induced seizures in the rat: involvement of gabaergic and opioids systems. phytomedicine. 2007; 14:256-262. 20. hosseinzadeh h, karimi gh, niapoor m, antidepressant effects of crocus sativus stigma extracts and its constituents, crocin and safranal, in mice. acta hortic. 2004; 650:435-445. 21. shamsa a, hosseinzadeh h, molaei m, et al. evaluation of crocus sativus l. (saffron) on male erectile dysfunction: a pilot study. phytomedicine. 2009; 16:690-3. 22. lowe fc. treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia: sexual function. bju int. 2005; 95 (suppl 4):12-8. *appendix idiprost® gold study group. università degli studi di napoli “federico ii” prof. vincenzo mirone: marco franco, roberto la rocca. università degli studi di catania prof. giuseppe morgia: costanza salamone, claudia calì. università degli studi di foggia prof. giuseppe carrieri: giuseppe di fino, mario de siati. università degli studi del piemonte orientale prof. carlo terrone: angela maurizi. università degli studi di milano prof. francesco rocco: franco gadda. correspondence tommaso cai, md (corresponding author) department of urology, santa chiara regional hospital, trento, italy. largo medaglie d'oro, 9 ktommy@libero.it giuseppe morgia, md department of urology and department of hygiene and public health university of catania, catania, italy giuseppe carrieri, md department of urology and renal transplantation university of foggia, foggia, italy carlo terrone, md division of urology, aso maggiore della carità university hospital university of eastern piedmont, novara, italy ciro imbimbo, md paolo verze, md vincenzo mirone, md department of urology university federico ii, napoli, italy cai_stesura seveso 18/12/13 10:43 pagina 189 stesura seveso introduction the efficacy and the cost-effectiveness analysis of bacille calmette-guérin (bcg) therapy in the management of high-risk superficial bladder cancer (nmibc) or treatment of carcinoma in situ (tis) has been demonstrated (1-3). the goal of bcg therapy is to eradicate the disease and to inhibit tumor recurrence and prevent the progression of cancer (4-6). although used in large number of patients, the immunotherapy mechanism of action of bcg has remained a black box for three decades. a local inflamma157archivio italiano di urologia e andrologia 2013; 85, 4 original paper dendritic cells in blood and urine samples from bladder cancer patients undergoing bcg immunotherapy raffaella rossi 1, miriam lichtner 2, francesco iori 3, angela ermocida 1, claudia mascia 1, fabio mengoni 1, ilaria sauzullo 1, danilo dini 3, claudio m. mastroianni 2, vincenzo vullo 1 1 department of public health and infectious diseases, “sapienza” university, rome, italy; 2 infectious diseases unit “sapienza” university, latina, italy; 3 department of urology, “sapienza” university, rome, italy. objectives: immunotherapy with bcg (bacille calmette-guérin) after transurethral resection of the bladder tumor represents a highly effective primary treatment for intermediate and high-risk superficial bladder cancer. the effectiveness of this therapy has been documented, but its mechanism of action is not clear yet. in the present study, we investigated the changes of dendritic cells (dc) numbers in peripheral blood and urine of patients with superficial bladder cancer undergoing bcg intravescical therapy material and method: we have enumerated plasmacytoid and myeloid dcs in the peripheral blood and in the urine of patients with bladder cancer in order to clarify the role of these cells in the evolution of the disease and the effect of therapy. dcs in blood and urine samples were assessed using the single-platform trucount assay with monoclonal antibodies. the study population included 37 healthy donors and 13 patients with diagnosis of primitive superficial bladder cancer. results: at the time of diagnosis a reduction of blood dcs was found in patients as opposed to healthy donors, while dcs were not found in the urine in the same way as in healthy subjects. six of these patients were followed before and after weekly and monthly instillations of bcg. in the peripheral blood, we observed an immunological recovery of dcs from the third weekly instillation up to the sixth. in the urine of patients, we didn’t find mdcs or pdcs at t0, but we found a statistically significant change from the third instillation up to the sixth. on the contrary, we didn’t find mdcs in urine during monthly instillation. conclusions: dc count could be used in the monitoring of patients undergoing bcg therapy. immunological restoration of mdc numbers in peripheral blood and the efflux in urine could be important for confirming the effectiveness of bcg instillation. key words: dendritic cells; trucount assay; bcg therapy; superficial bladder cancer; urine. submitted 10 may 2013; accepted 31 july 2013 no conflict of interest declared summary tion, characterized by an influx of mononuclear cells into the bladder wall and by the secretion of pro-inflammatory cytokines into the urine, has been described in patients undergoing bcg instillations (7-9). recently, a central role in the prevention bladder tumor recurrence has been suggested for granulocyte-macrophage colony-stimulating factor (gm-csf) and tumor necrosis factor (tnf)-!, which are essential cytokines in the induction of dendritic cell (dc) response (10). in fact, both natural and adapdoi: 10.4081/aiua.2013.4.157 archivio italiano di urologia e andrologia 2013; 85, 4 r. rossi, m. lichtner, f. iori, a. ermocida, c. mascia, f. mengoni, i. sauzullo, d. dini, c.m. mastroianni, v. vullo 158 tative immunity seem to be involved in the local response to bcg therapy. several studies showed the presence of natural killer (nk) cells, cd4+ and cd8+ t lymphocytes in the bladder wall in patients with superficial transitional cell carcinoma (tcc) undergoing bcg instillations. this presence was correlated with a reduction in superficial bladder cancer recurrence (11). few studies have examined the significance of the presence of dendritic cells (dc) in the urine from patients with bladder cancer. the importance of dcs as immunotherapy against cancer has been widely studied (12-14). in fact, dcs are considered professional antigen presenting cells (apcs) for inducing anticancer immunity, both in vitro and in vivo (15), and they can induce both primary and secondary immune responses. nishiyama et al, propose dc-based cancer immunotherapy as an additional treatment against advanced bladder cancer (16). cheadle et al. demonstrated in vitro that bcg-infected dc are potent activators of t-cells and adaptive immune response (17). two types of immature circulating dcs were found in human blood: myeloid dcs (mdcs) and plasmacytoid dcs (pdcs) that can be identified for their phenotypic markers and different function (18). a recent study tested the hypothesis that dcs may also migrate in the urine of bladder cancer patients. the authors speculate that variability in the percentage of urinary dcs may reflect changes in immunological activity at the tumor site (19). however, they did not enumerate circulating dcs in the periphery. in this study, we used a single-platform flow cytometric trucount assay to count the absolute number of the two subsets of dcs in both peripheral blood and urine samples from patients with bladder cancer before transurethral resection. in addition, in a longitudinal study, the enumeration of mdcs and pdcs count was done at different times of weekly and monthly bcg instillation. materials and methods the study population included 13 patients with diagnosis of primitive bladder cancer, confirmed by transurethral resection bladder (turb) (10 males, 3 females; age range, 55-81 years old). tnm (t: size or direct extent of the primary tumor. n (0-3): degree of spread to regional nodes. m (0/1): presence of metastasis) classification of tumors in studied patients was as follows: tag1 in 1 patient, tag2 in 3 patients, tag3 in 5 patients, t1g3 in 3 patients and t2g3 in 1 patient. six patients (3 with tag2 and 3 with tag3) were repeatly analyzed during weekly and monthly instillations with bcg, according to the lamm’s protocol (20). all patients were admitted to the department of urology of the azienda policlinico umberto i, sapienza university of rome. twentysix healthy donors were included as control group. informed consent was obtained from all subjects before being included in the present study. the study was approved by the institutional review board (department of infectious and tropical diseases, sapienza university of rome). blood and urine were collected in the first mornfigure 1. cytofluorimetric analysis of dc subsets in blood sample using trucount assay. this is one representative example of dc count in a healthy donor and a patient with superficial bladder cancer. in r1 gate we have identified lymphocytes and monocytes (pbmcs), using as parameters the side scatter channel (ssc) and the cd45-percp. beads are on the right of the dot plot (a). gate r2 recognized pbmcs that were lineage-negative (b). gate r4 represents trucount beads events and it was obtained in an ungated dot plot of fl1 vs. fl2 (c). finally, to define mdc and pdc, events from r1 and r2 were analyzed in a contour plot of cd11c or cd-123 vs. hla-dr (d). all cd11chi-hla-dr+ and cd123hi-hla-dr+ were included in this gating strategy. 159archivio italiano di urologia e andrologia 2013; 85, 4 dendritic cells in blood and urine samples from bladder cancer patients undergoing bcg immunotherapy figure 2. cytofluorimetric analysis of dc subsets in urine sample using trucount assay. this is one representative example of dc count in healthy donor and patient with superficial bladder cancer. the same strategy of blood sample was used and the figure shows the contour plot of mdcs and pdcs events (gate r3) in the urine. ing before turb. all patients had no change in lymphocytes and monocytes values. to identify dc subsets, we used a new single platform flow cytometric assay, based on trucount tm tubes, which contain a known number of fluorescent beads as inside control. this method has many advantages: first of all, we use whole blood and not conventional ficoll-density separation. the absolute number of pdcs or mdcs (cells/ml blood) was calculated by the following formula: (mdc or pdc events x known trucount beads)/ (beads events x 0.1 ml). in this way, we eliminate the count obtained from haematology blood analyzer data. besides, this count is highly reproducible with intra and inter assay, and fast to execute. for dc enumeration, peripheral blood was conserved in edta (ethylenediaminetetraacetic acid) tubes. whole blood (0.1 ml) was directly labeled in trucount tm tubes, adding monoclonal antibodies (mabs) and isotype control and using lyse/no wash assay. mabs for the labelling were: anti cd45-percp to identify peripheral blood mononuclear cells (pbmcs), anti hla-dr-apc that marks dcs and activated cells, lineage-fitc cocktail (composed of anti-cd3, anticd14, anti-cd16, anti-cd19, anti-cd20, anti-cd56) because dcs do not express this marker, anti-cd11c-pe or anti-cd123-pe specific markers for mdcs or pdcs respectively. finally mouse anti-igg1a-pe and mouse anti-igg2a-pe were used for isotype control. gating strategy is shown in figure 1. all antibodies and trucount tm tubes were purchased from becton dickinson (bd biosciences pharmingen, italy). after mixing, the tubes were incubated for 15 minutes in the dark at room temperature (rt); then 450 µl of facs lysing solution (bd) was added to each tube, after which they were vortexed and incubated for 15 minutes at rt. as for urine, before the staining of dcs, the samples were concentrated 1:100. then, mabs and isotype control were added following the protocol for dcs staining in peripheral blood (figure 2). all samples were analyzed within 1-3 h of staining using a facscalibur flow cytometer and cellquest 1.0, and 100.000 events were acquired (becton dickinson, mountain view ca). all data were collected using identical instrument settings. for statistical analysis sigma stat 2.2 (jandel scientific software, san rafael, ca) was used. values are given as median and ranges. the statistical differences of values were analyzed using the nonparametric mann-whitney u test and spearman coefficients were calculated to measure the association among parameters. results cross-sectional study the enumeration of both mdcs and pdcs was performed in peripheral blood and urine samples from 13 patients before transurethral resection (time 0). mdcs and pdcs were significantly reduced in peripheral blood from patients with superficial bladder cancer in comparison archivio italiano di urologia e andrologia 2013; 85, 4 r. rossi, m. lichtner, f. iori, a. ermocida, c. mascia, f. mengoni, i. sauzullo, d. dini, c.m. mastroianni, v. vullo 160 with healthy donors. in fact, the median value of mdcs in patients was 8825 cells/ml (range 4187-15317) vs 15300 cells/ml (8901-45917) in healthy donors (p < 0.001). similarly, a decrease in pdc count was found (bladder cancer: 5411 cells/ml, range: 2897-10693; healthy donors: 13553, 3875-52111; p < 0.001) (figure 3). when patients were stratified on the basis of cancer grading, we observed a significant reduction of mdcs (p = 0.004) in low grade groups (g1 and g2) when compared with the higher grade group (g3). no significant differences were found in pdcs count (p = 0.918) between the two groups. when urine samples were assessed by cytofluorimetric analysis, we did not detect the presence of mdcs and pdcs either in patients or healthy donors. longitudinal study after transurethral resection, six patients were followed during weekly and monthly instillations with bcg. during a median follow up of 24 months, all patients were free of recurrences. we counted dcs subpopulations in blood and urine before and after 24 hours of the first (t1-t2), third (t3-t4), fifth (t5-t6) and sixth (t7t8) weekly instillations and before and after 24 hours of the sixth monthly instillation (t9-t10). in the peripheral blood, the patients had a recovery of mdcs respect to figure 3. circulating mdc and pdc count in peripheral blood. two subsets of dcs were measured using trucount assay and asignificant reduction in both mdcs (a) and pdcs (b) was found in the patients. figure 4. circulating mdc and pdc count in peripheral blood post-instillations. mdcs and pdcs were measured using trucount assay. a significant increase was found in mdcs at t8 of weekly instillations compared to t0 (a). no significant differences in pdc count were found (b). lines ---represent the median values of mdcs and pdcs in the healthy donors. or lamina propria and frequently have a good response to therapy. the treatment for superficial tcc is transurethral resection bladder (turb), and 80% survival is achieved, but less than half are cured because of the relapse (50-70%). this resection is followed by intravescical therapy that has been shown to be the treatment of choice for intermediate and high superficial bladder cancer. this therapy was first used in the management of bladder cancer in 1976 by morales et al. and it is an immunotherapy based on instillations with live attenuated tuberculosis vaccine, bacille calmette-guérin (bcg). in the present study, we investigated the changes of dc numbers in peripheral blood and urine of patients with superficial bladder cancer undergoing bcg intravescical therapy (22). we found for the first time a significant decrease of both circulating mdcs and pdcs absolute count in patients with superficial bladder cancer, before transurethral resection, compared to healthy donors. the reduction of dcs in peripheral blood may have functional consequences on dcs activity against the progression of tumor: mdcs play an important role in cancer for their antitumor properties, while pdcs are the natural ifnproducing cells in the immune system. on the other hand, when patients were stratified for tumor grading, data showed that lower cancer grading was associated with the lowest count of mdcs in blood, suggesting that dcs deficit depends on a major recruitment of mdcs at the tumor site, rather than on a peripheral disruption. in a longitudinal study, we have followed six patients after transurethral resection and during weekly and monthly instillations of bcg. we observed a numerical recovery of both circulating dcs in these patients at the end of the weekly treatment. the number of dcs increased from the third instillation, and it may represent a good evidence for the efficacy of bcg immunotherapy in immunological recovery. bcg causes a local inflammation and an influx of mononuclear cells into the bladder wall (8). bcg induces maturation and activation of dcs with interaction with tlrs 2 and 9 and with dectin1 (17,19,24,25,26,27) that are important components of the innate immune response. in our patients, mdcs were found in urine after bcg therapy, particularly at the third instillation that corresponds to blood dcs increase. the mdcs found at the site of immunotherapy in those patients with lower grades may be involved in the protective immune responses elicited by the treatment. many studies underlined the presence of cells, such as nk cells, cd4+ and cd8+, t lymphocytes in the bladder wall, after bcg instillations in patients with superficial tcc. this presence was correlated with a reduction in superficial bladder cancer recurrence (10) but the results were often conflicting (28,29,30). in other studies, pro-inflammatory cytokines (il-1, il-2, il-6, tnf!, ifn-") were found in urine after bcg instillations (7, 9, 10, 31) but their role in weekly instillations is not 161archivio italiano di urologia e andrologia 2013; 85, 4 dendritic cells in blood and urine samples from bladder cancer patients undergoing bcg immunotherapy figure 5. mdc count in the urine, post-instillations, using trucount assay. a significant increase was found in mdcs from the third up to the sixth weekly instillations (t4, t6 and t8) compared to t0. no statistically increase was found at sixth monthly instillation (t10) if compared to t0. lines ---represent the median values of mdcs in the healthy donors. t0 (p = 0.04) and at the end of weekly instillations, the values were comparable to healthy donors (p = 0.7). at the sixth monthly instillation, none of the patients showed numerical reduction of mdcs. there was an increase from the third instillation (figure 4a). no significant changes were observed before and after 24 hours of the bcg instillations (data not shown). for the pdcs, we found only a partial increase compared to t0 at the end of weekly instillations without a statistical significance (p = 0.2) (figure 4b). at the sixth monthly instillation, the pdc values decreased to the pre-instillation levels, indicating that peripheral blood pdcs were partially affected by bcg instillation. the analysis of the urine showed that mdcs were detectable in the urine from the third instillation up to the sixth instillations. no changes were found before and after 24 hours of the bcg instillations. in fact, during the first instillation we didn't find mdcs before and after 24 hours. otherwise, at the third instillation, mdc were detected in urine and remained stable until the end of weekly instillation. little or no mdc release was found in urine during monthly instillations (figure 5). analysis using the spearman rank correlation test showed that there was no statistically significant correlation between mdcs in urine and blood (r = 0.240, p = 0.3). discussion transitional cell carcinoma (tcc) is found in more than 90% of patients with bladder cancer, and this type of cancer is either superficial (70%) or muscle-invasive. patients with muscle-invasive or metastatic disease have a poor prognosis and they will die within 2-3 years after diagnosis. superficial tumors are confined to the mucosa archivio italiano di urologia e andrologia 2013; 85, 4 r. rossi, m. lichtner, f. iori, a. ermocida, c. mascia, f. mengoni, i. sauzullo, d. dini, c.m. mastroianni, v. vullo 162 clear. recently, some studies correlated the presence of leukocytes in the urine of patients with bladder cancer undergoing bcg therapy with a reduction of recurrence (10). dcs were found in the urine of bladder cancer patients, and it was speculated that variability in the percentage of urinary dcs may reflect changes in immunological activity at the tumor site (32). it is conceivable that the mdcs we found in the urine of patients under bcg immunotherapy may play a crucial role in the antitumor activity of bcg therapy. they may interact with the nk cells, t cells and other leukocytes and with various cytokines, through a reciprocal cross-talk that activates anti-tumor responses (33, 34). indeed a very recent report showed that bladder tumour mature dendritic cells and macrophages are predictors of response to bcg therapy (34). in the last years there has been a lot of interest in the evaluation of peripheral blood dc subsets, as an improvement in the enumeration methods has been obtained (35). using flow cytometry for dc counts, a reduction of circulating mdcs and pdcs was demonstrated for the first time in hiv infection (36-38). several studies have shown that dcs in blood are decreased by viral, parasitic and bacterial infectious diseases (39, 40). in addition, recent studies have shown variations of dc counts in peripheral blood in some tumor such as breast cancer in advanced stage (41, 42) and in a urological tumor, prostate adenocarcinoma (43, 44). dcs are present in very low percentages in peripheral blood, and for this reason it is difficult to obtain a real and reproducible enumeration of these cells. in our study we have obtained an absolute count of dcs using a single platform tru count assay and a flow cytometric analysis for rare events that gives a standardization of dcs counting in clinical practice (35). all treated patients showed a release of dcs into the urine, with a burst increase at the third instillations. in agreement with previous data, we suggest that bcgmediated antitumor activity may be a localized phenomenon that induces immune responses against cancer, using mdcs antitumor proprieties. the quantification of dcs using a single platform tru count assay may be very important to understand the mechanism of bcg action and perhaps to monitor the treatment efficacy. finally, pdcs seem to have a different role: they decreased in patients with superficial bladder cancer, remained low during bcg treatment and they were never found in urine. from these data we can speculate that deficit of pdcs was a characteristic related to other tumor forms (breast, prostate) (41-44) rather than a consequence of the cancer development. conclusion the results of our study indicate that the number of dcs in blood and urine shows variations during endovescical instillations with bcg in patients after transurethral resection of superficial bladder cancer. mdcs seem to play a crucial role at the tumor site and they were recruited in urine by bcg instillations from the third instillations. we suggest that mdcs count in urine samples may be used as a marker to better understand the efficacy of bcg 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abadie v, badell e, douillard p, et al. neutrophils rapidly migrate via lymphatics after mycobacterium bovis bcg intradermal vaccination and shuttle live bacilli to the draining lymph nodes. 2005; blood. 106:1843. 34. ayari c, larue h, hovington h. bladder tumor infiltrating mature dendritic cells and macrophages as predictors of response to bacillus calmette-guérin immunotherapy. eur urol. 2009; 55:1386. 35. vuckovic s, gardiner d, field k, et al. monitoring dendritic cells in clinical practice using a new whole blood single-platform tru count tm assay. jim. 2004; 284:73. 36. grassi f, hosmalin a, mcilroy d, et al. autran b. depletion in blood cd11c-positive dendritic cells from hiv-infected patients. aids. 1999; 13:759. 37. pacanowski j, kahi s, baillet m, et al. reduced blood cd 123+(lymphoid) and cd 11 c+ (myeloid) dendritic cell numbers in primary hiv-1 infection. blood. 2001; 98:3016. 38. servet c, zitvogel l, hosmalin a. dendritic cells in innate immune responses against hiv: curr mol med. 2002; 2:739. 39. lichtner m, maranon c, vidalain po, et al. hiv type 1-infected dendritic cells induce apoptosis death in infected and uninfected primary cd4 lymphocytes. aids res hum retroviruses. 2004; 20:175. 40. lichtner m, rossi r, mengoni f, et al. circulating dendritic cells and interferon-! production in patients with tuberculosis: correlation with clinical outcome and treatment response. clin expl imm. 2006; 143:329. 41. manna pp, mohanakumar t. human dendritic cell mediated cytotoxicity against breast carcinoma cells in vitro. j leukoc biol. 2002; 72:312. 42. tschoep k, manning tc, harlin h, et al. disparate functions of immature and mature human myeloid dendritic cells: implications for dendritic cell-based vaccines. j leukoc biol. 2003; 74:69. 43. heiser a, coleman d, dannull j. autologous dendritic cells transfected with prostate-specific antigen rna stimulate ctl responses against metastatic prostate tumors. j clinic invest. 2002; 109:409. 44. sciarra a, lichtner m, autran ga, et al. characterization of circulating blood dendritic cell subsets dc123+ (lymphoid) and dc11c+ (myeloid) in prostate adenocarcinoma patients. prostate. 2007; 67:1. 163archivio italiano di urologia e andrologia 2013; 85, 4 dendritic cells in blood and urine samples from bladder cancer patients undergoing bcg immunotherapy correspondence raffaella rossi, md (corresponding author) raffaella.rossi@hotmail.it angela ermocida, md angela.ermocida@tiscali.it claudia mascia, md claumascia@tiscali.it fabio mengoni, md fabio.mengoni@ uniroma1.it ilaria sauzullo, md ilariasauzullo@libero.it vincenzo vullo, md vincenzo.vullo@uniroma1.it department of public health and infectious diseases, “sapienza” university, piazzale aldo moro 5 00161 rome, italy miriam lichtner, md miriam.lichtner@uniroma1.it claudio mastroianni, md claudio.mastroianni@uniroma1.it infectious diseases unit “sapienza” university, latina, italy francesco iori, md francescoiori@virgilio.it danilo dini, md danilo.dini@libero.it department of urology, “sapienza” university, rome, italy, stesura seveso archivio italiano di urologia e andrologia 2014; 86, 144 case report rare case of intra-testicular adenomatoid tumour filippo migliorini 1, roberto baldassarre 1, walter artibani 1, guido martignoni 2, matteo brunelli 2 1 urology department, university hospital, ospedale policlinico, azienda ospedaliera integrata, verona, italy; 2 department of pathology and diagnostic, university hospital, ospedale policlinico, azienda ospedaliera integrata, verona, italy. adenomatoid tumors are rare benign neoplasms considered of mesothelial origin. they are usually asymptomatic and slow growing masses. they account for 30% of paratesticular tumors and very rarely involve the testicular parenchyma. only ten such cases have been reported in the literature so far. ideal treatment should be excision of the tumor avoiding orchidectomy. nevertheless, because of the rarity of the lesion and the difficulty of distinguishing it from malignancy, radical orchidectomy is often performed. we describe a case of a 31 years old caucasian man who presented with a moderately symptomatic left testicular mass, normal tumor markers and normal sex hormones levels. the ultrasound showed an hypoechoic intratesticular nodule of 0.8 cm in diameter. the patient underwent intraoperative frozen section of the nodule which could not exclude malignancy with certainty. a radical orchiectomy was therefore performed. subsequent definitive histological and molecular report described an adenomatoid tumor involving the parenchyma of the testis. key words: adenomatoid tumour; testis; pathologic findings; orchifuniculectomy. submitted 7 february 2014; accepted 28 february 2014 summary introduction adenomatoid tumors are relatively uncommon benign tumors of mesothelial origin, usually occurring in the genital tract of both males and females. extragenital localization is rare and has been reported in adrenal glands, heart, mesentery, lymph nodes and pleura. adenomatoid tumors are responsible for 30% of all paratesticular masses and are most commonly found at the head of the epididymis. exceptionally, these tumors involve the testicular parenchyma and only ten cases have been previously reported in the literature (1-2). the ideal treatment should be excision of the nodule with preservation of the testicle. this is not always possible no conflict of interest declared because the morphological features on the frozen section don’t allow a certain exclusion of malignancy. case report and figures are posted in suppementary materials on www.aiua.it. discussion here we report a case of adenomatoid tumor of the testis with intratesticular growth and describe the ultrasound, gross and pathologic characteristics of this entity. to the best of our knowledge, only 10 cases have been previously reported in the literature (3). adenomatoid tumors are rare benign neoplasms occurring in both sexes and very rarely present as intratesticular masses. these tumors originate from the tunica albuginea but might also be found in the tunica vaginalis and rete testis. they present as well-circumscribed unencapsulated tumors with tan white cut surface and might be indistinguishable from seminoma (1-2). microscopically, they show different morphological patterns as tumor cells can form solid cords, nests, glandular-like spaces or tubules. a typical feature of the neoplastic cells is the presence of vacuolated cytoplasm and cytologic atypia with absence of mitosis. the stroma is usually fibrous although a smooth muscle component might be present. even though tumors may focally infiltrate between testicular tubules, such finding should not be considered as evidence of malignancy. a useful hint for the diagnosis of these lesions is the presence of lymphoid aggregates often localized at the periphery of the tumor. interestingly, this characteristic is usually lacking in tumors arising in females. the immunophenotipic profile of adenomatoid tumors shows positivity for pancytokeratins, podoplanin, wt1 and calretinin and can be very useful in the differential diagnosis with neoplasms that may resemble adenomatoid tumors, namely yolk sac tumor (negative for wt1 and calretinin), leydig cell tumor (negative for wt1) and metastatic carcinoma (1-2). also, negativity for vascular markers like cd34 helps in excluding tumors of vascular origin. a difficult differential diagnosis is represented by malignant mesothelioma which is distindoi: 10.4081/aiua.2014.1.44 migliorini cr_stesura seveso 26/03/14 10:41 pagina 44 45archivio italiano di urologia e andrologia 2014; 86, 1 intra-testis adenomatoid tumour guished from adenomatoid tumor for its larger size, invasive growth pattern and involvement of adjacent structures. since adenomatoid tumors have never shown malignant behavior, the aim in treating these masses is to prevent unnecessary orchidectomy thus preserving fertility and testosterone production. in this regard, accurate imaging and preoperative assessing of serum tumor markers like alpha-fetoprotein, ldh and beta-hcg might help in excluding a malignant lesion. intraoperative frozen section can also help in determining benignity of a testicular mass; accordingly, the value of intraoperative biopsy evaluation has become more popular in the last years, allowing organ-sparing procedure for non-malignant lesions. however, in the literature, only in one case of adenomatoid tumor with intratesticular growth was performed a conservative tumorectomy. this proves the extreme difficulty for a pathologist to rule out malignancy on frozen section in the case of an adenomatoid tumor with intratesticular growth. in our case, a diagnosis of benignity on the intraoperative biopsy was not possible and an orchidectomy was carried out. in conclusion, adenomatoid tumor with intratesticular growth is a rare neoplasm that can show different morphological features and therefore represents a diagnostic challenge, especially on frozen section. the pathologist must be aware of this entity when evaluating intraoperative biopsies of testicular masses. it must be stated, however, that ruling out malignancy is often not possible and orchidectomy cannot be avoided most of the times references 1. borislav aa, lauren fx, jonathon eh, et al. adenomatoid tumor of the testis with intratesticular growth: a case report and review of the literature. int j surg pathol. 2011; 19:838-842. 2. pacheco aj, torres jl, de la guardia fv, et al. intraparenchymatous adenomatoid tumor dependent on the rete testis: a case report and review of literature. indian j urology. 2009; 25:126-128. 3. alexiev ba, xu lf, heath je, et al. adenomatoid tumor of the testis with intratesticular growth: a case report and review of the literature. int j surg pathol. 2011; 19:838-842. correspondence filippo migliorini, md (corresponding author) filippo.migliorini@ospedaleuniverona.it roberto baldassarre, md roberto.baldassarre@ospedaleuniverona.it walter artibani, md walter.artibani@univr.it urology department, university hospital, ospedale policlinico, azienda ospedaliera integrata, p.le ludovico scuro 10 37134 verona, italy guido martignoni, md guido.martignoni@univr.it matteo brunelli, md matteo.brunelli@univr.it department of pathology and diagnostic, university hospital, ospedale policlinico, azienda ospedaliera integrata, p.le ludovico scuro 10 37134 verona, italy figure 1. intraoperative biopsy. note the nodule with an intra-testis localization (left side). normal testicular parenchyma inked on the right side (h&e, 4x). migliorini cr_stesura seveso 26/03/14 10:41 pagina 45 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 148 case report surgical repair of the iatrogenic falsepassage in the treatment of trauma-induced posterior urethral injuries faruk doğan 1, ali feyzullah şahin 1, tevfik sarıkaya 2, alper dırık 1 1 department of urology, şifa university medicine school, i̇zmir, turkey 2 department of urology, sivas public hospital, sivas, turkey pelvic fracture associated urethral injury (pfaui) is a rare and challenging sequel of blunt pelvic trauma. treatment of iatrogenic false urethral passage (fup) remains as a challenge for urologists. in this case report we reviewed the iatrogenic fup caused by wrong procedures performed in the treatment of a patient with pfaui and the treatment of posterior urethral stricture with transperineal bulbo-prostatic anatomic urethroplasty in the management of fup. a 37-year-old male patient with pfaui had undergone a laparotomy procedure for pelvic bone fracture, complete urethral rupture, and bladder perforation 8 years ago. after stricture formation, patient had undergone procedures that caused fup. following operations, he had a low urinary flow rate, and incontinence and urgency even with small amounts of urine. fup was diagnosed by voiding cystourethrography and retrograde urethrography. fup was fixed with open urethroplasty with the guidance of flexible antegrade urethtoscopy. false passage should always be taken into account in the differential diagnosis of patients with persistent symptoms that underwent pfaui therapy. in addition, we believe that in the evaluation of patients with pfaui suspected for having a false passage, bladder neck and urethra should be assessed by combining routine voiding cystourethrography and retrograde urethrography with preoperative flexible cystoscopy via suprapubic route. key words: false urethral passage; flexible cystoscoby; pelvic fracture; urethral injury. submitted 30 july 2013; accepted 31 december 2013 summary trauma may cause a life-long morbidity unless properly treated. while treatment approach in partial urethral rupture includes watchful waiting after performing a simple cystostomy, complete urethral rupture can be repaired with 3 methods: 1) realignment of the separated urethral ends over a catheter (urethral realignment), 2) primary anastomosis of separated urethral ends, and 3) immediate suprapubic cystostomy and delayed repair of the resulting stricture on an elective basis (3). emergency treatment of pfaui has not been standardized in developing countries. on majority of cases wrong procedures cause iatrogenic injuries in addition to trauma itself (4). sometimes, careless and/or repeated urethral dilatations also lead to false urethral passage (fup) formation, which results in infections and incontinence. treatment of iatrogenic fup remains as a challenge for urologists (5). furthermore, there is a paucity of data about the urethroplasty procedure performed for urethral stricture formed by fup. in this case report we reviewed the iatrogenic fup caused by wrong procedures performed in the treatment of a patient with pfaui and the treatment of posterior urethral stricture with transperinealbulbo-prostatic anatomic urethroplasty in the management of fup. case report and figures are posted in suppementary materials on www.aiua.it. discussion false passage is an abnormal passage between urinary bladder and urethra, which is observed in association with posterior urethral stricture and is caused by a iatrogenic injury resulting from careless and wrong treatment procedures after trauma. if unnoticed, this false passage between urethra and bladder causes very frequent complaints; furthermore, repeated endoscopic procedures (internal urethrotomy), catheterization, or urethral dilatation become necessary. following dilatation, hesitancy, incontinence, and urgency persist. furthermore, false passage scar tissue around traumatized tissue causes prolonged and chronic infections and hence leads to stricture formation (6). no conflict of interest declared introduction pelvic fracture associated urethral injury (pfaui) is a rare and challenging sequel of blunt pelvic trauma. in 425% of male patients with pelvic bone fractures, simultaneous posterior urethral injury is observed (1). injury to posterior urethra may be a simple contusion, or it may appear as partial or complete rupture (2). urethral doi: 10.4081/aiua.2014.1.48 sahin cr_stesura seveso 26/03/14 10:47 pagina 48 49archivio italiano di urologia e andrologia 2014; 86, 1 surgical repair of the iatrogenic falsepassage in the treatment of trauma-induced posterior urethral injuries methods used for diagnosis of posterior urethral strictures before reconstruction should clearly delineate stricture length and site, determine the anatomy of posterior urethra and bladder neck, and show false passages and fistulas if any. conventional methods include simultaneous ccug and dynamic retrograde urethrography. it is necessary to make a pre-treatment assessment via combined radiological and endoscopic methods especially in obliterated cases where prostatic and proximal urethra cannot be visualized. false passage is diagnosed with urethrography. combined voiding cystourethrography and retrograde urethrography can clearly show the site and path of the passage (7). cystourethroscopy plays a limited role in diagnosis since normal anatomical structures cannot be localized. this was also the case in our patient because his false passage could not be identified despite multiple endoscopic procedures at other medical facilities. a false passage should be taken into consideration for diagnosis in case normal anatomical markers like veru montanum, bladder trigone, and external sphincter could not be seen during cystourethroscopy. a flexible cystoscope advanced through a suprapubic route is highly useful for the diagnosis of false passage. while normal bladder neck is a funnel-shaped, soft, elastic, and of smooth structure, a false passage is a pale mucosal formation associated with a vertical circular dense scar and a coarse granulation that is located close to bladder neck (6). in conclusion, recurrent urethral strictures develop due to inappropriate and insufficient initial therapies in patients with pfaui with complete urethral separation; as a result, various endoscopic procedures and urethral dilatations become necessary. even after these therapies, hesitancy, incontinence, and urgency are observed. false passage should always be taken into account in the differential diagnosis of patients with persistent symptoms that underwent pfaui therapy. in addition, we believe that in the evaluation of patients with pfaui suspected for having a false passage, bladder neck and urethra should be assessed by combining routine voiding cystourethrography and retrograde urethrography with preoperative flexible cystoscopy via suprapubic route. the guidance of a flexible cystoscope via suprapubic route during the operation is quite helpful. it also guides procedures of curettage and dissection to determine the true anatomical structures and to identify the normal urethral tract, particularly in cases where prostatic urethra is blocked. references 1. koraitim mm, marzouk me, atta ma, et al. risk of urethral injury in pelvic fractures. br j urol. 1996; 77: 876-80. 2. lupu an, forrer jh, smith rb, kaufman j. urethral gap in complete disruption of membraneus urethra. urology. 1987; 29:378-82. 3. webstre gd, mathes gl, selli c. prostatomembranous urethral injuries: a review of the literature and a rational approach to their management. i. urol. 1983; 130:898. 4. barbagli g. history and evolution of transpubic urethroplasty: a lesson for young urologists in training. eur urol. 2007; 52:1290-2. 5. barbagli g, palminteri e, lazzeri m, guazzoni g. one-stage circumferential buccal mucosa graft urethroplasty for bulbous stricture repair. urology. 2003; 61:452-5. 6. qiang fu, jiong zhang, ying-long sa, san-bao jin, yue-minxu. transperineal bulbo-prostatic anastomosis for posterior urethral stricture associated with false passage: a single-centre experience. bju int. 2011; 108:1352-4. 7. secrest cl. staged urethroplasty: indications and techniques. urol clin north am. 2002; 29:467-75. correspondence faruk doğan, md (corresponding author) farukdogan58@gmail.com alper dırık, md a_dirik@yahoo.com specialist in urology department of urology, şifa university medicine school, izmir, turkey ali feyzullah şahin, md, febu ali.sahin@sifa.edu.tr asistant professor in urology department of urology, şifa university medicine school sanayi cad. no:7 bornova, izmir, turkey tevfik sarıkaya, md drts98@mynet.com specialist in urology department of urology, sivas public hospital, sivas, turkey figure. preoperative vcug and rug shows the location of a false passage and urethral stricture. the black arrow shows normal bladder neck and prostatic urethra, the blue arrow shows the urethral stricture and the beginning of the intraprostatic false passage, while the white arrow shows the false passage located close to bladder neck. sahin cr_stesura seveso 26/03/14 10:47 pagina 49 stesura seveso 41archivio italiano di urologia e andrologia 2014; 86, 1 case report first case of bilateral, synchronous anaplastic variant of spermatocytic seminoma treated with radical orchifunicolectomy as single approach: case report and review of the literature giorgio gentile 1, francesca giunchi 2, riccardo schiavina 1, alessandro franceschelli 3, marco borghesi 1, ziv zukerman 1, matteo cevenini 1, valerio vagnoni 1, daniele romagnoli 1, fulvio colombo 3, giuseppe martorana 1, eugenio brunocilla 1 1 department of urology, azienda ospedaliero-universitaria policlinico s.orsola-malpighi, bologna, italy; 2 department of pathology, azienda ospedaliero-universitaria policlinico s.orsola-malpighi, bologna, italy; 3 andrology unit, azienda ospedaliero-universitaria policlinico s.orsola-malpighi, bologna, italy. spermatocytic seminoma (ss) is less common than the classic variant, as its incidence ranges between 1.3% and 2.3% of all seminomas. generally ss is diagnosed in men older than 50 years. the anaplastic variant of spermatocytic seminoma is characterized by an earlier onset when compared to ss, but a benign behavior in spite of its histological patterns similar to classic seminoma. we reported the first case of bilateral, largest and synchronous anaplastic spermatocytic seminoma, in a patient treated with radical orchifunicolectomy alone and with long-term follow-up. the currently available data show that anaplastic ss reveals a clinically benign behavior, and no distant metastases have been reported so far. a close surveillance after surgery could be considered a valid option in the management of this rare testicular neoplasm. key words: testicular cancer; spermatocytic seminoma; anaplastic variant; bilateral disease; radical orchifunicolectomy submitted 5 november 2013; accepted 31 december 2013 summary aim of the paper in this paper we report the seventh case of anaplastic spermatocytic seminoma (ss) (1-14), the first with bilateral and synchronous presentation and unusual clinical features. discussion spermatocytic seminoma (ss) is a rare germ cell tumor, characterized by a benign behavior with slow growth, and is generally localized in the testis; this tumor has a good long term prognosis, and is always controlled by one of the simplest intervention in urology, such as radical orchiectomy with nearly absent risks of complications contrarily to many other urological interventions (15, 16); in literature over 200 cases of ss have been described with only three cases of clearly established metastasis for the no conflict of interest declared conventional type of this tumor (8). it is universally accepted that the sarcomatous differentiation of ss is associated with an aggressive behavior, the presence of metastasis and a poor prognosis (12, 13, 17, 18), despite aggressive surgical and adjuvant treatments (19). on the other hand the anaplastic variant of ss is still poorly known, as in literature only six cases of monolateral tumor have been described so far (6, 9, 14); this is the first case of bilateral, synchronous anaplastic ss described till today. still remain ambiguities about its biological behavior and about the most appropriate diagnostic and therapeutic protocol. however, the present tumor is the largest one described (20 cm) with the longest period of observation (60 months before the surgical intervention plus 36 months of follow-up), which confirm the low risk of metastatic pattern. the main clinical and pathological features of the seven cases (six available in literature and our case) are reported in supplementary materials (table 1). the mean age at the moment of the diagnosis was 45.8 years. this finding confirms the data reported by other authors regarding the early onset of anaplastic variant compared to the classical spermatocytic seminoma (6). furthermore our patient underwent medical examination 5 years after the initial clinical presentation of the disease, which strengthens the hypothesis of an earlier manifestation of the disease. the testicular mass was always asymptomatic and characterized by a slow growth and absence of metastasis; in particular in our case the delay of the diagnosis allowed the tumor to grow disproportionately, reaching an enormous size (20 cm diameter in the left mass) occupying the entire testis, but the growth was limited to the parenchyma without invasion of the tunica albuginea with no lymph node or distant metastases. in all cases there was no intratubular germ cell neoplasia unclassified (igcnu) associated. serum markers !-fp, "-hgb were negative in all cases. the markers commonly used for the diagnosis of classic seminoma (cs) were always negative but only in two cases has been observed the positivity for c-kit (cd117), which has also been reported to be positive in ss in some cases (20, 21); our case was the first with a focal positivity for plap and this is the first identification doi: 10.4081/aiua.2014.1.41 borghesi cr printed_stesura seveso 26/03/14 10:23 pagina 41 archivio italiano di urologia e andrologia 2014; 86, 1 gentile, giunchi, schiavina, franceschelli, borghesi. zukerman, cevenini, vagnoni, romagnoli, colombo, martoranaa, brunocilla 42 of this marker in an anaplastic variant of ss, even if isolated positivity for plap in classic ss has been reported (2022). all the patients underwent radical orchiectomy (ro), while the management after surgery was different but in any case there was the onset of metastasis or recurrence: in 3 cases ro was followed by radiotherapy applied to pelvic and retroperitoneal lymph nodes, in 2 cases the treatment was consolidated with 2 cycles of chemotherapy (carboplatin or cisplatin, etoposide and bleomycin), in two cases ro was followed by surveillance with clinical examination and imaging. histological findings in anaplastic ss, such as areas with extensive necrosis, solid growth pattern, multiple mitotic figures, vascular and tunical invasion, and anaplastic features in lymph node metastasis in primary ss have been described by albores-saavedra et al. (6). according to these findings, the anaplastic variant of ss would seem to have a more aggressive behavior compared to the classical form, even if all the cases described in literature showed a benign behavior and a good prognosis comparable to that of typical ss. in the absence of a specific radiotracer such as for other urological malignancies (23) the pet18f-fdg plus contrast enhanced whole body ct seems the most appropriate follow-up behaviour. references 1. masson p. etude sur le seminome. rev can biol. 1946; 5:361-87. 2. mostofi f, sesterhenn i. tumours of the testis and paratesticular tissue. in: world health organization classification of tumours: pathology and genetics-tumours of the urinary system and male genital organs. edited by jn eble, g sauter, ji epstein and ia sesterhenn. lyon: international agency for research on cancer (iarc) press 2004; chapt 4, pp 217-278. 3. looijenga lh, stoop h, hersmus r, et al. genomic and expression profiling of human spermatocytic seminomas: pathogenetic implications international. int j androl. 2007; 30:328-35; discussion 335-6. epub 2007 jun 15. 4. bomeisl pe, maclennan gt. spermatocytic seminoma. int j androl. 2007; 177:734. 5. stephenson aj, gilligan td. neoplasms of the testis. in: walsh pc, retik ab, vaughan jr ed, wein aj, editors. campbell’s urology. 10th ed. philadelphia (pa): saunders. 2012; p. 840. 6. albores-saavedra j, huffman h, alvarado-cabrero i, et al. anaplastic variant of spermatocytic seminoma. hum pathol. 1996; 27:650-655. 7. brunocilla e, pultrone cv, schiavina r, et al. testicular sclerosing sertoli cell tumor: an additional case and review of the literature. anticancer res. 2012; 32:5127-30. 8. malizia m, brunocilla e, bertaccini a, et al. liposarcoma of the spermatic-cord: description of two clinical cases and review of the literature. arch ital urol androl. 2005; 77:115-7. 9. dundr p, pesl m, et al. anaplastic variant of spermatocytic seminoma. pathol res pract. 2007; 203:621-4. 10. chung pw, bayley aj, sweet j, et al. spermatocytic seminoma: a review. eur urol. 2004; 45:495. 11. burke ap, mostofi fk. spermatocytic seminoma: a clinicopathologic study of 79 cases. j urol pathol. 1993; 1:21-32. 12. narang v, gupta k, gupta a, et al. rhabdomyosarcomatous differentiation in a spermatocytic seminoma with review of literature. indian j urol. 2012; 28:430-433. 13. menon s, karpate a, desai d. spermatocytic seminoma with rhabdomyosarcomatous differentiation: a case report with a review of the literature. j cancer res ther. 2009; 5:213-5. 14. lombardi m, valli m, brisigotti m, et alhttp://www.ncbi.nlm. nih.gov/pubmed?term=rosaij%5bauthor%5d&cauthor=true&cauthor_uid=21087978. spermatocytic seminoma: review of the literature and description of a new case of the anaplastic variant. nt j surg pathol. 2011; 19:5-10. 15. schiavina r, borghesi m, guidi m, et al. perioperative complications and mortality after radical cystectomy when using a standardized reporting methodology. clin genitourin cancer. 2013; 11:189-97. 16. brunocilla e, pultrone c, pernetti r, et al. preservation of the smooth muscular internal (vesical) sphincter and of the proximal urethra during retropubic radical prostatectomy: description of the technique. int j urol. 2012; 19:783-5. 17. chelly i, mekni a, gargouri mm, et al. spermatocytic seminoma with rhabdomyosarcomatous contingent. prog urol. 2006; 16:218-20. 18. true ld, otis cn, delprado w, et al. spermatocytic seminoma of testis with sarcomatous transformation. a report of five cases. am j surg pathol. 1988; 12:75-82. 19. robinson a, bainbridge t, kollmannsberger c. a spermatocytic seminoma with rhabdomyosarcoma transformation and extensive metastases. am j clin oncol. 2007; 30:440-1. 20. cummings ow, ulbright tm, eble jn, et al. spermatocytic semonima: an immunohistochemical study, hum pathol. 1994; 25:54-59. 21. kraggerud sm, berner a, bryne m, et al. spermatocytic seminoma as compared to classical seminoma: an immunohistochemical and dna flow cytometric study, apmis 1999; 107:297-302. 22. dekker i, rozeboom t, delemarre j, et al. placental-like alkaline phosphatase and dna flow cytometry in spermatocytic seminoma, cancer 1992; 69:993-996. 23. nanni c, schiavina r, boschi s, et al. comparison of 18ffacbc and 11c-choline pet/ct in patients with radically treated prostate cancer and biochemical relapse: preliminary results. eur j nucl med mol imaging. 2013; 40(suppl 1):s11-7. case report, table and figures are posted in supplementary materials on www.aiua.it correspondence giorgio gentile, md dr.giorgio.gentile@gmail.com riccardo schiavina, md, assistant professor rschiavina@yahoo.it marco borghesi, md mark.borghesi@gmail.com (corresponding author) ziv zukerman, md ziv.zukerman@gmail.com matteo cevenini, md matteoceve@gmail.com valerio vagnoni, md vagno07@libero.it daniele romagnoli, md danieleromagnoli@hotmail.it giuseppe martorana, md, professor giuseppe.martorana@unibo.it eugenio brunocilla, md, associate professor eugenio.brunocilla@unibo.it department of urology, azienda ospedaliero-universitaria policlinico s.orsola-malpighi, palagi 9 street, 40138 bologna, italy francesca giunchi, md francesca.giunchi@aosp.bo.it department of pathology, azienda ospedaliero-universitaria policlinico s.orsola-malpighi, palagi 9 street, 40138 bologna, italy alessandro franceschelli, md, phd alessandro.franceschelli@aosp.bo.it fulvio colombo, md fulvio.colombo@aosp.bo.it andrology unit, azienda ospedaliero-universitaria policlinico s.orsola-malpighi, palagi 9 street, 40138 bologna, italy borghesi cr printed_stesura seveso 26/03/14 10:23 pagina 42 stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 review and 20-70% of inability to conceive in those areas is attributable to the male gender (4). however, these percentages are not veracious due to an underestimation given by a low number of populations involved, the non-unique clinical definition of infertility and religious and cultural restrictions. furthermore, the effect of covid-19 infection on semen quality still needs to be verified, although mechanisms of testicular damage have been reported (5). this clinical condition depends on different underlying pathologies, which include anorchia (vanishing testis syndrome, swyer syndrome), sperm production dysfunction or obstruction from ejaculatory ducts to seminal colliculi. in particular, spermatozoa dysgenesis could be determined mostly by exogenous factors. indeed, environmental factors seem to influence semen quality aberration. several articles showed the impact of the environment on male infertility (6, 7), with various incidences according to the considered population (8). in a recent review, benatta et al. reported a strict correlation between nutrition and male infertily, especially due to the industrialized mass food production and the subsequent ingestion of xenobiotics (9). although the association between exposure to chemicals, such as pesticides (10), is supported, some doubts remain about the physical ones (11). therefore, this narrative review aims to discuss the main work-related male fertility risk factors. materials and methods search design we conducted a comprehensive literature search on studies discussing physical risk factors for male fertility, between april 4 and may 6, 2022, consulting pubmed and scopus. the following keywords were used: male infertility, male impairment, dna damage, human sperm, semen parameters, and genotoxicity. they were associated with the most discussed risk factors, such as heat, physical exertion, radiation, sedentary work, and psychological stress. identification of studies we considered the observational studies, published after the 2000s, describing the correlation between physical agents’ exposure and male infertility. we evaluated the papers according to the patient intervention comparison outcome studytype (picos) model. p: general population background: a decrease in semen quality is an increasingly widespread pathological condition worldwide. jobs and lifestyles have changed a lot with the advancement of technology in the last few decades, and a new series of risk factors for male infertility have spread. objective: this review aims to summarize the current literature on this relationship, evaluating alterations in semen parameters and hormonal profile. methods: a deep research was performed through medline via pubmed, scopus, and web of science on articles regarding the relationship between physical agents and male fertility over the last twenty years. some physical agents already associated with male infertility, such as heat and radiation, while emerging ones, such as physical exertion, psychological stress and sedentary activities, were newly considered. results: most studies described sperm quality after exposure. overall sperm impairment was shown after radiation and alteration of specific parameters, such as sperm concentration, were observed after psychological stress and sedentary work. in addition, an association was also reported between physical exertion and hormonal profile, especially pituitary hormones and testosterone. conclusions: although the associations between physical agents and male infertility are suggestive, the level of evidence of the studies is not adequate to define their influence, except for physical exertion. therefore, new prospective studies are necessary for the validation of the correlation and the possible safeguarding of the exposed working classes. key words: male fertility; semen parameters; hormonal profile; physical agents. submitted 25 september 2022; accepted 24 october 2022 introduction according to who, infertility is a disease of the reproductive system defined by the inability to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse. this dysfunction affects up to 15 % of couples, and the cause of over 1/3 of them is male infertility (1). it affects 60-80 million couples over the world (2), and the decline in semen quality occurred over the past century, concomitant to an increase in genitourinary abnormalities (such as cryptorchidism, testicular carcinoma, and hypospadias) (3). the percentage of male infertility ranges from 2 to 12%, with the highest rates in africa and central/eastern europe the role of physical agents’ exposure in male infertility: a critical review carlo giulioni 1, valentina maurizi 2, andrea benedetto galosi 1 1 department of urology, polytechnic university of marche region, umberto i hospital "ospedali riuniti", ancona, italy; 2 department of clinical and molecular sciences, polytechnic university of marche region, "ospedali riuniti" university hospital, ancona, italy. doi: 10.4081/aiua.2023.10890 summary archivio italiano di urologia e andrologia 2023; 95, 1 c. giulioni, v. maurizi , a.b. galosi or workers; i: exposure to heat, physical exertion, radiation, sedentary work, or psychological stress; c: comparison with healthy non-exposed male volunteers; o: semen parameters (ejaculate volume, sperm count, sperm concentration, total sperm motility, and sperm morphology) or sex hormone [follicle-stimulating hormone (fsh), luteinizing hormone (lh) and testosterone hormone (th)] levels or dna fragmentation; s: observational studies. eligibility criteria all published human articles in english have been reviewed. the evidence cited in this review comes only from human selected based on the following criteria: • exposure to the risk factor was occupational or environmental. • assessment of semen quality, histological examination, or sperm cells dna fragmentation. • evaluation of sex hormone profile and hypothalamicpituitary-gonadal (hpg) axis status. articles relating only to epidemiological investigations, sex chromosome ratio or other systems were excluded. the quality of all included studies was estabilished the newcastle-ottawa-scale and evaluation forms. results prisma flow diagram of the study was reported in figure 1. eight hundred and fifty-six (856) studies published were identified. two independent authors screened all retrieved records. seven hundred and seventy six (776) articles were excluded by the title and abstract reviewing. eighty (80) were assessed for full-text eligibility. fourty-four (44) studies were excluded due to the following resons: 38 articles regarded chemical agents’ exposure, and 6 were studies on the sperm sex chromosome ratio. the 36 remaining studies were divided according to the agent considered: • 4 for heat exposure. • 9 for physical exertion. • 12 for radiaton. • 5 for sedentary work. • 6 for psychological stress. heat in case of heating of the testicles, an increased metabolism without a corresponding increase in blood supply may occur, with subsequent local hypoxia and harmful effect on spermatozoa. in addition to idiopathic diseases, exogenous factors, such as lifestyle and work, may contribute to a higher temperature of the testicle (12). this risk factor encompasses many types of jobs in both developing and industrial countries. bakers in saudi arabia, exposed to a wet-bulb globe temperature (wbgt) of 37°c, had an infertility rate of 22.7% compared to 3% of the healthy volunteers (13). in a cohort study of the steel industry (workers undergoing wbgt of 36°c) there was a statistically significant difference in seminal parameters (semen volume, sperm morphology, motility, and count) compared to the a non-exposed group (14). nevertheless, shef et al. reported the reversible toxic effect of hyperthermia on semen quality after cessation of heat exposure (15). however, there is not always a significant reduction in semen quality also for workers exposed to extreme heat (16). all considered studies about heat exposure are summarized in table 1. physical exertion moderate physical activity (pa), in addition to better health and decreased stress, contributes substantially to increasing the chances of couples seeking pregnancy. however, an excessive intensity of the exercises may cause stress with an attached alteration of fertility. experimental human studies confirmed inflammatory pathogenesis. a reactive oxygen species (ros) and seminal cytokines increase during aerobic and nonaerobic isometfigure 1. prisma 2009 flow diagram. archivio italiano di urologia e andrologia 2023; 95, 1 the impact of physicial agents on male fertility ric exercise was reported, as demonstrated by malondialdehyde (a marker of lipid peroxidation), lipid hydroperoxide and carbonyls, regardless of concomitants augmented levels of superoxide dismutase (sod), catalase, and total antioxidant capacity (17-19). besides, semen impairment is associated with an altitude greater than 2000 m and the consequent risk of hypoxia among mountaineers (20, 21). hpg axis is also involved, with the reduction of gonadotropin-releasing hormone (gnrh) and production of inhibin (with consequent decrease of fsh, lh, total and free th and increase of prolactin) (22, 23). it is noteworthy that the complete recovery of fertility occurs at different times according to exposure and age (18). on the other hand, mínguez-alarcón et al. found in their study that there are no significant differences in semen at different intensities of exercise (24). physical effort occurs in various jobs, from professional athletes to manual workers. as for the first category, in the rugby and soccer players, both sod and neutrophil levels were higher after a match and the entire season (25, 26). furthermore, the cyclists have a lower proportion of spermatozoa with normal morphology (27), while there is also an impairment in volume, motility, count and dna fragmentation in contact sports (28). the strenuous work negatively impacts the mean sperm count and concentration more than other work-related risk factors (29). studies are shown in table 2 and reported an unequivocal association between physical effort and male impairment. radiation radiation is one of the most in-depth topics considering pathogenesis and its effects on men, as shown in table 3. the only experimental study was conducted on some prisoners: spermatocytes and spermatids can be damaged, respectively, at 2-3 gy and 4-6 gy, and infertility becomes permanent at 3-5 gy; furthermore, complete recovery can be obtained at 9-18 months if < 1 gy and 5years or more with a dose of 4-6 gy (30). nowadays, only observational studies occur for obvious ethical reasons. human studies can be divided according to whether the exposure was to not ionizing or ionizing radiation. the former includes low-frequency energies on the electromagnetic spectrum, including radiofrequency, microwaves, infrared and ultraviolet radiations. several routinely used sources emit them, such as mobile phones, which have a wide range of sar. in a study examining 371 male volunteers, the proportion of rapid progressive motile sperm was significantly lower in men who used their phone for over 60 minutes/day (31). as well, agarwal et al., dividing men according to their active cell phone use, reported a linear relationship between its use and the decrease in total sperm count, motility, viability, and normal morphology (32). not ionizing radiation exposure occurs in several jobs. telecommunications and sonar/radar operators have an increased risk of infertility (or = 1.72 and or = 2.28, respectively) (33). even men in the royal norwegian navy had a higher risk of infertility due to radiofrequency electromagnetic fields exposure, especially in men closer than 10 m from highfrequency aerials (or = 1.93) (34). ionizing radiation comprehends all high energy waves, including alpha, beta, and gamma rays, and removes electrons from atoms and molecules of materials. wdowiak et al. proved that natural and artificial alfa, beta, and gamma radioactive isotopes do not affect semen volume, count, density, and motility, but viability is negatively related to the gamma isotope, and the percentage of sperm with nortable 1. studies concerning the effects of heat on male fertility. reference type of clinical study examined population, n reproductive effects al-otaibi (12) cross-sectional study 137 bakers infertility rate of 22.7% vs 3% in control group hamerezaee et al. (13) cross-sectional study cohort study 30 steel industry workers exposed to heat; 14 workers not exposed significant reduction in sperm volume, normal morphology, motility, and count shefi et al. (14) cross-sectional study 11 infertile men after known hyperthermic exposure. sperm quality impairment improved after the termination of the exposure eisenberg et al. (15) cross-sectional study cohort study 98 workers exposed to extreme heat, 358 workes exposed work not associated with semen quality table 2. studies concerning the effects of physical exertion on male fertility. reference type of clinical study examined population, n exercise period reproductive effects hajizadeh maleki et al. (16) clinical trial 24 long-distance road cyclists 16 weeks low semen volume,sperm motility, normal morphology, concentration, and count pelliccione et al. (17) clinical trial 7 experienced mountaineers 10 days reduction of sperm concentration, increase in serum testosterone verratti et al. (18) clinical trial 7 mountain climbers 5 days reduction of sperm forward motility, increase in lh safarinejad et al. (19) randomized 143 subjects assigned to high-intensity 60 weeks reduction of sperm count, concentration and motility and lh, fsh and testosterone. controlled trial exercise, 286 to moderate-intensity exercis higher changes in high-intensity exercise than moderate – one. regular parameters after recovery period vaamonde et al. (20) randomized 8 non-professional athletes, 8 controls short-term exhaustive reduction of lh and fsh. changes in volume, sperm concentration, controlled trial endurance exercise, 2 weeks count, type “a” and “d” velocity, and moprhology mínguez-alarcón et al. (21) cross-sectional study 215 healthy young men no significative differences. gebreegziabher et al. (26) cross-sectional study 10 long distance competitive cyclists, reduction of sperm normal morphology 10 volunteers performing minimal or no exercise tartibian et al. (27) cross-sectional study 56 elite athletes, lower semen volume, motility, sperm count and normal morphology. 52 physically active volunteer men higher mda and ros levels and dna fragmentation rate eisenberg et al. (28) cross-sectional study 145 men doing strenous worlk, 311 controls lower semen concentration and total sperm count archivio italiano di urologia e andrologia 2023; 95, 1 c. giulioni, v. maurizi , a.b. galosi mal morphology is negatively associated with to beta and gamma ones (35). radiation therapy is also a dangerous risk factor, affecting every age range. over the threshold value of 7.5 gy, adult survivors of childhood tumours have a reduced or almost compromised ability to siring a pregnancy and more chances of becoming oligospermic than those not exposed (36). after 1-year of radiotherapy in adults, all semen parameters are significantly lower (37). even among all georgian soldiers, the exposure to cesium137 caused complete azoospermia or critical alterations of semen morphology and motility (38). in diagnostic radiation systems, sperm motility (p < 0.001), viability (p < 0.05), and normal morphology (p < 0.001) were lower in exposed personnel than in healthy men (39). furthermore, kumar et al. discovered that sperm dna denaturation is significantly higher (p < 0.0001) and associated with higher total seminal plasma glutathione (gsh) (p < 0.01) and total antioxidant concentration (p < 0.001) in seminal plasma always in health workers occupationally exposed to radiation than control (40). an increase in micronuclei (mns) derived from acentric chromosome fragments (or whole chromosomes) was also reported among interventional cardiologists (p = 0.02), with a subsequent higher levels of somatic dna damage (41). nevertheless, in a study on employees of the nuclear industries, there was no evidence of an increase in the incidence of infertility compared to the population, even though the median received radiation dose was 12.3 msv (42). sedentary work sedentary activity (sa) occurs in several occupations, such as doctors, engineers, administrators, car drivers, and office workers studies on men show that this risk factor is negatively related to sperm count and concentration (43) and th (44). as mentioned before, the scrotal temperature is closely associated and increases in these conditions with an average value of 0.7°c higher, even 1.7-2.2°c in car drivers (45), with an attached reduction in sperm count (46). hjollund also discovered that sperm concentration decreased by 40% for every 1°c increase, and inhibin b levels decreased in men with the highest daytime scrotal temperature (47). however, in another study, there are no statistically significant differences in semen parameters, although those who spend more than 50% of the seated work time have a higher dna fragmentation index (dfi) (48). although there is proven evidence of heat stress induced by prolonged sitting in table 4, further investigation is needed to demonstrate sedentary work as a risk factor or whether it requires a sedentary lifestyle. psychological stress the distribution varies according to gender, geography, and technological progress, with greater frequency in women, inhabitants in europe and cities than men, those in asia and rural environments, respectively (49, 50). men were analysed in different contexts, with several stressors. in a cross-sectional study, the stress levels in the general population according to a questionnaire were inversely proportional to the values of the semen parameters, affecting sperm count, volume, and concentration (51). eskiocak et al. evaluated the university students, noting table 3. studies concerning the effects of radiation on male fertility. reference type of clinical study examined population, n radiation type reproductive effects fejes et al. (30) cohort study 371 male volunteers: 59 high transmitters (use over 60 minutes/day), not ionizing high transmitters had a decrease in the proportion of rapid 195 control group 1; 88 humans keeping cell phone in the standby progressive motile sperm and an increase in slow progressive position for more than 20 hours daily, 106 control group 2 motile sperm. no differences in sperm based on duration of standby agarwal et al. (31) cross-sectional study 361 humans divided according to their active cell phone use: not ionizing decrease in sperm count, motility, viability, and normal group a: no use (40); group b: 4 h/day (107); morphology with the increase in daily use of cell phone group c: 2-4 h/day (100) and group d: > 4 h/day (114) møllerløkken et al. (32) cross-sectional study 1.487 norwegian navy personnel not ionizing telecommunications and sonar/radar operators have an or of 1.72 and 2.28 respectively baste et al. (33) cross-sectional study 10.497 currently and formerly employed military men not ionizing nearness to high frequency aerials is positively related to higher risk of infertility. or for low degree is 1.39 and or for high degree is 1.93 wdowiak et al. (34) cross-sectional study 4.250 patients attending at fertility center and spermiogram ionizing sperm viability is negatively associated with the gamma isotope, was rrelated to background radioactivity in the lublin region and normal morphology is negatively related to beta and gamma ones green et al. (35) cross-sectional study 6.224 adult survivors of childhood tumor ionizing reduced or almost compromise ability to siring a pregnancy gandini et al. (36) cross-sectional study 166 patients affected by testicular cancer, ionizing decrease in ejaculate volume, sperm concentration, 95 underwent to radiotherapy, 71 underwent to chemiothgerapy count and normal morphology. greater ricovery in subgroup exposed to < 26 gy for sperm conenctration and count bezold et al. (37) cross-sectional study 7 male soldiers ionizing in 57% complete azoospermia, associated with increase in fsh and lh, and in 14% severe oligozoospermia kumar et al. (38) cross-sectional study 83 workers occupationally exposed to ionizing radiation ionizing decrease in sperm motility, viability, and morphological abnormalities; and 51 non-exposed control increase in dna fragmentation and sperm head vacuoles kumar et al. (39) cross-sectional study 83 workers occupationally exposed to ionizing radiation ionizing higher dna fragmentation in exposed men and 51 non-exposed controls andreassi et al. (40) cross-sectional study 31 interventional cardiologists; 31 clinical cardiologists ionizing increase in micronuclei (mns), derived from acentric chromosome fragments or whole chromosomes, and it positively related to years of work doyle et al. (41) cross-sectional study 5.353 employers in nuclear industry ionizing no evidence of association between exposure to low level ionising radiation among men with primary infertility archivio italiano di urologia e andrologia 2023; 95, 1 the impact of physicial agents on male fertility lower levels of sperm concentration, total and rapid progressive motility, and arginase activity before their exams, associated with increased nitrogen monoxide (no) and superoxide dismutase (sod) (52) in seminal plasma. the most frequently encountered stressor in studies is the visit to infertility clinics: an alteration in sperm concentration and motility (53), normal morphology was reported, with a negative association between the degree of stress and the ability to sire a pregnancy (54). psychological stress also affects the work environment, influencing some of them heavily. consulting responses from the job content questionnaire, reduced sperm concentration and count values were detected (55), and men who experienced two or more stressful life events in the past year had a lower percentage of motile sperm and a lower percentage of morphologically normal sperm (56). cited studies, summarised in table 5, demonstrate the validity of psychological stress as an influencing agent for male impairment. discussion this paper reviewed the literature that investigated the impact of physical agents on male fertility. some agents with a known influence on male fertility have been considered, such as heat and radiation, likewise emerging ones, such as physical exertion and psychological stress. heat an optimal test temperature of 3°c lower than in arterial circulation is necessary for spermatogenesis (57). this process is ensured by a cooling process involving the scrotum, pampiniform plexus, and muscles due to the heat exchange mechanism between incoming arterial blood and outgoing venous blood (58). a correlation between testis heat and spermatogenesis occurs, as demonstrated by the latter improvement in patients undergoing after operation for varicocele (59). the environmental temperature also plays a role in fertility as it is inversely proportional to total sperm number, non-progressive motility, and normal morphology (60). in an extensive literature review from 1998, thonneau et al. reported that sperm morphology was the semen parameter most affected with a concomitant increase in time to pregnancy (61). many experimental studies on animals showed the activation of heat shock protein (hsp) by heat, with consequent dna damage, formation of pyknotic nuclei, autophagy and, at least, apoptosis (62, 63). various types of morphological and functional alterations in high-temperature environments have emerged. an experimental study on broiler breeders was carried out: the sperm quality index (sqi) of subjects with normal semen parameters had been reduced after exposure to constant high temperatures, concomitant with a higher percentage of dead sperm, while the heat stress does not cause further deterioration in cases with poor sqi (64). always karaca et al. showed that the sqi decreases after a mix of control sperm with the seminal plasma (sp) of cases exposed to t of 32°c, while the sperm of the exposed combined with the sp of healthy subjects determined lower levels of calcium (ca), with the consequent decrease in sperm motility, and lower fertility (65). only four papers on heat exposure were recently published. in two of them, alterations of several semen parameters were shown (such as sperm normal morphology, total motility, and count) (14, 15), and a higher rate of infertility was reported among bakers in another study table 4. studies concerning the effects of sedentary work on male fertility. reference type of clinical study examined population, n reproductive effects gaskins et al. (42] cross-sectional study 189 healthy young men sperm concentration and count were inversely related to sedentary activity. or of 5.45 of low sperm concentration in less active men compared to active men priskorn et al. (43] cross-sectional study 1210 healthy young men time spent watching television was associated with lower sperm counts, an increase in follicle-stimulating hormone and decreases in testosterone hjollund et al. (45] cross-sectional study 60 men doing sedentary work elevation in scrotal skin temperature is associated with a substantially reduced sperm concentration hjollund et al. (46] cross-sectional study 99 healthy men decrease in sperm concentration, count, fsh per 1°c increment of median daytime scrotal temperature gill et al. (47] cross-sectional study 152 men who spent ≥ 50% of their time at work no statistically significant differences in semen parameters although who in a sedentary position; 102 men who spent < 50% of their time spend more than 50% of the seated work time have a higher dfi table 5. studies concerning the effects of psychological stress on male fertility. reference type of clinical study examined population, n reproductive effects nordkap et al. [50] cross-sectional study 1215 young men sperm count, volume and concentration inversely related to stress eskiocak et al. [51] cross-sectional study 27 university students sperm concentration, total and rapid progressive motility reduction gollenberg et al. [52] cross-sectional study 744 healthy men men reporting 2 or more recent stressful life events had reduced sperm concentration, motility and morphology than < 2 boivin et al. [53] cohort study 818 males in fertility clinics more marital distress required more treatment cycles to conceive (or = 1,20) zou et al. [54] cross-sectional study 384 adult male workers, 88 with high work stress and 296 with low stress decrease in sperm concentration and or total sperm count in stressed workers janevic et al. [55] cross-sectional study 193 healthy men inverse association between perceived stress score and sperm concentration, motility, and normal morphology archivio italiano di urologia e andrologia 2023; 95, 1 c. giulioni, v. maurizi , a.b. galosi (13). another remarkable element is the reversibility of this effect on semen quality. eisenberg et al. showed that heat exposure in certain occupations, such as welders, is associated with altered semen quality, while other jobs have not demonstrated a detriment to semen production (16). therefore, an adequate temperature and sufficient exposure time are necessary to reach a condition of irreversible semen impairment. physical exertion although physical activity is recommended for a healthy lifestyle. indeed, an improvement of all semen parameters (primarily rapid progressive sperm motility) and a reduction of inflammation and oxidative stress markers occur after 3-6 months of training (66, 67). physical exertion may be related to male infertility, and it may be secondary to the immune system due to the proinflammatory cytokines increasing during heavy exertion (68). these proteins are negatively related to sperm motility and morphology (69), and they increase the activity of lipid peroxidation in the sperm cell membrane and dna damage in both mitochondrial and nuclear genomes (70) through a rise of ros production (71). higher antioxidants enzymes levels in athletes than in sedentary subjects occur (72, 73), although their synthesis in semen occurs mainly along the vas deferens, and, therefore, direct ros damage to the testicles and no compensation for spermatogenesis are conceivable (74). a comparison between triathletes and men who practice regular physical activity showed lower levels of sperm motility, morphology, and count (75); even cycling more than 5-h per week was associated with low sperm concentration (76). in a study on extreme mountain bikers, abnormal findings in the scrotal us were reported in 94% of cases, including the most frequent scrotal calculi, epididymal cyst and epididymal calcifications, compared to 16% of controls (77). furthermore, physically "more active" young men have a higher percentage of immotile sperm than "less active" subjects (78). in endurance-trained males, there is a significant reduction in resting testosterone hormone (th) after 6-months of intense training with attached altered prolactin and lutropin release (79). in the majority of the considered studies, physical exertion was associated with altered semen parameters. the most frequent were sperm motility and concentration, although sperm morphology, count, and semen volume were statistically different in most cases. furthermore, controversies about the effect of physical exertion on the hpg axis have emerged. only in 2 out of 4 studies evaluating the hormonal profile did a reduction in fsh, lh or testosterone occur. nevertheless, considering the period of exercise, it appears that, in the first few days of training, there is an increase in sex hormones and a subsequent decline. the overall evidence level of the included studies is noticeable due to the many clinical trials present. therefore, we can see a strong correlation between physical exertion and male infertility. radiation radiation is one of the most widespread physical agents, given its presence in the environment and the devices used routinely. the testis is one of the organs most sensitive to this risk factor because mature spermatozoa are unable to repair damage by radiofrequency (80), whose mechanism is entrusted to sertoli cells through non-homologous end joining (nhej) (81). bergonié reported that the less differentiated cells with higher reproductive activity are the most susceptible to x-rays (82). the sensitivity of spermatogenesis to radiation depends on the wavelength, the time and duration of the exposure, the higher number of non-differentiated cells, and the water content (the effect is directly proportional to the amount of water) (83). the amount of absorbed radiation depends on several factors, which influence the averaged whole-body specific absorption rate (sar). its threshold level is 1,6 w/kg, as decreed by federal communications commission in the usa, while europe follow international electrotechnical commission guidelines, so it is 2 w/kg (84). the irradiation of the spermatids at 3.5-6 gray can cause damage to the testis and may determine permanent infertility, with a risk of congenital anomalies to the offspring (85). nevertheless, infertility can be transitional with 150 msv (86) or 2-3 gy and 4-6 gy (with recovery times of 10-24 months and up to 10 years, respectively) (87). the long-lasting effect of radiation time depends on the foci of γh2ax formed after exposure (88); the repair occurs in two hours, but this period increases already in spermatocytes with exposure over 1 gy (89). dna damage from electromagnetic fields (emf) is also secondary to ros formation (90). although their small dose can favour capacitation, the acrosomal reaction and the fusion with the oocyte (91, 92), oxidative stress reduces sperm count, motility, and viability, inducing lipid peroxidation, a decrease in sperm motility, dna damage and apoptosis (93). besides, it seems responsible for increased apoptosis and is involved in testicular carcinogenesis (94). in the last in vivo experiments, three categories of topics have emerged: 1.effects on sperm cells: after exposure, count, motility, normal morphology, and viability decreased considerably (95). 2.spermatogonia radiosensitivity: sperm cells are less vulnerable than somatic ones due to the complex of the seminiferous tubules, but the repair mechanism to dna damage is slower or not present (96, 97). nevertheless, these considerations are not very relevant because the chromatin in the gametes of mice is more compact than humans and, therefore, less susceptible (98). 3.involvement of hpg axis: wang et al. found under electron microscopy that leydig cells are more susceptible to radiation damage with reduced serum th (99). the hypothalamic cells producing gnrh also seem to be affected (100), with a reduction in the circulation of fsh, lh and th (101). most included articles showed a correlation between radiation and male infertility, considering several variables, such as semen parameters, dna fragmentation index, and ability to siring a pregnancy. as for not ionizing radiation, both studies evaluating semen quality reported a decrease in sperm motility and viability, confirming a targeted action based on the concentration of superoxide anion in semen (102). almost 15,000 military men were archivio italiano di urologia e andrologia 2023; 95, 1 the impact of physicial agents on male fertility recruited in the other two studies to assess the risks associated with radiofrequency electromagnetic fields. proximity to a source that emits radiation is positively associated with the risk of male infertility, with an odds ratio ranging from 1.4 to 2.3 (33, 34). even ionizing radiation seems to harm semen parameters. among patients with testicular cancer who underwent radiotherapy, male soldiers and workers occupationally exposed to ionizing radiation, an overall semen quality impairment occurs, especially for sperm normal morphology and total count. in the three studies assessing its effect on the cell nucleus, two reported a higher dfi value than controls, whereas the micronuclei frequency was higher among interventional cardiologists in the other one. furthermore, adult survivors of childhood cancer have a reduced or almost compromised ability to siring a pregnancy (36). in summary, a negative impact of ionizing and non-ionizing radiation emerged, also focusing on children. sedentary work in a period of technological development and consequently the use of computers and prolonged sitting, the sedentary occupation has become widespread and more frequently associated with other risk factors that may contribute to infertility, such as physical inactivity and obesity. the etiopathogenesis is related to high scrotal temperature following prolonged sitting, which may imply a reduction in sperm count and concentration (103). although several times they were used as synonyms in literature, physical inactivity (pi) is a different concept compared to a sedentary lifestyle since it means failure to reach the recommended pa threshold value (at least 150 minutes of moderate pa per week) (104). even pi has a higher incidence in infertile men, with a decrease in almost all semen parameters (concentration, viability, motility, and morphology) and hormonal levels (fsh, lh and th) (105, 106). nevertheless, sa and pi frequently coexist and negatively affect male fertility. in two controlled trials, where men had to practice moderate exercise regularly, there were evident reductions in inflammation and oxidative stress with the improvement of all semen parameters, dna integrity, pregnancy rate and th in obese people (107, 108). in four out of the five articles sperm quality was affected and the most frequent were sperm concentration and total count (three out of four). in the two articles evaluating the hormonal profile, a reduction in fsh and th occurred, respectively. however, gill et al. reported no association between sa and semen quality alterations, although a higher dfi occurred in patients who spent ≥ 50% of their time at work in a sedentary position (48). given the low number of papers and their evidence level, no definitive conclusions can be obtained; further studies are necessary to establish a substantial correlation between sedentary work and male infertility. psychological stress in 1936 hans selye defined stress as the non-specific response of the organism to every request. this process consists of three distinct phases: alarm, resistance, and exhaustion. in the first two steps, the subject uses his resources and therefore tries to adapt, while, in the last one, the defences fall, and physical, physiological, and emotional symptoms occur. hypothalamic-pituitary-adrenal (hpa) axis mediates the stress response. the paraventricular nucleus activates the catecholaminergic system and produces the hormone crh, the starting point of the hpa axis, determining the production of glucocorticoids. the latter determines the suppression of the transcription of the gnrh receptor gene (109) and, consequently, of the hpg axis. furthermore, in subcortical structures, crh binds especially with the chr-r2 receptor also present in testicular cells (110), which would explain why, in stress, there are apoptosis and age-related degeneration of leydig cells (111) and inhibition of the conversion of androstenedione to th (112). moreover, romeo et al. have shown that some key enzymes involved in the synthesis of catecholamines are present in leydig cells, which could contribute to the regulation of spermatogenesis in times of stress (113). an experimental study validated the latter concept, showing that its effect on fertility depends on the type of stress and that it is not influenced only by adrenal hormones since the administration of th did not affect the outcomes (114). in recent years, animal studies have confirmed the reduction of hpg axis functionality during stress, with a consequent decrease in gnrh, fsh and lh, and the testicular cells apoptosis occurs (115, 116). one of the most noteworthy discoveries in this area was the b-endorphin (b-ep) effect. it is produced by both hypothalamus and pituitary in the testis (117) and, in a stressful time, it inhibits the secretion of gnrh, with a reduction of lh (118), which in turn stimulates the synthesis of b-ep in the testis, suppressing th and sperm production and inducing leydig cells apoptosis (119). in the included studies, sperm concentration was the most altered parameter, while sperm count, total motility and morphology were affected with reduced frequency. even the temporal proximity between the stressful event and the semen quality impairment was reported. indeed, an inverse relationship was reported between male infertility and perceived stress or several recent stressful life events (53, 56). furthermore, boivin et al. reported a higher number of treatment cycles for conception in women who reported more marital distress (54). in summary, the reported studies are promising, and others with higher evidence levels are desirable to ascertain the effect of psychological stress on male fertility. conclusions fertility is vulnerable to several environmental and occupational agents in men. unlike chemical agents, which are more sectorial, physical ones are present in both wellresourced and developing countries. sedentary work has shown a remarkable capacity to cause male impairment in studies. in addition to germ cells, even the testicular supporting ones are influenced by environmental exposure, such as leydig ones, with alteration of the hormonal profile, including th e and gonadotropins. despite these intriguing findings, a cause-effect relationship is hard to state due to the several confounders such as infections, smoking, previous surgeries and outdoor archivio italiano di urologia e andrologia 2023; 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8:709-12. 116. niederberger c. re: regulation of male fertility by the opioid system. j urol. 2012; 187:238-9. 117. xiong x, zhang l, fan m, et al. b-endorphin induction by psychological stress promotes leydig cell apoptosis through p38 mapk pathway in male rats. cells. 2019; 8:1265 118. hajizadeh maleki b, tartibian b. resistance exercise modulates male factor infertility through anti-inflammatory and antioxidative mechanisms in infertile men: a rct. life sci. 2018; 203:150-160. 119. rosety ma, díaz a, rosety jm, et al. exercise improved semen quality and reproductive hormone levels in sedentary obese adults. nutr hosp 2017; 34:608-612 correspondence carlo giulioni, md carlo.giulioni9@gmail.com andrea benedetto galosi, md galosiab@yahoo.it department of urology, polytechnic university of marche region, umberto i hospital "ospedali riuniti", 71 conca street, 60126, ancona, italy valentina maurizi, md valemauri92@gmail.com department of clinical and molecular sciences, polytechnic university of marche region, "ospedali riuniti" university hospital, ancona, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso 5archivio italiano di urologia e andrologia 2014; 86, 1 original paper is there any effect of insulin resistance on male reproductive system? ayhan verit 1, fatma ferda verit 2, halil oncel 3, halil ciftci 4 1 fatih sultan mehmet research & training hospital, dept. of urology, istanbul, turkey; 2 suleymaniye maternity, research & training hospital, dept. of obstetrics & gynaecology, infertility research & treatment centre, istanbul, turkey; 3 sanliurfa research & training hospital, dept. of urology, sanliurfa, turkey; 4 harran university, school of medicine, dept. of urology, sanliurfa, turkey. objectives: to investigate the possible effect of insulin resistance (ir) on male reproductive system via evaluation of semen analysis, male sex hormones and serum lipid profiles, and testicular volumes. methods: after the exclusions, a total of 80 male patients were enrolled in this prospective study. body mass index (bmi), testicular volume, semen samples, serum hormone/lipid profiles, high sensitive c-reactive protein (hscrp) were obtained from all the subjects. results: the patients were divided into two groups as study and control according to the presence of ir. there were no statistical differences in terms of age, marriage period, testicular volume, serum levels of hormone and lipid profiles and bmi between the groups. there were no relationship between homeostasis model assessment of insulin resistance (homa-ir) and semen volume (r = -0.10, p = 0.37), total sperm count (r = -0.09, p = 0.39), motility (r = -0.15, p = 0.16) and morphology (r = -0.14, p = 0.19). however, homa-ir was closely associated with hscrp levels (r = 0.94, p < 0.0001). conclusions: despite of the documented strong inverse relationships between diabetes mellitus (dm) and male/female fertility, and also between ir and female infertility via ovarian functions as in polycystic ovary syndrome, to our knowledge, there is no report about any influence of ir on male fertility. dm and metabolic syndrome (mets) have negative influence on fertility. thus, ir may be accused of causing detrimental effect on male infertility due to hyperinsulinemic state and being one of the components for mets. interestingly, due to our preliminary results, we do not found any inverse correlation between ir and male reproductive functions. key words: insulin resistance; male reproductive system; male fertility; sex hormones; sperm. submitted 22 september 2013; accepted 5 october 2013 summary introduction the impaired glucose metabolism as in diabetes mellitus (dm) is widely accepted as a negative effecting factor on human fertility in either gender (1, 2). however this no conflict of interest declared. detrimental effect of dm on male infertility has long been regarded as a controversial topic due to the fact that the literature knowledge mostly depended on the conventional semen analysis which is not a well predictor of male fertility (3, 4). nevertheless, it was reported that dm can inversely effect male fertility via sperm functions at molecular level especially on its nuclear and mitochondrial dna and also its repairing systems (3). moreover, dm is responsible for a kind of histological damage of the epididymis that resulted in a negative impact on sperm transit and also promotes inflammatory process in sexual male accessory glands (5). according the relatively new issue of the endless story of glucose metabolism, insulin resistance (ir), is defined as elevated serum insulin levels due to the end of organ resistance at molecular level with reduced glucose uptake (6). ir and hyperinsulinemia play a major role in the pathogenesis of type 2 diabetes (dm2). ir is claimed of inverse effect on female health such as infertility via ovarian functions as in polycystic ovary syndrome (pcos), increased risk pregnancy and elevated lifetime risk of developing type 2 diabetes (7). ir should be taken into account in the definition of metabolic syndrome (mets) which represents a group of abnormalities, including overweight, dyslipidemia, hypertension, endothelial dysfunction, systemic inflammation and impaired glucose metabolism that reflects our modern's world sedentary lifestyle accompanying with over nutrition and thus became one of the major public health challenges worldwide (8, 9). to our interest, the harm of mets on male infertility is mostly attributed to the various problems related with overweight such as high scrotal temperature, variations of serum testosterone levels or dyslipidemia other than ir component of mets (9). despite of the documented well known aforementioned strong inverse relationships between dm and male/female fertility, and also ir and female fertility, to our knowledge, there is no report about any influence of ir on male fertility. thus, in this preliminary study we investigate the possible effect of ir on male reproductive system via evaluation of semen analysis, male sex hormones and serum lipid profiles, and testicular volumes. doi: 10.4081/aiua.2014.1.5 verit_stesura seveso 26/03/14 09:53 pagina 5 archivio italiano di urologia e andrologia 2014; 86, 1 a. verit, f. ferda verit, h. oncel, h. ciftci 6 materials and methods a total of 80 male patients who attended outpatient infertility clinic of urology department of our university hospital between january 2009 and june 2012 were enrolled in this prospective study. this study was approved by university’s institutional review board and all the participants signed the informed consent before the onset of study. a detailed medical history and body mass index (bmi) were obtained from all participants. the patients over 40 years, with known erectile dysfunction, chronic/hereditary disease (including prostatitis, hypertension, dyslipidemia needing medical care), malignancy, and smokers, alcohol drinkers, drug abusers, azoospermics and patients who had varicocele were excluded. systemic and genital examination was performed for all subjects. testicular volume was measured by ultrasound and calculated as the formula of 0.71 x length x width x thickness. the patients were divided into two groups as study and control according to the presence of ir or not respectively. the blood samples were undertaken at 9:00 and 11:00 a.m. after an overnight fast (at least 12 hours) and centrifuged within 2 h after withdrawal and assessed on the same day. ir was determined by the homeostasis model assessment of insulin resistance (homa-ir) via the formula: fasting bloo sugar (mg/dl) × fasting insulin (μiu/ml)/405. a homa value above 4 was accepted for indication of ir. insulin was determined by electrochemiluminescent immunoassay (siemens immu lite 2000, los angeles, usa). gonado tro pins, testosterone and high sensitive c-reactive protein (hscrp) levels were also obtained for all subjects. two semen samples were evaluated in two weeks intervals. semen samples collected by masturbation in a clean specimen container after a sexual abstinence for 2 5 days were allowed to liquefy at 37º c and evaluated immediately according to who recommendations including ejaculate volume, ph, time to liquefaction, sperm concentration, motility and morphology. sperm concentration was expressed as 106 per millilitre of semen, whereas motility and morphology were expressed as percentage. statistical analysis baseline characteristics of the groups were presented as the mean ± sd. variables with a skewed distribution were log transformed for all analyses. demographic, laboratory and semen parameters between the study and control groups were assessed by student’s t test. correlations between homa-ir, semen parameters and hscrp, were assessed by pearson correlation analysis. p < 0.05 was considered as statistically significant. results the results of 80 male subjects were evaluated. of those, 40 were diagnosed with ir due to homa-ir and considered as study group and remaining 40 formed the control group. the data collection was stopped when each group reached to 40. median age of the patients with or without ir were 31.2 ± 5.0 (range 18-40) and 29.6 ± 5.0 (range 18-39) respectively. there were no statistical differences in terms of age, marriage period, testicular volume and bmi between the groups (table 1). semen and serologic characteristics (hormone and lipid profiles, glucose/insulin, hscrp levels and homa-ir) of the groups were also summarized in table 2. subjects with ir subjects without ir p (n = 40) (n = 40) age (year) 31.2 ± 5.0 29.6 ± 5.0 0.15 bmi (kg/m2) 25.6 ± 3.3 25.0 ± 3.3 0.44 testicular volume (cm3) 20.2 ± 3.2 20.9 ± 3.1 0.33 bmi: body mass index; ir: insulin resistance. subjects with ir subjects without ir p (n = 40) (n = 40) fsh (miu/ml) 5.8 ± 2.7 6.4 ± 2.7 0.36 lh (miu/ml) 7.8 ± 2.7 6.9 ± 2.7 0.14 total testosterone(ng/dl) 403.4 ± 66.2 427.9 ± 67.4 0.10 shbg (nmol/l) 23.9 ± 4.4 25.4 ± 4.4 0.13 tg (mg/dl) 158.2 ± 21.1 116.7 ± 20.3 < 0.0001 tc (mg/dl) 191.2 ± 28.8 166.3 ± 28.0 < 0.0001 hdl (mg/dl) 38.2 ± 4.0 44.2 ± 4.2 < 0.0001 ldl (mg/dl) 124.4 ± 20.0 105.9 ± 19.8 < 0.0001 fasting glucose (mg/dl) 111.3 ± 9.7 89.4 ± 9.5 < 0.0001 fasting insulin (µiu/ml) 22.5 ± 4.4 6.5 ± 4.3 < 0.0001 homa-ir 6.1 ± 1.2 1.4 ± 0.9 < 0.0001 hscrp (mg/l) 3.1 ± 1.1 0.9 ± 0.4 < 0.0001 semen parameters volume (ml) 2.6 ± 1.2 2.8 ± 1.3 0.50 total sperm count (sperm! 106/ml) 62.4 ± 39.1 72.1 ± 39.5 0.27 motility (%) 56.1 ± 15.6 60.8 ± 15.5 0.18 morphology (%) 42.7 ± 9.4 45.7 ±9.4 0.16 shbg: sex hormone binding globulin; tg: triglyceride; tc: total cholesterol; hdl: high density lipoprotein; ldl: low density lipoprotein; homa-ir: homeostasis model assessment of insulin resistance; hscrp: high sensitive; c-reactive protein; ir: insulin resistance. table 1. age, body mass index (bmi) and testicular volume of patients who presented to infertility center with/without insulin resistance. table 2. laboratory and semen characteristics of patients who presented to infertility center with/without insulin resistance. verit_stesura seveso 26/03/14 09:53 pagina 6 there were no relationship between homa-ir and semen volume (r = -0.10, p = 0.37), total sperm count (r = -0.09, p = 0.39), motility (r = -0.15, p = 0 .16) and morphology (r = -0.14, p = 0.19). however, homa-ir was closely associated with hscrp levels (r = 0.94, p < 0.0001). discussion although ir with related hyperinsulinemia classically is defined as a decreased sensitivity to the metabolic actions of insulin such as insulin-mediated glucose disposal, it should be considered that insulin itself also has vascular actions under healthy conditions and this issue is a focus of investigation (10). ir, solely itself, was accused of taking part somehow in the etiology of some urologic disease such as urolithiasis and erectile dysfunction, by similar mechanism as in dm via impairing endothelial functions depending on experimental studies (9-12). the suspicion of this detrimental clinical association extends to benign prostate hyperplasia/lower urinary tract symptoms (bph/luts), female incontinence, male infertility and hypogonadism, and even to prostate cancer, besides the risk for some common cancer such as breast, colorectal, liver, and pancreas, if ir is evaluated together with the topic of mets (8, 13). furthermore, in the light of current literature, there are strong evidences about that dm has negative effect on male reproductive functions in various ways as endocrine control of spermatogenesis, spermatogenesis itself or impairing penile erection and ejaculation (1, 3). ali et al. reported sperm dysfunction through sperm motility defect in patients with noninsulin depended dm even in conventional spermiograms (14) (the evaluation just with conventional spermiograms may also be the limitation of the present study) but some other authors did not found any motility defect in dm without complications (15). nevertheless, despite of the ongoing discussion about the mechanism, it is a fact that subfertility was reported in more than half of the diabetic patients (5). however, the independent negative influence of ir on human fertility was confirmed only for female infertility especially in the case of pcos a condition that is characterized by hyperandrogenism, chronic oligoor anovulation and polycystic ovaries. ir accompanies this clinical status with a high rate (50-70%) and is thought to have a central pathogenic role in pcos (16, 17). this relation between ir and ovarian dysfunction induced us to study the possible correlation between ir and male testicular functions through the evaluation of male sex hormones, testicular volumes and spermiograms. ir leads compensatory hyperinsulinemia that is considered to be a promoter of the hyperandrogenism and chronic oligoor anovulation in female with pcos (16). in our study, gonadotropins and testosterone levels were the same as in subjects with ir or not. however, depending on the experimental and clinical studies, it is a clinical fact that dm decrease serum testosterone and increase gonadotropins (3). as opposite to our results, in a preliminary study of small groups of normal, ir and dm subjects (n = 9, 9 and 3 respectively), pitteloud et al. noted that increase of ir leads to a decrease in leydig cell testosterone according to their insulin sensitivity on glucose tolerance tests (18). in the present study there was no significant difference between mean testicular volumes (around 20 cc for both study and control group) that can also be considered as one of the predictors of fertility. bahk et al. concluded that the testicular volume cut off value for fertility is 18 cc (19) and testicular atrophy is a well known clinical situation in dm (20). the proinflammatory cytokine tumor necrosis factor-a (tnf!), that is a known mediator of ir, is elevated either in obese or nonobese pcos patients. this unstable glucose metabolism leading to oxidative stress and proinflammatory status was claimed as the cause of hyperandrogenism and infertility (16). according to the present results, this explanation seemed not adaptable for subfertiles male with ir because gonadotropins and testosterone, and spermiograms were the similar in both groups, although hscrp, as a low-grade chronic inflammatory marker, seemed significantly higher in our subjects with ir. hscrp is found to be elevated in pcos patients with or without metabolic syndrome (21) and, in addition, ir is a factor that elevates hscrp (22). thus, we think that the reason of this elevation should be attributed to the ir rather than male infertility. moreover, insulin, insulin like growth factor 1 (igf-1) and growth hormone (gh) are supposed to be part of the complex coordination function of nutrient balance and metabolic stress. hyperinsulinemia elevates serum concentrations of free igf-1 that can provide important trophic (anti-apoptotic) effects, leading to changes in cellular metabolism (23). either oophorectomy or orchiectomy resulted in elevated igf-1 levels and this suggests that igf-1 may have some role in the infertility process (24-26). nevertheless, further studies especially at sperm molecular level are needed to accurately confirm our preliminary results about the relation between ir and male reproductive system. we think that our results were also independent from the effect of obesity, because bmi values of our study and control groups were similar (considered as slightly overweight for both). according to the limited number of studies, interestingly, it was supposed a loose inverse relation between male subfertility and obesity and that it occurred mostly via sperm quality and especially to the decreasing normal motility of spermatozoa (8). furthermore, dyslipidemia, as another component of mets which was not present in our subjects, was accused of causing negative effect on sperm/testicular functions in both animal and human studies (27-29). however our results are far away from demonstrating the inverse relationship between mets and male fertility with mets components other than ir. conclusions there is no doubt in the literature that dm and mets have a “bad fame” on human fertility. in connection to this statement, ir automatically may be accused of causing detrimental effect on male fertility as a component of mets due to hyperinsulinemic state and impaired glucose uptake as in dm2. thus in this study, we aimed to document the possible isolate effect of ir on male reproductive system via sperm functions, serum hormone and lipid profiles 7archivio italiano di urologia e andrologia 2014; 86, 1 insulin resistance and male reproductive system verit_stesura seveso 26/03/14 09:53 pagina 7 archivio italiano di urologia e andrologia 2014; 86, 1 a. verit, f. ferda verit, h. oncel, h. ciftci 8 and testicular volumes. interestingly, according to our preliminary results, we do not find any inverse correlation between ir and male reproductive system. however, to reach a conclusion on this topic, further studies at molecular level and/or long term clinical studies of male fertility based on birth rates are needed. references 1. agbaje im, rogers da, mcvicar cm, et al. insulin dependent diabetes mellitus: implications for male reproductive function. hum reprod. 2007; 22:1871. 2. codner e, merino pm, tena-sempere m. female reproduction and type 1 diabetes: from mechanisms to clinical findings. hum reprod update. 2012; 18:568. 3. o'neill j, czerwiec a, agbaje i, et al. differences in mouse models of diabetes mellitus in studies of male reproduction. int j androl. 2010; 33:709. 4. jequier am. is quality assurance in semen analysis still really necessary? a clinician's viewpoint. hum reprod. 2005; 20:2039. 5. la vignera s, di mauro m, condorelli r, et al. diabetes worsens spermatic oxidative "stress" associated with the inflammation of male accessory sex glands. clin ter. 2009; 160:363. 6. trussell jc, legro rs. erectile dysfunction: does insulin resistance play a part? fertil steril. 2007; 88:771. 7. pauli jm, raja-khan n, wu x, legro rs. current perspectives of insulin resistance and polycystic ovary syndrome. diabet med. 2011; 28:1445. 8. kasturi ss, tannir j, brannigan re. the metabolic syndrome and male infertility. j androl. 2008; 29:251. 9. gorbachinsky i, akpinar h, assimos dg. metabolic syndrome and urologic diseases. rev urol. 2010; 12:e157. 10. kim ja, montagnani m, koh kk, quon mj. reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. circulation. 2006; 113:1888. 11. steinberg ho, chaker h, leaming r, et al. obesity/insulin resistance is associated with endothelial dysfunction. implications for the syndrome of insulin resistance. j clin invest. 1996; 97:2601. 12. sánchez a, contreras c, martínez mp, et al. role of neural no synthase (nnos) uncoupling in the dysfunctional nitrergic vasorelaxation of penile arteries from insulin-resistant obese zucker rats. plos one. 2012; 7:e36027. 13. arcidiacono b, iiritano s, nocera a, et al. insulin resistance and cancer risk: an overview of the pathogenetic mechanisms. exp diabetes res. 2012; 2012:789174. 14. ali st, shaikh rn, siddiqi na, siddiqi pq. semen analysis in insulindependent/non-insulin-dependent diabetic men with/without neuropathy. arch androl. 1993; 30:47. 15. niven mj, hitman ga, badenoch df. a study of spermatozoal motility in type 1 diabetes mellitus. diabet med. 1995; 12:921. 16. gonzález f. inflammation in polycystic ovary syndrome: underpinning of insulin resistance and ovarian dysfunction. steroids. 2012; 77:300. 17. pauli jm, raja-khan n, wu x, legro rs. current perspectives of insulin resistance and polycystic ovary syndrome. diabet med. 2011; 28:1445. 18. pitteloud n, hardin m, dwyer aa, et al. increasing insulin resistance is associated with a decrease in leydig cell testosterone secretion in men. j clin endocrinol metab. 2005; 90:2636. 19. bahk jy, jung jh, jin lm, min sk. cut-off value of testes volume in young adults and correlation among testes volume, body mass index, hormonal level, and seminal profiles. urology. 2010; 75:1318. 20. wright jr jr, yates aj, sharma hm, et al. testicular atrophy in the spontaneously diabetic bb wistar rat. am j pathol. 1982; 108:72. 21. verit ff. high sensitive serum c-reactive protein and its relationship with other cardiovascular risk factors in normoinsulinemic polycystic ovary patients without metabolic syndrome. arch gynecol obstet. 2010; 281:1009. 22. llauradó g, gallart l, tirado r, et al. insulin resistance, lowgrade inflammation and type 1 diabetes mellitus. acta diabetol. 2012; 49:33. 23. clemmons dr. metabolic actions of insulin-like growth factor-i in normal physiology and diabetes. endocrinol metab clin north am. 2012; 41:425. 24. fogle rh, chang l, patel sk, et al. increased insulin-like growth factor-1 after oophorectomy in postmenopausal women. fertil steril. 2008; 90:1236. 25. sánchez-luengo s, fernández pj, romeu a. insulin growth factors may be implicated in human sperm capacitation. fertil steril. 2005; 83:1064. 26. gao f, yang m, luo cl, wu xh. local insulin-like growth factor-i of ventral prostate was upregulated during long-term castration and may function through the autocrine system. prostate cancer prostatic dis. 2011; 14:136. 27. yamamoto y, shimamoto k, sofikitis n, miyagawa i. effects of hypercholesterol aemia on leydig and sertoli cell secretory function and the overall sperm fertilizing capacity in the rabbit. hum reprod. 1999; 14:1516. 28. saez lancellotti te, boarelli pv, monclus ma, et al. hyper cholesterolemia impaired sperm functionality in rabbits. plos one. 2010; 18;5:e13457. 29. ramírez-torres ma, carrera a, zambrana m. high incidence of hyperestrogenemia and dyslipidemia in a group of infertile men. ginecol obstet mex. 2000; 68:224. correspondence ayhan verit, md (corresponding author) veritayhan@yahoo.com dept. of urology fatih sultan mehmet research and training hospital icerenkoy/atasehir tr34752 istanbul, turkey fatma ferda verit, md associate professor dept. of obstetrics & gynaecology, infertility research & treatment centre suleymaniye maternity, research & training hospital istanbul, turkey halil oncel, md dept. of urology ,sanliurfa research & training hospital sanliurfa, turkey halil ciftci, md associate professor dept. of urology harran university, school of medicine sanliurfa, turkey this study has been presented (poster no: 32) in american society of andrology (asa) xxiind 2013 testis workshop, april 10-13, in san antonio, texas, usa. verit_stesura seveso 26/03/14 09:53 pagina 8 stesura seveso 81archivio italiano di urologia e andrologia 2014; 86, 2 original paper evaluation of various active surveillance protocols in prostate cancer kayhan yılmaz 1, tahir karadeniz 2, orkunt özkaptan 3, oğuz yilanoglu 4 1 antalya korkuteli state hospital, turkey; 2 medicana hospital group istanbul, turkey; 3 kastamonu state hospital; 4 hatay dörtyol state hospital, turkey. objective: this study aims to investigate whether pathology results obtained by radical retropubic prostatectomy (rrp) were correlated with active surveillance (as) criteria defined by klotz, soloway and d’amico. materials and methods: in our clinic we evaluated 211 patients with diagnosis of localized prostate cancer who underwent rrp between 2007 and 2012. as criteria defined by soloway (ct ≤ t2, psa ≤ 15 ng/dl, gleason ≤ 6), klotz (ct1c-t2a; if age ≥ 70 psa ≤ 15 ng/dl, if age < 70 psa ≤ 10 ng/dl; if age ≥ 70 gleason ≤ 7(3+4), if age < 70 gleason ≤ 6) and d’amico (ct1c-t2a, psa ≤ 10 ng/dl, gleason ≤ 6) were used in our study. pathological stages and gleason scores were evaluated with coherence to as protocols, mis-staging rates, biochemical recurrence (bc) of the mis-staged patients and death due to prostate cancer data was analyzed using ncss 2007 & pass 2008 statistical software (utah, usa). chi square test and mann-whitney u test were applied for analyzing qualitative data. significance was determined as p < 0.05. results: 137 (64.9%) patients were coherent with soloway as criteria, 118 (55.9%) with klotz as criteria and 108 (51.1%) with d’amico as criteria. histopathological results of the patients grouped according to soloway, klotz and d’amico as protocols showed high stage prostate cancer in 40 (29.2%), 32 (27%) and 27 (24.9%) patients, respectively. high grade prostate cancer rates in soloway, klotz, d’amico groups were 55 (40.2%), 46 (38%) and 39 (36.1%); respectively. misstaging rates of soloway, klotz and d’amico as protocols were determined as 65 (47.4%), 54 (45.5%) and 46 (42.5%), respectively. in the soloway group bc rate was 21.9% in those with high stages. relation between bc and high stage was found to be statistically significant (p < 0.05). conclusion: misstaging rates were relatively high in the three groups and there was no difference between the three groups in bc rates. randomized studies with adequate follow up are needed. key words: active surveillance; prostate cancer; radical prostatectomy. submitted 23 august 2013; accepted 5 october 2013 summary no conflict of interest declared. introduction prostate cancer is a multifaceted disease in which genetic and environmental factors play an important role. studies show that prostate cancer is the most common cancer in man over 50 years age and is shown to be the second most reason for death due to cancer (1-3). currently prostate cancer has various treatment options according to the stage and clinical course of the disease such as radical retropubic prostatectomy (rrp), bra chy therapy, external radiotherapy, hormone therapy and chemotherapy. although there has been an increase in the early diagnosis and treatment rates in prostate cancer, there has been no significant decrease in mortality. this fact gives rise to the thought that clinically insignificant disease is being treated excessively and active follow up of these patients should be preferred instead of radical treatment. active surveillance which was first described by coo et al. (4, 5) aims to postpone radical treatment and prevent redundant early treatment. active surveillance in prostate cancer has become popular in the last decade (6, 7). patients who are adequate for active surveillance are determined with criteria; appropriate prostate specific antigen (psa) level, clinical stage and gleason score in the biopsy (8). however, there is no sufficient randomized data available for supporting these criteria. in our study, we retrospectively investigated patients diagnosed as having localized prostate cancer in which rrp was performed in relation to three different active surveillance criteria as established by klotz, soloway and d’amico. we evaluated whether the pathology results obtained from the rrp specimens were correlated with these three active surveillance criteria. materials and methods we evaluated 211 patients with localized prostate cancer diagnosis in which rrp was performed between 2007 and 2012 in okmeydanı training and research hospital/ istanbul. patients who underwent previous hormono the rapy and/or 5-alfa reductase inhibitor or pelvic radiotherapy were excluded from the study. clinical stages were determined using 2002 tmn classifidoi: 10.4081/aiua.2014.2.81 archivio italiano di urologia e andrologia 2014; 86, 2 k. yılmaz, t.karadeniz, o. özkaptan, o. yilanoglu 82 cation. all the rrp operations were performed by the same urologist and all biopsy and rrp specimens were evaluated by the same pathologist. since positive biopsy core number and tumor percentage were not present in most of the biopsy pathology results, these active surveillance criteria were not included in the study. the active surveillance criteria defined by soloway (ct ≤ t2, psa ≤ 15 ng/dl, biopsy gleason score ≤ 6), klotz (t1c-t2a; if age ≥ 70 psa ≤ 15 ng/dl, if age < 70 psa ≤ 10 ng/dl; if age ≥ 70 biopsy gleason score ≤ 7 (3 + 4), if age < 70 biopsy gleason score ≤ 6) and d’amico (clinical stage t1c-t2a, psa ≤ 10 ng/dl, biopsy gleason score ≤ 6) were used in our study. patients appropriated for the three active surveillance protocols were determined by retrospectively examination of the preoperative psa value, clinical stage and biopsy gleason score (table 1). pathological stages and rrp specimen gleason scores were evaluated with coherence to active surveillance protocols, misstaging rates, biochemical recurrence of the misstaged patients and death due to prostate cancer. the data of the study there analyzed using ncss (number cruncher statistical system) 2007 & pass 2008 statistical software (utah, usa). in addition to descriptive statistical analyses (mean, standard deviation), chi square test was used for analyzing qualitative data and in order to analyze qualitative data in cases of abnormal distribution mann-whitney u test was applied. significance was determined at the level of p < 0.05. results we evaluated 211 patients who underwent rrp according to total psa, clinical stage and biopsy gleason scores as active surveillance criteria. active surveillance criteria defined by d’amico, solo way and klotz were shown in table 1. 137 (64.9%) of the pa tients were coherent with solo way active surveillance criteria (9), 118 (55.9%) with klotz active surveillance criteria (7) and 108 (51.1%) with d’amico active surveillance (10) criteria (table 1). the clinical features found coherent with active surveillance protocols were compared to final pathology results. the pathology results that showed high grade prostate cancer, gleason score sum ≥ 7) (17), extracapsular extension (eci), seminal vesicle (svi) and/or lymph node involvement (lni) were studied and misstaging rates were determined (table 2). the histopathological results of the patients grouped according to soloway active surveillance protocol showed high stage prostate cancer in 40 patients (29.2%). eci, svi, lni was observed in 32 (23.3%), 7 (5.1%) and 1 (0.7%) patient, respectively. high grade prostate cancer was observed in 55 (40.2%) patients. of the 118 patients classified in the klotz active surveillance protocol 32 (27%) had high stage prostate cancer. eci, svi and lni were found in 26 (22%), 5 (4.2%) and 1 (0.8%), respecselection criteria all patients soloway klotz d’amico and coleman clinical stage ≤ t2 t1c-t2a t1c-t2a psa ≤ 15 if age ≥ 70 ≤ 15 ≤ 10 if age < 70 ≤ 10 biopsy gleason score ≤ 6 if age ≥ 70 ≤ 7 (3+4) if age < 70 ≤ 6 ≤ 6 ≤ 6 patients coherent 211 (%100) 137 (%64,9) 118 (%55,9) 108 (%51,1) with the criteria table 1. criteria for active surveillance protocols. eci extracapsular extension. svi seminal vesicle involvement. lni lymph nod involvement. all cases soloway klotz d’amico (n = 211) (n = 137) (n = 118) (n = 108) min-max min-max min-max min-max (mean ± sd) (mean ± sd) (mean ± sd) (mean ± sd) diagnosis age 44-79 44-79 44-79 44-79 (63,10 ± 64) (62,87 ± 7,24) (63,43 ± 64) (62,61 ± 7,19) preoperative psa 1,20-93 1,20-15 1,20-14 10-1,20 (14,12 ± 14,68) (7,19 ± 2,92) (6,59 ± 6,17) (6,15 ± 2,05) n (%) n (%) n (%) n (%) clinical stage t1c 89 (%42,2) 74 (%54) 65 (%55,1) 61 (%56,5) t2a 89 (%42,2) 55 (%40,1) 51 (%43,2) 47 (%43,5) t2b 33 (%15,6) 8 (%5,8) 2 (%1,7) preoperative 2-6 171 (%81) 137 (%100) 117 (%99,2) 108 (%100) gleason score 7 (3+4) 28 (%13,3) 1 (%0,8) 7 (4+3) 5 (%2,4) 8-10 7 (%3,3) eci 76 (%36) 32 (%23,4) 26 (%22) 22 (%20,3) svi 33 (%15,6) 7 (%5,1) 5 (%4,2) 5 (%4,6) lni 9 (%4,3) 1 (%0,7) 1 (%0,8) pathological 2-6 105 (%49,8) 82 (%59,9) 72 (%61) 69 (%63,9) gleason score 7 (3+4) 68 (%32,2) 43 (%31,4) 36 (%30,5) 32 (%29,6) 7 (4+3) 25 (%11,8) 9 (%6,6) 9 (%7,6) 6 (%5,6) 8-10 13 (%6,2) 3 (%2,2) 1 (%0,8) 1 (%0,9) pathological stage pt0 1 (%0,5) 1 (%0,7) 1 (%0,8) 1 (%0,9) pt2a 47 (%-22,3) 36 (%26,3) 35 (%29,7) 33 (%30,6) pt2b 73 (%34,6) 57 (%41,6) 46 (%39) 42 (%38,9) pt2c 13 (%6,2) 12 (%8,8) 10 (%8,5) 10 (%9,3) pt3a 44 (%20,9) 25 (%18,2) 21 (%17,8) 17 (%15,7) pt3b 30 (%14,2) 7 (%5,1) 5 (%4,2) 5 (%4,6) pt4a 3 (%1,4) misstaging (*) number (%) 65 (%47,4) 54 (%45,7) 46 (%42,5) %95 ci 40.4-54.4 38.9-54.1 34.6-50.2 table 2. pathology results and misstaging rates of rrp. tively. high grade prostate cancer was present in 46 (38%) patients. patients classified according to d’amico active surveillance criteria comprised 27 (24.9%) high stage prostate cancer patients. eci, svi rates were 22 (20.3%) and 5 (4.6%); respectively. in this group 39 (36.1%) patient were categorized as high grade cancer. patients diagnosed as organ confined disease on digital rectal examination had local advanced disease in the prostatectomy pathology result with rates of 21.3% in the group classified by soloway criteria, 22.8% in the group according klotz and 23.3% in the group according d’amico. misstaged patients and misstaging rates of soloway, klotz and d’amico active surveillance protocols were determined as 65 (47.4%), 54 (45.7%), 46 (42.5%); respectively (table 2). average follow up periods were 63 months in the soloway group, 63 months in the klotz group and 61 months in the d’amico group. time until recurrence was 9-48 in the three groups. total numbers of patients in which biochemical recurrence was detected were 16 (11.6%) in the soloway group, 13 (11%), in the klotz group, 11 (10.2%) d’amico group and the period until recurrence in each group was 21, 24 and 25 months, respectively. there was no difference in term of biochemical recurrence rates between the three groups (p > 0.05). in the soloway group biochemical recurrence rate was obtained to be 21.9% in those with high stages. the relation between biochemical recurrence and high stage was found to be statistically significant for solowoy group (p < 0.05) (tables 3, 4). no statistically significant difference was shown between biochemical recurrence rates and high stages according to d’amico and klotz criteria (p > 0.05). high gleason grade (≥ 7 in the prostatectomy specimen) had higher biochemical recurrence values, but this analysis did not reach significance (p > 0.05). there was no statistically significant difference between recurrence and death rates according to misstaging status (p > 0.05). in the soloway and klotz groups two deaths due prostate cancer per group and in the d’amico group one death due prostate cancer were reported. deaths due to prostate cancer were only among misstaged patients in the three groups. statistical analysis was not performed because of the low number of exitus patients (table 4). discussion after the description of active surveillance by coo et a.l, it became more popular for clinicians in the last ten years (4, 6, 7). mortality rates of prostate cancer did not decrease despite early diagnosis and treatment of the disease within this period. this fact led clinicians to come to the opinion that clinically insignificant disease is being treated excessively. our study was performed to evaluate the credibility of various criteria groups used for the selection of active surveillance patients in order to estimate pathological stage. misstaging rates of our study for the groups formed according to d’amico, klotz and soloway active surveillance criteria were found to be 42.4%, 45.7% and 47.4%, respectively. with regard to our results d’amico active surveillance protocol had the most firm patient selection criteria with lower misstaging rates compared to the other groups. in a study by marc et al., 2837 patients who underwent rrp were evaluated retrospectively. patients with appropriate clinical features for separate active surveillance protocols had a misstaging rate between 26-35% according to their pathological features (11). nazareno et al. evaluated 4308 patients treated with rrp in five separate active surveillance protocols including d’amico and klotz retrospectively. pathology reports of patients in groups appropri83archivio italiano di urologia e andrologia 2014; 86, 2 evaluation of various active surveillance protocols in prostate cancer chi square test and fisher’s exact was used. soloway klotz d’amico follow up period min-max 13-120 13-118 13-118 (month) mean ± sd 63,93 ± 32,26 63,93 ± 31,68 61,75 ± 31,92 time until recurrence min-max 9-48 9-48 9-48 mean ± sd 21,87 ± 12,19 24,17 ± 12,87 25,10 ± 13,79 n (%) n (%) n (%) recurrence number (%) 16 (7,3%) 13 (11%) 11 (10.2%) %95 ci 13.1-19.1 10,3-18.9 9,4-18,0 death number (%) 10 (7,3%) 8 (6,8%) 7 (6,5%) %95 ci 3.7-10.9 3.0-10.6 2.6-10.4 cause of death prostate cancer 2 (1,4%) 2 (1,6%) 1 (0,9%) other 8 (5,9%) 6 (5,2%) 6 (5,6%) table 3. follow up periods, recurrence and exitus rates distribution in the groups. misstaging present n (%) absent n (%) p soloway group recurrence 10 (%15,4) 6 (%8,3) 0,199 death 6 (%9,2) 4 (%5,6) 0,409 cause of death prostate 2 (%33,3) 0 (%0) other 4 (%66,7) 4 (%100) klotz group recurrence 9 (%16,7) 4 (%6,3) 0,072 death 5 (%9,3) 3 (%4,7) 0,467 cause of death prostate 2 (%40,0) 0 (%0) other 3 (%60,0) 3 (%100) d’amico group recurrence 7 (%15,2) 4 (%6,5) 0,136 death 4 (%8,7) 3 (%4,8) 0,456 cause of death prostate 1 (%25,0) 0 (%0) other 3 (%75,0) 3 (%100) table 4. recurrence and death rates according to misstaging status in the groups. archivio italiano di urologia e andrologia 2014; 86, 2 k. yılmaz, t.karadeniz, o. özkaptan, o. yilanoglu 84 ate for active surveillance were investigated and high stage and/or high gleason scores were detected in the range 39-56%. according to active surveillance criteria recommended by this study group (psa < 4 ng/ml, ct1 and gleason score < 7), the misstaging rate (7.2%) was found to be statistically significantly decreased. however, the patients’ ratio appropriate for active surveillance was found to be decreased to 6.9% (12) and this rate seemed to be low. in fact in our study the rate of patients suitable for soloway, klotz, d’amico active surveillance protocols were 64.9%, 55.9%, 51.2%, respectively. most important reason for misstaging was determined to be low prostate cancer grade in the biopsy results. the misstaging rate in the biopsy grades with regard to prostatectomy specimen grade were 36.1%, 38.9% and 40.1%, respectively. supporting our finding, dall’era et al. established in their study that the most important reason for changing from active surveillance to radical treatment was the increase in the gleason grades in prostate biopsies repeated periodically and this ratio was reported to be 38% (13). in another study performed by carter et al. this ratio was found to be 30% (14). in the light of these findings we believe that if tumor grade is detected more accurately at the beginning, approximately 30% of patients could be treated with active surveillance protocols instead of rrp without losing the chance of cure. several studies have determined that the sensitivity of digital rectal examination is low in the diagnosis and staging of prostate cancer (15-17). in our study patients with organ confined disease on digital rectal examination had local advanced disease in the prostatectomy pathology results with the rates 21.3%, 22.8%, and 23.3% according to soloway, klotz and d’amico active surveillance groups, respectively. in agreement with this results the evaluation of the propriety of patients for active surveillance showed that there was a misstaging rate of 21.3%-23.3% with digital rectal examination and 36.140.1% with gleason grade. in our study digital rectal examination was found to detect whether the disease is limited to the organ better than grade, however misstaging rates were very high. the final point in active surveillance is not pathological stage, but biochemical recurrence, metastasis and cancer related death. while radical prostatectomy can cure the disease without affecting the quality of life when performed by experienced surgeons, it is still debated whether one should risk this chance with active surveillance (18). warlick et al. compared 38 patients who underwent radical prostatectomy following active surveillance with 150 patients with similar characteristics in which radical prostatectomy was performed immediately. this study indicated that postponing prostate cancer surgery didn’t risk the chance of cure, however the evident difference between the patient population in the groups decreases the credibility of the study (19). in contrast, the toronto active surveillance study followed 299 patients and they performed radical prostatectomy in 24 patients which showed progression; in 14 (14%) pt3 and in two (8%) n1 was detected and these rates are high (20). this indicated the risk of losing the chance for curative treatment after active surveillance (21-23). also the prias (prostate cancer research international: active surveillance) study reported undesired pathological results in 29% of the patients in which radical surgery was performed following a period of 1.3 years: pt3-4 disease and /or gleason score ≥ 4+3 (24). john hopkins reported that the 10 year disease free rate of 23% patients in which rrp was performed due to grade progression in the control biopsy was lesser than 75% (25). however, this rate was not statistically significantly different than patients who have similar clinical features and were operated on with radical surgery within three months (25). in our study the average follow up periods were 61-63 months in three groups. biochemical recurrences and rates were 16 (11.6%) in the soloway group, 13 (11%), in the klotz group, and 11 (10.2%) d’amico group and the period until recurrence in each group was 21, 24 and 25 months, respectively. in comparing the three active surveillance groups in our study according to biochemical recurrence, no statistically difference was noted. statistical significance (p < 0.05) between biochemical recurrence and high stage was remarkable in the soloway group. although there was no statistically significant difference in biochemical recurrence rates in high stages according to d’amico and klotz criteria, high values of biochemical recurrence in high stage were observed. when evaluating the relationship between gleason grades in rrp pathologies and biochemical recurrence, patients with high gleason grades had higher biochemical recurrence values, however this analysis was not statistically significant (p > 0.05). in comparing the biochemical recurrence values of misstaged patients and patients who met the criteria in three active surveillance groups, no statistically significant difference (p > 0.05) was found, however biochemical recurrence rates were higher in misstaged patients. about death due to prostate cancer there were two deaths due to prostate cancer in the soloway and klotz group and one death in the d’amico group. this result was remarkable because all these patients were among the misstaged patients. conclusion all these findings show that there are serious problems in the selection of active surveillance patients. also, there is no consensus in the follow up of active surveillance patient. consequently the controversial status of active surveillance may result in various mood disorders in patients, and this psychological aspect should not be underestimated. after evaluating all the study results, it is evident that the data on radical surgery results following active surveillance in low risk prostate cancer patients are insufficient. at least one fourth of the pathological data are consistent with the need of treatment and it is unknown how this rate will change with longer surveillance periods and how this will affect the patient prognosis. thus, there is no current data that postponing active treatment in these patients decreases the chance of cure. since there are not sufficient randomized studies with adequate follow up periods, active surveillance should only be recommended to a well selected patient group and the patient should be informed about the inconsistencies about active surveillance and all the treatment options should be explained, and the decision should be up to the patient. references 1. sakr wa, grignon dj, crissman jd, et al. high 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klotz l. active surveillance for prostate cancer: for whom? j clin oncol. 2005; 23:8165-8169. 8. aus g, abbou cc, bolla m, et al. eau guidelines on prostate cancer. eur urol. 2005; 48:546-551. 9. mark s. soloway, cynthia t. et al. active surveillance; a reasonable management alternative for patients with prostate cancer: the miami experience. b.j.u. internatıonal. 2007; 101:165-169. 10. d'amico av, coleman cn. role of interstitial radiotherapy in the management of clinically organ-confined prostate cancer: the jury is still out. j clin oncol. 1996; 14:304-315. 11. smaldone mc, cowan je, carroll pr, davies bj. eligibility for active surveillance and pathological outcomes for men undergoing radical prostatectomy in a large, community based cohort. j urol. 2010; 183:138-143. 12. suardi n, capitanio u, chun fk, et al. currently used criteria for active surveillance in men with lowrisk prostate cancer: an analysis of pathologic features. cancer. 2008; 113:2068-2072. 13. dall'era ma., konety br, cowan je, et al. active surveillance for the management of prostate cancer in a contemporary cohort. cancer. 2008; 112:2664-2670. 14. carter hb, walsh pc, landis p, epstein ji. expectant management of nonpalpable prostate cancer with curative intent: preliminary results. j urol. 2002;167:1231-1234. 15. cevik d, dillioglugil o. staging and grading in prostate cancer. in: ozen h, turkeri l (eds), book of urooncology, ankara: ertem press publication, 2007; pp. 610621. 16. obek c, louis p, civantos f, soloway ms. comparison of digital rectal examination and biopsy results with the radical prostatectomy specimen. j. urol. 1999; 161:494-498. 17. huland h, hubner d, henke rp. systematic biopsies and digital rectal examination to identify nerve-sparing side for radical prostatectomy without risk of positive margin in patients with clinical stage t2, n0 prostatic carcinoma. urology. 1994; 44:211-214. 18. klotz l. active surveillance for prostate cancer: trials and tribulations. world j urol. 2008; 5:437-444. 19. warlick c, trock b, landis p, et al. delayed versus immediate surgical intervention and prostate cancer outcome. j natl cancer inst. 2006; 98:355-7. 20. klotz l. active surveillance with selective delayed intervention for favorable risk prostate cancer. urol oncol. 2006; 24:46-50. 21. simmons mn, stephenson aj, klein ea. natural history of biochemical recurrence after radical prostatectomy: risk assessment for secondary therapy. eur urol. 2007; 51:1175-1184. 22. porter cr, gallina a, kodama k, et al. prostate cancer-specific survival in men treated with hormonal therapy after failure of radical prostatectomy. eur urol. 2007; 52:446-454. 23. freedland sj, humphreys eb, mangold la, et al. risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. jama 2005; 294:433-439. 24. bul m, zhu x, rannikko a, et al. radical prostatectomy for low-risk prostate cancer following initial active surveillance: results from a prospective observational study. eur urol. 2012; 62:195-200. 25. soloway ms, soloway ct, eldefrawy a, et al. careful selection and close monitoring of low-risk prostate cancer patients on active surveillance minimizes the need for treatment. eur urol. 2010; 58:831-835. 85archivio italiano di urologia e andrologia 2014; 86, 2 evaluation of various active surveillance protocols in prostate cancer correspondence kayhan yılmaz, md kayhany@gmail.com aşağı pazar mah. hastane cad. no 71 korkuteli antalya, turkey tahir karadeniz, md karadeniz@gmail.com director of medicana hospital group beylikdüzü cad. no:3 beylikdüzü, istanbul, turkey orkunt özkaptan, md orkunt79@gmail.com fellow in heilbronn urology clinic tatlipinar caddesi yunus apt no 11 d3 fatih istanbul, turkey oğuz yilanoglu, md oyilanoglu@yahoo.com yilanoglu, istasyon cd. 31600 dörtyol hatay, turkey stesura seveso 9archivio italiano di urologia e andrologia 2014; 86, 1 original paper evaluation of penile cavernosal artery intima-media thickness in patients with erectile dysfunction. a new parameter in the diagnosis of vascular erectile dysfunction. our experience on 59 cases domenico prezioso, fabrizio iacono, umberto russo, giuseppe romeo, antonio ruffo, nicola russo, ester illiano department of urology, university federico ii of naples, italy. objective: a precise characterization of erectile dysfunction (ed) of vascular origin has not yet been achieved, although cavernous peak systolic velocity (psv) is generally considered a major parameter. nevertheless the penile dynamic color doppler is invasive and linked to several complications. the intima-media thicknesses (imt) of cavernosal artery would add to the predictive value of vasculogenic ed risk and outcomes. we also hypothesized the existence of a correlation between imt cavernosal artery and imt carotid arteries. this study seeks to evaluate these hypotheses with our experience, investigating the predictive accuracy of carotid and cavernosal doppler ultrasound findings for discriminating patients with vasculogenic ed. material and methods: a total of 59 subjects (32 vasculogenic ed patients group a and 27 no vasculogenic ed patients group b) were evaluated in our andrological center from september 2012 to june 2013 and enrolled in the study. all subjects underwent medical history, erectile function domain of the international index of erectile function, physical examination, routine and sex hormone blood tests, and high resolution dynamic color doppler ultrasound evaluation of carotid and penile districts and valutation of imt in both districts. results: the values of cavernosal artery imt in group a were higher than in group b (0,28 ± 0,06 mm vs 0,17 ± 0,07 mm). even the values of carotid artery imt in vasculogenic ed group were higher than in no vasculogenic ed group (0,74 ± 0,14 mm vs 0,59 ± 0,11 mm). the cavernosal imt showed a moderate (r = 0.61) positive linear correlation (p < 0.001) with the carotid artery imt. conclusions: an increased cavernous imt might predict ed of vascular origin with more accuracy than psv and could be a sensitive predictor also for systemic atherosclerosis at an earlier phase. key words: intima media thickness; vascular erectile dysfunction; endothelial dysfunction. submitted 19 august 2013; accepted 5 october 2013 summary no conflict of interest declared. introduction erectile dysfunction (ed) is a pervasive disorder that afflicts as many as 30 million men in the united states (1), with an estimated 100 million men affected worldwide (2, 3).the risk of ed is related to many factors, including age, smoking, diabetes, heart disease, depression, and hypertension (4, 5). vascular disease is by far the most common cause of ed (6) formerly dismissed as a psychological condition, ed has now assumed center stage as a readily treatable disorder and a powerful risk-marker for cardiovascular disease (cvd) (6, 7). infact because cvd and ed share etiologies as well as pathophysiology (endothelial dysfunction) and because of evidence that degree of ed correlates with severity of cvd, it has been postulated that ed is a sentinel symptom in patients with occult cvd (8). endothelial dysfunction is intimately linked to atherogenesis and increased cvd risk (9). dysfunction arises following alteration in the release of several vasoactive factors, mainly nitric oxide (no), from endothelial cells (9, 10). endothelial dysfunction due to an abnormality in the release and/or action of no is characterized by vasoconstriction, coagulation, increased leucocyte adhesion and stimulation of smooth muscle (sm) cell growth, and is, therefore, central to atherogenesis (9). several traditional cardiovascular risk factors, such as aging, smoking, hypertension, dyslipidemia and diabetes, and some less traditional risk factors, including inflammation, hypoxia, oxidative stress and homocysteinemia, are related to endothelial dysfunction (11, 12). therefore given that endothelial dysfunction predates atherosclerosis development, this possibility is consistent with the so-called ‘artery size’ hypothesis (13). this theory posits that atherogenesis is likely to present earlier with clinical symptoms in arteries of a smaller diameter, such as in the penis, than in larger sized arteries, such as in the coronary circulation (14). in as much as the vascular disease is the most common cause of ed, after an intracavernosal injection of a vasodilatory agent, color doppler sonography is performed to evaluate cavernosal arteries and dorsal vessels, and to demonstrate both arterial insufficiency (primary diagnostic criteria for arterial doi: 10.4081/aiua.2014.1.9 prezioso_stesura seveso 26/03/14 10:11 pagina 9 archivio italiano di urologia e andrologia 2014; 86, 1 d. prezioso, f. iacono, u. russo, g. romeo, a. ruffo, n. russo, e. illiano 10 insufficiency include a peak systolic velocity (psv) of less than 25 cm/sec and waveform dampening) (15) and venous incompetence (most investigators used to diagnose venous leakage when arterial end-diastolic velocity is greater than 5 cm/sec) (15). that makes it a valuable tool in the diagnostic evaluation of ed (15). color doppler ultrasonography is a valuable, informative and minimally invasive tool in the diagnosis of ed (16). color doppler imaging offers several advantages over duplex imaging, including rapid localization of the cavernosal artery and accurate angle correction; depiction of cavernosal artery and dorsal vein flow progression; and demonstration of venous flow and arterial variants (15). however, due to the common pathogenesis that characterizes ed and cvd, the classical color doppler could be complemented with a new method in use in the study of atherosclerosis of the carotid arteries, the intima-media thickness (imt). carotid-wall imt infact is a surrogate measure of atherosclerosis (17) associated with cardiovascular risk factors (18) and with cardiovascular outcomes (19-22). it is the distance from the lumen-intima interface to the media-adventitia interface of the artery wall, as measured on noninvasively acquired ultrasonographic images of the carotid arteries (20). the imt is increasingly used as a surrogate end point of vascular outcomes in clinical trials aimed at determining the success of interventions that lower risk factors for atherosclerosis and associated diseases (stroke, myocardial infarction and peripheral artery diseases, like disease of cavernosal artery). we hypothesized that the imt of cavernosal artery would add to the predictive value of vasculogenic ed risk and outcomes. we also hypothesized the existence of a correlation between imt cavernosal artery and imt carotid arteries. this study seeks to evaluate these hypotheses with our experience, investigating the predictive accuracy of carotid and cavernosal doppler ultrasound (cdu) findings for discriminating patients with vasculogenic ed. material and methods the study design consisted of a observational trial conduced from september 2012 to june 2013. the study was conducted according to the helsinki declaration. written informed consent was obtained from all patients. we enrolled 59 patients, mean age was 55,3 ± 3,7 years. inclusion criteria were: over 51,6 years of age, male patients with stable marital relations and affected by ed. exclusion criteria were: international index of erectile function (iief) score ! 26, alcoholism, smoking, hypertension, cvd, neurogenic syndrome (multiple sclerosis, multiple atrophy, parkinson’s disease, tumors, stroke, disk disease, spinal cord disorders, polyneuropathy, uraemia), peyronie’s disease, penile fracture, congenital curvature of penis, micropenis, hypospadias, epispadias, hyperprolattinemia, hyperand hypothyroidism, cushing’s disease, drug assumption (pde5 inhibitors, intracavernous administration of vasoactive drugs, antihypertensives, antidepressants, antipsychotics, antiandrogens, antihistamines, heroin, cocaine and methadone), radiotherapy (pelvis or retroperitoneum) and lower pelvic surgery (oncological pelvic surgery, lower urinary and genital tract surgery). we enrolled 59 patients presenting at the andrology department of our clinic. at visit patients were evaluated by means of a detailed medical and sexual history. a general (including assessment of body mass index bmi and blood pressure) and urological objective examination was carried out to identify the presence of any diseases that could interfere with erectile function such as peyronie's disease, cancer of the penis, hypospadias, epispadias, signs and symptoms suggestive of hypogonadism (small testes, alterations in secondary sexual characteristics, decreased libido), neurological disorders. in all patients in whom an autonomic neuropathy was suspected, especially in patients with diabetes, it was assessed by the evocation of the bulbo-cavernous reflex. each patient finally performed a rectal examination to search for a possible benign prostatic hypertrophy (bph) to be associated with the presence of lower urinary yract symptoms (luts). in each patient lipid and metabolic levels (triglycerides, total cholesterol, hdl cholesterol, fasting blood glucose), hormone levels (testosterone (t), dihydrotestosterone (dht), luteinizing hormone (lh), follicle-stimulating hormone (fsh), estradiol, prolactin), clinical examination were evaluated. we asked all patients to complete the international index of erectile function (iief) questionnaire: the iief domain was calculated and ed grading was so determined: absence of ed (ef score 26 to 30), mild ed (ef score 17 to 25), moderate ed (ef score 11 to16) and severe ed (ef score < 10) (23). all patients were evaluated with gray scale ultrasound and color doppler ultrasound just before injection and 1, 5, 15, 20 minutes after injection and the images were recorded. a 7.5 mhz linear transducer with a mechanical standoff wedge to produce a favorable insonating angle throughout the entire field of view was used for the doppler ultrasound examinations. the degree of erection was classified into flask erection, tumescence, full erection, rigid erection and detumescence phases by an urologist. spectrum pattern, peak systolic velocity (psv), end diastolic velocity (edv) values and compliance were measured with conventional penile doppler ultrasound 5 minutes after pharmacological stimulation for each subject. according to the reference levels given in the recommendations of the european association of urology (eau) guidelines, a positive test is a rigid erectile response (unable to bend the penis) that appears within 10 min after the intracavernous injection and lasts for 30 min, and a peak systolic blood flow higher than 30 cm/s and a resistance index higher than 0.8 are generally considered normal in a duplex ultrasound of penile arteries (24). patients were divided in 2 groups: vasculogenic ed (group a) and no vasculogenic ed (group b) according to color doppler image findings. the group a was composed of 32 patients, while the group b was composed of 27 patients. imt values of common carotid artery and of cavernosal artery were calculated in all patients. intimamedia interface lines were manually traced as continuous lines by a certified reader, and imt values were calculated (25). the mean imt of the common carotid artery was measured over a segment of the common carotid artery that was 1 cm long, located approximately 0.5 cm below the carotid-artery bulb, and considered not to contain any plaque (i.e., not to have any perceivable protrusion of the prezioso_stesura seveso 26/03/14 10:11 pagina 10 artery wall into the lumen) (26). in each individual patient, the measurement was made bilaterally while for the statistical study was considered the media of the two values obtained. imt of cavernosal artery was measured in the proximal artery, choosing the straight portion that offered the best visualization. also in this case the measurement was bilateral and the average of the values obtained was used for the study. the measurement was made by the same skilled operator for each patient, using a scanner philips iu22 xmatrix ultrasound system and a probe l12-5 50 mm broadband linear array transducer with a frequency range from 12 to 5 mhz. the results of both groups were compared by student t test (p < 0.05). results at initial evalutation in the group a the iief total score was 10.8 ± 3.2, moderate ed, while in the second group the iief total score was 17.4 ± 4.1, mild ed, (p < 0.001). this result was expected and is obviously in agreement with the belief that hemodynamic alterations of the penile vasculature are the factors that can mostly impair erectile function.in the group a the diastolic blood pressure was 92.3 ± 5.1 mmhg versus 86,9 ± 6,1 in group b, while the systolic blood pressure was 143.2 ± 7.5 mmhg and 134,4 ± 9,2 respectively (p < 0.001). furthermore in the group a glucose (p = 0.021) and triglycerides (p = 0.013) levels were higher than those in group b, while cholesterol levels were lower.(p = 0.016). infact the glucose levels in group a were 114,7 ± 20,3 mg/dl versus 103,4 ± 21,2 mg/dl in group b. triglycerides levels were 175,3 ± 30,6 mg/dl in vasculogenic ed group , and 160,2 ± 17,0 mg/dl in no vasculogenic group. different trend showed the cholesterol levels infact they were higher in group b (43,9 ± 10,2 mg/dl – group a – vs 49,3 ± 8,4 mg/dl – group b). there were not statistically significant differences between the groups in bmi values (28.1 ± 3.1 vs 26.5 ± 4.5). table 1 shows the characteristics of the two groups. these findings supported the association of ed with cvd, atherosclerosis and cardiovascular risk. table 2 shows the findigs of carotid and cavernosal artery imt. the values of cavernosal artery imt in group a were higher than in group b (0,28 ± 0,06 mm vs 0,17 ± 0,07 mm).this suggested that hemodynamic functional alterations evaluated in penile color doppler image were correlated with morphological alterations of cavernosal artery evaluated by ultrasound. even the values of carotid artery imt in vasculogenic ed group were higher than in no vasculogenic ed group (0,74 ± 0,14 mm vs 0,59 ± 0,11 mm). this result is in complete agreement with the association between carotid atherosclerosis and polydistrectual atherosclerosis like cavernosal atherosclerosis. lastly we wanted to analyze the possibility of a correlation between the values of cavernous imt and carotid imt in our study population. as graphically represented in figure 1, the cavernosal imt showed a moderate (r = 0.61) positive linear correlation (p < 0.001) with the carotid artery imt. the explanation of these results was that the same risk factors and pathogenesis of vascular injury caused simultaneously endothelial damage in different distrects. 11archivio italiano di urologia e andrologia 2014; 86, 1 evaluation of penile cavernosal artery intima-media thickness in patients with erectile dysfunction vasculogenic ed no vasculogenic ed p (n = 32) (n = 27) age mean (sd) 53,2 ± 8,2 49,6 ± 7,6 ns iief-5 mean (sd) 10,8 ± 3,2 17,4 ± 4,1 p < 0,001 bmi mean (sd) 28,1 ± 3,1 26,5 ± 4,5 ns systolic blood pressure (mmhg) mean (sd) 143,2 ± 7,5 134,4 ± 9,2 p < 0,001 diastolic blood pressure (mmhg) mean (sd) 92,3 ± 5,1 86,9 ± 6,1 p < 0,001 glycemia (mg/dl) mean (sd) 114,7 ± 20,3 103,4 ± 21,2 p = 0,021 total cholesterol (mg/dl) mean (sd) 193,3 ± 42,0 176,0 ± 24,8 ns cholesterol hdl (mg/dl) mean (sd) 43,9 ± 10,2 49,3 ± 8,4 p = 0,016 triglycerides (mg/dl) mean (sd) 175,3 ± 30,6 160,2 ± 17,0 p = 0,013 bmi: body mass index; ed: erectile dysfunction; hdl: high-density lipoprotein; iief-5: international index of erectile function. table 1. characteristics of patients: vasculogenic ed (group a) and no vasculogenic ed (group b). vasculogenic ed no vasculogenic ed p (n = 32) (n = 27) imt cavernosal artery mean (sd) 0,28 ± 0,06 0,17 ± 0,07 p < 0,001 imt carotid artery mean (sd) 0,74 ± 0,14 0,59 ± 0,11 p < 0,001 bed: erectile dysfunction; imt: intima–media thickness.. table 2. intima-media thickness (imt) values of common carotid artery and of cavernosal artery. prezioso_stesura seveso 26/03/14 10:11 pagina 11 archivio italiano di urologia e andrologia 2014; 86, 1 d. prezioso, f. iacono, u. russo, g. romeo, a. ruffo, n. russo, e. illiano 12 discussion the association between ed and cvd has previously been recognized (27). patients with cvd frequently describe preexisting ed (28).these patients must be clearly distinguished from those who have neither cvd nor cardiovascular risk factors and have a defect in the generating no-3-5-cyclic guanosine monophosphate peripheral vascular system in sm that is independent of other systemic vascular diseases (29). it has been suggested, but never demonstrated, that early treatment of coronary heart disease risk factors may reduce the later risk of ed (30). furthermore, it has been hypothesized that ed is a harbinger of cvd (31, 32). in a study of men with diabetes with vs without ed, ed was the most efficient predictor of coronary artery disease (33). a largescale study of 25 650 men found a 75% increased risk of peripheral vascular disease in men with preexisting ed (34). ian m. thompson demonstrated the substantial association between incident as well as prevalent ed and subsequent cvd, including angina, myocardial infarction, stroke, and transient ischemic attack (35). several epidemiological studies in selected patient populations have clearly shown that the major cardiovascular risk factors – aging, smoking, diabetes, hyperlipidemia and hypertension – have raised prevalence in individuals with ed (36, 37). the prevalence of ed is also directly related to the number of cardiovascular risk factors present, being highest in individuals with more than three. patients with coronary artery disease have a high frequency of ed (38, 39) which correlates with the number of stenotic and calcified arteries and predates symptomatic disease (40). notably, a patient with vasculogenic ed is likely to have one coronary artery with a 50% stenosis (38, 39). cardiometabolic risk in abdominally obese subjects is now well-defined as the metabolic syndrome (41). ed prevalence increases with the number of components of the metabolic syndrome, being as high as 40% in individuals with four components, and is especially prevalent in those with diabetes (42). in individuals with the metabolic syndrome, ed has a linear relationship with evidence of endothelial dysfunction (43). a plausible theoretical link between erectile and endothelial dysfunction posits that cardiovascular risk factors could induce ed by impairing no release from endothelial cells following neuronal activation and initiation of a penile erection. a residual, important question, however, is whether ed reflects endothelial dysfunction independent of traditional cardiovascular risk factors (43). carotid-artery imt, measured noninvasively with the use of carotid-artery ultrasonography, is an independent predictor of new cardiovascular events in persons without a history of cvd (43). a review of eight epidemiologic studies showed that the imt of the common carotid artery by itself (in all eight studies) or combined with the imt of the internal carotid artery and presented as a score (in one of the eight studies) had independent predictive power with respect to cardiovascular events (44) .the presence of plaque (defined as an internal-carotid artery imt ! 1.9 mm) has been shown to be associated with increased event rates (45). gokkaya investigated the predictive accuracy of carotid and cdu findings for discriminating patients with vasculogenic erectile dysfunction (edv). of total 50 patients, 29 (58%) were included in vasculogenic ed group and 21 (42%) in non-vasculogenic ed group according to p-cdu findings. there was a significant difference between groups for cavernosal imt (p = 0.012) but not for carotid imt (p = 0.601). when patients were reclassified according to carotid imt values (imt of the first group < 0.9 mm and the second > = 0.9 mm), carotid psv and edv values were different (p = 0.033 and 0.018, respectively). cavernosal psv and edv displayed no difference (p = 0.816 and 0.123) while cavernosal imt and percent change of cavernosal caliper were significantly different (p = 0.014 and 0.018) (46). caretta performed a high magnification ultrasonographic study in order to compare functional and morphological parameters of the cavernous artery to psv and their relation with penile and systemic atherosclerosis (47). a total of 109 subjects (84 ed patients and 25 controls) were evaluated. cavernous parameters were significantly different between ed and controls. multivariate model showed that imt was the only predicting parameter for ed of vascular origin. cavernous imt showed a strong direct correlation with carotid and femoral imt. ed patients with two or more cardiovascular risk factors had a significantly higher cavernous imt (47). ucar investigated the relationship between penile color doppler sonography (cds) findings and sonographic endothelial parameters in patients with ed, including imt of common carotid arteries (cca) and flow-mediated dilatation (fmd) of brachial artery (48). fifty-six ed patients were included in the study. imt values were higher in arterial/combined insufficiency group when compared to cavernous veno-occlusive disease but the difference was not statistically significant. the combined use of imt and fmd established the diagnosis of vasculogenic ed with 100% sensitivity and 59.2% specificity. the positive predictive value was 72%, negative predictive value 100% and accuracy 80%. the combined use of brachial artery fmd and carotid arteries imt measurements may be suggested as an alternative method to evaluate vasculogenic ed (48). vlachopoulos evaluated figure 1. correlation between carotid artery imt and cavernosal artery imt. imt: intima–media thickness. prezioso_stesura seveso 26/03/14 10:11 pagina 12 arterial structural and functional characteristics and measured systemic endothelial/inflammatory markers in 52 hypertensive men with vasculogenic ed and in 34 hypertensive men with normal erectile function, matched for age, blood pressure, risk factors and treatment (49). hypertensive patients with ed had higher common carotid imt (0.95 ±.19 vs. 0.83 ± 0.18 mm, p = 0.003) and carotid-femoral pulse-wave velocity (8.89 ± 1.38 vs. 8.11 ± 1.10 m/s, p = 0.007), lower flow-mediated dilation of the brachial artery (absolute values of 2.96 ± 1.64 vs. 4.07 ± 1.68%, p = 0.003). in hypertensive men, the presence but not the severity of vasculogenic ed is associated with subclinical atherosclerosis, impairment of arterial function and systemic endothelial and inflammatory activation (49). conclusion the increase of imt is an expression of morphological and structural alterations of the vessel wall due to atherosclerotic phenomena. both the carotid and cavernous imt proved significantly higher in patients suffering from ed vasculogenic, in association with the classical risk factors for cvd. in particular, the evaluation of imt cavernous arteries could be done, together with the color-doppler evaluation of psv, by edv, a new sonographic parameter useful in identifying those cases of vasculogenic ed in a more precise way than what can not be done with the alone assessment of psv. the penile color doppler with intracavernous injection of vasoactive substances is a diagnostic method for a long time widely used in the evaluation of patients with ed. however, it is invasive and linked to several complications such as bruising, hematoma and penile priapism, not to mention that this method is considered embarrassing by most of the patients. in addition, the anxiety that comes from intracavernous injection can induce an abnormal response in the patient who may have adrenergic inhibitory effect, in fact decreasing the sensitivity of this test. further studies should be aimed at understanding if the assessment of cavernous imt is a reliable screening test for those subjects with multiple cardiovascular risk factors at risk of vasculogenic ed, or even if it can completely replace the more invasive and less tolerated colordoppler investigation with intracavernous injection in the instrumental assessment of erectile function. references 1. lewis rw. epidemiology of erectile dysfunction. urol clin north am. 2001; 28:209-216. 2. nih consensus development panel on impotence. impotence. jama. 1993; 270:83-90. 3. zusman rm, morales a, glasser db, osterloh ih. overall cardiovascular profile of sildenafil citrate. am j cardiol. 1999; 83:35c-44c. 4. johannes cb, araujo ab, feldman ha, derby ca, et al. incidence of erectile dysfunction in men 40 to 69 years old: longitudinal results from the massachusetts male aging study. j urol. 2000; 163:460-463. 5. moinpour cm, lovato lc, thompson im jr, et al. profile of 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23. cappelleri jc, rosen rc, smith md, et al. diagnostic evaluation of the erectile function domain of the international index of erectile function. urology. 1999; 54:346-351. 24. eau guidelines 2013. 13archivio italiano di urologia e andrologia 2014; 86, 1 evaluation of penile cavernosal artery intima-media thickness in patients with erectile dysfunction prezioso_stesura seveso 26/03/14 10:11 pagina 13 archivio italiano di urologia e andrologia 2014; 86, 1 d. prezioso, f. iacono, u. russo, g. romeo, a. ruffo, n. russo, e. illiano 14 25. polak jf, pencina mj, meisner a, et al. associations of carotid artery intimamedia thickness (imt) with risk factors and prevalent cardiovascular disease: comparison of mean common carotid artery imt with maximum internal carotid artery imt. j ultrasound med. 2010; 29:1759-68. 26. polak jf, o’leary dh, kronmal ra, et al. sonographic evaluation of carotid artery atherosclerosis in the elderly: relationship of disease severity to stroke and transient 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giordanetti s, de amici e, et al. relationship between erectile dysfunction and silent myocardial ischemia in apparently uncomplicated type 2 diabetic patients. circulation. 2004; 110:22-26. 34. blumentals wa, gomez-caminero a, joo s, vannappagari v. is erectile dysfunction predictive of peripheral vascular disease? aging male. 2003; 6:217-221. 35. ian m. thompson, at al. erectile dysfunction and subsequent cardiovascular disease. jama. 2005; 21:2996-3002. 36. bortolotti a, et al. the epidemiology of erectile dysfunction and its risk factors. int j androl. 1997; 20:323-334. 37. feldman ha, et al. erectile dysfunction and coronary risk factors: prospective results from the massachusetts male aging study. prev med. 2000; 30:328-338. 38. greenstein a, et al. does severity of ischemic coronary disease correlate with erectile function?int j impot res. 1997; 9:123-126. 39. kloner ra, et al. erectile dysfunction in the cardiac patient: how common and should we treat? j urol 2003; 170 (suppl):s46-s50. 40. solomon h, et al. relation of erectile dysfunction to angiographic coronary artery disease. am j cardiol. 2003; 91:230-231. 41. grundy sm, et al. american heart association; national heart, lung, and blood institute diagnosis and management of the metabolic syndrome: an american heart association/national heart, lung, and blood institute scientific statement.circulation. 2005; 112:2735-2752. 42. esposito k, et al. high proportions of erectile dysfunction in men with the metabolic syndrome. diabetes care. 2005; 28:1201-1203. 43. giugliano f, et al. erectile dysfunction associates with endothelial dysfunction and raised proinflammatory cytokine levels in obese men j endocrinol invest. 2004; 27:665-669. 44. lorenz mw, markus hs, bots ml, et al. prediction of clinical cardiovascular events with carotid intimamedia thickness: a systematic review and meta-analysis. circulation. 2007; 115:459-67. 45. rundek t, arif h, boden-albala b, et al. carotid plaque, a subclinical precursor of vascular events: the northern manhattan study. neurology. 2008; 70:1200-7. 46. gokkaya cs, aktas bk, et al. is there a concordance between carotid and penile cavernosal artery intima-media thickness in patients with erectile dysfunction? international journal of impotence research 2012; 24:44-48. 47. caretta n, palego p, at al. cavernous artery intima-media thickness: a new parameter in the diagnosis of vascular erectile dysfunction. j sex med. 2009; 6:1117-26. 48. ucar g, et al. the combined use of brachial artery flow-mediated dilatation and carotid artery intima-media thicknessmeasurements may be a method to determine vasculogenic erectile dysfunction. int j impot res. 2007; 19:577-83. 49. vlachopoulos c, aznaouridis, et al. arterial function and intima-media thickness in hypertensive patients with erectile dysfunction. j hypertens. 2008; 26:1829-36. correspondence domenico prezioso, md dprezioso@libero.it fabrizio iacono, md fiacon@tin.it umberto russo, md umberto.russo@libero.it giuseppe romeo, md giuseppe.romeo85@gmail.com antonio ruffo, md antonio.ruffo7@gmail.com nicola ruffo, md stoiconk@hotmail.com ester illiano, md (corresponding author) ester.illiano@inwind.it department of urology university federico ii of naples via pansini 5 80131 naples, italy prezioso_stesura seveso 26/03/14 10:11 pagina 14 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 126 original paper present and future association between obesity and hypogonadism in italian male valentina boddi 1, valeria barbaro 2, paul mc nieven 3, mario maggi 1, carlo maria rotella 2 1 sexual medicine and andrology unit, department of clinical physiopathology university of florence, florence, italy; 2 department of biochemical experimental and clinical science, section of endocrinology and obesity agency, careggi university hospital; 3 strategyst consulting inc. objective: obesity prevalence is increasing worldwide and it is nowadays considered a real public health problem. obesity is associated with co-morbidities like cardiovascular diseases (cvd) and type 2 diabetes mellitus (t2dm), furthermore visceral obesity can be related to low testosterone (t) plasma levels. the link between obesity and hypogonadism (hg) is complex and not completely clarified. current guidelines suggest that screening for hg should be done in subjects with obesity and t2dm. the aim of this evaluation is to assess the estimated actual and future prevalence of obesity and related co-morbidities, in particular hg, in the italian general population. materials and methods: the strategyst consulting inc. recently completed an epidemiology forecast model for several countries, looking at hg and cv/metabolic disease, based on national health and nutrition examination survey (nhanes) data collected between 1999-2010. data from nhanes survey were used to evaluate the italian estimated prevalence of obesity and hg. results: results show that obesity estimated prevalence will increase in 2030 also in italy. in addition, also the prevalence of obese cvd and t2dm subjects will increase too. even italian hg prevalence is estimated to increase in the next two decades, irrespective of t threshold considered (< 8, 10 and 12 nmol/l). in obese cvd subjects the relative risk (rr) of developing hg (t < 8 nmol/l) is four times greater than in not-cvd obese subjects (rr = 4.1, 3.1 and 1.9 accordingly to the aforementioned t thresholds for defining hg). accordingly, the estimated percentage of hypogonadal obese cvd and t2dm subjects will rise in 2030. conclusions: the strategyst epidemiology forecast model has allowed to assess the current and future prevalence of obesity and its relative co-morbidities like hg in italy. data emerged from this evaluation suggest that obesity and hg prevalence will increase in italian population and confirm the complex link between adipose tissue and male t levels. key words: visceral obesity; hypogonadism; future prevalence; epidemiological forecast model. submitted 19 december 2013; accepted 28 february 2014 summary introduction obesity is an excessive accumulation of body fat mass relative to lean body mass, usually due to unbalanced diet and sedentary lifestyle (1). according to the world health organization (who) the diagnosis of obesity is often based on body mass index (bmi), calculated as weight in kilograms divided by height in meters squared (kg/m2). individuals with bmi higher than 30 kg/m2 are considered obese. obesity is categorized in grade 1, if bmi is of 30 to less than 35; grade 2, if bmi of 35 to less than 40 and grade 3, if bmi is of 40 kg/m2 or greater (2). obesity is the greatest public health problem in the world: several studies reported an association between obesity and increasing risk of developing cvd, cancer and common chronic disease, such as t2dm and hypertension, all diseases that can lead to a reduced quality of life and premature death (3). moreover, visceral obesity has been associated with alteration in sex steroid hormone concentrations like hg, especially in adult males (4-7). the organization for economic co-operation and development (oecd) projections suggest that more than 2 in 3 people will be overweight or obese in some of the oecd countries by 2020 (http://www.oecd.org/els/healthsystems/obesityandtheeconomicsofpreventionfitnotfat.htm). indeed, we are facing with a real global epidemic that is spreading in many countries and it can cause, in the absence of immediate action, very serious health problems in the coming years (1). the strategyst consulting inc. recently completed an epidemiology forecast model for several countries, looking at hg and cv/metabolic disease, based on nhanes data collected between 1999-2010. data from nhanes were used to show the degree of overlap between disease states and then to modify the raw prevalence values in nhanes in order to match the local prevalence in the particular countries, such as italy. the aim of this evaluation is to assess the current and future prevalence of obesity and its relative comorbidities, mostly hg, in italy. material and methods nhanes is a cross-sectional study designed to assess the health and nutritional status of adults and children in the no conflict of interest declared. note that barbaro v and boddi v equally contributed to the paper. doi: 10.4081/aiua.2014.1.26 boddi new_stesura seveso 26/03/14 10:17 pagina 26 27archivio italiano di urologia e andrologia 2014; 86, 1 obesity and hypogonadism in italy united states. in this survey every subject underwent an interview and an extensive physical examination. in some cases a morning blood sample was collected for biochemical and hormonal analyses, such as t in male (9). informations on age and race/ethnicity were self-reported. during physical examination, height and weight, as well as waist and hip circumferences were measured and bmi was calculated as weight in kilograms divided by the square of height in meters. participants were defined as having diabetes if they answered “yes” to the question, “have you ever been told by a doctor or other health professional you had diabetes or sugar diabetes?” and as having cvd if they answered yes to the question, “have you ever been told by a doctor you had heart attack, an angina pectoris or a coronary heart disease?” (9). detailed information regarding the collection of data in nhanes is available elsewhere (nhanes iii data files, documentation, and codebooks. available online from http://www.cdc.gov/nchs/ nhanes/about_nhanes.htm). the strategyst consulting inc recently completed an epidemiology forecast model for several countries, looking at hypogonadism and cardiovascular/metabolic disease, based on national health and nutrition examination survey (nhanes) data collected between 1999-2010. data from nhanes were analyzed for understanding the general cv/metabolic patient population, as well as the distribution of t levels within the pool, knowing that this differs by age and bmi, and possibly also by cv status. from this data the percentages of relative risk of developing cvd and t2dm were calculated in the u.s. population and then applied for other countries, including italy, on the basis of who data. who had previously performed several forecasting evaluation on cv and metabolic health across the world. this allowed strategyst consulting inc. to make projections for each country of the cv and metabolic diseases from 2013 to 2030. t levels are pretty consistent across the globe, with variations between countries being due to varying demographic profiles and levels of obesity and cv risk factors. for this reason, only nhanes testosterone data were used, as they were the only source that allowed to create hg populations with respect to all the risk factors (and their mutual comorbidities), and embody the very complex set of odds ratios that describe these populations. hence, data from nhanes were used to show the degree of overlap between disease states, then to modify the raw prevalence values in nhanes to match the local prevalence in the particular country analyzed. results and discussion prevalence and trends of obesity in italian adults in the last thirty years, the worldwide prevalence of obesity has almost doubled, not with homogeneously distribution (11). united states is one of the countries that experienced the largest absolute increase in the number of overweight and obese people between 1980 and 2008 (11). about 35% of u.s adults were obese in 2011-2012, with a higher percentage of middle-aged obese adults aged 40-59 than younger adults aged 20-39 or older adults aged 60 figure 1. panel a. male obesity prevalence from 2013 to 2030 in italy. panel b-c. percentage of obesity as a function of age bands in italy, actually (panel b) and in 2030 (panel c). o be si ty p re va le nc e (% ) o be si ty p re va le nc e (% ) obese obese 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 18-29 30-39 40-59 60-64 65* 2013 9.3% 13.6% 15.7% 17.9% 12.5% 11.3% 16.4% 22.6% 21.7% 15.0% 18-29 30-39 40-59 60-64 65+ 2030 20% 15% 10% 5% 0% 25% 20% 15% 10% 5% 0% 25% 20% 15% 10% 5% 0% age bands age bands a. b. c. boddi new_stesura seveso 26/03/14 10:17 pagina 27 archivio italiano di urologia e andrologia 2014; 86, 1 v. boddi, v. barbaro, p. mc nieven, m. maggi, c.m. rotella 28 and over (12). according to data released in 2008 by the oecd, in italy about 1 person in 10 was obese (http://www.oecd.org/els/health-systems/obesityandtheeconomicsofpreventionfitnotfat-italykeyfacts.htm). figure 1 shows the trend of obesity (bmi ! 30 kg/m2) prevalence in italy from 2013 to 2030, in the adult male population (18-over 65 years old). at present, according to strategyst estimated data, 13.8% of italian men is obese. this prevalence is similar to that referred by passi (progressi delle aziende sanitarie per la salute in italia), a monitoring system of italian population (http://www.epicentro.iss.it/problemi/obesita/epid.asp). obesity prevalence will increase in the coming years and, on the basis of our estimated data, it will reach 16.8% in 2030 (figure 1, panel a). nowadays, among italian adult obese subjects, there is a higher percentage of patients aged 60-64 (17.9%) than aged 40-59 (15.7%) or aged 65 and over (12.5%) (figu re 1, panel b). in the next future, the percentage of obesity is estimated to rise in each age group, but mostly in middle aged adults, reaching 22.6% among 40-59 years old men and 21.7% among 60-64 years old men, similarly to us male population (figure 1, panel c). prevalence and trends of cvd and t2dm in italian adults the interheart study group identified the abdominal (visceral) obesity as one of the nine major risk factors for myocardial infarction (including smoking, lipids, hypertension, t2dm, diet, physical activity, alcohol consumption, and psychosocial factors), accounting for more than 90% of the worldwide risk (15). these risk factors were shared by men and women, almost in every geographic region and every racial/ethnic group. it is well known that visceral obesity, versus subcutaneous fat, is characterized by a hypersecretion of pro-atherogenic, pro-inflammatory and pro-diabetic adipo-cytokines, and by an enhanced free fatty acid turnover and toxicity (16), an increased basal sympathetic tone, a hypercoagulable state and a chronic low-grade systemic inflammation (17). this causes the development of insulin resistance (ir) and the increased risk of cvd as ischemic heart diseases (angina and myocardial infarction, mi) and congestive heart failure (chf). in addition, visceral obesity can be considered a “conditional” risk for developing t2dm, dyslipidaemia and hypertension, all independent cv risk factors (17). figure 2, panel a shows that the prevalence of t2dm, angina, history of mi and chf is expected to grow highly in the coming a. b. figure 2. panel a. male prevalence of different co-morbidities from 2013 to 2030 in italy [history of myocardial infarction (mi), angina, congestive heart failure (chf) and type 2 diabetes mellitus (t2dm)]. panel b. male prevalence of different co-morbidities as a function of different age bands in italy (history of mi, angina, chf and t2dm). p re va le nc e of d iff er en t co -m or bi di ti es ( % ) p re va le nc e of d iff er en t co -m or bi di ti es ( % ) age deciles 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 0-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+ hx of mi angina chf t2dm hx of mi angina chf t2dm 20% 15% 10% 5% 0% 25% 20% 15% 10% 5% 0% boddi new_stesura seveso 26/03/14 10:17 pagina 28 29archivio italiano di urologia e andrologia 2014; 86, 1 obesity and hypogonadism in italy years. at the moment, the estimated italian proportion of men with a history of mi is 4.8%, of angina 5.4%, of chf 2.7% and of t2dm 9.8% reaching 7.4%, 8.2%, 4.2% and 14.4%, respectively, in 2030. hence, the prevalence of cv and metabolic diseases will be almost doubled within 17 years in italy. concerning the prevalence of angina, history of mi, chf and t2dm as a function of age, it rapidly increases for all these diseases with aging, especially after 40 years old. in particular, for t2dm reaches a prevalence of 21% in 70 years old men (figure 2, panel b). in 2013, among the estimated obese sample, 26% has co-morbidities like t2dm and cvd (12% and 14%, respectively), whereas 74% has not (figure 3, panel a). normal weight subjects have lower rates of cvd (13%) and t2dm (10%), respectively (data not shown). this is consistent with a higher prevalence of cv and metabolic diseases in obese subjects. it is estimated that the prevalence of “unhealthy” obese (with cvd and t2dm) will rise reaching 32% in 2030 (16% t2dm and 16% cvd) whereas “healthy” obese (without cv and metabolic morbidity) will decrease to 68% (figure 3, panel b). overall these data show that prevalence of obesity in italy will increase, in particular the percentage of obese male subjects with co-morbidities. prevalence and trends of hypogonadism in italian adults normal aging is characterized by a slight decline of t levels (18). considering changes in t levels by age, there is not a consensus for definition of hg (19). for example, the american association of clinical endocrinologists (20) and the endocrine society (21) proposed different t cutoffs for diagnosing hg, i.e. 7 nmol/l (200 ng/dl) and 10.4 nmol/l (300 ng/dl) respectively. according to a consensus among different scientific andrology societies (18, 19, 22) men with t levels below 8 nmol/l (231 ng/dl) should receive t replacement therapy, whereas those with t levels above 12 nmol/l (346 ng/dl) should not be treated. moreover, it was introduced the concept of the so-called “late-onset hypogonadism” (loh): a clinical and biochemical condition of the advancing age, characterized by peculiar symptoms and by low levels of serum t, i.e. total t below 12 nmol/l. (2123). recently, wu et al. (24) proposed a t cut off 11 nmol/l (230 ng/dl) and free t levels of less than 220 pmol/l (< 64 pg/ml) for diagnosing loh, in the presence of at least three sexual symptoms (low libido and reduced spontaneous and sex-related erections). therefore, the estimated number of hypogonadal men is different, depending on the t cut off used and on age (18). in italy, by strategyst model evaluation, the present estimated prevalence of hg is 7, 12.5 and 22% considering t < 8, 10 e 12 nmol/l, respectively. it is expected that, in 2030, this prevalence will rise reaching 8.1, 14.7 and 24.2%, respectively (figure 4, panel a). in observational studies involving male general population, the prevalence of hg is increasing as a function of age, although at a different rate, as observed in us (2527) and european male population (24). accordingly, analyzing strategyst italian forecast, hg prevalence increases by age irrespective of t threshold considered, with the highest rate in older subjects (> 65 years old) reaching 7, 12.5, 22%, for t levels < 8, 10, 12 nmol/l, respectively (figure 4, panel b). obesity and hypogonadism several studies have demonstrated an inverse relationship figure 3. panel a-b. estimated distribution of obese male sample in 2013 and 2030; panel a and panel b, respectively. panel c-d. estimated distribution of hypogonadal obese male sample in 2013 and 2030; panel c and panel d, respectively. a-b. c-d. obese+cvd obese+t2dm obese obese+cvd obese+t2dm obese obese+cvd obese+t2dm obeseobese+cvd obese+t2dm obese 2013 2030 2013 2030 boddi new_stesura seveso 26/03/14 10:18 pagina 29 archivio italiano di urologia e andrologia 2014; 86, 1 v. boddi, v. barbaro, p. mc nieven, m. maggi, c.m. rotella 30 between bmi and waist circumference, indicators of visceral obesity, and t levels over all age groups (28-30). an increase in bmi from normal weight to obese range may be equivalent to a 15 years fall in t levels (23). in the massachusetts male aging study (mmas) authors demonstrated that a healthy lifestyle, a normal body weight and the absence of chronic disease were more important determinants of androgen levels than ageing (25-26). the link between obesity and hg is complex and not completely understood. visceral obesity can probably be considered an important cause of hg, but at the same time, hg could be a cause of obesity and insulin resistance, consequently establishing a vicious cycle (31-35). figure 5, panel a shows that the estimated percentage of obese males in italy is higher in hg sample than in general population. there are some considerable evidences on the role of t in regulating body composition. it seems that t concurs in increasing and maintaining muscle mass and reducing fat mass (36). this suggests a possible role of t deficiency in the etiology of obesity so that hg might be considered an additional component of metabolic syndrome (mets) in males (37). in fact, in men undergoing androgen ablation therapy for advanced prostate cancer it was observed a significant increase in total body fat mass and reduction in lean body mass (38). criteria for mets were present in more than 50% of these men, predisposing them to higher cv risk (39). the relationship between reduced t levels and cvd still represents a matter of speculation. cross-sectional epidemiological studies clearly show a significant association between hg and cvd (40-41). in a recent meta-analysis araujo et al. demonstrated that hg was associated with an increased risk of all causes and cvd mortality (42). figure 5, panel b shows the estimated italian prevalence of hg (as different t threshold considered: 8, 10, 12 nmol/l) in obese subjects with or without previous cvd. in obese cvd subjects the relative risk (rr) of developing hg (t < 8 nmol/l) is four times greater than in not-cvd obese subjects (rr = 4.1, 3.1 and 1.9 accordingly to t cut off of 8, 10 e 12 nmol/l). this is a cross-sectional analyses, therefore we cannot establish a relationship of causality, however this suggests that the presence of previous cvd predispose obese subjects to develop hg and this risk is higher for lower t plasma levels. a large body of evidence supports the association between low t, t2dm and mets (31-35). according to data shown in figure 5b, in italy the estimated percentage of hypogonadal obese male subjects with t2dm and cvd is 19 and 16%, respectively (figure 3, panel c), higher than in subjects with only obesity (figure 3, panel a). figure 4. panel a. estimated italian hyponadism (hg) prevalence from 2013 to 2030, considering different testosterone (t) cut off. panel b. prevalence of hyponadism (hg) as a function of age bands, considering different testosterone cut off, in italy. a. b. p re va le nc e of h g ( % ) p re va le nc e of h g ( % ) age bands 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 18-29 30-39 40-49 60-64 > 65 below 12 nmlol/l below 10 nmol/l below 8 nmol/l % below 8 % below 10 % below 12 30% 28% 26% 24% 22% 20% 18% 16% 14% 12% 10% 8% 6% 4% 2% 0% 25% 20% 15% 10% 5% 0% boddi new_stesura seveso 26/03/14 10:18 pagina 30 31archivio italiano di urologia e andrologia 2014; 86, 1 obesity and hypogonadism in italy hence, the presence of hg confers a higher probability of developing cvd and t2dm. furthermore, the estimated percentage of obese hypogonadal subjects with cvd and t2dm will rise in 2030, reaching 26 and 20% respectively (figure 3, panel d). this is consistent with previously shown data. current guidelines suggest that screening for hg should be done in subjects with obesity, t2dm and mets (18, 19, 21). conclusion obesity prevalence is increasing worldwide and this phenomenon involves italy too. at this moment, 13.8% men are obese and they will became 16.8% in 2030. the increase of prevalence will be greater in middle aged adult male. in coming years also the prevalence of t2dm, angina, chf and history of mi will rise. italian obese subjects have a higher rate of t2dm and cvd and this rate is estimated to rise. obesity is also related to hg. the estimated prevalence of hg in italy differs according to different cut offs proposed by scientific society, from 2 to 22% and will increase until 8-24% in 2030. concerning the data shown in this evaluation, the estimated prevalence of hg increases as a function of age and hypogonadal subjects are more often obese than general population. conversely, obese subjects have a higher risk of developing hg, in particular if they have suffered from cvd. finally, obese-hypogonadal males have a higher rate of t2dm and cvd than eugonadal obese male. the strategyst epidemiology forecast model allowed to assess the current and future prevalence of obesity and its relative comorbidities like hg in italy. a limitation of the present report should be recognized: prevalence estimations for italy are based on epidemiological values of us male population which could be different from the italian one. however, data emerged from this evaluation suggests that obesity and hg prevalence will increase in the italian population and confirm the complex link between adipose tissue and male t levels. references 1. caterson id, gill tp. obesity epidemiology and possible prevention. best pract res clin endocrinol. 2002; 16:595-610. 2. world health organization physical status: the use and interpretation of anthropometry. technical report series 1995, no. 854. in: geneva: who, 1995. 3. prospective studies collaboration. body-mass index and causespecific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. lancet. 2009; 373:1083-1096. 4. haffner sm, valdez ra, stern mp, katz ms. obesity, body fat distribution and sex hormones in men. int j obes relat metab disord. 1993; 17:643-9. 5. corona g, rastrelli g, forti g & maggi m. update in testosterone therapy for men. j sex med. 2011; 8:639-654. 6. corona g, rastrelli g, vignozzi l & maggi m. emerging medication for the treatment of male hypogonadism. expert opin emerg drugs. 2012; 17:239-59. 7. corona g, rastrelli g, vignozzi l, mannucci e & maggi m. how to recognize late-onset hypogonadism in men with sexual dysfunction. asian j androl. 2012; 14:251-259. 8. http://www.oecd.org/els/health-systems/49716427.pdf 9. selvin e, feinleib m, zhang l, et al. androgens and diabetes in men: results from the third national health and nutrition examination survey (nhanes iii). diabetes care. 2007; 30:234-8. 10. http://www.cdc.gov/nchs/nhanes/about_nhanes.htm 11. pérez rodrigo c. current mapping of obesity. nutr hosp. 2013; 28 (suppl 5):21-31. 12. cynthia l ogden, margaret d carroll, brian k kit, et al. prevalence of obesity among adults: united states, 2011-2012 nchs data brief no. 131 october 2013. 13. http://www.oecd.org/els/health-systems/obesityandtheeconomicsofpreventionfitnotfat-italykeyfacts.htm 14. http://www.epicentro.iss.it/problemi/obesita/epid.asp. 15. yusuf s, hawken s, ounpuu s, et al. interheart study investigators. effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the interheart study): case-control study. lancet. 2004; 364:937-52. figure 5. panel a. percentage of obese and nonobese italian men in hypogonadal sample (hg sample) and general population. panel b. hypogonadism (hg) prevalence in obese and cardiovascular disease (cvd) and obese subjects in italy according to different testosterone thresholds. a. all sample hg sample obese non-obese 8 nmol/l 10 nmol/l 12 nmol/lb. p re va le nc e of h g ( % ) obese + cvd obese 100% 80% 60% 40% 20% 0% 80,00 70,00 60,00 50,00 40,00 30,00 20,00 10,00 0,00 boddi new_stesura seveso 26/03/14 10:18 pagina 31 archivio italiano di urologia e andrologia 2014; 86, 1 v. boddi, v. barbaro, p. mc nieven, m. maggi, c.m. rotella 32 16. hajer gr, van haeften tw, visseren fl. adipose tissue dysfunction in obesity, diabetes, and vascular diseases. eur heart j. 2008; 29:2959-71. 17. krauss rm, winston m, fletcher bj, grundy sm. obesity: impact on cardiovascular disease. circulation. 1998; 98:1472-76. 18. buvat j, maggi m, guay a, torres lo. testosterone deficiency in men: systematic review and standard operating procedures for diagnosis and treatment. j sex med. 2013; 10:245-84. 19. wang c, nieschlag e, swerdloff r, et al. investigation, treatment and monitoring of late-onset hypogonadism in males: isa, issam, eau, eaa and asa recommendations. eur j endocrinol. 2008; 159:507-514. 20. petak sm, nankin hr, spark rf, et al. american association of clinical endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients--2002 update. endocr pract. 2002; 8:440-56. 21. bhasin s, cunningham gr, hayes fj, et al. task force, endocrine society. testosterone therapy in men with androgen deficiency syndromes: an endocrine society clinical practice guideline. j clin endocrinol metab. 2010; 95:2536-2559. 22. nieschlag e, swerdloff r, behre hm, et al. investigation, treatment and monitoring of late-onset hypogonadism in males: isa, issam, and eau recommendations. int j androl. 2005; 28:125-7. 23. wu fc, tajar a, pye sr, et al. hypothalamic–pituitary–testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the european male aging study. j clin endocrinol metabol. 2008; 93:2737-2745. 24. wu fc, tajar a, beynon jm, et al. emas group. identification of late-onset hypogonadism in middle-aged and elderly men. n engl j med. 2010; 363:123-35. 25. mohr ba, guay at, o'donnell ab, mckinlay jb. normal, bound and nonbound testosterone levels in normally ageing men: results from the massachusetts male ageing study. clin endocrinol (oxf). 2005; 62:64-73. 26. yeap bb, almeida op, hyde z, et al. 2008. healthier lifestyle predicts higher circulating testosterone in older men. the health in men study. clin. endocrinol. (oxf.) 2009; 70:455-63. 27. rohrmann s, platz ea, selvin e, et al. the prevalence of low sex steroid hormone concentrations in men in the third national health and nutrition examination survey (nhanes iii). clin endocrinol. (oxf). 2011; 75:232-9. 28. traish am, feeley rj, and guay a. mechanisms of obesity and related pathologies: androgen deficiency and endothelial dysfunction may be the link between obesity and erectile dysfunction. febs j 2009; 276:5755-67. 29. traish am, saad f, guay a. the dark side of testosterone deficiency: ii. type 2 diabetes and insulin resistance. j androl. 2009; 30:23-32. 30. corona g, mannucci e, ricca v, et al. the age-related decline of testosterone is associated with different specific symptoms and signs in patients with sexual dysfunction. int j androl. 2009; 32:720-8. 31. corona g, rastrelli g, morelli a, et al. hypogonadism and metabolic syndrome. j endocrinol invest. 2011; 34:557-567. 32. corona g, monami m, rastrelli g, et al. type 2 diabetes mellitus and testosterone: a meta-analysis study. int j androl. 2011; 34:528-540. 33. corona g, monami m, rastrelli g, et al. testosterone and metabolic syndrome: a meta-analysis study. j sex med. 2011; 8:272-283. 34. corona g, mannucci e, forti g, maggi m. following the common association between testosterone deficiency and diabetes mellitus, can testosterone be regarded as a new therapy for diabetes? int j androl. 2009; 32:431-441. 35. saad f, aversa a, isidori am, et al. onset of effects of testosterone treatment and time span until maximum effects are achieved. eur j endocrinol. 2011; 165:675-685. 36. emmelot-vonk mh, verhaar hj, nakhai pour hr, et al. effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. jama. 2008; 299:39-52. 37. corona g, mannucci e, forti g, maggi m. hypogonadism, ed, metabolic syndrome and obesity: a pathological link supporting cardiovascular diseases. int j androl. 2009; 32:587-98. 38. chen z, maricic m, nguyen p, et al. low bone density and high percentage of body fat among men who were treated with androgen deprivation therapy for prostate carcinoma. cancer. 2002; 95:2136-2144. 39. braga-basaria m, dobs as, muller dc, et al. metabolic syndrome in men with prostate cancer undergoing long-term androgendeprivation therapy. j clin oncol. 2006; 24:3979-3983. 40. ruige jb, mahmoud am, de bacquer d, kaufman jm. en do ge nous testosterone and cardiovascular disease in healthy men: a metaanalysis. heart. 2011; 97:870-5. 41. corona g, monami m, boddi v, et al. low testosterone is associated with an increased risk of mace lethality in subjects with erectile dysfunction. j sex med. 2010; 7:1557-64. 42. araujo ab, dixon jm, suarez ea, et al. clinical review: endogenous testosterone and mortality in men: a systematic review and meta-analysis. j clin endocrinol metab. 2011; 96:3007-19. correspondence valentina boddi, md vboddi@gmail.com mario maggi, md m.maggi@dfc.unifi.it sexual medicine and andrology unit, department of clinical physiopathology university of florence viale pieraccini 6 50139 florence, italy paul mc nieven, md pm@strategyst-consulting.com strategyst consulting inc. carlo maria rotella, md (corresponding author) c.rotella@dfc.unifi.it valeria barbaro, md valeb2282@gmail.com department of biochemical experimental and clinical science section of endocrinology and obesity agency careggi university hospital, florence, italy boddi new_stesura seveso 26/03/14 10:18 pagina 32 stesura seveso 43archivio italiano di urologia e andrologia 2014; 86, 1 case report penile strangulation: an unusual sexual practice that often presents an urological emergency lucio dell’atti department of urology, arcispedale “s. anna”, ferrara, italy placement of constricting devices around the penis for autoerotic purposes or increasing of sexual performance represents a well-known challenge for urologists. penile incarceration is a urologic emergency with potentially severe clinical consequences. in many cases a rapid intervention and a sudden removal of the foreign body it is enough so that patients need no further intervention. we report three different cases of strangulating objects (metallic ring, metal bearing and plumbing pipe) presented at our emergency department and three different methods of devices extraction practiced. remove these devices can be challenging and often requires resourcefulness and multidisciplinary approach. key words: penile strangulation; ring; penis; ischemia. submitted 11 november 2013; accepted 31 december 2013 summary case report the frequency of self-injuries on penis is currently increasing in certain cultures. the aim of their use may be to enhance the sexual performance, to prolong the erection, to achieve erotic or auto-erotic effects or simply sexual curiosity (1,2). penile incarceration is a rare but serious problem, which can easily lead to strangulation and infarction. therefore it is a urological emergency that needs a quick treatment in order to prevent long-tail claims. failure in removing those devices can lead to significant ischemia and loss of tissue (3). the treatment of penile strangulation is decompression of the constricted penis to facilitate free blood flow and micturition (4). we report three cases of penile strangulation that have been presented at our attention. case report and figures are posted in suppementary materials on www.aiua.it discussion there are sporadic reports of penile strangulation in the medical literature (5). this condition is not common, but it is certainly a urological emergency as prompt removal of the constricting object and the decompression of the penis are required to prevent long-term complications (6). strangulation may occur when various items, made of metal or non-metal no conflict of interest declared material, are pulled over the penis. non-metallic objects can cause much more serious injuries, but they are more easily removed than metal objects. the reason for the higher level of damage in case of non-metallic objects is that they are more elastic and can therefore exert a greater pressure on the penis (2) . among the objects pulled onto the penis there are: metal rings, wedding rings, iron sleeves, nuts, pipes, bearings, bicycle parts, all kinds of bottles, tools and rubber bands. objects pulled onto or wound round the penis can cause mechanical damage. clamping of the penis causes venous stasis or blockage. as result of venous stasis, the penis lymph vessels and arteries may be blocked, with consequence of ischaemia or infarction (5). after several hours, necrosis and gangrene may develop. in some case, such as ours, not only the penis, but also the scrotum is ligated. the most important task is to remove the foreign body, which can involve serious technical difficulties in the case of metal devices. an equipment with various tools is essential for a successful removal of different forms of strangulating object. this is followed by conservative or surgical treatment of the damaged tissue of penis. in these cases a psychological or psycho-sexual evaluation of the patients seems to be suitable, but unfortunately our patients refused any further assessment. references 1. osman m, al kadi h, al hafi r. gangrene of the penis due to strangulation by a metallic ring. scand j urol nephrol. 1996; 30:77-78. 2. perabo fg, steiner g, albers p, muller sc. treatment of pe ni le strangulation caused by costricting devices. urology. 2002; 59:137. 3. ivanovski o, stankov o, kuzmanoski m, et al. penile strangulation: two case reports and review of the literature. j sex med. 2007; 4:17751780. 4. pannek j, martin w. penile entrapment in a plastic bottle. j urol. 2003; 170:2385. 5. noh j, kang tw, heo t, et al. penile strangulation treated with the modified sting method. urology. 2004; 64:591. 6. kimber rm, mellon jk. the role of special cutting equipment and corporeal aspiration in the treatment of penile incarceration with a barbell retaining collar. j urol. 2004; 172:975. correspondence lucio dell’atti, md, phd (corresponding author) dellatti@hotmail.com department of urology, arcispedale “s. anna”, via a. moro 8 44124 cona, ferrara, italy doi: 10.4081/aiua.2014.1.43 dell'atti cr_stesura seveso 26/03/14 10:37 pagina 43 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2144 case report giant isolated renal cyst hydatid: from diagnosis to treatment senol adanur, erdem koç, tevfik ziypak, turgut yapanoglu, ozkan polat department of urology, medical faculty, ataturk university, erzurum, turkey hydatid cyst disease is a parasitic infestation caused by echinococcus granulosus. renal involvement is rarely seen as 2-4% of all cases. rarely renal involvement is isolated whereas commonly it accompanies involvement of other organs. we aimed to present a 30-year-old male patient with renal involvement reaching a giant size and undiagnosed in another center. key words: hydatid disease; renal; nephrectomy. submitted 24 march 2014; accepted 31 may 2014 summary introduction hydatid cyst disease is a parasitic infestation caused by echinococcus granulosus (1). echinococcus granulosus may involve any part of the body but the urinary tract involvement is extremely rare (2-4%) (2). cyst hydatid disease cannot be diagnosed preoperatively in one out of three patients despite existing serological tests and imaging modalities (3). we aimed to present an isolated hydatid cyst renal involvement that reached giant size and was undiagnosed in another center who referred to our clinic. case a 31-year-old male patient was admitted to our clinic with the complaint of left flank pain radiating to the back during last 2 months. patient's past medical history included endoscopic right ureteral stone treatment with right ureteral double-j (dj) stent placement in another center one month before. microscopic hematuria and leukocyturia were present at urine analysis of the patient. creatinine level was 1.2 mg/dl in biochemical blood tests. eosinophil ratio was 10.1% (normal range: 0.9-6) respectively at blood count. a 89 x 144 mm sized septate multicystic mass lesion in the left kiney and grade i hydronephrosis in the right kidney was demonstrated at urinary tract ultrasonography (us). contrast enhanced computed abdominal tomography (ct) also displayed a 118 x 165 mm sized hypodense multicystic mass lesion arising from mid-lower pole at the level of the renal pelvis level extending to the anterior and right lateral no conflict of interest declared side and containing septa belonging to daughter vesicles (figure 1a-b). the ct scan was negative for cystic lesions in liver, lung and spleen. preoperative indirect hemagglutination test was positive. total nephrectomy was planned and preoperatively albendazole at the daily dose of 400 mg twice daily dose was administered one month before the surgical procedure (figure 1c-d). no postoperative complication was registered. discussion hydatid disease is a parasitic infestation caused by the larval form of echinococcosis granulosus. the disease is most common in sheep-raising countries including doi: 10.4081/aiua.2014.2.144 figure 1. a. ct view of giant cystic lesion containing septa belongs to the daughter vesicles in the left kidney. b. 3d volume rendering techniques imaging view of the left renal hydatid cyst. c. macroscopic appearance of nephrectomy material. d. macroscopic appearance of daughter vesicles. 145archivio italiano di urologia e andrologia 2014; 86, 2 giant isolated renal cyst hydatid turkey. all parts of the human body are exposed to the disease although liver and lungs are the most common locations. isolated renal involvement constitutes 2-3% of all cases (4). hydatid cysts rarely affect the renal function. diagnostic approach includes ultrasonography, kub radiography or more often by abdomen ct displaying the calcified thick-walled spherical cyst filled with liquid (5). serological tests are helpful in diagnosis but they have only 60-90% sensitivity. our case was admitted to our clinic due to the increase in the complaint of left flank pain radiating to the back that was related to the undiagnosed left renal hydatid cyst but the history of endoscopic intervention for right ureteral stone one month before. blood count showed eosinophilia. contrast enhanced computed abdominal tomography imaging was compatible with giant multicystic isolated renal hydatid cysts with septation by daughter vesicles inside. serological tests were also positive. preoperative praziquantel and albendazole treatment for 7 to 10 days is recommended to prevent and minimize cultivation of daughter vesicles if the accidental contamination of operation field occurs (6). we also administered albendazole at the dose of 400 mg twice daily for one month before total nephrectomy in order to minimize the effect of accidental contamination of the operation field in the case of rupture of the giant hydatid cyst by pressure of the surrounding tissue. surgery is the main treatment modality of renal hydatid cyst disease. the type of surgical procedure should be decided according to the cyst size, localization, relationship with adjacent tissues and degree of renal parenchymal mass destruction. simple nephrectomy, partial nephrectomy, endocystectomy plus link closure, pedunculated omentoplasty may be performed. perioperative albendazole treatment should be given for a reasonable period of time to prevent disease recurrence and anaphylaxis (7). in the present case total nephrectomy was performed but we were anable to remove the cyst en bloc due to its giant size. nephrectomy was completed after reduction of cyst size by draining daughter vesicles to prevent contamination of the abdomen. post-operatively medical treatment with albendazole was continued for one month. renal hydatidosis has the tendency to slow growing to reach giant size and may cause renal function loss by the compression of the renal parenchyma of the affected renal unit. although extremely rare, the diagnosis of renal hydatid cyst should be kept in mind in the differential diagnosis especially in endemic areas. references 1. schantz pm, chai j, craig ps. epidemiology and control of hydatid disease. in: thompson rca, lymberg aj, editors. echinococcus and hydatid disease. wallingford: cab international, 1995; 233. 2. gogus c, safak m, baltaci s, turkolmez k. isolated renal hydatidosis: experience with 20 cases. j urol. 2003; 169:186-189. 3. angulo jc, sanches-chapado m, diego a, et al. renal echinococcosis: clinical study of 34 cases. j urol. 1997; 157:787-794. 4. gögüs o, bedük y, topukçu z. renal hydatid disease br j urol. 1991; 68:466-469. 5. horchani a, nouira y, chtourou m, et al. retrovesical hydatid disease: a clinical study of 27 cases eur urol. 2001; 40:655-60. 6. the medical letter, 2010. the medical letter: drugs for parasitic infections. med lett treat guide 2010; 8:1-13. 7. unsal a1, cimentepe e, dilmen g, et al. an unusual cause of renal colic: hydatiduria . int j urol. 2001; 8:319-21. correspondence senol adanur, md s.adanur61@hotmail.com erdem koç, md tevfik ziypak, md turgut yapanoglu, md ozkan polat, md department of urology, medical faculty, ataturk university 25240 erzurum, turkey stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2152 case report delayed-onset ureteral lesions due to thermal energy: an emerging condition cesare selli, filippo maria turri, cristina gabellieri, francesca manassero, maurizio de maria, andrea mogorovich department of urology, university of pisa, italy. objectives: to describe the risks of ureteral damage occurring during urological and gynecological procedures utilizing energybased surgical devices (esd) during both laparoscopic and open procedures. materials and methods: during the last 20 months we observed five cases of iatrogenic ureteral lesions caused by esd which required open surgery. there were 3 lesions of the lower ureter occurring during gynecological laparoscopic or robotic procedures, and 2 lesions of the upper ureter occurring during open enucleation of low-stage renal cell carcinomas. results: in the laparoscopic gynecological lesions the cause was attributable to monopolar cutting and bipolar coagulation: they presented with urine extravasation after 20, 15 and 15 days respectively and required ureteral reimplantation in 2 out of 3 cases. in the upper ureteral lesions the causes were bipolar coagulation and ligasure impact tm used for perirenal fat dissection: they presented after 2 and 4 months respectively and required uretero-ureterostomy and inferior nephropexy in one case and nephrectomy in the other. in 3 out of 5 cases there was an unsuccessful attempt at placing an ureteral double j stent, and in the 2 cases where it was placed it did not prevent the formation of subsequent stricture in one. conclusions: the widespread diffusion of esd has the potential drawback of inadvertent thermal energy transmission to the ureter. delayed presentation of ureteral lesions and difficulties in ureteral stent placement were the common features of the cases observed. inadvertent ureteral damage by different thermal energy sources is an emerging condition, requiring awareness, prompt recognition and adequate treatment with the reconstructive urology principles. key words: ureteral injury; energy-based surgical devices; reconstructive urology. submitted 24 october 2013; accepted 31 january 2014 summary no conflict of interest declared. presented as an oral communication at the 24th sun congress in modena, november 2012. trolled bipolar) and ultrasonic (1-3). the ureter, due to its relatively small caliber and continuous flow of urine is particularly susceptible to inadvertent damage with thermal energy: monopolar energy is the most destructive one and laparoscopic lesions tend to be more extensive than those occurring in open surgery (4-5). case report we report herein our experience with the management of inadvertent ureteral lesions due to esd occurring during both open and laparoscopic gynecological and urological procedures. cases report are described in supplementary materials posted on www.aiua.it discussion in a review of laparoscopic ureteral injury in pelvic surgery, ostrenski et al. (6) in 2003 reported a delayed clinical occurrence in 70% of cases, with thermal injury accounting for only 1.4%. however with the present spread of minimally invasive gynecologic surgery and the use of esd also in open procedures, this percentage is presumably higher. in laparoscopic gynecological procedures the ureter is likely to be injured in three locations: at the infundibolopelvic ligament, deep to the ovarian fossa and at the ureteral canal (6). in the three cases that came at our attention the site of thermal damage was likely to be of the third type. a constant care of the ureteral location should characterize all female pelvic dissections, and this applies particularly to robotic surgery, where the tri-dimensional vision and the possibility of a very fine dissection, possibly minimizing the amount of thermal energy, are intrinsic advantages of the technology. thermal injury of the upper ureter has been reported following percutaneous radiofrequency treatment of small renal tumors (7) or as a consequence of laparoscopic partial nephrectomy using a microwave tissue coagulator (8), while to the best of our knowledge there is no description of ureteral damage caused by esd for dissection of the perirenal fat during open conservative surgery for kidney tumors. doi: 10.4081/aiua.2014.2.152 aim energy-based surgical devices (esd) are increasingly used both in laparoscopic and open procedures in many surgical branches the most frequently used systems are electrosurgical (monopolar, bipolar, impedance-con153archivio italiano di urologia e andrologia 2014; 86, 2 thermal ureteral lesions in our experience, as well as in that of others, ureteral lesions secondary to esd present a delayed clinical appearance, in common with other iatrogenic damages (9-11). this can be explained by the fact that thermal injury damages vascular supply beyond the area of actual contact, leading to delayed necrosis or scarring of the ureteral wall (11). the real extent of tissue damage is greater than that appearing with imaging techniques, and adequate ureteral mobilization is necessary for tensionfree surgical repair. in the present experience upper ureteral lesions became clinically evident later than lower ureteral lesions associated with gynecological procedures, which all became apparent between two and three post-operative weeks with the appearance of either vaginal discharge or with acute abdomen due to uroperitoneum. an endourological approach should be obviously attempted first, but in our experience in 3 out of 5 cases the placement of a double j stent was unsuccessful and in one out of 2 case when it was placed it did not prevent the formation of subsequent stricture. we believe that, in case of failure of conservative management, an open surgical approach provides the best chances for and adequate ureteral mobilization, necessary for tension-free surgical repair, but robot-assisted ureteral reconstructive procedures are showing promising results (12). figures are reported in supplementary materials posted on www.aiua.it references 1. song c, tang b, campbell pa, et al. thermal spread and heat absorbance differences between open and laparoscopic surgeries during energized dissections by electrosurgical instruments. surg endosc. 2009; 23:2480-2487. 2. alkatout i, schollmeyert t, haldawar n, et al. principles and safety measures of electrosurgery in laparoscopy. j soc lap surg. 2012; 16:130-139. 3. kennedy js, stranahan pl, taylor kd, chandler jg: high burststrength feedback-controlled bipolar vessel sealing. surg endosc. 1998; 12:876-878. 4. phillips ck, hruby gw, durak e, et al. tissue response to surgical energy devices. urology. 2008; 71:744-748. 5. tulikangas pk, smith t, falcone t, et al. gross and histologic characteristics of laparoscopic injuries with four different energy sources. fertil steril. 2001; 75:806-810. 6. ostrzenski a, radolinski b, ostrzenska km. a review of laparoscopic ureteral injury in pelvic surgery. obstet gynecol surv. 2003; 58:794-799. 7. doody o, given mf, harper m, et al. rendezvous technique following thermal ureteric injury after radiofrequency ablation in a solitary kidney. j vasc interv radiol. 2008; 19:1112-1114. 8. harabayashi t, shinohara n, kakizaki h, et al. ureteral stricture developing after partial nephrectomy with a microwave tissue coagulator: case report. j endourol. 2003; 17:919-921. 9. manoucheri e, cohen sl, sandberg em, et al. ureteral injury in laparoscopic gynecologic surgery. rev obstet gynecol. 2012; 5:106-111. 10. gao js, leng jh, liu zf, et al. ureteral injury during gynecological laparoscopic surgeries: report of twelve cases. chin med sci j. 2007; 22:13-16. 11. oh br, kwon dd, park ks, et al. late presentation of ureteral injury after laparoscopic surgery. obstet gynecol. 2000; 95:337-339. 12. kozinn si, canes d, sorcini a, et al. robotic versus open distal ureteral reconstruction and reimplantation for benign stricture disease. j endourol. 2012; 26:147-151. correspondence cesare selli, md (corresponding author) c.selli@med.unipi.it filippo maria turri, md fm.turri@gmail.com cristina gabellieri, md gabelliericristina@interfree.it francesca manassero, md francy.manassero@hotmail.com maurizio de maria, md m.demaria@ao-pisa.toscana.it andrea mogorovich, md mogorovich@hotmail.it urologia universitaria via paradisa 2 50124 pisa, italy figure 1. case 1. uro-ct scan demonstrating uroperitoneum and a jet of contrast medium originating from the right pelvic ureter. stesura seveso archivio italiano di urologia e andrologia 2014; 86, 146 case report use of inflatable penile prostheses ams cx with momentary squeeze in a patient with peyronie’s disease after removal of two previously implanted penile prostheses patrizio vicini 1, ferdinando de marco 1, gabriele antonini 2, ettore de berardinis 2, riccardo giovannone 2, stefano pecoraro 3, luigi azzarri 1, vincenzo gentile 2 1 department of urology, “i.n.i.” italian neurotraumatologic institute grottaferrata, rome, italy; 2 department of urology, “sapienza” rome university, rome, italy; 3 department of urology, malzoni institute avellino, italy. objective: peyronie's disease (pd) is a fibrotic wound-healing condition of the tunica albuginea that results in penile deformity, curvature, hinging, narrowing and shortening, penile pain, and in some cases, erectile dysfunction (ed). surgery remains the gold standard treatment option, ensuring the faster and trustworthy treatment. for those patients who have erectile dysfunction and pd, penile prosthesis placement with straightening procedure is the best method to solve both diseases. the aim of this article is to present the use of hydraulic penile prostheses ams cx with momentary squeeze associated with a complete isolation of the neurovascular bundle in a complex case after removal of two previously implanted prostheses in a man suffering from peyronie’s disease and erectile dysfunction. material and method: a 50 year-old patient underwent two previous prosthetic implants in another hospital. the first implantation was performed using an infrapubic approach followed by placement of a three-component hydraulic penile prosthesis. after six months the prosthesis was removed using an infra-pubic approach and two soft prosthesis virilis ii were implanted during the same surgery. one year after the second operation we implanted a hydraulic penile prosthesis ams cx with mo mentary squeeze after complete isolation of the neurovascular bundle, fixing the two crural tips at the same level of albuginea of the two corpora cavernosa. result: twelve months after surgery the penis was completely straight without penile shortening and the patient was fully satisfied with his sexual life. conclusion: the procedure enabled a perfect alignment of the cylinders along the longitudinal axis and penile prosthetic symmetry to obtain a good penile rigidity and a perfect penile straightening. key words: inflatable penile prosthesis; peyronie’s disease; erectile dysfunction; isolation of the neurovascular bundle. submitted 17 september 2013; accepted 5 october 2013 summary introduction peyronie's disease (pd) is a fibrotic wound-healing condition of the tunica albuginea that results in penile deformity, curvature, hinging, narrowing and shortening, penile pain, and in some cases, erectile dysfunction (ed) (1-3). although a lot of non-surgical options have been proposed, none to date offers a trustworthy and effective correction of the penile curvature. as a result, surgery remains the gold standard treatment option, ensuring the faster and trustworthy treatment (4). tunica albuginea plication is the recommended method of straightening for patients with adequate rigidity and less severe deformity described as curvature less than 70° without narrowing/hinging (5-7). patients who have more serious, complex peyronie’s disease, but maintain good preoperative erectile function should be submitted to a straightening consisting in plaque incision or partial excision and grafting (5-7). in the end, for those patients who have erectile dysfunction and pd, penile prosthesis placement with straightening procedure is the best method to solve both diseases (5, 6, 8, 9). the aim of this article is to present the use of hydraulic penile prostheses ams cx with momentary squeeze associated with a complete isolation of the neurovascular bundle in a complex case after removal of two previous prostheses in a man suffering from pd and ed. after insertion of two crural tips, both tips have been attached symmetrically at the same level of the albuginea of the two corpora cavernosa. this has enabled a perfect alignment of the cylinders along the longitudinal axis and penile prosthetic symmetry to obtain a good penile rigidity and a perfect penile straightening. case report and figures are posted in suppementary materials on www.aiua.it. discussion the first and the second surgery did not correct penile curvature as the isolation of neurovascular bundle was no conflict of interest declared doi: 10.4081/aiua.2014.1.46 vicini cr_stesura seveso 26/03/14 10:44 pagina 46 47archivio italiano di urologia e andrologia 2014; 86, 1 use of inflatable penile prostheses ams cx with momentary squeeze in a patient with peyronie’s disease... not done. before surgery we planned to make a geometrical incision of relaxation as well as application of a-cellular collagen matrix graft in order to allow better lengthening and straightening of the penis; this was not necessary, as the complete isolation of neurovascular bundle has allowed a good penile straightening by itself. we performed an apical dilation of the right corpus cavernosum to correctly reposition the right prosthetic cylinder, we fixed the crural tips of the two prosthetic cylinders with prolene 2/0 at the same crural level in order to obtain the alignment of the cylinders along the longitudinal axis and the symmetry of both cylinders of penile prosthesis (figures 4-5). as described in literature, the most common postoperative complaint from men who have undergone the penile implant is the length loss, for these reason we suggest an early activation of penile prostheses to avoid penile shortening (10-11). references 1. rosen r, catania j, lue t, et al. impact of peyronie’s disease on sexual and psychological functioning: qualitative findings in patients in patients and controls. j sex med. 2008; 5:1997-84. 2. smith jf, walsh tj, conti s, et al. risk factors for emotional and relationship problems in peyronie’s disease. j sex med. 2008; 5: 2179-84. 3. el-sakka ai, hassoba hm, chui rm, et al. an animal model of peyronie’s like condition associated with an increase of transforming growth factor beta mrna and protein expression. j urol. 1997; 158:2284-90. 4. larsen sm, levine la. review of non surgical treatment options for peyronie’s disease. int j impot res. 2012; 24:1-10. 5. mulhall j, anderson m, parker m. a surgical algorithm for men with combined peyronie’s disease and erectile dysfunction. functional and satisfaction outcomes. j sex med. 2005; 2:132-8. 6. levine la, lenting el. a surgical algorithm for the treatment of peyronie’s disease. j urol. 1997; 158:2149-52. 7.ralph dj, minhas s. the management of peyronie’s disease bju int. 2004; 93:208-15. 8. mulhall j, anderson m, parker m. a surgical algorithm for men with combined peyronie’s disease and erectile dysfunction. functional and satisfaction outcomes. j sex med. 2005; 2:132-8 9. levine la, dimitriou rj, a surgical algorithm for penile prosthesis placement in men with erectile failure and peyronie’s disease. int j impot res. 2000; 12:147-51. 10. montague dk. penile prostheses implantation: size matters. eur urol. 2007; 51:887-8. 11. wang r, howard ge, hoang a, et al. prospective and long-term evaluation of erectile penile length obtained with inflatable penile prostheses to that induced by intracavernosal injection. asian j androl. 2009; 411-5. correspondence patrizio vicini, md (corresponding author) patriziovicini@gmail.com ferdinando de marco, md luigi azzarri, md department of urology, “i.n.i.” italian neurotraumatologic institute grottaferrata, rome, italy gabriele antonini, md ettore de berardinis, md riccardo giovannone, md vincenzo gentile, md department of urology, “sapienza” rome university, rome, italy stefano pecoraro, md department of urology, malzoni institute avellino, italy vicini cr_stesura seveso 26/03/14 10:44 pagina 47 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2156 case report triorchidism: genetic and imaging evaluation in an adult male arben belba 1, valentina riversi 2, francesca mari 3, eleonora cellesi 1, roberto ponchietti 1 1 urological and andrological unit, department of medicine, surgery and neuroscience, siena, italy; 2 imaging department aous of siena, italy; 3 medical genetics unit, department of medical biotechnologies, siena, italy. we report the results of imaging and cytogenetic studies in a case of triorchidism in a 54 years old male without any associated anomaly. a scrotal ultrasonography revealed the presence of two testes within the left hemiscrotum with complete septation and echotexture and vascular flow pattern similar to the vascular flow of the normal right testis. there was no focal abnormal echogenicity suggesting malignancy. scrotal mri confirmed two soft-tissue structures in the left hemiscrotum with normal signal intensity at t1w and t2w images. both testes had a tunica albuginea with low-signal intensity. cytogenetic analysis resulted in normal male karyotype 46xy. array-cgh analysis detected the presence of two interstitial rearrangements: a ~120 kb deletion of chromosome 1 and a ~140 kb deletion of chromosome 16. currently there are little details on the functions of both genes. key words: polyorchidism; ultrasonography; mri; cytogenetic evaluation. submitted 4 january 2014; accepted 31 january 2014 summary introduction polyorchidism is a rare genital anomaly defined by the presence of supernumerary testes usually within the scrotum. to date there have been almost 200 cases reported in the literature (1, 2). the most common presentation of polyorchidism is triorchidism with the supernumerary testis being confined to the left side. the exact mechanism for occurence of polyorchidism is still unknown. several theories have been proposed, including peritoneal folding, segmentation of the primitive gonads, longitudinal or transverse division of the genital ridge. no single theory can explain all types of polyorchidism since some involve testicular tissue only and others involve complete duplication of the testis, epididymis and vas deferens (3, 4). most cases of polyorchidism are found incidentally in association with undescended testis, hydrocele, hernia or torsion. it is also reported as increased risk of testicular malignancy. no conflict of interest declared. case report a 54 years old man presented to our outpatients department with complaints of erectile dysfunction. his past medical history revealed diabetes type 1 since the age of 28 years and 10-year history of a left-sided scrotal swelling associated with some discomfort. he was married and fathered two daughters. abdominal examination was normal with no palpable mass or groin herniae. scrotal examination revealed a normal right testis and scrotal content, but on the left side there were two similar size lumps. laboratory studies, including hormonal and oncological markers, were within normal limits. a scrotal ultrasonography revealed the presence of 2 testes within the left hemiscrotum with complete septation and echotexture and vascular flow pattern similar to the vascular flow of the normal right testis. there was no focal abnormal echogenicity suggesting malignancy (figure 1). scrotal mri confirmed 2 soft-tissue structures in the left hemiscrotum with normal signal intensity at t1w and t2w images. both testes had a tunica albuginea with low-signal intensity (figure 2). chromosomal preparations for the karyotype analysis were obtained according to standard techniques. cytogenetic analysis at a resolution of 400 bands resulted in normal male karyotype 46xy. patient dna was analysed by array-cgh analysis using a commercially available oligonucleotide microarrays containing about 44.000 60-mer probes (human genome cgh microarray 44b kit, agilent technologies, santa clara, california) according to the manufacturer’s instructions. array-cgh analysis detected the presence of two interstitial rearrangements: a ~120 kb deletion of chromosome 1(arr1q31.1(79,356,819-79,476,571)x1) and a ~140 kb deletion of chromosome 16 (arr 16q22.1(70,052,16470,193,889)x1). parents were not available for testing. the microdeletion of chromosome 1 includes the eltd1 (latrophilin and seven transmembrane domain containing1) gene, while the microdeletion of chromosome 16 includes the pdpr (pyruvate dehydrogenase phosphatase regulatory subunit) gene. currently there are little details on the functions of both genes. the protein encoded by eltd1 could be involved in cardiac development. the doi: 10.4081/aiua.2014.2.156 157archivio italiano di urologia e andrologia 2014; 86, 2 triorchidism: genetic and imaging evaluation in an adult male protein encoded by pdpr is a regulatory subunit of human mitochondrial pyruvate dehydrogenase phosphatase. it decreases the sensitivity of pdp1 to magnesium ions, and this inhibition is reversed by the polyamine spermine. both these proteins are expressed also in testis. a diagnosis of triorchidism was made and the patient was placed in sonographic follow up. figures are reported in supplementary materials posted on www.aiua.it discussion polyorchidism is a rare congenital anomaly defined by the presence of more than two histologically proven testes. the commonest variant is triorchidism, the supernumerary testis being commonly reported on the left side which often appears as a painless scrotal mass or may be found as an incidental finding on sonography. ultrasonography is diagnostic, mri plays a confirmatory role and may provide additional information in conditions that may complicate polyorchidism, such as torsion, cryptorchidism and neoplasia (4-6). most patients with polyorchidism have a normal 46xy karyotype and adult patients have normal secondary sexual characteristics. because polyorchidism is rare and poorly described, genetic studies are lacking. chromosomal abnormality such deletion of the long arm of chromosome 21 has been reported in a severe malformed male newborn (7). the current knowledge does not allow to attribute a causative role to the aploinsufficency of two genes in determining the phenotype of our patient. additional array-cgh analysis in patients with supernumerary testis are required to increase data and to define the role of these genes in the pathogenesis of polyorchidism. management of polyorchidism has been the subject of much debate (8). the incidence of testicular malignancy in polyorchidism is between 5.7-7% and was found only in a non-scrotal (abdominal or inguinal) supernumerary testis. with recent improvements in imaging techniques such as ultrasound and mri scans, most cases of polyorchidismc can be diagnosed and followed up accurately without any need for surgical exploration or histological examination. conservative treatment with sonographic follow-up is the choice of treatment in uncomplicated cases (9). references 1. bergholz r, wenke k, polyorchidism: a meta-analysis. j urol. 2009; 182:2422-2427. 2. savas m, yeni e, ciftci h, et al. polyorchidism: a three-case report and review of the literature andrologia 2010; 42:57-61. 3. thum g, polyorchidism: case report and review of literature. j urol. 1991; 145:370-372. 4. singer br, donaldson jg, jackson ds. polyorchidism: functional classification and management strategy. urology. 1992; 39:384-388. 5. chung tj, yao wj. sonographic features of polyorchidism. j clin ultrasound. 2002; 30:106-108. 6. yalçınkaya s, sahin c, sahin af. polyorchidism: sonographic and magnetic resonance imaging findings. can urol assoc j. 2011; 5:84-86. 7. arslanoglu a, tuncel sa, hamarat m. polyorchidism: color doppler ultrasonography and magnetic resonance imaging findings. clin imaging. 2013; 37:189-191. 8. shabtai f, schwartz a, hart j, et al. chromosomal anomaly and malformation syndrome with abdominal polyorchidism. j urol. 1991; 146:833-834. 9. nayak sp, sreejayan mp. management of supernumerary testis in an adult: case report and review. andrologia 2011; 43:149-152. correspondence roberto ponchietti, md (corresponding author) roberto.ponchietti@unisi.it eleonora cellesi, md arben belba, md urological and andrological unit, department of medicine, surgery and neuroscience, university of siena, siena, italy valentina riversi, md imaging department aous of siena, siena, italy francesca mari, md phd medical genetics unit, department of medical biotechnologies, siena, italy figure 1. a. sagittal sonographic image of the left scrotum showing two testicles completely separated. the supernumerary testis is smaller and superior to the more normal-sized and it appears as an oval, isoechoic mass with a homogeneously echogenic pattern identical to that of the other testicle; they share the epididymis and the vas deferens. b. color doppler image showing the same vascular pattern of the normal and accessory testicle. c. both testicles have approximately the same size. stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2140 case report a case report of urethral prolapse in a 38 year old female with 46xy karyotype helena watson, ewa stasiowska university hospital lewisham, london, uk. a 38-year old female presented with the acute onset of a vulval mass associated with pain and vaginal bleeding. she is female phenotype but has 46xy karyotype and complete androgen insensitivity syndrome (cais). at 15 years old she had a laparotomy and bilateral orchidectomy. following admission, an examination under anaesthesia and cystoscopy was performed. a diagnosis of strangulated complete urethral prolapse was made. the lesion was excised with diathermy and the meatal skin was reanastomosed to the urethra. at follow-up, the urethra was well healed. the patient now attends menopause clinic for oestrogen-replacement therapy. we hope this case raises awareness of the possibility of urethral prolapse in younger women who are oestrogen deficient. it provides further incentive for compliance with hormonereplacement therapy for patients with cais following gonadectomy, or other women with premature menopause. key words: complete urethral prolapse; complete androgen insensitivity syndrome; oestrogen deficiency. submitted 22 april 2014; accepted 31 may 2014 summary case report a 38-year old female was referred to a district general hospital in south london. she presented with the acute onset of a vulval mass over a few days, associated with pain and vaginal bleeding. she had dysuria and urinary frequency, but no voiding problems. she is female phenotype but has 46xy karyotype and complete androgen insensitivity syndrome (cais). her family history includes an aunt and cousin who had cais. at 15 years old she had a laparotomy and bilateral orchidectomy. she was commenced on hormone-replacement therapy following her surgery but had been non-compliant for a few years before presentation. following admission, an examination under anaesthesia and cystoscopy was performed. an erythematous, cyanotic, doughnut-shaped mass was protruding from the anterior vaginal wall containing distal urethral mucosa. the bladder and proximal urethra appeared normal. no conflict of interest declared she had a normal length vagina with a well-supported vaginal vault. a diagnosis of strangulated complete urethral prolapse was made. the lesion was excised with diathermy, the meatal skin was re-anastomosed to the urethra and a vaginal pack and in-dwelling catheter were inserted. the pack was removed the next day and the patient discharged to return in one week for review and a trial without catheter. at follow-up, the urethra was well healed. the patient now attends menopause clinic for oestrogen-replacement therapy. discussion we present this case because of its rarity among women in this age group and because of its connection to the individual’s genetic status and her oestrogen deficiency. urehral prolapse is defined as the complete eversion of the terminal urethra through the external urethral meatus. it is an uncommon condition usually seen in prepubertal girls and postmenopausal women. approximately 80% of cases are in the paediatric population where the incidence is 1:3000 (1). there is no reference in the literature to cases amongst women in their 30s, nor in the androgen insensitivity syndrome population. the urethra is composed of inner longitudinal and outer circular-oblique smooth muscle layers. it is a disruption in the natural cleavage plane between these two layers, which results in eversion of the urethral mucosa through the meatus. thus, although the precise cause of urethral prolapse is unknown, likely causes are congenital or acquired defects of the urethra, in particular where there is a weakened attachment between the two muscle layers. congenital defects include abnormally wide or patulous urethra, neuromuscular disorders or abnormal elastic tissue. acquired causes include trauma from childbirth, and rarely periurethral bulking agents (1). a further acquired risk factor is oestrogen deficiency: the mucosa and submucosal vascular plexus are both responsive to oestrogen, when they become atrophied the mucosal seal may be lost, predisposing to stress incontinence and urethral prolapse. oestrogen deficiency certainly seems to have played a role in our case, in light of the patient’s cais. in cais there are no visible signs of androgen action and the subjects are born with normal female external genitalia. the diagdoi: 10.4081/aiua.2014.2.140 141archivio italiano di urologia e andrologia 2014; 86, 2 a case report of urethral prolapse in a 38 year old female with 46xy karyotype nostic criteria also include male (46xy) karyotype, presence of testes, normal testosterone production, absence of mullerian duct remnants and spontaneous feminisation at puberty with no virilisation (1). in cais it is the usual practice to perform a gonadectomy due to an increased risk of testicular malignancies in these patients. in nakhal et al. retrospective evaluation of retained testes in adolescents with cais, pre-malignant foci were found in three out of 25 patients (1). after gonadectomy, oestrogen-only hormone replacement therapy is commenced to prevent menopausal symptoms and osteoporosis. the correlation of non-compliance with oestrogen therapy and presentation of urethral prolapse, suggests that oestrogen deficiency was a contributory cause. another possibility is that given 5α-dihydrotestosterone’s role in embryological development of the urogenital sinus, our patient has some subtle anatomical variation that contributed to urethral prolapse. the phenotypic variations in partial androgen insensitivity syndrome range from hypospadias in male genitalia to female genitalia with a blind-ending vaginal pouch. however there are no urological abdormalities described in the literature for cais, and if an anatomical variation in the urethra was significant, we might have expected it to cause paediatric urethral prolapse. the clinical presentation of urethral prolapse depends on the age group. in the paediatric population it is typically asymptomatic, but occasionally urinary frequency, dysuria or pain are present. postmenopausal women are usually symptomatic with vaginal bleeding, dysuria, urinary frequency and/or haematuria. on examination, urethral prolapse appears as an erythematous doughnutshaped mass protruding form the anterior vaginal wall. it may be infected, ulcerated or necrotic depending on the degree of ischaemia. confirmation that the central opening of this mass is the urethral meatus, either by observation of micturition, catheterisation or cystoscopy, is diagnostic of urethral prolapse. occasionally the diagnosis may only be confirmed on histology after excision of the mass. regarding management of urethral prolapse there are no randomised controlled trials comparing medical with surgical treatment and the majority of the experience reported in the literature is in the paediatric population. traditionally urethral prolapse was treated surgically with excision or cautery. more recently medical treatments have become more popular. rudin et al. experience with 58 cases, treated 20 medically, of which 5 had recurrence, 2 ultimately requiring surgery. in our case, the urethral mucosa was strangulated and ischaemic on presentation, necessitating surgical excision. however, if she had presented earlier topical oestrogens may well have been suitable, particularly in light of her hypo-oestrogenic state. we hope this case raises awareness of the possibility of urethral prolapse in younger women who are oestrogen deficient. it provides further incentive for compliance with hormone-replacement therapy for patients with cais following gonadectomy, or other women with premature menopause. consent the patient’s consent was acquired for publication, under the understanding that her name, initials or hospital number, would not be published and all attempts made to ensure anonymity. the patient understood that material may be published in print and/or online, but that material would not be used for advertising or out of context. the signed consent form is retained by the corresponding author. references 1. agzarian ae & agzarian ay. urethral prolapse, report of a case, proceedings of ucla healthcare 2010; vol. 14. 2. harris rl, cundiff gw, coates kw, et al. urethral prolapse after collagen injection, ajog. 1998; 178:p614-615. 3. jaaskelainen j, hughes ia. androgen insensitivity sundromes, in balen ah (ed.) paediatric and adolescent gyanecology: a multidisciplinary approach, cambridge university press, cambridge 2004, pp 253-263. 4. nakhal rs, hall-craggs m, freeman a, et al. evaluation of retained testes in adolescent girls and women with complete androgen insensitivity syndrome, radiology. 2013; 268:153-60. 5. rudin je, geldt vg, evgeny b. a prolapse of urethral mucosa in white female children: experience with 58 cases, j ped surg. 1997; 32:423-525. correspondence dr helena watson, mb bchir mrcog (corresponding author) helenawatson85@gmail.com miss ewa stasiowska, md phd mrcog university hospital lewisham, lewisham high street, se13 6lh, london, uk stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2148 case report a case with primary signet ring cell adenocarcinoma of the prostate and review of the literature orcun celik, salih budak, gokhan ekin, ilker akarken, yusuf ozlem ilbey tepecik educational and research hospital urology department, 35140, izmir, turkey primary signet cell carcinoma of the prostate is a rare histological variant of prostate malignancies. it is commonly originated from the stomach, colon, pancreas, and less commonly in the bladder. prognosis of the classical type is worse than the adenocarcinoma of the prostate. primary signet cell adenocarcinoma is diagnosed by eliminating the adenocarcinomas of other organs such as gastrointestinal tract organs. in this case report, we present a case with primary signet cell adenocarcinoma of the prostate who received docetaxel chemotherapy because of short prostate specific antigen doubling time. key words: signet cell; adenocarcinoma; prostate adenocarcinoma. submitted 28 april 2014; accepted 31 may 2014 summary introduction primary signet cell carcinoma of the prostate is a rare histological variant of the prostate malignancies. it is a subtype of the prostate adenocarcinomas, which releases mucin. it is called signet cell because the mucin released pushes the nucleus to the periphery and makes the cell looks like a signet cell. however, there are also some other types that do not release mucin (1). generally, it is originated from the stomach, colon and pancreas and less commonly from the bladder. it constitutes approximately 3-4% of the all stomach cancers (2). it is rare in the prostate and at a later stage when diagnosed (1). classical type has a worse prognosis when compared to prostatic adenocarcinoma (5). in this manuscript, we present a case with primary signet cell adenocarcinoma of the prostate that was diagnosed at a later stage, gave a poor response to the anti-hormonal treatment and had a short prostate specific antigen (psa) doubling time, therefore received chemotherapy. additionally, we reviewed the current literature in relation with our case. case report a 66-year-old man presented to an outpatient service complaining of difficulty in urination. at rectal examinano conflict of interest declared tion, his prostate was found to be hard in texture. apart from chronic obstructive pulmonary disease (copd) and diabetes mellitus (dm) he had no prior disease history. a transrectal ultrasound-guided 10-quadrant fine needle biopsy of the prostate was performed as his psa level was above 100 ng/dl. we detected the classical type of the prostate adenocarcinoma with gleason score of 4 + 5 in all of the 10 quadrants and planned a whole body bone scintigraphy to grade the carcinoma. there were multiple bone metastases. abdominal computerized tomography showed bilateral hydronephrosis, enlarged para-aortic and para-iliac lymph nodes. therewith, the patient with a urinary catheter was referred to our center, which is a tertiary clinic. his psa level was above 6658 ng/dl and his bone scintigraphy indicated a very dense metastasis in the vertebra. thus, we planned leuprolide acetate monotherapy and palliative radiotherapy to prevent bone fractures. we performed transurethral prostate resection as he had the catheter and detected poorly differentiated signet cell adenocarcinoma with a gleason score of 5 + 5. because of the diagnosis of the signet cell adenocarcinoma, we explored for a primary adenocarcinoma locus but we did not detect any other malignity. following a 3-month hormonotherapy, his psa level was 441 ng/dl. however, it increased again and we planned antiandrogen treatment. following leuprolide acetate and antiandrogen treatment, at the end of the ninth month, his psa level was 84.4 ng/dl and testosterone level was < 20 ng/ml. subsequently, his psa level increased again and three months later was 271 ng/dl. we considered the case as castration resistant and we graded it again. docetaxel on day one of a 3-week cycle with a dose of 75 mg/m2 was administered with a 3-week cycle. after the 12th cycle, his symptoms decreased, although his psa level remained between 200 and 281 ng/dl. he developed urosepsis during the chemotherapy and received antibiotic therapy. however, he died of urosepsis after 22 months. discussion primary signet cell adenocarcinoma of the prostate was described first in 1979. since then, there are only 69 cases reported and mean duration of survival in those reported cases was 28 months (3, 4). mean age of these doi: 10.4081/aiua.2014.2.148 149archivio italiano di urologia e andrologia 2014; 86, 2 a rare pathology type of prostate cancer cases was 68.2 years (1). the tumor can present with voiding problems as in the classical presentation of the prostate cancer. however, it can present with symptoms related to metastasis. our case presented with urination problems. in total, 42% of the cases in the literature are at stage t4 and this indicates the aggressive nature of the signet cell adenocarcinoma of the prostate (1, 2). the name signet cell was given because of the appearance of the cell as large vacuoles push the cell nucleus to the periphery (1). it is generally originated from colon, pancreas and breast. prostate as a primary location of signet cell adenocarcinoma is rare. some similar conditions should be considered and eliminated before diagnosing a primary signet cell adenocarcinoma. such conditions include prostate lymphoma in which the prostate is infiltrated by lymphocytes and has aspects of the muscle cells as after radiotherapy and antihormonal therapy (1, 2). we diagnosed our case after leuprolide acetate treatment. thus, we considered that the condition might be related to antihormonal therapy. however, we eliminated this diagnosis using immunohistochemical staining. negative results of leucocyte common antigen (lca), alpha-smooth muscle actin (asma), cytokeratin-7 and 20 and positive psa results favor the diagnosis (3-6). carcinoembryonic antigen (cea) was positive in 20% of the cases in the literature (10) whereas psa and prostate specific acid phosphatase (psap) were positive in 87% of the cases (10). additionally, in the literature, positive staining with periodic acid-schiff stain (pas) was positive in 60%, with alcian blue 60% and with mucicarmin 50% (11). some authors suggested that signet cells should be present in more than 20% of the tumor tissue (10, 11). in the current case, psa, pas, psap, alcain blue were positive. on the other hand, lca, asma, cea and cytokeratin 7 and 20 were negative. diagnosing the primary signet cell adenocarcinoma of the prostate is difficult because it is problematic to exclude the possibility of the metastases of other organs to the prostate. presence of a tumor in the gastrointestinal tract should be explored with radiologic and endoscopic methods (3). in our case, we screened the gastrointestinal tract with colorectal and gastro esophageal endoscopy and did not find any locus. primary signet cell adenocarcinoma of the prostate is more aggressive with less treatment response and poor prognosis when compared to the classical type of the prostate adenocarcinoma. three-year survival is 55% and 5-year survival is 12%. in previous publications poor response to antihormonal therapy was reported (7, 9). in our case, treatment response to antihormonal therapy was good for a short period of time, but later tumor became castration resistant. roldan et al., had almost full response with oxaliplatin, 5-fu, and leucovorin (folfox) combination which are used for colorectal cancer (8). studies indicate that prognosis is related to the grade of the tumor when diagnosed (8). conclusions primary signet cell carcinoma of the prostate is a rare histological variant of prostate adenocarcinomas. gastrointestinal tract should be screened for other tumor loci and this possibility should be eliminated for diagnosing cases with primary signet cell adenocarcinoma of the prostate. in contrast to the other signet cell carcinomas, treatment of the primary signet cell adenocarcinoma of the prostate is the same with the classical adenocarcinoma. prognosis of this carcinoma is bad as it is a rare and aggressive tumor and diagnosis is generally made at an advanced stage of the disease. references 1. fujita k, sugao h, gotoh t, et al. primary signet ring cell carcinoma of the prostate: report and review of 42 cases. int j urol. 2004; 11:178-81. 2. kwon w, oh th, ahn sh, et al. primary signet ring cell carcinoma of the prostate. can urol assoc j. 2013; 7:768-71. 3. skodras g, wang j, kragel pj. primary prostatic signet-ring cell carcinoma. urology. 1993; 42:338-42. 4. smith c, feddersen rm, dressler l, et al. signet ring cell adenocarcinoma of prostate. urology. 1994; 43:397-400. 5. kuroda n1, yamasaki i, nakayama h, et al. prostatic signet-ring cell carcinoma: case report and literature review. pathol int. 1999; 49:457-61. 6. guerin d, hasan n, keen ce. signet ring cell differentiation in adenocarcinoma of the prostate: study of five cases. histopathology. 1993; 22:367-71. 7. akagashi k, tanda h, kato s, et al. signet-ring cell carcinoma of the prostate effectively treated with maximal androgen blockade. int j urol. 2003; 10:456-8. 8. roldán am, núñez nf, grande e, et al. primary signet ring cell carcinoma of the prostate with bone metastasis with ımpressive response to folfox and cetuximab. clin gen cancer. 2012; 10:199-201. 9. lilleby w, axcrona k, alfsen gc, et al. diagnosis and treatment of primary signet-ring cell carcinoma of the prostate. acta oncol. 2007; 46:1195-7. 10. randolph tl, amin mb, ro jy, et al. histologic variants of adenocarcinoma and other carcinomas of prostate: pathologic criteria and clinical significance. mod pathol. 1997; 10:612-29. 11. torbenson m, dhir r, nangia a, et al. prostatic carcinoma with signet ring cells: a clinicopathologic and immunohistochemical analysis of 12 cases, with review of the literature. mod pathol. 1998; 11:552-9. correspondence orcun celik, md (corresponding author) orcuncelik82@hotmail.com salih budak,, md gokhan ekin, md ilker akarken, md yusuf ozlem ilbey, md associate professor endourology section urology department, tepecik educational and research hospital gaziler cd.no:468, yenisehir 35140, izmir, turkey stesura seveso 207archivio italiano di urologia e andrologia 2013; 85, 4 introduction neoplastic invasion of the inferior vena cava occurs in 515% of the patients with renal cancer (1). in these cases, curative resection might be possible with reasonablelong-term survival. various surgical techniques have been described for these tumors (2, 3). because of the complexity of achieving vascular control, surgical treatment in deep hypothermic circulatory arrest using cardiopulmonary bypass has been established as an interdisciplinary concept (3-6). we report the case of a patient affected by severe double coronary artery disease and voluminous renal cell carcinoma with extended intravascular growth into the inferior vena cava. case report in a 75-year-old man (180 cm, 75 kg) a computed tomography (ct) scan demonstrated a malignant tumor (85x64x88 mm) of the right kidney with continuous growth of a tumor cone into the subdiaphragmal vena cava (figure 1). case report simultaneous management of renal carcinoma with caval vein thrombosis and double coronary artery disease marco grasso 1, salvatore blanco 1, francesco formica 2, giovanni paolini 2, angelica anna chiara grasso 3 1 urology department, san gerardo hospital, university of milano-bicocca; 2 cardiac surgery clinic department of surgical science and translational interdisciplinary medicine university of milano-bicocca; 3 urology department, fondazione irccs ca’ granda ospedale maggiore policlinico, university of milan, italy. introduction: recent advances in surgical and anesthesiology techniques allow simultaneous thoracic and abdominal operations to be performed for severe heart disease and benignant or malignant abdominal diseases. case report: the simultaneous surgical management in a 75-year-old patient suffering from severe double coronary artery disease and a renal cell carcinoma with extended intravascular growth into the inferior vena cava is reported. conclusion: the postoperative course was uneventful. simultaneous surgery proved to be beneficial and safe, showing optimal results in our patient. key words: kidney tumor; coronary heart disease; caval thrombus; hypothermic circulatory arrest. submitted 3 july 2013; accepted 31 july 2013 no conflict of interest declared summary figure 1. right kidney mass with continuous growth into the subdiaphragmal vena cava. doi: 10.4081/aiua.2013.4.207 archivio italiano di urologia e andrologia 2013; 85, 4 m. grasso, s. blanco, f. formica, g. paolini, angelica a.c. grasso 208 the reported symptoms were microhematuria, cough and evening fever. the ecg demonstrated signs of a small previous lateral infarction. coronary angiography and ventriculography revealed a severe double-vessel coronary artery disease and a concentric remodeling hypertrophy of the left ventricular with normal ejection fraction (0.63). the operation was conducted with an interdisciplinary approach by urologists and cardiothoracic surgeons. in the first step of the operation, urologists performed the radical right nephrectomy through a median laparotomy. in the second step a median sternotomy was performed. the left internal mammary artery (lima) and a segment of saphenous vein were harvested. systemic heparinization was established by administering 300 iu/kg with an activated clotting time target > 480 seconds. cardiopulmonary bypass (cpb) was initiated by ascending aorta cannulation with a 22 f arterial cannula and by a right atrial appendage cannulation with a 52 f venous cannula. cpb was started and the patient’s body was cooled up to 20°c of esophageal temperature. during body cooling, coronary artery bypass grafts were performed on beating heart. vein graft was distally anastomosed on the obtuse marginal branch with a running 7-0 monofilament polypropylene suture. the proximal site of the vein graft was anastomosed on the ascending aorta by the heartstring device (maquet, hirrlingen, germany) with a running 6-0 monofilament polypropylene suture without clamping the ascending aorta. finally, the lima was distally anastomosed on the left anterior descending artery with a running 8-0 monofilament polypropylene suture. the heart initiated to fibrillate at 27°c degree and the left ventricle was vented trough a 18 f catheter inserted into the left ventricle through the right upper pulmonary vein. hypothermic circulatory arrest (hca) was established when the body reached a 20°c of esophageal temperature and it was maintained while tumor-thrombus was being removed from the abdominal inferior vena cava (ivc). abdominal ivc was open through a 5 cm longitudinal incision. complete tumor-thrombus resection was performed under direct vision by advancing a foley catheter and by forceps. direct vision, several index finger maneuvers and the use of intraoperative transesophageal echocardiography confirmed the complete tumor resection. the opening of right atrium was not necessary. cavotomy was closed with a running 4-0 monofilament polypropylene suture without narrowing the lumen. cpb was restarted after 32 minutes of hca and the body was progressively heated until 36°c of esophageal temperature. then the cpb was rapidly weaned off and heparin was antagonized with sulphate protamine. after closure of the thorax and the abdomen the patient was transferred to the post-operative intensive care unit. perioperatively the patient received 6 units of red blood cells, 3 units of fresh frozen plasma and 1 unit of platelets. extubation was achieved 12 hours postoperatively. anticoagulation using only intravenous heparin was applied for 7 days. the patient was transferred to the normal ward on the second post-operative day. the postoperative course in the ward was uneventful and the patient was transferred to the rehabilitation clinic on the 30th postoperative day. discussion the number of patients who have both critical coronary artery disease (cad) and surgically resectable cancer concomitantly has been raising as the proportion of elderly in the general population increases, therefore new figure 2. cavotomy. figure 3. intraoperative endoesophageal ultrasound, showing the caval thrombus. 209archivio italiano di urologia e andrologia 2013; 85, 4 simultaneous management of renal carcinoma with caval vein thrombosis and double coronary artery disease routes have been attempted to deal with concomitant life-threatening pathologies (7). tumors invading the juxtahepatic caval vein require an interdisciplinary therapeutic approach and hypothermic circulatory arrest. recent advances in surgical and anesthesiology techniques allow simultaneous thoracic and abdominal operations. despite the aggressiveness and biological invasiveness of the tumor and the intervention performed in deep hypothermia and circulatory arrest, the results are encouraging (8). westaby documented the increased operative risk for non-cardiac procedures performed on individuals with major coronary artery disease (9), but postponing the tumor resection might increase the risk of exposure to the immunosuppressive effects of cardio-pulmonary bypass, which can have a harmful effect on tumor growth and spreading (10-11). furthermore the doubling of costs which can be avoided has to be considered. conclusion to our knowledge only few similar cases were reported in literature,franke reports a case in which the bypass was performed during cardioplegia in the heating phase (12), whereas in our patient the bypass was performed on the beating heart during the cooling phase. in high surgical experience centers, a multidisciplinary approach can ensure a safe and optimal treatment. references 1. langenburg se, blackbourne lh, sperling jw, et al. management of renal tumors involving the inferior vena cava. j vast surg. 1994; 20:385-8. 2. welz a, schmeller n, schmitz c, et al. resection of hypernephromas with vena caval or right atrial tumor extension using extracorporeal circulation and deep hypothermic circulatory arrest: a multidisciplinary approach. eur j cardio-thorac surg. 1997; 12:127-132. 3. baumgartner f, milliken j, scudamore c, et al. extracorporeal methods of vascular control for difficult ivc procedures. am surg. 1996; 62:246-248. 4. glazer aa, novick ac. long-term followup after surgical treatment for renal cell carcinoma extending into the right atrium. j urol. 1996; 155:448-450. 5. laas j, schmid c, allhoff e, borst hg. tumor-related obstruction of the inferior vena cava extending into the right heart – a plea for surgery in deep hypothermic circulatory arrest. eur j cardio-thorac surg. 1991; 5:653-656. 6. wickey gs, martin de, larach dr, et al. combined carotid endarterectomy, coronary revascularization, and hypernephroma excision with hypothermic circulatory arrest. anesth analg. 1988; 67:473-476. 7. takahashi t, nakano s, shimazaki y, et al. concomitant coronary bypass grafting and curative surgery for cancer. surg today. 1995, 25:131-135. 8. navia jl, brozzi na, nowicki er, et al. simplified perfusion strategy for removing retroperitoneal tumors with extensive cavoatrial involvement. j thorac cardiovasc surg. 2012; 143:1014-21. 9. westaby s. complement and the damaging effects of cardiopulmonary bypass. thorax. 1983; 38:321-325. 10. hill ge, whitten cw, landers df. the influence of cardiopulmonary bypass on cytokines and cell-cell communication. j cardiothorac vasc anesth. 1997; 11:367-375. 11. darwazah ak, osman m, sharabati b. use of off-pump coronary artery bypass surgery among patients with malignant disease. j card surg. 2010; 25:1-4. 12. franke uf, wahlers t, wittwer t, schubert j. renal carcinoma with caval vein infiltration and triple coronary disease: one-stage surgical management. eur j cardiothorac surg. 2001; 20:877-9. correspondence marco grasso, md (corresponding author) urology department grasso.m@virgilio.it salvatore blanco, md urology department sblanco_74@yahoo.it francesco formica, md cardiac surgery clinic department of surgical science and translational interdisciplinary medicine f.formica@hsgerardo.org giovanni paolini, md cardiac surgery clinic department of surgical science and translational interdisciplinary medicine g.paolini@hsgerardo.org azienda ospedaliera san gerardo via pergolesi 33 20900 monza, italy angelica anna chiara grasso, md urology department angelicagrasso84@gmail.com fondazione irccs ca’ granda ospedale maggiore policlinico, via della commenda 15, 20100 milano, italy stesura seveso 161archivio italiano di urologia e andrologia 2014; 86, 3 original paper penile prosthesis surgery in out-patient setting: effectiveness and costs in the “spending review” era nicola mondaini 1, enrico sarti 1, gianluca giubilei 2, andrea gavazzi 3, antonio costanzi 1, arben belba 3, tommaso cai 4, riccardo bartoletti 1 1 urology unit, santa maria annunziata hospital (iot), florence, italy; 2 urology unit, leonardo da vinci hospital, empoli, italy; 3 urology unit, cfo oncology center florence, italy; 4 department of urology, santa chiara regional hospital, trento, italy. introduction: penile implant patients are required to remain in the hospital after the operation for monitoring, antibiotic and analgesia administration. cost containment, however, has resulted in the increased use of ambulatory surgery settings for many surgical procedures. few studies have studied the feasibility of performing penile prosthesis insertion in an outpatient setting. the results are controversial and nowadays, in the most of centers that deal with prosthetic surgery, patients are still hospitalized. aim: the aim of our investigation was to compare the feasibility of the performance as well as the complication profiles of penile implant surgery performed in an in-patient and an outpatient setting at a single center by a single surgeon. methods: from january 2009 to june 2014, 50 patients of the same uro-andrological unit underwent penile prosthesis implantation performed by a single surgeon (n.m.). twenty implantations were performed in an ambulatory day surgery setting. main outcome measures: effectiveness and costs of outpatient setting versus the in-patient setting of the penile prosthesis surgery. results: there were some differences between the two groups in the intra-operative parameters, such as, operating time. time lost from work was similar in both groups approximating 14 days. the mean number of analgesic pills ingested by the patients post-operatively was similar in both groups, averaging just under 25 pills per patient. there weren’t post-operative complications in the outpatient group. cost were 17% less in outpatient clinic. conclusions: the outpatient setting for this surgery is safe and effective even in patients with comorbidities or in case of secondary procedures. costs are reduced by 17%. key words: penile prosthesis; out-patient; erectile dysfunction; costs; spending review. submitted 15 july 2014; accepted 31 july 2014 summary no conflict of interest declared. introduction inflatable penile prosthesis often represent the last or the only chance to get back to a normal life for patients with erectile dysfunction, reporting 70-87% satisfaction rates (1). prosthesis can be either malleable or inflatable; the second one are preferred by most of patients but are much more expensive. at the moment, penile implant patients are required to remain in the hospital following the operation for monitoring, antibiotic and analgesia administration. cost containment however, has resulted in the increased use of ambulatory surgery settings for many surgical procedures (2). few studies have studied the feasibility of performing penile prosthesis insertion in an ambulatory setting (table 1) (3-6). the results are controversial and nowadays, in the most of centers that deal with prosthetic surgery, patients are still hospitalized. the aim of our investigation was to compare the feasibility of performance as well as the complication profiles of penile implant surgery performed in an inpatient and an outpatient setting at a single center by a single surgeon. materials and methods from january 2009 to june 2014, 50 patients of the same uro-andrological unit underwent penile prosthesis implantation performed by a single surgeon (n.m.). the first 30 were operated in an inpatient setting; the other 20 implantations were performed in an ambulatory day surgery setting. the day of the operation, all patients had intravenous antibiotics administrated: the inpatient group had teicoplanin 200 mg and imipenem/cilastatin 500 mg x 3, while the out-patient group had amoxicillin/clavulanic acid 1 gr and gentamicin 80 mg x 2. all procedures were performed through a transverse scrotal incision. the twopiece implant used was the ambicor1 device (ams, minneapolis, usa), while the three-piece implant used was the cx 700 device (ams minneapolis, usa). the indications for insertion of a two-piece rather than a three-piece device included a history of radical cystectomy, bilateral inguinal hernia surgery and patient choice. in both groups doi: 10.4081/aiua.2014.3.161 mondaini_stesura seveso 08/10/14 11:42 pagina 161 archivio italiano di urologia e andrologia 2014; 86, 3 n. mondaini, e. sarti, g. giubilei, a. gavazzi, a. costanzi, a. belba, t. cai, r. bartoletti 162 the foley catheter, which was placed intra-operatively, was removed the day after and a large scrotal compression dressing was placed (a scrotal support filled with fluffed gauze dressings) with also a large amount of ice, which was prescribed for the first 24 hours. the patients of the inpatient group where discharged after 1-3 days; while the patients of the outpatient group were discharged 3 hours after operation, on treatment with amoxicillin/clavulanic acid (1 gr po twice daily for 10 days), gentamicin (80 mg im twice daily for 10 days) and oral analgesics (paracetamol/codeine 1 pill every 4-6 hours). the patients treated in ambulatory setting were seen the day after and at 1-4 and 8 weeks post-operatively. at the 4-week follow up visit, the patients were asked to count all analgesic pills taken, as well as the date of their return to work. on this date, they were also counseled regarding the proper utilization of their penile implant. indeed, they were instructed to inflate and deflate the device daily for the next month. costs were calculated using the actual price of antibiotics, hospital stay and penile prosthesis in our country. statistical analysis between the groups was conducted using a student’s ttest (excel, microsoft corp., usa). results there were not any demographic statistical differences in patient age, co-morbidity profile between the two groups of patients (table 2). follow-up was longer in the inpatient group. there were some differences between the two groups in the intra-operative parameters, such as, operating time (table 3). time lost from work was similar in both groups, approximating 14 days. the mean number of analgesic pills ingested by the patients post-operatively was similar in both groups, averaging just under 25 pills per patient (table 3). there weren’t post-operative complications in the outpatient group (table 3). cost were 17% less in outpatient setting (table 4). author year out-patient age prosthesis complications anesthesia two-piece ipp three-piece ipp mondaini n. 2014 n = 20 64,2 (53-74) 10 ams ambicor 10 ams 700 cx 0 spinal hsu gl. 2004 n = 10 67.4 ± 9.9 7 ams ambicor 3 ams 700 cx na crural nerve block 278 mg 0,8% lidocaine sol. and adrenaline mulhall j. 2001 n = 46 64 ± 10 9 ams ambicor 37 mentor alpha-1 2 (4,3%) spinal/general (laringeal mask) + 0,5% plain bupivacaine infiltrated in the scrotal incision garber bb. 1997 n = 95 57 0 94 mentor alpha-1/ams 700 6 (6,3%) general lubensky jd. 1991 n = 74 42-79 0 74 ams 700 (100%) 2 (2,7%) spinal/general table 1. out-patient setting for penile prosthesis implantation in literature. in-patient out-patient (n = 30) (n = 20) age (y) 63,3 (22-78) 64,2 (53-74) follow-up (months) 56,5 (36-77) 12,1 (1-24) two-piece device 5 (16,6%) 10 (50%) three-piece device 25 (83,3%) 10 (50%) secondary procedures 5 (16,6%) 2 (10%) in-patient out-patient (n = 30) (n = 20) intra-operative blood loss (mls) 100 80 or time (min) two-piece device 80 55 three-piece device 120 90 time lost from work (days) 14 13 narcotic use (pills) 25 26 overall complications 2 (6,6%) 0 device infection 1 (3,3%) 0 table 2. patient demographics. in-patient out-patient (1-3) days 1 day hospital stay ! 800 x 3 = 2400 ! 800 intravenous antibiotics (targosid) 41,61 x 3 = 124,83 ! 3,75 (tenacid) ! 23,97 x 9 = 215,73 (gentalyn) ! 2,30 x 2 = 4,60 cost ! 2.740,56 ! 808,35 total cost ! 11.240 ! 9.308,35 * cost are reduced by 17%. table 4. cost difference between in-patient and out-patient settings for three-piece-device. table 3. operative and post-operative data. mondaini_stesura seveso 08/10/14 11:42 pagina 162 discussion when available, outpatient surgery is well tolerated and often preferred by patients and in the past decade various studies were conducted about cost containment and safety of the management in outpatient setting in an increasing number of different surgery procedures (711). nowdays, in italy, the total cost for an implantation of an inflatable prosthesis is about ! 9000-15000, depending on conventions between hospitals and the local administrations. the cost includes pre-operative examinations, imaging, prosthesis, surgeon, anesthesiologist, hospital stay and medications. for this reason, living in a period of spending review involving all the western countries, the cost of this surgery restricted to 500 the total operations made annually in italy. our data demonstrate that in terms of safety and effectiveness the ambulatory setting is absolutely similar to the inpatient setting, reducing days of hospitalization (1-3) and using less expensive antibiotics (table 4). this results in an overall saving of 17%. previous studies (9-13) about the feasibility of implantation of inflatable penile prosthesis in ambulatory settings showed complications rate of 1.86%. to our knowledge only mulhall (9) in 2001 compared performance and complications of inpatient and outpatients groups with penile prosthesis insertion. overall complication rates were 6% for the inpatient group and 4% for the outpatient group, infection rate was 3% for the first group and 2% for the second. our data confirm mulhall study strengthening it, as our outpatient complications and infection rates are 0%. the main study limitation is the small sample size, but emphasizes that surgeon’s experience and a tight followup are essential in order to perform this procedure in an ambulatory setting, discharging the patient a few hours after surgery. it’s also important underline that complications rate are now lower thanks to the evolution of prosthetic materials (12), which today are covered by antibiotic substances and discharging the patient with catheter and prosthesis inflated reduce the risk of postoperative hematoma, which often leads to infection. about the post-operative use of analgesics our data are similar to the literature. conclusion the outpatient setting for this surgery is safe and effective even in patients with comorbidities or in case of secondary procedures. costs are reduced by 17%. acknowledgments we thank the team of anesthesia of the day service iot hospital, florence: antonella orvieto, anna mancini, elena gandini, eleonora gentili, eleni kastamoniti, anna cian ciullo, vanna viviani. references 1. parsons kf, fall m, irani j, llorente c. guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. [internet]. european urology. 2013. available from: http://www.uroweb.org/guidelines/online-guidelines/ 2. hollingsworth jm1, saigal cs, lai jc, et al. medicare payments for outpatient urological surgery by location of care. j urol. 2012; 188:2323-7. 3. hsu g-l, hsieh c-h, wen h-s, et al. outpatient penile implantation with the patient under a novel method of crural block. int j androl. 2004; 27:147–51. 4. mulhall jp, bloom k. comparison of in-patient and out-patient penile prosthesis surgery. int j impot res. 2001; 13:251-4. 5. garber bb. outpatient inflatable penile prosthesis insertion. urology. 1997; 49:600-3. 6. lubensky jd. outpatient inflatable penile prosthesis. j urol. 1991; 145:1176-7. 7. krummenauer f, günther k-p, witzlebf w-c. the incremental cost effectiveness of in-patient versus out-patient rehabilitation after total hip arthroplasty results of a pilot investigation. eur j med res. 2008; 13:267-74. 8. pineault r, contandriopoulos ap, valois m, et al. randomized clinical trial of one-day surgery. patient satisfaction, clinical outcomes, and costs. med care. 1985; 23:171-82. 9. morgan m, beech r. variations in lengths of stay and rates of day case surgery: implications for the efficiency of surgical management. j epidemiol community health. 1990; 44:90-105. 10. roos np. what is the potential for moving adult surgery to the ambulatory setting? cmaj. 1988; 138:809-16. 11. weale a r. randomized clinical trial of the effectiveness of emergency day surgery against standard inpatient treatment (br j surg. 2002; 89:423-7). brit j surg 2002; 89:1323. 12. muench pj. infections versus penile implants: the war on bugs. j urol. 2013; 189:1631-7. 163archivio italiano di urologia e andrologia 2014; 86, 3 penile prosthesis surgery in out-patient setting: effectiveness and costs in the “spending review” era correspondence nicola mondaini, md info@nicolamondaini.it enrico sarti, md antonio costanzi, md riccardo bartoletti, md urology unit, santa maria annunziata hospital (iot), florence, italy gianluca giubilei, md urology unit, leonardo da vinci hospital, empoli, italy andrea gavazzi, md arben belba, md urology unit, cfo oncology center florencen, italy tommaso cai, md department of urology, santa chiara regional hospital, trento, italy mondaini_stesura seveso 08/10/14 11:42 pagina 163 stesura seveso 135archivio italiano di urologia e andrologia 2014; 86, 2 note on surgical technique pseudo-capsule “coffin effect”: how to prevent penile retraction after implant of three-piece inflatable prosthesis enrico caraceni 1, lilia utizi 2, giovanni angelozzi 3 department of urology, civitanova marche hospital, italy. objective: following three-component implantation of a penile prosthesis, some patients are dissatisfied with their penile length. this may be due to the procedure by itself or pre-existing risk factors or psychological reasons. we supposed that formation of a restricted pseudo-capsule due to a late prosthesis activation can inhibit later system expansion. we aimed to identify the presence or absence of penile retraction after implant and to prevent it by immediate prosthesis activation after implantation. material and methods. forty-six patients operated with three-piece inflatable penile prosthesis (ams 700 cx o lgx) were enrolled. in 27 patients prosthesis was first activated four weeks after surgery (nea group) and in 19 patients prosthesis was activated immediately after surgery (dea group). length and girth of the penis was evaluated before (in dea group) and after the surgical procedure. results. the average post implant dorsal length of the erect penis in group nea was found 3.28 cm shorter than in group with early activation (dea). in dea group there was no lenght difference between pre-operative stretching (14.57 cm) and post operative erection (14.98 cm). when early activation was not performed, the clinical result was a smaller penis in erect phase. conclusion. reduced lenght of the penis after implantation can be caused by the presence of a pseudo-capsule that limits the elongation of the prosthesis and of the penis (“coffin effect”). timing of first activation seems to be the key in order to prevent the risk of penile retraction after implantation. early activation is identified as the best measure to maintain the length of the pre implant erect penis after the prosthetic hydraulic implant. key words: penile prosthesis length; penile retraction; early activation; lgx penile prosthesis; ams 700 cx penile prosthesis; coffin effect, three piece penile prosthesis; size of the penis; shortening of the penis. submitted 23 december 2013; accepted 29 march 2014 summary no conflict of interest declared pointment can be severe and in some cases can lead to loss of use of the prosthesis even when it is working well. first montorsi et al. in 2000 (4) reported that about 30% of patients complained a decrease in penile size after three-piece prosthesis implantation. the authors explained the finding as follows: this dissatisfaction is linked with the loss of engorgement of the glans or to the recall of the natural preexisting erection, or to the pre-operatory penis size loss. deveci et al. in 2007 (5) wrote there were no statistically significant differences in penile length after the surgery compared to preoperative measurements in a group of 56 patients affected of erectyle dysfunction (ed) of various nature, excluding peyronie’s disease. patients had the penile length measured at the beginning of the operation prior to device implantation (stretched flaccid length), and at 1 and 6 months postoperatively (dorsal length with activated prosthesis). length was measured from the pubic bone to meatus along the dorsum of the shaft. they did not find significative difference in preoperative stretched penis and postoperative penile length with the activated device. in their experience about two of three patients (72%) surprisingly complained decreased in penile length. they explained that this feeling might be related to a comparison with their penile length before the onset of ed, or to pre-implant penile length reduction related to radical prostatectomy or other penile fibrotics changes. they concluded that patient and partner education from the beginning may limit unrealistic expectations after implantation. patient should be advised that penile implants may not restore the full length once achieved by natural erections. treatment satisfaction appears not to be fully dependent on subjective penile length and then the failure in sizing (told by 72% of their patients) is not real but subjective. montague (6) in 2007 published a review of literature on the penis size matter after penile implants. he recognized that it is likely that inflatable penile prosthesis implantation does not provide a prosthetic erection quite as long as a natural erection. he believed that the loss of penile sizing could be attributed to the fact that prosthetic erection does not include glans tumescence or to penile retraction due to preoperatory factors, like radical prostatectomy. however, he concluded it is necessary to speak to the patient telling him: “your preoperative doi: 10.4081/aiua.2014.2.135 introduction following implants of a penile prosthesis some couples are dissatisfied with penile length and girth (1-3). this may be one reason for implant dissatisfaction: disaparchivio italiano di urologia e andrologia 2014; 86, 2 e. caraceni, l. utizi, g. angelozzi 136 stretched penile length will approximately be like your erect length after prosthetic surgery”. shaeer et al. (7) in a recent paper published in sexual medicine in 2010 about his surgical technique to improve penile size after inflatable prosthesis implantation, classified the possible causes of the loss of penis size after implantation. they wrote “decrease in size may sometimes be a mental impression due to unrealistic expectations, poor counseling, or dysmorphophobia”. alternatively, diminished phallic size may be real and due to the inherent nature of the procedure or to a preexisting pathology. the latter includes cases of fibrosis following radiotherapy, neglected priapism, and peyronie’s disease, all of which exhibit shortening and/or narrowing, or cases with overhanging suprapubic fat leading to concealment. in such cases, diminished size is not a result of the procedure itself, but rather due to an ignored preexisting complaint of undersized phallus, shadowed by erectile dysfunction (ed), a complaint that the physician failed to recognize and address. on the other hand, actual diminution in size may be iatrogenic, caused by the procedure itself. shaeer and al recognized that there is a real loss of penis size after implantation techniques and proposes expansion to correct the defect and improve patient and partner’s satisfaction. however, he lacked the demonstration of his statements about the real loss in size after installation. his work is only about the surgical technique to supersize the penis following penile prosthesis implantation. levine and rybak in 2011 (8) concluded that there is not recognised reliable technique to gain length once the device is placed and proposed the use of external traction therapy prior to inflatable penile prosthesis placement to solve the problem. moskovic (9) obtained the same results in a case treated using the same method of levine. finally, other authors proposed preoperatory vacuum device treatment (10, 11). we believe the loss of length and girth of the penis after prosthetic hydraulic implant is a multi-factorial phenomenon: preexisting factors like obesity, penile fibrosis (post priapism or post induratio penis plastica), pelvic surgery (radical prostatectomy, cystectomy or abdominal amputation of the rectus) can reduce “per se” penile size (12, 13), but in addition to these factors pseudo-capsule formation could play an important role in reducing the penis after implant. in fact in case of late activation of the prosthetic device a pseudo-capsule can form around the deactivated empty implant that is smaller in size with respect to the fully activated implant. when the prosthesis is activated after three or four weeks, as recommended by the manufacturers (14, 15), it cannot expand further due to the resistance of pseudo-capsule, which is so far fully formed. in other words the pseudo-capsule prevents the full prosthesis expansion, thus determining a reduction of the true size of the penis working like an inextensible wall. we have called this phenomenon “coffin effect” of pseudo capsule. the “coffin effect” should be added to other predisposing factors of penile size reduction and it is always present. if the prosthesis is not left inflated immediately after the surgery and for subsequent two or three weeks the result will be a smaller penis with similar dimensions to the non activated prosthesis. aim of this study was to identify the presence or absence of penile retraction after implant with three-component prosthesis and to evaluate the possibility to prevent it by immediate activation of the prosthesis after the surgical procedure without use of other device or other surgical strategies before or after the operation (16-19). conclusions according to our observations we confirmed the occurrence of a “true” penile shortening after prosthetic implant (11.70 cm in the nea group). this can be caused by the formation of a pseudo capsule, that develops around the non activated implant that acts as a “wall” that subsequently prevents the prostesis expansion and the potential elongation of the penis after implantation. the pseudo capsule limits the dimension of the penis and the prosthesis can only move like a “sliding door” inside it forward during activation and backward when it is deactivated. the result is a larger penis in flaccid state but smaller in erect phase expecially when early activation was not performed. the implant can work like an expander, if well used, but the size of the penis is limited by the pseudocapsule. this “coffin effect” explains the retraction and the lower elasticity of the penis that can occur after implantation as a consequence of the formation of the pseudo capsule. the decreased elastic capacity of the penis after penile prosthesis implantation involves a lower difference between penile length in flaccid and erect state and larger length and girth of the flaccid penis. this is confirmed by the observation that early activation as an effective measure to prevent penile shortening after implantation. lgx implant can improve the length (15.35 in dea group versus 11.90 in nea group) and girth (12.43 in dea group versus 11.90 in nea group) of the penis only if early activated. in conclusions early activation is a measure to prevent the loss of length of the erect penis after implantation. materials and methods, results, tables and discussion are fully described in supple mentary materials posted on www.aiua.it length preoperative girth preoperative (available with fic in 12 patients, with str. in 14 patients) group δ δ1 ici str 2.61 3.23 dea (lgx and cx) 2.75 length postoperative girth postoperative group �δ �δ1 nea (lgx and cx) 1.55 1.02 dea (lgx and cx) 1.65 1.69 table. penile elasticity (δ and δ 1). references 1. candela jv, hellstrom wj. three-piece inflatable penile prosthesis implantation: a comparison of the penoscrotal and infrapubic surgical approaches. j la state med soc. 1996; 148:296-301. 2. bernal rm, henry gd. contemporary patient satisfaction rates for three-piece inflatable penile prostheses. adv urol. 2012; 2012:707321. 3. trost lw, baum n, hellstrom wj. managing the difficult penile prosthesis patient. j sex med. 2013; 10:893-906. 4. montorsi f, rigatti p, carmignani g, et al. ams three-piece inflatable implants for erectile dysfunction: a long-term multi-institutional study in 200 consecutive patients. eur urol. 2000; 37:50-55. 5. deveci s, martin d, parker m, mulhall jp. penile length alterations following penile prosthesis surgery. eur urol. 2007; 51:1128. 6. montague dk. penile prosthesis implantation: size matters. europ urol. 2007; 51:887-888. 7. shaeer o. supersizing the penis following penile prosthesis implantation. j sex med. 2010; 7:2608-16. 8. levine la, rybak j. traction therapy for men with shortened penis prior to penile prosthesis implantation: a pilot study. j sex med. 2011; 2112-7. 9. moskovic dj, pastuszak aw, lipshultz l, khera m. revision of penile prosthesis surgery after use of the penile traction therapy to increase erect penile length: case report and review of the literature. j sex med. 2011; 8:607-11. 10. raheem aa, garaffa g, raheem ta, et al. the role of vacuum pump therapy to mechanically straighten the penis in peyronie's disease. bju int. 2010; 106:1178-80. 11. soderdahl dw, petroski ra, mode d, et al. the use of an external vacuum device to augment a penile prosthesis. tech urol. 1997; 3:100-2. 12. montague dk, angermeier kw. increasing size with penile implants. curr urol rep. 2008; 9:483-486. 13. sansalone s, garaffa g, djinovic r, et al. simultaneous total corporal reconstruction and implantation of a penile prosthesis in patients with erectile dysfunction and severe fibrosis of the corpora cavernosa. j sex med. 2012; 9:1937-44. 14. american medical system (ams). available at the website: http://www.americanmedicalsystems.com 15. henry gd, brinkman mj, mead sf, et al. a survey of patient with inflatable penile prostheses: assessment of timing and frequency of intercourse and analysis of implant durability. j sex med. 2012; 9:1715-21. 16. borges f, hakim l, kline c. surgical technique to maintain penile length after insertion of an infatable penile prosthesis via infrapubic approach. j sex med. 2006; 3:550-3. 17. henry g, houghton l, culkin d, et al. comparison of a new length measurement technique for inflatable penile prosthesis implantation to standard techniques: outcomes and patient satisfaction. j sex med. 2011; 8:2640-6. 18. hakky ts, suber j, henry g, et al. penile enhancement procedures with simultaneous penile prosthesis placement. adv urol. 20123; 314-612. 19. rolle l, ceruti c, timpano m, et al. a new, innovative, lengthening surgical procedure for peyronie’s disease by penile prosthesis implantation with double dorsal-ventral patch graft: the “sliding technique”. j sex med. 2012;9:2389-95. 137archivio italiano di urologia e andrologia 2014; 86, 2 early activation to prevent penile retraction after prosthesis implant correspondence enrico caraceni, md director of department of urology civitanova marche hospital civitanova marche, italy ecarace@libero.it lilia utizi, clinical psychologist (corresponding author) sexual behavior consultant department of urology civitanova marche hospital civitanova marche, italy l.utizi@libero.it. giovanni angelozzi, md department of urology civitanova marche hospital civitanova marche, italy giovauro@yahoo.it stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2108 original paper management of bladder stones associated with foreign bodies following incontinence and contraception surgery abdulmuttalip simsek 1, faruk ozgor 1, mehmet fatih akbulut 1, erkan sönmezay 1, bahar yuksel 2, omer sarılar 1, ahmet yalcın berberoglu 1, zafer gokhan gurbuz 1 1 haseki research and education hospital, department of urology, istanbul, turkey; 2 istanbul medical faculty, gynecology and obstetric department, istanbul, turkey. aim of the study: to investigate success of endoscopic lithotripsy for bladder stone following stress urinary incontinance surgery and contraception surgery. materials and methods: charts of patients admitted in two centers between january 2006 and march 2013 were retrospectively reviewed and seven women were enrolled in our study. patients demographic parameters including age, main complaint(s), previous surgery type, time to diagnosis were analyzed. also operative time, hospitalisation lenght, perioperative and postoperative complication(s) were evaluated. results: five patients had undergone tension free vaginal tape procedure and one patient had undergone transobturator tape procedure. median age was 62 (50-71) years. in one patient bladder stone formed around an intrauterine device. dysuria (85%), hematuria (57%) and recurrent urinary tract infection (57%) were the main complaints. the median diagnosis time was 44.1 months. abdominal ultrasonography and non contrast enhanced computer tomography were performed for five and two patients respectively and diagnosis was confirmed cystoscopically. endoscopic lithotripsy using holmium laser lithotripter or pneumatic lithotripter was used for all cases. the mean operation time was 41.2 minutes (20-70) and success was 100%. there was no intraoperative complication. only one patient had fever higher than 38ºc postoperatively and was treated by appropriate antibiotic. the median hospitalisation time was 1.57 day. conclusion: in conclusion endoscopic lithotripsy is a safe and effective approach to manage bladder stone associated with mid-urethral synthetic slings and intrauterine devices. key words: bladder stone; endoscopic cystolithotripsy; intrauterine device; mid urethral synthetic sling. submitted 17 september 2013; accepted 5 october 2013 summary introduction bladder stones (bs) are rare in women and consist 5% of all cases (1). generally stone formation in the bladder is no conflict of interest declared. related with an underlying pathology such as neurogenic bladder, pelvic organ prolapse or foreign bodies (2). benefits of intrauterin devices (iud) and mid-urethral synthetic slings (muss) were well described in contraception and stress urinary incontinence, respectively (3-4). migration of iud and muss into the bladder leads to dysuria, urgency, pelvic pain, recurrent urinary tract infection and bs (5). when bs occur, removal of bs and foreign body is mandatory. several authors have defined different approaches to solve this medico-legal problem. despite acceptable success rate of all techniques, open approaches as cystotomy and partial cystectomy are associated with new incision scar, painful post operative period and longer hospitalisation time when compared with endoscopic treatment modalities (6-7). in this paper we aim to present our experience about bs associated with iud and muss. materials and methods we conducted an observational study through chart review of patients who were treated for bs. from january 2006 to may 2013, eighteen patients were treated for bs in sultangazi goverment hospital and haseki training and research hospital. seven women had bs associated with iud or muss and were enrolled in the study. diagnosis was confirmed by imaging studies (ultrasonography or non-contrast enhanced computer tomography) and endoscopically. the operative procedure was similar for all patients. endoscopic cystolithotripsy was perfomed using holmium-yag laser or pneumatic lithotripter to expose iud or muss (figure 1). to disconnect the muss from the bladder wall, endoscopic scissors and transurethral resection (tur) with monopolar diathermy were used. when the foreign body was completely separated from the wall of the bladder, an endoscopic forcep was used to remove the iud or muss. patients’ age, main complaints, diagnosis method and time from surgery to diagnosis were evaluated. also operative time, treatment modality and lenght of hospitalization were analyzed. median diagnosis time was defined as the doi: 10.4081/aiua.2014.2.108 109archivio italiano di urologia e andrologia 2014; 86, 2 management of bladder stones associated with foreign bodies following incontinence and contraception surgery period from incontinence or contraception surgery to diagnosis of bs. all patients charts were rewieved by two author (fo and as). variables were defined before data collection. microsoft excel 2010 software (microsoft corporation, redmond, wa) was used for data entry. results demographic characteristics of the patients are presented in table 1. median age was 62 years. six patients had undergone stress incontinance surgery including tension free vaginal tape (tvt) and trans obturator tape (tot). one patients had an history of iud insertion (figure 2). all patients were symptomatic and had more than one complaint. main complaints were dysuria (85%), hematuria (57%) and recurrent urinart tract infection (uti) (57%). patients also reported urgency, frequency and pelvic pain. the median diagnosis time was 44.1 months (range from 9 to 218 months). pelvic x-ray was performed all patients. to evaluate upper urinary system and perivesical area abdominal ultrasonography was also performed in 5 patients and non contrast enhanced computer tomography was performed in other 2 patients (figure 3). median operative time was 41.2 minutes (range from 20 minutes to 70 minutes) and median hospitalisation time was 1.57 day (range from 1 day to 4 days). holmium laser was used in 3 cases and pneumatic lithotripter was used in 4 cases. there was no intra operative complication. post operative period was uneventfully for six patients. only one patient had fever > 38ºc on the first day of operation and ceftriaxone was started empirically at the dose of 2 g/day. in urine culture, ceftiraxone sensitive esbl producing escherichia coli was isolated. the patient was discharged at the 4th day after operation. in follow up, endoscopy was performed in six patients who underwent tur. cystoscopy revealed recovered bladder mucosa without protrusion of the tape into the bladder in each patient. recurrent stress urinary incontinence was developed in two patients but both of them refused new surgical manipulation. discussion bladder stones are uncommon in women and mostly result of pathological conditions such as neurogenic bladder, bladder diverticulum and foreign material. during storage of urine a foreign body is an ideal nidus for stone formation and encrustation by calcium oxalate. also infection in bladder accelerate the process (8). most of foreign bodies are related with complications of urogynecologic procedures. suture materials from bladder suspension procedures, sling procedures or iud insertion are the most common source of an intravesical foriegn body (9). insertion of muss or iud into the bladder leads to the development of significant symtomps and impact negatively on quality of life. dysuria, hematuria, urgency, frequency, resistant and recurrent uti are the most common symptoms (10). on the other hand stone formation requires time. it should be questioned why why the patients were not admitted to hospital despite they comfigure 1. bladder stone formed on tvt sling. pneumatic lithotripter was used to fragment the stone. figure 2. image of iud and fragmented stones after operation. endoscopic forceps was used to remove iud. figure 3. image of bladder stone at non-contrast enhanced computer tomography. archivio italiano di urologia e andrologia 2014; 86, 2 a. simsek, f. ozgor, m. fatih akbulut, e. sönmezay, b. yuksel, o. sarılar, a. yalcın berberoglu, z. gokhan gurbuz 110 plaints and why the diagnosis was so delayed. that may be explained by socio-cultural conditions of the country. all these symptoms are mostly considered as a natural sign of aging by patients. furthermore in rural areas its difficult to achieve health care and physicians tend to treat the symptoms without investigating underlying pathology. to prevent further complications, it is very important to recognize intraoperatively bladder injury during stress incontinance surgery. cystoscopy is a part of tvt procedure and the best method to evaluate the presence of bladder injury (11). nevertheless in this paper we present five cases who underwent tvt procedure. two hypothesis can explain the unfortunate event: sling mesh in the bladder was missed at cystoscopy or mesh was placed in the submucosal area close but outside to the bladder mucosa. experience of surgeon can affect recognizement of bladder injury at cystoscopy. to increase the accuracy of cystoscopy, bladder must be filled with at least 300 ml of fluid to have better vision and use of 7º or 12º optics allows a more extensive view (12). cystoscopy is not routinely performed after tot because of the low risk of bladder injury (13). tayrac et al. and abdel-fattah et al. found less than 1% incidence of lower urinary tract injury mostly associated with outin technique (14-15). due to longer operative time and requirement of endoscopic instruments, cystoscopic inspection after tot is not accepted by most surgeons. to avoid injury emptying the bladder completely is very important. we perform cystoscopy only if hematuria occurs intraoperatively or for persistance of irritative bladder symptoms. due to their safety and efficacy, iuds are the most preferred method of reversible contraception all over the world (16). however insertion of iud by paramedics and irregular followup evaluations can lead to serious complications such as uterine perforation (17). harrison et al. emphased on the experience of the surgeon to prevent uterine perforation (18). after perforation, iud could be found in any extrauterine location as rectum, omentum, peritoneum or wall of iliac vein but migration into the bladder is very rare (19-20). pathophysiology is still unknown but some authors believe that uterine and bladder contractions have a significant role in the migration of iud into the bladder. also uterin atrophy contributes to movement of iud (21). misplacement of iud can cause pain, bleeding and loss of its contraception ability. in our case, the patient was 32 years-old when the t-shape iud was placed. she had no pregnancies after insertion and symptoms were accepted as normal by the patient. treatment options are variable according to the experience of the physician and can be divided in open and endoscopic procedures. open cystotomy is an alternative for big and hard stones to shorten operation time. if the mesh or iud is very adherent and it is impossible to remove the foreign body from the bladder wall partial cystectomy may be performed (10). pikaart et al. performed laparoscopic stone removal by following the steps of open surgery (22). with the application of technological advances in medicine, endoscopic treatments is become equally effective and more comfortable than open surgeries. tyzortis et al. presented two case of bladder stone associated with tvt and both stones were treated endoscopically (23). also mustafa et al. used transurethral mesh resection and pneumotic lithotripsy for the same problem (24). feiner et al. used holmium laser to fragment bladder stones after tot procedure (25). endoscopic therapies are the first choice for us because most of bladder stones are easily fragmented. furthermore endoscopic manipulations are not affected from body mass index of the patient and by previous surgeries. in conclusion, misplacement of muss or iud into bladder during stress incontinance surgery or contraception surgery lead to several lower urinary tract symtomps. bladder stones are developed if the foreign material remains in the bladder. our experience with seven cases revealed that endoscopic lithotripsy using holmium laser and pneumotic lithotripter is a safe and effective method to manage these stones. references 1. stav k, dywer pl. urinary bladder stones in women. obstet gynecol surv. 2012; 67:715-25. 2. papatsoris ag, varkarakis i, dellis a, deliveliotis c. bladder lithiasis: from open surgery to lithotripsy. urol res. 2006; 34:163-7. 3. mwalwanda cs, black ki. immediate post-partum initiation of intrauterine contraception and implants: a review of the safety and guidelines for use. aust n z j obstet gynaecol. 2013; 53:331-7 4. ulmsten u, falconer c, johnson p, et al.. a multicenter study of tension-free vaginal tape (tvt) for surgical treatment of stress urinary incontinence. int urogynecol j pelvic floor dysfunct. 1998; 9:210-3. 5. tunn r, wildt b, rohne j, gauruder-burmester a. management of postoperative objectified intravesical position of the tvt tape two casereports. urologe a 2006; 45:347-50 6. irer b, aslan g, cimen s. development of vesical calculi following tension-free vaginal tape procedure. int urogynecol j pelvic floor dysfunct. 2005; 16:245-246. 7. minaglia s, ozel b, klutke c. bladder injury during transobturator sling. urology. 2004; 64:376-377. 8. chew r, thomas s, mantha ml, et al. large urate cystolith associated with proteus urinary tract infection. kidney int. 2012; 81:802-3. 9. peyromaure m, dayma t, zerbib m. development of a bladder stone following a tension-free vaginal tape intervention. j urol. 2004; 171:337. 10. deng dy, rutman m, raz s, rodriguez lv. presentation and management of major complications of midurethral slings: are complications under-reported? neurourol urodyn. 2007; 26:46-52. 11. gold rs, groutz a, pauzner d, et al. bladder perforation during tension-free vaginal tape surgery: does it matter? j reprod med. 2007; 52:616-8. 12. giri sk, drumm j, flood hd. endoscopic holmium laser excision of intravesical tension-free vaginal tape and polypropylene suture after anti-incontinence procedures. j urol. 2005; 174:13061307. 13. delorme e. transobturator urethral suspension: mini-invasive procedure in the treatment of stress urinary incontinence in women. prog urol. 2001; 11:1306-1313. 111archivio italiano di urologia e andrologia 2014; 86, 2 management of bladder stones associated with foreign bodies following incontinence and contraception surgery 14. detayrac r, deffieux x, droupy s, a prospective randomized trial comparing tension-free vaginal tape and transobturator suburethral tape for surgical treatment of stress urinary incontinence. am j obstet gynecol. 2004; 190:602-628. 15. abdel-fattah m, ramsay i, and pringle s. lower urinary tract injuries after transobturator tape insertion by different routes: a large retrospective study. bjog. 2006; 113:1377-1381. 16. xie zw, zhang yn, wan s, et al. levonorgestrel-releasing intrauterine device is an efficacious contraceptive for women with leiomyoma. j int med res. 2012; 40:1966-72. 17. ebel l, foneron a, troncoso l, et al. intrauterine device migration to the bladder: four case reports. actas urol esp. 2008; 32:530-532. 18. harrison-woolrych m, ashton j, coulter d. uterine perforation on intrauterine device insertion: is the incidence higher than previously reported? contraception. 2003; 67:53-56. 19. mosley fr, shahi n, kurer ma. elective surgical removal of migrated intrauterine contraceptive devices from within the peritoneal cavity: a comparison between open and laparoscopic removal jsls.. 2012; 16:236-41. 20. mccombie jj, le fur r. colonoscopic removal of an ectopic intrauterine device. anz j surg. 2012; 82:369-70. 21. atakan h, kaplan m, erturk e. intravesical migration of intrauterine device resulting in stone formation. urology. 2002; 60:911-913. 22. pikaart dp, miklos jr, moore rd. laparoscopic removal of pubovaginal polypropylene tension-free tape slings. jsls. 2006; 10:220-225 23. tzortzis v, mitsogiannis ic, moutzouris g. bladderstone formation after a tension-free vaginal tape procedure: reporton two cases. urol int. 2007; 79:181-182. 24. mustafa m, wadie bs. bladder erosion of tension-free vaginal tape presented as vesical stone; management and review of literature. int urol nephrol. 2007; 39:453-5. 25. feiner b, auslender r, mecz y, et al. removal of an eroded transobturator tape from the bladder using laser cystolithotripsy and cystoscopic resection. urol. 2009; 73:681.e15681.e16. correspondence abdulmuttalip simsek, md (corresponding author) simsek76@yahoo.com faruk ozgor, md mehmet fatih akbulut, md erkan sönmezay, md omer sarılar, md ahmet yalcın berberoglu, md zafer gokhan gurbuz, md haseki research and education hospital, department of urology, millet cad. no: 11 34000 fatih, istanbul, turkey bahar yuksel, md istanbul medical faculty, gynecology and obstetric department istanbul, turkey stesura seveso archivio italiano di urologia e andrologia 2013; 85, 4180 introduction urolithiasis represents a process of unwanted calcification and the recurrence is the rule (1). the underlying mechanisms of stone formation are not clearly known. in addition, there are no markers able to distinguish between patients who will have stone recurrence from those who will not. therefore, it is clinically important to identify potential factor(s) that may help clinicians in making decision. original paper serum fetuin-a and recurrent urolithiasis in young adults domenico prezioso 1, alberto saita 2, mario motta 2, massimo porena 3, carla micheli 3, ester illiano 1, dario bruzzese 4, vincenzo bisesti 5, paolo ferrari 6, tullio lotti 7, domenico russo 5 1 department of gynecology, obstetric and urology, university federico ii, naples, italy; 2 department of urology, “ospedale vittorio emanuele”, university of catania, catania, italy; 3 department of urology and andrology, ospedale santa maria della misericordia, university of perugia, perugia, italy; 4 department of preventive medical sciences, university federico ii, naples, italy; 5 department of nephrology, university federico ii, naples italy; 6 department of urology, ospedale hesperia, modena, italy; 7 university federico ii, naples, italy. objective: recurrence of urolithiasis is frequent. there are no reliable markers able to indicate recurrent stone former patients. fetuin-a inhibits hydroxyapatite crystals formation and expansion. this study aims at evaluating whether serum fetuin-a may predict recurrent urolithiasis in young adults. materials and methods: this is a multicentre study. young adults patients with recurrent urolithiasis attending 3 urology clinics were enrolled from july 2011 to december 2012. inclusion criteria were: age 18-40 years, presence of more than one kidney stone. exclusion criteria were: diabetes mellitus, metabolic disorders, obesity, hypertension, cardiovascular disease, infection diseases. controls were participants without history of urolithiasis and currently undetected stones. routine biochemistry, serum concentration of oxalate, fetuin-a, and parathyroid hormone (pth) were assessed; 24/h urinary excretion of creatinine, uric acid, calcium, sodium, phosphorus, potassium, magnesium, glucose, oxalate, amylase, and protein was measured. kidney ultrasonography and plain x-ray examination was performed. results: the total cohort was represented by 120 young adults participants (90 patients, and 30 controls). clinical characteristics were not different between patients and controls. no significant differences were found in serum concentrations as well as in 24/h urinary excretion of recorded variables. no significant difference was found in serum concentration of fetuin-a (median 35.1 ± 18.62 sd vs 35.12 ± 14.12, µg/ml; p = 0,908). conclusions: the data of present study do not substantiate the hypothesis that serum fetuin-a may be a reliable predictor of recurrent urolithiasis in young adults. key words: calcification; inhibition; extra osseous calcification; fetuin-a; recurrent urolithiasis. submitted 14 april 2013; accepted 30 april 2013 no conflict of interest declared summary along with the multiple traditional pathogenic factors involved in stone formation (1-3), great relevance has been recently given to inhibitors of ectopic calcification (4, 5). inhibitors raise the concentrations of calcium and oxalate required for spontaneous formation of new crystals and decrease crystal growth, aggregation, and binding to renal cells. fetuin-a plays a crucial role in the extra osseous calcifidoi: 10.4081/aiua.2013.4.180 prezioso_stesura seveso 18/12/13 10:42 pagina 180 181archivio italiano di urologia e andrologia 2013; 85, 4 serum fetuin-a and recurrent urolithiasis in young adults cation process by inhibiting the formation and expansion of hydroxyapatite crystals (6-8). unfortunately there is scarce information on fetuin-a in patients with recurrent urolithiasis. one sole study evaluated urine fetuin concentration in patients with urolithiasis (9). since urinary excretion of fetuin-a may result inaccurate as ascertained in several renal injury models (10, 11), in the present study serum fetuin-a was assessed in patients with recurrent multiple urolithiasis and compared with that of normal subjects. so far there is no data on this issue. materials and methods this is a multicentre study performed in outpatients attending 3 urology clinics from july 2011 to december 2012. the study protocol was approved by the institutional review board of catania. procedures were carried out according to the declaration of helsinki. before enrollment all patients signed informed consent. inclusion criteria were: age 18-40 years, recurrent urolithiasis, current presence of kidney stones. exclusion criteria were: diabetes mellitus, metabolic disorders, congenital or acquired dyslipidemia, obesity, hypertension, cardiovascular disease, infection diseases. serum concentration of glucose, creatinine, sodium, potassium, uric acid, calcium, phosphorus, magnesium, total cholesterol, triglycerides, oxalate, fetuin-a, and parathyroid hormone (pth) was assayed. urinary excretion of creatinine, uric acid, calcium, sodium, phosphorus, potassium, magnesium, glucose, oxalate, amylase, protein was assessed on 24-hour collections. kidney ultrasonography and plain x-ray examination was performed. serum fetuin-a was measured by human fetuin-a elisa (biovendor laboratory medicine). the intraand interassay variations were evaluated by measuring three different samples in 33 replicates (intra-assay coefficient of variation < 5,2%, inter-assay coefficient of variation < 3,8%, limit of detection 0.35mg/l). the body mass index (bmi) of patients and controls was calculated. mann-whitney test (abnormal data distribution), nonpaired t-test (normal data distribution), chi square, and fisher exact test were used to compare data of subjects with and without urolithiasis; p < 0.05 was considered as significant. results we enrolled 90 young adults patients (30 patients in each centre; 58 men, 32 women) with documented recurrent formation of urinary stones, and 30 individuals (10 in each centre; 14 men, 16 women) without urolithiasis. clinical characteristics and laboratory variables of patients with and without urolithiasis are reported in tables 1, 2 and 3. both groups were homogeneous for age, and bmi. there were no significant differences in serum concentration except for serum calcium and phosphorus; both ions controls patients p mean ± sd median (range) mean ± sd median (range) age 28.47 ± 5.75 27.5 [19-40] 31.21 ± 7.18 32 [18-42] 0.068 bmi 23.47 ± 3.06 24 [18-31] 23.03 ± 2.73 23 [18-30] 0.413 table 1. clinical characteristics of controls and patients with urolithiasis. controls patients variables mean ± sd mean ± sd p fetuin-a (µg/ml) 35.1 ± 18.6 (35.1 ± 18.6 µg/ml ) 35.1 ± 14.1 (35.1 ± 14.1µg/ml) 0.908 oxalate (µmol/l) 97 ± 22 (8.7 ± 1.9 mg/l) 124 ± 73 (11.1 ± 6.6 mg/l) 0.612 pth (ng/l) 46 ± 20 (46 ± 20 pg/ml) 47 ± 18 (47 ± 18 pg/ml) 0.701 sodium (mmol/l) 144 ± 3.4 (144 ± 3.4 meq/l) 142 ± 2.2 (142 ± 2.2 meq/l) 0.177 potassium (mmol/l) 4.6 ± 0.9 (4.6 ± 0.9 meq/l) 4.7 ± 0.4 (4.7 ± 0.4 meq/l) 0.028 calcium (mmol/l) 2.3 ± 0.10 (9.22 ± 0.42 mg/dl) 2.4 ± 0.10 (9.56 ± 0.42 mg/dl) 0.041 phosphorus (mmol/l) 1.29 ± 0.20 (4.0 ± 0.62 mg/dl) 1.15 ± 0.29 (3.57 ± 0.89 mg/dl 0.028 total cholesterol (mmol/l) 4.65 ± 0.75 (181 ± 29 mg/dl) 4.78 ± 1.16 (187 ± 45 mg/dl) 0.331 triglycerides (mmol/l) 0.85 ± 0.21 (75 ± 19 mg/dl) 1.06 ± 0.55 (94 ± 49) 0.396 table 2. baseline serum concentration of variables measured in controls and patients with urolithiasis. bmi: body mass index. pth: parathyroid hormone. prezioso_stesura seveso 18/12/13 10:42 pagina 181 archivio italiano di urologia e andrologia 2013; 85, 4 d. prezioso, a. saita, m. motta, m. porena, c. micheli, e. illiano, d. bruzzese, v. bisesti, p. ferrari, t. lotti, d. russo 182 were significantly different between patients with and without urolithiasis (serum calcium: mean 9.22 mg/dl ± 0.42 sd vs 9.56 mg/dl ± 0.42 sd; p 0.041; serum phosphorus: mean 4.0 mg/dl ± 0.62 sd vs 3.57 mg/dl ± 0.89 sd; p 0.028). there were no significant differences in 24/h urinary excretion of measured variables. serum concentration of fetuin was similar in patients and controls (mean 35.1 ± 18.62 sd vs 35.12 ± 14.12 µg/ml; p = 0.908). discussion in this study a potential association was investigated between serum concentration of fetuin-a and recurrent urolithiasis in young adults. formation of stones within the urinary tract is a complex process driven by multiple factors. although normal urine is frequently supersaturated with respect to calcium and oxalate, most individuals do not form stones. typically, any crystals formed are rapidly passed before achieving a size sufficient for retention. increased quantities of calcium and/or oxalate are excreted by many stone former. therefore, increased supersaturation alone does not account for urinary stone; as a consequence, other factors may influence their formation and growth. therefore, it is clinically relevant to identify new potential factor(s) that may help clinicians in making decision. fetuin-a inhibits the precipitation of hydroxyapatite from supersaturated solutions of calcium and phosphate by forming fetuin-mineral complex, a high molecular mass complex (6-8, 12). this inhibitory action is at least in part facilitated by the transient formation of soluble, colloidal spheres, so-called calciprotein particles, containing fetuina, calcium, and phosphate. the action of fetuin-a is most prominent in organs involved in the secretion or transport of mineral-rich fluids or in the generation of local ph changes such as the kidney. fetuin-a deficient rats have calcification in the pelvis but not in the medulla or the cortex compared to wild type; in this experimental model, calcification was primarily a consequence of the lack of fetuin-a and not of renal damage. interestingly, animals had calcium and phosphate concentrations within the normal range; this finding rules out hypocalcaemia or hyperphosphatemia as a cause of the ectopic calcification. therefore, the underlying mechanism may involve a direct interaction of fetuin-a with the mineral phase and the prevention of large crystal formation. owing to the crucial role of fetuin-a in the process leading to extra osseous calcification, it was stimulating to evaluate its potential role in patients with recurrent urolithiasis. ascertaining a role of serum fetuin a in recurrent urolithiasis should be of clinical interest considering that the recurrence of urolithiasis is the rule in all formingstone patients and that there are no laboratory markers able to distinguish between patients who will have stone recurrence from those who will not. there is at present scarce information on urine fetuin-a in patients with recurrent urolithiasis. in one sole study, urine fetuin concentration was found lower in 38 patients with urolithiasis who were compared to 22 controls (9). the lower urine fetuin-a levels were not due to other conventional promoters and inhibitors of urine crystallization. on the basis of these data, measurement of urinary fetuina was suggested as more reliable risk predictor than the traditional markers of recurrent urolithiasis (9). this interesting suggestion, however, should be viewed with caution taking in account the data attained by proteonomics that have shown that urinary excretion of fetuin-a is altered in several renal injury models (11). urinary exosomal fetuin-a is elevated in patients with acute kidney injury in intensive care unit (11). recently, urinary exosomal fetuin-a levels was found significantly increased after cisplatin-induced tubule damage (11). thus, urinary fetuin-a excretion may be strongly affected in presence of structural renal injury. the data of the present study do not confirm the hypothesized relationships between serum fetuin-a concentration and recurrent urolithiasis. in fact, there was no significant difference in serum fetuin-a concentration between patients and controls. similarly, there were no significant differences in traditional variables. these data confirm that there are no markers able to distinguish between patients who will have stone recurrence from controls patients phosphate (mmol/24 h) 368 ± 68 (1141± 211 mg) 334 ± 108 (1037 ± 335 mg) 0.451 uric acid (μmol/24 h 39792 ± 10290 (669 ± 173 mg) 38365 ± 14454 (644.97 ± 242.67 mg) 0.634 calcium (mmol/24 h) 37.4 ± 9.2 (150 ± 37 mg) 59.6 ± 34.9 (239 ± 140 mg) 0.095 amylase (u/24 h) 236 ± 171.42 247.77 ± 100.5 0.158 sodium (mmol/24 h) 164.14 ± 36.06 179.33 ± 61.58 0.315 potassium (mmol/24 h) 73.67 ± 22.36 57.29 ± 21.6 0.058 chlorine (mmol/24 h) 182.7 ± 46.6 186 ± 69.97 0.747 proteinuria (mg/24 h) 142± 42 188 ± 134 0.508 magnesium (mmol/24 h) 58 ± 25.1 (141 ± 61 mg) 44.4 ± 17.8 (108 ± 43 mg) 0.148 glycosuria (mmol/24 h) 4.8 ± 1.5 (87 ± 27 mg) 4.7 ± 1.9 (85 ± 35 mg) 0.771 table 3. 24/h urinary excretion of variables measured in controls and patients with urolithiasis. prezioso_stesura seveso 18/12/13 10:42 pagina 182 183archivio italiano di urologia e andrologia 2013; 85, 4 serum fetuin-a and recurrent urolithiasis in young adults those who will not. in addition, neither serum concentration nor urinary excretion of fetuin-a may be regarded as reliable predictors of recurrent urolithiasis. hopefully, studies performed with proteonomics may find true predictor(s) of recurrent urolithiasis. conclusions the data of present study do not substantiate the hypothesis that serum fetuin-a may be a reliable predictor of recurrent urolithiasis in young adults. references 1. coe fl, favus mj, asplin jr. nephrolithiasis. in brenner bm, ed. the kidney. 7th ed, philadelphia:saunders. 2004; 1819-1866. 2. de yoreo jj, qiu sr, hoyer jr. molecular modulation of calcium oxalate crystallization. am j physiol renal physiol. 2006; 291: f1123-f1132, 3. asplin jr, parks jh, coe fl. dependence of upper limit of metastability on supersaturation in nephrolithiasis. kidney int. 1997; 52:1602-1608, 4. schinke t, amendt c, trindl a, et al. the serum protein alpha2hs glycoprotein/fetuin inhibits apatite formation in vitro and in mineralizing calvaria cells. a possible role in mineralization and calcium homeostasis. j biol chem. 1996; 271:20789-20796. 5. schafer c, heiss a, schwarz a, et al. the serum protein alpha 2heremans-schmid glycoprotein⁄fetuin-a is a systemically acting inhibitor of ectopic calcification. j clin invest. 2003; 112:357-366, 6. heiss a, duchesne a, denecke b, et al. structural basis of calcification inhibition by alpha 2-hs glycoprotein⁄fetuin-a. formation of colloidal calciprotein particles. j biol chem. 2003; 278:1333313341. 7. westenfeld r, schafer c, kruger t, et al. fetuin-a protects against atherosclerotic calcification in ckd. j am soc nephrol 2009; 20:1264-74. 8. schlieper g, westenfeld r, brandenburg v, ketteler m. inhibitors of calcification in blood and urine. semin dial. 2007; 20:113-21. 9. stejskal d, karpisek m, vrtal r. et al. urine fetuin-a values in relation to the presence of urolithiasis bju international. 2008; 101:1151-1154. 10. heiss a, pipich v, jahnen-dechent w, schwahn d. fetuin-a is a mineral carrier protein: small angle neutron scattering provides new insight on fetuin-a controlled calcification inhibition. biophys j. 2010; 99:3986-95. 11. zhou h, pisitkun t, aponte a, et al. exosomal fetuin-a identified by proteomics: a novel urinary biomarker for detecting acute kidney injury. kidney int. 2006; 70:1847-1857. 12.price pa, lim je. the inhibition of calcium phosphate precipitation by fetuin is accompanied by the formation of a fetuin-mineral complex j biol chem. 2003; 278:22144-22152. correspondence ester illiano, md (corresponding author) ester.illiano@inwind.it domenico prezioso, md dprezioso@libero.it department of gynecology, obstetric and urology, university federico ii, naples, italy alberto saita, md alsaurol@hotmail.com mario motta, md mmotta@unict.it; mmotta@mbox.unict.it department of urology “ospedale vittorio emanuele”, university of catania, catania, italy massimo porena, md uropg@rdn.it carla micheli, md carla.micheli@libero.it department of urology and andrology, ospedale santa maria della misericordia, university of perugia, perugia, italy dario bruzzese, md dbruzzes@unina.it department of preventive medical sciences, university federico ii, naples, italy vincenzo bisesti, md vincenzo.bisesti@libero.it domenico russo, md domenicorusso51@hotmail.com department of nephrology, university federico ii, naples, italy paolo ferrari, md pferrari@hesperia.it department of urology, ospedale hesperia, modena, italy tullio lotti, md pferrari@hesperia.it university federico ii, naples, italy prezioso_stesura seveso 18/12/13 10:42 pagina 183 stesura seveso 23archivio italiano di urologia e andrologia 2014; 86, 1 original paper treatment of urethral strictures in balanitis xerotica obliterans (bxo) using circular buccal mucosal meatoplasy: experience of 15 cases abdulmuttalip simsek 1, sinasi yavuz onol 2, omer kurt 3 1 bakırkoy dr. sadi konuk training and research hospital, department of urology istanbul, turkey; 2 bezmi alem vakıf university, department of urology, istanbul, turkey; 3 bayrampasa state hospital, department of urology, istanbul, turkey. objectives: balanitis xerotica obliterans (bxo) related strictures involving the external urethral meatus. we reviewed our result with the use of circular mucosal graft in the reconstruction of strictures. methods: between march 1997 and january 2012, 15 patients underwent circular buccal mucosal urethroplasy for bxo related anterior urethral strictures. urethral catheter was removed within 2 weeks. follow-up included patient symptoms assessment, cosmetic outcome and uroflowmetry. results: median follow-up was 20.5 months (range 4 to 96). mean postoperative peak urinary flow rate obtained 1 month after catheter removal was 22.4 ml per second. all patients had a normal meatus and none had recurrent stricture, chordee or erectile dysfunction. a functional and cosmetic outcome was achieved in 100% of the patients. conclusions: circular mucosal graft technique for treatment of meatal strictures is an efficient method for the restoration of a functional and cosmetic penis. key words: buccal mucosa; bxo; urethral stricture; meatoplasty. submitted 16 september 2013; accepted 5 october 2013 summary introduction the term balanitis xerotica obliterans (bxo) was first described by stuhmer in 1928, for the chronic, progressive scleroatrophic inflammatory process of unknow etiology affecting the glans penis, prepuce and urethral meatus. the lesions occur as plaques or papules on the glans penis and result in urethral meatal stenosis (1). bxo has been managed both medically and surgically. medical treatment can provide useful palliation but is generally regarded to be limited. the surgical options are more definitive, and include circumcision, dilatation or surgically correction of meatal stenosis and some urethroplasty techniques (2, 3). a large veriety of free extragenital graft tissues have been used for urethroplasty no conflict of interest declared. such as bladder mucosa, buccal mucosa, vein and appendix (4). humby was the first to describe the use of buccal mucosa for the urethral substitution (5). the glandular urethra is unique in that it is most undistensible and the narrowest portion of the urethra. when strictured, this portion becomes extremely narrow. we describe our reconstructive technique for bxo using circular buccal mucosal graft urethroplasty. materials and methods between 1997 and 2012, 15 patients with a mean age of 39.3 years (range 36 to 49) with meatal stenosis underwent circular buccal mucosal substitution urethroplasty in our department. all patients were subjected to preoperative urine culture, uroflowmetry and retrograde urethrogram to document the severity and length of the stricture. stricture etiology was balanitis xerotica obliterans in all patients. all had previously undergone a number of dilatations, the average number of prior formal surgical prosedures was 1.4 (including meatotomy and urethral dilatation). most cases had symptoms of hesitancy, intermittent urine stream, decreased caliber of urine stream, incomplete bladder emptying, nocturia, pain with voiding or even urinary retention. inclusion criteria included bxo and strictures length < 2 cm. exclusion criteria were unhealthy oral cavity, urinary tract infection, strictures length > 2 cm and loss of follow-up. in this study mean duration of disease was 13.3 ± 4.9 months. uroflowmetry demonstrated urinary peak flows ranging from 2.5 ml/s and 14 ml/s (mean 4.18 ml/s). preoperatively, 15 patients underwent suprapubic cystostomy and 3 patients presented with urethrocutaneous fistulae. the catheter was removed 2 weeks after the meatoplasty. the patients were advised self meatal calibration with a 16 f foley catheter two times in a week for 1 month. at each visit of follow up, patient symptoms assessment, cosmetic outcome and uroflowmetry was done. at 6month follow up calibration of distal penile urethra with 16 f foley catheter was also done to evaluate urethral lumen. doi: 10.4081/aiua.2014.1.23 simsek_stesura seveso 26/03/14 10:16 pagina 23 archivio italiano di urologia e andrologia 2014; 86, 1 a. simsek, s. yavuz onol, o. kurt 24 operative technique all cases were performed by the same surgeon (syo). the patient was placed in a standard supine position on the operating table. all surgeries were performed under general anesthesia and a circular submeatal incision was made (figure 1). bad stricture tissue was mobilized until the proximal extent extending about 1 cm into the healthy segment. incision of the stricture was performed, the length of the strictured urethra was measured and the incision was extended at least 0.5 cm into the healthy urethral tissue. a buccal mucosa graft was harvested from one or both cheeks and lower lip using a standard technique. for meatal reconstruction the circular buccal mucosa graft was sutured to the dorsally cut margins of the meatus using a 4-5-zero monofilament suture (figure 2). the patients were discharged from the hospital on first or second postoperative day. results after catheter removal 3 patients did not come to control. therefore, these patients were excluded from this study. stricture length was less than 2.0 cm in all cases (range 0.5 to 1.6). mean operation duration was 45 minutes. patients were followed for a median of 20.5 months (range 4 to 96). durable functional and cosmetic outcome was obtained in all cases. we did not use any of cosmetic outcomes scale. however, not only patients opinion but also surgeons point of view is important for evaluation of cosmetic outcomes. we noticed no significant complications with this technique. mean postoperative peak urinary flow rate obtained 1 month after catheter removal was 22.4 ml per second (range 16 to 38). there were no recurrent strictures or obstructive voiding symptoms during follow up (table 1). discussion glandular strictures are difficult to treat and are sometimes associated with recurrence. the glans becomes inelastic and shows significant scarring, especially in patients of bxo. strictures involving the distal urethra and fossa navicularis are particularly challenging because successful reconstruction requires the creation of a functional urethral conduit as well as maintaining a cosmetically appealing glans penis. treatment of distal urethral strictures developed in the last decades from dilatation, internal urethrotomy to definitive reconstruction techniques such as penile fasciocutaneous flap urethroplasty and buccal mucosa graft urethroplasty (6, 7). urethral meatal stenosis can be treated by ventral meatotomy or dorsal v-meatoplasty. meatotomy in bxo is often followed by restenosis. surgical correction of the meatus, however does not improve the common loss of sensitivity in the glans penis. zungri et al., reported that a complete resection of the glans mucosa and meatoplasty produced complete resolution of the disease in their cases (8). penile skin flap urethroplasty has been used for 1-stage reconstruction of bxo strictures with encouraging short term results (9-11). however the long term outcomes of this technique have been uniformly disappointing (12, 13) venn and mundy reported an almost 100% recurrence rate for 1-stage urethroplasy with genital skin flap (12). in their series all patients with penile characteristics mean range age (y) 39.3 36-49 stricture length (cm) 1.4 0.5-1.6 graft length (cm) 1.8 0.8-2.4 operative time (min) 45 28-94 preoperative peak flow rate (ml/sn) 4.18 2.5-14 postoperative peak flow rate (ml/s) (at 1 mo) 22.4 16-38 follow up (mo) 24.6 4-96 (meadian, 20.5) figure 1. the strictured meatus was circular incised and bad stricture tissue was mobilized until healthy segment appeared. figure 2. the circular buccal mucosa graft was sutured to the dorsally margins of the meatus using a 4-5-zero monofilament on the benique dilator. table 1. patient characteristics (n = 15). simsek_stesura seveso 26/03/14 10:16 pagina 24 skin reconstruction had failure within 2 years with evidence of bxo. ramon et al. reported that using ventral transverse penile skin island flap an overall success rate of 83% with a mean long-term follow-up of 10.2 years (14). we have previously investigated the use of transverse island fasciocutaneous penile flap for reconstruction of strictures of the fossa navicularis and meatus with positive functional and cosmetic outcome in 96% after a mean follow up of 30.2 months (range 4 to 96) (15). deepak dubey et al. reported buccal mucosal urethroplasy for bxo related urethral strictures. they investigated 1-stage dorsal onlay and 2-stage buccal mucosal urethroplasty for strictures. patients with a severely scarred urethral plate,focally dense segments or active infection underwent 2-stage urethroplasty (16). our results demonstrate that circular buccal mucosal meatoplasty provides satisfactory results in selected cases of bxo related anterior urethral strictures. circular buccal mucosal graft can be successfully used for reconstructive distal urethral segment including the meatus. to our knowladge prior to this study there have been no reports in the literature describing circular buccal mucosal graft reconstruction urethral strictures for bxo. goel et al. presented their experience with 10 patients with glandular or meatal strictures treated with double buccal mucosal graft technique. they reported a functional and cosmetic outcome in 100% of patients presenting with anterior urethral stricture (range length 4-6.5 cm) after a mean follow-up of 13.5 months (17). palminteri et al. described the use of buccal mucosa graft both on the dorsal and ventral aspects in cases of severe bulbar urethral strictures with good results (18). the main long term donor site complications included intraoperative hemorrahage, postoperative infection, pain, swelling, damage to the parotid duct, limitations of oral opening and loss or altered sensation of the cheek and lower lip (19). therefore some reconstructive surgeons advocate a 2stage approach involving excision of the diseased urethra and buccal mucosal grafting, followed by stage 2 urethroplasty after 4 to 6 months (12, 13). patients with anterior urethral stricture need lip mucosa and cheek mucosa for urethroplasty and therefore have more morbidity in the form of scar contracture and lip deviation or retraction and long lasting paresthesia and numbness of the lower lip. however in our practice, only 1 patient had a lip retraction and there was no another complication. to our knowledge, this is the largest series of buccal mucosal graft urethroplasties used for repairing anterior urethral strictures. the overall success rate in our series was 100%, which included the repair of meatus in the process of bxo. the results of our study have shown that the circular mucosal graft can be suitable as the transverse ısland fasciocutaneous penile flap for the reconstruction of anterior urethral strictures. circular buccal mucosal graft urethroplasy is easy harvesting and with minimal donor site complications. references 1. stuhmer, a. balanitis xerotica obliterans (post operationem) und ihre beziehungen zur “kraurosis glandis et praeputii penis£. archiv fur dermatologie und syphilis. 1928; 156:613-623. 2. wright je. the treatment of childhood phimosis with topical steroid. australian nz j surg. 1994; 64:327-8. 3. fischer go. lichen sclerosus in childhood. australasian j dermatol. 1995; 36:166-7. 4. dessanti a, rigamonti w, merulla v, et al. autologous buccal mucosa graft for hypospadias repair: an initial report. j urol. 1992; 147:1081-1084. 5. humby g. a one-stage operation for hypospadias. br j surg. 1941; 29:84-92. 6. jordan gh. reconstruction of the fossa navicularis. j urol. 1987; 138:102-4. 7. armenakas na, morey af, mcaninch jw. reconstruction of resistant strictures of the fossa navicularis and meatus. j urol. 1998; 160:359-63. 8. zungri e, chéchile g, algaba f, mallo n. balanitis xerotica obliterans: surgical treatment. eur urol. 1988; 14:160-162. 9. armenakas na, morey af, mcaninch jw. reconstruction of resistant strictures of the fossa navicularis and meatus. j urol. 1998; 160:359. 10. wessels h, morey af, mcaninch jw. single-stage reconstruction of complex anterior urethral strictures: combined tissue transfer techniques. j urol. 1997; 157:1271. 11. morey af, tran lk, zinman lm. q-flapreconstruction of panurethral strictures. bju int. 2000; 86:1039. 12. venn sn, mundy ar. urethroplasty for balanitis xerotica obliterans. bju int. 1998; 81:735. 13. depasquale i, park aj, bracka a. the treatment of balanitis xerotica obliterans. bju int. 2000; 86:459. 14. virasoro r, eltahawy ea, jordan gh. long-term follow-up for reconstruction of strictures of the fossa navicularis with a single technique. bju int. 2007; 100:1143-5. 15. onol sy, onol ff, onur s, et al. reconstruction of strictures of the fossa navicularis and meatus with transverse island fasciocutaneous penile flap. j urol. 2008; 179:143. 16. dubey d, sehgal a, srivastava a, et al. buccal mucosal urethroplasty for balanitis xerotica obliterans related urethral strictures: the outcome of 1 and 2-stage techniques. j urol. 2005; 173:463-6. 17. goel a, dalela d, sankhwar sn. meatoplasty using double buccal mucosal graft technique. int urol nephrol. 2009; 41:885-7. 18. palminteri e, manzoni g, berdondini e, et. al. combined dorsal plus ventral double buccal mucosa graft in bulbar urethral reconstruction. eur urol. 2008; 53:81-90. 19. bhargava s, chapple cr. buccal mucosal urethroplasty: is it the new gold standard? br j urol. 2004; 93:1191-1193. 25archivio italiano di urologia e andrologia 2014; 86, 1 bxo meatoplasy correspondence abdulmuttalip simsek, md (corresponding author) simsek76@yahoo.com department of urology bakırkoy dr. sadi konuk training and research hospital tevfik saglam cad. no: 11 34000 zuhuratbaba, istanbul, turkey sinasi yavuz onol, md department of urology bezmi alem vakıf university, istanbul, turkey omer kurt, md department of urology bayrampasa state hospital, istanbul, turkey simsek_stesura seveso 26/03/14 10:16 pagina 25 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 3202 original paper empiric antibiotics therapy for mildly elevated prostate specific antigen: helpful to avoid unnecessary biopsies? andrea fandella 1, sara benvenuto 1, elisa guidoni 1, marco giampaoli 2, alessandro bertaccini 2 1 urology, casa di cura giovanni xxiii monastier, treviso, italy; 2 clinica urologica, alma mater studiorum, università di bologna, italy. purpose: the management of mildly elevated (4.0-10.0 ng/ml) prostate specific antigen (psa) is uncertain. immediate prostate biopsy, antibiotic treatment, or monitoring psa level for 1-3 months is still in controversy. materials and methods: we retrospectively analysed the effect of empiric antibiotics on an increased psa in a mono-institutional study. we analysed the data of 100 patients with a psa of 4-10 ng/ml and normal digital rectal examination undergoing their first prostate biopsy. patients were divided in two different cohorts. one cohort was submitted to antibiotic therapy (levoxacin 500 mg daily for 20 days) and both cohort had a re-dosing of psa before the prostate biopsy. results: average age of the whole group of patients was 66.48 ± 8.32 years and their average initial psa level was 6.67 ± 1.57 ng/ml. in the treated group (n = 49) 29 patients had a decreasing psa value from mean baseline psa value of 6.6 ± 1.54 ng/ml to the re-dosed mean psa level of 5.4 ± 1,61 ng/ml (p = 0.7); 20 patients didn’t experience a decrease psa value, with a mean psa level of 6.9 ± 1.68 ng/ml. in the control group (n = 51), 30 patients had a decrease of psa level from mean baseline psa level of 6.5 ± 1,59 ng/ml to a re-dosed psa level of 5.5 ± 1.57 ng/ml; 21 patients didn’t experience a decrease of psa value, with a mean psa level of 6.7 ± 1.71 ng/ml. multivariate analysis of age, psa changes, antibiotics therapy and biopsy results (presence or absence of cancer) revealed no significant difference between the two cohorts. sepsis after biopsy occurred in 3 patient in the antibiotics group (6%) and in one of the control group (2%). conclusions: the study, even with some limitations, does not seem to show an advantage due to the administration of antibacterial therapy to reduce psa values before prostate biopsy and subsequently to reduce unnecessary prostate biopsies. key words: psa; antibiotics; biopsy; prostate cancer; fluorquinolone. submitted 21 august 2014; accepted 30 august 2014 summary no conflict of interest declared. introduction prostate specific antigen (psa) is a serum protein secreted by prostate tissue both in benign and malignant conditions. elevated values of serum psa are not pathognomonic for prostate cancer but they can be found in various clinical conditions, including inflammation and infection (1). in men with an increasing psa without clinical evidence of infection, a common clinical approach is to empirically prescribe antibiotics and subsequently re-dose the psa. until today, several researchers have examined the impact of empiric antibiotics therapy in patients with an increased psa, in order to find a balanced costs/effective therapy to avoid unnecessary prostate biopsies and to decrease patient discomfort and morbidity from biopsies (2, 3). the common rational is to treat a subclinical prostate infection, having as result a lower serum psa. this might lead to lower the rate of unnecessary prostate biopsies, since unproven sub clinical prostatitis are responsible for the majority of false positive psa elevations (4-6). however, most of the studies available in the literature are limited because they lack a control arm, so it is unclear if the observed psa changes were secondary to natural variations or to the effect of the antibacterial therapies (7). the potential disadvantages of an empiric antibiotic approach include unnecessary expenses, side effects and possible adverse reactions related to the drug intake and an increase in multidrug resistant organisms (8). our goal was to investigate if an antibiotic therapy in patients eligible for prostate biopsies might be effective in order to avoid unnecessary biopsies so reducing false positive psa elevation. materials and methods we conducted a retrospective mono-institutional study (casa di cura giovanni xxiii monastier, treviso, italy). we analysed the data of two different cohort of patients, all submitted to their first prostate biopsy set in the last 3 years in our institution. the first cohort (n = 49) included patients treated with an antibiotic therapy (levofloxacin 500 mg daily) for at least 20 days and then doi: 10.4081/aiua.2014.3.202 fandella_stesura seveso 08/10/14 12:12 pagina 202 203archivio italiano di urologia e andrologia 2014; 86, 3 empiric antibiotics therapy for mildly elevated prostate specific antigen: helpful to avoid unnecessary biopsies? submitted to psa re-dosing prior to the prostate biopsy. otherwise, the second cohort (n = 51) included patients with no antibiotic therapy but with psa re-dosing before prostate biopsy. both cohort presented psa levels between 4.0-10 ng/ml, no prior diagnosis of prostate cancer or pre-neoplastic lesions (hgpin/asap), a negative digital rectal examination (dre) and no clinical or laboratory signs of urinary infections (negative urine sediment and negative urine culture). the analysed data included patient’s age and history. cases with reported events that could have falsely elevated the psa result (e.g. urinary tract infection, urinary retention, urinary catheterization…) were excluded from the study. all the specimens were analysed in our laboratory (using beckam coulter access ii immunoassay system psa). analysis of data [age, psa changes, antibiotic therapy, biopsy result (presence of cancer)] was carried out using spss statistical analysis software (ibm spss statistics 21). data of the second cohort (n = 51) was used as control group. kolmogorov-smirnov test (cut off at p < 0.01) was performed. continuous variables were described using mean ± standard deviation. categorical variables were described using frequency distributions (frequency %). psa values prior to and following antibiotic therapy were compared using the student’s-t-test for independent samples and a multivariate logistic regression analysis was performed. all tests were two-sided and considered significant at p < 0.05. all the patients underwent to a 12-core prostate biopsy according to our standard biopsy procedure (presti procedure) (9). results average age of the whole group of patients (first and second cohort) was 66.48 ± 8.32 years and average initial psa level was 6.67 ± 1.57 ng/ml with no significant difference between first and second cohort. in the treated cohort (n = 49) 29 patients showed a decrease of psa values from mean baseline psa of 6.6 ± 1,54 ng/ml to a mean re-dosed psa of 5.4 ± 1,61 ng/ml (p = 0.7), while 20 patients did not experience a lowering of psa value, with a mean psa level of 6.9 ± 1.68 ng/ml. in the sub-group with decreasing psa levels (n = 29, 59% of first cohort) 6 patients turned out to have prostate cancer (21%), 5 chronic inflammation (17%) and 18 benign prostatic hyperplasia (bph) (62%). in the sub-group with no decrease of psa levels (n = 20, 41% of first cohort) 4 patients demonstrated to have prostate cancer (20%), 8 chronic inflammation (40%) and 8 bph (40%). in the control group (n = 51), 30 patients showed a decrease of psa values from a mean baseline psa of 6.5 ± 1,59 ng/ml to a mean redosed psa of 5.5 ± 1,57 ng/ml, while 21 patients did not experience a lowering of psa value, with a mean psa level of 6.7 ± 1.71 ng/ml. in the sub-group with decreasing psa level (n = 30, 59% of second cohort) 7 patients turned out to have prostate cancer (23%), 5 chronic inflammation (17%) and 18 bph (60%). in the sub-group with no decrease of psa levels (n = 21, 41% of second cohort) 6 patients demonstrated to have prostate cancer (29%), 3 chronic inflammation (14%) and 12 bph (57%). the difference in psa changes between the two cohort was not statistically significant (p = 0.3 ). furthermore there weren’t any statistically significant differences between the two sub-groups in each cohort for cancer detection (p > 0.5) multivariate analysis of age, psa changes, antibiotics therapy and biopsy results (presence or absence of cancer) revealed no significant difference between the two cohorts (p value > 0.05 in all categories). table 1 shows the distribution of diagnoses and performance of biopsies for each subgroup. prostate cancer detection rates were not significantly associated with the changes in psa (either decreasing or increasing). sepsis after biopsy occurred in 3 patient in the antibiotics group ( 6%) and in 1 of control group (2%). discussion in chronic prostatitis, it has been shown that total psa and free psa are all significantly higher in patients with infection. a course of fluoroquinolone therapy in patients with chronic bacterial prostatitis resulted in a median psa decrease from 8.3 to 5.3 ng/ml (10). on the other hand, habermacher et al. (11) demonstrated that most cases of asymptomatic prostatitis are not caused by bacteria, thus eliminating the rationale for antibacterial therapy. in the study of kaygisiz et al. (5), antibiotics were administered to 48 patients who underwent to prostate biopsies. the psa levels decreased below 4 ng/ml in 18 (37%) of them and the biopsies of these men were negative for malignancies. in the subgroup of other 30 men prostate cancer was found in 10.8%. the authors suggested a long course of antibiotic treatment (at least 3 weeks), regardless of inflammation findings, when psa levels are mildly high (i.e. 4-10 ng/ml), in order to decide whether or not to carry out the biopsy on the basis of the subsequent re-dosed psa results. bozeman et al. reported that when serum psa had been normalized with treatment there was no longer an indication for transrectal ultrasound-guided biopsy in almost cohort 1 cohort 2 49 pts 51 pts antibiotics no antibiotics significant decrease of psa (> 10%) + 29 20 + 30 -21 prostate cancer 6 4 7 6 chronic inflammation 5 8 5 3 bph only 18 8 18 12 + affirmative/negative bph = prostate benign hyperplasia psa = prostate specific antigen pts = patients table 1. fandella_stesura seveso 08/10/14 12:12 pagina 203 archivio italiano di urologia e andrologia 2014; 86, 3 a. fandella, s. benvenuto, e. guidoni, m. giampaoli, a. bertaccini 204 half of their 95 patients diagnosed with elevated psa and chronic inflammation, suggesting that chronic prostatitis is an important cause of elevated psa and that, when identified, treatment can decrease the percent of negative biopsies (12). a recent editorial by scardino criticized the unjustified use of antibiotics in a group of patients similar to ours. he emphasized the various inherent disadvantages associated with this approach, such as costs, toxicity, and the promotion of resistant bacterial species development that would have exposed the biopsied patient to more resistant and aggressive sepsis (8). significant fluctuations in psa should raise the suspicion of inflammation or infection as an aetiology, however in these patients it remains controversial; empiric antibiotics therapy prior to a prostate biopsy in order to “normalize” the psa value remains a non evidence-based practice. those who underwent a course of fluoroquinolone antibiotics treatment should not have a prostate biopsy within one month from completing the therapy to allow the colonic flora to re-establish itself to a normal state. akduman et al. demonstrated that patients who received 3 weeks of fluoroquinolones before biopsy had a significantly greater incidence of post-biopsy sepsis (5.4% vs 1.7%) and all sepsis episodes were attributable to quinolone resistant bacteria (13). other studies have similarly shown that previous therapy with quinolones predisposes to rectal flora resistance (14). the results of this study seems to show no advantages due to an empiric antibiotic therapy (full dose floroquinolone for 20 days, in this specific case) to reduce psa values and avoid unnecessary biopsy in patients with psa levels between 4-10 ng/ml and no signs or symptoms of infections. a psa decrease after antibiotic therapy does not rule out prostate cancer and at the same time a lack of decrease does not exclude it. thus antibiotics therapy does not seem to eliminate unnecessary prostate biopsy. our trial does have some limitations: patients number and retrospective design. we had few cases with histological evidence for chronic prostatitis in our study. this might explain why administration of antibacterial therapy was not helpful in our series. we also studied only a single class of antibiotic for 20 days, which we believed to be the most commonly used in current clinical practice. it is possible that a different class or length of therapy might alter the above findings. it is possible that a larger prospective trial might identify a clinical benefit for empiric antibiotic treatments. conclusions it is of crucial importance to use properly and responsibly antibiotics. in patients with an increased psa, antibiotics are appropriate if there is any clinical suspicion or evidence of urinary infection. any rise of psa should be an indication to repeat psa testing. at the same time we advocate the use of antibiotic therapies only if a bacterial cause has been identified. empiric use doesn’t seem to be of clinical benefit in absence of a clinical or laboratory evidence of infection and it might paradoxically be harmful. repeating a new psa test before scheduling a biopsy remains the only acceptable approach. references 1. ornstein dk, smith ds, rao gs, et al. biological variation of total, free and percent free serum prostate specific antigen levels in screening volunteers. j urol. 1997; 157:2179-82. 2. lorente ja, arango o, bielsa o, et al. effect of antibiotic treatment on serum psa and percent free psa levels in patients with biochemical criteria for prostate biopsy and previous lower urinary tract infections. int j biol markers. 2002; 17:84-9. 3. ozen h, aygün c, ergen a, et al. combined use of prostate-specific antigen derivatives decreases the number of unnecessary biopsies to detect prostate cancer. am j clin oncol. 2001; 24:610-3. 4. kaygisiz o, ugurlu o, kosan m, et al. effects of antibacterial therapy on psa change in the presence and absence of prostatic inflammation in patients with psa levels between 4 and 10 ng/ml. prostate cancer prostatic dis. 2006; 9:235-8. 5. baltaci s, suer e, haliloglu ah, et al. effectiveness of antibiotics given to asymptomatic men for an increased prostate specific antigen. j urol. 2009; 181:128. 6. serretta v, catanese a, daricello g, et al. psa reduction (after antibiotics) permits to avoid or postpone prostate biopsy in selected patients. prostate cancer prostatic dis. 2008; 11:1485. 7. erol h, beder n, caliskan t, et al. can the effect of antibiotherapy and anti-inflammatory therapy on serum psa levels discriminate between benign and malign prostatic pathologies? urol int. 2006; 76:20-6. 8. scardino pt. the responsible use of antibiotics for an elevated psa level. nat clin pract urol. 2007; 4:1. 9. presti jc jr; prostate biopsy strategies. nat clin pract urol. 2007; 4:505-11. 10. schatteman ph, hoekx l, wyndaele jj, et al. inflammation in prostate biopsies of men without prostatic malignancy or clinical prostatitis: correlation with total serum psa and psa density. eur urol. 2000; 37:404-12. 11. habermacher gm, chason jt, schaeffer aj. prostatitis/chronic pelvic pain syndrome. ann rev med. 2006; 57:195-206. 12. bozeman cb, carver bs, eastham ja, venable dd. treatment of chronic prostatitis lowers serum prostate specific antigen. j urol. 2002; 167:1723-6. 13. akduman b, akduman d, tokgoz h, et al. long-term fluoroquinolone use before the prostate biopsy may increase the risk of sepsis caused by resistant microorganisms. urology 2011; 78:250. 14. owens rc jr., ambrose pg. antimicrobial safety: focus on fluoroquinolones. clin infect dis. 2005 (suppl.); 41:s144. correspondence andrea fandella, md afandella@libero.it sara benvenuto, md elisa guidoni, md casa di cura giovanni xxiii monastier, treviso, italy marco giampaoli, md giampaoli.marco85@gmail.com alessandro bertaccini, md (corresponding author) alessandro.bertaccini@gmail.com clinica urologica, alma mater studiorum, università di bologna ospedale sant’orsola-malpighi, bologna, italy fandella_stesura seveso 08/10/14 12:12 pagina 204 stesura seveso introduction the international continence society defines urinary incontinence as the involuntary loss of urine per urethra that can be objectively demonstrated and that causes social or hygienic problems (1, 2) and affects the psychological, social and sexual life of the patient (3). in spain the prevalence of urinary incontinence in persons older than 60 years was 40% in 2003. others reported a 35.1% prevalence of incontinence in persons older than 64 years of age, namely 23% in women older than 18 149archivio italiano di urologia e andrologia 2013; 85, 3 original paper results of the surgical correction of urinary stress incontinence according to the type of transobturator tape utilized bárbara padilla-fernández 1, maria begoña garcía-cenador 2, ana gómez-garcía 3, josé antonio mirón-canelo 4, ángel gil-vicente 1, juan miguel silva-abuín 1, maría fernanda lorenzo-gómez 1 1 department of urology. university hospital of salamanca; 2 department of surgery, university of salamanca; 3 family and community medicine. university hospital of salamanca; 4 department of preventive medicine and public health, university of salamanca. objectives: to analyze the short and long term results of tapes of different materials used to treat stress urinary incontinence (sui). a secondary objective was to evaluate the ability to adjust the tape after implantation. materials and methods: retrospective chart review of 355 patients with sui operated between march 2003 and october 2011. eight different types of transobturator tapes were used: gynecare tvt-o®, monarc®, safyre®, contasure kim®, i-stop®, dynamesh®, aris® bandellete and swing-band®. results and complications were recorded. results: the mean age at operation was 61 years. correction of sui was achieved in 87.88% of cases. the best results were obtained with contasure kim® (98.26 % continence). the tape was well tolerated and was elastic enough to be able to be adjusted 48-72 hours after implantation without deformation. slings with macropores and over lock stiches on the superior and inferior borders presented the lower rates of postoperative urinary retention, pain, perior postoperative bleeding and urinary tract infections. conclusions: transobturator tension free tapes require a short operation time and have a low complication rate. the possibility of adjustment in the early postoperative period increases the success rate and reduces complications. knotless meshes with macropores and over lock stiches appear to be better balanced, are quite resistant to stretching and deformation when readjusted after implantation and present a low infection rate. key words: urinary tract; polypropylene; suburethral transobturator tape; physical characteristics. submitted 24 june 2013; accepted 30 june 2013 no conflict of interest declared summary years of age, 20% in women of working age and 14% among women between 40 and 64 years of age (4, 5). the surgical treatment of stress urinary incontinence (sui) in females has changed over time. delancey pointed out the importance of the suburethral sector in any successful surgical strategy for sui (6). in 2001, delorme reported the transobturator approach (tot) which consists of placing a mesh through the obturator foramen behind the mid-urethra (7). doi: 10.4081/aiua.2013.3.149 archivio italiano di urologia e andrologia 2013; 85, 3 b. padilla-fernández, m. begoña garcía-cenador, a. gómez-garcía, j.a. mirón-canelo, á. gil-vicente, j.m. silva-abuín, m.f. lorenzo-gómez 150 there is a multitude of products available for the correction of sui. previous studies have focused on the durability and resistance of the materials but few have addressed clinical results in the short and long term for the various types of tapes available. the goals of our study were to analyze the results obtained with different meshes of various types of materials. materials and methods we conducted a retrospective, multicentric study in a cohort of 363 patients with sui who underwent tot implantation between march 2003 and october 2011 at the university hospital of salamanca and the hospital santísima trinidad of salamanca. a standard study protocol which consisted of anamnesis, general and uro-gynecological physical examination, the iciq-sf incontinence questionnaire (6) and the king’s health or sf36 quality of life tests (7, 8). routine laboratory tests, urine culture and renal and bladder ultrasonography were performed as well. cystography, urodynamic studies, urine cytology and cystoscopy were performed when indicated according to standard practice. surgical procedure: all procedures were performed in a short stay unit with 1 night of hospitalization under spinal anesthesia and under antibiotic coverage. the patient was placed in the dorsal lithotomy position with hyperabducted thighs. a 16 ch balloon catheter with 20 ml in the balloon was inserted in the bladder. extensive hydrodissection between the anterior vaginal wall and the urethra was done. the specially designed fine atraumatic needles were introduced from outside in (figure 1). the tape was attached to the needle and the tape was passed from inside out (figure 2). a vaginal pack was left in place for 12-24 hours. forty-eight to 72 hours later, a revision was performed to evaluate the adjustment of the tape. postoperative controls were performed at one month and one year with anamnesis, and repeat iciq/sf and kings health or sf-36 questionnaires. we compared the results according to the 8 different types of tape utilized. • gynecare tvt-o® (ethicon): polypropylene mesh with macro pores. low density woven mesh (60% porosity). • monarc® (ams): polypropylene mesh with 1 mm diameter macro pores. low density woven mesh (46% porosity). it has acceptable elasticity. • safyre® (promedon) (6): monofilament polypropylene mesh with selfretaining columns of polydimethylsiloxane-polymer . • contasure kim® (neomedic international): knotless monofilament polypropylene tape with over lock stitches in the superior and inferior borders as well as in the middle of the tape. • i-stop® (cl medical): polypropylene mesh with macro pores with spiral borders to maintain rigidity, allow fibrosis and minimize the risk of erosion and migration. • dynamesh® (feg textiltechnik): mesh made of monofilament polyvinylidene fluoride with smooth atraumatic edges. • aris® bandelette (coloplast): woven monofilament polypropylene mesh with macropores. • swing-band® (tht bioscience): light or ultra-light monofilament polypropylene tapes with pores 0.7 to 1.5 cm with low elasticity. we recorded effectiveness and complications taking into account not only continence but overall wellbeing of the patients. complications included lesions to other organs, hemorrhage, hematoma formation, urinary retention, and the development of new urinary incontinence. the data were recorded in an excel® worksheet and imported to ncss® for statistical analysis. fisher exact test, wilcoxon non-parametric test for 2 samples, friedman non-parametric test for more than 2 samples, student’s t-test and pearson chi-square test were used. figure 1. introduction of the fine atraumatic needle from outside-in. figure 2. suburethral tape passed through both obturator foramina. results we implanted tot on 355 women with sui. the median age was 61.16 years (range 41-81 years). incontinence was corrected in 87.88 % of the patients, the rest remained incontinent. the past medical and surgical histories and concomitant treatments were not different among the 8 groups. monarc® tape was used in 42 patients, safyre® in 44, gynecare® in 47, kim system® in 173, i-stop® in 20, dinamesh® in 11, aris® in 4 and swing-band® in 4 (figure 3). contasure kim® presented the best success rate. 98.26% of the women were continent after the operation and tolerated the procedure well. the tape was elastic enough to allow adjustment without deformation (table 1). the success rate with monarch® tapes was overall good (90.47%); however, this tape was inadequate when adjustments were needed because it became elongated and deformed when applying tension. in 4 of the 44 patients who underwent implantation of safyre® tape the retention column became detached from the mesh resulting in incontinence. there was local discomfort and the patients required local anesthesia for the adjustment. the success rate for gynecare® tapes was 82.45%. the tape could be adjusted without deformation. six of 47 women had acute urinary retention which, when corrected, led to permanent urinary incontinence. i-stop®, dynamesh®, aris® and swing-band® tapes had success rates less than 80%, were not malleable and could not be adjusted after implantation. as a group they were less well tolerated and presented a greater rate of urinary retention. tapes with overlock stiches on the superior and inferior edges caused lower rates of postoperative urinary retention (p = 0.0013), patients had less pain (p = 0.0023), intra or post-operative bleeding (p = 0.00013) and urinary tract infections (p = 0.0045). these tapes also allowed postoperative adjustment. tapes made of material with macropores and without knots appear to be better balanced, are highly resistant to deformation allowing a correct and effective postoperative adjustment. 151archivio italiano di urologia e andrologia 2013; 85, 3 results of the surgical correction of urinary stress incontinence according to the type of transobturator tape utilized figure 3. suburethral tapes used. tape success failure comments n = 319 n = 44 n % n % •monarc® 38 90.47 4 9.53 well tolerated. cannot be adjusted because it deforms and elongates. •safyre® 30 68.18 14 31.82 more local discomfort. 4 failures from dissociation of the silicon columns •gynecare® 47 82.45 10 17.55 6 urinary retentions. 4 urinary incontinences. •kim system® 170 98.26 3 1.74 no urinary retention. 3 urinary incontinences. elasticity sufficient to allow adjustment without deformation. well tolerated. •i-stop® 14 70 6 30 4 urinary retention. 2 urinary incontinences. •dynamesh-sis direct: 8 72.72 3 27.27 inelastic. cannot be adjusted. well tolerated. polyvinylidene fluoride (pvdf)® 1 urinary retention. •coloplast bandelette aris® 3 75 1 25 dense, inelastic. cannot be adjusted. •tht swing-band® 3 75 1 25 suburethral with less material to anchor to the fascia. table 1. success rate, complications and tolerability associated to the type of mesh used. archivio italiano di urologia e andrologia 2013; 85, 3 b. padilla-fernández, m. begoña garcía-cenador, a. gómez-garcía, j.a. mirón-canelo, á. gil-vicente, j.m. silva-abuín, m.f. lorenzo-gómez 152 discussion the use of biomaterials in urology is extensive ranging from suture and ligature materials to the use of ureteral and urethral catheters to drain fluids. within this spectrum are the meshes used to correct sui which act as permanent prostheses implanted at the level of the midurethra. the meshes used for this purpose must be biocompatible fulfilling the following conditions (7): • should not induce an inflammatory reaction since both an exaggerated inflammatory reaction and the presence of dead spaces between the mesh and surrounding tissues increase the risk of seroma formation. this is the case when the mesh is slowly or not incorporated into the surrounding tissues such as is the case with meshes with micropores or of high density. (8, 9). • should not induce an allergic reaction since this will lead to rejection and extrusion of the prosthesis (10). • should not induce tumor formation. experimental studies in rats have shown that type 1 meshes induce the development of a surrounding fibrous capsule which becomes integrated from top to bottom through the pores and small spaces between the monofilaments thus producing a firm anchoring to the surrounding tissues (11). this peripheral capsule allows future identification and removal of the tape when necessary. the integration of the capsule on the center decreases mechanical irritation and the chances of extrusion. this encapsulation also facilitates a better blood supply which might lead to less chances of infection (11). meshes with small pores and without structural homogeneity generate a greater local inflammatory reaction and less collagen synthesis. these meshes induce a foreign body reaction rather than fibrosis with the above mentioned consequences (12, 13). moalli et al. (14) studied 5 commonly used meshes in the usa for the correction of siu by the tvt method. the meshes were subjected to traction and elongation to test their resistance and hardness. this study showed that gynecare® and monarc® were easily deformed with low loads which would be clinically manifested by elongation and deformation with minimal tensions. the elongation caused by cyclic loads (such as coughing) might be irreversible. on the other hand, these features lessen the probability of erosion or migration and might reduce the risk of urinary retention (14). the same authors remark that the gynecare® mesh has an initial region of low hardness which allows the mesh to elongate easily in response to small tensions. this is followed by a transition zone and an area that is very hard. they stated that the mesh increases more than 10% of the usual length in response to a series of cyclical loads (14). nevertheless, neymeyer et al. (15) reported that the gynecare® tape presents better tolerance to tension and less elongation, that is better integrated despite loads or tension. mascarenhas studied in depth the mechanical features of the tapes used to treat sui and the mechanical properties of the pelvic floor during delivery and in genital prolapse (16). her intention was to improve the biomechanical analysis of the pelvic floor tissues and improve understanding of the etiology of pelvic floor dysfunction that leads to the development of meshes and prosthesis. this requires interdisciplinary collaboration including engineers and clinicians (16). studies have found significant differences between aris® and gynecare® in regards to hardness tested both by tension and compression (17). others have analyzed the thermal and structural differences of meshes that could in theory influence the development of urethral and vaginal erosions and extrusion. using calorimetric scanning, infrared spectroscopy and analyzing the geometry and lineal and relative densities it was concluded that there is a direct correlation between the diameter of the fibers, the linear density, the degree of crystallinity, the resistance to flexion and the mechanical properties of the tapes (18). the ability of tapes to be adjusted postoperatively appears to be related to the resistance and elasticity which are determined by the porosity, density, type of material used to manufacture the tapes as well as the manner in which the filaments are knitted and the interaction with the host. overlock stiches at the edges of the mesh confers resistance without decreasing elasticity and malleability. in such tapes elongation in response to tension is less both under physiologic conditions and during adjustments. one must be reminded of the fundamental role of careful patient selection, the investigation of risk factors and the selection of a tape with which the surgeon feels comfortable to achieve a successful correction of sui (19, 20). the weakness of our study lies in its retrospective nature and the scant number of patients in some groups. conclusions surgical correction of sui with transobturator tape (tot) is the procedure of choice because of a shorter surgical time and a lower complications rate compared with retropubic tension free tapes (tvt). with this technique, the possibility of adjustment in the early postoperative period increases the chances of cure and reduces complications. macropore meshes without knots and over lock stitches seem to be better balanced, are resistant to elongation and deformation when subjected to the necessary tension for postoperative adjustment. they also present a low rate of infection. references 1. abrahams p, blaivas j, stanton s. the standarization of terminology of lower urinary tract function. scan j urol nephrol 1988; 114-5. 2. international-continence-society. standardization of terminology of lower urinary tract function. urol. 1977; 9:237. 3. serrano r. el 90% de las iu de esfuerzo se evitan con medidas preventivas. madrid: recoletos.es; 2003 [cited 2003 21-10-2003]; http://www.diariomedico.com/edicion/noticia/0,2458,404697,00.html] 4. médico-interactivo-diario-electrónico-de-la-sanidad. más de 800.000 españoles sufren incontinencia urinaria. madrid: meditex, s.l; 2003 [cited 2003]; nº 892, del 10 de enero de 2003 5. norton p, macdonald l, sedgwick p, stanton s. distress and delay associated with urinary incontinence, frequency, and urgency in women. br med j. 1988; 297:1187-9. 6. palma p, riccetto c, herrmann v, et al. transobturator safyre sling is as effective as the transvaginal procedure. int urogynecol j. 2005; 16:487-91. 7. galmés belmonte i, díaz gómez e. ¿son iguales todos los sistemas empleados para corregir la incontinencia urinaria mediante mallas libres de tensión? actas urológicas españolas. 2004; 28:487-96. 8. cervigni m, natale f. the use of synthetics in the treatment of pelvic organ prolapse. curr opin urol. 2001; 11:429-35. 9. falconer c, soderberg m, blomgren b, ulmsten u. influence of different sling materials on connective tissue metabolism in stress urinary incontinent women. int urogynecol j pelvic floor dysfunct. 2001; 12(suppl 2):s19-s23. 10. debodinance p, delporte p, engrand j, boulogne m. development of better tolerated prosthetic materials: applications in gynecological surgery. j gynecol obstet biol reprod. 2002; 31:527-40. 11. slack m, sandhu j, staskin d, grant r. in vivo comparison of suburethral sling materials. int urogynecol j. 2006; 17:106-10. 12. white r. the effect of porosity and biomaterial on the healing and long-term mechanical properties of vascular prostheses. trans am soc artif intern organs. 1988; 34:95-100. 13. white r, hirose f, sproat r, et al. histopathologic observations after short-term implantation of two porous elastomers in dogs. biomaterials. 1981; 2:171-6. 14. moalli pa, papas n, menefee s, et al. tensile properties of five common used mid-urethral slings relative to the tvttm. int urogynecol j. 2008; 19:655-63. 15. neymeyer jn, abdul-wahab waw, spethmann js, et al. material laboratory testing of suburethral mesh slings: a comparison of their static and dynamic properties. eur urol suppl. 2008; 7:316. 16. da silva-filho a, martins p, parente m, et al. translation of biomechanics research to urogynecology. arch gynecol obstet. 2010; 282:149-55. 17. afonso j, martins p, girao m, et al. mechanical properties of polypropylene mesh used in pelvic floor repair. int urogynecol j pelvic floor dysfunct. 2008; 19:375-80 18. afonso j, jorge r, martins p, et al. structural and thermal properties of polypropylene mesh used in treatment of stress urinary incontinence. acta bioeng biomech. 2009; 11:3. 19. lorenzo gómez mf, gómez garcía a, padilla fernández b, et al. factores de riesgo de fracaso de la corrección de la incontinencia urinaria de esfuerzo mediante cinta suburetral transobturatriz. actas urol esp. 2011; 35:454-8. 20. díez-calzadilla na, march-villalba ja, ferrandis c, et al. factores de riesgo en el fracaso de la reparación quirúrgica del prolapso de suelo pelviano. actas urol esp. 2011; 35:448-53. 153archivio italiano di urologia e andrologia 2013; 85, 3 results of the surgical correction of urinary stress incontinence according to the type of transobturator tape utilized correspondence bárbara padilla-fernández, phd, md (corresponding author) padillaf83@hotmail.com juan miguel silva-abuín, phd, md elviso@usal.es ángel gil-vicente, md mflorenzogo@yahoo.es maría fernanda lorenzo-gómez, phd, md mflorenzogo@yahoo.es department of urology, university hospital of salamanca paseo de san vicente, 58-182 37007 salamanca, spain maría begoña garcía-cenador, phd, biol mbgc@usal.es department of surgery, university of salamanca 37007 salamanca, spain ana gómez-garcía, phd, md agogarci@hotmail.com family and community medicine, university hospital of salamanca 37007 salamanca, spain josé antonio mirón-canelo, phd, md miroxx@usal.es department of preventive medicine and public health university of salamanca campus miguel de unamuno faculty of medicine c/ alfonso x el sabio, s/n 37007 salamanca, spain stesura seveso 1archivio italiano di urologia e andrologia 2014; 86, 1 original paper antioxidant cosupplementation therapy with vitamin c, vitamin e, and coenzyme q10 in patients with oligoasthenozoospermia yoshitomo kobori, shigeyuki ota, ryo sato, hiroshi yagi, shigehiro soh, gaku arai, hiroshi okada department of urology, dokkyo medical university, koshigaya hospital, japan. objective: overproduction of reactive oxygen species results in oxidative stress, a deleterious process that damages cell structure as well as lipids, proteins, and dna. oxidative stress plays a major role in various human diseases, such as oligoasthenozoospermia syndrome. materials and methods: we evaluated the effectiveness of antioxidant co-supplementation therapy using vitamin c, vitamin e, and coenzyme q10 in men with oligoasthenozoospermia. overall, 169 infertile men with oligoasthenozoospermia received antioxidant therapy with 80 mg/day vitamin c, 40 mg/day vitamin e, and 120 mg/day coenzyme q10. we evaluated spermiogram parameters at baseline and at 3 and 6 months of follow-up. results: significant improvements were evident in sperm concentration and motility following coenzyme q10 therapy. treatment resulted in 48 (28.4%) partner pregnancies, of which 16 (9.5%) were spontaneous. significant improvements in sperm cell concentration and sperm motility were observed after 3 and 6 months of treatment. conclusions: vitamin c, vitamin e, and coenzyme q10 supplementation resulted in a significant improvement in certain semen parameters. however, further studies are needed to empirically determine the effect of supplementation on pregnancy rate. key words: vitamin c; vitamin e; coenzyme q10; male infertility. submitted 27 august 2013; accepted 5 october 2013 summary introduction there is much evidence to show that oxidant radicals and reactive oxygen species play a harmful role in human reproduction and male infertility (1). testicular oxidative stress is important in a number of conditions known to be detrimental to male infertility. these include a broad spectrum of diseases and conditions due to lifestyle factors such as smoking, alcohol, and obesity (2), environmental hazards such as pestino conflict of interest declared. cides, plasticizers, and heavy metals (3), systemic infections (4), chronic diseases and inflammation such as diabetes, chronic renal failure, and varicocele (5), and a number of iatrogenic or idiopathic causes (6). a previous open, controlled pilot study of a cohort of infertile men with idiopathic asthenozoospermia showed that exogenous administration of coenzyme q10 (coq10) increases the level of both coq10 and ubiquinol (qh2) in semen and is effective in improving sperm kinetics (7). in addition, administration of vitamins e and c significantly reduced hydroxyguanine levels in spermatozoa and led to an increased sperm count (8). we previously found that a relatively low intake of coq10 (30-60 mg/day) improved semen parameters (unpublished data). these data encouraged us to assess the possible effectiveness of this therapeutic approach by conducting a 6month trial of cosupplementation antioxidant therapy (vitamin c, vitamin e, and coq10) in a cohort of infertile men with idiopathic oligoasthenozoospermia. change in semen parameters and achievement of pregnancy were evaluated after 6 months of treatment. materials and methods patients a total of 169 consecutive patients (mean age 36, range 25-58 years) with idiopathic oligoasthenoteratozoospermia were enrolled in the study. all presented with infertility after at least 2 years of unprotected intercourse. male infertility was diagnosed if one or more standard semen parameters were below the cutoff levels according to the criteria of the world health organization, 1999 (sperm concentration < 20 ! 106/ml, sperm motility < 50%, normal morphology < 30%, and/or semen volume < 2 ml) based on at least two semen analyses performed 3 months apart to eliminate accidental and possible adverse effects of exogenous factors on spermatogenesis. after providing a complete medical and reproductive history exploring all aspects that might be related to fertility, patients underwent physical examination and doi: 10.4081/aiua.2014.1.1 kobori_stesura seveso 26/03/14 10:10 pagina 1 archivio italiano di urologia e andrologia 2014; 86, 1 y. kobori, s. ota, r. sato, h. yagi, s. soh, g. arai, h. okada 2 serum chemical and hematological laboratory tests. testicular volume was measured using an orchidometer. serum follicle stimulating hormone, luteinizing hormone, and testosterone levels were measured in all patients. patients with infection, liver dysfunction, renal dysfunction, or a metabolic disease (e.g., diabetes mellitus) were excluded, as were patients with malignant neoplasm and those with spouses with diseases or conditions that may affect conception. study design all patients underwent antioxidant therapy with 120 mg coq10, 80 mg vitamin c, and 40 mg vitamin e daily (two tablets of so support; partners, yokohama, japan). semen parameters were evaluated before and at 3 and 6 months of treatment with co-supplementation. pregnancy outcome and use of assisted reproduction technology was evaluated after 3 and 6 months of treatment. ethics all patients provided informed consent. the study design was approved by the institutional review board. statistical analysis statistical analysis was performed using spss 17.0 (spss inc., chicago, il). data are expressed as mean ± sd values. differences between groups were estimated using the paired t-test. p < 0.05 was considered statistically significant for hypothesis testing. results baseline patient characteristics are shown in table 1. the mean duration of infertility was 2.3 years. table 2 shows mean (± sd) semen parameters before and at 3 and 6 months of treatment. the t-test performed on single variables for the homogeneity at baseline showed that there were no significant differences regarding atypical sperm cells and semen volume. on the contrary, significant improvements in sperm cell concentration and sperm motility were observed after 3 and 6 months of treatment. a total of 48 (28.4%) pregnancies were achieved, including 16 (9.5%) spontaneous pregnancies as follows: seven after 3 months, eight after 6 months, and one after 9 months of treatment. overall, 32 pregnancies were achieved using assisted reproductive technology. six couples used artificial insemination by husband (aih), eight couples used conventional in vitro fertilization (ivf) and 18 couples used intracytoplasmic sperm injection (icsi). oral administration of coq10, vitamin c, and vitamin e was generally well tolerated, and no adverse effects or laboratory abnormalities were observed. discussion several approaches have been proposed for the management of infertility caused by oxidative stress. once an individual has been identified as having oxidative stressrelated infertility, treatment should be aimed at identification and amelioration of the underlying cause before considering antioxidant treatment. lifestyle behaviors such as smoking, poor diet, alcohol abuse, pollution and environmental toxins, obesity, and psychological stress have all been linked to oxidative stress. while the effectiveness of eliminating these lifestyle triggers on oxidative stress has not been formally tested, it is likely that characteristic range mean ± sd age (yrs) 25-58 36 ± 9 age of wife (yrs) 22-44 34 ± 8 serum hormones testosterone (ng/dl) 169-988 406 ± 88 lh (iu/l) 1.1-11.5 3.5 ± 2.4 fsh (iu/l) 1.6–26.8 5.0 ± 4.1 testicular volume (ml) right 8-26 18 ± 5 left 4-26 16 ± 5 fsh: follicle stimulating hormone; lh: luteinizing hormone table 1. baseline patient demographics, serum hormone levels, and semen parameters. baseline 3 months 6 months sperm variable mean ± sd mean sd mean sd sperm concentration (n x 106/ml) 26.3 ± 36.0 37.5 54.0 49.0 ± 59.0 p value 0.03 < 0.001 sperm motility (%) 25.2 ± 18.1 39.1 ± 20.3 41.3 ± 22.1 p value < 0.001 < 0.001 atypical sperm cells (%) 25.4 ± 10.0 22.6 ± 10.3 23.4 ± 12.0 p value 0.43 0.44 semen volume (ml) 3.1 ± 1.9 3.1 ± 2.2 4.3 ± 2.9 p value 0.78 0.08 table 2. descriptive statistics of sperm variables throughout the study. kobori_stesura seveso 26/03/14 10:10 pagina 2 making positive lifestyle changes such as changing to a diet high in fruit and vegetables, maintaining normal weight, and reducing smoking or alcohol intake would have at least some beneficial effects on sperm health. several studies have reported that levels of reactive oxygen species within semen can be reduced by augmenting the scavenging capacity of seminal plasma using oral antioxidant supplements. vitamin e is a major chain-breaking antioxidant in sperm membranes and this effect appears to be dose dependent. vitamin e scavenges the three major types of free reactive species, namely superoxide, hydrogen peroxide, and hydroxyl radicals. in a randomized, doubleblind, placebo-controlled trial (9), in vitro functional tests of human spermatozoa improved after 3 months of vitamin e (600 mg/day) therapy. while some studies suggest a potential role for vitamin e in the management of male infertility, another randomized trial failed to confirm these findings (10). vitamin c is another important chain-breaking antioxidant and is present at a higher concentration in seminal fluid than in plasma as well as being present in low but detectable amounts in sperm cells (11). vitamin c neutralizes hydroxyl, superoxide, and hydrogen peroxide reactive species and prevents sperm agglutination, while preventing lipid peroxidation, recycling vitamin e, and protecting against dna damage induced by hydrogen peroxide radicals (12). it has been suggested that oral administration of vitamin c with vitamin e significantly reduces hydroxyguanine levels in spermatozoa and also leads to an increased sperm count (8). coq10 is a component of the mitochondrial respiratory chain and plays a crucial role in energy metabolism and as a liposoluble chain-breaking antioxidant for cell membranes and lipoproteins (13). recently, the role of coq10 as a gene inducer has also been investigated (14). coq10 biosynthesis is markedly active in the testis (15), and high levels of its reduced form, qh2, are present in sperm (16), suggesting a protective antioxidant role. levels of coq10 and qh2 in seminal plasma and sperm cells of infertile men with idiopathic and varicocele-associated asthenospermia were reduced significantly (17). on the basis of this finding, coq10 likely contributes to the total antioxidant buffer capacity of semen, and a decrease in levels is deleterious in terms of dealing with oxidative stress. the mode of action of coq10 in male infertility is not clear but may be useful for vitalizing cells by providing greater energy to mitochondria, thereby improving motility and preventing oxidative damage through its actions as a free radical scavenger. coq10 recycles vitamin e and prevents its pro-oxidant activity (18). qh2 also acts as an antioxidant by preventing lipid peroxidation, whereas coq10 inhibits hydrogen peroxide formation in the seminal fluid and seminal plasma of infertile men (19). in a randomized, double-blind, placebo-controlled trial, the exogenous administration of coq10 increased the level of both coq10 and qh2 in semen and was effective in improving sperm kinetics in patients with idiopathic asthenozoospermia (17). when a molecule of vitamin e neutralizes a free radical it loses its antioxidant ability which is subsequently restored by the actions of other antioxidants such as vitamin c and coq10 (20). the synergy provided by combination supplementation may improve the qualitative and quantitative parameters of the seminogram in patients with oligoasthenoteratozoospermia. conclusion co-administration of vitamin c, vitamin e, and coq10 may play a positive role in the treatment of oligoasthenozoospermia, possibly mediated by the mitochondrial respiratory chain and by its antioxidant effects. however, further studies are needed to draw firm conclusions; the effect of such supplementation on pregnancy rate is currently being investigated in a randomized, double-blind, placebo-controlled trial. references 1. alvarez jg, storey b. spontaneous lipid preoxidation in rabbit epididymal spermatozoa: its effect on sperm motility. biol reprod. 1982; 27:1102-8. 2. singer g, granger dn. inflammatory responses underlying the microvascular dysfunction associated with obesity and insulin resistance. microcirculation. 2007; 14:375-87. 3. aitken rj, koopman p, lewis sem. seeds of concern. nature 2004; 432:48-52. 4. reddy mm, mahipal sv, subhashini j, et al. bacterial lipopolysaccharide-induced oxidative stress in the impairment of steroidogenesis in rats. reprod toxicol. 2006; 22:493-500. 5. fretz pc, sandlow ji. varicocele: current concepts in pathophysiology, diagnosis, and treatment. urol clin north am. 2002; 29:921-38. 6. arnon j, meirow d, lewis-roness h, ornoy a. genetic and teratogenic effects of cancer treatments on gametes and embryos. hum reprod update. 2001; 7:394-403. 7. balercia g, arnoldi g, fazioli f, et al. coenzyme q10 levels in idiopathic and varicocele-associated asthenozoospermia. andro lo gia. 2002; 34:107-11. 8. kodama h, yamaguchi r, fukuda j, et al. increased oxidative deoxyribonucleic acid damage in the spermatozoa of infertile male patients. fertil steril. 1997; 68:519-24. 9. kessopoilou e, powers hj, sharma kk, et al. a double blind randomized placebo cross over controlled trial using the antioxidant vitamine e to treat reactive oxygen species associated male infertility. fertil steril. 1995; 64:825-31. 10. rolf c, cooper tg, yeung ch, nieschlag e. antioxidant treatment of patients with asthenozoospermia or moderate oligoasthenozoospermia with high-dose vitamin c and vitamine e: a randomized, placebo-controlled, double-blind study. hum reprod. 1999; 14:1028-33. 11. saeid g, ismail l. antioxidant therapy in human endocrine disorders. med sci monit. 2010; 16:9-24. 12. buettner gr. the pecking orded of free radicals and antioxidants: lipid peroxidation, alpha-tocopherol, and ascorbate. arch biochem biophys. 1993; 300:535-43. 13. ernster l, forsmark-andree p. ubiquinol: an endogenous antioxidant in aerobic organisms. clin invest. 1993; 71:60-5. 3archivio italiano di urologia e andrologia 2014; 86, 1 antioxidant cosupplementation therapy with vitamin c, vitamin e, and coenzyme q10 in patients with oligoasthenozoospermia kobori_stesura seveso 26/03/14 10:10 pagina 3 archivio italiano di urologia e andrologia 2014; 86, 1 y. kobori, s. ota, r. sato, h. yagi, s. soh, g. arai, h. okada 4 14. groneberg d, kindermann b, althammer m, et al. coenzyme q10 affects expression of genes involved in cell signaling, metabolism and transport in human caco-2 cells. int j biochem cell biol. 2005; 37:1208-18. 15. kalen a, applekvist el, chojnaki t, dallner g. nonaprenyl-4hydroxibenzoate transferase, an enzyme involved in ubiquinone biosynthesis in endoplasmic reticulum-golgi system. j bio chem. 1990; 25:1158-64. 16. mancini a, de marinis l, littarru gp, balercia, g. an update of coenzume q10 implications in male infertility: biochemical and therapeutic aspects. biofactors. 2005; 25: 165-74. 17. balercia g, buldreghini e, vigini a, et al. coenzyme q10 treatment in infertile men with idiopathic asthenozoospermia: a placebo-controlled, double blind randomized trial. fertil steril. 2009; 91:1785-92. 18. thomas sr, neuzil j, stocker r. cosupplementation with coenzyme q prevents the prooxidant effect of alpha-tocopherol and increases the resistance of ldl to transition mental-dependent oxidation initiation. arterioscler thromb vasc biol. 1996; 17:687-96. 19. alleva r, scararmucci a, mantero f, bompadre s, leoni l et al. the protective role of ubiquinol-10 against formation of lipid hydroperoxides in human seminal fluid. mol aspects med. 1997; 18:s221-8. 20. huang hy, caballero b, chang s, et al. multivitamin/mineral supplements and prevention of chronic diseases. evid rep technol assess (full rep) 2006; 139:1-117. correspondence yoshitomo kobori, md (corresponding author) ykobori@dokkyomed.ac.jp shigeyuki ota, md ryo sato, md hiroshi yagi, md shigehiro soh, md gaku arai, md hiroshi okada, md department of urology, dokkyo medical university, koshigaya hospital 2-1-50, minamikoshigaya, koshigaya (japan) 343-8555 kobori_stesura seveso 26/03/14 10:10 pagina 4 stesura seveso 99archivio italiano di urologia e andrologia 2014; 86, 2 original paper urolithiasis in italy: an epidemiological study domenico prezioso 1, ester illiano 1, gaetano piccinocchi 2, claudio cricelli 2, roberto piccinocchi 3, alberto saita 4, carla micheli 5, alberto trinchieri 6 1 department of neuroscience, reproductive sciences and dentistry, university federico ii of naples, naples, italy; 2 simg, italian society of general medicine; 3 university “campus biomedico” of rome, rome, italy; 4 department of urology, “vittorio emanuele hospital”, university of catania, catania, italy; 5 department of urology and andrology, santa maria della misericordia hospital, university of perugia, perugia, italy; 6 department of urology alessandro manzoni hospital of lecco, lecco, italy. objectives: worldwide the urolithiasis is the third most frequent urological disease affecting both males and females. in literature there are not recent italian epidemiological data about stone disease. the objective of this study is the evaluation of current epidemiology of urolithiasis in italy using the health search/csd longitudinal patient database (hs) database. material and methods: an observational, descriptive, retrospective trial was conducted. inclusion criteria were: family physicianassisted italian living population member of hs database within 31 december 2012, both genders, age over 17 years, at least two years of clinical history recorded from the beginning the trial. data were collected by hs database and elaborated by its software millewin®. results: in italy prevalence of urolithiasis in 2012 was 4.14%, it was higher in males than in females (4.53% versus 3.78%) with a positive relation with increasing age. the highest prevalence rate of urolithiasis was reported in the region campania (6.08%). the general incidence was 2.23 *1000, with the highest incidence in the region sicilia (3.15 *1000). incidence was higher in group age 65-74 years (3.18 *1000). conclusions: in italy the incidence and prevalence of urolithiasis is increasing with particular distribution in relation to gender, age and regional position. key words: urolithiasis, prevalence; incidence; epidemiological trial. submitted 26 january 2014; accepted 31 march 2014 summary introduction urolithiasis is a major clinical and economic burden for healthcare systems; infact is a highly prevalent condition with a high recurrence rate that has a large impact on the quality of life of those affected (1). in 1994 in italy the national institute of statistics (istat) database showed the prevalence as 1.7% and the incidence as 0.17 case/1000 patient with 95000 new cases/year. a national study of family physicians of the società italiana di me dicina generale (simg) in 2006 showed that 19% patients with urolithiasis undergo urologic visit, 4.6% hospitalization, 48.8% ultrano conflict of interest declared. sonography (us), 7.2% urography, 2.6% non-contrast enhanced computed tomography (ncct), 3.4% kidneyureter-bladder radiography (kub) (2). international epidemiological data suggest that the incidence and prevalence of stone disease is increasing (3-11) and an increase is recorded mainly in industrialized countries, as well in western countries probably resulting from improvements in clinical-diagnostic procedures and changes in nutritional and environmental factors (12). many population-based studies investigated prevalence and incidence rates of urolithiasis in different countries. nevertheless it is important to emphasize that precise data on the epidemiology of a disease or disorder can only be determined if geographical position, race, age and sex, climate, nutrition and other environmental factors are also taken in consideration. when analysing the literature, we can highlight the scarcity of new italian epidemiological data about stone disease. these epidemiological data are very important in the planning of health services and social-health; in clinical governance and in assessing the quality of services performed and their impact in terms of both clinical benefits as well as financial savings. to achieve these goals is needed to draw the real dimension of problem, especially the epidemiological dimension. in the latter part of the 20th century and in the early of 21th century a growing application of epidemiological methods was observed, with well-structured analysis of prescriptive profile and flow chart. in italy this system was combined with an evolution in the management of health informatics systems from the collection and storage of performance data and the related reimbursement by the regional health system (eg. hospitalizations, outpatient specialist care, pharmaceutical prescriptions). these are business systems, however are used as economic, clinical and epidemiological database also. this study seeks to evaluate current italian epidemiological situation about stone disease using health search/csd longitudinal patient database (hs) database used by simg. material and methods the study was designed as a observational, descriptive, retrospective trial. the objective is the evaluation of total doi: 10.4081/aiua.2014.2.99 archivio italiano di urologia e andrologia 2014; 86, 2 d. prezioso, e. illiano, g. piccinocchi, c. cricelli, r. piccinocchi, a. saita, c. micheli, a. trinchieri 100 prevalence and incidence of urolithiasis in italian population in 2012 divided by region, age and gender. inclusion criteria were: family physicianassisted italian living population members included in hs database within 31 december 2012 of both genders, aged over 17 years, with at least two years of clinical history recorded from the beginning the trial. the physicians participating to the study were 650 and were considered the most reliable among 1000 family physicians using hs. in fact in 1998 1000 italian familyphysicians were involved in a project of electronic medical recording (emr) in order to create a large hs database. in 2009, 650 italian family-physicians out of the total 1000 italian family-physician initially involved were selected according to their geographical distribution (northeast, northwest, central, south, islands). this group of “selected” 650 family physicians is composed by family physicians who ensured the best quality of reporting in epidemiological research. in order to select this group a quality score was calculated for each family physician. the geographical distribution of patients of these family physicians is similar to general italian population census by istat, without significant differences both in geographical location and age distribution. registered informations were: demographic informations and clinical informations such as body mass index (bmi), smoking, pressure blood value, biochemistry data, imaging, hospitalization, drugs etc. each patient was labelled with a nameless code, so all informations of each patient were reported with equivalent code. the nomenclature of was concordant with official journal, drug’s names were concordant with coding of anatomical therapeutic chemical classification system (atc) and diseases were concordant with coding of international classification of diseases 9° edition (icd-9). data were collected by the database health search and elaborated by its software millewin®. results the examined population is 900.994 with a regional allocation showed in table 1. this table shows the numbers (and rates) of family physician-assisted italian living population members included in hs database within 31 total male female region n % n % n % piemonte/aosta 61701 6.85 29756 6.87 31945 6.82 liguria 29791 3.31 14081 3.25 15710 3.36 lombardia 140973 15.65 69138 15.97 71835 15.34 trentino/fvg 46451 5.16 22196 5.13 24255 5.18 veneto 72553 8.05 35135 8.12 37418 7.99 emilia romagna 54403 6.04 25421 5.87 28982 6.19 toscana 46800 5.19 22555 5.21 24245 5.18 umbria 25127 2.79 11996 2.77 13131 2.80 marche 24930 2.77 12249 2.83 12681 2.71 lazio 79945 8.87 37788 8.73 42157 9.00 abruzzo/molise 29723 3.30 14035 3.24 15688 3.35 campania 77616 8.61 37134 8.58 40482 8.65 puglia 65505 7.27 31682 7.32 33823 7.22 basilicata/calabria 41207 4.57 20052 4.63 21155 4.52 sicilia 81595 9.06 38830 8.97 42765 9.13 sardegna 22666 2.52 10765 2.49 11901 2.54 total 900.994 100.00 432816 100.00 468178 100.00 ffvg: friuli venezia giulia. hs: health search/csd longitudinal patient database. n: number. table 1. family physician-assisted italian living population member of database hs within 31 december 2012 by italian region and gender. total male female region n % n % n % piemonte/aosta 2237 3.63 1241 4.17 996 3.12 liguria 1104 3.71 634 4.50 470 2.99 lombardia 4413 3.13 2547 3.68 1866 2.60 trentino/fvg 1216 2.62 699 3.15 517 2.13 veneto 2119 2.92 1222 3.48 897 2.40 emilia romagna 2486 4.57 1436 5.65 1050 3.62 toscana 1756 3.75 1063 4.71 693 2.86 umbria 960 3.82 592 4.94 368 2.80 marche 1334 5.35 770 6.29 564 4.45 lazio 3160 3.95 1635 4.33 1525 3.62 abruzzo/molise 1306 4.39 659 4.70 647 4.12 campania 4718 6.08 2105 5.67 2613 6.46 puglia 3072 4.69 1461 4.61 1611 4.76 basilicata/calabria 2107 5.11 977 4.87 1130 5.34 sicilia 4355 5.34 2135 5.50 2220 5.19 sardegna 966 4.26 446 4.14 520 4.37 total 37316 4.14 19626 4.53 17690 3.78 ffvg: friuli venezia giulia. hs: health search/csd longitudinal patient database. n: number. table 3. prevalence of urolithiasis in family physician-assisted italian living population member of database hs within 31 december 2012 by italian region and gender. total male female age n % n % n % 15-24 92113 10.22 47883 11.06 44230 9.45 25-34 121663 13.50 60975 14.09 60688 12.96 35-44 160896 17.86 79737 18.42 81159 17.34 45-54 163813 18.18 80216 18.53 83597 17.86 55-64 135266 15.01 66156 15.29 69110 14.76 65-74 114032 12.66 54314 12.55 59718 12.76 75-84 80967 8.99 33309 7.70 47658 10.18 ≥ 85 32244 3.58 10226 2.36 22018 4.70 hs: health search/csd longitudinal patient database. n: number. table 2. family physician-assisted italian living population member of database hs within 31 december 2012 by class age and gender. december 2012 divided by italian re gion and gender (432.816 male versus 468.178 female) while table 2 shows the same population divided by class age (64.55% 25-64 years, while 12.57% ≥ 75 years) and gender (66.33% 2564 years males versus 62.92% 25-64 years females). patients members of hs database within 31 december 2012 with urolithiasis were 37.316, 4.14% of total family physician-assisted italian living population members of hs database within 31 december 2012 (table 3). this table shows an higher prevalence in males compared to females (m 4.53% versus f 3.78%) also, while table 4 shows a positive relation with increasing age. the highest prevalence (6.08%) of urolithiasis was observed in campania (table 3), followed by marche 5.35% and sicilia 5.34% whereas the lowest was recorded in trentino/friuli ve ne zia giulia 3.15% (table 3). in almost all the italian regions the prevalence of stone disease is higher in males (table 3), but in some regions such as campania (m 5.67% vs f 6.46%), puglia (m 4.61% vs f 4.76%), basilicata/cala bria (m 4.87% vs f 5.34%), and sar degna (m 4.14% vs f 4.37%) the prevalence is higher in females (table 3). the higher prevalence was observed in 65-74 years class age (table 4), rating 6.71% (m 8.02% and f 5.51%), follo wed by the 75-84 years (6.35%) and 55-64 years (5.92%) age groups (table 4). in ci dence of urolithiasis in family physician-assisted italian living population member of hs database within 31 december 2012 was 2.23 *1000, with the highest rate in sicilia (3.15 *1000) (table 5). in emilia romagna an higher incidence was recorded among males (3.43 *1000), while in sicilia among females (3.49 *1000) (table 5). as well as the prevalence, the incidence was higher in 65-74 years group age (3.18 *1000) (table 6). female are more affected in this group age (3.03 *1000), while male in 55-64 years group age (3.53 *1000) (table 6). discussion when comparing the epidemiological data of this study with those from literature, temporal references should be taken into account in fact population members of hs database were included within 31 december 2012, whereas those in the literature are related to previous periods, and this condition may have influence on the epidemiology of this chronic disease whose prevalence and incidence trends in recent decades have been changing. the lifetime prevalence of kidney stone disease is estimated at 1% to 15%, with the probability of having a stone varying according to age, gender, race, and geographic location. in previous reports the prevalence of kidney stones varied greatly between geographic locations, ranging from 8% to 19% in males and from 3% to 5% in females in western countries (12). it has been apparent for several years that the inci101archivio italiano di urologia e andrologia 2014; 86, 2 urolithiasis in italy: an epidemiological study total male female region n *1000 n *1000 n *1000 piemonte/aosta 106 1.71 61 2.05 45 1.39 liguria 77 2.54 36 2.52 41 2.55 lombardia 296 2.05 163 2.31 133 1.80 trentino/fvg 53 1.10 29 1.27 24 0.95 veneto 105 1.40 57 1.58 48 1.23 emilia romagna 153 2.72 90 3.43 63 2.10 toscana 78 1.44 45 1.73 33 1.17 umbria 45 1.77 32 2.66 13 0.97 marche 51 2.02 33 2.67 18 1.40 lazio 230 2.72 107 2.71 123 2.73 abruzzo/molise 63 1.97 30 2.00 33 1.95 campania 218 2.71 114 2.97 104 2.47 puglia 174 2.53 78 2.36 96 2.70 basilicata/calabria 113 2.66 64 3.10 49 2.24 sicilia 260 3.15 108 2.76 152 3.49 sardegna 61 2.52 30 2.61 31 2.44 total 2090 2.23 1082 2.42 1008 2.06 ffvg: friuli venezia giulia. hs: health search/csd longitudinal patient database. n: number. table 5. incidence of urolithiasis in family physician-assisted italian living population member of database hs within 31 december 2012 by italian region and gender. total male female age n *1000 n *1000 n *1000 15-24 81 0.95 34 0.77 47 1.15 25-34 184 1.49 89 1.44 95 1.54 35-44 309 1.86 179 2.18 130 1.54 45-54 438 2.56 226 2.70 212 2.42 55-64 447 3.12 246 3.53 201 2.74 65-74 388 3.18 193 3.34 195 3.03 75-84 211 2.40 100 2.75 111 2.15 ≥ 85 32 0.86 15 1.26 17 0.67 hs: health search/csd longitudinal patient database. n: number. table 6. incidence of urolithiasis in family physician-assisted italian living population member of database hs within 31 december 2012 by age and gender. total male female age n % n % n % 15-24 601 0.65 236 0.49 365 0.83 25-34 2303 1.89 928 1.52 1375 2.27 35-44 4903 3.05 2384 2.99 2519 3.10 45-54 7381 4.51 3941 4.91 3440 4.12 55-64 8012 5.92 4562 6.90 3450 4.99 65-74 7646 6.71 4355 8.02 3291 5.51 75-84 5142 6.35 2633 7.91 2509 5.27 ≥ 85 1328 4.12 587 5.74 741 3.37 hs: health search/csd longitudinal patient database. n: number. table 4. prevalence of urolithiasis in family physician-assisted italian living population member of database hs within 31 december 2012 by age and gender. archivio italiano di urologia e andrologia 2014; 86, 2 d. prezioso, e. illiano, g. piccinocchi, c. cricelli, r. piccinocchi, a. saita, c. micheli, a. trinchieri 102 dence rates of lithiasis vary dramatically, not only from continent to continent, but also between adjacent regions of a country, even if one allows for differences in methodology and criteria selection among epidemiology studies (13, 14) infact epidemiological data on the occurrence of urolithiasis ranges between 2% and 20% worldwide (15, 16) (being most common in south and south eastern regions of united states, as well as in central europe and the me diterranean area, india and northern pakistan, northern australia and china) (17) in our study the prevalence in 2012 in italy is 4.14%, while the incidence is 2.23 *1000, with a geographic distribution showing higher prevalences and incidences in southern regions. this can be easily explained, by the well documented knowledge that the incidence of urinary stones is higher in countries with warm or hot climates, probably due to low urinary output and scant fluid intake (18). seasonal variation in stone disease is likely related to temperature by way of fluid losses through perspiration and perhaps by sunlight –induced increases in vitamin d (19). in a previous study of the simg (2) in 2008, the prevalence of urolithiasis in italy was evaluated at a lower rate of 3.1%. the higher rate demonstrated in the present study confirm in our country the increasing trend reported in the rest of the world. stone disease typically affects adult men more commonly than adult woman (12). howerver scales et al. (20) observed a dramatic increase from 1997 to 2002 of the adjusted rate of discharges for stone disease in females in american population with a change from 1.7:1 to 1.3:1 of the male-tofemale ratio. the increasing incidence of nephrolithiasis in women might be due to lifestyle associated risk factors, such as obesity (20). in italy the rates in 2012 confirm the 2008 data (2) with higher prevalence in males than in females (m 3.4 vs. f 2.8%) but contrasting results were observed in southern regions.. data from the american database national health and nutrition examination survey (nhanes) indicate that stone prevalence increased in all age groups from 1980 to 1994 though, despite more than 15,000 participants at each time point, the increase was statistically significant only for men aged 60-74 (21). in italy hypercalciuria was more frequent in patients aged 20-39 years (50.3%) than in older patients (36%) and hyperuricosuria was lower in the younger patients (5%) than in the older patients (10%) (22). in our study the age group most affected is 65-74 years (6.71%, m 8.02% and f 5.51%), instead of the 55-64 years age group (4.5% m 5.40% and f 3.60%) in 2008 (2), however in both studies a similar trend was observed. conclusions this is the first study that evaluated prevalence and incidence of urolithiasis in italy by age, gender and italian region. these data are important for clinical workforce planning, training, service delivery and research in the field of urolithiasis. references 1. semins mj. medical evaluation and management of urolithiasis. ther adv urol. 2010; 2:3-9. 2. campo s, pasqua a, simonetti m, mazzaglia g. studio sulla nefrolitiasi nel setting delle cure primarie italiane. rivista della società italiana di medicina generale 2011; 2:1-5. 3. pearle m, calhoun e, curhan g. urologic diseases in america project: urolithiasis j urol. 2005; 173:848-57. 4. romero v, akpinar h, assimos d. kidney stones: a global picture of prevalence, incidence, and associated risk factors. rev urol. 2010; 12:86-96. 5. stamatelou k, francis m, jones c, et al. time trends in reported prevalence of kidney stones in the united states: 1976-1994. kidney int. 2003; 63:1817-23. 6. soucie j, thun m, coates r, et al. demographic and geographic variability of kidney stones in the united states. kidney int. 1994; 46:893-9. 7. sánchez-martín f, millan rodríguez f, esquena fernández s, et al. incidence and prevalence of published studies about urolithiasis in spain. a review. actas urol esp. 2007; 31:511-20. 8. amato m, lusini m, nelli f. epidemiology of nephrolithiasis today. urol int. 2004; 72 (suppl. 1):1-5. 9. serio a, fraioli a. epidemiology of nephrolithiasis. nephron. 1999; 81 (suppl. 1):26-30. 10. hesse a, brändle e, wilbert d, et al. study on the prevalence and incidence of urolithiasis in germany comparing the years 1979 vs. 2000. eur urol. 2003; 44:709-13. 11. trinchieri a, coppi f, montanari e, et al. increase in the prevalence of symptomatic upper urinary tract stones during the last ten years. eur urol. 2000; 37:23-5. 12. trinchieri a. epidemiology of urolithiasis: an update clinical cases in mineral and bone metabolism. 2008; 5:101-106. 13. andersen da. histological and geographical differences in the pattern of incidence of urinary stones in relation to possible aetiological factors. renal stone research. edinburgh: churchill livingstone 1969; 22-29. 14. pak cy. kidney stone. lancet. 1998; 351:1797-1801. 15. hesse a, siener r. current aspects of epidemiology and nutrition in urinary stones.world j urol. 1997; 15:167-171. 16. trinchieri a. epidemiology of urolithiasis. arch it urol. 1996; 68:203-250. 17. finlayson b. renal lithiasis in review. urologic clinics of north america 1974; 180-1. 18. lópez m, hoppe b. history, epidemiology and regional diversities of urolithiasis pediatr nephrol. 2010; 25:49-59. 19. sternberg k, greenfield sp, williot p, wan j. pediatric stone disease: an evolving experience. j urol. 2005; 174:1711-1714. 20. scales cd jr, curtis lh, norris rd, et al. changing gender prevalence of stone disease. j urol. 2007; 177:979-82. 21. stamatelou kk, francis me, jones ca, et al. time trends in reported prevalence of kidney stones in the usa:1976-1994. kidney int. 2003; 64:1817-1823. 22. vitale c, tricerri a, manganaro m, et al. clinical and metabolic features of renal calculi in adults in regard to age of onset. minerva urol nefrol. 1999; 51:71-74. correspondence domenico prezioso, md (corresponding author) ester illiano, md department of neuroscience, reproductive sciences and dentistry. university federico ii of naples, naples, italy gaetano piccinocchi, md simg. italian society of general medicine claudio cricelli, md simg. italian society of general medicine roberto piccinocch, md university “campus biomedico” of rome, italy alberto saita, md department of urology. “vittorio emanuele hospital”. university of catania, italy carla micheli, md department of urology and andrology. santa maria della misericordia hospital. university of perugia, perugia, italy alberto trinchieri, md department of urology alessandro manzoni hospital of lecco, lecco, italy stesura seveso archivio italiano di urologia e andrologia 2014; 86, 290 original paper comparison of the urethrovesical anastomoses with polyglecaprone (monocryl®) and bidirectional barbed (v-loc 180®) running sutures in laparoscopic radical prostatectomy murat arslan 1, altug tuncel 2, yilmaz aslan 2, zafer kozacioglu 3, bulent gunlusoy 3, ali atan 2 1 izmir university school of medicine, department of urology, izmir-turkey; 2 ministry of health, ankara numune research and training hospital, third department of urology, ankara-turkey; 3 ministry of health, bozyaka research and training hospital, department of urology, izmir-turkey. . objective: we compared polyglecaprone (monocryl®) and bidirectional barbed (v-loc® 180) running sutures during urethrovesial anastomosis (uva) in laparoscopic radical prostatectomy (lrp). materials and methods: a total of 92 consecutive patients underwent extraperitoneal lrp for prostate cancer. in the first 47 patients, the running uva was performed using 3-0 monofilament polyglecaprone (monocryl®) suture (group 1). in the subsequent 45 patients, the running uva was performed with the 3-0 barbed suture (v-loc® 180) (group 2). rhabdosphincter reconstruction was performed in all the patients. results: the mean prostatectomy time was 196 and 179 minutes in group 1 and 2, respectively (p < 0.001). moreover, the mean uva time was 40 and 24 minutes in group 1 and 2, respectively (p < 0.001). also, catheterization time, lenght of hospital stay and the number of the patients with urine leakage were significantly lower in group 2 than the other (p < 0.001). no patients in v-loc® 180 suture group and 5 patients in monocryl® suture group experienced postoperative drain leakage in the present study. overall pad usage at 6th month was higher in group 1 than the other group. in group 1 and 2, 78.7% and 93.3% of the patients reported 0 to 1 pads daily, whereas 21.3% and 6.7% reported ≥ 2 pads daily (p = 0.002). conclusions: we therefore consider that use of barbed suture running uva during lrp is associated with a significantly shorter operative time maintaining a proper suturing tension compared with standard suture and it is not associated with a higher incidence of adverse events with no postoperative complications. key words: radical prostatectomy; laparoscopy; barbed suture; anastomosis. submitted 5 december 2014; accepted 31 january 2014 summary no conflict of interest declared. introduction the first laparoscopic radical prostatectomy (lrp) series were published by schuessler and co-workers in 1997 (1). after that, lrp was developed to paralel the success achieved with the open approach, while offering the advantages of minimally invasive surgery (2). intracorporeal suturing is considered to the most challenging and difficult procedure in laparoscopic surgery. the urethrovesical anastomosis (uva) is definitely one of the critical and time consuming step of the lrp and requires an experienced surgeon with advanced laparoscopic skills (3, 4). moreover, suturing and knot tying can be often be challenging in the confines of true pelvis, which requires cautious handling of the suture and tissues.5 to facilitate the uva technique, several techniques with using monofilament sutures have been advised in the international literature (5-7). greenberg and associates demonstrated that monofilament suture has the potential of localized tissue necrosis, reduced fibroblast proliferation, and excessive tissue overlap, all of these factors can reduce the strength of the healed wound (8). to deal with this problem, a barbed suture (v-loc®, covidien healthcare, ma, usa) has been introduced into the surgical practice. the undirectional barbs maintain running suture line tension and purportedly obviate the need for knot tying. in the international literature, this suture has been extensively used during uva in robot-assisted radical prostatectomy (rarp) (916). to our knowledge, there is no publication about barbed suture usage during uva in lrp. in the current study, we compared the efficacy and safety of polyglecaprone (monocryl®, ethicon, nj, usa) and bidirectional barbed (v-loc 180®, covidien healthcare, ma, usa) running sutures during uva in extraperitoneal lrp. material and methods the institutional review board approval was taken for data collection in our radical prostatectomy patients. a doi: 10.4081/aiua.2014.2.90 91archivio italiano di urologia e andrologia 2014; 86, 2 barbed suture in laparoscopy total of 92 consecutive patients underwent extraperitoneal lrp for prostate cancer between august 2010 to september 2012. inclusion criteria included clinically organ confined or locally advanced prostate cancer (clinical ≤ t3a). in the first 47 patients, the uva was performed using 30 standard monofilament polyglecaprone (monocryl®, ethicon, nj, usa) suture (group 1). for the uva, a bidirectional suture with 2 needles was prepared from two 15 cm sutures knotted on the distal ends and used to perform running anastomosis. in the subsequent 45 patients, the uva was performed with the 3-0 barbed suture (v-loc®180, covidien healthcare, ma, usa) (group 2). for the uva, a bidirectional barbed suture with 2 needles was prepared from two 15 cm sutures. after than 3-0 barbed sutures by passing the needle of each suture though the looped end effecter the other and the running anastomosis was performed. the uva was performed in each group by using conventional van velthoven (running) method which has been previously described (6). in group 2, standart van velthoven technique was performed without knot tying at the end of anastomosis. at the end of the anastomosis, we passed a foley urethral catheter into the bladder, and we filled the bladder with 150 ml of sterile saline solution while under direct visualization. just before completion the operation, we routinely placed a jackson-pratt drain to the perianastomotic region. the rhabdosphincter re-construction is performed in all the patients as described previously with using either monocryl® or v-lock®180 barbed suture (17). all the operations were performed by one of us (m.a.). the surgeon had performed 40 lrp until beginning of the current study. the primary outcome measured was the uva time; starting once the anchoring suture was placed and finished when two running sutures were tied together in group 1 and without knot tying in the other group. secondary outcome measured included urinary leak defined as either perioperative saline leakage or postoperative increased drain output confirmed by an elevated drain fluid creatinine level. contrast extravasation on postoperative 10th day was characterized as delayed healing; postoperative day of catheter removal was defined as lenght of urethral catheterization time. postoperative urinary incontinence was assessed at 6th month follow-up visit by patient recorded total daily pad using. statistical analysis statistical analysis was performed with using statistical packet for social sciences for windows (chicago, il, usa) version 13.0 software. descriptive statistics of the groups were calculated. the outcomes were expressed as the mean ± standard deviation. the numerical data with normal distribution were compared with independent sample t test, and the data without normal distribution were compared among groups with the mann-whitney u test. in addition, chi-square and fisher exact tests were used to compare categorical variables. a p value less than 0.05 was significant. results baseline patients characteristics which did not different the each group are summarized in table 1. during the operation, the mean prostatectomy time was 196 and 179 minutes in group 1 and 2, respectively (p < 0.001). moreover, the mean uva time was 40 and 24 minutes in parameters group 1 group 2 p value (n = 47) (n = 45) age (yr) 63.1 ± 6.3 65.2 ± 5.7 0.740 (46-75) (49-76) preoperative psa (ng/ml) 9.0 ± 5.9 11.0 ± 11.5 0.439 (1.3-28.6) (3.5-68) bmi (kg/m2) 27.0 ± 5 26.9 ± 4.5 0.385 (17.0-37.6) (18.3-39.7) biopsy gleason score (n) 6 31 39 0.204 7 16 5 ≥ 8 1 previous abdominal surgery (n) 15 16 0.966 prostate volume (ml) 39.6 ± 14.0 40.4 ± 20.2 0.440 (18-76) (14-108) table 1. effetti clinici e impatto economico della dutasteride e finasteride su uomini italiani con luts. table 2. intraoperative and postoperative parameters of the patients. data presented as median ± standard deviation with minimum and maximum values in parenthesis. parameters group 1 group 2 p value (n = 47) (n = 45) prostatectomy time (min) 196.1 ± 24.2 179.7 ± 20.5 < 0.001 (160-276) (132-220) uva completion time (min) 40 ± 7.1 24.0 ± 5.5 < 0.001 (24-58) (16-45) estimated blood loss (ml) 424.6 ± 172.7 415.1 ± 223,1 0.851 (160-810) (120-900) postoperative leakage 5 0.001 in cystogram (n) catheterization time (d) 14.0 ± 1.7 9.0 ± 1.9 < 0.001 (12-21) (7-13) lenght of hospital stay (d) 4.2 ± 1.5 2.1 ± 0.4 < 0.001 (2-10) (2-4) surgical gleason score (n) 6 21 26 0.987 7 17 18 ≥ 8 9 1 6th month urinary continence rate 0-1 pads daily 37(78.7%) 42 (93.3%) 0.002 ≥ 2 pads daily 10 (21.3%) 3 (6.7%) archivio italiano di urologia e andrologia 2014; 86, 2 m. arslan, a. tuncel, y. aslan, z. kozacioglu, b. gunlusoy, a atan 92 group 1 and 2, respectively (p < 0.001). also, catheterization time, lenght of hospital stay and the number of the patients with urine leakage were significantly lower in group 2 than the other (p < 0.001). all other perioperative parameters were statistically equivalent between the groups, including estimated blood loss and gleason scores (table 2). we did not experience difficulty with the urethral catheter exchange end of the uva in each group. five patients in group 1 and no patient in group 2 experienced the postoperative drain leakage in the present study. the urine leakage was confirmed with using postoperative cystogram. the dranaige was treated with prolonged foley urethral catheterization. three of the patients in group 1 had experienced urinary retention due to bladder neck contracture at a mean follow-up of 4.1 months. all bladder neck contractures were treated using with cold knife incision. overall pad usage at 6th month was higher in group 1 than the other group. in group 1 and 2, 78.7% and 93.3% of the patients reported 0 to 1 pads daily, with 21.3% and 6.7% reported ≥ 2 pads daily (p = 0.002) (table 2). discussion although rarp has tremendously changed the art of performing prostatectomy, lrp still have being routinely performed for localized prostate cancer in many centers that do not have a robot. laparoscopic intracorporeal suturing is one of the most challenging and time-consuming taks for surgeons (8). in lrp and rarp, the initial results indicated on the technical difficulty on uva leading to prolonged operation time. the uva technique was firstly performed with using vicryl® suture on a small 5/8-circle needle in interrupted fashion that was associated with difficulty of multiple knots (18). the difficulties as mentioned above lead to development of continuous uva techniques that dramatically reduced the number of intracorporeal knots (6). uva with monocryl® requires follow-through by assistant when continuous anastomosis is performed. an assistant in training may find it difficult to follow-through, leading to loose throws as well as pure-stringing, instrument clashes, and suture entangling around instrument (16). intracorporeal suturing with the use of standart suture materials having smooth configuration and placement of knots to secure them is a standard practice. though widely used these suture’s may become loose or entangled, necessitating constant traction by an assistant or repeated tightening of suture by the operating surgeon (5). this may potentially lead to instrument collision, tissue tearing, and purse stringing resulting in prolongation of suturing. to overcome these problems, barbed suture has been introduced into the clinical practice. these selfanchoring knotless sutures incorporate tiny barbs spaced evenly in a helical array on the suture. they require little technical skill to deploy making suturing expeditious, requiring less time than standard suturing (19). firstly, weld and associates evaluated the role of barbed suture in urinary tract reconstruction in a porchine model (20). according to in vitro analysis, the authors stated that barbed suture secures tissue approximation at load equivalent to tissue approximation with standard sutures. later, technical feasibility of uva using barbed suture was reported by moran et al. in a microfiber synthetic material experimental model; they found barbed suture better than standard monocryl® in terms of faster deployment and higher security score (21). in the international literature, barbed suture is mainly evaluated in uva during rarp cases. in a study by tewari et al, barbed suture (n = 50) and polyglactine suture (n = 50) were used in uva during rarp (10). they reported that uva time significantly shorter in barbed suture group. also, they did not observe clinically significant urine leak or retention in barbed suture group. in a prospective series by kaul et al., 51 patients underwent uva during rarp with using barbed suture (11). they reported 27% reduction in uva time. also there were no urine leakage at 1 week and no bladder neck stricture. in another recent study, 64 patients underwent uva during rarp with either barbed suture (n = 31) or monofilament polyglecaprone (n = 33) suture (12). the authors demonstrated that uva 26% decreased with no increase in the adverse events, no instances of urinary retention. in a study, a total of 84 patients were divided into two groups underwent rarp, undergoing rhabdosphicter reconstruction and uva using with the v-loc® standard monoflament suture (13). the authors reported that barbed suture associated with a significantly shorter time for uva compared the standard monofilament suture and is not associated with a higher incidence of clinical urinary leak. at a 9-month follow-up no patients in either group has a clinical bladder neck stricture. moreover, they found similar urinary continence rates between the groups at 6 weeks (52% and 48%, respectively) and at 6 months (88% and 84%, respectively). the authors concluded that although urinary continence rates in both groups will continue to improve at longer follow-up, it is reasonable to assume the use of barbed suture for the rhabdosphincter reconstruction and the uva does not affect urinary incontinence. zorn et al. recently published their prospective series in which 30 v-loc®180 barbed uva cases during rarp (14). in their analysis, the mean anastomosis time was 14.6 min with using two knotless, interlocked 6inches 3-0 v-loc®180 sutures. they did not report urinary leak, urinary retention and urinary incontinence after catheter removal in their patients. hence the authors concluded that using the interlocked v-loc®180 suture during rarp for uva appears to be safe and efficient. in a study by hemal and co-workers, 50 patients underwent rarp and uva was performed with using either barbed suture (n = 25) or polyglecaprone suture (n = 25) (16). the authors concluded that barbed suture significantly decreases anastomosis time, hospitalization duration. none of the patient had presented with urine leaks, urinary retention or anastomosis stricture at follow-up of 6 months. in a study by manganiello et al., a total of 70 patients underwent rarp for prostate cancer (15). in this study, first 35 patients, the uva was performed using a two separate monofilament sutures. in the subsequent 35 patients, the uva was performed using two running unidirectional barbed suture. the authors reported that comparing the groups, average 93archivio italiano di urologia e andrologia 2014; 86, 2 barbed suture in laparoscopy time to complete the anastomosis was similar (27.4 vs. 26.4 minutes, p = 0.73) as was the rate of urinary extravasation on cystogram (5.7% vs. 8.6%, p = 0.65). there were no symptomatic bladder neck contractures noted at 5 months of follow-up. the authors also reported that at 5th months, rates of urine leak also were comparable. conversely; in a randomized clinical trial, the authors compared uva using either barbed polyglyconate (n = 45) or polyglactine 910 (n = 36) sutures in rarp (9). although baseline characteristics and overall operative times were similar, barbed sutures were associated with shorter mean anastomosis times (9.7 min vs. 9.8 min, p = 0.019). however, they reported more frequent extravasation (20% vs. 2.8%, p = 0.019), longer catheterization time (11.1 d vs. 8.2 d, p = 0.048) and greater suture costs per case (51.5 usd vs. 8.44 usd, p < 0.001) in barbed suture group. the authors concluded that compared to traditional sutures, barbed suture is more costly and requires technical modification to avoid overtightening, delayed healing, and longer catheterization time. to our knowledge barbed suture has not been evaluated in uva and total operation time in lrp. our results showed that barbed suture led to reduced prostatectomy time, uva time, catheterization duration and lenght of hospital stay in patients underwent lrp. furthermore, we did not detect postoperative urine leakage from drain and cystogram in barbed suture group. manganiello and associates previously claimed that barbed suture obviates the need for an assistant to follow the suture to continually reapply tension to previous throws (15). according to their opinion once the bladder neck and urethral tissue are re-approximated, the tissue stays in place and does not migrate unless there is significant counter tension. we believe that this mechanism may facilitate uva step of the lrp. in the international literature, urine leaks have been reported to be as high as 6.8% at different centers (22). urine leaks may result in clinical problems such as bladder neck contraction, infection, bladder neck contracture and urinary incontinence (23). as we mentioned above, some studies reported that urinary incontinence rate were similar between the standard polyglactine and barbed sutures in rarp (13, 14). in our study, overall pad usage for urinary incontinence at 6th month follow-up was significantly higher in group 1. according to our results, 5 patients in group 1 experienced the postoperative drain leakage in the present study. the urinary incontinence was seen all of those patients. we believe that urine leakage and bladder neck contracture may fascilitate to develop urinary incontinence. conclusions we therefore consider that by using v-loc®180 barbed suture running uva during lrp is associated with a significantly shorter time with maintaining a proper suturing tension compared with standard suture is not associated with a higher incidence of adverse events with no instances of urine leakage, bladder neck contraction, urinary retention and urinary incontinence. in the light of our results, v-loc®180 barbed suture seems to significantly facilitate the surgeon’s duty in uva during lrp. references 1. schuessler ww, schulam pg, clayman rv, kavoussi lr. laparoscopic radical prostatectomy:initial short-term experience. urology. 1997; 50:854. 2. stolzenburg j-u, do m, ranenalt r, et al. endoscopic extraperitoneal radical prostatectomy:initial experience after 70 procedures. j urol. 2003; 169:2066. 3. branco aw, kondo w, henrique a, et al. laparoscopic running urethrovesical anastomosis with posterior fixation. urology. 2007; 70:799. 4. chung sd, tai hc, lai mk, et al. novel inaninate training model for urethrovesical anastomosis in laparoscopic radical prostatectomy. asian j surg. 2010; 33:188. 5. shah hn, nayyar r, rajamahanty s, hemal ak. prospective evaluation of unidirectional barbed suture for various indications in surgeon-controlled robotic reconstructive urologic surgery:wake forest university experience. int urol nephrol. 2012; 44:775. 6. van velthoven rf, ahlering te, peltier a, et al. technique for laparoscopic running urethrovesical anastomosis:the single knot method. urology. 2003; 61:699. 7. shichiri y, kanno t, oida t, kanamaru h. facilitating the technique of laparoscopic running urethrovesical anastomosis using lapra-ty absorbable suture clips. int j urol. 2006; 13:192. 8. greenberg ja. the use of barbed sutures in obstetrics and gynecology. rev obstet gynecol. 2010; 3:82. 9. williams sb, alemozaffar m, lei y, et al. randomized controlled trial of barbed polyglyconate versus polyglactin suture for robotassisted laparoscopic prostatectomy anastomosis:tecnique and outcomes. eur urol. 2010; 58:875. 10. tewari ak, srivastava a, sooriakumaran p, et al. use of novel absorbable barbed plastic surgical suture enables a “self-cinching” technique of vesicourethral anastomosis during robot-assisted prostatectomy and improves anastomotic times. j endourol. 2010; 24:1645. 11. kaul s, sammon j, bhandari a, et al. a novel method of urethrovesical anastomosis during robot-assisted radical prostatectomy using a unidirectional barbed wound closure device:feasibililty study and early outcomes in 51 patients. j endourol. 2010; 24:1789. 12. sammon j, kim t-k, trinh q-d, et al. anastomosis during robot-assisted radical prostatectomy:randomized controlled trial comparing barbed and standard monofilament suture. urology. 2011; 78:572. 13. polland ar, graversen ja, mues ac, badani kk. polyglyconate undirectional barbed suture for posterior reconstruction ans anastomosis during robot-assited prostatectomy:effect on procedure time, efficacy, and minimum 6-month follow-up. j endourol. 2011; 25:1493. 14. zorn kc, widmer h, lattouf j-b, et al. novel method of knotless vesicourethral anastomosis during robot-asisted radical prostatectomy:feasibility study and early outcomes in 30 patients using the interlocked barbed undirectional v-loc180 suture. can urol assoc. 2011; j 5:188. 15. manganiello m, kenney p, canes d, et al. undirectional barbed suture versus standard monofilament for urethrovesical anastomosis archivio italiano di urologia e andrologia 2014; 86, 2 m. arslan, a. tuncel, y. aslan, z. kozacioglu, b. gunlusoy, a atan 94 during robotic assisted laparoscopic radical prostatectomy. int braz j urol. 2012; 38:89. 16. hemal ak, agarwal mm, babbar p. impact of newer undirectional and bidirectional barbed suture on vesicourethral anastomosis during robot-assisted radical prostatectomy and its comparison with polyglecaprone-25 suture:an initial experience. int urol nephrol. 2012; 44:125. 17. rocco f, gadda f, acquati p, et al. personal research: reconstruction of the urethral striated sphincter. (ita) arch ital urol androl. 2001; 73:127. 18. guillonneau b, cathelineau x, doublet jd, et al. laparoscopic radical prostatectomy:assessment after 550 procedures. crit rev onc hemat. 2002; 43:123. 19. hruby g, weld kj, marruffo f, et al. comparison of novel tissue apposing device and standard anastomotic technique for vesicourethral anastomoses. urology. 2007; 70:190. 20. weld kj, ames cd, hruby g, et al. evaluation of a novel knotless selfanchoring suture material for urinary tract reconstruction. urology. 2006; 67:1133. 21. moran me, marsch c, perotti m. bidirectional-barbed sutured knotless running anastomosis v classic van velthoven suturing in a model system. j endourol. 2007; 21:1175. 22. hu j, nelson r, wilson t. perioperative complicationsof laparoscopic and robotic assisted laparoscopic radical prostatectomy. j urol. 2006; 175:541. 23. kostakopoulos a, argiropoulos v, protogerou v, et al. vesicourethral anastomotic strictures after radical retropubic prostatectomy: the experience of a single institution. urol int. 2004; 72:17. correspondence murat arslan, md izmir university school of medicine, department of urology, izmir-turkey altug tuncel, md (corresponding author) tuncelaltug@yahoo.com yilmaz aslan, md ali atan, md ministry of health, ankara numune research and training hospital, third department of urology 06120, sihhiye ankara, turkey zafer kozacioglu, md bulent gunlusoy, md ministry of health, bozyaka research and training hospital, department of urology, izmir-turkey stesura seveso archivio italiano di urologia e andrologia 2013; 85, 3138 introduction penile prosthesis (pp) is reserved for man who cannot use or fail to respond to first and second line treatments of erectile dysfunction (ed). although majority of patients were satisfied with pp, satisfaction rates sometimes drop to 80 percent (1, 2). in a european study, the satisfaction rate decreased to 75 percent for specific pp types (3). according to the latter study, patients’ dissatisfaction was especially related to the rigidity of pp. comparison of the hardness of erections before and after implantation revealed that hardness varied with the diforiginal paper axial penile rigidity influences patient and partner satisfaction after penile prosthesis implantation abdulla al ansari, raidh a. talib, onder canguven, ahmad shamsodini urology department, hamad general hospital, doha, qatar introduction: penile prosthesis implantation is one of the treatment choices that is kept for patients who were not satisfied with other treatments. although penile prosthesis satisfaction rates are higher, there are some dissatisfied patients. the patients’ reasons are mostly shortness and softness of implanted prosthesis. it was previously demonstrated that penile axial rigidity of more than 500 grams is enough for successful vaginal intromission. to our knowledge, there is no study comparing axial rigidity of penile prosthesis and satisfaction. objectives: the aim of this study was to examine whether axial rigidity of penile prosthesis had impact on patient and partner satisfaction. materials and methods: we enrolled one hundred patients who were implanted penile prosthesis before to evaluate their penile axial rigidity. we used rigidometry (by using the digital inflection rigidometer) to assess the minimal axial pressure to bend the implanted penis. results: we demonstrated that mean axial pressure to bend the implanted penis was 984.8 ± 268.7 grams. overall satisfaction score with the penile prosthesis implant was 4.55 and 4.49 (out of 5) in patients and partners, respectively. in total, seven men were unsatisfied with their implant and reported a mean satisfaction score of 0.6 ± 0.48 (out of 5). all prostheses types showed good and more than 500 grams axial rigidity. the patients with ambicor type, which were buckled at about 710.5 grams, showed worse satisfaction rates in comparison to other prostheses in two patients. digital inflection rigidometer results of other penile prosthesis types in unsatisfied patient were 842.0, 872.0, 887.0 and 920 g. in cx700, titan, genesis and titan otr, respectively. conclusion: we demonstrated that dissatisfaction rate was highest in ambicor prosthesis implanted patients. additionally, patients with 3-piece penile prosthesis were more satisfied than 2-piece or malleable ones, interestingly, although some cases had lower axial rigidity results. key words: axial buckling test; erectile dysfunction; penile rigidity, satisfaction. submitted 10 july 2013; accepted 31 july 2013 no conflict of interest declared summary ferent prosthesis types; patients reported that erections were harder than before in its’ natural form (3). in order to evaluate newly introduced pp, the researchers also investigated patients’ satisfaction rates (4, 5). in most of the studies, patients were requested to fill questionnaires by phone or mail, researchers did not evaluate the patients by objective measurement techniques in addition to questionnaires (3, 6, 7). the aim of this study was to assess axial rigidity of six types of pp (ambicor, cx700, genesis, spectra, titan and doi: 10.4081/aiua.2013.3.138 139archivio italiano di urologia e andrologia 2013; 85, 3 axial penile rigidity influences patient and partner satisfaction after penile prosthesis implantation titan otr) in 100 consecutive patients with ed. se con dary objective included assessment of patients’ and partners’ satisfaction with these pps. to our knowledge this is the first report of objective and subjective pp performance by measuring their axial rigidity. material and methods a chart review was performed on patients that underwent pp implant surgery from january 2008 through january 2013. all surgeries were performed by the same team. all prostheses were placed through penoscrotal incision and cylinder sizes used were primarily 15-21 cm. enrollment and data collection were conducted at a follow-up visit at least 3 months and up to 5 years after implantation. at the follow-up visit, medical history and demographic data were collected, along with operative data and rigidity measurements. additionally, a 10-question questionnaire from the literature (8) was used to assess satisfaction with various domains related to the pp (table 1). the questions were designed with a likert grading scale scored 1 through 5 (1-very unsatisfied, 2moderately unsatisfied, 3-satisfied, 4-moderately satisfied, 5-very satisfied). scores ! 3 to the question were classified as satisfied. answers for partner’s satisfaction were attained from participants. moreover, total score was calculated by addition of 7 questions’ results (7-35). the primary efficacy endpoint for the clinical evaluation of penile rigidity by the investigators was a positive penile buckling test using the digital inflection rigidometer (dir). rigidometry was carried out to evaluate the minimal axial pressure to bend the implanted penis, using the dir (h501, electromedicina, baleares, spain). with the patient in a supine position, the plastic cap was applied to the tip of the penis in a downward direction by the investigator. a force of nearly 1.0 kg was slowly achieved on the weight scale by steadily increasing the downward force. the shaft of the penis was observed for buckling resulting from the load. three consecutive readings of the actual axial (buckling) rigidity were averaged. procedure rigidity measurements were performed by same study investigator and technician with the dir using the following procedure. 1. after ensuring the inflatable pp was completely deflated, the subject was asked to inflate his pp to a point where he thought it would be sufficient for sexual intercourse. (this phase was omitted in malleable pp implanted patients). 2. the investigator held the dir in their primary hand and pushed the dir pressure pad on the head of the penis. 3. the pressure pad was held for at least 5 seconds with a moderate pressure (500-1500 gram) or until penis buckled. the output from the dir was recorded. 4. if penis buckled, the output from the dir as the buckling force was recorded. 5. the investigator inflated pump when penis buckled with low pressures to see if inflation could be performed sufficiently. statistical analysis statistical package spss version 16.0 (chicago, il, usa). for continuous variables, statistics included means, standard deviations, and 95% confidence intervals for the means when normal distribution assumptions are not violated. comparison of the dir and the satisfaction rate between the various pps was performed using the pearson chi-square test. further patient data were obtained retrospectively from medical records. a p-value of " 0.05 was considered significant. the study was carried out with the approval of the review board of medical research center and all patients provided informed, written consent. results a total of hundred patients was enrolled in this study to assess the axial penile rigidity of implanted pp. mean age of the study participants was 61.4 ± 9.8 years and the questions for patients responses* 1. how would you rate the ease of use of your pp? 1-5 2. how would you rate the rigidity of your pp for intercourse? 1-5 3. how satisfied are you with the length of your pp? 1-5 4. how satisfied are you with the width of your pp? 1-5 5. how satisfied are you with the orgasms you achieve with your pp? 1-5 6. how satisfied do you think your sexual partner is with your pp? 1-5 7. what is your overall satisfaction with your pp? 1-5 8. in retrospect, would you undergo this procedure again? yes no 9. would you recommend this procedure to other patients? yes no 10. how many times do you use your pp for sexual activity each month? as numbers per month; e.g. 4/month frequency table 1. the questionnaire administered to patients and their sexual partners (8). *1-5 (1-very unsatisfied, 2-moderately unsatisfied, 3-satisfied, 4-moderately satisfied, 5-very satisfied). pp: penile prosthesis archivio italiano di urologia e andrologia 2013; 85, 3 a. al ansari, r. a. talib, o. canguven, a. shamsodini 140 common causes of ed were diabetes mellitus (74), atherosclerotic disease (18), and radical surgery (8). only 8 patients had peyronie’s disease. mean follow-up was 7 months (range: 3-60). the results of each question were given in table 2. types of the implants and unsatisfaction rates were described in table 3. mean male and female satisfaction with the pp implant was 4.55 and 4.49 (out of 5), respectively. interestingly, nearly one third (28/100) of patients admitted that their wives do not know that they had pp. overall, seven men were unsatisfied with their pp implant and reported a mean satisfaction score of 0.6 ± 0.48 (out of 5). pp types of unsatisfied patients and the rates according to the same type implantation were ambicor (3/15), cx700 (1/42), genesis (1/9), titan (1/13), titan otr (1/15) (table 3). average dir of all types of pp was 984.8 ± 268.7 g. in three patients, investigator inflated pump when penis buckled with low pressures and found that the inflation was not sufficiently obtained by the patients. the mean age of these patients were 74 ± 1.33 years. we found dir results of pp in unsatisfied patient as 710.5, 842.0, 872.0, 887.0 and 920 g. in ambicor, cx700, titan, genesis and titan otr, respectively. especially, dir results of 3 ambicor pp that were implanted 5 years ago were significantly lower than the other satisfied patients’ average dir. in general, main reasons of dissatisfaction were hardness and shortness of penis. for retrospective question (#8), 89 patients responded that they would undergo this procedure again. for recommendation question (#9), 91 patients responded that they would recommend this procedure to other patients. the average of pp usage for sexual activity was 9.18 ± 5.31 per month. pearson’s correlation analysis suggested a direct correlation between answers for questions #2 and #7 (p < 0.01; r = 0.723). there was a significant correlation between average dir and overall satisfaction (p < 0.05; r = 0.232). interestingly, there was no statistically significant relation between total score and penile length and width (table 4). discussion the pp implantation is one of the modality of treatment with high success rate for ed. although axial rigidity objectively defines the capability of the pp to resist buckle during vaginal intromission, there is no study specifically assessing axial rigidity of implanted pp. this study extends current knowledge in the satisfaction of pp by further examining the axial rigidity of the different types of pps. in this study, we demonstrated that five different pp types other than ambicor pp had good axial rigidity that is needed for a successful intercourse. we showed that 95% male participants were satisfied with pp implantation. the history of surgical implantation for ed was first recorded in 1930s by bogoras, who used a tailored section of rib cartilage to create the os penis of animals and produce rigidity in a reconstructed penis (9). today pps can broadly be divided into malleable and inflatable ones. since pp implants are associated with a high level of patient satisfaction, researchers always investigate and compare firstly introduced pp with the previous types from different points of satisfaction (3, 4, 6). axial and radial rigidity of penis share a common dependency upon intracavernosal pressure. however, axial rigidity, not radial penile mean ± std. deviation age (year) 61.42 9.77 1st q score (1-5) 4.82 0.54 2nd q score (1-5) 4.55 1.15 3rd q score (1-5) 4.41 1.39 4th q score (1-5) 4.58 1.11 5th q score (1-5) 4.67 1.03 6th q score (1-5) 4.49 1.18 7th q score (1-5) 4.55 1.09 total score of 7 questions (7-35) 32.10 6.10 average dir (g) 984.78 268.74 minimum dir (g) 647.53 278.69 maximum dir (g) 1275.12 337.83 sexual intercourse frequency/month 9.18 5.31 table 2. the scores of each question and results of mean digital inflection rigidometer (dir). types of prostheses n n/n (%) mean dir (implanted) (unsatisfied) cx700 ((3-piece, ams) 42 1/42 (2.4%) 985 ambicor (2-piece, ams) 15 3/15 (20%) 870 titan (3-piece, coloplast) 13 1/13 (7.7%) 1068 titan otr (3-piece, coloplast) 15 1/15 (6.6%) 953 genesis (coloplast) 9 1/9 (11.1%) 857 spectra (ams) 6 837 total 100 7/100 (7%) 984.8* table 3. mean digital inflection rigidometer (dir) and dissatisfaction percentages of six type of penile prosthesis. * there was no statistically difference between mean digital inflection rigidometer of all types (984.8 grams) and each type of penile prosthesis (p > 0.05). (ams: american medical system; otr: one touch release). average digital inflection rigidometer penile length penile width total score p = 0.022* p = 0.252 p = 0.146 table 4. correlation between the total score of 7 questions (32.1 ± 6.1) with digital inflection rigidometer, penile length and penile width, provided by pearson correlation analysis. *p-value of ! 0.05 was considered significant. m al le a i nf la ta bl e 141archivio italiano di urologia e andrologia 2013; 85, 3 axial penile rigidity influences patient and partner satisfaction after penile prosthesis implantation deformation, is the physical parameter which best defines the capability of the erect penis to resist buckle during vaginal intromission, and pelvic thrusting following penetration (10). the penile buckling force classically measures axial rigidity. axial rigidity assessment was introduced during the early 1980s at some stage in sleep laboratory research and remains a simple and inexpensive diagnostic tool (11). later, during the evaluation of efficacy of interventions for ed, researchers used and recommended axial rigidity parameter in their studies (10, 12-14). karacan et al. demonstrated that force on a rod less than 500 gram (g.) were unable to achieve intromission in any female subject (11). based on karacan's study, it has been assumed that 500 g. axial force is the minimum pressure necessary for vaginal penetration. in our study, mean average dir for all types of prosthesis was about 985 g. that is sufficient for intromission. on the other hand, although our unsatisfied patients’ dir results were above 500 g. they were less than the average. according to our results, axial rigidity, which is nearly 1000 g. by dir, is necessary for pp implanted patients’ satisfaction. in our study, we found that dissatisfaction rate was highest in ambicor pp implanted patients. significantly, dir results were almost 30% less in unsatisfied ambicor implanted patients than the average dir. ambicor is a 2piece inflatable pp which was introduced in 1994 and underwent reinforcement of the pump tubing connection to decrease fluid leak failure in 1998 (5). unfortunately, one of our ambicor unsatisfied patient also revealed spontaneous deflation during intercourse, which occurred 5 years after the implantation. in a multicentre study, examining 3 different pp, ambicor was found as the less hard than the other two pp (3). in literature, the ratio of mechanical failure is found in between 0.7% to 15% with the ambicor pp (3, 5). previosuly, less hardness of ambicor was connected to the limited volume of fluid transferred out of the cylinders in the ambicor (5). although pp is the last option in treatment of ed, almost all the patients and their partners were satisfied after pp implantation (3, 4, 6). as has been found in the previous study, pp has the second highest satisfaction rate after oral medications among other treatment modalities e.g. intracavernosal injections and vacuum device (15). in order to describe satisfaction and partner sexual function after pp implantation, moskovic et al. designed a survey to assess various aspects of patient and partner satisfaction related to their pp (8). according to their study results, partner satisfaction scores were higher, respectively, in men with higher pp satisfaction than those with lower pp (8). studies, which are examining satisfaction of patients and partners at the same time, offer us both objective and subjective satisfaction rates. the more impressive functional results of studies investigating both patients and partners are that the results are mostly in close proximity to each other (4, 8). it was demonstrated that both patients and their female partners report high levels of satisfaction several years after inflatable pp implantation (6). we found very high satisfaction rates for both patients and partners. this result is consistent with literature about this subject (3, 4, 6). in a european study, natali et al. reported a satisfaction in 97% of patient who underwent pp implantation and in 91% of their partners (3). the results of the present study showed that majority (89%) of our study participants responded that they would undergo pp procedure again. we believe that this high rate positive answer for the latter has important clinical implication from point of satisfaction. an important observation of our study was that three of our study patients could not inflate the pp until the requested rigidity. this was mostly due to the fact that they evaluate the degree of rigidity obtained was enough good for penetration. there is no available data in the literature on the number of squeezes necessary to get enough hardness of erection, because of variability of volumes needed in relation to the patient’s penis size. although the number of patients who could not inflate pp properly was minor in this study, we propose that this point should be kept in mind in differential diagnosis of patients’ complain for reduced hardness of pp, especially in elder people. on the other hand, 3-piece inflatable pps (ams cx700 and titan otr) demonstrated good results in terms of rigidity measured by dir. additionally, these 3-piece inflatable pps also did not show any mechanical failure in long-term follow up of in our study participants. a recent study conducted by bernal and henry who reviewed last 20 years’ articles that included more than 30 patients showed that patients with ed who underwent 3-piece pp placement reported the highest satisfaction rates (16). the present study was designed with the purpose of assessing axial rigidity in association with patients and partners satisfaction. to our knowledge, this is the first study evaluating pp by axial rigidity. however, the present study might have some limitations. a limitation of this study is that we could not apply our satisfaction questions directly to the partners. this was mainly because of culture difference in our region that our study patients did not want us to speak with their wives on this subject. it should be pointed out that the patient-reported partner satisfaction might have been overestimated because of this reason. however, regarding partner satisfaction, we surprisingly discovered that nearly one-third our patients’ partner do not have any knowledge about their spouses’ prosthesis. a further limitation is the difference in the numbers of different pp types evauated. since we implant 3-piece inflatable pp more than the others, there was a big discrepancy in numbers, which could not be avoided. conclusion using dir, we demonstrated that five different pp types have good axial rigidity for successful intercourse with high patient and partner satisfaction. dir results of 2piece ambicor pp were significantly lower than the other pp especially in dissatisfied patients. patient and partner satisfaction rates were roughly similar to those reported in the literature. we believe that reporting specific data for different implant types with axial rigidity for patient and partner satisfaction is significant for the future researches. archivio italiano di urologia e andrologia 2013; 85, 3 a. al ansari, r. a. talib, o. canguven, a. shamsodini 142 acknowledgements a grant from the hamad medical corporation primarily supported this research. we would also like to acknowledge the careful work of dr. abdulbari benar for his assistance with the statistics used in this study and also our technician mr. ahmed sandly for his help while using rigidometer. references 1. porena m, mearini l, mearini e, et al. penile prosthesis implantation and couple's satisfaction. urol int 1999; 63:185-7. 2. mulhall jp, ahmed a, branch j, parker m. serial assessment of efficacy and satisfaction profiles following penile prosthesis surgery. j urol. 2003; 169:1429-33. 3. natali a, olianas r, fisch m. penile implantation in europe: successes and complications with 253 implants in italy and germany. j sex med. 2008; 5:1503-12. 4. jensen jb, madsen ss, larsen eh, et al. patient and partner satisfaction with the mentor alpha-1 inflatable penile prosthesis. scand j urol nephrol. 2005; 39:66-8. 5. lux m, reyes-vallejo l, morgentaler a, levine la. outcomes and satisfaction rates for the redesigned 2-piece penile prosthesis. j urol. 2007; 177:262-6. 6. bettocchi c, palumbo f, spilotros m, et al. patient and partner satisfaction after ams inflatable penile prosthesis implant. j sex med. 2010; 7:304-9. 7. carson cc, mulcahy jj, govier fe. efficacy, safety and patient satisfaction outcomes of the ams 700cx inflatable penile prosthesis: results of a long-term multicenter study. ams 700cx study group. j urol. 2000; 164:376-80. 8. moskovic dj, gittens p, avila d jr., et al. favorable female sexual function is associated with patient satisfaction after inflatable penile prosthesis implantation. j sex med. 2011; 8:1996-2001. 9. kaneko s, mizunaga m, yachiku s, et al. clinical applicability of a new tactile sensor for evaluating rigidity of the penis: a comparative study with rigiscan. int j urol. 1996; 3:379-82. 10. udelson d, park k, sadeghi-nejad h, et al. axial penile buckling forces vs rigiscan radial rigidity as a function of intracavernosal pressure: why rigiscan does not predict functional erections in individual patients. int j impot res. 1999; 11:327-37; discusion 37-9. 11. karacan i, moore ca, sahmay s. measurement of pressure necessary for vaginal penetration. sleep res. 1985; 14:269-72. 12. henry gd, jennermann c, eid jf. evaluation of satisfaction and axial rigidity with titan xl cylinders. adv urol. 2012; 1-6. 13. sidi aa, lange ph. recent advances in the diagnosis and management of impotence. urol clin north am. 1986; 13:489-500. 14. goldstein i, auerbach s, padma-nathan h, et al. axial penile rigidity as primary efficacy outcome during multi-institutional inoffice dose titration clinical trials with alprostadil alfadex in patients with erectile dysfunction. alprostadil alfadex study group. int j impot res 2000; 12:205-11. 15. hassan a, el-hadidy m, el-deeck bs, mostafa t. couple satisfaction to different therapeutic modalities for organic erectile dysfunction. j sex med. 2008; 5:2381-91. 16. bernal rm, henry gd. contemporary patient satisfaction rates for three-piece inflatable penile prostheses. adv urol. 2012; 1-5. correspondence abdulla al ansari, md associate professor raidh a. talib, md urology department onder canguven, md (corresponding author) associate professor ocanguven@yahoo.com ahmad shamsodini, md urology department urology department, hamad general hospital hamad medical corporation 3050, doha, qatar stesura seveso 171archivio italiano di urologia e andrologia 2014; 86, 3 original paper impact of cystic fibrosis transmembrane regulator (cftr) gene mutations on male infertility jlenia elia 1, rossella mazzilli 1, michele delfino 1, maria piane 2, cristina bozzao 2, vincenzo spinosa 1, luciana chessa 2, fernando mazzilli 1 1 sant’andrea hospital, unità di andrologia, department of clinical and molecular medicine, university of rome “sapienza”, rome, italy; 2 sant’andrea hospital, unità di genetica medica, university of rome “sapienza”, rome, italy. objective. the aim of this study was to evaluate the prevalence of most common mutations and intron 8 5t (ivs8-5t) polymorphism of cftr gene in italian: a) azoospermic males; b) non azoospermic subjects, male partners of infertile couples enrolled in assisted reproductive technology (art) programs. material and methods. we studied 242 subjects attending our andrology unit (44 azoospermic subjects and 198 non azoospermic subjects, male partners of infertile couples enrolled in art programs). semen analysis, molecular analysis for cftr gene mutations and genomic variant of ivs8-5t polymorphic tract, karyotype and chromosome y microdeletions, hormonal profile (lh, fsh, testosterone) and seminal biochemical markers (fructose, citric acid and l-carnitine) were carried out. results. the prevalence of the common cftr mutations and/or the ivs8-5t polymorphism was 12.9% (4/31 cases) in secretory azoospermia, while in obstructive azoospermia was 84.6% (11/13 cases; in these, the most frequent mutations were the f508del, r117h and w1282x). regarding the non azoospermic subjects, the prevalence of the cftr and/or the ivs8-5t polymorphism was 11.1% (11/99 cases) in severe dyspermia, 8.1% (6/74 cases) in moderate dyspermia and finally 4.0% (1/25 cases) in normospermic subjects. conclusions. this study confirms the highly significant prevalence of cftr mutations in males with bilateral absence of the vas deferens or ejaculatory ducts obstruction compared with subjects with secretory azoospermia. moreover, the significant prevalence of mutations in severely dyspermic subjects may suggest the possible involvement of cftr even in the spermatogenic process. this could explain the unsatisfactory recovery of sperm from testicular fine needle aspiration in patients affected by genital tract blockage. key words: semen analysis; azoospermia; male infertility; molecular analysis; cftr gene mutations; ivs8-5t polymorphic tract. submitted 27 december 2013; accepted 15 may 2014 summary no conflict of interest declared. introduction in recent years, increasing attention has been paid to the pathogenesis of dyspermia with a genetic basis (1, 2). in particular, after the development of assisted reproductive techniques (art), genetic screening has taken on an important role in the diagnostic approach to couple infertility. regarding the male factor, in addition to the usual genetic investigations in clinical practice to identify factors, such as karyotype and chromosome y microdeletions, the study of cystic fibrosis transmembrane regulator (cftr) gene mutations, implicated in the genesis of cystic fibrosis (cf) (3), has acquired a great significance. beyond the classic aspects (pulmonary and pancreatic involvement) there are also atypical forms of cf. these atypical forms include male reproductive disorders. to date, a clear correlation with cftr mutations has been demonstrated only in obstructive azoospermia due to congenital bilateral absence of the vas deferens (cbavd) (4-8). it has also been suggested that there is the direct involvement of the cftr on spermatogenesis (9-15), and on pathogenesis of seminal hyperviscosity (17), as well as its having a potential action on the maturation of spermatozoa in vitro (16). the aim of this study was to evaluate the prevalence of the common mutations and the ivs8-5t polymorphism of the cftr gene in: a) azoospermic males and b) non azoospermic male partners of infertile couples enrolled in art programs. material and methods subjects we studied 242 males attending our andrology unit from january 2005 to december 2012. among these there were 44 azoospermic and 198 non azoospermic subjects, male partners of infertile couples taking part in art programs. semen analysis semen analysis was performed in all the subjects at least twice at a distance of 30 days; the mean values were doi: 10.4081/aiua.2014.3.171 elia_stesura seveso 08/10/14 12:06 pagina 171 archivio italiano di urologia e andrologia 2014; 86, 3 j. elia, r. mazzilli, m. delfino, m. piane, c. bozzao, v. spinosa, l. chessa, f.mazzilli 172 recorded and analyzed. the semen samples were collected by masturbation after 3-5 days of sexual abstinence. the samples were stored in a controlled incubator (37°c). after liquefaction, semen samples were analyzed according to world health organization (who) guidelines (18). the superimposed image analysis system (sias) was used to assess sperm motility parameters (19, 20). in azoospermic males three further tests, fructose, l-carnitine and citric acid were also carried out. molecular analysis written informed consent was obtained from each subject enrolled in this study. genomic dna was extracted from peripheral blood, according the standard procedure. molecular analysis of the most frequent mutations of cftr and the ivs8-5t polymorphic tract was performed by inno-lipa cftr 19, cftr 17+tn update and cftr italian regional kits (innogenetics, belgium), providing a screening for 57 cftr gene mutations and following the manufactures instructions. other analyses the hormonal profile was studied in all the subjects (lh, fsh, testosterone), as well as karyotype and chromosome y microdeletions. statistical analysis statistical analysis was performed using the chi-square test on frequency differences between two samples. a p value < 0.05 was considered significant. results prevalence of mutations and polymorphism of cftr gene in subjects with azoospermia. azoospermic males (n. 44) were divided into two groups: a) subjects with secretory azoospermia (n. 31); b) subjects with obstructive azoospermia (n. 13). the clinical examination, the hormonal profile, the biochemical study of seminal plasma (fructose, l-carnitine and citric acid as markers respectively of prostate, vesicles and epididymis), genetic screening, ultrasound examination and, when indicated, cytomorphological study by testicular needle aspiration permitted the differential diagnosis between secretory and obstructive azoospermia. secretive azoospermia (31 subjects) was due to: a) spermatogenic arrest (n.4); b) bilateral cryptorchidism, epididymo-orchitis and radioor chemo-therapy (n.20); c) chromosomal anomalies (klinefelter's and robertsonian translocations) (5 cases); d) y chromosome microdeletions (2 cases). altogether in 4 of these 31 subjects (12.9%) a classic mutation of cftr and/or the ivs8-5t polymorphism were identified. in particular, one male (3.2%) with previous cryptorchidism showed the most common mutation of the cftr gene (f508 del), while in the other 3 subjects (9.7%) was detected the ivs8-5t polymorphism. obstructive azoospermia (n. 13 subjects) was due to: a) obstruction of the vas deferens (n. 2); b) obstruction of the ejaculatory ducts (n. 10); epididymal obstruction, seen at surgery (n. 1). altogether 11 of these 13 subjects (84.6%) were affected by a classic mutation of the cftr and/or the ivs8-5t polimorphysm. in particular, in 9 cases (69.2%; p < 0.01 vs secretory azoospermia) a classical mutation was found; in the remaining 2 cases (15.4%) the ivs8-5t variant allele was found. the mutations found are listed in table 1. prevalence of mutations and 5t polymorphism of cftr gene in non azoospermic males genetic screening was carried out in 198 male partners of subfertile couples enrolled in programs of art. according to the seminal profile, the subjects were subdivided into: a) severe dyspermia (n. 99) (seminal parameters: n/ml !5 x 106, ! 5 progressive motility; atypical forms " 85%); b) moderate dyspermia (74); c) normospermia (n. 25) (who guidelines 1999) (18). hormonal profile biochemistry subjects cftr site karyotype microdel fsh lh test. ph vol eiac. fructose l-carnitine citric acid genotype of obstruction crom y mu/ml mu/ml ng/ml (ml) (mg/dl) (mg/dl) (mg/dl) 1 f508del/n ejaculatory duct 46,xy negative 4.9 3.2 5.1 6.3 0.4 10 0.4 1100 2 f508del/n ejaculatory duct 46,xy negative 4.8 5.4 5.6 6.7 0.5 20 0.2 1200 3 f508del/n ejaculatory duct 46,xy negative 5.3 2.8 6.7 6.5 0.4 10 0.3 1100 4 f508del/5t ejaculatory duct 46,xy negative 6.4 5.8 2.9 6.5 0.3 30 0.3 > 1200 5 f508del/5t vas deferens 46,xy negative 5.6 4.9 3.9 6.5 0.4 20 0.4 > 1200 6 r117h/n vas deferens 46,xy negative 6.5 4.7 4.9 6.5 0.5 210 0.1 1100 7 d1152h/n ejaculatory duct 46,xy negative 5.2 3.9 3.8 6.5 0.4 10 0.1 1200 8 l1065p/n intra-epididymal 46,xy del azf b 11.3 9.8 3.4 6.7 0.3 10 0.4 1200 9 w1282x/n ejaculatory duct 46,xy negative 4.7 5.1 5.8 7.4 2.1 180 0.1 450 10 5t/n ejaculatory duct 46,xy negative 3.9 2.8 6.5 6.0 0.2 20 0.3 > 1200 11 5t/n ejaculatory duct 46,xy negative 4.2 7.1 2.8 6.7 0.3 10 0.2 > 1200 table 1. genotype-phenotype correlation in males with obstructive azoospermia. elia_stesura seveso 08/10/14 12:06 pagina 172 in subjects with severe dyspermia (n. 99), 11 cases (11.1%) showed a classic mutation and/or the ivs8-5t polymorphism. in particular, 7 subjects (7.1%; p = 0.465 vs moderate dyspermia) had a classic mutation (one of them was compound heterozygous f508del/5t), 1 male was homozygote 5t/5t (0.9%), and finally 3 subjects (2.7%) were heterozygotes for the 5t polymorphism (table 2). in subjects with moderate dyspermia (n. 74), 6 subjects (8.1%) had a classic mutation of the cftr gene and/or the ivs8-5t polymorphism; in particular, 2 subjects (2.7%) were heterozygous w1282x/n and the r117h/n) and 4 subjects (5.4%) had the 5t polymorphism. in normospermic subjects (n. 25), only one moresubject (4.0%) with 5t polymorphism was found. discussion after the introduction of the art programs, genetic screening gradually took on a leading role in the diagnostic process of infertility counselling. in fact, such techniques have “put in play” also couples with high genetic risk. regarding genetic screening of the male partner, the search for mutations in the cftr gene has become increasingly important. in this study we evaluated the prevalence of mutations in the cftr gene in subjects with seminal tract obstructions as well as in subjects with varying degrees of dyspermia. regarding the first group, our study confirmed the high prevalence of cftr mutations in subjects with bilateral absence of the vas deferens or ejaculatory ducts obstruction. the most frequent mutations were, according to the literature, f508del, r117h and w1282x. with regard to the male d1152h/n, his partner carried the heterozygous genotype 621+3a>g/n. this opened a debate between operators on the opportunities and possibilities of using pre-implantation diagnosis as part of a program of assisted reproduction. in disagreement with karpman et al. (21), who reported significant association of cftr mutations with y chromosome microdeletion, in our study we found such association only in one case. on the other hand, the prevalence of mutations in subjects with classical secretory azoospermia was significantly lower compared with obstructive azoospermia. the second part of the study was conducted on the prevalence of mutations and/or genomic variants in a population of male partners (dyspermic and normospermic) of subfertile couples enrolled in art programs. there are sharply conflicting reports in the literature. according to some authors (9-11) there are no significant changes in the prevalence of mutations or genomic variants of cftr in subjects affected by moderate dyspermia and population controls. in partial agreement with other authors (12-15) this study highlights a significant prevalence of mutations in the cftr gene in males with severe dyspermia compared to normospermic ones. conclusions in conclusion, this study confirms the direct involvement of the cftr gene in the pathogenesis of seminal tract obstructions. the significant prevalence of mutations in severely dyspermic subjects may suggest the possible involvement of cftr even in the spermatogenic process. this could explain the unsatisfactory recovery of sperm from testicular fine needle aspiration in patients affected by genital tract blockage. references 1. mak v, jarvi ka. the genetics of male infertility. j urol. 1996; 156:1245-56. 2. lee jy, dada r, carpi a, et al. role of genetics in azoospermia. urology, 2011; 77:598-601. 3. knowles mr, durie pr. what is cystic fibrosis? n engl j med, 2002; 347:439-42. 173archivio italiano di urologia e andrologia 2014; 86, 3 cftr gene and male infertility hormonal profile biochemistry subjects cftr karyotype microdel fsh lh test. n/ml progressive atypical genotype crom y mu/ml mu/ml ng/ml (x 106/ml) motility (%) form (%) 1 n1303k/n 46,xy negative 14.3 5.2 7.6 2 5 87 2 621+3 a>g/n 46,xy negative 13.8 4.2 5.3 1 < 5 98 3 w1282x/n 46,xy negative 12.9 4.5 3.8 0.5 < 5 94 4 f508del/n 46,xy negative 18.3 2.8 6.5 < 0.1 < 5 96 5 3120+1g>a/n 46,xy negative 3.8 6.3 4.2 5 5 89 6 r117h/n 46,xy negative 14.1 3.9 5.6 1 < 5 96 7 f508del/5t 46,xy negative 11.8 5.4 5.4 < 0.1 < 5 97 8 5t/5t 46,xy negative 11.4 3.6 5.8 0.2 < 5 98 9 5t/n 46,xy negative 6.8 3.8 6.3 3 5 87 10 5t/n 46,xy negative 4.6 4.1 5.0 4 5 86 11 5t/n 46,xy negative 15.6 4.2 4.6 2 5 88 table 2. genotype-phenotype correlation in males with severe dyspermia. elia_stesura seveso 08/10/14 12:06 pagina 173 archivio italiano di urologia e andrologia 2014; 86, 3 j. elia, r. mazzilli, m. delfino, m. piane, c. bozzao, v. spinosa, l. chessa, f.mazzilli 174 4. dohle gr, veeze hj, overbeek se, et al. the complex relationships between cystic fibrosis and congenital bilateral absence of the vas deferens: clinical, electrophysiological and genetic data. hum reprod. 1999; 14:371-4. 5. chillon m, casals t, mercier b, et al. mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferent. n eng j med. 1995; 332:1475-80. 6. jarzabek k, zbucka m, pepinski w, et al. cystic fibrosis as a cause of infertility. reprod biol. 2004; 4:119-29. 7. chen h, ruan yc, xu wm, et al. regulation of male fertility by cftr and implications in male infertility. hum reprod update. 2012; 18:703-13. 8. mocanu e, shattock r, barton d, et al. all azoospermic males should be screened for cystic fibrosis mutations before intracytoplasmic sperm injection. fertil steril. 2010; 94:2448-50. 9. riccaboni a, lalatta f, caliari i, et al. genetic screening in 2,710 infertile candidate couples for assisted reproductive techniques: results of application of italian guidelines for the appropriate use of genetic tests. fertil steril. 2008; 89:800-8. 10. larriba s, bonache s, sarquella j, et al. molecular evaluation of cftr sequence variants in male infertility of testicular origin. int j androl. 2005; 28:284-90. 11. foresta c, garolla a, bartoloni l, et al. genetic abnormalities among severely oligospermic men who are candidates for intracytoplasmic sperm injection. j clin endocrinol metab. 2005; 90:152-6. 12. mennicke k, klingenberg rd, bals-pratsch, et al. rational approach to genetic testing of cystic fibrosis (cf) in infertile men. andrologia. 2005; 37:1-9. 13. schulz s, jakubicza s, kropf s, et al. increased frequency of cystic fibrosis transmembrane conductance regulator gene mutations in infertile males. fertil steril. 2006; 85:135-8. 14. tamburino l, guglielmino a, venti e, et al. molecular analysis of mutations and polymorphisms in the cftr gene in male infertility. reprod biomed online. 2008; 17:27-35. 15. chan hc, ruan yc, he q, et al. the cystic fibrosis transmembrane conductance regulator in reproductive health and disease. j physiol. 2009; 587:2187-95. 16. li cy, jiang ly, chen wy, et al. cftr is essential for sperm fertilizing capacity and is correlated with sperm quality in human. hum reprod. 2010; 25:317-27. 17. rossi t, grandoni f, mazzilli f, et al. high frequency of (tg)m tn variant tracts in the cystic fibrosis transmenbrane conductance regulator gene in men with high semen viscosity. fertil steril. 2004; 82:1316-22. 18. world health organization. who laboratory manual for the examination of human semen and sperm-cervical mucus interaction. 4th ed. cambridge uk; new york ny; 1999. 19. mazzilli f, rossi t, sabatini l, et al. superimposed image analysis system (sias) software: a new approach to sperm motility assessment. fertil steril. 1995; 64:653-6. 20. mazzilli f, rossi t, delfino m, et al. application of the upgraded image superimposition system (sias) to the assessment of sperm kinematics. andrologia. 1999; 31:187-94. 21. karpman e, williams dh, wilberforce s, et al. compound genetic abnormalities in patients with cystic fibrosis transmembrane regulator gene mutation. fertil steril. 2007; 87:1468.e5-8. correspondence jlenia elia, md. rossella mazzilli, md michele delfino, md vincenzo spinosa, md fernando mazzilli, md (corresponding author) fernando.mazzilli@uniroma1.it sant’andrea hospital, unit of andrology, university of rome, “sapienza” via di grottarossa 1035 00189 roma, italy maria piane, md cristina bozzao, md luciana chessa, md sant’andrea hospital, unità genetica medica, university of rome, “sapienza” via di grottarossa 1035 00189 roma, italy elia_stesura seveso 08/10/14 12:06 pagina 174 stesura seveso archivio italiano di urologia e andrologia 2013; 85, 4170 introduction it is well-known the importance of urethral sphincter in the preservation of the continence control and it is also known that the “success” of radical prostatectomy for prostate cancer should be defined on the evaluation of five elements including continence that are parts of the so called “pentafecta” (1). in the classic “open” retropubic radical prostatectomy (rrp), bladder dissection from the prostate and bladder neck involves the incision of the bladder neck along its entire circumference and requires the reconstruction according to the so-called “tennis racket” technique or by original paper modified radical retropubic prostatectomy: personal technical variation “tension free continuum-urethral anastomosis (t.f.c.u.a)” with optical magnification in the preservation of the bladder neck, and estimation of the urinary continence alberto roggia 1, emilio pozzi 1, guglielmo mantica 1, maurizio salvadore 2, dimitrios choussos 3, carmelo di franco 3, carlo maria bianchi 3 1 division of urology hospital sant’antonio abate gallarate (va); 2 division of anatomopathology hospital sant’antonio abate gallarate (va); 3 graduate school of urology university of pavia. objective: to reassess the double continence technique for open retropubic radical prostatectomy, proposed by malizia and employed by pagano et al., with the “tension free continuum-urethral anastomosis” (t.f.c.u.a.) personal modification and the use of image magnification optical systems and appropriate and delicate surgical tools. materials and methods: a total of 173 radical retropubic prostatectomies, performed by the same surgeon, were evaluated in terms of early and late continence. results: the presence of residual prostate cancer cells within the muscle layer was always excluded by the histopathological examination that also demonstrated that the muscle layer was well represented; satisfactory outcomes were obtained in terms of both early urinary continence (60%) and urinary continence at 6-12 month follow-up (92.4% for the whole series and 97.2% for the last series of patients). conclusions: the “tension free” anastomosis obtained by the suspension of the anterior bladder wall to the the pubis along the median line allowed to achieve satisfactory outcomes in terms of urinary continence, even if these data obviously need to be confirmed by other series and comparative trials. key words: prostate cancer; modified radical prostatectomy; urinary continence; double continence technique; tension free anastomosis. submitted 27 december 2012; accepted 30 june 2013 no conflict of interest declared summary multiple sutures along converging lines, in order to obtain a neo-urinary bladder neck with a caliber proportionate to the diameter of the membranous urethra. the urology school of padova (2) employed the “double continence technique”, proposed by malizia in 1989 (3), by carrying out a meticulous dissection of the bladderprostate furrow along its entire circumference during retrograde prostatovesciculectomy. in this way the prostate block is excised by the bladder, leaving as much as possible untouched the mucosa of the bladder neck and of the urethra, defined as “epithelial continuum”. doi: 10.4081/aiua.2013.4.170 roggia_stesura seveso 18/12/13 10:34 pagina 170 171archivio italiano di urologia e andrologia 2013; 85, 4 modified radical retropubic prostatectomy: personal technical variation “tension free continuum-urethral anastomosis (t.f.c.u.a)” materials e methods from 1st june 2009 to 30th june 2012, 195 open retropubic radical prostatectomies were performed at the department of urology of the gallarate hospital: out of them 173 prostatectomies performed by a single surgeon (a.r.) were taken into account for this survey in order to obtain a more homogeneous series. retropubic antegrade prostatovesciculectomy was performed after opening of the endopelvic fascia, section of the pubo-prostatic ligaments and double ligature of the dorsal venous plexus. in particular, the surgical technique was aimed to the careful preservation of the bladder-prostatic epithelial continuum (figures 1, 2) by means of image magnification by a 9 x autofocus frontal microscope or 6 x telescopic lenses, by use of delicate surgical tools such as metzenbaun-fino scissors and micro pliers for the dissection and at the same time by avoiding use of both mono and bipolar electrosurgical tools (since january 2012 malis forceps, jones i.m.a. forceps, micro forceps, jones i.m.a. scissors, micro spring scissors were also used in order to reach greater accuracy in the meticulous dissection at the bladder-prostate furrow level). two stitches , that also incorporated the striated muscle of the urethra, were placed in order to fix firmly the membranous urethra to the elevator muscle of the anus; the rabdosphincter was recovered according to the technique used by rocco (4); the anastomosis between the distal section of the continuum and the membranous urethra was obtained by single stitches after the subversion of the mucous membrane of the continuum. occasionally an incisional biopsy was obtained in correspondence of the bladder-prostate continuum. during the procedure biopsies were marked by sutures of different colours in order to allow the pathologist to obtain sections perpendicular to the mucous surface. histological samples were stained with hematoxylin-eosin (figure 3) and in some cases with anti-actin and anti-desmin antibodies for the research of muscular antigens (figure 4). we revisited the technique described by malizia and pagano by adding an original modification in order to stabilize the anterior bladder wall to the pubis along the median line: a twisted absorbable suture stitch was placed between the anterior bladder wall and the pubic periosteum at a distance of 20 mm from the anastomosis. this original modification (“t.f.c.u.a. = tension free continuum-urethral anastomosis”) aimed to relieve the tension along the anastomotic stitches between the continuum and the membranous urethra. urinary continence was evaluated in 171 patients (98.8%), divided into two groups a and b. continence was considered achieved by the use of no pads or the use of one security liner in 24 hours. in the first group (a) (135 cases), composed by patients subjected to rrp from 1 june 2009 to 31 december 2011, continence was evaluated at 12 months. in the second group (b) (36 cases), composed by patients subjected to rrp from january 2012 to june 2012, continence was evaluated after 6-12 months but also earlier after 7 days from catheter removal. two patients were lost at follow up for urinary continence. results at 6-12 month follow up, out of a total of 171 patients, 158 patients were considered continent (92.4%), while the remaining 13 patients were considered incontinent (7.6%). continence was higher in patients with organconfined tumors pt1-pt2, taking into account that patients with pt3-4 stages were also submitted to adjuvant therapies (radiotherapy +/hormone therapy). figure 1. isolation of the bladder-prostate epithelial continuum. figure 2. muscular structure of the bladder neck after a complete circular section along the circumference of the continuum. roggia_stesura seveso 18/12/13 10:34 pagina 171 archivio italiano di urologia e andrologia 2013; 85, 4 a. roggia, e. pozzi, g. mantica, m. salvadore, d. choussos, c. di franco, c.m. bianchi 172 in the 135 patients of group a, continence was present in 123 (91.1%); in group b, which included 36 patients subjected to rrp in the first semester 2012, continence at 6 -12 month was obtained in 35 (97.2%) while early continence after 7 days from catheter removal was observed in 21 patients (60%) (table 1). histological sections, obtained by the incisional biopsies that were taken at the bladder-prostate continuum, were always negative for neoplastic infiltration; in the sections it was possible to identify the mucosa and, below it, corion and muscle layer (figures 3, 4). discussion the meticulous dissection of the bladder-prostate furrow, using appropriate systems of image magnification (5) such as 6 x telescopic lenses or 9 x autofocus frontal microscope, and delicate surgical tools, and avoiding mono-bipolar electrosurgical tools, allows to isolate carefully and to maintain the continuity of the bladder-urethral mucosa along the entire circumference of the bladder-prostate furrow. in this personal series, the histopathological evaluation never showed the presence of residual prostate glands or cells in this specific anatomic area, while it was clearly shown the presence of the muscle layer. it is known that the preservation of the urinary bladder neck reduces the incidence of anastomotic strictures (6) and achieves a greater incidence of early continence (65% vs 25%) at 4 months from the operation (7). the anastomosis between the more distal section of the continuity of the bladder-urethral mucosa and the membranous urethra is possible without reducing the lumen of the bladder neck, as the bladder neck presents a caliber proportionate to that of the urethral stump. retropubic radical prostatectomy is associated to postoperative bladder descent (8) that could be a contributing factor to the onset of urinary stress incontinence, due to a compression of the bladder-urethral anastomosis by the bladder and the abdominal organs. in order to improve urinary continence, tan et al. (9-10) proposed, after a series of 1383 robotic-assisted laparoscopic prostatectomies, a technical modification entitled a.r.t. (total anatomic restoration technique) which provides an antero-lateral “suspension” of the bladder with some suture stitches between the bladder itself and the pubic tendinous arch: in this way, during the urination, the contractile action of the detrusor would be distributed along several stitches, avoiding increases of pressure on the anastomosis and on the muscular urethral structures (rabdosphincter). the approximating stitch between the anterior wall of the bladder and the pubic periosteum, that we propose (t.f.c.u.a.) in conjunction to the double continence technique used by malizia, has the same assumption, that is to reduce the tension along the stitches of the anastomosis, but also to reduce compression on the bladder-urethral anastomosis due to the intra-abdominal pressures and the contraction of the detrusor. in literature, rates of continence, after open retropubic surgery and robotic and laparoscopic prostatectomy, range from 38.6% to 98.5% at 3, 6, 12 and 18 months of follow-up (table 2) in relation to the definition of continence used, the modality of evaluation of the functional outcome (validated questionnaires) and the population studied (multicenter versus single center survey). hu et al. (11) in a 18-month follow up of a large series of 8.837 radical prostatectomies, including 6899 open radical prostatectomy (rrp) and 1938 minimally invasive radifigure 3. section of an incisional biopsy of the bladder-prostate continuum: in the upper left the mucous surface (hematoxylin-eosin, x40). figure 4. histological section of a incisional biopsy of the continuum: in evidence the muscular tunica (anti-desmin, x40). number of patients n. 171 n. 105 pt 1-2 n. 66 pt 3-4 continence n. 158 (92,4%) n. 98 (93,3%) n. 60 (90,9%) group a n. 123 (91,1%) group b n. 35 (97,2%) early continence 60,0% table 1. personal results. roggia_stesura seveso 18/12/13 10:34 pagina 172 173archivio italiano di urologia e andrologia 2013; 85, 4 modified radical retropubic prostatectomy: personal technical variation “tension free continuum-urethral anastomosis (t.f.c.u.a)” cal prostatectomy (mirp), showed a greater incontinence rate in the minimally invasive group compared to the open surgery one: 15.9% incontinence rate in the mirp against 12.2% in the rrp, with a p value 0.02. in our experience, continence rate at 6-12-month was 92.4%, with a further increase in the last series of patients (group b) in term of both early (60%) and 6-12 month continence rate (97.2%), and can be explained by a greater accuracy in the anatomic dissection by the use of appropriate tools and the greater experience of the surgeon. conclusions it is known that optical magnification is considered one of the greater advantage of laparoscopy and that the level of accuracy of the dissection obtained by the robotic assisted procedure can make the preservation of the urinary sphincter more manageable (31). however also the open retropubic radical prostatectomy with use of optical image magnification systems and delicate tools in order to obtain the meticulous preservation of the bladder-prostate epithelial continuum and so the preservation of the muscular sphincterial structure of the bladder neck in conjunction with a tension free anastomosis (“t.f.c.u.a.”) allows to achieve satisfactory outcomes in terms of both early urinary continence (60%) and urinary continence at 6-12 month follow-up (92.4% for the whole series and 97.2% for the last series of patients). however these data obviously need to be confirmed by other series and comparative trials. references 1. patel vr, sivaraman a, coelho rf, et al. pentafecta: a new concept for reporting outcomes of robot-assisted laparoscopic radical prostatectomy. eur urol. 2011; 59:702-707. 2. pagano f, artibani w, zattoni f. prostatectomia radicale per via retropubica: tecnica chirurgica. atlante fotografico. edizioni meb, 1993. 3. malizia a. modified radical retropubic prostatectomy: double continence technique. aua, abstract 585, 316a, 1989. 4. rocco f, gregori a, stener s, et al. posterior reconstruction of the rhabdosfincter allows a rapid recovery of continence after transperitoneal videolaparoscopic radical prostatectomy. eur urol. 2007; 51:996-1003. 5. varkarakis j, wirtenberger w, pinggera gm, et al. evaluation of urinary extravasation and results after continence-preserving radical retropubic prostatectomy (rrp). bju. 2008, 94:991-95. 6. shelfo sw, obek c, soloway ms. update on bladder neck preservation during radical retropubic prostatectomy: impact on pathologic outcome, anastomotic strictures, and continence. urology. 1998; 51:73-78. 7. freire mp, et al. anatomic bladder neck preservation during robotic-assisted laparoscopic radical prostatectomy: description of technique and outcomes. eur urol. 2009; 56:972-980. 8. dev hs, sooriakumaran p, srivastava a, tewari ak. optimizing radical prostatectomy for the early recovery of urinary continence. nat rev urol. 2012; 9:189-95. 9. tan gy, jhaveri jk, tewari ak. anatomic restoration technique (art): a biomechanics-based approach for early continence recovery after minimally invasive radical prostatectomy. urology. 2009; 74:492-96. tecnica autore anno n° pz 3 6 12 > 18 open rrp stanford (12) 2000 1295 38.6% 60.5% 58% kundu (13) 2004 3477 93% lepor (14) 2004 500 70.1% 87.2% 92.1% 98.5% marien (15) 2008 1110 97% touijer (16) 2008 222 95% rocco (17) 2009 120 70% 93% 97% krambeck (18) 2009 564 93.7% hu (11) 2009 6899 87,80% lrp anestesiadis (19) 2003 230 59.2% 89% lein (20) 2006 952 76% eden (21) 2009 1000 94.9% touijer (16) 2008 193 48% 62% krambeck (18) 2009 286 91.8% stolzemburg (22) 2009 2400 71.7% 94.7% mariano (23) 2009 780 87.9% ralp ahlering (24) 2004 202 77% menon (25) 2006 1142 90% 95% patel (26) 2006 500 89% 95% zorn (27) 2007 300 47% 68% 90% borin (28) 2007 400 89% 97% krambeck (15) 2009 286 91.8% tewari (29) 2009 777 90% 97% rocco (17) 2009 120 70% 93% 97% murphy (30 2009 395 91.4% mirp hu (11) 2009 1938 84,10% table 2. evaluation of the continence. roggia_stesura seveso 18/12/13 10:34 pagina 173 archivio italiano di urologia e andrologia 2013; 85, 4 a. roggia, e. pozzi, g. mantica, m. salvadore, d. choussos, c. di franco, c.m. bianchi 174 10. tan gy, srivastana a, grover s, et al. optimizing vescico-urethral anastomosis healing after robot-assisted laparoscopic radical prostatectomy: lessons learned from three techniques in 1900 patients. j endourol. 2010; 12:1975-1983. 11. hu jc, gu x, lipsitz sr, et al. comparative effectiveness of minimally invasive vs open radical prostatectomy. jama. 2009; 302:1557-1564. 12. stanford jl, feng z, hamilton as, et al. urinary and sexual function after radical prostatectomy for clinically localized prostate cancer: the prostate cancer outcomes study. jama. 2000; 283:354-60. 13. kundu sd, roehl ka, eggener se, et al. potency, continence and complications in 3477 consecutive radical retropubic prostatectomies. j urol. 2004; 172:2227-31. 14. lepor h, kaci l. the impact of open radical retropubic prostatectomy on continence and lower urinary tract symptoms: a prospective assessment using validated self-administered outcome instruments. j urol. 2004; 171:1216-9. 15. marien tp, lepor h. does a nerve-sparing technique or potency affect continence after open radical retropubic prostatectomy? bju int. 2008; 102:1581-84. 16. touijer k, eastham ja, secin fp, et al. comprehensive prospective comparative analysis of outcomes between open and laparoscopic radical prostatectomy conduced in 2003 to 2005. j urol. 2008; 179:1811-7. 17. rocco b, matei dv, melegari s, et al. robotic vs open prostatectomy: a systematic review and cumulative analysis of comparative studies,. eur urol. 2009; 104: 991-5. 18. krambeck ae, di marco ds, rangel lj, et al. radical prostatectomy for prostatic adenocarcinoma: a matched comparison of open retropubic and robot-assisted techniques. bju int. 2009; 103:448-53. 19. anestesiadis ag, salomon l, katz r, et al. radical retropubic versus laparoscopic prostatectomy: a prospective comparison of functional outcome. urology. 2003; 62:292-7. 20. lein m, stibane i, mansour r, et al. complications, urinary continence, and oncologic out come of 1000 laparoscopic transperitoneal radical prostatectomies-experience at the charité hospital berlin, campus mitte. eur urol. 2006; 50:1278-82. 21. eden cg, neill mg, louie-johnsun mw. the first 1000 cases of laparoscopic radical prostatectomy in the uk: evidence of multiple “learning curves”. bju int. 2009; 103:1224-30. 22. stolzemberg ju, kallidonis p, minh d, et al. endoscopic extraperitoneal radical prostatectomy: evolution of the technique and experience with 2400 cases. j endourol. 2009; 23:1467-72. 23. mariano mb, tefilli mv, fonseca gn,goldraich ih. laparoscopic radical prostatectomy: 10 years experience. int braz j urol. 2009; 35:565-72. 24. ahlering te, skarecky d, lee d, clayman rv. successful transfer of open surgical skills to a laparoscopic environment using a robotic interface: initial experience with laparoscopic radical prostatectomy. j urol. 2003; 170:1738-41. 25. menon m, shrivastava a, kaul s, et al. vattikuti institute prostatectomy: contemporary technique and analysis of results. eur urol. 2007; 51:648-58. 26. patel vr, thaly r, shah k. robotic radical prostatectomy: outcomes of 500 cases. bju int. 2007; 70:173-7. 27. zorn kc, gofrit on, orvieto ma, et al. robotic-assisted laparoscopic prostatectomy: functional and pathologic outcomes with interfascial nerve preservation. eur urol. 2007; 51:755-62. 28. borin jf, skarecky dw, narula n, alhering te. impact of urethral stump length on continence and positive surgical margins in robot-assisted laparoscopic prostatectomy. urology. 2007; 70:173-7. 29. tewari a, jhaveri j, rao s, et al. total reconstruction of the vesico-urethral junction. bju int. 2008; 101:871-877. 30. murphy dg, kerger m, crowe h, et al. operative details and oncological and functional outcome of robotic-assisted laparoscopic radical prostatectomy: 400 cases with a minimum of 12 months follow-up. eur urol. 2009; 55:1358-66. 31. ficarra v, novara g, mottrie a, artibani w. robotic and laparoscopic prostatectomy: a critical review of existing data. aua update series. 2010, 29 (lesson 30). correspondence alberto roggia, md profroggia@libero.it director of the division of urology emilio pozzi, md (corresponding author) pozzi.emilio@libero.it division of urology guglielmo mantica, md guglielmo.mantica@gmail.com division of urology maurizio salvadore, md maurizio.salvadore@ao.gallarate.it director of the division of anatomopathology hospital sant’antonio abate via pastori 4 21013 gallarate (va), italy dimitrios choussos, md segreteria.chirgen2@smatteo.pv.it graduate school of urology carmelo di franco, md segreteria.chirgen2@smatteo.pv.it graduate school of urology carlo maria bianchi, md segreteria.chirgen2@smatteo.pv.it director of the graduate school of urology university of pavia viale golgi 19 pavia, italy roggia_stesura seveso 18/12/13 10:34 pagina 174 stesura seveso 193archivio italiano di urologia e andrologia 2014; 86, 3 original paper the impact of sexual activity on serum hormone levels after penile prosthesis implantation onder canguven, raidh a. talib, ahmed shamsodini, abdulla al ansari hamad general hospital, urology department, doha, qatar. objectives: penile prosthesis implantation is the final treatment option for patients who have erectile dysfunction. most of the patients use their penile prosthesis successfully and frequently for penile-vaginal intercourse. previous literature showed that decrease in sexual activity resulted in decreased serum testosterone levels and vice versa. the aim of this study was to examine the impact of sexual activity on serum sex hormone levels after penile prosthesis usage. material and methods: in this study, we examined sixtyseven patients for their sex hormone changes who had penile prosthesis surgery 2.7 ± 1.5 years ago. results: patients were using their penile prosthesis for sexual activity with a mean of 9.9 ± 5.7 times per month. dehydroepiandrosterone sulfate was significantly higher compared to pre-surgery results (5.3 ± 2.6 vs 4.5 ± 2.9; p = 0.031). mean serum total testosterone levels of patients before and after penile prosthesis usage were clinically significant 15.78 ± 4.8 nmol/l and 16.5 ± 6.1 nmol/l, respectively. mean serum luteinizing hormone levels of patients before and after penile prosthesis usage were 3.98 ± 2.16 iu/l and 5.47 ± 4.76 iu/l, respectively. no statistical significance difference was observed in the mean total and free testosterone, estradiol and luteinizing hormone levels between preand post-surgery. conclusion: this study results demonstrated that sexual activity changed sex hormone levels positively among those men who were implanted penile prosthesis because of erectile dysfunction. key words: androgens; erectile dysfunction; hypogonadism; prosthesis; testosterone. submitted 9 april 2014; accepted 30 june 2014 summary no conflict of interest declared. healthy men (1, 2). testosterone, which has androgenic and anabolic effects on human body, decline gradually with aging in males. major benefits of testosterone on sexual function, mood, and strength are well known from the ancient times. currently, evidence supports the concept that normal testosterone levels reduce cardiovascular disease risk, decrease fat, decrease total cholesterol, increase muscular body mass, and display good glycemic control (3). moreover, epidemiological studies imply that many important disease states and related comorbidities are linked to low testosterone levels (4). although there are mixed results from animal studies (5), male testosterone concentrations before and after sexual activity were shown as increased in human studies (6, 7). insertion of a penile prosthesis (pp) for men who cannot use or fail to respond to first and second line treatments is the final treatment option for ed. actually pp provides a satisfactory, definitive solution for ed. in different patient satisfaction studies it was shown that, of the pp implanted men more than 90% stated they were still using the pp for sexual intercourse with an average frequency of coitus of 5 times monthly (8-10). a recent study conducted by escasa et al. supported previous studies and confirmed that sexual activity increases testosterone level which was more prominent in participants who had sexual intercourse (7). the aim of this study is to examine the influence of sexual activity on serum sex hormone levels after pp practice. materials and methods after institutional review board approved the study, a retrospective chart analysis was performed on patients that underwent pp implantation surgery from january 2009 through january 2013. all participants provided written informed consent. enrollment and data collection were conducted at follow-up visits at least 6 months and up to 4 years after implantation. the 67 patients with pp implantation reported in this study were ambulatory patients seen at our andrology clinic who met all of the following criteria. the principal eligibility criteria included patients who were requested hormonal profile examined in this study (total and free testosterone, estradiol, dehydroepiandrosterone sulfate (dheas) and lh) in the last month before the surgery doi: 10.4081/aiua.2014.3.193 introduction erectile dysfunction (ed) is defined as the inability to achieve or maintain an erection sufficient for satisfactory sexual intercourse. many of patients with ed have not had a normal erection in many months or years. previous studies demonstrated that sexual inactivity results in reversible reduction of luteinizing hormone (lh) and serum testosterone levels in ed patients compared to canguven_stesura seveso 08/10/14 12:09 pagina 193 archivio italiano di urologia e andrologia 2014; 86, 3 o. canguven, r.a. talib, a. shamsodini, a. al ansari 194 they had. another important inclusion criteria for the participation was regular sexual intercourse with his wife after pp implantation surgery. prostate cancer, creatinine > 2 mg/dl, myocardial infarction or stroke within 6 months, or congestive heart failure, and use of androgens, antiandrogens comprised major exclusion criteria. medications that influence hormone levels, such as high-dose opiates, glucocorticoids, antiepileptics or any kind of herbal drugs also excluded participation. fasting blood samples were obtained between 7-9 am in the morning. testosterone, lh, dheas and estradiol levels were measured by standard ria kits. we also asked global satisfaction question (gsq) “did the implant permit you to experience satisfactory sexual relations?” and a frequency question “how many times do you use your pp for sexual activity each month?” to all participants at the time of their participations. statistical analysis qualitative and quantitative data values were expressed as frequency (percentage) and mean ± sd. quantitative variables means between pre and post surgery groups were compared using paired t-test. pearson correlation coefficient was used to examine and assess the linear relationship between the two quantitative variables. pictorial presentations of the key results were made using appropriate statistical graphs. a two-sided p value < 0.05 was considered to be statistically significant. all statistical analyses were done using statistical packages spss 19.0 (spss inc. chicago, il). results sixty-seven male subjects who had active sexual life with aid of pp were enrolled in the study. mean age of patients was 59.9 ± 10.9 (range: 30-82) years. the mean duration of ed problem was 2.7 ± 1.5 years. with the gsq, sixtyseven patients who responded as ‘yes’ were included to our study group. with the frequency question, we aimed to learn frequency of the penile intercourse: 64 patients (95.5%) responded to use it frequently, while three (4.5%) declared they use it rarely because of partner related problems. the average of pp usage for sexual activity was 9.9 ± 5.7 (range: 2-28) times per month. the mean time from surgery was 22.6 months (range: 6 months-48 months). paired t-test revealed that post-surgery mean dheas was significantly higher compared pre-surgery results (5.3 ± 2.6 vs 4.5 ± 2.9 μmol/l; p = 0.031) (figure 1). no statistical significance difference was observed in the mean total and free testosterone, estradiol and lh between preand post-surgery results. mean values following post-surgery was found to be observationally higher compared to pre-surgery group for total testosterone (16.5 ± 6.1 vs 15.8 ± 4.8 nmol/l; p = 0.195), free testosterone (86.7 ± 15.9 vs 79.7 ± 20.4 pmol/l p = 0.258), estradiol (11.67 ± 4.69 vs 10.58 ± 3.79 pmol/dl; p = 0.191), and lh (5.1 ± 4.5 vs 4.2 ± 2.2 iu/l); p = 0.158), however these differences were statistically insignificant (p > 0.05). further, pearson’s correlation analysis revealed that variable monthly intercourse were inversely or negatively related to estradiol, lh and age (correlation coefficient r <-0.3) again this correlation coefficient values were not statistically significant (p > 0.05). discussion we tested whether pp usage after a long period of time having no penile-vaginal intercourse and sexual activity in ed patients’ impact on sex hormone levels. we showed that pp usage caused a significant increase in dheas levels after pp usage. we also demonstrated that mean total and free testosterone, estradiol, lh levels were clinically increased after pp usage, however the results were statistically insignificant. our results carry important clinical implications. in particular, the findings suggest that pp implantation presents not only a change in sex life of a man but also change in hormone levels in a positive direction. these increases, especially, becomes more important when we take longitudinal studies into account. because, longitudinal studies in male aging researches have demonstrated that serum testosterone levels decline with age (11). more than forty years ago, a motivating observational study published in journal nature and provided some clues about the effects of sexual activity on testosterone (12). a lone man on an island noted that his beard appeared to grow more around the time of trips to the mainland. as beard growth could be accepted as an indirect sign for testosterone levels, he hypothesized that the sexual interest and activity increased his testosterone, which in turn increased his beard growth (12). in forthcoming years, researchers found that androgens and estrogens were significantly higher following masturbation, but interestingly not after “sham masturbation” (13). in different studies, it was also proven that sexually explicit movies increase men’s testosterone compared with sexually neutral films (6, 14). the development and easy use of salivary testosterone measurement has greatly simplified the inclusion of endocrine variables in biobehavioral research (7, 15). in one of these studies, it was demonstrated that testosterone increased in heterosexual figure 1. serum values of total testosterone, luteinizing hormone (lh), estradiol and dehydroepiandrosterone sulphate (dheas) levels. values are expressed as means of 67 patients before and after usage of penile prosthesis. * p < 0.05 canguven_stesura seveso 08/10/14 12:09 pagina 194 men even exposed to brief conversations with women (15). moreover, show off behaviors was associated with the increase in degree of testosterone. assorted research results have indicated that testosterone increases can occur in a short period, often within 15 min, in response to relevant stimuli, such as sexual activities or competitions (7, 16). in a sex club, researchers found that increase in men’s testosterone level were more pronounced among those participating in sexual activity rather than observing (7). additionally, men's testosterone changes were unrelated to their age (7). according to previous studies, it is obvious that any sexual activity influences testosterone levels in a positive direction more or less (7, 13, 16). in a previous study, jannini et al found dramatic increase in serum total and free testosterone levels three months after various ed therapies including two pp implanted patients (1). contrary to the latter study, although testosterone levels increased in our study, it was not significant. this could be due to the fact that the experimental setting in our study used evaluated testosterone levels not acutely or some weeks after treatment, but after years. the small population size (two pp implanted patients) in jannini et al study might be another explanation for the dramatic increase in testosterone level (1). another study also demonstrated that married men have reduced morbidity and mortality compared with single men (17). on the other hand, gray et al investigated a population of men and found that married men have parallel testosterone levels as single men, but that polygamously married men had higher testosterone than all other men (18). a variety of species have repeatedly been shown to respond to different female stimuli by triggering an increase in luteinizing hormone which was followed by a rise in plasma testosterone levels (19). it is well known and proven that normal testosterone level is vital for general health (3, 20). testosterone has been shown to produce positive effects on endothelial function, glucose metabolism, body composition and mood. although the significance of testosterone is well known, the extent to which testosterone deficiency is involved in the pathogenesis of these conditions is unknown. additionally, which type of testosterone formula could be useful in treatment of hypogonadism is an area of great interest and being searched. at the present time, it is recommended that androgen replacement should be taken in the form of natural testosterone. the significance of hormone alterations related to sexual activity is not known and has not been studied directly. however, it is obvious that acute increase of testosterone should present some benefits to body during sexual intercourse or after it. most studies investigated the effects of hormones on behavior, because hormones have powerful effects on the different body systems throughout life (21). on contrary, our behaviors also affect our hormones that were verified in different studies (2, 7). the “challenge hypothesis” suggests that social interactions affect testosterone levels in males, and testosterone should be high when challenges for sources or the likelihood of challenges are present (22). if we accept the “challenge hypothesis” as true, there should be more in details of testosterone increase. non-genomic actions of steroid hormones are those in which gene transcription is not directly implicated and involves second messenger participation and are rapid in action (within seconds to minutes) (23). scientific information regarding the testosterone is not limited to its’ genomic effect, it has also non-genomic effect (23, 24). animal experiments and clinical studies showed rapid non-genomic relaxant effects of androgens on the smooth musculature of coronary arteries and the aorta (25, 26). a possible protective effect of testosterone during sexual activity might be against skeletal muscle fatigue that was suggested earlier while investigating neuromuscular activity and hormonal profile in athletes (24). it is intriguing to speculate about the possible mechanisms linking testosterone and sexual activity. additionally, according to epidemiological studies there is a positive correlation between testosterone levels and mood (27). therefore there may be different and important issues involved in the testosterone-sexual activity relation. increase in testosterone and so on mood might be translated into increased confidence and behavior in difficult circumstances e.g. sexual activities. we propose, based on results of prior non-genomic testosterone research, that acute elevations in testosterone concentration may be able to reduce or compensate the effects of fatigue during sexual activities in addition to prepare the body for a successful intercourse. however, other possible explanations of increase in testosterone levels among men during sexual activity are warranted. in this study, we demonstrated significant increase in dheas levels after pp usage. actually, dhea has very low androgenic potency, but serves as the major direct or indirect precursor for most sex-steroids. dhea is secreted by the adrenal gland and production is at least partly controlled by adrenocorticotropic hormone. the bulk of dhea is secreted as a 3-sulfoconjugate i.e. dheas. in gonads and several other tissues, most notably skin, steroid sulfatases can convert dheas back to dhea, which can then be metabolized to stronger androgens and to estrogens. significant increase in dheas levels after pp usage may be due to utilize it as precursor of t in addition to testicular production. in our study, the testosterone increase was being driven from the higher levels. as has been demonstrated in the previous studies (1, 2, 6), the current study showed that sexual activity influence serum testosterone levels by increase in lh secretion in males. in a recent review article, researchers looked for potential health benefits of various sexual activities and focused on the effects of different sexual activities (28). among different sexual activities, penile-vaginal intercourse was shown associated with better psychological and physiological health indices (28). from a practical standpoint, our findings imply that penile-vaginal intercourse augmented by pp improved our patients’ testosterone level that is crucial for general health. despite its practical value, our study has limitations. firstly, it consists of lack of prospective study design. secondly, the difference in the time interval between surgery and blood taken for controlling testosterone levels were not same. thirdly, sample size was relatively small. this was mainly due to reluctance of our pp patients to participate in this study that was done years after the surgery. since they did not have any problem and satisfied 195archivio italiano di urologia e andrologia 2014; 86, 3 impact of sexual activity on hormone levels canguven_stesura seveso 08/10/14 12:09 pagina 195 archivio italiano di urologia e andrologia 2014; 86, 3 o. canguven, r.a. talib, a. shamsodini, a. al ansari 196 with their pp, they did not want to participate and give blood samples. according to literature, androgen levels have circadian rhythm and exhibit daily and seasonal fluctuations in addition to age-related decline (21). unfortunately, we did not classify our study patients’ testosterone levels according to their season when blood samples given. however, all blood samples after pp usage were taken in the same month from all participants. conclusions studies, especially in the last decades, demonstrated that sex hormones are closely related with health risks and promotes health. our study investigated possible correlations of the sex hormone levels and sexual intercourse in patients with pp. in conclusion, the present study suggests that penile-vaginal intercourse by pp usage appears to be increasing sex hormone levels relative to baseline levels that were before the pp implantation. however, further prospective controlled studies with large sample size are needed to determine why and how pp usage leads to change in sex hormone levels and how long this alteration continues. ethical standards written informed consent was obtained from patients who participated in this study. acknowledgements a grant from the hamad medical corporation primarily supported this research. we would also like to acknowledge the careful work of dr. prem chandra for his assistance with the statistics used in this study. references 1. jannini ea, screponi e, carosa e, et al. lack of sexual activity from erectile dysfunction is associated with a reversible reduction in serum testosterone. int j androl. 1999; 22:385-92. 2. carosa e, benvenga s, trimarchi f, et al. sexual inactivity results in reversible reduction of lh bioavailability. int j impot res. 2002; 14:939; discussion 100. 3. traish am, saad f, feeley rj, guay a. the dark side of testosterone deficiency: iii. cardiovascular disease. j androl. 2009; 30:477-94. 4. stanworth rd, jones th. testosterone for the aging male; current evidence and recommended practice. clin interv aging. 2008; 3:25-44. 5. hilliard j, pang cn, penardi r, sawyer ch. effect of coitus on serum levels of testosterone and lh in male and female rabbits. proc soc exp biol med. 1975; 149:1010-4. 6. stoleru sg, ennaji a, cournot a, spira a. lh pulsatile secretion and testosterone blood levels are influenced by sexual arousal in human males. psychoneuroendocrinology 1993; 18:205-18. 7. escasa mj, casey jf, gray pb. salivary testosterone levels in men at a u.s. sex club. arch sex behav. 2011; 40:921-6. 8. lux m, reyes-vallejo l, morgentaler a, levine la. outcomes and satisfaction rates for the redesigned 2-piece penile prosthesis. j urol. 2007; 177:262-6. 9. carson cc, mulcahy jj, govier fe. efficacy, safety and patient satisfaction outcomes of the ams 700cx inflatable penile prosthesis: results of a long-term multicenter study. ams 700cx study group. j urol. 2000; 164:376-80. 10. bettocchi c, palumbo f, spilotros m, et al. patient and partner satisfaction after ams inflatable penile prosthesis implant. j sex med. 2010; 7:304-9. 11. harman sm, metter ej, tobin jd, et al. longitudinal effects of aging on serum total and free testosterone levels in healthy men. baltimore longitudinal study of aging. j clin endocrinol metab. 2001; 86:724-31. 12. anon. effects of sexual activity on beard growth in man. nature. 1970; 226:869-70. 13. purvis k, landgren bm, cekan z, diczfalusy e. endocrine effects of masturbation in men. j endocrinol. 1976; 70:439-44. 14. pirke km, kockott g, dittmar f. psychosexual stimulation and plasma testosterone in man. arch sex behav. 1974; 3:577-84. 15. roney jr, lukaszewski aw, simmons zl. rapid endocrine responses of young men to social interactions with young women. horm behav. 2007; 52:326-33. 16. dabbs jr jm, mohammed s. male and female salivary testosterone concentrations before and after sexual activity. physiology & behavior. 1992; 52:195-7. 17. hu yr, goldman n. mortality differentials by marital status: an international comparison. demography. 1990; 27:233-50. 18. gray pb. marriage, parenting, and testosterone variation among kenyan swahili men. am j phys anthropol. 2003; 122:279-86. 19. gleason ed, fuxjager mj, oyegbile to, marler ca. testosterone release and social context: when it occurs and why. front neuroendocrinol. 2009; 30:460-9. 20. laughlin ga, barrett-connor e, bergstrom j. low serum testosterone and mortality in older men. j clin endocrinol metab. 2008; 93:68-75. 21. anders s, watson n. social neuroendocrinology: effects of social contexts and behaviors on sex steroids in humans. human nature. 2006; 17:212-37. 22. wingfield jc, hegner re, dufty jr. am, ball gf. the 'challenge hypothesis': theoretical implications for patterns of testosterone secretion, mating systems and breeding strategies. the american naturalist. 1990; 136:829-46. 23. waldkirch e, uckert s, schultheiss d, et al. non-genomic effects of androgens on isolated human vascular and nonvascular penile erectile tissue. bju international. 2008; 101:71-5; discussion 5. 24. bosco c, colli r, bonomi r, et al. monitoring strength training: neuromuscular and hormonal profile. med sci sports exerc. 2000; 32:202-8. 25. yue p, chatterjee k, beale c, et al. testosterone relaxes rabbit coronary arteries and aorta. circulation. 1995; 91:1154-60. 26. deenadayalu vp, white re, stallone jn, et al. testosterone relaxes coronary arteries by opening the large-conductance, calcium-activated potassium channel. am j physiol heart circ physiol. 2001; 281:h1720-7. 27. barrett-connor e, von muhlen dg, kritz-silverstein d. bioavailable testosterone and depressed mood in older men: the rancho bernardo study. j clin endocrinol metab. 1999; 84:573-7. 28. brody s. the relative health benefits of different sexual activities. j sex med. 2010; 7:1336-61. correspondence onder canguven, md ocanguven@yahoo.com raidh a. talib, md ahmed shamsodini, md abdulla al ansari, md hamad general hospital urology department 3050, doha, qatar canguven_stesura seveso 08/10/14 12:09 pagina 196 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2118 original paper low-cost semirigid ureteroscopy is effective for ureteral stones: experience of a single high volume center roberto giulianelli, barbara cristina gentile, giorgio vincenti, luca mavilla, luca albanesi, francesco attisani, gabriella mirabile, francesco pisanti, manlio schettini division of urology, nuova villa claudia, rome, italy. aim of the study: to demonstrate how, in a center with a large number of patients, as our center is, it is possible to perform ureterolithotripsy using a limited set of instruments. methods: we evaluated medical charts of our center related to semirigid ureteral ureteroscopy (urs) with ureterolithotripsy using holmium laser performed from july 2004 to july 2011. overall, 658 urs for ureteral stones were performed in 601 patients, of which 204 in proximal ureter (31%), 86 in the mid (13.06%) and 368 (57.76%) in the distal ureter. in 504 patients (76.5%) ureterohydronephrosis (grade ii-iii) was observed. in 57 patients (8.6%), we performed a bilateral approach at the same time, but most patients had a solitary distal ureteral stone. 106 patients (16.1%) had more than one stone in their distal ureter and 96 (14.8%) had a proximal ureteral stone treated in the same surgery as well. results: the overall stone-free rate for ureteral stones was 86.1% (567/658). success rates for proximal, medial and distal ureteral stones were 68.13% (139/204 patients), 84.8% (73/86 patients) and 96.4% (355/368 patients), respectively. one hundred and twenty patients (18.3%) required additional surgical treatment for their stones beyond the initial urs, including a second urs in 97 patients (14.74%) and urs plus retrograde intra-renal surgery (rirs) in 23 patients (3.54%). the overall stonefree rate after the second treatment was 99.3%. intra-operative complications accounted for 5.92% and consisted of ureteral perforations in 16 pts (2.4%), erosions of urothelium leading to significant bleeding in 15 pts (2.27%), severe pain in 4 pts (0.6%), fever in 3 pts (0.45%) and one case of ureteral avulsion (0.15%). conclusions: this study demonstrates that the use of holmium laser lithotripsy is a safe and effective means of treating ureteral stones regardless of sex, age, stone location, or stone size. the instrumentation we used was extremely limited, in order to reduce costs related to the procedure to an absolute minimum whilst maintaining the two quality indicators for the procedure, namely successrate and length of hospitalisation (86.1% and 34 hours). key words: ureteral calculi; ureteroscopy; holmium laser; lithotripsy. submitted 25 february 2014; accepted 19 may 2014 summary no conflict of interest declared. doi: 10.4081/aiua.2014.2.118 introduction urolithiasis is a common and costly disease displaying increasing worldwide prevalence and incidence rates (1). the lifetime risk of urolithiasis is estimat-ed to be between 5% and 12% in europe and usa, afflicting 13% of men and 7% of woman (2). extracorporeal shock wave lithotripsy (eswl) remains the recommended first-line treatment for most stones (3) but for those stones lodged in the ureter, ureteroscopy (urs) has become the most common treatment method (4). urs is the most commonly advocated treatment for patients with ureteral calculi with a stone-free rate higher than 90% after a single treatment. open ureterolithotomy is no longer considered as a valid op-tion in a well equipped endourological center. with the introduction of in situ extracorporeal shock wave lithotripsy and different intracorporeal techniques in urology practice, up to 95% of ureteral stones can be successfully treated with a minimally invasive method (5-10). in 2007 the eau guideline recom-mended that for ureteral stones requiring removal, because up to 98% of ure-teral calculi < 5 mm in diameter are likely to pass spontaneously, both swl and urs are acceptable first-line treatments in healthy non-pregnant adults who have unilateral calculi (2). in this meta-analysis, overall stone-free rates for swl and urs differed, depending on stone size, location, and treatment method. technological progress in the field of semirigid ureteroscope tech-nology, chiefly involving the miniaturization of the scopes and improved durability, and the introduction of the holmium:yag laser, with its precise and powerful thermal decomposition mechanism, its excellent safety profile and the ability of laser energy to be delivered through small flexible fibers, have opened up the path for fragmentation of stones of all composition types (5-10). use of this increasingly highperformance instrumentation (11), along with the use of dedicated devices which promote access to the ureter or prevent ret-ropulsion of the kidney stone (12), have considerably increased the costs of these procedures. the aim of this study was to demonstrate how, in an high volume center, such our center is,it is possible to perform a ureterolithotripsy for ureteral stones using a minimum set of instruments to complete the treat-ment. 119archivio italiano di urologia e andrologia 2014; 86, 2 low-cost semirigid ureteroscopy is effective for ureteral stones: experience of a single high volume center materials and methods we evaluated medical charts of our centre related to semirigid ureteral ureteroscopy (urs) with ureterolithotripsy using holmium laser performed, from july 2004 to july 2011, by four urologists. of these, two performed more than 200 upper tract endourological procedures, one almost 100, and one less than 50. in total they performed 658 urs in 601 patients, 457 males and 144 females, with an average age of 43.5 years (15-72 years). stones were in the proximal ureter in 204 patients (31%), in the mid ureter in 86 (13.06%) and in the distal ureter in 368 (57.76%). the average stone diameter was 9.1 mm (range 3-22). most patients had a solitary distal ureteral stone, but 106 (16.1%) had multiple stones in the distal ureter and 96 (14.8%) were treated also for proximal ureteral stones whilst undergoing the same surgery. in 57 patients (8.6%) urs was bilaterally performed and in 37 (5.6%) the procedures were performed under emergency conditions due to acute renal failure. urs was offered in cases where the stone failed a trial of passage for up to 10-12 days from the start of expulsive therapy. preoperative work-up consisted of renal ultrasound (rus) in 645 patients (98.02%), plain kidneyureter-bladder x-ray (kub) in 453 patients (68.8%) and computerized tomography (tc) in 67 patients (10.1%). in 504 patients (76.5%) a ureterohydronephrosis was observed (grade ii-iii), in 534 patients (81.5%) drugresistant pain, in 64 patients (9.7%) haematuria, and in 65 patients (9.87%) fever. all patients were hospitalised on the same day on which we carried out the endoscopic procedure, 602 of those (92.4%) were performed under general anaesthesia. only 56 patients (8.5%), due to severe chronic obstructive pulmonary disease (copd), were given an epidural anaesthesia. our technique involved use of a storz semirigid ureteroscope to make an initial inspection of the bladder to rule out the simultaneous presence of other diseases (e.g. malignancies, flat bladder lesions), and to identify the ureteral orifice to be approached. having assessed its characteristics, and in particular its shape, orifice was cannulated using a 4 f open-toe ureteral catheter advanced through the working channel of the ureteroscope up to about 3-4 cm from the orifice, acting as a “working wire”. at this point, using the pressure of the irrigation flow and relying on the catheter, the affected ureter was reached with an initial movement which involved a delicate lifting of the instrument with subsequent abduction. we proceeded with extreme caution along the ureter, minimizing the flow of water washing, to reduce the risk of pushing the stone upwards, thus reaching the stone and then proceeding with the ureterolithotripsy using the holmium laser with an 0.8 to 1j energy pulse and 8 to 10 hz frequency. the stone was then fragmented with the laser until all pieces were approximately 2 mm or smaller. stone fragments were not routinely extracted and the decision to place a ureteral stent upon completion of the procedure was based on preoperative grade of ureterohydronephrosis and intra-operative findings. we positioned a jj stent in all patients with severe ureterohydronephrosis or when other conditions rendered it necessary (i.e., ureteral wall injury, bleeding, severe inflammatory reaction against the ureteral wall). on the other hand, in 214 patients we left in place the ureteral catheter previously used as a guide, fixed by its distal end to a foley catheter, positioned at the end of the procedure for 24 hours. we did not use a basket to prevent the stone from being pushed upwards. fluoroscopy was not requested for treatment of distal ureteral stones, when calculi were positioned below the intersection with the iliac vessels, whatever their diameters. we used fluoroscopy in 18 patients (2.73%) including 14 with stones (2.12%) in the proximal ureter and 5 (0.75%) in the mid ureter. some patients had concomitant renal calculi that were deemed to be clinically insignificant (usually < 3 mm) and were not treated at the time of urs. patients were instructed to strain their urine postoperatively and to bring the retrieved fragments to their next outpatient appointment so they could be sent for analysis. the charts, including operative reports, were reviewed and data concerning patient and stone characteristics, duration of surgery, use of stents and use of secondary procedures were collected. we recorded data concerning body mass index (bmi) and gender. we also reviewed imaging studies of the patients at 30-day postoperative follow up to assess stone-free rates. computed tomography (ct), renal ultrasound (us) and plain abdominal radiography (kub) were used for imaging. we compared preand postoperative imaging to determine whether renal stones seen on postoperative films were consistent with pre-existing, untreated renal stones or with new, proximally migrated fragments of a ureteral stone. data concerning complications was also recorded. statistical analyses were performed using student t test and chisquare analysis. results overall, 658 urs for ureteral stones were performed in 601 patients, of which 204 in proximal ureter (31%), 86 in the mid (13.06%) and 368 (57.76%) in the distal ureter. in 504 patients (76.5%) ureterohydronephrosis (grade ii-iii) was observed. in 57 patients (8.6%), we performed a bilateral approach at the same time, but most patients had a solitary distal ureteral stone. 106 patients (16.1%) had more than one stone in their distal ureter and 96 (14.8%) had a proximal ureteral stone treated in the same surgery as well. the overall stone-free rate for ureteral stones was 86.1% (567/658). success rates for proximal, medial and distal ureteral stones were 68.13% (139/204 patients), 84.8% (73/86 patients) and 96.4% (355/368 patients), respectively. one hundred and twenty patients (18.3%) required additional surgical treatment for their stones beyond the initial urs, including a second urs in 97 patients (14.74%) and urs plus retrograde intra-renal surgery (rirs) in 23 patients (3.54%). the overall stonefree rate after the second treatment was 99.3%. four patients (0.6%) were judged to be failures (i.e. not stonefree) in that they had new renal stones postoperatively, consistent with proximal migration of ureteral stones after fragmentation that did not clear up. these fragments, however, were 2 mm in size in 75% of patients; in one patient, a 5 mm fragment was found in the ureter by postoperative imaging but the patient was subsequently lost archivio italiano di urologia e andrologia 2014; 86, 2 r. giulianelli, b.c. gentile, g. vincenti, l. mavilla, l. albanesi, f. attisani, g. mirabile, f. pisanti, m. schettini 120 in the follow-up, and was therefore classified as a failure. the overall stone-free rate for the treatment of ureteral stones was worse in the obese group than in the nonobese group, but not statistically significant (82% vs 76%, p = ns). the mean operating time was 32 minutes (1252 minutes, depending on stone burden and impaction) and mean hospital stay was 34 hours (26-42 h). two hundred and twelve patients (32.2%) had a ureteral stent placed before their urs. we performed a bilateral approach in 57 patients (8.6%), and of these the procedure was performed under emergency conditions of acute renal failure in 37 patients (5.6%). fifty-three patients (8.05%) had concomitant urinary tract infection, 69 (10.4%) had severe ureterohydronephrosis (iii grade), 11 (1.94%) ureteral wall injury, 9 (1.36%) bleeding and 13 (1.97%) a severe inflammatory response of the ureteral wall. in all other cases we left the 4 or 5 f ureteral catheter used during the procedure after completely removing all of the ureteral fragments over 3 mm, leaving it out of the external urethral meatus where it was attached to the foley catheter. complications were uncommon. intra-operative complications accounted for 5.92% and consisted of ureteral perforations in 16 pts (2.4%), erosions of urothelium leading to significant bleeding in 15 pts (2.27%), severe pain in 4 pts (0.6%), fever in 3 pts (0.45%) and one case of ureteral avulsion (0.15%). conversion to open surgery was carried out in one patient (0.15%) with a distal ureter stone associated with a neoplasm of the upper tract, where the endoscopic ureteral avulsion manoeuvre occurred accidentally. there was no immediate postoperative mortality. fifty-three patients (8.05%) presented a postoperative urinary tract infection, none of whom required hospitalisation. late complications were persistent haematuria in 66 patients (10.03%) and severe dysuria in 146 patients (25.2%). in 87 patients with dysuria (13.25%) long term use of nsaids was required. early stent removal (within 30 days from surgery) was necessary in 116 patients (17.6%) whereas 98 patients (14.8%) presented at the emergency department complaining of pain in the side of the procedure which was related to the stent, but did not require hospitalisation. discussion the management of ureteral stones has seen a change from open surgery to swl and to endoscopic and laparoscopic surgery. intracorporeal lithotripsy devices and urs have made treatment of ureteric stones much more convenient. rigid urs was first applied for the treatment of distal ureteral calculi in the 1980s. although large (> 10f) diameter ureteroscopes were used, success rates of > 90% were achieved (13). with the development of smaller caliber ureteroscopes and the introduction of improved instrumentation, including the holmium:yag laser, ureteroscopy has evolved into a safer and more effective method of treating ureteral stones. in our study, the overall stone-free rate of urs was comparable to other studies, with stone-free rates ranging from 75% to 93% (14). in fact we obtained an 86.1% overall stone-free rates after holmium laser uretero lithotripsy. leijte ja et al. (15) showed in 105 ureteroscopic holmium laser lithotripsies procedures a total success rate of 84.8% and ullah et al. in 88 ureteral stone cases treated with ureteroscopic holmium laser lithotripsy reported an overall success rate with satisfactory fragmentation in 85.15% (16). safwat et al. observed 239 patients (199 males and 40 females) with an average stone burden of 9.8 mm (range 4 to 20 mm) and reported a success rate of 96.3% after a single session which increased to 99% after 2 sessions (17). in our experience, we have obviously observed different results in terms of stone-free rates, according to the site in which the stone was located. in fact, success rates for proximal, mid and distal ureteral stones were 68.13%, 84.8% and 96.4%,respectively. similarly,in a total of 88 stones, 22 (25%) in the upper ureter, 24 (27.27%) in the middle ureter and 42 (47.72%) in the lower ureter, ullah et al. (17) showed success rates of 72.72%, 87.5% and 95.23%, respectively. similar results were also obtained by subhani et al. (18), who carried out ureteroscopic holmium laser lithotripsy in 209 patients with stones in the lower ureter, 266 in the middle ureter and 65 in the upper tract of the ureter, achieving success rates of 94.73%, 95.11% and 44.61%, respectively. use of flexible ureteroscopy for treating stones located in the proximal tract, would have propably improved our results in terms of stone-free rates in line with available data (68.13% vs 93.1%) (19). however, owing to the costs in-volved, use of this method in our center is exclusively limited to the treatment of complex calculi or for the treatment of intrarenal lithiasis > 2 cm. in our experience, one hundred and twenty patients (18.3%) required addi-tional surgical treatment for their stones beyond the initial urs to achieve an overall stonefree rate of 99.3%. these results, including a second urs in 97 pts (14.74%) and urs plus rirs in 23 pts (3.54%). the holmium laser pro-vides the gold standard for intracorporeal lithotripsy (20) and its use proved to be crucial in our experience. holmium laser can effectively fragment any stone regardless of composition or size and can reach the entire urinary tract since it can be deployed on rigid and flexible ureteroscopes. furthermore, compared to other intracorporeal lithotripsy, holmium laser yields the smallest fragment size, with many even smaller than 1 mm (20). according to international experiences, the use of the holmium laser, enabled us to attain complete pulverization of the stones at the end of our procedures (21, 22). this reduced risk of complications to a minimum (none steinstrasse) and reduced the risk of retropulsion of the stone to a minimum, whereas figures are undoubtedly higher when ballistic lithotripsy is used (23). bapat et al. compared the success rates of lithoclast and holmium laser-assisted ureterorenoscopy in 394 patients assessing at 2 weeks fragmentation into fine pieces of stones and their passage. this occurred in 166/193 (86.01%) patients in the lithoclast group and in 195/201 (97.01%) in the laser group (24). in general complications are uncommon. in bapat’s experience, the complications and the need for auxiliary procedures were significantly less for holmium laser-assisted 121archivio italiano di urologia e andrologia 2014; 86, 2 low-cost semirigid ureteroscopy is effective for ureteral stones: experience of a single high volume center ureteroscopy when compared with pneumatic lithotripsy (24). ullah et al. reported an overall complication rate of 17.04%; the main complications included ureteral perforation (n = 2), ureteral avulsion (n = 1), urosepsis (n = 2) and stone migration (n = 10) (17). subhani et al. described an overall complication rate of 11.83%. the main complications included mucosal lacerations (9.25%), perforation (2.40%), ureteric avulsion (0.18%) (18). in our experience, intra-operative complications accounted for 5.92% of our cases and consisted of ureteral perforations in 16 patients (2.4%) and erosions of urothelium leading to significant bleeding in 15 patients (2.27%). in one patient which presented with a distal ureter stone associated with a neoplasm of the upper tract, we had to convert the endoscopic procedure to open surgery (0.15%), because the endoscopic manoeuvre accidentally caused ureteral avulsion. late complications included persistent haematuria in 66 patients (10.03%) and severe dysuria in 146 (25.2%). out of them 87 patients required long term nsaids treatment (13.25%). costs conducting a stone-free holmium laser-assisted urete roscopy is less costly than a swl procedure (higher number of treatments required to obtain stone-free condition with swl, higher risk of steinstrasse after swl) (25). a study reported the cost of stone removal for both the upper and lower ureter using swl significantly higher compared to endoscopic procedures (ureteroscopy with semirigid ureteroscope and the use of pneumatic lithoclast, or ureteroscopy with flexible ureteroscope and the use of holmium yag laser). the median cost for the upper ureter was € 828 vs € 474.50 and € 396 respectively, and for the lower ureter, € 826 vs € 396 and € 271, p < 0.001 (26). esuvaranathan et al. observed, in a prospective consecutive series of 64 patients who underwent transurethral laser uretero lithotripsy using a 7.2 f semirigid ureteroscope, that the 3-year cost-benefit analysis revealed a smaller difference in cost than expected and the 5-year analysis was advantageous for laser lithotripsy because of its higher success rate (27). at present, costs constitute an increasingly important problem and, unfortunately, they have an increasing influence on the treatment choices in the clinical setting. all this has in fact prompted us to gradually reduce our instrumentation to a minimum and to choose the semirigid ureteroscope as a first choice instead of the flexible one. the latter is instead used only for treating complex ureteral calculi. we have gradually developed a technique for accessing the ureter which requires the use of a simple ureteral catheter, avoiding the use of additional guide wires or instruments to dilate the ureteral ostium. we rely on a simple manoeuvre exploiting the pressure of the washing fluid and the presence of the catheter. the affected ureter is reached with an initial movement which involves a delicate lifting of the instrument and its subsequent abduction. the extreme attention and care with which the movement is carried out reduces the risk of lesions to the ureter and/or its intussusception to a minimum. in our experience, intra-operative complications accounted for 5.92% and we performed conversion to open surgery in only one patient (0.15%). needless to say, we are in complete agreement with all those that sustain that the experience of the surgeon is of the utmost importanc (15) and plays a crucial role in determining a reduced rate of method-related complications. we also feel it is important to have procedure-dedicated surgeons who exclusively carry out all these procedures. in our experience, the mean hospital stay was 34 hours (26-42 h), whilst rombi et al. observed a hospital stay for upper ureter cases of 2.48 days, and 2.43 days for lower ureter, respectively (26). conclusions this study demonstrates that the use of holmium laser lithotripsy is a safe and effective means of treating ureteral stones regardless of sex, age, stone location, or stone size. we found that the overall stone-free rates before holmium laser ureterolithotripsy were 86.1% and 99.3% after the first and second treatment, respectively. complications were uncommon. the instrumentation we used was extremely limited, in order to reduce costs related to the procedure to an absolute minimum whilst maintaining the two quality indicators for the procedure, namely success-rate and length of hospitalisation (86.1% and 34 hours), which reflect those obtained with other experiences. references 1. hesse a, brandle e, wilbert d, et al. study on the prevalence and incidence of urolithiasis in germany comparing the years 1979 vs 2000. eur urol. 2003; 44:709-13. 2. preminger gm, tiselius hg, assimos dg, et al.: guideline for the management of ureteral calculi. j.urol 2007; 178:2418-34. 3. osman mm, alfano y, kamp s, et al. 5-years follow up od patients with clinically insignificant residual fragmenta and after extracorporeal shock wave lithotripsy. eur urol. 2005; 47:860-4. 4. bader mj, eisner b, porpiglia f, et al. contemporary management of ureteral stones. eur urol. 2012; 61:764-771. 5. yinghao s, linhui w, songxi q, et al. swiss lithoclast pneumatic lithotripter: report of 150 cases. j endourol. 2000; 14:281-3. 6. ather mh, paryani j, memon a, sulaiman mn. a 10-year experience of managing ureteric calculi: changing trends towards endourological interven-tion-is there a role of open surgery? bju int. 2001; 88:173-177. 7. dirim a, tekin mi, aytekin c, et al. ureteroscopic treatment of proximal ureter stones with aid of an antegrade occlusion balloon catheter. acta radiol. 2006; 47:103-6. 8. kupeli b, biri h, isen k, et al. treatment of ureteral stones: comparison of extracorporeal shock wave litho-tripsy and endourologic alternatives. eur urol. 1998; 34:474-479. 9. naqui sa, khalogi m, zafar mn, rizwi sa. treatment of ureteric stones. comparison of laser and pneumatic lithotripsy. br j urol. 1994; 74:694-698. 10. maislos sd, volpe m, albert ps, raboy a. efficacy of the stone cone for treatment of proximal ureteral stones. j endourol. 2004; 18:862-4. 11. sofer m, watterson jd, wollin ta, nott et al.: holmium:yag archivio italiano di urologia e andrologia 2014; 86, 2 r. giulianelli, b.c. gentile, g. vincenti, l. mavilla, l. albanesi, f. attisani, g. mirabile, f. pisanti, m. schettini 122 laser lithotripsy for upper urinary tract calculi in 598 patients. j urol. 2003; 44:482-6. 12. kijvikai k, haleblian ge, preminger gm, de la rosette j. shock wave lithotripsy or ureteroscopy for the management of proximal ureteral calculi: an olddiscussion revisite. j urol. 2007; 178:1157-63. 13. tawfiek er, bagley dh.: management of upper urinary tract calculi with ureteroscopic techniques. urology. 1999; 53:25-31. 14. park h, park m, park t. two-year experience with ureteral stones: extracorporeal shockwave lithotripsy v ureteroscopic manipulation. j endourol. 1998; 12:501-504. 15. leijte ja, oddens jr, lock tm. holmium laser lithotripsy for ureteral calculi: predictive factors for complications and success. j endourol. 2008; 22:257-60. 16. ullah i, wazir bg, alam k, et al. evaluation of safe-ty and efficacy of ureteroscopic lithotripsy in managing ureteral calculi. ann pak inst med sci. 2011; 7:119-112. 17. safwat as, bissada nk, kumar u, et al. a multi-institutional study demonstrating the safety and effica-cy of holmium laser ureterolithotripsy. urotoday int j. 2012; 5:349. 18. subhani gm, javed sa, iqbal z, et al. outcome of retrograde ureteroscopy for the management of ureteric calculi: four years experience. a.p.m.c. 2009; 3;8-12. 19. cocuzza m, colombo jrjr, cocuzza al, et al. outcomes of flexible ureteroscopic lithotripsy with holmium laser for upper urinary tract calculi. int braz j urol. 2008; 34:143-9. 20. preminger gm, tiselius hg, assimos dg, et al. guideline for the management of ureteral calculi. j urol 2007; 178:2418-34. 21. jong-hyun lee, seung hyo woo, eun tak kim, dae kyung kim, jinsung park comparison of patient satisfaction with treatment outcomes between ureteroscopy and shock wave lithotripsy for proximal ureteral stones korean j urol. 2010; 51:788-793. 22. wu cf, shee jj, lin wy, et al. comparison between extracorporeal shock wave lithotripsy and semirigid ureterorenoscope with holmium:yag laser lithotripsy for treating large proximal ureteral stones. j urol. 2004; 172:1899. 23. teichman jm1, vassar gj, bishoff jt, bellman gc holmium:yag lithotripsy yields smaller fragments than lithoclast, pulsed dye laser or electrohydraulic lithotripsy. j urol. 1998; 159:17-23. 24. bapat ss, pai kv, purnapatre ss, et al. comparison of holmium laser and pneumatic lithotripsy in managing upper-ureteral stones. j endourol. 2007; 21:1425-7. 25. nabi g, downey p, keeley f, et al. extracorporeal shock wave lithotripsy (eswl) versus ureteroscopic management of ureteric calculi. cochrane database syst rev. 2007; cd006029. 26. rombi t, triantafyllidis a, fotas a, et al. socioeconomic evaluation of the treatment of ureteral lithiasis. hippokratia. 2011; 15:252-7. 27. esuvaranathan k, tan ec, tan pk, tung kh. does transurethral laser ureterolithotripsy justify its cost? j urol. 1992; 148:1091-4. correspondence roberto giulianelli, md (corresponding author) roberto.giulianelli@virgilio.it barbara cristina gentile, md giorgio vincenti, md luca mavilla, md luca albanesi, md francesco attisani, md gabriella mirabile, md francesco pisanti, md manlio schettini, md division of urology, nuova villa claudia via flaminia nuova, 280 rome, italy stesura seveso 15archivio italiano di urologia e andrologia 2014; 86, 1 original paper urinary and sexual functions after surgical treatment of penile fracture concomitant with complete urethral disruption ali abdel raheem, hassan el-tatawy, ahmed eissa, abdel hamid elbahnasy, mohamed elbendary urology department, tanta university hospital, egypt. objectives: penile fracture with concomitant complete urethral disruption is an uncommon urologic disorder. data about the treatment and outcome measurements of this condition are scarce in the literature. the aim of the present study is to evaluate the long term urinary and sexual functions of patients with penile fracture associated with complete urethral injury after immediate surgical reconstruction. patients and methods: twelve patients met our inclusion criteria and were included in this retrospective case series study; however, one was lost during follow-up. patient's medical records were reviewed and all patients were interviewed for clinical evaluation. urinary function was assessed by history, uroflometry and retrograde urethrography, while, sexual function was assessed by questionnaire (sexual health inventory for men) and penile doppler for patients with erectile dysfunction. results: patients’ mean age was 32.3 ± 7.5 years (range 21-43) and the mean follow-up period was 72.6 ± 45.4 months (range 14-187). vigorous sexual intercourse was the main cause in 91% of our patients. no serious long term complications was found. only 1 patient (9%) suffered from anterior urethral stricture, 1 patient (9%) complained of weak erection, 3 patients (27%) had a palpable fibrosis and 2 patients (18%) reported a slight penile curvature during erection. ninety one percent of all our patients maintained their normal urinary and sexual functions. conclusion: on the long term follow-up, most of the patients maintained their normal erectile and voiding functions with no harmful long-term complications. we advocate immediate surgical intervention and reconstruction of both corpora cavernous and urethra as a first line treatment for those patients.. key words: urinary function; sexual function; penile fracture; surgical treatment. submitted 31 july 2013; accepted 5 october 2013 summary introduction penile fracture is a rare emergent urologic condition, which is characterized by disruption of the tunica albuginea of one corpus cavernosum or both (1). till the year 2001, only 1331 cases had been reported in the literature (2). it seems that its incidence is higher in middle-east countries than in usa and western countries (3, 4). penile fracture may be associated with urethral injury in up to 38% of cases (5). many causes of penile fracture have been reported, including sexual intercourse, sudden forced flexion, masturbation, and direct blunt trauma or rolling over in bed onto an erect penis (6). with fully erected penis, the tunica albuginea which is one of the strongest fascia in the human body – can withstand pressures up to 1500 mmhg – stretches and becomes as thin as 0.25-0.5 mm thick, while in the flaccid state it is 2.4 mm (7, 8). so the erected penis is much more vulnerable to rupture after trauma than the flaccid penis. fracture penis is a clinical diagnosis, typically the patient describes hearing a popping or snapping sound followed by sudden detumescence and pain. clinically penile swelling, hematoma, ecchymosis and penile deformity are present (figure 1) (2). no conflict of interest declared figure 1. the classic clinical picture for penile fracture (swelling, hematoma and penile deformity). doi: 10.4081/aiua.2014.1.15 raheem_stesura seveso 26/03/14 10:12 pagina 15 archivio italiano di urologia e andrologia 2014; 86, 1 a. abdel raheem, h. el-tatawy, a. eissa, a. hamid elbahnasy, m. elbendary 16 suspicion of urethral injury is increased with presence of blood at the external meatus or hematuria (3), therefore, retrograde urethrography is prefered by many authors to confirm urethral injury diagnosis (9, 10). regarding the role of imaging studies in the diagnosis of penile fracture still there is controversy. some studies showed the usefulness of ultrasound, cavernosography and mri (11, 12) with superiority of mri in identification of corporal injury (13). however, a recent study showed that mri is not able to reveal detailed information about extent of corporal and urethral injury over surgical exploration (14). for treatment of penile fracture immediate surgical exploration and repair has the advantages of short hospital stay, better patient satisfaction, and improved outcomes with lower incidence of erectile dysfunction (6, 15, 16). the aim of this retrospective study is to report our experience and to assess the long-term urinary and sexual functions for patients with penile fracture and complete urethral injury who were treated with immediate surgical reconstruction. material and methods this retrospective study was approved by our ethical committee review board. the medical records and database at our institute were reviewed to identify all patients with penile fracture who were treated surgically from 1985 till 2012. overall 246 patients were detected of whom 34 patients had associated urethral injury (22 partial and 12 complete). we included only patients with complete urethral disruption. we reviewed the history, presentations, investigations, operative and postoperative data of these patients. surgical technique: prophylactic antibiotic was used before surgery. under spinal anesthesia all patients underwent an immediate surgical exploration through a subcoronal circumcising incision with degloving of the penis (figure 2a). once the site of the tunical tear was identified and the hematoma was evacuated we closed the tear with 3/0 absorbable (polydioxanone or polyglycolic acid) either continues or interrupted sutures (figure 2b-2c). an artificial erection test through intracorporal saline injection was done to detect any leakage from the tunical tear or curvature at the repaired site. the urethra was repaired over 18 french silicon catheter. the urethral edges were dissected at both sides, trimmed, spatulated and closed with interrupted absorbable sutures using (3/0 or 4/0 polydioxanone) after ensuring tension-free end-to-end anastomosis (figure 2d-2e). suprapubic catheter insertion or not was determined by the surgeon preference. postoperative care: patients received oral antibiotics for 1 week, analgesics on demand and diazepam 5 mg nightly in an attempt to prevent nocturnal erections. all patients were instructed to abstain from sexual activity for at least 8 weeks. the urethral catheter was left in place for at least 3 weeks and then removed. if a suprapubic catheter was inserted it was closed for at least 3 days after urethral catheter removal to ensure adequate and normal voiding before its removal. follow-up: we contacted patients through the telephone and an interview was done with each patient at the followup in our outpatient clinic. all patients were examined with particular concern for local penile examination to detect penile curvature and/or fibrotic nodules. patients' sexual function was evaluated subjectively through the sexual health inventory for men (shim), a questionnaire of 5 questions which is a short version of the long international index of erectile function (iief-15) questionnaire (17). color doppler ultrasonography was performed for patients with erectile dysfunction. the urinary function was evaluated objectively with uroflowmetry. retrograde urethrography was done for all patients early after catheter removal to ensure urethral healing and during follow-up if voiding symptoms present. figure 2. surgical technique description: a) degloved penis with large hematoma at the fracture site. b) after hematoma evacuation both corpora was injured with complete urethral separation. c) after closure of the tunical tear with continuous 3/0 pds suture. d) the urethral edges were dissected at both sides, trimmed and spatulated with stay sutures. e) the urethral edges were closed with interrupted absorbable sutures after ensuring tension free end-to-end anastomosis. raheem_stesura seveso 26/03/14 10:12 pagina 16 results twelve patients who met our inclusion criteria were included in this retrospective series. all patients were married and their mean age was 32.3 years (range: 21-43) and mean follow-up period was 72.6 months (table 1). all patients (100%) presented with penile swelling, hematoma and urethral bleeding on examination, while, 3 patients (25%) and 4 patients (33%) were presented with acute urinary retention (aur) and voiding difficulties, respectively. the mean time elapsed between the occurrence of the trauma and the patients' arrival was 5.5 hours (range: 1-15) (table 1). the most common cause of penile fracture was vigorous sexual intercourse in 11 patients (91%) while one patient reported a history of forced penile pending (table 1). a routine urethrography was done in all patients and showed extravasation of dye with loss of urethral patency at the anterior penile urethra. the site of the tear was at penile mid-shaft in all patients and the urethra disruption level was opposite to and at the same tear level (figure 3). suprapubic catheter was inserted in 5 patients. the mean operative time was 60.3 minutes, the duration of catheterization ranged from 21 to 29 days, and the mean hospital stay was 2.1 days (table 1). one patient was lost during follow-up due to unknown causes and was excluded from our study. during patients' assessment a palpable fibrosis and slight penile curvature during erection were found in 27% and 18% of patients respectively. ten out of 11 patients reported good voiding function with mean qmax 20.9 ± 4.2, no significant post voifing residual (pvr) urine and normal urethrography. only one patient complained of voiding difficulites and his urethrography showed a ring stricture at the anterior urethra which was treated successfully by regular urethral dilatation (figure 4). regarding the sexual function, all patients maintained normal sexual activity with complete recovery of their erectile function as shown in their shim with mean value 22.2 ± 3, except one patient who suffered from weak erection and was treated successfully with oral sildenafil® 100 mg on demand. 17archivio italiano di urologia e andrologia 2014; 86, 1 urinary and sexual functions after surgical treatment of penile fracture concomitant with complete urethral disruption clinical presentation: – penile swelling all patients (100%) – hematoma all patients (100%) – urethral bleeding all patients (100%) – sever pain all patients (100%) – acute urinary retention 3 patients (25%) – voiding difficulties 4 patients (33%) predisposing factors: – vigorous sexual intercourse 11 patients (91%) – forced penile pending 1 patient (9%) perioperative data: mean ± sd (range) – age (years) 32.3 ± 7.5 (21-43) – time of presentation (hours) 5.5 ± 3.9 (1-15) – operative time (minutes) 60.3 ± 6.5 (45-68) – hospital stay (days) 2.1 ± 0.7 (1-3) – duration of catheterization (days) 22.5 ± 2.5 (21-29) – follow-up period (months) 72.6 ± 45.4 (14-178) long term complications: – stricture urethra 1 patient (9%) – erectile dysfunction 1 patient (9%) – palpable fibrosis 3 patients (27%) – penile curvature during erection 2 patients (18%) uroflometry: mean ± sd (range) – qmax (ml/s) 20.9 ± 4.2 (14-28) – voided volume (ml) 29.9 ± 18.5 (0-70) – pvr urine (ml) 264.7 ± 66.5 (160-370) sexual health inventory questionnaire mean ± sd (range) 22.2 ± 3 (14-25) table 1. patients' characteristics, perioperative and follow-up data. figure 3. showing the usual site of the tear at mid-shaft of the penis in and the urethra disruption level was opposite to and at the same tear level with retraction of urethral edges. figure 4. a retrograde urethrogram showing a ring stricture at the anterior urethra. raheem_stesura seveso 26/03/14 10:12 pagina 17 archivio italiano di urologia e andrologia 2014; 86, 1 a. abdel raheem, h. el-tatawy, a. eissa, a. hamid elbahnasy, m. elbendary 18 discussion this retrospective study is the biggest series reported in the literature for long term functional outcomes of 11 patients with penile fracture associated with complete urethral disruption. to our knowledge, only few case reports and some case series with small number of patients reported this rare condition (18-21). in the present study the incidence of urethral injury in patients with penile fracture was 13.8% (34/246), and this finding was in accordance with koifman et al. who showed an incidence 12.5% for associated urethral injury (22). the result of our study refers to both hematuria and blood at the external meatus as a hallmark findings for concomitant urethral injury diagnosis, since all of our patients (100%) showed both findings on examination, the same findings were reported by derouiche et al. who observed that 10 out of 10 patients (100%) who presented with bloody urethral discharge had associated urethral injury (3). other clinical presentations such as penile swelling, hematoma, pain and penile deformity are common findings in all patients with penile fracture, but not specific for diagnosis of urethral injury. although 58% of our patients had voiding difficulties and aur, however, these findings may present in the absence of urethral injury, due to the presence of penile deformity, large hematoma and severe edema causing urethral obstruction (23). it seems to us that the association of complete urethral injury and penile fracture need more forcible trauma to occur and this was evident in our study, since, the main underlying etiology in 11/12 patients was due to vigorous sexual intercourse. el-assmy et al. reported that vigorous coital trauma was the commonest cause (50%) of penile fracture associated with urethral injury (19). and this may also explain that all our patients had a bilateral corporal rupture owing to the severity of the trauma. in our series all patients underwent retrograde urethrography as it is a routine investigation in our department for patients with penile fracture if a high clinical suspicion of associated urethral injury is present. the sensitivity of retrograde urethrography in the diagnosis of associated urethral injury was 100%. in contrast, mydlo, found that the sensitivity of this test is only 50% with a possibility of a false negative results (1). conservative treatment for penile fracture treatment consisted mainly of cold compresses, pressure dressings, antibiotics and anti-inflammatory drugs (24-26). nowadays, many studies supported the superiority of surgical treatment over conservative treatment (27, 28). moreover, excellent long-term results and lower complication rates have been reported with immediate surgical repair (1, 6, 29). the mean follow-up for our patients was 72.6 months; of them 91% showed no voiding difficulties. several studies and case reports aroused the important role of immediate surgical repair on restoring back the normal urinary function even with complete urethral disruption (6, 19, 20) and their findings was in match with our results. ninety one percent maintained normal erectile function and sexual activity of our patients, whereas other studies reported similar result in 83% and 93% respectively (19, 30). of the long-term complications a palpable fibrosis was found in 27% of patients and slight penile curvature on erection in 18%, but this did not affect their sexual activity. a palpable penile fibrosis is a common long-term complication with an incidence ranging from 41% up to 93 % (30, 4). a limitation of the present study is being a retrospective case series: in addition to, the surgical technique was not uniform regarding suprapubic catheter insertion and suturing of the tunica albuginea. however, being a retrospective study with a small number of patients may be explained by the rarity of this condition and the difficulty to be evaluated prospectively in regard to optimal initial treatment. also it seems that the difference in some surgical steps did not affect the outcome of surgery during follow-up. in summary, penile fracture concomitant with complete urethral rupture, although being uncommon, however, is still a urological emergency which if not managed correctly may carry the risk of many long-term complications such as erectile dysfunction, penile curvature, fibrosis and urethral stricture. to our knowledge penile fracture is diagnosed clinically, in addition, the presence of urethral bloody discharge represents an alarm for an associated urethral injury and a retrograde urethrography is recommended. the risk of concomitant complete urethral injury is increased with increase of the severity of the trauma, and most cases are due to vigorous sexual intercourse. complete urethral disruption often present at the same level of the tunical tear and usually the tear involve both corpora. after final diagnosis we recommend immediate surgical repair of both ruptured corpora and urethra as it carries a lower risk of complication and better long-term functional outcomes for both urinary and sexual functions. conclusion penile fracture associated with complete urethral injury is a very rare, yet, an emergent urological condition. vigorous sexual intercourse was found to be the most common cause of concomitant complete urethral disruption. blood at the external urethral meatus and hematuria represents a hallmark for urethral injury. immediate surgical treatment reduces the serious long-term complications and improves the functional outcomes. references 1. mydlo jh. surgeon experience with penile fracture. j urol. 2001; 166:526-8. 2. eke n. fracture of the penis. br j surg. 2002; 89:555-65. 3. derouiche a, belhaj k, hentati h, et al. management of penile fractures complicated by urethral rupture. int j impot res. 2008; 20:111-4. 4. zargooshi j. sexual function and tunica albuginea wound healing following penile fracture: an 18-year follow-up study of 353 patients from kermanshah, iran. j sex med. 2009; 6:1141-50. 5. fergany af, angermeier kw, montague dk. review of cleveland clinic experience with penile fracture. urology. 1999; 54:352-5. 6.ibrahiem ei, el-tholoth hs, mohsen t, et al. penile fracture: longraheem_stesura seveso 26/03/14 10:12 pagina 18 term outcome of immediate surgical intervention. urology. 2010; 75:108-11. 7. bitsch m, kromann-andersen b, schou j, sjontoft e. the elasticity and the tensile strength of tunica albuginea of the corpora cavernosa. j urol. 1990; 143:642-645. 8. de rose af, giglio m, carmignani g. traumatic rupture of the corpora cavernosa: new physiopathologic acquisitions. urology. 2001; 57:319-22. 9. cross m, arnold t, peters p. fracture of the penis with associated laceration of the urethra. j urol. 1977; 117: 725. 10. zargooshi j. penile fracture in kermanshah, iran: report of 172 cases. j urol. 2000; 164:364-6. 11. mydlo jh, hayyeri m, macc rj. urethrography and cavernosography imaging in a small series of penile fractures: a comparison with surgical findings. urology 1998; 51:616-9. 12. rahmouni a, hoznek a, duron a, et al. magnetic resonance in penile rupture: aid to diagnosis. j urol 1995; 153:1927-8. 13. fedel m, venz s, anderssen r, et al. the value of magnetic resonance imaging in the diagnosis of suspected penile fracture with atypical clinical findings. j urol. 1996; 155:1924-1927. 14. hatzichristodoulou g, gschwend j, herkommer k, niko z. accuracy of magnetic resonance imaging for diagnosis of penile fracture – comparative analysis with intraoperative finding. j urol. 2013; 189, 4s. 15. nicolaisen gs, melamud a, williams rd, mcaninch jw. rupture of the corpus cavernosum: surgical management. j urol. 1983; 130:917-9. 16. asgari ma, hosseini sy, safarinejad mr, et al. penile fractures: evaluation, therapeutic approaches and long-term results. j urol. 1996; 155:148-9. 17. rosen rc, cappelleri jc. the sexual health inventory for men (shim): a 5-year review of research and clinical experience. int j impot res 2005; 17:307-19. 18. el-assmy a, el-tholoth hs, mohsen t, ibrahiem ei. long-term outcome of surgical treatment of penile fracture complicated by urethral rupture. j sex med. 2010; 7:3784-3788. 19. tanello m, bettini e, griggi s, et al. a rare case of penile fracture with complete urethral rupture during sexual intercourse. arch ital urol androl. 2005; 77:153-4. 20. soylu a, yilmaz u, davarci m, baydinc c. bilateral disruption of corpus cavernosum with complete urethral rupture. int j urol. 2004; 11:811-2. 21. tsang t, demby am. penile fracture with urethral injury. j urol. 1992; 147:466-8. 22. koifman l, cavalcanti ag, manes ch, et al. penile fracture experience in 56 cases. int braz j urol. 2003; 29:35-9. 23. davies dm, mitchell i. fracture of the penis. br j urol. 1978; 50:426. 24. creecy aa, beazlie fsjr. fracture of the penis: traumatic rupture of corpora cavernosa. j urol. 1957; 78:620. 25. farah rn, stiles r jr, cerny jc. surgical treatment of deformity and coital difficulty in healed traumatic rupture of the corpus cavernosa. j urol. 1978; 120:118-20. 26. mydlo jh, gershbein aband macchia rj. non-operative treatment in patients with presumed penile fracture. j urol. 2001; 165:424-425. 27. muentener m, suter s, hauri d, sulser t. long term experience with surgical and conservative treatment of penile fracture. j urol. 2004; 172:576-579. 28. yapanoglu t, aksoy y, adanur s, et al. seventeen years’ experience of penile fracture: conservative vs. surgical treatment. j sex med. 2009; 6:2058-63. 29. mansi mk, emran m, el-mahrouky a, el-mateet ms. experience with penile fractures in egypt: long-term results of immediate surgical repair. j trauma 1993; 35:67-70. 30. ateyah a, mostafa t, nasser ta, et al. penile fracture: sur gical repair and late effects on erectile function. j sex med. 2008; 5:1496-502. 19archivio italiano di urologia e andrologia 2014; 86, 1 urinary and sexual functions after surgical treatment of penile fracture concomitant with complete urethral disruption correspondence ali abdel raheem, md hassan el-tatawy, md ahmed eissa, md abdel hamid elbahnasy, md mohamed elbendary, md (corresponding author) professor of urology mbendary@hotmail.com urology department tanta university hospital, egypt raheem_stesura seveso 26/03/14 10:12 pagina 19 stesura seveso 215archivio italiano di urologia e andrologia 2014; 86, 3 short communication association of erectile dysfunction and urolithiasis alper otunctemur 1, emin ozbek 2, suleyman sami cakir 3, murat dursun 4, emre can polat 5, levent ozcan 6, osman kose 2, huseyin besiroglu 1 1 okmeydani training and research hospital, department of urology, istanbul, turkey; 2 katip celebi university, ataturk training and research hospital, department of urology, izmir, turkey; 3 bayburt state hospital, department of urology, bayburt, turkey; 4 bahcelievler state hospital, department of urology, istanbul, turkey; 5 !stanbul medipol university, faculty of medicine, department of urology, istanbul, turkey; 6 derince training and research hospital, department of urology, kocaeli, turkey. objectives: in recent years, it has been shown that there is association between metabolic syndrome and urinary stone disease. stone disease and erectile dysfunction (ed) are considered as systemic diseases which are associated with hormonal and metabolic disorders. therefore we investigated the relationship between ed and urinary tract calculi. material and methods: 98 male patients with urolithiasis and 59 randomly selected male patients without stone disease were included in the study. serum testosterone (t) levels were measured and international index of erectile function (iief)-15 questionnaire forms were used to assess ed. results: the prevalence of ed was found 29% (29 patients) in the urolithiasis group. sixty-nine patients (71%) had no ed; 16 (16.3%) had mild, 5 (5.1%) had moderate and 8 (8.2%) had severe ed. none of the patients in the control group had severe or modarete ed, six patients (10.2%) had mild ed. serum t levels were detected at the level of biochemical hypogonadism on 13 patients with stones (13.3%) and t levels were detected at the lower limit in 18 (18.3%) patients. conclusion: in our study we have shown that ed and low t levels are significantly associated with urolithiasis. we propose that the patients with urolitiasis should be evaluated for ed and hypogonadism. key words: urolithiasis; erectile dysfunction; metabolic syndrome; testosterone; hypogonadism; iief. submitted 29 june 2014; accepted 1 august 2014 summary no conflict of interest declared. introduction erectile dysfunction (1) is defined as the consistent inability to obtain and/or maintain a penile erection which is sufficient to permit satisfactory sexual intercourse (2). it is estimated that more than 150 million men worldwide have ed and the global prevalence is increasing along with aging population trends (3, 4). ed has been associated with signs of generalized arterial disease, as it frequently coexists with diseases with a high component of endothelial dysfunction, such as coronary artery disease, idiopathic systemic arterial hypertension, doi: 10.4081/aiua.2014.3.215 atherosclerosis and end-stage chronic kidney disease. ed is also associated with cardiovascular disease risk factors, such as diabetes mellitus, dyslipidemia, and smoking (1, 5-7). low testosterone levels are significantly associated with prevalence of mets (8, 9). obesity and components of metabolic syndrome have been associated with nephrolithiasis, and several studies have suggested that metabolic syndrome is linked directly to the formation of urolithiasis (10-12). the higher prevalence of stone disease in patients with metabolic syndrome suggests that insulin resistance might have a role in the pathophysiology of nephrolithiasis (13, 14). although, stone disease and ed are defined as systemic diseases which are associated with hormonal and metabolic disorders, there are few studies on the association of ed and stone disease. we estimated the association of ed with urolithiasis and testosterone levels in the patients who were admitted to our clinic. material and methods this study assessed the prevalence rate of ed in men with urolithiasis. we identified as the study group 98 male patients with urolithiasis who had experienced spontaneous stone passage or surgery for urolithiasis (percutaneous nephrolithotomy, ureterorenoscopy) or whose stones were radiologically (ultrasonography, computed tomography or intravenous urography) visible at the onset of clinical symptoms and 59 randomly selected male patients as the controls. mean age of the study group was 48.49 ± 10.87! years (range: 28-67) and mean age of controls was 47.28 ± 8.62 years (range:31-64). there was no significant difference between mean age of patients and control group. the study population for this case-control study consisted of patients who were admitted to our clinic. subjects having severe cardiovascular disease, endocrine or neurological disease were excluded from study. serum testosterone (t) levels were evaluated on blood samples taken between 08.00 and 10.00 in the fasting state. serum t was measured using enzymatic methods with an autoanalyzer. international index of erectile function (iief)-15 questionnaire which was validated for use in turkey was otunctemur sc_stesura seveso 08/10/14 12:14 pagina 215 archivio italiano di urologia e andrologia 2014; 86, 3 a. otunctemur, e. ozbek, s. sami cakir, m. dursun, e. can polat, l. ozcan, o. kose, h. besiroglu 216 applied to all patients. according to the iief-15 questionnaire, we evulated scores between 6 and 10 as severe dysfunction, between 11 and 18 as moderate dysfunction, between 19 and 24 as mild dysfunction and between 25-30 no dysfunction. low testosterone level was considered when < 110 ng/dl whereas levels from 110 to 285 ng/dl were considered as the lower limit of testosterone level. local ethics committee approval had been obtained before the commence of the study. statistics analyses were completed using chi-square tests. odds ratios (or) were calculated. statistical determinations were within the 95% confidence interval (ci). all p values were two-tailed, and p 0.05 was considered statistically significant. the data were analyzed with an spsstm (spss version 13.0, chicago, il) statistical software package. results the prevalence of ed was found 29% (29 patients) in the urolithiasis group. sixty-nine patients (71%) had no ed, 16 (16.3%) mild ed, 5 (5.1%) moderate ed and 8 (8.2%) severe ed. none of the patients in the control group had severe or modarete ed and six patients (10.2%) had mild ed (p = 0.0084). a significantly higher proportion of ed was found among patients with urolithiasis compared with controls (table 1). serum t levels were detected at the level of biochemical hypogonadism on 13 (13.3%) of patients with stones and t levels were detected at the lower limit in other 18 (18.3%) patients. biochemical hypogonadism was never observed in the controls whereas t levels at the lower range were detected in only 8 patients (p = 0.018) (table 2). serum t levels were dedected at the lower limit in 3 patients with mild ed and at the level of biochemical hypogonadism in 7 patients with severe ed. conclusions in our study we have shown that ed and low t levels are significantly associated with urolithiasis. we suggest that the patients with urolitiasis should be evaluated for ed and hypogonadism, and consequently life-style arrangements are to be planned for treatment. references 1. mesquita jf, et al. prevalence of erectile dysfunction in chronic renal disease patients on conservative treatment. clinics (sao paulo) 2012; 67:181-3. 2. santos t, drummond m, botelho f erectile dysfunction in obstructive sleep apnea syndrome prevalence and determinants. rev port pneumol. 2012; 18:64-71. 3. lewis rw, et al. definitions/epidemiology/risk factors for sexual dysfunction. j sex med. 2010; 7:1598-607. 4. ayta ia, mckinlay jb, krane rj the likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. bju int. 1999; 84:50-6. 5. vlachopoulos c, et al. arterial function and intima-media thickness in hypertensive patients with erectile dysfunction. j hypertens. 2008; 26:1829-36. 6. koca o, et al vasculogenic erectile dysfunction and metabolic syndrome. j sex med. 2010; 7:3997-4002. 7. lee yc, et al. the potential impact of metabolic syndrome on erectile dysfunction in aging taiwanese males. j sex med. 2010; 7:3127-34. 8. kupelian v, et al. inverse association of testosterone and the metabolic syndrome in men is consistent across race and ethnic groups. j clin endocrinol metab. 2008; 93:3403-10. 9. goncharov np, et al. three definitions of metabolic syndrome applied to a sample of young obese men and their relation with plasma testosterone. aging male 2008; 11:118-22. 10. taylor en, stampfer mj, curhan gc obesity, weight gain, and the risk of kidney stones. jama 2005; 293:455-62. 11. taylor en, stampfer mj, curhan gc. diabetes mellitus and the risk of nephrolithiasis. kidney int. 2005; 68:1230-5. 12. curhan gc. et al. body size and risk of kidney stones. j am soc nephrol. 1998; 9:1645-52. 13. west b, et al. metabolic syndrome and self-reported history of kidney stones: the national health and nutrition examination survey (nhanes iii) 1988-1994. am j kidney dis. 2008; 51:741-7 14. obligado sh, goldfarb ds the association of nephrolithiasis with hypertension and obesity: a review. am j hypertens. 2008; 21:257-64. correspondence alper otunctemur, md alperotunctemur@yahoo.com huseyin besiroglu, md okmeydani training and research hospital, department of urology, 34384, sisli, istanbul, turkey emin ozbek, md osman kose, md katip celebi university, ataturk training and research hospital, department of urology, izmir, turkey suleyman sami cakir, md bayburt state hospital, department of urology, bayburt, turkey murat dursun, md bahcelievler state hospital, department of urology, istanbul, turkey emre can polat, md !stanbul medipol university, faculty of medicine, department of urology, istanbul, turkey levent ozcan, md derince training and research hospital, department of urology, kocaeli, turkey iief-5 iief-5 iief-15 iief-15 severe ed moderate ed mild ed no ed (6-10) (11-18) (19-24) subject with stone 8 (9.2%) 5 (5.1%) 16 (16.3%) 69 (71%) subject without stone 6 (8.2%) 53 (89%) p 0.0084 table 1. iief-15: international index of erectile function. stl < 110 ng/dl stl between 110 to 285 ng/dl subject with stone 13 (13.3%) 18 (18.3%) subject without stone 8 (13.5%) p = 0.018 table 2. stl: serum testosterone level. otunctemur sc_stesura seveso 08/10/14 12:14 pagina 216 stesura seveso archivio italiano di urologia e andrologia 2013; 85, 4200 introduction lower urinary tract symptoms (luts) are common in aging men with a prevalence ranges from 10.3 to 25.1% depending on the severity threshold (1). benign prostatic hyperplasia (bph) and benign prostatic enlargement original paper clinical effects and economical impact of dutasteride and finasteride therapy in italian men with luts luca cindolo 1, francesco berardinelli 1, caterina fanizza 2, marilena romero 2, luisella pirozzi 2, fabiola raffaella tamburro 1, fabrizio pellegrini 1, fabio neri 1, andrea pitrelli 3, luigi schips 1 1 s. pio da pietrelcina hospital, dept. of urology, vasto, italy; 2 department of clinical pharmacology and epidemiology, consorzio mario negri sud, santa maria imbaro, italy; 3 access to medicine, glaxosmithkline spa, verona, italy. objectives: to investigate differences in the risk of benign prostatic hyperplasia (bph)related hospitalization, for surgical and non-surgical reasons, and of new prostate cancer (pca) diagnosis between patients under dutasteride or finasteride treatment. material and methods: a retrospective cohort study was conducted using data from record-linkage of administrative databases. men aged ≥ 40 years old who had received a prescription for at least 10 boxes/year (index years: 2004-06) were included. the association of the outcomes was assessed using a multiple cox proportional hazard model. propensity scorematched analysis and a 5-to-1, greedy 1:1 matching algorithm were performed. the budget impact analysis of dutasteride vs finasteride in bph-treated patient was performed. results: from an initial cohort of about 1.5 million of italian men, 19620 were selected. the overall hospitalization for bph-non surgical reasons, for bph-related surgery and for new detection of pca incidence rates (irs) were 8.20 (95% ci, 7.62-8.23), 18.0 (95% ci, 17.12-18.93) and 8.62 (95% ci, 8.03-9.26) per 1000 person-years, respectively. the multivariate analysis after the propensity score-matching showed that dutasteride was associated with an independent reduced likelihood of hospitalization for bph-related surgery (hr 0.82; 95% ci 0.73-0.93; p = 0.0025) and of newly detected pca (hr: 0.76,95% ci, 0.65-0.85; p = 0.0116). the ir for bph-non surgical reasons was 8.07 (95% ci, 7.10-9.17) and 9.25 (95% ci, 8.19-10.44) per 1000 person-years, respectively. the ir for bph-related surgery was 18.28 (95% ci, 17.17-20.32) and 21.28 (95% ci, 19.24-23.06) per 1000 person-years among patients under dutasteride compared with those under finasteride, respectively. for new-onset pca, the ir was 8.01 (95% ci, 7.07-9.08) and 9.38 (95% ci, 8.32-10.58) per 1000 person-years the pharmacoeconomical evaluation showed that the net budget impact of the use of dutasteride vs. finasteride in 1000 bph-treated patient for 1 year induces a saving of 3933 €. conclusions: the clinical effects of dutasteride and finasteride are slightly different. the likelihood of hospitalization for bph-related surgery and of newly detected pca seems to be in favor of dutasteride. the budget impact analyses showed a slightly benefit for dutasteride. comparative prospective studies are necessary to confirm these results. key words: benign prostatic hyperplasia (bph); dutasteride; finasteride; epidemiology; medical record-linkage. submitted 14 april 2013; accepted 5 october 2013 summary (bpe) have been recognized as the major contributing factors to the development of luts. the first-line pharmacological therapy for moderate-to-severe non-neurogenic male luts includes alpha-adrenoreceptor antagodoi: 10.4081/aiua.2013.4.200 201archivio italiano di urologia e andrologia 2013; 85, 4 5aris comparison. who is the best? nists (abs) and 5alpha-reductase inhibitors (5aris) alone or in combination (2). abs induce a rapid symptom relief, while the 5aris modify the bph natural history by delaying the disease progression (3-6). finasteride and dutasteride are the two 5aris: finasteride inhibits the 5-alpha-reductase isoenzyme type 2, whereas dutasteride inhibits both isoenzyme 1 and 2. the clinical value of the greater serum dihydrotestosterone suppression achieved by dutasteride (7) remains unclear (2). nowadays due to the limited literature (811) the question of “what is the best 5ari" remains unanswered. another point of uncertainty is about the economic impact of the use of dutasteride instead of finasteride. in an attempt to clarify these aspects, we previously performed an observational study on an unselected population that showed a reduction in bph-related hospitalization risk in dutasteridecompared to finasteride-treated patients (12). in that paper (12) we also dealt with the hard issue of the detection of prostate cancer (pca) under 5aris treatments (13-16) showing a positive trend in favor of dutasteride. herein, we report the new results of extended analysis investigating the clinical and economic differences between dutasteride and finasteride treatment in an italian male population ≥ 40 years with luts. material and methods a retrospective study was conducted based on information from three databases: italian population registry, pharmaceutical prescription data, and hospital discharge record including information on about 1.500.000 male aged ≥ 40 years from 22 local health units from northern and southern italy for 6 consecutive years (january 1st 2004 and december 31st 2009). data sources the italian population registry provide demographic information (date of birth, sex and date of death if this occurred) on each subject. the pharmaceutical prescription database records all prescriptions reimbursed by the nhs (drugs coded according to the international anatomical therapeutic chemical system atc) (17). the hospital records include detailed information on primary diagnosis and up to five coexisting diagnoses, performed procedures, and admission/discharge dates. the diagnoses were classified according to the international classification of diseases-ninth revision, clinical modification (icd9-cm) (18). a record linkage of these three databases was carried out and pharmacological and clinical history for each patients was obtained. the reliability of this strategy to produce an epidemiological survey has been previously validated and reported (19-21). all security and protection measures for patient’s data was performed according to national laws on privacy protection. patients and drugs the cohort consisted of men aged ≥ 40 years, who received prescription for at least 10 boxes/year of finasteride or dutasteride between 1 january 2004 and 31 december 2006 (index years). the first prescription of one of these drugs during the index years was considered as index date (day 0). the exclusion criteria were either abs monotherapy and/or short-term 5-ari therapy (< 10 boxes/year). for all patients, the databases were searched during the 12-months period preceding the index date to verify the absence of bph-complications and pca. specifically, patients with an urethral stricture (icd9cm: 598, 589.0, 598.00, 598.01, 598.1, 598.2, 598.8, 598.9) and/or with pca diagnoses (icd9-cm: 185, 198.82, 233.4, 236.5, 239.5, v10.46) and/or at least a prescription of lhrh analogues and/or antiandrogens, were not considered eligible. patients using abs (alfuzosin, tamsulosin, terazosin) were included in the study. patients with acute or chronic urinary retention secondary to bph and treated at the emergency department without hospital admission were not considered. moreover, to assess the comorbidities, the charlson comorbidity index (cci) with the dartmouth-manitoba modification was used (22). clinical outcomes follow-up for each identified patient is extended from the index date to five years or until the occurrence of the following major events: 1) hospitalization for bph-non surgical reasons); 2) hospitalization for bph-related surgery; 3) new diagnosis of pca. bph-related hospitalization was considered when the hospital records included primary diagnosis and/or procedures related to bph. the presence of the icd9-cm 600.xx (prostate hyperplasia) and 222.2 (benign prostate tumor) codes as primary diagnosis without surgical procedures was considered hospitalization for “bph-non surgical reasons”. the presence of icd9-cm 57.0, 57.91, 57.92, 60.21, 60.29, 60.3, 60.4 codes (open or transurethral resection/ablation of prostate or bladder neck), as primary or secondary surgical procedures with any primary diagnoses, was considered hospitalization for “bph-related surgery”. the new diagnosis of pca was identified through hospitalization (icd9-cm:185, 198.82, 233.4, 236.5, 239.5, v10.46) and/or pca medical therapy (gonadotripins releasing hormones agonists l02ae01, l02ae02, l02ae03, l02ae04; and/or antiandrogens: l02bb01, l02bb02, l02bb03). analysis of health resources utilization the budget impact analysis of dutasteride vs. finasteride in bph-treated patient according to the italian nhs perspective has been performed starting form an hypothetical cohort of 1000 bph-treated men under finasteride for one year, here and after “current scenario”; in our analysis this hypothetic cohort has been fully switched to dutasteride, here and after “alternative scenario”. the incidence rates for 1000 person-years by outcomes after propensity score matching were used as source for the budget impact analysis model. drug consumption has been calculated assuming an annual 80% compliance to both treatment (300 days of therapy); in both scenarios patients undergoing to bph-related surgery withdrawn from treatment (assuming they don’t need further treatment for bph). the health resources utilization in both scenarios has been calculated starting from the inciarchivio italiano di urologia e andrologia 2013; 85, 4 l. cindolo, f. berardinelli, c. fanizza, m. romero , l. pirozzi, f.r. tamburro, f. pellegrini, f. neri, a. pitrelli, l.schips 202 dence rates (both surgical and non surgical reasons) for 1000 persons/years after propensity score matching. hospital records have been used to estimate the average hospitalization costs according to nhs perspective. the impact on nhs annual budget related to variation of pca detection rate observed with dutasteride vs. finasteride was not analyzed. statistical analysis for the whole sample, patients’ characteristics were reported as frequency (percentage) and mean±standard deviation. differences between patients’ treatment subgroups were assessed using standardized difference. for major outcomes, crude incidence rates (irs) per 1000 men-year were calculated as the number of events divided by the number of person-years of follow-up. furthermore, to check consistency of our results, a propensity score (ps)-matched analysis was performed (24-25). a logistic model -including the same covariates used in the multivariate cox model, plus quadratic terms and a set of two-term interactions between the same covariateswas performed to predict the probability to be assigned to study drugs. ps logistic model was selected in a stepwise fashion and pair-wise comparisons were performed. a 5-to-1, greedy 1:1 matching algorithm (26) was used to identify a unique matched control for treated patient according to their ps. adequacy of covariate balance in the matched sample was assessed via standardized difference between the two groups, considering differences less than 10% as good balance (27). the association of hospitalization for bph, bph-related surgery, pca was assessed using a multiple cox proportional hazard model. all multivariate analyses were adjusted for the following variables: age, charlson comorbidity score, previous hospitalization for bph, previous bph-related surgery, pre-existing severity factors, previous pharmacological treatment with abs. results are expressed as hazard ratios (hrs) and 95% confidence intervals (cis). p-values < 0.05 were considered significant. all analyses were performed using sas statistical package release 9.2 (sas institute, cary, nc, usa). results patients characteristics from 1.417.969 men aged ≥ 40 years, 19620 were chronically exposed to 5aris; 13195 received finasteride and 6425 dutasteride. no significant differences were observed between these two groups with exception of previous abs therapy (table 1). clinical outcomes during follow-up during 5 years, 841 patients were hospitalized for bphnon surgical reasons, 2006 for bph-related surgery and 749 were newly diagnosed with pca. the overall hospitalization ir for bph-non surgical reasons and for bph-related surgery were 8.20 (95% ci, 7.62-8.23) and 18.0 (95% ci, 17.12-18.93) per 1000 person-years, respectively. the matched analysis identified 6362 men under dutasteride that were matched with a similar cohort under finasteride, without significant differences between groups (table 2). among patients under dutasteride compared with those under finasteride the ir for bph-non surgical reasons was 8.07 (95% ci, 7.10-9.17) and 9.25 (95% ci, 8.19-10.44) per 1000 person-years, respectively. moreover, the ir for bph-related surgery was 18.28 (95% ci, 17.17-20.32) and 21.28 (95% ci, 19.24-23.06) per 1000 person-years variable finasteride (13195 pz) dutasteride (6425 pz) standardized n (%) n (%) difference (%) mean age (mean ± sd) 72.25 (9.14) 71.62 (8.46 -7.1538 age 40-55 509 (3.86) 178 (2.80) -5.9106 56-65 4917 (37.26) 2647 (41.61) 8.8940 66-75 5254 (39.82) 2589 (40.69) 1.7876 76-85 2515 (19.06) 948 (14.90) -11.0948 charlson score 0 10945 (82.95) 5312 (83.50) 1.4657 1-2 1397 (10.59) 686 (10.78) 0.6326 >=3 853 (6.46) 364 (5.72) -3.1069 previous hospitalization for bph (non surgical reasons) 924 (7.00) 533 (8.38) 5.1632 previous hospitalization for bph-related surgery 39 (0.30) 32 (0.50) 3.2896 previous bph complications (severity factors) 583 (4.42) 272 (4.28) -0.7011 previous alphablockers therapy 5519 (41.83) 3893 (61.19) 39.4960 table 1. patients' characteristics according to drug used (finasteride or dutasteride). * standardized difference greater than 10% represents meaningful imbalance in explored variables between treatment groups. 203archivio italiano di urologia e andrologia 2013; 85, 4 5aris comparison. who is the best? among patients under dutasteride compared with those under finasteride, respectively. for new-onset pca, the ir was 8.01 (95% ci, 7.07-9.08) and 9.38 (95% ci, 8.3210.58) per 1000 person-years (table 3). the multivariate analysis after the propensity score matching cox model showed that dutasteride was associated with an independent reduced likelihood of hospitalization for bph-related surgery (hr 0.82; 95% ci 0.73-0.93; p = 0.0025) and of newly detected pca (hr: 0.76, 95% ci, 0.65-0.85; p = 0.0116) (table 4). annual budget impact analysis in the “current scenario” an hypothetical cohort of 1000 bph-treated patient for 1 year with finasteride generates a total annual impact on nhs budget of 1.017.444 €: 13,4% of this cost is related to finasteride cost (136.145 €), 66,4% is related to hospitalizations due to bph-related surgery (675.423 €) and 20,2% is related to hospitalizations for bph-non surgical reasons (205.872 €). in the “alternative scenario” is generated a total annual variable finasteride (6362 pz) dutasteride (6362 pz) standardized n (%) n (%) difference (%) mean age (mean ± sd) 71.68 (8.42) 71.62 (8.46) 0.71092 age 40-55 175 (2.75) 178 (2.80) 0.28712 56-65 2641 (41.51) 2647 (41.61) 0.19137 66-75 2589 (40.69) 2589 (40.69) 0.00000 76-85 957 (15.04) 948 (14.90) -0.39649 charlson score 0 5294 (83.21) 5312 (83.50) 0.75957 1-2 695 (10.92) 686 (10.78) -0.45479 >=3 373 (5.86) 364 (5.72) -0.6056 previous hospitalization for bph (non surgical reasons) 528 (8.30) 533 (8.38) 0.28427 previous hospitalization for bph-related surgery 19 (0.30) 32 (0.50) 3.23449 previous bph complications (severity factors) 292 (4.59) 272 (4.28) -1.52745 previous alphablockers therapy 3890 (61.14) 3893 (61.19) 0.09675 table 2. patients' characteristics according to drug used (finasteride or dutasteride) after propensity score matching. * standardized difference greater than 10% represents meaningful imbalance in explored variables between treatment groups. outcome finasteride dutasteride incidence rate 95% ci incidence rate 95% ci hospitalization for bph (non surgical reasons) 9.25 8.19-10.44 8.07 7.10-9.17 hospitalization for bph-related surgery 21.28 19.24-23.06 18.28 17.17-20.32 newly detected prostate cancer 9.38 8.32-10.58 8.01 7.07-9.08 table 3. incidence rate for 1000 person-years by outcome considered in finasteride and dutasteride groups after propensity score matching. outcome hr 95% ci p value hospitalization for bph (non surgical reasons) 0.87 0.73-1.05 0.1377 hospitalization for bph-related surgery 0.82 0.73-0.93 0.0025 newly detected prostate cancer 0.76 0.65-0.85 0.0116 table 4. results of propensity score matching cox model: dutasteride vs. finasteride. archivio italiano di urologia e andrologia 2013; 85, 4 l. cindolo, f. berardinelli, c. fanizza, m. romero , l. pirozzi, f.r. tamburro, f. pellegrini, f. neri, a. pitrelli, l.schips 204 impact on nhs budget of 10.103.507 €: 25% of this cost is related to dutasteride cost (253.693 €), 57,2% is related to hospitalizations for bph-related surgery (580.204 €) and 17,7% is related to hospitalizations for bph-non surgical reasons (179.610 €) (figure 1). the full switch from finasteride to dutasteride in an hypothetical cohort of 1000 bph-treated patients for one year generates a net saving of 3.933 € to the nhs annual budget. discussion dutasteride and finasteride are the two currently available 5aris, and are widely recommended in patients with moderate-to-severe bph-related luts (2, 4-6). large-scale clinical trials have demonstrated that dihydrotestosterone (dht) suppression with 5aris is effective in the treatment of bph and might have a role in the prevention of pca (4, 5, 13, 14). previous studies confirmed that dutasteride consistently induces a near-maximal suppression of both serum and intraprostatic dht in men with bph and those with pca (7). even if the two available 5-aris are considered to be virtually equivalent regarding the clinical outcomes (13, 14), unfortunately, a direct comparison of the two drugs evaluating the long term effects is still lacking. the epics study, the only randomized clinical trial comparing dutasteride vs. finasteride, did not show significant differences between the drugs in terms of clinical efficacy. however, as pointed out by the authors, given the long-term, progressive nature of bph, the one-year duration of epics may limit the potential to observe major differences between dutasteride and finasteride treatment (11). in lack of relevant, prospective comparative studies, the purpose of this record-linkage study was to analyze the clinical effect of dutasteride and finasteride on bph-related hospitalizations and on pca diagnosis and the economical impact on nhs budget in an italian cohort. after the propensity score matching cox model, the multivariate analysis showed that dutasteride was associated with a statistically significant lower likelihood of hospitalization for bph-related surgery (table 4). these findings are in line with our previous study (12) and the reports from issa (10) and fenter (28. the results of the pharmacoeconomic analysis support health decision maker in the choice of whether or not to implement the treatment of bph patient with dutasteride instead of less costly finasteride. in two papers fenter and naslund (28-29) made a real world economic evaluation of dutasteride vs. finasteride for the treatment of bph patient analyzing restrictively medical and pharmacy claims in two large us administrative databases. these studies were based on american medicare-aged population and showed that dutasteride-therapy resulted in less medical costs than finasteride, suggesting that the higher price of dutasteride may be offset by decreased medical resource consumption. in our analysis we also estimated the cost consequence for the italian nhs of the use of dutasteride instead of finasteride in a hypothetical cohort of 1000 bph-treated patient for one year starting from the clinical differences in major outcomes (hospitalization for surgical and non surgical reason). as a results of our analysis, even in a different nhs framework, the net budget impact of the use of dutasteride instead of finasteride is slightly in favor of dutasteride with a total annual saving of 3.933 €. this overall cost saving for men taking dutasteride could create a overall cost advantage for dutasteride despite its higher price. there is also significant additional value to patients who have a lower risk of bph progression and than prostate surgery under dutasteride, although the figure 1. dutasteride vs finasteride: comparison of nhs costs for one year treatment of 1000 bph patient. finasteride € 1.200.000 € 1.000.000 € 800.000 € 600.000 € 400.000 € 200.000 € dutasteride hospitalization for bph-related surgery hospitalization for bph drug cost€ 205.872 € 675.423 € 136.145 € 179.610 € 580.204 € 253.693 205archivio italiano di urologia e andrologia 2013; 85, 4 5aris comparison. who is the best? monetary value of these benefits is difficult to measure and quantify. as far as the new diagnosis of pca is concerned, we found a pca incidence lower in dutasteridevs. finasteride-treated patients. although our previous study showed only a positive trend in dutasteride group without a statistical significance, however, in the current study, the wider cohort allowed to reach a statistically significant difference in reduction of pca diagnosis (hr: 0.76, 95% ci, 0.65-0.85; p = 0.0116) (table 4). all these evidence suggest that the clinical benefit of the dual 5a-reductase-isoenzymes inhibition might be slightly better. the two molecules are effective in bph; nevertheless, due to its peculiar pharmacokynetic and pharmacodynamic characteristics (longer half-life and dual inhibition of 5a-reductase-isoenzymes), dutasteride seems to be more active. although our results suggest that there are differences between the two 5aris in terms of clinical and economic outcomes, interpretation of the results is limited by the retrospective, non-randomized nature of the study. moreover, no information about symptomatic burden of the disease, urodynamic parameters, baseline psa values, number and kind of core biopsies and gleason score were available in our database. this is a main limitation of the study that hinders any inference about specific outcomes. however, the administrative database are widely used with all the inherent limitations and are considered a valuable source of clinical information (19-21). moreover, the pharmacoeconomic analysis contains further limitations. firstly, in clinical practice physician preferences based on clinical characteristics can impact treatment selection which mathematical model can not account for. secondly, our results are specific to italy and are driven by local practice and healthcare costs and prices. conclusions in conclusion, our results suggest slight differences in clinical and economic outcomes between dutasterideand finasteride-treated patients. further clinical trials are warranted in order to confirm these results and to evaluate the long term effectiveness of these drugs. acknowledgments this study was financially supported by an unconditional grant from glaxosmithkline. references 1. füllhase c, chapple c, cornu jn, et al. systematic review of combination drug therapy for non-neurogenic male lower urinary tract symptoms. eur urol. 2013; 64:228. 2. oelke m, bachmann a, descazeaud a, et al. eau guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. eur urol. 2013; 64:118. 3. boyle p, roehrborn c, harkaway r, et al. 5-alpha reductase inhibition provides superior benefits to alpha blockade by preventing aur and bph-related surgery. eur urol. 2004; 45:620. 4. mcconnell jd, roehrborn cg, bautista o, et al. medical therapy of prostatic symptoms (mtops) research group. the long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. n engl j med 2003; 349:2387. 5. roehrborn cg, siami p, barkin j, et al. the effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the combat study. eur urol. 2010; 57:123. 6. robert g, descazeaud a, de la taille a. lower urinary tract symptoms suggestive of benign prostatic hyperplasia: who are the high-risk patients and what are the best treatment options? curr opin urol. 2011; 21:42. 7. clark rv, hermann dj, cunningham gr, et al. marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5alpha-reductase inhibitor. j clin endocrinol metab 2004; 89:2179. 8. naslund m, black l, eaddy m, batiste lr. differences in alpha blocker usage among enlarged prostate patients receiving combination therapy with 5 aris. am j manag care. 12007; 3:s17. 9. naslund m, regan ts, ong c, hogue sl. 5-alpha reductase inhibitors in men with an enlarged prostate: an evaluation of outcomes and therapeutic alternatives. am j manag care. 2008; 14:s148. 10. issa mm, runken mc, grogg al, shah mb. a large retrospective analysis of acute urinary retention and prostate-related surgery in bph patients treated with 5-alpha reductase inhibitors: dutasteride versus finasteride. am j manag care. 2007; 13:s10. 11. nickel jc, gilling p, tammela tl, et al. comparison of dutasteride and finasteride for treating benign prostatic hyperplasia: enlarged prostate international comparator study (epics). bju int. 2011; 108:388. 12. cindolo l, fanizza c, romero m, et al. the effects of dutasteride and finasteride on bph-related hospitalization, surgery and prostate cancer diagnosis: a record-linkage analysis. world j urol. 2013; 31:665. 13. thompson im, goodman pj, tangen cm, et al. the influence of finasteride on the development of prostate cancer. n engl j med. 2003; 349:215. 14 andriole gl, bostwick dg, brawley ow, et al. effect of dutasteride on the risk of prostate cancer. n engl j med. 2010; 362:1192. 15. theoret mr, ning ym, zhang jj, et al. the risks and benefits of 5α-reductase inhibitors for prostate-cancer prevention. n engl j med. 2011; 365:97. 16. cohen sa, parsons jk. combination pharmacological therapies for the management of benign prostatic hyperplasia. drugs aging. 2012; 29:275. 17. who collaborating centre for drug statistics methodology. atc index with ddds. oslo, norway: who; 2003 18. us centers for disease control and prevention. international classification of diseases, ninth revision, clinical modification (icd-9-cm). http://www.cdc.gov/nchs/icd/icd9cm.htm. accessibility verified 14 august 2013. 19. monte s, macchia a, pellegrini f, et al. antithrombotic treatment is strongly underused despite reducing overall mortality among high-risk elderly patients hospitalized with atrial fibrillation. eur heart j 2006; 27:2217. 20. macchia a, monte s, romero m, et al. the prognostic influence of chronic obstructive pulmonary disease in patients hospitalized for chronic heart failure. eur j heart fail. 2007; 9:942. archivio italiano di urologia e andrologia 2013; 85, 4 l. cindolo, f. berardinelli, c. fanizza, m. romero , l. pirozzi, f.r. tamburro, f. pellegrini, f. neri, a. pitrelli, l.schips 206 21. macchia a, monte s, pellegrini f, et al. depression worsens outcomes in elderly patients with heart failure: an analysis of 48,117 patients in a community setting. eur j heart fail. 2008; 10:714. 22. charlson me, pompei p, ales kl, mackenzie cr. a new method of classifying prognostic comorbidity in longitudinal studies: development and validation. j chronic dis. 1987; 40:373. 23. romano ps, roos ll, jollis jg. adapting a clinical comorbidity index for use with icd-9-cm administrative data: differing perspectives. j clin epidemiol. 1993; 46:1075. 24. d’agostino rb jr. propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. stat med. 1998; 17:2265. 25. yanovitzky i, zanutto e, hornik r. estimating causal effects of public health education campaigns using propensity score methodology. eval program plann. 2005; 28:209. 26. parsons ls. reducing bias in a propensity score matched pair sample using greedy matching techniques. in: proceedings of the twenty-sixth annual sas users group international conference. 2004, sas institute, cary, nc 27. austin pc, grootendorst p, anderson gm. a comparison of the ability of different propensity score models to balance measured variables between treated and untreated subjects: a monte carlo study. stat med. 2007; 26:734. 28. fenter tc, runken mc, black l, eaddy m. finasteride versus dutasteride: a real-world economic evaluation. am j manag care. 2007; 13:s23. 29. naslund m, eaddy mt, kruep ej, hogue sl. cost comparison of finasteride and dutasteride for enlarged prostate in a managed care setting among medicare-aged men. am j manag care. 2008; 14:s167. correspondence luca cindolo, md, febu (corresponding author) lucacindolo@virgilio.it francesco.berardinelli, md berardinelli.francesco@gmail.com fabiola raffaella tamburro, md fabiola.tamburro@libero.it fabrizio.pellegrini, md fabriziopellegrini85@hotmail.it fabio neri, md info@fabioneri.eu luigi schips, md luigischips@hotmail.com s. pio da pietrelcina hospital, dept. of urology, vasto, italy caterina fanizza, md fanizza@negrisud.it marilena romero, md romero@negrisud.it luisella.pirozzi, md pirozzi@negrisud.it department of clinical pharmacology and epidemiology-consorzio mario negri sud, santa maria imbaro, italy andrea pitrelli, md andrea.n.pitrelli@gsk.com access to medicine, glaxosmithkline spa, verona, italy stesura seveso 183archivio italiano di urologia e andrologia 2014; 86, 3 original paper influence of hcg on inducible nitric oxide synthase gene expression in ram testicular arteries maria matteo 1, annalisa rizzo 2, ettore cicinelli 3, elvira grandone 4, giuseppe cardo 5, donatella colaizzo 4, giuseppe minoia 2, laura castellana 6, ugo indraccolo 7, sonia marrocchella 1, pantaleo greco 1, raffaele luigi sciorsci 2 1 operative unit of obstetric and gynecology, department of surgical sciences, university of foggia, italy; 2 department of animal production, university of bari, italy; 3 3rd unit of obstetrics and gynecology, department of biomedical and human oncological science (dimo), university of bari, italy; 4 atherosclerosis and thrombosis unit, irccs “casa sollievo della sofferenza”, s. giovanni rotondo, foggia, italy; 5 operative unit of urology “s. giacomo” hospital, monopoli, italy; 6 department of biomedical sciences, university of foggia, italy; 7 operative unit of gynaecology and obstetrics of civitanova marche area vasta 3, marche, italy. background. experimental evidence suggests a relationship between the vasodilatory effect of hcg and the nos system in the testis. the influence of hcg administration on testicular vascular nos gene expression has not been fully investigated. objective: this study aimed to evaluate the presence of the nitric oxide syntheses gene in ram testicular arteries and the influence of hcg administration on its expression. materials and methods: both testicular arteries of sixteen rams were extracted before and after i.v. administration of 5000 iu of hcg or placebo. the expression of the inos gene was investigated by real time pcr. data were analyzed by means of wilcoxon and mann-whitney tests. a p value of < 0.05 was considered statistically significant. results: pcr revealed the presence of inos mrna in all basal samples but the expression of the inos gene was significantly reduced in all arteries obtained 24 h after the administration of either hcg or placebo. a significant reduction in the expression of inos gene was observed in the testicular arteries extracted after 24 h in both treated and placebo groups. on the other hand hcg stimulation did not significantly influence inos expression following its administration compared to a placebo. conclusion: ram testicular arteries express the inos gene but hcg stimulation did not significantly influence inos expression. a significant reduction in the expression of this gene was observed in the testicular arteries extracted after 24 h in both treated and placebo groups, suggesting that inos expression on the testicular artery could be influenced by the spermatic vessel ligation of the controlateral testis. key words: inos gene, testicular artery; hcg; ram; intratesticular blood flow. submitted 17 january 2014; accepted 15 may 2014 summary no conflict of interest declared. introduction gonadotrophin treatment is capable of increasing intratesticular blood flow (1-3). several mechanisms are described in the literature for explaining hcg induced vasodilatation in the testicular arteries (4). hcg was found to increase the expression of angiogenic factors such as vascular endothelial growth factor (vegf) and angiopoietin 2 (ang2) (5, 6). hcg was also found to induce an inflammation-like response via a local increase of pro-inflammatory cytokines such as il1 by the leydig cells (7, 8). several authors have suggested that the nitric oxide syntheses (nos) system may play a pivotal role in increasing testicular blood flow after hcg administration (9). under basal conditions, the vasodilatory effect of no resulted of limited importance in the testis than in other tissues but, after hcg treatment, nos activity was found to be increased, suggesting that the increase in testicular blood flow observed in hormonally stimulated testis could be related to an increase in testicular no synthesis (9). although several studies have suggested a strong relationship between the vasodilatory effect of hcg and the activity of the nos system, the influence of hcg administration on testicular vascular nos gene expression has not been fully investigated. the aim of this study was to evaluate the influence of exogenous hcg administration on inos expression in the ram testicular vasculature. material and methods testicular arteries were collected from 16 rams aged 4 to 6 years and weighing between 60 and 90 kg using an approach approved by the local ethical committee, in accordance with the national research council's (nrc) publication (10). rams were randomly allocated into two groups: eight animals received 5000 iu of hcg i.v. (corulon, intervet, italy), eight rams (control group), received an i.v. injection of placebo. before surgery, sedadoi: 10.4081/aiua.2014.3.183 matteo_stesura seveso 08/10/14 12:07 pagina 183 archivio italiano di urologia e andrologia 2014; 86, 3 m. matteo, a. rizzo, e. cicinelli, e. grandone, g. cardo, d. colaizzo, g. minoia, l. castellana, u. indraccolo, s. marrocchella, p. greco, r.l. sciorsci 184 tion of the rams was achieved by means of an i.v. administration of 0.1 ml/20kg of xilazina cloridrato 2% (rompum, bayer ag, germany) combined with an i.m. injection of 0.44 mg/10 kg of atropina solfato (ati, italy) and of 0.04 ml/10 kg of butorfanolo (dolorex, intervet, italy). the spermatic funiculus was isolated after a longitudinal incision of the skin and the testicular arteries were isolated and extracted from the right testis (figure 1). arteries of the opposite testis were isolated and extracted from the same rams, 24 hours (h) after the administration of hcg or placebo. the vascular samples obtained were immediately incubated in tubes containing 3 ml of trizol reagent (invitrogen, san giuliano milanese, milano, italy) and stored at -80°c until the examination. total rna was isolated from the tissue according to the manufacturer's instructions. phenol-phase separation was performed with gel-phase tube (eppendendorf) in order to prevent protein contamination of the rna. rna was then dissolved in 20 µl of rnase-free water and exposed to 55°c for 5 min to increase solubility. the rna concentration was determined at 260 nm with a plate-reading spectrophotometer. for the cdna synthesis, a mixture of 0.5 µg of total rna and 0.25 µg oligo dt (invitrogen) per sample was subjected to 65°c for 5 min to promote primer annealing. a volume of 20 µl of rt reaction solution containing 200 u of moloney murine leukimia virus reverse transcriptase and 8 µl of rt master mix composed of 1× rt buffer, 25 mm dtt and 1.25 mm dntp was incubated at 37°c for 70 min. the quantity inos gene mrna expression was evaluated by the abi 7700tm quantitative real time pcr system (applied biosystems, warrington, uk) and compared to the ovis aries housekeeping ! actin gene. the mgb probes used for quantification of the targets and endogenous controls were designed according to the taqman technology (applied byosistems) employing the primer express (applied biosystems) computer software using published gene sequences. the fluorescent signal from the dye 6carboxyfluorescein (6-fam) at the 5' end of the probe was quenched by another fluorochrome, vic, at the 3' end. the quenching effect terminated as the probe was cleaved due to the 5' exonuclease activity of the amplitaq gold (applied biosystems) enzyme and a fluorescent signal was emitted. the emittance resulted proportional to the amount of amplified product, until it reached the lag phase of the pcr. a threshold value set above the baseline reflected the average change in emittance during the first pcr cycles. the real-time pcr reactions were performed on plates using adhesive seals as covers. to quantify the mrna levels we used a relative standard curve method in which the untreated control was used as an appropriate calibrator. the sequences of the primers and probe are shown in table 1. each sample contained: 3 μl of cdna, taqman universal pcr master mix (12.5 μl), ! actin primers 900 nm and probe 200 nm, inos primers 900 nm and probe 200 nm and rnase-free water to a volume of 25 μl. amplification was performed for 10 min at 95°c, 45 cycles of 15 seconds at 95°c, 60 seconds at 60°c. gene expression levels were calculated using standard curves generated by serial dilutions of cdna. a strong correlation between pcr efficiency of the internal control (! actin) and the target allowed the use of the ""ct-method (applied biosystems) to quantify comparable mrna levels (11). three independent analyses were performed with replicates. data were analyzed by means of wilcoxon and mann-whitney tests and a p value of < 0.05 was considered statistically significant. results were expressed as means + standard deviation. results the real time pcr revealed the expression of inos mrna in samples obtained from all the 16 rams, without surgical complications. the descriptive statistics of the data are reported in table 2. figure 1. testicular artery isolated and extracted from the spermatic funiculum of the ram. primers ! actin primers inos fw: tcaagatcatcgcgccc rev: gccgccaatccacacg fw: caacatcaggtcggccatc rev: agtcatgcttcccatcgct probe ! actin mgb (vic): probe inos mgb (fam): ctgagcgcaagtac cgtgttcccccagc table 1. quantitative real time pcr system. sequences of the primers and probe used to evaluate inos gene mrna expression. n mean std. deviation minimum maximum percentiles 25th 50th median) 75th basal 1 8 1.00 0.000 1.00 1.00 1.00 1.00 1.00 24h trattati 8 0.34 0,39 0.01 1.08 0.05 0.13 0.68 24h placebo 8 0.36 0.28 0.03 0.81 0.13 0.28 0.66 table 1. descriptive statistics: the mean and median inos mrna expression in the arteries extracted after 24 h in both the treated and placebo groups matteo_stesura seveso 08/10/14 12:07 pagina 184 the mean and median inos mrna expression in the arteries extracted after 24 h in both the treated and placebo groups were reduced compared to the basal samples. moreover the mean and median in the group exposed to 24 hours of treatment were lower than those in the group exposed to 24 hours of placebo. the wilcoxon rank test was performed to evaluate differences both between basal versus 24 h treated samples and basal versus 24 h placebo. we found a significant (p < 0.05) decrease in the inos mrna expression in the arteries extracted after 24 h both when we compared basal versus 24 h treated samples (p = 0.017) and basal versus 24 h placebo samples (p = 0.012). the mann-whitney test was performed to evaluate differences between treated and controls after 24 h, and no significant difference was found (p > 0.05). discussion the study demonstrates that the inos gene is expressed in the testicular artery of the ram and that inos activity is not influenced by i.v. administration of hcg. in fact the effects on inos gene expression observed after 24 h in the hcg group did not differ from that observed in the placebo group (figure 2). several reports have been published concerning the role of the nos system in the male reproductive tract (1214). no was found to be of importance for sperm quality and sperm fertilization potential (15-18) and to influence the testicular vascular relaxation by increasing cgmp levels (12). however, under basal condition, in the unstimulated intact testis only low levels of nos activity have been detected (21, 22). accordingly the vasoconstrictor response to l-name nos inhibition is weak (5) and acetylcholine does not increase testicular blood flow (19, 20). conversely, experimental evidence suggests that, after hormonal stimulation, the nos system could play a role in the regulation of the testicular vascular system since the intensity of nadph staining of the testicular artery, known to be directly correlated with the nos activity, was found to increase after hcg treatment (9, 23, 24). furthermore treatment with l-name nos was found to increase vascular resistance in the testis after stimulation with hcg (9). notably we did not observe any difference in the inos gene expression of the testicular artery extracted 24 h after hcg administration, compared with the placebo group (means 0.36 + 0.28 and 0.29 + 0.23 respectively) (figure 2). these findings suggest that hcg treatment does not have a direct effect on inos activity in the testicular artery but the effects on testicular blood flow could be mediated by other factors. several reports could support this discrepancy. firstly, hcg treatment is known to induce an increase in testicular blood flow, but this effect is not observed in leydig cell-depleted animals, suggesting that the effect on blood flow is mediated by the increase in sex steroid secretion via stimulation of the leydig cells (2). secondly, studies have reported that hcg treatment results in local secretion within the testis of potent vasoconstrictors such as serotonin and endothelin-1 and that the increase in no synthesis occurs to balance the effects of such local vasoconstrictors (25, 26). moreover, other authors have speculated upon the presence of a permeability-inhibiting factor in testicular microvessels that is down regulated by hcg (7, 27). finally, hcg was found to increase the expression of angiogenic factors such as vegf (6) and the ang2, which are associated with an increase in vascular permeability (5, 6). in a previous report we demonstrated the presence of thromboxane a2 (txa2) receptors, known as tp# receptor, in the testicular artery of the ram. in addition, our results showed that tp# receptor gene expression was completely suppressed in all samples 24 hours after i.v. administration of 5000 iu of hcg, suggesting that a down regulation of txa2 activity could be an additional mechanism explaining the vasodilatory effect of hcg in the testis (28). this study support the hypothesis that the testicular vascular relaxation observed after hcg administration is not related to a direct effect of hcg on the testicular nos system, but could be mediated by the up and down regulation of the inhibiting and stimulating factors described above. unexpectedly, a significant reduction in inos gene expression was observed in the testicular arteries extracted after 24 h in both groups (figure 3), suggesting that the decrease in inos activity could be related to the spermatic vessel ligation of the contralateral testis. only a limited number of studies have reported the effect 185archivio italiano di urologia e andrologia 2014; 86, 3 hcg, nitric oxide on spermatic vessels figure 2. inos mrna expression in arteries obtained after 24 hours from the hcg and placebo groups. figure 3. inos mrna expression before and 24 hours after the administration of hcg or placebo. matteo_stesura seveso 08/10/14 12:07 pagina 185 archivio italiano di urologia e andrologia 2014; 86, 3 m. matteo, a. rizzo, e. cicinelli, e. grandone, g. cardo, d. colaizzo, g. minoia, l. castellana, u. indraccolo, s. marrocchella, p. greco, r.l. sciorsci 186 of spermatic vessel ligation (named fowler-stephens maneuver) on inos expression and no levels in the ipsilateral and contralateral testis, although it is the most popular method in the surgical management of high testes (29-31). these studies showed an increase in no levels and in inos immunostaining in both testes, whereas moderate inos immunostaining expression and germ cell apoptosis were observed in the contralateral testis 24 hours after ligation (31). these findings are partially in agreement with the results of the present study which point to potentially important physiological implications of the nos system in the physiopathology of testicular germ cell apoptosis observed after the fowler stephens maneuver. moreover, it may be supposed that an ipsilateral flow obstruction (as it happens during testicular torsion) may cause a contralateral vascular injury (32). conclusion the ram testicular artery expresses the inos gene but its expression and functional activity is not directly influenced by hcg stimulation. further investigations are needed to confirm these results and to elucidate the functional role and the mechanisms involved in the regulation of the testicular vascular nos system. references 1. matteo m, cicinelli e, baldini d, et al. influence of human menopausal gonadotrophin treatment on testicular blood flow and on seminal plasma nitric oxide levels in infertile males int j androl. 2006; 29:441. 2. bergh a, damber je, et al. does follicle-stimulating hormone or pregnant mare serum gonadotrophin influence testicular blood flow in rats? int j androl. 1992; 15:365. 3. causio f, matteo m, cicinelli e, et al. variation of intratesticular blood flow in response to urinary folliclestimulating hormone treatment in men with severe oligoteratoasthenozoospermia fertil steril. 2002; 78:1133. 4. damber j.e, bergh a, fagrell b, et al. testicular microcirculation in the rat studied by videophotometric capillaroscopy, fluorescence microscopy and laser doppler flowmetry acta physiol scand. 1986; 126:371. 5. rudolfsson sh, johansson a, franck lissbrandt i, et al. localized expression of angiopoietin 1 and 2 may explain unique characteristics of the rat testicular microvasculature biol reprod. 2003; 69:1231. 6. rudolfsson sh, wikstrom p, jonsson a, et al. hormonal regulation and functional role of vascular endothelial growth factor a in the rat testis biol reprod. 2004; 70:340. 7. bergh a, damber je, hjertkvist m. human chorionic gonadotrophin-induced testicular inflammation may be related to increased sensitivity to interleukin-1 int j androl. 1996; 19:229. 8. assmus m, svechnikov k, von euler m, et al. single subcutaneous administration of chorionic gonadotropin to rats induces a rapid and transient increase in testicular expression of pro-inflammatory cytokines pediatr res. 2005; 57:896. 9. lissbrant e, lofmark u, collin o, bergh a. is nitric oxide involved in the regulation of the rat testicular vasculature? biol reprod. 1997; 56:1221. 10. nrc guide for the care and use of agricultural animals in agricultural research and teaching. consortium for developing a guide for the care and use of agricultural animals in agricultural research and teaching. champaign, il, 1988. 11. livak jk, schmittgen td. analysis of relative gene expression data using real-time quantitative pcr and the 2(-delta delta c (t)) methods. 2001; 25:402. 12. middendorff r, muller d, wichers s, et al. evidence for production and functional activity of nitric oxide in seminiferous tubules and blood vessels of the human testis j clin endocrinol metab. 1997; 82:4154. 13. battaglia c, giulini s, regnani g, et al. seminal plasma nitrite/nitrate and intratesticular doppler flow in fertile and infertile subjects hum reprod. 2000; 15:2554. 14. zini a, o'bryan m.k, magid m.s, schlegel pn. immu nohistochemical localization of endothelial nitric oxide synthase in human testis, epididymis, and vas deferens suggests a possible role for nitric oxide in spermatogenesis, sperm maturation, and programmed cell death biol reprod. 1996; 55:935. 15. zhang h, zheng rl. possible role of nitric oxide on fertile and asthenozoospermic infertile human sperm functions free radic res. 1996; 25:347. 16. herrero mb, viggiano jm, perez-martinez s, et al. evidence that nitric oxide synthase is involved in progesterone-induced acrosomal exocytosis in mouse spermatozoa reprod fertil dev. 1997; 9:433. 17. o'bryan mk, zini a, cheng cy, schlegel pn. human sperm endothelial nitric oxide synthase expression: correlation with sperm motility fertil steril. 1998; 70:1143. 18. sengoku k, tamate k, yoshida t, et al. effects of low concentrations of nitric oxide on the zona pellucida binding ability of human spermatozoa fertil steril. 1998; 69:522. [19. noordhuizen-stassen en, beijer g, wensing cj. the effect of norepinephrine, isoprenaline and acetylcholine on testicular and epididymal circulation in the pig int j androl. 1983; 6:44. 20. whittle bj. nitric oxide in physiology and pathology histochem j. 1995; 27:727. 21. burnett al, ricker dd, chamness sl, et al. localization of nitric oxide synthase in the reproductive organ of the male rat biol reprod. 1995; 52:1. 22. ehren i, adolfsson j, wiklund np. nitric oxide synthase activity in the human urogenital tract urol res. 1994; 22:287. 23. brendt ds , hwang pm, synder s.h. localization of nitric oxide synthase indicating a neuronal role for nitric oxide nature. 1990; 347:768. 24. hope bt, michael gj, knigge km, vincent s. neuronal nadph diaphorase is a nitric oxide synthase proc natl acad sci usa 1991; 88:2811. 25. collin o, damber je, bergh a. 5-hydroyxytryptamine a local regulator of testicular blood flow and vasomotion in rats j reprod fertil. 1996; 106:17. 26. collin o, damber je, bergh a. effects of endothelin-1 on the rat testicular vasculature j androl. 1996; 17:360. 27. hjertkvist m, bergh a. the time response and magnitude of hcg induced vascular changes are different in scrotal and abdominal testes int j androl. 1993; 16:63. matteo_stesura seveso 08/10/14 12:07 pagina 186 28. matteo m, cicinelli e, sciorsci rl, et al. expression and hormonal modulation of the thromboxane a2 receptor gene in mammalian testicular arteries fertil steril 2006; 85:1276. 29. levy da, abdul-karim fw, miraldi f, elder js. effect of human chorionic gonadotropin before spermatic vessel ligation in the prepubertal rat testis j urol. 1995; 154:738. 30. taneli f, vatansever s, ulman c, giray g, genc a, tanel c. pre-ischemic administration of nitric oxide synthase inhibitors reduced germ cell apoptosis after spermatic vessel ligation in the rat testis urol int. 2005; 75:70. 31. taneli f, vatansever s, ulman c, et al. the effect of spermatic vessel ligation on testicular nitric oxide levels and germ cell-specific apoptosis in rat testis acta histochem. 2005; 106:459. 32. ozkan ku, küçükaydin m, muhtaroglu s, kontas o. evaluation of contralateral testicular damage after unilateral testicular torsion by serum inhibin b levels j pediatr surg. 2001; 36:1050. 187archivio italiano di urologia e andrologia 2014; 86, 3 hcg, nitric oxide on spermatic vessels correspondence maria matteo, md, phd (corresponding author) maria.matteo@unifg.it sonia marrocchella, md pantaleo greco, md institute of obstetrics and gynecology department of medical and surgical sciences, university of foggia, viale pinto 71100 foggia, italy annalisa rizzo, md giuseppe minoia, md raffaele luigi sciorsci, md department of animal production, university of bari, bari, italy ettore cicinelli, md 3rd unit of obstetrics and gynecology, department of biomedical and human oncological science (dimo) university of bari, bari, italy elvira grandone, md donatella colaizzo, md atherosclerosis and thrombosis unit, irccs “casa sollievo della sofferenza” s. giovanni rotondo, foggia, italy giuseppe cardo, md operative unit of urology “s. giacomo" hospital, monopoli, italy laura castellana, md department of biomedical sciences, university of foggia, foggia, italy ugo indraccolo, md operative unit of gynaecology and obstetrics of civitanova marche area vasta 3 civitanova marche, italy matteo_stesura seveso 08/10/14 12:07 pagina 187 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2126 review painful bladder syndrome/interstitial cystitis: aetiology, evaluation and management william rourke 1, shahid aziz anwer khan 2, kamran ahmed 1, shikohe masood 3, prokar dasgupta 1, muhammad shamim khan 1 1 mrc centre for transplantation, king’s college london, department of urology, guy’s hospital, london, uk; 2 east surrey hospital, canada ave, redhill, uk; 3 medway maritime hospital, windmill road, gillingham, kent, uk. interstitial cystitis or bladder pain syndrome (bps) is often a chronic debilitating condition characterised by predominantly storage symptoms and associated frequently with pelvic pain that varies with bladder filling. the aetiology is uncertain as the condition occurs in the absence of a urinary tract infection or other obvious pathology. resulting discomfort may vary and ranges from abdominal tenderness to intense bladder spasms. diagnosis and management of this syndrome may be difficult and is often made by its typical cystoscopic features. this review discusses the diagnosis and management of interstitial cystitis according to the current available best evidence and advises a multimodal approach in its management. key words: bladder pain syndrome; interstitial cystitis; chronic pelvic; treatment; management; diagnosis. submitted 26 august 2013; accepted 15 january 2014 summary introduction interstitial cystitis (ic)/painful bladder syndrome (pbs) was defined in 2005 by the international society of bladder pain syndrome (essic) as “the complaint of suprapubic pain related to bladder filling, accompanied by other symptoms, such as increased daytime and night-time frequency, in the absence of proven urinary infection or other obvious pathology”. the definition of ic is the same as pbs, while also including “typical cystoscopic and/or histological features”. the essic collectively term ic and pbs as bladder pain syndrome (bps), however it’s important that the distinction is made as this can affect patient management (1). to further define bps, it’s important to recognise that it is a form of chronic pelvic pain (cpp), and therefore this review investigates not only its role but also other factors relating to cpp (2). cpp is difficult to classify, as it is defined by the symptom of pain and has no obvious associated cause, much the same as bps (2). rackow et al. define cpp as ‘pain that persists for six months requiring medical evaluation and intervention’. they concluded that in young women bps is an aetiological factor for no conflict of interest declared. cpp (3). this highlights the importance of considering both of them together by examining other factors beyond the bladder, as the cause of bps. in their case study, warren et al. found that the strongest risk factor for bps is non-bladder syndromes (4). therefore, studying the pathogenesis of non-bladder syndrome, of which cpp is included, might reveal the pathogenesis of bps (4). prevalence rand interstitial cystitis epidemiology (rice) conducted 146,231 household telephone calls in the united states and found that, according to the high sensitivity definition, 6.53% (95% ci 6.28, 6.79) of women met the symptom criteria of a bps sufferer. based on the high specificity definition, 2.70% (95% ci 2.53, 2.86) women met the criteria of a bps sufferer. the study showed that bps is an under-diagnosed condition and its prevalence may be higher in the population (5). parsons et al. concur with rice’s study in as much that ic/pbs has a substantially underestimated prevalence (6). after surveying 8 studies, carried out between 1975 and 2005, they suggested that the prevalence over the last decade was 197 for every 100,000 women and 41 for every 100,000 men in the united states (6). nickel et al. found the prevalence of interstitial cystitis to be 7.9% in women and 0.4% men when 48 urologists completed an audit on the cases seen in their outpatient practice, showing it’s a condition that affects women more often than men (7). aetiology a lack of consensus on how to classify bps means that its aetiology is still uncertain. a number of theories have been proposed as the mechanisms involved are poorly understood and in order to obtain a clear understanding, it is imperative that the risk factors are fully evaluated. kennedy et al. surveyed 645 women, and noted a positive correlation with smoking, irritable bowel syndrome (ibs) and generalised pain disorder (8). a twins study by tettamanti et al. contradicted this result, concluding that smoking is likely to be the confounding factor. they however found that tea consumption increased the likelihood of experiencing bps (9). nickel et al. noted ibs is doi: 10.4081/aiua.2014.2.126 rourke_stesura seveso 04/07/14 12:04 pagina 126 127archivio italiano di urologia e andrologia 2014; 86, 2 painful bladder syndrome/interstitial cystitis: aetiology, evaluation and management more prevalent in sufferers of bps (10). this association is important, the understanding of which may be significant in comprehending the aetiology of bps. one suggestion put forward was that the clinical components of sufferers of bps, ibs or systemic pain syndromes could be the three stages of a single combined syndrome. this proposed syndrome progresses from being organ specific initially, which is the bladder in the case of bps, then progressing regionally and finally eventually leading to systemic pain syndrome (10). this theory is similar to that proposed by butrick et al. who described the bladder as a ‘symptom generator’ for cpp (11). 1a. genetics the importance of genetic factors responsible for bps is mounting and is based on the high prevalence of bps in first degree relatives (12). in a study of 25,000 twins, altman et al. found that there was a genetic component to the aetiology of bps. for the first time, they were able to assess the importance of genetic and environmental influences on the possibility of developing bps in a large population of monozygotic and dizygotic twins (13). 1b. previous surgery ingber et al. found in a survey carried out on women with bps, that here was a statistically higher prevalence of pelvic surgeries. they state that most of the surgeries were carried out before the diagnosis of bps, inferring that the increase in surgeries observed is not due to the bps diagnosis (14). langenberg et al. study shows more bps suffers have had pelvic surgery than the control group. however, the study does conclude that there is a high chance that the reason for the pelvic surgery is a confounding factor. the study provides evidence that cpp in particular may be the reason for many of the surgeries whilst also being the cause of it (15). 1c. infection warren et al. carried out a case-control study and found that 18% to 36% women showed evidence of a urinary tract infection (uti) at the onset of bps (16). warren et al. proposed two hypotheses for the pathogenesis of utis that could cause bps. the first hypothesis is that the acute symptoms are the start of the chronic disease. the other possibility is that uti causes a physiological response that result in bps (16). 1d. glycosaminoglycan layer defects urothelial glycosaminoglycans (gags) line the bladder’s surface and it has been hypothesised that a deficiency in gags reduces protection of the bladder wall, resulting in bps. engelhardt et al. describe the gag layer as the urinetissue barrier and showed the long-term efficacy of treatment with intravesical hyaluronan; this successful treatment is the best indication that the urine-tissue barrier hypothesis is correct (17). maccari et al. conducted a study that shows that this hypothesis cannot be proven by levels of urinary gags, as they are not representative of the amount of urothelial gags. this study is important to oppose the use of urinary gags concentration as a diagnostic tool (18). 1e. neurobiology/no metabolism in a study by aizawa et al. it was found that nitric oxide (no) has a major role in the control of bladder filling by modulating the afferent nerves in rats. no signalling may therefore play a major role in the hypersensitivity of bps (19). kumar et al. found that adenosine triphospahte (atp) is released from the urothelium of bladders with overactive detrusor activity; which has been observed in bps sufferers (20). daly et al. concluded that recent studies showed further evidence of the role of excitatory and inhibitory mediators, from the urothelium, which act on afferent nerves. these afferent nerves have been implicated in the symptoms of urgency and frequency in bps. the review concludes that a better understanding of the afferent system of the bladder will provide a good therapeutic target for bps (21). 1f. mast cells/autoimmunity whilst experimenting on mice, chen et al. showed that bps is associated with the activation of distinct mast cell pools in the bladder. this release was found to be mediated by tumour necrosis factor (tnf). the pain in bps may be attributed to the release of the inflammatory mediators from the mast cells. it has been further hypothesised that an autoimmune response may be responsible for the irritation of the bladder (22, 23). patient evaluation in the aua guidelines by hanno et al, the complications with diagnosis of bps become apparent. the variety of definitions, the complex aetiology and the insufficient number of publications makes its diagnosis complex. therefore, diagnosis is partly based on the exclusion of other diseases. diagnosis is often based on a ‘clinical principle’ which is an informal consensus among urologist that may or may not be based on evidence from within the medical literature (24). when a patient presents with symptoms of cpp, a full history and examination must first be carried out with the elimination of differential diagnoses. in the event of a complicated diagnosis, a cystoscopy and/or urodynamics should be considered (25). when taking a full history, physicians should put emphasis on the symptoms and common risk factors. nipkow et al. describe the symptoms to be urgency, frequency and suprapubic pain (26). hanno et al. reported that the pain sufferers of bps describe is related to bladder filling and occurs suprapubically but in can include pain in the urethra, vulva, vagina and the rectum (24). it is important to recognise that this pain can be described as a feeling of ‘pressure’. the symptoms can be affected by the consumption of specific food and drinks and the presence of these symptoms strongly suggests bps. hanno et al. state that, alongside the patient’s pain history, the general history should include assessment of risk factors such as: previous pelvic operations, urinary tract infections (uti), history of urological diseases, previous pelvic radiation treatment and the presence of autoimmune diseases (24). in a cohort study by butrick et al., significant number of patients presented not with pain but with either stress/urge urinary incontinence or pelvic rourke_stesura seveso 04/07/14 12:04 pagina 127 archivio italiano di urologia e andrologia 2014; 86, 2 w. rourke, s. aziz anwer khan, k. ahmed, s. masood, p. dasgupta, m.shamim khan 128 organ prolapse. therefore, these should also be considered during evaluation (11). a common physical exam of the lower abdomen should followed by assessment of bladder fullness and suprapubic tenderness. in female patients, a vaginal exam should be carried out and the presence of pain involving the vulva, vagina or the surrounding organs should be carefully documented. in men, digital rectal exam is recommended with pain mapping of the scrotal-anal region (24). a urine dipstick should be used to eliminate the differential diagnosis of an infection. if ‘sterile pyuria’ is detected then, a culture for tuberculosis and fastidious organisms should be performed (25). in complicated presentations, it is recommended that urodynamics and cystoscopy should be included. kuo et al. found that the common urodynamic findings in bps sufferers were the presence of early sensory urgency and reduced bladder capacity. their study showed that symptoms of urgency and pain coupled with a small cystometric bladder capacity of less than 350 ml and a positive potassium chloride test is diagnostic of bps with a positive predictive value of 91.2% (27). the essic define ic based on the classic findings of ulcer’s noted on a cystoscopy (28). the classic patch of red urothelium with radiating small blood vessels was first described by hunner in 1914 (29). the presence of these lesions is associated with pain and urinary urgency and removal of these lesions can improve these urinary symptoms. glomerulations can also be identified during cystoscopy of patients affected by bps (30, 31). the cytoscopic features are considered in the context of the essic standardised procedure for cystoscopy involving systematic inspection of the bladder wall and grading of the lesions based on the lesion type (table 1) (28). management the poorly understood aetiology of bps has brought about many different treatment and management options. they include different types of behavioural, dietary, interventional, pharmacologic and surgical therapies. conservative conservative therapy options should be exhausted before providing less reversible surgical therapies. initial therapy for bps should focus on educating the patient and providing them with an understanding of the common exacerbating factors and treatment options. hanno et al. state that behaviour modification can improve symptoms and therefore should be the first avenue of treatment. patients should be told to avoid certain foods and drink; commonly, coffee and citrus products as these are irritants. certain types of exercise, sexual intercourse, stress, tight-fitting clothing and constipation may also be exacerbating factors in some patients. relieving factors should be explained such as local heat or cooling over the bladder region and pelvic floor relaxation techniques (24). oral therapy 2a. pentosan polysulfate oral pentosan polysulfate (pps) is the only oral medication approved by the us food and drug administration (fda) for bps. it has a structure similar to that of the gags in the urinary tract and therefore allows restoration of the urothelial layer, reducing the amount of noxious substance stimulating the sub-mucosal nerves (32, 33). 2b. analgesics pain management is an important part in the management of bps, however it is not sufficient and other avenues of treatment should be explored. in complicated cases, a multidisciplinary team approach to pain management may be required (24). gabapentin, an epileptic drug used in combination with amitriptyline and nsaids has shown considerable promise in reducing the oab symptoms after 4 weeks of treatments. large scale studies are however needed to verify these results (34). 2c. antidepressants amitriptyline is recommend by the american urological association for its mast cell stabilising effect (24). however, evidence to support this is mainly from single site clinical trials and case reports. a multicentre, randomised control trial carried out by foster et al. showed that there was no significant improvement in symptoms of bps sufferers when treated with amitriptyline. however, they conclude that if a daily dose of 50 mg or greater can be achieved, then amitriptyline may be of benefit (35). 2d. h2-receptor antagonist in a pilot study, seshadri et al. found encouraging results with the use of cimetidine in the treatment of bps. using the h2-antagonists (300 mg bd orally); 66% of patients experienced symptom relief while 44% reported a complete and sustained response (36). 2e. antihistamines hydroxyzine, a mast cell stabilizer seems and thus may play a role in mediating the inflammatory processes observed in pbs/ic. however the only reported study reporting hydroxyzine as a treatment for ic is an open label, non-consecutive case series. given the multifactorial aetiology of pbs/ic, patients with bladder mastocytosis seemed to benefit more from the treatment (37). grade lesion type 0 normal mucosa 1 petechiae in at least 2 quadrants 2 large sub-mucosal bleeding 3 diffuse global mucosal bleeding 4 mucosal disruption with or without bleeding/oedema table 1. essic grading based on lesion type identified by cystoscopy (28). rourke_stesura seveso 04/07/14 12:04 pagina 128 129archivio italiano di urologia e andrologia 2014; 86, 2 painful bladder syndrome/interstitial cystitis: aetiology, evaluation and management intravascular tanezumab mast cell degranulation is a proposed aetiology for bps. in the study by evans et al. the degranulation of mast cells resulted in the release pro-inflammatory agents, one of which is the neurotrophin ngf. ngf is involved in the generation of pain in tissue injury and inflammation (38). tanezumab is a proposed drug that is administered intravenously and is composed of anti-ngf antibodies and thus it prevents interaction with pain receptors on afferent neurones. the results showed that patients that took tanezumab were 7 times more likely to have a 50% or greater reduction in pain compared to the placebo arm. they also observed a significant reduction in urgency episodes. intravesical therapy 3a. dimethylsulfoxide dimethylsulfoxide is an anti-inflammatory, analgesic and muscle relaxant (39). it was approved to treat bps since 1977 and is the most commonly prescribed intra-vesical therapy. it results in symptom improvement in 50% of patients with bps (33). 3b. heparin heparin acts by replacing the damaged gag layer and therefore restores the urothelial barrier. it is used alone or in combination with pps and can provide immediate symptom relief (33, 39). 3c. liposomes a study carried out by lee et al. concluded that intravesical administration of liposomes once a week for one month resulted in 50% improvement with the effect being maintained for 2 months. it was concluded that liposomes help maintain the urothelial barrier. the study also concluded that the use of intravesical liposomes, injected once a week for 4 weeks could achieve either a similar or better effect compared to oral pentosan polysulfate. they suggested that more frequent treatment may improve clinical outcome. however, they further large-scale studies, with placebo controls, are required to fully evaluate the effect of intravesical liposomes (32). 3d. bacillus calmette-guerin (bcg) bcg works on the basis of an autoimmune aetiology therefore acting via an immunological mechanism (39). peters et al. showed in a long-term follow up of patients treated with bcg that 89% continued to have excellent response when evaluating 24 to 33 months after treatment was initiated (40). 3e hyaluronic acid and chondroitin sulphate intravesical hyaluronic acid (gag) mono therapy or in combination with sodium chondroitin sulphate (synthetic gag) offers effective symptom improvement and long-term efficacy in the treatment of bps (41). nickel et al. demonstrated in their rct that sodium chondroitin offers safe and effective treatment leading to a greater reduction in icsi (interstitial cystitis symptom index) and vas (visual analogue score) when compared with controls. however, it must be made clear that replacement therapy should only be effective in patients with ic/bps and gag abnormalities or deficiencies. the uncertain aetiology of bps/ic therefore requires a multimodal approach and monotherapy with the above agents is therefore not advocated (42). surgical 4a. botulinum toxin pinto et al. used the noxious relieving effects of botulinum toxin as pain relief in bps patients (43). their study investigated the effect of trigonal botulinum toxin injections and established that the treatment was both safe and effective. a pilot study by gottsch et al. showed that periurethral injections of botulinum toxin however did not effectively treat the pain symptoms of bps (44). botox should be considered when other intra-vesical therapies have failed. 4b. hydrodistension as explained by aihara et al., hydro-distension has an unknown mechanism of action but it has been shown in animal studies to damage the sub-mucosal nerve plexus forming the basis of its therapeutic use. they reported that hydro-distension was therapeutically effective in 71% of patients after one month but the affect diminished over time and only 37% of patients reported improvement at 6 months. in conclusion, therapeutic use of hydro-distension has a poor long term efficacy (45). 4c. transuretheral resection – coagulation of hunners lesions hunner first described the lesion that could be resected to relieve symptoms. cystoscopic ablation of ‘hunners lesions’ can result in temporary improvement in symptoms and the procedure could be repeated if symptoms recurred (29, 30). 4d. sacral neuromodulation sacral neuromodulation is a minimally invasive procedure in which the s3 sacral nerve is stimulated by a mild electrical current generated via a pulse generator. several studies have demonstrated it to be effective in the management of refractory pbs with good long-term outcomes. the main reported adverse effects of this treatment apart from the risks of bleeding or infection relate to lead displacement, device malfunction and early replacement which have cost implications (46). 4e. cystoplasty enterocystoplasty is a popular technique when bps is refractory to conservative therapies. the basis for the treatment is to enlarge the bladder and provide symptom relief. trigone sparing techniques allow for reduced complications by avoiding ureteral reflux. it has also been found that ileocecal bowel segments offer better results. ophoven et al. concluded that enterocytoplasty remains a rourke_stesura seveso 04/07/14 12:04 pagina 129 archivio italiano di urologia e andrologia 2014; 86, 2 w. rourke, s. aziz anwer khan, k. ahmed, s. masood, p. dasgupta, m.shamim khan 130 valuable surgical intervention with 15 of the 18 patients reporting excellent therapeutic results (47). 4f. urinary diversion the most common surgical treatment for bps is urinary diversion with the formation of an ileal conduit (25). this is the most invasive option and being irreversible requires strict selection criteria and careful patient evaluation. rossberger et al. found that 94% of patients with hunner-type disease reported complete resolution of their symptoms (48). it was also found that the treatment for those with hunner-type disease is far more unpredictable and this should be factored in when urinary diversion is being contemplated. furthermore, before contemplating irreversible intervention, patients must be made clear that the pain may not disappear even after a urinary diversion. conclusions this review shows the complexity behind the aetiology of bladder pain syndrome. this tangled web of hypothesis creates confusion in the diagnosis and its subsequent m<anagement. the importance of research particularly pertaining to the aetiology of bps has been highlighted. this should provide physicians with a common understanding of the syndrome so that diagnosis is established early and an effective management plan tailored to the patient needs are devised. references 1. van de merwe jp, nordling j, bouchelouche p, et al. diagnostic criteria, classification, and nomenclature for painful bladder syndrome/interstitial cystitis: an essic proposal. eur urol. 2008; 53:60-7 2. fall m, baranowski ap, elneil s, et al. eau guidelines on chronic pelvic pain. eur urol 2010; 57:35-48. 3. rackow bw, novi jm, arya la, pfeifer sm. interstitial cystitis is an etiology of chronic pelvic pain in young women. j pediatr adolesc gynecol 2009; 22:181-5. 4. warren jw, clauw dj, wesselmann u, et al. sexuality and reproductive risk factors for interstitial cystitis/painful bladder syndrome in women. urology. 2011; 77:570-5. 5. berry sh, elliott mn, suttorp m, et al. prevalence of symptoms of bladder pain syndrome/interstitial cystitis among adult females in the united states. j urol 2011; 186:540-4. 6. parsons jk, kurth k, sant gr. epidemiologic issues in interstitial cystitis. urology. 2007; 69(4 suppl):5-8. 7. nickel jc, teichman jmh, gregoire m, et al. prevalence, diagnosis, characterization, and treatment of prostatitis, interstitial cystitis, and epididymitis in outpatient urological practice: the canadian pie study. urology. 2005; 66:935-40. 8. kennedy cm, bradley cs, galask rp, nygaard ie. risk factors for painful bladder syndrome in women seeking gynecologic care. int urogynecol j pelvic floor dysfunct 2006; 17:73-8. 9. tettamanti g, nyman-iliadou a, pedersen nl, et al. influence of smoking, coffee, and tea consumption on bladder pain syndrome in female twins. urology. 2011; 77:1313-7. 10. nickel jc, tripp da, pontari m, et al. interstitial cystitis/painful bladder syndrome and associated medical conditions with an emphasis on irritable bowel syndrome, fibromyalgia and chronic fatigue syndrome. j urol 2010; 184:1358-63. 11. butrick cw, sanford d, hou q, mahnken jd. chronic pelvic pain syndromes: clinical, urodynamic, and urothelial observations. int urogynecol j pelvic floor dysfunct 2009; 20:1047-53. 12. warren jw, jackson tl, langenberg p, et al. prevalence of interstitial cystitis in first-degree relatives of patients with interstitial cystitis. urology 2004; 63:17-21 13. altman d, lundholm c, milsom i, et al. the genetic and environmental contribution to the occurrence of bladder pain syndrome: an empirical approach in a nationwide population sample. eur urol 2011; 59:280-5. 14. ingber ms, peters km, killinger ka, et al. dilemmas in diagnosing pelvic pain: multiple pelvic surgeries common in women with interstitial cystitis. int urogynecol j pelvic floor dysfunct 2008; 19:341-5. 15. langenberg pw, wallach ee, clauw dj, et al. pelvic pain and surgeries in women before interstitial cystitis/painful bladder syndrome. am j obstet gynecol 2010; 202:286.e1-6. 16. warren jw, brown v, jacobs s, et al. urinary tract infection and inflammation at onset of interstitial cystitis/painful bladder syndrome. urology 2008; 71:1085-90. 17. engelhardt pf, morakis n, daha lk, et al. long-term results of intravesical hyaluronan therapy in bladder pain syndrome/interstitial cystitis. int urogynecol j 2011; 22:401-5. 18. maccari f, buzzega d, galeotti f, volpi n. fine structural characterization of chondroitin sulfate in urine of bladder pain syndrome subjects. int urogynecol j 2011; 22:1581-6. 19. aizawa n, igawa y, nishizawa o, wyndaele j-j. effects of nitric oxide on the primary bladder afferent activities of the rat with and without intravesical acrolein treatment. eur urol 2011; 59:264-71. 20. kumar v, chapple cr, rosario d, et al. in vitro release of adenosine triphosphate from the urothelium of human bladders with detrusor overactivity, both neurogenic and idiopathic. eur urol 2010; 57:1087-92. 21. daly dm, collins vm, chapple cr, grundy d. the afferent system and its role in lower urinary tract dysfunction. curr opin urol 2011; 21:268-74. 22. chen mc, blunt lw, pins mr, klumpp dj. tumor necrosis factor promotes differential trafficking of bladder mast cells in neurogenic cystitis. j urol 2006; 175:754-9. 23. ratliff tl, klutke cg, hofmeister m, et al. role of the immune response in interstitial cystitis. clin immunol immunopathol 1995; 74:209-16. 24. hanno pm, burks da, clemens jq, et al. aua guideline for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome. j urol 2011; 185:2162-70. 25. vij m, srikrishna s, cardozo l. interstitial cystitis: diagnosis and management. european j obstetr gynecol reprod biol 2012; 161:1-7. 26. nipkow l, chai tc. interstitial cystitis: modern tools for an accurate diagnosis. curr urol rep 2003; 4:381-4. 27. kuo yc, kuo hc. potential factors that can be used to differentiate between interstitial cystitis/painful bladder syndrome and bladder oversensitivity in women. int j clin pract 2012; 66:146-51. 28. van de merwe jp, nordlingg jr, editors. interstitial cystitis : definitions and confusable diseases 2005. rourke_stesura seveso 04/07/14 12:04 pagina 130 131archivio italiano di urologia e andrologia 2014; 86, 2 painful bladder syndrome/interstitial cystitis: aetiology, evaluation and management 29. hunner gl. a rare type of bladder ulcer in women; report of cases. the boston medical and surgical journal 1915; 172:660-4. 30. payne ra, connor rco, kressin m, guralnick ml. endoscopic ablation of hunner’s lesions in interstitial cystitis patients can urol assoc j. 2009; 3:473-7. 31. tomaszewski je, landis jr, russack v, et al. symptoms in interstitial cystitis: results from the interstitial cystitis database study. 1993; 4295:67-81. ??? 32. lee w-c, chuang y-c, lee w-c, chiang p-h. safety and dose flexibility clinical evaluation of intravesical liposome in patients with interstitial cystitis or painful bladder syndrome. kaohsiung j med sci 2011; 27:437-40. 33. parsons cl. current strategies for managing interstitial cystitis. expert opin pharmacother 2004; 5:287-93. 34. lee jw, han dy, jeong hj. bladder pain syndrome treated with triple therapy with gabapentin, amitriptyline, and a nonsteroidal anti-inflammatory drug. int neurourol j 2010; 14:256-60. 35. foster he, hanno pm, nickel jc, et al. effect of amitriptyline on symptoms in treatment naïve patients with interstitial cystitis/painful bladder syndrome. j urol 2010; 183:1853-8. 36. seshadri p, emerson l, morales a. cimetidine in the treatment of interstitial cystitis. urology 1994; 44:614-6. 37. hanley rs, stoffel jt, zagha rm, et al. multimodal therapy for painful bladder syndrome/interstitial cystitis: pilot study combining behavioral, pharmacologic, and endoscopic therapies. int braz j urol 2009; 35:467-74 38. evans rj, moldwin rm, cossons n, et al. proof of concept trial of tanezumab for the treatment of symptoms associated with interstitial cystitis. j urol 2011; 185:1716-21. 39. dawson te, jamison j. intravesical treatments for painful bladder syndrome/interstitial cystitis. cochrane database syst rev. 2007; (4):cd006113 2 40. peters km, diokno ac, steinert bw, gonzalez ja. the efficacy of intravesical bacillus calmette-guerin in the treatment of interstitial cystitis: long-term followup. j urol 1998; 159:1483-6 41. engelhardt pf, morakis n, daha lk, et al. long-term results of intravesical hyaluronan therapy in bladder pain syndrome/interstitial cystitis. int urogynecol j. 2011; 22:401-5 42. nickel jc, hanno p, kumar k, thomas h. second multicenter, randomized, double-blind, parallel-group evaluation of effectiveness and safety of intravesical sodium chondroitin sulfate compared with inactive vehicle control in subjects with interstitial cystitis/bladder pain syndrome. urology 2012; 79:1220-4 43. pinto r, lopes t, frias b, et al. trigonal injection of botulinum toxin a in patients with refractory bladder pain syndrome/interstitial cystitis. eur urol 2010; 58:360-5. 44. gottsch hp, miller jl, yang cc, berger re. a pilot study of botulinum toxin for interstitial cystitis/painful bladder syndrome. neurol urodyn 2011; 30:93-6. 45. aihara k, hirayama a, tanaka n, et al. hydrodistension under local anesthesia for patients with suspected painful bladder syndrome/interstitial cystitis: safety, diagnostic potential and therapeutic efficacy. int j urol 2009; 16:947-52. 46. gajewski jb, al-zahrani aa. the long-term efficacy of sacral neuromodulation in the management of intractable cases of bladder pain syndrome: 14 years of experience in one centre. bju int 2011; 107:1258-64 47. van ophoven a, oberpenning f, hertle l. long-term results of trigone-preserving orthotopic substitution enterocystoplasty for interstitial cystitis. j urol 2002; 167:603-7. 48. rössberger j, fall m, jonsson o, peeker r. long-term results of reconstructive surgery in patients with bladder pain syndrome/interstitial cystitis: subtyping is imperative. urology 2007; 70:638-42. correspondence william rourke, md kamran ahmed, phd, mrcs prokar dasgupta, md, frcs (urol), febu muhammad shamim khan, obe, frcs (urol), febu mrc centre for transplantation, king’s college london, department of urology, guy’s hospital, london (uk) se1 9rt shahid aziz anwer khan, frcs (urol) febu (corresponding author) saak_2000@yahoo.co.uk east surrey hospital, canada ave redhill (uk) rh1 5rh shikohe masood, frcs, frcs (urol), febu medway maritime hospital, windmill road gillingham, kent (uk) me7 5ny rourke_stesura seveso 04/07/14 12:04 pagina 131 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2154 case report a rare complication of eswl: focal metastatic multiple organ abscesses in a horseshoe kidney ugur kuyumcuoglu 1, bilal eryildirim 2, murat tuncer 2, gokhan faydaci 2, tevfik aktoz 1, hakan akdere 1, kemal sarıca 2 1 trakya university, faculty of medicine, urology clinic, edirne,turkey; 2 lutfi kirdar training and research hospital urology clinic, istanbul, turkey. extracorporeal shock wave lithotripsy (eswl) is an effective treatment modality in the minimal invasive management of urinary system stone disease. although the majority of the complications occuring after eswl are minor ( most common ones are gross haematuria, pain, perinephritic hematoma); bacteriuria may also occur in some cases which sometimes can lead to sepsis and even metastatic abscess formation in a very rare part of the cases treated. in this rare situation infection agent spreads quickly via hematogenous route and causes abscess formation in different parts of the body. majority of such cases usually have an underlying systemic disease like diabetes mellitus (dm), malignancy, hiv or steroid use which lead to disruption of immune system functions. abscess formation following eswl is extremely rare and usually limited with some case reports published in the literature. herein, we present a diabetic case with formation of multiple abscess foci in kidney, as well as in lungs and liver following eswl. the patient was first admitted to our emergency department with high fever and respiratory distress and misdiagnosed as metastatic tumor foci based on radiologic findings. to the best of our knowledge, our case is the first one in the literature in whom simultanous abscess formation in multiple organ systems has been documented following an otherwise uneventful eswl. key words: eswl (extracorporeal shockwave lithotripsy); abscess; complications. submitted 11 september 2013; accepted 31 january 2014 summary introduction as a minimal invasive management alternative eswl is an effective, safe and practicle treatment in the treatment of urinary system stones (1). however, accumulated experience so far has clearly shown that despite its safe nature; some certain complications ( majority of which are minor) may occur following this procedure . in addition to the traumatizing effects of high energy shock waves (hesw) on renal parenchyma: these complications may also originate no conflict of interest declared. from residual stone fragments and infection after the procedure. the trauma induced by hesw during eswl may allow spread of the bacteria in urine to the bloodstream resulting in infectious complications like bacteriuria, bacteraemia, urinary tract infection, urosepsis, perinephric abscess formation and even death in rare cases (2). related with this subject, bacteriemia may occur in 4% of patients treated with eswl which constitutes the main underlying risk for the formation of distant organ metastatic abscesses. last but not least, these infectious complications can cause urosepsis in a rarely encountered manner (3). herein we present a diabetic case admitted to our emergency department with high fever and respiratory distress findings. he was first hospitalized with the diagnosis of acute pneumonia and hyperglycemia attack by chest diseases department. computerized tomography (ct) of thorax and abdomen revealed multiple metastatic masses in lungs, liver and also in parenchyma of horseshoe kidney with an unknown origin. case report we present a diabetic case admitted to our emergency department with high fever and respiratory distress findings. he was first hospitalized with the diagnosis of acute pneumonia and hyperglycemia attack by chest diseases department. computerized tomography (ct) of thorax (figure 1) and abdomen revealed multiple metastatic masses in lungs, liver and also in parenchyma of horseshoe kidney with an unknown origin. case report description and figures are in supple mentary materials posted on www.aiua.it discussion following its clinical introduction in 1982, eswl became the preferred treatment modality in the management of urinary calculi with its successful results (4). accumulated experience in this field of urology did prove the efficacy and safety of this approach based on its minimally invasive nature. however despite its highly successful and safe results, studies did clearly show that this some certain side doi: 10.4081/aiua.2014.2.154 figure 1. 155archivio italiano di urologia e andrologia 2014; 86, 2 metastatic multiple organ abscesses after eswl effects can occur following this procedure. related with this subject the reported complications namely gross haematuria, pain, perinephritic hematoma are generally minor problems which could be treated in a conservative manner in the majority of the cases (5). however, studies again demonstrated that some certain infectious complications such as bacteriuria can also be anticipated after management and it can sometimes lead to sepsis (6). gram (-) bacteria are the most common agent found after eswl which could sometimes lead to metastatic abscess formation (5). related with this subject again metastatic abscess is defined as hematogenous spreading of an infective agent which causes abscess formation in the different parts of the body. concerning the etiopathogenesis of metastatic abscess formation, patients usually suffer from an underlying systemic disease like diabetes mellitus (dm), malignancy, hiv or steroid use which leads to disruption of immune system functions. the release of bacteria from fragmented stones or infected urine due to tissue injury can also sometimes be responsible for abscess formation. when a focal intraparenchymal abscess occurs, depending on the body defense mechanisms, associated co-morbidities along with the type and efficacy of the treatment, enlargement and rupture of this focal infection may result in spread of infection into the perinephritic area causing perinephritic abscess formation. although parenchymal and/or perinephritic abscess formation following eswl has been reported with limited case reports in the literature (7); metastatic abscess formation in other areas of the body following this procedure is an extremely rare complication. while brain abscess formation following eswl was reported by zannoud et al. (3); unal et al reported a giant abscess formation after eswl which was attached to the abdominal wall enlarging towards the thorax (7). in our present case, in addition to the multiple abscess foci in the treated kidney, additional metastatic abscess foci have also been detected in other organs including lungs and liver which probably originated from the hematogenous spread of the infection following eswl. another interesting aspect of our case is that radiologists misdiagnosed the simultaneous hypodense noduler lesions as metastatic tumors of unknown origin involving lungs, liver, and horseshoekidney. to the best of our knowledge, there is no report in the literature demonstrating the simultaneous abscess formation in multiple organs following eswl. li et al. presumed that the predisposing factors for sepsis and abscess formation following eswl are the presence of stones larger than 2 cm, struvite stones, nephrostomy or stents and lastly obstruction in urinary system (5). diabetes mellitıus could be a predisposing risk factor for abscess formation in our case besides, we assume that the patient has not been well evaluated with respect to the presence and degree of urinary system infection before eswl procedure. in that case the procedure might have resulted in bacteriemia originating from an untreated infection before eswl. last but not least, the formation of abscess in right perirenal area following an eswl procedure for the left kidney stone is also an interesting consideration. this can be attributed again with the horseshoe kidney malformation in our case which may predispose the kidney for such a complication. references 1. labanaris ap, kühn r, schott ge, zugor v. perirenal hematomas induced by extracorporeal shock wave lithotripsy (eswl). therapeutic management. scientific world journal. 2007; 17:1563-66. 2. skolarikos a, alivizatos g, de la rosette j. extracorporeal shock wave lithotripsy 25 years later: complications and their prevention. eur urol. 2006; 50:981-90. 3. zannoud m, ghadouane m, kasmaoui eh, et al. metastatic cerebral abscess from klebsiella pneumoniae after extracorporal shock wave lithotripsy for kidney stone (a case report). ann urol. 2003; 37:81-84. 4. chaussy c, schmiedt e. shock wave treatment for stones in the upper urinary tract. urol clin north am. 1983; 10:743-50. 5. li l, shenn z, wang h, eyt al. investigation of infection risk and the value of urine endotoxin during extracorporeal shock wave lithotripsy. chin med j. 2001: 114:510-13. 6. michaels ek, fowler je jr, mariano m. bacteriuria following extracorporeal shock wave lithotripsy of infection stones. j urol. 1988; 140:254-56. 7. unal b, kara s, bilgili y, et al. giant abdominal wall abscess dissecting into thorax as a complication of eswl. urology. 2005; 65:389. correspondence ugur kuyumcuoglu, md, professor kuyumcuugur@yahoo.com bilal eryildirim, md, associate professor bilaleryildirim@yahoo.com murat tuncer, md (corresponding author) murattuncer77@hotmail.com gokhan faydaci, md faydacig@yahoo.com tevfik aktoz, md, associate professor taktoz01@yahoo.com hakan akdere, assistant professor hakdere@yahoo.com kemal sarıca, md, professor saricakemal@gmail.com altunizade mah. atif bey sok.gokdeniz sitesi e blok d:20 kosuyolu, istanbul, turkey a. anterior-posterior chest radiography showing multiple nodular lesions in lungs. b. computerized tomography (thorax) showing multiple nodular lesions in lungs. stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2158 case report rare type of bladder cancer: malign fibrous histiocytoma orcun celik, hakan turk, salih budak, yusuf ozlem ilbey tepecik educational and research hospital, urology clinic, izmir, turkey malignant fibrous histocytoma (mfh) is the most common soft tissue sarcoma in adults. urinary tract is a very rare location for mfh. involvement of the bladder is more common in males and at the 6th decade of life. a case of mfh of the bladder with poor prognosis is presented. prognostic factors for mfh are tumor grade, amount of invasion, age, tumor size, and histological type. survival rate is very low and 3-year disease specific survival is approximately 40%. key words: malignant fibrous histocytoma; bladder; tumour. submitted 28 april 2014; accepted 31 may 2014 summary introduction malignant fibrous histocytoma (mfh) is a mesenchimal tumor, which was described by o’brien and stout in 1964 (1). mfh is an aggressive tumor with fusiform cells that is the most common soft tissue sarcoma in adults (2). urinary tract, especially bladder is a very rare location for mfh with only 29 previously reported cases. involvement of the bladder is more common in males and at the 6th decade of life. clinical presentation is similar to other bladder tumors. in the bladder this mesenchimal tumor and its variants should be distinguished with immunohistochemical methods from sarcomatoid carcinoma, inflammatory myofibroblastic tumor and leiomyosarcoma (3). mfh spreads fast and is generally metastatic. size, depth and histologic features of the tumor are important factors for metastasis (4). because of its rapid local and distant metastatic character, radical cystectomy, lymph node dissection and adjuvant radiotherapy are the first line treatments (5, 6). despite this treatment, 3-year survival is approximately 40%. this is probably due to its low frequency and lack of consensus on treatment. in the current article, we aim to review the relevant literature in the light of a case. case report a 57-year old man applied to our clinic with hematuria for one month. he had a trauma history that occurred 20 no conflict of interest declared years before and he was using tak. following the initial examination and investigation, we detected a bladder tumor and transurethral resection (tur) was performed. pathological examination showed a muscle-invasive tumour with the characteristics of a malignant fibrous histocytoma. toraco-abdominal tomography, hemogram, and biochemical tests were planned for staging. hydronephrosis in the left kidney and high calcium levels (15 mg/dl) were detected. because of the high calcium levels, we performed a bone scintigraphy and detected suspicious areas in ribs and femur head probably indicating the presence of bone metastasis. all these lesions were confirmed with magnetic resonance imaging (mri). high calcium level could not be lowered with medical treatment. therefore, patient underwent haemodialysis, but calcium levels remained high even after dialysis. after patient and patient’s relatives request, patient was discharged and died one month later. discussion mfh as a common soft tissue sarcoma in adults that constitutes 10-21% of all sarcomas. it is observed more commonly in lower extremities (50%), upper extremities (20%) and retroperitoneal space (15%). it is rare in the urinary tract and if seen, it is located mostly in the kidneys. non-epithelial tumors of the bladder consist of 2% of all bladder tumors and mesenchimal tumors of the bladder consist of 0.23-0.67% of all bladder tumors (7). mfh in the bladder is more common in males (4:1) and at the 6th decade of life and commonly presents with macroscopic hematuria. some experts suggested that it is related to radiotherapy and chemotherapy and it often cooccurs (approximately 13%) with other tumors (leukemia, hodgkin lymphoma, multiple myeloma) (5, 8). mfh in bladder presents as a large-sized tumor, with diameter of approximately 6.4 cm (1-15 cm). in our case, the diameter of tumor was 10 cm and extracted material was 30 cc. at diagnosis, 16% of patients are t2, 72% of patients t3 and 14% t4 (9). disease specific survival is 47.8% at 1 year and 31.9% at 2 years (9). as it is an aggressive and rare type of tumor and there is limited number of studies, treatment is not very successful. there are mainly four morphological types (3): 1) inflammatory type (36%), 2) storiform-fascicular type (40%), 3) pleomorphic type (13%) and 4) myxoid type (9%) (10). at immunohistodoi: 10.4081/aiua.2014.2.158 159archivio italiano di urologia e andrologia 2014; 86, 2 rare type of bladder cancer: malign fibrous histiocytoma chemical evaluation, it is vimentin, alpha-1 antichymo trypsin and factor 13a positive. in our case, the tumor was positive for vimentin and cd68. conclusion mfh in the bladder is a rare tumor and there are approximately 29 cases reported in the literature. it presents with macroscopic hematuria and is more common in men and in the 6th decade of life. the tumor is generally large and locally advanced or metastatic like in our case. survival rate is low and there is no consensus on treatment strategies. histochemical evaluation is needed to distinguish mfh that has four morphological variants from similar tumors. prognostic factors for mfh are tumor grade, amount of invasion, age, tumor size, and histological type. because of its aggressive characteristics, local and distant metastases are likely. therefore, cystectomy and lymph node dissection and further adjuvant radiotherapy to prevent local recurrence and adriamicin chemotherapy for distant metastasis can be used. however, there is no consensus on treatment strategies (11). survival rate is very low and 3-year disease specific survival is approximately 40% (9). further studies are needed in this topic. references 1. kearney mm, oule eh, ivins jc. malignant fibrous histiocytoma. a retrospective study 0f 167 cases. cancer. 1980; 45;167-78 2. weiss sw, enzinger fm. malignant fibrous histiocytoma: an analysis of 200 cases. cancer. 1978; 41:2250. 3. lott s, lopez beltran a, montironi r, et al. soft tissue tumors of the urinary bladder. part ii: malignant neoplasms. human pathology. 2007; 38:963-77. 4. brennan m, singer s, maki rg, et al. sarcomas of the soft tissues and bone 7th ed. philadelphia, lippincott williams & wilkins. 2005; 1581-1631. 5. beltran a, pacelli a, rothenberg hk, et al. carcinosarcoma and sarcomatoid carcinoma of the bladder: clinicopathological study of 41 cases. j urol. 1998; 159:1497-503. 6. froehner m, manseck a, haase m, et al. locally recurrent malignant fibrous histiocytoma: a rare and aggressive genitourinary malignancy. urologia internationalis. 1999; 62:164-70. 7. kunze e, theuring f, kruger g. primary mesenchymal tumors of the urinary bladder. a histological and immunohistochemical study of 30 cases. pathol res pract. 1994; 190:311-32. 8. helpap b. nonepithelial neoplasms of the urinary bladder, virchows arch. 2001; 439:497-503. 9. gunia s, may m, koch s, et al. is radical oncosurgery justified for the treatment of primary malignant fibrous histiocytoma of the urinary bladder? report of two cases and analyses of diseasespecific survival rates based on a review of the literature urol int. 2011; 86:261-268. 10. martín lp, vilar dg, sanz mb, et al. malignant fibrous histiocytoma of the bladder. a literature review actas urol esp. 2010; 34:378-85. 11. oesterling je, epstein ji, brendler cb. myxoid malignant fibrous histiocytoma of the bladder. cancer. 1990; 66:1836-1842. correspondence orcun celik, md (corresponding author) orcuncelik82@hotmail.com hakan turk, md salih budak, md yusuf ozlem ilbey, md tepecik educational and research hospital, urology clinic 35140 izmir, turkey stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2146 case report post-renal acute renal failure due to a huge bladder stone orcun celik, tufan suelozgen, salih budak, yusuf ozlem ilbey tepecik educational and research hospital urology department, 35140, izmir, turkey a 63-year old male was referred to our emergency unit due to acute renal failure. the level of serum renal function tests levels, blood urea nitrogen (bun)/creatinine, were 63 mmol/l/848 µmol/l. ct (computarised tomography) scan showed a huge bladder stone (5 cm x 6 cm x 5 cm) with increased bladder wall thickness. post-renal acute renal failure due to bilateral ureterohydronephrosis was diagnosed. the huge bladder stone was considered to be the cause of ureterohydronephrosis and renal failure. the patient was catheterised and received haemodialysis immediately. he received haemodialysis four times during ten days of hospitalization and the level of serum renal function tests levels (bun/ creatinine) decreased 18 mmol/l/123 µmol/l. after improvement of renal function, we performed cystoscopy that demonstrated normal prostatic urethra and bladder neck and bilaterally normal ureteral orifices. bladder wall was roughly trabeculated and bladder outlet was completely obstructed by a huge bladder stone. after cystoscopy open, cystolithotomy was performed to remove calcium phosphate and magnesium ammonium phosphate stone weighing 200 g removed. four days after operation the patient was discharged uneventfully and urethral catheter was removed on the seventh day. post-renal acute renal failure due to large bladder stones is rare in literature. according to the our knowledge; early diagnosis of the stone avoid growth to large size and prevent renal failure. key words: bladder calculus; acute renal failure; open cystolithotomy; ureterohydronephrosis. submitted 28 april 2014; accepted 31 may 2014 summary introduction the pathogenesis of bladder stones has not been well studied (1). bladder stones account for 5% of urinary stones and occur in association with urinary tract infection, foreign bodies and neurogenic voiding dysfunction (2). in our recent urology practice, massive bladder stone is a rare entity. the association between bladder calculi and urinary stasis is not completely clear. unlike studies of upper urinary tract stone disease, factors contributing no conflict of interest declared to the pathogenesis of bladder calculi have not been well explored. although, bladder stones are usually associated to ureteral or renal stones, they may occasionally occur alone in absence of stones of the supravesical tract, as in our case (3). case report we present a 63-year-old man referred to our emergency unit for recurrent urinary tract infection , lower abdominal pain, oliguria and weight loss since six months. hepresented lower urinary tract symptoms including weak urine stream, urgency, urinary frequency, voiding difficulty and urinary intermittency. at physical examination he was anorexic and weak. blood urea nitrogen (bun) and serum creatinine levels were 63 mmol/l and 848 µmol/l respectively. ct (computerised tomography) scan showed a huge bladder stone (6 cm x 6 cm x 5 cm) with increased bladder wall thickness and bilateral ureterohydronephrosis (figures 1-2). neurologic examination was normal, therefore urodynamic evaluation was not indicated pre and post-operatively. haemodialysis and urethral catheterization improved renal function, whereas we simultaneously treated urinary tract infection with intravenous antibiotics during ten days hospitalization. we planned cystoscopy and open cystolithotomy. doi: 10.4081/aiua.2014.2.146 figures 1. the huge pelvic calculi seen in ct scan. 147archivio italiano di urologia e andrologia 2014; 86, 2 a huge bladder stone of bladder cystoscopic examination and open procedure were done together on the same operative day. no anatomic urethral obstruction was observed and prostatic urethra and bladder neck were normal too. cystoscopy normal demonstrated bilaterally normal ureteral orifices and a bladder stone which completely obstructed the bladder outlet as it was severely adherent to the bladder mucosa. the stone weighed 200 g and measured 5.0 cm x 6.0 cm x 5.0 cm in size (figure 3). post-operative period was uneventful. the patient was discharged on fourth post-operative day and urethral catheter was removed on the seventh day. at the first month post-operative outpatient control, no residual bladder stone or ureterohydronephrosis was present. discussion the presence of a huge bladder calculus is a rare cause of acute renal failure. according to the recent study from komeya et al, it was reported that, according to english literature of the last several decades, only six papers reported acute renal failure caused by stones (4). the median age of patients was 62 years and the heavier weight was 200 g. the level of serum creatinine on admission was higher than 672 µmol/l whereas in our patient was 848 µmol/l. nygaard et al reported that their patient’s serum creatinine level was 1264 µmol/l on admission and the stone weighted 1640 g which was the largest stone ever removed by open cystolithotomy in literature(5). additionally, in this patient an inoperable carcinoma of the bladder was detected more than four years later after cystolithotomy. in these papers, limited information was provided about the underlying disease which caused voiding disorder and bladder stones before admission. patients usually complained recurrent urinary tract infection and long-term persistent urinary symptoms. our patient had urinary tract infection on admission and we detected 100.000 e.coli cfu/ml in urine culture that was treated by intravenous antibiotics before surgical operation. conclusions in order to summarize about our case report, although single huge bladder stones rarely cause acute renal failure with respect to upper tract urinary stones, we should always remember this rare condition. we need to carefully consider two important aspects: 1) long-term urinary symptoms and recurrent urinary tract infections especially in men may cause huge bladder stone and acute renal failure 2) a 2-fold increase in bladder cancer risk was observed in association with a history of bladder stones in a case-control study (6). therefore the long delay in diagnosis of giant stones can cause squamous cell carcinoma of bladder. we should strictly follow-up patients with huge bladder stones for the risk of bladder cancer after operation. references 1. childs ma, mynderse la, rangel lj, et al. pathogenesis of bladder calculi in the presence of urinary stasis j urol. 2013; 189:1347-1351. 2. aydogdu o, telli o, burgu b, beduk y. infravesical obstruction results as giant bladder calculi, can urol asoc j. 2011; 5:77-78. 3. hammad ft, kaya m, kazim e. bladder calculi: did the clinical picture change? urology 2006; 67:1154-8. 4. komeya m, sahoda t, sugiura s, et al. a huge bladder calculus causing acute renal failure urolithiasis 2012; 12:517-8. 5. nygaard e, terjesen t. giant vesical calculas and anuria scand j urol nephrol. 1976; 10:88-90. 6. kantor af, hartge p, hoover rn, et al. urinary tract infection and risk of bladder cancer. am j epidemiol. 1984; 119:510-5. correspondence orcun celik, md (corresponding author) orcuncelik82@hotmail.com tufan suelozgen, md salih budak, md yusuf ozlem ilbey, md associate professor endourology section urology department, tepecik educational and research hospital gaziler cd.no:468, yenisehir 35140, izmir, turkey figures 2. bilateral ureterohydronephrosis that cause of acute renal failure seen in ct scan. figures 3. a 6 x 5 cm bladder stone was extracted by open cystolithotomy. stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2142 case report idiopathic spontaneous perforation of the upper urinary tract. a presentation of 4 cases ioannis katafigiotis 1, ioannis adamakis 2, alexandra zormpala 3, christos pournaras 1, konstantinos stravodimos 2 1 resident in urology, university of athens medical school, athens, greece; 2 assistant professor in urology, university of athens medical school, athens, greece; 3 radiologist, radiology department, laikon general hospital, athens, greece. spontaneous perforation of the collecting system constitutes a rare entity masked by the presentation of a typical renal colic. however, it should not be forgotten when managing patients with colic, since missed diagnoses may carry significant morbidity. we herein present a series of spontaneous perforation of the collecting system without an apparent obstruction site evident in helical ct urography. four consecutive patients who presented with typical renal colic were initially subjected to kub and renal ultrasound imaging and were ultimately diagnosed with perforation of the collecting system via contrast enhancedhelical ct urography. despite thorough evaluation, the cause responsible obstructive was not discovered and an exclusion diagnosis of idiopathic collecting system perforation was assigned to all patients. due to the rarity of a spontaneous perforation traditional retrograde urography was performed in an effort to identify the possible cause but was also unrevealing. all patients were successfully treated with endourological means. perforation of the collecting system without an evident obstructive cause is a rare entity with obscure etiology. a reasonable but yet unconfirmed speculation is that of a transient obstruction capable of a significant increase of intraluminal pressures. key words: spontaneous ureter rupture; idiopathic upper urinary tract perforation. submitted 28 april 2014; accepted 31 may 2014 summary introduction spontaneous perforation of the collecting system is a rather rare disease entity with relevant reports dating back to the 60s. several latter reports presented a variety of cases each within an individual clinical setting. in fact, spontaneous perforation of the ureter has been encountered as a complication of cystectomy with orthotopic ileal neobladder formation (1) or lupus vasculitis (2). even though these reports have termed respective cases no conflict of interest declared of upper tract perforation as spontaneous, it is reasonable to assume that ureteral rupture with impaction of a ureteral calculus as the triggering event would represent the most common scenario. interestingly, certain cases with no obvious cause (excluding even calculus disease) have also been reported (3). helical computed tomography (ct) urography is currently considered the standard of practice in the evaluation of an episode of renal colic. delayed scans are already reported as the optimum for the diagnosis of traumatic ureteral rupture and respective urine leaks (4). even though no data have been published on their value in diagnosis of spontaneous upper tract rupture, it seems reasonable to apply the technique in this setting. after thorough evaluation with the above mentioned techniques in 4 cases of persistent renal colic with confirmed urinoma formation an obstructive cause was not revealed. therefore a diagnosis of spontaneous rupture of the upper tract was set and respective data and comments are herein presented. materials and methods during a 14 month period, from may 2011 to july 2012, 4 patients (2 male, 2 female, mean age 71.5 years, age range 67-79 years) presented with signs and symptoms of acute renal colic in 3 different urological departments (2 to an urban university referral centre-university of athens, athens, greece and 2 to rural county-affiliated hospitals). patients underwent the conventional diagnostic work-up routinely performed in such cases including blood and urine tests (urinalysis with urine culture, blood cell counts and biochemical panel). imaging studies all patients underwent renal ultrasonography and kidneys, ureters and bladder (kub) x-ray. in all patients abdominal helical ct urography was performed using a helical scanner from the level of the kidneys to the pubic symphysis, in breath-hold status, with a slice thickness of 5 mm and a pitch of i.5. intravenous non-ionic contrast was administered at a rate of 3 ml per second for a doi: 10.4081/aiua.2014.2.142 143archivio italiano di urologia e andrologia 2014; 86, 2 idiopathic perforation of the upper urinary total volume of 100-130 ml. the ct scans were obtained as part of a ct renal protocol that included nonenhanced imaging and imaging in both nephrographic and delayed excretory phases. delayed excretory phase scans of the urinary tract were acquired 10-15 minutes after the injection. in order to obtain a more accurate view of the urinary tract and increase the sensitivity of the work-up, retrograde urography was also used. the latter was used after the patient had undergone evaluation with delayed ct scan, so the conclusions based on ct imaging were minimally biased. results ultrasound findings raised the suspicion for urinary tract continuity disruption with perinephric fluid collection of mixed echogenic characteristics in all cases. delayed scans of helical ct-urography set the diagnosis of upper tract disruption in all four patients. contrast medium leakage in the periureteral and perirenal space was the main finding (figures 1, 2). retrograde pyelography (performed during stent insertion) confirmed the point of extravasation at the ureteropelvic junction in three patients and the upper third of the ureter in the remaining. an obvious obstructive cause was not demonstrated in either case. all patients were then managed by endourological approaches using a double j stent under fluoroscopic guidance. drainage of the urinoma was eventually required in one patient who developed septic complications rendering the case an absolute emergency. discussion and full list of references are posted in supplementary materials on www.aiua.it references 1. deliveliotis ch, chrisofos m, argyropoulos v, et al. spontaneous rupture of the ureter after cystectomy and creation of orthotopic ileal neobladder: treatment with percutaneous nephrostomy and drainage. j endourol. 2003; 17:33-5. 2. benson ch, pennebaker jb, harisdangkul v, songcharoen s. spontaneous ureteral rupture in a patient with systemic lupus erythematosus. south med j. 1983; 76:1053-5. 3. ertugrul a, yücel s, ilker y, akdas a. use of double j stent in a case of spontaneous ureteral extravasation of urine. arch esp urol. 2000; 53:491-3. correspondence ioannis katafigiotis, md (corresponding author) katafigiotis@yahoo.com christos pournaras, md christpourn@gmail.com ioannis adamakis, md yianton@hotmail.com konstantinos stravodimos, md kgstravod@yahoo.com alexandra zormpala, md azormpala@med.uoa.gr department of urology, athens university medical school laiko hospital, 17 agiou thoma str., 11527 athens, greece figures 1, 2. delayed excretory ct scans demonstrating contrast medium leakage in the perirenal and periureteral space compatible with urinary tract disruption. stesura seveso archivio italiano di urologia e andrologia 2013; 85, 4190 introduction prostatitis is a common urological disorder mainly affecting males 18-35 years of age, but also constitutes a frequent diagnosis in those aged over 65 primarily as a histological finding or in relation to benign prostatic hypertrophy symptoms (1-3). between 1990 and 1994, more than 2 million outpatient visits in the usa related to chronic prostatitis cases, whereas currently 15% of men who visit a doctor due to urinary tract symptoms are diagnosed with prostatitis (4). this particular disease has been characterized as a significant and developing clinical enigma given that its aetiopathogenesis remains to a great extent unclear. its presentation is related to an infective focus in the distant (mainly) prostatic glandular element and ducts involving gram-negative uropathogens and less frequently grampositive bacteria (5). it exhibits an array of symptoms, most notably pelvic pain (at various sites and of varying intensity), urinary symptoms (obstructive and irritative) original paper serenoa repens extract additionally to quinolones in the treatment of chronic bacterial prostatitis. the preliminary results of a long term observational study konstantinos stamatiou, nikolaos pierris urology department, tzaneio hospital, pireas, greece. introduction: chronic prostatitis displays a variety of symptoms (mainly local pain exhibiting variability in origin and intensity). the purpose of this article is to briefly present the preliminary results of our study examining the role of phytotherapeutic agents in the treatment of chronic prostatitis patients. materials and methods: the study included in total fifty-six consecutive patients who visited the outpatient department. subjects were randomized into two groups. subjects in the first group (28 patients) received prulifloxacin 600 mg for 15 days, while subjects in the second group (28 patients) received prulifloxacin 600 mg for 15 days and serenoa repens extract for 8 weeks. the response was tested using laboratory and clinical criteria. results: we found statistically significant differences between the two groups regarding pain regression and no statistically significant regarding bacterial eradication. moreover however while sexual dysfunction improvement was equally achieved in both groups, improvement of urinary symptoms was more evident in the 2nd group especially after the completion of the antibiotic treatment. conclusions: serenoa repens extract for 8 weeks seems to improve prostatitis related pain. further randomized, placebo-controlled studies are needed to substantiate safer conclusions. key words: chronic prostatitis, phytotherapeutics; quinolones; pain; serenoa repens. submitted 6 june 2013; accepted 20 june 2013 no conflict of interest declared summary as well as erectile and sexual dysfunction. similar symptoms are also encountered in benign prostatic hypertrophy and are attributed to both obstruction and secondary inflammation. the effectiveness of phytotherapeutic agents used for symptoms related to benign prostatic hypertrophy justifies their use in the treatment of chronic prostatitis (6). the best known phytotherapeutic is serenoa repens, a constituent of the acid-loving plant saw palmetto. it contains fatty acids, phytosterols and vitamins. its mechanism of action has not been fully elucidated, however is attributed to hormonally and non-hormonally mediated anti-inflammatory activity (6). the former is related to the inhibition of conversion of testosterone to the more potent antiandrogen dihydrotestosterone at the level of androgen receptors. this results in a reduction of the hormonal response of macrophages and leukocytes and the inhibition of their migration to the site of inflammation. as a consequence doi: 10.4081/aiua.2013.4.190 stamatiou_stesura seveso 20/12/13 11:04 pagina 190 191archivio italiano di urologia e andrologia 2013; 85, 4 serenoa repens extract additionally to quinolones in the treatment of chronic bacterial prostatitis there is a reduction in the release of myeloperoxidase which causes destruction of the inflamed tissue and of platelet-derived growth factor and growth factor-beta which induce inflammation. existing evidence regarding serenoa repens’ antiandrogenical antiproliferative and/or antiapoptotic action through inhibition of 5-alpha reductase is probably conflicting (7, 8). there is experimental proof of inhibition of signaling of growth factors such as igf-1 (insulin-like growth factor) as well as cytokines such as mcp-1/ccl2 (monocyte chemotactic protein1/chemokine cl2) a fact which interferes with inflammatory activity in human prostate epithelial cells (9, 10). the aim of the study is to assess the effectiveness of phytotherapeutics in the management of these symptoms. materials and methods the study was designed as a prospective randomized study and was conducted at “tzaneio” general hospital of piraeus. patients enrolled in the study had symptoms and signs of chronic prostatitis and visited the specialist clinic between 1 may 2011 and 30 may 2012. patients suffering from neurological disorders, those with anatomic abnormalities of the urinary tract and immunosuppressed patients were excluded from the study, as these are all conditions which can affect the clinical manifestation of the disease and could alter the outcome of the study. patients were randomized into two groups depending on the date of attendance (odd/even day of the month). patients in the first group (group a) received prulifloxacin 600 mg for 15 days and patients in the second group (group b) received prulifloxacin 600 mg for 15 days and an extract of serenoa repens for 8 weeks. urine specimens from all patients were collected before and after prostatic massage and were cultured while, depending on the medical history, urethral discharge or urethral swabs were also sent to the laboratory for examination in a number of patients. all patients filled in questionnaires relating to chronic prostatitis (nhi-cpsi), urinary symptoms (ipss) and sexual function (iief-5). initial evaluation (1st and 2nd follow up visit) was performed 15 days after the completion of antimicrobial therapy and during the course of treatment with serenoa repens microbial response was assessed by urine culture before and after prostatic massage and the response to symptoms by questionnaires nhi-cpsi, ipss, iief-5 at 4 weeks from the beginning of the study (1st follow up) and 8 weeks from the beginning of the study (2nd follow up). the final outcome was assessed 3-6 months later (3rd follow up visit). microbiological assessment: the stamey-meares test was deemed positive if: 1) bacteria were cultured in the prostatic secretion (eps) and the vb3 urine specimens (or ppm) and were not cultured in the vb1 and vb2 (or pm) specimens, 2) bacterial colony count in the vb3 specimen was 10 times that in the vb1 and vb2 specimens, 3) leukocyte numbers in the eps and vb3 were 10 times those in the vb1 and vb2. no lower cut-off value for the number of colonies was set. cultures for gonococcus, mycoplasma and ureaplasma and the semi-quantitative assessment were performed using biomerieux reagents. chlamydia trachomatis was detected using direct immu nofluorescence (kallestad anti-membrane lipopoly saccharide monoclonal antibodies). urine specimens were centrifuged and cultured in blood and macconkey agar for aerobic and anaerobic gram-positive and negative bacteria (biomerieux culture media). all processing and final assessment of samples in this study were performed by the same specialist microbiologist to whom the medical history of the patients was not disclosed. questionnaires: the chronic prostatitis nhi-cpsi questionnaire includes 9 questions in 3 sections (character-site of pain, urinary symptoms, effect on quality of life). the resultant sum ranges from 0 to 43 (character-site of pain: 0-21, urinary symptoms: 0-10 and quality of life: 0-12). the greater the resulting sum the greater the disturbance. however, questions with the highest scores affect the final result as they contribute more to the total sum of the nihcpsi. the ipss questionnaire includes 8 questions in 8 fields (incomplete bladder voiding, frequency, intermittency, urgency, poor urine flow, dribbling, nocturia and effect on quality of life) each question scoring 0-5 points. results from the first 7 questions are used to assess urination. a final score of less than 7 indicates mild disturbance, a score of 8-19 indicates moderate disturbance and a score of 20-35 severe disturbance. finally, the iief-5 questionnaire includes 5 questions each scoring 0-5 points. a sum score of 1-7 points suggests serious erectile dysfunction, a score of 8-11 moderate dysfunction, a score of 12-16 suggests moderate to mild dysfunction, a score of 17-21 indicates mild erectile dysfunction, whereas a score of 22-25 does not indicate erectile dysfunction. statistical analysis: analysis was performed using the spss 12 program and fisher’s exact test of significance was used. the accepted statistical significance cut-off value was 0.05 (p value < 0.05). differences between study groups n mean p value group 2 group 1 group 2 group 1 age (years) 28 28 41,9643 45,5714 ,223 prostatitis related history 28 28 ,4643 ,5714 ,415 baseline nih-cpsi score 28 28 26,96 26,64 ,843 baseline ipss score 27 28 10,6296 14,70 ,140 baseline iief score 28 28 20,57 19,4643 ,172 table 1. difference between groups 1 and 2 with regard to age, prostatitis related history and baseline questionnaire scores. stamatiou_stesura seveso 20/12/13 11:04 pagina 191 archivio italiano di urologia e andrologia 2013; 85, 4 k. stamatiou, n. pierris 192 age main symptom microorganism 28 haemospermia, suprapubic pain chlamydia trachomatis 53 dysuria, raised psa e. coli 42 perineal pain proteus 52 suprapubic, perineal pain, luts e. coli 36 scrotal pain cons 47 penile pain e. coli 52 suprapubic, scrotal pain e. coli 48 perineal pain proteus, cons 51 suprapubic, perineal pain, dysuria gonococcus 50 irritative luts chlamydia 49 febrile prostatitis, epididymitis proteus 39 perineal, testicular pain 4 types of gram + cocci 41 scrotal, penile pain e. coli 44 perineal pain e. coli 56 penile pain, erectile dysfunction e. coli 56 dysuria, irritative symptoms of urination 3 types of gram + cocci 35 perineal pain, raised psa cons 52 perineal pain, irritative luts e. coli 45 perineal pain, malaise e. coli 36 perineal, testicular pain e. coli 44 perineal pain e. coli 58 perineal, testicular pain cons 56 luts, haemospermia, suprapubic pain e. coli, proteus 43 testicular pain cons 37 scrotal, perineal pain, luts proteus 44 perineal, penile pain e. coli 44 suprapubic, scrotal pain klebsiella, staphylococcus 38 perineal pain, erectile dysfunction e. coli table 2. age, main symptoms and pathogens of patients of group 1 (prulifloxacin) at baseline. results in 16 of the 72 patients initially included in the study no pathogen was cultured and these patients were excluded from the study. the remaining 56 patients were equally assigned to the first group and the second group. the average age in the first group was 45.5 years and in the second group was 41.9 years. no statistically significant difference was noted between groups 1 and 2 with regard to mean age (table 1) and prior history of prostatitis (table 1) upon introduction into the study. the primary symptom for patients in both groups was pain, while urinary disturbances as a primary symptom were reported by 7 patients in group a and 6 in group b and erectile dysfunction as a primary symptom was reported by 2 patients in group a and 2 patients in group b (tables 2, 3). assessment of the questionnaires revealed moderate to severe urinary symptoms (obstructive or irritative) in more than 50% of patients in both groups (17 patients in the 1st group and 14 in the 2nd group) and erectile or sexual dysfunction in less than 30% of patients in both groups (9 patients in the 1st group and 7 patients in the 2nd group). no significant difference was noted between groups 1 and 2 with regard to individual questionnaire fields upon introduction into the study (table 1). 1st follow up visit: at the first follow-up 16/28 patients in the first group reported persistence of symptoms compared to 10/28 patients in the second group. four patients in group 1 and 3 patients in group 2 age main symptom microorganism 27 haemospermia, suprapubic pain 3 types of gram + cocci 62 luts, perineal pain, raised psa cons 34 penile, scrotal pain mycoplasma 58 scrotal pain e. coli 45 perineal, scrotal pain mycoplasma 35 suprapubic, perineal pain, dysuria unknown 47 febrile prostatitis e. coli 32 febrile prostatitis proteus 28 febrile prostatitis enterococcus 34 perineal pain e. coli 25 perineal pain, irritative luts e. coli 47 penile pain, erectile dysfunction enterococcus 32 scrotal pain streptococcus mitis oralis 61 perineal pain cons 25 irritative luts enterococcus 52 dysuria, irritative symptoms of urination e. coli, cons 49 suprapubic, perineal pain e. coli 38 haemospermia e. coli 48 testicular pain cons, staphylococcus aureus 31 perineal pain e. coli 21 scrotal, testicular pain enterococcus 27 penile, scrotal pain e. coli 56 suprapubic pain proteus 65 perineal pain, luts cons, enterococcus 37 suprapubic, perineal pain e. coli 61 penile, suprapubic pain, e. coli erectile dysfunction 64 haemospermia enterococcus 34 febrile prostatitis e. coli table 3. age, main symptoms and pathogens of patients of group 2 (prulifloxacin and serenoa repens) at baseline. stamatiou_stesura seveso 20/12/13 11:04 pagina 192 193archivio italiano di urologia e andrologia 2013; 85, 4 serenoa repens extract additionally to quinolones in the treatment of chronic bacterial prostatitis outcome (table 7). in contrast, symptoms questionnaire analysis revealed statistically significant differences between the two groups with regard to symptoms regression (table 7). 3rd follow up visit: at the third follow-up, 5/23 patients in the first group (5 patients did not attend) reported persistence of symptoms (3 of these patients were asymptomatic at the 2nd follow-up) whereas only 1/22 patients in the second group (6 patients did not attend) reported persistence of symptoms. only one patient from the 1st group had a positive culture (tables 4, 5). comparison of symptoms questionnaire results before and after treatment analysis revealed statistically significant differences between the two groups with regard to outcome while comparison of culture results not (table 8). notably, in most cases the microorganism grown was different to that of the initial culture. comparison of the ipss and iief-5 questionnaire scores revealed statistically significant differences with regard to improvement of urinary symptoms (p < 0.05) and no statistically significant differences with regard to erectile and sexual dysfunction (p > 0.05). 1st 2nd 3rd 1 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 2 symptomatic bacterial eradication asymptomatic bacterial eradication symptomatic bacterial eradication 3 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 4 symptomatic bacterial eradication symptomatic bacterial eradication asymptomatic bacterial eradication 5 asymptomatic bacterial eradication asymptomatic bacterial eradication did not attend 6 symptomatic bacterial eradication asymptomatic bacterial eradication symptomatic morganella 7 symptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 8 symptomatic proteus asymptomatic bacterial eradication asymptomatic bacterial eradication 9 symptomatic bacterial eradication asymptomatic bacterial eradication symptomatic bacterial eradication 10 symptomatic cons symptomatic bacterial eradication symptomatic bacterial eradication 11 symptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 12 symptomatic bacterial eradication symptomatic bacterial eradication asymptomatic bacterial eradication 13 asymptomatic bacterial eradication asymptomatic bacterial eradication did not attend 14 symptomatic proteus symptomatic enterococcus asymptomatic bacterial eradication 15 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 16 symptomatic bacterial eradication symptomatic bacterial eradication symptomatic bacterial eradication 17 symptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 18 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 19 asymptomatic bacterial eradication did not attend did not attend 20 symptomatic bacterial eradication symptomatic bacterial eradication asymptomatic bacterial eradication 21 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 22 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 23 symptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 24 asymptomatic bacterial eradication asymptomatic bacterial eradication did not attend 25 symptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 26 asymptomatic bacterial eradication symptomatic bacterial eradication asymptomatic bacterial eradication 27 symptomatic chlamydia asymptomatic bacterial eradication asymptomatic bacterial eradication 28 asymptomatic bacterial eradication did not attend did not attend table 4. outcome at follow-up in group 1. had positive cultures. bacterial eradication was achieved in 24 patients in group 1 and 25 patients in the second group (tables 4, 5). comparison of culture results before and after treatment as well as symptoms questionnaire analysis revealed not statistically significant differences between the two groups with regard to outcome (table 6). in contrast, symptoms questionnaire analysis revealed statistically significant differences between the two groups with regard to symptoms regression (table 6). 2nd follow up visit: at the second follow-up 7/26 patients in the first group and 1/25 in the second group (5 patients did not attend) reported persistence of symptoms. of note, two of these patients (one in each group) reported recurrence of the symptoms despite being asymptomatic at the first follow-up. since, only one patient from each group had a positive culture, bacterial eradication was achieved in 25/26 patients of the first group and 24/25 patients of the second group (tables 4, 5). comparison of culture results before and after treatment as well as symptoms questionnaire analysis revealed not statistically significant differences between the two groups with regard to stamatiou_stesura seveso 20/12/13 11:04 pagina 193 archivio italiano di urologia e andrologia 2013; 85, 4 k. stamatiou, n. pierris 194 1st 2nd 3rd 1 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 2 asymptomatic bacterial eradication asymptomatic bacterial eradication did not attend 3 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 4 symptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 5 asymptomatic bacterial eradication asymptomatic bacterial eradication symptomatic bacterial eradication 6 symptomatic proteus asymptomatic bacterial eradication asymptomatic bacterial eradication 7 asymptomatic cons asymptomatic cons asymptomatic bacterial eradication 8 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 9 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 10 asymptomatic bacterial eradication did not attend asymptomatic bacterial eradication 11 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 12 asymptomatic bacterial eradication asymptomatic bacterial eradication did not attend 13 symptomatic enterococcus symptomatic bacterial eradication asymptomatic bacterial eradication 14 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 15 symptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 16 asymptomatic bacterial eradication did not attend did not attend 17 symptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 18 symptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 19 asymptomatic bacterial eradication symptomatic bacterial eradication asymptomatic bacterial eradication 20 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 21 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 22 symptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 23 symptomatic bacterial eradication asymptomatic bacterial eradication did not attend 24 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 25 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 26 asymptomatic bacterial eradication did not attend asymptomatic bacterial eradication 27 symptomatic bacterial eradication asymptomatic bacterial eradication did not attend 28 symptomatic bacterial eradication asymptomatic bacterial eradication did not attend table 5. outcome at follow-up in group 2. n mean p value group 2 group 1 group 2 group 1 differences in symptom regression between group 1 and 2 28 28 ,64 ,46 ,022 differences in bacterial eradication between group 1 and 2 28 28 ,1429 ,1071 ,326 table 6. statistical evaluation of outcomes at 1st follow up. ranks n p value differences in symptom regression between group 1 and 2 negative ranks 5(a) ,025 positive ranks 0(b) ties 20(c) total 25 differences in bacterial eradication between group 1 and 2 negative ranks 0(a) ,317 positive ranks 1(b) ties 24(c) total 25 table 7. statistical evaluation of outcomes at 2nd follow up. stamatiou_stesura seveso 20/12/13 11:04 pagina 194 195archivio italiano di urologia e andrologia 2013; 85, 4 serenoa repens extract additionally to quinolones in the treatment of chronic bacterial prostatitis ranks n p value differences in symptom regression between group 1 and 2 negative ranks 4(a) ,046 positive ranks 0(b) ties 18(c) total 22 differences in bacterial eradication between group 1 and 2 negative ranks 1(a) ,317 positive ranks 0(b) ties 21(c) total 22 table 8. statistical evaluation of outcomes at 3rd follow up. discussion the most widely known phytotherapeutic is saw palmetto. its fruit are rich in fatty acids and phytosterols and its extract known as serenoa repens is prescribed in many countries (mainly in europe) under different brand names (permixin, prostamol uno, permixon etc). it has been the object of intense research into the treatment of symptoms of benign hypertrophy and (lately) of infections of the urinary tract, having been used as a sole agent, in combination with or in comparison to other phytotherapeutics, combined with antibiotics, with alpha-blockers, anti-inflammatory agents and 5-alpha reductase inhibitors. results are conflicting given that in these studies the outcomes measured as well as the materials and methods used differ. on the other hand, conditions such as chronic bacterial and chronic nonbacterial prostatitis and prostatic hypertrophy overlap, many of the symptoms are common, while conditions and diseases of organs other than the prostate can contribute towards the presentation or deterioration of these symptoms. a prospective multi-centre double-blind randomized trial by debruyne et al. compared tamsulosin (0.4 mg/24 h) to permixon (320 mg/24 h) in a substantial number of patients (542) suffering from symptomatic prostatic hypertrophy (ipss ! 10). after 12 months of follow-up no differences in ipss were noted (average reduction of 4.4 in each group, with a respective improvement in both irritative and obstructive symptoms) and the improvement in qmax (1.8 ml/s permixon vs. 1.9 ml/s tamsulosin) and psa fluctuations were similar in both groups. by contrast, a small reduction in prostate size was noted in the permixon group. both treatments were well tolerated (11). a multicenter trial by the italian society of oncological urology studied the effectiveness of serenoa repens in patients with chronic non-bacterial prostatitis comparing it to a combination of serenoa repens and alpha-blocker. after a 6 month follow-up, similar changes in the uroflowmetry parameters of both groups were found and no changes were noted in the iief-5 sexual function questionnaire (a fact which may be related to both the lack of antiandrogen activity as well as reduced effectiveness in erectile dysfunction). a notable improvement in findings relating to inflammation was reported (on digital rectal examination, ultrasound and prostate biopsy) (12). aliaev et al. retrospectively studied the effectiveness of prostamol uno (320 mg/24 h) as complementary treatment in the prevention of relapses of chronic bacterial prostatitis. after 5 years the improvement in both subjective (ipss) and objective (reduction in percentage of relapse and progression, improvement in sexual function) measures of the study was greater with the addition of prostamol uno to the standard therapy consisting of anti-inflammatory and antimicrobial agents (13). similar results are reported by reissigl et al. with permixin used for chronic pelvic pain syndrome, while the safety profile noted was equivalent to studies mentioned above (14). in addition to the findings of the above mentioned studies, we demonstrated the early onset of the effect of serenoa repens on symptoms regression as well as the maintenance of this effect during the study period. of note, barry et al. researched any potential clinical benefit in increasing the dose administered to patients with lower urinary tract symptoms. according to their results a gradual increase in the dose administered (3 times the standard dose in 16 months) does not reduce urinary symptoms more than placebo. interestingly, no negative effects were observed which could distinctly be attributed to serenoa repens (15). on the other hand, kaplan et al. in a prospective study comparing the extract of saw palmetto against finasteride found no appreciable long term improvement (at 1 year follow-up) in type iii prostatitis symptoms (16), while pavone et al. noted a greater reduction in pain and irritative symptoms (albeit with no changes in flow rate and prostate volume) using combinations of phytotherapeutic agents (serenoa repens, urtica dioica and pinus pinaster) (17). based on the above we expect the effectiveness of serenoa repens in an array of symptoms related to prostatitis to depend on the type of prostatitis, the presence of prostatic hypertrophy, any preexisting obstruction, coadministered treatments and the duration of treatment. this hypothesis explains the differences between the present study and what has been discussed above. however, the small number of patients included in the above mentioned studies as well as differences in methodology and outcomes render the drawing of conclusions problematic. conclusions serenoa repens extract is effective in the treatment of pain symptoms in chronic bacterial prostatitis. an adminisstamatiou_stesura seveso 20/12/13 11:04 pagina 195 archivio italiano di urologia e andrologia 2013; 85, 4 k. stamatiou, n. pierris 196 activated protein kinase/c-jun n-terminal kinase phosphorylation in human prostate epithelial cells. endocrinology 2004; 145:3205-3214 10. latil a, libon c, templier m, et al. hexanic lipidosterolic extract of serenoa repens inhibits the expression of two key inflammatory mediators, mcp-1/ccl2 and vcam-1, in vitro. bju int. 2012; 110:e301-7. 11. debruyne f, koch g, boyle p, et al. (groupe d'étude permal). comparison of a phytotherapeutic agent (permixon) with an alphablocker (tamsulosin) in the treatment of benign prostatic hyperplasia: a 1-year randomized international study. prog urol. 2002; 12:384-92. 12. bertaccini a, giampaoli m, cividini r, et al. observational database serenoa repens (dosser): overview, analysis and results. a multicentric siuro (italian society of oncological urology) project. arch ital urol androl. 2012; 84:117-22. 13. aliaev iug, vinarov az, et al. treatment of chronic prostatitis in prophylaxis of prostatic adenoma. urologiia. 2012; 39-40, 42-3. 14. reissigl a, djavan b, pointner j. prospective placebo-controlled multicenter trial on safety and efficacy of phytotherapy in the treatment of chronic prostatitis/chronic pelvic pain syndrome. program and abstracts of the american urological association 2004 annual meeting; may 8-13, 2004; san francisco, ca. abstract 233. 15. barry mj, meleth s, lee jy, et al. (complementary and alternative medicine for urological symptoms study group). effect of increasing doses of saw palmetto extract on lower urinary tract symptoms: a randomized trial. jama. 2011; 306:1344-51. 16. kaplan sa, volpe ma, te ae. a prospective, 1-year trial using saw palmetto versus finasteride in the treatment of category iii prostatitis/chronic pelvic pain syndrome. j urol. 2004; 171:284-8. 17. pavone c, abbadessa d, tarantino ml, et al. associating serenoa repens, urtica dioica and pinus pinaster. safety and efficacy in the treatment of lower urinary tract symptoms. prospective study on 320 patients. urologia. 2010; 77:43-51. tration period of 8 weeks appears to improve the effect of antibacterial therapy on pain while a longer duration of administration possibly alleviates the remaining symptoms. more randomized placebo-controlled studies are required to substantiate safer conclusions. references 1. cheah py, liong ml, yuen kh, et al. chronic prostatitis: symptom survey with follow-up clinical evaluation. urology. 2003; 61:60-64. 2. nickel jc, elhilali m, vallancien g. alf-one study group. benign prostatic hyperplasia (bph) and prostatitis: prevalence of painful ejaculation in men with clinical bph. bju int. 2005; 95:571-574. 3. de la rosette jj, hubregtse mr, karthaus hf, debruyne fm. results of a questionnaire among dutch urologists and general practitioners concerning diagnostics and treatment of patients with prostatitis syndromes. eur urol. 1992; 22:14-19. 4. collins mm, stafford rs, o'leary mp, barry mj. how common is prostatitis? a national survey of physician visits. j urol. 1998; 159:1224-1228. 5. nickel jc, moon t. chronic bacterial prostatitis: an evolving clinical enigma. urology. 2005; 66:2-8. 6. levin rm, das ak. a scientific basis for the therapeutic effects of pygeum africanum and serenoa repens. urol res. 2000; 28:201-9. 7. hill b, kyprianou n. effect of permixon on human prostate cell growth: lack of apoptotic action. prostate. 2004; 61:73-80. 8. marks ls, hess dl, dorey fj, et al. tissue effects of saw palmetto and finasteride: use of biopsy cores for in situ quantification of prostatic androgens. urology. 2001; 57:999-1005. 9. wadsworth t, carroll j, mallinson r, et al. saw palmetto extract suppresses insulin-like growth factor-i signaling and induces stresscorrespondence konstantinos stamatiou, md (corresponding author) urology department, tzaneio hospital, pireas, greece stamatiouk@gmail.com nikolaos pierris, md urology department, tzaneio hospital, pireas, greece stamatiou_stesura seveso 20/12/13 11:04 pagina 196 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 3208 review chronic inflammation of the prostate type iv with respect to risk of prostate cancer antonio b. porcaro 1, emanuele rubilotta 1, aldo petrozziello 2, claudio ghimenton 3, filippo migliorini 1, stefano zecchini antoniolli 1, vincenzo lacola 1, carmelo monaco 1, pierpaolo curti 1, stefano cavalleri 1, romeo pianon 1, walter artibani 1 1 urologic clinic, 2 geriatric medicine/endocrinology, 3 pathology, university hospitals, ospedale policlinico and ospedale civile maggiore, azienda ospedaliera universitaria integrata, verona, italy. background: chronic inflammatory infiltrate (cii) might be involved in prostate cancer (pca) and benign hyperplasia (bph); however, its significance is controversial. chronic inflammatory prostatitis type iv is the most common non cancer diagnosis in men undergoing biopsy because of suspected pca. objective: to evaluate potential associations of coexistent cii and pca in biopsy specimens after prostate assessment. design, setting, and participants: between january 2007 and december 2008, 415 consecutive patients who underwent prostate biopsy were retrospectively evaluated. the investigated variables included age (years) and psa (ug/l); moreover, cii+, glandular atrophy (ga+), glandular hyperplasia (gh+), prostate intraepithelial neoplasm (pin+), atypical small acinar cell proliferation (asap+) and pca positive cores (p+) were evaluated as categorical and continuous (proportion of positive cores). outcome measurements and statistical analysis: associations of cii+ and pca risk were assessed by statistical methods. results and limitations: in the patient population, a biopsy core positive for pca was detected in 34.2% of cases and the rate of high grade pca (hgpca: bgs ! 8) resulted 4.82%. cii+ significantly and inversely associated with a positive biopsy core p+ (p < 0.0001; or = 0.26) and hgpca (p = 0.0005; or = 0.05). moreover, the associations indicated that patients with coexistent cii+ on needle biopsy were 74% less likely to have coexistent pca than men without cii+ as well as 95% less likely to have hgpca in the biopsy core than men without coexistent cii+. there were limits in our study which was single centre and included only one dedicated pathologist. conclusions: there was an inverse association of chronic inflammation of the prostate type iv and risk of pca; moreover, hgpca was less likely to be detected in cancers associated with coexistent cii. in prostate microenvironment, prostate chronic inflammation may be protective; however, its role in pca carcinogenesis remains controversial and needs further research. key words: prostate; prostate cancer; prostate-specific antigen; prostate biopsy; chronic inflammation; biopsy gleason score. submitted 23 december 2014; accepted 31 march 2014 summary no conflict of interest declared. introduction chronic inflammation plays an important role in human carcinogenesis (1, 2). development and progression of cancer might be related to reactive oxygen and nitrogen species developing in tissue microenvironment after related damage and regeneration. prostate cancer (pca) carcinogenesis has also been related to chronic inflammation. presence of chronic inflammatory infiltrate (cii) has been detected in pca specimen from prostatectomies, transurethral resection of the prostate (turp) and transrectal ultrasound (trus) biopsies (3, 4). literature investigations suggest that cii might be involved in chronic diseases of the prostate including pca and benign prostatic hyperplasia (bph) (5). the prostatitis syndromes have been classified in four categories by the national institutes of health (nih) (6). the last category, named type iv, has been coded as asymptomatic inflammatory prostatitis which is diagnosed in patients who have no history of genitourinary tract pain complaints, but undergo prostate biopsy for evaluation of possible pca because of elevated serum prostate-specific antigen (psa) level. as a result, chronic prostatitis is the most common non cancer diagnosis, based on histological criteria, in these men. since the significance of cii in prostate specimens with and without cancer is still unclear and controversial, we evaluated the association, if any, of coexistent cii and pca in patients undergoing trus biopsies after prostate assessment. material and methods between january 2007 and december 2008, we retrospectively evaluated 475 men referred to our institute for prostatic biopsy because of increased serum psa and/or abnormal digital rectal exam (dre). psa was measured by immuno-radiometric test (2-4 ug/ml) and abnormal dre findings were as follows: diffusely hard prostate, discrete firm area, irregular contours or prominent lobe asymmetry. patients with dre findings associated with painful prostate were excluded. the 14-core trus guided prostate biopsy technique was routinely performed and additional cores were taken with a lesion on either trus or dre was evident. for each biopsy core, the dedicated pathologist systematically assessed the following issues: doi: 10.4081/aiua.2014.3.208 porcaro abbr_stesura seveso 08/10/14 12:13 pagina 208 209archivio italiano di urologia e andrologia 2014; 86, 3 chronic inflammation of the prostate type iv with respect to risk of prostate cancer (i) pca and its grade according to the gleason score system (biopsy gleason score: bgs); (ii) prostatic intraepithelial neoplasia (pin); (iii) chronic inflammatory infiltrate (cii); (iv) glandular atrophy (ga); (v) atypical small acinar cell proliferation (asap); (vi) glandular hyperplasia (gh). atypical adenomatous hyperplasia (aah), since not systematically assessed, was not included in the present analysis. chronic inflammation criteria included the following findings: (i) inflammatory cell infiltrate within the stroma of the prostate; (ii) inflammatory cell infiltrate composed predominantly of lymphocytes with admixed plasma cells; (iii) peri-glandular distribution of the inflammatory cell infiltrate. criteria excluding a diagnosis of chronic inflammation of the prostate type iv were as follows: (i) sheets of neutrophils around and within the glands; (ii) granulomatous prostatitis. a diagnosis of chronic inflammation of the prostate type iv (6) was carried out after excluding other types of inflammation. statistical analyses the variables were evaluated as both categorical and continuous; moreover, the histological ones were coded as proportion of the number of positive cores and were labelled as cii+, ga+, gh+, pin+, asap+ and p+, respectively. summary statistics of population, subpopulations (with or without pca) and relative groups was computed. student t-tests were used to compare subpopulations and relative groups. in populations and subpopulation of patients, !2 tests were used to evaluate associations of cii+ with age at the first quartile (q1), psa at q1, ga+, gh+, asap+, pin+, p+, bgs ! 8 and dre. moreover, to evaluate the strength of associations, the odds ratio (or) and relative 95% confidence interval (95%ci) were also computed. cii+ independent associations with age, psa, ga+, gh+, asap+, pin+, p+ and dre (1 = abnormal, 0 = normal) were evaluated by multivariate regression analysis in the population and subpopulations of patients. because of the high level of correlation between cii+ and ga+ (correlation coefficient = 0.49, p < 0.0001), the multivariate independent associations of bgs were separately evaluated for cii+ and ga+. all tests were two-sided, with a significance level of 0.05. results after removing cases with incomplete data or excluding criteria, 415 of the 475 cases were able to be evaluated. overall clinical characteristics of population and subpopulations with relative groups are reported in table 1. compared with cases without pca, the pca subpopulation was significantly older at diagnosis (69.23 years vs. 66,56; p < 0.0007); less likely to have larger cii+ (0.06 vs. 0.38, p < 0.0001), ga+ (0.16 vs. 0.50, p < 0.0001) and gh+ (0.01 vs. 0.10, p = 0.0002); but more likely to have higher psa serum levels (29,6 ng/ml vs. 13,69, p = 0.02) and higher pin+ (0.07 vs. 0.03, p = 0.001). in the subpopulation without pca, the group without cii+ was less likely to have larger ga+ (0.44 vs. 0.58, p = 0.001), but more likely to have larger proportion of gh+ (0.14 vs. 0.07; p = 0.06). however, in the pca subpopulation, the cii+ group was significantly older (72.6 years vs. 68.10; p = 0.003), more likely to have larger proportion of ga+ (0.33 vs. 0.11; p = 0.0003), but less likely to have greater psa values (11.2 vs. 36.10 ug/l; p = 0.04) as well larger proportions of p+ (0.25 vs. 0.42; p < 0.0001). the group with bgs " 6, showed lower proportions of p+ than bgs = 7 (0.25 vs. 0.48; p < 0.0001) and bgs ! 8 (0.25 vs. 0.65; p < 0.0001) as well as of asap+ than bgs ! 8 (0.01 vs. 0.00; p = 0.01); interestingly, the bgs " 6 group was more likely to have increased proportions of cii+ than bgs = 7 (0.17 vs. 0.07; p = 0.02) and bgs ! 8 (0.17 vs. 0.005; p < 0.0001); moreover, significantly increased ga+ proportions were detected in the bgs " 6 group than bgs ! 8 (0.22 vs. 0.03; p < 0.0001). the group with bgs ! 8 was more likely to be detected with increased proportions of p+ than the bgs = 7 group (0.65 vs. 0.48; p = 0.04), but less likely to have increased proportions of cii+ (0.005 vs. 0.07; p = 0.008) and ga+ (0.03 vs. 0.14; p = 0.01) than the bgs = 7 group. table 2 and figure 1 show the associations of cii+ with the investigated variables in population and subpopulations of patients. cii+ was detected at a rate of 45.06% in the population, 26.65% in the subpopulation with pca and 44.32% in the subset without pca. age " q1 resulted 61.67 years in population, 64.37 in the pc subpopulation and 60.93 in the subset without pca. cii+ inversely associated with age in the pca subpopulation (p < 0.0001; or = 0.40). total psa serum levels " q1 were 4.99 ng/ml in the population, 4.71 in the pca subpopulation and 5.14 the other subset. cii+ inversely associated with psa " q1 in the population (p = 0.002; or = 0.47) and subpopulation without pca (p = 0.005; or = 0.44). ga+ was detected at a rate of 58.3% in the population, 38.7% in the pca subpopulation and 68.5 in the other subset. cii+ directly associated with ga+ in the population (p < 0.0001; or = 5.14), pca subpopulation (p < 0.0001; or = 5.34) and subset without pca (p < 0.0001; or = 3.77). a biopsy core positive for pca was detected in 34.2% of the population. cii+ inversely associated with a positive biopsy core p+ (p < 0.0001; or = 0.26). in the pca subpopulation, cii+ inversely (p = 0.0004; or = 0.28) associated with a proportion of positive cores larger than the median (p+ > 0.33). the rate of high grade pca (hgpca: bgs ! 8) resulted 4.82% in the population and 14.08% in the pca subpopulation. cii+ inversely associated with hgpca in both population (p = 0.0005; or = 0.05) and subpopulation (p = 0.05; or = 0.13). an abnormal dre was detected in 30.84% of the patient population and inversely associated with cii+ (p = 0,01); however, the association was weak (or = 0.58) and was not confirmed in the two subpopulations. the independent and multivariate associations of cii+ and bgs are reported in table 3. in the population of patients, cii+ associated with ga+ (p < 0.0001), gh+ (p = 0.02) and bgs (p = 0.05); moreover, the association was positively related to ga+ (regression coefficient, b = 0.38), but negatively related to gh (b = -0.16) and bgs (b = -0.01). in the analysis excluding ga+, bgs positively associated with p+ (p < 0.0001; b = 9.85); pin+ (p = 0.0004; b = 2.67) and age (p = 0.02; b = 0.02), but inversely with cii+ (p = 0.003; b = -0.68). in the analysis excluding cii+, bgs directly associated with p+ (p < 0.0001; b = 9.77), pin+ (p = 0.007; b = 2.58) and porcaro abbr_stesura seveso 08/10/14 12:13 pagina 209 archivio italiano di urologia e andrologia 2014; 86, 3 porcaro, rubilotta, petrozziello, ghimenton, migliorini, zecchini antoniolli, lacola, monaco, curti, cavalleri, pianon, artibani 210 age (p = 0.02; b = 0.02), but inversely with ag+ (p< 0.002; b = -0.68). in the pca subpopulation, cii+ directly associated with ga+ (p = 0.001; b = 0.30), but inversely with bgs (p = 0.05; b = -0.03). in the analysis excluding ga+, bgs directly associated with p+ (p < 0.0001; b = 2.007), psa (p = 0.04; b = 0.001), but inversely with cii+ (p = 0.03; b= -0.82). in the analysis excluding cii+, bgs directly associated with p+ (p < 0.0001; b = 2.06) and psa (p = 0.05; b = 0.001); however, there was no association with ga+ (p = 0.31; b = 0.36). in the subpopulation without pca, cii+ directly associated with ga+ (p < 0.0001; b = 0.39), but inversely with gh+ (p = 0.02; b = -0.18). in the analysis excluding ga+, cii+ inversely associated with gh+ (p = 0.01; b = -0.23) and pin+ (p = 0.05; b = -0.56). in the analysis excluding cii+, ga+ inversely associated only with pin+ (p = 0.03; b = -0.63). tables and figure 1 are posted in supplementary materials on www.aiua.it discussion our findings showed that, in a patient population undergoing prostate biopsy, chronic inflammation was independently and inversely associated with pca. cii+ in men with positive biopsy cores was detected less frequently (8.43%) than in those without (25.78%); moreover, the or of pca in men with chronic inflammation was 0.26. these findings suggest that, on biopsy cores, the presence of cii+ decrease the probability of detecting pca by 76%. we stress out that these findings indicate only an inverse independent association of cii+ with pca; moreover, the relation does not necessary mean causation. the result of our investigation concord with previous studies discovering an evident inverse association between chronic inflammation and pca (4, 7-9). as a result, cii+ might protect from the different steps involving genesis of cancer. the relation between chronic inflammation and pca was further investigated by our study which showed that, in the population, cii+ independently and inversely associated with hgpca. as a result, cii+ in biopsy cores with hgpca was found less frequently (0.2%) than men without (4.8%); moreover, the or of hgpca was 0.05. these results suggest that, on biopsy needle cores, the presence of cii+ decreases the probability of hgpca by 95%. similar findings were detected in the pca subpopulation. indeed, cii+ in positive biopsy cores with hgpca was found less frequently (0.7%) than in those without chronic inflammation (14.1%). the or of hgpca in cii+ was 0.13 which means that, in men with needle core biopsies positive for pca, the probability of detecting hgpca was decreased by 87%; moreover, cii+ was more common in needle biopsy cores with low intermediate grade cancers (23.9%) than in those with hgpca (0.70%). these findings agree with the results of zhang et al. who showed that chronic inflammation was more common in radical prostatectomy specimens with low grade tumours than in those with hgpca (10). once again; the protective association of cii+ should not be considered as causation; however, these findings suggest the chronic inflammation might protect from pca progressing from low to high grade disease. our data also showed that, in the pca subpopulation, chronic inflammation was inversely and independently associated with a larger volume of percentage of positive biopsy cores. indeed, a cii+ was detected less frequently (6.3%) in men with p+ > 0.33 than in patients without coexistent cii (41.6%). the or of pca with p+> 0.33 in men with cii+ was 0.28. this finding indicated that, on positive biopsy cores, the coexistence of chronic inflammation reduces the chance of having a proportion of p+ > 0.33 by 72%. once again these findings, although not meaning causation, confirmed that there is inverse association between cii+ and pca (4, 7-10). the subject dealing with pca associated with chronic inflammation has also been approached by other investigators, who, however, failed to detect any association (1113). our investigation is a single centre study including a large number of patients collected consecutively in an appropriate time of interval (24 months); also, biopsy specimens have been evaluated by a dedicated pathologist, who routinely reports the presence or absence of cii+ in each biopsy core. moreover, our investigation, although consistent with other reports (4, 7-10), clearly shows that the coexistence of cii+ in needle biopsy specimens reduces the risk of aggressive prostate cancer. this issue might have important drawbacks when approaching treatment options for pca cancer such as active surveillance. it has been postulated that the exposure to non-steroidal anti-inflammatory drugs (nsaid) reduces the risk of cancer-genesis (14, 15). however, observational studies has shown that the pca risk is increased after nsaid exposure (16, 17). moreover, cancer susceptibility and severity may be associated with functional polymorphisms of inflammatory cytokine genes, and deletion or inhibition of inflammatory cytokines inhibits the development of experimental cancer (18). our study outlines the predictive role of chronic inflammation in pca biology; it also supports the non appropriate role of nsaid exposure in prostate cancer genesis. our results indicated that, in a subpopulation without pca, chronic inflammation inversely associated with psa " q1 (5.14 ug/l) which means that psa serum levels " q1 were detected less frequently (10.3%) in patients with coexistent cii+ in the biopsy specimen than in those without (25.3%). the or of 0.44 indicates that the presence of cii+ in the specimens decreases the probability of detecting psa serum levels " q1 by 56%. these results agree with other investigations showing that chronic inflammation associates with elevated psa serum levels (19-21). moreover, it has recently been reported that baseline prostate inflammation is associated with a reduced risk of pca in men undergoing repeat prostate biopsy (22). as a theory, cii+ associates with increased psa serum levels when there is contact and disruption of the glandular epithelium of the prostate. there are limits in our study which was single centre and including only one dedicated pathologist. ga+ was not porcaro abbr_stesura seveso 08/10/14 12:13 pagina 210 211archivio italiano di urologia e andrologia 2014; 86, 3 chronic inflammation of the prostate type iv with respect to risk of prostate cancer characterized according to the atrophy classification, proposed in 2006 by the working group for histology classification of prostate atrophy lesions which include simple atrophy, simple atrophy with cist formation, post atrophic hyperplasia and partial atrophy (23). the classification of low and high grade pin was also not computed. another limit of the present study may be related to the missed measurement of prostate volume with negative drawbacks on sampling procedures. indeed biopsy procedures might not sample appropriately the large prostates with respect the smaller ones. finally, patients with inflammation may undergo to biopsy procedures more frequently than men without inflammation because of potential higher psa levels. conclusions there is an inverse negative association of chronic inflammation of the prostate type iv and risk of pca. chronic inflammation of the prostate type iv is less frequently detected in prostates with cancer. moreover, hgpca is less likely to be detected in cancers associated with coexistent cii. as a consequence, chronic inflammation of the prostate type iv might have important drawbacks for approaching and managing prostate diseases. moreover, chronic inflammation in prostate microenvironment might be protective; however, the role of chronic inflammation in pca carcinogenesis remains a controversial issue which needs further clinical and basic research. references 1. coussens lm, werb z. inflammation and cancer. nature. 2002; 420:860-67. 2. mantovani a, allavena p, sica a, balkwill f. cancer related inflammation. nature. 2008; 464:436-44. 3. welson wg, de marzo am, isaacs wb. prostate cancer. n engl j med. 2003; 349:366-81. 4. blumenfeld w, tucci s, marayan p. incidental lymphocytic prostatitis. selective involvement with non malignant glands. am j surg pathol. 1992; 16:975-81. 5. de nunzio c, kramer g, marberger m, et al. the controversial relationship between benign prostatic hyperplasia and prostate cancer: the role of inflammation. eur urol. 2011; 60:106-17. 6. krieger jn, nyberg l jr, nickel jc. nih consensus definition and classification of prostatitis. jama. 1999; 282:263-67. 7. gerstenbluth re, seftel ad, maclennan gt, et al. distribution of chronic prostatitis in radical prostatectomy specimens with up-regulation of bcl-2 in areas of inflammation. j urol. 2002; 167:2267-70. 8. irani j, goujon jm, ragni et al. high-grade inflammation in prostate as a prognostic factor for biochemical recurrence after radical prostatectomy. pathologist multi center study group. urology. 1999; 54:467-72. 9. karakiewicz pi, benayoun s, begin lr, et al. chronic inflammation is negatively associated with prostate cancer and high-grade prostatic intraepithelial neoplasia on needle biopsy. int j clin pract. 2007; 61:425-430. 10. zhang w, sesterhenn ia, connelly rr, et al. inflammatory infiltrate (prostatitis) in whole mounted radical prostatectomy specimens from black and white patients is not an etiology for radical difference in prostate specific antigen. j urol. 2000; 163:131-36. 11. roberts ro, bergstralh ej, bass se, et al. prostatitis as a risk factor for prostate cancer. epidemiology. 2004; 15:93-99. 12. davidsson s, fiorentino m, andren o, et al. inflammation, focal atrophic lesions, and prostatic intraepithelial neoplasia with respect to risk of lethal prostate cancer. cancer epidemiol biomarkers prev. 2010; 20:2280-87. 13. engelhardt pf, brustmann h, seklehner s, riedl cr. chronic asymptomatic inflammation of the prostate type iv and carcinoma of the prostate: is there a correlation? scand j urol. 2013; 47:230-5. 14. thun mj, henley sj, patrono c. nonsteroidal anti-inflammatory drugs as anticancers agents: mechanistic, pharmacologic, and clinical issues. j natl cancer inst 2002; 94:252-66. 15. gridley g, mclaughlin jk, ekbom a et al. incidence of cancer among patients with rheumatoid arthritis. j nat. cancer inst. 1993; 85:307-11. 16. langman mj, cheng kk, gilman ea, lancashire rj. effect antiinflammatory drugs on overall risk of common cancer: case-control study in general practice research data base. bmj. 2000; 320:1462-66. 17. neugut ai, rosenberg dj, ahsan h, et al. association between coronary heart disease and cancer of the breast, prostate and colon. cancer epidemiol biomarkers prev. 1998; 7:869-73. 18. balkwill f, mantovani a. inflammation and cancer: back to virchow? the lancet. 2001; 357:539-45. 19. hoekx l, jeuris w, van marck e, wyndaele jj. elevated serum prostate specific antigen (psa) related to asymptomatic prostatic inflammation. acta urol bel. 1998;66:1-2. 20. sindhwani p, wilson cm. prostatis and serum prostate-specific antigen. curr urol rep. 2005; 6:306-12. (21) hochreiter ww. the issue of elevated prostate cancer evaluation in men with elevated prostate-specific antigen and chronic prostatitis. andrologia 2008; 40: 130-33. 12. moreira dm, nickel jc, gerber l, et al. baseline prostate inflammation is associated with a reduced risk of prostate cancer in men undergoing repeat prostate biopsy. cancer. 00, 2013. 23. de marzo am, platz ea, epstein ji, et al. a working group classification of focal prostate atrophy lesions. am j surg pathol. 2006; 30:1281-91. correspondence antonio benito porcaro, md drporcaro@yahoo.com filippo migliorini, md stefano zecchini antoniolli, md vincenzo lacola, md carmelo monaco, md pierpaolo curti, md stefano cavalleri, md romeo pianon, md walter artibani, md, professor azienda ospedaliera universitaria integrata verona, dipartimento ad attività integrata di chirurgia ed oncologia, pancreas center, divisione clinicizzata di urologia, policlinico gb rossi p.le la scuro, 10 37134 verona, italy emanuele rubilotta, md aldo petrozziello, md dpt. geriatric medicine/endocrinology, azienda ospedaliera universitaria integrata, ospedale policlinico and ospedale civile maggiore, verona, italy claudio ghimenton, md dpt. pathology, azienda ospedaliera universitaria integrata ospedale policlinico and ospedale civile maggiore, verona, italy porcaro abbr_stesura seveso 08/10/14 12:13 pagina 211 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2150 case report mixed primary prostatic carcinoma with acinar, neuroendocrine and ductal components alfredo e. romero-rojas 1, julio a. diaz-perez 1, 2, 3, abhinay reddy 2 1 national institute of cancer, bogotá, colombia; 2 university of california san diego, la jolla, ca, usa; 3 university of santander, bucaramanga, colombia. mixed tumors in the prostate gland have been described; they are primarily originate in the gland or are the product of metastatic compromise. mixed primary epithelial carcinomas of the prostate are very rare; here we report the case of a 72-years-old man with histopathologic findings of a primary prostate mixed carcinoma, showing characteristics of acinar, ductal and neuroendocrine adenocarcinoma. we also discuss the clinical, diagnostic, and therapeutic aspects of these uncommon mixed neoplasms. key words: prostatic carcinoma; neuroendocrine carcinoma; ductal carcinoma; acinar adenocarcinoma; mixed tumor. submitted 15 march 2014; accepted 31 may 2014 summary case report here we report the case of a 72-year-old man with histopathologic findings of primary prostate mixed carcinoma, showing characteristics of acinar, ductal and neuroendocrine adenocarcinoma. we also discuss the clinical, diagnostic, and therapeutic aspects of these uncommon mixed tumors. case report and figures are posted in suppementary materials on www.aiua.it discussion mixed prostatic carcinomas are rare; they demonstrate a combination of malignant epithelial or sarcomatoid components (1, 4). the epithelial variant of these carcinomas is often a high-grade acine adenocarcinoma mixed with squamous, urothelial, neuroendocrine, ductal, mucinous (colloid), signet ring, oncocytic, basal cell, and lymphoepithelioma-like components (4). the origin and utility of identification of these mixed carcinomas has been highly controversial; they have been thought by some authors to be derived from a single cell of origin, and are the product of one or multiple types of differentiation or no conflict of interest declared metaplastic changes, rather than representing a combination of separate epithelial neoplasms. however the hypothesis of neoplasm collision has been formulated, in which these neoplasms develop independently in the prostate (14, 15) formed by heterologous elements with lack of morphological and immunophenotipical connection. in our case we found a similar immunophenotypical pattern that is in accordance with the first hypothesis that is also supported by previous studies with analysis of loss-of-heterozygosity (14-16). also multiple authors and classifications refer to these mixed tumors as descriptive variants with no known prognostic significance other than that of acinar adenocarcinoma (2, 7, 9), but it is currently known that these tumors are aggressive neoplasms with an associated poor prognosis (7), and an actual risk of death of 20% within one year of diagnosis. clinically, most patients are older (range 50-89) and present with urinary tract obstruction and symptoms of frequency, urgency, and nocturia (4), similar to our case. other secondary symptoms including bilateral flank pain, microscopic hematuria, and renal insufficiency are also reported (7). serum pap and psa can be normal or elevated (4, 7, 12). in about half of the cases, the initial biopsy diagnosis is an acinar (conventional) adenocarcinoma, followed by hormonal and/or radiation therapy, with a subsequent diagnosis of the mixed component in the histopathologic analysis of the surgical specimen (13). the histopathological analysis conducted with hematoxilin and eosin and is the key to allow for a correct diagnosis and evade diagnostic pitfalls in these tumors. microscopically, the morphology is highly variable and is challenging for the pathologist; metastatic tumors from other sites need to be considered in the differential diagnosis (16, 17). the most common primary sites of tumors to be considered and excluded in the differential diagnosis include carcinomas from the bladder and colon (17). clinical exams by cystoscopy, colonoscopy, chest and abdominal tomography, and others are helpful (16, 17), also a careful immunophenotypical examination, with psa, prostein (p501s), amacr, pap and ck7 positivity, and b-catenin, and cdx2 negativity are beneficial (13, 15, 18, 19). other markers such as thrombodoi: 10.4081/aiua.2014.2.150 151archivio italiano di urologia e andrologia 2014; 86, 2 mixed primary prostatic carcinoma with acinar, neuroendocrine and ductal components modulin, uroplakin and villin that have been used in identifying tumors of urothelial and colonic origin have suboptimal sensitivities (15). immunohistochemistry is also relevant in proving different types of elements, which may be unapparent on hematoxylin and eosin (h&e)-stained sections, like neuroendocrine areas (13). the present case is unique, since a combination of primary acinar, neuroendocrine and ductal adenocarcinoma has not been previously reported in the literature, although is mentioned as a possibility in the rosai textbook (20). in our case the proliferation index assessed by the ki 67 antigen was high in all the components, in accordance with some previous reports (21), and in disagreement with other reports (8), suggesting that the labeling index is variable, and also suggesting that in combined mixed tumors, the choice of the treatment should dictated by the tumor type and stage (1, 14). due to the limited experience, there are no standard treatment recommendations for the management of mixed tumors of the prostate. operable carcinomas are frequently treated with surgery (8). surgeries with curative intent include radical retro-pubic prostatectomy, radical cysto-prostatectomy, supra-pubic prostatectomy, and pelvic exenteration (8, 10). non-surgical therapy (androgen ablation treatment and chemotherapy) seems to be ineffective, and androgen deprivation therapy might provide palliative relief; however, 55.5% of patients are unresponsive to conventional chemotherapy (8). in conclusion, we presented a case of mixed epithelial prostatic malignant tumor, and we discussed clinically relevant aspects for the correct diagnosis and management of these neoplasms, and posit that a careful immuno-phenotypical evaluation is needed to generate a correct diagnosis. references 1. adlakha h, bostwick dg. paneth cell-like change in prostatic adenocarcinoma represents neuroendocrine differentiation: report of 30 cases. hum pathol. 1994; 25:135-9. 2. mazzucchelli r, lopez-beltran a, cheng l, et al. rare and unusual histological variants of prostatic carcinoma: clinical significance. bju int. 2008; 102:1369-74. 3. ergen a, balbay md, irwin m, torno r. collision metastasis of bladder and prostate carcinoma to a single pelvic lymph node. int urol nephrol. 1995; 27:743-5. 4. parwani av, kronz jd, genega em, et al. prostate carcinoma with squamous differentiation: an analysis of 33 cases. am j surg pathol. 2004; 28:651-7. 5. hansel de, epstein ji. sarcomatoid carcinoma of the prostate: a study of 42 cases. am j surg pathol. 2006; 30:1316-21. 6. oliai br, kahane h, epstein ji. a clinicopathologic analysis of urothelial carcinomas diagnosed on prostate needle biopsy. am j surg pathol. 2001; 25:794-801. 7. rogers cg, parwani a, tekes a, et al. carcinosarcoma of the prostate with urothelial and squamous components. j urol. 2005; 173:439-40. 8. parada d, peña kb, riu f. sarcomatoid carcinoma of the prostate: ductal adenocarcinoma and stromal sarcoma-like appearance: a rare association. case rep urol. 2011; 2011:702494. 9. epstein ji, algaba f, yang xj, et al. tumours of the prostate. in eble jn, sauter g, epstein ji, sesterhenn ia eds, tumours of the urinary system and male genital organs, chapter 3. lyon: iarc press, 2004:160-208. 10. curtis mw, evans aj, srigley jr. mucin-producing urothelialtype adenocarcinoma of prostate: report of two cases of a rare and diagnostically challenging entity. mod pathol. 2005; 18:585-90. 11. osunkoya ao, epstein ji. primary mucin-producing urothelialtype adenocarcinoma of prostate: report of 15 cases. am j surg pathol. 2007; 31:1323-9. 12. rahmanou f, koo j, marinbakh ay, et al. squamous cell carcinoma at the prostatectomy site: squamous differentiation of recurrent prostate carcinoma. urology. 1999; 54:744. 13. tamas ef, epstein ji. prognostic significance of paneth cell-like neuroendocrine differentiation in adenocarcinoma of the prostate. am j surg pathol. 2006; 30:980-5. 14. egilmez t, bal n, guvel s, et al. adenosquamous carcinoma of the prostate. int j urol. 2005; 12:319-21. 15. chuang ay, demarzo am, veltri rw, et al. immunohistochemical differentiation of high-grade prostate carcinoma from urothelial carcinoma. am j surg pathol. 2007; 31:1246-55. 16. gohji k, nomi m, kizaki t, et al. “collision phenomenon” of prostate and bladder cancers in lymph node metastases. int j urol. 1997; 4:222-4. 17. ergen a, balbay md, irwin m, torno r. collision metastasis of bladder and prostate carcinoma to a single pelvic lymph node. int urol nephrol. 1995; 27:743-5. 18. wang w, epstein ji. small cell carcinoma of the prostate. a morphologic and immunohistochemical study of 95 cases. am j surg pathol. 2008; 32:65-71. 19. cohen rj, wheeler tm, bonkhoff h, rubin ma. a proposal on the identification, histologic reporting, and implications of intraductal prostatic carcinoma. arch pathol lab med. 2007; 131:1103-9. 20. rosai j. male reproductive system –prostate and seminal vesicles, chapter 18. in: rosai j. rosai and ackerman's surgical pathology. mosby; 10 edition 2011. 21. pacchioni d, casetta g, piovano m, et al. prostatic duct carcinoma with combined prostatic duct adenocarcinoma and urothelial carcinoma features: report of a case. int j surg pathol. 2004; 12:293-7. correspondence alfredo e. romero-rojas, md (corresponding author) national institute of cancer, bogotá, colombia julio a. diaz-perez, md, ms jdiazperez@ucsd.edu stein clinical research building 245, university of california san diego, 9500 gilman drive, la jolla, ca 92093-0637 abhinay reddy, bs, ms university of santander, bucaramanga, colombia stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2138 case report treatment of penile strangulation by the rotating saw and 4-needle aspiration method: two case reports raidh a. talib, onder canguven, abdulla al ansari, ahmad shamsodini hamad general hospital, urology department, doha, qatar. introduction: the aim of this article was to describe our experience in using rotating saw and also combination of the instrument with 4-needle aspiration. methods: a comprehensive review of the literature was performed using pubmed. “penile strangulation, -constriction, -incarceration, -entrapment” were used as search terms, and a manual bibliographic review of cross referenced items was performed. results: search results yielded nearly 70 cases of penile strangulation caused by a variety of objects. various instruments have been described in the literature for their safe removal, each with its own pros and cons. conclusions: penile strangulation should be accepted as a self-induced priapism and managed as an emergency in order to preserve erectile function and to prevent penile necrosis. surgical creativity and patience are necessary in order to have a successful outcome. key words: emergency treatment; incarceration; penis; strangulation. submitted 10 march 2014; accepted 30 april 2014 summary introduction penile strangulation, which is a compartment syndrome, requires urgent treatment in order to nourish corpora cavernosa as well as corpus spongiosum. although the appearance of this disturbance in the medical literature dates back to as early as the mid 1700s, it is on the odd occasion and has been described nearly 70 times in the english literature. constricting rings are the most common cause of penile strangulation. they can be metallic or non-metallic and are mostly used for sexual purposes. unless treated promptly, the rings can result in permanent and severe damage, including penile amputation. here, we report on two cases of penile strangulation due to metallic constricting rings that presented to our emergency department with different clinical presentations and were treated surgically. no conflict of interest declared case 1 a 52-year-old man presented to the emergency department with a strangulated penis of eight-hour history. physical examination showed a metallic ring, 2.5 cm wide and 1.5 cm thick, in the proximal part of the penis, with gross swelling and congestion distal to the ring. the patient had difficulty in voiding and urinary retention. transurethral catheter placement was unsuccessful. by history, he was married and had erectile dysfunction due to venous leakage. after placing a ring, he was unable to remove it from his engorged penile shaft after autostimulation. in the emergency room, removal of the ring was initially attempted using lubricants and aspiration of corporal blood from lateral sides under local anesthesia (penile block with 1% lidocaine), but was unsuccessful due to the tight ring and engorged penis. a handheld rotating saw equipped with a metallic blade was utilized for removal. a metal spatula was placed under the metal ring and the ring was continuously irrigated with cold water during the procedure. following removal of the ring, penile detumescense was achieved in 5 minutes and the patient was able to void. the next day, he had no penile edema and no complication and he was discharged with an oral anti-inflammatory drug, antibiotic, and anti-tetanus injection. two weeks later, the patient returned to the outpatient clinic and stated that he had no difficulty in urination or erections. case 2 a 22-year-old single man presented to the emergency department with a grossly swollen penis. he used a heavy-duty ball-bearing ring for masturbation six hours before. the ring was stuck at the coronal sulcus, causing edema of the penile shaft and glans penis. a handheld rotating saw equipped with a metallic blade was utilized for removal of the ball bearing. however, only the outer layers (1 upper and 2 side layers) of the ball bearing could be cut and removed. attempts to cut the inner layer failed due to its thickness (about 1-cm) and balls on it. as it appeared difficult to cut and remove the ring by available instruments without injuring the doi: 10.4081/aiua.2014.2.138 139archivio italiano di urologia e andrologia 2014; 86, 2 treatment of penile strangulation glans penis, we discontinued cutting with a saw. then, penile aspiration was performed under local anesthesia (penile block with 1% lidocaine) by using four needles (18-gauge), which were introduced from the glans. two needles were placed in distal corpus cavernosa and the other two were placed in the glans penis in an attempt to decrease the girth of the penile shaft and glans immediately (figure 1). in order to relieve skin edema, multiple needle pricks on the skin were performed. because of the high pressure inside the skin, black-colored blood gushed out from the sites of needle insertion. simultaneously, antibacterial liquid soap was applied under the ring to facilitate lubrication. the ring was successfully removed without clear necrosis or iatrogenic damage to the penis. however, the penile edema resolved in 24 hours. one month later, the patient had no difficulty in urination or erections. discussion penile strangulation is a rare clinical entity that is mostly caused by the patient himself for sexual purposes. although either metal or non-metal rings are used for pleasure, the most commonly reported objects causing strangulation are metal rings. silberstein et al. developed a grading system with a modification of two broad categories as lowand high-grade penile injuries (1). highgrade injuries are defined as injuries that are likely to require surgical intervention (1). the patients presented here had low-grade injuries and no surgical intervention was performed after removal of the rings. the treatment of penile strangulation is decompression of the constricted penis to facilitate free blood flow and micturition. non-metallic rings can usually be removed simply by cutting the constricting object. interestingly, highgrade penile injuries are more frequently caused by nonmetallic constricting objects (1). although metallic constricting rings placed around the penis present a challenge to urologists, various instruments may be used whenever available, such as a string, modified string, hammer (2), gigli saw, rotating saw (1), and electric grinder. sometimes, combination (3) or alteration of treatment modalities might be needed as in our second case. penile aspiration technique in penile strangulation was first described by chang et al. who used two 21-gauge butterfly needles. in our case, for the first time to our knowledge, we performed penile aspiration by using four needles in order to achieve rapid detumescence. while protecting the patients’ organ, the surgical team should be aware of potential work injuries for both the patient and staff. horstmann et al. reported an eye problem in one of the medical staff (3). other than risk for blood or fluid spillage, heavy-duty technical equipments scatter metal sparks; therefore, wearing eye-protective glasses should not be neglected. conclusion penile strangulation may result from self-induced priapism and should be treated as an emergency urologic case. if the surgical team fails to remove a constricting ring, alternative treatment modalities should be considered. supplementary figures, extended discussion and full list of references are posted in supplementary materials on www.aiua.it references 1. silberstein j, grabowski j, lakin c, goldstein i. case reports: penile constriction devices: case report, review of the literature, and recommendations for extrication. j sex med. 2008; 5:1747-57. 2. bhat al, kumar a, mathur sc, gangwal kc. penile strangulation. br j urol. 1991; 68:618-21. 3. horstmann m, mattsson b, padevit c, et al. successful removal of a 3.6-cm long metal band used as a penile constriction ring. j sex med. 2010; 7:3798-801. correspondence raidh a. talib, md onder canguven, md, assoc. prof. (corresponding author) ocanguven@yahoo.com abdulla al ansari, md ahmad shamsodini, md hamad general hospital, urology department 3050 doha, qatar figure 1. two needles placed in the distal corpus cavernosa and the other two in glans penis in an attempt to decrease the girth of the penile shaft and glans. stesura seveso 33archivio italiano di urologia e andrologia 2014; 86, 1 original paper in-vitro effects of pde5 inhibitor and statin treatment on the contractile responses of experimental mets rabbit's cavernous smooth muscle yasin erden 1, esat korgalı 1, gokce dundar 1, semih ayan 1, gökhan gokce 1, sahin yildirim 2, emin yener gultekin 1 1 cumhuriyet university school of medicine department of urology, turkey; 2 cumhuriyet university school of medicine department of pharmachology, turkey. objective: hypercholesterolaemia promotes erectile dysfunction through increased superoxide formation and decreased nitric oxide bioactivity in cavernosal tissue. the role of nitric oxide on erectile function is well known. statins have lipid lowering properties and can modulate endothelial nitric oxide bioavailability. sildenafil, enhances smooth muscle relaxation in corpus cavernosum. we invastigated in-vitro effects of sildenafil and rosuvastatin on nonadrenergic, non-cholinergic and nitric oxide mediated cavernosal smooth musle relaxation in metabolic syndrome rabbits, since alterations in this pathway are recognised in diabetic and hypercholesterolemic erectile dysfunction. methods: ten male rabbits were fed a standart diet as control group, fourty male rabbits were fed a hypercholesterolemic diet for 12 weeks. hypercholesterolemic group were divided for without treatment, rosuvastatin treatment, sildenafil teratment, and rosuvastatin + sildenafil treatment (n = 10 per groups). results: serum levels of cholesterol and glucose were significantly higher in the experimental group than in the control group (p < 0.05). after theraphy no differences were found among the groups in relaxation responses to sodium nitroprusside. the relaxation responses to carbachol and efs were significantly reduced in metabolic syndrome group to control group (p < 0.05), but there were no differences between the other groups and control group. there was a significantly lower in-vitro relaxation response in the metabolic syndrome rabbits than in controls and the others (p < 0.05). conclusion: both agents improve in-vitro relaxation responses of erectile tissue from metabolic syndrome rabbits to endothelial non-adrenergic, non-cholinergic and nitric oxide. this finding supports to the results of other clinical studies with these drugs. key words: erectile dysfunction; metabolic syndrome; sildenafil; rosuvastatin. submitted 6 september 2013; accepted 31 december 2013 summary introduction metabolic syndrome (mets) is characterized by insulin resistance (impaired glucose tolerance, hyperinsulinemia and type 2 diabetes), visceral fat accumulation, dyslipidemia (low levels of high-density lipoprotein cholesterol and hypertriglyceridemia) and hypertension and increased risk of metabolic and cardiovascular diseases and erectile dysfunction (1). subjects with mets have a higher prevalence of sexual dysfunction, and in particular erectile dysfunction (ed) (2, 3). in subjects with sexual dysfunction, the prevale nce of mets is age dependent and at midlife could affect almost the half of the population (4). moreover, ed has been recognized as a precursor of forthcoming cv diseases due to same factors impairing both penile and systemic vascular blood flow (5, 6). hyperglycemia, oxidative stress, and impaired lipid profiles conduce to vascular complications, including peripheral nerve perfusion deficits, which play an important role in the etiology of diabetic neuropathy. epidemiological studies have detected that dyslipidemia is an independent risk factor for diabetic neuropathy and ed among diabetic and mets patients (7-9). nowadays selective pde5 inhibitors are used as first line therapy in the treatment of ed and are highly effective and safely. the efficacy of sildenafil was approved in vivo and in vitro, in both animal and human studies (10, 11). the efficacy of pde5 inhibitors in diabetes mellitus, hyperlipidemia or dyslipidemia and hypertension extensively studied and demonstrated beneficial effect with several studies (12). statins are the mainstay of the management of dyslipidemia (13). rosuvastatin is a statin, of which potency has been proved remarkably proved in reducing lowdensity lipoprotein cholesterol levels. on the other hand, rosuvastatin has extra-lipid effects and these effects are on endothelial function, oxidized low-density lipoprotein, inflammation, plaque stability, vascular remodeling, homeostasis, cardiac muscle, and components of the nervous system (14). the effect of lipid-lowering therapies on erectile function have been studied in men with ed, along with some studies including pde5 inhibitors (15-18). these studies sugno conflict of interest declared doi: 10.4081/aiua.2014.1.33 erden_stesura seveso 26/03/14 10:19 pagina 33 archivio italiano di urologia e andrologia 2014; 86, 1 y. erden, e. korgalı, g. dundar, s. ayan, g. gokce, s. yildirim, e. yener gultekin 34 gested that as statins improve erectile function and also may ameliorate endothelial function as well, through its lipid-lowering, anti-inflammatory and antioxidant impacts (19). the use of animal models is important in the researches of ed with dyslipidemia. a non-genomic model of mets was developed by exposing rabbits to a high-fat diet (hfd) and dislipidemia has been shown to cause reduced erectile function in rabbits in in vitro studies, it has yet to be confirmed in a conscious in vivo model (20). in this experimental study, we aimed to investigate the effects of sildenafil, rosuvastatin and combination of both drug therapy in normal and mets rabbits, as the phosphodiesterase-5 (pde-5) inhibitor sildenafil is widely used for treating erectile dysfunction (ed) and as hmgcoa (3-hydroxy-3methylglutaryl coenzyme a) reductase inhibitor rosuvastatin is one of the most common drugs used in hyperlipidemic patients. materials and methods animals adult male new zealand white rabbits (saki yenilli experimental animal production laboratory ankara, turkey), weighing about 3 kg, were individually caged under standard conditions in a temperature and humidity controlled room on a 12-hr light/dark cycle. water and food were unrestricted during the study period. all experimental procedures were approved by animal experimental study local ethics committee of our medical school and were conducted in accordance with nih guidelines for the care and use of laboratory animals. creating metabolic syndrome model after 1 week of standard rabbit diet, animals were randomly divided into control (n = 10), mets (group a) (n = 10) and treatment groups (b, c, d) (n = 10 each group). the control group was maintained to be fed with a standard diet (control) while mets and the treatment groups received hfd, modified form of a previously described protocol, constituted by 0.5% cholesterol and 20% butter providing 65% of total energy need from lipids (hfd rabbit) for 12 weeks (20). at the end of 12th week, therapy group was divided three groups. all of therapy groups and mets group were fed high fat diet and one group received rosuvastatin (crestor; astrazeneca) 20 mg/kg/day (group b) as an oral gavage, the other group received sildenafil (viagra; pfizer) 5 mg/kg/day (group c) as an oral gavage, and the remaining group received combination of rosuvastatin 20mg/kg/day and sildenafil 5 mg/kg/day (group d) during 6 weeks. rabbits weights were recorded at the beginning of study, at 12th week and at the end of the study. blood samples for glucose, total cholesterol, triglycerides, ldl, hdl analyses were obtained from the animals via marginal ear vein at week 0 (baseline), at week 12 and at the end of the study in all groups. plasma cholesterol, triglycerides, and glucose levels were measured by using an automated system (advia 1800 24004 siemens chemistry system; siemens science medical solution diagnostic, ny, usa). in vitro functional studies all rabbits were anesthetized with isoflurane and euthanized. the entire penis was then removed, separated corpus spongiosum and urethra. each corpus cavernosa was dissected into four strips of 5 x 15 mm. isolated cavernous strips were suspended in 10 ml organ baths containing krebs-hco3 solution with the following composition. (mm): 118 nacl, 4.7 kcl, 2.5 cacl2, 1.2 mgso4, 1.2 kh2po4, 25 nahco3, and 11 glucose, ph 7.4, at 37°c and bubbled with a gas mixture of 95% o2 and 5% co2. the cavernous strips were equilibrated for approximately 60 min during which the buffer solution was refreshed every 15 min. pretension of 2 gr was applied to all strips, isometric contractions were measured with a force transducer (grass ft 03 force displacement italy), and normalized based on strip cross-sectional area. following the equilibration, the tissues were challenged with 124 mm potassium chloride (kcl) for 6 min and contracted all strips; washed again with fresh buffer. after more cavernous strips left to settle for the implementation of the agonist and antagonist substances, neurally evoked contractions were induced using electrical field stimulation (efs) via platinum wire electrodes. isolated cavernous strips obtained from control, mets and mets + therapy groups were treated with 124 mm kcl and responses received by kcl graphed; checked the contractility of strips before and after performing the contractile studies (3x 10-6 tox 10-4 m). the strips were pre-contracted with 1x 10-5 m fenilephrine. after the contraction reached a plateau the strips were subjected to electrical field stimulation (efs) using ring platinum electrodes. cavernous strips was evoked with efs 50 v, 0.8 msn; 2, 4, 8, 16, 32, 64 hz frequencies during 10 sec after the equilibration and responses were recorded. before applying the efs atropine 6x 10-5 m and guanetidin 5x 10-5 m was added the organ bath. chemicals carbachol, kcl, atropine, guanetidin, lname, snp, larginine were obtained from sigma-aldrich. statistical analysis arithmetic averages and the standard deviations of serum values were calculated. friedman and wilcoxon tests were used to assess the changes in values. this experiment results were tested by student-t test for the differences between two groups. the significance of differences between groups were evaluated with scheffe's f test. spss 14.0 (spss, chicago, il, usa) was used for the statistical analysis and p < 0.05 was considered statistically significant. results effects of hfd to metabolic parameters in rabbits at the end of the first twelve weeks, there was a significant increase in plasma levels of glucose, total cholesterol, triglycerides, ldl and body weight (p < 0.05) and plasma hdl level was decreased significantly in the hfd group. control rabbits that were fed with a standard chow for 12 weeks did not show any significant difference in all these erden_stesura seveso 26/03/14 10:19 pagina 34 variables. at the end of the treatment phase which is the second phase of the study, plasma levels of glucose, total cholesterol, triglycerides, ldl, hdl in group b and d were comparable with in the initial levels of the study and with the levels in control group. significant changes in plasma levels of glucose, total cholesterol, triglycerides, ldl, hdl observed in the first twelve weeks were observed to continue in group a and c (table 1). in-vitro contraction and relaxation responses there was no difference in contractile response to kcl (124mm) between corporal strips from the all of mets groups and control group. but there was a significant increase in contractile response to fenilefrin in corporal strips mets as compared to control group and other mets groups which received any of the therapeutic intervention (figure 1). relaxation of corpus cavernosum smooth muscle in response to carbachol was significantly decreased in strips from the mets group compared to controls and mets + therapy groups (figure 2). when the strips incubated with 3 x 10-5 m l-name, the relaxation response to carbachol was inhibated and basal tonus was increased. 35archivio italiano di urologia e andrologia 2014; 86, 1 in-vitro effects of pde5 inhibitor and statin treatment on the contractile responses of experimental mets rabbit's cavernous smooth muscle group initial first twelve weeks last six weeks (mg/dl ± sd) (mg/dl ± sd) (mg/dl ± sd) glucose a 129.54 ± 2,30 *162.42 ± 8,67 *178.39 ± 10,85 b 128,40 ± 5,41 *161,80 ± 17,43 170,40 ± 18,64 c 127.60 ± 2,30 *159.80 ± 8,67 *184.60 ± 10,33 d 128.20 ± 5,50 *166.80 ± 22,22 181.00 ± 26,10 total cholesterol a 46.66 ± 2,64 *85.58 ± 3,17 *104.62 ± 2,98 b 54,60 ± 5,68 *103,00 ± 11,34 106,00 ± 11,31 c 49.80 ± 1,64 *88.80 ± 2,17 *103.80 ± 2,77 d 49.60 ± 5,77 *97.00 ± 11,09 93.00 ± 6,24 triglyceride a 46.20 ± 5,96 *94.00 ± 10,95 *116.20 ± 5,68 b 43,80 ± 73 *114,00 ± 17,71 113,20 ± 20,09 c 47.40 ± 5,77 *96.00 ± 9,35 *113.00 ± 5,00 d 47.00 ± 7,00 *105.60 ± 16,08 110.80 ± 14,32 ldl a 12.76 ± 1,14 *23.28 ± 3,87 *32,54 ± 4,92 b 12,20 ± 2,39 *20,00 ± 5,29 22,20 ± 6,10 c 12.60 ± 1,14 *22.20 ± 3,63 *28.60 ± 4,22 d 11.40 ± 1,52 *25.40 ± 3,58 26.00 ± 3,81 hdl a 20,51 ± 4,96 *12,47 ± 3,85 *10.65 ± 2,69 b 21,60 ± 4,83 *11,00 ± 2,92 10,40 ± 3,29 c 21.00 ± 4,36 *11.60 ± 2,07 *10.20 ± 2,17 d 19.80 ± 5,63 *12.00 ± 1,22 12.60 ± 1,67 body weight a 3254,55 ± 82,36 *3396,65 ± 122,32 *3566,85 ± 107,67 b 3220.80 ± 129,22 *3373.40 ± 114,80 3418.40 ± 250,58 c 3183.80 ± 73,96 *3357.80 ± 114,28 *3492.80 ± 104,84 d 3147.40 ± 98,60 *3414.20 ± 143,55 3492.20 ± 155,72 table 1. analysis of serum and body weight change according to the groups. figure 1. concentration-response curve for phenylephrine. figure 2. relaxation responses for carbachol. * p < 0,05 erden_stesura seveso 26/03/14 10:19 pagina 35 archivio italiano di urologia e andrologia 2014; 86, 1 y. erden, e. korgalı, g. dundar, s. ayan, g. gokce, s. yildirim, e. yener gultekin 36 there was not significant difference in relaxation responses to sodium nitroprusside in all groups compared control group (figure 3). efs following phenylephrine precontraction in the presence of 1 x 10-5 m/l atropine and 4x10-5 m/l guanethidine produced frequency-dependent nanc relaxation. relaxtion responses to efs was decreased when strips incubated with 3 x 10-5 m l-name and relaxation response to efs return with 4x10-5 m l-arginin. this findig supported the previous detection. relaxation of corpus cavernosum smooth muscle in response to efs was significantly less in strips from the mets group than controls and all mets + theraphy groups at all frequencies. there was no significant difference between theraphy groups each other and control group (figure 4). discussion in this study, we aimed to investigate in vitro effects of systemic treatments of rosuvastatin, sildenafil and combination of these two agents on contractile responses of cavernous tissue in experimental metabolic syndrome model. the corporal tissue strips of mets rabbits were observed to have significantly decreased in vitro erectile responses than that of the control group whereas in mets groups received a treatment either with a pde5 inhibitor or with a statin, in vitro erectile responses were comparable to each other and to control goup. epidemiological studies have demonstrated that elevated serum cholesterol and diminished high-density lipoprotein (hdl) cholesterol levels are associated with an increased risk of erectile dysfunction (ed). whether restoring a dyslipidemic profile will result in a reduced risk of developing ed has not been established. similarly, it is not known if such an intervention will improve symptoms in patients with established ed. the situation is even more complex by the likelihood that one of the rarer side effects of statins is ed (21). penile erection is the result of relaxation of smooth muscles in the cavernous sinusoids and associated blood vessels (23). smooth muscle relaxation is mediated primarily by nitric oxide (no), which one of the most potent endogenous smooth muscle relaxants. no is synthesized by neuronal no synthase (nnos) in the autonomic postganglionic parasympathetic nerves (nitrergic nerves) 2, 3 and by endothelial nos in the endothelium lining the blood vessels and cavernous sinusoids (23, 24). the negative effects of hyperlipidemia on erectile function are revealed by clinical and experimental studies. azadzoi et al. (25) showed in cavernous tissues of rabbits that atherosclerosis due to hyperlipidemia decreases the activity of nos, upregulates the production of thromboxane and prostaglandin, and accordingly this negatively affects smooth muscle relaxation occurring in response to electrical stimulation which forms the basis of erection. kim et al. (26) also found that the negative effects of hyperlipidemia on cavernous smooth muscle relaxation are related to the contractile effect of oxidized low-density lipoprotein, release of superoxide radicals and elevated levels of nos inhibitors. in our study, in accordance with the findings of these studies, we found that relaxation responses in untreated hypercholesterolemia were significantly reduced. similarly, firoozi et al. reported in their study that relaxation responses were significantly decreased in the hypercholesterolemic group. in their study, when sildenafil and vardenafil were added in vitro to hypercholesterolemic group relaxation response to efs significantly increased however failed to reach the level of response of the control group (20). in our study, apart from the situation indicated above, in all groups where mets model was formed and systemic therapy was added, we found that when atropine and guanetidin added to the therapy, the relaxation response to efs was significantly increased compared to untreated mets group. moreover, these responses were similar compared to responses of the control group. snp-induced relaxation responses were similar in all groups and this suggested that the problem existed until the no release process. this finding indicates that systemic rosuvastatin, sildenafil and combination therapy prevent the development of endothelial dysfunction and ed in hypercholesterolemic group. the beneficial effects of daily use of pde5 inhibitors on erectile function have been shown in many experimental and clinical studies. it is shown that chronic pde5 inhibition improves endothelial function, protects vascular smooth muscle and reduces fibrotic changes in diabetic patients with cardiovascular disease (27, 28). chen et al. (29) reported antioxidative effect of the chronic use of tadalafil prevented the development of diabetic ed with diabetic rats. a study investigating the effect of chronic use of sidenafil figure 3. relaxation responses for sodium nitroprusside. figure 4. relaxation responses for efs. erden_stesura seveso 26/03/14 10:19 pagina 36 in a different ed model formed with cavernous nerve injury in rats showed that sildenafil, independent from endogenous inos, prevents histological changes that occur because of cavernous nerve damage (30). in our study, we have demonstrated that the daily use of sildenafil in hypercholesterolemic rabbits of our mets model significantly improved cavernosal tissue relaxation responses. statins are the most commonly used group of drugs in the treatment of dyslipidemia. recently it has been reported that beside lipid-lowering effects, the beneficial effects of these drugs on vascular system process through modulating enos, inos, nnos enzymes, causing relaxation of smooth muscle cells, affecting the anti-inflammatory and antioxidant mechanisms (14). nangle et al. (31) investigated the effect of use of rosuvastatin on nitric oxide-dependent function in aorta and corpus cavernosum of diabetic mice and reported that rosuvastatin, independent from its extra-lipid effects, restores the defective no-mediated nerve and vascular function in diabetic mice. moreover, dependent on its cholesterol biosynthesis pathway inhibition and anti inflammatory effects, rosuvastatin restores relaxation response which is reduced due to diabetes. maximum no-dependent nonadrenergic, noncholinergic nervemediated relaxations of cavernosum were reduced 2533% by diabetes. rosuvastatin treatment prevented 75% and reversed 71% of this diabetic deficit. morelli et al. (32) reported that atorvastatin did not act on glycemia, plasma lipid levels or the hypogonadal condition in experimental diabetic rat models. in diabetic rabbits, atorvastatin improved the erectile response to electrical stimulation of the cavernous nerve and normalized the sildenafil effect on erectile function which is strongly decreased in diabetic patients. in accordance with literature, results of our study demonstrated that rosuvastatin therapy that was administered to rabbits of mets model provided significantly increased relaxation responses of cavernosal strips. in the literature, although there are experimental studies available concerning various vascular pathologies in which effects of use of systemic statins in combination with pde5 inhibitors were evaluated (33, 34). our study is the first in vitro study investigating the effect of use of systemic rosuvastatin in combination with sildenafil on cavernosal tissue in mets model. we observed that the treatment with either sildenafil or rosuvastatin significantly improves cavernosal smooth muscle relaxation responses in created mets model rabbits as compared to the untreated mets group. however, the combination of these two drugs does not yield an additional advantage in terms of cavernosal tissue contraction responses. the lack of an additive restoring effect of combined treatment might be attributed to no dependent effect which was alraedy provided by either of two drugs. references 1. després jp, lemieux i. abdominal obesity and metabolic syndrome. nature 2006; 14:881-7. 2. esposito k, giugliano d. obesity, the metabolic syndrome, and sexual dysfunction. int j impot res 2005; 17:391-8. 3. esposito k, giugliano f, martedì e, et al. high proportions of erectile dysfunction in men with the metabolic syndrome. diabetes care 2005; 28:1201-3. 4. corona g, mannucci e, forti g. hypogonadism, ed, metabolic syndrome and obesity: a pathological link supporting cardiovascular diseases. int j androl 2009; 32:587-98. 5. corona g, forti g, maggi m. why can patients with erectile dysfunction be considered lucky? the association with testosterone defciency and metabolic syndrome. aging male 2008; 11:193-9. 6. inman ba, sauver jl, jacobson dj, et al. a population-based, longitudinal study of erectile dysfunction and future coronary artery disease. mayo clin proc 2009; 84:108-13. 7. cameron ne, eaton sem, cotter ma, et al. vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy. diabetologia 2001; 44:1973-1988 8. sima aaf, sugimoto k. experimental diabetic neuropathy: an update diabetologia 1999; 42:773-788. 9. tesfaye s, stevens lk, stephenson jm, et al. prevalence of diabetic peripheral neuropathy and its relation to glycaemic control and potential risk factors: the eurodiab iddm complications study. diabetologia 1996; 39:1377-1384. 10. goldstein i, lue tf, padma-nathan h, et al. oral sildenafil in the treatment of erectile dysfunction. the sildenafil study group. n engl j med 1998; 338:1397-1404. 11. choi s, o’connell l, min k, et al. efficacy of vardenafil and sildenafil in facilitating penile erection in an animal model. j androl 2002; 23:332-7. 12. nehra a. erectile dysfunction and cardiovascular disease: efficacy and safety of phosphodiesterase type 5 inhibitors in men with both conditions. mayo clin proc. 2009; 84:139-48. 13. ong ht. the statin studies from targeting hypercholesterolaemia to targeting the high-risk patient. qjm. 2005; 98:599-614. 14. kostapanos ms, milionis hj, elisaf ms. an overview of the extra-lipid effects of rosuvastatin. j cardiovasc pharmacol ther. 2008; 13:157-74. 15. bruckert e, giral p, heshmati hm, et al. men treated with hypolipidaemic drugs complain more frequently of erectile dysfunction. j clin pharm ther 1996; 21:89-94. 16. saltzman ea, guay at, jacobson j. improvement in erectile function in men with organic erectile dysfunction by correction of elevated cholesterol levels: a clinical observation. j urol 2004; 172:255-8. 17. bank aj, kelly as, kaiser dr, et al. the effects of quinapril and atorvastatin on the responsiveness to sildenafil in men with erectile dysfunction. vasc med 2006; 11:251-7. 18. solomon h, samarasinghe yp, feher md, et al. erectile dysfunction and statin treatment in high cardiovascular risk patients. int j clin pract 2006; 60:141-5. 19. miner m, billups kl. erectile dysfunction and dyslipidemia: relevance and role of phosphodiesterase type-5 inhibitors and statins. j sex med. 2008; 5:1066-78. 20. firoozi f, longhurst pa, white md. in vivo and in vitro response of corpus cavernosum to phosphodiesterase-5 inhibition in the hypercholesterolaemic rabbit. bju international. 2005; 96:164-8. 21. schachter m. erectile dysfunction and lipid disorders. curr med res opin. 2000; 16 (suppl-1):s9-s12. 37archivio italiano di urologia e andrologia 2014; 86, 1 in-vitro effects of pde5 inhibitor and statin treatment on the contractile responses of experimental mets rabbit's cavernous smooth muscle erden_stesura seveso 26/03/14 10:19 pagina 37 archivio italiano di urologia e andrologia 2014; 86, 1 y. erden, e. korgalı, g. dundar, s. ayan, g. gokce, s. yildirim, e. yener gultekin 38 22. gratzke c, angulo j, chitaley k, et al. anatomy, physiology, and pathophysiology of erectile dysfunction. j sex med 2010; 7:445-475. 23. moncada s, higgs a, furchgott r. international union of pharmacology nomenclature in nitric oxide research. pharmacol rev 1997; 49:137-142. 24. cellek s. let’s make no mistake! int j impot res 2005; 17:388-389. 25. azadzoi km, kim n, brown m, et al. endothelium-derived nitric oxide and cyclooxygenase products modulate corpus cavernosum smooth muscle tone. j urol. 1992; 147:220-225. 26. kim sc, kim ik, seo kk, et al. involvement of superoxide radical in the impaired endothelium-dependent relaxation of cavernous smooth muscle in hypercholesterolemic rabbits. urol res. 1997; 25:341-346. 27. francis sh, corbin jd. pde5 inhibitors: targeting erectile dysfunction in diabetics. opin pharmacol. 2011; 11:683-8. 28. deyoung l, chung e, kovac jr, et al. daily use of sildenafil improves endothelial function in men with type 2 diabetes. j androl. 2012; 33:176-80. 29. chen y, li xx, lin hc, et al. the effects of long-term administration of tadalafil on stz-induced diabetic rats with erectile dysfunction via a local antioxidative mechanism. asian j androl. 2012; 14:616-20. 30. kovanecz i, rambhatla a, ferrini m, et al. long-term continuous sildenafil treatment ameliorates corporal veno-occlusive dysfunction (cvod) induced by cavernous nerve resection in rats. int j impot res. 2008; 20:202-12. 31. nangle mr, cotter ma, cameron ne. effects of rosuvastatin on nitric oxide-dependent function in aorta and corpus cavernosum of diabetic mice: relationship to cholesterol biosynthesis pathway inhibition and lipid lowering. diabetes. 2003; 52:2396-402. 32. morelli a, chavalmane ak, filippi, et al. atorvastatin ameliorates sildenafil-induced penile erections in experimental diabetes by inhibiting diabetes-induced rhoa/rhokinase signaling hyperactivation. j sex med. 2009; 6:91-106. 33. zhang wh, liu cp, zhang yj, et al. additive effect of tadalafil and simvastatin on monocrotaline-induced pulmonary hypertension rats. scand cardiovasc j. 2012; 46:374-80. 34. wang qm, wei y, zheng y, et al. efficacy of combined atorvastatin and sildenafil in promoting recovery after ischemic stroke in mice. am j phys med rehabil. 2013; 92:143-50. correspondence yasin erden, md esat korgalı, md (corresponding author) estkorgali@hotmail.com, estkorgali@gmail.com gokce dundar, md semih ayan, md gökhan gokce, md emin yener gultekin, md cumhuriyet university school of medicine department of urology kampus, merkez sivas (turkey) 58140 sahin yildirim, md cumhuriyet university school of medicine department of pharmachology erden_stesura seveso 26/03/14 10:19 pagina 38 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 3224 case report treatment of tuberculous ureteritis. what is the appropriate time for invasive treatment? a case report and review of literature özgür haki yüksel, ahmet ürkmez, ayhan verit fatih sultan mehmet research & training hospital, dept. of urology, istanbul, turkey. we report a case of isolated distal ureter tuberculosis who presented with irritative voiding symptoms treated with sole medical therapy and discuss the clinical, imaging, diagnostic and therapeutical features. in case of irritative voiding symptoms and radiological presentation of ureteral pathologies, genitourinary tuberculosis should be considered in the differential diagnosis. we believe that medical therapy should be the main option before the invasive procedures. key words: ureter tuberculosis; medical therapy; invasive treatment. submitted 14 june 2014; accepted 1 august 2014 summary no conflict of interest declared. introduction nearly one third of the world’s population is estimated to be infected with mycobacterium tuberculosis. genitourinary tuberculosis is not very common but it is considered as a severe form of extra pulmonary tuberculosis. extra pulmonary tuberculosis accounts for approximately 20% of cases of active tuberculosis. only 20 to 30% of the patients with genitourinary tuberculosis have a history of lung infection (1). urogenital tuberculosis is characterized by clinical polymorphism. however, the isolated ureteric form is very rare (2). we report a case of isolated distal ureter tuberculosis who presented with irritative voiding symptoms treated with sole medical therapy and discuss the clinical, imaging, diagnostic and therapeutical features. case report our case was a 55-year-old woman without significant medical history. the patient consulted us for urinary frequency and microscopic hematuria for the past eight months. the physical examination revealed an exhausted patient. the patient presented with weight loss as 10 kg in eight months. laboratory investigations showed appropriate kidney function with a creatinine of 0.97 mg/dl, an inflammatory syndrome with an erythrocyte sedimentation rate of 54 mm/hour and c-reactive protein of doi: 10.4081/aiua.2014.3.224 2.69 mg/l, whereas the remaining laboratory investigations were unremarkable. the patient then underwent a renal and pelvic ultrasound which showed left hydro nephrosis and hydroureter. this examination was completed by a magnetic resonance urography that revealed a left ureterohydronephrosis in the left distal ureter secondary to focal wall thickening (figure 1). furthermore, considering the irritative voiding symptoms, we suggested a koch’s bacillus assessment of the patient’s urine which resulted strongly positive. the treatment consisted of antituberculous antibiotics. after 6 months of treatment was observed a decline of hydroureteronephrosis (fıgure 2). mycobacterial culture came to be negative. discussion the incidence of tuberculosis is estimated as 26 per 100.000 in turkey. according to the who 2006, extrapulmonary tuberculosis rate is 15-25%. in 2005, surveillance of ministry of health in turkey resulted in 20535 cases suffering from tuberculosis, out of them 91.3% were new cases, 73% and 27% were pulmonary and extrapulmonary tuberculosis, respectively. extrapulmonary tuberculosis cases were genitourinary locations in 4.5%, gastroıntestinal and peritoneal locations in 4.5%; intrathoracic lymphadenitis in 5.5%, extrathoracic lymphadenitis in 26% and pleuric locations in 37%. more rarely bone and central nervous system were affected. risk factors for extrapulmonary tuberculosis are hiv infection, tumour necrosis factor-! antagonists (e.g. infliximab), corticosteroids, malignancy, female gender. being female gender is the unique risk factor for our patient. urogenital tubercolosis comprises renal disease, ureteric disease and genital infection. the diagnosis of renal disease is easily missed, as back or flank pain, dysuria or general symptoms occur in only 30% of patients. renal tubercolosis is usually unilateral and rarely causes renal failure; the exception is tuberculous interstitial nephritis, which may affect both kidneys. renal abscesses may destroy the entire renal parenchyma. pelvo-calyceal involvement may result in thickening of the collecting system; more distally, ureteric fibrosis and stricture formation may cause hydronephrosis, whereas tubercolosis yukselcr_stesura seveso 08/10/14 12:17 pagina 224 225archivio italiano di urologia e andrologia 2014; 86, 3 treatment of tuberculous ureteritis. what is the appropriate time for invasive treatment? a case report and review of literature of the bladder wall may lead to fibrosis. renal biopsy may show granulomatous interstitial nephritis, often with multifocal caseous necrosis. cystoscopy with biopsies of bladder, ureteric or prostate tissue may also be helpful. the ct/mrg urography and intravenous urography with micturition examinations are designed to make an extended assessment of the urogenital tuberculosis lesions. imaging or the renal tract may show a characteristically ‘beaded’ ureter (ureteritis cystica) (3). this is probably due to an extending fibro-inflammatory process with thickening of the ureteral wall that could be confused with a ureteral tumor in evaluation of imaging (4). urogenital tuberculosis is characterized by varied clinical symptoms (5). ureteral localization was always described as secondary to renal disease because it represents the extension of mucosal lesions from the kidney (6). the case reported here did not reveal any visible renal impairment by imaging exploration except hydrourete ronephrosis. endoscopy must always be performed with the patient under general anesthesia with a muscle relaxant to reduce the risk of hemorrhage. the phase of bladder filling should be performed under direct vision. bladder biopsy is contraindicated in the presence of acute tuberculous cystitis (7). indications for ureteroscopy are rare but renal tuberculosis should be included in the differential diagnosis of lateralizing hematuria, especially in the absence of an obvious cause for the bleeding. in this case direct culture of urine from the renal pelvis may have more sensitivity than culture of voided urine (8). the confirmation of the diagnosis is based on assessing microscopically the presence koch’s bacilli in the urine by direct testing for alcohol-acid-resistant bacillus. the koch’s bacillus culture requires a long time for obtaining the final results as long as eight weeks. the identification of koch’s bacillus using polymerase chain reaction is faster and takes 24 to 48 hours, but with a sensitivity reduced to 48.5% (9). according to the who, the antituberculous drug treatment is based on an initial 2 months intensive phase of treatment with three or four drugs (rıfampicın, isoniazid, pyrazinamide, etambutol or streptomycin) to destroy almost all tuberculous bacilli. this is followed by a 4 months manteinance phase with only two drug mostly rıfampicin and ısoniazid (10). the most common site for tuberculous stricture is the ureterovesical junction. uretheral strictures may develop in more than 50% of patients with renal involvement (11). strictures of the lower end of the ureter, which can either be managed medically or surgically, occur in approximately 9% of patients. if obstruction at the lower end of the ureter is present at the start of chemotherapy careful observation is required. these strictures may result from edema and they respond to chemotherapy. the patient should receive chemotherapy and should be monitored by intravenous urograms at weekly intervals. corticosteroids can be added to chemotherapy if there is deterioration or no improvement after 3 weeks. if there is still deterioration or no improvement after a 6 week period, surgical reimplantation should be carried out if an initial attempt of dilatation has failed. double j ureteral catheter drainage may be used during this period for assessing the efficacy of medical therapy. early ureteral stenting or pcn (percutaneous nephrostomy) in patients with tuberculous ureteral strictures may increase the opportunity for later reconstructive surgery and decrease the likelihood of renal loss (12). in all other situations, patients should have at least 4 weeks of extensive chemotherapy before surgery (7). the overall incidence of surgical management of genitourinary tuberculosis in the past 20 years was reported to be about 0.5% of all urological surgical procedures (13). although chemotherapy is the mainstay of treatment, ablative surgery as a first-line management may be unavoidable for sepsis or abscesses (14). medical treatment is the first-line therapy in genitourinary tuberculosis. both radical and reconstructive surgery should be carried out in the first 2 months of intensive chemotherapy (15). the duration of medical therapy has been figure 2. magnetic resonanse urography: at the lower end of the left ureter was observed a significant decrease in contrast enhancement (marked by the arrow). figure 1. magnetic resonanse urography: the left distal ureter secondary to focal wall thickening (marked by the arrow). yukselcr_stesura seveso 08/10/14 12:17 pagina 225 archivio italiano di urologia e andrologia 2014; 86, 3 ö. haki yüksel, a. ürkmez, a. verit 226 reduced to 6 months in uncomplicated cases. only in complicated cases (recurrences of tuberculosis, immunosuppression and hiv/aids) a 9 to 12 month therapy is necessary (6). in conclusion, in the presence of irritative voiding symptoms and radiological imaging showing a pathological ureter, genitourinary tuberculosis should be considered in the differential diagnosis. we believe that medical therapy should be the main option before the invasive procedures. references 1. world health organization (who) (2010) global tuberculosis control 2010: epidemiology, strategy, financing. who/htm/tb 2010. 7. 2. matos mj, bacelar mt, pinto p, ramos i. genitourinary tuberculosis. euro j radiol. 2005; 55:181. 3. figueiredo aa, lucon am, arvellos an, et al. a better understanding of urogenital tuberculosis pathophysiology based on radiological findings. eur j radiol. 2010; 76:246. 4. dhar nb, angermeier kw. idiopathic ureteral strictures without evidence of malignancy. urology. 2004; 64:377. 5. el khader k, lrhorfi mh, el fassi j, et al. tuberculose urogénitale expérience de 10 ans. prog urol. 2001; 11:62. 6. cek m, lenk s, naber kg, et al. members of the urinary tract infection (uti) working group of the european association of urology (eau) guidelines office. eau guidelines for the management of genitourinary tuberculosis. euro urol. 2005; 48:353. 7. warren d, johnson jr, johnson cw, franklin c. lowe: genitourinary tuberculosiscampbell’s urology. 8th ed. saunders; 2002. 8. chan sw, shalhav al, clayman rv. renal tuberculosis presenting as lateralizing hematuria diagnosis by ureteronephroscopy and selective upper tract urine culture. endourol. 1998; 12:363. 9. bouchikhi aa, amiroune d, tazi mf, et al. pseudotumoral tuberculous ureteritis: a case report. j med case rep. 2013; 15:45. 10. world health organization (who) anti-tuberculosis drug resistance in the world. report no. 4. who/htm/tb/2008.394. 11. allen fj, dekock ml. genito-urinary tuberculosis–experience with 52 urology in patients. s afr med j. 1993; 83:903. 12. shin ky, park hj, lee jj, et al. role of early endourologic management of tuberculous ureteral strictures. j endourol. 2002; 16:755. 13. rizzo m, ponchietti r, di loro f, et al. twenty-years experience on genitourinary tuberculosis. arch ital urol androl. 2004; 76:83. 14. carl p, stark l. indications for surgical management of genitourinary tuberculosis. world j surg. 1997; 21:505. 15. gow jg. tuberculosis: genitourinary tuberculosis. br j hosp med. 1979; 22:556. correspondence özgür haki yüksel, md (corresponding author) ozgurhaki@gmail.com ahmet ürkmez, md ayhan verit, md, prof fatih sultan mehmet research and training hospital, dept. of urology, icerenkoy/atasehir tr3 4752 istanbul, turkey yukselcr_stesura seveso 08/10/14 12:17 pagina 226 stesura seveso 233archivio italiano di urologia e andrologia 2014; 86, 3 case report endometriosis localized to urinary bladder wall mimicking urinary bladder carcinoma mine genç 1, berhan genç 2, serap karaarslan 3, aynur solak 2, musa saraçoğlu 4 1 şifa university school of medicine, department of obstetric and gynecology, izmir, turkey; 2 şifa university school of medicine, department of radiology, izmir, turkey; 3 şifa university school of medicine, department of pathology, izmir, turkey; 4 şifa university school of medicine, department of urology, izmir, turkey. although endometriosis is a common disease in women of reproductive age, urinary system endometriosis is an exceedingly rare disease that may cause important clinical problems. in this paper we discussed a 42-year-old woman who had urinary bladder endometriosis misdiagnosed as urinary bladder tumor in imaging modalities. the diagnosis of endometriosis was made by histopathological examination of the operative material after partial resection of the urinary bladder. urinary bladder endometriosis causes nonspecific signs and symptoms in many patients. in female patients presenting with unexplained urinary symptoms the differential diagnosis should include urinary bladder endometriosis that may mimic urinary bladder cancer and lead to difficulties in making definitive preoperative diagnosis. key words: endometriosis; urinary bladder; urinary tract endometriosis. submitted 22 december 2013; accepted 31 march 2014 summary introduction endometriosis is the presence of functional endometrial tissue in ectopic foci outside the uterine cavity. approximately 10% of women of reproductive age suffer from endometriosis (1). urinary tract endometriosis (ute) is observed in 1-2% of women with endometriosis. among women with ute, about 80% have urinary bladder involvement (2). we presented herein a patient presenting to our clinic with pelvic pain and dysuria who was diagnosed with an endometriosis focus on the roof of the urinary bladder, which was initially misdiagnosed as primary urinary bladder cancer. case report a 42-year-old woman, who had two previous deliveries with caesarean section, presented with pelvic pain and dysuria worsening in the last 6 months. she had no hematuria. her menstrual cycles were regular; however, she stated that the pelvic pain and dysuria worsened during menstrual period. the gynecological examination was no conflict of interest declared. not remarkable. transabdominal ultrasonographic examination revealed an irregular contoured, solid, hypoechoic lesion of 4 x 1.5 cm on the roof of the urinary bladder. magnetic resonance imaging showed a mass lesion with homogenous contrast uptake that appeared hypointense in t1w and hyper-intense in t2w (figure 1). mri images suggested a malignant diagnosis. flexible cystoscopy was performed and a biopsy sample was taken from the lesion. biopsy result was reported as nonspecific urinary bladder tissue. the tumoral mass was then removed with laparotomy and partial cystectomy. examination of the excised tumoral tissue showed macroscopic hemorrhagic foci on the urinary bladder wall. microscopic examination revealed some areas consistent with cystitis glandularis and, in addition, other areas consistent with endometrial glands and stroma inside the muscular layer (figure 2). discussion endometriosis is the presence of functional endometrial tissue in ectopic foci outside the uterine cavity. urinary tract endometriosis (ute) is observed in 1-2% of women with endometriosis. among women with ute, about 80% have urinary bladder involvement (2). this is followed by, in descending order of frequency, ureters, kidney, and urethra. endometrial lesions may assume the appearance of a polypoid mass similar to that of urinary bladder carcinoma when they grow towards the mucosa alongside the muscle layers. urinary bladder endometriosis is termed as “primary” or “secondary” depending on its type of onset: the primary urinary bladder endometriosis occurs when the endometrial tissue is congenitally located within the urinary bladder wall. the secondary urinary bladder endometriosis, on the other hand, is a iatrogenic lesion occurring in patients delivering a baby with caesarean section or undergoing a pelvic operation such as hysterectomy. up to 50% of patients with urinary bladder endo metriosis have a previous history of a pelvic operation. symptoms of urinary bladder endometriosis may vary depending on the localization and the site of the lesion. the symptoms may include recurrent cystitis, pelvic pain, dysuria, tenesmus, and burning sensation. hematuria is present in 20-35% of cases. menouria (hematuria with doi: 10.4081/aiua.2014.3.233 genc cr_stesura seveso 08/10/14 12:20 pagina 233 archivio italiano di urologia e andrologia 2014; 86, 3 m. genç, b. genç, s. karaarslan, a. solak, m. saraçoglu 234 menstruation) is not as common as the acute urethral syndrome, and it is seen in only 20-25% of cases when the mucosa is affected. negative urinary cultures in symptomatic individuals at premenopausal period may suggest urinary bladder endometriosis. ultrasonography (usg) is the first step in the diagnosis of urinary bladder endometriosis. usg may provide information with respect to lesion size and localization as well as the degree of infiltration of mucosa and detrusor muscle. magnetic resonance imaging (mri) is an excellent modality for demonstrating urinary bladder endometriosis (3). the role of cystoscopy is limited in diagnosing urinary bladder endometriosis since the lesion of urinary bladder endometriosis is usually located on the serosal surface or in the submucosal layer of the urinary bladder. cystoscopic findings may be normal despite a positive transvaginal ultreasonography (tv usg). endoscopic biopsy is of pivotal importance for differentiating the lesions from carcinomas, varices, papillomas, angiomas, and also detrusor mesenchymal tumors. however, cystoscopic biopsies except for transurethral resection (tur) procedures are not always diagnostic. also in our case, the lesion went unnoticed in cystoscopy as it was localized to submucosal and intramuscular regions. the differential diagnosis of urinary bladder endometriosis include epithelial tumors of urinary bladder, hemangiomas, myomas of anterior uterine wall, detrusor muscle leiomyomas, fibromas, glandular cystitis, nephrogenic adenoma, and diverticulitis. treatment of disease varies by certain factors including age, fertility preferences, disease extension, severity of lower urinary system symptoms, presence of other pelvic lesions, and degree of menstrual dysfunction. the therapy may be in the form of medical therapy (hormonal agents), surgery, or a combination of the two. in young women willing to maintain their fertility gonadotropin releasing hormone (gnrh) agonists and antagonists, progestins, danazol, and combined oral contraceptives are used. surgical therapy consists of transurethral surgery (tur) and partial cystectomy (laparotomic or laparoscopic). in conclusion, the urinary system is the second most commonly involved site by extrapelvic endometriosis. it constitutes 1-2% of all endometriosis cases. fifty percent of patients with urinary bladder endometriosis have a previous history of a pelvic operation (including caesarean section). the diagnosis may be done by ultrasonography (usg), mri, or cystoscopy. the therapy may be in the form of medical therapy (hormonal agents), surgery, or a combination of the two. the diagnosis of endometriosis should definitely be remembered in patients in whom usg detects a mass at the urinary bladder wall but cystoscopy fails to show any lesion. references 1. olive dl, schwartz lb. endometriosis. n engl j med. 1993; 328:1759-69. 2. shook te, nyberg lm. endometriosis of the urinary tract. urology 1988; 31:1-6. 3. beaty sd, silva ac, de petris g. bladder endometriosis:multrasound and mri findings. radiology case reports. 2006; 1:92-95. figure 1. a. b. figure 2. a. b. c. d. sagittal t1-weighted images: the pre-contrast image (a) demonstrates a mass grown within the muscle layer that shows no luminal projection at the posterior part of the urinary bladder roof (arrows). post-contrast image (b) demonstrates that the mass has a diffuse homogenous contrast uptake (arrows). (a) at the upper part of the image there are areas with features of cystitis glandularis at the urinary bladder’s urothelial epithelium (red arrow) and areas of endometriosis (green arrow) composed of foci of endometrial glands and stroma within muscularis propria at the submucosal layer (h&e x 10); (b) foci of endometriosis within the muscularis propria of the urinary bladder (h&e x 10); (c) a closer view of the areas of endometriosis (h&e x 40); and (d) estrogen receptor (er) positivity in the foci of endometriosis (er x 20). correspondence mine genç, md (corresponding author) doktorminegenc@gmail.com sifa university school of medicine, department of obstetric and gynecology fevzipasa boulevard, n: 172/2 basmane 35240 izmir, turkey berhan genç, md aynur solak, md sifa university school of medicine, department of radiology izmir, turkey serap karaarslan, md sifa university school of medicine, department of pathology izmir, turkey musa saraçoglu, md sifa university school of medicine, department of urology izmir, turkey genc cr_stesura seveso 08/10/14 12:20 pagina 234 stesura seveso 219archivio italiano di urologia e andrologia 2014; 86, 3 short communication self and partner satisfaction rates after 3 part inflatable penile prosthesis implantation abdulmuttalip simsek, onur kucuktopcu, faruk ozgor, unsal ozkuvanci, murat baykal, omer sarilar, zafer gokhan gurbuz haseki research and training hospital, department of urology, turkey. objective: to evaluate and present satisfaction rates of our patients and their partners after 3 part inflatable penile prosthesis implantation. materials and methods: we searched our hospital electronic data for patients who underwent inflatable penile prosthesis implantation between january 2008 and july 2013. computer and archived file data were used to get information and reach the patients. we made telephone calls to patients and asked questionnaires about self and partner satisfaction rates. results: 36 patients underwent prosthesis implantation during the 5 year period. we were able to reach by telephone call 18 of them. the mean age of 18 patients was 55.7 ± 9.4 years and mean body mass index was 24.6 ± 2.1 kg/m2. the etiology was diabetes mellitus on 14 (77.8%) and radical pelvic surgery on 4 (22.2%) patients. 14 of 18 patients had penile doppler ultrasound test. doppler ultrasound demonstrated venous insufficiency in 8 and arterial insufficiency in 6 patients. mean time from implantation to study was 20.8 ± 13.9 months. out of 18 patients 2 had prosthesis removal operation because of infection in one patient and perforation in the other. satisfaction rate was 88.9%, and recommendation rate was 94.4%. causes of dissatisfaction were pain in one patient and insufficient rigidity plus shortening of the penis in the other one. partner satisfaction rate was 94.4%. conclusion: penile prosthesis implantation (ppi) is the gold standard treatment of erectile dysfunction (ed) irresponsive to medical treatment. infection and mechanical failure rates are going to be less according to the improvements in synthetic materials and coverings of the prosthesis, so patient and partner satisfaction rates will be higher. key words: penile prosthesis; erectile dysfunction; satisfaction rate. submitted 30 june 2014; accepted 1 august 2014 summary no conflict of interest declared. introduction erectile dysfunction (ed) affects more than half of men between 40 and 70 years of age. oral phosphodiesterase type-5 inhibitors and intracavernosal injections (ici) are doi: 10.4081/aiua.2014.3.219 first and second line therapies respectively. penile vascular surgery is indicated for healthy men with acquired ed due to isolated stenosis of extra penile arteries without any kind of generalized vascular disease (1). phosphodiesterase type 5 inhibitors will fail in approximately 25-30% of patients and they will therefore be offered intracavernosal injection. since most patients drop out ici treatment, around 10-15% of patients with ed will be candidate for penile prosthesis implantation (ppi) (2). prosthetic implants for ed have been used successfully for many years. scott et al in 1973 introduced the inflatable penile prosthesis (ipp) and initiated the modern treatment of erectile dysfunction (3). 5-year survival rate is greater than 90% and more than 90% of patients are satisfied with the function of their prosthesis (4). in this retrospective study using a non-validated questionnaire, we aimed to evaluate the satisfaction rates of the patients and their partners, reasons of unsatisfaction and need for sexual partner change. materials and methods between january 2008 and july 2013, three part ipp implantation was performed in 36 patients. patient data was obtained by searching of computer data base of our hospital and archived files of the patients. computer data base is searched for the term of “penile prosthesis”. so we could find the patients who underwent penile prosthesis implantation or penile prosthesis removal. patients data were evaluated for the etiologies and for prosthesis removal in the same hospital or not. all patients were interviewed by phone using number which were recorded in the archived files or in the computer data base. if we could reach the patients by the recorded telephone number we asked several questions to evaluate the use of prosthesis. the questions are shown in table 1 (supplementary materials). patient and partner satisfaction rates, co morbidities, etiology of ed, penile doppler ultrasound results, time between start of complaints and implantation, prosthesis failure rates and causes, and need for partner change were evaluated. all the parameters were evaluated as means, standard deviations, percentages and number of patients. simsek sc_stesura seveso 08/10/14 12:16 pagina 219 archivio italiano di urologia e andrologia 2014; 86, 3 a. simsek, o. kucuktopcu, f. ozgor, u. ozkuvanci, m. baykal, o. sarilar, z. gokhan gurbuz 220 results between january 2008 and july 2013, we implanted three-part ipp to 36 patients depending on computer database search results. according to the data from computer and archived files of patients, the etiology of erectile dysfunction was diabetes mellitus in 18, priapism in 1, radical pelvic surgery in 9 and unknown in 8 patients. of these 36 patients 4 were recorded for removal of prosthesis. the cause of prosthesis removal was infection in 3 patients and perforation in 1 patient. out of 36 patients recorded on computer, we could reach only 18 patients by telephone. all of them answered our questionnaire. the mean age of 18 patients was 55.7 ± 9.4 years and mean body mass index was 24.6 ± 2.1 kg/m2. the etiology was diabetes mellitus in 14 (77.8%) and radical pelvic surgery in 4 (22.2%). fourteen of 18 patients had penile doppler ultrasound test which demonstrated venous insufficiency in 8 and arterial insufficiency in 6 patients. the patients suffered from erectile dysfunction from a mean of 4 ± 3 years. mean time from implantation to study was 20.8 ± 13.9 months. patients used their prosthesis on a mean of 8 ± 3.1 times per month. of these 18 patients 2 had prosthesis removal operation because of infection in one case and perforation in another case. sixteen (88.9%) patients were satisfied with their prosthesis and 2 (11.1%) were dissatisfied. causes of dissatisfaction were pain in one patient and insufficient rigidity and shortening of penis in the other one. surprisingly 5 patients reported shortening of penis but 4 of them did not complain about and only one of them was dissatisfied because of shortening. none of them reported cosmetic problems and none of the patients needed to change their sexual partners after implantation. patients reported 17/18 (94.4%) partner satisfaction rate. but the unsatisfaction cause of this one partner was urinary incontinence of the male because of radical prostatectomy rather than the erection status. only one patient that was dissatisfied because of insufficient rigidity and penile length reported that he could not recommend the implantation. the recommendation rate was 94.4%. discussion ppi surgery is the treatment method in patients with end stage ed when oral and ici treatments are ineffective or contraindicated (5). arterial and venous dysfunctions caused by systemic diseases (6) or non nerve sparing surgery on bladder, prostate or rectum can cause ed needing prosthesis implantation (7, 8). inflatable devices have been initially introduced by scott in 1973 (3) and now are available in a two and three pieces version. ipp can be deflated mimicking the flaccid penile state. they are associated with higher patient and partner satisfaction rates than malleable prosthesis as they allow expansion of penis, thus preventing the risk of “pencil penis” syndrome and cosmetic problems (9). none of our patients in this study reported occurrence of such cosmetic problems after implantation. reliability of the device has been significantly improved and mechanical failure rates declined from 61% to 1020% at approximately 5-10 years of follow up (10). if the failure occurs in the early months, it is not necessary to remove the entire device and the identification and exchange of the faulty component usually suffices. if the mechanical failure occurs after 2 years instead, it is advisable to exchange the entire device (9). in this study prosthesis removal surgery was done for 2 (6%) patients in the total group of 36 patients and for one (6%) patient out of 18 patients interviewed by phone because of perforation of prosthesis. infection ranges from 1.8% to 10% and is an important complication which could cause the revision or the removal of the device (11). infections are generally caused by staphylococcus epidermidis and s. aureus, followed by gram-negative bacteria and anaerobic organisms (12). in our study infection rates was 6 % for both the total group and the group of interviewed patients. patients who have already undergone this kind of treatment defined really high rates of satisfaction, up to 97% of cases (9, 13). satisfaction rates are better assessed with the use of validated questionnaires such as the international index of erectile function (iief) and the erectile dysfunction inventory of treatment satisfaction (edits)(14-15). the edits questionnaire was first validated in 1999 as an instrument by which patients’ and partners’ satisfaction with treatments for erectile dysfunction could be assessed (15). satisfaction can be affected by many variables. partner behavior plays a role (16) and patient expectations can have a great impact (17). satisfied patients have favorable partner sexual function compared to that of unsatisfied patients. the correlation observed suggests that patients not satisfied with their inflatable penile prosthesis (ipp) are likely to have female partners at high risk for female satisfaction. also female satisfaction rate correlates satisfaction rates of the patients. studies suggested a direct linear correlation of satisfaction between the sexual partners (16). also in our study, patient and partner satisfaction rates were 88.9% and 94.4% respectively, similarly to the literature. none of our patients defined dissatisfaction due to bad partner sexual performance and none of them needed to change their partners. of the 8% who were unsatisfied in the bettocchi et al. paper, the main reasons given were insufficient rigidity and penile length (9). moreover, the same could be said for the garber’s study where 8% were dissatisfied with penile length. one of our patients dissatisfied because of pain, and one patient (5.6%) was dissatisfied because of insufficient rigidity and shortening of the penis. five patients (27.8%) had shortening problem but only one of them was dissatisfied. one limitation in this study is that we did not use validated questionnaires for evaluating the satisfaction of patients and partners. we asked only if the patient was satisfied and if he recommended this treatment to another patient or not. according to our questionnaire our satisfaction rate was 88.9% and this was compatible with the literature. seventeen (94.4%) patients recommended ppi treatment. one patient who was dissatisfied because of pain also recommended this treatment because of good rigidity of penis. another limitation of our study was a low patient number. bettocchi et al. studied 79 patients between 2004-2008. in simsek sc_stesura seveso 08/10/14 12:16 pagina 220 their study 92% of patients defined improvement in sex and 97% would recommend the same surgery to others (9). montorsi et al. studied 200 patients between 19861997 and 92% patients had satisfactory sexual activity (18). goldstein et al. studied 234 patients between 19891993 and 86% of patients recommended surgery to others (19). our results correlate with rate reported on literature. conclusion today, ppi is the gold standard treatment of ed irresponsive to medical treatment. patient and partner satisfaction rates are high. infection and mechanical failure rates are going to be less according to the improvements in synthetic materials and coverings of prosthesis. more studies about factors effecting dissatisfaction after surgery, especially about female factors resulting in partner changes, should be done. references 1.montague dk, jarow jp, broderick ga, et al. erectile dysfunction guideline update panel. chapter i: the management of erectile dysfunction: an aua update. j urol. 2005; 174:230-239. 2. montague dk. penile prosthesis implantation in the era of medical treatment for erectile dysfunction. urol clin north am. 2011; 38:217-25. 3. scott fb, bradley we, timm gw. management of erectile impotence: use of implantable inflatable prosthesis. urology. 1973; 2:80. 4. carson cc, mulcahy jj, govier fe. efficacy, safety, and patient satisfaction outcomes of an ams 700 cx inflatable penile prosthesis: results of a long term multicenter study. j urol. 2000; 164:376-382. 5. montorsi f, deho f, salonia a, et al. penile implants in the era of oral drug treatment for erectile dysfunction. bju int. 2004; 94:745-51. 6. hatzimouratidis k, hatzichristou dg. treatment options for erectile dysfunction in patientsfailing oral drug therapy. eau updates series. 2004; 2:75. 7. meuleman ej, mulders pf. erectile function after radical prostatectomy: a review. eur urol. 2003; 43:95-101. 8. bettocchi c, palumbo f, spilotros m, et al. penile prostheses. ther adv urol. 2010; 2:35-40. 9. bettocchi c, palumbo f, spilotros m, et al. long term patient satisfaction and quality of life with ams700cx inflatable penile prosthesis. j sex med. 2010; 7:304-9. 10. kim sc mechanical reliability of ams hydraulic penile prostheses. j korean med sci. 1995; 10:422-425. 11. al-enezi a, al-khadhari s, al-shaiji tf. three-piece inflatable penile prosthesis: surgical techniques and pitfalls. j surg tech case rep. 2011; 3:76-83 12. evans c. the use of penile prostheses in the treatment of impotence. bju. 2001; 81:591-598. 13. natali a, olianas r, fisch m. penile implantation in europe: successes and complications with 253 implants in italy and germany. j sex med. 2008; 5:1503-1512. 14. mulhall jp, ahmed a, branch j, parker m. serial assessment of efficacy and satisfaction profiles following penile prosthesis surgery. j urol. 2003; 169:1429-1433. 15. althof se, corty ew, levine sb, et al. edits: development of questionnaires for evaluating satisfaction with treatments for erectile dysfunction. urology. 1999; 53:793-9. 16. gittens p, moskovic dj, avila d jr, et al. favorable female sexual function is associated with patient satisfaction after inflatable penile prosthesis implantation. j sex med. 2008; 8:1996-2001. 17. kramer ac, schweber a. patient expectations prior to coloplast titan penile prosthesis implant predicts postoperative satisfaction, j sex med. 2010; 7:2261-2266. 18. montorsi f, rigatti p, carmignani g, et al. ams three-piece inflatable implants for erectile dysfunction: a long-term multi institutional study in 200 consecutive patients. eur urol. 2000; 37:50-55. 19. goldstein i, newman l, baum, et al. safety and efficacy outcome of mentor alpha-1 inflatable penile prosthesis implantation for impotence treatment. j urol, 1997; 157:833-839. 221archivio italiano di urologia e andrologia 2014; 86, 3 satisfaction rates of penile prosthesis implantation correspondence abdulmuttalip simsek, md (corresponding author) simsek76@yahoo.com onur kucuktopcu, md faruk ozgor, md unsal ozkuvanci, md murat baykal, md omer sarilar, md zafer gokhan gurbuz, md haseki training and research hospital,department of urology, millet cad. no: 11, 34000 fatih, istanbul, turkey simsek sc_stesura seveso 08/10/14 12:16 pagina 221 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 150 review the impact of non-urologic drugs on sexual function in men ferdinando fusco, marco franco, nicola longo, alessandro palmieri, vincenzo mirone department of neurosciences, reproductive science and odontostomatology federico ii university, naples, italy. sexual dysfunctions have commonly been reported as the resulting side effects of many drugs. to understand the impact of a single drug, the mechanism of action of the most commonly prescribed drugs and the physiological mechanisms of sexual function have to be taken into dual consideration. psychotropic drugs (antidepressants, antipsychotics and antiepileptic) in particular result in both short and long-term effects on sexual function. antihypertensive drugs have also produced evidence certifying their role in determining sexual dysfunction. patients affected with sexual dysfunction are often aged and assume several drugs and, while iatrogenic sexual dysfunction is prevalent in men, urological drugs are not the only drugs to be held accountable. many different drugs acting on different sites and with several mechanisms of action can induce sexual dysfunction. the drug classes involved are widely diffused and frequently assumed in combination therapies. key words: sexual dysfunctions; psychotropic drugs; antihypertensive drugs. submitted 17 february 2014; accepted 28 february 2014 summary introduction sexual function is our physiological capacity to experience desire, arousal and orgasm. male sexual activity is a multifaceted activity, involving complex interactions between the nervous system, the endocrine system, the vascular system and a variety of structures that are instrumental in sexual excitement, intercourse and satisfaction (1). as defined by kaplan, this process consists of three phases: desire, arousal (excitement) and orgasm (2). however, the division between the three is arbitrary and only assists in organizing clinical and research oriented problems involving sexuality. in clinical practice sexual desire, arousal and orgasmic difficulties more often than not coexist, suggesting an integration of phases. in males, arousal basically the ability to achieve and maintain an erection. the orgasm is the mental and physical phenomenon that signifies the climax of coital no conflict of interest declared activity and is accompanied by the ejaculation of seminal fluid (3). normal sexual functioning requires not only an ability to interact with others (i.e. a certain level of social skills) but also a combination of different physiological factors, such as the integrity of the genitalia, the reliable co-ordination of blood flow, the activation of various smooth and skeletal muscles and the stimulation of local secretions (3) sexual dysfunction can result from a wide variety of psychological and physical causes. pathophysiology of sexual dysfunction involves derangements in the levels of sex hormones and neurotransmitters (4), and different drugs affect sexual function in different ways depending on their mechanism of action. drugs that affect libido usually act on the central nervous system and may reduce desire by causing sedation or hormonal disturbance. likewise, drugs that interfere with the autonomic system will have negative effects on erectile function, ejaculation and orgasm (5). many drug classes, other than “prostatic” drugs, have the potential to interfere with the physiology of sexual function. knowledge of the normal biology of sexual function may allow one to predict whether a medication might potentially cause sexual dysfunctions. furthermore, clinical experience acquired on different drug classes and molecules can confirm this potential. the purpose of this article is to review the impact of non-urologic drugs on sexual function in men. materials and methods in june 2013 a literature search was conducted from medline to identify original articles published up to this date with no time limitation and analysis was conducted on previously published reviews and any other relevant articles suitable for the purposes of this review. the search was limited to articles published in english and was conducted by combining the following terms: ed and/or sexual dysfunction; aexual dysfunction and/or drugs, and or antidepressant, antiepileptics, antihypertensive, antipsycothic, antiparkinsonian, proton pump inhibitors, recreational drugs. the retrieval was then extended to the reference list and to the related articles. in the case of the availability of more than one publicadoi: 10.4081/aiua.2014.1.50 fusco_stesura seveso 26/03/14 10:50 pagina 50 51archivio italiano di urologia e andrologia 2014; 86, 1 the impact of non-urologic drugs on sexual function in men tion sharing the same information, the most recently published article was included in this review. two independent reviewers evaluated the output listings to identify the references matching the selection criteria and checked each article to ensure consideration of further relevant published articles from the respective reference lists. drugs that affect sexual function several drug classes are reported to interfere with sexual function. evidence was found for medications that differed greatly both for their indications and mechanisms of action, e.g.: antihypertensive, as beta blockers and thiazides, acting on peripheral blood flow and the sympathetic autonomous nervous system; proton pump inhibitors, acting on testosterone metabolism; drugs acting on the central nervous system as antidepressants, antiepileptics and antipsychotics, with their central mechanism of action on ions channels or nervous transmission (table 1). antidepressants treatment-emergent sexual dysfunction caused by antidepressants is a considerable issue with a large variation across compounds (6). this is primarily due to the activation of 5-ht2 receptors which inhibit both noradrenergic and dopaminergic transmission. generally, antidepressants with fewer 5-ht2 effects tend to cause less treatmentemergent sexual dysfunctions (7). depression itself can cause sexual problems, thus it is sometimes difficult to recognize what is causing any occurring sexual dysfunction (8). it is therefore useful to try to get some idea of a person’s sexual functioning prior to starting antidepressants. serretti et al. (6) showed in a recent work on depressed men treated with antidepressants, that there was a significantly higher rate of total and specific treatment-emergent sd and specific phases of dysfunction compared with placebo for the following drugs in decreasing order of impact: sertraline, venlafaxine, citalopram, paroxetine, fluoxetine, imipramine, phenelzine, duloxetine, escitalopram, and fluvoxamine, with sd ranging in 25.8% to 80.3% of patients. no significant difference with placebo was found for the following antidepressants: agomelatine, amineptine, bupropion, moclo bemide, mirtazapine, and nefazodone. in conclusion the use of antidepressant therapy associated with the depression itself, has to be carefully considered in patients with a history of sexual dysfunction. as different antidepressants may have a different impact on sexual function, in the case of antidepressantinduced sd, a switch to an alternative antidepressant may be worth trying. anti-epileptics epileptic men may experience hormonal changes and altered levels of biologically active testosterone; changes that could alter semen quality and sexual function. in addition, 22% to 67% of men with epilepsy have been found to have reduced sexual interest and an impaired quality of sex life (9) moreover, men with epilepsy are at a five-fold higher risk of erectile dysfunction (ed) than men without epilepsy (10). alterations in male sexual and reproductive parameters may also be due to treatment with antiepileptic drugs (aeds) to control seizures (11, 12). carbamazepine: adverse effects of carbamazepine (cbz) use including impaired hepatic p450 enzyme system function and changes in serum sex hormone have been reported. moreover, epileptic men taking cbz present altered semen quality, ed, and a reduction in coital frequency (9). these aeds related effects are explicable if considered as sexual hormonal changes. levetiracetam: the relationship between the older antiepileptic drugs (aeds) and sexual dysfunction has long been known and is likely to be related to sexual hormonal changes. instead, rare reports on sexual disorders related to new aeds suggest the possibility of complex and poorly understood mechanisms as well as alterations of the central nervous system neurotransmitters table 1. different classes and single drugs causing sexual dysfunction. medication class subclasses and single drugs antidepressants tricyclic antidepressants selective serotonin reuptake inhibitors (ssris) monoamine oxidase inhibitors (maois) viloxazine, nefazodone, venlafaxine, reboxetine, mirtazepine, trazodone, duloxetine antipsychotics typical: aliphatic phenothiazines (e.g. chlorpromazine), thioridazine atypical: risperidone, quetiapine, aripiprazole olanzapine clozapine antihypertensives thiazide diuretics beta blockers anti-parkinsonian drugs l-dopa ssris recreational drugs psychostimulants, amphetamine, ecstasy, crystal methamphetamine, alcohol, anabolic steroids, cannabis opiates, poppers, tobacco proton pump inhibitors esomeprazole fusco_stesura seveso 26/03/14 10:50 pagina 51 archivio italiano di urologia e andrologia 2014; 86, 1 f. fusco, m. franco, n. longo, a. palmieri, v. mirone 52 such as glutamate, serotonin, and dopamine. in this regard calabrò et al. (13) reported two men affected by epilepsy in which levetiracetam (lev) intake appeared to induce a severe loss of libido and anhedonia. topiramate: common side effects of topiramate (tpm) comprise of fatigue, somnolence, dizziness, paresthesias and loss of appetite, but sexual dysfunctions including ed and anorgasmia are rarely reported (14, 15) civardi et al. hypothesized that the inhibition of carbonic anhydrase could interfere with production of vip and nitric oxide, two known intracavernosal vasoactive compounds that play a key role in the peripheral erectile mechanism, leading to a reduction in genital blood flow (16). indeed, calabrò et al. (17) have suggested that tpminduced ed may be secondary to a blockage of ampa receptors with inhibition of the glutamatergic pathway, whereas glutamate is considered a candidate neurotransmitter of reflexive erection. to support this hypothesis, recent studies have shown the presence of both ampa and nmda glutamatergic receptor subunits in the lumbosacral spinal cord. moreover, ampa and nmda receptor antagonists are known to block reflexive erection (18). in conclusion, the data reported in literature confirms the alteration of hormonal levels as mechanism of sexual dysfunction in men taking antiepileptic drugs and shows possible different mechanisms for the sexual effects caused by new anti-epileptics drugs. antihypertensives several reports collectively spanning more than three decades indicate that 2.4%-58% of hypertensive males experience one or more symptoms of sexual dysfunction of varying degrees of severity during antihypertensive drug therapy. it is also true, however, that hypertensive patients experience sexual dysfunction prior to taking medication, when compared to normotensive subjects. this finding, while quite consistent with the physiologic changes noted in hypertensive individuals, is often neglected in the overall assessment of subjects and in the formulation of a therapeutic scheme (19). the different anti hypertensive drugs have peculiar mechanisms through which sexual dysfunction is caused. beta blocker: beta blockers (e.g., atenolol and propranolol) may potentially impact sexual functioning through a variety of mechanisms, including a reduction in central sympathetic outflow, impairment of vasodilatation of the corpora cavernosa, effects on luteinizing hormone and testosterone secretion, and a tendency to produce sedation or depression thereby causing a loss of libido (19). an italian study (20) on sexual activity and plasma testosterone in hypertensive men, evaluated the effects of the beta 1-selective beta-blocker atenolol on sexual activity and plasma testosterone levels in newly diagnosed, previously untreated essential hypertensive, sexually healthy men. one of the proposed mechanisms inducing sexual dysfunction is represented by an inhibition of the sympathetic nervous system which is involved in the integration of erection, emission and ejaculation in the regulation of luteinising-hormone secretion and the stimulation of release of testosterone (21). in this study atenolol significantly reduced plasma testosterone values thus confirming previous observations about the depression in testosterone levels in patients receiving this beta-blocker (22, 23). in contrast, a recent important review by ko et al. (24) showed that the conventional wisdom that beta-blocker therapy is associated with substantial risks of sexual dysfunction is not supported by data from clinical trials and that the risk of sexual dysfunction is only minimally increased. the risk of these adverse effects, therefore, should be seen within the context of the documented benefits of these medications. moreover, nebivolol seems to have a beneficial effect on ed, possibly due to increased nitric oxide availability (25). the possible occurrence of ed with metoprolol has, for the most part, been attributed to the prejudice (the so called “hawthorne effect”) on the “easy incidence” of this side-effect in hypertensive men. since the etiology of this ed is largely psychological, it is not surprising that placebo is as effective as a pde5inhibitor, namely tadalafil, in reversing this side effect (26). thiazides: the associations that have been noted between the clinical use of the thiazide diuretics and impairment of male sexual performance remain enigmatic. a medical research council working party in 1981 reported a 16% incidence of impotence in patients taking thiazide diuretics after 12 weeks of treatment (medical research council working party, 1981). a later study of diuretics in mild hypertension showed a significant increase in sexual dysfunction compared with placebo. the disorders noted included a reduction in libido, difficulty in obtaining and maintaining erection and problems with ejaculation. patients on diuretics were 2 to 6 times more likely to experience sexual dysfunction than those on placebo (27). recent studies investigated aspects of the male sexual dysfunction in hypertensive men following treatment with thiazide diuretics. the results suggest that penile erectile defects and decrements in sexual activities are specifically related to thiazide administration. a rodent model of thiazide-induced male sexual dysfunction, that documents dose-related impairment by hydrochlorothiazide of penile erectile reflexes and male copulatory performance is available (28). the etiology of thiazide-induced male sexual dysfunction is hypothesized to result from alterations in sodium excretion that alter afferent renal nerve input to hypothalamic areas regulating male sexual responses. other antihypertensive drugs calcium channel blockers (ccb) and angiotensin-converting enzyme (ace) inhibitors have not been associated with major negative impact on ed. it has also been suggested that angiotensin ii type 1 receptor blockers (arb) would affect sexual function less than other antihypertensive treatment. some data even suggests that sexual function and ed may improve during treatment with arb (29). in conclusion, two groups of antihypertensive drugs were examined in this review which have produced evidence on their role in determining sexual dysfunction. however, in both groups of drugs, individual mechanisms of action through which such alterations of sexual function was perpetrated, have not yet been well defined. antipsychotics human sexual function is affected in many different ways by schizophrenia and the antipsychotic drugs used in its fusco_stesura seveso 26/03/14 10:50 pagina 52 53archivio italiano di urologia e andrologia 2014; 86, 1 the impact of non-urologic drugs on sexual function in men treatment. the evaluation of the effects of antipsychotics on sexual function in patients with schizophrenia is also complex because the deleterious effects of conventional antipsychotics are superimposed on the effects of the disease itself (30). studies have suggested that, although antipsychotic drugs often restore sexual desire lost due to schizophrenia, they may impair patients’ sexual performance (30, 31). in a recent study evaluating a sample of male psychotic patients, both sexual dysfunction and hyperprolactinemia were very prevalent (32). based on their findings in 72 patients, 45.9% of the patients reported diminished sexual desire, whereas 35.9% and 36.1% reported erectile and ejaculatory dysfunction, respectively. a total of 20 patients used risperidone, 26 olanzapine, 9 quetiapine, 13 ziprasidone, and 1 aripiprazole. more than half the sample was hyperprolactinemic, and about one fifth had prolactin levels more than 3 times the upper threshold, none of which were caused by the biologically inert macroprolactin fraction. differences were noted among the drug groups, with risperidone-treated patients having the highest prolactin levels and the highest rate of hyperprolactinemia. hyperprolactinemia has received new attention lately as potential long-term complications have been identified, including osteoporosis and carcinogenic effects (32). no association was found in the present study between prolactin levels and sexual dysfunction. in many case reports and few non-systematic reviews priapism was found to be associated with antipsychotic drug administration (33-38). particular interest should be given to the frequency of priapism. drug-induced priapism accounts for as many as 15% to 41% of all cases, and antipsychotics are the most frequently involved drugs, followed by antidepressants and antihypertensive medications (39). in conclusion, a therapy with antipsychotics medications have to be thoroughly considered in patients reporting sexual dysfunction. there is no definitive evidence that correlates hyperprolactinemia and sexual dysfunction, however since a high incidence of both conditions in treated psychotic patients has been reported, prolactin levels should be measured irrespective of whether sd symptoms are present or not. anti-parkinsonian drugs the reported prevalence of sexual symptoms in men with parkinson disease (pd) ranges from 37% to 65% (40). bronner et al. (41) reported that use of medications (selective serotonin reuptake inhibitors used for comorbid depression), and advanced pd stage contributed to the development of ed. it is possible that levodopa and other antiparkinsonian medications may affect sexual function in pd. however, it is not entirely clear to what extent levodopa influences sexual dysfunction in pd. pathological hypersexuality may occur together with (42) or without delirium (43), which is attributed to the dopamine dysregulation syndrome in this disorder. deep brain stimulation in the subthalamic nucleus has produced either improved sexual wellbeing (44) or transient mania with hypersexuality (45) in patients with pd (40). more studies are needed to better understand the etiology and probable mechanism of action of levodopa in determining sexual dysfunction in men with parkinson disease. proton pump inhibitors a case report recently described a 42-year-old woman with previously normal sexual function who gradually developed loss of libido during treatment with esomeprazole. while taking esomeprazole, the patient's loss of libido improved with oral testosterone supplementation and deteriorated after testosterone withdrawal. steady improvement in both sexual function and serum free testosterone concentration after discontinuation of esomeprazole was observed. based on this evidence, proton pump inhibitors (ppi) could determine sexual dysfunction by modulation of the isoformes of cytochrome enzymes involved in testosterone metabolism (46). only 1 case report was found regarding sexual dysfunction induced by ppi (46). given the large number of prescription and administrations of these medications, further investigation of the role that these drugs may play in sexual dysfunction should be conducted. pde5 and combination therapy: interaction and patient’s safety the phosphodiesterase-5 inhibitors (pde5i) sildenafil, vardenafil, and tadalafil are considered first-line therapy for the treatment of patients with erectile dysfunction (ed). the widespread application of pde5i, that causes the potential for drug-drug interactions emerges as a relevant factor in determining the safety profile of pde5i. the use of nitrates remains the only contraindidcation for all 3 pde5i. vardenafil is also not recommended in patients taking type 1a (such as quinidine, or procainamide) or type 3 antiarrhythmics (such as sotalol, or amiodarone) while no other major limitations have been reported for tadalafil and sildenafil. in contrast to previously reported labeling, recent studies have suggested only precaution, but not contraindication, with the concomitant use of alpha-blockers agents. in addition, precaution is also suggested in the presence of potent cyp3a inhibitors such as azole antifungals, antiretroviral protease inhibitors, or macrolide antibiotics. this is because sildenafil, vardenafil, and tadalafil are metabolized mainly via the cyp3a4 pathway. on the other hand, statins and testosterone seem to have synergic effects with pde5i on sexual activity (47). the safety and efficacy of the 3 currently available pde5 inhibitors (sildenafil, tadalafil, and vardenafil) have been evaluated extensively in patients with ed and concomitant cardio vascular disease (cvd), hypertension, dyslipidemia, or diabetes with or without additional risk factors. overall, these studies have shown similar efficacy for the 3 agents resulting in significant improvement of erectyle function in patients with any of these comorbid conditions. their safety profile was also similar. no adverse effects on cardiac contraction, ventricular repolarization, or ischemic threshold was noted, and there was no evidence of increased cardiovascular risk from using any of these agents. however, because ed is known to be a harbinger of cardiovascular events in some men, the presence of ed should prompt investigation and intervention for cardiovascular risk factors (48). lastly, in a recent study of men with high systolic blood pressure who had initiated ed therapy, was showed an improvement in the systolic blood pressure control. fusco_stesura seveso 26/03/14 10:50 pagina 53 archivio italiano di urologia e andrologia 2014; 86, 1 f. fusco, m. franco, n. longo, a. palmieri, v. mirone 54 after initiating therapy with pde5i, patients were more likely to start an antihypertensive medication (17.3%) versus stop therapy (2.3%) and add additional antihypertensive medication to their existing therapy (42.2%) versus decrease the number of medications (17.3%). surveillance also increased with total number of systolic bp measurements increasing by 42%. in conclusion, men with high systolic bp who initiated ed therapy had improvements in systolic bp control that may be related to clinically relevant behaviors, such as more aggressive monitoring and treatment with antihypertensive medications. future research should further explore the underlying reasons and mechanisms for the observed improvements in systolic bp and whether cessation of ed therapy results in worsening bp control (49). conclusions patients affected with sexual dysfunction are often aged and assume several drugs (figure 1). slabaugh et al. published a study reporting that 39.4% of patient over 65 years were exposed to multi-drug consumption during the study period (50). elderly people are substantial consumers of medications and communitybased surveys reveal that they take an average of 2.7 to 3.9 prescription and nonprescription medications (51). coadministration of drugs may be a factor for sexual dysfunction in single patients, and effects on sexual function may be unforeseeable. in our search we did not find any trial exploring the effects of multiple drugs prescription on sexual function. however, considering the results of available data, a negative synergic effect on sexual function is plausible. when evaluating an elderly man with ed, medical history should be attentively focused on pharmacological therapies. the “myth” of sex-killer drugs, e.g. 5alpha reductase inhibitors or beta-blockers, that should be identified amongst a number of several “innocent” drugs possibly assumed by a single patient should be put into perspective. many widely diffused drug classes that would most commonly be defined as “unsuspectable” have the potential to affect sexual function on their own, and even more so when the number of co-administered drugs makes a synergistic, multidrug impact plausible. while iatrogenic sexual dysfunction is prevalent in men, urological drugs are not the only drugs to be held accountable for this. many different drugs acting on different sites and with several mechanisms of action can induce sexual dysfunction. the drug classes involved are widely diffused and frequently assumed in combination therapies. therefore, both general practitioners and specialists must consider the importance of pharmacological therapy in their clinical practices. references 1. 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patients on depot neuroleptic medication. eur psychiatry 1996; 11:81-86. 32. johnsen e, kroken r, løberg em, et al. sexual dysfunction and hyperprolactinemia in male psychotic inpatients: a cross-sectional study. adv urol. 2011; 2011:686924 33. pais vm, ayvazian pj. priapism from quetiapine overdose: first report and proposal of mechanism. urology. 2001; 58:462. 34. davol p, rukstalis d. priapism associated with routine use of quetiapine: case report and review of the literature. urology. 2005; 66:880. 35. andrés prado mj, vidal formoso m. j priapism associated with quetiapine in an elderly patient actas esp psiquiatr. 2006; 34:209-10. 36. kirshner a, davis rr. priapism associated with the switch from oral to injectable risperidone. clin psychopharmacol. 2006; 26:626-8. 37. torun f, yılmaz e, gümüs e. priapism due to a single dose of quetiapine: a case report. turk psikiyatri derg. 2011; 22:195-9. 38. sinkeviciute i, kroken ra, johnsen e. priapism in antipsychotic drug use: a rare but important side effect. case rep psychiatry. 2012 ;2012:496364. 39. sinkeviciute i, kroken ra, johnsen e. priapism in antipsychotic drug use: a rare but important side effect. case rep psychiatry. 2012; 2012:496364. 40. sakakibara r, kishi m, ogawa e, et al. bladder, bowel, and sexual dysfunction in parkinson's disease. parkinsons dis. 2011; 2011:924605.9. 41. bronner g, royter v, korczyn ad, giladi n. sexual dysfunction in parkinson’s disease. journal of sex and marital therapy. 2004; 30:95-105. 42. klos kj, bower jh, josephs ka, et al. pathological hypersexuality predominantly linked to adjuvant dopamine agonist therapy in parkinson’s disease and multiple system atrophy. parkinsonism and related disorders. 2005; 11:381-386. 43. kessel bl. a case of hedonistic homeostatic dysregulation. age and ageing. 2006; 35:540-541. 44. castelli l, perozzo p, genesia ml, et al. sexual well being in parkinsonian patients after deep brain stimulation of the subthalamic nucleus. journal of neurology, neurosurgery and psychiatry. 2004; 75:1260-1264. 45. romito lm, raja m, daniele a, et al. transient mania with hypersexuality after surgery for high-frequency stimulation of the subthalamic nucleus in parkinson’s disease. movement disorders. 2002; 17:1371-1374. 46. rosenshein b, flockhart da, ho h. induction of testosterone metabolism by esomeprazole in a cyp2c19*2 heterozygote. am j med sci. 2004; 327:289-93. 47. corona g, razzoli e, forti g, maggi m. the use of phosphodiesterase 5 inhibitors with concomitant medications. endocrinol invest. 2008; 31:799-808. 48. nehra a. erectile dysfunction and cardiovascular disease: efficacy and safety of phosphodiesterase type 5 inhibitors in men with both conditions. mayo clin proc. 2009; 84:139-148. 49. scranton re, lawler e, botteman m, et al. effect of treating erectile dysfunction on management of systolic hypertension. am j cardiol. 2007; 100:459-63. 50. slabaugh sl, maio v, templin m, abouzaid s. prevalence and risk of polypharmacy among the elderly in an outpatient setting: a retrospective cohort study in the emilia-romagna region, italy. drugs aging. 2010; 27:1019-28. 51. hanlon jt, landerman lr, wall we jr, et al. is medication use by community-dwelling elderly people influenced by cognitive function? age ageing. 1996; 25:190-6. correspondence ferdinando fusco, md ferdinando-fusco@libero.it marco franco, md (corresponding author) marcofranco87@gmail.com nicola longo, md alessandro palmieri, md vincenzo mirone, md department of neurosciences, reproductive science and odontostomatology federico ii university, naples, italy fusco_stesura seveso 26/03/14 10:50 pagina 55 stesura seveso 229archivio italiano di urologia e andrologia 2014; 86, 3 case report a rare cause of renal colic pain: chilaiditi syndrome murat tuncer, cahit sahin, ozgur yazici, alper kafkaslı, kemal sarica dr. lutfi kirdar training and research hospital urology clinic, istanbul, turkey. chilaiditi syndrome, first described in 1910 by the radiologist chilaiditi from vienna, is the interposition of right colon between liver and right hemi diaphragm. it occurs most often in males and its incidence increases with age. it is often detected incidentally during radiological examination. it’s rarely symptomatic; symptoms can differ from mild abdominal pain to severe acute intestinal obstruction. our case applied to emergency service with right flank pain. there was no calculus or dilatation in the urinary system at non-contrast abdominopelvic computerized tomography. ascending colon was interposed between liver and diaphragm so that the patient was diagnosed as chiliaditi syndrome. the patient was treated conservatively and discharged with dietary suggestions by the gastroenterology consultant. the conclusion of this report is that the chilaiditi syndrome must be considered in differential diagnosis for patients presenting with urinary colic pain symptoms with no urinary pathology on radiologic imaging. key words: chilaiditi syndrome; renal colic; hepatodiaphragmatic interposition. submitted 3 february 2014; accepted 30 june 2014 summary case report we present a patient with chilaiditi syndrome referred to emergency department for severe right renal colic pain, who was diagnosed with the help of radiological examinations and treated conservatively. case report details in supplementary materials posted on www.aiua.it discussion as in the majority of the cases of asymptomatic anatomical abnormalities, chilaiditi’s sign is a characteristic radiological finding of hepatodiaphragmatic interposition of bowel segment. as chiladiti syndrome has no specific clinical finding(s) which will let the clinician to consider the pathology at once and make the diagnosis, this pathology is usually incidentally diagnosed during a routine chest and/or abdominal plain film (4) whereas ct and/or ultrasonography examination have been reported to be necessary for the differential diagnosis. although no conflict of interest declared. the majority of the cases are clinically symptom free, in case of associated symptoms (abdominal pain, nausea, vomiting, distension, anorexia, constipation, respiratory distress and chest pain (2, 6, 7) it is called chilaiditi syndrome (8). the pathology is extremely rare and up to now approximately a total of 160 cases have been reported in the literature (9). in our present case radiological images were not obtained during an asymptomatic period but ct evaluation done during symptomatic period confirmed the diagnosis. hepatodiaphragmatic interposition of right colon is the most common radiological sign of chiliaditi syndrome. although an anterior interposition is the most common radiologic finding; posterior interposition is also possible in a certain percent of the cases (7). on the other hand, ileal or gastric form of interpositions have also been described in the literature (7). this condition may be permanent or temporary (10). although the precise underlying causes of this pathologic interposition are still to be clarified, some liver (small or ptotic liver, cirrhosis, abnormal or deficient falciform ligament), diaphragm (diaphragmatic muscle degeneration, phrenic nerve palsy, and intrathoracic pressure increase due to tuberculosis or emphysema) and lastly colon related factors (abnormal dilatation of colon, abnormal or deficient suspensory ligament and congenital malposition or malrotation of colon, chronic constipation, aerophagia) could be responsible for this anatomical abnormal location of the colon (2, 11). the differential diagnoses of chilaiditi syndrome can also include bowel obstruction, volvulus, intussusception, ischemic bowel, or inflammatory conditions (eg, appendicitis or diverticulitis) and diaphragmatic hernia (2) pneumoperitoneum and subphrenic abcesses (12). in our case, at physical examination, lung auscultation was normal and there was no rebound or defence during abdominal palpation. furthermore there were no signs of infection like fever and leucocytosis. in the light of the present clinical signs, symptoms and laboratory findings along with the normal anatomy of the gallbladder on ct (which may cause right upper quadrant abdominal pain), and absence of other characteristic radiologic signs which may be attributed to other well known pathologies (volvulus, intussusception, ischemic bowel or inflammatory conditions such as appendicitis or diverticulitis, etc.) and should be considered in differential diagnosis we took in consideration this syndrome. colonic doi: 10.4081/aiua.2014.3.229 tuncer cr_stesura seveso 08/10/14 12:19 pagina 229 archivio italiano di urologia e andrologia 2014; 86, 3 m.tuncer, c. sahin, o. yazici, a. kafkaslı, k. sarica 230 interposition between liver and diaphragm and the presence of aforementioned symptoms, made us to diagnose the case as a chilaiditi syndrome. this syndrome is generally asymptomatic however patients can refer with symptoms of abdominal pain, nausea, vomiting, distension, anorexia, constipation, respiratory distress, cardiac arrhythmia (12). occasionally, it may be associated with some severe complications such as internal hernias, colonic volvulus and acute intestinal obstruction (7). treatment of chilaiditi syndrome is generally conservative. this approach requires bed rest, nasogastric and/or rectal decompression, high fiber diet, fluid supplementation and stool softeners in symptomatic cases (7). although conservative management is successful to relieve the existing symptoms in the majority of the cases, surgical treatment (such as subtotal colectomy, peritoneal fixation of colon, and hepatopexy) may be necessary in cases with persistent pain, refractory ileus, colonic volvulus or bowel ischemia (10, 13). conservative management was successful in our case and the clinical course was uneventful without any serious complication. chilaiditi syndrome generally presents with gastrointestinal, respiratory and cardiac symptoms. however, patients can rarely refer with symptoms mimicking renal colic pain as shown in our present case. to our knowledge there is only one case with this syndrome reported in the literature referring with renal colic symptoms (14) although another case has been reported to have urological problems such as complaints of prostatism and right renal stone (15). references 1. chilaiditi d. on the question of the hepatoptosis ptosis and generally in the exclusion of three cases of temporary partial liver displacement. progr field roentgenst. 1910; 11:173-208. 2. moaven o, hodin ra. chilaiditi syndrome: a rare entity with important differential diagnoses. gastroenterol hepatol. 2012; 4: 276-8. 3. mcnamara rf, cusack s, hallihan p. chilaiditi’s syndrome. west j emerg med. 2009; 10:250. 4. chen sy, liu ct, tsai yc, et al. sigmoid volvulus associated chilaiditi’s syndrome. rev esp enferm dig. 2007; 99:482-3. 5. dogu f, reisli i, ikinciogullari a, et al. unusual cause of respiratory distress: chilaiditi syndrome. pediatrics international. 2004; 46:188-190. 6. angulo cuesta j, gonzález zorraquino a, unda urzaiz m, flores corral n. chilaiditi syndrome in the differential diagnosis of renal colic. arch esp urol. 1991; 44:300-1. 7. qubenaıssa a, perrault lp, ridoux g, et al. hepatodiaphragmatic interposition of the colon: an unusual case of combined anterior and posterior types treated with an original operative technique. dis colon rectum. 1999; 42:278-80. 8. sorrentino d, bazzocchi m, badano l, et al. heart-touching chilaiditi’s syndrome. world j gastroenterol. 2005; 11:4607-9. 9. yagnik vd. chilaiditi syndrome with carcinoma rectum. saudi j gastroenterol. 2011; 17:85-6. 10. haddad cj, lacle j. chilaiditi’s syndrome: a diagnostic challange. postgrad med. 1991; 89:249-52. 11. white jj, chavez ep, macon sj. internal hernia of the transverse colon chilaiditi syndrome in a child. j pediatr surg. 2002; 37:802-4. 12. dogu f, reisli i, ikinciogullari a, et al. unusual cause of respiratory distress: chilaiditi syndrome. pediatr int. 2004; 46:188-90. 13. hsu hl, liu kl. hepatodiphragmatic interposition of the colon.cmaj. 2011; 183:132. 14. alva s, shetty-alva n, longo we. image of the month. chilaiditi sign or syndrome.arch surg 2008; 143:93-4. 15. özer c, zenger s. chilaiditi syndrome in a patient with urological problems: incidental diagnosis on computed tomography. can urol assoc j. 2012; 6:75-6. interposition of colon between diaphragm and liver: the chilaiditi sign. correspondence murat tuncer, md (corresponding author) murattuncer77@hotmail.com. cahit sahin, md cahitsahin129@hotmail.com ozgur yazici, md md.ozguryazici@yahoo.com.tr alper kafkaslı, md alpkafkasli@hotmail.com kemal sarıca, md professor saricakemal@gmail.com altunizade mah.atif bey sok.gokdeniz sitesi e blok d:20 kosuyolu, istanbul, turkey tuncer cr_stesura seveso 08/10/14 12:19 pagina 230 stesura seveso 237archivio italiano di urologia e andrologia 2014; 86, 3 case report efficacy of pentoxifylline in peyronie’s disease: clinical case of a young man lucio dell’atti, gianni ughi urology unit, arcispedale “s. anna”, university of ferrara, italy. peyronie’s disease (pd) is a localized connective tissue disorder of the tunica albuginea of the penis and its surrounding tissue which results in a painful erection, penile curvature and erectile dysfunction. the great number and variety of purposed treatments for pd is in proportion to the difficulty of its management.in fact no medical treatment is currently available to cure patients with pd. pentoxifylline (ptx) is a non specific phosphodiesterase inhibitor with anti-inflammatory properties that has been used to treat claudication. ptx has also been used to decrease inflammation and fibrosis in kidney transplants, open heart surgery, dermatological conditions and after radiation injury. with respect to penile diseases, clinical studies have suggested that ptx decreases calcification in new-onset pd. these traits make ptx an interesting potential option for pd therapy. key words: peyronie’s disease; pentoxifylline; ultrasound; phosphodiesterase inhibitor. submitted 5 september 2013; accepted 30 june 2014 summary no conflict of interest declared. introduction peyronie’s disease (pd) is a relatively common disorder in men (3-9%) and a frequent cause of sexual distress (1). pd (or induratio penis plastica) is characterized by the formation of a fibrous plaque within the tunica albuginea of the penile corpora cavernosa. most patients present with concerns about a penile lump, curvature, painful erections or erectile dysfunction. a short list of differential diagnoses, such as congenital chordee, dorsal vein thrombosis, infiltrative cancer or a sexually transmitted disease need to be excluded. oral pharmacotherapy should be considered as a treatment option for acute and earlier chronic phases. many oral medicines, including vitamin e, potassium para-aminobenzoate, tamoxifen, colchicines, propionyl-lcarnitine, have been used, but there is no satisfactory oral medical treatment available (2). pentoxifylline (ptx) has anti-inflammatory and antifibrogenic properties, with inhibitory effects on the basic mechanisms of fibrogenesis, cell proliferation and extracellular matrix synthesis (3). these mechanisms of actions might reverse the fibrotic process in pd. doi: 10.4081/aiua.2014.3.237 case report a 35 years old caucasian male had for about 5 years difficulties in penetration during sexual act due to a lack of rigidity and tumescence in the terminal part of the penis. however the patient during erection did not report the presence of curving of the penis. this disorder was not associated with erectile dysfunction, ejaculatory dysfunction or low libido. there is no personal or family history of fibrotic disorders. he does not smoke and has an occasional alcoholic beverage, moreover his general health was excellent and he doesn’t make use of medicines or drugs. physical examination revealed nothing abnormal in his testicles, epididymis or scrotum. however, a large fibrotic lesion was palpable in correspondence of the dorsal portion of the penis approximately below the root to the glans. laboratory evaluation was normal including complete blood count, routine biochemistry analyses, kidney and liver function tests, sex hormones, prolactin and serum lipid measurement. penile b-mode sonography revealed a calcified peyronie plaque that involved about 1cm in length below the glans the entire tunica albuginea of both corpora cavernosa. this plaque created a deep notch on the medial profile that in addition to affect both the corpora cavernosa on one side penetrated ventrally causing dislocation and compression of the cavernous arteries, while on the other side back penetrated leading to removal of albuginea from buck’s fascia (figure 1). to evaluate the penile vasculature, an intracavernosal injection with 20 µg of prostaglandin e1 was administered and color and duplex doppler sonography were performed during tumescence. the study revealed a peak systolic flow velocity (psv) of 60 cm/s (figure 2), an end-diastolic flow velocity (edv) of 4 cm/s with resistivity index (ri) 0,93 in the cavernosal arteries below the plaque, while in the cavernosal arteries above the plaque psv was 20 cm/s (figure 3), edv 5 cm/s and ri 0.73. the patient was given sildenafil citrate at 50 and 100 mg orally for addressing erectile dysfunction without any benefit in terms of tumescence of the terminal part of the penis. the patient was prescribed ptx 400 mg three times a day for 6 months. upon re-evaluation 6 months dell'atti cr_stesura seveso 09/10/14 10:32 pagina 237 archivio italiano di urologia e andrologia 2014; 86, 3 l. dell’atti, g. ughi 238 later, the patient reported improvement of tumescence of the glans with the possibility to have penetration during sexual intercourse in association of occasional use of 5phosphodiesterase inhibitors. pentoxifylline use was continued, and, upon reassessment one years later, improved erectile function was reported without the use of erectogenic agents. conclusion the management of patients with pd would be improved by the development of a treatment strategy that can reverse the abnormal fibrotic reaction of the tunica albuginea. although the case reported certainly presents as an atypical form of pd, it was improved by ptx administration that increased tissue perfusion and psv and showed anti-inflammatory and antifibrogenic properties, with inhibitory effects on the basic mechanisms of fibrogenesis, e.g. cell proliferation and extracellular matrix synthesis. we believe that more studies are required to determine the optimal doses and treatment duration. references 1. schwarzer u, sommer f, klotz t, et al. the prevalence of peyronie’s disease: results of a large survey. bju int. 2001; 88:727-30. 2. abern mr, larsen s, levine l. combination of penile traction, intralesional verapamil and oral therapies for peyronie’s disease, j sex med. 2012; 9:288-295. 3. windmeier c, gressner am. pharmacological aspects of pentoxifylline with emphasis on its inhibitory actions on hepatic fibrogenesis. gen pharmacol. 1997; 29:181-96. discussion and full list of references are posted in supplementary materials on www.aiua.it correspondence lucio dell’atti, md, phd (corresponding author) dellatti@hotmail.com gianni ughi md gianniughi@ospfe.it urology unit, arcispedale “s. anna” via a. moro 8 44124 cona, ferrara, italy figure 1. penile b-mode sonography revealed a calcified peyronie plaque. figure 2. penile color-doppler sonography revealed a psv of 60 cm/s in the cavernosal arteries below the plaque. figure 3. penile color-doppler sonography revealed a psv of 20 cm/s in the cavernosal arteries above the plaque. dell'atti cr_stesura seveso 09/10/14 10:32 pagina 238 stesura seveso 205archivio italiano di urologia e andrologia 2014; 86, 3 original paper injection devices for bulking agents in uro-gynaecology maria angela cerruto, carolina d’elia, pierpaolo curti urology clinic, a.o.u.i. verona, italy. stress urinary incontinence (sui) affects a large proportion of middle-aged and elderly women. when all conservative means are ineffective, a surgical treatment including retropubic suspension, pubovaginal and tension-free slings, is contemplated. intra-urethral injections with bulking agents have been used as an alternative to the mentioned surgical procedures with alternate results. many urethral bulking agents are available, such as bovine glutaraldehyde cross linked (gax) collagen, polytetrafluoroethylene (teflon), polydimethyl-sillxane elastomer (silicone), carbon coated zirconium beads, hyaluronic acid/dextranomer, and autologous tissues such as fat and cartilage. these substances may be injected in a retrograde or antegrade fashion in the periurethral tissue and whether one route of injection is better than another is not well documented in the literature. we briefly describe the main injection techniques and devices of the most common bulking agents used in the treatment of female sui. key words: stress urinary incontinence; bulking agents; transurethral injections. submitted 3 october 2013; accepted 31 december 2013 summary introduction stress urinary incontinence (sui) affects a large proportion of middle-aged and elderly women, considerably lowering their quality of life and causing major economical costs to the society. when all conservative means are ineffective, a surgical treatment is contemplated, including retropubic suspension, pubovaginal and tension-free slings. tensionfree tapes are considered minimally invasive procedures, yielding a lesser degree of discomfort and a faster return to normal daily activities for the patients, but they still require the use of the operating room, troncular anaesthesia, and an overnight hospital stay in most instances. intra-urethral injections with bulking agents have been used as an alternative to the mentioned surgical procedures with alternate results, also due to the different characteristics of the various agents utilized, the most common shortcomings being lack of biocompatibility, allergenicity and short permanence in the tissue. continuous advances in materials technology have provided the possibility that many urethral bulking agents are available (1), such as bovine glutaraldehyde cross linked (gax) collagen, polytetrafluoroethno conflict of interest declared. ylene (teflon), polydimethyl-sillxane elastomer (silicone), carbon coated zirconium beads, hyaluronic acid/dextranomer, and autologous tissues such as fat and cartilage (2). these substances may be injected in a retrograde (more common) or antegrade fashion in the periurethral tissue around the bladder neck and proximal urethra. whether one route of injection is better than another is not well documented in the literature. schulz et al. compared the transurethral injection route with paraurethral one (3). the authors showed a trend towards better subjective and objective outcomes in favour of transurethral injection without reaching statistical significance. although there is no evidence that transurethral route is better than paraurethral, the argument in favour of the former is supported by the finding of more complications following paraurethral injection (4). we briefly describe the main injection techniques and devices of the most common bulking agents used in the treatment of female sui. transurethral and periurethral injection technique and devices of collagen the precise placement of the injected material is essential to ensure the most desired clinical outcome (5). the injection may be performed through a needle placed directly through the cystoscope or periurethrally with a spinal needle placed percutaneously at the introitus and positioned in the tissue adjacent to the urethra. the collagen implant syringe contains 2.5 ml of sterile bovine gax collagen dispersed in phosphate buffered physiological saline. transurethral injection is performed using a 18 fr cystoscope. the needle is advanced into the urethral wall just below the bladder neck and the implant is injected submucosally until the urethral coaptation is observed at the needle penetration site. injections may be repeated at multiple sites (from 1 up to 5 injections) as needed until closure of the proximal urethral lumen is achieved (6). periurethral injection could minimize possible complications such as bleeding and extrusion of the injected substance (5). it should be easy to handle the spinal needle and cystoscope simultaneously to ensure precise placement of the needle tip in the periurethral tissue in the proximal urethra just below the bladder neck. the patient is placed in the lithotomy position, and after the anaesthetic procedures, a 20or 22-gauge spinal needle, doi: 10.4081/aiua.2014.3.205 cerruto_stesura seveso 08/10/14 12:12 pagina 205 archivio italiano di urologia e andrologia 2014; 86, 3 m.a. cerruto, c. d’elia, p. curti 206 with the obturator in place, is placed at 4 o’clock position with the bevel of the needle directed medially toward the lumen of the urethra (5). the needle is advanced through the urethral muscle into the lamina propria, remaining entirely submucosally. in this plane, the needle should advance with ease. during needle advancement, a 17-18 fr cystoscope employing either a 0or 30-degree lens may be used to ensure optimal needle placement. the needle should be positioned 0.5 cm below the vesical neck within the lamina propria (6). after removing the spinal needle obturator, the substance is injected with one hand while stabilizing the cystoscope with the other one. the collagen is seen accumulating first within the lining of the urethra as a whitish bulging of the urethral mucosa. the material should be injected slowly to allow accommodation within the tissues. when the urethra is 50% or greater occluded, the needle is removed and reinserted on the opposite side in the 8 o’clock position. additional collagen may be injected until the urethral mucosa coapts, creating the desired urethral occlusion. to prevent remodelling of the injected material, care should be taken not to advance the cystoscope proximal to the injected material. should the urinary bladder become over-distended during the injection process, the cystoscope may me removed and a 12fr catheter inserted to drain the bladder (5). transurethral injection technique and devices of silicone microimplants (macroplastique; polydimethylsiloxane) macroplastique is a soft tissue bulking agent and is comprised of soft, flexible, highly-textured irregularly shaped implants of heat vulcanized polydimethylsiloxane (a solid silicone elastomer) suspended in a bio-excretable carrier gel. the carrier gel is a pharmaceutical grade, water-soluble, low molecular weight polyvinylpyrrolidone (pvp or povidone) hydrogel which is absorbed by the reticuloendothelial system and excreted unchanged in the urine. polydimethylsiloxane elastomer and polyvinylpyrrolidone have favorable biocompatibility properties. polydimethylsiloxane is well tolerated by the cellular immune system and is non-genotoxic, non-carcinogenic and non-teratogenic (7). the endoscopic injection procedure can be performed under general, regional or local anaesthesia. during the transurethral procedure, under direct cystoscopic vision, the needle, inserted through the cystoscope operative channel, is placed submucosally into the urethra at the six, ten and two o’clock positions 1.5 to 2.0 cm distal from the bladder neck. the material is slowly injected until a sufficient mucosal bleb is achieved. the procedure is completed if there is a total mucosal apposition together with occlusion of the urethral lumen. the injectable can also be administered periurethrally, under cystoscopic control by inserting a spinal needle percutaneously adjacent to the urethra. after injecting, the cystoscope should not be advanced past injected areas and only small ‘in and out’ catheters (8-12 fr) should be inserted because this may result in compression or extrusion of the bulking agent afterwards. to improve and simplify the transurethral implantation technique and to minimize problems associated with endoscopic procedures, the macroplastique implantation system (mis) was developed for the treatment of female sui. the device seems to allow a constant placement of the implants at predefined depth and angles at the six, ten and two o’clock position of mid-urethra within the same circumferential plane. to identify the site of implantation correctly, the ruler measuring scale on the topside of the device is used. the site of the bladder neck is identified as the position where the water flow from the fluid drainage channel ceases while the tip of the device is slowly withdrawn from the fluid-filled bladder. the standard implantation position is defined by withdrawing the device from the urethra to the appropriate location of the mid-urethra, i.e., 10-15 mm distance from the level of the bladder neck. before withdrawing the needle, it is advisable to wait for at least 30 seconds in order to avoid any material leakage. transurethral injection technique and devices of zirconium oxide beads (durasphere) durasphere injection is performed using pre-packaged syringes containing 1.0 ml durasphere and a 18 g needle delivery device. urethral bulking agent injections are usually performed transurethrally at the level of the bladder neck under direct vision. more than one site may be injected. in 2003 majar et al. described a modified technique for an easier implantation of this agent (8). after routine video monitored cystoscopy the bladder is completely drained. the cystoscope is withdrawn to the distal urethra, so that the mid-urethra, proximal urethra and bladder neck are viewed simultaneously. the needle is introduced through the cystoscopic sheath. with the bevel pointing toward the urethral lumen, the needle is directed at 45 degrees to the lumen and into the urethral wall at the 4 o’clock position (left hand dominant surgeons may find the 8 o’clock position preferable). after the needle tip penetrates the urethral wall and the bevel is no longer seen, the needle is advanced, this time parallel to the urethral lumen, for 1 to 2 cm. at this point 1.5 ml 1% lidocaine solution are injected into the submucosal layer. this step results in partial coaptation of the urethral walls and hydrodissection of the space to which the beads are eventually injected. using this technique the whole circumference of the urethra coapts with no need to change the needle location from its original 4 o’clock position. the bulking agent is then injected with steady and consistent thumb or thenar eminence pressure on the plunger using 1 hand, while holding the cystoscope with the contralateral hand. resistance to injection at this point is managed by gradual withdrawal/advancement of the needle tip and by turning the bevel in a clockwise or counterclockwise direction. insistence on injecting the beads at exactly the same location and bevel orientation would result in further bead impaction and limits the capability of bead delivery. complete needle withdrawal is avoided. this step is repeated as needed with the surgeon steadily holding the delivery system and maintaining the needle at exactly the same location under cystoscopic guidance: the assistant replaces the used syringe with a new, full syringe, so that further material can be injected (usually cerruto_stesura seveso 08/10/14 12:12 pagina 206 207archivio italiano di urologia e andrologia 2014; 86, 3 injection devices for bulking agents correspondence maria angela cerruto, md mariaangela.cerruto@univr.it carolina d’elia, md, f.e.b.u. (corresponding author) karolinedelia@gmail.com pierpaolo curti, md curtipierpaolo@gmail.com urology clinic, a.o.u.i. verona, policlinico g.b. rossi piazzale l.a. scuro 10 37134 verona, italy 2 to 3 syringes are needed) until nearly complete urethral lumen coaptation is achieved. when almost complete coaptation is attained, the syringe is replaced and 1.5 ml normal saline are injected at the same position. this step enables beads remaining in the needle to be deployed at the injection site. the needle tip is then maintained at the same position for another 10 seconds. at the end of the procedure the bladder is emptied using a 12fr straight catheter. carbon bead bulking agent may be injected also periurethrally (9). a rigid 0° cystoscope is introduced into the urethra to allow visualization of the bladder neck. a 1.5-in, bent, 18 g needle is then inserted periurethrally at either 4-o’clock or 8-o’clock position at approximately 0.5 cm distal to the bladder neck.. then the material is injected until either the luminal appearance demonstrates mucosa coaptation or 6 ml of the product has been used. if good circumferential coaptation of the tissue has been achieved by injecting the carbon beads from just one injection site, the needle is not inserted on the other side. transurethral injection technique and devices of nasha/dx copolymer (zuidex) nasha/dx copolymer comprises dextranomer (dx) microspheres (80 to 250 m) in a carrier gel of non-animalstabilized hyaluronic acid (nasha). the gel is a biocompatible, biodegradable material free of animal products, has no immunogenic properties, and has been shown not to migrate to different organs after submucosal injection. a guiding instrument, named the implacer, has been developed to facilitate reproducible and standardized transurethral injection of nasha/dx copolymer, without the need for surgical facilities or cystoscopic guidance (10). zuidex™ gel is a dextranomer/hyaluronic acid (dx/ha) copolymer. dextranomer (dextran 2.3 dihydropropyl 2-hydroxy-1.3 propane-diethylethers) is made by hydrophylic dextran polymer particles (microspheres 80-120 micron), configurated as a network. it acts as a cell carriers, recruiting connective fibers from the surrounding tissues. it is non-alergic, as it has no free dextran molecules. hyaluronic acid is a 1% solution, highly viscous, highly molecular weight polysaccaride. it is non-immugenic as it is not extracted from animals but from bacteria. the zuidex system is composed of: 4 pre-filled syringes, each containining 0.7 ml of zuidex™ gel, and a zuidex implacer. the latter is a plastic device that consists of i) one hand piece, ii) a head with 4 thin channels where the 21 g needles of the 4 syringes are passed, and iii) a specially designed sliding cannula. the cannula covers the needles for the smooth insertion into the urethral lumen and once withdrawn, enables the prick of the urethral submucosa in 4 sites. the procedure may not require the use of the operating room and it is made on an outpatient basis, in the office, under local anaesthesia. nevertheless, general and/or local anaesthesia may be administered, depending on investigator preference. the first step is the urethral length measurement. this is done by means of a foley catheter with the filled balloon gently snuggled against the bladder neck, by marking the catheter surface at the exit from the external meatus. in an office setting, only 5 mg of anaesthetic gel are instilled into the urethra and left in place for 10 minutes. the implacer and the four syringes are assembled. the needles are thereafter covered by the cannula pushed to its bottom position. at this point the distal tip of the cannula is advanced through the meatus as far as the mid-urethra, and is firmly kept in this position throughout the whole procedure. the cannula is slid backward to uncover the needles in the urethral lumen. each needle is withdrawn 1 cm and push forward again to perforate the urethral mucosa and the zuidex gel is injected into the urethral wall. this manoeuvre may be started at 2 o’clock position in a clockwise direction. subsequently, all the syringes and the implacer itself are removed. no transurethral catheter is used after the procedure. the patient is observed until she voids with no significant residual urine. conclusions as bulking materials develop, understanding of the preferred injection technique also is being gained, as well as the best delivery method and injection site. every effort should be done for making these devices safe and easy to manage, more and more. references 1. appell ra, dmochowski rr, herschorn s. urethral injections for female stress incontinence. bju int. 2006; (98 suppl) 1:27-30. 2. smith arb, daneshgari f, dmochowski r, et al. surgery for urinary incontinence in women. in: abrams p, cardozo l, khoury s, wein a: incontinence. 3rd edition 2005; 1297-1370. 3. schulz ja, nager cw, stanton sl, baessler k. bulking agents for stress urinary incontinence: short-term results and complications in a randomized comparison of periurethral and transurethral injections. int urogynecol j pelvic floor dysfunct. 2004; 15:261-5. 4. pickard r, reaper j, wyness l, et al. periurethral injection therapy for urinary incontinence in women. cochrane database of systematic reviews 2003, issue 2. cd003881. 5. winters jc, appell r. periurethral injection of collagen in the treatment of intrinsic sphincter deficiency in the female patient. urol clin north am. 1995; 22:673-678. 6. groutz a, blaivas jg, kesler ss, et al. outcome results of transurethral collagen injection for female stress incontinence: assessment by urinary incontinenc score.j urol. 2000; 164:2006-9. 7. ter meulen ph, berghmans lcm, van kerrebroeck p. systematic review: efficacy of silicone microimplants (macroplastique®) therapy for stress urinary incontinence. eur urol. 2003; 44:573-582. 8. madjar s, covington-nichols c, secrest cl. new periurethral bulking agent for stress urinary incontinence: modified technique and early results. j urol. 2003; 170: 2327-2329. 9. kershen rt, dmochowski rr, appell ra. beyond collagen: injectable therapies for the treatment of female stress urinary incontinence in the new millennium. urol clin north am. 2002; 29:559-574. 10. von kerrebroeck p, ter meulen p, larsson g, et al. efficacy and safety of a novel system (nasha/dx copolymer using the implacer device) for treatment of stress urinary incontinence. urology. 2001; 58:12-15. cerruto_stesura seveso 08/10/14 12:12 pagina 207 stesura seveso 241archivio italiano di urologia e andrologia 2014; 86, 4 original paper robotic simple prostatectomy: a consideration for large prostate adenomas joshua b. nething 1, daniel j. ricchiuti 2, rhys irvine 1, david drevna 1 1 northeastern ohio medical university department of urology, akron, ohio; 2 st. elizabeth health center, division of urology, youngstown, ohio. background: the management of benign prostatic hyperplasia (bph) has changed considerably over the last several decades. first line treatment of bph and lower urinary tract symptoms (luts) with medical therapy has created a population of men with much larger prostate glands, many of whom require surgical intervention. patients with prostate glands greater than 80 to 100 grams may be better managed surgically with a retropubic prostatectomy. we explore our experience with robotic assisted simple prostatectomy and review the relevant literature. database: the database reviewed includes our experience with seven patients undergoing robotic simple prostatectomy, and a comprehensive review of the previously published series of this procedure. in addition, the literature pertaining to a pure laparoscopic approach to simple prostatectomy is reviewed. conclusion: robotic experience and training has become a standard in resident training programs; while classic transurethral resection is being performed less for large prostate glands. the robotic approach to simple prostatectomy provides an excellent option for surgical treatment of very large prostate glands, providing patients acceptable results in terms of operative time, estimated blood loss, hospital stay and duration of foley catheter. key words: robotics; prostatectomy; prostatic hyperplasia; laparoscopy; transurethral resection of prostate; adenoma. submitted 5 may 2014; accepted 31 may 2014 summary no conflict of interest declared. have gradually decreased from 229.2 to 268.3 per 100,000 men in 1980 through 1991 to 131.3 per 100,000 in 1994. in 2005 turp represented 39% of bph procedures compared with 81% in 1999 (4). as a result, graduating urologists leaving residency training have performed fewer electrosurgical turps and the complication rate requiring a second procedure has increased (5). this lack of experience is exaggerated in very large glands as the potential for complications is expected to be higher. while urologists who trained in the “golden age” of turp are often confident approaching the largest adenomas transurethrally, less experience has led to reluctance to do so by younger urologists. with the rapid increase in popularity of robotic surgical techniques, recent graduates are often more familiar with this minimally invasive technique to surgery. we present seven patients who underwent robotic assisted laparoscopic simple prostatectomy and a review of the contemporary literature on this subject. patients and methods our experience consists of seven patients, all of which had failed multimodal medical treatment, with persistent bothersome luts leading to subsequent surgical intervention. each patient underwent a successful robotic assisted laparoscopic simple prostatectomy without open conversion. the data that was collected through the course of our research is presented in table 1. post-operative pathologic diagnosis on all specimens was prostatic hyperplasia. the foley catheter was removed on the above-mentioned days (table 1) after a cystogram was negative for leak. with an average follow-up time of 10 months, all patients were doing well with no noted longterm complications. no patients required further catheterization and all report overall improvement in their luts. a detailed report of the operative technique is described elsewhere in the literature (6). briefly the key operative steps in this approach include dropping the bladder from the anterior abdominal fascia to enter the space of retzius, then entering the bladder using a transverse incision 1 cm proximal to the bladder neck. a circumferential incision is made through the bladder mucosa and a plane is developed between prostate and capsule with combination of doi: 10.4081/aiua.2014.4.241 introduction in the united states, more than $4 billion is spent annually on the medical management (1) of benign prostatic hyperplasia (bph) and more than $2 billion on the surgical management (2). electrosurgical transurethral resection of the prostate (turp) is the “gold-standard” for surgical treatment of bph, growing in popularity since it was first described in 1911 by hugh young (3). the introduction of medications, the development for various lasers, the bipolar button and other novel technologies have all further decreased the number of turps being performed (4). the number of turps being performed nething_stesura seveso 15/01/15 12:52 pagina 241 archivio italiano di urologia e andrologia 2014; 86, 4 j.b. nething, d.j. ricchiuti, r. irvine, d. drevna 242 blunt dissection and electrocautery. the prostate is than removed piecemeal at times and larger portions are morselated or removed using a reusable tissue retrieval bag. the mucosa of the bladder neck is tacked to the prostatic fossa using 2-0 vicryl, and the bladder closed in 2 layers ensuring it is watertight. discussion the 2003 aua guidelines recognize transurethral resection of prostate (turp) as the benchmark for therapy of bph as it permits a high success rate in symptom scores, urinary flow, post void residual and low retreatment rate on long term follow up (7). this is a statement that the revised 2010 guidelines avoid making, further highlighting the decreased favorability of turp. multiple complications can be observed with turp, including perioperative bleeding requiring blood transfusions, transurethral resection syndrome, prolonged catheterization, long hospital stay, urinary incontinence and retrograde ejaculation (4). these drawbacks obviate the need for alternative treatment modalities, particularly with larger adenoma size, where the technical challenge and complication rate are magnified. for patients with very large glands, typically defined as greater than 80 to 100 ml, management options often include open simple prostatectomy (8). open prostatectomy accounts for 14-32% of the total invasive procedures for bph in europe, and as many as 68% in some developing countries (9). traditional approaches for this procedure have been through an open incision, using a retropubic, suprapubic or perineal approach. simple prostatectomy may be more effective than turp at relieving obstruction of urinary flow, however it is usually associated with a larger blood loss, increased pain and longer hospital stay (8). in an effort to reduce these sequelae, laparoscopic and robotic approaches to this procedure have been explored. the initial reported case of laparoscopic simple prostatectomy was in 2002 by mariano et al. (10). the procedure was preformed in 225 minutes with an ebl of 800 ml and the patient was discharge home in four days. mariano recently published his six year data, reviewing 60 patients, and demonstrated shorter hospital stay (3.46 days ± 0.89), lower intraoperative blood loss (330.98 ml ± 149.52) and more rapid removal of urinary catheter (4.6 days ± 1.2) (11). similar results have been published by several other authors, validating laparoscopic simple prostatectomy. zhou et al. (12) used an extraperitoneal approach to laparoscopic adenomectomy. in their series of 45 patients, average surgical time was 105.4 ± 26.5 minutes, ebl was 360.1 ± 165.4 ml, and average adenoma resected was 78.2 ± 16.3 grams. patients required a catheter for an average of 4.6 days and hospital stays of 4.6 days. yun et al. (13) published series of 11 patients undergoing laparoscopic retropubic simple prostatectomy and found an average or time of 191.9 minutes, mean ebl of 390.9 ml, and resected adenoma weight of 72.4 grams. the foley catheter remained indwelling for 5.6 days and postoperative hospitalization was 6.5 days. baumert et al. (14) compared their data 30 consecutive laparoscopic simple prostatectomies to 30 open prostatectomies. the results showed laparoscopic simple prostatectomy is associated with lower blood loss (367 ml vs. 643 ml), a shorter postoperative catheterization (4 days vs 6.8 days) and shorter hospital stay at the expense of a longer operative time (115 mins vs 54 mins). since this time, the approach has been studied by several other authors (15-18) and been shown to provide patients with a feasible alternative with acceptable symptom relief, and importantly reduced ebl. despite these series showing favorable outcomes (table 1), this technique is still not widely utilized due to its complexity. robotic surgery provides a more favorable learning curve (19) and provides surgeons with a speed and dexterity advantage over even expert laparoscopists (20). series avg. or ebl foley hospital adenoma adenoma time (ml) duration stay size trus size (mins) (days) (days) (grams) (grams) patient 1 188 min 100 ml 7 days 2 days 187.04 g. 111 g. patient 2 175 min 1200 ml 7 days 2 days 94.39 g. 125 g. patient 3 135 min 300 ml 9 days 2 days 70 g. 71 g. patient 4 225 min 200 ml 7 days 2 days 144 g. 56 g. patient 5 213 min 400 ml 7 days 2 days 169 g. 86 g. patient 6 245 min 50 ml 12 days 7 days 200 g. 123 g. patient 7 242 min 1400 ml 9 days 1 days 150 g. 102 g. averages 204.7 min 521.4 ml 8.28 days 2.57 days 144.9 g. 96.3 g. table 1. data of patients. series # pts. avg. or ebl foley hospital adenoma adenoma time (ml) duration stay size trus size path (mins) (days) (days) (grams) (grams) van velthoven, 2004 18 145 192 3 5.9 95.1 47.6 mariano, 2005 60 138.48 330.98 4.6 3.46 144.5 131 sotelo, 2005 17 156 516 6.3 2 93 72 baumert, 2006 30 115 367 4 5.1 121.8 77.2 zhou, 2008 45 105.4 360.1 4.6 6.3 85.4 78.2 yun, 2010 11 191.9 390.9 5.6 6.5 109.3 72.4 castillo, 2011 59 123 415 4.2 3.5 108.5 95.2 table 2. published series for laparoscopic simple prostatectomy. nething_stesura seveso 15/01/15 12:52 pagina 242 sotelo et al. (2008) (7) was the first to report their series of seven patients with robotic simple prostatectomy. he reported an ebl of 298 ml, average operative time of 205 minutes, average hospital stay of 1.4 days and foley duration of 7 days. when comparing their findings to their previously reported series on laparoscopic simple prostatectomy, they concluded that robotics approach allows for greater precision and visualization with similar cost analysis (laparoscopic $10,465 vs. $12,093 for robotics). several recent publications on robotic simple prostatectomy showed similar results. yuh et al. (21), in 2008, reported on a case series of three simple prostatectomies with average or time of 211 minutes, ebl of 558 ml and mean hospital stay of 1.3 days. next, john et al. (22) reported their experience using an extraperitoneal approach. the series consisted of 13 patients with average or time of 210 minutes, ebl of 500 ml, adenoma weight of 82 grams, foley duration of 6 days and hospital stay of 6 days. in 2010, uffort (23) series of 15 patients provided further evidence substantiating robotic simple prostatectomy as a valid treatment option. average operative time was 128.8 minutes, ebl was 139 ml, average hospital time was 2.5 days and foley duration was 4.6 days. finally, coelho et al. (24) further contribute to the published data in their series of six consecutive patients. the authors suggest a slightly modified procedure. following resection of the adenoma, instead of performing the usual “trigonization” of the bladder neck, they proposed three modified steps as follows: placation of the posterior capsule, a modified van velthoven continuous visco-urethral anastomosis and suturing of the anterior prostatic capsule to the anterior bladder wall. detailed description of the procedure and illustrations can be referenced in the original publication. the authors reported a mean or time of 90 minutes, ebl 208 ml, hospital stay of 1 day and foley duration was 4.8 days. the authors suggest that technical modification offers the potential advantage of decreased blood loss, no need for postoperative continuous bladder irrigation, and shorter length of hospital stay. a complete review of the written literature, included our experience of robotic simple prostatectomy is summarized in table 3. conclusion the 2010 aua clinical guidelines cite longer catheter duration, greater ebl and longer hospital stay with the open prostatectomy, but continue to list this as a more effective treatment than turp at relieving blockage of urine flow in men with very large glands (greater than 80 to 100 ml). as opposed to the theory that laparoscopic and robotic approaches are investigational, we believe that the advantage of a robotic approach is relevant and clearly defined by our experience and the referenced landmark papers discussed here. robotic surgery offers an obvious advantage to traditional laparoscopy in regards to visual enhancement, and wristed movements allowing for increased dexterity. the robotic approach allows for a shorter learning curve to a complex case. this article should highlight the excellent patient outcomes achievable with laparoscopic simple prostatectomy, and one that is feasible with most contemporary urologists comfort and skill for robotic surgical assistance. references 1. holtgrewe hl, ackermann r, bay-nielsen h, et al. report from the committee on the economics of bph. in: cockett atk et al., eds. third international consultation on benign prostatic hyperplasia (bph). jersey: scientific communication international. 1996; 51-70. 2. mcconnell jd, barry mj, bruskewitz rc, et al. benign prostatic hyperplasia: diagnosis and treatment. clinical practice guidelines no. 8. ahcpr publication no. 940582. rockville, maryland: agency for health care policy and research. public health service, us dept of health and human services, 1994. 3. ellis h. the early days of prostatectomy for benign prostatic hypertrophy. j perioper pract. 2011; 10:359. 4. rocco b, albo g, ferrreira r, et al. recent advances in the surgical treatment of benign prostatic hyperplasia. ther adv urol. 2011; 3:263-272. 5. sandhu j, jaffe w, chung d, et al. decreasing electrosurgical transurethral resection of the prostate surgical volume during graduate medical education training is associated with increased surgical adverse events. j urol. 2010; 183:1515-1519. 6. sotelo r, clavijo r, carmona o, et al. robotic simple prostatectomy. j urol. 2008; 179:513-515. 7. american urologic association. guidelines for management of bph, 2003. available at: http://www.auanet.org/content/clinicalpractice-guidelines/clinical-guidelines/archived-guidelines/chapt_ 1_appendix.pdf. accessed february 24, 2012. 8. american urologic association. management of bph (revised, 2010). available at: http://www.auanet.org/content/clinical-practice-guidelines/clinical-guidelines.cfm. accessed february 24, 2012. 9. vela navarette r, gonzales enquita c, garcia cardoso, et al. the impact of medical therapy on surgery for benign prostatic hyperplasia: a study comparing changes in a decade. bju int. 2005; 96:1045-1048. 243archivio italiano di urologia e andrologia 2014; 86, 4 robotic simple prostatectomy: a consideration for large prostate adenomas series # pts. avg. or ebl foley hospital adenoma adenoma time (ml) duration stay size trus size path (mins) (days) (days) (grams) (grams) sotelo, 2008 7 205 298 7 1.4 77.66 50.48 yuh, 2008 3 211 558 na 1.3 323 301 john, 2009 13 210 500 6 6 100 82 uffort, 2010 15 129 139 4.6 2.5 70.85 46.4 coelho, 2011 6 90 208 4.8 1 157 145 this series 5 187.2 440 7.4 1.8 132.89 89.8 table 3. published series of robotic simple prostatectomy. nething_stesura seveso 15/01/15 12:52 pagina 243 archivio italiano di urologia e andrologia 2014; 86, 4 j.b. nething, d.j. ricchiuti, r. irvine, d. drevna 244 10. mariano mb, graziottin tm, tefilli mv. laparoscopic prostatectomy with vascular control for benign prostatic hyperplasia. j urol. 2002; 167:2528-2529. 11. mariano mb, tefilli mv, graziottin tm, et al. laparoscopic prostatectomy for benign prostic hyperplasiaa six year experience. eur urol. 2006; 49:127-132. 12. zhou ly, xiao j, chen h, et al. extraperitoneal laparoscopic adenomectomy for benign prostatic hyperplasia. worl j urol. 2009; 27:385-387. 13. yun hk, kwon jb, cho sr, et al. early experience with laparoscopic retropubic sumple prostatectomy in patients with voluminous benign prostatic hyperplasia (bph). korean j urol. 2010; 51:323-329. 14. baumert h, ballaro a, dugardin f, et al. laparoscopic versus open simple prostatectomy. j urol. 2006; 175:1691-1694. 15. sotelo r, spaliviero m, garcia sequi a, et al. laparoscopic reteropubic simple prostatectomy. j urol. 2005; 173:757-760. 16. castillo oa, bolufer e, lopezfontana g, et al. laparoscopic simple prostatectomy (adenomectomy): experience in 59 consecutive patients. actas urol esp. 2011; 35:433-437. 17. van velthoven r, peltier a, laguna mp, et al. laparoscopic extraperitoneal adenomectomy (millin): pilot study on feasibility. eur urol. 2004; 45:103-109. 18. desai m, aron m, canes d, et al. single port transvesical simple prostatectomy: initial clinical report. urology. 2008; 72:960-965. 19. yohonnes p, rotariu p, pinto et al. comparison of robotic versus laparoscopic skills: is there a difference in the learning curve? urology. 2002; 60:39-45. 20. sarle r, tewari a, shrivastava a, et al. surgical robotics and laparoscopic training drills. j endourol. 2004; 18:63-67. 21. yuh b, laungani r, et al. robotic assisted millins retropubic prostatectomy: case series. can j urol. 2008; 15:4101-4105. 22. john h, bucher c, engel n, et al. preperitoneal robotic prostate adenomectomy. urology. 2009; 73:811-815. 23.uffort e, jensen j. robotic assisted laparoscopic simple prostatectomy: an alternative minimally invasive approach for prostate adenoma. j robotic surg. 2010; 4:7-10. 24.coelho r, chauhan s, sivaraman a, et al. modified technique of robotic assisted simple prostatectomy: advantages of a vesico-urethral anastomosis. bju int. 2012; 109:426-433. correspondence joshua b. nething, md jnething@gmail.com rhys irvine, md (corresponding author) rwirvine@gmail.com dave drevna ddrevna@neomed.edu northeastern ohio medical university department of urology 215 west bowery street, suite 3500, akron, ohio 44308 daniel j. ricchiuti, md dricchiuti@yahoo.com st elizabeth health center, division of urology 1044 belmont avenue, youngstown, ohio 44501 nething_stesura seveso 15/01/15 12:52 pagina 244 stesura seveso 123archivio italiano di urologia e andrologia 2014; 86, 2 original paper awareness and timing of pelvic floor muscle contraction, pelvic exercises and rehabilitation of pelvic floor in lifelong premature ejaculation: 5 years experience giuseppe la pera department of urology, san camillo forlanini hospital, rome, italy. objectives: to assess the cure rate of patients with premature ejaculation who underwent a treatment involving: 1) awareness of the pelvic floor muscles 2) learning the timing of execution and maintenance of contraction of the pelvic floor muscles during the sensation of the pre-orgasmic phase 3) pelvic floor rehabilitation (bio feed back, pelvic exercises and electrostimulation). materials and methods: we recruited 78 patients with lifelong premature ejaculation who completed the training. the patients were informed of the role of the pelvic floor. they were taught to carry out the execution and maintenance of contraction of the pelvic floor muscles during the sensation of the pre-orgasmic phase to control the ejaculatory reflex. in order to improve the awareness, the tone and the endurance of the pelvic floor muscles, patients were treated with the rehabilitation of pelvic floor (rpf) consisting mainly in biofeedback, pelvic exercises and in some cases also in electro-stimulation (es). the training was carried out for a period of about 2-6 months with an average of 2-5 visits per cycle. results: 54% of patients who completed the training were cured of premature ejaculation and learned over time to be able to postpone the ejaculation reflex. in a subgroup of 26 patients was also measured the ielt which on the average increased from < 2 minutes to >10 minutes. the best results occurred mainly in patients aged less than 35 where the cure rate was 65%. there were no side effects. conclusions: in this study, approximately half of patients with premature ejaculation were cured after applying the above treatment.this therapy, necessitates a fairly long period of time (2-6 months) and a great commitment on the part of the patient, nevertheless it can be a valid and effective treatment for patients with premature ejaculation. this treatment makes the patient independent in that he is not bound to specific times for taking medication. furthermore there are no side effects and this therapy is particularly effective in young males. key words: premature ejaculation; awareness; timing; pelvic floor muscles; pre-orgasmic sensation. submitted 26 may 2014; accepted 16 june 2014 summary no conflict of interest declared. doi: 10.4081/aiua.2014.2.123 introduction the pelvic floor rehabilitation (pfr) consisting in biofeedback, pelvic exercises (kinesis-therapy) and pelvic floor electrical stimulation in the treatment of lifelong premature ejaculation has been introduced since 1996 (1) and was later confirmed by other authors (2). since then, from 2008, compared to the previously described technique, i introduced some changes in the therapeutic protocol: 1. adopting the new definition of premature ejaculation (pe) of the essm (3); 2. introducing into the protocol the awareness of the pelvic floor muscles (4); 3. teaching patients when to execute and maintain the contraction of the pelvic floor muscles. in order to inhibit the ejaculatory reflex this contraction must occur during the sensation of the pre-orgasmic phase. as regards the changes to the protocol of training, these are based on the observation that patients with premature ejaculation very often are not aware of the role of the pelvic floor muscles (4). therefore some patients may suffer premature ejaculation simply because they do not know what to do or are not able to make a selective effective contraction of the pelvic floor and not because of an early arrival of the stimulus. the purpose of this study was to evaluate the cure rates in an unselected population of patients with lifelong premature ejaculation undergoing rehabilitation treatment of the pelvic floor who have been taught the role of the pelvic floor and the timing of contraction of these muscles. materials and methods recruitment of patients we retrospectively reviewed the charts of 108 patients with lifelong premature ejaculation. out of them 78 patients (72%) completed the protocol training. patients with erectile dysfunction and patients with signs of prostatitis were excluded. the majority of patients excluded from treatment or who did not complete the protocol preferred an immediate drug treatment instead of a treatment that archivio italiano di urologia e andrologia 2014; 86, 2 g. la pera 124 required numerous sessions spread over a period of several months. the average age was 41 +/8 and a median age of 40 (range 18 to 64). definition of a patient with premature ejaculation the definition of a patient with premature ejaculation refers to the definition adopted by the essm 2008 (3); all patients had the ielt (5) in less than one minute and a pedt (6) test > 11. in the hormone screening was found only one patient with hyperthyroidism; in all the other patients, the hormonal values of the thyroid function were always found normal. eight patients had a significantly low testosterone. in all these cases of hormonal alteration, the hormonal treatment implemented to correct hypogonadism or hyperthyroidism did not change the symptoms of premature ejaculation. description of the technique the technique to inhibit the ejaculatory reflex and to teach the patient how to take greater control consists of four steps. the 4 steps are: 1) have the patient become aware of the existence of the pelvic floor muscles; 2) teach the patient the selective contraction of the muscles of the pelvic floor; 3) teach the patient and have him try out the timing of the execution and maintenance of contraction of the muscles of the pelvic floor during the sensation of the pre-orgasmic phase; 4) reinforcement of the pelvic floor muscles. awareness of the role of pelvic floor muscles at the beginning of treatment, all patients were made aware of the role of the pelvic floor through a test described in 2012 (4). in practice, the patient lying down is asked to contract his pelvic floor muscles while performing a digital rectal examination. at the end of this procedure the patient is asked whether he is aware that the contraction of the muscles of the pelvic floor is able to inhibit the ejaculatory reflex. a more accurate description of this technique and the demonstration of its validation was previously published (4) pelvic floor rehabilitation (pfr) to learn how to selectively use the muscles of the pelvic floor, i.e. without activating antagonist muscles such as the abdominal muscles, we used the technique of pfr that involves biofeedback, pelvic exercises and in some cases electro-stimulation. this technique has already been described for fecal and urinary incontinence and in the treatment of premature ejaculation (1). the pfr not only reinforces the tone and strength of contraction of the pelvic floor muscles but at the same time allows the patient to better understand the role of these muscles and acquire the capacity to perform the contraction selectively. a more detailed description of the technique was previously published in 1996 (1). nearing the orgasmic phase and timing of the contraction of the pelvic floor muscles one of the techniques used up to now for the treatment of premature ejaculation has historically been that of “stop and start” proposed by masters and johnson since the 1960’s (7). basically it consists in stopping the stimulation when the excitation reaches the pre-orgasmic phase and and when the ejaculation is about to arrive. the innovation we have brought to our technique is that of adding, during the sensation of the pre-orgasmic phase, the execution and maintenance of contraction of the muscles of the pelvic floor until the sensation of upcoming orgasm has passed. to obtain this result obviously the first step is to be informed of the existence and the role of the pelvic floor muscles. the second moment is to be able to carry out the contraction of the muscles of the pelvic floor in a selective manner and this can be obtained through biofeedback. the third element consists of the selective and coordinated contraction of the pelvic floor muscles to be carried out at the very pre-orgasmic moment before ejaculation becomes irreversible. this technique starts from the assumption that the contraction, performed in a coordinated and timely way, would be able to inhibit the ejaculatory reflex similarly to what happens in the bladder where the contraction of the pelvic floor muscles if done at a certain moment is capable of delaying the urge of urination through inhibition of detrusor contraction (8). in order to teach the patient the “timing” of the contraction and have him figure out at what moment of preorgasmic sensation it is still possible to inhibit the ejaculatory reflex, exercises of masturbation are assigned to do at home. in these focusing exercises the patient begins to masturbate and gets to a stage of pre-orgasmic excitement; through “trial and error” he must learn to be able to recognize in what moment during the sensation of pre-orgasmic excitement it is still possible to inhibit the ejaculatory reflex in stopping masturbation, contracting the muscles of the pelvic floor and maintaining the contraction until the sensation of imminent orgasm ceases. once the patient has achieved inhibition of the ejaculatory reflex and the sensation of imminent orgasm ceases the patient resumes masturbation and in the same session repeats this cycle 3 or 4 times. after 4 or 5 cycles the patient can let himself reach ejaculation. the results of this training and in particular the way the contraction is performed and its effectiveness in postponing the ejaculatory reflex are discussed with the patient once a month; any doubts are cleared up and further improvements made. measurement of results and definition of healing patients were considered cured if able to control their ejaculatory reflex and when they pass from a pdet score above 10 to one equal or less than 8. furthermore in one group of patients was evaluated the ielt (5) both before and at the end the training. results all patients at the end of the training due to awareness tests (4) have become conscious of the role of the pelvic floor in the control of ejaculation; 43 patients or 55% of all those who completed the training were cured of premature ejaculation and learned to be able to postpone the moment of ejaculation. in a subgroup of 26 patients was also measured the ielt which on the average went from < 2 minutes to > 10 minutes. the best results occurred mainly in patients aged less than 35 where the cure rate was 65%. in the course of more than five years, there were no side effects in the whole sample involved. thirty-five patients (45%) after a minimum period of three months did not demonstrate any benefit from the technique proposed here and drug therapy was begun with them. the non-response to treatment was mainly due to the fact that the patient was not able to selectively contract the pelvic floor muscles or could not recognize the moment to make the contraction. among these 35 patients, however, there were 12 in which the patient, even though making a regular and effective contraction of the muscles of the pelvic floor and even recognizing the moment when it was necessary to perform the contraction, had no beneficial effect on the length of ejaculatory latency. probably this subset of patients is that in which premature ejaculation is the consequence of the early arrival of the ejaculatory stimulus. discussion awareness of the role of the pelvic floor muscles, the pfr and learning to recognize the timing of the execution and maintenance of contraction of the pelvic floor muscles are the crucial elements of this technique in order to inhibit and improve control over the ejaculatory reflex. the limit of this method is that it takes a few months for the patient to understand the dynamics of the sequence of events, learn control over the ejaculatory reflex and naturally carry it during sexual intercourse. in many family and clinical situations there is not always a long time available and thus the patient may request something faster such as drug therapy available today. another limitation of this technique is that not all patients are able to perform a selective contraction of the pelvic floor muscles without activating other antagonist muscles or are not able to recognize the sensation that precedes the inevitability of ejaculatory reflex in order to perform the contraction of the muscles of the pelvic floor to block and inhibit ejaculation. in the course of this experience, we observed that although some patients were able to correctly perform the contraction of the muscles of the pelvic floor this technique did not prove effective. this percentage of patients is typically around 15%. these limits are, however, largely offset by the fact that recovery from premature ejaculation with this technique brings the patient around to be “independent”, not influencing his sexual activity by taking a drug and not exposing him to potential side effects or drug interactions. these results confirm moreover the fact that the population of patients with premature ejaculation is a heterogeneous population with different etiological factors. there are not only patients in whom there is an early arrival of the ejaculatory reflex. the positive results of this technique, which does not act on the arrival of the ejaculatory reflex but only on the control, suggest the hypothesis that premature ejaculation, in some cases, may be due to another four causes: – lack of knowledge of the fact that is necessary to contract the pelvic floor muscles; – inability to contract these muscles; – inability to know how to recognize at what moment during the sensation of the pre-orgasmic phase it is still possible to block the ejaculatory reflex; – result of a disease of the muscles of the pelvic floor. these data raise therefore the urgent need not only to reassess the definition of premature ejaculation or at least redefine the concepts that define it but to re-evaluate the criteria for inclusion or exclusion in therapeutic trials on premature ejaculation taking into consideration the variables of awareness and neuromuscular coordination of the pelvic floor, the perception of the arrival of the ejaculatory reflex and diseases of the pelvic floor muscles. conclusions in this study, approximately half of the patients with premature ejaculation were cured after they learned role and use of the muscles of the pelvic floor, having learned the timing of execution and maintenance of contraction of the pelvic floor muscles during the sensation of the pre-orgasmic phase and having undergone pfr. despite the fact that this therapy in order to achieve positive results requires a fairly long period of time (2-6 months) and a greater commitment on the patient’s part, it can be a valid and effective treatment to offer a patient with premature ejaculation. this treatment makes the patient independent in that he is not bound to specific times for taking medication. furthermore there are no side effects and this therapy is particularly effective in young males. references 1. la pera g, nicastro a. a new treatment for premature ejaculation: the rehabilitation of the pelvic floor. j sex marital ther. 1996; 22:22-6. 2. pastore al, palleschi g, leto a, et al. a prospective randomized study to compare pelvic floor rehabilitation and dapoxetine for treatment of lifelong premature ejaculation. int j androl. 2012; 35:528-33. 3. mcmahon cg, althof se, waldinger md, et al. an evidence-based definition of lifelong premature ejaculation: report of the international society for sexual medicine (issm) ad hoc committee for the definition of premature ejaculation. j sex med. 2008; 5:1590-606. 4. la pera g. awareness of the role of the pelvic floor muscles in controlling the ejaculatory reflex: preliminary results. arch ital urol androl. 2012; 84:74-8. 5. waldinger md, hengeveld mw, zwinderman ah, olivier b. an empirical operationalization study of dsm-iv diagnostic criteria for premature ejaculation. int j psychiatry clin pract 1998; 2:287-293. 6. symonds t, perelman ma, althof s, et al. development and validation of a premature ejaculation diagnostic tool. eur urol. 2007; 52:565-73. 7. masters wh, johnson ve. premature ejaculation. in: human sexual inadequacy. boston, mass: little brown & company. 1970; 92-115. 8. burgio kl, et al. behavioral vs drug treatment for urge urinary incontinence in older women. jama 1998; 280:1995-2000. 125archivio italiano di urologia e andrologia 2014; 86, 2 awareness and timing of pelvic floor muscle contraction, pelvic exercises and rehabilitation of pelvic floor in lifelong premature ejaculation correspondence giuseppe la pera, md (corresponding author) lapera@libero.it dept of urology, san camillo forlanini hospital, rome, italy stesura seveso 253archivio italiano di urologia e andrologia 2014; 86, 4 original paper percutaneous nephrolithotomy in patients with a solitary kidney tufan süelözgen, salih budak, orcun celik, okan yalbuzdag, oguz mertoglu, selcuk isoglu, mehmet yoldas, yusuf ozlem ilbey tepecik training and research hospital, urology clinic, izmir, turkey. material and method: the results of percutaneous nephrolithotomy applied to 716 patients in our clinic between january 2008 and january 2014 were retrospectively evaluated. age, gender, urinary calculi size (mm2), urinary calculi localization, eswl history, operation duration (min), fluoroscopy duration (sec), access type, reason of solitary kidney, hemoglobin drawdown (g/dl) and operation success of the patients with a solitary kidney were recorded. the patients having no preoperative and postoperative non contrast abdominal tomography were excluded from the study. results: fifteen of nineteen patients (79%) were men and 4 of them (21%) were women. the average age of the patients was 42.52 ± 16.72 (14-72). ten patients had anatomical solitary kidney and nine patients had physiological solitary kidney. in fact counter kidney was non functional in 9 patients (47%) whereas there was agenesis in 2 (11%) and outcome of nephrectomy in 8 (42%) patients. in our study, presence of residual stone less than 4 mm at 1st month postoperative non contrast abdominal tomography was accepted as a successful result and accordingly our success rate was detected as 84%. mean urinary calculi size was 405 ± 252.9 mm2; urinary calculi localization was pelvic, lower pole, upper-middle pole, middle-lower pole and staghorn in 11 (58%), 4 (21%), 1 (5%), 1 (5%) and 1 (5%) patients, respectively; previous eswl history was 16%; operation duration was 55.47-± 28.1 min and fluoroscopy duration 131.10 ± 87.6 sec; access type was subcostal in 79%, supracostal in 10.5% and multiple in 10.5%; hemoglobin drawdown was 1.75 ± 0.97 mg/dl. conclusions: pnl can be effectively and safely administered for the treatment of solitary kidney. in the treatment of large urinary calculi in patients with a solitary kidney, pnl has some advantages such as short surgery duration, less complication, acceptable hemoglobin drawdown and high success rates. according to our study, pnl operation in patients with a solitary kidney is a good option for carefully and poisedly selected cases. key words: percutaneous nephrolithotomy; solitary kidney; urinary calculi. submitted 21 july 2014; accepted 18 august 2014 summary no conflict of interest declared. introduction urinary tract calculus disease continues to be a major health problem in our country. in a study conducted in 2011, calculus prevalence was determined as 11.1% and it was emphasized that our country has been among endemic countries (1). it was stated that 2.2% of general population was treated due to urinary tract calculus disease and 16% of them had more than one procedure (2). percutaneous nephrolithotomy (pnl) in the trratment of urinary calculi was firstly described by fernström and johansson in 1976 (3). since it was first developed, pnl procedure has been refined by means of improvements of optical system, endo-camera, lithotripsy energy systems, design of the nephroscope and advances in its accessories. as a result of all these improvements, need for open surgery in current urology practice is decreased to 0.7-4% and pnl has replaced it as first choice in the treatment of large urinary calculi (4). in this study, we retrospectively examined the patients with a solitary kidney who underwent pnl operation and we evaluated the results of the treatment. material and methods the results of percutaneous nephrolithotomy applied to 716 patients in our clinic between january 2008 and january 2014 were retrospectively evaluated. nineteen patients with a solitary kidney were included in the study. in our clinic, preoperative complete blood count, biochemical tests, including urea and creatinine levels, and urine culture are carried out for all patients who are planned to be treated with pnl. the patients were informed about operation and informed consent was obtained. one hour before the operation, antibiotic prophylaxis was carried out via parenteral administration of second generation cephalosporin. age, gender, urinary calculi size (mm2), urinary calculi localization, extracorporeal shock wave lithotripsy (eswl) history, operation duration (min), fluoroscopy duration (sec), access type, reason of solitary kidney, hemoglobin drawdown (mg/dl) and operation success of the patients with a solitary kidney were recorded. the patients having no preoperative and postoperative non contrast abdominal tomography were excluded from the study. doi: 10.4081/aiua.2014.4.253 budak_stesura seveso 15/01/15 12:56 pagina 253 archivio italiano di urologia e andrologia 2014; 86, 4 t. süelözgen, s. budak, o. celik, o. yalbuzdag, s. isoglu, s. isoglu, m. yoldas, y.ozlem ilbey 254 in lithotomy position, a 5 f open-end catheter was inserted in the ureter via a 22 f cystoscope under general anesthesia and set to a foley catheter by a silk suture. then, prone position was given to the patient. collecting system was visualized with fluoroscopy by injection of opaque contrast through the ureteral catheter. percutaneous needle access to the urinary tract was obtained by bi-planar planning of the access site. tract was dilated with amplatz dilators over guide wire and a 30 f amplatz sheath was placed. kidney collecting system was entered by a 22 f rigid nephroscope. ultrasonic lithotripter was preferred for litotripsy and pneumatic lithotripter was used when necessary. after evaluation of the last fluoroscopy images, a 14 f malecot nephrostomy catheter was placed and the operation was completed. all patients were followed up with non contrast abdominal tomography one month after operation. results fifteen of nineteen patients (79%) were men and 4 of them (21%) were women. the average age of the patients was 42.52 ± 16.72 (1472). ten patients had anatomical solitary kidney and 9 patients had physiological solitary kidney. in fact counter kidney was non functional in 9 patients (47%) whereas there was agenesia in 2 (11%) and outcome of nephrectomy in 8 (42%) patients. there was no previous history of surgery of the solitary kidney in all the patients. eswl was administered to three patients (16%) but it was not successful. stones location was pelvic, lower pole, upper-middle pole, middle-lower pole and staghorn in 11 (58%), 4 (21%), 1 (5%), 1 (5%) and 1 (5%) patients, respectively. average stone size was 405 ± 252.9 mm2 (100-1050). subcostal lower calyx access was performed in 15 of 19 patients (79%). intercostal upper pole access was carried out in two patients (10.5%) and multiple intercostal and subcostal accesses were required in two patients (10.5%). average operation duration was 55.47 ± 28.1 (21-139) minutes and average duration of fluoroscopy use was 131.10 ± 87.6 (35-351) seconds. average decrease in hemoglobin level of patients was 1.75 ± 0.97 (03-4.4) g/dl in postoperative period, but blood transfusion was not required. three patients developed fever in postoperative period. no further complication developed. at follow-up of the patients, residual stones were detected in 4 patients (21%) at non contrast abdominal tomography one month after operation. three of these (75%) were larger than 4 mm and 1% (25%) was less than 4 mm. presence of residual stones less than 4 mm was considered as a successful result and therefore our success rate was estimated as 84%. no age gender stone-size stone eswl operation skope approach why soliter decrease of operation (mm2) location history time(min) time(sec) time hemoglobine succes 1 43 m 625 pelvis no 67 94 subcostal nonfunctional 1.4 residue (more than 4 mm) 2 53 m 277 upper middle pole no 90 222 multiple access nonfunctional 3.7 stonefree 3 20 m 625 pelvis no 55 141 subcostal nonfunctional 0.9 stonefree 4 66 m 280 pelvis no 28 82 subcostal nonfunctional 0.5 stonefree 5 21 m 256 middle-lower pole no 56 86 subcostal nephrectomy 1.2 stonefree 6 39 f 280 pelvis yes 60 89 subcostal nonfunctional 1,7 stonefree 7 45 m 900 pelvis no 60 354 subcostal nonfunctional 2 stonefree 8 65 m 500 pelvis no 60 138 subcostal nonfunctional 0,7 stonefree 9 38 m 350 pelvis no 60 53 subcostal nonfunctional 1,2 residue (more than 4 mm) 10 19 f 130 lower pole no 64 105 subcostal agenesis 0,3 stonefree 11 33 m 300 pelvis yes 77 96 subcostal nephrectomy 2,8 residue (less than 4 mm) 12 55 m 175 middle pole no 30 139 intercostal nephrectomy 1,9 stonefree 13 43 m 250 pelvis no 65 140 intercostal nonfunctional 1,6 stonefree 14 72 f 1050 staghorn no 139 340 multiple access nephrectomy 4.4 residue (more than 4 mm) 15 41 m 350 lower pole no 25 45 subcostal nephrectomy 1,8 stonefree 16 38 m 297 lower pole no 40 150 subcostal nephrectomy 1,2 stonefree 17 44 m 100 lower pole yes 21 93 subcostal nephrectomy 2 stonefree 18 59 m 600 pelvis no 27 31 subcostal agenesis 1,5 stonefree 19 14 f 300 pelvis no 30 93 subcostal nephrectomy 1,5 stonefree table 1. characteristics and clinical outcome of percutaneous nephrolithotomy in patients with a solitary kidney. budak_stesura seveso 15/01/15 12:56 pagina 254 discussion the main aim of pnl is to clear more calculi with the least morbidity. although pnl is accepted as a minimal invasive treatment method, severe complications such as bleeding requiring transfusion, internal organ injuries, hydrothorax and sepsis can occur. nephrectomy may be necessary due to uncontrollable bleeding. this event in a patient with solitary kidney involve that the patient will become anephric. a multi-center study of complications occurring after pnl was coordinated by the croes (clinical research office of the endourological society). the global pnl study group published it in 2011 reporting that general complication rate of pnl was 25% (1175/5724); 80% of these were minor and 20% major complications and the most common complications were fever and bleeding (5, 6). some studies showed that access to calyceal system can lead to a decrease in hemoglobin levels (2.1-3.3 g/dl.) (7). bleeding after pnl can be prevented by clamping the nephrostomy tube. when bleeding cannot be stopped, selective arterial occlusion may be required (8, 9). staghorn and large calculi, obesity, prolonged operation time and absence of hydronephrosis were reported as the risk factors causing excessive bleeding during pnl (10). in our study, average decrease in hemoglobin levels in postoperative period was 1.75 g/dl. in the treatment of staghorn calculi, more severe bleeding can occur due to need for multiple access (11). in fact the patient with staghorn calculus and multiple accesses was the patient with the most severe bleeding which caused a < 4.4 g/dl decrease in the hemoglobin level. it was stated that 28.7% of the patients with negative preoperative urine culture who had prophylactic antibiotic therapy developed fever after pnl and that urgent bacteriological evaluation was not necessary if hemodynamic stability was balanced in patients with negative preoperative urine culture who had fever higher than 38.5°c and started to receive prophylactic antibiotic therapy (12). in our series, 3 of 19 patients (15%) developed fever after pnl, however none of them had sepsis. pulmonary complications after pnl are usually seen in case of supracostal access. it was stated that pneumothorax and hydrothorax rate after pnl was about 6-12% (6). four patients needed supracostal access in our study, but we did not face with any pulmonary complication. success rate after pnl ranges between 40% and 90% depending on number of stones, location, chemical structure and experience of the surgeon (12). escape of the calculus or of its fragments to an unapproachable calyx and termination of operation due to bleeding or prolonged time can be the reasons for not providing a complete calculus clearance in pnl. residual calculus fragments imply postoperative risks such as pain, urinary infection, calculus enlargement, obstruction and need for secondary surgery to patient. therefore, it is quite important to obtain a stone-free status after pnl and non-contrast abdominal tomography was recommended for evaluation of stone-free situation (13). in our study, our success rate was estimated as 84% at first month postoperative control. modern treatment of upper urinary tract calculi of solitary kidneys includes mini-invasive techniques as eswl, pnl and retrograde intrarenal surgery (rirs). in solitary kidney calculi, the results of eswl treatment are promising and it was stated that eswl was a safe and feasible method with low complications rates in the patients having only one kidney (14). efficiency of eswl was reported as 92% for kidney calculi smaller than 10 mm, 5989% for 10-20 mm calculi and 39-70% for calculi larger than 20 mm (15). rirs is a good option to remove kidney calculus in the patients having one kidney due to its high success and low morbidity rates. however, more than one procedure can be required for the patients having large urinary calculi (16, 17). yet, there are limiting factors such as that rirs is not available everywhere, operation duration is relatively longer, requires experience and is more suitable for 1.5-2 cm calculi. although pnl is today accepted as a safe and minimal invasive treatment method for treatment of urinary calculi, it is recommended that it should be always administered in high case-volume centers and by expert urologists in the patients with solitary kidney because of the risk of causing an anephric condition in case of severe complications (18). in the literature, success rates of pnl and its complications in the patients with a solitary kidney were reported in the range of acceptable levels (19, 20). conclusions pnl can be effectively and safely administered for the treatment of solitary kidney. in the treatment of large urinary calculi in patients with a solitary kidney, pnl has some advantages such as short surgery duration, less complication, acceptable hemoglobin drawdown and high success rates. according to our study, pnl operation in patients with a solitary kidney is a good option for carefully and poisedly selected cases. references 1. muslumanoglu ay, binbay m, yuruk e, et al. updated epidemiologic study of urolithiasis in turkey. i: changing characteristics of urolithiasis. urol res. 2011; 39:309-14. 2. akinci m, esen t, tellaloglu s. urinary stone disease in turkey: an updated epidemiological study. eur urol. 1991; 20:200-3. 3. fernstrom i, johansson b. percutaneous pyelolithotomy. a new extraction technique. scand j urol nephrol. 1976; 10:257-9. 4. matlaga br, assimos dg. changing indications of open stone surgery. urology. 2002; 59:490-4. 5. labate g, modi p, timoney a, et al. on behalf of the croes pcnl study group. the percutaneous nephrolithotomy global study: classification of complications. j endourol. 2011; 25:1275-80. 6. türk c, knoll t, petrik a, et al. guidelines on urolithiasis. european association of urology 2013. 7. kessaris dn, bellman gc, pardalidis np. management of hemorrhage after percutaneous renal surgery. j urol. 1995; 153:604-8. 8. bedir s, bozlar u, tahmaz l, et al. severe uncontrolled delayed bleeding after percutaneous nephrolithotomy. 24th world congress of endourology, august 17-20, cleveland, ohio, usa, 2006. 9. keoghan sr, cetti rj, rogers ae, walmsley bh. blood transfu255archivio italiano di urologia e andrologia 2014; 86, 4 solitary kidney percutaneous nephrolithotomy budak_stesura seveso 15/01/15 12:56 pagina 255 archivio italiano di urologia e andrologia 2014; 86, 4 t. süelözgen, s. budak, o. celik, o. yalbuzdag, s. isoglu, s. isoglu, m. yoldas, y.ozlem ilbey 256 sion, embolisation and nephrectomy after percutaneous nephrolithotomy (pcnl). bju int. 2013; 111:628-32. 10. nouralizadeh a, ziaee sa, hosseini sharifi sh, et al. delayed post percutaneous nephrolitotomy hemorrhage: prevalance, predictive factors and management. scand j urol. 2013; 21. 11. martin x, tajra lc, gelet a, et al. complete staghorn stones: percutaneous approach using one or multiple percutaneous accesses. j endourol. 1999; 13:367-8. 12. cadeddu ja, chen r, bishoff j, et al. clinical significance of fever after percutaneous nephrolitotomy. urology. 1998; 52:48. 13. park j, hong b, park t, park hk. effectiveness of noncontrast ct. in evaluation of residual stones after percutaneous nephrolithotomy. j endourol. 2007; 21:684-7. 14. graff j, diederichs w, schulze h. long term follow-up in 1003 extracorporeal shock wave lithotripsy patients. j urol. 1988; 140:479-83. 15. penn ha, demarco rt, sherman ak, et al. extracorporeal shock wave lithotripsy for renal calculi. j urol. 2009; 182 (4 suppl):1824-7. 16. gıustı g, proietti s, cindolo l, et al. is retrograde intrarenal surgery a viable treatment option for renal stones in patients with solitary kidney?. world j urol. 2014; 1-6. 17. palmero jl, castello a, miralles j, et al. results of retrograde intrarenal surgery in the treatment of renal stones greater than 2cm. actas urológicas españolas. 2014; 38:257-262. 18. mahboub dmr, shakıbı mh. percutaneous nephrolithotomy in patients with solitary kidney. urology journal. 2009; 5:24-27. 19. akman t, binbay m, tekinarslan e, et al. outcomes of percutaneous nephrolithotomy in patients with solitary kidneys: a singlecenter experience. urology. 2011; 78:272-276. 20. bucuras v, gopalakrishnam g, wolf js, et al. the clinical research office of the endourological society percutaneous nephrolithotomy global study: nephrolithotomy in 189 patients with solitary kidneys. j endourol. 2012; 26:336-341. correspondence tufan süelözgen, md tsuelozgen@hotmail.com salih budak,md (corresponding author) salihbudak1977@gmail.com orcun celik, md orcuncelik82@hotmail.com okan yalbuzdag, md oguz mertoglu, md selcuk isoglu, md selcukisoglu@hotmail.com mehmet yoldas, md myoldas@hotmail.com yusuf ozlem ilbey, md, associate prof. ozlemyusufilbey@hotmail.com tepecik training and research hospital, urology clinic, izmir, turkey budak_stesura seveso 22/01/15 10:28 pagina 256 stesura seveso 217archivio italiano di urologia e andrologia 2014; 86, 3 short communication comparison of individuals consuming natural spring water and tap water in terms of urinary tract stone disease mustafa resorlu 1, muhammet arslan 2, eylem burcu resorlu 3, murat tolga gulpinar 4, gurhan adam 1, eyup burak sancak 4, alpaslan akbas 4, nilufer aylanc 1, huseyin ozdemir 1 1 department of radiology, canakkale onsekiz mart university, faculty of medicine, canakkale, turkey; 2 department of radiology, vefa hospital, manisa, turkey; 3 department of radiology, canakkale state hospital, canakkale, turkey; 4 department of urology, canakkale onsekiz mart university, faculty of medicine, canakkale, turkey. objectives: to compare individuals consuming natural spring water and tap water in terms of presence of urinary tract stone disease. patients and methods: patients were divided into two groups on the basis of the type of water: tap water (group i) vs natural spring water consumers (group ii). the two groups were compared in terms of presence of urolithiasis. in addition to the type of water consumed, participants were investigated in terms of age, sex, occupation, body mass index (bmi) and presence of hypertension (ht) and diabetes mellitus in order to evaluate if they constituted a risk factor for urolithiasis. results: two hundred fifty-nine patients consuming tap water and 254 consuming natural spring water were included in this study. presence of urinary stone disease was determined in 27% of patients in group i and 26% of group ii (p = 0.794). at multivariate analysis involving all variables that might be correlated with the presence of urolithiasis; male gender, high bmi and presence of ht emerged as being significantly associated with urolithiasis. conclusions: although we showed that male gender, presence of ht and high bmi affect stone formation, no difference was demonstated in terms of presence of stone among patients consuming tap or natural spring water key words: tap water; natural spring water; ultrasound; urolithiasis. submitted 3 july 2014; accepted 14 july 2014 summary no conflict of interest declared. introduction urinary system stone disease is a common pathology, with a lifetime prevalence across the world of between 1% and 15% (1). the disease is more common in some geographical regions probably in relation with various genetic and environmental factors. considering environmental factors alone, stone disease is more common in mountaineous areas and in people living in dry and hot climatic conditions, such as deserts and tropical re gions (2). studies have implicated temperature-related fluid loss from the body and rise in vitamin d stimulated by solar rays as the main reasons for this (3,4). doi: 10.4081/aiua.2014.3.217 several studies have proved that increasing daily fluid intake plays a protective role against stone formation by leading to diuresis and preventing supersaturation of stone components in urine (5-7). as much as the amount of fluid consumed, however, several studies have also considered the effect on stone formation of mineral content, electrolyte level, hardness and ph level of water consumed (8-15). however, no studies to date have investigated the widespread popular idea that consumption of chlorinated tap water can lead to stone disease. in order to answer that question, we used renal ultrasound (us) to compare individuals consuming natural spring water or tap water in terms of presence of stone in the urinary system. materials and methods study population five hundred thirteen patients aged over 18 who underwent urinary system us due to abdominal or flank pain and meet study conditions were included in the study following approval of its design by the çanakkale onsekiz mart university ethical committee. subjects with renal malformation that might constitute a risk factor for urinary stone formation (horseshoe kidney, polycystic renal disease, malrotated or ectopic kidney, ureteropelvic junction obstruction etc.), with known glomerular or tubular renal disease or a family predisposition (with stone first detected in childhood) to stone disease were excluded from the study. patients were divided into two groups on the basis of the type of water they had principally consumed in the previous 2 years: those consuming tap water (group i) and those consuming natural spring water (group ii). patients drinking both types of water or had changed the type of low urin e volume urine supersat uration high uri ne concent ration crystal aggregat ion high fluid intake tiselius oxalate-calcium crystallization risk index: 1.9 x (ca)0.84 x (ox) x (mg)-0.12 x (cit)-0.22 x urine volume-1.03 stone formatio n resorlu sc_stesura seveso 08/10/14 12:15 pagina 217 archivio italiano di urologia e andrologia 2014; 86, 3 m. resorlu, m. arslan, e. burcu resorlu, m. tolga gulpinar, g. adam, e. burak sancak, a. akbas, n. aylanc, h. ozdemir 218 water consumed over the preceding 2 years or stating to consumed less than 7 glasses of water a day (< 1.5 l/day) were excluded. in addition to the type of water consumed, demographic data such as participants’ age, sex, occupation, body mass index (bmi) and presence of chronic diseases such as hypertension (ht) and diabetes mellitus (dm) were recorded. all these variables were investigated in terms of whether or not they constituted a risk factor for presence of stone in the urinary system. ultrasound measurements all examinations were performed by radiologists with experience of ultrasound. sonographic examinations were performed with gray scale ultrasound machines (toshiba aplio xg and general electric logiq 9) using two convex transducers with 3.5 mhz, 4.0 mhz frequency. the presence of the stone was defined as presence of an echogenic image with or without posterior acoustic shadowing, clearly located within the urinary tract. statistical analysis all statistical analyses were performed using spss, version 16.0. all values are shown as mean ± standard deviation. comparisons were performed using the chi-square test. differences between groups were considered statistically significant at p < 0.05. results two hundred fifty-nine patients consuming tap water (group i) and 254 consuming natural spring water (group ii) were included in the study. in terms of gender, 52% of males stated that they used to drink tap water and 48% natural spring water, while 49% of women used to drink tap water and 51% natural spring water. mean age of patients was 52.2 (18-88) years in group i and 48.6 (1886) in group ii (p = 0.75). mean bmi values were 25.7 kg/m2 in group i and 26.2 kg/m2 in group ii (p = 0.58). in terms of chronic diseases, ht was determined in 22% and dm in 17% of patients in group i, and in 16% and 12%, respectively, of those in group ii. stone was detected in 26% (n = 145) of the patients in the study, in 33% of men and 18% of women (p < 0.001). presence of stone in the urinary system was determined in 27% of patients in group i and 26% of group ii (p = 0.794). mean bmi of the patients with stone in the urinary system was 27.2 kg/m2 whereas it was 25.5 kg/m2 in those with no stone. dm was observed in 17% and ht in 31% of the patients with stone and in 14% and 15%, respectively, in those with no stone. at multivariate analysis involving all variables that might be correlated with the presence of a stone in the urinary system, male gender and presence of ht emerged as being significantly associated with urolithiasis. variables such as age, occupation, type of water consumed and presence of dm were not risk factors for development of stone. conclusions in this study we therefore investigated whether there is any association between consumption of tap or natural spring water and urolithiasis in patients receiving us due to abdominal or flank pain. although we showed that male gender, presence of ht and high bmi affect the risk of stone formation, no difference was determined in terms of presence of stone among patients consuming tap versus natural spring water. references 1. curhan gc. epidemiology of stone disease. urol clin north am. 2007; 34:287-93. 2. soucie jm, thun mj, coates rj, et al. demographics and geographic variability of kidney stones in the united states. kidney int. 1994; 46:893-9. 3. curhan gc, willett wc, rimm eb, et al. a prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. n engl j med. 1993; 328:833-8. 4. urinary volume, water and recurrences in idiopathic calcium nephrolithiasis: a 5-year randomized prospective study. j urol. 1996; 155:839-43. 5. borghi l, meschi t, amato f, et al. urinary volume, water and recurrences in idiopathic calcium nephrolithiasis: a 5-year randomized prospective study. j urol. 1996; 155:839-43. 6. lotan y, daudon m, bruye f, et al. impact of fluid intake in the prevention of urinary system diseases: a brief review. curr opin nephrol hypertens. 2013; 22(suppl):1-10. 7. parks jh, goldfischer er, coe fl. changes in urine volüme accomplished by physicians treating nephrolithisis. j urol. 2003; 169:863-6. 8. aras b, kalfazade n, tugcu v, et al. can lemon juice be an alternative to potassium citrate in the treatment of urinary calcium stones in patients with hypocitraturia? a prospective randomized study. urol res. 2008; 36:313-7. 9. koff sg, paquette el, cullen j, et al. comparison between lemonade and potassium citrate and impact on urine ph and 24-hour urine parameters in patients with kidney stone formation. urology. 2007; 69:1013-6. 10. penniston kl, steele th, nakada sy. lemonade therapy increases urinary citrate and urine volumes in patients with recurrent calcium oxalate stone formation. urology. 2007; 70:856-60. 11. goldfarb ds, asplin jr. effect of grapefruit juice on urinary lithogenicity. j urol. 2001; 166:263-7. 12. shuster j, finlayson b, scheaffer r, et al. water hardness and urinary stone disease. j urol. 1982; 128:422-5. 13. bellizi v, de nicola l, minutolo r, et al. effects of water hardness on urinary risk factors for kidney stones in patients with idiopathic nephrolithiasis. nephron 1999; 81(suppl1):66-70. 14. rodgers al. effect of mineral water containing calcium and magnesium on calcium oxalate urolithiasis risk factors. urol int. 1997; 58:93-9. 15. massey lk, sutton ra. acute caffeine effects on urine composition and calcium kidney stone risk in calcium stone formers. j urol. 2004; 172:555-8. correspondence mustafa resorlu, md (corresponding author) mustafaresorlu77@gmail.com gurhan adam, md huseyin ozdemir, md nilufer aylanc, md department of radiology, canakkale onsekiz mart university, faculty of medicine, canakkale onsekiz mart universitesi, terzioglu yerleskesi barbaros mh, 17100, canakkale, turkey muhammet arslan, md department of radiology, vefa hospital, manisa, turkey eylem burcu resorlu, md department of radiology, canakkale state hospital, canakkale, turkey murat tolga gulpinar, md eyup burak sancak, md alpaslan akbas, md department of urology, canakkale onsekiz mart university, faculty of medicine, canakkale, turkey resorlu sc_stesura seveso 08/10/14 12:15 pagina 218 stesura seveso 371archivio italiano di urologia e andrologia 2014; 86, 4 original paper modifications of echogenicity of the testis during acute torsion may be a predictive factor of organ damage? giuseppe benedetto, filippo nigro, emiliano bratti, andrea tasca department of urology, san bortolo hospital, vicenza, italy in the setting of symptoms of testicular torsion the absence of diastolic flow or color flow on doppler ultrasound has traditionally prompted emergent scrotal exploration. this practice emanates from the difficulty on ultrasound of distinguishing salvageable testes from those that are not salvageable. we evaluated the changes of echogenicity in the course of testicular torsion of the testis to identify characteristics predictive of irreversible organ damage. key words: testicular torsion; echogenicity of testicular torsion. submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. flow in the testis wrong. six boys underwent orchiectomy for testicular necrosis and histological examination documented hemorrhagic necrosis of the testis consistent with testicular torsion. the ultrasound pattern of these patients documented in all the presence of a dishomogeneous and heterogeneous echotexture of the testis. in the other eight patients an hypoechoic and isoechoic homogeneous testicular framework was documented, compatible with the integrity of the testis as assessed at scrotal exploration the average time between the onset of symptoms and the scrotal exploration was 9 hours (range 6-18) in patients in whom the testis was preserved, and 15 hours (range 9-21) in patients undergoing then to orchiectomy. there were no intraand postoperative complications in patients undergoing orchiectomy discussion in our series the heterogeneously hypoechoic testicular parenchyma showed an irreversible organ damage that required removal of the organ. doi: 10.4081/aiua.2014.4.371 presented at 19th national congress sieun, fermo 2014 introduction and aims during the acute torsion of the testis, in addition to clinical signs and symptoms, the scrotal doppler ultrasound can be of support in evaluating the absence of testicular flow. we evaluated the changes of echogenicity in the course of testicular torsion of the testis to identify characteristics predictive of irreversible organ damage. material and methods we retrospectively analyzed, the scrotal ultrasound of patients undergoing scrotal exploration for testicular torsion in the last year in our department, evaluating the sonographic features and comparing them to the outcome of the scrotal exploration, and in case of orchiectomy to outcome for histology. was also evaluated the average time between the onset of symptoms and evaluation in the emergency room and the scrotal exploration. results during the past year, 14 children were evaluated at our department for acute torsion of the testis and underwent scrotal exploration. all underwent preoperative scrotal doppler ultrasound that documented the absence of figure. dishomogeneous torsion testis alteration. benedetto_stesura seveso 16/01/15 10:59 pagina 371 archivio italiano di urologia e andrologia 2014; 86, 4 g. benedetto, f. nigro, e. bratti, a. tasca 372 therefore, taking into account echotexture and obvious signs of torsion scrotal exploration cannot be emergent. on the other hand, an homogeneous echotexture heralds testicular viability and the need to scrotal exploration in emergency. conclusion we evaluated the changes of echogenicity in the course of testicular torsion of the testis to identify characteristics predictive of irreversible organ damage. however the smallness of our sample requires confirmation by in-depth studies of larger series. references 1. kaye jd, shapiro ey, levitt sb, et al. parenchymal echo texture predicts testicular salvage after torsion: potential impact on the need for emergent exploration.j urol. 2008; 180(4 suppl):1733-6. 2. nistal m, paniagua r, gonzalez-peramato p, reyes-múgica m. testicular torsion, testicular appendix torsion and other forms of testicular infarction. pediatr dev pathol. 2014. correspondence giuseppe benedetto, md g_benedetto@yahoo.it filippo nigro, md filippo.nigro@ulssvicenza.it emiliano bratti, md emiliano.bratti@ulssvicenza.it andrea tasca, md andrea.tasca@ulssvicenza.it uoc urologia, ospedale san bortolo, via rodolfi, 37 vicenza, italy benedetto_stesura seveso 16/01/15 10:59 pagina 372 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2132 note on surgical technique preservation of the smooth muscular internal (vesical) sphincter and of the proximal urethra during retropubic radical prostatectomy: a technical modification to improve the early recovery of continence eugenio brunocilla, riccardo schiavina, marco borghesi, cristian pultrone, matteo cevenini, valerio vagnoni, giuseppe martorana university of bologna s. orsola-malpighi hospital, bologna, italy. objective: we describe our technique for preservation of the smooth muscular internal (vesical) sphincter and proximal urethra during radical retropubic prostatectomy (rrp) and present our preliminary clinical results. materials and methods: the first steps of the prostatectomy reflect the standard rrp, while for the final phases the procedure continues in an anterograde manner with incision of the fibers of the detrusor muscle at the insertion of the ventral surface of the base of the prostate. at this level, the inner circular muscle of the bladder neck forms a sphincteric ring of smooth muscle that covers the longitudinally oriented smooth muscle component of the urethral musculature that extends distally to the verumontanum. these two proximal structures represent the internal sphincter that envelops and locks the proximal urethra. a blunt dissection is continued until the ring shaped vesical sphincter is separated from the prostate and the longitudinally oriented smooth muscle component of the urethral musculature is identified. the base of the prostate is then gently separated from the urethra and from the bladder until the maximal length of the urethral musculature is isolated and preserved. results: after 30 initial set-up procedures, 40 consecutive patients with organ confined prostate cancer were submitted to radical retropubic prostatectomy with the preservation of muscular internal sphincter and the proximal urethra and compared to 40 patients submitted to standard procedure who served as control group. the group of patients submitted to our technical modification had a faster recovery of early continence than control group at 3 and 7 days. conclusions: the described technique is a feasible and safe method for preservation of the internal urethral sphincter and allows improving the early recovery of urinary continence. the technique does not increase the rate of positive margins and the duration of the procedure. key words: radical prostatectomy; urinary continence; internal sphincter; proximal urethra; surgical margins. submitted 9 september 2013; accepted 31 march 2014 summary no conflict of interest declared. introduction retropubic radical prostatectomy (rrp) is one of the standard surgical methods for the treatment of clinically localised prostate cancer (pca). the preservation of urinary continence is one of the most important endpoints of the procedure. numerous mechanisms have been advocated as responsible for male postoperative urinary continence but the preservation of the integrity of the external urethral sphincter muscle, of the pelvic floor as well as anterior and posterior urethral support seem to play the most important role (1). young age and nervesparing procedure have been proposed as additional protective factors (2). during the last few decades, many technical modifications have been described in order to improve clinical results (3-6). in particular, the rocco stitch has shown an important potential role for the early recovery of continence (5, 6). in this paper, we describe our approach of preservation of the smooth muscular internal (vesical) sphincter (mis) as well as of the proximal urethra (pa) during bladder neck dissection as part of the conservation of the full functional length of the urinary sphincter and we present our preliminary results. materials and methods anatomic considerations and surgical technique the first part of the procedure is similar to the standard rrp described by walsh and co-workers (7) concerning the maintenance of the anterior and posterior urethral supports. in all cases we preserve the pubourethral and puboprostatic ligaments and we reconstruct the posterior musculofascial plate as described by rocco (6); great attention is made in preserving the integrity of the external urethral sphincter muscle, with clear visualization of the circular orientated horseshoe-shaped urethral sphincter (with its striated and smooth components, the rabdomyosphincter) and with the preservation of the maximal part of the longitudinally oriented smooth muscle of the urethra (the intrinsic sphincter or lissosphincter) that is close to the urethral lumen. doi: 10.4081/aiua.2014.2.132 133archivio italiano di urologia e andrologia 2014; 86, 2 internal sphincter and radical prostatectomy in the second part of the prostatectomy, the procedure becomes antegrade, with the aim of preserving the internal vesical sphincter and the pa. we cut the fibers of the detrusor muscle at the insertion of the ventral aspect of the base of the prostate; at this level, the inner circular smooth muscle of the bladder neck forms a sphincteric ring of smooth muscle that extend distally to the verumontanum and covers the longitudinally oriented smooth muscle component of the urethral musculature (the cranial prolongation of the lissosphincter). these structures represent the internal (vesical) sphincter that covers the pa (figure 1). presence of nodules of benign prostatic hyperplasia within the wall of the internal sphincter, previous surgery for benign prostatic obstruction (bpo) as well as loss of the integrity of the circular smooth muscle during radical prostatectomy may impair the function of the internal sphincter. a blunt dissection is continued till the ring shaped vesical sphincter is separated from the prostate and the longitudinally-oriented smooth muscle component of the urethral musculature is identified. thus, the base of the prostate is gently separated from the urethra till the maximal length of the internal (vesical) sphincter is preserved and the urethra is incised to remove the catheter. finally, the anastomotic sutures are placed through the distal urethral stump of external sphincter and the pa structure and are fixed to the circular fibers of the bladder neck. to assess the oncologic safety of our surgical technique, we perform circumferential biopsies of the pa and of the base of the prostate during the dissection in all cases. case-control study after 30 initial set-up procedures, we performed a prospective case-control study to assess the impact of our technique on urinary continence (8, 9): 40 consecutive patients with organ confined pca were submitted to radical retropubic prostatectomy with the preservation of muscular internal sphincter (mis) and the pa and compared to 40 patients submitted to standard procedure who served as control group. exclusion criteria were large mid lobe prostate or large prostate volume (> 80 cc) and high-risk pca (defined as psa > 20 ng/ml or clinical t3 or clinical gleason score > 7). the same surgeon with 25 years experience in rrp performed all surgical procedures. in all cases the catheter was removed after 12 days. continence rates were assessed using a self-administrated questionnaire at 3, 7, 30 days and 3, 12 months after removal of the catheter. results the group of patients submitted to our technical modification had a faster recovery of early continence than control group at 3 days (45% vs. 22%; p = 0.029) and at 7 days (75% vs. 50%; p = 0.018); considering the number of pads, group 1 had faster recovery of continence at 3, 7 and 30 days and a minor incidence of severe incontinence. there were no statistically difference in terms of continence at 3 and 12 months among the two groups. multivariate logistic regression analysis of continence in relation to the clinical, pathological and surgical characteristics showed that surgical technique and young age were significantly associated with earlier time to continence at 3 and 7 days, while there were no significant correlations with continence at 30 days, 3 and 12 months. the two groups had no significant differences in terms of positive surgical margins. there were no cases of bladder neck sclerosis/stricture or acute urinary retention. discussion recently others authors described the first clinical trial with the same technique, with optimal results in terms of early recovery of the continence (10). they demonstrated significantly lower urine loss, higher objective and social continence rates and higher qol-scores in patients who underwent this technique, thus confirming the positive impact of this technique in urinary incontinence after radical prostatectomy. conclusion in conclusion, in well-selected patients, our modified technique may accelerate the recovery of urinary continence and may improve the continence when the rabdosphincter has not been perfectly preserved. no additional positive margins were noted in both the two clinical trials and we look forward for the follow-up data to confirm its oncological safety. our preliminary results show optimal rates of recovery of urinary continence after surgery. however, because of the small number of patients who underwent this technique, further evaluation and comparative studies are needed to confirm these encouraging initial results. figure 1. identification and isolation of about 10 mm of proximal urethra during the dissection of the dorsal surface of the prostate from the bladder neck, with the preservation of the internal vesical sphincter. archivio italiano di urologia e andrologia 2014; 86, 2 e. brunocilla, r. schiavina, m. borghesi, c. pultrone, m. cevenini, v. vagnoni, g. martorana 134 references 1. xylinas e, ploussard g, durand x, et al. evaluation of combined oncological and functional outcomes after radical prostatectomy: trifecta rate of achieving continence, potency and cancer control a literature review. urology. 2010; 76:1194-8. 2. walz j, burnett al, costello aj, et al. a critical analysis of the current knowledge of surgical anatomy related to optimization of cancer control and preservation of continence and erection in candidates for radical prostatectomy. eur urol. 2010; 57:179-92. 3. licht mr, klein ea, tuason l, et al. impact of bladder neck preservation during radical prostatectomy on continence and cancer control. urology. 1994; 44:883-7. 4. schlomm t, heinzer h, steuber t, et al. full functional-length urethral sphincter preservation during radical prostatectomy. eur urol. 2011; 60:320-9. 5. rocco f, carmignani l, acquati p, et al. restoration of posterior aspect of rhabdosphincter shortens continence time after radical retropubic prostatectomy. j urol 2006; 175:2201-6. 6. gautam g, rocco b, patel vr, et al. posterior rhabdosphincter reconstruction during robot-assisted radical prostatectomy: critical analysis of techniques and outcomes. urology. 2010; 76:734-41. 7. walsh pc, lepor h, eggleston jc, et al. radical prostatectomy with preservation of sexual function: anatomical and pathological considerations. prostate. 1983; 4:473-85. 8. brunocilla e, pultrone c, pernetti r, et al. preservation of the smooth muscular internal (vesical) sphincter and of the proximal urethra during retropubic radical prostatectomy: description of the technique. int j urol. 2012; 19:783-5. 9. brunocilla e, schiavina r, pultrone cv, et al. preservation of the smooth muscular internal (vesical) sphincter and of the proximal urethra for the early recovery of urinary continence after retropubic radical prostatectomy: a prospective case-control study. int j urol. 2013 jun 26. 10. nyarangi-dix jn, radtke jp, hadaschik b, et al. impact of complete bladder-neck preservation on urinary continence, quality of life and surgical margins after radical prostatectomy: a randomised controlled single-blind trial. j urol. published on line: 24 sep 2012. correspondence eugenio brunocilla, md riccardo schiavina, md (corresponding author) rschiavina@yahoo.it marco borghesi, md cristian pultrone, md matteo cevenini, md valerio vagnoni, md giuseppe martorana, md university of bologna s. orsola-malpighi hospital, bologna, via palagi 9 40134 bologna, italy stesura seveso archivio italiano di urologia e andrologia 2014; 86, 3212 short communication evaluation of depression and self-esteem in children with monosymptomatic nocturnal enuresis: a controlled trial orhan koca 1, mehmet akyüz 1, bilal karaman 1, zeynep yeşim özcan 2, metin öztürk 1, zülfü sertkaya 1, muhammet ihsan karaman 1 1 haydarpasa numune training and research hospital, department of urology, istanbul, turkey; 2 haydarpasa numune training and research hospital, department of family medicine, istanbul, turkey. objectives: nocturnal enuresis (ne) is very common and is one of the most common causes for patients to be admitted to urology, pediatrics, child psychiatry and child surgery departments. we aimed to investigate the effect on depression and self-esteem of this disorder that can cause problems on person's social development and human relations. material and methods: 90 patients who were admitted to our clinic with complaints of nocturnal enuresis were enrolled. investigations to rule out organic causes were performed in this group of patients. out of them 38 children and adolescents (age range 8-18 years) with primary monosymptomatic nocturnal enuresis (pmne) agreed to participate in the study in the same period 46 healthy children and adolescents with a similar age range without bed wetting complaint were included in the study as a control group. the age of the family, educational and socioeconomic level were questioned and piers-harris children's self-concept scale (phcscs) and children's depression inventory (cdi) forms were filled out. results: mean age of the cases (18 females or 47.4% and 20 males or 52.6%) was 10.76 ± 3.82 years whereas mean age of controls (26 females or 56.5% and 20 males or 43.5%) was 10.89 ± 3.11 years. depression scale was significantly higher (p = 0.001) in the case group than in the control group (10.42 ± 4.31 vs 7.09 ± 4.35). in both groups there was no statistically significant difference by age and sex in terms of depression scale (p > 0.05). conclusion: ne is widely seen as in the community and is a source of stresses either for children and for their families. when patients were admitted to physicians for treatment, a multidisciplinary approach should be offered and the necessary psychological support should be provided jointly by child psychiatrists and psychologists. key words: depression; self-esteem; nocturnal enuresis. submitted 13 june 2014; accepted 1 august 2014 summary introduction nocturnal enuresis (ne) is very common in the society and is one of the most common causes for patients to be admitted to urology, pediatrics, child psychiatry and child no conflict of interest declared. surgery departments. ne is recurrent urinary incontinence in children over the 5 years old that is observed during the sleep (1). the prevalence of nocturnal enuresis has been reported as 5.5-16.8% (2,3). ne is classified as primary and secondary. ne may cause stress and emotional problems in person and families. on the other hand ne may develop secondary to stress on patients and families (4). however, there are conflicting results as to whether these stressful situations cause psychological problems in enuretic children. some authors assert that there is no difference of the psychological problems between the normal population and monosymptomatic enuretic children, but some others have argued that ne cause clinical or subclinical psychological problems (5). in a study of bed wetting and behavioral problems, conduct problems and deficits in attention up to age 13 and internalizing problems up to age of 15 have been reported more frequently in children whose bedwetting continue over 10 years of age (6). it may seem that there is a relationship between ne and behavioral problems increasing with age, but cause and effect relationship has not been clearly elucidated (7). we aimed to investigate the effect on depression and selfesteem of this disorder that can cause problems on person's social development and human relations. material and method ninety patients who were admitted to our clinic with complaints of nocturnal enuresis were enrolled. out of them 38 children and adolescents (age range 8-18 years) with primary monosymptomatic nocturnal enuresis (pmne) agreed to participate in the study and filled out questionnaires. in the same period 46 healthy children and adolescents with a similar age range without bed wetting complaint were included in the study as a control group. investigations (history, urinalysis, urine culture, urinary tract ultrasonography) were performed in the case group patients to rule out organic causes. age and educational and socioeconomic levels were questioned in both groups and piers-harris children's self-concept scale (phcscs) and children's depression inventory (cdi) forms were filled out. patients in both groups were classified accorddoi: 10.4081/aiua.2014.3.212 koca sc_stesura seveso 08/10/14 12:14 pagina 212 213archivio italiano di urologia e andrologia 2014; 86, 3 depression and self-esteem in enuretic children ing to age in 2 groups 8-11 years and > 12 years. nonpmne wetting bed or patients on any type of treatment were excluded from the study. patients who missed to fill all or a part of the questionnaire were excluded from the study. student t test via spss 13 for windows was used for statistical analyzes. p value < 0.05 was considered statistically significant. results mean age of the cases (18 females or 47.4% and 20 males or 52.6%) was 10.76 ± 3.82 years whereas mean age of controls (26 females or 56.5% and 20 males or 43.5%) was 10.89 ± 3.11 years. twenty six patients (68.4%) out of the case group were 8-11 years of age and 12 (31.6%) were > 12 years whereas 32 (69.6%) out of the control group were 8-11 years of age, and 14 (30.4%) were > 12 years. there were statistically significant differences between the two groups in self-esteem scale (table 1). no statistically significant difference in term of gender was found (p > 0.05). in the case group no statistically significant difference of the total score was found by age (p > 0.05), but a statistically significant difference was detected in in term of behavior and comply (p = 0.022). in the control group, no statistically significant difference of the total score was found by age (p > 0.05). depression scale was significantly higher (p = 0.001) in the case group than in the control group (10.42 ± 4.31 vs 7.09 ± 4.35). in both groups there was no statistically significant difference by age and sex in terms of depression scale (p > 0.05). in both groups, occupation of parents, education and socioeconomic status didn't affect phcscs and cdi scores (p > 0.05). discussion ne is fairly common all over the world and this disease averagely affects one in 10 children. effects on children's social and psychological development are frequently observed. self-identity and sexual identity are acquired during childhood and adolescence, therefore a number of additional problems like mood disorders are seen with ne. ne is fairly common in our country and causes many negative effects on individuals and families. this condition may cause the fear of being noticed by others, humiliation, anxiety, social withdrawal, high anxiety levels and behavior problems (8). in a study that investigated how children see enuresis it was reported that bedwetting is the most stressful events after family fights and divorce (9). adverse effects on mothers have also been described (11). ne has depressive effects on children and their families (10). in our study, a statistically significant difference of depression scores (cdi) was detected between enuretic patients and controls without difference by age, gender, education and socio-economic level. decreased self-esteem, social adjustment problems in school and with friends and behavior problems have been reported in children with enuresis (12). in our study, a statistically significant difference of self-esteem phcscs scores was detected between patients with enuresis and controls with significant difference of sub-titles of happiness, anxiety and popularity. in contrast hirasing et al reported no significant relationship between nocturnal enuresis and behavioral and emotional problems (13). decreased self-esteem was detected in enuretic adults as in children (14). liu et al. reported that there were more problems with behavior, emotional, and academic achievement in children with ne and observed that they increased with age (15). delay of the family to apply to health institutions for therapy increases children self-esteem problems. in our study, only the behavior and adaptation sub-title was significantly different in terms of age whereas age-related differences were not observed by other parameters although this could be explained by insufficient size of the sample. in fact a limitation of our study could be low number of patients from a single center and lack of graduation of the severity of ne. conclusions in conclusion, ne that is frequently observed in the community is a source of stresses for either children or their families. it should be considered that ne may cause loss of self-confidence and depression in children. trust should be provided for children and families and training should be given according to treatment planning. when patients were admitted to physicians for treatment, a multidisciplinary approach should be offered and the necessary psychological support should be provided jointly by child psychiatrists and psychologists. references 1. nevéus t, von gontard a, hoebeke p, et al. the standardization of terminology of lower urinary tract function in children and adolescents: report from the standardisation committee of the international children's continence society. j urol. 2006; 176:314-24. case group n= 38 control group n=46 p value happiness 9.26 ± 3.1 10.71 ± 1.96 0.012 anxiety 7.47 ± 2.64 9.35 ± 2.0 < 0.001 popularity 7.95 ± 1.99 9.41 ± 1.44 < 0.001 behavior and compliance 9.97 ± 3.19 11.28 ± 2.86 0.051 physical appearance 8.05 ± 1.87 8.22 ± 1.74 0.677 mental and school 5.13 ± 1.3 5.65 ± 1.12 0.052 total 54.26 ± 12.98 63.41 ± 9.14 < 0.001 table 1. comparison of the two groups in terms of self-confidence. koca sc_stesura seveso 08/10/14 12:14 pagina 213 archivio italiano di urologia e andrologia 2014; 86, 3 o. koca, m. akyüz, b. karaman, z.y. özcan, m. öztürk, z. sertkaya, m.i. karaman 214 2. bower wf, moore kh, shepherd rb, adams rd. the epidemiology of childhood enuresis in australia. br j urol. 1996; 78:602-6. 3. kalo bb, bella h. enuresis: prevalence and associated factors among primary school children in saudi arabia. acta paediatr. 1996; 85:1217-22. 4. chang ss, ng cf, wong sn. behavioural problems in children and parenting stres associated with primary nocturnal enuresis in hong kong. acta pediatr. 2002; 91:475-9. 5. butler rj. impact of nocturnal enuresis on children and young people. scand j urol nephrol. 2001; 35:169-76. 6. fergusson dm, horwood lj. nocturnal enuresis and behavioral problems in adolescence: a 15-year longitudinal study. pediatrics. 1994; 94:662-8. 7. rocha mm, costa nj, silvares ef. changes in parents' and selfreports of behavioral problems in brazilian adolescents after behavioral treatment with urine alarm for nocturnal enuresis. int braz j urol. 2008; 34:749-57. 8. hägglöf b, andrén o, bergström e, et al. self-esteem in children with nocturnal enuresis and urinary incontinence: improvement of self-esteem after treatment. eur urol. 1998; 33 suppl 3: 16-9. 9. van tijen nm, messer ap, namdar z. perceived stress of nocturnal enuresis in childhood. br j urol. 1998; 81 suppl 3:98-9. 10. hjalmas k, arnold t, bower w, et al. nocturnal enuresis: an international evidence based management strategy. j urol. 2004; 171:2545-61. 11. egemen a, akil i, canda e, et al. an evaluation of quality of life of mothers of children with enuresis nocturna. pediatr nephrol. 2008; 23:93-8. 12. hägglöf b, andrén o, bergström e, et al. self-esteem before and after treatment in children with nocturnal enuresis and urinary incontinence. scand j urol nephrol. suppl. 1997; 183:79-82. 13. hirasing ra, van leerdam fj, bolk-bennink lb, bosch jd. bedwetting and behavioural and/or emotional problems. acta paediatr. 1997; 86:1131-4. 14. theunis m1, van hoecke e, paesbrugge s, et al. self-image and performance in children with nocturnal enuresis. eur urol. 2002; 41:660-7. 15. liu x, sun z, uchiyama m, et al. attaining nocturnal urinary control, nocturnal enuresis, and behavioral problems in chinese children aged 6 through 16 years. j am acad child adolesc psychiatry. 2000; 39:1557-64. correspondence orhan koca, md (corresponding author) drorhankoca@hotmail.com mehmet akyüz, md bilal karaman, md metin öztürk, md zülfü sertkaya, md muhammet ihsan karaman, md haydarpasa numune training and research hospital department of urology tıbbiye st. no:2 üsküdar zip:34718 istanbul, turkey zeynep yeşim özcan, md haydarpasa numune training and research hospital department of family medicine, istanbul, turkey koca sc_stesura seveso 08/10/14 12:14 pagina 214 stesura seveso 353archivio italiano di urologia e andrologia 2014; 86, 4 original paper improvement of lower urinary tract symptoms and sexual activity after open simple prostatectomy: prospective analysis of 50 cases lorenzo montesi, luigi quaresima, marco tiroli, vito lacetera, ubaldo cantoro, giulia sbrollini, giovanni muzzonigro, massimo polito institute of urology, aou united hospitals, polytecnic university of marche region, ancona, italy. objectives: to evaluate the improvement of lower urinary tract symptoms (luts) and erectile function (ef) evaluated before and after open simple prostatectomy, focusing on which patients this procedure allows better outcomes in term of sexual activity. material and methods: 50 men with large size benign prostatic hyperplasia (bhp) greater than 80 gr were prospectively evaluated before and 6 months after open simple prostatectomy (freyer procedure) between october 2012 to september 2013. patients had a pre-operative transrectal ultrasound (trus) for volume evaluation and filled pre and post operative questionnaires for international prostate symptom score (ipss) and international index of erectile function (iief-5) score. results: mean patients age was 71 years (d.s. 3,5), mean prostate volume results 103 ml (d.s. 23,7); regarding luts and ef, mean improvement of ipss score was 15,3 (d.s. 4) and mean increase of iief-5 score was 3,4 (d.s.3). this study highlights a correlation between patients’ age and increase of iief-5 score; no correlation with prostate size was found. conclusion: according to the eau guidelines 2014, large size bph (over 80-100 ml) with luts refractory to medical management continue to have open prostatectomy as the treatment of choice. in our experience we found not only an reduction of luts after the procedure but also an improvement of erectile function; this improvement was related with patient’s age. key words: prostate; benign prostatic hyperplasia (bph); open simple prostatectomy; erectile dysfunction; lower urinary tract symptoms (luts). submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. the gland has been related with the level of dihydrotestosterone (dht), although in the last years it has progressively gained credibility the hypothesis of a possible involvement of environmental factors in the pathogenesis of bph. inflammation seems to play a significant role, and this evidence was frequently reported in the literature. recently zlotta et al. (1) evaluated the association between acute and chronic inflammation and prostatic hypertrophy; from their study on cadavers was evident the association between chronic flogosis and volume of the prostate gland, with a probability to observe bph 6.8 times greater in those with chronic inflammation than in those whitoutt. the growth of the prostate is responsible of lower urinary tract symptoms (luts) such as urinary frequency, nocturia, hesitancy, feeling of incomplete voiding, terminal dropping that involve a substantial reduction in quality of life (qol) for the patient (2, 3). associated with these symptoms has evolved over time the idea that inflammatory bph may affect the reduction of sexual potency in the old man, especially if associated with other contributing factors such as diabetes, hypertension or vascular disease. by now it is well established the beneficial role of surgery, either endoscopic or open, in the improvement of urinary symptoms. recently, garcia et al. (4) compared the open simple prostatectomy (osp) with laparoscopic extraperitoneal adenomectomy showing how obtain great results with this technique especially in terms of intraoperative bleeding and days of hospitalization. the technique is a feasible alternative to the intervention of osp which is still today the gold standard procedure. more uncertain remain instead the apparent benefit on the recovery of erectile function. in 1997 goriunov et al. (5) assessed erectile function in 818 patients undergoing to surgery for bph. it appeared that the osp deteriorated the erectile function (ef) of sexually active patients, but also that, in a low percentage of cases (5%), sexual function was recovered in patients previously not sexually active. over time, new researches have shown the association between prostatic hypertrophy and reduction of ef: with the improvement of surgical techniques, the recovery of sexual function becomes a goal to be pursued both clinically and surgically. doi: 10.4081/aiua.2014.4.353 presented at 19th national congress sieun, fermo 2014 introduction benign prostatic hyperplasia (bph) affects the male population indiscriminalety and its incidence is increasing in relation to the raise of the population’s average age. it affects approximately 5-10% of men under 40 years and up to 80% of men between 70-80 years. the growth of quaresima 2_stesura seveso 15/01/15 12:50 pagina 353 archivio italiano di urologia e andrologia 2014; 86, 4 l.montesi, l. quaresima, m. tiroli, v. lacetera, u. cantoro, g. sbrollini, g. muzzonigro, m. polito 354 aim of our study was to evaluate the improvement of luts and ef valued before and after osp, focusing in particular to show in which patients this procedure allows better outcomes in term of sexual activity. materials and methods the study was conducted prospectively. were included in the study patients who underwent osp between september 2012 and february 2014. all the patients were subjected before surgery to uroflowmetry and filling of the validated questionnaires international index of erectile function (iief5) and international prostate syntoms score (ipss). the same were repeated 6 months after the surgery, in presence of negative urine cultures and without use of phosphodiesterase-5 (pde-5) inhibitors drugs. the surgical procedures were performed by three different surgeons with more than 10 years of experience. exclusion criteria were drop outs at follow-up, presence of significant comorbidities and use of 5alpha reductase inhibitor (5-ari) and/or 5-pde drugs in the 6 months before enrollment, data were analyzed with the statistical program spss. a value of p < 0.05 was considered statistically significant (figure 1). results fifty patients who underwent osp between september 2012 and february 2014 were included in the study; the average age of the patients was 71 years (sd 6.5), mean prostate volume was 103 ml (sd 33.7 ) with a maximum volume of 200 ml and a minimum of 40 ml. six patients showed preoperatively at least one episode of acute retention of urine and 4 of them came to surgery with catheter placed for chronic retention. forty-one patients were treated at least once with alpha-blockers, while 22 of them have been submitted at least once to therapy with 5-ari but not in the months before completing the questionnaire. the average improvement in ipss was 15.3 (ds 8) with a maximum value of 32 and a minimum value of 0 (figure 2). the average improvement of iief5 was 3.4 (ds 5) with maximum improvement of 19 and minimum improvement of 0 mean improvement in subgroup of patients less than 70 years resulted 4.6 (ds 5,3). no difference between patients with different prostate size was observed. six patients had positive urine cultures at subsequent checks for which it was set an appropriate antibiotic therapy; one patient had wound infection. no episode of acute retention occurred in our study in the six months follow-up after surgery and in none of the patients it was necessary to reset the alpha-blocking therapy (figure 3). discussion our study proved to be concurring with the current european guidelines for the treatment of prostatic hypertrophy. in fact, in agreement with the eau guidelines 2014, bph with high volume (greater than 80 ml) had as first line treatment the open simple prostatectomy procedure (6-8). new techniques have been compared with osp: raimbault et al. (9) have compared the results obtained with photo-selective vaporization of the prostate to those obtained by osp in high volume prostates (> 80 ml): it resulted a lower cost compared to the benefit obtained and an inferior percentage of reoperations in the one year follow-up. kim et al. (10) have recently tested the effect of the holmium laser enucleation of the prostate demonstrating a good improvement of the sexual function of patients, especially when associated with an improvement of irritative luts. to sum up, a huge number of studies in international literature have compared surgical results of different techniques, some of them analyzed the ef, but few studies tried to find prognostic factors to predict which category of patients has the best outcome in term of improvement of ef after ops; in our experience the only patients characteristic that predict ef outcome was patients age. figure 2. ipss scores pre and 6 months after osp procedure. figure 3. iief-5 scores pre and 6 months after osp procedure figure 1. distribution of patients’ prostate sizes. quaresima 2_stesura seveso 15/01/15 12:50 pagina 354 conclusions the results obtained show how osp procedure provides excellent results as regards the obstructive voiding symptoms. encouraging results were also obtained with regard to the recovery of sexual potency, in particular correlated to the patient's age; additional studies with a bigger sample size are strongly recommended to confirm this theory. references 1. zlotta ar, egawa s, pushkar d, et al. prevalence of inflammation and benign prostatic hyperplasia on autopsy in asian and caucasian men. eur urol. 2014; 66:619-22. 2. abrams p, cardozo l, fall m, et al. the standardisation of terminology of lower urinary tract function:report from the standardisation sub-committee of the international continence society. neurourol urodyn. 2002; 21:167-78. 3. chapple cr, wein aj, abrams p, et al. lower urinary tract symptoms revisited: a broader clinical perspective. eur urol. 2008; 54:563-9. 4. garcía-segui a, gascón-mir m. comparative study between laparoscopic extraperitoneal and open adenomectomy. actas urol esp. 2012; 36:110-6. 5. goriunov vg, davidov mi. sexual readaptation after the surgical treatment of benign prostatic hyperplasia. urol nefrol (mosk). 1997; (5):20-4 6. tubaro a, carter s, hind a, et al. a prospective study of the safety and efficacy of suprapubic transvesical prostatectomy in patients with benign prostatic hyperplasia. j urol. 2001; 166:172-6. 7. mearini e, marzi m, mearini l, et al. open prostatectomy in benign prostatic hyperplasia: 10-yearexperience in italy. eur urol 1998; 34:480-5. 8. serretta v, morgia g, fondacaro l, et al. open prostatectomy for benign prostatic enlargement in southern europe in the late 1990s: a contemporary series of 1800 interventions. urology. 2002; 60:623-7. 9. raimbault m, watt s, bourgoin h, et al. comparative analysis of photoselective vaporization of the prostate with the greenlight laser and open prostatectomy for high volume prostate hypertrophy. prog urol. 2014; 24:470-6. 10. kim sh, yang hk, lee he, paick js, oh sj. holep does not affect the overall sexual function of bph patients: a prospective study. asian j androl. 2014. 355archivio italiano di urologia e andrologia 2014; 86, 4 improvement of lower urinary tract symptoms and sexual activity after open simple prostatectomy: prospective analysis of 50 cases correspondence lorenzo montesi, md lorenzomontesi@yahoo.it luigi quaresima, md (corresponding author) luigiquaresima@yahoo.it marco tiroli, md marcotiroli@libero.it vito lacetera, md vlacetera@gmail.com ubaldo cantoro, md ubymaior@libero.it giulia sbrollini, md giuliasbrollini@libero.it giovanni muzzonigro, md g.muzzonigro@univpm.it massimo polito, md max_polito@virgilio.it institute of urology, aou united hospitals, polytecnic university of marche region, ancona, italy quaresima 2_stesura seveso 15/01/15 12:50 pagina 355 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 3222 case report bladder tumours in children: an interesting case report of tcc with a partial inverted growth pattern davide abed el rahman 1, giuseppe salvo 2, carlotta palumbo 3, bernardo rocco 3, francesco rocco 3 1 u.o.c. di urologia azienda ospedaliera “g. salvini”, presidio di rho, rho (mi), italy; 2 dipartimento universitario materno-infantile di andrologia ed urologia, università degli studi di palermo, italy; 3 istituto di urologia fondazione irccs ospedale maggiore policlinico “ca granda”, università degli studi di milano, italy. bladder urothelial carcinoma is typically a disease of older individuals and rarely occurs below the age of 40 years. there is debate and uncertainty in the literature regarding the clinicopathologic and prognostic characteristics of bladder urothelial neoplasms in younger patients compared with older patients, although no consistent age criteria have been used to define "younger" age group categories. we report on a 16 years old girl with transitional cell carcinoma of the bladder with a partial inverted growth pattern who presented with gross hematuria. ultrasonography revealed a papillary lesion in the bladder; cystoscopic evaluation showed a 15 mm papillary lesion with a thick stalk located in the left bladder wall. pathologic evaluation of the specimen was reported as “low grade transitional cell carcinoma of the bladder with a partial inverted growth pattern”. key words: bladder cancer; young adults; inverted papilloma; pathology. submitted 24 april 2014; accepted 30 june 2014 summary no conflict of interest declared. introduction bladder urothelial cancer is predominately a disease of males and occurs mainly among the elderly adults (1), less than 1% of bladder urothelial cancer has been reported during the first four decades of life. reported cases of transitional cell carcinoma of the bladder in the pediatric population are less than 150. in 1969 javadpour and mostofi studied the records of 10,000 patients with urothelial malignancy and found that just 40 patients were younger than 20 years old. large series have described the characteristics of these tumours as low grade and seldom recurring (2). although the biologic behaviour and treatment of bladder cancer has been well studied, conflicting reports exist about clinical behavior and prognosis for patients under 40 years of age; whether younger patients have a better prognosis than their older counterparts has long been a subject of debate; indeed, some groups observed similar patterns of clinical behavior and prognosis for doi: 10.4081/aiua.2014.3.222 bladder cancer in young and older patients (3), whereas other investigators reported lower rates of disease recurrence and progression, and better survival, in younger patients (4). moreover even if inverted papilloma of the urinary bladder is not uncommon in adults this is not the case in the pediatric population in which tumors of the urinary bladder are rare and more commonly of mesenchymal origin. paschkis first described this lesion in 1927 and named it polypoid adenoma (5). later, potts and hirst designated it as inverted papilloma (6). this lesion exhibits a polypoid configuration with an inverted papillomatous architecture lined by transitional epithelium. it also may have submucosal cyst formation and brunn’s nests so some authors refer to this lesion as brunnian adenoma (7). this lesion is rare in children, with the first case described in 1979 (8) and the youngest case described in a 11-year-old boy in 2000 (9). furthermore, the exact biological behaviour of inverted papilloma of the urinary bladder remains uncertain. we report an additional case of a low grade transitional cell carcinoma of the bladder with a partial inverted growth pattern in a 16 years old girl and emphasize the need for an intense and long-term follow-up of the pediatric population affected by bladder tumours (in its various histological types) to fully define its prognostic significance and potential biological behaviour in a near future. case report we report the case of a non-smoking 16 years old girl without a clinically significant pathologic anamnesis who referred to another urology department for a double episode of asymptomatic macrohematuria in two months spontaneously resolved. the patient underwent an ultrasound scan of urinary bladder showing an endovescical papillary lesion of 15 mm located on the left side of bladder without associated ureterohydronephrosis. cystoscopy demonstrated a 15 mm papillary lesion of the left bladder wall far from omolateral ureteral orifice; the lesion was connected to the bladder wall by a thin stalk. el rahman cr_stesura seveso 08/10/14 12:17 pagina 222 223archivio italiano di urologia e andrologia 2014; 86, 3 bladder tumours in children: an interesting case report of tcc with a partial inverted growth pattern the patient underwent a transurethral resection of the bladder (turb) and a 13 grams resection of newly formed tissue was performed. the hystopathologic examination performed by an expert urological pathologist revealed a “low grade transitional cell carcinoma of the bladder with a partial inverted growth pattern in absence of subepithelial connective tissue infiltration”. after turb the patient underwent a contrast enhanced computed tomography (tc) that showed a normal high urinary tract. urologists gave indication for a “single shot” 40 ml mytomicin c instillation, but the patient refused the treatment. two months later the patient contacted our department and, considering the rarity of the case and the extension of the neoplasm, we gave the indication of a “2nd look” turb that was performed after a few days. preoperative cystoscopy showed the area of previous resection interested by edema and partially covered by fibrin; there were not instead secure signs of persistent disease. we performed a deep resection of the described area and a separate collection of resection margins (medial, lateral, anterior and posterior). the biopsied areas were sent to the same expert pathologist who had done the previous diagnosis that revealed the absence of any suspicious area for recurrence. the patient is now followed with cistoscopy and urinary citology every 3 months. conclusions younger patients with bladder cancer appear to have a more favourable prognosis, because they usually present with superficial stage and low-grade tumours. however, the risk of disease progression is the same, influenced by grade and stage at the time of presentation. patients younger than 40 years old diagnosed with bladder cancer should be offered the same stage and grade appropriate management as older ones. a diagnosis of bladder cancer should be considered in all patients with haematuria and bladder irritative symptoms, regardless of age. references 1. zhang zl, xiong yh, li yh, et al. reassessment of the predictive role of perivesical fat invasion in invasive bladder cancer prognosis in 151 chinese patients. chin med j. 2011; 124:2915-2919. 2. javadpour n, mostofi fk. primary epithelial tumors of the bladder in the first two decades of life. j urol. 1969; 101:706-710. 3. johnson de, hillis s. carcinoma of the bladder in patients less than 40 years old. j urol. 1978; 120:172-3. 4. witjes ja, debruyne fm. bladder carcinoma in patients less than 40 years of age. urol int. 1989; 44:81-3. 5. paschkis r. uber adenoma der harnblase. z urol chir. 1927; 21:315-325. 6. potts if, hirst e. inverted papilloma of the bladder. j urol. 1963; 90:175-179. 7. kim yh, reiner l. brunnian adenoma (inverted papilloma) of the urinary bladder: report of a case. hum pathol. 1978; 9:229. 8. lorentzen m, rohr n. urinary bladder tumours in children. scand j urol nephrol. 1979; 13:323-327. 9. isaac j, lowicik a, et al. inverted papilloma of the urinary bladder in children: case report and review of prognostic significance and biological potential behavior j pediatr surg. 35:1514-1516. correspondence davide abed el rahman, md (corresponding author) davide.adel@libero.it u.o.c. di urologia azienda ospedaliera “g. salvini” presidio di rho, viale europa, 250 rho (mi) giuseppe salvo, md dipartimento universitario materno-infantile di andrologia ed urologia, università degli studi di palermo, palermo, italy carlotta palumbo, md bernardo rocco, md francesco rocco, md istituto di urologia fondazione irccs ospedale maggiore policlinico “ca granda”, università degli studi di milano via delle forze armate, 260 20152 milan, italy el rahman cr_stesura seveso 08/10/14 12:17 pagina 223 stesura seveso 103archivio italiano di urologia e andrologia 2014; 86, 2 original paper medical expulsive therapy for distal ureteric stones: tamsulosin versus silodosin vittorio imperatore 1, ferdinando fusco 2, massimiliano creta 1, sergio di meo 1, roberto buonopane 1, nicola longo 2, ciro imbimbo 2, vincenzo mirone 2 1 department of urology, buon consiglio fatebenefratelli hospital, naples, italy; 2 department of urology, policlinico federico ii of naples, naples, italy. objectives: to compare the efficacy and safety of tamsulosin and silodosin in the context of medical expulsive therapy (met) of distal ureteric stones. patients and methods: observational data were collected retrospectively from patients who received silodosin (n = 50) or tamsulosin (n = 50) as met from january 2012 to january 2013. inclusion criteria were: patients aged ≥ 18 years with a single, unilateral, symptomatic, radiopaque ureteric stone of 10 mm or smaller in the largest dimension located between the lower border of the sacroiliac joint and the vesico-ureteric junction. stone expulsion rate, stone expulsion time, number of pain episodes, need for analgesics use, incidence of side effects were compared. results: stone-expulsion rate in the silodosin and in the tamsulosin groups were 88% and 82%, respectively (p not significant). mean expulsion times were 6.7 and 6.5 days in the silodosin and tamsulosin group, respectively (p not significant). mean number of pain episodes were 1.6 and 1.7 in the silodosin and tamsulosin group, respectively (p not significant). the mean number of analgesic requirement was 0.84 and 0.9 for the silodosin and tamsulosin group, respectively (p not significant). overall, incidence of side effects was similar in both groups. patients taking silodosin experienced an higher incidence of retrograde ejaculation but a lower incidence of side effects related to peripheral vasodilation when compared to patients taking tamsulosin. subgroup analysis demonstrated significantly lower mean expulsion times and pain episodes in patients with stones ≤ 5 mm in both groups. conclusions: tamsulosin and silodosin are equally effective as met for distal ureteric stones sized 10 mm or smaller. met with silodosin is associatd with a lower incidence of side effects related to peripheral vasodilation but an higher incidence of retrograde ejaculation when compared to tamsulosin. key words: silodosin; tamsulosin; medical expulsive therapy; stones. submitted 26 august 2013; accepted 15 january 2014 summary no conflict of interest declared. introduction ureteric stones account for 20% of urinary tract stones and about 70% of them are found in the lower third of the ureter at presentation (1). to date, minimally invasive therapies, such as extracorporeal shock wave lithotripsy and ureterolithotripsy, represent efficacious treatment modalities in almost all cases. nevertheless, these procedures imply high costs and are not risk-free (2). a watchful waiting approach has been reported to be associated with spontaneous stone expulsion in up to 50% of cases but some complications may occur such as urinary tract infections, hydronephrosis and colic events (2). in recent years, the use of the expectant approach for distal ureteric stones has been extended thanks to the use of adjuvant medical expulsive therapy (met), that is able to reduce symptoms and facilitate stone expulsion. in 1970, malin et al. demonstrated the presence of alpha and beta adrenergic receptors (ar) in the human ureter (3). alpha1 are the most abundant ar subtypes at the level of ureteric smooth muscle cells (4). itoh et al. demonstrated that three types of alpha1 ar are expressed in the human ureter (alpha1a, alpha1b and alpha1d) (5-7). antagonists of these receptors have been proved to decrease ureteric basal tone, peristaltic activity, and contractions thus decreasing intraureteric pressure and increasing urine transport (5). three metaanalyses have confirmed a positive effect of alpha-blocker therapy on the stone expulsion rates (8-11). alphablockade has been proved to improve the likelihood of spontaneous stone passage, and to decrease both the time to stone passage and analgesic requirements (12). according to european association of urology guidelines, alpha-blockers or nifedipine are recommended for met (grade of recommendation a) (13). patients who elect for met should have well controlled pain, no clinical evidence of sepsis, and adequate renal functional reserve (13). the alpha1a/d selective alpha-blocker tamsulosin has been demonstrated to be a safe and effective drug that enhances spontaneous passage of distal ureteral stones sized 10 mm or smaller (8). recent studies have demonstrated that the alpha1a subtype plays the major role in mediating phenylephrine-induced contraction in doi: 10.4081/aiua.2014.2.103 archivio italiano di urologia e andrologia 2014; 86, 2 v. imperatore, f. fusco, m. creta, s. di meo, r. buonopane, n. longo, c. imbimbo, v. mirone 104 the human isolated ureter (7). kobayashi et al. found that the selective alpha1a adrenergic receptor antagonist, silodosin, was more effective than the selective alpha1d adrenergic receptor antagonist, bmy-7378, for noradrenaline-induced contraction in the human ureter (14). silodosin is effective as met for ureteric stones (16). according to tsuzaka et al., silodosin was clinically superior for stone expulsion when compared to the selective α1d ar antagonist naftopidil (16). to date, however there are no clinical studied that compare silodosin to tamsulosin as met for lower ureteric stones. we aimed to compare the efficacy of tamsulosin and silodosin as met for symptomatic, uncomplicated distal ureteric stones. materials and methods observational data were collected retrospectively from patients who received silodosin or tamsulosin as met from january 2012 to january 2013. inclusion criteria were: patients aged ≥ 18 years with a single, unilateral, symptomatic, radiopaque ureteric stone of 10 mm or smaller in the largest dimension located between the lower border of the sacroiliac joint and the vesicoureteric junction as assessed on intravenous urography. exclusion criteria were: renal insufficiency, urinary tract infections, high-grade hydronephrosis, previous therapies for the stone, solitary kidney, history of ureteral surgery or previous endoscopic procedures, concomitant calcium-antagonists or corticosteroids medications, ureteric strictures, cardiovascular diseases, incomplete data. the following data were recorded and compared: patients demographics, stone size and side, type of met, stone expulsion rate, stone expulsion time, number of pain episodes, need for analgesics use, incidence of side effects. patients who experienced stone expulsion before first medication, or who were lost to follow-up were excluded from the analysis. statistical analysis of mean values was carried out with the student t test and the chi square test. subgroup analysis was performed according to stone size ≤ or > 5 mm. results overall, data from a total of 100 patients which met inclusion and exclusion criteria were recorded. of them, 50 patients (50%) received a prescription of a daily single dose of tamsulosin 0.4 mg for 28 days and 50 (50%) a prescription of a daily single dose of silodosin 8 mg for 28 days. all patients were advised to drink a minimum of 2 l of water daily and to use symptomatic therapy with injection of 75 mg diclofenac on demand. all patients were advised to filter their urine to detect spontaneous stone passage and to stop taking the medications when the stone was expulsed. patients were followed up weekly with x-ray of the kidney, ureter, and bladder region and with ultrasonography. absence of stone expulsion after day 28 was considered failed therapy. discontinuation of met and intervention within 28 days from the start of the met due to uncontrollable pain, adverse events, urinary tract infections, acute renal failure, or the patient’s desire for stone removal were also considered failed therapy. baseline patients characteristics in both study arms are reported in table 1. the two groups were comparable in terms of mean age, mean stone size, stone side. moreover, the number of patients with smaller stones (≤ 5 mm) and larger (> 5 mm) stones were also comparable in both groups. spontaneous stone expulsion within 28 days was observed in 41 patients in the tamsulosin arm (82%) and in 44 patients in the the silodosin arm (88%) without statistically significant differences (table 2). hospitalization and ureteroscopy were required in 3 patients belonging to the tamsulosin arm and in 2 patients belonging to the silodosin arm. six patients in the tamsulosin arm and 3 in the silodosin arm experienced unsuccessful expulsion after 4 weeks of treatment and required ureteroscopy. not statistically significant differences emerged in terms of mean expulsion tamsulosin silodosin p value expulsion rate n (%) 41 (82) 44 (88) n.s. expulsion time days mean (range) 6.5 (3-9) 6.7 (3-9) n.s. pain episodes mean (range) 1.7 (0-4) 1.6 (0-4) n.s. need for analgesics 0.9 (0-3) 0.84 (0-3) n.s. side effects (n %) retrograde ejaculation 1 (2) 8 (16) < 0.05 side effects related to peripheral vasodilation dizziness 4 (8) 1(2) n.s. nasal congestion 3 (6) 1 (2) n.s. postural hypotension 3 (6) 1 (2) n.s. headache 3 (6) 1(2) n.s. total 13 (26) 4 (8) < 0.05 total side effects 14 12 n.s. n.s.: not statistically significant difference. table 2. overall results. tamsulosin silodosin p value mean age, year (range) 53.5 (33-77) 50.1 (30-77) n.s. ureteric stone side left n (%) 27 (54) 21 (42) n.s. right n (%) 23 (46) 29 (58) n.s. gender n (%) male 50 (100) 50 (100) n.s. mean stone size, mm (range) 6.7 (3-10) 6.5 (3-10) n.s. size n (%) ≤ 5 mm 22 (%) 24 (48) n.s. > 5 mm 28 (%) 26 (52) n.s. n.s.: not statistically significant difference. table 1. baseline patients’ characteristics in both treatment groups. time, mean number of pain episodes and need for analgesics (table 2). overall, the incidence of side effects was similar in both groups. they were mild and did not require cessation of therapy in any patient. the incidence of retrograde ejaculation was significantly higher in the silodosin arm while the incidence of side effects related to peripheral vasodilation (dizziness, postural hypotension, headache, nasal congestion) were significantly higher in the tamsulosin arm (table 2). results from subgroup analysis according to stone size are reported in table 3. the mean expulsion times and the mean number of pain episodes were significantly lower in patients with smaller stones, in both treatment arms. discussion advances in endourology have diverted the management of ureteric stones by open surgery to minimal invasive methods like extracorporeal shock wave lithotripsy and ureterorenoscopy. nevertheless, these techniques are not risk-free. met has recently emerged as an alternative strategy for the initial management of selected patients with distal ureteric stones (17). the stimulation of the alpha1 ar in the ureter increases the force of ureteric contraction and the frequency of ureteric peristalsis. blockade of alpha1 ar inhibits basal tone, reduces peristaltic amplitude and frequency, and decreases intraluminal pressure while increasing the rate of fluid transport and the chances of stone expulsion. alpha1a and alpha1d are the ar subtypes that are more densely expressed in the distal ureter (18). tamsulosin has been widely studied in the context of met for patients with distal ureteric stones smaller than 10 mm. it has been proved that tamsulosin increases stone expulsion rates, decreases pain, reduces mean time to stone expulsion and decreases analgesic usage when compared to placebo (1,5, 19-21). however, a possible class effect has been supported by trials demonstrating increased stone expulsion rates using tamsulosin, doxazosin, terazosin , alfuzosin, and naftopidil (5, 13). itoh performed the first prospective randomized study evaluating the use of silodosin in the management of ureteric stones ≤ 10 mm (15). tsuzaka compared the efficacy of the selective alpha1d ar antagonist naftopidil and the selective alpha1a ar antagonist silodosin in the management of symptomatic ≤ 10 mm ureteral stones (16). to our knowledge, we compared for the first time tamsulosin and silodosin in the context of met for distal ureteric stones. spontaneous stone expulsion rates without met in patients with distal ureteric stones ≤ 10 mm have been reported to vary between 35.2% to 61% with mean expulsion times ranging from 9.87 to 24.5 days (1, 5, 1921). tamsulosin enhances stone expulsion rates and mean expulsion times in this subset of patients with reported values ranging from 79.31% to 89.5% and from 6.31 to 12.3 days, respectively (1, 5, 19-21). stone expulsion rate in patients with distal ureteric stones treated with silodosin has been reported to be 72.7% with mean expulsion time of 9.29 days (15). tsuzaka et al. reported a stone expulsion rate significantly higher in patients treated with silodosin than naftopidil (84% vs 61%, respectively) without significant differences in terms of stone expulsion time or rate of interventions (16). results from the present study demonstrate stone expulsion rates and stone expulsion times in patients treated with tamsulosin that are within the published ranges. patients treated with silodosin exhibit stone expulsion rates and mean expulsion times that are comparable to those reported in the tamsulosin arm. however, stone expulsion rates and times with silodosin in the present study are better than that reported by other authors (15). stone size has been identified as an important predictive factor for ureteral stone expulsion. the probability for distal ureteric stones to pass spontaneously is as high as 71-98% for stones ≤ 5 mm and only 25-51% for stones > 5 mm. studies on met with sub analysis according to stone size demonstrated higher expulsion rates for stones ≤ 5 mm with respect to larger stones (1, 19). stone expulsion rate of 89.5% and 70% in patients treated with tamsulosin with stone size ≤ 5 mm and > 5 mm, respectively, have been reported (1). results from the present study demonstrated higher expulsion rates in patients with stones ≤ 5 mm and this was true for both patients treated with tamsulosin and silodosin. however the difference was not statistically significant. most trials on met for lower ureteric stones with tamsulosin demonstrated significant lower mean number of pain episodes with respect to placebo (1, 5, 19-21). this difference may be attributable to the accelerated stone expulsion with a consecutive shorter time at risk for painful events. however, a true analgesic effect of tamsulosin has been also reported. results from the present study in terms of mean number of pain episodes and need for analgesics are within the published ranges for tamsulosin and similar data have also emerged for silodosin. safety issues and adverse events spectra differ considerably between the available alpha-blockers. adverse side effects commonly reported with different alpha1 ar 105archivio italiano di urologia e andrologia 2014; 86, 2 medical expulsive therapy tamsulosin silodosin ≤ 5 mm > 5 mm p ≤ 5 mm > 5 mm p expulsion rate n (%) 20 (90.90) 21 (75) n.s. 23 (95.83) 21 (80.76) n.s. expulsion time days mean (range) 5.4 (3-8) 7.7 (6-9) < 0.05 5.7 (3-8) 7.9 (6-9) < 0.05 pain episodes mean (range) 1.1 (0-3) 2.1 (0-4) < 0.05 1.1 (0-4) 2.0 (0-4) < 0.05 need for analgesics 0.8 (0-3) 0.9 (0-3) n.s. 0.6 (0-2) 1.0 (0-3) n.s. n.s.: not statistically significant. table 3. results of subgroup analysis according to stone size. archivio italiano di urologia e andrologia 2014; 86, 2 v. imperatore, f. fusco, m. creta, s. di meo, r. buonopane, n. longo, c. imbimbo, v. mirone 106 blockers include dizziness, headache, asthenia, postural hypotension, syncope, rhinitis, sexual dysfunction (22, 23). alpha1 ar subtypes are implicated in blood vessel contraction. the main alpha1 subtype in the large vasculature is the alpha1b ar. the blockage of this receptor is mainly responsible for side effects related to peripheral vasodilation, such as postural hypotension, dizziness, and headache (24-26). the alpha1d subtype is predominant and functional in human epicardial coronary arteries, and its inhibition might mediate coronary vasodilation (26). studies indicate differences among the various alpha1 blockers in terms of cardiovascular side effects (22). studies of pharmacy databases in europe suggest that the administration of alpha1 ar blockers increases the incidence of hip fractures (chosen as a surrogate for clinically important orthostatic hypotension) (25). further analysis with regard to the precise alpha1 ar antagonists prescribed suggests that avoidance of alpha1b ar blockade may result in fewer overall hip fractures (25). interestingly, alpha1 ar expression increases with aging, with the ratio of alpha1b: alpha1a increasing (25). alpha1 ar inhibitors with higher selectivity for the alpha1a subtype have been developed in order to reduce the cardiovascular side effects, while maintaining efficacy on urinary tract (26). tamsulosin preferentially blocks alpha1a and alpha1d ar, with a 10-fold greater affinity than for alpha1b ar. in contrast, silodosin is highly selective for alpha1a ar, with a 162fold greater affinity than alpha1b ar and about a 50-fold greater affinity than for alpha1d ar. the weak cardiovascular effects of silodosin have been demonstrated in many in vivo models (26). studies conducted recently have suggested that silodosin as a consequence of its high subtype selectivity is less likely than tamsulosin to have significant cardiovascular side effects either when used alone or in combination with other agents, which may affect blood pressure (24). an important characteristic of silodosin is the lack of clinically relevant or statistically significant changes in blood pressure or heart rate versus placebo (24). however, a minor but statistically significant difference versus placebo was observed with tamsulosin (24). in a study by yu hg et al., tamsulosin treatment resulted in a significant reduction in mean systolic blood pressure relative to the negligible change of silodosin (27). the incidence of orthostatic hypotension with silodosin has been reported to be < 3% (28). in a study by marks et al., the proportions of patients with treatment emergent orthostatic hypotension were similar for silodosin (2.6%) and placebo (1.5%) (29). results from the present study demonstrate higher incidence of retrograde ejaculation in patients treated with silodosin but lower incidence of side effects related to peripheral vasodilation when compared to tamsulosin. the incidence of side effects is similar to that reported by other authors (23). the lower incidence of side effects related to peripheral vasodilation associated with silodosin use make it more suitable for older patients (24). by contrary, according to literature data, retrograde ejaculation does not appear to be particularly bothersome and only a small percentage of patients reporting this adverse effect enrolled in clinical studies discontinued treatments because of it (23). furthermore, this effect is fully and promptly reversible within a few days after discontinuation of treatment (23). by contrary, cardiovascular side effects may have a greater clinical relevance especially in older patients. the main limit of the present study is the retrospective design. further studies are needed to elucidate the efficacy of silodosin as met for distal ureteric stones. conclusions in conclusions, tamsulosin and silodosin are safe and effective treatments that enhance spontaneous passage of distal ureteric stones sized 10 mm or smaller. they appear to have similar profiles in terms of expulsion rates and times, mean number of pain episodes and need for analgesics. or study demonstrate a lower incidence of side effects related to peripheral vasodilation and an higher incidence of retrograde ejaculation with silodosin thus making this drug mainly suitable for older patients. acknowledgement of financial support there are no financial support. references 1. ahmed af, al-sayed ay. tamsulosin versus alfuzosin in the treatment of patients with distal ureteral stones:prospective, randomized, comparative study. korean j urol. 2010; 51:193-7. 2. dellabella m, milanese g, muzzonigro g. randomized trial of the efficacy of tamsulosin, nifedipine and phloroglucinol in medicalexpulsive therapy for distal ureteral calculi. j urol. 2005; 174:167-72. 3. malin jm jr, deane rf, boyarsky s. characterisation of adrenergic receptors in human ureter.br j urol. 1970; 42:171-4. 4. küpeli b, irkilata l, gürocak s, et al. does tamsulosin enhance lower ureteral stone clearance with or without shock wavelithotripsy? urology. 2004; 64:1111-5. 5. yilmaz e, batislam e, basar mm, et al. the comparison and efficacy of 3 different alpha1-adrenergic blockers for distal ureteral stones. j urol. 2005; 173:2010-2. 6. itoh y, kojima y, yasui t, et al. examination of alpha 1 adrenoceptor subtypes in the human ureter. int j urol. 2007; 14:749-53. 7. sasaki s, tomiyama y, kobayashi s, et al. characterization of α1-adrenoceptor subtypes mediating contraction in human isolated ureters. urology. 2011; 77:762.e13-7. 8. de sio m, autorino r, di lorenzo g, et al. medical expulsive treatment of distal-ureteral stones using tamsulosin: a single-center experience. j endourol. 2006; 20:12-6. 9. singh a, alter hj, littlepage a. a systematic review of medical therapy to facilitate passage of ureteral calculi. ann emerg med 2007; 50:552-63. 10. parsons jk, hergan la, sakamoto k, lakin c. efficacy of alpha-blockers for the treatment of ureteral stones. j urol. 2007; 177:983-7 11. hollingsworth jm, rogers ma, kaufman sr, et al, hollenbeck medical therapy to facilitate urinary stone passage: a meta-analysis. .lancet. 2006; 368:1171-9. 12. watts hf, tekwani kl, chan cw, et al. the effect of alphablockade in emergency department patients with ureterolithiasis. j emerg med. 2010; 38:368-73. 13. türk c, knoll t, petrik a, et al. guidelines on urolithiasis european association of urology updated march 2011. 14. kobayashi s, tomiyama y, hoyano y, et al. gene expressions and mechanical functions of α1-adrenoceptor subtypes in mouseureter. world j urol. 2009; 27:775-80. 15. itoh y, okada a, yasui t, et al. efficacy of selective α1a adrenoceptor antagonist silodosin in the medical expulsive therapy for ureteral stones. int j urol. 2011; 18:672-4. 16. tsuzaka y, matsushima h, kaneko t, et al. naftopidil vs silodosin in medical expulsive therapy for ureteral stones: a randomized controlled study in japanese male patients. int j urol. 2011; 18:792-5. 17. tzortzis v, mamoulakis c, rioja j, et al. medical expulsive therapy for distal ureteral stones. drugs. 2009; 69:677-92. 18. griwan ms, singh sk, paul h, et al. the efficacy of tamsulosin in lower ureteral calculi. urol ann. 2010; 2:63-6. 19. al-ansari a, al-naimi a, alobaidy a, et al. efficacy of tamsulosin in the management of lower ureteral stones: a randomized double-blind placebo-controlled study of 100 patients. urology. 2010; 75:4-7. 20. abdel-meguid ta, tayib a, al-sayyad a. tamsulosin to treat uncomplicated distal ureteral calculi: a double blind randomized placebo-controlled trial. can j urol. 2010; 17:5178-83. 21. agrawal m, gupta m, gupta a, et al. prospective randomized trial comparing efficacy of alfuzosin and tamsulosin inmanagement of lower ureteral stones. urology. 2009; 73:706-9. 22. chapple cr. a comparison of varying alpha-blockers and other pharmacotherapy options for lower urinary tract symptoms. rev urol. 2005; 7 suppl 4:s22-30. 23. montorsi f. profile of silodosin eur urol suppl. 2010; 491-495 24. chapple cr, montorsi f, tammela tl, et al. silodosin therapy for lower urinary tract symptoms in men with suspected benign prostatic hyperplasia: results of an international, randomized, doubleblind, placeboandactive-controlled clinical trial performed in europe. eur urol. 2011; 59:342-52. 25. yoshida m, kudoh j, homma y, et al. safety and efficacy of silodosin for the treatment of benign prostatic hyperplasia. clin interv aging. 2011; 6:161-72. 26. rossi m, roumeguère t. silodosin in the treatment of benign prostatic hyperplasia. drug des devel ther. 2010; 27; 4:291-7. 27. yu hj, lin at, yang ss, et al. non-inferiority of silodosin to tamsulosin in treating patients with lower urinary tract symptoms (luts) associated with benign prostatic hyperplasia (bph). bju int. 2011; 108:1843-8. 28. schilit s, benzeroual ke. silodosin: a selective alpha1a-adrenergic receptor antagonist for the treatment of benign prostatic hyperplasia. clin ther. 2009; 31:2489-502. 29. marks ls, gittelman mc, hill la, et al. rapid efficacy of the highly selective alpha1a-adrenoceptor antagonist silodosin in men with signs and symptoms of benign prostatic hyperplasia: pooled results of 2 phase 3 studies. j urol. 2009; 181:2634-40 107archivio italiano di urologia e andrologia 2014; 86, 2 medical expulsive therapy correspondence vittorio imperatore, md v.imperatore@alice.it massimilano creta, md (corresponding author) max.creta@gmail.com sergio di meo, md sedime72@yahoo.it roberto buonopane, md roberto.buonopane@libero.it department of urology, buon consiglio fatebenefratelli hospital via a. manzoni, 220 80123 naples, italy ferdinando fusco, md ferdinando-fusco@libero.it nicola longo, md nicolalongo20@yahoo.it ciro imbimbo, md ciro.imbimbo@unina.it vincenzo mirone, md vmirone@unina.it department of urology, policlinico federico ii of naples via s. pansini, 5 80131 naples, italy stesura seveso 231archivio italiano di urologia e andrologia 2014; 86, 3 case report primary carcinoid tumour of the testis: a case-report letterio d’arrigo 1, angela costa 1, filippo fraggetta 2, antonio cacciola 1, astrid bonaccorsi 1, francesco savoca 1, francesco aragona 1 1 urology and 2 pathology unit, cannizzaro hospital, catania, italy. testicular carcinoid tumours (tct) account for less than 1% of all testicular neoplasms. a 17-year-old male underwent radical orchiectomy for a painful indurated and increased in size right testicle; a mixed echogenic mass, with a central homogeneous area surrounded by a hypoechoic edge with calcifications was found at ultreasound with increased vascularity at color doppler examination. biochemical markers were within normal limits. these symptoms are not specific and the majority of tct are only diagnosed on histopathology. patients should undergo long-term biochemical and radiological follow-up given potential for delayed metastases, in one case 17 years after primary treatment. key words: testicular neoplasms; neuroendocrine tumour; carcinoid. submitted 20 december 2013; accepted 31 march 2014 summary introduction testicular carcinoid tumours (tct) account for less than 1% of all testicular neoplasms (1). tct may be a component of teratoma, or it may occur in pure form, either as a primary growth or as a metastasis from an extratesticular source. herein, we report a case of primary tct presenting as a painful mass without features of carcinoid syndrome. case report is described in supplementary materials posted on www.aiua.it discussion the term “carcinoid” was introduced to distinguish a group of low malignant neoplasms of the small intestine arising from ne cells. overall, 70 cases of tct have been reported in literature, including primary forms, carcinoid differentiation within a mature teratoma and metastases from an extratesticular site. the histogenesis of primary tct is still debated as the presence of ne cells within the testis has not been described. several hypothesis have been proposed. mai et al. (2) no conflict of interest declared. suggest that tct originate from the same precursor cell from which leydig cells derive; in abbosh et al. opinion (3), the tct results from a chromosomal abnormality. a scrotal mass, either painful or indolent, is the most common presenting symptom. a specific ultrasound (us) pattern is not reported: in most cases, an isoechoic mass with a peripheral hypoechoic rim (4) is found, in some cases scanty intralesional calcifications have been described (5). in a literature review reported by strooma and delaere (6) (61 cases plus a personal one) 16% of the patients had symptoms of carcinoid syndrome (diarrhoea, sweating, palpitations, bronchoconstriction, headache, flushing, abdominal pain) that occur when serotonin, produced by the tumour, is released into the systemic circulation (7). serotonin is metabolised to 5-hiaa and excreted through the urine; thus, it is advisable that any patient with vasoactive symptoms and a testicular mass should have a 24 hour urinary dosage of 5-hiaa prior surgery. however, these symptoms are not specific and the majority of tct are only diagnosed on histopathology. when a tct is diagnosed, a metastasis or an extratesticular primary tumour should be excluded, especially if the tct is larger than 4 cm and/or is associated to carcinoid syndrome. as most carcinoid tumours are found in the ileum and all six testicular carcinoid metastases mentioned by strooma and delaere (6) originated from the ileum, barium contrast studies, computed tomography (ct) scan and gastro-intestinal (gi) video-endoscopy can be used to search for primary intestinal tumours. nowadays, i-111 labelled octreotide scintigraphy has replaced ct scan in localizing metastases with a sensitivity of up to 96% (8). 5-hiaa urinary levels must be measured in a 24 hour urine sample, although only 88% of all carcinoid tumours produce 5-hiaa (10). radical orchidectomy is the treatment of choice of tct and is curative for testis-confined primary forms. a retroperitoneal lymphadenectomy is recommended when tct is a component of teratoma. adjuvant chemo/radiotherapy are known to have little effect on these tumours (9). patients should undergo long-term biochemical and radiological follow-up given potential for delayed metasdoi: 10.4081/aiua.2014.3.231 d'arrigo cr_stesura seveso 08/10/14 12:54 pagina 231 archivio italiano di urologia e andrologia 2014; 86, 3 l. d’arrigo, a. costa, f. fraggetta, a. cacciola, a. bonaccorsi, f. savoca, f. aragona 232 tases, in one case 17 years after primary treatment (5). sutherland et al. (11) suggest three monthly 5-hiaa measurements for the first year after diagnosis and annually thereafter although disease progression may occurs in the absence of elevated urinary 5-hiaa levels. serum chromogranin a, secreted by carcinoid tumours, correlates with relapse in gi carcinoids and may be of use in the follow-up of tct (9). most primary tct have good prognosis even if associated with mature teratoma. a cancer-related death is reported only in patients with metastases from or to the testis. references 1. wang w, guo c, berney d, et al. primary carcinoid tumour of thetestis: a clinicopathologic study of 29 cases. am j surg pathol. 2010; 34:519. 2. mai k, park p, yazdi h, carlier m. leydig cell origin of testicular carcinoid tumor: immunoistochemical and electron microscopic evidence. histopathology. 2006; 49:548. 3. abbosh p, zhang s, maclennan g, et al. germ cell origin of testicular carcinoid tumors. clin cancer res. 2008; 14:1393. figures and full list of references are posted in supplementary materials on www.aiua.it correspondence letterio d’arrigo, md ldarrigo@alice.it angela costa, md ang.urolog@gmail.com antonio cacciola, md tonycacciola@tiscali.it astrid bonaccorsi, md astridbonaccorsi@libero.it francesco savoca, md francescosavoca@virgilio.it francesco aragona, md frank.aragona@virgilio.it urology unit cannizzaro hospital catania via messina 829 95127 catania, italy filippo fraggetta, md filippofra@hotmail.com pathology unit cannizzaro hospital catania via messina 829 95127 catania, italy figure 1. the neoplastic cells were arranged in a nesting and trabecular pattern. no evidence of intratubular germ cell neoplasia. tumor cells showed pale eosinophilic cytoplasm with round to oval nuclei and inconspicuous nucleoli; mitoses were not seen. no evidence of vascular invasion. the histological features were in accordance with a pure testicular carcinoid tumour without teratomatous components. d'arrigo cr_stesura seveso 08/10/14 12:54 pagina 232 stesura seveso 383archivio italiano di urologia e andrologia 2014; 86, 4 cas e report enterovesical fistula and acute pyelonephritis in renal transplantation. role of ultrasound antonio de pascalis, alessandro d’amelio nephrology and dialysis unit, v fazzi hospital, lecce, italy. the enterovesical fistula is a communication between the urinary tract and the colon and is a rare complication of various inflammatory and cancer diseases. the most frequent cause is represented by diverticulitis of the sigmoid colon and less frequently from crohn's disease, tumors of the colon and bladder, trauma, radiation therapy and appendicitis. in this report we describe the occurrence of an enterovesical fistula in a patient with renal allograft from a cadaveric donor, which onsetted with signs of acute pyelonephritis and pneumaturia due to diverticulitis of the sigmoid colon, clinically silent. the ultrasound in the diagnosis of enterovesical fistula, yet with a minor role compared to computed tomography (ct), is fundamental being always the first level examination. key words: fistula; bladder; pyelonephritis. submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. the presence of a fistula between the sigmoid colon and the left side wall of the bladder, associated with numerous diverticula of the colon (figure 2). after starting antibiotic therapy with ciprofloxacin and teicoplanin we assisted to a dramatic improvement of the clinical picture. subsequentely patient underwent surgical sigmoidectomy and bladder repair. discussion enterovesical fistulas account for over 80% of fistulas between digestive and urinary tract and, the most frequent between the bladder and sigmoid colon. diverticulitis of the colon is the most frequent cause of fistula with the bladder, followed by crohn's disease and colon cancers (1). in the case reported the patient had complicated diverticulitis of the colon, with a very few symptoms (the patient reported only alternating diarrhea and constipation) evidently because of steroid therapy. however, the clinical picture dominating the majority of patients with enterovesical fistula, as reported in the literature and as moreover observed in our case, are the urinary symptoms (fever, dysuria, or even pneumaturia and fecaluria) (2). the occurrence of pneumaturia is a highly specific sign of a communication between the intestine and bladder, reported in 60-85% of cases described in the literature (3). in the literature there are few reports about the ultrasound scan for pneumaturia and then about the diagnosis of enterovescical fistula by ultrasound examination. the typical signs described are: the presence of the socalled echogenic beak, i.e. an area of hyperechoic beak, between the bladder and adjacent bowel, without solution of continuity; the passage of air and echogenic material in the urine, after the abdominal compression; the presence of irregular hyperechoic foci with shadow cone back (4). the most sensitive and specific test is, of course, ct which allows you to directly highlight the presence of the fistula, the cause that generated it and its associated complications (5). less sensitive and specific and therefore not indicated, is the intravenous urography. cystoscopy is obviously highly sensitive and specific and is often performed as an examination of the level before the ct in suspected enteric fistula with bladder. doi: 10.4081/aiua.2014.4.383 presented at 19th national congress s ieun, fermo 2014 case report a 64 years old male, with a kidney transplantation from cadaveric donor for about 5 years and treated with prednisone, tacrolimus and mycophenolate, presented to the emergency room with signs and symptoms suggestive of urinary sepsis (fever, hypotension, dysuria, pain in the right iliac fossa, where the graft was allocated). laboratory tests showed: mild worsening of renal function (creatinine 2.4 mg/dl), neutrophilic leukocytosis (gb 14.440/ml with 91% neutrophils), elevated inflammatory markers (esr 120, crp 153 mg/dl, procalcitonin 5 mg/l), urine examination revealed leukocyturia, hematuria, bacteriuria. the patient reported that he had noticed at home the issue of foamy urine. an ultrasound of the kidney and urinary tract showed a transplanted kidney of globular shape with multiple hypoechoic areas suggestive for hydroureteronephrosis grade ii, presence of intrapyelic hyperechogenic material and a diffusely thickened bladder (figure 1); color doppler evaluation showed an increased intraparenchymal doppler ri (0.84). we therefore decided to perform a computed tomography (ct) scan which confirmed the signs of acute pyelonephritis of the graft, showing also the presence of hydro-air level and archivio italiano di urologia e andrologia 2014; 86, 4 a. de pascalis, a. d’amelio 384 in conclusion, we reported a case, one of the few in the literature, of enterovesical fistula secondary to diverticulitis of the colon in a kidney transplanted patient. concomitant immunosuppressive therapy and steroids in particular, has probably masked the clinical picture until the onset of acute graft pyelonephritis. the ultrasound in the diagnosis of enterovesical fistula, yet with a minor role compared to ct, is fundamental being always the first level examination because of its non-invasiveness, repeatability and low cost, and it can provide guidelines that address the diagnosis. bibliography 1. krco mj, jacobs sc, malangoni ma, lawson rk. colovescical fistulas. urology. 1984; 23:340-342. 2. vesallane´s j, llado carbonell c, valverde sintas j, bielsa gali o. fistulas vesico-sigmoideas. arch espurol. 1991; 44:1133-1138. 3. kirsh gm, hampel n, shuck jm, resnick mi. diagnosis and management of vesicoenteric fistulas. surg gynecol obstet. 1991; 173:91-97. 4. long ma, boultbee je. case report: the transabdominal ultrasound appearances of a colovesical fistula. br j radiol. 1993; 66:465-467. 5. jarrett tw, vaughan ed. accuracy of computerized tomography in the diagnosis of colovesical fistula secondary to diverticular disease. j urol. 1995; 153:44-46. figure 1. us. hyperechoic material in pelvis with acoustic shadowing and thickened ureteral wall. figure 2. ct. air-urine level in the bladder. correspondence antonio de pascalis, md (corresponding author) depascalis.a@libero.it alessandro d’amelio, md nephrology and dialysis unit, v fazzi hospital piazza muratore 1 73100 lecce, italy stesura seveso 95archivio italiano di urologia e andrologia 2014; 86, 2 original paper musculoskeletal disorders among robotic surgeons: a questionnaire analysis claudio giberti 1, fabrizio gallo 1, luca francini 2, alessio signori 3, marco testa 2 1 department of surgery, division of urology, san paolo hospital, savona, italy; 2 department of neuroscience, rehabilitation, ophthalmology, genetics, maternal and child health, university of genova, campus of savona, italy; 3 department of health science biostatistics unit, university of genoa, italy. objective: robotic surgical systems offer better workplace in order to relieve surgeons from prolonged physical efforts and improve their surgical outcomes. however, robotic surgery could produce musculoskeletal disorders due to the prolonged sitting position of the operator, the fixed position of the console viewer and the movements of the limbs. until today, no one study has been reported concerning the association between robotics and musculoskeletal pain. the aim of this work was verify the prevalence of musculoskeletal disorders among italian robotic surgeons. material and methods: between july 2011 and april 2012 a modified standardized nordic questionnaire was delivered to thirty-nine italian robotic centres. twentytwo surgeons (56%) returned the questionnaires but only seventeen questionnaires (43.5%) were evaluable. results: seven surgeons (41.2%) reported musculoskeletal disorders, by since their first use of the robot which significantly persisted during the daily surgical activity (p < 0.001). regarding the body parts affected, musculoskeletal disorders were mainly reported in the cervical spine (29.4%) and in the upper limbs (23.5%). six surgeons (35.3%) defined the robotic console as less comfortable or neither comfortable/uncomfortable with a negative influence on their surgical procedures. conclusions: in spite of some important limitations, our data showed musculoskeletal disorders due to posture discomfort with negative impact on daily surgical activity among robotic surgeons. these aspects could be due to the lack of ergonomic seat and to the fixed position of the console viewer which could have produced an inadequate spinal posture. the evaluation of these postural factors, in particular the development of an integrated and more ergonomic chair, could further improve the comfort feeling of the surgeon at the console and probably his surgical outcomes. key words: robotics; musculoskeletal diseases; pain; neck pain; posture; ergonomics. submitted 26 august 2014; accepted 15 january 2014 summary no conflict of interest declared. introduction the implementation of advanced robotic instruments today offers operators minimally invasive options for a wide range of complex surgical procedures (1-2). in fact, the use of the robot allows the surgeon to operate on small areas with an improved technical accuracy reducing the size of the surgical wound and providing many advantages in the postoperative recovery of the patient (3). as with all the newer working technologies, robotic surgical systems also offer better workplaces in order to relieve surgeons from prolonged physical efforts and improve their surgical outcomes (4). in fact, when using the robot, the surgeon operates seated at the console with the arms and elbows placed on a soft plane in order to allow free movement of the wrists and fingers which grasp two master controls located below the display. however, in spite of this more comfortable workplace, compared to traditional surgical approaches, robotic surgery can also produce many musculoskeletal disorders due to the prolonged sitting position of the operator who needs to maintain the image of the operative area through a semi-vertically oriented binocular viewer and adequately coordinate arm, wrist and lower limb movements (5-9). to date, no previous study has investigated the association between robotic surgery and musculoskeletal pain, probably due to the recent introduction of this technology. the aim of this work is to verify, using a specific questionnaire, the development of recurrent musculoskeletal disorders in a sample of italian robotic surgeons. materials and methods in the period between july 2011 and april 2012, a simplified version of the validated standardized nordic questionnaire was prepared and delivered to thirty-nine italian robotic centers (10-11). the questionnaire focused on the pain reported by the surgeon from the beginning of his robotic experience and during his daily robotic activity. in particular, the items took into consideration the amount of robotic experience achieved by each surgeon, the weekly use of the robot, the development of any recurrent musculoskeletal pain during the doi: 10.4081/aiua.2014.2.95 archivio italiano di urologia e andrologia 2014; 86, 2 c. giberti, f. gallo, l. francini, a. signori, m. testa 96 robotic procedures and the possible influence of this pain on daily surgical activity. lastly, a self reported ergonomic evaluation of the comfort feeling during robotic surgery was also included. twenty-two surgeons (56%) returned the questionnaires. five questionnaires were excluded due to incomplete or inaccurate compilation. in total, seventeen questionnaires (43.5%) received from different italian robotic centers were deemed evaluable (table 1). in december 2011, all questionnaire data were analyzed anonymously and statistically evaluated. statistical analysis the data was analyzed using the median and 25th-75th percentile for numerical variables and counts, and percentages for categorical variables were also reported. the fisher test was used in order to evaluate the association between the development of pain from the first use of the robot and its persistence during subsequent daily surgical activities and the association between the comfort posture and the development of musculoskeletal disorders. a non-parametric mann-whitney test was performed to evaluate any differences between groups with and without musculoskeletal pain regarding the number of months and hours per week spent at the robotic console. a p-value of 0.05 was considered statistically significant. the analyses were performed using spss (version 18.0; ibm corporation). results the questionnaire data reported by the seventeen robotic surgeons are shown in table 2. all of the surgeons were expert robotic operators and none of them reported any musculoskeletal pain before starting robotic surgery. seven operators (41.2%) declared having recurrent musculoskeletal pain which started with the first use of the robot, while six surgeons (35.3%) reported feeling pain during their daily surgical activities. as regards the association between these data, among the surgeons who reported the onset of pain from the first robotic procedure, a significant amount (85.7%) declared its persistence during the following daily surgical activities (p < 0.001). concerning the association between musculoskeletal pain and the duration of robot use, although both the median values related to the time spent from the first robotic procedure and the weekly use of the robot resulted higher among those surgeons who declared musculoskeletal pain, no statistically significant difference was assessed between these data (figures 1 and 2). as regards the body parts affected by musculoskeletal disorders, they were mainly reported in the cervical spine (29.4%) and in the upper limbs (23.5%). concerning the self-reported ergonomic evaluation of the comfort feeling during robotic surgery, six surgeons (35.3%) defined the robotic console as less comfortable or neither comfortable/uncomfortable with a negative influence on the surgical procedures. with regard to the association between comfort posture evaluation and the development of musculoskeletal disorders, despite 8 out of 10 surgeons who didn’t report any musculoskeletal disorder defining the robot console as comfortable while 4 out of 7 surgeons affected by musculoskeletal pain number (n) 17 age (years) 51.3 (32-61) gender male 16/17 (94%) female 1/17 (6%) italian geographical area (n -%-) north-west 5/17 (29.6%) north-east 6/17 (35.2%) middle 6/17 (35.2%) duration of robot use/surgeon’s robotic experience (months) 36 (12-63) weekly use of the robot (hours) 6 (5-7) weekly number of robotic procedures (n) 2.2 (2-3) robotic surgery (n -%-) urology 12/17 (70.5%) general surgery 4/17 (23.5%) gynaecology 1/17 (6%) concomitant standard laparoscopy (n -%-) 3/17 (17.6%) table 1. surgeons’ characteristics. the data regarding the age, duration of robot use and number of procedures are reported as mean with range between parentheses. the data concerning the gender, geographical area and type of robotic surgery are reported as percentages. questionnaire n° of patients (%) musculoskeletal pain before the first robotic operation no 17/17 (100%) yes 0/17 (0%) recurrent musculoskeletal pain since the first robotic operation no 10/17 (58.8%) yes 7/17 (41.2%) recurrent musculoskeletal pain during daily surgical activity no 9/17 (52.9%) yes 6/17 (35.3%) non-responders 2/17 (11.8%) body parts affected by pain* cervical spine 5/17 (29.4%) thoracic spine 2/17 (11.8%) upper limbs 4/17 (23.5%) lower limbs 1/17 (5.9%) lombar spine 1/17 (5.9%) none 10/17 (58.8%) console posture evaluation less comfortable 2/17 (11.8%) neither comfortable nor uncomfortable 4/17 (23.5%) comfortable 11/17 (64.7%) interference with surgical procedures no 6/17 (35.3%) yes 6/17 (35.3%) non-responders 5/17 (29.4%) table 1. answers to the questionnaire items reported by the robotic surgeons. the data shows the number of patients with percentages in parentheses. *: each operator could mark more than one answer. defined the robotic console as less comfortable or neither comfortable/uncomfortable, no statistical association (p = 0.16) was assessed between these two data. discussion work related musculoskeletal disorders represent a frequent problem among the general population with a prevalence ranging from 13.5 and 47% (12-14). many studies have also investigated this aspect among the health workforce showing musculoskeletal pain between 17-66%, 81.5-82.9% and 28-70% in dental operators, open and laparoscopic surgeons, respectively (15-18). robotic surgical systems offer better workplaces which should relieve surgeons from prolonged physical efforts and decrease the incidence of musculoskeletal pain. however, until today, no one study has been available in literature concerning the association between robotic surgery and musculoskeletal pain. the aim of this study was to verify the development of recurrent musculoskeletal disorders among surgeons who usually work with this new and high-tech surgical system. we also focused our attention on the robotic surgeons’ feeling of comfort during the operations and the possible interference of any discomfort on their daily surgical activity. in our study, 41.2% of surgeons reported a recurrent musculoskeletal disorder, mainly neck pain, which started from the beginning of the robotic experience and substantially continued to impact negatively on the daily surgical activity (p < 0.001). furthermore, 35.3% of surgeons defined the robotic console as rather uncomfortable with a negative influence on the surgical procedures. these data seem to point out the presence of some ergonomic problems at the robotic workstation. actually, the correlation between the sitting working position and the presence of musculoskeletal discomfort or neck pain has already been reported in literature by many authors, especially among those workers who need to maintain an even gaze, only 20° below the horizontal line, for at least one hour, like robotic surgeons (19-21). in fact, as recommended by the united states department of labor’s occupational safety and health administration (osha), a correct working sitting position requires many conditions including an appropriate positioning of the upper and lower limbs and a relaxed spinal posture with less inclination of the cervical region and adequate lumbar support (22). in spite of the fact that robotic workplaces allow good positioning of the upper arms with alignment of the forearms and hands, moderate relaxation of the arms and shoulders and bending of the elbows between 90 and 120 degrees, they don’t provide similar attention to the positioning of the spine or the lower limbs. in fact, because a chair is not usually sold together with the robotic console, surgeons often resort to using a simple stool which doesn’t provide any support to the hips or the lumbar spine (figure 3). furthermore, although all the da vinci surgical systems provide the opportunity to adapt the height of the console binocular viewer, only the newest model also allows the surgeon to modify its inclination, the height of the forearm supports and the position of the pedals (23). in our study, none of the robotic surgeons reported using this latest version of the da vinci system and this aspect could contribute to explaining the posture discomforts derived from the questionnaire data. further studies will certainly verify the impact of the newest surgical robotic system on surgeons’ postural pain. however, a more correct design of the sitting workstation remains a crucial point in order to respect the posture of the spine and to reduce neck and shoulder pain among people working with a protracted or retracted head position (20, 24-26). as regards the da vinci robotic system, an integrated and more ergonomic seat could further improve the comfort of the surgeon, thus minimizing the risk of musculoskeletal pain. this study has some important limitations: it is a retrospective, not comparative, study and it is based on a low number of questionnaires. these aspects could decrease the reliability of our statistical evaluation especially since surgeons who reported musculoskeletal pain after robotic surgery may have been more likely to join the study than those who experienced no pain. this is mainly due to the presence of few robotic centers in italy and, in particular, 97archivio italiano di urologia e andrologia 2014; 86, 2 musculoskeletal disorders and robotics figure 1. the figure shows the association between musculoskeletal pain and the time spent from the first robotic procedure. figure 2. the figure shows the association between musculoskeletal pain and the weekly use of the robot. archivio italiano di urologia e andrologia 2014; 86, 2 c. giberti, f. gallo, l. francini, a. signori, m. testa 98 few surgeons who use the da vinci robot regularly. in this setting, the aim of this study was to present our preliminary data which strongly needs to be confirmed by a larger study among all european robotic surgeons. conclusion in spite of the new workplaces, our data showed recurrent musculoskeletal disorders and posture discomfort with a negative impact on daily activity in 41.2% and 35.3% of robotic surgeons, respectively. these aspects could be due to the lack of an ergonomic seat and to the fixed position of the console binocular viewer which could have produced an inadequate spinal posture with consequent musculoskeletal disorders. the evaluation of these postural aspects, in particular the development of an integrated and more ergonomic chair, could further improve the comfort feeling of the surgeon at the console and probably his surgical outcomes. acknowledgements we thank dr. jennifer mcdermott for the language revision. references 1. jayaraman s, quan d, al-ghamdi i, et al. does robotic assistance improve efficiency in performing complex minimally invasive surgical procedures? surg endosc. 2010; 24:584-588. 2. stefanidis d, wang f, korndorffer jr jr, et al robotic assistance improves intracorporeal suturing performance and safety in the operating room while decreasing operator workload. surg endosc. 2010; 24:377-382. 3. lang bh, chow mp. a comparison of surgical outcomes between endoscopic and robotically assisted thyroidectomy: the authors' initial experience. surg endosc. 2011; 25:1617-1623. 4. lee j, chung wy. current status of robotic thyroidectomy and neck dissection using a gasless transaxillary approach. curr opin oncol. 2012; 24:7-15. 5. bagrodia a, raman jd. ergonomics considerations of radical prostatectomy: physician perspective of open, laparoscopic, and robot-assisted techniques. j endourol. 2009; 23:627-633. 6. aaras a, horgen g, bjorset hh, et al. musculoskeletal, visual and psychosocial stress in vdu operators before and after multidisciplinary ergonomic interventions. a 6 years prospective study--part ii. appl ergon. 2001; 32:559-571. 7. côté p, van der velde g, cassidy jd, et al. the burden and determinants of neck pain in workers: results of the bone and joint decade 2000-2010 task force on neck pain and its associated disorders. j manipulative physiol ther. 2009; 32:s70-86. 8. lorusso a, bruno s, caputo f, l'abbate n. risk factors for musculoskeletal complaints among microscope workers. g ital med lav ergon. 2007; 29:932-937. 9. szeto gp, ho p, ting ac, et al. work related musculoskeletal symptoms in surgeons. j occup rehabil. 2009; 19:175-184. 10. kuorinka i, jonsson b, kilbom a, et al. standardised nordic questionnaires for the analysis of musculoskeletal symptoms. appl ergon. 1987; 18:233-237. 11. gobba f, ghersi r, martinelli s, et al. italian translation and validation of the nordic irsst standardized questionnaire for the analysis of musculoskeletal symptoms. med lav. 2008; 99:424-443. 12. cimmino ma, ferrone c, cutolo m. epidemiology of chronic musculoskeletal pain. best pract res clin rheumatol. 2011; 25:173-183. 13. hogg-johnson s, van der velde g, carroll lj, et al. the burden and determinants of neck pain in the general population: results of the bone and joint decade 2000-2010 task force on neck pain and its associated disorders. j manipulative physiol ther. 2009; 32:s46-60. 14. madan i, reading i, palmer kt, coggon d. cultural differences in musculoskeletal symptoms and disability. int j epidemiol. 2008; 37:1181-1189. 15. klussmann a, gebhardt h, liebers f, rieger ma. muscu lo ske letal symptoms of the upper extremities and the neck: a cross-sectional study on prevalence and symptom-predicting factors at visual display terminal (vdt) workstations. bmc musculoskelet disord. 2008; 9:96-98. 16. harcombe h, mcbride d, derrett s, gray a. prevalence and im pact of musculoskeletal disorders in new zealand nurses, postal workers and office workers. aust n z j public health. 2009; 33:437-441. 17. capone ac, parikh pm, gatti me, et al. occupational injury in plastic surgeons. plast reconstr surg. 2010; 125:1555-1561. 18. stomberg mw, tronstad se, hedberg k, et al. work-related musculoskeletal disorders when performing laparoscopic surgery. surg laparosc endosc percutan tech. 2010; 20:49-53. 19. caneiro jp, o'sullivan p, burnett a, et al. the influence of different sitting postures on head/neck posture and muscle activity. man ther. 2010; 15:54-60. 20. o’sullivan pb, dankaerts w, burnett af, et al. effect of different upright sitting postures on spinal-pelvic curvature and trunk muscle activation in a pain-free population. spine. 2006; 31:707-712. 21. bonney ra, corlett en. head posture and loading of the cervical spine. applied ergonomics. 2002; 33:415-417. 22. united states departement of labor. occupational safety & health administration. [homepage on the internet] washington. available from: http://www.osha.gov/sltc/etools/computerworkstations/positions.html 23. matthew, lux mm, marshall m, erturk e, joseph jv. ergonomic evaluation and guidelines for use of the davinci robot system.j endourol. 2010; 24:371-375. 24. rempel dm, wang pc, janowitz i, et al. a randomized controlled trial evaluating the effects of new task chairs on shoulder and neck pain among sewing machine operators: the los angeles garment study. spine. 2007; 32:931-938. 25. stuart j. horton gillian m. johnson, margot a. skinner. changes in head and neck posture using an office chair with and without lumbar roll support. spine. 2010; 35:e542-548 26. falla d, o’leary s, fagan a, jull g. recruitment of the deep cervical flexor muscles during a postural-correction exercise performed in sitting. manual therapy. 2007; 12:139-143. correspondence claudio giberti, md fabrizio gallo, md (corresponding author) fabrizio.gallo@fastwebmail.it department of surgery, division of urology, san paolo hospital via genova, 30 -17100 savona, italy luca francini, md marco testa, md department of neuroscience, rehabilitation, ophthalmology, genetics, maternal and child health, university of genova, campus of savona, savona, italy alessio signori, md department of health science biostatistics unit, university of genoa, genova, italy stesura seveso 235archivio italiano di urologia e andrologia 2014; 86, 3 case report renal epithelioid angiomyolipoma mimicking urothelial carcinoma of the upper urinary tract senol adanur 1, ercüment keskin 2, tevfik ziypak 1, erdem koc 1, elif demirci 3, turgut yapanoglu 1, i̇sa ozbey 1, ozkan polat 1 1 department of urology, medica faculty, ataturk university, erzurum, turkey; 2 department of urology, regional training and research hospital, erzurum, turkey; 3 department of pathology, medica faculty, ataturk university, erzurum, turkey. epithelioid angiomyolipoma is a rare mesenchymal tumor arising mainly in the kidney that can potentially behave aggressively. epithelioid angiomyolipoma can often resemble sarcomatoid renal cell carcinoma, high grade renal carcinoma or sarcoma. its similarity to renal cell carcinoma has been emphasized in most of the cases reported in literature. with the purpose of contributing to the awareness of this similarity, a 32-year-old female patient with renal epitelioid angiomyolipoma in the left kidney which radiologically mimicked urothelial cell carcinoma of the upper urinary tract is presented. key words: renal; epithelioid angiomyolipoma; treatment. submitted 12 november 2013; accepted 30 june 2014 summary no conflict of interest declared. introduction angiomyolipomas (aml) are benign tumours of the kidney and are composed of blood vessels, smooth muscle cells and mature fat cells. they comprise 2-6.4% of all renal tumors. angiomyolipomas are among the most common benign lesions of the kidney (1, 2). these tumors may be formed either as a part of the tuberous sclerosis complex (tsc) or as an isolated renal lesion (3). in 50% of patients with tsc, amls tend to be multifocal and bilateral involvment may occur (3). angiomyolipomas are most frequently seen in the kidneys and less commonly found in extra-renal sites such as the retroperitoneum and liver (4). epithelioid angiomyolipoma (eaml) is a variant of aml. although it is histologically a benign tumor, it may show clinically aggressive behavior and may mimick renal cell carcinoma in imaging studies. most reports in literature regarding eaml are related to its radiologic and histologic similarity to renal cell carcinoma. presented in this paper is a case of eaml radiologically mimicking urothelial cell carcinoma of the upper urinary tract. case report a 32-year-old female patient who referred with the complaint of left flank pain for a nine month period was hospitalized in our clinic. the physical examination findings were normal. urine test displayed the presence of many erythrocytes and blood chemistry was normal. at urinary doi: 10.4081/aiua.2014.3.235 system ultrasonography, a solid mass lesion of 76 x 49 mm in size was observed at the mid pole of the left kidney. the right kidney was found to be normal. the upper-lower abdominal phase contrast-enhanced computed tomography (ct) and abdominal dynamic magnetic resonance (mr) images that the patient had prior to coming to our hospital were studied. the abdominal dynamic mr imaging showed a mass lesion 8 x 4 x 6.5 cm in size localized at the mid pole of the renal pelvis which extended towards the exterior and contained hemorrhagic foci. in the postcontrast sections, the lesion showed hemorrhagic foci of minimal heterogenous contrast which decreased in number as the lesion extended towards the renal parenchyma (figure 1). the urine cytology was benign. with diagnostic flexible ureteroscopy, a tumoral lesion filling the left renal pelvis and calyces was observed. urethelial carcinoma was suspected and radical nephro-ureterectomy was performed with removal of the cuff from the bladder. at histopathological examination, tumoral structure including thick-walled vascular structures, wide necrotic and hemorrhagic areas are observed adjacent to the kidney tissue. the tumoral structure consisted of round-oval nucleoled spindle-shaped cells, some multinucleated, some ganglion-like ap pe a rance, showing pa lisading areas and a few mitotic figures. tumoral cells were immunohistoche mically hmb45 po sitive, focally cd68 positive, vimentin positive and nonreactive with s-100, sma, msa, ema, panck, desmin, cd34, cd10, nse, melan-1, factor xiiia, c-kit. the tumor was histo pathologically reported as an epithelioid angiomyolipoma (figure 2a-b). seventeen months postoperatively, abdominal mr imaging confirmed that there was no local recurrence or far metastasis in the patient. figure 1. abdominal mri appearance of the left kidney mass lesion. adanur cr_stesura seveso 08/10/14 12:21 pagina 235 archivio italiano di urologia e andrologia 2014; 86, 3 s. adanur, e. keskin, t. ziypak, e. koc, e. demirci, t. yapanoglu, i̇. ozbey, o. polat 236 dıscussıon angiomyolipoma is a mesenchymal tumor composed of dysmorphic blood vessels, fat tissue, and smooth muscle tissue in varying proportions. only 1% of renal angiomyolipomas show only epithelioid morphology (5). epithelioid angiomyolipoma is a rare mesenchymal tumor recognized in recent years and first reported by mai et al. (6) in 1996. for many years, the tumor was misclassified as an aml. in 2004, the international agency for research on cancer (iarc) of the world health organization classified eaml as an entity different from typical or classical aml and described it as a mesenchymal tumor with malignant potential. the tumor is primarily composed of epithelioid cells, whereas in some cases, it may show similarity to typical aml (7). although the growth pattern of eaml may be similar to that of aml, eaml may also display an invasive growth pattern where the tumor tissue shows hemorrhage, necrosis, and degeneration. it sometimes causes lymph metastasis. however, true cystic lesions and peripheral vascular and renal sinus invasion are rarely seen (8). the epithelioid morphology combined with cytologic atypia may render diagnosis difficult and lead to inaccurate diagnoses such as metastatic melanoma or renal cell carcinoma. immunohistochemistry plays the key role in differential diagnosis (5). the tumor cells of eaml stain negative for the s-100 protein and epithelial markers and stain positive for variable expressions of smooth muscle markers (smooth muscle actin, muscle specific actin) and melanocytic markers (hmb-45 and/or melana) (9). in our case, the immunohistochemical staining was positive for hmb-45, cd-68, and vimentin and negative for desmin and cytokeratin. it is difficult to differentiate malignant eaml from other solid renal tumors such as oncocytoma, renal cell carcinoma and sarcomatous lesions with only imaging studies. ct or mr imaging is frequently used to detect the fat foci which are characteristic of the tumor. however, the diagnosis of eaml is difficult because abnormal blood vessels and mature fat cells are also present in typical aml, but not apparent in eaml. the specific image characteristics of eaml have not been described in literature until recently (10). most eaml reports in literature are related to its radiologic and histologic similarity to renal cell carcinoma. in our case, due to the suspicion of urothelial carcinoma on the abdominal mr images, diagnostic flexible ureteroscopy was performed as a first step. in ureteroscopy, a tumor completely filling the renal pelvis and calyces was observed. according to the prediagnosis of urethelial carcinoma of the upper urinary tract, the cuff was removed from the bladder and nephro-ureterectomy was performed. the reported histopathological diagnosis of the tumor was eaml. the patient was not given any adjuvant therapy. at post-operative 17 months, abdominal mr images of the patient confirmed that there was no local recurrence or any far metastasis. in conclusion, eaml is a rare tumor that can mimic malignant or benign tumors and has unpredictable behaviour. it should be kept in mind that this potentially malignant tumor may radiologically and histologically be confused with renal cell carcinoma and sarcomatous lesions and that it may radiologically mimic urethelial carcinoma of the upper urinary tract. references 1. gamé x, soulié m, moussouni s, et al. renal angiomyolipoma associated with rapid enlargement [correction of enlargement] and inferior vena cava tumor thrombus. j urol. 2003; 170:918-19. 2. tallarigo c, baldassarre r, bianchi g, et al. diagnostic and therapeutic problems in multicentric renal angiomyolipoma. j urol. 1992; 148:1880-4. 3. neumann hp, schwarzkopf g, henske ep. renal angiomyolipomas, cysts, and cancer in tuberous sclerosis complex. semin pediatr neurol. 1998; 5:269-75. 4. prasad sr, sahani dv, mino-kenudson m, et al. neoplasms of the perivascular epithelioid cells involving the abdomen and the pelvis: crosssectional imaging findings. j comput assist tomogr. 2007; 31:688-96. 5. aydin h, magi-galluzzi c, lane br, et al. renal angiomyolipoma: clinicopathologic study of 194 cases with emphasis on the epithelioid histology and tuberous sclerosis association. am j surg pathol. 2009; 33:289-97. 6. mai kt, perkins dg, collins jp. epithelioid cell variant of renal angiomyolipoma. histopathology. 1996; 28:277-80. 7. faraji h, nguyen bn, mai kt. renal epithelioid angiomyolipoma: a study of six cases and a meta-analytic study. development of criteria for screening the entity with prognostic significance histopathology. 2009; 55:525-34. 8. cui l, zhang jg, hu xy, et al. ct imaging and histopathological features of renal epithelioid angiomyolipomas. clin radiol. 2012; 67:77-82. 9. bing z, maclennan gt. renal epithelioid angiomyolipoma. j urol. 2009; 182:2468-69. 10. huang kh, huang cy, chung sd, et al. malignant epithelioid angiomyolipoma of the kidney. j formos med assoc. 2007; 106 (2 suppl):51-4. correspondence senol adanur, md (corresponding author) s.adanur61@hotmail.com department of urology school of medicine ataturk university 25240 erzurum, turkey ercüment keskin, md tevfik ziypak, md erdem koç, md turgut yapanoglu, md isa özbey, md ozkan polat, md department of urology, regional training and research hospital erzurum, turkey elif demirci, md department of pathology, medica faculty, ataturk university erzurum, turkey figure 2. a. (hex400) atypical cells with prominent nucleoli, exhibiting multinucleated or ganglion-like appearance. b. (hex100) tumoral formation including palisades areas (thin arrow) and thick-walled vascular structures (thick arrow). adanur cr_stesura seveso 08/10/14 12:21 pagina 236 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2112 original paper managing female urinary incontinence: a regional prospective analysis of cost-utility ratios (curs) and effectiveness elisabetta costantini 1, massimo lazzeri 1, vittorio bini 2, alessandro zucchi 1, emanuele scarponi 1, massimo porena 1 1 department of medical-surgical specialties and public health, urology and andrology section, university of perugia, perugia, italy; 2 department of internal medicine, university of perugia, perugia, italy. introduction: to evaluate the cost-utility of incontinence treatments, particularly anticholinergic therapy, by examining costs and quality-adjusted life years. materials and methods: a prospective cohort study of women who were consecutively referred by general practitioners (gps) to the urology department because of urinary incontinence. the primary outcome was evaluation of the cost-utility of incontinence treatments (surgery, medical therapy and physiotherapy) for stress and/or urgency incontinence by examining costs and quality-adjusted life years. results: 137 consecutive female patients (mean age 60.6 ± 11.6; range 36-81) were enrolled and stratified according to pathologies: sui and uui. group a: sui grade ii-iii: 43 patients who underwent mid-urethral sling (mus); group b: sui grade i-ii 57 patients who underwent pelvic floor muscle exercise and group c: uui: 37 patients who underwent antimuscarinic treatment with 5 mg solifenacin daily. the cost utility ratio (cur) was estimated as saving more than !1200 per qaly for surgery and physiotherapy and as costing under ! 100 per qaly for drug therapy. conclusions: this study shows that appropriate diagnosis and treatment of a patient with incontinence lowers national health service costs and improves the benefits of treatment and quality of life. key words: female urinary incontinence; cost-utility analysis; anti-muscarinic therapy; mid urethral slings; physiotherapy, qaly. submitted 30 september 2014; accepted 31 december 2014 summary introduction female urinary incontinence (ui) affects between 10% and 60% of women worldwide (1-2). as a major health problem it has a marked social impact, with significant worsening of quality of life (qol) and high costs for national health system (nhs), which vary with the country (3). incontinence imposes very different expenses on payers, providers and patients which can lead to complex no conflict of interest declared. arrangements for where patients get care and what services are covered by health insurance, thus ultimately determining outcomes for patients (4). as the average life-span of western populations is rapidly lengthening, the prevalence of incontinence will continue to rise and the demand for incontinence services will increase (5). since costs are assuming a greater role in health-care decision-making, the aim of the present study was to evaluate the cost-utility of three incontinence treatments by examining costs and quality-adjusted life years. since the type of therapy varies with the nature of incontinence, our objective in this prospective cohort study was not to compare different strategies of incontinence therapy but to determine whether each therapy is cost-useful. this type of assessment is of particular interest in italy as the italian nhs does not fund anticholinergic drugs. material and methods study design a prospective descriptive observational study with no inter-group comparisons was designed and approved as a “research project” by the “umbria region” (annex) to test an innovative organizational model of ui treatment in an attempt to reduce costs and increase patient satisfaction. the approval to conduct the study (number 718) was obtained by regional research scientific committee with the protocol number 0096568, classification xvii.4. before starting the study general practitioners (gps) in the no 2 local health board in perugia (italy) were asked how many patients used nhs-supplied pads. approximately 8% used them, but only about 2% were suitable for recruitment to the present study as the others were very elderly or had other major pathologies such as double incontinence or were bedridden. the study was conducted on women who were consecutively referred by gps to the urology and andrology division (university of perugia) because of ui. patients were affected by stress urinary incontinence (sui), urge urinary incontinence (uui), mixed urinary incontinence doi: 10.4081/aiua.2014.2.112 113archivio italiano di urologia e andrologia 2014; 86, 2 female urinary incontinence: cost utility ratios and effectiveness (mui). in patients with mixed incontinence, the dominant symptom of either stress or urge incontinence was treated. patients were divided into three groups according to the type and severity of incontinence, in accordance with international continence society (ics) criteria and the ingelman sunderberg classification (6) and were treated with surgery, drugs or physiotherapy. only patients who gave written informed consent to participating in this observational study were included in each group. all information was obtained using validated questionnaires: the iiq 7 and udi6 questionnaires for outcome evaluation and life expectancy eq-5d (see quality of life below) for quality of life evaluation at baseline and at the 3 month follow-up. pad use preand post-treatment was also included in the analysis the primary outcome was evaluation of the cost-utility of 3 incontinence treatments by examining costs and quality-adjusted life years without an inter-group statistical comparison. our aim was to assess the cost-utility of each strategy and its impact on the italian national health service bearing in mind that each treatment was not funded in the same way. cost utility analysis (cua) cost is typically measured in currency, and should reflect the present value of total future expenditures that would be incurred by making a certain decision. utilities are typically measured in quality adjusted life years (qalys). a qaly accounts for the morbidity of a health state, based on the assumption that a year of life with morbidity is not equal to a year of life without morbidity. the value of a year with morbidity, the “utility weight”, can be determined through validated survey instruments. to calculate the cost-utility ratios for incontinence therapy we calculated quality of life and costs. cost-utility ratios are normalized values that reveal how much money (cost) must be paid for a single extra qaly (utility). when deciding between two management options, one should consider the cost of the gain of qalys. this ratio, the cost-utility ratio, is calculated as (cost1 – cost2)/(qaly1-qaly2). if one of the interventions costs less and yields more qalys, that decision is “cost-saving” and “prevails over” the other option. confidence intervals for the cost per qaly ratio were estimated using the non-parametric bias-corrected percentile bootstrap method (7). because of the limited degree of modeling in this cost utility analysis, we carried out sensitivity analyses only on the use of different utility measures: eq-5d index and eq-5d visual analogue scale (vas). quality of life health-related qol was assessed by patients before therapy and 3 months after treatment by means of the life expectancy eq-5d questionnaire, a non-disease-specific self-report instrument for measuring health-related qol. it consists of the eq-5d self-classifier and the eq-5d visual analogue scale ranging from 0 to 100 (8). patients classify their own health status in five dimensions: mobility, selfcare, usual activities, pain/discomfort, and anxiety/depression. answers are given on a three point scale: 1 = no problems, 2 = moderate problems, and 3 = severe problems. theoretically, 243 health statuses could be generated by this classification. each health status can be given a value from -0.59 to 1.0 by means of the time-trade method developed for uk population (9). as incontinence does not impact on life expectancy, qaly was calculated for each patient by subtracting her age at the start of the study from the age-specific life-expectancy values relative to the general female population in the umbria region in 2010 (source istat, national institute of statistics) and then adjusted for eq-5d scores. no further or additional adjustment was done. two types of qaly was obtained as one is calculated on the basis of the descriptive self-classifier and the other on the vas scores. costs according to our regional legislation urodynamic tests are performed only in patients who are candidates for surgery and all the other tests and procedures are performed under an accurate spending review in order to contain costs as much as possible. direct costs, based on prices from the italian diagnosis related groups (drg), were calculated for: 1. diagnosis out-patient appointments and laboratory tests urodynamic testing (only in the surgery group) 2. treatment and/or prevention drug therapy (recommended pharmaceutical company prices) hospital stays in the ward and in the day hospital surgical intervention physiotherapy 3. the following costs could not be quantified in our study treatment for incontinence-related skin infections treatment for urinary tract infections these costs were derived from the arlandis-guzman study published on biomed central ltd. in 2011 (10). all costs are presented as mean costs evaluated in 2011. as the italian national health service does not cover the costs of anticholinergic therapy the astellas company kindly provided the 3 months supply to avoid patients stopping therapy because of the cost of the drugs. we expected to find that no single treatment was worse than any other (the null hypothesis) or that all treatments, though not to the same measure, reduced pad use and incontinence-related complications, thus lowering costs and providing a gain in qaly. statistical analysis preand postincontinence treatment data from the three intervention groups were analyzed using the wilcoxon non-parametric tests for paired discrete data. since the type of therapy varies with the nature of incontinence, our objective in this prospective cohort study was not to compare incontinence treatments but to determine whether each was cost-useful. all analyses were performed using ibm spss release 20.0.0, 2011, with significance level set at p ! 0.05. results from january 2010 to december 2011 gps identified 190 patients as suitable for recruitment to this study. archivio italiano di urologia e andrologia 2014; 86, 2 e. costantini, m. lazzeri, v. bini, a. zucchi, e. scarponi, m. porena 114 after a complete urogynaecological examination the senior urologist divided the patients into three groups according to the type and severity of incontinence. pelvic floor exercises were recommended for patients with mild sui, mid-urethral sling surgery for patients with moderate-severe sui, and anticholinergic therapy for patients with uui or mui with urgency as predominant symptom. figure 1 illustrates the enrolment process and the patients who were included in the study. thirty of the 190 patients were excluded: 10 because poor health status prevented routine check-ups or patients were unable to understand or respond to the questionnaires: 10 because of diabetes, oncological or neurological diseases; 5 in the anticholinergic drug therapy group because of contraindications and 5 because of associated low urinary tract symptoms (luts). of the remaining 160 patients, 50 were assigned to the surgery group, 67 to the physiotherapy group and 43 to the drug group. ultimately only 137/160 female patients (mean age 60.6 ± 11.6; range 36-81) gave written informed consent and were enrolled according to the ui type and severity. group a: sui grade ii-iii: 43 patients (mean age 61 ± 12; range 38-80 years) underwent mid-urethral sling (mus); 7/50 refused surgery. group b: sui grade i-ii 57 patients (mean age 66 ± 10; range 49-79 years) undertook a pelvic floor muscle exercise programme; 10/67 refused to participate and perform the exercises regularly for at least 3 months. group c: uui: 37 patients (mean age 58 ± 11; range 36-77 years) who underwent antimuscarinic treatment with solifenacin 5 mg; 6/43 refused drug therapy (3 because of constipation risk, and 3 because of undeclared personal reasons). no patients were lost during the 3 month follow-up, the principal reasons for not having any drop-outs were the relatively short follow-up and free supply of medication in the drug group. in the surgery and physiotherapy groups additional check-ups at 6 and 12 months confirmed the 3-month results. table 1 shows the estimated costs for each group. table 2 shows questionnaire scores and pad use before and after each treatment. scores improved significantly after treatment in all 3 groups. improvements were confirmed by the cost utility ratio (cur) assessment according to both sections of the eq-5d questionnaire (table 3). the cost was then modified to include pad use (table 4) and the cost of treating skin and urinary tract infections before and after treatment (table 5). estimated costs (!) surgery drug physiotherapy out-patient appointmentsa 33.06 33.06 33.06 urodynamic testing 56.81 uroflussimetry 11.62 11.62 11.62 drug therapyb 61.90 surgical interventionc 4324.00 physiotherapyd 204.58 pade 0.31 0.31 0.31 a: 2 appointments; b: recommended pharmaceutical company prices for 1 months of therapy; c: included hospital stay; d: 24 sessions; e: included waste disposal. table 1. estimated costs applied for each group. table 1. flow chart of patients’ distribution across the three different categories 115archivio italiano di urologia e andrologia 2014; 86, 2 female urinary incontinence: cost utility ratios and effectiveness surgery and physiotherapy were associated with strong savings for each qaly and drug treatment was linked to a very low cost per qaly. according to both the eq-5d index and the eq-5d vas, the cost utility ratio was estimated at a saving of more than "1200 per qaly for surgery and physiotherapy. drug therapy cost under "100 per qaly. since there are no italian threshold values per qaly,we referred our findings to what the uk nice proposed. according to nice, costs are commonly classified as acceptable up to "30000 per qaly, as possibly acceptable between "30000"45000 per qaly and rejected over "45000 (11). discussion we found that in an italian regional setting appropriate diagnosis and treatment of incontinence may lower national health service costs and improve the benefits of treatment and quality of life. all interventions for incontinence showed a cost per qaly far below the acceptable cut-off according to nice (10). over the past 25 years, health and medical services have become a major part of our economy. applying economics to medical practice does not necessarily mean that less can or should be spent. instead, the underlying belief is that resources should be allocated to treatments that maximize social welfare (4). cost-benefit analyses inform decision makers about how to allocate resources to maximize societal well-being within a limited budget there are different typologies or frameworks for categorizing costs in health care e.g. direct, indirect and intangible costs. direct costs for incontinence include diagnosis, treatment, routine care, (including cost of absorbent type of intervention iiq score iiq score udi score udi score eq-5d eq-5d eq-5d vas eq-5d vas pads pads pre* post* pre* post index pre* index post pre* post* pre* post surgery n 43 43 43 43 43 43 43 43 43 43 median 37 0 20 0 0.59 1 25 90 6 0 minimum 4 0 3 0 -0.17 0.74 10 70 1 0 maximum 65 6 51 4 0.59 1 45 100 15 1 mean 35.37 1.00 22.47 0.28 0.45 0.95 26.42 88.67 6.35 0.05 std. deviation 15.99 1.91 10.05 0.91 0.25 0.08 11.00 5.61 3.04 0.21 drug n 37 37 37 37 37 37 37 37 37 37 median 31 0 21 0 0.59 1 21 90 3 0 minimum 9 0 3 0 0 0.76 11 80 1 0 maximum 48 6 51 3 0.59 1 45 90 7 2 mean 31.38 1.15 24.46 0.62 0.43 0.93 23.08 88.77 3.31 0.38 std. deviation 12.83 2.23 13.15 1.19 0.28 0.11 11.04 2.86 1.60 0.65 physiotherapy n 57 57 57 57 57 57 57 57 57 57 median 28 0 19 0 0.59 1 22 90 2 0 minimum 8 0 3 0 -0.005 0.79 10 70 0 0 maximum 48 6 51 4 0.59 1 45 100 10 2 mean 27.02 0.65 20.96 0.14 0.40 0.96 24.86 88.44 2.54 0.46 std. deviation 10.79 1.56 10.18 0.61 0.21 0.09 10.79 5.07 1.83 0.68 * p < 0.0001 pre vs post in overall type of intervention groupsof therapy; c: included hospital stay; d: 24 sessions; e: included waste disposal. table 2. questionnaire scores and the pad use before and after each type of therapy. cost-utility ratio surgery drug physiotherapy eq-5d index 702 (582; 851) 1453 (1026; 2438) 35 (30; 42) eq-5d vas 560 (486; 651) 1149 (875; 1674) 28 (25; 32) table 3. cost-utility ratios (cur) with 95%ci expressed in euros as the cost of each qaly, according to both sections of the eq-5d questionnaire and treatment. cost-utility ratio surgery drug physiotherapy eq-5d index -735 (-609; -890) 995 (703; 1701) -610 (-529; -732) eq-5d vas -586 (-509; -681) 787 (599; 1147) -494 (-444; -563) table 4. change of the cur (!) when pad use is factored in cost-utility ratio surgery drug physiotherapy eq-5d index -1677 (-1390; -2031) 87 (62; 149) -1519 (-1317; -1822) eq-5d vas -1337 (-1161; -1553) 69 (52; 100) -1229 (-1104; -1402) table 5. cur including the cost of treating skin and urinary tract infections before and after treatment (estimated from published reports) (9). archivio italiano di urologia e andrologia 2014; 86, 2 e. costantini, m. lazzeri, v. bini, a. zucchi, e. scarponi, m. porena 116 pads which, is one of the largest items), incontinencerelated consequences such as fractures from falls, nursing home admissions and uti (12). however the causal link between iu and its consequences is less clear. indirect costs are the value of lost productivity or lost employment due to morbidity (lost productivity and fewer hours of productive work). intangible costs are the monetary value of pain and suffering. the present study included only direct costs because they are easier to assess. costs of incontinence-related consequences were derived from a spanish study in 2011 (10). costs can also be categorized by type or by perspective (i.e who bears the cost: provider, society, patient etc.). cost/utility, cost benefit and cost effectiveness analysis use the perspective category. in a cost of illness analysis (coi) analysis no attempt is made to measure the “value” of treatment while cost-utility and cost -benefit analysis address this particular issue. cost effectiveness analysis (cea) refers to the broad class of calculations where the effectiveness measure is a general health outcome. in studies on incontinence cea focused on strategies for nursing home management (13-14), compared surgical techniques for stress incontinence (15-16), assessed pharmacological therapy of urgency incontinence and overactive bladder (17). two studies using the perspective of the health care system (16, 18) provided evidence that trans-vaginal tape (tvt) is better than colposuspension although it remains unclear if the results would have been different if lifetime costs and benefits had been assessed and if a societal perspective had been included. there are many limitations to cea and there has been widespread convergence on the use of qalys as the preferred health outcome in cost-effectiveness analysis. since the cua is the gold standard in medicine (4) it was used in the present study. it refers to cea using qalys as the outcome measure: qalys denote the relationship between the value of a given health state and the length of time a person lives in that health state. the value of a given health state is measured in “utilities” which represent preferences for a given health state. the present study demonstrated that mid-urethral slings provided considerable savings ranging from 1337 to 1677 " per qaly, in patients with moderate-severe stress urinary incontinence as did physiotherapy in patients with mild stress urinary incontinence, which saved from 1229 to 1519 ". these data confirm that appropriate diagnosis and treatment of incontinence lower national health service costs and clearly improve the benefits of treatment and quality of life. a small but growing area of research has found that urinary incontinence and overactive bladder are associated with important and costly consequences (3) that can have a large impact on costs, morbidity, quality of life and mortality. arlandis-guzman s et al. compared the economic value of overactive bladder (oab) treatment with fesoterodine and extended release tolterodine and solifenacin from the social perspective (9). their results were not comparable with ours because our study did not compare treatments as our aim was to evaluate the cost-utility of each treatment by examining costs and quality-adjusted life years. however, even though our drug treated group was small in number, the present study demonstrated that anti-cholinergic therapy with solifenacin was linked to a much lower cur than 30,000" which the nice adopted as the cost-useful threshold per qaly gained (11). although the cost per qaly appears highly reasonable (less than 100 "), reasons other than cost have to be taken into account before recommending this regimen to patients. furthermore intermittent treatment may be suitable for some cases but needs in depth investigation to assess costs. finally, variations in the cost of drugs from country to country becomes a pressing problem when the national health service does not fund the medication. the major strength of the present study is that clinical research data derived mainly from gp referrals to the national health service urology unit in perugia general hospital. the entire cohort constitutes a representative sample from national health service records in a small region with no private medicine, meaning that all patients could be traced. even though it might be objected that our evaluation is restricted to one italian region and that costs as calculated in this paper would be completely different for each item (pads, surgery) in another healthcare system, we are of the view that umbria provides a good example of a national health service model, which could be translated to other areas. although gp referrals should have ensured matched groups, groups were not in fact matched as allocation to a treatment option depended upon the type and severity of incontinence. surgery, for example, was reserved for the worst cases. in the patients who underwent surgery we had no surgical complications and were unable to assess the costs of possible re-treatments due to the relatively short follow-up (1 year). however, data on midurethral sling outcomes confirm durability (19, 20) and low complication rates (21). other limitations of the present study are lack of a “usual care” arm in which either effectiveness or costs are modeled for comparison, the absence of perspective/ model, secondary effects, and inability to quantify the prevalence, and costs of treating, skin and urinary tract infections in our patients. in fact we had to resort to published reports for these figures. we were also unable to quantify the number, and treatment costs of episodes of depression. therefore these three groups differed in incontinence severity and life expectancy. the costs of other pathologies and incontinence-related personal hygiene are unknown but probably similar in all three groups, though conceivably higher in patients who underwent surgery as they were affected by the most severe incontinence. despite these differences drug therapy emerged as costing more than surgery and physiotherapy. future investigations will have to attempt to create more homogeneous groups on age and life expectancy grounds. for ethical reasons severity of incontinence can never be uniformly distributed across groups. finally, in a certain percentage of patients incontinence is so severe that no treatment has any chance of success. the natural history of ui is not well understood but if it worsens over time, then rather than waiting until it becomes severe before starting therapy. early stage e.g. mild to moderate iu diagnosis and treatment would reduce national health service costs. 117archivio italiano di urologia e andrologia 2014; 86, 2 female urinary incontinence: cost utility ratios and effectiveness conclusions this study shows that appropriate diagnosis and treatment of a patient with incontinence lowers national health service costs and clearly improves the benefits of treatment and quality of life. references 1. hunskaar s, burgio k, diokno a, et al. epidemiology and natural history of urinary incontinence in women. urology. 2003; 62:suppl 1:s16-23. 2. thom d. variation in estimates of urinary incontinence prevalence in the community: effects of differences in definition, population characteristics and study type. j am geriatr soc. 1998; 46:473-80 . 3. foxman b. epidemiology of urinary tract infections: incidence, morbidity, and economic costs. dis mon. 2003; 49:53-70. 4. the-wei hu, th wagner, g hawthorne, et al. economics of incontinence in incontinence abrams p, cardozo l, kohury s and wein a (eds),health publication ltd, plymouth (uk) 2002; 14:965. 5. gold m, siegel je, russell l, weinestein mc. (eds). cost-effectiveness in health and medicine. oxford university press, oxford. 1996. 6. ingelman sunderberg a, ulmsten u. surgical treatment of female urinary stress incontinence. contrib gynecol obstet. 1983; 10:51-69. 7. campbell mk, torgenson dj. bootstrapping: estimation confidence intervals for cost-effectiveness ratios. q j med. 1999; 92:177-82. 8. euroqolgroup: euroqol-a new facility for the measurement of health related quality of life. health policy. 1990; 16:199-208. 9. dolan p. modeling valutations for euroqol health states. med care. 1997; 35:1095-108. 10. arlandis-guzman, et al. cost-effectiveness analysis of antimuscarinics in the treatment of patients with overactive bladder in spain: a decision-tre model. bmc urology. 2011; 11:9. 11. national institute for health and clinical excellence (2012). guide to the methods of technology appraisal. http://www.nice.org.uk/media/ cb1/43/guidetomethodsoftechnologyappraisal2012 12. darkow t, fontes cl, williamson te. costs associated with the management of overactive bladder and related comorbidities. pharmacotherapy. 2005; 25:511-9. 13. schnelle jf, keeler e, simmons d, ouslander, et al. a cost and value analysis of two interventions with incontinence nursing home residents. j am geriatr soc. 1995; 43:1112-7. 14. hu tw, kaltreider dl, igou lc, rohner tj. cost effectiveness of training incontinent elderly in nursing homes: a randomized clinical trial. health serv res. 1990; 25:455-77. 15. ramsey sd, wagner th, bavendam tg. estimating costs of treating stress urinary incontinence in elderly women according to the ahcpr clinical practice guidelines. am j man care. 1996; 2:147-54. 16. manca a, sculpher mj, ward k, hilton p. a cost-utility analysis of tension-free vaginal tape versus colposuspension for primary urodynamic stress incontinence. bjog. 2003; 110:255-62. 17. o’brien bj, goeree r, bernard l, , et al. cost-effectiveness of tolterodine for patients with urge incontinence who discontinue initial therapy with oxybutinin: a canadian perspective. clin ther. 2001; 23:2038-49. 18. quievy a, couturier f, prudohn c, et al. economic comparison of 2 surgical techniques for the treatment of stress urinary incontinence in women: burch’s technique versus the tvt technique. prog urol. 11: 347-53. 19. albo me, litman hj, richter e, et al. for the urinary incontinence treatment network. treatment success of retropubic and transobturator mid urethral slings at 24 months. j urol. 2012; 188:2281-7. 20. porena m, costantini e, frea b, et al. tension-free vaginal tape versus transobturator tape as surgery for stress urinary incontinence: results of a multicentre randomised trial. eur urol. 2007; 52:1481-1490. 21. novara g, artibani w, barber md, et al. updated systematic review and meta-analysis of the comparative data on colposuspensions, pubovaginal slings, and midurethral tapes in the surgical treatment of female stress urinary incontinence. eur urol. 2010; 58:218-38. correspondence elisabetta costantini, md massimo lazzeri, md alessandro zucchi, md (corresponding author) azucchi@unipg.it emanuele scarponi, md massimo porena, md department of medical-surgical specialties and public health urology and andrology section, ospedale s. maria della misericordia loc. s. andrea delle fratte 06100 perugia, italy vittorio bini, md department of internal medicine, university of perugia, perugia, italy stesura seveso 297archivio italiano di urologia e andrologia 2014; 86, 4 short communication viburnum opulus: could it be a new alternative, such as lemon juice, to pharmacological therapy in hypocitraturic stone patients? devrim tuglu 1, erdal yılmaz 1, ercan yuvanc 1, imge erguder 2, ucler kisa 3, fatih bal 1, ertan batislam 1 1 university of kirikkale, faculty of medicine, department of urology and 3 biochemistry, 2 university of ankara faculty of medicine, department of biochemistry, turkey. objective: citrate, potassium, and calcium levels in viburnum opulus (v. opulus) and lemon juice were compared to evaluate the usability of v. opulus in mild to moderate level hypocitraturic stone disease. materials and methods: v. opulus and lemon fruits were squeezed in a blender and 10 samples of each of 100 ml were prepared. citrate, calcium, sodium, potassium, magnesium, and ph levels in these samples were examined. results: potassium was found to be statistically significantly higher in v. opulus than that in lemon juice (p = 0.006) whereas sodium (p = 0.004) and calcium (p = 0.008) were found to be lower. there was no difference between them in terms of the amount of magnesium and citrate. concusions: because v. opulus contains citrate as high as lemon juice does and it is a potassium-rich and calciumand sodium-poor fluid, it can be an alternative to pharmaceutical treatment in mild-to-moderate degree hypocitraturic stone patients. these findings should be supported with clinical studies. key words: viburnum opulus; hypocitraturic; urinary stone; lemon juice. submitted 24 october 2014; accepted 31 october 2014 summary no conflict of interest declared. recurrence. however, patient compliance to pharmacotherapy with potassium citrate can be difficult. due to gastrointestinal side effects and the high number of tablets to take throughout the day, 3-year treatment dropout rates of patients are as high as 25 percent (2, 5). natural citric acid intake can be used as an alternative to pharmacotherapy in patients who are incompatible, or who cannot tolerate potassium citrate. there are studies that have used lemonade, orange, grapefruit, lime, or tomato to aim this target (6-11). these studies emphasize that they can be a good alternative to pharmacotherapy in mild to moderate hypocitraturia. oxidative stress and renal tubular cell injury are observed in urinary tract stone patients. lipid peroxidation begins in the cell membrane as a consequence of the toxicity of free radicals. when cell membrane integrity breaks down, cell balance begins to disappear, and cell death starts. antioxidants may be used in order to avoid this situation (12). viburnum opulus (v. opulus) has antioxidant properties (13-15) and we think that it may have a place in the medical treatment of stone disease. not only with its antioxidant properties, but also with its content of potassium and citrate, it suggests being beneficial in the prevention of stone disease. in our study, v. opulus is compared in terms of citrate, calcium, phosphorus, magnesium, sodium, potassium and ph to lemon, which is known as a source of natural citrate, and the usability of v. opulus in hypocitraturic stone disease patients is discussed. material and method because v. opulus has a bitter taste when first collected, the fruit was kept in brine water for a month to make it lose its bitterness. after having made it drinkable, it was squeezed in a blender and 10 samples of each of 100 ml were collected. ten samples of 100 ml each were taken from lemons in the same manner. during evaluation, no dilutions were made with water or any other solution and no sugar was added to prevent the direct effect of a liquid or sugar to the variables to evaluate. the resulting extract was centrifuged for 15 min at 2000 g. citrate, oxalate, calcium, phosphorus, magnesium, sodidoi: 10.4081/aiua.2014.4.297 introduction urinary tract stone disease affects 12% of the world's population and its recurrence can be as high as 50% at 10 year follow up (1). with the widespread use of swl and introduction of endoscopic techniques, studies on medical stone treatment have been reduced and pushed to the background (2). urinary tract stones are formed through a marked increase in the saturaton of a solute substance in the urine. one of the changeable factors affecting solubility is ph. increase in the value of urinary ph raise the point of solubility and may prevent stone formation (3). the agents commonly used to treat hypocitraturia and alkalinizing urine are sodium citrate and potassium citrate (4, 5). many studies have shown that citrate replacement reduces rates of stone tuglu_stesura seveso 14/01/15 13:02 pagina 297 archivio italiano di urologia e andrologia 2014; 86, 4 d. tuglu, e. yılmaz, e. yuvanc, i. erguder, u. kisa, f. bal, e. batislam 298 um, potassium, chloride, and ph levels were examined in all samples. samples were grouped as follows: group 1. v. opulus juice held in brine; group 2. fresh lemon juice an enzyme-spectrophotometric method was used to determine citrate in biological fluids it is based on citrate lyase and phenylhydrazine reactions. the enzyme converts citrate into oxaloacetate, which, in the presence of phenylhydrazine, is transformed into the corresponding phenylhydrazone. the ultraviolet-absorbing product is determined by absorbance measurement at 330 nm (16). the method is based on the following reactions: citrate lyase citrate oxaloacetate + acetate malate dehydrgenase oxaloacetate + nadh + h+ malate + nad+ calcium, phosphorus and magnesium (roche diagnostics gmbh, mannheim) were colorimetrically measured by a hitachi p800 autoanalyser (hitachi high-technologies co., japan). sodium and potassium were analyzed in the hitachi p800 autoanalyser using ion-selecting electrodes. a ph meter precisa ph 900 device was used to verify ph. wilcoxon rank-sum test was used in the statistical evaluations for comparison of the parameters. results the citrate and magnesium contents of v. opulus have been found not statistically different from than of lemon juice. potassium has been found statistically higher than in lemon juice (p: 0.006) whereas sodium (p: 0.004) and calcium (p: 0.008) were lower. table 1 shows the citrate, calcium, sodium, potassium, phosphorus, magnesium and ph values in lemon juice and v. opulus contents. discussion a well known inhibitor of calcium-based stones is citrate. citrate reduces calcium oxalate and phosphate saturation by forming calcium-soluble complexes and by inhibiting crystal nucleation and growh (4). with an incidence of 16-63%, hypocitraturia is an important etiological factor in recurrent calcium nephrolithiasis (3). it has been demonstrated that pharmacological potassium citrate intake increases urine citrate levels and reduces urine calcium excretion as well as relative saturation of calcium oxalate in hypocitraturia (2). alternatives to potassium citrate have been sought in recent years due to patient non-compliance, particularly due to gastrointestinal poor tolerance (17-45%), and to the severe financial burden (a daily dose price of $ 3.90 in turkey) (5). significant increases in urinary volume, ph, potassium, magnesium and citrate excretion have been obtained in patients with hypocitraturic stone disease by the addition of fruit and vegetable juices to the diet (7, 17, 18). in addition, this has also been reported to provide dilution of lithogenic risk factors in the urine without affecting the concentration of potassium and citrate (19). in particular, various studies have established that the use of citrate extracts and juices as a natural source of citrate can be an alternative to potassium citrate (6, 8). it has been shown that high concentrations of citrate in citrus products may affect urine citrate excretion (20, 21). orange juice causes an alkali load by increasing net gastrointestinal alkali absorption, increases urinary ph and citrate and reduces ammonium and net acid excretion. it is also reported that daily consumption of one liter of orange juice increases citraturia and ph and prevents stone formation and reduces crystallization risk factors for calcium phosphate (8, 22, 23). although grapefruit juice has been shown to have higher citrate content, it has not been possible to demonstrate that it reduces urinary risk factors (24, 25). in addition, grapefruit juice may affect metabolism of commonly used drugs by inhibiting the cytochrome p-450 (24). the citraturic effect of lemonade have been established by a variety of studies. an advantage of lemonade to orange juice is that its citric acid content is high and calcium content is low (9, 20, 26). v. opulus is known to be widely used in turkey, especially in stone disease. this plant is a species within the caprifoliaceae (honeysuckles) family within the dipsacales order. the plant's trunk, bark and fruits are utilized in pharmacology and as food in the form of pickles, jams, and in various other ways (27). in central anatolia, turkey, especially in the city of kayseri, it is widely termed as gilaburu. there are no studies in literature about the mechanism of action of v. opulus in stone disease. we believe that it may be active by two ways: 1. antioxidant properties 2. possible citrate and potassium content of the plant. several studies have been carried in recent years establishing that v. opulus has a high potential of antioxidant activity and antimicrobial characteristics depending on the composition of the substances it contains (13-15, 28). it has also been shown to have beneficial effects in the gastrointestinal mucosa thanks to its antioxidant properties (29). comparison of citrate and potassium content of v. opulus, which has also antioxidant properties, to citrate and potassium content in lemon juice was the purpose of this study. we demonstrated that if v. opulus is citrateand potassium-rich, therefore in relation to both its antioxidant properties and its high content in citrate and potassium, it could be argued that it can be an alternative to pharmacological agents in the treatment of hypocitraturic stone patients. in our study it has been found that potassium content in v. opulus content is higher than that of lemon juice whereas calcium content is lower. no statistically sigv. opulus lemon juice citrate (mmol/l) 65.22 ± 5.86 54.04 ± 5.05 potassium (mmol/l) 40.51 ± 2.78 27.55 ± 2.12 calcium (mmol/l) 0.05 ± 0.01 1.52 ± 0.02 magnesium (mmol/l) 1.57 ± 0.26 1.44 ± 0.21 sodium (mmol/l) 2.54 ± 0.19 6.35 ± 0.98 ph 4.02 ± 0.16 4.03 ± 0.18 table 1. concentration of solutes and ph value in the two fluids. tuglu_stesura seveso 14/01/15 13:02 pagina 298 nificant difference from lemon juice in terms of the content of citrate was observed. this result suggests us that v. opulus may have a citraturic effect as much as lemon juice and can also provide an alkali load due to its high content of potassium. this alkali load increases urinary citrate excretion by reducing renal tubular reabsorption and citrate metabolism. in addition to alkalinizing urine, alkali load also affects citrate reabsorption from the kidneys. the low calcium and sodium content of v. opulus could also be considered as an advantage for stone patients. conclusions in our study, we have identified citrate and potassium v. opulus content as high as that in lemon juice. due to its antioxidant properties as well as to its high content of both citrate and potassium, v. opulus can be recommended to stone patients. we think that it is advisable just as lemon or orange juice in mild-to-moderate hypocitraturia as an alternative to potassium citrate. however, clinical trials on this subject are desirable. references 1. menon m, parulkar bg, drach gw. urinary lithiasis: etiology, diagnosis and medical management. in: walsh pc, retik ab, vaughan ed jr, wein aj, editors. campbell’s urology. 7th ed. philadelphia, pa: w.b. saunders co.1998, pp 2659-2752. 2. pak cy. medical management of urinary stone disease. nephron clin pract. 2004; 98:c49-c53. 3. pak cy. kidney stones. lancet. 1998; 351:1797-1801. 4. pak cy. citrate and renal calculi: an update. miner electrolyte metab. 1994; 20:371-377. 5. barcelo p, wuhl o, servitge e, et al. randomized double-blind study of potassium citrate in idiopathic hypocitraturic calcium nephrolithiasis. j urol. 1993; 150:1761-1764. 6. koff sg, paquette el, cullen j, et al. comparison between lemonade and potassium citrate and impact on urine ph and 24-hour urine parameters in patients with kidney stone formation. urology. 2007; 69:1013-1016. 7. meschi t, maggiore u, fiaccadori e, et al. the effect of fruits and vegetables on urinary stone risk factors. kidney int. 2004; 66:2402–2410. 8. odvina cv. comparative value of orange juice versus lemonade in reducing stone-forming risk. clin j am soc nephrol. 2006; 1:1269-1274. 9. seltzer ma, low rk, mcdonald m, et al. dietary manipulation with lemonade to treat hypocitraturic calcium nephrolithisis. j urol. 1996; 156:907-909. 10. tosukhowong p, yachantha c, sasivongsbhakdi t, et al. citraturic, alkalinizing and antioxidative effects of limeade-based regimen in nephrolithiasis patients. urol res 2008; 36:149-155. 11. yilmaz e, batislam e, basar m, et al. citrate levels in fresh tomato juice: a possible dietary alternative to traditional citrate supplementation in stone-forming patients. urology. 2008; 71:379-383. 12. selvam r. calcium oxalate stone disease: role of lipid peroxidation and antioxidants. urol res. 2002; 30:35-47. 13. rop o, reznicek v, valsikova m, et al. antioxidant properties of european cranberrybush fruit (viburnum opulus var. edule) molecules. 2010; 15:4467-4477. 14. altun ml, citoglu gs, yılmaz bs, coban t. antioxidant properties of viburnum opulus and viburnum lantana growing in turkey. int j food sci nutr. 2007; 5:1-6. 15. andreeva ti, komarova en, yusubov ms, korotkova ei. antioxidant activity of cranberry tree (viburnum opulus l.) bark extract. pharma chem j. 2004; 38:548-550. 16. petrarulo m, facchini p, cerelli e, et al. citrate in urine determined with new citrate lyase method. clin chem. 1995; 41:15181521. 17. parivar f, low rk, stoller ml. the influence of diet on urinary stone disease. j urol. 1996; 155:432-440. 18. siener r, hesse a. the effect of different diets on urine composition and the risk of calcium oxalate crystallisation in healthy subjects. eur urol. 2002; 42:289-296. 19. borghi l, meschi t, maggiore u, prati b. dietary therapy in idiopathic nephrolithiasis. nutr rev. 2006; 64:301-312. 20. aras b, kalfazade n, tugcu v, et al. can lemon juice be an alternative to potassium citrate in the treatment of urinary calcium stones in patients with hypocitraturia? a prospective randomized study. urol res. 2008; 36:313-317. 21. gettman mt, ogan k, brinkley lj, et al. effect of cranberry juice consumption on urinary stone risk factors. j urol. 2005; 174:590-594. 22. campoy martínez p, arrabal martín m, blasco hernández p, et al. orange juice in the prevention of calcium oxalate lithiasis. acta urol esp. 1994; 18:738-743. 23. wabner cl, pak cy. effect of orange juice consumption on urinary stone risk factors. j urol. 1993; 149:1405-1408. 24. goldfarb ds, asplin jr. effect of grapefruit juice on urinary lithogenicty. j urol. 2001; 166:263-267. 25. hönow r, laube n, schneider a, et al. influence of grapefruit-, orangeand apple-juice consumption on urinary variables and risk of crystallization. br j nutr. 2003; 90:295-300. 26. kang de, sur rl, haleblian ge, et al. lemonade-based dietary manipulation in patients with hypocitraturic nephrolithiasis. j urol. 2007; 177:1358-1362. 27. soylak m, elci l, saracoglu s, divrikli u. chemical analysis of fruit juice of european cranberry bush (viburnum opulus) from kayseri, turkey. asian j chem. 2002; 14:135-138. 28. cesonienè l, daubaras r, viškelis p, sarkinas a. determination of the total phenolic and anthocyanin contents and antimicrobial activity of viburnum opulus fruit juice. plant foods hum nutr. 2012; 67:256-61 29. zayachkivska os, gzhegotsky mr, terletska oi, et al. influence of viburnum opulus proanthocyanidins on stress-induced gastrointestinal mucosal damage. j physiol pharmacol. 2012; 57 suppl 5:155-67. 299archivio italiano di urologia e andrologia 2014; 86, 4 viburnum opulus: could it be a new alternative, such as lemon juice, to pharmacological therapy in hypocitraturic stone patients? correspondence devrim tuglu, md (corresponding author) devrimtuglu@gmail.com erdal yılmaz, md ercan yuvanc, md fatih bal, md ertan batislam, md university of kirikkale, faculty of medicine, department of urology saglik sokak, 71100, kirikkale, turkey imge erguder, md university of ankara faculty of medicine, department of biochemistry ankara, turkey ucler kisa, md university of kirikkale, faculty of medicine, department of biochemistry kirikkale, turkey tuglu_stesura seveso 14/01/15 13:02 pagina 299 stesura seveso 261archivio italiano di urologia e andrologia 2014; 86, 4 original paper the importance of internet usage for urologic patients cahit sahin 1, murat tuncer 1, ozgur yazici 1, alper kafkasli 1, utku can 1, bilal eryildirim 1, orhan koca 2, kemal sarica 1 1 dr. lutfi kirdar training and research hospital, urology clinic, istanbul, turkey; 2 hydarpasa numune training and research hospital, urology clinic, istanbul, turkey. objectives: to evaluate internet usage frequency, rate of searched diseases and impact of internet derived data on future patientphysician relationship in patients applying to an urology department. methods: a well prepared questionnaire has been given to 1000 referring cases, out of which 589 accepted to participate on a volunteer basis to a face to face interview. patients were divided into subgroups with respect to age, gender and as well as their educational and economical status. regarding internet, questions inquired the use of internet, the point of view about it, opinions about healthcare system and most commonly urological diseases searched in internet. results: of 589 patients participating, 38.2% reported access to the internet; in relation to subgroup analysis of data, there was a statistically significant relationship between the use of internet and age (p < 0.001), gender (p = 0.048), educational status (p < 0.001) and economical status of (p = 0.002) the cases evaluated. diseasespecific information was most frequently sought: 18.2% searched for urolithiasis, 14.2% for non-cancer related kidney diseases, and 14.2% for urologic cancers. conclusions: younger patients with higher educational status tended to use internet and the majority of these cases share all these information with their physicians during their visit. these findings indicate that all physicians should consider this fact seriously and make their future plans in the light of internet based activities which provides numerous advantages. key words: internet; urologic patient; urological diseases. submitted 2 february 2014; accepted 31 march 2014 summary no conflict of interest declared. use it for medical purposes (3). a questionnaire study of andreassen et al. about 7934 people in 7 different european countries reported that frequency of internet usage and rate of searching for medical knowledge were 61% (81-42) and 71% (79-54), respectively (4). internet usage allows the patients to have the chance of following the disease course effectively by providing rapid, suitable, easy, real information about their diseases (5). related with this subject, particularly, the patients with uro-oncological diseases search internet in a more effective manner to obtain information concerning the etiology, treatment and follow up of the disease after first diagnosis of the pathology (6). they also tend to read some guideline information from internet before referring to a physician. parallel to these developments, traditional patient-physician relationship, which gives a passive position to the patient, has evolved in a situation where the patient came into a central position (7). the aim of this study was to evaluate the internet usage frequency and the rate of searched diseases along with the impact of internet derived data on future patientphysician relationship in patients applying to an urology policlinic of a training and research hospital in a developing country. material and methods our present prospective study aimed to evaluate the use of internet in detail among the patients referring with urological complaints to our outpatient department between june 2013 and july 2013. a well prepared questionnaire was given to 1000 referring cases, out of which 589 accepted to participate on a volunteer basis to a face to face interview. the questionnaire had two parts consisting of questions concerning the demographic characteristics of the cases and other questions assessing the use of internet in a detailed basis (tables 1, 2). patients were divided into subgroups with respect to age, gender and as well as their educational and economical status. regarding internet questions aimed to inquiry the use of internet, point of view and opinions of patients about the healthcare system and most commonly searched urological diseases from the internet (table 2). doi: 10.4081/aiua.2014.4.261 introduction internet is a perfect tool which enables easy access to existing information in all parts of lives and to share it with whole world in a very practical manner (1). in addition to its extremely common usage in all parts of life, medical aspect of its usage also show an increasing popularity (2). in a recent study, it was shown that 74% of adult people in usa use internet and out of them 90% were found to archivio italiano di urologia e andrologia 2014; 86, 4 c. sahin, m. tuncer, o. yazici, a. kafkasli, u. can, b. eryildirim, o. koca, k. sarica 262 patients being able to use internet (almost every day or at least once in a week) have been accepted as true users. patients between 18 and 90 years participating into the questionnaire study in a voluntarily basis have been included into the study program; patients with mental retardation, severe psychiatric disorders and illiterate ones were excluded from the study program. the study program has been approved by the ethics committee of the institution and a informed consent has been obtained from all cases included into the program. statistical analysis was performed with ncss (number cruncher statistical system) 2007&pass (power analysis and sample size) 2008 statistical software (utah, usa). in addition to descriptive statistics (frequency, ratio), chi-square and fisher-freeman-halton test were used for the examination of qualitative data. statistical significance was defined at p < 0.05. results among 1000 consecutive cases referring to our outpatient department, 600 accepted to participate into our study program. however, only a total of 589 completed the inquiry form, of which 390 were male (66.2%) and 199 (33.8%) were female (m/f: 1.96). evaluation of the percentage of internet use on an age based manner revealed that while 19. 4 % was < 30 years; 298 cases (50.6 %) were among 30-60 years and the remaining 177 cases (30.1%) were over 60 years. with respect to their educational status again, intenet use among cases with primary, intermediate and high school degrees were 441 (74.9%), 53 (9%) and 95 (16.1%), respectively. lastly, evaluation of the cases based on their economical status showed that the percentage of internet use was 35.7 % (210 cases) in cases with lower income, 63.3% (373 cases) in intermediate and 1% (6 cases) in cases with high income. overall analysis of our data among subgroups demonstrated that there was a statistically significant relationship between the use of internet and age (p < 0.001), gender (p = 0.048), educational status (p < 0.001) and economical status (p = 0.002) of the cases evaluated (table 1). of all the cases partecipating into the study program, 225 (38,2%) acknowledged routine use of internet; of these users 165 (73.3%) were able to get the necessary healtcare information from the internet (table 2). additionally among the internet users 169 cases (75.1%) had an e mail account in order to institute a mutual cooperation. the overall attitude of the cases with respect to internet use and search for medical information is summarized in table 2. concerning the area of interest for medical problems, our data clearly demontotal sample nternet users internet users (n = 589) (+) (n = 225) (-) (n = 364) n % n % n % age (year) < 30 114 19.4 87 76.3 27 23.7 a0.001** 30-60 298 50.6 122 40.9 176 59.1 > 60 177 30.0 16 9.0 161 91.0 gender male 390 66.2 160 41.0 230 59.0 a0.048* female 199 33.8 65 32.7 134 67.3 educational status primary school 441 74.9 115 26.1 326 73.6 a0.001** intermediate school 53 9.0 33 62.3 20 37.7 high school 95 16.1 77 81.1 18 18.9 economical status < 1000 tl 210 35.7 71 33.8 139 66.2 b0.002** 1000-4000 tl 373 63.3 148 39.7 225 60.3 > 4000 tl 6 1.0 6 100.0 0 0.0 a pearson chi-square test; b fisher-freeman-halton test; *p < 0.05; **p < 0.01 table 1. demographic characteristics of the patients n % do you use internet? no 364 61.8 yes 225 38.2 do you have email address? 169 75.1 do you check the internet related with your problem prior to the examination? 165 73.3 do you share the healtcare information obtained from the internet with your physician? 89 39.7 do you find the healthcare information derived from the internet as useful? 173 77.2 do you rely on the healthcare information derived from the internet? 119 53.1 table 2. multiaspect evaluation of the information derived from the interner by the patients strated that while 41 cases (18.2%) searched for urinary system stone disease, 32 (14.2%) cases searched for noncancer related kidney diseases, 32 (14.2%) for urologic cancer, 22 (9.7%) for sexual disorders, 21 (9.3%) for infertility, 17 (7.6%) for lower urinary tract symptoms (luts), 9 (4%) for overactive bladder (oab) and 12 (5.3%) for other medical subjects. the remaining 39 cases (17.3% ) however quoted that they did not search any subject related with health care from the internet (table 3). discussion the rapid, easy and practical aspects of internet search has made it a very useful tool to look for as well as obtain the required healthcare information on various medical problems. the efficiency of internet in global circulation of the information is being accepted as the second revolutionary innovation following the invention of printing systems in 1447 by johannes gutenberg (1). the internet has been first proposed to supply the military needs of usa army during nuclear armament after 1960’s (advanced research projects agency of the united states department of defense to produce acomputer communications network arpanet) following its introduction this system gained an enormous importance which brought it in an irresistable position as a highly important part of the daily life (8). at our present time this amazing revolution is further going on with the use of mobile phones which enable us for an extremely easy and practical search of all necessary information with an evident accelaration (9). determining the percentage of internet use and its utility in developing countries is highly important. taking this fact into account, we aimed to evaluate the attitude of the urology patients in turkish society concerning the use of internet facility in their daily life. similarly to other studies dealing with the relationship between demographic variables and internet use (10, 11), the evaluation of our data also showed a positive correlation between educational (p < 0.001) and economical status (p = 0.002) of the cases and percentage of internet use. furthermore, there was a negative correlation between the age of the cases and the percentage of internet use (p < 0.001), and a positive correlation in favor of male gender (p = 0.048). similarly, in their original study, kendra et al. were able to show a positive correlation between internet use and educational as well as economical status of the evaluated population (10). they also demonstrated that younger generation used the internet in a more common and practical manner than adults (12). in relation to this subject pew internet and american life project studies again well demonstrated that the use of internet increased steadily in older ages with values of 2% in 1996, 15% in 2002 and 22% in 2004 (13, 11). in the same study they recorded a higher internet use rate (68%) among subjects with higher educational degree (university) when compared with relatively lower educational levels (high school graduated) (52%) (11). although no direct relationship between socioeconomic status and internet use could be shown, education opportunity and being able to buy a computer system indicate an indirect positive relationship between these two important parameters. studies point out that the use of internet is enormously inceased during the last 2 decades. in relation with this subject, internet world states 2012 data revealed that the whole worldwide number of users is 2.405.518.376 (14) and 200 million in usa (15). with respect to these values, in our country turkish statistics institution has announced that the percentage internet users among 1674 class age was 47.4% whereas the percentage of regular users seemed to drop to 37.8% (16). in addition to the common use of the internet in every part of daily life, its use is apparently increasing worldwide also in healthcare sector (17). currently internet has proven itself to have an extraordinary potential in offering the necessary healthcare information to both normal healthy people as well as to patients suffering from different pathologies (18). in accordance with this fact again it has been reported that the use of internet in order to obtain the necessary pathology-related information is again evidently increasing among the urology patients (19). studies indicate that as much as one third of internet user patients share the obtained information with their physicians (4). as a result of the all these achievements, the paradigm between patient and physician seems to change in a considerable manner (7). last but not least, it is very well known that the specific aims of using the internet in healthcare system is to obtain information (content), share the obtained information (community) and send this information to others (communication, e-mail) (7). furthermore the use of internet in this sector may give the advantages of communication between patients and physicians as well as getting the necessary support from family, friends and related environment (20). of course, another additional advantage will be to get appoinment from the hospitals as well as physician’ offices in a quick and practical manner. in their study dealing with emergency department cases pourmand et al. noted that 92.6% of the cases used the intenet and of these users 94.5% had a personal email address (21). michele et al. reported that among all internet users, 55% used their personal e-mail addresses to cooperate with medical institutions providing medical 263archivio italiano di urologia e andrologia 2014; 86, 4 use of internet in the urological outpatient n % urinary system stone disease 41 18.2 non-cancer related kidney diseases 32 14.2 urologic cancers 32 14.2 sexual disorders 22 9.7 i̇nfertility 21 9.3 luts 17 7.6 other subjects 12 5.3 oab 9 4.0 remaining (not-searching for any spesfic topic) 39 17.3 table 3. urologic problems searched in the internet by the patients referred to our department (n = 225). archivio italiano di urologia e andrologia 2014; 86, 4 c. sahin, m. tuncer, o. yazici, a. kafkasli, u. can, b. eryildirim, o. koca, k. sarica 264 support (22). pew internet and american life project 2009 study reported the use of personal e-mail address among the internet users to be 91% (23). in our current study, 75.1% of our cases reported to have a personal e-mail address. the use of e-mail in healthcare sector will make the communication between medical support providers and patients more practical and quicker. additionally, patient follow-up, scheduling the appoinments and planning other medical procedures will be more practical in a highly effective manner (24). concerning this issue, schwartz et al. reported that while 7.6 % of the internet user patients shared this information with their physicians in a permanent manner, 52,6% shared it occasionally (10). however taylor et al. reported that 53% of internet user patients shared these data with their physicians (25). similarly to reported literature, according to our data 39.7% of the participants of our study shared the internet derived information with their physicians in a permanent manner which in turn again indicated the highly important role of internet use for a proper and cooperative communication between the patients and physicians. regarding the use of internet in order to get information about present health related problems, it has been shown that the patients may look for either specific or general topics on this aspect. with respect to this issue, in their study, nicholas et al. found that out of 1322 internet users 97% searched for specific topics related with their problems (26), while this rate has been reported to be 79% by kendra et al. (10). our data showed that among the participants referring to an urology department, 82.7 % searched for urology related topics (table 3). further evaluation of the topics searched demonstrated that 18.2 % of our cases searched for urolithiasis, 14% searched for urologic cancers and 14% for general kidney diseases. in another study, concerning the inquiries in patients from 7 countries in europe, andreassen et al. reported that 52% of the cases searched for specific topics in internet [4]; pew internet and american life project 2013 study revealed that 55% of the users searched for specific diseases or medical conditions (27). the relatively lower rate of search for some specific medical topics demonstrated in our study could be related to the fact that patients suffering from sexual as well as andrologic problems could refrain from using internet for this aim. one further aspect of internet use is the benefit for the patients to discuss about internet-obtained data during the interview with their physician. there are studies in the literature dealing with consideration and satisfaction of the patients with respect to the internet derived data (11, 28). in our current study 77.2% of the cases expressed the usefulness of the data obtained from internet. ybarra et al. were able to show that 73.3% of their cases were satisfied with the data obtained and 78% of the cases stated that the internet derived data eased their daily life conditions (22). baker et al. reported that 67% of relatively older users noticed that internet data let them to realize their healthcare problems in a more understandable manner (28). last but not least in the european union eurobarometer inquiry study, 41.5% of the participants found the internet derived data were highly useful to deal with their healthcare problems (29). another aspect of internet use is the reliance of users on the data obtained with respect to their adequacy and safety: a concern that has been subjected to numerous studies in the literature (30). in relation with this subject, 53.1% of the cases in our study found the internet obtained medical data reliable and useful; traver et al. reported the rate of treliability in urology and nephrology web sites as 41% and 51% respectively (31). on the other hand however, in their original study, smith et al. found the internet derived data for medical problems as reliable in 21%, adequate in 77% and useless in 2% of the cases evaluated (6). depending on our as well as on similar published data in the literatüre, we may say that patients seemed to be careful and selective in using internet to derive information for their medical problems. the limited number of subjects evaluated and the lack of data concerning a detailed evaluation of the web sites used as well as their individual reliability from patient’ perspective are possible limitations of our study. however, we believe that despite all these certain limitations, in consideration of the highly limited data regarding the use of internet among urology patients in our country as well as in developing countries, our findings could be accepted as valuable enough to give further information about the use of internet in healthcare system. we again believe that further studies with larger number of participants and focusing on specific parameters are certainly needed. conclusion in the light of our data as well as of the published literature findings, it seems that younger patients with higher educational status tend to use internet to derive information about their health problems in a more common and efficient manner. the majority of these cases share all these information with their physicians during their visit. we believe that use of internet data in a proper manner will provide reliable information with respect to the diagnosis and management of the health problems which will contribute to patient-physician relationship in a more positive manner. all physicians should consider this fact seriously and make their future plans in the light of internet based activities which provides numerous advantages. references 1. ullrich pf jr, vaccaro ar. patient education on the internet: opportunities and pitfalls. spine (phila pa 1976). 2002; 27:e185-8. 2. vance k, howe w, dellavalle rp. social internet sites as a source of public health information. dermatol clin. 2009; 27:133-6. 3. rainee l. internet, broadband, and cell phone statistics. washington dc, usa: pew internet and american life project. 2010. 4. andreassen hk, bujnowska-fedak mm, chronaki ce, et al. european citizens' use of e-health services: a study of seven countries. bmc public health. 2007; 7:53. 5. goldsmith j. how will the internet change our health system? health aff (millwood). 2000; 19:148-56. 6. smith rp, devine p, jones h, et al. internet use by patients with prostate cancer undergoing radiotherapy. urology. 2003; 62:273-7. 7. mc mullan m. patients using the internet to obtain health information: how this affects the patient-health professional relationship. patient educ couns. 2006; 63:24-8. 8. doyle dj, ruskin kj, engel tp. the internet and medicine: past, present, and future. yale j biol med. 1996; 69:429-37. 9. smith a. mobile access. washington dc, usa: pew internet and american life project. 2010. 10. schwartz kl, roe t, northrup j, et al. family medicine patients' use of the internet for health information: a metronet study. j am board fam med. 2006; 19:39-45. 11. fox s. older americans and the internet. washington dc, usa: pew internet and american life project. 2004. 12. fast am, deibert cm, boyer c, et al. partial nephrectomy online: a preliminary evaluation of the quality of health information on the internet. bju int. 2012; 110:e765-9. 13. pautler se, tan jk, dugas gr, et al. use of the internet for selfeducation by patients with prostate cancer. urology. 2001; 57:230-3. 14. internet world stats.internet users in the worl. 2012; available at:http://www.internetworldstats.com/stats.htm. accessed december 2013. 15. sadasivam rs, kinney rl, lemon sc, et al. internet health information seeking is a team sport: analysis of the pew internet survey. int j med inform. 2013; 82:193-200. 16. t.c. basbakanlık türkiye istatistik kurumu haber bülteni. hanehalkı bilisim teknolojileri kullanım arastırması (turkey prime ministry turkish statistical institute news bulletin. household informatics technology usage investigation). 2012; available at:http://www.tuik.gov.tr. accessed december 2013. 17. eng tr, maxfield a, patrick k, et al. access to health information and support: a public highway or a private road? jama. 1998; 280:1371-5. 18. weaver jb 3rd, mays d, lindner g, et al. profiling characteristics of internet medical information users. j am med inform assoc. 2009; 16:714-22. 19. hellawell go, turner kj, le monnier kj, brewster sf. urology and the internet: an evaluation of internet use by urology patients and of information available on urological topics. bju int. 2000; 86:191-4. 20. mechanic d. how should hamsters run? some observations about sufficient patient time in primary care. bmj. 2001; 323:266-8. 21. pourmand a, sikka n. online health information impacts patients' decisions to seek emergency department care. west j emerg med. 2011; 12:174-7. 22. ybarra ml, suman m. help seeking behavior and the internet: a national survey. int j med inform. 2006; 75:29-41. 23. jones s, fox s. generations online in 2009. new york, ny, usa: pew internet and american life project. 2009. 24. anderson jg, rainey mr, eysenbach g. the impact of cyberhealthcare on the physician-patient relationship. j med syst. 2003; 27:67-84. 25. taylor h. cyberchondriacs. in: on the rise? . new york, ny, usa: harris interactive. 2010. 26. nicholas d, huntington p, gunter b, et al. the british and their use of the web for health information and advice: a survey. aslib proc. 2003; 55:261-76. 27. fox s. health online. new york, ny, usa: pew internet and american life project. 2013. 28. baker l, wagner th, singer s, bundorf mk. use of the internet and e-mail for health care information: results from a national survey. jama. 2003; 289:2400-6. 29. european commission survey of online health information. 2003; available at http://europa.eu.int/comm/public_opinion /archives/eb/eb59/eb59_rapport_final_en.pdf; accessed december 2013. 30. ziebland s, chapple a, dumelow c, evans j, prinjha s, rozmovits l.how the internet affects patients' experience of cancer: a qualitative study. bmj. 2004; 6;328:564 31. traver ma, passman cm, leroy t, et al. is the internet a reliable source for dietary recommendations for stone formers? j endourol. 2009; 23:715-7. 265archivio italiano di urologia e andrologia 2014; 86, 4 use of internet in the urological outpatient correspondence cahit sahin, md (corresponding author) cahitsahin129@gmail.com murat tuncer, md ozgur yazici, md alper kafkasli, md utku can, md bilal eryildirim, md kemal sarica, md dr. lutfi kirdar training and research hospital, urology clinic gömeç sok. sabancı -2 sitesi a1 kat 4 daire 24 acıbadem/kadıköy istanbul, turkey orhan koca, md hydarpasa numune training and research hospital, urology clinic istanbul, turkey stesura seveso 227archivio italiano di urologia e andrologia 2014; 86, 3 case report localised prostate cancer and hemophilia a (aha): case report and management of the disease francesco celestino 1, cristian verri 2, francesco de carlo 2, savino mauro di stasi 2 1 urologic oncology unit, policlinico casilino, rome, italy; 2 department of experimental medicine and surgery, tor vergata university, rome, italy. acquired hemophilia a (aha) is a rare bleeding diathesis characterized by the development of autoantibodies against factor viii (fviii). about half of the cases are idiopathic and the other half are associated with autoimmune diseases, postpartum problems, infections, inflammatory bowel disease, drugs, lymphoproliferative disorders or solid tumors . aha is associated with malignancies in 7-15% of cases. we report a case of aha in a 65 year old patient with prostatic carcinoma, who underwent retropubic radical prostatectomy (rp). key words: activated partial thromboplastin time; factor viii; hemophilia a; prostate cancer; radical prostatectomy. submitted 14 july 2014; accepted 1 august 2014 summary no conflict of interest declared. introduction aha is a bleeding disorder in which autoantibodies, usually igg, are produced against factor viii (fviii). the clinical presentation varies from light bleeding to acute and life-threatening hemorrhages. the mortality rate ranges from 7.9 to 22% (1, 2). case report a 65-year-old caucasian male, with no significant medical history, underwent retropubic radical prostatectomy (rp) for prostatic carcinoma. his psa was 5.2 ng/ml, hb was 14.6 g/dl. coagulation studies revealed an elevated activated partial thromboplastin time (aptt) of 37.4 seconds (20.0-35.0 sec.) and normal prothrombin time (pt). in the immediate postoperative period, hb was 10.7 g/dl. on 7th postoperative day, hb was 6.7 g/dl, the urine was clear and surgical drainage showed no significant traces, whereas the patient had a ct scan showing active bleeding in the prostate bed anterior to the rectum. the patient underwent surgical revision that showed no major bleeding. on the 11th postoperative day, massive hematuria was noted in the patient. the endoscopic revision showed multiple and small hemorrhagic areas at the bladder neck and posterior bladder wall, which were coagulated. doi: 10.4081/aiua.2014.3.227 the aptt was 61.0 seconds. two days later there was another massive hematuria, for which the patient underwent selective angiography that showed spreading of the contrast medium from a very thin and tortuous branch of the vesical artery. after several failed attempts at selective cannulation of the vesical artery branch, the patient underwent surgical revision. ten days later, following another massive hematuria, the patient underwent endoscopic revision. on the 34th postoperative day, he was diagnosed with autoantibodies against fviii (6 u bethesda; normal range 0.55 u bethesda) by a specialized hematological laboratory. the fviii assay was 20% (normal range 60-140%). initial management was aimed at controlling acute bleeding and then eradicating the inhibitor. recombinant factor viii (rfviia, novoseven®, novo nordisk, bagsvaerd, denmark) was adopted as a primary agent, using the dose of 90 µg/kg every 4 hours when major bleeding occurred and prior to planned invasive procedures. immunosuppression was initiated with 1 mg/kg of prednisone daily. six weeks after immunosuppressive therapy, fviii autoantibodies were measured at < 0.55 u bethesda. discussion aha is a bleeding disorder in which autoantibodies, usually igg, are produced against fviii. its incidence ranges from 0.2-4 cases/million/year, but this figure may be underestimated, given the difficulty in achieving its diagnosis. when preoperative coagulation studies reveal an elevated aptt and normal pt, aha should be suspected. some patients may show a normal aptt and no bleeding during and immediately after surgery. in this cases, the development of fviii inhibitors can be viewed as a paraneoplastic phenomenon. aha is confirmed by detecting the fviii inhibitor in laboratory tests, but these tests are available only at specialized hematological laboratories. this lengthens the time needed for diagnosis, resulting in a delay in administering the appropriate anti-hemorrhagic treatment. therefore, the patient often undergoes surgical or invasive diagnostic procedures that can cause complications requiring blood transfusions. celestino cr_stesura seveso 09/10/14 10:20 pagina 227 archivio italiano di urologia e andrologia 2014; 86, 3 f. celestino, c. verri, f. de carlo, s.m di stasi 228 management principles entail controlling bleeding and then eradicating autoantibodies through immunosuppression using a combination of steroids, immunoglobulins, cyclophosphamide and monoclonal antibodies (table 1). the treatment of acute bleeding episodes involves the use of different bypassing agents, such as recombinant activated factor vii (rfviia), activated prothrombin complex concentrate (apcc, feiba®), desmopressin and human or porcine fviii concentrates. fresh frozen plasma is often ineffective, because it contains a low concentration of fviii that is quickly inactivated by antibodies. in patients with a low fviii antibody titer, desmopressin (minirin®, ferring, sweden), synthetic vasopressin analogues can be used to stop bleeding. this is due to the ability of desmopressin to release fviii from the vascular endothelium to the circulatory system. there is no optimal regimen for inhibitor eradication. the most common strategy is to use steroids alone or steroids in combination with cyclophosphamide. the average time to remission with steroids is about 5 weeks. references 1. franchini m, gandini g, di paolantonio t, mariani g. acquired hemophilia a: a concise review american journal of hematology. 2005; 80:55-63. 2. shetty s, bhave m, ghosh k. acquired hemophilia a: diagnosis, aetiology, clinical spectrum and treatment options autoimmun rev. 2011; 10:311-6. 3. reitter s, knoebl p, pabinger i, lechner k. postoperative paraneoplastic factor viii auto-antibodies in patients with solid tumours. haemophilia. 2011; 17:e889-94. correspondence francesco celestino, md (corresponding author) frapichi@libero.it policlinico casilino via casilina, 1049 00169 rome, italy home: via g. rossini, 26 81040 curti (ce), italy cristian verri, md verricris@tiscali.it francesco de carlo, md francescodecarlo03@yahoo.it savino mauro di stasi, md sdistas@tin.it department of experimental medicine and surgery tor vergata university, rome, italy table 1. algorithm of acquired hemophilia a patient management (rfviia recombinant activated factor vii (novoseven®); apcc activated prothrombin complex concentrate; vwf von willebrand factor). celestino cr_stesura seveso 09/10/14 10:20 pagina 228 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 4288 original paper evaluation of the pathologic results of prostate biopsies in terms of age, gleason score and psa level: our experience and review of the literature selcuk sarıkaya 1, mustafa resorlu 2, ural oguz 3, mustafa yordam 1, omer faruk bozkurt 1, ali unsal 1 1 keçioren training and research hospital, departmant of urology, ankara, turkey; 2 canakkale onsekiz mart university, faculty of medicine, departmant of radiology, canakkale, turkey; 3 giresun university, faculty of medicine, departmant of urology, giresun, turkey. objective: to evaluate the pathologic and clinic results of our large series of transrectal prostate biopsies in relation to gleason score, age and psa level. materials and methods: we reviewed the pathologic results of transrectal prostate biopsies performed because of high psa levels and abnormal digital rectal examination findings between january 2008 and february 2012. results: the pathologic result of 835 prostate biopsies was benign in 82.2% and malign in 17.8%. furthermore in 3.7% high grade pin (prostatic intraepitelial neoplasia) or asap (atypical small acinar proliferation) was shown. in the interval of total psa values between 4 and 10 ng/dl, that is thw so-called grey zone, cancer detection rate was 12.4%. there was a significant relationship between cancer detection and cancer stage at all high levels of psa also in the grey zone. the most common gleason score observed was 3 + 3 wirh a rate of 7.4% whereas the second most commonly observed scare was 3 + 4 with a rate of 2.5%. in the patients with abnormal digital rectal examination findings but normal psa levels according to age the cancer detection rate was 8.7%, in patients with only high psa levels the rate was 41.2% and in the patients with both high psa levels and abnormal digital rectal examination findings. the rate was 49.3%. conclusion: our study underlines the relationship between age, psa level and pathologic stage of prostate cancer and also the importance of digital rectal examination. key words: prostate biopsy; gleason score; prostate specific antigen. submitted 20 september 2014; accepted 30 november 2014 summary no conflict of interest declared. diagnosis of prostate cancer is important as it gives direction to the treatment improving long-term survival (4). serum psa level is the most commonly examination used to screen prostate cancer (5). prostate biopsy, is the main method for the diagnosis of prostate cancer and higher psa levels and abnormal digital rectal examination findings are the indications of prostate biopsy (4, 6). in the united states of america it is reported that over 1 million prostate biopsies are performed annually (3). pain, infection and hemorrage are some of the complications of transrectal ultrasonography guided prostate biopsy (6). gleason score of prostate cancer is used for determining treatment and follow-up modalities (7, 8). in this study, we reviewed the pathologic results of prostate biopsies and their relationships with gleason score, age and psa level. materials and methods the results of prostate biopsy performed between january 2008 and february 2012 were reviewed retrospectively. the indications to prostate biopsy were higher psa levels according to age and abnormal digital rectal examination findings. in our clinic, transrectal ultrasonography guided prostate biopsies were performed for the patients under the age of 50 whewn psa level was over 2.5 ng/dl, for the patients with age between 50 and 60 when psa was over 3.5 ng/dl and for the patients over the age of 60 when psa level was over 4 ng/dl. biopsies were also performed for the patients with abnormal digital rectal examination findings regardless of psa level. after digital rectal examination, biopsies were performed in the left lateral decubitus position. four ml lidocaine (2%) or prilocaine (2%) were used for local anesthesia. diposable or re-usable guides and 18-gauge biopsy needles were used for the biopsies. biopsies were performed taking 12 cores (6 for right lobe, 6 for left lobe). detailed consent forms were obtained from the patients who were given detailed information before the biopsy procedure. after the procedure the patients were directed to the uro-oncology polyclinic with the results of biopsies and treatment modalities were decided according to the results. doi: 10.4081/aiua.2014.4.288 introduction prostate cancer, is the most common cancer observed in men and when deaths due to cancer are considered, prostate cancer ranks second after the lung cancer (1, 2). in 2008, 340.000 patients were diagnosed with prostate cancer and over 70.000 deaths were reported due to prostate cancer in european union countries (3). early sarikaya_stesura seveso 22/01/15 10:01 pagina 288 289archivio italiano di urologia e andrologia 2014; 86, 4 evaluation of the pathologic results of prostate biopsies in terms of age, gleason score and psa level: our experience and review of the literature results the results of 835 prostate biopsies showed 656 benign findings (78.5%), 4 gleason 2+3 adenocarcinomas (adenoca) (0.5%), 1 gleason 3+2 adenoca (0.1%), 61 gleason 3+3 adenoca (7.4%), 21 gleason 3+4 adenoca (2.5%), 14 gleason 4+3 adenoca (1.7%), 16 gleason 4+4 adenoca (1.9%), 1 gleason 5+3 adenoca (0.1%), 20 gleason 4+5 adenoca (2.5%), 6 gleason 5+4 adenoca (0.7%) and 4 gleason 5+5 adenoca (0.4%). finally high grade pin or asap were reported in 31 patients (3.7%) (table 1). prostate cancer detection rate was 17.8% in our prostate biopsy series. there was a significant relationship between higher psa levels and cancer detection and cancer stage in the interval of total psa values between 4 and 10 ng/dl, that is the so-called grey zone, cancer detection rate was 12.4%. when the pathologic results were revie wed by the range of serum psa levels, in patients with benign prostatic hyperplasia (bph) psa level was < 4 ng/dl in 9.3%, 4-10 ng/ml in 66.8% and > 10 ng/dl in 23.9% of the patients whereas in patients with adenocarcinoma psa level was < 4 ng/dl in 4%, 4-10 ng/dl in 49.3% and > 10 ng/dl. in 52%. when pathologic data of the patients with adenocarcinoma were examined, gleason score was higher than 7 in 33% of the patients with psa level < 4 ng/dl, in 13.8% of the patients with psa level 4-10 ng/dl and in 46.7% of the patients with psa level > 10 ng/dl (table 2). when the digital rectal examination findings (dre) were reviewed, in 71% of the patients with bph dre findings were normal and in 29% were abnormal, whereas in 41.9% of the patients with adenocarcinoma digital rectal examination findings were normal and in 58.1% abnormal (p < 0.005). adenocarcinoma detection rate was 8.7% in the patients with normal psa levels but abnormal dre findings, 41.2% in the patients with normal dre findings but higher psa levels and 49.3% in the patients with both higher psa levels and abnormal dre findings. furthermore, cancer was diagnosed in 7.5% of the patients under the age of 50, 14.4% of the patients between the age of 50 and 60, 27% of the patients over the age of 70. gleason score was higher than 7 in 2.5% of the patients under the age of 50, in 3.7% of the patients with age between 50 and 70, in 10.3% of the patients over the age of 70 (p < 0.05) (table 3). discussion transrectal ultrasonography guided prostate biopsy is the main method used for diagnosing prostate cancer.9 the pathological results of 82.2% of prostate biopsies were reported as benign and in 66.8% of the cases with benign pathological results, psa levels before biopsy procedure were between 4 and 10 ng/dl. on the other hand, according to the literature reviewing the two indications to prostate biopsy, digital rectal examination is considered a subjective parameter (10). there are several studies about pathologic results of prostate biopsies performed because of high psa level and abnormal dre findings. according to the results of ojewola et al. the total average cancer detection rate was 44% and more specifically in presence of high psa level with normal dre finding the rate was 30%, in presence of normal psa level and abnormal dre finding the rate was 17% and in presence of both high psa level and abnormal dre finding the rate was 62% (11). in the study of shim et al. (12) the patients were divided in two groups: 721 patients with normal dre findings and 192 patients with abnormal dre findings. prostate cancer detection rate was higher in the group with abnormal dre findings but the result was not significant in the patients that had psa levels between 2.5 and 3.9 ng/dl and also in the patients with age between 45 and 59 (12). in another study of thompson et al, including 2950 patients, cancer detection rate was 6.6% for the patients with psa level < 0.5 ng/dl, 10.1% for the patients with psa level between 0.6 and 1 ng/dl, 17% for patients with psa level between 1.1 and 2.0 ng/dl, 23.9% for patients with psa level between 2.1 and 3.0 ng/dl and 26.9% for patients with psa level between 3.1 and 4 ng/dl. the result of this study is important as it shows that prostate cancer would be detected also at lower psa levels (13). another study by catalona et al. (14) about biopsies performed only for abnormal digital rectal findings demonstrated a cancer detection rate of 0%. this rate was 6% for the study by brawer et al. (15) and 17% for another pathologic number abnormal high psa abnormal result of patients dre level according dre (+) findings to age high psa levels 2+3 adenoca 4 3 3 2 3+2 adenoca 1 1 1 1 3+3 adenoca 61 30 54 24 3+4 adenoca 21 10 19 8 4+3 adenoca 14 8 14 8 4+4 adenoca 16 11 15 10 5+3 adenoca 1 1 1 1 4+5 adenoca 20 14 17 11 5+4 adenoca 6 6 6 6 5+5 adenoca 4 2 4 2 total 148 86 (%58.1) 134 (%90.5) 73 (%49.3) table 2. the distibution of the patients according to pathologic results and relationship between pathologic results, dre findings and psa levels. pathologic result number percentage benign 656 %78.5 2+3 adenoca 4 %0,5 3+2 adenoca 1 %0,1 3+3 adenoca 61 %7,4 3+4 adenoca 21 %2,5 4+3 adenoca 14 %1,7 4+4 adenoca 16 %1,9 5+3 adenoca 1 %0,1 4+5 adenoca 20 %2,5 5+4 adenoca 6 %0,7 5+5 adenoca 4 %0,4 asap/high pin 31 %3.7 total 835 %100 table 1. the distribution of pathologic results and gleason scores of the prostate biopsies. age 40-50 50-60 60-70 70 ↑ psa 0-4 ng/dl 5 19 23 10 4-10 ng/dl 26 112 161 130 > 10 ng/dl 9 26 113 101 total 40 157 397 241 table 3. the age distribution of psa levels. sarikaya_stesura seveso 22/01/15 10:01 pagina 289 archivio italiano di urologia e andrologia 2014; 86, 4 s. sarıkaya, m. resorlu, u. oguz, m. yordam, o. faruk bozkurt, a. unsal 290 study by mettlin et al. (16) the cancer detection rate of the biopsies performed only for high psa levels was 16% in the study by catalona et al. (14) and 19% for the study by brawer et al. (15) the review of the pathologic results of the biopsies performed for the presence of both high psa levels and abnormal dre findings showed a cancer detection rate of 33% in the study by catalona et al. (14), 16% in the study by brawer et al. (15), and 38% in the study by mettlin et al. (16). in our study, prostate cancer detection rate was 8.7% for the patients with normal psa level but abnormal dre finding, 41.2% for the patients with high psa level and normal dre and 49.3% for the patients with both high psa level and abnormal dre finding. when we look at the results of our study; the rate for the patients with only abnormal dre finding is consistent with the literature, but the rates for the patients with only high psa level or with both two indications, are higher than the rates of literature. the rate in presence of two indications was higher than in presence of only one of the indications. this results shows the importance of dre altough it is a subjective parameter. pain, hemorrhage and infection are some of the complications of prostate biopsy as it is an invasive procedure and the rate of temporary bacteriemia is 70% and the rate of bacteriuria is 53% (6, 17, 18). according to our previous observations,there was a significant relationship between presence of prostate cancer and risk of bleeding complication after prostate biopsies (19). furthermore the bleeding complication was observed at higher rates for the patients with higher gleason scores (19). serum psa level and digital rectal examination are important parameters for the diagnosis and the choice of the method of treatment of prostate cancer. the cancer detection rates are higher when are present both high psa levels according to age and abnormal digital rectal examination findings. other results of our study that are consistent with the literature, are the increase of psa levels with age and the increase of gleason score with age. there are several limitations about our study and the most important is that the free/total psa ratio was not evaluated for the patiens with the psa level between 4 and 10 ng/dl. in fact free psa values for some patients were not found and accordingly this parameter was excluded from the analysis. another important limitation was that the analysis was not extended to psa levels in the follow-up and to re-biopsy requirements for the patients with normal pathologic results. despite all these, we think that the results of this study are relevant as they show the relationship between age, psa level and pathologic stage and also the importance of digital rectal examination. references 1. alptekin a, ozgok iy, kilciler m, et al. our results of transrectal ultrasonography guided prostate biopsies. turkish journal of urology. 1998; 24:140-144. 2. jemal a, siegel r, ward e, et al. cancer statistics. cancer j clin. 2008; 58:71-96. 3. carignan a, roussy jf, lapointe v, et al. increasing risk of infectious complications after transrectal ultrasound-guided prostate biopsies: time to reassess antimicrobial prophylaxis?. eur urol. 2012; 62:453-459. 4. tuygun c, demirel f, imamoglu a, et al. comparison of two different prediction systems for calculating the prostate cancer risk before prostate biyopsy. international haematology-oncology journal. 2009; 2:75-81. 5. ozden e, inal t, kupeli s, et al. the diagnostic value of transrectal ultrasonography for detecting the prostate cancer of the patients that have psa level of < 4 ng/ml. turkish journal of urology. 2004; 30:155-159. 6. erturhan s, seckiner i, yagci f, et al. antibiotic prophlaxis for transrectal ultrasonography guided prostate biopsy: the comparison of two different antibiotics. turkish journal of urology. 2007; 33:487-490. 7. bostwick dg. grading prostate cancer. am j clin pathol. 1994; 102:38-56. 8. gleason df. classification of prostatic carcinoma. cancer chemoter rep. 1966; 50:125-8. 9. akyol i, ates f, adayener c, et al. the effects of age, prostate volume and number of cores on pain score for transrectal ultrasonography guided protate biopsy. turkish journal of urology. 2008; 34:22-26. 10. kurtulus f, fazlioglu a, evirgen m, et al. the accuracy of digital rectal examination, prostate spesific antigen, transrectal ultrasonography, psa density, free/total psa ratio for the diagnose of prostate cancer. turkish journal of urology. 2004; 30:40-44. 11. ojewola rw, tijani kh, jeje ea, et al. an evaluation of usefulness of prostate spesific antigen and digital rectal examination in the diagnosis of prostate cancer in an unscreened population:experience in an nigerian teaching hospital. west afr j med. 2013; 32:8-13. 12. shim hb, lee se, park hk, ku jh. digital rectal examination as a prostate cancer-screening method in a country with a low incidence of prostate cancer. prostate cancer and prostatic diseases. 2007; 10:250-255. 13. thompson im, pauler dk, goodman pj, et al. prevalence of prostate cancer among men with a prostate-specific antigen level ≤ 4.0 ng per milliliter. n engl j med. 2004; 350:2239-46. 14. catalona w, smith d, ratcliff t, et al. measurement of prostate specific antigen in serum as a screening test for prostate cancer. n engl j med. 1991; 324:1156-1161. 15. brawer mk, aramburu eag, chen gl, et al. the inability of psa index to enhance the predictive value of psa in the diagnosis of prostatic carcinoma. j urol. 1993; 150:369-373. 16. mettlin c, lee f, drago j, et al. the american cancer society national prostate cancer detection project finding on the detection of early prostate cancer in 2425 men. cancer. 1991; 67:2949-2958. 17. ruebush tk, mcconville jh, calia fm. a double-blind study of trimetoprim-sulfamethoxazole prophylaxis in patients having transrectal needle biopsy of the prostate. j urol. 1979; 122:492-494. 18. melekos md. eficacy of prophylactic antimicrobial regimens in preventing infectious complications after transrectal biopsy of the prostate. int urol nephrol. 1990; 22:257-262. 19. oguz u, resorlu b, bayindir m, unsal a. does existance of prostate cancer increase the risk of bleeding as a complication of transrectal ultrasonography guided prostate needle biopsies? turkish clinics j urology. 2012; 3:41-5. correspondence selcuk sarıkaya, md mustafa yordam, md omer faruk bozkurt, md ali unsal, md keçioren training and research hospital, departmant of urology, ankara, turkey mustafa resorlu,md mustafaresorlu77@gmail.com canakkale onsekiz mart university, faculty of medicine, departmant of radiology, terzioglu yerleskesi, barbaros mh, 17100, canakkale ural oguz, md giresun university, faculty of medicine, departmant of urology, giresun, turkey sarikaya_stesura seveso 15/01/15 13:20 pagina 290 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 3164 review is there a place for nutritional supplements in the treatment of idiopathic male infertility? davide arcaniolo 1, vincenzo favilla 2, daniele tiscione 3, francesca pisano 4, giorgio bozzini 5, massimiliano creta 1, giorgio gentile 6, filippo menchini fabris 7, nicola pavan 8, italo antonio veneziano 9, tommaso cai 4 on behalf of young commision of italian andrological society (sia) 1 department of urology, university of federico ii, naples, italy; 2 department of urology, university of catania, catania, italy; 3 department of urology, santa chiara hospital, trento, italy; 4 department of urology, university of turin, turin, italy; 5 department of urology, istituto di ricovero e cura a carattere scientifico, policlinico san donato, university of milan, milan, italy; 6 department of urology, azienda ospedaliero-universitaria policlinico s.orsola-malpighi, bologna; 7 department of urology, university of pisa, pisa, italy; 8 department of urology, university of trieste, trieste, italy; 9 department of urology, ospedale madonna delle grazie, matera, italy. objective: infertility affects 15% of couples in fertile age. male factor is a cause of infertility in almost half of cases, mainly due to oligoasthenoteratozoospermia (oat). the purpose of this study is to review the effects of nutritional supplements as medical treatment for idiopathic male infertility. material and methods: a pub med and medline review of the published studies utilizing nutritional supplements for the treatment of male infertility has been performed. results: clinical trials on vitamin e, vitamin a, vitamin c. arginine, carnitine, n-acetyl-carnitine, glutathione, coenzyme q10, selenium and zinc were reviewed. although there is a wide variability in selected population, dose regimen and final outcomes, nutritional supplements both alone and in combination seems to be able to improve semen parameters (sperm count, sperm motility and morphology) and pregnancy rate in infertile men. conclusions: there are rising evidences from published randomized trials and systematic review suggesting that nutritional supplementation may improve semen parameters and the likelihood of pregnancy in men affected by oat. this improvement, however, is not consistent and there is a wide variation in the treatment regimens used. well designed and adequately powered rcts are needed to better clarify the role of nutritional supplements as treatment for male infertility. key words: phytotherapy; male fertility; oligoasthenotera tozoospermia; n-acetyl-carnitine; vitamin e; semen parameters. submitted 15 july 2014; accepted 31 july 2014 summary no conflict of interest declared. introduction almost 15% of all couples trying to conceive are affected by infertility and seek treatment for this condition (1). in a 50% of childless couples, it is possible to recognize a male-infertility-associated factor (2). male infertility could be consequence of some definable conditions (varicocele, cryptorchidism, hypogonadism, genetic abnormalities), but in 30-40% of infertile male no cause may be determined. such idiopathic infertility is characterized by a decreased number of spermatozoa, decreased sperm motility and abnormal sperm morphology in men with no history of diseases impairing fertility and with normal findings on physical examination and laboratory testing (3). idiopathic oligoasthenoteratozoospermia is supposed to be determined by several causes, including endocrine disorders, genetic abnormalities or reactive oxygen species (4). high ros level and oxidative stress have been implicated in the pathophysiology of male infertility (5) and correlated with sperm dna damage, reduced sperm motility, impaired fertilization and embryo development (6, 7). ros affect sperm function as they damage lipids, amino acids, carbohydrates, protein, and dna of the spermatozoa (8). in human ejaculate there are some endogenous antioxidants, but many studies have shown that seminal antioxidant capacity is suppressed in infertile men with high ros levels compared to men with normal levels of ros (9, 10). many medical therapies have been historically used for male fertility, including herbs, vitamins, and nutritional supplements, and many of them rely on antioxidant properties. according to eau guidelines on male infertility there is little scientific evidence for an empirical approach and medical therapy should be reserved only in case of hypogonadotropic hypogonadism (4). doi: 10.4081/aiua.2014.3.164 arcaniolo_stesura seveso 09/10/14 10:23 pagina 164 165archivio italiano di urologia e andrologia 2014; 86, 3 phytoterapy and idiopathic male infertility treatment the aim of this manuscript is to accurately review the role of nutritional supplements in the treatment of male infertility, evaluating their effect on semen parameters and pregnancy rate. materials and methods the medline database was searched using pubmed with various keywords, including various combinations of search terms. “male infertility”, “nutraceuticals”, “nutritional supplements”, “antioxidants” and “antioxidant therapy” were the most relevant search terms, combined via boolean operators. from the numerous search results, studies were selected on the basis of their quality: studies that were biased, incomplete or otherwise considered untrustworthy were excluded. data were analyzed in order to provide a complete overview of the literature. results vitamin e vitamin e is a fat-soluble vitamin belonging to the tocopherol family. it acts inhibiting free-radical-induced damage to cell membranes, preventing lipid peroxidation and improving the activity of other antioxidants. (11, 12). it has been demonstrated that vitamin e is able to decrease seminal ros in infertile males and there are some epidemiological data that support a direct correlation between improvement of seminal parameters and increased dietary intake of vitamin e. (13-15). vitamin e has been widely used for the treatment of male infertility and many randomized controlled trials have been performed to assess the effect of this compound in infertile men. pre-clinical evidences demonstrated that vitamin e alone or in combination with vitamin c is able to reduce lipid peroxidation, improve dna fragmentation and improve binding of the spermatozoa to the zona pellucida (13, 16, 17). however, often these data “in vitro” do not correlate with clinical evidences. suleiman et al. demonstrated increased sperm motility, with 21% of couples treated with 300 mg of vitamin e achieved pregnancy compared with 0% in the placebo group, but kessopoulou et al. failed to demonstrate an improvement in semen parameters or seminal ros levels compared to placebo. a recent trial assessed the synergic effect of vitamin e, coenzyme q10 and vitamin c in men with oat. authors demonstrated an improvement of sperm count and sperm motility after 3 and 6 months of treatment with a pregnancy rate of 28%. the big limitation of this trial is the lack of a control group. (18). vitamin c vitamin c is a water soluble vitamin that act as a potent antioxidant. it is involved in the synthesis of collagen, proteoglycans, and components of the intercellular matrix (19). few studies have been published using vitamin c alone in the treatment of male infertility. so any possible effect on semen parameters could be the effect of synergistic combinations of vitamin c and other antioxidants like vitamin e, beta carotene, zinc, selenium, etc (15, 20, 21). in vitro studies demonstrated that vitamin c plays a crucial role in preserving sperm from oxidative damage and reducing dna fragmentation (17, 22, 23). dawson et coll. demonstrated the effectiveness of high dose supplementation of vitamin c (1000 mg/die), compared to placebo, in improving sperm quality (count and viability, motility and morphology) in heavy smokers (24). vitamin a vitamin a is a fat-soluble vitamin with a slight antioxidant activity (25). there is a lack of studies investigating the effect of vitamin a alone in male fertility. combined treatment with vitamin a and other nutraceuticals (vitamin e, zinc, selenium, vitamin c) can improve sperm motility up to 30% in infertile man (26) and sperm count after varicocele repair (27). arginine arginine is a semi-essential amino acid which is involved in various human biochemical process as ammonia detoxification, hormone secretion and immune modulation. it is also a precursor of nitric oxide (no) (28) and it is necessary for the synthesis of putrescine, spermidine, and spermine, which are thought to be essential to sperm motility (29). many studies have been carried out to investigate the role of arginine supplementation in male infertility, but to date it is not possible to give evidence-based recommendation on its use. some historical studies have reported that arginine can improve sperm concentration and motility (30-32), while others have failed to demonstrate any improvement in semen parameters or pregnancy rates (33, 34). there is a lack of recent, well-designed studies on arginine supplementation in male infertility, so it is difficult to conclude definitively that arginine supplementation improves male fertility. carnitine carnitines are amines derived from the synthesis of lysine and methionine. carnitines stimulate both fatty acid breakdown and glycolysis in sertoli cells (35) and have an antioxidant effect protecting cells from ros. lcarnitine and l-acetylcarnitine are concentrated in the epididymis, spermatozoa, and seminal plasma (36). carnitines are the most studied nutritional supplements for the treatment of idiopathic male infertility. lenzi et al. demonstrated an increase in all sperm parameters and in pregnancy rate after combined carnitine treatment (2 g/d l-carnitine and 1 g/d l-acetyl-carnitine for 6 months) in 60 men suffering from oat, compared to placebo. the most significant improvement was observed in sperm motility in patients who had lower initial absolute values of motile sperm (37). similarly, balercia et al showed a significant improvement in both sperm motility and morphology in men treated with lcarnitine or l-acetyl-carnitine supplementation, for 24 weeks compared to placebo (38). the role of carnitines in patient with varicocele-associated oat has been investigated by cavallini et al. in a placebo controlled randomized study (39). pregnancy rates increased in patients treated with carnitine alone or in combination with cinnoxicam, over the placebo arm. in addition, improvements in sperm concentration, motility and arcaniolo_stesura seveso 09/10/14 10:23 pagina 165 archivio italiano di urologia e andrologia 2014; 86, 3 d. arcaniolo, v. favilla, d. tiscione, f. pisano, g. bozzini, m. creta, g. gentile, f. menchini fabris, n. pavan, et al. 166 morphology were observed in patients with no varicocele or small or moderate-grade varicoceles treated with carnitine, alone or in combination with cinnoxicam, while no improvement was noted in those with large varicoceles. the combination of carnitine and nonsteroidal anti-inflammatory drugs resulted effective also in improving semen parameters in men with abacterial prostatovesiculoepididymitis and elevated seminal leukocyte concentrations (36). other studies confirmed the positive effect of carnitine therapy on sperm count and motility (40-44). nevertheless sigman et al. in a randomized placebo controlled trial showed no improvements of semen parameters in men treated with carnitines (45). more recently, busetto et al. demonstrated the beneficial effect of an antioxidant complex containing carnitines (l-carnitine, acetyl-l-carnitine, fructose, citric acid, selenium, coenzyme q10, zinc, ascorbic acid, cyanocobalamin, folic acid) in improving sperm progressive motility compared to baseline (46). coenzyme q-10 coenzyme q-10 (coq10) acts as an electron carrier in the mitochondrial respiratory chain (hidaka et al., 2008) and therefore it is involved in mitochondrial bioenergetics, which is important in sperm maturation (47). some studies in the past showed a positive effect of coq10 in improving sperm concentration and motility, although no differences in pregnancy rate were found (48-50). a more recent small trial demonstrated the effectiveness of coq10 in improving semen parameters in men with varicocele (51). two big randomized placebo-controlled trials confirmed that coq10 and its reduced form, ubiquinol, are safe and effective in improving sperm density, sperm motility and sperm morphology in men with unexplained infertility compared to placebo arm. patients treated with coq10 and ubiquinol presented higher catalase and sod, higher inibin b levels and lower fsh if compared to placebo (52, 53). safarinejad et al. found also a partner pregnancy rate of 34% in infertile men with idiopathic oat treated with coq10, but this study lack of a control group (54). a recent metaanalysis concluded that there is no evidence in the literature that coq10 increases either live birth or pregnancy rates, but there is a global improvement in sperm parameters (55). glutathione glutathione plays a significant role in the antioxidant defences of the spermatogenic epithelium, the epididymis, and perhaps in ejaculated spermatozoa. it is produced endogenously in the liver and is one of the most abundant antioxidants found in the body (56) few and dated studies have been published on the role of glutathione in male infertility. these data showed improved sperm motility, sperm concentration and decreased sperm dna fragmentation in infertile men treated with glutathione or a combination of glutathione and other antioxidants (56-58). intramuscular glutathione therapy resulted effective in increasing sperm motility in patients suffering from varicocele (57). glutathione is not well adsorbed in gastrointestinal tract and the parenteral use represents the major limitation for this therapy. n-acetylcysteine nac is an amino acid precursor to glutathione and acts as ros scavenger (59) (zembron-lacny et al., 2009). in vitro data showed a positive effect of nac in improving total sperm motility and reducing ros levels (60). in a randomized placebo-controlled trial, conducted in 120 men with idiopathic infertility, has been demonstrated that nac therapy (600 mg/daily for 3 months) significantly increase seminal volume, sperm motility and viscosity (61). another randomized trial confirmed the beneficial role of nac alone or in combination with selenium in improving all semen parameters if compared to baseline and placebo treatment (62). combination therapy with selenium resulted in a significant improvement of sperm count, motility and morphology, suggesting a synergistic effect. selenium selenium is an essential trace element which is involved in antioxidant reactions (63) and it seems to be necessary for normal testicular development, spermatogenesis, and the process of sperm capacitation (64). as previously described, selenium alone or in combination with other antioxidants can ameliorate sperm count, motility, and morphology (62) and many other studies confirmed the synergic activity of selenium combined with other nutraceuticals like vitamin e (65-67). selenium demonstrated positive effects on male infertility, which appear synergistic when used with other supplements. optimal dosing appears to be between 100 and 210 mg on the basis of the studies above. zinc zinc is a trace mineral essential for normal functioning of the male reproductive system. it plays a role in testicular steroidogenesis, testicular development, spermatozoa oxygen consumption, nuclear chromatin condensation, the acrosome reaction, acrosin activity, sperm chromatin stabilization, and conversion of testosterone to 5a-dihydrotestosterone (68). many biochemical mechanism are zinc-dependent and it acts as cofactor for more than 200 enzyme in the whole body, including those involved in dna transcription and protein synthesis (68). zinc deficiency is related to oligospermia, hypogonadism and compromised immune system function (69). in addition, zinc deficiency is involved in the pathogenesis of oligoasthenospermia in diabetic patients (70). a prospective randomized controlled study was carried out to investigate the effects of zinc sulfate, folic acid and combination of both on sperm quality, protamine content and acrosomal integrity after surgical treatment of varicocele. researchers concluded that co-administration of zinc and folic acid significantly improved sperm parameters and increased varicocelectomy outcomes (71). more recently, raigani et al. investigated in a randomised, double-blind, placebo-controlled clinical trial, the effects of folic acid and zinc sulphate supplementation on the improvement of sperm function in subfertile oligoasthenoteratozoospermic men. this study failed to demonstrate that zinc sulphate and folic acid supplementation ameliorate sperm quality in infertile men with severely compromised sperm parameters (72). arcaniolo_stesura seveso 09/10/14 10:23 pagina 166 167archivio italiano di urologia e andrologia 2014; 86, 3 phytoterapy and idiopathic male infertility treatment discussion despite the big amount of studies published on nutraceuticals and male infertility, to date it is not possible to give any recommendation about their use as therapy in infertile male. a significant number of studies lack randomization and placebo-controlled arms and in many cases the pregnancy rate is not the primary endpoint. additionally, many studies have been unable to control or account for dietary intake of potential fertility-affecting food sources. in fact, usually a balanced diet cannot make it necessary the supplementation. another limitation of the proposed studies is the inherent tendency of biological fluctuation in consecutive semen samples from the same individual, the geographical variation in semen quality, the lack of standardization in carrying out the tests used in assessing semen variables and the intra-observer and inter-observer semen assessment bias. nevertheless, based upon the results of the selected studies, it seems that selective supplementation with nutritional supplements could have beneficial consequences on sperm parameters, even if there is a wide range of dosing regimens used across the different trials. unfortunately, the clinical heterogeneity of the included studies meant a meta-analysis of their results could not be performed. a systematic review published by ross et al. in 2010, selected 17 randomized trial to evaluate the effects of oral antioxidants on sperm quality and pregnancy rate in infertile men. their results showed that treatment of infertile men with oral antioxidants reduces seminal oxidative stress and could improve sperm motility, but has a less predictable impact on sperm concentration and morphology. furthermore, oral antioxidant therapy was associated with a significant improvement in spontaneous and assisted conception pregnancy rates in 6 out of the 10 randomized studies included in the analysis (14). the role of antioxidants therapy for the treatment of male infertility has been reviewed extensively by the cochrane collaboration (73). the primary end point of this review was to identify whether supplementation with oral antioxidants would improve outcomes of assisted reproductive techniques when used in male partners of couples undergoing assisted reproduction techniques (art), while secondary endpoint was to assess how antioxidants may influence pregnancy rate, sperm parameters and sperm dna fragmentation. 34 trials were included in the pooled analysis with 2876 couples in total. antioxidants therapy is associated with a statistically significant increase in live birth rate (or 4.85, 95% ci 1.92 to 12.24; p = 0.0008) and in pregnancy rates (or 4.18, 95% ci 2.65 to 6.59; p < 0.00001), if compared with the men in control group. however, authors stated that it is not possible to draw conclusions on the effect of antioxidants on sperm parameters, due to the very poor quality of evidence in the reviewed trials and concluded that antioxidant supplementation might improve live birth and pregnancy rate outcomes for subfertile couples undergoing art in addition, data from this review are not sufficient to draw any conclusions from the head to head comparisons between antioxidants. so, to date, one antioxidant did not appear to have any effect on pregnancy rate per couple or sperm parameters over those of another antioxidant (73). starting from 2013, eau guidelines changed their recommendation according to these findings (4). more recently, clark et al. reviewed 37 rcts on complementary and alternative medicine, including antioxidant and nutritional supplements, for the treatment of male infertility. they concluded that despite some preliminary evidences of the effectiveness of cam interventions among infertile patients, there is a need for further investigation before they can be considered for routine clinical use (74). the same conclusions have been reached by imamovic kumalic et al. they reviewed 32 studies from 2000 to 2013 and found that the majority of these studies confirmed beneficial effect of antioxidants on at least one of the semen parameters, with the most relevant effect on sperm motility, confirming a possible role of nutritional supplements for the treatment of idiopathic oligoasthenoteratozoospermia (75). comhair et al. evaluated the clinical efficacy of different treatment for male infertility by calculating the numbers needed to treat (nnt) in 4143 infertile couples, based on controlled trials. antioxidant therapy resulted in a nnt of 7.8, while varicocele treatment yielded a nnt of 6.3. the nnt of the combination of varicocele treatment with nutraceuticals supplementation was 2.6 and combination of nutraceuticals and ivf had a nnt of 4.0. so authors concluded that there may be a trend for the use of nfs to improve the success rate of varicocele treatment and of ivf (76). nutritional supplements are usually well tolerated and must be considered safe, nevertheless there are some possible dose-related adverse events that must be taken into consideration (table 1). conclusions even if it is not possible to give any firm recommendation about nutritional supplementation for the treatment of idiopathic male infertility, rising evidences from randomized trials and systematic review suggests that oral antioxidant supplementation may improve semen parameters and the likelihood of pregnancy. this improvement, however, is not consistent and there is a wide variation in the treatment regimens used. there is therefore a need to plan further large randomized controlled studies, with clear inclusion/exclusion criteria, to evaluate the effect of standardized doses of specific antioxidants on both spontaneous and assisted conception pregnancy rates, in order to select the population that could benefit from oral antioxidants therapy. references 1. 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of nutritional supplements in primary infertile patients with idiopathic astenoteratozoospermia arch ital urol androl. 2012; 84:137-40. 47. littarru gp, tiano l. clinical aspects of coenzyme q10: an update. nutrition. 2010; 26:250-254. 48. balercia g, buldreghini e, vignini a, et al. coenzyme q10 treatment in infertile men with idiopathic asthenozoospermia: a placebo-controlled, double-blind randomized trial. fertil steril. 2009; 91:1785-1792. 49. balercia g, mancini a, paggi f, et al. coenzyme q10 and male infertility. j endocrinol invest. 2009; 32:626-692. 50. safarinejad mr. efficacy of coenzyme q10 on semen parameters, sperm function and reproductive hormones in infertile men. j urol. 2009; 182:237-248. 51. festa r, giacchi e, raimondo s, et al. coenzyme q10 supplementation in infertile men with low-grade varicocele: an open, uncontrolled pilot study andrologia. 2013 aug 22 doi: 10.1111/and.12152. 52. safarinejad mr, safarinejad s, shafiei n, safarinejad s. effects of the reduced 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63. brown km, arthur jr. selenium, selenoproteins and human health: a review. public health nutr. 2001; 4:593-599. 64. ursini f, heim s, kiess m, et al. dual function of the selenoprotein phgpx during sperm maturation. science. 1999; 285:1393-1396. 65. burton gw, traber mg. vitamin e: antioxidant activity, biokinetics, and bioavailability. annu rev nutr. 1990; 10:357-382. 66. vezina d, mauffette f, roberts kd, bleau g. selenium-vitamin e supplementation in infertile men. effects on semen parameters and micronutrient levels and distribution. biol trace elem res.1996; 53:65-83. 67. keskes-ammar l, feki-chakroun n, rebai t, et al. sperm oxidative stress and the effect of an oral vitamin e and selenium supplement on semen quality in infertile men. arch androl. 2003; 49:83-94. 68. ebisch im, thomas cm, peters wh, et al. the importance of folate, zinc and antioxidants in the pathogenesis and prevention of subfertility. hum reprod (oxf). 2007; 13:163-174. 69. prasad as. zinc in human health: effect of zinc on immune cells. mol med. 2008; 14:353-357. 70. zhao y1, zhao h, zhai x, et al. effects of zn deficiency, antioxidants, and low-dose radiation on diabetic oxidative damage and cell death in the testis. toxicol mech methods. 2013; 23:42-7. 71. azizollahi g, azizollahi s, babaei h, et al. effects of supplement therapy on sperm parameters, protamine content and acrosomal integrity of varicocelectomized subjects. j assist reprod genet. 2013; 30:593-9. 72. raigani m, yaghmaei b, amirjannti n, et al. the micronutrient supplements, zinc sulphate and folic acid, did not ameliorate sperm functional parameters in oligoasthenoteratozoospermic men. andrologia. 2013 oct 23. 73. showell mg, brown j, yazdani a, et al. antioxidants for male subfertility. cochrane database syst rev. 2011; 1:cd007411. 74. clark na, will m, moravek mb, fisseha s. a systematic review of the evidence for complementary and alternative medicine in infertility. int j gynaecol obstet. 2013; 122:202-6. 75. imamovic kumalic s, pinter b. review of clinical trials on oligoasthenoteratozoospermia. biomed res int. 2014; 2014:426951. 76. comhaire f, decleer w. comparing the effectiveness of infertility treatments by numbers needed to treat (nnt). andrologia. 2012; 44:401-4. correspondence davide arcaniolo, md massimiliano creta, md max.creta@gmail.com department of urology, university of federico ii, naples, italy vincenzo favilla, md department of urology, university of catania, catania, italy daniele tiscione, md tommaso cai, md ktommy@libero.it department of urology, santa chiara hospital, trento, italy francesca pisano, md department of urology, university of turin, turin, italy giorgio bozzini, md department of urology, istituto di ricovero e cura a carattere scientifico, policlinico san donato, university of milan, milan, italy massimiliano creta, md department of urology, university of federico ii, naples, italy giorgio gentile, md department of urology, azienda ospedaliero-universitaria policlinico s.orsola-malpighi, bologna, italy filippo menchini fabris, md department of urology, university of pisa, pisa, italy nicola pavan, md department of urology, university of trieste, trieste, italy italo antonio veneziano, md department of urology, ospedale madonna delle grazie, matera, italy arcaniolo_stesura seveso 09/10/14 10:23 pagina 170 microsoft word 04barozzi.docx no conflict of interest declared. 319 archivio italiano di urologia e andrologia 2014; 86, 4 presented at 19th national congress sieun, fermo 2014 review contrast enhanced ultrasound in the assessment of urogenital pathology libero barozzi 1, diana capannelli 2, michele imbriani 1 doi: 10.4081/aiua.2014.4.319 1 department of diagnostic imaging, radiology unit, maggiore hospital, bologna, italy; 2 cardio-thoracic-vascular department, radiology unit, university of bologna, policlinico sant’orsola-malpighi, bologna, italy. . summary contrast enhanced ultrasound (ceus) is an innovative technique that ceus also allows evaluation of renal ischemia, infections and trauma. employs microbubble contrast agents to demonstrate parenchymal perfusion. although initial clinical applica tion was focused on the liver pathology, a wide variety of clinical conditions can be assessed now with ceus. ceus is a well-tolerated technique and is acquiring an increasing role in the assessment of renal pathology because contrast agents are not excreted by the kidney and do not affect the renal function. ceus demonstrated an accuracy similar to contrast enhanced multi-detector computed tomography (ce mdct) in detecting focal lesions, with the advantage of the real-time assessment of microvascular perfusion by using time-intensity curves. the aim of this paper is to review the main indications of ceus in the assessment of renal and urogenital pathology. imaging examples are presented and described. advantages and limitations of ceus with ref erence to conventional us and ce-mdct are discussed. key words: ultrasonography; contrast enhanced ultrasonography; urology. submitted 3 october 2014; accepted 31 october 2014 introduction ceus contrast enhancement ultrasound (ceus) is a new tech nique that employs microbubble contrast agents and complementary harmonic pulse sequences to demon strate parenchymal perfusion. ceus is widely employed in several fields of clinical prac tice the 2011 updated european federation of societies of ultrasound in medicine and biology (efsumb) guidelines and recommendations on the clinical practice of ceus have identified the current indications for the administra tion of us contrast agents for the study of different parts of the body, including the kidneys (1). ceus is useful in the detection and characterization of lesions, by differentiating solid neoplastic masses from pseudotumors or by graduating complex cystic lesions according with the bosniak system (2, 3). ceus allows a real-time multiplanar evaluation of microvasculature, which colour doppler ultrasound can not detect: it is useful to characterize the perfusional pat tern of solid lesions (arterial and late phase). other advantages of ceus include its safety, simplicity, patient tolerance, lack of irradiation (conversely to ce-mdct scans) (4-6). microbubble contrast agents are not excret ed by the kidney and do not affect renal function: they can be safely administrated to patients with renal insuf ficiency. current contraindications are known hypersen sitivity to any of the contrast agent components (even if ultrasound contrast agents have low rate of anaphylactic reactions) and recent acute cardiopulmonary diseases. the main limit of this technique in the urinary tract assessment is that contrast agents are not concentrated in the collecting system and ceus cannot give information about urinary excretory system. ceus also have the same limitations of conventional ultrasound (us): poor sonic window due to bowel gas, ribs or patients with large body habitus (obesity) prevents good quality images. in these cases, ce-mdct can give more information. microbubble contrast agents microbubble contrast agents consists of gas microbubbles (air or perfluorocarbon) stabilized by a biodegradable shell of protein, lipid or polymer. the small size of microbubbles (from 1 to 10 micrometres, as the size of a red blood cell) allows their passage unfiltered through the lungs but prevents entry into the interstitium allowing them to remain entirely intravascular (“pure blood pool” agents) (4-5, 7). under us exposition, microbubbles oscillatory contract and expand themselves with the same resonance frequency of us waves, by amplifying the us signal. after circulating for several minutes, microbubbles dissolves: the gas is exhaled by the lungs whereas the biodegradable shell is metabolised by the liver. technique kidney has a single arterial blood supply, conversely to the liver. after endovascular bolus injection of the con trast agent, microbubbles diffuse to the blood pool. at first, it can be detected an arterial phase with corti comedullary differentiation lasting for 20-40 seconds. 320 archivio italiano di urologia e andrologia 2014; 86, 4 l. barozzi, d. capannelli, m. imbriani during the later phase (45-120 sec), the enhancement is homogeneous and the differentiation between cortex and medulla is lost. the lesion contrast enhancement is eval uated in comparison with the surrounding parenchyma (4). kidneys are highly vascularized and the contrast enhancement is faster than other abdominal organs: this allows the characterization of renal parenchyma but also the evaluation of liver (in the remaining 3 minutes after kidneys) and spleen (that retrains the contrast agent for as long as 7 minutes). kidney renal infections the diagnosis of acute pyelonephritis is based on clinical evaluation and laboratory findings (1). conventional baseline us demonstrates increased size of the kidney and cortical scarring, suggestive of previous episodes of infections. ceus has an important role when the patient is still febrile after 72 hours despite of antibiotic treat ment and a complicated pyelonephritis is suspected. as ce-mdct, ceus can show focal parenchymal areas of pyelonephritis that appear as wedge-shaped areas of reduced enhancement because of the parenchymal oede ma (figure 1). sometimes pyelonephritis can complicate with parenchy mal abscessualization: a focal inhomogeneous non enhancing area with intense peripheral uptake (figure 2). purulent material in pelvicalyceal system can be easily detected as echogenic material with no contrast uptake, since contrast agents are not concentrated in the collect ing system. this finding is useful to differentiate pus from uro-endothelial tumours (5). renal ischaemia kidney has an abundant blood flow but can undergo a variety of vascular injuries. ceus demonstrates high accuracy in detecting kidney parenchymal ischaemia, comparable to ce-mdct. ceus shows a higher sensibility in comparison to colour doppler by detecting smaller blood vessels with slower blood flow. microbubbles reach the microvasculature and amplify the us signal, allowing a direct evaluation of parenchy mal perfusion. renal ischaemia appears as a triangular o wedge-shaped area with no contrast uptake, easily detectable in comparison to the surrounding normal parenchyma (figure 3). ceus may also provide more precise information about tissue vitality: it can differentiate infarcts from areas of diminished perfusion. even if both injuries appear at colour doppler as non-vascularized areas, the key find ing is that only infarcts show complete lack of contrast enhancement after injection. kidney transplant the renal transplant represent the ideal application of ceus because the organ is superficial and well vascular ized. renal transplant can undergo a wide range of possi ble complications in the early post-operative period. the main important is the acute rejection. figure 1. contrast enhancement ct shows an inhomogeneous parenchymal enhancement due to the presence of parenchymal oedema (a). baseline us (b) demonstrates a wedge-shaped ipoechogenic area with poor vascularization on colour doppler evaluation (c). ceus confirms the lack of contrast enhancement in this area (d). figure 2. abscessualization. ceus shows a poor-defined area of lack of contrast with an early and intense peripheral enhancement. a b figure 3. baseline us examination shows an ipoechogenic area involving the upper pole of the right kidney (a). ceus demonstrates a well-defined, triangular-shaped area of enhancement defect, suggestive of renal ischaemia (b). the first-line evaluation is typically performed with spec tral doppler measurements in order to assess abnormal values in resistance index (ri). contrast enhanced ultrasound in the assessment of urogenital pathology 321 archivio italiano di urologia e andrologia 2014; 86, 4 figure 4. normal kidney transplant: regular and homogeneous perfusion (a). acute rejection in kidney transplant: ceus demonstrates a dishomogeneous perfusion (b). figure 6. contrast enhancement ct scan shows a complicated cystic lesion with diffuse/smooth contrast enhancement (a). colour doppler examination demonstrate a heterogeneous mass with ipoechoic and fluid component without significant vascular apply (b). ceus reveals an internal enhancing soft tissue component, suggestive of bosniak iv category (c). spectral doppler assess ment only provide indi rect information about the parenchymal perfu sion, whereas micro bubble contrast agents allow a direct visualiza tion of microcircula tion. ceus findings are also earlier than abnormal ri (8 10). in acute rejection, the parenchymal perfusion is delayed. the time-intensity curves can demonstrate a diffuse delayed and slow contrast enhancement of the renal parenchyma. in a later phase, ceus can also show perfusional defects (figure 4). ceus is also useful in monitoring the anti-rejection therapy, by assessing an improved parenchymal perfusion (11). cystic lesions renal cysts are a common finding, but any cyst that does not show the typical features of a benign cyst is by defi nition “complicated” and requires further assessment. ceus can be useful in differentiating benign cysts from cystic tumours. even if the bosniak classification system was developed on the basis of contrast-enhancement findings of cystic renal masses on ce-mdct (2-3), ceus can provide useful information for the manage ment of these lesions: surgical treatment or observation. ceus is acquiring an increasing role in the assessment of indeterminate cystic lesions (bosniak iif and iii) by detecting the presence and the enhancement of solid components. recent comparative studies (12) between ceus and ct revealed that ceus imaging was superior figure 5. contrast enhancement ct scan shows a complicated cystic lesion with grossly thicked walls (a), well marginated, without significant ce of the walls (b), suggestive of bosniak category iii. baseline us examination shows echoic content (solid/haemorrhagic echo in the liquid content of the cyst) and confirms the ct finding of thicked walls (c). ceus demonstrates a well enhancing mural nodule (arrow) within the lesion, suggestive of bosniak iv category (d). to ct in term of detecting additional septa, thickness of the wall or septa and solid components. microbubble contrast agents circulate in the micro vessels of septa and walls and ceus provides the evaluation of sophisticated internal structures of cystic renal masses with a higher resolution than ct. in particular, the demonstration of solid components is the key factor in differential with the categories iii and iv, that are considered malignant and must be surgically removed (figures 5, 6). solid masses the majority of renal tumours are renal cell carcinomas, whereas oncocytomas and angiomyolipomas represent a small part of renal solid lesions. renal malignancies have a rich blood supply and ceus can show an increased and heterogeneous enhancement (figure 7), fast filling and rapid wash-out (figure 8). however, the kidney itself has abundant blood supply and the lesion may appear isoechoic to the surrounding renal cortex (5, 13). ceus is not currently used for differentiating between benign and malignant solid lesions. even if several stud ies propose new methods for qualitative and quantitative assessment of contrast enhancement, solid malignancies does not show a specific perfusion pattern (5, 14). ceus may provide useful information in case of haem orrhage by detecting an underlined lesion into the haematoma that appear to conventional us evaluation as a large heterogeneous mass. another important role of ceus is to differentiate pseudo tumors (or renal column dysplasia) from solid malignan figure 7. contrast enhancement ct scan shows a heterogeneous solid lesion, with intense peripheric enhancement (a). colour doppler examination shows an increased vascularization, both intralesional and peripherical (b). ceus demonstrates an intense peripherical hyperenhancement, suggestive of renal clear cell carcinoma (c). l. barozzi, d. capannelli, m. imbriani 322 archivio italiano di urologia e andrologia 2014; 86, 4 figure 8. time-intensity curves display two different pattern of solid lesion contrast enhancement. in the first case (a), the red roi was drawn in a suspicious area whereas the yellow roi was drawn in an area representing the normal renal cortex. the red time-intensity curve shows a higher fast filling hyperenhancement with reference to the normal renal parenchyma, suggestive of renal clear cell carcinoma. whereas in the second case (b), the red time-intensity curve show a later and lower enhancement with reference to the normal cortex, suggestive of ipovascularizated solid malignant lesion. figure 10. baseline us examination (a) is inadequate to detect renal laceration because it is isoechoic to the surrounding parenchyma. colour doppler (b) shows a relative homogeneous perfusion. after contrast injection, ceus demonstrates a filling defect due to parenchymal laceration (c, d). a b figure 9. baseline us examination (a) shows an ipoechoic mass, suggestive of a solid occupying lesion. ceus reveal a normal intravascular flow within this region, with homogeneous vascular enhancement without vessels distortion, suggestive of renal column dysplasia (b). cies. renal column hypertrophy is a congenital renal dys plasia that mimic a solid lesion of the cortex. ceus demon strates normal courses of renal vessels without an occupy ing lesion and a dynamic pattern of contrast enhancement identical to the surrounding parenchyma (figure 9). trauma ceus with second-generation contrast agents shows a high sensitivity both in lesion detection and grading, but ceus should be reserved for the assessment of stable, low-energy isolated trauma patients with unilateral pain. these patients have low risk for multi-organ and severe traumatic involvement, are haemodynamically stable and can be conservatively treated and evaluated during the follow-up (15-16). instead, the modality of choice for the first-line evalua tion in emergency room of severe traumatic patients is the conventional fast (focus assessment with sonography in trauma) us. fast-us allows to exclude free abdomi nal, pleural and pericardial fluids, but it has low sensi tivity in detection of parenchymal traumatic lesions, which may be isoechoic and can be missed (17). ce-mdct remains the reference examination in high energy multitrauma because of high spatial resolution, very fast execution and higher sensibility. ce-mdct also allows to exclude active bleeding, multitraumatic involvement of deep organs (pancreatic trauma) and gut perforations. the main indication ceus is in the second line evaluation of patients with low-energy isolated abdominal trauma. ceus demonstrates an accuracy sim ilar to ce-mdct in detecting and grading renal trau matic lesions. parenchymal lacerations and haematomas appear as non-enhancing areas after contrast injection (figure 10). the main limit of ceus in kidney traumat ic lesions is the impossibility to visualize pelvicalyceal and ureter injuries, since contrast agents are not concen trated in the collecting system. in these cases, ce-mdct should be always performed in ceus-positive patients to exclude active bleeding and urinomas. urinary excretory system the main limit of ceus in urinary excretory system is that contrast agents are not concentrated in the collect ing system and only voluminous pelvicalyceal neoplastic masses can be detected. ceus is also acquiring an increasing role in the assess ment of vesicoureteral reflux in children, because of the safety of the technique and the lack of irradiation (con versely to retrograde cystourethrography). after intra bladder administration of microbubble, ceus is able to assess and quantify the grade of vesicoureteral reflux. urethra can also be involved in coital trauma. the intraurethral administration of microbubble constrast agent may improve the visualization of traumatic lesions or the detection of active urine extravasion. prostate trans-rectal ceus has a high sensitivity in showing the cancer induced neovascularization and significantly improves ultrasound imaging for prostate cancer detection and localisation. in 85% of cases, prostate cancer is multi focal and it tends to grow along the capsule of the gland contrast enhanced ultrasound in the assessment of urogenital pathology 323 archivio italiano di urologia e andrologia 2014; 86, 4 figure 11. hipoechoic prostatic lesion on conventional trans-rectal us assessed with ceus. the red roi was drawn in a suspicious area whereas the yellow roi was drawn in an area representing the normal prostatic parenchyma. the red time-intensity curve shows a poor contrast enhancement within the lesion, suggestive of hypovascularized prostatic tumour. with an oblong shape. prostate cancer differs from benign prostate tissue because of the loss of normal glandular architecture, increased cellular density and altered microvasculature. the loss of normal glandular architec ture, characteristic of high-grade prostate cancer, results in fewer reflective interfaces and reduced echotexture on con ventional ultrasound. the classic gray scale ultrasound finding of cancer is a hypoechoic lesion (figure 11). however, prostate cancer may appear echogenic or isoechoic and conventional us examination can miss them (18). in these cases, ceus can help in the detection of malig nant lesions by demonstrating an area with early and increased enhancement, with reference to the surround ing parenchyma. the main differential diagnosis includes chronic prostatitis that can mimic the gray scale appearance of prostate cancer. prostatitis may result in a heterogeneous appearance in the prostate peripheral zone and can present with hypoechoic lesions that are indistinguishable from cancer. ceus evaluation with time-intensity curves may help in the differentiation. ceus also provides useful information to precisely target biopsies: a tailored approach to prostate biopsy based on contrast-enhanced ultrasound represents an innovative approach to detecting significant disease with fewer biopsy cores. scrotum acute scrotal pain is a challenging clinical problem that requires prompt diagnosis to determine appropriate treatment. it can be the result of a variety of causes, including torsion, epididymo-orchitis and tumours. the first-line examination in patients with a painful scro tum is conventional us with colour doppler. according with the 2011 updated efsumb guidelines (1), ceus is acquiring an increasing role in the management of acute scrotal pain, because ceus allow the correlation of macroscopic anomalies with possible perfusion alter ations, providing a working diagnosis that would enable the urologist to pursue appropriate management: surgi cal treatment or observation. in case of epididymitis or epididymo-orchitis, convention al us show a heterogeneous enlarged epididymis or testis with thickening. both colour doppler and ceus demon strate increased vasculatization of the epididymis or testis. sometimes inflammation can complicate with abscessu alization. us tipically shows a sharp heterogeneous area without vascular signal inside the focal lesion on colour doppler. ceus demonstrates focal absence of enhance ment with hyperechoic peripheral rim. ceus aquired an important role in emergency practice also in the detection of testicular torsion. the testis appears on conventional us as a normal sized testicle with decreased flow on colour doppler. ceus can shows the reduction or the complete absence of contrast enhancement of the testis, respectively in case of partial or complete torsion (figure 12) (19). ceus is the imaging investigation of choice in case of scrotal trauma because it is able to depict parenchymal disorders on the basis of vascularity, helping in the dif ferential diagnosis of scrotal lesions and traumatic changes. the key factor is to exclude testicular rupture and, in particular, the interruption of the tunica albug inea, allowing the urologist to decide when remove the injured testis or attempt salvage (15). testicular trauma appears as a hypoechoic interruption of the border of the testis with large surrounding haematoma. the integrity of the tunica albuginea may always be assessed. intratesticular hyperechoic areas are suggestive of haemorragia. in case of testicular rupture, ceus demonstrates a lack of contrast enhancement in the hypoechoic area. ceus can also detect active bleeding. ceus also help in detecting and characterizing testicular lesion of undefined nature at us. testicular neoplasms have a wide range of us presenta tion and the diagnosis is not possible on the basis of con ventional us. tumour can appear as heterogeneous hypoechoic area with poor vascularization on colour doppler. ceus has a higher sensitivity in detecting ves figure 12. acute testicular torsion. conventional us (b) shows a normal sized testicle. ceus demonstrates the complete lack of contrast enhancement within the testis due to the absolute absence of testicular blood flow (a). l. barozzi, d. capannelli, m. imbriani 324 archivio italiano di urologia e andrologia 2014; 86, 4 figure 13. hypoechoic lesion on conventional us is assessed with ceus. the red roi was drawn in a suspicious area whereas the yellow roi was drawn in an area representing the normal testicular parenchyma. the red time-intensity curve shows a higher fast filling hyperenhancement with reference to the normal testicular parenchyma and a rapid wash-out in the later phase, suggestive of testicular tumour. sels within the lesion and can show a slight or strong enhancement within the lesion in the early phase, that become hypoechoic compared to the surrounding parenchyma in the late phase. time-intensity curves demonstrates an increased enhancement in early phase and rapid wash-out (figure 13). penis sometimes penis can be involved in scrotal trauma, typ ically coital trauma. as for the testis, the key finding is the integrity of the tunica albuginea. the intracavernous administration of microbubble constrast agent may improve the visualization of traumatic lesions or the detection of active bleeding. references 1. piscaglia f, nolsøe c, dietrich cf, et al. the efsumb guidelines and recommendations on the clinical practice of contrast enhanced ultrasound (ceus): update 2011 on non-hepatic applications. ultraschall med. 2012; 33:33. 2. bosniak ma. diagnosis and management of patients with compli cated cystic lesions of the kidney. ajr am j roentgenol. 1997; 169:819. 3. bosniak ma.the use of the bosniak classification system for renal cysts and cystic tumors. j urol. 1997; 157:1852. 4. mcarthur c, baxter gm. current and potential renal applications of contrast-enhanced ultrasound. clin radiol. 2012; 67:909. 5. cokkinos dd, antypa eg, skilakaki m, et al. contrast enhanced ultrasound of the kidneys: what is it capable of? biomed res int. 2013; 59:5873 6. jakobsen ja, oyen r, thomsen hs, morcos sk. members of contrast media safety committee of european society of urogenital radiology (esur). safety of ultrasound contrast agents. eur radiol. 2005; 15:941. 7. correas jm, bridal l, lesavre a, et al. ultrasound contrast agents: properties, principles of action, tolerance, and artifacts. eur radiol. 2001; 11:1316. 8. lebkowska u, janica j, lebkowski w, et al. renal parenchyma per fusion spectrum and resistive index (ri) in ultrasound examinations with contrast medium in the early period after kidney transplanta tion.transplant proc. 2009; 41:3024. 9. fischer t, filimonow s, dieckhöfer j, et al. improved diagnosis of early kidney allograft dysfunction by ultrasound with echo enhancer-a new method for the diagnosis of renal perfusion. nephrol dial transplant. 2006; 21:2921. 10. granata a, andrulli s, fiorini f, et al. diagnosis of acute pyelonephritis by contrast-enhanced ultrasonography in kidney trans plant patients.nephrol dial transplant. 2011; 26:715. 11. fischer t, mühler m, kröncke tj, et al. early postoperative ultra sound of kidney transplants: evaluation of contrast medium dynamics using time-intensity curves. rofo. 2004; 176:472. 12. park bk, kim b, kim sh, et al. assessment of cystic renal masses based on bosniak classification: comparison of ct and contrast enhanced us. eur j radiol. 2007; 61:310. 13. ignee a, straub b, schuessler g, dietrich cf. contrast enhanced ultrasound of renal masses. world j radiol. 2010; 2:15. 14. wang xh, wang yj, lei cg. evaluating the perfusion of occupy ing lesions of kidney and bladder with contrast-enhanced ultrasound. clin imaging. 2011; 35:447. 15. valentino m, de luca c, barozzi l, et al. contrast-enhanced us evaluation in patients with blunt abdominal trauma. j ultrasound. 2010; 13:22. 16. cokkinos dd, antypa e, kalogeropoulos i, et al. contrast enhanced ultrasound performed under urgent conditions. indications, review of the technique, clinical examples and limitations. insights imaging. 2013; 4:185. 17. smith za, wood d. emergency focused assessment with sonogra phy in trauma (fast) and haemodynamic stability. emerg med j. 2014; 31:273. 18. mitterberger m, pelzer a, colleselli d, et al. contrast-enhanced ultrasound for diagnosis of prostate cancer and kidney lesions. eur j radiol. 2007; 64:231. 19. valentino m, bertolotto m, derchi l, et al. role of contrast enhanced ultrasound in acute scrotal diseases. eur radiol. 2011; 21:1831. correspondence libero barozzi, md (corresponding author) libero.barozzi@ausl.bologna.it michele imbriani, md michele.imbriani@ausl.bologna.it department of diagnostic imaging, radiology unit, maggiore hospital largo nigrisoli 22 40100 bologna, italy diana capannelli, md diana.capannelli@yahoo.it cardio-thoracic-vascular department, radiology unit, university of bologna, policlinico sant’orsola-malpighi via massarenti 9 40138 bologna, italy stesura seveso 311archivio italiano di urologia e andrologia 2014; 86, 4 review repeated biopsy in the detection of prostate cancer: when and how many cores vincenzo scattoni, andrea russo, ettore di trapani, umberto capitanio, giovanni la croce, francesco montorsi department of urology, university vita-salute, scientific institute san raffaele, milan, italy purpose: we performed an analysis of the literature about the optimal prostate biopsy (pbx) scheme in the repeated setting methods: we performed a clinical and critical literature review by searching medline database from january 2005 up to january 2014. electronic searches were limited to the english language. the keywords were: prostate cancer, prostate biopsy, transrectal ultrasound, transperineal prostate biopsy. results: the recommended approach in repeated setting is still the extended scheme (epbx) (12 cores). an approach with more than 12 cores according to the clinical characteristics of the patients may optimize cancer detection. saturation pbx (> 20 cores) clearly improves cancer detection if clinical suspicion persists after previous negative biopsy. nevertheless international guidelines do not strongly recommended spbx in all situations of repeated setting. epbx or spbx may be, in the future, substituted by multiparametric mri-targeted biopsies. conclusions: since the scenario in which a pbx is changing, the issue about the number and location of the cores in pbx is still a matter of debate in repeated setting. at present, epbx are still the gold standard even if spbx seems to be necessary in many cases. however, random pbx does not represent the approach of the future, but rather imaging targeted biopsy. key words: prostate cancer; prostate biopsy; transrectal ultrasound; ttransperineal prostate biopsy. submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. tocol in each patient, or whether to modify the protocol for different clinical situations. moreover, it is still controversial whether the detection rate may increase with additional biopsies or whether it is necessary to modify the locations where the cores are taken (1, 3). methods we performed a clinical and critical review of electronic databases by searching medline, web of knowledge and the cochrane library from january 2005 up to january 2014 to identify all relevant studies. electronic searches were limited to the english language, and the keywords prostate cancer, prostate biopsy, transrectal ultrasound, transperineal prostate biopsy were used. two independent authors performed all aspects of the search strategy, screening the titles and abstracts of all articles and then reviewing the full-text articles in detail. prostate biopsy strategy in the repeat setting candidates to repeat pbx include patients with a prior negative pbx but with a persistent suspicion of pca on the basis of repeated psa values and/or dre findings (and other markers such us %fpsa, complexed psa, psad, psa velocity and urinary pca3 score), previous peculiar hystological diagnosis (such as atypical small acinar proliferation of prostate asap or high-grade prostatic intraepithelial neoplasia hgpin), candidates to active surveillance or to focal therapy. how and how many cores should be taken in these different scenarios is still unclear and schemes may significantly change in the different patients. based on the findings that even initial extended pbx (epbx) miss almost a third of cancers, a spbx has been adopted to improve pca dr in patients with suspicious clinical findings following previous negative standard pbx. there is now good evidence in the literature that spbx are superior than epbx in this setting. zaytoun et al. reported their experience at cleveland clinic where they compared epbx with spbx in a clearly defined, heterogeneous population of patients undergoing repeat biopsy after a single prior biopsy that failed to diagnose pca (2). they showed that office-based spbx significantly increases dr in repeat biopsy compared to epbx. spbx detected almost onethird more cancers. for patients with benign initial biopdoi: 10.4081/aiua.2014.4.311 presented at 19th national congress sieun, fermo 2014 introduction management of patients with negative biopsy often presents a dilemma. urologists know well that a negative biopsy does not mean the absence of cancer, and a second biopsy is one of the options. the saturation prostate biopsy (spbx) was initially introduced to improve prostate cancer (pca) detection rates (dr) in the repeat setting because initial 10to 12-core biopsy schemes may miss almost a third of cancers (1). nevertheless, the most efficient scheme with the optimal number and location of cores has not been defined yet (1). it is not clear when and how to perform a second biopsy, whether it is necessary to perform the same sampling proscattoni_stesura seveso 15/01/15 10:46 pagina 311 archivio italiano di urologia e andrologia 2014; 86, 4 v. scattoni, a. russo, e. di trapani, u. capitanio, g. la croce, f. montorsi 312 sy, spbx demonstrated significantly greater pca detection. for previous asap and/or hgpin, a trend for higher pca dr was demonstrated in the saturation group but did not reach statistical significance. similarly, scattoni et al. recently tried to identify the optimal combination of sampling sites (number and location) to detect pca in patients previously submitted to an initial negative prostatic biopsy (3). they prospectively performed a transrectal ultrasound (trus)-guided systematic 24-core pbx in 340 consecutive patients after a first negative biopsy (at least 12 cores). subsequently, they set the cancer-positive rate of the 24-core pbx at 100% and calculated pca dr for 255 possible combinations of sampling sites. they reported that the more cores taken, the higher the cancer dr. they showed a continuum of improvement of the cancer dr when increasing the number of cores, even if the cancer dr of the 24 cores was significantly higher than only the mean dr rates of 14-core schemes. moreover, at a given number of cores, the dr rates varied significantly according to the different combination of sites considered. all of these studies demonstrate that spbx provides a higher cancer dr than the extended approach in the repeat setting and that the higher the number of cores, the higher the number of cancers detected. nevertheless the regular use of spbx in clinical practice is not approved (4-5). the national comprehensive cancer network (nccn) suggests performing a second extended protocol after an initial negative extended scheme and suggests considering spbx only in patients with a high risk of cancer after multiple negative biopsies. the 2013 european association of urology (eau) guidelines on pca do not indicate the template that should be used. consequently, the ideal strategy for a second pbx procedure has yet to be fully elucidated. recently, interest has increased in defining more efficient biopsy schemes for pca detection with the minimum number of cores. different variables, both clinical and not clinical, may have an impact on the cancer dr. apart from the clinical characteristics of the patients, some procedural characteristics may have an even greater impact on the cancer dr. intuitively, adding more biopsies to prostatic areas not sampled by common extended schemes should increase the dr. it should be noted, however, that increasing the number of biopsy cores is not the solution to the problem and that the relationship between the number of biopsy cores and the resulting cancer dr does not correlate linearly. as a matter of fact, the curve of saturation tends to plateau, and the increase of cores taken in the template is not equivalent to the increase of cancer detected. kawakami et al. analyzed the pca detection rate by using a three-dimensional (3d) 26-core systematic super-epbx protocol (6). in these analyses, subset biopsy schemes were determined by recursive partitioning to achieve a maximum cancer detection rate at a given number of biopsy cores through a single transrectal approach, a single transperineal approach, or a 3d combination of transrectal and transperineal approaches. they were able to extract a 3d 14-core biopsy protocol that could detect 95% of cancers with the fewest number of cores. nevertheless, their approach has the disadvantage of requiring general anesthesia to perform the double approach (transrectal and transperineal). moreover, they have not specified the most advantageous biopsy protocol according to the clinical characteristics of the patients. all of these data demonstrate that cancer detection is influenced not only by the number of cores but also by the exact location of the cores. the report by delongchamps et al. is a reminder that the urologist needs to do a better job of biopsying the prostate (7). a fairly extensive 36-core biopsy performed in 48 autopsied prostates (median volume: 35 ml) missed 5 of 12 (42%) cancers found on whole-mount pathologic analysis. in fact, the 36-core biopsy offered no benefit over an 18-core protocol in terms of pca detection (7). adopting a scheme that is able to maximize the dr with the fewest number of cores represents a possible new modality of performing pbx. this approach is clinically preferable to adopting a saturation scheme that is unable to increase the cancer dr with the same proportion of increasing numbers of cores. scattoni et al. recently demonstrated that both the number and the location of biopsy cores taken affect cancer dr in a repeated biopsy setting (3). they also showed that the “optimal” repeat biopsy scheme varies according to the clinical characteristics of the patients. analysis revealed that for patients with previous asap diagnosis, the most advantageous scheme was a combination of a 14-core biopsy (without tz biopsies). for patients with no previous asap diagnosis and percentage of free prostate-specific antigen (%fpsa) of 10% or less, the most advantageous scheme was a 14-core biopsy (including four tz biopsies). the most advantageous sampling scheme for patients with no previous asap and %fpsa greater than 10% was a combination of a 20-core biopsy (including 4 tz biopsies). moreover, the number of repeated biopsy is controversial, also because the dr is inversely related to the subsequent procedure. djavan et al. reported in 2001 an original work on the risk of pca on repeat biopsies performed 6 weeks after an initial negative set. these investigators found that cancer detection rates on biopsies 1, 2, 3 and 4 were 22%, 10%, 5% and 4%, respectively, and that 58%, 60.9%, 86.3% and 100% of patients who had rp had organ confined disease on biopsies 1, 2, 3 and 4. the investigators concluded that biopsy 2 in all cases of a negative finding on biopsy 1 seems justified (8). similarly, campos-fernandes et al. in a cohort with extended biopsies found that 18%, 17%, and 14% of patients had pca in second, third, and fourth biopsies, respectively. pca detected at these sets of biopsies was significant in 85% of cases (9). detection of clinically insignificant pca (according to epstein’s criteria) is an inevitable risk of repeat biopsy, and its association with the number of biopsy cores is an issue of considerable debate. moreover, spbx has been evaluated as a staging tool to improve the characterization of low-volume and well-differentiated pca, but whether spbx improves prediction of tumor insignificance remains open to debate. it should be also noted that, in general, cancer missed on initial prostate biopsy is likely to be smaller or more insignificant than those cancers identified on first attempt. in this context, the real issue with pca detection is not overdiagnosis, since only diagnosis or misdiagnosis exist, but rather potential overtreatment. detection and treatment of pca should always be considered independent processes, and concern about overdetecscattoni_stesura seveso 15/01/15 10:46 pagina 312 tion must be weighed against the risk of missing clinically significant cancers. finally, in patients with a diagnosis of pca candidate to active surveillance spbx is preferable even if not mandatory, while in cases of focal therapy spbx may not be sufficient and considered a surrogate to transperineal grid template biopsy. however, the optimal number and location of prostate biopsies in patients in active surveillance with a low grade and low volume pca and patients who are candidate to focal therapy has not been established. several benefits appear to be associated with an image guided approach to prostate biopsy. in summary, fewer men are biopsied overall, a greater proportion of men with clinically significant prostate cancer are biopsied, and fewer men are attributed a diagnosis of clinically insignificant. even if the randomized epbx and spbx remain the gold standard, many patients demand advances beyond the ‘‘old-fashioned’’ randomized biopsy, which is not considered the “future”. nowadays, multiparametric mri (mpmri) has demonstrated to have a high degree of accuracy for the detection of clinically significant prostate cancer and can be used to define a target area before prostate biopsy. in the last five years, the role of image-guided targeted biopsy has grown. the likelihood of detecting cancer in such a visible lesion is definitely higher than with a randomized biopsy if the detection rate per core is considered. mpmri-targeted biopsies have demonstrated superiority over systematic randomized biopsies for the detection of clinically significant disease and representation of disease burden, while deploying fewer cores. there is evidence that the gleason score obtained in a targeted biopsy reflects the true gleason score better than the gleason score obtained by a randomized pbx (10). hambrock et al. have demonstrated that mri-guided biopsies significantly improve pretreatment risk stratification by obtaining cores that are representative of the true gleason grade (11). in a recent review about mpmri-targeted biopsies, men with a clinical suspicion of prostate cancer, a biopsy of the prostate that used mri to inform the sampling was associated with a detection rate of clinically significant prostate cancer of 42%. this approach might permit a reduction in the number of men who need to undergo biopsy if they are deemed to have a normal mri. the efficiency of the targeted sampling appeared superior to the standard approach (70% vs 40%). since the randomized pbx was associated with a diagnosis of insignificant prostate cancer in 10% of men biopsied, this cancer diagnosis might have been avoided if men had undergone targeted biopsy alone (11). the authors also concluded that adopting mpmri-targeted biopsies rather than randomized pbx, fewer men are biopsied overall, a greater proportion of men with clinically significant prostate cancer are biopsied, and fewer men are attributed a diagnosis of clinically insignificant prostate cancer. on the contrary, other authors have shown that in cases combining targeted and randomized biopsies during one pbx session, a substantial number of cancers were detected in only the randomized cores (12). relying on the targeted biopsy alone would have led to a significant rate of underdetection in these studies. there is no doubt that epbx might better characterize pca volume and cancer extent than just a targeted biopsy: the positive cores give us information on not only the cancer extent but also the number of negative cores. targeted biopsies seem to reflect the true gleason score, yet they might underestimate the extent of the cancer. probably the combination of both targeted and extended biopsies will show the most appropriate information about the correct cancer characteristics. conclusions the issue about the number and location of the cores is still a matter of debate in repeat setting also because the scenarios in which pbx is required are changing. at present, spbx seems to be necessary in most of the cases. however, random prostate pbx do not represent the future while imaging target biopsy are becoming more popular. references 1. scattoni v, zlotta s, montironi r, et al. extended and saturation prostatic biopsy in the diagnosis and characterisation of prostate cancer: a critical analysis of the literature. eur urol. 2007; 52:1309-1322. 2. zaytoun om, moussa as, gao t, et al. office based transrectal saturation biopsy improves prostate cancer detection compared to extended biopsy in the repeat biopsy population. j urol. 2011; 186:850-4. 3. scattoni v, raber m, capitanio u, et al. the optimal rebiopsy prostatic scheme depends on patient clinical characteristics: results of a recursive partitioning analysis based on a 24-core systematic scheme. eur urol. 2011; 60:834-41. 4. scattoni v, maccagnano c, capitanio u, et al. random biopsy: when, how many and where to take the cores? world j urol. 2014; 32:859-69. 5. ukimura o, coleman ja, de la taille a, et al. contemporary role of systematic prostate biopsies: indications, techniques, and implications for patient care. eur urol. 2013; 63:214-30. 6. kawakami s, okuno t, yonese j, et al. optimal sampling sites for repeat prostate biopsy: a recursive portioning analysis of threedimensional 26-core systematic biopsy. eur urol. 2007; 51:675-83. 7. delongchamps nb, de la roza g, jones r, et al. saturation biopsies on autopsied prostates for detecting and characterizing prostate cancer. bju int. 2009; 103:49-54. 8. djavan b, ravery v, zlotta a, et al. prospective evaluation of prostate cancer detected on biopsies 1, 2, 3 and 4: when should we stop? j urol. 2001; 166:1679-83. 9. campos-fernandes jl, bastien l, nicolaiew n, et al. prostate cancer detection rate in patients with repeated extended 21-sample needle biopsy. eur urol. 2009; 55:600-6. 10. moore cm, robertson nl, arsanious n, et al. image-guided prostate biopsy using magnetic resonance imaging-derived targets: a systematic review. eur urol. 2013; 63:125-40. 11. hambrock t, hoeks c, hulsbergen-van de kaa c, et al. prospective assessment of prostate cancer aggressiveness using 3-t diffusion-weighted magnetic resonance imaging-guided biopsies versus a systematic 10-core transrectal ultrasound prostate biopsy cohort. eur urol. 2012; 61:177-84. 12. kuru th, roethke mc, seidenader j, et al. critical evaluation of magnetic resonance imaging targeted, transrectal ultrasound guided transperineal fusion biopsy for detection of prostate cancer. j urol. 2013 ; 190:1380-6. 313archivio italiano di urologia e andrologia 2014; 86, 4 the optimal number of cores in the detection of prostate cancer after an initial negative biopsy correspondence vincenzo scattoni, md (corresponding author) scattoni.vincenzo@hsr.it andrea russo, md ettore di trapani, md umberto capitanio, md giovanni la croce, md francesco montorsi, md department of urology, university vita-salute, scientific institute h san raffaele. via olgettina 60 20132 milan, italy scattoni_stesura seveso 15/01/15 10:46 pagina 313 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 4278 original paper neoadjuvant chemotherapy versus cystectomy in management of stages ii, and iii urinary bladder cancer mohammed a. osman 1, ayman m. gabr 2, mohammad s. elkady 3 1 general organization for teaching hospitals institutes, egypt; 2 national institute of urology & nephrology, egypt; 3 ain shams university, egypt. purpose: this phase iii trial was de signed to compare the survival benefit, surgical respectability, and toxicities among patients treated by neoadjuvant chemotherapy followed by radical cystectomy (arm a), with those treated by radical cystectomy (arm b) in the management of stage ii, iii urinary bladder cancer. patients and methods: for inclusion, patients should have pathologically proven urothelial carcinoma in urinary bladder, clinical stages from t2n0m0 to t4an0m0, patient age less than 65 years, and performance state ≤ 2. additionally, patients should have adequate hematological, renal, and liver functions. arm a patients underwent 3 cycles of neoadjuvant cisplatin and gemcitabine followed by radical cystectomy, while arm b patients underwent radical cystectomy directly. results: thirty patients had been enrolled in each arm between september 2009 and april 2014 in 3 educational institutes in egypt. the 3 year os (overall survival) for arm a, and b were 60% and 50% respectively. the median os for arm a was 36+ months and that for arm b was 32.5 months. the 3 year progression-free survival (pfs) for arm a, and b were 57% and 43% respectively. the median pfs for arm a was 36+ months and for arm b was 28 months. a subgroup analysis was performed to correlate between 3 year os and predetermined prognostic factors including age, tumor size, pathological stage, and the response to neoadjuvant chemotherapy. the later was performed only in arm a. both treatment arms were tolerated well with mild toxicities profiles. conclusion: neoadjuvant chemotherapy achieved better survival, surgical respectability, with nearly equivalent toxicities when compared with radical cystectomy. key words: neoadjuvant; cisplatin; cystectomy; survival; 3yos; arm a. submitted 14 july 2014; accepted 30 september 2014 summary no conflict of interest declared. incidence of transitional cell carcinoma (tcc) has been increasing while squamous cell carcinoma (scc) has been decreasing. active exposure to tobacco smoke has a strong relationship to tcc. previous studies have reported a 2.6 fold risk of developing bladder cancer in smokers compared to nonsmokers (1). stage ii bladder cancer refers to stages pt2an0m0, where the tumor invades superficial muscularis propria, and pt2bn0m0, where it invades deep muscularis propria. stage iii refers to pt3n0m0, where the tumor invades perivesical tissue, and pt4an0m0, where it invades prostatic stroma, uterus, vagina (2). according to the recent nccn guidelines, the standard management of stages ii, and iii bladder cancer included radical cystectomy, with strong consideration of neoadjuvant chemotherapy (3). a trial conducted by the medical research council and the european organization for research and treatment of cancer randomly assigned 976 patients with locally advanced (t3 or t4a) or high grade muscle-invasive (t2) bladder cancer to undergo either definitive treatment immediately or definitive treatment (surgery or radiotherapy) preceded by three cycles of neoadjuvant cisplatin, vinblastine, and methotrexate. at a median follow-up of 8.0 years, os was significantly greater in the arm randomly assigned to receive neoadjuvant chemotherapy. the authors concluded that, the survival benefit from neoadjuvant chemotherapy conferred a 6% absolute increase in the likelihood of being alive at 3 years (56% vs. 50%), 5 years (49% vs. 43%), and 10 years (36% vs. 30%) (p 0.037) (4). a meta-analysis of ten randomized trials of neoadjuvant chemotherapy, including updated data for 2,688 individual patients, showed that cisplatin-based combination chemotherapy was associated with a significant 13% relative reduction in the risk of death and resulted in 5% improvement in 5-year survival from 45% to 50% (p 0.016) (5). a subsequent meta-analysis of eight trials used multiagent, cisplatin-based chemotherapy, showed neoadjuvant chemotherapy was associated with a 6.5% absolute benefit in 5-year os (50% vs. 56.5%) (p 0.006) (6). study objective was to compare the survival benefit, surdoi: 10.4081/aiua.2014.4.278 background bladder cancer is the ninth most common cancer throughout the world and is considerably more common in developing countries. recently, it was shown that, osman_stesura seveso 15/01/15 13:09 pagina 278 279archivio italiano di urologia e andrologia 2014; 86, 4 nact versus cystectomy in bladder cancer gical resectability, and toxicities among patients treated by neoadjuvant chemotherapy followed by radical cystectomy with those underwent radical cystectomy in the management of stage t2n0, t3n0, and t4an0 urinary bladder cancer. the primary end point was survival benefit. patients and methods patients were eligible to be enrolled in the study if they had pathologically proven urothelial carcinoma in urinary bladder. patients should have clinical stages from t2n0m0 to t4an0m0 (as defined by ct scan) (7). patient age had to be less than 65 years and performance state had to be ≤ 2. patients should have adequate hematological, renal, and liver functions. written informed consent was taken from patients before enrolment. female patients in the childbearing period must had a negative pregnancy test (serum β-hcg) and both male and female patients must employ effective contraceptive measures prior to start of until four weeks after the last dose of chemotherapy. additionally, patients must had no concurrent malignancy. patients were allocated to either arms; arm a consisted of 3 cycles of neoadjuvant chemotherapy in the form of cisplatin and gemcitabine followed by radical cystectomy, arm b consisted of radical cystectomy. settings the study was conducted at the oncology unit, ain shams university hospitals, ismailia oncology teaching hospital, and national institute of nephrology and urology. the last 2 hospitals are run under the general organization for teaching hospitals institutes, egypt. study design the study design was shown in table 1. the neoadjuvant chemotherapy administration protocol for arm 1 was as follows: 1. cisplatin: pre-chemotherapy, normal saline 0.9% 1 litre over 30-60 minutes, followed by cisplatin iv in normal saline 0.9% 500 ml over 1 hour. postchemotherapy, normal saline 0.9%1 litre, with kcl (potassium chloride) 20meq, mgso4 (magnesium sulphate) 1 gm, and mannitol 30 gm over 1 hour. 2. gemcitabine iv in normal saline 0.9% 250 ml over 30 minutes. cycles of chemotherapy were administered after checking cbc, renal function tests, gfr, liver function tests, bilirubin, before day 1, and 8 of each cycle, with subsequent dose modification based on the following table 2 (7). evaluation baseline ct thoracic-abdominal-pelvic (tap) was performed before treatment protocol at the time of diagnosis. after the end of chemotherapy, patients underwent ct ap to evaluate chemotherapy response (table 3). two weeks after cycle 3 of chemotherapy, patients underwent radical cystectomy, pelvic lymphadenectomy, and urinary diversion, with transurethral resection (tur) prior to the surgery to know the disease extent. after surgery, pathological evaluation was performed to evaluate the chemotherapy response in arm a, and to confirm pathological staging in arm b. follow-up after the end of the treatment protocol, patients were followed according to the nccn guideline for follow-up after bladder cancer treatment; by regular clinic visits every 3 months for the first 2 years, then every 6 months for the following 3 years, then annually thereafter. in each visit, patients were evaluated by history taking, physical examination, laboratory investigations in the form of cbc, liver, renal functions every 3months for the first 2 years then as clinically indicated. ct tap were done every 6 months in the first 2 years, then as clinically indicated (3). toxicity toxic effects were graded according to the national cancer institute common toxicity criteria, version 2.0 (8). early chemotherapy toxicities were defined as toxicities that occurred during treatment till 8-10 weeks post chemotherapy. surgical early morbidities were defined 1. hematology for day 1 of each cycle: neutrophils (10³/ml) platelets (10³/ml) dose ≥ 1 and > 100 100% both 0.5 to 0.99 or 75 to 100 75% of gemcitabine only < 0.5 or < 75 delay both drugs for gemcitabine only day 8: ≥ 1 and > 100 100% 0.5 to 0.99 or 75 to 100 75% < 0.5 or < 75 omit 2. renal function test (gfr) (ml/min) gfr cisplatin dose gemcitabine dose ≥ 60 100% 100% 45 to 59 35 mg/m2 d1+2 100% (same pre-hydration as 70 mg/m2 dose) < 45 delay delay table 1. treatment protocol of the current trial. table 2. dose modification based on hematological, and renal function results. treatment protocol arm 1 arm 2 neoadjuvant chemotherapy; cisplatin (70 mg/m2 day 1), gemcitabine (1250 mg/m2 day 1,8) q 3 weeks for radical cystectomy 3 cycles radical cystectomy osman_stesura seveso 15/01/15 13:09 pagina 279 archivio italiano di urologia e andrologia 2014; 86, 4 m.a osman, a.m. gabr, m.s. elkady 280 as complications that occurred from day 1 postoperative till full recovery from the surgery usually 6-8 weeks postoperative. late toxicities referred to those occurred > 10 weeks after finish of treatment protocol. statistical analysis all calculations were carried out using prism 6 software for windows. all analyses were carried by intention to treat. mean and median values were used for the description of continuous data. for comparison between the 2 group characteristics, t test, and p value were used. overall survival (os) and progression-free survival (pfs) for each arm were analyzed by the kaplan-meier method. further, they were compared using the log rank and wilcoxon tests. os was measured from the time of randomization till death from bladder cancer or the last follow-up visit. pfs was measured from the time of randomization till relapse, or the last follow-up visit. log rank approach and hazard ratio were used to examine the effects of pre-specified prognostic factors including age, tumor size, pathological staging, and pathological response to neoadjuvant chemotherapy on the 3 year os. p value was significant at ≤ 0.05. results between september 2009 and april 2014, 60 patients were enrolled in the current study. 30 patients were assigned to each treatment arm. all patients fulfilled eligibility criteria for enrolment in the current study. the mean age was 50.6 years (range 30-65 years). 56 patients were males, and 4 were females (93.3%, 6.7% respectively). the median performance status was 1 (range 0-2). the mean tumor size was 3.75 cm (range 1.8-5.5 cm). 12 patients had stage t2n0, 38 had stage t3n0, and 10 had stage t4an0. (20%, 63.3%, 16.7% respectively) (table 4). treatment protocol for arm a: all arm a patients received neoadjuvant chemotherapy, and a total of 89 cycles were performed. mean chemotherapy cycles were 3 (range 2-3). to evaluate treatment response, ct ap was checked at mean time of 2.2 weeks after cycle 3 (range 1-3 weeks). neoadjuvant chemotherapy response among the 30 patients enrolled, cr was achieved in 6 patients (20%), pr was observed in 16 patients (53.3%), and sd was in 6 patients (20%). the remaining 2 patients had dp (6.7%). surgery radical cystectomy, pelvic lymphadenectomy, and urinary diversion were performed in 58 out of the 60 patients. for arm a patients, 28 underwent cystectomy, the remaining 2 refused surgery and lost follow-up. of them, 19 had neobladder, 7 ileal conduit, and 2 underwent cutaneous urinary diversion. surgery was done at a mean of 2 weeks after cycle 3 chemotherapy (range 1021 days). the mean admission time for surgery was 8.3 days (range 7-14 days). the average blood loss was 900 ml (range 500-2000 ml). pathological evaluation after cystectomy was done in all the 28 patients. r0 was achieved in all except 2 patients who had r1 disease. pcr (pathological complete remission) (pt0) was achieved in 10 patients (35%), ppr (pathological partial remission) in 12 patients (43%) (8 pt1, and 4 patients pt2). the remaining 6 had sd (stable disease) (22%) (2 pt2, 3 pt3, and 1 pt4). the mean number of dissected pelvic lymph nodes was 15 (range 7-20): 4 patients had positive lymph node biopsies. for arm b, all the 30 patients underwent cystectomy. of them, 18 underwent neobladder, 6 ileal conduit, 5 cutaarm a arm b characteristics number % number % p value age 35-40 40-50 50-60 60-65 mean age 48.9 --52.3 --0.04 sex male female performance status 0 1 2 performance status (mean, median) 0.7, 1 --0.9, 1 --0.1 tumor size 12 cm 2.1-4 cm > 4 cm mean tumor size 3.7 --3.8 --0.1 histopathological grade 1 2 3 grade mean, median 2.5, 3 --2.6, 3 --0.1 tumor stage pt2n0 pt3n0 pt4an0 tumor stage median t3 t3 0.07 table 3. response definitions. table 4. patients and diseases characteristics of each treatment. complete response (cr) complete disappearance of the tumor partial response (pr) 50% or more reduction in the size of the tumor disease progression (dp) 25% or more increase in the size of the tumor stable disease (sd) all other situations 1 20 7 2 3.3% 67% 23% 6.7% 0 14 10 6 0% 47% 33% 20% 0.1 0.1 0.1 0.03 4 17 9 13.3% 56.7% 30% 3 15 12 10% 50% 40% ------3 7 20 10% 23.3% 66.7% 2 6 22 6.7% 20% 73.3% ------6 18 6 20% 60% 20% 8 18 4 26.7% 60% 13.3% ------28 2 93% 7% 29 1 96.7% 3.3% ----11 17 2 36.3% 56.7% 7% 9 16 5 30% 53.3% 16.7% ------osman_stesura seveso 22/01/15 10:20 pagina 280 281archivio italiano di urologia e andrologia 2014; 86, 4 nact versus cystectomy in bladder cancer neous reservoir, and 1 had cutaneous urinary diversion. surgery was done at mean of 3 weeks after diagnosis (range 17-30 days). the mean admission time for surgery was 7 days (range 6-10 days). the average blood loss was 850 ml (range 4502000 ml). pathological evaluation was done in all the 30 patients. r0 was achieved in 26 patients. the remaining 4 had r1 disease. pathological staging was pt2, pt3, and pt4a in 7, 18, and 5 patients respectively. the mean number of dissected pelvic lymph nodes was 13 and 6 patients had positive lymph node biopsies. adjuvant chemotherapy was given to 4 patients from arm a for positive lymph node in the form of cisplatin and gemcitabine for 3 cycles. additionally, 13 patients from arm b received adjuvant chemotherapy (6 positive lymph nodes, 2 r1, and 5 pt4a) in the form of either cisplatin and gemcitabine, or carboplatin and gemcitabine. (6, and 7 patients respectively), for a mean of 4 cycles (range 3-6). survival data the 3 year os for arm a, and arm b were 60%, 50% respectively (figure 1) . the median os for arm a was 36+ months and that for arm b was 32.5 months. the 3 year pfs for arm a and b were 57% and 43% respectively (figure 2). the median pfs for arm a was 36+ months and that for arm b was 28 months. during the 36 months follow-up period, 11 patients died from arm a (9 bladder cancer relapses, 1 cardiovascular cause, and 1 unknown cause). for arm b, 15 patients died (12 bladder cancer relapses, 2 pulmonary embolism, and 1 unknown cause). during the 36 months follow-up period, 12 patients from arm a relapsed, (9 locoregional, and 3 metastatic), and 17 relapsed from arm b (11 locoregional and 6 metastatic). for subgroup analysis, the 3 year os for arm a patients who were < 60 y.o was 64%, and for those > 60 years was 50%. the 3 year os for arm b patients who were < 60 y.o was 54%, and for those > 60 years was 17%. (p value 0.02, chi square 5.5). the 3 year os for arm a t2 patients was 83%, and for t3-t4a patients was 54.5%. the 3 year os for arm b t2 patients was 75%, and those with t3-t4a was 41% (p value 0.01, chi square 5.7). the 3 year os for arm a patients who have tumors < 4 cm was 70%, and for those > 4 cm was 37.5%. the 3 year os for arm b patients who figure 1. the 3 year os for the study groups p value = 0.05, chi square = 3.66. figure 3. the kaplan-meier survival curve for arm a patients grouped by their pathological response to neoadjuvant chemotherapy. p value = 0.3. figure 2. the 3 year pfs for the study groups p value = 0.02, chi square = 4.88. arm a (%) arm b (%) p value hazard ratio 1. age < 60 years old 64 54 0.02 1.8 > 60 years old 50 17 0.2 1.1 2. pathological stage pt2 83 75 0.05 1.6 pt3-t4a 54.5 41 0.08 1.55 3. tumor size < 4 cm 70 61 0.1 2.0 > 4 cm 37.5 33 0.09 1.2 table 5. the 3 year os for each treatment arm categorized by the prognostic factors. osman_stesura seveso 22/01/15 09:58 pagina 281 archivio italiano di urologia e andrologia 2014; 86, 4 m.a osman, a.m. gabr, m.s. elkady 282 have tumors < 4cm was 61%, and for those > 4 cm was 33% (p value 0.1, chi square 2.2). for the 3 year follow-up for arm a patient, all those who achieved pcr were still alive (100%). of them, only 1 patient relapsed (10%) after 26 months of treatment. for those who achieved ppr, 8 patients were still alive (67%), and 3 died from cancer recurrence. further, 1 patient recurred, and was still alive. for those who achieved sd pathologically, all of them died. (p value 0.0001, chi square 23.3) (figure 3). toxicity profile chemotherapy side effects: for arm a, among the 89 chemotherapy cycles given, dose reduction was done in 10% of cycles for leuconeutropenia. treatment delay was in 10% of cycles. the mean delay time was 1 week (range 1-2 weeks). cisplatin was replaced by carboplatin in the last 2 cycles for 1 patient for persistent low gfr. treatment was stopped in the last cycle in 1 patient for persistent urinary tract infection (uti), and poor general condition. no deaths occurred related to treatment in each group (table 6-7). table 6 summarize grade 3-4 side effects, and their percentage for arm a group. table 7 showed the early surgical complications in both arms and their percentage. all patients who developed early surgical complications recovered smoothly. late toxicities during the 36 months follow-up period, 1 patient from arm a died by congestive cardiac failure at 30 months. further, 1 patient developed impaired renal function from repeated uti and he still alive and did not require dialysis, yet. for arm b patients, 2 patients died from pulmonary embolism (18, 27 months). discussion the role of neoadjuvant chemotherapy in urinary bladder cancer was strongly encouraged in stages pt2-t4a bladder cancer, based on 3 important trials, including that of griffiths et al., 2011, vale et al., 2003, and winquist et al., 2004 (4-6). however, there are still controversies about its impact on survival. griffiths et al., 2011 (4), reported that, neoadjuvant chemotherapy (mvac) slightly improved survival by 6% over 5 years. however, this slight improvement in survival can be attributed to their use of mvac regimen, which was associated with significant toxicity profile (9). the aim of neoadjuvant chemotherapy is to achieve tumor downstaging, improved respectability, and better survival (10, 11). neoadjuvant chemotherapy is considered better than adjuvant chemotherapy in relation to its tolerability, and patients usually receive adequate cycles of neoadjuvant chemotherapy with effective doses. it is still unclear which neoadjuvant chemotherapy regimen offers the best results. in patients with advanced or metastatic tcc the combination of gemcitabine and cisplatin achieved comparable survival results with mvac, and was associated with less toxicity (10). for the current study, although, there was no clear epidemiological trials that reported definite disease characters among the egyptians, our patient cohort, and distribution were nearly equivalent to that of fedewa et al., 2009 (1), which showed the incidence of bladder cancer in the nile delta region of egypt. further, our patients were properly randomized with no significant differences in patient characters between the 2 arms. there were non-statistically significant differences between the 2 groups in relation to age, tumor size, and performance state in favor of arm a. however, the difference in age was statistically significant for the group of patients > 60 years. this was explained by the fact that the investigators tried to avoid giving chemotherapy in older ages to avoid its long term complications , as well as to avoid delay in the definitive surgery especially with larger tumor sizes in this group. in the current trial, the primary end point was survival for neoadjuvant chemotherapy as compared with the standard treatment that is cystectomy. we believed that survival benefit had to be the main concern for trials like ours that treated cancers with curative intent. however, the follow-up period was not long enough to show clear survival benefit over a long period of time. the researchers of the current trial used to define survival in side effect arm a grade 4 (%) grade 3 (%) leuconeutropenia 12.2 2.2 anemia 2.2 --thrombocytopenia 17.8 --febrile neutropneia 2.2 --nausea, vomiting 4.4 ---mucositis 5.5 --others (uti) 7% ---table 6. grade 3-4 side effects, and their percentage for arm a group. side effect arm a grade 4 (%) grade 3 (%) leuconeutropenia 12.2 2.2 anemia 2.2 --thrombocytopenia 17.8 --febrile neutropneia 2.2 --nausea, vomiting 4.4 ---mucositis 5.5 --others (uti) 7% ---table 7. the early surgical complications in both arms and their percentage. osman_stesura seveso 15/01/15 13:09 pagina 282 283archivio italiano di urologia e andrologia 2014; 86, 4 nact versus cystectomy in bladder cancer relation to several subgroup analysis for better evaluation, and to define which subgroup would benefit most from treatment protocol. further, the researchers planed to make an updated report for the survival benefit, and toxicity profile after 5 years, and hopefully after 10 years follow-up periods. for the diversion procedures, although orthotopic diversion was the standard in our institutes, the authors tried to avoid the metabolic complications of orthotopic diversion especially after neoadjuvant cisplatin containing regimen. the current study clearly showed survival benefit for neoadjuvant cisplatin and gemcitabine combination over radical cystectomy. further, the survival was better for each subgroup for arm a over arm b. the current study showed better surgical resectability for arm a patients, when compared with arm b patients. arm a patients had higher r0 number over arm b (100% vs 86% respectively). further, neoadjuvant chemotherapy achieved tumor downstaging in 78% of patients. for toxicity profile, neoadjuvant chemotherapy was tolerated well, and was associated with mild grade 3-4 toxicities. surgery after chemotherapy was associated with very comparable side effects with that of arm b. bleeding complication were relatively higher among the group who received neoadjuvant chemotherapy. for the delayed side effects, the incidence of them was nearly equivalent between the 2 treatment groups. further, reports with relatively longer follow-up durations are needed before confirming that point. conclusion neoadjuvant chemotherapy before cystectomy achieved better survival results, surgical respectability, and nearly equivalent toxicities when compared with radical cystectomy in the management of stage ii, and iii urothelial bladder cancer. references 1. fedewa sa, soliman as, ismail k, et al. incidence analyses of bladder cancer in the nile delta region of egypt. cancer epidemiol. 2009; 33:176-181. 2. edge sb, byrd dr, compton cc, et al. eds.: ajcc cancer staging manual. 7th ed. urinary bladder. new york, ny: springer, 2010, pp 497-505. 3. nccn clinical practice guidelines in oncology, bladder cancer, version 1, 2014, http://www.nccn.org/professionals/physician_gls/ f_guidelines. asp#bladder. 4. griffiths g, hall r, sylvester r, et al. international phase iii trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the ba06 30894 trial. j clin oncol. 2011; 29:2171-2177. 5. vale c, advanced bladder cancer meta-analysis collaboration mrc clinical trials unit: neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. lancet. 2003; 361:1927-1934. 6. winquist e, kirchner ts, segal r, et al. neoadjuvant chemotherapy for transitional cell carcinoma of the bladder: a systematic review and meta-analysis. j urol. 2004; 171:561-569. 7. bcca protocol summary for palliative therapy for urothelial carcinoma using cisplatin and gemcitabine. http://www.bccancer. b c . c a / n r / r d o n l y r e s / a 2 4 5 1 2 0 5 5 c 1 3 4 3 3 c a a d e 2e0dc1519d71/67037 /guavpg_protocol_1nov2013. pdf, 2013. 8. common toxicity criteria (ctc) version 2.0, http://www.eortc. be/services/doc/ctc/ctcv20 4-30-992.pdfpublished april 30, 1999. 9. calabrò f, sternberg cn. localized and locally advanced bladder cancer. curr treat options oncol. 2002; 3:413-28. 10. von der maase h, sengelov l, roberts jt, et al. long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin plus cisplatin in patients with bladder cancer. j clin oncol. 2005; 23:4602-4605. 11. herr hw, dotan z, donat sm, bajorin df. defining optimal therapy for muscle invasive bladder cancer. j urol. 2007; 177:437-443. correspondence mohammed a osman, md (corresponding author) mmoneam@hotmail.com oncology consultant, general organization for teaching hospitals institutes egypt ayman m gabr, md keshta64@gmail.com urology consultant, national institute of urology & nephrology, egypt mohammad s elkady, md mselkady@hotmail.com ass. professor oncology, ain shams university, egypt osman_stesura seveso 15/01/15 13:09 pagina 283 stesura seveso 197archivio italiano di urologia e andrologia 2014; 86, 3 review to evaluate the etiology of erectile dysfunction: what should we know currently? orcun celik 1, tumay ipekci 2, ilker akarken 1, gokhan ekin 1, turker koksal 2 1 tepecik education and research hospital, urology clinic, 35140, izmir, turkey; 2 akdeniz university, faculty of medicine, department of urology, 07070, antalya, turkey. erectile dysfunction (ed) is the inability to develop normal erection or an hardening problem at various extent that causes inability to maintain the erection for the sufficient time required for a complete sexual activity. it can be the result of neurologic, psychogenic, vascular, urogenital and hormonal abnormalities. it is reported that it affects 52-67% of men between 40 and 70 years old. numerous theories and opinions are issued in the literature in order to explain the hemodynamic changea that occur during erection and detumescence. especially the effects of chronic diseases and psychogenic factors on the pathophysiology of erectile dysfunction are common matters of discussion in recent years. in this review, we will evaluate the current developments in the literature about the etiology of erectile dysfunction. key words: erectile dysfunction; ethiology; erection. submitted 13 june 2014; accepted 30 june 2014 summary no conflict of interest declared. as aterial muscular bolsters (von enbner, 1990; kiss, 1921), arterial and venous bolsters (conti, 1952), duct theory (deysach, 1939), arteriovenous shunt (newman et al., 1964; wagner et al., 1982) and cavernous smooth muscle contraction (goldstein et al., 1982) (3). most of the information regarding to erection physiology is obtained along 1980s and 1990s. in addition to the role of smooth muscles that regulate arterial and venous blood stream, the role of three dimensional structure of the tunica albuginea and its role in venous occlusion are explained. an important stage for understanding the nervous control was to determine that nitric oxide (no) is the primary neurotransmitter for erection and that phosphodiesterases turns penis back to its flask condition for the adjustment of smooth muscle tone. furthermore it was revelead the role of endothelium and the connection between the cells by “gap junctions” (3). prevalence of erectile dysfunction ed is one of the primary problems that affect the quality of life of people and its incidence is gradually increasng. in 2025, it is estimated that more than 322 million men will be affected from ed (4). on the basis of the epidemiological data, patient population and definition of ed, it has been shown that ed prevalence is between 16-25% (5). the overall prevalence of erectile dysfunction in men aged > 20 years was 18.4% suggesting that erectile dysfunction affects 18 million men aged 16-20 in the us (6). according to the results of this studies about ed prevalence, it has been shown that ed prevalence increases with age. ed prevalence ratios in the study of “national health and social life survey” (nhsls) is found as 7% between the ages 18 and 29, 11% between the ages 40 and 49 and 18% between the ages 50 and 59 (7). the prevalence of sexual activity declined with age to 73% among respondents who were 57 to 64 years of age, 53% among respondents who were 65 to 74 years of age, and 26% among respondents who were 75 to 85 years of age. among men, the most prevalentsexual problems were erectile difficulties (37%). fourteen percent of all men reported using medication or supplements to improve sexual function (8). in a study performed in our country, it was determined that in men over 40 years old mild ed is foun in 35.7%, doi: 10.4081/aiua.2014.3.197 introduction erectile dysfunction (ed) is defined as not providing or not continuing, when provided, the required penis hardening in order to perform a successful sexual intercourse (1). various aspects have been introduced in order to explain the mechanism of erection. in 19th century, it has been hypothesized that the essential factor for the success of erection could be venous occlusion. in 1933, howell revealed the role of the arterial system and, in the same years, oswald lowsey showed that there was no erection in dogs after ischiocavernous and bulbocavernous muscles ablation and that erection easily occurred as the result of separated plication of these muscles by catgut stiches and more plication caused priapism (2). newman et al. (1964) have shown that erection may occur in volunteers and human cadavers simply by isotonic solution infusion without venous construction (3). shiari et al. (1978) concluded that despite the increase of venous drainage, arterial flux was excessively increased to overtop venous drainage. wagner (1981) demonstrated that arterial flux was increased and, in return, venous drainage was decreased. various theories were developed celik4_stesura seveso 08/10/14 12:11 pagina 197 archivio italiano di urologia e andrologia 2014; 86, 3 o. celik, t. ipekci, i. akarken, g. ekin, turker koksal 198 moderate ed in 23% and severe ed in 6%. in this study, it was determined that the factors increasing ed prevalence are advanced age, low educational level, diabetes mellitus (dm), hypertension, psychological stress and prostate diseases (9). in another study; ed prevalence in turkey was measured as 69.2% and it was shown that especially the moderate-severe level of ed prevalence increased by age (10). in the study of massachusetts men aging (mmas), it was shown that 9.6% of men between the ages 40 and 70 have severe, 25.2% moderate and 17.2% mild ed. rate of complete ed increased from 5.1% in 40-year-old to 15% in 70-year old (9). this and similar studies have obviously shown that ed increases by age and libido possibly decreases by loss of erections. there are some evidences showing that decrement rate of erection is related to the frequency of sexual activities and that men with more active sexual lives are better protected (10). in various studies, it was observed that there is a strong relationship between diabetes and ed. ed incidence in diabetics treated at mmas is about 28% (11). according to a study, more than 6% of usa population is diabetic and ed is present in approximately 8 million of them (13). ed is observed in 32% of men with type 1 dm and in 46% of men with type 2 dm (14). ed occurs in 50% of men with dm within 10 years and 12% of men with dm are diagnosed after they have applied for ed (15). ed in patients with dm is seen three times more frequently than in the normal population (11). cardiovascular diseases may affect potency with various mechanisms. although ed has occurred up to 45% in men after myocardial infarction, there are also evidences that there is a high incidence in the period before having a cardiac attack. in a recent cross-sectional multicentered survey study among randomly selected males visiting a cardiologist, overall, 56% had ed, with up to 86% in patients with heart failure (16). oaks and moyer reported that 8 ± 10% of all untreated hypertensive patients had ed at the diagnosis of hypertension (17). a recent study using the validated international index of erectile function questionnaire reported a higher incidence of severe ed amongst hypertensive men than in the general population (18). in spite of the fact that hypertension causes ed by itself, frequently used antihypertensive drugs can also be a cause of ed (19). ed is more frequent after cerebrovascular events with up to 85% incidence of ed reported. there is strong relationship between various neurological diseases and ed. it is reported that ed incidence is high in men with multiple sclerosis (about 70-80%) and that more than 50% of such men have also complaint about decreased libido. such effects are not only based on autonomic and somatic neuropathies that affect men with multiple sclerosis, but they are also related to concomitant psychological factors such as depression and anxiety. chronic renal insufficiency (cri) is related to a decrease in erectile function, decrease of libido and infertility. ed incidence in men with cri is about 40%. it is thought that occlusion of cavernous arteries, veno-occlusive dysfunction, lack of testosterone, increase in prolactin levels, various drugs used, autonomic and somatic neuropathy and especially psychological factors are the reasons for ed in patients with renal insufficiency (20, 21). after a successful renal transplantation, 50-80% of the patients may return to their potency levels before the disease (22, 23). the relationship between ed and psychiatric diseases, chronic alcohol usage and chronic liver disease, malignancies, trauma and smoking was shown in various studies (24). psychogenic reasons psychogenic ed generally occurs in young adults under the age of 40. although psychogenic ed rate in men over the age of 50 is approximately 10%, 45% of all ed patients have psychogenic problems (25). sexual behaviors and penile erection are controlled by hypothalamus, limbic system and cerebral cortex. thus stimulating or inhibiting messages may be transferred to spinal erection centers in order to ease or prohibit erection. psychogenic reasons may be emotional problems such as depression and anxiety, previous traumatic sexual experiences, lack of self-confidence, suspicions in sexual roles, physical disorders in spouses and lack of attraction and also interparental conflicts or cultural differences, sexual myths or socioeconomical factors such as job stress. two possible mechanisms explaining the inhibition of erection in psychogenic ed are the direct inhibition of the spinal erection center of the brain by excessive normal suprasacral inhibition or over sympathetic discharge and the increased peripheral catecholamine levels that inhibit the relaxation required for erection by increasing the penis smooth muscle tonus (26). clinically it is reported that serum norepinephrine level is higher in patients with psychogenic ed when compared to normal controls or patients with vasculogenic ed (27). organic reasons 1. vascular pathologies in middle aged men, ed is generally vascular-derived accounting for 40-50% of all the etiological factors. according to the general population, pudendal artery lesions are seen more frequently in men with ed (28). apart from that, ed is frequently seen in men with atherosclerotic diseases such as ischemic heart disease and arterial foot disease. furthermore ed and cardiovascular diseases have similar risk factors such as hypertension, diabetes mellitus, hypercholesterolemia and smoking (29). such findings show that ed is a different form of vascular diseases. in a study it was observed that low penile brachial pressure index can be a predictive factor for myocardial infarction and cerebrovascular events (30). arterial diseases causing atherosclerotic or traumatic occlusion in hypogastric-cavernous-helix arterial branching decrease perfusion pressure and arterial blood flow through sinusoidal gaps, prolong time to maximum erection and reduce the rigidity of the erected penis. in most of arteriogenic ed patients, the decrease in penile perfusion is common. at arteriography of atherosclerotic ed patients, it was observed bilateral diffuse pathologic involvement of penile and cavernous arteries. focal stenosis in penile or cavernous arteries is mostly observed in young patients who have been exposed to pelvic or perineal blunt trauma (31). long-distance bicycle riding is a risk factor for neurogenic and vascular ed (32). in cavernous arteries of old men and men with dm, it were frequently observed fibrotic lesions together with intimal celik4_stesura seveso 08/10/14 12:11 pagina 198 proliferation, calcification or lumen stenosis. nicotine does not only reduce the blood flow of the penis but also inhibits the corporeal smooth muscle relaxation and thus the normal venous occlusion and may affect negatively erectile function. it was reported that ed rate is about 70% at 30 year age in patients who are consuming 1 package of cigarettes per day and at 15 year age in patients who are consuming 2 packages of cigarettes per day (33). as a result of uncontrolled venous leak, blood cannot be maintained in the cavernous bodies and erection cannot be obtained. such group of pathologies account for 2025% of all ed cases. veno-occlusive dysfunction that is an important reason of ed may occur following the below mentioned pathophysiological conditions: 1. presence or development of wide venous channels that drains corpus cavernosum 2. insufficient compression of subtunical and emissary veins that are formed after degenerative changes in tunica albuginea (peyronie’s disease, advanced age, dm) or traumatic damage (penile fracture). in fat tunica albuginea that has lost its elasticity during peyronie’s disease may inhibit the obstruction of emissary veins 107,108. tunica albuginea alteration may contribute to ed in men due to the reduction in elastic fibers and modification of its micro structure. although rare, in patients who underwent to surgery for peyronie’s disease, changes in the subtunical aerolar layer may violate the veno-occlusive mechanism. 3. structural changes in the fibroelastic content of trabecula, cavernous smooth muscle and endothelium may also cause venous leakage. 4. individuals with anxiety may have insufficient neurotransmitter release or excess adrenergic tonus; insufficient smooth muscle relaxation and subsequent insufficient expansion of sinusoids and insufficient compression of subtunical venules may result in ed. it is shown that the changes in ! adrenergic receptors or the decrease of nno release may increase smooth muscle tonus and reduce the relaxation related to endogenous muscle relaxants (34). 5. acquired venous shunts, operative correction of priapism, permanent shunts between glans/cavernosal body or cavernous body/spongiform body may cause ed. 2. neurogenic reasons neurogenic reasons explain approximately 10-20% of ed cases. medial preoptic area (mpoa), paraventricular nucleus and hippocampus are important integration centers for penile erection and sexual drive. pathological situations that affect these regions such as parkinson’s disease, stroke, encephalitis or temporal lobe epilepsy are generally associated with ed. the negative effect of parkinson’s disease on erectile function may occur as a result of the imbalance in dopaminergic pathways. tumor, dementia, alzheimer’s disease, shy-drager syndrome and trauma are other important brain lesions accompanying ed. the grade of erectile function in spinal cord traumatic patients is mostly related to the quality, location and prevalence of the spinal lesion. while reflex in the upper motor neuron complete lesions of spinal cord is conserved at about 95%, erection can be provided in only 25% in the lower motor neuron complete lesions (35). it is known that sacral parasympathetic neurons have an important role in the protection of reflex of erection. furthermore thoracolumbar pathway may compensate the losses related to sacral lesion via synaptic connections. other diseases at spinal level (spina bifida, discal hernia, syringomyelia, tumor, transverse myelitis and multiple sclerosis etc.) may affect the afferent or efferent nerve pathways similarly (36). 3. post-trauma and post-surgery ed the mechanism of ed that develops after radical prostatectomy or cystoprostatectomy is generally neurogenic but ed may also be due to vascular reasons. after radical surgery, neurogenic lesion may generally develop in the cavernosal nerves in the posterolateral of prostate or in the pelvic plexus. in the past ed frequency after radical prostatectomy or urinary bladder surgeries was estimated about 100%; today this ratio varies between 35% and 68% depending on the surgical clinic, clinical and pathological stage and age of the patient as the result of the development of neuroprotective techniques (37, 38). ed prevalence in the patients exposed to transurethral prostate resection (tur-p) due to benign prostate hyperplasia (bph) varies between 4-10% (39). cavernous nerve progresses at 5 and 7 o’ clock at prostatic urethra level, 3 and 9 o’clock at membranous urethra level and 11 and 1 o’clock at penile urethra level. during tur-p, the nerves may be damaged due to the energy released. deep resection and coagulation at cavernous nerve transition points may cause the loss of erection. it is reported that ed develops in 59% after abdominoperineal resections performed for rectum cancer (40). after retroperitoneal lymph node dissection and lumber symphatectomy, and during aorta-iliac and aorta-femoral surgery, ed develops in 10-20% due to the damage of nerves who regulate the reflex of erection (41). due to the surgeries performed for head trauma and intracranial pathologies, influence of limbic system, destruction of hypothalamo-hypophyseal axis and modification of hormonal control may cause ed. like perineal trauma (like overriding) and penis fracture, ed may develop after the traumas causing amendments in the anatomic structure of the penis. additionally traumas causing posterior urethra ruptures destruct the reflex pathways of erection and may cause ed development at a rate of 10-50%. 4. endocrinologic reasons hypogonadism in ed patients is a commonly seen pathology. any disorder in hypothalamo-hypophyseal axis may result in hypogonadism. as hypogonadotropic hypogonadism can be congenital, it may also develop depending on a tumor or trauma. hypergonadotropic hypogonadism develops as a result of various causes such as tumor, trauma, surgery or mumps orchitis. hypophysis adenoma or drug-induced hyperprolactinemy can also cause ed. in hyperprolactinemy cases, symptoms such as decrease in libido, ed, galactorrhea, gyneacomastia and infertility may occur. high serum prolactin levels suppress the releasing hormone levels and reduce the testosterone levels. ed can be seen together with hyperthroidism and hypothyroidism. hyperthyroidism is associated to loss of libido that may be caused by the increase of levels of cir199archivio italiano di urologia e andrologia 2014; 86, 3 current evaluation of erectile dysfunction celik4_stesura seveso 08/10/14 12:11 pagina 199 archivio italiano di urologia e andrologia 2014; 86, 3 o. celik, t. ipekci, i. akarken, g. ekin, turker koksal 200 culating estrogen and rarely with ed. in hypothyroidism, plasma testosterone is decreased because of the reduced testosterone binding globulin. as a result, hypothyroidism may participate in ed pathogenesis by causing low testosterone release and high prolactin level. 5. diabetes mellitus and ed dm is a chronic disease that is commonly seen throughout the world with a prevalence ranging 0.5-2%. ed prevalence is three times more frequent in diabetic men (%28/%9,6). diabetic ed occurs in young age and its incidence is the course of the disease. although ed is seen more frequently in patients with neuropathic complications, its relationship with vascular damage is not yet clear. dm causes ed due to various physiopathologic mechanisms involving psychological functions, central nervous system functions, androgen release, peripheral nerve activation, endothelial cell proliferation and smooth muscle cell contraction (42). in comparison to non-diabetic men, major atherosclerotic vascular lesions are seen 40 times more frequently in diabetic men and frequently dm accompanies ed. in men with dm, it was demonstrated that there is a decrease in the quantity and rigidity of night erections during sleep. again some studies have specified that penile arterial insufficiency occurred in men with dm with rate ranging 75-100% (43). the presence of ultra-structural changes is seen in the cavernosal tissues of diabetic men. these can be summarized as increased collagen ratio at smooth muscle level, thickening in basal lamina and loss of endothelial cells (41). it was also shown that there is a significant decrease in the relaxation responses to endothelial and neuronal no. it was observed that neurogenic no formation was significantly decreased in men with vascular ed when compared to patients with non-vascular ed and controls. a possible etiology that explains all these findings is the advanced stage of glycation end products (age) levels that are seen in diabetics. in various studies there are evidences showing alterations of the mechanisms causing no release in relation to the increase of free oxygen radical production in diabetes that causes the decrease of vasodilatator response. 6. ed related to ageing and chronic diseases in the literature, it is shown that there is a progressive deterioration in sexual functions due to ageing in healthy men. changes, as prolongation of time to erection, erection weakening, strong loss of ejaculation, decrease in the ejaculate volume and prolongation in the resting period between two sexual intercourses have been described in association with ageing. hypertension is an independent risk factor in the development of ed (44) and ed is seen more frequently in the patients who are treated for hypertension. complications developed after hypertension such as ischemic heart disease and renal insufficiency increase the prevalence of ed. severe ed prevalence in men submitted to hemodialysis for chronic renal insufficiency (cri) is reported as high as 45% (45) and risk increases with increasing age, dm and not using angiotensin-converting enzyme (ace) inhibitors. various physiopathological effects such as permanent uremia, deterioration in the hypothalamus-hypophysis-testis sex hormone axis, hyperprolactinemia, increase in atheromatous diseases and psychological diseases cause ed development (46). chronical diseases such as tuberculosis, tumors, leukemia can also cause loss of libido and ed. in scleroderma the rate of ed is about 60% due to thin penile arteries. in a study performed in brucella patients it is reported a ed rate of 68% in parallel with the duration of disease. 7. ed related to priapism and peyronie’s disease priapism is a pathological penile erection that is not related to sexual stimulation or that continues after sexual stimulation. sickle cell anemia, trauma, neuoplasias, leukemia, intracavernosal injection, total parenteral nutrition and drugs (anti-depressants, anti-psychotics, ! blockers as prazosin, heparin, warfarin, cocaine, etc.) are the agents that cause priapism. ed is observed in patients with priapism at a rate of about 11% (47). peyronie’s disease is one of the pathologies that affect the penis anatomy. ed incidence in peyronie’s disease is related to the severity of the disease. it is reported that anomalies due to the plaque have been observed at nocturnal penile tumescence in 5-7%. conclusion in historical literature erection physiology was explained by different mechanisms. aristo described 3 nerve fibers that carry spirit and energy to the penis and explained penile erection by air ingress (13), in 1504 leonardo da vinci showed that there is blood in the penis of men who were hung on (14), in 1573 varolio showed that ischiocavernous and bulbocavernous muscles constrict the penis stem to achieve erection. finally in 1585 in the book titled “ten books and production book about surgery”, ambroise pare described the penis as formed of concentric layers including nerves, veins, arteries,two ligament (corpora cavernosa), an urinary system and four muscles in 1585 in the book titled “ten books and production book about surgery” (11, 14). these observations show us that ed has been a popular research area throughout history. we suggest that researches will be effective in increasing the knowledge of the etiology and pathophysiology of ed especially at molecular level and will offer us a deeper insight in the future. references 1. consensus development conference statement. national institutes of health. impotence. december 7-9, 1992. int j impot res. 1993; 5:181-284. 2. boylu u, miroglu c. history of erectile dysfunction. bju inter national. 2002; 90:433-441. 3. walsh pc. campbell’s urology. 2005; 2:1591-2. 4. mckinlay jb. the worldwide prevalance and epidemiology of erectile dysfunction. int j impot res. 2000; 12(suppl 4):6-11. 5. rosen rc, fisher wa, eardeley i. the multinational mens’s attidues to life events and sexuality (males) study: prevalence of erectile dysfunction and related health concerns in the general population. curr med res opin. 2004; 20:607-17. 6. selvin e, burnett al, platz ea. prevalence and risk factors for erectile dysfunction in 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erectile dysfunction in the patient with diabetes mellitus. am j manag care. 2004; 100(suppl 1):3-11. 15. lewis rw. epidemiology of erectile dysfunction. urol clin north am. 2001; 28:209-16. 16. nicolai mp, van bavel j, somsen ga, et al. erectile dysfunction in the cardiology practice-a patients' perspective. am heart j. 2014; 167:178-85. 17. oaks ww, moyer jh. sex and hypertension. med asp hum sex. 1972; 6:128-37. 18. burchardt m, burchardt t, baer l et al. hypertension is associated with severe erectile dysfunction. j urol. 2000; 164:1188-91. 19. silvestri a, galeta p, cerquetani e. report of erectile dysfunction after therapy with beta-blockers is related to patient knowledge of side effects and isreversed by placebo. eur heart j. 2003; 24:1928-32. 20. kaufman jm, hatzichristou dg, mulhall jp. impotence and chronic renal failure: a study of the hemodynamic pathophysiology. j urol. 1994; 151:612-8. 21. bellinghieri g, santoro d, mallamace a, savica v. sexual dysfunction in chronic 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28:289-308. 41. nusbaum mr. erectile dysfunction: prevelance, etiology and major risk factors. j am osteopath assoc. 2002; 102-1-6. 42. dunsmuir wd, holmes s. the etiology and management of erectile, ejaculatory and fertility problems in men with diabetes mellitus. diabet med. 1996; 13:700-708. 43. bemelmans blh, meuleman ejh, doesburg wh, notermans lh, debruyne fmj. erectile function in diabetic men: the neurological factor revisited. j urol. 1994; 151:884-889. 44. burchardt m, burchardt t, baer l, et al. hypertension is associated with severe erectile dysfunction. j urol. 2000; 164:1188-1191. 45. rosas se, joffe m, franklin e, et al. prevelance and determinants of erectile dysfunction in haemodialysis patient. kidney int. 2001; 59:2259-66. 46. ayub w, fletcher s. end stage renal disease and erectile dysfunction: is there any hope? nephrol dial transplant. 2000; 15:1525-28. 47. iacono f, bara s, de rosa g. microstructural disorders of tunika albuginea in patients affected by impotance. eur urol. 1994; 26:233-239. 201archivio italiano di urologia e andrologia 2014; 86, 3 current evaluation of erectile dysfunction correspondence orcun celik, md (corresponding author) orcuncelik82@hotmail.com ilker akarken, md gokhan ekin, md tepecik education and research hospital, urology clinic, gaziler cd.no:468 35110, yenisehir, izmir, turkey i. turker koksal, md, prof tumay ipekci, md akdeniz university, faculty of medicine, department of urology 07070 antalya, turkey celik4_stesura seveso 08/10/14 12:11 pagina 201 stesura seveso 239archivio italiano di urologia e andrologia 2014; 86, 3 case report first case of 18f-facbc pet/ct-guided salvage radiotherapy for local relapse after radical prostatectomy with negative 11c-choline pet/ct and multiparametric mri: new imaging techniques may improve patient selection eugenio brunocilla 1, riccardo schiavina 1, cristina nanni 2, marco borghesi 1, matteo cevenini 1, enrico molinaroli 1, valerio vagnoni 1, paolo castellucci 2, francesco ceci 2, stefano fanti 2, caterina gaudiano 3, rita golfieri 3, giuseppe martorana 1 1 department of urology, university of bologna, s. orsola-malpighi hospital, bologna, italy; 2 department of nuclear medicine, university of bologna, s. orsola-malpighi hospital, bologna, italy; 3 department of radiology, s. orsola-malpighi hospital, bologna, italy. we present the first case of salvage radiotherapy based on the results of 18f-facbc pet/ct performed for a psa relapse after radical prostatectomy. the patients underwent 11ccholine pet/ct and multiparametric mri that were negative while 18f-facbc pet/ct visualized a suspected local relapse confirmed by transrectal ultrasound-guided biopsy. no distant relapse was detected. thus the patient was submitted to salvage radiotherapy in the prostatic fossa. after 20 months of follow-up, the psa was undetectable and 18f-facbc pet/ct was negative. salvage radiotherapy after surgery, provided that it is administered at the earliest evidence of the biochemical relapse, may improve cancer control and favourably influence the course of disease as well as the adjuvant approach. new imaging techniques may increase the efficacy of the salvage radiotherapy thus helping in the selection of the patients. preliminary clinical reports showed an improvement in the detection rate of 20-40% of 18f-facbc in comparison with 11c-choline for the detection of disease relapse after radical prostatecomy, rendering the 18f-facbc the potential radiotracer of the future for prostate cancer. key words: prostate cancer; pet/ct; 11c-choline; 18ffacbc; salvage radiotherapy; biochemical relapse; local relapse. submitted 12 september 2013; accepted 30 june 2014 summary no conflict of interest declared. introduction about 30% of all patients undergoing radical prostatectomy (rp) or radiation therapy for prostate cancer (pca) will develop local or distant recurrences within 10 years from initial therapy, and a third of patients will receive secondline treatment within five years (1, 2). generally the biochemical relapse precedes the disease relapse by many doi: 10.4081/aiua.2014.3.239 years and disease relapse with undetectable psa is exceptionally rare (3). conventional imaging techniques are not adequate in localizing the site of recurrence in the early phase of the psa relapse. nowadays, positron emission tomography/computerized tomography (pet/ct) with 11carbonium or 18-fluoro-choline may identify the site of recurrence earlier, with better accuracy than conventional imaging and in a single step (4). however, choline pet/ct has showed limited accuracy in the detection of local recurrence in patients with low level of psa. multiparametric magnetic resonance showed encouraging results to detect local recurrence in patients with low psa and with small disease relapse (5). in recent years the investigational synthetic l-leucine analogue (anti1amino-3-18f-fluorocyclobutane-1-carboxylic acid, in brief 18f-facbc) has been proposed as a possible alternative radiopharmaceutical to detect pca relapse (6). from a clinical point of view the performance of 18ffacbc for the evaluation of pca relapse showed first very promising results (7). in the setting of the salvage treatments for disease relapse of pca, many observational studies of salvage radiotherapy (rt) have shown complete responses in a substantial proportion of patients in the early phase of the psa relapse with comparable results as adjuvant radiotherapy (6). we present the first case to our knowledge of salvage radiotherapy based on the results of 18f-facbc pet/ct performed for a psa relapse after radical prostatectomy. case report 57 years-old men was scheduled for radical treatment for clinical t2 prostate cancer with biopsy gleason score of 4+3 and preoperative psa of 12.0 ng/ml. preoperative evaluation with bone scan and 11c-choline pet/ct showed the absence of distant or lymphatic metastases. the patients underwent radical prostatectomy plus extended pelvic lymph-node dissection including interbrunocilla cr_stesura seveso 08/10/14 12:22 pagina 239 archivio italiano di urologia e andrologia 2014; 86, 3 brunocilla, schiavina, nanni, borghesi, cevenini, molinaroli, vagnoni, castellucci, ceci, fanti, gaudiano, golfieri, martorana 240 nal, external, obturator lymph-nodes and common lymph-nodes up to the cross of the ureters. the final histology after surgery showed a pt3a pca with gleason score = 4 + 4 and no lymph-node metastases (lnms) out 21 lymph-nodes retrieved. after 24 months from surgery, psa increased up to 1.1 ng/ml (psa doubling time of 10 months). bone scan was negative. he underwent endorectal multiparametric mri, 18f-facbc pet/ct and 11ccholine pet/ct within one week in the setting of a comparative study protocol approved by the ethical committee of our hospital (9). 11c-choline pet/ct and mri were negative (figures 1, 2) while 18f-facbc showed a positive uptake within prostatic fossa (figure 3). transectal ultrasound-guided biopsy confirmed the presence of prostate cancer relapse (gleason score = 4 + 4) and intensity modulated radiotherapy (64.8 gy) plus androgen deprivation therapy for 6 months were administrated. after 20 months after radiotherapy psa was undetectable with no androgen deprivation therapy. no treatment complications were recorded. figures are posted in supplementary materials on www.aiua.it discussion choline-pet/ct is nowadays the most important imaging technique in the assessment of pca relapse and can detect the site of disease recurrence even with very low psa level. the most important limitation is the limited spatial resolution of pet/ct scanner with little detection rate for small local relapse. furthermore, when cholinepet/ct identifies a suspected lesion, almost twice as many metastases are present and the detection rate of choline-pet/ct is still suboptimal (4). one important reason for this low sensitivity is the slow proliferation of pca cells reflecting a slow membrane metabolism and resulting in a small amount of choline uptake. for this reason, some metastatic deposit even greater than 10 mm may be completely negative at pet/ct scan. multiparametric mri has demonstrated higher global accuracy than choline-pet/ct for local relapse detection but small lesion can be missed (5). the functional activity of the new radiotracer 18ffacbc for pet/ct is related to two different amino acid transporters (asc and lat1) which appears to be upregulated in prostate cancer progression to metastatic disease (6, 7). preliminary clinical reports with 18f-facbc showed an improvement in the detection rate of 20-40% in comparison with 11c-choline, rendering the 18f-facbc the potential radiotracer of the future (7). although data from randomized trials are lacking, substantial evidence from retrospective, observational studies shows that salvage rt is effective at controlling local recurrence and reduces the risk of distant metastasis and disease specific mortality (1, 8). new diagnostic tools such as 18ffacbc pet/ct may improve the potential of this approach by increasing the assessment and the selection of the patients. the ability of 18f-facbc pet/ct of visualizing the site of recurrence in the early phase of prostate cancer relapse may improve the tailoring of the treatment planning and may enhance the response to salvage treatments. the present clinical report and fist clinical studies encourage going on in the research of new imaging techniques in the detection of prostate cancer recurrence. references 1. stephenson aj, bolla m, briganti a, et al. postoperative radiation therapy for pathologically advanced prostate cancer after radical prostatectomy. eur urol. 2012; 61:443-51. 2. brunocilla e, pultrone c, pernetti r, et al. preservation of the smooth muscular internal (vesical) sphincter and of the proximal urethra during retropubic radical prostatectomy: description of the technique. int j urol. 2012; 19:783-5. 3. pepe p, fraggetta f, tornabene f, et al solitary lung metastasis after radical prostatectomy in presence of undetectable psa. arch ital urol androl. 2012;84:208-10. 4. farsad m, schiavina r, franceschelli a, et al. positron-emission tomography in imaging and staging prostate cancer. cancer biomarker. 2008; 4:277-84. 5. panebianco v, sciarra a, lisi d, et al. prostate cancer: 1hmrsdcemr at 3t versus [(18)f]choline pet/ct in the detection of local prostate cancer recurrence in men with biochemical progression after radical retropubic prostatectomy (rrp). eur j radiol. 2012; 81:700-8. 6. schuster dm, savir-baruch d, nieh p, et al. detection of recurrent prostate carcinoma with anti-3-18f-fluorocyclobutane-1carboxylic acid pet/ct and 111in-capromab pendetide spect/ct. radiology 2011; 259:852-861. 7. nanni c, schiavina r, boschi s, et al. comparison of 18f-facbc and 11c-choline pet/ct in patients with radically treated prostate cancer and biochemical relapse: preliminary results. eur j nucl med mol imaging 2013, apr 17. 8. tramacere f, gianicolo ea, pignatelli a, portaluri m. analysis of survival in radical and postoperative radiotherapy for prostate cancer. arch ital urol androl 2011; 83:188-94. correspondence eugenio brunocilla, md riccardo schiavina, md (corresponding author) rschiavina@yahoo.it marco borghesi, md matteo cevenini, md enrico molinaroli, md valerio vagnoni, md giuseppe martorana, md department of urology of university of bologna, s. orsola-malpighi hospital, via palagi 9, 40134, bologna, italy cristina nanni, md paolo castellucci, md francesco ceci, md stefano fanti, md department of nuclear medicine of university of bologna, s. orsola-malpighi hospital, bologna, italy caterina gaudiano, md rita golfieri, md department of radiology, s. orsola-malpighi hospital, bologna, italy brunocilla cr_stesura seveso 08/10/14 12:22 pagina 240 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 3188 original paper a study on the effects of the hydroalcholic extract of the aerial parts of alhagi camelorum on prolactin and pituitary-gonadal activity in rats with hypercholesterolemia ali zarei 1, saeed changizi ashtiyani 2, gholam hassan vaezi 3 1 young researchers club, abadeh branch, islamic azad university, abadeh, iran; 2 department of physiology, arak university of medical sciences, arak, iran; 3 department of biology, islamic azad university, damghan branch, semnan, iran. background: although endocrine disorders are not a common cause of infertility, in some cases, testing thyroid function, and hypothalamus pituitary gonadal axis can determine the cause of infertility. we aimed to investigate the effect of the aerial parts of alhagi camelorum extract on prolactin, cortisol and pituitary gonadal axis activities in rats with hypercholesterolemia. materials and methods: in this study, 35 male wistar rats in 5 groups (n = 7) were assigned as: control group with normal diet, the sham group with fat diet and three experimental groups of hypercholesterolaemic animals which received alhagi camelorum extract at a minimum dose of 100 mg/kg, average dose of 200 ml/kg and maximum dose of 300 mg/kg over a period of 21 days. at the end of the period, blood samples were collected from all groups and blood factors were then measured and analyzed. results: in the sham group compared to the control, cholesterol levels increased and fsh levels decreased, whereas cholesterol levels reduced in the experimental groups. alhagi camelorum extract also reduced testosterone level and increased prolactin and gonadotropins. conclusion: alhagi camelorum extract at low and average doses reduced cortisol, testosterone and cholesterol and increased gonadotropins. so it can cause reproductive disorders in male rats. the extract at maximum dose can increase cortisol and prolactin. as these two hormones work together to produce milk, this plant can help to boost breastfeeding. key words: alhagi camelorum; prolactin; testosterone; cholesterol; gonadotropin. submitted 8 april 2014; accepted 30 january 2014 summary no conflict of interest declared. state in which no pregnancy occurs after a year of sex activity without using birth control methods. when discussing infertility, people generally believe that most problems are related to women. in fact, nearly 30% of infertility problems are related to men and 20% are common problems between women and men. so, 50% of men are involved in problems related to infertility. however, this rate is different in different countries and in different studies. obesity is associated with various hormonal changes that can be responsible for changes in sperm motility and abnormal sexual function. evidence suggests that in obese men, more androgen changes into estrogen in fat tissue and serum testosterone level decreases. however, by increasing the negative feedback of estrogen on pituitary gland, gonadotropin levels decrease. pulse obesity also affects gnrh-fsh-lh which may affect sex hormones secretion and sperm maturation by disrupting leydig and sertoli cells (1, 2). endocrine disorders are not among the common causes of infertility; however, in some cases, the cause of infertility can be determined by testing thyroid, gonadotropins, prolactin and testosterone. the level of fsh rises with germinal cell aplasia and the level of testosterone in men with hypogonadotropic hypogonadism decreases (1). leydig cells are the main source of testosterone and have receptors for prolactin which at normal levels increases testosterone secretion. these studies suggest a synergy between prolactin, lh and testosterone. however, high levels of prolactin reduces testosterone and leads to frigidity (1, 2). prolactin is regulated by dopamine and some other factors such as trh. dopamine is a neurotransmitter that has an inhibitory effect on the hypothalamic-pituitary-gonadal axis (2). trh, secreted from the hypothalamus gland, stimulates prolactin secretion. cholesterol is the precursor of steroid hormones and cholesterol changes into pregnenolone by p450 in mitochondria (1, 3, 4). on the other hand, increased level of blood cholesterol is associated with coronary artery disease, fat liver and infertility. excessive fat causes the male hormone of testosterone to be converted to estrogen which reduces the production of sex cells. doi: 10.4081/aiua.2014.3.188 introduction today, with advances in science and technology, it is recognized that infertility is not just a problem for women. male factors are also involved. infertility is defined as a zarei_stesura seveso 09/10/14 10:38 pagina 188 189archivio italiano di urologia e andrologia 2014; 86, 3 effects of the hydroalcholic extract of the aerial parts of alhagi camelorum on prolactin and pituitary-gonadal activity in rats with hypercholesterolemia cholesterol levels can be lowered by diet or drugs (1, 4). many plants and compounds can be effective in reducing cholesterol. alhagi camelorum is one of the plants in traditional medicine which is used to treat metabolic, gastrointestinal and liver diseases, rheumatic disorder, migraines and warts. laboratory studies indicate that alhagi camelorum extract reduces body temperature and heart rate. the extract also inhibits the action of acetylcholine to relax the muscles and is helpful in opening the urinary tract and disposal of kidney stones (5). this plant, commonly called camel thorn (figure 1), with the scientific name of alhagi maurorum belongs to the plant family of leguminosae (papilionaceous). the family has about 550 genera and more than 13000 species (6). other chemical researches on this plant indicate that it contains sterols and fatty acids (7, 8), flavonoids (9, 10), coumarins (8), alkaloids (6, 8), and vitamins. about 12 types of flavonoids have been isolated from this plant (1). studies have shown that flavonoids have antiandrogenic and antifertility effects on the reproductive system of dogs (12, 13). studies on the bioactive compounds which have the potential to inhibit or stop cancer cells can pave the way to discover more effective drugs (14). nowadays, people are increasingly using fruits and vegetables due to their protective effects against illnesses like cancer, cardiovascular and liver diseases (15, 16). this is due to the antioxidant compounds present in plants, including vitamins b and c, carotenoids, lycopene and flavonoids, which prevent the damages caused by free radicals (17, 19). as infertility and lipid disorders are increasing and most of the anti-fat drugs and contraceptives available in the pharmaceutical market of iran and the world have multiple side effects, and also thanks to the increasing tendency towards herbal remedies because of their fewer side effects, any study on medicinal plants is of great value (4). with this in mind, the present study aimed to investigate the effects of the extract of the aerial parts of alhagi camelorum on prolactin and pituitary-gonadal axis activities in rats with hypercholesterolemia. methods this is an experimental study .all animals were taken from razi institute in fars province and were kept in standard conditions of temperature and light.this study is based on observing all moral codes of working with laboratory animals established by the ministry of health and medical training (iran). before the research, all the animal were weighed to be within a certain weight range. initially, 35 male wistar rats with the average weight of 5 ± 170 g were randomly divided into 5 groups (n = 7) as follows: controls the animals in this group did not receive any drug or solvent during the experiment and their diet was normal. sham group consisted of hypercholesterolemic rats which received 0.2 ml of solvent (normal saline) for 21 days as gavage; (2% cholesterol was added to their food to make them hypercholesterolemic); experimental group 1, hypercholesterolaemic rats which received a minimum dose of 100 mg/kg of alhagi camelorum extract for 21 days as gavage; experimental group 2: hypercholesterolemic rats that were gavaged for 21 days with an average dose of 200 mg/kg of the extract; and experimental group 3 were hypercholesterolemic rats receiving maximum dose of 300 mg/kg of the extract for the same period as gavage feeding. preparation method for high cholesterol food to obtain a 2% high-cholesterol diet, 20 grams of merck pure cholesterol powder (fluke chemika) was solved in 5 ml of olive oil and the solution was well mixed with a kilogram of rat diet. to avoid deterioration of the food it was kept in the refrigerator for only two days (20, 21). extraction alhagi camelorum plants were collected from the suburb of abadeh (fars province/iran) and were identified and confirmed by the pnu (payame noor university) department of botany (herbarium code was 002/040/073). to prepare the alhagi camelorum alcoholic extract, after providing the aerial parts and removing impurities, 800 grams of the collected plant samples were crushed and mixed with ethyl alcohol 98% by the ratio of 1 to 5. the content obtained was kept in a package for 48 hours in vitro and it was carefully filtered by passing it through different small and big filters. then it was placed in a water bath to concentrate. finally, different concentrations of the obtained extract (about 15 g per 100 g of crushed plant) was prepared by adding different amounts of normal saline. during the experimental period all experimental groups were fed with high fat diet. during the test period (21 days) the animals were daily injected at 9 am. after completing this course and in order to measure plasma biochemical factors of the animals, they were mildly anesthetized with ether and their blood was collected and then centrifuged at 3000 rpm. the serum was separated and transferred to the laboratory for measurement of factors. to measure cholesterol, prolactin, testosterone, cortisol, and gonadotropin ria (ria), pars azmoon kits and ria 1000 machine (made in usa) were used. for statistical analysis the mean obtained (mean ± sem), one way figure 1. the aerial parts of camel thorn (alhagi camelorum). zarei_stesura seveso 09/10/14 10:38 pagina 189 archivio italiano di urologia e andrologia 2014; 86, 3 a. zarei, s. changizi ashtiyani, g. hassan vaezi 190 anova test and tukey and duncan tests were used. all statistical analyses were done using spss software version 17 (p < 0.05). results as shown in table 1 the amount of cholesterol in the sham group increased significantly compared to the control group and in the group receiving the minimum dose of the extract the cholesterol level significantly decreased compared to the sham group (p = 0.02). the differences between experimental groups are not significant. in the case of fsh, mean value in the sham group shows a significant decrease than in the control group. and the group receiving an average dose of alhagi camelorum extract shows a significant increase compared to the sham group and the groups receiving the minimum and maximum doses of the extract (p = 0.001). lh level in the sham group did not show significant changes than in the control group. however, in groups with minimum and average doses there is a significant increase compared to both the sham group and the group receiving the highest dose of the extract (p = 0.01). in the case of testosterone in the sham group no significant change was seen if weighed against the control group, however, the amount of it in groups receiving minimum and average doses a significant decrease was seen compared to the sham group (p = 0.02). none of the changes in experimental groups were significant. prolactin level increased in the sham group compared to the control group, but these changes were not significant. its level in the group receiving the maximum dose showed a significant increase as compared to the sham group and the groups which received minimum or average doses of the extract (p = 0.007). however, no significant difference was observed between the average and minimum groups. cortisol levels in the sham group did not show any significant changes as compared to the control group, but in the groups receiving minimum and average doses of the extract it was significantly lower than in the sham group. cortisol levels in the group receiving the highest dose of the extract compared to sham group as well as the group receiving the least and average doses of the extract showed a significant increase (p = 0.000). discussion test results showed that by increasing the amount of cholesterol in the sham group, fsh levels decreased. the administration of the extract to hypercholesterolaemic rats increased gonadotropin and prolactin levels and decreased the level of testosterone. the level of cortisol in the group receiving the highest dose of the extract reduced, but it decreased in groups with the minimum and average doses. nowadays, with the prevalence of obesity, it has become an important issue that how fertility in men is affected by obesity and fat. in this study, the relationship between increased cholesterol level and functions of pituitarygonadal axis in the sham group was measured. it is important because if obesity is the cause of male infertility, it can be treated. obesity affects fertility in men by various mechanisms, among which we can refer to changes in gonadotropin secretion from the pituitary gland, changes in sex hormone-binding globulins, decreased libido, sperm dna damage ,and so on. another important effect of obesity on fertility is the reduced testicular activity. in adipose tissue ten percent of testosterone which is male hormone turns into estradiol which is a female hormone. increased estradiol makes the breasts grow larger in men and obese men typically have larger breasts (24-22). however, studies in this field are controversial. for example, pauli et al. (25) and relvany et al. (26) showed that weight gain does not affect the fertility of the semen quality parameters while wagner et al. (2010) and paasch et al. (2010) stated that increased bmi has a negative impact on sperm quality and fertility indices (27-28), which is consistent with the results of the present study as it was seen that in the control group by increasing cholesterol, the level of fsh decreased. on the effect of the extract on pituitary gonadal axis activities it can be said that on one hand, the extract reduced cholesterol, testosterone and on the other, it in creased prolactin and gona do tro pin levels. one of the most important ways to adjust lh and fsh groups control sham ac ac ac (100 mg/kg) (200 mg/kg) (300 mg/kg) parameters cholesterol 69.8 ± 2.9 86.57 ± 1.9 66.33 ± 3.3 70.83 ± 7.24 76.16 ± 5.2 * ! lh 1.07 ± 0.2 0.71 ± 0.03 1.40 ± 0.3 1.54 ± 0.2 0.85 ± 0.03 " ! # ! fsh 2.8 ± 0.4 1.03 ± 0.07 1.64 ± 0.45 3.34 ± 0.5 1.60 ± 0.2 * $ ! # testosterone 6.9 ± 2.7 5.94 ± 1.8 1.65 ± 0.3 0.55 ± 0.1 2.67 ± 0.6 ! ! prolactin 3.45 ± 0.25 5.16 ± 0.55 6.49 ± 0.7 6.28 ± 1.4 9.84 ± 1.8 " # ! cortisol 20.2 ± 0.8 20.77 ± 4.8 10.27 ± 0.2 10.33 ± 1.40 27.15 ± 2.4 ! ! " # ! * marks a significant change compared with the control group, ! represents a significant change compared with the sham group. " represents a significant change between the minimum and maximum doses of alhagi camelorum extract. % indicates significant change between average and maximum doses of alhagi camelorum extract. ! represents a significant change in minimum and average doses of alhagi camelorum extract. table 1. effects of different doses of the extract of the aerial parts of alhagi camelorum (ac) on cholesterol, cortisol, testosterone, prolactin and gonadotropin. zarei_stesura seveso 09/10/14 10:38 pagina 190 191archivio italiano di urologia e andrologia 2014; 86, 3 effects of the hydroalcholic extract of the aerial parts of alhagi camelorum on prolactin and pituitary-gonadal activity in rats with hypercholesterolemia gonadotropin levels is through negative feedback effect of testosterone. that is when the level of this hormone increases, gonadotropin levels decrease and vice versa (29). in this study it seems reasonable that by increasing testosterone gonadotropins decreased. leydig cells are the main source of testosterone. leydig cells have receptors for prolactin that at normal levels increases testosterone. this suggests a collaboration between prl and lh and testosterone. however, high levels of prolactin, reduce testosterone (1). the results of this study showed that the alhagi camelorum extract reduced cholesterol and testosterone, but it increased gonadotropins and prolactin. lhrh hormone can be another possibility for the reduction of testosterone level. this hormone increases lh and fsh hormones and at the same time inhibits testicular testosterone synthesis and secretion by reducing lh receptors (30, 31). therefore, in this study, despite the increase in fsh and lh, lower testosterone seems to be reasonable and the results of this study is consistent with previous studies on effect of blue plate extract (centella asiatica) on spermatogenesis, as studies show the chemical compounds in both plants are similar (32). testosterone is one of the hormones needed for spermatogenesis. lower level of this hormone could possibly reduce the number of spermatogonial and spermatocytes cells. these cells produce growth factors such as activin and in the presence of calcium ions, cause karyokinesis, cytokinesis and sperm differentiation (33-34). studies on alhagi camelorum plant indicates that on one hand this herb may inhibit calcium channels and on the other active components of the plant including flavonoids have contraceptives and anti-androgenic effects on reproductive system (12, 13). alkaloids are key ingredients in this plant. alkaloids by reducing androgens lead to atrophy of epithelial cells and subsequently prohibits androgenic effects on tissues and thus cancer is treated (4, 35). alkaloids also easily cross the cell membrane and thus they destroy the cytoskeleton, help a variety of free radicals to release and ultimately cause detrimental changes in cellular structure which in turn causes higher activity of white blood cells (anti-inflammatory), while some studies suggest that they have also antioxidant effects (35, 36-38) in addition, alkaloids inhibit cholesterol synthesis (39). similar studies on berberis indicates that the alkaloid compounds in this plant such as berberine and berbamine can be effective in the prevention of coronary artery diseases and could possibly reduce total cholesterol levels . blocking calcium channel is the major effect of berbamine. berberine increases the production of a receptor in the liver that binds with cholesterol and facilitates its disposal (20, 21). since cholesterol is the precursor of steroid hormones, the extract probably lowers testosterone by reducing cholesterol. bashtiny et al. in a study on feeding animals with alhagi camelorum showed that it increased their milk production. this is consistent with our findings as increased prolactin level is one of the most important factors for increasing milk (40). injecting prolactin and hydrocortisone acetate lactogenic hormone in a variety of lactating mammals induces the synthesis and accumulation of beta-carotene in the mammary glands of rats. research shows that glucocorticoids can be effective only when they are accompanied by prolactin. studies also showed that milk secretion is the result of several hormones, and herbal extracts directly stimulate endogenous prolactin secretion. as a result, it works effectively on mammary glands. for example, pectin compounds in plants are capable of stimulating the secretion of prolactin, growth hormone, lh and endorphins from rat pituitary. most active fractions of the plant that cause prolactin secretion are made of polysaccharides because they have higher amounts of pectin. in addition, there are other compounds involved including prolactin, cortisol and growth hormones (41). conclusion based on the findings in this study, alhagi camelorum extract at the average and minimum doses decreases cortisol, cholesterol, testosterone and increases gonadotropins. so 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20:61-72. correspondence ali zarei, phd young researchers club, abadeh branch, islamic azad university, abadeh, iran saeed changizi ashtiyani, phd (correspondig author) dr.ashtiyani@arakmu.ac.ir department of physiology, arak university of medical sciences, arak, iran gholam hassan vaezi, phd department of biology, islamic azad university, damghan branch, semnan, iran zarei_stesura seveso 09/10/14 10:38 pagina 192 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 4340 original paper lidocaine spray administration in transrectal ultrasoundguided prostate biopsy: five years of experience lucio dell’atti department of urology, university hospital “s. anna”, ferrara, italy. objectives: we report in this singlecenter study our results of a five-year experience in the administration of lidocaine spray (ls) during ultrasound-guided prostate biopsy (tpb). material and methods: between august 2008 and july 2013 a total of 1022 consecutive male patients scheduled for tpb with elevate psa (≥ 4 ng/ml) and (or) abnormal digital rectal and (or) suspect trus were considered eligible for the study. each patient was treated under local anaesthesia with ls (10 gr/100 ml), applied two minutes before the procedure. tpb was performed with the patient in the left lateral decubitus using multi-frequency convex probe “end-fire”. two experienced urologists performed a 14-core biopsy, as first intention. after the procedure each patient was given a verbal numeric pain scale (vns). the evaluation was differentiated in two scales vns: vns 1 for the insertion of the probe and the manoeuvres associated, while vns 2 only for the pain during needle’s insertion. results: pain scores were not statistically significant different with regard to the values of psa and prostate gland volume. pain score levels during probe insertion and biopsy were significantly different: the mean pain score according to vns was 3.3 (2-8) in the first questionnaire (vns1) (p < 0.001) and 2.1 (1-7) in the second one (vns2) (p < 0.125). the 8.2% of cases referred severe or unbearable pain (score ≥ 7), 74% of patients referred no pain at all. only 21 patients would not ever repeat the biopsy or would request a different type of anaesthesia, while 82% of them would repeat it in the same way. in only eight patients we have not been able to insert trus probe. conclusions: our pain score data suggest that ls provides efficient patient comfort during tpb reducing pain both during insertion of the probe and the needle. this non-infiltrative anaesthesia is safe, easy to administer, psychologically well accepted by patients and of low cost. key words: prostate biopsy; lidocaine spray; pain; anaesthesia; age. submitted 3 october 2014 ; accepted 31 october 2014 summary no conflict of interest declared. introduction transrectal ultrasound-guided prostate biopsy (tpb) is the most commonly used procedure to detect prostate cancer. during the last decade, the number of needle biopsy cores taken has increased, as have biopsies in younger patients and repeated biopsies (1). currently, there is no universally accepted anaesthetic method for prostate biopsy as evidenced by numerous methods that have been tried and published in the literature. two factors are usually responsible for pain during tpb: anal pain due to ultrasound probe, that causes pressure and stretching of muscle fibres, and insertion pain of the needle through the prostate (2). there are several different approaches that can be used for this purpose, including a rectal lidocaine gel, a periprostatic nerve blocks, sedation and caudal blockage (3-5). the selection of a method includes patient tolerance to pain, existing pathologies (especially anorectal diseases), medical history, biopsy experience, socio-cultural level and age (6). we report in this single-centre study, our results of five years of experience in the use of lidocaine spray (ls) administration tpb. to knowledge, this is the first study analysing ls as local anaesthetic technique for prostate biopsy (7). matherials and methods between august 2008 and july 2013 a total of 1022 consecutive male patients scheduled for tpb with elevate psa (≥ 4 ng/ml) and (or) abnormal digital rectal and (or) suspect trus were considered eligible for the study. patients were excluded if they had a history of previous prostate biopsy, had chronic prostalgia/pelvic pain syndrome, anal surgery, concomitant analgesic medication or any other medical condition that could potentially interfere with pain assessment. patients on anticoagulation/antiplatelet therapy were considered eligible for the study, providing they had followed the instructions of stopping antiplatelet drugs at least 5 days before the biopsy, or stopping anticoagulation drugs and replacing them with low molecular weight heparin at least 5 days before the biopsy. patients were instructed to take antibiotics, usually levofloxacin 500 mg orally, for 5 days starting the evening before the procedure and a small evacudoi: 10.4081/aiua.2014.4.340 presented at 19th national congress sieun, fermo 2014 dell'atti_stesura seveso 15/01/15 12:19 pagina 340 341archivio italiano di urologia e andrologia 2014; 86, 4 lidocaine spray and prostate biopsy ative enema two hours before the procedure. all procedures were performed after emptying of the bladder, since we believe that even the state of bladder repletion may be an element of discomfort during the performance of mapping biopsy. each patient was treated under local anesthesia with ls (10 gr/100 ml), applied two minutes before the procedure (figure 1). tpb was performed with the patient in the left lateral decubitus using an general electric logiq 7 machine equipped with a 5-9 mhz multi-frequency convex probe “end-fire”. each transrectal ultrasound that was performed included an assessment of the prostatic diameter, the volume of the whole prostate, the transition zone, capsular and seminal vesicle characteristics, as well as morphological description of potential pathological features. after imaging of the prostate, sampling was carried out with a 18-gauge tru-cut needle powered by an automatic spring-loaded biopsy disposable gun. two experienced urologists performed a 14-core biopsy, as first intention, including 2 lateral peripheral (1 basal and 1 apical), the 3 conventional parasagittal, and 2 midline peripheral samples (1 basal and 1 apical) on each side. after the procedure each patient was given a verbal numeric pain scale (vns), which was designed with 0 representing absence of pain and 10 the maximum pain they perceived in life. the evaluation was differentiated in two scales vns: vns 1 for the insertion of the probe and the manoeuvres associated, while vns 2 only for insertion pain of the needle through the prostate biopsy. additionally, was determined the relationship between the level of pain, prostate volume, age and psa. after the procedure, all patients underwent follow-up for at least one hour for any complications and were discharged. chi square test was used to assess differences in the response between the two questionnaires and fisher’s test if necessary. p value less than 0.05 was considered statistically significant. results in only eight (0.8%) patients we were not able to insert trus probe: in six of them because of the presence of fibrous anal lesion and in the other two cases the reason was the presence of a severe haemorrhoidal prolapse. the mean age of patients was 68 years (range 48-78), the mean value of the psa ng/ml was 8.2 (range 2.5-17.8), total prostate mean volume was 57 ml (range 36-135). the number of biopsies performed in each patient was 14 (range 6-21). a statistically difference was determined when vns1 and vns2 were evaluated; in fact pain score levels during probe insertion and biopsy were significantly different: the mean pain in the visual numerical scales in patients was 3.3 (2-8) in the first questionnaire (vns1) (p < 0.001), 2.1 (1-7) in the second one (vns2) (p < 0.125) (table 1). the 8.2% of cases (83/1014) referred severe or unbearable pain (score ≥ 7), 749 patients (74%) referred no pain at all. only 21 patients would not ever repeat the same biopsy or would request a different type of anaesthesia, while 831 (82%) of them would repeat it in the same way. the relationship between the level of patient pain, age, psa and prostate volume was analysed. it was determined that pain level decreased, whereas age increased (≥ 65 years old), and this result was statistically significant (p = 0.001). it is also shown that subjects aged ≥ 65 years tolerate the procedure better in the two questionnaires (average pain was respectively vns1: 2.4 and vns2: 1.7) (figure 2). the patients were homogeneous in terms of pain with regard to the values of psa and prostate gland volume and pain scores were not statistically significant. prostate cancer was diagnosed in 35% (357/1014) of patients who had undergone biopsy. pain scores were compared variables n° of patients 1022 age (yrs) 68 (48-78) serum psa (ng/ml) 8.2 (2.5-17.8) prostate volume (ml) 57 (36-135) n° of biopsy 14 (6-21) pain vns 1 3.3 (2-8) pain vns 2 2.1 (1-7) patients not able to insert probe 8 – fibrous anal 6 – severe haemorrhoidal prolapse 2 table 1. patiens’ clinical characteristics and vns results.figure 1. figure 2. comparison of pain score between patients ≥ 65 years old and patients < 65 years old. administration of lidocaine spray before transrectal prostate biopsy. dell'atti_stesura seveso 15/01/15 12:19 pagina 341 archivio italiano di urologia e andrologia 2014; 86, 4 l. dell’atti 342 between the 357 patients with prostate cancer (vns 1: 3.4 and vns2: 1.9) and the 657 patients (65%) without cancer (vns 1: 3.6 and vns2: 2.5). we found out that pain scores were statistically lower in vns 2 of patients with prostate cancer (p < 0.001). a minimal rectal bleeding was observed in 38% of the patients after the biopsy. a short duration of hypotension was detected in ten patients, but the patients recovered from this condition in a short time. complication requiring active treatment occurred in 1.3% (13/1014): 4 acute urinary retention, 6 rectal bleeding and 3 urosepsis. discussion pain during tpb can occur during transrectal probe insertion and when the needle pierces the capsule of the prostate through the rectal wall. lidocaine was synthesized by lofgren and lundqvist in sweden in 1943 and introduced into clinical practice in 1947 (8). lidocaine gel (lg) is the most widely used lubricant agent during tpb, but its efficacy when instilled transrectally is controversial (9, 10). lg has a small effect on anal sphincter tone and low efficacy for the insertion and movements of the probe during the procedure (11). in fact, intrarectal lubricant agents with lg alone had no impact on the general tolerance of tpb compared to placebo. thus, the analgesic efficacy of this method has not been universally confirmed (12, 13). after the introduction of periprostatic nerve block (ppnb) by nash et al. (14), several studies reported the necessity of local anesthesia, because the pain during tpb from insertion and movements of the probe is somatic, as the rectum is innervated by the inferior rectal branches of the pudendal nerve (15). in another study from philip et al. (16), the authors concluded that the introduction of the trus probe was significantly more painful than the biopsy after the application of ppnb anaesthesia and suggested the use of a topical perianal anaesthetic/muscle relaxant, especially in young patients. to our knowledge, this is the first study analysing ls as local anaesthetic technique for prostate biopsy (7). the present study is focused on the comparison of pain scores between patients who underwent tpb receiving ls as the only form of local anaesthesia, due to the fact that in our opinion probe insertion and movements were more painful than needle puncture of the prostate capsule, requiring some form of anaesthesia. ls applied at anal sphincter’s level has a rapid and effective action on muscle fibres causing a reduction of the secretion of cytokines, prostaglandins and leukotrienes associated with pain during tpb (17). the analgesic effect starts two minutes after application. the goal of clinicians should be the reduction of the pain and discomfort associated with tpb. acceptable pain scores were reported in patients who received ls; in fact the 82% of them would repeat it in the same way. in only eight patients we have not been able to insert trus probe for anal diseases and a short duration of hypotension was detected in ten patients, but the patients recovered from this condition in a short time. however, an important result is the fact that subjects aged ≥ 65 years tolerated the procedure better in the two questionnaires. many factors may contribute to reducing pain perception, including the decrease in the number of nociceptors; nociceptive afferents account for the high threshold and tolerance pain, reduction of nociceptive information related to the multiplicity of stimuli and reduced ability to discriminate of older, probably a consequence of a disease process rather than ontogenetic changes or development dependent on age (6, 18). our study had three several limitations: the first concerns the study design and the statistical power related to the lack of a placebo group that influenced the statistical results; the second one was that impossibility in determine the optional dosage of ls for the muscle fibres of anal sphincter anaesthesia. finally, the third limitation is that it represents a singlecentre study that should be extended to other urological departments and experienced by various specialists. conclusions in our experience, tpb is generally well tolerated with ls as the only anaesthesia. our pain score data suggest that ls provides efficient patient comfort during tpb by reducing pain both during insertion probe and needle. this new technique represents an excellent alternative to those currently practiced by most urologists, causing a sharp reduction of anal sphincter tone with better patient compliance and tolerability to the ultrasound probe in the performance of biopsies. this non-infiltrative anaesthesia is safe, easy to administer, psychologically well accepted by patients and low cost. to determine the optimal dose of ls for anal sphincter anaesthesia, further well-designed, placebo-controlled prospective studies involving larger populations will be needed. references 1. loebs s, vellekoop a, ahmed hu. et al. systematic review of complications of prostate biopsy. eur urol. 2013; 64:876-92. 2. lee hy, lee hj, byun ss, lee se, et al. effect of intraprostatic local anesthesia during transrectal ultrasound guided prostate biopsy: comparison of 3 methods in a randomized, double-blind, placebo controlled trial. j urol. 2007; 178:469-472. 3. noh dh, cho mc, park hk, et al. the effects of combination perianal-intrarectal lidocaine-prilocaine cream and periprostatic nerve block for pain control during transrectal ultrasound guided biopsy of the prostate: a randomized, controlled trial. korean j urol. 2010; 51:463. 4. turgut a, ergun e, kosar u, et al. sedation as an alternative method to lessen patient discomfort due to transrectal ultrasonography-guided prostate biopsy. eur j radiol. 2006; 57:148-153. 5. cesur m, yapanoglu t, erdem af, ozbey i, et al. caudal analgesia for prostate biopsy. acta anaesthesiol scand. 2010; 54:557-561. 6. dell’atti l, borea pa, russo gr. age: “a natural anesthetic” in pain perception during the transrectal ultrasound-guided prostate biopsy procedure. urologia 2011; 78:257-261. 7. dell’atti l, daniele c. lidocaine spray administration during transrectal ultrasound guided prostate biopsy modified the discomdell'atti_stesura seveso 15/01/15 12:19 pagina 342 343archivio italiano di urologia e andrologia 2014; 86, 4 lidocaine spray and prostate biopsy fort and pain of the procedure: results of a randomized clinical trial. arch ital urol androl. 2010; 82:125-127. 8. tammalin le, lofgren n: the action of anesthetics upon interfaces; on the mechanism of anesthesia. acta chem scand. 1947; 1:871-883. 9. hergan l, kashefi c, parson jk. local anesthetic reduces pain associated with transrectal ultrasound –guided prostate biopsy: a meta-analysis. urology. 2007; 69:520-525. 10. cevik i, ozveri h, dillioglugil o, akda a. lack of effect of intrarectal lidocaine for pain control during transrectal prostate biopsy: a randomized prospective study. eur urol. 2002; 42:217-220. 11. saad f, sabbagh r, mccormack m, peloquin f. a prospective randomized trial comparing lidocaine and lubricating gel on pain level in patients undergoing transrectal ultrasound biopsy. can urol. 2002; 9:1592-1594. 12. stirling bn, shockley kf, carothers gg, maatman tj. comparison of local anesthesia techniques during transrectal ultrasound-guided biopsies. urology. 2002; 60:89-92. 13. galosi ab, minardi d, dell’atti l, et al. tolerability of prostate transrectal biopsies using gel and local anesthetics: results of a randomized clinical trial. j endourol. 2005; 19:738-743. 14. nash pa, bruce je, indudhara r, et al. transrectal ultrasound guided prostate nerve blockade eases systematic needle biopsy of the prostate. j urol. 1996; 155:607-609. 15. jones js, ulchaker jc, nelson d, et al. periprostatic local anesthesia eliminates pain of office-based transrectal prostate biopsy. prostate cancer disease. 2003; 6:53-57. 16. philip j, mccabe je, roy sd, et al. site of local anaesthesia in transrectal ultrasonography-guided 12-core prostate biopsy:does it make a difference? bju int. 2004; 93:1218-1220. 17. zisman a, leibovici d, kleinmann j, et al. the impact of prostate biopsy on patient well-being: a prospective study of pain, anxiety, and erectile dysfunction. j urol. 2001; 165:445-454. 18. miller pf, sheps ds, bragdon ee, et al. aging and pain perception in ischemic heart disease. am heart j. 1990; 120:22-30. correspondence lucio dell’atti, md, phd (corresponding author) dellatti@hotmail.com department of urology university hospital “s. anna” via a. moro 8 44124 cona, ferrara, italy dell'atti_stesura seveso 15/01/15 12:19 pagina 343 stesura seveso 175archivio italiano di urologia e andrologia 2014; 86, 3 original paper diagnosis and treatment of participants of support groups for hypersexual disorder els tierens, johan vansintejan, jan vandevoorde, dirk devroey department of family medicine, vrije universiteit brussel, belgium. background: the aim of this study is to examine the extent to which members of support groups for hypersexual disorder meet the proposed criteria for hypersexual disorder of kafka, how the diagnosis of hypersexual disorders is made and what treatments are currently given. methods: in this non-interventional research survey, members of support groups for hypersexual disorder received a questionnaire in which the criteria for hypersexual disorder according to kafka were included as well as the way the disease was diagnosed and treated. results: the questionnaire was presented to 32 people but only 10 completed questionnaires were returned. five of the ten respondents met the criteria of kafka. for the other five respondents a hypersexual disorder was not confirmed but neither excluded. only for three respondents the diagnosis was made by a professional healthcare worker. the treatment included – besides the support group in nine cases – also individual psychotherapy. two respondents took a selective serotonin re-uptake inhibitor (ssri), as recommended in the literature. conclusions: the members of support groups for sex addiction were difficult to motivate for their participation. the way hypersexual disorders were diagnosed was far from optimal. only two participants received the recommended medication. key words: sexual disorders, addiction, treatment. submitted 4 november 2013; accepted 15 january 2014 summary introduction definition hypersexual disorder, better known as “sex addiction” is a clinical phenomenon that has received only little attention from researchers up to now. hypersexual disorder was first introduced in the diagnostic and statistical manual of mental disorders (dsm)-iii. the dsm-iii-r specified that hypersexual disorder was different from paraphilia. in the dsm-iv hypersexual disorder was removed because there was a great lack of empirical research and consensus on definition, aetiology and pathogenesis (1). in the dsm-iv hypersexual disorder was placed under “sexual disorder not otherwise specified”. it was specified as “distress about a no conflict of interest declared. pattern of repeated sexual relationships involving a succession of lovers who are experienced by the individual only as things to be used” (2). the proposal to include the condition as “sex addiction” to the dsm-v was rejected for similar reasons. there is still disagreement whether such a condition really exist as a separate entity. it may be a manifestation of another psychiatric disorder (3). kafka suggested in 2010 to include hypersexual disorder as a new psychiatric disorder in the dsm-v (1). the name does not impose any causal link or does not suggest any particular pathogenesis. the criteria (figure 1) a. over a period of at least 6 months, recurrent and intense sexual fantasies, sexual urges, or sexual behaviors in association with 3 or more of the following 5 criteria: a1. time consumed by sexual fantasies, urges or behaviors repetitively interferes with other important (non-sexual) goals, activities and obligations. a2. repetitively engaging in sexual fantasies, urges or behaviors in response to dysphoric mood states (e.g., anxiety, depression, boredom, irritability). a3. repetitively engaging in sexual fantasies, urges or behaviors in response to stressful life events. a4. repetitive but unsuccessful efforts to control or significantly reduce these sexual fantasies, urges or behaviors. a5. repetitively engaging in sexual behaviors while disregarding the risk for physical or emotional harm to self or others. b. there is clinically significant personal distress or impairment in social, occupational or other important areas of functioning associated with the frequency and intensity of these sexual fantasies, urges or behaviors. c. these sexual fantasies, urges or behaviors are not due to the direct physiological effect of an exogenous substance (e.g., a drug of abuse or a medication). specify if: – masturbation – pornography – sexual behavior with consenting adults – cybersex – telephone sex – strip clubs – other:_____________________________ figure 1. proposed criteria for hypersexual disorder (2) used in our study. doi: 10.4081/aiua.2014.3.175 tierens_stesura seveso 09/10/14 10:37 pagina 175 archivio italiano di urologia e andrologia 2014; 86, 3 e. tierens, j. vansintejan, j. vandevoorde, d. devroey 176 were drawn up based on a thorough literature review: there must be a disorder of sexual desire and a problem of loss of control over impulses that leads to negative consequences. none of the proposed theories such as disinhibiting of behavior, impulsivity, compulsivity or addiction were proven, but they overlapped. these criteria are not yet tested on a population (1). currently, the american psychiatric association investigates whether or not hypersexual disorder should be included in dsm-v (4). several studies among people with hypersexual disorder showed that 35 to 73% practiced excessive masturbation, 49 to 51% frequently searched pornography, in 13 to 70% consenting adults are involved and 24% practiced phone sex (1, 5-7). kafka also added strip clubs and cybersex to the specifications. however, this cannot be supported by the literature (1). differential diagnosis hypersexuality can also fit in many other psychiatric disorders (3). the most common disorders in the differential diagnosis are paraphilias, sexual disorders not otherwise specified, impulse control disorder not otherwise specified, bipolar affective disorder (type i or ii), posttraumatic stress disorder and adjustment disorder (disturbance of conduct). rather infrequent disorders are substance-induced anxiety disorder (obsessive-compulsive symptoms), substance-induced mood disorder (manic features), delusional disorder (erotomania), obsessive-compulsive disorder, gender identify disorder and finally delirium, dementia, or other cognitive disorders. comorbidity hypersexual disorder can result in many other problems such as sexually transmitted diseases, unwanted pregnancy, relationshipand marital problems and domestic violence. it may also have legal consequences (8). hypersexual disorder is associated with other psychiatric disorders and risky behaviors such as smoking, excessive drinking, illegal drug use and gambling (5, 9). professionals specialised in addiction often look for sexually compulsive behavior after identifying a substance dependence. sex addiction is often associated with substance dependence and is a frequent cause of relapse. this would occur in 39 to 45% of sex addicts. mainly cocaine, alcohol and metamphetamines are concerned. only 17 to 34% of the surveyed population had no other addiction. different addictions can occur simultaneously, reinforce and alternate each other as well (3, 10). within a homosexual population, 45% of those who scored high on sexual compulsivity frequently used alcohol during sex, in contrast to the non-compulsive group in which this was 39%. for drugs this was 37% and 28% respectively (11). epidemiology there are no reliable epidemiological data on hypersexual disorder available. the lack of consensus on a definition and on an empirically validated instrument hampers further research and collection of epidemiological data. for that reason, no large-scale studies have taken place. (3, 5) it is estimated that 3 to 6% of the general population has a hypersexual disorder. it seems to be more common in men than in women; the male-female ratio is estimated at three to five (8). there is an issue of over-and underestimation. an overestimation could be caused by the current social climate and the perception of sexuality. the popularisation of the concept of hypersexual disorder could also play a role. an underestimation is due to shame, secrecy and depression that people refrain to seek professional help (8). the number of sex addicts that looked for help in flanders has increased exponentially in the recent years. in 2010, 14,396 people participated in a study on human sexuality. of the 6,458 men in the study, 107 (1.7%) ever searched help for sexual compulsivity. of the 7,938 included women 69 (0.9%) searched help. the help-seeking men watch more pornography than women. the women seeking help had more psychological symptoms such as depression and anxiety. the study population is not representative because the participants were recruited in the united states and canada through internet sites that provide sexual advice (12). in new zealand, 940 people at the age of 32 were questioned on excessive sexual behavior and risky sexual behavior. in total 3.8% men and 1.7% women reported excessive sexual behavior that interfered with their lives in the past year. they rarely sought help for their sexual behavior. if so, they consulted a psychiatrist, a psychologist, a lawyer or a priest (13). in a swedish study with 2,450 people aged between 18 and 60 years, 12% men and 7% women had “high hypersexuality”. this study enquired about masturbation, use of pornography, number of sexual partners, adultery, multiple sexual relationships at the same time and group sex (9). in 1993, a study recruited people with compulsive sexual behavior through newspapers. in total 36 participants (28 men and 8 women) with sexual preoccupation or excessive sexual behavior and subjective suffering were included. their medical history showed in 39% of the cases depression, phobia in 42% and in 64% substance addiction. the average age of onset of the hypersexual disorder was 18 years and participants suffered on average since nine years. three quarters linked this behaviour to the use of alcohol or drugs (14). treatment persons with hypersexual disorder more often visit a doctor for sexual advice (9). carnes already emphasised the importance of the first line in the detection and counselling of people with an addictive sexual dysfunction (10). if the sexual compulsive behavior is secondary to an addiction or another psychiatric condition, then the latter should be treated first (3). in addition to education, a combination of individual psychotherapy and group therapy is indicated. an early start with the 12-step program based on alcoholics anonymous is highly recommended. several support groups, where peers meet, follow this pattern. these sessions take place without a therapist (3, 5, 10). the effect of the 12-step program has not yet been demonstrated but 23% would complete the first nine tierens_stesura seveso 09/10/14 10:37 pagina 176 steps in 18 months and among them relapse is rare. in the beginning, for 30 to 90 days, total abstinence is recommended. this period may be associated with acute depression, insomnia, irritability, difficulty concentrating, and nausea. the symptoms would only emerge in the first 3 weeks and improve during the two months thereafter. later participants comply with this total abstinence or turn it over to a partial abstinence. this means a total denial of compulsive, destructive sexual behavior. the abstinence means not only a change of behavior but also the avoidance of fantasies (3). in a second phase individual psychotherapy is initiated: cognitive-behavioral and psychodynamic therapy are recommended (3, 5, 10). the effect of this therapy is not yet proven, because it is very difficult to organise a randomised controlled trial because of the complexity of the interaction between the caregiver and the patient (15). the intervention of sexologists would be most effective at a later stage, in the second year and later (3). also couple or family therapy can be added. there are no empirical studies that demonstrate the effect of couple therapy, but partners of addicts are demanding more support from therapists (16). reasons to choose for an inpatient treatment are: suicidal tendencies, little social support, failure of outpatient treatment, multiple addictions and serious consequences (legal, financial, marriage-bound or public exposure). outpatient treatment may be successful when patients are supported by their family. one of the best predictors of success is the will of the patient to succeed (10). although the etiology is unknown, researchers focus on the neurophysiology of sexual arousal that depends on neurological, hormonal and genetic factors. but in humans, culture and context play also a major role (9, 10). patients with pronounced symptoms are advised to start with psychotherapy and medication at the same time because a combination of both gives better results. a therapy with ssris is preferred although tricyclic antidepressants are also prescribed (15). for the more severe cases, particularly offenders, a combination of an ssri with an anti-androgen (cyproterone acetate or medroxyprogesterone acetate) is preferred but lhrh agonists and estrogens are also used (17). evidence about the drug treatment is not available. the study populations are often too small or non-representative population are examined (3, 15, 17). benzodiazepines are not recommended, as these can disinhibit patients (5). for these kind of disorders there is always a risk of relapse. in the first year there is a great agitation but the following six months include the greatest risk. only after 18 months an improvement in quality of life occurs and in the fourth and fifth year relationships can improve. a final recovery is, in principle, never reached (3). aim of the study the aim of this study is to examine the extent to which members of support groups for sex addiction meet the proposed criteria for hypersexual disorder of kafka. secondly, the authors try also to have a better insight on how the diagnosis of hypersexual disorders is made and what treatments are currently provided. methods participating support groups sexaholics anonymous (sa), sexual compulsives anonymous (sca) and sex and love addicts anonymous (slaa), the three support groups active in belgium were invited to participate in the study. only sa and sca decided to participate. the slaa preferred not to contribute to the research because during the meeting they just want to concentrate on the treatment. sa was founded in 1979 in the united states. in 2011, sa had 1611 groups in 42 countries. in belgium there are currently four sa groups. in the course of the four years in which they have operated, there are a few thousand people who attended at least once and about one hundred who attended regularly the meetings. most of the people (95%) attend only once. in december 2011, there were five regular members in each of the four groups. the meetings are chaired by the members themselves, in no sa-meeting professional counsellors are present. sca reported that in their support groups 15 to 20 members worked on their recovery. there is no register of members, so they cannot provide exact figures. procedure non-interventional research was organised in march 2012. the questionnaire was anonymously proposed to members of the participating support groups for sex addiction. the questionnaire consisted of a paper and electronic form and was distributed by the contact person of each support group. the questionnaire was available in dutch as well as in french. after the collection and the analyses of data, the contact persons of the support groups were interviewed in order to clarify and comment the results. ethical approval the protocol for this study was approved by the ethical committee of the university hospital of the vrije universiteit brussel. the participants were informed about the purpose and course of the study, possible risks, confidentiality and the right to information, on the front page of the questionnaire. informed consent was obtained in an alternative manner. by participating in the study and by completing the questionnaire the subject confirmed that he/she was aware of the purpose and course of the study and possible risks. this was the only way to guarantee absolute anonymity. questionnaire the questionnaire consisted of three parts. in a first part, some socio-demographic data were collected. the criteria for hypersexual disorder were collected in the second part. the last section included questions related to diagnosis, treatment and satisfaction with treatment. the socio-demographic variables in the questionnaire were: sex, age, highest degree, ethnicity, sexual orientation and relationship status. to assess whether the members of the support groups actually meet the criteria of kafka a newly developed ques177archivio italiano di urologia e andrologia 2014; 86, 3 diagnosis and treatment of participants of support groups for hypersexual disorder tierens_stesura seveso 09/10/14 10:37 pagina 177 archivio italiano di urologia e andrologia 2014; 86, 3 e. tierens, j. vansintejan, j. vandevoorde, d. devroey 178 tionnaire that reflects these criteria as strong as possible was administrated. there were already several questionnaires used for disease screening and diagnosis. however, these questionnaires were not studied in detail and none of them specifically sets the criteria of kafka (18, 19). they were therefore not eligible for our study. in the third part, participants were asked which health professional made the diagnosis, which professionals did the treatment follow-up, what was the treatment and what the medication was the patient received. it was also checked whether a physician – if any – was involved. finally, the participants were asked for how long they already suffered from hypersexual disorder, for how long the disease was already diagnosed and whether they were satisfied with the treatment so far. statistical analyses all used statistics are descriptive. ibm spss 20 was used for the analyses. results demographics the contact person of sa presented the questionnaire to 25 members and 7 completed questionnaires were returned. the contact person of sca presented the questionnaire to 7 members and 3 completed questionnaires were returned. the response rate was 31%. all participants were male. their ages ranged between 33 and 62 years and averaged 48.2 years. they were all caucasians except two. one participant was partly south american and partly caucasian. the other participant did not answer this question. most of the participants obtained a degree of non-university higher education. all participants of the study were heterosexual except one who was homosexual. seven participants had a partner, the other three had no relationship. diagnosis five out of 10 participants met the three criteria of kafka. all respondents met the first criterion and nine met also the second criterion (table 1). five participants were addicted to substances. the sexual activity of all respondents took place on the field of masturbation and pornography. six respondents had regular sex with consenting adults, four respondents took part in cybersex, one in phone sex and three participants regularly visited strip clubs. four respondents reported other inappropriate behavior like voyeurism in public places, cinemas, nudist beaches and swingers clubs. the diagnosis was made by a professional healthcare worker in three cases, which was in each of these cases a psychologist. one of these three psychologists was an expert in hypersexual disorder by experience. three respondents made the diagnosis themselves, twice the diagnosis was made by the support group and twice the partner made the diagnosis. on average the respondents suffered for 31 years of hypersexual disorder. the age at which it started varied between 4 and 24 years, with an average of 17.5 years, but the diagnosis was on average made at the age of 37 years. treatment eight participants had a family physician. all family physicians (except one) were aware of the diagnosis. four of these eight family physician were involved in the treatment. six participants were treated by a psychologist, four by a sexologist and five by a psychiatrist. one participant indicated that “the literature” was responsible for his treatment. no one sought help from a support group only. the treatment included ambulatory individual psychotherapy in nine participants, two followed relational therapy, one followed an online treatment and one was hospitalised. none of them attended ambulatory family therapy or another group therapy. homeopathy and hypnotherapy were also recorded once each. seven of the ten participants took medication such as aripiprazole, sertraline, escitalopram and benperidol. two participants took complementary or alternative medicine: st. john's wort and homeopathy. a a1 a2 a3 a4 a5 b c participant 1 1 1 1 1 1 1 1 0 participant 2 1 1 1 1 1 1 1 0 participant 3 1 1 1 1 1 1 1 1 participant 4 1 1 1 1 1 1 1 1 participant 5 1 0 1 1 1 1 1 1 participant 6 1 1 1 1 1 1 1 0 participant 7 1 1 1 1 1 0 1 1 participant 8 1 1 1 0 1 1 0 0 participant 9 1 1 1 1 1 1 1 0 participant 10 1 1 1 1 1 1 1 1 (1 = participant meets criterion, 0 = participant does not meet criterion). table 1. results per participant of the kafka 2010 criteria for hypersexual disorder. tierens_stesura seveso 09/10/14 10:37 pagina 178 satisfaction with treatment satisfaction with treatment ranged from neutral to very satisfied. in this study, participants had also the possibility to comment. most comments were positive: the healthcare workers did not judge or condemn. the participants experienced a lot of understanding, help and support. the 12-step program was evaluated as very supportive. one person claimed to have reached a final stabilisation with the 12-step program. one of the reasons is that the support group is much more accessible in case of an emergency. homeopathy and hypnotherapy were perceived as positive. the importance of complementarity was emphasised. some indicated that psychiatrists behaved too formally, they experienced a lack of involvement and participants found a 20-minute consultation too short. some were not satisfied with the treatment in hospitals, others found the results obtained with a sexologist and psychologist insufficient. shame, taboo and sensationalism were perceived as negative elements concerning the treatment. some complained about the high cost of several years of treatment. discussion the low response rate is not surprisingly because the target group was probably cautious and restrained. the discontinuity of anonymity and the fear of stigmatisation is not to be underestimated. the selfishness that accompanies addiction and perhaps also hypersexual disorder, may also play a role. the contact persons indicated that mainly the long-time members participated in the research. in order to achieve a larger study group, more time is needed to build a trusted relationship with the participants by proxy of the contact persons. demographics all participants were male. from the epidemiological studies we know that the majority is male with a ratio between one in three, to one in five (8). the average age of the study group was 48 years. in a similar study, the participants all belonged to the age group between 20 and 29 years (14). this difference in average age seems rather a selection bias problem of that specific study than a significant difference with our study. our participants were recruited in support groups whereas the latter study recruited by advertisements. however, the contact persons indicated that the population attaining the support groups is getting older and that young members are less interested to attend a meeting every week. they prefer quick result. one participant refused to answer the question on ethnicity. immigrants are rare in the support groups. for immigrants hypersexual disorder is a lot harder to endure than for natives because of cultural aspects (14). religion was not questioned in our study. questions about religion are probably delicate for the participants. nevertheless these questions are interesting because religion would play an important role in the perception of hypersexual disorder and in the treatment. a religious person would be faster to accept helplessness and therefore attend faster aid (13). one of the steps of the program is a search for spirituality. in non-religious people this is a taboo but for religious people this is an additional reason to join. according to one study, about 50% of people with hypersexual disorder are homosexual or bisexual (13). in our study all participants (except one) were heterosexual. this reflects better the sexual orientation in the general population. it seems to be speculation to suggest that hypersexual disorder is more common among homosexuals or bisexuals. a fortiori, there is almost no epidemiological evidence about the prevalence of hypersexual disorder among groups with a different sexual orientation. on average, the participants had a degree of non-university higher education. this degree is somewhat higher than in the general population. however, this educational level might be biased by the fact that participants were recruited in support groups. it is known that well-educated patients are more likely to attend support groups. this was at least confirmed for cancer patients (20). seven participants had no partner. this is probably related to difficulties in sexual relationships and the pressure on intimacy. criteria for hypersexual disorder only five of the 10 participants met the criteria of kafka. for the others, the diagnosis was possible but not confirmed by the questionnaire. it is not sure that all participants should attend the support groups because the diagnosis of hypersexual disorder was not confirmed for all of them. before attending a support group the diagnosis of an underlying psychiatric or neurologic disorder should be excluded. otherwise precious time can be lost in a support group. the five participants not meeting the kafka criteria suffered from hypersexual disorder, mainly related to substance addiction. this is in line with the expected comorbidity. substance addiction would occur in 39 to 45% of the hypersexual disorder population. for these participants, one cannot exclude that the substance dependence is the primary disorder. the question is whether this criterion is necessary. dependence of substances and behaviors may have the same aetiology and pathogenesis, making a strict differential diagnosis unnecessary to be able to provide a proper treatment. the distribution of sexual activity in our study reflects relatively well the results from the literature. in the literature review masturbation (35 to 73%) and pornography (49 to 51%) were the leading activities, followed by sex with consenting adults (13 to 70%) (1, 5-7). masturbation and pornography were reported by all participants in our study. six participants had contacts with consenting adults. having cybersex, prostitution and visiting strip clubs were not reported in previous studies. respectively four and three participants of our study mentioned this. probably it is useful to add these common sexual activities in further research. only one participant reported phone sex. this low proportion corresponds with other studies were for example 1 in 36 participants reported phone sex (14). the other reported behaviors are not included in previous research. 179archivio italiano di urologia e andrologia 2014; 86, 3 diagnosis and treatment of participants of support groups for hypersexual disorder tierens_stesura seveso 09/10/14 10:37 pagina 179 archivio italiano di urologia e andrologia 2014; 86, 3 e. tierens, j. vansintejan, j. vandevoorde, d. devroey 180 diagnosis only in three participants the diagnosis was made by a professional healthcare worker, which is regrettable. for the three cases this was a psychologist other healthcare professionals were not listed. in all other cases, the diagnoses were made by themselves, their partner or the support group. previous studies show that patients mainly seek help from psychiatrists, psychologists, lawyers or religious people (15). from the literature we know that the average age of onset of hypersexual disorder is 18 years (16). in our study, the average onset age is also 17.5 years and ranged between 4 and 24.5 years. it is remarkable that some participants show the first signs of the disorder at a very young age. a similar young age of onset was also described in patients with (other) obsessive-compulsive disorder (21). but most remarkable is that the diagnosis was on average only made 20 years after the onset of the problem. many have undergone a long ordeal before they received any help. more attention for the detection and diagnosis of such problems and the possible underlying psychiatric or neurological disorder is desirable in primary healthcare (22). treatment the strong involvement of the family physicians is striking. eight family physicians were informed about the diagnosis and in half of the cases they were involved in the treatment. sexologists can offer help mainly from the second year of treatment. four participants of our study were all already treated by a sexologist and often also by a psychologist. five participants were consulting a psychiatrist and received medication. all participants received – on top of the support group – also another treatment. nine participants received individual psychotherapy. this combination is the recommended treatment. none of the participants with a partner followed no relationship therapy. this is optionally recommended from the second year of treatment but the effectiveness is not documented. two other participants followed relationship therapy with a former partner. an online therapy is not discussed in the literature. only two of the ten patients received an ssri as it is recommended. ssri are the first choice drugs for hypersexual disorder (15, 17). other patients received atypical psychotics, neuroleptics and homeopathic preparations which are not recommended. however, there is almost no evidence for the treatment of hypersexual disorder. before the diagnosis of hypersexual disorder is made, any other underlying psychiatric and neurological disorder should be excluded. therefore, a consultation with a physician before the start of a treatment in a support group or with a psychologist or a sexologist is recommended. the participants were positive about their treatment. this finding is probably not representative, since most of the participants attended the support groups for a long time. they are more likely to continue the treatment and therefore are more satisfied. they indicated that the support groups had a considerable added value in their treatment. participants were generally satisfied about the psychologists, psychiatrists and sexologists. however, some participants were dissatisfied about them. weaknesses and future research the statistical significance of this research is very limited, due to the small number of participants. however, this research may contribute to the awareness of health care workers for hypersexual disorders. they should receive a training to firstly detect such patients and secondly to refer them for treatment. but primary health care workers also have the very import task to inform and follow-up these patients. the number of participants was limited for this research. the short inclusion period on the one hand and the inability to directly recruit subjects on the other hand probably played a major role. the number of questions in the survey was deliberately limited to facilitate parti cipation. the anonymity of the participants was absolutely guaranteed, according to their explicit desire. tendentious questions were avoided to prevent negative reactions and feelings. information about the presence of other psychiatric disorders and risky behavior would have been useful. more detailed questions on the third criterion of kafka were preferable. this would have allowed us to detect hypersexual behavior secondary on substance abuse. meanwhile, the american psychiatric association (apa) investigated whether or not hypersexual disorder should be included in the dsm-v. in april 2012, the kafka criteria were adapted again and finally included in chapter iii (= appendix) of the new dsm-v. criteria included in this chapter require more research and evidence. we cannot estimate how many of our participants would be diagnosed with the adapted criteria because question a was adapted and more detailed information on the third criterion, including manic episodes and general medical conditions are needed. further research to illuminate the cause, the diagnosis and the treatment of hypersexual disorder is needed. for future research, a qualitative methodology such as focus group research should be considered. conclusions it seems very difficult to motivate the members of anonymous support groups to participate in research. in our study, five out of the 10 participants met the criteria of kafka for hypersexual disorder. for the others the diagnosis was possible but not confirmed by the questionnaire. the method of diagnosis is far from optimal. this is certainly due to a lack of well-defined criteria for the diagnosis and validated diagnostic instruments. primary care workers should be sensitised to consider the diagnosis much faster. today, on average, it takes 20 years before a diagnosis is made. especially concerning the pharmacological treatment, there seems to exist a lot of uncertainty. at the moment, a combination of medication, support groups and individual psychotherapy is the recommended treatment. tierens_stesura seveso 09/10/14 10:37 pagina 180 181archivio italiano di urologia e andrologia 2014; 86, 3 diagnosis and treatment of participants of support groups for hypersexual disorder 1a. gender: ! man ! woman 1b. age: ________ in years 1c. ethnicity: ! caucasian ! negroid ! asian ! hispano american ! other: ____________________________ 1d. highest qualification attained: ! primary education or no diploma ! secondary education ! higher non-university education ! university 1e. sexual orientation: ! heterosexual ! homosexual or lesbian ! bisexual 1f. relationship status: ! in a relationship ! single 2.a0. i had for ________________ years_______________ months lots of sex, sexual fantasies and/or a great need for sex (approximate) 2.a1. the time i spent on sex, sexual fantasies and/or a great need for sex repeatedly brought other important (non sexual) goals, activities and commitments into question yes/no 2.a2. i repeatedly had lots of sex, sexual fantasies and/or a great need for sex in response to sadness, anxiety, depression, boredom or irritability yes/no 2.a3. i repeatedly had lots of sex, sexual fantasies and/or a great need for sex in response to stressful events yes/no 2.a4. i have repeatedly tried to control or reduce the amount of sex, sexual fantasies and/or a great need for sex, but failed yes/no 2.a5. i have repeatedly had sex while there was a risk that this would lead to physical or emotional harm for myself or others yes/no 2.b. my social life, hobbies or other important areas suffered from the frequency and intensity of sex, sexual fantasies and/or the need for sex yes/no 2.c. i was addicted to substances such as drugs, alcohol or medication in the period in which i had much sex, sexual fantasies and/or a great need for sex yes/no 2.s. my sexual activity took place primarily on the following areas: (multiple answers possible) ! masturbation ! pornography ! sex with consenting adults ! cybersex ! phone sex ! strip clubs ! other: ____________________________ 3a. my diagnosis was first made by: ! family physician ! psychologist ! sexologist ! psychiatrist ! other: ____________________________ ! in addition to the support group i have consulted no other care providers 3b. the diagnosis was made ______________________ years ___________________ months ago (approximately). 4c. i have a family physician yes/no 4c1. if so, my family physician is aware of my diagnosis yes/no 4d. i am/was treated by the following healthcare professional(s): (multiple answers possible) ! family physician ! psychologist ! sexologist ! psychiatrist ! other: ____________________________ ! in addition to the support group, i was treated by no one else 4e. my treatment consists/consisted, in addition to the support group, of: ! ambulatory individual psychotherapy ! ambulatory relational therapy ! ambulatory family therapy ! ambulatory group therapy other than the support group ! hospitalisation in a (psychiatric) hospital ! hospitalisation in a specialised institute ! online treatment ! other: ____________________________ 4f. my treatment includes medication yes/no 4f1. if so, which? _________________________ 4g. are you satisfied with the treatment you receive? ! not at all satisfied ! rather not satisfied ! not satisfied, not dissatisfied ! rather satisfied ! completely satisfied 4g1. why? ______________________________________________________ ______________________________________________________ ______________________________________________________ ______________________________________________________ questionnaire (translated from the dutch version). the questionnaire consists mainly of multiple choice and yes/no questions. you can always indicate an answer. if multiple answers are possible this is indicated. if none of the answers apply to you, please indicate the most appropriate answer. may i ask you to fill in the questionnaire completely. tierens_stesura seveso 09/10/14 10:37 pagina 181 archivio italiano di urologia e andrologia 2014; 86, 3 e. tierens, j. vansintejan, j. vandevoorde, d. devroey 182 12. winters j, christoff k, gorzalka b. dysregulated sexuality and high sexual desire: distinct constructs? arch sex behav. 2010; 39:1029-1043. 13. skegg k, nada-raja s, dickson n, paul c. percieved “out of control” sexual behavior in a cohort of young adults from the dunedin multidisciplinary health and development study. arch sex behav. 2010; 39:968-978. 14. black d, kehrberg l, flumerfelt d, schlosser s. characteristics of 36 subjects reporting compulsive sexual behavior. am j psychiatry 1997; 154:243-249. 15. guay d. drug treatment of paraphilic and nonparaphilic sexual disorders. clin ther. 2009; 31:1-31. 16. bird m. sexual addiction and marriage and family therapy: facilitating individual and relationship healing through couple therapy. j marital fam ther. 2006; 32:297-311. 17. bradford j. the neurobiology, neuropharmacology, and pharmacological treatment of the paraphilias and compulsive sexual behavior. can j psychiatry 2001; 46:26-34. 18. reid r, garos s, carpenter b. reliability, validity and psychometric development of the hypersexual behavior inventory in an outpatient sample of men. sexual addiction & compulsivity. 2011; 18:30-51. 19. miner m, coleman e, center b, ross m, rosser b. the compulsive sexual behavior inventory: psychometric properties. arch sex behav. 2007; 36:579-587. 20. bauman l, gervey r, siegel k. factors associated with cancer patients’ participation in support groups. j psychosoc oncol. 1992; 10:1-20. 21. lochner c, hemmings sm, kinnear cj, et al. cluster analysis of obsessive-compulsive spectrum disorders in patients with obsessivecompulsive disorder: clinical and genetic correlates. compr psychiatry. 2005; 46:14-19. 22. kaplan ms, krueger rb. diagnosis, assessment, and treatment of hypersexuality. j sex res. 2010; 47:181-198. acknowledgement the authors are grateful to david proot for the english editing and the participants of the support groups for the great cooperation and the fascinating conversations about their world. references 1. kafka m. hypersexual disorder: a proposed diagnosis for dsmv. arch sex behav. 2010; 39:377-400. 2. american psychiatric association. diagnostic and statistical manual of mental disorders, fourth edition. 1994: 538-621. 3. schneider j, irons r. assessment and treatment of addictive sexual disorders: relevance for chemical dependency relapse. subst use misuse. 2001; 36:1795-1820. 4. http://www.dsm5.org/proposedrevision/pages/proposedrevision. aspx?rid=415# 2012, march 2. dsm-v development. american psychiatric association. 5. mick t, hollander e. impulsive-compulsive sexual behavior. cns spectr. 2006; 11:944-955. 6. reid r, carpenter b. exploring relationships of psychopathology in hypersexual patients using the mmpi-2. j sex marital ther. 2009; 35:294-310. 7. dodge b, reece m, cole s, sandfort t. sexual compulsivity among heterosexual college students. j sex res. 2004; 41:343-350. 8. coleman e. is your patient suffering from compulsive sexual behavior? psychiatr ann. 1992; 22:320-325. 9. langström n, hanson k. high rates of sexual behavior in the general population: correlates and predictors. arch sex behav 2006; 35:37-52. 10. carnes p, schneider j. recognition and management of addictive sexual disorders: guide for the primary care clinician. lippincotts prim care pract. 2000; 4:302-318. 11. kelly b, bimbi d, nanin j, izienicki h, parsons j. sexual compulsivity and sexual behaviors among gay and bisexual men and lesbian and bisexual women. j sex res. 2009; 46:301-308. correspondence els tierens, md johan vansintejan, md jan vandevoorde, phd, md vrije universiteit brussel (vub), dept of family medicine laarbeeklaan 103, b-1090 brussels, belgium dirk devroey, phd, md (corresponding author) dirk.devroey@vub.ac.be vrije universiteit brussel (vub), head of the dept of family medicine laarbeeklaan 103, b-1090 brussels, belgium tierens_stesura seveso 09/10/14 10:37 pagina 182 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 4304 letter to editor about: penile fracture: penoscrotal approach with degloving of penis after magnetic resonance imaging (mri) reply by authors we read with interest the paper “penile fracture: penoscrotal approach with degloving of penis after magnetic resonance imaging (mri)” by antonini et al. in your journal (2014; 86(1) 39-40). the statement “early surgical exploration is paramount” does not take into consideration the excellent results reported for delayed repair of the fracture (1). delayed repair also makes clinical identification of the fracture site more accurate since, when the acute swelling settles, the rolling sign (caused by clot at the torn cavernosum) becomes even more obvious. this is even more evident in late delayed repair (2). the authors correctly point out that “degloving a bruised edematous penis can be quite challenging” especially since most fractures are in the proximal shaft. the peno scrotal incision is also easier to perform in a delayed repair as much of the swelling and deformity are reduced. thus, we believe that in most cases, the fracture site can be accurately identified by the rolling sign on presentation (3). if, however, this is not evident, a delay of 712 days makes accurate identification and repair via a penoscrotal incision much easier (1). thus, we do not share the view that “mri should be the first choice modality of investigation” since it is both costly and unnecessary. it should be reserved for cases of suspected urethral rupture, bilateral cavernosal injury or doubtful diagnosis. references 1. nasser ta, mostafa t. delayed surgical repair of penile fracture under local anesthesia. j sex med. 2008; 5:2464-9. 2. naraynsingh v, hariharan s, goetz l, dan d. late delayed repair of fractured penis. j androl. 2010; 31:231-3. 3. naraynsingh v, raju gc. fracture of the penis. br j surg. 1985; 72:305-6. vijay naraynsingh, ravi maharaj, shamir cawich department of clinical surgical sciences, the university of the west indies, eric williams medical sciences complex, mount hope trinidad w.i. magnetic resonance imaging (mri) scan of the penis is highly sensitive at detecting the exact location of the tunical tear and allows the surgeon to chose the best surgical approach. as 2/3 of fractures occur all the way down on the proximal aspect of the shaft, a complete degloving becomes an unnecessary procedure, as a penoscrotal approach would guarantee adequate exposure in these patients (1-4). magnetic resonance imaging or uss of the penis play therefore a pivotal role for the identification of the exact location of the tear and therefore allow the surgeon to adequately choose the most appropriate surgical approach. surgery should be immediate, in order to preserve as much cavernosal tissue as possible and to minimize the formation of corporeal fibrosis, which would lead to ed, penile shortening and curvature (5-7). when readily available, mri should be the first choice modality of investigation due to its superior sensitivity in detecting tunical injuries (8). references 1. ozcan s, akpinar e. diagnosis of penile fracture in primary care: a case report. cases j. 2009; 2:8065. 2. kowalczyk j, athens a, grimaldi a. penile fracture: an unusual presentation with lacerations of bilateral corpora cavernosa and partial disruption of the urethra. urology. 1994; 44:599-601. 3. dever dp, saraf pg, catanese rp, feinstein mj, davis rs. penile fracture: operative management and cavernosography. urology. 1983; 22:394-6. 4. srinivas bv, vasan ss, mohammed s. a case of penile fracture at the crura of the penis witout urethral involvement.indian j urol. 2012; 28:335-337. 5. garaffa g, raheem aa, ralph dj. penile fracture and penile reconstruction. curr urol rep. 2011; 12:427-31. 6. sharma mb, singh ts, khumucham s, chito t, sharma bb. fracture of the penis – report of seven cases. j indian med assoc. 2011; 109:45-6. 7. hatzichristodoulou g, dorstewitz a, gschwend je, herkommer, zantl n. surgical management of penile fracture and long-term outcome on erectile and voiding. j sex med. 2013; 10:1424-30. 8. agarwal mm, singh sk, sharma dk, et al. fracture of the penis: a radiological or clinical diagnosis? a case series and literature review. can j urol. 2009; 16:4568-4575. gabriele antonini 1, patrizio vicini 3, salvatore sansalone 4, giulio garaffa 4, antonio vitarelli 5, ettore de berardinis 1, magnus von heland 1, riccardo giovannone 1, emanuele casciani 2, vincenzo gentile 1 1 department of urology, “sapienza” rome university, rome, italy; 2 department of radiology, “sapienza” rome university, rome, italy; 3 department of urology, “i.n.i.” italian neurotraumatologic institute grottaferrata, rome, italy; 4 department of experimental medicine and surgery, “tor vergata” rome university, rome, italy; 5 department of urology, bari university, bari, italy. doi: 10.4081/aiua.2014.4.304 stesura seveso 257archivio italiano di urologia e andrologia 2014; 86, 4 original paper urolithiasis in renal transplantation: diagnosis and management elisa cicerello, franco merlo, mario mangano, giandavide cova, luigi maccatrozzo unità complessa di urologia, ospedale ca’ foncello, treviso, italy obiectives: to report our experience of diagnosis and multimodal management of urolithiasis in renal transplantation. patients and methods: from january 1995 to december 2012, 953 patients underwent renal transplantation in the kidney transplant unit of treviso general hospital. ten (10%) of them developed urinary calculi and were referred at our institution. their mode of presentation, investigation and treatment were recorded. results: seven had renal and 3 ureteral calculi. urolithiasis was incidentally discovered on routine ultrasound in 6 patients, 1 presented with oliguria, 1 with anuria and acute renal failure and in 2 urolithiasis was found at removal of the ureteral stent. nephrostomy tube was placed in 5 patients. hypercalcemia with hyperparathyroidism (hpt) was present in 5 patients and hyperuricemia in 3. two patients were primary treated by shock wave lithotripsy (swl) and one of them was stone-free after two sessions. two patients, one with multiple pielocaliceal calculi and the other with staghorn calculus in the lower calyx, were treated with percutaneous nephrolitothotomy (pcnl). three patients were treated by ureteroscopy (urs) and in one of them two treatments were carried out. one patient had calculus impacted in the uretero-vesical anastomosis and surgical ureterolithotomy with re-do ureterocystoneostomy was performed after failure of urs. two patients with calculi discovered at removal of the ureteral stent were treated by urs. conclusions: the incidence of urolithiasis in renal transplantation is uncommon. in the most of patients the condition occurs without pain. metabolic anomalies and medical treatment after renal transplantation may cause stone formation. advancements in endourology and interventional radiology have influenced the management of urolithiasis that can be actually treated with a minimal incidence of risk for the renal allograft. key words: urolithiasis management, renal transplantation. submitted 15 march 2014; accepted 30 june 2014 summary no conflict of interest declared. in the most of cases stone formation appears to form “de novo” after renal transplantation, although some studies suggest that the calculi are more often transplanted with the graft to the recipient (1, 5, 6). theremore, metabolic anomalies causing stone formation could be present in allograft rather than native kidneys (7). urolithiasis is often asymptomatic and the clinicians are not able to diagnose urinary calculi in renal transplant at an earlier stage. neverthless, the prompt diagnosis and the subsequently stone removal is necessary to prevent adverse effects on a solitary kidney whose renal function is often borderline. today the development of endourological tecniques for calculi management and interventional radiology for the emergency management of acute obstruction have minimized the potential risk for renal graft. however, such minimally invasive procedures could be performed only in centers that are well equipped and have expertise to offer the appropriate treatment. we evaluated our experience of renal transplant patients with urolithiasis, regarding the risk factors associated with the condition and the management by endourological and open procedures. patients and methods from january 1995 to december 2012, 953 patiens underwent renal transplantation in the kidney transplant unit of treviso general hospital. the transplant were performed in the right or left iliac fossa with vascular anastomosis to the iliac artery and vein. ureteral implantation (ureterocistoneostomy) was performed using the extravesical tecnique of lich-gregoir, with routine use of ureteral catheter that was removed 4-6 weeks later by flexible cystoscopy. immunosoppression varied with the transplantation era. ten (10%) of them developed urinary calculi and referred to our institution. for the diagnosis of urolithiasis one or more of the following investigations were required: ultrasonography (us), plain abdominal x-ray, intravenous urography (ivp), nephrostography and computed tomography (ct). chemistry profile including serum analysis for urea, creatinine, calcium, phosphate, urate, sodium, potassium, phosphate, alkaline phosphatase and parathyroid hormon and urine analysis (routine and culture) were performed. management of doi: 10.4081/aiua.2014.4.257 introduction urolithiasis in renal transplantation is uncommon, with reported prevalence rates between 0.2% and 6.3% (1-4). cicerello_stesura seveso 15/01/15 12:58 pagina 257 archivio italiano di urologia e andrologia 2014; 86, 4 e. cicerello, f. merlo, m. mangano, g. cova, l. maccatrozzo 258 these calculi involved shock wave lithotripsy (swl), ureteroscopy (urs), percutaneous nephrolithotomy (pcnl) and ureterolithotomy with re-do ureterocistoneostomy. results six patients were females and 4 males. ages ranged from 31 to 59 years (mean 43 years). seven had renal and 3 ureteral calculi. the overall diameter range was 0.7-3 cm (mean 1.2 cm). urolithiasis was incidentally discovered on routine ultrasound in 6 patients with calculi located in the calices. one patient with multiple pielocaliceal calculi presented with oliguria and 1 with calculus impacted in the vesico-ureteral anastomosis with anuria and acute renal failure. in 2 patients urolithiasis was found at removal of the ureteral stent. nephrostomy tube was quickly placed in the following cases: calculi causing oliguria, anuria or hydronephrosis and in 2 patients with calculi discovered removing ureteral stent. hypercalcemia with hyperparathiroidism was present in 5 patients and hyperuricemia in 3. four patients had urinary tract infections (utis), in 3 infecting organism was e. coli and in 1 proteus mirabilis (table 1). two patients were primary treated by swl (lithostar plus siemens) in prone position and one of them with calculus in the upper calyx was stone free after two sessions, while in the other with calculus in the lower calyx urs was performed after failure of swl. two patients, one with multiple calculi and the other with staghorn in the lower calyx, were treated with pcnl. three patients were treated with ureteroscopy and in one of them two treatments were carried out. one patient had calculus impacted in the uretero-vesical anastomosis and ureterolithotomy with re-do ureterocistoneostomy was performed after the failure of urs (table 2). discussion urolithiasis in patients with kidney transplantation is often asymptomatic. a possible explanation for this observation is denervation of the transplanted graft (1, 2, 5, 8). in some cases, concomitant increase of serum creatinine should be considered with caution to avoid a misdiagnosis of episode of acute rejection (9). in our experience urolithiasis was incidentally discovered on routine ultrasound in one-half of them. the presence of uncomplicated calculus is not a contraindication to urological procedures. in fact, as it has previously been reported, calculus in the kidney transplantation, such as in patients with solitary kidney, must be removed in every case because it may cause urinary infection or pass in the ureter causing anuria with acute renal failure (10). previous studies have shown that swl is the treatment of choice for unobstructive calculi with diameter less than 1.5 cm (11). however, there are potential difficulties in locating transplant calculi because of the overlying bony pelvis which may limit visualization of stones on fluoroscopy as well mitigate the propagation of shock waves energy. prone position with ultrasound targeting may counter these disadvantages (12). an additional disadvantage of swl is the need for multiple sessions. challacombe et al. have reported stone free rate in 13 patients with kidney transplantation and urolithiasis who underwent swl, but in 8 of them multiple procedures were required. in our study two patients with asymptomatic calculi were primarily treated by swl and pts ex age clinics metabolic anomalies utis 1 f 31 oliguria hpt no 2 f 41 anuria hpt yes 3 m 45 renal us hyperuricemia yes 4 m 47 renal us no no 5 f 48 hydronephrosis hyperuricemia no 6 m 51 renal us no no 7 f 59 renal us hpt no 8 f 34 failure to remove dj hpt yes 9 f 42 failure to remove dj hpt yes 10 m 35 renal us hyperuricemia no table 1. characteristic of patients with renal transplantation and urolithiasis. diameter location nephrostomy swl urs pcn ureterolithotomy (cm) with re-do ureterocystoneostomy 1 3 pielocaliceal yes yes 2 1.3 ureteral-vesical anastomosis yes failure yes 3 0.8 lower calix no failure yes 4 0.7 upper calix no yes 5 1.2 upj yes yes 6 1.1 upper calix no yes 7 1.0 middle calix no yes 8 1.4 distal ureter yes yes 9 1.5 distal ureter yes yes 10 1.2 lower calix no yes table 2. characteristic of calculi and urologic treatments. cicerello_stesura seveso 15/01/15 12:58 pagina 258 only one of them was stone-free. in both cases not more than 2 treatments were performed and urs was carried out in 1 patient after failure of swl. actually urs is the treatment of choice emerging as for small renal and ureteral calculi within kidneys transplantation (13). access to these kidneys may be difficult because of their position in the pelvis and the location of the neo-ureteric orifice. using both retrograde and anterograde approaches, stone-free rate of the calculi in kidney transplantion could be obtained with minor complications. we used both approaches in those patients with nephrostomy tube placed because urinary tract obstruction and after failure to remove ureteral stent, while in the other cases only a retrograde approach was performed. however, as endoscopes have become increasingly miniaturized and deflectable, ureteral dilation has become unnecessary and all urinary collecting system can be accessed in a straightforward manner. in our experience semirigid retrograde urs was performed over a decade ago and the access to the ureter was facilitated with angled catheters and hydrophilic wires and ureteral orifice was balloon dilated with a high-pressure balloon dilator. nowday, urs has carried out by flexible ureteroscopy. this method and disintegration of calculi with holmium laser is an effective method for the treatment of urolithiasis in kidney transplantion and the access to the neoureteric orifice and to the pelvis may be achieved by introducing the ureteroscope over a guide wire. instruments with “active” secondary deflection are particularly useful in reaching calculi in transplanted kidney. in our experience, according to hymas et al., we could suggest that urs is a viable treatment modality as well. for renal calculi with diameter greater then 1.5 cm, pcnl has been effective to remove all stone fragments in one procedure. the superficial position of transplanted kidney makes straightforward percutaneous procedure so that may be justified by maximal stone clearance and carried out in special centers because of the greater risk in patients with solitary kidney (14). in fact, due to the proximity of the bowels to the renal graft, the risk of perforation is high. furthemore, there have been reports of allograft renal artery injury and arteriovenous fistulae after trans abdominal access. theremore, tract dilatation can become difficult to perform because of the presence of a fibrous sheath and limited mobility of the kidney during rigid nephroscopy (15). in our experience percutaneous nephrolithotomy was only carried out in two patients, one with staghorn calculus located in the lower calyx and the other with multiple pielocaliceal calculi. previous reports have reported that calculi occurring in transplanted kidney are composed of calcium oxalate and calcium phosphate (5, 7). infected stone consisting of struvite or mixed form of struvite and calcium phosphate are also relatively common (4, 16). lithogenic factors include hyperparathyroidsm, hypercalciuria, hypocitraturia, hyperuricosuria, chronic urinary tract infection (utis), urinary stasis, incrusted double j stent and nidus such as nonabsorbable suture (7). hyperparathyroidism has been reported the most important factor in calculus formation in kidney transplantion (16, 17). medical treatments, such as cinecalcet hydrochloride, have been shown to be efficacious in treating hyperparathyroidism by soppression of the action of parathyroid hormone. however, if the hyperparathiroidism persist after 1 or 2 years, a parathyroidectomy must be carried out (2). furthemore, immunosoppressive agents may have a contributory role in the cause of calculi in transplant. ciclosporin, a calcineurin inhibitor used more commonly in the past, is associated with hypeuricemia (18). however, this has not been necessarily associated to an an increase in uric acid calculi risk (16, 19). ciclosporin has been superseded by tacrolimus, another calcineurin inhibitor which has not been shown to affect uric acid levels (20). stapenhorst et al. have reported that calcineurin inhibitor, treatment can lead to hypocitraturia, whereas hyperoxaluria can be primarily the result of a removal of significant body oxalate stores deposited during the dialysis (21). these authors have suggested to treat these patients with alkaline citrate to increase their urinary citrate excretion and urinary solubility index decreasing the risk for calculi formation. in our experience hyperparathiroidism was present in 5 patients and hyperuricemia in 3, but complete metabolic assessment was not carried out in all patients. however, it has been reported that low urinary excretion of citrate could also due to chronic urinary infections (22), that can be present in patients with renal transplantation (incrusted ureteric stents, retention of suture materials, immunosopression agents). consequently, if urinary infection is present, antibiotic prophilaxis could be associated to specific therapies for underlying metabolic anomalies present in patients with renal transplantation and urolithiasis. conclusions the incidence of urolithiasis in renal transplantation is low. in our experience hyperparathyroidism is the most frequent cause of stone formation. urs for its safety and effectiveness could be the treatment of choice of urolithiasis in renal transplantation. open surgery could be carried out after failure of endourological procedures in selected cases. references 1.shoskes da, hanbury d, cranston d, morris pj. urological complications in 1,000 consecutive renal transplantation recipients. j urol. 1995; 153:18-21. 2. benoit g, blanchet p, eschwege p, et al. occurrence and treatment of kidney graft lithiasis in a series of 1500 patients. clin transplant. 1996; 10:176-180. 3. crook tj, keoghane sr. renal transplant lithiasis: rare but timeconsuming. bju int. 2005; 95:931-933. 4. khositseth s, gillingham kj, cook me, chavers bm. urolithiasis after kidney transplantation in pediatric recipients: a single center report. transplantation. 2004; 78:1319-1323. 5. klinger hc, kramer g, lodde m, marberger m. urolithiasis in allograft kidneys. urology. 2002; 59:344-348. 6. lu hf, shekarriz b, stoller ml. donor gifted allograft urolithiasis: early percutaneous management. urology. 2002; 59:25-27. 259archivio italiano di urologia e andrologia 2014; 86, 4 urolithiasis in renal transplantation: diagnosis and management cicerello_stesura seveso 15/01/15 12:58 pagina 259 archivio italiano di urologia e andrologia 2014; 86, 4 e. cicerello, f. merlo, m. mangano, g. cova, l. maccatrozzo 260 7 harper jm, samuell ct, halllson pc, et al. risk factors for calculus formation in patients with renal transplants. br j urol. 1994; 74:147-150. 8. lancina-martin ja, garcia-buitron jm, diaz-bermudez j. urinary lithiasis in transplanted kidney. arch esp urol. 1997; 50:141-150. 9. rhee bk, breatan pn jr, stooler ml. urolithiasis in renal and combined pancreas renal/transplant recipients. j urol. 1999; 161:14581462. 10. cicerello e, merlo f, maccatrozzo l. management of residual fragments after swl. arch ital urol. 2008, 80:34-38. 11. montanari e, zanetti g. management of urolithiasis in renal transplantation. arch ital urol. 2009; 81:175-181. 12. challacome b, dasgupta p, tiptaft r, et al. multimodal management of urolithiasis in renal transplantation. bju int. 2005; 96:385-389. 13. hymas e, marien t, bruhn a, et al. ureteroscopy for transplant lithiasis. j endourol. 2012; 26:819-822. 14. krambeck ae, leroy aj, patterson de, gettman mt: percutaneous nephrolithotomy success in the transplant kidney. j urol. 2008; 180:2545-2549. 15. francesca f, felipetto m, mosca f, et al. percutaneous nephrolithotomy of transpanted kidney. j endourol. 2002; 16:225-227. 16. kim h, cheigh js, ham jw. urinary stones foolowing renal transplantation. korean j intern med. 2011; 16:118-122. 17. stravodimos kg, adamis s, tyritzis s, et al. renal transplant lithiasis: analysis of our series and review of literature. j endourol. 2012; 26:38-44. 18. noordzij tc, leunissen km,van hooff jp. renal handling of urate and the incidence of gouty arthritis during cyclosporine and diuretic use. transplantation 1991; 52:64-67. 19. numakura k, satoh s, tsuchiya n, et al. hyperuricemia at 1 year after renal transplantation, its prevalence, associated factors, and graft survival. transplantation. 2012; 94:145-171. 20. malheiro j, almeida m, fonseca i, et al. hyperuricemia in adult renal allograft recipients: prevalence and predictors. transplant proc. 2012; 44:2369-72. 21.stapenhorst l, sassen r, beck b, et al. hypocitraturia as a risk factor for nephrocalcinosis after kidney transplantation. pediatr nephrol 2005; 20:652-656. 22.cicerello e, merlo f, fandella a, maccatrozzo l. metabolic evaluation of infected urolithiasis. eur urol. suppl 2009; 8:2005. correspondence elisa cicerello, md elisa.cicerello@tin.it franco merlo, md f.merlo@ulss.tv.it mario mangano, md m.mangano@ulss.tv.it giandavide cova, md gd.cova@ulss.tv.it luigi maccatrozzo, md l.maccatrozzo@ulss.tv.it unità complessa di urologia, ospedale cà foncello piazza ospedale 31100 treviso, italy cicerello_stesura seveso 15/01/15 12:58 pagina 260 stesura seveso 387archivio italiano di urologia e andrologia 2014; 86, 4 case report prolonged antibiotic therapy increases risk of infection after transrectal prostate biopsy: a case report after pancreasectomy and review of the literature guevar maselli, giacomo tucci, daniele mazzaferro, asim ettamimi, giulia sbrollini, marco cordari, gaetano donatelli, andrea benedetto galosi division of urology, “augusto murri” general hospital, asur marche, fermo, italy. infection due to prostate biopsy afflicted more than 5% of patients and is the most common reason for hospitalization. a large series from us seer-medicare reported that men undergoing biopsy were 2.26 times more likely to be hospitalized for infectious complications within 30 days compared with randomly selected controls. the factors predicting a higher susceptibility to infection remain largely unknown but some authors have higlighted in the etiopathogenesis the importance of the augmented prevalence of ciprofloxacin resistant variant of bacteria in the rectum flora. we present one case of sepsis after transrectal prostate biopsy in a patient with history of pancreatic surgery. based on our experience patients candidated to prostate biopsy with transrectal technique with history of recent major surgery represent an high risk category for infective complication. also major pancreatic surgery should be consider an high risk category for infection. a transperineal approach and preventive measures (such as rectal swab) should be adopted to reduce biopsy driven infection. key words: prostate; biopsy; infection; sepsis; abdominal surgery. submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. antibiotics presented 9 days after 12 core transrectal prostate biopsy. ciprofloxacin 1000 mg extended release was given before biopsy according local guidelines (4), preoperative urine culture was negative. the patient was submitted in the june 2013 to cephalo-pancreatic-duodenectomy and reconstructive surgery due to a carcinoma of vater papilla; surgical recovery was complicated by infection and treated with attention. during hospitalization he was treated with prolonged antibiotics (imi penem-cilastatin). we consider a review of the literature to establish factors associated with higher susceptibility to infection and to highlight possible relationship between pancreatic surgery and risk of infective complications during prostate biopsy. pubmed search was performed using key words: prostate biopsy; urosepsis; pancreatitis and pancreatic surgery, 76 papers were retrieved and 25 were considered as pertinent to our aim. result the infective course showed 2 episodes of recurrence with fever and urine culture positive for e. coli with multidrug resistant. the first hospital admission: after an empiric therapy with ciprofloxacin the patient was treated with i.v. association (ceftriaxone and piperacillintazobactam) for 10 days, then discharged with oral antibiotics. after 15 days, the second hospital admission was due to fever (39°c) and urinary symptoms and the hospital stay was 5 days. transrectal ultrasound was negative for abscess or significant post-void urinary residue. a second cycle of i.v. antibiotic association (ceftriaxone and piperacillin-tazobactam) resolved the fever. further follow-up was uneventful. discussion several reports have recently suggested an increased rate of infective complications following transrectal prostate biopsy in both north america (5) and europe (6). the reasons for this increase and the factors associated with a higher susceptibility to infection remain largely unknown. based on our experience, candidates to transrectal prostate biopsy with anamnesis of recent major doi: 10.4081/aiua.2014.4.387 presented at 19th national congress sieun, fermo 2014 introduction prostate biopsy presents a significant percentage of complication. the infection afflicted more than 5% of patients submitted to prostate biopsy (1) and is the most common reason for hospitalization for prostate biopsy (2, 3). the factors predicting a higher susceptibility to infection remain largely unknown but some authors have highlighted in the etiopathogenesis the importance of augmented prevalence of ciprofloxacin resistant bacterial strains (e. coli) in the rectum flora. we present one case of sepsis after transrectal prostate biopsy in patient with history of pancreatic surgery due to a carcinoma of vater papilla. material and methods a 53 years-old men was admitted in january 2014 by access in emergency ward with fever not responsive to maselli_stesura seveso 16/01/15 11:34 pagina 387 archivio italiano di urologia e andrologia 2014; 86, 4 g. maselli, g. tucci, d. mazzaferro, a. ettamimi, g. sbrollini, m. cordari, g. donatelli, a.b. galosi 388 surgery represent an high risk category for infective complication. so this category should be consider to reducing risk of sepsis by bacteria resistant to the common antibiotics adopted in prophylaxis. a transperineal approach should be chosen for this reason in such cases. in prospective multinational study on infective complications after prostate biopsy florian et al. (7) supports the findings that the presence of fecal fluoroquinolone-resistant bacteria is the most important risk factor. strategies to identify fluoroquinolone-resistant bacteria should be sought so as to decrease infective complications. multivariate analysis did not identify any patient subgroups with a significantly higher risk of infection after prostate biopsy. causative organisms were isolated in 10 cases (37%) with 6 resistant to fluoroquinolones. fluoroquinolone resistance has increased globally, and the presence of fluoroquinoloneresistant organisms on rectal swab culture is a significant predictor of infection after prostate biopsy (8). a rectal swab has been proposed at the visit preceding prostate biopsy and is plated on macconkey agar containing ciprofloxacin (9). patients with ciprofloxacin sensitive bacteria can then receive ciprofloxacin prophylaxis, while culture results can guide an alternative selection for those with resistance. a few non-randomized studies have examined the results of targeted prophylaxis with results in accordance. to date, there are no randomized studies showing that targeted prophylaxis using rectal swabs results reduces infection and cost compared with standard or expanded prophylaxis. in the specific population represented by patient afflicted with acute necrotic pancreatitis result changing the bowel, like alteration of ph, that conduce to a selection in some germs (e.g.: e. coli) to the disadvantage of the usual dominant microorganism (bifidus). this may represent the cause of an increased growth of opportunist pathogenous (10). besides the exposition to prolonged antibiotic prophylaxis or prolonged antibiotic therapy (like is usual in patient submitted to major surgery) is the cause of the selection of species drug resistant (11). it not well understood if the change in enteric-biliar circule resulting by pancreatic surgery could be also a cause of the develop of drug resistence of the enteric flora. therefore in this patient group it may be useful to perform a fecal swab before transrectal prostate biopsy to verify bacterial resistence and consider an adequate antibiotic prophylaxis alternative to fluoroquinolones. history of a previous surgery of the pancreas with consequent exposure to prolonged antibiotic therapy might suggest to use transperineal approach to perform prostate biopsy for reduce dissemination of bacteria present in the rectum. the prolonged antibiotic therapy performed after prosthetic or major surgery changes the enteric flora and select multi-resistant strains (12). literature does not investigate if the enterohepatic bile alteration secondary to pancreatic surgery could further contribute to antibiotic resistance of the bacteria flora. conclusion prolonged antibiotic therapy associate with major pancreatic surgery may increase the risk of infective complications after prostate biopsy. this result is linked to fecal fluoroquinolone-resistant bacteria that increase after prolonged antibiotic therapy. the transperineal approach should be considered in this category of patients. in addition preoperative rectal swab are suggested to identify antibiotic resistance in bacterial strains. references 1. loeb s, carter hb, berndt si, et al. complications after prostate biopsy: data from seer-medicare. j urol. 2011; 186:1830-4. 2. stacy loeb, annelies vellekoop, hashim u. ahmed, et al. systematic review of complications of prostate biopsy. eur urol. 2013; 64:876-892. 3. williamson da, roberts sa, paterson dl, et al. escherichia coli bloodstream infection after transrectal ultrasound-guided prostate biopsy: implications of fluoroquinolone-resistant sequence type 131 as a major causative pathogen. clin infect dis 2012; 54:1406-12. 4. martino p, galosi ab, bitelli m, et al. imaging working groupsocietà italiana urologia and società italiana ecografia urologica andrologica nefrologica. practical recommendations for performing ultrasound scanning in the urological and andrological fields. arch ital urol androl. 2014; 86:56-78. 5. wolf js j, bennett cj, dmochowski rr, et al. urologic surgery antimicrobial prophylaxis best practice policy panel. best practice policy statement on urologic surgery antimicrobial prophylaxis. american urological association web site. www.auanet.org/content/clinicalpracticeguidelines/clinicalguidelines. updated 2012. 6. grabe m, bjerklund-johansen te, botto h, et al. guidelines on urological infections. european association of urology web site. www.uroweb.org/gls/pdf/17_ urological%20infections_lr%20ii. pdf. updated 2012. 7. florian me wagenlehner, edgar van oostrum, et al. infective complications after prostate biopsy: outcome of the global prevalence study of infections in urology (gpiu) 2010 and 2011, a prospective multinational multicentre prostate biopsy study. eur urol. 2013; 63:521-7. 8. williamson da, masters j, freeman j, roberts s. travel-associated extended-spectrum beta-lactamase-producing escherichia coli bloodstream infection following transrectal ultrasound-guided prostate biopsy. bju int. 2012; 109:e21-2. 9. duplessis ca1, bavaro m, simons mp, et al. rectal cultures before transrectal ultrasound-guided prostate biopsy reduce post-prostatic biopsy infection rates. urology. 2012; 79:556-61. 10. wu ct, li zl, xiong dx. relationship between enteric microecologic dysbiosis and bacterial translocation in acute necrotizing pancreatitis. world j gastroentero, 1998; 4:242-245. 11. taylor s1, margolick j, abughosh z, et al. ciprofloxacin resistance in the faecal carriage of patients undergoing transrectal ultrasound guided prostate biopsy. bju int. 2013; 111:946-53. 12. walder m, leandoer l, törnqvist a, forsgren a. long-term ef fects on bacterial sensitivity patterns of preoperative antibiotic pro phylaxis in colorectal surgery. scand j infect dis. suppl. 1988; 53:59-64. correspondence guevar maselli, md, urologist (corresponding author) guevarmaselli@katamail.com giacomo tucci, md tucci.giacomo@virgilio.it daniele mazzaferro, md, urologist mazzaferro.dr@gmail.com asim ettamimi, md ettamimi.asim@tiscali.it giulia sbrollini, md, resident in urology giuliasbrollini@libero.it marco cordari, md, urologist, m.cordari@tin.it gaetano donatelli, md, urologist g.donatelli@als11.marche.it andrea benedetto galosi, md, phd, urologist galosiab@yahoo.it division of urology, “augusto murri” general hospital, asur marche, fermo, italy maselli_stesura seveso 16/01/15 11:34 pagina 388 stesura seveso 249archivio italiano di urologia e andrologia 2014; 86, 4 original paper clinical presentation of urolithiasis in older and younger population murat dursun 1, emin ozbek 2, alper otunctemur 3, suleyman sahin 4, suleyman sami cakir 5 1 bahcelievler state hospital, department of urology, istanbul, turkey; 2 katip celebi university, ataturk training and research hospital, department of urology, izmir, turkey; 3 okmeydani training and research hospital, department of urology, istanbul, turkey; 4 bilecik state hospital, department of urology, bilecik, turkey; 5 bayburt state hospital, department of urology, bayburt, turkey. aim of the study: we compared stone size, localization, complaint at the time of applying, comorbidity, treatment and complications between older (60 years of age and older) and younger patients with urolithiasis (59 years of age and younger). materials and methods: we retrospectively reviewed the records of 950 consecutive patients who presented to our clinic and underwent surgery for urolithiasis from january 2007 to march 2012. the patients were divided into two groups: patients ≥ 60 years an patients < 60 years. results: there were 174 men and 61 women in elderly group, 528 men and 187 women in younger group. ureteral stones were found more often in the younger group compared to elderly patients (p < 0.05). conversely, bladder stone was more frequent in the elderly group. in the elderly group comorbidities are more frequent (diabetes mellitus, hypertension, ischemic heart disease, congestive heart disease, osteoarthritis and chronic obstructive lung). patients ≥ 60 years significantly had larger kidney and bladder stones compared the younger, but ureteral stone sizes were not statistically different between the two groups. older patients had a higher postoperative complication rate than younger patients (16% versus 3%, p < 0.05) although postoperative complications (e.g. urinary retention, cardiac dysrythmia, fever, constipation) were not serious and resolved with medical treatment. the average length of stay in hospital was longer in the elderly group, but the difference was not statistically significant. conclusions: elderly patients with urolithiasis usually have larger and more complex stone disease, more comorbidities and atypical presentation. key words: urinary calculi; elderly; comorbidities. submitted 5 february 2014; accepted 30 june 2014 summary no conflict of interest declared. both men and women (3,4). the lifetime recurrence risk is 50% with an estimated time to recurrence < 1 year in 10% of cases, < 5 years in 35 to 50% of cases and < 10 years in 50% or greater (5). stones along the urinary tract can be located in the kidneys, ureters and urinary bladder. while approximately 90% of stones are successfully passed out of the urinary tract, the remaining stones generally have to be surgically removed by ureteroscopy or percutaneous nephro lithotomy or comminuted by non-invasive shock wave lithotripsy (6). stone occurrence is relatively uncommon before age 20 but peaks in incidence in the fourth to sixth decades of life. geriatric stone formers comprise 10%-12% of all stone formers and may have a proclivity to develop stones due to metabolic changes associated with ageing (7, 8). altough it has been shown that geriatric patients with stones tend to have their first episode after age 50, it is not well described how the presentation of stones differs in elderly patients (7). according to the world health organization (who), ageing is defined as living beyond 60 years in a developing country or 65 years in a developed country. the number of ageing people is increasing faster than is any other age group; in 2025, there will be an estimated 1.2 billion individuals over the age of 60, and this number could reach 2 billion by 2050 (9). so, we reported a study of clinical presentation of urolithiasis in elderly compared to younger. we compared the stone size, localization, complaint at the time of applying, comorbidity, treatment and complications between the old (60 years of age and older) and young patients (59 years of age and younger). material and methods we retrospectively reviewed the records of 950 consecutive patients who presented to our clinic and underwent surgery for urolithiasis from january 2007 to march 2012. the diagnosis of urolithiasis was assessed by either ultrasonography, intravenous urography or abdominal ct. we excluded the patients who did not have surgery or eswl and were followed by medical therapy because doi: 10.4081/aiua.2014.4.249 introduction urolithiasis is the third most common urological disease affecting the urinary tract after urinary infection and prostatic pathology (1). the prevalence of urolithiasis varies between 2 and 20% throughout the world (2). the worldwide prevalence of the disease appears to have increased in the last quarter of the twentieth century for dursun_clin_stesura seveso 16/01/15 09:22 pagina 249 archivio italiano di urologia e andrologia 2014; 86, 4 m. dursun, e. ozbek, a. otunctemur, s. sahin, s. sami cakir 250 the follow up of these patients is difficult in our hospital. we also excluded the patients who have hormonal therapy which is associated with urolithiasis. the patients were evaluated by internal medicine specialist and consent was acquired in all the patients. the patients were divided into two groups: patients ≥ 60 years an patients < 60 years. there were 235 patients in the elderly group and 715 patients in the younger group. stone size, localization, complaint at the time of applying, comorbidity, treatment and complications were compared between groups. a retrospective case-control study was used and data were analyzed by univariate statistics. frequency analyses and descriptive statistics, i.e. mean and standard deviation (sd), were performed. the student’s t test was used to compare the groups. results there were 174 men and 61 women in elderly group, 528 men and 187 women in younger group. the mean age of elderly patients was 66.86 ± 0 years and 35 ± 2,82 years in young group. there were 85 (36.2%) patients with renal stones, 76 (32.3%) patients with ureteral stones and 74 (31.5%) patients with bladder stones in the elderly group and 257 (36%), 411 (57.4%) and 47 (6.6%) patients respectively in the younger group. so, ureteral stones were found more often in younger group compared to elderly patients (p < 0,05). also bladder stone was more frequent in the elderly group as shown in figure 1. elderly and young patients were compared for comorbidities and in the elderly group comorbidities are more frequent (table 1). there was a statistically significant difference for diabetes mellitus, hypertension, ischemic heart disease, congestive heart disease, osteoarthritis and chronic obstructive lung disesase prevalence between groups. the presenting complaints were compared as flank pain, hematuria, dysuria, urinary tract infection and no symptoms (figure 2). flank pain seems more often in the younger population and other complaints seems more often in the elderly group, but no statistically siginificant difference was shown. mean stone size was found 28 ± 5.65 mm for the largest stone diameter in ≥ 60 years group and 20 ± 14.14 mm in < 60 years group. elderly patients had larger stones compared the younger (p < 0.05). for localization as kidney, ureter and bladder; mean stone size was measured 34.23 ± 5.65 mm, 14.28 ± 12.72 mm and 25.94 ± 6.36 mm in elderly patients and 21 ± 12.72 mm, 15 ± 7.07 mm and 19 ± 1.41 mm in younger patients respectively (figure 3). patients ≥ 60 years significantly had larger kidney and bladder stones compared the younger, but ureteral stone sizes were not statistically different between groups. comorbidity prevelence in ≥ 60 prevelence in < 60 years group (%) years group (%) diabetes mellitus 32.3 11 hypertension 57.4 29 congestive heart failure 17.4 1 ischemic heart disease 34.1 9 gastroesophageal reflux disease 31.9 17.4 stroke 5.5 1.9 chronic obstructive lung disease 27.6 7.1 osteoarthritis 43.4 7.5 table 1. comparison of some comorbidities between groups. figure 1. comparison of stone location between younger and elderly groups. figure 3. comparison of mean kidney, ureter and bladder stone size between elderly and younger groups. figure 2. comparison for presenting complaints between groups (no significant difference was found for each complaint) (uti= urinary tract infection). dursun_clin_stesura seveso 16/01/15 09:22 pagina 250 patients in both groups were treated by similar treatment methods as percutaneous nephrolithotomy (pcnl), ureteroscopy (urs), extracorporeal shock wave lithotripsy (eswl), cystolithotripsy or open surgery according to stone localization. in younger group, 9 patients (19%) underwent cystholitotomy and 38 (81%) cystolithotripsy for bladder stone. cystholithotomy was seen more frequently in older patients, in fact 24 patients (32%) underwent open surgery for bladder stone in the older group. in the older group 3 patients (3%) underwent open surgery for kidney stones, 26 patients (30%) eswl and 26 patients (65%) pcnl. in the younger group the numbers of patients were respectively 32 (12%), 84 (32%) and 141 (56%). in elderly populations, pcnl was used more frequently for kidney stones, but difference was not statistically significant. in younger group, 21 patients (5%) underwent open surgery, 156 patients (38%) eswl and 234 (57%) urs for ureteral stones. similarly, in the older group 55% of patients underwent urs and 40% of eswl. there was no difference in the rate of intraoperative complications between groups, but older patients had a higher postoperative complication rate than younger patients (16% versus 3%, p < 0,05). postoperative complications (e.g. urinary retention, cardiac dysrythmia, fever, constipation) were not serious and resolved with medical treatment. in our study, all patients underwent surgery or eswl, and 465 patients of the younger group and 179 patients of the older group stayed in hospital for a period. the average length of stay in hospital was longer in the elderly group compared to the younger group (2.3 and 2 day, respectively), but difference was not statistically significant. discussion the geriatric population is the fastest growing segment in many parts of the world. most developed countries have accepted the chronologic age of 65 years as a definition of “elderly” or older person; however, the united nations agreed a cut off of 60 years to refer to the older population. age itself is not an illness, however, the changes in cardiopulmonary reserve of the elderly patients make them less tolerant to certain stressors, such as an increase in demand during the perioperative period, bleeding, or medical complications (10, 11). on the other hand, increasing incidence and considerable recurrence along with severe renal functional consequences make urolithiasis a surgical and a medical problem which needs a prompt diagnosis and appropriate management in elderly populations (12, 13). therefore, careful selection and preparation of the patients are very important in the geriatric population with urolithiasis for decreasing lifethreatening complications. accordingly, in this study we compared comorbidities, stone size, localization, treatment options and complications between elderly and younger populations in order to contribute in treatment choice and patient selection in the elderly population with urolithiasis. like in our study, bladder stones have been found to be frequent in the elderly as reported by some studies (14) but not in others (15). according to daudon et al. (14), 40.0% of the patients they analyzed were men over 80 years. in our study, 6.6% of the stones were from the bladder in the younger group, but elderly men were most affected (31.35%). in contrast to, ureteral stone rate was found higher in the younger group. prostatic hyperplasia, which is considered a frequent cause of bladder outlet obstruction, is frequent in old men and could be a possible explanation for the high frequency of bladder stones in the elderly (14, 16). our findings confirmed that older patients with urolithiasis had more comorbidities than younger as shown in previous studies (17-19). in our study, especially comorbidities related to metabolic syndrom seems to be more frequent in the elderly group. the association between metabolic syndrome and kidney stones has been established by some studies (20-22). furthermore, the risk of a stone former to develop diabetes mellitus is partially supported by two recent investigations (23, 24) and some studies provide evidence of an association between kidney stone formation and cardiovascular disease (25, 26). in fact these comorbidities were more frequent in the elderly group and may be cause of stone formation in these patients. our data suggest that elderly patients had a more atypical presentation of disease as shown in figure 2 and these atypical presentations cause delay in the diagnosis. this may explain why mean kidney stone size was found larger in older group compared to the younger. this finding confirm what previously described by mccarthy et al. (19) although in their study were described only 26 older patients whereas in our study we reported a larger number of 235 older patients. another explanation is the steady decline in renal function that occurs with advanced age, as supersaturation and stone formation have been attributed to renal tubular cell damage (27-29). for the treatment modalities, there were no statistical difference between groups. according to comorbidities, stone size and localization, patients underwent different treatment options. in previous studies, pcnl was demonstrated to be a safe and effective treatment for urinary calculi in both elderly patients and those with comorbid conditions (30, 31) and we did not found statistical difference for different treatment options between older and younger patients. the average length of stay in hospital was longer in the elderly group, probably owing to the occurence of more postoperative complications in older patients. in fact, in our study, older patients had a higher postoperative complication rate than younger patients (16% versus 3%, p < 0.05). urinary retention may be caused by benign prostate hyperplasia (bph) that is more frequent in older patients. other comorbidities like cardiac problems and hypertension are more often in older group, consequently older patients are usually at risk of ischemic cardiac disease and arythmia. infections be cause fever in postoperative period in consideration of the poor immune system of older patients. in conclusion, elderly patients with urolithiasis usually have larger and more complex stone disease, more comorbidities and atypical presentation. because of that physicians have to be careful in the preoperative and 251archivio italiano di urologia e andrologia 2014; 86, 4 relation between age and urolithiasis dursun_clin_stesura seveso 16/01/15 09:22 pagina 251 archivio italiano di urologia e andrologia 2014; 86, 4 m. dursun, e. ozbek, a. otunctemur, s. sahin, s. sami cakir 252 postoperative period for the treatment of urolithiasis in elderly populations. treatment of stones in elderly patients can be delayed and they may admitted to the hospital due to other problems, because they usually have silent stone disease. like in our study, older patients may have larger stones when they admitted to hospital. we must plan carefully the treatment algoritm in older patients with urolithiasis because of the risk of postoperative complications the complaints of older patients may be serious and require prompt intervention. references 1. smith lh. the medical aspects of urolithiasis: an overview. j urol. 1989; 141:707. 2. curhan gc. epidemiology of stone disease. urol clin n am. 2007; 34:287-293. 3. stamatelou kk, francis me, jones ca et al. time trends in reported prevalence of kidney stones in the united states: 1976–1994. kidney int. 2003; 63:1817-1823. 4. hesse a, brandle e, wilbert d, et al. study on the prevalence and incidence of urolithiasis in germany comparing the years 1979 vs. 2000. eur urol. 2000; 44:709-713. 5. pearle ms, calhoun ea, curhan gc. urolithiasis. in: litwin ms, saigal cs, editors. urologic diseases in america. us department of health and human services, public health service, national institutes of health, national institute of diabetes and digestive and kidney diseases. washington, dc: us government publishing office; 2007. pp. 283-319. nih publication no. 07-5512. 6. lingeman je, matlaga b, evan ap. surgical management of urinary lithiasis. in: walsh pc, retik ab, vaughan ed, wein aj, editors. campbell’s urology, chap 44. philadelphia: saunders. 2006; pp. 1431-1507. 7. gentle dl, stoller ml, bruce jr, leslie sw. geriatric urolithiasis. j urol. 1997; 158:2221-2224. 8. mhiri mn, achiche s, maazoun f, et al. urinary calculi in a geriatric setting. ann urol (paris) 1995; 29:382-388. 9. biggs a, bloom d, burtless g, fujiwara m, hayashi k, kanzler l, et al. a slow burning fuse; a special report on aging populations. the economist. 2009; 27:1-15. 10. tonner ph, kampen j, scholz j. pathophysiological changes in the elderly. best practi res clin anaesthesiol. 2003; 17:163-177. 11. ng cf. the effect of age on outcomes in patients undergoing treatment for renal stones. curr opin urol. 2009; 19:211-214. 12. lancina martín ja, novás castro s, rodríguez-rivera garcía j, et al. age of onset of urolithiasis: relation to clinical, metabolic risk factors. arch esp urol. 2004; 57:119-125. 13. trinchieri a, ostini f, nespoli r, et al. prospective study of recurrence rate and risk factors for recurrence after a first renal stone. j urol. 1999; 162:27-30 14. daudon m. évolution de la composition et de la localisation des calculs chez le sujet âgé. feuillets de biologie. 2003; 25:51-4. 15. neuzillet y, lechevallier e, ballanger p, et al. urinary stones in subjects over the age of sixty. prog urol. 2004; 14:479-84. 16. el-reshaid k, mughal h, kapoor m. epidemiological profile, mineral metabolic pattern and crystallographic analysis of urolithiasis in kuwait. eur j epidemiol. 1997; 13:229-34. 17. pinkawa m, fischedick k, gagel b, et al. impact of age and comorbidities on health-related quality of life for patients with prostate cancer: evaluation before a curative treatment. bmc cancer. 2009; 9:296. 18. mao jj, armstrong k, bowman ma, et al. symptom burden among cancer survivors: impact of age and comorbidity. j am board fam med. 2007; 20:434-443. 19. mccarthy j-p, skinner taa, norman rw. urolithiasis in the elderly. the canadian journal of urology. 2011; 18:5717-5720. 20. west b, luke a, durazo-arvizu ra, et al. metabolic syndrome and selfreported history of kidney stones: the national health and nutrition examination survey (nhanes iii) 1988–1994. am j kidney dis 2008; 51: 741-747. 21. rendina d, mossetti g, de filippo g, et al. association between metabolic syndrome and nephrolithiasis in an inpatient population in southern italy: role of gender, hypertension and abdominal obesity. nephrol dial transplant. 2009; 24:900-906. 22. jeong ig, kang t, bang jk, et al. association between metabolic syndrome and the presence of kidney stones in a screened population. am j kidney dis. 2011; 58:383-388 23. ando r, suzuki s, nagaya t, et al. impact of insulin resistance, insulin and adiponectin on kidney stones in the japanese population. int j urol. 2011; 18:131-138. 24. chung sd, chen yk, lin hc. increased risk of diabetes in patients with urinary calculi: a 5-year followup study. j urol. 2011; 186:1888-1893. 25. elmfeldt d, vedin a, wilhelmsson c, et al. morbidity in representative male survivors of myocardial infarction compared to representative population samples. j chronic dis. 1976; 29:221-231. 26. westlund k. urolithiasis and coronary heart disease: a note on association. am j epidemiol. 1973; 97:167-172. 27. kumar s, sigmon d, millet t, et al. a new model of nephrolithiasis involving tubuler dysfunction/injury. j urol. 1991; 146:1384-1389. 28. khan sr, canales bk. genetic basis of renal cellular dysfunction and the formation of kidney stones. urol res 2009; 37:169-180. 29. khan sr. renal tubuler damage/dysfunction: key to the formation of kidney stones. urol res. 2006; 34:86-91. 30. patel sr, haleblian gl, pareek g. percutaneous nephrolithotomy can be safely performed in the high-risk patient. urology. 2010; 75: 51-55. 31. karami h, mazloomfard mm, golshan a, et al. does age effect outcomes of percutaneous nephrolithotomy? j urol. 2010; 7:17-21. correspondence murat dursun, md mrt_drsn@hotmail.com bahcelievler state hospital, department of urology 34180, kocasinan merkez, bahcelievler, istanbul, turkey emin ozbek, md katip celebi university, ataturk training and research hospital, department of urology, izmir, turkey alper otunctemur, md okmeydani training and research hospital, department of urology, istanbul, turkey suleyman sahin, md bilecik state hospital, department of urology, bilecik, turkey suleyman sami cakir, md bayburt state hospital, department of urology, bayburt, turkey dursun_clin_stesura seveso 16/01/15 09:22 pagina 252 stesura seveso 291archivio italiano di urologia e andrologia 2014; 86, 4 case report peripheral primitive neuroectodermal tumor of seminal vesicles: is there a role for relatively aggressive treatment modalities? alessandro crestani 1, andrea guttilla 1, mario gardi 2, marina gardiman 3, fabrizio dal moro 1, claudio valotto 1, filiberto zattoni 1 1 department of gastroenterological, oncological and surgical sciences, urology clinic, university of padua, italy; 2 department of urology, s. antonio hospital, padua, italy; 3 department of oncological and surgical sciences, division of pathology, university hospital of padua, italy. a 50 year old white man received an incidental ultrasound diagnosis of hypoechoic mass interesting the right seminal vesicle. a ct scan showed the presence of a 7.8 cm roundish cyst, originating from the right seminal vesicle. he had been followed by the removal of the right seminal vesicle and both the cystic lesion. the histological findings of the specimen documented the presence of small round cells compatible with ewing’s sarcoma/ppnet. the patient received also adjuvant chemotherapy and radiation treatment. after 10 years, the follow-up is still negative. key words: seminal vesicles, sarcoma, peripheral primitive neuroectodermal tumor. submitted 27 august 2013; accepted 30 september 2014 summary no conflict of interest declared. urine analysis were all normal. the general physical examination did not reveal anything particular. at dre, a palpable mass was recognized at the level of the right portion of the anterior rectal wall dislocating the prostate gland. the abdominal ultrasound examination of the pelvis showed a roundish cyst within the right seminal vesicle of 8 cm in the widest diameter, with septa and corpuscular material, inside (figure 1). the further imaging diagnostic work up consisted in a pelvic computed tomography (ct) scan and intravenous pyelography (ivp). the ct scan confirmed the presence of a 7.8 cm roundish cyst, originating from the right seminal vesicle; the urinary bladder resulted compressed and anteriorly dislocated (figure 2). no wall contrast enhancement was detected and a plane of dissection was appreciable from the bladder, rectum and the lateral pelvic wall (internal obturator muscle). ct scan revealed another oval-shaped cyst of 3 cm in the widest diameter originating from the right seminal vesicle with the same densitometric features. the ivp confirmed also that the right supero-external margin of the bladder wall was compressed (figure 3). the patient underwent a tc guided fine needle agobiopsy (fnab) of the larger lesion that gave no significant findings. therefore the patient was surgically explored through a midline incision of the lower abdomen. a cystic lesion was found against the right seminal vesicle that raised-up the bladder. frozen section biopsies of the cystic lesion documented fibrous tissue with chronic inflammation. the removal of the right seminal vesicle and both the cystic lesions was performed. the post operative period was uneventful and the patient was discharged in few days. the histological findings of the specimen documented the presence of small round cells compatible with ewing’s sarcoma/ppnet (figures 4-5). after surgery the patient received adjuvant chemotherapy with a total of 13 cycles (adriamycin, vincristine, cyclophosphamide, actinomycin d, ifosfamide, etopo side), as well as radiation treatment (48 gy) on the pelvis. after 10 years, the follow-up is still negative: pet total body was always negative and the patient is in a good general condition with normal urinary continence and good erectile function. doi: 10.4081/aiua.2014.4.291 introduction the seminal vesicles are an unusual site of primary malignancy in the urinary tract and primary malignant ewing’s sarcoma or its variant peripheral primitive neuroectodermal tumor (ppnet) are even more rare (1-2). the prognosis of extraskeletal ppnet is generally poor and an aggressive, multimodal approach is usually required (3). at our knowledge only one case of ppnet involving the seminal vesicles has been reported, with scarce information about the follow-up. herein is described a case of ppnet arising from the right seminal vesicle with a ten year follow-up. case report a 50 year old white man received an incidental ultrasound diagnosis of hypoechoic mass interesting the right seminal vesicle. at the time, he was 174 cm in height, 82 kg in weight and the body surface area was 1,97 m2; the performance status was grade 0. the family and his own personal medical history was not significant. he did not refer any professional exposure to carcinogens and used to smoke 7-8 cigarettes per day. complete blood cell count, routine chemistry profile and crestani_stesura seveso 14/01/15 13:00 pagina 291 archivio italiano di urologia e andrologia 2014; 86, 4 a. crestani, a. guttilla, m. gardi, m. gardiman, f. dal moro, c. valotto, f. zattoni 292 way was related to ct scan images that showed only roundish cystic lesions without any contrast enhancement in the cystic wall and the presence of a well defined plane of dissection from the bladder, rectum and lateral pelvic wall. usually in case of sarcoma of the seminal vesicles, they are treated by means of an aggressive surgical approach as radical prostatectomy or radical cystectomy with an inevitably negative impact on the quality of life of the patients. in the case here described, the very conservative surgical approach was followed by an adjuvant therapy: such a treatment provided good clinical results, lasted in the long term period. figures are posted in supplementary materials” on www.aiua.it references 1. agrawal v, kumar s, sharma d, et al. primary leiomyosarcoma of the seminal vesicle. int j urol. 2004; 11:253-5. 2. baschinsky dy, niemann th, maximo cb, bahnson rr. seminal vesicle cystadenoma: a case report and literature review. urology. 1998; 51:840-5. 3. lawrentschuk n, appu s, chao i, et al. peripheral primitive neuroectodermal tumor arising from the seminal vesicle. urol int. 2008; 80:212-5; discussion 216. 4. llombart-bosch a, machado i, navarro s, et al. histological heterogeneity of ewing's sarcoma/pnet: an immunohistochemical analysis of 415 genetically confirmed cases with clinical support. virchows arch. 2009; 455:397-411. 5. berg t, kalsaas ah, buechner j, busund lt. ewing sarcomaperipheral neuroectodermal tumor of the kidney with a fus-erg fusion transcript. cancer genet cytogenet. 2009; 194:53-7. 6. zanetti g, gazzano g, trinchieri a, et al. a rare case of benign fibroepithelial tumor of the seminal vesicle. arch ital urol androl. 2003; 75:164-5. discussion ppnet, histologically characterized by the presence of small round cells extracranially in soft tissues and bones. ewing’s sarcoma and primitive peripheral neuroectodermal tumor (ppnet) have been originally described as two distinct pathologic entities (4). because of their similar histologic and cytogenetic characteristics, these tumors are now considered to derive from a common origin cell and to be a part of a spectrum of neoplastic diseases known as the ewing sarcoma family of tumors (esft), which also includes extraosseous ewing sarcoma (ees), adult neuroblastoma, malignant small-cell tumor of the thoracopulmonary region (askin tumor), paravertebral small-cell tumor, and atypical ewing’s sarcoma. they all derive from embryonal neural crest cells. the essential feature to diagnose ppnet or ewing’s sarcoma is the histoimmunochemistry with cd99. ewing family of tumors (efts) represents a neoplastic entity characterized by specific chromosomal rearrangements. the most commonly detected translocation involves the fusion of ewsr1 to one of the genes encoding ets family of transcription factors, usually fli1 or erg. the detection of specific translocations by fluorescence in situ hybridization (fish), reverse transcription-polymerase chain reaction (rt-pcr), or both has become the diagnostic hallmark for the efts (5). ppnets are uncommon and the primary ppnet of the seminal vesicles is quite exceptional. differential diagnosis must include rhabdomyosarcomas, leyomiosarcomas, phylloides tumors, malignant fibrous histiocytomas, chondrosarcomas. differential diagnosis must also include benign conditions like benign fibroepithelial tumor (6), prostatic utricle cyst, the prostatic abscess, the hydrops, the cyst and the empyema of seminal vesicles or the ectopic ureterocele. usually surgical treatment of sarcomas of the pelvis is extremely aggressive. the choice to treat the present patient in a conservative correspondence alessandro crestani, md (corresponding author) alessandro.crest@gmail.com andrea guttilla, md fabrizio dal moro, md claudio valotto, md filiberto zattoni, md department of gastroenterological, oncological and surgical sciences urology clinic, university of padua via giustiniani, 2 padova, italy mario gardi, md department of urology, s. antonio hospital, padova, italy marina gardiman, md department of oncological and surgical sciences, division of pathology, university hospital of padua via giustiniani, 2 padova, italy crestani_stesura seveso 14/01/15 13:00 pagina 292 microsoft word 17valentino.docx no conflict of interest declared. 378 archivio italiano di urologia e andrologia 2014; 86, 4 presented at 19th national congress sieun, fermo 2014 original paper doi: 10.4081/aiua.2014.4.378 incidentally detection of non-palpable testicular nodules at scrotal ultrasound: what is new? massimo valentino 1, michele bertolotto 2, pasquale martino 3, libero barozzi 4, pietro pavlica 5 1 uo di radiologia, ospedale s. antonio, tolmezzo, udine, italy; 2 dipartimento di radiologia, università di trieste, trieste, italy; 3 uo di urologia i universitaria, università di bari, italy; 4 uo di radiologia, ospedale maggiore, bologna, italy; 5 gvm care and research, villalba hospital, bologna, italy. summary the increased use of ultrasound in patients with urological and andrologi significant role in the characterization of focal lesions in liver, pancreas, spleen and kidneys. their use in the cal symptoms has given an higher detection of intra-testic ular nodules. most of these lesions are hypoechoic and their interpretation is often equivocal. recently, new ultrasound techniques have been developed alongside of b-mode and color-doppler ultrasound. although not completely standardized, contrast-enhanced ultrasound (ceus) and tissue elastography (te), added to traditional ultrasonography, can provide useful infor mation about the correct interpretation of incidentally detected non-palpable testicular nodules. the purpose of this review article is to illustrate these new techniques in the patient management. key words: testicular lesions; ultrasound; contrast enhanced ultrasound; elastography. submitted 3 october 2014; accepted 31 october 2014 introduction the increased use of ultrasound (us) in patients with uro logical and andrological symptoms has given an higher detection of intra-testicular nodules. most of these lesions are hypoechoic and their interpretation is often equivocal (1). the incidence of non-palpable testicular lesions depends on their size. non-palpable nodules with a diam eter of 10 mm account for about 0.2-1% of the patients with testicular nodules investigated with us (2-5). most of these nodules are benign, including leydig cell tumor as the main lesion. nevertheless, if us is inconclusive, surgi cal exploration is the treatment of choice due to possible malignant nature of the nodule (6). by overcoming the limitation of b-mode and color doppler ultrasound, new techniques such as contrast enhanced ultrasound (ceus) and tissue elastography (te) were explored for characterizing the testicular nodules in order to select the appropriate treatment. contrast-enhanced ultrasound over the past decade, us contrast agents have gained a testis is not well establish, even if some authors advo cated their utility in trauma, infarction, and tumors. us contrast agents are gas-filled microbubbles of small size (less than 10 µm) able to diffuse in the blood allow ing the visualization of the vascularization of the nod ules. they are administered intravenously at the dose of 4.8 ml (one vial of contrast agent) followed by 10 ml of saline solution by an antecubital vein. after a mean delay of 20 seconds, the contrast agent reaches the testes giv ing its vascular map. the nodules can be depicted as hyper-enhancing, hypo-enhancing or non-enhancing masses in comparison with surrounding tissue. some authors advocated use of ceus in the preoperative assessment of testicular lesions with hypervascularity as an important feature in the diagnosis of malignancy (7). bubbles remain visible for 2-3 minutes after injection, therefore contrast intensity gradually decreases. tissue elastography tissue elastography (te) has been recently introduced for making non-invasive measurements of the mechanical properties of tissue. it is an imaging method of assess ment for the elasticity of biological tissues (8). it repre sents a “new way” of palpation, where a portion of tissue is compressed and the degree to which it displaces is assessed. the most common way to displace the tissue is a manual application of a slight longitudinal compres sion with a conventional probe (so called “strain imag ing”): the different tissues create different responses according to their specific elastic modulus (9). te evalu ates the relative elasticity of different tissues in a selected region of interest by using a fast cross correlation tech nique and a combined autocorrelation method. it creates an elastogram that is superimposed to the b-mode ultra sound image of the tissue and updated in real-time. by convention, the elastograms display a colour-coded map of the relative elasticity. the normal testis in color scale elasticity imaging shows homogenous, soft stiff ness. focal lesions depicted as hard on elastography are suspicious for malignancy. some authors found 87.5% 379 archivio italiano di urologia e andrologia 2014; 86, 4 m. valentino, m. bertolotto , p.martino, l. barozzi, p. pavlica sensitivity, 98.2% specificity, 93.3% ppv, 96.4% npv and 95.8% accuracy in differentiating malignant from benign lesions in 144 nodules/pseudo-nodules using te (8). they concluded that te was a very useful technique in assessing small testicular nodules and all types of pseusonodules and could be helpful in deciding the most appropriate clinical approach, allowing in particular con servative management in selected cases. testicular adrenal rests testicular adrenal rests are benign corticotropin-depend ent lesions that are often asymptomatic and occur fre quently in male patients with congenital adrenal hyperpla sia (cah) but have also been described in patients with cushing’s syndrome and addison’s disease (10). the reported prevalence by sonography however varies between 24% and 94%. histologically, testicular adrenal rests consist of hyperplastic adrenal cortical tissue origi nating from aberrant adrenal tissue that descends with the gonads during embryonic migration (11). on sonog raphy, the testicular adrenal rests mostly appear hypoe choic although they may be heterogeneous or hypere figure 1. adrenal rest. a) b-mode us shows a hypoechoic nodule with calcifications. b) on color doppler the nodule appear hypovascular. c) at ceus the nodule shows to be hyperenhancing in the arterial phase. d) on te the nodule is soft, similar to the surrounding testis. choic. calcifications may be present. the adrenal rests are usually bilateral. an important finding in adrenal rests is that vessels coursing through the lesion are not deviated and this is considered an important feature. ceus shows the nodules to be hyperenhancing in arte rial phase with isoenhancement in the venous and later phase. on te the nodules are usually soft, similar to the surrounding testis (figure 1). segmental testicular infarction segmental testicular infarction is an uncommon clinical situation. etiology is largely considered idiopathic, but cases have been described occurring in patients with hyper-coagulability disorders, vasculitides, or following torsion, trauma, infection (12), and iatrogenic vascular injury (13-15). according with bilagi et al. (1), segmen tal testicular infarction typically presents as a solitary solid wedge shaped or round area in the testis, hypoe choic or with mixed echogenicity, with markedly dimin figure 2. segmental testicular infarction. a) b-mode us shows a hypoechoic nodule with mixed echogenicity. b) on color doppler the vascularity is absent. c) ceus shows a characteristic with a perilesional rim of enhancement. d) on te consistency is slightly soft. incidentally detection of non-palpable testicular nodules at scrotal ultrasound: what is new? 380 archivio italiano di urologia e andrologia 2014; 86, 4 ished or absent vascularity. differential diagnosis with a tumor less vascularised than surrounding testicular parenchyma may be problematic in rounded lesions and when vascularity is not completely absent at color doppler interrogation. ceus improve characterization showing a non-enhancing lesion formed by ischemic parenchymal lobules. it therefore provided additional information that may be useful to differentiate this non surgical lesion from hypovascular tumors also in cases with equivocal features at color doppler interrogation by presence of intralesional color spots. as the nodule is composed of necrotic tissue, on te segmental testicular infarction is usually soft, although in acute cases consis tency may be slightly increased due to edema (figure 2). leydig cell tumor leydig cell tumor is a relatively uncommon condition that is characterized by focal proliferation of the andro gen-synthesizing interstitial cells of leydig (16). histologically, it is characterized by an increased number of testicular leydig cells which displace and compress the seminiferous tubules. leydig cell tumor constitute about 1-3% of all testicular tumors, and it affects males of 22 to 61 years with a mean age of 37 years (17). on b-mode us, leydig cell tumor commonly appears as an hypoechoic nodule within the testicular parenchyma. the vascularity within the nodules is variable but usual figure 3. leydig cell tumor. a) b-mode us shows a hypoechoic nodule. b) at color doppler vascularity is present. c) at ceus the nodule demonstrates early contrast enhancement, more than the normal testis. d) on te leydig cell tumor a hard pattern, probably depending on the number of the cells. ly increased. the nodule usually demonstrates early con trast enhancement at ceus, more than the normal testis. wash-out is often rapid. on te leydig cell tumor can demonstrate a soft or a hard pattern, depending on the number and in the size of the leydig cells, lymphatic or vascular invasion, cytonuclear atypia, number of mitoses, absence of well-defined edge or a capsule (figure 3). seminoma classic seminomas histologically are usually homoge neously solid, lobulated masses that may contain sharply circumscribed areas of necrosis. microscopically, tumor cells are uniform with abundant clear cytoplasm charac teristically arranged in nests outlined by fibrous bands; in 80% of cases, these bands are infiltrated by lympho cytes and plasma cells, possibly due to a host reaction to the tumor (18). the imaging features of seminomas reflect their histologic characteristics and their uniform cellular nature. on us, seminoma is a homogeneously figure 4. seminoma. a) b-mode us shows a hypoechoic rounded lesion. b) at color doppler the lesion appears hypovascular. c) ceus shows a rapid enhancement of the lesion. d) on te the nodule is hard. m. valentino, m. bertolotto , p.martino, l. barozzi, p. pavlica 381 archivio italiano di urologia e andrologia 2014; 86, 4 hypoechoic rounded lesion; it may be lobulated or multinodular appearance. cystic-like spaces are uncom mon. seminoma is usually hypervascular at color doppler interrogation. ceus shows a rapid enhance ment of the lesion with an abnormal depiction of cross ing vessel within the nodule. there is a rapid wash-out but a persistence of the crossing vessels sign. on te the nodule is usually hard, on occasion, with soft intrale sional areas due to necrotic changes (figure 4). nonseminomatous germ cell tumors this is a large group of histologically heterogeneous neo plasms. four basic types can be recognized: embryonal carcinoma, teratoma, choriocarcinoma, and yolk sac tumor. the combination of two or more types of these neoplasms results in mixed gcts. embryonal carcinoma has a more variable appearance than seminoma. it is mainly a solid tumor containing foci of hemorrhage and necrosis. teratoma is predominantly cystic and multiloc ulated. all types of tissues can be seen within the tumor, most commonly fat, cartilage and various types of epithelium. these tumors are further divided into mature and immature teratomas and those with malig nant areas. choriocarcinoma represents the most lethal form of testicular carcinomas. this tumor is often small, usually hemorrhagic, and partially necrotic. yolk sac tumor has a soft consistency and a microcystic appear figure 5. teratoma. a) b-mode us shows a hypoechoic not homogeneous nodule. b) at color doppler vascularity is poor. c) ceus demonstrates some bubbles within the nodule suggesting the malignancy. d) on te the nodule appears clearly hard ance. therefore, nonseminomatous testicular tumors are expected to appear as hypoechoic not homogeneous masses on us, with anechoic areas of necrosis and hyper echoic areas of calcification. increased vascularity may or may not be demonstrated. however, ceus is more able to demonstrate the vascularity of the nodule, sometimes with rare microbubbles within the lesion suggesting the malignancy. on te these nodules appear clearly hard (figure 5). conclusion us is the imaging modality of choice for scrotal patholo gies. opposite to palpable testicular masses, non-palpable incidental testicular nodules are often benign and an accu rate diagnosis is relevant for the appropriate treatment. advanced and innovative us technology allows a better characterization of small testicular nodules. ceus and te are a useful adjunct to traditional b-mode and color doppler examination, clearly identifying vascularization and consistency of the nodule. although no ultrasound appearances may be entirely diagnostic, a combined evaluation of the grey-scale, vas cular, and elastographic features of the nodule may allow a better confidence in the final diagnosis guiding the urologist to the appropriate treatment. references 1. carmignani l, gadda f, gazzano g, et al. high incidence of benign testicular neoplasms diagnosed by ultrasound. j urol. 2003; 170:1783-6. 2. avci a, erol b, eken c, ozgok y. nine cases of nonpalpable tes ticular mass: an incidental finding in a large scale ultrasonography survey. int j urol. 2008; 15:833-6. 3. connolly ss, d'arcy ft, gough n, et al. carefully selected intrat esticular lesions can be safely managed with serial ultrasonography. bju int. 2006; 98:1005-7. 4. müller t, gozzi c, akkad t, et al. management of incidental impalpable intratesticular masses of < or = 5 mm in diameter. bju int. 2006; 98:1001-4 5. toren pj, roberts m, lecker i, et al. small incidentally discovered testicular masses in infertile men-is active surveillance the new stan dard of care? j urol. 2010; 183:1373-7 6. albers p, albrecht w, algaba f, et al. european association of urology. eau guidelines on testicular cancer: 2011 update. eur urol. 2011; 60:304-19. 7. lock g, schmidt c, helmich f, et al. early experience with con trast-enhanced ultrasound in the diagnosis of testicular masses: a feasibility study. urology. 2011; 77:1049-53. 8. goddi a, sacchi a, magistretti g, et al. real-time tissue elastog raphy for testicular lesion assessment. eur radiol. 2012; 22:721-30. 9. aigner f1, de zordo t, pallwein-prettner l, et al. real-time sonoelastography for the evaluation of testicular lesions. radiology. 2012; 263:584-9. 10. dogra v, nathan j, bhatt s. sonographic appearance of te sticular adrenal rest tissue in congenital adrenal hyperplasia. j ultrasound med. 2004; 23:979-81. 11. stikkelbroeck nm, suliman hm, otten bj, et al. testicular adrenal incidentally detection of non-palpable testicular nodules at scrotal ultrasound: what is new? 382 archivio italiano di urologia e andrologia 2014; 86, 4 rest tumours in postpubertal males with congenital adrenal hyperpla sia: sonographic and mr features. eur radiol. 2003; 13:1597-603. 12. bilagi p, sriprasad s, clarke jl, et al. clinical and ultrasound features of segmental testicular infarction: six-year experience from a single centre. eur radiol. 2007; 17:2810-8. 13. magill p, jacob t, lennon gm. a rare case of segmental testicu lar infarction. urology. 2007; 69:983 e987-8. 14. mincheff t, bannister b, zubel p. focal testicular infarction from laparoscopic inguinal hernia repair. jsls. 2002; 6:211-3. 15. secil m, kocyigit a, aslan g, et al. segmental testicular infarc tion as a complication of varicocelectomy: sonographic findings. j clin ultrasound. 2006; 34:143-5. 16. mati w, lam g, dahl c, et al. leydig cell tumour--a rare tes ticular tumour. int urol nephrol. 2002; 33:103-5. 17. carmignani l1, salvioni r, gadda f, et al. long-term followup and clinical characteristics of testicular leydig cell tumor: experi ence with 24 cases. j urol. 2006; 176:2040-3. 18. ulbright tm germ cell tumors of the gonads: a selective review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues. mod pathol. 2005;18 suppl 2:s61-79. correspondence massimo valentino, md massimo.valentino@ass3.sanita.fvg.it uo di radiologia, ospedale s. antonio, 33028 tolmezzo, udine, italy michele bertolotto, md dipartimento di radiologia, università di trieste, trieste, italy pasquale martino, md uo di urologia i universitaria, università di bari, italy libero barozzi, md uo di radiologia, ospedale maggiore, bologna, italy pietro pavlica, md gvm care and research, villalba hospital, bologna, italy stesura seveso archivio italiano di urologia e andrologia 2014; 86, 4270 original paper the adverse influence of spina bifida occulta on the medical treatment outcome of primary monosymptomatic nocturnal enuresis basri cakiroglu 1, tuncay tas 2, seyit erkan eyyupoglu 3, aydın !smet hazar 2, mustafa bahadır can balcı 2, yunus nas 4, fazli yilmazer 4, suleyman hilmi aksoy 5 1 hisar intercontinental hospital, department of urology, umraniye, istanbul, turkey; 2 taksim training and research hospital, department of urology, taksim, istanbul, turkey; 3 amasya training and research hospital, department of urology, amasya, turkey; 4 hisar intercontinental hospital, department of pediatry, umraniye, istanbul; 5 hisar intercontinental hospital, department of radiology, umraniye, istanbul, turkey. objective: previous reports have suggested that the incidence of spina bifida occulta (sbo) in patients with primary monosymptomatic nocturnal enuresis (pmne) is higher than the general population. the purpose of this study was to investigate the effect of spina bifida occulta on the medical treatment outcome of pmne. material and methods: between january 2008 and december 2011, a total of 223 children (151 boys and 72 girls, aged 6-16 years; mean age: 10.1 ± 3.04 years) with pmne were reviewed retrospectively. all of the children underwent physical examination, urine analysis, urinary tract ultrasonography and kidney ureter bladder (kub) scout film. all patients were initially treated with a timed voiding program and were given desmopressin acetate when necessary. results: spina bifida occulta was detected in 75 children (33.6%). spina bifida occulta affected l4 in 2 children, l5 in 6 children, l4-l5 in 3 children, s1 in 52 children, s2 in 7 children and s1-s2 in 2 children. treatment was successful in 79% of the children without sbo, and in only 48% of the children with sbo. medical treatment success rates differed significantly between the study groups. conclusion: the presence of spina bifida occulta significantly affects the response to medical treatment in patients with pmne. thus, verifying spina bifida occulta status in pmne can facilitate prognostic predictions about the response to medical treatment. key words: spina bifida occulta; primary monosymptomatic nocturnal enuresis; children; desmopressin. submitted 15 june 2014; accepted 14 july 2014 summary no conflict of interest declared. decreases to 1-2% above 17 years of age. the spontaneous recovery rate in enuretic patients has been estimated to be 15%/year (1). although many factors have been suggested to play a role in the etiology of enuresis including nocturnal polyuria, sleep disturbances, reduced bladder capacity, detrusor instability and urinary tract infections, the exact cause is still unclear (2, 3). in the absence of any additional lower urinary tract symptoms of, including urgency or daytime incontinence enuresis is defined as mono-symptomatic nocturnal enuresis (mne) (4). treatment gains more importance in order to improve self-esteem and life standard of these children. nowadays, a variety of treatment modalities have been used for the treatment of enuresis nocturna including desmopressin, tricyclic antidepressants and behavioral therapy. however, the reason why some enuretic children respond poorly to medical treatment is not clearly elucidated. spina bifida (sb) is a congenital deformity involving failure of normal midline fusion of the neural tube. the exact etiology of sb is still unknown, but there is growing evidence in favor of a multifactorial origin. the term includes both spina bifida occulta (sbo), which involves only a bony (vertebral) arch defect and spina bifida (sb) cystica (aperta), which involves a bony defect and a neural tube (spinal cord) defect (5). in sbo, there’s a small defect or gap in one or more vertebrae. the commonest type is sbo, in which there is a defect in the vertebral arch of l5 or s1, resulting in the failure of posterior arch to fuse in the midline. many authors have published data on the frequency of sbo, with varying results. in fact, it’s been estimated that 12-23% of healthy people have sbo (6, 7). interestingly it has been reported earlier that; among patients with enuresis, the incidence of sbo has been increased up to 37.5% (8). however, the effect of sbo on the response to nocturnal enuresis (ne) treatment is controversial. in this study, we aimed to investigate the association between the presence of sbo and medical treatment outcome in patients with primary monosymptomatic mne. doi: 10.4081/aiua.2014.4.270 introduction enuresis nocturna is a common health problem among children and adolescents. while the prevalence of enuresis at the age of 5 is as high as 15-20%, the prevalence cakiroglu_ad_stesura seveso 15/01/15 13:04 pagina 270 271archivio italiano di urologia e andrologia 2014; 86, 4 primary nocturnal enuresis and spina bifida material and methods a total of 223 children, aged 6-16 years, who have been diagnosed with pmne in the urology outpatient clinic of hisar intercontinental hospital between january 2008 and december 2011, were enrolled to the study. the study protocol was approved by the ethical committee, of taksim training and research hospital (ethical code: taksim training and research hospital, etics committee of clinical research no.31/04.12.2013). the diagnosis of mne was in accordance with the international children’s continence society standardization (4). children with a minimum of one wet night per week were included in the study. all patients underwent a detailed clinical evaluation including; medical history, physical examination, urinalysis, urinary tract ultrasonography, and kidney-ureter-bladder scout film. plain radiography of the spine had been performed to all patients before the start of treatment patients with a history of urinary tract infection or neurological disease and dysfunctional elimination syndrome (children who have problems with both bowel and bladder control with chronic constipation, fecal retention, stool withholding and encopresis). written informed consents were obtained from the parents of the patients. on plain x-ray films of the spine, the presence or absence of the fusion of the posterior elements of the lumbar and/or sacral spinous processes were examined to in order to detect sbo. x ray films were evaluated by experienced radiologists and, the initial sbo diagnosis was confirmed with subsequent computed tomography imaging. the children were assigned to one of the 2 treatment groups according to the treatment they receive; either desmopressin monotheraphy or combination therapy including tolteradine with desmopressin patients were homogenously assigned to treatment groups with regard to the presence or absence of sbo. the children and parents had underwent thorough counseling which involved a review of the usual interval between dinner and bedtime (aiming to prolong that period to over 3 hours), a review of the hydration state of each child (aiming to restrain night-time hydration), and a discussion of the treatment plan and its goals. in the single drug therapy group, the initial daily doses were 0.2 mg for desmopressin. in the desmopressin only group dosage had been adjusted by increments of 0.2 mg at 2 weeks in case of insufficient response and the maximal dosage for desmopressin was 0.4 mg at bedtime. the drug was administered orally 30 minutes before bedtime. patients had been asked to record whether they were “wet” or “dry” the next morning. “wet” and “dry” nights were documented daily for 14 days before treatment (baseline) and during the 6-month treatment period. we calculated the baseline enuretic frequency from the data collected prior to medical treatment commencement. we also calculated the frequency of enuresis from the data collected at 1, 3 and 6 months after the initiation of medical treatment. efficacy was measured based on the percentages of 5 patient responses. response was categorized as “excellent” when the frequency of ne decreased to zero or to once monthly, “good” when frequency decreased by more than 90% compared to baseline, “fair” when frequency decreased by more than 70%, “partial” when frequency decreased by 50% or more and “no response” when frequency decreased by less than 50%. the final follow-up visit was performed at 6 months after the start of treatment. complete and good response was considered as successful treatment. statistical analyses all analyses were performed using spss 11.5 (statistical package for social sciences,chicago, usa). data were expressed as mean values ± standard deviation. chisquare analysis was used to examine the significance of response to treatment between the 2 groups. a value of p < 0.05 was considered as statistically significant. results charts of a total of 223 children (151 boys and 72 girls, aged 6-16 years; mean age: 10.1 ± 3.04 years who have been diagnosed with pmne were reviewed retrospectively. spina bifida occulta was detected in 75 children (33.6%). sbo affected l4 in 2 children, l5 in 6 children, l4-l5 in 3 children, and s1 in 52 children, s2 in 7 children and s1-s2 in 2 children (table 2). response to treatment among patients with and without sbo is summarized in table 3. treatment was successful in 79% of the children without sbo, and in only 48% of the children with sbo. the difference between those with and without sbo was statistically significant in terms of the medical treatment success rate (p < 0.001). response to treatment m/f age (years) n % nocturnal enuresis without spina bifida 92/56 9.6 ± 2.9 117 79* group i (n = 148) nocturnal enuresis with spina bifida 59/16 11.1 ± 3.0 36 48 group ii (n = 75) chi-square tests: value = 17,33 significance (p) = 0.0001. table 1. demographical features of the study groups. male female total l4 1 1 2 l5 5 1 6 l4-5 1 2 3 l5-s1 3 3 s1 5 47 52 s2 3 4 7 s1-s2 1 1 2 16 59 75 table 2. incidence and distribution of spina bifida occulta in the study population. cakiroglu_ad_stesura seveso 15/01/15 13:04 pagina 271 archivio italiano di urologia e andrologia 2014; 86, 4 b. cakiroglu, t. tas, s. erkan eyyupoglu, a. ismet hazar, m. bahadır can balcı, y. nas, f. yilmazer, s. hilmi aksoy 272 discussion spina bifida occulta (sbo) is a variable syndrome with manifestations such as vertebral cleft, foot deformities, midline skin lesions, spondylolysis, syringomyelia, tethered cord syndrome and genitourinary dysfunction. enuresis may be the only evidence of the disease (9). the data concerning the effect of sbo in treatment response among patients with enuresis nocturna is controversial. in a recent study, similar to our findings, shin et al. studied 160 children with enuresis and reported a higher success rate with desmopressin response rate in the group without sbo compared to the group with sbo (10). in another study conducted by miyazato et al., although there was no difference in the overall response rates between children with and without sbo, patients with l and l/s sbo were less responsive to treatment compared to the patients with s sbo (11). on the other hand kumar et al., reported that outcome of patients with sbo was not different than the patients without sbo. however, they only compared the outcome of patients on behavioral therapy (12). in an earlier study, ritchew et al. compared the treatment success rates among 127 children with diurnal enuresis. among those, 48 patients were having sbo and all 127 patients were initially treated with a timed voiding program and 28 with persistent enuresis were given anticholinergic medications. the mean follow-up for both groups was 3 years and the authors determined that the outcome for enuretic children with sbo was comparable to those with normal spine x-rays (13). in their prospective study, kajbafzadeh et al. evaluated 109 children with less than 50% reduction in wet nights despite different treatments for at least 6 months. they specifically looked for the presence of associated sbo and compared the treatment outcome with the outcomes of 40 healthy children. they determined that sbo was present in 86 (78,9%) patients with persistent primary ne and 10 (25%) normal children and the difference was statistically significant (14). despite the fact that, this was a cross-sectional study and a direct causal relationship could not be made with these findings, this data also supports that there may be a common developmental etiology between unresponsive enuretic patients and sbo. this finding is also imperative to realize the increased rates of medical treatment unresponsiveness among patients with enuresis nocturna. in normal healthy children the incidence of sbo is about 17-23% while sbo incidence reaches 35-60% in enuretic children (15-17). although the exact mechanism linking these two pathologies is not obvious, everyone should be aware of this association since these two conditions, are common in childhood. moreover recent increase in the prevalence of sbo may also result in an increased prevalence of ne because of this association. sbo of the sacrum is the most common type of spinal deformity. spina bifida cystica and occulta present with a wide spectrum of urodynamic abnormalities including upper and lower motor neuron types of bladder and urethral dysfunction (18). it has been suggested that sbo might be associated with incomplete neurogenesis of the sympathetic nerves that control the internal sphincter at the vesicourethral junction. these dysfunctions may be the cause of association of sbo and enuresis nocturna but studies are warranted to determine the exact link between these disorders (10). in another interesting study dealing with this subject, dik et al. studied 241 patients with sb and determined that 13 of them had true ne. these patients were treated with desmopressin (0,4 mg, 1x1) and the drug was successful in 12 patients: only 1 of whom relapsed during the follow-up follow up (19). this study is also important in terms of that; response rate was very high despite the presence of sbo. however since the number of patients was as low as 13, strict conclusions can not be drawn with this data. in our study with 223 subjects with pmne, we have determined that children with sbo have poorer medical treatment response at 6 months than those without this deformity. enuresis nocturna is an important health problem, distressing social lives of all affected children and their families. although many treatment modalities are present; it is still not clear why some children do not respond to medical treatment while some of them recover spontaneously. in that aspect, it may be helpful for the physicians to determine associated conditions that may play a role in predicting medical treatment success rate in enuresis nocturna. conclusion the presence of sbo affects the response to medical treatment among patients with primary mne. if the increasing prevalence of sbo is considered, this phenomenon gains more importance. in the light of these data, we suggest that determination of the existence of sbo may be helpful to predict the response to treatment in pmne. future prospective, randomized studies comparing the efficacy of different treatment modalities with regard to the presence of absence of sbo are warranted in order to assess sbo’s real prognostic value in this setting. references 1. alon u. nocturnal enuresis. pediatr nephrol. 1995; 9:94-103. 2. ozden c, ozdal ol, altinova s, et al. prevalence and associated factors of enuresis in turkish children. int braz j urol. 2007; 33:216-22. 3. pereira rf, silvares ef, braga pf. behavioral alarm treatment for nocturnal enuresis. int braz j urol. 2010; 36:332-8. treatment outcome en patients with sbo en patients without sbo (n = 75) (n = 148) complete response 30 (40,0%) 106 (71,6%) good response 6 (8,0%) 11 (7,4%) partial response 26 (34,7%) 12 (8,1%) no response 13 (17,3%) 19 (12,8%) en: enuresis nocturna, sbo: spina bifida occulta. table 3. treatment outcomes in the study groups. cakiroglu_ad_stesura seveso 15/01/15 13:04 pagina 272 273archivio italiano di urologia e andrologia 2014; 86, 4 primary nocturnal enuresis and spina bifida 4. neveus t, von gontard a, hoebeke p, et al. the standardization of terminology of lower urinary tract function in children and adolescents; report from the standardization committee of the international children’s continence society. j urol. 176:314-324. 5. de marco p, merello e, mascelli s, et al. current perspectives on the genetic causes of neural tube defects. neurogenetics.. 2006; 7:201-21. 6. eubanks jd, cheruvu vk. prevalence of sacral spina bifida occulta and its relationship to age, sex, race, and the sacral table angle: an anatomic, osteologic study of three thousand one hundred specimens. spine (phila pa 1976). 2009; 34:1539-43. 7. fidas a, macdonald hl, elton ra, et al. prevalence and patterns of spina bifida occulta in 2707 normal adults. clin radiol. 1987; 38:537-42. 8. agarwal hc, mohan d, mukerji dp. eneuresis. an etiological and therapeutic review. indian j med sci. 1967; 21:668-75. 9. zambito a, dall'oca c, polo a, et al. spina bifida occulta. foot deformities, enuresis and vertebral cleft: clinical picture and neurophysiological assessment. eur j phys rehabil med. 2008; 44:437-40 10. shin sh, im yj, lee m-j, et al. spina bifida occulta: not to be overlooked in children with nocturnal enuresis. int j urol. 2013; 20:831-5. 11. miyazato m, sugaya k, nishijima s, et al. location of spina bifida occulta and ultrasonographic bladder abnormalities predict the outcome of treatment for primary nocturnal enuresis in children. int j urol. 2007; 14:33-38. 12. kumar p, aneja s, kumar r, et al. spina bifida occulta in functional enuresis.. indian j pediatr. 2005; 72:223-5. 13. ritchey ml, sinha a, di pietro ma, et al. significance of spina bifida occulta in children with diurnal enuresis. j urol. 1994; 152:815-8. 14. kajbafzadeh a, espandar l, mehdizadeh m, et al. spina bifida occulta in persistent primary nocturnal enuresis. iran j radiol. 2004; 66. 15. kawauchi a, kitamori t, imada n, et al. urological qbnormalities in 1,328 patients with nocturnal enuresis. eur. urol. 1996; 29:231-4. 16. samuel m, boddy sa. is spina bifida occulta associated with lower urinary tract dysfunction in children? j urol. 2004; 171:2664-6. 17. boone d, parsons d, lachmann sm, et al. spina bifida occulta: lesion or anomaly? clin. radiol. 1985; 36:159-61. 18. sakakibara r, hattori t, uchiyama t, et al. uroneurological assessment of spina bifida cystica and occulta. neurourol. urodyn. 2003; 22:328-34. 19. dik p, veenboer pw, and de jong t. desmopressin in the treatment of nocturnal enuresis in patients with spina bifida. cerebrospinal fluid research 2010; 7(suppl 1):s10. correspondence basri cakıroglu, md, urologist (corresponding author) drbasri@gmail.com hisar intercontinental hospital, department of urology saray mah. siteyolu cad.no:7, 34768 umraniye, istanbul, turkey tuncay tas, md, urologist drtastuncay@gmail.com aydın !smet hazar, md, urologist mdhazar@yahoo.com mustafa bahadır can balcı, md, urologist drbalci@yahoo.com taksim training and research hospital, department of urology taksim, istanbul, turkey seyit erkan eyyupoglu, md, urologist seeseesee@hotmail.com amasya training and research hospital, department of urology amasya, turkey yunus nas, md, pediatrist ynas@hisarhospital.com fazli yilmazer, md, pediatrist fyilmazer@hisarhospital.com hisar intercontinental hospital, department of pediatry umraniye,istanbul suleyman hilmi aksoy, md, radiologist saksoy@hisarhospital.com hisar intercontinental hospital, department of radiology umraniye, istanbul, turkey cakiroglu_ad_stesura seveso 15/01/15 13:04 pagina 273 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 4328 original paper quick prostate test (qpt): motion for a tool for the active contribution of the general pratictioner to the diagnosis and follow up of benign prostatic hyperplasia giuseppe albino 1, ciro michele niro 2, cristina muscarella 3 1 department of urology asl bat, andria, italy; 2 siicp (società italiana interdisciplinare per le cure primarie) course coordinator of specific training in general medicine of puglia region, foggia, italy; 3 course of specific training in general practice, doctors order of foggia, italy. introduction: less than 40% of men with luts consult their doctor. patients consider the luts as physiological and are resigned to endure them. it is necessary to foster awareness of the micturition disorders, to monitor their development and to assess the effectiveness of therapies. at present the only validated test is the ipss-q8, but in italy it is used by only 4% of general practitioners (gps). because the ipss is complex and not easy to handle, we need a more simple test but nevertheless efficient. the italian society of urology (siu) and the italian society for interdisciplinary primary care (siicp) presented the "quick prostate test" (qpt) in november 2012. we aimed to evaluate the efficiency of qpt versus the ipssq8 and its suitability in primary care. materials and methods: the qpt is composed of 3 questions to be answered "yes" or "no." the answer "yes" just to one question makes "positive" the test. we enrolled 64 men, ≥ 50 years old, suffering from bph, extracted from the database of five gps. the patients were randomized into two arms: to the arm 1 only qpt was administered, to verify efficiency of the test; to the arm 2 both the qpt that the ipss-q8 were administered. results: into the arm 1, the 96.4% has tested positive for qpt. into the arm 2, the 89% of patients with one or two positive responses to the qpt showed a moderate ipssq8 score; the 75% of the patients with three positive responses to the qpt had a serious ipss-q8 score. the gps (80%) have expressed the highest level of satisfaction for the qpt for the "time of administration" and for the "simplicity" of the test. conclusions: the experience with the qpt has shown that the test is efficient and suitable in the primary care setting. we want to encourage the gps to use the qpt for the monitoring of patients with lower urinary tract symptoms (luts) and to contribute to the validation of the test. key words: benign prostatic hyperplasia; lower urinary tract symptoms; international prostate symptom score. submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. introduction the benign prostatic hyperplasia (bph) is a chronic disease characterized by prostate alterations resulting in the lower urinary tract symptoms (luts), related to the phases of filling, emptying of the bladder and to the postvoiding period, that interfere with quality of life of male subjects (1). in clinical practice, only 30-40% of patients with overt bph starts a diagnostic and therapeutic program, for a moderate-severe symptomatology, and about half of these for the appearance of more or less serious complications (infections, urinary retention). the 60% of men with bph, for the slow onset of symptoms, lives together with them, thus favoring the deterioration of the bladder. they will contact their physicians when the detrusor alterations will be irreversible. as these aren’t disorders that endanger life, bph and luts are likely to be underestimated, regarded as disorders inexorably associated with aging. in fact they represent a real socio-economic problem because have an impact both on the quality of life of patients and on the health system that supports the costs of these disorders, characterized by their high prevalence and progression over time (1-3). the progression of bph is not identifiable only by an increase in the gland volume but also by a worsening of the uroflowmetry, of the clinical symptomatology and, consequently, of the quality of life (4, 5). the symptoms related to bph can be divided into three groups (1): • symptoms of bladder emptying phase: starting hesitancy, intermittency, weak urinary stream, use of abdominal pressure, spraying or bifid urinary stream, terminal drip; • symptoms of bladder filling phase: urgency, frequent urination, nocturia, urge incontinence, altered bladder sensation; • symptoms of post micturition phase: feeling of failure to empty the bladder, post-voiding dribbling. the perception of his urinary disorders is fundamentally subjective. for their assessment, we need simple, easily repeatable and validated tools (reliable and reproducible), in order to quantify the severity of luts, their doi: 10.4081/aiua.2014.4.328 presented at 19th national congress sieun, fermo 2014 albino2_stesura seveso 15/01/15 12:05 pagina 328 329archivio italiano di urologia e andrologia 2014; 86, 4 quick prostate test (qpt): motion for a tool for the active contribution of the general pratictioner to the diagnosis and follow up of benign prostatic hyperplasia finally, the ipss includes an eighth question, which quantifies the quality of life in relation to own urinary condition at the time and must not be added to the scores of the previous seven questions. quick prostate test (qpt) the qpt test consists of 3 questions that the patient must answer "yes" or "not". it is a quick and simple test that can help to optimize the management of the health status of the patient with bph, facilitating doctor-patient dialogue in the first visit and on subsequent visits for follow-up. it allows you to monitor the well-being of patients with bph with or without ongoing treatments. it consists of three questions related to luts, but it is not associated with a rating/score. the composition of the test takes into account the following aspects: it evaluates the most prevalent and troublesome symptoms; the severity of symptoms is proportional to the discomfort; the severity of the symptoms and discomfort is proportional to the risk of progression. two questions investigate irritative or "filling" symptoms, one question investigates the obstructive or "emptying" symptoms, for a total of only three questions (table 1). the affirmative answer to one of the three questions indicates that the test is positive. study design the study lasted five months, from 1 may 2012 to 30 september 2012. in the first phase of recruitment we have obtained the lists of patients to be included in the study by extrapolating data from gps softwares and using the following search criteria (keywords): the diagnosis of bph or drugs used in the medical treatment of bph: α-blockers (alfuzosin, doxazosin, terazosin, tamsulosin, silodosin), or 5-α-reductase inhibitors (5ari) (dutasteride, finasteride). the inclusion criteria were: ≥ 50 years old men; bph diagnosed; therapy with α-blockers for at least a month and with inhibitors of 5-alpha reductase (5ari) for at least three months or in combined therapy. some of the extracted patients were invited to a phone interview for medical history and for each of them has been agreed on a date. other patients were subjected to the test in an "opportunistic" way: on the occasion of their visit to the general practitioner, that occurred for other reasons. patients were randomized into two arms: “the arm 1” has been subjected to administration of the interview only variation over time (also in relation to the various treatments) and the impact on quality of life. in this regard, the experts of the consensus conference on guidelines for the management of bph recommended "an increasing involvement of the general practitioner in the follow up of the patient in treatment for luts/bph, so that clinical monitoring of these patients is more consistent and effective" (1). the most used rating scale of the symptoms is the ipss (international prostate symptom score). the ipss is recommended as a tool to measure the symptoms, to be used for the initial assessment of their severity in men with luts. to perform the test you have to answer 7 questions, each corresponding to a score from 0 to 5. the score obtained by the sum of all seven questions allows you to categorize urinary disorders in 'absent', 'mild', 'moderate', 'severe'. the ipss finally provides an eighth question, which quantifies the quality of life (qol = q8) in relation to own urinary condition at the time and must not be added to the previous seven questions. despite "the symptom scores" in general, and the ipss-q8 in particular, are recommended they are rarely used in italy: only 3.5% of general practitioners uses the ipssq8 and in addition, because of the poor handling of the test only 15% of urologists uses it (2). given the complexity, the poor handling of the ipss questionnaire and the closer times of work in the primary care setting, the general practitioner needs for a "symptom questionnaire" to be easier administered than ipss, but at the same time efficient, both to put the suspected diagnosis and for the subsequent follow-up of patients with bph and during medical therapy. for this reason, in november 2012, jointly by the siu (italian society of urology) and by the siicp (italian society for interdisciplinary primary care) the "quick prostate test" (qpt) was presented as a quick and easy tool to put the suspicion of luts and to assess the development of the bph and the effectiveness of the therapies, appropriate to the setting and the time of the "basic medicine". waiting for cohort studies on large series are completed, since there is no data in the literature, we wanted to evaluate the efficiency of the qpt versus the ipss-q8, in the patient with luts/bph and during pharmacological treatment and its suitability in primary care. materials and methods ipss-q8 the international prostate symptom score (ipss) is recommended as a tool for measurement of the symptoms to be used for baseline assessment of their severity on men with luts (6, 7). the ipss also incorporates a question that assesses the overall impact of luts on the quality of life (qol = q8). to perform the test you have to answer 7 questions each corresponding to a score from 0 to 5. the sum of the scores of the seven questions allows you to classify urinary disorders in: • absent or mild urinary disorders if the sum is between 0 and 7 • moderate urinary disorders if the sum is between 8 and 19 • severe urinary disorders if the sum is between 20 and 35. table 1. quick prostate test: yes to one question indicates positive test. quick prostate test 1. in the last month, did you get up at least twice from bed by night to urinate (from when you go to sleep in the evening until you wake up in the morning? 2. in the last month, had you difficulties several times to delay the urination? 3. in the last month, had you ever the feeling of not to be able to completely empty your bladder? albino2_stesura seveso 15/01/15 12:05 pagina 329 archivio italiano di urologia e andrologia 2014; 86, 4 g. albino, c.m. niro, c. muscarella 330 with qpt, to verify efficiency of the test in relation to the ongoing therapy (α-blockers, 5ari, α-blockers + 5ari); “the arm 2” has been subjected to interview with administration of both the qpt and the ipss-q8 to evaluate efficiency of qpt compared to the validated test (ipss-q8). a total of 64 patients were interviewed. at 28 patients (arm 1) it was administered the qpt (quick prostate test) and at 25 patients (arm 2) they were administered both the qpt and the ipss-q8. age, pharmacological treatments, associated diseases and treatment for bph were recorded for each enrolled patient. at the end of the study, the general practitioners who participated in the data collection were invited to express their level of satisfaction after using the qpt taking into account two parameters: "time used for administration of the qpt" and "simplicity of the questions". a linear scale was made to assess the acceptance of the qpt by physician: it quantifies the level of satisfaction of each general practitioner (figure 1). the satisfaction level is represented on a line that brings numeric values from 0 to 5 in ascending order (useful to display the wedge drawn on the line that represents numeric values in increasing order). the zero indicates dissatisfaction while 5 indicates the maximum satisfaction and approval. results for administration of the test it was necessary a time varying from 5 to 20 minutes, with the variability associated with the type of questionnaire (time for qpt < time for ipss-q8). the choice to not participate to the study was made for the following reasons: patients no longer in therapy, which in most cases has been voluntarily suspended without inform their doctor; patients who had undergone prostate surgery (not reported in the software of general practitioners), and therefore not eligible in our study; lack of real willingness on the part of some physicians "for time problem"; patients who did not come to the appointment set. sixty-four patients were interviewed: 9 patients had discontinued therapy, and therefore the qpt had not been administered to them (group of patients excluded); 2 patients, despite having already undergone turp, were excluded from the study, but were also submitted to the qpt for follow-up after the surgery. the mean age of patients was 69 years. the prevalence of the most important comorbidities calculated on the total sample (64 patients) are: 62.5% hypertension; 21.87% diabetes mellitus; 12.5% dyslipidemia; 6.25% chronic obstructive pulmonary disease; 4.68% gastro-esophageal reflux; 4.68% arthrosis. the effectiveness and/or appropriateness of ongoing therapy has been evaluated on the 28 patients of qpt group. twenty-five patients in medical therapy for bph were submitted to both qpt and ipss (qpt-ipss group) with the aim to evaluate the efficacy of the ongoing therapy and to get results able to demonstrate the efficiency of the qpt, performing a comparison with its validated predecessor (ipss). results obtained in the “qpt-ipss group” (arm 2) are summarized in table 2. qpt 0 = all “negative to qpt” patients had a mild ipss score (< 8); qpt 1 = the majority of the patients with only one positive response to the qpt obtained a moderate ipss score (8-19); qpt 2 = the majority of the patients with two positive responses to the qpt obtained a moderate ipss score (815); qpt 3 = the majority of the patients with three positive responses to the qpt obtained a severe ipss score (> 19). the two patients who had undergone turp were both positive to qpt test, index of disease progression, and were sent to the attention of their general practitioners. four out of five gps expressed a level of satisfaction equal to 5 (highest level of satisfaction), and one expressed a level of satisfaction equal to 4. discussion the qpt has helped to assess the effectiveness and/or appropriateness of ongoing medical therapy for patients with bph. the use of qpt allows to analyze in a short time the prostatic symptoms in their main aspects. the arm 2 (patients underwent both qpt and ipss) revealed a close correlation between the positivity to the qpt and the increasing of the ipss score. from the comparison of the two tests it results that the majority of patients who got one or two affirmative answers to qpt had a medium ipss score, therefore between 8 and 19. a significant correlation has also emerged among patients who have given three affirmative answers to the qpt, in fact they have shown an ipps score between 20 and 35, expression of severe urinary disorders. these surprising data form the basis for the validation of the qpt and for the applicability as a more simple substitute for the ipss, test figure 1. level of satisfaction of the general practitioner displaying the qpt. dear colleague, on the basis of your level of satisfaction in the completion of the qpt-bph test, please cross a number from zero (lower level of satisfaction) to five (highest level of satisfaction), considering the parameters “time” and “simplicity” of application. qpt0 qpt1 qpt2 qpt3 ipss slight (1-7) xxx x x ipss moderate (8-19) xxxxxxxxxx xxxxxx x ipss severe (20-35) xxx table 2. level of satisfaction of the general practitioner displaying the qpt. albino2_stesura seveso 15/01/15 12:05 pagina 330 331archivio italiano di urologia e andrologia 2014; 86, 4 quick prostate test (qpt): motion for a tool for the active contribution of the general pratictioner to the diagnosis and follow up of benign prostatic hyperplasia that has not reached the so expected widespread diffusion due to the complexity of the eight questions and answers that compose it. from the data obtained by comparing the two tests you can think of the qpt as a suitable replacement for the ipss, perfect for the work of the general practitioner which is subject to the "time" factor. in fact it is evident as the time required for the administration of the two tests is very much in favor of qpt, simple test and easy to handle, which analyzes with only three questions the urinary problems associated with benign prostatic hyperplasia (2). furthermore, given its simplicity, the qpt could be conceived as a test of self-administration unlike the ipss, more specialised test, which requires the aid of a qualified personnel. data in the literature show that the ipss is used only by 3.5% of general practitioners and 15% of urologists. therefore the low level of use even among specialists demonstrates its poor practicality in terms of ease of administration and of time needed for administration. the study has also allowed us to make an assessment of the "satisfaction" of the 5 general practitioners who participated in the enrollment of patients, based on "time required" and "simplicity of the questions" of the qpt. eighty percent of the gps expressed a level of satisfaction equal to 5 (the highest level of satisfaction), and the remaining 20% expressed a satisfaction level of 4. these data show the suitability of the qpt, relatively to the time spent on administration and to the simplicity of the three questions that comprise it, in the general practice setting. the qpt can be an "opportunistic" test, that can evaluate the progress of the urinary disease during a normal office visit for reasons of other nature, and to assess from the outset the need for diagnostic procedures and/or of any adjustment in course of therapy. the general practitioner needs a tool that is fast in administration and efficient for the evaluation of patients with bph. by our study, although conducted on a small sample of patients (64), it was found that the quick prostate test could effectively replace the ipss for the monitoring of the patient with bph in the setting of general practice. in fact the experts of the consensus conference on guidelines for the management of bph recommend "an increasing involvement of the general practitioner in the follow up of the patient in treatment for luts/bph, so that the clinical surveillance of these patients is more constant and effective" (1). conclusions based on the data we collected in our experience with the qpt, despite the small number of patients enrolled in the study, we verified the possible efficiency of the test and the sure suitability for the setting of primary care, taking into account the simplicity and rapid time of administration. while we await trials on a much larger number of patients and therefore statistically validating, we want to encourage general practitioners to use the qpt in the setting of general practice to monitor the patient with luts, with the opportunity to contribute with the number of their patients in the validation of the test. references 1. spatafora s, casarico a, fandella a, et al. evidence-based guidelines for the treatment of lower urinary tract symptoms related to uncomplicated benign prostatic hyperplasia in italy: updated summary from auro.it. ther adv urol. 2012; 4:279-301 2. spatafora s, conti g, perachino m, et al. for the auro.it bph guidelines committee evidence-based guidelines for the management of lower urinary tract symptoms related to uncomplicated benign prostatic hyperplasia in italy: updated summary. curr med res opin. 2007; 23:1715-32. 3. van exel n, koopmanschap m, mcdonnell j, et al. for the triumph pan-european expert panel. medical consumption and costs during a one-year follow-up of patients with luts suggestive of bph in six european countries: report of the triumph study. eur urol. 2006; 49:92-102. 4. sciarra a, cistini c, gentilucci a, et al. ipertrofia prostatica benigna: una patologia in progressione. ipotesi per una terapia preventiva, urologia. 2006; 73:257-64. 5. emberton m, cornel e, bassi p, et al. benign prostatic hyperplasia as a progressive disease: a guide to the risk factors and options for medical management. int j clin pract. 2008; 62:1076-86. 6. barry mj, fowler fj jr, o'leary mp, et al. the american urological association symptom index for benign prostatic hyperplasia. the measurement committee of the american urological association. j urol. 1992; 148:1549-57. 7. badia x, garcia-losa m, dal-re r. ten-language translation and harmonization of the international prostate symptom score: developing a methodology for multinational clinical trial. eur urol. 1997; 31:129-40. correspondence giuseppe albino, md, phd peppealbino@hotmail.com department of urology asl bat, andria, italy cristina muscarella, md, general practitioner cri.musca@libero.it medical doctor, foggia, italy ciro michele niro, md, general practitioner and urologist ciro.niro@alice.it siicp (società italiana interdisciplinare per le cure primarie) course coordinator of specific training in general medicine of puglia region, foggia, italy albino2_stesura seveso 15/01/15 12:05 pagina 331 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 4284 original paper transrectal versus transperineal 14-core prostate biopsy in detection of prostate cancer: a comparative evaluation at the same institution maria angela cerruto 1, fabio vianello 2, carolina d’elia 1, walter artibani 1, giovanni novella 1 1 department of surgery, urology clinic, aoui verona, italy; 2 urology clinic, university of padua, italy. background: the ideal bioptic strategy for cap detection is still to be completely defined. the aim of our study is to compare transperineal (tp) and transrectal (tr) approaches, in a 14-core initial prostate biopsy for cap detection. material and methods: a prospective controlled study was conducted enrolling 108 consecutive patients with a psa level greater than 4 ng/ml and/or an abnormal dre. tr versus tp 14-core initial prostatic biopsies were performed on 54 and 54 patients, respectively, with a randomisation ratio of 1:1. results: the cancer detection rates were 46.29 (25 out of 54 patients), and 44.44% (24 out of 54 patients), respectively, using the tr or the tp approach (p = 0.846). the overall cancer core rate was significantly higher when the tp approach was used: 21.43% (162 out of 756 cores) and 16.79% (127 out of 756 cores), with the tp and the tr approach, respectively (p = 0.022). the cores were significantly longer performing tp approach: at the site “1” (14.92 versus 12.97 mm, p = 0.02); at “5” (15.53 versus 13.69 mm, p = 0.037); at “7” (15.06 versus 12.86 mm, p = 0.001); at “9” (14.92 versus 13.38 mm, p = 0.038); at “11” (16.32 versus 12.31 mm, p = 0.0001); at “12” (15.14 versus 12.19 mm, p = 0.0001); at “13” (17.49 versus 13.98 mm, p = 0.0001); at “14” (16.77 versus 13.36 mm, p = 0.0001). as to the biopsy related pain, the mean pain level perceived by patients during the tr approach was 1.56 ± 1.73 versus 1.42 ± 1.37 registered during tp approach (p = 0.591). conclusions: no significant differences were found in cancer detection rate, cancer core rate between tp and tr approaches for prostatic biopsy. even in terms of complication rate or pain level, it cannot be concluded that one procedure is superior to the other one. apparently, strictly following our protocol, tp approach seems to offer a better sampling at the level of the apex and the tz, however without adding any significant advantage in terms of overall cancer detection rate. key words: prostatic neoplasm; transrectal biopsy; transperineal biopsy; diagnosis; cancer detection rate; prostatespecific antigen. submitted 12 february 2014; accepted 30 june 2014 summary no conflict of interest declared. introduction the widespread use of serum prostate specific antigen (psa) measurement as an opportunistic screening tool to detect early prostate cancer (cap) led to optimise an effective biopsy technique. unfortunately, the ideal bioptic strategy for cap detection is still to be completely defined. at the present, there is still a lack of standardisation regarding both transperineal (tp) and transrectal (tr) approaches. in 2003, emiliozzi et al. carried out a prospective study aiming of comparing the efficacy of tp and tr six-core prostatic biopsy. they performed both biopsy approaches, on the same patients, stating that tp biopsy resulted superior to tr one to detect cap (p = 0.012) (1). in 2007, firstly, kawakami et al. demonstrated that an extended tp biopsy was as effective as its tr counterpart in detecting the presence and the characteristics of the cap, as far as sampling sites were selected to maximize the cancer detection rate (2). more recently, hara et al. carried out a prospective randomized study comparing tp with tr 12-core biopsy, in 246 patients with psa levels ranging from 4.0 to 20.0 ng/ml (3). with patients in lithotomy position, all procedures were performed using spinal anaesthesia (0.5% bupivacaine) or a caudal block (1% lidocaine) according to tp and tr approaches, respectively. the authors did not find any significant difference in cancer detection rate, cancer core rate or complications between the two approaches: they concluded that the preferred approach, as the initial prostate biopsy, might be the tr one as it did not require spinal anaesthesia or other burdensome related processes (3). nevertheless, the same study group even reported that, with a psa in the so-called “grey zone”, significantly more cores were positive when the tp approach was applied, especially for cores coming from the transition zone (4). conclusions were that urologist’s preference could be sufficient for choosing the ideal approach, except for a possible small advantage for tp biopsy when psa is in the “grey zone”. just to compare tp and tr approaches, in a 14-core initial prostate biopsy for cap detection, we have performed a prospective controlled study and these results are herein presented. doi: 10.4081/aiua.2014.4.284 cerruto_stesura seveso 15/01/15 13:18 pagina 284 285archivio italiano di urologia e andrologia 2014; 86, 4 transrectal versus transperineal prostate biopsy: a comparative evaluation material and methods a prospective controlled study was conducted enrolling 108 consecutive patients at our urological center with a psa level greater than 4 ng/ml and/or an abnormal digital rectal examination (dre). tr versus tp 14-core initial prostatic biopsies were performed on 54 and 54 patients, respectively, with a randomisation ratio of 1:1. the inclusion criteria foresaw no previous prostate biopsy, no history of cap and no clinical evidence of acute or chronic prostatitis. all patients were adequately informed on the execution modalities of the bioptic procedure and on its potential complications. they were asked to provide a written consent. each patient underwent a clinical evaluation that included dre and transrectal ultrasound (trus). prostate volume (pv) was measured by means of trus and was calculated as the height per the width per the length per 0.52. table 1 lists patients’ characteristics: no significant differences were found in background factors between the two groups. all patients were instructed to discontinue an eventual anticoagulant therapy for at least 7 days before and after the prostate biopsy. all patients were given an enema the same morning of the procedure and an antibiotic coverage was provided in all cases using an oral fluoroquinolone (prulifloxacin, 600 mg, once a day) for 3 days, starting from the day before the biopsy. for both approaches, the patients were placed in lithotomy position, and all biopsies were carried out only by two skilled urologists included as the co-authors of this paper: gn for the tp approach, and fv for the tr one. all the tp biopsies were performed using a single median tp access 1.5 cm above the anal sphincter, as previously described (5). in all cases, local anaesthesia was provided releasing 2 ml of 1% mepivacaine at the level of the prostate apex. a 18-gauge coaxial needle (truguide bard, 13 cm long) was inserted up to the prostate apex through the anesthetised perineal path under trus guidance. on the removal of the blunt tip stylet, the guiding cannula of the coaxial needle was used as a tp metallic path for repeated atraumatic passages of the biopsy needle. with the tp approach, firstly, a traditional sextant biopsy was performed; then, additional lateral sextant peripheral cores were added and, lastly, two cores were taken from the anterior transitional zone (tz) (6). for systematic tr biopsy, a bilateral periprostatic nerve block was obtained using a 1% lidocaine solution, transrectally injected under ultrasound guidance at the prostate apex and the seminal vesicle-prostatic angles. eight cores were added to the standard tr protocol described by hodge et al (7): six, far laterally in the peripheral zone (pz), and two in the middle tz. tp and tr approaches were both performed under trus guidance (siemens sonoline omnia diagnostic ultrasound system with a 7.75-mhz linear probe was used). with both approaches, an 18-gauge tru-cut needle with a cutting length of 23 mm was applied to obtain specimens. overall 14-core trus guided prostate biopsies have been obtained: 12 specimens from pz and two from tz for each approach. cores of the standard sextant were conventionally labelled from 1 to 6. likewise, additional peripheral cores from the lateral part of prostatic apex, were numbered as “7” and “8”. additional lateral peripheral cores, from the mid prostate, were numbered as “9” and “10”. other cores, from the anterior horn, were numbered as “11” and “12”. finally, biopsies taken from the tz were labelled as “13” and “14”. in all cases, pain level during the bioptic procedure , was evaluated by means of a visual analogue scale/numeric analogue scale in which 0 corresponded to “no pain” and 10 to “the worst, imaginable pain” (5, 6). all patients were clinically evaluated 30 days after the biopsy to record eventual complications related to procedures (5). we determined the cap detection rate, the cancer core rate (ratio of the number of cancer-positive cores to the total number of biopsy specimens) and any complications occurred in order to define efficacy and tolerability of the tp biopsy compared with the tr one. for statistical analysis, chi-square and the mannwhitney u tests were used and a p < 0.05 was considered significant. results patients’ characteristics are listed in table 1. the cancer detection rates were 46.29 (25 out of 54 patients), and 44.44% (24 out of 54 patients), respectively, using the tr or the tp approach (p = 0.846). among patients with psa levels of less than 10.0 ng/ml, the detection rate was 42.22 characteristics tp approach tr approach p value patients (n) 54 54 ns mean age (year) (sd) 66.50 ± 8.87 67.30 ± 8.05 0.627 mean psa (ng/ml) (sd) 15.95 ± 41.04 12.36 ± 39.65 0.646 bmi (kg/cm2) (sd) 27.16 ± 3.18 27.00 ± 3.12 0.794 mean prostate volume 56.29 ± 31.33 61.49 ± 33.39 0.408 (cm3) (sd) abnormal dre 11/54 (20.37) 10/54 (18.52%) 0.810 sd = standard deviation; ns = not significant. table 1. patients’ characteristics. variables tp approach (%) tr approach (%) p value overall 24/54 (44.44) 25/54 (46.29) 0.846 (ns) psa (ng(ml) 0.303 (ns) ≤ 10 15/39 (38.46) 19/45 (42.22) > 10.1 9/15 (60.00) 6/9 (66.67) prostate volume (cm3) 0.283 (ns) < 30 8/9 (88.89) 8/10 (80) 30-50 11/20 (55.00) 7/13 (53.85) > 50 5/25 (20.00) 10/30 (33.33) ns = not significant. table 2. comparison of cancer detection rate according to psa level and prostate volume (determined by trus), between tp and tr approach. cerruto_stesura seveso 15/01/15 13:18 pagina 285 archivio italiano di urologia e andrologia 2014; 86, 4 m.a. cerruto, f. vianello, c. d’elia, w. artibani, gi. novella 286 (19 out of 45) and 38.46% (15 out of 39) when the tr or the tp approach was applied, respectively (p = 0.728). stratifying patients for either psa level or pv, no significant differences were found in the two groups (table 2). the overall cancer core rate was significantly higher when the tp approach was used: 21.43% (162 out of 756 cores) and 16.79% (127 out of 756 cores), with the tp and the tr approach, respectively (p = 0.022). the cancer core rate, in pz cores, was 17.59% (114 out of 648 cores) in case of tr approach, and 21.43% (140 out of 648 cores) going transperineally (p = 0.068). in tz, the corresponding rate was 12.04 (13 out of 108 cores) versus 20.37% (22 out of 108 cores), respectively (p = 0.097) (table 3). the cores were significantly longer performing tp approach, as it follows: at the site “1” (14.92 versus 12.97 mm, p = 0.02); at “5” (15.53 versus 13.69 mm, p = 0.037); at “7” (15.06 versus 12.86 mm, p = 0.001); at “9” (14.92 versus 13.38 mm, p = 0.038); at “11” (16.32 versus 12.31 mm, p = 0.0001); at “12” (15.14 versus 12.19 mm, p = 0.0001); at “13” (17.49 versus 13.98 mm, p = 0.0001); at “14” (16.77 versus 13.36 mm, p = 0.0001). overall, no significant differences were found in terms of post-biopsy complications between the two groups (table 4). as to the biopsy related pain, the mean pain level perceived by patients during the tr approach was 1.56 ± 1.73 versus 1.42 ± 1.37 registered during tp approach (p = 0.591). discussion to our knowledge, the present study is the first prospective controlled evaluation that compares systematic 14-core biopsy using tr and tp approaches, both under local anaesthesia. in 2003, emiliozzi et al. reported a comparison between the two approaches, using the same patients, under local anaesthesia. the aim of that study was to compare the efficacy of tp versus tr six-core prostate biopsies, performing six tp plus six tr biopsies in a group of 107 patients with psa greater than 4 ng/ml. the authors highlighted the superiority of the tp approach with a cancer detection rate of 40% (43 out of 107) using the combination of both approaches; of 38% (41 of 107) with the tp approach alone, and 32% (34 of 107) when the tr approach had been applied alone (1). more recently, hara et al prospectively compared tp and tr approaches and they did not show any significant differences in overall cancer detection rate (3). as to the suggested superiority of the tp approach in detecting tz cancer, shannon et al. reported that the tp approach was more successful in detecting tz cancer because the correct diagnosis rate was greater when the tp approach was used in comparison with the tr approach (89 versus 68%)(8). furthermore, furuno et al., performing a tp ultrasound-guided template biopsy in men with psa levels ranging between 4 and 10 ng/ml, reported that the cancer core rate of the biopsies from the anterior part of the prostate was significantly greater than that from the posterior region (9). they suggested that tr sextant biopsy might be inadequate for detecting cancer localized in the anterior region. on the contrary, hara et al. did not find any differences in cancer core rates whatever zones or approaches were (3). in authors’ opinion, the increased number of biopsy specimens to 12 might reduce the differences in cancer detection rates between the two approaches. in our study, cancer core rates in pz, tz, apex and mid prostate were always higher when tp approach was used, but without reaching any statistical significance. more recently, takenada, hara et al. found that, in patients with psa in the “grey zone” (ranging between 4.1 and 10.0 ng/ml), significantly more cores were positive when tp approach was applied, especially regarding to tz cores (4). they concluded that urologists’ preferences should be sufficient for choosing the best approach, except for possible small advantages for tp biopsy when psa is in the “grey zone”. the results of our study might even support this trend towards a possible advantage of tp biopsy in better sampling both tz and prostate apex. some of our group had previously reported that tp approach would allow a greater sampling of the prostate apex compared with midgland and prostate base (p < 0.001) (10). to possibly characteristics tp approach tr approach p value overall (%) 7/54 (12.96) 7/54 (12.96) ns rectal bleeding (%) 0 (0) 4 (57.16) 0.04 urinary retention (%) 0 (0) 1 (14.28) 0.315 (ns) urethral bleeding (%) 5 (71.43) 0 (0) 0.022 vasovagal event (%) 2 (28.57) 1 (14.28) 0.56 (ns) fever > 38.5°c (%) 0 (0) 1 (14.28) 0.315 (ns) not significant. table 4. complication rates. approach total pz tz apex mid prostate base tp biopsy cores (n) 756 648 108 216 216 216 162 140 22 49 48 46 21.43% 21.60% 20.37% 22.68% 22.22% 21.30% tr biopsy cores (n) 756 648 108 216 216 216 cancer cores (n) 127 114 13 38 40 44 cancer core rate (%) 16.7% 17.59% 12.04% 17.59% 18.52% 20.47% p value 0.022 0.068 0.097 0.186 0.340 0.814 (ns) (ns) (ns) (ns) (ns) ns = not significant. table 3. comparison of cancer-positive core rate by anatomic location between transperineal and transrectal approaches cerruto_stesura seveso 15/01/15 13:18 pagina 286 287archivio italiano di urologia e andrologia 2014; 86, 4 transrectal versus transperineal prostate biopsy: a comparative evaluation confirm this statement, in the present series, the cores resulted significantly longer with the tp rather than with the tr approach, mainly at the apex and in the tz. however, the real advantage of these data is still uncertain as these findings are supported by no significant differences in terms of cancer detection rate reached when the two approaches are used. as to the adverse events, no differences were found in the overall incidence of complications as a result occurring with the two approaches, except for the urethral bleeding in tp group, and the rectal bleeding in tr group. as to some technical difficulties, many authors stated the tr approach is a by far easier procedure and patients’ discomfort may be prevented, using only local anaesthesia. moreover, the tp approach may be not familiar to the majority of the urologists and many patients may complain of some pain when only local anaesthesia is used. however, in our hands, both approaches showed a similar, small, and acceptable discomfort. in our opinion, both methods should be or become equally familiar to urologists. conclusions our results confirmed no significant differences were found in cancer detection rate, cancer core rate between tp and tr approaches for prostatic biopsy. even in terms of complication rate or pain level, it cannot be concluded that one procedure is superior to the other one. apparently, strictly following our protocol, tp approach seems to offer a better sampling at the level of the apex and the tz, however without adding any significant advantage in terms of overall cancer detection rate. references 1. emiliozzi p, corsetti a, tassi b, et al. best approach for prostate cancer detection: a prospective study on transperineal versus transrectal six-core prostate biopsy. urology. 2003; 61:961-6. 2. kawakami s, yamamoto s, numao n, et al. direct comparison between transrectal and transperineal extended prostate biopsy for detection of cancer. int j urol. 2007; 14:719-24. 3. hara r, jo y, fuji t, et al: optimal approach for prostate cancer detection as initial biopsy: prospective randomized study comparing transperineal versus transrectal systematic 12-core biopsy. urology. 2008; 71:191-5. 4. takenaka a, hara r, ishimura t, et al. a prospective randomized comparison of diagnostic efficacy between transperineal and transrectal12-core prostate biopsy. prostate cancer prostatic dis. 2008; 11:134-8. 5. novella g, ficarra v, galfano a, et al. pain assessment after original transperineal prostate biopsy using a coaxial needle. urology. 2003; 62:689-92. 6. ficarra v, novella g, novara g et al. the potential impact of prostate volume in the planning of optimal number of cores in the systematic transperineal prostate biopsy. eur urol. 2005; 48:932-7. 7. hodge kk, mcneal je, terris mk, et al: random systematic versus directed ultrasound guided transrectal core biopsies of the prostate. j urol. 1989; 142:71-5. 8. shannon ba, mcneal je, cohen rj. transitional zone carcinoma of the prostate gland: a common indolent tumor type that occasionally manifests aggressive behaviour. pathology. 2003; 35:467-71. 9. furuno t, demura t, kaneta t, et al. difference of cancer core distribution between first and repeat biopsy in patients diagnosed by extensive transperineal ultrasound guided template prostate biopsy. prostate. 2004; 58:76-81. 10. ficarra v, martignoni g, novella g, et al. needle core length is a quality indicator of systematic transperineal prostate biopsy. eur urol. 2006; 50:266-71. correspondence maria angela cerruto, md mariaangela.cerruto@univr.it carolina d’elia, md, febu (corresponding author) karolinedelia@gmail.com walter artibani, md walter.artibani@univr.it giovanni novella, md giovanni.novella@ospedaleuniverona.ir urology clinic, aoui verona piazzale l. scuro 10 37134 verona, italy fabio vianello, md fabio.vianello@unipd.it urology clinic, university of padua, padova, italy cerruto_stesura seveso 15/01/15 13:18 pagina 287 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 156 practical recommendations for performing ultrasound scanning in the urological and andrological fields aim: us scanning has been defined as the urologist’s stethoscope. these recommendations have been drawn up with the aim of ensuring minimum standards of excellence for ultrasound imaging in urological and andrological practice. a series of essential recommendations are made, to be followed during ultrasound investigations in kidney, prostate, bladder, scrotal and penile diseases. methods: members of the imaging working group of the italian society of urology (siu) in collaboration with the italian society of ultrasound in urology, andrology and nephrology (sieun) identified expert urologists, andrologists, nephrologists and radiologists. the recommendations are based on review of the literature, previously published recommendations, books and the opinions of the experts. the final document was reviewed by national experts, including members of the italian society of radiology. results: recommendations are listed in 5 chapters, focused on: kidney, bladder, prostate and seminal vesicles, scrotum and testis, penis, including penile echo-doppler. in each chapter clear definitions are made of: indications, technological standards of the devices, the method of performance of the investigation. pasquale martino 1, andrea benedetto galosi 2, marco bitelli 3, paolo consonni 4, fulvio fiorini 5, antonio granata 6, roberta gunelli 7, giovanni liguori 8, silvano palazzo 1, nicola pavan 8, vincenzo scattoni 9, guido virgili 10, and imaging working group società italiana urologia (siu) in collaboration with the società italiana ecografia urologica andrologica nefrologica (sieun) reviewers: libero barozzi 11, michele bertolotto 12, andrea fandella 13, paolo rosi 14, carlo trombetta 8 1 department of emergency and organ transplantation-urology i, university “aldo moro”, bari, italy 2 division of urology, “murri” general hospital, asur marche, fermo, italy 3 department of urology andrology unit, ospedale san sebastiano martire, frascati, roma 4 u.o. urologia casa di cura “s. maria”, castellanza, italy 5 nefrologia soc azienda sanitaria ulss 18 rovigo, rovigo, italy 6 u.o. nefrologia e dialisi asp agrigento, agrigento, italy 7 u.o. urologia ospedale g.b. morgagni-l. pierantoni azienda usl di forlì, forlì, italy 8 department of urology, university of trieste, ospedale di cattinara, trieste, italy 9 department of urology, university vita-salute, scientific institute san raffaele, milan, italy 10 department of urology, university of tor vergata, rome, italy 11 emergency, surgery and transplants department radiology unit, s. orsola-malpighi university hospital, bologna, italy 12 uco di radiologia, dipartimento di scienze mediche, chirurgiche e della salute università degli studi di trieste, ospedale di cattinara, trieste, italy 13 divisione urologica, casa di cura giovanni xxiii, monastier (treviso), italy 14 clinica urologica ed andrologica, university of perugia, perugia, italy. summary review the findings to be reported are described and discussed, and examples of final reports for each organ are included. in the tables, the ultrasound features of the principal male uro-genital diseases are summarized. diagnostic accuracy and second level investigations are considered. conclusions: ultrasound is an integral part of the diagnosis and follow-up of diseases of the urinary system and male genitals in patients of all ages, in both the hospital and outpatient setting. these recommendations are dedicated to enhancing communication and evidence-based medicine in an interand multi-disciplinary approach. the ability to perform and interpret ultrasound imaging correctly has become an integral part of clinical practice in uro-andrology, but intra and inter-observer variability is a well known limitation. these recommendations will help to improve reliability and reproducibility in uro-andrological ultrasound scanning. key words: recommendation; ultrasound scanning; kidney; bladder; prostate; scrotum; penis. history of the papers submitted 24 february 2014; accepted 3 march 2014 no conflict of interest declared doi: 10.4081/aiua.2014.1.56 lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 56 57archivio italiano di urologia e andrologia 2014; 86, 1 practical recommendations for performing ultrasound scanning in the urological and andrological fields introduction these recommendations have been drawn up by the “imaging” working group of the società italiana di uro logia (siu) in collaboration with the società italiana di ecografia urologica andrologica nefrologica (sieun). the specialists involved in the work include urologists, andrologists, nephrologists and radiologists. the aim of this work is to support urologists in clinical practice, supplying a series of recommendations to be followed during the phases of ultrasound diagnosis of renal, prostatic, bladder, scrotal and penile diseases. these recommendations are based on a review of the literature, on previous recommendations and on the opinions of the experts (1-3). this document is the first to be devoted to this sector, although the american urological association (aua) and the american institute of ultrasound in medicine (aium) recently (november 2011) published practical guidelines for the performance of ultrasound in the urological field [www.aium.org] (2). the references will serve to make a constructive comparison with other clinical experiences. these recommendations were developed and drawn up with the aim of ensuring minimum standards of excellence for ultrasound imaging in urological practice, based on the assumption that ultrasound plays an essential part in this practice. doctors specializing in urology can gain particular skills and training in the use of ultrasound scanning during their residency years, in post-graduate dedicated courses organized by universities, in training courses organized by urological scientific societies (siu, sia, eau, aua) and dedicated societies (esui, sieun), both nationally and internationally. for the urologist, us scanning is an integral part of the processes of diagnosis and follow-up to manage diseases of the urinary tract and male genitals in patients of all ages, in both a hospital and an outpatient setting. the ability to perform and interpret imaging studies has become an integral part of clinical practice in all nations, also in order to optimize resources and provide patients with efficacious, rapid care. us scanning has been defined as the urologist’s stethoscope. this also applies in the andrological field. urologists must combine skilful use of sophisticated imaging devices with a deep knowledge of the physiological and pathological processes affecting the human body. if the diagnostic test will be performed in another department they must be able to select the best test or series of tests to be made for the specific patient, to optimize the management of the urological patient. these recommendations may be useful to ensure minimum shared or reference standards in the urological and andrological fields also for other medical specialists who perform urological us scanning, such as radiologists, internists, geriatricians, gynecologists or other doctors who study the urinary tract. the aims of the present recommendations are: • to define the purpose of each specific ultrasound investigation (to clarify what each investigation aims to discover). • to define the indications. • to establish the requisite technological standards of the devices. • to outline the method of performance of the investigation. • to establish the expected accuracy of the investigation in question. • to indicate the reporting method. apart from their utility as a theoretical-practical tool for making a correct ultrasound examination of the genito-urinary apparatus, these recommendations we propose have the aim of guiding the urologist in the assessment of the risks and benefits of diagnostic imaging so as to optimize the management of the urological patient [“patient care is optimized when urologists coordinate the use of imaging techniques and dedicated devices in the most advantageous place for their patients” – see (aua, aium develop joint guidelines for urologic ultrasound exams)] (2). below, brief recommendations regarding the equipment, documentation, reporting of the findings, training requirements and patient safety in ultrasound studies, are listed. equipment ultrasound scanning must be performed with devices that can provide images in real-time, thanks to the use of transducers that can optimize the penetration of the ultrasound waves inside the tissues, with excellent resolution obtained by setting appropriate frequency intervals. the advised transducer frequencies are 3.0-5.0 mhz for abdominal scanning, 6.0-9 mhz for transrectal and 7.012.0 mhz for genital scanning, while intraoperative renal or testicular scanning can be done with the transducer set at 6-10 mhz in linear mode. the correct setting of the device must also include the generation of good documentation of the investigations made. documentation each ultrasound investigation must be concluded with the production of appropriate, unequivocally clear images, recorded on a durable support (digital format is preferable) and saved in the patient's clinical files. the operator must check that the images are correctly recorded on the electronic support and readable in terms of contrast and luminosity. the ultrasound images must also be labeled with the patient's personal data and those of the health care facility where the investigation is made (hospital department or outpatients clinic). the date and type of probe are automatically specified by the device. reporting of findings apart from acquiring full documentation of the investigation, complete reporting of the findings must be made, specifying any conditions during the execution phase that could affect the reliability or accuracy of the test (e.g. anatomical causes [bowel gas, malformations], causes depending on the patient [poor compliance, pain during lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 57 archivio italiano di urologia e andrologia 2014; 86, 1 p. martino, a.b. galosi 58 the test], conduction in emergency regime, etc.). the report must include the name and signature of the doctor. ultrasound scanning is performed for specific purposes and the simple production of images, even of good quality, can never replace a description of the clinical picture and the interpretation of the findings by the operator. training requirements adequate training is an essential prerequisite for the correct performance and interpretation of ultrasound investigations. this training must be obtained both by residents at the specialist schools and by those who are already specialists in urology. they should all undergo regular updating of their ultrasound scanning skills, the former during their specialist studies and the latter at regular periodical updating courses. the main scientific societies are active in organizing such updates, and issue certificates of attendance at such training and updating courses. patient safety ultrasound procedures must be performed only for the specific indications of the case, like any other imaging technique. in fact, like all specialists, urologists should comply with the principles of alara (4), reducing to a minimum patients' exposure to acoustic energy (5). in addition, the operator must ensure that the ultrasound probe is clean and protected, to comply with the guidelines of the cdc (centers for disease control and prevention) for the standards of disinfection and sterilization of the devices (6, 7), as well as the technical recommendations specified by the manufacturers of the various devices. regular periodical controls of the devices must be made, with the collaboration of the manufacturers and complying with the safety norms they list. process of assessment of the recommendations an assessment of the true effectiveness of these recommendations in modifying behavior and improving the clinical outcome will be made using control procedures that are currently being defined. updating in the expectation of upcoming technological and/or diagnostic advances, the present recommendations will be integrated by further publications, likely every 3 years. ultrasound scanning of the kidney introduction the kidneys are a pair of organs located at the retroperitoneal level: each kidney is situated along the lateral margin of the psoas muscle, that lines it posteriorly, while it is adjacent to the bowel anteriorly. the right kidney lies about 2-3 cm lower than the left. the kidneys have the function of purging the organism of a great number of substances, and also play a part in many metabolic pathways (protein, lipid and glucides), including the metabolism of hormones and vitamins, as well as control of the blood pressure. healthy kidneys are easily assessed by ultrasound scanning because the parenchymal component is well delineated by the capsule and has a different echostructure from the perirenal fat and the pyelic structures. measurements measurements of the kidney length are made by scanning along the major axis parallel to the adjacent psoas muscle. the oblique plane of this long axis is measured by scanning the superior pole more medially and the inferior plane more laterally/anteriorly. the angle between the long axis and the sagittal plane ranges between 8 and 10 degrees (1). variations in this angle produce the variability between ultrasound measurements of the length and measurements made with conventional radiology or urography (2). with ultrasound scanning it is easy to make reliable, repeatable real-time measurements of the kidney long axis. it is clear that to make a precise measurement of the kidney axis it is necessary to identify the superior and inferior poles: this may be complex in cases of a malrotated, ectopic, ptosic, or scoliotic kidney, etc. measurement of the interpolar renal diameter is more accurate when the patient is placed in supine decubitus, slightly turned toward the contralateral side. oblique posterior longitudinal scanning is performed with the patient holding the homolateral arm above the head and breathing deeply, to shift the kidney under the ribs. measurements in prone position tend to result in an underestimation of the kidney length, but may need to be done if the kidney is poorly visualized in other scans (3). in clinical practice ultrasound measurement of the kidney volume is not performed because it is difficult to do and highly error-prone, even if it can be useful to assess renal anomalies (4). renal volume can be assessed by measuring the 3 orthogonal diameters and applying the following formula: volume v = 0.49 x l x w x ap where l is the length of the major axis (longitudinal scan), w is the length measured at the renal hilum (transverse scan) and ap the anteroposterior diameter again measured at the hilum (transverse scan) (5). the photos on which the measurements were based should be stored in the documentation of the investigation. it may soon be possible to make ultrasound measurements of the renal volume using 3d probes, that allow a greater precision than the common 2d probes (6). in any case, correct measurement of the volume of the kidneys requires good operator skills and knowledge of the renal anatomy, consisting of three different components: 1) the hyperechogenic external capsule; 2) the hypo-isoechogenic parenchyma as compared to the echostructure of the liver and spleen, between the capsule and pelvis, consisting of lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 58 59archivio italiano di urologia e andrologia 2014; 86, 1 practical recommendations for performing ultrasound scanning in the urological and andrological fields a. the external echogenic cortex, being the functional portion b. the internal hypoechogenic medulla, corresponding to the medullary pyramids with a triangular structure and the base toward the outside. 3) the kidney sinus, hyperechogenic due to the presence of many interfaces consisting of intrarenal adipose tissue. indications renal ultrasound scanning is indicated in the first approach to patients with renal disease and in the follow-up. the investigations include: • assessment of the kidneys, in normal or ectopic sites; • assessment of the ultrasound morphology; • diagnostic workup in patients with acute or chronic kidney disease; • assessment of any dilation of the excretion pathways and differential diagnosis between obstructive and non obstructive acute renal failure (arf); • identification of space-occupying lesions (cysts and tumors); • searching for stones; • echocolordoppler assessment of the renal vascularization (both with color-powerdoppler and, in selected cases, contrast enhanced ultrasound [ceus]) (11); • assessment of the intrarenal resistance indexes (ri) at the level of the interlobar and/or arcuate arteries in nephropathic, hypertense, diabetic, nephroangiosclerotic patients; • guidance of renal needle biopsy performed in the course of kidney disease or to exclude cancer; • guidance of renal puncture in the course of hydrone phrosis, abnormal cysts inducing symptoms; • assessment of kidney transplant/s (just like the native kidney) and complications. • intraoperative guidance in conservative kidney surgery, percutaneous lithotrypsy, non surgical ablation of expanding lesions; • post-surgical monitoring or endourological treatments. preparation for the investigation although no specific preparation is considered strictly necessary, some suggestions are made with the aim of optimizing the performance of the investigation. it is better if the patient is asked to refrain from drinking fizzy drinks, fermented cheeses, vegetables, fruit and wholemeal foods, pulses. in cases of a “sluggish” bowel the patient should take a laxative the evening before. since renal studies should always include a study of the bladder, this should be replete but not distended. specifications of the minimum requirements for the echograph and probes to study the kidney, a latest generation echograph, if necessary portable, should be used, of average range equipped with color-powerdoppler module and if possible, suitable software for contrast enhancement. multi fre quency convex probes allow study of the native and transplanted kidney, but for facilities that receive kidney transplant patients it is very useful to be able to employ a multifrequency linear probe. a thermal printer is indispensable, as is a magnetic image storing system. a recent generation us device offers pre-settings of the parameters to be assessed for each organ and probe, especially during echocolor-doppler investigations. these settings are defined during the installation but must be checked by the operator, updated or modified according to need and the characteristics of the tools available, as approved by the manufacturer. parameter assessed 1. position of each kidney, including malpositioning: unilateral agenesis, ptosic, malrotated, or dysmorphic kidney, (horseshoe, etc.); 2. kidney size (7): maximum interpolar diameter (normal.: right cm 10.646 ± 1.345, left cm 10.130 ± 1.165) transverse diameter (normal.: right cm 4.920 ± 0.638, left cm 5.303 ± 0.744) parenchymal thickness (normal: 1.5-2.0 cm) [measurement of cortical thickness is not always possible due to poor cortico-medullary differentiation, and suffers from high inter and intraobserver variability, so it is not commonly used] (8, 9); 3. assessment of the kidney outline, that may feature the persistence of fetal lobes in the tract between two consecutive pyramids and/or the presence of grooves (scars after pyelonephritis) at one or more calyces; 4. check for stones (hyperechogenic image measurable by posterior shadow cast); 5. check for distension of the kidney ampulla and calyces (pyelic ectasia, calico-pyelic ectasia or hydronephrosis); 6. check for distension of the ureter (hydrouretero nephrosis); 7. check for space-occupying lesions and differentiate between fluid (cysts) and solid lesions (neoplasia); 8. assess renal vascularization using color and powerdoppler to identify “minus” signs (9); 9. assess renal vascularization by contrast enhancement (ceus), that improves diagnostic confidence in the assessment of deficiency signs (11); 10. assess the intrarenal resistance indexes (ri): vn < 0.70 (10) (optional, depending on the clinical picture). example of report kidney ultrasound kidneys in situ, maximum longitudinal/transverse size within normal limits (right cm____/____; left cm____/____), regular outlines. parenchyma thickness normal (_____mm). regular echogenicity of parenchyma. no direct or indirect signs of kidney stones. regular excretion pathways with no ectasia or calicopyelic dilation (or distinguish ectasic/ pyelic, calico-pyelic dilation, associated or not with ureteral dilation). no space-occupying lesions. adrenal loggia, no expanding lesions. lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 59 archivio italiano di urologia e andrologia 2014; 86, 1 p. martino, a.b. galosi 60 renal echo-color-doppler intrarenal resistance indexes (interlobar or arcuate arteries) within normal limits (ri < 0.70) systolic peak velocity (spv) of the renal arteries at the ostium, initial, medial, distal and anterior and posterior segmentary tracts within normal limits. flowmetry normal. pervious renal veins. at powerdoppler, good vascular appearance of parenchyma. minimum imaging documentation to be included: 1. two images per kidney: transverse and longitudinal scans with measurements. 2. orientation of images (liver/spleen on left). 3. arrow on photo, indicating organ analyzed and side 4. accessory images illustrating any anomalies. 5. if the bladder is described in the findings, at least one bladder scan image must be included. ultrasound of the bladder indications • to measure post-voiding residue. • to measure bladder filling volume. • to assess anatomic modifications/complications associated with obstruction (diverticuli, trabeculation/columnar thickening, stones, detrusor thickness). • to assess hypermobility of the bladder neck in women with stress incontinence. • to assess hematuria originating in the lower urinary tract. • to assess lower urinary tract symptoms luts. • to check for suspected ureteral stone migrating intramurally. • to check for congenital malformations (ureterocele, diverticuli, etc.). • post-surgical monitoring (vesical bleeding, position of catheter, etc). • follow-up in non infiltrating cancer. • follow-up of bowel loop orthotopic bladder after cystectomy. tools during standard investigations in the adult a convex 3.5mhz probe (range 3-5.5 mhz) is used (in pediatric patients a higher frequency transducer can be used). to measure bladder volume in post voiding controls, automatic equipment can be used. in dynamic studies (e.g. assessment of cystocele) trans-rectal or trans-vaginal probes can be used. to stage bladder tumors trans-rectal probes can be used. technique use adequate amounts of gel. for optimal imaging of the bladder it should be full but not overdistended, especially in cases of obstruction. the patient should be lying supine (supine or lithotomic or in orthostatic position in cases of use of a trans-rectal probe). the bladder wall and lumen will be assessed during the investigation, with both transverse and sagittal scans (1). systematic search and documentation must be made of: any changes in the echographic appearance of the bladder wall and neck at rest, trabeculature of the detrusor, endophytic neoplasia, diverticuli, stones, the presence of a third prostatic lobe. any focal lesions observed (in particular masses) and other diseases (diverticuli, stones, clots, etc.) must be described, specifying site and size. when indicated, the distal ureters should be assessed to exclude dilation or other anomalies (intramural or juxtavesical stones, ureterocele). echo-doppler study may be useful to assess ureteral jet and make a differential diagnosis of bladder tumors (2). fine regulation of the light is essential to obtain a significantly improved image quality and correctly visualize the anterior wall (superficial as compared to the skin) and posterior wall (deep). use the second tissue harmonic imaging tool to improve the imaging and reduce reverberation artefacts. calculate bladder volume: (ellipsoid formula) v = 0.52 ! r1 ! r2 ! r3. it is recommendend to assess post-voiding urine residue by ultrasound using automatic measurement tools or using the ellipsoid formula based on bladder diameters. in cases of a significant post voiding residue the patient should be asked to make a further attempt to void and then the measurements repeated until a reliable indication of the voiding capacity is obtained. in cases of assessment of the detrusor thickness (not normally more than 3 mm) the study will be conducted with moderate bladder filling (calculated as between 250 and 350 ml, with 250 ml as threshold value), the mean of 3 measurements made on the same image is calculated. to obtain the best results the assessment must be made at the level of the anterior wall/apex and it is better if a high frequency (7.5 mhz) convex or linear probe is employed (1). the ultrasound appearance of the detrusor is as a sandwich structure (hypoechogenic muscular wall between the mucosa and adventitial layers, that are slightly hyperechogenic). the detrusor thickness must always be measured in areas that are orthogonal to the ultrasound focus (3-8). the findings report should include: • the patient’s name and surname; • the name of the service where the investigation was performed and the telephone number (in case further clarification should be required); • the date of the ultrasound examination; • if possible include all pertinent clinical information, including the indications for the investigation; • the type of ultrasound examination performed, and if endocavitary techniques are employed the method must be specified; lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 60 61archivio italiano di urologia e andrologia 2014; 86, 1 practical recommendations for performing ultrasound scanning in the urological and andrological fields • specify the orientation of the image, if different from standard (superior part on the right of the screen); • use appropriate anatomical and ultrasound terminology; in cases of variations from normal sizes the measurements must be specified (e.g. increased detrusor thickness, diverticuli, endoluminal masses, etc.); • compare with previous imaging studies if available; suggest types of studies for further investigation, any differential diagnosis hypotheses; • name and signature of the examiner, date; • if the results of the ultrasound are considered by the doctor performing the investigation to be of particular clinical importance and unexpected, such as to require urgent intervention to guarantee proper patient care, ideally the doctor who did the investigation should contact the patient’s doctor directly to check that the findings report has been received; • describe the state of other organs in the abdomen only if qualified to do so; • pay attention to the degree of distension of the bladder, that can negatively affect the visualization of the ureters in the juxtavesical tract, and the seminal vesicles; • use the tissue harmonic imaging tool to reduce reverberation artifacts and obtain better detail; • indicate any difficulties encountered while performing the investigation (patient’s collaboration and constitution, presence of bowel gas), underlining any limits of the test and so its diagnostic value. example of final report 1. presence or absence of bladder. 2. orthotopic site and symmetry. 3. shape. 4. degree of bladder distension (essential for reliability of investigation). 5. presence or absence of wall alterations (assessment of lesions > 3 mm). 6. presence or absence of third lobe (in cases where present, volume and/or degree of extension into the bladder: intravesical prostatic protrusion). 7. presence and size of calcifications (diameter > 3 mm), fixed or mobile with patient’s movements in decubitus. 8. characteristics of bladder neck (in man, protrusion of prostate). 9. presence of the ureters and any dilation or abnormal outlet or stones. 10. presence of pelvic masses and ab-extrinseco compression of the bladder. 11. quantification of post voiding residue. note: it is necessary to calculate the bladder filling volume only if needed to measure the detrusor thickness or estimate the bladder weight (reliable for values ! 250 ml) or if needed for clinical reasons. describe any clinical conditions that prevent adequate bladder filling (incontinence, pain due to reduced compliance). images to be included (not all are always indispensable, depending on the clinical picture) 1. one image of the bladder in transverse scan. 2. one image of the bladder in longitudinal scan. 3. one image of the bladder in transverse/longitudinal scan showing the bladder neck. 4. one or more images of any anomaly. 5. in cases of a lesion obstructing the juxtavesical ureter (stone or vegetating lesion) oblique scanning must be done. preparation for investigation and patient position 1. the patient does not need to be fasting. 2. the bladder must be replete with at least 300 cc; to ensure this it is necessary: a. for the patient to drink at least 500 cc of fluids during the three hours before the investigation; b. for the patient to refrain from urinating within two hours before the investigation; c. for the patient to feel the urge to urinate (this latter parameter is extremely subjective and not always reliable). the investigation is normally performed with the patient in supine position. lateral right or left decubitus may rarely be necessary, in cases where a lesion extends into the lumen (neoplastic disease, clots, “intravescical prostatic protrusion”) and its mobility must be checked. in cases requiring oblique scanning, this is done by rotating the probe by about 40° to its longitudinal axis, taking care that the bladder filling is not more than 250-300 cc (otherwise the ureters would appear crushed by the bladder volume itself). us paremeters to evaluate bladder modifications in patients with bladder outlet obstruction progressive changes in the bladder wall are observed in men with lower urinary tract obstruction secondary to benign prostatic enlargement (bpe). the high pressure discharge cause initially an increase in the proportion of smooth muscle (hyperplasia/hypertrophy of the detrusor) to changes in the advanced stages of bladder decompensation (fibrosis), hyperactivity and decreased functional capacity. early identification of bladder changes by noninvasive transabdominal ultrasound can move towards therapeutic choices that can prevent further organ damage in the bladder wall. measurement of the bladder wall thickness (bwt) or detrusor wall thickness (dwt) by us is reliable, at least 3 measurements of the anterior bladder wall taken at a filling volume of ! 250 ml. in particular, the dwt [thickness of the muscle hypoechoic between two layers hyperechoic serosa and mucosa] is considered the best diagnostic tool to measure detrusor hypertrophy using cut-off value > 2.9 mm in men. us derived measurements of bladder weight (estimated bladder weight, ebw) is another noninvasive tool for assessing bladder modifications in patients with bladder outlet obstruction (boo): cut-off value 35 gr. technique for measuring the bwt and lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 61 archivio italiano di urologia e andrologia 2014; 86, 1 p. martino, a.b. galosi 62 ebw relies in conventional us 7.5-4 mhz or using the automatic system of calculation (bvm 6500 3.7 mhz). the variability of measuring intra (4.6 to 5.1%) and interoperator (12.3%) is acceptable. also conventional us detects established signs of bladder damage: diverticulosis, trabecolations in the bladder wall (pseudo-diverticula), calculi and post-void residual urine (> 50 cc). furthermore the intravescical prostate protrusion (ipp), easy measured by transabdominal ultrasound, is strongly correlated to obstruction in men with bpe (cut-off 12 mm). measure, quantify and monitor the cervico-urethral obstruction in men with symptomatic bpe is possible by non-invasively us monitoring the response of the bladder wall. early identification has the advantage of adopting therapeutic measures sufficient to prevent progression of bladder damage measuring dwt, ebw in addition to established us paremeters (3, 5-10). diagnostic accuracy in the diagnosis and follow-up of bladder tumors or hematuria, it should be noted that the standard method is uretero-cystoscopy. ultrasound scanning is an alternative for non invasive low grade tumors and for the initial assessment of hematuria. cystoscopy allows the operator to assess and solve any doubts about the integrity and regularity of the bladder wall raised at ultrasound scanning. bladder lesions smaller than 5 mm may not be identified at ultrasound. not all bladder tumors are observed at ultrasound: slow-growing non vegetative tumors like carcinoma in situ are not diagnosed by imaging. the diagnostic capacity for vegetating/papillary lesions > 5 mm is high, even if in some circumstances differential diagnosis with clots may be difficult despite echocolordoppler. parameter pattern acute cystitis wall thickness and echogenicity. increased hypoechogenicity, increased thickness of bladder wall, between the serosa and mucosa. chronic cystitis no characteristic pattern, assessment of post-micturition residue, search for foreign bodies in bladder. bullous cystitis wall thickness, echogenicity. increased bladder wall thickness, anechogenic areas wall hypoechogenicity. diverticuli presence/absence. formation of anechogenic paravesical areas with the presence of asonic funnelling to bladder (diverticular neck): transrectal scanning can better reveal the diverticular neck. color-doppler can enable dd between tumors and endodiverticular clots, although it is not the ultimate test. in doubtful cases ceus or other radiological or endourological imaging should be done. detrusor hypertrophy thickness detrusor wall (calculated increased (> 3 mm) with irregularities (trabeculatures or even pseudo (5-7, 9) at ! 250 ml of filling, as mean of 3 diverticuli). measurements, hypoechogenic tissue low level evidence, recommendations need to be verified on vast scale, included between two lines of evidence levels based on opinions of experts and case series. hyperechogenic tissue: mucosa parameter to be assessed, advised by experts. for use in clinical studies. and bladder serosa). ureterocele anechogenic formation (cyst) at the level of the ureteral meatus with evidence at color-doppler of ureteral jet. juxtavesical juxtavesical ureter obstructive lesion hyperechogenic image with posterior shadow included in the thickness ureter lesion (stone or vegetating lesion). of the ureteral wall (between hyperechogenic serosa). eco-color-doppler: useful to identify color signals (artifacts) in the shadow area and in dd of vegetating lesions also with eco-power-doppler. evidence or not of urethral jet at color-doppler. stones hyperechogenic images with shadow, mobile depending on decubitus movements. hyperactive bladder bladder weight (uebw-ultrasoundno consensus in literature as to standardized cut-off values to be used (5, 10) estimated bladder weight). in clinical studies. non neoplastic diseases parameter pattern superficial lesions bladder wall structure generally no echostructural alterations of the wall. endophytic tumors appear as hypoechogenic, fixed proliferative lesions, but sometimes they are hyperechogenic due to the presence of superficial calcifications. at color-doppler hypervascularization is observed. infiltrating lesions bladder wall structure interruption/deformation of the wall, that appears thickened, sometimes extension beyond the bladder wall. neoplastic diseases although staging is not currently approved on the basis of the ultrasound findings, we report indications for a possible interpretation. lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 62 63archivio italiano di urologia e andrologia 2014; 86, 1 practical recommendations for performing ultrasound scanning in the urological and andrological fields addendum: possible use of 3d studies, especially for post surgical assessment (sling). clinical studies to assess the presence of funneling of the neck, hypermobility of the neck-urethra complex, cystocele, ureteral fixity. no standards have yet been established for mobility parameters (among proposals see schaer et al. int urogynecol j pelvic floor dysfunc 1996, pajoncini c. in atlante di ecografia uro nefrologica ed andrologica 1996 ed. cic, merz et al. ultraschall med 2004, tunn r. et al. update recommendations on ultrasonography in urogynecology. int urogynecol j 2005 16, 236-241). trans-perineal introital trans-vaginal trans-rectal instruments convex sector endfire linear biplanar linear biplanar 3.5-5 mhz probe 5 7.5 mhz probe 7.5 mhz probe 7.5 mhz probe patient position lithotomic lithotomic orthostatic lithotomic orthostatic quality of image + + +++ +++ measurement of mobility ++ ++ +++ +++ invasiveness + + ++ +++ artifacts in 3-4 grade cystocele ++ ++ +++ + ultrasound of the pelvic floor (4, 11-24) prostate and seminal vesicles prostatic ultrasound scanning with the suprapubic technique method the prostate must be analyzed on two orthogonal planes: transverse and longitudinal. in this study it is essential to examine: • juxtavesical ureters. • bladder. • prostate. • seminal vesicles (1-6). the prostate diameters to be assessed are: latero-lateral, antero-posterior and cranio caudal. in cases of an obstructive lesion of the juxtavesical ureter (stone or vegetating lesion) oblique scans must be made. images to be included (not all are always indispensable, depending on the clinical picture). 1. one image of the bladder in longitudinal/transverse scan. 2. one image of the prostate in transverse scan showing the bladder. 3. one image of the prostate in longitudinal scan showing the bladder. 4. one image of the right juxtavesical ureter in oblique scan. 5. one image of the left juxtavesical ureter in oblique scan. 6. one or more images of any anomalies. report of the findings 1. date and place of performance of the investigation. 2. patient data (including birth date). 3. mention of clinical history and diagnostic purpose. 4. value of last total psa blood test. 5. comparison with previous tests if available. both the images and findings must be easy to read by other operators and at later dates. the findings must therefore be reported as unambiguously as possible. in cases of any diagnostic doubt, this must be pointed out, indicating possible hypotheses and suggesting any further instrumental investigations that may help to solve any doubts. terminology 1. identification of the medial lobe and its size and relations with the pelvic floor 2. any picture of cervico-ureteral obstruction due to prostatic hypertrophy causing severe detrusor impairment, any presence of bladder stones (table 1). indications 1. to assess the size and volume of the prostate gland before medical, surgical or radiation treatment (in particular, to assess the volume displacement caused by the third lobe and correlations with detrusor hypertrophy, the presence of bladder pseudodiverticuli and diverticuli (1, 6). 2. to assess the patient with lower urinary tract symptoms (1). 3. to assess congenital anomalies. essential parameters to be specified in the final report prostate 1. presence or absence of the prostate. 2. orthotopic or heterotopic site. 3. shape. 4. size. lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 63 archivio italiano di urologia e andrologia 2014; 86, 1 p. martino, a.b. galosi 64 5. presence or absence of third lobe (if present, volume and/or size of protrusion into the bladder: intravesical prostatic protrusion). 6. presence and size of any gross calcifications (diameter > 5 mm). 7. presence and size of any gross abscesses/cysts (diameter > 5 mm). 8. presence of the ureters and any dilation or anomalous outlet. 9. quantification of post voiding residue. note: lesions of any nature with a diameter of " 5 mm are not identifiable with suprapubic ultrasound scanning. the suprapubic technique cannot visualize the echostructure of the peripheral zone of the prostate due to technical image resolution limitations. seminal vesicles 1. presence or absence. 2. site. 3. symmetry. bladder an accurate description of the bladder is essential, see previous chapter. preparation for investigation and patient position 1. the patient does not need to be fasting 2. the bladder must be replete with at least 300 cc; to ensure this it is necessary: a. for the patient to drink at least 500 cc of fluids during the three hours before the investigation; b. for the patient to refrain from urinating within two hours before the investigation; c. for the patient to feel the urge to urinate (this latter parameter is extremely subjective and not always reliable). the investigation is normally performed with the patient in supine position. lateral right or left decubitus may rarely be necessary, in cases where a lesion extends into the lumen and its mobility must be checked. example of final report mention of clinical history: _______________________ diagnostic purpose_____________________________ last total psa value: the bladder… yes/no hyperechogenic bladder images depicting stones, nor dilation of the juxtavesical and intramural bilateral ureters. the prostate is shown in orthotopic/heterotopic site and is grossly triangular, size within normal limits (more/less), (ll x ap x cc), having a theoretical calculated volume of about ___ml. presence of third lobe protruding into the bladder by __cm. post voiding residue is about cc. non/mild/fair/marked tenderness or pain on palpation of the hypogastrium at the start/throughout the duration of the investigation. diagnostic accuracy it is important to note that the elective method for the study of the prostate gland includes the use of endocavitary probes (7, 8). in fact, suprapubic ultrasound scanning is not contemplated in the guidelines for the study of the prostate drawn up by the main scientific societies due to its limited diagnostic power (2-5). in particular, it is thought that prostate ultrasound results in an overestimation by more than 30% to 50% of the true prostate volume. according to some authors, moreover, the use of the ellipsoid formula to calculate the prostate gland volume with the aid of suprapubic ultrasound leads to an error of about 20% (9). notes on clinical practice a. attention must be paid to the degree of distension of the bladder, that can affect the visualization of the juxtavesical ureters and seminal vesicles b. use the tissue harmonic imaging tool to reduce reverberation artifacts and obtain better detail c. indicate any difficulties encountered while performing the investigation (patient’s collaboration and constitution, presence of bowel gas), underlining any limits of the test and so its diagnostic value. d. remember that if the prostate is larger than normal, its morphology may vary, especially in cases of prostatic hyperplasia. devices and transducers used convex transducer with a frequency of 3.5 mhz, or multifrequency 5-2 mhz probes depending on the patient’s constitution and how deeply the gland is located. transrectal prostatic ultrasound method the investigation is dynamic and apart from longitudinal and transverse scans, with the probe inclined more craniocaudally than for the study of the bladder, oblique scans will also be performed to study the seminal vesicles, that generally lie on the transverse/oblique plane. the prostate must be analyzed on two orthogonal planes: transverse and longitudinal, from the apex to the base of the gland. at the same time, it is essential to study: • the urethra sphincter, cowper’s glands; • the seminal vesicles; • the juxtavesical tract of the ureters; • the deferens ducts; • the bladder (insofar as it is explorable). additionally, any gross alterations of the rectal wall should be pointed out, and referred to the competent specialist colleague. lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 64 65archivio italiano di urologia e andrologia 2014; 86, 1 practical recommendations for performing ultrasound scanning in the urological and andrological fields the diameters to be assessed is latero-lateral, antero-posterior and cranio-caudal, to calculate the total volume, and also the volume of the transition zone (periureteral hypertrophy). for the seminal vesicles the diameters assessed are: antero-posterior. the apparent size of the latter may be affected by the degree of distension of the bladder, by ejaculation and by forms of obstruction (1-4). images to be included (not all are always indispensable, depending on the clinical picture) 1. one image of the prostate in transverse scan (indicating the diameters of both the entire gland and adenoma). 2. one image of the prostate in longitudinal scan (indicating the diameters of both the entire gland and adenoma). 3. one image of the prostate in transverse scan showing the bladder. 4. one image of the prostate in longitudinal scan showing the bladder. 5. one image of the seminal vesicles in transverse scan. 6. one or more images of any anomalies. 7. any images of the juxtavesical ureter in longitudinal scan. calculate total prostatic volume and transition zone volume it is important to note that all latest generation ultrasound devices automatically calculate the volume of the prostate, bladder and seminal vesicles. if this is not possible, multiply the 3 diameters by 0.52 according to the ellipsoid formula. data on the volume of the entire gland and adenoma are clinically essential for therapeutic and surgical workup purposes (5-11). orientation of the ultrasound images the ultrasound probe always appears at the bottom of the image. in transverse scans: the patient’s right side is conventionally on the left side of the image (as also in ct and mr images). in longitudinal scans: the superior/proximal part/patient’s head is conventionally on the left side (as in abdominal ultrasound imaging), and the distal part on the right side. documenting the findings 1. date and place where the investigation was performed. 2. patient data (including birth date). 3. mention of clinical history and diagnostic query. 4. value of last total psa blood test. 5. outcome of rectal exploration, that should always be done before the investigation. 6. comparison with previous examinations, if available. both the images and findings must be easy to read by other operators and at later dates. the findings must therefore be reported as unambiguously as possible. in cases of any diagnostic doubt, this must be pointed out, indicating possible hypotheses and suggesting any further instrumental investigations that may help to solve any doubts. terminology 1. hypoechogenic pars adenomatosa, as compared to pars peripherica of the prostate (6, 8). 2. identification of medial lobe, and its size and relationships with the bladder floor (5). 3. presence of calcifications (diameter ! 3 mm), that appear hyperechogenic with a posterior shadow (possibly showing signs of previous inflammation). 4. presence of focal hyperechogenic areas with no posterior shadow (diameter ! 3 mm) (possibly showing signs of previous inflammation). 5. presence of abscesses and/or hypo/anechogenic areas (diameter ! 3 mm), that appear prevalently with a fluid anechogenic or dyshomogenenous component, possibly showing inflammation processes in active phase. anechogenic/echogenic areas of inflamed abscesses table 2. 6. in a picture of cervico-ureteral obstruction due to prostatic hypertrophy causing severe detrusor impairment, any presence of bladder stones table 1. 7. dilation/cysts of the ejaculatory ducts. 8. perviousness and funneling of the cervical or anastomotic region in surgical scars. indications 1. to assess the size and volume of the gland for medical/surgical workup, regardless of the type of treatment or underlying disease (1-14). 2. prostatic biopsy guidance. 4. suspected prostatitis and/or prostatic abscess. 5. to examine congenital anomalies. 6. in infertility of the couple (morphological study of the seminal tracts). 7. study of the bladder neck – functional diseases of the bladder neck (sclerosis, iatrogenic stenosis or ndd); – neurological bladder; – outcome of surgery of the cervico-prostatic region (prostatic trans-vesical adenomectomy, endoscopic resection or enucleation of prostatic adenoma, endoscopic incision of bladder neck); – identification and examination of cysts of bladder neck or third prostatic lobe; 8. postoperative controls (post disobstructive surgery or radical prostatectomy). 9. post-treatment controls for prostatic tumors (radiotherapy, hifu, cryotherapy) (8). essential parameters that must be specified in final report for all types of report preliminarily, transrectal exploration must be performed, indicating the presence, size (x 2-3), surface, consistenlineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 65 archivio italiano di urologia e andrologia 2014; 86, 1 p. martino, a.b. galosi 66 cy, margins, presence or absence of a medial groove, any nodules, their characteristics and localization), tenderness or pain on palpation of the gland. prostate 1. presence or absence of the prostate. 2. orthotopic or heterotopic site. 3. symmetry. 4. size/volume of the gland (latero-lateral, antero-posterior and cranio-caudal, to be multiplied by 0.52, according to the ellipsoid formula, if the device does not make an automatic calculation). 5. size/volume of the transition zone/adenoma. 6. presence or absence of third lobe (if present, volume and/or measurements of protrusion into the bladder) (5, 16). 7. presence and size of calcifications (diameter ! 3 mm) table 1. 8. presence and size of abscesses/cysts (diameter ! 3 mm) (17). 9. presence and size of intra-prostatic cysts or bladder neck cysts (diameter ! 3 mm) (17). 10. echostructure of the peripheral portion (18). 11. integrity of prostatic capsule. 12. presence of the ureters and any dilation or anomalous outlet. 13. any pain elicited during the investigation table 2. addendum in particular cases presence of the deferens and any dilation. urethra any lesions evident at ultrasound. morphology and function of the internal urethral sphincter (only in cases of ultrasound performed for functional purposes). seminal vesicles 1. presence or absence. 2. site. 3. symmetry. 4. morphology. 5. any dilation (> 12 mm in antero-posterior site). bladder 1. morphology of walls. 2. morphology of content. 3. presence of vegetation and description. 4. presence of stones. a. prostatic biopsy guidance 1. in cases of suspected tumor areas, describe: – site; – size; – morphology; – ultrasound appearance; – margins; – relations of lesion with the capsule, bladder neck, seminal vesicles in cases of basal nodules with extracapsular extension. if several nodules are present, each must be detailed as described above (19-20). 2. in cases of multiple prostatic biopsy sampling, indicate: – type of patient preparation; – antibiotic prophylaxis administered*; – results of preliminary rectal exploration (and any agreement between increased consistency areas at palpation and suspicious ultrasound images); – type of anesthesia (site, drug and dosage); – number of samples, specifying scheme adopted – course of procedure; – indications for patient care in days after the manoeuvre; – any home antibiotic therapy*. b. assessment of congenital anomalies in particular, apart from studying alterations of the course of the juxtavesical ureters, transrectal prostatic ultrasound is able to demonstrate intraprostatic cysts. cystic lesions appear as round or oval, with distinct margins and an asonic content. the definition of the site is particularly important, namely: 1. vesical. 2. medial posterior: mullerian/prostatic utricle. 3. paramedial/lateral: ductal dilatation/cysts of ejaculatory duct. 4. due to retention (17). c. morphologic study of the seminal tract ejaculatory ducts 1. presence or absence. 2. presence or absence of calcifications and any obstruction caused. 3. any dilation. deferens ducts 1. presence or absence. 2. presence or absence of calcifications or lesions and any obstruction caused. 3. any dilation. seminal vesicles 1. diameters (latero-lateral, antero-posterior and craniocaudal). 2. any dilation. 3. any congestion. 4. anomalies with the deferens. * antibiotic prophylaxis has proven useful for the prevention of complications such as asymptomatic bacteriuria, urinary tract infections, bacteremia and sepsis (1). the fluoroquinolones (such as ciprofloxacin xr 1000 mg), due to a better prostatic penetration, allow maintenance of constant levels of antibiotic in tissue, thus ensuring optimum prophylactic efficacy (2). references 1. zani el, clark oa, rodrigues netto n jr. antibiotic prophylaxis for transrectal prostate biopsy. cochrane database syst rev. 2011; (5):cd006576. 2. grabe m (chairman), bjerklund-johansen te, botto h, et al. guidelines on urological infections. european association of urology 2013. lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 66 67archivio italiano di urologia e andrologia 2014; 86, 1 practical recommendations for performing ultrasound scanning in the urological and andrological fields d. study of the bladder neck 1. morphology (5). 2. symmetry. 3. any calcifications. 4. any cysts (17). e. study of the prostatic loggia after radical prostatectomy or other treatments presence of areas suggesting disease recurrence in the perianastomotic region: – site; – size; – localization with respect to the anastomotic region and rectal wall; – ultrasound appearance; – margins; – vascularization; – presence/absence of seminal vesicles residues. the ultrasound data must necessarily be correlated with the total psa values and clinical history, because subsequent treatments for postoperative urinary incontinence may modify the echostructure and mimic lesions (macroplastique, collagen, bulkamid). if biopsy samples are taken of the perianastomotic region, all suspicious areas should be sampled; this can be done under ultrasound guidance (15). preparation for the investigation and patient position the patient must undergo at least one enema two hours before the investigation, to avoid artifacts caused by fecal matter in the rectum. fasting is not necessary. the patient must not urinate for at least two hours before the investigation (the bladder must be replete). the investigation is normally performed with the patient in lateral left decubitus. if this is impossible, it can be done in lateral right decubitus or semilithotomic position. example of final report standard transrectal prostatic ultrasound mention of clinical history:________________________ last total psa value:____________________________ preliminary rectal exploration shows the prostate in situ, enlarged (x), with a smooth surface, parenchymatous consistency, distinct margins, flattened medial groove. no tenderness or pain on palpation. the prostate, investigated with a transrectal “end-fire” ultrasound probe with variable frequency, is visible in situ and roughly triangular in shape; the size is x x mm (ll x ap x cc), for a theoretical calculated volume of about cc. a central nodular area of hyperplasia is present, with a dyshomogeneous echostructure, and theoretical calculated volume of about cc. along the cleavage plane of the nodular hyperplasia, and in the periureteral site, calcifications are evident, likely the outcome of previous inflammatory processes. within the nodular hyperplasia area there are gross calcifications as well as some anechogenic images compatible with cysts due to retention/microabscesses. the peripheral gland shows a substantially homogeneous structure, with no signs of disease foci in course. the seminal vesicles are orthotopic and normal in shape. the bladder is in situ, moderately distended. no ultrasound alterations of the posterior bladder wall are apparent, insofar as the area is visible through the transrectal acoustic window. post-voiding urinary residue is … transrectal prostatic ultrasound to study the seminal vesicles the prostate is described as above. no evidence of obstructive lesions of the ejaculatory ducts and deferens ducts bilaterally. the seminal vesicles are orthotopic and normal in shape. the maximum diameters of the right seminal vesicles are x x x mm (cc x ap x ll), for a theoretical calculated volume of about cc. the maximum diameters of the left seminal vesicle are x x x mm (cc x ap x ll), for a theoretical calculated volume of about cc. post-voiding urinary residue is cc. deferens present, symmetrical and not dilated. prostatic ultrasound of the perianastomotic region after prostatectomy the perianastomotic region appears homogeneous/dyshomogeneous, showing areas of .. in size, localized at the level of .., with …margins, vascularized, suspicious for growth processes. diagnostic accuracy the diagnostic accuracy of transrectal prostatic ultrasound varies according to the diagnostic query. in particular, as regards assessing the size of the prostatic adenoma, the diagnostic accuracy of transrectal prostatic ultrasound is extremely high, while the risk of overestimation of the true prostatic volume and weight (later measured in the various studies on the anatomic piece) ranges between 4 and 10% (21-28). as regards the identification of prostatic nodules suspected of growth processes, it should be noted that 60% of them appear hypoechogenic, 30% isoechogenic and 10% hyperechogenic. therefore, the overall diagnostic accuracy of this method alone is about 30% (this is why in most cases prostatic biopsy sampling is done randomly, in the absence of ultrasound areas raising suspicion (19-20). the presence of a hypoechogenic image alone is not the only criterion indicating the need for prostatic biopsy. the criteria for mapping prostatic biopsies are clinical and based on the psa values and trend, on rectal exploration, the presence of risk factors, and also on the prostatic volume and ultrasound findings. granulomatous prostatitis (acute or chronic) can induce hypoechogenic modulations that are indistinguishable from those of neoplasia. finally, as regards the use of transrectal ultrasound to assess the perianastomotic region, the diagnostic accuracy of this investigation is strictly linked to the total lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 67 archivio italiano di urologia e andrologia 2014; 86, 1 p. martino, a.b. galosi 68 psa value. the positive predictive value is about 65%, and the negative predictive value about 20% (15). for all lesions suspected to be cancerous, ultrasound alone can never replace biopsy. notes on clinical practice • use tissue harmonic imaging to reduce reverberation artifacts and obtain better detail. • indicate any difficulties encountered while performing the investigation (patient’s collaboration and constitution, presence of bowel gas, presence of artifacts due to insufficient bowel cleansing), underlining any limits of the test and so its diagnostic value. • if the prostate is larger than normal, its morphology may vary, especially in cases of prostatic hyperplasia. • when performing ultrasound guidance for prostatic biopsy sampling, it is useful to ask the patient to void the bladder after the diagnostic phase • the longitudinal diameter of the seminal vesicles varies according to the size of the gland and also the degree of bladder repletion. • in cases with many gross calcifications along the cleavage plane between the pars adenomatosa and pars peripherica, in the periureteral intra-adenomatous site, the shadow created by the calcifications may make ultrasound exploration of the bladder or pars peripherica difficult. the role of ecocolordoppler color doppler and power doppler are generally used to identify neovascularization foci, possibly expressing abscesses (vascularization absent in the center) or tumors (29-31). new technologies the limited sensitivity and specificity of gray-scales ultrasound in transrectal prostatic ultrasound has led to the adoption of new technologies based on the different vascular pattern identifiable in neoplastic foci, and hence on doppler techniques. the use of 3d ultrasound and histoscanning seems to be able to reduce the overall number of cores necessary, contributing to a better definition of the target, but such investigations should only be considered in clinical studies (20, 32). the use of contrast medium recent studies have not reported any increased sensitivity in the detection rate of prostatic tumors by contrast enhanced ultrasound (ceus), as compared to extensive mapping (33, 34). elastosonography the use of elastosonography increases the detection rate by about 20% as compared to traditional ultrasound, ultimately leading to a reduction in the number of necessary cores. however, operator experience and the degree of pressure exerted on the tissues strongly limit large scale use of this technique (35). 3d ultrasound thanks to the inclusion of the coronal plane, 3d ultrasound provides information helping to assess the seminal vesicles and ejaculatory ducts, as well as offering a better detection rate of prostatic tumors, according to some studies (20). devices and transducers real time endocavitary transducer (transrectal) with a frequency ! 6 mhz (or anyway high). high frequency is used because the prostate is superficial as compared to the probe plane (internal rectal wall): • a linear monoplanar probe: for prostate sections along the longitudinal plane. • a convex-linear or bi-convex biplanar probe: associates transverse and longitudinal scanning, through two orthogonal convex probes. • a variable frequency probe (end-fire): allows transverse, longitudinal and oblique scanning. pathologic mechanism size macroscopic evidence number site (increased intraprostatic ph and increased precipitation of calcium salts) endogenous amyloid bodies macrolithiasis disseminated single periurethral reaction to foreign body in intra-acinar site (max. diameter ! 2 mm) +/posterior shadow exogenous stasis of prostatic secretion microlithiasis thickened multiple lobar intraprostatic reflux (max. diameter " 2 mm) +/ posterior shadow perinodular prostatitis ejaculatory ducts table 1. stones and hyperechogenic prostatic images. lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 68 69archivio italiano di urologia e andrologia 2014; 86, 1 practical recommendations for performing ultrasound scanning in the urological and andrological fields ultrasound of the scrotum indications 1. to evaluate the acute scrotum: testicular trauma, ischemia, suspected torsion and infectious or inflammatory diseases (4, 7, 16). 2. to assess palpable masses in the inguinal or scrotal site (18, 22). 3. to assess any asymmetry and increased volume of the scrotum (21). 4. to assess a possible scrotal hernia (13). 5. for diagnosis and staging of varicocele. 6. to evaluate male infertility. 7. in follow-up of previous lesions shown at ultrasound (10). 8. to assess cryptorchidism (12). 9. to search for an occult primitive tumor in a patient with germinal tumor metastases. 10. in follow-up of patients with a primitive testicular tumor, lymphoma or leukemia (23). 11. in follow-up after testicular surgery. 12. in diagnostic workup for anomalies observed at other imaging studies like ct, mri or pet. 13. to assess intersexual conditions. essential parameters in the study of the scrotum (20) 1. the scrotal wall. 2. the testicular volume. 3. the testicular echostructure. 4. the epididymis (volume and echostructure). 5. vascularization. 6. the pampiniform plexus. preparation for the investigation and patient position the investigation must be performed in a darkened room, to protect the patient’s privacy, and the room temperature must not be cold because this could elicit the cremasteric reflex, in a more accentuated form in children, that could cause the testicle to rise up. initially, the patient should lie supine with a scrotal support to facilitate exposure. the penis will be positioned superiorly or supero-laterally (5, 8).after examining the content of the scrotal sac in clinostatic position, the investigation should be continued with the patient in orthostatic position, making a careful evaluation of the venous flow of the spermatic cords. b-mode study will already reveal table 2. definition of ultrasound characteristics of different disease pictures. peculiarities shows pars peripherica separated from pars adenomatosa thanks to a cleavage plane and different echogenicity (pars adenomatosa is more hypoechogenic than pars peripherica) there may be nodular oval or rounded areas, with distinct margins, and an isoechogenic appearance to the surrounding parenchyma, expressing prostatic hyperplasia intra-adenomatous areas or focal prostatitis areas in cases of abscess, this will show distinct margins and a highly hypo/anechogenic content. hyperechogenic lesions may be present within the abscess area, showing an irregular morphology demonstrating partial colliquation of such abscesses. in cases of inveterate chronic prostatitis, there may be a dyshomogeneous appearance, with alternating hypo-isoechogenic and hyperechogenic areas differential diagnosis abscess areas, in very hypoechogenic images calcification areas, in very hyperechogenic images tumoral areas (possible only with biopsy) neoplasia, especially in cases of suspected abscess colliquation neoplasia, especially in cases of granulomatous prostatitis observed in subjects with a history of endovesical chemo-immunoprophylaxis with bcg. disease picture prostatic hypertrophy acute prostatitis chronic prostatitis morphology increased size due especially to enlarged pars adenomatosa increased gland size increased size or no change echogenicity showing pars peripherica separated from pars adenomatosa thanks to an evident cleavage plane and different echogenicity (pars adenomatosa is hypoechogenic and dyshomogeneous as compared to pars peripherica) less than normal tendency to be increased, in cases with calcifications as inflammatory outcomes vascularization no variation increased doppler signal, correlated to increased vascularization due to inflammatory processes variable margins free normally free, sometimes blurred in cases of sub capsular abscess and direct involvement of the margins free lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 69 archivio italiano di urologia e andrologia 2014; 86, 1 p. martino, a.b. galosi 70 the presence of varicose veins, but it is convenient to go on immediately to color doppler study to examine the characteristic patterns of varicocele (11). notes on clinical practice and indications for echocolordoppler the first task in scrotal ultrasound is to make a correct calculation of the testicular volume. the formula most commonly used today is the ellipsoid (volume in ml = product of the three diameters (in cm) x 0.52) (3). the testicles must be assessed on two planes: longitudinal and transverse. the transverse plane is focused on the superior medial and inferior testicular portions, and the longitudinal plane on the central portion, as also medial and lateral. once the whole testicle has been measured, the investigation continues with the epididymis (head, body and tail) (6). the testicular measurements and echogenicity should then be compared with those of the contralateral testicle. color doppler can be helpful, especially in cases of acute pain (2). in this case, both longitudinal and transverse scanning is useful, as well as comparison of the two testicles. the doppler parameters must be set to analyze slow flow. should it be impossible to visualize the flow, power doppler can be employed to highlight the images (9). color doppler is essential in the diagnosis and staging of varicocele. devices and transducers the investigation is conducted using a real time scanner, preferably with a linear transducer. the transducer is set to scanning mode at the highest frequency of the device. in the latest ultrasound devices the frequency may range from 8 to 15 mhz or more (1, 19). the transducer length may range between 4 and 8 cm. resolution must be sufficient to discriminate different ultrasound characteristics in any lesions observed. if there is a markedly increased volume of the scrotum, the use of lower frequencies is indicated to make a correct study of the gonads (15); alternatively it is possible to rely on the trapezoid assessment available in more modern ultrasound devices (14). the doppler frequencies must be as high as possible to optimize the resolution and show the blood flow. modern devices offer a frequency range of 5 to 10 mhz (17). example of final report scrotal echocolor doppler toshiba aplio; examination performed with linear probe 11.5 mhz history: previous right orchiectomy for embryonal testicular k. known left varicocele. didymi: left didymis in situ with normal echostructure and volume, markedly hyopotrophic approx 3.5 cc (ellipsoid formula calc. 0.52 x 3 diameters) epididymi: normal echostructure and size; small cyst of head of left epididymis. small scrotolite present. vascularization of didymis-epididymis: within normal limits left pampiniform plexus: severe peritesticular ectasia with vessel diameter exceeding 4mm. colordoppler investigation of pampiniform plexus in orthostatic position. left pampiniform plexus: basal reflux little modified by functional manoeuvers. diagnostic conclusion: left varicocele, grade v according to sarteschi classification. images to be included (not all are always indispensable, depending on the clinical picture) 1. one image of each testicle and epididymis in transverse scan. 2. one image of each testicle and epididymis in longitudinal scan. 3. one image of both testicles and epididymi for direct comparison. 4. one image of the prostate in longitudinal scan showing the bladder. 5. one or more images of the pampiniform plexus at rest and under valsalva. 6. one or more images of any palpable anomalies. important notes in clinical practice cause ultrasound appearance second level investigations non inflammatory heart failure thickened scrotal wall, with alternating idiopathic lymphedema hyperechogenic and hypoechogenic layers lymphatic and venous obstruction (onion-like appearance) epidermoid cysts inflammatory cellulitis thickening of the scrotal wall and presence of hypoechogenic areas, showing increased blood flow fournier gangrene thickening of the scrotal wall with signs ct; mri of inflammation; gas may be visible as numerous hyperechogenic foci table 1. lesions of the scrotal wall. lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 70 71archivio italiano di urologia e andrologia 2014; 86, 1 practical recommendations for performing ultrasound scanning in the urological and andrological fields ultrasound appearance second level investigations non inflammatory shows bowel wall, presence of peristalsis, hyperechogenic area if omentum present. ct distinguish direct or indirect if inferior epigastric artery shown by doppler. presence of stricture (ss 90%; sp 93%) hydrocele anechogenic fluid collection surrounding the testicular parenchyma hematocele appearance similar to cysts, with septs and loculi pyocele table 2. inguinal or scrotal swelling. ultrasound appearance second level investigations varicocele multiple tortuous vascular structures, hypoechogenic with variable diameters spermiogram exceeding 2 mm. color doppler set for low flow to show a characteristic flow pattern, with phase alterations and retrograde filling during valsalva (ss and sp 100%) grading varicocele accordig to an established classification. the suggested classification is the grading system according to sarteschi classification. tumors lipoma, sarcoma and rhabdomyosarcoma have the same non specific ct, and better mri, to enhance of spermatic cord ultrasound appearance visualization of the tissues table 3. spermatic cord (22). ultrasound appearance orchi-epididymitis epididymis enlarged and hyperechogen or hypoechogenic. a reactive hydrocele may be present, and if there is testicular involvement the didymis will be enlarged, with a dyshomogeneous ultrasound appearance. doppler will show hyperemia and increased blood flow (peak systolic rate > 15 cm/sec) chronic epididymitis epididymis enlarged, increased echogenicity and possibly calcifications epididymis masses spermatocele and epididymis cysts are shown as hypoechogenic lesions that may be as much as 1-2 cm in diameter, with acoustic enhancement in the posterior wall. they may contain protein fluid or spermatozoa with a low echogenicity. adenomatoid tumors can be hypoechogenic, isoechogenic or hyperechogenic table 4. epididymis (18). ultrasound appearance second level investigations testicular torsion absence of intratesticular blood flow (ss 86%, sp 100%) increased testicular volume and reduced echogenicity (4-6 h) after 24 h, dyshomogeneous echostructure due to vessel congestion, hemorrhage and infarction. spiral appearance under the torsion point, that appears as a homogeneous extratesticular oval or rounded mass, with or without blood flow orchitis hyperemia and dyshomogeneous ultrasound appearance. increased or enhanced intratesticular blood flow testicular microlithiasis multiple echogenic foci with no shadow (at least 5 microliths per field) benign lesions cysts of tunica albuginea: may be unilocular or multilocular, with calcifications simple cysts: may be multiple or solitary, generally adjacent to the mediastinum. they appear anechogenic and with no wall. epidermoid cysts: ultrasound appearance of a halo with a central area and increased echogenicity or else as a mass defined by an echogenic circle, or else a classic “onion” appearance. doppler will not show blood flow ectasia of rete testis: visible at us as fluid-filled tubular structures. possible presence of cysts intratesticular varicocele: multiple, anechogenic tortuous tubular structures. bloodflow shows characteristic reflux during valsalva malignant lesions seminomatous tumors: homogeneous hypoechogenic lesions, with uniform tumoral markers smooth margins. very often the tumor occupies much of the parenchyma non seminomatous tumors: may have very variable us appearance: tumoral markers dyshomogeneous echostructure (71%), irregular or with poorly defined margins (45%), echogenic foci (35%) and a cystic component (61%) lymphomas: testicles homogeneously hypoechogenic or with multifocal hypoechogenic lesions of various diameters. the didymis, in diffuse forms, appears hypervascularized (d.d. with orchitis) testicular trauma rupture or interruption of the albuginea, irregular echostructure with poorly mri defined margins. color /power doppler can help to show the vascular pattern of the parenchyma, capsule table 5. testicle (4, 12). lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 71 archivio italiano di urologia e andrologia 2014; 86, 1 p. martino, a.b. galosi 72 ultrasound of the penis introduction penile us is an essential tool in urological clinical practice both as an investigation in itself and integrated with color doppler of the penile vascularization (1). indications indications for penile us: 1. erectile dysfunction. 2. priapism. 3. penile fibrosis and plastic induratio penis. 4. penile or urethral anomalies observed at physical examination. 5. neoplasia of the penis. 6. penile trauma. 7. thrombosis of the dorsal vein. 8. urethral disorders (cysts, diverticuli, stenosis). 9. stones or foreign bodies in urethra or penis. technique of investigation at least two scans must be performed: transverse and longitudinal. the probe is positioned dorsally or centrally to obtain a better visualization of the corpi cavernosi, the intercavernous septum, the tuniche albuginea and buck’s fascia and the urethra (3). the transverse scan must be done in the proximal, medial and distal portions of the penis. the longitudinal scan must be done on the two corpi cavernosi, visualizing the cavernosum artery. in addition, to study the crural portion of the corpi cavernosi, the transducer is placed perineally (4). size, echogenicity (hyper, hypo, iso) and symmetry of the corpi cavernosi must be described and documented with appropriate images. any alterations of the tuniche, either echogenic or structural, must be documented by accurate measurements both on longitudinal and transverse scans. any palpable alteration or penile anomaly must be closely studied directly on the involved zone, documented by appropriate images. assessment of the vascular integrity is done by integrating color doppler (6). to study of the urethra (2, 5), hydrosoluble gel is injected through a catheter positioned at the level of the navicular fossa; longitudinal scans are done to study any alterations of the urethral lumen (7-9) . specific devices penile us is done in real time b-mode scanning, using a linear probe with a frequency of 7.5/10 mhz and more (10). penile echo color doppler penile echocolor doppler (1) is generally performed in the following cases: • erectile dysfunction [after intra cavernous injection (fic) of pge1). • peyronie’s disease. • to assess penile morphology and vascularization after trauma. • in cases of blood collection or infection. methodology assessment pre fic: • the investigation must be performed in calm surroundings avoiding outside interruptions. detailed explanation of the different phases must be given, as • grade 1: prolonged reflux in vessels in the inguinal channel only during valsalva’s manoeuvre, while scrotal varicosity is not evident in the previous grey-scale study. • grade 2: small posterior varicosity that reaches the superior pole of the testis and whose diameter increases after valsalva’s manoeuvre. the cdu evaluation clearly demonstrates the presence of a venous reflux in the supratesticular region only during valsalva’s manoeuvre. • grade 3: is characterised by vessels that appear enlarged to the inferior pole of the testis when the patient is evaluated in a standing position, while no ectasia is detected if the examination is performed in a supine position. cdu demonstrates a clear reflux only under valsalva’s manoeuvre. • grade 4: is diagnosed if vessels appear enlarged, even if the patient is studied in a supine position; dilatation increases in an upright position and during valsalva’s manoeuvre. enhancement of the venous reflux after valsalva’s manoeuvre is the criteria that allows the distinction between this grade from the previous and the next one. hypotrophy of the testis is common at this stage. • grade 5: is characterised by an evident venous ectasia even in an upright position. cdu demonstrates the presence of an important basal venous reflux that does not increase after valsalva’s manoeuvre. table 6. color doppler ultrasound (cdu) grading classification of varicocele. in accordance with sarteschi, varicocele can be divided into five grades according to the characteristics of the reflux and its length, and to changes during valsalva’s manoeuvre (24, 25). lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 72 73archivio italiano di urologia e andrologia 2014; 86, 1 practical recommendations for performing ultrasound scanning in the urological and andrological fields well as of the possible complications, obtaining written informed consent. • the basal study must include longitudinal and transverse scans to make an accurate study of the corpora cavernosa, corpus spongiosum, intercavernous septum, the morphology of the cavernous arteries, the gland and the urethra. the cavernous arteries are shown as parallel lines, fine and echogenic, and any anatomical variants, even lacking clinical significance (e.g. duplication of the cavernous artery must be documented) (2). fic: • single intracavernous injection of pge1 in basal cavernous site, at variable doses (2.5 mcg in young, psychogenic men with a high risk of priapism due to correlated disease) and if necessary redosing. remember that a state of anxiety in the patient could delay the effect of the drug. post fic assessment: • spectral doppler must be done at 0,5,10,15,20,25 and 30 minutes after fic at the level of the proximal third of the cavernous arteries and/or in crural site. • measurement of peak systolic velocity (psv), telediastolic velocity (tdv) and resistence index (ri) using an ideal spectral angle of 60°. • manual or visual stimulation is not usually necessary to obtain an adequate erection. • if the flowmetry result is considered adequate, the investigation can be interrupted before the measurements at 25 and 30 minutes. • after flowmetry it is useful to make a morphological study of the penile vascularization by power imaging, to assess the microcirculation, describing whether the helical branches are visible or not, and their angle of incidence on the cavernous artery (normally > 90°) (3). this method is also used to visualize traumatic lesions (4). • the dynamic phase after fic is also useful to study peyronie’s disease plaques, both in b-mode and color power imaging, as well as fibrosis, structural variations and any zones of venous leakage around the plaques. • describe the degree of erectile response in terms of tumescence and rigidity at 20/30 minutes after fic. diagnostic criteria: • b-mode: detailed description of the anatomical symmetry of the corpi cavernosi, fibrous septum, any plaques or calcifications of the intracavernous zone or tuniche, any hypoechogenic lesions. • arterial compartment: any increased diameter post fic, intravascular flow. values of psv > 35 cm/sec are considered normal in the literature, between 25 and 35 cm/sec “borderline”, that should be integrated with the degree of erectile response, values < 25 cm/sec are considered pathologic (5). • venous compartment: with an increased intracavernous pressure and so increased psv there is a decrease in tdv that may become negative with inversion of the diastolic wave, a sign of integrity of the venoocclusive mechanism. a persistence of tdv values > 5-7 cm/sec throughout all the phases of the test indicates a deficit of the venoocclusive mechanism. • it is important always to integrate flowmetry data with the degree of erectile response to fic because a poor rigidity (low dosage of pge1, a state of anxiety) and hence a minor arterial inflow will limit the degree of response of the venous compartment and hence the sensitivity and specificity of the test (6). • in the findings, note the patient’s psychoemotional approach to the test. after the test: • ascertain complete detumescence before the patient leaves, informing him of the possibility of a prolonged erection/priapism and the management of this complication, as well as how to obtain further assistance if necessary. • produce an accurate report with appropriate images both of the flowmetry and the morphology. tools high frequency 7.5 mhz or more linear transducer, us device equipped with color-power spectral doppler; high doppler frequencies are advisable (higher than 10 mhz) because they provide optimal resolution and facilitate the examination of intravasal flow (7). example of final report test performed with linear probe (7.5/10) mhz. test performed in basal conditions and after drug infusion of … mcg. of prostaglandins (pge1); patient gave written informed consent to the procedure. normal conformation of the corpi cavernosi, that appear symmetrical and of the corpus spongiosus of the urethra.; otherwise describe any alterations/irregularities of the tunica and septum, such as hyper-reflection, hyperechogenicity and any images suggesting induratio penis plastica. cavernous arteries present, with a twisted course, pulsating. after fic, increased volume of the corpi cavernosi with dilation and straightening of the cavernous arteries, that appear pulsating/non pulsating. erectile response to fic at ….minutes (poor/fair/good/excellent) for tumescence and rigidity with/without deviation of the penile axis (in cases of deviation describe whether it is dorsal, ventral or lateral, and the degree) grade of eas (erection assessment scale): 1 to 5 (no erectile response/full rigidity) flowmetry study performed in crural site: measurement of the systo-diastolic velocities with spectral doppler analysis at 5,10,15,20,25 and 30 minutes after fic. psv (peak systolic velocity) equal to ….cm/sec on left and …cm/sec on right at …minutes after fic showing normal/reduced arterial inflow. tdv (tele diastolic velocity) …cm/sec with/ without progressive reduction or with/without negativization of the diaslineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 73 archivio italiano di urologia e andrologia 2014; 86, 1 p. martino, a.b. galosi 74 tolic wave at 20/30 minutes after fic, showing integrity/deficit of the veno-occlusive mechanism. ir </=/> 1 phase 3 obtained at …minutes phase 4 obtained/not obtained at ….minutes morphological study performed with color power doppler: cavernous arteries morphologically normal, well distended and straightened. good/fair/poor visualization of the helicine branches by 1°,2°and 3° presenting an angle of incidence </> 90°, demonstrating integrity/deficit of the microcirculation (in cases of ipp) presence/absence of peri-plaque venous leakage at ….. minutes after fic there is/is not progressive penile detumescence. psychoemotional attitude to test: poor/fair/good images to include (not all are indispensable, depending on clinical picture) 1. two basic images. 2. six doppler spectral images with relative flowmetry values. 3. two images showing microcirculation. references introduction 1. documento siumb per le linee guida in ecografia. giornale italiano di ecografia (siumb editore) i.r. al vol. 8-n 4. december 2005: 2. aua, aium practice guideline for the performance of an ultrasound examination in the practice of urology, 2011. www.aium.org 3. linee guida sieog società italiana di ecografia ostetrico gine co logica, edition 2010. 4. bevelacqua jj. practical and effective alara. health phys. 2010; 98 (suppl 2):s39-47. 5. eeg kr, khoury ae, halachmi s, et al. single center experience with application of the alara concept to serial imaging studies after blunt renal trauma in children--is ultrasound enough?. j urol. 2009; 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(ed) color doppler us of the penis. springer, berlin heidelberg 2008, isbn:978-3-540-36676-8. acknowledgment we would like to thank mary v.c. pragnell, b.a., for language assistance. lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 77 archivio italiano di urologia e andrologia 2014; 86, 1 p. martino, a.b. galosi 78 correspondence coordinators pasquale martino, md (corresponding author) department of emergency and organ transplantation-urology i, university "aldo moro", bari, italy pasqualeluciomartino@libero.it andrea benedetto galosi, md division of urology, “murri” general hospital, asur marche, fermo, italy galosiab@yahoo.it authors marco bitelli, md urologist, rome, italy paolo consonni, md u.o. urologia casa di cura “s. maria”, castellanza (va), italy fulvio fiorini, md nefrologia soc azienda sanitaria ulss 18 rovigo, italy fiorini.fulvio@azisanrovigo.it antonio granata, md u.o. nefrologia e dialisi asp agrigento, agrigento, italy roberta gunelli, md u.o. urologia ospedale g.b. morgagni-l. pierantoni azienda usl di forlì via carlo forlanini, 34 forlì, italy giovanni liguori, md department of urology, university of trieste, ospedale di cattinara, trieste, italy silvano palazzo, md department of emergency and organ transplantation-urology i, university "aldo moro", bari, italy silvano.palazzo@alice.it nicola pavan, md urologist, trieste, italy vincenzo scattoni, md department of urology, university vita-salute, scientific institute san raffaele, milan, italy scattoni.vincenzo@hsr.it guido virgili, md department of urology, university of tor vergata, rome, italy guidovirgili@tiscali.it reviewers libero barozzi, md società italiana radiologia emergency, surgery and transplants department radiology unit s. orsola-malpighi university hospital via albertoni 10, bologna, italy michele bertolotto, md uco di radiologia, dipartimento di scienze mediche, chirurgiche e della salute, università degli studi di trieste, ospedale di cattinara strada di fiume 447, trieste, italy andrea fandella, md divisione urologica, casa di cura giovanni xxiii monastier (treviso), italy afandella@alice.it paolo rosi, md clinica urologica ed andrologica, university of perugia, perugia, italy uropg@unipg.it carlo trombetta, md member of esui-eau department of urology, university of trieste, trieste, italy trombcar@units.it lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 78 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 4344 original paper diagnostic and therapeutic utility of transrectal ultrasound in urological office prostatic abscess management: a short report from a single urologic center andrea fabiani 1, alessandra filosa 2, valentina maurelli 1, fabrizio fioretti 1, lucilla servi 1, mara piergallina 1, giovanni ciccotti 1, matteo talle’ 1, gabriele mammana 1 1 surgery dpt, section of urology, asur marche area vasta 3, macerata hospital, macerata, italy; 2 section of pathological anatomy, department of clinical pathology, area vasta 3, asur marche, macerata hospital, macerata, italy. objectives: prostatic abscess (pa) is an infrequent condition in the modern antibiotic era. the everyday use of transrectal ultrasound (trus) during diagnostic work-up and the widespread recurrence to prostatic biopsies may lead to an increase of pa diagnosis. in this short report we analyze the patients characteristics and the management of seven recent cases of pa diagnosed in our institution. materials and methods: the records of 7 patients admitted to our center for luts associated to septic fever or acute urinary retention, was prospectively collected. suspect of pa was done on digital rectal examination (dre) and confirmed by trus performed after urinary system ultrasound (uus) evaluation. patients were admitted to hospital only in case of septic signs. a sovrapubic (spc) or urethral catheter (uc) was placed depending on symptoms. a trus-guided aspiration of pa was performed with patient in lithotomic position, using a 18 gauge two-part needle, side/end fire needle access. patient was discharged with antibiotic therapy and followed up until complete resolution of the pa and symptoms. results: mean age was 62 years (range 24-82). two patients were diabetics and one was affected by the immunodeficiency acquired syndrome (hiv). in one case, pa was detected after a persistent fever post trus guided prostate biopsy. average prostate volume was 69 ml (range 19-118 ml). dre was able to diagnose pa only in 2 cases (29%), uus evaluation in 1 case (14%). all cases were confirmed by trus as hypo-anechoic areas with or without internal echoes in all patients. mean pa dimension was 3.64 cm (range 1.5-8). spc was placed in 3 cases (43%), uc in 3 patients (43%). only 1 patient refused catheterization. side fire needle aspiration was performed in all cases and in combination with end fire access in case of particular location of abscess cavities. second look was needed in 2 cases (29%). antibiotics were administered in all cases. the aspirated pus showed a positive culture for escherichia coli (43%), klebsiella pneumoniae (29%), pseudomonas aeruginosa (14%) and enterococcus faecalis (14%). pa resolution time mean was 9 days (range 3-24). conclusions: trus evaluation in case of persistent luts associated with fever or acute urinary retention is determinant in the diagnosis of pa. office or institutional management with trus needle aspiration is a good option in these cases. key words: prostatic abscess; trus; end fire probe; side fire access luts; uroseptic fever. submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. introduction prostatic abscess (pa) is an infrequent condition in the modern antibiotic era. nevertheless, the wide use of antibiotics in patients with lower urinary tract symptoms (luts) could be responsible of the growing pa incidence in the last years (1). the diagnosis may be difficult because at onset of the symptoms pa may mimic several other diseases of the lower urinary tract. simple interpretation of the clinical symptoms and digital rectal examination (dre) could be not able to make a diagnosis. the routine use of transrectal ultrasound (trus) evaluation in each case of luts associated to fever or predisposing factors for the development of pa may aid the clinician in the daily practice (2). in this short report we present data about seven patients diagnosed with prostatic abscess, discussing clinical findings, diagnostic criticisms and treatment results obtained by trus guided needle aspiration. material and methods we prospectively collected the clinical and instrumental data of a short series of 7 patients admitted from emergency department to our section of urology in macerata hospital for luts associated to septic fever and/or acute urinary retention in a 12 months period. at the urologic evaluation, the patients underwent to dre and systematically to trus after an urinary system ultrasound (uus) study. in case of confirmed suspect of pa, a sovrapubic (spc) or urethral catheter (uc) was placed depending on symptoms. a trus-guided needle aspiration of pa was performed with patient in lithotomic position, using a 18 gauge two-part needle, with a probe b-k type 8818 (bk medical, denmark), side/end fire needle access, without local anesthesia. all procedures were performed in an ambulatory setting. patients were admitted to hospital only in case of septic signs. the patients were discharged with antibiotic therapy and followed up with trus until complete resolution of the pa and symptoms. results diagnostic and management data are presented in tables 1 and 2. the figures show particular aspects of pa diagdoi: 10.4081/aiua.2014.4.344 presented at 19th national congress s ieun, fermo 2014 345archivio italiano di urologia e andrologia 2014; 86, 4 diagnostic and therapeutic utility of transrectal ultrasound in urological office prostatic abscess management nosis and treatment in same patients. mean age was 62 years (range 24-82). two patients were diabetics and one was affected by the immunodeficiency acquired syndrome (hiv). in one case, pa was detected after a persistent fever post trus guided prostate biopsy (24 biopsy cores). average prostate volume was 69 ml (range 19118 ml). dre was able to diagnose pa only in 2 cases (29%), uus evaluation in 1 case (14%). pa was confirmed by trus (both bi-plane and end-fire probe) as a hypo-anechoic areas with or without internal echoes in all patients. pa was located in transitional zone in 4 cases, peripheral zone was involved in 1 case. combined localization was observed in 2 cases. pa dimension mean was 3.68 cm (range 1.5-8). spc was placed in 3 case (43%), uc in 3 patients (43%). only 1 patient refused catheterization. side fire needle aspiration was performed in all cases. combination with end fire needle access was performed in four cases (57%) due to the localization of abscess cavities. second look was needed in 2 cases (29%). intravenous parenteral antibiotics (imipenem plus teycoplanine) was administered only in case of hospitalization (43%). in cases managed at home, a combination of 3-rd generation cephalosporine and aminoglycoside was administered. the aspirated pus showed a positive culture in all patients (escherichia coli n = 3, klebsiella pneumoniae n = 2, pseudomonas n = 1 and enterococcus faecalis n = 1). mean pa resolution time was 9 days (range 3-24). no patients died for this condition. discussion pa is a potential life threatening condition that, when not adequately treated, may progress to sepsis and death. thus, an accurate diagnostic and an efficient treatment are both required. in available scientific literature data about pa consisted in cases reports and there is no standardization of the diagnostic and therapeutic routine. in review articles, we found several reports discussing clinical presentation, diagnostic work up and therapeutic approach to pa. the summary of these individual experiences permitted to delineate some lines of action (3-4). first of all, we think that pa incidence will be increasing in the next years. in the modern antibiotic era incidence is estimated between 0.5% to 2.5% of diseases accompanying prostatic symptoms. we should expect a shift of the epidemiological profile of pa due to a widespread routine use of broad-spectrum antibiotics to patients with luts, without the investigation required (1), and to an increase in population longevity that lead to a further need to manage chronic illness, such as diabetes mellitus or chronic renal failure, promoting the infectious risk. also others diseases altering the immune system could be responsible, e.g. immunodeficiency patient age co-morbidities clinical presentation dre diagnostic + uus diagnostic * abscess location pathogen 1 61 bph fever post trus biopsies + tz k. pneumoniae (24 cores)* 2 70 bph luts and fever pz pseudomonas 3 68 dmnid fever * tz pz k. pneumoniae 4 24 infertility aur and fever after tz e.coli recurrent hematospermia 5 82 bph fever* tz e.coli 6 60 dmnid fever and aur tz enterococcus faecalis 7 69 hiv fever* + tz pz e. coli * hospitalization. bph: benign prostatic hyperplasia. dmnid: non insulin dependent diabetes mellitus. hiv: immunodeficiency acquired syndrome. aur: acute urinary retention. trus: transrectal ultrasound. dre: digital rectal examination. uus: urinary system ultrasound. tz: transitional zone. pz: peripheral zone. table 1. diagnostic findings of cases series. patient age prostate volume (ml)/ soprapubic catheter urethral catheter side fire (sf)/ second look time resolution abscess diameter (cm) positioned * positioned ° side fire + end fire needle aspiration + (days) (sfef) accesss 1 61 75 ml/3,9 cm * sf 7 2 70 71 ml/3,1 cm sf 5 3 68 69 ml/4,9 cm * sfef + 9 4 24 19 ml/2,1 cm ° sf 9 5 82 118 ml/8 cm ° sfef 6 6 60 68 ml/1,5 cm ° sfef 3 7 69 61 ml/2,3 * sfef + 24 sf: side fire access. sfef: combined accessside fire and end fire. table 2. technical management of cases. archivio italiano di urologia e andrologia 2014; 86, 4 a. fabiani, a. filosa, v. maurelli, f. fioretti, l. servi, m. piergallina, g. ciccotti, m. talle’, g. mammana 346 acquired syndrome (5). then, if we recognize that the abscess is a result of the retrograde flow of contaminated urine during micturition into prostatic ducts that promotes the formation of microabscesses that coalesce and form prostatic abscesses (6-7), the rate of this disease is certainly more important than what reported in the scientific literature. differential diagnosis between acute bacterial prostatitis and pa is difficult if based only on clinical symptoms and digital rectal examination (dre) (2) or lower abdominal ultrasound evaluation. the routine use of trus evaluation in each case of luts associated to fever or predisposing factors for the development of pa may aid the clinician in the daily practice (3). at dre prostatic abscess could be appreciate as a painful fluctuating area (4). in our short report this findings was observed in 2 cases. similarly, prostate lower abdominal ultrasound evaluation was able to pose the pa suspect only in 1 case in which the exam revealed an hypoechoic irregular area within prostate parenchyma suggesting the diagnosis confirmed by trus (figures 1a, 1b). in the other cases, abdominal ultrasound was unremarkable. in our experience trus showed to be an excellent tool in making the diagnosis. the most common finding is the presence of one or more hypo-anechoic areas, of several sizes, containing thick liquid and located in the transition zone and/or in central zone of the prostate, permeated by hyperechogenic areas and anatomical gland distortion. in our series these findings were variably observed in 100% of the cases. although other conditions could have a similar trus appearance, as neoplastic process, cystic lesions and granulomas (8-10), the trus appearance of pa is quite characteristic and can be differentiated on the basis of determined criteria (11). as reported in the literature, trus should also be considered the diagnostic study of choice to assist the treatment and follow-up of patients with prostatic abscess (12). figures 2a-2b show the results of trus guided needle aspiration at follow up of one patient. as observed in our cases, clinicians need to suspect pa in case of fever with luts especially in patients presenting with fever and persistent luts despite antibiotics use, for diabetics or immune-deficient men with protracted symptoms, for those with luts and fever progressing to urinary retention and after the performance of prostatic biopsy. in all scientific reports, diabetes mellitus and hiv infection are invariably referred as risk factors for the development of pa. in our series, a peculiarity was represented by case 4 (figure 3) that was a young patient (24 years old) who developed aur due to infectious enlargement of a midline cyst and was symptomatic for recurrent hematospermia, as revealed by clinical history taken at the moment of emergency evaluation. these results highlight the importance to investigate with trus younger patients with genito-urinary symptoms (13). in reference to prostate biopsy as risk factor of pa, it should be underlined that data from european randomized study of screening for prostate cancer (rotterdam section) (erspc) revealed growing evidence of increasing hospitalizations for serious infectious complications within 2 week of prostate biopsy (14). specifically, the authors found a 10% increase in the frequency of hospital admissions and most of these were for infectious complications figure 1a. bladder ultrasound: 68 years old, presented at our attention for persistent fever and prostatic abscess (*). figure 1b. transrectal ultrasound (end-fire probe) view of the figure 1a confirm a multisided prostatic abscess (*). figure 2a-b. trus evaluation (endfire probe) at follow up of patient in figures 1a-b, axial (a) and longitudinal (b). 347archivio italiano di urologia e andrologia 2014; 86, 4 diagnostic and therapeutic utility of transrectal ultrasound in urological office prostatic abscess management probably related to rising antimicrobial resistance. it is well known that men with prostatic enlargement and diabetes or major co-morbidities had an increased risk of febrile complications after prostate biopsy (15). these results highlight the importance of judicious patient selection for psa screening because these men may be less likely to benefit from early prostate cancer detection and also have a greater risk of complications from the diagnostic work-up. however, we considered that in case of patient number 1 of our series, neither prostate volume (57 ml) neither co-morbidities predicted pa onset, due to a multi resistant klebsiella pneumoniae. in our local experience with trus guided biopsies, on 1382 procedures performed in the last 6 years, we found only thissingle case of pa (0.07%) and 10 cases of hospitalizations for septic fever (0.72%) with 1 admission to intensive care unit. no deaths from this complication was observed (unpublished data). we can confirm that the frequency of hospital admission for septic fever after prostate biopsy is low (< 1%) (15). the problem is represented by the high level of antimicrobial resistance. we must take into consideration the use of a combination of 3-rd generation cephalosporine and aminoglycoside or imipenem and teicoplanine as better antibiotic therapy than traditional fluorquinolones. trus-guided needle aspiration is the method of choice for treatment of pa (16). the treatment options included also surgical intervention such as transurethral prostate incision (tuip), transurethral de-roofing (turp) or transperineal tube placement. turp is a more invasive approach and it is associated with several risks such as hemorrhage, retrograde ejaculation and sepsis. an alternative to simple aspiration could be the continuous drainage with a tube placed under trus guidance either by transperineal or transrectal route. however, this approach is fraught with a serious risk of developing a prostate-rectal fistula formation and prolonged hospitalization (17-18). tiwari et al. (19) reported 24 patients treated with transurethral de-roofing in 17 cases, transperineal needle aspiration trus guided in 3 cases. the remnants patients was managed conservatively. invasive treatment was applied in case of dimension of cavities abscess > 1 cm or multi-loculated. vias et al. (3) published one of the largest series of pa managed with trus-guided needle aspiration. of 48 patients, they report a 100% of diagnostic accuracy by trus and a success treatment rate of 85.42%, avoiding the risk of potential disadvantages of tur. the diameter “cut off” of cavities considered eligible for aspiration was 2 cm. in our short report, we confirm the high diagnostic accuracy (100%) of trus with a similar success rate. applying the dimensional cut-off proposed by vias, only two patient needed a second look aspiration due to the persistence of cavities within the prostate. no tur de-roofing was performed. in all cases, our trus follow up revealed a complete resolution of pa. technically, our trus guided needle aspiration consisted in the use of a biplane probe (6-12mhz, type 8818, bk medical, denmark) with a side fire needle access in all patients (figure 4). when pa was multifocal (four patients), especially in two cases in which cavities was located in the anterior zone of the prostate, we resorted to an end fire access (figure 5) in view of the potential increased capacity of this configuration, showed during prostate biopsies, to sample this anatomical area of the gland (20). we approached all cases with catheterization. suprapubic catheter was placed in three case. in one case, patient refused catheterization both urethral and suprapubic. also in this case the evolution of treatment was positive without need of ancillary procedures. figure 3. a midline prostatic utricle cyst after trus guided needle aspiration in young men with acute urinary retention. wall cyst presents small calcification. the surrounding right seminal duct is shown in figure 5. figure 4. trus guided aspiration with a biplane probe, side fire needle access. archivio italiano di urologia e andrologia 2014; 86, 4 a. fabiani, a. filosa, v. maurelli, f. fioretti, l. servi, m. piergallina, g. ciccotti, m. talle’, g. mammana 348 conclusions the diagnosis of prostatic abscess should be warranted for patients presenting with fever and persistent luts despite antibiotics use, for diabetics or immune-deficient patients with protracted symptoms and for those with luts and fever progressing to urinary retention and after the performance of prostatic biopsy. trus evaluation is determinant and mandatory for the diagnosis.. in our experience, office or institutional management with trus needle aspiration is a good option in all cases. references 1. granados ea, riley g, salvador j, vicente j. prostatic abscess: diagnosis and treatment. j urol. 1992; 148:80-2 2. oliveira p, andrade ja, porto hc, et al diagnosis and treatment of prostatic abscess int braz j urol. 2003; 29:30-4. 3. vias bj, ganpule sa, ganpule ap, et al. transrectal ultrasoundguided aspiration in the management of prostatic abscess: a singlecenter experience indian j radiol imaging. 2013; 23:253-257. 4. granados ea, caffaratti j, farina l, hocsman h: prostatic abscess drainage: clinical-sonography correlation. urol int. 1992; 48:358-61. 5. trauzzi sj, kay cj, kaufman dg, lowe fc. management of prostatic abscess in patients with human immunodeficience syndrome. urology. 1994; 43:629-33. 6. meares em, jr. prostatic abscess. j urol. 1996; 129:1281-2. 7. porfyris o, kalomoiris p. prostatic abscess: case report and review of the literature arch ital urol androl. 2013; 85,3:154-6. 8. galosi ab, parri g, lacetera v. et al. management of large prostatic abscess associated with urethral stenosis and penile cancer recurrence. arch ital urol androl. 2010; 82:181-5. 9. galosi ab, montironi r, fabiani a, et al. cystic lesions of the prostate gland: an ultrasound classification with pathological correlation j urol. 2009; 181:647-657. 10. hamper um, epstein ji, sheth s, et al. cystic lesions of the prostate gland: a sonographic-pathologic correlation. j ultrasound med. 1990; 9:395-402. 11. barozzi l, pavlica p., menchi i., et al. prostatic abscess: diagnosis and treatment. ajr am j roentgenol 1998;170:753-7 12. lee f jr, lee f, solomon mh, et al. sonographic demonstration of prostatic abscess. j ultrasound med. 1986; 5:101-2. 13. akhter w., khan f., chinegwundoh f. should every patient with hematospermia be investigated? a critical review cent european j urol. 2013; 66:79-82. 14. loeb s, van den heuvel s, zhu x, et al. infectious complications and hospital admissions after prostate biopsy in a european randomized trial eur urol 2012; 6 1:1110-14. 15. loeb s, carter hb, berndt si, et al. complications after prostate biopsy: data from seer-medicare. j urol. 2011; 186:1830-4. 16. lim jw, ko yt, lee dh, et al. treatment of prostatic abscess: value of transrectal ultrasonographycally guided needle aspiration. j utrasound med. 2000; 19:609-17. 17. aravantinos e, kalogeras n, zygoulakis n, et al. ultrasound – guided trasrectal placement of drainage tune as therapeutic management of patients with prostatic abscess. journal of endourology. 2008; 22:1751-4. 18. arrabal-polo ma, jimenez-pacheco a, arrabal-martin m. percutaneous drainage of prostatic abscess: case report and literature review. urol int. 2012; 88:118-20. 19. tiwari p, pal kd, tripathi a. et al. prostatic abscess: diagnosis and management in the modern antibiotic era. saudi j kidney dis transpl. 2011; 22:298-301. 20. galosi ab, tiroli m, cantoro d, et al. biopsy of the anterior prostate gland: technique with end-fire transrectal ultrasound. arch ital urol androl. 2010; 82:248-52. correspondence andrea fabiani, md (corresponding author) andreadoc1@libero.it valentina maurelli, md valentinamaurelli@hotmail.it fabrizio fioretti, md, phd fa.fioretti@libero.it lucilla servi, md lucilla.servi@sanita.marche.it mara piergallina, md mara.piergallina@tiscali.it giovanni ciccotti, md giovanni.ciccotti@sanita.marche.it matteo talle’, md matteo.talle@gmail.com gabriele mammana, md gabriele.mammana@sanita.marche.it surgery dpt, head of section of urology asur marche area vasta 3, macerata hospital, macerata, italy alessandra filosa, md, phd alessandrafilosa@yahoo.it section of pathological anatomy, department of clinical pathology, area vasta 3, asur marche, macerata hospital, macerata, italy figure 5. longitudinal view of patient in figure 3: trus guided aspiration with an endfire probe, endfire needle access. stesura seveso archivio italiano di urologia e andrologia 2014; 86, 4314 review pathological issues in biopsy specimens of men with prostate cancer eligible for active surveillance roberta mazzucchelli 1, andrea benedetto galosi 2, antonio lopez-beltran 3, marina scarpelli 1, liang cheng 4, rodolfo montironi 1 1 section of pathological anatomy, polytechnic university of the marche region, school of medicine, united hospitals, ancona, italy; 2 division of urology, “augusto murri” general hospital, asur marche, fermo, italy; 3 department of surgery, cordoba university medical school, cordoba, spain; 4 department of pathology and laboratory medicine, indiana university school of medicine, indianapolis, in, usa. active surveillance (as) is an important management option for men with lowrisk, clinically localized prostate cancer. the clinical parameters for patient selection and definition of progression for as protocols are evolving as data from several large cohorts become mature. vital to this process is the critical role pathologic parameters play in identifying appropriate candidates for as. these findings need to be reproducible and accurately reported by pathologists. repeated biopsy after initial diagnosis of prostate cancer is recommended before inclusion in active surveillance for early detection of significant cancer. key words: prostate cancer; prostate biopsy; active surveillance; tumour extent; immunohistochemistry. submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. often with psa kinetics and serial biopsy. any progression of the cancer while patients are monitored appears unlikely to threaten length of life (6). through this report we aim at facilitating dissemination of information on the critical role pathological parameters play in identifying appropriate candidates for as. clinical perspective on as specific inclusion criteria for as vary across institutions (7, 8). patients are selected for as on the basis of their age, psa density (psa/prostate volume), measures of psa kinetics, such as psa velocity, percent of positive biopsy cores, the extent of prostate cancer in any core, and gleason score 3 + 3 = 6 (9). some of these cohorts include patients with intermediate-risk clinical parameters, allowing for inclusion of patients with psa at diagnosis greater than 10 ng/ml or including selected men with gleason 3 + 4 = 7 pca. surveillance schedules for as are variable across institutions. most pca experts agree that surveillance should include a combination of serial psa and rectal examinations as well as repeat prostate biopsy. biopsy grade reclassification has emerged as a more meaningful endpoint for men on as. higher-grade tumors (gleason 7 and higher) clearly confer a higher likelihood of clinical progression. a finding of upgrading cancer on repeat biopsy commonly prompts treatment. this upgrading may represent undersampling at the time of initial diagnostic biopsy where the pre-existing highgrade prostate cancer was missed (10). tables 1 and 2 include, as an example, inclusion criteria, surveillance schedule and the definition of progression of three as protocols. repeated biopsy repeated biopsy after initial diagnosis of prostate cancer is recommended before inclusion in active surveillance, since repeated biopsy improves cancer grading and reduce the risk of undersampling of significant cancer. repeated biopsy should follow criteria of saturation doi: 10.4081/aiua.2014.4.314 presented at 19th national congress sieun, fermo 2014 introduction the overwhelming majority of men diagnosed with prostate cancer (pca) opt for primary curative therapy, such surgery to remove the prostate, i.e., radical prostatectomy, or radiation therapy to eradicate the tumor. however, most pcas are indolent and the number of newly diagnosed cases far outnumbering that of lethal cases (1). the magnitude of this so-called overdiagnosis, where cancers are identified that would never progress or cause harm to the patient if left untreated, ranges from 15% to 84% of new pca cases (2, 3). patients are exposed to the risk of overtreatment. even if overtreatment is avoided, overdiagnosis induces anxiety associated with the new cancer diagnosis, often resulting in further tests and expenses, and confers upon the patient a ‘cancer survivor’ label he carries for the rest of his life (4). male offspring may worry about familial inheritance and increased risk of the disease. given the indolent course of many pca detected by psa screening (5), active surveillance (as) has emerged as an initial management alternative, thus men avoiding the side effects of pca treatment. under most as strategies, patients undergo careful monitoring of the cancer, most mazzucchelli_stesura seveso 15/01/15 11:01 pagina 314 315archivio italiano di urologia e andrologia 2014; 86, 4 pathology in prostate cancer active surveillance biopsy (20 core or more based on prostate volume) (11). anterior gland should be included in the repeated biopsy. magnetic resonance imaging can be performed before re-biopsy since the negative predictive value for significant cancer raise 95%, however the positive predictive value is lower. men who experience early upgrading likely represent initial sampling error, whereas later upgrading may reflect tumor dedifferentiation. the role of the pathologist the essential reporting items for cancer containing prostatic needle biopsies are listed in table 3. tumor extent measurements and the gleason score are the most important pathologic parameters in needle biopsies determining eligibility for as protocols. tumor extent measurements there is no consensus on the best tumor quantification methods, which include: cancer percentage in each core, greatest percentage of cancer, cancer length in each core, greatest length of cancer (glc), total percentage of carcinoma in all cores, total length carcinoma in all cores, fraction of positive cores, total carcinoma surface area and total percentage of carcinoma surface area in all cores. tumor measurements are performed as a visual estimate or using an ocular micrometer or other morphometric measurement such as computerized methods. visual estimation of percentage without morphometric measurements is commonly performed, although many recent studies do not actually describe whether visual estimation or morphometric measurements were used. some use a regular ruler or the side graticule available on most microscopes for estimation of length and percentage. the knowledge of the diameter of the field at each magnification for the microscope used to measure tumor extent can also help maximize accuracy of visual estimation of length. in a recent abstract, mahamud et al. found no overall difference between visual estimation and measurement when determining percent involvement of prostate biopsies assessed only by whole slide images. however, there was a significant difference between the two methods when they considered a subset of cores deemed to have 40-60% involvement by visual estimation. it is unclear whether the accuracy of visual estimation of an image can be compared with that of a tissue core on a glass slide on a microscope. data are conflicting whether morphometric measurements are superior to visual estimation and whether differences in the two methods would affect clinical management. computerized morphometric measurements are considered time-consuming and not practical for most pathologists. measurements of core length given in gross descriptions should not be used as these may not always be accurate. a few studies have assessed the value of the different methods of tumor extent measurement in prostate needle biopsy in predicting pathological stage or prognosis. quintal et al. (12) found that total percentage of carcinoma in all cores and number and percentage of cores with cancer were significantly stronger than other methods inclusion criteria johns hopkins university of toronto prias n° of patients 870 453 2494 clinical stage t1c ≤ t2 psa density ≤ 0.15 ng/ml/cc ≤ 0.20 ng/ml/cc psa ≤ 15 ng/ml ≤ 10 ng/ml no. of +ve cores ≤ 2 ≤ 2 % cancer per core ≤ %50 gleason score ≤ 6 ≤ 7 (3+4) ≤ 6 surveillance schedule institutions psa and dre repeat prostate biopsy definition of progression johns hopkins every 6 months yearly gleason score > 6, or > 2 cores, or > 50% any core university of toronto every 3 months for 2 yrs, 6-12 months after diagnosis, psadt < 3 years then every 6 months then every 3-4 years prias every 3 months for 2 yrs 1, 4, 7 and 10 yrs gs > 6, or ≥ 3 positive cores, and then every 6 months after diagnosis or psadt < 3 yearly table 1. active surveillance inclusion criteria for selected institutions (see text). 1. location of positive cores 2. tumor extent 3. gleason grades and score 4. histologic type 5. other (reported only if present) • extraprostatic extension • perineural invasion • lymphovascular invasion • intraductal carcinoma 6. other atypical acinar foci suspicious for carcinoma table 3. essential reporting elements for cancer bearing prostatic needle biopsies. table 2. surveillance schedule and definition of progression for selected institutions (see text). mazzucchelli_stesura seveso 15/01/15 11:01 pagina 315 archivio italiano di urologia e andrologia 2014; 86, 4 r. mazzucchelli, a.b. galosi, a. lopez-beltran, m. scarpelli, l. cheng, r. montironi 316 such as greatest percentage of cancer or length in a single core in predicting biochemical recurrence. total percentage of carcinoma in all cores had the strongest correlation and when combined with preoperative psa and gleason score improved prediction of pt3 in multivariate analysis. this was also independent for risk of biochemical recurrence. bismar et al. (13) found that although many tumor measurements such as greatest percentage of cancer, total tumor length in millimeters, fraction of positive cores and total percentage of carcinoma were significant in univariate analysis, only the fraction of positive cores was significant in multivariate analysis in predicting pt3 disease or positive margins. in this study all the measures were highly related to one another in a formal correlation analysis. park et al. (14) examined the significance of the number of cores positive for cancer, percentage of positive biopsy cores, total linear cancer length, total percentage of carcinoma and maximum cancer core length and found that, when considering psa and gleason score, none were significant in predicting pt3 disease in multivariate analysis. in a study by brimo et al. (15), it was found that the fraction of positive cores, total percentage of carcinoma and both total and greatest cancer core length were closely associated with pathological stage and biochemical failure. the fraction of positive cores was found to be the factor most closely associated with pt3 disease in radical prostatectomy. correlating needle biopsy cancer measurements with tumor volume in radical prostatectomy, poulos et al. (16) found that the highest percentage of carcinoma in any biopsy site, percentage of adenocarcinoma at the biopsy site with the highest grading, the number of positive biopsy sites and tumor bilaterality were significant with the percentage of biopsy sites positive for disease the most significant predictor of tumor volume. in a study by lewis et al. (17), tumor volume was best predicted by a combination of linear extent of carcinoma and number of positive cores. in a survey sent to 93 genitourinary pathologists the extent of cancer on needle biopsies was quantified by all the respondents with 80% reporting the number of cores involved by cancer. linear extent was estimated by almost all, either as a percentage (80%) or millimeters of cancer length (41%) or both (22%). considering the tumor quantification methods actually requested by urologists, in a 2005 study, 95% french and belgian urologists requested the number of positive cores compared with 53% requesting length of cancer. in a study by rubin et al. (18) 30 67% of urologists requested the percent involvement of each core by cancer, 33%, the number of cores with prostate cancer and 29% the length of core involvement. recommendations by the college of american pathologists, association of directors of anatomic and surgical pathology and the world health organization for reporting carcinoma extent have been summarized. given these recommendations, the extent parameters currently in use in as protocols and the evidence from the literature, it is suggested that pathologists should report the absolute number of involved cores out of total number cores and the amount of cancer in the single core with the greatest amount of tumor expressed as the percentage involvement by carcinoma, with or without the linear extent of carcinoma in that core. percentage involvement by carcinoma and or linear extent of carcinoma in each positive core may also be provided. all other measurements are optional. linear extent of carcinoma in each core may also be provided. other measurements are optional. the extent of cancer in prostate needle biopsy cores in patients potentially candidates for as should based on the recording of: 1. number of positive cores/total number of cores. the number of positive cores could possibly affect subsequent therapy in terms of suitability for as, such that it is justified to perform an immunohistochemical work-up of additional atypical foci (either hmwck or p63 or combination of the two with amacr). 2. linear percentage of prostatic tissue involved and/or total linear measurement of carcinoma and total core length. this can be done calculating the percentage of each core involved by cancer, based on the linear length of cancer (mm) divided by the core length, then multiplied by 100. the other method is to provide a percentage estimate of involvement of each of the cores derived by visual estimation. it has been shown that the former is more accurate and reproducible when patients are evaluated for eligibility for an as protocol. problems associated with tumor extent measurements measuring discontinuous foci of cancer when measuring discontinuous foci of cancer on a prostate needle biopsy core, the pathologist has to specify presence of discontinuous foci, linear extent in aggregate of discontinuous foci, percentage involvement of the core, and the core length spanned by discontinuous foci. the following sentence is suggested as a template for the pathology report: “prostate biopsy core (length: 1.2 cm) with two discontinuous foci, measuring 1.5 and 1.2 mm (measuring 2.7 mm in aggregate), respectively, of gleason score 3 + 3 = 6 acinar pca separated by 4 mm of intervening benign tissue. the tumor spans 56% of the core length, involving 22% of the core”. tissue core and tumor fragmentation concerning the number of cores per cassette, the ideal would one core per cassette. two biopsies from the same location could be embedded together. it has been shown that simultaneous inclusion of 3 biopsies in the same cassette can lead to the loss of a mean length of 1.15 cm of assessable tissue which corresponds to the average length of one prostate biopsy. when multiple cores are submitted in a single cassette or jar by the urologist and processed in a single cassette, many pathologists give the overall percentage of cancer for the entire slide as opposed to the percentage for each individual core. at the pathology laboratory of united hospitals, ancona, we attempt to give the percentage of cancer per core for each individual positive core, regardless of how many cores are on a given slide. mazzucchelli_stesura seveso 15/01/15 11:01 pagina 316 317archivio italiano di urologia e andrologia 2014; 86, 4 pathology in prostate cancer active surveillance when reporting biopsies with multiple cores in the same jar, the pathologist has to provide linear measurement (in millimeters) or linear extent (as percentage) of prostatic tissue involved for the most involved core and the overall linear percentage or measurement in millimeters of tissue submitted from the site(s) with cancer. if there are multiple fragmented small cores containing cancer, an accurate assessment of percentage of cancer per core cannot be determined, and only an overall percentage of cancer per fragmented specimen can be noted. in this scenario, one cannot even determine with certainty the number of positive cores. there is evidence in the literature that there is a greater tendency to core fragmentation when > 1 core is submitted in a container. it is our experience that needle biopsies collected onto gauze or paper are more likely to fragment. assessment of number of cores involved by pca is difficult in the presence of core fragmentation. a comment should be made suggesting that the urologist/clinician obtaining the biopsy is in the best position to make determination of number of cores involved based on the original submission of number of cores, and, if necessary, to undertake clinico-pathologic correlation (19). minimum acceptable core length currently there is no definition for adequate or minimum acceptable core length. the percentage of cancer in a short core (e.g. < 5-10 mm) versus that in a sufficiently long core mean entirely different tumor lengths. this has implications for interpretation of percent core involvement in the setting of as. since percent core involvement is based only on total length of prostatic parenchyma, non-prostatic elements should not be included in total core length assessment. gleason score the previous decade has seen considerable change in practice relating to gleason grading of prostatic carcinoma, and in 2005 the international society of urological pathology (isup) undertook a major revision of the gleason grading system. this was designed to reflect current practice and to incorporate recently gained knowledge on the biology of prostate cancer. the isup 2005 modification of the gleason grading system has resulted in changes to the definitions of gleason patterns 3 and 4 tumors. this is of particular importance for those patients in which deferred treatment is contemplated, as grade is central to the criteria utilized for identifying patients suitable for inclusion in as programs. two features define gleason pattern 3 glands: clearly infiltrating glands (in contrast to the overall nodular configuration of glands in gleason patterns 1 and 2) and each gland being a single discrete individual glandular structure that is well formed. the 2005 isup modification of the gleason grading system defined virtually all cribriform glands as gleason pattern 4, although in this classification well circumscribed, small, ovoid to round cribriform glands with regular bridging were included in gleason pattern 3. more recently it has been suggested that as all cribriform glands appear to be associated with a less favorable prognosis; these glands should also be classified as pattern 4. glands with a glomeruloid architecture are also considered as pattern 4. using these criteria, classification as gleason pattern 3 should be confined to tumors consisting of well formed, separate glands with lumina. accurate distinction of gleason pattern 3 from gleason pattern 4 is critical for eligibility for most as protocols. when there is doubt, it is suggested: • defaulting to a lower grade, • following the focus on deeper serial sections, • sharing such borderline cases with a colleague as the presence of a gleason pattern 4 may preclude the patient from as. biopsy gleason grade reclassification has emerged as one of the most meaningful intervention criteria for men on as. situations that should exclude a patient from as the presence of perineural invasion does not represent an exclusion criterion. however, there are rare pathologic situations that should likely exclude a patient from as: • histologic types: prostatic adenocarcinoma with predominant ductal carcinoma histology, sarcomatoid carcinoma, small cell carcinoma • intraductal carcinoma without invasive carcinoma • extraprostatic extension in needle biopsy • lymphovascular invasion in needle biopsy. conclusions given the overdiagnosis and overtreatment of low risk prostate cancer, as should be a ubiquitously adopted and formalized strategy. men who experience early upgrading likely represent initial sampling error, whereas later upgrading may reflect tumor dedifferentiation. there are several issues and key questions that arise from the combined clinico-pathologic experience from formal and informal as treatment management strategies that would be applicable to the management of prostate cancer patients outside of academic centers and clinical trials. these need to be resolved over the next few years to tighten criteria of selection for patients contemplating as and their subsequent management. references 1. heidenreich a, bastian pj, bellmunt j, et al. eau guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent-update 2013. eur urol. 2014; 65:124-37. 2. carter hb, kettermann a, warlick c, et al. expectant management of prostate cancer with curative intent: an update of the johns hopkins experience. j urol. 2007; 178:2359-64. 3. dall’era ma, konety br, cowan je, et al. active surveillance for the management of prostate cancer in a contemporary cohort. cancer. 2008; 112:2664-70. 4. ercole b, marietti sr, fine j, albertsen pc. outcomes following active surveillance of men with localized prostate cancer diagnosed in the prostate specific antigen era. j urol. 2008; 180:1336-9. 5. roemeling s, roobol mj, de vries sh, et al. active surveillance for prostate cancers detected in three subsequent rounds of a screening trial: characteristics, psa doubling times, and outcome. eur urol. 2007; 51:1244-51. mazzucchelli_stesura seveso 15/01/15 11:01 pagina 317 archivio italiano di urologia e andrologia 2014; 86, 4 r. mazzucchelli, a.b. galosi, a. lopez-beltran, m. scarpelli, l. cheng, r. montironi 318 6. van as nj, norman ar, thomas k, et al. predicting the probability of deferred radical treatment for localised prostate cancer managed by active surveillance. eur urol. 2008; 54:1297-305. 7. dall’era ma, cooperberg mr, chan jm, et al. active surveillance for early-stage prostate cancer: review of the current literature. cancer. 2008; 112:1650-9. 8. van den bergh rcn, roemeling s, roobol mj, et al. prospective validation of active surveillance in prostate cancer: the prias study. eur urol. 2007; 52:1560-3. 9. klotz l. active surveillance with selective delayed intervention is the way to manage “good-risk” prostate cancer. nat clin pract urol. 2005; 2:136-42. 10. lacetera v, galosi ab, cantoro d, et al. transrectal ultrasound (trus) and trus-biopsy’s accuracy in potential candidates for prias active surveillance protocol but treated with immediate radical prostatectomy. arch ital urol androl. 2012; 84:4:272-275. 11. ploussard g, xylinas e, salomon l, et al. the role of biopsy core number in selecting prostate cancer patients for active surveillance. eur urol. 2009; 56:891-8. 12. quintal mm, meirelles lr, freitas ll, et al. various morphometric measurements of cancer extent on needle prostatic biopsies: which ispredictive of pathologic stage and biochemical recurrence following radicalprostatectomy? int urol nephrol. 2011; 43:697-705. 13. bismar ta, lewis js jr, vollmer rt, humphrey pa. multiple measures of carcinoma extent versus perineural invasion in prostate needle biopsy tissue in prediction of pathologic stage in a screening population. am j surg pathol. 2003; 27:432-40. 14. park hj, ha ys, park sy, et al. incidence of upgrading and upstaging in patients with low-volume gleason score 3+4 prostate cancers at biopsy: finding a new group eligible for active surveillance. urol int. 2013; 90:301-5. 15. brimo f, montironi r, egevad l, et al. contemporary grading for prostate cancer: implications for patient care. eur urol. 2013; 63:892-901. 16. poulos ck, daggy jk, cheng l. prostate needle biopsies: multiple variables arepredictive of final tumor volume in radical prostatectomy specimens. cancer. 2004; 101:527-32. 17. lewis js jr, vollmer rt, humphrey pa. carcinoma extent in prostate needle biopsy tissue in the prediction of whole gland tumor volume in a screening population. am j clin pathol. 2002; 118:442-50. 18. rubin ma, bismar ta, curtis s, montie je. prostate needle biopsy reporting: how are the surgical members of the society of urologic oncology using pathology reports to guide treatment of prostate cancer patients? am j surg pathol. 2004; 28:946-52. 19. galosi ab, muzzonigro g, lacetera v, mazzucchelli r. specimen orientation by marking the distal end: (potential) clinical advantages in prostate biopsy. prostate cancer. 2011; 2011:270403. correspondence roberta mazzucchelli, md r.mazzucchelli@univpm.it marina scarpelli, md m.scarpelli@unvpm.it rodolfo montironi, md (corresponding author) r.montironi@univpm.it pathological anatomy, polytechnic university of the marche region, school of medicine, united hospitals, via conca 71, i−60126 torrette, ancona, italy andrea benedetto galosi, md galosiab@yahoo.it division of urology, “augusto murri” general hospital, asur marche fermo, italy antonio lopez-beltran, md em1lobea@gmail.com department of surgery, cordoba university medical school cordoba, spain liang cheng, md linag_cheng@yahoo.com department of pathology and laboratory medicine, indiana university school of medicine, indianapolis, in, usa mazzucchelli_stesura seveso 15/01/15 11:01 pagina 318 stesura seveso 39archivio italiano di urologia e andrologia 2014; 86, 1 case report penile fracture: penoscrotal approach with degloving of penis after magnetic resonance imaging (mri) gabriele antonini 1, patrizio vicini 3, salvatore sansalone 4, giulio garaffa 4, antonio vitarelli 5, ettore de berardinis 1, magnus von heland 1, riccardo giovannone 1, emanuele casciani 2, vincenzo gentile 1 1 department of urology, “sapienza” rome university, rome, italy; 2 department of radiology, “sapienza” rome university, rome, italy; 3 department of urology, “i.n.i.” italian neurotraumatologic institute grottaferrata, rome, italy; 4 department of experimental medicine and surgery, “tor vergata” rome university, rome, italy; 5 department of urology, bari university, bari, italy. fracture of the penis, a relatively uncommon emergency in urology, consists in the traumatic rupture of the tunica albuginea of the corpus cavernosum. examination and clinical history can be highly suspicious of penile fracture in the majority of cases and ultrasonography (uss) can be useful to identify the exact location of the tunical rupture, which is proximal in 2/3 of cases and therefore manageable through a penoscrotal approach. although expensive and not readily available in the acute setting, magnetic resonance imaging (mri) may play a role in the differential diagnosis with rupture of a circumflex or dorsal vein of the penis or when the tunical rupture is not associated with tear of the overlying buck’s fascia. this form of imaging is more sensitive than uss at identifying the presence of a tunical tear. the treatment of choice is immediate surgical repair, which allows preserving erectile function and minimizing corporeal fibrosis. key words: penile fracture; magnetic resonance imaging (mri); ultrasonography; fibrosis; erectile dysfunction. submitted 13 february 2014; accepted 28 february 2014 summary introduction fracture of the penis, which consists in the traumatic rupture of the tunica albuginea of the corpus cavernosum, is a relatively uncommon emergency in urology and it may be associated with urethral trauma in 1% to 38% of cases. it usually occurs when the erected penis hits the female pelvis during enthusiastic sexual intercourse. as the thickness of tunica albuginea decreases from 2 mm in the flaccid state to 0.25 mm during the erect state, a sudden increase in intracorporeal pressure due to blunt trauma during an erection could easily result in a rupture. all penile fractures occur on the shaft penis and in 2/3 of cases the tear is located at the level of the penoscrotal junction. no conflict of interest declared although trauma during intercourse is the most common cause of penile fracture in the western world, penile selfmanipulation to stop erection is the most common etiology in the middle east and the persian gulf (1-8). accurate history taking and clinical examination represent the mainstay in the diagnosis of penile fracture. typically the patient reports a “popping” sound followed by immediate detumescence. generally the penis appears diffusely swollen; if buck’s fascia is breached, a diffuse hematoma is visible on the penis (“eggplant deformity”) and may extend to the scrotum, groin and perineum (the “butterfly sign”). early surgical exploration is paramount to guarantee the preservation of the erectile function, to minimize the formation of corporeal fibrosis and to identify and repair an associated urethral rupture. although several reports suggest that diagnostic investigations, add little information to the clinical diagnosis, add extra costs to the treatment and potentially can delay surgery, penile ultrasonography (uss) is promptly available, reasonably cheap and allows to identify the exact location of the tunical tear (9). magnetic resonance imaging (mri) is not frequently performed, as uss can provide all the necessary information and may not be available in the out of hour settings. however, it guarantees superior image quality and allows better differentiating between penile fracture and other conditions such as rupture of the deep dorsal vein or circumflex veins, which produce a penile hematoma similar to the one present in case of tunical tear, but do not require surgical treatment. mri is also an adjunctive tool in the evaluation of atypical presentation of a suspected penile fracture, as has the ability to identify disruption of the corpus cavernosum due to excellent tissue contrast and visualization of soft tissue pathological processes (10). over the last 3 decades, management of penile fracture has progressively shifted from a conservative approach to early surgical repair, as non surgical management was associated with the formation of fibrosis of the corpora cavernosa and led invariably to a degree of curvature and erectile dysfunction (4). surgical treatment aims at repairing the torn tissue of tunica albuginea. although adequate expodoi: 10.4081/aiua.2014.1.39 antonini cr_stesura seveso 26/03/14 10:21 pagina 39 archivio italiano di urologia e andrologia 2014; 86, 1 g. antonini, p. vicini, s. sansalone, g. garaffa, a. vitarelli , e. de berardinis, m. von heland, r. giovannone, e. casciani, v. gentile 40 sure of the penile shaft can be achie ved through a subcoronal circumferential incision, 2/3 of penile fractures occur in the proximal third of the shaft and these pa tients would be the refore better ser ved with a pe no scrotal approach (7, 8). furthermore, de glo ving a bruised edematous penis can be quite challenging and a circumcision would be required to prevent preputial complications. imaging can be extremely helpful for the surgeon in order to identify distal fractures, which require a degloving, from proximal fractures, which can be easily dealt with through a penoscrotal approach. discussion penile fracture occurs during erection, as the expansion of the corpora stretches the tunica albuginea and renders it thinner and more vulnerable to trauma. although the diagnosis of penile fracture is often based on history and physical examination, imaging can be particularly useful when the clinical picture is not fully clear and when planning the type of surgical approach. among the radiological investigation, uss is the most widely used, as it is readily available and relatively inexpensive. however, although this form of imaging is highly specific in detecting a fracture, it is not very sensitive for detecting a cavernosal tear (6, 8, 9). on the contrary, mri scan of the penis is highly sensitive at detecting the exact location of the tunical tear and allows the surgeon to chose the best surgical approach. therefore, although more expensive and not always readily available in the acute setting, mri should be considered the gold standard diagnostic investigation in case of suspected penile fracture.although penile degloving is the most commonly used surgical approach, as it allows visualizing and inspecting adequately all the corpora cavernosa and urethra, it can be very morbid, due to the presence of diffuse bruising and edema of the dartos fascia. as 2/3 of fractures occur all the way down on the proximal aspect of the shaft, a complete degloving becomes an unnecessary procedure, as a penoscrotal approach would guarantee adequate exposure in these patients (7, 8). magnetic resonance imaging or uss of the penis play therefore a pivotal role for the identification of the exact location of the tear and therefore allow the surgeon to adequately choose the most appropriate surgical approach. surgery should be immediate, in order to preserve as much cavernosal tissue as possible and to minimize the formation of corporeal fibrosis, which would lead to ed, penile shortening and curvature (3-5). although patient history and clinical examination are highly sensitive and accurate in predicting the presence of a penile fracture, diagnostic imaging such as mri and uss of the penis can be very useful to confirm the diagnosis and to identify the exact location of the tunical tear and to plan the type of surgical approach (9). when readily available, mri should be the first choice modality of investigation due to its superior sensitivity in detecting tunical injuries (9). references 1. garcía gómez b, romero j, villacampa f, et al. early treatment of penile fractures: our experience. arch esp urol. 2012; 65:684-688. 2. murray ks, gilbert m, ricci lr, et al. penile fracture and magnetic resonance imaging. int braz j urol. 2012; 38:287-8. 3. wen j, li hz, ji zg, li hj. immediate surgical intervention for penile fracture: a case report and literature review. chin med sci j. 2011; 26:132-4. 4. garaffa g, raheem aa, ralph dj. penile fracture and penile reconstruction. curr urol rep. 2011; 12:427-31. 5. hatzichristodoulou g, dorstewitz a, gschwend je, et al. surgical management of penile fracture and long-term outcome on erectile and voiding. j sex med. 2013; 10:1424-30. 6. choi mh, kim b, ryu ja, et al. mr imaging of acute penile fracture. radiographics. 2000; 20:1397-405. 7. ozcan s, akpinar e. diagnosis of penile fracture in primary care: a case report. cases j. 2009; 2:8065. 8. srinivas bv, vasan ss, mohammed s. a case of penile fracture at the crura of the penis without urethral involvement.indian j urol. 2012; 28:335-337. 9. agarwal mm, singh sk, sharma dk, et al. fracture of the penis: a radiological or clinical diagnosis? a case series and literature review. can j urol. 2009; 16:4568-4575. 10. koifman l, barros r, júnior ra, et al. penile fracture: diagnosis, treatment and outcomes of 150 patients. urology. 2010; 76:1488-92. case report and figures are posted in suppementary materials on www.aiua.it. correspondence gabriele antonini, md ettore de berardinis, md magnus von heland, md riccardo giovannone, md vincenzo gentile, md department of urology, “sapienza” university. rome, italy emanuele casciani, md department of radiology, “sapienza” university, rome, italy patrizio vicini, md (corresponding author) patriziovicini@gmail.com department of urology, “i.n.i.” italian neurotraumatologic institute grottaferrata, rome, italy salvatore sansalone, md giulio garaffa, md department of experimental medicine and surgery, “tor vergata” university, rome, italy antonio vitarelli, md department of urology, bari university, bari, italy figure. magnetic resonance imaging with gadolinium showing the interruption of tunica albuginea at the level of the proximal third of right corpus cavernosum without urethral involvement. antonini cr_stesura seveso 26/03/14 10:21 pagina 40 stesura seveso 359archivio italiano di urologia e andrologia 2014; 86, 4 original paper penile fracture: retrospective analysis of our case history with long-term assessment of the erectile and sexological outcome nicola pavan 1, giorgia tezzot 1, giovanni liguori 1, renata napoli 1, paolo umari 1, michele rizzo 1, giovanni chiriacò 1, gaetano chiapparrone 1, francesca vedovo 1, michele bertolotto 2, carlo trombetta 1 1 urology department, cattinara hospital, university of trieste, italy; 2 radiology department, cattinara hospital, university of trieste. objectives: to review the cases of patients with suspected penile fracture and asses erectile and sexological outcomes. materials and methods: from 1987 to 2013 presented to the urology clinic of trieste and at the aied of pordenone a total of 41 cases that were divided into two groups according to the timing of treatment: 18 patients with anamnestic diagnosis of penile fracture treated nonimmediately and 23 patients treated immediately after the trauma. for all patients we evaluated the type of treatment adopted, the occurrence of complications and reoperations and the follow-up. the erectile function was also evaluated through the iief, as well as the psychological impact of the trauma on social and sex life, using a psycho-sexological questionnaire. results: among patients treated immediately after the trauma 14 were subjected to surgery. about a year after surgery, penile curvature was reported in 1 patient, pain in 3 patients, urinary disorders in 1 patient, while none reported erectile dysfunction (ed). out of these, only 3 patients underwent reoperation. among those treated conservatively 1 patient reported curvature, 1 patient reported pain and none reported ed. among patients who were admitted at a later date, 14 reported curvature and 4 reported pain whereas urinary disorders were reported in 1 and ed in 4 patients. from a psychological point of view, the trauma caused in most cases a fear of new trauma and of repercussions on erectile function and sensitivity. conclusions: the diagnosis is mainly clinical; however, radiological investigation is essential to confirm the diagnosis, assess the site and extent of the trauma and possible urethral involvement, so as to plan the most appropriate treatment. in addition, immediate treatment leads to better long-term results, with a lower incidence of ed and penile curvature. psychologically, penile trauma intensifies the fear of reoccurrence; it decreases, however, with the passage of time. key words: penile fracture; outcomes; penile surgery; penile ultrasound; erectile deficiency. submitted 4 september 2014; accepted 31 october 2014 summary no conflict of interest declared. introduction the penile fracture is a more or less extensive lesion of the tunica albuginea and the underlying corpora cavernosa. usually the lesion involves only a cavernous body, but in some cases both can be damaged (1, 2). in 20-30% of cases, the tear can extend to the spongy body, resulting in the partial or complete rupture of the urethra (3-5). it is considered a rare urological emergency: an incidence of about 1 in 175,000 has been estimated (2). the incidence, however, is certainly underrated because many patients do not seek medical care for the embarrassment of the condition and/or are often reticent to tell the truth about the cause of the trauma (6, 7). instead, admission to hospital after months from injury is frequent, due to the onset of late complications. in literature, most cases are reported in the middle east and north africa (8, 9) where the frequency of the disease is 10 to 100 times higher than in europe or north america. the incidence of associated urethral injury is instead significantly greater in the united states and europe, reaching 20% of cases, compared to asia, the middle east and north africa where it is 3% (6, 10, 11). the lesion usually occurs during erection when the albuginea is in tension, and its thickness is reduced to a minimum. the most frequent causes of penile lesion are related to the geographical areas considered. in western countries the most common cause is sexual intercourse (6, 12-14), particularly vigorous, with the penis stroking the bony structures of the pelvis, in 30-50% of cases (6). in middle eastern countries and in north africa (8, 9, 15-18) fractures are almost always due to handling or masturbation, as a custom widespread in these regions, called "taqaandan", a maneuver which consists of bending upwards, downwards or sideways, suddenly and vigorously, a part of the penis in erection, keeping the other part in place, to facilitate the detumescence (8, 9). the diagnosis of fractures of the penis is clinical, based on history and physical examination. as a rule, the patient's presentation at the health facilities occurs in the acute phase. the age varies between 12 and 82 years with an average that is concentrated in the fourth decade. doi: 10.4081/aiua.2014.4.359 presented at 19th national congress sieun, fermo 2014awarded as first sieun article prize pavan_stesura seveso 16/01/15 10:50 pagina 359 archivio italiano di urologia e andrologia 2014; 86, 4 n. pavan, g. tezzot, g. liguori, r. napoli, p. umari, m. rizzo, g. chiriacò, g. chiapparrone, f. vedovo, m. bertolotto, c. trombetta 360 the symptoms of the penile fracture are various. patients commonly refer to hearing a sudden clicking sound at the time of the injury, which is comparable to the noise of a bar of glass that breaks (6, 20), usually also felt by the partner (21-23). the intensity of the pain, however, is highly variable from patient to patient, and is not directly proportional to the size of the lesion (20, 24). it is characterized by quick detumescence accompanied by the appearance of swelling, with or without bruising and deformation of the integument of the shaft. following the fracture a hematoma is formed; the fascial layers of the genitals determine the distribution and extent of the extravasation: if buck's fascia remains intact, the extravasation is confined along the penile shaft with typical ovoid "eggplant" distribution; if buck's fascia is involved, extravasation will expand to the limits of the colles band resulting in a "butterfly-like" perineal hematoma due to involvement of the scrotum, perineum and the suprapubic area (8, 22, 25-29). the fracture of the corpora cavernosa may be associated with rupture of the corpus spongiosum of the urethra (approximately 10-20% of cases) (24). usually this occurs when there is an extended penile trauma involving both corpora cavernosa. the history and physical examination of the patient with penile fracture usually makes the use of radiological investigations unnecessary. in any case, the x-ray imaging may be required, especially in patients with atypical clinical presentation (1). the doppler ultrasound (ecd) is a non-invasive investigation, inexpensive and easy to perform and therefore considered by some authors the radiological investigation of choice in cases of penile trauma. there is also growing evidence of the use of ultrasonography for the evaluation of urethral injury (30). an indirect sign of urethral injury is the presence of air in the corpora cavernosa (31). the magnetic resonance imaging (mri) is the most accurate test in diagnosing a fracture of the penis due to its high contrast resolution between tissues and the ability to identify the pathological processes of the soft tissues (32, 33). however, it is not widely used because of high costs and long execution times. conservative treatment was considered the conduct of choice in case of penile fracture (22, 34). however, several studies comparing the long-term results of conservative treatment with the surgical one have demonstrated the superiority of the latter in terms of late complications, in particular the appearance of curvature and erectile dysfunction, better results and shorter hospitalization time (19, 24). therefore, currently immediate surgery is considered the treatment of choice. it allows the evacuation of the hematoma with hemostasis of the blood vessels (21, 35, 36), the proper cleaning of the injured area and the suture of the albuginea (22, 37). the surgery also consists of exploration of the urethra with possible stenting (37, 38) or suture of the urethral wound with end-to-end anastomosis (39). one of the most frequent complications is the penile curvature, secondary to the fibrosis at the site of the trauma; it has been estimated to affect more than 10% of patients with conservative treatment, percentage reduced to less than a half in patients who undergo surgical treatment (9). the incidence of plaque formation similar to those of la peyronie disease (induratio penis plastica), abscesses and penile tissue necrosis reaches up to respectively 25% and 30% in patients treated conservatively. materials and methods in this retrospective study were included all patients with suspected penile fracture that, from january 1987 to june 2013, were admitted to the urology clinic at the hospital of trieste and the urology ambulatory of associazione italiana per l’educazione demografica (aied) in pordenone. a total of 41 patients were examined, then divided into two groups on a clinical basis (signs and symptoms of acute trauma and post-traumatic long-term complications) and according to the time elapsed between the occurrence of the trauma and the urologic evaluation: • group 1 (g1): 23 patients referred from the emergency department with a clinical diagnosis of penile fracture, treated "acutely" or shortly after the trauma (hours-days); • group 2 (g2): 18 patients with anamnestic diagnosis of penile fracture, treated at a distance of time from the trauma for the onset of complications (months). each patient was evaluated in the following manner: 1. cause of the trauma; 2. clinical presentation (signs and symptoms); 3. radiological imaging (performed or not, type, reliability); 4. site of the lesion; 5. urethral involvement; 6. type of treatment adopted (surgical or conservative); 7. complications in the short and long term; 8. reinterventions; 9. follow-up one year after the first visit; 10.international index of erectile function (iief) 15 preand post-trauma; 11.psychological impact of the trauma on the social and sex life of the patient one year after the trauma, evaluated by psycho-sexological questionnaire created “ad hoc” (satisfaction during sexual intercourse, sexual habits, fear and feelings before and after the trauma, coital pain, interpersonal relationships/anxiety before and after the trauma). the patients of g1 were subdivided into two subgroups according to the type of treatment adopted (surgical/conservative). for the surgically treated patients, the following data were also taken into consideration: 1. type of surgery; 2. incision; 3. suture (albugineal, buck's fascia, urethral, dermal); 4. catheter; 5. drainage; 6. dressing and medication. most of the data (points 1 to 9) were collected from the analysis of medical records in the general archive and the g2 system of insiel for patients consulted in trieste, and from internal archives of patients consulted at the aied of pordenone. since the follow-up data resulted often incomplete, patients were contacted via telephone pavan_stesura seveso 16/01/15 10:50 pagina 360 and/or e-mail and invited to the urology clinic of the hospital of cattinara in trieste, for an andrological examination. on this occasion it was decided to administer the iief 15 questionnaire and also a psycho-sexological questionnaire, which was created specifically after specialist consultation in order to assess the psychological impact of the trauma on the social and sex life of the patient one year after its occurrence. a total of 9 patients of those contacted joined the study. in g1, the diagnosis of penile fracture was made on a clinical basis, with the exception of two cases with atypical presentation, in which radiological imaging was used, in one case, and surgical exploration, in the other. in more than half of the patients, both to confirm the diagnosis and to evaluate the extent of damage and then decide the most suitable treatment for the situation, radiological examinations were performed (penile ecd in 16 cases; cavernography in 2 cases one intraoperative; mri of the lower abdomen in 3 cases, always in association penile ecd). based on clinical and imaging findings, 3 patients were found to be false positives. of the 5 patients with suspected tear in the tunica albuginea with concomitant urethral injury, all patients except one reported hematuria. in the latter case, the radiological imaging result was negative, but the surgery confirmed the diagnosis of urethral involvement. uretrography was not performed in any of the cases in order to confirm the diagnosis of urethral injury, unlike what is reported in literature. in 5 cases, a conservative approach was adopted. of the remaining patients, 14 underwent surgical exploration with evacuation of the hematoma, suture of the albugineal laceration and eventual closure of the urethral gap, while one patient refused surgery. to patients undergoing conservative treatment medical therapy was set, variable from case to case, consisting mostly of antibiotics, antiinflammatory drugs, and heparin cream for topical use, ice bags, compression bandages, and anti-androgens. in all cases, a one-month long abstinence from sexual intercourse was recommended. 3 of the 5 patients with lesion of the tunica albuginea associated with suspected urethral injury were candidates for repair surgery and the diagnosis was confirmed during surgical exploration. patients in g2, with anamnestic trauma and admitted for onset of late complications, have been investigated by medical history and physical examination and subsequently with radiological examinations (dynamic penile ecd in 9 cases; cavernography in 2 cases; ecd + cavernography in 3 cases; mri of the lower abdomen + ecd in 1 case; ecd + cavernography + mri in 1 case), which confirmed previous trauma to the corpora cavernosa. of these 18 patients, 5 were submitted to surgery for the appearance of curvature: in 2 cases corporoplasty for straightening according to the technique of nesbit was performed; in 1 case the technique of yachia was employed and in 2 cases patches were used (lyophilized dura patch in one patient, and a venous patch from the right saphenous vein in the other patient). in order to assess the impact of the fracture on the erectile function and other areas of sexual function, and since the study was retrospective, the patients were asked to fill out two iief 15 questionnaires (international index of erectile function): one in reference to the period before the trauma, the other in reference to the year following the penile fracture. to complete the assessment of the impact of penile trauma on social life and sex life of the patient, an ad hoc questionnaire was drawn up with the help of a sex therapist, in order to be understandable and completed by the patient himself. with this questionnaire, we tried to investigate the possible difference in satisfaction during sexual relations between preand posttrauma, the position taken during fracture in cases of post-coital trauma, possible changes in sexual habits and numerical differences in sexual and/or emotional relationships after the trauma (qualitative analysis with yes/no answers). in addition, the following aspects were evaluated quantitatively by using 7-point likert scales: fear (of a new trauma, of repercussions on erectile function, of losing sensitivity, of pain during intercourse), penile sensitivity, pain during sexual intercourse, anxiety (in social relations, of performance, of position). results a total of 41 patients were included in the study, of which 23 belonging to g1 and 18 to g2. in g1 the average age was 40.2 years (range: 26-65) with a prevalence of cases in the third decade (8/23: 34.7%); in g2, the average age was 42 years (range: 23-62) with a prevalence of cases in the fifth decade (5/18: 27.8%). the two groups are therefore age-homogenous. a detailed summary of the characteristics of patients, symptoms, diagnosis and intraoperative findings is described in table 1. diagnosis of penile fracture in g1 the diagnosis of penile fracture was suspected in 23 cases, of which 20 (87%) had a typical clinical presentation (hematoma, swelling, pain, detumescence, noise). in two of these patients (10%), however, the diagnosis was not confirmed by radiological examinations (negative ecd), which therefore were considered to be false positives (fp). in the 3 cases (13%) with atypical clinical appearance (pain, detumescence, urethral bleeding), the diagnosis of penile fracture was confirmed in only 2 patients (66.7%), one case with surgical exploration and the other with radiological imaging, the third resulting therefore fp. thus excluding from the total count the three fp cases, overall the penile fracture was diagnosed in 20/23 (87%) patients. the diagnosis was clinical in 18/20 (90%) cases and radiological imaging was performed in 14/20 (70%) (10/14 ecd, 1/14 ecd + cavernography, 3/14 ecd + mri), which in 13/14 (92.9%) of the patients confirmed the diagnosis of penile fracture, while 1/14 (7.1%) cases was negative (negative ecd). in the latter case, the diagnosis of penile fracture was confirmed by surgery. 14 of 20 patients (70%) underwent surgical exploration; one patient refused the recommended surgery, while 5 of 20 patients (25%) were treated conservatively. the decision for surgical repair was made on the basis of clinical findings and imaging of the extent of the damage, in cases in which it was performed. 361archivio italiano di urologia e andrologia 2014; 86, 4 penile fracture: retrospective analysis of our case history with long-term assessment of the erectile and sexological outcome pavan_stesura seveso 16/01/15 10:50 pagina 361 archivio italiano di urologia e andrologia 2014; 86, 4 n. pavan, g. tezzot, g. liguori, r. napoli, p. umari, m. rizzo, g. chiriacò, g. chiapparrone, f. vedovo, m. bertolotto, c. trombetta 362 in all cases of g2, i.e. 18 patients, the diagnosis was based on remote case history and clinical presentation. we performed a radiological examination in 16 of 18 patients (88.9%) (9/16 ecd, 2/16 cavernography, 3/16 ecd + cavernography, 1/16 ecd + mri, 1/16 ecd + cavernography + mri) confirming the diagnosis of penile fracture in 16/16 (100%) of the cases. five of 18 patients (27.8%) were submitted to surgery and in all cases, corporoplasty was performed for straightening of the penile curvature. even in this case, the decision for the corrective action was taken based on clinical and imaging findings. patients with urethral lesion the urethral involvement associated with the laceration of the tunica albuginea was diagnosed in 5/20 (25%) patients in g1. in 4 (80%) cases, the cause of the trauma was sexual intercourse, while in 1 (20%) case it was non assessable. four of these 5 patients (80%) reported urethral bleeding; one out of five (20%) had no suggestive signs or symptoms of urethral injury and even the x-ray imaging (ecd) resulted negative, a fact contradicted by the surgical findings. of the 16 patients with unilateral rupture of the tunica albuginea, 1 also had a urethral laceration (6.3%) and 4/4 (100%) of the patients with bilateral rupture of the albuginea had a concomitant urethral injury. three of 5 (60%) patients with suspected urethral involvement associated with rupture of the tunica albuginea underwent surgical treatment with simultaneous suturing of the tunica and the urethral mucosa; in 3/3 (100%) of the cases the urethral rupture was confirmed by surgical exploration. among patients treated surgically only one reported post-operative urinary disorders. this patient complained of recurrent urinary tract infections and difficulty in urination; through targeted radiological investigations (voiding cystourethrogram and ecd), he was diagnosed with a urethral stenosis due to the presence of a foreign body granuloma (suture). the patient was re-operated for the removal of the granuloma. two of 5 patients (30%) with suspected urethral trauma treated conservatively showed no complications during the follow-up. of the 18 patients in g2 none had concomitant urethral involvement, as confirmed by the clinical appearance (due to the absence of urethral bleeding in all cases), and by imaging findings. follow-up of patients in acute care immediately after the trauma of the 20 patients receiving acute care immediately after the trauma (g1), 14 underwent surgery; no patients (100%) showed post-surgical complications in the short term. in addition, 9/14 (64.3%) patients during followup did not show long-term complications, whereas 5/14 (35.7%) patients had at least one complication. in particular, in 5 cases out of 14 (35.7%) on examination it was possible to appreciate plaques/nodules along the penile shaft, and 3 out of 14 patients (21.4%) reported pain and paresthesia during sexual intercourse; 1/14 (7.1%) presented penile curvature, secondary to the corpora cavernosa suturing at surgery, and 1/14 (7.1%) complained of urinary disorders. of the 14 surgically treated patients 3 were re-operated (21.4%) for the correction of complications: the patient with penile curvature was subjected to corporoplasty, another patient had removal of a foreign body granuloma causing urethral stricture and urinary disorders, patients with suspected penile fracture (n) 23 average age of patients with range (years) 40,2 (26-65) causes of trauma • sexual intercourse 18/23 (78,6%) • masturbation 1/23 (4%) • non assessable 4/23 (17,4%) clinical signs and symptoms • penile hematoma 19/23 (82,6%) • penile swelling 10/23 (43,5%) • pain 14/23 (60,9%) • detumescence 19/23 (82,6%) • noise 8/23 (34,8%) • curvature 3/23 (13%) • urethral bleeding 5/23 (21,7%) • erectile dysfunction (ed) 0/23 (0%) diagnosis of penile fracture 20/23 (87%) • clinical 18/20 (90%) • clinical (-) with radiological imaging (+) 1/20 (5%) • clinical (-) with surgical exploration (+) 1/20 (5%) • radiological imaging 14/20 (70%) • radiological confirmation of penile fracture diagnosis 13/14 (92,9%) false positives 3/23 (13%) • atypical clinical presentation 1/3 (33,3%) • clinical presentation (+), radiological imaging (-) 2/3 (66,7) patients subjected to surgery 14/20 (70%) access to the tunica albuginea • degloving with circumcision 11/14 (78,6%) • peno-scrotal skin incision on the median raphe 1/14 (7,1%) • degloving+second access 2/14 (14,3%) penile fracture confirmed by surgical exploration 14/14 (100%) rupture of the tunica albuginea • unilateral 16/20 (80%) • bilateral 4/20 (20%) unilateral rupture of the tunica albuginea • right corpus cavernosum 10/16 (62,5%) • left corpus cavernosum 6/16 (37,5%) urethral involvement 5/20 (25%) average of hospitalization days 4,5 (0-11) • average of hospitalization days of patients with surgical treatment 5,6 (15-3) • average of hospitalization days of patients with conservative treatment 2,5 (4-0) re-intervention 3/14 (21,4%) table 1. characteristics, clinical symptoms, intraoperative findings of patients in g1. • absence of complications 12/19 (63,1%) • plaques/nodules along the penile shaft 7/19 (36,8%) • pain/paresthesia 4/19 (21%) • curvature 2/19 (10,5%) • urinary disorders 1/19 (5,3%) • erectile dysfunction (ed) 2/7 (28,6%) table 2. long term complications of patients in acute care immediately after the trauma. pavan_stesura seveso 16/01/15 10:50 pagina 362 while the third was subjected to dorsal incision of the prepuce for the onset of phimosis, secondary to ischemia of the skin flaps for excessive devascularization linked to degloving, since he had not been circumcised during the repair surgery of the tunica albuginea. among the 5 patients treated conservatively in g1, 3 (60%) did not present long-term complications. in 2 of 5 patients with late complications (40%), on physical examination plaques/nodules along the penile shaft were palpable in both cases, and in 1 patient (20%) penile curvature was also present. in the latter case, the patient also complained of pain and paresthesia during sexual intercourse. overall, 19 of 20 patients were available for follow-up, as for one patient with clinical diagnosis of penile fracture, which had refused surgical treatment, it was not possible to collect the documentation. of these, 12 patients (63.1 %) did not report any complications, while 7/19 presented plaques/nodules, 4/19 (21%) pain/paresthesia during sexual intercourse, 2/19 (10.5%) curvature, and 1/19 (5.3%) reported urinary disorders. with regard to follow-up about erectile deficiency (ed), 7 of the 20 patients contacted (35%) agreed to fill out two iief 15 questionnaires. the analysis of the pretrauma iief data showed that 7/7 (100%) patients had no disorder of the sexual sphere, with a total score of 72 to 54 and in all patients the erectile function was between 27 and 30 points. taking into account the iief post-trauma (about 1 year), 2 out of 7 patients (28.6%) developed post-traumatic ed: mild in one case (24 points) and moderately severe in the other (16 points) (table 2). follow-up of patients treated at a distance of time fromthe trauma due to the onset of complications of the 18 patients treated at a distance of time from the trauma (g2) all have manifested long-term complications, as they reported to the urologist just for the onset of symptoms/signs related to the complications. in particular, 8/18 (44.4%) presented penile plaques/nodules, 4/18 (22.2%) reported pain and paresthesia during sexual intercourse, 14/18 (77.8%) had penile curvature and 1/18 (5.6%) complained of urinary disorders. in one case of 18 (5.6%), herniation of the corpora cavernosa was present. in this group of patients, the data related to the ed were collected by consulting the medical records and it was found that 6 patients (33.3%) experienced an ed (table 3). four of the 18 patients contacted responded to the iief questionnaire and of these, 3 had an ed. in one case the dysfunction was moderately severe (score of 15) and in two cases mild (score of 19 and 21 respectively). follow-up of patients subject to the psycho-sexological questionnaire nine of the 41 patients contacted (22%) attended the psycho-sexological evaluation. of these, 7 belonged to g1 and 2 to g2. four out of 9 (44.4%) patients interviewed have not noticed any difference in preand posttrauma sexual intercourse. the 5 patients (55.6%) who noticed a difference, responded however in different manners, mentioning: changes in their sexual habits (1 pt.), fear of a new trauma (1 pt.), fear of their partner to cause further trauma (1 pt.), fear of the trauma itself (1 pt.), and one patient was not able to answer . the cause of trauma was in 8 out of 9 cases (88.9%) sexual intercourse and in 1 case (11.1%) related to masturbation. with regard to the position that led to penile fracture, 4 of 8 patients (50%) reported having had trauma while the woman stood over the man, 3 of 8 (37.5%) while the man penetrated the woman from behind and 1 in 8 (12.5%) while the man stood over the woman. among patients with post-coital trauma, 4 (50%) still practice the position that caused the fracture, while 4 (50%) avoid it: 2/4 (50%) because they are afraid of a second trauma, 1/4 (25%) because their partner is afraid to cause a new fracture and in 1/4 (25%) because of both coexisting fears. none of the patients surveyed, however, reported a variation in the number of emotional and/or sexual relationships before and after the trauma and none has attributed the cause of the trauma to their personal sex knowledge. seven out of 9 (77.8%) patients in the year following fracture reported that they had been afraid of a new trauma, fear that has however diminished with the passage of time. by classifying the level of fear according to a 7-point likert scale, the level of fear was maximum (7 on the likert scale) in 2 patients, mediumhigh (4 and 5) in 3 patients and average low (3 and 2) in 2 patients. at the time of completing the questionnaire, therefore over a year after the trauma, the level of fear had lowered by about two points in all patients. eight of 9 post-trauma patients (88.9%) were afraid of repercussions on the erectile function, such fear in 2 cases was "very high" (7 on the likert scale), high in 1 case (6), medium-high in 2 cases (4) and medium-low and low in the other 2 cases (2 and 1). the fear of losing penile sensitivity after trauma was reported in 7 out of 9 patients (77.8%); in these 7 cases the fear was highest in 2 (7 on the likert scale), high in 1 (6), medium-high in another one (5), medium-low in 2 (3 and 2) and low in one other case (1). six of 9 patients (66.7%) had fear of experiencing pain during sexual intercourse after the trauma: in 1 patient the fear was high (7 on the likert scale), in 2 patients medium-high (5 and 4), in 1 medium-low (2) and in 2 cases low (1 on the scale). the questionnaire also investigated the penile sensitivity preand posttrauma, which in 6 of 9 patients (66.7%) was found to be unchanged. in the three cases in which a change was reported, for two patients the cause was attributed to surgery, and for one patient to both surgery and trauma itself. within one year from the trauma, five of 9 patients (55.6%) experienced pain during sexual intercourse. the intensity of pain varied from patient to patient: in 1 patient it was very high (7 on the likert 363archivio italiano di urologia e andrologia 2014; 86, 4 penile fracture: retrospective analysis of our case history with long-term assessment of the erectile and sexological outcome • absence of complications 0/18 (0%) • plaques/nodules along the penile shaft 8/18 (44,4%) • pain/paresthesia 4/18 (22,2%) • curvature 14/18 (77,8%) • urinary disorders 1/18 (5,6%) • hernation of the corpora cavernosa 1/18 (5,6%) • erectile dysfunction (ed) 6/18 (33,3%) table 3. long term complications in patience treated at a distance of time after the trauma. pavan_stesura seveso 16/01/15 10:50 pagina 363 archivio italiano di urologia e andrologia 2014; 86, 4 n. pavan, g. tezzot, g. liguori, r. napoli, p. umari, m. rizzo, g. chiriacò, g. chiapparrone, f. vedovo, m. bertolotto, c. trombetta 364 scale), in 1 patient medium-high (4) and in 3 patients very low (1). the penile fracture in 3 out of 9 patients (33.3%) increased anxiety in social relations: in 1 patient the anxiety level increased by 2 points on the likert scale, from 0 (corresponding to "no anxiety") at 2 ("low anxiety"); in 1 patient it augmented from 1 ("very low") to 4 ("moderately high"); in 1 patient the trauma increased anxiety in social relations with a shift from 0 to 7 (corresponding to "very high"). five of 9 patients (55.6%) reported an increase in anxiety from performance in response to the trauma: in 1 patient, the increase was from 0 to 1; in another patient from 2 to 3 ("moderately low"); in one other case the increase was from 6 ("very high") to 7. in 2 cases, however, the increased anxiety from performance was more significant, from a score of 0 to 6 in one case and from 0 to 5 in the other case. the penile trauma also induced in 6 of 9 patients (66.7%) an increase in anxiety from position (meaning as "anxiety from position” a fear of experiencing certain positions during intercourse). of these 6 patients: one patient has gone from 1 to 2; 1 from 0 to 2; 1 other increased from 1 to 7; another from 0 to 3, and finally 2 patients shifted from 0 to 4. comparison between surgically treated patients and conservatively treated patients in group 1 the average age of patients treated surgically in g1 was 35.9 years (27-63) and that of the treated conservatively was 43.4 years (26-65). analyzing the incidence rate of complications developed in the long-term by patients in g1, it was showed that there is no difference comparing the surgically treated patients (35.7%, ie 5/14 pcs.) with those treated conservatively (40%, ie 2/5 pcs.). the data relative to each type of complications are summarized in the table below (table 4). in particular, an erectile dysfunction (ed) of mild severity (iief of 24) occurred in 25% (1/4) of the surgically treated patients who responded to the iief 15, unlike patients treated conservatively in which the ed was of modest severity (iief of 16 ) in 33.3% (1/3). the results were compared using fisher's exact test; from the general analysis and that of each single complication. no statistically significant information was revealed (p > 0.05) with regard to the correlation between the type of treatment adopted and the onset of complications. three out of 14 patients (21.4%) treated surgically were re-operated for the onset of a complication, while none of the patients to whom medical therapy was prescribed has been subjected to surgery for the onset of complications at a distance of time. comparison between patients treated "acutely" and the patients treated at a distance of time for the onset of complications the average age of patients in g1 was 40.2 years (26-65) and in g2 of 42 years (23-62): the two groups therefore are fairly homogeneous in respect to age. the incidence rate of long-term complications was 36.8% (7/19) and 100% (18/18) in g1 and g2 respectively. erectile dysfunction (ed) of medium/mild severity occurred in 28.6% (2/7) of patients in g1 and of medium/high severity in 33.3% (6/18) of patients in g2. the results were compared using fisher's exact test; from the general analysis of long-term complications in the two groups a p value < 0.0001 with a relative risk (rr) equal to 0.3684 were obtained. with these data, it may be concluded that patients treated at a distance of time from the trauma have the probability of manifesting long-term complications 36.8 times higher than those receiving care immediately after the trauma. the specific analysis of each individual complication has not revealed anything statistically significant, except for the occurrence of penile curvature. in this case, in fact, comparing with fisher's exact test the occurrence rates of this complication in the two different groups, we obtained a p value < 0.0001 (rr of 0.1353 and confidence interval (ci) between 0.03564 and 0.5139). based on these data it can be stated that the treatment at a distance of time from the trauma is likely to lead to penile curvature 13.5 times more than the immediate treatment. regarding the ed, according to the results obtained, one cannot assert that patients with treatment at a distance of time have a greater risk of developing ed compared to patients treated immediately after the trauma. the only difference was the degree of ed (mild to moderate in patients of g1/moderate to severe in patients of g2), but other assessments in this matter cannot be made because a few patients were available for completing the iief 15 questionnaire and this was the only method used in this study for the evaluation of erectile function. finally, again from the data obtained, it can be concluded that an inevitable long-term complication in the healing of the rupture of the tunica albuginea, reported in almost all patients, including those undergoing surgical treatment, is the permanent but clinically irrelevant formation of fibrotic scar nodules on the side of the repaired tissue. discussion the fracture of the penis is rare urological emergency, even if the total number of cases is certainly underestimated, as many patients do not seek medical care because of embarrassment or report to the urologist belatedly for the occurrence of complications (penile curvature, erectile dysfunction). however, the number of patients long-term complications patients in acute care patients treated at a distance of time p presence of complications 7/19 (36,8%) 18/18 (100%) < 0,0001 • plaques/nodules 7/19 (36,8%) 8/18 (44,4%) n.s. • pain/paresthesia 4/19 (21%) 4/18 (22,2%) n.s. • curvature 2/19 (10,5%) 14/18 (77,8%) < 0,0001 • herniation 0/19 1/18 (5,6%) n.s. • urinary disorders 1/19 (5,3%) 1/18 (5,6%) n.s. • ed 2/7 (28,6%) 6/18 (33,3%) n.s. table 4. comparison of long-term complications. pavan_stesura seveso 16/01/15 10:50 pagina 364 in our case archive is in line with european case studies. the penile fracture or traumatic rupture of the corpora cavernosa is an injury that occurs in the erect penis. many authors (17, 24, 25, 37) in fact recommend that the term "fracture" should be restricted to cases of trauma that occur during penile erection. in western countries it is mainly caused by sexual intercourse (6, 14), in middle-eastern countries instead the predominant cause is masturbation (8, 14, 40, 41). the etiological difference in these two regions may be explained by the strict prohibition in the muslim areas of sexual relations outside of marriage (6, 23) resulting in increased frequency of masturbation among the population. the high incidence of penile fracture in these regions of the mediterranean could be because the time to reach orgasm with penile manipulation is longer than with sexual intercourse, and thus the risk of tearing the tunica albuginea increases. in addition, the preponderance of post-coital penile trauma in western countries, including the united states, could reflect a more permissive culture in relation to sexual intercourse (6). in this study, the causes of trauma have been sexual intercourse and masturbation in 31/41 (75.6%) and 2/41 (4.9%) patients, respectively, reflecting the situation in western countries. in most cases, the coital trauma occurred while the woman was on top of the man, when the full weight of the partner presses on the erect penis or when the erect penis, out of the vagina, is accidentally pushed against the woman’s perineum. in 8 of 41 patients (19.5%) it was not possible to investigate the etiology of the trauma, and this reflects the natural embarrassment to which this condition can lead (14, 42). in the 23 patients of g1 with suspected penile fracture who reported immediately after the trauma, 19/23 (82.6%) showed a hematoma along the penile shaft, and in 10 of these (43.5%) a swelling of the penis was associated. pain and detumescence were reported in 14/23 (60.9%) and 19/23 (82.6%) cases, respectively. however, only 7 of the 20 patients (35%) with a confirmed diagnosis of penile fracture confirmed by radiological imaging and/or surgical exploration presented the classical clinical triad (hematoma, noise and immediate detumescence). in literature, noise is reported in 47.7 to 100% of patients, while pain is present in 48.5 to 100% of cases, demonstrating a variable constellation of symptoms associated with this condition (7, 9, 12, 14, 34, 40, 43). in addition to the clinical diagnosis in doubtful cases with atypical clinical appearance, radiological imaging can be made use of to obtain a differential diagnosis of diseases that can mimic penile fracture and thus avoid an unnecessary surgery (33, 34, 44). in this study the radiological investigations were performed both in clinically typical and atypical cases, for a total of 16 of 23 patients (69.6%) with suspicion of penile fracture, and this data comes in contrast with information reported in literature. in our case study, we preferred to investigate and ascertain the rupture of the tunica albuginea, drawing on the advice of a great team of radiology specialists with high experience in the field of urology, before subjecting the patient to surgical exploration. all 16 patients who underwent xray examination were also subject to penile ecd, the radiological technique of choice for evaluating patients with penile trauma (1, 31). the anatomy and the penile vasculature can in fact be accurately described by the shades of gray of the doppler ultrasound technique, so that the nature and extent of the lesion can be fully accounted for in many cases (1). the ecd is able to detect the location of the lesion through the interruption of the echogenic line of the tunica albuginea (1, 31). however there have been reports of false-negative results (1, 45, 46), as pronounced in the presence of a hematoma or edema which render the interpretation difficult (6). in this retrospective analysis, the ecd has confirmed the diagnosis of penile fracture in 13 of 16 cases (81.3%), while in 2 cases (12.5%) it excluded the rupture of the tunica albuginea and in 6.3% of cases (1/16), penile edc was found to be a false negative. the cavernography is an easy procedure to perform on the operating table, with or without anesthesia (37); however, being a noninvasive diagnostic technique with potential complications such as priapism (25, 47), infection (14) and allergic reactions (6), which could lead to cavernous fibrosis (1, 37), it was performed in only 2 out of 16 cases (12.5%): in one case in combination with edc and intraoperative in the other one. the mri is a noninvasive procedure, very accurate in the evaluation of penile fracture and that can help determine the most appropriate type of treatment; however because of its high cost (6), it is rarely used in acute situations and many penile trauma cases are been diagnosed only with clinical presentation and ecd. in this study, it has been employed only in 18.8% (3 /16) of cases and always in combination with edc. the prevalence of urethral lesions in this study was 25% (5 /20) and this is in line with literature, which reports a proportion of cases of urethral involvement between 20% and 25% (24). four out of 5 (80%) patients with urethral involvement reported urethral bleeding, demonstrating that the lesion of the urethra occurs very commonly with an initial macroscopic presence of red blood cells in the urine. urethral bleeding (25), hematuria and voiding difficulties (3, 24) indeed indicate urethral rupture, however the absence of these signs and symptoms does not exclude possible urethral involvement (3, 5, 43, 48). in medical literature, there have been reports of urethral laceration even in the absence of a rupture of the corpora cavernosa (13, 49). the clinical presentation in these cases of isolated urethral injury differs from typical penile fractures for the absence of noise, penile deformity and for the absence of palpable penile defects (49). as reported in the literature (6, 24), in this study the bilateral fracture of the corpora cavernosa is very frequently associated with urethral injury; in fact, 100% of patients with bilateral rupture of the tunica albuginea had a concomitant urethral injury. in the case of bilateral laceration of the albuginea, the urologist should always give in the operating room special attention to the urethra (6, 14, 24). fergany et al. also suggest exploring the other cavernous body when one is broken and the urethra is injured simultaneously. three out of 5 (60%) patients with urethral injury were subjected to surgical repair, but the type of treatment, surgical or conservative, of partial lesions of the urethra remains controversial (14, 42). 365archivio italiano di urologia e andrologia 2014; 86, 4 penile fracture: retrospective analysis of our case history with long-term assessment of the erectile and sexological outcome pavan_stesura seveso 16/01/15 10:50 pagina 365 archivio italiano di urologia e andrologia 2014; 86, 4 n. pavan, g. tezzot, g. liguori, r. napoli, p. umari, m. rizzo, g. chiriacò, g. chiapparrone, f. vedovo, m. bertolotto, c. trombetta 366 in our series of patients with urethral involvement, 1 in 5 (20%) developed a urethral stenosis with associated urinary disorders. patients with rupture of the tunica albuginea with concomitant urethral injury are much more likely to develop post-operative complications, so a close follow-up is recommended (42). some authors recommend the use of retrograde cystourethrography or urethroscopy in cases of suspected urethral injury (1, 30); an indirect sign of urethral injury is the presence of air in the corpus cavernosum (1, 31). however, false negative results may be reported (5, 7), since the urethrography has limitations and might not detect the tear in the case of post-coital urethral bleeding (6, 23, 19). none of our cases with suspicion of concomitant urethral involvement, however, has been subjected to such radiological investigations. a direct approach was preferred, looking intraoperative urethral injury (7, 12). kamdar et al. (7) recommend, in the case of high suspicion of urethral injury, to use a flexible cystoscopy in the operating room prior to inserting the bladder catheter, in order to allow the examination of the urethral mucosa and display the extension of the rupture before placing the catheter. the urethral injury is much more common when the fracture occurs during sexual intercourse, compared to other causes of penile fracture, and this is because on this occasion the force applied is stronger than during masturbation (7, 8, 12, 23, 24). this finding was also confirmed by our study. in literature it is widely confirmed that immediate surgical repair of the albugineal rupture is the best method of treatment of a penile fracture, leading to excellent results with less time and less risk of hospitalization for erectile dysfunction and curvature in the long term (24). in our case study, 14 of 20 patients (70%) underwent surgical exploration; of these, 5 patients (35.7%) had complications during follow-up. specifically, all 5 patients (35.7%) presented plaques/nodules along the penile shaft; in addition, 3 of these (21.4%) reported paresthesia and pain during sexual intercourse, 1 (7.1%) reported penile curvature and 1 (7.1%) complained of urinary disorders. in this study, 1 in 4 (25%) patients with confirmed diagnosis of penile fracture treated surgically immediately after the trauma, to whom it was possible to administer the iief questionnaire, developed post-traumatic ed. this percentage is much higher than the 0-17% reported in literature (5, 12, 14, 40). this discrepancy may be due to many reasons, first the lack of availability of patients contacted to participate in the study and, consequently, to the scarcity of data obtained from the compilation of the iief questionnaire by patients themselves. in addition, the average age of patients treated surgically immediately after the trauma was 35.9 years in our study, an age higher than that reported in several case studies (27-29 years) (10, 34, 43). an older age may be associated with a higher prevalence of ed before the trauma and consequently this data in our study may have led to a higher percentage of post-traumatic ed. in this context, therefore, the erectile function before the trauma should always be assessed to monitor more precisely any posttraumatic changes, because patients with a preexisting ed are much more prone to deterioration after surgery (14). in our study, erectile function, both pre-and posttrauma, was assessed through the administration of two iief questionnaires to the patients. although the pretrauma state was estimated retrospectively, and thus represents a source of bias in the study, it is still useful as a reference, although in our series of 4 patients who completed the iief, no one had a pretrauma ed. in any case, this data, albeit limited to the small sample size, cannot be compared in literature, since all of the studies examined lack a preevaluation of the erectile function domain of trauma patients who underwent surgical exploration, and there is only sporadic data on this important issue (14). none of our patients with post-traumatic ed, however, necessitated therapy. this suggests that these patients, still able to have satisfactory sexual intercourse, may not seek the attention of the urologist after surgery, even if they suffer from ed, assuming a higher percentage of ed than that reported in literature. another important aspect is the adequate evaluation of ed, since in medical literature there is a high variability of measurement criteria (9, 12, 41), which means that adopting different systems of evaluation leads to equally diverse results and therefore not comparable with each other. the best way to classify ed is the iief and penile dynamic ecd (14), but in our study, the penile ecd during follow-up was not performed in all patients. some patients may show a normal ecd but with a pathological iief score in a context of psychological ed (12). in the study of ibrahiem et al., 36.4% of men with erectile dysfunction after penile fracture had a normal penile ecd. these patients reported extreme fear of incurring another trauma, and this led to a very limited sex life despite the absence of erectile dysfunction (12). in this regard, the psycho-sexological questionnaire administered to our patients revealed that the only patient with post-traumatic ed in our case series had a very strong fear of impact on the erectile function, of losing penile sensitivity and experiencing pain during sexual intercourse. he also reported, again after the trauma, high social and performance anxiety and a moderate anxiety from position. taking these data into consideration, therefore, we may consider the ed of this patient is not so much organic, thus linked to the alterations caused by trauma to the erectile tissue and the tunica albuginea, but especially psychological, as described by ibrahien. considering the period of follow-up of patients who have suffered a fracture of the penis, it should long enough, to the point of unmasking any ed (40, 43). in a recent study led by gamal et al., ed appeared in 4% of cases after a mean follow-up of 20.8 months (34), while other studies with a longer follow-up of 90 months showed an ed incidence of between 6.6% and 17% (5, 12). this relationship is not clear and should be evaluated in future studies (14). finally, many reports on penile fracture are based on a patient population of the middle east (12, 41). in the different ethnic groups, however, considering the different etiology of penile fractures, there might be a different percentage of post-traumatic ed, which might explain the higher rate of ed in our study. pavan_stesura seveso 16/01/15 10:50 pagina 366 only one case in 14 (7.1%) treated surgically developed a penile curvature. in 13 cases out of 14 (92.8%), a subcoronal incision with degloving of the penile skin was performed. this surgical technique allows in fact an excellent exposure of both the corpora cavernosa and the corpus spongiosum of the urethra (6, 29). in 2 cases, however, a second incision was necessary because the lesion was proximal. in only 1 case a penoscrotal cutaneous incision was performed on the median raphe, a procedure which avoids excessive disconnection from degloving and delivers good cosmetic results. this incision allows the evacuation of the hematoma and repair of the corpora cavernosa and is recommended in case of widespread edema and hematoma that prevent degloving (7). in addition, it can also serve as a guide for the proximal degloving (50). while the laceration of the tunica albuginea is usually sutured longitudinally along the axis of the penis, the skin closure in the case of peno-scrotal incision could be performed transversely if the longitudinal closure should cause a throttling (51). the need for catheterization should be evaluated carefully to reduce the risk of infection and possible urethral trauma (15), but in all patients in our study a bladder catheter was positioned to identify the urethra and thus prevent accidental injuries during inspection of the corpora cavernosa to search the albugineal breach, and also to allow possible repair of a concomitant urethral injury. in the absence of urethral laceration in our patients, the catheter was removed in the first post-operative day, while in patients with concomitant urethral injury the catheterization time was longer, in order to allow the urethral suture to stabilize. according to medical literature, in case of simultaneous rupture of the albuginea and the urethra, the catheter may also be left for 7-10 days after surgery (7). the search for the albugineal lesion and therefore the state of the corpora cavernosa and further the sealing of the suture were investigated on the operating table by means of the intracavernous injection of isotonic saline, sometimes mixed with methylene blue dye, causing an artificial tumescence. this is achieved by placing a tourniquet at the base of the penis. all patients in our case study was finally given a semicompressive dressing after surgery. the post-surgical therapy consisted, in all cases, of abstinence from sexual intercourse for a month, of administration of antibiotics, painkillers/analgesics. only in one case, an anti-androgen was administered, as normally the postoperative pain prevents erection. in literature, conservative treatment today is more the exception than the rule, because its results are less satisfactory than those of surgical treatment (6). conservative therapy is recommended when the corpora cavernosa are intact, but in the case of acute penile fracture, it may be difficult to exclude the complete rupture of the corpora cavernosa, even with a diagnostic radiological procedure (25, 48). in our study, five of 20 (25%) patients were treated conservatively. one of these had atypical clinical presentation, but the ecd and mri were suggestive of penile fracture. medical therapy adopted involved in the majority of cases the administration of anti-inflammatory/pain relievers, antibiotics, anti-androgens, topical heparin gels, ice bags and the positioning of a compressive dressing which allowed exposure of the glans so as to prevent or detect any penile ischemia (38, 52). two patients, 1 with clinical diagnosis of penile fracture confirmed by ecd and 1 with only a radiological diagnosis of penile trauma (ecd and positive mri), have developed long-term complications such as plaques/nodules along the penile shaft in both cases, pain and paresthesia during intercourse and penile curvature in one case (20%); ed was reported in only 1 patient (20%). these data are in contrast with what is described in literature, as the penile curvature and ed following conservative treatment are reported in 50-80% of cases, for a total of long-term complications after conservative therapy of 80% (34, 41). in the group treated “acutely” the average number of days of hospitalization (4.5 days overall) was higher in patients who underwent surgical exploration (5.6 days) compared to patients treated conservatively (2.5 days) and this is in stark contrast to the literature that shows the average number of days of hospitalization for patients treated conservatively to be 14 (24). a longer stay in operated patients enrolled in our study may be sought in the presence of cases with concomitant urethral injury, whose post-operative course was linked to the need to maintain the bladder catheter in place for longer, even if the incidence of urethral lesion in our patients was in line with other studies reported in literature. in a study by el-sherif (15), patients treated conservatively spent on average 2.3 days in the hospital, while those treated surgically 4.1 days. the author explains this finding by showing that the conservatively treated group had not been catheterized and did not require special medical treatment. the most common long-term complications of penile trauma are: plaques/nodules along the penile shaft at the site of injury, pain and paresthesia during sexual intercourse, painful erections, penile curvature, erectile dysfunction and urinary disorders. they can occur both in patients treated conservatively and in patients treated surgically (6). in our study, the incidence rate of long-term complications was similar in patients treated surgically immediately after the trauma and in those treated conservatively. in fact, in the first group (treated surgically), the complication rate was 35.7%, while in patients treated conservatively was 40%. this difference in our study is not statistically significant. in light of this data, we can state that the acute conservative treatment does not have a higher risk of long-term complications compared to acute surgical treatment, and that the type of treatment adopted does not affect the overall incidence of long-term complications, which depend on the trauma itself, unlike what is instead reported in literature (22, 34). in this study we also took into consideration 18 patients treated at a distance of time from the trauma for the onset of complications. these patients had not resorted to urological examination immediately after the trauma and therefore had not been subjected to any kind of acute care. they have turned to the doctor in the moment in which long-term complications related to anamnestic penile fracture appeared. one hundred percent of these patients experienced a complication and 367archivio italiano di urologia e andrologia 2014; 86, 4 penile fracture: retrospective analysis of our case history with long-term assessment of the erectile and sexological outcome pavan_stesura seveso 16/01/15 10:50 pagina 367 archivio italiano di urologia e andrologia 2014; 86, 4 n. pavan, g. tezzot, g. liguori, r. napoli, p. umari, m. rizzo, g. chiriacò, g. chiapparrone, f. vedovo, m. bertolotto, c. trombetta 368 therefore this finding fits with what has been described in literature, as the overall rate of complications after conservative treatment corresponds to 80% (34, 41). in 77.8% of cases penile curvature was reported, which in 35.7% of patients was treated surgically because it constituted an obstacle in their intimate life; 33.3% of cases developed ed. the ratio of penile curvature in this group of patients was in line with the data for post-conservative treatment curvature reported in the literature (50-80%) (34, 41), while the incidence of ed was lower (50-80%). this can be explained by the fact that many patients with previous penile trauma, who had a mild ed that did not prevent normal sexual relations, have not felt the need for a urological examination. comparing the incidence rates of long-term complications of patients receiving acute care (g1) and patients treated at a distance of time (g2), it was shown that nonimmediate treatment after the trauma has a 36.8% risk of leading to complications and in particular a 13.5% risk of generating a penile curvature. from these data it may be concluded that the acute treatment of a penile fracture would be more suitable, reducing the overall risk of long-term complications secondary to trauma, particularly the risk of penile curvature. the immediate treatment, whether surgical or conservative, then turns out to be the ideal treatment of penile fractures, but it the choice does not depend on the doctor, but rather the patient, which for the embarrassment generated by the situation does not seek medical care immediately and requires specialist advice only when complications are already notable. given the small number of patients who responded to the iief, we do not have sufficient data to enable us to assess the post-traumatic ed. however, the lack of participation in completing the iief questionnaire may presume a certain well-being of patients, who then have no interest in contacting the urologist. from the analysis of the psycho-sexological questionnaire no conclusions can be drawn, as only few patients from an already small group, were available to answer the questions submitted. this might also indicate a reluctance to face again the traumatic event, perhaps to relive the negative experience, or, on the contrary, it could indicate a certain well-being of the patient, who does not feel the need to undergo a medical evaluation. considering all the above, the interpretation of the data can be very variable. this questionnaire, not being validated, but purposebuilt by a sex therapist to investigate certain personal aspects not investigated by the iief, does not allow for a quantitative analysis of data; it only allows a qualitative analysis of data that differ greatly from patient to patient. however, we can affirm that the penile fracture definitely has a psychological impact on the patient, especially in the year following the trauma. the psychological sphere that is mainly affected is that of fear. the majority of patients admitted in fact that in the year following the trauma they experienced fear of new trauma, fear that in several cases was experienced also by the partners. the same thing can be said about the fear of the repercussions on erectile function, fear of losing penile sensitivity and fear of experiencing pain during intercourse. however, all these fears diminish with the passage of time, perhaps for the reacquisition by the patient of selfconfidence, and having ascertained that despite the trauma “everything was back to normal". despite the fear, patients have not noticed differences in sexual relationships before and after the trauma; the few patients who have noticed these differences, however, gave very different answers, so it was difficult to make a quantitative analysis of the data. in general, even anxiety in social relationships, anxiety from position and performance have not undergone much change between the preand posttrauma states. limitations of the study this study is limited by the number of patients, especially in comparison with other studies from the middle east or the mediterranean basin (9, 12, 41). in our case series, already numerically limited from the start, it was possible to evaluate the erectile function and psychosexological impact of the trauma on the emotional and sex lives of the patients only in 9 cases out of a total of 41; therefore, the interpretation of the data obtained has proven difficult in some respects. many patients with penile fracture have not turned to the doctor for their possible welfare and/or the non-occurrence of complications. however, this is not clear and must be taken into account when interpreting the results of this study. in addition, the retrospective evaluation of patient status before the injury might have caused some bias, but this should be considered as a benefit of the study, since the evaluation before the occurrence of a penile fracture is not possible. conclusions the fracture of the penis is a rare urological emergency, even if underestimated, probably because of socio-cultural inhibition of the patients, who are ashamed to report to the doctor. sexual intercourse and penile manipulation are the most frequent causes of this type of trauma, depending on the geographical area analyzed. the radiological imaging does not replace clinical evaluation, but in our experience, it is very useful in cases with atypical clinical presentation and in cases of doubt, especially because it allows assessing the need for surgical exploration. the penile doppler ultrasound is the radiological technique of choice, given its diagnostic accuracy, non-invasiveness, speed of execution and low cost. a concomitant urethral injury must always be taken into account especially in case of urethral bleeding or bilateral lesion of the corpora cavernosa. in the literature, the surgical technique most recommended is the incision with sub-glandular de-gloving of the penile skin, which allows a good exposure and viewing of the corpora cavernosa and the corpus spongiosum of the urethra, in order to simultaneously repair the tunica albuginea and the eventual urethral injury. in our study, in contrast to what is reported in literature, we found no difference in the onset of long-term complications among patients treated surgically compared to those treated conservatively. instead, comparing patients treated "acutely" with those treated at a distance of time after the trauma, it was found that the latter have a higher probability of experiencing complications, and in parpavan_stesura seveso 16/01/15 10:50 pagina 368 ticular of experiencing penile curvature. however, taking into account the small number of patients who were available for filling the iief 15 questionnaire, we cannot state that patients treated after a long time have a higher risk of developing ed than those treated immediately after the trauma. from the results obtained, we can only say that in the two groups ed occurred with varying severity: 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pavan, md (corresponding author) nicpavan@gmail.com giorgia tezzot, md giorgiatez@hotmail.it giovanni liguori, md gioliguori@libero.it renata napoli, md renata.napoli@libero.it paolo umari, md paoloumari@alice.it; michele rizzo, md mik.rizzo@gmail.com giovanni chiriacò, md gio.chiriaco@gmail.com gaetano chiapparrone, md g.chiapparrone@gmail.com francesca vedovo, md superv@libero.it carlo trombetta, md trombcar@units.it urology department, cattinara hospital, university of trieste strada di fiume 447 34149 trieste, italy michele bertolotto, md bertolot@units.it radiology department, cattinara hospital, university of trieste strada di fiume 447 34149 trieste, italy pavan_stesura seveso 16/01/15 10:51 pagina 370