this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information bladder cancer, gadolinium mri none declared. patient consent: obtained. received on september 20, 2021 accepted on september 27, 2021 soc int urol j.2021;3(1):48 doi: 10.48083/ofwx4645 [james.kovacic@health.nsw.gov.au] gadolinium contrast in the bladder: a malignant mimic james kovacic, jonathan kam, edward latif in affiliation with the division of surgery and anaesthesia, department of urology, gosford district hospital a 50-year-old female presented to hospital with diplopia and unsteady gait. the patient was identified to have a disconjugate gaze palsy involving the right medial rectus muscle. investigation for an ischaemic event proved negative, with an unremarkable mri of the brain. a paraneoplastic screen, including a ct of the chest, abdomen, and pelvis, was undertaken to identify an alternative cause for her symptoms. an incidental finding of a large, enhancing bladder mass was identified on ct imaging (figures 1 and 2). the bladder mass was hyperdense arising from the anterior bladder wall and had an atypical serpiginous appearance. there was no hydroureteronephrosis. differentials included a bladder lesion or, less likely, an organised haematoma. the patient had a significant smoking history but no prior haematuria. urine cytology was negative, and a renal tract ultrasound failed to identify the lesion. flexible cystoscopy was performed, demonstrating a normal appearing bladder. further discussion with the radiologists identified that the gadolinium contrast given for her mri scan 2 hours before the ct scan was likely layering within the bladder, masquerading as a bladder lesion. acknowledgements the authors wish to thank the gosford district hospital staff involved with this case. figure 1. figure 2. 48 siuj • volume 3, number 1 • january 2022 siuj.org clinical picture mailto:james.kovacic%40health.nsw.gov.au?subject=siuj http://siuj.org remarkable case of a right renal flank hernia james kovacic, stephen ruthven central coast local health district, urology, gosford, australia a 95-year-old female presented to hospital with a 3-day history of worsening right-sided flank pain, on background of recent heavy lifting. the pain was dull in nature and centred over a bulge at her right flank. it was not associated with any subjective fevers, bowel disturbance, or urinar y sy mptoms. examination identif ied an uncomfor table but haemody nica lly normal patient. abdominal examination revealed a soft abdomen with a tender, palpable mass over the right flank in line with a surgical scar. the mass was reducible but would spontaneously re-herniate on cessation of pressure. the patient had a significant history of a rightsided minima lly invasive latera l transpsoas l1-5 spinal fusion (also known as a direct lateral interbody fusion [dlif]) 6-years earlier. other significant history included atrial fibrillation on anticoagulation, cerebrovascular attack on aspirin, breast cancer, and recurrent urinary tract infections. she lived at home independently. biochemistr y and inf lammator y markers were norma l. ct imaging demonstrated a right rena l flank hernia through the retroperitoneum into the subcutaeneous tissue (figures 1a and 1b). the renal artery and vein were significantly stretched, without evidence of acute pathology. there was no evidence of hydronephrosis or delayed nephrogram. t he p at ient w a s mon itore d over n i g ht a nd discharged on simple a na lgesia. af ter fol low-up discussion with the patient, and given her age and comorbidities, the decision at this stage has been to take a conservative approach with use of a body vest to keep the kidney within the retroperitoneum. this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information hernia, retroperitoneal, flank conflict of interest: none declared. patient consent: obtained. received on october 14, 2021 accepted on october 17, 2021 soc int urol j.2022;3(2):111 doi: 10.48083/yera5234 figure 1a. axial ct figure 1b. sagittal ct 111siuj.org siuj • volume 3, number 2 • march 2022 clinical picture mailto:james.kovacic%40health.nsw.gov.au?subject=siuj http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. xanthogranulomatous pyelonephritis (xgp) is a rare but severe form of inflammatory renal disease associated with renal stones and results in granulomatous tissue invading and destroying normal parenchyma. a serious complication of xgp is fistulization to surrounding structures. we present a case of xgp with pyeloduodenal fistula (pdf) in a 48-year-old female with a history of hypertension and recurrent urinary infections but no previous stones. the patient initially presented to the emergency room in march 2020 with f lank pain, nausea, hematuria, and weight loss. abdominal ct revealed right-sided 4 cm partial staghorn and 2.7 cm ureteropelvic junction stones. there was no abscess and there were no signs of xgp. the patient was referred to our center in april and booked for percutaneous nephrolithotomy (pcnl). her procedure was delayed because of the covid-19 pandemic. on may 15, she developed proteus mirabilis urosepsis and new renal abscesses. she was admitted to a peripheral hospital and underwent ureteroscopy and ureteric stent insertion for purulent drainage. on may 27, she presented for pcnl, and the retrograde pyelogram showed communication of the kidney with the duodenum (figure 1a). the procedure was aborted, and an urgent esophagoduodenoscopy confirmed the diagnosis of pdf. the patient underwent a n open si mple neph rec tomy a nd rou x-en-y duodenojejunostomy with loop gastrojejunostomy and pyloric exclusion. the pdf was identified with a traversing ureteric stent intraoperatively (figure 1b). t he rema i nder of her cou rse i n hospita l was unremarkable and there have been no further urinary infections or stones after one year follow-up. final patholog y revealed diffuse xanthogranulomatous inflammation of the kidney invading through the duodenum. xgp is challenging to diagnose and pdfs are exceedingly rare. only a handful of cases have been reported[1–3]. this case was remarkable for the rapid progression from staghorn renal calculus to fistulizing xgp over a matter of months. pyeloduodenal fistula in xanthogranulomatous pyelonephritis ryan yan, mark t. dawidek, drew phillips, ben h. chew department of urologic sciences, university of british columbia, vancouver, canada this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. figure 1a. retrograde pyelogram with ureteral catheter in right renal pelvis and contrast collecting in duodenum and stomach key words competing interests article information xanthogranulomatous pyelonephritis, staghorn calculus, pyeloduodenal fistula, proteus mirabilis, xgp none declared. patient consent: obtained. received on june 3, 2021 accepted on june 5, 2021 soc int urol j.2021;2(4):265–266 doi: 10.48083/nslu7720 265siuj.org siuj • volume 2, number 4 • july 2021 clinical picture mailto:ben.chew%40ubc.ca?subject=siuj.org http://siuj.org references 1. cheatle t r, waldron rp, a rkell dg. x anthogranulomatous pyelonephritis associated with pyeloduodenal fistula. br j surg.1985 sep;72(9):764. doi: 10.1002/bjs.1800720934. 2. sallami s, rhouma s ben, kchir n, dagudagui n, nouira y, horchani a. spontaneous pyeloduodenal fistula complicating a xanthogranulomatous pyelonephritis: a case report. urotoday int j.2010 apr;3(2). doi:10.3834/uij.1944-5784.2010.04.09 3. laberge m, kulkarni gs, sreeharsha b. p yeloduodenal fistula complicating xanthogranulomatous pyelonephritis. int urol nephrol.2018;50(6):1071–3. doi.org/10.1007/s11255-018-1886-x figure 1b. intraoperative photograph after transecting the fistula tract revealing a ureteral double-j stent traversing from the right renal pelvis to the duodenum 266 siuj • volume 2, number 4 • july 2021 siuj.org clinical picture http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information testis, yolk sac, germ cell tumor, alpha-fetoprotein none declared. patient consent: obtained. received on july 22, 2021 accepted on july 27, 2021 soc int urol j.2021;2(5):327 doi: 10.48083/ vigd9881 pure yolk sac tumor (yst) is most commonly seen in infants and young children, accounting for 80% of all germ cell tumors in this age group[1]. pure yst is rare in adults, constituting up to 2.4% of tumors, and is associated with a less favorable prognosis in adults than in children[2-3]. here, we describe a rare case of pure yst of the testis in an adult with scrotal invasion. a 62-year-old male presented with a 3-month history of an enlarging scrotal mass. on examination, the patient was found to have a 10 cm to 12cm fungating and necrotic mass with superficial bleeding, ulceration, and breakdown of the overlying skin (figure 1). only the left testicle was palpable. bilateral inguinal lymphadenopathy with mobile, firm, rubbery lymph nodes was noted. given the lymphatic drainage networks of the scrotum, these may represent reactive adenopathy from infection or regional metastases[4]. serum tumor markers included afp 17 418 ng/ml, β-hcg <0.06 iu/l, ldh 234 u/l. contrast-ct was negative for lymphadenopathy of the chest, abdomen, and pelvis. no abdominal and pelvic visceral metastases were visualized. in the scrotum, there was a 10.9 cm heterogenous mass without demonstration of the right testicle. radiologic lymphadenopathy of the bilateral inguinal regions was confirmed. the patient was taken to the operating room for biopsy, and surgical pathology demonstrated extensive necrosis and pure yolk sac pathology. immunohistochemistry was positive for sall4, glypican-3, afp, and cd117, and negative for oct3/4 and cd30. microscopic inspection revealed classic schiller-duval bodies. the patient was initiated on neoadjuvant chemotherapy with etoposide and cisplatin for 4 cycles. bleomycin was withheld from the regimen because the patient had a long-standing smoking history. he tolerated the treatment protocol without significant adverse events. figure 1. anterior view of the large fungating, ulcertative scrotal mass with breakdown of the overlying skin on follow-up, the patient had experienced a reduction in the size of the scrotal mass and resolution of the inguinal lymphadenopathy, and he will be scheduled for surgical consolidation. pure yolk sac tumor of the testis with scrotal invasion in an adult male jas singh department of urology, division of surgery, the university of texas md anderson cancer center, houston, united states references 1. leão r, ahmad ae, hamilton rj. testicular cancer biomarkers: a role for precision medicine in testicular cancer. clin genitourin cancer.2019 feb;17(1):e176-e183. doi: 10.1016/j.clgc.2018.10.007 2. khan s, jetley s, pujani m, neogi s. pure yolk sac tumor of testis in an adult: a rare occurrence. j postgrad med.2014;60:351–353. 3. pagaro pm, bedarshi b. pure yolk sac tumor of testis in a 50 years old: a rare case report. med j dy patil univ.2016;9(4):499–502. doi: 10.4103/0975-2870.186078 4. o’lear y cg, allen ja, o’brien f, tuthill a, power dg. scrotal involvement with testicular nonseminomatous germ cell tumour. case rep oncol med.2016;2016:1-3. doi: 10.1155/2016/5471862 327siuj.org siuj • volume 2, number 5 • september 2021 clinical picture mailto:jsingh2%40mdanderson.org?subject=siuj http://www.siuj.org siuj.org siuj • volume 2, number 2 • march 2021 73 zzzz volume 2, number 2 | march 2021 issn 2563-6499 doi: 10.48083/xefq9131 editorial office info@siuj.org tel: 514-875-5665 ext. 26 siuj.org managing editor jane fairbanks jane.fairbanks@siu-urology.org the siuj is published 6 times a year by the société internationale d'urologie (siu). it is the official peer-reviewed publication of the siu but retains editorial independence. the siuj is circulated to urologists, urology residents, family medicine specialists, family medicine residents, general practitioners, nurses, medical libraries, and hospital and university departments of urology worldwide, for a total circulation of over 10,000. this publication was developed under the direction of the siuj editorial board. the siuj is published under an exclusive licence. the siuj is owned and published by the société internationale d’urologie (siu). marketing lillian petrusa lillian.petrusa@siu-urology.org advertising gerri-lynn sendyk advertising@siuj.org neither the siu nor the siuj endorses any service or the contents of any product referred to in any advertisement in the siuj. the siu and the siuj assume no responsibility or liability for damages arising from any error or omission, or from the use of any information or advice contained in the siuj. all editorial matter in siuj represents the opinions of the authors and not necessarily those of the siu or the siuj. all canadian prescription drug advertisements have been cleared by the pharmaceutical advertising advisory board. editorial board editor-in-chief peter black, md, canada associate editors thomas herrmann, md, switzerland kathleen kobashi, md, united states philippe spiess, md, united states henry woo, mbbs, australia social media editor jeremy y. c. teoh, mbbs, hong kong sar statistical editor alice dragomir, phd, canada icud editor luc valiquette, md, canada innovators editor amanda chung, mbbs, australia regional editors north america margarett shnorhavorian, md united states middle east danny rabah, mbbs saudi arabia south america sandro esteves, md brazil east asia tianxin lin, md china eastern europe roman sosnowski, md poland south asia sanjay sinha, mch india western europe tamsin greenwell, md united kingdom southeast asia edmund chiong, mbbs singapore africa yasser osman, mbbch egypt mailto:info%40siuj.org?subject=siuj http://siuj.org mailto:jane.fairbanks%40siu-urology.org?subject=siuj mailto:lillian.petrusa%40siu-urology.org%20?subject=siuj mailto:advertising%40siuj.org?subject=siuj 74 siuj • volume 2, number 2 • march 2021 siuj.org editorial board liaquat ali, mbbs pakistan abdol mohammad kajbafzadeh, md iran fahad alyami, mbbs saudi arabia wayne lam, mbbs hong kong sar mohsen azli, md algeria sang dong lee, md korea erdem canda, md turkey evelyn moshokoa, mbchb south africa yao-chi chuang, md taiwan dedan opondo, mbchb kenya archil chkhotua, md georgia mohammed shahait, mbbs jordan renu eapen, mbbs australia khurram siddiqui, mbbs oman agus rizal ardy hariandy hamid, md indonesia yaya sow, md senegal christopher ho chee kong, md malaysia chuan-liang xu, md china theocharis karaolides, md cyprus the société internationale d’urologie (siu). the society’s mission is to enable urologists in all nations, through international cooperation in education and research, to apply the highest standards of urological care to their patients. the siu is a major international platform for sustainable urological education and collaborative philanthropic activities aimed at improving urological care with more than 10,000 members from over 130 countries. siu central office 1155 robert-bourassa blvd., suite 1012 montreal, quebec, canada h3b 3a7 tel: +1 514 875-5665 fax: +1 514 875-0205 communications@siu-urology.org executive director susie petrusa susie.petrusa@siu-urology.org graphic design sam design info@studiosamdesign.com web design/ technical support aiki informatique info@aikitech.ca neither the siu nor the siuj endorses any service or the contents of any product referred to in any advertisement in the siuj. the siu and the siuj assume no responsibility or liability for damages arising from any error or omission, or from the use of any information or advice contained in the siuj. all editorial matter in siuj represents the opinions of the authors and not necessarily those of the siu or the siuj. all canadian prescription drug advertisements have been cleared by the pharmaceutical advertising advisory board. mailto:communications%40siu-urology.org?subject=siuj mailto:susie.petrusa%40siu-urology.org?subject=siuj mailto:susie.petrusa%40siu-urology.org?subject=siuj mailto:info%40studiosamdesign.com%20?subject=siuj mailto:info%40studiosamdesign.com%20?subject=siuj mailto:%20info%40aikitech.ca?subject=siuj 335siuj.org siuj • volume 2, number 6 • november 2021 volume 2, number 6 | november 2021 issn 2563-6499 doi: 10.48083/ebym4017 editorial office info@siuj.org tel: 514-875-5665 ext. 26 siuj.org managing editor jane fairbanks jane.fairbanks@siu-urology.org the siuj is published 6 times a year by the société internationale d'urologie (siu). it is the official peer-reviewed publication of the siu but retains editorial independence. the siuj is circulated to urologists, urology residents, family medicine specialists, family medicine residents, general practitioners, nurses, medical libraries, and hospital and university departments of urology worldwide, for a total circulation of over 10,000. this publication was developed under the direction of the siuj editorial board. the siuj is published under an exclusive licence. the siuj is owned and published by the société internationale d’urologie (siu). marketing lillian petrusa lillian.petrusa@siu-urology.org advertising gerri-lynn sendyk advertising@siuj.org neither the siu nor the siuj endorses any service or the contents of any product referred to in any advertisement in the siuj. the siu and the siuj assume no responsibility or liability for damages arising from any error or omission, or from the use of any information or advice contained in the siuj. all editorial matter in siuj represents the opinions of the authors and not necessarily those of the siu or the siuj. all canadian prescription drug advertisements have been cleared by the pharmaceutical advertising advisory board. editorial board editor-in-chief peter c. black, md, canada associate editors thomas herrmann, md, switzerland kathleen kobashi, md, united states philippe spiess, md, united states henry woo, mbbs, australia social media editor jeremy y. c. teoh, mbbs, hong kong sar statistical editor alice dragomir, phd, canada icud editor luc valiquette, md, canada innovators editor amanda chung, mbbs, australia regional editors north america margarett shnorhavorian, md united states middle east danny rabah, mbbs saudi arabia south america sandro esteves, md brazil east asia tianxin lin, md china eastern europe roman sosnowski, md poland south asia sanjay sinha, mch india western europe tamsin greenwell, md united kingdom southeast asia edmund chiong, mbbs singapore africa yasser osman, mbbch egyptvisit bms.com to see how we’re bringing a human touch to everything we do. © 2021 bristol-myers squibb company. all rights reserved. noca21mm00001-01 02/21 we are in the business of breakthroughs—the kind that transform patients’ lives. dedicated to our mission of discovering, developing and delivering life-saving innovations that help patients prevail over serious diseases, we’ll never give up our search for more hope, for more people, around the world. 336 siuj • volume 2, number 6 • november 2021 siuj.org editorial board liaqat ali, mbbs pakistan abdol mohammad kajbafzadeh, md iran fahad alyami, mbbs saudi arabia wayne lam, mbbs hong kong sar mohsen azli, md algeria sang dong lee, md korea erdem canda, md turkey evelyn moshokoa, mbchb south africa yao-chi chuang, md taiwan dedan opondo, mbchb kenya archil chkhotua, md georgia mohammed shahait, mbbs jordan renu eapen, mbbs australia khurram siddiqui, mbbs oman agus rizal ardy hariandy hamid, md indonesia yaya sow, md senegal christopher ho chee kong, md malaysia chuan-liang xu, md china theocharis karaolides, md cyprus the société internationale d’urologie (siu). the society’s mission is to enable urologists in all nations, through international cooperation in education and research, to apply the highest standards of urological care to their patients. the siu is a major international platform for sustainable urological education and collaborative philanthropic activities aimed at improving urological care with more than 10,000 members from over 130 countries. siu central office 1155 robert-bourassa blvd., suite 1012 montreal, quebec, canada h3b 3a7 tel: +1 514 875-5665 fax: +1 514 875-0205 communications@siu-urology.org executive director susie petrusa susie.petrusa@siu-urology.org graphic design sam design info@studiosamdesign.com web design/ technical support aiki informatique info@aikitech.ca neither the siu nor the siuj endorses any service or the contents of any product referred to in any advertisement in the siuj. the siu and the siuj assume no responsibility or liability for damages arising from any error or omission, or from the use of any information or advice contained in the siuj. all editorial matter in siuj represents the opinions of the authors and not necessarily those of the siu or the siuj. all canadian prescription drug advertisements have been cleared by the pharmaceutical advertising advisory board. siuj.org siuj • volume 2, number 3 • may 2021 133 volume 2, number 3 | may 2021 issn 2563-6499 doi: 10.48083/asds5361 editorial office info@siuj.org tel: 514-875-5665 ext. 26 siuj.org managing editor jane fairbanks jane.fairbanks@siu-urology.org the siuj is published 6 times a year by the société internationale d'urologie (siu). it is the official peer-reviewed publication of the siu but retains editorial independence. the siuj is circulated to urologists, urology residents, family medicine specialists, family medicine residents, general practitioners, nurses, medical libraries, and hospital and university departments of urology worldwide, for a total circulation of over 10,000. this publication was developed under the direction of the siuj editorial board. the siuj is published under an exclusive licence. the siuj is owned and published by the société internationale d’urologie (siu). marketing lillian petrusa lillian.petrusa@siu-urology.org advertising gerri-lynn sendyk advertising@siuj.org neither the siu nor the siuj endorses any service or the contents of any product referred to in any advertisement in the siuj. the siu and the siuj assume no responsibility or liability for damages arising from any error or omission, or from the use of any information or advice contained in the siuj. all editorial matter in siuj represents the opinions of the authors and not necessarily those of the siu or the siuj. all canadian prescription drug advertisements have been cleared by the pharmaceutical advertising advisory board. editorial board editor-in-chief peter black, md, canada associate editors thomas herrmann, md, switzerland kathleen kobashi, md, united states philippe spiess, md, united states henry woo, mbbs, australia social media editor jeremy y. c. teoh, mbbs, hong kong sar statistical editor alice dragomir, phd, canada icud editor luc valiquette, md, canada innovators editor amanda chung, mbbs, australia regional editors north america margarett shnorhavorian, md united states middle east danny rabah, mbbs saudi arabia south america sandro esteves, md brazil east asia tianxin lin, md china eastern europe roman sosnowski, md poland south asia sanjay sinha, mch india western europe tamsin greenwell, md united kingdom southeast asia edmund chiong, mbbs singapore africa yasser osman, mbbch egyptvisit bms.com to see how we’re bringing a human touch to everything we do. © 2021 bristol-myers squibb company. all rights reserved. noca21mm00001-01 02/21 we are in the business of breakthroughs—the kind that transform patients’ lives. dedicated to our mission of discovering, developing and delivering life-saving innovations that help patients prevail over serious diseases, we’ll never give up our search for more hope, for more people, around the world. mailto:info%40siuj.org?subject=siuj http://siuj.org mailto:jane.fairbanks%40siu-urology.org?subject=siuj mailto:lillian.petrusa%40siu-urology.org%20?subject=siuj mailto:advertising%40siuj.org?subject=siuj 134 siuj • volume 2, number 3 • may 2021 siuj.org editorial board liaqat ali, mbbs pakistan abdol mohammad kajbafzadeh, md iran fahad alyami, mbbs saudi arabia wayne lam, mbbs hong kong sar mohsen azli, md algeria sang dong lee, md korea erdem canda, md turkey evelyn moshokoa, mbchb south africa yao-chi chuang, md taiwan dedan opondo, mbchb kenya archil chkhotua, md georgia mohammed shahait, mbbs jordan renu eapen, mbbs australia khurram siddiqui, mbbs oman agus rizal ardy hariandy hamid, md indonesia yaya sow, md senegal christopher ho chee kong, md malaysia chuan-liang xu, md china theocharis karaolides, md cyprus the société internationale d’urologie (siu). the society’s mission is to enable urologists in all nations, through international cooperation in education and research, to apply the highest standards of urological care to their patients. the siu is a major international platform for sustainable urological education and collaborative philanthropic activities aimed at improving urological care with more than 10,000 members from over 130 countries. siu central office 1155 robert-bourassa blvd., suite 1012 montreal, quebec, canada h3b 3a7 tel: +1 514 875-5665 fax: +1 514 875-0205 communications@siu-urology.org executive director susie petrusa susie.petrusa@siu-urology.org graphic design sam design info@studiosamdesign.com web design/ technical support aiki informatique info@aikitech.ca neither the siu nor the siuj endorses any service or the contents of any product referred to in any advertisement in the siuj. the siu and the siuj assume no responsibility or liability for damages arising from any error or omission, or from the use of any information or advice contained in the siuj. all editorial matter in siuj represents the opinions of the authors and not necessarily those of the siu or the siuj. all canadian prescription drug advertisements have been cleared by the pharmaceutical advertising advisory board. mailto:communications%40siu-urology.org?subject=siuj mailto:susie.petrusa%40siu-urology.org?subject=siuj mailto:susie.petrusa%40siu-urology.org?subject=siuj mailto:info%40studiosamdesign.com%20?subject=siuj mailto:info%40studiosamdesign.com%20?subject=siuj mailto:%20info%40aikitech.ca?subject=siuj this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. 271siuj.org siuj • volume 2, number 5 • september 2021 editorial impact factor dynamics peter c. black, editor-in-chief  soc int urol j.2021;2(5):271–272 doi: 10.48083/zkhi7989 every journal has its particular focus and also mission. the siuj, for example, strives for global representation and to provide relevant content to the global urologic audience. however, all journals share the goal of disseminating high-quality scientific content and, to some degree, journals are competing with one another for the same content. that is where the impact factor (if) comes in. for better or worse, the if has become the principle quantitative measure of quality of a journal. this is one of several factors that authors use to select a journal to which to submit their scientific articles. another factor may be the target audience of the journal. a paper may be better suited for a subspeciality journal rather than one targeting a broader audience. journals in fields of research with a smaller audience may have lower ifs but still maintain high quality. a journal may develop strategies to ma ximize if by developing content known to attract many citations (eg, review papers and guidelines), while another journal in the same field choses instead to provide a platform for publication across a broader spectrum of the specialty. the quality of the content in these two journals may be the same, but the former will claim a higher if and the latter will feel the pressure to change publication policies in an attempt to match the higher impact journal. journals with higher ifs attract higher quality manuscripts, which makes the process self-fulfilling. on the other hand, new journals like the siuj can struggle to attract articles because of the lack of if, which takes several years to obtain. indeed, many prospective authors question why they should submit to journals like the siuj if they cannot list an if in their curriculum vitae. the only motivation is for authors to support the mission and philosophy of the journal with the intent of building a high-quality journal that will eventually have a desirable if. the european urology family of journals has done a remarkable job in this regard. we have observed if inflation in all areas of medical publishing, including urologic publishing. there are numerous new urologic journals available. this implies that more papers are being published, which would mean that there is more opportunity for published papers to be cited. on the other hand, this also means that citations could be spread over more papers, which would result in if deflation. in an analysis by althouse et al. in 2008, most of the increase in if was attributed to more references per manuscript rather than more manuscripts[1]. the weighted if for 23 urologic journals in 2004 was 2.132, and it increased by 3.2% annually between 1995 and 2004. in their analysis, however, just as many journals left the field as entered the field, and that is not the case in urologic publishing in recent years. they reported that larger fields do not have larger ifs based on size alone. however, if every paper cites key articles on the topic of investigation, and there are many more papers, it does stand to reason that some journals will see an increase in if due to this increase in publication. the digital boom and open access could also contribute to if inflation. easier access to journal articles allows easier citation. a trip to the library and coins for the photocopy machine are no longer required to read a published article. in this regard, if inflation is a positive trend. it is also positive if it means more investigators are conducting and publishing research. there is no question that there are significant flaws in the use of the if as a measure of quality research and especially as a measure of an individual researcher’s output, which can be used to determine funding and promotion. the if of a journal is ultimately determined by technical factors not related to an article’s quality[2]. utrecht university in the netherlands has recently made a very clear statement with respect to the simmering debate about use of if in academia[3]. this institution will abandon the use of the if in all hiring and promotion decisions. instead, they will judge scholars on the basis of commitment to teamwork, efforts to promote open science, and other measures. means to evaluate those measures need to be established. other institutions will likely follow the lead of utrecht university, but there is no reason yet to think that the importance of the if in publishing and in academia will decline any time soon. http://siuj.org mailto:editorinchief%40siuj.org?subject=siuj 272 siuj • volume 2, number 5 • september 2021 siuj.org editorial references 1. althouse, bm west jd, bergstrom t, bergstrom ct. differences in impact factor across fields and over time. 2008 april 23. available at: https://escholarship.org/uc/item/76h442pg. accessed august 7, 2021. 2. seglen po. why the impact factor of journals should not be used for evaluating research. bmj.1997feb 15;314(7079):498–502. doi: 10.1136/bmj.314.7079.497 3. woolston c. impact factor abandoned by dutch university in hiring and promotion decisions. nature.2021 june 25;595:462. available at: https://www.nature.com/articles/d41586-021-01759-5. accessed august 7, 2021. doi: https://doi.org/10.1038/d41586-021-01759-5 http://siuj.org https://escholarship.org/uc/item/76h442pg https://www.nature.com/articles/d41586-021-01759-5 https://doi.org/10.1038/d41586-021-01759-5 5siuj.org siuj • volume 3, number 1 • january 2022 this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. editorial our billion-dollar donation to the publishing industry peter c. black, editor-in-chief soc int urol j.2021;3(1):5–6 doi: 10.48083/roge9523 critical issues related to the current system of peer review have been raised in a recent paper by aczel et al. on the cost of peer review[1]. the authors of this analysis estimated that 9.5 million manuscripts are submitted for peer review in one year, requiring 21.8 million reviews. if each reviewer requires 6 hours per review (a very generous estimate from the urologic perspective), that adds up to 130 million reviewer hours in one year, which is equivalent to 15 000 years of work. applying estimated average salaries to this time requirement, the cost adds up to $1.5 billion for the us, $626 million for china, and $391 million for the uk in one year. while the accuracy of the different numbers can be debated, the conclusion is very clear: we as a scientific community invest an extraordinary amount of time and effort in a peer review process that lines the pockets of the large publishing houses. t he response to t his a r t icle on socia l med ia demonstrated differing perspectives on this issue. the publishing industry was notably absent from the conversation. most scientists see the putative cost of peer review as a sign of a flawed system, but others have been less critical. some scientists make the point that this is “part of our job,” regardless of whether or not it is written into our contracts. the cost does not necessarily fall on the reviewer but instead on the university or other large institution paying the reviewer’s salary, which in turn may come from a public source. many researchers, however, are undertaking peer reviews on their own time, and this is perhaps even more common with clinicians reviewing for publications in fields like urology. some reviewers may not actually have the benefit of an institutional salary but still perform peer review. at the same time institutions will not necessarily be interested in seeking compensation for the peer review their faculty members are providing, since their priority is to facilitate dissemination of the results of scientific research. the main driving force for the current peer review model is the notion that we all gain from the peer review services provided by others when we publish ourselves, so we feel an obligation to give back. academics consider this a service to the scientific community, although the burden of peer review is not distributed equitably, which increases the burden on individual reviewers. i am often surprised by the unwillingness of actively publishing young investigators in our field to provide peer review. some clearly feel more of an obligation to give back than others, while others perhaps more readily see peer review as an opportunity, and still others probably are just less likely to say no when asked to do something. the bottom line is that the publishing industry is profiting enormously from our doing what most of us consider to be a necessary service. peer review activities are also underappreciated in the academic setting. we often see in the curriculum vitae of researchers a simple indication of the journals for which they have reviewed, but without any quantification of the number of reviews over a defined period of time, and no metric on the quality of reviews. david smith (@dvsneuro), assistant professor in psychology at temple university, suggested on twitter that peer review should be captured with a metric similar to the h-index for publishing (google scholar). payment of reviewers for their peer review is not an optimal solution to the problem. this would eat into publishers’ profits, unless the cost were simply defrayed by higher subscription fees. however, it would impair the ability of smaller journals to compete, and it would make diamond open access impossible. diamond open access is defined by authors paying nothing to publish while retaining copyright for their work and readers being able to access the content without charge. it is important to highlight the benefits peer review offers the reviewer. peer review is an essential component of the research process, and i have always been an advocate of urologists conducting peer review. some of the benefits are clear: it improves critical thinking, enhances writing skills, provides early exposure to the latest science, makes junior investigators more visible to editors, and allows reviewers to learn from each other. http://siuj.org mailto:editorinchief%40siuj.org?subject=siuj https://twitter.com/dvsneuro 6 siuj • volume 3, number 1 • january 2022 siuj.org editorial an article like the one by aczel et al. has the potential to stir discussion and trigger cries of dismay about the current system, but the important question is how we can rectify the issue[1]. aczel et al. provide insight into innovative measures that could reduce the cost and increase the value of peer review. open peer review, for example, at least makes the review available to the greater community, which adds value but does not diminish the financial impact of the current model. the problem is not the peer review–the problem lies in the profit margins of the publishers. as a community we need to re-think the publishing models. open access is important, but as long as authors are paying publication fees, the authors and the reviewers are still providing the product that is making the publishers wealthy. is diamond open access the key? as editor-in-chief of a diamond open access journal, my bias is clear. but should we as a field not be making a concerted effort to separate ourselves from the publishing companies and move towards this publishing model? reference 1. aczel b, szaszi b, holcombe ao. a billion-dollar donation: estimating the cost of researchers’ time spent on peer review. res integr peer rev.2021 nov 14;6(1):14. doi: 10.1186/s41073-021-00118-2 http://siuj.org 53siuj.org siuj • volume 3, number 2 • march 2022 this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. editorial calling all urologists around the globe to tell their stories peter c. black, editor-in-chief soc int urol j.2022;3(2):53–54 doi: 10.48083/eqqm2273 a key objective of the siu journal is to build an inclusive environment for exchange between all urologists around the world in a way that reflects the truly international spirit of the siu. first and foremost, this includes representation on the editorial board from all corners of the globe, peer review conducted by urologists in many different countries, and the solicitation of submissions from authors who may often encounter barriers to publication with other journals. however, there is more to it than that. “urology around the world” is a column that we would like to include in each issue of the siuj. this feature offers the microphone to any urologists or group of urologists who have a story to tell about the practice of urology in their part of the world. the story does not have to be exotic, and in fact will likely seem quite mundane to the urologist telling it, but it should reflect something specific about the urologic culture in that country or region. we have had diverse examples of this up to now, coming from africa, the middle east, and australia. each has had a specific story to tell. our first contribution came from australia in the middle of their second wave of the covid-19 pandemic[1]. australia’s two-tiered health care system is designed to allow more rapid and efficient access to private care if limited resources in the public system lead to delays in care. the private and public sectors are separate, and potentially have competing interests, but the pandemic galvanized the health care sector, allowing private and public to come together to increase staffing, resources, and patient care capacity. as we have learned over the past two years, the ability of a health care system to adapt to extreme and unanticipated demand is critical, and the australian system has done this robustly. urological training is a topic that is relevant to urologists everywhere, and there are countless different models for training urologists. the second “urology around the world” described the experiences of a senior trainee in nigeria seeking higher level training at a tertiary care center in ghana[2]. specialty care for patients with urologic conditions is not easily accessible in sub-saharan africa, so training models to develop local expertise are particularly important. a subsequent contribution from nigeria focused more on access to specialized equipment in the region[3]. this commentary described the ongoing use of open surgery for urinary tract stones in a resource-poor environment that lacks endoscopic equipment for ureteroscopy and percutaneous nephrolithotomy. successful introduction of endoscopic stone treatment would require not only acquisition of the equipment but also training of urologists to use this equipment and removal of economic barriers that would prevent patients from accessing these treatments. this is a unique perspective with which many are perhaps familiar, but it prompts us all to consider our own working environment and value the infrastructure available to us. importantly, this contribution also conveys the desire of urologists in countries like nigeria to upgrade their infrastructure and training so that they are able to elevate the standard of care in their regions. there is no doubt that they are excellent at what they practice, but less invasive methods would benefit their patients. the reader is again prompted to ponder how to achieve this kind of progress. the most recent contribution to “urology around the world” portrayed how a newly minted urologic oncologist just out of fellowship established himself in the world of private practice in aman, jordan while also consulting on the development of a pan-arab electronic medical record and launching an educational television series[4]. not many of us can claim to combine this exceptional skill set! we anticipate a future contribution about implementing a robotics surgery program in a country with limited access to new technologies and one on the challenges of being a woman in urology in a muslim country. in both instances these are stories of urologic practice that is specific to the author’s country and region but is also of broader interest to the urologic community. this is the goal of “urology around the world.” http://siuj.org mailto:editorinchief%40siuj.org?subject=siuj 54 siuj • volume 3, number 2 • march 2022 siuj.org editorial the siuj will be introducing another regular feature in the near future: “global personalities in urology.” this feature will again strive for inclusivity and diversity and will be dedicated to individuals, living or recently deceased, who have had a major impact on urologic practice in their community and beyond. stay tuned to find out who our first global personality will be! we are always open to suggestions and nominations. in the meantime, what is your story? it may seem trivial to you because you take it for granted, yet it may be quite different from anything anywhere else. please reach out if you want to test an idea—or simply tell us your story. all of us have different ways of delivering optimal care to our patients. maybe you also have a novel means to conduct research in your hospital, or perhaps you want to write about an issue related to practice plans and payment structures. one of these days i will have to write my own story about the canadian universities that do not pay their academic faculty a salary. but that is a topic for another day... references 1. hanna b, chung a. australia’s two-tier health care system. soc int urol j.2020;1(1):4–5. 2. khalid a. west africa sub-regional training and skills transfer: my experience at the urology unit of the korle-bu teaching hospital, accra, ghana soc int urol j.2020;2(1):7–9. 3. agbo c. open surgery for urinary stones in a resource poor setting: a look at dalhatu araf specialist hospital, lafia, nigeria. soc int urol j.2021;2(2):79–81. 4. a b u g h o s h z . p r i v a t e p r a c t i c e in j o r d a n . so c i nt u ro l j.2021;2(6):345–346. http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. 193siuj.org siuj • volume 2, number 4 • july 2021 editorial the two faces of open access peter c. black, editor-in-chief  soc int urol j.2021;2(4):193–194 doi: 10.48083/erok5654 the two faces of open access remain a point of contention in the global world of scientific publishing, and this carries over into the microcosm of urologic publishing. many of us are part of the research community and all of us are consumers of new research findings. on both sides of the research enterprise—as providers and consumers—our interests are best met by broad dissemination and universal access to all published research. these are the underlying objectives of open access publishing. there are societal and academic advantages to open dissemination of knowledge[1]. “open access,” however, has almost become a bad word in the medical community because of connotations of predatory journals and high publication fees. high publication fees are not pathognomonic for predatory journals—highly reputable journals that publish top research after rigorous review processes (not offered by predatory journals) can and do charge exorbitant publication fees. more importantly, however, open access should not be equated with high publication fees. open access can be offered at no cost to authors. i congratulated a colleague recently on a high impact publication that represented several years of carefully designed and executed translational research, only to discover that publication of that manuscript had consumed €5500 of his research budget. the draw of the impact factor seems to have justified the cost. if this manuscript had been published in the prestigious nature, it would have cost €9500 for open access[2]. as researchers and authors, we should be asking what happens to those high publication fees. the publisher bears the cost of processing the manuscript for publication, which does involve professional editorial staff. however, the researchers provide the content of the published material, their scientific peers carry out the review on a voluntary basis, and even the scientific editors are generally not remunerated, or only at a rate that does not compare on an hourly basis to their academic salaries or clinical revenues. lack of compensation for editors and reviewers is not necessarily a problem in itself, as it can be considered a return of service to the scientific community, but it becomes a significant problem when the publishers earn large profits from our academic services. the bottom line is that a large part of those €5500 publication fees goes back to the publisher as profit. scientific publishing is a lucrative business. elsevier, which is one of the largest publishers of scientific research, is owned by the parent company relx. relx reported us$9.8b profit in 2019, 34% of which was derived from elsevier[3]. this is an extraordinary sum of money that is taken out of the research enterprise and diverted to investors. in some cases, the €5500 publication fee may be provided by institutional accounts, but more often it is derived from a government funder, a charity funder, or perhaps a grateful patient donor. those parties pay for the research to be conducted and pay again to read about the results of that research. how do we justify taking money from these sources to generate profit for publishers for the dissemination of research results? these issues are not new, and initiatives have been undertaken to break down some of these financial barriers and push for financial transparency. plan s represents an effort by european funding agencies demanding open access publication of research funded by these agencies (although they do not account for publication fees). academic libraries, most notably the libraries of the university of california, have taken a stance in negotiating better deals with publishers to allow broader access to published literature. library subscription fees represent an important component of revenue for the publishers. it takes large institutions or conglomerates to challenge the immense influence of the publishing companies. there are two other stakeholders in the publication process who cou ld a lso inf luence t he current environment if they adopted a coordinated approach to work towards lower cost open access: industry partners advertising in scientific journals and the researchers publishing in scientific journals. advertising revenue remains a large part of journal profits[4]. those advertising dollars would likely cover open access publishing costs with no need for publication fees. if advertisers took a stand on the high cost of academic publishing, this could alter publishing practices. however, advertisers want the widest audience from the most prestigious journals, just as authors want the http://www.siuj.org mailto:editorinchief%40siuj.org?subject=siuj 194 siuj • volume 2, number 4 • july 2021 siuj.org editorial highest impact factor, so it is difficult to break the vicious cycle. on the authors’ side there have been initiatives to boycott publishers in protest over the cost of publication. “the cost of knowledge” was one such initiative that was started in 2012[5], but it appears to have had little impact on publishing practices despite attracting the signatures of 18 778 researchers from around the world[6]. another approach is for medical organizations to provide open access journals with no publication fees. several urological organizations have already done this, including the canadian urological association, the urological society of india, the brazilian society of urology, and the chilean society of urology. the siu has followed the model of these organizations with the launch of the siu journal. these journals provide high quality editorial processing, peer review, and prompt open access publication. the efforts of all involved in the process are dedicated to knowledge dissemination and not profit, and any profit that is generated feeds back into the society that supports the activities of the members who are reading and publishing in the journal. these journals all provide excellent alternatives to the more recognized high-cost journals. the economics of urologic publishing relate to supply and demand. we have to ask ourselves as physicians and researchers what we can do to shift the demand away from the profitdriven large publishing houses and towards the open access free journals. if we shift, the impact factors that we all chase will follow. references 1. tennant jp, waldner f, jacques dc, masuzzo p, collister lb, har tgerink chj. the academic, economic and societal impacts of open access: an evidence-based review. f1000res. 2016 apr 11;5:632. doi: 10.12688/f1000research.8460.3. ecollection 2016. 2. brainard j. for €9500, nature journals will now make your paper free to read. sciencemag.org.2020. available at: https://w w w. sciencemag.org/news/2020/11/9500-nature-journals-will-nowmake-your-paper-free-read. accessed june 14, 2021. doi:10.1126/ science.abf8491 3. rel x. annual report and financial statements 2019. available at: https://www.relx.com/~/media/files/r/rel x-group/documents/ repor ts/annual-repor ts/2019-annual-repor t.pdf. accessed june 14, 2021. 4. bhat tarcharjee m. publishers still rely on traditional revenue streams, research shows. what’s new in publishing. available at: ht tps://whatsnewinpublishing.com/publishers-still-rely-ontraditional-revenue-streams-research-shows/. accessed june 14, 2021. 5. https://gowers.files.wordpress.com/2012/02/elsevierstatementfinal. pdf. accessed june 14, 2021. 6. http://www.thecostofknowledge.com/. accessed june 14, 2021. http://www.siuj.org https://www.sciencemag.org/news/2020/11/9500-nature-journals-will-now-make-your-paper-free-read https://www.sciencemag.org/news/2020/11/9500-nature-journals-will-now-make-your-paper-free-read https://www.sciencemag.org/news/2020/11/9500-nature-journals-will-now-make-your-paper-free-read https://www.relx.com/~/media/files/r/relx-group/documents/reports/annual-reports/2019-annual-report.pdf https://www.relx.com/~/media/files/r/relx-group/documents/reports/annual-reports/2019-annual-report.pdf https://whatsnewinpublishing.com/publishers-still-rely-on-traditional-revenue-streams-research-shows/ https://whatsnewinpublishing.com/publishers-still-rely-on-traditional-revenue-streams-research-shows/ https://gowers.files.wordpress.com/2012/02/elsevierstatementfinal.pdf https://gowers.files.wordpress.com/2012/02/elsevierstatementfinal.pdf http://www.thecostofknowledge.com/ this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. open surgery for urinary stones in a resource poor setting: a look at dalhatu araf specialist hospital, lafia, nigeria christian a. agbo  institution-dalhatu araf specialist hospital, lafia, nigeria soc int urol j.2021;2(2):79–81 doi: https://10.48083/kfqz6048 dalhatu araf specialist hospital the dalhatu araf specialist hospital is a tertiary multispecia lt y public hospita l located in laf ia, a northern part of nigeria, which, because of the climate, has a high incidence of urologic stones even in children as young as one year old. within the state, which has a population of about 2 million, there is another tertiary institute (in keffi) that has 2 urologists. further afield, there are bigger hospitals in abuja, jos, and lagos that can undertake other procedures. some patients are referred to abuja, but it is a 3-hour drive from lafia, and we can refer only those who can afford to pay—about 90% cannot. management of urinary stones in our environment the dalhatu araf specialist hospital has x-ray and ultrasound equipment, and ct is available at a nearby centre. the hospital also has video equipment, but there is no funding for instruments. i have, therefore, purchased 2 cystoscopes, but they are rigid, rather than flexible, representing technology from the 1960s or 1970s, and they do not provide the same view as the more modern flexible scopes. the lack of technology is particularly frustrating because i spent 6 months in india training in the endoscopic management of stones, so i have the skill to undertake minimally invasive procedures if the equipment were available. table 1 overview of the open surgery done for urinary stones seen at dalhatu araf specialist hospital, lafia, nigeria within a 2-year period location of stone n % types of open surgery renal single 6 21.4 anatrophic nephrolithotomy extended pyelolithotomy staghorn 3 10.7 anatrophic nephrolithotomy extended pyelolithotomy ureter 5 17.9 ureterolithotomy bladder 11 39.3 cystolithotomy urethral 3 10.7 urethrolithotomy total 28 100.0 introduction urinary stone disease has aff licted humankind since antiquity[1]. it remains a common urological condition worldwide, including in our environment[2]. although open surgery was previously the main option for stone removal, advances in technology mean that treatment is now largely through minimally invasive surgery, as recommended by a number of urological guidelines[3,4]. unfortunately, at our centre, we still treat urinary stones solely through open surgery, mostly because we lack endoscopic equipment. in addition, most of our patients, even if referred to facilities where endoscopic management is possible, cannot afford the cost of treatment. 79siuj.org siuj • volume 2, number 2 • march 2021 urology around the world http://www.siuj.org urinary stones account for about 30% of my caseload as the hospital’s single urologist. in the last 2 years, 28 open surgeries for urinary stones were underta ken at the hospita l (table 1), including anatrophic nephrolithotomy, extended pyelolithotomy, ureterolithotomy, cystolithotomy (figure 1), and urethrolithotomy. patients with urinary stones are referred here from other smaller centres within the state. a good proportion (55.4%) of the patients are managed non-surgically, in accordance with the european association of urology guidelines. these are patients who are asymptomatic or non-obstructing and those that have medical expulsive therapy for lower ureteric stone. the patients are financially responsible for their health care but at a very subsidized rate because of the low socioeconomic status of the people, many of whom are subsistence farmers, growing rice and yams. cost is therefore a major consideration in treatment. if patients come in for surgery, they pay the hospital us$100 for stone management (more if there are complications). for a lot of patients, this is more than one month’s salary, and about 2/3 of patients are still managed without surgery. the commonest indication for surgery is persistent pain (61.2%) followed by obstruction. all patients who meet the indication for surgery are managed by open surgeries. although open surgery still has a role in stone management in cases of complex stone, hippocrates discouraged open surgeries for stone. his oath reads: ‘i will not cut persons labouring under the stone, but will leave this to be done by practitioners of this work’[5]. the majority of urinary stones can be managed endoscopically[6]. in the near future, we hope to manage stones endoscopically, which will require additional training and equipment. when surgery is required, patients are admitted a day before the procedure. the average hospital stay is 5 days. both external and internal stents are used here depending on the availability and affordability at time of surgery. when patients undergo pyelolithotomy, stents are usually put in, which can entail a hospital stay of up to 5 to 7 days (when external stent is used), depending on drainage. in some cases (when internal stent is used), they stay 2 to 3 days, and then come back for removal at 6 weeks post-procedure. when an external stent is used, it is passed through the kidney, as with nephrostomy. instead of a single j stent, we use a feeding tube, which is far less expensive and works just as well. as the sole urologist at the centre, i am also responsible for the patient’s postoperative care, which can be quite challenging. although we do have residents in general surgery, who assist me, as well as residents doing a three-month rotation in urology and subspecialties, there are no urology residents—and as the hospital does not have accreditation, we do not have visiting residents from abuja or lagos. postoperatively, the patient’s family is responsible for a lot of the care, including provision and preparation of food. pain medications are provided while the patient is in hospital, but at discharge, the patient assumes responsibility and must obtain needed drugs from the nurses or the pharmacy within the hospital. the hospital also sees a lot of benign prostatic hyperplasia. currently, it is not possible to do anything but retropubic simple prostatectomy because the hospital does not yet have the equipment to permit transurethral resection of prostate. we are looking forward to getting equipment. many patients cannot afford medical therapy, so they undergo simple prostatectomy, which i do here (probably 2 a month). postoperatively, patients are catheter-dependent for 7 to 10 days for transvesical prostatectomy, and most are comfortable with that. difficulty in getting to the centre or concerns about the cost of treatment means that patients with bladder cancer often present at an advanced stage. once the diagnosis has been confirmed by cystoscopy, patients are referred to a higher-level centre for transurethral resection of bladder tumour. chemotherapy is also available if patients can afford it. otherwise, radical cystectomy is performed at our centre. regardless, patients are often lost to follow-up. figure 1. a stone from the urinary bladder via open cystolithotomy 80 siuj • volume 2, number 2 • march 2021 siuj.org urology around the world http://www.siuj.org conclusion although open surgery still has a role in complex stone disease and in patients with anatomical and physiological anomalies, the majority of urinary stones can be managed by minimally invasive surgeries. to date, attempts to secure funding (from government bodies and from private foundations) for equipment that would allow stones to be managed endoscopically have been unsuccessful. we continue to seek support and funding for training and provision of endoscopic equipment that will enable us to meet the global standard of care. references 1. tefekli a, cezayirli f. the history of urinary stones: in parallel with civilization.  scientific world journal.2013;article id 423964. doi. org/10.1155/2013/423964 2. çakici öu, ener k, keske m, altinova s, canda ae, aldemir m, et al. open stone surgery: a still-in-use approach for complex stone burden. cent european j urol.2017;70(2):179–184. 3. tzelves l, türk c, skolarikos a. european association of urology urolithiasis guidelines: where are we going? eur urol focus. 2020;s2405–4569(20):30270-30274. doi: 10.1016/j.euf.2020.09.011. 4. zumstein v, betschart p, abt d, schmid hp, panje cm, putora pm. surgical management of urolithiasis – a systematic analysis of available guidelines. bmc urol.2018 apr 10;18(1):25. 5. buchholz n, elhowairis me, bach c, moraitis k, masood j. from ‘stone cutting’ to high-technology methods: the changing face of stone surgery. arab j urol.2011 mar;9(1):25–27. 6. el-husseiny t, buchholz n. the role of open stone surgery. arab j urol.2012;10(3):284–288. 81siuj.org siuj • volume 2, number 2 • march 2021 open surgery for urinary stones in a resource poor setting https://doi.org/10.1155/2013/423964 https://doi.org/10.1155/2013/423964 http://www.siuj.org key words competing interests article information verteporfin, fibrosis, urinary tract, inflammation none declared. received on october 14, 2021 accepted on october 17, 2021 soc int urol j. 2022;3(1):41–43 doi: 10.48083/gztk5882 41siuj.org siuj • volume 3, number 1 • january 2022 this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. commentary verteporfin: a novel antiproliferative agent for urinary tract fibrosis? jas singh department of urology, the university of texas md anderson cancer center, houston, united states urinary tract fibrosis following injury, ischemia, or chronic inflammation can produce clinically significant obstruction, organ dysfunction, and debilitating urinary symptoms. fibrosis is characterized by the excessive deposition of extracellular matrix, collagen, and glycoproteins by fibroblasts in response to the release of pro-fibrotic mediators such as tgf-β by macrophages[1]. this scarring often leads to the replacement of normal parenchymal tissue with fibrotic tissue, resulting in organ dysfunction and failure following chronic progression of this process[2]. efforts to minimize fibrosis and scarring have implications for improving post-surgical outcome, preventing urinary organ dysfunction, and improving patient quality of life. the objective of this paper is to review the mechanism of action of verteporfin, prior clinical use, and potential avenues for urological implementation. specifically, we seek to examine the novel use of this agent in urinary tract fibrosis. the process of wound healing is divided into linear but overlapping phases including hemostasis/coagulation, inf lammation, proliferation, and maturation. during the proliferation phase, wound contraction leads to the activation of tension sensing pathways[3]. yes-associated protein (yap) along with its transcriptional coactivator, taz, are activated and undergo translocation into the nucleus. in the nucleus, yap/taz promotes the transcription of engrailed-1 (en1) which then stimulates the conversion of en1-lineage-negative fibroblasts into en1-lineage-positive fibroblasts. these activated fibroblasts then drive the fibrotic response leading to increased collagen deposition and increased wound tension, thereby driving a positive feedback loop of proliferative fibrosis. the importance of the yap/taz signaling pathway has also been elucidated in oncogenesis as overexpression has been linked to the proliferation of tumor cells. yap is a critical component of the hippo tumor suppressor pathway where it promotes growth factor independent proliferation, epithelial mesenchymal transition, and suppression of tumor necrosis factor[4]. as well, yap overexpression has been linked to poor prognosis in some cancers, including urothelial carcinoma, secondary to its ability to confer resistance to cisplatin therapy[5]. therefore, this molecular target has numerous potential clinical implications. verteporfin is an inhibitor of the yap/taz pathway, whereby it binds to yap and interferes with its interaction with taz, leading to downregulation of yap and the fibrotic response[4]. as of 2000, the only approved clinical use of verteporfin by the u.s. food and drug administration is as a photosensitizer for photodynamic therapy in the treatment of age-related macular degeneration. as a photosensitizer, it facilitates mitochondrial damage in target tissues through the generation of reactive oxygen species and anti-vascular endothelial growth factor (vegf) activity[6]. however, its anti-tumor activity has been demonstrated to occur without the requirement for light stimulation[7]. recently, the role of yap/taz activation in renal tubulointerstitial inflammation and fibrosis following treatment with verteporfin was evaluated. a key component of renal fibrosis is release of the cytokine, tgf-β1. tgf-β1 is a potent mediator of fibrosis and therefore provides a critical therapeutic target for preventing the progression of renal fibrosis following acute kidney injury and subsequent chronic kidney disease development. jin et al. investigated the effect of verteporfin on unilateral ureteral obstruction (uuo)-induced http://siuj.org mailto:jsingh2%40mdanderson.org?subject=siuj renal fibrosis. they found that verteporfin treatment of kidneys with uuo showed decreased levels of tubular dilation, inflammatory cell infiltration, and tubulointerstitial fibrosis compared with controls. as well, verteporfin treated kidneys with uuo exhibited an attenuated response with respect to α-smooth muscle actin and fibroblast specific protein-1 expression, which are central to renal fibroblast activation. finally, the amount of type i collagen expression was reduced significantly in kidneys treated with verteporfin[8]. the anti-fibrotic activity of verteporfin has also been studied in relation to combination usage with triamcinolone acetonide, a corticosteroid with anti-angiogenic and anti-fibrotic properties mediated by the inhibition of proinflammatory prostaglandins and leukotrienes. ophthalmological studies demonstrated a synergistic effect of verteporfin and triamcinolone acetonide[9]. triamcinolone acetonide has been utilized in the treatment of urethral stricture disease and vesicourethral anastomotic stenosis, following incisional urethrotomy. as well, it maintains clinical applications in the management of pathologic phimosis and refractory interstitial cystitis. it may be that verteporfin is as efficacious as corticosteroids (or more so) for these indications, while avoiding the potentially serious adverse side effects. outside the urinary tract but within the scope of the genitourinary system, verteporfin has been evaluated in patients with peyronie’s disease. mohede et al. treated biopsies of peyronie’s disease plaques obtained from 5 patients at the time of surgery with verteporfin and then examined the tissue by immunofluorescent staining for myofibroblast activity. verteporfin was shown to reduce the expression of type i and iv collagen, fibronectin (component of the extracellular matrix), and loxl2 and plod2, enzymes involved in collagen cross-linking which occurs during scar contraction. the reduced expression of plod2 leads to a softer scar, which in turn is more readily degraded by matrix metalloproteinases[10]. at present, verteporfin is approved for clinical use only in the photodynamic therapy of age-related macular degeneration; however, the potential applications of this agent extend far beyond ocular disease, given its regulatory role in the yap/taz signaling pathway. preclinical studies have provided early data regarding its use in the urological domain, both as an anti-tumor agent and in the attenuation of renal interstitial and peyronie’s disease fibrosis. fibrosis and scarring can occur anywhere along the urinary tract leading to pain, infection, and obstruction, necessitating chronic indwelling stent and catheter placement. attempts to mitigate scarring and prevent organ dysfunction and failure are paramount in mitigating increasing morbidity and mortality in patients. there may be a role for verteporfin treatment of urinary tract fibrosis and scarring both in the primary prevention and secondary treatment setting. to answer these questions, additional studies are required to evaluate the effect of verteporfin on fibrotic strictures obtained from the urinary tract including the ureters, bladder, and urethra. if the attenuation and prevention of scar formation can be demonstrated on a preclinical basis, then perhaps verteporfin may prove a formidable antiproliferative option for the treatment and prevention of urinary tract fibrosis. 42 siuj • volume 3, number 1 • january 2022 siuj.org commentary http://siuj.org references 1. lichtman mk, otero-vinas m, falanga v. transforming growth factor beta (tgf-β) isoforms in wound healing and fibrosis. wound repair regen.2016;24(2):215-222. doi: 10.1111/wrr.12398 2. rockey dc, bell pd, hill ja. fibrosis–a common pathway to organ injury and failure. n engl j med.2015;372(12):1138-1149. doi: 10.1056/ nejm ra1300575 3. reinke jm, sorg h. wound repair and regeneration. eur surg res.2012;49(1):35-43. doi: 10.1159/000339613. epub 2012 jul 11. 4. mascharak s, desjardins-park he, davitt mf, griffin m, borrelli mr, moore al, et al. preventing engrailed-1 activation in fibroblasts yields wound regeneration without scarring. science.2021;372(6540):e aba2374. doi: 10.1126/science.aba2374 5. ciamporcero e, shen h, ramakrishnan s, yu ku s, chintala s, shen l, et al. yap activation protects urothelial cell carcinoma from treatmentinduced dna damage. oncogene.2016;35(12):1541-1553. doi: 10.1038/ onc.2015.219. epub 2015 jun 29. 6. chan wm, lim th, pece a, silva r, yoshimora n. verteporfin pdt for non-standard indications–a review of current literature. graefes arch clin exp ophthalmol.2010;248(5):613-626. doi: 10.1007/s00417-0101307-z. epub 2010 feb 17. 7. wei c, li x. the role of photoactivated and non-photoactivated verteporfin on tumor. front pharmacol.2020; 11:557429. doi: 10.3389/ fphar.2020.557429 8. jin j, wang t, park w, li w, kim w, park sk, et al. inhibition of yes-associated protein by verteporfin ameliorates unilateral ureteral obstruction-induced renal tubulointerstitial inflammation and fibrosis. int j mol sci.2020;21(21):8184 doi: 10.3390/ijms21218184 9. augustin a j, schmidt-er fur th u. ver tepor fin therapy and triamcinolone acetonide: convergent modes of action for treatment of neovascular age-related macular degeneration. eur j ophthalmol.2006;16(6):824-834. doi: 10.1177/112067210601600607 10. mohede dcj, de jong ij, bank ra, van driel mf. verteporfin as a medical treatment in peyronie’s disease. sex med.2018;6(4):302-308. doi: 10.1016/j.esxm.2018.08.002. epub 2018 sep 28. 43siuj.org siuj • volume 3, number 1 • january 2022 a rare case of hypersensitivity reaction associated with sacral neuromodulation hardware http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. effect of metallic ureteric stents on magnetic resonance imaging: implications for malignant ureteral obstruction mahima tellambura,1 isaac thangasamy,1,2 kwang chin,1 declan murphy1,3 1 division of cancer surgery, peter maccallum cancer centre, melbourne, australia 2 faculty of medicine, university of queensland, australia 3 the sir peter maccallum department of oncology, university of melbourne, melbourne, australia abstract metallic ureteric stents are increasingly used for the management of malignant ureteric obstruction, a commonly encountered complication in urological and other malignancies. however, there has been limited evaluation of complications associated with these stents, including those that might arise from the use of magnetic resonance imaging (mri). while most devices are deemed nominally “mri-safe,” their implication on the quality of imaging produced has not been evaluated in clinical trials, and in our practice, significant artefact has been encountered with some ureteric stents—specifically, the teleflex rüsch dd tumour stent—compromising image quality and diagnostic certainty. key words competing interests article information ureteric stents, metallic stents, magnetic resonance imaging, malignant ureteric obstruction none declared. received on march 20, 2021 accepted on may 14, 2021 soc int urol j.2021;2(4):256-258 doi: 10.48083/ wlvr1509 in managing malignant ureteric obstruction, metal or metal-incorporating stents are an increasingly popular option, owing to evidence suggesting improved patency compared with conventional polymeric stents[1]. in our practice, 44% of patients undergoing ureteral stenting between march 2017 and march 2018 (n = 77) had one or more metallic stents inserted. depending on t he ma ligna nc y, a signif ica nt proportion of patients undergoing stenting will require further pelvic magnetic resonance imaging (mri) for staging or re-staging. this is particularly the case in the management of rectal cancer. while all the stents are certified mri-safe, their effect on the quality of mri images produced has not been fully elucidated. mri compatibility has largely focused on energy absorption and safety within mri systems; however, their effect on the quality of diagnostic imaging has received limited mention. metals produce aberrancy within mri images through several mechanisms[2,3]: • inhomogeneities in the strong magnetic field, pr o d u c e d b y p a r a m a g n e t i c /f e r r o m a g n e t i c components. • frequency-encoding misregistration, due to changes in frequency of dephasing. • signal loss, due to increase in the rate of t2 phase decay. • failure of fat suppression, owing to the effect of metallic implants on the resonance frequency of nearby fat. the following factors contribute to the extent of artefact formed[3]: • the size of metallic implant. • specific composition of the implant. • artefact worsens with ferromagnetic implants (steel, iron) compared with those of paramagnetic or diamagnetic metals (titanium, platinum, copper). 256 siuj • volume 2, number 4 • july 2021 siuj.org brief communication mailto:mahima%40tellambura.com?subject=siuj http://www.siuj.org • most ureteral stents incorporate nitinol into their structure—a proven mri-safe nickel-titanium alloy with limited ferromagnetism. developed in 1963, it is used widely in implantable biomedical devices across all specialties, including surgery, cardiology,and interventional radiology[4]. • the orientation of the implant relative to the strong magnetic field. while ureteral stents produce markedly less artefact than larger metallic implants (such as joint prostheses), their location (particularly where mri of the pelvis is concerned) can have impact on diagnosis and staging. in mri of pelvic cancer, the posterior relation of the stented ureter may impact the diagnostic imaging produced[5] (figure 1). the figures (using the teleflex rüsch dd tumour stent) highlight the potential for metallic stents to produce clinically significant artefact. the patient is a 39-year-old woman with metastatic squamous cell carcinoma of the cervix, with locally advanced pelvic disease, and retroperitoneal metastasis. she presented with malignant right ureteric obstruction and urosepsis. the ureteric stent was inserted to improve drainage while on chemotherapy, and management of malignant obstructive uropathy. in patients such as the above, the role of mri is multifaceted, in that it is used for treatment planning, local staging, and for consideration of radical salvage surgery (for example, anterior or total pelvic exenteration, which is offered at this centre). as seen on this re-staging study, the artefact produced by the stainless steel crossbraiding component of the stent markedly compromises image quality, and with it, diagnostic certainty. a similar effect is not seen in ct imaging (figure 2). limited high-quality studies exist in comparing the current array of metallic stents available, including evaluation of their impact on imaging; a 2018 systematic review by khoo et al.[6] found high heterogeneity in 21 studies evaluated, and an overall “low quality of evidence” in evaluating efficacy. this was echoed in the 2021 review by corrales et al.[7]. significantly, no randomized controlled trials exist to evaluate outcomes between devices, and none of the existing literature considers impact on imaging. the mri compatibility and safety information for the available stents (provided by the manufacturers, and regulatory bodies) also differs. for example, resonance is a full-metallic stent (compared with alternatives, which are silicon polymer with metallic framework—for example, rüsch tumour stents, used commonly at our institution). manufacturer specification states that the device is “mr conditional,” stipulating the following: • a spatial gradient field (sgf) ≤450 gauss/cm. • whole-body averaged specif ic absorption rate (sar) of 1.5w/kg for 20mins, with an associated temperature rise < 0.800c. within these constraints, however, the manufacturer nevertheless acknowledges that image quality may be compromised when the area of interest relatively close to the position of the stent, with an artefact radius approximately 16mm per manufacturer testing protocol[8]. manufacturers of other metallic stents do not provide a similar level of detail with respect to their mri compatibility; most are classified as mri-safe (table 1). the only exception is the telef lex rüsch dd stent: during post-marketing surveillance, the manufacturer has released new advice recommending that mri not be performed. the manufacturer has reaffirmed, however, that the product is mri-safe, and that further testing is currently being undertaken. for patients with rüsch stents already implanted, however, the options are limited to stent exchange (if required); given the significant impact on imaging, most of these patients cannot be offered mri with stents in situ. while corrective techniques exist to account for these artefacts, there is limited research on the potential for clinically significant degradation in image quality. given the role that mri plays in the diagnosis and staging of malignancy, particularly pelvic malignancy, the artefact produced by ureteral stents has the potential to compromise mri as a diagnostic/staging tool. of particular concern is the potential for under-staging of cancer because the extent of peri-ureteral invasion may not be fully apparent. figure 1. gross stent-related artefact on coronal mri of patient with teleflex rüsch dd tumour stent in situ 257siuj.org siuj • volume 2, number 4 • july 2021 effect of metallic ureteric stents on magnetic resonance imaging: implications for malignant ureteral obstruction http://siuj.org further clarification is required on the part of manufacturers regarding the effect of metallic ureteral stents on mri imaging. clinicians in centres where such devices are implanted should be aware of these limitations before inserting these stents. references 1. asakawa j, iguchi t, tamada s, ninomiya n, kato m, yamasaki t, et al. treatment outcomes of ureteral stenting for malignant extrinsic ureteral obstruction: a comparison between polymeric and metallic stents. cancer manag res.2018;10:2977-2982. doi: 10.2147/cmar. s172283. 2. hargreaves b a , wor ters p w, pauly k b, pauly jm, koch k m, gold ge. metal-induced ar tifacts in mri. ajr am j roentgenol.2011;197(3):547-555. doi: 10.2214/ajr.11.7364. 3. fowler kj, maxwell j, saad ne, yano m, raptis c, menias c, et al. magnetic resonance imaging of iatrogeny: understanding imaging artifacts related to medical devices. abdom imaging. 2014;39(2):411423. doi.org/10.1007/s00261-013-0065-x. 4. szold a. nitinol: shape-memory and super-elastic materials in surgery. surg endosc.2006;20(9):1493-1496. doi: 10.1007/s00464-005-0867-1. 5. chin k. coronal magnetic resonance image of patient with teleflex rüsch dd tumour stent in situ. in: 1.jpg f, editor. melbourne, vic, australia: peter maccallum cancer centre; 2019. 6. khoo cc, abboudi h, cartwright r, el-husseiny t, dasgupta r. metallic ureteric stents in malignant ureteric obstruction: a systematic review. urology.2018;118:12-20. doi: 10.1016/j.urology.2018.01.019. 7. corrales m, doizi s, barghouthy y, kamkoum h, somani b, traxer o. a systematic review of long-duration stents for ureteral stricture: which one to choose? world j urol.2021.online ahead of print. doi: 10.1007/ s00345-020-03544-x. 8. teleflex rüsch tumour stents. manufacturer specifications. teleflex medical australia. table 1. sample of metallic stents available in australia stent design material mri data resonance (cook medical) metallic coil stent nickel–cobaltchromiummolybdenum alloy mri-safe memokath 051 (pnn medical) thermo-expandable shape-memory alloy nitinol–nickeltitanium alloy mri-safe allium (allium medical) polymer stent with nitinol mesh nitinol–nickeltitanium alloy mri-safe uventa (taewoon medical) layered polymer stent with nitinol mesh nitinol–nickeltitanium alloy mri-safe rüsch dd tumour stent (teleflex) polyurethane stent with metallic crossbraiding stainless steel braiding mri-safe not recommended per manufacturer figure 2. ct of patient with teleflex rüsch dd tumour stent in situ 258 siuj • volume 2, number 4 • july 2021 siuj.org brief communication https://www.dovepress.com/getfile.php?fileid=43943 https://www.dovepress.com/getfile.php?fileid=43943 https://www.ajronline.org/doi/10.2214/ajr.11.7364 https://link.springer.com/article/10.1007%2fs00261-013-0065-x https://pubmed.ncbi.nlm.nih.gov/16858524/ https://pubmed.ncbi.nlm.nih.gov/29408390/ https://pubmed.ncbi.nlm.nih.gov/33386951/ https://pubmed.ncbi.nlm.nih.gov/33386951/ http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information penile prosthesis, infection, erectile dysfunction, salvage surgery, revision prosthesis none declared. received on august 8, 2021 accepted on august 27, 2021 soc int urol j.2021;2(6):380–381 doi: https://doi:10.48083/gvcc5010 380 siuj • volume 2, number 6 • november 2021 siuj.org commentary expert roundtable discussion on penile prosthesis infection prevention measures eric chung,1, 2 martin s. gross,3 koenraad van renterghem,4 jay simhan5 1 university of queensland, princess alexandra hospital, brisbane, australia 2 androurology centre, brisbane and sydney, australia 3 dartmouth-hitchcock medical center, lebanon, united states 4 department of urology, jessa hospital and hasselt university, hasselt, belgium 5 einstein medical center, philadelphia, united states inflatable penile prosthesis (ipp) implantation remains the standard of care for men with medical-refractory erectile dysfunction. however, ipp infection remains one of the most consequential complications of penile prosthesis surgery[1,2]. apart from the patient morbidity and explant of the infected device, infection can also be associated with significant corporal fibrosis with ensuing reduction in penile size and more difficult re-implantation, as well as adverse psychosexual and socioeconomic effects[3,4]. the incidence of ipp infection has decreased over the last decade because of better surgical care pathways coupled with antibiotic-coated prostheses and surgical technique improvements[5]. ipp infection should be differentiated from infection of the surgical site alone[4]. most implant infections usually occur within the first 6 weeks because of bacterial contamination at the time of surgery. in contrast, chronic infections or infections occurring after 6 weeks are often subclinical, with patients presenting with chronic pain around the device components or device extrusion[6]. the following commentary is a summary of the experts’ round table discussion by key opinion leaders and high-volume surgeons from north america, europe, and asia pacific regions at the recent société internationale d'urologie (siu) academy educational webinar. contemporary literature and clinical evidence regarding the prevention and management of penile implant infection were discussed[2,6,7]. a detailed analysis of all relevant studies, including a full surgical description, is not feasible in this commentary. 1. primary penile implant infection modifications of preoperative and perioperative risk factors with appropriate use of antibiotic coverage and modern ipp have significantly reduced infection rates over the years. pre-existing medical comorbidities such as diabetes, smoking status, immunosuppression, radiation history, neurological disorder, previous pelvic surgery, older age, and obesity have all been shown to increase the risk of peri-prosthetic infection[2–4,6–9], and optimisation of these risk factors might mitigate ipp infection. all patients should undergo routine preoperative urine microscopy tests and skin checks. appropriate precautions to minimize contamination by common skin organisms include a preoperative shower with an antibacterial agent, intraoperative hair removal and use of alcoholic formulations for skin preparation[6,7]. perioperative antibiotic prophylaxis, ideally given at least 1 hour before surgery, and the use of antibiotic-coated devices have been well documented to minimize intraoperative infection risk[2,6,7]. while the nature of intravenous antibiotics is likely dependent on local institution antibiotics policy, the combination of antibiotics covering both gram-positive and gram-negative bacteria is preferred. the co-administration of an antifungal is usually reserved for patients with obesity or poorly controlled diabetes, or in certain geographical locations, or in the setting of salvaging an infected ipp[2,3]. the group consensus recommendation to augment coverage with antifungals is in contradistinction to existing antimicrobial recommendations of the american urological association and the european association of urology but is felt to be necessary given contemporary studies that have demonstrated the prevalence of fungal organisms in these high-risk penile implant populations. standard surgical protocols such as appropriate full protective surgical attire and limiting the number of staff and traffic within the operating room should be instituted[7]. attention to surgical wound sterility with a small surgical field, the use of antibiotic solution irrigation and minimizing device-skin contact, have been described to improve surgical sterility[6,7]. there is currently no evidence to suggest that a particular surgical approach has a higher infection risk[1]. postoperative antimicrobial prophylaxis is often given especially in high-risk groups (eg, people with diabetes) although this remains a surgeon preference. patients are advised to maintain high standards of hygiene and refrain from sexual activity in the first 4 to 6 weeks after surgery. any signs of impending infection such as fever or early cellulitis should be brought to the attention of the surgeon immediately. 2. revision penile implant infection patients with pre-existing risk factors will always have a higher risk of ipp infection after revision surgery compared with after primary surgery[3,6]. those operated on for impending device component erosion are at increased risk of infection, especially if the revision surgery requires additional or complex procedures such as graft reconstruction[3]. in revision surgery, aggressive irrigation of all surgical sites and excision of pseudo-capsule may remove bacterial seeding within the biofilm, which is often responsible for delayed device infection[2,4,7]. any device that is older than 5 years should ideally be exchanged at the revision surgery. the existing reservoir can be retained in the absence of infection or eroded penile prosthetic component if the defunctionalized reservoir is located within the extraperitoneal and retropubic space[6,7], but needs to be emptied and capped to prevent fluid accumulation and subsequent risk of infection[1]. many surgeons will prescribe postoperative antibiotics for patients in revision and salvage cases. 3. salvage penile implant infection in the early stage of ipp infection, a trial course of intravenous antibiotics with or without antifungal may be appropriate in the absence of systemic sepsis or purulent discharge[1,2]. however, the decision for surgical intervention should be made if there is a progression of sepsis or evidence of device extrusion[1,3,4]. the decision to conserve an ipp or not depends on the patient’s presentation and clinical status, the timeline and onset of infection, and response to the antibiotic treatment[10]. while explant of the infected device without salvage remains the safest option, salvage protocol with revision penile prosthesis implant can be carried out if there is an absence of tissue necrosis and purulence in the corporal bodies or scrotum[1–3,7]. in the salvage cases, all components of the device should be removed with aggressive mechanical lavage based on various versions of mulcahy’s washout protocols using a series of antiseptic solutions consisting of half-strength povidone-iodine, half-strength hydrogen peroxide, and combination antibiotic agents. an immediate device replacement importantly preserves sexual function and penile length and further prevents corporal fibrosis. a malleable implant is a simpler and cheaper alternative to ipp that can be used at the time of salvage surgery and facilitate eventual conversion to inflatable implant in the near or long-term future[1]. for a delayed re-implantation, use of a vacuum erection device may help in obtaining good results and reducing fibrosis and the shortening of the penis. references 1. levine l a, becher e, bella a, brant wo, kohler ts, martinezsalamanca ji. penile prosthesis surgery: current recommendations from the international consultation on sexual medicine. j sex med.2016;13:489–518. doi: 10.1016/j.jsxm.2016.01.017 2. swanton ar, munarriz rm, gross ms. updates in penile prosthesis infections. asian j androl.2020;22(1):28-33. 3. chung e. penile prosthesis implant in the special populations: diabetics, neurogenic conditions, fibrotic cases, concurrent urinary incontinence, and salvage implants. asian j androl.2020;22(1):39-44. 4. al-shaiji tf, yaiesh sm, al-terki ae, alhajeri fm. infected penile prosthesis: literature review highlighting the status quo of prevention and management. aging male.2020;23(5):447-456. 5. chung e. penile prosthesis implant: scientific advances and technological innovations over the last four decades. transl androl urol.2017;6(1):37-45. 6. hebert kj, kohler ts. penile prosthesis infection: myths and realities. world j mens health.2019;37(3):276-87 7. best jc, clavijo ri. best practices for infection prevention in penile prosthesis surgery. curr opin urol.2020;30(3):302-308. 8. gon lm, de campos ccc, voris br, passeri la, fregonesi a, zanettini riccetto cl. a systematic review of penile prosthesis infection and meta-analysis of diabetes role. bmc urol.2021;21:35. doi: https://doi.org/10.1186/s12894-020-00730-2 9. carrasquillo rj, munarriz rm, gross ms. infection prevention considerations for complex penile prosthesis recipients. curr urol rep.2019;20(3):12. 10. barlotta r, foote c, simhan j. penile prosthesis salvage: review of past and current practices. curr sex health rep.2019;11:185-189. 381siuj.org siuj • volume 2, number 6 • november 2021 expert roundtable discussion on penile prosthesis infection prevention measures this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. increasing awareness about male infertility: an overview of the sperm dna fragmentation study group (sfrag) guidelines sandro c. esteves  sandro c. esteves: https://orcid.org/0000-0002-1313-9680 androfert, andrology and human reproduction clinic, referral center for male reproduction, campinas, brazil department of surgery (division of urology), university of campinas (unicamp), campinas, brazil. faculty of health, aarhus university, aarhus, denmark sperm dna integrity is indispensable for the birth of healthy offspring[1]. increasing evidence indicates that sperm dna fragmentation (sdf), a marker of damaged chromatin, has an independent and critical role in male infertility and reproductive success[2]. the reasons relate to the often higher sdf levels in ejaculated semen of infertile men (versus their fertile counterparts) and the adverse impact of sdf on the sperm’s ability to fertilize the egg and promote healthy embryo development[2,3]. consequently, couples in whom the male partner exhibits high sdf on neat semen may have longer time-to-pregnancy, increased risk of pregnancy loss, and decreased success in medically assisted reproductive (mar) modalities (eg, intrauterine insemination [iui] and in vitro fertilization/intracytoplasmic sperm injection [ivf/icsi])[4]. the adverse effect of sdf on reproductive success is modulated by the oocyte’s dna repair capacity intrinsically related to female age[5]. sperm dna damage exceeding the oocyte’s repair capacity–or the oocyte’s failure to repair dna damage–negatively influences the embryo’s development potential and the offspring’s health[6]. routine semen analysis–the laboratory backbone of infertility investigation–has shown little progress over the last century. semen analysis results have low discriminatory power (except at extremely low levels) as there is considerable overlap between semen characteristics (eg, sperm count, motility, and morphology) of fertile and infertile men[7]. the need for more robust male infertility diagnosis methods has been the driving force of the ongoing efforts to develop and implement sdf testing in clinical practice. indeed, sdf tests represent one of the best examples of translational medicine in andrology. while it is not a replacement for the current tools for infertility diagnosis, sdf testing may add independent information about sperm quality at the molecular level, and its integration into practice may provide better counseling, diagnosis, and treatment planning. despite that, societies like the american urological association and the american society for reproductive medicine have not recommended using sdf testing routinely during the infertility evaluation, albeit acknowledging that the tests’ results might be informative. insufficient clinical data, tests’ technical limitations and lack of effective treatment options to overcome sdf-related infertility have been the common grounds for the reluctance to endorse the clinical application of sdf tests[8]. however, evidence on these areas has increased steadily, justifying the development of clinical practice guidelines to refine efficiency in diagnosing and treating clinical conditions associated with sdf. key words competing interests article information male infertility, practice guideline, sperm dna fragmentation, semen analysis, assisted reproductive technology sce declares the receipt of unrestricted research grants and lecture fees from merck outside the submitted work. the author is a member of the sperm dna fragmentation group and lead author of the sfrag guidelines. received on november 2, 2020 accepted on december 13, 2020 soc int urol j.2021;2(2):129–132 doi: https://doi.10.48083/ wnau8209 129siuj.org siuj • volume 2, number 2 • march 2021 commentary mailto:s.esteves%40androfert.com.br?subject=siuj https://orcid.org/0000-0002-1313-9680 https://doi.10.48083/wnau8209 http://www.siuj.org this commentary highlights the recently published ev idence-based guideline from the sperm dna fragmentation study group (sfrag), which provides a comprehensive summary about the role of sdf in infertility and offers best practice advice on testing and care of couples with sdf[9]. the primary goals of the sfrag guideline are to provide clinicians– urologists, andrologists, gynecologists, and reproductive endocrinologists–with clear advice on best practices in sdf. the sfrag recommendations were based on the best available evidence, which ranged from moderate to low quality. the guideline may be used to help standardize care while securing physician autonomy, making it an invaluable resource for a broad range of professionals providing infertility care, particularly urologists. the first part of the sfrag guideline outlines the sdf pathophysiology and explains each sdf test. in brief, many conditions, including varicocele, chronic illness, accessory gland infections, advanced paternal age, lifestyle, obesity, occupational and environmental factors, medications, ionizing and non-ionizing radiation, and heat exposure, have been associated with elevated sdf levels. these conditions can promote sdf by causing defective spermatogenesis, evoking abortive apoptosis, or increasing the generation of reactive oxygen species (ros). excessive ros causes oxidative stress, a significant causative factor of sdf in live sperm. the sfrag guideline states there are 4 reliable tests to measure sdf. these tests are grouped in methods that use (a) enzymatic reactions to label the dna breaks (eg, terminal deoxynucleotidyl transferase‐mediated dutp‐biotin nick end labeling [tunel] assay) and (b) controlled dna denaturation combined with protein depletion as intermediates to reveal the dna breaks (eg, sperm chromatin structure assay [scsa], sperm chromatin dispersion test [scd], and the comet assay). this guideline includes 13 recommendations on how testing should be carried out and results analyzed. notably, it states that a standardized protocol with strict quality control is essential for a reliable test result and that a neat semen sample should be used for sdf testing, collected after ejaculatory abstinence of 2 to 5 days. it notes that although the results provided by the most common sdf tests do not necessarily line up, there is a good correlation between sdf rates reported by tunel, scsa, scd, and alkaline comet. thresholds of about 20% by tunel, scsa, scd, and alkaline comet, assessed on neat semen, best discriminate fertile from infertile men. additionally, thresholds of 20% to 30% evaluated by scsa, alkaline comet, and scd are clinically useful for classifying infertile couples into those with a statistical probability of longer time to achieve natural pregnancy, a decreased chance of pregnancy with mar, and an increased miscarriage risk. lastly, it highlights that a fixed ejaculatory abstinence length should be used for sdf testing when monitoring the effects of medical and surgical interventions aimed at decreasing sdf levels. the second part describes 7 clinical situations that may benefit from sdf testing: 1. varicocele 2. unexplained/idiopathic infertility 3. recurrent pregnancy loss 4. intrauterine insemination 5. in vitro fertilization/intracytoplasmic sperm injection 6. infertility risk factors 7. sperm cryopreservation. • varicocele: repairing a clinical varicocele may alleviate sdf, potentially increasing the likelihood of reproductive success. sdf testing may help identify patients with a profile that would not fit the standard indication of varicocele repair (eg, clinical varicocele of any grade and normal/borderline routine semen analysis) but would benefit from varicocele repair. sdf testing may be used to monitor treatment outcomes. however, sdf testing in subfertile men with subclinical varicocele is not currently recommended. • unexplained/idiopathic infertility: couples with unexplained/idiopathic male infertility should be informed that abnormal sdf levels may adversely impact their chances of achieving a live birth. an abnormal test result should prompt a complete male fertility evaluation by a reproductive urologist to help identify and possibly treat conditions associated with poor sperm dna quality. icsi may be considered if no correctable male factor is identified, or if abnormal sdf levels persist after treatment, particularly among couples with a limited reproductive time window. • medically assisted reproduction: infertile couples eligible for mar treatment should be informed that abnormal sdf levels may adversely impact their chances of achieving a live birth. as in idiopathic/ unexplained infertility, a reproductive urologist’s evaluation is recommended to help identify and possibly treat conditions associated with sdf. among couples with icsi failure and elevated sdf, sperm retrieved from the testis may be considered for sperm injection in subsequent treatment cycles because of the lower sdf rates in testicular than in epididymal and ejaculated sperm and the higher icsi success rates with use of testicular sperm rather than ejaculated sperm. 130 siuj • volume 2, number 2 • march 2021 siuj.org commentary http://www.siuj.org • risk factors: sdf testing is recommended in men with infertility risk factors (eg, tobacco smoking, obesity, metabolic syndrome, exposure to environmental or occupational toxicants, use of drugs with gonadotoxic effects, and advanced paternal age). an abnormal sdf test result may be used for counseling, reinforcing the importance of lifestyle changes and avoiding exposure to toxins, and monitoring the effect of lifestyle changes. it should also prompt a urologist’s evaluation to help identify other hidden and potentially correctable conditions linked to sdf. the sfrag guideline was developed by reproductive urologists with clinical experience in diagnosing and treating male factor infertility and a reproductive endocrinologist with insight into the application of sdf testing in couples undergoing assisted conception. additionally, a group of scientists pivotal in developing the main sdf assays worked together, making the interpretation of tests' results and their limitations easy to understand. for each recommendation, a strength rating based on both expert judgment and evidence levels is provided. the guideline emphasizes the central role of urologists in the evaluation of the male partner and highlights the importance of corrective measures to improve the male reproductive health overall and sdf in particular (figure 1). lastly, the sfrag guideline discusses the main gaps in knowledge and provides recommendations for future research. figure 1 a pictorial summary of the recommendations for sdf testing and possible management in couples with high sdf reprinted with permission. esteves sc, et al.[9] iui: intrauterine insemination; ivf: in vitro fertilization; icsi: intracytoplasmic sperm injection; rpl: recurrent pregnancy loss. 131siuj.org siuj • volume 2, number 2 • march 2021 increasing awareness about male infertility: an overview of the sperm dna fragmentation study group (sfrag) guidelines http://www.siuj.org references 1. krawet z sa. paternal contribution: new insights and future challenges. nat rev genet. 2005;6:633–642. 2. esteves sc, santi d, simoni m. an update on clinical and surgical interventions to reduce sperm dna fragmentation in infertile men. andrology. 2020;8:53-81. 3. champroux a, torres-carreira j, gharagozloo p, drevet jr, kocer a . mammalian sperm nuclear organization: resiliencies and vulnerabilities. basic clin androl. 2016;26:17. 4. esteves sc, santi d, simoni m. an update on clinical and surgical interventions to reduce sperm dna fragmentation in infertile men. andrology. 2020;8:53-81. 5. jin j, pan c, fei q, ni w, yang x, zhang l, et al. effect of sperm dna fragmentation on the clinical outcomes for in vitro fertilization and intracy toplasmic sperm injection in women with dif ferent ovarian reserves. fertil steril. 2015;103:910-916. 6. aitken r j. dn a damage in human spermatozoa; impor tant contributor to mutagenesis in the offspring. transl androl urol. 2017;6:s761-s764. 7. esteves sc. clinical relevance of routine semen analysis and controversies surrounding the 2010 world health organization criteria for semen examination. int braz j urol. 2014;40:443-53. 8. esteves sc, agar wal a , cho cl , majzoub a . a strengthsweaknesses-opportunities-threats (swot) analysis on the clinical utilit y of sperm dna fragmentation testing in specific male infertility scenarios. transl androl urol.2017;6(suppl 4):s734-s760. 9. esteves sc, zini a, coward rm, evenson dp, gosálvez j, lewis sem, et al. sperm dna fragmentation testing: summary evidence and clinical practice recommendations. andrologia. 2020;oct 27:e13874. epub ahead of print. 132 siuj • volume 2, number 2 • march 2021 siuj.org commentary http://www.siuj.org key words competing interests article information penile cancer, cancer staging, circumcision none declared. received on september 22, 2021 accepted on december 30, 2021 this article has been peer reviewed. soc int urol j. 2022;3(2):102–107 doi: 10.48083/oikh5959 102 siuj • volume 3, number 2 • march 2022 siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. brief communication the relationship of circumcision with clinical tumor staging of penile cancer marco bandini,1 philippe e. spiess,2 yao zhu,3 antonio a. ornellas,4 benjamin a. ayres,5 oliver w. hakenberg,6 friederike haidl,7 filippo pederzoli,1 giuseppe basile,1 alberto briganti,1 francesco montorsi,1 juan chipollini,2 mounsif azizi,2 gert de meerleer,8 oscar r. brouwer,9 maarten albersen,8 andrea necchi,10 peter a. s. johnstone2 1 san raffaele hospital and scientific institute, milan, italy; vita-salute san raffaele university, milan, italy 2 moffitt cancer center and research institute, tampa, united states 3 fudan university shanghai cancer center, shanghai, china 4 hospital mário kröeff and brazilian cancer institute, rio de janeiro, brazil 5 st george’s university hospitals, nhs foundation trust, london, united kingdom 6 university hospital rostock, rostock, germany 7 universitätsklinikum köln, köln, germany 8 university hospitals leuven, leuven, belgium 9 the netherlands cancer institute, antoni van leeuwenhoek hospital, amsterdam, the netherlands 10 fondazione irccs istituto nazionale dei tumori, milano, italy abstract in this report, we look at the relationship between prior circumcision and presenting stage of penile cancer. we performed an analysis of an international, multicenter database of 1254 penile cancer patients diagnosed from 1980 to 2019 in the united states, europe, brazil, and china, and analyzed the relationship between circumcision and presenting t and n stage. a total of 710 patients met the inclusion criteria and were statistically analyzed. we found that uncircumcised men with locally advanced tumors (t3–t4) had significantly higher risk of lymph node metastasis compared with circumcised men. the genital microbiome is the only shared human microbiome[1]. since circumcised men harbor different bacterial communities than uncircumcised men[2], we hypothesized that circumcised men may present with a different penile squamous cell carcinoma (pscc) disease burden than uncircumcised men. were this the case, it could manifest as a difference in either the t or n stage of the subsequent disease. to our knowledge, no prior study has discussed the relationship of prior circumcision with the presenting tumor stage. in order to do so, we performed a retrospective cohort study. large clinical datasets of patients with pscc are uncommon given the rarity of the disease[3]. we have collaborated on an international, multicenter retrospective database of 1254 penile cancer patients diagnosed from 1980 to 2019 in the united states, europe, brazil, and china. previous publications from our group have discussed correlates of chemotherapy and lymph node dissection use by participating institutions[4–6], and association between human papillomavirus (hpv) infection and radiosensitivity[7]. for this report, we analyzed the relation between circumcision and presenting t and n stage. patients treated with circumcision during the surgery of the primary lesion or those without data on time of circumcision were excluded. http://siuj.org mailto:peter.johnstone%40%20moffitt.org?subject=siuj for this analysis, 710 patients met the inclusion criteria (figure 1). patient characteristics are summarized in table 1. descriptive statistics included frequencies and proportions for categorical variables. medians and interquartile ranges (iqr) were reported for continuous variables. the statistical significance of differences in medians and proportions between circumcised and uncircumcised men with penile cancer was tested with the kruskal-wallis and chi-square tests, respectively. ana lyses were organized in several steps. first, we explored predictors of inguina l ly mph node metastases (ilnm) among several variables including circumcision, histology (squamous cell versus nonsquamous cell), t stage (t< 2 versus t2 versus t3–t4), age at penile cancer diagnosis, use of perioperative chemotherapy, surgical procedure to the primary (total penectomy versus partial penectomy versus no surgery/ local surgical procedures). the choice of the predictors for this multivariable model has been made based on clinical relevance. second, to assess whether the higher risk of ilnm in locally advanced tumors (t3–t4) was different by circumcision status, we tested an interaction with t stage and circumcision. third, we depicted the probability of inguinal lymph node metastases for circumcised and uncircumcised men with penile cancer across t sub-stages. figure 1. inclusion/exclusion criteria and study population 710 patients enrolled in this study cohort 1254 patients with penile cancer 475 patients without circumcision data 779 circumcised and uncircumcised patients with penile cancer 2 patients without available pt and pn stage data 777 patients with available pt and pn stage data 20 patients without type of surgery of the primary data 757 patients received surgery of the primary 47 patients without available follow-up data table 1. epidemiological, geographical, and disease-specific characteristics of 710 penile cancer patients treated within 9 tertiary referral institutions variable overall (n = 710) circumcised (n = 550) not circumcised (n = 160) p-value median age at diagnosis (range) 59 (50–69) 59 (50.2–68.8) 58 (48.8–69) 0.98 median ilmn (range) 13.3 (4.3–25) 13.3 (4.8–25) 12.5 (0–26.8) 0.89 geographical areas (%) europe brazil united kingdom united states 388 (54.6) 173 (24.4) 77 (10.8) 72 (10.1) 304 (55.3) 145 (26.4) 66 (12) 35 (6.4) 84 (52.5) 28 (17.5) 11 (6.9) 37 (23.1) < 0.001 hpv infection (%) yes no na 371 (52.3) 38 (5.4) 301 (42.4) 284 (51.6) 26 (4.7) 240 (43.6) 87 (54.4) 12 (7.5) 61 (38.1) 0.21 smoking habit (%) current or former never na 246 (34.6) 166 (23.4) 298 (42) 204 (37.1) 121 (22) 225 (40.9) 42 (26.2) 45 (28.1) 73 (45.6) 0.04 cht: chemotherapy; ilnm: inguinal lymph node metastasis; lnd: lymph node dissection; rt: radiotherapy; scc: squamous cell carcinoma 103siuj.org siuj • volume 3, number 2 • march 2022 the relationship of circumcision with clinical tumor staging of penile cancer http://siuj.org table 1. epidemiological, geographical, and disease-specific characteristics of 710 penile cancer patients treated within 9 tertiary referral institutions variable overall (n = 710) circumcised (n = 550) not circumcised (n = 160) p-value histology (%) scc non-scc 622 (87.6) 88 (12.4) 477 (86.7) 73 (13.3) 145 (90.6) 15 (9.4) 0.21 pt stage (%) pt<2 pt2 pt3-4 277 (39) 279 (39.3) 154 (21.7) 190 (34.5) 235 (42.7) 125 (22.7) 87 (54.4) 44 (27.5) 29 (18.1) < 0.001 pn stage (%) nx-n0 n1-n2 n3 230 (32.4) 193 (27.2) 287 (40.4) 182 (33.1) 151 (27.5) 217 (39.5) 48 (30) 42 (26.2) 70 (43.8) 0.60 inguinal lnd (%) bilateral unilateral not performed 479 (67.5) 143 (20.1) 88 (12.4) 364 (66.2) 107 (19.5) 79 (14.4) 115 (71.9) 36 (22.5) 9 (5.6) 0.01 node metastasis side (%) negative ilnm bilateral ilnm unilateral ilnm ilnd not performed na 112 (15.8) 174 (24.5) 158 (22.3) 21 (3) 245 (34.5) 78 (14.2) 133 (24.2) 120 (21.8) 19 (3.5) 200 (36.4) 34 (21.2) 41 (25.6) 120 (21.8) 2 (1.2) 45 (28.1) 0.1 type of surgery of the primary penile lesion (%) total penectomy no surgery/ local procedures partial penectomy 162 (22.8) 97 (13.7) 451 (63.5) 141 (25.6) 40 (7.3) 369 (67.1) 21 (13.1) 57 (35.6) 82 (51.2) < 0.001 perioperative cht (%) no cht cht na 328 (46.2) 258 (36.3) 124 (17.5) 249 (45.3) 193 (35.1) 108 (19.6) 79 (49.4) 65 (40.6) 16 (10) 0.02 perioperative rt (%) no rt rt na 509 (71.7) 82 (11.5) 119 (16.8) 388 (70.5) 57 (10.4) 105 (19.1) 121 (75.6) 25 (15.6) 14 (8.8) < 0.01 pelvic lnd (%) no yes na 366 (51.5) 264 (37.2) 80 (11.3) 271 (49.3) 207 (37.6) 72 (13.1) 95 (59.4) 57 (35.6) 8 (5) 0.01 cht: chemotherapy; ilnm: inguinal lymph node metastasis; lnd: lymph node dissection; rt: radiotherapy; scc: squamous cell carcinoma 104 siuj • volume 3, number 2 • march 2022 siuj.org brief communication http://siuj.org table 2a. univariable and multivariable analysis testing the risk of ilmn according to several predictors univariable analysis multivariable analysis covariates or 5% 95% p-value or 5% 95% p-value previous circumcision 0.72 0.46 1.14 0.2 0.63 0.36 1.10 0.1 non-scc histology 5.19 2.10 17.28 0.002 2.82 1.00 10.17 0.07 pt2 stage (ref t < 2) 1.36 0.87 2.14 0.2 1.82 1.06 3.15 0.03 pt3-t4 stage (ref t < 2) 2.22 1.25 4.14 0.009 2.83 1.42 5.86 0.004 age at diagnosis 1.01 0.99 1.02 0.4 1.01 0.99 1.03 0.2 perioperative cht unknown (ref. no perioperative cht) 13.62 4.11 84.31 < 0.001 7.36 1.92 48.71 0.01 perioperative cht (ref. no perioperative cht) 9.59 5.40 18.42 < 0.001 10.57 5.88 20.54 < 0.001 total penectomy versus no surgery/local surgical procedures 0.90 0.46 1.83 0.9 2.42 0.97 6.20 0.06 total penectomy versus partial penectomy 0.96 0.58 1.56 0.9 1.28 0.71 2.26 0.4 cht: chemotherapy; or: odds ratio; scc: squamous cell carcinoma table 2b. interaction between circumcision and pt stage for prediction of lymph node invasion adjusted for all the other covariates: histology, age, perioperative cht, surgical procedure on the primary penile lesion variable or 5% 95% p-value previous circumcision*t2 stage 0.48 0.14 1.61 0.2 previous circumcision*t3-t4 stage 0.21 0.04 0.92 0.03 105siuj.org siuj • volume 3, number 2 • march 2022 the relationship of circumcision with clinical tumor staging of penile cancer http://siuj.org uncircumcised patients harbored t< 2 tumors more frequently than did circumcised men (54.4% versus 34.5%; p < 0.001) (table 1). no statistical difference was found regarding n stage between circumcised and uncircumcised men. furthermore, circumcision rates differed with smoking and geographic patient variables, and with several treatment variables including extent of surgery and delivery of chemotherapy and radiotherapy. multivariable analyses showed a clear and expected association between advanced pt stages and higher risk of ilnm, as well as between use of perioperative chemotherapy and higher risk of ilnm. conversely, no association was found between circumcision and the risk of ilnm. nevertheless, we found that circumcision, compared with no-circumcision, conferred a lower risk of ilnm (table 2) in patients with locally advanced tumors (t3–t4). the risk of ilnm according to t stage in circumcised versus uncircumcised penile cancer patients is depicted in figure 2. debate continues about the potential role of circumcision in subsequent development of pscc[8,9]. to our knowledge, no prior study has discussed the association of prior circumcision with tumor stage at presentation. our data reveal correlations between circumcision and pscc staging. first, there is an association of prior circumcision with presenting t stage on multivariable analysis. second, there is no association of circumcision with presenting n stage. these findings suggest there may be a difference in local microbiota in uncircumcised compared with circumcised individuals, which might contribute to development of pscc. limitations of this analysis include a lack of broad generalizability, since data are lacking from africa, india, and most of south america, and we consider our coverage of north america and europe to be suboptimal. lack of data on hpv status on these patients is a limitation in terms of understanding its potential etiology in penile cancer, most notably in non-circumcised men. specific analysis of large populations with equal access to health care would help clarify the potential role of the genital microbiome in this process. figure 2. risk of ilnm according to t-stage in circumcised versus uncircumcised penile cancer patients uncircumcised circumcised60 t<2 t2 t3–4 70 80 90 t stage pr ob ab ili ty o f l n in va si on ilnm: inguinal lymph node metastasis 106 siuj • volume 3, number 2 • march 2022 siuj.org brief communication http://siuj.org references 1. liu cm, hungate ba, tobian aa, ravel j, prodger jl, serwadda d, et al. penile microbiota and female partner bacterial vaginosis in rakai, uganda. mbio.2015;6(3). doi:10.1128/mbi0.00589-15 2. nelson de, dong q, van der pol b, toh e, fan b, katz bp, et al. bacterial communities of the coronal sulcus and distal urethra of adolescent males. plos one.2012;7(5):e36298. doi: 10.1371/journal.pone.0036298. epub 2012 may 11. 3. bandini m, zhu y, ye d-w, ornellas aa, watkin n, ayres b, et al. contemporary treatment patterns and outcomes for patients with penile squamous cell carcinoma: identifying management gaps to promote multi-institutional collaboration. eur urol oncol.2021;4(1):121– 123. doi:10.1016/j.eu0.2020.07.007. epub 2020 sep 14. 4. necchi a, lo vullo s, mariani l, zhu y, ye d-w, ornellas a a, et al. nomogram-based prediction of overall survival after regional lymph node dissection and the role of perioperative chemotherapy in penile squamous cell carcinoma: retrospective multicenter study. urol oncol.2019 aug;37(8):531.e7–531.e15. doi: 10.1016/j. urolonc.2019.04.003. epub 2019 may 1. 5. johnstone pas, boulware d, djajadiningrat r, ottenhof s, necchi a, catanzaro m, et al. primary penile cancer: the role of adjuvant radiation therapy in the management of extranodal extension in lymph nodes. eur urol focus.2019 sep;5(5):737–741. doi: 10.1016/j.euf.2018.10.007. epub 2018 oct 14. 6. tang dh, djajadiningrat r, diorio g, chipollini j, ma z, schaible bj, et al. adjuvant pelvic radiation is associated with improved survival and decreased disease recurrence in pelvic node-positive penile cancer after lymph node dissection: a multi-institutional study. urol oncol.2017;35(10):605.e17– 605.e23. doi:10.1016/j. urolonc.2017.06.001 7. bandini m, ross js, zhu y, ye d-w, ornellas aa, watkin n, et al. association between human papillomavirus infection and outcome of perioperative nodal radiotherapy for penile carcinoma. eur urol oncol.2021 oct;4(5):802–810. doi: 10.1016/j.eu0.2020.10.011. epub 2020 nov 14. 8. thomas a, necchi a, muneer a, tobias-machado m, tran ath, van rompuy a-s, et al. penile cancer. nat rev dis primers.2021;7(1):11. doi:10.1038/s41572-021-00246-5 9. bandini m, ahmed m, basile g, watkin n, master v, zhu y, et al. a global approach to improving penile cancer care. nat rev urol.2021 dec 22;1–9. doi: 10.1038/s41585-021-00557-y. 107siuj.org siuj • volume 3, number 2 • march 2022 the relationship of circumcision with clinical tumor staging of penile cancer http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information vesicouterine fistula, caesarean, bladder, uterus, burkina faso none declared. received on february 13, 2021 accepted on may 13, 2021 soc int urol j. 2021;2(4):210–215 doi: 10.48083/nfmo2987 210 siuj • volume 2, number 4 • july 2021 siuj.org original research vesicouterine fistula in burkina faso: report of 36 cases in a multicentric study boureima ouedraogo,1 brahima kirakoya,2 moussa kabore,2 adama millogo,2 adama ouattara,3 fasnewinde aristide kaboré2 1urology department university hospital of tingandogo, burkina faso 2department of urology and andrology, university hospital yalgado ouédraogo of ouagadougou, burkina faso 3urology department university hospital souro sanou of bobo-dioulasso, burkina faso abstract objective to report etiological and therapeutic features of vesicouterine fistulas (vuf) in burkina faso. patients and methods we performed a retrospective, descriptive, and multicentric study based on the medical records of women treated for vuf from january 2010 to december 2016. results vuf accounted for 7.2% (36/497) of urogenital fistulas managed during the study period. the median age of the 36 patients was 35 years (interquartile range = 27 to 37.5 years) with values ranging from 16 years to 64 years old. among vuf, obstetric fistula accounted for 26 cases (26/36) versus 10 cases (10/36) of iatrogenic fistula. obstetric vuf were consecutive to emergency caesarean section (n = 16) and vaginal delivery (n = 10) after prolonged obstructed labor. the 10 cases of iatrogenic vuf were subsequent to prelabour caesarean section. the main circumstance of vuf occurrence was caesarean section (26/36). in 10 cases (10/36), vuf was associated with a vesicovaginal fistula. thirty days after the removal of the catheter, the success rate fell from 89% to 80.6%. conclusion vuf is rare but its frequency is not negligible in our context. the main circumstance of occurrence remains caesarean section. the best treatment remains prevention introduction vesicouterine fistula (vuf) is an abnormal communication between the posterior wall of the bladder and the anterior wall of the uterus[1,2]. it is an uncommon condition compared with vesicovaginal fistula and mainly affects young women in their thirties[1,3]. it is such a rare phenomenon that the literature consists mainly of cases reports and case series. vuf accounts for 1% to 4% of all urogenital fistulas, with an increasing trend reported in the literature[1,4,5]. in 2014, kaboré et al. performed a prospective cohort study of 170 patients in burkina faso managed for urogenital fistula (ugf) and reported a frequency of 8.2% for vuf[6]. vuf usually presents with a classic triad of symptoms described by youssef: cyclical hematuria, amenorrhea, and urinary continence[7], although patients with vuf may sometimes present with a permanent urine leakage through the genital tract. like vesicovaginal fistulas, vufs have a devastating psychosocial and economic impact on the women who experience them. the most common etiology of vuf is iatrogenic through pelvic surgery. caesarean section is the most common http://siuj.org cause reported in the literature, accounting for approximately 83% to 93% of cases of vuf[8]. in burkina faso, sombié et al. reported an increase in caesarean section rate from 0.48% in 2000 to 2.1% in 2014[9]. this trend of increasing caesarean section rates will likely be accompanied by an increase in the incidence of vuf. treatment of vuf can be conservative or surgical. however, conservative treatment has shown a low success rate in contrast to surgical treatment which provides good results[10]. the aim of the present study was to analyze the etiological and therapeutic aspects of vuf in burkina faso through a multicentric study. materials and methods study design and period we conducted a multicentric retrospective study over a 7-year period (from january 1, 2010, to december 31, 2016). study site and population our study popu lation consisted of a l l patients managed for urogenital fistula at 7 referral centers for the treatment of urogenital fistulas in burkina faso: university hospital yalgado ouédraogo of ouagadougou, regional hospital of fada n’gourma, regional hospital of dori, saint camille hospital in ouagadougou, new polyclinic of the center in ouagadougou, medical center with surgical antenna in boromo, and medical center with surgical antenna of schipphra in ouagadougou. we analyzed the medical records of all patients managed for vuf. definition of variables the following variables were studied for patients with vuf: age, parity, female genital mutilation (yes or no), history of prior fistula repair (yes or no), duration of labor, time between fistula onset and the surgical repair, fistula size, jóźwik's classification, etiological factors (obstetric and iatrogenic), duration of bladder catheterization, and postoperative results (success or failure). etiological factors were divided into 2 groups: iatrogenic fistulas following prelabour caesarean section, and obstetrical fistulas following vaginal delivery or emergency caesarean section performed too late. we used the classification of vuf into 3 types proposed by jóźwik[11]: type i presents with amenorrhea and cyclic menouria without urinary incontinence; type ii presents with cyclic menouria, but has regular menses and urinary incontinence; and type iii presents with only urinary incontinence, without menouria and with normal menses. data were collected on an individual and anonymous data sheet. this study was performed in accordance with the ethical standards laid down in the declaration of helsinki. analysis and measures data were analyzed using the spss software, version 21.0. the categorical variables were analyzed through the study of frequencies. the continuous variables were analyzed through the study of median and interquartile range (iqr), minimum and maximum. we defined a successful surgical repair outcome at one month as a complete closure of the defect attested by a methylene blue test and without urinary incontinence. the shapiro-wilk test was used to assess the normality for continuous variables. the continuous variables do not follow a normal distribution in the sample of 36 patients. we therefore used the medians. results during the study period, 497 cases of urogenital fistula were managed in the 7 centers. vuf accounted for 7.2% (36/497) of all urogenital fistulas. the annual frequency of vuf was 5.14. the annual distribution of vuf is presented in figure 1. the median age of the 36 patients was 35 years (iqr = 27 to 37.5 years), with values ranging from 16 years to 64 years old. according to jóźwik’s classification, 31 cases (31/36) were type ii. in 10 cases (10/36), vuf was associated with a vesicovaginal fistula. obstetric fistula was noted in 26 cases (26/36) versus 10 cases (10/36) for iatrogenic fistula. among patients with obstetric fistulas, 5 patients (05/26) gave birth at home without medical assistance. the main circumstance of vuf occurrence was caesarean section (26/36). the median duration of vuf was 125.8 months (iqr = 108 to 136.5), with values ranging from 24 months to 144 months. patient and vuf characteristics are summarized in table 1. the management of vuf was surgical in all patients. the transperitoneal route was used in 30 cases (30/36). a vaginal hysterectomy was performed in 6 cases (06/36). the 10 cases of associated vesicovaginal fistula were repaired during the same surgical procedure. urine drainage was performed by systematic transurethral bladder catheterization in all cases after the surgery. the median duration of bladder catheterization was 14 days (iqr = 12 to 15.8), with values ranging from 10 to 21 days. four patients (4/36) had postoperative complications: urinary tract infection in 3 patients, and hematuria in 1 patient. all patients were evaluated on abbreviations iqr interquartile range ugf urogenital fistula vuf vesicouterine fistula 211siuj.org siuj • volume 2, number 4 • july 2021 vesicouterine fistula in burkina faso: report of 36 cases in a multicentric study http://siuj.org the day of bladder catheter removal and 1 month after. discussion vuf is a very rare condition that has been estimated to accou nt for 1% to 4% of a l l genitourina r y fistulas[1,4,5,12]. however, recent studies have shown an increase in the prevalence of vuf. in a study of 272 women with obstetric fistula, egziabher et al. reported 23% had vuf[13]. in 2020, richter et al., describing the characteristics of genitourinary fistulas in kigali, rwanda, reported 185 (29%) cases of vesicouterine/ vesicocervical fistula[14]. in our series, we report 36 cases of vuf, accounting for 7.2% of all genitourinary fistulas. to our knowledge it is one of the largest case series published to date. indeed, these 7 centers are referral centers for the treatment of urogenital fistulas in burkina faso. most of the published literature consists of cases reports and case series. benchekroun et al. reported 30 cases over a 25-year period[15]. hadzidjokic et al. reported 14 cases over a 37-year period[16]. two main factors may explain the increasing trend in the prevalence of vuf in low-resource countries: the trend of increasing caesarean section rate (with nonspecialist staff sometimes deciding on the procedure without strong medical indication), and the high number of unassisted deliveries[5,17]. according to sombié et al., the rate of caesarean section delivery in burkina faso increased from 0.48% in 2000 to 2.14% in 2014[9]. vufs most commonly occur following lowsegment caesarean section[1,2,10,11,18,19]. in a review including reports from 1986 to 1997, 83% of vuf were associated with caesarean section[20]. in the present study, most vuf (26/36) occurred following caesarean section. the mechanism by which communication occurs between bladder and uterus may be a bladder injury during incision of the lower segment of the uterus, during vesicouterine detachment or by uterine rupture affecting the bladder. excessive intraoperative bleeding may also lead to injury from attempts to achieve hemostasis[2,5]. vuf has been described following dystocic vaginal deliveries. it occurs in patients with a scarred uterus or af ter instrumenta l extraction[1,3,21,22]. the posterior wall of the bladder becomes progressively devitalized due to changes in the vascular network at the scar of the first operation. a dehiscence of the uterine scar and simultaneous injury of the bladder wall at the vesicouterine interface may occur with the thinning of the lower segment during labor, leading to the fistula[2,5]. in the present study, dystocia was the second most common cause of vuf. drissi et al.[1] and hodonou et al.[3] made the same observation. none of the patients in our study had a scarred uterus, and no instrumental extraction was noted. deliveries were often unassisted, and 5 patients delivered at home. other causes of vuf reported in the literature are gynecological (migration of an intrauterine device, degenerated or adherent myoma of the bladder) or congenital[1,2,7]. we did not find these causes in our study. the purpose of vuf treatment is to suppress communication between uterus and bladder. two therapeutic approaches are possible: conser vative management and surgical management. conservative m a n a g e m e n t c o m b i n e s i n d w e l l i n g b l a d d e r catheterization with hormonal treatment that suppresses menstruation for 3 to 6 months[2,23,24]. spontaneous closure of small fistulas seen at an early stage has been reported[2,23], providing some justification for conservative management. however, results are generally disappointing, with jóźwik et al. estimating the success rate to be about 5%[24]. in our series, no patients were conservatively managed. we agree with sylla et al. that large or late-onset vuf should receive surgical treatment[25]. dimarco et al. in a series of 8 cases of vuf undertook conservative management of 2 patients, but this was not successful, and surgical intervention was eventually required[10]. this consists of the excision of the fistulous pathway and necrotic tissue and separate suturing of the bladder and uterus by either the extraperitoneal or transperitoneal route[1]. bladder catheterization is maintained for about 2 weeks[5,21]. hysterectomy is an option if no further pregnancy is desired. vaginal hysterectomy was performed in 6 cases (16.7%) in our series. the laparoscopic approach is reported in the literature with similar results to open surgery[4,25]. vuf repair was performed by open surgery in our study. our results were similar to those 0 2 6 8 10 12 4 2016 11 2015 9 2014 6 2013 5 2012 2 2011 1 2010 2 figure 1. annual distribution vesicouterine fistulas (n = 36) 212 siuj • volume 2, number 4 • july 2021 siuj.org original research http://siuj.org table 1. patient characteristics and vesicouterine fistula characteristics (n=36) median iqr (min, max) frequency age, years 35 27–37.5 (16, 64) parity 4.1 2.6–5.6 (1, 11) genital mutilation • no 30 • yes 06 etiology obstetric • vaginal delivery 10 • emergency caesarean section performed too late 16 iatrogenic (prelabour caesarean section) 10 jóźwik’s classification • type i 02 • type ii 31 • type iii 03 duration of fistula, months <24 3 24–48 1 48–72 2 72–96 1 96–120 4 ≥ 120 25 duration of labor, hours 19.7 17.6–22.6 (01, 24) fistula size, cm 02 1.4–2.8 (01, 04) prior repair of vuf • yes 17 • no 19 reported in the literature, with a successful closure rate of 88.9% 1 week after indwelling catheter removal. this excellent early result decreased to 80.6% after 1 month. this finding suggests the need for monitoring of patients undergoing vuf or, more generally, urogenital fistula surgery. poor tissue vascularization and fibrosis are responsible for poor wound healing after surgery[26]. in addition, special attention has to be paid to the complete excision of perifistular necrotic tissue during surgery to allow better healing of tissues already weakened by ischemia. the postoperative failure rate reflects the difficulty of closing some urogenital fistula, sometimes after several re-interventions[11,26]. in the present study, 17 patients (17/36) had a prior surgical repair of their vuf. caesarean section must be medically indicated, and more obstetricians and specialized nurses may be required to perform this procedure more proficiently. meda et al. showed that in burkina faso, only 39.2% of caesarean sections are performed by obstetricians and 28.7% by nurses specialized in surgery[27]. every effort 213siuj.org siuj • volume 2, number 4 • july 2021 vesicouterine fistula in burkina faso: report of 36 cases in a multicentric study http://siuj.org must be made to prevent urogenital fistula, in particular by ensuring all women have access to prenatal care and to skilled medical assistance in delivery. the limitations of this study lie in its retrospective nature, which means that some data were not available. also, the postoperative follow-up of our patients was limited to one month. this study did not take into account data from all the urogenital fistula centers in burkina faso. conclusion globally, vuf is rare, but it presents a significant challenge in some areas. it occurs mainly af ter caesarean section. the results of surgical treatment are good, but the best treatment remains prevention through pregnancy monitoring and delivery in medical facilities. acknowledgments the authors thank mr boyo pare for english language revision. references 1. drissi m, karmouni t, tazi k, el khader k, koutani a, ibn attya a, et al. vesico-uterine fistulas: a 17-year experience. prog urol.2008;18:173– 176. doi: 10.1016/j.purol.2007.12.011. 2. karaltı mo, tınar s, öztürk nt, öztekin dc, öztürk dc. a case with vesicouterine fistula: mini review. arch gynecol obstet.2012;285:667-70. 3. hodonou r, hounnasso p, biaou o, akpo c. vesico-uterine fistula: about 15 cases at the cotonou university urology clinic. prog urol.2002;12:641–645. 4. alamoudi oj, altheneyan ma, aldhaam n, moazin m. early robotic repair of vesicouterine fistula : a case report and literature review. urol case rep.2017;11:76–78. 5. sefrioui o, benabbes taarji h, azyez m, aboulfalah a, el karroumi m, matar n, et al. vesico-uterine fistulas of obstetrical origin. about 3 cases. ann urol (paris).2002;36:376–380. 6. kaboré fa, kambou t, ouattara a, zango b, yaméogo c, kirakoya b, et al. epidemiological, etiological aspects and psychosocial impact of urogenital fistula in a cohort of 170 consecutive patients managed in three centers in burkina faso from 2010 to 2012. prog urol.2014;24:526–532. 7. youssef af. the uterine isthmus and its sphincter mechanism, a radiographic study. i. the uterine isthmus under normal conditions. am j obstet gynecol.19 5 8;75:13 0 5 –1319. doi:ht tps://doi. org/10.1016/0002-9378(58)90721-x 8. bhat tacharjee s, kohli ua, sood a, tripathy s, gupta m. vesicouterine fistula: youssef’s syndrome. med j armed forces india.2015;71:175–177. 9. sombié i, meda zc, savadogo g, sanou g, dadjoari m. trends in the rate and place of cesarean section deliveries in burkina faso. santé publique.2017;29:133. 10. dimarco cs, dimarco ds, klingele cj, gebhart jb. vesicouterine fistula : a review of eight cases. int urogynecol j.2006;17:395–399. 11. józwik m, józwik m. clinical classification of vesicouterine fistula. int j gynecol obstet.2000;70:353–357. 12. saeed s, nawaz n, murtaza b, mahmood a. urogenital fistula in females – a four years experience. pak armed forces med j.2016;66:361–366. 13. egziabher tg, eugene n, ben k, fredrick k: obstetric fistula management and predictors of successful closure among women attending a public tertiary hospital in rwanda: a retrospective review of records. bmc res notes.2015;8:774. doi: 10.1186/ s13104-015-1771-y. 14. richter la, lee h, nishimwe a, niteka lc, kielb sj. characteristics of genitourinary fistula in kigali, rwanda; 5-year trends. urology.2021; 150:165–169. doi: 10.1016/j.urology.2020.05.077. epub 2020 jun 24. 15. benchekroun a, el alj ha, el sayegh h, lachkar a, nouini y, benslimane l, et al. les fistules vésico-vaginales : à propos de 1050 cas. ann urol.2003;37:194–198. 16. hadzi-djokic jb, pejcic tp, colovic vc. vesico-uterine fistula: report of 14 cases. bju int.2007;100:1361–1363. 17. ouédraogo cm, ouédraogo a, ouattara a, lankoandé j. the practice of cesarean section in a district hospital in ouagadougou epidemiological, clinical and prognostic aspects for 3,381 cases. med sante trop.2015;25:194–199. 18. józwik m, józwik m, łotocki w. vesicouterine fistula — an analysis of 24 cases from poland. int j gynecol obstet.1997;57:169–172. 19. birge o, ozbey eg, erkan mm, arslan d, kayar i. youssef’s syndrome following cesarean section. case rep obstet gynecol.2015;2015:1–4. 20. yip sk, leung t y. vesicouterine fistula: an updated review. int urogynecol j pelvic floor dysfunct.1998;9:252-256. doi: 10.1007/ bf01901500. 214 siuj • volume 2, number 4 • july 2021 siuj.org original research https://doi.org/10.1016/0002-9378(58)90721-x https://doi.org/10.1016/0002-9378(58)90721-x http://siuj.org 21. goyal ld. vesicouterine fistula following vaginal birth after caesarean section in a multiparous woman-a rare case report and review of literature. arc journal of gynecology and obstetrics.2016;1:1-2. http ://dx.doi.org/10.20431/2456-0561.0103001 22. nouira y, feki w, rhouma sb, salah ib, horchani a. vesicouterine fistula as a complication of forceps delivery : a case report. int urogynecol j pelvic floor dysfunct.2005;16:512–514. 23. bastakoti r, saha r. conservative management of uterovesical fistula following primary caesarean section. journal of kathmandu medical college.2013;2:211–113. 24. józwik m, józwik m. spontaneous closure of vesicouterine fistula. account for effective hormonal treatment. urol int.1999;62:183–187. 25. sylla c, fall pa, diallo ab, ndoye ak, ba m, gueye sm, et al. vesicouterine fistulas: about 5 cases. prog urol.2000;634–637. 26. sjøveian s, vangen s, mukwege d, onsrud m. surgical outcome of obstetric fistula: a retrospective analysis of 595 patients. acta obstet gynecol scand.2011;90:753–760. 27. meda ib, millogo t, baguiya a, ouédraogo/nikiema l, coulibaly a, kouanda s. rate of and factors associated with indications for cesarean deliveries: results of a national review in burkina faso. int j gynaecol obstet.2016;135(suppl 1):s51-7. 215siuj.org siuj • volume 2, number 4 • july 2021 vesicouterine fistula in burkina faso: report of 36 cases in a multicentric study http ://dx.doi.org/10.20431/2456-0561.0103001 http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. 339siuj.org siuj • volume 2, number 6 • november 2021 guest editorial the rising tide of women in urology pilar laguna department of urology, istanbul medipol university, turkey soc int urol j.2021;2(6):339–343 doi: 10.48083/jhek4332 i read with pleasure the editorial “a global pandemic is not our only challenge in urology” in the january 2021 issue of siuj[1]. indeed, the pandemic has not only challenged us professionally but has also highlighted a social unrest and accelerating global claims at all societal levels. not least among these are the calls for gender equity and equality in our profession in general, and urology in particular. i believe the genders possess equal intellectual capacity, the same ability to acquire professional and surgical skills, and the same qualities that lead to a successful career (academic or not). the gender differences in the ways of approaching and solving a conflict—or even the small events of daily life—are, like all diversity, enriching. equity, although connected to equality in several respects, is more complex in substance and more difficult to achieve; once achieved, effort must continue if it is to be maintained. belonging to the first generation of “women of urology” does not grant me any authority, but it does give me a wider experience and a log-book full of anecdotes. most laughable, some embarrassing, and a few definitely unpleasant. the last usually the fruit of the limited minds of some male individuals, but a few from females. as a matter of fact, i must disclose that the incident i remember as the most cruelly discriminative came from the mouth of a women—and not so many years ago. taken together, they illustrate how it has been working in a male-dominated surgical specialty and how some characteristics and attitudes are unfortunately not gender exclusive. in almost 4 decades working as a urologist, i have witnessed the increasing number of women incorporated into the urology workforce. very slowly at the beginning, but steadily and more prominently when the gen x-ers and the first millennials reached our specialty with a refreshing impetus. like the excellent young professional females named in the january editorial, we also won prizes, became chairs of departments, were involved in academic work, and did our best to care for our patients. there were a handful of us, likely with different values and perceptions and with fewer opportunities to communicate than today’s young professionals. we accepted that it would take some time to become fully integrated in that “male-dominated” world. nonetheless, paving the way for the next generation of females in urology, that is what we did. gender disparity is not a new concern in medicine or in our specialty. a lot has been written exposing the problems and the inequalities, but quite a lot has been done and more is on the way to minimize and remediate the differences. the urological community started to become seriously concerned about the subject in the late 1990s. surveys from that time show that although the majority of female urologists encouraged other women to enter the specialty, ultimately 44% of the potential female graduates or trainee candidates were discouraged at some point. most believed that gender discrimination had or could have some negative effect on their training and practice, that gender played a limiting role in our specialty, and that there was a lack of adequate mentoring for females[2,3]. although the information was scant and somewhat subjective, and although neither causality nor remediation was explored or proposed, these reports were the tip of the iceberg and exposed an underlying chronic problem. after these first reports, more information surfaced pointing to different forms of employment and work inequality between female and male urologists, ranging from different salaries for the same workload, practice setting, or fellowship training, and unequal work opportunities, to verbal and other forms of harassment and discrimination. always detrimental for females—and even more so for those pursuing surgical specialties[4–7]. differences and possible inequity have also been described in the academic setting. about a decade ago, a pubmed query showed that female residents who graduated as urologists from 2002 to 2009 had fewer publications than their male counterparts and that they were less frequently first authors[8]. the phenomenon is not unique to our specialty and although the rate of overall female authorship in the highest rated journals has improved in the last 15 years, it is still half the rate for males in specialties with a more balanced male: female ratio than urology, eg, general oncology[9]. furthermore, despite the same proportion of women as men pursuing a fellowship and ultimately choosing an academic career, a significantly higher proportion of men than women (24.7% versus 2.9%) attained the rank of associate professor[8]. most recent data show that in the academic setting, too, professional careers do not turn out as well for females as for males. of the 2926 us academic urologists who were assistant, associate, or full professors, only 11.2% were female, and, on average, it took females 1.2 years longer than men to advance from assistant to associate professor[8]. only gender (not race or ethnicity) was associated with this disparity[10]. the data were in line with previous information on gender-based academic inequity in medicine and in surgery after correcting for possible confounders (number of years since residency completion, graduate degrees, fellowship training, and markers of research production)[11,12]. as the cherr y on the sundae, female urologic surgeons have been reported as having fewer children, higher induction rates, and higher incidence of pregnancy complications than women in the general population[13]. in common with female surgeons in other specialties, they are also likely to delay childbearing, and to experience fertility problems and rates of miscarriage up to 38%, which is very high and likely attributable to the demanding nature of the surgical work[14,15]. given this, it is perhaps surprising that although burnout is a major concern in our specialty, it is not more prevalent in female urologists[16,17]. overall, the literature provides an extensive list of comparative detrimental differences for the female gender in medicine. as female surgeons, we seem to be particularly subjected to offences or frustrations that go beyond inequality to plain and flagrant inequity and discrimination. far from ignoring the data, we should strive to analyse how the evidence has been gathered. yes, there is an association between the variable “female gender” and inequality in urology, but this does not necessarily imply causality. in fact, a non-negligible portion of the information comes from surveys, some with small sample sizes, and it is likely to be influenced by perceptions, which change with time and experience. if we aim—and we do—to be fully acknowledged, recognized, and integrated into the “urology task force,” and to have access to the higher academic ranks and positions of power, the sensitive matter of inequality and inequity deserves a more rigorous and objective approach. only with honesty, integrity, reflection, and an open and inclusive mind are we going to overcome the challenge. while all this information points in the direction of “de facto” environmental inequality and lack of equal opportunities for women in urology, much of the extensive body of information does not reflect the current picture. social and working conditions are not the same now as they were 30—or even 20—years ago, and it is undeniable that women have already become visible in urology. according to the recently released census of the american urological association (aua), females for the first time surpassed 10% of the urology workforce[18]. not a lot, but a milestone in a “male-dominated specialty.” an unprecedent increase of nearly 50% in the number of women in urology occurred in the last 5 years, with the higher proportion of female urologists being in the younger age groups[19]. even more encouraging are the figures just released by the european association of urology (eau) indicating that 16.6% of their members are women[20]. although not quantified, the major increase of women in urology over the last few years in europe has been more than evident. i would even dare to say that the phenomenon started earlier here than in north america. at present, the number of female urology trainees surpasses 50%, and it is even higher in some european countries—far more than the 24.4% reported by the aua[18]. although this may be the result of women having increased access to medical university places, we cannot ignore the fact that changes in social attitudes about male and female roles and structural modifications in the training and work environment may have had a definitive influence. there are indeed differences between female and male urologists in patterns of practice, and gender shapes the clinical landscape. women more frequently subspecialize in female urology and work in academic centers and in metropolitan areas[21,22]. according to the aua census, women already account for 46.5% in female pelvic medicine and reconstructive surgery (fpmrs) [18,23]. considering the female prevalence in the aua task force report, this is disproportionate[18]. whether the choice is driven by personal preferences or patient preferences or is imposed by restrictive access to other subspecialties is unknown, but inevitably, it is going to skew the prevalence of females in other subspecialties. of note, fpmrs also had the highest proportion of members of groups categorized as “underrepresented in medicine” (urim) compared with the other subspecialties[23]. in canada, a country with high social equality standards, there are significantly more male than female academic urologists. a retrospective study published in 340 siuj • volume 2, number 6 • november 2021 siuj.org guest editorial 2020 found that as academic rank increases, the proportion of female urologists decreases, and male urologists have significantly higher academic ranks, h-index values, number of publications, and citations. the lack of females in senior academic leadership is not surprising given that the history of females in urology goes back only 50 years[24,25]. the accompanying editorial stresses the need to clarify the reported gender discrepancies in academic urology and incorporate different measures of academic productivity such as educational and continuing medical education (cme) activities. moreover, the authors make a plea for considering ability, talent, dedication, and innovation above gender[25]. female urologists are increasingly included in working groups and panels in international meetings[20] with 2021 seeming to be a turning point. the american college of surgeons is planning measures to address inequities that affect women in medicine and those who are seeking to enter the profession[26]. major journals and important health institutions have echoed the need for inclusion and diversity and taken measures to promote equity and equality at all levels of medicine[27,28]. in 2020, at least 4 prestigious awards were given to brilliant female urologists—role models practicing in subspecialties beyond the ones conventionally reserved for female urologists. so far in 2021, 4 “women of urology” have been recognized by the aua: catherine r. devries with the humanitarian recognition award of the aua urology care foundation; tracey l. krupski with the robert c. flanigan education award; maryann lynn stothers with the victor a. politano award; and stacy loeb with the gold cystoscope award. in europe, véronique phé, a young female urologist, received the prestigious eau crystal matula award. also, the society of women in urology turns 40 this year. siu has had women on its board for many years, and for the last 4 years, the society’s scientific committee has devoted special attention to inclusivity and diversity. this without forgetting all the “women of urology” who have become chairs, professors, and academicians. thus, it seems clear to me that we do not need to be indoctrinated in how to become “women in the lead,” because we are not doing so badly. on february 9, 2019, the lancet dedicated an issue to women in medicine that included an enjoyable piece entitled “working toward gender diversity and inclusion in medicine: myths and solutions”[29]. it is about the major myths that prevent diversity and inclusion and the possible solutions beyond individual behavior. it is also about the need to see the problem beyond the number of women in the field and to create lasting changes based on fair and transparent institutional policies, on the commitment of all involved parties to change group dynamics, on changes in societal values, and on understanding that promoting diversity does not contravene meritocracy. i would like to finish by mentioning briefly a disturbing phenomenon that is no doubt familiar to you, namely, the “manel,” or panel consisting only of men. they are unbalanced and exclusive, but the same applies to the “wanels,” which do now exist. both are toxic and equally discriminative. the latter may be even worse because of the implicit and troubling tokenism. i hear with concern the increasingly raised voices of both males and females, expressing dissatisfaction and discomfort. the former afraid they will be discriminated against in the interests of redressing the balance, and the latter afraid they will be invited only because they are women. and i do not like it. although some think that numbers are irrelevant when equity is the issue, the truth is that we have used them to build up our case, so we should be consistent in using them to measure our progress. in summary, the turmoil regarding disparity and the need for diversity and equity—for all underrepresented groups—has never been so evident and urgent as it is now. the speed of media diffusion and the increasing penetration of these groups makes it different from the past. it seems to me that we females are navigating quite well in the ocean of our specialty, but there is still a lot to do. all of us—male and female—must do the work well, ensure that we have a solid vessel, remain steadfast at the helm, and modify the course to avoid the storms. finally, i have nothing but praise and thanks to offer the major societies in urology—eau, aua, siu, the endourological society, and the many others—that have never made me feel discriminated against. 341siuj.org siuj • volume 2, number 6 • november 2021 the rising tide of women in urology references 1. black p. a global pandemic is not our only challenge in urology. soc int urol j.2021;2:5–6. doi: https://doi.org/10.48083/gozd2340 2. bradbury cl, king dk, middleton rg. female urologists: a growing population. j urol.1997;157: 1854–1856. 3. lightner dj, terris mk, tsao ak, naughton ck, lohse cm. status of women in urology: based on a report to the society of university urologists. j urol.2005 feb;173(2):560 – 563. doi: 10.1097/01. ju.0000149739.51103.d3. 4. spencer es, deal am, pruthi nr, gonzalez cm, kirby ew, langston j, et al. gender differences in compensation, job satisfaction and other practice patterns in urology. j urol.2016 feb;195(2):450–455. doi: 10.1016/j.juro.2015.08.100. epub 2015 sep 15. 5. schlik cjr, ellis rj, etkin cd, greenberg cc, greenberg ja, turner pl, et al. experiences of gender discrimination and sexual harassment among residents in general surgery programs across us. jama surg.2021jul;28:e213195. doi: 10.1001/jamasurg.2021.3195. online ahead of print. 6. myers sp, dasari m, brown jb. ef fects of gender bias and stereotypes in surgical training: a randomized clinical trial. jama surg.2020;155(7):552–560. 7. dossa f, simpson an, sutradhar r, urbach dr, tomlinson g, detsky as, et al. sex-based disparities in the hourly earnings of surgeons in the fee-for-service system in ontario, canada. jama surg.2019 dec 1;154(12):1134–1142. doi: 10.1001/jamasurg.2019.3769. 8. yang g, villalta jd, weiss da, caroll pr, breyer bn. gender differences in academic productivity and academic career choice among urology residents. j urol.2012;188:1286–1290. 9. yalamanchali a, zhang es, jagsi r. trends in female authorship in major journals of 3 oncology disciplines. jama network open.2021;4(4):e212252. 10. breyer bn, butler c, fang r, meeks w, porten sp, north ac, et al. promotion disparities in academic urology. urology.2020 apr;138:16– 23. doi: 10.1016/j.urology.2019.10.042. epub 2020 jan 7. 11. gawad n, tran a, martel ab, baxter nn, allen m, manhas n, et al. gender and academic promotion of canadian general surgeons: a cross-sectional study. cmaj open.2020 jan 28;8(1):e34–e40. doi: 10.9778/cmajo.20190090. print jan-mar 2020. 12. jena ab, khullar d, ho o, olenski ar, blumenthal dm. sex differences in academic rank in us medical schools in 2014. jama. 2015sep;15;314(11):1149–1158. doi: 10.1001/jama.2015.10680. 13. lerner lb, baltrushes rj, stolzmann kl, garshick e. satisfaction of women urologists with maternity leave and childbirth timing. j urol.2010 jan;183(1):282–286. doi: 10.1016/j.juro.2009.08.113. 14. phillips ea, nimeh t, braga j, lerner lb. does a surgical career affect a woman’s childbearing and fertility? a report on pregnancy and fertility trends among female surgeons. j am coll surg.2014;219:944–950. 15. poon s, luong m, hargett d, lorimer s, nguyen c, payares m, friedman s. does a career in orthopaedic surgery affect a woman’s fertility? orthop surg.2021;29(5):e243–e250. doi: 10.5435/jaaos-d-20-00198. 16. ilin j, langlois e, jalal s, khosa f. gender disparity within academic canadian urology. can urol assoc j.2020;14:106–110. 17. cox a, siemens dr. continued gender disparity in urology? only time will tell. can urol assoc j.2020;14(4):79–80. doi: 10.5489/cuaj.6519. epub 2020 apr 1. 18. american urological association (aua) 2020 annual census report, “the state of the urology workforce and practice in the united states. american urological association, 2020. available at: https://www. auanet.org/research/research-resources/aua-census/census-results. accessed september 25, 2021. 19. female urologists make history in urology. news release. american urological association. may 27, 2021. available at: http://auanet. mediaroom.com/2021–05–27-female-urologists-make-history-inurology#.yk-qh1v3eew.twitter. accessed september 25, 2021. 20. chapple cr, albers p, denstedt j. addressing equality of representation in urology societies. eur urol.2021 oct;80(4):454–455. https://doi. org/10.1016/j.eururo.2021.07.001 21. saltzman a, hebert k, richman a, prats s, togami j, rickey l, et al. women urologists: changing trends in the workforce. urology.2016 may;91:1–5. doi: 10.1016/j.urology.2016.01.035. epub 2016 mar 4. 22. oberlin dt, vo ax, bachrach l, flury sc. the gender divide:.the impact of surgeon gender on surgical practice patterns in urology. j urol.2016 nov;196(5):1522–1526.doi: 10.1016/j.juro.2016.05.030. epub 2016 may 10. 342 siuj • volume 2, number 6 • november 2021 siuj.org guest editorial 23. dielubanza ej, enemchukwu ea, atiemo ho. urology workforce diversity in female pelvic medicine and reconstructive surgery: an analysis of the american urological association census data. urology.2021 jul 15;s0090 – 4295(21)00641– 5. doi: 10.1016/j. urology.2021.06.031. epub ahead of print. 24. franc-guimond j, mcneil b, schlossberg sm, north ac, sener a. urologist burnout: frequency, causes and potential solutions to an unspoken entity. can urol assoc j.2018;12:137–142. published online 2017 dec 22. doi: 10.5489/cuaj.4668 25. marchalik d, goldman cc, carvalho ffl, talso m, lynch jh, francesco esperto f, et al. resident burnout in usa and europe urology residents: an international concern. bju int.2019 aug;124(2):349–356. doi: 10.1111/bju.14774. epub 2019 may 8. 26. stephens eh, heisler ca, temkin sm, miller p. the current status of women in surger y: how to af fect the future. jama surg. 2020;155:876–885. 27. fontanarosa pb, flanagin a, ayanian jz, bonow ro, bressler nm, christakis d, et al. equity and the jama network. jama surg.2021 aug 1;156(8):705–707. doi: 10.1001/jamasurg.2021.3098. 28. the editors of the lancet group. the lancet group’s commitments to gender equity and diversity. lancet.2019 aug 10;394(10197):452–453. doi: 10.1016/s0140–6736(19)31797–0. epub 2019 aug 8. 29. kang sk, kaplan s. working toward gender diversity and inclusion in medicine: myths and solutions. lancet.2019 feb 9;393(10171):579– 586.doi: 10.1016/s0140–6736(18)33138–6 343siuj.org siuj • volume 2, number 6 • november 2021 the rising tide of women in urology key words competing interests article information placenta accreta spectrum, placenta percreta, placenta accreta, placenta increta, multidisciplinary management none declared. received on august 6, 2021 accepted on september 7, 2021 this article has been peer reviewed. soc int urol j. 2022;3(1):28–32 doi: 10.48083/olra4694 28 siuj • volume 3, number 1 • january 2022 siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. original research urological involvement in the multidisciplinary management of placenta accreta spectrum in a centralised, high-volume centre: a retrospective analysis brian d. kelly,1,2 rebecca moorhead,1,3 david wetherell,1 tracey gilchrist,3 marcalain furrer,1 marlon perera,4 briony norris,1 david wrede,3,4 mark umstad,3,4 jamie kearsley,1 faris al-shammaa3,5 1 department of urology, the royal melbourne hospital, melbourne, australia 2 department of surgery, peter maccallum cancer centre, university of melbourne, melbourne, australia 3 department of obstetrics and gynaecology, the royal women's hospital, melbourne, australia 4 department of surgery, university of melbourne, melbourne, australia 5 department of obstetrics and gynaecology, the university of melbourne, melbourne, australia abstract objectives placenta accreta spectrum (pas) significantly increases the complexity of childbirth and frequently involves urologic organs. multidisciplinary team (mdt) care is paramount to ensure optimal outcomes. we aimed to evaluate urologic interventions in patients with pas at a centralised, tertiary referral centre. methods an analysis of a prospectively collected data set, consisting of all women presenting with pas at our institution between november 2013 and june 2019. patients who required urological intervention were identified, and perioperative details were retrieved. results forty-two cases of pas were identified. the mean maternal age was 35 years, and mean gestational age at delivery was 34 weeks. thirty-seven cases were managed electively, with 5 cases managed conservatively (no hysterectomy) and 5 requiring emergency management. fifteen patients (36%) had suspected bladder invasion on mri. a total of 36 patients (86%) had ureteric catheters inserted, 14 (33%) required bladder repair, and 2 had ureteric injuries (5%). conclusions pas frequently requires urological intervention to prevent and repair injury to the urinary bladder and ureter. pas is a rare condition that is best managed in an mdt setting in a centralised, tertiary, high-volume centre with access to a variety of medical and surgical sub-specialities. introduction placenta accreta spectrum (pas) describes the range of pathologic adherence of the placenta: accreta, in which placental villi encroach on the decidual layer; increta, in which the myometrium is invaded; and percreta, in which the myometrium is fully penetrated by placental villi, breaching the serosa and invading adjacent organs including the bladder (most common), broad ligament, or sigmoid colon[1,2]. these disorders confer substantial risk for foetal and maternal death, with maternal mortality rates of up to 7%[3]. the overall incidence ranges from 1 in 435 to 1 in 5882 deliveries[4]. placenta previa and increasing number of prior caesarean section deliveries are independent risk factors for abnormally adherent placenta[5]. other risk factors include advancing maternal age, in vitro fertilisation and other assisted reproductive technologies, previous operative uterine procedures, and previous pas[4]. http://siuj.org mailto:marlonlperera%40gmail.com?subject=siuj major maternal morbidity is due to the risk of massive maternal haemorrhage, subsequent major transfusions, and associated sequelae such as peripartum hysterectomy, icu admission, cystotomy, infections, multi-organ failure, and even death[6,7]. three main approaches to delivery have been described in women with pas, all involving caesarean section. these include caesarean hysterectomy, the extirpative approach (in which the adherent placenta is removed post-delivery), and conservative management. conservative management (when preservation of fertility is desired) involves delivery by caesarean section without hysterectomy, with the placenta or part of it left in situ. specific concerns with this approach include massive secondary postpartum haemorrhage and sepsis. the extirpative approach is widely criticised because of the significant rate of increased maternal morbidity and massive postpartum haemorrhage[6,8]. scheduled caesarean hysterectomy and avoidance of placental removal is associated with reduced maternal morbidity and is the preferred management[6]. placenta percreta is the leading cause of peripartum hysterectomy in western countries[2]. urologist intervention is not uncommon in the management of pas[9,10]. the rate of urinary tract injury during caesarean hysterectomy for pas is 29% compared with 4.8% in standard hysterectomy[11]. this risk plus the potential of bladder invasion requires antenatal diagnosis for prevention of injury (via ultrasound, magnetic resonance imaging and/or cystoscopy) and cohesive multidisciplinary team (mdt) involvement throughout the entire pregnancy[12,13]. in 2016, we published a retrospective analysis of women presenting with pas to a major tertiary centre, showing the need for urological intervention in these patients[9]. we have prospectively maintained a database of cases to strengthen the case for multidisciplinary involvement. we aimed to evaluate urological interventions in patients with placenta accreta spectrum at a centralised, tertiary referral centre. materials and methods forty-two women who presented to the royal women’s hospital (rwh) with pas between november 2013 and june 2019 were identified. a retrospective analysis of the prospectively collected data was undertaken using perioperative details. further data pertaining to imaging and pathology results were retrieved retrospectively from the medical records of patients. all data were collected with permission granted by the human research and ethics committees at the royal women’s hospital (project aqa 20/18). the management of pas is centralised to the rwh in melbourne, with smaller peripheral hospitals in the city of melbourne and surrounding areas in the state of victoria referring patients to this service. the mdt consists of obstetricians, specialised nursing staff, gynaecological surgical oncologists, urologists, general surgeons, paediatricians, diagnostic radiologists, and interventional radiologists. when a patient with suspected pas is referred, doppler-enhanced ultrasound is repeated in the rwh radiology department and, if necessary, an mri of the pelvis is performed to further characterise the pas. the case is then discussed at a pas mdt and a date decided to perform surgery and a determination made whether hysterectomy or conservative management (no hysterectomy) will be attempted. all team members are also aware of the case in the event of emergency admission and subsequent emergency surgery. urological involvement primarily consisted of rigid cystoscopy for assessment of bladder involvement of the placenta and placement of ureteric catheters before caesarean section. experienced urologists scrubbed in with the gynaecologist during hysterectomy and performed cystotomy and repair when necessary. for more advanced cases, interventional radiologists inserted internal iliac artery occlusion balloons, and an intraoperative cell salvage machine was available in the event of catastrophic haemorrhage. all patients were managed in intensive care postoperatively. results between november 2013 and june 2019, a total of 42 patients presented with an antenatally suspected pas. patient characteristics are shown in table 1. the mean maternal age was 35 (sd 4.9). within this cohort, the mean number of prior caesarean section deliveries was 2, and mean gestational age at delivery 34 weeks. for 39 patients, intended treatment was primarily planned admission for elective caesarean hysterectomy; for 3 patients, it was planned conservative management (no hysterectomy). elective operations eventuated in 37 patients, with 5 requiring emergency management. urologists performed cystoscopy and placement of bilateral ureteric catheters in 36 patients (86%); fluoroscopy was not used. bladder wall involvement was suspected on preoperative imaging (placental mri) in 15 cases (35%). however, only 7 patients were found to have bladder invasion intraoperatively. in another 7 cases, inadvertent iatrogenic cystotomies were performed with no imaging to suggest bladder involvement. placental invasion of the bladder requiring cystotomy and repair by the urology team intraoperatively was found at caesarean hysterectomy in 14 cases (33%). there were 2 cases of ureteric injury. one case had ureteric catheters in situ and the other was an emergency case where ureteric catheters were not placed. both ureteric injuries 29siuj.org siuj • volume 3, number 1 • january 2022 urological involvement in the multidisciplinary management of placenta accreta spectrum in a centralised, high-volume centre http://siuj.org were recognised intraoperatively, and the ureters were re-implanted. five emergency cases did not have ureteric catheters inserted in the interests of time and patient safety. there was 1 case of a small suspected placenta accreta in which ureteric catheters were not inserted as advised by the mdt. average blood loss across all cases was 3025 ml, ranging from 700 ml to 17 litres. on further analysis, those who underwent elective procedure had an average loss of 2541 ml whereas those requiring emergency management had and mean loss of 6600 ml. there were 8 cases of placenta percreta in which balloon catheters were inserted into the internal iliac arteries. there was no maternal mortality. one case of foetal death in utero occurred when the mother suffered major blood loss per vaginam requiring caesarean hysterectomy at 19 weeks’ gestation. discussion patients within our own institution are identified and their cases brought forward for discussion at our pas mdt. other institutions within the city of melbourne or the state of victoria also refer patients to our mdt for further management. the mdt meetings are arranged with an obstetrician, a radiologist, a urologist, and a g y naecologic surgica l oncologist present. other members of the extended mdt team include representatives from the haematology department to ensure plans are in place for catastrophic haemorrhage, as well as members of the general surgery, vascular surger y, and neonatolog y teams. an anaesthetic team with significant obstetric and complex surgical experience with massive haemorrhage is required. the appropriate surgical expertise is paramount for these complex cases[13]. intraoperative cell salvage is not always required but is set up in the operating theatre for all cases. the first intraoperative role of the urology team is to assess the urothelium of the bladder and then the placement of ureteric catheters. the urology team will remain in theatre during the caesarean section and hysterectomy to reduce the risk of bladder or ureteric injury and for reconstruction as required. the placement of ureteric catheters reduces the risk of ureteric injury but also allows for the earlier identification of injury[14,15]. most patients in our series received preoperative ureteral catheterisation with resulting low risk of ureteric injury. the accurate diagnosis of pas is imperative for the management planning of these cases. all suspected cases in our institution have repeat imaging in our radiology department with doppler-enhanced ultrasound and mri. there is evidence to suggest that there is less severe haemorrhage when pas is correctly identified antenatally rather than as an incidental finding at the time of elective or emergency delivery[6,16]. the reported sensitivity of mri for the diagnosis of pas is 80% to 85% and the specificity is 65% to 100%[17]. interestingly, mri does not necessarily improve upon the accuracy of ultrasound imaging[18]. in our series, the mri had suggested 7 cases of bladder involvement but had not identified 7 others that were recognised intraoperatively. however, as these cases are managed in a high-volume unit, a urologist was present in the operating theatre for all cases, as per our mdt protocol. 30 siuj • volume 3, number 1 • january 2022 siuj.org original research table 1. patient characteristics and perioperative data number of patients n = 42 preoperative characteristics mean (sd) age, years 35 (4.9) mean (sd) previous caesarean sections 2 (1.1) preoperative bladder involvement on imaging 15 (35%) mean gestational age (sd) at delivery, weeks 34 (3.4) planned caesarean hysterectomy 39 (93%) planned conservative 3 (7%) perioperative data mean (sd) blood loss, ml 3025 (3147) ureteric catheter/stent placement 36 (86%) elective surgery 37 (88%) emergency surgery 5 (12%) bladder invasions with repair 14 (33%) ureteric injury with ureteric reimplantation 2 (5%) postoperative diagnosis percreta 29 (70%) increta 8 (19%) accreta 4 (9%) non-pas 1* (2%) * antenatal suspected mild accreta on imaging, no evidence found intra operatively or on formal histology http://siuj.org one case in our series was identified as a placenta accreta on the basis of ultrasound imaging and mri. at the time of surgery, it was found to not be a case of pas, but this potential high-risk case was managed appropriately as per our mdt protocol. we had 8 cases of placenta percreta in which interventional radiologists inserted balloon catheters into the internal iliac arteries. upon delivery of the neonate, the balloons were inflated to reduce blood loss. many high-volume centres also perform this procedure for selected placenta percreta cases, but it is not without risks. there is evidence that it can result in tissue infarction, infection, and elevated temperature postoperatively. a recent randomised controlled trial identified that balloon catheter occlusion of the internal iliac artery was not cost-effective, had significantly higher rates of postoperative fever, and made no significant difference in the rates of blood transfusion[19–21]. the neonatal paediatric team are also an integral part of the mdt. they are present in theatre at the time of delivery. some series have advocated delivery at 34 to 35 weeks’ gestation[12,22]. in our series the mean gestational age was 34 weeks. pas may not have an adverse effect on neonatal outcomes, but given that the neonates are in general born pre-term, early involvement of the neonatal team will maintain high standards of care[23]. all patients in our series were admitted postoperatively to the icu at the royal melbourne hospital (rmh), an adjoining building. the rwh does not have an icu, and the rmh has access to 24 hour on-call interventional radiology, general surgery, vascular surgery, and urology. if patients require embolization or a return to theatre, it is more practical for these patients to be managed at the rmh for the initial postoperative period. liaising with the haematology department is also undertaken early; in our series, the mean blood loss was 3025 ml but the maximum blood loss recorded was 17 litres. the mean was higher for emergency cases at 6600 ml. given the risk of having to instigate a massive transfusion protocol, it is imperative that the haematology department is fully aware in advance of the planned elective cases, and in the event of its proceeding as an emergency. other high-volume series have discussed the importance of multidisciplinary planning in all aspects of the journey from diagnosis of pas, intraoperative management and postoperative care[12,13,24,25]. in our current series of 42 pas cases there were 36 (86%) that required ureteric catheter insertion and 14 (33%) that required bladder repair, and there were 2 ureteric injuries (5%) managed with a tension-free ref luxing ureteric reimplantation. the rate of bladder repair is similar to that in our series of 49 cases published in 2016, but there are fewer ureteric injuries in our current series. limitations of this work include the nature of a retrospective review of a prospectively maintained database. despite this, meaningful conclusions may be drawn from the current data. while rare, pas can have catastrophic outcomes for both the mother and the foetus. we highlight the acceptable outcomes of a centralised multidisciplinary service. conclusions the evolution of the mdt management of these complex cases is paramount to maintain high standards and outcomes. these rare 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center of excellence for placenta accreta. am j obstet gynecol.2015 may;212(5):561–568. doi:10.1016/j.ajog.2014.11.018 25. al-khan a, gupta v, illsley np, mannion c, koenig c, bogomol a, et al. maternal and fetal outcomes in placenta accreta after institution of team-managed care. reprod sci.2014 jun;21(6):761–771. doi:10.1177/1933719113512528 32 siuj • volume 3, number 1 • january 2022 siuj.org original research http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. long-term outcomes following surgical management of urethral catheter injuries in men with spinal cord injury kirtishri mishra,1,2 rodrigo a. campos,3 laura bukavina,1,2 reynaldo g. gómez 3 1 urology institute, university hospitals cleveland medical center, cleveland, united states 2 case western reserve university school of medicine, cleveland, united states 3 urology service, hospital del trabajador, santiago, chile abstract introduction to evaluate the outcomes of surgical management of men with spina cord injury (sci) with subsequent catheter damage to the urethra that prevents clean intermittent catheterization (cic). materials and methods we performed a retrospective analysis of male sci individuals on cic with catheterinduced urethral injuries who had undergone an operative intervention in the last 30 years at our institution. the offered surgical managements were direct vision internal urethrotomy (dviu) or urethroplasty (up). continent diversion (cdiv) was indicated when reconstruction was not possible. results a total of 43 male sci patients were identified. median age was 50 years (iqr 41 to 57), and follow-up was 69 months (iqr 34 to 125). inability to perform cic was due to urethral stricture (25), false passages (11), fistula (4), diverticulum (2), and urethral erosion (1). primary intervention techniques were dviu, up, and cdiv. overall primary success, defined by the ability to return to continent cic, was 25/43 (58%); secondary surgery (10 cdiv, 3 up, 1 dviu) rescued 14/18 failures for a final 91% success rate. conclusion urethral injuries in men with sci are complex, but individualized continued surgical management can be successful in up to 90% of patients. therefore, reconstruction should be considered in this population to restore continent intermittent catheterization. introduction urologic care in individuals with a history of spinal cord injury (sci) continues to pose a medical challenge for urologists[1–5].there are advantages and disadvantages to each approach the provision of urologic care for a patient with a neurogenic bladder. since its introduction in the early 1970s by lapides and diokno, clean intermittent catheterization (cic) has become the mainstay for the management of neurogenic bladder in the sci population[6,7]. before the routine use of cic, the leading cause of death in these patients was renal failure and urinary sepsis[2,8,9]. those patients with an open sphincter/external sphincterotomy were managed with a condom catheter, and those with a closed sphincter were subjected to a chronic indwelling catheter, with urinary diversion being the most invasive option[1]. key words competing interests article information catheter urethral injury, urethral reconstruction, urethroplasty, intermittent catheterization, neurogenic bladder, spinal cord injury, reconstructive urology none declared. received on january 11, 2021 accepted on april 3, 2021 soc int urol j.2021;2(3):144–150 doi 10.48083//agbn5610 144 siuj • volume 2, number 3 • may 2021 siuj.org original research mailto:rgomez%40ext.achs.cl?subject=siuj http://www.siuj.org while condom catheters, indwelling catheters, and cic are all efficacious in appropriately selected patients, they each have their own shortcomings[10]. a condom catheter can lead to a diverticulum, stricture, or erosion, a chronic indwelling catheter may lead to erosion and recurrent urinary tract infections, and cic can lead to a false passage, stricture, or a fistula. in fact, numerous studies indicate that with a long enough course of chronic instrumentation and repeated trauma, most of these patients suffer some degree of catheter related complication[10–12]. in our practice at a large volume sci rehabilitation referral center, we strongly advocate for maintaining urinary continence by means of cic, instead of incontinent condom catheter or chronic indwelling catheters. however, as may be expected, over time the urethra is at risk for damage and complications[12]. within the reconstructive field, there is continued debate about the utility of reconstruction in these patients, with some providers arguing that there is a high likelihood of failure[13,14]. therefore, incontinent urinary diversions, such as an ileal conduit or an indwelling catheter, are used instead of reconstructive options. however, we believe that there is a benefit in restoring continent cic, minimizing the use of indwelling catheters or external appliances, particularly for individuals with sci who are already self-conscious about their appearance. the goal of this study was to evaluate our experience of more t ha n 30 yea rs to determi ne whet her interventions to restore continent cic in these patients provides a durable option for urinary management. we hy pot hesize t hat cat heter-induced uret hra l complications in sci patients can be successfully managed with a selective surgical approach that can restore continent cic and that should be routinely considered in this population. materials and methods with the approval of the institutional review board (cec/12/2020), we undertook a retrospective review of sci patients with surgically managed with dviu, up, or cdiv and subsequent catheter urethral injuries from march 1988 to december 2019. additional patient inclusion criteria were age >18 years and complete medical records and >10 months of follow-up. the procedures were performed by 6 different surgeons with half of the cases being performed by rgg. our institution is a high-volume tertiary referral center for trauma and rehabilitation, specializing in work-related injuries. after trauma stabilization, sci patients are admitted to a comprehensive rehabilitation program that includes regular annual visits for life after discharge. urological management is based on cic, and able patients are quickly instructed in selfcatheterization. baseline urodynamics and upper tract imaging are performed at the end of the spinal shock; afterwards, patients are followed with lifelong regular visits as required. treatment is oriented to obtain a good capacity and low-pressure continent bladder. anticholinergics, botulinum toxin, bladder augmentation, or sphincter reinforcing procedures are indicated as needed. long-term periodic monitoring includes renal function test and urinary tract imaging. individuals presenting with catheter urethral injuries making cic difficult or impossible were evaluated with endoscopy and urethrography. all patients considered as good surgical candidates were offered surgery. surgical management was individualized according to the type of urethral pathology, including direct vision internal urethrotomy (dviu), urethroplasty (up), or continent diversion (cdiv). dviu was used in patients with bulbar strictures up to 2 cm in length. penile strictures, bulbar strictures > 2 cm, or any recurrence after dviu were managed with a dorsal buccal mucosa graft (dbmg) urethroplasty. posterior (membranous) urethral strictures were mostly related to neurogenic spasticity of the external sphincter and were managed with a dviu plus simultaneous intrasphincter botulinum toxin injection. diverticula were managed with tailoring and closure, with use of dbmg if a stricture was present. penile urethral erosions were managed with primary closure with or without dbmg, depending on urethral plate. fistulas were managed with resection and repair of concomitant stricture, diverticulum, or false passage, with use of dbmg as necessary. continent diversion (cdiv) was indicated after failure of other options or when reconstruction was not possible. our preference is for a continent cutaneous ileal cecocystoplasty as it avoids ureteral reimplantation, provides good bladder augmentation, and provides a reliable continent channel for catheterization. an indwelling urethral silicone catheter is left for 2 to 3 days after dviu and for 3 weeks after up, before cic is resumed. pericatheter urethrography is performed before cat heter w it hdrawa l. a lt houg h reusable polyurethane catheters are the standard, hydrophilic coated catheters are prescribed after urethral surgery. abbreviations cdiv continent diversion cic clean intermittent catheterization dbmg dorsal buccal mucosa graft urethroplasty dviu direct vision internal urethrotomy sci spinal cord injury spt suprapubic tube up urethroplasty 145siuj.org siuj • volume 2, number 3 • may 2021 long-term outcomes following surgical management of urethral catheter injuries in men with spinal cord injury http://www.siuj.org cdiv patients are left with a catheter through the channel and a discharge suprapubic tube (spt) cystostomy for 3 weeks, and cic is started through the channel afterwards. a continued surgical management protocol was followed; therefore, patients who failed primar y intervention were evaluated and offered individualized secondar y rescue surger y. those who were not candidates for further surgery were managed with a definitive spt. false passages managed by simple urethral catheter stenting and external sphincter spasticity receiving botulinum toxin without associated urethral stenosis were not included in this series. the goal of all procedures was to recover easy, non-traumatic, continent cic. failure was defined as inability to return to continent cic requiring a secondary surgical procedure or definitive spt. the clavien-dindo classification was used for surgical complications. results there was a total of 43 patients, with a median age of 50 years (iqr 41 to 57) and follow-up of 69 months (iqr 34 to 125). all patients were compliant with their regular appointments and no patient was lost to follow-up. five individuals died from unrelated causes 23 to 293 months after the initial surgery. figure 1 summarizes the urethral pathology. four patients with false passage and both patients with diverticulum also had a stricture; these patients are not counted doubly as strictures. table 1 describes the types of injuries and the primary surgical interventions with associated success rates. the primary success rate for the cohort as a whole was calculated at 25/43 (58%). table 2 highlights the outcomes according to the type of surgical intervention. the primary success of dviu, up, or cdiv was fairly similar (53%, 64%, and 58%, respectively); however, cdiv had the highest perioperative morbidity (41%), with 36% of the patients suffering clavien-dindo ≥ 3 complications. in contrast, dviu and up had 17% and 18% morbidity, with none of the patients in the dviu group suffering a claviendindo ≥ 3 complication. complications are listed in table 3. complications were observed in 15/57 (26%) of procedures, and 10 of them (18%) were clavien-dindo ≥ 3. the most common complication was chimney failure (5), which refers to anything that leads to channel kinking and difficult catheter passage needing revision. table 1. the cohort categorized by the presenting pathology and the associated interventions. success was defined as the ability to return to continent intermittent catheterization type of injury primary procedure (patients) success n (%) stricture dviu (16) 9 (58) up (6) 5 (83) cdiv (3) 2 (67) total 25 58 (64) false passages up (4) 2 (50) cdiv (6) 3 (50) dviu (1) 0 (0) total 11 5 (45) fistulas up (2) 0 (0) cdiv (2) 2 (100) total 4 2 (50) catheter erosion up (1) 0 (0) total 1 0 (0) diverticulum up (2) 2 (100) total 2 2 (100) overall 43 25 (58) classi�cation of urethral injury inhibiting further cic use mean follow-up (months) = 69 [iqr 34, 125] 43 males total type of urethral injury false passage 26% stricture 58% fistula 9% catheter erosion 2% diverticulum 5% figure 1. 146 siuj • volume 2, number 3 • may 2021 siuj.org original research http://siuj.org the continued management of primary failures is also shown in table 2. rescue surgery was offered to 14 of 18 patients in whom primary failure occurred, while the remaining 4 patients were not considered surgical candidates and were left with a spt. all secondary procedures were successful in re-establishing cic. the final success of dviu was 10/18 (56%), of up 12/17 (71%), and cdiv 17/22 (77%). of the 10 patients in the dviu and botulinum toxin group, 6 did not require any further procedure, while the remaining 4 patients required up (2), cdiv (1), and spt (1). additionally, the re-do cdiv (table 2) group refers to failure of the channel requiring a completely new channel. isolated stomal stenosis was reconstructed at the stomal level only. ultimately, after a total of 57 surgical procedures, the reconstruction goals were achieved in 39 of 43 patients (a 91% overall success rate), and there was no surgical mortality. discussion the management of neurogenic bladder in patients with sci continues to be an evolving issue[1–5]. since the advent of cic, most providers would agree that patients with good upper extremity function status should be afforded this modality of bladder management. although recently reported patient outcomes suggest individuals with sci may prefer indwelling catheters for convenience, there is support in the literature for the benefits of avoiding long-term indwelling catheters or external condom catheters, as well as for the benefits of avoiding major surgeries for urinary diversion[6,7,15,16]. because of this, we believe every reasonable effort should be made to maintain cic. there is a lack of consensus on the optima l management strategy for patients who are unable to continue performing cic because of catheter-induced urethral pathology, such as obstruction, false passage, diverticulum, or fistula, and very little has been published on this issue. in this study, we investigated the outcomes of our management of these described pathologies over the course of 30 years at our institution [13]. we hypothesized that surgical interventions aimed at restoring continent cic would be successful in the majority of these patients. overa l l, we found t hat 91% of patients who underwent continued surgical intervention to restore cic were successful through the course of our followup. these interventions included dviu, up, and cdiv. the secondary procedure was determined on the basis of the status of the urethra. dviu is considered as the first option, mainly for short and simple strictures; for longer, heavy fibrous or complex cases (like associated false passages) a more definitive reconstruction was necessary. unreconstructible urethras were considered for diversion. although dviu showed the lowest success table 2. the cohort categorized by the type of surgical intervention performed. the overall final success rate was 91% and only 4 patients ultimately failed surgical interventions and required a definitive suprapubic tube primary procedure (patients) primary procedure failure n (%) secondary procedure (patients) secondary procedure success (patients) final success* (%) overall morbidity* (%) clavien ≥3 (%) dviu 17 8 (47) up 3 3 14/17 (82) 3/18 (17%) 0 dviu 1 1 cdiv 1 1 spt 3 – up 14 5 (36) cdiv 5 5 14/14 (100) 3/17 (18%) 2/17 (12) cdiv 12 5 (42) cdiv 4 4 11/12 (92) 9/22 (41) 8/22 (36) spt 1 – total 43 18 (42) 14 39 (91) * final success and overall morbidity were calculated combining primary and secondary surgeries. 147siuj.org siuj • volume 2, number 3 • may 2021 long-term outcomes following surgical management of urethral catheter injuries in men with spinal cord injury http://www.siuj.org (56%), as mentioned above it is the best choice for short bulbar and membranous strictures because of its simplicity and low complication rate. in contrast, cdiv achieved the highest success (77%) but was linked to the highest morbidity. the up subgroup had a 71% success rate, which contrasts with previous reports. specifically, in 2003, secrest et al. noted a 65% (11/17 patients) failure rate in urethral reconstruction in a similar cohort, so the authors concluded that these patients are best treated with urinary diversion from the beginning[13]. in our series, however, we found that 71% of the patients who underwent a up were able to successfully return to cic, avoiding a diversion and with a tolerable 18% complication rate. our results also emphasize the value of continued surgical management: 14 of the 18 failures (and 33% of the whole series) were taken for selective individualized secondary surgery with 100% secondary success. reconstruction was considered a failure in only 4 patients (9%), who left with a chronic spt. after these results, providers should strongly consider reconstruction for patients who are good candidates to restore continent cic. the field of reconstruction has evolved significantly in the last 15 years, so that instead of reported 65% failure rate, most studies now cite a 70% to 90% success rate after urethroplasty[17]. urethral reconstruction is an evolving art, with more fellowship-trained reconstructive urologists practicing at the current time, with an improvement in graft techniques and postoperative care[18]. in 2004, ronzoni et al. cited a 73% success rate in 48 neurological patients with urethral diverticulum[19]. following this finding, meeks et al. reported a 63% success rate after urethroplasty to restore cic in 2008[20]. they cited the presence of a good urethral plate as an important prerequisite for successful repair. in a follow-up study by the same group, casey et al. reported a 70% success rate in 23 neurogenic patients after urethral reconstruction, with no patients requiring urinary diversion[21]. of note, we favor a dorsal buccal mucosal graft urethroplasty as we believe it allows a smoother passage of the catheter for patients performing cic; a ventral graft or flap may produce ventral irregularity, which may be a risk factor for a false passage. it is impor ta nt to ack nowledge t hat despite i mprovement i n tech niques a nd postoperat ive ma nagement, reconst r uct ion fa i lure rema ins a possibility, and the surgeon must have a secondary procedure in mind for these patients. therefore, patients should be thoroughly evaluated before undergoing procedures, and should be provided comprehensive counseling to ensure they are aware that they have a higher failure rate than non-neurogenic patients. factors that may lead to worse outcomes include but are not limited to poor tissue quality, poor nutrition, subpar hygiene, lack of social support, and persistent insults to the urethra. strict postoperative care with delayed wheelchair usage and avoidance of perineal pressure may prevent wound breakdown and pressure ulcers. furthermore, the outcome is also associated with the complexity of the case and team’s experience. if any of these issues are non-modifiable and appear to be a significant impediment to undertaking a reconstruction, then diversion should be considered. factors that may stratify a urethra as “unreconstructible” include persistent or recurrent fibrosis, large false passage with persistent infection, large fistula, severe panurethral stricture, poor vascularity of the urethral plate, poor quality of local tissues, and a small capacity bladder requiring bladder augmentation. in these patients, a continent or incontinent urinary diversion with or without bladder sparing should be considered. the authors of this study favor bladdersparing continent diversion if possible. the advantages of such diversion are that no ureteral reimplantation is needed and patients can continue to perform continent cic via a catheterizable channel (continent cutaneous ileal cecocystoplasty, or channels like mitrofanoff, yang-monti, or casale). bladder augmentation may be considered in these patients if appropriate. patients with poor performance status or recurrent reconstruction failures are elected for a definitive suprapubic tube placement. table 3. list of observed complications complication n chimney failure 5 stomal stenosis 4 perineal phlegmon 1 peritonitis 1 wound infection and graft loss 1 clot retention 1 pressure ulcer 1 febrile uti 1 148 siuj • volume 2, number 3 • may 2021 siuj.org original research http://siuj.org one of the weaknesses of this study is its retrospective nature. however, most of these patients were treated by a single provider (rgg), who operated on and managed the follow-up care of these patients for most of the 30-year follow-up. furthermore, despite being a comparatively large series with sci individuals who underwent reconstructive urethral surgery, this study still has a limited cohort. overall, this shortcoming can be addressed with a prospective analysis, which may require a multi-institutional effort. conclusion we pre s e nt ou r lon g-t e r m re s u lt s of s u r g ic a l reconst r uc t ive ma nagement of c at heter-i nduced u re t h r a l i nju r ie s i n t he m a le s c i p at ie nt . a selective surgical approach is described, depending on the t y pe of injur y and patient’s condition. our findings suggest that surgery should be considered to restore cont i nent c at heter i z at ion. w h i le t he pr i ma r y succe s s r ate is lower t ha n i n non-sci cases, properly selected secondar y rescue surger y may improve success up to 90%, so reconstruction is well worth the effort to restore continent cic in these complex cases. author contributions kirtishri mishra: data analysis, manuscript writing and editing; laura bukavina: data analysis, figure, manuscript writing and editing; reynaldo g. gómez: protocol and project management, data analysis, manuscript writing and editing; rodrigo a. campos: data collection. 149siuj.org siuj • volume 2, number 3 • may 2021 long-term outcomes following surgical management of urethral catheter injuries in men with spinal cord injury http://www.siuj.org reference 1. l a r s e n l d, c h a m b e r lin d a , k h o n s a r i f, a hle r in g t e . retrospec tive analysis of urologic complications in male patients with spinal cord injur y managed with and without ind welling urinar y catheters. urology.19 9 7;5 0 (3):418 – 42 2. doi: 10.1016/s0090–4295(97)00224–0. 2. weld kj, dmochowski rr. ef fect of bladder management on urological complications in spinal cord injured patients. j urol.2000;163(3):768–772. 3. singh r, rohilla rk, sangwan k, siwach r, magu nk, sangwan ss. bladder management methods and 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reconstruction of urethral erosion in men with a neurogenic bladder. bju int.2009;103(3):378–381. doi: 10.1111/j.1464–410x.2008.08020.x. epub 2008 sep 3. 21. casey jt, erickson ba, navai n, zhao lc, meeks jj, gonzalez cm. urethral reconstruc tion in patient s with neurogenic bladder dysfunction. j urol.2008;180(1):197–200. doi: 10.1016/j. juro.2008.03.056. epub 2008 may 21. 150 siuj • volume 2, number 3 • may 2021 siuj.org original research http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information prostate cancer, radical prostatectomy, lymph node dissection none declared. received on july 26, 2021 accepted on august 27, 2021 soc int urol j.2021;2(6):347–353 doi: https://doi:10.48083/hahe3801 347siuj.org siuj • volume 2, number 6 • november 2021 original research protocol for a pilot study of the node trial, a prospective multicentre randomised trial of extended pelvic lymph node dissection for high-risk prostate cancer george mcclintock,1 hadia khanani,1 antonella de rosa,2 scott leslie,1,2,3 nariman ahmadi,1 jeremy fallot,1 peter ferguson,2,4 henry woo1,3 1 chris o’brien lifehouse hospital, camperdown, australia 2 royal prince alfred hospital, camperdown, australia 3 the university of sydney, camperdown, australia 4 the university of sydney medical school, sydney, australia abstract objectives to test the hypothesis that a randomised trial of extended pelvic lymph node dissection (eplnd) can recruit at a rate acceptable for a larger scale trial. to compare the following secondary endpoints between the 2 arms: the rate of protocol violations, the intraoperative and postoperative morbidity of eplnd, and complications, and to evaluate short-term oncological outcomes comparing biochemical recurrence, clinical recurrence, and survival between arms. patients and methods a pilot study will be undertaken at chris o’brien lifehouse and royal prince alfred hospitals for the node trial. twenty patients will be randomised 1:1 to radical prostatectomy with or without eplnd. eligible participants will have high-risk prostate cancer and will be scheduled for robotic radical prostatectomy. high-risk disease will be defined as in the 2019 nccn guidelines (stage ≥ t3a, isup grade group ≥ 4 or psa ≥ 20ng/ml). psma pet/ct staging not showing any extraprostatic disease will be required. quality control measures to ensure consistent delivery of high-quality extended lymph node dissections are in place, and surgeons have been selected for their consistent ability to perform such procedures. results the trial is currently underway. conclusion on current available evidence, it is unclear if eplnd provides additional benefit over radical prostatectomy. introduction prostate cancer is one of the most commonly diagnosed cancers in men; however, the basic question of whether to perform a lymph node dissection at the time of radical prostatectomy remains unanswered. pelvic lymph node dissection (plnd) is the most accurate test for staging and prognosis[1,2] and has substantial theoretical plausibility for survival benefit by removing micro-metastases in lymph node confined disease. there is, however, no robust evidence to support improved survival or improvement in other oncological outcomes[3]. because of the lack of a sentinel node and the wide bilateral primary drainage area, an adequate plnd is a significant undertaking[4], and current guideline recommendations to perform the procedure are based on limited evidence[5]. the current literature is affected by multiple issues including a lack of standardisation of definitions and a preponderance of retrospective data. the extent of plnd (limited, standard, and extended) and anatomical boundaries vary between surgeons and centres, and evidence regarding both harms and benefits of plnd is conflicting[3]. extended lymph node dissection consistently yields more lymph nodes, which would theoretically offer a larger therapeutic benefit, although there is little high-quality evidence for this either. risks and benefits plnd is associated with a higher risk of lymphocele and longer operative time[6,7]. limited evidence exists for other purported risks including increased risk of lymphoedema, mortality, and worse functional outcome s (u r i na r y i ncont i nenc e a nd erec t i le dysfunction)[3]. a recent systematic review by fossati et al. 2016, evaluated the benefits and harms of plnd, in which the primary outcome measures were biochemical recurrence, clinical recurrence, and survival. overall, the quality of the evidence was low, and the risk of bias high. three randomised control trials were available, of which one was reported as conference abstracts only[8,9], and only 4 of the remaining studies were performed prospectively. evidence is very mixed regarding risks and benefits. twenty-one retrospective studies compared oncological outcomes in no plnd with those in any form of plnd. none of the studies showed statistically significant differences in support of plnd for biochemical recurrence, distant metastases, or survival. eight studies compared limited/standard plnd with extended plnd (eplnd) with conflicting results. there is some evidence of therapeutic benefit however, patients undergoing plnd showing lower biochemica l recurrence rates and an additiona l retrospective study showing the removal of higher number of lymph nodes being associated with better cancer specific survival. two rcts have been published in this area. the first[10] recruited 291 patients with intermediateor high-risk prostate cancer, who were randomly assigned to undergo eplnd on one side of the pelvis and limited plnd on the other. after a median follow-up of 35.2 months, eplnd was associated with better tumour staging and increased morbidity. the second, more recent study[11] found no difference between the groups, though a post hoc subgroup analysis found improvement in outcomes in patients with higher gleason grade cancers. currently, the european association of urology (eau) guidelines recommend performing an eplnd in high-risk patients and not performing limited or standard dissection at all[5]. limited dissection exposes the patient to additional risk of harm, but it will miss many nodal metastases and is associated with a significant risk of understaging. all patients recruited into this study, by virtue of meeting the nccn guidelines definition of high-risk prostate cancer, also meet criteria in the eau guidelines to recommend eplnd[12], thus the experimental arm in this trial is actually the no eplnd arm, with eplnd forming standard of care. extent of dissection lymph node metastases from the prostate are highly variable, and the impact of the extent of dissection on outcomes reported by previous studies is unclear. although definitions vary, limited plnd is most commonly defined as the removal of nodal tissue from the area along the external iliac vein and above the obturator nerve; standard plnd is area covered by limited plnd plus the area below the obturator nerve and onto the internal iliac vessels; eplnd as removal of all nodes overlying the external iliac artery and vein, within the obturator fossa, and medial to the internal iliac artery. the current definitions are somewhat arbitrary in their extent, and novel mapping study methods of lymph node drainage have shown that nodal drainage patterns are wider than previously described and extend well beyond the obturator region[4]. on the basis of these studies, a standard dissection is likely to remove only 38% of primary draining lymph nodes, but concerningly even the recommended extended lymph node dissection will remove only 63%, thus a new nodal dissection template is required. the lack of level 1 evidence to support the therapeutic role of plnd highlights the need for a robust, adequately powered rct. the aim of this pilot study is to determine the feasibility of the randomised trial design before the development of a full-scale rct. patients and methods the node trial is a planned multicentre randomised control trial of eplnd. this protocol is for a pilot study assessing the ability of such a trial to recruit patients in a timely fashion and to determine plausibility given previous difficulties with other similar trials. three surgeons at 2 institutions will recruit patients over a 12-month period. the recruitment target is 20 patients, chosen without reference to any previous trial recruitment data, as none are available. numbers of abbreviations eplnd extended plnd isup international society of urological pathology plnd pelvic lymph node dissection psma prostate specific membrane antigen 348 siuj • volume 2, number 6 • november 2021 siuj.org original research eligible patients and reasons for non-participation will be recorded. surgeons in this study have a documented history of performing high-quality eplnd, 2 are fellowship trained robotic surgeons and the third has > 20 years’ experience performing open and robotic radical prostatectomy. the primary and secondary objectives are listed in table 1. the study is approved (2019/eth09765) by the sydney loca l hea lt h district human research ethics committee (ec00113) and is registered on the australian new zealand clinical trials registry (actrn12620000881932). this pilot study will require no funding. it will be conducted according to local laws and regulations, the declaration of helsinki, and the principles of good clinical practice. the trial schema is outlined in figure 1. recruitment and randomisation patients w il l be screened for recruitment af ter histological diagnosis of prostate cancer has occurred. patients will be assessed for eligibility using the inclusion and exclusion criteria listed in table 2. the standard of care in australia for staging high-risk prostate cancer is to perform a psma pet/ct. patients with non-metastatic disease on psma pet will form the population to be evaluated in this study. patients will be randomised 1:1 to robotic radical prostatectomy without plnd (experimental arm) or to robotic radical prostatectomy with bilateral eplnd (standard of care). the participating surgeons in this trial share the opinion that the current evidence has not shown superiority of either approach and thus the 2 arms of the trial are at equipoise. the trial will be of 349siuj.org siuj • volume 2, number 6 • november 2021 protocol for a pilot study of the node trial table 2. inclusion and exclusion criteria[12] inclusion criteria • histologically proven prostate cancer scheduled for robotic assisted radical prostatectomy • psma pet negative for metastatic disease • non-metastatic, high-risk, or very high-risk disease (2019 nccn guidelines), consisting of any of: • stage ≥ t3a or • isup grade group ≥ 4, or • psa ≥ 20ng/ml exclusion criteria • history of deep venous thrombosis • history of lower limb lymphedema • history of previous pelvic radiotherapy • psma: prostate specific membrane antigen; nccn: national comprehensive cancer network; isup: international society of urological pathology. table 1. primary and secondary objectives primary to determine the proportion of eligible patients for which trial participation is achieved and to assess the rate of recruitment of eligible patients secondary to determine the incidence and nature of protocol violations to evaluate the morbidity of plnd including complications, intraoperative and postoperative outcomes, and postoperative morbidity to evaluate the short-term oncological outcomes assessed by biochemical recurrence, clinical recurrence, and survival figure1. flow diagram screening of patients ineligible eligible patients approached by trial investigators non-participation reasons recorded randomisation robotic prostatectomy without plnd robotic prostatectomy with eplnd intraoperative data collection and review of procedure performed, including photographs postoperative data collection open label design. data will be analysed on an intention to treat basis. intraoperative protocols robotic radical prostatectomy will occur at royal prince alfred hospital or chris o’brien lifehouse. the eplnd template is represented diagrammatically in figure 2 and consists of removal of lymph nodes located along the external iliac vein, those in the obturator fossa and along the internal iliac artery up to the midcommon iliac region where the ureter crosses the iliac vessels, those that are dorsolateral to the external iliac vessels and at the bifurcation of the common iliac vessels, in the fossa of marcille, and on the medial aspect of the internal iliac vessels. to ensure quality of surgical resection, 3 still photographic images will be taken for each side: • photo 1: medial view showing internal, external, and common iliac vessels • photo 2: space between external iliac vein and artery • photo 3: lateral view (by medial retraction of the external iliac vessel) to show the deep obturator space and fossa of marcille. these photographs will be reviewed by the researchers at the conclusion of the study. failure to adequately dissect the structures or document their dissection will be considered a protocol violation. all patients will have a pelvic drain inserted at the time of surgery. perioperative, operative, and postoperative data will be recorded, as per fields outlined in table 3. histopathology lymph node specimens will be submitted separately by drainage region for right and left side as external iliac, internal iliac, common iliac, and fossa of marcille. the histopathology will be reviewed at the department of tissue pathology and diagnostic oncology at royal prince alfred hospital by specialist uropathologists. all the submitted nodal tissue will be embedded for microscopic analysis. follow-up following discharge, patients will be followed up by their urologist. they will have planned follow-ups at 4 weeks, 3 months, 6 months, and 12 months postoperatively, with a psa test before each appointment. sample size and power calculation no sample size or power calculation was performed for this study given its nature as a pilot study. twenty patients will be recruited, or if <20 patients are recruited after 12 months, recruitment will cease, and patient numbers will be capped at that level. results recruitment the ability of this pilot study to recruit patients for a larger trial forms the primary outcome. this will be reported as a proportion of eligible patients who are successfully enrolled and randomised. reasons for nonenrolment of eligible patients will be recorded. failure to recruit the target number of patients will not preclude progression to a larger trial, but may influence its design. protocol violations performing the large lymph node dissection required in this study consistently while maintaining a high standard will add significant time and complexity to the procedures. monitoring both the intraoperative and postoperative rate of study protocol violations will therefore ensure that this approach can be successfully deployed in a larger trial. protocol violations will be reported by procedure stage and nature. adverse events intraoperative, immediate postoperative and post discharge adverse events will be reported in both arms using the clavien-dindo classification. oncological outcomes the occurrence of biochemical recurrence (serum psa ≥ 0.2ng/ml[13,14]), clinical (radiological) recurrence, and survival time will be recorded between the 2 arms. discussion there are a number of causes of the current lack of clarity regarding the therapeutic benefit of pelvic lymph node dissection. figure 2. extended plnd template the orange, yellow and green regions represent the external, internal, and common iliac regions, respectively. dashed lines indicate the fossae of marcille. reprinted with permission from maderthaner et al. “more extended lymph node dissection template at radical prostatectomy detects metastases in the common iliac region and in the fossa of marcille.” bju int. 2018 may;121(5):725-731. 350 siuj • volume 2, number 6 • november 2021 siuj.org original research as discussed above, no trials comparing eplnd with no plnd have been reported. of the 2 published rcts, one randomised patients to one side extended and one side limited dissection, limiting its ability to provide prognostic data[10]. a second rct[11] has reported no significant difference between limited and extended plnd, but on post hoc subgroup analysis, found it to be beneficial in patients with higher gleason scores. multiple factors make randomised trials in this area difficult, and clear level 1 evidence is lacking as a result. difficulties inherent in surgical randomised trials are exacerbated for trials of plnd in prostate cancer. despite a lack of proven therapeutic benefit, pelvic lymph node dissection has substantial biological plausibility and forms a widespread component of surgical practice. reluctance to have patients randomised to one arm of a trial is a common impediment to surgical trials, and many surgeons would feel uncomfortable not performing a lymph node dissection on high-risk patients. performing large pelvic lymph node dissections is also time-consuming and difficult, and participating surgeons need to be motivated to perform an adequate dissection. a large, bilateral lymph node dissection is likely to add significantly to the length of a case, even in the hands of a surgeon experienced at performing the procedure. it requires dissection around the large blood vessels of the pelvis, and this may be outside skill set of many surgeons, especially if performed robotically. for this reason, the intraoperative photographs have been included, in an attempt to monitor and maintain dissection quality. trials in this area have previously had difficulty recruiting[15]; given this and the above reasons, it is prudent to perform a pilot study. previous trials comparing limited with eplnd may have been easier to perform, and they sidestepped the potential ethical issue of not performing a plnd in high-risk patients, but their trial design is not the right one for answering this question. the current state of the literature is that there is no level 1 evidence for the performance of lymph node dissection, and the inclusion of a limited plnd is likely only to act as a confounder. there is good evidence that eplnd provides superior staging, and the eau guidelines thus recommend performing an eplnd if any lymph node dissection is going to be performed. regarding the ethical issue of not performing a plnd at all compared with a limited dissection, limited plnd is a procedure with the risks but not the benefits of a larger dissection, and should thus be regarded as inferior to both eplnd and no dissection[16]. patient selection needs to be judicious to ensure the highest likelihood of showing, or definitively disprov351siuj.org siuj • volume 2, number 6 • november 2021 protocol for a pilot study of the node trial table 3. data collected patient characteristics • age • comorbidities and medications • charlson comorbidity index cancer characteristics • isup grade group • psa • local clinical t stage • briganti nomogram % chance of lymph node involvement • mri • psma pet/ct • other imaging intraoperative • operative time (total) • operative time (console time) • estimated blood loss • blood transfusion • correct procedure performed as per randomisation • if randomised to eplnd, as per template? • still photographs of extent of plnd • use of drain postoperative • postoperative duration of hospital stay • complications: early (< 30 days) and late (< 90 days) • duration of catheterisation • duration of pelvic drain • 30-day readmission • 90-day mortality pathology • weight of gland • gleason score/isup grade group • tumour volume • extraprostatic extension • seminal vesicle invasion • surgical margin status • lymphovascular invasion • periprostatic fat lymph node status • numbers of lymph nodes dissected • nodal metastases • presence of ductal carcinoma oncological outcomes • biochemical failure (psa) • clinical recurrence (radiological evidence of localised recurrence or distant metastases) • survival (alive at one year or date of death) morbidity/ complications > 90 day • eg, thromboembolic events/ lymphocele/ lymphoedema, neuropraxia, other isup: international society of urological pathology; psma: prostate specific membrane antigen. ing, a benefit of plnd. patients with no lymph node metastasis will derive no benefit from plnd, nor are those with established distant metastatic disease likely to benefit, as their prognosis will be substantially determined by their distant disease. patients with high risk of lymph node metastases but the lowest chance of distant metastatic disease are thus the ideal target population. with reference to targeting this population, it is likely that multiple factors have overlapped to make previous trials inadequately powered to detect differences in outcomes. new technology in the form of psma scans and new research in the form of the above-mentioned technetium node mapping studies may allow this to be addressed in this trial. importantly, previous trials in this area have not used psma staging. data from the recent propsma study has shown that traditional staging (ct and bone scan) fails to detect distant metastatic disease in two-thirds of cases[17]. previous studies would have included these patients as they would have been staged as having localised disease. these patients will not benefit from local treatment, and although randomisation would ensure they were evenly distributed, their inclusion would lead to significant dilution of the effect of any lymph node dissection. psma accurately predicts the presence of lymph node metastases[18]. however, in patients with lymph node metastases identified on psma, biochemical recurrence rates approach 50%, even in patients treated with eplnd[19], pointing to the presence of micrometastatic disease outside the pelvis. the selection of patients with no extra prostatic disease on psma aims to select patients who have only early nodal disease and thus use the greater accuracy from this new modality to target patients with the best likelihood of surgical cure. the extent of dissection chosen in previous retrospective and prospective studies is also likely to have diluted previous evidence of effect. the publication of data indicating that for clearance of 75% of draining lymph nodes[4] a bilateral eplnd must be performed indicates that previous trials would have diminished effect size by missing as much as half of lymph node metastases. a trial assessing dissection matching this new mapping pattern is required. as a pilot study, this study has many limitations. to test recruitment and the suitability of the protocol in a reasonable amount of time, this study has been kept intentionally small, with few patients, surgeons, and centres. if the study is converted to a full randomised control trial, these limitations will be addressed. the pilot study of the node trial has commenced recruitment and aims to complete recruitment within 12 months. the protocol may be altered before the commencement of the node trial proper. references 1. perry‐keene j, ferguson p, samaratunga h, nacey jn, delahunt b. total submission of pelvic lymphadenectomy tissues removed during radical prostatectomy for prostate cancer increases lymph node yield and detection of micrometastases. histopathology.2014;64(3):399–404. https://doi.org/10.1111/his.12262 2. yaxley jw, raveenthiran s, nouhaud f-x, samartunga h, yaxley aj, coughlin g, et al. outcomes of primary lymph node staging of intermediate and high risk prostate cancer with 68 ga-psma p osit r on emis sion tomo gr ap hy/c ompu t erize d tomo gr ap hy compared to histological correlation of pelvic lymph node pathology. j urology.2019;201(4):815–820. https://doi.org/10.1097/ ju.0000000000000053. 3. fossati n, willemse p-pm, van den broeck t, van den bergh rcn, yuan cy, briers e. the benefits and harms of different extents of lymph node dissection during radical prostatectomy for prostate cancer: a systematic review. eur urol.2017;72(1):84–109. https://doi. org/10.1016/j.eururo.2016.12.003. 4. mattei a, fuechsel fg, dhar nb, warncke sh, thalmann gn, krause t. the template of the primary lymphatic landing sites of the prostate should be revisited: results of a multimodality mapping study. eur urol.2008;53(1):118 –125. ht tps://doi.org/10.1016/j. eururo.2007.07.035. 5. mottet n, van den bergh rcn, briers e, van den broeck t, cumberbatch mg, santis md. eau-eanm-estro-esur-siog guidelines on prostate cancer—2020 update. part 1: screening, diagnosis, and local treatment with curative intent. eur urol.2020;79(2):243–262. https://doi.org/10.1016/j.eururo.2020.09.042. 6. briganti a, blute ml, eastham jh, graefen m, heidenreich a, karnes jr. pelvic lymph node dissection in prostate cancer. eur urol. 2 0 0 9;5 5 (6) :12 51–12 6 5. h t t p s: //doi.or g /10.1016/ j. eururo.2009.03.012. 7. zheng y, gao y, cheng y, qi f, zou q. whether extended pelvic lymph node dissection should be performed in prostate cancer: the present evidence from a systematic review and meta‐analysis. precis medical sci.2020;9(1):23–30. https://doi.org/10.1002/prm2.12005. 8. lestingi jfp, guglielmetti g, pontes j jr, mitre ai, sarkis a, bastos da, et al. extended versus limited pelvic lymphadenectomy during radical prostatectomy for intermediateand high-risk prostate cancer: early outcomes from a randomized controlled phase iii study. j clin oncol.2017;35(15 suppl):5018–5018. https://doi.org/10.1200/ jco.2017.35.15_suppl.5018. 352 siuj • volume 2, number 6 • november 2021 siuj.org original research 9. schwerfeld-bohr j, kaemper m, krege s, heidenreich a. 270 prospective randomized multicenter study comparing limited vs extended pelvic lymphadenectomy in intermediate and high risk prostate cancer – comparison of complications (seal, auo ap 55/09). eur urol suppl.2014;13(1):e270. https://doi.org/10.1016/ s1569-9056(14)60266-9. 10. clark t, parekh dj, cookson ms, chang ss, smith er jr, wells n, et al. randomized prospective evaluation of extended versus limited lymph node dissection in patients with clinically localized prostate cancer. j urology.2003;169(1):145–147;discussion:147-148. doi:10.1097/01. ju.0000039647.16278.17.. 11. lestingi jfp, guglielmetti gb, trinh q-d, coelho rf, pontes j, bastos da. extended versus limited pelvic lymph node dissection during radical prostatectomy for intermediateand high-risk prostate cancer: early oncological outcomes from a randomized phase 3 trial. eur urol.2021;79(5):595 – 604. https://doi.org/10.1016/j. eururo.2020.11.040. 12. mohler jl, antonarakis es, armstrong aj, d’amico av, davis bj, dorff t. prostate cancer, version 2.2019, nccn clinical practice guidelines in oncology. j natl compr canc netw.2019;17(5):479–505. https://doi.org/10.6004/jnccn.2019.0023. 13. cookson ms, aus g, burnett al, canby-hagino ed, d’amico av, dmochowski rr, et al. variation in the definition of biochemical recurrence in patients treated for localized prostate cancer: the american urological association prostate guidelines for localized prostate cancer update panel repor t and recommendations for a s t andar d in t he repor ting of sur gic al ou t comes. j urol.2007;177(2):540–545. https://doi.org/10.1016/j.juro.2006.10.097. 14. cornford p, van den bergh rcn, briers e, van den broeck t, cumberbatch mg, santis md, et al. eau-eanm-estro-esur-siog guidelines on prostate cancer. part ii—2020 update: treatment of relapsing and metastatic prostate cancer. eur urol.2020;79(2):263–282. https://doi.org/10.1016/j.eururo.2020.09.046. 15. prospective study to compare a limited versus extended pelvic lymphadenectomy during prostatectomy (se al). clinicaltrials. gov-b. available at: https://clinicaltrials.gov/ct2/show/nct01555086. accessed december 2, 2020. 16. briganti a, giannarini g, karnes rj, gandaglia g, ficarra v, montorsi, f. what evidence do we need to support the use of extended pelvic lymph node dissection in prostate cancer? eur urol.2015;67 (4):597– 598. https://doi.org/10.1016/j.eururo.2014.09.025. 17. hofman ms, lawrentschuk n, francis rj, tang c, vela i, thomas p, et al.; for the propsma study group collaborators. prostatespecific membrane antigen pe t-ct in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (propsm a): a prospective, randomised, multi-centre study. lancet. 2020;395 (10231):1208 –1216. ht tps://doi.org /10.1016/ s0140-6736(20)30314-7. 18. petersen lj, zacho hd. psma pet for primary lymph node staging of intermediate and high-risk prostate cancer: an expedited systematic review. cancer imaging.2020;20(1):10. https://doi.org/10.1186/ s40644-020-0290-9. 19. leeuwen pj, donswijk m, nandurkar r, stricker p, ho b, heijmink s, et al. gallium‐68‐prostate‐specific membrane antigen (68ga‐psma) positron emission tomography (pet)/computed tomography (ct) predicts complete biochemical response from radical prostatectomy and lymph node dissection in intermediate‐ and high-risk prostate cancer. bju int.2019;124(1):62–68. https://doi.org/10.1111/bju.14506. 353siuj.org siuj • volume 2, number 6 • november 2021 protocol for a pilot study of the node trial key words competing interests article information radiotherapy, urethral stricture, dilation, intermittent catheterization none declared. received on july 28, 2021 accepted on august 27, 2021 this article has been peer reviewed. soc int urol j. 2022;3(1):14–20 doi: 10.48083/xfyl6260 14 siuj • volume 3, number 1 • january 2022 siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. original research the efficacy and safety of a conservative management approach to radiation-induced male urethral strictures in elderly patients with comorbidities alexander t. rozanski,1 matthew j. moynihan,1 lawrence t. zhang,1 alexandra c. muise,2 daniel d. holst,2 steven a. copacino,1 leonard n. zinman,1 jill c. buckley,2 alex j. vanni1 1 lahey hospital and medical center, burlington, united states 2 university of california san diego school of medicine, san diego, united states abstract objectives to assess the outcomes of a conservative management approach to radiation-induced urethral stricture disease (r-usd) in an elderly population with comorbidities. methods patients with r-usd managed with endoscopic procedures and/or clean intermittent catheterization (cic) between 2007 and 2019 were included. patients were excluded if they had an obliterative stricture, prior urethral reconstruction/urinary diversion surgery, or < 3 months follow-up. primary outcome measures were urinary tract infection (uti), acute urinary retention (aur), serum creatinine, uroflowmetry/post-void residual, and urinary incontinence (ui). failure was defined as progression to reconstructive surgery or permanent indwelling catheterization. results ninety-one men were analyzed with a median follow-up of 15.0 months (iqr 8.9 to 37.9). median age was 75.4 years (iqr 70.0 to 80.0), body mass index was 26.5 kg/m2 (iqr 24.8 to 30.3), and charlson comorbidity index was 6 (iqr 5 to 8). median stricture length was 2.0 cm (iqr 2.0 to 3.0). stricture location was bulbar (12%), bulbomembranous (75%), and prostatic (13%). a total of 90% underwent dilation, and 44% underwent direct visual internal urethrotomy (dviu). for those that underwent these procedures, median number of dilations and dvius per patient was 2 (iqr 1 to 5) and 1 (iqr 1 to 3), respectively. forty percent used cic. thirty-four percent developed a uti, and 15% had an aur episode requiring urgent treatment. creatinine values, uroflowmetry measurements, and ui rates remained stable. eighty percent avoided reconstructive surgery or indwelling catheterization. conclusion most elderly patients with comorbidities with r-usd appear to be effectively managed in the shortterm with conservative strategies. close observation is warranted because of the risk of utis and aur. the potential long-term consequences of repetitive conservative interventions must be considered. introduction radiotherapy is a commonly used modality for the treatment of pelvic malignancies, particularly prostate cancer and anorectal cancers. according to a large retrospective analysis of the surveillance, epidemiology, and end results (seer) program from 2004 to 2013, 38% of patients with localized prostate cancer chose radiation as initial therapy[1]. http://siuj.org mailto:rozanskia%40uthscsa.edu?subject=siuj although significant technical in recent years have allowed for more targeted therapy of the malignancy, ionizing radiation treatment can still result in ischemia and fibrosis of the surrounding tissues through direct and indirect damage to cellular deoxyribonucleic acid, with significant clinical consequences. radiationinduced urethral stricture disease (r-usd) is one of these consequences, with a reported incidence of 1.7% to 31.6% depending on the type of radiation used[2–4]. this subset of usd is of particular importance to the reconstructive urologist because of the risk of stricture recurrence and development or worsening of urinary incontinence (ui) after surgical treatment. strictures after pelvic radiotherapy most commonly affect the bulbomembranous urethra[5], although isolated bulbar strictures or prostatic stenoses can occur. recurrence rates after urethroplasty for r-usd are reported to range from 10% to 27% in series with short median follow-up[5,6], in comparison with the 15.6% recurrence rate reported in long-term follow-up of urethroplasties of any kind[7]. reported ui rates range from 7% to 50% for those patients who have undergone urethroplasty for r-usd[5,6,8–11]. these patients may require subsequent artificial urinary sphincter (aus) placement, and are subject to the increased risk of aus erosion in a radiated field[12–14]. these well-documented risks in reconstructive surgery for r-usd lead some to instead consider endoscopic management with urethral balloon dilation, direct vision internal urethrotomy (dviu), and/or clean intermittent catheterization (cic) despite stricture recurrence rates reported in the range of 40% to 60%[15]. additionally, many of these patients are elderly and have comorbidities resulting in suboptimal surgical candidacy. there is a dearth of literature on the outcomes of conservative treatment strategies for r-usd with the goal of avoiding invasive surgery or permanent indwelling catheterization; in particular, there is little on the safety, associated complications, and effect on quality of life of such an approach. the objective of this multi-institutional study was to evaluate the outcomes of conservative management for r-usd in patients who were not optimal surgical candidates or who were unwilling to accept the risks associated with stricture recurrence and new or worsening ui following urethroplasty. methods after obtaining institutional review board approval, we retrospectively identified patients with r-usd placed on a conservative treatment regimen by 3 fellowship-trained reconstructive urologists at 2 participating institutions between 2007 and 2019. the decision to manage r-usd with conservative techniques, urethral reconstruction, urinary diversion surgery, or permanent indwelling catheterization was based upon a patient-centered decision-making model including thorough counseling on the risks and benefits of all treatment options. conservative management was defined as urethral balloon dilation, dviu, or cic. patients were excluded from analysis if they had an obliterative stricture, separate stricture of the pendulous urethra or fossa navicularis/meatus, isolated bladder neck contracture, prior history of urethral reconstruction or urinary diversion surgery, or less than 3 months’ follow-up. patient demographics, pelvic radiation details, previous urologic interventions, and stricture-related urinary symptoms were evaluated. stricture characteristics were assessed by retrograde urethrogram, voiding cystourethrogram, and/or cystourethroscopy. the choice of diagnostic tool(s) was based on surgeon discretion, consistent with american urological association guidelines for male urethral stricture[16]. treatment details were recorded, including the number of dilations and dvius per patient and cic regimen details. patients who underwent multiple different management techniques were included to reflect real-life clinical practice. during the study period, we evaluated several primary outcome measures. these included the incidence of culture-proven urinary tract infections (uti) requiring antibiotic therapy and acute urinary retention (aur) episodes requiring urgent intervention such as complex urethral catheter placement or suprapubic tube placement. objective outcomes including changes in serum creatinine levels, uroflowmetry values, and postvoid residual measurements over time were captured. the effect of conservative management strategies on urinary continence status and the need for incontinence treatment was also assessed. conservative management failure was defined as progression to reconstructive surgery or permanent indwelling catheterization. categorical variables were compared with the mcnemar test, chi-square test, and fisher exact test. continuous variables were compared with the wilcoxon signed-rank test and the wilcoxon rank-sum test. statistical significance was predefined at p < 0.05. abbreviations aur acute urinary retention aus artificial urinary sphincter cci charlson comorbidity index cic clean intermittent catheterization dviu direct visual internal urethrotomy r-usd radiation-induced urethral stricture disease ui urinary incontinence uti urinary tract infection 15siuj.org siuj • volume 3, number 1 • january 2022 the efficacy and safety of a conservative management approach to radiation-induced male urethral strictures http://siuj.org results a total of 91 men were analyzed with a median followup of 15.0 months (iqr 8.9 to 37.9). median age was 75.4 years (iqr 70.0 to 80.0), bmi was 26.5 kg/m2 (iqr 24.8 to 30.3), and charlson comorbidity index (cci) was 6 (iqr 5 to 8). the indication for pelvic radiation was prostate cancer (97%) and anorectal cancer (3%). two patients who received radiation for prostate cancer also received radiation for other pelvic malignancies (one for bladder cancer and one for testicular cancer). radiation type included external beam radiation alone (63%), brachytherapy alone (26%), combination external beam radiation and brachytherapy (5%), and protonbeam therapy (5%). of those with prostate cancer, 81% received radiation as primary therapy, and 19% received adjuvant or salvage radiation. there were no salvage prostatectomies in this cohort. median stricture length was 2.0 cm (iqr 2.0 to 3.0). the majority of patients (75%) had a bulbomembranous stricture location with or without more proximal prostatic involvement. isolated bulbar strictures and prostatic stenoses were seen in 12% and 13%, respectively. the most common urinary symptoms were slow f low (59%), urgency/frequency (52%), and nocturia (45%). ui was reported in 59% of patients at initial evaluation (42% stress ui, 34% urgency ui, 24% mixed ui). a total of 82 patients (90%) underwent urethral balloon dilation, and 40 patients (44%) underwent dviu. for those that underwent these procedures, median number of dilations and dvius per patient was 2 (iqr 1 to 5) and 1 (iqr 1 to 3), respectively. cic was used in 40% of patients. treatment outcomes median serum creatinine, urof lowmetry values, and post-void residual measurements remained stable between first and last visits (table 1). fourteen patients (15%) had an aur episode requiring urgent treatment, with a median of 1 episode per patient (iqr 1 to 2). median time to first aur episode after initiation of conservative management was 14.4 months (iqr 1.7 to 48.6). thirty-one patients (34%) developed a uti requiring antibiotic therapy, with a median of 2 utis per patient (iqr 1 to 3). median time to first uti after initiation of conservative management was 14.3 months (iqr 4.5 to 39.4). two patients developed urosepsis requiring hospitalization, 1 episode per patient. no patient developed severe or end-stage chronic kidney disease secondary to their stricture disease. ui rates remained stable over the study period (59% to 56%, p = 0.47). for those patients who used incontinence products, median number of pads per day (2.0 versus 1.5, p = 0.47) and median number of diapers per day (1.0 versus 1.0, p > 0.90) remained stable. four patients (4%), none of whom progressed to urethral reconstruction, under went subsequent aus placement w it h no postoperative complications to date. treatment failures eighteen patients (20%) started and subsequently failed conservative management strategies (figure 1). three patients (17%) pursued urethral reconstruction and 1 (6%) opted for ileal conduit diversion. definitive indwelling urethral catheterization and suprapubic catheterization was pursued in 4 patients (22%) and 10 patients (56%), respectively. failure rate stratified by radiation type was external beam radiation alone (19%), brachytherapy alone (13%), combination external beam radiation and brachytherapy (60%), and proton-beam therapy (20%). in the 55 of 91 patients (60%) with at least 1-year follow-up, failure rate was 22%. the incidence of uti episodes was significantly higher in those who failed conservative management (p = 0.03) (table 2). median cci was also statistically significantly higher in the failure group (p = 0.003). the success group and failure group were comparable with respect to which conservative interventions were performed and median follow-up. discussion to our knowledge, this is the largest multi-institutional study to date focusing on conservative management outcomes for r-usd. the majority of patients (80%) who were placed on a conservative management regimen over a median follow-up of 15.0 months were able to avoid invasive surgery or permanent indwelling catheterization with stable serum creatinine levels, uroflowmetry values, and post-void residual measurements. ui rates were not affected by conservative strategies, and this is an important reason why many patients elect to pursue conservative treatment rather than 16 siuj • volume 3, number 1 • january 2022 siuj.org original research table 1. objective urinary outcomes median (iqr) n creatinine (mg/dl)(first visit) 1.0 (0.9 to 1.2) 72 creatinine (mg/dl)(last visit) 1.1 (0.9 to 1.2) 53 qmax (ml/sec)(first visit) 8.0 (4.8 to 10.0) 29 qmax (ml/sec)(last visit) 10.0 (8.5 to 14.0) 19 post-void residual (ml)(first visit) 31.0 (15.0 to 100.5) 68 post-void residual (ml)(last visit) 24.0 (4.0 to 156.0) 45 http://siuj.org urethroplasty, which leads to new or worsening ui in 7% to 50% of patients[5,6,8–11]. given that 34% of this population developed a uti and 15% developed an aur episode requiring urgent intervention, it is important to counsel patients on these risks when discussing stricture management options. there were few other serious stricture-related complications, including hospitalizations for urosepsis and development of severe or end-stage chronic kidney disease. notably, the incidence of utis was significantly higher in the failure group (p = 0.03), and thus patients who develop utis should be monitored more carefully. our observational retrospective cohort is consistent with other studies on r-usd in that a majority of patients (97%) underwent radiotherapy for treatment of prostate cancer[17], and a majority of strictures were bulbomembranous (75%)[9,18]. median stricture length was 2.0 cm, which is important to consider because the american urological association guidelines for male urethral stricture recommend initially offering urethroplasty for bulbar urethral strictures ≥ 2 cm[16]. however, our cohort had a median age of 75.4 years and a median cci of 6 (corresponding to a predicted 10-year survival rate of approximately 2.25%), highlighting the fact that this patient population is often elderly with significant comorbidities, which can negatively impact their candidacy for urethral reconstructive surgery[19]. additionally, a majority of our patients already presented with ui before stricture management. one of the key challenging decisions that patients and physicians must make in this scenario is whether to proceed with urethroplasty with the potential need for subsequent aus. there is an inherent increased risk of aus erosion in the setting of prior radiation, and an even higher risk of erosion in patients who have had both prior radiation and urethroplasty[12–14]. in a 2009 study by sullivan et al., 38 patients who developed r-usd after high-dose brachytherapy were followed to determine the need for intervention based on their stricture disease and symptoms[20]. all patients were initially treated with dilation or dviu, with 49% requiring further endoscopic management or intermittent catheterization and only 1 patient proceeding to urethroplasty. our study included multiple forms of radiotherapy and demonstrated similar results with respect to the need for repeat intervention, suggesting that although the risk of development of r-usd may differ between radiation modalities, the progression and outcomes may be similar once the stricture has developed. the genesis for this study was patient-driven, as with many clinical studies. not surprisingly, many patients hope to avoid invasive reconstructive surgery if possible and desire information on the efficacy and safety of pursuing more conservative approaches. there is a paucity of recent literature on conservative management specifically for r-usd and the unique characteristics of these strictures. this disease process is challenging to manage surgically, even in expert hands, and carries a well-documented risk of stricture recurrence and either new or worsening postoperative ui. additionally, patients undergoing urethroplasty complicated by bothersome ui need to wait an additional 6 months before pursuing aus placement. as seen in our cohort, r-usd also commonly occurs in elderly patients with multiple 17siuj.org siuj • volume 3, number 1 • january 2022 the efficacy and safety of a conservative management approach to radiation-induced male urethral strictures table 2. conservative management successes versus failures successes (n = 73) failures (n = 18) p-value* age (years) [median(iqr)] 73.8 (69.9 to 79.7) 78.0 (71.0 to 84.0) 0.16 bmi (kg/m2) [median(iqr)] 26.5 (24.8 to 30.6) 27.6 (25.1 to 28.9) > 0.90 cci [median(iqr)] 6 (5 to 6) 7 (6 to 9) 0.003 history of uti (%) 21 (29%) 10 (56%) 0.03 no. of utis [median(iqr)] 1 (1 to 3) 2 (1 to 3) > 0.90 history of aur (%) 10 (14%) 4 (22%) 0.46 no. of aur [median(iqr)] 1 (1 to 2) 1 (1 to 1.5) 0.79 history of urosepsis (%) 1 (1%) 1 (6%) 0.46 stricture length (cm) [median(iqr)] 2.0 (2.0 to 3.0) 2.0 (1.5 to 3.0) 0.55 history of dilation (%) 66 (90%) 16 (89%) > 0.90 no. of dilations [median(iqr)] 2 (1 to 5) 2 (1 to 3.5) 0.18 history of dviu (%) 33 (45%) 7 (39%) 0.63 no. of dviu [median(iqr)] 2 (1 to 3) 1 (1 to 2) 0.25 history of cic (%) 29 (40%) 7 (39%) > 0.90 follow-up (months) [median(iqr)] 15.0 (8.8 to 37.0) 18.0 (9.1 to 50.7) 0.47 * continuous variables: wilcoxon rank-sum test; categorical variables: fisher exact test or chi-square test http://siuj.org comorbidities at baseline. for all these reasons, we felt it was important to further evaluate less invasive treatment strategies for r-usd at our reconstructive centers. our study has several limitations, including its retrospective nature. a prospective study with direct randomization to a conservative management arm and a urethral reconstruction arm would allow for better comparison of efficacy and safety. furthermore, separately analyzing and comparing each conservative management technique may also be helpful but would not adequately reflect reallife clinical practice. for example, some patients may not be able to continue to effectively perform cic over time or may be unable to tolerate cic because of radiation-induced lower urinary tract sensitivity/cystitis-like symptoms and thus require endoscopic interventions instead. selection bias is present, as this cohort focuses on those patients who specifically pursued conservative strategies after thorough patient-centered counseling on all available treatment options. nevertheless, we strongly believe there is utility in assessing the efficacy of such strategies in this patient population. further analysis of this population over longer follow-up with robust patient-reported outcome data should be pursued to assess how many patients will be successfully managed with conservative techniques indefinitely. the potential long-term consequences of repetitive conservative interventions in worsening the usd must be considered when using this treatment approach[21]. this study is not advocating for conservative management over surgical reconstruction for all patients with r-usd, as many patients do benefit from both anastomotic and substitution urethroplasty techniques[10,22,23]. however, the management of usd at its core is a quality-of-life issue with often more than one lower urinary tract symptom involved. patients should be counseled on all available treatment options for this disease process to make a well-informed decision that meets their goals of care. this study provides important data for all urology providers, and specifically reconstructive urologists, to improve patient counseling, refine clinical decision-making, and assess which patients should be followed more closely. regardless of treatment approach, we strongly advocate for fellowship-trained reconstructive urologists to manage this complex and challenging disease process to optimize outcomes. 91 total patients on conservative management for r-usd 73/91 (80%) avoided reconstructive surgery or permanent catheterization 18/91 (20%) failed conservative management 3/18 (17%) urethral reconstruction 1/18 (6%) ileal conduit diversion 4/18 (22%) permanent urethral catheter 10/18 (56%) permanent suprapubic tube figure 1. treatment failures 18 siuj • volume 3, number 1 • january 2022 siuj.org original research http://siuj.org conclusion in short-term follow-up, conservative management strategies for r-usd, such as endoscopic techniques and cic, appear to be effective for most elderly patients with comorbidities. this is important to consider in these patients, who may not be optimal surgical candidates and in patients who strongly desire to avoid invasive surgery, the risk of worsening ui, or permanent indwelling cat heterization. close obser vation is warranted because of the risk of utis and aur. the potential long-term consequences of repetitive conservative interventions must be considered as well. ultimately, management decisions should focus on achieving patient-specific goals of care. acknowledgements the biostatistics, epidemiology, and research design (berd) center of tufts clinical and translational science institute (ctsi) provided assistance with statistical analysis. references 1. chen j, oromendia c, halpern ja, ballman kv. national trends in management of localized prostate cancer: a population based analysis 2004-2013. prostate.2018;78:512–520. doi: 10.1002/pros.23496 2. hofer md, liu js, morey af. treatment of radiation-induced urethral strictures. urol clin north am.2017;4 4:87–92. doi: 10.1016/j. ucl.2016.08.005 3. elliott sp, meng mv, elkin ep, mcaninch jw, duchane j, carroll pr, et al. capsure investigators. incidence of urethral stricture after primary treatment for prostate cancer: data from capsure. j urol.2007;178:529–534. doi: 10.1016/j.juro.2007.03 4. awad ma, gaither tw, osterberg ec, murphy gp, baradaran n, breyer bn. prostate cancer radiation and urethral strictures: a systematic review and meta-analysis. prostate cancer prostatic dis.2018; 21:168– 174. doi: 10.1038/s41391-017-0028-3 5. glass as, mcaninch jw, zaid ub, cinman nm, breyer bn. urethroplasty after radiation for prostate cancer. urology.2012;79:1402–1405. doi: 10.1016/j.urology.2011.11.077 6. meeks jj, brandes sb, morey af, thom m, mehdiratta n, valadez c, et al. urethroplasty for radiotherapy induced bulbomembranous strictures: a multi-institutional experience. j urol.2011;185:1761– 1765. doi: 10.1016/j.juro.2010.12.038 7. meeks jj, erickson ba, granieri ma, gonzalez cm. stricture recurrence after urethroplasty: a systematic review. j urol.2009;182:1266–1270. doi: 10.1016/j.juro.2009.06.027 8. chung ph, esposito p, wessells h, voelzke bb. incidence of stress urinary incontinence after posterior urethroplasty for radiationinduced urethral strictures. urology.2018;114: 188–192. doi: 10.1016/j. urology.2017.11.024 9. hofer md, zhao lc, morey a, scott jf, chang aj, brandes sb, et al. outcomes af ter urethroplast y for radiotherapy induced bulbomembranous urethral stricture disease. j urol.2014; 191:1307– 1312. doi: 10.1016/j.juro.2013.10.147 10. policastro cg, simhan j, martins fe, lumen n, venkatesan k, angulo jc, et al. a multi-institutional critical assessment of dorsal onlay urethroplasty for post-radiation urethral stenosis. world j urol.2020; epub ahead of print. doi: 10.1007/s00345-020-03446-y. 11. ahyai sa, schmid m, kuhl, m, kluth la, soave a, riechardt s, et al. outcomes of ventral onlay buccal mucosa graft urethroplasty in patients after radiotherapy. j urol.2015;194:441–446. doi: 10.1016/j. juro.2015.03.116 12. brant wo, erickson ba, elliott sp, powell c, alsikafi n, mcclung c, et al. risk factors for erosion of artificial urinary sphincters: a multicenter prospective study. urology.2014;8 4:934 – 938. doi: 10.1016/j. urology.2014.05.043 13. mcgeady jb, mcaninch jw, truesdale md, blaschko sd, kenfield s, breyer bn. artificial urinary sphincter placement in compromised urethras and survival: a comparison of virgin, radiated and reoperative cases. j urol.2014;192:1756–1761. doi: 10.1016/j.juro.2014.06.088 14. fuller tw, ballon-landa e, gallo k, et al. outcomes and risk factors of revision and replacement artificial urinary sphincter implantation in radiated and nonradiated cases. j urol.2020;204:110–114. doi: 10.1097/ju.0000000000000749 15. herschorn s, elliott s, coburn m, wessells h, zinman l. siu/icud consultation on urethral strictures: posterior urethral stenosis after treatment of prostate cancer. urology.2014;83:s59–70. doi: 10.1016/j. urology.2013.08.036 16. wessells h, angermeier k w, elliott s, gonzalez cm, kodama r, peterson ac, et al. male urethral stricture: american urological association guideline. j urol.2017;197:182–190. doi: 10.1016/j. juro.2016.07.087 17. vetterlein mw, kluth la, zumstein v, meyer cp, ludwig ta, soave a, et al. buccal mucosal graft urethroplasty for radiation-induced urethral strictures: an evaluation using the extended urethral stricture surgery patient-reported outcome measure (uss prom). world j urol.2020;38:2863–2872. doi.org/10.1007/s00345-020-03102-5 18. merrick gs, butler wm, wallner ke, galbreath rw, anderson rl, allen za, et al. risk factors for the development of prostate brachytherapy related urethral strictures. j urol.2006;175:1376–1380. doi: 10.1016/ s0022-5347(05)00681-6 19. charlson me, pompei p, ales kl, mackenzie cr. a new method of classif ying prognostic comorbidit y in longitudinal studies: development and validation. j chronic dis.1987;40:373–383. doi: 10.1016/0021-9681(87)90171-8 19siuj.org siuj • volume 3, number 1 • january 2022 the efficacy and safety of a conservative management approach to radiation-induced male urethral strictures http://siuj.org 20. sullivan l, williams sg, tai kh, foroudi f, cleeve l, duchesne gm. urethral stricture following high dose rate brachytherapy for prostate cancer. radiother oncol.2009;91:232–236. doi: 10.1016/j. radonc.2008.11.013. 21. hudak sj, atkinson th, morey af. repeat transurethral manipulation of bulbar urethral strictures is associated with increased stricture complexity and prolonged disease duration. j urol.2012;187: 1691– 1695. doi: 10.1016/j.juro.2011.12.074 22. keith cg, davenport mt, kavoussi m, yi ya, bergeson rl, morey af. long-term outcomes of anastomotic urethroplasty for radiationinduced strictures. world j urol.2020;38:3055–3060. doi: 10.1007/ s00345-019-03028-7 23. rozanski at, vanni aj. ventral buccal mucosa graft urethroplasty with gracilis muscle flap for high risk, long segment urethral strictures: a 20-year experience. urology.2020;140:178–180. doi: 10.1016/j. urology.2020.03.008 20 siuj • volume 3, number 1 • january 2022 siuj.org original research http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information prostate cancer, awareness, movember, google trends, breast cancer, pinktober none declared. received on june 9, 2021 accepted on september 8, 2021 soc int urol j.2021;2(6):362–369 doi: https://doi:10.48083/uhsi5324 362 siuj • volume 2, number 6 • november 2021 siuj.org original research is “movember” an effective prostate cancer awareness campaign beyond the english language? insights from google trends among spanish speakers daniel a. gonzález-padilla,1 rodrigo españa-navarro,2 josé daniel subiela,3 raj kumar,4 luis g. medina,4 júlia aumatell,5 josé manuel de la morena-gallego,1 giovanni e. cacciamani4 1 department of urology, university hospital infanta sofía, madrid, spain 2 department of urology, regional university hospital, málaga, spain 3 department of urology, university hospital ramón y cajal, madrid, spain 4 usc institute of urology and catherine and joseph aresty department of urology, keck school of medicine, university of southern california, los angeles, united states 5 fundació puigvert, barcelona, spain abstract objective to evaluate the impact of the “movember” awareness campaign (men’s health campaign that takes place every november) on internet search trends for information online about prostate cancer and to compare the results with those for “pinktober” (the breast cancer awareness campaign that takes place in october) in the spanish language as an indirect measure of its effectiveness. methods google trends was used to evaluate the monthly relative search volumes (rsv) of the terms “cáncer de próstata” (prostate cancer), “cáncer de mama” (breast cancer), and “movember” from january 2009 to december 2019 both in spain and worldwide (in the spanish language). breast cancer was used as a comparator of the campaign impact. mean increase in rsv on-campaign and off-campaign was calculated and compared using the mannwhitney u test and joinpoint regression analysis to assess loss or gain of interest. results the term “cáncer de próstata” showed a statistically significant increase during the campaign months both in spain (17.4%; p < 0.001) and worldwide (35.4%; p < 0.001). both “cáncer de próstata” and movember showed a decreasing trend worldwide and in spain, while “cáncer de mama” showed an increasing trend. conclusion the movember campaign generates a statistically significant increase in the search trends on “cancer de próstata” (prostate cancer) during the month of november (both in spain and worldwide); when compared with the breast cancer campaign “pinktober” these increases are of a lesser magnitude but still significant, suggesting that the campaign is effective beyond the english language, although the interest has been decreasing throughout the years. introduction prostate cancer is the second most frequently diagnosed neoplasm in men and causes 3.8% of all cancer deaths worldwide[1]. in spain, 89.8% of patients are diagnosed in the localized stage, 6.4% in the locally advanced, and only 3.8% in the metastatic stage[2]. the awareness campaign of men’s health that is celebrated every november with a blue ribbon as a symbol, also known as “movember,” was started in australia in 2003, aiming to increase awareness about prostate cancer, testicular cancer, mental health, and suicide prevention[3]. “pinktober” is the breast cancer equivalent of movember, held every october. using a pink ribbon as a symbol, this campaign has been effective in encouraging women to get informed about breast cancer and in becoming part of an early detection program[4]. although these campaigns receive strong support from governments and non-governmental organizations, the true impact of the movember campaign in terms of public health is not well-known. while positive results have been found in the english language[4,5], the campaign’s impact in non-english-speaking countries remains uncertain, even though the movember website is available in 11 languages. in 2019, more than 4.1 billion people worldwide had access to the internet[6]. the national statistics institute (ine) in spain report that by 2019, 90.7% of the spanish population between 16 and 74 years had used the internet. this value drops to 63.5% for those aged 65 to 74 years[7], which is the age group in which most of the prostate cancer diagnoses occur, both in spain and worldwide[2,8], which could limit the reach of the movember campaign. google is the most popular search engine in the western world, used for 93.39% of all searches carried out in europe and 92.18% worldwide[9,10]. google trends is a free-access tool that allows users to analyze the frequency with which a term is registered in the google search engine in relation to the total volume of searches carried out during a certain period of time and in predetermined geographical regions. these features have contributed to its use in health research as an epidemiological tool with a methodology that is yet to be standardized[11]. the objective of this study is to identify the reach and impact of the movember campaign on the search trends seeking information about prostate cancer in the spanish language. as spanish has the second most native speakers of all languages worldwide[12], google trends offers an indirect measure of the effectiveness of the campaign. material and methods we used google trends (https://trends.google.es), a publicly accessible and free tool designed by google (santa clara, united states). google trends provides information on the volume of searches on google, which has records from 2004 onwards available; this volume is represented by the metric “rsv” (relative search volume) which is represented by a number from 0 to 100, with 100 being the maximum search activity for the term or terms entered in the specified time. the search was carried out on october 4, 2020, using the terms “cáncer de próstata” (from now on, “prostate cancer”), “movember,” and “cáncer de mama” (from now on “breast cancer”). search trends from january 2009 to december 2019 were analyzed. these criteria were filtered geographically into “worldwide” and “spain.” “pinktober” was used as a comparator as a widely recognized successful awareness campaign and to allow direct comparison with prior publications. google trends provides a monthly rsv value, from which we calculated the average overall rsv, analyzing separately the months on-campaign (november for prostate cancer and october for breast cancer) and off-campaign (rest of the year). the joinpoint regression (jpr) model (national cancer institute) was used to identif y significant changes in mean annual rsv (arsv) over time for each term. the jpr model is used to better describe trends that are not constant over time, and it enables evaluation of statistically significant changes (join-points) in trends as previously described[13–16]. linear trends in rsv were summarized using the estimated arsv and annual percentage in change (apc). apc was used to measure differences in arsv between 2 join-points. average annual percentage in change (aapc) and the respective 95% confidence intervals were estimated to summarize linear trends in arsv during the entire period. the use of the natural log-linear model ([ln(y)=xb]) enables the analysis of aapc in rate over time. a positive value of aapc indicates an increasing rsv (increasing search volume or interest), while a negative rate refers to a decreased interest. when a dependent variable was “0” a log (x+1) transformation was applied to the entire dataset. a permutation test, allowing up to 4 join-points, was used to evaluate any inflection points with a significant variation in the slope of the trend. a trend was defined as “non-constant” or “constant” if slopes were identified or not identified, respectively. mea n rsv va lues were compa red using t he mann-whitney u test and a p-value < 0.05 was considered statistically significant. the statistical analysis was performed using the statistical package spss v26. abbreviations aapc average annual percentage in change apc annual percentage in change arsv annual rsv rsv relative search volume 363siuj.org siuj • volume 2, number 6 • november 2021 is “movember” an effective prostate cancer awareness campaign beyond the english language? results analyzing the searches between 2009 and 2019, we observed that the term “cancer de próstata” (prostate cancer) filtered “worldwide” reached the maximum rsv (rsvmax 100) in november 2017 and the minimum rsv (rsvmin) was 38, in january 2017, the mean annual rsv (rsvmean) was 50.9 off-campaign (all months of the year, excluding november) and 78.9 on-campaign (all novembers), observing a statistically significant increase of 35.4% (p < 0.001) during the campaign months. in figure 1a (blue lines) we can see the blue spikes of searches carried out in the months of november, which are more evident from the year 2013 onwards. when analyzing the same strategy (“cancer de próstata,” 2009 to 2019) in spain, rsvmax was also reached in november 2017 (100) and the rsvmin (28) in december 2009. the rsvmean was 42.3 off-campaign and 51.9 on-campaign, with a statistically significant increase of 17.4% (p < 0.001), these values are summarized in table 1 and represented in figure 1a (orange lines), showing no clear spikes in search trends in the months of november, except for the year 2017. regarding the term “cancer de mama” (breast cancer), filtered “worldwide” the rsvmean off-campaign and on-campaign months were 21.3 and 69.8 respectively, with an increase of 69.4% in the months on-campaign for breast cancer. figure 1b shows how the trends in search for “breast cancer” have been increasing gradually each year during the campaign months, while trends for prostate cancer (figure 1a) show a minimal increase relative to breast cancer. analyzing breast cancer filtered by “spain,” we observe an rsvmean for breast cancer of 14.5 off-campaign, and 56.5 on-campaign, with an increase of 74.3% (p < 0.001) during the campaign months; these results are summarized in table 2. figure 1b shows increases of trends in searches for breast cancer in the months of october with the same trend as “worldwide,” while for prostate cancer such increases are imperceptible. prostate cancer – worldwide prostate cancer – spain figure 1a. search trends for the term “prostate cancer” table 1. cáncer de próstata (prostate cancer), trends from january 2009 to december 2019    worldwide spain rsvmax, date 100, november 2017 100, november 2017 rsvmin, date 38, january 2017 28, december 2009 rsvmean offcampaign 50.9 42.3 rsvmean oncampaign 78.9 51.9 rsv increase during the campaign months 35.4% 17.4% rsv: relative volume of searches; rsvmax: maximum rsv; rsvmin: minimum rsv; rsvmean: average rsv. 364 siuj • volume 2, number 6 • november 2021 siuj.org original research finally, for the term “movember” filtered “worldwide,” the rsvmax was reached in november 2012 and the rsvmin (1) in multiple months over the years. rsvmean off-campaign was 3.0, while on-campaign was 43.7 with a statistically significant increase of 91.5% (p < 0.001). figure 1c (blue lines) shows the spikes in search trends every november, and a virtual disappearance of searches in the rest of the year. in turn, the trend in the months of november reached its maximum in november 2012 and gradually decreased from november 2013 to november 2019 worldwide. when analyzing the same term filtered in “spain” (figure 1c, orange lines) the rsvmax was reached in november 2013 and the rsvmin (1) several months over the years. rsvmean was 2.4 off-campaign and 55.9 on-campaign, with an increase of 99.2% (p < 0.001). these results are summarized in table 3. join point regression analysis for the geographical region category “world,” the web search for the term “cancer de próstata” (prostate cancer in english) showed a constant non-statistically significant decreasing trend (aapc −0.5%, 95%ci −1.7 to 0.7; p = 0.4) from 2009 to 2019. the web search for “cancer de mama” (breast cancer in english) showed a non-constant increasing statistical interest trend from 2009 to 2019 (aapc 3.8%, 95%ci 2 to 5.5; p < 0.0001). from 2009 to 2012 a non-statistically significant decreasing trend is seen (aapc −0.5%, 95%ci −6.2 to 5.5; p = 0.8). interestingly, between 2012 and 2019, a statistically significant increasing interest trend is seen (aapc 5.7%, 95%ci 4 to 7.3; p < 0.0001). the web search for the term “movember” showed a non-constant and non-statistically significant decreasing trend (aapc −5.4%, 95%ci −17.2 to 8; p = 0.4). a non-statistically significant increasing interest trend (aapc 87.6%, 95%ci −12.1 to 300,4; p = 0.1) from 2009 to 2011. however, we found a statistically significant decreasing interest trend between 2011 and 2019 (aapc −20.3%, 95%ci −26.6 to −13.5; p < 0.0001). in the category for the geographical region “spain,” the web searches for the term “cancer de próstata” breast cancer – worldwide breast cancer – spain figure 1b. search trends for “breast cancer” table 2.  cáncer de mama (breast cancer), trends from january 2009 to december 2019   worldwide spain rsvmax, date 100,  october 2019 100,  october 2013 rsvmin, date 12,  december 2012 8,  december 2009 rsvmean off campaign 21.3 14.5 rsvmean on campaign 69.8 56.5 rsv increase during the campaign months 69.4% 74.3% rsv: relative volume of searches; rsvmax: maximum rsv; rsvmin: minimum rsv; rsvmean: mean rsv. 365siuj.org siuj • volume 2, number 6 • november 2021 is “movember” an effective prostate cancer awareness campaign beyond the english language? (prostate cancer in english) displayed a constant and non-statistically significant decreasing trend (aapc 1%, 95%ci −0.5 to 2.6; p = 0.2). the web searches for “cancer de mama” (breast cancer in english) showed a statistically significant increase interest trend from 2009 to 2019 (aapc 7.8%, 95%ci 5.3 to 10.5; p < 0.0001). the web search for the term “movember” showed a non-constant and statistically significant increasing trend (aapc 24.6%, 95%ci 18.3 to 31.2; p < 0.0001). there is statistically significant increasing interest trend (aapc 106.3%, 95%ci 81.8 to 132.2; p < 0.0001) from 2009 to 2013. nonetheless, there is evidence of a statistically significant decreasing trend between 2013 and 2019 (aapc −11%, 95%ci −16.8 to −4.8; p < 0.0001). discussion this study is the first to indirectly evaluate the impact and extent of the prostate cancer awareness campaign known as movember in a non-english language, using the google trends tool. our results show a statistically significant increase in search trends for “prostate cancer” and “movember” during the campaigning months from 2009 to 2019, both in spain and worldwide. nonetheless, when directly compared with breast cancer awareness campaigns, the apparent impact is much more limited. further, the term “movember” has sharp spikes in the months of november but practically disappears from search trends for the rest of the year, which makes us wonder if the movember campaign achieves a long lasting effect or remains only a cyclic event. additionally, this urological awareness campaign fails to reach a strong impact on search trends when compared with pinktober, the breast cancer campaign. interest in breast cancer not only remains in some form during the rest of the year but also increases year after year, both in spain and in the rest of the world. these data are congruent with the findings of the study published by patel et al. comparing the impact of the breast, prostate, and testicular cancer campaigns in the united states, which showed a strong increase of rsv in movember – worldwide movember – spain figure 1c. search trends for the term “movember” table 3. movember, trends from january 2009 to december 2019    worldwide spain rsvmax, date 100, november 2012 100, november 2013 rsvmin, date 1, several months 1, several months rsvmean off-campaign 3.0 2.4 rsvmean on-campaign 43.7 55.9 rsv increase during the campaign months 91.5% 99.2% rsv: relative search volume; rsvmax: maximum rsv; rsvmin: minimum rsv; rsvmean: average rsv. 366 siuj • volume 2, number 6 • november 2021 siuj.org original research the month of october for breast cancer versus a minor increase in rsv in november for prostate cancer[17]. similarly, cacciamani et al. previously showed a correlation between the campaign pinktober in the month of october and an increase in search trends for breast cancer, mammograms, and pink ribbons during this period[4]. another relevant point is the celebrity phenomenon: a socially prominent person’s disclosure that they have cancer increases public interest in that cancer. this phenomenon can generate increases in search trends greater than those produced by awareness campaigns. this was demonstrated in the cases of angelina jolie and steve jobs[18,19], and it may account for the search trends peak observed in november 2017 in spain and worldwide following media coverage of the diagnosis of prostate cancer at 48 years of age of latin american ex-football player eduardo berizzo[20]. meanwhile, the success of the pinktober campaign on breast cancer can be explained by its having been promoted over a longer time. awareness campaigns on breast cancer began in 1985 with the alliance of the american cancer society and imperial chemical industries (now part of astrazeneca)[21]. additionally, the early detection programs for breast cancer started in the late 1970s[22], while the equivalent in prostate cancer started in the 1990s[23], and this screening program has suffered multiple setbacks, including the recommendation against it by the us preventive services task force (uspstf) in 2012[24], which was maintained until the 2018 update[25]. the use of google trends as a tool for the indirect analysis of urological and non-urological diseases from a public health perspective has been previously addressed. schootman et al. couldn’t show a direct correlation between search trends and use of screening programs for colon, cervix, lung, breast, and prostate cancer in a state-level analysis in the united states[26]. nonetheless, other authors have shown a positive correlation in the number of searches on cosmetic surgery modalities and the volume of procedures performed[27] or associations in search trends on sexually transmitted diseases in areas where the incidence of these is greater[28]. our study has some limitations. first, the demographic characteristics of the population that carry out these searches are unknown. it must be considered that the campaigns intend to reach men whose age makes them candidates for programs for early detection of prostate cancer. this is recommended for the average male from the age of 50 according to the european association of urology[29] and from the age of 55 according to the american urology association[30] and the uspstf[31]. another limitation is the impossibility of distinguishing those individuals seeking information on prevention and early detection strategies from those already diagnosed seeking information on available treatments. similarly, the tools provided by google trends do not allow a direct comparison of the interest between different early detection strategies (mammography versus prostate-specific antigen) since the acronyms for these in english and spanish are shared by other words from other sectors, and it is not possible to separate the results, while terms without acronyms do not yield useful results for comparison. however, although the information derived from google trends does not replace formal epidemiological studies, it can be a complementary tool relevant to better understanding the scope, impact, and limitations of awareness campaigns on men’s health and other public health campaigns. overall, we found increases in search trends every november, which correlate with a positive impact of the movember campaign in the spanish language worldwide. conclusion the prostate cancer awareness campaign “movember” correlates with a statistically significant increase in search trends for “cancer de próstata” (prostate cancer) in the spanish language worldwide. when compared with the breast cancer campaign “pinktober” these increases are of a lesser magnitude but still significant. google trends appears to be a useful tool for indirectly assessing the effectiveness of awareness campaigns; however, other epidemiological studies are necessary to directly confirm these findings. 367siuj.org siuj • volume 2, number 6 • november 2021 is “movember” an effective prostate cancer awareness campaign beyond the english language? references 1. sung h, ferlay j, siegel rl, laversanne m, soerjomataram i, jemal a, et al. global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin.2021;71:209–249. https://doi.org/10.3322/caac.21660 2. cózar jm, miñana b, gómez-veiga f, rodríguez-antolín a, villavicencio h, on behalf of 25 urology units, asociación española de urología.prostate cancer incidence and newly diagnosed patient profile in spain in 2010. bju int.2012;110:e701–706. https://doi. org/10.1111/j.1464–410x.2012.11504.x 3. movember. in: movember. ht tps://es.movember.com/about / foundation. accessed 4 oct 2020 4. cacciamani ge, stern mc, medina lg, gill k, sotelo r, gill is. cancer awareness crusades—pink ribbons and growing moustaches. lancet oncol. 2 019;2 0:14 91–14 9 2. ht tps://doi.or g /10.1016/ s1470–2045(19)30639–4 5. cacciamani ge, gill k, gill is. web search queries and prostate cancer. lancet oncol.2020;21:494–496. https://doi.org/10.1016/ s1470–2045(20)30138–8 6. international telecommunication union (itu). measuring digital development: facts and figures 2019. https://www.itu.int/en/itu-d/ statistics/pages/facts/default.aspx. accessed 4 oct 2020 7. ins titu to nacional de e s t adis tic a (2 019) e ncues t a sobre equipamiento y uso de tecnologías de información y comunicación en los hogares. in: ine. https://www.ine.es/ss/satellite?l=es_ es&c=ineseccion_c&cid=1259925528782&p=1254735110672& pagename=productosyservicios%2fpyslayout. accessed 4 oct 2020. 8. rawla p. epidemiology of prostate cancer. world j oncol.2019;10:63–89. https://doi.org/10.14740/wjon1191 9. search engine market share worldwide. in: statista. https://www. statista.com/statistics/216573/worldwide-market-share-of-searchengines/. accessed 25 jul 2020. 10. search engine market share worldwide. in: statcounter global stats. https://gs.statcounter.com/search-engine-market-share.accessed 1 jun 2021 11. nuti sv, wayda b, ranasinghe i, wang s, dreyer rp, chen si, et al. the use of google trends in health care research: a systematic review. plos one.2014;9:e109583. https://doi.org/10.1371/journal.pone.0109583 12. babbel.com, gmbh ln the 10 most spoken languages in the world. in: babbel magazine. https://www.babbel.com/en/magazine/the-10most-spoken-languages-in-the-world. accessed may 4, 2021. 13. cacciamani ge, dell’oglio p, cocci a, russo gi, de castro abreu a, gill is, et al. asking “dr. google” for a second opinion: the devil is in the details. eur urol focus.2019;7(2):479–481. https://doi.org/10.1016/j. euf.2019.10.011. 14. cacciamani ge, bassi s, sebben m, marcer a, russo gi, cocci a, et al. consulting “dr. google” for prostate cancer treatment options: a contemporary worldwide trend analysis. eur urol oncol.2019; 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it has a low incidence (1% to 4%)[2-4], and the follow-up requires lifelong contrast-enhanced imaging. key words competing interests article information upper tract urothelial cancer, transitional cell carcinoma, non-muscle invasive bladder cancer, bladder cancer, recurrence, predictors none declared. received on january 30, 2021 accepted on april 3, 2021 soc int urol j. 2021;2(3):151–157 doi: https://10.48083/nztc6259 151siuj.org siuj • volume 2, number 3 • may 2021 original research mailto:mmelawdy%40gmail.com?subject=siuj https://10.48083/nztc6259 http://www.siuj.org whether routine annual computed tomography (ct) imaging should be performed on all nmibc patients or if ct should be individualized is still an open issue. some guidelines still recommend routine upper tract imaging[5]. however, ivu/ct is reported to have poor sensitivity for the detection of utuc, which is usually low grade and low stage[6]. moreover, most of the utuc patients are symptomatic, and the follow-up procedure requires lifelong ct with contrast administration. in 2 large separately published studies that involved more than 1500 and 1000 nmibc patients, the highrisk (hr-nmibc) group constituted the majority of the patients[7,8]. regarding the incidence of secondary utuc, a statistically significant difference was reported between lowand high-risk groups (0.6, 4% and 1, 9.8%, respectively)[3,4]. moreover, it was reported that utuc has low incidence in the lowand intermediate-risk groups (le: 2b)[9]. new studies were therefore necessary to focus on the high-risk group alone. we aimed to study the predictors of secondary utuc and survival rates in patients with hr-nmibc. the study may help in stratifying patients to determine who requires strict routine upper tract imaging and in whom the benefits could outweigh the risks. our data will help in validating the existing knowledge and in patient counseling. materials and methods after institutional board approval (r/18.04.217), a retrospective analysis was conducted between january 2004 and december 2018. the data of patients with non-muscle invasive urothelial bladder cancers who were managed with transurethral resection (tur) were reviewed. patients’ files were further reviewed to identify those who had developed utuc on follow-up. patients were classified into 3 risk groups according to european association of urology guidelines[9]: low, intermediate, and high. the low-risk group included all of the following: primary, solitary, ta, g1 tumor < 3 cm, and no cis. the high-risk group included any of the following: t1, g3, cis, and multiple and recurrent and large (> 3 cm) ta g1g2 tumors. the intermediate-risk group included tumors that were not identified in the other 2 groups. inclusion and exclusion criteria: the high-risk group was the only group included in our study, and we eliminated those with lowand intermediate-risk nmibc. additionally, patients who had previous and/or concomitant utuc were eliminated. preoperative workup: this included medical history, physical examination, and routine laboratory and imaging workup. office f lexible cystoscopy was used as an initial tool for the diagnosis of patients who had hematuria, persistent irritative lower urinary tract symptoms, or any suspicious bladder mass on ultrasound. operative details: cystoscopy and bladder tumor resection were performed under spinal anesthesia, and general anesthesia was used if the spinal failed or was contraindicated, or if obturator jerk occurred, jeopardizing the resection. instillation of a single dose of intravesical chemotherapy (epirubicin, 50 mg) was standard practice as a part of a prospective randomized 4-year study in our hospital. its aim was to evaluate the effectiveness of the therapy in intermediateand highrisk groups[10]. postoperative care: all patients were kept in the hospital, and the urethral catheter was kept in place for 48 hours unless other recommendations were given in cases of deep resection or suspected bladder perforation. routine second look tur for all high-risk patients was introduced at our institute in 2010; before 2010, it was performed based on surgeon’s recommendations. eligible patients received adjuvant intravesical instillation of chemotherapy or immunotherapy (bacillus ca lmette-guérin, bcg) according to european association of urolog y g uidelines. a ll patients underwent routine flexible cystoscopy every 3 months for the first 2 years, every 6 months for the next 3 years, and then annually. patients with recurrent tumors were scheduled for repeat tur followed by resumption of intravesical immunotherapy. patients were screened annually by ct for any utuc recurrence. for tumor grading, the 3-tiered world health organization grading system[11] was used to determine the pathologic grade by different pathologists. the tumor was staged according to the 2009 tnm classification. the primary outcome was development of secondary utuc (dependent variable) in patients who had nonmuscle invasive bladder tumor that was correlated with possible risk factors (independent variables) and to study its clinical implementation on routine imaging. abbreviations bcg bacillus calmette-guérin ct computed tomography ivu intravenous urography nmibc non-muscle invasive urinary bladder cancer tur transurethral resection utuc upper tract urothelial cancer 152 siuj • volume 2, number 3 • may 2021 siuj.org original research http://siuj.org table 1. demographics of 1501 patients and bivariate analysis of risk factors for development of upper urothelial cancer in patients with non-muscle invasive bladder cancer demographics (r/18.04.217) development of upper urothelial cancer n (%), total number (1501) * pvalue value (%) * no, n=1442 yes, n= 59 gender male 1290 (86) 1240 (96) 50 (4) 0.7 female 211 (14) 202 (96) 9 (4) tumor size less than 3cm 780 (52) 757 (97) 23 (3) 0.7 3cm or more 721 (48) 685 (95) 36 (5) tumor site posterior 330 (22) 320 (97) 10 (3) 0.6 lateral walls 495 (33) 479 (97) 16 (3) anterior, and domal 135 (9) 129 (96) 6 (4) trigone and bn 90 (6) 85 (95) 5 (5) multicenteric 451 (30) 429 (95) 22 (5) tumor number single 753 (50) 732 (98) 21 (2) 0.01 multiple 748 (50) 710 (95) 38 (5) tumor stage ta 10 (1) 10 (100) – 0.6t1 1470 (98) 1411 (96) 59 (4) primary cis 21 (1) 21 (100) tumor grade grade i 168 (11) 159 (95) 9 (5) 0.6grade ii 784 (52) 755 (96) 29 (4) grade iii 549 (37) 528 (96) 21 (4) cis no 1350 (90) 1297 (96) 53 (4) 0.7yes, concomitant 130 (8) 124 (96) 6 (4) yes, primary 21 (2) 21 (100) – – number of recurrences first time 810 (54) 792 (97) 18 (3) 0.008 previous 1 recurrence 316 (21) 307 (97) 9 (3) previous 2 recurrences 180 (12) 171 (95) 9 (5) previous 3 recurrences 105 (7) 94 (89) 11 (11) more than 3 recurrences 90 (6) 78 (86) 12 (14) * percentage was given for rows; decimals were deleted for simplification 153siuj.org siuj • volume 2, number 3 • may 2021 incidence and predictors of secondary upper tract urothelial cancer http://siuj.org statistical analysis: the data were collected using ibm spss version 21 (armonk, ny: ibm corp.). for univariate analysis, frequency and percentage were used to express nominal and ordinal variables. mean and standard deviation were used to express scale variables with normally distributed data. median and range were used for non-normally distributed data. for bivariate analysis, chi-square test was used for nominal variables. multivariate analysis with a logistic regression model in a forward lr-selection strategy was generated for significant variables in bivariate analysis. in all tests, the p value was 2-sided, and significance was set at p < 0.05. results of 1565 patients, 64 were not compliant to upper tract imaging and were eliminated from the analysis, leaving 1501 patients eligible for analysis. the mean age was 58±11, 90% (1354/1501) were male, and median follow-up was 21 months (6 to 210). nearly half of the patients (51%) had a single bladder tumor, and (53%) had tumors less than 3cm in diameter and of gii. upper tract urothelial cancer developed in 59 patients (4%). demographic information and nmibc tumor criteria for the remaining patients are shown in table 1. most of the secondary utuc were in the ureter: alone (39/59 = 66%), also in the kidney (10/59 = 17%), or in the kidney alone (10/59 = 17%). in the ureteral tumor group (n = 49), distal ureteral tumors were more common (30/49 = 61%) than multicentric or proximal ureter tumors (11/49 = 23% and 8/49 = 16%, respectively). the median time for the development of utuc was 20 months (6 to 106 months). hematuria was the most common symptom in this cohort (64%), while utuc was discovered on follow-up imaging in 28% of the patients. cytology was used in detecting utuc with overall diagnostic accuracy of 75%. the other utuc characteristics are shown in table 2. bivariate analysis of the risk factors showed that none of the following were predictors for the development of secondary utuc: gender, tumor size, site, tumor stage or grade; only bladder tumor number (single or multiple) and the number of bladder recurrences were the predictors for secondary utuc (p = 0.01 and p = 0.008, respectively), table 1. on multivariable analysis, multiple tumors remained significant when compared with the presence of a single tumor (p = 0.04). also, as the number of previous recurrences increased, the chance of utuc increased; previous recurrences (1 to 2) were not predictors (p = 0.5, and p = 0.6, respectively), but 3 or more previous recurrences were strongly significant predictors for secondary utuc (p = 0.04 and p = 0.003, respectively) table 3. table 2. tumor characteristics of 59 patients who had secondary utuc post-surgical management of nmibc characteristics value (%) * gender male 50 (83) female 9 (17) side of the tumor right 41 (70) left 18 (30) presentation symptomatic: 42 (72) hematuria + flank pain 39 (66) microscopic hematuria, luts incidentally on follow-up imaging 3 17 (6) (28) site of the tumor ureter 39 (66) kidney (pelvi-calyceal) 10 (17) kidney and ureter 10 (17) tumor grade grade i tcc 6 (10) grade ii tcc 39 (65) grade iii tcc 14 (25) tumor stage ta, t1, tis 41 (70) t2 12 (20) t3 6 (10) the final size in cm, median (range) renal pelvis tumors length 3 (2–8) width 4 (3–10) ureteric tumors length 4 (1–6) width 2 (0.5–3) management of utuc nephroureterectomy (laparoscopic and open) 40 (67) endoscopic management 13 (23) nephron-sparing (ureterectomy) 6 (10) *decimals were removed for simplification 154 siuj • volume 2, number 3 • may 2021 siuj.org original research http://siuj.org discussion urothelial cancer is a field-change disease. the multiple foci of urothelial cancers on different anatomical sites in the urothelium is a common feature of the disease[12]. recurrence, either synchronous or metachronous, is an inherent behavior of urothelial cancer. in treating nmibc, which is quite a common tumor, synchronous utuc can be detected at the time of initial evaluation of bladder tumor, but metachronous utuc is of greater concern. it requires not only routine radiation exposure but also contrast administration that may increase the risk of contrast-induced nephropathy, especially in the elderly and in those with borderline renal function. moreover, metachronous recurrence has a lifelong risk and could present after many years (7 to 15 years)[13]. in addition, patients with metachronous recurrence require repeated contrast administration, which increases the odds of contrast-induced nephropathy. because of these issues, our study and other published studies have aimed to identify those at high risk and to determine whether the risk outweighs the benefit. the incidence of secondary utuc in our series is 4%, which is consistent with the majority of published data (1% to 4%)[2,3]. this small range in incidence can be explained by the different bladder tumor characteristics between series, in terms of bladder tumor grade, stage, cis, and recurrence. the ureter is the site most frequently affected in secondary utuc. in our series, 80% of the cases were in the ureter, either alone or with involvement of the renal pelvis. others have reported similar results regarding ureteral involvement, especially in the pelvic ureter and intramural ureter[4,14]. this observation can be explained by vesicoureteral reflux; however, this theory cannot explain utuc recurrence post radical cystectomy that was reported with similar incidence (3.9%) in a study of 1420 patients[15], or an even higher incidence (6.4%) in a large meta-analysis[16]. the theory of the panurethral nature of utuc is therefore more widely accepted than the theory that it is due to reflux. of 59 patients who had secondary utuc in our series, 72%, were symptomatic, and hematuria, either microscopic or macroscopic, was the most common complaint. patients in this situation usually seek medical attention and undergo imaging, so utuc is discovered at an early stage. nevertheless, the issue remains for the 28% (17/59) who had no symptoms but were discovered incidentally with routine imaging to the upper tract. sternberg et al., in a series of 935 patients of nmibc, and picozzi et al., in a large meta-analysis of utuc recurrence post radical cystectomy in more than 13 000 patients, reported similar percentages (30% and 38%)of asymptomatic patients[6,16]. on bivariate analysis, multiple bladder tumors at the time of turbt and bladder recurrences were the only predictors for secondary utuc. this was consistent with the findings of millan-rodriguez et al.[4] and with a series of 375 patients all of whom had ta bladder tumors[2]. the natural behavior of urothelial cancer, urothelial instability, field-change disease, and multicentricity all explain our findings and those of other studies. the results of cox regression multivariable analysis solidified this. although this was not calculated in our series, the recurrence time of bladder tumor could indicate more bladder instability. recurrence within 12 months increases the risk of utuc recurrence by 4.5fold, as reported by canales et al.[2]. other predictors were reported in a few studies: tumor grade, cis, and bcg failure[5], tumor morphology (being non-papillary increases the risk)[14], and in some cases, no predictors were found[17]. a statistically significant difference in the incidence of utuc between lowand high-risk nmibc patients was reported by hurle et al. (0.6% and 4%) and millan-rodriguez et al. (1% and 9.8%), respectively[3,4]. for that reason, we focused only on the high-risk group in our series. we aimed to address the debate in the literature regarding the necessity and frequency of upper tract imaging post management of nmibc. the majority of published studies do not support its routine use for many reasons (low incidence, low grade and stage, lifelong risk), and many patients who developed utuc are symptomatic. moreover, this imaging requires contrast administration with known side effects on the kidney. contrast nephropathy is one of the reasons for hospital-acquired renal insufficiency[18], and this is in table 3. multivariate logistic regression analysis of the possible risk factors parameters binary logistic regression models odds ratio (or) 95% ci p -value number of tumors single ref multicentric 1.7 1.1–2.2 0.04 number of recurrences no recurrence ref previous 1 recurrence 1.2 0.6–2.5 0.5 previous 2 recurrences 1.2 0.5–3 0.6 previous 3 recurrences 2.4 1.1–6.7 0.04 more than 3 recurrences 3.5 1.6–8.7 0.003 155siuj.org siuj • volume 2, number 3 • may 2021 incidence and predictors of secondary upper tract urothelial cancer http://siuj.org addition to the radiation exposure and its side effects. stenberg et al. reported more than 3 thousand routine imaging scans were conducted for an overall efficiency of 0.49%. in our series, more than 4 thousand were performed to detect utuc in 59 patients (4000/59 = 68), only 17 of whom were asymptomatic (4000/17 = 235) [5]. therefore, 235 patients were exposed to imaging in order to diagnose 1 asymptomatic patient. most of the comments in the literature recommend imaging for symptomatic patients, those with abnormal cytology, or those with new urinary tract obstruction. urine cy tolog y can be taken through regular surveillance by outpatient cystoscopy. it would be considered an excellent way to monitor the urothelium, and unexplained positive for high grade cells should warrant imaging of the ut. instead of routine imaging, sternberg et al. recommended a combination of history and urine cytology with lower side effects[6]. holmang et al. and others recommended routine imaging in the case of tumor progression[17,19]. we agree that patients could be more stratified to detect those in whom the benefits of routine imaging with contrast would outweigh the risks. in the 17 asymptomatic patients who developed utuc in our series, 9 had 2 or more intravesical recurrences, while the remaining 8 presented with silent hydronephrosis. patients with recurrent bladder tumors may require routine ultrasonography surveillance for the upper tract, while those having 3 or more recurrences require a stricter follow-up. these data require more validation with prospective studies. the treatment of recurrent utuc, post management of nmibc, follows the same standards as primary u tuc . nephrou reterec tomy, whet her open or laparoscopic and with excision of the bladder cuff, was the primary surgical modality in our series. however, distal ureterectomy and ureterovesical reimplantation was performed in select patients with localized tumor and no other upper urothelial foci of cancers. the conventional 3-tiered who grading system was used in our series. there is still limited data regarding intraobserver and interobserver variability differences between the who 1973 and 2004 classification systems. the european association of urolog y currently recommends reporting both who 1973 and who 2004/2016 classifications[20]. we preferred spinal over general anesthesia for many reasons: the procedure is brief, and the patient is awake and can describe any abdominal pain for early detection of bladder perforation. a limitation of our study is its retrospective nature; however, with the low incidence of secondary utuc, it is difficult to conduct prospective studies. also, it has been reported that peripheral blood levels of neutrophil to lymphocyte ratio are associated with an increased risk of disease recurrence in patients who have undergone turbt for nmibc[21]. our data lacked information on white blood cell count. also, we did not include the time of recurrence of the utuc in bcg unresponsive and refractory populations because the dates of this group were absent for many patients and could not be retrieved. despite these limitations, our study included a large hr-nmibc cohort of patients who were treated at a single tertiary urology institute. conclusion utuc post management of high-risk nmibc is uncommon (4%). utuc was discovered on routine follow-up ct in 28% of patients; all others were symptomatic. imaging surveillance should be performed in patients with multiple bladder tumors and those with 3 or more bladder tumor recurrences. for the other patients, the benefits of imaging surveillance have to be weighed against the risks. the optimum protocol and frequency for upper tract imaging is to be determined by future prospective studies. author contributions ebra him elsaeed abouelenein: data col lect ion; mohamed elawdy: project development, data analysis; diaa-eldin taha: data collection; yasser osman: manuscript writing; bedeir ali-el dein: manuscript reviewing; ahmed mosbah: manuscript reviewing. 156 siuj • volume 2, number 3 • may 2021 siuj.org original research http://siuj.org references 1. elawdy mm, taha de, elbaset ma, abouelkheir rt, osman y. histopathologic characteristics of upper tract urothelial carcinoma with an emphasis on their effect on cancer sur vival: a singleinstitute experience with 305 patients with long-term follow-up. clin genitourin cancer.2 016;14 (6):e6 0 9 e615. doi: 10.515 2 / tud.2019.02185. 2. canales bk, anderson jk, premoli j, slaton jw. risk factors for upper tract recurrence in patients undergoing long-term surveillance for stage ta bladder cancer. j urol.2006;175(1):74-77. doi: 10.1016/ s0022-5347(05)00071-6. 3. hurle r, losa a, manzetti a, lembo a. upper urinary tract tumors developing after treatment of superficial 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barakat ts, nabeeh a, ibrahiem el hi. construction of predictive models for recurrence and progression in >1000 patients with non-muscle-invasive bladder cancer (nmibc) from a single centre. bju int.2013;111(8):e331-341. doi: 10.1111/bju.12026. epub 2013 feb 27. 8. millán-rodríguez f, chéchile-toniolo g, salvador-bayarri j, palou j, vicente-rodríguez j. multivariate analysis of the prognostic factors of primar y superficial bladder cancer. j urol.2000;163(1):73-78. doi: 10.1016/s0022-5347(05)67975-x. 9. babjuk m, oosterlinck w, sylvester r, kaasinen e, böhle a, palouredorta j, et al. eau guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2011 update. eur urol.2011;59(6):9971008. doi: 10.1016/j.eururo.2011.03.017. 10. elsawy a a, el-assmy am, bazeed ma, ali-el-dein b. the value of immediate postoperative intravesical epirubicin instillation as an adjunct to standard adjuvant treatment in intermediate and highrisk non-muscle-invasive bladder cancer: a preliminary 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i : 10 .10 16 / s0009-9260(99)90834-6. 19. holmang s, hedelin h, anderstrom c, holmberg e, johansson sl. long-term followup of a bladder carcinoma cohort: routine followup urography is not necessary. j urol.1998;160(1):45-48. 20. compérat em, burger m, gontero p, mostafid ah, palou j, rouprêt m, et al. grading of urothelial carcinoma and the new "world health organisation classification of tumours of the urinary system and male genital organs 2016". eur urol focus.2019;5(3):457-466. doi: 10.1016/j.euf.2018.01.003. epub 2018 jan 20. 21. vartolomei md, porav-hodade d, ferro m, mathieu r, abufaraj m, foerster b, et al. prognostic role of pretreatment neutrophilto-lymphocyte ratio (nlr) in patients with non-muscle-invasive bladder cancer (nmibc): a systematic review and meta-analysis. urol oncol.2018;36(9):389-399. doi: 10.1016/j.urolonc.2018.05.014. epub 2018 jun 6 157siuj.org siuj • volume 2, number 3 • may 2021 incidence and predictors of secondary upper tract urothelial cancer http://siuj.org key words competing interests article information prostate cancer, targeted biopsy; prostate biopsy, micro-ultrasound, pri-mus, 29mhz, learning curve there was no funding for this analysis. exact imaging assisted in the collection of the data. hannes cash, christian p. pavlovich, laurence klotz, and neal shore have received speaking honoraria from exact imaging. laurence klotz has received research support from exact imaging. neal shore has received consulting fees from exact imaging. received on august 12, 2021 accepted on december 4, 2021 this article has been peer reviewed. soc int urol j. 2022;3(2):62–68 doi: 10.48083/kkvj7280 62 siuj • volume 3, number 2 • march 2022 siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. original research prostate cancer detection by novice micro-ultrasound users enrolled in a training program hannes cash,1,2 sebastian l. hofbauer,3 neal shore,4 christian p. pavlovich,5 stephan bulang,6 martin schostak,1 erik planken,7 joris j. jaspars,7 ferdinand luger,8 laurence klotz,9 georg salomon10 1department of urology, otto-von-guericke-university magdeburg, germany 2 prouro, berlin, germany 3 department of urology, charité university medicine berlin, berlin, germany 4 carolina urologic research center, myrtle beach, united states 5 the brady urological institute, the johns hopkins school of medicine, baltimore united states 6 diakonissenkrankenhaus, dresden, germany 7 department of urology, admiraal de ruyter ziekenhuis in goes, the netherlands 8 department of urology, ordensklinikum krankenhaus der elisabethinen, linz, austria 9 sunnybrook hospital, toronto, canada 10 martini klinik, university hospital hamburg, hamburg, germany abstract objective micro-ultrasound is an imaging modality used to visualize and target prostate cancer during transrectal or transperineal biopsy. we evaluated the effectiveness of a micro-ultrasound training program and estimated the learning curve for prostate biopsy. methods a training program registry was assessed for the rate of clinically significant prostate cancer (cspca, grade group ≥ 2), negative predictive value, and specificity at each stage of the program. nine metrics of biopsy quality were evaluated in 4 stages for each practitioner. non-linear fitting and logistic regression models were used to evaluate the time-course of these metrics over training. results thirteen practitioners from 8 institutions completed stages 1 to 3 of the program, and 9 completed all 4 stages. over 1190 micro-ultrasound biopsy procedures were performed. detection of cspca increased from 40% to 57% from stage 1 to stage 4 (p < 0.01). stage 4 “expert” level was independently associated with higher detection of cspca when correcting for overall risk factors (or 1.95; p = 0.03). limitations include the retrospective analysis and variation in biopsy protocols. conclusion the micro-ultrasound training program was effective in improving biopsy quality and rate of cspca detection. the presented learning curve provides an initial guide for acquiring expertise with real-time microultrasound image-guided biopsy. introduction conventional transrectal ultrasound is typically used to guide prostate biopsy. this conventional ultrasound guided systematic biopsy strategy results in a significant proportion of false negatives and frequent under-grading of cancer[1,2]. micro-ultrasound imaging of the prostate at 29mhz provides an improvement in detail resolution compared with conventional ultrasound. this detailed imaging required the development of educational techniques for interpreting micro-ultrasound images. with appropriate training, micro-ultrasound appears to provide improved sensitivity compared with conventional ultrasound and allows image-guided targeted prostate biopsy[3–5]. however, adoption of these new techniques requires training and quality assurance. http://siuj.org mailto:hannes.cash%40prouro.de?subject=siuj expertly performed, micro-ultrasound guided biopsy has been demonstrated to provide risk stratification[6,7], improve rate of significant cancer detection[8–10], and aid in fusion biopsy accuracy[11,12]. micro-ultrasound is therefore a promising imaging technology to reduce costs and improve accessibility for early detection of clinically significant prostate cancer (cspca). while some studies have demonstrated promising results from practitioners new to the technology[4,13], it is unclear how many procedures are required before competence is achieved. to assist in the training of new users, exact imaging (manufacturer of the exactvu micro-ultrasound system) instituted a voluntary comprehensive training program in 2018. the program included 4 scheduled feedback stages in which practitioners must score above a set value over 9 metrics of biopsy quality to proceed to the subsequent stage. this retrospective study presents the data from these feedback reports. methods micro-ultrasound guided biopsy biopsy cases were performed transrectally using the exactvu micro-ultrasound system and ev29l transducer (exact imaging inc., markham, canada). all biopsy procedures were performed according to site-specific protocols conforming to general practice guidelines and by urologists experienced in prostate biopsy and/or fusion biopsy. these procedures were diverse, including various anesthesia protocols (local or general, or conscious sedation) and service locations (or, ambulatory surgical center, or clinic). however, all cases included 8 to 14 systematic samples (mean 12), as well as micro-ultrasound-targeted biopsy samples. target locations were selected based on the pri-mus protocol[4], and in some cases were informed by prior mpmri imaging. cases including mpmri-based targets were completed either cognitively[11,12] or using the fusionvu sof tware-based mr i/micro-ultrasound fusion feature of the exactvu system. we defined clinically significant prostate cancer (cspca) as any gleason grade > 3 + 4 = 7 cancer, a convention used by many other groups including in the precision trial and prostate biopsy collaborative group (pbcg) risk calculator[14,15]. training program all practitioners completed a standardized training program including 6 online learning modules and 1 hour of didactic instruction before undertaking their first live cases. an expert proctor was present for the first 10 to 15 live cases, until the practitioner demonstrated confidence in image interpretation and biopsy technique, after which the practitioner proceeded independently. the curriculum was developed and implemented by exact imaging on the basis of a structured review of cases from the initial clinical trial of micro-ultrasound and expert consensus amongst proctors[5]. de-identified data were collected according to stage, as presented in table 1. in cases where there were delays in collection leading to additional cases performed, the cases used for analysis were randomly selected to avoid bias. practitioners had to complete each stage of the program successfully to move to the next stage. after successfully completing stage 4, practitioners were awarded a certificate of quality assurance. feedback metrics nine metrics associated with biopsy quality were selected on the basis of previous findings during the first micro-ultrasound based randomized trial (nct02079025). these metrics are shown in table 1. with 3 exceptions, each metric was assigned a point value based on importance and used to judge whether a practitioner could proceed to the next stage. the exceptions were for data saving, cancer detection rate, and anesthesia technique, used only for informational purposes, or in the case of data saving to recommend repeating the stage, because of insufficient data. statistical analysis the mann-whitney u-test was used to compare non-parametric values, with a threshold of p < 0.05 considered significant. a gompertz function[16] was used to model learning curve through non-linear curve fitting. a multivariate logistic regression model was used to compare the detection rates at each stage with clinical risk factors such as age, psa, dre status, and family history. clinical risk factors were combined using the validated pbcg nomogram[15] into a single value to prevent overfitting on this limited dataset. only practitioners who had successfully completed stages 1 to 3 of the program were included in this analysis to avoid bias from having different individuals at stage 1 compared with the later stages. all computational modeling was performed in matlab (mathworks, natick, united states). the study was approved by the local ethics committees and the authors certify that the study was performed in accordance with the ethical standards as laid down in the 1964 declaration of helsinki and its later amendments. informed consent was obtained from all individual participants included in the study. results in total, 60 feedback reports from 13 practitioners at 8 institutions in germany, austria, the netherlands, and the united states between january 2018 and january 2020 were included. these 60 reports include data from 412 biopsy sessions, including 200 at stage 1, 69 at stage 2, 63siuj.org siuj • volume 3, number 2 • march 2022 prostate cancer detection by novice micro-ultrasound users enrolled in a training program http://siuj.org table 1. summary of training program stages and feedback metrics used in judging whether a practitioner is ready to proceed to the next stage stage cases before analysis cases analyzed effective sampling 1 10 10 100% 2 10 5 50% 3 20 5 25% 4 50 5 10% 79 at stage 3, and 64 at stage 4. in total, this group of practitioners completed over 1190 micro-ultrasound g uided prostate biopsy sessions (each w it h >12 individual biopsy samples) with a range of total cases per practitioner of 40 to 160. of the feedback reports,12/60 (20%) required the practitioner to repeat the assessment stage. the majority of these repeats were at stage 1 (8/12, 67%), as presented in more detail in table 2. median patient age was 70 (iqr 64 to 74) with psa 7.6 (iqr 5.9 to 11.7) ng/ml. a total of 95/412 cases had a positive dre (23%), and 89/412 (22%) had a prior biopsy. a pre-biopsy mpmri was available in 134/412 cases. the demographics did not vary significantly between feedback stages. detection of cspca increased from 40% to 57% from stage 1 to stage 4 (p < 0.01). the rate of cspca detected is shown in figure 1 by stage. the result of the multivariate analysis is presented in table 3 and shows improvement in stages 3 and 4 “expert” level with odds ratios of 1.71 and 1.95 and p = 0.06 and 0.03, respectively. this model was tested using leave-one-out validation with an area under the curve (auc) of 0.675. the use of mpmri was not standardized between centers, with 33 feedback reports incorporating mpmri targeting (cspca rate 44%) and 27 feedback reports not incorporating mpmri targeting (average cspca rate 54%). in order to investigate this difference in light of confounding variables such as psa and age, mpmri was added to the multivariate model presented in table 3. the multivariate or was not significant (or 1.07, p = 0.77) and the model auc dropped slightly from 0.675 to 0.672 suggesting the use of mri did not influence the learning curve. ability to correctly identify negative cases also varied with stage of training, although the relationship appears more complex. figure 2 shows an initial negative predictive value (npv) of 86% in stage 1 with 11% of cases marked as non-suspicious or negative. the number of cases marked as non-suspicious increased through stages 2 and 3 while npv declined. this trend reversed in stage 4 in which the fraction of cases marked non-suspicious decreased somewhat to 17% while npv rose to 91%. despite these changes in false negative rate, specificity showed a simple improvement over the course of the program increasing from 16% to 37% (p = 0.01). discussion appropriate training and quality control are necessary for any diagnostic imaging technology, and have been instrumental in the adoption of ct colonography and mammography. training and quality control have also been acknowledged as important in the diagnosis of prostate cancer through mri. recent expert consensus is that 1000 reads are necessary to be considered an expert in prostate mri[17]. this educational program metric points description data saving n/a quantity of data provided for analysis. should include at least 1 sweep through the prostate, and cine loops showing each biopsy location image quality 4 includes overall gain, tgc, and contrast settings, as well as presence of artifacts due to transducer preparation (air bubbles, etc.) systematic spacing 2 lateral and axial spacing of systematic samples to ensure good coverage pri-mus target identification 10 number of serious (pri-mus 4/5) lesions not sampled or annotated apical horn technique 4 distance of apical samples from capsule of the prostate. this is meant to ensure that the apical horn tissue is correctly sampled sample core length 2 mean length in millimeters. small values may indicate more pressure is required for tissue compression targeted sampling 2 all annotated lesions should be correctly sampled with clear visualization of needle traversing lesion cancer detection rate n/a rate of all cancer and significant (gg >1) cancer compared to validated clinical risk calculators anesthesia technique n/a presence of hematoma or other artifact causing significant image degradation over course of procedure stage 1 begins after the practitioner has been certified as independent by the proctor and includes an analysis of the first 10 cases completed. upon successful completion, the user completes an additional 10 independent cases of which 5 are analyzed. this process continues until successful completion of stage 4 (5/50 cases) which can occur after as little as 90 total cases. 64 siuj • volume 3, number 2 • march 2022 siuj.org original research http://siuj.org analysis demonstrates that a formal training and quality control program was effective in increasing the ability to detect clinically significant cancer by 17%. optimizing the negative predictive value appears to be a more prolonged process, with the number of false negatives increasing through stage 3 of the program. however, this effect appears transient with higher values in stage 4 and a steady increase in specificity throughout. the improvement occurred over the duration of the feedback program, which was established at 90 cases. the ability to consistently evaluate suspicious lesions according to the pri-mus protocol, with an impact on the pca detection rate, is important to ensure adequate biopsy quality performance of the new micro-ultrasound system. the learning curve and reproducibility of the evaluation of the prostate using micro-ultrasound is the basis for the adoption of this new technology and the potential practitioner acceptance. of note, there is a large body of literature about the importance of training and feedback during interpretation of mpmri. akin et al. demonstrated an increase in auc from 0.52 to 0.66 for identifying lesions in the peripheral zone using mpmri after didactic lectures[18]. similarly, rosenkrantz et al. demonstrated that with feedback accuracy interpreting prostate mri using pi-rads v1 improved from 58.1% to 77.4% over 124 examinations[19]. these studies both report reader accuracy rather than detection rate, which complicates any comparison with the work described here. meng et al. table 2. number of feedback sessions completed at each stage, with failure rate (required to repeat stage) and rate of significant cancer detected stage number of feedback sessions (unique practitioners) number required to repeat stage (%) age psa dre n (%) previous biopsy n (%) rate of cspca 1 21 (13) 8 (38) 69 (62–73) 7.6 (5.8–10.4) 43 (22) 42 (21) 40%±3% 2 13 (13) 0 (0) 70 (68–75) 7.6 (6.2–13.1) 20 (29) 15 (22) 45%±7% 3 15 (13) 2 (13) 70 (63–76) 7.6 (5.6–13.0) 15 (19) 12 (15) 58%±5% 4 11 (9) 2 (18) 71 (66–74) 8.8 (6.6–13.2) 17 (27) 20 (31) 57%±4% rate of cspca is presented as mean ± standard error of the mean. table 3. multivariate logistic regression model results accounting for patient risk levels variable or p -value stage 1 reference n/a stage 2 0.835 0.551 stage 3 1.714 0.057 stage 4 1.953 0.029 pbcg risk score 23.987 <0.001 stages 3 and 4 were associated with increased odds of detecting clinically significant cancer, with stage 4 achieving statistical significance at p = 0.03. ra te o f c sp ca stage 0.7 0.65 0.6 0.5 0.45 0.4 0.35 0.3 1 2 3 4 0.55 blue error bars represent the standard error of the mean. black dashed line is the gompertz function fit with 95% ci shown in magenta. the fit indicates the most likely learning curve with clear improvement by stage outside of the 95% ci. the lack of a plateau suggests further improvement may be possible. figure 1. rate of cspca detected by feedback program stage 65siuj.org siuj • volume 3, number 2 • march 2022 prostate cancer detection by novice micro-ultrasound users enrolled in a training program http://siuj.org demonstrate a 26% improvement in targeted detection rates over a 4-year period with mpmri fusion biopsy, which more closely aligns with the results presented here, while calio et al. demonstrated an 11.6% improvement in fusion biopsy detection rate over a 9-year period[20,21]. however, in both these cases the population is limited to men with suspicious mpmris. these data reflect an improvement in positive predictive value rather than overall detection rate in a general biopsy population. similar studies of fusion biopsy accuracy have focused on accuracy in reaching a prespecified target position, showing improvement within the first 98 cases for a robotic fusion system[22]. other studies have investigated complication rates and differences in use between junior and senior operators without reference to number of cases performed on a particular system, which was not investigated here[23]. the primary limitation of this study is the retrospective nature. as data were compiled from the feedback program registry, the biopsy procedures themselves were not standardized and differences in biopsy technique may be associated with different learning curves. in particular, use of mpmri was not standardized between centers. to examine this effect, we added mpmri to the multivariate model presented in table 3; however, the multivariate or was not significant, suggesting the use of mri did not influence the learning curve. complications during biopsy were not recorded as part of this study, but complication rates for the procedure are generally low and unrelated to the guidance/imaging device used[5]. further, the broad cross-section of physicians evaluated included those with prior ultrasound fellowship training who may be expected to have developed expertise in the technique earlier than those without this training. conclusion a formal training and feedback program for microultrasound establishes a standardized scan, and reporting with micro-ultrasound and adds significant value in improving clinically significant cancer detection rates. the learning curve presented here suggests expert sensitivity is achieved within the first 20 to 40 cases, while expert specificity generally takes 40 to 90 cases to develop. this provides a guide for practitioners who are interested in acquiring expertise with real-time microultrasound image-guided biopsy. educational program enhancements and prospective registries are currently evolving. acknowledgments the aut hors wou ld like to ack nowledge dr brian wodlinger for his help with the registry data and dr sangeet ghai for editorial review of the manuscript. 0.1 0.12 0.14 0.16 0.18 0.2 0.22 0.24 0.9 0.7 0.4 0.8 0.6 0.5 1 2 3 4 1 n eg at iv e pr ed ic tiv e va lu e fr ac tio n of n on -s us pi ci ou s ca se s stage initially, practitioners appear hesitant to label a case non-suspicious; however, npv is high. a larger percentage of cases were marked nonsuspicious in stages 2 and 3, with an observed decline in npv. this trend appears to reverse in stage 4 with a lower number of non-suspicious cases but very high npv. error bars denote the standard error of the mean. figure 2. number of cases marked non-suspicious on micro-ultrasound and negative predictive value (npv) by stage of feedback program 0.6 0.7 0.4 0.3 0.2 0.1 0 1 2 3 4 sp ec i� ci ty stage blue error bars represent the standard error of the mean. black dashed line is the gompertz function fit with 95% ci shown in magenta. the fit shows a good match to the data points with clear increasing trend with stage, although no plateau is reached suggesting possible further improvement. figure 3. specificity to recognize benign cases by feedback program stage 66 siuj • volume 3, number 2 • march 2022 siuj.org original research http://siuj.org references 1. roehl ak, antenor jav, catalona wj. serial biopsy results in prostate cancer screening study. j urol.2002;167(6):2435–2439. available at: http://www.ncbi.nlm.nih.gov/pubmed/11992052 2. andriole gl, catalona wj. the diagnosis and treatment of prostate cancer. annu rev med.1991;42(1):9–15. doi:doi:10.1146/annurev. me.42.020191.000301 3. pavlovich c, hyndman me, eure g, ghai s, fradet v. a multi-institutional randomized controlled trial comparing novel first generation highresolution micro-ultrasound with conventional frequency ultrasound for transrectal prostate biopsy. j urol.2019;201(supplement 4):e394– e394. doi:10.1097/01.ju.0000555772.65881.fd 4. ghai s, eure g, fradet v, hyndman me, mcgrath t, wodlinger b, et al. assessing cancer risk on novel 29 mhz micro-ultrasound 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micro-ultrasound users enrolled in a training program http://siuj.org 18. akin o, riedl cc, ishill nm, moskowitz cs, zhang j, hricak h. interactive dedicated training curriculum improves accuracy in the interpretation of mr imaging of prostate cancer. eur radiol. 2010;20(4):995–1002. doi:10.1007/s00330-009-1625-x 19. rosenkrantz ab, ayoola a, hoffman d, khasgiwala a, prabhu v, smereka p, et al. the learning curve in prostate mri interpretation: self-directed learning versus continual reader feedback. am j roentgenol.2017;208(3):w92–w100. doi:10.2214/ajr.16.16876 20. meng x, rosenkrantz ab, huang r, deng f-m, wysock js, bjurlin ma, et al. the institutional learning curve of magnetic resonance imagingultrasound fusion targeted prostate biopsy: temporal improvements in cancer detection in 4 years. j urol.2018;200(5):1022–1029. doi:10.1016/j.juro.2018.06.012 21. calio b, sidana a, sugano d, gaur s, jain a, maruf m, et al. changes in prostate cancer detection rate of mri-trus fusion vs systematic biopsy over time: evidence of a learning curve. prostate cancer prostatic dis.2017;20(4):436–441. doi:10.1038/pcan.2017.34 22. kasabwala k, patel n, cricco-lizza e, shimpi a a, weng s, buchmann rm, et al. the learning curve for magnetic resonance imaging/ultrasound fusion-guided prostate biopsy. eur urol oncol.2019;2(2):135–140. doi:10.1016/j.euo.2018.07.005 23. porpiglia f, cossu m, de luca s, manfredi m, mele f, bertolo r, et al. mp77-04 the role of the operator in the cancer detection with mri/trus fusion transrectal prostate biopsy. j urol.2018;199(4,suppl):e1028. doi:10.1016/j.juro.2018.02.2592 68 siuj • volume 3, number 2 • march 2022 siuj.org original research http://siuj.org key words competing interests article information female urethroplasty, pelvic fracture urethral injury, fistula, urethra, stricture none declared. patient consent: obtained for clinical images. received on october 6, 2021 accepted on january 5, 2022 this article has been peer reviewed. soc int urol j. 2022;3(2):77–86 doi: 10.48083/mbxr6354 77siuj.org siuj • volume 3, number 2 • march 2022 this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. original research pelvic fracture urethral injury in females pankaj m. joshi,1 marco bandini,1,2,3 christian yepes,1 shreyas bhadranavar,1 vipin sharma,1 sandeep bafna,1 sanjay b. kulkarni1 1 kulkarni reconstructive urology center, pune, india 2 unit of urology, urological research institute (uri), irccs ospedale san raffaele, vita-salute san raffaele university, milan, italy 3 centro chirurgico toscano, arezzo, italy p.j., m.b., and c.y. contributed equally to the manuscript abstract background pelvic fracture urethral injuries (pfui) in females are very rare. the available literature on the management of this condition is scarce and not clear, mainly because of limited experience among reconstructive surgeons. we present our experience of management of these complex urethral injuries in female patients. materials and methods we collected data, retrospectively and prospectively for 22 female patients referred to our center for pfui repair between 1995 and 2021. during the clinical assessment of these complex injuries, following our internal institutional protocol, all patients underwent pelvic mri (bladder and urethra are filled with saline solution and jelly to enhance the urethral lumen and the level of the distraction) before anastomotic urethroplasty. results pfui compromised the mid urethra in 10 patients (45.5%). a transabdominal approach was used in 8 patients (80%), and urethra-vaginal fistula repair was undertaken in 6 patients (60%). after a median follow-up of 36 months, only 1 patient with proximal pfui required a surgical revision without compromising urinary continence. conclusions the most common site of urethral involvement in pelvic fracture is mid urethral, which is owing to avulsion. urethra-vaginal fistula should be suspected. treatment consists in anastomotic urethroplasty, mainly through the abdominal approach. introduction urethral injury in females with pelvic fractures is very rare[1–8]. the literature on the management of female urethral injuries is sparse and not consistent, largely because of limited experience worldwide. further, patients include a wide spectrum from young girls to adult women, and so the referral may be to a pediatric urologist, a gynecologist, or a urologist. the earliest report of such injures was by perry and hussmann in 1992[5]. injuries reported before this were longitudinal injuries, which may go unnoticed. the injuries we see in practice are usually avulsion injuries. the kulkarni reconstructive urology center is a unique center with referrals from all over the world. over last 2 decades we have treated 22 patients with pelvic fracture urethral injury (pfui) and have acquired substantial experience. we believe these injuries should be classified differently in terms of age, with different management algorithms for prepubertal girls compared with adult females. http://siuj.org mailto:drpankajmjoshi%40gmail.com?subject=siuj we present our experience of management of female pelvic fracture urethral injuries, and we note that many of our findings have been published in reports on complex urethral injuries[9–11]. materials and methods we retrospectively and prospectively collected data on girls and women referred to our center for pfui repair between 1995 and 2021. a detailed history was obtained, and patients were examined in the outpatient clinic. we obtained an ultrasound of the abdomen. additionally, we annotated the position of suprapubic catheter and any previous scars on the abdomen, and we performed a local examination of the vulva. the female urethra is about 4 cm in length, and even smaller in young women and girls. retrograde urethrogram and voiding cystourethrogram were considered critical for assessment of the urethral injury, and all patients received pelvic mri, in which the bladder and urethra were filled with saline solution and jelly to enhance the lumen and the level of the urethral distraction (figures 1 and 2)[12]. all patients proceeded to surgery within 1 day of coming to the hospital. patients were admitted and received a single dose of preoperative antibiotics. intraoperatively, we used the dorsal lithotomy position. preoperative endoscopy was a critical part of evaluation, and the urethra was best visualized with a 0-degree endoscope. the best instrument for this proved to be the 7 fr mini nephroscope or a 4.5 fr ureteroscope, which was passed retrograde from the meatus to assess the distal urethra. urethrovaginal fistula should be suspected in every female patient with pfui, and we found a urethrovaginal fistula in most of our patients. if possible, a guide wire was passed through the urethra into the bladder with the outside end brought out through the introitus. subsequently, we performed a vaginoscopy, which usually showed a normal vagina with visualization of the cervix (figure 3), a post-traumatic transverse vaginal septum preventing visualization of the cervix, or stenosis of the vagina at the site of trauma. the next step was to perform endoscopy from the suprapubic catheter tract to visualize the bladder, the bladder neck, and the urethra proximal to the site of injury. we typically saw urethral avulsion at the bladder neck, in the proximal urethra, or in the mid urethra. some patients also exhibited meatal stenosis and/or accompanying urethrovaginal fistula and/or vaginal stenosis. approach the approach in prepubertal girls was always abdominal (figure 4). in adult women, a vaginal approach was possible in some cases. figure 1. mri in female patient with pelvic fracture urethral injury figure 2. mri showing grossly dilated vagina and hematocolpos in a patient with prior repair of pelvic fracture urethral injury 78 siuj • volume 3, number 2 • march 2022 siuj.org original research http://siuj.org transection at bladder neck injury at the bladder neck can result in transection of the bladder neck. when suprapubic endoscopy was performed in these cases, we could usually see a dimple that suggested the position of the bladder neck. identification of the ureteric orifices and trigone also helped to locate the position of transected bladder neck. surgical repair was performed through a lower abdominal incision. the extraperitoneal space was entered and the bladder was released from its anterior attachments. a posterior and superior pubectomy was then performed (figure 5). scar tissue at the site of injury was excised. the urethra distal to the injury was incised over a dilator passed through the urethra from the meatus (figure 6). a 12 fr mini nephroscope was passed through the suprapubic catheter site to guide the incision of the bladder. the anastomosis between the bladder neck and the figure 3. vaginoscopy demonstrating cervix figure 4. clinical picture of a girl after surgical revision of a pelvic fracture urethral injury figure 5. abdominal approach with posterior and superior pubectomy figure 6. abdominal approach with posterior and superior pubectomy 79siuj.org siuj • volume 3, number 2 • march 2022 pelvic fracture urethral injury in females http://siuj.org urethra was performed with six 5-0 polydiaxone sutures. the posterior sutures were tied down (figure 7) before passing a 14fr silicon catheter across the anastomosis and tying down the anterior sutures. the omentum was mobilized and transposed onto the anastomosis. a drain was not usually required. transection at proximal urethra in cases with a proximal urethral injury a short length of intact urethra remained attached to the bladder. the surgical steps were the same as for a bladder neck injury, except that the anastomosis was performed between the 2 urethral ends. this was more challenging than bladder neck repair, as there is very narrow space to work in the female pelvis. transection at mid urethra the mid urethra was the commonest site of female pfui. this type of injury is almost always associated with a urethrovaginal fistula, which can be missed (figure 8). in these cases, transection of the mid urethra allows the distal urethra to connect to the anterior vaginal wall to form a fistula. intraoperative endoscopy, preferably with a 7 fr or 12 fr mini nephroscope, depending on the age of the patient, was more important in these cases. endoscopy through the meatus into the distal urethra showed the urethrovaginal fistula. a guide wire was passed through the fistula and back through the vagina. a confirmatory vaginoscopy was performed. the surgical steps were similar to the previously described procedure but more challenging. a more extensive posterior and superior pubectomy was necessary to expose healthy edges of the proximal and distal urethra. the distal urethra was opened, and the previously inserted guide wire was pulled through the abdominal wound. the vaginal fistula was then clearly visible. the edges were freshened, and the fistula closed with interrupted polydiaxone sutures. a long stay suture was placed and used to tuck the omentum between the urethral anastomosis and the anterior vaginal wall to create an intervening layer. transection at meatus rarely, the injury was observed at the level of meatus (figure 9), and this was usually associated with a vaginal injury. the meatus became hypospadic. the vaginal injury healed with scarring leading to vaginal outlet stenosis. these patients voided through the vagina, where urine accumulated, and the patients presented with intermittent incontinence. the diagnosis was confirmed by vaginoscopy with small caliber endoscope. these patients needed to be treated with vaginotomy. figure 7. anastomosis figure 8. urethrovaginal fistula seen on ct 80 siuj • volume 3, number 2 • march 2022 siuj.org original research http://siuj.org vaginal examination (which was difficult in pediatric patients because of narrow introitus) often revealed an almost bone-like scar on the posterior vaginal wall. older patients sometimes needed a vaginal pull-through surgery, involving mobilization of the healthy edge of vagina down to be sutured to the introitus. urethral lengthening in cases of meatal injur y where treatment with meatotomy would result in a hypospadiac urethra and intravaginal voiding, we usually recommend a urethral lengthening procedure. this can be done with a pedicled inner labial skin flap which is sutured to the urethra. we performed this in 1 patient, who was satisfied with the result. vaginal injury as stated earlier, urethrovaginal fistula was commonly seen in mid-urethral injuries. occasionally, the vagina was also transected. resultant scarring sometimes led to the formation of a vaginal septum. as a result, the proximal vagina and uterus could become compartmentalized and separated from the distal vagina. affected patients presented with amenorrhea and hematocolpos. diagnosis was made by demonstrating these findings on ultrasound. intraoperative vaginoscopy was very important in such cases. inability to visualize the cervix during intraoperative vaginoscopy confirmed the presence of a vaginal septum. these cases were treated with either laser incision of the septum or vaginal pull-through. complete urethral loss this is the rarest ty pe of injur y and requires a vascularized f lap for repair. this is most easily accomplished by making a bladder wall f lap and tubularizing it to form a neo-urethra. there remains a high risk of incontinence. we carried out this procedure in only 1 patient. uroflow was performed after surgery to assess the success of the operation. urinary continence was also assessed after surgery using a voiding diary. results we retrieved the data of 22 patients: 10 girls (median age 9 years) and 12 women (median age 25 years). median time from injury to surgery was 10 months. urethral injury was in the proximal urethra in 5 cases (22.7%, 4 prepubertal girls and 1 adult woman), in the mid urethra in 10 cases (45.5%, 4 prepubertal girls and 6 adult women), and in the distal urethra in 6 cases (27.3%, 2 prepubertal girls and 4 adult women). one case presented with complete urethral loss (table 1). of the 10 patients presenting with mid pfui, 8 were approached transabdominally and 6 (2 girls and 4 adults) underwent urethrovaginal fistula repair. the approach was transvaginal in all 6 distal patients with pfui. two prepubertal girls with distal injury had vaginal introital stenosis and required vaginotomy. we observed a transverse vaginal septum that was attributed to trauma in 2 patients who both required vaginal pull-through. the patient with complete urethral loss needed a bladder figure 9. distal urethral injury 81siuj.org siuj • volume 3, number 2 • march 2022 pelvic fracture urethral injury in females http://siuj.org table 1. summary of treatments and outcome no age at accident (years) interval to surgery (months) group mechanism of trauma associated injuries mode of treatment location of injury approach and surgery continence day night uroflow (ml /s) follow-up (months) further intervention final result 1 5 3 prepubertal collapsing wall urethrovaginal fistula delayed proximal abdominal, closure of uvf, anastomotic urethroplasty yes no 9 47 none success 2 2 36 prepubertal collapsing wall urethrovaginal fistula delayed proximal abdominal, closure of uvf, anastomotic urethroplasty yes yes 0a 36 redo success 3 9 4 prepubertal road traffic accident urethrovaginal fistula delayed proximal abdominal, closure of uvf, anastomotic urethroplasty yes no 14 42 none success 4 10 6 prepubertal road traffic accident urethrovaginal fistula, lower limb fractures, degloving injury in thigh delayed mid abdominal, closure of uvf, anastomotic urethroplasty yes yes 18 46 none success 5 11 4 prepubertal road traffic accident none delayed mid abdominal, anastomotic urethroplasty yes yes 16 63 none success 6 10 3 prepubertal road traffic accident urethrovaginal fistula, lower limb fracture delayed mid abdominal, closure of uvf, anastomotic urethroplasty yes yes 20 80 none success 7 43 24 postpubertal road traffic accident urethrovaginal fistula delayed mid abdominal, closure of uvf, anastomotic urethroplasty yes yes 16 66 none success 8 23 6 postpubertal road traffic accident lower limb fracture delayed distal vaginal yes yes 19 112 none success 9 35 3 postpubertal road traffic accident none delayed mid vaginal yes yes 20 132 none success 10 30 0b postpubertal road traffic accident vaginal injury, lower limb fracture primary mid vaginal yes yes 22 156 none success 11 22 10 postpubertal road traffic accident vaginal injury delayed distal vaginal, meatoplasty yes yes 18 72 none success 12 5 11 prepubertal road traffic accident vaginal stenosis delayed distal vaginal, meatoplasty, vaginotomy yes no 11 60 vaginal pull-through success 13 21 3 postpubertal road traffic accident lower limb fracture, complete urethral loss delayed proximal, mid, distal abdominal, bladder flap yes no 6 37 none success 14 6 24c prepubertal road traffic accident lower limb fracture, anterior vaginal wall loss delayed mid abdominal, closure of uvf, anastomotic urethroplasty, martius flap with skin forming the anterior vaginal wall yes yes 12 12 none success 15 26 37d postpubertal road traffic accident urethrovaginal fistula delayed mid abdominal, closure of uvf, anastomotic urethroplasty yes yes 22 14 none success 16 24 10 postpubertal road traffic accident lower limb fracture, vaginal stenosis delayed distal vaginal, pedicled labial flap, vaginotomy yes no 14 48 none success 17 27 14 postpubertal road traffic accident none delayed distal vaginal, urethroplasty with laser incision of vaginal septum yes yes 14 24 vaginal pullthrough vaginal septum amenorrhea 18 21 11 postpubertal road traffic accident urethrovaginal fistula delayed mid abdominal, closure of uvf, anastomotic urethroplasty yes yes 22 32 none success uvf: urethro-vaginal fistula afailed; bimmediately; c14 prior interventions before referral; dprior mitrofanoff 82 siuj • volume 3, number 2 • march 2022 siuj.org original research http://siuj.org table 1. summary of treatments and outcome no age at accident (years) interval to surgery (months) group mechanism of trauma associated injuries mode of treatment location of injury approach and surgery continence day night uroflow (ml /s) follow-up (months) further intervention final result 1 5 3 prepubertal collapsing wall urethrovaginal fistula delayed proximal abdominal, closure of uvf, anastomotic urethroplasty yes no 9 47 none success 2 2 36 prepubertal collapsing wall urethrovaginal fistula delayed proximal abdominal, closure of uvf, anastomotic urethroplasty yes yes 0a 36 redo success 3 9 4 prepubertal road traffic accident urethrovaginal fistula delayed proximal abdominal, closure of uvf, anastomotic urethroplasty yes no 14 42 none success 4 10 6 prepubertal road traffic accident urethrovaginal fistula, lower limb fractures, degloving injury in thigh delayed mid abdominal, closure of uvf, anastomotic urethroplasty yes yes 18 46 none success 5 11 4 prepubertal road traffic accident none delayed mid abdominal, anastomotic urethroplasty yes yes 16 63 none success 6 10 3 prepubertal road traffic accident urethrovaginal fistula, lower limb fracture delayed mid abdominal, closure of uvf, anastomotic urethroplasty yes yes 20 80 none success 7 43 24 postpubertal road traffic accident urethrovaginal fistula delayed mid abdominal, closure of uvf, anastomotic urethroplasty yes yes 16 66 none success 8 23 6 postpubertal road traffic accident lower limb fracture delayed distal vaginal yes yes 19 112 none success 9 35 3 postpubertal road traffic accident none delayed mid vaginal yes yes 20 132 none success 10 30 0b postpubertal road traffic accident vaginal injury, lower limb fracture primary mid vaginal yes yes 22 156 none success 11 22 10 postpubertal road traffic accident vaginal injury delayed distal vaginal, meatoplasty yes yes 18 72 none success 12 5 11 prepubertal road traffic accident vaginal stenosis delayed distal vaginal, meatoplasty, vaginotomy yes no 11 60 vaginal pull-through success 13 21 3 postpubertal road traffic accident lower limb fracture, complete urethral loss delayed proximal, mid, distal abdominal, bladder flap yes no 6 37 none success 14 6 24c prepubertal road traffic accident lower limb fracture, anterior vaginal wall loss delayed mid abdominal, closure of uvf, anastomotic urethroplasty, martius flap with skin forming the anterior vaginal wall yes yes 12 12 none success 15 26 37d postpubertal road traffic accident urethrovaginal fistula delayed mid abdominal, closure of uvf, anastomotic urethroplasty yes yes 22 14 none success 16 24 10 postpubertal road traffic accident lower limb fracture, vaginal stenosis delayed distal vaginal, pedicled labial flap, vaginotomy yes no 14 48 none success 17 27 14 postpubertal road traffic accident none delayed distal vaginal, urethroplasty with laser incision of vaginal septum yes yes 14 24 vaginal pullthrough vaginal septum amenorrhea 18 21 11 postpubertal road traffic accident urethrovaginal fistula delayed mid abdominal, closure of uvf, anastomotic urethroplasty yes yes 22 32 none success uvf: urethro-vaginal fistula afailed; bimmediately; c14 prior interventions before referral; dprior mitrofanoff continued on page 84 83siuj.org siuj • volume 3, number 2 • march 2022 pelvic fracture urethral injury in females http://siuj.org wall flap. one child needed a complex reconstruction with use of a martius flap along with the overlying labial skin to reconstruct the vaginal wall. overall, 17 patients (77.3%) were continent at night and during the day. of those with proximal pfui, 3/5 patients (60%) were continent at night and during the day. the patient with bladder wall flap was continent but voided with low pressure. this patient’s urethra was patent on urethroscopy, and there was no obstruction. the median postoperative qmax was 18 ml/s. after a median follow-up of 36 months, 1 patient with proximal pfui required a surgical revision but was continent thereafter. discussion management of female pfui is evolving slowly, and only a few reports are available in the literature. ours is one of the largest reported series of such patients to date. usually, the injury goes unnoticed in the acute post trauma evaluation. it is recognized by the inability to catheterize the patient or the presence of acute urinary retention. examination of the vulva needs the lithotomy position, which is challenging in the acute setting of trauma. in the series by perry and husmann[5], the patients presented with extravasation and persistent incontinence, which suggests that the urethral injuries were overlooked on initial evaluation. the favored management strategy for pfui is to place a suprapubic catheter in the acute setting, stabilize the patient, and perform a definitive repair after 3 months. rarely, if there is an acute transection that is accessible, and no other injuries, a primary repair can be attempted in an adult female. the true incidence of female urethral injuries is unknown. pelvic fracture urethral injuries are generally less common in females[8]. factors likely include the flexibility provided by the vagina, as well as the inherent elasticity of female urethra in adults. podestá et al. reported a concurrent vaginal laceration in 75% to 87% of cases[13], which is consistent with the experience of venn et al.[8]. singh et al. described a case of urethral distraction defect causing complete urethrovaginal avulsion[14]. venn et al. reported 12 female patients, aged 7 to 51, with urethral injuries[8]. four had concomitant rectal injuries. in 5 cases urethral continuity was preserved because the urethral injury was longitudinal. two of these 12 patients presented in follow-up with stress urinary incontinence. although the cause of incontinence is unclear, the authors suggested a mixed etiology including direct urethral damage and damage to innervation. in our study, the majority of patients were continent after urethroplasty, although 5 had nocturnal incontinence. the fear of incontinence should not deter the urologist from performing anastomotic urethroplasty in women with pfui. an artificial urinary sphincter can even be considered[8], although this was not needed in our patients. over the last 2 decades, we have gained the greatest experience of male pfui[10], and our experience with female pfui has simultaneously grown. female pfui is particularly challenging to manage because of the diversity of urethral injuries observed. venn et. suggested that it was difficult to produce recommendations on treatment of these injuries based on their patients. after operating on 22 such patients we are able to provide a table 1. summary of treatments and outcome no age at accident (years) interval to surgery (months) group mechanism of trauma associated injuries mode of treatment location of injury approach and surgery continence day night uroflow (ml /s) follow-up (months) further intervention final result 19 38 22 postpubertal road traffic accident urethrovaginal fistula, limb fracture delayed proximal abdominal, closure of uvf, anastomotic urethroplasty yes yes 21 18 none success 20 9 11 prepubertal road traffic accident urethrovaginal fistula delayed bladder neck abdominal, anastomotic urethroplasty yes yes 19 12 none success 21 10 10 prepubertal road traffic accident none delayed distal meatoplasty, vaginal pull-through yes yes 11 12 none success 22 24 9 postpubertal fall from train urethrovaginal fistula delayed mid abdominal, anastomotic urethroplasty yes yes 22 12 none success uvf: urethro-vaginal fistula afailed; bimmediately; c14 prior interventions before referral; dprior mitrofanoff , cont’d 84 siuj • volume 3, number 2 • march 2022 siuj.org original research http://siuj.org clear algorithm to assist reconstructive urologists in the management of these injuries (figures 10 and 11). we suggest categorizing patients in 2 groups: young females and adult females. always suspect a urethrovaginal fistula in urethral injuries, especially in prepubertal girls. anastomotic urethroplasty through an abdominal approach is the favored procedure. the urethra can be accessed with posterior and superior pubectomy keeping the rim of pubic bone intact. incontinence is rare in such patients. figure 10, figure 11. algorithm for management of female pelvic fracture urethral injury mid urethral mid • look for associated urethrovaginal �stula • commonest injury • can have vaginal septum proximal • posterior pubectomy • scar excision • anastomotic urethroplasty bladder neck / proximal distal • meatal stenosis • vaginal introital stenosis vaginotomy / pull through algorithm distal female pfui history, clinical examination mri with our protocol: full bladder and lignocaine jelly in urethra preoperative urethroscopy look for urethrovaginal �stula anastomotic urethroplasty (urethrovaginal �stula closure) vaginoscopy (look for cervix) if cervix not visualized, suspect traumatic vaginal septum table 1. summary of treatments and outcome no age at accident (years) interval to surgery (months) group mechanism of trauma associated injuries mode of treatment location of injury approach and surgery continence day night uroflow (ml /s) follow-up (months) further intervention final result 19 38 22 postpubertal road traffic accident urethrovaginal fistula, limb fracture delayed proximal abdominal, closure of uvf, anastomotic urethroplasty yes yes 21 18 none success 20 9 11 prepubertal road traffic accident urethrovaginal fistula delayed bladder neck abdominal, anastomotic urethroplasty yes yes 19 12 none success 21 10 10 prepubertal road traffic accident none delayed distal meatoplasty, vaginal pull-through yes yes 11 12 none success 22 24 9 postpubertal fall from train urethrovaginal fistula delayed mid abdominal, anastomotic urethroplasty yes yes 22 12 none success uvf: urethro-vaginal fistula afailed; bimmediately; c14 prior interventions before referral; dprior mitrofanoff 85siuj.org siuj • volume 3, number 2 • march 2022 pelvic fracture urethral injury in females http://siuj.org few patients need a tai lored approach to eit her lengthen the urethra if short or a full reconstruction in case of complete urethral loss. for these cases bladder or vaginal flaps are harvested for reconstruction. a bladder pubovaginal stenosis should be suspected in dista l injuries. such patients can present with amenorrhea and hematocolpos in the adolescent age. scar excision, good tension-free anastomosis, and omental interposition are key steps in performing the anastomotic urethroplasty. conclusions female pelvic fracture urethral injuries are uncommon. when they occur, the commonest pfui is the mid urethral avulsion. urethrovaginal fistula should be suspected. the injury is best repaired with anastomotic urethroplasty, mostly through the abdominal approach, which we show leads to excellent outcomes. this surgery requires specialized expertise. we present here our experience of management of these injuries with an operative algorithm. references 1. simpson-smith a . traumatic rupture of the urethra: eight personal cases with a review of 3 81 recorded ruptures. br j surg.1936;24:309–332. 2. antoci jp, schic mr jr. bladder and urethral injuries in patients with pelvic fractures. j urol.1982;128: 25 –26. doi: 10.1016/ s0022-5347(17)52734-2 3. bredael jj, kramer sa, cleeve lk, webster gd. traumatic rupture of the female urethra. j urol.1979;122:560 –561. doi: 10.1016/ s0022-5347(17)56504-0 4. patil u, nesbitt r, meyer r. genitourinary tract injuries due to fracture of the pelvis in females: sequelae and their management. br j urol.1982;54:32–38. 5. perr y mo, husmann da. urethral injuries in female subjects following pelvic fractures. j urol.1992;147:139–143. doi: 10.1016/ s0022-5347(17)37162-8 6. barach e, martin g, tomlanovich m, nowak r, littleton r. blunt pelvic trauma with urethral injury in the female: a case report and review of the literature. j emerg med.1984;2:101–105. doi: 10.1016/0736-4679(84)90328-7 7. carter ct, schafer n. incidence of urethral disruption in females with traumatic pelvic fractures. am j emerg med.1993;11:218–220. doi: 10.1016/0735-6757(93)90128-x. 8. venn sn, greenwell tj, mundy ar. pelvic fracture injuries o f t h e f e m ale ur e t h r a. bj u i nt.19 9 1; 8 3 : 6 2 6 – 6 3 0 . d oi: 10.1046/j.1464-410x.1999.00001.x. 9. kulkarni sb, surana s, desai dj, orabi h, iyer s, kulkarni j, et al. management of complex and redo cases of pelvic fracture urethral injuries. asian j urol. 2018 apr;5 (2):107–117. doi: 10.1016/j. ajur.2018.02.005. epub 2018 mar 2. 10. joshi pm, kulkarni sb. management of pelvic fracture urethral injuries in the developing world. world j urol.2020 dec;38(12):3027–3034. doi: 10.1007/s00345-019-02918-0. epub 2019 aug 29. 11. kulkarni sb, joshi pm, hunter c, surana s, shahrour w, alhajeri f. complex posterior urethral injury. arab j urol.2015 mar;13(1):43–52. doi: 10.1016/j.aju.2014.11.008. published online 2015 jan 20. 12. joshi pm, desai dj, shah d, joshi dp, kulkarni sb. magnetic resonance imaging procedure for pelvic fracture urethral injuries and recto urethral fistulas: a simplified protocol. turk j urol.2021 jan;47(1):35–42. doi: 10.5152/tud.2020.20472. epub 2021 jan 1. 13. podestá ml, jordan gh. pelvic fracture urethral injuries in girls. j urol.2001 may;165(5):1660–1665. 14. singh rk, kaushal d, khattar n, nay yar r, manasa t, sood r. pediatric pelvic fracture urethral distraction defect causing complete urethrovaginal avulsion. indian j urol.2018 jan-mar;34(1):76–78. doi: 10.4103/iju.iju_118_17 86 siuj • volume 3, number 2 • march 2022 siuj.org original research https://dx.doi.org/10.1016%2fj.aju.2014.11.008 https://dx.doi.org/10.4103%2fiju.iju_118_17 http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. predictors for retrograde ureteral stenting failure as an initial drainage method for emergent complicated acute calculus obstructive uropathy m. a. elbaset, mohamed edwan, rasha t. abouelkheir, rawdy ashour, mohamed ramez, abdalla abdelhamid, yasser osman urology and nephrology center, mansoura university, egypt abstract objective to define predictors for initial retrograde ureteral stenting (rus) failure with the need for the percutaneous nephrostomy (pcn) insertion as a drainage method in patients with complicated acute calculus obstructive uropathy. methods we undertook a retrospective evaluation of patients who presented with complicated obstructive calculus uropathy (acute renal failure or obstructive pyelonephritis) between january 2016 and january 2020. patients in whom there was failure to visualize ipsilateral ureteric orifice and those with extrinsic ureteral obstruction were excluded. patient demographics and radiological data including stone site, hydronephrosis grade, maximum transverse stone diameter, periureteral density (pud) and pericalcular ureteric thickness (p-cut) at the maximum transverse stone diameter were assessed using non-contrast computed tomography at the time of admission. results the study included 256 patients who were managed initially by rus trial. of them, 48 (18.8 %) had rus failure. the presence of acute pyelonephritis, increased maximum transverse stone diameter ≥ 9.5 mm, p-cut ≥ 7.5 mm, and pud at stone level ≥ 17.5 hu were risk factors associated with rus failure (p = 0.007, 0.002, < 0.001, and < 0.001, respectively). conclusion initial radiological stone and ureteric characteristics, in addition to the clinical diagnosis of obstructive pyelonephritis, can be used to determine pcn insertion as the preferred option over rus for urinary drainage. introduction intrinsic calculus obstructive uropathy is one of the most commonly encountered conditions in daily urological practice. in this situation, urgent temporary drainage of the urinary tract is indispensable, especially in the presence of infection also with infection or higher serum creatinine[1]. in this situation, retrograde ureteral stenting (rus), percutaneous nephrostomy (pcn) placement, or percutaneous placement of a jj stent are considered viable options for urinary system drainage [2-4]. this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information retrograde stenting, ureteral wall density, percutaneous nephrostomy, pyelonephritis, ureteral wall thickness, obstructive uropathy, stone, jj stent none declared. received on february 10, 2021 accepted on may 1, 2021 soc int urol j.2021;2(4):229–238 doi: 10.48083/ozul6913 siuj.org siuj • volume 2, number 4 • july 2021 229 original research mailto:abdelbaset.m.i%40gmail.com?subject=siuj http://www.siuj.org abbreviations pcn percutaneous nephrostomy p-cut pericalcular ureteric thickness pud periureteral density rus retrograde ureteral stenting urs ureteroscopy pcn insertion and rus have been shown to achieve comparable success rates in patients with obstructive urolithiasis. nonetheless, rates of sepsis, hospital stay, radiation exposure, and increased costs were higher in patients who were managed by pcn insertion[5,6]. likewise, failure of the retrograde approach for the urinary system might increase the risk of ureteral bleeding, perforation, and stricture formation. there is little evidence to suggest that either rus or pcn is a better choice as a primary treatment in complicated acute calculus obstruction[7]. both radiologists and urologists have indicated that the choice of drainage method is largely inf luenced by personal assessment and stone size[8-10]. in most studies, the larger the stone size, the more likely it was that pcn was chosen as a drainage method. other factors, including institutional burden and clinician familiarity with the procedure can direct treatment, and there are no universally applied rules for making the choice[11]. in a previous study, the presence of extrinsic obstruction and a higher degree of hydronephrosis were associated with increased risk for rus failure. inclusion of heterogeneous intrinsic causes of obstruction in addition to extrinsic causes was a limitation of this study[12]. we aimed to define a precise objective model to select the optimal way to decompress the urinary system obstruction by urolithiasis exclusively. the primary outcome was to define the predictors for initial rus trial failure in acute complicated calculus obstructive uropathy. the secondary outcome was to delineate the shortand long-term clinical outcomes post initial drainage. materials and methods subjects after institutional review board approval, we undertook a retrospective evaluation of patients who presented with acute calculus obstructive uropathy complicated with acute renal failure or obstructive pyelonephritis in a single center between january 2016 and january 2020. patients were excluded if there was failure to visualize ipsilateral ureteric orifice at the time of rus or if they had multiple obstructing stones, renal infection (eg, emphysematous pyelonephritis), previous history of urinary diversion or renal transplants, extrinsic ureteral obstruction, or causes of obstruction other than urolithiasis. patient demographics and laboratory investigations were collected, including age, gender, body mass index, clinical presentation, medical and surgical history, previous history of ipsilateral stone passage, definitive figure 1. radiological measurements for p-cut and pud at and below the stone level an impacted lumbar ureteral calculus is demonstrated in axial section. the maximum transverse stone diameter (4.85 mm) is subtracted from the overall ureteral width (13.4 mm) at this same level to get the p-cut (8.55 mm). an elliptical region of interest is drawn over the ureter at the level of the calculus (pud at the level of maximum transverse stone diameter) is 35.4 hu. another region of interest is drawn over the ureter distal to the calculus. (9.4 hu). average hounsfield unit density is calculated by the imaging software. care is taken not to include the retroperitoneal fat or calculus in the region of interest. 230 siuj • volume 2, number 4 • july 2021 siuj.org original research http://www.siuj.org table 1. univariate analysis for rus failure in acute emergent calcular obstruction variable failed rus (n=48) successful rus (n=208) p -value age in years (mean±sd)* 60.3±15.6 57.3±15.2 0.2 gender, n (%)** • male 27 (56.3) 122 (58.7) • female 21 (43.7) 86 (41.3) 0.4 presenting symptoms, n (%)** • obstructive pyelonephritis 33 (68.8) 72 (34.6) • acute renal failure 15 (31.2) 136 (65.4) 0.005 duration of symptoms before initial drainage in days*** (median & range) 7 (3-30) 5 (1-21) 0.1 medical history, n (%)** • irrelevant 17(35.4) 32(15.4) • diabetes mellitus 13 (27.1) 82 (39.4) 0.2 • hypertension 18 (37.5) 94 (45.2) * independent sample t-test **chi-square test ***mann-whitney test intervention, and ureteral stenting post definitive intervention, hospital stay, and serum creatinine and leucocytic count at admission. radiologica l parameters were collected using preoperative non-contrast computed tomography (120 kv and 100 ma, slice thickness was 5 mm with a 2 mm overlap using a 64-multislice helical ct scanner [brilliance, philips, the netherlands]), eg, average stone density in hounsfield unit (hu), laterality, site of the stones (proximal, iliac, or pelvic according to the location to the sacroiliac joints), and degree of hydronephrosis (lower and higher grade)[13,14] were analyzed. also, maximum transverse stone diameter in mm was calculated on axial images (figure 1). periureteral density (pud) in hu was measured below the stone level and at the stone level at its maximum transverse diameter[15]. the pericalcular ureteric thick ness (p-cut) was measured as the widest transverse measurement of the ureter involving the stone and the corresponding maximum transverse diameter of the stone at this level. p-cut was then calculated by subtracting the stone width from the overall stone and ureteral width[16] (figure 1). radiological data were interpreted by 2 expert radiologists (> 10 years’ experience) blinded to the study objectives. methods trial rus was performed under fluoroscopic guidance by urology senior residents under the supervision of the consultant in charge. with the patient in the lithotomy position, a terumo hydrophilic guidewire was gently introduced into the collecting system, using a 22 fr cystoscopy sheath and 30° telescope, and was followed by the introduction of a 6 fr open tip catheter (minimal amount of contrast could be injected to ensure the correct position inside the pelvicalyceal system). a 6 fr jj stent was later introduced over a ptfe straight guidewire. if the rus trial failed, patients were referred for ultrasound-guided pcn placement, using xario 100 system (toshiba medical system corp., tokyo, japan) ultrasound scanner, with the patient in the prone position. a 12 or 14 fr pigtail nephrostomy tube was placed over the guidewire inside the pelvicalyceal system. contrast was instilled via the pcn to confirm its location in the renal pelvis. after initial drainage, alpha-blockers were given in case of stones ≤ 10 mm to promote spontaneous expulsion. patients were selected for definitive treatment according to european association of urology and american urological association guidelines[2,3]. a ureteral stent post definitive intervention was inserted continued on page 232 231siuj.org siuj • volume 2, number 4 • july 2021 predictors for retrograde ureteral stenting failure as an initial drainage method http://www.siuj.org table 1. univariate analysis for rus failure in acute emergent calcular obstruction variable failed rus (n=48) successful rus (n=208) p -value asa score, n (%)** • i 28 (58.3) 110 (52.9) • ii 20 (41.7) 96 (46.2) 0.4 • iii 0 2 (0.9) hx of previous stone passage, n (%)** • yes 17 (35.4) 128 (61.5) 0.4 • no 31 (64.6) 80 (38.5) past surgical history on the same side, n (%)** • irrelevant 34 (70.8) 132 (63.5) • pnl 5 (10.4) 14 (6.7) • swl 1 (2.1) 20 (9.6) 0.1 • urs 5 (10.4) 20 (9.6) • previous jj stenting 3 (6.3) 22 (10.6) bmi (kg/m2) (mean ± sd)* 27.4±6.7 28.8 ±6.9 0.8 serum creatinine mg/dl (median & range )*** 1.8 (1-13.1) 2.4 (0.7-18) 0.07 wbcs at admission x 103 (mean ± sd)* 17.2 ± 6.5 14.1 ± 7 0.2 side, n (%) ** • right 25 (52.1) 118 (56.7) 0.4 • left 23 (47.9) 90 (43.3) stone location, n (%)** • proximal 30 (62.5) 118 (56.7) • mid-ureter 11 (22.9) 40 (19.2) 0.3 • distal 7 (14.6) 50 (24.1) degree of hydronephrosis, n (%)** • low grade 17 (35.4) 158 (76) • high grade 31 (64.6) 50 (24) <0.001 maximum transverse stone diameter in mm (mean ± sd)* 10.6 ± 3.5 7.9 ± 2.7 <0.001 average stone hu (median &range)*** 915 (580-1461) 825 (162-1517) 0.2 p-cut at maximum transverse stone diameter in mm (mean ± sd)* 13.5 ± 6 5.5 ± 2.6 <0.001 pud at maximum transverse stone diameter in hu (mean ± sd)* 26 ± 7.9 14.2 ± 6.9 <0.001 pud below the stone level in hu (mean ± sd)* 21.6 ± 10.3 11.3 ± 5.9 <0.001 * independent sample t-test **chi-square test ***mann-whitney test , cont’d 232 siuj • volume 2, number 4 • july 2021 siuj.org original research http://www.siuj.org in case of ureteral edema or presence of stone fragments, or to promote healing in case of ureteral injury[17]. analysis patient demographics and laboratory and radiological data were compared using t he chi-square test, independent sample t-test, or mann-whitney test as appropriate. univariate and multivariate analyses were performed to identify factors predicting rus failure. receiver operating characteristic (roc) was used to identify the cut-off value for the best sensitivity and specificity for significant continuous variables in the univariate analysis. all statistical analyses were performed using spss version 21, and p < 0.05 was considered statistically significant. results the study included 256 patients who presented with acute complicated calculus obstructive uropathy and were managed initially by rus trial (figure 2). four patients were excluded because of failure to visualize ipsilateral ureteric orifice associated with obstructing stones located in sites in the ureter other than the pelvic ureter (2 in the lumbar ureter and others in the iliac ureter away from intramural ureter). forty-eight patients (18.8 %) had rus failure and then were managed by pcn insertion. the patient characteristics were illustrated in table 1. in univariate analysis, acute pyelonephritis, higher maximum transverse stone diameter, the higher degree of hydronephrosis, increased p-cut, and increased pud below and at the stone level were predictors for initial rus failure (table 1). roc curve was then calculated to identify the cut-off values associated with the best greatest sensitivity and specificity for significant continuous variables in univariate analysis (figure 3). in multivariate analysis, acute pyelonephritis, increased the maximum transverse stone diameter ≥ 9.5 mm, p-cut ≥7.5 mm, and pud at stone level ≥ 17.5 table 2. multivariate analysis for predictors of rus failure variable multivariable logistic regression analysis or (95% ci) p -value presentation (obstructive pyelonephritis ) 2.9 (1.2–7.2) 0.007 degree of hydronephrosis (high grade) 1.1 (0.3–6.1) 0.8 maximum transverse stone diameter ≥ 9.5 mm 2.1 (1.6–6.8) 0.002 p-cut at the maximum transverse stone diameter ≥ 7.5 mm 6.1 (2.4–15.6) <0.001 pud at the maximum transverse stone diameter ≥ 17.5 hu 12.8 (4.7–23.1) <0.001 pud below the stone ≥ 19.5 hu 0.8 (0.3–2.1) 0.6 failed rus = 48 patients successful rus = 208 patients excluded = 46 • failure to visualize ureteric ori�ce associated with obstructing stone (all stones were not located at the pelvic ureter) = 4 • multiple ureteric stones = 22 • extrinsic obstruction = 20 initial patients included = 302 figure 2. flow chart of the study 233siuj.org siuj • volume 2, number 4 • july 2021 predictors for retrograde ureteral stenting failure as an initial drainage method http://www.siuj.org auc: 0.67 p-value: < 0.0001 cut-off value: 19.5 hu (sensitivity 67% and specificity 73%) auc: 0.82 p-value: < 0.0001 cut-off value: 9.5 mm (sensitivity 80% and specificity 75%) auc: 0.9 p-value: < 0.0001 cut-off value: 17.5 hu (sensitivity 83% and specificity 85%) auc: 0.86 p-value: < 0.0001 cut-off value: 7.5 mm (sensitivity 81.5% and specificity 91%) figure 3. roc curve for rus failure predictors 234 siuj • volume 2, number 4 • july 2021 siuj.org original research http://www.siuj.org hu were associated with increased the risk for rus failure (p = 0.007, 0.002, <0.001, and <0.001, respectively) (table 2). the median (range) of the hospital stay between both groups was comparable at the time of temporary drainage (p = 0.4) (2[2 to 7] days in rus failure versus 2[2 to 10] in rus success). only one patient in each group required intensive care unit (icu) admission due to urosepsis post the primary drainage, and both were subsequently discharged. in the rus failure group, ureteral stenting post definitive endourological procedures were required in 23 patients (60.5%), and of these, 20 patients (52.6%) had prior rus failure due to stone impaction and ureteral mucosal laceration. of patients with successful rus, 8 (3.8%) passed the stone spontaneously (mean stone size was 5 ± 1.2 mm). ureteral stenting post definitive intervention was required in only 35 patients (18.5%) because of stone impaction with a significant difference compared to patients with rus failure (p < 0.0001) (table 3). at a median of 14 (6 to 32) months at follow-up, 3 patients were admitted in the rus failure group. one patient with recurrent stone on the same side and managed by semirigid urs with evidence of passable narrowing below the stone level. the other 2 patients were diagnosed with ureteric strictures; one was managed by open surgery and the other was managed by retrograde laser endoureterotomy). discussion stone disease concomitant with pyelonephritis or acute renal failure is a commonly encountered complication in urology. using rus, pcn insertion, or percutaneous placement of a jj stent as temporary relief of the urinary tract obstruction is unavoidable[4,5]. in some situations, using the rus approach may be associated with intraoperative complications such as the failure of t he procedure, retroperitonea l extravasation, abscess formation, and sepsis. using the pcn as a primary drainage method could guard against these complications. opinions on the management of obstructive uropathy vary considerably. urologists are prone to insert ureteral stents especially in patients with benign disease and in those with coagulopathy[11,18]. studies have indicated that rus is an efficient method for drainage in 80% to 100% of patients in comparison with 95% to 100% table 3. clinical outcome post rus trial variable rus failure (n = 48) rus success (n = 208) type of management post rus trial, n (%) • ureteroscopy (semirigid or flexible ) 24 (50) 169 (82.6) • percutaneous nephrolithotomy (pnl) 14 (29.2) 20 (9.6) • shockwave lithotripsy (swl) 7 (14.6) 11 (5.3) • open surgery 3 (6.3) 0 duration between initial management and definitive treatment in days 30 (15–120) 20 (7–90) stone status at radiological follow-up, n (%) • static in previous place 48 (100) 135 (64.9) • pushed upwards 0 58 (27.9) • migrated downwards 0 7 (3.4) • passed spontaneously 0 8 (3.8) need for jj stenting post definitive intervention, n (%) 23 (60.5) /38 58 (30.7) /189 • passage of fragments (without evidence of edema and perforation) 3 (13) 23 (39.7) • mucosal laceration and stone impaction 5 (21.7) 1 (1.7) • stone impaction without laceration 15 (65.3) 34 (58.6) 235siuj.org siuj • volume 2, number 4 • july 2021 predictors for retrograde ureteral stenting failure as an initial drainage method http://www.siuj.org of patients managed by pcn placement in cases with urinary obstruction[6,12,19]. the preoperative physician preference was the main factor controlling the selection of diversion type in patients with obstructive uropathy. only stone size, independent of other factors, is a reliable predictor of procedure chosen. the overall rus failure rate in obstructive calculus uropathy complicated with sepsis was 2.3%[9]. in this study, patients who were selected for pcn insertion had a higher stone burden than those selected for rus (10 [2 to 145] mm2 versus 7[2 to 40] mm2). according to these data, we could elucidate the lower failure rate during the rus trial. in another study, the mean stone size was 9.7 mm in patients who were selected for pcn placement versus 2.6 mm in patients managed by rus. additionally, the median surface area of the stone in patients selected for pcn placement was 92 mm2 versus 47 mm2 in patients managed by rus[8,10]. the cut-off stone size that would indicate a high risk of rus failure has yet to be determined. in our study, a maximum transverse stone diameter of 9.5 mm was associated with 2.1 times increased risk for rus failure. the rus failure rate in our study was identified as 18.8%. in addition to the larger stone size in the rus failure group, we also noticed that the time between the initial symptoms and the first drainage was greater in patients with failed rus, reflecting greater ureteral inflammation. not only stone para meters but a lso uretera l characteristics on imaging should be considered in the decision to proceed with urs versus pcn. we have identified stone impaction as an additional parameter that predicts clinical outcome[15,16,20]. stone impaction can be explained by pathological changes in the ureteral wall, such as edema and hypertrophy at the site of the stone[21]. this pathological change may in turn lead to endourological procedures failure[22]. in a retrospective study of patients who had undergone ureteroscopic treatment of an impacted ureteral stone, tran et al. used a likert scale to classify stone impaction into nonimpacted (1: mobile stone with no edema or 5: stone stuck to the ureter with mild edema) and impacted stones (6: stone stuck in ureter with moderate edema and requiring moderate pressure/irrigation) or 10: stone embedded within ureteral tissue with disimpaction failure. numerous studies have highlighted the predictors for stone impaction during urs and determined preoperative radiological parameters such as increased ureteral wall thickness and ureteral wall density at the stone level to be predictors for stone impaction[15,16,23]. higher pud below the stone level has been considered to be another co-factor responsible for urs failure as it may represent more ureteral inf lammation and spasm precluding passage of the ureteroscope to reach stones[15,16]. other studies have found the severity of hydronephrosis and increased serum creatinine to be associated with impacted ureteral stones during urs[24, 25]. in our study, neither pud below the stone level nor the degree of hydronephrosis was a significant predictor for rus failure. conversely, p-cut ≥ 7.5 mm and pud at maximum transverse stone diameter ≥ 17.5 hu were associated with a 6.1-fold and a 12.8fold increase, respectively, in the rate of rus failure necessitating subsequent pcn insertion for emergent urinary drainage. pearl et al. showed that rus failure was more obvious in the elderly with high grade fever[19]. also, in previous studies predicting rus failure in the presence of intrinsic obstructive factors rather than urolithiasis, including male sex, a higher degree of hydronephrosis, and increased serum creatinine at presentation[12,26]. acute pyelonephritis was a predictor of rus failure in our experience. this could be indicated by the presence of a higher degree of hydronephrosis, urine stasis, and pathogen proliferation for a prolonged period before sepsis occurrence. spont a ne ou s stone pa s s a ge a nd dow nwa rd displacement of stones were encountered in 3.8 % and 3.4% of patients with successful urs, respectively. yoshida et al. concluded that in addition to the passive ureteral dilation caused by the ureteral stent, ureteral wall thickness is a substantial factor for spontaneous passage of ureteric stones ≤ 10 mm[27]. on the contrary, it was reported that spontaneous stone passage in patients with pcn was higher than in patients with rus[8]. in our study, all patients in the rus failure group had a static stone position after the initial drainage and before the definitive intervention. higher pud below the stone level and at the stone level in addition to increased p-cut might explain the progressive ureteral inflammation and spasm that hindered stone movement. cevik et al. showed that routine placement of a ureteral stent is not mandatory in patients without complications after urs for impacted ureteral stones[17]. even though the time interval between emergent urinary drainage and definitive endurological stone treatment was short, the rate of ureteral stenting in patients with successful rus was only 18.5%. the rate of stenting was higher at 52.6% in patients with initial failed rus. there was a higher rate of ureteral stenting in patients with rus failure after the definitive intervention: 52.6 % versus 18.5 % in patients with successful rus. also, the rates of ureteral laceration associated with stone impaction during definitive intervention and ureteral stricture occurrence during follow-up were higher in patients with rus failure. morgentaler et al. 236 siuj • volume 2, number 4 • july 2021 siuj.org original research http://www.siuj.org references 1. c ampbell s, l ane b. malignant renal tumors in: wein a j, kavoussi lr, partin aw, peters ca., eds. campbell-walsh urology. philadelphia, pa, usa: elsevier; 2016. 2. assimos d, krambeck a , miller nl, monga m, murad mh, nelson cp, et al. surgical management of stones: american urological association/endourological society guideline, part i. j urol.2016;196(4):1153–1160. 3. turk cna, petrik a, seitz c, et al. (2020) guidelines on urolithiasis. https://uroweb.org/guideline/urolithiasis/. 4. masood j, ismail m, el-husseiny t, moraitis k, albanis s, papatsoris a, et al. ‘an interventional urology list’–a novel concept for uk urological services. ann r coll surg engl.2011;93(1):27–30. 5. weltings s, schout bm, roshani h, kamphuis gm, pelger rc. lessons from literature: nephrostomy versus double j ureteral catheterization in patients with obstructive urolithiasis—which method is superior? j endourol.2019;33(10):777–786. 6. skolarikos a , alivizatos g, papatsoris a , constantinides k, z er b as a , deliveliotis c. ultr asoundguided per cu t aneous nephrostomy per for med by urologists: 10 -year ex perience. urology.2006;68(3):495–499. 7. türk c, petr̆ ík a, sarica k, seitz c, skolarikos a, straub m, et al. e au guidelines on inter ventional treatment for urolithiasis. eur urol.2016;69(3):475–482. 8. de sousa morais n, pereira jp, mota p, carvalho-dias e, torres jn, lima e. percutaneous nephrostomy vs ureteral stent for hydronephrosis secondary to ureteric calculi: impact on spontaneous stone passage and health-related quality of life—a prospective study. urolithiasis.2019;47(6):567–573. 9. goldsmith zg, oredein‐mccoy o, gerber l, bañez ll, sopko dr, miller mj, et al. emergent ureteric stent vs percutaneous nephrostomy for obstructive urolithiasis with sepsis: pat terns o f u s e a n d o u t c o m e s f r o m a 15 ‐ y e ar e x p e r ie n c e. bj u int.2013;112(2):e122–e8. 10. yoshimura k, utsunomiya n, ichioka k, ueda n, matsui y, terai a. emergency drainage for urosepsis associated with upper urinary tract calculi. j urol.2005;173(2):458–462. 11. lynch mf, anson km, patel u. current opinion amongst radiologists and urologists in the uk on percutaneous nephrostomy and ureteric stent insertion for acute renal unobstruction: results of a postal survey. bju int.2006;98(6):1143–1144. 12. yossepowitch o, lifshitz da, dekel y, gross m, keidar dm, neuman m, et al. predicting the success of retrograde stenting for managing ureteral obstruction. j urol.2001;166(5):1746–1749. 13. elbaset m, ezzat o, elgamal m, sharaf m, elmeniar a, abdelhamid a, et al. supranormal differential renal function in adults with ureteropelvic junction obstruction: does it really exist? indian j urol.2020;36(3):205. 14. elbaset ma, osman y, elgamal m, sharaf ma, ezzat o, elmeniar am, et al. long-term outcomes after pyeloplasty for pelvi-ureteric junction obstruction in adults associated with renal congenital anomalies: age, sex and renal function matched analysis. arab j urol.2020:1–6. 15. tran ty, bamberger jn, blum ka, parkhomenko e, thai j, chandhoke ra, et al. predicting the impacted ureteral stone with computed tomography. urology.2019;130:43–47. 16. chandhoke r, bamberger jn, gallante b, atallah w, gupta m. peri-calculus ureteral thickness on computed tomography predicts stone impaction at time of surgery: a prospective study. j endourol.2020;34(1):107–111. 17. cevik i, dillioglugil o, akdas a, siegel y. is stent placement necessar y af ter uncomplicated ureteroscopy for removal of impacted ureteral stones? j endourol.2010;24(8):1263–1267. 18. sammon jd, ghani kr, karakiewicz pi, bhojani n, ravi p, sun m, et al. temporal trends, practice patterns, and treatment outcomes for infected upper urinary tract stones in the united states. eur urol.2013;64(1):85–92. higher in patients with rus failure. morgentaler et al. concluded that 28.5% of patients (12/42) with impacted ureteral stones developed ureteral trauma during stone manipulation. two patients later developed ureteral stricture[28]. in addition to the beneficial role of alphablockers use to facilitate ureteral dilation and stone access during ureteroscopy[29,30]. the use of nsaids and/or chymotrypsin as add-on therapy in severely impacted stones before definitive intervention has also been suggested. the study was limited by small sample size and inherent selection bias due to the retrospective nature of the study. failure to assess the quality of life, lack of radiation exposure estimation, and financial cost calculation were other limitations. conclusion in acute obstructive uropathy complicated with acute pyelonephritis and associated with a stone diameter around 1 cm, it is not only the stone profile index that is responsible for rus failure. the ureteral profile is also substantial finding which can help in drainage type selection. increased p-cut ≥ 7.5 mm, and pud ≥ 17.5 hu were predictive parameters for initial rus trial failure and the necessity of pcn placement. in this group of patients after definitive intervention, ureteral stenting is still needed in 52.6 % due to persistent ureteral edema and lacerations. pre-definitive intervention use of alpha-blockers besides nsaids or chymotrypsin may reduce stone impaction ureteral lacerations and facilitate stone passage. 237siuj.org siuj • volume 2, number 4 • july 2021 predictors for retrograde ureteral stenting failure as an initial drainage method https://uroweb.org/guideline/urolithiasis/ http://www.siuj.org 19. pearle ms, pierce hl, miller gl, summa ja, mutz jm, petty ba, et al. optimal method of urgent decompression of the collecting system for obstruction and infection due to ureteral calculi. j urol.1998;160(4):1260–1264. 20. elbaset m, elkarta a, eraky a, badawy m, sheir k, shokeir a. role of pretreatment doppler ultrasound in the prediction of factors affecting stone-clearance post-shockwave lithotripsy for ureteral stones: a prospective study. int urol nephrol.2020;52(9):1643–1649. doi: 10.1007/s11255-020-02465-3. epub 2020 apr 15. 21. brito ah, mitre ai, srougi m. ureteroscopic pneumatic lithotripsy of impacted ureteral calculi. int braz j urol.2006;32(3):295–299. 22. oliver r, wells h, traxer o, knoll t, aboumarzouk o, biyani cs, et al. ureteric stents on extraction strings: a systematic review of literature. urolithiasis.2018;46(2):129–136. 23. legemate jd, wijnstok nj, matsuda t, strijbos w, erdogru t, roth b, et al. characteristics and outcomes of ureteroscopic treatment in 2650 patients with impacted ureteral stones. world j urol.2017;35(10):1497–1506. 24. tran ty, hernandez bustos n, kambadakone a, eisner b, pareek g. emergency ureteral stone treatment score predicts outcomes of ureteroscopic intervention in acute obstructive uropathy secondary to urolithiasis. j endourol.2017;31(9):829–834. 25. sarica k, er yildirim b, sahin c, sabuncu k, cetinel c, narter f. impaction of ureteral stones into the ureteral wall: is it possible to predict? urolithiasis.2016;44(4):371–376. 26. wenzler dl, kim sp, rosevear hm, faerber gj, rober ts w w, wolf j, j stuart. success of ureteral stents for intrinsic ureteral obstruction. j endourol.2008;22(2):295–300. 27. yoshida t, inoue t, taguchi m, omura n, kinoshita h, matsuda t. ureteral wall thickness as a significant factor in predicting spontaneous passage of ureteral stones of≤ 10 mm: a preliminary report. world j urol.2019;37(5):913–919. 28. morgentaler a, bridge ss, dretler sp. management of the impacted ureteral calculus. j urol.1990;143(2):263–266. 29. alsaikhan b, koziarz a, lee jy, pace k t. preoperative alphablockers for ureteroscopy for ureteral stones: a systematic review and met a-analysis of randomized controlled trials. j endourol.2020;34(1):33–41. 30. koo kc, yoon j-h, park n-c, lee hs, ahn hk, lee ks, et al. the impact of preoperative α-adrenergic 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(6):1622–1630. 238 siuj • volume 2, number 4 • july 2021 siuj.org original research http://www.siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information transitional cell carcinoma, nephrostomy, tumor seeding none declared. patient consent: obtained. received on september 6, 2021 accepted on september 17, 2021 soc int urol j.2021;2(6):382 doi: 10.48083/zvxi1252 figure 1a. cross-sectional ct scan showing the tumor extending from the kidney along the previous nephrostomy tract to the skin externally figure 1b. mass seen at the patient's flank next to the nephrostomy 382 siuj • volume 2, number 6 • november 2021 siuj.org clinical picture urothelial carcinoma seeding at site of nephrostomy ala'a farkouh, mohammed shahait king hussein cancer center, department of surgery, amman, jordan a 57-year-old man, with a history of nephrolithiasis and heavy smoking (80 pack years at presentation), presented to a tertiary cancer center 2 years ago with urothelial carcinoma (uc) in the right distal ureter associated with lung metastasis. on initial presentation, the patient complained of right flank pain, gross hematuria, and weight loss. imaging revealed a 3.7 cm right distal ureter mass with severe right hydronephrosis (figure 1a) and a 3.2 cm lung lesion, which was proven by biopsy to be metastatic uc. a right nephrostomy was inserted for palliation of symptoms and to manage recurrent obstructive pyelonephritis. the patient’s disease progressed despite multiple lines of chemotherapy and immunotherapy. he developed infection at the nephrostomy site with associated emphysematous pyelonephritis. this was managed with antibiotics and placement of a new nephrostomy at a different site, and palliative nephrectomy was considered. after resolution of the infection, the patient was noted to have a small malodorous mass at the site of the previous nephrostomy t hat progressively grew in size over 4 mont hs (figure 1b). biopsy of the mass revealed uc. this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information implantable neurostimulators, adverse effects, hypersensitivity, urinary retention, therapy none declared. patient consent: obtained. received on september 24, 2021 accepted on september 27, 2021 soc int urol j.2021;3(1):44–45 doi: 10.48083/nade9605 figure 1. 44 siuj • volume 3, number 1 • january 2022 siuj.org clinical picture a rare case of hypersensitivity reaction associated with sacral neuromodulation hardware kendall a. vignaroli,1 shreeya popat,2 kathleen c. kobashi2 1 elson s. floyd college of medicine, washington state university, spokane, united states 2 department of urology, virginia mason franciscan health, seattle, united states a 77-year-old female with history of lymphoma status post radiation therapy presented with approximately 10 years of intermittent urinary retention, managed with clean intermittent catheterization. urodynamic studies revealed minimal detrusor contraction (3 cm h2o) and a low amplitude, interrupted flow curve with maximum flow 9.5 ml/sec, average flow 2 ml/second, and appropriate emg silencing. cystoscopy was within normal limits. we proceeded with staged placement of medtronic interstim device. after stage 1 placement of the sacral neuromodulation device, the patient reported voiding larger volumes with less straining (an approximate 80% subjective improvement), denied further episodes of urinary retention, and her pvr improved from between 100 ml and 300 ml to 50 ml. however, she rapidly developed an erythematous skin reaction overlying the device lead (figure 1). physical examination revealed a discrete area of ery thema overlying the neuromodulation lead from percutaneous entrance to exit site. the initial differential diagnosis included infection versus inf lammatory response. due to concern for infection, the device was promptly removed, at which time no purulence was noted along the course of the device components. subsequent patch allergy testing revealed a strong reaction to vanadium, which is often used in titanium alloy, an external component of the interstim implant. both newer generation medtronic and axonics devices contain this titanium alloy; therefore, because of allergic intolerance to all available sacral neuromodulation devices, the patient’s urinary symptoms were subsequently managed with percutaneous tibial nerve stimulation. while there are documented cases of adverse events after sacral neuromodulation including device migration[1,2], device infection[3], and gluteal hematoma[4], to our knowledge there are no cases in the literature describing a hypersensitivity to sacral neuromodulation devices. the american contact dermatitis society does not recommend preoperative hypersensitivity evaluation for patients undergoing hardware implantation but does recommend a risk-benefit analysis when considering device re-implantation in patients who demonstrate hypersensitivity to a metal implant[5]. http://siuj.org mailto:kendall.vignaroli%40wsu.edu?subject=siuj references 1. karapanos l, chon sh, kokx r, schmautz m, heidenreich a. a rare case of tined lead migration of interstim device into the rectum with subsequent novel combined surgical-endoscopic removal technique. turk j urol.2020 nov;46(6):492–495. doi: 10.5152/tud.2020.20320 2. guzman-negron jm, derisavifard s, goldman hb. sacral neuromodulation lead twisting causes migration and loss of efficacy. female pelvic med reconstr surg.2020 mar;26(3):e13–e15. doi: 10.1097/spv.0000000000000818 3. lai hh, grewal s. bacterial colonization rate of interstim and infection outcome with staged testing. urology.2013 dec;82(6):1255–1260. doi: 10.1016/j.urology.2013.08.034 4. kalyanar aman b, mahd y a . e x tensive gluteal hematoma following interstim implant: a case report. int urogynecol j.2012 dec;23(12):1805–1807. doi: 10.1007/s00192-012-1791-2 5. schalock pc, crawford g, nedorost s, scheinman pl, atwater ar, mowad c, et al. patching testing for evaluation of hypersensitivity to implanted metal devices: a perspective from the american contact dermatitis society. dermatitis.2016 sep-oct;27(5):241–247. doi: 10.1097/der.0000000000000210 45siuj.org siuj • volume 3, number 1 • january 2022 a rare case of hypersensitivity reaction associated with sacral neuromodulation hardware http://siuj.org 189siuj.org siuj • volume 2, number 4 • july 2021 volume 2, number 4 | july 2021 issn 2563-6499 doi: 10.48083/asds5361 editorial office info@siuj.org tel: 514-875-5665 ext. 26 siuj.org managing editor jane fairbanks jane.fairbanks@siu-urology.org the siuj is published 6 times a year by the société internationale d'urologie (siu). it is the official peer-reviewed publication of the siu but retains editorial independence. the siuj is circulated to urologists, urology residents, family medicine specialists, family medicine residents, general practitioners, nurses, medical libraries, and hospital and university departments of urology worldwide, for a total circulation of over 10,000. this publication was developed under the direction of the siuj editorial board. the siuj is published under an exclusive licence. the siuj is owned and published by the société internationale d’urologie (siu). marketing lillian petrusa lillian.petrusa@siu-urology.org advertising gerri-lynn sendyk advertising@siuj.org neither the siu nor the siuj endorses any service or the contents of any product referred to in any advertisement in the siuj. the siu and the siuj assume no responsibility or liability for damages arising from any error or omission, or from the use of any information or advice contained in the siuj. all editorial matter in siuj represents the opinions of the authors and not necessarily those of the siu or the siuj. all canadian prescription drug advertisements have been cleared by the pharmaceutical advertising advisory board. editorial board editor-in-chief peter c. black, md, canada associate editors thomas herrmann, md, switzerland kathleen kobashi, md, united states philippe spiess, md, united states henry woo, mbbs, australia social media editor jeremy y. c. teoh, mbbs, hong kong sar statistical editor alice dragomir, phd, canada icud editor luc valiquette, md, canada innovators editor amanda chung, mbbs, australia regional editors north america margarett shnorhavorian, md united states middle east danny rabah, mbbs saudi arabia south america sandro esteves, md brazil east asia tianxin lin, md china eastern europe roman sosnowski, md poland south asia sanjay sinha, mch india western europe tamsin greenwell, md united kingdom southeast asia edmund chiong, mbbs singapore africa yasser osman, mbbch egyptvisit bms.com to see how we’re bringing a human touch to everything we do. © 2021 bristol-myers squibb company. all rights reserved. noca21mm00001-01 02/21 we are in the business of breakthroughs—the kind that transform patients’ lives. dedicated to our mission of discovering, developing and delivering life-saving innovations that help patients prevail over serious diseases, we’ll never give up our search for more hope, for more people, around the world. http://www.siuj.org mailto:info%40siuj.org?subject=siuj http://siuj.org mailto:jane.fairbanks%40siu-urology.org?subject=siuj mailto:lillian.petrusa%40siu-urology.org%20?subject=siuj mailto:advertising%40siuj.org?subject=siuj http://bms.com 190 siuj • volume 2, number 4 • july 2021 siuj.org editorial board liaqat ali, mbbs pakistan abdol mohammad kajbafzadeh, md iran fahad alyami, mbbs saudi arabia wayne lam, mbbs hong kong sar mohsen azli, md algeria sang dong lee, md korea erdem canda, md turkey evelyn moshokoa, mbchb south africa yao-chi chuang, md taiwan dedan opondo, mbchb kenya archil chkhotua, md georgia mohammed shahait, mbbs jordan renu eapen, mbbs australia khurram siddiqui, mbbs oman agus rizal ardy hariandy hamid, md indonesia yaya sow, md senegal christopher ho chee kong, md malaysia chuan-liang xu, md china theocharis karaolides, md cyprus the société internationale d’urologie (siu). the society’s mission is to enable urologists in all nations, through international cooperation in education and research, to apply the highest standards of urological care to their patients. the siu is a major international platform for sustainable urological education and collaborative philanthropic activities aimed at improving urological care with more than 10,000 members from over 130 countries. siu central office 1155 robert-bourassa blvd., suite 1012 montreal, quebec, canada h3b 3a7 tel: +1 514 875-5665 fax: +1 514 875-0205 communications@siu-urology.org executive director susie petrusa susie.petrusa@siu-urology.org graphic design sam design info@studiosamdesign.com web design/ technical support aiki informatique info@aikitech.ca neither the siu nor the siuj endorses any service or the contents of any product referred to in any advertisement in the siuj. the siu and the siuj assume no responsibility or liability for damages arising from any error or omission, or from the use of any information or advice contained in the siuj. all editorial matter in siuj represents the opinions of the authors and not necessarily those of the siu or the siuj. all canadian prescription drug advertisements have been cleared by the pharmaceutical advertising advisory board. http://www.siuj.org mailto:communications%40siu-urology.org?subject=siuj mailto:susie.petrusa%40siu-urology.org?subject=siuj mailto:susie.petrusa%40siu-urology.org?subject=siuj mailto:info%40studiosamdesign.com%20?subject=siuj mailto:info%40studiosamdesign.com%20?subject=siuj mailto:info%40aikitech.ca?subject=siuj 49siuj.org siuj • volume 3, number 2 • march 2022 visit bms.com/ca to see how we’re bringing a human touch to everything we do. © 2022 bristol-myers squibb company. all rights reserved. no-ca-2200002 02/22 we are in the business of breakthroughs—the kind that transform patients’ lives. dedicated to our mission of discovering, developing and delivering life-saving innovations that help patients prevail over serious diseases, we’ll never give up our search for more hope, for more people, around the world. volume 3, number 2 | march 2022 issn 2563-6499 doi: 10.48083/ebym4017 editorial office info@siuj.org tel: 514-875-5665 ext. 26 siuj.org managing editor jane fairbanks jane.fairbanks@siu-urology.org the siuj is published 6 times a year by the société internationale d'urologie (siu). it is the official peer-reviewed publication of the siu but retains editorial independence. the siuj is circulated to urologists, urology residents, family medicine specialists, family medicine residents, general practitioners, nurses, medical libraries, and hospital and university departments of urology worldwide, for a total circulation of over 10,000. this publication was developed under the direction of the siuj editorial board. the siuj is published under an exclusive licence. the siuj is owned and published by the société internationale d’urologie (siu). marketing lillian petrusa lillian.petrusa@siu-urology.org advertising mikaela tierney advertising@siuj.org neither the siu nor the siuj endorses any service or the contents of any product referred to in any advertisement in the siuj. the siu and the siuj assume no responsibility or liability for damages arising from any error or omission, or from the use of any information or advice contained in the siuj. all editorial matter in siuj represents the opinions of the authors and not necessarily those of the siu or the siuj. all canadian prescription drug advertisements have been cleared by the pharmaceutical advertising advisory board. editorial board editor-in-chief peter c. black, md, canada associate editors thomas herrmann, md, switzerland kathleen kobashi, md, united states philippe spiess, md, united states henry woo, mbbs, australia social media editor jeremy y. c. teoh, mbbs, hong kong sar statistical editor alice dragomir, phd, canada icud editor luc valiquette, md, canada innovators editor amanda chung, mbbs, australia regional editors north america margarett shnorhavorian, md united states middle east danny rabah, mbbs saudi arabia south america sandro esteves, md brazil east asia tianxin lin, md china eastern europe roman sosnowski, md poland south asia sanjay sinha, mch india western europe tamsin greenwell, md united kingdom southeast asia edmund chiong, mbbs singapore africa yasser osman, mbbch egypt http://siuj.org http://bms.com/ca mailto:info%40siuj.org?subject=siuj http://siuj.org mailto:jane.fairbanks%40siu-urology.org?subject=siuj mailto:lillian.petrusa%40siu-urology.org%20?subject=siuj mailto:advertising%40siuj.org?subject=siuj 50 siuj • volume 3, number 2 • march 2022 siuj.org editorial board liaqat ali, mbbs pakistan abdol mohammad kajbafzadeh, md iran fahad alyami, mbbs saudi arabia wayne lam, mbbs hong kong sar mohsen azli, md algeria sang dong lee, md korea erdem canda, md turkey evelyn moshokoa, mbchb south africa yao-chi chuang, md taiwan dedan opondo, mbchb kenya archil chkhotua, md georgia mohammed shahait, mbbs jordan renu eapen, mbbs australia khurram siddiqui, mbbs oman agus rizal ardy hariandy hamid, md indonesia yaya sow, md senegal christopher ho chee kong, md malaysia chuan-liang xu, md china theocharis karaolides, md cyprus the société internationale d’urologie (siu). the society’s mission is to enable urologists in all nations, through international cooperation in education and research, to apply the highest standards of urological care to their patients. the siu is a major international platform for sustainable urological education and collaborative philanthropic activities aimed at improving urological care with more than 10,000 members from over 130 countries. siu central office 1155 robert-bourassa blvd., suite 1012 montreal, quebec, canada h3b 3a7 tel: +1 514 875-5665 fax: +1 514 875-0205 communications@siu-urology.org executive director susie petrusa susie.petrusa@siu-urology.org graphic design sam design info@studiosamdesign.com web design/ technical support aiki informatique info@aikitech.ca neither the siu nor the siuj endorses any service or the contents of any product referred to in any advertisement in the siuj. the siu and the siuj assume no responsibility or liability for damages arising from any error or omission, or from the use of any information or advice contained in the siuj. all editorial matter in siuj represents the opinions of the authors and not necessarily those of the siu or the siuj. all canadian prescription drug advertisements have been cleared by the pharmaceutical advertising advisory board. http://siuj.org mailto:communications%40siu-urology.org?subject=siuj mailto:susie.petrusa%40siu-urology.org?subject=siuj mailto:susie.petrusa%40siu-urology.org?subject=siuj mailto:info%40studiosamdesign.com%20?subject=siuj mailto:info%40studiosamdesign.com%20?subject=siuj mailto:info%40aikitech.ca?subject=siuj key words competing interests article information urethra, carcinoma, squamous cell, urinary retention, urethral stricture, penile neoplasms conflict of interest: none declared. patient consent: obtained. received on october 15, 2021 accepted on october 17, 2021 soc int urol j.2022;3(2):109–110 doi: 10.48083/bujm3438 figure 1. pelvic mri demonstrating 2 lesions in the perineum peri-urethral lesion with corpus spongiosum, left crus corpus cavernosum, and subcutaneous tissue involvement. lesion posterior to the prostate with invasion of the left ano-rectal junction. 109siuj.org siuj • volume 3, number 2 • march 2022 this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. clinical picture down the not so straight and narrow: a rare case of primary urethral squamous cell carcinomas in a young patient kevin yinkit zhuo,1,2 aditya sharma,1,2 chloe wilcox,1,2 cameron parkin,1,2 nicola jeffery,3 amanda chung1,2 1 department of urology, royal north shore hospital, sydney, australia 2 north shore urology research group, sydney, australia 3 department of urology, royal prince alfred hospital, sydney, australia primary urethral squamous cell carcinomas (sccs) are rare, with a variable clinical presentation, and occur infrequently in patients younger than 45 years of age [1–3]. the surgical management for advanced urethral sccs remains challenging, given it occurs in less than 1 in 100 000 men[1,4]. we describe the diagnosis and management of urethral scc in a 37-year-old male presenting with urinary retention. the patient initially presented to our emergency department with fevers, perineal pain on voiding, and high post-void residuals. his history included recurrent bulbar urethral strictures, utis, smoking, and intravenous drug use. his urethral stricture was previously endoscopically managed with dilatation, but the patient had been lost to follow-up. an initial pelvic ultrasound revealed a complex perineal mass inferior to the prostate and contiguous with the urethra. pelvic mri subsequently revealed 2 lesions in the perineum (figure 1). fdgpet-scan demonstrated avid lesions in the right inguinal and meso-rectal http://siuj.org mailto:k.zhuo2%40gmail.com?subject=siuj nodes with no distal metastatic disease. urine cytology suggested malignant cells suspicious for scc. on pelvic examination, 2 distinct masses were palpable in the bulbar urethra and rectum. cystoscopy demonstrated an obliterated urethra that could not be cannulated with a wire, thus a suprapubic catheter was placed. because of the severity of local symptoms, the patient was discussed in a multi-disciplinary team meeting and transferred to a specialist centre for pelvic exenteration. before adjuvant chemo-radiotherapy was begun, the patient was identified to have significant local disease recurrence and opted instead for palliative treatment. primary urethral sccs are a rare cause for advanced cancer in young men. this case exhibits the need for considering neoplasms as a differential diagnosis for young patients presenting with urinary retention and perineal pain. it also highlights the need for close follow-up of recurrent urethral stricture patients to ensure there are no complications of their disease. references 1. hakenberg ow, compérat e, minhas s, necchi a, protzel c, watkin n, et al. eau guidelines on penile cancer.2019. available at: http:// uroweb.org/guideline/penile-cancer/. accessed january 11, 2022. 2. ant werpen i, gstrein l, moskovszk y l, gissler hm, möltgen t, kwiatkowski m, et al. primar y urethral squamous cell carcinoma: a unique manifestation of a penile tumor. j int med res.2019 feb;47(2):999–1004. published online 2018 dec 5. doi: 10.1177/0300060518813506 3. castiglione f, alnajjar hm, christodoulidou m, albersen m, parnham a, freeman a, et al. primary squamous cell carcinoma of the male proximal urethra: outcomes from a single centre. eur urol focus.2021 jan;7(1):163-169. doi: 10.1016/j.euf.2019.02.016. epub 2019 mar 7. 4. janisch f, abufaraj m, fajkovic h, kimura s, iwata t, nyirady p, et al. current disease management of primary urethral carcinoma. eur urol focus.2019 sep;5(5):722–734. doi: 10.1016/j.euf.2019.07.001. epub 2019 jul 13. 110 siuj • volume 3, number 2 • march 2022 siuj.org clinical picture http://siuj.org 117siuj.org siuj • volume 3, number 3 • may 2022 visit bms.com/ca to see how we’re bringing a human touch to everything we do. © 2022 bristol-myers squibb company. all rights reserved. no-ca-2200002 02/22 we are in the business of breakthroughs—the kind that transform patients’ lives. dedicated to our mission of discovering, developing and delivering life-saving innovations that help patients prevail over serious diseases, we’ll never give up our search for more hope, for more people, around the world. volume 3, number 3 | may 2022 issn 2563-6499 doi: 10.48083/ebym4017 editorial office info@siuj.org tel: 514-875-5665 ext. 26 siuj.org managing editor jane fairbanks jane.fairbanks@siu-urology.org the siuj is published 6 times a year by the société internationale d'urologie (siu). it is the official peer-reviewed publication of the siu but retains editorial independence. the siuj is circulated to urologists, urology residents, family medicine specialists, family medicine residents, general practitioners, nurses, medical libraries, and hospital and university departments of urology worldwide, for a total circulation of over 10,000. this publication was developed under the direction of the siuj editorial board. the siuj is published under an exclusive licence. the siuj is owned and published by the société internationale d’urologie (siu). marketing lillian petrusa lillian.petrusa@siu-urology.org advertising mikaela tierney advertising@siuj.org neither the siu nor the siuj endorses any service or the contents of any product referred to in any advertisement in the siuj. the siu and the siuj assume no responsibility or liability for damages arising from any error or omission, or from the use of any information or advice contained in the siuj. all editorial matter in siuj represents the opinions of the authors and not necessarily those of the siu or the siuj. all canadian prescription drug advertisements have been cleared by the pharmaceutical advertising advisory board. editorial board editor-in-chief peter c. black, md, canada associate editors thomas herrmann, md, switzerland kathleen kobashi, md, united states philippe e. spiess, md, united states henry woo, mbbs, australia social media editor jeremy y. c. teoh, mbbs, hong kong sar statistical editor alice dragomir, phd, canada innovators editor amanda chung, mbbs, australia regional editors north america margarett shnorhavorian, md united states middle east danny rabah, mbbs saudi arabia south america sandro esteves, md brazil east asia tianxin lin, md china eastern europe roman sosnowski, md poland south asia sanjay sinha, mch india western europe tamsin greenwell, md united kingdom southeast asia edmund chiong, mbbs singapore africa yasser osman, mbbch egypt http://siuj.org http://bms.com/ca mailto:info%40siuj.org?subject=siuj http://siuj.org mailto:jane.fairbanks%40siu-urology.org?subject=siuj mailto:lillian.petrusa%40siu-urology.org%20?subject=siuj mailto:advertising%40siuj.org?subject=siuj 118 siuj • volume 3, number 3 • may 2022 siuj.org editorial board liaqat ali, mbbs pakistan abdol mohammad kajbafzadeh, md iran fahad alyami, mbbs saudi arabia wayne lam, mbbs hong kong sar mohsen azli, md algeria sang dong lee, md korea erdem canda, md turkey evelyn moshokoa, mbchb south africa yao-chi chuang, md taiwan dedan opondo, mbchb kenya archil chkhotua, md georgia mohammed shahait, mbbs jordan renu eapen, mbbs australia khurram siddiqui, mbbs oman agus rizal ardy hariandy hamid, md indonesia yaya sow, md senegal christopher ho chee kong, md malaysia chuan-liang xu, md china theocharis karaolides, md cyprus the société internationale d’urologie (siu). the society’s mission is to enable urologists in all nations, through international cooperation in education and research, to apply the highest standards of urological care to their patients. the siu is a major international platform for sustainable urological education and collaborative philanthropic activities aimed at improving urological care with more than 10,000 members from over 130 countries. siu central office 1155 robert-bourassa blvd., suite 1012 montreal, quebec, canada h3b 3a7 tel: +1 514 875-5665 fax: +1 514 875-0205 communications@siu-urology.org executive director susie petrusa susie.petrusa@siu-urology.org graphic design sam design info@studiosamdesign.com web design/ technical support aiki informatique info@aikitech.ca neither the siu nor the siuj endorses any service or the contents of any product referred to in any advertisement in the siuj. the siu and the siuj assume no responsibility or liability for damages arising from any error or omission, or from the use of any information or advice contained in the siuj. all editorial matter in siuj represents the opinions of the authors and not necessarily those of the siu or the siuj. all canadian prescription drug advertisements have been cleared by the pharmaceutical advertising advisory board. http://siuj.org mailto:communications%40siu-urology.org?subject=siuj mailto:susie.petrusa%40siu-urology.org?subject=siuj mailto:susie.petrusa%40siu-urology.org?subject=siuj mailto:info%40studiosamdesign.com%20?subject=siuj mailto:info%40studiosamdesign.com%20?subject=siuj mailto:info%40aikitech.ca?subject=siuj 1siuj.org siuj • volume 3, number 1 • january 2022 volume 3, number 1 | january 2022 issn 2563-6499 doi: 10.48083/ebym4017 editorial office info@siuj.org tel: 514-875-5665 ext. 26 siuj.org managing editor jane fairbanks jane.fairbanks@siu-urology.org the siuj is published 6 times a year by the société internationale d'urologie (siu). it is the official peer-reviewed publication of the siu but retains editorial independence. the siuj is circulated to urologists, urology residents, family medicine specialists, family medicine residents, general practitioners, nurses, medical libraries, and hospital and university departments of urology worldwide, for a total circulation of over 10,000. this publication was developed under the direction of the siuj editorial board. the siuj is published under an exclusive licence. the siuj is owned and published by the société internationale d’urologie (siu). marketing lillian petrusa lillian.petrusa@siu-urology.org advertising gerri-lynn sendyk advertising@siuj.org neither the siu nor the siuj endorses any service or the contents of any product referred to in any advertisement in the siuj. the siu and the siuj assume no responsibility or liability for damages arising from any error or omission, or from the use of any information or advice contained in the siuj. all editorial matter in siuj represents the opinions of the authors and not necessarily those of the siu or the siuj. all canadian prescription drug advertisements have been cleared by the pharmaceutical advertising advisory board. editorial board editor-in-chief peter c. black, md, canada associate editors thomas herrmann, md, switzerland kathleen kobashi, md, united states philippe spiess, md, united states henry woo, mbbs, australia social media editor jeremy y. c. teoh, mbbs, hong kong sar statistical editor alice dragomir, phd, canada icud editor luc valiquette, md, canada innovators editor amanda chung, mbbs, australia regional editors north america margarett shnorhavorian, md united states middle east danny rabah, mbbs saudi arabia south america sandro esteves, md brazil east asia tianxin lin, md china eastern europe roman sosnowski, md poland south asia sanjay sinha, mch india western europe tamsin greenwell, md united kingdom southeast asia edmund chiong, mbbs singapore africa yasser osman, mbbch egyptvisit bms.com to see how we’re bringing a human touch to everything we do. © 2021 bristol-myers squibb company. all rights reserved. noca21mm00001-01 02/21 we are in the business of breakthroughs—the kind that transform patients’ lives. dedicated to our mission of discovering, developing and delivering life-saving innovations that help patients prevail over serious diseases, we’ll never give up our search for more hope, for more people, around the world. http://siuj.org mailto:info%40siuj.org?subject=siuj http://siuj.org mailto:jane.fairbanks%40siu-urology.org?subject=siuj mailto:lillian.petrusa%40siu-urology.org%20?subject=siuj mailto:advertising%40siuj.org?subject=siuj http://bms.com 2 siuj • volume 3, number 1 • january 2022 siuj.org editorial board liaqat ali, mbbs pakistan abdol mohammad kajbafzadeh, md iran fahad alyami, mbbs saudi arabia wayne lam, mbbs hong kong sar mohsen azli, md algeria sang dong lee, md korea erdem canda, md turkey evelyn moshokoa, mbchb south africa yao-chi chuang, md taiwan dedan opondo, mbchb kenya archil chkhotua, md georgia mohammed shahait, mbbs jordan renu eapen, mbbs australia khurram siddiqui, mbbs oman agus rizal ardy hariandy hamid, md indonesia yaya sow, md senegal christopher ho chee kong, md malaysia chuan-liang xu, md china theocharis karaolides, md cyprus the société internationale d’urologie (siu). the society’s mission is to enable urologists in all nations, through international cooperation in education and research, to apply the highest standards of urological care to their patients. the siu is a major international platform for sustainable urological education and collaborative philanthropic activities aimed at improving urological care with more than 10,000 members from over 130 countries. siu central office 1155 robert-bourassa blvd., suite 1012 montreal, quebec, canada h3b 3a7 tel: +1 514 875-5665 fax: +1 514 875-0205 communications@siu-urology.org executive director susie petrusa susie.petrusa@siu-urology.org graphic design sam design info@studiosamdesign.com web design/ technical support aiki informatique info@aikitech.ca neither the siu nor the siuj endorses any service or the contents of any product referred to in any advertisement in the siuj. the siu and the siuj assume no responsibility or liability for damages arising from any error or omission, or from the use of any information or advice contained in the siuj. all editorial matter in siuj represents the opinions of the authors and not necessarily those of the siu or the siuj. all canadian prescription drug advertisements have been cleared by the pharmaceutical advertising advisory board. http://siuj.org mailto:communications%40siu-urology.org?subject=siuj mailto:susie.petrusa%40siu-urology.org?subject=siuj mailto:susie.petrusa%40siu-urology.org?subject=siuj mailto:info%40studiosamdesign.com%20?subject=siuj mailto:info%40studiosamdesign.com%20?subject=siuj mailto:info%40aikitech.ca?subject=siuj 267siuj.org siuj • volume 2, number 5 • september 2021 volume 2, number 5 | september 2021 issn 2563-6499 doi: 10.48083/ebym4017 editorial office info@siuj.org tel: 514-875-5665 ext. 26 siuj.org managing editor jane fairbanks jane.fairbanks@siu-urology.org the siuj is published 6 times a year by the société internationale d'urologie (siu). it is the official peer-reviewed publication of the siu but retains editorial independence. the siuj is circulated to urologists, urology residents, family medicine specialists, family medicine residents, general practitioners, nurses, medical libraries, and hospital and university departments of urology worldwide, for a total circulation of over 10,000. this publication was developed under the direction of the siuj editorial board. the siuj is published under an exclusive licence. the siuj is owned and published by the société internationale d’urologie (siu). marketing lillian petrusa lillian.petrusa@siu-urology.org advertising gerri-lynn sendyk advertising@siuj.org neither the siu nor the siuj endorses any service or the contents of any product referred to in any advertisement in the siuj. the siu and the siuj assume no responsibility or liability for damages arising from any error or omission, or from the use of any information or advice contained in the siuj. all editorial matter in siuj represents the opinions of the authors and not necessarily those of the siu or the siuj. all canadian prescription drug advertisements have been cleared by the pharmaceutical advertising advisory board. editorial board editor-in-chief peter c. black, md, canada associate editors thomas herrmann, md, switzerland kathleen kobashi, md, united states philippe spiess, md, united states henry woo, mbbs, australia social media editor jeremy y. c. teoh, mbbs, hong kong sar statistical editor alice dragomir, phd, canada icud editor luc valiquette, md, canada innovators editor amanda chung, mbbs, australia regional editors north america margarett shnorhavorian, md united states middle east danny rabah, mbbs saudi arabia south america sandro esteves, md brazil east asia tianxin lin, md china eastern europe roman sosnowski, md poland south asia sanjay sinha, mch india western europe tamsin greenwell, md united kingdom southeast asia edmund chiong, mbbs singapore africa yasser osman, mbbch egyptvisit bms.com to see how we’re bringing a human touch to everything we do. © 2021 bristol-myers squibb company. all rights reserved. noca21mm00001-01 02/21 we are in the business of breakthroughs—the kind that transform patients’ lives. dedicated to our mission of discovering, developing and delivering life-saving innovations that help patients prevail over serious diseases, we’ll never give up our search for more hope, for more people, around the world. http://siuj.org mailto:info%40siuj.org?subject=siuj http://siuj.org mailto:jane.fairbanks%40siu-urology.org?subject=siuj mailto:lillian.petrusa%40siu-urology.org%20?subject=siuj mailto:advertising%40siuj.org?subject=siuj http://bms.com 268 siuj • volume 2, number 5 • september 2021 siuj.org editorial board liaqat ali, mbbs pakistan abdol mohammad kajbafzadeh, md iran fahad alyami, mbbs saudi arabia wayne lam, mbbs hong kong sar mohsen azli, md algeria sang dong lee, md korea erdem canda, md turkey evelyn moshokoa, mbchb south africa yao-chi chuang, md taiwan dedan opondo, mbchb kenya archil chkhotua, md georgia mohammed shahait, mbbs jordan renu eapen, mbbs australia khurram siddiqui, mbbs oman agus rizal ardy hariandy hamid, md indonesia yaya sow, md senegal christopher ho chee kong, md malaysia chuan-liang xu, md china theocharis karaolides, md cyprus the société internationale d’urologie (siu). the society’s mission is to enable urologists in all nations, through international cooperation in education and research, to apply the highest standards of urological care to their patients. the siu is a major international platform for sustainable urological education and collaborative philanthropic activities aimed at improving urological care with more than 10,000 members from over 130 countries. siu central office 1155 robert-bourassa blvd., suite 1012 montreal, quebec, canada h3b 3a7 tel: +1 514 875-5665 fax: +1 514 875-0205 communications@siu-urology.org executive director susie petrusa susie.petrusa@siu-urology.org graphic design sam design info@studiosamdesign.com web design/ technical support aiki informatique info@aikitech.ca neither the siu nor the siuj endorses any service or the contents of any product referred to in any advertisement in the siuj. the siu and the siuj assume no responsibility or liability for damages arising from any error or omission, or from the use of any information or advice contained in the siuj. all editorial matter in siuj represents the opinions of the authors and not necessarily those of the siu or the siuj. all canadian prescription drug advertisements have been cleared by the pharmaceutical advertising advisory board. http://siuj.org mailto:communications%40siu-urology.org?subject=siuj mailto:susie.petrusa%40siu-urology.org?subject=siuj mailto:susie.petrusa%40siu-urology.org?subject=siuj mailto:info%40studiosamdesign.com%20?subject=siuj mailto:info%40studiosamdesign.com%20?subject=siuj mailto:info%40aikitech.ca?subject=siuj this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information robot-assisted surgery, laparoscopy, robotics, urology none declared. received on october 6, 2020 accepted on june 1, 2021 soc int urol j.2021;2(5):300–310 doi: 10.48083/ewwq2677 300 siuj • volume 2, number 5 • september 2021 siuj.org review a scoping review of emerging and established surgical robotic platforms with applications in urologic surgery braden millan,1 shavy nagpal,1 maylynn ding,1 jason y. lee,2 anil kapoor1 1 urologic cancer centre for research and innovation (uccri), mcmaster university, hamilton, canada 2 department of surgery, division of urology, university of toronto, canada abstract objectives since the introduction of the first master–slave robotic platform for surgical procedures, there have been ongoing modifications and development of new platforms, but there is still a paucity of commercially available systems. our study aims to identify all master–slave robotic surgical platforms currently commercially available or in development around the world with applications in urologic surgery. methods a scoping literature search was performed using prisma methodology to identify all relevant publications in english in pubmed, pubmed central, and embase, with additional information being obtained from official company websites. results ten robotic platforms with either proven or potential application in urologic surgery were identified: the da vinci surgical system (intuitive), senhance surgical system (transentrix), versius surgical (cmr ltd), enos surgical system (titan medical), revo –i (meere company), mirosurge (dlr), avatera system (avatera medical), hugo surgical robot (medtronic), ottava (j&j, ethicon, areus), and hinotori (medicaroid corporation). conclusions this review highlights the distinct features of emerging master–slave robotic platforms with applications in urologic surgery. research and development are now focused on finding wider applications, improving outcomes, increasing availability, and reducing cost. additional research is required comparing newly developed master–slave robotic platforms with those already well established. http://siuj.org mailto:akapoor%40mcmaster.ca?subject=siuj introduction the f ield of urolog y has played a major role in t he adva ncement of su rg ic a l robot ic s, d at i ng back to the mona robot, the prototy pe of the modern day da  vinci surgical robot[1]. the most advanced surgical robotic platforms currently are the ‘‘master–slave systems’’ in which the surgeon controls robotic arms remotely from a console. in a dry laboratory setting, choussein and colleagues were able to demonstrate that robot-assisted laparoscopy nearly eliminated operative handedness, which persists in conventional laparoscopy[2]. robotic platforms can be categorized by some of their key features, and there are many similarities amongst them. one major distinction is the open versus the closed robotic platform console. in an open console, there is no ability for the operator to fix his or her head in position; instead, the head can be moved freely during the procedure. these alterations in the field of view from the display during an operation can result in errors and decreased efficiency[3]. a development in newer generations of robotic platforms is the addition of haptic feedback from the robot for the operating physician. abiri and colleagues tested a multi-modal system for haptic force feedback in robotic surgery that results in nearly a 50% force reduction in comparison to a system with no haptic feedback[4]. laparoendoscopic single-site surgery (less) is another feature of surgical robotic platforms that is an advancement from original laparoscopy. one disadvantage of less is the challenge of instruments interfering with one another, although early success has been reported[5–7]. no head-to-head comparison of any robotic platforms from different companies exists in the urologic literature. this paper provides a scoping review on established and emerging master–slave robotic platforms in urologic surgery. methods in the absence of a clear population, intervention, comparison, and outcome research question, we elected to perform a systematic scoping review of the currently available literature on this topic[8]. the goal of this article is not to compare surgical or oncologic outcomes of procedures performed with the different robotic platforms, but to highlight the emerging technologies in robotic platforms. three databases were searched for articles published in english. pubmed and pubmed central (n = 3644) were searched using the following terms: "robotic surgica l procedures," “robotics,” "urology," "urology department, hospital," “urologic surgical procedures,” “urologic surgical procedures, male.” embase (n  =  3252) was searched using the following terms: “robot,” “robotics,” “robotic surgical procedures,” “robot assisted surgery,” “urology,” “child urology,” “urologic surgery.” additional records were identified through screening the citations of selected texts (n  = 20; figure 1). additional information was obtained by searching through google.com (google inc, mountain view, united states) and official company websites (n  =  9). all case reports, case series, cohort studies, and randomized controlled trials written in english were included. articles were excluded if they were abstracts, editorials, expert opinions, or review articles, if they did not report the surgical platform used, or if the platform has been discontinued. preferred reporting items for systematic reviews and metaanalyses (prisma) guidelines were used to ensure reproducibility of our scoping review[9]. results after initial screening of titles, 57 articles underwent final review, and 41 articles were included in the final paper (figure 1)[10]. a total of 10 master–slave surgical robots were identified through our scoping systematic review. for each surgical platform we sought to provide information regarding the current company with proprietary rights to the device, whether or not it had regulatory approval, the main features of the robotic platform, and a review of any pre-clinical or clinical data (table 1). a summary of the major features of each system is shown in table 2. da vinci surgical system the da  vinci surgica l system is a master–slave laparoscopic robotic platform, designed and owned by intuitive surgica l (sunny va le, united states) (figure 2). it has played a crucial role in enhancing minimally invasive surgery and was food and drug administration (fda) approved in the year 1998, originally for laparoscopic cholecystectomies, and received the conformitè europëenne (ce) mark in 2017. one of its early competitors, zeus (computer motion), was discontinued following the company’s merger with intuitive surgical in 2003. iterations of the da  vinci have been in use for over 2 decades, and its applications include general, cardiac, colorectal, otolaryngology, neurosurgery, thoracic, g ynecologic and urologic surgery. its features include a 3-dimensional (3-d) highdefinition (hd) camera with a binocular view, and 301siuj.org siuj • volume 2, number 5 • september 2021 a scoping review of emerging and established surgical robotic platforms with applications in urologic surgery abbreviations dof degrees of freedom hd high definition less laparoendoscopic single-site surgery mis minimally invasive surgery n/a not available records identified from: databases (n = 6896) pubmed/central (n = 3644) embase (n = 3252) records removed before screening: duplicate records (n = 874) editorials (n = 189) reply by authors (n = 200) this month in... (n = 16) reports sought for retrieval (n = 64) reports assessed for eligibility (n = 57) records screened (n = 5617) records excluded (n = 5553) identification of studies via databases and registers id en tif ic at io n sc re en in g in cl ud ed reports excluded: did not report robotic platform used (n = 4) language other than english (n = 1) not master–slave robotic platform (n =1) did not meet inclusion/exclusion criteria (n = 10) studies included in review (n = 41) records screened (n = 5617) figure 1. prisma flow diagram[10] 302 siuj • volume 2, number 5 • september 2021 siuj.org review table 1. emerging and currently available master–slave robotic platforms with applications in urologic surgery company intuitive surgical transenterix cmr surgical titan medical meere company robotic platform da vinci (si, x, xi, and sp) senhance versius enos** revo i headquarters united states united states united kingdom canada republic of korea approach laparoscopic, less laparoscopic laparoscopic less laparaoscopic advertised application urology, gynecology, general surgery, & otolaryngology urology, gynecology, general, colorectal & limited cardiothoracic surgery urology, gynecology, colorectal & upper gi urology, general surgery urology, gynecology & general surgery status commercially available commercially available commercially available under development commercially available regulatory approval fda approved (1998) european ce mark (2017) fda approved (2017) european ce mark (2016) european ce mark (2019) tga approval (2020) not approved korean ministry for drug and food safety (2019) maximum number of robotic arms 4 4 5 1 4 degrees of freedom 7 6 7 6 12 console seated, closed seated, open seated/standing, open (3d glasses) seated, open seated, open camera hd – 3d hd – 3d hd – 3d hd – 3d hd – 3d haptic feedback no yes yes no yes less: laparoendoscopic single site surgery; gi: gastrointestinal; n/a :not available; hd-3d: high definition three dimensional; fda: us food and drug administration; tga: therapeutic goods administration (australia); ce: conformitè europëenne; * previously the verb and auris robotic platform; **rebranded from the single port orifice robotic technology (sport) surgical system continued on page 303 303siuj.org siuj • volume 2, number 5 • september 2021 a scoping review of emerging and established surgical robotic platforms with applications in urologic surgery table 1. emerging and currently available master–slave robotic platforms with applications in urologic surgery, cont’d company robotics and mechatronics center at german aerospace center (dlr) avatera medical medtronic johnson & johnson/ ethicon/ verily medicaroid corporation (kawasaki/ sysmex) robotic platform dlr mirosurg avatera hugo ottava* hinotori headquarters germany germany ireland united states japan approach laparoscopic laparoscopic laparoscopic laparoscopic laparoscopic advertised application urology, general & thoracic surgery urology & gynecology urology, baratric, colorectal & thoracic surgery n/a urology status under development under development under development under development under development regulatory approval not approved european ce mark (2019) not approved not approved japanese ministry of health, labor & welfare (2020) maximum number of robotic arms 5 4 4 6 4 degrees of freedom 3 7 7 n/a 8 console seated, open (3d glasses) seated, closed seated, semi-open (3d glasses) n/a seated, semi-open (polarized glasses) camera hd – 3d hd – 3d hd – 3d n/a hd 3d haptic feedback yes yes n/a n/a n/a less: laparoendoscopic single site surgery; gi: gastrointestinal; n/a :not available; hd-3d: high definition three dimensional; fda: us food and drug administration; tga: therapeutic goods administration (australia); ce: conformitè europëenne; * previously the verb and auris robotic platform; **rebranded from the single port orifice robotic technology (sport) surgical system 304 siuj • volume 2, number 5 • september 2021 siuj.org review up to 3 instrument arms, which articulate at the wrist of the instrument with 7 degrees of freedom (dof). there several available series, including the da vinci s, si, x, xi, and sp (single port), with the newest versions having haptic feedback for the operator. although modifications are aimed at improvement in currently available technology, reports suggest that changing from one model to another still poses some challenges for the surgeons[11]. however, certain models may be better suited for certain procedures, for example, the xi resulted in a 48 minute shorter operative time for nephroureterectomies[12]. intuitive has also made advances in the field of less, where in addition to the sp platform, they have developed software to allow for same-sided hand–eye control of the instruments that enables the surgeon’s right hand to control the screen right instrument even though the instrument is in the left robotic arm and vice versa[13]. less using the da vinci sp system allows a smaller incision with superior cosmesis and non-inferior oncologic and surgical outcomes, although there appears to be a great learning curve[6,7,14–17]. additionally, side docking for urologic procedures has been made possible with the da  vinci s and si systems, allowing better access to the perineum and the urethra throughout the procedure[18]. successful use of the da vinci has been reported for surgeries including radical prostatectomy, simple enucleation of the prostate, radical cystectomy w it h int ra or ex t ra-cor porea l i lea l conduit or neobladder, radical and simple nephrectomy, live donor nephrectomy, pyeloplasty, adrenalectomy, sural nerve grafting, vaso-vasostomy, ureteral reimplant, and renal transplantation[14,19–25]. in addition to surgery on adults, da vinci has also been successfully used in pediatrics using 5mm instruments as well as a less approach with no conversion to open procedure and with high success rates[26,27]. there are few direct comparisons of the costs of robot-assisted laparoscopy in urologic surgery, although previous reports dating back nearly a decade suggested use of the da  vinci surgical platform was more expensive secondary to capital cost, maintenance of the robot, and limited life of the instruments[28]. intuitive surgical has grown its da vinci surgical system installed base to 6142 systems as of march 31, 2021, an increase of 8% compared with 5669 as of the end of the first quarter of 2020, continuing its near monopoly on the field of master–slave surgical platforms globally. table 2. summary of major features of identified master–slave robotic platforms feature degrees of freedom 6 enos 7 da vinci, senhance, avatera, hugo, versius, mirosurge 8 hinotori 12 revo-i approach laparoscopic senhance, avatera, hugo, revo i, versius, mirosurge, hinotori less enos both da vinci console closed davinci, avatera, revo-i open senhance, enos, microsurge semi-open hugo, hinotori semi-closed medicaroid seated/standing-open versius haptic feedback yes da vinci, senhance, avatera, revo-i, versius, mirosurge no enos n/a hugo, hinotori less: laparoendoscopic single site surgery; n/a: not available; ottava excluded as details of system unknown figure 2. da vinci surgical system (credit: intuitive surgical) 305siuj.org siuj • volume 2, number 5 • september 2021 a scoping review of emerging and established surgical robotic platforms with applications in urologic surgery senhance surgical system the senhance surgical system is a master–slave robotic platform designed by transenterix (figure 3). it was renamed from the alf – x in 2016, developed by sofar spa (milan, italy), which was used to perform its first clinical cases in 2015[29,30]. this system and the da vinci by intuitive are the 2 master–slave robotic platforms that have both a ce mark (2014) and fda approval (2017)[31]. its features include a seated-open concept control centre with haptic handles, a 2-d or 3-d hd monitor, depending on surgeon preference, an infrared eye-tracking system, a keyboard and touch pad, a single pedal, up to 4 detached and independent robotic arms, and reusable 5mm endoscopic instruments[32,33]. the major benefit of the open structure is reduced cost, as it allows for use of conventional laparoscopic equipment and operating t heaters. criticisms include a larger size, restricting space in the operating room, and longer time to dock the robotic arms[30]. plans for the senhance surgical system include a “machine vision system,” a form of augmented intelligence whereby the system moves the camera on the basis of prior procedures and the movements of the surgeon’s instruments. initial report of the first 40 extra-peritoneal radical prostatectomies performed by kaštelan et al. showed higher than expected length of hospital stay and indwelling catheter time; however, this was thought to be related to the learning curve of using a new platform[34]. samalavicius and colleagues performed 31 radical prostatectomies using senhance, with few complications and no conversion to open procedures[35]. a subsequent case series reported decreases in positive surgical margin rate and lower rates of postoperative incontinence in patients undergoing radical prostatectomy, and expanded the application of the senhance robotic platform to adrenalectomies, nephrectomy, kidney cyst fenestration, and pyeloplasty with success[36]. the aforementioned developments and clinical data showing the success of the senhance platform will make it a strong competitor in the field of master–slave surgical robots. versius surgical robotic system the versius system is a master–slave surgical platform developed by cambridge medical robotics limited (cmr ltd) surgical in the united kingdom (figure 4). it received the ce mark in 2019 and therapeutic goods administration (australia) approval in 2020. the platform is ergonomic, with an open console that enables both sitting and standing for the operator, with hd-3d visual aid. the surgeon can use up to 5 lightweight robotic arms, each as a solitary robotic unit for greater freedom of port placement. v-wrist technology allows 360-degree wrist motion, 7 dof, with haptic feedback[37]. although not performed with the final product, pre-clinical trials using versius were completed, with a total of 24 surgeries performed (radical nephrectomy, radical prostatectomy, and pelvic lymph node dissection), with no device or non-device intraoperative complications[38]. human clinical trials using the platform have been limited to gynecologic and general surgery procedures[39]. enos surgical system the enos surgical system, rebranded in 2020 from the single-port orifice robotic technology (sport) surgical system is master–slave robotic platform created by the canadian company, titan medical (toronto, canada). enos does not have fda approval or ce mark to date. the surgeon workstation is a seated-open design, with 3d-hd visualization. it has a single-arm mobile patient cart to allow for less, and a multi-articulating endoscope and instruments that provide 6 dof. in 2018, seeliger and colleagues showed promising feasibility and operator improvement with the sport platform by figure 3. senhance surgical system (credit: asensus surgical, transenterix) figure 4. versius surgical robotic system (credit: cmr surgical) 306 siuj • volume 2, number 5 • september 2021 siuj.org review completing 12 minimally invasive procedures in porcine and human cadaveric pre-clinical trial procedures[5]. there are currently no pre-clinical or clinical data specifically on the enos platform since it was rebranded. revo-i model msr-5000 meere company incorporated, a korean company, began development on the revo-i model msr-5000, a master–slave robotic surgical platform, in 2006. the revo-i model msr-5000 received approval for commercial use from the korean government in august 2017, but it has not received fda or ce mark to date. the revo-i model msr-5000 (figure 5) consists of a seated-closed surgeon control console, a 4-arm robotic operation cart, a 3d-hd vision cart, and reusable endoscopic instruments[40,41]. previous models of the robotic platform had a seated-open surgical console[42]. the revo-i model msr-5000 robotic instruments also offer the greatest f lexibility with 12 dof compared with the 7 dof built into its contemporaries. chang and colleagues successfully completed 17 retziussparing robotic prostatectomy using the revo-i model msr-5000 with no conversion to open or laparoscopic procedures or systems failures. one major limitation of this study, however, was that no pelvic lymph node dissections were performed for fear of intraoperative pelvic vessel injury[41]. despite these successes, there has not been widespread use of the revo-i model msr5000 outside korea. mirosurge the dlr (deutsches zentrum für luftund raumfahrt e.v) telesurgery mirosurge is a master–slave robotic platform made by german aerospace center. it currently does not have any regulatory body approval. the dlr mirosurge (figure 6) is a modular system that combines several robotic components, including 3 robot arms (dlr miro) and at least 2 instruments (dlr mica). it offers a seated-open console with a 3-d hd video display, with instruments with 3 dof and haptic feedback. one of the arms guides the laparoscopic view while the video screen updates the status of currently used instruments and prevents collision of instruments via force feedback[43]. no current pre-clinical or clinical data are available; the last publication was in 2011. figure 6. mirosurge (credit: mirosurge, german aerospace center) figure 5. revo-i model msr-5000 (credit: revo-i, robotic surgical system (meerecompany) 307siuj.org siuj • volume 2, number 5 • september 2021 a scoping review of emerging and established surgical robotic platforms with applications in urologic surgery avatera system the avatera system (figure 7) is a master–slave robotic platform which has been in development since 2011 as a joint venture between avateramedical (jena, germany) and force dimension (nyon, switzerland). it received european ce mark approval in 2019. it offers a seatedclosed console, with 4 robotic arms mounted on a single cart, forceps-like handles with haptic feedback, singleuse 5mm instruments with 7 dof, and an hd-3d camera. unique features include the absence of external fans, which decreases the noise level, and a space-saving compact design. no clinical data on the use of the avatera system have been published to date. hugo ras system the hugo ras system is a master–slave robotic platform created by medtronic, following the acquisition of german-based robotic system mirosurge as part of the acquisition of covidien in 2014. it does not currently have regulatory approval in europe. the surgeon console employs a seated, semi-open design, requiring 3-d glasses with hd visualization. each robotic arm is attached to an individualized cart, allowing robotic arms to be split up and used for different procedures, each with 7 dof. currently, no pre-clinical or clinical data are available. ottava ottava, previously the verb master–slave robotic platform, is in development, and is a joint venture by ethicon, johnson & johnson (j & j), and verily (a life sciences research organization within google, inc). in addition, in 2019, j & j acquired auris health who had developed the monarch platform for endoscopy. the platform does not have any regulatory body approval. initial reports suggest that there may be 6 robotic arms directly attached to the operating table, but there is no credible information about the robotic platform currently available and no identified pre-clinical or clinical data on the ottava platform. hinotori the hinotori master–slave surgical platform was developed through a joint venture begun in 2013 between 2 japanese companies, kawasaki heav y industries, ltd and sysmex company. the hinotori surgical system, which received japanese regulatory approval in august 2020, is advertised as an easy docking system, with 4 robotic arms attached to the cart, and instruments with 8 dof. the surgeon wears polarized glasses, using a semi-open console with a microscope-like ocular lens. although a simulation system is in development for use on this platform, no pre-clinical or clinical data have been published to date. conclusions we provide a scoping review of identified master– slave robotic surgical platforms with applications in urology. despite increasing use of these platforms in surgery, there is still a paucity of published literature comparing different robotic platforms, many of which are still awaiting regulatory approval. cost comparisons are currently not possible as many of these emerging platforms are not yet commercially available. further research with direct comparisons of robotic platforms will be necessary to assess clinical outcomes, surgeon preference, and economic and environmental sustainability. to 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review of emerging and established surgical robotic platforms with applications in urologic surgery 28. ahmed k, ibrahim a, wang tt, khan n, challacombe b, khan ms, et al. assessing the cost effectiveness of robotics in urological surgery a systematic review. bju int.2012;110(10):1544–1556. doi: 10.1111/j.1464-410x.2012.11015.x 29. bozzini g, gidaro s, taverna g. robot-assisted laparoscopic par tial nephrectomy with the alf-x robot on pig models. eur urol.2016;69(2):376–377. doi: 10.1016/j.eururo.2015.08.031 30. falavolti c, gidaro s, ruiz e, altobelli e, stark m, ravasio g, et al. experimental nephrectomies using a novel telesurgical system: (the telelap alf-x)-a pilot study. surg technol int.2014;25:37–41. 31. brodie a, vasdev n. the future of robotic surgery. ann r coll surg engl.2018;100(suppl 7):4–13. doi: 10.1308/rcsann.supp2.4 32. debeche-adams t, eubanks ws, de la fuente sg. early experience with the senhance(r)-laparoscopic/robotic platform in the us. j robot surg.2019;13(2):357–359. doi: 10.1007/s11701-018-0893-3 33. kaštelan ž, knežević n, hudolin t, kuliš t, penezić l, goluža e, et al. extraperitoneal radical prostatectomy with the senhance surgical system robotic platform. croat med j.2019;60(6):556–559. doi: 10.3325/cmj.2019.60.556 34. kastelan z, hudolin t, kulis t, penezic l, gidaro s, bakula m, et al. extraperitoneal radical prostatectomy with the senhance robotic platform: first 40 cases. eur urol.2020;78(6):932–934. doi: 10.1016/j. eururo.2020.07.012 35. samalavicius ne, janusonis v, siaulys r, jasenas m, deduchovas o, venckus r, et al. robotic surger y using senhance® robotic platform: single center experience with first 100 cases. j robot surg.2020;14(2):371–376. doi: 10.1007/s11701-019-01000-6 36. kastelan z, hudolin t, kulis t, knezevic n, penezic l, maric m, et al. upper urinary tract surgery and radical prostatectomy with senhance® robotic system: single center experience-first 100 cases. int j med robot.2021 aug;17(4):e2269. doi: 10.1002/rcs.2269 37. haig f, medeiros acb, chitty k, slack m. usability assessment of versius, a new robot-assisted surgical device for use in minimal access surgery. bmj surg interv health technol.2020;2:e000028. doi:10.1136/ bmjsit-2019-000028 38. thomas bc, slack m, hussain m, barber n, pradhan a, dinneen e, et al. preclinical evaluation of the versius surgical system, a new robot-assisted surgical device for use in minimal access renal and prostate surgery. eur urol focus.2021;7(2):444–452. doi: 10.1016/j. euf.2020.01.011 39. kelkar d, borse ma, godbole gp, kurlekar u, slack m. interim safety analysis of the first-in-human clinical trial of the versius surgical system, a new robot-assisted device for use in minimal access surgery. surg endosc.2020. doi: 10.1007/s00464-020-08014-4 40. kim dk, park dw, rha kh. robot-assisted partial nephrectomy with the revo-i robot platform in porcine models. eur urol.2016;69(3):541– 542. doi: 10.1016/j.eururo.2015.11.024 41. chang kd, abdel raheem a, choi yd, chung bh, rha kh. retziussparing robot-assisted radical prostatectomy using the revo-i robotic surgical system: surgical technique and results of the first human trial. bju int.2018;122(3):441–448. https://doi.org/10.1111/bju.14245 42. abdel raheem a, troya is, kim dk, kim sh, won pd, joon ps, et al. robot-assisted fallopian tube transection and anastomosis using the new revo-i robotic surgical system: feasibility in a chronic porcine model. bju int.2016;118(4):604–609. doi: 10.1111/bju.13517 43. hagn u, konietschke r, tobergte a, nickl m, jorg s, kubler b, et al. dlr mirosurge: a versatile system for research in endoscopic telesurgery. int j comput assist radiol surg.2010;5(2):183–193. doi: 10.1007/s11548-009-0372-4 310 siuj • volume 2, number 5 • september 2021 siuj.org review 5siuj.org siuj • volume 2, number 1 • january 2021 the société internationale d'urologie journal a global pandemic is not our only challenge in urology peter black, editor-in-chief  soc int urol j. 2021;2(1):5–6 rarely has the transition from one year to the next been so eagerly anticipated as when we said goodbye (and good riddance!) to 2020 and ushered in 2021. we all would like a return to our “old” lives as they were in 2019. the launch of global vaccination programs against the sars-cov-2 virus makes the light at the end of the tunnel clearly visible. covid-19, however, has not prevented us from addressing some important challenges in urology, including the issue of gender inequality, which is more prevalent in urology than in any other medical specialty. less than 10% of urologists in the us are women, compared with 50% of pediatricians and obstetriciangynecologists[1–3]. this number has increased over time, and the fact that approximately one third of applicants to the us and canadian urology residency matches are female indicates that these numbers are on the rise. the ultimate goal of gender equality is to develop a diverse urologic workforce that provides optimal patient care[4]. since approximately one half of medical students are female[5], there is no question that the most imperative objective is to attract more talented female medical students into urology training programs. this goes beyond simply overcoming misconceptions about urologists dealing strictly with prostates and the male genitalia. providing role models and mentorship for female medical students considering their career options is critical for enhancing female representation in urology. this is equally critical for inspiring young women in urology to seek academic and leadership positions. there have been some notable achievements of women in urology in 2020, each of which is linked to an outstanding role model in the field. the most prestigious awards for early career urologists in the us (the american urological association gold cystoscope award[6]) and in europe (the european association of urology crystal matula award) both went to remarkable women: stacy loeb and derya tilki, respectively. it is noteworthy that both have research and clinical expertise in prostate cancer, which emphasizes that women in urology should not be cornered into a focus on pediatric or female urology, as has often happened in the past. the gender gap in urologic oncology has been particularly stark, but this year two major awards of the society of urologic oncology in the us were given to women who are real trailblazers in the field: the huggins medal to eila skinner[7], and the young investigator award to angela smith[8]. these are just a handful of examples of women in urology being recognized for their outstanding achievements and contributions. they offer grounds for optimism that we are slowly overcoming some of the gender barriers. these signs of progress in addressing the gender gap in urology are all from north america and to a lesser degree europe. we know much less about the relative numbers of women in urology in the rest of the world, but it is likely the gender gap remains a much bigger issue, especially in lowand medium-income countries . for example, the organization women in surgery africa reports that 7% of practicing surgeons in the college of surgeons of east central and southern africa region are women. the siu is a global organization with global representation well beyond north america and europe. racial and ethnic diversity are the very fabric of the organization, but addressing gender disparity remains a challenge. the board of directors of the siu has recognized gender equality as a priority. two members of the current board are women, and the organization continues to work towards full representation. as we build our new journal, the siuj, we also need to be particularly cognizant of female representation. a glance across the editorial boards of leading urological journals around the world would suggest that we all need to be much better in this regard. are journal editorial boards the last bastion of the “old boys club” in urology? this question is posed not as a criticism of other journals, but as a call to action for us all to improve representation of women in the editorial process in urology. these are important leadership positions that shape our field. an effort to increase female representation now should lead to equality in the future. the core editorial group at siuj has made it a priority to tackle the gender gap. we are not necessarily experts in this mission, so missteps are likely—but we intend to be flexible and responsive, and we welcome input from all stakeholders. we are faced with the added challenge mailto:pblack%40mail.ubc.ca%20?subject=siuj 6 siuj • volume 2, number 1 • january 2021 siuj.org editorial of requiring global representation as a top priority for the siuj yet having few women in urology in many of the global urologic communities. this, however, can be viewed not as a limitation but as an opportunity. it allows the siuj to contribute to breaking down barriers. ultimately, we all aim for a global urology community in which gender equality is a given and not something we need to think about and promote. for now, however, there is a lot of work to be done. references 1. medscape physician compensation repor t 2015. available at: ht tps:// w w w.medsc ape.com /slideshow/compensation -2 015 overview-6006679. accessed december 18, 2020. 2. ilin j, langlois e, jalal s, khosa f. gender disparity within academic canadian urology. can urol assoc j. 2020 apr;14(4):106-110. doi: 10.5489/cuaj.6117. epub 2019 oct 28. 3. american urological association. the state of urology workforce and practice in the united states 2017. 2018. available at: https:// w w w.auanet.org/common/pdf/research/census/state-urologyworkforce-practice-us.pdf. accessed june 22, 2018. 4. meara jg, leather ajm, hagander l, alkire bc, alonso n, ameh ea, et al. global surgery 2030: evidence and solutions for achieving health, welfare, and economic development. lancet. 2015 aug 8;38 6 (9 9 9 3):5 69 624. pmid: 259 24 8 3 4 doi: 10.1016/s014 0 6736(15)60160-x. epub 2015 apr 26. 5. association of american medical colleges. more women than men are enrolled in medical school. ht tps://w w w.aamc.org / news-insights/more-women-men-are-enrolled-medical-school 6. the american urological association gold cystoscope award. 2021 award winners. available at: https://www.auanet.org/about-us/ aua-governance/awards/award-winners. accessed december 18, 2020. 7. society of urologic oncology inc. the huggins medal. available at: ht tps://suonet.org/awards/ huggins-medal.aspx. accessed december 18, 2020. 8. society of urologic oncology inc. the young investigator award. available at: https://suonet.org/awards/young-investigator-award. aspx. accessed december 18, 2020. 9. xepoleas md, munabi nco, auslander a, magee wp, yao ca. the experiences of female surgeons around the world: a scoping review. review hum resour health. 2020 oct 28;18(1):80. doi: 10.1186/ s12960-020-00526-3. pmid: 33115509 pmcid: pmc7594298 doi: 10.1186/s12960-020-00526-3 this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. 345siuj.org siuj • volume 2, number 6 • november 2021 urology around the world private practice in jordan zeid abughosh soc int urol j.2021;2(6):345–346 doi: https://doi:10.48083/ahop2343 “nothing prepares you for this!” this is what you will hear from every urologist working in the private sector in jordan. so, why am i here? when i finished my fellowship in canada in 2010, there were no jobs available at the university or in the public sector hospitals, so the only options for those beginning their careers were to go abroad and work in a foreign country or to try their luck with private practice. for those of you who do not know what private practice means in this system, i will explain. basically, you rent a space and become licensed to operate a urology clinic. then, since physicians are prohibited by law from advertising, word-of-mouth recommendations bring patients to you (they may refer themselves), and if you are lucky, other physicians will refer their patients to your care. you have the choice to admit your patients to any private hospital. patients pay a fee for service, which is often covered by their private insurance, but is sometimes paid out of pocket. after surgery, although there are hospitalists to take care of the patients, the surgeon is responsible for more than the usual follow-up care— including things like the insertion of a foley catheter at 2:00 a.m. on a weekend. if you are not available at all times, the emergency room physician will automatically call another urologist next time. your patients also expect you to be available all the time: it is not unheard of for patients to call at midnight for advice or to interrupt a special occasion to book an appointment. even if you have a good office assistant, all the logistics other than answering the phone are your job. for example, if you need to book an operation, you have to call the hospital to negotiate a suitable time and date, as well as to establish that they have the necessary equipment and related disposables. most of the time, you then have to call a supplier for the device or the disposables, and you have to coordinate with everyone. getting to know your essential clinic supplies and where to buy them is an art in itself. it takes time—and a lot of disappointment—to perfect that art and find the reliable suppliers. another thing is sub-specialization. i trained as a urologic oncologist, but i was faced with a market in which a urologist cannot afford not to do the “bread and butter” work. therefore, any case that comes into the clinic is served, regardless of specialization. furthermore, i do my own diagnostics too. urodynamics, ultrasounds, and minor procedures like flexible cystoscopy, foley catheter insertion, suprapubic catheter change, percutaneous tibial nerve stimulation and shock wave therapy and intravesical instillations—all are done by me in the clinic without any assistance. so why do i keep on doing this? for one thing, it pays relatively well. you never get rich being a physician, but you and your family live a comfortable life. it has not been easy: the first year of my private practice generated just enough money to pay the rent and the office assistant. the income doubled in the second year, so there were some earnings to take home. even so, to support myself and my family during the first 5 years in practice, i had to supplement my income with a salaried job from 8:00 a.m. to 2:00 p.m., working in my own clinic after 2:00 p.m. another good thing about private practice is that you are your own boss. nobody can tell you when and where to work, although your workday is 12 to 16 hours, and you work 6 days a week. hospitals look at the doctor as a respected client who brings them his patients’ business. some pamper you more with free services to attract you and your patients, and this makes your life easier. as my practice has expanded, i prefer to do all my outpatient and inpatient care at one hospital for convenience; however, when a patient has a lower budget, we will move to another, less expensive, hospital. what hospitals charge the patients depends on the level of care and prestige. most of the time you know in advance what the costs will be, and you can tell the patient what to expect. in the rare event of a complication, however, everything changes, so if your patient is paying out of pocket, it is best to be cautious. you can see that with all this disorganized organization, a little standardization would be a big improvement. to that end, i implemented cloud-based electronic health records to ensure patient data are secure and accessible, and i work with laboratories and radiology departments that have online access to the images and information. as collecting my patients’ data is one of my responsibilities, this system makes my life easier; without it i would have to ask patients to bring in their results and reports. finally, to reach a broader population and to promote our services without breaking the rules on advertising, i established a tv show. seven doctors runs on a local jordanian television channel and delivers medical tips for the general public in plain, non-technical language. a few colleagues and i funded the development of the programme and learnt the tricks of trade, and for the past seven years, we have produced a one-hour weekly show that we sell (without profit) to the local tv station, which benefits from having a less expensive but much higher quality programme than they could have produced themselves. to increase the reach, we also turned to social media to offer advice and short tips to the public. all this, combined with word-of-mouth referrals based on honest scientific practice, has resulted in a fairly busy practice. my next goal? to work to establish here the style of practice i saw in canada, with group practice and specialization. 346 siuj • volume 2, number 6 • november 2021 siuj.org urology around the world www.siu-urology.org #b2bgucancertriad kidney cancer proceedings from the siu b2b uro-oncology: gu cancers triad virtual meeting may 21–22, 2021 https://www.siu-urology.org https://twitter.com/search?q=%23b2bgucancertriad b2b: kidney cancer summary 19 proceedings from the siu b2b uro-oncology: gu cancers triad • may 21–22, 2021 – siuj volume 2, supplement 1, july 2021 simon tanguay,a,* e. jason abel,b laurence albigès,c toni choueiri,d axel bex,e umberto capitanio,f maxine tran,e alessandro volpe,g peter c. blackh,† adivision of urology, mcgill university, montreal, canada bdepartments of urology and radiology, university of wisconsin school of medicine and public health, madison, united states cgustave roussy institute, villejuif, france ddana-farber cancer institute, harvard medical school, boston, united states edivision of surgery and interventional science, university college london, london, united kingdom fsan raffaele scientific institute, milan, italy gdepartment of urology, university of eastern piedmont, novara, italy hdepartment of urologic sciences, university of british columbia, vancouver, canada *co-chair of the scientific programme committee (rcc) †chair of the scientific programme committee the bench-to-bedside uro-oncology gu cancer triad meeting was organized by the société internationale d’urologie and was held online on may 21st and 22nd, 2021. the session on kidney cancer took place on the morning of friday, may 21st, and was chaired by dr. simon tanguay (canada). this session covered practice-changing advances on the horizon for renal cell carcinoma (rcc), optimal sequencing of systemic therapy, hif-α inhibition as a novel therapy for rcc, the use of local therapy for metastatic disease, as well as the multimodal management of localized rcc. the first presentation was led by dr. jason abel (united states). he discussed five practice-changing advances on the horizon for differing rcc settings, including recent developments for small, sarcomatoid, and papillary tumours, as well as early-stage von hippel-lindau syndrome (vhl) and high-risk, nonmetastatic rcc. first, dr. abel focused on strategies for improving risk stratification for active surveillance of small rcc, which represents the majority of initially diagnosed kidney cancers[1]. most patients diagnosed with small rcc will not progress to metastatic disease or die from kidney cancer, as pointed out by dr. abel. active surveillance is an established management approach for small rcc, as indicated in several guidelines[2,3]. however, as more natural history data become available, improved risk stratification strategies may help to select patients and determine follow-up for active surveillance. while active surveillance is usually recommended for elderly patients with limited life expectancy, new data are providing additional insights for managing younger patients with small rcc. in the dissrm registry, which evaluated 224 patients aged 60 or younger, 30% of whom were managed with active surveillance, no patient developed metastatic disease or had disease recurrence following delayed intervention[4]. this study suggests that active surveillance is a safe initial strategy for selected younger patients and potentially avoiding some interventions. however, longer follow-up is necessary given the long natural history of the disease. improved risk stratification based on genetic alterations may further help to select patients for active surveillance. in a study by the national cancer institute (nci), patients with pathologic germline alterations and rcc were shown to have differing tumour growth rates[5]. while it may be difficult to extrapolate the results to the general rcc population, these findings are encouraging given the paucity of genetic characterization of kidney cancers in the context of active surveillance. dr. abel emphasized that, as the understanding of small rcc biology improves, active surveillance will become more personalized. the presence of sarcomatoid features in rcc is associated with aggressive tumour biology and early mortality[6]. although sarcomatoid dedifferentiation occurs in only ~5% of tumours overall, these patients have some of the worst outcomes: they frequently present with metastatic disease and have poor survival despite aggressive treatment[6]. while management of this patient population remains challenging, recent efforts have improved the molecular characterization of sarcomatoid tumours and identified the basis of response to immune checkpoint inhibitor (ici) therapy[7]. in parallel, a post hoc subgroup analysis of doi: 10.48083/scpm5983 b2b: kidney cancer summary 20 proceedings from the siu b2b uro-oncology: gu cancers triad • may 21–22, 2021 – siuj volume 2, supplement 1, july 2021 139 patients with sarcomatoid rcc enrolled in the checkmate 214 trial demonstrated positive outcomes in response to dual ici therapy with nivolumab + ipilimumab[8]. compared to treatment with sunitinib, treatment with nivolumab + ipilimumab resulted in significantly improved median overall survival (os) (not reached vs. 14.2 months; hr=0.45 [95% ci 0.3–0.7]; p=0.0004) and higher confirmed objective response rate (orr). dr. abel also highlighted the high proportion of patients achieving complete response (cr) with nivolumab + ipilimumab, which was almost double that observed in rcc without sarcomatoid dedifferentiation. these advances in tumour characterization and ici combination therapy development may significantly improve outcomes for patients with sarcomatoid rcc. historically, most research in systemic therapies for metastatic rcc has targeted the most prevalent clear cell subtype. by contrast, very few clinical trial data are available for papillary rcc, the second most common subtype[9]. papillary rcc is generally characterized by alterations in the met pathway, which can be further classified into type 1 and type 2 tumours. however, the pathologic heterogeneity of this rcc subtype may be challenging. a recent trial with cabozantinib, a tyrosine kinase inhibitor (tki) targeting vascular endothelial growth factor (vegf) receptors and the met pathway, has shown promising results for patients with papillary rcc. in this open-label, randomized, phase 2 trial, treatment with cabozantinib significantly improved median progression-free survival (pfs) compared to sunitinib in patients with metastatic papillary rcc (9.0 vs. 5.6 months; hr=0.60 [95% ci 0.37–0.97]; onesided p=0.019)[10]. while data for systemic therapy in papillary rcc may be difficult to evaluate given the low frequency and complex pathology of this disease subtype, the promising results of combined met and vegfr2 inhibition with cabozantinib may lead to improved outcomes in this patient population in the future. additionally, improved molecular characterization of the disease may help inform the selection of novel agents for treating papillary rcc. dr. abel also discussed the recent potentially practice-changing use of hif-2α inhibitors for the treatment of vhl disease, a syndrome caused by germline inactivation of the vhl gene[11]. patients with vhl disease may develop clear cell rcc (ccrcc), as well as hemangioma, pheochromocytoma, and other tumours in the pancreas, retina, and other sites. the treatment of patients with vhl is challenging. many of these patients undergo multiple partial nephrectomies for ccrcc over their lifetime and can progress to metastatic disease. in addition, repeated treatment can also lead to renal dysfunction. in an open-label, phase 2 trial, the efficacy of belzutifan (mk-6482) was evaluated in patients with vhl disease and nonmetastatic rcc[12]. belzutifan is an inhibitor of hif-2α, a transcription factor that becomes constitutively active and drives tumour growth due to vhl gene inactivation. in the trial, the orr was 36% for vhl-associated ccrcc per recist v1.1 by independent review committee (irc). tumour response was also observed for non-rcc tumours, including orr of 64% for pancreatic lesions, 30% for hemangioblastomas, and 69% for retinal lesions. only one patient discontinued treatment due to a treatment-related adverse event (trae) and no grade 4 or 5 traes were observed. these early results are encouraging and show the potentially practice-changing application of systemic therapy with hif-2α inhibitors for treatment of rcc tumours associated with vhl disease. lastly, dr. abel presented recent advances for the treatment of high-risk nonmetastatic rcc. generally, this patient population is treated with nephrectomy and surveillance. however, patients with pathologic t3 disease are more likely to develop metastasis after surgery compared to patients with t1 or t2 tumour stage. two hypotheses may explain metastatic progression in this patient population: failure to detect micrometastasis by conventional imaging at the time of surgery or failure of the patient’s immune system to prevent any tumour cells from implanting and growing at different sites. the latter could be improved with the use of icis as adjuvant therapy. adjuvant therapy with pembrolizumab for high-risk nonmetastatic rcc is under investigation in the randomized phase 3 keynote-564 trial. in a recent press release, it was announced that the trial had met its primary endpoint of improved disease-free survival (dfs) compared to b2b: kidney cancer summary 21 b2b: kidney cancer summary placebo[13]. these data are positive and have important future implications for managing patients with high-risk nonmetastatic rcc. during the q&a, dr. abel discussed whether early biopsy may help identify patients with a sarcomatoid subtype who could benefit from neoadjuvant therapy for locally advanced rcc. although this is a rare subtype and biopsies are typically performed pre-operatively in patients with metastatic disease only, in the context of a clinical trial, dr. abel believes this is a logical approach that bears investigation in the future. next, dr. abel addressed the utility of genetic profiling in patients with small rcc. he believes this will provide better insights on management options, particularly in patients who are neither very young or elderly and correspond to the majority of small rcc diagnoses. lastly, dr. abel provided his perspective on the recently positive results of adjuvant ici therapy in rcc. he believes that if ongoing clinical trials in this setting are able to demonstrate os benefit, it will lead to important changes that would change clinical practice. next, dr. laurence albigès (france) presented the optimal sequencing strategies in metastatic rcc. over the past decades, advances in understanding the rcc pathophysiology have led to the identification of two major therapeutic targets: first, the role of the hifαvegf axis in tumour angiogenesis[14] and, second, the development of icis as drivers of immune response to tumours[15]. in addition, management of metastatic rcc is also influenced by the imdc risk assessment, not only to evaluate patient prognosis but also to guide treatment decisions[16]. the new guidelines of the european society for medical oncology (esmo) outline two main approaches for standard systemic first-line treatment of intermediate and poor risk ccrcc (adapted from [17]). the first approach uses dual ici combination therapy with nivolumab + ipilimumab, which has demonstrated long-term benefits in os and pfs[18]. the second approach combines vegfr tki with ici. multiple studies over the past 3 years have reported positive results for different tki + ici combinations in the treatment of metastatic rcc[19–21]. these studies have demonstrated that tki + ici combination may result in modulation of immune response by targeting vegf inhibition, which may underlie the os benefit with tki + ici versus standard of care observed in the trials. most notably, tki + ici has been shown to result in high tumour response rate and sustained response over time, as well as clinical benefit across imdc patient risk groups[19–21]. at the moment, both the dual ici and tki + ici combination have demonstrated clinical benefits and there is no evidence to support one approach over the other. as highlighted by dr. albigès, clinical trials comparing dual ici versus tki + ici would help guide treatment decisions between the two approaches. in the second-line setting, there are well-defined treatment recommendations for patients who received single-agent first-line therapy[3]. however, the new combination therapy options available as first line may impact treatment decisions in the second-line setting. while ongoing clinical trials may help to identify the optimal second-line approach, several critical considerations are still unanswered. dr. albigès summarized those as the following questions: 1) is there a role for salvage ipilimumab, if not used in the first line, for patients who progressed after programmed cell death protein 1 (pd-1)/programmed death-ligand 1 (pd-l1) therapy? 2) is there a role for combination therapy as second-line or subsequent treatment? 3) is there a role for sustained pd-1 inhibition in the second-line therapy? 4) are there any new targets that should be considered in this setting? for salvage ipilimumab, several studies have shown only a small benefit of combining ipilimumab to nivolumab in patients who did not respond to anti-pd-1/pd-l1 as first-line monotherapy[22–24]. while dual ici combination therapy following first-line ici has shown orr around ~10%– 15% across studies[22,23], the vegfr-ici combination with lenvatinib + pembrolizumab reached 50%[25]. dr. albigès believes more data are necessary to elucidate the role of sustained pd-1 inhibition. this is currently under investigation in the phase 3 contact-03 trial, which randomized patients to receive either atezolizumab + cabozantinib or cabozantinib following progression with ici therapy[26]. b2b: kidney cancer summary 22 proceedings from the siu b2b uro-oncology: gu cancers triad • may 21–22, 2021 – siuj volume 2, supplement 1, july 2021 among non-ccrcc subtypes, distinct response to ici is observed depending on the tumour type. in papillary rcc, the encouraging results observed in the swog trial may result in the adoption of cabozantinib as the new standard to treat patients with this rcc subtype[10]. ongoing studies are aiming to provide insights into molecular met screening for papillary rcc, which may reveal new therapeutic targets. other trials may also help to guide the choice of combination therapy in patients with non-ccrcc subtypes. lastly, dr. albigès highlighted the critical implications of adjuvant ici therapy on subsequent first-line metastatic treatment options, given the positive results of the keynote-564 trial, which may lead to important practice changes in advanced rcc. in the q&a period, dr. albigès was asked whether patients who progress while on treatment with nivolumab + ipilimumab could be rechallenged with ipilimumab. she indicated that there are no data supporting ipilimumab rechallenge and very limited information on ipilimumab activity at later stages. instead of a rechallenge, she would recommend patient inclusion in a clinical trial with different agents. next, dr. albigès detailed her approach for stopping treatment in patients who achieved cr or prolonged stable disease (sd). she emphasized that this is a discussion to be had with the tumour board as well as the patient. generally, dr. albigès will only recommend discontinuation with at least 1 year of treatment if the patient has an overall good safety profile and has achieved cr. otherwise, these discussions may occur between 1 to 2 years following the beginning of treatment. lastly, dr. albigès discussed her perspective on new strategies for improving patient response to systemic therapy. she believes that a triple ici-tki combination may be a way to intensify treatment and potentially improve outcomes. she also emphasized that this approach may have an increased toxicity profile and that early identification of patients who could benefit from triple agent combination is critical. the following presentation was made by dr. toni choueiri (united states), who discussed the role of hif-2α inhibitors as a novel therapeutic class for rcc treatment. hif-α activity is intrinsically associated with oxygen concentration and vhl gene alterations. during hypoxia or when there are mutations in vhl, such as in vhl syndrome and ccrcc, hif-α becomes intrinsically active, leading to downstream transcriptional effects[27]. hif-2α is one of the three subunits of hif-α and regulates multiple oncogenic pathways, making it an important therapeutic target for ccrcc[28]. pt2385 was the first generation of hif-2α inhibitors. it was validated for the treatment of heavily pretreated patients with metastatic ccrcc in a phase  1 trial, resulting in an orr of 13%[29]. modifications of pt2385 led to the development of belzutifan a second generation of hif-2α inhibitor with greater efficacy, increased bioavailability, and less protein binding[30]. in a recently published phase 1 trial of patients with metastatic ccrcc who had previously received systemic therapy, belzutifan resulted in an orr of 25%, with a median pfs of 14.5 months[31]. this second-generation hif-2α has also been investigated in vhl syndrome-associated rcc, which typically presents as localized ccrcc. in the preliminary analysis of a phase 2 trial, treatment with belzutifan resulted in an orr of 28%, with ~87% of patients exhibiting tumour shrinkage[32]. in an updated analysis of this trial, discussed earlier by dr. abel, the orr was improved to 36% for vhl-associated ccrcc[12]. in terms of safety profile, hif-2α inhibitors have different toxicity compared to vegf inhibitors. in a phase 1 trial, 15% of patients with metastatic ccrcc who received belzutifan developed grade 3 hypoxia[31]. this was seen without any concomitant cardiac or pulmonary complications. hif-2α has an important role in the pulmonary vasculature and carotid body physiology. while the underlying mechanism is not fully understood, blocking hif-2α might exacerbate ventilation-perfusion mismatch and ventilatory sensitivity to hypoxia. this is an important consideration for patients with chronic pulmonary diseases or those at high altitude, who may be relying on enhanced sensitivity to hypoxia to maintain adequate ventilation. combination therapy with hif-2α inhibitor and ici/tki is also under investigation. in the phase 1 trial, patients with advanced rcc treated with pt2385 + nivolumab combination had an orr of 22% and median pfs of 10 months, for those who were exposed b2b: kidney cancer summary 23 b2b: kidney cancer summary to therapeutic doses of pt2385[33]. in a phase 2 trial, preliminary analysis of patients with up to two prior systemic therapies, including ici (cohort 2), demonstrated tumour shrinkage in 88% of patients and a median pfs of 16.8 months following treatment with belzutifan + cabozantinib[34]. phase 3 studies are underway to evaluate the efficacy and safety of belzutifan either in combination with lenvatinib[35] or as monotherapy[36] for the treatment of advanced rcc. dr. choueiri emphasized the importance of examining the potential mechanisms of resistance as part of the development of a new therapeutic agent. for hif-2α inhibition, pre-clinical and translational models suggest that mutations in hif-2α and hif-1β may preclude binding of hif-2α inhibitors and lead to increased affinity between the two subunits, resulting in activation of the hif pathway (summarized in [28]). rna interference (rnai) may provide an alternative to small-molecule hif-2α inhibition by targeting and silencing hif-2α expression. this approach is under investigation in a phase 1 trial evaluating the efficacy of a proprietary targeted rnai molecule delivery platform (aro-hif2) for the treatment of ccrcc[37] and has shown encouraging results in pre-clinical models[38]. with positive results from several trials and ongoing development, hif-2α represents a novel therapeutic target whose implications may expand beyond vhl syndrome and rcc. the presentation was followed by a q&a session during which dr. choueiri discussed his perspective on how different vhl mutations may affect treatment response to hif-2α inhibition in patients with rcc. he believes that most rcc patients likely have some form of vhl mutation that may be difficult to detect. he pointed out that, under these circumstances, downstream alterations may help identify other rcc syndromes that could be targeted with hif-2α inhibitors. next, dr. choueiri discussed the potential role of hif-2α inhibitors in triple-agent combination therapy for rcc. he explained that the latest advances in hif-2α inhibition are promising and may lead to the development of improved molecules that could be combined with other agents. however, he advised caution in regards to the cost and potentially increased toxicities of combination approaches. next, dr. axel bex (united kingdom) discussed why and when local therapy should be used to manage metastatic kidney cancer. first, dr. bex focused on the why. in general, patients who undergo resection of multiple metastases over time may have 5-year os that are comparable to those who underwent single metastasectomy[39]. if achievable, complete resection of metastases may lead to cure, potential improvement of dfs, pfs, and os (although not yet evaluated in a randomized clinical trial setting), as well as delay or discontinuation of targeted therapies. however, dr. bex questioned whether metastasectomy is indeed required to achieve these objectives. for instance, active surveillance may be a viable, safe option for patients with oligometastasis to manage the disease prior to starting systemic therapy[40]. in addition, cure is generally not achievable in high-risk patients treated for recurrence[41]. finally, while a systematic review favours metastasectomy based on the hazard ratio for os, this may be biased because of the distinct patient populations evaluated in retrospective studies[42]. rcc has different pathways of metastatic evolution and management approaches. in patients who present with the primary tumour and single metastasis, treatment involves nephrectomy and resection of the metastatic lesion, which may result in several years of survival without the disease. these patients generally present with a linear evolution driven by vhl mutation or an attenuated progression, as a result of pbrm1 mutations. on the other end of the spectrum, there are patients who present with multiple metastatic sites and follow a punctuated evolution with rapid progression, mainly driven by bap1 alterations[43]. by contrast, translational data in prostate cancer suggest that metastasis-to-metastasis spread can occur[44]. the time to transformation into a more aggressive subtype may also be unpredictable and lead to a metastatic shower[45], which would further support the role of metastasectomy in patient management. nevertheless, these treatment decisions remain challenging in the absence of prospective randomized studies to evaluate the true impact of metastasectomy on survival. dr. bex then discussed the timing for performing metastasectomy. although early presentation of b2b: kidney cancer summary 24 proceedings from the siu b2b uro-oncology: gu cancers triad • may 21–22, 2021 – siuj volume 2, supplement 1, july 2021 recurrence is a strong indicator of poor prognosis[46], it is impossible to predict the momentum of metastatic progression. general predictors associated with positive outcomes after metastasectomy include: the presence of solitary or oligometastatic lesions, a complete resection, disease-free interval of over 2 years, single-organ site, no sarcomatoid features or highgrade tumour, absence of nodal metastases, good performance status, and a favourable-to-intermediate risk imdc[47]. dr. bex emphasized the importance of keeping these factors in mind when deciding the management approach for metastases, given the high complication rates of metastasectomies[48]. there are ongoing phase 3 trials evaluating the role of adjuvant ici therapy in rcc that have included patients who also underwent complete metastasectomy, namely keynote-564 (pembrolizumab vs. placebo) and immotion 010 (atezolizumab vs. placebo). if these trials demonstrate dfs or os benefit, metastasectomy followed by ici may become the new standard based on prospective randomized data. during the q&a, dr. bex discussed whether some sites should not undergo metastasectomy due to poor associated outcomes. he advised that the site as well as the complexity of the surgical procedure should be considered. in general, metastases in the liver, pancreas, and brain may require a different management approach. next, dr. bex provided his insights on the advances of stereotactic body radiation therapy (sbrt) to manage multiple metastatic lesions. he believes that sbrt may provide an alternative, and even preferable, approach to metastasectomy, although data comparing both strategies are needed. lastly, dr. bex discussed his management approach for patients who achieve partial response to ici and have one or two metastatic sites. if the lesions are small and stable, he does not see a benefit for metastasectomy. by contrast, if the lesions grow during treatment, he recommends controlling the metastatic growth with a focal therapy (e.g., sbrt) rather than switching to a different line of systemic therapy. the session concluded with a case-based panel on multimodal management of localized rcc. this was led by dr. umberto capitanio (italy), with the discussion based on the input of drs. simon tanguay (canada), maxine tran (united kingdom), and alessandro volpe (italy). the case was a 51-year-old male with a high body mass index (bmi) of 42 kg/m2 who had a small renal mass incidentally detected during an abdominal ultrasound. computed tomography (ct) revealed a 35-mm renal tumour, which was >50% endophytic and lay in close proximity to the renal calices and sinus, representing intermediate complexity for surgery. the tumour was staged as ct1an0m0, with a very low risk of metastasis, meaning that chest imaging and bone scan were not necessarily indicated according to published nomograms[49]. other imaging options that may be considered for further evaluation include magnetic resonance imaging (mri), if the patient had low estimated glomerular filtration rate (egfr); sestamibi positron emission tomography (pet)/ct, to differentiate between rcc and oncocytoma; and contrast-enhanced ultrasound scan for equivocal lesions in patients with low egfr. biopsies are not performed routinely in this patient population. however, they may provide additional insights given that small renal masses are heterogeneous and may have differing patterns of growth and spread that can be predicted through diagnostic biopsies[50]. in addition, renal biopsies have high sensitivity and specificity to detect malignancies[51], with minimal complications associated with the procedure. in the patient case, biopsy revealed a grade 2 ccrcc. in this clinical case, the patient underwent robotic-assisted partial nephrectomy and final pathology indicated a grade 2 pt1a ccrcc with negative surgical margins. surgery is the preferred management option for patients with small renal masses. focal therapy and active surveillance may also be considered for some patients, such as the elderly and frail[2]. focal therapies (such as cryoablation, radiofrequency ablation, and microwave ablation) generally have low morbidity and may be performed in the outpatient setting but should be reserved to tumours ≤3 cm[2]. in addition, while these focal approaches show generally good outcomes in clinical practice, evidence supporting the preferred use of either focal therapies or surgery in managing small renal masses is currently lacking. active surveillance may also be considered for patients with low-grade small rcc, although the tumour size b2b: kidney cancer summary 25 b2b: kidney cancer summary at diagnosis should also play a role in management selection[52]. currently, the prospective ease study is investigating the use of active surveillance in small rcc to determine standards for indication, follow-up, criteria for progression, and delayed intervention with this management approach[53]. other approaches such as neoadjuvant treatment, systemic therapy, and radiotherapy are only recommended in this disease setting through clinical trial enrolment. neoadjuvant therapy is usually implemented to reduce tumour size prior to surgery and would unlikely benefit the patient in the case. by contrast, the recent positive experience with hif-2α inhibitors in patients with vhl and rcc[12] might lead to important developments in this setting. sbrt allows the delivery of precise radiation doses to the target tumour, with the additional benefit of being performed in the outpatient setting. while this may be a compelling option for morbid and inoperable patients, particularly with metastatic disease, sbrt may have limited applicability in the localized setting, in which other treatment options are available. abbreviations used in the text bmi body mass index ccrcc clear cell renal cell carcinoma ci confidence interval cr complete response ct computed tomography dfs disease-free survival egfr estimated glomerular filtration rate esmo european society for medical oncology hr hazard ratio ici immune checkpoint inhibitor imdc international metastatic rcc database consortium irc independent review committee mri magnetic resonance imaging nci national cancer institute orr objective response rate os overall survival pd-1 programmed cell death protein 1 pd-l1 programmed death-ligand 1 pet positron emission tomography pfs progression-free survival rcc renal cell carcinoma recist response evaluation criteria in solid tumours rnai rna interference sbrt stereotactic body radiation therapy sd stable disease tki tyrosine kinase inhibitor trae treatment-related adverse event vegf vascular endothelial growth factor vhl von hippel-lindau syndrome b2b: kidney cancer summary 26 proceedings from the siu b2b uro-oncology: gu cancers triad • may 21–22, 2021 – siuj volume 2, supplement 1, july 2021 references 1. jonasch e, gao j, rathmell wk. renal cell carcinoma. bmj. 2014;349(11):g4797 doi:10.1136/bmj.g4797 2. escudier b, porta c, schmidinger m, et al. renal cell carcinoma: esmo clinical practice guidelines for diagnosis, 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doi:10.14694/edbook_am.2015.35.e239 48. meyer cp, sun m, karam ja, et al. complications after metastasectomy for renal cell carcinoma—a populationbased assessment. european urology.2017;72(2):171-174. doi:10.1016/j.eururo.2017.03.005 49. larcher a, dell’oglio p, fossati n, et al. when to perform preoperative chest computed tomography for renal cancer staging. bju international.2017;120(4):490-496. doi:10.1111/bju.13670 50. volpe a, finelli a, gill is, et al. rationale for percutaneous biopsy and histologic characterisation of renal tumours. european urology.2012;62(3):491-504. doi:10.1016/j. eururo.2012.05.009 51. marconi l, dabestani s, lam tb, et al. systematic review and meta-analysis of diagnostic accuracy of percutaneous renal tumour biopsy. european urology. 2016;69(4):660-673. doi:10.1016/j.eururo.2015.07.072 52. jewett mas, mattar k, basiuk j, et al. active surveillance of small renal masses: progression patterns of early stage kidney cancer. european urology.2011;60(1):39-44. doi:10.1016/j.eururo.2011.03.030 53. trial in progress: the european active surveillance of renal cell carcinoma study (ease rcc study). accessed june 2, 2021. https://uroweb.org/publications/trial-inprogress-the-european-active-surveillance-of-renalcell-carcinoma-study-ease-rcc-study/ 403 forbidden<br> this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. the right instrument for the right purpose: spreading the use of small caliber ureteroscope for the inspection of the male and female urethra sanjay b. kulkarni,1 marco bandini,1,2,3 amey patil,1 shreyas bhadranavar,1 vipin sharma,1 sandeep bafna,1 shreeranga l. yatam,1 guido barbagli,3 francesco montorsi,2 pankaj m. joshi1 1kulkarni reconstructive urology center, pune, india 2unit of urology, urological research institute (uri), san raffaele hospital, vita-salute san raffaele university, milan, italy 3center for reconstructive urethral surgery, arezzo, rome, milan, italy abstract the inspection of the urethra in patients with documented or suspected urethral stricture should be carried out with small caliber ureteroscope of 6/7.5ch. different from flexible cystoscope (16ch) or resectoscope (26ch), small caliber ureteroscope allows a comprehensive evaluation of the stricture, including its length and the status of the mucosa in its proximity, without injuring or overstretching the urethra. with a small caliber ureteroscope it is also possible to cross the stricture, allowing the evaluation of the proximal urethra, the external urethral sphincter, and the bladder. a 6/7.5ch ureteroscope also allows estimation of the real caliber of the stricture, providing a useful landmark for further treatment decisions. as members of the reconstructive urology community and experts in the field of urethroplasty, it is our duty not only to discover new surgical techniques[1] but also to provide advice that can change our daily practice to the advantage of our patients. in this regard, we are honored to share our view of the correct management of patients with urethral stricture. we believe the assessment of patients with urethral stricture starts with the appropriate and judicious evaluation of the urethra. in a patient complaining of poor flow, when the urethrogram shows a narrowing along the urethra, the choice of the right endoscopic instrument for inspection is pivotal. based on our long experience of urethroplasty and urethral disease management, we recommend the use of a small caliber ureteroscope to inspect the urethra. specifically, a 6/7.5ch ureteroscope; the first digit refers to the size of the ureteroscope at the tip and the second to the size of the instrument at the base. the normal caliber of the bulbar urethra is 30ch[2], which means that the diameter is around 1cm. a resectoscope, which is commonly adopted for transurethral resection of the prostate, is 26ch, and f lexible cystoscopes are approximately 16ch. according to smith et al.[3], urethral strictures become symptomatic (ie, require dilatation and antibiotic treatment) when the urine flow is below 7ml/min, which corresponds approximately to a urethral caliber below 16ch. in other words, when patients come for initial evaluation, the urethral lumen, at the level of the stricture, typically does not allow “common” instruments to go across the stricture (figure 1). this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information small caliber instrument, education, urethra; ureteroscope, reconstructive urology none declared. received on april 21, 2021 accepted on may 19, 2021 soc int urol j.2021;2(4):259–263 doi: 10.48083/nvko4969 siuj.org siuj • volume 2, number 4 • july 2021 259 brief communication mailto:bandini.marco%40hsr.it?subject=siuj http://www.siuj.org kulkarni’s �ow-chart for bulbar urethral stricture 1) post-turp 2) obese patients 3) young sexually active male redo-case with stricture >7ch circumferantial mobilization and barbagli dorsal or ventral onlay in complex cases in straightforward cases stricture > 3ch kulkarni one-side dissection with dorsal onlay bmg asopa ventral onlay urethral stricture length <5mm: • mucosa-to-mucosa anastomosis with/without opposite side bmg augmentation urethral stricture length 5 -15mm: • double face augmented bmg urethroplasty • augmented non-transecting anastomotic urethroplasty augmented anastomotic urethroplasty urethral stricture length >15mm 2-stages graft + flap if failure non-traumaticobliterated stricture (<3ch) anastomotic urethroplastypost-traumatic different sizes of bulbar urethra 30ch 26ch 16ch 7ch 3ch guidewire resectoscope flexible cystoscope small caliber ureteroscope (6/7.5ch) 0ch figure 1. the choice of the correct instrument according to the different sizes of urethra. kulkarni’s flow chart for urethroplasty techniques according to stricture characteristics 2 siuj • volume 2, number 4 • july 2021 siuj.org brief communication http://www.siuj.org the 6/7.5ch ureteroscope was introduced into urological practice more than 10 years ago. since then, it has been employed mainly for stone management[4] and/or pediatric urolog y[5], and its use has not been popularized among reconstructive urologists. nonetheless, we believe that small caliber ureteroscope should become the gold standard for the inspection of the urethra in patients referred for stricture management. first and foremost, it decreases the risk of injuring the urethra. indeed, the 6/7.5ch ureteroscope allows the surgeon to navigate the urethra away from the urethral walls, preventing accidental injury of the mucosa. it also avoids trauma to the surrounding spongy tissue, preventing over-distension and stretching. second, a sma ll ca liber ureteroscope may a llow close-up visualization of the stricture and may enable visualization across the length of the stricture. this second aspect is very important, especially for planning the subsequent t reat ment. indeed, ret rog rade a nd a nterog rade urethrograms may underestimate the real complexity of the stricture (video 1). in particular, retrograde and anterograde urethrograms may not always give a realistic representation of either the extension or the severity of the urethral stricture. moreover, urethrograms do not provide information on the status of the mucosa across and in proximity to the stricture (figure 2). assessing the real length of the stricture and the status of the surrounding mucosa is pivotal in patients with lichen sclerosus or any non-traumatic etiologies, which may involve longer segments of the urethra. surgical decisionmaking may change considerably depending on the length of the stricture or the aspect of the forthcoming urethral mucosa. for instance, the choice of end-to-end anastomosis, augmented urethroplasty, or stricturoplasty can be made only with knowledge of the extension of the stricture and the status of the urethra before and after the stricture. this vital information can be acquired only with a full inspection of the urethral lumen. in our experience, the estimation of stricture length is more accurate when it is carried out with the endoscopic view rather than urethrograms. indeed, the endoscopic findings more frequently match with the surgical view. only with the use of these small caliber instruments does the surgeon have the advantage of a comprehensive evaluation of the urethra for planning the correct treatment. third, only small ureteroscope may give access to false passage or fistulae encountered during the inspection of the urethra with minimal risk of extravasation or perforation. the latter is extremely important in patients referred for redo surgery, pelvic fracture urethral injury, or stricture related to infection with concomitant abscess. fourth, with a small caliber ureteroscope it is possible to cross the stricture reaching the proximal urethra and the bladder. this opportunity is of paramount importance, especially video 1. patient with distal anastomotic stenosis after dorsal onlay bmg urethroplasty. the 6/7.5ch ureteroscope was able to cross the stricture and to allow the inspection of the proximal urethra 3siuj.org siuj • volume 2, number 4 • july 2021 the right instrument for the right purpose: spreading the use of small caliber ureteroscope http://www.siuj.org to rule out the presence of stones or neoplasms, which can radically change the management of the patient. the use of small caliber ureteroscope is particularly advantageous in female patients. to rule out the presence of stricture in women, the inspection of the urethra must be carried out with great care and attention because the female urethra is short, poorly distensible, and has great mobility. larger caliber instruments are inappropriate for this task because they do not allow a comprehensive evaluation of the length and severity of the stricture. indeed, larger caliber instrument may be unable to enter the meatus when fibrotic or, when the stricture is more proximal, they may overstretch the urethra, hiding the presence of the stenosis and its extension. last but not least, small caliber instruments provide a useful calibration of the urethral lumen to determine the most appropriate urethroplasty technique. according to our personal flow chart (figure. 1), a stricture which allows only a 6/7.5ch ureteroscope can be approached with augmented urethroplasty following the barbagli[6] or kulkarni[7] principles. conversely, an obliterated or semi-obliterated stricture (<3 ch) can be repaired with anastomotic urethroplasty when secondary to trauma, or with non-transecting approaches (including double face[8], mucosa-to-mucosa[9], augmented nontransecting anastomotic urethroplasty[10]), graft plus flap or two-stage urethroplasty when secondary to nontraumatic etiologies. finally, we acknowledge that the use of small caliber ureteroscope can be challenging at the beginning because of the difficulties of handling and maneuvering this long and thin instrument, as well as the suboptimal view. however, we believe that the great benefit derived from its use justifies the effort needed for the learning curve. in summary, we suggest that all reconstructive urologists dealing with urethroplasty consider discontinuing the use of flexible or rigid cystoscopes with caliber above 16ch. instead, we recommend they embrace a small caliber ureteroscope (6/7.5ch) for the evaluation of the urethra in patients, male or female, with a confirmed or suspected diagnosis of urethral stricture, before surgery. figure 2. examples of retrograde urethrograms where length and characteristics of the strictures cannot be assessed without endoscopic inspection 4 siuj • volume 2, number 4 • july 2021 siuj.org brief communication http://www.siuj.org references 1. barbagli g, bandini m, balò s, sansalone s, butnaru d, lazzeri m. surgical treatment of bulbar urethral strictures: tips and tricks. int braz j urol.2020;46:511– 8. https://doi.org/10.1590/s1677-5538. ibju.2020.99.04. 2. brandes sb, morey af, eds. advanced male urethral and genital reconstructive surgery.2004; springerlink. available at: https:// link.springer.com/book/10.1007%2f978-1-4614-7708-2. accessed april 15, 2021. 3. smith jc. the measurement and significance of the urinary flow rate. br j urol.1966;38:701– 6. ht tps://doi.org/10.1111/j.14 6 4 410x.1966.tb09783.x. 4. francesca f, scattoni v, nava l, pompa p, grasso m, rigatti p. failures and complications of transurethral ureteroscopy in 297 cases: conventional rigid instruments vs. small caliber semirigid ureteroscopes. eur urol.1995;28:112– 5. ht tps://doi. org/10.1159/000475032. 5. zhu j, phillips t m, mathews ri. operative management of pediatric urolithiasis. indian j urol.2010;26:536 – 43. https://doi. org/10.4103/0970-1591.74454. 6. barbagli g, montorsi f, guaz zoni g, l archer a , f ossati n, sansalone s, et al. ventral oral mucosal onlay graft urethroplasty in nontraumatic bulbar urethral strictures: surgical technique and multivariable analysis of result s in 214 p atient s. eur urol.2013;64:440–7. https://doi.org/10.1016/j.eururo.2013.05.046. 7. kulkarni s, barbagli g, sansalone s, lazzeri m. one-sided anterior urethroplasty: a new dorsal onlay graft technique. bju int.2009; 104:1150–5. https://doi.org/10.1111/j.1464-410x.2009.08590.x. 8. palminteri e, manzoni g, berdondini e, di fiore f, testa g, poluzzi m, et al. combined dorsal plus ventral double buccal mucosa graft in bulbar urethral reconstruction. eur urol.2008;53:81–9. https:// doi.org/10.1016/j.eururo.2007.05.033. 9. andrich de, mundy ar. non-transecting anastomotic bulbar urethroplast y: a preliminar y repor t. bju int.2012;109:1090 – 4. https://doi.org/10.1111/j.1464-410x.2011.10508.x. 10. welk bk, kodama rt. the augmented nontransected anastomotic urethroplast y for the treatment of bulbar urethral strictures. urology.2012;79:917–21. https://doi.org/10.1016/j.urology.2011.12.008. 5siuj.org siuj • volume 2, number 4 • july 2021 the right instrument for the right purpose: spreading the use of small caliber ureteroscope https://link.springer.com/book/10.1007%2f978-1-4614-7708-2 https://link.springer.com/book/10.1007%2f978-1-4614-7708-2 https://link.springer.com/book/10.1007%2f978-1-4614-7708-2 https://link.springer.com/book/10.1007%2f978-1-4614-7708-2 https://doi.org/10.1111/j.1464-410x.1966.tb09783. https://doi.org/10.1111/j.1464-410x.1966.tb09783. https://doi.org/10.1159/000475032 https://doi.org/10.1159/000475032 https://doi.org/10.4103/0970-1591.74454 https://doi.org/10.4103/0970-1591.74454 https://doi.org/10.1016/j.eururo.2013.05.046 https://doi.org/10.1111/j.1464-410x.2009.08590.x https://doi.org/10.1016/j.eururo.2007.05.033 https://doi.org/10.1016/j.eururo.2007.05.033 https://doi.org/10.1111/j.1464-410x.2011.10508.x https://doi.org/10.1016/j.urology.2011.12.008 http://www.siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information prostatic artery embolization, penile tip necrosis, benign prostate hyperplasia, embozene none declared. patient consent: obtained. received on may 19, 2021 accepted on july 17, 2021 soc int urol j.2021;2(5):323–326 doi: 10.48083/uczq9737 prostatic artery embolization (pae) is an emerging inter ventiona l radiologica l procedure performed under local anaesthesia, which provides an alternative treatment for benign prostatic hyperplasia (bph) in patients whose preference or medical comorbidities preclude either a general anaesthetic or surgical intervention[1,2]. pae has been shown to improve lower urinary tract symptoms (luts), although not with the same efficacy as a transurethral resection of prostate (turp)[3–5]. the largest case series reported is of 630 patients, in which 35% of patients reported an immediate improvement in symptoms, 82% had clinical success at medium-term follow-up (1 to 3 years), and 76% had clinical success at long-term follow-up (3 to 6.5 years)[3]. reported complications following pae include dysuria (16.9%) and frequency (11.6%), generally lasting no more than one week, and acute urinary retention (4.6%)[6]. penile tip necrosis as a complication is reported as being exceedingly rare[3,4,6,7]. this paper describes 3 cases of penile tip necrosis following pae to enable clinicians to readily identify the complication and manage patients appropriately. the first patient was a 63-year-old man with significant medical comorbidities with an american society of anesthesiologists physical status classification system (asa) score of 4, who presented to emergency in acute urinary retention. he had a history of obstructive symptoms and had trialled pharmacotherapy to limited effect, with an international prostate symptom score (ipss) of 17. he had undergone a successful pae 3 years earlier, which resulted in an improvement in his urinary flow with a voided volume of 156 ml, a peak flow rate of 15.1ml/sec, but a slightly elevated post-void residual volume of 85 ml. following his re-presentation, he was referred back for consideration of repeating pae. his prostate prior to the procedure measured 210 cc. a pae via radial artery puncture was performed using 250 μm 323siuj.org siuj • volume 2, number 5 • september 2021 brief communication non-target embolization of the glans penis during prostatic artery embolization cameron james parkin,1,2,3 cecile pham,3,4 amanda chung,1,3,4,5 stuart menogue,4 jules catt,6,7 gavin gottschalk,8 cherie wong,9 venu chalasani1,3,4,5 1 department of urology, royal north shore hospital, northern sydney local health district, australia 2 school of medicine, the university of notre dame, sydney, australia 3 north shore urology research group, royal north shore hospital, nsw, australia 4 department of urology, northern beaches hospital, nsw, australia 5 faculty of health and medicine, university of sydney, australia 6 department of interventional radiology, liverpool hospital, australia 7 department of radiology, prince of wales hospital, nsw, australia 8 chatswood dermatology centre, nsw, australia 9 department of anatomical pathology, douglass hanly moir pathology, macquarie park, australia abstract prostatic artery embolization is becoming increasingly popular in the management of benign prostatic hyperplasia, particularly for patients with significant comorbidities that make them poor candidates for either general anaesthesia or surgical intervention. penile tip necrosis as a complication following prostatic artery embolization is exceedingly rare, with only 4 cases previously reported in the world literature. it occurs as a result of the embolization material passing into and occluding collateral arterial networks such as those supplying the glans penis. this paper identifies 3 further cases of penile tip necrosis, outlines its natural history, and proposes management strategies, so that clinicians can better identify and treat this condition. http://siuj.org mailto:cameron.parkin%40health.nsw.gov.au?subject=siuj abbreviations asa american society of anaesthesiologists physical status classification system bph benign prostatic hyperplasia idc indwelling urethral catheter ipss international prostate symptom score luts lower urinary tract symptoms pae prostatic artery embolization turp transurethral resection of prostate embozene microspheres. pelvic angiography revealed the prostate arteries originating from the obturator arteries bilaterally. small accessory pudendal arteries were identified originating from the obturator arteries, forming an arterial anastomosis between the prostate and penis (figure 1). one week following the procedure, the patient noticed a rash developing over his glans penis. he was later referred to a dermatologist who noted full thickness epidermal necrosis and slough covering most of the glans (figure 2a). the edge of the slough was lifted, and a punch biopsy performed. this revealed complete ulceration of the epithelium, inf lammation and non-refractile spherical foreign bodies within the arterioles of the tissue, correlating with embozene microspheres used during the pae procedure (figure 2b). three months following the pae procedure, the necrotic areas over the glans had completely healed (figure 2c). these had been managed with regular dressings and daily 2% lignocaine ointment. the patient subsequently passed a trial of void. the second patient was an 84-year-old man, with an asa score of 4, who was referred for management of bph in the context of failed medical management. he had been experiencing worsening luts over 5 years and had been dependent on an indwelling urethral catheter (idc). a pre-procedural computed tomography angiogram of the pelvis had revealed both the left and the right prostatic arteries arising from a gluteopudendal trifurcation. a pae was undertaken via puncture of the right femoral artery. the left prostatic artery was embolized with 250 μm embozene microspheres until complete stasis was achieved. no right-sided figure 1. pelvic angiography of a 63-year-old male (case 1) undergoing prostatic artery embolization, with a catheter placed in the left internal iliac artery. the left prostatic artery is derived from the left obturator artery which is also is supplying an accessory pudendal artery to the penis. figure 2. penile tip necrosis encountered following prostatic artery embolization: (a) a 63-year-old male (case 1) who developed penile tip necrosis 1 week following pae; (b) areas of necrosis over the glans were biopsied which revealed embolization of the embozene microspheres (circled) from the prostatic artery embolization within the vessels of the specimen, with surrounding inflammation and ulceration; (c) three months following pae, the areas of necrosis had completely healed; (d) an 84-year-old male (case 2) who developed penile tip necrosis day 7 postprocedure. 324 siuj • volume 2, number 5 • september 2021 siuj.org brief communication http://siuj.org embolization was performed secondary to significant stenosis at the origin of the right prostatic artery. the day following the procedure, the patient developed penile tip pain and erythema. this was initially treated with simple analgesia and lignocaine 2% topical gel. pain persisted and patchy areas of necrosis developed over the glans penis (figure 2d). the patient was continued on regular tablet analgesia and clotrimazole 1% topical cream. by postoperative day 19, the penile wounds had completely healed. the idc was removed on postoperative day 60, and the patient was able to void spontaneously. the final patient was a 77-year-old man who initially presented to emergency in acute clot retention. a cystoscopy revealed the cause of haematuria to be a grossly enlarged trilobar prostate with a prominent vascularised median lobe. ultrasound revealed a prostatic volume of 176cc. he too had significant medical comorbidities and so was referred for pae. left radial artery access was obtained under local anaesthesia. left internal iliac ar teriography revea led t he lef t prostatic ar ter y branching from the middle rectal artery (figure  3a). the left prostatic artery was catheterized and embolized with 250 μm embozene microspheres. right internal iliac arteriography revealed significant supply from an accessory pudendal artery (figure  3b). the right prostatic artery was embolized with 250 μm embozene microspheres distal to the origin of the accessory pudendal artery. the patient presented to the emergency department on day 7 postoperatively with worsening penile pain. he was noted to have an area of necrosis on the glans penis, just ventral to the urethral meatus, which was exquisitely tender. he was admitted and managed conservatively. at 1-month follow-up, he had ongoing penile pain and had developed ulceration at the urethral meatus. he was commenced on chloramphenicol 1% topical ointment twice daily. the idc was removed at time of review, and he was able to void spontaneously. at 6-month follow-up, the patient had no pain, and the ulceration of the glans penis had healed. penile tip necrosis as a result of prostate artery embolization is rare, occurring in < 1% of cases[5]. nontarget embolization refers to the process in which the passage of the particles used to occlude the prostate arter y have passed into other arteria l networks supplying pelvic organs[5]. penile tip necrosis is a result of non-target embolization in which, during pae, these particles have likely passed from the prostatic artery into the pudendal circulation supplying the penis. patients who are vasculopaths with resultant abundant pelvic collaterization are at greater risk of non-target embolization[5]. the arterial supply of the penis as a result can be highly variable, where it can derive from the internal pudendal artery directly, from an accessory pudendal artery, or from a combination of the 2[8]. the accessory pudendal artery typically is a branch of the internal obturator artery or inferior vesical artery; the latter also supplies the prostatic arteries more proximally, thus forming an anastomosis between the prostate and the penis[8]. patients who have accessory pudendal arteries are at higher risk of penile complications following pae as a result[9]. bilhim et al., in a retrospective study of 186 patients who underwent pae for lower urinary tract symptoms, identified 9 patients (4.8%) who developed small skin lesions on the glans penis following pae[9]. these were likely small areas of necrosis, all of which had spontaneously healed within 1 month of the procedure[9]. the pelvic angiography of these cases revealed that all patients who suffered from this minor complication had prominent accessory pudendal arteries[9]. thus, for patients in whom accessory pudendal arteries are identified, care must be taken with the embolization technique to clearly identify the arterial anatomy to minimize the occurrence of non-target embolization[9]. in all 3 cases discussed, 250 μm embozene microspheres were used to occlude the prostatic arteries. currently there is a wide variety in the size and composition of embolic agents available, with no consensus on a preferable agent. there is debate as to whether smaller particles, between 100 μm and 300 μm, may predispose patients to nontarget embolization and recanalization of the arterial supply[10,11]. a small prospective randomised controlled trial has compared outcomes in 15 patients undergoing pae who were embolized with smaller particles (100 μm to 300 μm) with outcomes in 15 patients embolized with larger particles (300 μm to 500 μm)[10]. functionally, figure 3. three-dimensional reconstructions of a pelvic angiogram of a 77-year-old patient (case 3) undergoing prostatic artery embolization revealing selective catheterization of the left and right prostatic arteries (lpa & rpa – white arrows). (a) the left prostatic artery originated from the middle rectal artery; (b) the right prostatic artery was identified to originate from an accessory pudendal artery (red arrow) which is also seen supplying the penis. 325siuj.org siuj • volume 2, number 5 • september 2021 non-target embolization of the glans penis during prostatic artery embolization http://siuj.org both groups showed significant improvement in lower urinary tract symptoms as determined by mean ipss scores. there were no major complications reported in either group, with no reports of penile tip necrosis. the patient cohort embolized with smaller agents did, however, report greater rates of complications, though these were not statistically significant (p = 0.066). these were mainly characterised by ejaculatory dysfunction and haematochezia. as this is an uncommon occurrence following pae, clinicians should still undertake a thorough clinical history and examination when approaching a new penile lesion. penile lesions with similar appearance to that seen in these cases can be divided into benign, infective, inflammatory, and malignant aetiology. penile biopsy should be reserved for those cases in which the diagnosis is unclear, or in which malignancy is suspected. given its low incidence, there are no guidelines on the prevention and management of penile tip necrosis following pae. although certainly alarming in appearance, all cases reported have healed in time. current literature suggests that in addition to local wound care, patients should be commenced on regular acetylsalicylic acid to reduce platelet aggregation at the site of necrosis and tadalafil to reduce cytokine mediated inf lammation[5]. in the cases discussed, a stepwise analgesic regimen was followed, consisting of regular paracetamol, non-steroidal anti-inf lammatories, and topical local anaesthesia in the form of 2% lignocaine. when concurrent infection is suspected, use of topical antimicrobials such as 1% chloramphenicol should be considered. references 1. huang m, winoker j, matlaga b, allaf m, koo k. evidence-based analysis of online consumer information about prostate arter y embolization for benign prostatic hyperplasia. prostate cancer prostatic dis.2021;24:106-113. doi: 10.1038/s41391-020-0242-2 2. kasivisvanathan v, challacombe b, eds. the big prostate. 1st ed. springer international publishing;2017. 3. pisco j, bilhim t, pinheiro lc, fernandes l, pereira j, costa nv, et al. mediumand long-term outcome of prostate artery embolization for patients with benign prostatic hyperplasia: results in 630 patients. j vasc interv radiol.2016;27(8):1115–1122. doi: 10.1016/j. jvir.2016.04.001 4. ray a, powell j, speakman m, longford nt, dasgupta r, bryant t, et al. the uk rope study: efficacy and safety of prostate artery embolization for benign prostatic hyperplasia. an observational study and propensity matched comparison with transurethral resection of the prostate. bju int.2018;122(2):270–282. doi: 10.1111/bju.14249 5. isaacson a, bagla s, raynor m, yu h, eds. prostatic ar ter y embolization. 1st ed. springer international publishing; 2020. 6. kably i, richardson a, naidu a, sinha v, bhatia s. coil embolization of penile arterial collaterals during pae efficacy and safety profile. j vasc interv radiol.2018;29(4):s8. 7. kisilevzk y n, laudanna neto c, cividanes a. ischemia of the glans penis following prostatic artery embolization. j vasc interv radiol.2016;27(11):1745–1747. 8. henry b, pękala p, vikse j, sanna b, skinningsrud b, saganiak k, et al. variations in the arterial blood supply to the penis and the accessory pudendal artery: a meta-analysis and review of implications in radical prostatectomy. j urol.2017;198(2):345–353. doi: 10.1016/j. juro.2017.01.080 9. bilhim t. endovascular resection of the prostate: how much is enough for prostate artery embolization? j vasc interv radiol.2019;30(2):225– 227. doi: 10.1016/j.jvir.2018.10.009 10. goncalves o, carnevale f, moreira a, antunes a, rodrigues v, srougi m. comparative study using 100-300 versus 300-500 μm microspheres for symptomatic patients due to enlarged-bph prostates. cardiovasc intervent radiol.2016;39:1372-1378. doi: 10.1007/s00270-016-1443-x 11. bilhim t, pisco j, pereira j, costa n, fernandes l, campos pinheiro l, et al. predictors of clinical outcome after prostate artery embolization with spherical and nonspherical polyvinyl alcohol particles in patients with benign prostatic hyperplasia. radiology.2016;281(1):289–300. doi: 10.1148/radiol.2016152292 326 siuj • volume 2, number 5 • september 2021 siuj.org brief communication http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. we present the case of a 64-year-old man with intermit tent hematuria dating back more t ha n 6  months. a bladder mass was found on ultrasound, and endoscopic evaluation revealed a necrotic whitish intraluminal bladder mass (figure 1). the patient underwent complete transurethral resection of this bladder mass. the anatomopathological examination found a necrotic inflammatory lesion, with ghosts of neoplastic cells but no viable neoplastic cells throughout (figure 2). cross-sectional imaging revealed no additional disease. the patient was followed up with cystoscopy and computed tomography, and no recurrence was noted after 6 months. burned-out tumor, in which the initial tumor has completely or partially necrosed, is reported rarely in testicular cancer[1], but, to the best of our knowledge, has never previously been reported in bladder cancer. burned-out bladder tumor achraf chatar,1 jihad el anzaoui,2 ali akjay,2 ahmed ameziane,1 abdenasser lakrabti,2 abdelghani ammani2 1 chu hassan ii, fes, fès-meknès, morocco 2 military hospital moulay ismail meknes, morocco key words competing interests article information burned-out, tumor, bladder cancer none declared. patient consent: obtained. received on february 17, 2021 accepted on march 11, 2021 soc int urol j.2021;2(3):188 doi: 10.48083/qgju1775 figure 1. endoscopic aspect of bladder tumor figure 2. anatomopathological aspect of the tumor reference 1. cheng l, lyu b, roth lm. perspectives on testicular germ cell neoplasms. hum pathol.2017;59:10–25. doi: 10.1016/j.humpath.2016.08.002. 188 siuj • volume 2, number 3 • may 2021 siuj.org original research mailto:chatarachraf%40gmail.com?subject=siuj http://www.siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information type 1 diabetes, male infertility, clinical predictors dr hehemann is a consultant for boston scientific corporation. the remaining authors declare no competing interests. received on december 22, 2020 accepted on march 1, 2021 soc int urol j.2021;2(3):139–143 doi: https://doi 10.48083/ vvmv5977 does type 1 diabetes affect male infertility: type 1 diabetes exchange registry-based analysis omer a. raheem,1 marah c. hehemann,2 marc j. rogers,3 judy n. fustok,1 irl b. hirsch,4 thomas j. walsh2 1 department of urology, tulane university, new orleans, united states 2 department of urology, university of washington, seattle, united states 3 department of urology, medical university of south carolina, united states 4 division of metabolism, endocrinology and nutrition, university of washington, seattle, united states abstract introduction the prevalence of type 1 diabetes (t1d) has been increasing over the last few decades and is commonly believed to negatively impact male fertility. we aimed to estimate the prevalence of infertility among men with t1d and to characterize potential clinical predictors for male infertility among men with t1d. methods we used data collected from the t1d exchange registry from 2012 to 2017. men with t1d completed an infertility questionnaire indicating whether they had ever had problems conceiving a child or had ever received abnormal results from infertility testing. collected data included age at questionnaire, age at diagnosis of t1d, duration of t1d, race/ethnicity, insurance status, education level, annual household income, hemoglobin a1c (hba1c), low density lipoprotein (ldl), diabetic retinopathy, micro/macroalbuminuria, and renal failure. results the survey was completed by 2171 registry members, 33 (1.5%) of whom reported male infertility. mean age at questionnaire was 38 and 56 years in the fertile and infertile groups, respectively (p < 0.001). there was no statistically significant difference in the mean age at t1d diagnosis (16 and 27 years), mean duration of t1d at questionnaire (22 and 30 years), white non-hispanic ethnicity (1906/2138, 89% versus 30/33, 91%), private insurance (1509/2138, 79% versus 30/33, 91%), and annual household income in us dollars ≥ $100 000 (757/2138, 45% versus 16/33, 55%) in the fertile and infertile men, respectively. on multivariate analysis, for each year of advancing age, men were 5% more likely to experience infertility. age at questionnaire was the only significant predictor of infertility (or 1.05; 95%ci 1.03 to 1.08). age at t1d diagnosis (or 1.01; 95%ci 0.99 to 1.04), duration of t1d (or 0.99; 95%ci 0.96 to 1.01), mean hba1c (or 1.03; 95%ci 0.77 to 1.37), diabetic retinopathy (or 1.04; 95%ci 0.50 to 2.15), and mean ldl (or 1.01; 95%ci 0.99 to 1.02) failed to independently predict infertility; however, presence of renal failure (or 3.38; 95%ci 0.94 to 12.13) and micro/macroalbuminuria (or 1.27; 95%ci 0.42 to 3.82) trended toward increased odds of infertility. conclusions this study highlights the prevalence of male infertility among men with t1d. beyond age, there were no independent clinical predictors for male infertility among men with t1d; however, men with clinical evidence of diabetes-associated renal compromise trended toward greater odds of infertility. further studies of fertility in this growing, at-risk population are warranted. 139siuj.org siuj • volume 2, number 3 • may 2021 original research mailto:oraheem%40tulane.edu?subject=siuj http://www.siuj.org table 1. patient demographics and characteristics variable fertile n = 2138 n (%) infertile n = 33 n (%) age at questionnaire years (mean)a 18–25 26–34 35–49 ≥ 50 38 872 (41) 239 (11) 407 (19) 620 (29) 56 0 0 13 (39) 20 (61) age at diagnosis years (mean) <6 6–12 13–17 18–25 26–49 ≥ 50 16 340 (16) 784 (37) 345 (16) 231 (11) 396 (19) 42 (2) 27 4 (12) 6 (18) 4 (12) 5 (15) 8 (24) 6 (18) duration of t1d at questionnaire years (mean) 1–9 10–19 20–49 ≥ 50 22 400 (19) 818 (38) 817 (38) 103 (5) 30 2 (6) 7 (21) 23 (70) 1 (3) race/ethnicity white non-hispanic black non-hispanic hispanic or latino others 1906 (89) 46 (2) 118 (6) 68 (3) 30 (91) 1 (3) 2 (6) 0 insurance status private insurance other insurance no insurance 1509 (79) 381 (20) 11 (<1) 30 (91) 3 (9) 0 education level <high school high school/associates bachelors masters professional/doctorate 95 (5) 981 (46) 660 (31) 239 (11) 136 (6) 0 10 (30) 11 (33) 6 (18) 6 (18) annual household income (us$) < 35 000 35 000–< 50 000 50 000–< 75 000 75 000–< 100 000 ≥ 100 000 285 (17) 133 (8) 232 (14) 263 (16) 757 (45) 3 (10) 2 (7) 3 (10) 5 (17) 16 (55) a p < 0.001 introduction the prevalence of type 1 diabetes (t1d) has been increasing worldwide and in the united states over last few decades and commonly manifests during childhood. t1d is an autoimmune destruction of the pancreatic beta-cells that ultimately leads to failure of insulin production. several important risk factors for t1d have been identified and include obesity, family history, and genetic polymorphisms[1,2]. more importantly, t1d is associated with an increased risk of cardiovascular disease and mortality, and clinical prognosis worsens if t1d is left untreated[3]. it has been suggested that male infertility is not a unique disease of the reproductive axis, but rather a clinical marker underpinning overall health and well-being in men[4,5]. while research has focused on the relationship between metabolic syndrome, obesity, dyslipidemia, hypertension, and insulin resistance or genitourinary malignancies on male infertility, there is paucity of contemporary literature specifically addressing the detrimental effects of t1d on male fertility[6,7]. in this study, we sought to characterize the prevalence of infertility among men with t1d. we hypothesized that the rate of infertility among men with t1d would be higher than rate reported in the general population. additionally, we sought to identify clinical predictors of infertility among men with t1d. materials and methods study population and design the study was conducted using the large dataset collected from the t1d exchange registry[8]. the protocol was approved by the university of washington institutional review board, and study participants provided written informed consent. the t1d exchange registry provides demographic and clinical information on individuals diagnosed with t1d in the united states, offering a broad representation of pediatric and adult patients with t1d. data are collected for the registry database at enrollment and then once a year. data are obtained through (1) completion of a questionnaire by the participant or parent of the participant and (2) retrieval of information collected from the medical records[8]. fertility was determined using 2 questions on male infertility in the t1d exchange registry questionnaire: (1) have you ever had problems conceiving a child? yes/no (2) have you ever received infertility testing? yes/no; if yes, (2a) were the test results normal? yes/ no (appendix 1). men were considered infertile if they indicated they had previously had problems conceiving a child and/or if they had abnormal test results on infertility testing. otherwise, men were assigned to the 140 siuj • volume 2, number 3 • may 2021 siuj.org original research http://siuj.org fertile group. collected data included age at questionnaire, age at diagnosis of t1d, duration of t1d, race/ethnicity, insurance status, education level, annual household income, hemoglobin a1c (h ba1c), low densit y lipoprotein (ldl), diabetic retinopat hy, micro/ macroalbuminuria, and renal failure. linear regression multivariate models were performed to assess the clinical predictors of t1d patients associated with male infertility. we sought to determine the prevalence of infertility in males with t1d. secondarily, we sought to identify the clinical predictors of infertility among t1d men. statistical analysis we used the mann-whitney u test and chi-square test for continuous and categorical variables, comparing the fertile and infertile groups. multivariable analysis was also performed to identify these clinical factors associated with male fertility. statistical significance was defined by p-value < 0.05. all data analysis was performed using statistical software r version 3.3.2. results in this study, a total of 2171 out 3955 men completed the infertility portion of the year 5 questionnaire within the t1d exchange registry from 2012 to 2017. this database includes 18 743 participants from 79 clinic sites. t1d exchange clinic network is coordinated by the jaeb center for health research, a nonprofit clinical research coordinating center in tampa, florida. thirty-three men (1.5%) reported male infertility. mean age at questionnaire was 38 and 56 years in the fertile and infertile groups, respectively (p < 0.001). there was no statistically significant difference in the mean age at t1d diagnosis (16 versus 27 years), mean duration of t1d at questionnaire (22 versus 30 years), white non-hispanic ethnicity (1906/2138, 89% versus 30/33, 91%), private insurance (1509/2138, 79% versus 30/33, 91%), and annual household income in us dollars ≥ $100 000 (757/2138, 45% versus 16/33, 55%) in the fertile and infertile men, respectively (table 1). on multivariate analysis, for each year of advancing age men were 5% more likely to experience infertility. age at questionnaire was the only significant predictor of infertility (or 1.05; 95%ci 1.03 to 1.08). age at t1d table 2. multivariate analysis for clinical predictors of t1d patients associated with male infertility variables/predictors fertile n (%) infertile n (%) unadjusted or (95% ci) adjusted or (95% ci) age at diagnosis, years (mean) 16 27 1.05 (1.03–1.07) 1.01 (0.99–1.04) duration of t1d at questionnaire, years (mean) 22 30 1.04 (1.01–1.06) 0.99 (0.96–1.01) hemoglobin a1c (hba1c) mg/dl (mean) 8.0 7.7 0.84 (0.64–1.10) 1.03 (0.77–1.37) diabetic retinopathy 566 (28) 14 (42) 0.54 (0.27–1.08) 1.04 (0.50–2.15) renal status renal failure micro/macroalbuminuria no albuminuria 32 (2) 156 (8) 1887 (91) 3 (10) 4 (13) 23 (77) 7.69 (2.20–26.93) 2.10 (0.72–6.16) ref 3.38 (0.94–12.13) 1.27 (0.42–3.82) ref low density lipoprotein level, mg/dl (mean) 90.5 88.4 1.00 (0.98–1.01) 1.01 (0.99–1.02) aadjusted for age at questionnaire 141siuj.org siuj • volume 2, number 3 • may 2021 does type 1 diabetes affect male infertility: type 1 diabetes exchange registry-based analysis http://www.siuj.org diagnosis (or 1.01; 95%ci 0.99 to 1.04), duration of t1d (or 0.99; 95%ci 0.96 to 1.01), mean hba1c (or 1.03; 95%ci 0.77 to 1.37), diabetic retinopathy (or 1.04; 95%ci 0.50 to 2.15), and mean ldl (or 1.01; 95%ci 0.99 to 1.02) failed to independently predict infertility; however, presence of renal failure (or 3.38; 95%ci 0.94 to 12.13) and micro/macroalbuminuria (or 1.27; 95%ci 0.42 to 3.82) trended toward increased odds of infertility (table 2). discussion recent studies have linked diabetes mellitus (dm) (type 1 or 2) and infertility with an increased risk of developing dm among infertile men which can reach as high as 30%[9]. this association has been reproduced in a large prospective danish in vitro fertilization registry by glazer et al. of 39 516 men who had undergone fertility treatment with their female partner with a median follow-up time of 5.6 years. this study found 651 (1.6%) cases of type 1 or 2 dm among men with infertility (eg, oligospermia, azoospermia) with the risk being related to the severity of the underlying fertility problem[10]. in our study, 33 men out of 2171 (1.5%) with t1d reported infertility, which supports the findings of glazer et al.[10]. furthermore, several previous studies have suggested dm has a mild impact on semen quality. for example, dm may have its effects on male reproductive function by endocrine control of spermatogenesis, sperm maturation, and impairment of ejaculation[11]. the prevalence of abnormalities such as azoospermia, oligospermia, and aspermia may be higher in patients with dm and in elderly men[12-14]. in our study, men who were older at the time of the questionnaire were more likely to have experienced infertility, suggesting that the longer the duration of t1d, the greater likelihood of infertility in these men. moreover, this study highlighted some common dm sequalae such as renal failure and micro/macroalbuminuria, which were found to be significantly more prevalent among infertile men. it is worth mentioning that this study did not report specific sperm abnormalities as it is questionnaire-based study (appendix 1). the findings of this study reinforce the importance of understanding the common metabolic pathway linking dm and male infertility. cross-sectional studies have shown that even at the time of a fertility evaluation, men with reduced fertility already present with more medical comorbidities than their fertile peers[15,16]. the observation of a higher baseline prevalence of dm among men with infertility is concordant with this evidence. however, the relationship between male infertility and overall health is rather complex as several confounders may affect both. for example, as both age and smoking are known to affect semen quality[14] and diabetes risk[17], the results of this study must be interpreted with caution. furthermore, a genetic link between dm and male infertility may exist as a recent study identified over 100 genes associated with both male infertility and several disease mechanisms, including metabolic disease pathways[18]. further, as many genes are expressed during male germline cell differentiation, it seems plausible that possible mutations in this process could lead to both male infertility and risk of dm[19]. our study does have some limitations that should be noted. our questionnaire did not ask specific questions about when these patients experienced infertility, so it is difficult to interpret whether men in the infertile group experienced infertility in their 20s and 30s, or at an older age. however, we did find that men with advancing age were more likely to experience infertility, which we believe suggests that a greater duration with t1d might increase the likelihood of infertility. secondly, our study questionnaire does not specify whether the difficulty conceiving a child was due solely to male factors or also female factors. finally, this study asked patients with t1d to identify whether they had experienced trouble conceiving and whether they had undergone fertility testing, but did not report specific abnormalities, which would have been of interest. we believe more research should be conducted in the future to look at specific fertility abnormalities associated with dm, while our study attempted to address the overall prevalence of infertility in this population. conclusions this study highlights the prevalence of male infertility among men with t1d. beyond age, there were no independent clinical predictors for male infertility among men with t1d; however, men with clinical evidence of diabetes-associated renal compromise were more likely to be infertile. further studies of fertility in this growing, at-risk population are warranted. 142 siuj • volume 2, number 3 • may 2021 siuj.org original research http://siuj.org references 1. arora r, koch mo, eble jn, ulbright tm, li l, cheng l. 1. jangir rn, jain gc. diabetes mellitus induced impairment of male reproductive functions: a review. curr diabetes rev.2014;10:147–157. 2. kasturi ss, tannir j, brannigan re. the metabolic syndrome and male infertility. j androl.2008;29:251–259. 3. gu k, cowie cc, harris mi. mortality in adults with and without diabetes in a national cohort of the u.s. population, 1971–1993. diabetes care.1998;21:1138–1145. 4. american diabetes association. economic costs of diabetes in the u.s. in 2012. diabetes care.2013;36:1033–1046. 5. monga m, alexandrescu b, katz se, stein m, ganiats t. impact of infertility on quality of life, marital adjustment, and sexual function. urology.2004; 63:126–130. 6. walsh tj, schembri m, turek pj, chan jm, carroll pr, smith jf, et al. increased risk of high-grade prostate cancer among infertile men. cancer.2010;116:2140–2147. 7. hotaling jm, walsh tj. male infertility: a risk factor for testicular cancer. nat rev urol.2009;6:550–556. 8. beck rw, tamborlane w v, bergenstal rm, miller km, dubose sn, hall ca; t1d exchange clinic network. the t1d exchange clinic registry. j clin endocrinol metab.2012;97: 4383–4389. 9. eisenberg ml, li s, cullen mr, baker lc. increased risk of incident chronic medical conditions in infertile men: analysis of united states claims data. fertil steril.2015;105:629–636. 10. glazer ch, bonde jp, giwercman a, vassard d, pinborg a, schmidt l, et al. risk of diabetes according to male factor infertility: a registerbased cohort study. hum reprod.2017 may;32(7):1474–1481. doi: 10.1093/humrep/dex097. 11. eisenberg ml, li s, behr b, pera rr, cullen mr. relationship bet ween semen production and medical comorbidit y. fertil steril.2015;103:66–71. 12. fedder j, kaspersen md, brandslund i, hojgaard a. retrograde ejaculation and sexual dysfunction in men with diabetes mellitus: a prospective, controlled study. andrology.2013;1:602–606. 13. kasturi ss, tannir j, brannigan re. the metabolic syndrome and male infertility. j androl.2008;29:251–259. 14. sharma r, agarwal a, rohra vk, assidi m, abu-elmagd m, turki rf.effects of increased paternal age on sperm quality, reproductive outcome and associated epigenetic risks to offspring. reprod biol endocrinol.2015;13:35. 15. ventimiglia e, capogrosso p, boeri l, serino a, colicchia m, ippolito s, et al. infertility as a proxy of general male health: results of a cross-sectional survey. fertil steril.2015;104:48-55. 16. salonia a, matloob r, gallina a, abdollah f, sacca a, briganti a, et al. are infertile men less healthy than fertile men? results of a prospective case-control survey. eur urol.2009;56:1025–1031. 17. biggs ml , mukamal k j, luchsinger ja , i x jh, c ar nethon mr, new man a b, et al. association bet ween adiposit y in midlife and older age and risk of diabetes in older adults. jama.2010;303:2504–2512. 18. tarin jj, garcia-perez ma, hamatani t, cano a. infertility etiologies are genetically and clinically linked with other diseases in single meta-diseases. reprod biol endocrinol.2015;13:31. doi: 10.1186/ s12958-015-0029-9. 19. matzuk mm, lamb dj. the biology of infertility: research advances and clinical challenges. nat med.2008;14:1197–1213. infertility the next questions are about infertility history this will be shown to participants ≥ 18 years old. do not wish to answer the following questions 1. have you ever had problems conceiving a child? yes no 2. have you ever received infertility testing? yes no if you answered yes to question 2, please answer 2a. 2a. were the test results normal? yes no appendix 1. participating research centres 143siuj.org siuj • volume 2, number 3 • may 2021 does type 1 diabetes affect male infertility: type 1 diabetes exchange registry-based analysis http://www.siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information follicle-stimulating hormone, biomarker, androgen deprivation therapy, oncologic outcomes, prostate cancer paul toren reports research funding from bristol-myers-squibb and janssen, as well as personal fees as a consultant from sanofi, ferring, astellas, bayer, and abbvie. funding: this project was funded by a fonds de recherche du québec – santé clinicianscientist award (#32774) and a prostate cancer canada movember discovery grant (d2016-1393). received on august 6, 2021 accepted on september 7, 2021 this article has been peer reviewed. soc int urol j. 2022;3(2):56–61 doi: 10.48083/lwhq7760 56 siuj • volume 3, number 2 • march 2022 siuj.org original research follicle-stimulating hormone (fsh) levels during androgen deprivation therapy are not associated with survival or development of castration-resistant prostate cancer kaleem atchia,1 france-hélène joncas,1 lily summers trasiewicz,2 wei phin tan,3 keyue ding,2 brant a. inman,3 paul toren1 1 department of surgery, faculty of medicine, université laval; centre hospitalier universitaire (chu) de québec research centre, oncology division, québec city, canada 2 canadian cancer trials group (cctg), queen’s university, kingston, canada 3 division of urology, duke cancer institute, duke university, durham, united states abstract background follicle-stimulating hormone (fsh) dysregulation plays a potential role in prostate cancer progression. the objective of this study was to evaluate whether higher fsh levels during androgen deprivation therapy (adt) for recurrent prostate cancer could predict the development of castration-resistant prostate cancer (crpc), prostate cancer-specific survival (css), and overall survival (os). methods serum fsh levels were measured in cryopreserved samples of the continuous adt arm of the pr.7 trial, supplemented with analogous samples from a large contemporaneous biobank. univariate and multivariate analyses assessed the relationship between fsh tertiles and time to crpc, as well as css, and os. results a total of 172 patients were included in our analysis. of these, 54 patients (31%) developed crpc during the 9-year follow-up. median fsh for the tertiles was 4.35, 6.13, and 11.32 miu/ml. fsh tertiles were not significantly associated with the time to crpc, or with css or os. fsh levels were not a significant prognostic factor for these oncologic outcomes. conclusion as previously reported, the use of gonadotropin-releasing hormone (gnrh) antagonists for adt has significantly more suppression of fsh levels than gnrh agonists. our results do not suggest that differences in circulating fsh 1 year following adt initiation influence long-term oncologic outcomes or development of crpc. introduction there is mounting evidence that follicle-stimulating hormone (fsh) dysregulation may play a role in prostate cancer development and progression[1]. selective expression of fsh receptor by endothelial cells has been demonstrated in a wide range of tumors as well as in the majority of tumor metastases, including prostate cancer[2,3]. higher preoperative levels of serum fsh have been linked with lower levels of testosterone, higher grade cancer, and extraprostatic extension[4,5]. in patients undergoing androgen deprivation therapy (adt) for advanced prostate http://siuj.org mailto:paul.toren%40crchudequebec.ulaval.ca?subject=siuj cancer, an association between serum fsh levels and the time to the development of castration-resistant prostate cancer (crpc) has been reported in a retrospective, single-center study[6]. adt has also been associated with a higher risk of cardiovascular events[7,8]. moreover, in the context of adt, data suggest that fsh can promote cardiovascular, metabolic, and skeletal comorbidities through atherosclerotic plaque formation, metabolic syndrome, insulin resistance, and bone resorption[9,10]. of particular interest, recent reports have highlighted the differences in cardiovascular events between gonadotropin-releasing hormone (gnrh) agonists and antagonists. for instance, a randomized phase ii study by margel et al. suggested that gnrh antagonist therapy, which lowers circulating fsh levels, is associated with an 18% absolute risk reduction in major adverse cardiovascular and cerebrovascular events[11]. more recently, the randomized phase iii hero trial comparing leuprolide with the oral gnrh antagonist relugolix has shown a 54% relative risk reduction of major adverse cardiovascular events (mace)[12]. an important difference between gnrh agonists and antagonists during adt is superior suppression of serum fsh with antagonists, which has been a leading hypothesis in explaining the differences in cardiovascular and other comorbidities. however, the role of fsh biology and its impact on clinical outcomes remains to be fully defined. the role of fsh suppression on clinical outcomes and safety has so far been researched mainly in studies comparing gnrh agonists with antagonists. in the cs21 trial, rapid decrease in psa and more profound suppression of fsh was noted with degarelix compared with leuprolide, including upon crossover from leuprolide to degarelix[13]. few studies have reported on the association of fsh levels before or during adt, as an independent prognostic factor, on clinical outcomes. in a recent study, kourbanhoussen et al. showed no significant association between fsh levels before prostatectomy with biochemical recurrence, time to crpc, time to metastasis, or occurrence of mace[14]. in the context of adt, it has been reported that fsh levels could predict time to the development of crpc[6]. in this study, using cryopreserved serum samples from the pr.7 trial with long annotated clinical follow-up[15], we sought to evaluate whether higher fsh levels correlate with lower overall survival (os) and cancer-specific survival (css), as well as a reduced time to development of crpc. methods inst itut iona l resea rch et hics approva l for t his retrospective study was obtained from the chu de québec-université laval (2016-2835) and from the duke university institutional review board (pro00044627). for this analysis, we identified 163 patients with cryopreserved serum samples taken 12 months post randomization from the continuous androgen deprivation (cad) arm of the pr.7 trial for whom demographic information and long-term clinical follow-up were available in the canadian cancer trials group (cctg) database. informed consent was obtained for the biobank for all participants in the pr.7 trial. for 100 of those patients, serum samples taken 24 and 36 months post randomization were also available and were included in our analysis. details of the pr.7 trial are provided in the original publication[15]. notably, all patients received gnrh agonists in this cohort. to increase our statistical power, we included 9 additional contemporaneous cryopreserved serum samples from patients identified in a large biobank at duke university with long clinical follow-up. these patients also received continuous adt following psa recurrence following radiotherapy and met the inclusion criteria of the pr.7 trial. fsh levels were measured using 20 µl of plasma with immunoassays according to the manufacturer’s instructions (cayman chemicals, ann arbor, mi, us). statistical analyses assessed the relationship between fsh levels and clinical outcomes such as os, css, and time to crpc. crpc was defined as at least 2 rising psa values or as new or progressing metastases despite castrate levels of testosterone (< 1.7 mmol/l). patients were divided into tertiles based on fsh levels during cad and kaplan-meier survival curves estimated os, css, and time to crpc for these tertiles. cox multivariable proportional hazards analyses were performed for the same outcomes, with adjustment for baseline clinical factors: age, gleason score, baseline psa, time since radiotherapy, and eastern cooperative oncology group (ecog) status. results a total of 172 patients were included in this study. the mean age was 73.4 years, and almost 80% of patients abbreviations adt androgen deprivation therapy crpc castration-resistant prostate cancer css cancer-specific survival fsh follicle-stimulating hormone gnrh gonadotropin-releasing hormone os overall survival 57siuj • volume 3, number 2 • march 2022 siuj.org follicle-stimulating hormone (fsh) levels during androgen deprivation therapy http://siuj.org had a gleason score ≤7 at diagnosis. the median fsh during adt was 6.19 iu/ml (interquartile range: 4.82 to 9.81). median fsh for the tertiles was 4.35, 6.13, and 11.32 miu/ml. only 10% of patients had prostatectomy before adt. over the 9 years of follow-up, 54 patients (31%) developed crpc, and 48 patients (28%) died, of whom 20 (12%) died of prostate cancer. demographic and clinical characteristics are outlined by fsh tertile and for the whole cohort in table 1. baseline patient characteristics were similar across all tertiles, except that gleason scores were similar for tertiles 1 and 3, while tertile 2 had fewer patients with a score > 7. univariate and multivariate cox regression analysis adjusted for age, gleason score, baseline psa, time since radiotherapy, and ecog status found no significant association between fsh tertile and os, css, or time to development of crpc (figure 1, table 2). for the subset of 100 patients with 3 annual fsh measurements after randomization, median and maximum fsh levels were similarly analyzed, but no statistically significant association was found. lastly, within the latter subset of patients, a comparison of patients with increasing fsh levels (≥ 30% from baseline) with those who had no increase (< 30%) yielded no significant association with the clinical outcomes. discussion the role of fsh in prostate cancer clinical outcomes and comorbidities during adt is not yet fully understood. in this analysis, we were not able to demonstrate a significant association between circulating fsh levels during adt and os, css, or time to development of crpc. given that low testosterone levels before radical prostatectomy have been associated with poor prognosis[16–19], table 1. demographic and clinical characteristics of patients according to fsh tertile fsh tertile 1 fsh tertile 2 fsh tertile 3 all patients number of patients 56 59 57 172 age–mean (sd) 73.2 (7.7) 73.1 (5.8) 74.0 (5.3) 73.4 (6.3) age–median (iqr) 74.95 (68.4, 78.9) 74.1 (69.8, 77.5) 74.6 (69.5, 77.2) 74.4 (69.2, 77.95) gleason score–n (%) ≤ 7 > 7 not available 44 (78.6) 9 (16.1) 3 (5.3) 50 (84.7) 6 (10.2) 3 (5.1) 43 (75.4) 11 (19.3) 3 (5.3) 137 (79.7) 26 (15.1) 9 (5.2) baseline psa–median (iqr), ng/ml 8.04 (5.45, 10.75) 7.53 (5.90, 13.90) 8.10 (6.40, 12.10) 7.96 (5.92, 12.05) baseline testosterone–median (iqr), nmol/l 12.55 (9.00, 16.75) 11.90 (8.90, 14.90) 12.20 (9.85, 16.10) 12.10 (9.30, 16.00) testosterone during adt–median (iqr), nmol/l 0.50 (0.40, 0.92) 0.80 (0.50, 1.20) 0.70 (0.40, 1.00) 0.70 (0.40, 1.10) fsh during adt–median (iqr), miu/ml 4.35 (3.82, 4.98) 6.13 (5.32, 7.13) 11.32 (9.85, 14.78) 6.19 (4.82, 9.81) prior prostatectomy – n (%) no yes 48 (86) 8 (14) 53 (90) 6 (10) 53 (93) 4 (7) 154 (90) 18 (10) crpc during follow-up – n (%) 18 (32) 17 (29) 19 (33) 54 (31) cancer-specific mortality – n (%) 6 (11) 5 (8) 9 (16) 20 (12) overall mortality – n (%) 17 (30) 11 (18.6) 20 (35) 48 (28) baseline ecog status – n (%) 0 1 45 (80) 11 (20) 51 (86) 8 (14) 44 (77) 13 (23) 140 (81) 32 (19) fsh: follicle-stimulating hormone; sd: standard deviation; iqr: interquartile range; crpc: castration-resistant prostate cancer 58 siuj • volume 3, number 2 • march 2022 siuj.org original research http://siuj.org 59siuj • volume 3, number 2 • march 2022 siuj.org follicle-stimulating hormone (fsh) levels during androgen deprivation therapy 100 80 60 pe rc en ta ge 100 20 1/3tertl 2/3tertl 3/3tertl 0 0186420 100 80 60 pe rc en ta ge time (years) 100 20 1/3tertl 2/3tertl 3/3tertl 0 0186420 100 80 60 pe rc en ta ge 100 20 1/3tertl 2/3tertl 3/3tertl 0 0186420 overall survival development of crpc time (years) time (years) figure 1. kaplan-meier curves for overall survival, cancer-specific survival, and development of crpc by fsh tertile http://siuj.org it would be reasonable to hypothesize that physiologic feedback increase in fsh might also be a marker for adverse disease course. however, a recent retrospective study of 492 patients showed no association between fsh levels and long-term oncologic and cardiovascular outcomes[14]. although several studies found some evidence for preoperative fsh levels as a prognostic marker for more aggressive disease in patients undergoing radical prostatectomy[4,5,20], we found no differences in long-term clinical outcomes for advanced prostate cancer under adt. few studies have directly investigated the prognostic value of fsh levels during adt. for example, a prior study of patients treated with adt reported that higher fsh levels may predict shorter time to development of crpc[6]. nonetheless, fsh measurement in this retrospective cohort occurred in less than a third of patients, raising the potential for selection bias. our contradictory results feature a greater number of patients, a lower proportion of patients who later developed crpc, and longer follow-up. our study has a reasonably sized, multi-centric cohort of patients with long-term clinical follow-up from a robust clinical trial. limitations intrinsic to the cohort of the clinical trial are discussed elsewhere[21]. however, the limitations of this study include the fact that only one fsh measurement was available for the main analysis 1 year into adt and 3 measurements over 3 years for a subset of patients. there was also no standardization of the time of sampling during the day, which may have small effects on circulating fsh levels due to circadian rhythms. no details were available on whether patients had medical comorbidities that might have affected fsh production. finally, the number of events limits the power to detect differences between the fsh tertiles. accumulating research comparing gnrh agonists with antagonists suggests gnrh antagonists are associated with lower overall mortality and cardiovascular events[22]. superior fsh suppression has been hypothesized to play an important role in this comparison. nonetheless, our results suggest fsh values following adt with gnrh agonists do not predict survival. thus, our results cast doubt on whether fsh levels are causative in any relationship between gnrh antagonists and cardiovascular outcomes. this is concordant with the recent report by kourbanhoussen et al.[14]. in summary, this retrospective analysis does not suggest that circulating fsh levels during adt for recurrent prostate cancer predict clinical outcomes. further clinical research is warranted to better understand the role of fsh level in prostate cancer patients. table 2. association between fsh tertile and long-term clinical outcomes variable fsh tertile 1, adjusted hr fsh tertile 2, adjusted hr (95% ci) fsh tertile 3, adjusted hr (95% ci) overall survival 1.00 0.544 (0.264–1.122) 1.106 (0.594–2.057) cancer-specific survival 1.00 0.639 (0.221–1.843) 1.250 (0.493–3.168) time to crpc 1.00 0.739 (0.393–1.388) 1.089 (0.595–1.995) fsh: follicle-stimulating hormone; crpc: castration-resistant prostate cancer; hr: hazard ratio; ci: confidence interval 60 siuj • volume 3, number 2 • march 2022 siuj.org original research http://siuj.org references 1. crawford ed, rove ko, schally av. the role of the fsh system in the development and progression of prostate cancer. am j hematol oncol.2014;10(6):5–13. 2. radu a, pichon c, camparo p, antoine m, allory y, couvelard a, et al. expression of follicle-stimulating hormone receptor in tumor blood vessels. n engl j med.2010;363:1621–1630. 3. siraj a, desestret v, antoine m, fromont g, huerre m, sanson m, et al. expression of follicle stimulating hormone receptor by the vascular endothelium in tumor metastases. bmc cancer.2013;13:246. 4. porcaro ab, siracusano s, de luyk n, corsi p, sebben m, tafuri a, et al. simultaneous measurements of follicle stimulating hormone and total testosterone and associations in clinically localized prostate cancer. curr urol.2017;10:174–181. doi: 10.1159/000447177. epub 2017 oct 22. 5. ide h, terado y, sakamaki k, inoue m, nakajima a, lu y, et al. serum level of follicle-stimulating hormone is associated with extraprostatic extension of prostate cancer. prostate int.2013;1:109 –112. doi: 10.12954/pi.13019. epub 2013 sep 27. 6. hoare d, skinner taa, black a, siemens, rd. serum follicle-stimulating hormone levels predict time to development of castration-resistant prostate cancer. can urol assoc j.2015;9:122–127. doi: 10.5489/ cuaj.2545. 7. carneiro a, sasse ad, wagner aa, peixoto g, kataguiri a, neto as, et al. cardiovascular events associated with androgen deprivation therapy in patients with prostate cancer: a systematic review and meta-analysis. world j urol.2015;33:1281–1289. doi: 10.1007/s00345014-1439-6. epub 2014 nov 12. 8. wallis cjd, mahar al, satkunasivam r, herschorn s, kodama rt, lee y, et al. cardiovascular and skeletal-related events following localized prostate cancer treatment: role of surgery, radiotherapy, and androgen deprivation. urology.2016;97:145–152. doi: 10.1016/j. urology.2016.08.002. epub 2016 aug 5. 9. crawford ed, schally av, pinthus jh, block nl, rick fg, garnick mb, et al. the potential role of follicle-stimulating hormone in the cardiovascular, metabolic, skeletal, and cognitive effects associated with androgen deprivation therapy. urol oncol.2017;35:183–191. doi: 10.1016/j.urolonc.2017.01.025. epub 2017 mar 18. 10. crawford ed, schally av. the role of fsh and lh in prostate cancer and cardiometabolic comorbidities. can j urol.2020;27:10167–10173. 11. margel d, peer a, ber y, shavit-grievink l, tabachnik t, sela s, et al. cardiovascular morbidity in a randomized trial comparing gnrh agonist and gnrh antagonist among patients with advanced prostate cancer and preexisting cardiovascular disease. j urol.2019;202:1199–1208. doi: 10.1097/ju.0000000000000384. epub 2019 jun 12. 12. shore nd, saad f, cookson ms, george dj, saltzstein dr, tutrone r, et al., for the hero study investigators. oral relugolix for androgen-deprivation therapy in advanced prostate cancer. n engl j med.2020;382:2187–2196. doi: 10.1056/nejmoa2004325 13. crawford ed, tombal b, keane t, boccardo f, miller k, shore n, et al. fsh suppression and tumour control in patients with prostate cancer during androgen deprivation with a gnrh agonist or antagonist. scand j urol.2018;52:349–357. doi: 10.1080/21681805.2018.1522372. epub 2019 jan 9. 14. kourbanhoussen k, joncas f-h, wallis cjd, hovington h, dagenais f, fradet y, et al. follicle-stimulating hormone (fsh) levels prior to prostatectomy are not related to long-term oncologic or cardiovascular outcomes for men with prostate cancer. asian j androl.2021; doi:10.4103/aja.aja_58_21. 15. crook jm, o’callaghan cj, duncang, dearnaley dp, higano cs, horwitz em, et al. intermittent androgen suppression for rising psa level after radiotherapy. n engl j med.2012;367:895–903. doi: 10.1056/nejmoa1201546 16. xylinas e, ploussard g, durand x, fabre a, salomon l, allory y, et al. low pretreatment total testosterone (< 3 ng/ml) predicts extraprostatic disease in prostatectomy specimens from patients with preoperative localized prostate cancer. bju int.2011;107:1400–1403. doi: 10.1111/j.1464-410x.2010.09816.x. epub 2010 nov 2. 17. dai b, qu y, kong y, ye d, yao x, zhang s, et al. low pretreatment serum total testosterone is associated with a high incidence of gleason score 8-10 disease in prostatectomy specimens: data from ethnic chinese patients with localized prostate cancer. bju int.2012;110:e667–672. doi: 10.1111/j.1464-410x.2012.11465.x. epub 2012 sep 14. 18. garcía-cruz e, piqueras m, huguet j, peri l, izquierdo l, musquera m, et al. low testosterone levels are related to poor prognosis factors in men with prostate cancer prior to treatment. bju int.2012;110:e541–546. doi: 10.1111/j.1464-410x.2012.11232.x. epub 2012 may 15. 19. llukani e, katz bf, agalliu i, lightfoot a, yu s-js, kathrins m, lee z, et al. low levels of serum testosterone in middle-aged men impact pathological features of prostate cancer. prostate int.2017;5:17–23. doi: 10.1016/j.prnil.2016.12.003. epub 2017 jan 12. 20. heracek j, urban m, sachova j, kuncova j, eis v, mandys v, et al. the endocrine profiles in men with localized and locally advanced prostate cancer treated with radical prostatectomy. neuro endocrinol lett.2007;28:45–51. 21. klotz l, o’callaghan c, ding k, toren p, dearnaley d, higano cs, horwitz e, et al. nadir testosterone within first year of androgendeprivation therapy (adt) predicts for time to castration-resistant progression: a secondary analysis of the pr-7 trial of intermittent versus continuous adt. j clin oncol.2015;33:1151–1156. doi: 10.1200/ jco.2014.58.2973. epub 2015 mar 2. 22. abufaraj m, iwata t, kimura s, haddad a, al-ani h, abusubaih l, et al. differential impact of gonadotropin-releasing hormone antagonist versus agonist on clinical safety and oncologic outcomes on patients with metastatic prostate cancer: a meta-analysis of randomized controlled trials. eur urol.2020; doi:10.1016/j.eururo.2020.06.002. 61siuj • volume 3, number 2 • march 2022 siuj.org follicle-stimulating hormone (fsh) levels during androgen deprivation therapy http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. novel extravesical versus transvesical technique for abdominal repair of vesicovaginal fistula ibrahem ismail samaha, kareem m. taha, islam elbabouly, maged ali department of urology, faculty of human medicine, zagazig university, zagazig, egypt abstract objectives to compare the transvesical transabdominal repair of vesicovaginal fistula with novel extravesical transabdominal repair with respect to operative time, blood loss, hospital stay, catheterization time, postoperative lower urinary tract symptoms, urodynamic changes, and recurrence rate. methods a prospective randomized controlled study of 94 consecutive female patients who underwent transabdominal vesicovaginal fistula (vvf) repair from march 2013 to march 2018 in our center. the patients had high vesicovaginal fistula that could not be operated on transvaginally: 47 cases were treated with extravesical transabdominal technique, and 47 cases were treated with transvesical transabdominal technique. the primary endpoint is the functional outcome regarding postoperative lower urinary tract symptoms (luts); secondary outcomes are early recovery and success rates. the follow-up period was 3 months for reporting and dealing with any complications. results there was no significant difference between the groups regarding demographic data. extravesical repair of vvf had significantly higher (106.56±10.46 min) operating time than transvesical repair (95.08±7.6 min) p <0.001. there was no significant difference regarding intraoperative blood loss between the extravesical (365.42±81.29 ml) and transvesical (353.12±73.9 ml) groups; p = 0.44). the extravesical group had a significant shorter hospital stay (62.35±12.25 hours) than the transvesical repair group (85.07±12.0 hours) p < 0.001. postoperative storage luts 6 weeks assessed by overactive bladder symptom score was significantly lower for extravesical repair (1.75±0.59) than for transvesical repair (6.87±2.24) p = 0.001). this was confirmed by urodynamic evaluation. two patients (4.2%) in the transvesical group but none in the extravesical group experienced fistula recurrence. conclusions the extravesical transabdominal approach for repair of vesicovaginal fistula is a novel, successful, and versatile technique with reduced hospital stay, reduced postoperative luts and possibly fewer recurrences than the transvesical technique, and should be considered for all vvf requiring abdominal repair. introduction vesicovaginal fistula (vvf) is an abnormal communication between the bladder and the vagina resulting in continuous leakage of urine[1]. vvf remains a devastating disease with social stigma and psychological strain on patients, as well as physical repercussions[2]. etiology of vvf includes obstetric injury, gynecological and pelvic surgeries, radiation therapy, inflammation, and malignancy, but the obstetric complications with prolonged labour remain the predominant cause in the developing countries. inadvertent bladder injury during hysterectomy is the most common cause in developed countries with reported rates of 0.3% to 2% after simple hysterectomy and 10% after radical hysterectomy[3,4]. this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information vesicovaginal fistula, transvesical repair, lower urinary tract symptoms, overactive bladder symptoms score, urodynamic study none declared. received on september 17, 2020 accepted on january 4, 2021 soc int urol j.2021;2(2):113–119 doi: https://10.48083/tvyu2515 113siuj.org siuj • volume 2, number 2 • march 2021 original research mailto:dr_ibrahemsamaha%40yahoo.com?subject=siuj https://10.48083/tvyu2515 http://www.siuj.org fistula occurs when devascularized tissue is sloughed. leakage of urine through this focus of erosion leads to the formation of a tract through fibrotic tissue that connects the urinary tract to the bladder. this fistula is usually recognized 2 weeks after the trauma[5]. the o’conor transvesical technique was performed via laparotomy for more than 30 years before the first laparoscopic case was published in 1994[6]. it was not until 1998 that von theobold described the first laparoscopic extravesical vvf repair. von theobold describes a simple dissection of the bladder away from the vagina and a single-layer bladder closure, noting “closure of the vagina was not necessary” coupled with an omental j flap[7]. the extravesical approach is not a modification of the o’conor technique, as a cystotomy is not required to identify the fistula, but it still uses the basic principles of fistula repair as cited by couvelaire in the 1950s[8]. the extravesical approach, first described by von dittel in 1893[9], focuses on targeted dissection, avoiding cystotomy, and preferentially dissecting to the fistulous tract via the vesicovaginal plane. the superiority of either the transvesical or the extravesical approach has not been established in the literature and at the time of writing, no study has compared the 2 techniques[10]. the aim of this study was to compare the effectiveness of the extravesical technique of transabdominal repair with the transvesical technique of transabdominal repair for vesicovaginal fistula with respect to operative time, blood loss, length of hospital stays, urethral catheter time, postoperative lower urinar y tract symptoms and recurrence rate. the primary endpoint is the functional outcome regarding postoperative lower urinary tract symptoms (luts); secondary outcomes are early recovery and success rates. the follow-up period was 3 months for reporting and dealing with any complications. a c b figure 1. sagittal section of ct cystogram 3d format: red arrow shows the high vvf and opacification of the vagina with contrast axial section 114 siuj • volume 2, number 2 • march 2021 siuj.org original research http://www.siuj.org materials and methods we undertook a prospective randomized controlled study w it h 94 consecutive fema le patients who underwent transabdominal vesicovaginal repair from march 2013 to march 2018 in our center (zagazig university hospital). patients with fistulas close to the ureteric orifice and high fistulas that could not be accessed through the vagina, as well as those with previous recurrent vaginal surgeries that precluded vaginal repair were enrolled in this study and underwent abdominal repair. patient consent and institutional review board approval were obtained. between 2013 and 2018, 94 consecutive female patients with high vesicovaginal fistula or previous vaginal surgery that precluded transvaginal fistula repair were randomized to f istula repair by an extravesical transabdominal technique (n = 47) or by a transvesical transabdominal technique (n = 47) at our center. preoperative patient evaluation included history, physical examination (local vaginal examination, inspection with speculum, dye test), and ct cystogram (figure 1). informed consent was obtained from all patients prior to surgery, and institutional review board approval was granted. operation diagnostic cystoscopy was done first to identify the fistula tract with stent insertion inside it, a vaginal pack was then inserted, and a vertical lower abdominal midline incision was made for better exposure and easy access for omental flap formation. all vvf in our series were repaired 3 months after the initial trauma to allow edema and inflammation to subside and allow better tissue handling and healing. the fundamental surgical principles for repair (adequate exposure, tension-free approximation of the fistula edges, non-overlapping suture lines, good hemostasis, watertight closure, and adequate postoperative bladder drainage) were achieved. transvesical approach this is based on the technique described by o’conor and sokol. after exposure of the pelvic structures, mobilization of bladder was obtained[11]. a cystotomy (4 to 5 cm) along the sagittal plane near the dome was done. the incision was then extended down to the site of the fistulous tract. both ureteral orifices were identified before dissection along the tract course and a fullthickness excision of the tract and the devascularized edges, followed by double-layered closure of the bladder and vaginal defects with omental f lap interposition. the bladder was filled with saline to ensure watertight closure. a urethral catheter remained in place for 2 weeks postoperatively. extravesical approach this approach focuses on targeted dissection with preferential dissection to the fistulous tract via the vesicovaginal plane, thereby avoiding cystotomy. the fistulous tract was excised. a multilayered closure, with non-overlapping suture lines was done. the vaginal defect was closed in a double layer, using interrupted 2-0 absorbable sutures. the bladder defect was repaired in 2 layers with continuous suturing using a 2-0 absorbable suture as shown in figure 2. retrograde filling of the bladder was done to ensure a watertight seal. an omental flap was used as a tissue interposition between bladder and vagina. the urethral catheter remained in place for 5 days postoperatively. in all patients after both approaches lower urinary tract symptoms were evaluated after 6 weeks with the overactive bladder symptom score (oabss) by filling cystometry. results clinical and pathologic characteristics ni net y-fou r pat ient s w it h h ig h vesicovag i na l fistula underwent transabdominal repair. patients were randomly assigned to receive transvesica l steps of extravesical repair of vvf. b bladder v vagina with the yellow omental flap in between figure 2. 115siuj.org siuj • volume 2, number 2 • march 2021 novel extravesical versus transvesical technique for abdominal repair of vesicovaginal fistula http://www.siuj.org transabdominal repair (47 patients) or extravesical transabdominal vvf repair (47 patients). there was no significant difference between the groups with respect to age, body mass index (table 1), or cause of vesicovaginal fistula (table 2). clinical outcomes the operative time was greater for the extravesical approach (106.56±10.46 min) than the transvesical approach (95.08±7.6 min) (p < 0.001) due to the more delicate dissection to mobilize the posterior bladder away from the vagina without cystotomy. intraoperative blood loss was not significantly different for the extravesical repair group (365.42±81.29 ml) and for the transvesical repair group (353.12±73.9 ml; p = 0.44). however, the extravesical group had a significantly shorter hospital stay (62.35±12.25 hours) than the transvesical repair group (85.07± 12.0 hours) (p < 0.001). we also compared the functional outcomes for both techniques of repair in terms of storage luts, using the oabss 6 weeks postoperatively. extravesical repair of vvf caused significantly lower postoperative oabss (1.75±0.59) compared with transvesical repair (6.87±2.24) p = 0.001 (table 3). this was confirmed objectively by urodynamic evaluation (table 5), which revealed detrusor overactivity in 14 patients (31.1%) in the transvesical group and 5 patients (10.6%) in the extravesical group (p = 0.002). detrusor overactivity incontinence was observed in 7 patients (15.5%) in the transvesical group and in 2 patients (4.2%) in the extravesical group (p = 0.018). this was managed with antimuscarinic drug. post repair stress urinary incontinence was observed in 3 patients (6.6%) in the transvesical group and 1 patient (2.1%) in the extravesical group (p = 0.15). this was managed conservatively. fistula recurrence was observed in 2 patients (4.2%) within 4 weeks in the transvesical group and none in the extravesical group (p = 0.11) (table 3). discussion vesicovaginal fistula is one of the most distressing complications of obstetric and gynecologic procedures. it has a negative impact on life with important medicolegal implications. obstetric vvfs remain a major medical problem in many low-resource countries with a low standard of antenatal and obstetric care[12]. table 1. age and bmi distribution transvesical extravesical t p n = 47 (mean ±sd) n = 47 (mean ±sd) age 45.16±10.6 47.01±11.26 -1.645 0.074 bmi 29.75±3.37 30.0±3.62 -0.535 0.584 no significant difference between both groups for demographic data table 2. causes of vesicovaginal fistula cause group total n(%) χ 2 p transvesical n(%) extravesical n(%) cystocele repair 7(14.8) 8(17) 15(19.2) 0.29 0.59 hysterectomy 21(44.6) 23(49) 44(53.6) 0.26 0.61 obstructed labour 13(27.6) 10(21.2) 23(20.5) 0.75 0.38 pvs 1(2.1) 2(4.2) 3(0.9) 0.72 0.39 tvt 5(10.6) 4(8.5) 9(5.8) 0.15 0.69 total 47 47 94 116 siuj • volume 2, number 2 • march 2021 siuj.org original research http://www.siuj.org transabdominal repair is the preferred approach when the fistula is high on the posterior bladder or the fistula is complex, or if the vaginal anatomy precludes adequate surgical exposure of the defect (retracted defect or narrow vagina), or the fistula is closely related to the distal ureters[13]. in the present study 53.6% fistulas were secondary to gynecological procedures (hysterectomy) and 20.5% resulted from obstetric problems, which ref lects the findings of the study by kapoor et al.[14]. in other series, however, vvf was reported as predominantly secondary to gynecological causes, as shown in table 4. we wished to evaluate the outcomes of extravesical vvf repair and compare them with the classical transvesical technique because we believed that avoiding cystostomy could reduce postoperative drawbacks in the form of long hospital stay, long catheterization time, and high incidence of storage luts. dolan et al. report that 16.1% of patients experience stress urinary incontinence after fistula repair[15]. this results from defunctionalization of the detrusor muscle because of prolonged vvf exposure[8]. the substantial loss of bladder tissue from scarring leads to a smaller functional bladder capacity. the bladder then becomes stiff and non-compliant leading to stress incontinence or de novo urge incontinence. vaginal scarring and shortening of the vagina impair physiologic urethral function and prevent adequate urethral coaptation[16]. in a study of obstetric fistula in ethiopia, where urodynamic investigation was undertaken after repair, 55% of patients were incontinent despite successful closure of their fistula; stress urinary incontinence was most commonly identified abnormality[17]. another study demonstrated stress urinary incontinence in 47% of women prior to repair in a series of largely surgical fistulae in the united kingdom. although in only 3% did this persist after repair, these findings are more common in obstetric fistula. detrusor overactivity was found in 40% at presentation and persisted in half of these at follow-up[18]. we believe that the extravesical technique is a more successful, less invasive, and less traumatic repair with a lower incidence of detrusor overactivity. the key difference is the targeted dissection of the vvf site and the layered-closure technique discussed here. in contrast, the bivalving of the bladder required with the traditional transvesical approach increases the size of the bladder defect, which may be responsible for the varied success rate (70% to 97%). this rationale is supported by fistula experts who have stated that there is a greater chance of surgical failure with larger fistulas[16] and have advised minimizing the size of the cystotomy (<2 cm) during an o’conor transvesical repair. others table 3. clinical outcomes transvesical n = 47 extravesical n = 47 t p operation time (min) 95.08±7.6 106.56±10.46 -8.121 0.001 blood loss (ml) 353.12±73.9 365.42±81.29 -0.684 0.44 length of hospital stay (hour) 85.07±12.0 62.35±12.25 14.015 < 0.001 postoperative oabss 6.87±2.24 1.75±0.59 20.988 0.001 recurrence 2 (4.2%) 0 fisher 0.11 2.41 table 4. causes of vvf in different studies causes present study kapoor et al., 2007 roy et al., 2006 kam et al., 2008 obstetric 4 4 60 22 25 gynecological 23 40 74 70 other causes (pop repair, continence surgeries) 27 table 5. urodynamic evaluation procedure detrusor overactivity n(%) detrusor overactivity incontinence n(%) stress urinary incontinence n(%) transvesical (45) 14 (31.1) 7(15.5) 3 (6.6) extravesical (47) 5 (10.6) 2 (4.2) 1 (2.1) p 0.002 0.018 0.15 117siuj.org siuj • volume 2, number 2 • march 2021 novel extravesical versus transvesical technique for abdominal repair of vesicovaginal fistula http://www.siuj.org have reported great success using the nonbivalving extravesical layered-closure technique with and without omental flaps[20,21]. it was clear in this series that the success rate with the transvesical approach was 95%, with failure in 2 cases, compared with extravesical repair, which had a success rate of 100%. we attribute the high success rate to meticulous and site-specific dissection as well as a triple-layer closure, which included a double-layered bladder closure and single vaginal wall closure, as supported by sokol et al.[22], as well as aggressive testing of the bladder’s suture line. in a study using a canine model, sokol et al. suggest that a double-layer closure of cystotomy is superior to a single-layer closure and may prevent fistula. also good tissue approximation and watertight closure are fundamentals for successful vvf repair. to determine whether a “watertight seal” had been achieved, we undertook retrograde filling of the bladder; we then sutured any leaking points in the suture line. however, the technique to determine a “watertight seal” has never been adequately defined and lacks consistency, as suggested in the literature[23]. in this series we fixed omental flap as interpositioning layer in all cases, whether transvesical or extravesical, to promote healing and better lymphatic drainage, although the use of interposition flaps in non-irradiated patients has been questioned[24,25]. in a recent retrospective review of 49 patients without malignancy or a history of radiation therapy, the primary surgeon determined that transvaginal repair of benign recurrent vvfs without tissue interposition can be as successful as primary repairs without tissue interposition[26]. an interposition graft for vvfs functions as a barrier and introduces vascularity and, theoretically, lymphatics to improve tissue growth and maturation. decisions about approach, technique, interposition grafts, and layers of closure are still debated and must be based on the individual surgeon’s experience and comfort level. thus, a surgeon’s decision to approach a vvf vaginally, laparoscopically, or via laparotomy is based primarily on the individual’s skill, comfort, and ability. to our knowledge, this study is the first to compare and discuss the outcomes of transabdominal vvf and transvesical repair. we believed that extravesical repair of vvf had better outcomes than the traditional transvesical repair, and this randomized controlled trial provided support for that view. no matter which approach decided upon, we believe that the most important aspects of vvf repair remain adequate dissection, a watertight seal, and good postoperative bladder drainage. conclusions the extravesical abdominal approach for repair of vesicovaginal fistula is associated with significantly reduced hospital stay, significantly reduced postoperative overactive bladder symptoms, and a reduced recurrence rate compared with the transvesical approach. we recommend this technique for closure of vvf that must be repaired abdominally. 118 siuj • volume 2, number 2 • march 2021 siuj.org original research http://www.siuj.org references 1. zacharin rf. a history of obstetric vesicovaginal fistula. aust n z j surg.2000;70(12):851–854. 2. alio ap, merrell l, roxburgh k, clayton hb, marty pj, bomboka l, et al. the psychosocial impact of vesico-vaginal fistula in niger. arch gynecol obstet.2011; 284(2):371–378. 3. eilber ks, kavaler e, rodriguez lv, rosenblum n, raz s. ten-year experience with transvaginal vesicovaginal fistula repair using tissue interposition. j urol.2003;169(3):1033–1036. 4. duong th, taylor dp, meeks gr. a multicentre study of vesicovaginal fistula following incidental cystotomy during benign hysterectomies. int urogynecol j.2011;22(8):975–979. 5. malik ma, sohail m, malik mt, khalid n, akram a. changing trends in the etiology and management of vesicovaginal fistula. int j urol.2018;25(1):25–29. 6. nezhat ch, nezhat f, nezhat c, rot tenber h. l aparoscopic r ep air of a v e sic o v agin al f is t ula: a c as e r ep or t .  obstet gynecol.1994;83(5pt2):899–901. 7. von theobold p, hamel p, febrarro w. laparoscopic repair of a vesicovaginal fistula using an omental j flap.  br j obstet gynaecol.1998;105 (11):1216 –1218.doi:10.1111/j.1471-0528.1998. tb09980.x. 8. couvelaire r. reflections on a personal statistic of 136 vesicovaginal fistulas. j urol med chir.1953;59:150–160. 9. von dittel l. abdominale blasenscheidenfistel-operation. wein klin wochenschr.1893;6:449-452. 10. miklos jr, moore rd, chinthakanan o. laparoscopic and roboticassisted vesicovaginal fistula repair: a systematic review of the literature. j minim invasive gynecol.2015;22(5):727–736. 11. o’conor vj, sokol jk. vesicovaginal fistula from the standpoint of the urologist. j urol.1951 oct;66(4):579-585. doi: 10.1016/ s0022-5347(17)74381-9. 12. hadley hr. vesicovaginal fistula. curr urol rep.2002;3(5):401-407. 13. romics i, kelemen z, fazakas z. the diagnosis and management of vesicovaginal fistulae. bju int.2002;89(7):764–766. 14. kapoor r, ansari ms, singh p, gupta p, khurana n, mandhani a, et al. management of vesicovaginal fistula: an experience of 52 cases with a rationalized algorithm for choosing the transvaginal or transabdominal approach. indian j urol.2007 oct;23(4):372. 15. dolan lm, dixon we, hilton p. urinary symptoms and quality of life in women following urogenital fistula repair: a long-term follow-up study. bjog.2008;115:1570e4. 16. ayed m, el atat r, hassine lb, sfaxi m, chebil m, zmerili s. prognostic factors of recurrence after vesicovaginal fistula repair. int j urol.2006;(4):345–349. doi: 10.1111/j.1442-2042.2006.01308.x 17. murray c, goh j t, f ynes m, carey mp. urinar y and faecal incontinence following delayed primary repair of obstetric genital fistula. bjog.2002;109:828–832. 18. hilton p. the urodynamic findings in patients with urogenital fistulae. br j urol.1998;81:539–42. 19. riz vi s j, gup t a r, p atel s, trivedi a , trivedi p, modi p. m o di f ie d la p a r o s c o p i c a b d o min al v e si c o v a gin al f is t ula repair—“mini-o’conor” vesicotomy. j laparoendosc adv surg tech.2010;20(1):13–15. 20. das mahapatra p, bhattacharyya p. laparoscopic intraperitoneal repair of high-up urinary bladder fistula: a review of 12 cases. int urogynecol j.2007;18:635–639. 21. abdel-karim am, mousa a, hasouna m, elsalmy s. laparoscopic transperitoneal extravesical repair of vesicovaginal fistula. int urogynecol j.2011;22(6):693–697. 22. sokol ai, paraiso mf, cogan sl, bedaiwy ma, escobar pf, barber md. prevention of vesicovaginal fistulas af ter laparoscopic hysterectomy with electrosurgical cytostomy in female mongrel dogs. am j obstet gynecol.2004;190:628–633. 23. shah sj. laparoscopic transabdominal transvesical vesicovaginal fistula repair. j endourol.2009;23(7):1135–1137. 24. miklos jr, moore rd. laparoscopic transperitoneal extravesical approach to vesicovaginal fistula repair without omental flap: a novel technique. int urogynecol j.2014;26(3):441–446. 25. kohli n, miklos jr. meeting the challenge of the vesicovaginal f is t ula r ep air : c ons er v a ti v e and sur gic al me asur e s.  obg manag.2003;8:16–27. 26. pshak r, nikolavsky d, terlecki r, flynn bj. is tissue interposition always necessar y in transvaginal repair of benign, recurrent vesicovaginal fistula. urology.2013;82(3):707–712. doi: 10.1016/j. urology.2013.03.076. 119siuj.org siuj • volume 2, number 2 • march 2021 novel extravesical versus transvesical technique for abdominal repair of vesicovaginal fistula http://www.siuj.org 121siuj.org siuj • volume 3, number 3 • may 2022 this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. editorial international conflict in urology peter c. black, editor-in-chief soc int urol j.2021;3(3):121–122 doi: 10.48083/eqqm2273 urologic societies and associations with global reach are unavoidably drawn into conflict between different countries and regions, and even between different factions within one country. the stakeholders in these conf licts are represented in the membership of the corresponding societies, and the societies are therefore forced to address the potential political strife in their own committees, meetings, educational events, and research initiatives. the ongoing war in ukraine is a particularly stark example of this phenomenon. the european association of urology (eau) and the société internationale d’urologie (siu) are two prominent organizations that are obviously affected by this war. i have no particular insight into how either organization is handling this conflict. instead, i look upon it as an outside observer, much like the vast majority of readers of the siuj. my comments are my own and do not reflect the position of the siu leadership. the eau and the siu both made early statements, communicating to their members their dismay over the unfolding situation in ukraine and their solidarity with the ukrainian people. many bodies have focused on assistance for the victims of the humanitarian crisis in ukraine. the american college of surgeons, for example, circulated a list of opportunities for its members to provide support. the european cancer organisation (eco) and the american society of clinical oncology (asco) have launched initiatives to support cancer patients affected by the war in ukraine. the canadian institutes of health research have launched a “special response fund for trainees” to support graduate and post-graduate students from ukraine who cannot continue their research because of the crisis in their home country. some individuals have shown remarkable initiative, courage, and sacrifice, and have traveled to the border regions around ukraine to care directly for the millions of ukrainian refugees fleeing the war. the unprovoked russian invasion in ukraine deserves the highest level of condemnation, but should that condemnation extend beyond the russian leadership and the military and their supporters? governments around the world have instituted harsh sanctions against the russian state and individual oligarchs, but should we in organized urology be sanctioning our russian urologic colleagues? one of the first messages i received related to the potential impact of russia’s invasion of ukraine on february 24 was a plea from a reputable journal to exercise fairness in the peer review of articles submitted by russian authors. reviewers were asked to avoid prejudice related to the ongoing conflict. to some degree we all would like protest against russia by whatever means available to us, and it may seem tempting to use peer review as an opportunity to send a message of dissent. i do not believe that many in academic medicine would consider this type of academic sanction, but it is an example of how international conflict can play out in our professional spheres. i also received a message from a subspecialty society in ukraine asking one of the urologic societies to expel russian and belorussian members from its ranks and to block them from the society’s activities and conferences. the implication of such a call for academic sanctions against urologists is that they are complicit in their government’s actions simply by being russian. while we would all like to see the russian people speak out against their leadership, we should not conclude that the russian population is complicit with the government simply because they are not protesting en masse in the streets of russia. we have read of the misinformation disseminated by the russian propaganda apparatus, and we have little concept of what the russian people know about the conflict in ukraine. furthermore, we cannot expect widespread protests in an authoritarian state like russia. it would therefore be extraordinarily unfair to punish russian urologists and researchers because of the conflict in ukraine. http://siuj.org mailto:editorinchief%40siuj.org?subject=siuj 122 siuj • volume 3, number 3 • may 2022 siuj.org editorial some organizations have taken action to limit scientific collaboration with russia. the german research foundation (deutsche forschungsgemeinschaft) stopped all funding to projects with russian participation. this was intended to send a clear signal to the russian leadership and was accompanied by a call to preserve the dialogue with russians on a personal level and also an acknowledgement that many russian scientists are distressed by their government’s actions. in this vein, we may consider official russian medical organizations as likely representing the state’s interests, but we do not know the political leanings of any individual urologist and we should therefore refrain from condemning individuals. the eau has suspended all joint activities with the national urological societies of russia and belarus. we should denounce the actions of the russian leadership and military and declare our solidarity with the people of ukraine, but our condemnation should not extend to the russian people, and especially not to our russian colleagues. let the governments do the politicking, and let us support the ukrainian people in general, and our colleagues and urologic trainees in particular. as stated by the president of the siu: as a global society, the siu embraces peace and freedom for all, and opposes violence. we remain committed to our members and our mission: to elevate patient care through international co-operation in education and research — a peaceful environment is fundamental in achieving this. our thoughts are with the victims, and it is our hope that peace will prevail quickly. http://siuj.org 193siuj.org siuj • volume 3, number 4 • july 2022 editorial gender disparity on editorial boards 195 peter c. black urology around the world the cabem initiative: saving patients with muscle-invasive bladder cancer 198 fernando korkes, josé henrique d. santiago, guilherme andrade peixoto, frederico timóteo, suelen p. martins, narjara p. leite, daisy barreiros, sidney glina research overnight ambulatory urodynamics change patient management strategies and improve symptomatic outcomes 202 richard g. axell, habiba yasmin, kristina aleksejeva, eskinder solomon, bogdan toia, mahreen h. pakzad, jeremy l. ockrim, tamsin j. greenwell review systematic review of comparative patient reported outcomes and health-related quality of life after management of localized renal masses or renal cell carcinomas 209 laura sandbergen, muhammad imran omar, lavin othman, faridi van etten-jamaludin, mustafa soytas, jean j. de la rosette, m. pilar laguna a systematic review of plant-based diets and bladder cancer: a call for further research 240 jacob taylor, natasha gupta, jamie blanck, stacy loeb predictive biomarkers in the management of bladder cancer: perspectives in an evolving therapeutic landscape 245 patrick j. hensley, niyati lobo, kelly k. bree, wei shen tan; paolo gontero, stephen b. williams, charles c. guo, gianluca giannarini, lars dyrskjøt, ashish m. kamat impact of androgen deprivation therapy on cardiovascular outcomes in prostate cancer 259 laurence klotz, stephen van komen, sanja dragnic, william b. white brief communication the value of conflicts of interest disclosures in oral presentations at major urological conferences 276 anique le roux, naji j. touma clinical picture malakoplakia causing poor bladder compliance and bilateral hydroureteronephrosis 281 cecile t. pham, melanie edwards, amanda s.j. chung, venu chalasani table of contents http://siuj.org key words competing interests article information prostate cancer, multi-parametric mri, micro-ultrasound, pi-rads, pri-mus none declared. received on july 5, 2021 accepted on august 14, 2021 this article has been peer reviewed. soc int urol j. 2022;3(1):8–13 doi: 10.48083/dhnc9428 8 siuj • volume 3, number 1 • january 2022 siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. original research comparing micro-ultrasound with mpmri in detecting clinically significant prostate cancer guan hee tan,1,2 brian wodlinger,3 christian pavlovich,4 laurence klotz2 1 sunway medical centre, petaling jaya, malaysia 2 department of urology, sunnybrook health sciences centre, university of toronto, toronto, canada 3 exact imaging, markham, canada 4 department of urology, the james buchanan brady urological institute, johns hopkins university school of medicine, baltimore, united states abstract objectives to compare the performance of micro-ultrasound (mus) with multi-parametric magnetic resonance imaging (mpmri) in detecting clinically significant prostate cancer. materials and methods retrospective data from consecutive patients with any indication for prostate biopsy in 2 academic institutions were included. the operator, blinded to mpmri, would first scan the prostate and annotate any mus lesions. all mus lesions were biopsied. any mpmri lesions that did not correspond to mus lesion upon unblinding were additionally biopsied. grade group (gg) ≥ 2 was considered clinically significant cancer. the jeffreys interval method was used to compare performance of mus with mpmri with the non-inferiority limit set at −5%. results imaging and biopsy were performed in 82 patients with 153 lesions. mus had similar sensitivity to mpmri (per-lesion analysis: 78.4% versus 72.5%), but lower specificity, positive predictive value, negative predictive value, and area under the curve. micro-ultrasound found gg ≥ 2 in 13% of cases missed by mpmri, while mpmri found gg ≥ 2 in 11% of cases missed by mus. the difference 0.020 (95% ci −0.070 to 0.110) was not statistically significant (p  =  0.33). conclusion the sensitivity of mus in detecting gg ≥ 2 disease was similar to that of mpmri, but the specificity was lower. further evaluation with a larger sample size and experienced operators is warranted. introduction prostate biopsies are usually guided by transrectal ultrasound (trus) platforms that operate at 6 to 9 mhz[1]. systematic biopsies of the prostate, the mainstay of prostate cancer diagnosis for the last 30 years, have many limitations, including both under-diagnosis of significant cancer and the identification of many men with clinically insignificant cancer. multi-parametric magnetic resonance imaging (mpmri) detects clinically significant cancer on the basis of alterations in cell density and ductal anatomy[2–4]. the prostate imaging reporting and data system (pi-rads 2.0) was developed to standardize interpretation and reporting of mpmri findings[5]. many national guidelines now recommend mpmri before trus biopsy[6–7]. multi-parametric mri with targeted biopsy appears to reduce the number of men requiring a biopsy and the over-detection of clinically insignificant cancer without compromising significant cancer detection[2,8]. however, in many regions of the world access to mpmri is limited, and performing an mpmri in all men at risk is not feasible. multi-parametric mri before biopsy also means 2 procedures, requiring that the patient to return for fusion targeted biopsy if suspicious lesions are detected. http://siuj.org mailto:laurence.klotz%40sunnybrook.ca?subject=siuj to address these limitations, a novel micro-ultrasound (mus) platform that operates at 29mhz was developed. this system generates high-resolution (70µ) images of the prostate. this resolution, compared with 200µ in conventional ultrasound, is the diameter of prostatic ducts, and therefore detects alterations in ductal anatomy. this offers the opportunity for improved detection of high-grade cancers characterized by loss of normal acinar lumens and tighter cellular packing. as with pi-rads for mpmri, a prostate risk identification using mus (pri-mus) protocol has been developed to standardize sonographic lesions[9]. in addition to superior resolution, this technology offers the convenience of conventional ultrasound such as real-time imaging and targeted biopsy during the same procedure, office-based set-up, relatively easy access compared with mri, and considerably less expensive equipment. the mus platform is novel, and evidence regarding its accuracy in prostate cancer diagnosis is lacking. this study compares the performance of mus in detecting clinically significant prostate cancer with that of mpmri. materials and methods inclusion and exclusion criteria data for this study were retrospectively gathered from electronic health records. we included consecutive patients between april 2019 and april 2020 who had any indication for prostate biopsy: (1) elevated psa, (2) abnormal digital rectal examination (dre), and/or (3) any suspicious mpmri lesions. all patients must have had an mpmri of the prostate before biopsy within the last year. mpmris were 3t with an abdominal coil. data were obtained from sunnybrook health sciences centre and johns hopkins university school of medicine. these procedures were performed as a standard of care, and research ethics board approval was not required or sought for the study. procedure a single urologist who had been trained on the device performed the trus biopsies or provided direct supervision of the fellow. all patients were prepared with prophylactic antibiotics and enema and placed in the left lateral position as for standard trus biopsy. trus was performed using the mus platform that operated at 29 mhz with a side-firing mus probe. critically, for the patients in this study, high-resolution ultrasound was performed and formally annotated with the operator scrupulously blinded to the patient’s prostate cancer history and mpmri findings. the prostate gland was measured and scanned for any visible target lesions. trus abnormalities were formally annotated and given a pri-mus score. the trus annotation was “locked” before the mpmri findings were reviewed. one percent lignocaine was then injected into the prostate-seminal vesicle angle as local anaesthesia. the operator then reviewed the mpmri. the locations of visible mpmri lesions were identified from the radiologist’s report. targeted samples of every mus and mpmri lesions were performed. in most cases, 3 cores were taken of each region of interest. cognitive targeting was performed on mpmri-only visible lesions. we did not perform systematic biopsy. analysis clinically significant prostate cancer was defined as gg ≥ 2. per target lesion and per-patient analyses were performed. sensitivity, specificity, positive predictive value (ppv), negative predictive value (npv), and area under the receiver operating characteristic (roc) curve were used as performance measures for mus and mpmri. the added value of mus was the number of cases with pri-mus ≥ 3 and gg ≥ 2 in which mpmri was pi-rads < 3, or pi-rads ≥ 3 and gg < 2. the added value of mpmri was the number of cases with pi-rads ≥ 3 and gg ≥ 2 in which mus was pri-mus < 3, or pri-mus ≥ 3 and gg < 2. the jeffreys interval method was used to compare the performance of mus with that of mpmri, with the non-inferiority limit set at −5%. p ≤ 0.05 was considered significant. all statistical calculations were performed using ibm spss statistics version 26. results between april 2019 and april 2020, imaging and biopsy were performed in 82 patients with 153 lesions. gg ≥ 2 prostate cancer was diagnosed in 33 patients (40.2%) and 51 (33.3%) of the biopsied lesions. the median age was 68.3 (iqr = 63.3 to 74.8) years, and median psa was 8.0 (iqr = 5.7 to 11.6) ng/ml. sixty patients (73.2%) had been diagnosed with prostate cancer in the past. among them, 39 patients (65%) were on active surveillance, and 21 patients (35%) were being followed up after prior focal therapy. table 1 shows the breakdown of normal, equivocal, and suspicious mpmri and mus studies. abbreviations auc area under the curve gg grade group mpmri multi-parametric magnetic resonance imaging mus micro-ultrasound npv negative predictive value pi-rads prostate imaging reporting and data system ppv positive predictive value pri-mus prostate risk identification using micro-ultrasound trus transrectal ultrasound 9siuj.org siuj • volume 3, number 1 • january 2022 comparing micro-ultrasound with mpmri in detecting clinically significant prostate cancer http://siuj.org the per-lesion analysis of mus and mpmri performance in detection of gg ≥ 2 prostate cancer showed similar sensitivity with mus (78.4%) and mpmri (72.5%). there was concordance in 73 lesions (47.7%) between mus and mpmri, ie, visible on both imaging modalities. the specificity, ppv, npv, and auc of mus were lower than mpmri (table 2). when the threshold for biopsy was set at pri-mus/pi-rads ≥ 3, mus maintained similar sensitivity but lower specificity, ppv, npv, and auc than mpmri. however, when the threshold for biopsy was set at pri-mus/pi-rads ≥ 4, mpmri showed better sensitivity, ppv, npv, and auc than mus. the specificity of the 2 imaging modalities was equal in this case at 60.8% (table 3). in per-patient analysis, the sensitivity of mus was again similar to that of mpmri (97.0% versus 97.0%). the specificity, ppv, npv, and auc of mus in per-patient analysis were lower than mpmri (table 4). micro-ultrasound found gg ≥ 2 in 13% of cases missed by mpmri while mpmri found gg ≥ 2 in 11% of cases missed by mus. the difference 0.020 (95% ci −0.070 to 0.110) was not statistically significant (p = 0.33). twenty-one lesions (13.7%) detected by mus in this study were located anteriorly. seven of these (33.3%) table 1. patient demographics variables patients, n 82 lesions, n 153 age, years, median (iqr) 68.3 (63.3 to 74.8) psa, ng/ml, median (iqr) 8.0 (5.7 to 11.6) prostate volume, ml, median (iqr) 33.0 (24.3 to 44.2) prior biopsy with cancer, n (%) 60 (73.2) number of pri-mus 5 lesions, n (%) 11 (7.2) number of pri-mus 4 lesions, n (%) 55 (36.0) number of pri-mus 3 lesions (equivocal mus), n (%) 68 (44.4) number of pri-mus <3 lesions (mus invisible or clinically insignificant lesions), n (%) 19 (12.4) number of pi-rads 5 lesions, n (%) 25 (16.3) number of pi-rads 4 lesions, n (%) 49 (32.0) number of pi-rads 3 lesions (equivocal mpmri), n (%) 16 (10.5) number of pi-rads <3 lesions (mpmri invisible or clinically insignificant lesions), n (%) 63 (41.2) iqr: interquartile range; mus: micro-ultrasound; mpmri: multi-parametric magnetic resonance imaging table 2. per-lesion analysis of performance metrics comparing mus and mpmri for detection of gg ≥ 2 pca modality sensitivity specificity ppv npv auc mus 78.4% 7.8% 29.9% 42.1% 0.52 mpmri 72.5% 46.1% 40.2% 77.0% 0.65 mus: micro-ultrasound; mpmri: multi-parametric magnetic resonance imaging; gg: grade group table 3. per-lesion analysis of performance metrics comparing mus and mpmri for detection of gg ≥ 2 pca at various pri-mus/pi-rads thresholds for biopsy modality and pri-mus/pi-rads threshold for biopsy sensitivity specificity ppv npv auc mus, pri-mus ≥3 78.4% 7.8% 29.9% 42.1% 0.431 (95% ci 0.332 to 0.531) mpmri, pi-rads ≥3 72.5% 48.0% 41.1% 77.8% 0.603 (95% ci 0.509 to 0.697) mus, pri-mus ≥4 51.0% 60.8% 39.4% 71.3% 0.559 (95% ci 0.462 to 0.656) mpmri, pi-rads ≥4 68.6% 60.8% 46.7% 79.5% 0.647 (95% ci 0.555 to 0.739) mus: micro-ultrasound; mpmri: multi-parametric magnetic resonance imaging; gg: grade group 10 siuj • volume 3, number 1 • january 2022 siuj.org original research http://siuj.org were clinically significant cancers. one (14.3%) was not detected by mpmri. twenty-five mpmri lesions (16.3%) were labelled as anterior. eleven (44.0%) were clinically significant cancer, and 1 (9.1%) was missed by mus. discussion micro-ultrasound technology that offers high-resolution real-time images of the prostate has the potential to enhance prostate cancer diagnosis. little has been published on the performance of mus compared with mpmri. preliminary studies demonstrate comparable sensitivity and specificity to mpmri[10–14]. a limitation of many of these studies is the lack of rigorous blinding of the mpmri results when interpreting the mus. the results of this current study represent an early comparative experience with mus blinded to mpmri at 2 academic institutions. our awareness of the learning curve mandated an aggressive approach to identifying and biopsying subtle abnormalities to minimize the risk of missing significant cancer. this resulted in a small number of biopsied locations, n = 19 (12.4%) assigned as invisible (pri-mus < 3). in contrast, 40% of biopsied lesions were assigned pi-rads < 3 on mpmri. in a series reported by a highly experienced mpmri centre, the proportion of non-suspicious mpmri cases was as high as 49%, and equivocal cases were only 6%[15]. we biopsied considerably more equivocal mus lesions (pri-mus 3) n = 68 (44.4%) compared with only 16 (10.5%) pi-rads 3 mpmri lesions. this is likely because this is an early experience with the mus technology, and the operators were anxious not to miss cancers. it is likely that the low specificity will improve with experience, as clinicians become more familiar with non-significant mus patterns and acquire the confidence to exclude these from biopsy. refraining from biopsy of smaller pri-mus 3 lesions will facilitate this. this inclusive strategy resulted in a comparable sensitivity to mpmri in the detection of gg ≥ 2 disease (78.4% versus 72.5%) in the per-lesion analysis. this was also apparent in the per-patient analysis in which the sensitivity of mus was 97.0% compared with 97.0% for mpmri, using a biopsy threshold of pri-mus/pi-rads ≥ 3. this approach with mus resulted in low specificity (7.8%) with an auc of 0.52 in per-lesion analysis. per-patient analysis also showed low specificity (8.2%) and auc 0.64 at a biopsy threshold of pri-mus ≥ 3. despite the difference in specificity, the aucs of mus and mpmri were similar. this trend of high sensitivity but low specificity with mus was also apparent in another contemporary study[16]. importantly, we demonstrated that mus was able to detect gg ≥ 2 in 13% of cases not diagnosed by mpmri. wiemer et al. analyzed 159 patients and found 20 (12.6%) patients who were negative on targeted mpmri-guided biopsy had in fact harboured clinically significant prostate cancer when biopsied with mus guidance[17]. their finding in this aspect was very similar to our result. about 44% of the mus scans were categorized as pri-mus 3. among the 68 pri-mus 3 lesions, 14 (20.6%) were found to be significant cancers. in contrast, only 2 (12.5%) of the pi-rads 3 lesions showed clinically significant cancer. much as the pi-rads grading system has been repeatedly modified over the last decade, the low specificity of pri-mus 3 in this series suggests that further refinement of the pri-mus 3 pattern is warranted. for example, mri studies published in the years 1985 to 1993 showed the auc for seminal vesicle invasion (svi) was 0.57 ± 0.25. subsequent articles published between 1993 and 2001 described an auc for svi of 0.64 ± 0.21[18]. in a later study, the auc for tumour localization ranged from 0.72 to 0.83 with mpmri[19]. the auc for gg ≥ 2 prostate cancer in the present study was 0.647 (95% ci 0.555 to 0.739) if pi-rads ≥ 4 lesions were biopsied. improved accuracy of mpmri can be attributed to better technology and image quality, as well as greater individual and collective experience in image interpretation and refinement of the criteria for each score. there are concerns that mus may not detect anterior tumours effectively because of the reduced depth of tissue visualization at higher ultrasound frequencies. this is a major limiting factor only in men with marked prostatomegaly. we did not encounter this problem in the present study. among the 7 anterior mus lesions with gg ≥ 2 prostate cancer, 1 was missed by mpmri. micro-ultrasound did not detect 1 of 11 gg ≥ 2 prostate cancer that were anteriorly located on the basis of mpmri findings. therefore, it appears that mus and mpmri were similar in their ability to diagnose anterior tumours. a recent publication demonstrated that mus was also compatible with the transperineal biopsy approach[20]. this method could be considered if there are anterior lesions that are harder to reach via the transrectal route. 11siuj.org siuj • volume 3, number 1 • january 2022 comparing micro-ultrasound with mpmri in detecting clinically significant prostate cancer table 4. per-patient analysis of performance metrics comparing mus and mpmri for detection of gg ≥ 2 pca modality sensitivity specificity ppv npv auc mus 97.0% 8.2% 41.5% 80.0% 0.64 mpmri 97.0% 18.4% 43.8% 90.0% 0.69 mus: micro-ultrasound; mpmri: multi-parametric magnetic resonance imaging; gg: grade group http://siuj.org the key strength of this study, compared with most other studies, was that the operators were blinded to mpmri findings prior to mus. this approach gave us an unbiased reflection of the mus performance. the study had limitations. all patients had at least 1 target lesion seen on mus and/or mpmri. patients with both negative mpmri and mus were excluded from the analysis, since in most cases they did not have a biopsy. therefore, the true npv for significant cancer cannot be accurately estimated. sixty patients (73.2%) had prior diagnosis of prostate cancer. therefore, the results of this study might not reflect the performance of mus in men who have only clinical suspicion of cancer. although we included 22 patients who did not have prior prostate cancer, this number was too small to yield a reliable conclusion from this sub-group. patients in this cohort had targeted biopsies only, without systematic biopsies. the role of systematic biopsies in men having targeted biopsies is evolving, and recent data emphasize the importance of systematic biopsies in higher risk patients. had systematic biopsies been performed, prostate cancer would undoubtedly have been found in some of the patients in this trial who had negative targeted biopsies. blinding to the mpmri results before annotating the ultrasound findings was self-imposed by the clinicians performing the biopsy. having one clinician document the mus findings and a second clinician performing the biopsy after reviewing the mpmri findings would have enhanced this process, but it was not feasible. in addition, the mpmri lesions were not targeted with image fusion technology. it should be taken into consideration when interpretating the results of this study. conclusion micro-ultrasound is an appealing alternative to mpmri by virtue of reduced cost, complexity, and absence of contrast requirement. in this study, the sensitivity of mus in detecting clinically significant prostate cancer was found to be similar to that of mpmri. the specificity of mus was found to be lower than mri. further evaluation with a larger sample size and operators who have surmounted the learning curve is warranted. references 1. rohrbach d, wodlinger b, wen j, mamou j, feleppa e. high-frequency quantitative ultrasound for imaging prostate cancer using a novel micro-ultrasound scanner. ultrasound med biol.2018 jul;44(7):1341– 1354. doi:10.1016/j.ultrasmedbio.2018.02.014. 2. ahmed hu, el-shater bosaily a, brown lc, gabe r, kaplan r, parmar mk, et al. diagnostic accuracy of multiparametric mri and trus biopsy in prostate cancer (promis): a paired validating confirmatory study. lancet.2017 feb 25;389(10071):815 – 822. doi: 10.1016/ s0140-6736(16)32401-1. 3. turkbey b, brown am, sankineni s, wood bj, pinto pa, choyke pl. multiparametric prostate magnetic resonance imaging in the evaluation of prostate cancer. c a cancer j clin.2016; 66: 326–336. doi: 10.3322/caac.21333 4. mowatt g, scotland g, boachie c, cruickshank m, ford ja, fraser c, et al. the diagnostic accuracy and cost-effectiveness of magnetic resonance spectroscopy and enhanced magnetic resonance imaging techniques in aiding the localisation of prostate abnormalities for biopsy: a systematic review and economic evaluation. health technol assess.2013; 17: vii–xix, 1–281. doi: 10.3310/hta17200 5. turkbey b, choyke pl. pirads 2.0: what is new? diagnostic interv radiol.2015;21(5):382–384. doi:10.5152/dir.2015.15099 6. mottet n, van den bergh rcn, briers e, de santis m, gillessen s, grummet j, et al. eau – eanm – estro – esur – siog guidelines on prostate cancer. available at: https://uroweb.org/wp-content/ uploads/eau-eanm-esur-estro-siog-guidelines-on-prostatecancer-2019.pdf. accessed june 11, 2020. 7. schaeffer e, srinivas s, antonarakis es, armstrong aj, bekelman je, cheng h, et al. nccn clinical practice guidelines in oncology. prostate cancer v2.2020. available at: https://www.nccn.org/professionals/ physician_gls/pdf/prostate_detection.pdf. accessed june 11, 2020. doi: 10.6004/jnccn.2021.0008 8. kasivisvanathan v, rannikko as, borghi m, panebianco v, mynderse la, vaarala mh, et al. for the precision study group collaborators. mri-targeted or standard biopsy for prostate-cancer diagnosis. n engl j med.2018 may 10;378(19):1767–1777. doi: 10.1056/ nejm oa1801993. 9. ghai s, eure g, fradet v, hyndman me, mcgrath t, wodlinger b, et al. assessing cancer risk on novel 29 mhz micro-ultrasound images of the prostate: creation of the micro-ultrasound protocol for prostate risk identification. j urol.2016;196(2):562– 569. doi:10.1016/j. juro.2015.12.09 12 siuj • volume 3, number 1 • january 2022 siuj.org original research http://siuj.org 10. eure g, fanney d, lin j, wodlinger b, ghai s. comparison of conventional transrectal ultrasound, magnetic resonance imaging, and micro-ultrasound for visualizing prostate cancer in an active surveillance population: a feasibility study. can urol assoc j.2019 mar;13(3):e70–e77. doi: 10.5489/cuaj.5361. epub 2018 aug 30. 11. lughezzani g, saita a, lazzeri m, paciotti m, maffei d, lista g, et al. comparison of the diagnostic accuracy of micro-ultrasound and magnetic resonance imaging/ultrasound fusion targeted biopsies for the diagnosis of clinically significant prostate cancer. eur urol oncol.2019 may;2(3):329–332. doi: 10.1016/j.euo.2018.10.001. 12. claros or, tourinho-barbosa rr, fregeville a, gallardo ac, muttin f, carneiro a, et al. comparison of initial experience with transrectal magnetic resonance imaging cognitive guided micro-ultrasound biopsies versus established transperineal robotic ultrasound magnetic resonance imaging fusion biopsies for prostate cancer. j urol.2020 may;203(5):918–925. doi: 10.1097/ju.0000000000000692. epub 2019 dec 10. 13. socarrás mer , rivas jg, rivera vc, elbers jr, gonzález ll, mercado im, et al. prostate mapping for cancer diagnosis: the madrid protocol. transperineal prostate biopsies using mpmri fusion and microultrasound guided biopsies. j urol.2020 oct;204(4):726–733. doi: 10.1097/ju.0000000000001083. epub 2020 apr 21. 14. cornud f, lefevre a, flam t, dumonceau o, galiano m, soyer p, et al. mri-directed high-frequency (29mhz) trus-guided biopsies: initial results of a single-center study. eur radiol.2020 sep;30(9):4838–4846. doi: 10.1007/s00330-020-06882-x. epub 2020 apr 29. 15. van der leest m, erik cornel e, bas israël b, hendriks r, padhani ar, hoogenboom m, et al. head-to-head comparison of transrectal ultrasound-guided prostate biopsy versus multiparametric prostate resonance imaging with subsequent magnetic resonance-guided biopsy in biopsy-naïve men with elevated prostate-specific antigen: a large prospective multicenter clinical study. eur urol.2019 apr;75(4):570–578. doi: 10.1016/j.eururo.2018.11.023. 16. cornud f, lefevre a, flam t, dumonceau o, galiano m, soyer p, et al. mri-directed high-frequency (29mhz) trus-guided biopsies: initial results of a single-center study. eur radiol.2020 sep;30(9):4838– 4846. doi: 10.1007/s00330-020-06882-x. epub 2020 apr 29. pmid: 32350662. 17. wiemer l, hollenbach m, heckmann r, kittner b, plage h, reimann m, et al. evolution of targeted prostate biopsy by adding microultrasound to the magnetic resonance imaging pathway. eur urol focus.2020 jul 9:s2405 – 4569(20)30188-7. doi: 10.1016/j. euf.2020.06.022. epub ahead of print. pmid: 32654967. 18. engelbrecht mr, jager gj, laheij rj, verbeek alm, van lier hj, barentsz jo, et al. local staging of prostate cancer using magnetic resonance imaging: a meta-analysis. eur radiol.2002 sep;12(9):2294– 302. doi: 10.1007/s00330-002-1389-z. 19. mullerad m, hricak h, kuroiwa k, pucar d, chen h-n, kattan mw, et al. comparison of endorectal magnetic resonance imaging, guided prostate biopsy and digital rectal examination in the preoperative anatomical localization of prostate cancer. j urol.2005 dec;174(6):2158–2163. doi: 10.1097/01.ju.0000181224.95276.82. 20. rodríguez socarrás me, gomez rivas j, cuadros rivera v, reinoso elbers j, llanes gonzález l, michel mercado i, et al. prostate mapping for cancer diagnosis: the madrid protocol. transperineal prostate biopsies using multiparametric magnetic resonance imaging fusion and micro-ultrasound guided biopsies. j urol.2020 oct;204(4):726– 733. doi: 10.1097/ju.0000000000001083. epub 2020 apr 21. pmid: 32314932. 13siuj.org siuj • volume 3, number 1 • january 2022 comparing micro-ultrasound with mpmri in detecting clinically significant prostate cancer http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. evaluation of the guidelines for penile cancer treatment: overview and assessment abdulmajeed aydh,1,2 shahrokh f. shariat,1,3,4,5,6,7,8,9 reza sari motlagh,1 ekaterina laukhtina,1,9 fahad quhal,1,10 keiichiro mori,1,11 hadi mostafaei,1,12 andrea necchi,13 benjamin pradere1,14 1 department of urology, comprehensive cancer center, medical university of vienna, vienna, austria 2 department of urology, king faisal medical city, abha, saudi arabia 3 department of urology, weill cornell medical college, new york, united states 4 department of urology, university of texas southwestern, dallas, united states 5 department of urology, second faculty of medicine, charles university, prague, czech republic 6 european association of urology research foundation, arnhem, netherlands 7 karl landsteiner institute, vienna, austria 8division of urology, department of special surgery, jordan university hospital, the university of jordan, amman, jordan 9 institute for urology and reproductive health, sechenov university, moscow, russia 10 department of urology, king fahad specialist hospital, dammam, saudi arabia 11 department of urology, jikei university school of medicine, tokyo, japan 12 research center for evidence based medicine, tabriz university of medical sciences, tabriz, iran 13 fondazione irccs istituto nazionale dei tumori, milan, italy 14 department of urology, university hospital of tours, tours, france abstract introduction medical organizations have provided evidence-based guidelines for penile cancer treatment. this current review aims to compare and appraise guidelines on penile cancer treatment to provide a useful summary for clinicians. materials and methods we searched in pubmed and medline for guidelines published between january 1, 2010, and february 1, 2020. the search query terms were “penile cancer,” “penile tumor,” “guidelines,” and “penile malignancy.” in the final analysis, we include the most recent versions of relevant guidelines published in english. the appraisal of guidelines for research and evaluation ii (agree ii) instrument was used to appraise the quality of each guideline. results in the final analysis, we included guidelines from the national comprehensive cancer network (updated in 2020), the european association of urology (updated in 2018), and the european society for medical oncology (published in 2013). the overall agreement among reviewers was excellent. the range of scores for each domain was as follows: scope and purpose (46% to 61%); stakeholder involvement (33% to 60%); rigor of development (34% to 69%); clarity and presentation (61% to 81%); applicability (33% to 59%) and editorial independence (52% to 78%). the european association of urology and national comprehensive cancer network clinical practice guidelines received better scores according to the agree ii evaluation. conclusion despite the effort made by the guidelines groups to make a practical guideline regarding penile cancer treatment, the actual available evidence is weak. however, we believe our recommendations offer clear guidance. introduction penile cancer is an aggressive disease that represents less than 1% of all malignancies in the united states and europe[1,2]. penile cancer is common in the elderly, with a peak incidence in the seventh decade of life[3]. the most com¬mon histological subtype for penile cancer is squamous cell carcinoma[4]. given the complex nature of penile cancer, different therapeutic options are available. furthermore, there is growing interest in molecularly targeted key words competing interests article information guidelines, penile cancer, penile malignancy, penile tumor none declared. received on december 22, 2020 accepted on march 1, 2021 soc int urol j.2021;2(3):171–186 doi: https://doi:10.48083/tkfp8406 171siuj.org siuj • volume 2, number 3 • may 2021 review mailto:shahrokh.shariat%40meduniwien.ac.at?subject=siuj https://doi:10.48083/tkfp8406 http://www.siuj.org therapy, and tyrosine kinase inhibitors are showing promising results[5]. however, because of its rarity, most of the recommendations mainly rely on retrospective studies[6,7]. in the last decade, several scientific organizations have provided evidence-based guidelines to improve patients' selection of each treatment modality. the european association of urology (eau) guidelines on penile cancer were first published in 2000 and were last updated in 2018. the national comprehensive cancer network (nccn) penile cancer guidelines were last updated in 2020, while the last european society for medical oncology (esmo) clinical practice guidelines was released in 2013. this study aims to conduct a review, comparison, and appraisal of the guidelines on the treatment of penile cancer to provide universal and practical guidance for physicians in their clinical decision-making. we aimed to provide authoritative guidance with clear recommendations from the best guidelines. materials and methods we searched pubmed and medline for guidelines published between january 1, 2010, and february 1, 2020. the search terms were “penile cancer,” “penile tumor,” “guidelines,” and “penile malignancy.” also, we searched through the websites of international urology and oncology societies for the most recent guidelines on penile cancer. in the final analysis, we included the most recent english version of each guideline. non-english national guidelines were excluded. the appraisal of guidelines for research and evaluation abbreviations agree ii appraisal of guidelines for research and evaluation ii nccn national comprehensive cancer network eau european association of urology esmo european society for medical oncology ebrt external beam radiation therapy plnd pelvic lymph node dissection loe level of evidence gor grade of recommendation table 1. guidelines for the management penile cancer according to t stage treatment eau guidelines nccn guidelines esmo guidelines recommendation grade of recommendation level of evidence recommendation grade of recommendation level of evidence recommendation grade of recommendation level of evidence stage tis topical treatment with 5-fluorouracil (5-fu) or imiquimod 5-fu is an effective first-line treatment strong recommendation tis, ta, and t1 penile cancer lesions may be amenable to conservative penile organ-sparing approaches, including topical therapy considered appropriate 2a penile-preserving techniques, including topical therapy (5% 5-fluorouracil and 5% imiquimod cream) c iv laser ablation (nd:yag) or carbon dioxide (co2) laser is an effective treatment option strong recommendation the use of therapeutic lasers to treat selected primary penile tumors has been reported with acceptable outcomes considered appropriate 2b laser therapy using co2 or nd: yag laser c iii glans resurfacing glans resurfacing, total or partial, can be a primary treatment for pein or a secondary strong recommendation glansectomy, removal of the glans penis, may be considered for patients with distal tumors considered appropriate 2b partial/total glans resurfacing c iii wide local excision with circumcision glans resurfacing, total or partial, can be a primary treatment for pein or a secondary penile tumors of the shaft may be treated with wide local excision, with or without circumcision considered appropriate 2a wide local excision and circumcision c iv mohs surgery historical technique mohs surgery is an alternative to wide local excision in select cases 2b 172 siuj • volume 2, number 3 • may 2021 siuj.org review http://siuj.org ii (agree ii) instrument was used to appraise the quality of guidelines[8]. this instrument permits the evaluation of the scope and purpose of the guidelines, stakeholder involvement, rigor of development, clarity of presentation, applicability, and editorial independence. the overall assessment is the final mean of all domains, which gives an overview of each guideline score. the agree ii recommends 2 or more appraisers. therefore, each guideline was evaluated by 5 appraisers (bp, el, fq, hm, and km) to enhance the authenticity of the assessment. the appraisal was performed after the completion of an online training module on agree ii website[9]. the 5 reviewers were experienced in urologic oncology and were mentored by 2 oncologic urologists (sfs, bp) experienced in guidelines writing and grade of recommendation rating. results guidelines from 3 international organizations were included in the final analysis: the 2020 update of the nccn guideline[10], the 2018 update of the eau guidelines[11], and the 2013 update of the esmo guidelines[12]. level of evidence assessment and grading of recommendations two guidelines (eau and nccn) provided a detailed and strict methodology for searching and acquisition of evidence from the literature. the esmo guideline is an expert consensus statement so did not include a systematic literature search. all 3 guidelines (eau, nccn, and esmo) provided a description of the systems used for grading the level of evidence. in the eau guidelines, a modified grading of recommendations assessment, development, and evaluation (grade) was used[13,14]. for each recommendation within the guidelines, there was also an accompanying online strength rating form, which addresses several elements. the nccn guidelines used the categories of evidence and consensus to grade the recommendations; they also provide categories of preference to help users chose the optimal recommendation based on efficacy, safety, evidence, or affordability. the esmo guidelines adapted the infectious diseases society of america-united states public health service grading system[15]. continued on page 174 table 1. guidelines for the management penile cancer according to t stage treatment eau guidelines nccn guidelines esmo guidelines recommendation grade of recommendation level of evidence recommendation grade of recommendation level of evidence recommendation grade of recommendation level of evidence stage tis topical treatment with 5-fluorouracil (5-fu) or imiquimod 5-fu is an effective first-line treatment strong recommendation tis, ta, and t1 penile cancer lesions may be amenable to conservative penile organ-sparing approaches, including topical therapy considered appropriate 2a penile-preserving techniques, including topical therapy (5% 5-fluorouracil and 5% imiquimod cream) c iv laser ablation (nd:yag) or carbon dioxide (co2) laser is an effective treatment option strong recommendation the use of therapeutic lasers to treat selected primary penile tumors has been reported with acceptable outcomes considered appropriate 2b laser therapy using co2 or nd: yag laser c iii glans resurfacing glans resurfacing, total or partial, can be a primary treatment for pein or a secondary strong recommendation glansectomy, removal of the glans penis, may be considered for patients with distal tumors considered appropriate 2b partial/total glans resurfacing c iii wide local excision with circumcision glans resurfacing, total or partial, can be a primary treatment for pein or a secondary penile tumors of the shaft may be treated with wide local excision, with or without circumcision considered appropriate 2a wide local excision and circumcision c iv mohs surgery historical technique mohs surgery is an alternative to wide local excision in select cases 2b 173siuj.org siuj • volume 2, number 3 • may 2021 evaluation of the guidelines for penile cancer treatment: overview and assessment http://siuj.org table 1. guidelines for the management penile cancer according to t stage, cont'd treatment eau guidelines nccn guidelines esmo guidelines recommendation grade of recommendation level of evidence recommendation grade of recommendation level of evidence recommendation grade of recommendation level of evidence stage ta, t1a (g1, g2) wide local excision with circumcision partial glansectomy or total glansectomy with reconstruction are surgical options strong recommendation penile tumors of the shaft may be treated with wide local excision, with or without circumcision considered appropriate 2a penile-preserving techniques, including wide local excision plus reconstructive surgery c iii glans resurfacing partial glansectomy or total glansectomy with reconstruction are surgical options strong recommendation glansectomy may be considered for select patients with distal tumors considered appropriate 2b glansectomy with reconstruction partial glansectomy or total glansectomy with reconstruction are surgical options strong recommendation glansectomy is not recommended unless required to ensure complete tumor eradication with negative margins considered appropriate 2a radiotherapy external beam radiotherapy or brachytherapy is radiotherapeutic options strong recommendation 2b consider <4 cm: brachytherapy or ebrt >4 cm: ebrt with chemotherapy considered appropriate 2b radiotherapy delivered as ebrt or brachytherapy with interstitial implant c iv laser ablation small lesions can also be treated by laser therapy strong recommendation the use of therapeutic lasers to treat selected primary penile tumors has been reported with acceptable outcomes considered appropriate 2b laser therapy c iv partial penectomy strong recommendation partial or total penectomy when invasion into the corpora cavernosum is necessary to achieve a negative margin considered appropriate 2a mohs surgery strong recommendation mohs surgery is an alternative to wide local excision in select cases. considered appropriate 2b stage t1b (g3) and t2 wide local excision plus reconstruction local excision, partial glansectomy or total glansectomy with reconstruction are surgical options strong recommendation penile tumors of the shaft may be treated with wide local excision considered appropriate 2a if tumor <50% of the glans and no invasion of the corpora cavernosa b iii glansectomy with circumcision and reconstruction local excision, partial glansectomy or total glansectomy with reconstruction are surgical options strong recommendation glansectomy may be considered for select patients with distal tumors considered appropriate 2a if tumor <50% of the glans and no invasion of the corpora cavernosa b iii radiotherapy external beam radiotherapy or brachytherapy is radiotherapeutic options strong recommendation consider <4 cm: brachytherapy or ebrt >4 cm: ebrt with chemotherapy considered appropriate 2b <4 cm: brachytherapy or ebrt >4 cm: ebrt with chemotherapy iii total penectomy or partial total glansectomy, with or without resurfacing of the corporeal heads, is recommended strong recommendation partial or total penectomy when invasion into the corpora cavernosum is necessary to achieve a negative margin considered appropriate 2a tumors with invasion into corpora cavernosa b iii 174 siuj • volume 2, number 3 • may 2021 siuj.org review http://siuj.org table 1. guidelines for the management penile cancer according to t stage, cont'd treatment eau guidelines nccn guidelines esmo guidelines recommendation grade of recommendation level of evidence recommendation grade of recommendation level of evidence recommendation grade of recommendation level of evidence stage ta, t1a (g1, g2) wide local excision with circumcision partial glansectomy or total glansectomy with reconstruction are surgical options strong recommendation penile tumors of the shaft may be treated with wide local excision, with or without circumcision considered appropriate 2a penile-preserving techniques, including wide local excision plus reconstructive surgery c iii glans resurfacing partial glansectomy or total glansectomy with reconstruction are surgical options strong recommendation glansectomy may be considered for select patients with distal tumors considered appropriate 2b glansectomy with reconstruction partial glansectomy or total glansectomy with reconstruction are surgical options strong recommendation glansectomy is not recommended unless required to ensure complete tumor eradication with negative margins considered appropriate 2a radiotherapy external beam radiotherapy or brachytherapy is radiotherapeutic options strong recommendation 2b consider <4 cm: brachytherapy or ebrt >4 cm: ebrt with chemotherapy considered appropriate 2b radiotherapy delivered as ebrt or brachytherapy with interstitial implant c iv laser ablation small lesions can also be treated by laser therapy strong recommendation the use of therapeutic lasers to treat selected primary penile tumors has been reported with acceptable outcomes considered appropriate 2b laser therapy c iv partial penectomy strong recommendation partial or total penectomy when invasion into the corpora cavernosum is necessary to achieve a negative margin considered appropriate 2a mohs surgery strong recommendation mohs surgery is an alternative to wide local excision in select cases. considered appropriate 2b stage t1b (g3) and t2 wide local excision plus reconstruction local excision, partial glansectomy or total glansectomy with reconstruction are surgical options strong recommendation penile tumors of the shaft may be treated with wide local excision considered appropriate 2a if tumor <50% of the glans and no invasion of the corpora cavernosa b iii glansectomy with circumcision and reconstruction local excision, partial glansectomy or total glansectomy with reconstruction are surgical options strong recommendation glansectomy may be considered for select patients with distal tumors considered appropriate 2a if tumor <50% of the glans and no invasion of the corpora cavernosa b iii radiotherapy external beam radiotherapy or brachytherapy is radiotherapeutic options strong recommendation consider <4 cm: brachytherapy or ebrt >4 cm: ebrt with chemotherapy considered appropriate 2b <4 cm: brachytherapy or ebrt >4 cm: ebrt with chemotherapy iii total penectomy or partial total glansectomy, with or without resurfacing of the corporeal heads, is recommended strong recommendation partial or total penectomy when invasion into the corpora cavernosum is necessary to achieve a negative margin considered appropriate 2a tumors with invasion into corpora cavernosa b iii continued on page 176 175siuj.org siuj • volume 2, number 3 • may 2021 evaluation of the guidelines for penile cancer treatment: overview and assessment http://siuj.org table 1. guidelines for the management penile cancer according to t stage, cont'd treatment eau guidelines nccn guidelines esmo guidelines recommendation grade of recommendation level of evidence recommendation grade of recommendation level of evidence recommendation grade of recommendation level of evidence stage t2 total glansectomy total glansectomy, with or without resurfacing of the corporeal heads, is recommended strong recommendation 3 c iii radiotherapy radiation therapy is an option strong recommendation consider <4 cm: brachytherapy or ebrt >4 cm: ebrt with chemotherapy considered appropriate 2b <4 cm: brachytherapy or ebrt >4 cm: ebrt with chemotherapy d total penectomy or partial partial amputation should be considered in patients unfit for reconstructive surgery strong recommendation partial or total penectomy when invasion into the corpora cavernosum is necessary to achieve a negative margin considered appropriate 2a tumors with invasion into corpora cavernosa b iii stage t3 partial amputation with reconstruction or total penectomy glansectomy with distal corporectomy and reconstruction or partial amputation with reconstruction are standard strong recommendation partial or total penectomy when invasion into the corpora cavernosum is necessary to achieve a negative margin considered appropriate 2a t3-4 or n+: circumcision followed by ebrt with chemotherapy d radiotherapy radiation therapy is an option strong recommendation ebrt with chemotherapy are treatment options considered appropriate 3 stage t3 with invasion of the urethra partial penectomy or total penectomy glansectomy with distal corporectomy and reconstruction or partial amputation with reconstruction are standard strong recommendation partial or total penectomy when invasion into the corpora cavernosum is necessary to achieve a negative margin considered appropriate 2a t3-4 or n+: circumcision followed by ebrt with chemotherapy d radiotherapy radiation therapy is an option strong recommendation ebrt with chemotherapy are treatment options considered appropriate 2b stage t4 partial penectomy or total penectomy extensive partial amputation or total penectomy with perineal urethrostomy is the standard advisable treatment weak recommendation partial or total penectomy when invasion into the corpora cavernosum is necessary to achieve a negative margin considered appropriate 2a t3-4 or n+: circumcision followed by ebrt with chemotherapy d radiotherapy palliative radiotherapy is an option ebrt with chemotherapy are treatment options considered appropriate 3 176 siuj • volume 2, number 3 • may 2021 siuj.org review http://siuj.org table 1. guidelines for the management penile cancer according to t stage, cont'd treatment eau guidelines nccn guidelines esmo guidelines recommendation grade of recommendation level of evidence recommendation grade of recommendation level of evidence recommendation grade of recommendation level of evidence stage t2 total glansectomy total glansectomy, with or without resurfacing of the corporeal heads, is recommended strong recommendation 3 c iii radiotherapy radiation therapy is an option strong recommendation consider <4 cm: brachytherapy or ebrt >4 cm: ebrt with chemotherapy considered appropriate 2b <4 cm: brachytherapy or ebrt >4 cm: ebrt with chemotherapy d total penectomy or partial partial amputation should be considered in patients unfit for reconstructive surgery strong recommendation partial or total penectomy when invasion into the corpora cavernosum is necessary to achieve a negative margin considered appropriate 2a tumors with invasion into corpora cavernosa b iii stage t3 partial amputation with reconstruction or total penectomy glansectomy with distal corporectomy and reconstruction or partial amputation with reconstruction are standard strong recommendation partial or total penectomy when invasion into the corpora cavernosum is necessary to achieve a negative margin considered appropriate 2a t3-4 or n+: circumcision followed by ebrt with chemotherapy d radiotherapy radiation therapy is an option strong recommendation ebrt with chemotherapy are treatment options considered appropriate 3 stage t3 with invasion of the urethra partial penectomy or total penectomy glansectomy with distal corporectomy and reconstruction or partial amputation with reconstruction are standard strong recommendation partial or total penectomy when invasion into the corpora cavernosum is necessary to achieve a negative margin considered appropriate 2a t3-4 or n+: circumcision followed by ebrt with chemotherapy d radiotherapy radiation therapy is an option strong recommendation ebrt with chemotherapy are treatment options considered appropriate 2b stage t4 partial penectomy or total penectomy extensive partial amputation or total penectomy with perineal urethrostomy is the standard advisable treatment weak recommendation partial or total penectomy when invasion into the corpora cavernosum is necessary to achieve a negative margin considered appropriate 2a t3-4 or n+: circumcision followed by ebrt with chemotherapy d radiotherapy palliative radiotherapy is an option ebrt with chemotherapy are treatment options considered appropriate 3 177siuj.org siuj • volume 2, number 3 • may 2021 evaluation of the guidelines for penile cancer treatment: overview and assessment http://siuj.org treatment strategy according to stage organ-sparing treatment in tis, ta, and t1a tumors all 3 guidelines (eau, nccn, and esmo), advise organ-sparing approaches in patients diagnosed with tis, ta, and t1 penile cancer lesions. however, the eau guidelines highlight the absence of randomized cont rol led t r ia ls or compa rat ive obser vat iona l studies for treatment options for localized penile cancer. nevertheless, from a cosmetic and functional standpoint, balanced with the risk of recurrence and progression of these stages, penile preservation is considered superior to partial or total penectomy and should be performed for localized penile cancer (staged ≤ t1)[16]. topical agents are the least invasive and easiest treatment options for superficial and localized lesions. table 2. author recommendations for penile cancer guidelines topical laser surgery radiotherapy tis 5-fluorouracil (5fu) or imiquimod 5% for superficial lesions ± photo dynamic control tis t2 glans laser ablation with co2 or nd:yag laser • glans resurfacing (removal of glans epithelium) for lesions confined to glans • glansectomy (leaving corpora intact compared to partial penectomy) • circumcision for lesions confined to prepuce • wide local excision + reconstruction ± skin grafting ta, t1 & t2 confined to the glans x ta t2 radiotherapy by • external beam • (ebrt) or as • brachytherapy t2 corpora cavernosa (cc) x x • partial penectomy + reconstruction t3 (three) invasion of urethra x x • partial penectomy • total penectomy with perineal urethrostomy t4 adjacent structures x x • neoadjuvant chemo + surgery in responders or palliative ebrt nodal metastases no palpable inguinal nodes palpable (cn1/cn2) fixed (cn3) pelvic lymphadenopathy tis, ta g1, t1g1 > t1g2 radical inguinal lymphadenectomy neoadjuvant chemotherapy ± followed in responders by radical inguinal lymphadenectomy ipsilateral pelvic lymphadenectomy if (pn2) ≥ 2 inguinal nodes are involved on one side and if (pn3) extracapsular nodal metastasis surveillance staging by dynamic sentinel node biopsy chemotherapy • neoadj.: t4, fixed n3 • adjuvant: pn2/pn3 adjuvant chemo in pn2/pn3 patients after radical lymphadenectomy 3–4 cycles of tpf: paclitaxel, cisplatin, 5-fluorouracil (5fu) 178 siuj • volume 2, number 3 • may 2021 siuj.org review http://siuj.org before their use, the eau guidelines recommend performing a circumcision. the eau and nccn guidelines make clear that there is a requirement for long-term surveillance. another option is laser therapy, which could be performed as day-case surgery. when laser therapy is performed, the eau guidelines mandate a second biopsy before treatment is initiated. a partial or total glans resurfacing can be an alternative in the firstline treatment for penile intraepithelial lesions (pein) or could be proposed after topical or laser therapy failure. in the case of wide local excision, mohs surgery can be proposed in selected cases according to the eau and nccn guidelines (table 1). summary of treatment recommendations: for patients w it h penile tis or ta, we recommend topical therapy[17,18] and excisional organ-sparing technique[19], a topical agent such as imiquimod (5%) or 5-fluorouracil (5fu) cream, circumcision and wide local excision, laser therapy, or complete glansectomy (table 2). invasive disease treatment confined to the glans t1/t2 for t1 and t2 tumors localized to the glans, the 3 guidelines proposed different strategies, including surgery with laser therapy, local excision, partial glansectomy, or total glansectomy, and radiotherapy or brachytherapy. for the treatment of invasive disease confined to the glans, the eau and the esmo guidelines agree on conservative approaches, such as wide local excision or glansectomy, while the nccn guidelines recommended it only in t1 high grade (g3–4). for radiotherapy, the nccn and the eau guidelines recommended brachy t herapy or ex terna l bea m radiation therapy  (ebrt) for tumors less than 4 cm. a circumcision is mandated by the nccn guidelines before radiot herapy (rt) to prevent radiationrelated complications. for tumors larger than 4 cm, a multimodal treatment combining radiotherapy and chemotherapy is recommended (table 1). summary of treatment recommendations: our recommendation for the treatment of invasive disease confined to the glans is a glansectomy with or without resurfacing with a partial thickness skin graft of the corporeal heads[20]. a partial amputation for patients who are not candidates for reconstructive surgery should be performed[21]. radiotherapy may also be an option[22] (table 2). treatment of invasive disease t3/t4 for tumors with invasion of the corpora cavernosum, a partial or total penectomy is mandatory to achieve a total resection with negative margin according to the nccn and the eau guidelines. ebrt with concurrent chemotherapy is also an option in the nccn guidelines, while it is the primar y treatment in the esmo guidelines. the eau guidelines consider radiation as a treatment option only for t3 and as a palliative treatment in t4 disease (table 1). summary of treatment recommendations: for the treatment of ct3, we recommend glansectomy with corporectomy and reconstruction or partial penectomy with reconstruction as a standard of care[23,24]. total penectomy with perineal urethrostomy is considered in selected cases. for ct4 disease, the recommended treatment remains a total penectomy with perineal urethrostomy[24]. neoadjuvant chemotherapy for the locally advanced disease should be systematically considered and proposed[25,26] (table 2). guidelines for treatment strategies for nodal metastases: cn0 the esmo, nccn, and eau guidelines all recommend surveillance for tis, ta g1, and t1g1 stages. invasive lymph node staging either by bilateral modified inguinal lymphadenectomy or by dynamic sentinel node biopsy is recommended for ≥ t1g2 (table 3). there is currently no role for prophylactic radiation to the inguinal lymph nodes instead of lymph node dissection or biopsy[27]. summary of treatment recommendations: there are considerable discussions among researchers in the management of cn0 disease. nonetheless, we believe that it is justif ied to  recommend surveillance for tis, ta g1, and t1g1 if the patient is compliant[28]. in contrast, at least a dynamic sentinel node biopsy should be recommended to improve the outcome for ≥ t1g2 disease[29] (table 2). guidelines for treatment strategies for nodal metastases: cn1/cn2 a ll 3 guidelines recommend a radica l inguina l lymphadenectomy for clinically positive lymph nodes. the confirmation of clinically positive lymph nodes should be made by surgical resection and frozen section according to the eau guidelines, while, according to the nccn, the confirmation can be made by percutaneous biopsy, or by fine-needle aspiration (fna) in the esmo guidelines (table 3). summa r y of treatment recommendations: radi cal inguinal lymphadenectomy seems to improve survival and should be recommended for every patient with cn1/n2[30] (table 2). guidelines for treatment strategies for nodal metastases: cn3 f o r f i x e d i n g u i n a l n o d a l m a s s o r p e l v i c lymphadenopathy (cn3), neoadjuvant chemotherapy 179siuj.org siuj • volume 2, number 3 • may 2021 evaluation of the guidelines for penile cancer treatment: overview and assessment http://siuj.org continued on page 182 table 3. guidelines for the management of nodal metastasis and adjuvant therapy for penile cancer eau guidelines nccn guidelines esmo guidelines recommendation grade of recommendation level of evidence recommendation grade of recommendation level of evidence recommendation grade of recommendation level of evidence stage cn0 surveillance is only recommended in patients with ptis/pta tumors strong recommendation most low-risk patients are followed with a surveillance as the probability of occult micro metastases in ilns is low considered appropriate 2a lowrisk (tis, ta, t1g1) and intermediate-risk (t1g2) are followed with surveillance b > t1g2: invasive lymph node staging is recommended by either bilateral modified inguinal lymphadenectomy or dynamic sentinel node biopsy strong recommendation 2b for high-risk standard or modified ilnd or dsnb is strongly recommended in high-risk considered appropriate 2a dsnb is recommended in patients with non-palpable inguinal lymph nodes t1g2 or greater b stage cn1/cn2 a radical inguinal lymphadenectomy should be performed strong recommendation 2b percutaneous lymph node biopsy is considered standard positive findings warrant an immediate ilnd 2a fine-needle aspiration (fna) of the ln is standard for these patients (omitting the procedure for high-risk tumors to avoid delay of ilnd) stage cn3 multimodal treatment with neoadjuvant chemotherapy followed by radical lymphadenectomy in responders is recommended weak recommendation should receive neoadjuvant chemotherapy followed by radical inguinal and plnd lymphadenectomy in responders considered appropriate 2a patients with fixed nodes should be considered for neoadjuvant chemoradiotherapy c iii consider postoperative radiotherapy or chemoradiotherapy 2b responders receive consolidation surgery (bilateral and deep ilnd and ipsilateral plnd if possible) stage pelvic lymph nod patients with 2 or more inguinal lymph node metastases on one side and/or extracapsular lymph node extension need to undergo ipsilateral pelvic lymphadenectomy strong recommendation 2b plnd should be considered at the time or following ilnd in patients with ≥ three positive inguinal nodes on the ipsilateral ilnd site considered appropriate 2a patients with fixed nodes should be considered for neoadjuvant chemoradiotherapy c iii bilateral plnd should be considered either at the time or following ilnd in patients with ≥4 positive inguinal nodes considered appropriate 2a responders receive consolidation surgery (bilateral and deep ilnd and ipsilateral plnd if possible) 180 siuj • volume 2, number 3 • may 2021 siuj.org review http://siuj.org followed by a radical lymphadenectomy is supported by both nccn and eau guidelines. the esmo guidelines recommend a multimodal treatment including chemoradiot herapy fol lowed by consolidation surger y (inguinal lymph node dissection [ilnd] and ipsilateral pelvic lymph node dissection [plnd]). this treatment regimen is one of the options in the nccn guidelines but is considered only as a palliative treatment in the eau guidelines (table 3). summary of treatment recommendations: for cn3, we recommend a radical lymphadenectomy after neoadjuvant chemotherapy for every responder to improve disease-free survival[25] (table 2). enlarged pelvic lymph nodes for surgically resectable lesions, all 3 guidelines recommend neoadjuvant systemic chemotherapy, followed by unilateral/bilateral plnd in case of treatment response. the eau guidelines recommend lymphadenectomy for ipsilateral plnd if 2 or more inguinal lymph nodes are affected on one side or if extracapsular nodal metastasis is reported, followed by adjuvant chemotherapy. for enlarged pelvic lymph nodes where surgery is not possible, the nccn and the esmo guidelines recommend chemo-radiotherapy (table 3). summary of treatment recommendations: plnd is recommended for patients with 2 or more inguinal lymph nodes affected on one side or if extra-nodal extension is found[31] (table 2). guidelines for chemotherapy both the eau and esmo guidelines state that neoadjuvant chemotherapy followed by radical surgery is advisable in unresectable lymph node metastases. the nccn g uidelines recommend neoadjuvant chemotherapy in patients with ≥ 4 cm inguinal lymph nodes (fixed or mobile). the eau and esmo guidelines recommend adjuvant chemotherapy after lymphadenectomy in patients with pn2/pn3 disease. in contrast, the nccn guidelines recommended adjuvant chemotherapy only if it was not given preoperatively, and if the pathology shows high-risk features (tables 3,4). su m ma r y of t re at ment recom mend at ions: a neoadjuvant chemotherapy should be proposed systematically for patients with cn3 inguinal lymph nodes and discussed for all clinical lymph nodes ≥ 4cm. an adjuvant chemotherapy should be offered to patients with pn2/pn3 disease without previous systemic treatment. three to 4 cycles of paclitaxel, cisplatin, 5-fluorouracil (5fu) are the recommended regimen[32–34] (table 2). continued on page 182 table 3. guidelines for the management of nodal metastasis and adjuvant therapy for penile cancer eau guidelines nccn guidelines esmo guidelines recommendation grade of recommendation level of evidence recommendation grade of recommendation level of evidence recommendation grade of recommendation level of evidence stage cn0 surveillance is only recommended in patients with ptis/pta tumors strong recommendation most low-risk patients are followed with a surveillance as the probability of occult micro metastases in ilns is low considered appropriate 2a lowrisk (tis, ta, t1g1) and intermediate-risk (t1g2) are followed with surveillance b > t1g2: invasive lymph node staging is recommended by either bilateral modified inguinal lymphadenectomy or dynamic sentinel node biopsy strong recommendation 2b for high-risk standard or modified ilnd or dsnb is strongly recommended in high-risk considered appropriate 2a dsnb is recommended in patients with non-palpable inguinal lymph nodes t1g2 or greater b stage cn1/cn2 a radical inguinal lymphadenectomy should be performed strong recommendation 2b percutaneous lymph node biopsy is considered standard positive findings warrant an immediate ilnd 2a fine-needle aspiration (fna) of the ln is standard for these patients (omitting the procedure for high-risk tumors to avoid delay of ilnd) stage cn3 multimodal treatment with neoadjuvant chemotherapy followed by radical lymphadenectomy in responders is recommended weak recommendation should receive neoadjuvant chemotherapy followed by radical inguinal and plnd lymphadenectomy in responders considered appropriate 2a patients with fixed nodes should be considered for neoadjuvant chemoradiotherapy c iii consider postoperative radiotherapy or chemoradiotherapy 2b responders receive consolidation surgery (bilateral and deep ilnd and ipsilateral plnd if possible) stage pelvic lymph nod patients with 2 or more inguinal lymph node metastases on one side and/or extracapsular lymph node extension need to undergo ipsilateral pelvic lymphadenectomy strong recommendation 2b plnd should be considered at the time or following ilnd in patients with ≥ three positive inguinal nodes on the ipsilateral ilnd site considered appropriate 2a patients with fixed nodes should be considered for neoadjuvant chemoradiotherapy c iii bilateral plnd should be considered either at the time or following ilnd in patients with ≥4 positive inguinal nodes considered appropriate 2a responders receive consolidation surgery (bilateral and deep ilnd and ipsilateral plnd if possible) 181siuj.org siuj • volume 2, number 3 • may 2021 evaluation of the guidelines for penile cancer treatment: overview and assessment http://siuj.org table 3. guidelines for the management of nodal metastasis and adjuvant therapy for penile cancer, cont'd eau guidelines nccn guidelines esmo guidelines recommendation grade of recommendation level of evidence recommendation grade of recommendation level of evidence recommendation grade of recommendation level of evidence stage chemotherapy neoadjuvant chemotherapy using cisplatinand the taxanebased triple combination should be used in patients with fixed, unresectable, nodal disease strong recommendation 2a neoadjuvant chemotherapy with tip (paclitaxel, ifosfamide, and cisplatin) is preferred (prior to ilnd) in patients with ≥4 cm inguinal lymphnodes (fixed or mobile) considered appropriate 2a neoadjuvant chemotherapy followed by radical surgery is advisable in unresectable or recurrent ln metastases c strong recommendation 2b adjuvant chemotherapy it is reasonable to give four courses of tip in the adjuvant setting if it was not given preoperatively and the pathology shows high-risk features 2a adjuvant chemotherapy is recommended in pn2-3 patients c stage radiotherapy not recommended for nodal disease except as a palliative option strong recommendation adjuvant ebrt or chemoradiotherapy can also be considered for patients with high-risk features considered appropriate 2b the role of adjuvant postoperative radiation is controversial table 4. guidelines of chemotherapy regimen for penile cancer eau guidelines nccn guidelines esmo guidelines treatment grade of recommendation level of evidence treatment grade of recommendation level of evidence treatment grade of recommendation level of evidence neoadjuvant chemotherapy (4 cycles) cisplatinand taxanebased regimen weak 2a (4 courses) tip (paclitaxel, ifosfamide, and cisplatin) 2a considered appropriate (4 courses) tip (paclitaxel, ifosfamide, and cisplatin) c iii adjuvant chemotherapy (3 to 4 cycles) cisplatin, a taxane and 5-fluorouracil or ifosfamide strong 2b (4 courses) preferred regimen is tip (paclitaxel, ifosfamide, and cisplatin) other recommended regimen is 5fluorouracil + cisplatin 2a considered appropriate no clear recommendation 182 siuj • volume 2, number 3 • may 2021 siuj.org review http://siuj.org guidelines for adjuvant radiotherapy nccn guidelines indicate that adjuvant ebrt or chemo-radiotherapy can be considered for patients with high-risk features, but the eau guidelines do not recommend it except for palliative treatment. according to the esmo guidelines, the role of adjuvant radiotherapy in the management of penile cancer remains controversial (tables 3,4). summa r y of treatment recommendations: adjuvant radiotherapy is recommended after plnd for patients with positive results in ilnd[35,36]. assessment of the quality of the guidelines with the agree ii instrument the agree instrument is a 23-item tool comprising 6 quality and 2 overall assessment domains. a unique dimension of guideline quality is captured in each domain. table 3 shows the results of the guidelines appraisal by the 5 reviewers. for the domain 1 scope and purpose, which is related to the specific health questions, the overall aim of the guideline, and the target population, eau and nccn both scored 61%, while esmo scored only 46%. concerning the stakeholder involvement focuses on the extent to which the guidelines were developed by the appropriate stakeholders, the lowest score was 33% for esmo, while eau and nccn reached approximately the same score with 59% and 60%, respectively. regarding rigor of development concerned with the approaches to formulate the recommendations and the process used to gather and make the evidence and to update them, the appraiser gave the best score to the eau and nccn guidelines with 69% and 61%, respectively; while the esmo, with a score of 34% did not reach the expected standard. with respect to structure, language, format, and clarity of presentation, the nccn had a score of 81%, followed by the eau, with 77%, and the esmo with 61%. resource implications of applying the guideline, strategies to improve uptake, and applicability pertaining to the likely barriers to and facilitators of implementation were scored at 33%, 53%, and 59% for the esmo, nccn, and eau guidelines, respectively. for editorial independence, which concerns there being no competing interests that might bias the formulation of recommendations, the scores were 78% for the eau guidelines, 57% for the esmo guidelines, and 52% for the nccn guidelines. overall assessment includes rating the recommendation of guidelines for practice use and the overall quality of the guidelines. the highest score was reached by the eau guidelines with a total rate of 77%, and the lowest score by the esmo guidelines with a rate of 40%, while the nccn guidelines also reached a high rate with 73% (table 5). table 3. guidelines for the management of nodal metastasis and adjuvant therapy for penile cancer, cont'd eau guidelines nccn guidelines esmo guidelines recommendation grade of recommendation level of evidence recommendation grade of recommendation level of evidence recommendation grade of recommendation level of evidence stage chemotherapy neoadjuvant chemotherapy using cisplatinand the taxanebased triple combination should be used in patients with fixed, unresectable, nodal disease strong recommendation 2a neoadjuvant chemotherapy with tip (paclitaxel, ifosfamide, and cisplatin) is preferred (prior to ilnd) in patients with ≥4 cm inguinal lymphnodes (fixed or mobile) considered appropriate 2a neoadjuvant chemotherapy followed by radical surgery is advisable in unresectable or recurrent ln metastases c strong recommendation 2b adjuvant chemotherapy it is reasonable to give four courses of tip in the adjuvant setting if it was not given preoperatively and the pathology shows high-risk features 2a adjuvant chemotherapy is recommended in pn2-3 patients c stage radiotherapy not recommended for nodal disease except as a palliative option strong recommendation adjuvant ebrt or chemoradiotherapy can also be considered for patients with high-risk features considered appropriate 2b the role of adjuvant postoperative radiation is controversial table 4. guidelines of chemotherapy regimen for penile cancer eau guidelines nccn guidelines esmo guidelines treatment grade of recommendation level of evidence treatment grade of recommendation level of evidence treatment grade of recommendation level of evidence neoadjuvant chemotherapy (4 cycles) cisplatinand taxanebased regimen weak 2a (4 courses) tip (paclitaxel, ifosfamide, and cisplatin) 2a considered appropriate (4 courses) tip (paclitaxel, ifosfamide, and cisplatin) c iii adjuvant chemotherapy (3 to 4 cycles) cisplatin, a taxane and 5-fluorouracil or ifosfamide strong 2b (4 courses) preferred regimen is tip (paclitaxel, ifosfamide, and cisplatin) other recommended regimen is 5fluorouracil + cisplatin 2a considered appropriate no clear recommendation 183siuj.org siuj • volume 2, number 3 • may 2021 evaluation of the guidelines for penile cancer treatment: overview and assessment http://siuj.org discussion clinical guidelines help physicians to choose the best treatment available for individual patients. fewer guidelines are available in the case of rare diseases, and only 3 guidelines in english have been published on the management of penile cancer. the recommendations made in these guidelines are not always in agreement. therefore, to help urologists in their decision-making process regarding therapy, we evaluated and compared the guidelines of the nccn, eau, and esmo on the management of penile cancer. using the agree ii tool, we assessed the quality of the guidelines. we discuss the differences in terms of loe and gor that arise as a result of different methods of evaluation used. the eau and nccn guidelines incorporate more recent literature than the esmo guidelines, which have not been updated for 7 years. the eau guidelines use a modif ied grading of recommendations assessment, development, and evaluation (gr ade) methodolog y. for each recommendation within the guidelines, there is an accompanying online strength rating form that addresses several elements. the esmo adapted the infectious diseases society of america-united states public health service grading system. the level of evidence assessment and grading of recommendations in nccn guidelines are based on randomized controlled trials, clinical trials, guidelines, systematic reviews, meta-analysis, and validation studies. evaluation of loe and gor are more specified clearly in the nccn guidelines than in the other 2 guidelines. although these 3 guidelines developed in different ways, it is reassuring that they have considerable similarities, albeit some small but potentially significant differences between them. the evidence available is weak in penile cancer, and a consequence of the scarcity in evidence is that way, some recommendations are based on the panel’s review of the low-level evidence and expert opinion. one of the contentious points is the advantage of both neoadjuvant and adjuvant radiotherapy in the treatment of penile cancer patients with ln metastases. there is some evidence for adjuvant nodal radiotherapy in in vulvar carcinoma, which shares many characteristics with penile cancer[37,38]. however, high-quality evidence to suggest a clear benefit to radiotherapy in penile cancer is lacking[39,40]. in a retrospective study of 2458 patients in the seer database (national cancer institute surveillance, epidemiology and end results program), no advantage was observed with the use of ebrt for penile cancer patients compared to surgery alone on cancer-specific survival[41]. a similar conclusion was reached by franks et al., who reported poor long-term survival for patients treated with adjuvant radiotherapy[42]. these essential findings are consistent with those of other studies, which showed no patient benefit[43,44–48]. however, a series of recent studies have indicated that  adjuvant radiotherapy i mprove d su r v iv a l a nd de c re a s e d re c u r renc e rate[35,36,49]. table 5. agree ii evaluation of guidelines for the management of penile cancer scope and purpose % stakeholder involvement % rigor of development % clarity of presentation % applicability % editorial independence % overall assessment % final recommendations eau guidelines 61 59 69 77 59 78 77 yes–3, yes with modifications–2, no–0 nccn guidelines 61 60 61 81 53 52 73 yes–3, yes with modifications–2, no–0 esmo guidelines 46 33 34 61 33 57 40 yes–0, yes with modifications–2, no–3 184 siuj • volume 2, number 3 • may 2021 siuj.org review http://siuj.org conclusion this is the first attempt to review and appraise guidelines for penile cancer management systematically. although all guidelines strive to be evidence-based, some recommendations differ between the guidelines because the underlying evidence is poor. also, these guidelines are produced in the united states and europe, so that their applicability in other regions with a high incidence of penile cancer is uncertain. this point may encourage organizations in other areas to produce their own guidelines. the best way to improve the guidelines is to conduct more prospective trials to strengthen the data underlying the 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tang l-y, wang y-j, liang j-y, zhang r-c, et al. radiocolloid-based dynamic sentinel lymph node biopsy in penile cancer with clinically negative inguinal lymph node: an updated systematic review and met a-analysis. int urol nephrol.2016;48(12):2001–2013. doi: 10.1007/s11255–016–1405-x. epub 2016 aug 30. 29. hegarty pk, dinney cp, pettaway ca. controversies in ilioinguinal lymphadenectomy. urol clin north am.2010;37(3):421–434. 30. lughezzani g, catanzaro m, torelli t, piva l, biasoni d, stagni s, et al. the relationship between characteristics of inguinal lymph nodes and pelvic lymph node involvement in penile squamous cell carcinoma: a single institution experience. j urol.2014;191(4):977– 982. doi: 10.1016/j.juro.2013.10.140. epub 2013 nov 18. 31. noronha v, patil v, ostwal v, tongaonkar h, bakshi g, prabhash k, et al. role of paclitaxel and platinum-based adjuvant chemotherapy in high-risk penile cancer. urol ann. 2012;4 (3):15 0 –15 3. doi: 10.4103/0974–7796.102659 32. giannatempo p, paganoni a, sangalli l, colecchia m, piva l, torelli mct, et al. survival analyses of adjuvant or neoadjuvant combination of a taxane plus cisplatin and 5-fluorouracil (t-pf) in patients with bulky nodal metastases from squamous cell carcinoma of the penis (pscc): results of a single high-volume center. j clin oncol.2014;32(4,suppl):377. doi: 10.1200/jco.2014.32.4_suppl.377. 33. bandini m, pederzoli f, necchi a. neoadjuvant chemotherapy for lymph node-positive penile cancer: current evidence and knowledge. curr opin urol. 2020;30(2):218 –222. doi: 10.1097/ mou.0000000000000719. 34. kulkarni jn, kamat mr. prophylactic bilateral groin node dissection versus prophylactic radiotherapy and surveillance in patients with n0 and n1–2a carcinoma of the penis. eur urol.1994;26(2):123–128. 35. graafland nm, moonen lmf, van boven hh, van werkhoven e, kerst jm, horenblas s. inguinal recurrence following therapeutic lymphadenectomy for node positive penile carcinoma: outcome and implications for management. j urol.2011;185(3):888 – 893. doi: 10.1016/j.juro.2010.10.059. epub 2011 jan 15. 36. franks kn, kiran kancherla, brinda sethugavalar, peter whelan, ian eardley, anne e kiltie, et al. radiotherapy for node positive penile cancer: experience of the leeds teaching hospitals. j urol.2011;186(2):524 – 529. doi: 10.1016/j.juro.2011.03.117. epub 2011 jun 22. 37. winters br, kearns jt, holt sk, mossanen m, lin dw, wright jl. is there a benefit to adjuvant radiation in stage iii penile cancer after lymph node dissection? findings from the national cancer database. urol oncol.2018;36(3):92.e11–92.e16. doi: 10.1016/j. urolonc.2017.11.005. epub 2017 nov 27. 38. tang dh, djajadiningrat r, diorio g, chipollini j, ma z, schaible bj, et al. adjuvant pelvic radiation is associated with improved survival and decreased disease recurrence in pelvic node-positive penile cancer after lymph node dissection: a multi-institutional study. urol oncol.2017;35(10):605.e17– 605.e23. doi: 10.1016/j. urolonc.2017.06.001. epub 2017 jun 27. 39. homesley hd, bundy bn, sedlis a, adcock l. radiation therapy versus pelvic node resection for carcinoma of the vulva with positive groin nodes. obstet gynecol.1986;68(6):733–740. 40. parthasarathy a, cheung mk, osann k, husain a, teng nn, berek js. the benefit of adjuvant radiation therapy in single-node-positive squamous cell vulvar carcinoma. gynecol oncol.2006;103(3):1095–9. doi: 10.1016/j.ygyno.2006.06.030. 41. de vries hm, ottenhof sr, van der heijden ms, pos fj, horenblas s, brouwer or. management of the penile squamous cell carcinoma patient after node positive radical inguinal lymph node dissection: current evidence and future prospects. curr opin urol. 2020; 30(2):223–228. doi: 10.1097/mou.0000000000000714. 42. crook j. radiotherapy approaches for locally advanced penile cancer: neoadjuvant and adjuvant.curr opin urol.2017;27(1):62–67. doi: 10.1097/mou.0000000000000346. 43. burt lm, shrieve dc, tward jd. stage presentation, care patterns, and treatment outcomes for squamous cell carcinoma of the penis. int j radiat oncol biol phys.2014;88(1):94–100. 44. ravi r, chaturvedi hk, sastry dv. role of radiation therapy in the treatment of carcinoma of the penis. br j urol.1994;74(5):646–651. 45. demkow t. the treatment of penile carcinoma: experience in 64 cases. int urol nephrol.1999;31(4):525–531. 46. chen mf, chen w-c, wu c-t, chuang c-k, ng k-f, chang jt-c. contemporar y management of penile cancer including surger y and adjuvant radiotherapy: an experience in taiwan. world j urol.2004;22(1):60–66. 47. djajadiningrat rs, graafland nm, van werkhoven e, meinhardt w, bex a, van der poel hg, et al. contemporar y management of regional nodes in penile cancer-improvement of sur vival? j urol.2014;191(1):68–73. doi: 10.1016/j.juro.2013.07.088. 48. robinson r, marconi l, macpepple e, hakenberg ow, watkin n, yuan y, et al. risks and benefits of adjuvant radiotherapy after inguinal lymphadenectomy in node-positive penile cancer: a systematic review by the european association of urology penile cancer guidelines panel. eur urol.2018;74(1):76–83. 49. ager m, njoku k, serra m, robinson a, pickering l, afshar m, et al. long-term multicentre experience of adjuvant radiotherapy for pn3 squamous cell carcinoma of the penis. bju int.2020 nov 29; online ahead of print. doi: 10.1111/bju.15309. 186 siuj • volume 2, number 3 • may 2021 siuj.org review http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information malakoplakia, urinary tract infections, urinary bladder, lower urinary tract symptoms none declared. patient consent: obtained. received on december 3, 2021 accepted on december 11, 2021 soc int urol j.2021;3(4):281–282 doi: 10.48083/qfcw5582 figure 1. cystoscopy showing (a) malakoplakia nodules in the bladder and surrounding a severely dilated ureteric orifice (b) 281siuj.org siuj • volume 3, number 4 • july 2022 clinical picture malakoplakia causing poor bladder compliance and bilateral hydroureteronephrosis cecile t. pham,1,2 melanie edwards,3 amanda s.j. chung,1,2 venu chalasani1,2 1 department of urology, northern beaches hospital, frenchs forest, australia 2 north shore urology research group, st leonards, australia 3 department of anatomical pathology, douglass hanley moir pathology, macquarie park, australia an 81-year-old female presented with lower urinary tract symptoms (luts) including frequency, urgency and urge incontinence. she had a 2-year history of recurrent urinar y tract infections (uti) with escherichia coli of varying susceptibility. background history included rheumatoid arthritis treated with longterm corticosteroids, and stage-4 chronic kidney disease due to hypertensive nephrosclerosis. non-contrast ct imaging showed severe bilateral hydroureteronephrosis to the level of the vesicoureteric junction and circumferential bladder wall thickening. the patient had a creatinine level of 221 μmol/l and egfr rate of 18ml/min/1.73m2. cystoscopy revealed diffuse erythema and white-yellow nodules (figure  1). histopathological examination of bladder biopsies demonstrated numerous michaelis-gutmann bodies, pathognomic for the rare chronic inf lammatory condition malakoplakia (figure 2)[1–5]. there was no evidence of dysplasia or malignancy. urodynamic assessment revealed increased bladder sensation and poor bladder compliance with impaired detrusor contractility. malakoplakia is usually associated with recurrent uti, particularly escherichia coli, staphylococcus aureus, proteus, and klebsiella[4]. the patient was commenced on trimethoprim/sulfamethoxazole 150/100mg daily http://siuj.org https://orcid.org/0000-0002-5954-565x mailto:cecile.pham%40icloud.com?subject=siuj https://orcid.org/0000-0002-0111-4961 https://orcid.org/0000-0003-1356-9610 prophylaxis, which was switched to cephalexin 500mg daily prophylaxis due to poor tolerance. she was also commenced on methenamine hippurate, supplemental vitamin c, and completed a course of uromune for uti prophylaxis. the nodules had largely resolved on progress cystoscopy four months later. at this time, she was treated with intravesical antibiotic wash using gentamicin 480mg diluted in 1l 0.9% sodium chloride. this case demonstrates that malakoplakia can cause obstructive uropathy. it serves as a reminder to consider malakoplakia as a differential, particularly in women with recurrent uti and immunosuppression. references 1. kogulan pk, smith m, seidman j, chang g, tsokos m, lucey d. malakoplakia involving the abdominal wall, urinary bladder, vagina, and vulva: case report and discussion of malakoplakiaassociated bacteria. int j gynecol pathol.2001;20:403-406. doi: 10.1097/00004347-200110000-00016 2. bylund j, pais vm jr. a case of acute renal failure caused by bilateral, multifocal malacoplakia lesions of the bladder and ureters. nat clin pract urol.2008;5(9):516-519. doi:10.1038/ncpuro1173 3. sanchez lm, sanchez si, bailey jl. malacoplakia presenting with obstructive nephropathy with bilateral ureter involvement. nat rev nephrol.2009;5(7):418-422. doi: 10.1038/nrneph.2009.86 4. cavallone b, serao a, audino p, di stasio a, tiranti d, vota p. bilateral hydroureteronephrosis with renal failure caused by malacoplakia. urologia.2017;85(1):36-37. doi: 10.5301/uj.5000268 5. stamatiou k, chelioti e, tsavari a, koulia k, papalexandrou a, efthymiou e, et al. renal failure caused by malakoplakia lesions of the urinary bladder. nephrourol mon.2014;6(4). doi: 10.5812/ numonthly.18522 figure 2. histopathological images at x40 magnification with white arrows demonstrating the michaelis-gutmann bodies on (a) h&e stain and (b) von kossa calcium stain 282 siuj • volume 3, number 4 • july 2022 siuj.org clinical picture http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. 195siuj.org siuj • volume 3, number 4 • july 2022 editorial gender disparity on editorial boards peter c. black, editor-in-chief soc int urol j.2021;3(4):195–196 doi: 10.48083/tkcx3667 we are seeing concerted efforts across the field of urology to address substantial racial and gender disparities. while racial biases vary according to region of the world, gender disparities are more or less universal in global urology. the siu is able to capture racial diversity better than some other organizations simply by ensuring that all the regions of the world that it represents are included in its activities. on the other hand, this same global representation makes it particularly challenging to address gender disparities within the siu. most countries still have very few female urologists, so that broad geographic inclusion may counteract our objective of gender equity. the editorial board of our journal, the siuj, is a microcosm of the parent organization. nguyen et al. recently reported on gender diversity in editorial boards of four of the five urology journals with the highest impact factors and how this changed from 2015 to 2020. the four journals were european urology, journal of urology, european urology focus, and british journal of urology international. the proportion of women on these editorial boards was approximately consistent with the proportion of women in urology in the united states (although only one of the journals was from the united states), and there was a noticeable increase in the proportion of women on the editorial boards over the five years from 7.5% to 11.9%. does this proportionality and growth over time suggest that we should be satisfied with the gender representation, or do we need to strive for better inclusion of women in urology on these editorial boards? certainly, these numbers need to increase as the number of women in urology also needs to increase. however, we cannot wait for the number of women in our specialty to increase before seeking greater equity in our editorial boards. providing positive role models of women on the editorial boards of major urologic journals is an important step to attract women into our field. at some point we would like to arrive at the point where we do not need to think about gender equity because we have natural balance at all levels of organized urology. although we are a long way from that target, i was involved in two recent committees that demonstrated the progress we would like to see. in the one committee we were reviewing nominations for leadership of the committee and only women were nominated. in the other setting, the top scoring applicant for an award was a female urologist from an underrepresented minority. in both cases an environment had been created where the best and brightest rose to the top, and these stars or rising stars just happened to be a ringing endorsement for equity and diversity. nguyen et al. focused on the academic productivity of male and female editors, highlighting that female editors had a median of 96 publications (“research documents”) and an h-index of 25 while men had 217 publications and an h-index of 39.5. women were also less likely to have attained the rank of professor. the authors discuss some of the factors that could impact the differential research productivity of men and women, but perhaps this is also a measure of women being promoted into these editorial board positions at earlier stages in their careers in an effort to overcome the gender gap. the age of the editorial board members is unfortunately not known. this is not to say that the underlying issues of the “leaky pipeline” discussed in the paper are not highly relevant, but we should nonetheless embrace the promotion of early career women into these roles, and we should recognize that this will impact the type of metrics measured by nguyen et al. the one finding of the study by nguyen et al. that is particularly pertinent to the siuj is the fact that all but one of the female editors were affiliated with institutions from high-income countries. the gender disparity, at least in academic urology, would appear to be greater in middleand lower-income countries than in high-income countries[1]. this is of particular interest to the siuj because the siu membership spans all income categories, and we pride ourselves in serving the entire membership. our editorial board reflects this mission with similarly broad http://siuj.org mailto:editorinchief%40siuj.org?subject=siuj 196 siuj • volume 3, number 4 • july 2022 siuj.org editorial geographic representation, but ultimately with a large gender gap. one of our key challenges is to identify women from many of our member countries who would be interested in the editorial activities of the siuj. how can we overcome the gender disparity on our editorial board? two of the other urology journals have made noteworthy recent additions to their editorial boards that are likely to have future impact on diversity and equity. the journal of urology has introduced early career editors[2] and urology has added a monthly feature under the direction of a dedicated associate editor[3] on issues of diversity, equity, and inclusion. both moves demonstrate the creativity required to take on these important issues in our field. in this vein, we at the siu journal would like to create an environment where the best and brightest from all over the world can rise to the top in our editorial board. we would love to hear from contributors around the globe who would be interested in serving the journal by performing peer review and contributing to the editorial process at the journal. we really need a grass-roots effort to increase gender equity and racial diversity on our editorial board. we would love to hear your thoughts on how we can improve gender representation in the siuj. references 1. statista. least gender equal countries in the world in 2020. available at: https://www.statista.com/statistics/1221085/least-gender-equalcountries-in-the-world/. accessed june 23, 2022. 2. javier-desloges j, siemens dr. early career editors: a new initiative for the journal of urology®. j urol.2022;207(6):1176–1177. doi: 10.1097/ ju.0000000000002689. epub 2022 apr 1. 3. @erickleinmd. based on the success of the april & may issues of urology devoted to dei i am pleased to announce a new regular monthly section of @urogoldjournal devoted to these topics to be led by @yawnyame, who joins our editorial board as associate editor. please send us your manuscripts! june 15, 2022. https://mobile.twitter.com/erickleinmd/status/1537223428662386689. accessed june 23, 2022. http://siuj.org https://www.statista.com/statistics/1221085/least-gender-equal-countries-in-the-world/ https://www.statista.com/statistics/1221085/least-gender-equal-countries-in-the-world/ https://mobile.twitter.com/erickleinmd/status/1537223428662386689 this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information bladder cancer, histological variants, lymph node dissection, lymph node metastasis none declared. received on april 18, 2021 accepted on july 4, 2021 soc int urol j.2021;2(5):282–298 doi: 10.48083/dhhv3158 282 siuj • volume 2, number 5 • september 2021 siuj.org original research dissecting patterns of care in patients with variant histology of bladder cancer and lymph node invasion marco bandini,1* filippo pederzoli,1* andrea necchi,2 roger li,3 roberta lucianò,4 giuseppe basile,1 simone scuderi,1 riccardo leni,1 alberto briganti,1 andrea salonia,1 francesco montorsi,1 andrea gallina,1 philippe e. spiess3 1 unit of urology, urological research institute (uri), san raffaele hospital, vita-salute san raffaele university, milan, italy 2 unit of oncology, san raffaele hospital, vita-salute san raffaele university, milan, italy 3 moffitt cancer center and research institute, tampa, united states 4 department of pathology, irccs ospedale san raffaele, milan, italy * marco bandini and filippo pederzoli equally contributed to the manuscript. abstract objectives lymph node invasion (lni) is related to long-term survival in patients with muscle-invasive bladder cancer. however, in the case of variant histology (vh), data on pelvic lymph node dissection (plnd) and lni are sparse. we described the pattern of care of plnd in patients with vhs of bladder cancer, exploring predictors of lni. methods using the 2001–2016 seer registry, 20 767 bladder cancer patients who underwent plnd were identified. included histological variants were pure urothelial carcinoma (uc), micropapillary uc, sarcomatoid uc, lymphoepithelioma-like uc, adenocarcinoma, sarcoma, giant and spindle cell carcinoma, squamous cell carcinoma (scc), and neuroendocrine tumor. uniand multivariable logistic regression analyses tested for lni predictors. cox regression was used to test for predictors of overall mortality (om) among both lni positive and lni negative patients. results overall, 2464 (11.9%) harbored a vh. on multivariate analysis, only micropapillary uc was associated with higher risk (or = 3.39) of lni. this association was maintained when only the subset of patients treated without perioperative chemotherapy were analyzed (or = 3.30). similarly, higher t stage (t2 stage or = 2.24; t3–4 stage or = 9.44) and the use of chemotherapy (or = 2.29) were associated with a higher risk of lni. among patients with lni (5299, 25.5%), scc (hr = 1.87), t3–4 stage (hr = 1.94), age at diagnosis (hr = 1.01) and geographic region (south) (hr = 1.22) were predictors of higher risk of om. conversely, chemotherapy (hr = 0.69) and number of removed ln (hr = −0.99) were associated with lower risk of om. finally, in a subgroup of patients without lni, sarcomatoid uc (hr = 1.58) and giant and spindle cell carcinoma (hr = 1.83) were the only vh predictors of om. conclusions we described different patterns of care in patients with vhs of bladder cancer. micropapillary uc was an independent risk factor for lni. among patients harboring lni, those with scc vh had higher om compared to pure uc. conversely, sarcomatoid uc and giant and spindle cell carcinoma were predictors of om in patients without nodal involvement. http://siuj.org mailto:basile.giuseppe%40hsr.it?subject=siuj introduction lymph node metastases may occur in up to one fourth of patients with muscle-invasive urothelial cancer of the bladder (mibc)[1], and their presence is an important indicator of long-term survival and cancer recurrence[2–4]. therefore, radical cystectomy with pelvic lymph node dissection (plnd) is the standard treatment for mibc[5,6]. while general agreement exists with respect to pure urothelial carcinoma, fragmentary evidence suggests caution in generalizing these findings to all the other histological variants of urothelial carcinoma and nonurothelial histology[7–11]. histological variants are present in up to 25% of cystectomy specimens, and they have been traditionally associated with aggressive behavior[12–14]. here, paucity of data about the use and the role of the plnd and the prevalence of lymph node metastases in these histological subtypes makes it difficult to determine a standard of care. given the lack of consensus, the european association of urology (eau) partnered with the european society of medical oncology (esmo) and provided recommendations to guide specialists in this setting[7]. however, novel studies must address several gaps in the management of variant histology bladder cancer, including the different patterns of lymph node involvement according to the specific histology. using a population-based registry, we provided a description of the plnd patterns and the prevalence of lymph node invasion (lni) in bladder cancer of urothelial and variant histology. additionally, we explored potential predictors of lymph node metastasis. materials and methods study population within the surveillance, epidemiology, and end results (seer) database (2001–2016)[15], we selected patients aged 18 years or older with histologically confirmed bladder cancer (international classification of disease for oncology [icd-o] site codes c670-679), excluding patients with urachal tumors (icd-o site code c677) (supplementary figure 1; available at siuj.org). for the purpose of our analysis, we focused on patients with bladder cancer and non-systemic metastasis (t0-4n0-3) who underwent any form of treatment to the primary tumor, as well as plnd, and who harbored the following primary bladder histological variants (supplementary table 1; available at siuj.org): urothelial carcinoma (uc), micropapillary uc, lymphoepithelioma-like uc, sarcomatoid uc, adenocarcinoma, squamous cell carcinoma (scc), giant and spindle cell carcinoma, neuroendocrine tumor and sarcoma[16]. these selection criteria yielded an initial study population of 20767 patients. variables definition the variables considered included variant histology together with the presence of lni. study covariates included age at the time of bladder cancer diagnosis, sex, race (white, black, hispanic, asian, and other), marital status (married, never married, previously married, unk nown), geographica l region (west, midwest, north-east, south), socioeconomic status (high versus low), administration of perioperative chemotherapy (either neoadjuvant or adjuvant), local treatment modality (radical cystectomy [rc], partial cystectomy, transurethral resection of the bladder [turb] only, radiotherapy, trimodal therapy [tmt], no local treatment, other/unknown), t stage (t0/x, t<2, t2, t3–4), tumor grade (g1–4, unknown), number of lymph nodes removed (nnr), number of positive lymph nodes (npn), and lymph node density (ln density). statistical analysis descript ive stat ist ics i ncludes f requencies a nd proportions for categorical variables. means, medians, and ranges were reported for continuously coded variables. chi-square was used to test the statistical significance in proportions’ differences. the t test and kruskal-wallis test examined the statistical significance of differences in means and medians[17]. univariable and multivariable logistic regression analyses were used to test for predictors of lni among patients who received plnd among several covariates. sub-analyses focused on patients treated with rc. univariable and multivariable cox regression analyses were used to test for predictors of overall mortality (om) among patients with lni. moreover, we performed sensitivity analyses focusing on patients who did not receive perioperative chemotherapy to mitigate the possible effect of either neoadjuvant or adjuvant chemotherapy treatments on both lni and om prediction. finally, univariable and multivariable cox regression analyses were also used to test for predictors of om among patients without nodal disease (n0). p-values were adjusted using the conservative bonferroni correction method, which 283siuj.org siuj • volume 2, number 5 • september 2021 dissecting patterns of care in patients with variant histology of bladder cancer and lymph node invasion abbreviations lni lymph node invasion mibc muscle-invasive urothelial cancer om overall mortality plnd pelvic lymph node dissection scc squamous cell carcinoma seer surveillance, epidemiology, and end results turb transurethral resection of the bladder uc urothelial carcinoma http://www.siuj.org http://www.siuj.org http://siuj.org multiplies the raw p-values by the number of tests. for all statistical analyses, r software environment (version 3.6.1) was used. all tests were 2-sided with a level of significance set at p < 0.05. results overall descriptive characteristics overall, we identified 20 767 patients diagnosed with bladder cancer between 2001 and 2016 who underwent plnd (table 1). among them, 18 303 (88.1%) patients had uc, 889 (4.3%) scc, 592 (2.9%) adenocarcinoma, 382 (1.8%) neu roendocr i ne t u mor, 283 (1.4%) sarcomatoid uc, 177 (0.9%) micropapillary uc, 85 (0.4%) giant and spindle cell carcinoma, 38 (0.2%) lymphoepithelioma-like uc and 18 (< 0.1%) sarcoma. the vast majority of patients were diagnosed with t ≥ 2 disease (17 843, 85.9%), without major differences across the histologic subtypes. rc represented the main primary treatment in all groups. among non-rc primary treatments, a high percentage (132, 22.3%) of partial cystectomies was performed in adenocarcinoma patients (figure 1). perioperative chemotherapy was evenly administered in t he dif ferent histologic subty pes, with patients with lymphoepitheliomalike uc (25, 65.8%), neuroendocrine tumor (250, 65.4%) and micropapillary uc (91, 51.4%) being most frequently treated with chemotherapy. the median number of removed lymph nodes ranged from 11 to 19 in all the study groups (figure 2): patients with lymphoepithelioma-like uc had the highest number of lymph nodes removed (median 19, interquartile range [iqr]: 7–26), while patients with giant and spindle cell carcinoma had the lowest (11, 5–19). lni cohort in the study population, lni was reported in 5299 (25.5%) patients (supplementary table 2; available at siuj.org), specifically 88 (49.7%) micropapillary uc, 117 (30.6%) neuroendocrine tumor, 175 (29.6%) adenocarcinoma, 11 (28.9%) lymphoepithelioma-like uc, 72 (25.4%) sarcomatoid uc, 4596 (25.1%) uc, 220 (24.7%) scc, 17 (20.0%) giant and spindle cell carcinoma, 3 (16.7%) sarcoma. patients with lni had a higher stage disease (t3–4 stage 77.0% versus 41.6%; p < 0.001) and were more frequently treated with chemotherapy (55.1% versus 32.9%; p < 0.001) than patients without malignant nodal involvement (table  2). among different histological variants, uc (3.1%) and micropapillary uc (3.4%) presented the highest rates of lni in non-muscleinvasive disease. compared with uc (19.9%), all the other histological variants had lower rates of lni in t2 disease, with the exception of micropapillary uc, which presented higher (27.3%) rates of lni (supplementary table 2; available at siuj.org). at multivariate logistic regression analysis (table 3), only micropapillary uc was associated with a higher risk (or [95%ci] = 3.39 [2.43–4.74]; p < 0.001, bonferroni adjusted p < 0.001) of lni among the histological variants. similarly, higher t stage (t2 stage or [95%ci] = 2.24 [1.88–2.69], p  <  0.001, bonferroni adjusted p < 0.001; t3–4 stage or [95%ci]  =  9.44 [7.98–11.2], p < 0.001, bonferroni adjusted p < 0.001), and the use of chemotherapy (or [95%ci]  =  2.29 [2.13–2.46]; p < 0.001, bonferroni adjusted p < 0.001) were associated with a higher risk of lni. analyses restricted to the population who received rc are shown in supplementary table 3 (available at siuj. org). sensitivity analysis of lni among patients without perioperative chemotherapy treatment overall, 12 761 (61.4%) patients did not receive either neoadjuvant or adjuvant chemotherapy. particularly, 11 187 (87.7%) patients had uc, 683 (5.4%) scc, 402 (3.2%) adenocarcinoma, 132 (1.0%) neuroendocrine tumor, 182 (1.4%) sarcomatoid uc, 86 (0.7%) micropapillary uc, 63 (0.5%) giant and spindle cell carcinoma, 13 (0.1%) lymphoepithelioma-like uc and 13 (0.1%) sarcoma, as shown in supplementary table  4 (available at siuj.org). among these, lni was reported in 2380 (18.6%) patients (supplementary table 5; available at siuj.org). at multivariate logistic regression analysis (supplementary table 6; available at siuj.org), both micropapillary uc (or [95%ci] = 3.30 [2.01–5.37]; p < 0.001, bonferroni adjusted p < 0.001) and higher t stage (t2 stage or [95%ci] = 3.31 [2.54–4.37]; p  <  0.001, bonferroni adjusted p < 0.001; t3–4 stage or [95%ci] = 15.39 [12–20.1]; p < 0.001, bonferroni adjusted p < 0.001) were confirmed to be associated with a higher risk of lni. overall mortality data when considering patients with lni, median om rate was 24 months (iqr 23–25) with a median follow-up of 22 months (iqr 9–42.7) regardless of histology variant. om rates according to variant histology in patients with lni is reported in supplementary table 7 (available at siuj.org). among patients with lni (table 4), predictors of higher risk of om were scc (hazard ratio, hr [95%ci] = 1.87 [1.56–2.24]; p < 0.001, bonferroni adjusted p < 0.001), histology, t3–4 stage (hr [95%ci] = 1.94 [1.52–2.47]; p < 0.001, bonferroni adjusted p = 0.03), age at diagnosis (hr [95%ci] = 1.01 [1.01–1.01]; p < 0.001, bonferroni adjusted p < 0.001), never married (hr [95%ci] = 1.24 [1.11–1.39]; p < 0.001, bonferroni adjusted p < 0.001), and south region (hr [95%ci] = 1.22 [1.10–1.35]; p < 0.001, bonferroni adjusted p < 0.001). conversely, chemotherapy (hr [95%ci] = 0.69 [0.64–0.74]; p < 0.001, bonferroni adjusted p < 0.001) and number of removed ln (hr [95%ci] = 0.99 [0.99–0.99]; p < 0.001, bonferroni adjusted p = 0.03) were associated with lower risk of om. 284 siuj • volume 2, number 5 • september 2021 siuj.org original research http://www.siuj.org http://www.siuj.org http://www.siuj.org http://www.siuj.org http://www.siuj.org http://www.siuj.org http://www.siuj.org http://www.siuj.org http://siuj.org analyses restricted to the population who received rc are shown in supplementary table 8 (available at siuj.org). sensitivity analysis of overall mortality among patients without perioperative chemotherapy treatment among patients with lni and no perioperative chemotherapy treatment (n = 2380, supplementary table 9; available at siuj.org), scc (hr [95%ci] = 2.06 [1.64–2.59]; p < 0.001, bonferroni adjusted p  <  0.001) was conf irmed to be the only histolog y variant predictor of om. moreover, number of removed ln (hr [95%ci] = 0.98 [0.98–0.99]; p < 0.001), bonferroni adjusted p < 0.001) was associated with lower risk of om. sensitivity analysis of overall mortality among patients without lni when considering patients without lymph node invasion (n = 15 468, supplementary table 10; available at siuj.org), sarcomatoid uc (hr [95%ci] = 1.58 [1.28– 1.94]); p < 0.001, bonferroni adjusted p = 0.001) and giant and spindle cell carcinoma (hr [95%ci]  =  1.83 [1.29–2.59]; p < 0.001, bonferroni adjusted p  =  0.026) were the only histology variants predictors of om, as compared to the lni cohort. conversely, both chemotherapy (hr [95%ci] = 0.89 [0.83–0.95]; p < 0.001, bonferroni adjusted p = 0.015) and number of removed ln (hr [95%ci] = 0.99 [0.99–0.99]; p < 0.001, bonferroni adjusted p < 0.001) were confirmed to be associated with lower risk of om. discussion in this study, we explored the patterns of care associated with the diagnosis of a non-pure urothelial carcinoma of the bladder in the seer database. we focused our attention on the lni distribution according to the histological diagnosis in plnd patients, eventually exploring potential predictors of lymph node metastasis. in general, histological variants are considered more aggressive than pure uc, which requires an aggressive therapeutic management even in case of non-muscleinvasive disease. for instance, the micropapillary, plasmacytoid and sarcomatoid variants of urothelial carcinoma have a worse prognosis than comparable high-grade, pure uc[18–21]. therefore, the european association of urology (eau) guidelines have included them in the highest risk group of non-muscle-invasive bladder cancer, for which radical cystectomy +/₋ neoadjuvant treatments should be considered[19]. our study confirmed the aggressiveness of some variants in terms of overall mortality when considering patients with lni, reporting a higher om risk for scc among all the vhs considered, regardless of perioperative chemotherapy treatment. conversely, among patients without lni, sarcomatoid uc and giant and spindle cell carcinoma were associated with higher om risk. moreover, the survival advantage for bladder cancer patients linked to lymphadenectomy at the time of radical surgery has been shown by several studies[22], including a registr y-based analysis[23], and it is supported by the fact that up to 25% of patients with organ-confined muscle-invasive bladder cancer have metastatic nodal disease[24]. it is still debated whether the presence of histological variants affects the incidence of lymph node metastasis, potentially affecting progression and survival. kim et al. analyzed the outcomes of a cohort of 132 patients with bladder cancer showing squamous differentiation, 41 with glandular differentiation, and 13 with both variants[25]. the presence of differentiations, compared with a control cohort of pure uc patients, was associated with a higher rate of extravesical disease (pt3-t4 stage 70% versus 38%; p < 0.001) and lymph node involvement (20% versus 15%; p = 0.05), but it did not affect 10-year cancer-specific survival (52% versus 51%; p = 0.71). similarly, a long-term analysis of a cohort of 52 patients with nested variant reported a positive association between the nested variant and the presence of locally advanced disease and lymph node metastases[26]. nevertheless, the presence of nested variant did not influence either 10-year recurrence-free survival (80% versus 83%; p = 0.46) or cancer-specific survival (41% versus 46%; p = 0.75), when compared with pure uc patients. another recent cohort study[27] of 525 bladder cancer patients treated with open radical cystectomy at a single tertiary center reported a histological variant in 131 patients (25.0%). their data suggested that the presence of a variant histology was associated with a more advanced and biologically aggressive malignancy, including a higher frequency of lymphovascular invasion and nodal disease at radical cystectomy. conversely, other studies did not find an association between histological variants and lni, as reported by marks et al. in their cohort of 138 patients with nodal metastases[28]. a variant histology was present in 96 patients, and the presence of variant histology was not associated with either the presence of lymph node metastases or extranodal extension. in our analysis, we found that the presence micropapillary uc was an independent risk factor for lni after multivariate correction, and also after accounting for the possible effect of perioperative chemotherapy on nodal disease status. micropapillary morphology in solid malignancies is known to have a distinct propensity for lymphovascular invasion, which can lead to a higher rate of lni compared with the non-micropapillary histological variants[29,30]. therefore, these observations suggest the need for further studies involving an accurate analysis of the biological, pathological, and clinical factors of the urothelial and non-urothelial bladder cancer variants 285siuj.org siuj • volume 2, number 5 • september 2021 dissecting patterns of care in patients with variant histology of bladder cancer and lymph node invasion http://www.siuj.org http://www.siuj.org http://www.siuj.org http://siuj.org table 1. descriptive characteristics of the overall population of study (n = 20 767) according to the different histological subtypes urothelial carcinoma (n = 18303) micropapillary uc (n = 177) lymphoepithelioma-like uc (n = 38) sarcomatoid uc (n = 283) adenocarcinoma (n = 592) giant and spindle-cell carcinoma (n = 85) squamous cell carcinoma (n = 889) neuroendocrine tumor (n = 382) sarcoma (n = 18) age at diagnosis, median (iqr) 68 (61–76) 70 (61–76) 68 (62–75) 69 (61–76) 63 (54–71) 71 (59–77) 68 (58–76) 68 (61–75) 75 (61–78) female sex, n (%) 4163 (22.7) 31 (17.5) 9 (23.7) 91 (32.2) 226 (38.2) 27 (31.8) 439 (49.4) 70 (18.3) 6 (33.3) race, n (%) white black hispanic asiatic other 15165 (82.8) 1055 (5.8) 1158 (6.3) 828 (4.5) 97 (0.5) 153 (86.4) 5 (2.8) 8 (4.5) 10 (5.6) 1 (0.6) 28 (73.7) 4 (10.5) 2 (5.3) 4 (10.5) 0 (0) 225 (79.5) 20 (7.1) 19 (6.7) 18 (6.4) 1 (0.4) 410 (69.3) 81 (13.7) 59 (10) 36 (6.1) 6 (1) 70 (82.4) 3 (3.5) 8 (9.4) 3 (3.5) 1 (1.2) 707 (79.5) 75 (8.4) 74 (8.3) 26 (2.9) 7 (0.8) 319 (83.5) 15 (3.9) 27 (7.1) 19 (5) 2 (0.5) 14 (77.8) 1 (5.6) 3 (16.7) 0 (0) 0 (0) socioeconomic status, n (%) high low 9144 (49.9) 9159 (50.1) 86 (48.6) 91 (51.4) 18 (47.4) 20(52.6) 131 (46.3) 152 (53.7) 314 (53) 278 (47) 47 (55.3) 38 (44.7) 442 (49.7) 447 (50.3) 192 (50.3) 190 (49.7) 12 (66.7) 6 (33.3) region, n (%) west midwest north-east south 9927 (54.2) 2104 (11.5) 3146 (17.2) 3126 (17.1) 84 (47.5) 30 (16.9) 16 (9) 47 (26.6) 24 (63.2) 3 (7.9) 5 (13.2) 6 (15.8) 129 (45.6) 45 (15.9) 48 (17) 61 (21.6) 327 (55.2) 47 (7.9) 112 (18.9) 106 (17.9) 46 (54.1) 6 (7.1) 19 (22.4) 14 (16.5) 463 (52.1) 103 (11.6) 155 (17.4) 168 (18.9) 204 (53.4) 38 (9.9) 74 (19.4) 66 (17.3) 13 (72.2) 0 (0) 3 (16.7) 2 (11.1) marital status, n (%) married never married previously married unknown 11771 (64.3) 2005 (11) 3870 (21.1) 657 (3.6) 117 (66.1) 17 (9.6) 36 (20.3) 7 (4) 28 (73.7) 6 (15.8) 4 (10.5) 0 (0) 175 (61.8) 27 (9.5) 73 (25.8) 8 (2.8) 345 (58.3) 102 (17.2) 118 (19.9) 27 (4.6) 45 (52.9) 12 (14.1) 24 (28.2) 4 (4.7) 493 (55.5) 124 (13.9) 242 (27.2) 30 (3.4) 260 (68.1) 46 (12) 63 (16.5) 13 (3.4) 12 (66.7) 2 (11.1) 4 (22.2) 0 (0) treatment, n (%) radical cystectomy partial cystectomy turb only radiotherapy tmt no local treatment other/unknown 16155 (88.3) 796 (4.4) 684 (3.7) 8 (0) 101 (0.6) 37 (0.2) 522 (2.9) 159 (89.8) 7 (4) 3 (1.7) 0 (0) 3 (1.7) 0 (0) 5 (2.8) 33 (86.8) 2 (5.3) 2 (5.3) 0 (0) 0 (0) 0 (0) 1 (2.6) 254 (89.8) 14 (4.9) 3 (1.1) 0 (0) 0 (0) 0 (0) 12 (4.2) 389 (65.7) 132 (22.3) 13 (2.2) 0 (0) 8 (1.4) 3 (0.5) 47 (7.9) 72 (84.7) 5 (5.9) 3 (3.5) 0 (0) 1 (1.2) 0 (0) 4 (4.7) 730 (82.1) 59 (6.6) 20 (2.2) 1 (0.1) 2 (0.2) 8 (0.9) 69 (7.8) 317 (83) 29 (7.6) 11 (2.9) 0 (0) 4 (1) 1 (0.3) 20 (5.2) 16 (88.9) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (11.1) ct: chemotherapy; iqr: interquartile range; ln: lymph node; lni: lymph node invasion; nnr: number of lymph nodes removed; tmt: trimodal therapy; turb: transurethral resection of the bladder; uc: urothelial carcinoma continued on page 288 286 siuj • volume 2, number 5 • september 2021 siuj.org original research http://siuj.org table 1. descriptive characteristics of the overall population of study (n = 20 767) according to the different histological subtypes urothelial carcinoma (n = 18303) micropapillary uc (n = 177) lymphoepithelioma-like uc (n = 38) sarcomatoid uc (n = 283) adenocarcinoma (n = 592) giant and spindle-cell carcinoma (n = 85) squamous cell carcinoma (n = 889) neuroendocrine tumor (n = 382) sarcoma (n = 18) age at diagnosis, median (iqr) 68 (61–76) 70 (61–76) 68 (62–75) 69 (61–76) 63 (54–71) 71 (59–77) 68 (58–76) 68 (61–75) 75 (61–78) female sex, n (%) 4163 (22.7) 31 (17.5) 9 (23.7) 91 (32.2) 226 (38.2) 27 (31.8) 439 (49.4) 70 (18.3) 6 (33.3) race, n (%) white black hispanic asiatic other 15165 (82.8) 1055 (5.8) 1158 (6.3) 828 (4.5) 97 (0.5) 153 (86.4) 5 (2.8) 8 (4.5) 10 (5.6) 1 (0.6) 28 (73.7) 4 (10.5) 2 (5.3) 4 (10.5) 0 (0) 225 (79.5) 20 (7.1) 19 (6.7) 18 (6.4) 1 (0.4) 410 (69.3) 81 (13.7) 59 (10) 36 (6.1) 6 (1) 70 (82.4) 3 (3.5) 8 (9.4) 3 (3.5) 1 (1.2) 707 (79.5) 75 (8.4) 74 (8.3) 26 (2.9) 7 (0.8) 319 (83.5) 15 (3.9) 27 (7.1) 19 (5) 2 (0.5) 14 (77.8) 1 (5.6) 3 (16.7) 0 (0) 0 (0) socioeconomic status, n (%) high low 9144 (49.9) 9159 (50.1) 86 (48.6) 91 (51.4) 18 (47.4) 20(52.6) 131 (46.3) 152 (53.7) 314 (53) 278 (47) 47 (55.3) 38 (44.7) 442 (49.7) 447 (50.3) 192 (50.3) 190 (49.7) 12 (66.7) 6 (33.3) region, n (%) west midwest north-east south 9927 (54.2) 2104 (11.5) 3146 (17.2) 3126 (17.1) 84 (47.5) 30 (16.9) 16 (9) 47 (26.6) 24 (63.2) 3 (7.9) 5 (13.2) 6 (15.8) 129 (45.6) 45 (15.9) 48 (17) 61 (21.6) 327 (55.2) 47 (7.9) 112 (18.9) 106 (17.9) 46 (54.1) 6 (7.1) 19 (22.4) 14 (16.5) 463 (52.1) 103 (11.6) 155 (17.4) 168 (18.9) 204 (53.4) 38 (9.9) 74 (19.4) 66 (17.3) 13 (72.2) 0 (0) 3 (16.7) 2 (11.1) marital status, n (%) married never married previously married unknown 11771 (64.3) 2005 (11) 3870 (21.1) 657 (3.6) 117 (66.1) 17 (9.6) 36 (20.3) 7 (4) 28 (73.7) 6 (15.8) 4 (10.5) 0 (0) 175 (61.8) 27 (9.5) 73 (25.8) 8 (2.8) 345 (58.3) 102 (17.2) 118 (19.9) 27 (4.6) 45 (52.9) 12 (14.1) 24 (28.2) 4 (4.7) 493 (55.5) 124 (13.9) 242 (27.2) 30 (3.4) 260 (68.1) 46 (12) 63 (16.5) 13 (3.4) 12 (66.7) 2 (11.1) 4 (22.2) 0 (0) treatment, n (%) radical cystectomy partial cystectomy turb only radiotherapy tmt no local treatment other/unknown 16155 (88.3) 796 (4.4) 684 (3.7) 8 (0) 101 (0.6) 37 (0.2) 522 (2.9) 159 (89.8) 7 (4) 3 (1.7) 0 (0) 3 (1.7) 0 (0) 5 (2.8) 33 (86.8) 2 (5.3) 2 (5.3) 0 (0) 0 (0) 0 (0) 1 (2.6) 254 (89.8) 14 (4.9) 3 (1.1) 0 (0) 0 (0) 0 (0) 12 (4.2) 389 (65.7) 132 (22.3) 13 (2.2) 0 (0) 8 (1.4) 3 (0.5) 47 (7.9) 72 (84.7) 5 (5.9) 3 (3.5) 0 (0) 1 (1.2) 0 (0) 4 (4.7) 730 (82.1) 59 (6.6) 20 (2.2) 1 (0.1) 2 (0.2) 8 (0.9) 69 (7.8) 317 (83) 29 (7.6) 11 (2.9) 0 (0) 4 (1) 1 (0.3) 20 (5.2) 16 (88.9) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (11.1) ct: chemotherapy; iqr: interquartile range; ln: lymph node; lni: lymph node invasion; nnr: number of lymph nodes removed; tmt: trimodal therapy; turb: transurethral resection of the bladder; uc: urothelial carcinoma 287siuj.org siuj • volume 2, number 5 • september 2021 dissecting patterns of care in patients with variant histology of bladder cancer and lymph node invasion http://siuj.org table 1. descriptive characteristics of the overall population of study (n = 20 767) according to the different histological subtypes urothelial carcinoma (n = 18303) micropapillary uc (n = 177) lymphoepithelioma-like uc (n = 38) sarcomatoid uc (n = 283) adenocarcinoma (n = 592) giant and spindle-cell carcinoma (n = 85) squamous cell carcinoma (n = 889) neuroendocrine tumor (n = 382) sarcoma (n = 18) perioperative ct, n (%) yes no/unknown 7116 (38.9) 11187 (61.1) 91 (51.4) 86 (48.6) 25 (65.8) 13 (34.2) 101 (35.7) 182 (64.3) 190 (32.1) 402 (67.9) 22 (25.9) 63 (74.1) 206 (23.2) 683 (76.8) 250 (65.4) 132 (34.6) 5 (27.8) 13 (72.2) t stage, n (%) t0/x t<2 t2 t3–4 110 (0.6) 2563 (14) 6694 (36.6) 8936 (48.8) 0 (0) 23 (13) 64 (36.2) 90 (50.8) 0 (0) 4 (10.5) 12 (31.6) 22 (57.9) 2 (0.7) 25 (8.8) 81 (28.6) 175 (61.8) 6 (1) 76 (12.8) 137 (23.1) 373 (63) 1 (1.2) 4 (4.7) 25 (29.4) 55 (64.7) 17 (1.9) 52 (5.8) 188 (21.1) 632 (71.1) 1 (0.3) 36 (9.4) 129 (33.8) 216 (56.5) 1 (5.6) 3 (16.7) 3 (16.7) 11 (61.1) grade, n (%) g1 g2 g3 g4 gx 114 (0.6) 614 (3.4) 5577 (30.5) 11169 (61) 829 (4.5) 0 (0) 2 (1.1) 39 (22) 127 (71.8) 9 (5.1) 0 (0) 0 (0) 8 (21.1) 26 (68.4) 4 (10.5) 1 (0.4) 3 (1.1) 85 (30) 175 (61.8) 19 (6.7) 21 (3.5) 149 (25.2) 241 (40.7) 115 (19.4) 66 (11.1) 0 (0) 1 (1.2) 22 (25.9) 48 (56.5) 14 (16.5) 58 (6.5) 344 (38.7) 308 (34.6) 136 (15.3) 43 (4.8) 1 (0.3) 3 (0.8) 101 (26.4) 200 (52.4) 77 (20.2) 0 (0) 0 (0) 4 (22.2) 11 (61.1) 3 (16.7) lni, n (%) 4596 (25.1) 88 (49.7) 11 (28.9) 72 (25.4) 175 (29.6) 17 (20) 220 (24.7) 117 (30.6) 3 (16.7) nnr, median (iqr) 12 (6–22) 15 (9–26) 19 (7–26) 13 (6–22) 11 (6–21) 11 (5–19) 11 (6–20) 12 (7–23) 13 (6–23) ln density, mean 7.8 21 8.9 7.1 11.1 4.7 8.7 9.7 1.5 ct: chemotherapy; iqr: interquartile range; ln: lymph node; lni: lymph node invasion; nnr: number of lymph nodes removed; tmt: trimodal therapy; turb: transurethral resection of the bladder; uc: urothelial carcinoma , cont’d to define the best multidisciplinary (surgery, radiation therapy, chemotherapy, and innovative treatment strategies) approach for each histological subtype, with a particular emphasis on immunotherapy and targeted therapies[31–34]. it is clear that the time has come to gain a clear, ordered and practice-changing knowledge about these rare entities. singleand small multi-institutional studies are generally unable to collect enough cases belonging to the different subtypes, potentially resulting in underpowered findings. although retrospective registry-based analyses have access to greater numbers, they are frequently incomplete and suffer from the lack of or underreporting of variables that may have had an impact on patient outcomes. with respect to bladder cancer variants, the lack of centralized pathological review of the cases, as well as the possible under recognition of rare histological entities outside highvolume centers, may hamper the generalization of the study conclusions. for all these reasons, to further advance the knowledge in the field of bladder cancer, centralized initiatives are needed to create prospective, centralized, multicenter bladder cancer registries, like the bravery (bladder variants registry) protocol sponsored by the eau research foundation[35]. with 288 siuj • volume 2, number 5 • september 2021 siuj.org original research http://siuj.org table 1. descriptive characteristics of the overall population of study (n = 20 767) according to the different histological subtypes urothelial carcinoma (n = 18303) micropapillary uc (n = 177) lymphoepithelioma-like uc (n = 38) sarcomatoid uc (n = 283) adenocarcinoma (n = 592) giant and spindle-cell carcinoma (n = 85) squamous cell carcinoma (n = 889) neuroendocrine tumor (n = 382) sarcoma (n = 18) perioperative ct, n (%) yes no/unknown 7116 (38.9) 11187 (61.1) 91 (51.4) 86 (48.6) 25 (65.8) 13 (34.2) 101 (35.7) 182 (64.3) 190 (32.1) 402 (67.9) 22 (25.9) 63 (74.1) 206 (23.2) 683 (76.8) 250 (65.4) 132 (34.6) 5 (27.8) 13 (72.2) t stage, n (%) t0/x t<2 t2 t3–4 110 (0.6) 2563 (14) 6694 (36.6) 8936 (48.8) 0 (0) 23 (13) 64 (36.2) 90 (50.8) 0 (0) 4 (10.5) 12 (31.6) 22 (57.9) 2 (0.7) 25 (8.8) 81 (28.6) 175 (61.8) 6 (1) 76 (12.8) 137 (23.1) 373 (63) 1 (1.2) 4 (4.7) 25 (29.4) 55 (64.7) 17 (1.9) 52 (5.8) 188 (21.1) 632 (71.1) 1 (0.3) 36 (9.4) 129 (33.8) 216 (56.5) 1 (5.6) 3 (16.7) 3 (16.7) 11 (61.1) grade, n (%) g1 g2 g3 g4 gx 114 (0.6) 614 (3.4) 5577 (30.5) 11169 (61) 829 (4.5) 0 (0) 2 (1.1) 39 (22) 127 (71.8) 9 (5.1) 0 (0) 0 (0) 8 (21.1) 26 (68.4) 4 (10.5) 1 (0.4) 3 (1.1) 85 (30) 175 (61.8) 19 (6.7) 21 (3.5) 149 (25.2) 241 (40.7) 115 (19.4) 66 (11.1) 0 (0) 1 (1.2) 22 (25.9) 48 (56.5) 14 (16.5) 58 (6.5) 344 (38.7) 308 (34.6) 136 (15.3) 43 (4.8) 1 (0.3) 3 (0.8) 101 (26.4) 200 (52.4) 77 (20.2) 0 (0) 0 (0) 4 (22.2) 11 (61.1) 3 (16.7) lni, n (%) 4596 (25.1) 88 (49.7) 11 (28.9) 72 (25.4) 175 (29.6) 17 (20) 220 (24.7) 117 (30.6) 3 (16.7) nnr, median (iqr) 12 (6–22) 15 (9–26) 19 (7–26) 13 (6–22) 11 (6–21) 11 (5–19) 11 (6–20) 12 (7–23) 13 (6–23) ln density, mean 7.8 21 8.9 7.1 11.1 4.7 8.7 9.7 1.5 ct: chemotherapy; iqr: interquartile range; ln: lymph node; lni: lymph node invasion; nnr: number of lymph nodes removed; tmt: trimodal therapy; turb: transurethral resection of the bladder; uc: urothelial carcinoma the creation of this multicenter registry, it will be possible to capture for the first time the therapeutic and surgical management of urothelial-histological variants and non-urothelial-histological variants in a real-life setting. despite its novelty, our study is not devoid of limitations. first, the presented retrospective seer data[15] are influenced by inherent selection biases, as well as by the lack of variables that may have an impact on lni, such as lymphovascular invasion, treatment choice, and patient eligibility for chemotherapy. one of the main limitations of our study is related to the impossibility of distinguishing between neoadjuvant a nd adjuva nt chemot herapy t reat ment. is wel l recognized, neoadjuvant chemotherapy could affect lymph node positivity rates, and patients who have neoadjuvant chemot herapy genera lly have more favorable oncological outcomes than patients who do not. as well, neoadjuvant treatments could be used differentially between histological variants. nevertheless, micropapillary uc was confirmed to be the only histological variant predictor of lni, even when patients who had not received any perioperative chemotherapy treatment were considered. furthermore, scc histology was found to be associated with a higher 289siuj.org siuj • volume 2, number 5 • september 2021 dissecting patterns of care in patients with variant histology of bladder cancer and lymph node invasion http://siuj.org risk of om than any of the other vhs considered, regardless of perioperative chemotherapy use, probably due to the inherent pathobiological behavior of this type of vh. moreover, the seer database does not allow identification of the reason for plnd, and some patients may have received plnd for staging purposes or have had aborted procedures, which have also been reported for prostate cancer[36]. further, the seer database does not include all the histological variants of bladder cancer identified by the 2016 world health organization classification of tumors of the urinary tract[37]; our analysis is therefore limited to the coded entities. the seer database does not provide a central pathological review, which may have an impact on the accuracy of the reported variants, as bladder cancer variants are commonly underrecognized outside tertiary, highvolume centers[38,39]. additionally, the seer database does not discriminate between the histologic diagnosis at transurethral resection of the bladder tumor and the histologic diagnosis at partial or radical cystectomy and does not provide a quantitative evaluation of the variant component compared with the total tumor volume. finally, the high heterogeneity of local treatments considered may have affected the detection rate of variant histology included in this study. conclusions we described different patterns of care according to the histological variants in bladder cancer using the seer database. in particular, we analyzed the rate at which plnd was performed and the prevalence of lni, as is well as the potential predictors of each. we found that the presence of micropapillary uc was an independent risk factor for lni after multivariate correction, regardless of perioperative chemotherapy treatment. additionally, among patients with lni, scc histology was associated with higher om compared with pure uc. our analysis highlights the need for international collaborations to advance knowledge with respect to urothelial and non-urothelial bladder cancer variants. figure 1. radar plot showing the main clinical and pathological characteristics in the study population according to histological variant figure 2. violin plot showing the number of removed lymph nodes (above) and wave plot (below) showing the lymph node density, according to histological variant lel: lymphoepithelioma-like; scc: squamous cell carcinoma; uc: urothelial carcinoma 290 siuj • volume 2, number 5 • september 2021 siuj.org original research http://siuj.org table 2. descriptive characteristics according to the lymph node invasion status in the study population (n = 20 767) overall (n = 20 767) no lni (n = 15 468) lni (n = 5299) p value age at diagnosis, median (iqr) 68 (60–76) 69 (61–76) 68 (60–75) < 0.001 sex, n (%) male female 15 705 (75.6) 5062 (24.4) 11 844 (76.6) 3624 (23.4) 3861 (72.9) 1438 (27.1) < 0.001 race, n(%) white black hispanic asiatic other 17 089 (82.3) 1260 (6.1) 1359 (6.5) 944 (4.5) 115 (0.6) 12 811 (82.8) 873 (5.6) 984 (6.4) 712 (4.6) 88 (0.6) 4278 (80.7) 387 (7.3) 375 (7.1) 232 (4.4) 27 (0.5) < 0.001 socioeconomical status, n (%) high low 10 385 (50.1) 10 382 (49.9) 7730 (50) 7738 (50) 2655 (50.1) 2644 (49.9) 0.9 region, n (%) west midwest north-east south 11 217 (54.0) 2376 (11.4) 3578 (17.2) 3596 (17.3) 8363 (54.1) 1804 (11.7) 2674 (17.3) 2627 (17.0) 2854 (53.9) 572 (10.8) 904 (17.1) 969 (18.3) 0.1 histology, n (%) urothelial carcinoma micropapillary uc lymphoepithelioma-like uc sarcomatoid uc adenocarcinoma giant and spindle cell carcinoma squamous cell carcinoma neuroendocrine tumor sarcoma 18 303 (88.1) 177 (0.9) 38 (0.2) 283 (1.4) 592 (2.9) 85 (0.4) 889 (4.3) 382 (1.8) 18 (0.1) 13 707 (88.6) 89 (0.6) 27 (0.2) 211 (1.4) 417 (2.7) 68 (0.4) 669 (4.3) 265 (1.7) 15 (0.1) 4596 (86.7) 88 (1.7) 11 (0.2) 72 (1.4) 175 (3.3) 17 (0.3) 220 (4.2) 117 (2.2) 3 (0.1) < 0.001 marital status, n (%) married never married previously married unknown 13 242 (63.8) 2339 (11.3) 4440 (21.4) 746 (3.6) 9983 (64.5) 1683 (10.9) 3226 (20.9) 576 (3.7) 3259 (61.5) 656 (12.4) 1214 (22.9) 170 (3.2) < 0.001 ct: chemotherapy; iqr: interquartile range; ln: lymph node; lni: lymph node invasion; nnr: number of lymph nodes removed; tmt: trimodal therapy; turb: transurethral resection of the bladder; uc: urothelial carcinoma continued on page 292 291siuj.org siuj • volume 2, number 5 • september 2021 dissecting patterns of care in patients with variant histology of bladder cancer and lymph node invasion http://siuj.org table 2. descriptive characteristics according to the lymph node invasion status in the study population (n = 20 767) overall (n = 20 767) no lni (n = 15 468) lni (n = 5299) p value treatment, n (%) radical cystectomy partial cystectomy turb only radiotherapy tmt no local treatment other/unknown 18 125 (87.3) 1044 (5) 739 (3.6) 9 (0) 119 (0.6) 49 (0.2) 682 (3.3) 13 677 (88.4) 911 (5.9) 473 (3.1) 2 (0) 40 (0.3) 19 (0.1) 346 (2.2) 4448 (83.9) 133 (2.5) 266 (5.0) 7 (0.1) 79 (1.5) 30 (0.6) 336 (6.3) < 0.001 perioperative ct, n (%) yes no/unknown 8006 (38.6) 12 761 (61.4) 5087 (32.9) 10381 (67.1) 2919 (55.1) 2380 (44.9) < 0.001 t stage, n (%) t0/x t<2 t2 t3–4 138 (0.7) 2786 (13.4) 7333 (35.3) 10 510 (50.6) 87 (0.6) 2628 (17.0) 6325 (40.9) 6428 (41.6) 51 (1.0) 158 (3.0) 1008 (19.0) 4082 (77.0) < 0.001 grade, n (%) g1 g2 g3 g4 gx 195 (0.9) 1116 (5.4) 6385 (30.7) 12007 (57.8) 1064 (5.1) 167 (1.1) 936 (6.1) 4579 (29.6) 8949 (57.9) 837 (5.4) 28 (0.5) 180 (3.4) 1806 (34.1) 3058 (57.7) 227 (4.3) < 0.001 nnr, median (iqr) 12 (6–22) 12 (6–22) 13 (6.5–21) 0.4 positive ln, median (iqr) 0 (0–1) 0 (0) 2 (1–4) < 0.001 ct: chemotherapy; iqr: interquartile range; ln: lymph node; lni: lymph node invasion; nnr: number of lymph nodes removed; tmt: trimodal therapy; turb: transurethral resection of the bladder; uc: urothelial carcinoma , cont’d 292 siuj • volume 2, number 5 • september 2021 siuj.org original research http://siuj.org table 3. univariable and multivariable logistic regression analysis predicting lymph node invasion in the overall population (n = 20 767) univariate multivariate   or (95%ci)   p value or (95%ci)   p value adjustedp value* histology urothelial carcinoma micropapillary uc lymphoepithelioma-like uc sarcomatoid uc adenocarcinoma giant and spindle cell carcinoma neuroendocrine tumor squamous cell carcinoma sarcoma – 2.95 (2.19–3.97) 1.22 (0.58–2.39) 1.02 (0.77–1.33) 1.25 (1.05–1.50) 0.75 (0.42–1.24) 1.32 (1.06–1.64) 0.98 (0.84–1.14) 0.60 (0.14–1.81) < 0.001 0.6 0.9 0.01 0.3 0.01 0.8 0.4 reference 3.39 (2.43–4.74) 0.84 (0.38–1.76) 0.89 (0.66–1.18) 1.22 (0.99–1.50) 0.60 (0.33–1.03) 1.04 (0.81–1.32) 0.90 (0.75–1.08) 0.45 (0.10–1.48) < 0.001 0.7 0.4 0.06 0.07 0.8 0.3 0.2 < 0.001 1 1 1 1 1 1 1 age at diagnosis (years) 0.99 (0.99–1.00) < 0.001 0.99 (0.99–1.00) 0.04 1 sex male female – 1.22 (1.14–1.31) < 0.001 reference 1.12 (1.03–1.22) 0.006 0.2 race white black hispanic asiatic other – 1.32 (1.17–1.50) 1.14 (1.01–1.29) 0.98 (0.84–1.13) 0.92 (0.59–1.40) < 0.001 0.04 0.7 0.7 reference 1.17 (1.01–1.34) 1.16 (1.01–1.34) 0.98 (0.83–1.16) 0.85 (0.52–1.35) 0.03 0.03 0.8 0.5 1 1 1 1 socioeconomic status low high – 1.01 (0.94–1.07) 0.9 reference 0.99 (0.92–1.06) 0.7 1 region west midwest north-east south – 0.93 (0.84–1.03) 0.99 (0.91–1.08) 1.08 (0.99–1.18) 0.2 0.8 0.07 reference 0.84 (0.74–0.94) 0.93 (0.84–1.02) 1.02 (0.92–1.12) 0.003 0.1 0.7 0.1 1 1 marital status married never married previously married unknown – 1.19 (1.08–1.32) 1.15 (1.07–1.25) 0.90 (0.76–1.08) < 0.001 < 0.001 0.3 reference 1.13 (1.01–1.26) 1.12 (1.03–1.23) 1.04 (0.86–1.26) 0.03 0.008 0.7 1 0.3 1 ci: confidence interval; ct: chemotherapy; or: odd ratio; nnr: number of lymph nodes removed; uc: urothelial carcinoma * p values were adjusted using the conservative bonferroni correction method which multiplies the raw p-values by the number of tests continued on page 294 293siuj.org siuj • volume 2, number 5 • september 2021 dissecting patterns of care in patients with variant histology of bladder cancer and lymph node invasion http://siuj.org , cont’d table 3. univariable and multivariable logistic regression analysis predicting lymph node invasion in the overall population (n = 20 767) univariate multivariate   or (95%ci)   p value or (95%ci)   p value adjustedp value* perioperative ct no yes – 2.50 (2.35–2.67) < 0.001 reference 2.29 (2.13–2.46) < 0.001 < 0.001 treatment no local treatment radical cystectomy partial cystectomy turb only radiotherapy tmt other/unknown – 0.21 (0.11–0.36) 0.09 (0.05–0.17) 0.36 (0.19–0.63) 2.21 (0.48–15.9) 1.25 (0.62–2.48) 0.62 (0.33–1.11) < 0.001 < 0.001 < 0.001 0.4 0.5 0.1 reference 0.18 (0.09–0.34) 0.09 (0.04–0.18) 0.57 (0.29–1.07) 1.42 (0.27–11.23) 0.76 (0.35–1.61) 0.32 (0.16–0.62) < 0.001 < 0.001 0.09 0.7 0.5 < 0.001 < 0.001 < 0.001 1 1 1 0.03 t stage t < 2 t2 t3–4 t0/x – 2.65 (2.23–3.16) 10.6 (8.98–12.5) 9.74 (6.63–14.2) < 0.001 < 0.001 < 0.001 reference 2.24 (1.88–2.69) 9.44 (7.98–11.2) 6.21 (4.08–9.35) < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 grade g1 g2 g3 g4 gx – 1.15 (0.76–1.80) 2.35 (1.60–3.60) 2.04 (1.39–3.11) 1.62 (1.07–2.52) 0.5 < 0.001 < 0.001 0.03 reference 0.78 (0.50–1.27) 1.50 (0.98–2.37) 1.33 (0.87–2.10) 1.16 (0.74–1.87) 0.3 0.07 0.2 0.5 1 1 1 1 nnr 1.00 (0.99–1.00) 0.5 1.00 (0.99–1.00) 0.3 1 ci: confidence interval; ct: chemotherapy; or: odd ratio; nnr: number of lymph nodes removed; uc: urothelial carcinoma * p values were adjusted using the conservative bonferroni correction method which multiplies the raw p-values by the number of tests 294 siuj • volume 2, number 5 • september 2021 siuj.org original research http://siuj.org table 4. univariable and multivariable cox regression analyses predicting overall mortality among patients with lymph node invasion (n = 5299) univariate multivariate   hr (95%ci)  p value hr (95%ci)  p value adjusted p value* histology urothelial carcinoma micropapillary uc lymphoepithelioma-like uc sarcomatoid uc adenocarcinoma giant and spindle cell carcinoma neuroendocrine tumor squamous cell carcinoma sarcoma – 0.97 (0.72–1.30) 0.46 (0.11–1.82) 1.55 (1.16–2.08) 1.17 (0.97–1.42) 0.69 (0.29–1.66) 1.33 (1.06–1.68) 2.03 (1.72–2.40) 4.69 (1.17–18.8) 0.84 0.27 < 0.001 0.10 0.40 0.01 < 0.001 0.03 reference 1.09 (0.81–1.47) 0.47 (0.12–1.87) 1.37 (1.02–1.84) 1.10 (0.90–1.34) 0.67 (0.28–1.60) 1.34 (1.06–1.70) 1.87 (1.56–2.24) 4.84 (1.21–19.4) 0.55 0.28 0.04 0.36 0.36 0.01 < 0.001 0.03 1 1 1 1 1 0.35 < 0.001 1 age at diagnosis (years) 1.01 (1.01–1.01) <0.001 1.01 (1.01–1.01) < 0.001 < 0.001 sex male female – 1.12 (1.04–1.21) < 0.001 reference 1.04 (0.96–1.13) 0.37 1 race white black hispanic asiatic other – 1.27 (1.12–1.45) 0.93 (0.81–1.08) 0.97 (0.82–1.15) 1.02 (0.62–1.67) < 0.001 0.33 0.76 0.94 reference 1.18 (1.03–1.36) 0.97 (0.84–1.13) 1.04 (0.88–1.24) 1.04 (0.63–1.70) 0.02 0.73 0.65 0.89 0.7 1 1 1 socioeconomic status low high – 1.01 (0.94–1.08) 0.77 reference 1.00 (0.93–1.08) 0.96 1 region west midwest north-east south – 1.07 (0.95–1.21) 1.15 (1.04–1.27) 1.28 (1.16–1.41) 0.23 < 0.001 < 0.001 reference 1.10 (0.97–1.25) 1.05 (0.95–1.17) 1.22 (1.10–1.35) 0.12 0.33 < 0.001 1 1 < 0.001 marital status married never married previously married unknown – 1.27 (1.14–1.41) 1.21 (1.11–1.32) 0.94 (0.76–1.18) < 0.001 < 0.001 0.61 reference 1.24 (1.11–1.39) 1.10 (1.01–1.21) 0.90 (0.71–1.12) <0.001 0.03 0.34 <0.001 1 1 ci: confidence interval; ct: chemotherapy; hr: hazard ratio; nnr: number of lymph nodes removed; tmt: trimodal therapy; turb: transurethral resection of the bladder; uc: urothelial carcinoma * p values were adjusted using the conservative bonferroni correction method which multiplies the raw p-values by the number of tests continued on page 296 295siuj.org siuj • volume 2, number 5 • september 2021 dissecting patterns of care in patients with variant histology of bladder cancer and lymph node invasion http://siuj.org table 4. univariable and multivariable cox regression analyses predicting overall mortality among patients with lymph node invasion (n = 5299) univariate multivariate   hr (95%ci)  p value hr (95%ci)  p value adjusted p value* perioperative ct no yes – 0.65 (0.61–0.70) < 0.001 reference 0.69 (0.64–0.74) < 0.001 < 0.001 treatment no local treatment radical cystectomy partial cystectomy turb only radiotherapy tmt other/unknown – 0.77 (0.46–1.27) 0.67 (0.38–1.16) 0.92 (0.54–1.56) 3.08 (1.19–7.93) 0.82 (0.46–1.46) 0.94 (0.56–1.59) 0.30 0.15 0.76 0.02 0.51 0.82 reference 0.83 (0.48–1.45) 0.65 (0.36–1.18) 1.12 (0.63–1.98) 3.82 (1.46–9.98) 1.13 (0.61–2.09) 0.98 (0.55–1.75) 0.51 0.16 0.70 0.01 0.70 0.96 1 1 1 0.35 1 1 t stage t<2 t2 t3–4 t0/x – 1.05 (0.82–1.35) 1.83 (1.45–2.33) 1.64 (1.04–2.56) 0.70 <0.001 0.03 reference 1.12 (0.87–1.45) 1.94 (1.52–2.47) 1.32 (0.81–2.15) 0.37 <0.001 0.27 1 0.03 1 grade g1 g2 g3 g4 gx – 1.36 (0.80–2.29) 1.15 (0.70–1.88) 1.00 (0.61–1.63) 1.08 (0.64–1.81) 0.25 0.59 0.99 0.78 reference 0.95 (0.56–1.62) 1.05 (0.64–1.72) 0.99 (0.61–1.63) 0.98 (0.58–1.66) 0.86 0.85 0.98 0.94 1 1 1 1 nnr 0.99 (0.99–0.99) <0.001 0.99 (0.99–0.99) <0.001 0.03 ci: confidence interval; ct: chemotherapy; hr: hazard ratio; nnr: number of lymph nodes removed; tmt: trimodal therapy; turb: transurethral resection of the bladder; uc: urothelial carcinoma * p values were adjusted using the conservative bonferroni correction method which multiplies the raw p-values by the number of tests , cont’d 296 siuj • volume 2, number 5 • september 2021 siuj.org original research http://siuj.org references 1. ku jh, kang m, kim hs, jeong cw, kwak c, kim 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cancer: a systematic review. eur urol.2014;66(6):1065–1077. epub 2014 jul 26.doi: 10.1016/j.eururo.2014.05.031 297siuj.org siuj • volume 2, number 5 • september 2021 dissecting patterns of care in patients with variant histology of bladder cancer and lymph node invasion http://siuj.org 23. larcher a, sun m, schiffmann j, tian z, shariat sf, mccormack m, et al. differential effect on survival of pelvic lymph node dissection at radical cystectomy for muscle invasive bladder cancer. eur j surg oncol.2015;41(3):353–360. epub 2014 nov 21. doi: 10.1016/j. ejso.2014.10.061 24. perera m, mcgrath s, sengupta s, crozier j, bolton d, lawrentschuk n. pelvic lymph node dissection during radical cystectomy for muscleinvasive bladder cancer. nat rev urol.2018;15(11):686–692. doi: 10.1038/s41585-018-0066-1 25. kim sp, frank i, cheville jc, thompson rh, weight cj, et al. the impact of squamous and glandular differentiation on survival after radical cystectomy for urothelial carcinoma. j urol.2012;188(2):405–409. epub 2012 jun 14. doi: 10.1016/j.juro.2012.04.020 26. linder bj, frank i, cheville jc, thompson rh, thapa p, tarrell rf, et al. outcomes following radical cystectomy for nested variant of urothelial carcinoma: a matched cohort analysis. j urol.2013 may;189(5):1670– 1675. epub 2012 nov 6. doi: 10.1016/j.juro.2012.11.006 27. naspro r, finati m, roscigno m, pellucchi f, la croce g, sodano m, et al. the impact of histological variants on outcomes after open radical cystectomy for muscle-invasive urothelial bladder cancer: results from a single tertiary referral centre. world j urol.2021 jun;39(6):1917– 1926. epub 2020 jul 21. doi: 10.1007/s00345-020-03364-z 28. marks p, gild p, soave a, janisch f, minner s, engel o, et al. the impact of variant histological differentiation on extranodal extension and survival in node positive bladder cancer treated with radical cystectomy. surg oncol.2019;28:208–213. epub 2019 jan 30. doi: 10.1016/j.suronc.2019.01.008 29. nassar h, pansare v, zhang h, che m, sakr w, ali-fehmi r, et al. pathogenesis of invasive micropapillary carcinoma: role of muc1 glycoprotein. mod pathol.2004;17(9):1045 –1050. doi: 10.1038/ modpathol.3800166 30. nassar h. carcinomas with micropapillary morphology: clinical significance and current concepts. adv anat pathol.2004;11(6):297–303. 31. pederzoli f, bandini m, marandino l, raggi d, giannatempo p, salonia a, et al. neoadjuvant chemotherapy or immunotherapy for clinical t2n0 muscle-invasive bladder cancer: time to change the paradigm? eur urol oncol.2020 aug 23;s2588-9311(20)30121-8. doi: 10.1016/j. euo.2020.07.006.32 32. bandini m, gibb ea, gallina a, raggi d, marandino l, bianchi m, et al. does the administration of preoperative pembrolizumab lead to sustained remission post-cystectomy? first survival outcomes from the pure-01 study☆. ann oncol.2020;31(12):1755–1763. epub 2020 sep 23. doi: 10.1016/j.annonc.2020.09.011 33. bandini m, pederzoli f, madison r, briganti a, ross js, niegisch g, et al. unfavorable cancer-specific survival after neoadjuvant chemotherapy and radical cystectomy in patients with bladder cancer and squamous cell variant: a multi-institutional study. clin genitourin cancer.2020;18(5):e543–e556. epub 2020 feb 8. doi: 10.1016/j. clgc.2020.01.007 34. basile g, bandini m, pederzoli f, gallina a, necchi a. re: siamak daneshmand, a zadeh nazemi. neoadjuvant chemotherapy in variant histology bladder cancer: current evidence. eur urol focus.2020;6:639–41. 35. necchi a, pederzoli f, bandini m, spiess pe. revolutionizing care for rare genitourinary tumours. nat rev urol.2021 feb;18(2):69-70. doi: 10.1038/s41585-020-00402-8 36. bandini m, preisser f, nazzani s, marchioni m, tian z, fossati n, et al. contemporary trends and survival outcomes after aborted radical prostatectomy in lymph node metastatic prostate cancer patients. eur urol focus.2019;5(3):381–388. epub 2018 feb 1. doi: 10.1016/j. euf.2018.01.009 37. moch, h m, humphrey p, ulbright t, reuter v. who classification of tumours of the urinary system and male genital organs. international agency for research on cancer; 2016. 38. linder bj, boorjian sa, cheville jc, sukov wr, thapa p, tarrell rf, et al. the impact of histological reclassification during pathology re-review—evidence of a will rogers effect in bladder cancer? j urol.2013;190(5):1692–1696. epub 2013 may 23. doi: 10.1016/j. juro.2013.05.040 39. shah rb, montgomery js, montie je, kunju lp. variant (divergent) histologic differentiation in urothelial carcinoma is under-recognized in community practice: impact of mandatory central pathology review at a large referral hospital. urol oncol.2013;31(8):1650–1655. epub 2012 may 17. doi: 10.1016/j.urolonc.2012.04.009 298 siuj • volume 2, number 5 • september 2021 siuj.org original research http://siuj.org 289siuj.org siuj • volume 3, number 5 • september 2022 editorial “so, is your journal listed on pubmed?” 291 peter c. black urology around the world urology in syria: a view from inside 294 khaled altopajee, mohammed shahait research relationship between serum testosterone and severity of lower urinary tract symptoms among malaysian men 296 suzliza shukor, fam xeng inn, zulkifli md zainuddin intra-diverticular bladder tumours: how to manage rationally 303 mohammed lotfi amer, hassan mumtaz, beth russell, jason gan, zahra rehman, rajesh nair, ramesh thurairaja, muhammad shamim khan a quality assessment of information available on renal cancer on youtube 315 jeremy saad, ramesh shanmugasundaram, darius ashrafi, daniel gilbourd review outcomes of robotic surgery for low-volume surgeons 323 sridhar panaiyadiyan, rajeev kumar systematic review and meta-analysis of response rates in bcg-unresponsive non–muscle-invasive bladder cancer: a consensus statement from the international bladder cancer group 333 kyle m. rose, herney a. garcia-perdomo, trinity j. bivalacqua, j. alfred witjes, joan palou, peter c. black, gary d. steinberg, seth p. lerner, sima p. porten, ashish m. kamat, roger li adjuvant systemic treatment for renal cancer after surgery: a network meta-analysis 341 niranjan j. sathianathen, marc a. furrer, christopher j. weight, declan g. murphy, shilpa gupta, nathan lawrentschuk clinical picture large accessory scrotal spleen masquerading as testicular tumor 354 sirish bharadwaj, sanjay sinha, meenakshi swain table of contents http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information bladder cancer, coordination of care, regional medical programs, hospital mortality, patient navigation, patient care team none declared. soc int urol j.2022;3(4):198–200 doi: 10.48083/dfbq7749 198 siuj • volume 3, number 4 • july 2022 siuj.org urology around the world the cabem initiative: saving patients with muscle-invasive bladder cancer fernando korkes, josé henrique d. santiago, guilherme andrade peixoto, frederico timóteo, suelen p. martins, narjara p. leite, daisy barreiros, sidney glina division of urology, centro universitário fmabc santo andré, são paulo, brazil abstract muscle-invasive bladder cancer (mibc) is an aggressive disease with a complex treatment. in brazil, as in most developing countries, data are scarce, but mortality seems exceedingly high. we have created a centralized program involving a multidisciplinary clinic in a region comprising 7 municipalities. helping patients with adequate performance status get the right treatment helped to reduce 90-day mortality after radical cystectomy from 37% to 1.9%. in brazil, as in many developing countries, taking care of oncologic patients is a considerable challenge. among oncologic diseases, bladder cancer poses an even more significant challenge because of the complexity of the treatment and aggressiveness of the disease. access to health treatment is a right unambiguously outlined in the brazilian constitution. aware that patients treated with radical cystectomy frequently died, we decided to conduct national studies to gather epidemiologic data[1] and study our region. we found an astonishing 90-day mortality rate of 37% after radical cystectomy in the public hospitals of our region[2]. in light of these unacceptable numbers, we started a program aimed at changing this terrible scenario. this was the so-called cabem initiative. it was based on principles of centralization of treatment, multidisciplinary approach, and patient navigation to coordinate the treatment, and our primary goal was to reduce mortality for muscle-invasive bladder cancer (mibc) patients. our project comprised 3 phases: gathering the data, designing the strategies, and acting to meet our objectives. we mapped 4 main reasons for the high mortality rate: (1) advanced stage of disease at diagnosis, (2) poor patient performance status, (3) lack of treatment protocols, (4) inadequate perioperative care. the advanced stage of the disease at diagnosis results from the difficulties and long waiting times our patients face to see a specialist. our patients have usually waited between 13 and 24 months to see a urologist, and almost half of the patients with bladder cancer are diagnosed with mibc. neoadjuvant chemotherapy (nac) had not previously been offered was not performed, in part because bureaucratic challenges made it difficult to coordinate in our public setting. we implemented a program to allow nac, which is currently administered in half of our mibc patients. it enables the downstaging of many cases of advanced disease—half our mibc patients have t3–t4 tumors—but also during this part of the treatment, we have found a fantastic opportunity to improve performance status. we were able to enhance nutritional therapy, support the cessation of tobacco consumption, give psychological support, reduce the risk of requiring transfusions in the future, and prepare the patient for the surgery. http://siuj.org https://orcid.org/0000-0003-4261-4345 mailto:fkorkes%40gmail.com?subject=siuj https://orcid.org/0000-0002-6883-1762 https://orcid.org/0000-0002-9022-1880 https://orcid.org/0000-0002-0731-3734 https://orcid.org/0000-0003-2697-5896 https://orcid.org/0000-0002-7258-9796 https://orcid.org/0000-0003-1598-8229 https://orcid.org/0000-0002-9053-5046 all patients seen at our centralized clinic were evaluated according to scores selected after mapping the main reasons for death and complications in a systematic review of the literature[3]. these patients were referred by other treating physicians, who were incentivized to send us their patients with our promise to coordinate their treatment. our team helped the patients navigate our complex public health system, aiming to avoid delays. after studying the medical literature, we concluded that, worldwide, most patients with mibc are not treated with radical cystectomy (rc), even though it is recommended in most guidelines. we have established a protocol to allow most patients to benefit from rc, but that recognizes that some of these patients are fragile and cannot tolerate frequent complications after intestinal urinary diversion[4]. for that reason, we created a scoring system to classify these patients. the fit patients should undergo rc with intestinal diversion (either bricker diversion or neobladder). those with an intermediate status we believed could receive the benefit of rc and extended pelvic lymphadenectomy but should not face the risk of an intestinal diversion. for these patients, we performed unilateral cutaneous ureterostomy with a single stoma. both ureters were placed side-by-side as a double-barrel, or a transureteroureterostomy was performed (figure  1). for the very fragile patients, we found alternative treatments such as radiotherapy (rdt), chemotherapy (ct), transurethral resection (turb), or combinations of these. bladder preservation protocols were also offered in specific situations according to disease characteristics and patient preferences[5]. our scoring system and decision algorithm have been previously published[5]. the principles of fast-track recovery programs were adopted, allowing better preparation and recovery. these strategies included avoiding prolonged fasting, avoiding nasogastric tubes, using chewing gum, avoiding opioids, early mobilization, avoiding excessive volume load, thromboembolism prevention, and minimally invasive procedures. either extraperitoneal open radical cystectomies (figure 2) or laparoscopic radical cystectomies were performed in most patients, aiming to reduce postoperative ileus and improve recovery. perioperative care was enhanced by establishing a dedicated team. in a short period, we observed remarkable results. ninety-day mortality was reduced from 37.0% to the current 1.9% rate. along with that, we could reduce median hospitalization time after surgery from 14 to 5 days. we have currently had 153 patients treated for mibc since the beginning of the cabem program. the higher survival rate has also resulted in nurses having more experience in caring for patients with ostomies and oncologists developing greater expertise in treating mibc, including nac, adjuvant, and palliative care. we could also improve the recruitment of our research unit[6,7], and we are nowadays the top recruiter center of some of the international trials on bladder cancer in brazil. we currently have a preceptorship program to share our experience with other centers, and our main goal is to contribute and share our results with the medical community. we believe that small initiatives can make a huge difference in developing settings. figure 1. 199siuj.org siuj • volume 3, number 4 • july 2022 the cabem initiative: saving patients with muscle-invasive bladder cancer http://siuj.org references 1. timoteo f, korkes f, baccaglini w, glina s. bladder cancer trends and mortality in the brazilian public health system. int braz j urol.2020;46(2):224–233. 2. korkes f, cunha fts, nascimento mp, rodrigues afs, baccaglini w, glina s. mortality after radical cystectomy is strongly related to the institution’s volume of surgeries. einstein (sao paulo).2020 dec 7;18:eao5628. doi: 10.31744/einstein_journal/2020ao5628. ecollection 2020. available at: ht tps://pubmed.ncbi.nlm.nih. gov/33295426/ accessed june 1,2022. 3. korkes f, palou j. high mortality rates after radical cystectomy: we must have acceptable protocols and consider the rationale of cutaneous ureterostomy for high-risk patients. int braz j urol.2019;45:1090–1093. doi: 10.1590/s1677-5538.ibju.2019.06.03 4. korkes f, fernandes e, gushiken fa, glina fpa, baccaglini w, timóteo f, et al. bricker ileal conduit vs. cutaneous ureterostomy after radical cystectomy for bladder cancer: a systematic review. int braz j urol.2022;48(1):18-30. doi: 10.1590/s1677-5538.ibju.2020.0892. available at: http://w w w.ncbi.nlm.nih.gov/pubmed/33861058. accessed may 17, 2022. 5. korkes f, timóteo f, martins s, nascimento m, monteiro c, santiago jh, et al. dramatic impact of centralization and a multidisciplinary bladder cancer program in reducing mortality: the cabem project. jco glob oncol.2021;7(7):1547–1555. available at: https://pubmed. ncbi.nlm.nih.gov/34767463/. accessed june 1, 2022. doi: 10.1200/ go.21.00104 6. monteiro cr de a, korkes f, krutman-zveibil d, glina s. fibroblast growth factor receptor 3 gene (fgfr3) mutations in high-grade muscleinvasive urothelial bladder cancer in a brazilian population: evaluation and prevalence. einstein (sao paulo).2022 apr 1;20:eao6450. doi: 10.31744/einstein_journal/2022ao6450. ecollection 2022. available at: https://pubmed.ncbi.nlm.nih.gov/35384983/. accessed apr 11, 2022. 7. korkes f, timóteo f, soledade lcb, bugalho ls, peixoto ga, teich vd, et al. stage-related cost of treatment of bladder cancer in brazil. pharmacoecon open.2022 may;6(3):461-468. doi: 10.1007/s41669022-00325-7. epub 2022 feb 14. available at: https://pubmed.ncbi. nlm.nih.gov/35165828/. accessed april 11, 2022. figure 2 . 200 siuj • volume 3, number 4 • july 2022 siuj.org urology around the world https://pubmed.ncbi.nlm.nih.gov/33295426/ https://pubmed.ncbi.nlm.nih.gov/33295426/ http://www.ncbi.nlm.nih.gov/pubmed/33861058 https://pubmed.ncbi.nlm.nih.gov/34767463/ https://pubmed.ncbi.nlm.nih.gov/34767463/ https://pubmed.ncbi.nlm.nih.gov/35384983/ https://pubmed.ncbi.nlm.nih.gov/35384983/ https://pubmed.ncbi.nlm.nih.gov/35384983/ http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information urology, syria, conflict zone none declared. soc int urol j.2022;3(5):294–295 doi: 10.48083/irjo4841 urology in syria: a view from inside khaled altopajee,1 mohammed shahait2 1 department of urology, damascus university, damascus, syria 2 department of surgery, clemenceau medical center, dubai, united arab emirates damascus is the capital of syria and one of the oldest continuously inhabited cities in the world. the city had an estimated population of 2 079 000 in 2019[1]. it is the birthplace of ibn al-nafis (1213 to 1288), who has been described as "the father of circulatory physiology." in his book, al-mugiza, ibn al-nafis distinguishes between kidney stones and bladder stones[2]. moreover, he was the first to describe the vesicoureteral anti-reflux mechanism, which our contemporary understanding corroborates[3]. the school of medicine at damascus university was founded in 1903 and is one of the top 10 international providers of licensed physicians in the united states[4]. in the last decade, the syrian crisis has led to an exodus of syrian physicians from different subspecialties, including urology[5]. it is mainly the young doctors who leave, because of concerns about safety and limited opportunities for comprehensive postgraduate training, as well as to avoid mandatory military service[6]. consequently, there is a shortage of specialized physicians outside major cities. the syrian crisis is not a traditional war. the whole society is a battlefield, with civilian facilities, including health care facilities, treated as targets[7]. moreover, the devaluation of the local currency (in 2009, 1 usd was worth 46 syrian pounds; in 2022, 1 usd is worth 4000 syrian pounds) and the militarization of the health care system have impacted health care spending. for example, more funds and resources are allocated to treat war victims who suffer from life-threatening injuries, and less is invested in chronic disease care and screening programs[5]. all these things have directly and indirectly changed the urology disease spectrum in syria, with increases in the number of complex urethral injuries, late presentations of prostate and kidney cancer, and the number of young patients with bladder cancer. at the same time, hospitals are less able to acquire or maintain equipment and disposables required for endourology surgery and laparoscopic surgery. the scarcity of resources has challenged practicing urologists in our country to tailor their practice accordingly. while the international urolog y community is embracing mini-pcnl for staghorn stones, urologists in syria are running backward in time to perform open pyelolithotomy and open nephrolithotomy. at the same time as international colleagues have the luxury of offering a cornucopia of procedures to treat bph, traditional turp in our part of the world might be canceled due to a shortage of irrigation fluid. as the data from the peace-1 trial showed that a triplet combination improves overall survival of de novo metastatic castration-sensitive prostate cancer, surgical castration might be the only option the urologist can offer in syria[8]. sharing the news with patients that they have metastatic renal cell and bladder cancer is like sharing a death sentence with them. even affluent citizens who can afford to travel to other countries for treatment and are lucky enough to get an entry visa are vulnerable to medical scams, to being overcharged, and to having unnecessary procedures recommended. some of these patients come back to syria without proper documentation of their treatment or a follow-up plan[9]. 294 siuj • volume 3, number 5 • september 2022 siuj.org urology around the world https://orcid.org/0000-0002-6523-4428 https://orcid.org/0000-0003-2609-5629 mailto:mshahait%40yahoo.com?subject=siuj http://siuj.org the training of future urologists locally is another challenge. intelligent, dedicated residents have limited exposure to new technologies such as laser treatment of kidney stones, pcnl, staplers, and sealing devices. added to this, opportunities to close the gaps in residency training through hands-on courses at international urology society meetings are now non-existent—as are opportunities for advanced postgraduate training abroad. several humanitarian agencies have worked tirelessly with different parties to facilitate access to primary care medications such as antibiotics, painkillers, and vaccines for children. in addition, in specific scenarios, these agencies were able to establish primary care centers and equip them with essential tools such as x-ray, ct, and hemodialysis machines[10]. we believe that international urology societies should coordinate with humanitarian agencies to play a role in ensuring that urologists in conflict zones have access to modern essential surgery tools and life-prolonging medications. another avenue of support for the urologist community in syria and other conflict zones around the world is to invest in training a new generation of urologists. this can be achieved by granting these urologists unlimited access to e-courses, podcasts, recorded webinars, and surgical educational material. as more platforms are available to facilitate tele-proctoring, international urology societies might collaborate to offer tele-proctoring programs to the global urology community. references 1. abu-lughod jl. damascus. in: dumper mrt, stanley be, eds. cities of the middle east and north africa: a historical encyclopedia. abc-clio;2007. isbn 978-1-5760-7919-5. 2. ibn al-nafis. al-mujaz fi al-tibb. al-ezbawy a, ed. 4th ed. cairo: islamic heritage revival committee, supreme council for islamic affairs, ministry of endowments.2004;239-241. 3. abdel-halim re, abdel-maguid te. the functional anatomy of the uretero-vesical junction. a historical review. saudi med j.2003;24:815-819. 4. young a, chaudhry hj, pei x, arnhart k, dugan m, steingard sa. fsmb census of licensed physicians in the united states. j med regul. 2018;105 (2):7-23. available at: ht tps://w w w.fsmb.org/ siteassets/advocacy/publications/2018census.pdf. accessed april 27, 2021. 5. fouad m, sparrow a, tarakji a, alameddine m, el-jardali f, coutts ap, et al. health workers and the weaponisation of health care in syria: a preliminary inquiry for the lancet–american university of beirut commission on syria. lancet.2017;390(10111):2516-2526. doi: 10.1016/ s0140-6736(17)30741-9. epub 2017 mar 15. 6. abbara a, orcutt m, gabbar o. syria’s lost generation of doctors. bmj.2015;350:h3479. doi: 10.1136/bmj.h3479. 7. shahait m, nasr rw. contemporary management of urogenital injuries. in: reconstructing the war injured patient.2017; springer:119-129. 8. fizazi k, foulon s, carles j, roubaud g, mcdermott r, fléchon a, et al. abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (peace-1): a multicentre, open-label, randomised, phase 3 study with a 2× 2 factorial design. lancet.2022;399(10336):1695-1707. doi: 10.1016/s0140-6736(22)00367-1. epub 2022 apr 8. 9. international association for medical assistance for travellers. how to avoid medical scams abroad. travel health journal.2021. available at: https://www.iamat.org/blog/how-to-avoid-medical-scams-abroad/. accessed august 1, 2022. 10. united nations office for the coordination of humanitarian affairs. syria humanitarian response plan 2021. available at: ht tps://f ts. uno cha.or g /ap p e als / 9 24 /p r oje c t s? f %5 b 0 %5 d = de s tina tion clusteridname%3a5226%3ahealth. accessed august 1, 2022. 295siuj.org siuj • volume 3, number 5 • september 2022 urology in syria: a view from inside https://www.fsmb.org/siteassets/advocacy/publications/2018census.pdf https://www.fsmb.org/siteassets/advocacy/publications/2018census.pdf https://www.iamat.org/blog/how-to-avoid-medical-scams-abroad/ https://fts.unocha.org/appeals/924/projects?f%5b0%5d=destinationclusteridname%3a5226%3ahealth https://fts.unocha.org/appeals/924/projects?f%5b0%5d=destinationclusteridname%3a5226%3ahealth https://fts.unocha.org/appeals/924/projects?f%5b0%5d=destinationclusteridname%3a5226%3ahealth http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information lower urinary tract symptoms, overactive bladder, urinary leakage, detrusor overactivity, urge urinary incontinence, stress urinary incontinence, voiding dysfunction, ambulatory urodynamics none declared. received on may 6, 2021 accepted on july 31, 2021 soc int urol j.2021;2(6):354–361 doi: 10.48083/mhmi1178 354 siuj • volume 2, number 6 • november 2021 siuj.org original research ambulatory urodynamic findings change patient outcomes richard g. axell,1 vahit guzelburc,2 habiba yasmin,1 bogdan toia,2 mahreen h. pakzad,2 rizwan hamid,2 jeremy l. ockrim,2 tamsin j. greenwell2 1medical physics and bioengineering, uclh nhs foundation trust, london, united kingdom 2department of urology, uclh nhs foundation trust, london, united kingdom this work was performed at uclh nhs foundation trust, london, united kingdom abstract objectives whilst ambulatory urodynamics (auds) may be used as a second-stage test for patients with refractory lower urinary tract symptoms (luts) having non-diagnostic conventional urodynamics (uds), the evidence for their use is limited. we have assessed the diagnostic utility and consequent symptomatic outcome of auds in patients with refractory luts. methods a retrospective review of a prospectively acquired urodynamics database was made of 84 consecutive patients (23 male) with a median age 50.5 years (range 18 to 79) having auds following non-diagnostic or contradictory baseline uds over a 12-month period. patient demographics and urodynamic and clinical diagnosis before and after auds were recorded. forty-six patients (55%) had formal urinary symptom assessment recorded before and a minimum of 6 months following auds-related change in management. results eighty-two patients (98%) had a urodynamic diagnosis made following auds, 57(68%) of whom had detrusor overactivity (do); the final 2 patients had no abnormalities detected on auds. change in primary uds diagnosis occurred in 66 patients (79%). of these 66 patients, 59 (89%) also had their clinical diagnosis changed, and 55 (83%) had their management pathway changed. there was a significant improvement in urinary symptoms 6 months following auds. conclusion change in primary diagnosis following auds led to a significant change in treatment care pathway and resulted in significant improvement in urinary symptoms. introduction conventional urodynamics (uds) is considered to be the gold standard investigation for lower urinary tract symptoms (luts)[1,2]. conventional uds use rapid bladder filling and are performed in an unnatural environment. in a significant sub-group of patients, up to 54% to 56% of conventional uds studies are unable to provide a urodynamic diagnosis that correlates with the patient’s presenting luts[3,4]. ambulatory urodynamics (auds) is recognised by the international continence society (ics) as an important second-line diagnostic tool for providing a definitive diagnosis in patients who have previously had a non-diagnostic or symptomatically contradictory conventional uds[5]. in contrast to conventional uds, auds allows for natural (orthograde) bladder filling in a more natural environment, with the patient able to undertake relatively normal daily activities away from the uds suite. auds also allow the patient to perform activities they know will provoke their most troubling urinary symptoms and improve the likelihood of a diagnostic test. they are, however, both time and personnel intensive and hence more costly than routine urodynamics, with limited availability in general urological practice. we aimed to determine the diagnostic value of auds in patients with refractory luts of unknown cause following non-diagnostic or symptomatically contradictory conventional uds (filling cystometry and pressure flow studies +/₋ video) and to assess if a change in patient diagnosis and/or treatment following auds led to a symptomatic improvement in patients. methods and methods study population eighty-four consecutive patients (23 male) having auds at our tertiary referral centre between 1 january 2015 and 31 december 2015 were identified from our prospectively acquired urodynamic database and their records retrospectively reviewed. this time period was chosen to allow sufficient time to evaluate diagnostic outcomes, change in treatment, and treatment outcomes. the median age of the patients was 50.5 years (range 18 to 79). forty-six unselected patients (55%) had formal assessment of their urinary symptoms recorded before and at a minimum of 6 months following auds. the remaining 38 patients did not have complete symptomatic follow-up data available for review. all patients had previously had conventional filling cystometry and pressure flow studies (n = 11) or video-urodynamics (vuds) (n = 73). auds was performed when conventional uds were non-diagnostic (n = 36) or when the conventional uds diagnosis was contradictory to the patients’ major presenting symptoms (table 1). all patients before proceeding to simple urodynamics (filling cystometry and pressure f low studies) had received (as appropriate) lifestyle advice, continence therapist input with respect to bladder training +/pelvic floor muscle exercise, and medications (as indicated by clinical diagnosis). those progressing to ambulatory urody namics w ished to consider more invasive treatments for their symptoms, and it is a requirement of our national health service (nhs) system and national institute for health and care excellence (nice) guidance that a urodynamic diagnosis is made prior to these more invasive treatments. urodynamics procedures auds studies were performed in accordance with the ics guidelines test protocol[1,5] using the mms solar luna module (medical measurement systems, gladbeck, germany) and a fluid filled catheter system. a flow rate and post-void residual and urinalysis were performed before the test. after residual urine was measured, a 4.5fr bladder catheter (mediplus 5716, wycombe, uk) and a 4.5fr rectal balloon catheter (mediplus 5410, wycombe, uk) were inserted for the measurement of intra-vesical and abdominal pressures respectively. a conductance leak pad sensor (digitimer pe-que sensor pad, welwyn garden, uk) was used in all patients reporting symptoms of urinary incontinence. after zeroing the f luid filled pressure measurement transducers and flushing the measurement lines with saline, a cough was used to ensure good cancellation and accurate pressure measurement readings. the patients were advised on the use of the luna module events buttons to mark urgency and leakage and to activate the f lowmeter to record voiding (figure 1). as per the ics guidelines, each patient was advised to drink 1l of water over the first hour and to delay micturition as long as possible. during studies the patients were encouraged to perform activities/ manoeuvres known to be provocative for their typical luts. this included coughing, walking, climbing stairs, performing star jumps, going from a seated to a standing position, listening to running water, and hand washing. patients were reviewed by the urodynamicist on an hourly basis to ensure patient compliance and the accuracy of the pressure measurement readings. studies typically lasted between 2 and 4 hours depending on the time taken to demonstrate a urodynamic cause for the patient’s most troubling urinary symptom. tests were continued until patient’s symptoms were reproduced in all studies. all conventional uds, vuds, and auds studies were analysed by an experienced urodynamicist in accordance with the ics guidelines, and boo was determined in males with the abrams-griff iths nomogram[6] and in females with the solomongreenwell nomogram[7]. the results were subsequently reviewed at a multidisciplinary team (mdt) meeting to ensure accuracy of diagnosis and to determine treatment options. statistical analysis data are expressed as mean ± standard deviation and p-values were calculated using a 2-tailed unpaired student abbreviations auds ambulatory urodynamics do detrusor overactivity ics international continence society luts lower urinary tract symptoms oab overactive bladder sui stress urinary incontinence uds urodynamics uui urge urinary incontinence vuds video-urodynamics 355siuj.org siuj • volume 2, number 6 • november 2021 ambulatory urodynamic findings change patient outcomes t-test for pairwise comparisons of parametric data, unless otherwise stated. categorical data are expressed as number (percentage) and compared with the fisher exact test. p < 0.05 was considered statistically significant. analysis was performed using sigmaplot 12.5 (systat software inc, san jose ca) statistical analysis package. results following auds, all studies were evaluable, and a definitive urodynamic diagnosis was made in 98% (n = 82) of patients, 68% (n = 57) of whom had detrusor overactivity (do) (figure 2). the 2 remaining patients (2%) were diagnosed as having normal bladder function. a change in the primary uds diagnosis occurred in 79% (n = 66) of patients following auds, as detailed in table 1. of these 66 patients 89% (n = 59) also had their clinical diagnosis changed and 83% (n = 55) subsequently had their management changed (figure 3). “clinical diagnosis” is the working diagnosis made after taking a full history, examining the patient, and performing simple tests such a mssu, blood tests, flow rate, and postvoid residual assessment. of the remaining 18 patients for whom auds did not change their initial uds diagnosis following conventional or vuds, change in clinical diagnosis occurred in 10 (56%), all of whom had their management changed. management was also changed in 4 (50%) of table 1. change in primary urodynamic diagnosis following ambulatory urodynamic assessment primary baseline urodynamic diagnosis (total) primary ambulatory urodynamic diagnosis change in diagnosis n (%)acon boo dsd hypo ido loc normal red cap su sui other acon (1) 1 1 (100) boo (9) 2 4 1 2 7 (78) dsd (1) 1 0 (0) hypo (2) 1 1 2 (100) ido (11) 11 0 (0) loc (2) 2 2 (100) normal (36) 2 1 23 1 2 4 3 35 (98) red cap (4) 2 1 1 3 (75) su (10) 1 8 1 9 (90) sui (8) 6 1 1 7 (89) other (0) na total n (%) 0 4 1 2 57 0 2 1 6 7 4 84 (100) acon: acontractile; boo: bladder outflow obstruction; dsd: detrusor sphincter dyssynergia; hypo: hypocontractile; ido: idiopathic detrusor overactivity; loc: loss of compliance; red cap: reduced capacity; su: sensory urgency. figure 1. luna ambulatory module 356 siuj • volume 2, number 6 • november 2021 siuj.org original research the 8 patients with no change in their uds or clinical diagnosis following auds (figure 3). overall, by providing a definitive urodynamic diagnosis in 98% of the patients, auds led to change in clinical diagnosis in 82% (n = 69) of patients and a change in management in 82% (n = 69) of patients, as detailed in table 2. sub-group analysis of symptoms preand postamb uds of the 46 unselected patients (55%) who had ≥ 6 months symptomatic follow-up data, change in clinical diagnosis and management following auds led to a statistically significant improvement in their symptoms of daytime frequency, nighttime frequency, urgency, urge urinary incontinence (uui), stress urinary incontinence (sui), urinary incontinence of unknown cause (not uui or sui), poor flow, and strain void (table 3). there was a significant improvement in iciq-oab (130±35 versus 55 ±70, p < 0.001) and iciq-su (15.1±9.6 versus 7.2 ±10.1, p < 0.001) scores following the changes to clinical diagnosis and management. symptoms as a predictor of definitive uds diagnosis the patients’ presenting symptoms were non-specific and were not significantly different between uds diagnostic categories following auds (table 4). discussion we have demonstrated that auds is an extremely useful diagnostic tool with a 98% definitive diagnosis rate. following auds, a change in urodynamic diagnosis was made in 79%, a change in clinical diagnosis in 70%, and a change in treatment in 75%. all patients felt ambulatory urodynamics was worth their while. they were all fully informed and had provided consent for the ambulatory urodynamics tests. their motivation was wishing to figure 3. change in urodynamic diagnosis, clinical diagnosis and management following auds urodynamic diagnosis changed n = 66 urodynamic diagnosis unchanged n = 18 auds performed n = 84 clinical diagnosis unchanged n = 7 clinical diagnosis changed n = 10 management changed n = 0 management changed n = 10 clinical diagnosis changed n = 59 management changed n = 59 clinical diagnosis unchanged n = 8 management changed n = 4 figure 2. a 47-year-old female patient presenting with frequency, urgency, flooding incontinence episodes (3 to 5 pads per day) (a) essentially normal filling phase urodynamics study with small leaks demonstrated on coughs (1ml to 2ml) on vuds. (b) do (pp137cmh2o) with associated urgency and large volume uui was demonstrated on auds. 357siuj.org siuj • volume 2, number 6 • november 2021 ambulatory urodynamic findings change patient outcomes have a definitive diagnosis and perhaps more effective treatment of their urological issues following a “normal” simple urodynamic study. all auds in this study were evaluable, which is much higher than the 74% evaluable auds studies reported by pannek and pieper[8] but similar to the 97% rate reported by gorton and stanton[9]. patient symptoms were reproduced in 100% of the auds studies, and a urodynamic diagnosis was made in 98%. this is higher than the 72% rate reported by pannek and pieper[8]. the 74% reported by cantu et al.[10], and the 77.3% in women with ui by dokmeci[4] our unit performs 80 to 100 auds per year, more than in either of the studies detailed, and therefore has significant experience in performing and interpreting auds, which may account for the 98% diagnosis rate. however, the lower diagnosis rate seen in the pannek and pieper[8] study may also be related to their patient group and/or advances in the technical aspects of auds since 2008. additionally, whilst both dokmeci[4] and pannek and pieper[8] relied on the patient pressing the leak event marker to indicate an episode of ui, both the auds system of gorton and stanton[9] and that used in this study incorporated a leak pad sensor, which allows for definitive diagnosis of a true episode of ui. auds has been shown to have a higher diagnostic y ield t ha n convent iona l / vu ds. r ad ley et a l. demonstrated this in 106 women presenting with symptoms of overactive bladder (oab); do was detected in 32 and 70 women on vuds and auds, respectively; ie, do was missed in up to 54% of women presenting with oab on conventional uds when compared with auds[3]. dokmeci et al. showed auds detected the underlying pathophysiology in 77% of women presenting with urinary incontinence as compared with only 6.8% of women on conventional uds[4]. while no cases of urodynamic sui were demonstrated on conventional uds in their study, 56% of patients table 2. changes in patient management following auds changes in patient management following auds number of patients intravesical botulinum toxin injection 16 sacral neuromodulation 14 percutaneous tibial nerve stimulation 7 combined medical therapy after refusing surgical intervention 7 continued conservative management after refusing surgical intervention 12 no intervention after normal urodynamic function confirmed 2 cognitive behavioural therapy for sensory urgency syndrome 5 reduced fluid intake after refusing surgical intervention 1 clean intermittent self-catheterisation after refusing surgical intervention 7 bladder neck incision 1 urethral dilatation 1 rectus facia sling 5 artificial urinary sphincter 2 milking bulbar urethra 1 vesicovaginal fistula repair* 1 clam cystoplasty 1 * the fistula repair was in a patient with a previous history of fistula repair (elsewhere), negative imaging, negative cystoscopy, and methylene blue test, normal simple urodynamics and ambulatory urodynamics indicating an ongoing continuous low volume leakage not related to abdominal or detrusor pressure changes. after full discussion of all options, the patient elected to have a repeat vaginal repair with complete separation of the bladder from the vagina, closure of any small fistula (none were seen), and interposition of a martius labial fat pad flap, with resolution of her symptoms. 358 siuj • volume 2, number 6 • november 2021 siuj.org original research had sui demonstrated on auds[4]. this diagnostic rate was similar to the 77% diagnostic rate reported following auds for women with normal conventional uds presented by patravali[11]. conversely, robertson et al.[12] demonstrated no significant difference in the proportion of men diagnosed with boo with simple uds compared with auds; although auds was more sensitive for diagnosing do. rademakers et al.[13] have shown auds to be particularly useful in determining true acontractility and do, and assigning a uds cause for ui of unknown cause. drossaerts et al. have also shown that auds is a valuable tool when assessing the effectiveness of sacral neuromodulation in patients with luts[14]. likewise, we found auds particularly useful in diagnosing detrusor overactivity, stress urinary incontinence, and sensory urgency. because of the complexity of performing and reporting auds, it may best be concentrated in specialist centres. auds must be performed by an experienced urodynamicist (doctor, clinical scientist, or nurse specialist) following a strict test protocol. conventional and vuds are performed with the urodynamicist in the same room as the patient observing the entire test, allowing them to identify measurement artefacts and directly relate provocations to the uds finding. this is not possible during auds where the patient leaves the table 4. symptoms as a predictor of definitive uds diagnosis urodynamic diagnosis symptoms, n (% of urodynamic diagnosis category) total, n (% of total urodynamic diagnosis) frequency (n = 91) urgency (n = 105) urge incontinence (n = 76) stress incontinence (n = 47) detrusor overactivity 43 (70) 53 (87) 43 (70) 22 (26) 61 (48) urodynamic stress urinary incontinence 15 (75) 16 (80) 11 (55) 11 (55) 20 (16) sensory urgency 5 (83) 5 (83) 2 (33) 3 (50) 6 (5) bladder outflow obstruction 7 (58) 9 (75) 6 (50) 3 (25) 12 (9) hypocontractile 10 (83) 10 (83) 6 (50) 2 (17) 12 (9) acontractile 1 (50) 2 (100) 2 (100) 0 (0) 2 (2) normal 2 (100) 1 (50) 1 (50) 1 (50) 2 (2) other (vaginal reflux/ urethral pooling/ detrusor sphincter dyssynergia/ reduced capacity) 8 (62) 9 (69) 5 (38) 5 (38) 13 (10) table 3. patients presenting urinary symptoms pre uds and 6 months post change in management following auds urinary symptom pre-simple uds n = 46 (%) 6 months post change in management consequent to auds n = 46 (%) p value day frequency 28 (61) 11 (24)* 0.0005 night frequency 25 (54) 10 (22)* 0.0021 urgency 28 (61) 11 (24)* 0.0005 uui 18 (39) 8 (17)* 0.0344 sui 14 (30) 4 (9)* 0.0158 ui of unknown cause 3 (7) 2 (4) 1.0 poor flow 13 (29) 2 (4)* 0.0034 strain void 11 (24) 2 (4)* 0.0137 pain on filling 3 (7) 1 (2) 0.6162 pain on voiding 5 (11) 0 (0)* 0.0554 359siuj.org siuj • volume 2, number 6 • november 2021 ambulatory urodynamic findings change patient outcomes uds suite and is relied upon to clearly annotate the recording with event markers. it is essential that patients having auds have the cognitive ability to comply with the instructions from their urodynamicist and that the test be performed using a strict protocol with regular review. following the test, the extensive traces generated must be reviewed by the same urodynamicist, allowing for accurate correlation between the patient’s bladder symptoms and urodynamic findings. while auds is a time-consuming and expensive test, it has been shown to be well tolerated[15], with 85% of patients happy to attend for further studies. following auds,18.6% of patients experience mild to moderate de novo dysuria, and 1.1% experience asymptomatic bacterial uti[16]. at our centre, we performed 1461 conventional/ vuds in the same time period as the 84 auds studies, or 1 auds to every 17.4 conventional/ vuds studies. w hilst auds is t he most accurate urody namic diagnostic test, it takes 2 to 4 hours to perform and 1 to 2 hours to interpret the results compared with 30 to 60 minutes in total for cmg/vuds. it is therefore not cost or time-effective to perform auds on all patients and auds should be reserved for patients with significantly bothersome symptoms, who are contemplating invasive treatment and in whom conventional and/or vuds have been non-diagnostic or contradictory to their symptomatology. in our study, urodynamic diagnosis was changed in 79% of our cohort following auds. this resulted in a change in clinical diagnosis in 89% of patients having their urodynamic diagnosis changed following auds, whilst a change in clinical diagnosis was made in 70% of all patients having auds. this is similar to the 72% to 89% [8–10] of successful clinical diagnosis made following auds in previous studies where auds traces were evaluable. these changes in urodynamic and subsequent clinical diagnosis allowed treatment to be modified in 83% of our patient cohort having change in urodynamic diagnosis post auds and in 75% of all patients having auds, which is higher than the 43%[9] to 63%[8] described in previous studies. the higher treatment change rates noted in our study might be a consequence of patients having auds only if they had non-diagnostic or contradictory prior conventional or vuds before consideration for operative intervention. we do not perform invasive urodynamic assessment prior to non-operative intervention, as per nice guidance[2]. it was an unexpected finding and of interest that some patients would have 2 different urodynamic tests to establish a diagnosis based on their wish to have further and more invasive treatment—and then decline this treatment. this is however their prerogative. our general experience is that while ambulatory urodynamics tests are time-consuming, most patients tolerate this well and all are happy that a correct urodynamic diagnosis can be provided and hence the most appropriate treatment offered. within the united kingdom health care system, invasive treatment options such as intravesica l botulinum toxin and sacral neuromodulation are offered only after a proven urodynamic diagnosis of do. at our centre we do not treat patients who have mild sui demonstrated on conventional uds if this does not correlate with their main presenting urinary symptom. our auds results demonstrated do and uui in 6 of the 8 patients who had symptomatically contradictory sui on conventional uds; therefore, auds ensured the patients were treated correctly and prevented any unnecessary surgical intervention for sui which would not have resolved their predominant urinary symptom. in the 21% of patients who did not have their urodynamic diagnosis changed following auds, a change in clinical diagnosis and management was effected in 56%. management was also changed in 50% of the patients in whom auds changed neither urodynamic nor clinical diagnosis. this is most likely due to increased clinician and patient confidence in the urodynamic and clinical diagnosis and hence treatment. previous studies have demonstrated satisfactory clinical outcomes in 40%[9] to 42%[8] of patients following treatment modification after auds. our higher rates of treatment modification following auds resulted in 79% of our patients having symptomatic improvement fol low ing auds-initiated cha nges in diagnosis a nd treat ment. this sy mptomatic improvement was a statistically significant reduction in day and night frequency, urgency, uui, sui, poor flow, strain void, and pain on voiding. pre-auds patients had a median of 4 symptoms (range 2 to 10), and postauds patients had a median of 0 symptoms (range 0 to 5). prior to auds, patients were having no or maximal conservative treatment for their “clinical” diagnosis. our confidence in the post-auds urodynamic and clinical diagnosis allowed for effective change in treatment and hence significant symptom improvement. there are some limitations to this study. whilst this was a retrospective study, it was of a prospectively acquired urodynamics database and of all consecutive patients having auds during our study time period. conclusion auds was able to provide a urodynamic diagnosis in 98% of patients. this resulted in a change in clinical diagnosis and subsequent change in treatment pathway in 82% of patients. this study confirms the diagnostic and clinical value of auds and is the first to clearly show an 79% improvement in patient reported symptoms as a consequence. 360 siuj • volume 2, number 6 • november 2021 siuj.org original research references 1. rosier p, schaefer w, lose g, goldman hb, guralnick m, eustice s, et al. international continence society good urodynamic practices and terms 2016: urodynamics, uroflowmetry, cystometry, and pressureflow study. neurourol urodyn.2017;36(5):1243–1260. 2. excellence nioc. urinary incontinence and pelvic organ prolapse in women: management (ng123) 2019. available at: https://www.nice. org.uk/guidance/ng123.accessed september 17, 2021. 3. radley sc, rosario dj, chapple cr, farkas ag. conventional and ambulatory urodynamic findings in women with symptoms suggestive of bladder overactivity. j urol.2001;166(6):2253–2258. 4. dokmeci f, seval m, gok h. comparison of ambulator y versus conventional urodynamics in females with urinary incontinence. neurourol urodyn.2010;29(4):518–521. 5. digesu ga, gargasole c, hendricken c, gore m, kocjancic e, khullar v, et al. ics teaching module: ambulatory urodynamic monitoring. neurourol urodyn.2017;36(2):364–367. 6. abrams ph, griffiths dj. the assessment of prostatic obstruction from urodynamic measurements and from residual urine. br j urol.1979; 51(2):129–134. 7. solomon e, yasmin h, duffy m, rashid t, akinluyi e, greenwell tj. developing and validating a new nomogram for diagnosing bladder outlet obstruction in women. neurourol urodyn.2018;37(1):368–378. 8. pannek j, pieper p. clinical usefulness of ambulatory urodynamics in the diagnosis and treatment of lower urinary tract dysfunction. scand j urol nephrol.2008;42(5):428–432. 9. gorton e, stanton s. ambulatory urodynamics: do they help clinical management? bjog.2000;107(3):316–319. 10. cantu h, sharaf a, bevan w, hassine a, hashim h. ambulatory urodynamics in clinical practice: a single centre experience. neurourol urodyn.2019;38(8):2077–2082. 11. patravali n. ambulatory urodynamic monitoring: are we wasting our time? j obstet gynaecol.2007;27(4):413–415. 12. robertson as, griffiths c, neal de. conventional urodynamics and ambulatory monitoring in the definition and management of bladder outflow obstruction. j urol.1996;155(2):506–511. 13. rademakers kl, drossaerts jm, rahnama'i ms, van koeveringe ga. differentiation of lower urinary tract dysfunctions: the role of ambulatory urodynamic monitoring. int j urol.2015;22(5):503–507. 14. drossaerts j, rademakers klj, rahnama'i sm, marcelissen t, van kerrebroeck p, van koeveringe g. the value of ambulatory urodynamics in the evaluation of treatment effect of sacral neuromodulation. urol int.2019;102(3):299–305. 15. oh sj, son h, jeong jy, ku jh. patients' experience with ambulator y urodynamics. a prospective study. scand j urol nephrol.2006;40(5):391–396. 16. anders k, cardozo l, ashman o, khullar v. morbidity after ambulatory urodynamics. neurourol urodyn.2002;21(5):461–463. 361siuj.org siuj • volume 2, number 6 • november 2021 ambulatory urodynamic findings change patient outcomes key words competing interests article information urethral stricture, dilatation, drug-coated balloon, paclitaxel, lower urinary tract symptoms the study was sponsored and funded by urotronic inc. received on july 28, 2021 accepted on september 2, 2021 this article has been peer reviewed. soc int urol j. 2022;3(1):21–27 doi: 10.48083/mlxk5817 21siuj.org siuj • volume 3, number 1 • january 2022 this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. original research one-year outcomes of the robust ii study evaluating the use of a drug-coated balloon for treatment of urethral stricture jessica m. delong,1 michael j. ehlert,2 bradley a. erickson,3 kaiser j. robertson,4 ramón virasoro,1 sean p. elliott5 1 urology of virginia, virginia beach, united states 2 metro urology, a division of minnesota urology, woodbury, united states 3 department of urology, university of iowa, iowa city, united states 4 chesapeake urology, hanover, united states 5 department of urology, university of minnesota, minneapolis, united states abstract objectives to report 1-year results of the robust ii study investigating the safety and efficacy of a paclitaxelcoated balloon for the treatment of recurrent urethral strictures. methods subjects were adult men with a single anterior urethral stricture ≤ 3 cm in length and at least 2 prior stricture treatments. after treatment with the optilume urethral drug-coated balloon (dcb), subjects were followed through 1 year. the primary safety endpoint was the rate of treatment-related serious complications at 90 days postprocedure. efficacy outcomes included symptomatic assessments, erectile function measured using the international index of erectile function (iief), qmax, and anatomic success. results sixteen men with an average of 4.1 prior dilations were treated with the dcb. anatomic success was achieved at 6 months in 73%. average ipss improved from 18.4 to 6.0 at 1 year (p < 0.001). qmax improved from 6.9 ml/sec to 20.8 ml/sec (p < 0.001). there was no change in iief. four subjects received additional treatment within 1 year. there were no treatment-related serious complications. conclusions short-term follow-up of men with urethral stricture treated with the optilume dcb showed durable anatomic results at 6 months and sustained symptomatic improvement through 1 year. treatment with the device was safe. introduction urethral stricture disease occurs in approximately 0.6% of men[1]. formation of scar tissue leads to narrowing of the urethral lumen resulting in obstructive lower urinary tract symptoms (luts) and associated morbidities that negatively impact patient quality of life[1]. several treatment options are available for stricture, including rigid rod or balloon dilation, direct visual urethrotomy (dviu), and urethroplasty[2]. although dilation and dviu are widely used for stricture treatment, durability is poor, with long-term stricture-free rates estimated between 8% and 30% after a single treatment[3–5]. furthermore, multiple treatments of the same stricture lead to progressively worse outcomes, with success rates approaching 0% at 2 years after a third treatment. urethroplasty is recommended for patients with recurrent strictures or strictures > 2 cm long and has reported success rates > 80% depending on approach and stricture characteristics[6]. http://siuj.org mailto:jdelong%40urologyofva.net?subject=siuj safe and durable minimally invasive solutions for stricture treatment are needed given the lack of long-term benefit from endoscopic procedures. the optilume urethral drug-coated balloon (urotronic, inc., plymouth, mn, us) is the first drug-coated balloon (dcb) developed for the management of urethral stricture disease. the device combines mechanical balloon dilation for immediate symptomatic relief with the localized delivery of paclitaxel to maintain long-term urethral patency. paclitaxel acts to inhibit cell division thereby preventing new tissue growth and scar tissue formation that can lead to stricture recurrence. the optilume dcb was initially evaluated in 53 patients in latin america in the robust i study, which showed symptomatic improvement through 2 years after treatment in men with urethral strictures ≤ 2 cm long and an average of 1.7 prior dilations[7,8]. at 2 years, 70% of subjects had an improvement in international prostate symptom score (ipss) of at least 50% without retreatment[7]. the robust ii trial was conducted to gain initial experience with the device in the united states and in patients with longer strictures (≤ 3 cm). materials and methods study design robust ii is an industry sponsored prospective, multicenter, non-randomized, open label study designed to assess the safety and efficacy of the optilume dcb for the treatment of anterior urethral stricture at 5 investigational sites in the united states (clinicaltrials. gov: nct03270384). institutional review board approval was obtained for all study sites. a baseline retrograde urethrogram was performed to obtain urethral and stricture measurements used to inform balloon size selection and define stricture characteristics. balloons with diameters of 18f, 24f, and 30f and lengths of 30 and 50 mm were available for use. per physician discretion, strictures were dilated directly with the optilume dcb or pre-dilated with an uncoated balloon, rigid rods, or dviu. the selected dcb was inflated to the rated burst pressure and held for at least 5 minutes (figure 1). a 12f or 14f foley catheter was inserted after treatment. subject follow-up occurred at foley removal (2 to 5 days), 30 days, 90 days, 6 months, and 1 year. study population subjects included adult men with a single anterior urethral stricture ≤ 3 cm in length with lumen diameter < 12f, at least 2 prior endoscopic treatments of the stricture, bothersome luts, ipss ≥ 13, and peak urinary flow (qmax) < 15 ml/sec. self-catheterization was not considered a prior dilation. patients were excluded if they had prior urethroplasty, radical prostatectomy, pelvic radiation, artificial urinary sphincter or urethral stent, or stricture dilation or incision within 6 weeks. additional exclusions were diagnosis of lichen sclerosus, urinary stone passage within 6 weeks, chronic renal failabbreviations dcb drug-coated balloon dviu direct vision internal urethrotomy iief international index of erectile dysfunction ipss international prostate symptom score luts lower urinary tract symptoms prom patient-reported outcome measure pvr post-void residual qmax peak urinary flow figure 1. dcb alignment utilizing fluoroscopy a b c a. retrograde urethrogram showing bulbar stricture b. markers visible across the stricture c. balloon inflated across stricture 22 siuj • volume 3, number 1 • january 2022 siuj.org original research http://siuj.org ure, neurogenic bladder, and history of carcinoma of the bladder or prostate within the last 5 years. eight of the 16 subjects had exhibited stricture recurrence within 6 months prior to enrollment. written informed consent was obtained from all subjects prior to study specific assessments. study endpoints the primary safety endpoint was the rate of treatment-related serious complications at 90 days defined as a composite of formation of fistula, new strictures requiring intervention, unresolved de novo stress urinary incontinence requiring > 1 pad/day, and urethral rupture. any change in sexual function was evaluated using the “overall satisfaction” domain of the international index of erectile function (iief). efficacy endpoints included ipss, anatomic success at 6 months, a urethral stricture-specific patient-reported outcome measure (prom)[9], qmax, and freedom from repeat intervention. the ipss responder rate was defined as the percent of subjects with ≥ 50% improvement in ipss without repeat treatment. anatomic success was assessed by the ability to pass a 16f flexible cystoscope through the treatment site. subjects re-treated with the study device or who received other treatment for their stricture prior to the 6-month visit were considered failures for the anatomic success and repeat intervention endpoints. pain was assessed using the visual analog scale (vas) before and after treatment. adverse events were adjudicated by the study medical monitor. statistical methods an intent-to-treat analysis was performed for all endpoints using a complete case approach with no imputation for missing data. descriptive statistics were used for data summaries including mean and standard deviation for continuous variables and percentages or proportions for categorical measures. the significance of improvements from baseline were assessed using a 2-sided student t test, in which p < 0.05 indicated significance. results the study enrolled 16 subjects from december 2017 to april 2019, and all were treated with the optilume dcb. nine subjects completed the 1-year follow-up visit. four subjects exited prior to or at the 6-month visit (3 treatment failures, 1 withdrawn consent), and 3 did not complete the 1-year visit (2 due to covid-19 pandemic and 1 was re-treated with the optilume dcb just prior to the 1-year visit). baseline characteristics and treatment procedure the study cohort included men with an average age of 63.8 years and 4.1 prior dilations of the treated stricture (table 1). stricture etiology was idiopathic (68.8%), traumatic (18.8%), or iatrogenic (12.5%). all subjects had bulbar strictures with an average length of 2.1 cm and urethral diameter of 2.3 mm. ten subjects underwent direct dilation with the optilume dcb, and 6 were predilated with an uncoated balloon or dviu. the dcb diameter used was 30f in 14/16 subjects (87.5%) and 24f in 2/16 subjects (12.5%), per surgeon discretion. subjects experienced minimal pain after the procedure, with mean vas scores of 1.7 ± 2.3 at baseline, 2.0 ± 2.0 at treatment, 1.1 ± 1.2 at foley removal, and 0.3 ± 0.6 at 30 days. safety a total of 21 adverse events in 10 subjects were reported in the study, most frequently urinary tract infection in 12.5% (2/16) and hematuria in 18.8% (3/16). the majority of the events (85.7%, 18/21) were clavien-dindo grade i-ii (table 2). none of the subjects experienced a serious treatment-related complication through 90 days postprocedure (0/16, 0.0%). grade iii events included 1 event 23siuj.org siuj • volume 3, number 1 • january 2022 one-year outcomes of the robust ii study evaluating the use of a drug-coated balloon for treatment of urethral stricture table 1. baseline characteristics and procedure type variable mean ± sd or n (%) age, years 63.8 ± 15.7 stricture etiology iatrogenic 2 (12.5) idiopathic 11 (68.8) traumatic 3 (18.8) stricture measurements length, cm 2.1 ± 0.7 urethral diameter at stricture, mm 2.3 ± 0.9 urethral diameter distal to stricture, mm 10.5 ± 5.2 number of prior dilations 4.1 ± 4.9 procedure type direct dcb dilation 10 (62.5) pre-dilation with uncoated balloon or dviu 6 (37.5) direct dcb dilation with post-dilation 0 (0.0) http://siuj.org each of bronchiectasis, coronary artery stenosis, and hematuria (post 3-month urethrogram). all grade iii events resolved within 2 weeks of onset, and none were related to the study device. there were 4 device-related events: 2 mild events of hematuria, 1 case of mild bladder spasms, and 1 case of acute urinary retention within 24 hours of foley catheter removal. all 4 events resolved without sequelae within a month of onset. there was no negative impact on sexual function through 1 year following treatment with the optilume dcb (table 2). the average iief score improved from 6.7 at baseline to 7.3 at 1 year (p = 0.596). efficacy efficacy outcome measures showed sustained improvement through 1 year post-procedure (table 3). the average ipss decreased from 18.4 at baseline to 7.5 at 90 days, 7.0 at 6 months, and 6.0 at 1 year (p < 0.001). the ipss responder rate was 75.0% (12/16) at 30 days and 61.5% (8/13) at 1 year. the average prom score also improved after the procedure, decreasing from 10.8 at baseline to 3.6 at 90 days, 4.2 at 6 months, and 4.3 at 1 year (p < 0.001). quality of life as measured by ipss qol improved from 4.4 at baseline to 1.4 at 1 year (p < 0.001). voiding function measured by qmax and post-void residual (pvr) urine volume also improved. average peak urinary flow increased from 6.9 ml/sec at baseline to 18.9 ml/sec at 3 months, 16.5 ml/sec at 6 months, and 20.8 ml/sec at 1 year (p < 0.001). the pvr volume improved from 187.1 ml at baseline to 79.3 ml, 59.5 ml, and 66.4 ml at 3 months, 6 months, and 1 year respectively, although the decrease was not statistically significant (p = 0.134). the anatomic success rate at 6 months was 73.3% (11/15). one subject did not have a cystoscopy performed at their 6-month visit and is considered missing for this analysis. of the 13 subjects who completed the 6-month cystoscopy, 2 were considered failures. two additional subjects were considered failures due to recurrence of their stricture requiring repeat treatment prior to the 6-month visit (1 re-treated with optilume dcb, 1 urethroplasty). the rate of anatomic success was not significantly impacted by the decision to directly dilate with the dcb or pre-dilate prior to dcb. the subgroup of subjects treated with direct dcb exhibited an anatomic success rate of 77.8% (7/9), while the anatomic success rate in those subjects receiving pre-dilation with uncoated balloon or dviu was 66.7% (4/6). a total of 4 subjects received repeat treatment through 1 year, resulting in a rate of freedom from repeat intervention of 73.3% (11/15). two subjects were re-treated with the dcb, and 2 subjects underwent urethroplasty. discussion results of the robust ii study showed that treatment of recurrent anterior urethral stricture with the minimally invasive optilume dcb was safe and achieved durable anatomic results at 6 months, with sustained reduction in severity of luts through 1 year. the study cohort represents a refractory population that is associated with poor endoscopic treatment 24 siuj • volume 3, number 1 • january 2022 siuj.org original research table 2. adverse events adverse events events (n) subjects n/n (%) clavien-dindo grade 1 10 8/16 (50) hematuria 2 2/16 (12.5) abdominal pain 1 1/16 (6.3) bladder spasm 1 1/16 (6.3) flank pain 1 1/16 (6.3) oropharyngeal pain 1 1/16 (6.3) pelvic pain 1 1/16 (6.3) shortness of breath 1 1/16 (6.3) urethral false passage 1 1/16 (6.3) urinary retention (acute) 1 1/16 (6.3) clavien-dindo grade 2 8 3/16 (18.8) urinary tract infection 4 2/16 (12.5) bronchiectasis 1 1/16 (6.3) hematuria 1 1/16 (6.3) urinary frequency 2 1/16 (6.3) clavien-dindo grade 3a 1 1/16 (6.3) epididymitisa 1 1/16 (6.3) clavien-dindo grade 3b 2 1/16 (6.3) coronary artery stenosisb 1 1/16 (6.3) hematuriac 1 1/16 (6.3) a pre-existing spermatocele necessitating spermatocelectomy, not study-related b coronary stent placement prior to 3-month followup, not study-related c hematuria onset after planned 3-month urethrography, not study-related http://siuj.org 25siuj.org siuj • volume 3, number 1 • january 2022 one-year outcomes of the robust ii study evaluating the use of a drug-coated balloon for treatment of urethral stricture table 3. results summary measure baseline 30 days 3 months 6 months 1 year ipss n 16 16 16 14 9 mean ± sd 18.4 ± 4.9 7.2 ± 5.3a 7.5 ± 6.4a 7.0 ± 6.7a 6.0 ± 6.1a range 11–28 1–18 1–19 0–19 1–21 median 18.0 5.5 5.5 4.5 5 ipss qol n 16 16 16 14 9 mean ± sd 4.4 ± 1.3 1.5 ± 1.5a 1.8 ± 1.8a 1.6 ± 1.5a 1.4 ± 1.5a range 3–6 0–5 0–6 0–5 0–4 median 4.0 1.0 1.0 1.5 1.0 qmax (ml /sec) n 16 13 15 13 9 mean ± sd 6.9 ± 3.7 16.9 ± 8.7a 18.9 ± 16.4a 16.5 ± 10.2a 20.8 ± 9.1a range 2.0–14.7 5.9–38.1 4.0–53.0 3.2–37.0 6.0–40.5 median 5.6 15.0 14.0 18.0 20.0 pvr (ml) n 16 16 15 14 9 mean ± sd 187.1 ± 227.1 84.4 ± 75.5 79.3 ± 80.3 59.5 ± 65.0a 66.4 ± 57.5 range 0.0–846.0 0.0–254.0 0.0–284.0 0.0–119.0 0.0–186.0 median 95.0 86.5 61.0 65.0 54.0 prom n 16 16 16 13 8 mean ± sd 10.8 ± 3.4 4.4 ± 4.4a 3.6 ± 3.6a 4.2 ± 3.6a 4.3 ± 4.0a range 5–18 0–17 0–12 0–10 0–11 median 10.5 3.5 3.0 4.0 3.5 iief n 16 16 16 14 9 mean ± sd 6.7 ± 2.9 6.4 ± 2.9 6.9 ± 3.1 7.5 ± 2.9 7.3 ± 2.8 range 2–10 2–10 0–10 2–10 2–10 median 7.0 7.0 7.0 7.0 8.0 freedom from repeat na na 16/16 13/16 11/15 intervention, n/n (%) (100.0%) (81.3%) (73.3%) ipss responder rate na 12/16 11/16 10/16 8/13 n/n (%) (75.0) (68.8) (62.5) (61.5) astatistically significant improvement from baseline (p < 0.05) http://siuj.org outcomes. subjects had moderate-to-severe luts at baseline with an ipss of 18.4. the majority of subjects (81.3%) had strictures that were ≥ 2 cm long; for these patients, current guidelines recommend urethroplasty as initial treatment given low success rates of dilation or dviu[6]. all subjects had at least 2 prior dilations of the treated stricture and an average of 4.1 prior interventions, meaning treatment with the optilume dcb represented the fifth dilation of the stricture on average. symptom severity as measured by ipss decreased to 6.0 at 1 year, indicating that subjects were experiencing mild symptoms post-treatment. this represents an average improvement in ipss of 12.4 points (67.4%) and is clinically meaningful based on a minimal clinically important difference of 6 points for patients with severe luts[10]. changes in the prom score for anterior urethral stricture mirrored the ipss, with an average of 10.8 at baseline improving to 4.3 at 1 year, representing a change of 60.2%. improvement in subjective symptom measures were accompanied by improvement in objective measures of voiding function. the average qmax improved 201.4%, from 6.9 ml/sec at baseline to 20.8 ml/sec at 1 year (p < 0.001). peak flow at 1 year was higher than the 15 ml/sec typically used to define patients free from clinically significant stricture recurrence. further, the observed reductions in pvr urine volume showed that more complete voiding could be achieved after treatment with the optilume dcb. flexible cystoscopy demonstrated an anatomic success rate of 73% at 6 months. despite these subjects having longer stricture lengths and a higher number of prior failed treatments, this was similar to the anatomic success rate previously reported in robust i of 76% at the same time point[8]. in contrast, published success rates for dilation or urethrotomy after 3 repeat dilations is around 20% to 30% at 6 months, which decreases to 0% at 24 months[3,5]. median time to stricture recurrence with endoscopic treatment is 6 to 12 months; for patients with 3 treatments, the median time to recurrence has been reported to be about 4.5 months[3]. results for the initial 6-month period following treatment are critical because a hazard function analysis showed that the risk of stricture recurrence after endoscopic treatment is greatest at 6 months[11]. the 6-month timepoint was therefore chosen in this study to assess anatomic success. data collected to date support the safety of the device and procedure. adverse events were generally mild and resolved shortly after onset. most events were associated with urethral stricture disease or were common post urinary intervention. erectile function was not affected by treatment. the advantages of dilation or dviu are hampered by low long-term success rates. multiple groups have investigated the use of antifibrotic agents to augment traditional urethrotomy in an attempt to achieve the durability of open urethroplasty[12]. two small randomized controlled trials have investigated urethrotomy with or without triamcinolone intralesional injection with mixed results; one study showed a lower rate of stricture recurrence in the triamcinolone treated group and the other study showed no difference between groups in the rate of stricture recurrence[13,14]. mitomycin c as well as hyaluronic acid and carboxymethylcellulose have also been evaluated in small randomized controlled trials showing encouraging results, although long-term follow-up is lacking and the safety of mitomycin c has recently been questioned[15–18]. indeed, even the combination of all 3 drugs has been proposed as a potential treatment[19]. to date, there is a lack of robust evidence to support adjunctive treatment with steroids, mitomycin c, or hyaluronidase. one potential advantage of a drug-coated balloon is the ability to deliver the drug more evenly around the circumference and along the length of the stricture, as compared with multiple manual injections of antifibrotic agents. the optilume dcb procedure is minimally invasive, has low complication rates, and leverages current methods of treating stricture. the potential to treat longer strictures with minimally invasive procedures would allow more patients access to interventions with intentto-cure and with lower associated morbidity. in contrast to robust i, subjects in robust ii could undergo direct dcb treatment without prior stricture dilation with an uncoated balloon or dviu. the rate of anatomic success at 6 months for subjects treated directly with the dcb was similar to the rate for those treated with pre-dilation. data reported previously in an animal model show urethral concentration of paclitaxel dropping by 73% at 7 days post-procedure, and low serum levels at all time points[7]. there were several important limitations in this early phase study. the open label study lacked a control arm, and the sample size was small. patients with higher risk of stricture recurrence, including those with bladder neck contractures, prior radiotherapy, or lichen sclerosus were excluded from the study; it is unknown how the dcb treatment would have performed in these subgroups. this small study was intended as an initial evaluation of the safety and efficacy of the therapy in the united states before initiation of the robust iii randomized controlled pivotal trial which is ongoing. finally, while the 1-year outcomes of this study are encouraging, longer follow-up is required to assess treatment durability with the optilume dcb. follow-up is expected up to 5 years and results from robust i have already shown a functional treatment success rate of 70% at 2 years[7]. 26 siuj • volume 3, number 1 • january 2022 siuj.org original research http://siuj.org conclusions early results of the robust ii study showed that treatment of recurrent male anterior urethral stricture with the optilume dcb was safe and showed durable anatomic results at 6 months and sustained symptomatic improvement through 1 year. data are preliminary, and follow-up to 5 years is planned. references 1. santucci ra, joyce gf, wise m. male urethral stricture disease. j urol.2007;177(5):1667–1674. doi: 10.1016/j.juro.2007.01.041. 2. verla w, oosterlinck w, spinoit af, waterloos m. a comprehensive review emphasizing anatomy, etiology, diagnosis, and treatment of male urethral stricture disease. biomed res int.2019;2019:9046430. doi: 10.1155/2019/9046430. 3. heyns cf, steenkamp jw, de kock ml, whitaker p. treatment of male urethral strictures: is repeated dilation or internal urethrotomy useful? j urol.1998;160(2):356–358. doi: 10.1016/s0022-5347(01)62894-5. 4. bullock tl, brandes sb. adult anterior urethral strictures: a national practice patterns survey of board certified urologists in the united states. j urol.2007;177(2):685–690. doi: 10.1016/j.juro.2006.09.052. 5. santucci r, eisenberg l. urethrotomy has a much lower success rate than previously reported. j urol.2010;183(5):1859–1862. doi: 10.1016/j. juro.2010.01.020. 6. wessells h, angermeier k w, elliott s, gonzalez cm, kodama r, peterson ac, et al. male urethral stricture: american urological association guideline. j urol.2017;197(1):182–190. doi: 10.1016/j. juro.2016.07.087. 7. mann ra, virasoro r, delong jm, estrella re, pichardo m, lay rr, et al. a drug-coated balloon treatment for urethral stricture disease: two-year results from the robust i study. can urol assoc j.2020. doi: 10.5489/cuaj.6661. 8. virasoro r, delong jm, mann ra, estrella re, pichardo m, lay rr, et al. a drug-coated balloon treatment for urethral stricture disease: interim results from the robust i study. can urol assoc j.2020;14(6):187–191. doi: 10.5489/cuaj.6323. 9. jackson mj, sciberras j, mangera a, brett a, watkin n, n'dow j m, et al. defining a patient-reported outcome measure for urethral stricture surgery. eur urol.2011;60(1):60–68. doi: 10.1016/j.eururo.2011.03.003. 10. barry mj, williford wo, chang y, machi m, jones km, walker-corkery e, et al. benign prostatic hyperplasia specific health status measures in clinical research: how much change in the american urological association symptom index and the benign prostatic hyperplasia impact index is perceptible to patients? j urol.1995;154(5):1770–1774. doi: 10.1016/s0022-5347(01)66780-6. 11. steenkamp jw, heyns cf, de kock ml. internal urethrotomy versus dilation as treatment for male urethral strictures: a prospective, randomized comparison. j urol.1997;157(1):98–101. doi: 12. shaw nm, venkatesan k. endoscopic management of urethral stricture: review and practice algorithm for management of male urethral stricture disease. curr urol rep.2018;19(3):19. doi: 10.1007/ s11934-018-0771-6. 13. tavakkoli tabassi k, yarmohamadi a, mohammadi s. triamcinolone injection following internal urethrotomy for treatment of urethral stricture. urol j.2011;8(2):132–136. doi: 14. mazdak h, izadpanahi mh, ghalamkari a, kabiri m, khorrami mh, nouri-mahdavi k, et al. internal urethrotomy and intraurethral submucosal injection of triamcinolone in short bulbar urethral strictures. int urol nephrol. 2010;42(3):565 –568. doi: 10.1007/ s11255-009-9663-5. 15. mazdak h, meshki i, ghassami f. ef fect of mitomycin c on anterior urethral stricture recurrence after internal urethrotomy. eur urol.2007;51(4):1089 –1092; discussion 92. doi: 10.1016/j. eururo.2006.11.038. 16. chung jh, kang dh, choi hy, jeong ty, ha us, han jh, et al. the effects of hyaluronic acid and carboxymethylcellulose in preventing recurrence of urethral stricture after endoscopic internal urethrotomy: a multicenter, randomized controlled, single-blinded study. j endourol.2013;27(6):756–762. doi: 10.1089/end.2012.0613. 17. ali l, shahzad m, orakzai n, khan i, ahmad m. efficacy of mitomycin c in reducing recurrence of anterior urethral stricture after internal optical urethrotomy. korean j urol.2015;56(9):650–655. doi: 10.4111/ kju.2015.56.9.650. 18. redshaw jd, broghammer ja, smith tg, 3rd, voelzke bb, erickson ba, mcclung cd, et al. intralesional injection of mitomycin c at transurethral incision of bladder neck contracture may offer limited benefit: turns study group. j urol.2015;193(2):587–592. doi: 10.1016/j.juro.2014.08.104. 19. kumar s, garg n, singh sk, mandal ak. efficacy of optical internal urethrotomy and intralesional injection of vatsala-santosh pgi tri-inject (triamcinolone, mitomycin c, and hyaluronidase) in the treatment of anterior urethral stricture. adv urol.2014;2014:192710. doi: 10.1155/2014/192710. 27siuj.org siuj • volume 3, number 1 • january 2022 one-year outcomes of the robust ii study evaluating the use of a drug-coated balloon for treatment of urethral stricture http://siuj.org key words competing interests article information urology, residency training, pandemic, covid–19, coronavirus none declared. received on september 5, 2021 accepted on october 29, 2021 this article has been peer reviewed. soc int urol j. 2022;3(1):33–40 doi: 10.48083/hmpr9995 33siuj.org siuj • volume 3, number 1 • january 2022 this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. review urology residency training during the pandemic: a review of the current literature ioannis glykas,1 panagiotis velissarios stamatakos,1 charalampos fragkoulis,1 mohamad moussa,2 athanasios papatsoris,3 georgios ntoumas,4 athanasios dellis5 1 department of urology, general hospital of athens “g. gennimatas,” athens, greece 2department of urology, al zahraa hospital, university medical center, lebanese university, beirut, lebanon 32nd department of urology, sismanoglio hospital, school of medicine, national and kapodistrian university of athens, athens, greece 4 medical school of athens, national and kapodistrian university of athens, athens, greece 5second department of surgery, aretaieion hospital, school of medicine, national and kapodistrian university of athens, athens, greece abstract background since covid–19 was declared a pandemic on march 11, 2020, health care systems worldwide have been under significant strain. although urology is not on the frontline of care for patients with covid-19, every practicing urologist has been affected by the global outbreak. the objective of this review is to evaluate the impact of covid–19 pandemic on urology residency training programs. methods we reviewed the current evidence on urology residency training during the covid-19 pandemic. relevant databases (medline, scopus, cochrane library) were searched for articles published to june 2021 that included residents’ or directors’ opinions on their residency training programs during the covid-19 crisis. results the literature search identified 72 articles. fifteen studies including more than 2500 residents were eligible for inclusion in the analysis. during the pandemic, learning activities carried out by urology residents have been extensively affected. worldwide, operation volume has decreased, especially for procedures in which residents were directly involved. similarly, there has been a decline in most academic activities, and many studies have reported the negative impact on residents’ mental well-being and lifestyle. on the other hand, the lockdown provided an opportunity to review the current training system and to increase the implementation of tools such as telemedicine and smart-learning surgical skill training programs. conclusions the covid-19 pandemic has resulted in significant changes in urology residency programs worldwide, which have had a negative impact on surgical training and academic activities. residents’ well-being and mental health have also been put at risk. however, this unprecedented situation has also generated new online learning modalities and technological innovations in the field of training in urology. introduction the covid-19 pandemic has led to major changes in medical training worldwide, including a massive reduction of face-to-face medical consultations and a decrease in elective surgical procedures, with many being postponed, sometimes indefinitely[1]. covid-19 has dramatically transformed urologic training for residents and fellows, who make up a large component of expert personnel and who have been redeployed by many hospitals to provide critical care for covid-19 patients [2,3]. http://siuj.org the covid-19 pandemic has had a significant effect on urology residency training programs, which have had to deal with not only the major reduction of residents’ involvement in medical visits and surgeries, but also the decrease of many educational and scientific activities [3,4]. worldwide, urology residents have dealt with major challenges, not only in their medical training but also in their personal lives and their health and well-being. concerns include social distancing, fear of contamination, and/or fear of transmitting the disease to relatives and patients, as well as reduction of income. many studies indicate that, because of this, a significant proportion of urology residents have experienced anxiety and depression disorders during the pandemic[5,6]. the objective of this review is to evaluate the impact of the covid-19 pandemic on clinical and surgical training, educational activities, health, and quality of life of urology residents worldwide, and to consider the residents’ point of view regarding these unprecedented circumstances. materials and methods this is a narrative review. two authors (i.g., p.v.) performed a literature search independently using pubmed/medline, scopus, and the cochrane library for papers published to june 2021, with no language restriction. the search algorithm was constructed using the following terms and their associated mesh terms and boolean operators: “training,” “urology,” “residency,” “covid-19.” duplicate studies were identified and removed. a review of citations within the articles identified additional relevant articles. any disagreements were resolved by a third reviewer (c.f.). the main inclusion criterion was the presence of residents’ or directors’ opinion on their residency training program during the covid-19 pandemic. therefore, all studies in which online resident and director surveys were conducted were included in the analysis. evidence synthesis a literature search revealed a total of 72 reports. fifteen of these (representing 2500 residents) met the inclusion criteria and were selected for analysis (table 1). the study by rosen et al.[3] was based on a 35-item questionnaire that was distributed to urology residency program directors by the society of academic urologists and had a response rate of 45% (65/144). the study reported that reserve employment and redeployment had started in 80% and 26% of the training programs, respectively. sixty percent of the programs reported concerns that residents will not meet case minimums because of covid-19. well-being activities focused on increased communication, while all programs had begun to use videoconferencing, and the majority planned to continue. programs in states with a higher incidence of covid-19 were more likely to report resident redeployment (48% versus 11%, p = 0.002) and exposure to covid-19 positive patients (70% versus 40%, p = 0.03), and were less likely to report concerns regarding residents’ exposure (78% versus 97%, p = 0.02) and personal protective equipment availability (62% versus 89%, p = 0.02)[3]. amparore et al. conducted a 25-item online survey sent to all italian residents one month after the first case of covid-19 in italy[4]. overall, 351 of 577 (60.8%) residents completed the questionnaire. before the covid-19 pandemic, the proportion of residents routinely involved in “clinical” and “surgical” activities ranged from 79.8% to 87.2% and from 49.3% to 73.5%, respectively. in the covid-19 period, the proportion of residents experiencing a severe reduction (> 40%) or complete suppression (> 80%) of training exposure ranged between 41.1% and 81.2% for “clinical” activities and between 44.2% and 62.1% for "surgical" activities. this reduction was even more pronounced for senior residents in their final year of training[4]. the paper by khusid et al.[7] was based on an anonymous, voluntary, 47-question survey sent to all certified urology residency programs in the united states. a total of 356 of the approximately 1800 residents in the united states (20%) responded. results of the study showed that important risk factors regarding mental health outcomes included the perception of access to personal protective equipment, local covid-19 severity, and perception of vulnerable household members. respondents would be more likely to decline redeployment if given the choice if they were not currently redeployed, had children, or had concern regarding ability to reach minimum operative case numbers in urology. respondents were more likely to have concern about reaching a surgical skill level that would allow them to operate independently after residency if elective surgeries were being cancelled and if the residents were in their final 2 years of training[7]. in the paper by busetto et al.[8], 387 of the 577 italian urology residents (67.1%) participated in an anonymous 36-item online survey. participants were categorized as those working only in covid-19 hospitals (and furthermore as “ junior” and “senior” residents) and those working in any of the 3 geographical areas created according to the prevalence of covid-19. the study reported that clinical and learning activities were significantly reduced for the overall group, while working in a covid-19 hospital and having “senior” resident status were independent factors associated with a greater decrease in outpatient activity. despite these facts, the study presented an optimistic point of view, report34 siuj • volume 3, number 1 • january 2022 siuj.org review http://siuj.org table 1. article information on urology residency training programs during the pandemic author month/ year of publication country number of participants comments rosen et al. 11/2020 united states 65 residency programs in the united states 35-item questionnaire distributed to urology residency program directors, exploring residency program changes related to the covid-19 pandemic amparore et al. 8/2020 italy 351 residents 25-item online survey to compare clinical and surgical training activities before and during the covid-19 period khusid et al. 9/2020 united states 332 residents 47-question survey on educational and well-being issues busetto et al. 11/2020 italy 387 residents 36-item online survey concerning clinical/surgical activities, social distancing, distance learning, and telemedicine rasyid et al. 11/2020 indonesia 369 urologists 220 residents cross-sectional questionnaire distributed to all practicing urologists and the chief resident in each center distributed the e-questionnaire to urology residents paesano et al. 7/2020 latin america and spain (18 countries) 148 residents cross-sectional designed, multiple-choice, non-validated, online survey. questionnaire was developed through the cau educacion platform fero et al. 9/2020 united states 64 program directors 106 residents 27-question cross-sectional survey of program directors and residents at accredited united states urology residencies campi et al. 1-2/2021 58 countries worldwide 501 residents from 58 countries cross-sectional, 30-item, web-based survey conducted through twitter, evaluating the urology residents’ perspective on smart-learning modalities abdessater et al. 6-7/2020 france 275 residents anonymous questionnaire evaluating the pandemic added stress, and its negative impact on work and training quality sent to all the members of the french association of urologists in training 35siuj.org siuj • volume 3, number 1 • january 2022 urology residency training during the pandemic: a review of the current literature http://siuj.org ing that the covid-19 era can offer an opportunity to implement innovative solutions that may be part of future urology training[8]. rasyid et al. designed a cross-sectional study based on a web questionnaire[9]. a link was sent to all practicing urologists in indonesia, and the chief residents in each urology center distributed it to urology residents. among residents, the response rate was 220/220 (100%). results showed that 26.8% of the urology residents had been covid-19 patients. meanwhile, trainees reported high rates regarding the availability and use of personal protective equipment. the study concluded that the covid-19 pandemic caused a decline in both outpatient clinic and surgery services[9]. paesano et al.[10] conducted a multiple-choice, online, non-validated survey that was answered by 148 residents from 18 countries in latin america and spain. eighty-two percent of the residents mentioned that their urology department’s activity was significantly reduced, while 15% stated that the urology activity had been completely terminated. only 3% of the participants continued their regular clinical activities. at the same time, 75% of the participants stated that their surgical training had been “completely affected,” and 65% stated that their academic training had been “partially” or “completely affected.” most of the residents supported an extension of their residency period[10]. a cross-sectional survey conducted by fer et al.[11] was distributed among program chiefs and residents at accredited united states urology residency training centers. the responses were reported and compared table 1. article information on urology residency training programs during the pandemic author month/ year of publication country number of participants comments teixeira et al. 1/2021 portugal 43 residents a 30-question online survey sent to all urology residents in portugal to evaluate the reduction of clinical workload and its impact on residency training programs yee et al. 2/2021 hong kong 33 residents institutional data from all urology centers in the hong kong public sector during the covid-19 pandemic were obtained. an online anonymous questionnaire was used to evaluate the impact of covid-19 on resident training prezotti et al. 7–8/2021 brazil 468 residents web-based survey sent to brazilian urology residents from postgraduate years 3 to 5 to collect data on clinical practice, training, and changes after 4 months of covid-19 rajwa et al. 9/2020 poland 229 urologists and urology residents 28-question online survey. the questionnaire evaluated basic demographic and professional characteristics, and the impact of the covid-19 pandemic on everyday work, mental status, and private life degraeve et al. 12/2020 belgium 62 residents self-administered anonymous questionnaire evaluating the risk of burnout in a pandemic situation and its impact on the quality of training sent to the members of the european society of residents in urology of belgium pang et al. 07/2020 european society of residents in urology european urology trainees european society of residents in urology has undertaken a survey on the the impact of covid-19 on european health care and urology trainees 36 siuj • volume 3, number 1 • january 2022 siuj.org review http://siuj.org between those in high versus low covid-19 contamination geographic regions and between program leaders and residents. the response rate was 43% from program leaders and 18% from residents. most residents (83%) claimed that they were participating in the care of covid-19 patients while the majority of participants reported decreased surgical volume (83% to 100%) and decreased size of inpatient resident teams (99%). regarding new technologies, 99% and 95% of participants reported increased use of telemedicine and a transition to virtual educational models, respectively. nevertheless, the article drew attention to the downstream effects of the covid-19 pandemic on urology residents’ training[11]. on the other hand, smart-learning modalities and contents were evaluated in detail by campi et al.[12] in a 30-item, web-based survey conducted through twitter. a total of 501 urology residents from 58 countries participated. more than half of the participants considered pre-recorded videos (78.4%), interactive webinars (78.2%), podcasts (56.9%) and social media (51.9%) as highly useful tools of smart learning. similarly, updates on guidelines and surgical videos were rated highly useful modalities by the 84.8% and 81.0% of the surveyed trainees, respectively. the preferred combination of smart learning included pre-recorded surgical videos, interactive webinars, and pre-recorded videos on guidelines[12]. teixeira et al.[13] evaluated the impact of covid-19 pandemic on urology residents in portugal. a 30-question online survey was sent to all urology trainees, and 54.4% responded to it. in all, 81% stated there had been a significant decrease (more than 75%) in outpatient clinical activity as well as (by 48.8%) diagnostic procedures. participants reported that laparoscopic/robotic, endoscopic, and major open surgeries were decreased by 67.5%, 29.3%, and 17.5%, respectively. as a result, covid-19 had a major impact on urology residency, and many residents (32.6%) considered the need to extend their residency[13]. similarly, yee et al.[14] examined the changes in urology practice and residency during the covid-19 pandemic with a perspective from the authors’ experience of sars in 2003. authors declared reduced numbers of operating sessions (by 40.5%), clinical attendance (by 28.5%), cystoscopy sessions (by 49.6%), prostate biopsy (by 44.8%), and shockwave lithotripsy sessions (by 38.5%). benign prostatic hyperplasia-related surgeries and ureteric stone related procedures were the most commonly delayed, while all centers gave priority to cancer-related procedures. the residents’ survey had a response rate of 48.5% and revealed that training and academic activities were heavily affected by the covid19 pandemic. urology residents’ surgical exposure was significantly hindered, while 53.3% of the respondents had their professional examinations cancelled because of covid-19[14]. a 28-question online national survey designed by rajwa et al.[15] to examine the impact of the covid19 pandemic on polish urologists had a response rate of 28.63% (229 participants). most of the residents (62.0%) claimed that the pandemic had harmed their training. a proportion of participants (38.9%) wanted telemedicine to permanently replace some of the consultations after the pandemic, with residents being significantly more positive about it than urologists (51.4% versus 33.1%). furthermore, the study showed that there was a significantly negative impact on the work, mental health, and private lives of polish urologists[15]. from another point of view, abdessater et al.[5] assessed the psychological impact of the pandemic on young french urologists in training. a self-administered anonymous questionnaire was sent to the members of the french association of urologists in training (afuf) via email. a total of 275 members (55.5%) responded. the study concluded that the covid-19 pandemic had a negative impact on the psychosocial well-being of the participants as more than 90% of the responders felt more stressed during the pandemic. independent factors associated with worsening of psychological condition were past medical history of respiratory disease and caring for covid-19 patients[5]. similarly, prezotti et al.[6] showed that covid-19 has had a significant impact on brazilian urology residents. a web-based survey was sent to 468 urology trainees in postgraduate years 3 to 5. major reductions in patient consultations, diagnostic procedures, and surgeries were reported, while the median damage to urological training was 6.0 (on a scale from 0 to 10). changes in health and lifestyle included weight gain (43.8%), reduced physical activity (68.6%), increased alcoholic intake (44.9%) and cigarette consumption (53.6%), decreased sexual satisfaction (25.2%), and feelings of sadness or depression (48.2%)[6]. a different perspective is highlighted in a survey by degraeve et al.[16]. a self-administered anonymous questionnaire based on the copenhagen burnout inventory score was emailed to the members of the european society of residents in urology of belgium (esru-b) with a response rate of 50% (62 participants). even though 93% of the responders mentioned a negative impact of the crisis on their practical training, most of the participants reported a positive impact on their life (56%) and their theoretical training (61.7%), with a significantly reduced burnout risk score. the authors report, therefore, that the lockdown did not have negative psychological impact on belgian residents in urology[16]. 37siuj.org siuj • volume 3, number 1 • january 2022 urology residency training during the pandemic: a review of the current literature http://siuj.org finally, a survey undertaken by the european society of residents in urology indicates that the pandemic has negatively affected the training of urology residents because of the loss of surgical exposure and inability to complete core surgical procedures. it was noted that smart-learning modalities are valuable in maintaining the learning curve of residents[17]. discussion the unprecedented scenario of covid-19 has affected residency training conditions worldwide, forming a challenging environment for both trainers and residents, exacerbated by uncertainty about the duration of the pandemic[18]. the most obvious impact of covid-19 on urology practice has been the reduction of diagnostic procedures and training operations[5,19]. several urological associations and societies have therefore released recommendations to guide the daily clinical and surgical activities of urologists. overall, the recommendations are based on the urgency of each procedure, the available resources of each clinic, and the risks of deferring elective interventions[20]. at the same time, recommendations from a panel of experts from the united states and europe have been published, suggesting a list of surgeries that should be prioritized[21]. as a result, many centers reserved operating room time for cancer cases and complicated stone surgeries, while the number of cystoscopy sessions and prostate biopsies was reduced[10,22]. in addition to the decrease in urological surgical procedures, the european association of urology clinical recommendations suggested that the few non-deferrable surgical procedures (oncological and for life-threatening conditions) that are performed during the pandemic must be carried out by surgeons experienced in each procedure. this resulted in further decrease of resident participation in surgical operations[23]. the common goal of these measurements, as noted by pang et al., was to reduce surgical times and risk of infection and complications, as well as to minimize spread and to free up nursing staff, anesthesiologists, ventilators, personal protective equipment, and beds[24]. with the proper use of personal protective equipment and nasopharyngeal swabs, controlled hospital access, and prompt management of suspected/positive cases, oncological and urgent cases can be managed during the covid-19 pandemic[25]. clinical rounds, inpatient, and outpatient care, as well as curricular and face-to-face academic activities were put on hold[18]. residents and fellows were redeployed to pathology and intensive care units[26]. it has also been reported that in some countries, residents have been advised to stay at home if there were no clinical or ward duties to be fulfilled[27]. this had significant impact on residents’ case diaries, with mandatory training requirements at risk of being unfulfilled[28]. meanwhile, many university laboratories were closed, as, for example, in the united kingdom, where those in phd programs had been asked to return to clinical practice[24]. these delays are likely to have consequences for both clinical and basic science research[13]. moreover, because of the suspension of non-urgent elective surgeries and the limitation of training activities, many residency examinations were postponed, as were many congresses, meetings, and national conferences[18]. fellow of the european board of urology (febu) 2020 and the uk postgraduate fellowship examinations, as well as the european urology residents education program course 2020 were either postponed or cancelled. extending residency programs to meet educational targets is another popular solution to the problem. residents from the last year had their consultant examinations postponed while residency admission examinations were deferred[6]. at the same time, studies reported several independent factors associated with worsening of residents’ mental health during the covid-19 pandemic. inadequate access to personal protective equipment and the redeployment to a “frontline” covid-19 service were associated with higher rates of anxiety among trainees[1]. additionally, a past medical history of respiratory disease, as well as the presence of a household member who was susceptible to covid-19 were associated with a higher degree of reported stress[5]. finally, changes in trainees’ lifestyle during the pandemic included increased alcohol intake and cigarette consumption and decreased sexual satisfaction[6]. another point of view was presented in a belgian study by degraeve et al., which reported a positive impact on residents’ lives and on their theoretical training during the pandemic, with a significantly reduced burnout risk score[16]. furthermore, the pandemic has brought virtual learning options to the fore, as well as alternative resident educational activities in which applications such as zoom and skype enable interaction between residents and experienced physicians[19]. initially, most urologic residency programs converted their standard conferences to digital platforms[29], and urologic educators worldwide have created daily didactic lectures, presented difficult cases on expert panels, and discussed innovative research[30]. several urologic oncologists have held interactive virtual viewings of their robotic surgeries, serving as alternative opportunities for trainees to learn basic surgical techniques[22]. as a result, telemedicine, pre-recorded surgical videos, interactive webinars on clinical cases, and pre-recorded videos on guidelines were implemented and considered as highly useful smart-learning modalities during the pandemic[12]. these modalities do not replace the learning process in an operating room, but they encourage a new educational technology strategy that could be 38 siuj • volume 3, number 1 • january 2022 siuj.org review http://siuj.org incorporated into educational programs in the future. the combination of the collective virtual resources of institutions worldwide may expose residents to a higher quality and more varied education[31]. in addition to maintaining resident training, telemedicine provides the opportunity of counseling patients, thus reducing unnecessary hospital visits and empowering patient selfcare[32]. the use of laparoscopic and robotic simulators and 3d printing of models enables experts in surgical simulation to lead residents through guided surgeries. this can not only help residents develop their surgical skills but also learn techniques or procedures not be performed at their institutions[33]. although distance teaching is still not considered routine, laparoscopic and robotic simulators are especially valuable because of the surgical volume is limited at most academic centers, and the likely duration of the pandemic remains uncertain[30]. these simulators also offer the chance of virtual surgical training in countries where laparoscopy and robot assisted surgery are not currently implemented in the urology residency training programs[34]. conclusions covid-19 may be the greatest challenge health care systems all over the world have faced in the modern era. the covid-19 pandemic has resulted in significant changes with negative impact in the heterogenous field of urology residency training programs worldwide. residents’ concerns are mainly focused on their surgical training, but their well-being and mental health are also at risk. the findings of studies in this paper offer some insight into the development of best practices such as the online training modalities that are now a fundamental tool for continuous updating. references 1. ficarra v, novara g, abrate a, bar tolet ti r, crestani a, de nunzio c, et al. urology practice during the covid-19 pandemic. minerva urol nefrol.2020 jun;72(3):369 –375. doi: 10.23736/ s0393-2249.20.03846-1. 2. stock ja. i was deployed to a covid unit. j pediatr urol.2020 jun;16(3):297–298. 3. rosen gh, murray ks, greene kl, pruthi rs, richstone l, mirza m. effect of covid-19 on urology residency training: a nationwide survey of program directors by the society of academic urologists. j urol.2020 nov;204(5):1039–1045. doi: 10.1097/ju.0000000000001155. epub 2020 may 28. 4. amparore d, claps f, cacciamani ge, esperto f, fiori c, liguori g, et al. impact of the covid-19 pandemic on urology residency training in italy. minerva urol nefrol.2020 aug;72(4):505–509. doi: 10.23736/ s0393-2249.20.03868-0 5. abdessater m, rouprêt m, misrai v, matillon x, gondran-tellier b, freton l, et al. covid-19 pandemic impacts on anxiety of french urologist in training: outcomes from a national survey. prog urol. jun-jul 2020;30(8-9):448–455. doi: 10.1016/j.purol.2020.04.015. epub 2020 apr 23. 6. prezotti ja, henriques jvt, favorito la, canalini af, machado mg, brandão tbv, et al. impact of covid-19 on education, health and lifestyle behaviour of brazilian urology residents. int braz j urol.jul-aug 2021;47(4):753–776. doi: 10.1590/s1677-5538.ibju.2021.99.09 7. khusid ja, weinstein cs, becerra az, kashani m, robins dj, fink le, et al. well-being and education of urology residents during the covid-19 pandemic: results of an american national survey. int j clin pract.2020 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d, checcucci e, claps f, teoh jy-c, serni s,et al. exploring the residents' perspective on smart learning modalities and contents for virtual urology education: lesson learned during the covid-19 pandemic. actas urol esp (engl ed ).jan-feb 2021;45(1):39– 48. doi: 10.1016/j.acuro.2020.08.008. epub 2020 sep 11. 13. teixeira bl, cabral j, mendes g, madenelo m, rocha ma, mesquita s, et al. how the covid-19 pandemic changed urology residency a nationwide survey from the portuguese resident's perspective. cent european j urol.2021;74(1):121–127. doi: 10.5173/ceju.2021.0278.r1. epub 2021 jan 9. 14. yee ch, wong hf, tam mhm, yuen skk, chan hc, cheung mh, et al. effect of sars and covid-19 outbreaks on urology practice and training. hong kong med j.2021 aug;27(4):258–265. epub 26 feb 2021doi.org/10.12809/hkmj208822 39siuj.org siuj • volume 3, number 1 • january 2022 urology residency training during the pandemic: a review of the current literature http://siuj.org 15. rajwa p, przydacz m, zapala 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of urology residents' learning curve during the covid-19 emergency. bju int.2020 jun;125(6):e15–e17. doi: 10.1111/bju.15076. epub 2020 apr 28. 20. amparore d, campi r, checcucci e, sessa f, pecoraro a, minervini a, et al. forecasting the future of urology practice: a comprehensive review of the recommendations by international and european associations on priority procedures during the covid-19 pandemic. eur urol focus.2020 sep 15;6(5):1032–1048. doi: 10.1016/j.euf.2020.05.007. epub 2020 may 31. 21. tan yq, lu j, chiong e. re: kristian d. stensland, todd m. morgan, alireza moinzadeh, et al. considerations in the triage of urologic surgeries during the covid-19 pandemic. eur urol.2020;77:663–666: the forgotten urological patient during the covid-19 pandemic: patient safety safeguards. eur urol.2020 sep;78(3):e135–e136. 22. westerman me, tabakin al, sexton wj, chapin bf, singer ea. impact of covid-19 on resident and fellow education: current guidance and future opportunities for urologic oncology training programs. urol oncol.2021 jun;39(6):357–364. doi: 10.1016/j.urolonc.2020.09.028. epub 2020 sep 30. 23. thomas c, grüllich c, erb hh. re: ribal mj, cornford p, briganti a, knoll t, gravas s, babjuk m, et al. european association of urology guidelines office rapid reaction group: an organisation-wide collaborative effort to adapt the european association of urology guidelines recommendations to the coronavirus disease 2019 era. eur urol focus.2020;78(1):21–28. doi: 10.1016/j.eururo.2020.04.056: metastatic prostate cancer and covid-19: do current data allow modification of established treatment recommendations? eur urol focus.2020 sep 15;6(5):1135–1136. doi: 10.1016/j.euf.2020.05.018 24. meyer c, kaulfuss j, grange p. re: karl h. pang, diego m. carrion, juan gomez rivas, et al. the impact of covid-19 on european health care and urology trainees. eur urol.2020:78;6–8. eur urol.2020 dec;78(6):e236. doi: 10.1016/j.eururo.2020.04.042 25. esperto f, prata f, civitella a, pang kh, marchioni m, tuzzolo p, et al. implementation and strategies to ensure adequate coordination within a urology department during the covid-19 pandemic. int braz j urol.2020 jul;46(suppl.1):170–180. doi: 10.1590/s1677-5538. ibju.2020.s122 26. diokno ac, devries jm. the impact of covid-19 on urologic practice, medical education, and training. int urol nephrol.2020 jul;52(7):1195– 1198. doi: 10.1007/s11255-020-02511-0. epub 2020 may 28. 27. esperto f, papalia r, pang kh, cataldo r, scarpa rm. what is the role of residents during a pandemic? minerva urol nefrol.2020 june;72(3):387–388. doi: 10.23736/s0393-2249.20.03903-x 28. tan yq, wang z, tiong hy, chiong e. the good, the bad, and the ugly of the covid-19 pandemic in a urology residency program in singapore. urology.2020 aug;142:244–245. doi: 10.1016/j.urology.2020.05.027. epub 2020 may 29. 29. smigelski m, movassaghi m, small a. urology virtual education programs during the covid-19 pandemic. curr urol rep.2020 oct 22;21(12):50. doi: 10.1007/s11934-020-01004-y 30. claps f, amparore d, esperto f, cacciamani g, fiori c, minervini a, et al. smart learning for urology residents during the covid-19 pandemic and beyond: insights from a nationwide survey in italy. minerva urol nefrol.2020 dec;72(6):647–649. doi: 10.23736/s0393-2249.20.03921-1. epub 2020 may 20. 31. kwon ys, tabakin al, patel hv, backstrand jr, jang tl, kim iy, et al. adapting urology residency training in the covid-19 era. urology.2020 jul;141:15–19. doi: 10.1016/j.urology.2020.04.065 32. papalia r, cataldo r, alloni r, pang kh, alcini a, flammia g, et al. urologic surgery in a safe hospital during the covid-19 pandemic scenario minerva urol nefrol.2021 june;73(3):384 –391. doi: 10.23736/s0393-2249.20.03923-5. epub 2020 jun 22. 33. tabakin a, patel hv, singer ea. lessons learned from the covid-19 pandemic: a call for a national video-based curriculum for urology residents. j surg educ.jan-feb 2021;78(1):324–326. doi: 10.1016/j. jsurg.2020.07.013 34. tzelves l, glykas i, lazarou l, zabaftis c, fragkoulis c, leventi a, et al. urology residency training in greece. results from the first national resident survey. actas urol esp.2021 jun 10;s0210-4806(21)00092-9. doi: 10.1016/j.acuro.2020.11.008. 40 siuj • volume 3, number 1 • january 2022 siuj.org review http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information urinary bladder neoplasm, diet, vegetarian, systematic review none declared. funding: s.l. is supported by the prostate cancer foundation, and a generous donation from patricia and michael berns. received on october 11, 2021 accepted on march 15, 2022 this article has been peer reviewed. soc int urol j. 2022;3(4):240–244 doi: 10.48083/gbma2534 240 siuj • volume 3, number 4 • july 2022 siuj.org review a systematic review of plant-based diet and bladder cancer: a call for further research jacob taylor,1 natasha gupta,1,2 jaime blanck,3 stacy loeb1,2 1 department of urology, new york university langone health, new york, united states 2 department of population health, new york university langone health and manhattan veteran affairs, new york, united states 3 johns hopkins welch medical library, johns hopkins university, baltimore, united states abstract the relationship between plant-based dietary patterns and bladder cancer has not been extensively studied. our objective was to perform a systematic review of the relationship between plant-based diets and bladder cancer risk and/or outcomes. we searched the literature for all relevant papers published before october 2020. of 74 identified records, only 2 references were included in the final qualitative analysis. these publications found that vegetarian diets are associated with a lower risk of bladder cancer diagnosis. we did not identify any studies investigating the impact of plant-based dietary patterns on outcomes for individuals diagnosed with bladder cancer, which represents an important area for further study. introduction previous studies have examined the relationship between specific foods and bladder cancer risk. a systematic review of modifiable risk factors for bladder cancer reported that consuming more fruits and vegetables was associated with a decreased risk, whereas the consumption of processed meat was associated with an increased risk of bladder cancer[1]. nutritional epidemiology is shifting toward evaluation of dietary patterns[2]. a previous systematic review suggested that the mediterranean diet is associated with lower bladder cancer risk, while the western diet is associated with increased risk[3]. plant-based diets have become increasingly popular, but relatively little is known about their relationship to bladder cancer risk and/or outcomes. therefore, our objective was to perform a systematic review of the relationship between plant-based diets (eg, vegetarian or vegan) and bladder cancer risk and/or outcomes. materials and methods the systematic review was conducted according to the european association of urology methodology, beginning with formulating the research question and writing the protocol, which was registered with prospero (id crd42020214023). we then conducted a search of pubmed, embase, cochrane, scopus, web of science, and amed for all relevant publications up to october 2020. the search terms were vegetarian or vegan diets and mesh term variations for bladder cancer or urothelial carcinoma (see appendix for details). of 74 identified records, 34 were screened after duplicates were removed (figure 1). only 2 references were included in the final qualitative analysis. the quality of evidence was assessed using the criteria outlined by hawker et al.[4], which use 9 question domains with scores ranging from “very poor” (1) to “good” (4), with 36 being the highest score. if multiple publications come from a single study, a composite score is reported including information from all publications. http://siuj.org https://orcid.org/0000-0003-2190-7309 mailto:jacob.taylor.mail%40gmail.com?subject=siuj https://orcid.org/0000-0003-2782-415x https://orcid.org/0000-0002-7235-0857 https://orcid.org/0000-0003-3933-9207 results the first publication by key et al. reported on a large prospective cohort study of 61 566 british men and women[5]. participants completed semi-quantitative food frequency questionnaires and were followed for an average of 12.2 years and were divided into 3 categories: meat eaters, fish eaters (did not eat meat but did eat fish), and vegetarians (did not eat meat or fish). the study population included > 20 000 vegetarians. multivariable models were performed to examine cancer risk after adjustment for potential confounders such as smoking and physical activity. compared with meat eaters, fish eaters had no difference in risk of bladder cancer (rr 0.81; 95% ci 0.36–1.81), but vegetarians had a significantly lower risk of bladder cancer (rr 0.47; 95% ci 0.25–0.89). a follow-up analysis by key et al. similarly found a significantly lower risk of bladder cancer among vegetarians compared with meat eaters (r r 0.62; 95% ci 0.38–0.99), although this was attenuated after adjustment for body mass index[6]. overall, the composite quality rating from both publications was 36, a high-quality rating. discussion overall, our systematic review identif ied only 2 publications from a single prospective uk cohort study that specifically evaluated plant-based dietary patterns and bladder cancer. the limited available evidence suggests a vegetarian diet might be protective against bladder cancer. these findings are not surprising in light of previous studies suggesting an association between higher fruit and vegetable consumption and lower bladder cancer risk, whereas consumption of meat products has been linked with higher risk[1,7]. we did not identify any studies that examined plantbased diets with outcomes among patients diagnosed *texts excluded due to lack of dietary or outcome data. figure 1. prisma flow chart records identi�ed through database searching (n = 74) in cl ud ed s cr ee ni ng records after duplicates removed (n = 34) records screened (n = 34) full-text articles assessed for eligibility (n = 10) studies included in qualitative synthesis (n = 2) records excluded (n = 24) full-text articles excluded, with reasons (n = 8)* additional records identi�ed through other sources (n = 0) es el ig ib il it y id en ti �c at io n 241siuj.org siuj • volume 3, number 4 • july 2022 a systematic review of plant-based diet and bladder cancer: a call for further research http://siuj.org with bladder cancer, representing an important area for future research. although the quantity of evidence is quite small, the quality of evidence that does exist is high based on these 2 publications. the association between diet and risk of cancer has been explored in almost every cancer type. for instance, vieira et al., in a 2017 systematic review, found a 12% increased risk of colorectal cancer for each 100g/day consumption of red and processed meat[8]. there are many potential explanations for this association, including the generation of oxidative stress from heme iron and the carcinogenic effect of n-nitroso compounds and heterocyclic amines[9]. these same compounds may incite the development of bladder cancer, and decreasing the consumption and formation of these toxic compounds could decrease the dwell time of these carcinogens in the urine. a plant-based diet may provide greater antioxidant protection against free radical damage[10]. for instance, selenium, a known antioxidant, was found to be inversely related to bladder cancer risk in a meta-analysis of 7 studies[11]. additional prospective studies are warranted to further explore the impact of plant-based dietary patterns in bladder cancer. conclusion given the importance of identifying modifiable factors that can affect bladder cancer risk and outcomes, our study highlights a great need for more research into the impact of plant-based diets. most previous studies have focused on individual dietary components rather than dietary patterns. observational data suggest that vegetarian diets may be associated with a lower risk of bladder cancer; however, we did not identify any studies investigating the impact of plant-based dietary patterns on oncologic or functional outcomes for individuals already diagnosed with bladder cancer, which represents an important area for further study. references 1. al-zalabani ah, stewart kf, wesselius a, schols am, zeegers mp. modifiable risk factors for the prevention of bladder cancer: a systematic review of meta-analyses. eur j epidemiol.2016;31(9):811–851. doi: 10.1007/s10654-016-0138-6 2. cespedes em, hu fb. dietary patterns: from nutritional epidemiologic analysis to national guidelines. am j clin nutr.2015;101(5):899–900. doi: 10.3945/ajcn.115.110213. epub 2015 apr 1. 3. dianatinasab m, forozani e, akbari a, azmi n, bastam d, fararouei m, et al. dietary patterns and risk of bladder cancer: a systematic review and meta-analysis. bmc public health.2022;22(1):73. doi:10.1186/ s12889-022-12516-2 4. hawker s, payne s, kerr c, hardey m, powell j. apprasing the evidence: reviewing disparate data systematically. qual health res.2002;12(9):1284–1299. doi: 10.1177/1049732302238251 5. key tj, appleby pn, spencer ea, travis rc, allen ne, thorogood m, et al. cancer incidence in british vegetarians. br j cancer.2009;101(1): 192–197. doi: 10.1038/sj.bjc.6605098. epub 2009 jun 16. 6. key tj, appleby pn, crowe fl, bradbury ke, schmidt ja, travis rc. cancer in british vegetarians: updated analyses of 4998 incident cancers in a cohort of 32,491 meat eaters, 8612 fish eaters, 18,298 vegetarians, and 2246 vegans. am j clin nutr.2014;100 (suppl. 1)1:378s–385s. doi: 10.3945/ajcn.113.071266. epub 2014 jun 4. 7. michaud ds, holick cn, giovannucci e, stampfer mj. meat intake and bladder cancer risk in 2 prospective cohort studies. am j clin nutr.2006;84(5):1177–1183. doi: 10.1093/ajcn/84.5.1177 8. vieira ar, abar l, chan dsm, vingeliene s, polemiti e, stevens c, et al. foods and beverages and colorectal cancer risk: a systematic review and meta-analysis of cohort studies, an update of the evidence of the wcrf-aicr continuous update project. ann oncol.2017;28(8):1788– 1802. doi: 10.1093/annonc/mdx171 9. song m, garrett ws, chan at. nutrients, foods, and colorectal cancer prevention. gastroenterology.2015;148(6):1244-1260 e16. doi: 10.1053/j.gastro.2014.12.035. epub 2015 jan 6. 10. world cancer research fund/american institute for cancer research. continuous update project expert report 2018. diet, nutrition, physical activity and bladder cancer. available at: https://www.wcrf.org/ wp-content/uploads/2021/02/bladder-cancer-report.pdf. accessed march 16, 2022. 11. amaral a, cantor k, silverman d, malats n. selenium and bladder cancer risk: a meta-analysis. cancer epidemiol biomarkers prev.2010;19(9):2407-2415. doi: 10.1158/1055-9965.epi-10-0544 242 siuj • volume 3, number 4 • july 2022 siuj.org review http://siuj.org embase 26 citations (“bladder cancer”/exp or “bladder adenocarcinoma” or “ bl a dd er a d eno c a rc i nom a” or “ bl a dd er cancerogenesis” or “ bladder carcinogenesis” or “ bladder carcinoma” or “ bladder diver ticu lum carcinoma” or “ bladder metastasis” or “ bladder cancer” or “transitional cell cancer” or “bladder carcinogen” or “urinary bladder metastasis” or “urothelial cancer” or “urothelial carcinoma” or “vesical cancer” or “vesical carcinomanesis” or “vesical carcinomatosis” or “bladder neoplasm” or “bladder neoplasms” or “bladder tumors” or “bladder tumor” or “malignant tumor of urinary bladder” or “cancer of the bladder” or “bladder cancers” or “transitional cell carcinoma”/exp or “transitional cell cancer” or “transitional cell cancers” or “transitional cell carcinoma” or “transitional cell carcinomas” or “transitional cell tumor” or “transitional cell tumors” or “transitional cell tumour” or “transitional cell tumours” or “urothelial cancer” or “urothelial cancers” or “urothelial carcinoma” or “urothelial carcinomas” or “urothelial cell cancer” or “urothelial cell cancers” or “urothelial cell carcinoma” or “urothelial cell carcinomas”) and (“vegetarian”/ de or “lactoovovegetarian”/exp or “lactovegetarian”/ exp or “vegan”/exp or “vegetarian diet”/de or “fruitarian diet”/exp or “lactovegetarian diet”/exp or “ovovegetarian diet”/exp or “vegan diet”/exp or “plant based” or “plant-based” or “vegan” or “veganism” or “vegans” or “vegetable based” or “vegetarian” or “vegetarianism” or “vegetarians’ or lactoovovegetarian* or lactovegetarian*) pubmed 10 citations (“urinary bladder neoplasms”[mesh] or “bladder adenocarcinoma” or “bladder adenocarcinoma” or “bladder cancerogenesis” or “bladder carcinogenesis” or “bladder carcinoma” or “bladder diverticulum carcinoma” or “ bladder metastasis” or “ bladder cancer” or “transitional cell cancer” or “bladder carcinogen” or “urinary bladder metastasis” or “urothelial cancer” or “urothelial carcinoma” or “vesical cancer” or “vesical carcinomanesis” or “vesical carcinomatosis” or “bladder neoplasm” or “bladder neoplasms” or “bladder tumors” or “bladder tumor” or “malignant tumor of urinary bladder” or “cancer of the bladder” or “bladder cancers” or “carcinoma, transitional cell”[mesh] or “transitional cell cancer” or “transitional cell cancers” or “transitional cell carcinoma” or “transitional cell carcinomas” or “transitional cell tumor” or “transitional cell tumors” or “transitional cell tumour” or “transitional cell tumours” or “urothelial cancer” or “urothelial cancers” or “urothelial carcinoma” or “urot helia l carcinomas” or “urot helia l cell cancer” or “urothelial cell cancers” or “urothelial cell carcinoma” or “urothelial cell carcinomas”) and (“vegetarians”[mesh] or “diet, vegetarian”[mesh] or “vegans”[mesh] or “diet, vegan”[mesh] or “plant based”[tw] or “plant-based”[tw] or “vegan”[tw] or “veganism”[tw] or “vegans”[tw] or “vegans”[tw] or “vegetable based ”[t w] or “vegeta ria n”[t w] or “vegetarianism”[tw] or “vegetarians”[tw] or lactoovovegetarian*[tw] or lactovegetarian*[tw]) cochrane 2 results ([mh “urinary bladder neoplasms”] or “ bladder adenocarcinoma” or “bladder adenocarcinoma” or “bladder cancerogenesis” or “bladder carcinogenesis” or “bladder carcinoma” or “bladder diverticulum carcinoma” or “ bladder metastasis” or “ bladder cancer” or “transitional cell cancer” or “bladder carcinogen” or “urinary bladder metastasis” or “urothelial cancer” or “urothelial carcinoma” or “vesical cancer” or “vesical carcinomanesis” or “vesical carcinomatosis” or “bladder neoplasm” or “bladder neoplasms” or “bladder tumors” or “bladder tumor” or “malignant tumor of urinary bladder” or “cancer of the bladder” or “bladder cancers” or [mh “carcinoma, transitional cell”] or appendix 1. search term strategy search summary embase 26 pubmed 10 cochrane 2 scopus 24 web of science 12 amed 2 total found 74 duplicates 40 grand total 34 243siuj.org siuj • volume 3, number 4 • july 2022 a systematic review of plant-based diet and bladder cancer: a call for further research http://siuj.org “transitional cell cancer” or “transitional cell cancers” or “transitional cell carcinoma” or “transitional cell carcinomas” or “transitional cell tumor” or “transitional cell tumors” or “transitional cell tumour” or “transitional cell tumours” or “urothelial cancer” or “urothelial cancers” or “urothelial carcinoma” or “urot helia l carcinomas” or “urot helia l cell cancer” or “urothelial cell cancers” or “urothelial cell carcinoma” or “urothelial cell carcinomas”) and ([mh “vegetarians”] or [mh “diet, vegetarian”] or [mh “vegans”] or [mh “diet, vegan”] or “plant based” or “plant-based” or “vegan” or “veganism” or “vegans” or “vegans” or “vegetable based” or “vegetarian” or “vegetarianism” or “vegetarians” or lactoovovegetarian* or lactovegetarian*) scopus 24 results title-abs-k ey((“ bladder adenocarcinoma” or “bladder adenocarcinoma” or “bladder cancerogenesis” or “bladder carcinogenesis” or “bladder carcinoma” or “bladder diverticulum carcinoma” or “bladder metastasis” or “ bladder cancer” or “transitional cell cancer” or “bladder carcinogen” or “urinary bladder metastasis” or “urot helia l cancer” or “urothelial carcinoma” or “vesical cancer” or “vesical carcinomanesis” or “vesical carcinomatosis” or “bladder neoplasm” or “bladder neoplasms” or “bladder tumors” or “bladder tumor” or “malignant tumor of urinary bladder” or “cancer of the bladder” or “bladder cancers” or “transitional cell cancer” or “transitional cell cancers” or “transitional cell carcinoma” or “transitional cell carcinomas” or “transitional cell tumor” or “transitional cell tumors” or “transitional cell tumour” or “transitional cell tumours” or “urothelial cancer” or “urothelial cancers” or “urothelial carcinoma” or “urothelial carcinomas” or “urothelial cell cancer” or “urothelial cell cancers” or “urothelial cell carcinoma” or “urothelial cell carcinomas”) and (“plant based ” or “plant-based” or “vegan” or “veganism” or “vegans” or “vegans” or “vegetable based ” or “vegetarian” or “vegetarianism” or “vegetarians” or lactoovovegetarian* or lactovegetarian*)) web of science 12 results t s = (“ bl adder adeno c a rc i nom a” or “ bl adder adenocarcinoma” or “bladder cancerogenesis” or “ bladder carcinogenesis” or “ bladder carcinoma” or “bladder diverticulum carcinoma” or “bladder metastasis” or “ bladder cancer” or “transitional cell cancer” or “bladder carcinogen” or “urinary bladder metastasis” or “urot helia l cancer” or “urothelial carcinoma” or “vesical cancer” or “vesical carcinomanesis” or “vesical carcinomatosis” or “bladder neoplasm” or “bladder neoplasms” or “bladder tumors” or “bladder tumor” or “malignant tumor of urinary bladder” or “cancer of the bladder” or “bladder cancers” or “transitional cell cancer” or “transitional cell cancers” or “transitional cell carcinoma” or “transitional cell carcinomas” or “transitional cell tumor” or “transitional cell tumors” or “transitional cell tumour” or “transitional cell tumours” or “urothelial cancer” or “urothelial cancers” or “urothelial carcinoma” or “urothelial carcinomas” or “urothelial cell cancer” or “urothelial cell cancers” or “urothelial cell carcinoma” or “urothelial cell carcinomas”) and ts=(“plant based” or “plant-based” or “vegan” or “veganism” or “vegans” or “vegans” or “vegetable based ” or “vegetarian” or “vegetarianism” or “vegetarians” or lactoovovegetarian* or lactovegetarian*) amed no results found (bladder neoplasms/ or “bladder adenocarcinoma” or “bladder adenocarcinoma” or “bladder cancerogenesis” or “bladder carcinogenesis” or “bladder carcinoma” or “bladder diverticulum carcinoma” or “bladder metastasis” or “ bladder cancer” or “transitional cell cancer” or “bladder carcinogen” or “urinary bladder metastasis” or “urot helia l cancer” or “urothelial carcinoma” or “vesical cancer” or “vesical carcinomanesis” or “vesical carcinomatosis” or “bladder neoplasm” or “bladder neoplasms” or “bladder tumors” or “bladder tumor” or “malignant tumor of urinary bladder” or “cancer of the bladder” or “bladder cancers” or “transitional cell cancer” or “transitional cell cancers” or “transitional cell carcinoma” or “transitional cell carcinomas” or “transitional cell tumor” or “transitional cell tumors” or “transitional cell tumour” or “transitional cell tumours” or “urothelial cancer” or “urothelial cancers” or “urothelial carcinoma” or “urothelial carcinomas” or “urothelial cell cancer” or “urothelial cell cancers” or “urothelial cell carcinoma” or “urothelial cell carcinomas”) and (vegetarianism/ or diet vegetarian/ or “plant based” or “plant-based” or “vegan” or “veganism” or “vegans” or “vegans” or “vegetable based” or “vegetarian” or “vegetarianism” or “veget a r ia ns” or lac toovoveget a r ia n* or lactovegetarian*) 244 siuj • volume 3, number 4 • july 2022 siuj.org review http://siuj.org 359siuj.org siuj • volume 3, number 6 • november 2022 volume 3, number 6 | november 2022 issn 2563-6499 10.48083/tdxu9303 editorial office info@siuj.org tel: 514-875-5665 ext. 26 siuj.org managing editor jane fairbanks jane.fairbanks@siu-urology.org the siuj is published 6 times a year by the société internationale d'urologie (siu). it is the official peer-reviewed publication of the siu but retains editorial independence. the siuj is circulated to urologists, urology residents, family medicine specialists, family medicine residents, general practitioners, nurses, medical libraries, and hospital and university departments of urology worldwide, for a total circulation of over 10,000. this publication was developed under the direction of the siuj editorial board. the siuj is published under an exclusive licence. the siuj is owned and published by the société internationale d’urologie (siu). marketing lillian petrusa lillian.petrusa@siu-urology.org advertising mikaela tierney advertising@siuj.org neither the siu nor the siuj endorses any service or the contents of any product referred to in any advertisement in the siuj. the siu and the siuj assume no responsibility or liability for damages arising from any error or omission, or from the use of any information or advice contained in the siuj. all editorial matter in siuj represents the opinions of the authors and not necessarily those of the siu or the siuj. all canadian prescription drug advertisements have been cleared by the pharmaceutical advertising advisory board. editorial board editor-in-chief peter c. black, md, canada associate editors thomas herrmann, md, switzerland kathleen kobashi, md, united states philippe e. spiess, md, united states henry woo, mbbs, australia social media editor jeremy y. c. teoh, mbbs, hong kong sar statistical editor alice dragomir, phd, canada innovators editor amanda chung, mbbs, australia regional editors north america margarett shnorhavorian, md united states middle east danny rabah, mbbs saudi arabia south america sandro esteves, md brazil east asia tianxin lin, md china eastern europe roman sosnowski, md poland south asia sanjay sinha, mch india western europe tamsin greenwell, md united kingdom southeast asia edmund chiong, mbbs singapore africa yasser osman, mbbch egypt visit bms.com/ca to see how we’re bringing a human touch to everything we do. © 2022 bristol-myers squibb company. all rights reserved. no-ca-2200002 02/22 we are in the business of breakthroughs—the kind that transform patients’ lives. dedicated to our mission of discovering, developing and delivering life-saving innovations that help patients prevail over serious diseases, we’ll never give up our search for more hope, for more people, around the world. http://siuj.org mailto:info%40siuj.org?subject=siuj http://siuj.org mailto:jane.fairbanks%40siu-urology.org?subject=siuj mailto:lillian.petrusa%40siu-urology.org%20?subject=siuj mailto:advertising%40siuj.org?subject=siuj http://bms.com/ca 360 siuj • volume 3, number 6 • november 2022 siuj.org editorial board liaqat ali, mbbs pakistan abdol mohammad kajbafzadeh, md iran fahad alyami, mbbs saudi arabia wayne lam, mbbs hong kong sar mohsen azli, md algeria sang dong lee, md korea erdem canda, md türkiye evelyn moshokoa, mbchb south africa yao-chi chuang, md taiwan andrea necchi, md italy archil chkhotua, md georgia dedan opondo, mbchb kenya renu eapen, mbbs australia khurram siddiqui, mbbs oman agus rizal ardy hariandy hamid, md indonesia yaya sow, md senegal christopher ho chee kong, md malaysia chuan-liang xu, md china theocharis karaolides, md cyprus the société internationale d’urologie (siu). the society’s mission is to enable urologists in all nations, through international cooperation in education and research, to apply the highest standards of urological care to their patients. the siu is a major international platform for sustainable urological education and collaborative philanthropic activities aimed at improving urological care with more than 10 000 members from over 130 countries. siu central office 1155 robert-bourassa blvd., suite 1012 montreal, quebec, canada h3b 3a7 tel: +1 514 875-5665 fax: +1 514 875-0205 communications@siu-urology.org executive director susie petrusa susie.petrusa@siu-urology.org graphic design sam design info@studiosamdesign.com web design/ technical support aiki informatique info@aikitech.ca volume 3, number 6 | november 2022 neither the siu nor the siuj endorses any service or the contents of any product referred to in any advertisement in the siuj. the siu and the siuj assume no responsibility or liability for damages arising from any error or omission, or from the use of any information or advice contained in the siuj. all editorial matter in siuj represents the opinions of the authors and not necessarily those of the siu or the siuj. all canadian prescription drug advertisements have been cleared by the pharmaceutical advertising advisory board. http:// mailto:communications%40siu-urology.org?subject=siuj mailto:susie.petrusa%40siu-urology.org?subject=siuj mailto:susie.petrusa%40siu-urology.org?subject=siuj mailto:info%40studiosamdesign.com%20?subject=siuj mailto:info%40studiosamdesign.com%20?subject=siuj mailto:info%40aikitech.ca?subject=siuj bladder cancer proceedings from the siu b2b uro-oncology: gu cancers triad virtual meeting may 21–22, 2021 www.siu-urology.org #b2bgucancertriad https://www.siu-urology.org https://twitter.com/search?q=%23b2bgucancertriad proceedings from the siu b2b uro-oncology: gu cancers triad • may 21–22, 2021 – siuj volume 2, supplement 1, july 2021 7 b2b: bladder cancer summary peter c. black,a,* ashish m. kamat,b,† angela b. smith,c sima porten,d renu eapen,e,f carmen mir,g jeremy teoh,h tilman todenhöfer,i tian zhang,j kilian m. gust,k srikala sridhar,l simon tanguaym,‡ adepartment of urologic sciences, university of british columbia, vancouver, canada bdepartment of urology, the university of texas md anderson cancer center, houston, united states cdepartment of urology, university of north carolina at chapel hill, chapel hill, united states ddepartment of urology, university of california, san francisco, united states epeter maccallum cancer centre, melbourne, australia folivia newton john cancer centre & austin health, melbourne, australia gcase western reserve university, cleveland, united states hdepartment of surgery, faculty of medicine, the chinese university of hong kong, hong kong, china ieberhard-karls university tübingen, tübingen, germany jdepartment of medicine, duke cancer institute, durham, united states kdepartment of urology, medical university of vienna, vienna, austria lprincess margaret cancer centre, university of toronto, toronto, canada mdivision of urology, mcgill university, montreal, canada *chair of the scientific programme committee †co-chair of the scientific programme committee (bca) ‡co-chair of the scientific programme committee (rcc) the bench-to-bedside uro-oncology gu cancer triad meeting was organized by the société internationale d’urologie and was held online on may 21st and 22nd, 2021. the session on bladder cancer (bca) took place on the morning of friday, may 21st, and was chaired by dr. peter c. black (canada) and dr. ashish kamat (united states). this session covered practicechanging advances on the horizon for bca, the use of urine markers in bca management, evolving therapies for non-muscle-invasive bca (nmibc), and recent advances for systemic therapy for muscle-invasive bca (mibc) and advanced urothelial carcinoma (uc). the faculty also discussed how to manage immune-related adverse events (aes). dr. angela smith (united states) presented five practice-changing advances on the horizon across the disease spectrum of bca and upper tract uc (utuc). one of these advances is in the treatment of low-grade intermediate-risk nmibc[1,2]. these are tumours that have high rates of recurrence but low risk of progression[2]. in this disease setting, transurethral resection of bladder tumour (turbt) plus intravesical therapy is considered standard of care[1,3], with mitomycin and gemcitabine instillation after turbt being shown to reduce the risk of recurrence[4,5]. however, repeat turbts expose patients to risks of repetitive anesthesia and surgically related complications[6]. the use of ugn-102, a thermoreversible hydrogel containing mitomycin, is being investigated for nonsurgical chemoablation in patients with low-grade intermediate-risk nmibc in the phase 2b optima ii trial[7]. in an interim analysis, complete response (cr) at 3 months was observed in 65% of patients (95% ci 52%–77%) following treatment with ugn-102. in the safety analysis, 91% of patients experienced ≥1 ae, with the most common aes occurring in ≥5% of patients related to lower urinary tract symptoms (luts), such as dysuria (91%), pollakiuria (41%), and hematuria (19%)[7]. with an estimated durability of response at the 12-month follow-up of 60%, these interim data demonstrate that primary chemoablation of low-grade intermediate-risk nmibc using ugn-102 results in a significant treatment response and encouraging durability, and may provide an alternative to turbt treatment for patients in this disease setting[7]. chemoablation with ugn-102 vs. turbt is now being investigated in the phase 3 trial atlas[8]. there have been multiple advances in the treatment of high-grade bacillus calmette-guérin (bcg)refractory nmibc, including the u.s. food and drug administration (fda) approval of pembrolizumab in this setting for carcinoma in situ (cis) and the recently published results of the novel gene therapy nadofaragene firadenovec in this population[9,10]. among the developments on the horizon is the investigation of combination intravesical gemcitabine and pembrolizumab therapy to treat bcg-unresponsive nmibc in the phase 2 alliance a031803 trial[11]. this trial is also assessing correlations of tumour genomic aberrations with therapy response, the results of which may assist in future patient selection for treatment. doi: 10.48083/njcd1236 8 proceedings from the siu b2b uro-oncology: gu cancers triad • may 21–22, 2021 – siuj volume 2, supplement 1, july 2021 b2b: bladder cancer summary in the localized mibc space, retain bladder is a phase 2 trial investigating a risk-adapted approach to treatment that may result in bladder preservation[12]. treatment was determined according to tumour stage and mutation status following neoadjuvant chemotherapy (nac) and turbt. patients with no residual tumour (ct0) and positive mutations proceeded to active surveillance. in an interim analysis of clinically meaningful endpoints, 39% of patients proceeded to active surveillance. at the data cut-off, 77% of patients on active surveillance were alive, had not developed metastasis, and had not undergone radical cystectomy. based on these favourable results, the phase 2 retain trial was initiated to investigate a risk-enabled treatment approach following neoadjuvant immunochemotherapy in mibc[13]. dual immunotherapy is showing encouraging results in the first-line treatment of locally advanced or metastatic bca. in an updated analysis of cisplatin-ineligible patients in the ev-103 trial, enfortumab vedotin plus pembrolizumab resulted in a 73.3% confirmed objective response rate (orr), regardless of programmed death-ligand 1 (pd-l1) expression, and promising 93% tumour reduction[14]. response to treatment appears to occur relatively quickly, with 88% of patients demonstrating response at first assessment (week 9±1 week). the median progression-free survival (pfs) in this patient cohort was 12.3 months and both median overall survival (os) as well as duration of response (dor) have not been reached. in addition to the positive efficacy results, treatment with enfortumab vedotin plus pembrolizumab has a favourable toxicity profile, with only 16% of patients experiencing serious treatment-related aes (traes). in the utuc setting, the phase 3 trial proof 302 is evaluating the efficacy and safety of infigratinib as adjuvant therapy in patients with high-risk invasive uc and susceptible fgfr3 alterations[15]. as a large proportion of patients with utuc shows alterations in fgfr3[16], infigratinib, a fibroblast growth factor receptor (fgfr) inhibitor, may be an attractive therapeutic agent for this population. during the q&a period, dr. smith was asked how the toxicities of novel bladder-sparing treatments will compare to those of current therapeutic options. according to dr. smith, patient-reported outcomes will play an important role in the toxicity evaluation of new therapies, which will also impact the treatment selection. as she pointed out, different treatments may differ considerably in terms of patient experience, regardless of similar efficacy. another important aspect that will affect treatment selection is the frequency of treatment delivery. therapies that require fewer visits to the hospital may pose a reduced logistical and financial burden that would ultimately benefit the patient. the following session was a panel discussion hosted by the siu innovators and provided insights on the selection and use of urinary biomarkers in the various stages of bca diagnosis, management, and follow-up. dr. sima porten (united states) moderated the discussion with input from a panel of experts comprising dr. renu eapen (australia), dr. carmen mir (spain), and dr. jeremy teoh (hong kong). the case was a 50-year-old male who received initial treatment with turbt with gemcitabine for a lowgrade ta tumour. at the 3-month follow-up, cytology showed atypical urothelial cells (paris 3 classification), despite no evidence of disease by cystoscopy. the panelists discussed if cytology is commonly performed at the time of cystoscopy, the use of the paris classification by cytopathologists, and whether other urinary biomarkers are routinely used for bca diagnosis. the use of cytology at the time of surveillance cystoscopy is variable and not always performed for low-grade tumours, and the paris classification is not always adopted. while cytology is considered the gold standard in this setting, the panelists highlighted other commercially available urinary biomarker tests that may be used in adjunction. adxbladder™ is an enzyme-linked immunosorbent assay (elisa) test that detects mcm5 in urine, a known biomarker for bladder tumours[17]. other options include gene expression analysis with messenger rna (mrna)-based tests for bca biomarkers, such as xpert® bladder cancer monitor[18] and cxbladder monitor™ tests[19]. another biomarker test is urovysion™, a multi-colour fluorescence in situ hybridization (fish) assay to detect chromosome aberrations associated with urothelial tumour cells[20]. b2b: bladder cancer summary 9 b2b: bladder cancer summary the discussion continued on to which steps would be taken following a positive cytology for paris 4 or paris 5, which indicate a higher risk for high-grade uc[21]. if no evidence of disease is seen by cystoscopy, enhanced imaging techniques, such as photodynamic diagnosis or narrow band imaging (nbi)[22], should be implemented to evaluate the presence of uc. random biopsies of the bladder as well as selective upper tract urine cytology may also be considered, particularly in patients with unexplained positive urine cytology. upper tract urine cytology may be performed by urine aspiration or lavage cytology and has a high sensitivity of up to 69.9% for high-grade utuc[23]. next, the case proceeded with the patient being diagnosed with high-risk nmibc and starting bcg induction. while not routinely used in clinical practice, urinary biomarkers may play an important role in predicting response to bcg therapy and evaluating patient prognosis. urovysion fish analysis has been shown to predict disease recurrence and progression in patients receiving bcg[24]. this may be particularly useful for guiding treatment discussions with patients. following bcg maintenance, no evidence of disease was found by cystoscopy and cytology was negative during surveillance for the patient case. however, the number of procedures, frequency of hospital visits, and current risk of covid-19 may pose an important burden on the patient. in this setting, some urinary biomarker tests demonstrate potential for providing a noninvasive alternative to cystoscopy. bladder epicheck is a kit that detects disease-specific dna methylation patterns in bca patients with high negative predictive values (npv)[25]. however, this test is not routinely implemented in the clinical practice. other options for patient surveillance may include adxbladder[26] and xpert bladder cancer monitor[27], both of which have shown high npv. dr. porten highlighted the use of cxbladder monitor during the covid-19 pandemic as an option for patient surveillance at home that has been adopted at the ucsf medical center. in the patient case, surveillance with cxbladder monitor showed values above cut-off. cystoscopy was performed, leading to a diagnosis of mibc. the patient received nac followed by radical cystoprostatectomy with lymph node dissection and neobladder diversion with favourable pathology. given the limited evidence for urinary biomarkers in this setting, computed tomography (ct) scans and urine cytology are typically the routine options for patient surveillance. however, emerging data may provide new insights on the use of urinary biomarkers for post-urinary diversion surveillance. next, dr. tilman todenhöfer (germany) discussed the evolving treatments for nmibc by focusing on three main topics: 1) identifying predictive molecular markers of bcg treatment response, 2) emerging treatment options for bcg-unresponsive patients, and 3) novel therapy delivery approaches in nmibc. recent studies examining the molecular alterations of nmibc have led to significant improvements in understanding the disease. in a recent report of the uromol project, four molecular subtypes of nmibc with differing recurrence rates were identified based on the transcriptomic analysis of 834 patients[28]. in the same study, chromosomal instability was also analyzed, leading to the identification of three genomic classes associated with varying risk of disease progression. both the molecular subtype and genomic class may have important implications for predicting treatment response. bcg is currently the gold standard for treatment of bcg-naïve nmibc and results in high rates of highgrade recurrence-free survival (rfs), as demonstrated in a recent retrospective analysis of a contemporary patient cohort[29]. despite these excellent outcomes, there is an ongoing need for alternative treatment approaches to bcg in nmibc. first, bcg shortage is an ongoing issue and limits the access of a high proportion of patients to this therapy, leading to significant impact on patient outcomes[30]. second, bcg intolerance is an ongoing issue, regardless of recent decreases in treatment discontinuation due to traes. lastly, many patients with nmibc do not respond to bcg therapy and require other treatment approaches. therefore, predicting bcg response is important to guide treatment decisions in nmibc. recent studies have further advanced this field by identifying genomic and histological markers for patient stratification and treatment outcome prediction[31–33]. 10 proceedings from the siu b2b uro-oncology: gu cancers triad • may 21–22, 2021 – siuj volume 2, supplement 1, july 2021 b2b: bladder cancer summary treatment of bcg-unresponsive disease continues to be a major challenge in nmibc. novel treatment options under investigation in this setting include intravesical approaches with nadofaragene firadenovec[34], oportuzumab monatox[35], and n803/ bcg[36], as well as systemic options with immune checkpoint inhibitors (icis), such as atezolizumab[37] and pembrolizumab[38]. while all of these agents are showing encouraging outcomes, treatment tolerability in this setting appears slightly improved with intravesical approaches. however, the role of ici may increase in the nmibc setting as the results of multiple ongoing trials in bcg-naïve high-risk disease (potomac, alban, and crest), bcg induction failure (kn676 and checkmate 7g8), and bcg-unresponsive nmibc (checkmate 9ut and a031803) become available. in addition, a novel approach for ici therapy was recently presented. in subdue-1, a dose-finding phase 1b trial, intravesical injection of durvalumab is under investigation for patients with nmibc[39], an approach that has shown promising results in the pre-clinical studies[40]. several ongoing trials are also investigating the use of targeted systemic therapies, currently approved for metastatic bca, in patients with bcg-unresponsive disease. a recent study in patients with fgfr-positive nmibc demonstrated promising efficacy results following treatment with infigratinib. however, trae in all patients led to discontinuation of treatment[41]. in order to improve tolerability of fgfr-targeted therapy in nmibc, ongoing trials are evaluating fgfr inhibitor doses lower than those used in the metastatic setting. in a current phase 2 trial led by dr. noah hahn at johns hopkins, a 9-mg dose of pemigatinib is being investigated to treat patients with nmibc, which corresponds to only two-thirds of the dose used in metastatic bca[42]. other studies are focusing on improving the efficacy and delivery of intravesical chemotherapy. hyperthermia-induced mitomycin, an approach frequently used in centres in europe, has become the focus of recent investigations. in a retrospective study of patients with bcg-unresponsive nmibc, conductive chemohyperthermia with mitomycin led to 12-month rfs rates >50% in patients with cis[43]. another way of improving the efficacy of intravesical treatment is the use of a slow-delivery device (tar-200, gemris™) that is inserted in the bladder, which allows continuous delivery and exposure to chemotherapy[44]. two clinical trials will evaluate the use of tar-200 in patients with nmibc. in an ongoing, prospective, randomized phase 2b trial, treatment delivery with tar-200 is being compared with standard of care intravesical chemotherapy in patients with bcg-unresponsive disease as monotherapy or in combination with the ici cetrelimab[45]. another randomized, phase 3 clinical trial will investigate the efficacy of tar-200 chemotherapy in combination with cetrelimab compared to bcg therapy in bcg-naïve nmibc, with disease-free survival (dfs) as the primary endpoint. in the q&a period, dr. todenhöfer provided his highlights of treatment advances in nmibc to look forward to in the next year. one of the highlights is the development of new drug classes that exceed the efficacy of chemotherapy, such as nadofaragene firadenovec and oportuzumab monatox. according to dr. todenhöfer, these therapies may have an important role not only in the treatment of bcg-unresponsive patients, but also in earlier settings. another highlight is the advance of systemic therapy for nmibc. as pointed out by dr. todenhöfer, these advances will be influenced by important treatment-related toxicities, which may be less tolerable in patients with nmibc. the following talk was by dr. tian zhang (united states) who discussed the advances in systemic therapy for mibc and advanced uc in 2021. the current treatment landscape for metastatic uc comprises platinum-based chemotherapy as first-line regimen and switch maintenance with the pd-l1 inhibitor avelumab, recently highlighted in the javelin bladder 100 study[46]. treatment then may follow with enfortumab vedotin for all patients or erdafitinib for those presenting with fgfr2 and fgfr3 genomic alterations. multiple clinical trials are ongoing and sacituzumab govitecan recently received fda accelerated approval in the third-line setting[47]. the successful results of different immunotherapeutic agents for metastatic disease have fomented several trials aiming to bring those treatment advances into earlier disease settings. in mibc, chemotherapy in combination with pembrolizumab was investigated b2b: bladder cancer summary 11 b2b: bladder cancer summary as neoadjuvant therapy prior to radical cystectomy in the lccc 1520 trial[48]. the primary endpoint has been met, with 56% of patients achieving a downstaging pathologic response rate <pt2n0m0 and 36% having a pathologic cr to treatment, along with a generally safe toxicity profile. a number of clinical trials have been reported in recent years using neoadjuvant immunotherapy or combination chemoimmunotherapy in mibc[48–53]. most of these studies have enrolled patients with t2, t3, t4, or n1 disease and demonstrated the effect of immunotherapies on pathologic response at the time of cystectomy. several trials are ongoing and aim to examine the role of icis, antibody-drug conjugates (adcs), and combination therapy in the neoadjuvant treatment of mibc. in the adjuvant setting, the checkmate 274 trial investigated the role of nivolumab in the treatment of mibc following cystectomy, in both patients with prior neoadjuvant cisplatin-based chemotherapy and those without nac and ineligible for adjuvant treatment[54]. treatment with nivolumab compared to placebo resulted in a significantly longer median dfs, the primary endpoint, in the intent-to-treat (itt) population (21.0 vs. 10.9 months, hr=0.70 [98.31% ci 0.54–0.89]; p<0.001), as well as in a subset of patients with pd-l1 expression ≥1% (not reached vs. 10.8 months, hr=0.53 [98.87% ci 0.34–0.84]; p<0.001). common aes included pruritus, fatigue, diarrhea, rash, and increased lipase, which are expected reactions from treatment with immunotherapies. additional trials currently enrolling patients to examine the role of adjuvant immunotherapies in mibc and utuc include the ambassador trial (pembrolizumab vs. observation[55]) and, with targeted therapies for fgfr-altered urothelial cancer, the proof-302 trial (infigratinib vs. placebo[15]). results of the javelin bladder 100 trial have changed practice in the locally advanced and metastatic uc setting. in patients with unresectable disease, treatment with avelumab and best supportive care (bsc) resulted in significant improvements in os (hr=0.69 [95% ci 0.56–0.86]; p<0.001) and pfs (hr=0.62 [95% ci 0.52–0.75]; p<0.001) compared to bsc alone[46]. the benefit of adding avelumab to bsc was observed in patients who had achieved cr, partial response (pr), or stable disease (sd) after initial chemotherapy. while shorter median os and pfs were observed in patients with pr or sd, additional treatment options may be available for this very frail patient population in the post-avelumab setting. additionally, in the metastatic uc setting, the positive results of the phase 3 trial ev-301 have cemented enfortumab vedotin for treatment of patients with refractory disease and prior immunotherapy[56]. in the trial, treatment with enfortumab vedotin resulted in significantly improved os (12.88 vs. 8.97 months, hr=0.70 [95% ci 0.56–0.89]; p=0.0142) and pfs (5.554 vs. 3.72 months, hr=0.62 [95% ci 0.51–0.75]; p<0.00001) compared to chemotherapy. among the grade 3 or higher aes observed in this trial, maculopapular rash occurred more frequently in patients who received enfortumab vedotin (7% vs. 0%), whereas decreased neutrophil count (6% vs. 13%), decreased white blood cell (1% vs. 7%), and febrile neutropenia (1% vs. 5%) were more frequently observed in the chemotherapy group. other ongoing trials (ev-302 and ev-103) are evaluating the use of enfortumab vedotin alone or in combination with pembrolizumab or chemotherapy as a first-line treatment option for metastatic uc[51,57]. during the q&a, dr. zhang provided her insights on firstand second-line therapy recommendations for metastatic uc. platinum-based chemotherapy is still the primary option for eligible patients. once achieving sd, dr. zhang recommends that patients undergo maintenance treatment with avelumab. second-line options will often include enfortumab vedotin for all patients or erdafitinib for patients with fgfr alterations. with each line of therapy in metastatic uc, the goal is to extend patient survival while preserving quality of life. she also pointed out that other options may become available in earlier disease settings, as many ongoing clinical trials are evaluating systemic therapy options in the localized and adjuvant settings. in addition, dr. zhang addressed the ideal timing to sequence tumour tissue in order to guide treatment decisions in the metastatic setting. she recommends that sequencing be performed following cystectomy, given the amount of tumour tissue available, particularly for patients who have residual disease after neoadjuvant treatment. 12 proceedings from the siu b2b uro-oncology: gu cancers triad • may 21–22, 2021 – siuj volume 2, supplement 1, july 2021 b2b: bladder cancer summary the session concluded with a case-based discussion on management of immune-related aes and toxicities, not specifically related to bca. this was led by dr. kilian gust (austria), with the discussion based on the input of dr. srikala sridhar (canada), dr. tilman todenhöfer (germany), and dr. tian zhang (united states). the first case was a 54-year-old female initially diagnosed with and treated for high-risk nmibc who progressed to mibc. following a radical cystectomy, the patient presented with lymph node metastasis in the surgical field. at this time, the patient started treatment with atezolizumab after enrolling in the saul trial[58]. after the first treatment cycle, the patient presented with a marked increase in thyroid-stimulating hormone (tsh), characteristic of thyroiditis. this ae is commonly observed in patients receiving immunotherapies. if the patient is asymptomatic or presents mild symptoms, immune-related thyroid dysfunction does not require immediate management or discontinuation of immunotherapy. changes in tsh, t3, and t4 hormone levels should be closely monitored. early referral to an endocrinologist may be considered[59]. the patient continued treatment with atezolizumab and reached cr. over time, she developed hypothyroidism, which was managed with thyroid hormones. at cycle 49 of atezolizumab, the patient relapsed and was treated with chemotherapy, after which she achieved pr and was put on avelumab maintenance. after receiving the first dose, the patient presented with fever and chills. these infusion reactions are commonly seen with avelumab[46] and may be prevented with premedication. the second case was a 76-year-old male with poor prognosis for mibc. after the patient refused nac, he underwent radical cystectomy and recovered well after surgery. results of checkmate 274 trial suggest that this patient could benefit from adjuvant treatment with nivolumab[54], which is not yet approved in this setting. two weeks after receiving the first dose of nivolumab, the patient reported feeling unwell. his blood work showed altered liver function. at this point, it is important to put the immunotherapy treatment on hold, discuss with the patient the possibility of a trae, and consider referral to a hepatologist. management of altered liver function may include prednisolone. if tests do not show improvement, a liver biopsy may be performed to guide alternative management decisions[59]. the patient in this case responded well to intravenous methylprednisolone and resumed immunotherapy with close monitoring of liver function. in an alternative scenario in which the patient had received nac, it would be important to discuss potential traes prior to starting treatment with nivolumab. patients in this setting who have no signs of active disease may be less tolerant to aes resulting from immunotherapy. the last case was a 67-year-old male with intermediate-risk renal cell carcinoma (rcc) who underwent cytoreductive nephrectomy prior to enrolling in the phase 3 clear trial, in which the patient received pembrolizumab plus lenvatinib[60]. at his first visit, the patient presented with grade 1 nausea and grade 1 hypertension. later, he also developed grade 2 rash on the back of the legs, corresponding to 18% of the body surface area (bsa). in this scenario, management of rash includes topical steroids, which may be complemented by oral antihistamines. early referral to a dermatologist is advised[59]. the patient continued combination therapy and started treatment with topical steroids, until developing intense grade 3 rash on the legs, corresponding to a bsa of 36%. in this case, the patient requires management with systemic steroids and a dermatological review is indicated[59]. therapy should be put on hold and continued only after symptoms have improved. combination therapy was resumed after symptoms had improved, until recurrent grade 3 rash led to permanent discontinuation of first pembrolizumab and later lenvatinib, due to tyrosine kinase inhibitor (tki)-related rash. in some practices, tki may be discontinued prior to ici due to its shorter-acting effects. steroid treatment may be considered if rash persists after tki discontinuation. if rashes improve after treatment discontinuation, treatment dose reduction may be considered. when evaluating additional treatment options, it is also important to keep the patient’s quality of life, which may be deeply impacted by skin rashes, in mind. b2b: bladder cancer summary 13 b2b: bladder cancer summary abbreviations used in the text adc antibody-drug conjugate ae adverse event bca bladder cancer bcg bacillus calmette-guérin bsa body surface area bsc best supportive care ci confidence interval cis carcinoma in situ cr complete response ct computed tomography dfs disease-free survival dor duration of response elisa enzyme-linked immunosorbent assay fda u.s. food and drug administration fgfr fibroblast growth factor receptor fish fluorescence in situ hybridization hr hazard ratio ici immune checkpoint inhibitor itt intent-to-treat luts lower urinary tract symptom mibc muscle-invasive bladder cancer mrna messenger rna nac neoadjuvant chemotherapy nbi narrow band imaging nmibc non-muscle-invasive bladder cancer npv negative predictive value orr objective response rate os overall survival pd-l1 programmed death-ligand 1 pfs progression-free survival pr partial response rcc renal cell carcinoma rfs recurrence-free survival sd stable disease tki tyrosine kinase inhibitor trae treatment-related adverse event tsh thyroid-stimulating hormone turb transurethral resection of bladder tumour uc 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enfortumab vedotin plus pembrolizumab and/or chemotherapy for locally advanced or metastatic urothelial cancer. journal of clinical oncology.2019;37(15_ suppl):tps4593. doi:10.1200/jco.2019.37.15_suppl. tps4593 58. sternberg cn, loriot y, james n, et al. primary results from saul, a multinational single-arm safety study of atezolizumab therapy for locally advanced or metastatic urothelial or nonurothelial carcinoma of the urinary tract. european urology.2019;76(1):73-81. doi:10.1016/j. eururo.2019.03.015 59. haanen jbag, carbonnel f, robert c, et al. management of toxicities from immunotherapy: esmo clinical practice guidelines for diagnosis, treatment and followup. annals of oncology.2017;28:iv119-iv142. doi:10.1093/ annonc/mdx225 60. motzer r, alekseev b, rha s-y, et al. lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. new england journal of medicine. 2021;384(14):1289-1300. doi:10.1056/nejmoa2035716 this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. 137siuj.org siuj • volume 2, number 3 • may 2021 editorial maybe next year? peter black, editor-in-chief  soc int urol j.2021;2(3):137 doi: 10.48083/avby2691 remember just a few short months ago when we bid farewell to pandemic-ridden 2020 and ushered in 2021 with eager anticipation of returning to normal social activities, regular travel, and participation in-person in urologic meetings? while the vaccine effort plods along, more efficiently in some countries and regions than others (and certainly without any sense of global equity), you could well wonder if we will not at the end of this year find ourselves eagerly awaiting the same events for 2022. coronamüde (corona-fatigued) rings loud for us all. which meeting will be the first big one in person? the american urological association (aua) 2021 annual meeting is planned for late september in las vegas. the leadership of the aua and the meeting organizers will certainly not take any public health risk in pulling off this meeting (they will not be swayed by their government’s penchant for deviating from good public health policy throughout the pandemic), but travel restrictions and quarantine regulations have been looser in the united states than elsewhere, so it would be fitting if the aua were the “homecoming” of sorts for the urologic community. covid numbers continue to surge, however, with concern rising over even more contagious variants, and other major meetings planned during similar dates (eg, esmo 2021) are sticking to the virtual format. perhaps the aua can pull off a successful meeting without cross-border travel, but many other organizations cannot, and it is not at all clear whether any of us will be traveling by september. our own 41st congress of the siu looms large, scheduled for november 10 to 14 in dubai, giving us two more months in the race to overcome social distancing. that is not to say that the advent of virtual meetings does not have some real advantages. which academic urologist f lying around the world from speaking engagement to guideline panel to visiting professorship has not enjoyed a break from the hectic travel circuit? and instead of catering to those with the time and means to travel, many of our meetings have become more accessible to urologists and allied health care workers in all corners of the globe. this is particularly important to an organization like the siu—but at the same time it is critically important that we interact in person with our colleagues from other regions to forge those relationships that bring us closer together and advance our field. the time and space for informal discussions is something that virtual meetings cannot provide. it is not just about meeting, but also about connecting. the siu introduced hybrid meetings with the launch of the siu@u in 2015 before we even really talked about such a thing. maybe this will be the way of the future— the anticipation, engagement, and camaraderie of inperson meetings for those who can attend, matched with the easy access and convenience of virtual meetings for those who cannot. of course, thoughts of travel restrictions and bemoaning the lack of in person meetings ring hollow during a true global health crisis. this is not to diminish the human cost of the pandemic, which is enormous and should always be in the foreground. nonetheless, these meetings are an important part of any society and indeed any medical specialty, and we are anxiously awaiting their return—whether it is in the fall of 2021 or maybe not until next year. http://www.siuj.org mailto:editorinchief%40siuj.org?subject=siuj key words competing interests article information tuberculosis, urogenital tuberculosis, extrapulmonary tuberculosis, sabah development of crpc none declared. received on july 17, 2021 accepted on october 17, 2021 this article has been peer reviewed. soc int urol j. 2022;3(2):69–76 doi: 10.48083/ whll5336 69siuj.org siuj • volume 3, number 2 • march 2022 this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. original research epidemiology and clinical characteristics of urogenital tuberculosis in sabah, malaysia karthikayenee ramasamy, shankaran thevarajah urology unit, hospital queen elizabeth, sabah, malaysia abstract objectives we aimed to describe the epidemiology and clinical characteristics of urogenital tuberculosis (ugtb) in sabah, malaysia. methods we performed a retrospective, descriptive study based on medical records of ugtb cases identified between january 1, 2014, and november 30, 2020. results we identified 131 cases of ugtb in sabah. patient gender was balanced except for a mild male predominance in the 35 to 44 age group. no cases were reported in children. the majority of the patients (96%) were diagnosed in the government facility. among the ugtb cases, 72% of patients were from rural areas, and 29% were illiterate. the commonest presentation was frequency of micturition (28%), followed by abdominal pain (26%) and loss of appetite (26%). the common sites included renal (32%) and scrotal (25%). diagnosis was achieved via histopathology in 39.7% of patients and smear microscopy in 35.9%. anti-tubercular treatment duration was 8.6 (±sd 4.0) months, and 81% of patients have completed treatment. a total of 50.4% of patients had received surgical intervention; 10.7% had undergone incision and drainage, 9.9% had cystoscopy, and 6.9% underwent orchidectomy. conclusion ugtb has varied non-specific symptoms, which poses a diagnostic challenge, leading to morbidity. ensuring awareness via widespread education within government and private health care, along with rural outreach programs, will contribute to early recognition and treatment. introduction tuberculosis (tb) is an ancient disease that constitutes a global epidemic. it is caused by mycobacterium tuberculosis, which was discovered by robert koch in 1882. genomic analyses suggest that m. tuberculosis co-evolved with humans. its early progenitor, mycobacterium prototuberculosis, possibly infected early hominids more than 3 million years ago[1,2]. according to the who global report 2019, around 10 million people fall ill with tb each year. tb is one of the top 10 causes of death, and the leading cause from a single infectious agent (mycobacterium tuberculosis), ranking above hiv/aids. of the 10 million annual cases, 5% to 45% have features of extrapulmonary tb[3]. in the early 1940s and 1950s, tb was the main cause of death in malaysia. realizing its significance, the malaysian government launched its national tb control program in 1961. in 2014, 92.2% of tb cases were in malaysian citizens. the incidence of tb in malaysia as of 2019 is 92 per 100 000, with various sources indicating that sabah has the highest number of tb cases in malaysia[1,4]. http://siuj.org mailto:karthika_87%40hotmail.com?subject=siuj urogenital tuberculosis (ugtb) is the third most common form of extrapulmonary tb. it occurs in 2% to 20% of individuals with pulmonary tb. ugtb affects 2 males for each female, with a mean patient age of 40 years (range 5 to 90 years)[5–7]. pathogenesis of ugtb is mainly from hematogenous spread and, rarely, venereal transmission. ugtb is often overlooked because of its non-specific symptoms, lack of awareness, and lack of foolproof diagnostic tests. delay in diagnosis often results in irreversible organ damage and renal failure. the most common symptom, found in more than 50% of patients, is irritative voiding. the other symptoms of ugtb are fever, weight loss, anorexia, backache, and abdominal pain[8]. in this study, we aim to delineate the epidemiology and clinical characteristics of ugtb in sabah, malaysia. materials and methods we conducted a retrospective, descriptive, sub-state analysis of all notified cases of ugtb disease in sabah state, malaysia between january 1, 2014, and november 30, 2020. all confirmed tb cases in sabah are recorded in “mytb,” a secure electronic database. using national notification data, we calculated the proportion of all cases in malaysia occurring in sabah state. descriptive analysis of demographic, epidemiological, and clinical data was done using spss software (version 26). the categorical variables were analyzed through the study of frequencies. maps were produced using paintmaps. this study was conducted in compliance with ethical principles outlined in the declaration of helsinki and malaysian good clinical practice guideline. results in the relevant time period, 35 157 tb cases were reported to the sabah state tb surveillance database (mytb). out of this number, 31 070 were pulmonar y tb and the remining 4087 cases were extrapulmonary tb (eptb). ugtb accounted for 131 cases, which represents 3.2% of eptb cases (january 1, 2014, to november 30, 2020). patient demographics the patient demographics are summarized in table 1. the number of patients remained fairly constant over time, with a minor peak in 2019. the mean patient age at diagnosis was 48.6 (sd: 15.0) years and patient gender was balanced except for a mild male predominance in the 35 to 44 age group (figure 1). the highest number of cases was reported in kota kinabalu (14.0%), the state capital, which has the largest population, and the lowest number was reported from kudat and kinabatangan, which are both remote rural abbreviations dots directly observed treatment short course eptb extrapulmonary tb fdc fixed-dosanation tb tuberculosis ugtb urogenital tuberculosis table 1. patient demographics variable n (%) n = 131 incidence of gutb/year 2014 2015 2016 2017 2018 2019 2020 20 (15.3) 20 (15.3) 14 (10.7) 19 (14.5) 17 (13.0) 28 (21.4) 13 (9.9) source of notification government hospital local health clinic health office private sector age (mean±sd) 107 (81.7) 14 (10.7) 5 (3.8) 5 (3.8) 48.64 (14.99) gender male female kg/m2 (mean±sd) 71 (54.2) 60 (45.8) 22.52 (5.32) nationality citizen peribumi sabah chinese others peribumi sarawak non-citizen indonesia philippines pakistan 118 (90.1) 108 (91.5) 6 (5.1) 3 (2.5) 1 (0.8) 13 (9.9) 8 (6.1) 4 (3.1) 1 (0.8) a3 missing; b6 missing; c8 missing. continued on page 71 70 siuj • volume 3, number 2 • march 2022 siuj.org original research https://paintmaps.com http://siuj.org regions (figure 2). the majority (81.7%) of patients were seen in government hospitals. patients were malaysian citizens in 90.1% of cases, indonesian in 6.1%, and filipino in 3.1%. clinical characteristics of patients the clinical characteristics of the patient cohort are summarized in table 2. the majority of the 131 cases (89.3%) were classified as new diagnoses. the most common sites of infection were renal (32.1%) and scrotal (25.2%), followed by endometrial and cervical (8.4% each) (figure 3). figure 1. number of gutb cases by age group and sex, 2014 to 2020 10 19 13 15 14 3 13 12 12 12 8 0 5 10 15 20 25 30 35 15-24 25-34 35-44 45-54 55-64 ≥65 male female figure 2. distribution of ugtb in sabah, 2014 to 2020 15 20 10 15 5 10 1 5 0 1 0 0 be au fo rt beluran ke ni ng au kinabatangan kota belud kota kinabalu kota marudu kuala penyu kudat kunak lahad datu nabawan papar pena. pitas putatan ranau sandakan semporna si pi ta ng ta m bu na n tawau te no m tongod tuaran table 1. patient demographics variable n (%) n = 131 years in malaysia 0–5 years 6–15 years 16–20 years 21–25 years > 25 years 2 (15.4) 3 (23.1) 3 (23.1) 3 (23.1) 2 (15.4) number of dependents 0 1–3 > 3 16 (12.2) 48 (36.6) 54 (41.2) location urban rural 37 (28.2) 94 (71.8) highest level of patient educationa illiterate/ no formal education higher secondary (form 4/5) lower secondary (up to form 3) primary school form 6/ certificate/ diploma course tertiary education 37 (28.2) 37 (28.2) 24 (18.3) 11 (8.4) 6 (4.6) 2 (1.5) employment and incomeb employed/income unemployed 48 (36.6) 77 (58.8) occupationc professionals (including health care) skilled semi-skilled unskilled/ labourers self-employed (unstated) retired 4 (3.1) 1 (0.8) 17 (13.0) 15 (11.5) 6 (4.6) 5 (3.8) a3 missing; b6 missing; c8 missing. , cont’d 71siuj.org siuj • volume 3, number 2 • march 2022 epidemiology and clinical characteristics of urogenital tuberculosis in sabah, malaysia http://siuj.org clinical presentation the clinical features at the time of presentation are summarized in table 3 and figure 4. urinary frequency was the commonest symptom (28.2%), followed by abdominal pain and loss of appetite (each 26.0%). overall, 45.8% of patients were found to have fever upon examination, and 3.1% presented with peripheral lymphadenopathy. method of diagnosis the means used to diagnose ugtb in the patient cohort are summarized in table 4. diagnosis was made by histopathological examination in 39.7%, microbial tests in 35.9%, urine for mtb culture in 3.8%, and radiological imaging in 0.8%. information was missing for the remaining 20.6% of patients tested for hiv, 87.0% were negative and 2.3% were positive at the time of diagnosis (6.1% declined testing and data were missing for the remaining 4.6%). the common risk factors were chronic kidney disease (17.6%), family history of tuberculosis(16.0%), and diabetes mellitus (9.9%). smokers made up of 20.6% of the cases. treatment outcomes treatment outcomes are summarized in table 5. the mean duration of treatment was 8.6 (sd: 4.0) months and the average hospital stay was 1.0 (sd: 1.7) month. table 2. clinical characteristics of study participants variable n (%) n = 131 case statusa new relapse 117 (89.3) 8 (6.1) sputum sample earlyb positive negative not done 4 (3.1) 81 (61.8) 13 (9.9) chest x-ray upon diagnosisa no lesions minimal not done moderately advanced far advanced 59 (45.0) 32 (24.4) 19 (14.5) 11 (8.4) 4 (3.1) presence of hiv during diagnosisa positive with hiv negative with hiv test not done on haart not on haart/ new hiv 3 (2.3) 114 (87.0) 8 (6.1) 2 (66.7) 1 (33.3) risk factorsc diabetes mellitus chronic kidney disease prior history of tb family history of tb malignancy on immunosuppressive drugs 13 (9.9) 23 (17.6) 7 (5.3) 21 (16.0) 7 (3.0) 4 (3.05) working with cattlea yes no 1 (0.8) 124 (94.7) smoking status smoker non-smoker 27 (20.6) 104 (79.4) a6 missing; b9 missing; c60 missing. figure 3. number of ugtb cases by site of involvement 15 10 5 20 25 30 35 40 45 re na l sc ro ta l en do m et riu m ce rv ic al bl ad de r a dr en al u re te r u ro ge ni ta l (n on -s pe ci �e d) pr os ta te pe ni s fa llo pi an tu be o va ria n la bi a fe m al e g en ita l (n on -s pe ci �e d) 0 72 siuj • volume 3, number 2 • march 2022 siuj.org original research http://siuj.org during the intensive phase, 44.2% of patients received 2 months of ethambutol, isoniazid, rifampicin, and pyrazinamide (2 ehrz regimen) and 41.2% received the fixed-dose combination (fdc) regimen. the majority of patients (77.9%) received 4 months of isoniazid and rifampicin (4hr regimen) during the maintenance phase. the most common adverse event during the intensive phase was death (3.8%). the directly observed treatment short course (dots) was used in 89.3% of patients in the intensive phase, and in 76.3% during the maintenance phase. the majority of observers for the dots treatment were the patient’s family members (63.6%). at the point of data compilation, 81.0% of the patients had already completed their treatment, and 6.1% were lost to follow-up. we found that 50.4% of patients had received surgical intervention; 10.7% had undergone incision and drainage, 9.9% had cystoscopy, and 6.9% underwent orchidectomy. discussion tuberculosis is a communicable disease that is a major cause of ill health, one of the top 10 causes of death worldwide, and the leading cause of death from a single infectious agent (ranking above hiv/aids). the disease typically affects the lungs (pulmonary tb) but can also affect other sites (extrapulmonary tb). about 90% of cases are in adults, and there are more cases among men than women. globally, an estimated 10 million people fell ill with tb in 2019. the incidence of tb in malaysia as of 2019 is 92 per 100 000 population[1]. our study provides a sub-state analysis of ugtb in sabah, malaysia, from january 2014 to november 2020. our findings highlight the burden of disease in sabah; however, there are no data for comparison with other states in malaysia. in 2019, the who southeast asia region had accounted for 44% of tb cases. malaysia, which is within that region, has a population of 32.7 million people, and sabah, its second largest state, accounts for 3.9 million[9]. geographically, sabah is situated between indonesia and the philippines, and these countries are amongst the top 8 countries that account for two-thirds of the global total of tb cases. indonesia, second to india, accounts for 8.5% and the philippines accounts for 6.0%[3]. in 2019, the philippines had an estimated incidence of 554 per 100 000 population, indonesia 312 per 100 000 population, and malaysia <100 cases per 100 000 population[1,10]. following the formation of malaysia in 1963, cross-border movement, which had previously been considered legal, became illegal. however, proximity to indonesia and the philippines, and a long and porous border have made it difficult to stop all movement, and figure 4. common presentations of ugtb, 2014–2020 36 34 34 32 23 22 22 18 17 15 13 9 6 6 4 2 2 1 1 5 10 15 20 25 30 35 40 frequency abdominal pain loss of appetite loss of weight pyrexia dysuria lethargy hematuria scrotal pain/swelling atypical/incidental pyuria nocturia per vaginal discharge costovertebral tenderness night sweats cough penile swelling labial swelling others 0 table 3. presentation features of patients in the study variable n (%) n = 131 bp statusa normotensive hypotensive shock 65 (49.6) 51 (38.9) 1 (0.8) temperaturea febrile afebrile 60 (45.8) 57 (43.5) peripheral lymphadenopathya yes no radial pulse glucose on arrival 4 (3.1) 113 (86.2) 111.80 (11.09) 8.77 (2.77) a14 missing. 73siuj.org siuj • volume 3, number 2 • march 2022 epidemiology and clinical characteristics of urogenital tuberculosis in sabah, malaysia http://siuj.org the presence of marginalized communities (sea-nomads) is of concern in eastern sabah[10]. most of the cases that we observed in migrants were reported in sandakan and lahad datu, the coastal region through which cross-border movement commonly occurs. topographically, sabah poses a challenge in term of gaining immediate health access, and delays in seeking treatment were common. during our study, 71.8% of cases were noted to be from rural areas. we also observed that most of our cases were detected by the government facilities: 96.3%, compared with 3.8% by non-governmental facilities. continuous health education on tb, aimed at raising awareness and correcting misconceptions, is needed and should be extended to include those who use non-government facilities[11,12]. economically, sabah has been challenged more than the rest of malaysia. in 2019, sabah was one of the 4 states with the lowest gdp per capita (rm 25 326). sabah had an unemployment rate of 5.8% in 2019[9]. our results have shown that 58.8% of ugtb patients were unemployed, with a high percentage of illiteracy (28.2%). this supports the view that poverty and poor education contribute to delays in access to diagnosis and care. ugtb has insidious onset, with varied or atypical presentation, which poses difficulty in diagnosis and can delay treatment. most patients present with local symptoms such as frequent voiding, dysuria, pyuria, or back, flank, or abdominal pain. the organs most commonly involved are kidney, bladder, fallopian tubes, and scrotum. it commonly affects middle aged subjects. the incidence is slightly higher in men, and it is uncommon in children[1,8,11–15]. patients with ugtb have been reported as having more local than systemic symptoms. our study concurs with common presentation of frequency of micturition (28.2%), followed by abdominal pain (26.0%). we also found that systemic symptoms, such loss of appetite (26.0%) and loss of weight (24.4%), were common. the sites most commonly seen in our study were kidney (32.1%) and scrotum (25.2%). we note that during our study period, treatment duration was 8.6 (±sd 3.97) months. the most common intensive phase regimens in the first 2 months were 2 ehrz (ethambutol, isoniazid, rifampicin, pyrazinamide) 44.2% and fixed-dose combinations (fdc) consisting of 41.2%. the most common maintenance regimen was 4 months of hr (77.9%). a total of 89.3% have observed dots during intensive phase, dots was observed by family members in 63.6% of our subjects. 76.3% observed dots during maintenance phase. 81.0% of patients have completed treatment at the time of this study. we note that 50.4% of patients received surgical intervention. in these patients, 10.7% had undergone incision and drainage, 9.9% had cystoscopy, 9.2% did not have surgical intervention, and orchidectomy was done for 6.9% of patients. however, limitation in terms of retrieving primary records and details led to difficulty in further description of interventions and outcome. an understanding of the local epidemiology and clinical characteristics of disease is essential to successful prevention measures and treatment implementation. no previous data collection has been done in malaysia table 4. method of diagnosis variable n (%) n = 131 presence of bcg scara yes no 92 (70.2) 34 (25.8) mode of diagnosisb histopathological diagnosis hpe testis hpe endometrium hpe cervix hpe bladder biopsy hpe kidney hpe prostate hpe fallopian tube hpe ovary hpe renal pelvis fna adrenal smear microscopy for afb urine for afb pus from scrotum for afb pus from kidney for afb pus from penis for afb pus from labia for afb urine mtb c&s urine for gene xpert radiology 52 (39.7) 13 (9.9) 11 (8.4) 11 (8.4) 7 (5.3) 3 (2.3) 2 (1.5) 2 (1.5) 2 (1.5) 1 (0.8) 1 (0.8) 47 (35.9) 22 (16.7) 17 (13.0) 5 (3.8) 2 (1.5) 1 (0.8) 5 (3.8) 1 (0.8) 1 (0.8) case detectionc active passive incidental/ screening 12 (9.2) 115 (87.8) 2 (1.5) method of testing special test contact tracing 10 (7.6) 2 (1.5) a6 missing; b10 missing; c3 missing. 74 siuj • volume 3, number 2 • march 2022 siuj.org original research http://siuj.org table 5. treatment of patients in the study variable n (%) n = 131 treatment length months (mean±sd) 8.60 (3.97) length of stay months (mean±sd) 1.00 (1.65) intensive phase regimena 2 ehrz 2 hrz fdc others 58 (44.2) 1 (0.8) 54 (41.2) 12 (9.2) intensive phase adverse events deaths mdr-tb none 5 (3.8) 0 126 (96.2) maintenance phase regimena 4h 2r 2e 4 hr fdc others 3 (2.3) 102 (77.9) 1 (0.8) 19 (14.5) current statusb still under treatment completed treatment lost to follow-up/ defaulted death change of diagnosis 5 (3.8) 106 (81.0) 8 (6.1) 7 (5.3) 2 (1.5) a6 missing; b3 missing; c9 missing; d14 missing; e58 missing. to evaluate ugtb. malaysia has a complex system of data collection and tb reporting, involving both paper and electronic methods. the sabah state tb notification system (mytb) database is the best data source available. it has been under regular audit and scrutiny of the sabah state department of health. the economic challenges in sabah, however, pose hurdles in terms of data collection which may have caused underreporting of ugtb. furthermore, mytb has shortfalls in terms of the extent of information provided, especially for eptb. lack of primary records and missing documentation created a significant challenge to obtaining necessary information such as previous surgical interventions and outcome, which would further enhance our understanding of this disease. conclusion ugtb is a relatively uncommon manifestation of extrapulmonary tb, which is challenging to diagnose. progression is insidious, symptoms are non-specific, awareness is poor, and bacteriological diagnosis is difficult. therefore, high levels of vigilance and clinical suspicion are required if it is to be recognized. ugtb is a contagious infectious disease that necessitates early diagnosis and treatment to prevent morbidity. patients from endemic areas need to be assessed with high suspicion and screened for ugtb for early diagnosis and treatment. ensuring awareness via widespread education within health care, in both the government and the private sector, along with rural outreach programs, will contribute to early recognition and treatment. table 5. treatment of patients in the study variable n (%) n = 131 underwent dots intensive phasec dots maintenance phased 117 (89.3) 100 (76.3) main observer for intensive phase dotsb family health care worker unobserved 84 (63.6) 43 (32.8) 1 (0.8) surgical interventione i&d cystoscopy orchidectomy colposcopy pipelle stenting nephrostomy ovarian cystectomy trus biopsy salpingectomy ureteroscopy nephrectomy renal biopsy fnac 14 (10.7) 13 (9.9) 9 (6.9) 8 (6.1) 4 (3.1) 4 (3.1) 3 (2.3) 3 (2.3) 2 (1.5) 2 (1.5) 1 (0.8) 1 (0.8) 1 (0.8) 1 (0.8) a6 missing; b3 missing; c9 missing; d14 missing; e58 missing. , cont’d 75siuj.org siuj • volume 3, number 2 • march 2022 epidemiology and clinical characteristics of urogenital tuberculosis in sabah, malaysia http://siuj.org acknowledgements the aut hors wou ld li ke to t ha nk t he director general of health, malaysia for his permission to publish this article. the authors are grateful to dr christina rundi, dr roddy teo, the sabah state department of hea lth, a long with the involved district hospitals of sabah for making data available. we acknowledge the generous support of dr sophia lee eu wei, dr prabakaran balakrishnan and the staff in urology clinic hospital queen elizabeth sabah. references 1. gutierrez mc, brisse s, brosch r, fabre m, omaïs b, marmiesse m, et al. ancient origin and gene mosaicism of the progenitor of mycobacterium tuberculosis. plos pathogens.2005;1(1):e5. doi.org/10.1371/journal.ppat.0010005 2. hershkovitz i, donoghue hd, minnikin de, may h, lee oyc, feldman m, et al. tuberculosis origin: the neolithic scenario. tuberculosis.2015;95 (suppl 1):s122–s126. doi.org/10.1016/j. tube.2015.02.021 3. world health organization. who | global tuberculosis report 2019. in world health organization.2020. doi.org/.1037//0033-2909.i26.1.78 4. iyawoo k. tuberculosis in malaysia: problems and prospect of treat ment and control. tuberculosis.2 0 0 4;8 4 (1–2):4 –7. doi.org/10.1016/j.tube.2003.08.014 5. visweswaran rk, bhat s. tuberculosis of the urinary tract. in: floege j, johnson rj, feehally j, eds. comprehensive clinical nephrology. science direct ;2010:6 41– 6 4 8. doi.org /10.1016/ b978-0-323-05876-6.00052-6 6. figueiredo a, lucon a, srougi m. urogenital tuberculosis. in schlossberg d, ed. tuberculosis and nontuberculous mycobacterial infections. 7th ed. asm press, washington, dc;2017:355 –370. doi:10.1128/microbiolspec 7. abbara a, davidson rn. etiology and management of genitourinary tuberculosis. nat rev urol.2011;8:678 – 688. doi.org/10.1038/ nrurol.2011.172 8. kapoor r, ansari ms, mandhani a, gulia a. clinical presentation and diagnostic approach in cases of genitourinary tuberculosis. indian j urol.2008;24(3):401–405. doi.org/10.4103/0970-1591.42626 9. department of statistics, malaysia. https://www.dosm.gov.my 10. dollah r, wan hassan ws, peters d, othman z. old threats, new approach and national security in malaysia: issues and challenges in dealing with cross-border crime in east coast of sabah. mediterranean journal of social sciences.2016;7(3,s1):178. 11. kulchavenya e, kholtobin d. diseases masking and delaying the diagnosis of urogenital tuberculosis. ther adv urol.2015;7(6):331–338. doi:10.1177/1756287215592604 12. merchant s, bharati a, merchant n. tuberculosis of the genitourinary system-urinary tract tuberculosis: renal tuberculosis-part i. indian j radiol imaging.2013;23(1):46–63. doi:10.4103/0971-3026.113615 13. kulchavenya e, zhukova i, kholtobin d. spectrum of urogenital tuberculosis. j infect chemother.2013;19(5):880–883. doi:10.1007/ s10156-013-0586-9 14. krishnamoorthy s, palaniyandi v, kumaresan n, govindaraju s, rajasekaran j, murugappan i, et al. aspects of evolving genito urinary tuberculosis-a profile of genito urinary tuberculosis (gutb) in 110 patients. j clin diagn res.2017;11(9):pc01–pc05. doi:10.7860/ jcdr/2017/25882.10557 15. zajaczkowski t. genitourinary tuberculosis: historical and basic science review: past and present. cent european j urol.2012;65(4):182–187. doi:10.5173/ceju.2012.04.art1 76 siuj • volume 3, number 2 • march 2022 siuj.org original research http://doi.org/10.1371/journal.ppat.0010005 http://doi.org/10.1016/j.tube.2015.02.021 http://doi.org/10.1016/j.tube.2015.02.021 http://doi.org/.1037//0033-2909.i26.1.78 http://doi.org/10.1016/j.tube.2003.08.014 http://doi.org/10.1016/b978-0-323-05876-6.00052-6 http://doi.org/10.1016/b978-0-323-05876-6.00052-6 doi:10.1128/microbiolspec http://doi.org/10.1038/nrurol.2011.172 http://doi.org/10.1038/nrurol.2011.172 http://doi.org/10.4103/0970-1591.42626 https://www.dosm.gov.my doi:10.1177/1756287215592604 doi:10.4103/0971-3026.113615 doi:10.1007/s10156-013-0586-9 doi:10.1007/s10156-013-0586-9 doi:10.7860/jcdr/2017/25882.10557 doi:10.7860/jcdr/2017/25882.10557 doi:10.5173/ceju.2012.04.art1 http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. 291siuj.org siuj • volume 3, number 5 • september 2022 editorial “so, is your journal listed on pubmed?” peter c. black, editor-in-chief soc int urol j.2021;3(5):291–292 doi: 10.48083/crdh3191 the most common question we receive from potential readers, reviewers, and authors is: “is the siuj listed in pubmed?” the follow-up question is: “what is your impact factor?” indexing and impact factors have become the currency of medical publishing. for authors to get academic credit for their work, the publication needs to be visible on international platforms like pubmed, pubmed central, medline, scopus, and web of science. the impact factor provides the quality stamp that ensures that the effort is worthwhile. although there are several means to determine the legitimacy of a journal, one of the easiest for the reader and the researcher is to search for the journal in pubmed. so where does that leave fledgling journals that are not yet indexed and do not yet have an impact factor? indexing is a complicated process. a medical journal must apply for indexing and archiving in the united states national library of medicine (nlm, through either medline or pubmed central), which then makes the journal content identifiable through pubmed, the search interface for the nlm[1-3]. most readers would probably be surprised to learn that only a small fraction of journals are accepted into the club of indexed journals on their first attempt. most in fact have to resubmit their portfolio, and they cannot do this for at least 2 years after a failed application. it is critical for the publisher to have its proverbial ducks lined up and to have robust content before submitting. criteria include number of published articles, scope and rigour of scientific content, editorial quality, and production quality. the journal must demonstrate that its practices adhere to various publication and editorial policies. the journal must offer a worthy contribution to the field of biomedicine, ideally covering an area of research and/or geographic location that is relatively under-represented in the scientific literature. journals must generally have at least 2 years of published content before applying for indexing, and they must maintain established publishing schedules to demonstrate sustainability. t he i mpac t f ac tor fol low s i nde x i ng more automatically. an indexed journal will generate an impact factor 2 to 3 years after indexing based on the number of citations per published manuscript. the time from launching a journal to acquiring an impact factor is therefore usually at least 4 to 5 years. many urologists and specialists in affiliated fields have demonstrated open disdain for unlisted journals, along the lines of “i don’t have time for you” and “why would i submit to a journal that is not indexed?” these comments come from prominent and less prominent members of our community, and anywhere along the spectrum from early career researchers to the most senior researchers. we are all busy and have to pick and choose the opportunities to which we can dedicate time. journals like the siuj are dependent on a certain altruistic desire to give back and support a new concept. reviewers will be less deterred by indexing and impact factor than authors. our biggest obstacle with peer review is that many potential reviewers do not recognize the journal and discount it as yet another junk journal asking for something in the daily deluge of emails. time, exposure, and indexing will help us overcome this obstacle. so why invest time in the siuj? the health of our journal is contingent on a grassroots effort by those who are convinced of the mission of the journal and want to contribute to its growth and future success. we are grateful that many members of the siu are loyal to the cause. we are also grateful that many other urologists and contributors from around the world recognize the value in our intent to provide open access content that reflects the global practice of urology at no cost to readers or authors—and that they are keen to promote this endeavour. we have seen remarkable investment http://siuj.org mailto:editorinchief%40siuj.org?subject=siuj 292 siuj • volume 3, number 4 • july 2022 siuj.org editorial from many individuals and networks. the australians probably top the list of contributors, especially on a per capita basis (just like they do in so many sporting events!), but we have received also high-quality input from many other countries including india, pakistan, and countries in africa and the middle east. we do not have an established parent journal on whose shoulders we can stand, which has been such a successful model for many other medical journals. indexing will not come until 2023 at the earliest, and our first impact factor in 2025 or later will undoubtedly be modest, but we have an opportunity to build something unique in the field, something global, diverse, and inclusive. we welcome the input of those who support the concept now—and will welcome those who need indexing and impact factor later. indexing is a priority for the siuj, so that we can increase the reach of our articles and better serve the needs of our authors. it requires careful planning but also continued support from our authors and reviewers who are willing to take the risk on a new journal. references 1. national librar y of medicine. journal selection for medline. available at: https://www.nlm.nih.gov/medline/medline_journal_ selection.html. accessed august 16, 2022. 2. national library of medicine; pubmed central. journal selection for pmc. available at: https://w w w.ncbi.nlm.nih.gov/pmc/pub/ journalselect/. accessed august 16, 2022. 3. national library of medicine; pubmed central. how to include a journal in pmc. available at: https://www.ncbi.nlm.nih.gov/pmc/ pub/addjournal/. accessed august 16, 2022. http://siuj.org https://www.nlm.nih.gov/medline/medline_journal_selection.html https://www.nlm.nih.gov/medline/medline_journal_selection.html https://www.ncbi.nlm.nih.gov/pmc/pub/journalselect/ https://www.ncbi.nlm.nih.gov/pmc/pub/journalselect/ https://www.ncbi.nlm.nih.gov/pmc/pub/addjournal/ https://www.ncbi.nlm.nih.gov/pmc/pub/addjournal/ 191siuj.org siuj • volume 3, number 4 • july 2022 visit bms.com/ca to see how we’re bringing a human touch to everything we do. © 2022 bristol-myers squibb company. all rights reserved. no-ca-2200002 02/22 we are in the business of breakthroughs—the kind that transform patients’ lives. dedicated to our mission of discovering, developing and delivering life-saving innovations that help patients prevail over serious diseases, we’ll never give up our search for more hope, for more people, around the world. volume 3, number 4 | july 2022 issn 2563-6499 doi: 10.48083/ebym4017 editorial office info@siuj.org tel: 514-875-5665 ext. 26 siuj.org managing editor jane fairbanks jane.fairbanks@siu-urology.org the siuj is published 6 times a year by the société internationale d'urologie (siu). it is the official peer-reviewed publication of the siu but retains editorial independence. the siuj is circulated to urologists, urology residents, family medicine specialists, family medicine residents, general practitioners, nurses, medical libraries, and hospital and university departments of urology worldwide, for a total circulation of over 10,000. this publication was developed under the direction of the siuj editorial board. the siuj is published under an exclusive licence. the siuj is owned and published by the société internationale d’urologie (siu). marketing lillian petrusa lillian.petrusa@siu-urology.org advertising mikaela tierney advertising@siuj.org neither the siu nor the siuj endorses any service or the contents of any product referred to in any advertisement in the siuj. the siu and the siuj assume no responsibility or liability for damages arising from any error or omission, or from the use of any information or advice contained in the siuj. all editorial matter in siuj represents the opinions of the authors and not necessarily those of the siu or the siuj. all canadian prescription drug advertisements have been cleared by the pharmaceutical advertising advisory board. editorial board editor-in-chief peter c. black, md, canada associate editors thomas herrmann, md, switzerland kathleen kobashi, md, united states philippe e. spiess, md, united states henry woo, mbbs, australia social media editor jeremy y. c. teoh, mbbs, hong kong sar statistical editor alice dragomir, phd, canada innovators editor amanda chung, mbbs, australia regional editors north america margarett shnorhavorian, md united states middle east danny rabah, mbbs saudi arabia south america sandro esteves, md brazil east asia tianxin lin, md china eastern europe roman sosnowski, md poland south asia sanjay sinha, mch india western europe tamsin greenwell, md united kingdom southeast asia edmund chiong, mbbs singapore africa yasser osman, mbbch egypt http://siuj.org http://bms.com/ca mailto:info%40siuj.org?subject=siuj http://siuj.org mailto:jane.fairbanks%40siu-urology.org?subject=siuj mailto:lillian.petrusa%40siu-urology.org%20?subject=siuj mailto:advertising%40siuj.org?subject=siuj https://siuj.org/index.php/siuj/issue/view/11 192 siuj • volume 3, number 4 • july 2022 siuj.org editorial board liaqat ali, mbbs pakistan abdol mohammad kajbafzadeh, md iran fahad alyami, mbbs saudi arabia wayne lam, mbbs hong kong sar mohsen azli, md algeria sang dong lee, md korea erdem canda, md turkey evelyn moshokoa, mbchb south africa yao-chi chuang, md taiwan andrea necchi, md italy archil chkhotua, md georgia mohammed shahait, mbbs jordan renu eapen, mbbs australia khurram siddiqui, mbbs oman agus rizal ardy hariandy hamid, md indonesia yaya sow, md senegal christopher ho chee kong, md malaysia chuan-liang xu, md china theocharis karaolides, md cyprus the société internationale d’urologie (siu). the society’s mission is to enable urologists in all nations, through international cooperation in education and research, to apply the highest standards of urological care to their patients. the siu is a major international platform for sustainable urological education and collaborative philanthropic activities aimed at improving urological care with more than 10,000 members from over 130 countries. siu central office 1155 robert-bourassa blvd., suite 1012 montreal, quebec, canada h3b 3a7 tel: +1 514 875-5665 fax: +1 514 875-0205 communications@siu-urology.org executive director susie petrusa susie.petrusa@siu-urology.org graphic design sam design info@studiosamdesign.com web design/ technical support aiki informatique info@aikitech.ca neither the siu nor the siuj endorses any service or the contents of any product referred to in any advertisement in the siuj. the siu and the siuj assume no responsibility or liability for damages arising from any error or omission, or from the use of any information or advice contained in the siuj. all editorial matter in siuj represents the opinions of the authors and not necessarily those of the siu or the siuj. all canadian prescription drug advertisements have been cleared by the pharmaceutical advertising advisory board. http:// mailto:communications%40siu-urology.org?subject=siuj mailto:susie.petrusa%40siu-urology.org?subject=siuj mailto:susie.petrusa%40siu-urology.org?subject=siuj mailto:info%40studiosamdesign.com%20?subject=siuj mailto:info%40studiosamdesign.com%20?subject=siuj mailto:info%40aikitech.ca?subject=siuj this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information penile cancer, treatment, resources none declared. soc int urol j.2022;3(6):367–369 doi: 10.48083/sxse9843 why should the indian urology and oncology community be “aatmanirbhar” in penile cancer research? gagan prakash department of surgical oncology, tata memorial centre, homi bhabha national institute, mumbai, india the hindi word “aatmanirbhar” means self-reliant. it became popular after the “aatmanirbhar bharat” policies of the current indian government, and it was named oxford hindi word of the year 2020[1]. the term should not be confused with being “self-contained” or “isolating away from the world” and it appropriately highlights the need for adopting this philosophy by indian urological, surgical, and oncological communities with respect to penile cancer research. india has one of the highest incidences of penile cancer, with an age-standardized rate(asr) of 1.4 and a crude rate of 1.3 which is almost the same as the rate for kidney cancer and not far behind that of bladder cancer[2]. in fact, penile cancer is the only urological cancer in which the asr in india exceeds that of world (figure 1). the european union defines rare cancers as those with an incidence of less than 6 per 100 000 population per year. by this definition, prostate, bladder, kidney, and penile cancers would all be considered rare in india. this is in contrast with high and high–medium-income countries (hic, hmic) where the incidence of penile cancer is much lower than that of other urological cancers. a recent editorial from the members of the newly formed global society of rare genitourinary tumors (gsrgt) pointed out the dichotomy of penile cancer research and incidence: 90% of the publications related to rare genitourinary cancers come from hic and hmic, despite these countries having the lowest incidence of these cancers[3]. despite having one of the highest incidences of penile cancer, india has hardly any ongoing clinical trials. the meagre involvement of low and low–middle-income countries (lmic) in clinical and translational cancer research is well-documented. a recent study reported that only 8% of randomized clinical trials in oncology are from lmic[4]. in other urological cancer sites, the evidence generated in hic bridges the need for clinical practice in lic and lmic. for instance, even though > 60% of prostate cancer patients in india present with metastases compared with < 4% in the united states, almost all practice-changing evidence that transformed the management of metastatic prostate cancer in the last decade was generated in the united states, the united kingdom, and europe[5]. this however may not be possible with rare tumors like penile cancer. india should consider this as both a responsibility and an opportunity to lead the way in generating evidence for this not so rare cancer here. the results of 2 recent surveys representing different parts of the world have clearly highlighted the lack of consensus and the variation in patterns of practice in penile cancer management. the first survey was conducted by eurogen across 10 european countries and found a significant variation in techniques of dynamic sentinel lymph node biopsy (dsnb) and templates and boundaries of inguinal lymph node dissection[6]. the more recent survey amongst 1003 members of the society of urologic oncology (suo) highlighted a poor utilization of dsnb despite strong evidence showing its oncological efficacy and favourable immediate and long-term morbidity[7]. while we expect similar lack of consensus amongst indian centres, the difference is that we have the potential to answer many of these questions for ourselves and for the rest of the world. the implication of human papilloma virus (hpv) is being explored in the west 367siuj.org siuj • volume 3, number 6 • november 2022 urology around the world https://orcid.org/0000-0003-1722-4337 mailto:gagan2311%40gmail.com?subject=siuj http://siuj.org in relation to aggressiveness of surgery of primary, selection of patients for radiotherapy, and prognostication. while similar studies have been done on indian patients with head and neck cancers, for penile cancer even basic data about incidence and serotyping of hpv are lacking. penile length has a global variation, and an indian study found flaccid and stretched lengths of our men to be shorter than those in the western countries[8]. shorter length combined with pre-pubic fat causes buried penis, which might translate into more patients requiring a total penectomy. construction and validation of tools to gather quality of life information with respect to urinary and sexual function and options of penile reconstruction need exploration. the european association of urology risk stratification has been conventionally used since 2016 when it was first published. recent studies have looked at factors that could better predict micro metastatic disease in clinically node negative groins, and it is encouraging to see 2 such large single-centre series from india[9]. reflecting the findings of the suo survey, the use of inguinal sentinel node biopsy in india is limited. the standardization of the more frequently used surgical procedure, its boundaries, and false negative rates are missing in urological guidelines, and india is clearly in a position to fill this gap. the perioperative management of node positive penile cancer patients has a series of unanswered questions related to chemotherapy, radiotherapy, sequencing, and extent. the inpact trial is a pragmatically designed study which should put to rest many of these issues and can make a difference in the outcome of many patients globally[10]. unfortunately, the trial has a slow accrual rate and although india sees a higher proportion of node positive patients at presentation and can potentially contribute significantly to the accrual rate of this trial, not even a single indian centre has been on board for this study so far. so, how to address this dichotomy of paucity of studies despite a higher incidence of disease in this part of the world? lack of centralization of health and cancer care has been considered by some as a possible impetus. considering the vastness of this country and variability in health insurance schemes, empowering decentralized cancer care is a more sustainable long-term solution. the national cancer grid (ncg) envisioned this almost a decade ago and has now close to 250 cancer centres on board[5]. one of the mandates of ncg is to facilitate basic, translational, and clinical research in cancer, and collaboration of centres treating penile cancer from ncg could be an easy pathway. india has the advantage of having a spectrum of treatment modalities across its centres. use of tc99m-nanocolloid and or indocyanine green when dsnb is performed, and open, laparoscopic, or robotic approaches when the groins are addressed invasively, are all practiced in the same country. collaboration across centres could convert this variation in treatment practice into an advantage that may not be possible in many other countries. the ongoing pandemic has made it very clear that geographical distance is not an impediment to education, and collaborative research should follow the same path. the urological society of india and the association of surgeons of india with its surgical oncology chapter (iaso) and ncg will support future penile cancer research that will put india on the map. figure 1. asr of urological cancers in india versus the world. a ge -s ta nd ar di ze d in ci de nc e/ 10 0 00 0 in di vi du al s prostate bladder renal testicular penile 0 5 10 15 20 25 30 35 30.7 5.5 5.6 1.6 4.6 1.3 1.8 0.63 0.8 1.6 cancer world india data source: globocan 2020 world health organization ©international agency for research on cancer 2020 all rights reserved 368 siuj • volume 3, number 6 • november 2022 siuj.org urology around the world http://siuj.org references 1. “aatmanirbharta” selected as oxford hindi word of 2020. times of india. february 4, 2021. available at: indiatimes.com. accessed september 28, 2022. 2. sung h, ferlay j, siegel rl, laversanne m, soerjomataram i, jemal a, et al. global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin.2021 feb 4:. doi: 10.3322/caac.21660 3. bandini m, ahmed m, basile g, watkin n, master v, zhu y et al. a global approach to improving penile cancer care. nat rev urol.2021 dec 22: 022 apr;19(4):231-239. doi: 10.1038/s41585-021-00557-y. epub 2021 dec 22. erratum in: nat rev urol.2022 apr;19(4):253. doi: 10.1038/s41585-022-00569-2. 4. wells jc, sharma s, del paggio jc, hopman wm, gyawali b, mukherji d, et al. an analysis of contemporary oncology randomized clinical trials from low/middle-income vs high-income countries. jama oncol.2021 mar1;7(3):379-385. doi:10.1001/jamaoncol.2020.7478 5. sirohi b, chalkidou k, pramesh cs, anderson bo, loeher p, el dewachi o, et al. developing institutions for cancer care in low-income and middle-income countries: from cancer units to comprehensive cancer centres. lancet oncol.2018 aug;19(8):e395-e406. doi: 10.1016/ s1470-2045(18)30342-5 6. fankhauser cd, ayres be, issa a, albersen m, watkin n, muneer a, et al. practice patterns among penile cancer surgeons performing dynamic sentinel lymph node biopsy and radical inguinal lymph node dissection in men with penile cancer: a eurogen survey. eur urol open sci.2021 jan 7;24:39-42. doi: 10.1016/j.euros.2020.12.009. pmid: 34337494; pmcid: pmc8317807. 7. marilin n, master va, pettaway ca, spiess pe. current practice patterns of society of urologic oncology members in performing inguinal lymph node staging/therapy for penile cancer: a survey study. urol oncol.2021 jul;39(7):439.e9-439.e15. doi:10.1016/j. urolonc.2021.03.007. epub 2021 mar 26. pmid: 33775532. 8. promodu k, shanmughadas k v, bhat s, nair kr. penile length and circumference: an indian study. int j impot res.20 07 nov-dec;19(6):558-63. doi:10.1038/sj.ijir.3901569. epub 2007 jun 14. pmid: 17568760. 9. sali ap, prakash g, de cássio zequi s, da costa wh, murthy v, soares fa, et al. a comparative study of ajcc and the modified staging system in pt2/pt3 penile squamous cell carcinoma a validation on an external data set. histopathology.2022 feb;80(3):566-574. doi: 10.1111/his.14575. epub 2021 dec 28. pmid:34586682. 10. canter dj, nicholson s, watkin n, hall e, pettaway c; inpact executive committee. the international penile advanced cancer trial (inpact): rationale and current status. eur urol focus.2019 sep;5(5):706-709. doi:10.1016/j.euf.2019.05.010. epub 2019 jun 1. pmid: 31160252. 369siuj.org siuj • volume 3, number 6 • november 2022 why should the indian urology and oncology community be “aatmanirbhar” in penile cancer research? http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information benign prostatic obstruction, endoscopic enucleation of the prostate, perioperative outcomes, robotic-assisted simple prostatectomy none declared. received on january 31, 2021 accepted on march 27, 2021 soc int urol j.2021;2(4):196–209 doi: 10.48083/lkvv8843 perioperative outcomes of anatomic endoscopic enucleation of the prostate, robotic and open simple prostatectomy from a multi-institutional database muhieddine labban,1 nassib abou heidar,1 vincent misrai,2 jad najdi,1 hani tamim,3 albert el-hajj1 1 american university of beirut medical center, department of surgery, division of urology, beirut, lebanon 2 department of urology, clinique pasteur, toulouse, france 3 american university of beirut medical center, clinical research institute, beirut, lebanon ml & nah contributed equally to the manuscript. abstract objective to compare the perioperative morbidity of robotic-assisted simple prostatectomy (rasp), anatomical endoscopic enucleation of the prostate (aeep) and open simple prostatectomy (osp) for the treatment of benign prostatic obstruction (bpo). methods the national surgical quality improvement program database was queried for aeep, rasp, and osp procedures. clavien-dindo-graded complications, length of hospital stay (los), and operative time were compared among the procedures. to control for the potentially confounding variables, we first conducted a multivariate backward conditional logistic regression, and then resorted to propensity score matching. results we identified 2867 aeep, 234 rasp, and 1492 osp procedures. after matching, the risk of pulmonary, renal, infectious, and thromboembolic adverse events was lower after aeep but not rasp in comparison with osp (p < 0.05). in comparison with rasp, aeep had lower cardiac and thromboembolic events (p < 0.05). when compared with osp, aeep had reduced odds of clavien-dindo grade i (or = 0.12; 95% ci 0.10 to 0.16) and ii (or = 0.38; 95% ci 0.24 to 9.58) complications. also, aeep had lower odds for grade i and ii as well as grade iv complications (or = 0.30; 95% ci 0.19 to 0.48, and or = 0.05; 95% ci 0.01 to 0.24, respectively) compared with rasp. conclusion aeep and rasp were associated with fewer perioperative adverse events, a shorter los and a reduced risk of transfusion compared with osp. aeep was associated with overall lower complication rates than rasp and osp. introduction benign prostatic obstruction (bpo) is a common cause of lower urinary tract symptoms with a 75% prevalence in men older than 50 years[1]. bpo significantly impacts quality of life, often necessitating medical or surgical treatment[2]. the current standard of care advocates for anatomical endoscopic enucleation of the prostate (aeep) of smaller prostates (< 80 grams) and recommends aeep or simple prostatectomy for the treatment of larger prostates (> 80 grams)[3]. nevertheless, open simple prostatectomy (osp) remains the goldstandard treatment for large glands[4]. recently, robotic-assisted simple prostatectomy (rasp) has gained popularity among robotic surgeons as a minimally invasive method to enucleate large prostatic adenomas. 196 siuj • volume 2, number 4 • july 2021 siuj.org original research mailto:ae67%40aub.edu.lb?subject=siuj http://www.siuj.org it has similar functional outcome to osp, while potentially limiting postoperative morbidity, especially bleeding and length of hospital stay[5–7]. the aeep imitates the traditional millins procedure by endoscopically enucleating the prostatic adenoma. holium laser enucleation of the prostate (holep) was first described by gilling in 1998. in comparison to osp, aeep has demonstrated similar functional outcomes and efficacy in larger prostates, but reduced rate of overa ll complications and postoperative transfusion[8–10]. currently, aeep, rasp, and osp are part of the surgical armamentarium when dealing with large prostates, and proponents of each technique defend its superiority over the others; however, there are no large studies comparing the 3 procedures, and certainly no randomized clinical trials. umari et al. showed that rasp has comparable functional outcomes to aeep, while zhang et al. showed that aeep conferred a shorter hospital stay, reduced catheter time, and had lower transfusion rates than rasp[11–13]. both studies showed similar complication rates between rasp and aeep. nevertheless, both studies are small retrospective series. sorokin et al. and mourmouris et al. retrospectively compared rasp and osp and found that despite having comparable functional outcomes, rasp had reduced blood loss and catheterization time at the expense of a longer operative time[7,14]. the systematic review of rasp by kordan et al. incorporated several single-center retrospective studies, which included a limited number of rasp procedures[15]. therefore, using a large multi-institutional real-world dataset, we sought to compare head-to-head the perioperative surgical outcomes of aeep, rasp, and osp using diffe rent statistical methods to cross-validate our findings. materials and methods the american college of surgeons national surgical quality improvement program is a prospectively filled, risk-adjusted, and validated 30-day outcome registry with contributions from 703 different hospitals, most of which are in the united states[16]. since our institution is a participating hospital, access to the deidentified database is granted and formal consent is not required. the database includes information on patients’ demographics, comorbidities, and 30-day postoperative outcomes that are entered by american college of surgeons (acs) trained surgical clinical reviewers. the database was queried for aeep, rasp, and osp without any concurrent procedures performed between 2008 and 2017. since there is no dedicated current procedural terminology (cpt) code for rasp, the cpt code for abbreviations aeep anatomical endoscopic enucleation of the prostate bpo benign prostatic obstruction copd chronic obstructive pulmonary disease cpt current procedural terminology holep holium laser enucleation of the prostate los length of stay mace major adverse cardiac event osp open simple prostatectomy rasp robotic-assisted simple prostatectomy figure 1. flowchart describing the selection criteria for patients who underwent anatomic endoscopic enucleation of the prostate (aeep) or robotic-assisted simple prostatectomy (rasp) or open simple prostatectomy (osp) from the national surgical quality improvement program (nsqip) patients registered in acs nsqip database 2008–2017 n = 6 274 508 comparision of the perioperative morbidity aeep-group rasp-group osp-group address procedure selection bias propensity score matching based on age, asa class, bmi, predisposition to bleeding, copd, congestive heart failure, functional status, hypertension, and diabetes, and operative year 4593 patients underwent either eep or rasp or osp between 2008 and 2017 49 371 patients were excluded if procedure was not done for benign prostatic obstruction (icd 9: 600.0-600.9) or because of concurrent procedures cpt 52 649 (eep = 2880) or cpt 55 866 (rasp = 49 299) or cpt 55 821 (osp = 1140) or cpt 55 831 (osp = 645 ) n = 53 964 197siuj.org siuj • volume 2, number 4 • july 2021 perioperative outcomes of anatomic endoscopic enucleation of the prostate http://siuj.org rarp (55866) is used by surgeons. to select procedures done for bpo, all cases were filtered by the international classification of diseases -9 (icd-9) codes 600.00600.90 or icd-10 n40.00-n40.90, corresponding to the postoperative diagnosis of bpo procured from either brief postoperative note, operative report, and/or the pathology reports (figure 1). the cpt codes for aeep (52649) and osp (55821 & 55831) were also selected. even though the energy source for aeep cannot be extracted from the database, holep is currently the most commonly used energy source for aeep in the united states[17]. as a primary endpoint, this study aimed to compare 30-day perioperative surgical complications and early mortality between aeep, rasp, and osp. baseline patient demographics, comorbidities, and laboratory markers were collected and managed. c omorbid it ie s i ncluded a mer ic a n s oc iet y of anesthesiologists (asa) class ≥ 3, corresponding to patients with severe systemic disease, diabetes, hypertension, being partially or totally physically dependent, chronic obstructive pulmonary disease (copd), history of heart failure, myocardial infarction, and disseminated cancer. additionally, the variables bleeding diathesis and long-term pharmaceutical steroid or immunosuppressant use were added. the variable bleeding diathesis incorporated patients on chronic anticoagulation therapy that had not been discontinued prior to the procedure, and patients with genetic hematological diseases. the variable chronic steroid use included patients who had regular intake of oral or parenteral corticosteroid medications or immunosuppressants for a chronic medical condition. we investigated the rate of anemia (hematocrit < 35%), thrombocytopenia (< 150 × 103/µl), and elevated serum creatinine (creatinine > 1 mg/dl). we performed 3 comparisons: (1) osp versus aeep, (2) osp versus rasp, and (3) rasp versus aeep. first, using a backward conditional logistic regression, we compared the 30-day perioperative procedural outcomes fac tored by orga n system, prolonged operative time, a nd ex tended leng t h of hospita l stay (los > 1 day) of the 3 procedures (rasp, aeep, and osp). second, to mitigate the effect of procedure selection bias and potential confounding variables, propensity score matching (psm) with replacement (giving priority to exact matches) was used to assess procedure-specific outcomes. this method would further decrease bias especially when dealing with very different numbers between the 3 arms[18]. baseline demographics before and after matching are found in supplementary table 1. we defined major adverse cardiac event (mace) as the incidence of one or more of the following: myocardial infarction, stroke/ cardiovascular events, cardiac arrest necessitating cardiopulmonary resuscitation (cpr), and death[19]. the pulmonary complications captured pneumonia and unplanned intubation events. we also identified patients with acute or progressive postoperative renal insufficiency requiring dialysis. then, we gathered the occurrences of urinary tract infections, sepsis, and septic shock under infectious outcomes, and pulmonary embolism and deep venous thrombosis under venous thromboembolism (vte). we also explored the rate of intraoperative and postoperative bleeding within the first 72 hours of surgery starting time. moreover, we designated composite morbidity as the combination of pulmonary, renal, infectious, m ace , v t e , a nd t ra nsf u sion outcomes. we further categorized acs-national surgical quality improvement program (nsqip) surgical outcomes in clavien-dindo grades according to previously published studies[20,21]. clavien-dindo grade i and grade ii represent occurrences of surgical site infection (ssi), deep incisional ssi, organ space ssi, fascial dehiscence, pneumonia, urinary tract infections, deep venous thrombosis, progressive renal insufficiency, bleeding requiring transfusion. grade iii represents reoperation. grade iv encompasses sepsis, septic shock, pulmonary embolism, myocardia l infarction, cardiac arrest necessitating cpr, unplanned intubation, ventilator dependence > 48 hours, acute renal failure necessitating dialysis, stroke, and coma. grade v represents death. statistics we compared patient demographics, comorbidities, and preoperative laboratory markers, and computed outcomes between the 3 procedures using mannwhitney u test for continuous variables and chisquare test or fisher exact test for categorical variables. furthermore, a multivariate conditional backward logistic regression was constructed for each of the designated outcomes and adjusted for demographics, comorbidities, surgical procedure and the year the procedure was performed in. since observational studies are subject to treatmentselection bias, psm allows estimation of treatment effect based on treatment assignment conditional to the accounted covariates[18,22]. propensity score matching was used to adjust for covariates that could influence the choice of treatment of bpo: age, asa class, body mass index, copd, congestive heart failure, functional status, diabetes, hypertension, predisposition for bleeding, and the year of surgery to account for possible effect of the learning curve and changes in technique across the years. using the generated propensity scores, weighted logistic regression analysis was conducted for the same outcomes. all analyses were conducted using the spss statistics for windows, version 25 (ibm corp., armonk, ny, us). 198 siuj • volume 2, number 4 • july 2021 siuj.org original research http://siuj.org results this series included 2867 aeep, 234 rasp, and 1492 osp procedures. figure 2 depicts the annual trends for the different procedures. while rasp has a constant proportion over the years, osp caseload decreased at the expense of more aeep procedures. a total of 24.3%, 25.2%, and 27.3% of patients undergoing aeep, rasp, and osp, respectively, had an average age > 75. patient demographics and comorbidities were similar for all 3 procedures, except a higher proportion of patients undergoing aeep had disseminated cancer (0.7%), were on chronic steroid treatment (2.5%), or were on anticoagulation (3.1%); (p = 0.019, p = 0.015, p = 0.012, respectively) (table 1). there was also no difference in the rates of diabetes, hypertension, and copd (p = 0.967, p = 0.470, and p = 0.304, respectively). in our cohort, there was an equal proportion of patients (0.4%) on dialysis who underwent either of aeep or osp (p > 0.05). additionally, the aeep group had the highest proportion of patients with hematocrit < 35% (22.9%) and platelet count < 150k (26.3%) while the osp group had the highest proportion of patients with inr ≥ 1.1 (19.1%) (p < 0.001 for all variables). aeep had the shortest median (interquartile range) operative time of the 3 procedures: 93 (59 to 131) minutes for aeep versus 184 (149 to 234) minutes for rasp and 109 (82 to 152) minutes for osp (p < 0.001; table 2). at the univariate level, fewer complications were observed with aeep and rasp compared to osp, yet there was no significant difference in rates of return to the operating room and 30-day mortality among the 3 procedures (p > 0.05). af ter adjusting for other covariates, aeep had decreased odds of postoperative pulmonary, renal, infectious, cardiac, and thromboembolic complications in comparison with osp (p < 0.05) (table 3). aeep versus rasp conferred lower odds of mace (or = 0.18; 95% ci 0.04 to 0.75) and vte (or = 0.22; 95% ci 0.06 to 0.82). these findings were echoed in the psm model. furthermore, after matching, aeep had lower odds of clavien-dindo grade i & ii adverse events (aeep versus osp, or = 0.14; 95% ci 0.10 to 0.20, and aeep versus rasp, or = 0.40; 95% ci 0.26 to 0.62) (table 4). aeep also had reduced odds of grade iv complications (aeep versus rasp, or = 0.20; 95% ci 0.09 to 0.45, and aeep versus osp, or = 0.29; 95% ci 0.12 to 0.71) in comparison with osp and r asp, respectively. nevertheless, the type of surgery did not predict early postoperative mortality (clavien-dindo grade v). despite having the largest proportion of patients with bleeding diathesis (3.1%), aeep was associated with a significantly lower risk for bleeding necessitating blood product transfusion than both osp and aeep; (aeep versus osp, or = 0.06; 95% ci 0.04 to 0.11, and aeep versus rasp, or = 0.18; 95% ci 0.10 to 0.35). additionally, aeep was associated with a shorter los and decreased risk of overall morbidity than both osp and rasp (p < 0.05). similarly, the odds of operative time exceeding 90 minutes were lower for aeep (aeep versus osp, or = 0.56; 95% ci 0.45 to 0.70; aeep versus rasp or = 0.08; 95% ci 0.05 to 0.14). discussion we used a real-world national database to provide objective operative outcome comparison between aeep, rasp, and osp: 3 procedures dedicated for the surgical management of symptomatic large prostates. when taking osp as a reference, both aeep and rasp had a shorter hospital stay and lower transfusion rates. additionally, in comparison with osp and rasp, aeep had shorter operative time, shorter los, lower transfusion rates, and decreased odds of grade i and ii as well as grade iv complications. bpo resulting from large adenomas poses a more challenging decision-making process. the american urologica l association 2020 guidelines indicate that treatment options for large glands include open, laparoscopic, or robotically assisted simple prostatectomy, and that laser enucleation with rasp and aeep have a lower risk profile because of their minimally invasive nature[4]. meyer et al. documented the shift in numbers from osp to rasp in the last decade, which they speculate occurred because the availability of robotics has made this the most costeffective approach and it requires no further training[23]. 2008 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 2009 2010 2011 2012 2013 2014 2015 pr op or tio n pe rc en t ( % ) operative year aeep osp rasp figure 2. annual trends for endoscopic enucleation of the prostate (aeep) or robotic-assisted simple prostatectomy (rasp) or open simple prostatectomy (osp) 199siuj.org siuj • volume 2, number 4 • july 2021 perioperative outcomes of anatomic endoscopic enucleation of the prostate http://siuj.org table 1. baseline demographics, comorbidities, and laboratory markers among patients who have benign prostate obstruction who underwent anatomic endoscopic enucleation of the prostate (aeep) or robotic assisted simple prostatectomy (rasp) or open simple prostatectomy (osp) variable aeep (n = 2867) n (%) rasp (n = 234) n (%) osp (n =1492) n (%) p-value non-white 259 (9.7) 32 (14.2) 210 (15.4) < 0.0001 ≤65 962 (33.9) 66 (28.2) 407 (27.4) < 0.0001 65 – ≤75 1187 (41.8) 109 (46.6) 674 (45.3) >75 692 (24.3) 59 (25.2) 406 (27.3) asa ≥ 3 1331 (46.4) 101 (43.2) 706 (47.3) 0.485 bmi ≥ 30 986 (34.4) 72 (30.8) 546 (36.6) 0.137 diabetes 522 (18.2) 44 (18.8) 270 (18.1) 0.967 smoker 265 (9.2) 20 (8.5) 130 (8.7) 0.816 dependenta 52 (1.8) 2 (0.9) 20 (1.3) 0.396 copd 115 (4.0) 7 (3.0) 47 (3.2) 0.304 heart failure 12 (0.4) 0 (0.0) 4 (0.3) 0.747 hypertension 1,646 (57.4) 144 (61.5) 861 (57.7) 0.470 dialysis 11 (0.4) 0 (0.0) 6 (0.4) 1.0000 disseminated cancer 20 (0.7) 0 (0) 2 (0.1) 0.019 chronic steroid 73 (2.5) 4 (1.7) 19 (1.3) 0.015 myocardial infarction 2 (0.1) 0 (0.0) 0 (0.0) 0.603 bleeding diathesisb 89 (3.1) 2 (0.9) 28 (1.9) 0.012 creatinine >1 1,235 (43.1) 105 (44.9) 686 (46.0) 0.182 albumin < 3.5 744 (26.0) 91 (38.9) 537 (36.0) < 0.0001 leukocyte > 6.5k 1,314 (45.8) 125 (53.4) 858 (57.5) < 0.0001 hematocrit < 35% 656 (22.9) 29 (12.4) 249 (16.7) < 0.0001 platelet < 150k 753 (26.3) 44 (18.8) 196 (13.1) < 0.0001 inr ≥ 1.1 366 (12.8) 31 (13.2) 285 (19.1) < 0.0001 asa: american society of anesthesiology; bmi: body mass index; copd: chronic obstructive pulmonary disorder; inr: international normalized ratio. adependent patients require partial or total assistance from another person for daily activities. b bleeding diathesis is defined as any chronic or persistent condition that places the patient at risk of excessive bleeding, including chronic anticoagulation that has not been discontinued prior to the procedure. 200 siuj • volume 2, number 4 • july 2021 siuj.org original research http://siuj.org our results ref lect the findings of a meta-analysis compiling 37 observational studies that explored the role of minimally invasive technique in simple prostatectomy and revealed that this procedure offers decreased blood loss and shorter los with comparable functional outcomes to osp[24]. the largest reported outcome series for laparoscopic simple prostatectomy and rasp (n = 1330) was from an american-european multicenter study[25]. the cohort had a median operative time of 100 minutes, a median estimated blood loss of 200 ml, and a median los of 4 days[25]. besides, 10.6% of the patients had a clavien-dindo grade l or grade ll complication[25]. although the findings are consistent with our results, no large studies have compared rasp with aeep. the patients in our cohort undergoing either procedure were similar in baseline characteristics with patient ≥ 75 representing around a quarter of patients undergoing any of the 3 procedures[26]. on the other hand, patients on chronic anticoagulation were more likely to undergo aeep. although the risk of bleeding was considerable for patients on anticoagulation, the rate of transfusion was significantly lower with aeep than with either osp or rasp. this could be table 2. univariate analysis for postoperative outcomes following anatomic endoscopic enucleation of the prostate (aeep), robotic-assisted simple prostatectomy (rasp), and open simple prostatectomy (osp) for benign prostatic obstruction variable aeep (n = 2867) n (%) rasp (n = 234) n (%) osp (n =1492) n (%) p-value pulmonarya 8 (0.3) 2 (0.9) 26 (1.7) < 0.0001 renalb 6 (0.2) 0 (0.0) 14 (0.9) 0.003 infectiousc 93 (3.2) 12 (5.1) 98 (6.6) < 0.0001 maced 8 (0.3) 3 (1.3) 15 (1.0) 0.002 vtee 8 (0.3) 3 (1.3) 29 (1.9) < 0.0001 transfusionf 38 (1.3) 16 (6.8) 275 (18.4) < 0.0001 los > 1 day 441 (15.4) 157 (67.1) 1 338 (89.7) < 0.0001 operative time 93 (59 – 131) 184 (149 – 234) 109 (82 – 152) < 0.0001 return to or 54 (1.9) 6 (2.6) 45 (3.0) 0.057 mortality 3 (1.3) 1 (0.4) 3 (0.2) 0.227 composite morbidityg 150 (5.2) 32 (13.7) 389 (26.1) < 0.0001 mace: major adverse cardiac event; vte: venous thromboembolism; los: length of hospital stay; or: operating room. apneumonia and unplanned intubation; bacute and progressive renal failure; curinary infections, sepsis, and septic shock; dmyocardial infarction, stroke/ cardiovascular events, cardiac arrest necessitating cardiopulmonary resuscitation, and death; epulmonary embolism and deep venous thrombosis; fbleeding requiring transfusion; gpulmonary, renal, infectious, mace, vte, transfusion outcomes. 201siuj.org siuj • volume 2, number 4 • july 2021 perioperative outcomes of anatomic endoscopic enucleation of the prostate http://siuj.org table 3. multivariate backward conditional logistic regression comparing the perioperative outcomes of endoscopic anatomic enucleation of the prostate (aeep), robotic-assisted simple prostatectomy (rasp),and open simple prostatectomy (osp) postoperative outcomes osp aeep or (95%ci) rasp or (95%ci) rasp aeep or (95%ci) pulmonarya reference 0.19 (0.09 – 0.44) p < 0.001 0.62 (0.14 – 2.68) p = 0.52 reference – renalb reference 0.14 (0.04 – 0.47) p = 0.002 – reference – infectiousc reference 0.49 (0.36 – 0.66) p < 0.001 0.89 (0.48 – 1.66) p = 0.71 reference 0.54 (0.29 – 1.01) p = 0.05 maced reference 0.27 (0.11 – 0.67) p = 0.005 1.12 (0.30 – 4.19) p = 0.87 reference 0.18 (0.04 – 0.75) p = 0.02 vtee reference 0.16 (0.07 – 0.35) p < 0.001 0.59 (0.17 – 2.03) p = 0.40 reference 0.22 (0.06 – 0.82) p = 0.03 ot > 90 min reference 0.48 (0.42 – 0.56) p < 0.001 7.36 (4.32 – 12.53) p < 0.001 reference 0.09 (0.05 – 0.15) p < 0.001 transfusionf reference 0.04 (0.03 – 0.07) p < 0.001 0.30 (0.17 – 0.52) p < 0.001 reference 0.14 (0.07 – 0.27) p < 0.001 los > 1 day reference 0.02 (0.01 – 0.03) p < 0.001 0.18 (0.13 – 0.27) p < 0.001 reference 0.08 (0.06 – 0.12) p < 0.001 composite morbidityg reference 0.14 (0.11 – 0.18) p < 0.001 0.45 (0.30 – 0.68) p < 0.001 reference 0.30 (0.20 – 0.46); p < 0.001 clavien-dindo grade complications grade i & ii cd reference 0.12 (0.10 – 0.16) p < 0.001 0.38 (0.24 – 9.58) p < 0.001 reference 0.30 (0.19 – 0.48) p < 0.001 return to or reference – – reference – grade iv cd reference 0.26 (0.16 – 0.42); p < 0.001 – reference 0.05 (0.01 – 0.24) p < 0.001 mortality reference – – reference – cd: clavien-dindo; ci: confidence interval mace: major adverse cardiac event; vte: venous thromboembolism; or: odds ratio; ot: operative time apneumonia and unplanned intubation; bacute and progressive renal failure; curinary infections, sepsis, and septic shock; dmyocardial infarction, stroke/ cardiovascular events, cardiac arrest necessitating cardiopulmonary resuscitation, and death; epulmonary embolism and deep venous thrombosis; fbleeding requiring transfusion; gpulmonary, renal, infectious, mace, vte, transfusion outcomes. logistic regression model adjusted for race, age, american society of anesthesiology (asa) class, functional dependence, body mass index (bmi), smoking, diabetes, hypertension, predisposition to bleeding (includes anticoagulation), chronic obstructive pulmonary disease (copd), history of heart failure, dialysis dependence, chronic steroid use, history of disseminated cancer, laboratory markers (creatinine, leukocyte count, hematocrit, platelet count), and surgical procedure (aeep versus rasp versus osp), and year of operation. 202 siuj • volume 2, number 4 • july 2021 siuj.org original research http://siuj.org table 4. propensity score matching comparing the perioperative outcomes of anatomic endoscopic enucleation of the prostate (aeep), robotic-assisted simple prostatectomy (rasp), and open simple prostatectomy (osp) postoperative outcomes osp aeep or (95%ci) rasp or (95%ci) rasp aeep or (95%ci) pulmonarya reference 0.15 (0.04 – 0.60) p = 0.007 0.45 (0.09 – 2.28) p = 0.336 reference 0.36 (0.07 – 1.92) p = 0.228 renalb reference 0.12 (0.02 – 0.90) p = 0.04 reference infectiousc reference 0.47 (0.28 – 0.77) p = 0.003 0.79 (0.41 – 1.54) p = 0.493 reference 0.61 (0.32 – 1.17) p = 0.608 maced reference 0.26 (0.06 – 1.15) p = 0.08 1.32 (0.35 – 5.00) p = 0.681 reference 0.22 (0.05 – 0.87) p = 0.03 vtee reference 0.13 (0.03 – 0.50) p = 0.003 0.67 (0.18 – 2.44) p = 0.544 reference 0.26 (0.09 – 0.92) p = 0.03 ot > 90 min reference 0.56 (0.45 – 0.70) p < 0.001 6.01 (3.45 – 10.45) p < 0.001 reference 0.08 (0.05 – 0.14) p < 0.001 transfusionf reference 0.06 (0.04 – 0.11) p < 0.001 0.33 (0.19 – 0.59) p < 0.001 reference 0.18 (0.10 – 0.35) p < 0.001 los > 1 day reference 0.02 (0.01 – 0.03) p < 0.001 0.24 (0.17 – 0.35) p < 0.001 reference 0.09 (0.06 – 0.12) p < 0.001 composite morbidityg reference 0.15 (0.11 – 0.22) p < 0.001 0.46 (0.30 – 0.71) p < 0.001 reference 0.35 (0.22 – 0.53) p < 0.001 clavien-dindo grade complications grade i & ii reference 0.14 (0.10 – 0.20) p < 0.001 0.40 (0.26 – 0.62) p < 0.001 reference 0.36 (0.23 – 0.56) p < 0.001 return to or reference – – reference – grade iv reference 0.20 (0.09 – 0.45) p < 0.001 0.76 (0.32 -1.79) p = 0.527 reference 0.29 (0.12 – 0.71) p = 0.007 mortality reference 0.56 (0.03 – 9.86) p = 0.693 2.19 (0.20 – 23.36) p = 0.518 reference 0.23 (0.02 – 2.39) p = 0.220 cd: clavien-dindo; ci: confidence interval; mace: major adverse cardiac event; vte: venous thromboembolism; or: odds ratio; ot: operative time. covariates included in the psm model were age category, asa class, bmi, copd, congestive heart failure, hypertension, diabetes, functional status, predisposition to bleeding, and year of operation. 203siuj.org siuj • volume 2, number 4 • july 2021 perioperative outcomes of anatomic endoscopic enucleation of the prostate http://siuj.org attributed to the use of lasers, with the ability to heat wel l-vascu la r i z ed t issue t hereby cou nterac t i ng bleeding[27]. further, a high power (80 to 100 w) energ y source can achieve simultaneous cutting and coagulation[27]. consequently, aeep is a safer modality than rasp for the treatment of patients on anticoagulation[28,29]. furthermore, our results echo the findings of other studies that show aeep is associated with the least blood loss among the 3 modalities[8,30]. in our study, aeep is also associated with a shorter operative time and shorter hospital stay. these findings are in concordance with the literature where a prolonged operative time is attributable to technical factors of robotic surgery, such as applying the ports and docking the robot[11–13]. in our study, the median operative time for rasp is slightly longer (184 [149 to 234] minutes) than reported in the literature (150 to 160 minutes). a systematic review by kordan et al. also revealed a shorter average operative time for osp (79 to 93 minutes) depending on the surgical series[15]. this is probably because the acs nsqip database reflects realworld outcomes of different levels of surgical expertise [23,25]. no information is available on catheterization time, but if we assume that the los is a surrogate for catheterization time, aeep should have a shorter catheterization time[12,13,25]. an increased need for continuous bladder irrigation because of bleeding may also lengthen hospital stay after rasp and osp compared with aeep. rasp is estimated to be more costly than its open counterpart and costs twice as much as aeep[31]. the case has been made that the procurement of aeep to hospitals is costly and necessitates a steeper learning curve[23]. however, diverse endonucleation techniques have an acceptable learning curve of 25 to 50 cases with similar perioperative and functional outcomes[32,33]. therefore, the availability of the modality and the surgeon’s level of comfort would dictate the type of surgery offered to patients. hence, aeep and rasp have both mitigated the risks associated with osp while conserving equivalent functional outcomes; however, aeep offers the advantage of a shorter operative time, reduced los, and safer profile than rasp[34]. in comparison to transurethral resection of the prostate, aeep has also demonstrated superiority as it reduces the risk of postoperative urinary tract infections and decreases the los[35]. therefore, aeep could be preferable for large adenomas except in the presence of co-existing conditions such as large bladder calculi that would require a long operative time to eradicate endoscopically, or diverticula where the robotic technique would more efficiently manage both conditions concomitantly[23,36]. treatment cost encompasses surgical instruments, complications, and hospita l stay among ot hers. in comparison to osp, rasp has higher operating expenses (usd 2797), but its safer profile (decreased transfusion rate and shorter los) might render it more cost-effective than its open counterpart[15,37]. on the other hand, aeep (holep) was found to be 9.6% (eur 2356) cheaper than osp[38]. the surgeons’ expertise and the institution caseload directly impact the perioperative and functional outcomes, which in turn influence costs. costs also vary according to country, type of institution (public versus private, military versus civil), and type of cost analysis conducted. further studies with more precise comparisons are needed to assess the costs of the 3 procedures[15]. our study is limited by its retrospective nature. while national databases like nsqip allow outcome comparison among a large sample population, they might not include surgery-specific clinical data such as prostate size, average gram resected per minute, and functional outcomes such as post-void residual, international prostate symptom score, quality of life scores, and incontinence rates. additionally, large databases do not consider surgeon experience and learning curve on the outcome. another limitation inherent to the database is the inability to capture events occurring more than 30 days after the procedure. moreover, we were not able to assess continence, lower urinary tract symptoms, and sexual function because they are not captured in nsqip. furthermore, we were unable to control for the selection bias that results from the choice of procedure being highly dependent on the expertise available in each institution. however, we conducted 2 forms of analysis to cross-check our results. our methodology might not have captured all rasp procedures performed in the study period. nonetheless, this study provides an accurate assessment of the feasibility of the use of aeep and rasp by a large number of surgeons with a wide range of expertise and experience. conclusion we report the outcomes of osp, aeep, and rasp in a large real-world cohort of patients. aeep was found to have a safer profile than osp and rasp as it conferred a shorter operative time, shorter hospital stay, and lower incidence of postoperative complications. thus, aeep could be advantageous for frail patients with large prostates or for those dependent on chronic anticoagulation. 204 siuj • volume 2, number 4 • july 2021 siuj.org original research http://siuj.org author contributions muhieddine labban: methodology, formal analysis, writing—original draft nassib abou heidar: conceptualization, methodology, writing—original draft vincent misrai: validation, writing—review and editing jad najdi: writing-original draft hani tamim: data curation, project administration albert el-hajj: conceptualization, methodolog y, writing—review and editing, supervision all authors read and approved the final version of the manuscript. acknowledgements the acs nsqip and the hospitals participating in the acs nsqip are the source of the data used herein; they have not verified and are not responsible for the statistical validity of the data analysis or the conclusions derived by the authors. references 1. egan kb. the epidemiology of benign prostatic hyperplasia associated with lower urinary tract symptoms: prevalence and incident rates. urol clin north am.2016;43(3):289-97. epub 2016/08/01. doi: 10.1016/j. ucl.2016.04.001. pubmed pmid: 27476122. 2. wei jt, calhoun e, jacobsen sj. urologic diseases in america project: benign prostatic hyperplasia. j urol.2008;179(5 suppl):s75-80. epub 2008/04/25. doi: 10.1016/j.juro.2008.03.141. pubmed pmid: 18405761. 3. gratzke c, bachmann a, descazeaud a, drake mj, madersbacher s, mamoulakis c, et al. e au guidelines on the assessment of 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jutzi s, roos fc, hampel c, et al. surgical treatment of large volume prostates: a matched pair analysis comparing the open, endoscopic (thuvep) and robotic approach. world j urol.2019;37(9):1927-31. epub 12/04. doi: 10.1007/s00345-0182585-z. pubmed pmid: 30515596. 37. sutherland de, perez ds, weeks dc. robot-assisted simple prostatectomy for severe benign prostatic hyperplasia. j endourol. 2011;25(4):641-4. epub 2011/03/19. doi: 10.1089/end.2010.0528. pubmed pmid: 21413877. 38. salonia a, suardi n, naspro r, mazzoccoli b, zanni g, gallina a, et al. holmium laser enucleation versus open prostatectomy for benign prostatic hyperplasia: an inpatient cost analysis. urology.2006;68(2):302-6. epub 2006/08/15. doi: 10.1016/j.urology. 2006.02.007. pubmed pmid: 16904441. 206 siuj • volume 2, number 4 • july 2021 siuj.org original research http://siuj.org supplementary table 1a. comparison of baseline demographics before and after propensity score matching for anatomic enucleation of the prostate (aeep) and open simple prostatectomy (osp) variable before matching after matching osp aeep p -value osp aeep p -value n (%) n (%) n (%) n (%) age ≥ 68* (median age) 861 (57.9) 1488 (52.4) 0.001 323 (61.5) 531 (55.7) 0.03 asa ≥ 3 706 (47.3) 1331 (46.4) 0.587 252 (48.1) 443 (46.4) 0.549 dependent functional status 52 (1.8) 20 (1.3) 0.262 6 (1.1) 14 (1.5) 0.649 bmi ≥ 30 546 (36.6) 986 (34.4) 0.151 200 (38.2) 345 (36.1) 0.464 diabetes mellitus 270 (18.1) 522 (18.2) 0.934 96 (18.3) 174 (18.2) 0.962 copd 47 (3.2) 115 (4.0) 0.177 14 (2.7) 32 (3.4) 0.533 congestive heart failure 4 (0.3) 12 (0.4) 0.6 1 (0.2) 2 (0.2) 0.938 hypertension 861 (57.7) 1646 (57.4) 0.872 303 (57.8) 549 (57.5) 0.912 bleeding disorder 28 (1.9) 89 (3.1) 0.018 8 (1.5) 20 (2.1) 0.551 year of operation ≥ 2014 988 (66.2) 2072 (72.3) < 0.001 315 (60.0) 642 (67.2) 0.006 asa: american society of anesthesia; bmi: body mass index; copd: chronic obstructive pulmonary disease 207siuj.org siuj • volume 2, number 4 • july 2021 perioperative outcomes of anatomic endoscopic enucleation of the prostate http://siuj.org supplementary table 1b. comparison of baseline demographics before and after propensity score matching for robotic-assisted simple prostatectomy (rasp) and open simple prostatectomy (osp) variable before matching after matching osp rasp p -value osp rasp p -value n (%) n (%) n (%) n (%) age ≥ 68 (median age) 861 (57.9) 133 (56.8) 0.759 741 (57.8) 113 (57.4) 0.938 asa ≥ 3 706 (47.3) 101 (43.2) 0.260 610 (47.5) 85 (43.4) 0.283 dependent functional status 20 (1.3) 2 (0.9) 0.758 18 (1.4) 2 (1.0) 0.761 bmi ≥ 30 546 (36.6) 72 (30.8) 0.092 483 (37.6) 62 (31.6) 0.112 diabetes mellitus 270 (18.1) 44 (18.8) 0.855 234 (18.2) 36 (18.4) 1 copd 47 (3.2) 7 (3.0) 1 40 (3.1) 6 (3.0) 1 congestive heart failure 4 (0.3) 0 (0.0) 0.649 3 (0.2) 0 (0.0) 1 hypertension 861 (57.7) 144 (61.5) 0.285 732 (57.1) 120 (60.9) 0.316 bleeding disorder 28 (1.9) 2 (0.9) 0.305 26 (2.0) 2 (1.0) 0.416 year of operation ≥ 2014 988 (66.2) 120 (51.3) < 0.001 883 (68.9) 105 (53.6) < 0.001 asa: american society of anesthesia; bmi: body mass index; copd: chronic obstructive pulmonary disease 208 siuj • volume 2, number 4 • july 2021 siuj.org original research http://siuj.org supplementary table 1c. comparison of baseline demographics before and after propensity score matching for open simple prostatectomy (osp) and robotic assisted simple prostatectomy (rasp) variable before matching after matching rasp aeep p -value osp rasp p -value n (%) n (%) n (%) n (%) age ≥ 68 (median age) 133 (56.8) 1488 (52.4) 0.189 177 (56.5) 1357 (51.9) 0.219 asa ≥ 3 101 (43.2) 1331 (46.4) 0.341 88 (42.7) 1211 (46.3) 0.345 dependent functional status 2 (0.9) 52 (1.8) 0.321 2 (1.0) 44 (1.7) 0.578 bmi ≥ 30 72 (30.8) 986 (34.4) 0.282 64 (31.1) 915 (35.0) 0.287 diabetes mellitus 101 (43.2) 1331 (46.4) 0.341 38 (18.4) 477 (18.2) 1 copd 2 (0.9) 52 (1.8) 0.321 6 (2.9) 106 (4.1) 0.468 congestive heart failure 72 (30.8) 986 (34.4) 0.282 0 (0.0) 12 (0.5) 0.619 hypertension 101 (43.2) 1331 (46.4) 0.341 126 (60.9) 1492 (57.1) 0.307 bleeding disorder 2 (0.9) 89 (3.1) 0.065 2 (1.0) 85 (3.3) 0.089 year of operation ≥ 2014 120 (51.3) 2072 (72.3) < 0.001 112 (54.4) 1946 (74.4) < 0.001 asa: american society of anesthesia; bmi: body mass index; copd: chronic obstructive pulmonary disease 209siuj.org siuj • volume 2, number 4 • july 2021 perioperative outcomes of anatomic endoscopic enucleation of the prostate http://siuj.org 287siuj.org siuj • volume 3, number 5 • september 2022 visit bms.com/ca to see how we’re bringing a human touch to everything we do. © 2022 bristol-myers squibb company. all rights reserved. no-ca-2200002 02/22 we are in the business of breakthroughs—the kind that transform patients’ lives. dedicated to our mission of discovering, developing and delivering life-saving innovations that help patients prevail over serious diseases, we’ll never give up our search for more hope, for more people, around the world. volume 3, number 5 | september 2022 issn 2563-6499 doi: 10.48083/ebym4017 editorial office info@siuj.org tel: 514-875-5665 ext. 26 siuj.org managing editor jane fairbanks jane.fairbanks@siu-urology.org the siuj is published 6 times a year by the société internationale d'urologie (siu). it is the official peer-reviewed publication of the siu but retains editorial independence. the siuj is circulated to urologists, urology residents, family medicine specialists, family medicine residents, general practitioners, nurses, medical libraries, and hospital and university departments of urology worldwide, for a total circulation of over 10,000. this publication was developed under the direction of the siuj editorial board. the siuj is published under an exclusive licence. the siuj is owned and published by the société internationale d’urologie (siu). marketing lillian petrusa lillian.petrusa@siu-urology.org advertising mikaela tierney advertising@siuj.org neither the siu nor the siuj endorses any service 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brazil east asia tianxin lin, md china eastern europe roman sosnowski, md poland south asia sanjay sinha, mch india western europe tamsin greenwell, md united kingdom southeast asia edmund chiong, mbbs singapore africa yasser osman, mbbch egypt http://siuj.org http://bms.com/ca mailto:info%40siuj.org?subject=siuj http://siuj.org mailto:jane.fairbanks%40siu-urology.org?subject=siuj mailto:lillian.petrusa%40siu-urology.org%20?subject=siuj mailto:advertising%40siuj.org?subject=siuj 288 siuj • volume 3, number 5 • september 2022 siuj.org editorial board liaqat ali, mbbs pakistan abdol mohammad kajbafzadeh, md iran fahad alyami, mbbs saudi arabia wayne lam, mbbs hong kong sar mohsen azli, md algeria sang dong lee, md korea erdem canda, md turkey evelyn moshokoa, mbchb south africa yao-chi chuang, md taiwan andrea necchi, md italy archil chkhotua, md georgia mohammed shahait, mbbs jordan renu eapen, mbbs australia khurram siddiqui, mbbs oman agus rizal ardy hariandy hamid, md indonesia yaya sow, md senegal christopher ho chee kong, md malaysia chuan-liang xu, md china theocharis karaolides, md cyprus the société internationale d’urologie (siu). the society’s mission is to enable urologists in all nations, through international cooperation in education and research, to apply the highest standards of urological care to their patients. the siu is a major international platform for sustainable urological education and collaborative philanthropic activities aimed at improving urological care with more than 10,000 members from over 130 countries. siu central office 1155 robert-bourassa blvd., suite 1012 montreal, quebec, canada h3b 3a7 tel: +1 514 875-5665 fax: +1 514 875-0205 communications@siu-urology.org executive director susie petrusa susie.petrusa@siu-urology.org graphic design sam design info@studiosamdesign.com web design/ technical support aiki informatique info@aikitech.ca volume 3, number 5 | september 2022 neither the siu nor the siuj endorses any service or the contents of any product referred to in any advertisement in the siuj. the siu and the siuj assume no responsibility or liability for damages arising from any error or omission, or from the use of any information or advice contained in the siuj. all editorial matter in siuj represents the opinions of the authors and not necessarily those of the siu or the siuj. all canadian prescription drug advertisements have been cleared by the pharmaceutical advertising advisory board. http:// mailto:communications%40siu-urology.org?subject=siuj mailto:susie.petrusa%40siu-urology.org?subject=siuj mailto:susie.petrusa%40siu-urology.org?subject=siuj mailto:info%40studiosamdesign.com%20?subject=siuj mailto:info%40studiosamdesign.com%20?subject=siuj mailto:info%40aikitech.ca?subject=siuj this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information retroperitoneal sarcoma, comprehensive genomic profiling, targeted therapy dr p grivas (all unrelated in the last 3 years): consulting: astrazeneca; bayer; bristol myers squibb; clovis oncology; dyania health, driver; emd serono; exelixis; foundation medicine; genentech/roche; genzyme; glaxosmithkline; heron therapeutics; immunomedics, janssen; merck; mirati therapeutics; pfizer; seattle genetics; qed therapeutics. research funding to institution: merck; pfizer, clovis oncology, bavarian nordic, immunomedics, debiopharm, bristol myers squibb, qed therapeutics, glaxosmithkline, kure it cancer research. dr a necchi: consultant and advisor, merck, roche, astra zeneca, janssen, clovis oncology, incyte, bioclin therapeutics; bayer, bristol myers squibb; research grants (institution): merck, astra zeneca. received on march 28, 2021 accepted on may 15, 2021 soc int urol j. 2021;2(4):216–228 doi: 10.48083/ vogf2319 primary adult retroperitoneal sarcoma: a comprehensive genomic profiling study andrea necchi,1 giuseppe basile,2 filippo pederzoli2, marco bandini,2 petros grivas,3 gennady bratslavsky,4 philippe e. spiess,5 j. keith killian,6 douglas i. lin,6 erik williams,6 shakti ramkissoon,6 eric a. severson,6 brian m. alexander,6 jeffrey venstrom,6 prasanth reddy,6 kimberly mcgregor,6 julia a. elvin,6 alexa b. schrock,6 dean c. pavlick,6 dexter x. jin,6 sally e. trabucco,6 natalie danziger,6 jeffrey s. ross5,6 1department of medical oncology, irccs ospedale san raffaele, vita-salute san raffaele university, milan, italy 2urological research institute (uri), unit of urology, irccs ospedale san raffaele, vita-salute san raffaele university, milan, italy 3university of washington, fred hutchinson cancer research center, seattle cancer care alliance, united states 4suny upstate medical university, syracuse, united states 5moffitt cancer center and research institute, tampa, united states 6foundation medicine inc., cambridge, united states abstract background adult primary retroperitoneal sarcomas (rpss) are a group of heterogeneous tumors with different histological subtypes. comprehensive genomic profiling (cgp) analyses have recently provided significant insights into the biology of sarcomas by identifying genomic alterations (gas) which could benefit from targeted therapies. methods rps were evaluated by cgp using next-generation sequencing of up to 406 cancer-related genes. tumor mutational burden (tmb) was determined on 0.83 to 1.14 mut/mb of sequenced dna. finally, pd-l1 expression was determined. results overall, 296 cases of primary rps were analyzed. liposarcoma (lps) subtype had more ga/tumor than leiomyosarcoma (lms) subtypes, with follicular dendritic cell sarcomas harboring the highest and synovial sarcomas the lowest. tp53 and rb1 alterations were the highest in lms, and cdk4/6 and mdm2 in lps. however, both the tmb and targetable ga rates were low across subtypes. pd-l1 immunostaining was low positive in 21% and high positive in 5% of patients, respectively. conclusions cgp analysis revealed that potentially actionable genomic targets were rare in our cohort of rps. moreover, rpss seem less likely to respond to immune checkpoint inhibitors based on putative biomarkers status. nevertheless, genomic stratification according to histological subtypes led to description of gas that can inform future clinical trials design. 216 siuj • volume 2, number 4 • july 2021 siuj.org original research mailto:basile.giuseppe%40hsr.it?subject=siuj http://www.siuj.org introduction adult primary retroperitoneal sarcomas (rpss) are rare malignancies that encompass a variety of clinical and pathological entities, with distinct histology and cancer biology[1]. the reported yearly crude incidence rate of soft-tissue sarcomas of the retroperitoneum and peritoneum is 0.31 per 100 000 individuals in europe, with a 5-year relative survival rate of 38.8%[2]. rpss are usually classified according to the normal mesenchymal tissue t hey most closely resemble. the correct identification of the histological subtype constitutes a mainstay in the multidisciplinary management of rps, as different entities are more or less responsive to systemic therapy and/or radiation, thus influencing the therapeutic plan[3,4]. nevertheless, together with traditional histology-based classification of sarcomas, novel data about t he genomic, epigenetic, a nd immunological landscape of these rare malignancies are emerging to potentially guide better stratification. pa r t icu la rly, sa rcomas have been t rad it iona l ly grouped into 2 broad categories based on genomic alterations: sarcomas with simple karyotypes harboring distinct alterations, such as reciprocal chromosomal translocations and specific oncogenic mutations, and those with more complex, unbalanced karyotypes[5]. however, this crude dichotomy does not account for the complex heterogeneity within a given histology and between different subtypes, highlighting the need for a widespread implementation of molecular profiles in sarcomas. in this context, comprehensive genomic profiling (cgp) analysis can provide significant insights into the biology of several tumors, allowing detection of numerous genomic alterations that could help elucidate the biolog y and potentially suggest strategies for precision oncology clinical trials[6,7]. in this study, we profiled a group of 296 rps and analyzed the frequency of genomic alterations (gas), hypothesizing that we would identify distinct therapeutic opportunities for patients affected by these rare malignancies. methods approva l for this study was obtained from the western institutional review board (protocol no. 20152817). a retrospective database search of a clinical laboratory improvement amendments certified, and college of american pathologists accredited reference molecular laboratory was performed for all available primary rps cases. the cases were previously assayed by cgp via both dnaand rna-based targeted next-generation sequencing (foundation medicine, cambridge, ma) during the course of standard clinical care at other institutions. clinicopathological data, including patient age and gender, routine histology and immunohistochemica l staining results, and confirmation that the sarcomas were primary in the retroperitoneum and not metastases from other nonretroperitoneal primary sarcomas, were extracted from clinicopathology reports. the pathologic diagnosis of primary rps and associated morphological features were centrally re-evaluated on routine h&e slides of tissue sections submitted for genomic profiling. particularly, all cases included in this study were evaluated by an experienced board-certified pathologist at the time of specimen arrival in the laboratory, and then reviewed by a single pathologist to confirm the diagnosis and origin in the retroperitoneum. all samples forwarded for dna and rna extraction contained a minimum of 20% tumor cells. the samples were assayed using next-generation sequencing for all coding exons from at least 406 cancer-related genes, plus additional select introns from up to 31 genes frequently rearranged in cancer. patient samples were sequenced and evaluated for genomic alterations including base substitutions, insertions, deletions, copy number alterations (amplifications and homozygous deletions), and gene f usions/rearrangements, as previously described[8,9]. rna-sequencing of 265 genes was performed for rearrangement analysis. the bioinformatics processes used in this study included bayesian algorithms to detect base substitutions, local assembly algorithms to detect short insertions and deletions, a comparison with process-matched normal control samples to detect gene copy number alterations, and an analysis of chimeric read pairs to identify gene fusions as previously described[8,9]. to visualize the sequencing data results, an oncoprint plot was abbreviations cgp comprehensive genomic profiling fdcs follicular dendritic cell sarcoma ga genomic alteration ici immune checkpoint inhibitor lms leiomyosarcoma lps liposarcoma mpnst malignant peripheral nerve sheath tumors msi microsatellite instability os overall survival pfs progression-free survival pls pleomorphic sarcoma prs primary retroperitoneal sarcoma sft solitary fibrous tumors ss synovial sarcomas tmb tumor mutational burden tki tyrosine kinase inhibitor 217siuj.org siuj • volume 2, number 4 • july 2021 primary adult retroperitoneal sarcoma: a comprehensive genomic profiling study http://siuj.org generated with the online tools as described by gao et al.[10] and cerami et al.[11]. tumor mutational burden (tmb) was determined on 0.83 to 1.14 mb of sequenced dna using an algorithm, as previously described[12]. in this study, low tmb scores were defined as < 6 mut/mb, intermediate tmb as 6 to 19 mut/mb, and high tmb as ≥20 mut/mb. the tmb cut-offs used in this study were the levels that had been in use prior to the u.s. food and drug administration (fda) approval of pembrolizumab in solid tumors featuring a tmb > 10 mut/mb. assessment of microsatellite instability (msi) was performed from dna sequencing across 114 significant loci[13]. each microsatellite locus had repeat length of 7 to 39 bp. the next-generation sequencing-based microsatellite instability score was translated into categorical msi high, msi intermediate, or microsatellite stable tumors by unsupervised clustering of specimens for which microsatellite instability status was previously assessed via gold standard methods[13]. pd-l1 expression was determined on subsets of the tumors using the dako 22c3 assay with low positive tumor cell scoring defined as 1% to 49% staining and high positive tumor cell scoring defined as ≥ 50% staining. the cut-offs for the dako 22c3 staining are those currently being used in the united states for the selection of patients with nonsmall cell lung cancer for treatment with single agent pembrolizumab. results the clinical and genomic features of the 296 cases of primary rps are shown in table 1. all cases were clinically advanced and frequently resistant to the most recent therapy the patient had received at the time sequencing was ordered. there were 155 liposarcomas (lps), 74 leiomyosarcomas (lms), 44 pleomorphic sarcomas (pls), 7 solitary fibrous tumors (sft), 6 malignant peripheral nerve sheath tumors (mpnst), 5 synovial sarcomas (ss), and 5 follicular dendritic cell sarcomas (fdcs). three cases of fibrosarcoma/ fibromyxoid sarcoma were included in the pls group. oncoprint plots of the most frequent gas recorded in the overall cohort and each subtype is reported in supplementary material 1. the median age of all patients was 59 years, similar in all groups except for mpnst and ss, with significantly younger patients. the number of gas per tumor was similar across the overall cohort and ranged from 5.1 to 7.4. lms and ss subtypes exhibited the lowest ga/ tumor, while fdcs had the highest (7.4 ga/tumor). the gas associated with the rps as a whole and in the 7 individual rps subtypes are shown in the longtail plots reported in figure 1. alterations in genes not currently linked to possible targeted therapies were identified. tp53 inactivation was frequently reported in lms and rarely identified in lps, ss or fdcs, while rb1 inactivating ga was essentially restricted to lms. moreover, mdm2 amplification was clearly linked to lps subtype, while frs2 amplification, identified in 46% of all rps cases, was predominantly associated with the lps and pls tumor types. alterations potentially linked to targeted therapy selection were identified throughout the rps cases in limited frequencies. examples included inactivating nf1/nf2 ga in mpnst, pik3ca activating mutations and pten inactivating mutations and deletions. moreover, potentially impacting the evaluation of cell cycle inhibitors were the high frequencies of cdk4/6 amplifications, mostly restricted to lps and pls, and the cdkn2a/b loss identified in pls, and relatively frequently in mpnst. it should be noted that mtap loss, which is nearly restricted to tumors with cdkn2a/b loss and potentially associated with potential targeted therapies focused on tumor cells arginine metabolism, was not tested for in the current study. tumor-defining gene fusions included the hmga2 fusions for the lps and pls groups, the stat6 fusions in sft type, and ss18 fusions in the ss cases. rare gene fusions that activate targetable gene kinase domains included very rare detection of alk, ntrk, and ros1 fusions, all identified at 1% of lps and pls, 2% of pls and in 1 out of 6 cases of mpnst. biomarkers currently associated with response to immune checkpoint inhibitors (icis) were also evaluated. no tumor featured msi high status. tmb was low throughout this group of tumors, with mpnst having the highest median tmb at 4.8 mut/mb and ss, sft, and fdcs all having a median tmb of < 1 mut/mb. low tumor cell pd-l1 expression (< 49%) was detected in 21% of rps cases, with pls having the highest frequency at 33%, and sft, mpnst, ss, and fdcs all having no low positive cases. high positive staining (≥ 50%) was present in only 5% of our cohort and mostly identified in pls (16%) and fdcs (20%) subtypes. boxplot of tmb analysis of all rps included and each subtype is reported in supplementary material 2. case examples of genomically profiled rps are shown in figures 2 and 3. in figure 2, a pls in a 77-year-old woman featured an activating fusion in the ntrk3 gene with the strn3 gene [5'-strn3(ex1-3 nm_014574)(b)ntrk3(ex12-19 nm_002530)]. in figure 3, a welldifferentiated retroperitoneal lps showed significant amplification of the cdk4 gene, which has potential to drive therapy selection using specific cdk4 inhibitors in clinical trials. figure 4 shows a retroperitoneal dedifferentiated liposarcoma which presented with pulmonary metastases and was found to contain an mdm2 amplification and an hmga2-tsfm fusion. this 218 siuj • volume 2, number 4 • july 2021 siuj.org original research http://siuj.org table 1. clinical and genomic features in adult retroperitoneal sarcomas all cases lps lms pls sft mpnst ss fdcs number of cases, n 296 155 74 44 7 6 5 5 female gender, % 53 42 78 49 57 33 60 60 median age in years, range 59 (20–88) 60 (29–88) 60 (31–86) 57 (20–85) 52 (31–71) 28 (20–53) 39 (22–46) 56 (30–71) ga/tumor 5.1 6 3.4 5.2 6 5.7 2.6 7.4 tp53 inactivating sv mutation, % 24 5 66 26 29 33 0 0 rb1 inactivating sv mutation, % 10 1 32 5 0 0 0 0 frs2 amplification 46 78 0 28 14 0 0 0 nf1/nf2 inactivating sv mutation, % 4 1 1 4 0 83 0 0 pik3ca activating sv mutations and amplifications, % 3 2 4 0 0 17 0 0 esr1 inactivating sv mutation, % 7 12 0 0 14 0 0 0 cdkn2a deletion, % <1 <1 1 15 0 83 0 0 cdkn2b deletion, % <1 <1 1 11 0 83 0 0 cdk4/6 amplification, % 52 89 0 28 14 0 0 20 pten deletion/ inactivating sv mutation, % 4 2 12 9 0 0 0 20 mdm2 amplification, % 54 91 1 30 14 17 0 20 alk kinase activating fusions, % <1 1 0 0 0 0 0 0 ros1 kinase activating fusions, % <1 1 1 0 0 0 0 0 ntrk1-3 kinase activating fusions, % 1 1 1 2 0 17 0 0 stat6 fusions, % 2 0 0 0 86 0 0 0 hmga2 fusions, % 17 28 1 11 0 0 0 0 ss18 fusions, % <1 0 0 0 0 0 100 0 msi-high, % 0 0 0 0 0 0 0 0 median tmb (mut/mb) 2.4 1.6 3.2 2.4 0.8 4.8 0.8 0.8 pd-l1 ihc low positive 21 25 10 33 0 0 0 0 pd-l1 ihc high positive 5 3 0 16 0 0 0 20 fdcs: follicular dendritic cell sarcoma; lps: liposarcoma; lms: leiomyosarcoma; mpnst: malignant peripheral nerve sheath tumor; pls: pleomorphic sarcoma; sft: solitary fibrous tumors; ss: synovial sarcoma. 219siuj.org siuj • volume 2, number 4 • july 2021 primary adult retroperitoneal sarcoma: a comprehensive genomic profiling study http://siuj.org tumor featured 100% tumor cell immunohistochemical staining for pd-l1 using the dako 22c3 assay. discussion adult rpss are a group of rare and heterogeneous tumors marked by aggressive behavior and poor prognosis. thus, the multidisciplinary management based on surgery, systemic therapy, and/or radiation has been the cornerstone of rps treatment for several years. however, a great number of patients still have poor outcomes despite t he implementation and continuous optimization of multimodal therapies[14]. the negative findings of the strass trial[15], which examined the effect of preoperative radiotherapy in rps, suggested the idea that treatment efficacy is deeply inf luenced by the intrinsic biological characteristics of the different sarcomas, thus highlighting the need for a better molecular understanding of these entities. in this context, the spread of novel genomic techniques has advanced the field in this direction, also revealing several potential molecular targets and biomarkers that could offer novel opportunities in the management of these malignancies. the palette trial was the landmark study to evaluate the effectiveness of a multitarget tyrosine kinase inhibitor (tki), pazopanib, over placebo in 362 non-adipocytic soft-tissue sarcomas. the authors reported significantly prolonged median progression-free survival (pfs) in the intention-totreat cohort (4.6 versus 1.6 months) resulting in fda approval of pazopanib in 2012 for advanced lps refractory to systemic chemotherapy[16]. similarly, the fda approved eribulin for the treatment of inoperable lps after chemotherapy, based on a phase iii study that compared eribulin and dacarbazine for lps and lms. although no difference was achieved in the overall figure 1. longtail plots of the frequencies and types of genomic alterations in all cases of primary retroperitoneal sarcomas 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% m d m 2 c d k 4 f r s 2 t p 5 3 r b 1 h m g a 2 a t r x ju n c d k n 2 a e s r 1 p t e n c d k n 2 b r ic t o r n f 1 c c n d 2 f g f 2 3 r o s 1 k m t 2 d g id 4 m c l 1 c c n e 1 ig f 1 r f g f 6 k m t 2 c l r p 1 b f g f 1 0 c d 3 6 c k s 1 b p ik 3 c a n t r k 1 f g f r 1 r a d 2 1 a k t 2 ig f 1 e t v 6 k d m 5 a k r a s t o p 1 n f 2 c r e b b p p a s k a x l z n f 2 1 7 n f k b ia s t a t 6 m u t y h g n a s a k t 1 z n f 7 0 3 a r id 2 all adult retroperitoneal sarcomas 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% m d m 2 c d k 4 f r s 2 h m g a 2 a t r x ju n e s r 1 c c n d 2 f g f 2 3 r o s 1 c d k n 2 a ig f 1 r e t v 6 t p 5 3 ig f 1 f g f 6 m c l 1 r ic t o r n t r k 1 c k s 1 b f g f r 1 c d k n 2 b n f 1 c c n e 1 t n f a ip 3 t o p 1 c d 3 6 r a d 2 1 a r id 2 k m t 2 c l r p 1 b c c n d 3 a k t 1 g n a s n f k b ia e p h b 1 a k t 2 p a s k c c n d 1 c r e b b p k m t 2 d p t e n a s x l 1 a u r k a z n f 2 1 7 ig h f g f 1 9 a t m s h 2 b 3 k r a s retroperitoneal lps 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% t p 5 3 r b 1 a t r x p t e n g id 4 k m t 2 d k m t 2 c r ic t o r p ik 3 c a m y c c d 3 6 c d k n 2 c ig f 1 r p m s 2 a k t 2 r a d 2 1 a x l s d h a f g f 1 0 m s h 6 k r a s e g f r n f 2 b r c a 2 d n m t 3 a m u t y h n u p 9 8 r a d 5 1 b t e t 2 a u r k b c d k 8 c h e k 2 h g f k a t 6 a l p p n k x 2 -1 r a d 5 1 a t r c h d 2 c t n n b 1 f l t 3 m a p 2 k 4 m d m 4 n f 1 r a d 5 0 s p e n a p c c c t 6 b c r k l k it retroperitoneal lms 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% stat6 tp53 notch4 palb2 atr frs2 mdm2 birc3 akt1 cdk4 esr1 pask 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% retroperitoneal mpnst retroperitoneal sft 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% m d m 2 c d k 4 f r s 2 t p 5 3 a t r x c d k n 2 a r ic t o r r b 1 h m g a 2 c d k n 2 b f g f 1 0 ju n p t e n z n f 7 0 3 n f 1 c k s 1 b e w s r 1 n f 2 s m a r c b 1 a t m m c l 1 k d m 5 a f g f r 1 b c l 2 l 2 z n f 2 1 7 c c n e 1 p b r m 1 s o c s 3 n c o a 2 k r a s c t n n b 1 n t r k 1 c u l 4 a p t c h 1 b ir c 3 d n m t 3 a n p m 1 s m a r c a 4 b l m c c n d 3 m u t y h n u p 9 8 a u r k b b a p 1 c h e k 2 e e d f g f 4 h g f h is t 1 h 2 b j k a t 6 a retroperitoneal pls 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% f g f 2 3 c c n d 2 k d m 5 a f g f 6 n r a s z n f 2 1 7 n o t c h 2 s f 3 b 1 a t r x c d k 4 c d k n 2 a r b 1 a r f r p 1 l r p 1 b n c o r 1 s r c a u r k a c r e b b p h is t 1 h 2 a c m d m 2 m e n 1 b r c a 2 p t e n c h e k 2 ju n m l h 1 a t r t o p 1 n f k b ia m e d 1 2 g n a s ja k 1 f b x o 1 1 retroperitoneal fdcs 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% ss18 palb2 ikzf3 sgk1 pdgfra pik3ca cd36 mll2 retroperitoneal ss fdcs: follicular dendritic cell sarcoma (n = 5); lps: liposarcoma (n = 155); lms: leiomyosarcoma (n = 74); mpnst: malignant peripheral nerve sheath tumor (n = 6); pls: pleomorphic sarcoma (n = 44); sft: solitary fibrous tumor (n = 7); ss: synovial sarcoma (n = 5) 220 siuj • volume 2, number 4 • july 2021 siuj.org original research http://siuj.org pfs between the 2 arms, eribulin demonstrated a statistically significant improvement in overall survival (os) (13.5 versus 11.5 months), especially for lps (15.6 versus 8.4 months)[17]. following these results, our study focused on a large cohort of patients with rps and explored targetable genomic alterations through cgp analysis. cgp analyses revealed that possible genomic targets were uncommon in our cohort of patients with rps. in particular, rpss were genomically stable tumors with low ga rate, low expression of pdl1 and low median tmb, suggesting low efficacy for ici approaches. nevertheless, genomic stratification according to histological subtypes led to the discovery of gas that might predict patient benefit from targeted therapy testing in clinical trials. co-amplification of mdm2 and cdk4 is thought to be the main driving factor in lps development, leading to tp53 inactivation and uncontrolled cell cycle progression[18]. mdm2 and tp53 are within the same pathway, in which mdm2 ubiquitinates tp53 and targets it for proteasomal degradation. in our cohort, lps cases showed higher ga/tumor rate than lms subtype, and mdm2 and cdk4 aberrations were the most frequent gas, detected in 91% and 89% of the specimens, respectively. similar results were recently reported by the cancer genome atlas (tcga) research network analysis of 206 adult sarcomas, in which the median tmb was low (1.06 mut/mb) across the different subtypes[19]. moreover, mdm2 or cdk4 amplification was found as the highest frequent gas in lps subtype, as reported by other series[20,21]. therefore, several clinical trials were launched testing mdm2/cdk4 antagonists[22]. phase i trials of mdm2 inhibitor amg-232 alone[23] or combined with radiation therapy (nct03217266) figure 2. pleomorphic sarcoma of the retroperitoneum in a 77-year-old woman a c b low magnification (figure 2a) and high magnification (figure 2b) of a pleomorphic sarcoma. this tumor had a very high mitotic rate (20 mitoses per hpf), extensive necrosis, and stained positively for s100, sox-10, caldesmon, and bcl2. the tumor was negative for ema, desmin, myo-d1, cd99, cd31, cd34, pankeratins and pan melanoma markers. comprehensive genomic profiling revealed an msi stable tumor with intermediate tmb at 7 mutations/mb. there was a deletion in cdkn2a/b, a short variant mutation in pbrm1 and an activating fusion in the ntrk3 gene with the strn3 gene (5'-strn3(ex1-3 nm_014574) (b)-ntrk3(ex12-19 nm_002530) (figure 2c). ntrk fusions, although extremely rare, are widely distributed in solid tumors and some hematologic malignancies. this fusion has been previously described in sarcomas. tyrosine kinases that target ntrk fusions have been approved by the regulatory agencies and include the drugs larotrectinib and entrectinib. 221siuj.org siuj • volume 2, number 4 • july 2021 primary adult retroperitoneal sarcoma: a comprehensive genomic profiling study http://siuj.org showed acceptable safety in solid tumors, as well as in a cohort of dedifferentiated-lps and ss subtypes treated with ds-3032b (nct01877382). similarly, encouraging results have been reported for cdk4/6 antagonists alone or in combination with doxorubicin, showing a 12-week pfs rate between 57.2% and 66% in retroperitoneal lps[24–26]. the second most common rps subtype in our cohort was lms. our results confirmed that lms is usually characterized by ga of tumor suppressors including tp53 (66%) and rb1 (32%) [19,20,27], but low frequency of ga in pten (12%), which underlie potential mechanisms of resistance to ici in lms subtypes[28]. conversely, mpnst subtype had the highest tmb compared with other subtypes. nevertheless, mpnst specimens were found to be cdkn2a/b rearranged, which is a biomarker often associated with poor prognosis and low expression of “druggable” target ga[29]. other “targetable” gene fusions, such as alk and ros1, were rare in our population, while ntrk 1-3 gene rearrangements were mainly found in the mpnst cohort. ntrk fusions, although rare, have been described in sarcoma, and novel opportunities for patients with ntrk fusionpositive solid tumors have recently been introduced[30]. furthermore, another ga potentially linked to targeted therapy selection is nf1 in mpnst subtype, while deletion was recently associated with mek inhibitors response[31]. in this context, novel opportunities for rps treatment could arise from tapur (nct02693535) and nci-match and the new combo-match trials testing several multi-target inhibitors according to the genomic variants expressed. finally, when considering pd-l1 status, 21% of rps in our cohort had a low expression, while only 5% amplifica)on of erbb3 (7 copies), cdk 4 (41 copies), mdm2 (90 copies), frs2 (46 copies and znf217 (12 copies) a c b figure 3. retroperitoneal well-differentiated liposarcoma in a 62-year-old man low magnification (figure 3a) and high magnification (figure 3b) of a retroperitoneal well-differentiated liposarcoma. this tumor was msi stable and featured a low tmb of 2 mut/mb. comprehensive genomic profiling revealed (figure 3c) amplifications of multiple genes on chromosome 12 including erbb3 (7 copies), cdk4 (41 copies), mdm2 (90 copies), frs2 (46 copies), and znf217 (12 copies). cdk4 encodes the cyclin-dependent kinase 4, which regulates the cell cycle, senescence, and apoptosis. cdk4 and its functional homolog cdk6 are activated by d-type cyclins and promote cell cycle progression by inactivating the tumor suppressor rb1. amplification of cdk4 has been reported in lung cancer, glioblastoma, and liposarcoma.amplification of the cdk4 and mdm2 genes, is a hallmark genetic alteration in well-differentiated liposarcoma. cdk4 amplification or activation may predict sensitivity to cdk4/6 inhibitors such as abemaciclib, palbociclib, and ribociclib. 222 siuj • volume 2, number 4 • july 2021 siuj.org original research http://siuj.org could be considered “high pd-l1,” with pls and fdcs subtypes associated with the highest pd-l1 expression rates. although sarcoma is generally considered a nonimmunogenic tumor, high heterogeneity of pd-l1 expression was found across different subtypes (0% to 65%), suggesting that each histological subtype should be considered as a separate therapeutic challenge[32,33]. preliminary results from the phase ii sarc028 trial testing pembrolizumab for soft-tissue sarcomas reported an objective response rate of 18% and a 12-week pfs rate of 55%, although the subgroup analysis identified no response in the lms cohort[34]. conversely, combination of nivolumab plus ipilimumab has provided promising efficacy for lms and pls subtypes[35]. to further advance the research and understanding of rps, it is crucial to establish joint networks to share clinical data, create centralized biobanks and prospective registries, and organize collaborative novel clinical trials. for instance, based on the increasing number of genomic alterations specifically associated with sarcoma subtypes, the design of histologyand genomic-based trials, irrespective of the tissue of origin of the sarcoma, appears a promising approach to test rational targeted agents or particular combinations. further prospective studies are needed to confirm safety, feasibility, and efficacy of these precision oncology approaches. this study is not devoid of limitations inherent in its nature. this was a retrospective study including available cases with a descriptive analytical approach without granular demographic and clinicopathologic features and clinical outcomes. the presence of selection and confounding biases is very likely. there was variability of tumor size, source, and viable content, and there was no central pathology review of the original tumor block; however, h&e sections were reviewed a b c figure 4. dedifferentiated liposarcoma of the retroperitoneum in a 74-year-old man figure 4a shows a dedifferentiated liposarcoma on hematoxylin and eosin staining at 10x magnification. figure 4b shows diffuse positive membranous immunohistochemical staining for pd-l1 using the dako 22c3 antibody at 10x magnification. on comprehensive genomic profiling, this ms-stable tumor has a low tmb at 3 mutations/mb. mdm2 amplification characteristic of liposarcoma was found along with amplifications of cdk4, ccnd3, frs2 and jun. this tumor also featured a hmga2-tsfm fusion [fusion:5'-hmga2(ex1-3 nm_003483)-tsfm(ex2-6 nm_005726)] (figure 4c). hmga2 rearrangements and fusions have been most frequently identified in benign neoplasms such as lipomas, uterine leiomyomas, angiomyxomas, as well as in malignant tumors such as well-differentiated liposarcomas and inflammatory myofibroblastic tumors. 223siuj.org siuj • volume 2, number 4 • july 2021 primary adult retroperitoneal sarcoma: a comprehensive genomic profiling study http://siuj.org by an expert pathologist. rps included have different stages and grades which could inf luence the results, since the degree of tumor aggressiveness may underlie a distinct biology. we did not consider prior therapies before tumor tissue collection, which could facilitate the selection of cell clones with specific gas and gene expression patterns. moreover, cgp explored only a limited variety of gas, leaving out methylomic and proteomic profile, which could possibly reveal additional important information about rps biology. we did not evaluate circulating cell-free tumor dna and did not pursue composite biomarker analysis. conclusions our study revealed very few potentially actionable genomic targets, suggesting that rpss seem unlikely to respond to targeted therapies or ici, at least based on putative molecular biomarker status. however, uncommon “targetable” kinase fusions were found depending on rps subtypes. further research in the different rps subtypes is needed to explore the biology, as well as the safety and efficacy of systemic treatment regimens according to the underlying biolog y in attempting a precision oncology strategy. references 1. who classification of tumours editorial board. who classification of tumours of soft tissue and bone. 5th ed. lyon, france: iarc press; 2020. 2. gatta g, 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dedifferentiated liposarcoma treated with cdk4 inhibitor palbociclib: a phase 2 clinical trial. jama oncol.2016;2:937– 40. doi.org/10.1001/jamaoncol.2016.0264. 25. dickson ma, tap wd, keohan ml, d’angelo sp, gounder mm, antonescu cr, et al. phase ii trial of the cdk4 inhibitor pd0332991 in patients with advanced cdk4-amplified well-differentiated or dedifferentiated liposarcoma. j clin oncol.2013;31:2024– 8. doi. org/10.1200/jco.2012.46.5476. 26. infante jr, cassier pa, gerecitano jf, witteveen po, chugh r, ribrag v, et al. a phase i study of the cyclin-dependent kinase 4/6 inhibitor ribociclib (lee011) in patients with advanced solid tumors and lymphomas. clin cancer res.2016;22:5696–705. doi.org/10.1158/10780432.ccr-16-1248. 27. chudasama p, mughal ss, sanders ma, hübschmann d, chung i, deeg ki, et al. integrative genomic and transcriptomic analysis of leiomyosarcoma. nat commun.2018;9:14 4. doi.org/10.1038/ s41467-017-02602-0. 28. george s, miao d, demetri gd, adeegbe d, rodig sj, shukla s, et al. loss of pten is associated with resistance to anti-pd-1 checkpoint blockade therapy in metastatic uterine leiomyosarcoma. immunity.2017;46:197–204. doi.org/10.1016/j.immuni.2017.02.001. 29. bui nq, przybyl j, trabucco se, frampton g, hastie t, van de rijn m, et al. a clinico-genomic analysis of soft tissue sarcoma patients reveals cdkn2a deletion as a biomarker for poor prognosis. clin sarcoma res.2019;9:12. doi.org/10.1186/s13569-019-0122-5. 30. doebele rc, drilon a, paz-ares l, siena s, shaw at, farago af, et al. entrectinib in patients with advanced or metastatic ntrk fusionpositive solid tumours: integrated analysis of three phase 1–2 trials. lancet oncol.2020;21:271–82. doi.org/10.1016/s1470-2045(19)30691-6. 31. dodd rd, mito jk, eward wc, chitalia r, sachdeva m, ma y, et al. nf1 deletion generates multiple subtypes of soft-tissue sarcoma that respond to mek inhibition. mol cancer ther. 2013;12:1906–17. doi. org/10.1158/1535-7163.mct-13-0189. 32. d’angelo sp, shoushtari an, agaram np, kuk d, qin l-x, carvajal rd, et al. prevalence of tumor-infiltrating lymphocytes and pd-l1 expression in the soft tissue sarcoma microenvironment. hum pathol. 2015;46:357–65. doi.org/10.1016/j.humpath.2014.11.001. 33. kim jr, moon yj, kwon ks, bae js, wagle s, kim km, et al. tumor infiltrating pd1-positive lymphocytes and the expression of pd-l1 predict poor prognosis of sof t tissue sarcomas. plos one.2013;8:e82870. doi.org/10.1371/journal.pone.0082870. 34. tawbi ha, burgess m, bolejack v, van tine ba, schuetze sm, hu j, et al. pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (sarc028): a multicentre, two-cohort, single-arm, openlabel, phase 2 trial. lancet oncol.2017;18:1493–501. doi.org/10.1016/ s1470-2045(17)30624-1. 35. d’angelo sp, mahoney mr, tine bav, atkins j, milhem mm, jahagirdar bn, et al. nivolumab with or without ipilimumab treatment for metastatic sarcoma (alliance a091401): two openlabel, noncomparative, randomised, phase 2 trials. lancet oncol.2018;19:416–26. doi.org/10.1016/s1470-2045(18)30006-8. 225siuj.org siuj • volume 2, number 4 • july 2021 primary adult retroperitoneal sarcoma: a comprehensive genomic profiling study http://siuj.org esr1 cdkn2a jun atrx hmga2 rb1 tp53 frs2 cdk4 mdm2 number of samples: 296 variant type point mutation/indel amplification deletion truncation fusion/rearrangement other multiple 0% 50%100% a lteration frequency supplementary material 1a. ros1 fgf23 ccnd2 esr1 jun atrx hmga2 frs2 cdk4 mdm2 number of samples: 155 variant type amplification deletion truncation fusion/rearrangement other multiple 0% 50%100% a lteration frequency supplementary material 1b. myc pik3ca rictor kmt2c kmt2d gid4 pten atrx rb1 tp53 number of samples: 74 variant type point mutation/indel amplification deletion truncation fusion/rearrangement other multiple 0% 50%100% a lteration frequency supplementary material 1c. 226 siuj • volume 2, number 4 • july 2021 siuj.org original research http://siuj.org cdkn2b hmga2 rb1 rictor cdkn2a atrx tp53 frs2 cdk4 mdm2 number of samples: 44 variant type point mutation/indel amplification deletion truncation fusion/rearrangement 0% 50%100% a lteration frequency supplementary material 1d. cdk4 akt1 birc3 mdm2 frs2 atr palb2 notch4 tp53 stat6 number of samples: 7 variant type point mutation/indel amplification truncation fusion/rearrangement 0% 50%100% a lteration frequency supplementary material 1e. ptpn11 nbn lrp1b akt2 suz12 eed tp53 cdkn2b nf1 cdkn2a number of samples: 6 variant type point mutation/indel amplification deletion truncation 0% 50%100% a lteration frequency supplementary material 1c. 227siuj.org siuj • volume 2, number 4 • july 2021 primary adult retroperitoneal sarcoma: a comprehensive genomic profiling study http://siuj.org ikzf3 kmt2d palb2 pdgfra pik3ca sgk1 znf703 ssx2 ssx1 ss18 number of samples: 5 variant type point mutation/indel amplification truncation fusion/rearrangement variant present in sample 0% 50%100% a lteration frequency supplementary material 1g. cdk4 atrx sf3b1 notch2 znf217 nras fgf6 kdm5a ccnd2 fgf23 number of samples: 5 variant type point mutation/indel amplification truncation 0% 50%100% a lteration frequency supplementary material 1h. 228 siuj • volume 2, number 4 • july 2021 siuj.org original research http://siuj.org supplementary table st1. validated proms used in the studies included in the systematic review questionnaire abbreviation author (year publication) measurement original target population 36-item short form health survey[1] sf-36 (g) ware & sherbourne (1992) physical and mental health status for use in clinical practice and research, health policy evaluations and general population survey medical and general population 12-item short-form health survey[2] sf-12(g) ware et al. (1996) physical and mental health status for use in clinical practice and research, health policy evaluations and general population survey medical and general population eortc quality of life questionnaire[3]a eortc qlq-c30 (cs) aaronson et al. (1993) five functional (physical, role, cognitive, emotional, and social), three symptom scales and single-item symptom measures plus a global health and quality of life scale patients with cancer participating in international trials (originally in nonresectable lung cancer for whom radiotherapy or chemotherapy was indicated) cancer rehabilitation evaluation system short form[4] cares-sf (cs) schag et al. (1991) cancer-specific rehabilitation needs and quality of life patients with cancer (originally in colorectal, lung, prostate, and breast cancer) impact of events scale[5] ies disease specific horowitz et al. (1979) psychological stress reactions after any major life events (frequency of intrusive thoughts and avoidance behaviour) healthy adults and frail older adults exposed to any specific trauma event impact of events scale revised[6] ies-r disease specific weiss & marmar (1997) psychological stress reactions after any major life events (intrusive thoughts, avoidance behaviour and hyperarousal) healthy and frail older adults exposed to any specific trauma eastern cooperative oncology group performance status[7] ecog (cs) oken et al. (1982) patients’ general well-being and activities of daily life (to determine whether they can receive chemotherapy, if dose adjustment is necessary and to assess the intensity of palliative care) cancer patients candidates to receive chemotherapy or palliative care fear of cancer recurrence[8] fcr (cs) greenberg et al. (1997) beliefs and anxiety about fear of cancer recurrence cancer survivors (mainly breast and leukemia) general health questionnaire[9] ghq-12 condition specific goldberg (1978) general state of health and emotional mental health problems/domains of depression, anxiety, somatic symptoms, and social withdrawal (current psychological distress) individuals at risk to have or developing psychiatric disorders including primary care hospital anxiety and depression scale[10] hads (condition specific) zigmond & snaith (1983) anxiety and depression medical population of patients list of threatening experiences questionnaire[11] lte-q condition specific brugha & cragg (1990) 12 major stressful life events in the last 6 months with established long-term consequences individuals with suspicion of any stressful situation (originally tested in psychiatric patients) postoperative quality of recovery score[12] qor-40 condition specific myles et al. (2000) quality of recovery after surgery and anaesthesia patients undergoing general anaesthesia and surgery social problem questionnaire[13] spq condition specific corney & clare (1985) social functioning (social problems, difficulties, and dissatisfaction) patients that require social assessment visual analogue scale[14]b vas generic aitken (1969) intensity or frequency of symptoms or satisfaction that ranges across a continuum of values from none to extreme patients and healthy individuals / general population functional assessment of cancer therapy -kidney symptoms index[15] fksi -15 cancer specific cella et al. (2006) renal cancer specific symptoms and concerns (fatigue, fever, loss of appetite, weight loss, hematuria, pain, pulmonary or urinary symptoms, distress or worry patients with advanced kidney cancer a for eortc qol c-30 questionnaires, versions 1.0, (+3), 2.0 and 3.0 were used in the different studies. as per instructions in eortc qlq c-30 scoring manual the original publication is cited. b used early in the 20th century, popularized by aitken in 1969 (guidelines for the application scoring and statistical analysis of vas) references 1. ware je, sherbourne cd. the mos 36-item short-form health survey (sf-36): i. conceptual framework and item selection. med care.1992;30:473–483. 2. ware j jr, kosinski m, keller sd. a 12-item short-form health sur vey: cons t r uc tion of s c ales and pr eliminar y tes t s of reliabilit y and validit y. med c are.19 9 6;3 4:2 2 0 –2 3 3. doi: 10.1097/00005650-199603000-00003 3. aaronson nk, ahmedzai s, bergman b, bullinger m, cull a, duez nj, et al. the european organization for research and treatment of cancer qlq-c30: a quality-of-life instrument for use in international clinical trials in oncology. j natl cancer inst.1993;85:365–376. doi: 10.1093/jnci/85.5.365 4. coscarelli-schag ca, ganz pa, heinrich rl. cancer rehabilitation evaluation system-short form (cares-sf). cancer.1991;68:1406– 1413 . d o i:10 .10 0 2 / 10 9 70 14 2 (19 9 10 9 15 ) 6 8 : 6 < 14 0 6 : : a i d cncr2820680638>3.0.co;2-2 5. horowitz m, wilner n, alvarez w. impact of event scale: a measure of subjective stress. psychosom med.1979; 41: 209 –218. doi: 10.1097/00006842-197905000-00004 6. weiss ds, marmar cr. the impact of event scale-revised. in: wilson jp, keane tm, eds. assessing psychological trauma and ptsd. new york: guilford press;1997. pp.399–411. 7. oken mm, creech rh, tormey dc, horton j, davis te, mcfadden pp, et al. toxicity and response criteria of the eastern cooperative oncology group. am j clin oncol.1982;5:649–655. 8. greenberg db, kornblith ab, herndon je, zuckerman e, schiffer ca, weiss rb, et al. quality of life for adult leukemia survivors treated on clinical trials of cancer and leukemia group b during the period 1971-1988. cancer.1997;80:1937–1944. doi: 10.1002/ (sici)1097-0142(19971115)80:10<1936::aid-cncr10>3.0.co;2-z. 9. goldberg dp. manual of the general health questionnaire. windsor, england; nfer publishing, 1978. 10. zigmond as, snaith rp. the hospital anxiety and depression scale. acta psychiatr scand.1983;67:361–370. doi: 10.1111/j.1600-0447.1983. tb09716.x. 11. brugha ts, cragg d. the list of threatening experiences: the reliability and validity of a brief life events questionnaire. acta psychiatr scand.1990:82:77–81. doi: 10.1111/j.1600-0447.1990.tb01360.x. 12. myles ps, weitkamp b, jones k, hensen s. validity and reliability of a postoperative quality of recovery score: the qor-40. br j anaesth.2000;84:1:11–15. doi: 10.1093/oxfordjournals.bja.a013366. 13. corney rh, clare aw. the construction, development and testing of a self-report questionnaire to identify social problems. psychol med.1985;15:637–649. doi: 10.1017/s0033291700031494. 14. aitken rcb. measurement of feelings using visual analogue scales. proc r soc med.1969;62:989–993. 15. cella d, yount s, du h, dhanada r, gondek k, langefeld k, et al. development and validation of the functional assessment of cancer therapy-kidney symptoms index (fksi). j suppor t oncol.2006;4:191-199. this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information bladder tumours, bladder cancer, robot-assisted surgery, bladder diverticula none declared. received on april 7, 2022 accepted on april 30, 2022 this article has been peer reviewed. soc int urol j. 2022;3(5):303–313 doi: 10.48083/jclw6772 intra-diverticular bladder tumours: how to manage rationally mohammed lotfi amer,1,2 hassan mumtaz,2 beth russell,2 jason gan,2 zahra rehman,2 rajesh nair,2 ramesh thurairaja,2 muhammad shamim khan2 1 tanta university faculty of medicine, urology, tanta, egypt 2 guy's and st thomas' nhs foundation trust, urology, london, united kingdom abstract objective to report changing practice in the management of intra-diverticular bladder tumours. methods we undertook a review of all intra-diverticular bladder tumours in our prospectively maintained institutional database. results a total of 28 patients (male = 27, female = 1) with a median age of 71 years (iqr 61 to 76) were diagnosed with intra-diverticular bladder tumours (idbt) between march 2013 and february 2021. fourteen had visible and 3 had non-visible haematuria, while 11 patients had lower urinary tract symptoms. median axial diameter of the diverticula was 46 mm (iqr 35 to 69), and median neck diameter was 9 mm (iqr 7 to 11). all patients had ct-urography and 5 patients also had an mri. surgical treatment consisted of diverticulectomy (n = 11), diverticulectomy and ipsilateral ureteric reimplantation (n = 11), radical cystectomy and ileal conduit (n = 4), or radical cystectomy and orthotopic bladder (n = 2). eleven patients had open procedures, and 17 had robotic assisted surgery. final pathological stages were t0 (n = 2), ta (n = 5), t1 (n = 7), t3a (n = 8) and t3b (n = 6). twenty-four patients had urothelial carcinoma (including one nested variant and 4 with squamous differentiation) and 2 had small cell carcinoma. three patients had neoadjuvant systemic chemotherapy, 2 had intravesical bacillus calmette-guerin (bcg) with mitomycin, and one had bcg monotherapy preoperatively. five patients had adjuvant systemic chemotherapy while 7 had adjuvant intravesical therapies. mean follow-up period was 37.8 months (±25.3). mean recurrence-free survival was 61.5% (ci 45.7 to 77.4) and mean overall survival 71.6 % (ci 57.4 to 85.8). ten patients (37%) died of cancer. conclusion management of intra-diverticular bladder tumours is evolving. bladder-sparing approaches are gaining popularity. robot-assisted diverticulectomy is preferable as it reduces the morbidity resulting from treatment. introduction intra-diverticular bladder tumours (idbt) are rare, accounting for approximately 1.5% of all bladder tumours. the first report of a diverticular tumour in the english literature was in 1896[1]. studies published since then have been either case reports or small case series from various centres. the most common histological type is urothelial carcinoma[2]. the challenges in managing idbt are multifactorial and involve all stages including initial diagnosis, resection/biopsy pathological staging, and subsequent treatment. 303siuj.org siuj • volume 3, number 5 • september 2022 original research http://siuj.org historically, idbt have been perceived to be associated with poor prognosis. the possible reasons include anatomical factors ie, lack of muscle layer, late presentation, delay in diagnosis due to limited access to digital imaging, and delayed treatment[3,4]. because of the rarity of the idbt, there is no universally accepted management algorithm. recommendations for management of idbt were published by cancer committee of the french association of urology in 2012[2]; however, because of changing surgical practice, these guidelines require revision. we report a series of 28 patients managed in our centre over the last 8 years. their management reflects the increasing adoption of robotic approach for excision of the diverticula ± reimplantation of ureters and radical cystectomy when required. an algorithm is proposed for the most rational management of this rare group of tumours (appendix 1). materials and methods we reviewed the prospectively maintained institutional database to identify all patients with idbt who were managed in our department between march 2013 and february 2022. all patients provided informed consent for use of their data with preservation of confidentiality. as our institutional data are prospectively maintained with approval of local and institutional governance, ethics committee approval was not required. the data collated included demographics, presenting symptoms, results of investigations including histology, neoadjuvant t herapy, t y pe of procedure, surg ica l approach, postoperative oncological and functional outcomes, adjuvant therapy, recurrences and their management, and estimated recurrence-free and overall survival. statistical analysis for continuous data with normal distribution, variables are presented as mean ± standard deviation (sd). for continuous data with skewed distribution, variables are presented as median ± interquartile range (iqr). kaplan-meier analysis and the log-rank tests were used to depict time to events during follow-up. statistical significance was set at p < 0.05. all statistical analysis was performed using spss version 26 software (ibm spss statistics, ibm corp., armonk, ny). robot-assisted bladder diverticulectomy t h e s t e p s i n t h e r o b o ta s s i s t e d pr o c e du r e diver t icu lectomy involve a n init ia l c ystoscopic examination to re-assess the bladder. it is advisable to mark the periphery of the diverticulum with a colling’s knife, aiming for a 1 cm surgical margin to act as guide for adequate oncological clearance. an appropriate length and diameter stent should be inserted in the ipsilateral ureter. we use a 6 port transperitoneal approach. once the diverticulum is identified it should be dissected from all sides until the neck is clearly defined. the bladder should be emptied before the neck of the diverticulum is opened to avoid spillage of the fluid to reduce the risk of cancer cell implantation. the diverticular neck should be opened at the 12 o’clock position initially to prevent spillover of any residual f luid in the diverticulum. previously placed diathermy marks should be followed to circumcise the diverticulum. it is important not to mobilize the bladder anteriorly during the procedure, as this makes subsequent dissection very difficult. once excision is complete, the specimen must be placed in the appropriate size bag immediately. the defect in the bladder should be closed with v-loc sutures in a single layer. if the ipsilateral ureter must be transected for complete removal of the tumour, it should be re-implanted over an appropriate length double-j stent. bilateral standard lymphadenectomy should then be performed. a drain may be left in the pelvis. a cystogram should be obtained 7 to 10 days after surgery and the catheter removed if this is satisfactory. results a total of 28 patients were identified from the database: 27 males and 1 female. the median age was 71 years (iqr 61 to 76), and the median charlson comorbidity index was 5 (iqr 4 to 7). the median body mass index was 26 (iqr 24.1 to 27.3). fourteen patients presented with visible and 3 with non-visible haematuria, and 11 patients presented with lower urinary tract symptoms. six had previous transurethral resection of the prostate (turp), 3 had prior bladder neck incision (bni), and 6 were on clean intermittent self-catheterisation (cisc) for incomplete bladder emptying. median axial diameter of the diverticula was 46 mm (iqr 35 to 69) and neck diameter 9 mm (iqr 7 to 11). all patients had ct-urography, but 5 patients additionally had magnetic resonance imaging (mri) of the bladder for precise staging. twenty-seven patients had resection biopsies, and one had diverticulectomy without prior tumour biopsy as the lesion was highly vascular and subsequently proved to be a small cell diverticular tumour. definitive surgical management consisted of diverticulectomy (n = 11), diverticulectomy and ipsilateral ureteric reimplantation (n = 11), radical cystectomy and ileal conduit (n = 4), and radical cystectomy and orthotopic bladder substitution (n = 2). three patients did not have lymphadenectomy because of poor general health; 14 had ipsilateral and 11 bilateral pelvic lymphadenectomy. eleven patients had open procedures and 17 had robot-assisted surgery. surgeries were done by 3 expert 304 siuj • volume 3, number 5 • september 2022 siuj.org original research http://siuj.org consultants with special interest in bladder cancer. the median operative time was 230 minutes (iqr 180 to 290), the median estimated blood loss was 200ml (iqr 100 to 300) and the median length of stay was 4 days (iqr 3 to 6). there were 23 postoperative complications; 20/23 (86%) of which were low-grade complications (claviendindo grade 1 or 2). three major complications (ie, clavien-dindo grade ≥ 3) occurred mainly in those who had radical cystectomy. the list of complications and their management is shown in table 1. on final histological examination, 2 patients had no residual tumour (t0); however, one had dysplasia and the other’s specimen showed extensive keratinizing metaplasia. the pathologic stage of the tumours in the remainder was as follows: pta (n = 5), pt1 (n = 7), pt3a (n = 8), pt3b (n = 6). tumours in 24 patients were urothelial carcinoma including nested variant in 1 patient and squamous differentiation in 4, and 2 had small cell carcinoma. the risk of clinical under-staging is well documented, and this occurred in 2 of the 6 patients in the radical cystectomy subgroup: the first was clinically staged as ct1 and was upstaged to pt3, while the other was cta in clinical staging and upstaged to pt1 on final histology (table 2). of 22 patients undergoing diverticulectomy, 4 were staged ascta, 11 as ct1 and 4 as ct3. the final stage in 12 of these patients was in concordance with initial clinical stage, 7 were upstaged and 3 were downstaged (table 3). three patients had systemic neoadjuvant chemotherapy for clinically locally advanced disease with only partial response. one patient had intravesical bacillus calmette-guerin (bcg) monotherapy before referral to our centre, and 2 had sequential intravesical mitomycin and bcg therapy. five patients had adjuvant systemic chemotherapy (for locally advanced disease on final histology), and 7 patients had adjuvant intravesical bcg and sequential electromotive drug administration mitomycin induction, followed by maintenance bcg after diverticulectomy[5]. eleven patients who underwent bladder-preserving surgery had normal voiding patterns postoperatively. eleven others had ongoing lower urinary tract symptoms after surgery. four patients were on meditable 1. complications and their management postoperative complications number of patients management clavien-dindo grade urinary infection 2 course of antibiotics 2 migrated stents 1 exploration to reposition stents 3b bleeding 1 transfusion 2 pyrexia due to small pelvic collection 2 iv antibiotics + antipyretics 2 hospital acquired pneumonia 2 iv antibiotics and chest physiotherapy 2 nausea and bloating 5 antiemetics 1 neuropraxia of the medial side of thigh 1 medical ttt for neuropathy like b12 1 postoperative ileus 3 ngt and antiemetics, bowel stimulants 2 hypotension and bradycardia 1 antiarrhythmics 1 high drain output 2 low creatinine content/ drain for 3 more days 1 ileus, aspiration, and pulmonary oedema 1 itu management 4a small bowel obstruction 1 laparotomy + adhesiolysis 3b scrotal swelling 1 scrotal support+ analgesics 1 305siuj.org siuj • volume 3, number 5 • september 2022 intra-diverticular bladder tumours: how to manage rationally http://siuj.org table 3. diverticulectomy: pathological data turbt histology clinical stage (with imaging) final histology g3 t1 + cis t1n0 g2 ta nx g3 t1 + cis t1n0 g3 t1 n0 + (squamous differentiation) g3 t1 t1n0 g3 t3a n0 g2 t1 t1n0 g2 t3a n0 g2 ta tan0 g2 ta n0 g3 t1 t3n0 g3 t3b n0 + (squamous differentiation) g2 ta tan0 g2 ta n0 g3 ta tan0 g3 t1 n0 g3 t1 t3n1 g3 t3a n0 g3 t1 t1n0 g3 t3a n0+ (squamous differentiation) g3 ta tan0 g3 ta n0 not performed t3n0 g3 t3a nx (small cell variant) g3 t1 t1n0 g3 t3b n0 (small cell variant) g3 t1 t1n0 g3 t3b n0 (nested variant) g3 t1 t1n0 g3 t1 n0 g3 t3 t3n0 g3 t3a n0 g2 t1 t1n0 g3 pt3a n0 not performed txn0 t0 n0dysplasia g3 t1 t1n0 g3 t1 n0 g3 t1 t1n0 g3 t1 n0 g2 ta tan0 t0n0 g3 t1 t1n0 g3 t1+ (squamous differentiation) cal treatment while 7 patients underwent surgeries for bladder outlet obstruction later (turp in 4 and bni in 3). finally, 6 patients had to continue to perform cisc, including 3 of after outlet surgery. mean follow-up was 37.8 ± 25.3 months. the estimated mean recurrence-free survival for this cohort was 61.8% (ci 46.0 to 77.6) (figure 1). recurrences and their management are listed in table 4. radical surgery did not seem to add therapeutic benefit in recurrent locally advanced disease. the estimated mean overall survival was 71.6 % (ci 57.4 to 85.8) (figure 2). ten patients (37%) died of cancer. by kaplan-meier estimate there was no significant difference in recurrence-free survival in patients who underwent open surgery versus those who had robot-assisted surgery (log-rank p = 0.57) (figure 3). discussion appendix 1 shows an algorithm that summarizes our approach to the management of idbt. there are 3 key factors to be taken into consideration in the management of these tumours: (1) tumour factors, (2) diverticular factors, and (3) patient factors. diverticular anatomy is particularly important. difficulties may arise in the initial identification of the tumour as tumour in a diverticulum with narrow neck may be missed. furthermore, the neck of the diverticulum may not be wide enough to allow the passage of the scope into the cavity of the diverticulum. the size and location in the bladder may also make the diverticulum inaccessible for thorough internal inspection particularly with a rigid cystoscope. similar factors may limit resection of tumour in a diverticulum. a thin-walled diverticulum increases the risk of perforation, and a large or deep tumour may preclude complete clearance table 2. radical cystectomy: pathological data turbt histology clinical stage (with imaging) cystectomy histology g3 t1 t1n1 g3 t3b n1 (squamous differentiation) g3 t1 t3n0 g3 t3b n0 g3 ta + cis tan0 g3 t1 n0 g3 t1 t1n0 g3 t1 n0 g3 t1 + cis t3n0 g3 t3a n0 g3 t1 t3n0 g3 t3b n0 306 siuj • volume 3, number 5 • september 2022 siuj.org original research http://siuj.org table 4. tumour recurrences and their management preoperative clinical stage neoadjuvant therapy initial operation final histology adjuvant therapy site and histology of recurrence management of the recurrence follow-up g3 t1 n0 no robotic diverticulectomy+ bilateral plnd g3 t3 n0 systemic chemotherapy bladder cis turbt bcg + emda mmc induction and bcg maintenance 28 months/ alive g3 t1 n0 local intravesical mmc + bcg induction open diverticulectomy + ureteric reimplantation+ ipsilateral lymphadenectomy g3 t3 n0 (nested variant) systemic chemotherapy bladder g3t1 salvage cystectomy 61 months/ alive g3 t1 n0 no robotic diverticulectomy + ureteric reimplantation+ ipsilateral lymphadenectomy g3 t1 n0 intravesical emda mmc+bcg maintenance bladder g3 t1+ cis unfit for salvage cystectomy, managed endoscopically 27 months/ dead g3 t1 n0 no robotic diverticulectomy + ureteric reimplantation+ ipsilateral lymphadenectomy g3 t1 (squamous differentiation) no bladder cis salvage cystectomy 27 months/ alive without risk of perforation and local spillage of the tumour. prognostically, the absence of the muscle layer allows diverticular tumours to spread locally or metastasize more readily than non-diverticular bladder tumours. high-grade diverticular tumours are likely to invade the peri-diverticular fat because of lack of detrusor muscle barrier, and are potentially associated with a worse outcome. because of the structural differences of the diverticulum, the standard bladder cancer staging system is not applicable to the idbt. diverticular tumour staging distinguishes non-invasive (tis/ta), superficially invasive (t1), and extra-vesical (t3) disease as well as tumours invading adjacent structures (t4) (figure 4) [6]. figure. 1 continued on page 308 307siuj.org siuj • volume 3, number 5 • september 2022 intra-diverticular bladder tumours: how to manage rationally http://siuj.org table 4. tumour recurrences and their management preoperative clinical stage neoadjuvant therapy initial operation final histology adjuvant therapy site and histology of recurrence management of the recurrence follow-up g3 t1 n1 systemic chemotherapy open radical cystectomy+ bilateral plnd+ orthotopic neobladder g3 t3 n1 (squamous differentiation) systemic chemotherapy orthotopic neobladder excision of orthotopic neobladder and ic formation+ adjuvant systemic chemotherapy 11 months/ dead g3 t1 n0 no robotic radical cysto-prostatectomy + bilateral plnd+ orthotopic neobladder g3 t3 n0 no orthotopic neobladder palliative radiation 12 months/ dead g3 t3 n0 systemic chemotherapy robotic radical cystoprostatectomy+ lymphadenectomy +ileal conduit diversion g3 t3 n0 no local in the hemipelvis palliative radiation 7 months/ dead g3 t3 n0 (squamous differentiation) no open diverticulectomy + bilateral-ureteric reimplantation bilateral plnd g3 t3 n0 (squamous differentiation) no bone metastasis (rib) palliative radiation 8 months/ dead g3 t1 n0 no open diverticulectomy+ bilateral plnd + ureteric reimplantation g3 t3 n0 no bladder with liver metastasis palliative symptomatic management 55 months/ alive g3 t3 n0 no open diverticulectomy+ bilateral plnd + ureteric reimplantation g3 t3 n0 no liver metastasis palliative symptomatic management 4 months/ dead , cont’d 308 siuj • volume 3, number 5 • september 2022 siuj.org original research http://siuj.org management options range from tumour resection followed by adjuvant intravesical chemotherapy or bacillus calmette-guerin (bcg) immunotherapy to diverticulectomy / partial cystectomy and radical cystectomy for high-grade tumours. radical cystectomy is appropriate for patients with concomitant high-grade or extensive disease of any grade with or without voiding dysfunction. the evolution in management has seen a shift from radical surgery for all to a more targeted approach in which a significant number have been managed with diverticulectomy / partial cystectomy with good longterm oncological outcomes, as well as preservation of patient quality of life. endoscopic management is most suitable for patients with low-grade non-invasive disease in a wide-neck diverticulum that can be completely resected, provided the main bladder is either clear or has minimal low-grade non-invasive disease. after complete tumour resection, patients should be given intravesical chemotherapy or immunotherapy as appropriate. bladder-preserving surgery with diverticulectomy, with or without ipsilateral ureteric reimplantation and pelvic lymphadenectomy is suitable for patients with tumours that cannot be resected endoscopically because of the bulk or poor access to the diverticulum irrespective of tumour grade. diverticulectomy should not be offered to patients with high-grade tumours or cis elsewhere in the bladder. traditionally, bladder diverticulectomy has been performed by an open surgical approach. bourgi et al. reported a series of 17 patients from their centre[7]. one had endoscopic resection, 11 had open diverticulectomy and 5 had radical cystectomy. nine patients (81.81%) were disease free after a mean of 33.63 months. one required radical cystectomy 6 months after diverticulectomy for recurrent high-grade tumour. one patient developed lymph node metastases 10 months after diverticulectomy and underwent palliative chemotherapy. five of 7 patients (71%) with invasive tumours treated with diverticulectomy alone were disease free at the end of the follow-up[7]. golijanin et al. published a series of 39 patients with idbt: 13 (33%) had non-invasive disease; 13 (33%) had ct1 tumours; and 13 (33%) had ct3 disease. actuarial 5-year disease-specific survival for the cohort was 72% (+/5.4%), but this varied widely by stage. mode of treatment of ct1 tumours did not correlate with outcome in this series; in a multivariate model, clinical staging was the only independent predictor of outcome[8]. sallami et al. reported 32 cases of idbt. clinical evaluation showed cta stage in 16 patients, ct1 stage in 8 patients, and ≥ct3 tumours in 8 patients. with an average follow-up of 27 months, 7 recurrences were found figure. 2 figure. 3 figure. 4 309siuj.org siuj • volume 3, number 5 • september 2022 intra-diverticular bladder tumours: how to manage rationally http://siuj.org in the group of non-invasive tumours, including 3 cases of progression to invasive disease. patients with highgrade invasive tumours were treated with radical cystectomy[9]. myer and wagner reported the first series of 5 patients who underwent robot-assisted bladder diverticulectomy for symptoms[10]. length of stay was 3 days (range 1 to 6). radical cystectomy would be the treatment of choice for patients with high-grade idbt and concomitant high-grade tumour elsewhere in the bladder. the same would be offered to a patient with severe voiding dysfunction or if the patient prefers radical surgery for maximal oncological safety. with the widespread adoption of robotic technology, it has become possible to minimise the trauma of surgery and the morbidity of diverticulectomy. in our centre with extensive experience in robotic surgery, robot-assisted diverticulectomy has become the standard of care in the management of these patients in recent years. other issues to consider in the management of idbt are voiding function, protection of the ureters, and patient preference. acquired diverticula are usually secondary to bladder outlet obstruction. incomplete bladder emptying, due to obstruction or to atonic bladder, is common. when the bladder is involved with multifocal tumours it is better to consider radical surgery to address both oncological and functional issues unless the patient is keen to persist in cisc, although patients should be advised against this. those with ibdt only but with outflow obstruction need either transurethral resection or bladder neck incision as appropriate after a urodynamic study post diverticulectomy. the ipsilateral ureter is at risk of injury during dissection of the diverticulum or may be draining into the diverticulum. hence, the ipsilateral ureter should be protected by stenting during dissection of the diverticulum, or if it is not possible to salvage the ureter, a reimplantation over a double-j stent should be performed. in 2018, a series of 115 patients was reported that included patients from 11 european centres (thus averaging about 10 patients per centre)[11]. the study suffers from a degree of heterogeneity due to the diverse management approaches in various centres. however, with a median follow-up of 5 years (95% confidence interval [ci] 4.0 to 6.2), it has shed light on few aspects of managing idbt and highlighted the current limitations of staging investigations[11]. moreover, it has provided some reassurance that bladder-sparing approach in carefully selected patients can yield equivalent oncological outcomes to radical cystectomy. although radical cystectomy may offer oncological benefit, it comes at the high cost of living with urinary diversion and a high risk of losing sexual function. therefore, the management should be tailored to the individual patient according to the volume and stage of the disease, status of the bladder, voiding function, and patient preference. on the basis of our experience and previously published series, we make the following recommendations: 1. prognosis is largely dependent on the stage, grade, and bulk of the tumour rather than the extent of surgery. hence, when appropriate (absence of cis or multifocal tumours/ normal voiding function), bladder preservation with meticulous follow-up should be the preferred treatment. 2. when considering radical surgery, particularly in locally advanced tumours or histological variants with poor prognosis, it is advisable to avoid complex reconstruction. 3. lymphadenectomy should be bilateral rather than ipsilateral on the side of tumour, although we have not come across any lymph node metastasis on the contralateral side in patients having ipsilateral lymph node dissection. 4. patients should be counselled about the possibility of needing completion cystectomy in the case of adverse final pathology or subsequent recurrences. 5. robot-assisted diverticulectomy has the advantages of minimal blood loss, shorter hospital-stay, and minimal would complications. hence, this approach should be offered in centres with surgical expertise. should a patient require completion cystectomy, this can also be performed using the robotic approach. limitations of the current study are low number of cases, heterogeneous cohort, and short follow-up, including patients who were treated in the past couple of years. therefore, more organized multicentre experience would be helpful to confirm the results. conclusion management of intra-diverticular bladder tumours is evolving. there is a shift from radical surgery for all to a more selective approach tailored to individual needs. the spectrum of procedures required lends itself to a robotic approach, and this should be applied where possible to reduce the surgical morbidity. 310 siuj • volume 3, number 5 • september 2022 siuj.org original research http://siuj.org reference 1. targett j. diverticula of the bladder associated with vesical growths. transactions of the pathological society of london. 1896;47. 2. neuzillet y, comperat e, rouprêt m, larre s, roy c, quintens h, et al. [intradiverticular bladder tumours: review of the cancer committee of the french association of urology]. prog urol.2012;22(9):495-502. doi: 10.1016/j.purol.2012.03.008. epub 2012 apr 28. 3. faysal mh, freiha fs. primary neoplasm in vesical diverticula. a report of 12 cases. br j urol.1981;53(2):141-143. doi: 10.1111/j.1464410x.1981.tb03153.x 4. mićić s, ilić v. incidence of neoplasm in vesical diverticula. j urol. 1983;129(4):734-735. doi: 10.1016/s0022-5347(17)52332-0. 5. gan c, amer y s, chatter ton k, khan ms, thomas k, o'brien t. sequential bacillus calmet te-guérin/electromotive drug administration of mitomycin c as the standard intravesical regimen in high risk nonmuscle invasive bladder cancer: 2-year outcomes. j urol.2016;195(6):1697-1703. doi: 10.1016/j.juro.2016.01.103. epub 2016 feb 2. 6. walker nf, gan c, olsburgh j, khan ms. diagnosis and management of intradiverticular bladder tumours. nat rev urol.2014;11(7):383-390. doi: 10.1038/nrurol.2014.131. epub 2014 jun 17. 7. bourgi a, ayoub e, merhej s. diverticulectomy in the management of intradiverticular bladder tumors: a twelve-year experience at a single institution. adv urol.2016;2016:2345306. doi: 10.1155/2016/2345306. published online 2016 mar 15. 8. golijanin d, yossepowitch o, beck sd, sogani p, dalbagni g. carcinoma in a bladder diverticulum: presentation and treatment outcome. j urol.2003;170(5):1761-1764. doi: 10.1097/01.ju.0000091800.15071.52 9. sallami s, ben rhouma s, hafsia g, nouira y, horchani a. intradiverticular tumors of the bladder: diagnostic and therapeutic problems: report of 32 cases. [article in french] tunis med.2011;89(89):663-667. pmid: 21948678 10. myer eg, wagner jr. robotic assisted laparoscopic bladder diverticulectomy. j urol.2007;178(6):2406-2410; discussion 2410. doi: 10.1016/j.juro.2007.08.012. epub 2007 oct 15. 11. voskuilen cs, seiler r, rink m, poyet c, noon ap, roghmann f, et al. urothelial carcinoma in bladder diverticula: a multicenter analysis of characteristics and clinical outcomes. eur urol focus.2020 nov 15;6(6):1226-1232. doi: 10.1016/j.euf.2018.12.002. epub 2018 dec 14. 311siuj.org siuj • volume 3, number 5 • september 2022 intra-diverticular bladder tumours: how to manage rationally http://siuj.org treatment options bladder sparing surgery (diverticulectomy/ partial cystectomy ± reimplantation of the ureter(s)/unilateral or bilateral plnd ± ivc or ivi radical cystectomy+ plnd +/adjuvant systemic chemotherapy or local radiotherapy lv lg idbt but with difficult angle/ inaccessible location/ narrow neck endoscopic management + ivc/ivi +orendoscopic management of ivo (bni/turp) lv lg idbt wide diverticcular neck lv hg idbt + no synchronous bladder tumours or extensive cis high volume / high risk of perforation hv hg idbt synchronous bladder tumours/extensive cis high volume / high risk of perforation vh nvh + luts recurrent uti symptoms of bladder tumour and/or ivo/bph: ghg2 mri pelvis laboratory investigations status of the urethra/prostate bladder mapping (associated tumours) accessibility to the tumour tissue sampling and hpe in ve st ig at io ns cystoscopy (rigid/flexible) ± biopsy/resection tumour factors stage state of lns synchronous bladder tumours histology size and neck diameter number location and relation to the uo age associated diseases (bph/ pca) patient preference diverticular factors patient factors comorbidities/ cci/ renal function appendix 1. algorithm of management of idbt 312 siuj • volume 3, number 5 • september 2022 siuj.org original research http://siuj.org treatment options bladder sparing surgery (diverticulectomy/ partial cystectomy ± reimplantation of the ureter(s)/unilateral or bilateral plnd ± ivc or ivi radical cystectomy+ plnd +/adjuvant systemic chemotherapy or local radiotherapy lv lg idbt but with difficult angle/ inaccessible location/ narrow neck endoscopic management + ivc/ivi +orendoscopic management of ivo (bni/turp) lv lg idbt wide diverticcular neck lv hg idbt + no synchronous bladder tumours or extensive cis high volume / high risk of perforation hv hg idbt synchronous bladder tumours/extensive cis high volume / high risk of perforation vh nvh + luts recurrent uti symptoms of bladder tumour and/or ivo/bph: ghg2 mri pelvis laboratory investigations status of the urethra/prostate bladder mapping (associated tumours) accessibility to the tumour tissue sampling and hpe in ve st ig at io ns cystoscopy (rigid/flexible) ± biopsy/resection tumour factors stage state of lns synchronous bladder tumours histology size and neck diameter number location and relation to the uo age associated diseases (bph/ pca) patient preference diverticular factors patient factors comorbidities/ cci/ renal function bni bladder neck incision bph benign prostatic hyperplasia cci charlton comorbidity index cect contrast enhanced ct cis carcinoma in situ e-gfr estimated glomerular filtration rate hg high grade hn hydronephrosis hpe histopathological examination hv high volume idbt intra-diverticular bladder tumour ivc intra-vesical chemotherapy ivi intra-vesical immunotherapy ivo infra-vesical obstruction lg low grade ln lymph node lv low volume luts lower urinary tract symptoms mri magnetic resonance imaging nac neoadjuvant chemotherapy nvh nonvisible haematuria plnd pelvic lymph node dissection pca prostate cancer uo ureteric orifice uti urinary tract infection vh visible haematuria 313siuj.org siuj • volume 3, number 5 • september 2022 intra-diverticular bladder tumours: how to manage rationally http://siuj.org 361siuj.org siuj • volume 3, number 6 • november 2022 editorial tackling kidney cancer through international consensus 363 philippe e. spiess urology around the world why should the indian urology and oncology community be “aatmanirbhar” in penile cancer research 367 prakash gagan 2nd wuof/siu-icud on kidney cancer chapter summaries kidney cancer screening and epidemiology 371 sabrina h. rossi, hajime tanaka, juliet a. usher-smith, jean-christophe bernhard, yasuhisa fujii, grant d. stewart genetics and tumor microenvironment of renal cell carcinoma 386 sari khaleel, christopher ricketts, w. marston linehan, mark ball, brandon manley, samra turajilic, james brugarolas, ari hakimi hereditary renal cell carcinoma syndromes 397 jodi k. maranchie, brian m. shuch, gennady bratslavsky, eamonn r. maher imaging of renal cell carcinoma 407 wai-kit lee, m. liza lindenberg, esther mena gonzalez, peter choyke, kevin g. king, raghunandan vikram, vinay a. duddalwar active surveillance of renal cell carcinoma 424 eric c. kauffman, mark w. ball, ravi barod, umberto capitanio, antonio finelli, m. carmen mir, brian shuch, marc c. smaldone, maxine g.b. tran, phillip m. pierorazio ablative therapies for localized primary renal cell carcinoma 437 muhammad ali, vanessa acosta ruiz, sarah p. psutka, david liu, shankar siva table of contents http://siuj.org 362 siuj • volume 3, number 6 • november 2022 siuj.org management of locally advanced renal cell carcinoma 451 vsevolod b. matveev, sarah p. psutka, grant d. stewart, gennady bratslavsky, e. jason abel neoadjuvant and adjuvant therapy for renal cell carcinoma 465 naomi b. haas, jeffrey shevach, ian d. davis, tim eisen, marine gross-goupil, anil kapoor, viraj a. master, christopher ryan, manuela schmidinger therapies in refractory metastatic renal cell carcinoma 478 stephanie berg, martin angel, kathryn e. beckermann, frede donskov, chung-han lee, pavlos msaouel, rana r. mckay, tian zhang management of toxicity and side effects of systemic therapy for renal cell carcinoma 485 kate young, andreas m. schmitt, deborah mukherji, lavinia spain, manuela schmidinger, lisa m. pickering clinical picture renal cell carcinoma with intratumoral pseudoaneurysm 501 daniel p. pierce, elias h. salloum, philippe e. spiess table of contents, cont'd http:// this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information renal cell carcinoma, pseudoaneurysm, renal artery embolization none declared. patient consent: obtained. received on may 21, 2022 accepted on may 24, 2022 soc int urol j. 2022;3(6):501–502 doi: 10.48083/rhxj2561 renal cell carcinoma with intratumoral pseudoaneurysm daniel p. pierce,1 elias h. salloum,2 philippe e. spiess2 1 university of south florida department of urology, tampa, united states 2 moffitt cancer center, tampa, united states pseudoaneurysms can be present both preand postoperatively, occurring as frequently as 23% of the time by postoperative day seven. this specific case was found secondary to a standard preoperative evaluation and workup in a patient with otherwise undisturbed surgical fields suggesting de novo formation within the renal tumor. factors considered for preoperative intervention included size of overall tumor, size of pseudoaneurysm, complex surgical anatomy of renal vasculature, and baseline risk of major intraoperative or postoperative hemorrhage. renal artery embolization was performed using multiple detachable concerto microcoils, resulting in complete occlusion. the following day via a subcostal incision the left upper pole and main renal arteries and vein were controlled, allowing for safe removal of the left kidney and adrenal gland with minimal measured blood loss at 300 ml and an uneventful postoperative course. figure 1. figure 2. coronal ct demonstrating a 10.3 cm × 8.7 cm × 6.5 cm solid and cystic enhancing left renal mass arising from the medial aspect of the upper pole, engulfing the left adrenal gland, and invading the left renal hilum. also captured within this image are 2 of 3 pseudoaneurysms (psa) with the largest measuring approximately 3 cm and an inferior multilobulated psa measuring 1.5 cm coronal ct depicting yet another psa at the origin of a more superior of 2 renal arteries measuring just under 1 cm 501siuj.org siuj • volume 3, number 6 • november 2022 clinical picture mailto:daniel.pierce%40moffitt.org?subject=siuj http://siuj.org figure 3. figure 4. digital subtraction angiogram of the superior left renal artery confirming a total of 3 psa, the more proximal originating at the renal artery orifice post embolization angiogram demonstrating stasis of the renal artery without opacification of the 3 cm psa. also noted is retained contrast within the inferior multilobulated psa confirming occlusion of the feeding vessel 502 siuj • volume 3, number 6 • november 2022 siuj.org renal cell carcinoma with intratumoral pseudoaneurysm http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information bacillus calmete-guerin, bcg, bcgunresponsive, bcg refractory, bcg relapsing, bladder cancer none declared. received on may 21, 2022 accepted on july 27, 2022 this article has been peer reviewed. soc int urol j. 2022;3(5):333–339 doi: 10.48083/ckyl2827 systematic review and meta-analysis of response rates in bcg-unresponsive non–muscle-invasive bladder cancer: a consensus statement from the international bladder cancer group kyle m. rose,1 herney a. garcia-perdomo,2 trinity j. bivalacqua,3 j. alfred witjes,4 joan palou,5 peter c. black,6 gary d. steinberg,7 seth p. lerner,8 sima p. porten,9 ashish m. kamat,10 roger li1 1 department of genitourinary oncology, h. lee moffitt cancer center, tampa, united states 2 division of urology/urooncology, department of surgery, universidad del valle, cali, colombia 3 department of urology, university of pennsylvania, philadelphia, united states 4 department of urology, radboud university nijmegen medical centre, mijmen, the netherlands 5 department of urology, fundacio puigvert, universitat autonoma de barcelona, barcelona, spain 6 department of urologic sciences, university of british columbia, vancouver, canada 7 department of urology, new york university langone health, new york, united states 8 scott department of urology, baylor college of medicine, houston, united states 9 department of urology, university of california san francisco, san francisco, united states 10 department of urology, md anderson cancer center, houston, united states abstract there is a critical need to establish reference response rates following bladder-sparing therapies administered in the setting of bacillus calmete-guerin (bcg)-unresponsive non–muscle-invasive bladder cancer (nmibc). we sought to determine the efficacy of different interventions in recent trials accruing patients fulfilling the strict bcgunresponsive definition established by the us food and drug administration. we performed a systematic review and meta-analysis for clinical trials in the bcg-unresponsive disease space to include published and presented results. the primary endpoints were complete response rate for cis±ta/t1 tumors, recurrence-free rate for patients with papillary-only disease, and disease-free rate in studies enrolling both papillary cis tumors (ta/t1/cis). i2 was used for assessing heterogeneity. eleven studies using 9 different therapeutic agents in a total of 909 patients with bcg-unresponsive nmibc were identified. the resulting outcomes at 3, 6, and 12 months were 44%, 38%, and 25% complete response rate in cis±ta/t1 tumors; 73%, 58%, and 48% recurrence-free rate in papillary-only; and 48%, 22%, and 43% disease-free rate in combined ta/t1/cis, respectively. relatively low levels of heterogeneity were observed amongst studies restricted to papillary-only or cis±ta/t1 tumors. future randomized controlled studies are needed and will likely require stratification between papillary-only and cis±ta/t1 tumors. introduction the decision of the united states food and drug administration (fda) to accept single-arm phase ii/iii clinical trials of novel agents for the treatment of bcg-unresponsive non–muscle-invasive bladder cancer (nmibc) in tumors with cis emphasizes the importance of reference efficacy rates to help frame the decision for approval. a previous systematic review that aimed to provide such reference benchmarks uncovered significant heterogeneity in patients enrolled in previous nmibc clinical trials regarding the number and timing of intravesical bcg instillation and the pathology of the subsequent recurrent tumor[1]. one method to circumvent these barriers is to homogenize the study population by using the standard bcg-unresponsive definition adopted by the fda in clinical trial design[2]. results from recent trials enrolling such patients will provide context for the interpretation of emerging data from ongoing clinical trials conducted in the bcg-unresponsive space. 333siuj.org siuj • volume 3, number 5 • september 2022 review mailto:roger.li%40moffitt.org?subject=siuj http://siuj.org methods we performed a systematic review and meta-analysis in accordance with preferred reporting items for systematic reviews and meta-analyses (prisma) statement recommendations. an updated search was performed using the previously published protocol (prospero crd42019130553)[1]. full search protocol, study review methodology, risk of bias assessment, and data synthesis are presented in supplementary appendix 1 (siuj.org). we included unpublished studies from phase ii-iii clinical trials presented at national urologic/oncology conferences that strictly accrued patients with bcg-unresponsive disease. the primary endpoints were complete response rate (crr) for cis±ta/t1 tumors, recurrence-free rate (rfr) for patients with papillary-only disease, and disease-free rate (dfr) in studies enrolling both papillary (ta/t1) and cis-containing patients as previously described (ta/t1/cis)[1,2]. we performed a meta-analysis of proportions with command metaprop and inverse method with logit transformed proportions and sensitivity analysis. information was pooled with a random effect meta-analysis according to the heterogeneity expected. i2 was used for assessing heterogeneity. results the initial search yielded 287 studies. after screening, 11 relevant studies were selected for analysis (figure 1). six studies were excluded in total. four studies performed before the establishment of the bcg-unresponsive definition in 2015 were excluded as they enrolled patients with low-grade recurrences following bcg [3–6]. another trial using cg0070 was excluded because of incomplete reporting[7]. one study was excluded because of the inclusion of bcg-intolerant patients rather than strictly those with bcg-unresponsive disease[8]. studies with cohorts consisting of ciscis±ta/t1 tumors and papillary-only disease were ana lyzed separately, as prev iously described[9]. the included studies used 9 different therapeutic agents in a total of 909 patients with bcg-unresponsive nmibc (table 1). of the reported study arms, 6 enrolled cis±ta/t1 tumors, 6 papillary-only tumors, and 4 ta/t1/cis tumors conjointly. the primary endpoints for cis±ta/t1, ta/t1, and ta/t1/cis are listed by timepoints following therapy in table 2 and illustrated in the forest plots in figure 2. only the durable 12-month crr from quilt 3.032 study[10] was used in the meta-analysis as this was the only timepoint unequivocally reported. by limiting the analysis to studies enrolling patients fulfilling the bcg-unresponsive definition, we found more uniform but divergent response rates within the cis±ta/t1 and papillary-only cohorts, with 3-month, 6-month, and 12-month benchmarks that can help to inform emerging data from ongoing studies. the only deviation was the 12-month crr of 44% reported in the quilt 3.032[10], increasing the overall 12-month crr from 21% to 25% and the i2 from 0% to 77% (figure 2). in contrast, results from studies conglomerating durable response rates between the 2 cohorts were marked by higher heterogeneity, supporting the differential responsiveness to bladder-sparing treatment between cis±ta/t1 and papillary-only nmibc. these results may ref lect different molecular pathways leading to the development of cis (originating from chromosome 9p+q loss and tp53 and rb mutations) and papillary tumors (originating from fgfr alterations and 9q loss)[11]. alternatively, divergent response and recurrence rates likely also reflect the fact that papillary tumors are amenable to complete transurethral resection but cis usually is not[12]. the lack of uniformity amongst trial results further underscores differences in the mechanisms of action between the investigational agents and indicate differences therapeutic efficacy. to further eliminate risks of bias and increase the rigor of the analysis, randomized controlled trials (rct) are likely required in the future. as there is no universally accepted bladder-preserving therapy for bcg-unresponsive nmibc, there is a need to standardize treatment used in the control arm. recent fda approval suggests pembrolizumab is an option; however, many consider its efficacy insufficient to offset the observed toxicity profile and the significant cost[13]. intravesical gemcitabine/docetaxel has also been proposed as an alternative by some on the basis of “expert opinion,” although its efficacy has not yet been established in prospective clinical trials. moreover, shortages of bcg in many countries have hampered administration according to the swog protocol, limiting the number of patients fulfilling the bcg-unresponsive definition and creating a bottleneck for completing rcts in this disease setting. this is the first meta-analysis to investigate the available studies that meet the strict definition of the bcg-unresponsive nmibc definition adopted by the fda in 2018[2]. our results demonstrate a weighted average crr of 38% at 6 months and 25% at 12 months in cis±ta/t1 bcg-unresponsive nmibc. of all completed trials, only one[10] achieved the 50% 6-month and 30% 12-month thresholds previously proposed to be clinically relevant[14,15] notably, crrs observed in trials using the 2 currently fda-approved agents, pembrolizumab and valrubicin, fell short of these benchmarks regarding the 12-month duration of response. several agents tested in similarly designed single-arm trials are currently under review by the fda 334 siuj • volume 3, number 5 • september 2022 siuj.org review http://siuj.org http://siuj.org http://siuj.org http://siuj.org records identified through databases searching (n= 287) full-text articles and presentations assessed for eligibility (n=95) 11 studies included in review records after duplicates removed (n=185) in cl ud ed sc re en in g el ig ib il it y records screened (n=1404) id en ti fi ca ti on 3 academic presentations 8 peer reviewed publications • interim or incomplete results (26) • non clinical trial (8) • not bcg unresponsive (27) • cg0070 (4) • not relevant (10) • reviews (4) • prior to 2015 (5) updates, letters, opinion papers excluded (n=90) full-text articles excluded (n=84) figure 1. flow diagram of literature review for bcg-unresponsive non-muscle-invasive bladder cancer studies 335siuj.org siuj • volume 3, number 5 • september 2022 systematic review and meta-analysis of response rates in bcg-unresponsive non–muscle-invasive bladder cancer http://siuj.org table 1. presentations and publications in bcg-unresponsive nmibc authors phase date of publication or presentation tumor characteristics agent administered navai et al. 2016[16] i 2016 ta/t1/cis nadofaragene firadenovec hahn et al. 2017[17] ii 2017 ta/t1/cis dovitinib li et al. 2017[9] ii 2017 papillary-only mcna a li et al. 2017[9] ii 2017 cis±ta/t1 mcna a shore et al. 2017[18] ii 2017 ta/t1/cis nadofaragene firadenovec o'donnell et al. 2019[19] ii 2019 papillary-only cadi-05 b decastro et al. 2020[20] i 2020 ta/t1/cis intravesical cgc c shore 2021[21] iii 2020 cis±ta/t1 vicinium d shore 2021[21] iii 2020 papillary-only vicinium d black et al. 2021[22] ii 2021 cis±ta/t1 atezolizumab black et al. 2021[22] ii 2021 papillary-only atezolizumab balar et al. 2021[23] ii 2021 cis-containing pembrolizumab boorjian 2021[24] iii 2021 cis±ta/t1 nadofaragene firadenovec boorjian 2021[24] iii 2021 papillary-only nadofaragene firadenovec chang et al. 2022[10] ii/iii 2022 cis±ta/t1 bcg + il-15 superagonist chang et al. 2022[10] ii/iii 2022 papillary-only bcg + il-15 superagonist a mycobacterium phei cell wall-nucleic acid complex b intradermal cadi-05 c cabazitaxel, gemcitabine, cisplatin d rad-ifnα/syn3 336 siuj • volume 3, number 5 • september 2022 siuj.org review http://siuj.org and have reported crr rates and 12-month durability that meet or exceed this bar. with the emerging data from recently completed and ongoing clinical trials, the crr and durability threshold required for approval, particularly for patients with cis, remains a moving target. if one or more new drugs receive fda approval, this will provide clarity around these endpoints. limitations of our study include a relatively low sample size of studies using a variety of different treatment agents. additionally, variability in study protocols allowing for therapeutic re-induction following initial non-response and/or mandating post-therapy random bladder biopsy may affect response rates seen. lastly, it is difficult to determine whether adjudication between cis±ta/t1 and papillary-only tumors was performed by central review in all included studies. despite the heterogeneity in the treatment agents used, we were successful in delineating a relatively narrow range of response rates at clinically relevant timepoints stratified by tumor stage to provide a frame-of-reference for emerging results from ongoing bcg-unresponsive clinical trials. conclusion our study indicates relatively uniform but disparate response rates to bladder-sparing therapies in bcgunresponsive cis±ta/t1 and papillary-only nmibc. to reduce risks of bias, randomized controlled studies with appropriate stratification of the 2 disease entities are likely to be required in the future. consensus is also needed on the ideal therapeutic agent to be used in the control arm. our results will help to formulate designs of future clinical trials and inform the interpretation of emerging data in this exciting treatment space. table 2. meta-analysis results by tumor characteristic and months following administration time cis±ta/ t1 crr (i2) papillary-only ta/ t1 rfr (i2) ta/ t1/cis dfr (i2) 3 months 44% (36%) n = 4 73% (0%) n = 3 48% (46%) n = 2 6 months 38% (58%) n = 3 58% (26%) n = 5 22% (63%) n = 3 12 months 25% (77%) n = 6 48% (49%) n = 6 43% (84%) n = 3 18 months 26% (88%) n = 2 50% (0%) n = 3 – 24 months 32% (95%) n = 2 40% (65%) n = 4 – crr: complete response rate; rfr: recurrence-free rate; dfr: disease-free rate 337siuj.org siuj • volume 3, number 5 • september 2022 systematic review and meta-analysis of response rates in bcg-unresponsive non–muscle-invasive bladder cancer http://siuj.org references 1. li r, sundi d, zhang j, kim y, sylvester rj, spiess pe, et al. systematic review of the therapeutic efficacy of bladder-preserving treatments for non-muscle-invasive bladder cancer following intravesical bacillus calmette-guerin. eur urol.2020;78(3):387-399. 2. united states food and drug administration: bcg-unresponsive nonmuscle invasive bladder cancer: developing drugs and biologics for treatment guidance for industry. 2018:1-10. 3. gacci m, bartoletti r, cai t, nerozzi s, pinzi n, repetti f, et al. intravesical gemcitabine in bcg-refractory t1g3 transitional cell carcinoma of the bladder: a pilot study. urol int.2006;76(2):106-111. 4. gunelli r, bercovich e, nanni o, ballardini m, frassineti gl, giovannini n, et al. activit y of endovesical gemcitabine in bcg-refractor y bladder cancer patients: a translational study. br j cancer.2007;97(11):1499-1504. 5. perdona s, di lorenzo g, cantiello f, damiano r, de sio m, masala d, et al. is gemcitabine an option in bcg-refractory nonmuscleinvasive bladder cancer? a single-arm prospective trial. anticancer drugs.2010;21(1):101-106. 6. skinner ec, goldman b, sakr wa, petrylak dp, lenz hj, lee ct, et al. swog s0353: phase ii trial of intravesical gemcitabine in patients with nonmuscle invasive bladder cancer and recurrence after 2 prior courses of intravesical bacillus calmette-guerin. j urol.2013;190(4):1200-1204. 7. packiam vt, lamm dl, barocas da, trainer a, fand b, davis rl 3rd, et al. an open label, single-arm, phase ii multicenter study of the safety and efficacy of cg0070 oncolytic vector regimen in patients with bcg-unresponsive non-muscle-invasive bladder cancer: interim results. urol oncol.2018;36(10):440-447. 8. hurle r gg, colombo p, santoro a, de cobelli o, trapani e, nohales g, llorente c, duran-merino r, lazzeri m, editor oncofid-p-b for the treatment of bcg unresponsive carcinoma in situ (cis) of the bladder: preliminary results of european multicentre phase 1 study at the end of 12 consecutive weeks intensive course and during ongoing monthly maintenance phase. american urologic association; 2020: j urol.2020 9. li r, amrhein j, cohen z, champagne m, kamat am. efficacy of mycobacterium phlei cell wall-nucleic acid complex (mcna) in bcg-unresponsive patients. bladder cancer.2017;3(1):65-71. doi: 10.3233/blc-160084 figure 2. forest plots of response rates from meta-analysis, stratified by tumor characteristic at 3 months (a), 6 months (b), and 12 months (c) subgroup total (95% ci) heterogeneity: tau2 = 0.2240; chi2 = 30.05, df = 8 (p < 0.01); i2 = 73% residual heterogeneity: tau2 = na; chi2 = 7.39, df = 6 (p = 0.29); i2 = 19% cis±ta/t1 papillary-only ta/t1/cis total (95% ci) total (95% ci) total (95% ci) heterogeneity: tau2 = 0.0255; chi2 = 4.67, df = 3 (p = 0.20); i2 = 36% heterogeneity: tau2 = 0; chi2 = 0.86, df = 2 (p = 0.65); i2 = 0% heterogeneity: tau2 = 0.3413; chi2 = 1.85, df = 1 (p = 0.17); i2 = 46% balar et al 2021 black et al 2021 boorjian 2021 chang et al 2022 li et al 2017 shore et al 2021 black et al 2021 boorjian 2021 chang et al 2022 li et al 2018 o’donnell et al 2019 shore et al 2021 decastro et al 2020 hahn et al 2017 navai et al 2016 shore et al 2017 study or events 39.36 30.00 55.00 . . 36.00 . 35.00 . . 7.00 27.00 . . 2.00 23.00 total 909 512 319 78 96 73 103 83 68 89 54 48 77 94 8 38 18 13 7 40 weight 100.0% 57.9% 25.9% 16.2% 14.6% 13.9% 14.9% 0.0% 0.0% 14.5% 0.0% 11.9% 0.0% 0.0% 2.9% 11.1% 0.0% 0.0% 4.2% 12.0% iv, random, 95% ci 0.53 [0.44; 0.63] 0.44 [0.38; 0.51] 0.73 [0.63; 0.81] 0.48 [0.24; 0.74] 0.41 [0.32; 0.51] 0.41 [0.30; 0.53] 0.53 [0.44; 0.63] 0.40 [0.31; 0.51] 0.73 [0.59; 0.84] 0.88 [0.46; 0.98] 0.71 [0.55; 0.83] 0.29 [0.07; 0.67] 0.58 [0.42; 0.72] 0 0.2 0.4 0.6 0.8 1 iv, random, 95% ci a b subgroup total (95% ci) heterogeneity: tau2 = 0.2346; chi2 = 35.47, df = 10 (p < 0.01); i2 = 72% residual heterogeneity: tau2 = na; chi2 = 15.59, df = 8 (p = 0.05); i2 = 49% cis±ta/t1 papillary-only ta/t1/cis total (95% ci) total (95% ci) total (95% ci) heterogeneity: tau2 = 0.0777; chi2 = 4.83, df = 2 (p = 0.09); i2 = 59% heterogeneity: tau2 = 0.0334; chi2 = 5.4, df = 4 (p = 0.25); i2 = 26% heterogeneity: tau2 = 1.0675; chi2 = 5.36, df = 2 (p = 0.07); i2 = 63% balar et al 2021 black et al 2021 boorjian 2021 chang et al 2022 li et al 2017 shore et al 2021 black et al 2021 boorjian 2021 chang et al 2022 li et al 2018 o’donnell et al 2019 shore et al 2021 decastro et al 2020 hahn et al 2017 navai et al 2016 shore et al 2017 study or events . 20 42 . 30 . 35 30 . 46 6 22 . 1 1 17 total 909 512 319 78 96 73 103 83 68 89 54 48 77 94 8 38 18 13 7 40 weight 100.0% 36.0% 48.5% 15.5% 0.0% 11.5% 12.7% 0.0% 11.9% 0.0% 11.0% 10.8% 0.0% 12.6% 3.9% 10.2% 0.0% 2.6% 2.5% 10.4% iv, random, 95% ci 0.47 [0.38; 0.56] 0.38 [0.28; 0.48] 0.58 [0.50; 0.66] 0.22 [0.06; 0.55] 0.27 [0.18; 0.39] 0.41 [0.31; 0.51] 0.44 [0.32; 0.57] 0.65 [0.51; 0.77] 0.62 [0.47; 0.76] 0.49 [0.38; 0.59] 0.75 [0.35; 0.97] 0.58 [0.41; 0.74] 0.08 [0.00; 0.36] 0.14 [0.00; 0.58] 0.42 [0.27; 0.59] 0 0.2 0.4 0.6 0.8 1 iv, random, 95% ci 338 siuj • volume 3, number 5 • september 2022 siuj.org review http://siuj.org 10. chang ss, chamie k, gonzalgo ml, kramolowsky ev, sexton wj, reddy sk, et al. positive efficacy and safety phase 3 results in both cis and papillary cohorts bcg-unresponsive nonmuscle invasive bladder cancer (nmibc) after il-15rαfc superagonist n-803 (anktiva) and bcg infusion. j clin oncol.2022;40(6 suppl):431. doi: 10.1200/ jco.2022.40.6_suppl.431 11. knowles ma, hurst cd. molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. nat rev cancer.2015;15(1):25-41. 12. dalbagni g. the management of superficial bladder cancer. nat clin pract urol.2007;4(5):254-260. doi: 10.1038/ncpuro0784 13. wymer km, sharma v, saigal cs, chamie k, litwin ms, packiam vt, et al. cost-effectiveness analysis of pembrolizumab for bacillus calmette-guerin-unresponsive carcinoma in situ of the bladder. j urol.2021;205(5):1326-1335. 14. jarow jp, lerner sp, kluetz pg, liu k, sridhara r, bajorin d, et al. clinical trial design for the development of new therapies for nonmuscle-invasive bladder cancer: report of a food and drug administration and american urological association public workshop. urology.2014;83(2):262-264. 15. kamat am, sylvester rj, bohle a, palou j, lamm dl, brausi m, et al. definitions, end points, and clinical trial designs for non-muscleinvasive bladder cancer: recommendations from the international bladder cancer group. j clin oncol.2016;34(16):1935-1944. 16. navai n, benedict wf, zhang g, abraham a, ainslie n, shah jb, et al. phase 1b trial to evaluate tissue response to a second dose of intravesical recombinant adenoviral interferon alpha2b formulated in syn3 for failures of bacillus calmette-guerin (bcg) therapy in nonmuscle invasive bladder cancer. ann surg oncol.2016;23(12):4110-4114. 17. hahn nm, bivalacqua tj, ross ae, netto gj, baras a, park jc, et al. a phase ii trial of dovitinib in bcg-unresponsive urothelial carcinoma with fgfr3 mutations or overexpression: hoosier cancer research network trial hcrn 12-157. clin cancer res.2017;23(12):3003-3011. 18. shore nd, boorjian sa, canter dj, ogan k, karsh li, downs tm, et al. intravesical rad-ifnalpha/syn3 for patients with high-grade, bacillus calmet te-guerin-refractor y or relapsed non-muscleinvasive bladder cancer: a phase ii randomized study. j clin oncol.2017;35(30):3410-3416. 19. o’donnell ma, singh s, sood r, amlani j, krishnamoorthy h, shukla k, et al. a clinical trial of the intradermal tlr2 agonist cadi-05 for bcg recurrent and unresponsive non-muscle invasive bladder cancer. bladder cancer.2019;5:171-180. doi: 10.3233/blc-190211 20. decastro gj, sui w, pak js, lee sm, holder d, kates mm, et al. a phase i trial of intravesical cabazitaxel, gemcitabine and cisplatin for the treatment of nonmuscle invasive bacillus calmette-guerin unresponsive or recurrent/relapsing urothelial carcinoma of the bladder. j urol.2020;204(2):247-253. 21. shore nd, ed. phase 3 results of vicinium in bcg-unresponsive non-muscle invasive bladder cancer. american urologic association annual meeting; june 2020; virtual. 22. black pc, tangen cm, singh p, mcconkey dj, lucia s, lowrance wt, et al. phase ii trial of atezolizumab in bcg-unresponsive non-muscle invasive bladder cancer: swog s1605 (nct # 02844816). j clin oncol.2021;39(15 suppl):4541-. 23. balar av, kamat am, kulkarni gs, uchio em, boormans jl, roumiguie m, et al. pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to bcg (keynote-057): an open-label, single-arm, multicentre, phase 2 study. lancet oncol.2021;22(7):919-930. doi: 10.1016/s1470-2045(21)001479. epub 2021 may 26. 24. boorjian sa, alemozaffar m, konety br, shore nd, gomella lg, kamat am, et al. intravesical nadofaragene firadenovec gene therapy for bcg-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. lancet oncol.2021;22(1):107-117. doi:https://doi.org/10.1016/s1470-2045(20)30540-4 c subgroup total (95% ci) heterogeneity: tau2 = 0.4214; chi2 = 83.57, df = 14 (p < 0.01); i2 = 83% residual heterogeneity: tau2 = na; chi2 = 44.84, df = 12 (p < 0.01); i2 = 73% cis±ta/t1 papillary-only ta/t1/cis total (95% ci) total (95% ci) total (95% ci) heterogeneity: tau2 = 0.2276; chi2 = 22.17, df = 5 (p < 0.01); i2 = 77% heterogeneity: tau2 = 0.0813; chi2 = 9.96, df = 5 (p = 0.08); i2 = 50% heterogeneity: tau2 = 2.2936; chi2 = 12.71, df = 2 (p < 0.01); i2 = 84% balar et al 2021 black et al 2021 boorjian 2021 chang et al 2022 li et al 2017 shore et al 2021 black et al 2021 boorjian 2021 chang et al 2022 li et al 2018 o’donnell et al 2019 shore et al 2021 decastro et al 2020 hahn et al 2017 navai et al 2016 shore et al 2017 study or events 18 11 25 37 18 19 28 21 44 33 5 19 15 . 0 14 total 909 512 319 78 96 73 103 83 68 89 54 48 77 94 8 38 18 13 7 40 weight 100.0% 45.5% 41.6% 13.0% 7.6% 7.0% 7.8% 7.9% 7.5% 7.6% 7.5% 7.3% 7.8% 7.9% 3.9% 7.1% 4.5% 0.0% 1.5% 7.0% iv, random, 95% ci 0.37 [0.28; 0.46] 0.25 [0.17; 0.33] 0.48 [0.40; 0.56] 0.43 [0.10; 0.84] 0.19 [0.12; 0.28] 0.15 [0.08; 0.25] 0.24 [0.16; 0.34] 0.45 [0.34; 0.56] 0.26 [0.17; 0.39] 0.21 [0.13; 0.31] 0.52 [0.38; 0.66] 0.44 [0.29; 0.59] 0.57 [0.45; 0.68] 0.35 [0.26; 0.46] 0.62 [0.24; 0.91] 0.50 [0.33; 0.67] 0.83 [0.59; 0.96] 0.00 [0.00; 0.41] 0.35 [0.21; 0.52] 0 0.2 0.4 0.6 0.8 1 iv, random, 95% ci 339siuj.org siuj • volume 3, number 5 • september 2022 systematic review and meta-analysis of response rates in bcg-unresponsive non–muscle-invasive bladder cancer http://siuj.org key words competing interests article information kidney cancer, cd34, fshr, tumor markers none declared. funding statement: dr giancarlo marra’s work at institut mutualiste montsouris and at institut curie has been funded by a grant from the european urology scholarship programme (eusp). received on august 22, 2021 accepted on january 15, 2022 this article has been peer reviewed. soc int urol j. 2022;3(3):132–143 doi: 10.48083/rqbn1626 132 siuj • volume 3, number 3 • may 2022 siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. original research cd34 and fshr expression to differentiate multiple subtypes of benign and malignant renal neoplasms giancarlo marra,1,2 didier meseure,3 marine lefèvre,2 andre nicolas,3 laetitia lesage,3 nicolae ghinea,4 marco moschini,1 caio pasquali,1 petr macek,1 claudia filippini,2 paolo gontero,2 rafael sanchez-salas,1 xavier cathelineau1 1 department of urology, institut mutualiste montsouris and université paris descartes, paris, france 2 department of urology and university of turin, turin, italy 3 platform of experimental pathology, department of diagnostic and theranostic medicine, institut curie, paris, france 4 department of pathology, institut mutualiste montsouris, paris, france abstract background currently, no markers accurately differentiate benign from malignant renal masses. cd34 and fshr are transmembrane proteins involved in neo-angiogenetic pathways and are differently expressed in several normal and cancerous tissues. however, little evidence exists on their distribution in different renal tumors. we aimed to evaluate their expressions in various renal tumors and adjacent normal tissue. methods we retrieved 810 histological samples from 26 patients who underwent surgery for suspected rca. in each case a core of 10 × 1 mm was selected perpendicular to the tumor capsule between normal kidney and tumor. within this core 30 regions of interest (roi), each measuring 669 μm × 500 μm, were acquired at 20× magnification (n = 2 adjacent normal tissue; n = 2 tumor capsule; n = 26 tumor). the surface area of fshr and cd34 immunostaining was quantified in each roi using number of stained pixels. the results were compared between rca and normal kidney. results immunostaining was significantly different in normal, tumor capsular, and tumor tissues (both cd34 and fshr p < 0.0001), with overall highest expression in normal and lowest in tumor tissues, where cd34 and fshr were differently expressed amongst different tumor subtypes (both p < 0.0001). cd34 and fshr were more expressed in benign versus malignant (both p < 0.0001) and in chromophobe carcinoma versus oncocytoma tumor tissues (cd34 p = 0.0003; fshr p < 0.0001). the discriminating ability of fshr alone for benign versus malignant (auc 0.805; 95% ci 0.771 to 0.837) and chromophobe carcinoma versus oncocytoma (auc 0.973; 95% ci 0.939 to 0.991) was high. in both cases fshr auc was significantly higher than cd34 (both p < 0.0001) and equivalent to the combination of cd34 and fshr (both p > 0.9). the correlation amongst levels of staining in tumor tissues and distance from the capsule were overall weak (spearman coefficient cd34 to 0.0644; fshr-0.16322). conclusion cd34 and fshr are differentially expressed across renal tumor subtypes and between tumor and surrounding tissues. fshr expression alone may be a useful tool to differentiate benign from malignant tumors and chromophobe carcinoma from oncocytoma. introduction neo-angiogenesis is an important process for malignant and benign tumors growth and progression, allowing unrestricted expansion[1,2]. cd34 and follicle-stimulating hormone receptor (fshr) are transmembrane proteins present in endothelial cells on the surface of blood vessels and differently expressed in several normal and cancerous tissues[2]. http://siuj.org mailto:drgiancarlomarra%40gmail.com?subject=siuj cd34 is an intercellular adhesion and cell-surface glycoprotein present in hematopoietic progenitor cells and endothelial vascular and lymphatic cells[2,3]. although its specific function is not yet precisely characterized, cd34 is a pan-endothelial marker, and anti-cd34 antibodies are highly sensitive for endothelial differentiation. cd34 is differentially expressed in neoplastic and normal endothelium and/or may yield a prognostic value for several cancers including cervical[2], gastric[4] hepatoellular[5], prostate[6,7], kidney[8], bladder[9], and other neoplasms. fshr is a glycosylated transmembrane protein of the g protein receptors family, normally found in human testis sertoli and ovarian granulosa cells[10,11]. its presence has also been demonstrated in other tissues including osteoclasts, monocytes, endometrial cells, and the thyroid and the prostate glands, where, however, its expression is usually limited[11]. on the contrary, several malignancies—ovarian[12], prostate[13,14], breast[15], and others[15,16]—are found with fshr expression. although in cancer cells fhsr presence has been shown to vary depending on tumor type, its expression is constant in the endothelial cells within several cancers[11]. kidney cancer is not infrequent, currently representing the sixth and eighth commonest cancer in men and women respectively, with more than 70 000 new cases detected yearly in the us[17]. in recent years, renal cancer (rca) diagnosis has undergone a shift, with more than 60% of cases being diagnosed in the form of incidental small renal masses when abdominal imaging is performed for other investigations[18]. these renal lesions can be benign or malignant, and the rca can vary widely with respect to prognosis. conventional imaging, including ct and/or mpmri, despite being currently able to identify renal masses, cannot reliably distinguish benign angiomyolipoma (aml) with minimal fat and oncocytoma from malignant lesions[19–21]. this diagnostic challenge holds even more true for oncocytoma as even when renal biopsies are performed, final histology of the surgical specimens confirms oncocytic neoplasms in only about 64.6% of cases, with the remaining tumors being mainly chromophobe carcinoma (18.7%)[22]. although several attempts have been made, to date no molecular markers are able to reliably differentiate benign from malignant renal lesions[23]. some studies previously detailed cd34 and fshr expression in renal tissues and renal cell carcinoma (rcc), but overall, little to no evidence exists on their distribution in different rca[11,24]. furthermore, as they are expressed in tumor endothelial cells and involved in neo-angiogenetic pathways at multiple levels, they represent a potential target for molecular imaging with specific contrast agents and for novel therapeutic agents[1,2,10,11]. our aim was to perform a preliminary evaluation of cd34 and fshr expression in surgical specimens of different types of benign and malignant renal neoplasms and surrounding normal tissues and to detail their ability to differentiate amongst different subtypes of renal neoplasms. materials and methods patients and tissue analysis we retrieved histological samples from 26 patients who underwent surgical removal of a renal tumor including chromophobe rcc (n = 4), type 1 papillary rcc (prcc1; n = 3), type 2 papillary rcc (prcc2; n = 3), clear cell rcc (ccrcc; n = 9), oncocytoma (n = 6), and aml (n = 1). paraffin-embedded tissue blocks were retrieved from the archives of the department of biopathology, institut mutualiste montsouris, paris, france. immunohistochemistry immunohistochemistry assay was performed using fshr-a02 antibodies (homemade antibody, mouse monoclonal, at 0.2µg/ml for 30min at rt) and cd34 antibodies (dako ref:m7165, mouse monoclonal qbend-10, at 1/200 for 30min at rt). all immunostainings were processed using a leica bond r x research automated immunostaining device. heat induced antigen retrieval was performed using citrate ph6 buffer (fshr) and edta ph9 buffer (cd34). immunodetection was performed using leica bond polymer refine detection kit according to the manufacturer’s instructions. antibodies specificity was confirmed on a panel of human testis tissue. quantitative analysis fshr and cd34 labeled whole slides were scanned with the perkin elmer vectra 3 scanner at ×10 magnification. sections of 3 µm were cut with a microtome perpendicularly from the paraffin-embedded tissue block, including samples from the normal kidney, the tumor capsular zone, if present, and the kidney tumor. in each case, a core of 10 mm (depth) × 1 mm (width) was selected perpendicular to the capsule between normal abbreviations aml angiomyolipoma chc chromophobe carcinoma fshr follicle-stimulating hormone receptor rca renal cancer rcc renal cell carcinoma 133siuj.org siuj • volume 3, number 3 • may 2022 cd34 and fshr expression to differentiate multiple subtypes of benign and malignant renal neoplasms http://siuj.org kidney and tumor to simulate a biopsy core. within this core, 30 regions of interest (roi), each measuring 669 μm × 500 μm, were acquired at 20× magnification. two roi were analyzed from normal kidney, 2 from the tumor capsular zone, when present, and 26 from the tumor (figure 1). these roi were then analyzed using the perkin elmer inform software, which made it possible to determine the number of positive pixels for the dab and thus to know the percentage of fshr and cd34 labeled surface. recorded variables included fshr and cd34 staining, distance from the capsule and/or normal tissue, and tumor type. figure 2 and figure 3 display examples for the different tumors that were assessed according to roi type for cd34 and fshr immunostaining, respectively. study aims our primary aim was to evaluate expression of cd34 and fshr in different ty pes of renal neoplasms including surrounding normal tissues, tumor capsular tissue, and tumor tissue. secondar y aims were to eva luate whether cd34 and fshr are differentially expressed in and can discriminate between (1) malignant versus benign renal tumor; (2) oncocy toma versus chromophobe carcinoma. statistical analysis su mma r y data were presented as media n a nd interquartile range for continuous variables and as frequency and percentages for categorical variables. in univariate analysis, continuous variables were compared with the use of wilcoxon-mann-whitney or kruskalwallis test as appropriate. spearman’s coefficient was used to evaluate correlation between cd34 and fshr immunostaining in cancerous tissues depending on the distance from the capsule. to investigate the ability of biomarkers to discriminate benign from malignant t u mor s a nd onc o c y tom a f rom c h romophob e carcinoma, cd34 and fshr immunostaining values in cancerous tissues and the combination of both were used to perform different receiver-operating characteristics curves (roc). results are given as area under the curve (auc) and 95% confidence interval (ci). comparison between auc was perform using delong’s test. all tests were two-tail, and the level of statistical significance was set at 0.05. all the analyses were performed with sas software, version 9.4 (sas institute inc., cary, us). results baseline analysis we a na ly zed 810 t issue sa mples, i nclud i ng 210 (26%) benign a nd 60 0 (74%) ma ligna nt tumors. the majority of samples were from tumor tissues (n = 702) and a minority from tumor capsular (n = 54) or normal (n  =  54) tissue surrounding the cancer. immunostaining values for cd34 and fshr stratified by tumor subtype and tissue source (normal adjacent tissue, tumor capsule or tumor) are displayed in figure 4a-b. overall distribution of cd34 and fshr in normal, capsular, and tumor tissues table 1 displays immunostaining values of cd34 and fshr depending on tumor subtypes and malignant or benign diseases. overall, we observed immunostaining was slightly but statistically significantly different in normal, tumor capsular, and tumor tissues (both cd34 and fshr p < 0.0001), with overall highest expression in normal tissues and lowest expression in cancerous tissues. expression was always higher in normal and tumor capsular tissues compared with tumor tissues with the exception of cd34 for chromophobe carcinoma. overall, capsular cd34 and fshr did not yield significant differences amongst different tumors with cd34 ranging from 4.47 for prcc2 to 11.16 for prcc1 (p = 0.1450) and fshr ranging from 1.05 for aml to 5.25 for oncocytoma (p = 0.14). cd34 expression was different amongst normal adjacent tissue from different tumors (range 6.98 for ccrcc to 13.33 for aml; p = 0.0196) while fshr did not yield any significant differences (range 0.92 for aml to 4.65 for oncocytoma; p = 0.1120). cd34 and fshr were significantly differently expressed across the different tumor tissues (both p < 0.0001). the range was relatively wide for cd34 (from 1.45 for prcc1 to 8.72 for chromophobe carcinoma), whereas fshr always had a mean staining percentage < 0.9 with the exception of oncocytoma (4.28). figure 1. tissue sampling methodology for cd34 and fshr quantification for each case acquisition of 30 zones of 669 µm x 500 µm (10 mm depth x 1 mm width) was performed. red: normal surrounding tissue; blue: capsular tissue; green: tumor tissue. 134 siuj • volume 3, number 3 • may 2022 siuj.org original research http://siuj.org figure 2. cd34 immunostaining in adjacent normal, tumor capsular and tumor tissue in different types of renal neoplasms figure 3. fshr immunostaining in adjacent normal, tumor capsular and tumor tissue in different types of renal neoplasms malignant versus benign renal cancers immunostaining values for cd34 and fshr stratified by cancer subtype and location (normal adjacent tissue, tumor capsule or tumor) are displayed in figure 4c-d and table 1. cd34 expression was highest in normal tissue, followed by tumor capsular and tumor tissues both for malignant and benign neoplasms (p = 0.0301 amongst benign and p < 0.0001 for malignant lesions) but no relevant differences were found between expression in the tumor capsule and normal tissue of benign versus malignant diseases (both p > 0.2). however, cd34 was slightly but statistically significantly more highly expressed in benign (5.69, iqr 3.5 to 7.3) versus malignant tumor tissues (4.92, iqr 1.7 to 7.1, p < 0.0001). 135siuj.org siuj • volume 3, number 3 • may 2022 cd34 and fshr expression to differentiate multiple subtypes of benign and malignant renal neoplasms http://siuj.org table 1. immunostaining values of cd34 and fshr stratified by tumor type and site cd34 % staining (iqr) all ccrcc cromophobe carcinoma prcc1 prcc2 oncocytoma aml p value normal 8.58 (5.9–11.0) 6.98 (4.5–9.8) 9.84 (8.3–10.8) 10,24 (10.0–10.5) 11.49 (11.0–12.2) 7.57 (5.8–8.3) 13.33 (9.4–17.2)* 0.0196 capsule 6.12 (2.7–8.6) 3.97 (1.8–5.8) 7.53 (5.3–9.5) 11.16 (3.8–18.9) 4.47 (1.2–8.0) 6.83 (5.3–8.8) 5.31 (1.4–9.2)* 0.1450 tumor 5.10 (2.0–7.2) 5.42 (2.7–7.3) 8.72 (5.2–12.2) 1.45 (0.9–2.0) 2.09 (1.5–2.5) 6.27 (4.5–7.7) 3.05 (2.2–3.5) <0.0001 p <0.0001 0.0399 0.6131 <0.0001 0.0002 0.4914 0.0663 all 5.41 (2.63–7.42) 8.69 (5.3–12.2) 2.33 (1.0–2.2) 2.96 (1.5–3.0) 6.43 (4.7–7.8) 3.89 (2.1–4.4) <0.0001 benign malignant normal 8.39 (5.9–9.4) 8.67 (6.9–11.0) 0.4274 capsule 6.61 (5.1–9.0) 5.93 (2.3–8.1) 0.2275 tumor 5.69 (3.5–7.3) 4.92 (1.7–7.1) <0.0001 p 0.0301 <0.0001 all 5.98 (3.7–7.7) 5.20 (1.8–7.6) <0.0001 chromophobe oncocytoma normal 9.84 (8.3–10.8) 7.57 (5.8–8.3) 0.0678 capsule 7.53 (5.3–9.5) 6.83 (5.3–8.8) 0.6160 tumor 8.72 (5.2–12.2) 6.27 (4.5–7.7) 0.0003 p 0.6131 0.4914 all 8.69 (5.3–12.2) 6.43 (4.67–7.8) <0.0001 fshr % staining (iqr) all ccrcc cromophobe carcinoma prcc1 prcc2 oncocytoma aml p value normal 2.22 (0.7–2.7) 2.03 (0.5–2.3) 3.12 (2.6–3.7) 1.29 (1.3–1.3) 1.35 (2.2–2.5) 4.65 (3.8–5.7) 0.92 (0.8–1.1) 0.1120 capsule 2.49 (2.7–8.6) 1.94 (0.2–3.2) 1.47 (0.4–1.7) 1.63 (0.5–2.5) 3.44 (0.8–5.0) 5.25 (3.3–6.3) 1.05 (1.0–1.1) 0.1400 tumor 1.28 (0.03–1.8) 0.82 (0.01–1.1) 0.08 (0.02–0.1) 0.29 (0.0–0.3) 0.82 (0.2–1.3) 4.28 (2.2–5.1) 0.02 (0–0.01) <0.0001 p <0.0001 0.0002 <0.0001 0.0005 0.0691 <0.0001 0.0059 all 0.98 (0.02–1.4) 0.32 (0.02–0.2) 0.41 (0.06–0.43) 1.07 (0.18–1.6) 4.35 (2.2–5.2) 0.15 (0–0.02) <0.0001 benign malignant normal 3.41 (1.2–5.1) 1.99 (0.5–2.6) 0.1932 capsule 4.32 (1.1–4.9) 2.05 (0.4–3.4) 0.0500 tumor 3.50 (1.5–4.5) 0.61 (0.02–0.65) <0.001 p 0.7875 <0.0001 all 3.55 (1.35–4.8) 0.80 (0.03–1.072) <0.001 chromophobe oncocytoma normal 3.12 (2-6–3.7) 4.65 (3.8–5.7) 0.4705 capsule 1.47 (0.4–1.7) 5.25 (3.3–6.3) 0.0268 tumor 0.08 (0.02–0.1) 4.28 (2.2–5.1) <0.0001 p <0.0001 <0.0001 all 0.32 (0.02–0.2) 4.35 (2.2–5.2) <0.0001 136 siuj • volume 3, number 3 • may 2022 siuj.org original research http://siuj.org table 1. immunostaining values of cd34 and fshr stratified by tumor type and site cd34 % staining (iqr) all ccrcc cromophobe carcinoma prcc1 prcc2 oncocytoma aml p value normal 8.58 (5.9–11.0) 6.98 (4.5–9.8) 9.84 (8.3–10.8) 10,24 (10.0–10.5) 11.49 (11.0–12.2) 7.57 (5.8–8.3) 13.33 (9.4–17.2)* 0.0196 capsule 6.12 (2.7–8.6) 3.97 (1.8–5.8) 7.53 (5.3–9.5) 11.16 (3.8–18.9) 4.47 (1.2–8.0) 6.83 (5.3–8.8) 5.31 (1.4–9.2)* 0.1450 tumor 5.10 (2.0–7.2) 5.42 (2.7–7.3) 8.72 (5.2–12.2) 1.45 (0.9–2.0) 2.09 (1.5–2.5) 6.27 (4.5–7.7) 3.05 (2.2–3.5) <0.0001 p <0.0001 0.0399 0.6131 <0.0001 0.0002 0.4914 0.0663 all 5.41 (2.63–7.42) 8.69 (5.3–12.2) 2.33 (1.0–2.2) 2.96 (1.5–3.0) 6.43 (4.7–7.8) 3.89 (2.1–4.4) <0.0001 benign malignant normal 8.39 (5.9–9.4) 8.67 (6.9–11.0) 0.4274 capsule 6.61 (5.1–9.0) 5.93 (2.3–8.1) 0.2275 tumor 5.69 (3.5–7.3) 4.92 (1.7–7.1) <0.0001 p 0.0301 <0.0001 all 5.98 (3.7–7.7) 5.20 (1.8–7.6) <0.0001 chromophobe oncocytoma normal 9.84 (8.3–10.8) 7.57 (5.8–8.3) 0.0678 capsule 7.53 (5.3–9.5) 6.83 (5.3–8.8) 0.6160 tumor 8.72 (5.2–12.2) 6.27 (4.5–7.7) 0.0003 p 0.6131 0.4914 all 8.69 (5.3–12.2) 6.43 (4.67–7.8) <0.0001 fshr % staining (iqr) all ccrcc cromophobe carcinoma prcc1 prcc2 oncocytoma aml p value normal 2.22 (0.7–2.7) 2.03 (0.5–2.3) 3.12 (2.6–3.7) 1.29 (1.3–1.3) 1.35 (2.2–2.5) 4.65 (3.8–5.7) 0.92 (0.8–1.1) 0.1120 capsule 2.49 (2.7–8.6) 1.94 (0.2–3.2) 1.47 (0.4–1.7) 1.63 (0.5–2.5) 3.44 (0.8–5.0) 5.25 (3.3–6.3) 1.05 (1.0–1.1) 0.1400 tumor 1.28 (0.03–1.8) 0.82 (0.01–1.1) 0.08 (0.02–0.1) 0.29 (0.0–0.3) 0.82 (0.2–1.3) 4.28 (2.2–5.1) 0.02 (0–0.01) <0.0001 p <0.0001 0.0002 <0.0001 0.0005 0.0691 <0.0001 0.0059 all 0.98 (0.02–1.4) 0.32 (0.02–0.2) 0.41 (0.06–0.43) 1.07 (0.18–1.6) 4.35 (2.2–5.2) 0.15 (0–0.02) <0.0001 benign malignant normal 3.41 (1.2–5.1) 1.99 (0.5–2.6) 0.1932 capsule 4.32 (1.1–4.9) 2.05 (0.4–3.4) 0.0500 tumor 3.50 (1.5–4.5) 0.61 (0.02–0.65) <0.001 p 0.7875 <0.0001 all 3.55 (1.35–4.8) 0.80 (0.03–1.072) <0.001 chromophobe oncocytoma normal 3.12 (2-6–3.7) 4.65 (3.8–5.7) 0.4705 capsule 1.47 (0.4–1.7) 5.25 (3.3–6.3) 0.0268 tumor 0.08 (0.02–0.1) 4.28 (2.2–5.1) <0.0001 p <0.0001 <0.0001 all 0.32 (0.02–0.2) 4.35 (2.2–5.2) <0.0001 137siuj.org siuj • volume 3, number 3 • may 2022 cd34 and fshr expression to differentiate multiple subtypes of benign and malignant renal neoplasms http://siuj.org aml oncocyt cromoph rcc tpp t1 tpp t2 aml cromoph oncocyt rcc tpp t1 tpp t2 20,00 15,00 0000 5,00 0,00 a b c d 34 fs h r 20,00 25,00 15,00 10,00 5,00 0,00 capsule normal tissue tumor capsule normal tissue tumor a. cd34 stratified per tumor subtype; b. fshr stratified by tumor subtype; c. cd34 stratified by malignant versus benign tumor; d. fshr stratified by malignant versus benign tumor; aml: angiomyolipoma; chromoph: chromophobe carcinoma; prcc: papillary renal cell carcinoma; ccrcc: clear cell renal cell carcinoma. figure 4. cd34 and fshr immunostaining in adjacent normal, tumor capsular and tumor tissue amongst different types of renal neoplasms c d capsule normal tissue tumor capsule normal tissue tumor c d 34 fs h r 20,00 15,00 10,00 5,00 0,00 25,00 20,00 15.00 10,00 5,00 0,00 benign malignantbenign malignant fshr was expressed similarly in normal, tumor capsular, and benign tumor tissues and no relevant differences with corresponding sites related to malignant tumors were noted (normal tissue p = 0.19 and tumor capsule p = 0.05). however, fshr expression was significantly greater in benign (3.55, iqr 1. 5 to 4.5) versus malignant tumor tissues (0.15, iqr 0.02 to 0.65, p < 0.0001). roc curves are displayed in figure 5a. the highest auc in differentiating malignant from benign tumors was for fshr (auc 0.805; 95% ci 0.771 to 0.837). the discriminating ability of fshr alone was comparable to the use of the combination of fshr and cd34 (auc 0.805; 95% ci 0.770 to 0.837, p = 0.9920) and superior to cd34 alone (auc 0.630; 95% ci 0.589 to 0.669, p <0.0001). 138 siuj • volume 3, number 3 • may 2022 siuj.org original research http://siuj.org oncocytoma versus chromophobe carcinoma cd34 expression was overall not significantly different amongst different sites within oncocy tomas and chromophobe subtypes (both p > 0.4). similarly, no significant staining differences were observed between tumor capsular and normal tissues of oncocytomas versus chromophobe carcinomas (both p > 0.05). nonetheless, cd34 was present at higher levels in chromophobe carcinoma (8.72; iqr 5.3 to 12.2) versus oncocytoma tumor tissues (6.27, iqr 4.5 to 7.8, p = 0.0003). fshr was expressed differently in normal, capsular, and tumor tissues both for chromophobe carcinomas and oncocytomas (both p < 0.0001). fshr was significantly higher in capsular sections related to oncocytoma compared with chromophobe carcinoma (5.25, iqr 3.3 to 6.3 versus 1.47, iqr 0.4-1.7; p = 0.0268) and even more markedly expressed in tumor tissue from oncocytoma (4.28, iqr 2.2 to 5.1) compared with chromophobe carcinoma, where the fshr was almost not expressed (0.08, iqr 0.02 to 0.1; p < 0.0001). roc curves are displayed in figure 5b. fshr expression in tumor tissues was able to accurately differentiate oncocytomas from chromophobe carcinomas (auc 0.973; 95% ci 0.939 to 0.991). the discriminating ability of fshr alone was comparable to the combination of fshr and cd34 (auc 0.973; 95% ci 0.939 to 0.991, p = 0.9875) and superior to that of cd34 alone (auc 0.666; 95% ci 0.595 to 0.731; p < 0.0001). capsular distance in cancerous tissue the correlation amongst levels of staining in tumor tissues and distance from the capsule were overall weak (spearman’s coefficient cd34 -0.0644; fshr0.16322) and different amongst different cancer subtypes (supplementary table s1). lowest and highest correlation for cd34 were with tprcc2 (0.01529) and chromophobe carcinoma (0.18685), respectively and for fshr with chromophobe carcinoma (0.01521) and aml (−0.349949), respectively. discussion in the current study, we assessed cd34 and fshr expression in different renal cancer subtypes, including benign and malignant neoplasms and cancerous and non-cancerous surrounding tissues. to our knowledge, this is the first work to detail cd34 and fshr expression in this context. several findings of our work are of interest. first, we found both markers can vary widely amongst different subtypes of renal cancers. this holds true especially for the expression of cd34 and fshr in cancerous tissues, but differences amongst cancer subtypes in normal surrounding tissues and in the capsule are less marked. a limited number of studies investigated immunostaining levels depending on kidney cancer histology for cd34[25,26], suggesting different levels of expression, and no studies assessed fshr. immunostaining differences need to be further explored to determine the possible roles of these molecules in different types of carcinogenetic pathways according to the corresponding cancer subtypes. second, within the same renal cancer subtype, cd34 and fshr also vary significantly, depending on whether we analyzed the normal peri-tumoral tissue, the capsule, or the cancer. some cancers, as for tpp1 and tpp2 for cd34, have markedly higher staining outside the cancerous areas, and others, like oncocytomas, have similar levels of expression throughout different sites. indeed, patterns of expression of these molecules, whether they are more or less present towards the cancerous or non-cancerous tissues or whether they are more or less uniform throughout different sites, also mandate further assessment as they may help in recognizing different renal cancers and in clarifying different molecular carcinogenetic pathways. an increased staining at the level of the cancer surface may suggest increased angiogenesis and invasive and metastatic potential for cancer cells, through newly formed vessels deriving from fshr pathway activation[27]. similarly, previous authors suggested vegfmediated downregulation of cd34 adhesion molecule may constitute a tumor-mediated escape mechanism from immune surveillance[28]. in this context, it was interesting to note there were only weak correlations/changes in cd34 and fshr expression depending on the depth within the cancerous tissues. others detailed a shell type distribution of the fshr receptor, reaching the highest level of expression at the border between normal and cancerous tissues and then gradually decreasing inside and outside the cancer. this finding was noted for all the 11 different cancers analyzed, except for renal cell carcinoma, where, as in our work, only mild differences between cancerous and non-cancerous tissues and overall weak correlation of fshr and cd34 expression and distance from the capsule were highlighted[15]. whether these findings may be related to different angiogenetic molecular pathways in kidney neoplasms and/or linked to the relatively high radiation and drug resistance of kidney neoplasms remains to be understood[29]. third, cd34 and fshr may help in differentiating benign and malignant renal cancers as, especially when looking at cancerous areas, they are both more expressed in benign tumors. importantly, this difference, although being statistically significant, remains weak for cd34 and possibly not clinically meaningful. by contrast, the expression difference of fshr between benign and 139siuj.org siuj • volume 3, number 3 • may 2022 cd34 and fshr expression to differentiate multiple subtypes of benign and malignant renal neoplasms http://siuj.org malignant renal cancers is more pronounced. in fact, if used as a diagnostic test, fshr has acceptable to excellent ability in discriminating between benign and malignant lesions. not only is the fshr discriminating ability superior to that of cd34 alone, but it does not significantly increase if used in combination with cd34. fourth, cd34 and fshr may also be useful in distinguishing oncocytoma from chromophobe carcinoma. again, while cd34 staining differs little between tumor types, fshr is expressed at very low levels in chromophobe carcinoma and at a high level in oncocytoma. as such, fshr has an outstanding discriminating ability in differentiating these 2 tumor types, with an auc of 0.973 (95% ci 0.939 to 0.991). currently, relatively poor evidence is present for diagnostic biomarkers and for the ability of differentiating amongst different renal cancer subtypes overall. several molecules have been tested in a diagnostic setting. however, even the most promising ones, including pax2 and pax8, vimentin, cytokeratine 7 and other subtypes, and c-kit, have a limited diagnostic ability and/or show relevant limitations such as negativizing in high-grade tumors, or not staining in some of the commonest renal malignancies[30]. contrarily, a recent meta-analysis highlighted several promising molecules that may help to differentiate chc from oncocytomas, warranting future comparisons with our results[24]. several groups already showed fshr expression in different cancerous tissues[15]. nonetheless, fshr figure 5. roc analysis and respective auc values to differentiate amongst subtype of kidney tumor se ns iti vi ty 100-speci�city speci�city benign versus malignant 0 100 20 40 60 80 100 0 20 40 60 80 100 80 60 40 20 0 se ns iti vi ty 100-speci�city speci�city oncocytoma versus chromophobeba 100 80 60 40 20 0 cd34 fshr cd34 fshr cd34 fshr cd34 fshr a. benign versus malignant tumors; cd34 cut-off for malignant tumor ≤ 2.6136% youden index 0.2740; fshr cut-off for oncocytoma identification ≤ 1.6025% youden index 0.6223. b. oncocytoma versus chromophobe carcinoma; cd34 cut-off for oncocytoma identification ≤ 9.2097% youden index 0.3661; fshr cut-off for oncocytoma identification > 0.5421% youden index 0.9176. auc 95% ci fshr 0.805 (0.771–0.837) cd34 0.630 (0.589–0669) fshr+cd34 0.805 (0.770–0.837) auc 95% ci fshr 0.973 (0.939–0991) cd34 0.666 (0.595–0731) fshr+cd34 0.973 (0.770–0991) 140 siuj • volume 3, number 3 • may 2022 siuj.org original research http://siuj.org expression in renal neoplasms has been explored in only a few reports limited to renal cell carcinoma. from a clinical perspective fshr may have important implications in a diagnostic setting. cancer misclassification on biopsy specimens is not infrequent overall and as many as 1 in 3 oncocytomas detected on biopsy are found to be chromophobe carcinoma on examination of the surgical specimen[22]. considering the global increase in the use of renal biopsy and the diagnostic shift towards small renal masses[18,31], the ability of fshr to rule out malignant disease and chromophobe carcinomas urgently requires further investigation. if confirmed, fshr use may have a relevant impact on clinical decision-making. another potential application may be represented by in vivo diagnostic imaging. radu et al. proved intravenous accessibility of the fshr using gold-labeled-antibodies in prostate cancer xenograft mouse models. furthermore, distribution in normal organs was low[15]. recently, ingels and colleagues showed in vivo ultrasound with targeted fshr microbubbles may correlate with sunitinib treatment response in mouse renal cell carcinoma[32]. if confirmed in patients, fshr-based imaging could be used to identify renal tumor subtype, which would dictate which lesions require further investigation and possibly intervention. in a prognostic setting, the value of fshr remains unknown. given our initial findings on its ability to discriminate between malignant and benign diseases and the findings of other studies detailing its ability in predicting treatment response[29], it is our intent to clarify their prognostic abilities within malignant diseases in the near future. similarly, previous reports found possible prognostic value for cd34, depending on its immunostaining pattern for renal cell carcinoma[8]. from a research perspective, further efforts should be made to elucidate possible roles of fshr and cd34 in kidney cancer pathways. cd34 may play a role in cancer immune escape but its role overall remains largely unknown[28]. on the contrary, amongst its several functions, the fsh/fshr axis has been shown to increase angiogenesis through the hif-1 and vegf pathway[33], with fshr overexpression promoting vegf/vegf-receptor binding, and, thus, angiogenesis. furthermore, the pathway also promotes activation of g proteins in endothelial cells with activate vegf receptor in the absence of vegf, possibly inducing proliferation and migration independent of vegf[34,35]. not surprisingly, some authors have speculated that blocking fsh-receptor may represent a valid antitumor strategy, inhibiting angiogenesis. furthermore, fshr is expressed on the luminal surface of endothelial cells, thus being an ideal target for ligands to induce peritumoral vascular infarction[36]. in this sense, our work also clarifies fshr may have a limited interest as a direct binding site for therapeutic drugs. others have hypothesized fshr may represent an important target because its expression is higher in cancerous than in normal sertoli and granulosa cells[15]. in the context of kidney cancer, we found fshr is more highly expressed in benign tumors and associated normal tissue than in malignant tumors and associated normal tissue. nonetheless, we sampled only normal tissue surrounding the cancer, possibly including areas where molecular alterations may be more reflective of tumor microenvironment than unaltered normal tissues, which calls for further analysis. our work has some limitations. we included a relatively small number of cases and, as a consequence, we did not perform multivariable analysis adjusting for patient features and/or investigating possible roles in patient prognosis. nonetheless, our aim was to perform a preliminary analysis. on the basis of our present results, we are in the process of increasing the number of patients to confirm our preliminary findings. conclusion from our preliminary analysis of cd34 and fshr in different subtypes of renal neoplasms, we found they are differently expressed in renal tumors and/or surrounding tissues depending on the ca histology. fshr expression alone may be a useful tool to differentiate amongst benign and malignant subtypes and chromophobe carcinomas and oncocy tomas. larger studies are needed to confirm our findings and to evaluate their potential applications. 141siuj.org siuj • volume 3, number 3 • may 2022 cd34 and fshr expression to differentiate multiple subtypes of benign and malignant renal neoplasms http://siuj.org references 1. folkman j, watson k , ingber d, hanahan d. induction of angiogenesis during the transition from hyperplasia to neoplasia. nature.1989;339:58–61. 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ghinea n. vascular endothelial fsh receptor, a target of interest for cancer therapy. endocrinology.2018;159:3268–3274. https://doi. org/10.1210/en.2018-00466 supplementary table s1. spearman’s coefficient for correlation amongst levels of staining in tumor tissue and distance from the tumor capsule overall and amongst different tumor subtypes kidney cancer subtype spearman’s coefficient cd34 fshr all −0.0644 −0.16322 aml 0.03701 −0.34994 chromophobe carcinoma 0.18685 0.01521 oncocytoma −0.16441 0.17977 clear cell renal cell carcinoma −0.09991 −0.19721 papillary renal cell carcinoma type 1 −0.01529 0.23871 papillary renal cell carcinoma type 2 −0.21508 0.11991 negative correlation: bold; positive correlation: underscored. 143siuj.org siuj • volume 3, number 3 • may 2022 cd34 and fshr expression to differentiate multiple subtypes of benign and malignant renal neoplasms https://doi.org/10.1136/jclinpath-2015-203585 https://doi.org/10.1136/jclinpath-2015-203585 https://doi.org/10.1007/bf03033722 https://doi.org/10.1007/s11255-006-9123-4 https://doi.org/10.1007/s11255-006-9123-4 https://doi.org/10.1016/s0304-3835(97)00310-8 https://doi.org/10.1111/j.1582-4934.2011.01495.x https://doi.org/10.1111/j.1582-4934.2011.01495.x https://doi.org/10.21037/tcr.2017.05.19 https://doi.org/10.4103/0974-7796.236516 https://doi.org/10.1038/s41598-020-64433-2 https://doi.org/10.1385/endo:25:1:49 https://doi.org/10.1385/endo:25:1:49 https://doi.org/10.1074/jbc.m209712200 https://doi.org/10.1074/jbc.m209712200 https://doi.org/10.1210/en.2018-00466 https://doi.org/10.1210/en.2018-00466 http://siuj.org key words competing interests article information urinary incontinence, robotic radical prostatectomy, conservative management none declared. received on july 28, 2021 accepted on august 27, 2021 this article has been peer reviewed. soc int urol j. 2022;3(2):88–100 doi: 10.48083/dprh8648 88 siuj • volume 3, number 2 • march 2022 siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. review postoperative non-surgical interventions to improve urinary continence after robot-assisted radical prostatectomy: a systematic review luigi candela,1,2 giancarlo marra,2,3,4 manuela tutolo,1 lara rodríguez-sánchez,2 petr macek,2 xavier cathelineau,2 francesco montorsi,1 andrea salonia,1 rafael sanchez salas2 1 division of experimental oncology/unit of urology; uri; irccs ospedale san raffaele, milan, italy 2 urology department, institut mutualiste montsouris, paris, france 3 department of surgical sciences, san giovanni battista hospital and university of turin, italy 4 department of urology and clinical research group on predictive oncourology, aphp, sorbonne university, paris, france abstract background the occurrence of postoperative urinary incontinence (ui) remains a problem for patients undergoing robot-assisted radical prostatectomy (rarp). non-surgical interventions (nsi) in addition to intraoperative techniques and patient behavioral changes have been proposed to improve urinary continence (uc) recovery after rarp. however, to date, the real clinical impact of postoperative nsi remains not well characterized. materials and methods we performed a systematic review in april 2021, using allied and complementary medicine (amed), embase, and medline according to the prisma recommendations and using the population, intervention, comparator and outcome (pico) criteria. primary outcome of interest was the impact of nsi on uc recovery rate and time to achieve uc after rarp. secondary outcomes of interest were the assessment of patient adherence to nsi, risk factors associated with ui, and correlation between postoperative nsi and sexual activity recovery. results a total of 2758 articles were screened, and 8 full texts including 1146 patients were identified (3 randomized controlled trials, 3 prospective single-arm trials, and 2 retrospective series). postoperative nsi of interest included pelvic floor muscle training (pfmt) (n = 6 studies) and administration of oral medications (solifenacin) (n = 2 studies). pfmt appeared to increase uc rates and to accelerate time to achieve uc in the early postoperative period. similarly, solifenacin provided higher rates of uc recovery and contributed to a certain degree of symptomatic relief. there was a great variability regarding nsi features and data reporting among studies. major limitations were the small sample sizes and the short follow-up. conclusion postoperative nsi to manage ui after rarp include pfmt and solifenacin administration. both seem to modestly improve early uc recovery. nonetheless, evidence supporting their routinely use is still weak and lacks appropriate follow-up to evaluate possible benefits on long-term uc recovery. introduction radical prostatectomy (rp), together with radiotherapy, represents the gold standard of care for patients with intermediateto high-risk clinically localized prostate cancer (pca)[1]. minimally invasive approaches have demonstrated non-inferior functional outcomes compared with open surgery and have a good safety profile[2–4]. in this context, http://siuj.org mailto:candela.luigi%40hsr.it?subject=siuj robot-assisted radical prostatectomy (rarp) is increasingly used in urological centers as the approach of choice for rp[5]. nevertheless, the rate of postoperative urinary incontinence (ui) remains consistent. ui rates at 1 year after rarp range from 4% to 31% in different studies, decreasing patient quality of life (qol) especially when associated with a new onset of erectile disfunction in previously sexually active men[6]. in the last decade, many intraoperative surgical strategies have been proposed to improve functional outcomes, demonstrating satisfactory urinary continence (uc) recovery rates[7–9]. preservation of bladder neck, endopelvic fascia, pubo-prostatic ligaments, neuro-vascular bundles, and urethral length together with anterior and posterior reconstructions are commonly used to maximize continence recovery. postoperative non-surgical interventions (nsi) in addition to patients’ behavioral changes have been proposed to improve uc after rp[10]. specifically, pelvic f loor muscle training (pfmt) and oral medication including duloxetine and muscarinic receptor antagonists represent the most used nsi[11–13]. therefore, nsi could represent a valuable tool to improve post-rarp uc recovery, especially in the setting of mild ui. however, to date, the real clinical impact of nsi on postoperative uc recovery after rarp has not been well characterized[14]. we therefore thought this the optimal time to perform a systematic review of the literature with the aim of summarizing the current evidence on postoperative nsi to improve uc recovery after rarp. materials and methods study population and aims the current systematic review was registered with the international prospective registry of systematic reviews (prospero). the population, intervention, comparator and outcome (pico) criteria were used to frame the aims of the current systematic review. the population of interest consisted of patients who had undergone rarp for pca (p). postoperative nsi for the management of postrarp ui were the evaluated interventions (i). a no-nsi comparator was considered mandatory for the specific purpose of the current review (c). the primary aim was to evaluate the impact of nsi strategies in uc recovery after rarp in terms of uc rate and/or time to achieve uc. secondary aims were to identify patient compliance with these treatments, risk factors associated with ui, and correlation between uc restoration and sexual activity recovery (o). the treatment options of interest included postoperative non-surgical strategies to manage ui and to improve uc recovery. stress, urgency, and mixed ui were taken into consideration, and uc was defined according to urinary pads/day used and/or according to validated questionnaires. literature search a systematic web search was performed according to the preferred reporting items for systematic reviews and meta-analyses (prisma) guidelines on april 19, 2021, through the ovid platform with no time restrictions, using allied and complementary medicine (amed), embase, and medline databases. the terms “continence’’ and “incontinence’’ were pooled together with the boolean operator “or.” the terms “rarp’’ and “robot radical prostatectomy’’ were pooled together with the boolean operator “or.” the results were then pooled together with the boolean operator “and.” the web search was supplemented by a manual search (authors consultation and references of included articles). two authors (l.c. and g.m.) independently screened all items. disagreements were resolved through discussion or by consultation with a third and senior author (r.s.s.). only full-text publications in english were considered. we included all randomized controlled trials (rcts) and prospective and retrospective series without restrictions. we excluded studies not providing (1) details on ui rate before and after rarp; (2) details on nsi; (3) continence rates after surgery; (4) appropriate definitions to categorize type and severity of ui including either the number of pads used/day or pre-defined validated questionnaires. case reports, editorials, letters, reviews, and meeting abstracts were excluded. risk of bias and study quality were assessed according to european association of urology recommendations for performing systematic reviews and meta-analysis[15]. the cochrane risk of bias assessment tool was used for rcts and the quality appraisal tool for case series using a modified delphi technique for retrospective studies[16] (table 1). results figure 1 details the literature search strategy and the included/excluded studies. of 2758 identified abstracts, abbreviations nsi non-surgical interventions pca prostate cancer pfmt pelvic floor muscle training rarp robot-assisted radical prostatectomy rct randomized controlled trial rp radical prostatectomy uc urinary continence ui urinary incontinence 89siuj.org siuj • volume 3, number 2 • march 2022 postoperative non-surgical interventions to improve urinary continence after robot-assisted radical prostatectomy: a systematic review http://siuj.org we included 8 studies (3 rcts, 3 prospective singlearm trials, and 2 retrospective series) reporting results of uc recovery following postoperative nsi of 1146 patients who had undergone rarp for pca. overall, 2 nsi strategies to improve uc recovery after rarp were found: pelvic floor muscle training (pfmt) (n = 6 studies) and solifenacin oral administration (n = 2 studies). only 1 rct was a multicenter study[17]. population sizes ranged between 39 and 623 patients. among the studies on pfmt efficacy, 4 out of 6 had a control group[18–21]. more precisely, the study by sayilan et al. compared pfmt with no intervention[20], while the other included studies compared modified pfmt strategy, including ultrasound-guided, biofeedback and visual-feedback pfmt, with the conventional one[18,19,21]. among the studies on solifenacin oral administration safety and efficacy, liss and colleagues conducted a single-arm prospective clinical trial[22], while bianco et al. performed a multicenter rct with a placebo arm as control group[17]. overall, nsi duration of treatments ranged from 1 to 3 months after surgery. primary endpoints were uc recovery rate and time to uc in the majority of the studies. follow-up periods ranged from 1 month to 9 months, with most of studies reporting 3 months post bladder catheter removal urinary outcomes. table 1a. quality / risk of bias of the included studies retrospective series (n = 2 studies) quality appraisal tool for case series using a modified delphi technique n (%) s tu d y p o p u la ti o n 1. hypothesis/aim/objective stated clearly 2 100 2. characteristics of the study participants described 2 100 3. multicentre study 0 0 4. inclusion and exclusion criteria explicit and appropriate 1 50 5. participants recruited consecutively 2 100 6. participants entering at a similar disease point 2 100 in te r v en ti o n s 7. intervention clearly described 2 100 8. cointerventions clearly reported 0 0 o u tc o m es 9. outcome measures clearly defined 2 100 10. relevant outcomes appropriately measured 2 100 11. outcomes measured before and after the intervention 0 0 s ta ts 12. statistical tests appropriate to assess outcomes 1 50 r es u lt s / c o n c lu si o n s 13. length of follow-up reported 2 100 14. loss to follow-up reported 2 100 15. estimates of the random variability in data analysis 1 50 16. adverse events reported? 0 0 17. conclusions of the study supported 2 100 c i 18. competing interests and sources of support reported 2 100 table 1b. quality / risk of bias of the included studies randomized controlled trials (n = 3 studies) the cochrane risk of bias assessment tool + – ? 1. random sequence generation 2 0 1 2. allocation concealment 1 2 0 3. blinding of participants 1 2 0 4. blinding of outcomes 0 3 0 5. incomplete outcome data 0 3 0 6. selective reporting 0 3 0 7. other bias 1 0 2 90 siuj • volume 3, number 2 • march 2022 siuj.org review http://siuj.org reported rates of uc varied between a minimum of 29.1% at 3 months in patients treated with solifenacin[17] to a maximum of 100% at 6 months in patients who have performed pfmt[21]. overall, 3 out of 5 studies comparing nsi group with a control group showed a statistically significant advantage of nsi in uc recovery rate[17,20,21] whereas 2 studies did not find significant differences among groups within the follow-up period[18,19]. regarding the time to achieve uc after rarp, pfmt has shown to decrease time to uc recovery in 2 studies with mean time ranging from 32 to 75±100 days[18,21]. similarly, in the study by liss et al., mean time to achieve uc was 95 days in patients treated with solifenacin[22]. tables 2a, 2b, 3a, and 3b show patient characteristics and general information for the included studies. among studies reporting urinary outcomes after pfmt, we found 100% adherence to treatment: no patient with complete follow-up dropped out the exercises for any reason. the rate of adherence to nsi among patients receiving pharmacological treatment was 85% to 100%, demonstrating its good tolerability and safety profile. overall, 2 studies reported post-rarp ui risk factors[21,23] and 1 reported data on patients’ sexual activity recovery[19]. tables 4a and 4b show secondary outcomes of the current systematic review. studies on pelvic floor muscle training yoshida et al. conducted a prospective cohort study of 116 men undergoing rarp to examine whether transperineal ultrasound-guided pfmt promoted early uc recovery after surgery[16]. overall, 36 men received us-guided pfmt (interventional group), and 80 received only verbal instructions for pfmt (control group). continence was defined as time in days needed to require a small pad (20g) per day by patient self-report. mean time for uc recovery was significantly shorter in the intervention group than in the control group (75±100 versus 121.8±132 days; p = 0.037). moreover, uc rates were higher in the intervention group at 30 days (52.8% versus 35.4%; p = 0.081); however, at 9 months no statistically significant differences were found between the 2 groups in terms of continence status (p = 0.558). oh et al. performed an rct with 84 patients who had undergone rarp to investigate the effectiveness of an extracorporeal biofeedback device (anykegel) for pfmt on uc recovery[19]. overall, 42 patients received biofeedback pfmt using the anykegel device, and 42 patients received pfmt with only oral and written instructions. uc was defined as a loss of 0 g of urine on a 24-hour pad test. in addition, patients were also asked to complete the international prostatic symptoms score (ipss) with qol and international index of erectile function (iief) questionnaires to identify differences from the baseline during the follow-up period (secondary outcomes). the follow-up duration of the study was 3 months, with control visits at 1, 2, and 3 months after catheter removal. in the intervention group, the authors found a statistically significant smaller volume of urine loss at 1 month than in the control group (71 g versus 120.8 g; p = 0.028). however, at 2 and 3 months no differences were reported between the 2 groups. likewise, the rate of continent patients was similar between the intervention and control groups throughout the study follow-up. at the end of the study, 67.5% and 61.9% of patients were continent, in the intervention and control groups, respectively. similarly, no differences were found among groups in terms of ipps, qol, and iief, despite the intervention group demonstrating a favorable change from the baseline to the 1-month follow-up visit in ipss score. sayilan and colleagues conducted an rct to determine the effect of pfmt after rarp in uc recovery [20]. the 30 patients of the intervention group were taught to perform kegel exercises 3 times a day for 6 months after surgery, while the control group of 30 patients did web and manual search n = 2758 id en ti� ca tio n sc re en in g el ig ib ili ty in cl ud ed after de-duplication n = 2067 screened n = 276 full-text assessed for eligibility n = 31 excluded n = 2045 excluded n = 23 reasons: no rarp no post-rarp nsi other outcomes full-text included n = 8 figure 1. prisma flowchart 91siuj.org siuj • volume 3, number 2 • march 2022 postoperative non-surgical interventions to improve urinary continence after robot-assisted radical prostatectomy: a systematic review http://siuj.org table 2a. general features of included studies on pfmt to improve uc recovery after rarp authors accrual, year center study type intervention duration of treatment primary endpoint exclution criteria n of patients uc rate (% pts) mean time to uc recovery definition of uc questionnaries / urodynamic evaluation yoshida et al. 2018 japan prospective cohort study us-guided pfmt vs. verbal-pfmt preoperatively and 1 month after rarp time to uc recovery severe mental disease or cognitive impairment, neurological disorder affecting urinary tract, inability to understand japanese 36 vs. 80 88.9% vs. 84.7% at 9 months (p = 0.558) 75±100 vs. 121.8±132 days (p = 0.037) 1 small pad (20g)/day none / none oh et al. 2020 korea rct biofeedback-pfmt vs. verbal-pfmt 3 month after rarp time to uc recovery neurologic deficiency, previous pelvic radiation therapy or urological surgery, total incontinence at catheter removal 42 vs. 42 67.5% vs. 61.9% at 3 months (p = 0.649) not reported loss of 0g on a 24h pad test ipss, iief-5 / none sayilan et al. 2018 turkey rct pfmt vs. no intervention preoperatively to 6 months after rarp self-reported uc recovery at 6 months urinary incontinence before rarp, bmi>30, age<30 or >75 years, absence of elementary school level of education 30 vs. 30 50% vs. 3.3% at 6 months (p = 0.001) not reported iciq-ui score of zero iciq-sf / none pan et al. 2019 taiwan prospective resistance band pfmt 3 month after rarp improvement in uc recovery, qol, anxiety and depression after rarp age < 40 years, patients uncapable of verbal communication or of getting out of bed and moving without assistance, ui before surgery, uti before surgery, patients not able to lie in supine position 43 34.9% at 3 months not reported using urinary incontinence scale after rp (uisrp) uisrp, iiq, hads / none manley et al. 2016 australia retrospective pfmt preoperatively to 1 month after rarp pfm stength not reported 98 49.4% at 1 month not reported the requirement of no continence aids none / none kim et al. 2021 korea retrospective visual feedback pfmt vs conventional pfmt 1 month time to uc recovery previous pelvic rt, poor compliance due to psychiatric or medical problems, previous prostate surgery, < 3 months fu 41 vs. 42 100% vs. 88.1% at 6 months (p = 0.023) 32.4 vs. 95.3 days (p < 0.001) cessation of pad use none / none table 2b. general features of included studies on solifenacin administration to improve uc recovery after rarp authors accrual, year center study type intervention duration of treatment primary endpoint exclution criteria n of patients uc rate (% pts) mean time to uc recovery definition of uc questionnaries / urodynamic evaluation liss et al. 2014 united states prospective clinical trial solifenacin 5mg daily 3 months safety and 3 months uc recovery < 3 pads/day 39 53.8% at 3 months 95 (61–202) days 0 pads/ day aua symptom score / yes bianco f. et al. 2015 united states rct solifenacin vs. placebo 3 months time to uc recovery < 2 pads/day 7 to 21 days after rarp 313 vs. 310 29.1% vs. 21.4% at 3 months (p = 0.04) not reported 0 pads/ day or 1 dry safety pad/ day none / none 92 siuj • volume 3, number 2 • march 2022 siuj.org review http://siuj.org table 2a. general features of included studies on pfmt to improve uc recovery after rarp authors accrual, year center study type intervention duration of treatment primary endpoint exclution criteria n of patients uc rate (% pts) mean time to uc recovery definition of uc questionnaries / urodynamic evaluation yoshida et al. 2018 japan prospective cohort study us-guided pfmt vs. verbal-pfmt preoperatively and 1 month after rarp time to uc recovery severe mental disease or cognitive impairment, neurological disorder affecting urinary tract, inability to understand japanese 36 vs. 80 88.9% vs. 84.7% at 9 months (p = 0.558) 75±100 vs. 121.8±132 days (p = 0.037) 1 small pad (20g)/day none / none oh et al. 2020 korea rct biofeedback-pfmt vs. verbal-pfmt 3 month after rarp time to uc recovery neurologic deficiency, previous pelvic radiation therapy or urological surgery, total incontinence at catheter removal 42 vs. 42 67.5% vs. 61.9% at 3 months (p = 0.649) not reported loss of 0g on a 24h pad test ipss, iief-5 / none sayilan et al. 2018 turkey rct pfmt vs. no intervention preoperatively to 6 months after rarp self-reported uc recovery at 6 months urinary incontinence before rarp, bmi>30, age<30 or >75 years, absence of elementary school level of education 30 vs. 30 50% vs. 3.3% at 6 months (p = 0.001) not reported iciq-ui score of zero iciq-sf / none pan et al. 2019 taiwan prospective resistance band pfmt 3 month after rarp improvement in uc recovery, qol, anxiety and depression after rarp age < 40 years, patients uncapable of verbal communication or of getting out of bed and moving without assistance, ui before surgery, uti before surgery, patients not able to lie in supine position 43 34.9% at 3 months not reported using urinary incontinence scale after rp (uisrp) uisrp, iiq, hads / none manley et al. 2016 australia retrospective pfmt preoperatively to 1 month after rarp pfm stength not reported 98 49.4% at 1 month not reported the requirement of no continence aids none / none kim et al. 2021 korea retrospective visual feedback pfmt vs conventional pfmt 1 month time to uc recovery previous pelvic rt, poor compliance due to psychiatric or medical problems, previous prostate surgery, < 3 months fu 41 vs. 42 100% vs. 88.1% at 6 months (p = 0.023) 32.4 vs. 95.3 days (p < 0.001) cessation of pad use none / none table 2b. general features of included studies on solifenacin administration to improve uc recovery after rarp authors accrual, year center study type intervention duration of treatment primary endpoint exclution criteria n of patients uc rate (% pts) mean time to uc recovery definition of uc questionnaries / urodynamic evaluation liss et al. 2014 united states prospective clinical trial solifenacin 5mg daily 3 months safety and 3 months uc recovery < 3 pads/day 39 53.8% at 3 months 95 (61–202) days 0 pads/ day aua symptom score / yes bianco f. et al. 2015 united states rct solifenacin vs. placebo 3 months time to uc recovery < 2 pads/day 7 to 21 days after rarp 313 vs. 310 29.1% vs. 21.4% at 3 months (p = 0.04) not reported 0 pads/ day or 1 dry safety pad/ day none / none 93siuj.org siuj • volume 3, number 2 • march 2022 postoperative non-surgical interventions to improve urinary continence after robot-assisted radical prostatectomy: a systematic review http://siuj.org table 3a. patient baseline and pathological features (pfmt cohorts) authors n of patients age (years) bmi (kg/m2) psa (ng/ml) prostate volume (ml) nerve sparing procedures (%) gleason score (n) or (%) pt stage (n) or (%) positive surgical margins (%) yoshida et al. 36 vs. 80 66.5 (±6.2) vs. 66.6 (±5.8) 24.4 (±3.2) vs. 24 (±2.9) 11.3 (±11.8) vs. 10.3 (±8.5) 48.3 (±15.7) vs. 47.6 (±20.4) 16.7% vs. 21.3% – >pt3a=13.9% vs. >pt3a=15.2% – oh et al. 40 vs. 42 67.5 (±6.9) vs. 65.9 (±6.8) 24.8 (±2.6) vs. 24.6 (±2.7) 19.7 (±28.1) vs. 15 (±16.3) 33.7 (±10.6) vs. 36.9 (±11.9) 100% vs. 100% g6=0, g3+4=10, g4+3=17, g≥8=13 vs. g6=1, g3+4=20, g4+3=10, g≥8=11 ≤pt2=55%, ≥pt3=45% vs. ≤pt2=61.9%, ≥pt3=38.1% 20% vs. 19% sayilan et al. 30 vs. 30 63 (±8.61) vs. 59.93 (±6.98) 26.4 vs. 25.8 – – – – – 30% vs. 13.3% pan et al. 43 65 25 9.7 47 – – – – manley et al. 98 64 (49 77) – 5.2 (4.5 7.1) – – g6=9, g3+4=60, g4+3=19, g≥8=10 pt2=63, pt3a=28, pt3b=6 17% kim et al. 41 vs. 42 68.4 (±5.98) vs. 67.7 (±4.9) – 45.4 (±78.7) vs. 16.8 (±20.5) 33.8 (±15.2) vs. 36.2 (±13.8) 19.5% vs. 16.7% g<8=56.1%,g≥8=43.9% vs. g<8=73.8%, g≥8=26.2% ≤pt2=46.3%, ≥pt3=53.7% vs. ≤pt2=57.1%, ≥pt3=42.9% – table 3b. patient baseline and pathological features (solifenacin cohorts) authors n of patients age (years) bmi (kg/m2) psa (ng/ml) prostate volume (ml) nerve sparing procedures (%) gleason score (n) or (%) pt stage (n) or (%) positive surgical margins (%) liss et al. 39 65 (57–70) 25.9 (24.6–28.7) 5.8 (4.1–7.4) 51 (43–65) – g6=8, g7= 26, g>7=5 pt2=26, pt3a=12, pt3b=1 – bianco et al. 313 vs. 310 60.5 vs. 61.2 28.4 vs. 28.66 – – – – – – not receive any instruction for pfmt. uc was defined as international consultation on incontinence questionnaire short form (iciq-sf) score of 0. the primary outcome of this study was the patients’ self-reported uc recovery at 6 months after bladder catheter removal, and the secondary outcomes were the score of incontinence scale and the number of pads/week used. the follow-up schedule consisted of interviews at 10 days and 1, 3, and 6 months after catheter removal. the authors found a significant difference between the 2 groups in pads/ week at 1 and 6 months after surgery (p < 0.01); likewise, iciq-sf scores were higher in the control group than in the intervention group at 3 and 6 months, but there were no differences at 10 days and 1 month. at 6 months after surgery, 50% of patients in the intervention group, but only 3.3% of patients in the control group, reported the use of 0 pads/week. pan et al. conducted a pre-experimental single-group study in 43 men undergoing rarp in order to examine the effects of resistance band pfmt (modified pfmt) on patients’ uc recovery, life impact, anxiety and depression after surgery[24]. patients were evaluated at 2 weeks, 1, 2, and 3 months after catheter removal via the urinary incontinence scale after radical prostatectomy (uisrp), incontinence impact questionnaire (iiq), hospital anxiety and depression scale (hads). authors showed that ui severity significantly decreased with the study period; at 2 weeks 88.4% of patients suffered from any degree of ui versus 65.1% at 3 months. in a retrospective study, manley et al. evaluated the effect of pfmt in improving pelvic floor strength and uc recovery[23]. a trained pelvic floor physiotherapist gave a daily pfmt program to each man undergoing rarp and graded patient pelvic floor muscle strength (pfms) before and 4 days and 4 weeks after catheter removal. uc was defined as the requirement for no pads, and it was assessed at the 4-week control visit. complete data were available for 98 patients, and the majority of them increased their pelvic floor strength during the study period. preoperatively, pfms was strong in 79% of patients, moderate in 12%, and weak in 9%. postoperatively, the majority of those with previous moderate and weak pfms improved to strong pfms; younger age 94 siuj • volume 3, number 2 • march 2022 siuj.org review http://siuj.org table 3a. patient baseline and pathological features (pfmt cohorts) authors n of patients age (years) bmi (kg/m2) psa (ng/ml) prostate volume (ml) nerve sparing procedures (%) gleason score (n) or (%) pt stage (n) or (%) positive surgical margins (%) yoshida et al. 36 vs. 80 66.5 (±6.2) vs. 66.6 (±5.8) 24.4 (±3.2) vs. 24 (±2.9) 11.3 (±11.8) vs. 10.3 (±8.5) 48.3 (±15.7) vs. 47.6 (±20.4) 16.7% vs. 21.3% – >pt3a=13.9% vs. >pt3a=15.2% – oh et al. 40 vs. 42 67.5 (±6.9) vs. 65.9 (±6.8) 24.8 (±2.6) vs. 24.6 (±2.7) 19.7 (±28.1) vs. 15 (±16.3) 33.7 (±10.6) vs. 36.9 (±11.9) 100% vs. 100% g6=0, g3+4=10, g4+3=17, g≥8=13 vs. g6=1, g3+4=20, g4+3=10, g≥8=11 ≤pt2=55%, ≥pt3=45% vs. ≤pt2=61.9%, ≥pt3=38.1% 20% vs. 19% sayilan et al. 30 vs. 30 63 (±8.61) vs. 59.93 (±6.98) 26.4 vs. 25.8 – – – – – 30% vs. 13.3% pan et al. 43 65 25 9.7 47 – – – – manley et al. 98 64 (49 77) – 5.2 (4.5 7.1) – – g6=9, g3+4=60, g4+3=19, g≥8=10 pt2=63, pt3a=28, pt3b=6 17% kim et al. 41 vs. 42 68.4 (±5.98) vs. 67.7 (±4.9) – 45.4 (±78.7) vs. 16.8 (±20.5) 33.8 (±15.2) vs. 36.2 (±13.8) 19.5% vs. 16.7% g<8=56.1%,g≥8=43.9% vs. g<8=73.8%, g≥8=26.2% ≤pt2=46.3%, ≥pt3=53.7% vs. ≤pt2=57.1%, ≥pt3=42.9% – table 3b. patient baseline and pathological features (solifenacin cohorts) authors n of patients age (years) bmi (kg/m2) psa (ng/ml) prostate volume (ml) nerve sparing procedures (%) gleason score (n) or (%) pt stage (n) or (%) positive surgical margins (%) liss et al. 39 65 (57–70) 25.9 (24.6–28.7) 5.8 (4.1–7.4) 51 (43–65) – g6=8, g7= 26, g>7=5 pt2=26, pt3a=12, pt3b=1 – bianco et al. 313 vs. 310 60.5 vs. 61.2 28.4 vs. 28.66 – – – – – – was the only predictor of pfms improvement. overall, at 4 weeks after catheter removal 49.4% of patients were incontinent, and pfms correlated with ui (p < 0.01); however, preoperatively pfms was not associated with uc rate after rarp. older men with baseline moderate and weak pfms were more likely to experience ui at 4 weeks after rarp (p = 0.07). kim et al. performed another retrospective study to determine the benefit of pfmt with visual biofeedback compared with conventional pfmt in improving uc recovery after rarp[21]. forty-one patients formed the intervention group in which pfmt was performed with visual biofeedback under the supervision of a physiotherapist, while 42 patients in the control group performed kegel exercises at home after only verbal instructions were given by the treating urologist. uc was defined as the cessation of urinary pad use. the follow-up schedule consisted of outpatient office visits at 1 week and at 1, 3, and 6 months after catheter removal. overall, uc rates were 18.1%, 49.4%, 77.1%, and 94% at 1 week and 1, 3, and 6 months, respectively. in the intervention group, the rates of uc restoration were higher at 1 (p = 0.037), 3 (p < 0.001), and 6 (p = 0.023) months than in the control group. likewise, the mean time to achieve uc was shorter in the exercise group (32.4 versus 95.3 days, p < 0.001). at multivariate analysis, patients < 65 years old were found to have no benefit from the exercises while patients ≥ 65 years old benefited significantly from pfmt, thus suggesting that pfmt with biofeedback is an effective treatment for promoting early uc recovery and that it is more effective in elderly patients. studies on oral medical treatment (solifenacin) liss a nd col leag ues per formed a n ex plorator y investigator-initiated phase 1 clinical trial to assess safety and efficacy of solifenacin (vesicare) in men with ui after rarp[22]. the authors hypothesized that anticholinergic agents can reduce ui because of their effect in reducing detrusor overactivity. men using ≥ 3 pads/day 7 days after catheter removal were enrolled in the study and were prescribed a daily dose of 5mg solifenacin for 3 months. continence was defined as the 95siuj.org siuj • volume 3, number 2 • march 2022 postoperative non-surgical interventions to improve urinary continence after robot-assisted radical prostatectomy: a systematic review http://siuj.org usage of 0 pads/day; moreover, aua and qol symptom scores were submitted preoperatively and 3 months after surgery to measure the effectiveness of the treatment. complete data were available for 39 patients. overall, 6 patients withdrew from the study because of side effects or adverse events, and 16 men achieved uc before 90 days of treatment. at 3 months, 21 patients (53.8%) were fully continent with a median time to achieve uc of 95 days. the aua symptom score improved during the study period, but the qol score worsened. bianco et al. conducted a multicentric doubleblind rct evaluating the efficacy and safety profile of solifenacin versus placebo in uc recovery in men who had undergone rarp and were still incontinent 7 to 21 days after catheter removal[17]. patients requiring 2 to 10 pads/day for 7 consecutive days were enrolled in the study and randomized 1:1 to solifenacin 5 mg daily versus placebo during the 12-week study period. continence was defined as zero pads/day or a dry security pad for 3 consecutive days, and qol was assessed table 4a. secondary outcomes of the systematic review (pfmt cohorts) authors intervention duration of treatment n of patients patient adherence to treatment, % ui risk factors erectile dysfunction rate sexual activity recovery yoshida et al us-guided pfmt vs. verbal-pfmt preoperatively and 1 month after rarp 36 vs. 80 100 not reported not reported not reported oh et al biofeedback-pfmt vs. verbal-pfmt 3 month after rarp 42 vs. 42 100 not reported not reported no differences in iief-5 scores among the 2 groups sayilan et al. pfmt vs. no intervention preoperatively to 6 months after rarp 30 vs. 30 100 not reported not reported not reported pan et al. resistance band pfmt 3 month after rarp 43 100 not reported not reported not reported manley et al. pfmt vs. no intervention preoperatively to 1 month after rarp 98 100 age not reported not reported kim et al. visual feedback pfmt vs. conventional pfmt 1 month 41 vs. 42 100 gleason score, psa, pfmt not reported not reported table 4b. secondary outcomes of the systematic review (solifenacin cohorts) authors intervention duration of treatment n of patients patient adherence to treatment, % ui risk factors erectile dysfunction rate sexual activity recovery liss et al. solifenacin 5mg daily 3 months 39 85% not reported not reported not reported bianco et al. solifenacin vs. placebo 3 months 313 vs. 310 100% not reported not reported not reported 96 siuj • volume 3, number 2 • march 2022 siuj.org review http://siuj.org by aua symptom score and iciq-sf questionnaires. overall, 623 patients completed the study and no differences in time to achieve uc were found between the 2 groups (p = 0.17). however, uc rate by the end of the observation period was 29% versus 21% (p = 0.04) in the intervention and control group, respectively. moreover, patients in both groups had a statistically significant decrease in the number of pads/day from baseline to the end of the study that was greater in the solifenacin arm at 12 weeks (p = 0.01). qol measures significantly improved by the end of the study (p < 0.001) without differences between groups. among patients on solifenacin, 33.2% reported at least 1 adverse event, dry mouth being the most common. discussion we performed a systematic review investigating postoperative nsi role in early uc recovery after rarp. our interest was motivated by the need for conservative interventions to manage mild ui in order to improve patient satisfaction and qol in the early postoperative period[25]. in this context, it is important to underline that surgery (eg, male slings) is not always recommended for patients who experience post-rarp ui[26]. overall, we focused our research on nsi carried out only in patients who have undergone rarp because of the wide availability of the robotic prostatectomy procedure and its technical advantages that can lead to optimal functional outcomes[27,28]. several findings are of interest. to date, pfmt and orally administered solifenacin have been proposed as the only available nsi to improve uc recovery after rarp. these nsi are carried out in the early postoperative period with a limited duration of treatment of 1 to 6 months, theoretically in all patients submitted to rarp. recently, marchioni et al. reviewed 6 articles, concluding that pfmt has the advantage of shortening the time to recovery of uc, while the use of solifenacin does not offer any significant advantages in post-rarp ui management[10]. studies included in our systematic review showed a possible association between pfmt and oral solifenacin administration and an early improvement in urinary functional outcomes after rarp. yoshida et al. found that the mean time for uc recovery was significantly shorter in the intervention group (ultrasound-guided pfmt) than in the control group (conventional pfmt) (75±100 versus 121.8±132 days; p = 0.037). moreover, uc rates were higher in the intervention group at 30 days (52.8% versus 35.4%; p = 0.08); however, at 9 months no statistically significant differences were found between the 2 groups in terms of continence status (88.9% versus 84.7%, p = 0.558)[18]. oh et al. found similar uc rates at 3 months in the intervention and control groups (67.5% and 61.9%, respectively; p = 0.649)[19]. sayilan et al. found a significant difference in pads/day at 1 and 6 months after surgery between pfmt and no-nsi cohorts (p < 0.01); at 6 months after surgery, 50% of patients in the intervention group but only 3.3% of patients in the control group reported the use of 0 pads/ day[20]. kim et al. found that in the interventional group (visual-feedback pfmt) the rates of uc restoration were higher at 1 (p = 0.037), 3 (p < 0.001), and 6 (p = 0.023) months than in the control group (conventional pfmt). likewise, the mean time to achieve uc was shorter in intervention group (32.4 versus 95.3 days; p < 0.001)[21]. pan et al. and manley et al. reported uc rates of 34.9% at 3 months and 49.4% at 1 month after bladder catheter removal, respectively[23,24]. regarding solifenacin administration, liss et al. reported that at 3 months, 21 patients (53.8%) were fully continent with a median time to achieve uc of 95 days[22] while bianco et al. reported 3 months uc rate of 29% versus 21% (p = 0.04) in the intervention group and placebo group, respectively; however, no differences in time to achieve uc was found between the 2 groups (p = 0.17)[17]. of note, among included studies, only bianco et al. provided level 1b clinical evidence supporting the use of nsi (solifenacin) to improve uc recovery after rarp[17]. nevertheless, liss et al. failed to demonstrate an obvious benefit of solifenacin administration in urinary outcomes except a potential symptomatic relief[22]. previously, other oral medications such as duloxetine showed a good efficacy profile in the ui following rp[29]. however, to the best of our knowledge, there are no studies exploring postrarp duloxetine administration since current evidence is available only for open or laparoscopic rp[30]. a variability in uc definition exists among studies reporting functional outcomes after prostatectomy, thus making difficult a standardized interpretation of the results[31]. in the literature, uc is mainly defined as the use of no pad or the use of 1 safety pad/day, and 5 out of 8 reviewed studies adopted this method. in this context, kuehhas et al. recommend adding the use of validated questionnaires to assess uc after prostatectomy[32]; however, in 4 studies of the current systematic review, the authors did not distribute questionnaires to patients[17,18,21,23]. in general, a comprehensive evaluation of both subjective and objective functional outcomes combined with assessment of satisfaction has not been conducted systematically. yoshida et al. defined uc as the need to require a small pad (20g) per day by patient self-report[18]; oh et al. used a loss of 0 g of urine on a 24-hour pad test to define uc[19]; sayilan et al. and pan et al. used validated questionnaires to score ui[20,24]; in the remaining studies uc was defined as no need of urinary pad usage[17,21–23]. 97siuj.org siuj • volume 3, number 2 • march 2022 postoperative non-surgical interventions to improve urinary continence after robot-assisted radical prostatectomy: a systematic review http://siuj.org importantly, among included studies only data on early urinary function outcomes are reported. therefore, follow-up is inadequate to evaluate mediumand long-term continence recovery rates in patients who performed pfmt or have been treated with solifenacin. several studies reported the natural history of urinary function in men who have undergone rarp and found that uc rates increase up to 90% to 95% especially during the first year after surgery, thus demonstrating a spontaneous improvement in uc rate with time [33–35]. even though mild ui can spontaneously improve in the first year after surgery, we believe that conservative strategies to accelerate this process should be taken into account by urologists to ameliorate patients’ qol in the early postoperative period. of note, we miss 2 of our secondary aims because of data insufficiency: to identify risk factors associated with ui after rarp and to find a correlation between postoperative uc and sexual activity recovery in patients enrolled to nsi. regrettably, the studies included in our review did not analyze the association among patient related characteristics such as age, bmi and comorbidities, pca features and surgical variables that may impact on post-rarp uc before surgery given that ui is a multifactorial condition[36]. however, we found high compliance to pfmt and solifenacin administration, thus suggesting the feasibility of these interventions to manage ui. from a research perspective our work highlights the gaps we should fill to improve evidence on nsi to manage mild ui after rarp. first, further multicenter randomized studies are needed, including large population studies comparing nsi—even pfmt in combination with solifenacin—with no postoperative intervention with longer follow-up. second, ui should be defined as the use of 0 pads/day or 1 safety pad/day and validated questionnaires should be submitted to patients. third, ui risk factors and sexual activity recovery might be reported to globally assess patients’ functional outcomes. the study has several limitations. first, there was great variability in the assessment and data reporting of ui and uc recovery among studies, thus making comparison between results difficult. moreover, some studies did not use a control group against which to compare nsi. second, all studies reported short-term follow-up functional outcomes, with the majority of them reporting results only to 3 months. third, the sample sizes of the studies were generally small and heterogeneous in terms of comorbidities and pca features. fourth, the different pfmt schedules used in the studies could influence patient outcomes. for these reasons we were not able to perform a meta-analysis of the 8 selected studies in order to integrate their results. conclusions ea rly postoperat ive nsi—including pfmt a nd oral administration of solifenacin—to manage ui after rarp may improve uc recovery. moreover, both interventions are safe and well tolerated, with high patient ad herence to treat ment. however, clinical evidence supporting their routine use is still weak. further multicenter prospective studies with longer follow-up, adequate number of patients, and standardized functional outcomes assessment are needed to confirm the efficacy of the nsi on uc recovery after rarp. 98 siuj • volume 3, number 2 • march 2022 siuj.org review http://siuj.org references 1. mottet n, van den bergh rcn, briers e, van den broeck t, cumberbatch mg, de santis m, et al. eau-eanm-estro-esur-siog guidelines on prostate cancer—2020 update. part 1: screening, diagnosis, and local treatment with curative intent. eur urol.2021 feb;79(2):243– 262. doi: 10.1016/j.eururo.2020.09.042. epub 2020 nov 7. 2. haglind e, carlsson s, stranne j, wallerstedt a, wilderäng u, thorsteinsdottir t, et al. urinary incontinence and erectile dysfunction after robotic versus open radical prostatectomy: a prospective, controlled, nonrandomised trial. eur urol.2015 aug;68(2):216–225. doi: 10.1016/j.eururo.2015.02.029. epub 2015 mar 12. 3. yaxley jw, coughlin gd, chambers sk, occhipinti s, samaratunga h, zajdlewicz l, et al. robot-assisted 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regain urinar y continence af ter robot-assisted radical prostatectomy. yeungnam univ j med.2021 jan;38(1):39–46. doi: 10.12701/yujm.2020.00276. epub 2020 jun 22. 22. liss ma, morales b, skarecky d, ahlering te. phase 1 clinical trial of vesicaretm (solifenacin) in the treatment of urinary incontinence after radical prostatectomy. j endourol.2014 oct;28(10):1241–1245. doi: 10.1089/end.2014.0342. epub 2014 jul 21. 23. manley l, gibson l, papa n, beharry bk, johnson l, lawrentschuk n, et al. evaluation of pelvic floor muscle strength before and after robotic-assisted radical prostatectomy and early outcomes on urinary continence. j robot surg.2016 dec;10(4):331–335. doi: 10.1007/ s11701-016-0602-z. epub 2016 may 9. 24. pan lh, lin mh, pang st, wang j, shih wm. improvement of urinary incontinence, life impact, and depression and anxiety with modified pelvic floor muscle training after radical prostatectomy. am j mens health.2019 may-jun;13(3):1557988319851618. doi: 10.1177/1557988319851618 25. waller j, pattison n. men’s experiences of regaining urinar y continence following robotic-assisted laparoscopic prostatectomy (ralp) for localised prostate cancer: a qualitative phenomenological study. j clin nurs.2013 feb;22(3-4):368–378. doi: 10.1111/jocn.12082 26. tutolo m, briganti a, montorsi f. re: kathrin meisterhofer, sereina herzog, karin a. strini, luca sebastianelli, ricarda bauer, orietta dalpiaz. male slings for postprostatectomy incontinence: a systematic review and meta-analysis. eur urol focus.2020;6:575–92. 27. martini a, falagario ug, villers a, dell’oglio p, mazzone e, autorino r, et al. contemporary techniques of prostate dissection for robotassisted prostatectomy. eur urol.2020 oct;78(4):583–591. doi: 10.1016/j.eururo.2020.07.017. epub 2020 aug 1 28. ficarra v, novara g, artibani w, cestari a, galfano a, graefen m, et al. retropubic, laparoscopic, and robot-assisted radical prostatectomy: a systematic review and cumulative analysis of comparative studies. eur urol.2009 may;55(5):1037–1063. doi: 10.1016/j.eururo.2009.01.036. epub 2009 jan 25. 29. neff d, guise a, guralnick ml, langenstroer p, see wa, jacobsohn km, et al. duloxetine for the treatment of post-prostatectomy stress urinary incontinence. can urol assoc j.2013 may-jun;7(5– 6):e260–262. doi: 10.5489/cuaj.318. 30. kotecha p, sahai a, malde s. use of duloxetine for postprostatectomy stress urinary incontinence: a systematic review. eur urol focus.2021 may;7(3):618–628. doi: 10.1016/j.euf.2020.06.007. epub 2020 jun 27. 31. borregales ld, berg wt, tal o, wambi c, kaufman s, gaya jm, et al. “trifecta” after radical prostatectomy: is there a standard definition? bju int.2013 jul;112(1):60–67. doi: 10.1111/bju.12002 32. kuehhas fe, naegele r, eckersberger e, margreiter m, herwig r, kazzazi a, et al. urinary continence after radical prostatectomy: the patient perspective. can j urol.2011 aug;18(4):5811–5818 33. wang l, chung sfcm, yip skh, lau wko, cheng cws, sim hg. the natural history of voiding function after robot-assisted laparoscopic radical prostatectomy. urol oncol.2011 mar-apr;29(2):177–182. doi: 10.1016/j.urolonc.2009.01.030. epub 2009 apr 11. 34. patel v r, thaly r, shah k. robotic radical prostatectomy: outcomes of 500 cases. bju int.2007 may;99(5):1109–1112. doi: 10.1111/j.1464-410x.2007.06762.x 35. menon m, shrivastava a, kaul s, badani kk, fumo m, bhandari m, et al. vattikuti institute prostatectomy: contemporary technique and analysis of results. eur urol.2007 mar;51(3):648–657; discussion 657–658. doi: 10.1016/j.eururo.2006.10.055. epub 2006 nov 3. 36. tutolo m, bruyneel l, van der aa f, van damme n, van cleynenbreugel b, joniau s, et al. a novel tool to predict functional outcomes after robot-assisted radical prostatectomy and the value of additional surgery for incontinence. bju int.2021 may;127(5):575–584. doi: 10.1111/bju.15242. epub 2020 oct 1 100 siuj • volume 3, number 2 • march 2022 siuj.org review http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. urine biomarkers for prostate cancer diagnosis and progression jeremy clark,1 rachel hurst,1 mark simon winterbone,1 hardev pandha,2 antoinette perry,3 sophie mcgrath,4,5 richard morgan,6 adele e. connor,3,7 asia c. jordan,3,7 deirdre winrow,3,7 colin cooper1 1 norwich medical school, university of east anglia, norwich research park, norwich, united kingdom 2 professor of medical oncology, faculty of health and medical sciences, university of surrey, guildford, united kingdom 3 cancer biology and therapeutics laboratory, school of biomolecular and biomedical science, conway institute, university college dublin, ireland4 the royal marsden nhs foundation trust, downs road, sutton, united kingdom 5 kingston hospital nhs foundation trust, galsworthy road, kingston-upon-thames, united kingdom 6 the institute of cancer therapeutics, school of pharmacy and medical sciences, university of bradford, united kingdom 7 school of biology and environmental science, university college dublin, ireland abstract prostate cancer (pca) can be highly heterogeneous and multifocal, and accurate assessment of the volume, grade, and stage of pca in situ is not a simple task. urine has been investigated as a source of pca biomarkers for over 70 years, and there is now strong evidence that analysis of urine could provide more accurate diagnosis and a better risk stratification that could aid clinical decisions regarding disease surveillance and treatment. urine diagnostics is a developing area, moving towards multi-omic biomarker integration for improved diagnostic performance. urine tests developed by strong collaborations between scientists and clinicians have the potential to provide targeted and meaningful data that can guide treatment and improve men’s lives. 1. introduction: urine as a source of prostate cancer biomarkers prostate cancers (pca) can be highly heterogeneous[1,2] and multifocal[2,3]. accurate assessment of the volume, grade, and stage of prostate cancer in situ is not a simple task. significant amounts of biopsy results can be upgraded or downgraded on prostatectomy analysis[4,5]. multi-parametric mri has improved enormously but has inter-operator inconsistencies[6], can miss significant cancers (gleason > 4), and has a false positive rate of around 50%[7]. urine has been investigated as a source of pca biomarkers for over 70 years[8–10], and there is now strong evidence that urine analysis could provide a better assessment of disease diagnosis and prognosis that could aid clinical decisions regarding disease surveillance and treatment. prostatic secretions make up 30% of the volume of semen, and its composition can reflect pre-neoplastic or malignant changes[11]. the prostate is continually secreting, and these secretions flow from all areas of the prostate where pca is found[12,13]. these secretions flow into the urethra whence they are flushed out of the body on urination[12]. when a cancer is present, tiny bits of tumour (cells, extracellular vesicles, and molecules) can also be carried in the secretions and these can be detected in urine[8,9]. urine is advantageous as a source for liquid biopsy because it can be collected at low cost, is completely non-invasively, and has the potential to sample all secretory areas of the prostate at the same time. key words competing interests article information urine, biomarkers, prostate cancer dr clark and professor cooper have a patent gb1905111.9 issued in relation to the pur (prostate urine risk) signatures discussed in this review. professor pandha and professor morgan have a patent issued for en2 as a diagnostic marker. dr perry reports grants from enterprise ireland, movember, prostate cancer foundation, and science foundation ireland during the conduct of the study. dr perry has a patent ep15831140.7 issued, and a patent 15/538928 pending. the remaining authors declare no competing interests. received on january 5, 2021 accepted on march 14, 2021 soc int urol j.2021;2(3):159–170 doi: https://doi 10.48083/sawc9585 159siuj.org siuj • volume 2, number 3 • may 2021 review mailto:jeremy.clark%40uea.ac.uk?subject=siuj https://doi 10.48083/sawc9585 http://www.siuj.org urine samples have been analysed for promising cancer biomarkers in the form of cells, dna, rna, proteins, and metabolites. the relative proportions of biomarkers vary between whole urine, cell sediment, and supernatant which will be discussed separately. the majority of the research presented here has been performed on small cohorts from which limited conclusions can be made. the current state and future directions of urine analysis for prostate cancer diagnosis and prognosis are described herein. table 1 provides an overview of the biomarkers discussed in this review. 2. analysis of whole unfractionated urine elevated levels of c3, c4, and transferrin proteins were found in prostatic fluid from pca patients by greyhack et al. in 1979[11], and in 1982 pca-1 (prostate cancer antigen-1) protein was detected in urine from pca patients but not in urine from age-matched non-pca men[10]. however, it was not until 2002, when pca3 (prostate cancer antigen 3) rna transcripts in urine were found that the potential for urine molecular diagnostics in clinical urological practice was realised. pca3 is a prostate-specific long non-coding rna overexpressed in ≥ 95% of prostate cancers that was first investigated as a urinary pca marker by de kok et al. in 2002[14]. in a multicentre validation study[15,16] it was shown to predict gleason score ≥ 7 cancer with an 80% negative predictive value. the fda-approved progensa pca3 urine test was approved in 2012. whole urine for this test is collected after prostate massage with the intent of predicting the likelihood of detecting pca on repeat prostate biopsy[17,18]. the pca3 score is calculated as the ratio of 2 mrnas: pca3/klk3 x1000[17]. a threshold score of 35 provided a sensitivity and specificity of 58% and 72%, respectively for presence of significant pca on rebiopsy[19,20]. investigations into a direct relationship between the pca3 test and pca volume or gleason pattern have been unclear, yielding opposing results in different studies[14,21,22]. metanalysis by luo et al. found great heterogeneity among published data sets with pca3 test sensitivity ranging from 47% to 82%[23]. the reasons for this were unknown, and they may underlie the poor uptake of the pca3 test in the clinic. however, the pca3 test is important as it was first to demonstrate that collection, transport, and centralised laboratory analysis of urine was a viable means of pca biomarker analysis. the tmprss2:erg fusion gene is found in ~50% of pca foci; however, as tmprss2:erg-positive and negative tumour foci can be found in individual prostates[24], a tmprss2:erg may be present in ~70% of pca-radical prostatectomies[25], making its detection more useful than was initially apparent. urine transcript levels of tmprss2:erg correlated with erg expression in pca tissue and aided prediction of pca by pca3. the mi-prostate score (mips) combined detection of pca3, tmprss2:erg and serum psa levels[26], providing significantly improved detection of any pca and gleason score (gs) ≥ 7 on biopsy compared with psa or the prostate cancer prevention trial risk calculator (pcpt-rc)[27]. further gene transcripts have been investigated for additional improvements. van neste et al. combined rt-pcr data from hoxc4, hoxc6, tdrd1, dlx1, klk3, and pca3 with clinical information from 2 independent mu lticentre prospective collections (n = 906)[28].an optimal model (selectmdx) required only a combination of psad, dre result, hoxc6 and dlx1, with klk3 used for relative biomarker quantitation[28]. selectmdx had a strong net benefit, potentially reducing unnecessary biopsies over the pca3 test, psa and the pcpt-rc with a validation cohort auroc of 0.9 for detection of gs ≥ 7 cancer. selectmdx has been reported to be able to reduce diagnostic costs in a study covering 5 european countries, the degree of benefit varying with the amount of overtreatment in each country’s clinical procedures[29]. 3. analysis of urine cell sediment 3.1 pca cells in urine urine can contain many different cell types, including bladder urothelial cells, squamous cells, seminal vesicle cells, prostate cells, red blood cells, and white blood cells[30], up to 80% of which can originate from the prostate[31,32]. prostate cancer cells were first detected in urine samples by microscopy in 1947[9] and are associated with higher risk and advanced cancers[31]. the relative proportions of the different cell types in urine can alter with a dre[31,33] or disease state such as prostatitis[34], prostate/urinary tract problems, or pca[30,35]. abbreviations dre digital rectal examination evs extracellular vesicles gs gleason score mips mi-prostate score pca prostate cancer pca3 prostate cancer antigen 3 pcpt-rc prostate cancer prevention trial risk calculator pur prostate urine risk vip vasoactive intestinal peptide 160 siuj • volume 2, number 3 • may 2021 siuj.org review urine cell pellet staining for amacr, nk x3.1, nucleolin, erg, and prostein[35,36] can detect prostate cancer cells but overall lacked sensitivity compared with biopsy[36]. two f luorescent approaches have shown promise: oligofish probes to detect alterations in chromosomes 7, 16, 18, and 20 has been shown to have an 80% specificity compared with biopsy data[32], while a f luorescent peptide detected vpac receptors with > 98% sensitivity and specificity[37]—vpac receptors bind vip, a neuropeptide linked to development, growth, immune system and cancer. 3.2 rna in urine sediment a disadvantage with urine sediment analysis is that the cell transcriptome is likely to alter on becoming detached and/or on contact with urine[38,39]. however, urine cell sediment has been found to be useful for pca diagnosis. pca3 has a reported sensitivity of detection of pca in urinary sediment of 62%, boosted to 73% by codetection of tmprss2:erg[40,41]. other combination markers used with pca3 have been found to aid pca detection in cell sediment: (1) amacr, trpm8, msmb[42], (2) tmprss2:erg, golph, spink1[43], and (3) hist1h2b, spp1, elf3[44]. however, leyten et al. found that pca3 was unnecessary when hoxc6, dlx1, and tdrd1 were used[45], tdrd1 being a direct target of erg and co-expressed with erg in pca[46]. in combination with the european randomised study of screening for pca (erspc) risk calculator[47], leyten et al. noted that tmprss2:erg added significant predictive value to the erspc calculator to predict biopsy gleason whereas pca3 did not. tmprss2:erg has been reported to be less common in chinese populations[48], and detection of ttty15:usp9y gene fusion transcripts found in 35% of chinese patients pca[48] has improved pca detection in urine sediments in that population (n = 226, auroc 0.83)[49]. other probe combinations excluding pca3 include a panel of 6 genes overexpressed in pca tissue (ccnd1, lmtk2, fn1, gstp1, hpn, and myo6), used in the analysis of 156 pca patients’ urine sediments (n = 67), which had a sensitivity of 80.6% and specificity of 62.9% for pca detection (auroc of 0.80)[50]. table 1. overview of relevant biomarkers biomarker type use of test urine fraction or source detection method largest cohort size results references pca cells amacr, nkx3.1, nucleolin, erg and prostein pca urine sediment antibody, microscopy 63 sensitivity 64%, specificity 69% 35, 36* chromosome alterations pca urine sediment fish microscopy 100 auroc 0.83, 81% accuracy 32 vpac receptors pca urine sediment fluorescent peptide, microscopy 176 > 98% sensitivity and specificity 37 protein c3, c4 transferrin pca prostatic fluid immunoelectrophoresis, radial immunodiffusion 10 significantly elevated in pca 11 pca-1 pca whole urine 2d gel electrophoresis 17 16/17 pca positive 10 itga3, itgb1 metastasis supernatant mass spectrometry, western blot 13 more abundant in 3 urines from metastatic patients 92 en2 pca, higher tumour stage (t1 v t2) supernatant antibody, elisa, graphene-based biosensor 184 pca auroc 0.8, sensitivity 66%, specificity 88% 99*–101, 104 as: active surveillance; auroc: area under receiver operating characteristic curve; fish: fluorescent in situ hybridisation. continued on page 162 161siuj.org siuj • volume 2, number 3 • may 2021 urine biomarkers for prostate cancer diagnosis and progression http://siuj.org table 1. overview of relevant biomarkers biomarker type use of test urine fraction or source detection method largest cohort size results references rna pca3 pca on repeat biopsy gs≥7 whole urine, supernatant qrt-pcr, nanostring, quantitative nucleic acid amplification 809 auroc 0.66-0.8. sensitivity 47%–82% 15, 16*–23, 69, 80–84, 97, 105 pca3, tmprss2:erg fusion gene pca detection gs≥7, higher vol pca whole urine, urine sediment, supernatant qrt-pcr, quantitative nucleic acid amplification 497 auroc 0.77-0.8. 26, 40, 41, 47*, 69, 80–84, 105 hoxc6, dlx1 (selectmdx) pca detection gs≥7 whole urine qrt-pcr 358 auroc 0.77 29, 45* klk3 control probe in analyses whole urine, sediment, supernatant qrt-pcr, nanostring linear amplification na na 14-23, 28, 29, 40, 41, 43, 69, 80–84, 87 amacr, trpm8, msmb pca cell sediment qrt-pcr 104 auroc 0.74 42 golph, spink1 pca cell sediment qrt-pcr 235 auroc 0.76, sensitivity 66%, specificity 76% 43 hist1h2b, spp1, elf3, pca3 pca cell sediment qrt-pcr 224 auroc 0.76, sensitivity 77%, specificity 67% 44 ttty15:usp9y pca cell sediment qrt-pcr 226 auroc 0.83 49 ccnd1, lmtk2, fn1, gstp1, hpn and myo pca cell sediment qrt-pcr 67 auroc of 0.80 50 agr2 pca supernatant qrt-pcr 32 auroc 0.96 85 birc5 pca supernatant qrt-pcr 207 auroc 0.67 81 cdh3 pca supernatant qrt-pcr 53 significantly decreased in pca, sensitivity 0.69 86 pur signatures 39 gene probes high risk, as monitoring to treatment intervention supernatant nanostring 535 auroc 0.77 for high risk, hr 8.2 for as monitoring 70 as: active surveillance; auroc: area under receiver operating characteristic curve; hr: hazard ratio; qrt-pcr: quantitative reverse transcribed and polymerase chain reaction. , cont’d continued on page 163 162 siuj • volume 2, number 3 • may 2021 siuj.org review table 1. overview of relevant biomarkers biomarker type use of test urine fraction or source detection method largest cohort size results references mirna mir-125b pca, high risk cell sediment exiqon mirna rt-pcr platform 415 auroc 0.76 53 mir-24, mir-30c pca cell sediment exiqon mirna rt-pcr platform, mircury lna mirna sybr green pcr 415 auroc 0.89 53,* 55 mir-148a, mir-375 pca cell sediment taqman low density array 72 auroc 0.79 52 mir-3195, let-7b-5p, mir-144-3p, mir451a, mir-148a3p, mir-512-5p, mir431-5p pca cell sediment nanostring 149 auroc 0.74 54 dna c-myc, bcas1, her2, ar, pten, tmprss2:erg pca supernatant qrt-pcr for copy number and mutations 10 auroc 0.8 91 methdna epicapture: gstp1, sfrp2, igfbp3, igfbp7, apc, ptgs2 pca gs≥8 cell sediment quantitative methylation-specific polymerase chain reaction 463 auroc 0.83 62 procure: hoxd3 and gstp1 pca gs≥7 cell sediment quantitative methylight 408 auroc 0.8 63 apc, crip3, gstp1, hoxd8 pca gs≥7 cell sediment multiplex quantitative methylight 153 or 2.6 64 as: active surveillance; auroc: area under receiver operating characteristic curve; methdna: methylated dna , cont’d 3.3 mirna in urine sediment mir na dysregulation is frequent ly obser ved in cancer[51], and a number of diagnostically useful mirnas are detectable in urine[52–55]. mir-21 and mir-125b are controlled by the androgen receptor (ar), and are overexpressed in pca and associated with apoptotic resistance[53,54]. in contrast, mir-205 is a tumour suppressor mirna, promoting apoptosis, and its loss is associated with the early stages of pca development[56]. despite mir-205 being dow nregulated in pca, it is a constituent of several mirna urinary biomarker panels. aurocs vary from 0.6 to 0.85 for detection of pca using multiple combinations of mirnas[52,53], and 0.74 for distinguishing low-risk from high-risk disease[54]. 3.4 dna-methylation in urine sediment epigenetic alterations are heritable changes in gene expression with no change to the dna code. in cancer, dna-hypermethylation silences tumour suppressors and other important regulatory genes[57]. it is easily detectable by pcr and it occurs early in tumorigenesis making it an ideal biomarker for early detection as well as disease progression monitoring and risk stratification of patients[58,59]. pioneering work in the detection of pca and significant pca (gs ≥ 7) was performed by cairns et al. in 2001, who showed that methylation of the gstp1 gene was detectable in urine of men with pca but at a low sensitivity (27%)[60]. gstp1 is hypermethylated in > 90% of pca[60] and is relatively pca-specific, it 163siuj.org siuj • volume 2, number 3 • may 2021 urine biomarkers for prostate cancer diagnosis and progression http://siuj.org typically being overexpressed in most other cancers. for these reasons, it is a stalwart of pca-methylation analysis. gene panels improved performance, and a combination of apc, r arbeta, r assf1a, ptgs2, abcb1 methylation was detectable in > 85% of cases[61]. notable examples include epicapture, a 6-gene dnamethylation panel (gstp1, sfrp2, igfbp3, igfbp7, apc, ptgs2) that can detect 85% of aggressive pca (gs ≥ 8) with a 70% improvement in the specificity of psa[62] and procure, a 2-gene dna-methylation panel (hoxd3 and gstp1) with a sensitivity of 57.1% and specificity of 97% for significant pca[63]. zhao et al. established a 4-gene panel (apc, crip3, gstp1, hoxd8) with some ability to predict cancer progression in patients on active surveillance (or 2.559; 95% ci 1.257 to 5.212) from post-dre urine[64]. they subsequently incorporated micrornas and reported that mir-24, mir-30c and crip3 methylation could predict reclassification of as patients[55]. currently, no commercially available standardised dna-methylation-based urine tests for pca are available[60], which presents an obstacle to clinical uptake[65]. sample storage conditions affect results as methylated-dna is only stable for up to 28 days in urine stored at −20/−80⁰c and a preservative is required at room temperature[66]. most urine assays use bisulfite conversion of unmethylated cytosines to uracil, leaving hypermethylated cytosines preserved for detection. however, a study of 12 different bisulfite kits discovered that conversion efficiency varied greatly[67], and storage of the less stable single-stranded bisulfite converted dna may also be an issue[68]. target sequence choice is critical, proximity to the transcription start site, transcription factor binding motifs, and dnasehypersensitivity are all factors that can affect sensitivity and specificity[59]. large, multicentre, standardised urine collections and clinical follow-up are needed to reduce the unknowns and bring pca methylation biomarkers to fruition. 4. urine supernatant 4.1 rna in urine extracellular vesicles large numbers of extracellular vesicles (evs) can be found in urine[69], the majority of which in first-catch adult male urine originate from the prostate[69,70]. evs are lipid-bound vesicles produced by a wide range of cell types[71]. evs function as inter-cellular messengers that can bind to and influence the phenotype of cells they come into contact with[72,73]. cancer cells produce evs, which can enhance vasculature[74], increase metastasis[75], and inf luence the immune system[76] and can contain pca-specific mrnas such as tmprss2:erg fusion gene transcripts[40]. evs contain lipids, rna, dna, and proteins including membrane receptors[72,77,78] which are protected from degradation by, for example, rnases by the ev lipid membrane[79]. the majority of publications refer to analysis of only small numbers of gene transcripts in evs, namely pca3, erg, tmprss2:erg, klk3, which have been found to be useful in pca diagnosis and detection of gleason ≥ 4 cancer[69,80–84]. additional genes with diagnostic potential are agr2 splice variants[85], birc5[81], and decreased expression of cdh3[86]. in contrast, connell et al. used a nanostring panel of 167 gene probes, mostly selected from published evidence of over-expression in pca tissue[70]. analysis of 535 urine ev samples from patients with and without pca led to the prostate urine risk (pur) signatures constructed from a subgroup of 39 gene probes. in contrast to all other urine analyses, instead of a single cancer signature they constructed 4 pur signatures, which were built around samples categorised as non-cancer (pur-1), plus the 3 d’amico risk groups for cancer aggression, namely low-risk (pur-2), intermediate-risk (pur-3), and high-risk (pur-4). each sample could have representation from all 4 signatures and the sum of the 4 pur signatures in each sample was ‘1’. connell et al. found that pur4 could predict the presence of significant cancer on trus biopsy (auroc 0.77). on examination of an active surveillance cohort (n = 87) pur-4 could be used to divide patients into 2 groups with rates of progression to treatment intervention of 10% and 60% up to 5 years after urine collection (hr 8.23). a strong pur-1 signature correlated with stability of low-grade disease that did not progress in the 5-year follow-up. the pur-2 and pur-3 signatures had less utility but were hypothesised as integral to the creation of a clearer signature for higher grade gleason cancer detectable by pur-4. a few studies have compared pca mrna transcripts in both cell and ev urine fractions. prostatic transcripts appear to be higher in ev fractions[69,80,87], but may have better diagnostic utility in the cell sediment[88] with a caveat that ~10% of cell sediments may not be analysable. hendriks et al. reported that pca3 transcripts were expressed significantly higher in pca patients than in non-pca patients in both the wholeurine and cell-sediment fractions but not in the ev fraction[87]. webb et al. compared rna yields from cell sediment and evs in 200 patients and found them to be highly variable with no apparent correlation. this observation suggests that examination of rna biomarkers in whole urine could be obfuscated by the unknown relative contribution of transcripts from the different urine fractions and suggests that separate analysis of the 2 fractions is to be recommended[80]. 4.2 cell-free dna in urine 164 siuj • volume 2, number 3 • may 2021 siuj.org review cell-free urine dna (cf dna) has been found both inside evs and bound outside ev membranes[79], the source of which has been hypothesised to be from apoptotic cells[79] and mitochondria[89]. cf dna yields from evs are low (18pg/ml urine[90]) but have been used to detect methylated gstp1 in men with pca that was not present in urine from men with bph[78]. casadio et al. used copy number analysis of c-myc, bcas1, and her2 by qrtpcr to distinguish pca from non-pca men with an auroc of 0.8, while copy number gains of ar, genomic deletions including pten, and tmprss2:erg fusion sequences have been detected in a small cohort of men with castrate-resistant cancer (n = 10)[91]. 4.3 supernatant proteins thousands of proteins on or encapsulated within evs have been identified by mass spectrometry analysis, with for example itga3 and itgb1 being linked to metastasis[92]. for a thorough review see recent papers by pang et al.[93] and wu et al.[94]. possibly the most thoroughly investigated urine protein biomarker is the transcriptional repressor en2[95]. unusually for a transcription factor, en2 can be secreted from normal and pca cells and then be internalised by other cells to effect transcriptional cha nges i n, for ex a mple, st roma[96]. en2 is involved with embryonic brain development and is inappropriately expressed in a range of cancers including bladder and prostate where en2 may regulate androgenreceptor activity in androgen-sensitive prostate cancer cells[97,98]. in a 2011 study by morgan et al., men with prostate cancer had a 10-fold higher level of en2 in their urine versus non-cancer controls, and en2 was identified in 66% of urine samples from biopsy-proven pca patients, some of whom had undetectable levels of serum psa[99]. this was in contrast to < 15% positivity in control groups (some of whom would have been expected to harbour occult prostate cancer), giving a specificity of 88.2% (auroc 0.8; p < 0.001). higher en2 levels correlated with advancing tumour stage, eg, pt3a versus pt2b (p = 0.027), positive margins (p = 0.008), increasing tumour volume[100,101], and subsequent diagnosis of pca in brca1/2 mutation carriers[102]. there have, however, been no large-scale en2 trials because there is no robust commercially available test for en2 protein in urine, which may be due to its very high net-charge causing non-specific attachment to some plastic surfaces (personal communication from h. pandha [co-author], 2019). indeed, a recent study looking at commercially available elisa kits for en2 found no significant diagnostic value for urinary en2 in pca patients[103]. novel approaches are in development, such as a graphene-based biosensor[104] and examining urine cfrna en2 transcripts[70]. 5. urine biomarkers and the dre a problem with urine is the inconsistency in the amounts of prostatic material between samples. the digital rectal examination (dre) of the prostate is one source of variation. when men present at a hospital, nerves very often mean that they would urinate before seeing the doctor and flush out all the prostatic secretions from the urethra. to replenish the prostatic biomarkers in the urethra, urine has usually been collected after a dre whereby the doctor would stroke the prostate with a finger pushing prostate secretions into the urethra shortly before urination. however, urine cfrna yields correlate with the clinician performing the dre, with 10-fold differences being found between clinicians, differences which were hypothesised as being linked to the clinician’s dre technique, finger length and prostate position[80]. a number of studies indicate that rna yields from urine collected in the clinic without a dre are less than a tenth of post-dre samples[69,80] and levels of prostate markers such as klk3 were also reduced approx imately 10 -fold[87]. however, studies by donovan et al. and mckiernan et al., using non-dre urine found aurocs of 0.8 and 0.77, respectively for detection of gs >7 using pca3 and erg combined with clinical parameters[82,83,105], strongly suggesting that non-dre urine has utility. webb et al. took this one step further[80]: their hypothesis centred on the finding by huggins et al. in 1945 that the prostate was constantly secreting[12], indicating that time since previous urination was key. urine samples collected at home from the first urination of the day were found to have rna yields comparable to samples collected postdre from the same patients in the clinic a week earlier. significantly, webb et al. found that detection of pca3 and tmprss2:erg by rt-pcr proved to be much more sensitive in these morning samples than in the post-dre samples. while this study was limited by the low number of men (n = 14) it does suggest that urine collections could be performed by mail, could enable mass screening, and could simplify disease monitoring of, for example, active surveillance cohorts. webb et al. also suggested that inter-sample consistency could be further improved by collecting a second urine sample at a fixed interval of 1-hour later. 165siuj.org siuj • volume 2, number 3 • may 2021 urine biomarkers for prostate cancer diagnosis and progression http://siuj.org conclusions the extensive interconnecting luminal structures of the prostate that carry prostatic secretions to the urethra make urine a valuable non-invasive resource to examine all parts of the prostate where pca arises. urine has proven utility in predicting disease load and monitoring disease progression, and its use could result in the development of a pca screening test. however, the translation of biomarkers from research to clinical practice is littered with failure[106]. the heterogeneity of pca and analysis of cohorts with different ranges of disease severity make data difficult to inter-compare. a further layer of obfuscation is provided by variabilities in sample collection, extraction and specifics of analysis compounded by inaccurate estimates of pca disease status by standard clinical means. however, urine diagnostics is a developing area, moving towards mu lti-omic biomarker integration for improved diagnostic 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high-grade prostate cancer in patients with prostate-specific antigen 2–10ng/ ml at initial biopsy. eur urol.2018 dec;74(6):731-738. doi: 10.1016/j. eururo.2018.08.019. epub 2018 sep 17. 106. locke wj, guanzon d, ma c, liew yj, duesing kr, fung kyc, et al. dna methylation cancer biomarkers: translation to the clinic. front genet. 2019;10:1150. 170 siuj • volume 2, number 3 • may 2021 siuj.org review book_2042_siuj-v03n6nov22_vf_print_.indb this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. 363siuj.org siuj • volume 3, number 6 • november 2022 editorial tackling kidney cancer through international consensus philippe e. spiess deputy editor, siuj director of publications and icud initiatives, société international d’urologie soc int urol j.2021;3(6):363–365 doi: 10.48083/mfmg8103 since 1981, the international consultation on urological diseases (icud) has been an important global initiative. conceived and promoted by the world health organization, it gathers international expertise, advancing fundamental knowledge and promoting evidence-based care across the spectrum of urologic conditions—most notably on thematic topics that are important to practicing urologists and that are not otherwise well covered in the scientific literature. over the past decade, the icud has participated in collaborative consultations with wuof and the siu, which is well established as a society dedicated to serving a global urological community. in this context, over the past few months, i have been proud to take on the role as the director of publications for the siu to oversee present and future icud initiatives. the current icud joint consultation, dedicated to kidney cancer, has been chaired by several international thought leaders on the subject (professors toni choueiri, grant stewart, and robert uzzo), with sections dedicated to epidemiology (including screening), diagnostic imaging, management of locally advanced disease, therapies in refractory metastatic disease, and management of toxicity and side effects[1]. in this editorial, i would like to highlight some of the exceptional articles within this issue of the siuj, which is dedicated to summarizing the findings of this most recent icud initiative—findings our readers will be able to integrate into their clinical practice. the article by dr sabrina rossi et al. on the epidemiology of renal cell carcinoma provides an in-depth review of the current incidence, prevalence, and mortality of kidney cancer across the globe[2]. the authors also draw attention to the increasing incidence of this malignancy in recent years, which can be attributed to most cases being incidentally detected on abdominal axial imaging studies obtained for often unrelated reasons. as a result, many of the suspicious renal masses presently detected are defined as small renal masses (≤ 3 centimeters), often with a low metastatic potential, for which active surveillance may represent an appropriate therapeutic option, most notably in elderly patients and/or those with multiple life-threatening medical comorbidities. the authors touch on the risk factors predisposing to the development of kidney cancer, and although for most individual patients we can’t specifically pinpoint the underlying causes for carcinogenesis, these are likely to include the increasing prevalence of obesity, exposure to insecticides/pollutants, and genetic predisposition to kidney cancer among a small subset of patients. the authors provide an intriguing discussion on potential screening strategies for kidney cancer, most notably in higher risk patient populations (those who are over 65 years, smokers, morbidly obese, and/or in families with a high preponderance of cases of an established genetic condition such as von hippel-lindau). ongoing trials including the consideration of screening for both thoracic aneurysms and kidney cancer should be followed carefully as they incorporate ultrasound imaging, which is non-invasive and cost-effective, but remains operator dependent. dr jodi maranchie and colleagues nicely detail the various known hereditary kidney cancer syndromes including von hippel-lindau, familial papillary, birt-hogg-dubé, as well as a number of others that are rapidly becoming recognized conditions[3]. there is no question there is increasing awareness about these conditions and the multiorgan clinical manifestations they may entail, and that urologists and other healthcare professionals must be aware of, most notably in patients with a family history of kidney cancer in 1 or more first-degree relatives and/or in patients less than 40 years of age with a diagnosis of kidney cancer. 364 siuj • volume 3, number 6 • november 2022 siuj.org editorial in a comprehensive review, dr vinay duddalwar and colleagues provide an excellent synopsis of the imaging modalities readily available in assessing a renal mass to determine whether it can be accurately characterized as suspicious for an underlying malignancy[4]. although ct or mri axial imaging with and without iv contrast remain the benchmark diagnostic imaging modalities for renal cell carcinoma in clinical practice, there are some exciting developments in renal contrast-enhanced ultrasonography, elastography, and pet-ct imaging that are rapidly gaining ground. artificial intelligence and radiomics likely represent the new horizons in diagnostics in not only accurately characterizing in a consistent and potentially automated manner the suspicion that a renal mass may represent an underlying malignancy but also potentially determining its specific tumor histology and characteristics, as well as attributable prognosis. in their article, dr mohammed ali et al. summarize the current state of knowledge relating to renal ablative therapies in the management of small renal masses (typically ≤ 3 cm)[5]. they provide a concise overview of the indications for renal ablation, typically conducted in an image-guided manner percutaneously rather than laparoscopically, because of its less invasive nature and non-inferior local therapeutic outcomes. a number of ablative energy modalities are readily available, including radiofrequency, cryoablation, and microwave. all have their merits and drawbacks but cryoablation remains the most favored because of its high success rate in terms of effective ablation, particularly if a double freeze–thaw cycle is used, and the procedure is completed by an experienced clinician (most commonly an interventional radiologist at a referral center). in a nicely detailed review on the surgical management of locally advanced renal cell carcinoma (most notably ivc tumor thrombi) dr vsevolod matveev et al. discuss important surgical tips and tricks in tackling such complex surgical cases, including the emerging role of pre-surgical systemic therapy in attempting to regress the burden of disease or allow acute medical conditions to be optimized before proceeding with surgical care[6]. dr naomi haas and colleagues present a thoughtful discussion on the rapidly evolving role of neoadjuvant and adjuvant therapy for renal cell carcinoma[7]. although neoadjuvant therapy can provide some local tumor burden reduction, making surgical resection in theory potentially less morbid and/or in certain instances rendering primary tumors more amenable to nephron-sparing surgery, individual responses are harder to predict and must be considered on a case-bycase basis—and in most instances should be considered as part of a clinical trial. in terms of adjuvant therapy, keynote 564 was truly pioneering in establishing the potential benefit of adjuvant pembrolizumab with respect to disease-free endpoints (overall survival to be reported) in patients with high-risk localized tumors (or following isolated site of metastatectomy < 1 year of prior nephrectomy) post-resection[8]. clearly, this has been paradigm-shifting, most notably as the prior adjuvant therapy studies using targeted therapies (assure and s-trac) were equivocal in terms of the benefits they rendered. in a critically important review, dr lisa pickering and colleagues provide a detailed summary of the acute and chronic (minor and major) toxicities of the rapidly evolving systemic therapeutic landscape of advanced renal cell carcinoma[9]. this includes a characterization of the immune-related adverse events, which although less frequent, can be life-threatening and occasionally more difficult to predict. the authors note that the emergence of triple agent combinations using a number of checkpoint inhibitors and/or targeted therapies offers an exciting new opportunity to improve patient outcomes but is fraught with apprehension in terms of the risk and severity of adverse events. although our experience with such triple agent combinations is early, it remains quite promising; a meticulous and systematic approach to screening and treating these patients on triple agent combinations is of pivotal importance. in conclusion, we are excited to share these important contributions with our readers. we deeply appreciate— and congratulate—all the chairs and the contributors to this 2nd wuof/siu-icud collaboration focused on renal cell carcinoma. it provides an important resource for all global healthcare professionals caring for kidney cancer patients. 365siuj.org siuj • volume 3, number 6 • november 2022 tackling kidney cancer through international consensus references 1. klotz l, stewart gd, uzzo rg, choueri tk, eds. 2nd wuof/siu icud on kidney cancer. world urologic oncology federation/société internationale d’urologie–international consultation on urological diseases;2022. 2. rossi s, tanaka h, usher-smith ja, bernhard j-c, fujii y, stewart gd. 20 22 w uof/siu-international consultation on urologic diseases: kidney cancer screening and epidemiology. soc int urol j.2022;3(6): doi: 10.48083/ xbcx3386 3. maranchie j, such bm, bratslavsky g, maher er. 2022 wuof/ siu-international consultation on urologic diseases: hereditar y renal cell carcinoma syndromes. soc int urol j.2022;3(6) doi: 10.48083/cbto5325 4. duddalwar va, lee w-k, lindenberg ml, gonzalez em, choyke p, king kg, vikram r. 2022 wuof/siu-international consultation on urologic diseases: imaging of renal cell carcinoma. soc int urol j.2022;3(6): doi: 10.48083/sdmv1045 5. a li m, ruiz va , p su t k a sp, l iu d, siv a s. 2 0 2 2 w uof/ siu-international consultation on urologic diseases: ablative therapies for localized primary renal cell carcinoma. soc int urol j.2022;3(6): doi: 10.48083/ueml5802 6. matveev v, psutka sp, stewart gd, bratslavsky g, abel ej. 2022 w uof/siu-international consultation on urologic diseases: management of locally advanced renal cell carcinoma. soc int urol j.2022;3(6): doi: 10.48083/egwh6536 7. haas n, shevach j, davis id, eisen t, gross-goupil m, kapoor a, et al. 2022 wuof/siu-international consultation on urologic diseases: neoadjuvant and adjuvant therapy for renal cell carcinoma. soc int urol j.2022;3(6): doi: 10.48083/ vsqg7437 8. choueiri tk, tomczak p, park sh, venugopal b, ferguson t, chang y-het al. adjuvant pembrolizumab af ter nephrectomy in renalcell carcinoma. n engl j med.2021;385(8):683-694. doi: 10.1056/ nejmoa2106391 9. young k, schmit t am, mukherji d, spain l, schmidinger m, pickering lm. 2022 w uof/siu-international consultation on urologic diseases: management of toxicity from rcc therapies. soc int urol j.2022;3(6): doi: 10.48083/syab9165 this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information renal cancer, immunotherapy, systematic review none declared. received on may 9, 2022 accepted on june 12, 2022 this article has been peer reviewed. soc int urol j. 2022;3(5):341–352 doi: 10.48083/ wixm2804 adjuvant systemic treatment for renal cancer after surgery: a network meta-analysis niranjan j. sathianathen,1,2 marc a. furrer,1 christopher j. weight,3 declan g. murphy,4 shilpa gupta,5 nathan lawrentschuk1,2,4 1 department of urology, royal melbourne hospital, parkville, victoria, australia 2 department of surgery, university of melbourne, parkville, victoria, australia 3 department of urology, cleveland clinic, cleveland, united states 4 department of uro-oncology, peter maccallum cancer centre, parkville, victoria, australia 5department of hematology and oncology, taussig cancer institute, cleveland clinic, cleveland, united states abstract background approximately 15% to 20% of patients will experience disease recurrence following surgical removal of renal cell carcinoma. a range of pharmacological agents is prescribed for metastatic renal cell carcinoma, but there are trials testing whether these have an earlier role in the adjuvant setting. we aim to assess the efficacy of adjuvant systemic treatment following surgery in patients with renal cell carcinoma and to determine the most effective treatment. methods the protocol for this review was published in prospero (crd42021281588). we searched multiple databases up to august 2021. we included only randomized trials of patients with renal cell carcinoma that had been completely resected. we included patients with locoregional nodal disease if it was surgically removed, and excluded all cases of metastatic disease. we included all adjuvant systemic therapies that were commenced within 90 days of renal surgery. a network meta-analysis was performed using a frequentist approach. results a total of 13 studies with 8103 patients were included for analysis. only pembrolizumab (hr 0.74; 95%ci 0.57 to 0.96) and pazopanib (hr 0.80; 95%ci 0.68 to 0.95) improved disease-free survival compared with observation. these 2 treatments were the 2 highest ranked comparisons with a p-score of 0.87 and 0.80. no agent improved overall survival. all agents increased the risk of severe adverse events compared with observation. conclusions pembrolizumab and pazopanib were the only 2 adjuvant agents that improved time to disease recurrence compared with observation, with the former likely being the more efficacious. none of the treatments improved overall survival and almost all increased severe adverse events. introduction there has been an increased incidence of renal cell carcinoma, especially in developed countries[1]. most of these cancers are localized to the kidney at the time of presentation and are curable by surgery. however, approximately 20% of patients will experience disease recurrence following surgery[2]. overall prognosis for advanced disease is poor with a median survival time of 21 months after recurrence[3]. 341siuj.org siuj • volume 3, number 5 • september 2022 review mailto:niranjan19%40gmail.com?subject=siuj http://siuj.org a range of pharmacological agents has been used to treat metastatic renal cell carcinoma (mrcc) with varying efficacy, including chemotherapy, immunotherapy, tyrosine kinase inhibitors, monoclonal antibody against circulating vascular endothelial growth factor, and mtor inhibitors. a network meta-analysis found that combination immunotherapy likely represents the current best available treatment[4]. the european association of urology guidelines support this by suggesting that immunotherapy (including combinations) should be used as first-line treatment in this setting[5]. as immunotherapy has come to the forefront of mrcc management, there has been increasing interest in employing these treatments at earlier stages of disease. many of the aforementioned treatments have been trialled in the adjuvant setting with varying results, and there are recent reports of use of adjuvant immunotherapy. however, these trials have primarily been conducted using observation or placebo as a comparator arm, which has not permitted direct comparisons of active agents. we therefore aimed to perform a systematic review and network-meta-analysis of systemic agents used in the adjuvant setting after surgery for kidney cancer. methods we registered the protocol of this systematic review in prospero (crd42021281588). we searched multiple databases (medline , embase , sciencedirect, cochrane libraries, hta database, and web of science) up to 20 august 2021, with a range of keywords associated with “renal carcinoma” and “adjuvant therapy.” we also searched the abstracts from leading urological and oncological meetings, including those of the european association of urology, american urological association, american society of clinical oncology, and european society of medical oncology in the last 5 years. we also searched trial registries such as clinicaltrials.gov. we did not place any restriction on language or date of publication. we included only randomized studies. our population of interest was patients with rcc that had been completely resected. surgical treatment included both radical and partial nephrectomy. we included patients with locoregional nodal disease if they underwent surgical removal at the time of kidney extirpation, ie, n+ cases were eligible. we included all histological subtypes of renal carcinoma. we excluded all patients with distant metastatic disease even if they had undergone metastectomy, ie, m1 cases were not eligible for inclusion. we included all adjuvant systematic therapies that were commenced within 90 days of renal surgery. we excluded autologous vaccine-based treatments because they are not widely available in clinical practice. we did not include adjuvant radiotherapy. control arms eligible for analysis were observation, placebo, and active treatments, although we did not find any studies with the last. following our search, titles and abstracts were screened by 2 independent authors according to the inclusion/exclusion criteria. full texts of relevant abstracts were then reviewed by 2 independent authors to confirm eligibility. any disagreements were resolved by a third senior author. data were then extracted independently. the efficacy outcomes of interest were disease-free survival (dfs), defined as time from randomization to disease recurrence (local or distant) and/or death; and overall survival (os), defined as time from randomization to death from any cause. the safety outcome of interest was severe adverse events defined as incidence of grade iii to v events per patient. we also intended to perform subgroup analysis on the efficacy outcome according to histological subtype (clear-cell versus other subtypes) and nodal disease (no nodal disease [n0] versus nodal disease [n1]). statistical analysis we first performed traditional pairwise meta-analysis of the included studies (data not shown). to do this, we applied the model proposed by woods et al. by extracting hazard rates for dfs and os and number of severe adverse events from each of the included studies[6]. we then performed a network meta-analysis of all included trials which enables indirect comparisons of treatments based on a common comparator arm. we adopted a frequentist approach and performed a fixed-effect consistency network meta-analysis. as a sensitivity analysis, we used the same approach with a random-effects model. we used p-scores that estimate the extent that one treatment is superior to another, averaged over all competing treatments, to determine which agent is the most efficacious. all analyses were performed using rjags and r (r foundation for statistical computing, vienna, austria) version 3.4. risk of bias was performed according to the cochrane framework[7]. results our search retrieved 4088 abstracts of which 41 proceeded to full text review. after inclusion/exclusion criteria were applied, 13 studies were eligible and included for analysis (online supplementary figure 1). the details of included studies are shown in table 1. 342 siuj • volume 3, number 5 • september 2022 siuj.org review http://siuj.org http://siuj.org the included trials tested a range of adjuvant treatments: axitinib[8], girentuximab[9], interferon-alpha[10–14], interleukin-2[10, 11], pazopanib[15], pembrolizumab[16], sorafenib[17,18], sunitinib[17,19], and thalidomide[20]. two of the trials tested combination adjuvant therapies of interleukin-2+interferon-alpha[10] and interleukin2+interferon-alpha+5-f lurouracil[11]. the protect trial that compared pazopanib with placebo included patients who received either 600 mg or 800 mg, and we included both in this analysis[15]. the trials were overall of moderate quality, and the detailed risk of bias classification can be found in online supplementary table 1. we also found a further 6 trials in progress (table 2). disease-free survival all eligible studies reported on dfs and were included in this analysis of 8103 patients. only the 2016 study by haas et al. reported on direct comparison between active agents[17]. the forest plot of hrs compared with control arm for each agent is shown in figure 1a. only pembrolizumab (hr 0.74; 95% ci 0.57 to 0.96) and pazopanib (hr 0.80; 95% ci 0.68 to 0.95) prolonged dfs compared with observation. these 2 treatments were the figure 1. treatment versus control for (a) dfs and (b) os a b table 1. characteristics of included studies author/ year adjuvant treatment number of participants inclusion criteria number of participants with ≤t2 disease, n number of participants with clearcell rcc number of participants with nodal disease gross-goupil et al. 2018[8] axitinib: 5 mg bd up to 3 years 724 • ≥pt2 and/or n+ • any fuhrman grade • ecog performance status 0/1 80 nr 36 chamie et al. 2017[9] girentuximab: iv 50mg week 1 followed by iv 20 mg week 2–24 864 histologically confirmed ccrcc pt3/pt4nx/n0m0 or ptanyn+m0 or pt1b/pt2nx/ n0m0 with nuclear grade 3 or greater 139 834 65 passalacqua et al. 2014[10] il-2 + ifn-a: il-2 sc 1 mil iu/m2 5 days per week for 4 weeks; inf-a sc 1.8 mil iu/m2 on day 3 and 5 each week. cycles repeated every 4 months for 2 years and 6 months for 3 years 310 partial or radical nephrectomy with no residual disease and free surgical margins: pt2-3b pn0-3 m0 182 254 12 nr: not reported , cont’d continued on page 344 343siuj.org siuj • volume 3, number 5 • september 2022 adjuvant systemic treatment for renal cancer after surgery: a network meta-analysis http://siuj.org http://siuj.org http://siuj.org table 1. characteristics of included studies author/ year adjuvant treatment number of participants inclusion criteria number of participants with ≤t2 disease, n number of participants with clearcell rcc number of participants with nodal disease aitchison et al.2014[11] il-2 + ifn-a + 5-fu: il-2 sc 20 mil iu/m2 on days 3-5 in weeks 1 and 4 and sc 5 mil iu/m2 on days 1, 3 and 5 in weeks 2 and 3; ifn-a sc 6 mil iu/m2 in weeks 2 and 3 and increasing to sc 9 mil iu/m2 in weeks 5-8 given on days 1, 3 and 5; 5-fu iv 750mg/m2 weekly in weeks 5-8 309 histologically proven stage t3b, t3c, t4 tumour or any pt stage and nodal status pn1 or 2, or any pt stage clinical n+ disease removed and had no metastatic disease or macroscopic residual disease as confirmed within 2–4 weeks prior to randomization by ct or mri plus cxr 65 nr 49 messing et al. 2003[12] interferon α-nl: sc 5 days every 3 weeks (3 mil iu/m2 day 1, 5 mil iu/m2 day 2, 20 mil iu/m2 day 3-5) up to 12 cycles 283 unilateral, locally advanced (pt3-4a) and/ or node-positive renal cancer following radical nephrectomy no disseminated disease 36 176 44 pizzocaro et al.2001[13] interferon α: im 6 mil iu 3 times per week for 6 months 247 radical nephrectomy with suggested unilateral paraaortic nodal dissection patients with pathologic stages ii and iii rcc (1987 tumour-node-metastasis categories t3an0m0 and t3bn0m0 or t2/3n1-3m0) were eligible for the study 16 nr 43 hinotsu et al.2013[14] interferon α: im 3-6 mil iu 3 times per week for 1 year 107 histopathological diagnosis of renal cell carcinoma resection of the primary tumour by nephrectomy, for which open or laparoscopic surgery could have been selected and lymph node dissection was possible no metastatic disease 40 82 5 nr: not reported , cont’d continued on page 345 344 siuj • volume 3, number 5 • september 2022 siuj.org review http://siuj.org table 1. characteristics of included studies author/ year adjuvant treatment number of participants inclusion criteria number of participants with ≤t2 disease, n number of participants with clearcell rcc number of participants with nodal disease motzer et al.2017[15] pazopanib: 600 mg or 800 mg once daily 1538 resected non-metastatic (m0) clear-cell or predominant clear-cell rcc histology within the following tnm classification and fuhrman grades: pt2g34n0, pt3-t4 ganyn0, or ptanyganyn1 235 1057 90 choueiri et al. 2021[16] pembrolizumab: iv 200 mg once every 3 weeks up to 17 cycles 994 histologically confirmed locoregional renal cell carcinoma with a clearcell component that is at high risk of recurrence (ie, tumour stage 2 with nuclear grade 4 or sarcomatoid differentiation, tumour stage 3 or higher, regional lymph node metastasis, or stage m1 with ned) surgery (partial or radical nephrectomy or metastasectomy) with negative surgical margins in those with m1 ned status, m1 disease was present in addition to the primary tumour at diagnosis, and metastases had to be completely resected at the time of nephrectomy or within 1 year after nephrectomy 86 994 62 eisen et al. 2020[18] sorafenib: 400 mg bd po 1711 histologically confirmed rcc no evidence of residual macroscopic disease on postoperative ct scan after resection of rcc 604 1455 74 nr: not reported , cont’d continued on page 346 345siuj.org siuj • volume 3, number 5 • september 2022 adjuvant systemic treatment for renal cancer after surgery: a network meta-analysis http://siuj.org http://siuj.org , cont’d table 1. characteristics of included studies author/ year adjuvant treatment number of participants inclusion criteria number of participants with ≤t2 disease, n number of participants with clearcell rcc number of participants with nodal disease haas et al. 2016[17] sunitinib: 50 mg po daily for first 28 days of each 6-week cycle 1943 histologically proven, completely resected highrisk clear-cell or non-clearcell rcc within 12 weeks of removal of the primary tumour. high-risk features: pt1b g3–4 n0 (or pnx where clinically n0) m0 to t(any) g(any) n + (fully resected) m0 sorafenib: 400 mg bd po daily nr 1541 nr ravaud et al. 2016[19] sunitinib: 50 mg po daily 4 weeks on, 2 weeks off schedule for 1 year 615 locoregional rcc (tumour stage 3 or higher, regional lymph node metastasis, or both) histologic confirmation of clear-cell rcc the absence of macroscopic residual or metastatic disease after nephrectomy, as confirmed on blinded independent central review of ct images nr 615 49 margulis et al. 2009[20] thalidomide: 100 mg/day for 2 weeks then 200 mg/day for 2 weeks followed by 300 mg/day 46 completely resected locally advanced high-risk rcc, as defined by one of the following criteria: pt2 (fuhrman grade 3 or 4), pt3a-c, t4, or n1–2 disease resected to no evidence of residual disease all tumour subtypes were eligible 7 34 13 nr: not reported 346 siuj • volume 3, number 5 • september 2022 siuj.org review http://siuj.org table 2. trials in progress trial name/ number interventions inclusion criteria current progress estimated completion date everest nct01120249 everolimus histologically or cytologically confirmed renal cell carcinoma considered pathologically either intermediate high-risk or very high-risk disease no history of distant metastases have undergone a full surgical resection (radical nephrectomy or partial nephrectomy) including removal of all clinically positive nodes no evidence of residual or metastatic renal cell cancer on ct scan of the chest, abdomen, and pelvis (all with oral and iv contrast) performed after nephrectomy active, not recruiting october 2021 sparc-1 nct04028245 spartalizumab and canakinumab histologically confirmed clear-cell or predominantly clear-cell rcc non-metastatic (localized) rcc that is clinical stage t2 and above, or clinical n1 disease with any t stage scheduled to undergo either radical or partial nephrectomy recruiting december 2022 prosper nct03055013 nivolumab – neo-adjuvant and adjuvant patients must have a renal mass consistent with a clinical stage ≥t2nx renal cell carcinoma (rcc) or tanyn+ rcc for which radical or partial nephrectomy is planned patients must have no clinical or radiological evidence of distant metastases (m0) unless the presumed m1 disease is planned to be resected/definitively treated (eg, thermal ablation, stereotactic radiation) active, not recruiting november 2023 immotion010 nct03024996 atezolizumab pathologically confirmed rcc with a component of either clear-cell histology or sarcomatoid histology that has not been previously treated in the adjuvant or neoadjuvant setting and classified as being at high risk of rcc recurrence radical or partial nephrectomy with lymphadenectomy in select participants absence of residual disease and absence of metastasis, as confirmed by a negative baseline ct of the pelvis, abdomen, and chest absence of brain metastasis, as confirmed by a negative ct with contrast or mri scan of the brain active, not recruiting february 2024 nr: not reported continued on page 348 347siuj.org siuj • volume 3, number 5 • september 2022 adjuvant systemic treatment for renal cancer after surgery: a network meta-analysis http://siuj.org table 2. trials in progress trial name/ number interventions inclusion criteria current progress estimated completion date checkmate 914 nct03138512 nivolumab nivolumab + ipilimumab kidney tumour has been completely resected with negative surgical margins obtained pathologic tnm staging meeting one of the following: pt2a, g3 or g4, n0 m0; pt2b, g any, n0 m0; pt3, (a, b, c), g any, n0 m0; pt4, g any, n0 m0; pt any, g any, n1 m0 post-nephrectomy tumour shows rcc with a predominantly clear-cell histology, including participants with sarcomatoid features participants must have no clinical or radiological evidence of macroscopic residual disease or distant metastases after nephrectomy recruiting july 2025 rampart nct03288532 durvalumab durvalumab + tremelimumab histologically proven rcc (all cell types of rcc are eligible, except for pure oncocytoma, collecting duct, medullary and transitional cell cancer [tcc]); no evidence of residual macroscopic disease on postoperative ct scan after resection of rcc patients with microscopically positive resection margins after radical nephrectomy at the nephrectomy bed, renal vein, or inferior vena cava are eligible provided the postoperative ct scan shows no evidence of residual macroscopic disease recruiting december 2034 nr: not reported 2 highest ranked comparisons with a p-score of 0.87 and 0.80, respectively. thalidomide was the lowest ranked treatment with a p-score of 0.03. interferon-alpha was inferior to axitinib, pazopanib, pembrolizumab and sunitinib. comparisons of all treatments are shown in table 3. these findings were the same in the sensitivity analysis when using a random-effects model (data not shown). overall survival the os analysis included 7063 patients from all the studies from above except margulis et al. (thalidomide, 2009)[20] and choueiri et al. (pembrolizumab, 2021) [16]. the forest plot of hrs compared with the control arm for each agent is shown in figure 1b. none of the agents demonstrated a survival benefit compared with observation. pazopanib was the highest ranked treatment with a p-score of 0.83. comparisons of all treatments are shown in online supplementary table 2. there was no difference between any of the treatment comparisons. these findings were the same in the sensitivity analysis when using a random-effects model (data not shown). severe adverse events data from 8 trials using the following interventions were included in the safety analysis: axitinib, girentuximab, interferon-alpha, pazopanib, pembrolizumab, sorafenib, su n it i n ib, a nd t ha l idom ide[8,9,12 ,15 –17,19, 20]. the forest plots of ors compared with control are shown in online supplementary figure 2. all of the active treatments except girentuximab significantly increased the likelihood of severe adverse events compared with observation. these findings were the same in the sensitivity analysis when using a random-effects model. subgroup analyses there were insufficient data to perform a network metaanalysis on the planned subgroups. , cont’d 348 siuj • volume 3, number 5 • september 2022 siuj.org review http://siuj.org http://siuj.org http://siuj.org http://siuj.org discussion ou r net work meta-a na lysis repor t fou nd t hat pembrolizumab is likely the most efficacious adjuvant agent in prolonging time to disease recurrence compared with other tyrosine k inase inhibitors, monoclonal antibody against circulating vascular endothelial growth factor, and/or chemotherapies. the only other therapy that was shown to improve dfs compared with observation was pazopanib. however, the absolute difference in recurrence-free survival at 3 years was only 3% between pazopanib and placebo[15]. we used data from patients who received both 600 mg and 800 mg where there were discrepancies in the results related to dose. although patients receiving the lower dose did not experience improved dfs, those receiving the higher dose were noted to have a prolonged diseasefree survival. therefore, it is likely that the benefit of pazopanib 800 mg is greater than the overall estimates in this review. it should also be noted that the sunitinib did show an improvement in dfs in the s-trac trial, although the estimates from this meta-analysis were not significant when including the ecog trial. the results from this network meta-analysis are consistent with those of previously published meta-analyses on the topic[21, 22]. despite these positive findings in delaying disease recurrence, none of the treatments improved overall survival. we acknowledge that the overall survival data have not matured for most of the recent studies and that there may still be a benefit with adjuvant therapy. importantly, there was an increased risk of severe adverse events with adjuvant treatment compared with observation. it should be considered that there are several factors that impact the use of adjuvant treatment and choice of agent. this review represented a population of patients with locoregional renal cancer who had undergone surgery, but there are sub-populations within this group in whom treatment effect may differ. for example, we believed there may have been differences based on histological subtype and nodal status but were unable to perform the preplanned subgroup analyses due to a lack of data. the polar-01 trial reported that patients with n0 disease had better outcomes with combination il-2 and ifn-alpha treatment than did those with n+ disease[10]. in contrast, the atlas trial demonstrated that patients with highest risk (pt3 with grade ≥ 3 or pt4 and/or n+, any t, any grade) benefitted with axitinib treatment compared with those with low risk (pt2 or pt3 with grade ≤ 2) who had no difference in outcomes with axitinib[8]. the wider literature, especially in the metastatic setting, highlights the increasing use of molecular biomarkers to tailor treatment choices[23]. this will increase in importance as immunotherapies are used more in this setting. therefore, patient selection is key in determining the benefit of adjuvant therapy and the choice of agent. the findings of this meta-analysis should be contextualised within its limitations. as mentioned above, there is heterogeneity within the populations of the included studies, and we were unable to perform the pre-planned subgroup analyses. there were also individual study limitations, especially with respect to blinding, that may have introduced bias into the estimates. additionally, we did not assess patient-reported outcomes, which is critical in determining whether adjuvant treatment improves quality in life[24]. future studies will need to assess the cost-effectiveness of these treatments because immunotherapies are expensive and thus may not be cost-effective[25]. health economics studies of advanced rcc have reported that a significant decrease in the cost of immunotherapy is required for it to be cost-effective at generally accepted thresholds[26]. it is likely that these would be generalizable to the use of immunotherapy in the adjuvant setting as the absolute benefits of treatment are small, albeit statistically significant, and come at significant cost. furthermore, this study will need to be updated following the publication of trials in progress. conclusions pembrolizumab and pazopanib were the only 2 adjuvant agents that improved time to disease recurrence compared with observation, with the former likely being the more efficacious. none of the treatments improved overall survival, and almost all increased severe adverse events. while it is promising to see these agents show efficacy in this setting, the duration and cost of treatment also need to be considered when determining utility. 349siuj.org siuj • volume 3, number 5 • september 2022 adjuvant systemic treatment for renal cancer after surgery: a network meta-analysis http://siuj.org table 3. matrix comparing hazard ratios [confidence intervals] for dfs between all therapies axitinib 1.15 [0.87; 1.52] 1.11 [0.79; 1.57] 0.97 [0.57; 1.63] 0.97 [0.65; 1.44] 1.45 [1.00; 2.10] 0.92 [0.67; 1.27] 0.85 [0.58; 1.24] 1.12 [0.82; 1.53] 1.07 [0.78; 1.47] 2.69 [1.04; 7.01] 0.87 [0.66; 1.15] control 0.97 [0.79; 1.19] 0.84 [0.54; 1.31] 0.84 [0.63; 1.12] 1.26 [0.99; 1.61] 0.80 [0.68; 0.95] 0.74 [0.57; 0.96] 0.97 [0.84; 1.13] 0.93 [0.80; 1.09] 2.34 [0.94; 5.86] 0.90 [0.64; 1.26] 1.03 [0.84; 1.26] girentuximab 0.87 [0.53; 1.41] 0.87 [0.61; 1.23] 1.30 [0.95; 1.79] 0.82 [0.64; 1.07] 0.76 [0.55; 1.06] 1.00 [0.78; 1.29] 0.96 [0.74; 1.24] 2.42 [0.95; 6.17] 1.04 [ 0.61; 1.75] 1.19 [0.76; 1.85] 1.15 [0.71; 1.88] il-2 + interferon 1.00 [0.59; 1.70] 1.50 [0.90; 2.49] 0.95 [0.59; 1.53] 0.88 [0.53; 1.47] 1.16 [0.73; 1.85] 1.11 [0.69; 1.77] 2.79 [1.01; 7.72] 1.04 [0.70; 1.54] 1.19 [0.89; 1.59] 1.15 [0.81; 1.64] 1.00 [0.59; 1.70] il-2 + interferon +5-fu 1.50 [1.03; 2.19] 0.95 [0.68; 1.33] 0.88 [0.60; 1.30] 1.16 [0.84; 1.60] 1.11 [0.80; 1.54] 2.79 [1.07; 7.28] 0.69 [0.48; 1.00] 0.79 [0.62; 1.01] 0.77 [0.56; 1.06] 0.67 [0.40; 1.11] 0.67 [0.46; 0.97] interferon-alpha 0.63 [0.47; 0.85] 0.59 [0.41; 0.84] 0.77 [0.58; 1.03] 0.74 [0.55; 0.99] 1.86 [0.72; 4.80] 1.09 [0.79; 1.50] 1.25 [1.06; 1.48] 1.21 [0.93; 1.57] 1.05 [0.65; 1.69] 1.05 [0.75; 1.46] 1.58 [1.17; 2.12] pazopanib 0.92 [0.68; 1.26] 1.22 [0.98; 1.52] 1.16 [0.93; 1.46] 2.93 [1.16; 7.43] 1.18 [0.80; 1.72] 1.35 [1.04; 1.75] 1.31 [0.94; 1.82] 1.14 [0.68; 1.90] 1.14 [0.77; 1.67] 1.70 [1.19; 2.44] 1.08 [0.79; 1.47] pembrolizumab 1.32 [0.98; 1.77] 1.26 [0.93; 1.71] 3.17 [1.22; 8.21] 0.89 [0.65; 1.22] 1.03 [0.89; 1.19] 1.00 [0.78; 1.28] 0.86 [0.54; 1.37] 0.86 [0.62; 1.19] 1.29 [0.97; 1.72] 0.82 [0.66; 1.02] 0.76 [0.56; 1.02] sorafenib 0.96 [0.77; 1.18] 2.41 [0.95; 6.08] 0.93 [0.68; 1.28] 1.07 [0.92; 1.26] 1.04 [0.81; 1.34] 0.90 [0.56; 1.44] 0.90 [0.65; 1.25] 1.35 [1.01; 1.81] 0.86 [0.68; 1.08] 0.79 [0.59; 1.08] 1.05 [0.85; 1.29] sunitinib 2.52 [0.99; 6.37] 0.37 [0.14; 0.97] 0.43 [0.17; 1.07] 0.41 [0.16; 1.06] 0.36 [0.13; 0.99] 0.36 [0.14; 0.94] 0.54 [0.21; 1.39] 0.34 [0.13; 0.87] 0.32 [0.12; 0.82] 0.42 [0.16; 1.05] 0.40 [0.16; 1.01] thalidomide light blue shading shows superiority, and dark blue shading shows inferiority of the row compared with the column. references 1. capitanio u, bensalah k, bex a, boorjian sa, bray f, coleman j, et al. epidemiology of renal cell carcinoma. eur urol.2019;75(1):74-84. 2. cindolo l, patard jj, chiodini p, schips l, ficarra v, tostain j, et al. comparison of predictive accuracy of four prognostic models for nonmetastatic renal cell carcinoma after nephrectomy: a multicenter european study. cancer.2005;104(7):1362-1371. 3. eggener se, yossepowitch o, pettus ja, snyder me, motzer rj, russo p. renal cell carcinoma recurrence after nephrectomy for localized disease: predicting survival from time of recurrence. j clin oncol.2006;24(19):3101-3106. 4. riaz ib, he h, ryu aj, siddiqi r, naqvi saa, yao y, et al. a living, interactive systematic review and network meta-analysis of first-line treatment of metastatic renal cell carcinoma. eur urol.2021. 5. ljungberg b, albiges l, abu-ghanem y, bensalah k, dabestani s, fernández-pello s, et al. european association of urology guidelines on renal cell carcinoma: the 2019 update. eur urol.2019;75(5):799-810. 6. woods bs, hawkins n, scott da. network meta-analysis on the log-hazard scale, combining count and hazard ratio statistics accounting for multi-arm trials: a tutorial. bmc med res methodol. 2010;10:54. 7. higgins jp, savović j, page mj, elbers rg, sterne ja. assessing risk of bias in a randomized trial. cochrane handbook for systematic reviews of interventions.2019:205-228. 8. gross-goupil m, kwon tg, eto m, ye d, miyake h, seo si, et al. a xitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase iii, randomized atlas trial. ann oncol.2018;29(12):2371-2378. 350 siuj • volume 3, number 5 • september 2022 siuj.org review http://siuj.org 9. chamie k, donin nm, klöpfer p, bevan p, fall b, wilhelm o, et al. adjuvant weekly girentuximab following nephrectomy for high-risk renal cell carcinoma: the ariser randomized clinical trial. jama oncol.2017;3(7):913-920. 10. passalacqua r, caminiti c, buti s, porta c, camisa r, braglia l, et al. adjuvant low-dose interleukin-2 (il-2) plus interferon-α (ifn-α) in operable renal cell carcinoma (rcc): a phase iii, randomized, multicentre trial of the italian oncology group for clinical research (goirc). j immunother.2014;37(9):440-447. 11. aitchison m, bray ca, van poppel h, sylvester r, graham j, innes c, et al. adjuvant 5-flurouracil, alpha-interferon and interleukin-2 versus observation in patients at high risk of recurrence after nephrectomy for renal cell carcinoma: results of a phase iii randomised european organisation for research and treatment of cancer (genito-urinary cancers group)/national cancer research institute trial. eur j cancer.2014;50(1):70-77. 12. messing em, manola j, wilding g, propert k, fleischmann j, crawford ed, et al. phase iii study of interferon alfa-nl as adjuvant treatment for resectable renal cell carcinoma: an eastern cooperative oncology group/intergroup trial. j clin oncol.2003;21(7):1214-1222. 13. pizzocaro g, piva l, colavita m, ferri s, artusi r, boracchi p, et al. interferon adjuvant to radical nephrectomy in robson stages ii and iii renal cell carcinoma: a multicentric randomized study. j clin oncol.2001;19(2):425-431. 14. hinotsu s, kawai k, ozono s, tsushima t, tokuda n, nomata k, et al. randomized controlled study of natural interferon α as adjuvant treatment for stage ii or iii renal cell carcinoma. int j clin oncol.2013;18(1):68-74. 15. motzer rj, haas nb, donskov f, gross-goupil m, varlamov s, kopyltsov e, et al. randomized phase iii trial of adjuvant pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma. j clin oncol.2017;35(35):3916-3923. table 3. matrix comparing hazard ratios [confidence intervals] for dfs between all therapies axitinib 1.15 [0.87; 1.52] 1.11 [0.79; 1.57] 0.97 [0.57; 1.63] 0.97 [0.65; 1.44] 1.45 [1.00; 2.10] 0.92 [0.67; 1.27] 0.85 [0.58; 1.24] 1.12 [0.82; 1.53] 1.07 [0.78; 1.47] 2.69 [1.04; 7.01] 0.87 [0.66; 1.15] control 0.97 [0.79; 1.19] 0.84 [0.54; 1.31] 0.84 [0.63; 1.12] 1.26 [0.99; 1.61] 0.80 [0.68; 0.95] 0.74 [0.57; 0.96] 0.97 [0.84; 1.13] 0.93 [0.80; 1.09] 2.34 [0.94; 5.86] 0.90 [0.64; 1.26] 1.03 [0.84; 1.26] girentuximab 0.87 [0.53; 1.41] 0.87 [0.61; 1.23] 1.30 [0.95; 1.79] 0.82 [0.64; 1.07] 0.76 [0.55; 1.06] 1.00 [0.78; 1.29] 0.96 [0.74; 1.24] 2.42 [0.95; 6.17] 1.04 [ 0.61; 1.75] 1.19 [0.76; 1.85] 1.15 [0.71; 1.88] il-2 + interferon 1.00 [0.59; 1.70] 1.50 [0.90; 2.49] 0.95 [0.59; 1.53] 0.88 [0.53; 1.47] 1.16 [0.73; 1.85] 1.11 [0.69; 1.77] 2.79 [1.01; 7.72] 1.04 [0.70; 1.54] 1.19 [0.89; 1.59] 1.15 [0.81; 1.64] 1.00 [0.59; 1.70] il-2 + interferon +5-fu 1.50 [1.03; 2.19] 0.95 [0.68; 1.33] 0.88 [0.60; 1.30] 1.16 [0.84; 1.60] 1.11 [0.80; 1.54] 2.79 [1.07; 7.28] 0.69 [0.48; 1.00] 0.79 [0.62; 1.01] 0.77 [0.56; 1.06] 0.67 [0.40; 1.11] 0.67 [0.46; 0.97] interferon-alpha 0.63 [0.47; 0.85] 0.59 [0.41; 0.84] 0.77 [0.58; 1.03] 0.74 [0.55; 0.99] 1.86 [0.72; 4.80] 1.09 [0.79; 1.50] 1.25 [1.06; 1.48] 1.21 [0.93; 1.57] 1.05 [0.65; 1.69] 1.05 [0.75; 1.46] 1.58 [1.17; 2.12] pazopanib 0.92 [0.68; 1.26] 1.22 [0.98; 1.52] 1.16 [0.93; 1.46] 2.93 [1.16; 7.43] 1.18 [0.80; 1.72] 1.35 [1.04; 1.75] 1.31 [0.94; 1.82] 1.14 [0.68; 1.90] 1.14 [0.77; 1.67] 1.70 [1.19; 2.44] 1.08 [0.79; 1.47] pembrolizumab 1.32 [0.98; 1.77] 1.26 [0.93; 1.71] 3.17 [1.22; 8.21] 0.89 [0.65; 1.22] 1.03 [0.89; 1.19] 1.00 [0.78; 1.28] 0.86 [0.54; 1.37] 0.86 [0.62; 1.19] 1.29 [0.97; 1.72] 0.82 [0.66; 1.02] 0.76 [0.56; 1.02] sorafenib 0.96 [0.77; 1.18] 2.41 [0.95; 6.08] 0.93 [0.68; 1.28] 1.07 [0.92; 1.26] 1.04 [0.81; 1.34] 0.90 [0.56; 1.44] 0.90 [0.65; 1.25] 1.35 [1.01; 1.81] 0.86 [0.68; 1.08] 0.79 [0.59; 1.08] 1.05 [0.85; 1.29] sunitinib 2.52 [0.99; 6.37] 0.37 [0.14; 0.97] 0.43 [0.17; 1.07] 0.41 [0.16; 1.06] 0.36 [0.13; 0.99] 0.36 [0.14; 0.94] 0.54 [0.21; 1.39] 0.34 [0.13; 0.87] 0.32 [0.12; 0.82] 0.42 [0.16; 1.05] 0.40 [0.16; 1.01] thalidomide light blue shading shows superiority, and dark blue shading shows inferiority of the row compared with the column. 351siuj.org siuj • volume 3, number 5 • september 2022 adjuvant systemic treatment for renal cancer after surgery: a network meta-analysis http://siuj.org 16. choueiri tk, tomczak p, park sh, venugopal b, ferguson t, chang y-h, et al. adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. n engl j med.2021;385(8):683-694. 17. haas nb, manola j, uzzo rg, flaherty kt, wood cg, kane c, et al. adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ecog-acrin e2805): a double-blind, placebo-controlled, randomised, phase 3 trial. lancet.2016;387(10032):2008-2016. 18. eisen t, frangou e, oza b, ritchie aws, smith b, kaplan r, et al. adjuvant sorafenib for renal cell carcinoma at intermediate or high risk of relapse: results from the sorce randomized phase iii intergroup trial. j clin oncol.2020;38(34):4064-4075. 19. ravaud a, motzer rj, pandha hs, george dj, pantuck aj, patel a, et al. adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. n engl j med.2016;375(23):2246-2254. 20. margulis v, matin sf, tannir n, tamboli p, shen y, lozano m, et al. randomized trial of adjuvant thalidomide versus observation in patients with completely resected high-risk renal cell carcinoma. urology.2009;73(2):337-341. 21. bai y, li s, jia z, ding y, gu c, yang j. adjuvant therapy for locally advanced renal cell carcinoma: a meta-analysis and systematic review. urol oncol.2018;36(2):79.e1-e10. 22. massari f, di nunno v, mollica v, graham j, gatto l, heng d. adjuvant tyrosine kinase inhibitors in treatment of renal cell carcinoma: a meta-analysis of available clinical trials. clin genitourin cancer. 2019;17(2):e339-e344. 23. pourmir i, noel j, simonaggio a, oudard s, vano ya. update on the most promising biomarkers of response to immune checkpoint inhibitors in clear cell renal cell carcinoma. world j urol.2021;39(5):1377-1385. 24. efficace f, fayers p, pusic a, cemal y, yanagawa j, jacobs m, et al. quality of patient-reported outcome reporting across cancer randomized controlled trials according to the consort patientrepor ted outcome extension: a pooled analysis of 557 trials. cancer.2015;121(18):3335-3342. 25. chien c-r, geynisman dm, kim b, xu y, shih y-ct. economic burden of renal cell carcinoma-par t i: an updated review. pharmacoeconomics.2019;37(3):301-331. 26. watson tr, gao x, reynolds kl, kong cy. cost-effectiveness of pembrolizumab plus axitinib vs nivolumab plus ipilimumab as first-line treatment of advanced renal cell carcinoma in the us. jama netw open.2020;3(10):e2016144. 352 siuj • volume 3, number 5 • september 2022 siuj.org review http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information nocturia, nocturnal enuresis, overnight ambulatory urodynamics, urinary symptoms, quality of life none declared. received on october 20, 2021 accepted on may 8, 2022 this article has been peer reviewed. soc int urol j. 2022;3(4):202–208 doi: 10.48083/rdtd8562 202 siuj • volume 3, number 4 • july 2022 siuj.org original research overnight ambulatory urodynamics change patient management strategies and improve symptomatic outcomes richard g. axell,1 habiba yasmin,1 kristina aleksejeva,1 eskinder solomon,2 bogdan toia,1 mahreen h. pakzad,1 jeremy l. ockrim,1 tamsin j. greenwell1 1 department of urology, university college london hospital nhs foundation trust, london, united kingdom 2 department of urology, guy’s and st thomas’ hospital nhs foundation trust, london, united kingdom this work was performed at university college london hospital nhs foundation trust, london, united kingdom abstract objectives to determine the diagnostic value of overnight ambulatory urodynamics (auds) and to assess if a urodynamic diagnosis of detrusor overactivity (do) or nocturnal enuresis resulted in a change in patient management and an improvement in their urinary symptoms. methods a retrospective review of 25 consecutive patients (28% male) with a median age of 38 years (range 18 to 86) having overnight auds for bothersome urinary symptoms of primarily nocturia and/or nocturnal enuresis following non-diagnostic conventional urodynamics between november 1998 and august 2018. urinary symptoms were assessed before overnight auds and again after urological treatment following any changes in urodynamics diagnosis and treatment. six patients were excluded as follow-up data were not available. results twenty-four patients (96%) presented with nocturia and 20 (80%) presented with nocturnal enuresis. do was demonstrated in 19 (76%) patients (mean pressure 69.1±53.3 cmh2o). uui was demonstrated in 16 (80%) out of the 20 patients who complained of nocturnal enuresis. of the 19 patients with follow-up data, following overnight auds a change in urodynamic diagnosis was made in 15 patients (79%); 16 patients (84%) also had their clinical diagnosis and subsequent management changed; and 15 patients (79%) reported an improvement in their urinary symptoms following these changes in diagnosis and treatment. there was a significant improvement in iciq-oab (120±44 versus 32±53, p < 0.0001) scores following the changes to clinical management post-overnight auds. conclusion in our study cohort, change in primary diagnosis following overnight auds led to a significant change in treatment care pathway and resulted in significant improvement in urinary symptoms at follow-up. introduction conventional urodynamics (uds) are considered the gold standard investigation for lower urinary tract symptoms (luts)[1,2]. conventional uds require rapid bladder filling and are performed in an unnatural environment. in a sub-group of patients who have failed medical therapy, conventional uds are unable provide a urodynamic diagnosis that correlates with the patient’s presenting symptoms of nocturia and /or nocturnal enuresis. ambulatory http://siuj.org https://orcid.org/0000-0001-8591-0174 mailto:richard.axell%40nhs.net?subject=siuj https://orcid.org/0000-0003-4272-7526 https://orcid.org/0000-0002-2913-5334 https://orcid.org/0000-0003-4382-0394 https://orcid.org/0000-0002-1215-6585 https://orcid.org/0000-0001-9672-8132 https://orcid.org/0000-0003-1208-9826 https://orcid.org/0000-0002-9074-7604 urodynamics (auds) are recognised by the international continence society (ics) as an important second-line diagnostic tool for providing a definitive diagnosis in patients who had previously had a non-diagnostic or symptomatically contradictory conventional uds[3]. in our specialist centre, auds can be performed overnight while the patient is sleeping. in contrast to conventional uds, auds allows for natural (orthograde) bladder filling and a more natural environment. the patient can be catheterised and connected to the urodynamics recording equipment and then allowed to go to sleep so that their bladder function and any urinary incontinence can be assessed overnight and improve the likelihood of a diagnostic test. the aims of this study were to determine the diagnostic value of overnight auds in patients presenting with isolated symptoms of nocturia and/or nocturnal enuresis following non-diagnostic or symptomatically contradictory conventional uds and to assess if a change in patient diagnosis and/or treatment following overnight auds led to a symptomatic improvement in patients. materials and methods study population twenty-five consecutive patients (28% male) having overnight auds for bothersome urinary symptoms of primarily nocturia and/or nocturnal enuresis seen at our tertiary referral centre between november 1998 and august 2018 were identified from our prospectively acquired database and retrospectively reviewed. none of the patients had an underlying neurological disorder or history of previous treatment with radiotherapy. their median age was 38 years (range 18 to 86). all patients had previously had conventional pressure flow studies or video uds (vuds). all overnight auds tests were performed following multidisciplinary team review when conventional uds were non-diagnostic or when the conventional uds diagnosis was contradictory to the patient’s primary presenting symptom(s) of nocturia and/or nocturnal enuresis. none of the patients had any daytime symptoms and therefore daytime auds were not performed as this was felt to not be indicated and a waste of resources and time for all involved. six patients were excluded because follow-up data were not available. before proceeding to conventional urodynamics (filling cystometry and pressure flow studies) all patients had received (as appropriate) lifestyle advice, continence therapist input re bladder training ± pelvic floor muscle exercise, medications (as indicated by clinical diagnosis). those progressing to overnight auds wished to consider more invasive treatments for their isolated nocturia or nocturnal enuresis symptoms, and it is a requirement of our nhs system and nice guidance that a urodynamic diagnosis is made before these more invasive treatments. urodynamics procedures auds stud ies were per formed as per t he ics guidelines[1,3] using the mms solar luna module (medical measurement systems, gladbeck, germany). a f low rate, post-void residual and urinalysis were performed before the test. after residual urine was measured, a 4.5fr bladder catheter (mediplus 5716, wycombe, united kingdom) and a 4.5fr rectal balloon catheter (mediplus 5410, wycombe, united kingdom) were inserted for the measurement of intravesical and abdominal pressures, respectively. a conductance leak pad sensor (digitimer pe-que sensor pad, welwyn garden, united kingdom) was used on all patients reporting symptoms of nocturnal enuresis. after zeroing the fluid filled pressure measurement transducers and flushing the measurement lines with saline, a cough was used to ensure good cancellation and accurate pressure measurement readings. the patients were then taken to a private ward side room and advised on the use of the luna module events buttons to mark urgency and leakage and to activate the flowmeter to record voiding the patients were encouraged to perform their normal nightly routine known to be provocative for their typical nocturia and/or nocturnal enuresis symptoms. the median study duration was 16 hours (range 13 to 18). the urodynamicist returned to the ward in the morning to remove the pressure lines and download the overnight auds data from the luna module. a cough was again used to ensure good cancellation before removal of the pressure lines and the patient was asked whether they had experienced their typical overnight symptoms during the test. the on-call urology specialist registrar was available for advice or to review the patient if there were any issues overnight—in particular, with the pressure lines. all conventional uds, vuds and overnight auds studies were analysed by an experienced urodynamicist and reviewed at a multidisciplinary team meeting to ensure accuracy of diagnosis and to determine treatment options. assessment of urinary symptoms urinary symptoms were assessed using iciq-oab scores in all patients before and after the changes to clinical management post-overnight auds. iciqoab scores were extrapolated from medical records in 5 patients treated at uclh prior to 2010. this extrapolation was based on the detailed history of day time frequency, nighttime frequency, urgency, and urgency urine leak, plus bother related to these symptoms available in the notes. 203siuj.org siuj • volume 3, number 4 • july 2022 overnight ambulatory urodynamics change patient management strategies and improve symptomatic outcomes http://siuj.org figure 1. an 18-year-old female patient presenting with daytime frequency, urgency, and nocturnal enuresis (2 pads per 24 hours) vuds trace showing a reduced 326 ml capacity bladder limited by pain due to loss of compliance (end-fill pressure 26cmh2o), with no do or sui demonstrated. a whole overnight auds study trace b continued on page 205 204 siuj • volume 3, number 4 • july 2022 siuj.org original research http://siuj.org statistical analysis data are expressed as median iqr and p-values were calculated using a 2-tailed paired student t test for pairwise comparisons of parametric data, unless otherwise stated. categorical data are expressed as number (percentage) and compared with the fisher exact test. p < 0.05 was considered statistically significant. analysis was performed using sigmaplot 12.5 (systat software inc, san jose,us) statistical analysis package. results following overnight auds, all studies were evaluable (as determined by replication of the patients’ nocturnal symptoms and good quality trace) and a definitive uds diagnosis of do was made in 79% (n = 19) of 24 patients presenting with nocturia (mean do pressure 69.1 ± 53.3 cmh2o) and in 90% (n = 18) of the 20 patients presenting with nocturnal enuresis. uui (median pad weight gain 103 ml, iqr 45–205) was demonstrated in 80% (n = 16) of the 20 patients presenting with nocturnal enuresis. of the remaining patients, 5 had a diagnosis of sensory urgency confirmed and 1 patient was diagnosed with reduced functional capacity due to high pvrs. a change in the primary uds diagnosis occurred in 80% (n = 20) of patients following auds. sub-group analysis of 19 patients with post auds treatment follow-up data all 25 patients attended for their initial post nocturnal auds review, at which time the outcome of the nocturnal auds was discussed along with their new clinical diagnosis and treatment recommendations. six patients failed to attend for further follow-up, whilst 19 proceeded with treatment recommendations and had ongoing follow-up data available for review. do was demonstrated in 14 of the 15 patients who presented with nocturnal enuresis, and the final patient was found to have a reduced functional capacity due to high pvrs. of the remaining 4 patients who presented with isolated nocturia symptoms, 1 was found to have do, and the remaining 3 patients had a diagnosis of sensory urgency confirmed. therefore, 84% (n = 16) of this patient sub-group had their clinical diagnosis and management changed following auds. in the 15 patients who had do demonstrated, 3 were treated with a clam cystoplasty, 5 were treated with intravesical botulinum toxin injections, and the remaining patients were treated with combination medical therapy. of the 3 patients with confirmed sensory urgency, 1 was treated with reduced f luid intake, 1 was treated with desmopressin, and the final patient was treated with cognitive behavioural therapy. figure 1. an 18-year-old female patient presenting with daytime frequency, urgency, and nocturnal enuresis (2 pads per 24 hours), cont’d extrapolated overnight auds trace showing high pressure do (up to pp145cmh2o) and 220 ml leak c 205siuj.org siuj • volume 3, number 4 • july 2022 overnight ambulatory urodynamics change patient management strategies and improve symptomatic outcomes http://siuj.org the patient diagnosed with reduced functional capacity due to high pvrs had their catheterisation technique reviewed by the urology clinical nurse specialist and was advised to catheterise more often. these treatment changes led to a statistically significant improvement in the reported urinary symptoms of daytime frequency, nocturia, and nocturnal enuresis in 79% of patients (table 1). there was a significant improvement in iciq-oab (120±44 versus 32±53, p < 0.0001) scores following the changes to clinical management post-overnight auds (table 2). sixty-one percent (11 out of 18) of patients had resolution of their nocturia and 73% (11 out of 15) of patients had resolution of their nocturnal enuresis. discussion this exploratory study is the first to demonstrate that overnight auds is an extremely useful final stage diagnostic tool in patients with isolated nocturnal symptoms in whom conventional or video urodynamics have been non-d iag nost ic or sy mptomat ica l ly contradictor y. all overnight auds studies were evaluable, and we were able to make a definitive diagnosis in all patients. do was demonstrated in 79% of patients presenting with nocturia and/or nocturnal enuresis. uui was demonstrated in 80% of patients presenting with nocturnal enuresis. of the others, their original diagnosis of sensory urgency was confirmed in 5 patients, and 1 patient was found to have a reduced functional capacity due to high pvrs. the finding of reduced functional capacity and high pvrs was not identified on routine flow rate and post-void residual or conventional pressure f low studies and appears to have been a nocturnal phenomenon of unknown cause. although there are no other overnight auds datasets for comparison, we reproduced patients’ symptoms in all studies, compared with published day time auds datasets, which reported rates of 72% to 77%[4,5]. equally, previous daytime auds studies have demonstrated that clinical outcomes are improved in 40% to 79%[4,6] following treatment modification. this is similar to the 61% of patients who had resolution of their nocturia and the 73% of patients who had resolution of their nocturnal enuresis following treatment modification. nocturia is defined by the ics as the complaint of waking to pass urine during the main sleep period[7]. the prevalence of nocturia increases with age[8]: approximately 50% of adults between the ages of 50 and 79 have nocturia, and it is estimated that men aged between 70 and 79 get up at least twice per night to pass urine[9]. if there are 2 or more episodes per night, nocturia can be a significant problem[10], affecting both sleep onset and ability to return to sleep[11]. nocturia is strongly associated with poor quality of life[12], mainly due to fatigue caused by sleep disturbances[11]. nocturia is often multifactorial. it can be caused by reduced functional table 1. urinary symptoms preand postchanges in diagnosis and treatment following overnight auds urinary symptoms pre-overnight auds post-overnight auds p-value isolated nocturia, n(%) 4(21) 0(0) – isolated nocturnal enuresis, n(%) 1(5) 1(5) – both nocturia and nocturnal enuresis, n(%) 14(74) 4(21) <0.001 table 2. urinary symptoms iciq-oab score preand postchanges in diagnosis and treatment following overnight auds symptom pre-overnight auds iciq-oab, (mean±sd) post-overnight auds iciq-oab, (mean±sd p-value isolated nocturia (n = 4) 80±46 0±0 – isolated nocturnal enuresis (n = 1) 120 80 – both nocturia and nocturnal enuresis (n = 14) 131±40 38±59 <0.001 206 siuj • volume 3, number 4 • july 2022 siuj.org original research http://siuj.org bladder capacity, increased nocturnal urine output, or can result from primary sleep related disorders such as obstructive sleep apnoea, which affects nocturnal urine production and consequently provokes nocturnal bladder symptoms[13]. nocturnal polyuria should be excluded as a cause, as this can be an indicator of a worsening underlying pathology[14]. sleep disorders should also be excluded, as patients with a primary sleep disorder, such as restless leg syndrome, may awaken due to this and then void but recall only waking to void when presenting clinically[15]. nocturnal enuresis is defined by the ics as the complaint of involuntary voiding that occurs at night during the main sleep period[7]. although nocturnal enuresis is considered as a physiological finding in children less than 5 years old, it is abnormal in adults[16]. in adults, the prevalence of nocturnal enuresis is reported as 0.5% to 3%[17–19]. typically, an adult presenting with isolated symptoms of nocturia and/or nocturnal enuresis will be managed by a primary care physician following history, physical examination, bladder diary, and urinalysis. however, assessment (with uroflowmetry and post-void residuals, cystoscopy and urodynamic evaluation) and treatment by a urologist may be required for those with the very bothersome or persistent symptoms[20]. hirasing et al. found that only 12% of adult men and 29% of adult women presenting with nocturnal enuresis had concomitant daytime incontinence[19], meaning that about 71% to 88% of patients with nocturnal enuresis will have a non-diagnostic conventional daytime urodynamic assessment. annually at our centre we perform 75 to 100 auds studies and 1 to 2 overnight auds studies. the 25 patients having auds were accrued over a 20-year period – and account for < 1% of our auds studies. during this time period, we have had 3 separate lead principal clinical scientists performing and interpreting both our auds and our overnight auds using a standardised technique and reporting pro forma, with no loss of continuity of care, and 1 change of auds equipment to a more modern version of the previous. although both auds and overnight auds are the most accurate urodynamic diagnostic tests available, it takes 2 to 4 hours to perform an auds or 12 to 16 hours to perform an overnight auds (in addition to the cost of a ward side room overnight) and 1 to 2 hours to interpret the results (versus 30 to 60 minutes in total for uds/ vuds). within the united kingdom health care system, invasive treatment options such as intra-vesical botulinum toxin and sacral neuromodulation are offered only following a proven urodynamic diagnosis of do. we do not perform invasive urodynamic assessment prior to non-operative intervention, as per nice guidance[2]. overnight auds is neither costnor time-effective as a first-line assessment tool. it should therefore be reserved for patients with significantly bothersome isolated symptoms of nocturia and/or nocturnal enuresis contemplating invasive treatment in whom conventional and/or vuds have been non-diagnostic or contradictory to patient symptomatology. there are some limitations of this study. whilst this was a retrospective study, we consecutively reviewed all patients who had an overnight auds over a 20-year time period, and this is the largest dataset presented worldwide to date. although sleeping with a urinary catheter in situ is not part of the natural environment, and tests were performed in a ward side room, our patient cohort tolerated this well, and all episodes of uui corresponded with large flooding leaks detected on the leak pad sensor. the patients reported that the urodynamic findings correlated with their typical nocturnal urinary symptoms and did not report that the 4.5fr urinary catheter used during the auds influenced the test. although overnight auds is a time-consuming and expensive test, auds in general have been shown to be well tolerated[21] with 85% of patients happy to attend for further studies. only 18.6% of patients experience mild to moderate de novo dysuria and 1.1% experience asymptomatic bacterial uti following auds[22]. there was no daytime auds performed in this group for the reasons cited in the methods section of this paper, and therefore there is no ability to compare daytime auds findings with overnight auds findings. if daytime auds permitted diagnosis (which we felt highly unlikely in the absence of symptoms—which is after all the goal of uds—to reproduce symptoms and assess the underlying pathophysiological cause), then overnight audss would have been avoided. extrapolation of urinary symptoms detailed in the notes of 5 early patients to retrospectively form an iciq-oab score is also a weakness. whilst the notes were detailed in terms of daytime frequency, nighttime frequency, severity of urgency and urgency incontinence, and bother, the actual iciq-oab was not contemporaneously completed by the patient, and this may introduce a degree of inaccuracy into the extrapolated score. overnight auds is a complex challenging test and as such should be performed only at specialist centres and reserved for highly selected patients with isolated nocturnal urinary symptoms following a non-diagnostic conventional or vuds. conclusion this is the first study to show that overnight auds studies are a useful clinical assessment technique in patients with isolated nocturnal symptoms. do 207siuj.org siuj • volume 3, number 4 • july 2022 overnight ambulatory urodynamics change patient management strategies and improve symptomatic outcomes http://siuj.org was demonstrated in 79% of patients presenting with nocturia and in 90% of patients presenting with nocturnal enuresis. of patients presenting with nocturnal enuresis, 80% were also demonstrated to have a diagnosis of uui. following overnight auds, the clinical diagnosis and subsequent management pathway was changed in 84% of patients. this resulted in a significant improvement in symptomatic outcomes. a total of 61% of patients had resolution of their nocturia, and 73% of patients had resolution of their nocturnal enuresis. references 1. rosier pf wm, schaefer w, lose g, goldman hb, guralnick m, eustice s, et al. international continence society good urodynamic practices and terms 2016: urodynamics, uroflowmetry, cystometry, and pressure-flow study. neurourol urodyn.2017;36(5):1243-1260. doi: 10.1002/nau.23124. epub 2016 dec 5. 2. national institute for health and care excellence. urinary incontinence and pelvic organ prolapse in women: management (ng123) 2019. available at: https://www.nice.org.uk/guidance/ng123. accessed may 30, 2022. 3. van waalwijk van doorn e, anders k, khullar v, kulseng-hanssen s, pesce f, robertson a, et al. standardisation of ambulatory urodynamic monitoring: repor t of the standardisation sub-commit tee of the international continence society for ambulatory urodynamic studies. neurourol urodyn.2000;19 (2):113-125. doi: 10.1002/ (sici)1520-6777(2000)19:2<113::aid-nau2>3.0.co;2-#. 4. pannek j, pieper p. clinical usefulness of ambulatory urodynamics in the diagnosis and treatment of lower urinary tract dysfunction. scand j urol nephrol.2008;42(5):428-432. doi: 10.1080/00365590802299056 5. dokmeci f, seval m, gok h. comparison of ambulator y versus conventional urodynamics in females with urinary incontinence. neurourol urodyn.2010;29(4):518-521. doi: 10.1002/nau.20821 6. gorton e, stanton s. ambulatory urodynamics: do they help clinical management? bjog.2000;107(3):316-319. doi: 10.1111/j.14710528.2000.tb13224.x 7. hashim h, blanker mh, drake mj, djurhuus jc, meijlink j, morris v, et al. international continence society (ics) report on the terminology for nocturia and nocturnal lower urinary tract function. neurourol urodyn.2019;38(2):499-508. doi: 10.1002/nau.23917. epub 2019 jan 15. 8. bosch jl, weiss jp. the prevalence and causes of nocturia. j urol.2013;189(1 suppl):s86-92. doi: 10.1016/j.juro.2012.11.033 9. tikkinen ka, tammela tl, huhtala h, auvinen a. is nocturia equally common among men and women? a population based study in finland. j urol.2006;175(2):596-600. doi: 10.1016/s0022-5347(05)00245-4 10. chen fy, dai yt, liu ck, yu hj, liu cy, chen th. perception of nocturia and medical consulting behavior among community-dwelling women. int urogynecol j pelvic floor dysfunct.2007;18(4):431-436. doi: 10.1007/ s00192-006-0167-x 11. vaughan cp, eisenstein r, bliwise dl, endeshaw yk, nagamia z j, wolf r a , et al. self-rated sleep charac teristics and bother from nocturia. int j clin pract.2012;66(4):369-373. doi. org/10.1111/j.1742-1241.2011.02868.x 12. van dijk mm, wijkstra h, debruyne fm, de la roset te jj, michel mc. the role of nocturia in the quality of life of men with lower urinary tract symptoms. bju int.2010;105(8):1141-1146. doi: 10.1111/j.1464-410x.2009.08969.x 13. marshall sd, raskolnikov d, blanker mh, hashim h, kupelian v, tikkinen k a, et al. nocturia: current levels of evidence and recommendations from the international consultation on male lower urinary tract symptoms. urology.2015;85(6):1291-1299. doi: 10.1016/j. urology.2015.02.043. epub 2015 apr 14. 14. hillier p, knapp ms, cove-smith r. circadian variations in urine excretion in chronic renal failure. q j med.1980;49(196):461-478. 15. pressman mr, figueroa wg, kendrick-mohamed j, greenspon lw, peterson dd. nocturia. a rarely recognized symptom of sleep apnea and other occult sleep disorders. arch intern med.1996;156(5):545550. doi: 10.1001/archinte.156.5.545. 16. sakamoto k, blaivas jg. adult onset nocturnal enuresis. j urol.2001; 165(6 pt 1):1914-1917. doi: 10.1097/00005392-200106000-00017. 17. yeung ck, sihoe jd, sit fk, diao m, yew sy. urodynamic findings in adults with primary nocturnal enuresis. j urol.2004;171(6 pt 2):25952598. doi: 10.1097/01.ju.0000112790.72612.0a. 18. yeung ck, sihoe jd, sit fk, bower w, sreedhar b, lau j. characteristics of primary nocturnal enuresis in adults: an epidemiological study. bju int.2004;93(3):341-345. doi: 10.1111/j.1464-410x.2003.04612.x 19. hirasing ra, van leerdam fj, bolk-bennink l, janknegt ra. enuresis nocturna in adults. scand j urol nephrol.1997;31(6):533-536. doi. org/10.3109/00365599709030657 20. a beygunasekera m, goonesinghe k. nocturnal enuresis in adults. curr bladder dysfunct rep.2013;8:217-222. doi i:10.1007/ s11884-013-0193-8 21. oh sj, son h, jeong jy, ku jh. patients' experience with ambulator y urodynamics. a prospective study. scand j urol nephrol.2006;40(5):391-396. doi: 10.1080/00365590600744014 22. anders k, cardozo l, ashman o, khullar v. morbidity after ambulatory urodynamics. neurourol urodyn.2002;21(5):461-463. doi: 10.1002/ nau.10040 208 siuj • volume 3, number 4 • july 2022 siuj.org original research https://www.nice.org.uk/guidance/ng123 http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information prostatectomy, prostate cancer, urinary incontinence, surveys and questionnaires none declared. funding statement: this was a researcherinitiated study that was supported by funding from westmead private physiotherapy services and the clinical research institute. received on january 13, 2022 accepted on february 7, 2022 this article has been peer reviewed. soc int urol j. 2022;3(3):124–130 doi: 10.48083/tiwq1657 124 siuj • volume 3, number 3 • may 2022 siuj.org original research pad weight, pad number, and incontinence-related patient-reported outcome measures after radical prostatectomy cecile t. pham,1 manish i. patel,1,2 sean f. mungovan3,4 1 specialty of surgery, faculty of medicine and health, university of sydney, camperdown, australia 2 department of urology, westmead private hospital, westmead, australia 3 westmead private physiotherapy services, westmead, australia 4 the clinical research institute, westmead, australia abstract objectives to evaluate the correlation between 3and 6-week postoperative 24-hour pad weight, daily pad number, and the international consultation on incontinence questionnaires for male lower urinary tract (iciq-mluts), iciq-short form (iciq-sf) and ucla prostate cancer index (ucla-pci) in patients undergoing robotic-assisted radical prostatectomy (rarp). methods this prospective study included patients undergoing rarp between february and november 2019. patients completed a 24-hour pad test, assessing pad weight and number, and 3 validated patient-reported outcome measures (proms); the iciq-mluts, iciq-sf and ucla-pci, preoperatively and at 3 and 6 weeks postoperatively. results a total of 47 patients were included in the study. there was a strong correlation between 24-hour pad weight and the iciq-sf at 3 weeks (r = 0.71, p < 0.001) and 6 weeks (r = 0.68, p < 0.001). there was a strong correlation between 24-hour pad weight and iciq-mluts incontinence (r = 0.80, p < 0.01) and incontinence qol burden (r = 0.79, p < 0.01) at 6 weeks. there was a moderate correlation between the 24-hour pad weight and ucla-pci urinary function (r = 0.58, p < 0.001) and urinary qol burden (r = 0.66, p < 0.001) at 6 weeks. the correlation between pad number and 24-hour pad weight was weak at 6 weeks (r = 0.34, p < 0.001). conclusion proms may be used as a substitute for the 24-hour pad weight test for post-prostatectomy incontinence (ppi) assessments in the early post-rarp period. the iciq-sf and ucla-pci urinary function and qol scores correlate with 24-hour pad weight. however, the iciq-mluts incontinence and qol scores provide the strongest correlation with ppi. introduction prostate cancer is a major public health concern and the second most commonly diagnosed cancer in men globally[1]. organ-confined disease is treated surgically by radical prostatectomy (rp). despite improvement in surgical technique, post-prostatectomy incontinence (ppi) affects 49% to 63% of patients in the early postoperative period (first 6 weeks)[2–5]. estimates of the incidence of ppi and continence recovery time vary because of the lack of a http://siuj.org https://orcid.org/0000-0002-5954-565x https://orcid.org/0000-0003-1409-9171 mailto:manish.patel%40sydney.edu.au?subject=siuj https://orcid.org/0000-0002-9949-2409 universally accepted definition of continence, the variety of assessment methods used to determine severity of ppi, and variability in ppi assessment time points. in clinical practice, ppi is commonly quantified by patientrecorded numbers of pads used daily. however, some studies have reported that the reliability of pad number may be limited by patient recall and poor correlation with the actual amount of urine loss[6,7]. pad weight testing protocols are used for the objective measurement of ppi with testing durations ranging from 20 minutes to 72 hours[6,8–10]. increasing the duration of the testing protocol to 48 or 72 hours increases reliability but has not been recommended, as it can result in decreased patient compliance[10]. the 24-hour pad weight test is considered the gold standard for objective measurement of urinary incontinence[11,12]. however, it can be burdensome and result in poor patient compliance. moreover, it does not take into consideration other markers of urinary function, such as frequency of incontinence and voiding. this has led to the development of accessible and validated patient-reported outcome measures (proms) for routine ppi assessments. however, there are limited data on whether proms for ppi assessment correlate with objective measures and whether they can be used as a reliable substitute for 24-hour pad weight. to our knowledge, no study has compared proms with the 24-hour pad weight test in the 6-week period following rp. commonly used proms include the international consultation on incontinence questionnaire for male lower urinary tract symptoms (iciq-mluts), the iciq-short form (iciq-sf) and the university of california los angeles prostate cancer index (ucla-pci). in this study, we evaluated the correlation between 24-hour pad weight, daily pad number, and the iciq-mluts, iciq-sf and ucla-pci in patients undergoing robotic-assisted radical prostatectomy (rarp). materials and methods patient selection patients undergoing rarp by a single surgeon at a high-volume robotic centre in a private metropolitan hospital were prospectively recruited between february and november 2019 during their initial consultation prior to surgery. patients who had a history of pad usage, pelvic surgery or pelvic radiotherapy were excluded. this study was approved by the western sydney local health district human research ethics committee (eth02769). all participants provided written informed consent. patient-reported outcome measures the iciq-mluts is derived from the international continence society male short-form (icsmalesf) questionnaire and is used to evaluate male lower urinary tract symptoms across multiple domains, including incontinence, voiding, leakage frequency, and impact on quality of life (qol)[13,14]. the iciqmluts is a 13-item questionnaire consisting of 5 items forming the voiding subscale, 6 items forming the incontinence subscale and 2 items regarding leakage frequency. each item is scored from 0 to 4, and each subscale is calculated. the iciq-sf is an abbreviated version that evaluates frequency and severity of urinary incontinence[15]. it consists of 4 items regarding leakage frequency, volume, and impact on qol. the first 3 items are scored from 0 to 5, 0 to 6 and 0 to 10, respectively, and they are added to produce a total score ranging from 0 to 21. the fourth item allows the patient to report when urinary incontinence occurs and does not contribute to the overall score. the ucla-pci assesses the impact of treatment (surgery and/or radiotherapy) on qol[16]. it is a 20-item questionnaire consisting of function and bother across 3 domains: sexual, urinary, and bowel function. the items are scored from 0 to 100, with higher scores representing better qol, and an average score for each domain is calculated. data collection at t he time of recr uit ment, each pa r ticipa nt’s demographic information, including age and body mass index (bmi), and information on prostate cancer disease characteristics, including prostate specific antigen (psa) and histopathology, was collected. all participants were referred to an independent physiotherapy clinic one month prior to surgery for the prescription of a preoperative pelvic floor muscle training program[17]. all patients were reviewed by the physiotherapist at 3 and 6 weeks postoperatively for a continence review abbreviations bmi body mass index iciq-mluts international consultation on incontinence questionnaires for male lower urinary tract iciq-sf international consultation on incontinence questionnaire short form icsmalesf international continence society male short form iqr interquartile range ppi post-prostatectomy incontinence prom patient-reported outcome measure psa prostate specific antigen qol quality of life rarp robotic-assisted radical prostatectomy rp radical prostatectomy sd standard deviation ucla-pci university of california los angeles prostate cancer index 125siuj.org siuj • volume 3, number 3 • may 2022 pad weight, pad number, and incontinence-related patient-reported outcome measures after radical prostatectomy http://siuj.org that included prescription of a postoperative pelvic floor muscle training program, until continence recovery had been achieved. referral for preoperative physiotherapy is standard of care; however, close postoperative physiotherapy follow-up is not routine. the patients were asked to complete 3 validated proms, the iciq-sf preoperatively and at 3 and 6 weeks postoperatively and the iciq-mluts and ucla-pci preoperatively and at 6 weeks postoperatively. at 3 weeks postoperatively, only the iciq-sf was conducted because of its brevity. the patients were also provided with an analytical weighing scale (accurate to 0.1g) and asked to weigh each pad before and after use for 24 hours on 3 consecutive days prior to the 3and 6-week postoperative assessment. the 24-hour pad weight used in the analysis was the mean 24-hour weight of the 3 consecutive days. statistical analysis statistical analysis was conducted using ibm spss statistics version 26 (ibm, armonk, us). p-values < 0.05 were considered statistically significant. continuous variables were summarized as means and standard deviations or medians and interquartile ranges. the correlations between variables were assessed using spearman’s rank correlation. the strength of the relationships was interpreted as follows: 0 to 0.19, very weak positive correlation; 0.20 to 0.39, weak positive correlation; 0.40 to 0.59, moderate positive correlation; 0.60 to 0.79, strong positive correlation; and 0.80 to 1, very strong positive correlation[18]. results a total of 54 consecutive patients were recruited. five patients were lost to follow-up, and 2 did not complete the proms. thus, a total of 47 patients were included in the analysis. all patients underwent rarp. the patients’ demographic, clinical, and operative characteristics are summarized in table 1. the median preoperative scores for the iciq-mluts incontinence domain, iciq-sf, and ucla-pci urinary function domain were 0, 1, and 100, respectively (table 2). the mean 24-hour pad weight was 24.2 ± 42.6g (0g to 200g) at 3 weeks and 7.6 ± 17.7g (0g to 77g) at 6 weeks. with continence defined as a 24-hour pad weight of ≤ 1g, 38% and 70% of the patients were continent at 3 and 6 weeks, respectively. the daily pad number ranged from 0 to 5 at 3 weeks and 0 to 2 at 6 weeks. the pad number correlated strongly with 24-hour pad weight at 3 weeks (r = 0.64, p < 0.001) and weakly at 6 weeks (r = 0.34, p < 0.001). the correlations between 24-hour pad weight and the proms are shown in figure 1. there was a strong and statistically significant correlation between 24-hour pad weight and the iciq-sf at 3 weeks (r = 0.71, p < 0.001) and 6 weeks (r = 0.68, p < 0.001). there was a strong and statistically significant correlation between 24-hour pad weight and iciq-mluts incontinence (r = 0.80, p < 0.01) and incontinence qol burden (r = 0.79, p < 0.01) at 6 weeks. there was a moderate and statistically significant correlation between the iciq-mluts nocturia score and 24-hour pad weight (r = 0.44, p = 0.049) but no significant correlation table 1. demographic, clinical and operative characteristics characteristic mean ± sd or n (%) median (iqr) age 65.2 ± 7.6 65 (59–71) ethnicity caucasian 34 (72.34) middle eastern/ mediterranean 10 (21.28) asian 3 (6.38) bmi (kg/m2) 29.1 ± 4.2 28.3 (59–71) psa (ng/ml) 8.5 ± 7 6.8 (4.2–9.2) prostate weight (g) 41.2 ± 15.1 40 (30–50) gleason grade group 2 25 (53.19) 3 15 (31.91) 4 2 (4.26) 5 5 (10.64) clinical stage t2 17 (36.17) t3 30 (63.83) d’amico risk group intermediate 17 (36.17) high 30 (63.83) nerve sparing procedure not performed 2 (4.26) unilateral 12 (25.53) bilateral 33 (70.21) sd: standard deviation; iqr: interquartile range; bmi: body mass index; psa: prostate specific antigen 126 siuj • volume 3, number 3 • may 2022 siuj.org original research http://siuj.org between nocturia qol burden (p = 0.67) and the 24-hour pad weight. there were no statistically significant correlations between 24-hour pad weight and the other iciq-mluts domains, including voiding (p = 0.73), voiding qol burden (p = 0.41), leakage frequency (p = 0.64), and leakage frequency qol burden (p = 0.44). there was a moderate correlation between the 24-hour pad weight and ucla-pci urinary function (r = 0.58, p < 0.001) and a strong correlation between 24-hour pad weight and urinary qol burden (r = 0.66, p < 0.001) at 6 weeks. there were no significant correlations between 24-hour pad weight and the ucla-pci bowel function (p = 0.41), bowel qol burden (p = 0.83), sexual function (p = 0.61), or sexual qol burden (p = 0.31) domains at 6 weeks. discussion this study evaluated multiple methods of assessing ppi to determine the most accurate and reliable. several assessment methods are currently used, including 24hour pad weight, pad number and validated proms. the 24-hour pad weight test is widely accepted as the gold standard for objective measurement of incontinence but can be burdensome for patients. most studies require patients to seal used pads in containers to minimize evaporation until the pads are submitted for evaluation. this may be seen by patients as an unacceptable, unsanitary practice and may lead to poor patient compliance[19,20]. a recent study showed that if patients are motivated and well-instructed, pad weight compliance can be high[21]. to increase patient satisfaction and compliance, we provided patients with analytical weighing scales and clear instructions to allow them to perform the measurements themselves at home. although this was well-received, pad weight measurements can still be a demanding and complex task for patients. to date, there is no consensus on the best substitute for the 24-hour pad weight test for ppi assessment. our study focuses on the early postoperative period, as technical modifications, improvements in surgical technique, and the increasing use of robotic surgery have accelerated continence recovery[4,5,22,23]. definitions of continence in the literature regarding the early postoperative period vary greatly. we defined continence as a 24-hour pad weight of ≤ 1g. according to this definition, 38% and 70% of our patients were continent at 3 and 6 weeks, respectively. our study demonstrates that proms are reliable substitutes for the 24-hour pad weight test for ppi assessment in the early postoperative period. the use of the daily pad number as a substitute for 24-hour pad weight remains controversial. nitti et al.[24] reported a strong correlation between perceived pad use and the 24-hour pad weight. in our study, we found a moderate correlation between pad number and 24-hour pad weight at 3 weeks and 6 weeks postoperatively. this is in line with previous studies reporting that the pad number is not a reliable measure of incontinence[4,5,21]. patients may change pads for a variety of reasons, including differing acceptable hygiene and pad wetness levels, convenience, and financial or physical access to pads. as previous studies did not evaluate pad number reliability specifically for ppi, our study serves to validate this finding in a post-prostatectomy population. proms rely on the patients’ own perceptions of their incontinence symptoms and their effect on qol. although many proms are used to assess incontinence, thus far, there is no universally accepted prom. we assessed the correlation between 24-hour pad weight and both generic and condition-specific proms. previous studies have attempted to define continence using such proms. some have defined continence as an iciq-sf score equal to or less than the preoperative score[25]. ito et al.[26] recently categorized iciqmluts scores amongst men seeking treatment for bothersome lower urinary tract symptoms as mild to moderate (incontinence score of 16 to 25 and bother, ie, qol burden, score of 22 to 80) and moderate to severe (incontinence score of ≥ 26 and bother score of ≥ 81) allowing luts to be expressed as categorical table 2. median and interquartile ranges for incontinence assessment methods preoperative 3 weeks postoperative 6 weeks postoperative 24-hour pad weight (g) nil 6 (0–21) 0 (0–4.5) pad number nil 1 (0–2) 0 (0–1) iciq-sf 0 (0–0) 6 (4–9) 1 (0–6) iciq-mluts incontinence score 1 (0–2) 2 (1–4) ucla-pci urinary function score 100 (81–100) 75 (58–100) prom: patient-reported outcome measure; iciq-sf: international consultation on incontinence questionnaires short form; iciq-mluts, international consultation on incontinence questionnaires for male lower urinary tract; ucla-pci, university of california los angeles prostate cancer index 127siuj.org siuj • volume 3, number 3 • may 2022 pad weight, pad number, and incontinence-related patient-reported outcome measures after radical prostatectomy http://siuj.org figure 1. scatter plot showing the correlation between 24-hour pad weight and (a) iciq-mluts incontinence score and bother (b) ucla-pci urinary function and bother (c) iciq-sf score at 6 weeks following rarp. (r = spearman’s rank correlation coefficient, p = p value) values. whilst these banding ranges can provide an indication of an individual’s luts severity relevant to a broader cohort, they do not provide a clear correlation with 24-hour pad weight. moreover, as these proms are subjective measures of incontinence severity, it is difficult to determine a definitive cut-off score for continence. for this reason, we used the prom scores as continuous variables and spearman’s rank correlation to evaluate their correlations with the 24-hour pad weight. whilst all 3 proms strongly correlated with 24-hour pad weight, the strongest correlations were between 24hour pad weight and iciq-mluts incontinence and qol burden. the brevity of the iciq-sf may account for its weaker correlation. although questionnaires should ideally be relatively short and simple to use in routine clinical practice, this must not compromise their clinical accuracy. ultimately, the best assessment method for ppi depends on the clinical context. proms can be used as a convenient and reliable substitute for 24-hour pad weight, particularly for routine ppi assessment. however, 24-hour pad weight remains important for situations when objective assessment is required, such as the decision to proceed to invasive therapy for ppi and monitoring of treatment response. our study has several limitations. we assumed that 24-hour pad weight is completely objective and did 128 siuj • volume 3, number 3 • may 2022 siuj.org original research ic iq -m lu ts in co nt in en ce s co re 24th pad weight (g) 0 0 5 10 15 20 40 60 r = 0.80 p < 0.01 ic iq -m lu ts in co nt in en ce b ot he r 24th pad weight (g) 0 0 5 10 20 40 60 r = 0.79 p < 0.01 ic iq -m lu ts in co nt in en ce s co re a u cl a -p ci u rin ar y fu nc tio n sc or e 24th pad weight (g) b 0 0 25 50 75 100 20 40 60 r = 0.58 p < 0.001 u cl a -p ci u rin ar y b ot he r s co re 24th pad weight (g) 0 0 25 50 75 100 20 40 60 r = 0.66 p < 0.001 ic iq -f s sc or e 24th pad weight (g) c 0 0 5 10 15 20 20 40 60 r = 0.68 p < 0.001 http://siuj.org references 1. sung h, ferlay j, siegel r, laversanne m, soerjomataram i, jemal a, et al. global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin.2021;71(3):209-249. doi.org/10.3322/caac.21660 2. wolin k, luly j, sutcliffe s, andriole g, kibel a. risk of urinary incontinence following prostatectomy: the role of physical activity and obesity. j urol.2010;183(2):629-633. doi: 10.1016/j.juro.2009.09.082. epub 2009 dec 16. 3. smither a, guralnick m, davis n, see w. quantifying the natural history of post-radical prostatectomy incontinence using objective pad test data. bmc urol.2007;7(1). doi: 10.1186/1471-2490-7-2 4. li x, zhang h, jia z, wang y, song y, liao l, et al. urinar y continence outcomes of four years of follow-up and predictors of early and late urinary continence in patients undergoing robotassisted radical prostatectomy. bmc urol.2020;20(1). doi: 10.1186/ s12894-020-00601-w 5. jia z, chang y, wang y, li j, qu m, zhu f, et al. sustainable functional urethral reconstruction: maximizing early continence recovery in robotic-assisted radical prostatectomy. asian j urol.2021;8(1):126133. doi: 10.1016/j.ajur.2020.01.003. epub 2020 jan 27. 6. dylewski d, jamison m, borawski k, sherman n, amundsen c, webster g. a statistical comparison of pad numbers versus pad weights in the quantification of urinary incontinence. neurourol urodyn. 2006;26(1):3-7. 7. tsui j, shah m, weinberger j, ghanaat m, weiss j, purohit r, blaivas j. pad count is a poor measure of the severity of urinary incontinence. j urol.2013;190(5):1787-1790. 8. l o s e g, r o s e n k il d e p, g a m m el g a a r d j, s c h r o e d e r t. pad-weighing test performed with standardized bladder volume. urology.1988;32(1):78-80. 9. machold s, olber t pj, hegele a, kleinhans g, hofmann r, schrader aj. comparison of a 20-min pad test with the 1-hour pad test of the international continence society to evaluate postprostatectomy incontinence. urol int.2009;83(1):27–32. https://doi. org/10.1159/000224864 10. groutz a, blaivas jg, chaikin dc, resnick nm, engleman k, anzalone d, et al. noninvasive outcome measures of urinary incontinence and lower urinary tract symptoms: a multicenter study of micturition diar y and pad tests. j urol.2000;164 (3 par t 1):698 –701. doi: 10.1097/00005392-200009010-00019. 11. rasmussen a, mouritsen l, dalgaard a, frimodt-møller c. twenty-four hour pad weighing test: reproducibility and dependency of activity level and fluid intake. neurourol urodyn.1994;13(3):261–265. doi: 10.1002/1520-6777(1994)13:3<261::aid-nau1930130308>3.0.co;2-t. 12. thind p, gerstenberg tc. one-hour ward test vs. 24-hour home pad weighing test in the diagnosis of urinary incontinence. neurourol urodyn.1991;10(3):241–245. doi.org/10.1002/nau.1930100304 13. donovan j, peters t, abrams p, brookes s, de la rosette j, schafer w. scoring the short form icsmalesf questionnaire. j urol.2000;164(6):1948-1955. 14. international consultation on incontinence questionnaire male lower urinary tract symptoms module (iciq-mluts) [internet]. iciq. 2022 [cited 23 may 2021]. available at: https://iciq.net/iciq-mluts. accessed march 17, 2022. 15. avery k, donovan j, peters t, shaw c, gotoh m, abrams p. iciq: a brief and robust measure for evaluating the symptoms and impact of urinary incontinence. neurourol urodyn.2004;23(4):322-330. doi: 10.1002/nau.20041. 16. litwin m, hays r, fink a, ganz p, leake b, brook r. the ucla prostate cancer index: development, reliability, and validity of a healthrelated quality of life measure. med care.1998;36(7):1002-1012. doi: 10.1097/00005650-199807000-00007 17. mungovan s, carlsson s, gass g, graham p, sandhu j, akin o, et al. preoperative exercise interventions to optimize continence outcomes following radical prostatectomy. nat rev urol.2021;18(5):259-281. doi: 10.1038/s41585-021-00445-5. epub 2021 apr 8. 18. swinscow t, campbell m. statistics at square one. 9th ed. [s.l.]: bmj publishing group; 1997. not consider variables that may have affected it, such as activity level and fluid intake[6,27]. this is a small, single-surgeon series, which may introduce patient selection bias and may not be representative of the broader rarp population. a larger, multicentre study should be considered to confirm our findings. furthermore, 6 weeks is a short follow-up period and correlation between 24-hour pad weight and proms may vary at greater follow-up intervals. however, our study focused on the early postoperative period because this is when incontinence is most significant. a large proportion of our cohort (70%) had reached continence by 6 weeks. beyond 6 weeks, the proportion of incontinent men is small and we did not feel that it would be meaningful to compare ppi assessment methods when the range of ppi symptoms is not appreciable. conclusion proms may be used as a substitute for the 24-hour pad weight test for ppi assessment in the early post-rarp period. iciq-sf and ucla-pci urinary function and qol scores strongly correlate with 24-hour pad weight. however, the iciq-mluts incontinence and qol scores provide the strongest correlation with ppi. 129siuj.org siuj • volume 3, number 3 • may 2022 pad weight, pad number, and incontinence-related patient-reported outcome measures after radical prostatectomy http://siuj.org 19. karantanis e, o'sullivan r, moore kh. the 24-hour pad test in continent women and men: normal values and cyclical alterations. bjog.2003;110(6):567–571. 20. singh m, bushman w, quentin clemens j. do pad tests and voiding diaries affect patient willingness to par ticipate in studies of incontinence treatment outcomes? j urol.2004;171(1):316–318. doi: 10.1097/01.ju.0000101844.65511.75. 21. sacco e, bientinesi r, gandi c, di gianfrancesco l, pierconti f, racioppi m, et al. patient pad count is a poor measure of urinary incontinence compared with 48-h pad test: results of a large-scale multicentre study. bju int.2018;123(5a):e69-e78. doi: 10.1111/bju.14566. epub 2018 oct 19. 22. stolzenburg j, holze s, neuhaus p, kyriazis i, do h, dietel a, et al. robotic-assisted versus laparoscopic surgery: outcomes from the first multicentre, randomised, patient-blinded controlled trial in radical prostatectomy (lap-01). eur urol.2021;79(6):750-759. doi: 10.1016/j. eururo.2021.01.030. epub 2021 feb 9. 23. aarsæther e, roaldsen m, knutsen t, patel h, soltun b. improvement in early continence after introduction of periurethral suspension stitch in robotic prostatectomy. j robot surg.2020;15(5):679-686. published online 2020 oct 14. doi: 10.1007/s11701-020-01156-6 24. nitti v, mourtzinos a, brucker b. correlation of patient perception of pad use with objective degree of incontinence measured by pad test in men with post-prostatectomy incontinence: the sufu pad test study. j urol.2014;192(3):836-842. doi: 10.1016/j.juro.2014.03.031. epub 2014 mar 18. 25. machioka k, kadono y, naito r, nakashima k, iijima m, kawaguchi s, et al. evaluating urinary incontinence before and after radical prostatectomy using the international consultation on incontinence questionnaire‐short form. neurourol urodyn.2018;38(2):726–733. doi: 10.1002/nau.23907. epub 2018 dec 21. 26. ito h, young gj, lewis al, blair ps, cotterill n, lane ja, et al. grading severity and bother using the international prostate symptom score and international consultation on incontinence questionnaire male lower urinary tract symptoms score in men seeking lower urinary tract symptoms therapy. j urol.2020;204(5):1003–1011. doi: 10.1097/ ju.0000000000001149. epub 2020 may 29. 27. painter v, karantanis e, moore kh. does patient activity level affect 24-hr pad test results in stress-incontinent women? neurourol urodyn.2011;31(1):143–147. doi: 10.1002/nau.21169. epub 2011 jul 20. 130 siuj • volume 3, number 3 • may 2022 siuj.org original research http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information pelvic organ prolapse (pop), bladder calculi, cystolitholapaxy, sacrocolpopexy none declared. received on july 12, 2022 accepted on, july 27, 2022 soc int urol j. 2023;4(1):8–10 doi: 10.48083/qjep9763 siu training scholarship: an unforgettable experience at the muljibhai patel urological hospital, nadiad-gujarat, india emmanuel ugbede oyibo urology unit, department of surgery, usmanu danfodiyo university teaching hospital sokoto, nigeria introduction the société internationale d’urologie (siu) provides 2 types of scholarships to young urologists around the world, especially those from developing countries who obtained their medical doctorate less than 10 years earlier. the scholar is given the rare opportunity to train in an siu-accredited centre located in their own geographical area, if available. the scholarship affords the trainee an observational role for a 3or 6-month period, with a stipend during the stay. although this is a highly competitive process, the siu has maintained a high sense of commitment to trainees all over the world. in this paper, i share my experiences at one of the most advanced and sought-after training centres—a personal account of my 6-month stay as an siu fellow from sokoto in north western nigeria, at the world-renowned hospital. muljibhai patel urological hospital(mpuh): siu-accredited centre mpuh (figure 1), a premier institute in india devoted entirely to urology and nephrology, was established in 1978 by dr virendra desai, an internationally trained urologist, in partnership with philanthropists jayaramdas patel, shri occhavlal parikh, and shri prahlad patel. today, mpuh has a 160-bed capacity (up from 25 beds at inception) and houses 6 operating theatres, 44 dialysis stations, and urology, nephrology, anesthesiology, radiology, and pathology departments, along with a modern clinical laboratory and blood bank. the hospital houses a state-of-the-art teaching and training centre, jayaramdas patel academic centre (jpac), an ultramodern library of an international standard containing a rich array of scholarly materials and internet access. the laparoscopic training skills laboratory is also located at the jpac, with facilities for dry and wet activities and for practice on models under a dedicated and committed staff. the activities at the laboratory include transurethral resection, percutaneous nephrolithotomy, and robotic and uro-mentor models, such as chicken pyeloplasty, an indigenous innovation from the mpuh team. institutional structure and clinical rotation during my stay at the hospital, the daily academic programmes, ot sessions, and lectures/teaching sessions were avenues for the consultants to teach all cadres of trainees. the trainers and trainees were so magnanimous with their knowledge and experience, sharing freely when opportunities arose. the activities at the urology unit commenced daily at 7:30 a.m. (except on fridays, which began at 8:00 a.m.) with teaching rounds by the consultants. the ot started at 9:00 a.m., and there were evening rounds for review of patients and preparation of the list for the next day. activities on wednesday were preceded by a transplant meeting, with the transplant team—the medical director, administrative staff representative, all urologists, nephrologists, anaesthetists, and nurses—discussing thoroughly the cases and patients’ progress. the uropathology meetings were held on tuesdays to discuss the histological results of all patients and decide on their further management. 8 siuj • volume 4, number 1 • january 2023 siuj.org urology around the world http://siuj.org on friday mornings, there were oncology board meetings to discuss the outcome of all oncological cases and their line of management vis-à-vis their current state. everyone was expected to attend these meetings. following all these meetings, there was a breakfast at the jpac reception for all doctors; it was never skipped once during my stay. achievements of the hospital the hospital remains one of the most well-attended centres under the siu training programme: 94 doctors from the geographic region have trained as consultants, and 11 are currently undergoing the same training. several doctors from around the world have had their training at the hospital, including those who have completed their siu training. over 225 international and national publications have come from the hospital, as well as patents associated with its highly revered scholars. many of its doctors have gone on to provide leadership in almost every stratum of the urological community both nationally and internationally. over the years, many devices have been innovated at the mpuh, including the laparoscopic needle holder to avoid wobble, the nadiad bag (specimen retrieval bag for laparoscopy), and the chicken model for training in urology (for laparoscopic pyeloplasty). procedures participated in during my fellowship training a total of 1840 urological procedures, including renal transplantation, were carried out in mpuh during the period of my training. figure 2 shows the distribution. the procedures include some of the latest interventions in urology. minor procedures consist of both open and endourological. figure 1. muljibhai patel urological hospital, nadiad-gujarat, india additional learning experience while in india the management of the hospital was very kind to allow me to spend 5 weeks of my training period at the widely recognised kulkarni endosurgery and reconstructive institute in pune, india (figure 3), under the tutelage of the world-renowned reconstructive surgeon and past president of the siu, professor sanjay b. kulkarni. the reception offered by his wife, dr jyotsna kulkarni (laparoscopic genera l surgeon), a nd dr pa nkaj joshi(urologist), fellows at the hospital, and the ot staff was heartwarming. during my short stay, i participated in the following procedures: turp (4), epididymis cyst excision (1), rgp/rt pyeloplasty (1), pfud and preputial skin tube (4), bmg urethroplasty (23), urs/dj stenting (3), urethroplasty (7), pfud (6), preputial skin graft (6), hypospadias repair (5), female bmg urethroplasty (3), dviu/injection paclitaxel (3), panurethral urethroplasty (2) and orandi flap urethroplasty (1). conclusion my experience in india was my first and best training experience outside my country. the facility is the envy of many, with the hospital always improving its services and imparting knowledge to all who visit. the sense of dedication to duty in mpuh by all and sundry is highly commendable and admired. my siu training at the mpuh was a huge success, and i am motivated to return to nigeria and offer the highest standards of urological care to our patients. recommendations the siu should continue to support and strengthen the bond of friendship with the mpuh, as their role image courtesy of hospital imaging department. 9siuj.org siuj • volume 4, number 1 • january 2023 siu training scholarship: an unforgettable experience at the muljibhai patel urological hospital, nadiad-gujarat, india http://siuj.org in training urologists around the world will remain relevant in the years to come. where possible, there should be a high premium on international recognition and support from donor agencies, which play an integral part in urological education around the world. acknowledgements i am grateful to professors ismaila arzika mungadi, ngwobia peter agwu, abdullahi abdulwahab-ahmed, abubakar umar and the entire management of the usmanu danfodiyo university teaching hospital, sokoto, nigeria, for their magnanimity and support. i want to express my appreciation of professor mahesh desai-mrd (former siu president), the medical director of the mpuh-col (dr) ak rastogi, mr george (secretary) and dr ravindra sabnis (chairman, department of urology), who facilitated my acceptance letter and ensured my license was successful despite all the hitches. i must also say thank you to all the consultants, fellows, and residents at the mpuh. appreciation to ana acosta at the siu central office in canada for her immense assistance all through my training. lastly, my sincere appreciation to my wife, modupe, and our lovely children, joshua, anna, and deborah, who endured my absence, and to my parents and siblings for their sacrifices to ensure i was comfortable. god remains to be appreciated immensely for giving me life. figure 2. procedures undertaken at mpuh during my siu training n um be r of p ro ce du re s categories of procedures 800 700 600 500 400 300 200 100 0 robotic renal transplant avf creation laparoscopic minor (open and endourological) endourologicalmajor open urological 91 94 110 123 196 505 721 figure 3. l-r.professor sanjay kulkarni (past president, siu), emmanuel oyibo (siu scholar), and other trainees at kulkarni endosurgery institute and reconstructive centre, pune, india 10 siuj • volume 4, number 1 • january 2023 siuj.org urology around the world http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information overactive bladder, therapeutics, urgency urinary incontinence none declared. received on march 15, 2021 accepted on july 4, 2021 soc int urol j.2021;2(5):311–322 doi: 10.48083/hzvq6675 311siuj.org siuj • volume 2, number 5 • september 2021 review overactive bladder: where we are and where we are going charan s. mohan,1 wai lee,1 kathleen c. kobashi2 1 the arthur smith institute for urology, northwell health, new hyde park, united states 2 section of urology and renal transplantation, virginia mason medical center, seattle, united states abstract overactive bladder (oab) is a heterogeneous syndrome estimated to affect approximately 10% to 15% of men and women globally. oab not only negatively impacts quality of life but also results in a significant financial burden to both patients and health systems. therefore, it is crucial that oab is properly addressed. this manuscript provides a general review of the diagnostic algorithm for oab and treatment per the aua/sufu guidelines, and an overview of new developments in oab therapy. given the wide array of therapeutic options that currently exist and those that are currently under development, there is tremendous opportunity to treat oab successfully and positively affect our patients’ lives. introduction impact of overactive bladder overactive bladder (oab) affects approximately 10% to 15% of men and women, with some estimates placing prevalence as high as 27% for men and 43% for women[1-3]. individuals with oab have been shown to have poorer quality of life, higher rates of depression, and decreased rates of sexual fulfillment when compared with individuals who do not have oab[4]. in a cohort of several north american and western european nations, oab-related expenses amounted to. €1.2 billion per year[5]. with the high prevalence of oab, the aging population, and the associated cost to the system, proper management of oab is essential. this manuscript provides an overview of current treatment options and a discussion regarding new developments in advanced therapies. defining overactive bladder oab was first described as a clinical entity in the late 1980s[6]. the american urological association (aua)/society of urodynamics, female pelvic medicine and urogenital reconstruction (sufu) oab guidelines acknowledge the challenges in defining oab, as reflected by the number of statements that are based upon expert opinion rather than scientific publications. joint work by the international urogynecological association (iuga) and international continence society (ics) defines oab as “urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence (uui), in the absence of urinary tract infection (uti) or other obvious pathology”[7]. figure 1 shows an algorithm proposed by the authors to guide the evaluation of patients with oab symptoms. while not a guideline, this pathway can offer clinicians, particularly those not familiar with oab management, a structured approach to managing these patients. http://siuj.org mailto:cmohan2%40northwell.edu?subject=siuj methods a comprehensive literature search was performed using pubmed regarding (1) the pathophysiology of oab, (2) treatment options for oab, and (3) special considerations with respect to oab management. approach to treatment is presented per the aua/sufu guidelines, summarizing lifestyle modifications (firstline), pharmacotherapy (second-line), and surgical and interventional therapies (third-line), and concluding with a discussion regarding new treatment developments in advanced therapies. pathophysiology several etiologies for oab have been defined: (1) myogenic detrusor overactivity (do), (2) overactive signaling by the central nervous system (cns) causing micturition (neurogenic), and (3) alterations within the urothelium of the lower urinary tract[8,9]. the myogenic hypothesis attributes do to changes within the bladder smooth muscle that result in increased excitability and spontaneous contraction[10]. in vivo tissue studies have suggested that structural changes within the detrusor muscle in oab could allow for increased conduction of electrical impulses with resultant contraction among a large proportion of muscles cells[11]. in the neurogenic hypothesis, bladder overactivity is attributed to increased neuroplasticity within the cns[12]. maladaptive sensory signaling from pelvic sensory nerves can instigate do and precipitate oab[13]. two neurotrophins, specifically brain-derived neurotrophic factor (bdnf) and nerve growth factor (ngf), have been implicated in oab. these are modulators of neural plasticity, and individuals with oab symptoms have demonstrated detectable amounts of these molecules in their urine[14–17]. additionally, individuals with oab exhibit varying degrees of functional connectivity in the cortex on functional mri (f mri) studies[18,19], and interestingly, sacral neuromodulation has been demonstrated to cause cerebral activity on fmri[20], emphasizing the role of cns function in oab. regarding the urothelial hypothesis, research in rat models indicates that chronic urothelial injury, as modeled by intravesical injection of protamine su lfate into rats, ca n cause increased urina r y frequency and decreased voided volumes[21]. a related hypothesis postulates that oab symptoms may also be urethrogenic, that is, arising from the urethra[22]. specifically, low urethral tone and subsequent stress urinary incontinence (sui) or contact of urine with the proximal urethra can stimulate the proximal urethral afferent nerves that can initiate micturition via the urethrovesical reflex and, in some cases, cause symptoms of oab. newer areas of exploration for oab pathophysiology include the role of sex hormones, mood disorders, and the effect of the urinary microbiome[23]. oab treatment guidelines the aua/sufu oab guidelines provide a framework clinicians can use to diagnose and stratify patients with oab. as acknowledged in the guidelines, there is a lack of evidence-based publications in the current literature regarding the diagnosis of oab. a clinical principle in the guidelines suggests that the initial evaluation for uncomplicated oab requires only a thorough history and physical examination and a urinalysis to rule out conditions that may mimic oab, such as urinary tract infection or malignancy. use of adjunct tests such as urine cultures or post-void residuals can be incorporated as deemed necessary. the guidelines also clarify that uds, cystoscopy, and renal imaging are not indicated in the initial workup. clinicians should also consider how oab symptoms may manifest in select populations, such as men with benign prostatic hypertrophy (bph) or women with genitourinary syndrome of menopause (gsm). the guidelines stratify oab treatment into several tiers: first-line (behavioral and non-pharmacologic), second-line (pharmacologic t herapy), t hird-line (surgical and interventional therapies) and fourth-line (urinary diversion or bladder augmentation)[1]. this discussion focuses on the first 3 tiers. abbreviations aua american urological association bph benign prostatic hypertrophy btx onabotulinumtoxina cns central nervous system do detrusor overactivity gsm genitourinary syndrome of menopause mri magnetic resonance imaging oab overactive bladder pro patient-reported outcomes rct randomized control trial snm sacral neuromodulation sufu society of urodynamics, female pelvic medicine, and urogenital reconstruction sui stress urinary incontinence uds urodynamics us ultrasound uti urinary tract infection uui urge urinary incontinence 312 siuj • volume 2, number 5 • september 2021 siuj.org review http://siuj.org figure 1. suggested clinical algorithm for management of oab evaluation and treatment of patient with oab symptoms* complete history & physical, ua, urine culture rule out • cystitis (infection and non-infectious) • neurologic etiology • urinary retention • urologic malignancy • gender speci�c causes of urgency (eg, bph in men, gsm in women) • other predominantly night time symptoms? rule out osa lower extremity edema? evaluate nighttime drinking habits no yes trial of therapy symptoms persist aqer trial of �rstand second-line therapies? first-line therapies • lifestyle modi�cations • pelvic �oor physical therapy second-line therapies • anticholinergics • beta 3 agonists consider ancillary testing uds cystoscopy imaging uds cystoscopy imaging third-line therapies • tibial nerve stimulation • intra-detrusor chemodenervation • sacral neuromodulation symptoms persist after third-line therapy? consider ancillary testing consider fourth-line therapies • bladder augmentation • urinary diversion * this is a suggested clinical algorithm proposed by the authors, recognizing other clinical approaches exist. 313siuj.org siuj • volume 2, number 5 • september 2021 overactive bladder: where we are and where we are going http://siuj.org first-line therapy first-line therapy for oab includes low-risk behavioral interventions, although much of the data supporting t hese t herapies is drawn from non-randomized controlled trials (rct). in a study of pelvic f loor biofeedback for oab symptoms in women, 9 weeks of emg-based biofeedback for pelvic floor muscle therapy resulted in significant symptom improvement[24]. a review exploring the role of pelvic f loor muscle therapy traditionally used for sui found the use of similar regimens in patients who had urinary urgency and oab symptoms effectively reduced symptoms[25]. in a comprehensive review regarding urinar y symptoms in overweight and obese women, weight loss showed no benefit in the reduction of urinary urgency[26]. however, in a cohort of morbidly obese patients who underwent laparoscopic sleeve gastrectomy, patients experienced a significant improvement in oab symptoms as measured by a 3-day voiding diary and improvement on the oab short form questionnaire. the mean reduction in bmi following surgery was 9 kg/m2, suggesting that the magnitude of weight loss to reduce symptoms may be unattainable for many patients[27]. smoking and dietary habits, particularly consumption of carbonated beverages, alcohol, and caffeine, can cause oab symptoms. accordingly, lifestyle modifications aimed at reducing smoking and dietary triggers can result in an improvement of oab[28]. finally, an association between functional constipation and oab has been shown[29–31], but these studies do not specifically report on the effect of treating constipation and relief of oab. second-line therapy anticholinergics anticholinergics are a well-established pharmacotherapy for oab[1]. there are 5 described subt y pes of muscarinic receptors, of which m2 and m3 are found in highest concentration within the bladder. while the m2 receptor is predominant in the bladder, the m3 receptors are most strongly associated with micturition control[32]. a review examining the effectiveness of anticholinergics versus behavioral therapy concluded that anticholinergics outperformed non-pharmacologic interventions for improvement in oab symptoms[33]. while dry mouth and constipation are the most frequent side effects of anticholinergic medications, cognitive side effects can be profound, particularly amongst older individuals. the rates of discontinuation of anticholinergics in trial settings have been shown to be as high 80%[34]. in a case– control study conducted in the united kingdom, anticholinergic exposure was associated with dose-dependent increased odds of developing dementia[35]. this relationship has been well documented and demonstrated, particularly in older individuals[36–38]. at a molecular level, trospium’s bulky quaternary amine structure limits its penetration across the blood–brain barrier, thereby reducing unwanted cognitive effects[39,40]. beta-3 agonists beta-3 agonists represent a newer class of oab medication. studies have demonstrated that mirabegron is equally efficacious as anticholinergics in their reduction of oab symptoms[41–43]. potential side effects include hypertension and cardiac arrythmia[44]. in a study examining the safety profile of mirabegron, there was a slight increase in hypertension with this drug compared with placebo and only among individuals over 75 (7% versus 5%)[45]. the absence of hypertension risk has also been reaffirmed on meta-analysis[46]. in an observational study from the uk, improvements in both quality of life and health status were seen for patients on mirabegron, with over 50% persisting on the drug at 12 months[47]. recently approved, vibegron is a novel beta-3 agonist that has also shown efficacy in placebo-controlled studies including reduction of micturition episodes and urge incontinence episodes[48,49]. furthermore, recent rct data showed no difference in the rates of hypertension between patients on vibegron versus placebo[50]. despite a higher per-pill cost of beta-3 agonists, recent studies have demonstrated a similar cost-effectiveness between beta-3 agonists and anticholinergics. this increased cost-effectiveness has been attributed to decreased discontinuation of beta-3 agonists, leading to improved quality of life, decreased need for third-line therapies, and decreased health care use due to adverse events[51–54]. third-line therapy third-line therapies represent a rapidly growing category of oab treatment, although they remain underutilized[55]. existing third-line therapies include bladder chemodenervation with onabotulinumtoxina (btx), percutaneous tibial nerve modulation (ptnm), and sacral neuromodulation (snm). bladder chemodenervation with onabotulinumtoxina chemodenervation involves the prevention of presynaptic release of acetylcholine (ach) thereby averting excitation of ach-dependent smooth muscle within the detrusor and reducing bladder contractions[56]. data also suggest that the toxin may decrease sensory input during bladder filling via its effect on atp-regulated signaling mechanisms[56–58]. btx is administered cystoscopically with injections distributed throughout the bladder[59,60]. complete 314 siuj • volume 2, number 5 • september 2021 siuj.org review http://siuj.org resolution of urinary incontinence has been shown to be higher amongst those receiving btx (27%) compared with those on anticholinergics (13%)[61]. btx also outperforms placebo for the reduction of oab symptoms, with 2.95 fewer daily uui episodes compared with 1 fewer observed with a placebo after 12 weeks of treatment[58]. btx injection also appears to be of therapeutic value for all patients with idiopathic oab, regardless of whether do is present on pretreatment urodynamics[62]. one of the potential risks of btx is urinary retention. however, the definition of retention is not standardized across the btx reports, and this has contributed to the widely variable (2% to 35%) rates reported in the literature. the risk of retention appears to be dose-dependent[63–66]. studies have demonstrated a median of 7.6 months of symptom relief following btx injection[67]. there are data suggesting that the production of neutralizing antibodies can result in tachyphylaxis with successive treatments with btx. however, this risk has been drastically lowered with newer formulation of the toxin[68]. percutaneous tibial nerve modulation performed in the clinic setting, ptnm involves 12 weekly in-office sessions during which a 34-gauge needle is placed cephalad to the medial malleolus and posterior to the tibia. the posterior tibial nerve is stimulated at varying frequencies with an external generator. the hy pothesized mechanism of action involves modulation of bladder contraction via both afferent and efferent pathways of the tibial nerve[69,70]. ptnm has shown success in patients with refractory oab. in a study of patients undergoing a 12-week study course, a 25% reduction in mean day time urinary urgency, a 35% reduction in number uui episodes, and a 21% reduction in nighttime frequency was reported[71]. adverse effects of ptnm are rare and include bruising, pain, and bleeding at the needle site[59]. ptnm therefore remains a well-tolerated and efficacious option for the treatment of oab. despite this, there remains a high drop-out rate, with retrospective data indicating an over 40% discontinuation rate[72], similar to the drop-out rates reported with btx. only 40% to 60% of patients receive a second injection, with subsequent treatments decreasing even further[73–75]. the updated oab guidelines include a specific statement that the guidelines do not represent a stepby-step algorithm that must be followed in successive order. consequently, a study that showed success with ptnm in drug-naïve oab patients was of interest. in a single-arm study of drug-naïve oab patients with >3 uui episodes a day, 78% of patients saw a 50% reduction in their uui episodes, with 40% achieving complete continence[76]. sacral neuromodulation sacral neuromodulation is an operative procedure, performed in 2 stages. during the first stage, a tined lead connected to an external generator is inserted into the s3 foramina. if the patient experiences a ≥ 50% improvement in their symptoms during the 1 to 2 week trial period, a permanent impulse generator (ipg) is inserted into a subcutaneous pocket low back/upper buttock[77]. alternatively, the first stage can be done in the office setting as a peripheral nerve evaluation with temporar y bilateral leads, with or without fluoroscopic guidance. if successful, the lead and ipg can subsequently be placed in a single procedure. snm has been shown to be well tolerated and more efficacious than standard medical therapy. in a study comparing snm with anticholinergic medical therapy, 76% of the snm arm experienced therapeutic success (≥ 50% improvement) compared with 49% of the medical arm[78]. while the rosetta trial suggested a slight advantage of btx over snm in reducing oab symptoms, this trial used an unconventional 200-unit dose of btx, as opposed to the accepted 100 units for idiopathic oab[79]. this initial advantage of btx was not noted at 2 years. in the 2-year follow-up, 72% of patients randomized to btx had required a second injection, with half of these individuals requiring a third[80]. in a retrospective analysis of state claims data, 38% of all patients who undergo snm implantation undergo a lead revision within 5 years of their initial lead implantation, approximately two-thirds for device malfunction and the remaining third for treatment failure[81]. another consideration with snm is magnetic resonance imaging (mri) compatibility. in mid-2020, a full-body mri-compatible lead became fda-approved and available for implantation; patients can safely undergo a full-body mri with a 1.5 or 3 tesla magnet for up to 30 minutes without a rest period. however, it is important to consider the implications of the leads placed before the availability of the new leads, with which patients should not undergo mri below the neck. a review examining neuromodulation, both ptns and snm, for oab found that overall snm was both well tolerated and effective in improving oab symptoms. there are no long-term data describing ptns success against snm[82]. new technologies in third-line therapy new chemodenervation options are being studied. data suggest that chimeric alternatives to the btx toxin, such as the bont/bmy-ww toxin have stronger affinity for nerve terminal binding, which modulates bladder effects[83]. intravesical instillation of btx mixed with hydrogel to promote a slower release of drug without 315siuj.org siuj • volume 2, number 5 • september 2021 overactive bladder: where we are and where we are going http://siuj.org the need for injection has been demonstrated to be well tolerated in interstitial cystitis patients[84]. while btx hydrogel is still in the trial phase as part of the apollo study, the potential to deliver btx “topically” via urinary catheter as opposed to via cystoscopic injections could significantly enhance the ease of delivery[85]. new technologies for ptnm are also in development. the ecoin is an implantable device, approximately the size of a nickel, that is placed along the course of the patient’s posterior tibial nerve. it can be placed in the office setting and implantation minimizes the need for weekly visits. during clinical trials, 68% of subjects demonstrated at least 50% reduction in uui episodes at 48 weeks[86]. another investigational technology is the stimguard device. an internal lead is placed near the posterior tibial nerve, which can be stimulated with an external device that remains with the patient. the ongoing protect trial is a multicenter rct designed to evaluate stimguard for non-inferiority of versus traditional snm for oab[87]. while traditional snm devices require a stepwise procedure to insert the leads and subsequently a permanent ipg, the ahlevees system from neuspera medical inc. provides an alternative approach. this new device is a miniature implantable stimulator that can be placed into the s3 foramen and differs from the existing snm technology in that in lieu of an internal ipg, the ahlevees system uses an external wireless generator. the use of this device in a small pilot study was seen to produce physiologic responses consistent with adequate stimulation of the s3 nerve root foramina, including bellows and great toe plantarflexion[88]. table 1 shows the major third-line therapies and the corresponding emerging technologies for oab. definition of success for interventions as the presentation of oab is heterogenous, defining success in the management of oab can be challenging. a systematic review published in 2014 sought to assess what current research uses to define success in oab trials. in this review, number of uui episodes was the most common metric used to assess treatment efficacy, with treatment response defined as a reduction in uui episodes of between 50% and 100% from baseline. other symptom-based markers of treatment response were number of urgency episodes per day, voids per day, and changes in urodynamic parameters[89]. the adoption of patient-reported outcomes (pros) has increased in biomedical and clinical research, and pro tools are now more commonly used in oab research[90,91]. the use of pros as opposed to disease-oriented or symptom-based endpoints can provide a standardized means of communicating symptoms between patients and their physicians in the preoperative setting, thereby facilitating improved expectation and goal-setting before medical or surgical intervention for oab[92]. special clinical considerations nocturia nocturia, defined as needing to awaken at least one or more times per night to void, is one of the most common lower urinary tract symptoms (luts)[93]. while nocturia can be related to urologic disorders such as oab or bph, a variety of non-urologic conditions can also cause nocturia. among these are diabetes, heart failure, and sleep apnea[60,93,94]. in patients with nocturia-predominant oab symptoms, urologists should investigate possible alternative diagnoses that may explain a patient’s symptoms. in patients with table 1. third-line therapies for oab and future directions therapy possible expansion bladder chemodenervation with onabotulinumtoxina chimeric alternate molecules for bpnt/a btx mixed with hydrogel sacral neuromodulation ahlevees implantable generator system percutaneous tibial nerve modulation ecoin implantable device stimguard implantable device 316 siuj • volume 2, number 5 • september 2021 siuj.org review http://siuj.org bothersome nocturia, 24-hour urine testing to evaluate for nocturnal polyuria should be considered, as should referral for sleep studies in patients who have a history of snoring or obstructive sleep apnea. considerations for neurogenic bladder luts and oab-like symptoms are highly prevalent in individuals with neurologic conditions, such as stroke or multiple sclerosis[95]. up to 80% of ms patients will have bladder dysfunction in their lifetime, with 10% of all ms patients demonstrating urinary symptoms as the initial manifestation[96]. the approach to patients with neurogenic bladder can mirror the approach to those without neurologic disease, starting with firstand second-line therapies and escalating to advanced therapies[97]. pharmacotherapy, particularly anticholinergics, have been shown eff icacious in managing oab amongst those with neurogenic bladder, although higher doses are often required[98]. while btx is the only fda-approved therapy for neurogenic bladder, it should be noted that some studies have demonstrated that neuromodulation provides benefit to neurogenic patients with refractory oab[99]. sex differences in overactive bladder management the genitourinary syndrome of menopause (gsm), previously referred to as vulvovaginal atrophy, refers to all collective genitourinary symptoms associated with a decreasing level of estrogen in perimenopausal women[100]. twenty percent of postmenopausal women report severe urinary urgency, and nearly 50% of these women have some form of urinary incontinence[101]. both topical therapies, such as vaginal estrogen, and non-topical options, such as selective estrogen receptor modulators (ospemifene and lasofoxifene in particular), have been shown to improve urinar y symptoms among women with gsm[99,100,102]. at the authors’ institutions, women with gsm and a history of breast or gynecological malignancy are frequently treated with local estrogen following consultation with their oncologist and shared-decision making with the patient. while oab prevalence is approximately equal between men and women, women are more likely to present with uui[103]. as alluded to in the aua/sufu guidelines, men presenting with oab-like symptoms should be screened for bph[1]. however, oab is still common among men with bph, with up to 75% of men with bph having clinical symptoms of oab or do on uds[104]. therefore, clinicians should consider a concomitant diagnosis of oab in men with persistent luts despite treatment for bph. in general, although sex-specific factors should be considered in any approach to oab evaluation, treatment should be patient-specific based on both the presenting symptoms and patient goals of care. conclusion oab is a complex clinical syndrome that can have a serious impact on patient quality of life. from lifestyle modifications to implantable devices, the wide spectrum of available oab therapies provides clinicians a large armamentarium to help alleviate oab symptoms for their patients. this review explores various treatment modalities for oab along with recent developments, with a particular emphasis on third-line therapies. despite their high-efficacy rates compared to firstand second-line therapies, third-line treatments for oab continue to be underutilized. in recent years, however, there has been a rapid growth and development of novel therapies. these new technologies allow for more patient-centered and tailored approaches to managing oab symptoms, making it an exciting time to be a clinician treating oab. 317siuj.org siuj • volume 2, number 5 • september 2021 overactive bladder: where we are and where we are going http://siuj.org references 1. gormley e, lightner d, burgio k, chai t, clemens j, culkin d, et al. diagnosis and 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efficacy and safety of sacral and percutaneous tibial neuromodulation in non-neurogenic lower urinary tract dysfunction and chronic pelvic pain: a systematic review of the literature. eur urol.2018 mar;73(3) doi:10.1016/j.eururo.2017.11.002 83. thaker h, zhang s, diamond d, dong m. beyond botulinum neurotoxin a for chemodenervation of the bladder. curr opin urol.2021;1;31(2):140146. doi:10.1097/mou.0000000000000843 84. rappaport y, zisman a, jeshurun-gutshtat m, gerassi t, hakim g, vinshtok y, et al. safety and feasibility of intravesical instillation of botulinum toxin-a in hydrogel-based slow-release delivery system in patients with interstitial cystitis-bladder pain syndrome: a pilot study. urology.2018 apr;114doi:10.1016/j.urology.2017.12.028 85. clinicaltrials.gov. apollo: the study of an investigational drug, patisiran (aln-t tr02), for the treatment of transthyretin (t tr)mediated amyloidosis. full text view. 2021. available at: https:// clinicaltrials.gov/ct2/show/nct01960348. 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10.1185/03007995.2013.860021 90. deshpande pr, rajan s, sudeepthi bl, abdul nazir cp. patient-reported outcomes: a new era in clinical research. perspect clin res.2011 oct;2(4):137-44. doi: 10.4103/2229-3485.86879. pmid: 22145124; pmcid: pmc3227331. 91. speight j, barendse s. fda guidance on patient reported outcomes. bmj.2010;340:c2921. doi: 10.1136/bmj.c2921. 92. marschall-kehrel d, roberts r, brubaker l. patient-reported outcomes in overactive bladder: the influence of perception of condition and expectation for treatment benefit. urology.2006 aug;68(2 suppl) doi:10.1016/j.urology.2006.02.046 93. weiss jp. nocturia: focus on etiology and consequences. rev urol.2012;14(3-4):48-55. 94. arslan b, gezmis c, çetin b, gönültas s, gökmen e, gürkan o, et al. is obstructive sleep apnea syndrome related to nocturia? low urin tract symptoms.2019 may;11(3)doi:10.1111/luts.12250 321siuj.org siuj • volume 2, number 5 • september 2021 overactive bladder: where we are and where we are going http://siuj.org 95. wein a, dmochowski r. neuromuscular dysfunction of the lower urinary tract. in: partin a, peters c, kavoussi l, dmchowski r, wein a, eds. campbell walsh wein urology. elsevier; 2020. 96. aharony s, lam o, corcos j. evaluation of lower urinary tract symptoms in multiple sclerosis patients: review of the literature and current guidelines. can urol assoc j.2017;11:61-64. 97. kurpad r, kennelly m. the evaluation and management of refractory neurogenic overactive bladder. curr urol rep.2014 oct;15(10) doi:10.1007/s11934-014-0444-z 98. kennelly m, devoe w. overactive bladder: pharmacologic treatments in the neurogenic population. rev in urology.2008;10(3). 99. sanford m, suskind a. neuromodulation in neurogenic bladder. transl androl urol.2016 feb;5(1)doi:10.3978/j.issn.2223-4683.2015.12.01 100. portamn d, ls gass m, panel vatcc. genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the international society for the study of women's sexual health and the north american menopause society. j sex med.2014 dec;11(12) doi:10.1111/jsm.12686 101. kim h, kang s, chung y, kim j, kim m. the recent review of the genitourinar y syndrome of menopause. j menopausal med.2015;21(2):65-71. doi:10.6118/jmm.2015.21.2.65 102. schiavi m, sciuga v, giannini a, vena f, d’oria o, prata g, et al. overactive bladder syndrome treatment with ospemifene in menopausal patients with vulvovaginal atrophy: improvement of sexuality? gynecol endocrinol.2018 aug;34(8)doi:10.1080/0951359 0.2018.1441398 103. eapen r, radomski s. gender differences in overactive bladder. can j urol.2016 feb 2016;23(suppl 1):2–9. 104. dmochowski r. overactive bladder in males. therapeutic adv urol.2009;1(4):209-221. 322 siuj • volume 2, number 5 • september 2021 siuj.org review http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information urodynamics, aging, bladder outlet obstruction, bladder contractilty, detrusor overactivity, bladder compliance none declared. received on march 31, 2021 accepted on june 5, 2021 soc int urol j.2021;2(5):274–281 doi: https://10.48083/lqxf2741 274 siuj • volume 2, number 5 • september 2021 siuj.org original research association of age with lower urinary tract function in adult men presenting for urodynamics: a database analysis sanjay sinha, lavina matai department of urology, apollo hospitals, hyderabad, india abstract background knowledge regarding lower urinary tract function in adult men could help in making informed choices. few studies have examined the entire spectrum of adult males. methods this is a retrospective analysis of all adult men with refractory non-neurogenic urinary symptoms presenting to a tertiary center over 9 years. international continence society defined indices bladder outlet obstruction index (booi) and bladder contractility index (bci) were calculated with established classification. storage abnormality was defined as presence of detrusor overactivity, poor compliance (< 20ml per cm h20) or both. data were analyzed by non-parametric tests using spss (version 20.0.0, armonk ny ) (p < 0.05 significant; 2-tailed). where appropriate, correction for multiple hypothesis testing was applied. results a total of 1596 men (range 18 to 91 years, median 51.0 years; iqr 34 to 64 years) were eligible. median bci and booi were 99.5 and 37.0, respectively, and a storage abnormality was noted in 41.7%. on multivariate analysis, age was significantly associated with urodynamic findings. while not strictly linear, for each 10 years increase in age, on average, the bci fell 2.4 points and the booi increased by 2.4 points. increasing age was also associated with increasing odds of finding a storage abnormality (or 1.015; 95%ci 1.008 to 1.022; p < 0.001). on post hoc analysis (bonferroni correction), men under 30 years were least likely of any group to show obstruction (30.3%; median booi 26). conclusions adult men with refractory urinary symptoms show age-associated differences in urodynamic findings. an awareness of these trends can help take more informed decisions in clinical care. introduction age is known to impact all aspects of lower urinary tract function[1]. knowledge regarding detrusor contractility, outlet obstruction and storage abnormality in men of different age groups could help in making more informed choices with regard to evaluation and treatment. men with an underactive detrusor or severe storage abnormality show an inferior outcome following prostate surgery[2,3]. the european association of urology guidelines recommends invasive urodynamics testing before surgery in specified age groups[4]. however, few large studies have examined the entire spectrum of adult males, with most excluding either the young or the elderly. http://siuj.org mailto:drsanjaysinha%40hotmail.com?subject=siuj this is a retrospective database analysis of all adult men who presented for urodynamics with a non-neurogenic lower urinary tract abnormality to a large volume referral center. material and methods data pertaining to all adult men with a non-neurogenic lower u ri na r y t rac t cond it ion who u nder went urodynamics over the last 9 years (may 2011 to february 2020) were retrieved. ethics committee approval was obtained (ahh‐acd‐ 001‐ 01‐20). exclusion criteria included prior surgery of the lower urinary tract, history of indwelling catheter or intermittent catheterization, another lower urinary tract pathology such as posterior urethral valves or reflux, neurological disease, and primary upper urinary tract pathology such as ureteropelvic junction obstruction or urolithiasis (except in men with incidental non-obstructive calyceal stones); also excluded were men in whom a voiding phase evaluation was not feasible (for instance due to severe storage abnormality precluding filling) and those for whom we had incomplete data. urodynamics was performed as per international continence society (ics) recommendations[5] using a two-catheter technique (both 5f). the peak detrusor contraction pressure of the tallest do was recorded as the do pressure. compliance was measured from the commencement to the end of filling phase. the end fill detrusor pressure was recorded as 1cm h20 whenever it was ‘0’. graphs were manually scrutinized to eliminate artifacts. when a patient produced a volitional contraction but failed to void, the maximum detrusor pressure (pdet.max) was recorded in place of pdet.qmax. bladder outlet obstruction index (booi) and bladder contractility index (bci) were calculated as per ics guidelines[6]. for patients with a calculated booi of ≤ 0, a value of 0 was recorded. the booi and bci were both recorded as ‘0’ in men with acontractility. bci was categorized as 0 (underactive, < 100), 1 (normal, 100 to 150) and 2 (strong, ≥ 150). booi was categorized as 0 (unobstructed, < 20), 1 (equivocal obstruction, 20 to 40) and 2 (unequivocally obstructed, ≥ 40). in the occasional patient who voided more than the volume filled, the post-void residual (pvr) was recorded as 0 ml. non-parametric tests were used since the data were not normally distributed on preliminary analysis. spss (version 20.0.0, armonk ny ) was used for analysis. the data were first analyzed by stratifying age into “age by decade” to assess the impact on different urodynamics outcome measures. post hoc analyses were performed for the categories of the 3 main urodynamic findings bci, booi, and storage abnormality. multivariate analysis was performed to assess the independent impact of age (un-stratified) on the numerical value of bci and booi, as well as the presence of storage abnormality. data for linear regression were presented as estimate of change in dependent variable with each unit change in independent variable with 95% confidence intervals (ci) and p-value. results a total of 3980 adult men with non-neurogenic lower urinary tract dysfunction underwent urodynamics between may 2011 and february 2020. after exclusions (indwelling or intermittent catheterization, 1629; prior urinary tract surgery, 264; dialysis or transplantation, 97; history of congenital lower urinary tract disorder, 49; voiding phase evaluation not feasible, 20; incomplete data, 325), there were 1596 (range 18 to 91 years, median 51.0 years; iqr 34 to 64 years) evaluable patients. urodynamic findings stratified by “age by decade” along with univariate analyses are shown in table  1. presence of detrusor overactivity, abnormal storage, and diabetes mellitus, as well as capacity, median booi, booi category, bci category, pdet.qmax, qmax, and pvr, all showed a significant association with age. detrusor overactivity was noted in 524 patients (32.8%) with median peak detrusor pressure 33cm h20 (iqr 20 to 55). a total of 17.2% of men presented with hydronephrosis of at least one kidney. numerical value of bci and booi stratified by “age by decade” and pressure-f low data are depicted in figures 1 to 3. intergroup post hoc analysis (crosstab chi-square; bonferroni correction) for association of “age by decade” with storage abnormality is shown in table 2. overall, the commonest major urodynamics finding was an underactive detrusor (bci < 100), noted in 834 men (52.3%). unequivocal bladder outlet obstruction (booi ≥ 40) was noted in 725 men (45.4%). abnormal storage was seen in 665 men (41.7%). isolated obstruction, isolated underactivity, and isolated storage abnormality were noted in 14.2%, 26.8%, and 5.4%, respectively. multiple regression analyses were performed to assess the impact of age on booi, bci, and presence of storage abnormality. the overall models to predict booi, bci, and storage abnormality were statistically abbreviations bci bladder contractility index booi bladder outlet obstruction index ci confidence interval iqr interquartile range or odds ratio pvr post-void residual 275siuj.org siuj • volume 2, number 5 • september 2021 association of age with lower urinary tract function in adult men presenting for urodynamics: a database analysis table 1. urodynamic findings based on “age by decade” along with univariate analyses in adult men with refractory lower tract symptoms overall <30 years 30–40 years 40–50 years 50–60 years 60–70 years 70–80 years > 80 years statistic n 1596 317 242 226 290 317 176 28 age, years median (iqr) 51.0 (34.0, 64.0) 25 (22, 28) 36 (33, 38) 45 (43, 48) 56 (53, 58) 65 (63, 68) 75 (72, 77) 83 (82, 84) p < 0.001 dm (%) 498 (31.2) 5 (1.6) 16 (6.6) 48 (21.2) 137 (47.4) 176 (55.5) 98 (55.7) 18 (64.3) p < 0.001 detrusor overactivity (%) 524 (32.8%) 84 (26.5) 66 (27.3) 58 (25.7) 79 (27.2) 131 (41.3) 96 (54.5) 10 (35.7) p < 0.001 c om pl ia nc e m l/ cm h 20 (% ) <10 118 (7.4) 25 (7.9) 19 (7.9) 13 (5.8) 23 (7.9) 20 (6.3) 14 (8.0) 4 (14.3) p = 0.09210–20 186 (11.7) 41 (12.9) 32 (13.2) 17 (7.5) 24 (8.3) 47 (14.8) 20 (11.4) 5 (17.9) ≥20 1292 (81.0) 251 (79.2) 191 (78.9) 196 (86.7) 243 (83.8) 250 (78.9) 142 (80.7) 19 (67.9) abnormal storage (%)a 665 (41.7%) 119 (37.5) 94 (38.8) 71 (31.4) 102 (35.2) 154 (48.6) 108 (61.4) 17 (60.7) p < 0.001 capacity (iqr) 320 (301, 377) 317 (303, 361) 333 (304, 398) 331 (304, 404) 330 (302, 392) 314 (266, 366) 301 (206, 325) 303 (197, 318) p < 0.001 efp (iqr) 6 (3, 13) 7 (3, 14) 7 (3, 13) 6 (3, 11) 6 (3, 12) 6 (3, 13) 6 (3, 10) 7 (4, 22) p = 0.256 bci (iqr) 98.5 (75.8, 128.0) 95 (74, 130) 100 (78, 130) 98 (70, 131) 102 (76, 133) 100 (80, 122) 96 (79, 115) 87 (76, 108) p = 0.356 booi (iqr) 37.0 (18.0, 64.0) 26 (11, 46) 35 (18, 63) 36 (17, 66) 42 (23, 77) 42 (24, 66) 41 (23, 63) 41 (19, 57) p < 0.001 pdet.qmaxb 53 (39, 78) 46 (35, 65) 52 (39, 78) 50 (35, 83) 58 (39, 91) 60 (41, 78) 56 (44, 74) 52 (39, 65) p < 0.001 qmax 7 (4, 10) 8 (5, 12) 7 (4, 11) 7 (4, 10) 7 (3, 9) 7 (4, 10) 7 (4, 10) 7 (4, 9) p < 0.01 pvr 55 (3, 166) 22 (0, 122) 44 (1, 168) 48 (2, 158) 79 (7, 191) 68 (6, 184) 63 (15,164) 107 (33,144) p < 0.001 aabnormal storage was defined as either presence of detrusor overactivity or compliance < 20 ml/cm h20 or both. bfor patients who could not void, the pdet.max was recorded instead of pdet.qmax efp end fill pressure; pdet.qmax: detrusor pressure at maximum flow; qmax: maximum flow rate. 276 siuj • volume 2, number 5 • september 2021 siuj.org original research significant. increasing age was associated with a higher booi and presence of storage abnormality but a lower bci. age (−0.240, 95%ci −0.352 to −0.127; p < 0.001) and booi (0.807; 95%ci 0.765 to 0.849; p < 0.001) but not presence of diabetes mellitus or storage abnormality was associated with bci. age (0.241; 95%ci 0.146 to 0.337; p < 0.001), bci (0.582; 95%ci 0.552 to 0.613; p < 0.001) and storage abnormality (10.887; 95%ci 7.869 to 13.905; p < 0.001) but not diabetes mellitus was associated with booi. age (or 1.015; 95%ci 1.008 to 1.022; p < 0.001) and booi (or 1.012; 95%ci 1.009 to 1.016; p < 0.001), but not diabetes or bci, were associated with presence of storage symptoms. discussion this study showed significant age-associated differences on urodynamics evaluation of men presenting with refractory lower urinary tract symptoms. increasing age was independently associated with reduced bladder contractility (measured by the bci), increasing degree of obstruction (measured by the booi), and increasing odds of f inding a storage abnormality (detrusor overactivity, reduced compliance < 20 ml per cm h20, or both). although not strictly linear, for each 10 years increase in age, on average, the bci fell 2.4 points and the booi increased by 2.4 points. increasing decadal age was also negatively associated with capacity and positively associated with storage abnormality and pvr. age (years) b ci 18–30 30–40 40–50 50–60 60–70 70–80 80–90 100.0 250 200 100 0 age (years) 250 200 100 18–30 30–40 40–50 b o o i 0 80–90 50 20.0 150 50–60 60–70 70–80 pdet.qmax 53.0 0 q m ax 0 10 20 7.0 30 30 100 200 300 400 figure 1. bladder contractility index values stratified by age in box plot a value over 100 is regarded as normal (horizontal marker line). note the trend of lower values for median bci with each advancing decade beyond the sixth decade. figure 2. bladder outlet obstruction index values stratified by age in box plot a value under 20 is regarded as unobstructed (horizontal marker line). note the numerically lower median booi in men in the 18 to 30 years age group. intergroup analysis showed that men in the 18 to 30 age group were least likely to show severe obstruction (p < 0.05; bonferroni correction). figure 3. scatter plot of qmax versus pdet.qmax the median value for qmax (7.0 ml per second) and median pdet.qmax (53 cm h20) are marked by the horizontal and vertical marker lines, respectively. 277siuj.org siuj • volume 2, number 5 • september 2021 association of age with lower urinary tract function in adult men presenting for urodynamics: a database analysis the median bci in adult men was noted to be about 100 in this study, which is similar to the findings of several other studies[7–9]. underactivity was noted in 52.3%, higher than the 11% to 40% reported in a review[10]. there was an independent age-associated decline in contractility. literature on the association of age and bladder contractility is conflicting[11], but others studies have reported a similar association with age[7,8,12]. age can impact bladder contractility by several possible mechanisms. these include changes in both afferent and efferent neuronal pathways as well as the smooth muscle and collagen within the bladder wall that might be mediated, at least in part, by ischemia[1]. while it is tempting to attribute all these changes simply to aging, it is often difficult to resolve whether the observations are due to disease processes that are increasingly common with aging. older men are also more likely to suffer from diabetes. however, diabetes mellitus was not independently associated with underactivity in our patients (n = 498; 31.2%) when controlled for age. lack of data on duration or control might have blunted our ability to identify its impact. bladder outlet obstruction was noted in 45.4% of our patients with median booi 37 (iqr 18 to 64) similar to the findings of rosier et al. (booi 37)[12] but somewhat lower than that reported by oelke et al. (booi 44) [9]. equivocal obstruction was noted in a further 428 (26.8%) of men. age was independently associated with the possibility of finding obstruction, which is not surprising, given that age is associated with prostate size. however, it is instructive to note that a significant minority of patients showed no obstruction at all. presence of a storage abnormality (detrusor overactivity, poor compliance < 20 ml per cm h20, or both) was associated with age. both detrusor overactivity and poor compliance were noted to be more common in the elderly, although the latter was not statistically significant (table 1). overall detrusor overactivity and poor compliance were noted in 32.8% and 19.1%, respectively. on multiple regression, presence of bladder outlet obstruction was independently associated with presence of a storage abnormality. in a study of 3357 men, detrusor overactivity and poor compliance was noted in 45% and 7.7%, respectively[7]. an association between poor bladder compliance (< 20 ml/cm h20) and older age, with a linear reduction for each decade beyond the sixth has been noted in another study[13]. alterations in afferent signaling systems and connective tissue matrix are important in the pathogenesis of detrusor overactivity and reduced compliance that are often seen with aging[14]. these changes might be accelerated by the presence of concomitant obstruction[15]. post hoc analyses of differences based on “age by decade” showed interesting sub-trends. the proportion of men with a strong detrusor dropped progressively with age from the sixth decade (figure 1). the proportion of men with a storage abnormality showed a progressive increase beyond the age of 60 years, being 35.2%, 48.6%, 61.4%, and 60.8% in the sixth, seventh, eighth and beyond eighth decade, respectively (table 2). men under 30 years of age undergoing urodynamics were the least likely of any age group to show obstruction (30.3%; median booi 26), with an additional 28.7% demonstrating equivocal obstruction (booi 20 to 40). underactive detrusor was noted in 54.6%. other authors examining young men with refractory urinary symptoms with urodynamics have reported different findings. a study of 86 men below the age of 45 years found obstruction in 62% and an underactive detrusor in 10%[16]. this study, however, did not provide the data for men under 30 years separately[16]. rosier et al. found a progressive reduction in detrusor contractility, as measured by the watt factor, from the second decade to the ninth decade[12]. young men might demonstrate the residual consequences of childhood disorders of lower urinary tract function, such as dysfunctional voiding, table 2. association between presence of storage abnormality and “age by decade” age by decade (years) and number of men with or without a storage abnormality storage abnormality 18–30 30–40 40–50 50–60 60–70 70–80 ≥ 80 total no storage abnormality 198 148 155 188 163 68 11 931 abnormal storage 119 94 71 102 154 108 17 665 abnormal, % 37.5 38.8 31.4 35.2 48.6 61.4 60.7 41.7 total 317 242 226 290 317 176 28 1596 storage abnormality defined as detrusor overactivity, poor compliance (<20cm h20), or both. 278 siuj • volume 2, number 5 • september 2021 siuj.org original research faulty toilet training, or bowel-bladder dysfunction. of note, dysfunctional voiding is a common diagnosis in young men with refractory urinary symptoms undergoing urodynamics[17,18]. maximum flow rate and bladder capacity showed a reduction with age, but although statistically significant, this was not clinically relevant. however, a concomitant increase in residual urine implied progressive reduction in voiding efficiency with age. in fact, the effective capacity reduced by about one-third in men above 80 years of age compared with those between 18 and 30 years. this has implications for storage symptoms such as frequency and nocturia. the european association of urology guidelines recommend use of preoperative urodynamics testing before surgery in men above 80 and below 50 years of age with predominant voiding symptoms (both weak recommendations), while acknowledging the lack of adequate data to support this guidance[4]. our study would suggest that such evaluation might be particularly important in men under 30 years of age. older men show a higher prevalence of storage disorders, underactivity, and obstruction, but the trends are gradual and noticeable well before the threshold of 80 years. of note, men above the age of 80 years made up only 1.8% of our study population. while universal use of urodynamics has not been shown to improve patient outcomes, it is important to define subsets of men who might be at higher risk of non-obstructive lower urinary tract symptoms[19]. such men might be less likely to have a satisfactory outcome after outlet surgery[2]. an important limitation of this study is the lack of clinical information with respect to symptoms. the method of recording symptoms varied during the study period, making it difficult to unify data. hence, it is important to understand the clinical context for this group. patients were typically offered urodynamics only when they failed medical management. a total of 17.2% had hydronephrosis of at least one kidney at presentation consistent with the refractory nature of their symptoms. men with isolated storage abnormality were seldom subjected to urodynamics. instead, they received treatment based on clinical judgment. consequently, only 5.4% of men had an isolated storage abnormality. however, as we have reported earlier, presence of storage phase abnormality was associated with an increased probability of finding hydronephrosis[20]. the duration of symptoms might have impacted bladder function. in a study of men with and without outlet obstruction, bci and flow rate reduced, while pvr increased over a follow-up of 10 years[21]. however, an earlier publication failed to show any change in detrusor contractility with time[22], and symptoms are not generally regarded as a reliable predictor of the underlying abnormality[23]. the policy with respect to surgery in men with a clinical diagnosis of bladder outlet obstruction would be expected to impact the findings of this (and similar studies). while elderly men often undergo surgical intervention without urodynamics this is unlikely to happen in young men. therefore, the data for elderly men are likely to omit men with unequivocal clinical findings suggestive of benign prostatic obstruction (who might be expected to have a higher booi and bci). of note, the bias introduced by this is likely to strengthen the significance of the lower propensity for finding obstruction that we noted in men less than 30 years of age. this database study examined urodynamics findings across the entire spectrum of adult men. while a few studies have provided these data, most studies have excluded either the young or the elderly.[7,9,24,25] conclusions examining all men in a single study offers the opportunity to apply a uniform yardstick to yield comparative data. the conclusions from this study are clearly not applicable to the general population of adult men. however, they give a clue to anticipated lower urinary tract function in adult men with refractory lower urinary tract symptoms in whom a urodynamic evaluation (and by extension a possible surgical intervention) is being contemplated. 279siuj.org siuj • volume 2, number 5 • september 2021 association of age with lower urinary tract function in adult men presenting for urodynamics: a database analysis references 1. vahabi b, wagg as, rosier pfwm, rademakers klj, denys m-a, pontari m, et al. can we define and characterize the aging lower urinary tract?—ici-rs 2015. neurourol urodyn.2017;36:854–858. doi: 10.1002/nau.23035 2. zhong p, zhao yr, qiao bm, yang f-j, zhu y, yang z-q, et al. comparison of two numerical parameters to assess detrusor contractility in prognosing short-term outcome after transurethral resection of the prostate. urol int.2020;104:361–366. doi: 10.1159/000503331 3. antunes aa, iscaife a, reis st, albertini a, nunes ma, lucon am, et al. can we predict which patients will experience resolution of detrusor overactivity after transurethral resection of the prostate? j urol.2015;193:2028–2032. doi: 10.1016/j.juro.2014.12.095 4. gravas s, cornu jn, gacci c, gratzke c, herrmann trw, mamoulakis c, et al. managment of non-neurogenic male lower urinary tract symptoms. european association of urology guidelines, 2020. available at: ht tps://uroweb.org/guideline/treatment-of-nonneurogenic-male-luts. accessed december 15, 2020. 5. rosier pf wm, schaefer w, lose g, goldman hb, guralnick m, eustice s, et al. international continence society good urodynamic practices and terms 2016: urodynamics, uroflowmetry, cystometry, and pressure-flow study. neurourol urodyn.2017;36:1243–1260. doi: 10.1002/nau.23124 6. abrams p. bladder outlet obstruction index, bladder contractility index and bladder voiding efficiency: three simple indices to define bladder voiding function. bju int.1999;84:14–15. doi: 10.1046/j.1464 410x.1999.00121.x 7. jeong sj, lee jk, kim km, kook h, cho sy, oh s-j. how do we diagnose detrusor underactivity? comparison of diagnostic criteria based on an urodynamic measure. investig clin urol.2017;58: 247–254. doi: 10.4111/icu.2017.58.4.247 8. namitome r, takei m, takahashi r, kikutake c, yokomizo a, yamaguchi o, et al. a prediction model of detrusor underactivity based on symptoms and noninvasive test parameters in men with lower urinary tract symptoms: an analysis of a large group of patients undergoing pressure-flow studies. j urol.2020;203:779 –785. doi: 10.1097/ ju.0000000000000616 9. oelke m, rademakers klj, van koeveringe ga. unravelling detrusor underactivity: development of a bladder outlet resistance—bladder contractility nomogram for adult male patients with lower urinary tract symptoms. neurourol urodyn.2016;35:980–986. doi: 10.1002/ nau.22841 10. jeong sj, kim hj, lee yj, lee jk, lee bk, choo ym, et al. prevalence and clinical features of detrusor underactivity among elderly with lower urinary tract symptoms: a comparison between men and women. korean j urol.2012;53:342–8. doi: 10.4111/kju.2012.53.5.342 11. beltrame f, ferreira ft, lorenzetti f, dambros m, bisogni s, dambros m. bladder function in obstructed men does age matter? aging male.2015;18:143–148. doi: 10.3109/13685538.2015.1025377 12. rosier pfwm, ten donkelaar cs, de kort lmo. clinical epidemiology: detrusor voiding contraction maximum power, related to ageing. urology.2019;124:72–77. doi: 10.1016/j.urology.2018.10.038 13. madersbacher s, pycha a, klingler ch, mian c, djavan b, stulnig t, et al. interrelationships of bladder compliance with age, detrusor instabilit y, and obstruction in elderly men with lower urinar y tract symptoms. neurourol urodyn.1999;18:3–15. doi: 10.1002/ (sici)1520-6777(1999)18:1<3::aid-nau2>3.0.co;2-4 14. bellucci chs, ribeiro w de o, de bessa j jr, antunes a a, leite kmr, et al. increased detrusor collagen is associated with detrusor overactivity and decreased bladder compliance in men with benign prostatic obstruction. prostate int.2017;5:70 –74. doi: 10.1016/j. prnil.2017.01.008 15. oelke m, baard j, wijkstra h, de la rosette jj, jonas u, höfner k. age and bladder outlet obstruction are independently associated with detrusor overactivity in patients with benign prostatic hyperplasia. eur urol.2008;54:419–426. 16. nitti vw, lefkowitz g, ficazzola m, dixon cm. lower urinary tract symptoms in young men: videourodynamic findings and correlation with noninvasive measures. j urol.2002; 168: 135–8. 17. kaplan sa, ikeguchi ef, santarosa rp, d'alisera pm, hendricks j, te ae, et al. etiology of voiding dysfunction in men less than 50 years of age. urology.1996;47:836–839. doi: 10.1016/s0090-4295(96)00038-6 18. wang cc, yang ssd, chen yt, hsieh jh. videourodynamics identifies the causes of young men with lower urinary tract symptoms and low uroflow. eur urol.2003;43:386–390. 19. drake mj, lewis al, young gj, abrams p, blair ps, chapple c, et al. diagnostic assessment of lower urinary tract symptoms in men considering prostate surgery: a noninferiority randomised controlled trial of urodynamics in 26 hospitals. eur urol.2020;78:701–710. doi: 10.1016/j.eururo.2020.06.004 20. sinha s, mat ai l . is isolated bladder outlet obstruc tion associated with hydronephrosis? a database analysis. neurourol urodyn.2020;39:2361-2367. 21. chen sf, lee cl, kuo hc. change of detrusor contractility in patients with and without bladder outlet obstruction at ten or more years of follow-up. sci rep.2019;9. doi:10.1038/s41598-019-55386-2. 22. thomas aw, cannon a, bartleh e, ellis-jones j, abrams p. the natural history of lower urinary tract dysfunction in men: minimum 10-year urodynamic follow-up of untreated detrusor underactivity. bju int.2005;96:1295–1300. 280 siuj • volume 2, number 5 • september 2021 siuj.org original research 23. ding yy, lieu pk, choo pwj. is the bladder “an unreliable witness ” in elderly males with persistent lower urinary tract symptoms ? geriatr nephrol urol.1997;7:17–21. doi: 10.1023/a:1008299528728 24. karami h, valipour r, lotfi b, mokhtarpour h, razi a. urodynamic findings in young men with chronic lower urinary tract symptoms. neurourol urodyn.2011;30:1580–1585. doi: 10.1002/nau.21095 25. jamzadeh ae, xie d, laudano m, seklehner s, elterman ds, shtromvaser l, et al. urodynamic characterization of lower urinary tract symptoms in men less than 40 years of age. world j urol. 2014;32:469–473. doi: 10.1007/s00345-013-1134-z 281siuj.org siuj • volume 2, number 5 • september 2021 association of age with lower urinary tract function in adult men presenting for urodynamics: a database analysis this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information urinary bladder neoplasms, postoperative complications, internal hernia, cystectomy none declared. patient consent: obtained. received on may 2, 2022 accepted on, may 9, 2022 soc int urol j. 2023;4(1):71–72 doi: 10.48083/zjne2733 incarcerated internal hernia posterior to the iliac vessels after uncomplicated radical cystectomy sydney sparanese, cyrus chehroudi, peter c. black department of urologic sciences, university of british columbia, vancouver, canada radical cystectomy (rc) with pelvic lymph node dissection (plnd) remains the standard of care for patients with muscle-invasive bladder cancer[1]. despite improvements in surgical technique and perioperative care, complications of any grade occur in up to 58% of patients after rc, with infectious and genitourinary complaints being the most common[2]. we present a clinical picture of a rare complication: an incarcerated internal hernia of the small bowel behind the external iliac artery after an uncomplicated rc, plnd, and ileal conduit in a 77-year-old male. the patient presented to a community hospital with a 2-day history of recurrent episodes of nausea, vomiting, and non-specific, crampy abdominal pain 6 weeks after rc. his abdomen was tender on examination, but there was no sign of peritonitis. bloodwork revealed mild leukocytosis and an abdominal computed tomography (ct) demonstrated no specific cause for his symptoms. a repeat ct 4 days later demonstrated abrupt termination of oral contrast in the right hemipelvis, immediately adjacent to the external iliac artery (figure 1, left). edematous small bowel was trapped posterior and inferior to the iliac artery, consistent with internal herniation. at this point, the patient had signs of peritonitis with rebound tenderness. the patient underwent emergent laparotomy. the intraoperative findings confirmed small bowel obstruction secondary to entrapment of the bowel behind the right external iliac artery that had been skeletonized by prior plnd (figure 1, right). the bowel was gangrenous and required resection. a re-look laparotomy was performed 2 days later with restoration of intestinal continuity. one week following his final procedure, the patient was transferred to a community hospital near his home in stable condition, and he made a full recovery. references 1. gakis g, efstathiou j, lerner sp, cookson ms, keegan ka, guru ka, et al. icud-eau international consultation on bladder cancer 2012: radical cystectomy and bladder preservation for muscle-invasive urothelial carcinoma of the bladder. eur urol.2013 jan 1;63(1):45–57. 2. hautmann re, de petriconi rc, volkmer bg. lessons learned from 1,000 neobladders: the 90-day complication rate. j urol.2010 sep;184(3):990–994. doi/abs/10.1016/j.juro.2010.05.037 71siuj.org siuj • volume 4, number 1 • january 2023 clinical picture https://orcid.org/0000-0003-1269-9798 https://orcid.org/0000-0002-2919-7068 http://siuj.org figure 1. incarcerated internal hernia of the small intestine. both the computed tomography (left panel) and the intraoperative photograph (right panel) show the gangrenous ileum (marked with star) trapped below the right external iliac artery (outlined with white lines). the point where the ileum traverses posterior to the artery is marked with the block arrow and the dilated small bowel proximal to this is marked with a triangle. the resected small bowel is shown in the inset. 72 siuj • volume 4, number 1 • january 2023 siuj.org clinical picture http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj.org siuj • volume 4, number 1 • january 2023 5 editorial standing on the shoulders of giants peter c. black, editor-in-chief soc int urol j.2023;4(1):5 doi: 10.48083/dmjd6674 isaac newton famously wrote in 1676: “if i have seen a little further it is by standing on the shoulders of giants.” in this issue of the siu journal we introduce a new feature article that we will include regularly going forward: giants in urology. in medicine and surgery, we have a certain reverence for the pioneers who established the practices we incorporate into daily practice—but at the same time we have a short collective memory of those who have gone before us. icons in the field who drift into retirement are quickly forgotten by the next generation of urologists emerging from training. for this reason, we wanted to feature some of these giants. we are certainly not the first urologic journal to do so, but, aligned with the mission of the siuj, we will do this from a global perspective, showcasing giants from around the world, including those whose impact was perhaps appreciated only regionally. our first giant is rudolf (“rudy”) hohenfellner, the long-time chairman of the department of urology at the johannes gutenberg university in mainz, germany. reading this contribution from jan fichtner and margaret fisch reveals that this giant was himself influenced by giants that preceded him—and hohenfellner has without question spawned multiple giants himself (the authors included). the legacy of passing on skills, techniques, and wisdom to one’s own trainees and junior faculty is without doubt a key feature of any giant in the field. hohenfellner is like a godfather figure in german urology, as many chairs across the country started their careers under his tutelage. his surgical innovation has influenced many urologists around the world, benefitted not only all the patients he cared for but also all those cared for by his former trainees. i am myself one of the many trainees influenced by rudy hohenfellner. i had no idea who he was at the time, but he was the inspiration for me to pursue a career in urology. my first urologic experiences were his weekly lectures in the middle years of medical school. he regularly brought patients to his lectures and interviewed them with his thick viennese accent to allow the students to learn from the individual medical histories and experiences of the patients. urinary diversion was a regular feature in his lectures (mainz is after all where he developed the mainz pouch), and this was part of the inspiration for me to do an elective in urology. about 25 years later, i still do a lot of urinary diversion (although not the mainz variety). as i finish a continent cutaneous reservoir or an orthotopic neobladder, i often wonder how we get away with these extensive reconstructive surgeries. at least we have decades of positive experiences on which to build, but imagine the early pioneers of urinary diversion like hohenfellner who were developing the techniques that we have all since adopted. perhaps more importantly, hohenfellner instilled in his trainees many other lessons that were critical to the budding surgeon: discipline, technical excellence, scientific rigor, innovation, and devotion to the patient. i like to say that i might not do what i do today if i had not encountered rudy hohenfellner in the late 1990s in mainz. i am reminded of a conversation i had with a very prominent canadian urologist a few years ago on a subway in washington dc. he was lamenting that the meeting to which we were both traveling used to attract many of the major “icons” (his term) in the field, but that he had noticed a gradual decline in this pattern over the years. what he did not recognize is that he had become an icon himself, and the urologists that he viewed as icons were mostly retired. there are many giants, and giants will come and go. every urologist will have a different perspective on who is a giant in their region of the world and in their area of subspecialty practice. the impact of any given giant may be quite varied, including especially clinical research, translational research, biomarker and drug development, surgical innovation, modification of standard clinical practice, or exemplary leadership. some giants will have contributed specifically to the success of urological organizations like the siu, or to different urologic journals. we therefore invite contributions from urologists around the world. share with us the inspiration your mentor has imparted to others. we would like to capture in the pages of the siu journal some of the main achievements of these giants, the quintessence of their personalities, and their legacy to our field. who are the giants are in your urologic sphere? upon whose shoulders do you stand? http://siuj.org mailto:editorinchief%40siuj.org?subject=siuj this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information accessory spleen, testicular tumor, scrotal swelling, splenogonadal fusion none declared. patient consent: obtained. received on april 22, 2022 accepted on april 24, 2022 soc int urol j. 2022;3(5):354–355 doi: 10.48083/ctuz3597 figure 1. large accessory scrotal spleen. mri of the scrotum showed a large 8cm left scrotal mass (white arrow) (a). the testis could not be identified separately. histologic images showed splenic tissue (b, c) adherent to the tunica albuginea but not enveloped by it (hematoxylin and eosin staining; 5x magnification in b, and 10x in c; blue arrows show white pulp; red arrow shows red pulp with sinusoids) and adjoining atrophic testicular tissue (d) with clusters of leydig cells (red arrow) and atrophic seminiferous tubules (red arrow; hematoxylin and eosin staining; 10x) large accessory scrotal spleen masquerading as testicular tumor sirish bharadwaj,1 sanjay sinha,1 meenakshi swain2 1 department of urology, apollo hospital, hyderabad, india 2 department of pathology, apollo hospital, hyderabad, india a 75-year-old male presented with left scrotal swelling of 1 year’s duration. the firm, non-tender swelling was indistinct from the testis and consistent with left testicular tumor. serum alpha fetoprotein, beta-human chorionic gonadotropin, and lactate dehydrogenase levels were normal. scrotal ultrasonography and mri showed 8.4x5.0x4.0cm mass in the left scrotum without calcification or necrosis (figure 1a). the left testis could not be identified separately. a possibility of spermatocytic seminoma or lymphoma was considered. left high inguinal orchidectomy was performed with uneventful recovery. at histopathology, the entire mass was noted to be an accessory spleen with adjoining atrophic compressed testicular tissue (figures 1b,c,d). 354 siuj • volume 3, number 5 • september 2022 siuj.org clinical picture https://orcid.org/ https://orcid.org/0000-0001-7090-2091 mailto:drsanjaysinha%40hotmail.com?subject=siuj https://orcid.org/0000-0002-2121-2518 http://siuj.org accessory splenic tissue is a common finding noted in 2% to 35% of individuals most often in and around the splenic hilum[1]. it can be classified as continuous or discontinuous with the spleen[2]. accessory splenic tissue presenting as a scrotal mass is very rare[1]. splenic tissue reaches the scrotum as a result of spleno-gonadal fusion, typically on the left side with tissue enveloped or adherent to the tunica albuginea[3]. this case is unusual because of the age of presentation, relatively short history, and large size of the mass. most men present as young adults[2,3]. surgery is unnecessary if the diagnosis can be made preoperatively[4]. making a preoperative diagnosis to avoid surgery is practically difficult unless the patient can categorically state that the mass has been present and stable for years. in such a setting, doppler imaging showing a hyper-vascular upper polar mass[1] confirmed by splenic scintigraphy using technitium-tc99m[2] may help avoid surgery. intraoperative frozen section histology might help avoid orchidectomy if exploration is deemed unavoidable[3,4]. the short history in our patient is difficult to explain. patients with splenic disease such as leukemia or malaria may show concurrent increase in size of the accessory spleen[2]. however, our patient did not show any such disease. references 1. marwah n, bhutani n, kalra r, kajal p. accessory spleen within the scrotum. j pediatr surg case rep.2019 mar 1;42:19-23. 2. kadouri y, carnicelli d, sayegh he, benslimane l, nouini y. pathogenesis, diagnosis, and management of splenogonadal fusion: a literature review. case rep urol.2020 oct 7;2020:8876219. 3. huang g, huang y, zeng l, yuan m, wu y, huang l. continuoustype splenogonadal fusion: a case report. exp ther med.2017 may;13(5):2019-2021. 4. abokrecha a, almatrfi a. discontinued splenogonadal fusion and bilateral empty scrotum in an 18-month-old boy. european j pediatr surg rep.2017 feb;5(1):e1-e3. 355siuj.org siuj • volume 3, number 5 • september 2022 large accessory scrotal spleen masquerading as testicular tumor http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. management recommendations for prostate cancer during the covid-19 pandemic: a systematic review alan de j. martinez-salas, iñigo navarro-ruesga, erick a. rodenas-gil, jesus s. muruato-araiza, aldo jimenez-garcía, irving reyna-blanco, jorge g. morales-montor, carlos pacheco-gahbler urology division, hospital general dr manuel gea gonzález, mexico city, mexico abstract introduction the covid-19 pandemic has delayed screening, diagnostic workup, and treatment in prostate cancer (pca) patients. our purpose was to review pca screening, diagnostic workup, active surveillance (as), radical prostatectomy (rp), radiotherapy (rt), androgen deprivation therapy (adt) and systemic therapy during the covid-19 pandemic. materials and methods we performed a systematic literature search of medline, embase, scopus, lilacs, and web of science, according to preferred reporting items for systematic reviews and meta-analyses protocols (prisma-p) statement for relevant material published from december 2019 to february 2021. results prostate biopsy can be delayed, except when high-risk pca is suspected or the patient is symptomatic. active surveillance is appropriate for patients with very low risk, low risk (lr) and favorable intermediate risk (fir). rp and rt for high risk and very high risk can be safely postponed up to 3 months. hypofractionated external beam rt (ebrt) is recommended when rt is employed. adt should be used according to standard pca-based indications. chemotherapy should be postponed until the pandemic is contained. conclusions the international urological community was not prepared for such an acute and severe pandemic. pca patients can be adequately managed according to risk stratification. during the covid-19 pandemic, lr and fir patients can be followed with active surveillance. delaying rp and rt in high risk and locally advanced disease is justified. introduction in december 2019, a series of acute atypical respiratory diseases occurred in wuhan, china, caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (sars-cov-2), responsible for the coronavirus disease 2019 (covid-19) pandemic[1]. by the end of july 2020, 11.456 million confirmed covid-19 cases and 530 937 deaths had been reported globally, and by mid-march 2021, 120 million cases and 2.6 million deaths had been reported, according to the covid-19 dashboard by the center for systems science and engineering (csse) at johns hopkins university[2]. some studies have suggested that men with covid-19 have a higher risk than women for sars-cov-2-related complications and death[3,4]. prostate cancer (pca) is the most frequently diagnosed urogenital neoplasm and is currently the second leading cause of cancer deaths in men in the united states and europe[5,6]. key words competing interests article information androgen receptor antagonists, adjuvant chemotherapy, prostatic neoplasms, radiotherapy, sars coronavirus none declared. received on january 20, 2021 accepted on march 27, 2021 soc int urol j.2021;2(4):240–254 doi: 10.48083/mbsb4196 240 siuj • volume 2, number 4 • july 2021 siuj.org review mailto:alanmsalas19%40gmail.com?subject=siuj http://www.siuj.org covid-19 remains a challenge for health care professionals all around the globe. radical treatment, such as radiotherapy with curative intent and surgical procedures, has been affected by this pandemic. bhat et al. reported an increase of approximately 22% of pca patients on the waiting list of radical prostatectomies in a robotic oncological center, revealing the negative effect of covid-19 on surgical pca treatment[7]. we performed a systematic review of the best management recommendat ions for pca pat ients during t he covid-19 pandemic, and sought to establish a foundation for pca management in future pandemics. our primary aim was to assess the evidence published to date with respect to the management of pca with surger y, radiotherapy, androgen deprivation and systemic therapy, for all stages and risk stratification categories, since the beginning of covid-19 pandemic. we also sought to determine whether studies on changes in pca workup and management made because of the pandemic have provided adequately robust evidence to establish guidelines for pca management in future pandemics. materials and methods protocol development and registration we registered our systematic review protocol in prospero (internat iona l prospect ive reg ister of sy s t em at ic re v ie w s , re g i s t r at ion nu mb er crd42020193332), following the prisma-p (preferred reporting items for systematic reviews and metaanalyses protocols) statement[8]. eligibility criteria and literature search we performed a systematic literature search using medline and embase, scopus, lilacs (literatura latinoamericana y del caribe en ciencias de la salud), and web of science, including all indexed publications in english, spanish, and french. we included recommendations, systematic reviews, clinical trials, and casecontrol, cohort, and cross-sectional studies related to the workup and management of pca, patients (such as screening, diagnosis, any modality of treatment, radical prostatectomy (rp), radiation therapy (rt), androgen deprivation therapy (adt), chemotherapy (cht) and follow-up), from december 1, 2019, to february 28, 2021. editorials, letters, and opinion articles were excluded. study selection and data extraction two independent investigators (ajms and jsma) performed the systematic literature search and screened all identified paper titles and abstracts. the full text of each identified article was reviewed by 3 independent investigators (ajms, jsma, inr). any disagreement about individual study inclusion was resolved by a fourth investigator (earg). information on included studies was entered into an excel database. information included the authors, country of research, publication title, date of publication, study design, indexed databases, management options studied in the publication methodology, outcome, and recommendations. risk of bias and quality assessment individual study quality assessment was performed using the appropriate tool for the study design and methodology: strobe (strengthening the report of observational studies in epidemiology-ii) for cohort, case-control, and cross-sectional studies[9], agree ii (appraisal of guidelines for research & evaluation) for guidelines and recommendations[10], and amstar-2 (a measurement tool to assess systematic reviews) for systematic reviews and meta-analysis[11]. the risk of bias (rob) was assessed using the robins-i[12] for individual included non-randomized studies, and the robis[13] for systematic reviews. all recommendations based on non-systematic reviews were managed as expert consensus; therefore, no rob was evaluated for such publications. outcome and synthesis methods we performed data synthesis for each element of pca management, including screening and diagnosis, surgica l treatment, radiation t herapy, androgen deprivation therapy, and systemic therapy. this synthesis was conducted for each pca risk group in abbreviations adt androgen deprivation therapy arat androgen-receptor-axis-targeted therapies as active surveillance bcr biochemical recurrence cht chemotherapy ebrt external beam radiation therapy fir favorable intermediate risk hr high risk lr low risk mcrpc metastatic castrate resistant pca mpmri multi-parametric mri nmcrpc non-metastatic castration-resistant prostate cancer pca prostate cancer psadt psa doubling time rob risk of bias rp radical prostatectomy rt radiation therapy uir unfavorable intermediate risk vhr very high risk vlr very low risk 241siuj.org siuj • volume 2, number 4 • july 2021 management recommendations for prostate cancer during the covid-19 pandemic: a systematic review http://siuj.org the national comprehensive cancer network prostate cancer guidelines risk stratification as well as for each stage group (localized, locally advanced, and metastatic pca)[14]. to determine adequate level of evidence and quality of recommendations for each different pca management strategy, publication quality of evidence was established, using the sign statement for the level of evidence[15]. the priority of management recommendations was based on the european urological association rapid reaction group level of priorit y for covid-19 pandemic[16]: emergency priority, labeled as black (cannot be postponed > 24 hours because of lifethreatening condition); high priority, red (should not be delayed > 6 weeks, since clinical harm such as progression, metastasis, loss of organ function, and death may occur); intermediate priority, yellow (cancel, but reconsider in case of increased capacity; delay of > 3 months may result in clinical harm and should therefore not be recommended); and low priority, green (clinical harm is very unlikely with delay of > 6 months). results literature search and study selection the literature search identified 349 papers from the different databases. after duplicates and articles not eligible for screening were eliminated, a total of 142 abstracts were screened, and 55 potentially eligible full text articles retrieved. of these, 27 papers were excluded since outcomes were not documented; therefore, 28 publications were included in our systematic review (figure 1). study characteristics, quality, and level of evidence of the included publications, 4 were systematic reviews, 16 expert opinion and consensus-based recommendations (non-systematic reviews), 1 case-control, and 3 cross-sectional and 4 cohort studies. regarding quality of evidence, most of the studies complied with more than two-thirds of the corresponding tool items. table 1 summarizes characteristics, study design, pca management approached during the covid-19 pandemic, results and recommendations, and sign level of evidence for each publication[15]. publications obtained with original search strategy n = 349 embase = 62 medline = 49 scopus = 102 lilacs = 51 web of science = 85 in c lu s io n s el ec ti o n s c r ee n in g id en ti fi c a ti o n screened publications (full abstract reading) n= 142 full text reading publications n= 55 included publications n= 28 excluded publications: duplication or not related to subject n = 207 excluded publications: opinion, editorials, not related to main outcome n = 87 publications excluded after full text reading n = 27 figure 1. prisma flow diagram 242 siuj • volume 2, number 4 • july 2021 siuj.org review http://siuj.org table 1. characteristics of included publications publication country date of publication methodology pca management level of evidence [15] rob assessment kokorovic et al.[20] canada june 2020 expert/consensus-based recommendations screening/diagnosis, as, rp, rt, adt 4 na heldwein et al.[34] international september 2020 systematic review screening/diagnosis, rp, rt, adt, cht 2 ++ lowa montopoli et al.[43] italy august 2020 case/control adt 2 moderateb gómez rivas et al.[21] spain february 2020 expert/consensus-based recommendations screening/diagnosis, rp, rt, adt, cht 4 na larrea et al.[41] spain may 2020 cross-sectional rt 3 na simcock et al.[29] international march 2020 expert/consensus-based recommendations as, rt 4 na amparore et al.[18] italy may 2020 systematic review screening/diagnosis, rp, rt, adt, cht 2 ++ higha würnschimmel et al.[32] germany may 2020 cross-sectional rp 2 na popert et al.[17] united kingdom may 2020 cross-sectional screening/diagnosis 2 na zaorky et al.[42] united states/ united kingdom march 2020 systematic review rt 2 ++ lowa méjean et al.[22] france march 2020 expert/consensus-based recommendations screening/diagnosis, rp, rt, adt, cht 4 na wallis et al.[39] international april 2020 expert/consensus-based recommendations rp, rt, adt 4 na narain et al.[23] india april 2020 expert/consensus-based recommendations screening/diagnosis, rp, rt, adt 4 na dovey et al.[24] international may 2020 expert/consensus-based recommendations screening/diagnosis, as, rp, rt, adt, cht 4 na katims et al.[36] united states june 2020 systematic review rp 2++ higha obek et al.[25] turkey july 2020 narrative review/ recommendations screening/diagnosis, rp, rt, adt 4 na tachibana et al.[40] united states november 2020 narrative review/ recommendations rp, rt, adt, cht 4 na tan et al.[31] united kingdom january 2021 cohort rp 2+ moderatea madan et al.[26] united states august 2020 narrative review/ recommendations screening/diagnosis, rp, rt, adt 4 na caffo et al.[45] italy september 2020 cohort adt 2+ higha a robis assessment tool[13] b robins-i assessment tool[12] adt: androgen deprivation therapy; as: active surveillance; na: not applicable; pca: prostate cancer; rob: risk of bias; rp: radical prostatectomy; rt: radiation therapy. continued on page 244 243siuj.org siuj • volume 2, number 4 • july 2021 management recommendations for prostate cancer during the covid-19 pandemic: a systematic review http://siuj.org screening and diagnosis of pca popert et al.[17] undertook a prospective cohort study of patients managed with prostate biopsy during the pandemic (april 2020) in the united kingdom. they established a 3-level risk stratification: • high risk (red): psa density > 0.2ng/ml/cc and mri suspicious lesions (likert/pi-rads 3, 4 and 5); biopsy should be performed within a month. • intermediate risk (amber): psa density < 0.2 and suspicious lesions; biopsy within 3 months. • low risk (green): psa density < 0.2 and no suspicious lesion; biopsy safely postponed indefinitely. amparore et al.[18] performed a systematic search of all urological association and society websites between april 8, and april 18, 2020, for guidelines on the management of urological pathologies during the pandemic. they concluded that prostate biopsies should be performed in men with suspected high-risk, locally advanced, or symptomatic pca and this should be done without preceding mri[19]. the remaining publications related to prostate biopsy are expert consensus recommendations[20–28]; most authors recommend that new psa screening and continuation of diagnostic workup should not be performed until the pandemic is contained and suggest delaying prostate biopsy except in symptomatic patients[21–23], psa > 10ng/ml[31,34,39], suspicion of ct3 disease, psa doubling time (psadt) < 6 months[24,27], or in case of medullary compression or obst r uct ive rena l fa i lure seconda r y to pca suspicion[22,27]. a summary of recommendations for screening and diagnosis is provided in table 2. active surveillance in pca six papers (all of them being either narrative reviews or consensus-based recommendations) addressed the role of active surveillance (as) in pca patients and concluded that in very low risk (vlr), low risk (lr), and favorable intermediate risk (fir) pca patients, as is an adequate management strategy[20,24,27,29,30]. for lr and fir patients, rodriguez-sanchez et al. and caicedo-martinez et al. suggest implementation of as while delaying rp and rt until the pandemic is controlled[27,30], and kokorovic et al. suggest either as or delaying rp up to 12 months[20]. detti et al. recommend multi-parametric mri (mpmri) of the prostate instead of re-biopsy in patients on as[28]. a summary of recommendations for as is provided in table 3. table 1. characteristics of included publications publication country date of publication methodology pca management level of evidence [15] rob assessment rodriguezsanchez et al.[27] international july 2020 narrative review/ recommendations screening/diagnosis, as, rp, rt, adt 4 na barthwal et al.[44] india july 2020 narrative review/ recommendations rt 4 na caicedo-martinez et al.[30] colombia july 2020 narrative review/ recommendations screening/diagnosis, as, rp, rt, adt 4 na detti et al.[28] italy february 2021 expert/consensus-based recommendations screening/diagnosis, as, rp, rt, adt 4 na diamand et al.[37] international june 2020 cohort rp 2++ lowa lalani et al.[46] canada april 2020 expert/consensus-based recommendations adt, cht 4 na shinder et al.[35] united states may 2020 expert/consensus-based recommendations rp, adt 4 na ginsburg et al.[38] united states october 2020 cohort rp 2++ lowb a robis assessment tool[13] b robins-i assessment tool[12] adt: androgen deprivation therapy; as: active surveillance; na: not applicable; pca: prostate cancer; rob: risk of bias; rp: radical prostatectomy; rt: radiation therapy. , cont’d 244 siuj • volume 2, number 4 • july 2021 siuj.org review http://siuj.org table 2. summary of prostate cancer screening and diagnostic evaluation recommendations during the covid-19 pandemic paper screening and diagnostic evaluation new pca screening symptomatic or mpca suspicion kokorovic et al.[20] new psa screening and diagnostic workup should be delayed heldwein et al.[34] individual patientbased decision. postpone until pandemic control; perform without mri if suspicion of advanced disease gómez rivas et al.[21] new psa screening and diagnostic workup should be delayed in symptomatic disease perform biopsy amparore et al.[18] delay until pandemic control biopsy without previous mri popert et al.[17] psa density ≥ 0.2 ng/ml/cc and mri likert/pi-rads 3, 4, 5 biopsy within 3 months, otherwise defer indefinitely méjean et al.[22] new psa screening and diagnostic workup should be delayed biopsy in case of medullary compression narain et al.[23] new psa screening and diagnostic workup should be delayed symptomatic disease or psa ≥ 10 ng/ml perform biopsy obek et al.[25] new psa screening and diagnostic workup should be delayed do not delay biopsy ≥ 3 months in: psa ≥ 20ng/ml, dre ct3 and psadt ≤ 6 months if suspicion of mpca, perform first imaging studies, if confirmed initiate adt, biopsy may be postponed madan et al.[26] delay diagnostic workup until pandemic control, no time specified rodriguez-sanchez et al.[27] delay biopsy unless psa ≥ 20 ng/ml, psadt ≤ 6 months, t3 or symptomatic eau rapid response priority level low priority intermediate priority recommendation summary pca screening and workup with psa and mri can be safely delayed until pandemic control; if suspicion of advanced, mpca, or symptomatic, consider biopsy without mri; if suspicion of mpca, perform imaging studies first dre: digital rectal examination; eau: european association of urology; mpca: metastatic prostate cancer; mri: magnetic resonance imaging; pca: prostate cancer; psa: prostate specific antigen; psadt: psa doubling time. surgical management of pca tan et al. performed a retrospective analysis of 282 patients who underwent rp between march and may 2020, 99% by robotic surgery, and none of the patients had developed sars-cov-2 infection at the 30-day follow-up after surgery[31]. in germany, würnschimmel et al. performed a retrospective analysis of all surgically treated pca patients, reporting a total of 784 patients, 447 (57%) patients before the pandemic (january and february 2020) and 337 (43%) patients in the first month and a half of the pandemic before operating room shutdown (march and april 2020)[32]. of a total of 784 patients, 623 (79%) patients were isup (international society of urological pathology) grades group 1, 2, and 3[33], corresponding to very low risk, low risk, favorable intermediate risk, and unfavorable intermediate risk. 245siuj.org siuj • volume 2, number 4 • july 2021 management recommendations for prostate cancer during the covid-19 pandemic: a systematic review http://siuj.org table 3. summary of active surveillance recommendations during the covid-19 pandemic paper active surveillance vlr lr fir kokorovic et al.[20] delay rp up to 12 months or as simcock et al.[29] as dovey et al.[24] as should be managed by telemedicine according to psa, genomic testing, and mri rodriguez-sanchez et al.[27] consider as, no rp or rt should be considered during the pandemic, psa testing may be postponed 3–6 months caicedo-martinez et al.[30] as indicated, delay rt until pandemic control detti et al.[28] as is preferred, consultation visits deferred by 6 months; if re-biopsy indicated during as, consider mpmri instead eau rapid response priority level low priority recommendation summary in vlr, lr and fir as is an adequate management strategy as: active surveillance; eau: european association of urology; fir: favorable intermediate risk; lr: low risk; mpmri: multi-parametric mri; mri: magnetic resonance imaging; psa: prostate specific antigen; rp: radical prostatectomy; rt: radiation therapy; vlr: very low risk. of these, 352 patients were treated before the pandemic, and 271 during the first month of the outbreak. the authors reported no statistical difference related to complications and outcomes and no covid-19 infection amongst the patients treated during the pandemic, and therefore concluded that performing surgery in these patients is feasible when adequate safety measures are in place[32]. heldwein et al. performed a systematic review of all urological management recommendations issued during the first months of the pandemic, including both consensus-based recommendations and opinionbased recommendations. on the basis of a previous european association of urology (eau) rapid reaction group statement[16], they proposed a 5-level, color-based triage for urological procedures priority: zero (red) for emergency: survivorship compromised if surgery not performed within hours; 1 (brown) proceed as planned, do not postpone: survivorship compromised if surgery nor performed within days; 2 (yellow), consider delaying up to 1 month: patient condition can deteriorate or survivorship be compromised if surgery not performed within 30 days or proceed as planned if covid-19 trajectory not in rapid escalation phase; 3 (green) safe delay 1 to 3 months: proceed as planned if covid-19 not in rapid escalation phase; 4 (blue) safe to delay > 3 months. for vlr, lr, fir, and uir prostate cancer, radical prostatectomy was considered blue level priority; therefore, delaying > 6 months is justified[34]. in a systematic search of rapid response recommendations and guidelines issued by european urological associations and societies, amparore et al. found that all recommended delaying surgical management for lowand intermediate-risk prostate cancer[18]. méjean et al. recommend delaying of rp in lowand intermediate-risk pca for at least 2 months[22], narain et al. and shinder et al. recommend delaying for up to 6 months[23,35], and 3 consensus-based recommendations state non-specific time delay of surgical treatment on lr and fir pca until the covid-19 pandemic is controlled[21,27,36]. in 2020, diamand et al. and ginsburg et al. published retrospective cohort studies of intermediateand high-risk pca patients who underwent rp before the covid-19 pandemic[37,38]. diamand et al. performed a european multicenter study of 926 patients who had a delay of surgical treatment after pca diagnosis and found no upgrading, lymph node involvement, or biochemical 246 siuj • volume 2, number 4 • july 2021 siuj.org review http://siuj.org recurrence (bcr) associated with a 3-month delay of rp in intermediateand high-risk pca[37]. ginsburg et al. studied 129 062 patients with the same characteristics and found no increase in adverse oncological outcomes after rp (upgrading, positive lymph nodes or need of adjuvant therapies) even after a 12-month delay[38]. for high-risk (hr) and very high-risk (vhr) pca patients, würnschimmel et al., included 148 (19%) high-risk patients (isup 4 and 5) managed with radical prostatectomy, 83 (56%) before the pandemic and 65 (44%) during the first month of the pandemic. they reported no covid-19 infections, and therefore suggested continuation of rp in high-risk patients with adequate covid-19 safety measures[32]. amparore et al. suggest not to continue rp for hr and locally advanced disease if possible[18]. heldwein et al. concluded that rp for high-risk patients can be safely delayed between 1 and 3 months. if there is a delay of more than 3 months because of the pandemic, or if there is suspicion of lymph node involvement, adt with or without rt can be initiated[34]. most expert consensus-based published recommendations conclude that rp for high-risk patients can be safely delayed for between 2 and 6 months[21–28,35,39,40]. if further delay is expected, adt should be considered until surgical management can be undertaken[21–26,40]. katims et al., however, report that in high-risk patients there may be an increased risk of biochemical recurrence (hr 2.19; ci 95% 1.24 to 3.87; p = 0.007) and positive surgical margins (or 4.08; ci 95% 1.52 to 10.9; p = 0.005) in case of > 9-month delay[36]. summary of recommendations for surgical management is provided in table 4. radiation therapy in pca larrea et al. retrospectively reported on 100 oncology patients treated with external beam radiation therapy (ebrt). only 9 had pca. no stage or risk stratification of these patients is specified; however, 7 were treated with hypofractionated ebrt with curative intent, and the remaining 2 because of bcr, with no reports of covid-19 infection in these patients[41]. for lowand intermediate-risk pca patients, all publications agree on active surveillance and delay of any modality of treatment[18,20–30,34,39,40]. for highrisk patients and locally advanced disease, 3 systematic reviews[18,34,42] conclude that if primary curative rt is planned, delay between 1 and 3 months is feasible. however, initiation of adt should be immediate or as soon as possible: according to eau priority, rt is considered level 2 (yellow)[34]. three expert consensusbased recommendations suggest the use of rt with adt in hr localized and locally advanced disease for patients not eligible for rp, with immediate initiation of long deposit adt[20,21]. a delay of up to 3 months is considered safe and feasible[16]; however, most expert consensus documents recommend delays of up to 6 months, with initiation of adt while waiting for rt[25–28,30,41]. for postprostatectomy rt, adjuvant rt should not be initiated; instead, salvage rt is recommended[18,20,22,28,29,34,39,42,43]. metastatic disease requiring palliative rt management should be undertaken as soon as possible on the basis of symptomatic disease or risk of fracture and medullary compression[20,21,28]. regardless of pca risk and stage, brachytherapy is not recommended, and the ideal ebrt treatment should be either hypofractionated or ultra-hy pofractionated[18,20-22,25-30,34,39,41,44]. follow-up with psa testing after rt may be at 6-month intervals to reduce hospital exposure[27,30]. a summary of recommendations is provided in table 5. androgen deprivation therapy in pca montopoli et al.[43] performed a retrospective analytical study of all prostate cancer patients in veneto, italy, reporting a total of 118 sars-cov-2-positive cases: 4 were on adt, and the remaining 114 were not. no pca risk or stage was specified, but the authors concluded that pca patients on adt have a significantly lower risk of covid-19 infection (or 4.05; 95% ci 1.55 to 10.59). caffo et al.[45] performed a multicenter retrospective study in italy (20 oncological centers), including 1433 men with metastatic castration-resistant pca (mcrpc), who continued oncological consultation during the pandemic (february to june 2020); 34 (2.3%) developed sars-cov-2 infection, all of them with adt, 9 with concomitant chemotherapy, and 19 with concomitant androgen-receptor-axis-targeted therapies (arat). thirteen patients (38.2%) died, 85.7% of whom had previously received 2 or more mcrpc therapies. the authors therefore concluded that mcrpc patients were at increased risk of sars-cov-2 infection and mortality, regardless of adt[38]. all included recommendations and systematic reviews conclude that adt in vlr, lr, and fir prostate cancer is not recommended[18,20–30,34,35,39,42,43,46]. for uir and hr, as well as for locally advanced disease (n1) eligible for radical curative treatment, when rp is delayed, adt can be safely initiated when pandemic-related delay is expected to surpass 3 to 6 months and in cases of patient cancer-related anxiety[18,20–30,34,35,39,42,43,46]. immediate adt, preferably a long depot (3or 6-month duration) formulation, is recommended for hormone sensitive metastatic prostate cancer (mhspc) [18,20–23,28,29,34,39,42,43,46]. for non-metastatic castration-resista nt prostate ca ncer (nmcr pc), adt plus arat, such as abiraterone, enzalutamide, apalutamide, or darolutamide is recommended. madan et al. recommend enzalutamide, since no concomitant steroid is needed[26]. for mcrpc, when no previous second-generation hormone therapy has been used, arat (except abiraterone) is recommended. in both 247siuj.org siuj • volume 2, number 4 • july 2021 management recommendations for prostate cancer during the covid-19 pandemic: a systematic review http://siuj.org table 4. summary of radical prostatectomy recommendations during the covid-19 pandemic paper radical prostatectomy vlr lr fir uir hr vhr kokorovic et al.[20] delay up to 12 months or as delay 3 months heldwein et al.[34] delay ≥ 6 months delay 1–3 months gómez rivas et al.[21] delay, time not specified delay 2–6 months; consider adt if locally advanced amparore et al.[18] delay indefinitely delay 1–3 months, before if control of pandemic würnschimmel et al.[32] safe to continue surgery planning, no infection among rp patients méjean et al.[22] delay ≥ 2 months delay 2 months wallis et al.[39] delay, time not specified delay 3–6 months narain et al.[23] delay 6 months delay, time not specified katims et al.[36] delay ≥ 9 months delay of up to 3 months does not increase the risk of bcr nor negative oncological outcomes obek et al.[25] delay between 6 and 12 months is safe delay of up to 6 months is safe for uir and hr; consider adt if further delay expected tachibana et al.[40] – delay between 60 days and 12 months is safe tan et al.[31] rp was safe despite pandemic scenario, no patient developed covid-19 on 30-day follow-up madan et al.[26] delay until pandemic control, no time specified delay up to 6 months, consider neoadjuvant adt for up to 6 months rodriguez-sanchez et al.[27] rp should not be considered during the pandemic delay unless psadt ≤ 3 months, alternative for hr consider adt detti et al.[28] if rp is planned, delay between 6 and 12 months delay 6 months, neoadjuvant adt is not recommended diamand et al.[37] a delay of rp up to 3 months has no impact on oncological outcomes in ir and hr shinder et al.[35] delay ≥ 3 months delay of 3 months adequate cut-off in most hr; hr already on 6-month delay should be managed as high priority, rp as soon as possible ginsburg et al.[38] rp can be safely postponed up to 12 months in ir and hr eau rapid response priority level low priority intermediate priority high priority recommendation summary rp in vlr, lr and fir can be safely delayed ≥ 6 months; hr and vhr delay should be based on individual patient case adt: androgen deprivation therapy; as: active surveillance; bcr: biochemical recurrence; eau: european association of urology; fir: favorable intermediate risk; hr: high risk; lr: low risk; rp: radical prostatectomy; psadt: psa doubling time; uir: unfavorable intermediate risk; vhr: very high risk; vlr: very low risk. 248 siuj • volume 2, number 4 • july 2021 siuj.org review http://siuj.org table 5. summary of radiation therapy recommendations during the covid-19 pandemic paper radiation therapy vlr lr fir uir hr vhr mpca kokorovic et al.[20] delay, time not specified hypofractionated, delay, time not specified, initiate adt immediately; short course rt in painful bone metastasis heldwein et al.[34] – delay 3 months, initiate adt in hr delay indefinitely, initiate adt gómez rivas et al.[21] – salvage rt is preferred in case of symptomatic oligometastasis palliative rt can be used larrea et al.[41] rt is safe in hypofractionated erbt modalities simcock et al.[29] as delay 3–4 months with adt initiation, hypofractionated delay, initiate instead adt for mpca, even if symptomatic amparore et al.[18] – if patient anxiety, hypofractionated erbt + adt zaorky et al.[42] delay until pandemic control delay up to 3 months, immediate adt initiation delay, initiate adt; in case of psadt ≤ 3 months and rt beneficial, do not delay méjean et al.[22] – follow national guidelines delay, time not specified wallis et al.[39] – delay 3 months; hypofractionated – narain et al.[23] – psa ≥ 20 ng/ml and locally advanced consider rt + adt – obek et al.[25] delay between 6 and 12 months delay up to 6 months; consider adt if further delay is expected; initiate within 6 weeks adt + ebrt as curative treatment for locally advanced disease – madan et al.[26] delay until pandemic control, no time specified delay up to 6 months, consider neoadjuvant adt for up to 6 months – rodriguez-sanchez et al.[27] rt should not be considered during the pandemic delay rt unless psadt ≤ 3 months, alternative for hr consider adt – barthwal et al.[44] brachytherapy should be avoided and converted to ebrt or adt – caicedo-martinez et al.[30] if rt indicated delay, time not specified adt alone to delay rt for 6 months regardless of risk or stage – detti et al.[28] – for uir, initiate adt and delay ebrt 6 months; for hr consider adt + ebrt, delaying rt for 3–6 months while on adt, hypofractionated for low volume, initiate adt; for high volume consider adt or systemic therapy and single dose ebrt for symptomatic bone metastasis eau rapid response priority level low priority intermediate priority recommendation summary rt should not be used in vlr, lr and fir; for hr and vhr eligible for rt, initiate adt and safely postpone ≤ 3 months; hypofractionated erbt is recommended; salvage rt is preferred adt: androgen deprivation therapy; as: active surveillance; eau: european association of urology; ebrt: external beam radiation therapy; fir: favorable intermediate risk; hr: high risk; lr: low risk; mpca: metastatic prostate cancer; psa: prostate specific antigen; psadt: psa doubling time; rt: radiation therapy; uir: unfavorable intermediate risk; vhr: very high risk; vlr: very low risk. 249siuj.org siuj • volume 2, number 4 • july 2021 management recommendations for prostate cancer during the covid-19 pandemic: a systematic review http://siuj.org cases (nmcrpc and mcrpc), ar at should be initiated as soon as possible[18,20–23,29,34,39,42,43,46]. the use of corticosteroids is controversial, and méjean et al. do not recommend it[22]. if indicated, the lowest possible dose should be used: prednisone 5 mg twice daily, decreasing to once daily if there are individual concerns, has been suggested[23,46]. a summary of recommendations for adt is provided in table 6. chemotherapy in pca five publications broached the subject of cht in pca patients during the covid-19 pandemic, all of them consensus-based recommendations, advising against the use of docetaxel in metastatic disease. méjean et al. recommend that in case of mcrpc, docetaxel or cabazitaxel may be used, but at a reduced dosage and with the concomitant use of granulocyte-colony stimulating factor (g-csf)[20–22,26]. lalani et al. recommend the use docetaxel in case of mcrpc patients who have previously received adt + arat with inadequate response, and in case of bone metastasis prefer only the use of radium-223[46]. a summary of recommendations is provided in table 7. discussion at the beginning of the pandemic, most institutions and countries issued non-specific and rapid response recom mend at ions; howe ver, a s t he pa ndem ic continued, new evidence and complete reviews and recommendations were published. the main objective of each country and individual health system during the covid-19 pandemic has been to limit the spread of sars-cov-2 infection. despite this, however, it is still necessary to provide individual management for urological oncology patients. although popert et al. reported no covid-19-related infection in prostate biopsy patients, all systematic reviews and recommendat ions suppor t delay ing biopsy a nd diagnostic workup in pca until the pandemic is contained[17]. würnschimmel et al. and tan et al. published studies about rp during the pandemic, and even though no sars-cov-2 infection occurred, it is evident that at least for patients with lowor intermediate-risk pca, active surveillance can be an adequate and safe alternative[32,31]. for high-risk patients, a delay of 6 months may be safe. in cases of patient anxiety or symptomatic pca, treatment may be indicated, either adt alone or adt + rt. for mhspc, adt is also recommended, while in nmcrpc and mcrpc, immediate arat is the treatment of choice. the pivot and protect trials proved that in localized pca, particularly in lowand intermediaterisk disease, curative treatment does not affect long-term mortality and survival on localized pca, yet the protect trial did find that active surveillance was associated with a higher incidence of biochemical recurrence and metastasis[47,48]. although these studies report good outcomes in patients with non-metastatic pca, oncological curative treatment in cases of uir, hr and vhr, continues to be the desired treatment but the sars-cov-2 pandemic has in many cases delayed its provision. we can conclude from this systematic review that all modalities of radical treatment for nonmetastatic pca can be safely delayed, and that adt can be used as an alternative treatment during the pandemic in order to prevent sars-cov-2 infection. the sudden onset of the covid-19 pandemic led to the rapid publication of papers and recommendations, sometimes with inadequate methodology and low levels of evidence, as well as expert consensus-based recommendations. because of this, few papers met our criteria, leaving a fairly small sample. the main limitation of our study is the lack of rob analysis of expert consensus-based recommendations. this is due to absence of an adequate tool, as well as the absence of clinical trials and the impossibility of performing any meta-analysis because of the scarce information in each study. conclusions the international urological community was not prepared for such a sudden and unprecedented global pandemic. evidently an immediate emergency response was necessary to prevent and control sars-cov-2 infections in patients with urological comorbidities needing treatment, such as prostate cancer patients; however, covid-19 paralyzed urologic oncolog y departments in most countries. this systematic review suggested that low-risk and intermediate-risk pca patients can be managed with active surveillance, that delaying surgical and radiation therapy treatment in high-risk and locally advanced disease is justified, and that adt is an adequate treatment option for hr and metastatic disease. it is very likely that there will be new pandemics with implications, effects, and long-term outcomes similar to those of covid-19. we hope that the present review will establish a foundation for the management of prostate cancer in future emergency scenarios and pandemics. 250 siuj • volume 2, number 4 • july 2021 siuj.org review http://siuj.org table 6. summary of androgen deprivation therapy recommendations during the covid-19 pandemic paper androgen deprivation therapy uir hr vhr mpca kokorovic et al.[20] rt + adt in locally advanced; hypofractionated oligometastatic hspc adt while delay rt; nmcrpc and mcrpc initiate arat heldwein et al.[34] if significant rp delay or rt is planned, initiate immediately initiate adt as soon as possible montopoli et al.[43] pca patients on adt have lower risk for sars-cov-2 infection (or 4.05; 95% ci 1.55 to 10.59) gómez rivas et al.[21] adt if rp is further delayed by uncontrolled pandemic mhspc initiate adt; nmcrpc and mcrpc initiate adt + arat simcock et al.[29] initiate adt even if rt delay amparore et al.[18] – consider adt if patient anxious about outcome zaorky et al.[42] initiate adt immediately if rt delay is planned méjean et al.[22] adt if rt or rp delay is foreseen in hr and locally advanced hspc initiate adt; nmcrpc and mcrpc initiate adt + arat wallis et al.[39] adt if rt or rp is planned to be delayed adt as soon as possible, mcrpc and nmcrpc along with arat narain et al.[23] consider adt if rp delay when risk of progression is suspected adt + arat if high volume mhspc or crpc obek et al.[25] for locally advanced disease, encourage adt + ebrt as curative treatment and initiate within 6 weeks – tachibana et al.[40] consider adt for a 3-month duration when rp delays ≥ 3 months in hr – madan et al.[26] – long depot adt should be used, if arat, enzalutamide is preferred caffo et al.[45] – mcrpc seem to have higher risk of sars-cov-2 and poor prognosis rodriguez-sanchez et al.[27] rp and rt should be deferred unless psadt ≤ 3 months, consider adt as an alternative for hr – caicedo-martinez et al.[30] adt alone to delay rt for 6 months is recommended regardless of risk stratification or stage – detti et al.[28] – for low volume, initiate adt; for high volume consider adt or arat and single dose ebrt for symptomatic bone metastasis lalani et al.[46] – in mhspc and mcrpc docetaxel should be avoided as possible, arat + adt should be used instead eau rapid response priority level high priority recommendation summary pca patients on adt seem to have a lower risk of sars-cov-2 infection; adt should be immediately initiated when pca-based indication exists; crpc should also be managed with arat as soon as possible adt: androgen deprivation therapy; arat: androgen-receptor-axis-targeted; crpc: castration-resistant prostate cancer; eau: european association of urology; hr: high risk; hspc: hormone sensitive prostate cancer; mcrpc: metastatic castration-resistant prostate cancer; mhspc: metastatic hormone sensitive prostate cancer; mpca: metastatic prostate cancer; nmcrpc: non-metastatic castration-resistant prostate cancer; psadt: psa doubling time; rp: radical prostatectomy; rt: radiation therapy; uir: unfavorable intermediate risk; vhr: very high risk. 251siuj.org siuj • volume 2, number 4 • july 2021 management recommendations for prostate cancer during the covid-19 pandemic: a systematic review http://siuj.org table 7. summary of chemotherapy recommendations during the covid-19 pandemic paper chemotherapy mpca kokorovic et al.[20] cht during the pandemic is not encouraged gómez rivas et al.[21] cht during the pandemic is not encouraged méjean et al.[22] preferably avoid, if used, cabazitaxel is preferred with concomitant g-csf use madan et al.[26] chemotherapy should not be recommended detti et al.[28] for high volume consider adt + systemic therapy other than cht; for symptomatic bone metastasis consider single dose ebrt lalani et al.[46] in mhspc and mcrpc docetaxel should be avoided as possible, arat + adt should be used instead eau rapid response priority level low priority recommendation summary cht is not recommended during the pandemic because of high infection risk adt: androgen deprivation therapy; arat: androgen-receptor-axis-targeted; cht: chemotherapy; eau: european association of urology; g-csf: granulocyte-colony stimulating factor; mcrpc: metastatic castration-resistant prostate cancer; mhspc: metastatic hormone sensitive prostate 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outcomes of cancer patients and management of solid tumors during the pandemic. cancer med.2020;9(24):92059218. doi: 10.1002/cam4.3534 27. sanchez lr, cathelineau x, pinto ama, borque-fernando á, gil mj, yee ch, et al. clinical and surgical assistance in prostate cancer during the covid-19 pandemic: implementation of assistance protocols. int braz j urol.2020;46(suppl.1):50-61. doi: 10.1590/ s1677-5538.ibju.2020.s106 28. detti b, ingrosso g, becherini c, lancia a, olmetto e, alì e, et al. management of prostate cancer radiotherapy during the covid19 pandemic: a necessar y paradigm change. cancer treat res commun.2021;27:100331. doi: 10.1016/j.ctarc.2021.100331 29. simcock r, thomas t v, estes c, filippi ar, katz ms, pereira ij, et al. covid-19: global radiation oncology’s targeted response for pandemic preparedness. clin transl radiat oncol.2020;22:55–68. doi: 10.1016/j.ctro.2020.03.009 30. caicedo-martinez m, gonzález-motta a, gil-quiñonez s, galvis jc. prostate cancer management 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lima fs, et al. a systematic review on guidelines and recommendations for urology standard of care during the covid-19 pandemic. eur urol focus.2020 sep 15;6(5):1070-1085. doi: 10.1016/j.euf.2020.05.020. epub 2020 jun 5. 35. shinder bm, patel hv, sterling j, tabakin al, kim iy, jang tl, et al. urologic oncology surgery during covid-19: a rapid review of current triage guidance documents. urol oncol.2020;38(7):609-614. doi: 10.1016/j.urolonc.2020.05.017 36. katims ab, razdan s, eilender bm, wiklund p, tewari ak, kyprianou n, et al. urologic oncology practice during covid-19 pandemic: a systematic review on what can be deferrable vs. nondeferrable. urol oncol.2020;38(10):783-792. doi: 10.1016/j.urolonc.2020.06.028 37. diamand r, ploussard g, roumiguié m, oderda m, benamran d, fiard g, et al. timing and delay of radical prostatectomy do not lead to adverse oncologic outcomes: results from a large european cohort at the times of covid-19 pandemic. world j urol.2020;10:1-8. doi: 10.1007/s00345-020-03402-w 38. ginsburg kb, curtis gl, timar re, george ak, cher ml. delayed radical prostatectomy is not associated with adverse oncologic outcomes: implications for men experiencing surgical delay due to the covid-19 pandemic. j urol.2020;204(4):720-725. doi: 10.1097/ ju.0000000000001089 253siuj.org siuj • volume 2, number 4 • july 2021 management recommendations for prostate cancer during the covid-19 pandemic: a systematic review http://uroweb.org/guideline/prostate-cancer/. http://siuj.org 39. wallis cjd, novara g, marandino l, bex a, kamat am, karnes rj, et al. risks from deferring treatment for genitourinary cancers: a collaborative review to aid triage and management during the covid-19 pandemic. eur urol.2020;78:29 – 42. doi: 10.1016/j. eururo.2020.04.063 40. tachibana i, ferguson el, mahenthiran a, natarajan jp, masterson ta, bahler c, et al. delaying cancer cases in urology during covid19: review of the literature. j urol.2020;204:926-933. doi: 10.1097/ ju.0000000000001288 41. larrea l, lópez e, antonini p, gonzález v, berenguer ma, baños mc, et al. covid-19: hypofractionation in the radiation oncology depar tment during the ‘state of alarm’: first 100 patients in a private hospital in spain. ecancer.2020;14:1052. doi: 10.3332/ ecancer.2020.1052 42. zaorky ng, yu jb, mcbride sm, dess rt, jackson wc, mahal ba, et al. prostate cancer radiation therapy recommendations in response to covid-19. adv radiat oncol.2020;5:659-665. doi: 10.1016/j. adro.2020.03.010 43. montopoli m, zumerle s, vettor r, rugge m, zorzi m, catapano cv, et al. androgen-deprivation therapies for prostate cancer and risk of infection by sars-cov-2: a population-based study (n = 4532). ann oncol.2020;31(8): 1040–1045. doi: 10.1016/j.annonc.2020.04.479 44. bar thwal m, pareek v, mallick s, sharma dn. brachy therapy practice during the covid-19 pandemic: a review on the practice changes. j contemp brachytherapy. 20 20;12(4):39 3 -39 6. doi: 10.5114/jcb.2020.9764 45. caffo o, gasparro d, di lorenzo g, volta a.d, guglielmini p, zucali p, et al. incidence and outcomes of severe acute respiratory syndrome coronavirus 2 infection in patients with metastatic castrationresistant prostate cancer. eur j cancer.2020;140:140-146. doi: 10.1016/j.ejca.2020.09.018 46. lalani a a, chi kn, heng dyc, kollmannsberger ck, sridhar ss, blais n, et al. prioritizing systemic therapies for genitourinar y malignancies: canadian recommendations during the covid-19 pandemic. can urol assoc j.2020;14(5):e154-e158. doi: 10.5489/ cuaj.6595 47. wilt tj, jones km, barr y mj, adriole gl, culkin d, wheeler t, et al. follow-up of prostatectomy versus obser vation for early prostate cancer. n engl j med.2017;377(2):132-142. doi: 10.1056/ nejmoa1615869 48. hamdy fc, donovan jl, lane ja, mason m, metcalfe c, holding p, et al. 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. n engl j med.2016;375(15):1415-1424. doi: 10.1056/nejmoa1606220 254 siuj • volume 2, number 4 • july 2021 siuj.org review http://siuj.org b2b gu cancers triad virtual meeting b2b men’s health virtual meeting mélanie aubé-peterkin canada robert e. brannigan united states sean elliott united states ranjith ramasamy united states scientific programme committee access all sessions on demand for free www.academy.siu-urology.org access all sessions on demand for free www.academy.siu-urology.org scientific programme committee peter c. black, chair canada stacy loeb united states ashish kamat united states simon tanguay canada access sessions from these exciting bench-to-bedside meetings for free on https://academy.siu-urology.org/siu/#!*menu=6*browseby=3*sortby=2*ce_id=1991 https://academy.siu-urology.org/siu/#!*menu=6*browseby=3*sortby=2*ce_id=2031*featured=17308 this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. effect of metallic ureteric stents on magnetic resonance imaging: implications for malignant ureteral obstruction mahima tellambura,1 isaac thangasamy,1,2 kwang chin,1 declan murphy1,3 1 division of cancer surgery, peter maccallum cancer centre, melbourne, australia 2 faculty of medicine, university of queensland, australia 3 the sir peter maccallum department of oncology, university of melbourne, melbourne, australia abstract metallic ureteric stents are increasingly used for the management of malignant ureteric obstruction, a commonly encountered complication in urological and other malignancies. however, there has been limited evaluation of complications associated with these stents, including those that might arise from the use of magnetic resonance imaging (mri). while most devices are deemed nominally “mri-safe,” their implication on the quality of imaging produced has not been evaluated in clinical trials, and in our practice, significant artefact has been encountered with some ureteric stents—specifically, the teleflex rüsch dd tumour stent—compromising image quality and diagnostic certainty. key words competing interests article information ureteric stents, metallic stents, magnetic resonance imaging, malignant ureteric obstruction none declared. received on march 20, 2021 accepted on may 14, 2021 soc int urol j.2021;2(4):256-258 doi: 10.48083/ wlvr1509 in managing malignant ureteric obstruction, metal or metal-incorporating stents are an increasingly popular option, owing to evidence suggesting improved patency compared with conventional polymeric stents[1]. in our practice, 44% of patients undergoing ureteral stenting between march 2017 and march 2018 (n = 77) had one or more metallic stents inserted. depending on t he ma ligna nc y, a signif ica nt proportion of patients undergoing stenting will require further pelvic magnetic resonance imaging (mri) for staging or re-staging. this is particularly the case in the management of rectal cancer. while all the stents are certified mri-safe, their effect on the quality of mri images produced has not been fully elucidated. mri compatibility has largely focused on energy absorption and safety within mri systems; however, their effect on the quality of diagnostic imaging has received limited mention. metals produce aberrancy within mri images through several mechanisms[2,3]: • inhomogeneities in the strong magnetic field, pr o d u c e d b y p a r a m a g n e t i c /f e r r o m a g n e t i c components. • frequency-encoding misregistration, due to changes in frequency of dephasing. • signal loss, due to increase in the rate of t2 phase decay. • failure of fat suppression, owing to the effect of metallic implants on the resonance frequency of nearby fat. the following factors contribute to the extent of artefact formed[3]: • the size of metallic implant. • specific composition of the implant. • artefact worsens with ferromagnetic implants (steel, iron) compared with those of paramagnetic or diamagnetic metals (titanium, platinum, copper). 256 siuj • volume 2, number 4 • july 2021 siuj.org brief communication mailto:mahima%40tellambura.com?subject=siuj http://www.siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information genitourinary malignancy, indigenous health, cancer, canadian first nations, urology none declared. received on july 7, 2022 accepted on july 22, 2023 this article has been peer reviewed. soc int urol j. 2023;4(2):85–87 doi: 10.48083/zdvm7715 genitourinary malignancy in canadian indigenous populations jonathan suderman, peter c. black department of urologic sciences, university of british columbia, vancouver, canada sowing the seeds of health care disparity universal access to health care is a foundational principle in canadian health care as set out by the canada health act. as with many indigenous groups around the world, canadian indigenous communities (first nations, métis, and inuit) have faced disparities in health care. the cause of these disparities is multifactorial. in canada, the indian act of 1876 enacted many colonial laws aimed at eliminating indigenous culture and assimilating indigenous people into a european-based canadian society. this permitted the development of residential schools and allowed indigenous populations to be moved onto reserve lands. in 1895 the indian act was amended to make any indigenous festival, dance, or ceremony illegal, despite these acts playing a fundamental role in the healing practices of many indigenous people. these policies have led to a long history of mistrust between indigenous populations and the canadian government. with government-funded health care and generations of negative experiences associated with canadian western health care, many disparities have arisen that limit indigenous health outcomes and access to health care services. genitourinary malignancy in canadian indigenous peoples cancer is among the leading causes of death in indigenous people[1]. canadian indigenous people have a higher incidence of several cancers, including colorectal and kidney cancer, and a lower incidence of others, including prostate, breast, and bladder cancer[2,3]. with several genitourinary cancers, the 5-year survival rate is worse in indigenous people than in their non-indigenous peers[4]. a paucity of data exists regarding genitourinary malignancies in canadian indigenous populations. a health report published in 2021 looking at the incidence and mortality of cancer in first nations people in ontario between 1991 and 2010 provides the best estimate of cancer burden in canadian indigenous populations[5]. kidney cancer an elevated incidence of kidney cancer has been reported in first nations females living in british columbia[2], and males and females living on reserves or northern cities in quebec[6]. in the ontario cohort, kidney cancer was the fifth most diagnosed cancer in first nations people, yet only the 12th most common in the general population. kidney cancer was identified as having significantly higher relative risk in first nations males and females in all age groups compared with the rest of the population. kidney cancer rates in first nations females also increased over time relative to other females in ontario. this may relate to a higher prevalence of risk factors (eg, smoking and obesity) within these populations[7]. mortality rates from kidney cancer were significantly elevated in all ages. 85siuj.org siuj • volume 4, number 2 • march 2023 urology around the world mailto:j.suderman%40alumni.ubc.ca?subject=siuj http://siuj.org prostate cancer in the ontario study, prostate cancer rates were unchanged in first nations males from 1991 to 2010, despite an increased incidence in males in the general population[5], suggesting that first nations populations did not follow the worldwide trend of overdiagnosis associated with widespread implementation of psa screening during the early 1990s. this may reflect access to and utilization of cancer screening protocols. this discrepancy was confirmed in the first nations regional health survey (2009) that showed that only 23.4% of first nations men over 18 have ever had a screening digital rectal examination or serum psa test[8]. the national estimates suggest that 35% to 75% of males over 50 years of age have had at least one psa test. this number seems profound but may be biased by the discrepant age ranges included in both populations[9]. prostate cancer incidence was significantly lower in first nations males compared to the general population[5], yet withrow et al. showed a significant excess mortality rate ratio (emrr) between 1992 and 2000 in canadian first nations men with prostate cancer (emrr 2.76; 95% ci 1.81 to 4.21)[4]. concurrently, prostate cancer rates were found to be lower in the quebec reservation cohort[6]. other genitourinary malignancies first nations males had significantly lower rates of bladder cancer compared with the general population (rate ratio of 0.47 [95% ci 0.36 to 0.61]). the trend in first nations females was similar but less pronounced (rate ratio of 0.73 [95% ci 0.50 to 1.01]). rates of testis cancer did not differ significantly from the rates in the general population (rate ratio of 0.76 [95% ci 0.57 to 1.00]), and rates of penile malignancy were not reported in the ontario study results[5]. putting the numbers into context differences have been shown in cancer rates and outcomes between canadian first nations people and the general population. while biological factors and variable exposure to risk factors are important, social determinants of health are likely most critical. these include historical trauma, poor access to health care, poor education, marginalization, and lower socioeconomic status[5]. jamal et al. suggested working towards “equitable access to a conducively built environment, affordable healthy foods, and a culturally safe and respectful health system” for indigenous people to help address discrepant medical experiences related to cancer diagnosis and treatment[5]. this sense of safety may be especially important relating to genitourinary cancers, as many clinical scenarios can include sensitive or uncomfortable examinations such as cystoscopy, genital examination, or digital rectal examinations. education and screening programs have yielded promising results in other body systems. lung and cervical cancer rates have fallen, which may be related to programs to reduce smoking and encourage cervical cancer screening in first nations communities[7]. similar programs may be beneficial for genitourinary malignancies. the canadian health care system divides responsibilities between federal, provincial, and territorial governments. the federal government has taken steps to work alongside indigenous populations, instituting independent programming such as indigenous services canada, which provides independent funding and health care services to first nations, inuit, and métis communities. multiple policies also exist at the provincial level, where legislation “recognizes the values and role of indigenous groups in the planning and delivery of health services in their communities.” some provinces have supported indigenous-led organizations to oversee delivery of health care in a culturally safe and appropriate fashion[10]. finally, canadian medical schools now set aside designated seats for students with indigenous heritage. this is an excellent step towards encouraging indigenous representation within the canadian medical community and bridging the gap between traditional and modern healing practices. 86 siuj • volume 4, number 2 • march 2023 siuj.org urology around the world http://siuj.org references 1. tjepkema m, wilkins r, senécal s, guimond é, penney c. mortality of métis and registered indian adults in canada: an 11-year follow-up study. health rep.2009;20(4):31-51. pmid: 20108604 2. mcgahan ce, linn k, guno p, johnson h, coldman aj, spinelli jj, et al. cancer in first nations people living in british columbia, canada: an analysis of incidence and survival from 1993 to 2010. cancer causes control.2017;28(10):1105-1116. doi: 10.1007/s10552-017-0950-7. 3. mazereeuw mv, withrow dr, diane nishri e, tjepkema m, marrett ld. cancer incidence among first nations adults in canada: follow-up of the 1991 census mortality cohort (1992–2009). can j public health.2018;109(5):700-709. doi: 10.17269/s41997-018-0091-0 4. withrow dr, pole jd, nishri ed, tjepkema m, marrett ld. cancer sur vival disparities between first nation and non-aboriginal adults in canada: follow-up of the 1991 census mortality cohort cancer sur vival in first nations. cancer epidemiol biomarkers prev.2017;26(1):145-151. doi: 10.1158/1055-9965.epi-16-0706. 5. jamal s, jones c, walker j, mazereeuw m, sheppard aj, henry d, et al. cancer in first nations people in ontario, canada: incidence and mortality, 1991 to 2010. health rep.2021;32(6):14-28. doi: 10.25318/82-003-x202100600002-eng. 6. louchini r, beaupre m. cancer incidence and mortality among aboriginal people living on reserves and northern villages in quebec, 1988-2004. int j circumpolar health.2008;67(5)445-451. doi: 10.3402/ ijch.v67i5.18355. 7. mazereeuw mv, yurkiewich a, jamal s, cawley c, jones cr, marrett ld. cancer risk factors and screening in first nations in ontario. health promot chronic dis prev can.2017;37(6):186-193. doi:  10.24095/ hpcdp.37.6.02 8. first nations information governance centre. first nations regional health survey (rhs) 2008/10: national report on adults, youth and children living in first nations communities. first nations information governance centre; 2012. 9. canadian partnership against cancer, screening action group. psa toolkit: psa screening and testing for prostate cancer. published july 2009. available at: https://www.partnershipagainstcancer.ca/topics/ prostate-cancer-screening-trials/. accessed july 7, 2022. 10. government of canada. indigenous health care in canada. published 2021-10-29. available at: https://www.sac-isc.gc.ca/eng/16268101 77053/1626810219482. accessed july 21, 2022. 87siuj.org siuj • volume 4, number 2 • march 2023 genitourinary malignancy in canadian indigenous populations https://www.partnershipagainstcancer.ca/topics/prostate-cancer-screening-trials/ https://www.partnershipagainstcancer.ca/topics/prostate-cancer-screening-trials/ https://www.sac-isc.gc.ca/eng/1626810177053/1626810219482 https://www.sac-isc.gc.ca/eng/1626810177053/1626810219482 http://siuj.org key words competing interests article information biopsy, extramammary paget disease, recurrence, oncology none declared. received on may 17, 2022 accepted on august 19, 2022 this article has been peer reviewed. soc int urol j. 2023;4(1):34–38 doi: 10.48083/lcme5237 oncologic outcomes of a novel mapping biopsy technique before surgical excision in the management of extramammary paget disease kyle m. rose,1 rosalie zurlo,2 roger li,1 gerard mosiello,3 philippe e. spiess1 1 department of genitourinary oncology, moffitt cancer center, tampa, united states 2 university of south florida, morsani college of medicine, tampa, united states 3 department of cutaneous oncology, moffitt cancer center, tampa, united states abstract objective to analyze oncologic outcomes of patients with extramammary paget disease (empd) undergoing a novel mapping biopsy before tumor excision (wle). methods we analyzed 19 consecutive patients with empd treated with biopsy and/or surgical excision at moffitt cancer center from 2013 to 2021. biopsy technique, patient demographics, pathology, and oncologic outcomes were analyzed. results in total, 19 patients were included in the analysis. median age at diagnosis was 72. no patients were diagnosed with secondary malignancy during mandatory workup. of the 17 patients receiving novel mapping biopsy, 8/17 had at least one positive core biopsy site, with a mean of 7% positivity of the total core sites (4/60). mapping biopsy positive sites helped shape perimeters for wide local excision (wle) for patients opting for surgical treatment. although an extensive mapping biopsy was performed, wle margins were positive in 11/17 patients. although positive pathologic margins following surgical excision were prominent, only one patient experienced recurrence of empd during a median follow-up period of 38 months. conclusions we have demonstrated a standardized mapping biopsy before surgical excision in the management of empd in men. despite extensive mapping biopsies, positive surgical margin rates are high, and this may reflect the occult nature of the disease process. close follow-up is warranted in patients regardless of margin status, but those with positive surgical margins may benefit from more aggressive regimens. introduction extramammary paget disease (empd) is a rare neoplasm presenting in the genital and perianal regions of men and women. it is characterized by a chronic erythematous plaque and is commonly associated with pruritis and pain[1]. the discomfort associated with the lesions often leads to mischaracterization as eczema or fungal infection, which may further delay treatment. unfortunately, despite standard of care measures, recurrence rates as high as 16% to 61% have been reported[2–5]. surgical excision with negative margins is the gold standard in management, but topical and systemic chemotherapy can also be used if there are contraindications to surgery[6]. 34 this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj • volume 4, number 1 • january 2023 siuj.org original research https://orcid.org/0000-0001-7728-1144 mailto:kyle.rose%40moffitt.org?subject=siuj https://orcid.org/0000-0003-1274-7200 https://orcid.org/0000-0002-5723-1972 http://siuj.org empd is treated by a variety of specialties including urologists, colorectal surgeons, and dermatologists, depending on location and patient access to care. as a result, there is no standardized biopsy or wide local excision (wle) technique for empd to ensure negative resection margins. dermatologists frequently utilize mohs micrographic surgery to provide pathological confirmation of negative margins intraoperatively. in contrast, wle is traditionally employed by urologists and colorectal surgeons, and requires a pre-resection biopsy. in either case, standardization of biopsy and excision technique is lacking. the establishment of a global strategy for mapping before excision is paramount in the surgical management of empd. herein, we describe a novel standardized technique in the mapping and treatment of empd at our institution. our objective was to determine the efficacy of this mapping technique before excision by analyzing recurrence rates of empd, thereby assessing the accuracy of surgical margin delineation. materials and methods after obtaining institutional review board approval, we performed an analysis on patients undergoing surgical excision for empd at our facility between 2013 and 2021. for inclusion, patients were required to have had a mapping biopsy and/or wle . a l l cases were per for med by a si ng le su rgeon. a l l pat ients u nder went ma nd ator y c ystoscopy a nd colonoscopy, which were required to be negative. patient demographics, clinicopathologic outcomes, and perioperative outcomes were collected. patient clinical stage was determined using the tnm staging system for empd as described by ohara et al.[7]. perioperative complications were scored using the modified clavien-dindo scale[8]. the technique for mapping biopsy before excision involves 60 total biopsy sites, taken in a clockwise fashion around the lesion. the biopsies are typically 1.5 mm in size, and 5 are taken for each “hour” of the clock face, spaced 1 cm apart. this technique allows the surgical team to clearly demarcate the required tissue needed to achieve a negative margin at the time of wle. all biopsy specimens were reviewed by a dedicated dermatopathologist. results from 2013 to 2021, 19 patients underwent mapping biopsy followed by wle. the median age (iqr) at surgery was 72 (66.5 to 76.0). table 1 details baseline patient characteristics. of note, 13 (65%) had a history of malignancy before empd diagnosis, the most common of which was a dermatologic carcinoma in 12 patients, followed by prostate cancer in 4 patients. eleven patients (58%) had a past or current history of smoking. most patients had at least one medical comorbidity, with 14 diagnosed with hypertension, 8 with hyperlipidemia, 7 with cad, and 7 with bph. three patients were treated with topical chemotherapy before presentation, while 6 patients were treated with topical antifungals due to misdiagnosis. preoperative irritative symptoms were reported in 9 patients (47%) at a median (iqr) duration of 2.5 (1.0 to 3.0) years, and included erythema in 17 (89%), itching in 10 (53%), pain in 8 (42%), and drainage in 2 (11%). empd occurred in the scrotum-alone in 8 (42%), the perineum in 1 (5%), the groin in 3 (16%), the penis in 2 (11%), and was multifocal in 6 (32%). seventeen patients received mapping biopsy, and 2 had shave biopsies. two patients decided against surgical excision of lesion after biopsy, opting for conservative monitoring. eight mapping biopsies (47%) were positive for empd in at least one core, with an average of 7% of cores positive (4/60). mapping biopsy results were used to delineate wle borders, and negative results typically indicated a smaller resection site. of the 17 patients undergoing surgical excision, 16 had wle. for wound closure, 8 patients required split thickness skin graft (stsg), in 3, local tissue mobilization was used to assist in closure, 2 patients required creation of a thigh flap, and in 1 case, primary re-approximation was used (figure 1). all patients were staged as primary pt1 empd on final pathology. margins were positive in 65% of lesions (11/17). of the 13 patients with immunohistochemistry table 1. clinical characteristics of patients before mapping biopsy age (median, iqr) 72 (76.0–66.5) prior cancer diagnoses 13 (68%) smoking history 11 (47%) prior failed treatment 3 (16%) symptomatic at presentation 9 (47%) presence of multifocality 1 (5%) positive mapping biopsy 10 (53%) cores positive on mapping biopsy 4 (6.7%) 35siuj.org siuj • volume 4, number 1 • january 2023 oncologic outcomes of a novel mapping biopsy technique before surgical excision in the management of extramammary paget disease http://siuj.org staining, ck7 was positively stained in 10 cases (77%). lymphovascular and adnexal invasion were uncommon, both occurring in 3 of 7 patients. the median follow-up for the cohort was 14 months, during which time 1 patient experienced recurrence with osseous metastasis 6 years following wle, and is currently undergoing chemoradiation therapy. during follow-up, there was 1 death of unrelated etiology. complications occurred in 5 patients (29%), all related to wound healing. there were 2 episodes of wound dehiscence, one episode of skin necrosis requiring debridement, one episode of tension discomfort requiring repeat stsg, and one episode of prolonged wound healing with abnormal drainage. table 2 illustrates the size of excised lesions in patients with and without wound complications, for which there were no differences between groups. discussion in this series, we describe a standardized mapping biopsy process for empd. our central finding is the high positive wle margin rate despite extensive preoperative punch biopsy mapping. while surgical excision with negative resection margins remains the gold standard treatment in empd, barriers to achieving negative margins include the multifocal nature of this figure 1. table 2. postoperative wound issue and size of primary lesion wound complications post-wle p -value yes no median size of lesion (cm) 121 124.6 0.74 iqr 66–168 85–147 patients with extramammary paget disease (empd) n = 19 patients with empd undergoing shave biopsy n = 2 rotational thigh �aps n = 2 split thickness skin grafts n = 8 patients empd undergoing surgical excision n = 17 primary closure with tissue mobilization n = 7 diagnosis biopsy treatment closure patients with empd undergoing novel mapping biopsy n = 17 patients deferring surgical excision n = 2 disease process, as well as the presence of skip lesions. positive margins have been identified as risk factors for tumor invasion, recurrence, and metastasis in prior empd series[9,10]. in a recently published review by leong and chung, the investigators complied composite scores for recurrence based on margin status at the time of excision. patients with positive margins at wle demonstrated a higher recurrence rate of 48% versus 15% in those with negative margins. similarly, the authors compared composite scores of wle and mohs micrographic surgery, and identified mohs as having a lower positive margin rate (18% versus 33%). the use of mohs surgery may be a limiting 36 siuj • volume 4, number 1 • january 2023 siuj.org original research http://siuj.org factor depending on resources available to certain institutions, but microdissection and pathologic review in real time appear to be beneficial. additional surgical augmentations include the use of intraoperative frozen sections, which has demonstrated a higher negative margin rate (92% versus 26%)[11]. additionally, surgeons have utilized f luorescein to augment visualization during excision, which has a 97% positive predictive value and 99.9% negative predictive value[12]. both of these tools add value in the surgeon’s armamentarium. the high positive surgical margin rate in our series is unfortunately a common, with previous studies reporting rates as high as 40% to 60% after surgical excision[13–17]. however, while recurrence rates are higher in margin-positive patients, the direct impact on cancer specific survival is less clear, especially in the non-invasive malignancy setting. in a survival analysis using the surveillance, epidemiology, and end results (seer) program, worse survival was associated with increased age and male sex, and in patients who did not receive surgery as primary therapy, especially those who had received radiotherapy[18]. a similar seer study performed by herrel and colleagues reported an overall survival of 60% at 120 months post diagnosis[19]. the authors identified that patient age and presence of empd in the perianal and truncal regions portended a worse prognosis[19]. however, it is important to note the limitations of these 2 large-sample studies, in that the seer database does not allow for analysis by margin status. alternatively, tumor invasion was identified as a significant contributor to survival, as described in the study by hegarty et al. of 20 patients, in which patients with invasive empd demonstrated a lower survival rate of 14.5 months versus 55 months in those with intra epidermal adenocarcinoma[9]. our findings suggest that positive surgical margins may not correlate as strongly with recurrence as previously thought. the presence of positive surgical margins does place the patient in a higher risk group, which prompts the surgical team to escalate outpatient follow-up and surveillance. in clinical practice, this could include more frequent examinations, repeat biopsies for recurrent disease, and photograph documentation. the novel mapping biopsy and wle in our study were performed by a single surgeon to improve uniformity and consistency. importantly, surgeons should be aware of the potential for wound complications following wle, which occurred in 5 patients in our series. limitations of our study include its retrospective natur e, presenting the potential for selection bias among patients with localized disease. the novel mapping biopsy and wle utilized in our study was performed by a single surgeon to improve uniformity and consistency. additionally, our patients were exclusively male, and therefore extrapolation of our findings to the gynecologic field should be limited. further, the median follow-up in our cohort was relatively short at 14 months. long-term follow-up data are needed to solidify the relationship between positive surgical margins and disease recurrence. due to the rarity of this disease process, large-scale randomized trials will be unlikely to accrue, and thus there is a need for uniform mapping biopsies and surgical techniques, as previously described. conclusions in this study, we have demonstrated a standardized mapping biopsy before surgica l excision in t he management of empd in men. despite extensive mapping biopsies, positive surgical margin rates are high, and this may ref lect the occult nature of the disease process. close follow-up is warranted in patients regardless of margin status, but those with positive surgical margins may benefit from more aggressive regimens. long-term follow-up is needed to determine the impact of microscopically positive margins on disease specific survival, which will aid the surgical team in determining aggressiveness of resection. 37siuj.org siuj • volume 4, number 1 • january 2023 oncologic outcomes of a novel mapping biopsy technique before surgical excision in the management of extramammary paget disease http://siuj.org references 1. mcdaniel b, brown f, crane js. extramammary paget disease. in: statpearls. treasure island (fl)2022 jan. available at: https://pubmed. ncbi.nlm.nih.gov/29630276/. accessed november 12, 2022. 2. hendi a, brodland dg, zitelli ja. extramammary paget’s disease: surgical treatment with mohs micrographic surgery. j am acad dermatol.2004;51(5):767-773. doi: 10.1016/j.jaad.2004.07.004. 3. lee k y, roh mr, chung wg, chung k y. comparison of mohs micrographic surgery and wide excision for extramammary paget’s disease: korean experience. dermatol surg.2009;35(1):34-40. 4. pierie jp, choudr y u, muzikansk y a, finkelstein dm, ott mj. prognosis and management of extramammar y paget’s disease and the association with secondary malignancies. j am coll surg. 2003;196(1):45-50. 5. wong ds-y ko lw-l, cheung t-h. extramammary paget’s disease: surgical control from the plastic surgery perspective. surg pract.2016;20(3):110113. doi.org/10.1111/1744-1633.12188 6. nih, national center for advancing translational sciences. extramammary paget disease.2021. available at: https://rarediseases. info.nih.gov/diseases/4192/extramammary-paget-disease. accessed september 17, 2021. 7. ohara k, fujisawa y, yoshino k, kiyohara y, kadono t, murata y, et al. a proposal for a tnm staging system for extramammary paget disease: retrospective analysis of 301 patients with invasive primary tumors. j dermatol sci.2016;83(3):234-239. doi: 10.1016/j.jdermsci.2016.06.004. 8. mitropoulos d, artibani w, biyani cs, bjerggaard jensen j, roupret m, truss m. validation of the clavien-dindo grading system in urology by the european association of urology guidelines ad hoc panel. eur urol focus.2018;4(4):608-613. 9. hegarty pk, suh j, fisher mb, taylor j, nguyen th, ivan d, prieto vg, et al. penoscrotal extramammary paget’s disease: the university of texas m. d. anderson cancer center contemporary experience. j urol.2011;186(1):97-102. doi: 10.1016/j.juro.2011.02.2685 10. leong jy, chung ph. a primer on extramammary paget’s disease for the urologist. transl androl urol.2020;9(1):93-105. 11. yang wj, kim ds, im yj, cho ks, rha kh, cho nh, et al. extramammary paget’s disease of penis and scrotum. urology.2005;65(5):972-975. doi: 10.1016/j.urology.2004.12.010 12. misas je, cold cj, hall fw. vulvar paget disease: fluorescein-aided visualization of margins. obstet gynecol.1991;77(1):156-159. 13. fanning j, lambert hc, hale tm, morris pc, schuerch c. paget’s disease of the vulva: prevalence of associated vulvar adenocarcinoma, invasive paget’s disease, and recurrence after surgical excision. am j obstet gynecol.1999;180(1 pt 1):24-27. 14. marchesa p, fazio vw, oliart s, goldblum jr, lavery ic, milsom jw. long-term outcome of patients with perianal paget’s disease. ann surg oncol.1997;4(6):475-480. 15. sarmiento jm, wolff bg, burgart lj, frizelle fa, ilstrup dm. paget’s disease of the perianal region--an aggressive disease? dis colon rectum.1997;40(10):1187-1194. 16. yugueros p, keeney gl, bite u. paget’s disease of the groin: report of seven cases. plast reconstr surg.1997;100(2):336-339. 17. zollo jd, zeitouni nc. the roswell park cancer institute experience with extramammary paget’s disease. br j dermatol.2000;142(1):59-65. 18. yao h, xie m, fu s, guo j, peng y, cai z, et al. survival analysis of patients with invasive extramammary paget disease: implications of anatomic sites. bmc cancer.2018;18(1):4 03. doi: 10.1186/ s12885-018-4257-1 19. herrel la, weiss ad, goodman m, johnson tv, osunkoya ao, delman ka, et al. extramammary paget’s disease in males: survival outcomes in 495 patients. ann surg oncol.2015;22(5):1625-1630. doi: 10.1245/ s10434-014-4139-y 38 siuj • volume 4, number 1 • january 2023 siuj.org original research https://pubmed.ncbi.nlm.nih.gov/29630276/ https://pubmed.ncbi.nlm.nih.gov/29630276/ https://rarediseases.info.nih.gov/diseases/4192/extramammary-paget-disease https://rarediseases.info.nih.gov/diseases/4192/extramammary-paget-disease http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information ergonomics, learning curve, robotic assistance, surgical outcomes, surgeon volume, urologic surgery none declared. received on april 5, 2022 accepted on may 22, 2022 this article has been peer reviewed. soc int urol j. 2022;3(5):323–330 doi: 10.48083/ppsc8658 outcomes of robotic surgery for low-volume surgeons sridhar panaiyadiyan, rajeev kumar department of urology, all india institute of medical sciences, new delhi, india abstract when the outcomes are equivalent to the open technique, conventional laparoscopy is a preferred surgical approach because of its minimal invasiveness. however, outcomes following laparoscopy depend on the surgeon’s expertise, and there is a significant learning curve to attain efficiency in complex reconstructing laparoscopic procedures. robotic assistance bridges the gap between open and laparoscopic procedures and allows surgeons with limited laparoscopy experience to offer the benefits of minimally invasive surgery to their patients. while existing data do not show better outcomes with robot assistance compared with laparoscopy for most procedures, these studies are based on data from high-volume surgeons and centers. in reality, a significant number of surgeries are performed by low-volume centers and surgeons, and robotic assistance may enable them to offer benefits of minimally invasive surgery equivalent to those of higher volume centers since robotic assistance is associated with a shorter learning curve than laparoscopy. we review the data on the outcomes of robotic surgery for low-volume surgeons with a focus on centers and surgeons in asia. introduction urology as a specialty has always been at the forefront of technological advancement and has rapidly embraced innovations in devices and techniques. acceptance of new technology usually depends on its being better for the patient or the health care system[1]. however, being “better” is often associated with being more expensive and thus new technologies must prove themselves to not only give better outcomes but also to do so at a cost that is acceptable for the improvements in outcome at a population level. being “better for the surgeon” is rarely considered a valid reason for accepting technology that may increase overall costs of treatment. among surgical approaches, laparoscopy is universally accepted as the preferred option wherever it has been shown to have outcomes equivalent to open surgery. this is because it provides better cosmesis, lower postoperative pain and earlier recovery; all outcomes that are better for the patient and the health care systems[2]. however, outcomes vary among surgeons and, depending on surgeon expertise, the possible procedures range from simple ablative to complex reconstructive ones that require intracorporeal suturing[3]. surgical outcomes improve with increasing case load and plateau after a certain level[4]. once expertise is achieved, outcomes are equivalent irrespective of the surgical approach. however, despite having been available over 30 years, laparoscopy remains challenging for complex reconstructive procedures and has a steep learning curve for such procedures[5]. the introduction of robotic assistance into the surgical armamentarium aimed to bridge the gap between open approaches and laparoscopy and to enable minimally invasive surgery[6]. however, despite having been available now for over 20 years, robotic surgery continues to be questioned and is often derided as a gimmick or marketing tool, primarily because of its high costs, longer operating times, and poor residency training[7,8]. these concerns 323siuj.org siuj • volume 3, number 5 • september 2022 review https://orcid.org/0000-0002-0783-1101 https://orcid.org/0000-0002-0783-1101 mailto:rajeev.urology%40aiims.edu?subject=siuj http://siuj.org are fuelled by a lack of studies showing the superiority of robotic assistance over laparoscopy[9]. in the absence of a difference, it is difficult to justify the use of expensive robotic assistance over pure laparoscopy. most of this data comes from surgeons and centers that have high volumes. it is only to be expected that once expertise has been acquired through high volumes the outcomes are likely to be similar with each technique. in the real world, most urologists do not have the high volumes of these surgeons or centers[10,11]. however, the patients they treat deserve the same outcomes as those at high-volume centers and it is pertinent to assess whether robotic assistance helps low-volume surgeons provide the benefits of minimally invasive surgery to their patients, which they may not have been able to do through pure laparoscopy. the learning curve for robot-assisted surgery is shorter than that for conventional laparoscopy in maiden users[12]. robot assistance allows surgeons trained in open surgery to transition easily to minimally invasive surgery without significant laparoscopy experience, and laparoscopy-naïve surgeons have rapidly gained competence in robot-assisted radical prostatectomy (rarp)[13]. as a corollary, it is plausible that robotic assistance may aid surgeons in a low-volume setting to deliver better outcomes than would be associated with laparoscopy, while providing all the advantages of minimally invasive surgery[11]. with this hypothesis, we reviewed the literature for data on outcomes of robot-assisted surgeries for low-volume surgeons for common urological surgeries such as robot-assisted radical prostatectomy (rarp), robot-assisted partial nephrectomy (rapn), robot-assisted radical cystectomy (rarc), and robot-assisted laparoscopic pyeloplasty (ralp). this is particularly relevant for asia since the penetration of robot-assisted surgeries in asia trails the western world. by 2017, there were 4271 da vinci surgical systems (intuitive surgical inc.) installations worldwide of which 82% were in the unites states europe as compared with 13% in asia but with a trend towards increasing asian installations by 2018[14]. as per the recent data, over 5500 da vinci surgical systems have been installed in 67 countries worldwide[15]. low-volume robotic surgeons and/or hospital what constitutes “ low-volume” for surgeons and hospitals is not clearly defined. considering rarp as the most common robotic urology surgery, in 2011, gershman et al. found that 70% of hospitals in the united states were performing less than 50 rarp per year and the complications, hospitalizations, and transfusion rates all declined with increasing experience until around 100 rarps were being performed per year[16]. while evaluating the impact of surgeon experience, bravi et al. reported a decline in positive margins from 16.7% to 9.6% with increase of surgeon experience from 10 to 250 procedures[17]. based on the evaluation of 9810 rarps in sweden, godtman et al.[18] defined very low-volume (surgeon < 13 or hospital < 50 cases), low-volume (surgeon 13 to 25 or hospital 50 to 100 cases), intermediate (surgeon 25 to 50 or hospital 100 to 150 cases), high-volume (surgeon 50 to 76 or hospital 150 to 200 cases) and very high volume (surgeon ≥ 75 or hospital ≥ 200 cases) surgeons and hospitals. based on the swedish national guidelines for prostate cancer, godtman et al. defined these cut-off values as a multiple of the minimum number of rarps that should be performed by the surgeon and the center. it is expected that these numbers would differ for other procedures. this lack of consensus on the definition of low-volume surgeon would be related to the different learning curve in achieving a benchmark optimum outcome. methods we searched pubmed/medline, embase, web of science, and google scholar databases for relevant studies published in english using the following mesh key words: (robotic urology surgery or robotic radical prostatectomy or r arp or radical cystectomy or rarc or partial nephrectomy or pyeloplasty) and (low-volume surgeons or low-volume center or learning curve). the abstracts and full articles of systematic reviews and meta-analyses were reviewed. case reports, letters, short communications, and articles in languages other than english language were excluded. radical prostatectomy reviewing the outcomes of radical prostatectomies done at high-volume centers, coelho et al. showed that rarp delivered better outcomes in terms of weighted mean psm, continence, and potency rates compared with retropubic and laparoscopic radical prostatectomies[19]. however, with the increasing adoption of robotic system in the recent years, there has been an increase in the abbreviations ebl estimated blood loss lny lymph node yield lpn laparoscopic partial nephrectomy ot operative time psm positive surgical margin ralp robotic-assisted laparoscopic pyeloplasty rapn robotic-assisted partial nephrectomy rarc robotic-assisted radical cystectomy rarp robotic-assisted radical prostatectomy wit warm ischemia time 324 siuj • volume 3, number 5 • september 2022 siuj.org review number of rarp being done at low-volume centers[20]. it is now estimated that between 33% and 70% of rarp in the united states are done by low-volume surgeons[10]. with conventional laparoscopic radical prostatectomy, the number needed to attain a 90% recurrence-free probability is estimated to be 750 cases[21]. in contrast, with rarp, about 80 to 120 cases are needed to attain a comparable perioperative, oncological, and functional outcomes[22]. further, with increasing experience in rarp, the perioperative complications declined from 9.8% in low-volume surgeons to 6.7% in intermediate-volume surgeons and to 2.2% in high-volume surgeons[23]. in a retrospective analysis from india, garg et al. showed an inverse stage migration pattern in their rarp practice. over the time, with increasing experience in rarp, patients with more unfavorable disease characteristics underwent rarp[24]. a recent multi-national and multicenter retrospective study discussed the rarp outcomes (n = 207) of 3 fellowship-trained surgeons from low-volume regions of gulf cooperation council countries[25]. this study showed trifecta outcomes comparable to those of international centers. at the 12-month follow-up, 35.8% of patients were potent, 94.6% were continent, and 9.2% had biochemical recurrence[25]. in a recent study from low-intermediate volume center, afferi et al. retrospectively analyzed 604 men who underwent nerve-sparing rarp[26]. at a median follow-up of 28 months, the authors reported an increase in the pentafecta outcomes from 38% to 44%, with erectile dysfunction being the main limiting factor for non-achievement of pentafecta in 71% cases. however, in high-risk prostate cancers, biochemical recurrence limited the pentafecta achievement (61%)[26]. partial nephrectomy t he cu rrent sta nda rd of ca re for sma l l rena l masses is partial nephrectomy[27]. prior reports showed equivalent oncological outcomes between open a nd lapa roscopic approaches for pa r t ia l nephrectomies[28,29]. however, laparoscopic partial nephrectomy (lpn) is a technica lly demanding procedure requiring intracorporeal suturing with si mu lta neous considerat ion of wa r m ischemia time (wit) to prevent ischemic renal injury[30]. considering that laparoscopic radical nephrectomy was easier to perform, it was hy pothesised that partial nephrectomy was underutilized for eligible candidates[31]. af ter successful incorporation of robotic assistance into radical prostatectomy, robotassisted partial nephrectomy (rapn) was quickly and widely adopted[32]. a surgeon needs to perform fewer rapn than lpn to attain a comparable level of competency[33]. it is estimated that about 565 cases are required to achieve the target wit (< 20 to 25 minutes) in lpn[34], whereas it requires about 20 and 50 cases, for rapn for equivalent wit and operative time (ot), respectively[5]. in contrast, expert renal surgeons require < 30 cases of rapn to achieve an equivalent proficiency. in a low-volume center in kuwait, a fellowship-trained robotic surgeon retrospectively assessed the perioperative, trifecta, and pentafecta outcomes following 43 rapn cases performed over 6 years. operative time and estimated blood loss (ebl) improved significantly after the first quartile of patients (n = 14). trifecta and pentafecta outcomes were achieved in 93% and 81.8% cases, respectively. a higher number of complex cases with renal nephrometry scores of 7 to 12 were performed in the second (n = 14) and third (n = 15) quartiles[35]. in a prospective study, dias et al. reported outcomes of rapn by a laparoscopy trained surgeon with no prior robotic surgery experience. in 108 cases performed over 5 years, wit ≤ 20 minutes, ot ≤ 150 minutes, and ebl < 100ml were achieved after 44, 44, and 54 cases, respectively. a trifecta outcome was achieved in 67.6% cases[36]. motoyama et al. in a retrospective study reported the outcomes of 65 rapn performed by a surgeon with no prior lpn experience but with extensive robotic surgery experience[37]. the learning curve was analyzed by dividing cases into 5 groups of 13 consecutive patients. trifecta outcomes were achieved in 89.2% cases. the authors reported a wit of ≤ 20 minutes and console time of ≤ 150 minutes could be achieved at fourth and sixth procedures, respectively[37]. in terms of complications, a multicenter study showed that a low-volume surgeon performing < 7 cases of rapn per year had a complication rate (18.1% versus 15.9% versus 16.1%, p = 0.81) comparable to high-volume (15 to 30 rapn cases/year) and very high-volume (> 30 rapn cases/year) surgeons[38]. in a recent database study involving 124 institutions in japan, yokoyama et al. reported the trends and safety of rapn done at low-volume (n = 616) and high-volume (n = 3106) institutions. after propensity score matching, the authors did not find any significant differences in anesthesia time, blood transfusions, and complication rates between low-volume and high-volume centers[39]. similarly, data from a single-center study in turkey confirmed that a comparable trifecta outcome (77%) can be achieved by low-volume surgeon[40]. radical cystectomy radical cystectomy with urinary diversion has one of the highest morbidity rates among urological procedures, with postoperative complication rates of up to 69%[41]. minimally invasive surgery, both pure laparoscopy 325siuj.org siuj • volume 3, number 5 • september 2022 outcomes of robotic surgery for low-volume surgeons http://siuj.org and robot-assisted, are feasible alternatives to open radical cystectomy. data from the razor trial suggest that rarc is associated with decreased blood loss, transfusion rate, and hospital stay compared with the open approach[41]. further, rarc has been shown to be non-inferior to the open approach in terms of 3-year progression-free and overall survival[42]. the learning curve for such complex procedures is estimated to be 21 to 30 cases when using benchmarks of operating time of < 6.5 hours, lymph node yield (lny) of 20, and < 5% positive surgical margin (psm). the number needed to reach the target ot was 21 cases. a total of 8, 20, and 30 cases were required to attain a lny of 12, 16, and 20, respectively. similarly, 30 cases were required to reach competency for psm[43]. guru et al. divided 100 consecutive rarc procedures into 4 quartiles. the overall mean ot and ebl were 343 minutes and 598 ml, respectively. the mean ot reduced from 375 minutes in first quartile to 352 minutes in the last quartile. similarly, the lny increased from 14 nodes in first quartile to 23 nodes in the last quartile. while there were 4 cases of psm in the first quartile, none of the patients in the last quartile had a positive margin. the authors reported no difference in the complication rate over time[44]. experience in one robot-assisted procedure helps improve outcomes in other procedures. hayn et al., using the international robotic cystectomy consortium database, report that surgeons with prior experience in rarp provide better rarc outcomes with significant differences in ot, ebl, and lny between surgeons with < 50 rarps and those with 51 to 100 rarps[45]. the adoption of rarc has been increasing in asian countries in recent years. a single-center retrospective analysis from india of the initial experience of 63 rarc with extracorporeal urinary diversion reported a mean ot, ebl, and hospital stay of 348 minutes, 868 ml, and 10.4 days, respectively. the mean lny was 12.4, ranging between 3 and 25 nodes[46]. these data are very similar to those reported from larger centers[44]. pyeloplasty robotic assistance has also helped lower the steep learning curve associated with laparoscopic pyeloplasty for uretero-pelvic junction obstruction[47]. it has been documented to be of particular advantage in patients with anatomical variations like lower moiety ureteropelvic junction obstruction, malrotated kidneys, and secondary uretero-pelvic junction obstruction[48–52]. ralp is a relatively simple procedure and has been considered as a gateway to advanced reconstructive procedures[53]. a novice can achieve an operating time within 1 standard deviation of the open pyeloplasty after 15 to 20 cases[54]. however, it takes only about 5 cases for a surgeon expert in open procedures[55]. it is not surprising that robotic assistance does not offer any benefit to experienced laparoscopic surgeons with good intracorporeal suturing skills[56]. however, a relatively faster learning curve could prompt low-volume surgeons to offer ralp to their patients to deliver comparable outcomes. ergonomics the ergonomics of the procedures for surgeons are often under-reported, and poor ergonomics affect physical, mental, and economic well-being. a greater degree of adverse ergonomic problems are expected among urologists who perform a wide range of operative procedures such as open, laparoscopic, robotic, endoscopic, and microscopic surgeries[57]. catanzarite et al. have shown that work-related musculoskeletal disorders are prevalent in 66% to 90%, 73% to 100%, and 23% to 80% for open, laparoscopic, and robotic surgeries, respectively[58]. surgeon fatigue after performing a conventional laparoscopic pyeloplasty may limit the number of procedures that may be performed on the same day[59]. specifically, post-procedure fatigue affects precise intracorporeal suture placement[60]. although table 1. learning curve of common robotic urological procedures procedure* number of cases required outcome measures rarpa 80–120 cases[21] perioperative, oncological, and functional outcomes rapn 20 cases[5] 50 cases[5] wit ot rarc 21–30 cases[41] ot < 6.5 hours; lny of 20; psm < 5% ralp 15–20 cases[52] ot rarp: robotic-assisted radical prostatectomy; rapn: robotic-assisted partial nephrectomy; rarc: robotic-assisted radical cystectomy; ralp: robotic-assisted laparoscopic pyeloplasty; wit: warm ischemia time; ot: operative time; lny: lymph node yield and psm: positive surgical margin * all the data provided here are originated from surgeons trained in both open and laparoscopy except (a) denotes the learning curve of a surgeon with no prior laparoscopic experience. 326 siuj • volume 3, number 5 • september 2022 siuj.org review robot-assisted surgery appears to be ergonomically better, it too can lead to a strain on trunk, wrist, and fingers[58]. for instance, one of the most common ergonomic issues while performing robotic surgery is abducted shoulder and not maintaining a right angle with the biceps, resulting in lifting off the elbows from the armrest. surgeons have to use the clutch control to mitigate the abnormal posture[57]. the learning curves of common robotic urological procedures are shown in table 1. these numbers should be interpreted with some caution as the data could be heterogenous as the data include different cohorts. further, various confounders affecting the outcomes of different robotic procedures were not addressed. however, our work provides an overview of data on outcomes of common robot-assisted surgeries for low-volume surgeons. role of various robotic training models various training models have the potential to help lowvolume robotic surgeons deliver a reasonable surgical outcome without compromising patient safety. in this context, expert proctorship helped trainees achieve efficiency and early performance of independent robotic procedures. with the introduction of dual-console da vinci si or xi surgical systems, the proctorship program has become more convenient for both proctor and trainee[61–63]. as the technology advances, the future looks promising for telementoring, which may facilitate remote proctorship[64]. a fellowship program has been considered the most structured robotic training model as it involves a systematic method of training[65]. the trainees perform progressive steps of the operation in succession under the guidance of an expert robotic surgeon with constant and immediate feedback[61]. lastly, simulation-based training allows trainees to develop surgical skills without risking patient safety. it provides an objective assessment of particular surgical skills. in recent years, various robotic simulation platforms have been developed and are commercially available. in particular, the da vinci skills simulator is closely attached to the surgeon console that would be otherwise used for robotic-assisted surgeries[66]. conclusion robotic assistance has the potential to help low-volume surgeons and hospitals offer minimally invasive surgery to their patients. robotic assistance enables surgeons to reach a higher degree of competence more quickly and easily. while the costs associated with robot assistance continue to be high, 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10.1089/lap.1998.8.69 61. santok gd, raheem aa, kim lh, chang k, chung bh, choi yd, et al. proctorship and mentoring: its backbone and application in robotic surgery. investig clin urol.2016;57(suppl 2):s114. doi: 10.4111/ icu.2016.57.s2.s114 62. chowdhury a, tan lgl, chiong e, rha kh, tiong hy. transitioning to robotic partial nephrectomy with a team-based proctorship achieves the desired improved outcomes over open and laparoscopic partial nephrectomy. updates surg.2021;73(3):1189-1196. doi: 10.1007/ s13304-021-01028-0 329siuj.org siuj • volume 3, number 5 • september 2022 outcomes of robotic surgery for low-volume surgeons http://siuj.org 63. mason md, herndon cda, herbst k w, poston tl, brandt ej, peters ca, et al. proctor environment facilitates faculty training in pediatric robotic-assisted laparoscopic pyeloplasty. j robotic surg.2014;8(4):365-369. doi: 10.1007/s11701-014-0481-0 64. santomauro m, reina ga, stroup sp, l’esperance jo. telementoring in robotic surgery. curr opin urol.2013;23(2):141-5. doi: 10.1097/ mou.0b013e32835d4cc2 65. el sherbiny a, eissa a, ghaith a, morini e, marzotta l, sighinolfi mc, et al. training in urological robotic surgery. future perspectives. arch esp urol. 2018;71(1):97-107. 66. canalichio kl, berrondo c, lendvay ts. simulation training in urology: state of the art and future directions. adv med educ pract.2020;11:391-396. doi: 10.2147/amep.s198941 330 siuj • volume 3, number 5 • september 2022 siuj.org review 1siuj.org siuj • volume 4, number 1 • january 2023 volume 4, number 1 | january 2023 issn 2563-6499 10.48083/aglr3780 editorial office info@siuj.org tel: 514-875-5665 ext. 26 siuj.org managing editor jane fairbanks jane.fairbanks@siu-urology.org the siuj is published 6 times a year by the société internationale d'urologie (siu). it is the official peer-reviewed publication of the siu but retains editorial independence. the siuj is circulated to urologists, urology residents, family medicine specialists, family medicine residents, general practitioners, nurses, medical libraries, and hospital and university departments of urology worldwide, for a total circulation of over 10,000. this publication was developed under the direction of the siuj editorial board. the siuj is published under an exclusive licence. the siuj is owned and published by the société internationale d’urologie (siu). marketing lillian petrusa lillian.petrusa@siu-urology.org advertising mikaela tierney advertising@siuj.org neither the siu nor the siuj endorses any service or the contents of any product referred to in any advertisement in the siuj. the siu and the siuj assume no responsibility or liability for damages arising from any error or omission, or from the use of any information or advice contained in the siuj. all editorial matter in siuj represents the opinions of the authors and not necessarily those of the siu or the siuj. all canadian prescription drug advertisements have been cleared by the pharmaceutical advertising advisory board. editorial board editor-in-chief peter c. black, md, canada deputy editor philippe e. spiess, md, united states associate editors lysanne campeau, md, canada sandro esteves, md, brazil sanjay sinha, mch, india henry woo, mbbs, australia social media editor jeremy y. c. teoh, mbbs, hong kong sar statistical editor alice dragomir, phd, canada innovators editor amanda chung, mbbs, australia regional editors north america kathleen kobashi, md united states middle east yasser osman, mbbch egypt south america gonzalo vitagliano, md argentina east asia tianxin lin, md china eastern europe roman sosnowski, md poland south asia gagan prakash india western europe tamsin greenwell, md united kingdom southeast asia edmund chiong, mbbs singapore africa evelyn moshokoa, mbchb south africa a new treatment option for patients with urothelial carcinoma (uc) propdivo® is indicated as a monotherapy for the adjuvant treatment of adult patients with uc who are at high risk of recurrence after undergoing radical resection of uc.1 please consult the opdivo product monograph at https://www.bms.com/assets/bms/ca/documents/productmonograph/opdivo_en_pm.pdf for contraindications, warnings, precautions, adverse reactions, drug interactions, dosing, and conditions of clinical use. the product monograph is also available by calling us at: 1-866-463-6267. reference: 1. opdivo product monograph. bristol-myers squibb canada co. opdivo and the opdivo logo are registered trademarks of bristol-myers squibb company used under license by bristol-myers squibb canada co. 1506-ca-2200026e opdivo is indicated for the adjuvant treatment of adult patients with urothelial carcinoma (uc) who are at high risk of recurrence after undergoing radical resection of uc. opdivo has been issued marketing authorization with conditions, pending the results of trials to verify its clinical benefit. patients should be advised of the nature of the authorization. for further information for opdivo please refer to health canada’s notice of compliance with conditions – drug products website. (https://w w w.canada.ca/en/health-canada/ser vices/drugs-health-products/drug-products/ notice-compliance/conditions.html) n e w i n d i c at i o n http://siuj.org mailto:info%40siuj.org?subject=siuj http://siuj.org mailto:jane.fairbanks%40siu-urology.org?subject=siuj mailto:lillian.petrusa%40siu-urology.org%20?subject=siuj mailto:advertising%40siuj.org?subject=siuj siuj cross-out 2 siuj • volume 4, number 1 • january 2023 siuj.org editorial board ahmed adam, mbbch south africa wayne lam, mbbs hong kong sar fahad alyami, mbbs saudi arabia sang dong lee, md korea mohsen azli, md algeria medina ndoye, md senegal erdem canda, md türkiye andrea necchi, md italy yao-chi chuang, md taiwan dedan opondo, mbchb kenya archil chkhotua, md georgia karima oualla, md morocco renu eapen, mbbs australia lourdes guerrios rivera, md puerto rico agus rizal ardy hariandy hamid, md indonesia mohammed shahait, md jordan thomas herrmann, md switzerland khurram siddiqui, mbbs oman christopher ho chee kong, md malaysia yaya sow, md senegal theocharis karaolides, md cyprus chuan-liang xu, md china abdol mohammad kajbafzadeh, md iran the société internationale d’urologie (siu). the society’s mission is to enable urologists in all nations, through international cooperation in education and research, to apply the highest standards of urological care to their patients. the siu is a major international platform for sustainable urological education and collaborative philanthropic activities aimed at improving urological care with more than 10 000 members from over 130 countries. siu central office 1155 robert-bourassa blvd., suite 1012 montreal, quebec, canada h3b 3a7 tel: +1 514 875-5665 fax: +1 514 875-0205 communications@siu-urology.org executive director susie petrusa susie.petrusa@siu-urology.org graphic design sam design info@studiosamdesign.com web design/ technical support aiki informatique info@aikitech.ca volume 4, number 1 | january 2023 neither the siu nor the siuj endorses any service or the contents of any product referred to in any advertisement in the siuj. the siu and the siuj assume no responsibility or liability for damages arising from any error or omission, or from the use of any information or advice contained in the siuj. all editorial matter in siuj represents the opinions of the authors and not necessarily those of the siu or the siuj. all canadian prescription drug advertisements have been cleared by the pharmaceutical advertising advisory board. http://siuj.org mailto:communications%40siu-urology.org?subject=siuj mailto:susie.petrusa%40siu-urology.org?subject=siuj mailto:susie.petrusa%40siu-urology.org?subject=siuj mailto:info%40studiosamdesign.com%20?subject=siuj mailto:info%40studiosamdesign.com%20?subject=siuj mailto:info%40aikitech.ca?subject=siuj 3siuj.org siuj • volume 4, number 1 • january 2023 table of contents editorial standing on the shoulders of giants 5 peter c. black urology around the world siu training scholarship: an unforgettable experience at the muljibhai patel urological hospital, nadiad-gujarat, india 8 emmanuel ugbede oyibo research implementing holep in an academic department with multiple surgeons in training: mentoring is the key for success 11 clément klein, thibault marquette, grégoire capon, eric alezra, peggy blanc, vincent estrade, jean-christophe bernhard, franck bladou, grégoire robert disparities in access to virtual care for urinary tract infections during the covid-19 era 20 molly e. dewitt-foy, jacob a. albersheim, shawn t. grove, lina hamid, sally berryman, sean p. elliott the larcg latin american renal cancer group: achievements in support, teaching, research, collaboration, and advocacy 27 stenio de cássio zequi, francisco rodriguez-covarrubias, ignacio pablo tobia, alberto jurado, anamaria autran gomez, luiz meza-montoya, walter henriques da costa, alejandro nolazco, thiago camelo mourao, diego abreu oncologic outcomes of a novel mapping biopsy technique before surgical excision in the management of extramammary paget disease 34 kyle m. rose, rosalie zurlo, roger li, gerard mosiello, philippe e. spiess review salvage versus adjuvant radiation therapy following radical prostatectomy in localised prostate cancer: a war without a winner 40 lara rodriguez-sanchez, petr macek, camille lanz, qusay mandoorah, nuno dias, gianmarco colandrea, fernando p. secin, amandeep m. arora, rafael sanchez-salas, xavier cathelineau urogenital malignancy and cannabis use: a narrative review 51 alice thomson, aoife mcvey, brennan timm, damien bolton http://siuj.org 4 siuj • volume 4, number 1 • january 2023 siuj.org table of contents, cont'd giants in urology rudolf hohenfellner, chairman, department of urology, johannes gutenberg university, mainz, germany, 1967 to 1996 67 jan fichtner, margit fisch clinical picture chronic pelvic organ prolapse and bladder calculi in an adolescent 69 reyhane ebrahimi, alireza soltani khaboushan, abdol-mohammad kajbafzadeh incarcerated internal hernia posterior to the iliac vessels after uncomplicated radical cystectomy 71 sydney sparanese, cyrus chehroudi, peter c. black http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj.org siuj • volume 4, number 1 • january 2023 5 editorial standing on the shoulders of giants peter c. black, editor-in-chief soc int urol j.2023;4(1):5 doi: 10.48083/dmjd6674 isaac newton famously wrote in 1676: “if i have seen a little further it is by standing on the shoulders of giants.” in this issue of the siu journal we introduce a new feature article that we will include regularly going forward: giants in urology. in medicine and surgery, we have a certain reverence for the pioneers who established the practices we incorporate into daily practice—but at the same time we have a short collective memory of those who have gone before us. icons in the field who drift into retirement are quickly forgotten by the next generation of urologists emerging from training. for this reason, we wanted to feature some of these giants. we are certainly not the first urologic journal to do so, but, aligned with the mission of the siuj, we will do this from a global perspective, showcasing giants from around the world, including those whose impact was perhaps appreciated only regionally. our first giant is rudolf (“rudy”) hohenfellner, the long-time chairman of the department of urology at the johannes gutenberg university in mainz, germany. reading this contribution from jan fichtner and margaret fisch reveals that this giant was himself influenced by giants that preceded him—and hohenfellner has without question spawned multiple giants himself (the authors included). the legacy of passing on skills, techniques, and wisdom to one’s own trainees and junior faculty is without doubt a key feature of any giant in the field. hohenfellner is like a godfather figure in german urology, as many chairs across the country started their careers under his tutelage. his surgical innovation has influenced many urologists around the world, benefitted not only all the patients he cared for but also all those cared for by his former trainees. i am myself one of the many trainees influenced by rudy hohenfellner. i had no idea who he was at the time, but he was the inspiration for me to pursue a career in urology. my first urologic experiences were his weekly lectures in the middle years of medical school. he regularly brought patients to his lectures and interviewed them with his thick viennese accent to allow the students to learn from the individual medical histories and experiences of the patients. urinary diversion was a regular feature in his lectures (mainz is after all where he developed the mainz pouch), and this was part of the inspiration for me to do an elective in urology. about 25 years later, i still do a lot of urinary diversion (although not the mainz variety). as i finish a continent cutaneous reservoir or an orthotopic neobladder, i often wonder how we get away with these extensive reconstructive surgeries. at least we have decades of positive experiences on which to build, but imagine the early pioneers of urinary diversion like hohenfellner who were developing the techniques that we have all since adopted. perhaps more importantly, hohenfellner instilled in his trainees many other lessons that were critical to the budding surgeon: discipline, technical excellence, scientific rigor, innovation, and devotion to the patient. i like to say that i might not do what i do today if i had not encountered rudy hohenfellner in the late 1990s in mainz. i am reminded of a conversation i had with a very prominent canadian urologist a few years ago on a subway in washington dc. he was lamenting that the meeting to which we were both traveling used to attract many of the major “icons” (his term) in the field, but that he had noticed a gradual decline in this pattern over the years. what he did not recognize is that he had become an icon himself, and the urologists that he viewed as icons were mostly retired. there are many giants, and giants will come and go. every urologist will have a different perspective on who is a giant in their region of the world and in their area of subspecialty practice. the impact of any given giant may be quite varied, including especially clinical research, translational research, biomarker and drug development, surgical innovation, modification of standard clinical practice, or exemplary leadership. some giants will have contributed specifically to the success of urological organizations like the siu, or to different urologic journals. we therefore invite contributions from urologists around the world. share with us the inspiration your mentor has imparted to others. we would like to capture in the pages of the siu journal some of the main achievements of these giants, the quintessence of their personalities, and their legacy to our field. who are the giants are in your urologic sphere? upon whose shoulders do you stand? http://siuj.org mailto:editorinchief%40siuj.org?subject=siuj save the date in conjunction with featuring the 5th b2b uro–oncology: gu cancers triad meeting this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information refractory metastatic clear cell renal cell carcinoma, vascular endothelial growth factor receptor tyrosine kinase inhibitor, immunotherapy resistance see "acknowledgments" for details. received on august 10, 2022 accepted on september 14, 2022 this article has been peer reviewed. soc int urol j. 2022;3(6):478–484 doi: 10.48083/kgtq6832 2022 wuof/siu international consultation on urological diseases: therapies in refractory metastatic renal cell carcinoma stephanie berg,1 martin angel,2 kathryn e. beckermann,3 frede donskov,4 chung-han lee,5 pavlos msaouel,6 rana r. mckay,7 tian zhang8 1 loyola university chicago, chicago, united states 2 instituto alexander fleming, buenos aires, argentina 3 vanderbilt university medical center, nashville, united states 4 university hospital of southern denmark, esbjerg, denmark 5 memorial sloan kettering cancer center, new york, united states 6 university of texas md anderson cancer center, houston, united states 7 university of california san diego, moores cancer center, san diego, united states 8 ut southwestern medical center, harold c. simmons comprehensive cancer center, dallas, united states abstract as the therapeutic landscape for metastatic clear cell renal cell carcinoma (mccrcc) expands to include vascular endothelial growth factor receptor tyrosine kinase inhibitors (vegfr tkis) and immunotherapies, new challenges are in place for evaluating and treating refractory disease. assessing and managing refractory disease has several elements: (1) the mechanism(s) of front-line treatment, (2) timing of progressive disease, (3) rapidity and sites of progressing disease, (4) use of adjuvant therapy, and (5) incorporation of surgical and radiation techniques. these variables all have distinct impact on the biology of refractory or resistant mccrcc. a better understanding of the essential mechanisms of both primary and secondary immunotherapy resistance will inform biomarker development and therapeutic strategies in the refractory setting. this paper addresses the current understanding of treatment sequencing in refractory mccrcc, focusing on treatment options with prospective clinical trial data, considers refractory mccrcc after adjuvant immunotherapy, and incorporates radiation or surgical resection for oligoprogressive disease. introduction refractory metastatic clear cell renal cell carcinoma (mccrcc) poses unique challenges regarding treatment sequencing, selection, and integration of definitive surgery or stereotactic body radiation therapy (sbrt). ultimately, one must consider choice of front-line treatment, resistance mechanisms, disease kinetics, and disease relapse after adjuvant immunotherapy to determine subsequent therapies at time of disease progression or relapse. currently, no validated biomarkers are approved to help guide treatment selection; however, certain strategies exist to help one navigate this ever-changing landscape and will be reviewed in this article. 477 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases https://orcid.org/0000-0001-6193-5350 https://orcid.org/0000-0002-1463-8887 https://orcid.org/0000-0002-4616-6140 https://orcid.org/0000-0002-8449-863x https://orcid.org/0000-0001-5511-0635 https://orcid.org/0000-0001-6505-8308 https://orcid.org/0000-0002-0581-7963 https://orcid.org/0000-0001-8914-3531 mailto:tian.zhang%40utsouthwestern.edu?subject=siuj http://siuj.org tyrosine kinase inhibitors in mccrcc the mainstay for mccrcc treatments relies on targeting angiogenesis and the vascular endothelial growth factor receptor (vegfr); these become upregulated following loss of the von hippel-lindau (vhl) protein and accumulation of hypoxia-inducible factor (hif), leading to aberrant signaling in angiogenesis, proliferation, and metabolism[1,2]. multiple therapies, predominantly antiangiogenic tyrosine kinase inhibitors (tkis), were developed to target the vascular endothelial growth factor (vegf) pathway, and seven of these therapies are currently by the united states food and drug administration (fda) and listed on the national comprehensive cancer network (nccn) guidelines: axitinib, cabozantinib, lenvatinib, pazopanib, sorafenib, sunitinib, and tivozanib[3]. while these therapies have served as the backbone of treatment, responses are heterogeneous, with some patients exhibiting intrinsic resistance and many patients developing acquired resistance despite initial response or disease stability. several mechanisms of resistance have been defined including upregulation of other angiogenic drivers and increased tumor invasiveness using alternative pathways (met or axl), which led to vegf resistance and eventual disease progression[4,5]. multiple trials in the second line after prior exposure to anti-vegf therapies have been conducted and demonstrated improvements in progression-free and overall survival. three tki therapeutics (axitinib, cabozantinib, and tivozanib) received their fda approval specifically for patients who have progressed on at least one or more prior systemic therapies[6–8]. the first phase 3 trial of axitinib versus sorafenib, entitled axis, and including patients who progressed after sunitinib or cytokines, demonstrated a progression-free survival (pfs) for axitinib over sorafenib (hazard ratio [hr], 0.66; 95% ci, 0.544–0.812; p  <  0.001)[6]. tolerability of axitinib was similar to sorafenib and also led to higher objective response rates (orrs), 19% for axitinib and 9% for sorafenib, and did not demonstrate a statistically significant difference in median overall survival between the two arms, but more than half the patients on each arm went on to subsequent therapy. cabozantinib inhibits the activity of c-met, vegfr, axl, and other tyrosine kinases, thereby leading to reduced tumor angiogenesis, motility, and invasiveness, which make it an ideal choice in the refractory mccrcc setting[7]. the phase 3 trial of cabozantinib versus everolimus, entitled meteor, demonstrated both an improvement in pfs and overall survival (os) for cabozantinib over everolimus (hr, 0.66; 95% ci, 0.53–0.83; p = 0.00026)[7]. tivozanib, which received fda approval in 2021, functions by selectively inhibiting the phosphorylation of vegfr-1, vegfr-2, and vegfr-3, and due to this potency and selectively it may confer less toxicity and improved tolerability for patients[8]. tivo-3, a phase 3 clinical trial of tivozanib versus sorafenib, studied patients who had disease progression on at least two prior therapies including anti-vegf and immune checkpoint inhibitors. the trial met its primary endpoint, and tivozanib as a thirdor fourth-line agent improved pfs compared with sorafenib (hr, 0.73; 95% ci, 0.56–0.94; p = 0.016)[9]. finally, combination therapy targeting the mammalian target of rapamycin (mtor) pathway and vegfr proved beneficial for patients in the refractory mccrcc setting. in a multicenter, open-label, phase 2 trial of lenvatinib plus everolimus versus lenvatinib or everolimus monotherapy, lenvatinib plus everolimus yielded a strong signal toward improved pfs compared w it h everolimus (hr, 0.40; 95% ci, 0.24– 0.68; p = 0.0005) but only a weak signal toward improved pfs compared with lenvatinib monotherapy (hr, 0.66; 95% ci, 0.39–1.10; p = 0.12)[10]. exploiting these pathways in refractory mccrcc is important and with more specific tkis approved—for example tivozanib, which has demonstrated improved pfs in heavily pretreated patients with better tolerability and manageable toxicity—should be the cornerstone of future treatment combinations. key phase 3 trials are listed in table 1. immune checkpoint inhibition in mccrcc mrcc is an immunogenic tumor, and therapies utilizing humanized monoclonal antibodies to block the negative regulatory signal between programmed death 1 (pd-1) on the t-cell and its ligand programmed death 1 ligand 1 (pd-l1) on the tumor cell, termed immune checkpoint inhibitors (icis), have shown remarkable and durable responses. ici monotherapy has been studied in refractory mccrcc with the pd-1 inhibitor nivolumab. checkmate-025 was a phase 3 clinical trial comparing nivolumab versus everolimus, where all patients had progressed on at least one prior antiangiogenic t herapy. nivolumab monot herapy improved t he abbreviations ctla-4 cytotoxic t-lymphocyte-associated protein 4 ici immune checkpoint inhibitor mccrcc metastatic clear cell renal cell carcinoma orr objective response rate os overall survival pd-1 programmed death 1 pfs progression-free survival sbrt stereotactic body radiation therapy tki tyrosine kinase inhibitor vegf vascular endothelial growth factor vegfr vascular endothelial growth factor receptor fda united states food and drug administration 478siuj.org siuj • volume 3, number 6 • november 2022 therapies in refractory metastatic renal cell carcinoma http://siuj.org orr over everolimus (25% vs. 5%; odds ratio, 5.98; 95% ci, 3.68–9.72; p < 0.001) and demonstrated a median os benefit of 25 months compared with 19.6 months (hr, 0.73; 98.5% ci, 0.57–0.93; p = 0.002) [11]. another immunogenic pathway in t-cell surface receptor signaling involves the cytotoxic t-lymphocyte associated protein 4 (ctla-4), which is a coreceptor that controls peripheral tolerance and development of autoimmunity. ipilimumab is a humanized monoclonal antibody against ctla-4 and was combined with nivolumab in the first-line setting for mrcc in the pivotal first-line mccrcc trial checkmate-214. this phase 3 clinical trial compared the combination of nivolumab plus ipilimumab versus sunitinib[12]. the os and orr were higher with the combination of nivolumab plus ipilimumab compared with sunitinib amid patients with international metastatic rcc database consortium (imdc) intermediateand poorrisk disease and remains superior at 4-year follow-up (hr, 0.65; 95% ci, 0.54–0.78)[13]. for the refractory mrcc setting, several trials have tested the dual ici combination ipilimumab plus nivolumab (ipi-nivo). fraction-rcc was a phase 2 clinical trial that tested the combination ipi-nivo in heavily pretreated patients with mccrcc who had previously received and progressed on icis. the study demonstrated a meager orr of 15.2% as well as a median pfs of only 16.1 weeks[14]. furthermore, risk-adaptive trials have been conducted with varying responses. three phase 2 clinical trials (titan-rcc, omnivore, hcrn gu16–620) investigated treatment intensification with the addition of ipilimumab after progression or lack of response on pd-1 monotherapy[15–17]. all three studies showed modest activity of ipilimumab in the salvage setting after nivolumab with limited responses, and the use of ctla-4 after pd-1 refractory disease remains uncertain. combination ici plus vegfr tki in refractory mccrcc additionally, front-line combinations of icis with or without vegfr tki are now standard of care for all imdc-risk mccrcc patients, but single-center retrospective studies have shown that patients who progress on ici plus vegfr tki or ici plus ici have an orr of 25% and a median pfs of 12 months (95% ci, 8.2–24.5) when initiated on further treatments[18]. the cantata study was a phase 3 trial of cabozantinib plus telaglenastat, an oral glutaminase (gls) inhibitor t hat block s g luta m i ne ut i l i z at ion a nd cr it ica l downstream pathways, versus cabozantinib plus placebo in previously treated mccrcc patients who received ≥ 1 antiangiogenic therapy or ipi-nivo. in this study, table 1. key phase 3 clinical trials in refractory metastatic kidney cancer axis meteor tivo-3 checkmate-025 cantata treatment axitinib vs. sorafenib cabozantinib vs. everolimus tivozanib vs. sorafenib nivolumab vs. everolimus cabozantinib + telaglenstat vs. cabozantinib mpfs (months) 6.7 7.4 5.6 4.6 9.2 hr (95% ci) 0.66 (0.544–0.812) 0.51 (0.42–0.62) 0.73 (0.56–0.94) 0.88 (0.75–1.03) 0.94 (0.74–1.21) orr (%) 19% 17% 12.3% 25% 31% mos (months) 20.1 21.4 16.4 25 not reported 479 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org 62% of the enrolled patients had progression on prior ici. cabozantinib plus telaglenastat demonstrated a median pfs of 9.2 months and cabozantinib plus placebo demonstrated a median pfs of 9.3 months (hr, 0.94; 95% ci, 0.74–1.21; stratified log-rank p = 0.65), which was not statistically significant. however, in a prespecified subgroup analysis for patients who received prior ici, cabozantinib plus telaglenastat yielded a numerically longer median pfs than cabozantinib plus placebo (11.1 vs. 9.2 months, respectively; unstratified hr, 0.77; 95% ci, 0.56–1.06)[19]. keynote-146 was a single-arm, phase 1b/2 clinical trial of the combination of lenvatinib plus pembrolizumab in treatment-naïve, previously treated ici-naïve and ici-pretreated mccrcc patients[20]. the objective response at week 24 in the ici-pretreated cohort was 55.8% (95% ci, 45.7–65.5), and the median pfs was 12.2 months (95% ci, 9.5–17.7), but due to the single-cohort nature of the trial, it is difficult to ascertain the effectiveness of these individual study drugs in this setting. current trials are ongoing to address the issue of ici continuation after progression on ici combination or monotherapy. contact-03 (nct04338269) is a randomized phase 3 study of cabozantinib plus atezolizumab versus cabozantinib monotherapy in patients with mrcc (clear cell and non-clear cell, papillary or unclassified) who had radiographic disease progression during or following firstor second-line ici treatment[21]. this trial has dual primary endpoints of pfs and os that will further elucidate the role of cabozantinib plus atezolizumab in the ici-refractory setting. contact-03 enrollment was completed in 2022. another ongoing trial, tinivo-2 (nct04987203), is a randomized phase 3 trial of tivozanib plus nivolumab versus tivozanib monotherapy in patients who have previously progressed on 1 or 2 lines of therapy, including an ici (during or within 6 weeks of treatment discontinuation)[22]. both trials will likely be completed by 2025, and yield insight as to whether combination therapy with vegf tki and either pd-1 or pd-l1 inhibition is superior to tki monotherapy in ici-refractory mccrcc. other select ongoing studies in the refractory setting are listed in table 2. treatment selection after adjuvant treatment recently published data from the large, randomized, phase 3 clinical trial keynote-564 of pembrolizumab versus placebo in high-risk ccrcc post-nephrectomy established the role of ici in the adjuvant setting. pembrolizumab monotherapy significantly prolonged disease-free survival (dfs) compared with placebo (dfs at 24 months, 77.3% vs. 68.1%; hr for recurrence or death, 0.68; 95% ci, 0.53–0.87; p = 0.002 [two sided])[23]. thus, high-risk ccrcc patients who progress af ter adjuvant ici pose a cha l lenging situation. one must factor in timing of relapse as well as incorporation of surgery or sbrt to sites of progression if amenable. when systemic therapy is required to treat relapsed disease, rechallenge with ici is possible, but no current data exists to provide efficacy of these treatments post-adjuvant ici therapy. other tumor types may provide some clues: for example, in malignant melanoma, retrospective studies have shown that patients who progressed during anti–pd-1 monotherapy had no response to subsequent anti–pd-1 systemic therapy to treat metastatic disease. however, they were able to retain sensitivity to future anti–pd-1 after completion of adjuvant therapy[24]. consequently, since adjuvant ici therapy was only approved in highrisk ccrcc in 2021, no data is available to infer that any rechallenge after completion of adjuvant treatment with ici would be beneficial. randomized clinical trials have proven that vegfr tki monotherapy or vegfr plus mtor inhibitors in mccrcc post-ici prolongs pfs and os, and these regimens may be the preferred treatment approach prior to an ici rechallenge. rechallenge ici in ccrcc patients after completion of adjuvant ici should only be conducted in randomized clinical trials. lastly, targeting other mechanisms will also depend on timing of disease relapse after completing adjuvant therapy. alternative modalities in refractory mccrcc incor poration of radiot herapy (rt) or surger y should be considered at time of first relapse or during oligometastatic progression. first, sbrt for extracranial sites and stereotactic radiosurgery (srs) for intracranial sites can provide both local control for patients with oligometastatic progression and palliative relief[25,26]. clinical studies have also examined the efficacy of sbrt with systemic vegfr tki or ici. rapport was a phase 1/2 trial that explored the safety and efficacy of total metastatic stereotactic ablative body radiotherapy (sabr) to oligometastatic mccrcc followed by anti– pd-1 treatment. orr was 63% in 30 evaluable patients and estimated 1and 2-year os rates were 90% and 74% , respec t ively[27]. ongoi ng cl i n ic a l t r ia ls (cytoshr ink [nct04090710] and samur ai [nct05327686]) are now accruing to study how to effectively combine sbrt or srs to the primary tumor, with systemic treatments to improve survival outcomes in f irst-line mccrcc[28]. second, consolidative surgery remains an option in the refractory mccrcc setting. either at the time of oligoprogression or for palliative purposes, surgical approaches can also be considered after the start of highly effective systemic therapy with ici combinations. two completed phase 3 clinical trials, surtime and carmena, both demonstrated that cytoreductive nephrectomy (cn) may be delayed until a stable or partial response is 480siuj.org siuj • volume 3, number 6 • november 2022 therapies in refractory metastatic renal cell carcinoma http://siuj.org achieved on vegfr tki[29,30]. however, both trials completed enrollment prior to approval of current combination therapies (ici plus ici or ici plus vegfr tki). there are three ongoing studies (nordic-sun [nct03977571], probe [nct04510597], and cytokik [nct04322955]) which will provide prospective evidence regarding optimal timing of cn in the setting of ici-based combinations in mccrcc. lastly, surgical resection of metastases at time of progression is undefined. one must consider size and location of the metastatic site as well as tumor biology, along with patient performance status, before taking a surgical approach. optimal management decisions require a multidisciplinary team approach. in conclusion, the treatment landscape is continually evolving in first-line mccrcc, and changes with preferred front-line options will dictate second-line therapy and beyond to limit cross-tolerance and overcome resistance mechanisms. combining other modalities (sbrt and surgery) may have roles in specific refractory settings, and we must also consider patient preferences and tolerability factors in refractory mccrcc. table 2. selected ongoing clinical trials in refractory mccrcc treatment regimen nct phase est. enrollment est. completion date olaparib (post ici/ vegfr) w/dna repair mutationsa nct03786796 2 20 march 2024 lenvatinib + everolimus vs. cabozantinibb nct05012371 2 90 april 2023 atezolizumab + cabozantinib vs. cabozantinibb (contact-03c) nct04338269 3 523 dec 2024 pazopanib ± abexinostat (renaviv)b nct03592472 3 413 june 2022 belzutifan + lenvatinib vs. cabozantiniba nct04586231 3 708 dec 2024 tivozanib + nivolumab vs. tivozanibb,d (ti-nivo2) nct04987203 3 326 aug 2025 nivolumab + rhuph20 vs. nivo (cm-67t)d,e nct04810078 3 454 jan 2026 a post ici/vegfr; b post ici; cenrollment completed; d > 1 or 2 treatments; e post vegfr tki. mccrcc: metastatic clear cell renal cell carcinoma 481 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org references 1. choueiri tk, kaelin wg, jr. targeting the hif2-vegf axis in renal cell carcinoma. nat med.2020;26(10):1519-1530. doi: 10.1038/ s41591-020-1093-z. 2. bacigalupa za, rathmell wk. beyond glycolysis: hypoxia signaling as a master regulator of alternative metabolic pathways and the implications in clear cell renal cell carcinoma. cancer lett.2020;489:19-28. doi: 10.1016/j.canlet.2020.05.034. 3. motzer rj, jonasch e, agarwal n, alva a, baine m, beckermann k, et al. kidney cancer, version 3.2022, nccn clinical practice guidelines in oncology. j natl compr canc netw.2022;20(1):71-90. doi: 10.6004/ jnccn.2022.0001 4. makhov p, joshi s, ghatalia p, kutikov a, uzzo rg, kolenko vm. resistance to systemic therapies in clear cell renal cell carcinoma: mechanisms and management strategies. mol cancer ther.2018;17(7):1355-1364. doi: 10.1158/1535-7163.mct-17-1299. 5. siska pj, beckermann ke, rathmell wk, haake sm. strategies to overcome therapeutic resistance in renal cell carcinoma. urol oncol.2017;35(3):102-110. doi 10.1016/j.urolonc.2016.12.002. 6. rini bi, escudier b, tomczak p, kaprin a, szczylik c, hutson te, et al. comparative effectiveness of axitinib versus sorafenib in ad vanced renal cell c ar cinoma ( a x is): a r andomised phase 3 trial. lancet.2011;378(9807):1931-1939. doi: 10.1016/ s0140-6736(11)61613-61619. 7. choueiri tk, escudier b, powles t, mainwaring pn, rini bi, donsko f, et al. cabozantinib versus everolimus in advanced renal-cell carcinoma. n engl j med.2015;373(19):1814-1823. doi: 10.1056/nejmoa1510016. 8. salgia nj, zengin zb, pal sk. tivozanib in renal cell carcinoma: a new approach to previously treated disease.  ther adv med oncol. 2020;12:175 88 35920923818. published 2020 may 22. doi:10.1177/1758835920923818 9. rini bi, pal sk, escudier bj, atkins mb, hutson te, porta c, et al. tivozanib versus sorafenib in patients with advanced renal cell carcinoma (tivo-3): a phase 3, multicentre, randomised, controlled, open-label study.  lancet oncol.2020;21(1):95-104. doi:10.1016/ s1470-2045(19)30735-1 10. motzer rj, hutson te, glen h, michaelson md, molina a, eisen t, et al. lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. lancet oncol.2015;16(15):1473-1482. doi: 10.1016/ s1470-2045(15)00290-9. 11. motzer rj, escudier b, george s, hammers hj, srinivas s, tykodi ss, et al. nivolumab versus everolimus in patients with advanced renal cell carcinoma: updated results with long-term follow-up of the randomized, open-label, phase 3 checkmate 025 trial. cancer.2 020;126(18):4156-4167. doi: 10.1002/cncr.3303 12. motzer rj, tannir nm, mcdermott df, frontera oa, melichar b, choueri tk, et al. nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. n engl j med.2018;378(14):1277-1290. doi:10.1056/nejmoa1712126 13. albiges l, tannir nm, burotto m, mcdermott d, plimack er, barthélémy p, et al. nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase iii checkmate 214 trial. esmo open.2020;5(6):e001079. doi:10.1136/esmoopen-2020-001079 14. choueiri tk, kluger hm, george s, tykodi ss, kuzel tm, perets r, et al. fraction-rcc: innovative, high-throughput assessment of nivolumab + ipilimumab for treatment-refractory advanced renal cell carcinoma (arcc). j clin oncol.2020;38(15_suppl):5007-5007. doi: 10.1200/jco.2020.38.15_suppl.5007 acknowledgments stephanie berg: advising/consulting: exelixis, bms, eisai, pfizer, seagen, sanofi martin angel: no relevant disclosures. kathryn e. beckermann: research funding: bristolmyers squibb-iaslc-lcfa. advising/consulting: aravive, aveo, bms, exelexis, sanofi, seagen, astellas. frede donskov: no relevant disclosures. chung-han lee: research funding: bms, calithera, eisai, eli lilly, exelixis, merck, pfizer; advising/ consulting: amgen, aveo, bms, exelixis, eisai, merck, pfizer, emd serono, cardinal health; honoraria: aicme, ideology health, intellisphere, research to practice. pavlos msaouel: research funding: takeda, bms, mirati therapeutics, gateway for cancer re-search, and ut md anderson cancer center; advising/consulting: mirati therapeutics, bms, exelixis, axiom healthcare, exelixis, pfizer takeda, bristol myers squibb, mirati therapeutics, gateway for cancer re-search, and ut md anderson cancer center. rana r. mckay: research funding: bayer, tempus; consulting: aveo, astra zeneca, bayer, bms, calithera, caris, dendreon, exelixis, jnj, myovant, merck, novartis, pfizer, sanofi, sorrento therapeutics, tempus. tian zhang: pi/research funding: acerta, novartis, merrimack, abbvie/stemcentrx, merck, regeneron, mirati therapeutics, janssen, astra zeneca, pfizer, omniseq, personal genome diagnostics, astellas, eli lilly, cprit; advisory board/consultant: merck, exelixis, sanofi-aventis, janssen, astra zeneca, pfizer, amgen, bms, pharmacyclics, seagen, calithera, qed therapeutics, eisai, aveo, eli lilly, aravive, astellas, mjh associates, vaniam, aptitude health, peerview. 482siuj.org siuj • volume 3, number 6 • november 2022 therapies in refractory metastatic renal cell carcinoma http://siuj.org 15. grimm m-o, esteban e, barthélémy p, schmidinger m, busch j, valderrama bp, et al. efficacy of nivolumab/ipilimumab in patients with initial or late progression with nivolumab: updated analysis of a tailored approach in advanced renal cell carcinoma (titanrcc). j clin oncol.2021;39(15_suppl):4576-4576. doi: 10.1200/ jco.2021.39.15_suppl.4576. 16. mckay rr, mcgregor ba, xie w, braun da, wei x, kyriakopoulos ce, et al. optimized management of nivolumab and ipilimumab in advanced renal cell carcinoma: a response-based phase ii study (omnivore). j clin oncol.2020;38(36):4240-4248. doi: 10.1200/jco.20.02295. 17. atkins mb, jegede o, haas nb, mcdermott df, bilen, ma, stein m, et al. phase ii study of nivolumab and salvage nivolumab + ipilimumab in treatment-naïve patients (pts) with advanced renal cell carcinoma (rcc) (hcrn gu16-260). j clin oncol.2020;38(15_suppl):5006-5006. doi: 10.1200/jco.2020.38.15(suppl.5006). 18. ged y, gupta r, duzgol c, knezevic a, shapnik n, kotecha r, et al. systemic therapy for advanced clear cell renal cell carcinoma after discontinuation of immune-oncology and vegf targeted therapy combinations. bmc urol.2020;20(1):84. doi: 10.1186/ s12894-020-00647-w. 19. tannir nm, agarwal n, porta c, lawrence nj, motzer rj, lee rj, et al. cantata: primary analysis of a global, randomized, placebo (pbo)controlled, double-blind trial of telaglenastat (cb-839) + cabozantinib versus pbo + cabozantinib in advanced/metastatic renal cell carcinoma (mrcc) patients (pts) who progressed on immune checkpoint inhibitor (ici) or anti-angiogenic therapies. j clin oncol.2021;39(15_suppl):45014501. doi: 10.1200/jco.2021.39.15_suppl.4501. 20. lee ch, shah ay, rasco d, rao a, taylor mh, di simone c, et al. lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (study 111/ keynote-146): a phase 1b/2 study. lancet oncol.2021;22(7):946-958. doi: 10.1016/s1470-2045(21)00241-2. 21. pal sk, albiges l, rodriguez c, liu b, doss j, khurana s, et al. contact-03: randomized, open-label phase iii study of atezolizumab plus cabozantinib versus cabozantinib monotherapy following progression on/after immune checkpoint inhibitor (ici) treatment in patients with advanced/metastatic renal cell carcinoma. j clin oncol.2021;39:6(suppl, tps370-tps370). 22. choueiri tk, albiges l, hammers hj, et al. tinivo-2: a phase 3, randomized, controlled, multicenter, open-label study to compare tivozanib in combination with nivolumab to tivozanib monotherapy in subjects with renal cell carcinoma who have progressed following one or two lines of therapy where one line has an immune checkpoint inhibitor. j clin oncol.2022;40:6(suppl, tps405-tps405). 23. choueiri tk, tomczak p, park sh, venugopal b, ferguson t, chang y-h, et al. adjuvant pembrolizumab after nephrectomy in renalcell carcinoma. n engl j med.2021;385(8):683-694. doi:10.1056/ nejmoa2106391 24. owen cn, shoushtari an, chauhan d, et al. management of early melanoma recurrence despite adjuvant anti-pd-1 antibody therapy. ann oncol.2020;31(8):1075-1082. doi: 10.1016/j.annonc.2020.04.471. 25. flippot r, dalban c, laguerre b, borchiellini d, gravis g, négrier s, et al. safety and efficacy of nivolumab in brain metastases from renal cell carcinoma: results of the getug-afu 26 nivoren multicenter phase ii study. j clin oncol.2019;37(23):2008-2016. doi: 10.1200/ jco.18.02218. 26. brown lc, desai k, wei w, kinsey em, kao c, george dj, et al. clinical outcomes in patients with metastatic renal cell carcinoma and brain metastasis treated with ipilimumab and nivolumab. j immunother cancer.2021;9(9):e003281. doi: 10.1136/jitc-2021-003281. 27. siva s, bressel m, wood st, shaw mg, loi s, sandhu sk, et al. stereotactic radiotherapy and short-course pembrolizumab for oligometastatic renal cell carcinoma-the rapport trial.  eur urol.2022;81(4):364-372. doi:10.1016/j.eururo.2021.12.006 28. lalani a-ka, swaminath a, pond gr, kapoor a, chu w, bramson jl,  et al. hot te phase ii trial of cy toreductive stereotactic hypofractionated radiotherapy with combination ipilimumab/ nivolumab for metastatic kidney cancer (cy toshrink). j clin oncol.2020;38:6(suppl, tps761-tps761). 29. méjean a, ravaud a, thezenas s, colas s, beauval j-b, bensalah k, et al. sunitinib alone or after nephrectomy in metastatic renalcell carcinoma. n engl j med.2018;379(5):417-427. doi:10.1056/ nejmoa1803675 30. bex a, mulders p, jewett m, wagstaff j, van thienen jv, blank cu, et al. comparison of immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: the surtime randomized clinical trial jama oncol.2019 feb 1;5(2):271. doi: 10.1001/jamaoncol.2019.0117.;5(2):164-170. doi:10.1001/jamaoncol.2018.5543 483 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases https://ascopubs.org/doi/abs/10.1200/jco.2022.40.6_suppl.tps405 https://ascopubs.org/doi/abs/10.1200/jco.2022.40.6_suppl.tps405 https://ascopubs.org/doi/abs/10.1200/jco.2022.40.6_suppl.tps405 https://ascopubs.org/doi/abs/10.1200/jco.2022.40.6_suppl.tps405 https://ascopubs.org/doi/abs/10.1200/jco.2022.40.6_suppl.tps405 https://ascopubs.org/doi/abs/10.1200/jco.2022.40.6_suppl.tps405 http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information reno-colic fistula, pneumaturia, chronic pyelonephretic kidney none declared. patient consent: obtained. received on july 21, 2022 accepted on july 31, 2022 soc int urol j. 2023;4(2):148–149 doi: 10.48083/scfa5828 a rare case of reno-colic fistula revealed by pneumaturia achraf chatar,1 nizare errabi,2 ibrahim el housni,2 abdelghani ammani2 1chu hassan ii, fes, morocco 2 military hospital moulay ismail, meknes, morocco reno-colic fistula is very rare, representing 5.1% of uro-digestive fistulas[1]. causes can include infection, stone disease, malignancy, or trauma to the kidney or the colon. pyelo-colic fistulas are in most cases of renal origin (lithiasis)[2]. traumatic causes are other major groups reported mainly related to renal interventional techniques (cryoablation, radiofrequency, percutaneous nephrolithotomy). infectious causes are rarer (tuberculosis, refractory infection of renal cysts)[3,4]. the general, digestive, or urinary clinical manifestations are often variable and non-specific, making the diagnosis difficult[5]. the research of fecaluria and/or pneumaturia helps to direct toward the diagnosis of uro-digestive fistula. abdominal-pelvic ct scan with contrast, upper and lower digestive radiography, or ureteropyelography retrograde and/or percutaneous descending pyelography often confirms the diagnosis by showing the passage of urinary contrast medium to the digestive tract or vice versa, thus providing information on the cause, nature, and location of the uro-digestive fistula. figure 1. cross section of the left kidney pyelocalycial dilation figure 2. one-piece resection: native left kidney (a) with fistula tract facing the left colon (b) b 148 siuj • volume 4, number 2 • march 2023 siuj.org clinical picture mailto:chatarachraf%40gmail.com?subject=siuj http://siuj.org the choice of conservative or radical treatment essentially depends on the etiology and renal clearance. the radical treatment is nephrectomy with the closure of the privileged digestive fistula if the kidney is destroyed or a tumor etiology makes radical treatment unavoidable. conservative treatment, if the fistula is post-traumatic with functional kidney, includes urinary drainage, antibiotic therapy, and rest of the digestive tract. our 65-year-old patient reported repeated renal colic, with air emission during urination, and presented with a pyelo-colic fistula (figures 1 and 2). radical treatment was carried out. the anatomo-pathological analysis showed a chronic pyelonephretic kidney abscessed. with a destroyed kidney. references 1. vidal sans j, reig ruiz c. fístulas urodigestivas: diagnóstico y tratamiento de 76 casos [urodigestive fistulae: the diagnosis and treatment of 76 cases]. arch esp urol.1995 apr;48(3):241-6. spanish. pmid: 7755430. 2. suhler a, schimmel f, viville c. fistules entéro-urinaires d'origine rénale et pyélique [intestinal urinary fistulas of renal and pelvis origin]. ann urol (paris).1995;29(1):8-10. french. pmid: 7771759. 3. el otmany a, hamada h, hachi h, benjelloun s, oukhira h, souadka a. fistule réno-sigmoïdienne sur un rein ectopique pelvien tuberculeux. prog urol.1999 feb;9(1):122–124.  4. iwashita y, negi s, iwashita y, higashiura m, shigi y, yamanaka s, ohya m, mima t, shigematsu t. severe refractory infection due to renocolic fistula in a patient with a giant kidney and adpkd undergoing long-term hemodialysis. cen case rep.2018 may;7(1):174-177. doi: 10.1007/s13730-018-0321-6. epub 2018 mar 14. pmid: 29536255; pmcid: pmc5886951. 5. suhler a, garbit jl, blitz m. fistules urétéro-intestinales [ureterointestinal fistulas]. ann urol (paris).1995;29(1):15-17. french. pmid: 7771751. 149siuj.org siuj • volume 4, number 2 • march 2023 a rare case of reno-colic fistula revealed by pneumaturia http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information pelvic organ prolapse (pop), bladder calculi, cystolitholapaxy, sacrocolpopexy none declared. patient consent: obtained. received on july 12, 2022 accepted on, july 27, 2022 soc int urol j. 2023;4(1):69–70 doi: 10.48083/qjep9763 references 1. hiremath ac, shivakumar ks. cystolitholapaxy and laparoscopic sacrocolpopexy in a case of multiple urinary bladder calculi & vault prolapse. eur j obstet gynecol reprod biol.2019 dec;243:12-15. doi: 10.1016/j.ejogrb.2019.10.002. epub 2019 oct 11. 2. thompson cd, henderson be, stanley r. bladder calculi causing irreducible urogenit al prolapse. bmj case rep. 2 018 sep 12;2018:bcr2018225695. doi: 10.1136/bcr-2018-225695. 3. wai cy, margulis v, baugh br, schaf fer ji. multiple vesical calculi and complete vaginal vault prolapse. am j obstet gynecol.2003;189(3):884-885. doi: 10.1067/s0002-9378(03)00131-5. 4. mahran m. vesical calculi complicating uterovaginal prolapse. j obstet gynaecol br commonw. 1972;79(12):1145-1146. doi: 10.1111/j.14710528.1972.tb11902.x 5. naidu a, nusee z, tayib s. uterine inversion with massive uterovaginal prolapse and multiple bladder stones. j obstet gynaecol res.2011;37(6):633-635. doi: 10.1111/j.1447-0756.2010.01401.x. epub 2011 feb 23. chronic pelvic organ prolapse and bladder calculi in an adolescent reyhane ebrahimi,1 alireza soltani khaboushan,1,2 abdol-mohammad kajbafzadeh1,3 1 pediatric urology and regenerative medicine research center, gene, cell and tissue research institute, children’s medical center, tehran university of medical science, tehran, iran 2 students’ scientific research center, tehran university of medical sciences, tehran, iran 3 pediatric urology and regenerative medicine research center, children’s hospital medical center, tehran university of medical sciences, tehran, iran vesical calculi complicating pelvic organ prolapse (pop) is very rare and usually be seen in older women. there are limited reports of pop associated with vesical calculi; the first was in 1950[1,2]. the pathophysiology of concomitant occurrence of pop and vesical calculi is still unknown. it has been mentioned that urinary stasis, along with the superimposed infection due to elevated residual urine volume, are among contributory factors and possible etiologies of bladder calculi in long-lasting pop cases[2,3]. a 17-year-old virgin female presented to our center with massive pop since birth, which had gradually increased in size. she had a history of recurrent non-febrile urinary tract infection episodes with urinary stone passing and difficulty in voiding. no symptoms of urinary or bowel incontinence were present. prior to admission, she had to push back the bulge protruding out of the vagina and perform the credé maneuver along with crossing her legs in  order  to empty  the  bladder satisfactorily. the patient did not meet the criteria for ehlers-danlos syndrome. prolapsed ureters and bladder and the stones within the bladder are shown in figures 1a and 1b, respectively. figure 1c shows the prolapsed bowel. biopsies from the interlabial mass revealed no dysplasia or malignancy. following transurethral cystolitholapaxy for removal of bladder stones, the patient underwent abdominal sacrocolpopexy to repair pop. the operation and postoperative period were uneventful, and the patient was discharged with a stable general condition. in short-term and long-term follow-up, she did not have a recurrence of symptoms, and she had 2 full-term pregnancies with successful vaginal delivery, 7 and 8 years after her surgery. all previous cases with pop and vesical calculi were reported in multiparous women aged over 40 years [1–5]. to the best of our knowledge, this is the first case of simultaneous pop and vesical calculi occurring in a virgin adolescent. transurethral cystolitholapaxy followed by abdominal sacrocolpopexy is a safe therapeutic approach with little associated morbidity. despite greater prevalence of pop in older women, it should also be considered in younger females to prevent the progression into more severe pop with serious complications. 69siuj.org siuj • volume 4, number 1 • january 2023 clinical picture https://orcid.org/0000-0002-4134-3320 https://orcid.org/0000-0002-5305-4219 https://orcid.org/0000-0002-1973-3509 mailto:kajbafzd%40sina.tums.ac.ir?subject=siuj http://siuj.org figure 1 a. intravenous pyelogram demonstrated prolapse of ureters (asterisks) and bladder (arrow) that are pushed down near the knee; b. the prolapsed bladder with six stones (arrow); c. barium enema showed a significant portion of the prolapsed bowel (arrow) a b c 70 siuj • volume 4, number 1 • january 2023 siuj.org clinical picture http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information covid-19, urinary tract infection, telemedicine, health care disparities see acknowledgements. received on june 12, 2022 accepted on august 20, 2022 this article has been peer reviewed. soc int urol j. 2023;4(1):20–26 doi: 10.48083/urdy6133 disparities in access to virtual care for urinary tract infections during the covid-19 era molly e. dewitt-foy,1 jacob a. albersheim,2 shawn t. grove,2 lina hamid,3 sally berryman,4 sean p. elliott2 1 glickman urological and kidney institute, department of urology, cleveland clinic, cleveland, united states 2 university of minnesota department of urology, minneapolis, united states 3 department of pharmacy, m health fairview, minneapolis, united states 4 university of minnesota department of medicine, minneapolis, united states abstract objective to characterize the difference in uptake of virtual care for urinary tract infections (utis) by demographic variables in the covid-19 era. methods we conducted a retrospective review of outpatient encounters for utis across a large health care system. the cohort was defined as patients with an encounter diagnosis of uti via in-person or virtual care (telephone or technology-supported care), between march 1, 2020, and february 28, 2021. analysis was limited to the first uti encounter of the year for each patient. we compared the use of in-person and virtual visits by demographic variables using chi-square tests and multivariate logistic regression. results a total of 6744 patients, with a mean age of 61 years, were seen for uti during the study period. the majority of patients were white (85.5%) and female (83.7%), and were seen in person (55.9%). of those seen virtually, 52.0% participated in telephone-only visits, and 47.9% were seen via technology-supported care, using video or chatbased platforms. on multivariate logistic regression, age under 30, lowest-quartile income, male sex, and a primary language other than english increased the odds that patients had been seen in person. among those seen virtually, age over 50 significantly increased the odds of a telephone visit, as did being black or native american, having a lower-quartile income, and speaking a non-english primary language. conclusions although the expansion in virtual care has given some patients easier access to necessary care, the “digital divide” has worsened existing disparities for certain vulnerable populations. we demonstrate a difference in uptake of virtual health care by age, race, primary language, and income. introduction the covid-19 pandemic forced a rapid expansion in virtual medical care[1,2]. although this transition has facilitated the provision of care for some patients, other vulnerable populations may have not been afforded the same access: prior studies have demonstrated less uptake of virtual visits among patients who are older or black, and patients with medicaid/medicare coverage[3]. telemedicine has distinct advantages: virtual visits obviate the need for travel and its associated costs and decrease the risk of exposure to pathogens such as covid-19. when telemedicine works well it can provide efficient, convenient access to medical professionals and can even prevent unnecessary emergency department visits[4].the downsides 20 siuj • volume 4, number 1 • january 2023 siuj.org original research https://orcid.org/0000-0002-5401-8340 mailto:%20dewittm2%40ccf.org?subject=siuj https://orcid.org/0000-0003-4546-9948 https://orcid.org/0000-0003-4546-9948 http://siuj.org of telemedicine include limitations in physical examination and testing, and the requirement for technology, with its associated costs and learning curve. virtual care can be difficult or impossible for the 25% of american adults who do not have broadband internet at home, the 20% who do not have access to a smartphone, or those who require an interpreter[5]. urinar y tract infections (utis) are common, accounting for 7 million medical visits per year in the united states, and cost roughly $1.6 billion dollars annually[6]. patients of all gender and racial identity groups, and of all ages and socioeconomic levels get utis, and are treated by providers from a range of specialties. many uncomplicated utis can be safely managed on virtual platforms, as physical examination is relatively unnecessary, and urine testing is optional[7–9]. these factors make uti an ideal candidate for examining the dynamics of virtual care in the wake of the covid-19 pandemic. the increase in use of telemedicine that has occurred since the onset of covid-19 pandemic comes with an opportunity to improve access for patients. which patients have benefited from this expansion in care and who has been left behind? we aim to evaluate the impact of patient demographics on the utilization of virtual care for the management of utis. our secondary aim is to characterize the demographics of those using different strata of virtual care, namely telephone versus technology-supported care (tsc) visits, defined as video or chatbased platforms. methods setting and data m health fairview is a large health care system with 10 hospitals, as well as an academic quaternary care center and 60 primary care clinics serving urban, suburban, and rural minnesotans. electronic health records were aggregated by the university of minnesota’s centralized informatics center and de-identified before analysis. patients were included in this study if they consented to inclusion in research studies upon establishing care with m health fairview. this study was approved by the m health fairview hospitals and the university of minnesota institutional review board. we defined our cohort as any patient with an icd-10 code diagnosis of uti (codes n10, n11, n30, n39, n99) in an ambulatory setting between march 1, 2020, and february 28, 2021. the time period was chosen to coincide with the first year of the covid-19 pandemic in minnesota (the first documented covid-19 case in minnesota was on march 6, 2020). this was a period of rapid transition to virtual care for all patients, including those seen in urgent care and outpatient clinics across numerous specialties, in primary care as well as specialty care clinics such as urology. utis diagnosed during emergency room visits or hospital admissions were excluded. data regarding encounter type included in-person office visits and virtual/telehealth encounters: telephone, video visits, and text-based chat visits via oncare, a chat-based platform for virtual care. patients log in from a computer or smartphone and text with a clinician. the case is reviewed, and the provider responds via text or email with a diagnosis and treatment plan within an hour. similar platforms have been developed across other health systems in response to covid-19 and have demonstrated the ability to provide convenient, cost-effective, and timely care for a range of conditions without need for an in-person visit[10]. patient demographic variables documented include age, race, and zip code of residence. patients younger than 18 years and without zip code information were excluded, as were those who lived out of state. median household income was assigned based on zip code using united states census integrated public use microdata series[11]. median household income was divided into quartiles and analyzed as a categorical variable. encounter type (in-person versus virtual and telephone versus tsc) was our primary outcome measure. univariate analysis was conducted using chi-square tests. multivariate logistic regression was used to identify the impact of clinically significant demographic variables on encounter type. results of the 6744 visits for uti, 3773 visits (55.9%) were conducted in person, and the remainder on one of the virtual platforms. the majority of patients were white (85.9%) and female (83.7%). the average age at the time of encounter was 59 years, and over a third of patients were 70 or older (table 1). office visit versus virtual visit patients < 30 years old were more likely than other age groups to be seen in person (63% of < 30-year-olds seen in-person versus 54% for 30 to 49 years, 55% for 50 to 69 years, and 56% for those over 70 years, p  <  0.001). black or african american patients were more likely to be seen in person (66.3% of black patients seen in person versus 55.6% of white patients and 59.7% of asian american or pacific islander patients, p < 0.001). patients in the lowest income quartile were seen in person more often than patients in higher income categories. patients who listed a language other than english as their primary language were also significantly more likely to attend an in-person visit (69.5% of non-english primary versus 55.8% of english primary language, p < 0.001). a larger proportion of men than women attended inperson visits (62% versus 55%, p < 0.001) (table 1). 21siuj.org siuj • volume 4, number 1 • january 2023 disparities in access to virtual care for urinary tract infections during the covid-19 era http://siuj.org on multivariate logistic regression, age over 30 decreased the odds of being seen in person (or 0.67 to 0.70, p  <  0.01). lowest income quartile (or 1.46, p  <  0.001), primary language other than english (or 1.61, p  =  0.003), and male sex (or 1.32, p  <  0.001) increased the odds of being seen in person (figure 1). virtual visits: telephone versus tsc of the virtual encounters, 52.0% were telephone-only visits, and 47.7% were conducted via tsc, defined as video or chat-based platforms; 9 (<  1%) did not fit into any of the virtual encounter type categories. the majority (68%) of virtual visit patients under the table 1. demographic variables by encounter type patient demographics total (n = 6744) office (n = 3773) virtual (n = 2971) p-value virtual: telephone (n = 1545) virtual: tsc (n = 1417) p-value age 18–29 30–49 50–69 70+ missing 803 1443 2031 2338 129 506 (63%) 773 (54%) 1117 (55%) 1299 (56%) 78 (60%) 297 (37%) 670 (46%) 914 (45%) 1039 (44%) 51 (40%) < 0.001 96 (32%) 255 (38%) 496 (54%) 668 (64%) 30 (60%) 200 (68%) 413 (62%) 416 (46%) 368 (36%) 20 (40%) < 0.001 race white black or african american asian, pacific islander or native hawaiian native american or alaskan native multiracial/other missing 5795 294 226 60 35 334 3224 (56%) 195 (66%) 135 (60%) 34 (57%) 23 (66%) 162 (49%) 2571 (44%) 99 (34%) 91 (40%) 26 (43%) 12 (34%) 172 (51%) < 0.001 1350 (53%) 63 (64%) 45 (50%) 17 (71%) < 11 (x%) 67 (39%) 1217 (47%) 35 (36%) 45 (50%) <11 (x%) <11 (x%) 105 (61%) < 0.001 ethnicity not hispanic or latino hispanic or latino missing 5680 147 917 3226 (57%) 87 (59%) 460 (50%) 2454 (43%) 60 (41%) 457 (50%) < 0.001 1319 (54%) 31 (53%) 195 (43%) 1127 (46%) 28 (47%) 262 (57%) < 0.001 median household income > $91 334 $74 903–$91 334 $62 091-$74 ,903 < $62 091 1690 1885 1538 1631 891 (53%) 1032 (55%) 822 (53%) 1028 (63%) 799 (47%) 853 (45%) 716 (47%) 603 (37%) < 0.001 390 (49%) 424 (50%) 379 (53%) 352 (58%) 407 (51%) 425 (50%) 335 (47%) 250 (42%) 0.002 language english missing not english 6475 43 226 3612 (56%) < 11 (x%) 157 (69%) 2863 (44% 39 (91%) 69 (31%) < 0.001 1490 (52%) < 11 (x%) 52 (75%) 1364 (48%) 36 (92%) 17 (25%) < 0.001 sex female male 5664 1080 3106 (55%) 667 (62%) 2558 (45%) 413 (38%) < 0.001 1312 (51%) 233 (57%) 1239 (49%) 178 (43%) < 0.001 22 siuj • volume 4, number 1 • january 2023 siuj.org original research http://siuj.org age of 30 used tsc as opposed to telephone-only care. patients over the age 70 were twice as likely to participate in a telephone-only visit as in a tsc visit (64.3% versus 35.4%, p < 0.001). black and native american patients participating in virtual visits were far more likely to have telephone-only visits than any other race group. patients whose primary language was not english were significantly more likely to have a telephone visit than were native english speakers (75.4% versus 52.0%, p < 0.001). men were slightly more likely than women to have telephone-only visits (57% versus 51%, p = 0.048) (table 1). on multivariate logistic regression, age > 50 (age 50 to 69 or 2.59, p < 0.001 and age > 70 or 3.9, p < 0.001), being black (or 1.8, p  =  0.014) or native american/ figure 1. multivariate logistic regression analysis describing odds of in person visit as compared with virtual visit 0 2 4 6 covariate or with 95% con�dence intervals or p-value age 18–30 years old (ref) ref 30–49 years old 0.67 < 0.001 50–69 years old 0.7 < 0.001 70+ years old 0.7 < 0.001 race white (ref) ref black or african american 1.29 0.06 aapi 1.04 0.81 native american 0.97 0.91 multiracial/other 1.46 0.29 ethnicity not hispanic or latino (ref) ref hispanic or latino 1.04 0.85 median household income > $91 334 (ref) ref $74 903–$91 334 1.07 0.32 $62 091–$74 903 1 0.99 < $62 091 1.46 < 0.001 primary language english (ref) ref not english 1.61 0.003 sex female (ref) ref male 1.32 < 0.001 figure 2. multivariate logistic regression analysis describing odds of telephone visit as compared with tsc 0 2 4 60 2 4 6 covariate or with 95% con dence intervals or p-value age 18–30 years old (ref) ref 30–49 years old 1.28 0.1 50–69 years old 2.59 < 0.001 70+ years old 3.87 < 0.001 race white (ref) ref black or african american 1.76 0.01 aapi 1.06 0.82 native american 2.6 0.04 multiracial/other 0.42 0.21 ethnicity not hispanic or latino (ref) ref hispanic or latino 1.06 0.83 median household income > $91 334 (ref) ref $74 903–$91 334 0.93 0.45 $62 091–$74 903 1.05 0.62 < $62 091 1.42 0.002 primary language english (ref) ref not english 2.11 0.02 sex female (ref) ref male 0.94 0.6 23siuj.org siuj • volume 4, number 1 • january 2023 disparities in access to virtual care for urinary tract infections during the covid-19 era http://siuj.org alaskan native (or 2.6, p  =  0.04), income <  $62 091 (or 1.42, p = 0.002), and primary language other than english (or 2.1, p = 0.016) increased the odds of having a telephone rather than a tsc visit (figure 2). sex did not demonstrate a significant effect. discussion the rapid expansion in virtual care since the start of the covid-19 pandemic has been profound[2] and likely permanent. unfortunately, not all patients have benefited from this increased access to medical professionals. we demonstrate disparities in access to virtual care among a number of traditionally marginalized and vulnerable populations, including patients who are black, those with low income, those for whom english is not the primary language, and patients over 70 years. the discrepancies in uptake of virtual, and specifically, tsc visits, identified here largely parallel known disparities in all fields of medical care. the etiology of these differences is multifactorial, with likely contributing factors including systemic racism, concerns about covid-19 infection, availability of interpreters, as well as access to and comprehension of required technology. as has been obvious since the beginning of the pandemic, this virus has amplified health care disparities among the most vulnerable[12,13]. we found that those who were black were less likely to use virtual care and, within the category of virtual care, had lower use of tsc than telephone visits. in a study of over 100 000 virtual visits between march and august of 2020, luo et al. found that white and higher income patients were more likely to use video platforms, while black and lower income patients were more likely to have telephone-only encounters[14]. our findings parallel these observations. similar studies conducted prior to the covid-19 pandemic warned of this digital divide. one study by mitchell et al. demonstrated significantly less use of technology for health-related purposes among black patients after accounting for other demographic characteristics, education, and health conditions[15]. availability of reliable broadband internet and digital literacy are generally lower in minority and low-income populations, making access to virtual care more difficult[16]. medical mistrust and concern about privacy may also contribute to lower rates of virtual care use among some populations[15]. patients over 70 in our study were less likely to access virtual care and less likely to use video, as has been observed previously[15,17]. older age is associated with slower rates of technology adoption, lower technologic literacy, and lower use of digital health technology, although this use is increasing[17]. in addition, age-related decreases in visual acuity and fine motor skills can make virtual visits less accessible to older adults[16,18]. our finding that women were more likely to use virtual visits than men is consistent with prior studies[15,19]. some authors have postulated that higher uptake of virtual care among women is related to the increase in domestic burdens on women as result of the covid-19 pandemic[19] or due to lower concern about covid-19 infection among men[17]. interestingly, higher uptake of virtual care was noted among women prior to the covid-19 pandemic. this shift may be attributed to convenience, as women are thought to be more likely to be “juggling work, childcare, and other responsibilities”[20]. specific to this study, men by definition have “complicated” utis, which may be more amenable to in-person care because of the higher risk of anatomic abnormalities and need for urine culture. patients who reported a primary language other than english were less likely to use virtual care, and less likely to use video visits. difficulties with telemedicine for those with limited english proficiency have been well documented, from challenges of navigating patient portals to coordinating interpreter assistance[21,22]. despite improved quality of interpreter-assisted virtual care when video is available[23], only 20% of telemedicine patients whose first language was not english had a video visit in our study. but are telephone visits inferior to video visits? one systematic review attempting to answer this question suggests that physicians made fewer medical errors and had greater diagnostic accuracy on video compared with audio-only visits[24]. in this study we compare access to telephone-only to tsc visits, which includes video and chat-based visits. although it seems likely that virtual care will continue in some capacity in the post-pandemic world, the future of telephone-only visits remains less certain. the passage of the coronavirus aid, relief, and economic security (cares) act in the united states allowed the centers for medicare services to reimburse providers for telemedicine visits during the public health emergency, including coverage of audio-only visits in some circumstances. if all payers do not make this change permanent, it is likely that vulnerable populations will lose access to virtual care[25]. virtual care has the potential to improve outcomes for underserved communities but in the united states, this requires systemic change with federal support[26]. broadband internet access— and the access to credible medical information and full use of telehealth that it affords—has been identified as an important social determinant of health[27]. expansions in access to broadband internet, use of cloud-based video conferencing platforms with lower bandwidth requirements, and public education on the availability of virtual care are possible interventions to reduce the digital divide[28]. 24 siuj • volume 4, number 1 • january 2023 siuj.org original research http://siuj.org this study demonstrates disparities in access to telemedicine by race, income, age, sex, and primary language, indicating a need for additional infrastructure to support this technology boom. though the rise in virtual care has been advantageous for some, these hastily constructed systems are allowing our most vulnerable patients to fall through the cracks. as with any retrospective review, this study is limited by the possibility of unmeasured confounding variables. because our focus was on the effect of demographic variables on encounter type, we did not include clinical variables in our analysis; the complexity of the uti or the patient’s comorbidities may push a patient or provider to prefer an office visit over virtual care. race and ethnicity information were missing for a portion of the patients in this cohort . to reduce the risk of bias we included these patients in the final analysis. other factors that may have had an impact on type of visit, including insurance status, distance from care, and patient preference, were not included. this study does not include longterm follow-up data to assess adequacy of virtual uti management. this is the first study to our knowledge that characterizes the demographic profile of patients seen for uti by encounter type in the covid-19 era. limitations are mitigated by the large sample size with over 6000 unique patients examined. conclusion in this study of over 6000 patients seen for uti between march 2020 and 2021, we demonstrate that many of the commonly seen demographic predictors of reduced access to medical care also predict for lower use of virtual care and, specifically, technology-supported virtual care (versus telephone care). these include being over 70, being black, and having a primary language other than english. acknowledgements ir b approva l: study approved by universit y of minnesota institutional review board, study number study00012449 competing interests mdf: none. jaa: none. stg: none. lh: none. sb: none. spe: consultant and speaker for boston scientific, pi of clinical trial and consultant for urotronic, investment interest for percuvision. author contributions: mdf, ja, stg, and spe contributed to the design and implementation of the research, stg to the analysis of the results. lh and sb contributed to the writing of the manuscript. spe conceived the original and supervised the project. references 1. bhatia rs, chu c, pang a et al. virtual care use before and during the covid-19 pandemic: a repeated cross-sectional study. cmaj open.2021 feb 17;9(1):e107-e114. doi: 10.9778/cmajo.20200311. pmid: 33597307; pmcid: pmc8034297. 2. mann dm, chen j, chunara r, testa pa, nov o. covid-19 transforms health care through telemedicine: evidence from the field. j am med inform assoc.2020 jul 1;27(7):1132-1135. doi: 10.1093/jamia/ocaa072. pmid: 32324855; pmcid: pmc7188161. 3. pierce rp, stevermer jj. disparities in use of telehealth at the onset of the covid-19 public health emergency. j telemed telecare.2023 jan;29(1):3-9. doi: 10.1177/1357633x20963893. epub 2020 oct 21. 4. shah mn, wasserman eb, wang h, gillespie sm, noyes k, wood ne, et al. high-intensity telemedicine decreases emergency department use by senior living community residents. telemed j e health.2016 mar;22(3):251-8.doi: 10.1089/tmj.2015.0103. 5. katzow mw, steinway c, jan s. telemedicine and health disparities during covid-19. pediatrics.2020 aug;146(2):e20201586.doi: 10.1542/ peds.2020-158 6. medina m, castillo-pino e. an introduction to the epidemiology and burden of urinary tract infections. ther adv urol.2019;11:1756287219832172. published 2019 may 2. doi:10.1177/1756287219832172 7. murray ma, penza ks, myers jf, furst jw, pecina jl. comparison of evisit management of urinary symptoms and urnary tract infections with standard care. telemed j e health.2020 may;26(5):639-644. doi: 10.1089/tmj.2019.0044. epub 2019 jul 15. 8. novara g, checcucci e, crestani a, abrate a, esperto f, pavan n, et al. telehealth in urology: a systematic review of the literature. how much can telemedicine be useful during and after the covid-19 pandemic? eur urol.2020 dec;78(6):786-811. doi: 10.1016/j.eururo.2020.06.025. epub 2020 jun 18. 9. grimes cl, balk em, crisp cc, antosh dd, murphy m, halder ge, et al. a guide for urogynecologic patient care utilizing telemedicine during the covid-19 pandemic: review of existing evidence. int urogynecol j.2020;31(6):1063-1089. doi:10.1007/s00192-020-04314-4 25siuj.org siuj • volume 4, number 1 • january 2023 disparities in access to virtual care for urinary tract infections during the covid-19 era http://siuj.org 10. melmed s. chat with a doctor: using asynchronous virtual care access 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ruggiero l, muramatsu n. the digital divide in health-related technology use: the significance of race/ethnicity. gerontologis t.2019;59(1):6-14. doi:10.1093/geront/gny138 16. mamedova s, pawlowski e. a description of u.s. adults who are not digitally literate. u.s. department of education; 2018:33. https://nces. ed.gov/pubs2018/2018161.pdf. 17. eberly la, kallan mj, julien hm, haynes n, khatana sam, nathn as, et al. patient characteristics associated with telemedicine access for primar y and specialt y ambulator y care during the covid-19 pandemic. jama netw open.2020 dec 1;3(12):e2031640. doi: 10.1001/jamanetworkopen.2020.31640. 18. levine dm, lipsitz sr, linder ja. trends in seniors’ use of digital health technology in the united states, 2011-2014. jama.2016;316(5):538– 540. doi:10.1001/jama.2016.9124 19. lattimore cm, kane wj, fleming ma 2nd, martin an, mehaffey jh, smolkin me, et al. disparities in telemedicine utilization among surgical patients during covid-19. plos one. 2021 oct 8;16(10):e0258452. doi: 10.1371/journal.pone.0258452. pmid: 34624059; pmcid: pmc8500431. 20. polinski jm, barker t, gagliano n, sussman a, brennan ta, shrank wh. patients’ satisfaction with and preference for telehealth visits. j gen intern med.2016 mar;31(3):269-75. doi: 10.1007/s11606-0153489-x. epub 2015 aug 13. pmid: 26269131; pmcid: pmc4762824. 21. tan-mcgrory a, schwamm lh, kirwan c, betancourt jr, barreto ea. addressing virtual care disparities for patients with limited english proficiency. am j manag care.2022 jan;28(1):36-40. doi: 10.37765/ ajmc.2022.88814. pmid: 35049259. 22. nouri s, khoong ec, lyles cr, karliner l. addressing equity in telemedicine for chronic disease management during the covid-19 pandemic. nejm catalyst. may 4, 2020. https://catalyst.nejm.org/ doi/full/10.1056/cat.20.0123 23. lion kc, brown jc, ebel be, klein ej, strelitz b, gutman ck, et al. effect of telephone vs video interpretation on parent comprehension, communication, and utilization in the pediatric emergency department: a randomized clinical trial. jama pediatr.2015;169(12):1117–1125. doi:10.1001/jamapediatrics.2015.2630 24. rush kl, howlett l, munro a, burton l. videoconference compared to telephone in healthcare delivery: a systematic review. int j med inform.2018;118:44–53. doi: 10.1016/j.ijmedinf.2018.07.007 25. anderson ke, mcginty ee, presskreischer r, barry cl. reports of forgone medical care among us adults during the initial phase of the covid-19 pandemic. jama netw open.2021;4(1):e2034882. doi:10.1001/jamanetworkopen.2020.34882 26. agate s. unlocking the power of telehealth: increasing access and services in underserved, urban areas. in: harvard kennedy school journal of hispanic policy, vol. 29, annual 2017: 85–96. available a t : h t t p s: // hjhp.hk sp ublic a tions.or g / w p c on t en t /uplo ads / sites/15/2019/03/hjhp-_-volume-29-_-2017.pdf. accessed march 6, 2022. 27. benda nc, veinot tc, sieck cj, ancker js. broadband internet access is a social determinant of health! am j public health. 2020;110(8):11231125. doi:10.2105/ajph.2020.305784 28. barbosa w, zhou k, waddell e, myers t, dorsey er. improving access to care: telemedicine across medical domains. annu r ev pu blic h e alth . 2 0 21 a p r 1;42 :4 6 3 4 81.doi: 10 .114 6 / annurev-publhealth-090519-093711. 26 siuj • volume 4, number 1 • january 2023 siuj.org original research https://catalyst.nejm.org/doi/full/10.1056/cat.20.0123 https://catalyst.nejm.org/doi/full/10.1056/cat.20.0123 https://hjhp.hkspublications.org/wp-content/uploads/sites/15/2019/03/hjhp-_-volume-29-_-2017.pdf https://hjhp.hkspublications.org/wp-content/uploads/sites/15/2019/03/hjhp-_-volume-29-_-2017.pdf http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information targeted biopsy, prostate cancer, multiparametric mri, fusion biopsy none declared. received on october 15, 2022 accepted on october 22, 2022 this article has been peer reviewed. soc int urol j. 2023;4(2):139–141 doi: 10.48083/rixc8512 mri to ultrasound cognitive targeted prostate biopsy provides all the benefit of ultrasound fusion without the increased resources jonathan suderman,1 miles mannas1,2 1 department of urologic sciences, university of british columbia, vancouver, canada 2 vancouver prostate centre, vancouver, canada a diagnostic dilemma in 2013, the american urological association (aua) set out to maximize the clinical utility of the diagnostic prostate biopsy[1]. goals included maximizing detection of clinically significant prostate cancer (cspca), minimizing overdetection of clinically insignificant prostate cancer (cipca), and decreasing cost to the patient and the system. historically, systematic template biopsies resulted in over-detection and overtreatment of cipca. the goal of prostate biopsy has shifted from merely identifying prostate cancer towards diagnosing only cspca. use of mri to riskstratify patients before biopsy and targeting regions of interest identified on mri increases detection of cspca, while minimizing detection of cipca[2]. mri targeted biopsies have been developed in 3 different modalities: cognitive targeted biopsy (cog-tb), mri to ultrasound fusion targeted biopsy (fus-tb) and in-bore. the most common modalities are fus-tb and cog-tb. despite multiple studies attempting to answer this question, debate remains over which method yields superior results. fus-tb is expensive, time-consuming, and resource-limited, and has not been definitively shown to improve diagnostic accuracy over cog-tb. arguments for fus-tb include a shorter operator learning curve, and a trend toward improved detection of cspca. there is no or low-quality evidence supporting these claims. fus-tb creates a significant burden on the health care system, while cog-tb is a simple and low-cost procedure. this commentary presents an argument for cog-tb to remain standard of care when completing diagnostic prostate biopsy. a brief literature summary in the seminal profus trial by wysock et al., cancer detection rates of fus-tb were compared with cog-tb. men with suspicious lesions on mri (n = 125) underwent transrectal fus-tb, then had 2 cog-tb cores collected with standard template 12-core biopsy. detection of cancer and cspca was not significantly different between fus-tb and cog-tb (32.0% and 20.3%; 26.7% and 15.1%, respectively)[3]. fus-tb did show increased detection of cspca in the anterior transition zone and in small lesions detected on mri. the study was not powered to detect differences in tumor location or size; therefore, interpretation of results must be made with caution. in 2019, the smarttarget biopsy trial assessed concordance between cog-tb and fus-tb. patients with a discrete lesion of pi-rads 3-5 were enrolled, and 129 patients had both biopsies performed. each modality detected 86% of cspca[4]. notably, each missed 14% of cspca that was detected by the alternate modality. in 2020, a systematic review and meta-analysis by watts et al. identified 9 studies (n = 1714) undergoing mri targeted biopsy[5]. studies included transperineal and transrectal biopsies, although findings were unchanged when transperineal biopsies were removed from the analysis. they did not find a statistically significant difference in odds 139siuj.org siuj • volume 4, number 2 • march 2023 pro and con: cognitive biopsy http://siuj.org ratios for overall and cspca detection (or 1.11, 95% ci 0.91 to 1.36, p = 0.30 and or 1.13, 95% ci 0.89 to 1.44, p = 0.32, respectively)[5]. the authors of this meta-analysis were unable to stratify their data based on user experience and did not assess the detection of cipca. in a recent study by izadpanahi et al., fus-tb was compared with cog-tb in a randomized controlled trial (n = 199)[6]. this trial showed a significantly higher detection of overall and cspca for fus-tb (44.4% and 33.3%, respectively) compared with cog-tb (31.0% and 19.0%, respectively)[6]. however, a higher detection rate of bph was reported in the cog-tb versus the fus-tb group (66.0% versus 47.5%). no subsequent analysis was completed on prostate size despite a known inverse correlation between size and cancer detection[7]. this critical methodological flaw again limits interpretation and generalizability of the results. putting the numbers into context no strong evidence exists suggesting fus-tb is superior to cog-tb. cog-tb is simple and costeffective, whereas fus-tb is cumbersome and costly. operation of fus-tb requires significant infrastructure including equipment maintenance, image acquisition/ segmentation, data processing, and device operation. the profus study suggests distinct situations (anterior transition zone and smaller lesions) in which fus-tb may be beneficial. however, this study was not powered to make such conclusions. regarding size, targeting accuracy for fus-tb has been studied, claiming accuracy for lesions ≥ 3 mm. the authors recognize that the study’s ex vivo prostate models do not fully represent critical in vivo conditions, given the model’s sharper image contours, and the lack of tissue movement and deformation seen during in vivo biopsy[8]. further, prostate cancer may exist within 10 mm of a lesion detected on mri, allowing a larger target for small radiographic lesions for fus-tb and cog-tb alike[9]. press et al. showed that targeting hypoechoic regions in close proximity to an mri identified region of interest independently predicts detection of cspca[10]. hypoechoic regions can be identified and directly applied to the cog-tb technique, improving biopsy success rates. with a mean target size of 12 mm (iqr 8 to 15mm)[2], 75% of lesions are greater than or equal to 8 mm. this suggests fus-tb might provide benefit for only a minority of cases, and certainly should not be widely adopted as standard of care for all mri identified prostate lesions. the smarttarget biopsy trial showed both modalities missed an equal number of cspca[4]. the meta-analysis by watts et al. showed no significant difference between the 2 modalities, and no conclusions can be drawn about the benefits of a faster learning curve for fus-tb[5]. one study does compare operator learning curves between fus-tb and cog-tb. the authors show that an experience plateau is reached more quickly with fus-tb than with cog-tb[11]. however, only 3 operators were compared in a retrospective manner, introducing selection bias. further, transrectal approach was used for all cog-tb, whereas transperineal was used in 55% of fus-tb, introducing significant heterogeneity into the sample, risking confounding the results. finally, the randomized controlled trial by izadpanahi et al. shows a difference between fus-tb and cog-tb. this study is significantly limited by its discrepant bph findings and lack of prostate size reporting, despite a known inverse correlation between prostate size and cancer detection rates[6]. returning to the aua’s 2013 mandate, data suggest that fus-tb does not maximize detection of cspca, minimize over-detection of cipca, or decrease cost to the patient and the system. therefore, cog-tb should remain the standard of care for targeted diagnostic prostate biopsy until clear evidence suggests otherwise. 140 siuj • volume 4, number 2 • march 2023 siuj.org pro and con: cognitive biopsy http://siuj.org references 1. carter hb, albertsen pc, barry mj, etzioni r, freedland sj, greene kl, et al. early detection of prostate cancer: aua guideline. j urol.2013 aug;190(2):419-426. doi: 10.1016/j.juro.2013.04.119. 2. kasivisvanathan v, rannikko as, borghi m, panebianco v, mynderse la, vaarala mh, et al. mri-targeted or standard biopsy for prostatecancer diagnosis. n engl j med.2018;378(19):1767-1777. doi: 10.1056/ nejmoa1801993 3. wysock js, rosenkrantz ab, huang wc, stifelman md, lepor h, deng fm, et al. a prospective, blinded comparison of magnetic resonance (mr) imaging-ultrasound fusion and visual estimation in the performance of mr-targeted prostate biopsy: the profus trial. eur urol.2014; 66:343-351. doi: 10.1016/j.eururo.2013.10.048 4. hamid s, donaldson ia, hu y, rodell r, villarini b, bonmatti e, et al. the smarttarget biopsy trial: a prospective, within-person randomised, blinded trial comparing the accuracy of visual-registration and magnetic resonance imaging/ultrasound image-fusion targeted biopsies for prostate cancer risk stratification. eur urol.2019;75:733740. doi: 10.1016/j.eururo.2018.08.007 5. watts kl, frechette l, muller b, ilinksy d, kovac e, sankin a, et al. systematic review and meta-analysis comparing cognitive vs. imageguided fusion prostate biopsy for the detection of prostate cancer. urol oncol.2020;38:734.e19-734.e25. doi: 10.1016/j.urolonc.2020.03.020 6. izadpanahi mh, elahian m, gholipour f, khorrami mh, zargham m, sichani mm, et al. diagnostic yield of fusion magnetic resonanceguided prostate biopsy versus cognitive-guided biopsy in biopsy-naïve patients: a head-to-head randomized controlled trial. prostate cancer prostatic dis.2021;24:1103-1109. doi: 10.1038/s41391-021-00366-9 7. ficarra v, novella g, novara g, galfano a, pea m, martignoni g, et al. the potential impact of prostate volume in the panning of optimal number of cores in the systematic transperineal prostate biopsy. eur urol.2005;48:932-937. doi: 10.1016/j.eururo.2005.08.008 8. wegelin o, henken kr, somford d, breuking fam, bosch rj, van swol cfp, et al. an ex vivo phantom validation study of an mri-transrectal ultrasound fusion device for targeted prostate biopsy. j endourol.2016;30:685-691. doi.org/10.1089/end.2015.0864 9. brisbane wg, priester am, ballon j, kwan l, delfin md, felker er, et al. targeted prostate biopsy: umbra, penumbra, and value of perilesional sampling. eur urol.2022;82:303-310. doi: 10.1016/j. eururo.2022.01.008 10. press b, rosenkrantz ab, huang r, taneja ss. the ultrasound characteristics of regions identified as suspicious by magnetic resonance imaging (mri) predict the likelihood of clinically significant cancer on mri-ultrasound fusion-targeted biopsy. bju int.2018;123:439-446. doi: 10.1111/bju.14615 11. stabile a, dell’oglio p, gandaglia g, fossati n, brembilla g, cristel g, et al. not all multiparametric magnetic resonance imaging-targeted biopsies are equal: the impact of the type of approach and operator expertise on the detection of clinically significant prostate cancer. eur urol oncol.2018;1:120-128. doi: 10.1016/j.euo.2018.02.002 141siuj.org siuj • volume 4, number 2 • march 2023 mri to ultrasound cognitive targeted prostate biopsy provides all the benefit of ultrasound fusion without the increased resources http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information medical misinformation, social media, urology, medical disinformation, twitter, nicki minaj, urology care foundation, wellprept none declared. received on, october 20, 2022 accepted on, november 18, 2022 this article has been peer reviewed. soc int urol j. 2023;4(2):125–126 doi: 10.48083/ngto5760 the influence of social medial influencers on urology information: where are all the urologists? brian robert stork university of michigan, department of urology, ann arbor, united states patient and physician–shared decision-making is an important part of the practice of urology. to actively take part in shared decision-making, patients need access to medically accurate, easy-to-understand, and up-to-date information. the growth of social media platforms has made it possible for patients to easily receive and share medical information with others around the world. social media platforms, however, are also actively being used to promulgate misleading medical information, false medical information, and medical disinformation. medical misinformation can lead to confusion, physician distrust, avoidance of evidence-based treatments, use of unproven treatments, and patient harm[1]. researchers have previously uncovered the presence of medical misinformation on a variety of different social media platforms. public discourse about vaccine safety, the covid-19 pandemic, and mask mandates, however, have increasingly put a spotlight on the issue. dr anthony fauci, former head of the united states national institute of allergy and infectious diseases and former member of the white house coronavirus task force, has previously observed and lamented, “we’re living in many ways in a sea of exaggeration and a sea of lies”[2]. “it is terrible how we’ve gotten into a situation, and i think it is the phenomenon of social media”[3]. social media differs from other types of media in a couple of important ways. first, not all social media users have the same influence or the same reach. for example, celebrity figures, politicians, and other influencers often have millions of followers. in addition, not all content on social media is treated equally. content that is shocking, scandalous, or salacious tends to be viewed and shared more frequently[4]. when medical misinformation is posted on a social media account with millions of followers, the impact can be astonishing. a notable example is a tweet made by rapper and songwriter nicki minaj on september 13, 2021. at the time, with more than 22.6 million followers, minaj tweeted, “my cousin in trinidad won’t get the vaccine cuz his friend got it & became impotent. his testicles became swollen. his friend was weeks away from getting married, now the girl called off the wedding. so just pray on it & make sure you’re comfortable with ur decision, not bullied”[5]. nicki minaj’s tweet, fueled by tens of thousands of retweets and likes, spread rapidly on twitter. the inaccurate information contained within the tweet was quickly called to twitter’s attention. the company elected not to place a warning label on the tweet, or remove the post, as the content reportedly did not violate the company’s covid-19 misleading information policy[6]. screenshots of the tweet were shared on other platforms, and the scientifically baseless information content of the tweet was reported by mainstream media. urologists on social media tried to repudiate the misinformation contained within the post[7]. the performer’s massive following, and loyal fan base, however, made this an almost impossible task. as the response to minaj’s tweet demonstrates, social media companies are struggling to safeguard their users from inaccurate and misleading medical information. urologists have an opportunity to help address this issue by regularly sharing medically correct information on their social media accounts. fortunately, high-quality digital resources, covering a wide range of urological conditions and treatments, are readily available and easy to share. 125siuj.org siuj • volume 4, number 2 • march 2023 commentary mailto:bstork%40med.umich.edu?subject=siuj http://siuj.org the urology care foundation (www.urologyhealth. org), the european association of urology (www. uroweb.org), and the canadian urological association (www.cua.org), for example, each offer a wide variety of medically accurate patient education materials on their websites[8]. these materials are guideline based, physician vetted, and available in a growing number of languages. many institutions, hospitals, urological societies, and collaboratives have created quality resources of their own, and a growing number of urologists are producing materials of their own, posting them, and becoming social media influencers themselves[9]. exploring new ways of disseminating medically accurate information is another way we can help educate the general public and our patients. toward this end, the urology care foundation has created bundles of condition-specific, qr-coded educational materials that can be readily accessed by patients with the swipe of a smartphone[10]. these codes can be electronically shared with patients during their visit or added to their after-visit summary. many patients experience anxiety between the time they make their appointment and the time they are first seen. to help address this, dr david canes, associate professor at the lahey institute of urology, recently launched wellprept, an online tool physicians can use to gather, collate, and customize patient educational materials[11]. wellprept gives patients the opportunity to educate themselves about specific urological conditions, and treatment options, before their visit. providing patients with medically accurate educational materials before their office visit can help relieve anxiety at a time when they might be vulnerable to medical misinformation. this “flipped classroom” approach makes it possible for urologists and their patients to have more time for discussion during their office or video visit. patients need access to medically accurate information to effectively participate in shared decision-making. medical misinformation on social media presents a challenge for both patients and urologists alike. urologists can help address this problem by calling attention to and refuting inaccurate information when we see it, sharing medically correct information, and incorporating new technology into our practices. references 1. sylvia chou w y, gaysynsk y a, cappella jn. where we go from here: health misinformation on social media. am j public health.20 20;110 (suppl 3):s273 – s275. doi: 10.2105/ ajph.2020.305905. pmid: 33001722. 2. “we are living in a sea of lies.” dr. anthony fauci on the devastating consequences of covid-19 misinformation [podcast]. el segundo, california: spectrum news. october 29, 2021. available at: https:// sp e c t r umn e w s1.c o m /c a / la w e s t /s o c al -in -17/ 2 0 21/ 10 / 2 8 /w e r e li v i n g i n a s e a o fli e s d ra n t h o n y f a u c i o n t h e devastatingconsequences-of-covid-19-misinformation. accessed january 29, 2023. 3. mcdevitt n. spreading of misinformation makes for the ‘worst possible environment’ for covid-19 pandemic, says fauci. montreal, canada: mcgillreporter. oct 5, 2021. available at: https://reporter.mcgill.ca/ spreading-of-misinformation-makes-for-worst-possible-environmentfor-covid-19-pandemic-says-fauci/. accessed january 29, 2023. 4. khullar d. social media and medical information. confronting new variant of an old problem. jama.2022;328(14):1393–1394. doi: 10.1001/jama.2022.17191. pmid: 36149664. 5. @nickiminaj. my cousin in trinidad won’t get the vaccine cuz his friend got it & became impotent. his testicles became swollen. his friend was weeks away from getting married, now the girl called off the wedding. so just pray on it & make sure you’re comfortable with ur decision, not bullied. september 13, 2021. https://twitter. com/nickiminaj/status/1437532566945341441?lang=en. accessed january 29, 2023. 6. fichera a. posts erroneously cite ‘clinical studies’ to back nicki minaj’s vaccine claim. ap news. september 22, 2021. available at: https:// apnews.com/article/fact-checking-776433819360. accessed january 29, 2023. 7. bateman t. nicki minaj tweeted that covid vaccines cause ‘swollen testicles’ and twitter did nothing about it. lyon, france: euronews. september 15, 2021. available at: https://www.euronews.com/ next/2021/09/15/nicki-minaj-told-22-6m-people-covid-vaccines-causeswollen-testicles-twitter-did-nothing. accessed january 29, 2023. 8. stork b, loeb s. the urology care foundation – trusted online resources in an era of misinformation. nat rev urol.2019;16(11):637– 638. doi: 10.1038/s41585-019-0215-1. pmid: 31300752. 9. houman j, weinberger j, caron a, hannemann a, zaliznyak m, patel d, et al. association of social medica presence with online physician ratings and surgical volume among california urologists: observation study. j med internet res.2019;21(8):e10195. doi: 10.2196/10195. pmid: 31411141. 10. qr codes. urology care foundation. october 19, 2022. available at: https://www.urologyhealth.org/media-center/covid-19-info-center/ telehealth/qr-codes. accessed january 29, 2023. 11. wellprept 2022. wellprept.com. available at: https://wellprept.com/. accessed january 29, 2023. 126 siuj • volume 4, number 2 • march 2023 siuj.org commentary http://www.urologyhealth.org http://www.urologyhealth.org http://www.uroweb.org http://www.uroweb.org http://www.cua.org http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information guidelines, twitter, instagram, tiktok, podcast, youtube, urology none declared. received on, december 3, 2022 accepted on, january 25, 2023 this article has been peer reviewed. soc int urol j. 2023;4(2):136–138 doi: 10.48083/rbaz4307 novel methods of social media dissemination in urology nikita r. bhatt,nikita r. bhatt,11 jeremy yuen-chun teoh, jeremy yuen-chun teoh,22 vito cucchiara, vito cucchiara,33 esther garcia rojo, esther garcia rojo,44 claudia mercader, claudia mercader,55 benjamin pradere,benjamin pradere,66 maria j. ribal, maria j. ribal,55 gianluca giannarini gianluca giannarini77; eau guidelines office dissemination committee; eau guidelines office dissemination committee 1norfolk and norwich university hospital, norwich, united kingdom 2department of surgery, s.h. ho urology centre, the chinese university of hong kong, hong kong 3department of urology, division of experimental oncology, urological research institute, vita-salute san raffaele university, irccs san raffaele scientific institute, milan, italy 4department of urology, hospital hm sanchinarro, madrid, spain 5uro-oncology unit, hospital clinic, university of barcelona, barcelona, spain 6department of urology-urosud, la croix du sud hôpital, quint fonsegrives, france 7urology unit, santa maria della misericordia university hospital, udine, italy abstract social media (some) platforms are widely used by urologists with over 99% using some and 63% of young urologists rating the influence of some on knowledge acquisition as moderate to high. the urology community is abreast with the some revolution in many ways but several new methods of some dissemination remain to be explored. these provide an exciting future for some enthusiasts in urology and beyond. in this article, the european association of urology dissemination committee explores these novel methods of some dissemination while discussing the importance of maintaining quality, ethics, and reliability in some and the role eau plays in it. social media (some) has become an integral part of our personal and professional lives. urology as a specialty has embraced some enthusiastically over the years, with a large presence on well-known some platforms such as twitter, facebook, and youtube[1]. these platforms are widely used by urologists, with over 99% using some and 63% of young urologists rating the influence of some on knowledge acquisition as moderate to high[2]. this has paved the way for several novel platforms in recent times including instagram, snapchat, and tiktok. these platforms have a prominent audiovisual component and have altered the way we share content on some. tiktok involves sharing 15-second videos and is one of the fastest-growing some platforms with over 1.1 billion active users worldwide. the hashtags #urology and #urologist have 411.7 and 68.4 million views, respectively, on tiktok[3]. similarly, #urology on instagram revealed 324k posts. videos on these platforms are most commonly published by physicians, but news media, independent users, and patients can also contribute to the videos. linkedin is a well-established online platform with an aim to improve networking among professionals, with several professional bodies and guideline associations having an online presence on linkedin—for example, the european association of urology (eau) and the american urological association (aua). existing platforms such as twitter and instagram are also constantly reinventing themselves to keep up with the changing face of some. reels are short videos, ranging from 90 seconds on instagram to 2 minutes on twitter, that provide descriptive and visually engaging content. twitter space allows you to have audio conversations live with up to 10 speakers and even record them. this would be a useful platform to have small journal clubs or in-depth educational discussions including guidelines and new evidence. instagram has recently introduced a subscription feature on a trial basis as part of the “precision some content,” the idea behind which is to utilize specific platforms to disseminate personalized and exclusive content to subscribed users[4]. caffeine and twitch are some platforms that allow live video broadcast that can also be used by journals, guideline associations, and congresses around the world. after the covid-19 pandemic, most congresses are using a hybrid approach to engage remote audiences. 136 siuj • volume 4, number 2 • march 2023 siuj.org brief communication mailto:nikitarb89%40gmail.com?subject= http://siuj.org some platforms play a key role in remote engagement through live tweeting, session broadcast, and interviews. one such example is eau tv during the eau congress each year, which discusses highlights from the congress with experts in the field. podcasts have revolutionized dissemination of educational content, by providing an on-the-go option for content that is convenient and free. a search for urology podcasts on google play returned over 75 relevant podcast channels. these include a range of urological association podcasts such as the eau guidelines podcasts discussing guidelines with the panel members[4], aua and british association of urological surgeons podcasts; journal podcasts, for example, journal of urology, british journal of urology international and its knowledge platform (bjui knowledge); and educational podcasts, for example, gu cast, the urology doc podcast, and empire urology. podcasts also improve patient engagement by providing reliable patient education on urology health issues, such as the urology care podcast by the aua. youtube is host to several urology videos, ranging from educational and surgical videos to patient information videos. a recent survey suggested that more than any other resource, youtube is the most used professional platform for urologists and young urologists for learning surgical skills[5]. in addition to newer platforms, newer methods of disseminating content on existing platforms has been explored and successfully implemented. the eau guidelines office as a pioneer of some for dissemination of its world-renowned guidelines, used in 75 countries around the world, has used “awareness days campaign” to engage patients and their advocates[1,6,7]. by disseminating relevant eau guidelines on awareness days, for example, prostate cancer screening during movember engagement and a separate patient information account (eau patient information), the eau dissemination committee has made a conscious effort to improve patient engagement. the dissemination committee has also implemented urology cheat sheets to format the guidelines into the schematic and practical format, thereby improving uptake. these sheets serve as an easy-to-digest educational resource for residents and clinicians looking for a prompt update of their clinical practice. additionally, the sheets are currently receiving significant social media engagement, with an average of 30 000 impressions on twitter alone. posts promoting abbreviations aua american urological association eau european association of urology some social media the eau guidelines cheat sheets were among the ones with the highest impact launched from the official eau account (@uroweb) in 2021 and 2022. some is a brilliant tool for education, patient engagement, and networking. it has its drawbacks in terms of sharing of misinformation on both old and new platforms. of 55 tiktok videos with the hashtag #prostatecancer, 98.2% were of moderate to poor quality, 41% of them contained a significant amount of misinformation, and 10.1% of all videos had an apparent commercial bias[8]. these videos had accumulated 134 944 individual views. the eau previously published a guideline on the use of some to assist clinicians[9]. to strengthen our commitment to ethical application and utilization of some within urology and the wider healthcare community, the dissemination committee is drafting a new guideline chapter on some utilization in healthcare[7]. the chapter provides a layout of the some platforms available and their potential benefits, in addition to an in-depth manual for using some as a healthcare professional, with several strategies to abide by if one is active on some in a professional capacity—for example, avoiding defamatory comments, knowing your employer’s policies on some, and avoiding self-promotion or advertisement[1]. the guideline chapter provides guidance on appropriate use of some analytics to ensure good engagement such as the effective use of hashtags. it also describes the current scale of the issue with some misinformation and ways of investigating misinformation such as the discern scoring system to assess quality of information in videos and the certificate of quality health on the net foundation code of conduct (honcode) to standardize the quality of medical information on the internet, among others. suggestions are provided on combating misinformation by promoting information from reliable sources such as professional bodies or guidelines, and appropriately qualifying the content using tools such as patient education pemat audio visual tools and global quality score (gqs), among others. in conclusion, the urology community is abreast with the some revolution in many ways, but several new methods of some dissemination remain to be explored. these provide an exciting future for some enthusiasts in urology and beyond. it is vital to ensure quality, ethics, and reliability are at the heart of our some journey, and as such investigating the content online and auditing it will help us improve the content we disseminate. the eau dissemination committee guidelines on some will provide a much-needed etiquette for some dissemination in the near future. 137siuj.org siuj • volume 4, number 2 • march 2023 novel methods of social media dissemination in urology https://twitter.com/search?q=%40uroweb&src=typed_query http://siuj.org references 1. pradere b, esperto f, van oort im, bhatt nr, czarniecki sw, van gurp m, et al.; european association of urology guidelines office dissemination committee. dissemination of the european association of urology guidelines through social media: strategy, results, and future developments. eur urol focus.2022;8(5):1541–1544. doi: 10.1016/j.euf.2021.10.010. pmid: 34774465. 2. rivas jg, socarrás mr, blanco lt. social media in urology: opportunities, applications, appropriate use and new horizons. cent european j urol.2016;69(3):293–298. doi: 10.5173/ceju.2016.848. pmid: 27729998; pmcid: pmc5057055. 3. teoh j yc, c acciamani ge, gómez rivas j. social media and misinfor mation in urolog y : w hat c an be done? bju int.2021;128(4):397. doi: 10.1111/bju.15517. pmid: 34581477. 4. bhatt nr, pradere b, teoh jy, cucchiara v, czarniecki sw, esperto f, et al.; eau guidelines office dissemination committee. navigating the next wave of social media: future plans to boost dissemination of the european association of urology guidelines. eur urol.2022;81(1):3–4. doi: 10.1016/j.eururo.2021.10.002. pmid: 34740502. 5. rivas jg, socarras mr, patruno g, uvin p, esperto f, dinis pj, et al. perceived role of social media in urologic knowledge acquisition among young urologists: a european survey. eur urol focus.2018;4(5):768– 773. doi: 10.1016/j.euf.2016.11.010. pmid: 28753825. 6. teoh jy, bhatt nr, cucchiara v, garcia rojo e, pradere b, borgmann h, et al.; european association of urology guidelines office dissemination committee. the power of hashtags in social media: lessons learnt from the urology tag ontology project. eur urol focus.2022;8(6):1565–1567. doi: 10.1016/j.euf.2022.05.002. pmid: 35668025. 7. bhatt nr, czarniecki sw, borgmann h, van oort im, esperto f, pradere b, et al.; eau guidelines office dissemination committee. a systematic review of the use of social media for dissemination of clinical practice guidelines. eur urol focus.2021;7(5):1195–1204. doi: 10.1016/j.euf.2020.10.008. pmid: 33172773. 8. xu aj, taylor j, gao t, mihalcea r, perez-rosas v, loeb s. tiktok and prostate cancer: misinformation and quality of information using validated questionnaires. bju int.2021;128(4):435–437. doi: 10.1111/ bju.15403. pmid: 33811424. 9. taylor j, loeb s. guideline of guidelines: social media in urology. bju int.2020;125(3):379–382. doi: 10.1111/bju.14931. pmid: 31631471. 138 siuj • volume 4, number 2 • march 2023 siuj.org brief communication http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information urology, social media, communication, crowdfunding, crowdsourcing none declared. received on, october 19, 2022 accepted on, november 28, 2022 this article has been peer reviewed. soc int urol j. 2023;4(2):128–130 doi: 10.48083/rvjx1845 crowdsource funding via social media platforms kevin byrnes,1 aqua asif,1 alex ng,1 sinan khadhouri,1 nikita bhatt,1 veeru kasivisvanathan1,2 1burst research collaborative 2division of surgery and interventional science, university college london, london, united kingdom abstract crowdfunding involves obtaining financial support for a project through public engagement. it is a form of crowdsourcing, where monetary and non-monetary contributions from the public are obtained for a common aim. crowdfunding is an increasingly popular way of gaining additional monetary support for medical research projects and may act as a supplement to conventional funding. social media can influence which projects are likely to be successful. engagement on social media can increase the funding obtained. in this brief communication, we introduce the concept of crowdfunding, give practical applications, and describe the characteristics of successful campaigns. the world health organization defines crowdfunding as the process of engaging large groups of people who make monetary and non-monetary contributions to a project[1]. crowdfunding is a form of crowdsourcing, where information, work, or monetary contributions from a group of people are pooled to achieve a goal. crowdfunding raises funds for a specific project, which differs from conventional fundraising directed toward a general cause. crowdfunding often engages a wider community, obtaining smaller individual investments from a larger group of investors. until recently, crowdsourcing and crowdfunding were limited by the reach of traditional media. in a notable example of crowdsourcing, the philological society of london began circulating journal articles in 1857 appealing for contributions to a dictionary. it took repeated public appeals and 71 years before the first edition of the oxford english dictionary was published. in comparison, wikipedia, which uses internet-based crowdsourcing, has generated over 6 million articles since its foundation 21 years ago. modern media, and in particular social media, can accelerate both crowdsourcing and crowdfunding efforts. within urology, one of the earliest uses of crowdfunding was for direct and indirect costs for patients with urological disease. di carlo et al. found that crowdfunding campaigns by patients are typically directed toward charitable organizations, and usually for cancer rather than benign disease[2]. rajwa and colleagues found that testicular cancer campaigns were most likely to be successful, which may reflect the younger age, wider social networks, and greater online presence of this patient cohort[3]. the applications of crowdfunding within urology are now expanding, with an emerging focus on crowdfunding to supplement funding for research. the world health organization provides a practical guide to public engagement and crowdfunding in health research and has profiled successful global health projects[1]. examples include those from lowand middle-income countries, such as a community health intervention to improve awareness about leishmaniasis and enhance adult sand fly vector control (reaching a total funding of us $7244). other examples include a cluster-randomized trial of hydroxychloroquine use in patients with covid-19, obtaining a total of €2.3 million through crowdfunding[4]. 128 siuj • volume 4, number 2 • march 2023 siuj.org brief communication mailto:veeru.kasi%40ucl.ac.uk?subject= http://siuj.org within urological research, tohi et al. recently used crowdsourcing for a new diagnostic tool for chronic prostatitis[5]. their campaign consisted of a dedicated website, youtube content, a social media campaign, and regular emails to engage investors. over a 3-month period, they raised over $50 000 from 116 investors. in their campaign, they focussed on maximizing engagement at the start and end of the process, a strategy used successfully by other researchers[6]. aleksina et al. have identified common themes to the success of crowdfunding campaigns for research projects[7]. firstly, disease characteristics define the audience of a campaign, which ideally should be large and readily engageable on social media. secondly, a unique project will catch attention and be shared among users online. thirdly, organizational reputation may convince potential investors that the venture will be successful. lastly, effective communication throughout the campaign and innovative use of social media draws in further investment. an overview of using social media in crowdfunding campaigns is outlined in figure 1. social media has become an important medium for interpersonal communication. social media includes any form of electronic communication through which users can share information, ideas, and content. within urology, social media has roles in education, peer networking, public and patient engagement, and more recently, crowdfunding campaigns. social media can improve the geographical reach of crowdfunding campaigns, enabling wider participation and promoting inclusivity and diversity among stakeholders in a project. interestingly, the success of a crowdfunding project has been linked to the size of personal networks on social media[8]. viral fundraising campaigns demonstrate the effectiveness of social media, and similar strategies could be applied to crowdfunding. within urology, movember is the highest profile fundraising campaign, which originated in 2003 in australia when two young men persuaded 30 friends to grow a moustache. while not a crowdfunding campaign, movember demonstrates that social media can be used to raise large-scale projects ($500 million to date), and also engage the public by encouraging men to talk more openly about their health. the movember campaign has successfully utilized twitter to engage global communities by running several regional accounts (eg, movember uk[8]). currently, multiple online crowdsourcing platforms exist to run campaigns (eg, kickstarter, gofundme, indiegogo, patreon). some platforms use an all-or-nothing model (funds received when a target is reached) or a flexible model where all funds are kept, regardless of targets. the former may appeal to investors who may not want to risk equity toward an underfunded project. platforms have different target audiences and visibility. some may be generalized, such as kickstarter, while others may be specific to an area, such as experiment. com, which attracts subject-specific investors who can bring external expertise to the project. • build email list • build follower base • encourage subscriptions • focus groups • webinar events • expand reach • celebrate milestones • contributions from ”in�uencers“ • provide progress updates • advertise future projects • informs campaign strategy • generates new ideas • establishes new community • maintains donation ”momentum“ • maximizes reach of campaign public and patient engagement social media strategies advantages of campaign before campaign during campaign after campaign • identify target audience • gather personal perspectives • identify project priorities • recruit patient base • funding/project updates • events to update • maintain community • share research �ndings • demonstrate use of funds (encourage sharing of content) figure 1. overview of role of social media in crowdfunding campaigns 129siuj.org siuj • volume 4, number 2 • march 2023 crowdsource funding via social media platforms http://siuj.org crowdfunding has disadvantages compared to traditional funding models. for some organizations, all-or-nothing funding is not a sustainable type of finance. additionally, failure to obtain funding in an all-or-nothing campaign consumes organizations’ resources. crowdfunding may also raise funds for scientifically unsupported or potentially dangerous treatments. lastly, crowdfunding may induce inequities to the funding process. an unregulated process may favor those with larger social networks who may be in an already more privileged position. it may also favor more sensationalist or sympathetic campaigns rather than the most deserving. the british urology researchers in surgical training (burst) research collaborative[9] do not currently use crowdfunding, rather we use social media to maximize crowdsourcing efforts—to improve site engagement, disseminate research findings, and network with collaborators. recognition, feedback, as well as raising the profile of individuals or institutions contributing to projects can often incentivize further collaboration. clearly, social media is key in inf luencing how, why, and which projects receive crowdfunding. given the widespread usage of social media, crowdfunding campaigns using social media have a wide reach to engage the public. crowdfunding should not be viewed as a competitor for typical funding mechanisms (eg, government grants), but rather a complement, especially to test new research questions and perform pilot work. references 1. world health organization. public engagement and crowdfunding in health research: a practical guide 2021. available at: https://apps.who. int/iris/bitstream/handle/10665/349220/9789240039087-eng.pdf. accessed january 30, 2023. 2. di carlo a, leveridge m, mcgregor tb. crowdfunding in urology: canadian perspective. can urol assoc j.2021;15(3):e139–e143. doi: 10.5489/cuaj.6572. pmid: 32807287; pmcid: pmc7943232. 3. rajwa p, hopen p, wojnarowicz j, kaletka j, paszkiewicz i, lachwojnarowicz o, et al. online crowdfunding for urologic cancer care. cancers (basel).2022;14(17):4104. doi: 10.3390/cancers14174104. pmid: 36077641; pmcid: pmc9454944. 4. mitjà o, corbacho-monné m, ubals m, alemany a, suñer c, tebé c, et al.; bcn-pep-cov2 research group. a cluster-randomized trial of hydroxychloroquine for prevention of covid-19. n engl j med.2021;384(5):417–427. doi: 10.1056/nejmoa2021801. pmid: 33289973; pmcid: pmc7722693. 5. tohi y, kakehi y, sugimoto m; project to develop a novel diagnostic tool for chronic prostatitis. successful establishment of crowdfunding to develop new diagnostic tools for chronic prostatitis. int j urol.2022;29(6):600–602. doi: 10.1111/iju.14856. pmid: 35229360. 6. schucht p, roccaro-waldmeyer dm, murek m, zubak i, goldberg j, falk s, et al. exploring novel funding strategies for innovative medical research: the horao crowdfunding campaign. j med internet res.2020;22(11):e19715. doi: 10.2196/19715. pmid: 33174857; pmcid: pmc7688388. 7. aleksina a, akulenka s, lublóy á. success factors of crowdfunding campaigns in medical research: perceptions and reality. drug discov today.2019;24:1413–1420. doi: 10.1016/j.drudis.2019.05.012. pmid: 31132416. 8. movember uk twitter. n.d. available at: https://twitter.com/ movemberuk. accessed november 17, 2022. 9. kasivisvanathan v, ahmed h, cashman s, challacombe b, emberton m, gao c, et al. the british urology researchers in surgical training (burst) research collaborative: an alternative research model for carrying out large scale multi-centre urological studies. bju int.2018;121(1):6–9. doi: 10.1111/bju.14040. pmid: 28972693. 130 siuj • volume 4, number 2 • march 2023 siuj.org brief communication http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information renal cell carcinoma, clear cell carcinoma, non-clear cell renal cell carcinoma, genetics, tumor microenvironment none declared. received on august 30, 2022 accepted on october 3, 2022 this article has been peer reviewed. soc int urol j. 2022;3(6):386–396 doi: 10.48083/blpv3411 2022 wuof/siu international consultation on urological diseases: genetics and tumor microenvironment of renal cell carcinoma sari khaleel,1 christopher ricketts,2 w. marston linehan,2 mark ball,2 brandon manley,3 samra turajilic,4,5 james brugarolas,6,7 ari hakimi1 1 urology service, department of surgery, memorial sloan kettering cancer center, new york, united states 2 urologic oncology branch, center for cancer research, national cancer institute, national institutes of health, bethesda, united states 3 department of genitourinary oncology, h. lee moffitt cancer center and research institute, tampa, united states 4 the francis crick institute, london, united kingdom 5 renal unit, the royal marsden hospital, london, united kingdom 6 kidney cancer program, simmons comprehensive cancer center, ut southwestern medical center, dallas, united states 7department of internal medicine, ut southwestern medical center, dallas, united states abstract renal cell carcinoma is a diverse group of diseases that can be distinguished by distinct histopathologic and genomic features. in this comprehensive review, we highlight recent advancements in our understanding of the genetic and microenvironmental hallmarks of kidney cancer. we begin with clear cell renal cell carcinoma (ccrcc), the most common subtype of this disease. we review the chromosomal and genetic alterations that drive initiation and progression of ccrcc, which has recently been shown to follow multiple highly conserved evolutionary trajectories that in turn impact disease progression and prognosis. we also review the diverse genetic events that define the many recently recognized rare subtypes within non-clear cell rcc. finally, we discuss our evolving understanding of the ccrcc microenvironment, which has been revolutionized by recent bulk and single-cell transcriptomic analyses, suggesting potential biomarkers for guiding systemic therapy in the management of advanced ccrcc. introduction understanding the genomic landscape of clear cell renal cell carcinoma (ccrcc), which accounts for approximately 75% of all renal cell carcinomas, has been critical to the development of targeted systemic therapies to treat this classically chemoand radiotherapy-resistant disease. however, malignant cells exist in a dynamic and heterogeneous ecosystem of immune cells, stromal cells, cytokines, and extracellular proteins that together constitute the tumor microenvironment (tme)[1], which modulates tumor development and response to systemic therapies in rcc[2]. better understanding of the tme of ccrcc has helped understand the heterogeneity of response to systemic therapies within ccrcc patients, particularly in the age of immuno-oncologic agent-based therapies. furthermore, while ccrcc constitutes the majority of rcc tumors, the remaining 25% are represented by an ever-expanding group of tumor subtypes, each with unique histologies and genetic features. this review begins with a summary of recent molecular analyses of clear and non-clear cell rcc subtypes, followed by a discussion of the current understanding of 386 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases https://orcid.org/0000-0002-0886-0860 https://orcid.org/0000-0003-4814-7207 https://orcid.org/0000-0003-1780-2627 https://orcid.org/0000-0002-7927-1510 https://orcid.org/0000-0001-8846-136x https://orcid.org/0000-0002-8575-499x https://orcid.org/0000-0002-0930-8824 mailto:hakimia%40mskcc.org?subject=siuj http://siuj.org the tme of ccrcc and its role in driving the response to systemic therapies in advanced ccrcc. genetics of clear cell rcc the first step toward malignant transformation in ccrcc is the loss of the short arm of chromosome 3 (3p loss), which harbors 4 tumor suppressor genes that constitute the most common sites of mutation in rcc: vhl on 3p.25, and pbrm1, bap1, and setd2 on 3p.21[3,4]. of these genes, vhl is the most commonly altered in both hereditary and sporadic rcc, through point mutations and methylation in 70%–80% and 5%–10% of patients, respectively[3,5]. inactivation of the vhl protein results in loss of regulation and thus constitutive activation of its ubiquitin ligase target, the protein hif. resulting de-regulation of hif targets, including vascular endothelial growth factor (vegf), promotes tumor cell proliferation, neoangiogenesis, and metastases[6,7]. pbrm1 is the second most commonly mutated gene (40% of cases) [3,4], and encodes baf180[6,8], a component of the switching defective/sucrose non-fermenting (swi/ snf) family of chromatin-remodeling complexes, which determine dna accessibility to transcription factors and poly merases[8–10]. similarly, bap1, mutated in 10%–15% of ccrcc patients[11], encodes a nuclear deubiqutinase protein that interacts with host cell factor-1 (hcf-1), which is involved in chromatin remodeling[12,13]. interestingly, bap1 and pbrm1 mutations are generally mutually exclusive[3,5,14]. lastly, while the mechanism by which setd2, mutated in 10%–15% of ccrcc, affects tumorigenesis remains unclear, it is suspected to involve dna double-strand break repair, dna methylation, and rna splicing[4,15] (table 1). the mechanism of 3p loss that results in loss of heterogeneity (loh) for the above genes frequently involves chromothripsis, a process in which some chromosomes undergo multiple breaks simultaneously, followed by random joining of chromosomal fragments, resulting in hundreds of genomic rearrangements[16]. this initial 3p loss constitutes the “first hit” event and occurs somatically years before the presentation of ccrcc. a “second hit” resulting in biallelic inactivation of vhl then promotes malignant transformation through upregulation of the hypoxia response in the presence of normoxia. this is usually followed by mutations involving the neighboring pbrm1, setd2, and bap1 genes, and less frequently, alterations of tp53, mtor, tsc1, tsc2, pik3ca, pten, kdm5c and smarca4[17]. although the repertoire of mutations and somatic copy number alterations (scnas) that drive ccrcc is relatively narrow, molecular diversity is achieved through clonal evolution, i.e., selection of cell subpopulations characterized by different driver mutations, resulting in intratumor heterogeneity (ith)[6]. consequently, molecular profiling of tumor samples collected from a single spatial location may capture clonal events propagated in all the cancer cells of a given tumor, but can easily miss events in subclones, and underor over-estimate the frequency of altered genes, an issue that is amplified by the particularly high levels of ith in ccrcc[18,19]. therefore, multi-region sampling is critical to capturing the clonal evolution of ccrcc, as demonstrated by the tracerx renal program[19]. in the interim analysis tracerx, molecular profiling of > 1200 primary tumor regions from 100 patients demonstrated clear evidence for highly conserved evolutionary mutational patterns in ccrcc within different clones[20]. broadly, 2 modes of evolution were observed: linear, in which only a single clonal population is evident, with consequently low ith; and branched, which involves multiple subclonal populations with high ith. these populations then evolve either through a linear darwinian-like process of sequentially selected mutational events, or punctuated evolution, which is noted by short bursts of many genomic alterations occurring in a relatively brief period early in the tumor’s evolution, most likely due to scnas and structural chromosomal alterations[21]. ccrcc tumors in the tracerx cohort that were characterized by linear evolution harbored only 3p loss and vhl mutation/methylation with low ith, and were thus termed “vhl mono drivers”[20]. these tumors were enriched for small renal masses (srms, < 4 cm in maximal dimension), with limited progression and metastatic risk given the limited fitness advantage provided by isolated vhl mutation[22]. in contrast, ccrcc tumors characterized by branched evolution harbored high levels of ith and parallel evolution[20], i.e., repeat selection of distinct driver mutations in the same gene or pathway, with a highly conserved order of genomic events across clones. intriguingly, these tumors were larger and more likely to produce metastases than their vhl mono driver counterparts, but with an intermediate metastatic efficiency resulting in solitary metastasis or oligometastases[20]. however, other studies suggest that vhl mutations alone are not abbreviations ccrcc clear cell renal cell carcinoma fh fumarate hydratase rcc renal cell carcinoma scnas somatic copy number alterations swi/snf switching defective/sucrose non-fermenting tams tumor-associated macrophages tme tumor microenvironment 387siuj.org siuj • volume 3, number 6 • november 2022 genetics and tumor microenvironment of renal cell carcinoma http://siuj.org sufficient for ccrcc development[23,24]. in contrast, ccrcc tumors characterized by punctuated evolution had low ith and were dominated by a single clone but exhibited additional molecular alterations in the dominant clone that distinguished them from the similarly monoclonal vhl mono drivers. this tumor evolution group included a vhl-wildtype subtype, a vhl followed by bap1 mutation (bap1-driven) subtype, and tumors with multiple clonal driver mutations (pbrm1, bap1, sted2 or pten). these tumors grew rapidly to a large size and were linked to widespread and rapid metastases[20]. within this group, bap1-deficient tumors were associated with higher grade and aggressiveness than pbrm1-deficient tumors[11,24,25], while pbrm1 loss was associated with metastasis tropism to the pancreas[26], and these tumors are characteristically indolent. however, pbrm1-deficient tumors can become more aggressive with further evolution and mutations in the mtor pathway[24] or setd2[27], with which pbrm1 cooperates[25]. genetics of non-clear cell carcinoma papillary renal cell carcinoma papillary renal cell carcinoma has been classically subdivided into 2 subtypes on the basis of histology and genetic features[28]. genetically, type 1 prcc is associated with frequent gains of chromosomes 7 and 17, as well as less frequent gains of chromosomes 2, 3, 12, 16, table 1. summary of most common genetic alterations of reviewed rcc subtypes rcc subtype most common and/or characteristic genetic alterations most common chromosomal alterations notes clear cell rcc vhl (75%-90%) pbrm1 (40%) bap1 (10%-15%) setd2 (10%-15%) kdm5c (6%-7%) loss of the short arm of chromosome 3 (3p), likely through chemothripsis vhl is altered through point mutations and methylation in 70%–80% and 5%–10% of patients bap1 and prbm1 mutations are generally mutually exclusive papillary rcc, type 1 met (10%-15%) in non-hereditary cases frequent gains of chromosomes 7 (almost universal) and 17 as well as less frequent gains of chromosomes 2, 3, 12, 16, and 20 papillary rcc, type 2 no specific pattern of mutations or scnas see section 2 chromophobe rcc tp53 (~30%) and pten (~8%) most frequently associated with combined loss of chromosomes 1, 2, 6, 10, 13, and 17. less frequent additional individual losses can occur for chromosomes 3, 5, 8, 9, 11, 18, and 21q chrcc tumors have a generally lower mutational burden than ccrcc or type i prcc tumors renal medullary carcinoma smarcb1 gain of chromosome 8q fh-deficient rcc fh loss of chromosome 1q fh gene germline mutations are seen with hlrcc, but fh gene can also be somatically mutated sdh-deficient rcc sdh enzyme subunit genes, including sdhb, sdhc, or sdhd deletion of chromosome 1p translocation rcc somatic translocations of tfe3, followed by tfeb and mitf gain of chromosome 17q and chromosome 9p loss 388 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org and 20[29–32]. the most frequent somatic mutational events in type 1 prcc are activating mutations of the met oncogene on chromosome 7, present in 10%–15% of type 1 prcc cases[33]. notably, germline activating mutations of the met oncogene are the pathogenic cause of hereditary papillary renal cell carcinoma (hprc) syndrome, in which patients present with bilateral, multifocal type 1 prccs[31,34] (table 1). in contrast, type 2 prcc tumors are not associated with a specific pattern of copy number alterations, and are now seen to represent a heterogenous group of what are now distinct rcc subtypes, including translocation rcc, fh-deficient rcc, and sdh-deficient rcc. in light of the above heterogeneity and the absence of characteristic genomic features for this group, prcc type 2 tumors may also be interpreted as aggressive, unclassified rcc that exhibit papillary features but require specific genomic subclassification for clinical outcome prediction[35]. similarly, while type i prcc is considered the “classical” morphologic entity, certain neoplasms that exhibit its features may also be considered variants or potential new rcc entities[36], with distinct molecular features, such as papillary renal neoplasm with reversed polarity (prnrp)[37] and biphasic hyalinizing psammomatous rcc (bhp rcc)[38], which have distinct driver mutations (kras and nf2, respectively). chromophobe renal cell carcinoma (chrcc) like ccrcc and prcc type 1 tumors, most chrcc are characterized by a distinct pattern of chromosomal alterations, defined by combined loss of chromosomes 1, 2, 6, 10, 13, and 17, seen in approximately 80% of chrcc. less frequent additional individual losses can occur for chromosomes 3, 5, 8, 9, 11, 18, and 21q in 12%–58% of cases[39,40]. the histology of chrcc can include a rarer eosinophilic variant in which the classic pattern of chromosomal losses is less common. chrcc have a lower mutation burden than ccrcc or prcc-1; only tp53 and pten are frequently mutated in ~30% and ~8% of cases, respectively[33,41]. loss of cdkn2a, by either loss of 9p21 or hypermethylation, is the next most common alteration, affecting 19.8%[33] (table 1). increased tert expression has been observed in approximately 17% of chrcc, resulting from either mutations or genomic rearrangements in the tert gene promoter, the latter including intra-chromosomal rearrangements and translocations with chromosome 13.11[42]. medullary renal carcinoma renal medullary carcinoma (rmc) is a rare and aggressive subtype of kidney cancer that accounts for less than 1% of all rcc and has a propensity for early metastases, resulting in a median overall survival of little more than a year[43–45]. rmc predominantly aff licts individuals with sickle cell trait, creating a preponderance of patients with african or mediterranean descent, and the young, with a median age from 19 to 22 years[43–49]. the characteristic genetic and immunohistochemical feature of rmc is the near universal loss of expression of the swi/snf-related matrix-associated actin-dependent regulator of chromatin subfamily b member 1 (smarcb1) protein, also known as integrase interactor 1 (ini1), brg1-associated factor 47 (baf47), or sucrose non-fermenting 5 (snf5). the smarcb1 protein is encoded by the smarcb1 gene on chromosome 22q11.23, and in most tumors both copies of this gene are lost through a combination of mutation and chromosomal deletion (table 1)[50]. smarcb1 is a core subunit of the swi/snf chromatin remodeling complex; its loss results in transcriptional dysregulation of many pathways[9,51]. fh-deficient and sdh-deficient renal cell carcinoma hereditary leiomyomatosis and renal cell carcinoma (hlrcc) is a familial cancer syndrome characterized by the development of cutaneous and uterine leiomyomas and a highly aggressive form of kidney cancer [52–55]. hlrcc is associated with germline mutation of the krebs cycle enzyme gene fumarate hydratase (fh); because the associated tumors demonstrate loss of fh enzyme activity, they are referred to as fh-deficient rcc[56–58]. fh can also be mutated somatically. similarly, germline mutations of several subunits of the krebs cycle succinate dehydrogenase enzyme, including sdhb, sdhc, or sdhd, have been associated with increased risk for paraganglioma (pgl), pheochromocytoma, gastrointestinal stromal tumor (gist), and rcc[59–61]. the complete loss of either fh or sdh enzyme activity impairs the normal function of the krebs cycle, resulting in accumulation of intracellular fumarate and succinate, respectively[62,63]. this accumulation promotes a pseudo-hypoxic state that upregulates several enzymes, particularly enzymes involved in chromatin hypermethylation[32,64–67]. furthermore, fh and sdh loss results in aberrant succination of keap1 protein, which promotes constitutive upregulation of the nrf2-antioxidant response element (are) pathway and inactivation of the core factors responsible for replication and proofreading of mitochondrial dna (mtdna), resulting in both a significant decrease in mtdna content and increased mtdna mutation[68,69]. while sdh and fh-deficient tumors share similar genetic characteristics, a recent germline analysis comparing these tumors noted that while most of these tumors harbored germline alterations in their respective genes, sdh-deficient rccs had a lower mutation burden and scna burden than fh-deficient rccs[70]. in addition to patients with germline mutation, a small 389siuj.org siuj • volume 3, number 6 • november 2022 genetics and tumor microenvironment of renal cell carcinoma http://siuj.org number of sporadic tumors have also been shown to have complete somatic loss of fh, resulting in a non-hereditary form of fh-deficient rcc[32]. translocation renal cell carcinoma involving tfe3, tfeb, or mitf gene fusions translocation renal cell carcinomas (t-rccs) are driven by somatic chromosomal translocations that fuse members of the mit transcription factor family genes, tfe3, tfeb, or mitf, with various partner genes that result in fusion proteins[31,71,72] that affect many pathways, such as organelle biogenesis, cell proliferation, and cellular fate commitment, all of which may promote tumorigenesis[72–74]. t-rccs represent one of the most common forms of rcc in children and young adults, making up 20%–50% of pediatric rcc patients and 15% of rcc patients under the age of 45[72,75]. t-rcc in adults can present with a variety of histologies, including both papillary or clear cell[32,72]. to date, fusions involving tfe3 are the most common, followed by tfeb[31,33,71,72,76]. tumor microenvironment of rcc while initial profiling studies of the tme of rcc tumors grouped its tumor phenotypes into either immune-infiltrated or excluded phenotypes[77,78], more recent studies have found infiltrating t cell populations to exist in a continuum from activated antitumor to dysfunctional “exhausted” t cells[79,80]. similarly, while the function of tumor-associated macrophages (tams) has classically been divided into either the proinflammatory/antitumor m1 or the anti-inflammatory/ pro-tumor m2 phenotypes (polarizations)[81–85], recent evidence shows that tam populations are highly plastic, existing in more of a phenotypic spectrum between the m1 and m2 phenotypes in vivo[81,83,84,86]. more recent studies have shifted to transcriptomic analyses that utilize microarray and next generation sequencing (rna-seq) technologies along with computational techniques to deconvolute the tme to its cellular components and explore their role in tumor response to systemic therapies through an array of gene expression signatures representative of novel cell phenotypes and processes[77,87–89]. such studies noted a generally negative correlation between enrichment of t-helper subtype 2 (th2) cells and t-reg cells and survival in ccrcc[77], explaining previously reported negative association between t cell infiltration and clinical outcomes in ccrcc[83,84,90,91]. similarly, worse overall survival and lower likelihood of response to tki agents were associated with higher levels of m2-type macrophage infiltration in the tme[92]. this understanding of the tme led to investigations of prognostic and theranostic transcriptomic gene signatures that may predict survival and response to systemic therapy in advanced rcc. these include angiogenesis-associated signatures to predict response to tyrosine kinase inhibitors[89,92,93] or immune signatures to predict response to immune checkpoint blockage (icb)-based combinations[89,93,94]; and transcriptomic classifiers such as the 4 molecular subtypes (ccrcc 1-4) described by beuselinck et al. for metastatic ccrcc (m-ccrcc)[95], which were shown to predict both survival outcomes as well as therapeutic response to tki (sunitinib or pazopanib) monotherapy, which were attributed to inherent differences in the their underlying tme[95–97]. prospective patient selection for icb-based or tki-monotherapy based on these subtypes was recently evaluated in the phase ii bionikk trial, which demonstrated the feasibility of biomarker-driven tailored systemic therapy in m-ccrcc[98], potentially maximizing therapeutic benefit while reducing unnecessary toxicity from systemic therapy regimens in m-ccrcc. understanding of the tme was further revolutionized by single-cell based analyses such as single-cell rna sequencing (scrna-seq) and single-cell mass cytometry (scmc), which allow for massively parallel, high-dimensional analyses of specific cell populations in the tme, enabling prediction of potential interactions between various cell populations based on their expressed surface molecules, promoting a much more granular understanding of the dynamics of the tme of rcc than what was offered by bulk rna-sequencing approaches, which are bound to oversimplify tumor cell populations and their dynamic interactions[81,83,84,86,99]. in this regard, chevrier et al.[86] used scmc to profile adaptive and innate (t cell and tam) populations in the tme of 73 patients with untreated advanced rcc and 5 healthy matched kidney samples. using computational phenotype clustering, they identified 22 t cell and macrophage phenotypes[86], noting a “terminally exhausted” pd1+ cluster and a corresponding “progenitor exhausted” cluster of potentially icb-responsive t cells. they also noted 17 different tam clusters, arguing that the m1/ m2 polarization phenotypes are an oversimplification of this plastic and dynamically changing cell population. finally, they noted immunosuppressed t cell compartments to be associated with high levels of regulatory cd4 cells and a pro-tumor tam population[86]. following this study, braun et al.[83] performed scrna-seq and t cell receptor (tcr) sequencing of ccrcc tissue from 13 patients with tumors of a range of clinical stages to explore changes in the immune tme with advancing disease. they again noted significant diversity within the tam and t cell populations, and found t cells to exhibit an overall trend of progressive dysfunction and exhaustion with advancement in disease stage, which was associated with a concurrent shift from m1 to m2-like signatures in the tam population and increasing t cell and tam interactions, again 390 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org confirming that tams play a key role in the progression of t cells toward exhaustion in ccrcc[83]. to examine the influence of icb on the rcc tme, krishna et al.[81] used scrna-seq to compare the tme of multi-regional tumor samples from 4 icb-treated to 2 icb-naïve advanced ccrcc patients. they noted significant intratumoral and inter-patient heterogeneity, along with differences in the overall tme between icb-treated versus naïve patients. focusing on tumor specimens from an icb-treated patient that exhibited complete response, they noted enrichment of cd8a+ tissue-resident populations and low tam infiltration in all tumor regions. in contrast, specimens from icb-resistant patients exhibited high tam infiltration but low t cell enrichment (i.e., t cell exclusion)[81]. similarly, bi et al. compared tumors from 5 icb-exposed to 3 icb-naïve patients with advanced ccrcc, and noted that while icb-exposed tumors were enriched in cd8+ t cells that expressed costimulatory molecules associated with the “progenitor exhausted” phenotype described by chevrier et al.[86], they also paradoxically expressed inhibitory molecules associated with terminally exhausted t cells, suggesting that these icb-responsive cells were potentially undergoing a shift toward terminal exhaustion as well. similarly, antitumor tam populations in icb-exposed patients were noted to paradoxically express molecules that correlate with a pro-inflammatory, antitumor phenotype, but again with upregulation of immune checkpoint and anti-inflammatory signaling genes. the authors proposed that these seemingly paradoxical changes in both t cell and tam populations within the tumors of icb-exposed patients may explain the initial response and eventual transition to resistance to 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https://ascopubs.org/doi/10.1200/jco.2020.38.15_suppl.5009 https://www.sciencedirect.com/science/article/pii/s0140673619307238?via%3dihub https://www.sciencedirect.com/science/article/pii/s0140673619307238?via%3dihub http://www.ncbi.nlm.nih.gov/pubmed/25583177 https://www.sciencedirect.com/science/article/pii/s0302283818300976 https://www.sciencedirect.com/science/article/pii/s0302283818300976 https://www.tandfonline.com/doi/full/10.1080/0284186x.2017.1388927 https://www.tandfonline.com/doi/full/10.1080/0284186x.2017.1388927 https://www.sciencedirect.com/science/article/pii/s1470204522001280#bib6 https://www.sciencedirect.com/science/article/pii/s1470204522001280#bib6 https://www.sciencedirect.com/science/article/pii/s1535610821001665?via%3dihub https://www.sciencedirect.com/science/article/pii/s1535610821001665?via%3dihub https://orcid.org/0000-0002-9500-2046 http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information twitter, social media, sex, specialty, technology, urology none declared. received on october 15, 2022 accepted on january 18, 2023 this article has been peer reviewed. soc int urol j. 2023;4(2):96–104 doi: 10.48083/tkek6928 social media network analysis of academic urologists’ interaction within twitter microblogging environment spencer h. bell,1 clara sun,2 emma helstrom,1 justin m. dubin,3 ilaha isali,4 kirtishri mishra,4 andrew gianakopoulos,2 seyed behzad jazayeri,6 mohit sindhani,7 lee ponsky,4 alexander kutikov,1 casey seideman,8 andres correa,1 diana magee,1 laura bukavina1,3 1 department of urologic oncology, fox chase cancer center, philadelphia, united states 2 case western reserve university school of medicine, cleveland, united states 3 loyola university, chicago, united states 4 department of urology, university hospitals cleveland medical center, cleveland, united states 5 department of urology, northwestern university feinberg school of medicine, chicago, united states 6 department of urology, university of florida, jacksonville, united states 7 indian institute of technology, delhi, india 8 oregon health and science university, portland, united states abstract objective to characterize academic urology twitter presence and interaction by subspecialty designation. methods using twitter application programming interface of available data, 94 000 specific tweets were extracted for the analysis through the twitter developer program. academic urologists were defined based on american urological association (aua) residency program registration of 143 residency programs, with a total of 2377 faculty. two of 3-factor verification (name, location, specialty) of faculty twitter account was used. additional faculty information including sex, program location, and subspecialty were manually recorded. all elements of microblogging were captured through anaconda navigator. analyzed tweets were further evaluated using natural language processing for sentiment association, mentions, and quote tweeted and retweeted. network analysis based on interactions of academic urologist within specialty for given topic were analyzed using d3 in javascript. analysis was performed in python and r. results we identified 143 residency programs with a total of 2377 faculty (1975 men and 402 women). among all faculty, 945 (39.7%) had registered twitter accounts, with the majority being men (759 [80.40%] versus 185 [19.60%]). although there were more male academic urologists across programs, women within academic urology were more likely to have a registered twitter account overall (46% versus 38.5%) compared with men. when assessing registered accounts by sex, there was a peak for male faculty in 2014 (10.05% of all accounts registered) and peak for female faculty in 2015 (2.65%). there was no notable change in faculty account registration during covid-19 (2019–2020). in 2022, oncology represented the highest total number of registered twitter users (225), with the highest number of total tweets (24 622), followers (138 541), and tweets per user per day (0.32). however, andrology (50%) and reconstruction (51.3%) were 2 of the highest proportionally represented subspecialties within academic urology. within the context of conversation surrounding a specified topic (#aua21), female pelvic medicine and reconstructive surgery (fpmrs) and endourology demonstrated the total highest number of intersubspecialty conversations. conclusions there is a steady increase in twitter representation among academic urologists, largely unaffected by covid-19. while urologic oncology represents the largest group, andrology and reconstructive urology represent the highest proportion of their respective subspecialties. interaction analysis highlights the variant interaction among subspecialties based on topic, with strong direct ties between endourology, fpmrs, and oncology. 96 siuj • volume 4, number 2 • march 2023 siuj.org original research mailto:laura.bukavina%40fccc.edu?subject=siuj http://siuj.org introduction the use of social media (some), specifically twitter, as a professional platform is increasingly common among healthcare workers, including urologists[1]. urology residents, medical students, programs, journals, and faculty have used twitter to advertise virtual events, gain information for the match process, form mentorships, promote publications, and share clinical information. the circumstances imposed by the covid-19 pandemic catalyzed the increasing use of twitter among the urological community[2]. the geographical and physical limitations spurred by the pandemic resulted in both academic programs and students alike having to adopt new approaches for communication with a focus on some. the dramatic reduction of clinical and research activities within the medical and surgical departments during covid-19, coupled with virtual electives and conferences, have all posed important implications within academics. furthermore, the current landscape of twitter use among academic urology faculty at accredited us institutions has yet to be assessed. given the heavy reliance on virtual interaction during the pandemic and the active role that some plays, our study aims to characterize the state of twitter use among current academic urology faculty. as twitter offers an information-rich reservoir created by the urologic academic community, the interactions among users shape complex network structures that have not been previously evaluated. the aim of our study was to characterize the currently academic urology twitter presence by sex and specialty. we hypothesize that while urologic oncology represents the total largest number of twitter participants within urology, there is a growing trend among other subspecialties of urology, with an increasing number of interactions. materials and methods data source data collection occurred from may 2021 to march 2022. a list of accredited us urology residency programs was pulled from the american urological association (aua). all md/do faculty associated with the us urolog y residency program and academic centers were included in the study. information including sex, program location, and subspecialty training were abbreviations api application programming interface aua american urological association fpmrs female pelvic medicine and reconstructive surgery some social media recorded from their respective websites. faculty twitter account was verified via a 2-factor verification process (name plus location) in addition to automated twitter match. transplant was not included in some analyses because of the low number of participating faculty on twitter, while fellowship-trained sexual medicine faculty was included in the andrology group. collection of twitter information collection of relevant tweets from 2006 until march 2022 was performed. the twitter streaming application programming interface (api) dataset creation has previously been described[1]. brief ly, tweets were collected using twitter streaming api using python (v3.10.8). all tweets from predesignated academic faculty were used for analysis. in addition, all accounts followed by the user (following), accounts following the user (followers), timelines, and geographic location (when available from twitter privacy setting) were collected using rtweet (r version 4.2.2). further information and code regarding extraction of user-specific data can be found here (https://github.com/ropensci/rtweet/)[3]. after data preprocessing, relevant tweets were selected and analyzed. tableau desktop was fed into csv and excel files for data visualization. natural language processing (nlp) pipeline all elements of microblogging, including retweets, likes, followers, following, sentiment, hashtags, and mentions were captured through anaconda navigator. full-text tweets were preprocessed by converting the sentences into words (tokenization) and removing unnecessary punctuations, tags, and stop words that do not have a specific semantic meaning (“the,” “are”). preprocessing was done using the natural language toolkit (nltk) on python (v3.10.8). sentiment analysis follow ing processing of tweets and remova l of duplicates and unnecessary punctuations, all tweets were split into 3 data frames based on sentiment (neural, negative, and positive). sentiment analysis refers to identifying and classifying tweets that are expressed in text using the machine learning sentiment analysis model to compute users’ perception. sentiment analysis was done using (https://github.com/yalinyener/ twittersentimentanalysis) package in python (v3.10.8). twitter interaction analysis while the rtweet package allows for downloading tweets and stream api, extraction of tweets relevant to a topic at hand (designated around a hashtag #), followed by building of interaction centered around users (nodes), was performed via twinetverse in r and is freely available here (http://graphtweets.johncoene.com/). each interaction consists of a source and a target; in other words, the source is the screen name 97siuj.org siuj • volume 4, number 2 • march 2023 social media network analysis of academic urologists’ interaction within twitter microblogging environment https://github.com/ropensci/rtweet/ https://github.com/yalinyener/twittersentimentanalysis https://github.com/yalinyener/twittersentimentanalysis http://graphtweets.john-coene.com/ http://graphtweets.john-coene.com/ http://siuj.org (faculty), the user who posted the tweet, while target is the users who were tagged or interacted with the tweet. this type of analysis allowed for interaction factor between subspecialties (grouped faculty) based on topic of discussion. although we chose to group based on urologic subspecialty, this analysis can be user specific or topic specific. interaction analysis was depicted as the number of interactions between the subspecialties only, and no regression analysis was performed to test for statistical significance as interaction is dependent on the topic. statistical analysis demographics were summarized using descriptive statistics. the categorical variables are presented as counts and percentages and were compared using a chi-square test. the continuous variables are expressed as means (standard deviation [sd]) or medians (interquartile range [iqr]). all statistical analyses were conducted by a statistician (m.s.) and cross referenced by a physician (l.b.) using r version 4.0.4. all tests were 2-sided with statistical significance defined by p < 0.05. all visualizations were performed by tableau desktop and corel draw. results demographics we identified 143 residency programs through the aua website with a total of 2377 faculty (1975 men and 402 women). among all faculty, 945 (39.75%) had registered twitter accounts, with the majority being men (760 [80.42%] versus 185 [19.58%]). however, while the overall number of male academic urologists was higher, proportionally, female urologists were more likely to have a registered twitter account (46 % versus 38.5%) (figure 1). the percentage of new twitter accounts created from 2006 to october 2021 stratified by sex was similarly assessed (figure 1). overall, there were more male than female accounts registered for every year, with a peak for male faculty in 2014 (10.05% of all accounts registered) and peak for female faculty in 2015 (2.65% of all accounts registered). conversely, there was no notable change during the covid-19 (2019–2020) peak epidemic. faculty fellowships were categorized into andrology, endourology, female pelvic medicine and reconstructive urology (fpmrs), general, oncology, pediatrics, reconstruction, robotics, and transplant. consistent with aua census, there are fewer female urologists across all fellowships compared with male urologists. sex differences among fellowship training and some use were also evident. for female faculty, andrology (60%), reconstruction (60%), and endourology (58.06%) had the highest proportion of twitter representation (figure 1). among men, androlog y (48.59%), reconstruction (48.56%), and oncology (48.33%) had the highest proportion of registered user accounts. general urology for both female (19.67%) and male faculty (17.86%) had the lowest twitter representation (figure 1). when comparing female and male twitter representation within each specialty, female faculty had the highest representation in female (45.77%), pediatric (28.29%), and reconstructive (24.59%) urology, while male faculty had the highest representation in oncology (93.30%), and robotics (91.85%) (figure 1). program representation when assessing program representation, the university of colorado (69.57%), mayo clinic rochester (67.86%), and case western reserve (65.22%) had the most faculty on some, proportional to the size of their program (supplementary appendix figure s1). the 5 cities with the highest overall twitter representation were philadelphia (52; 5.50%), new york (5.50%), cleveland (43; 4.55%), new hyde (34; 3.59%), and chicago (32; 3.38%) (supplementary appendix figure s1). twitter activity the top 5 words by occurrence since 2006 were “urology”, “dr”, “great”, “aua”, and “cancer” (supplementary appendix figure s1). the most frequently used hashtags used by academic faculty users on twitter were #prostatecancer (5369), #urology (3851), #bladdercancer (3122), and #covid19 (2839) (supplementary appendix figure s1). the top 3 mentions were @daviesbj (14 159), @amerurological (12 730), and @urogeek (5124). overall, 45.72% of all tweets were considered positive, while 43.64% were neutral, and 10.64% were negative. sex-specific differences were observed. although the top 2 hashtags among female academic urologists were #urology (1112) and #covid19 (801), women were more likely to mention other female urologists including @ loebstacy (1052), @ashleywinter (741), and caseyseidman (544) compared with male faculty (supplementary appendix figure s1). the “sentiment” distribution across tweets by male and female faculty was different, with female faculty noted to tweet more “positively” than male faculty (48.50% versus 45.08%), although the difference was not statistically significant (chi-square, p = 0.4) (figure 1). subspecialty analysis as prev iously hy pot hesized, urologic oncolog y represented the largest overall subspecialty on twitter, with the total number of active members of 225. the subspecialty also represented the highest tweets per day per user (0.32) and total tweets per day (73.72) and the highest total followers (333 951) and likes (143 261). androlog y and pediatric urolog y represented the second-highest group among the subspecialties for tweet 98 siuj • volume 4, number 2 • march 2023 siuj.org original research http://siuj.org per user per day (0.29) and similar number of followers (66 757 versus 66 425); however, pediatric urology was more likely to retweet a post than andrology (1 433 124 versus 448 264) (figure 2). when assessing temporal trends across specialties by month and day, urologic oncology represented the highest tweet count overall, with peaks in september 2021 (529), january 2022 (724), and february 2022 (731). january and february corresponded to similar trends among other specialties likely reflecting aua match, while many specialty meetings corresponded to peaks in activity. overall, monday represented the lowest activity day on average, with twitter activity increasing from thursday and peaking on friday night (figure 3). figure 1. general twitter presence and number of user accounts from 2007 to 2021. academic urology twitter presence is shown by number of twitter accounts by year (a) stratified by male vs female. in addition, total twitter academic urology presence is broken down by specialty and gender (b). overall academic twitter presence based on gender can be seen in c, showing overall percentage of twitter accounts (top) and broken down by proportion of all academic urologist (bottom). (d). sentiment analysis designated as neutral, negative or positive from each users’ tweets, with birdgram representative of most commonly utilized words within the tweets corresponding to the size of the word twitter network interaction analysis among subspecialties we assessed urology subspecialty interaction on twitter by counting the total number of interactions between specialties centered around the hashtags: #aua21, #auamatch, and #urosome. although any hashtag can be used for the interaction analysis, we chose these particular “specialty neutral” hashtags to visualize active direct communication. while urologic oncology consistently interacted with other subspecialties most frequently due to the total number of participants within urologic oncology (ie, 39 interactions with fpmrs), when assessing global proportional interaction, fpmrs represented the most diverse interaction network. 99siuj.org siuj • volume 4, number 2 • march 2023 social media network analysis of academic urologists’ interaction within twitter microblogging environment http://siuj.org as seen in figure 4, conversations focused within a subspecialty were also more likely to be seen within urologic oncology (visualized as blind ending blue node). while this interaction improved with #urosome and #auamatch, the interactions as seen in figure 4 are topic dependent, with more interactions seen between andrology and urologic oncology with #urosome than the other 2 topics. overall, pediatric urology and fpmrs did highlight more interactive ties compared with other subspecialties. discussion the steady increase in twitter representation among academic urologists since 2006 reflects the increasing awareness of twitter as a means of academic representation and promotion among individual programs and faculty. a recent study has also found increasing figure 2. twitter profiles of urologic subspecialties on twitter. hashtag results based on 2006 to present analysis, remainder of the reported features reflective of may 2021 to march 2022 data twitter usage among urologists, prompted by different incentives. urologists in the us and canada who were in lower academic ranking and had higher h-indices were more likely to have twitter accounts[4]. the challenges imposed by covid-19 limited in person interactions, forcing the medical community to embrace other forms of communication. although we did not see any notable changes in the number of registered accounts for faculty during covid-19 (2019–2020), there was a significant jump in urology program account creation in 2020, the largest increase since 2009[5]. while the majority of twitter representation is largely skewed toward male faculty, we found a steady increase in female faculty representation across all urology subspecialties over the past 16 years. proportionately, 100 siuj • volume 4, number 2 • march 2023 siuj.org original research http://siuj.org more female urologists use twitter. this might be an effort of female urologists to build their professional reputation and to inspire other aspiring female surgeons. besides the goal of improving healthcare, twitter presence has been shown to increase industry support, with surgeons with an active twitter account receiving 1.7 times the amount in payments compared with surgeons without an active account. furthermore, among twitter users, those with 321 to 172 000 followers received 4.7 times and 9.5 times the amount in payments compared with those with 0 to 80 followers[6]. one of the top hashtags used by female faculty, but not in the top for male faculty, was #ilooklikeasurgeon. the sex differences in twitter activity highlight how academic female urologists use some as a platform for advocacy and cultural change initiatives. women were figure 3. temporal distribution of online twitter activity by day and month, further categorized by sub-specialty within urology also more likely to mention or tweet to a male and female urologist on twitter, while male academic urologists limited their interaction to male colleagues as evidenced by top mentions. this finding is not unique to urology. in a recent study by zhu et al., which evaluated a total of 3148 health services researchers on twitter, women were more likely to follow other women (54.8% of users followed by women were women, whereas 42.6% of users followed by men were women)[7]. academic urologists fellowship trained in andrology, reconstruction, endourology, and oncology had the most twitter representation. this is supported by data previously published, showing that physicians in the us and canada trained in urological oncology, minimally invasive urology, and endourology were more likely to have twitter accounts[4]. one possible explanation for the high percentage of andrology faculty could be attributed to 101siuj.org siuj • volume 4, number 2 • march 2023 social media network analysis of academic urologists’ interaction within twitter microblogging environment http://siuj.org the stigma inherent to the topics within the subspecialty, such as sexual health and male infertility. because these conversations may be difficult for patients to discuss openly, andrology faculty are likely using some as an advocacy platform. the most frequently used hashtags by academic urologists were dedicated hashtags created for annual aua conferences. these hashtags not only organize posts associated with a certain conference but also reflect the increasing use of twitter during medical conferences. in a 2017 survey of aua members, a third of the 1280 respondents with some accounts reported following a medical conference virtually[8]. the 2018 aua annual conference had a significant, 5-fold increase in twitter posts compared to 2013[9]. another hashtag that dramatically increased in occurrence was #covid19. in just over 2 years, #covid19 surpassed others as one of the top 5 most frequently used hashtags in the past 16 years. this likely reflects the increased consumption of some figure 4. interaction analysis based on subspecialty direct interaction with others on three different topics including #aua21, #auamatch, and #urosome. interaction tables represent the number of direct conversations between members of each subspecialty focused on the topic at hand as a source of information on covid-19. valdez et al. showed that twitter volume increased consistently from early to late march 2020, around when covid-19 was declared a global pandemic[10]. our study is unique in that compares direct interaction among subspecialties within academic urology on twitter. while previous research has focused mainly on trends of utilization and growth, our innovative analysis fostered by information networks and a novel api network, highlights the communication and engagement among the subspecialties. based on our findings, we can establish that virtual interaction on twitter is dependent upon the topic; however, strong intersubspecialty ties are seen from fpmrs and pediatric urology. as we previously mentioned, while it may seem that urologic oncology by number alone had the highest level of interaction, proportionally, fpmrs and pediatric urology were more likely to engage other subspecialties. it is unclear why this network structure exists, 102 siuj • volume 4, number 2 • march 2023 siuj.org original research http://siuj.org and the implications of this type of interaction; however, a higher level of interaction is more likely to spread to other networks and enhance the spread of information (ie, reach more users). our study is not without limitations. we analyzed only academic urologists. thus, urologists who work in private practice or other non-academic institutions were not able to be accounted for. there are many urologists on social media who were not included in the analysis but represent an integral role in advocacy and growth of urologic knowledge (eg, ashley winter). furthermore, faculty designation to subspecialty was based on urologists’ academic institution information, and while most were able to be categorized into a subspecialty, the process was dependent on the accuracy of information listed by the institution. conclusion our research indicated that there is a growing representation of women in the field of academic urology on the social media platform twitter. this presence offers opportunities for enhanced communication and connection within the field. furthermore, the study revealed variations in interactions between various subspecia lties within urolog y, with fpmrs and pediatric urology found to have a notable higher level of intersubspecialty engagement compared with other subspecialties. references 1. bukavina l, dubin j, isali i, calaway a, mortach s, loeb s, et al. twitter footprint and the match in the covid-19 era: understanding the relationship between applicant online activity and residency match success. urol pract. 2022;9 (4):331– 339. doi: 10.1097/ upj.0000000000000306. 2. 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surgeons: a cross-sectional study. surg endosc.2022;36(9):6592–6600. doi: 10.1007/s00464-022-09062-8. pmid: 35103858. 7. zhu jm. pelullo ap, hassan s, siderowf l, merchant rm, werner rm. gender differences in twitter use and influence among health policy and health services researchers. jama intern med.2019;179(12):1726– 1729. doi: 10.1001/jamainternmed.2019.4027. pmid: 31609393. 8. loeb s, carrick t, frey c, titus t. increasing social media use in urology: 2017 american urological association survey. eur urol focus.2020;6(3):605–608. doi: 10.1016/j.euf.2019.07.004. pmid: 31351900. 9. ho p. margolin e, sebesta e, small a, badalato gm. #auamatch: the impact of covid-19 on social media use in the urology residency match. urology.2021;154:50–56. doi: 10.1016/j.urology.2021.05.019. pmid: 34033828. 10. valdez d, ten thij m, bathina k, rut ter l a, bollen j. social media insights into us mental health during the covid-19 pandemic: longitudinal analysis of twitter data. j med internet res.2020;22(12):e21418. doi: 10.2196/21418. pmid: 33284783. 103siuj.org siuj • volume 4, number 2 • march 2023 social media network analysis of academic urologists’ interaction within twitter microblogging environment http://siuj.org supplementary appendix figure s1. aua programs faculty twitter presence, listing of top 10 programs with percent of total faculty (a), as well as total number of registered academic twitter accounts by city (b). c-d representing overall, male and female specific hashtags and mentions from 2006 to present by faculty, with overall sentiment analysis shown in d and most commonly utilized words (e) 104 siuj • volume 4, number 2 • march 2023 siuj.org original research http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj • volume 4, number 3 • may 2023 siuj.org key words competing interests article information urology, morocco, health, developing countries none declared. received on march 17, 2023 accepted on april 5, 2023 soc int urol j.2023;4(3):162–163 doi: 10.48083/ wjro7072 162 urology around the world trends towards sub-specialization in urology: what about morocco? jihad el anzaoui,1 abdelghani ammani,1 jalal eddine el ammari,2 my hassan farih2 1 university sidi mohamed ben abdellah, faculty of medicine in fes, urology department; military hospital my ismail meknes, morocco 2 university sidi mohamed ben abdellah, faculty of medicine in fes, urology department; hassan ii hospital, fes, morocco the tremendous expansion of medical knowledge has created challenges for learners and practitioners. subspecialization, defined here as a limitation of practice to a confined and sophisticated niche of the whole specialty, has created experts who have delved into new fields of research and have presented new perspectives and new discoveries[1]. in the most developed countries, sub-specialization is becoming a standard of practice. elsewhere, however, limited resources make sub-specialization unaffordable, particularly in countries that are still struggling to achieve basic medical coverage for their populations. morocco is a developing country that has made great economic and social progress in recent decades. the health system has been revised in its social and economic aspects by the introduction and expansion of compulsory health insurance and the stimulation of private investment. productivity and profitability are defined as the new foundation. sub-specialization, as indicator of quality is, to our knowledge, rare in the moroccan context. in contrast to certain specialties that have been oriented towards sub-specialization, such as paediatrics and cardiology, the general practice remains dominant in the urology field, few urologists pursue a sub-specialized practice in morocco, and their influence is certainly limited. the main obstacle is the limited number of urologists. according to official statistics, there were 351 urologists in morocco in 2019 for 35.5 million inhabitants, that is 0.9 urologists per 100 000 inhabitants[2]. this figure is low compared with developed countries such as the united states, with 3.22 urologists per 100 000 inhabitants[3] or france, with 2.06 per 100 000 inhabitants[4]—and even compared with other specialties in morocco. the low number of urologists in morocco makes the issue of sub-specialization secondary to the establishment of adequate health coverage in the peripheral areas. however, a rapid increase in the number of urologists, thanks to the greater number of university teaching hospitals (currently 8), is improving medical coverage in the under medicalized zones. the objective is to increase the yearly number of medical school graduates from the current 2092 to 6530 in 2025[5]. on the educational level, the fellowship system for post-graduate sub-specialized training is predominant in english-speaking and commonwealth countries. morocco, however, follows the french system in which post-graduate education is based on university diplomas. while the fellowship training relies on a well-structured clinical and research path inside clinical departments, the moroccan system is based mainly on theoretical courses supported by less structured practical and research training. furthermore, moroccan universities do not offer a great choice of diplomas— in either number or area of coverage[6]. at the institutional level, although the university teaching hospital departments are currently well endowed with medical equipment, the orientation towards sub-specialized practices remains an individual decision rather than being dictated by a care policy. urology in particular is a dynamic and rich specialty. http://siuj.org mailto:jihad.elanzaoui%40usmba.ac.ma?subject=siuj the lack of sub-specialization in high-volume centres such as university teaching hospitals delays the learning curve and produces surgeons who lack the skills for some complex and time-demanding procedures. to find an equilibrium between “minor” surgical interventions, which are numerous and will consume operating room time, and “major” interventions, which bring prestige to the department, is challenging. in some countries, the organization of the health system requires a level of quality matching with a high level of sub-specialized practice. in france, for instance, the creation of national network for authorized centres to deal with rare cancers implies a highly specialized practice in these centres[7]. in the same country, the practice of oncological surgery is framed by a threshold of a minimal number of yearly cases[8]. this measure highlights the link between quality of care and level of expertise. in the moroccan context, however, it is widely recognized that maintaining a highly specialized practice in the private sector is not a great advantage in view of the scarcity of private urologists: 167 in references 1. ficarra v, mirone v, dasgupta p. urologists of tomorrow – the case for educational intervention. bju int.2016. doi:10.1111/bju.13732 2. royaume du maroc haut-commissariat au plan (2019). les indicateurs sociaux du maroc. available at: https://www.hcp.ma/file/231203/. accessed april 20, 2023. 3. american urological association (2019) the state of urology workforce and practice in the united states. linthicum, maryland, u.s.a. available at: https://www.auanet.org/common/pdf/research/ census/state-urology-workforce-practice-us.pdf. accessed april 20, 2023. 4. ministère des solidarités et de la santé. direction de la recherche, des études, de l’évaluation et des statistiques. démographie des professionnels de santé. available at: https://drees.shinyapps.io/ demographie-ps/. accessed april 20, 2023. 5. comment le gouvernement compte tripler le nombre des lauréats de médecine. le matin.ma. february 24, 2022. available at: https:// lematin.ma/express/2022/gouvernement-compte-tripler-nombre medecins/372519.html. accessed april 20, 2023. 6. el anzaoui j, ammani a. state of art of neuro-urology in the moroccan context. arab j urol.2021;20(2):105 –106. doi:10.1080/209059 8x.2021.2007465 7. institut national du cancer (inca) (2015) réseaux nationaux pour cancers rares de l’adulte, appui à la decision. available at: https://www.e-cancer.fr/content/download/118020/1407522/file/ resaux-nationaux-cancers-rares-adultes-2015.pdf. accessed april 20, 2023. 8. or der of m ar ch 2 9, 2 0 0 7 s e t ting t he minimum annual ac tivit y t hr esholds applic able to c ancer t r e at ment c ar e activity. nor: sanh0721406a jorf n°76 of march 30, 2007 text n° 68. available at: https://www.legifrance.gouv.fr/jorf/article_ jo/jorfarti000001885113. accessed april 20, 2023. 9. maroc-carte sanitaire 2019 : les derniers indicateurs chiffrés du secteur. october 1, 2019. available at: http://2m.ma/fr/news/ c ar t e s anit air e -2 019 -le c ar ten t r e -le p ublic e t-le p r i v e s e creuse-20191001/. accessed april 20, 2023. 10. arrêté du ministre de la santé n° 177-06 du 26 hija 1426 (27 janvier 2006) fixant la nomenclature générale des actes professionnels. available at: https://w w w.sante.gov.ma/reglementation/nomenclature/ documents/arrêté n° 177-06.pdf. accessed april 20, 2023. 2019[9]. additionally, in morocco, the pricing system of the social security bodies does not accept the excess fees imposed by sub-specialized expertise, creating an implicit disincentive[10]. for these reasons, it is difficult to abandon general urology practice in the private sector in favour of a sub-specialized practice. considering the accelerated development of medical knowledge in different fields, the evolution towards surgical excellence will certainly impose the expansion of sub-specialization in the near future. the creation of referral centres able to promote the level of local training and produce local guidelines, particularly in cancer and infectious diseases, is needed. making morocco a leader in its african environment and an exporter of medical knowledge is perhaps only feasible through a restoration of the entire health care system towards sub-specialty training in coming years. acknowledgments the authors would like to thank mme fiqhi zahra and mme smahane doukkali for their technical support. 163siuj.org siuj • volume 4, number 3 • may 2023 trends towards sub-specialization in urology: what about morocco? https://www.hcp.ma/file/231203/ https://drees.shinyapps.io/demographie-ps/ https://drees.shinyapps.io/demographie-ps/ https://lematin.ma/express/2022/gouvernement-compte-tripler-nombre%20medecins/372519.html https://lematin.ma/express/2022/gouvernement-compte-tripler-nombre%20medecins/372519.html https://lematin.ma/express/2022/gouvernement-compte-tripler-nombre%20medecins/372519.html https://www.e-cancer.fr/content/download/118020/1407522/file/resaux-nationaux-cancers-rares-adultes-2015.pdf https://www.e-cancer.fr/content/download/118020/1407522/file/resaux-nationaux-cancers-rares-adultes-2015.pdf https://www.legifrance.gouv.fr/jorf/article_jo/jorfarti000001885113 https://www.legifrance.gouv.fr/jorf/article_jo/jorfarti000001885113 http://2m.ma/fr/news/carte-sanitaire-2019-lecart-entre-le-public-et-le-prive-se-creuse-20191001/ http://2m.ma/fr/news/carte-sanitaire-2019-lecart-entre-le-public-et-le-prive-se-creuse-20191001/ http://2m.ma/fr/news/carte-sanitaire-2019-lecart-entre-le-public-et-le-prive-se-creuse-20191001/ https://www.sante.gov.ma/reglementation/nomenclature/documents/arr%c3%aat%c3%a9%20n%c2%b0%20177-06.pdf https://www.sante.gov.ma/reglementation/nomenclature/documents/arr%c3%aat%c3%a9%20n%c2%b0%20177-06.pdf http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information renal cell carcinoma, ultrasound, computed tomography, magnetic resonance imaging, positron emission tomography none declared. received on july 15, 2022 accepted on august 31, 2022 this article has been peer reviewed. soc int urol j. 2022;3(6):407–423 doi: 10.48083/sdmv1045 2022 wuof/siu international consultation on urological diseases: imaging of renal cell carcinoma wai-kit lee,1 m. liza lindenberg,2 esther mena gonzalez,2 peter choyke,2 kevin g. king,3 raghunandan vikram,4 vinay a. duddalwar5 1 department of medical imaging, st. vincent's health, university of melbourne, fitzroy, australia 2 molecular imaging branch, center for cancer research, national cancer institute, nih, bethesda, united states 3 keck school of medicine of usc, university of southern california, los angeles, united states 4 department of abdominal imaging, division of diagnostic imaging, the university of texas md anderson cancer center, houston, united states 5 keck school of medicine of usc and usc viterbi school of engineering, university of southern california, los angeles, united states abstract imaging plays a central role in the contemporary multidisciplinary management of renal cell carcinoma. this article provides an overview of the current imaging modalities, including ultrasound, computed tomography, multiparametric magnetic resonance imaging, and molecular imaging, used in the evaluation of renal cell carcinoma. a summary of the imaging strategies for renal cell carcinoma staging and restaging post-treatment is provided. introduction imaging allows for the detection, characterization, staging, treatment planning and guidance, post-treatment evaluation, and surveillance of renal cell carcinoma (rcc). an understanding of the advantages and limitations of each imaging modality, and the evolving role of imaging in newer management strategies (such as active surveillance, ablation, and embolization) and the utility of newer therapeutics (such as antiangiogenic treatments and immunotherapy) is critical. the purpose of this narrative review is to provide an overview of the current imaging modalities, such as ultrasound (us), multidetector computed tomography (ct), multiparametric magnetic resonance imaging (mri), and molecular imaging, used in the evaluation of rcc; highlight newer imaging techniques, such as contrast-enhanced us (ceus) and novel molecular imaging agents, as well as radiomics with artificial intelligence technology; and provide a summary of the imaging strategies for rcc staging and post-treatment restaging. imaging findings following newer treatment techniques, such as ablation and systemic therapy for advanced rcc, are beyond the scope of this article. detection and diagnosis clear cell renal cell carcinoma (ccrcc) (70%–80%), papillary renal cell carcinoma (prcc) (10%–15%), and chromophobe renal cell carcinoma (chrcc) (5%) are the 3 most common histologic subtypes of rcc[1], which as a group show a broad spectrum of imaging appearances. multiphase contrast-enhanced ct is the imaging modality most commonly used for the evaluation of rcc[2]. a systematic review found that the median sensitivity and specificity of ct for the diagnosis of rcc were 88% and 75%, respectively[3]. a limitation of ct is the necessity for intravenous contrast agent, which may be contraindicated owing to renal dysfunction or iodine allergy. 407siuj.org siuj • volume 3, number 6 • november 2022 2022 wuof/siu international consultation on urological diseases https://orcid.org/0000-0002-4808-5715 mailto:vinay.duddalwar%40med.usc.edu?subject=siuj http://siuj.org multiparametric mri is frequently used to further characterize renal masses that are indeterminate on ct, but can be used as the initial study for the evaluation of renal masses, especially in patients with contraindication to iodinated contrast material[2]. a systematic review showed that the median sensitivity and specificity of mr for the diagnosis of rcc were 87.5% and 89%, respectively[3]. a limitation of mri is the contraindication of intravenous contrast in advanced renal disease owing to potential for nephrogenic systemic fibrosis. conventional us can be utilized to triage an indeterminate renal lesion incidentally detected at single-phase ct to determine whether it is a simple or minimally complex cyst or a solid lesion. a systematic review showed that the sensitivity and specificity of conventional us for the diagnosis of rcc were 46% and 12%, respectively[3]. limitations of conventional us include its reduced sensitivity for the detection of small renal masses and the inability to further characterize solid renal masses. ceus is superior to ct and mri for the evaluation of septa and mural enhancement in complex cystic renal lesions[4,5] (figure 1), and its median sensitivity and specificity for the diagnosis of rcc in these lesions were reported to be 94.5% and 69%, respectively[3]. however, there is no current role for ceus in the bosniak classification scheme, but proposals for an adaptation of the scheme incorporating ceus features have been suggested[6]. suboptimal image acquisition owing to patient factors, such as obesity, inability to breath-hold, and acoustic shadowing from bowel gas or ribs, can limit the utility of ceus. 18f-f luorodeox yglucose (fdg) positron emission tomography/computed tomography (pet/ct) is not recommended by major societies, including the american urology association (aua), european associat ion of urolog y (e au), a nd nat iona l comprehensive cancer network (nccn), for the routine diagnosis or evaluation of rcc because the technique is limited by the physiologic excretion of radiotracer through the kidneys and the baseline fdg uptake in normal renal parenchyma, which can obscure part or all of the renal tumor[7–9]. systematic reviews found that fdg pet/ct for rcc detection showed high specificity but variable sensitivity depending on the size, subtype, and grade of rcc[3,10]. imaging features of common subtypes of rcc clear cell renal cell carcinom at us, ccrcc has variable appearances. it typically appe a rs a s a he terogene ou sly hy poechoic or isoechoic mass (figure 2), but may show hyperechoic component s[11,12]. f lu id component s may be present due to cystic, necrotic, or hemorrhagic change. doppler flow is readily identified owing to its hypervascular nature. at ceus, ccrcc shows avid, early enhancement, followed by washout[13] (figure 3). at ct and mri, ccrcc is typically exophytic and shows vivid early contrast enhancement[14]. it has low-tointermediate t1 signal and high t2 signal compared to adjacent renal parenchyma[15]. internal tumor heterogeneity can occur owing to areas of hemorrhage, necrosis, and/or cystic degeneration, which appear as nonenhancing regions[16]. ccrcc may show reduced signal on opposed-phase chemical shift mr images compared to in-phase images owing to intracellular fat[17]. a peritumoral pseudocapsule may be present, which appears as a regular low or high attenuation rim on ct[18], and low t1 and t2 signal on mr images[19]. calcifications are uncommon[20] (figures 4 and 5). papillary renal cell carcinoma at us, prcc may appear as a solid, well-circumscribed mass (figure 6), or sometimes may be partially solid with cystic or hemorrhagic components[11]. at ceus, it shows hypoenhancement with a later and lower peak of enhancement compared to ccrcc[13] (figure 7). at ct and mri, prcc is generally a small peripheral homogeneous mass that has low t2 signal compared to renal cortex, and shows weak enhancement that progressively increases on subsequent phases[21]. prcc may show loss of signal on in-phase images compared to opposed phase at chemical shift mri owing to hemosiderin[22]. some prccs appear as hemorrhagic cystic masses with enhancing papillary projections[23]. calcifications occur in 7% of cases[21] (figures 8 and 9). type 1 and 2 prccs cannot be reliably differentiated on imaging, but type 2 prccs are more likely to be heterogeneous, show infiltrative margins, and contain calcifications[24]. abbreviations aml angiomyolipoma aua american urological association caix carbonic anhydrase ix ccrcc clear cell renal cell carcinoma ceus contrast-enhanced us chrcc chromophobe renal cell carcinoma ct computed tomography fdg 18f-fluorodeoxyglucose mri magnetic resonance imaging pet/ct positron emission tomography/computed tomography prcc papillary renal cell carcinoma psma prostate-specific membrane antigen rcc renal cell carcinoma suvmax maximum standardized uptake value us ultrasound 408 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org figure 1. superior ability of ceus to demonstrate septal enhancement contrast-enhanced ct (a) shows a large cystic lesion (arrows) centrally in the right kidney with several internal enhancing septations. ceus (b) shows an even greater number of internal enhancing septations, and with superior detail. postsurgical pathological evaluation confirmed a mixed epithelial and stromal tumor. figure 2. clear cell renal cell carcinoma chromophobe renal cell carcinoma at imaging, chrcc is typically a solid, well-circumscribed mass that is more homogeneous than ccrcc. at ceus, its enhancement is often nearly isoenhancing to renal cortex and can be difficult to discriminate from ccrcc, especially with small tumors[13]. chrcc shows heterogeneous t2 signal on mri[25]. at ct and mri, it shows intermediate contrast enhancement in between that of ccrcc and prcc[14,23]. a central scar, spokewheel enhancement pattern and segmental enhancement inversion may be present, but these features overlap with oncocytoma[25–27]. calcifications occur in 14% to 38% of cases, and perinephric infiltration and venous invasion are uncommon[20,26]. greyscale ultrasound (a) shows a heterogeneous mass (arrows) with solid and cystic components, and color doppler ultrasound (b) shows flow in the solid portion. contrast-enha eterogeneous mass with avid enhancement. a a b c b 409siuj.org siuj • volume 3, number 6 • november 2022 imaging of renal cell carcinoma http://siuj.org figure 3. clear cell renal cell carcinoma at ceus corticomedullary phase (a) shows a heterogeneously hyperenhancing (relative to renal cortex) mass (arrows) exophytic from the right kidney (arrowheads). at delayed phase (b), the mass shows washout. axial unenhanced ct scan (a) shows an expansile mass involving the right kidney. postcontrast axial ct in corticomedullary phase (b) shows heterogeneous and intense enhancement of the mass. delayed-phase image (90 seconds) (c) shows contrast washout in the mass. this pattern of enhancement and contrast washout is typical of clear cell renal cell carcinoma. figure 4. sixty-year-old male patient with typical features of clear cell renal cell carcinoma on ct a a b b c 410 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org figure 5. sixty-year-old male patient with typical features of clear cell renal cell carcinoma on mri figure 6. papillary renal cell carcinoma axial t2-weighted image (a) shows a right renal mass with heterogeneous high signal. precontrast fat-suppressed t1-weighted image (b) shows a hypointense expansile central mass. postcontrast t1-weighted image in corticomedullary phase (c) shows intense and heterogeneous enhancement of the mass. diffusion-weighted image (b = 500) (d) and corresponding adc map (e) show restricted diffusion in the mass. greyscale ultrasound (a) shows a small solid, well-circumscribed mass (arrows) that is isoechoic to mildly hyperechoic, and color doppler ultrasound (b) shows internal flow. a d b e c d b 411siuj.org siuj • volume 3, number 6 • november 2022 imaging of renal cell carcinoma http://siuj.org figure 7. papillary renal cell carcinoma at ceus figure 8. fifty-year-old male patient with an asymptomatic papillary renal cell carcinoma on ct corticomedullary phase (a) shows only slight early enhancement of the mass (arrows), much less than adjacent cortex (arrowheads). the peak of enhancement is later, at nephrographic phase (b), but even at its peak, the mass is still slightly hypoenhancing (arrows) relative to the adjacent cortex (arrowheads). axial unenhanced (a), corticomedullary phase (b), and nephrographic phase (c) ct images show an expansile mass in the upper pole of the right kidney with low-grade enhancement. this appearance is commonly seen in type 1 papillary renal cell carcinoma. a a b c b 412 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org figure 9. fifty-year-old male patient with an asymptomatic papillary renal cell carcinoma on mri axial t2-weighted image (a) shows an expansile partially exophytic mass in the upper pole of the right kidney with relative low signal compared to the renal cortex. axial precontrast fat-suppressed t1-weighted image (b) and postcontrast fat-suppressed t1-weighted image in nephrographic phase (c) show relative hypoenhancement of the mass, compatible with papillary renal cell carcinoma. diffusion-weighted image (b = 500) (d) and corresponding adc map (e) show restricted diffusion in the mass. d a e b c differentiation of rcc from benign renal tumors imaging is unable to reliably discriminate between benign and malignant renal masses owing to overlapping imaging characteristics in 10% to 15% of cases[28]. rcc can be challenging to differentiate from oncocytoma and lipid-poor angiomyolipoma (aml). however, composite imaging features can suggest a likely diagnosis. aml is a typically homogeneous and markedly hyperechoic mass on us, but up to 30% of small rccs may be hyperechoic, and a definitive diagnosis of aml cannot be established on us appearances alone[12]. at ceus, aml typically shows homogeneous hypoenhancement relative to renal parenchyma and can be difficult to distinguish from prcc and chrcc[12,13]. macroscopic fat within a noncalcified renal mass on ct is almost diagnostic of an aml. macroscopic fat rarely occurs in rcc[29]. intracellular fat can be identified in clear cell rcc but this feature in isolation does not allow its differentiation from lipid-poor aml[30]. a renal mass containing fat with calcification or one that shows necrosis is more likely to be an rcc than aml[23,29]. prcc can be differentiated from a hemorrhagic cyst and lipid-poor aml because it shows weak progressive contrast enhancement. hemorrhagic cyst shows no contrast enhancement[31], and lipid-poor aml shows avid early contrast enhancement with subsequent contrast washout[32]. chrcc and oncocytoma show multiple overlapping imaging features and are most challenging to differentiate from each other[25,33]. at ceus, oncocytoma typically shows hyperenhancement and can show persistent delayed enhancement, but the features are inadequate to allow for confident discrimination from chrcc[12]. quantitative imaging parameters, such as tumor enhancement characteristics[34,35], diffusion-weighted mri[36], and texture analysis[37], have shown some ability to differentiate between benign and malignant renal masses. differentiation of subtypes of rcc imaging is as of yet unable to reliably differentiate between the subtypes of rcc owing to overlapping imaging characteristics. a study showed the performance of ct to predict ccrcc and chrcc on morphologic features alone had a positive predictive value of less than 75%, but evaluation of their contrast 413siuj.org siuj • volume 3, number 6 • november 2022 imaging of renal cell carcinoma http://siuj.org enhancement profile allowed for differentiation of ccrcc from other subtypes with a sensitivity, specificity, and accuracy of 64%, 87%, and 75%, respectively[34]. dynamic contrast-enhanced mri studies found that rcc subtypes showed contrast enhancement profiles concordant with ct findings, but considerable overlap occurs and does not allow for definitive tumor histologic subtyping[14,35]. the application of algorithmic and scoring systems, such as the clear cell likelihood score, would help to achieve greater accuracy[38,39]. type 1 and 2 prccs show overlapping imaging findings that do not permit reliable differentiation between them on morphological features[14,24] or metabolic parameters[40,41]. early dynamic imaging with fdg pet/ct may be more helpful than traditional static scanning in distinguishing aggressive rcc subtypes. a study showed that the maximum standardized uptake value (suvmax) from dynamic scans was higher in ccrcc than non-ccrcc[42]. another study showed that chrcc demonstrated lower suvmax values than ccrcc and prcc, but there was no significant difference between ccrcc and prcc[43]. grading of rcc nuclea r g rade of rcc correlates w it h pat ient survival[44]. imaging features that act as accurate surrogate markers of histologic grade of rcc would allow for noninvasive prediction of prognosis and triage management. most studies have attempted to differentiate between lowand high-fuhrman grade ccrcc. one study showed that the sensitivity and specificity of mri to diagnose low-grade ccrcc were 50% and 94%, respectively, and to diagnose highgrade ccrcc they were 93% and 75%, respectively[45]. another study showed no significant correlation between histologic grade and mri features for prcc and chrcc[46]. morphologic imaging features suggestive of higher grade tumor or sarcomatoid dedifferentiation include larger tumors with intratumoral necrosis, calcification, infiltrative margins, increased peritumoral neovascularity, larger peritumoral vessels, and renal vein thrombosis[45,47–48]. an uncommon predominantly cystic appearance of ccrcc has been shown to have low-grade malignant potential[49]. fdg pet/ct studies showed that higher suvmax and tumor-to-normal reference tissue ratios corresponded to more aggressive rcc features, such as higher tnm stage and fuhrman grade, as well as presence of venous and lymphatic invasion[42,43]. one fdg pet/ct study showed higher maximum, mean, and peak standardized uptake values in rcc with sarcomatoid differentiation compared to ccrcc[50]. other metabolic measures, such as metabolic tumor volume and tumor-to-liver ratios, also appear to correlate with rcc grade[51,52]. quantitative imaging parameters, such as tumor enhancement characteristics[53], diffusion-weighted mr imaging[54], and texture analysis[55,56], have shown some correlation with nuclear grading. staging the 8th edition of american joint committee on cancer tnm staging manual is the most commonly used staging system for rcc[57] (table 1). the american college of radiology appropriateness criteria recommend ct or mri of the abdomen without and with contrast as the most appropriate imaging modalities to stage rcc[58]. ct and mri have similar accuracy for the staging of the primary tumor[59,60]. however, ct is more commonly utilized owing to its ready availability and rapid acquisition time. mri is generally utilized when iodinated contrast medium administration is contraindicated. us is generally considered inferior to ct or mri in staging and post-treatment evaluation for rcc, but it has a role in select patients. ceus can be helpful in certain situations if ct/mri remains indeterminate, or if ct/mri cannot be performed with contrast (figure 10). ct chest is recommended at initial staging, as the lungs are the most common site of rcc metastases[8,61]. targeted imaging should be considered in patients with organ-specific symptoms, such as mri or ct of the brain in patients with neurological symptoms, or bone scintigraphy in patients with bone pain, elevated alkaline phosphatase, or radiographic f indings suggestive of bone metastases[61]. bone metastases from rcc are typically lytic, and the poor osteoblastic response may limit the uptake of radiotracer at bone scintigraphy. one study of patients with stage iv rcc showed that the sensitivity of bone scintigraphy for the detection of osseous metastases was 29%[62]. evaluation of primary tumor key imaging features of the primary tumor to be evaluated include the tumor’s size, location, degree of local invasion (into collecting system, perirenal fat, perirenal fascia, and adjacent organs), and renal vascular anatomy[63]. however, both ct and mri may underestimate tumor size, as well as early urinary collecting system, renal sinus fat, and perinephric fat invasion, compared to pathologic examination, which may result in tumor upstaging[64–67]. evaluation of nodes and distant metastases the most common sites of rcc metastases, in descending order of frequency, are the lungs, bones, liver, lymph nodes, adrenal glands, and brain[68,69]. however, metastases to any organ can occur. crosssectional imaging criteria for the diagnosis of metastatic lymph nodes rely on size larger than 1 cm in short-axis diameter, abnormal shape, disruption of the normal lymph node architecture, and abnormal contrast enhancement characteristics mirroring those of the primary tumor[70]. the accuracy of ct and mri for 414 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org figure 10. renal vein tumor invasion on ceus noncontrast ct (a) shows a left renal lower pole mass (arrow), and a more cranial image (b) shows expansion of the renal vein (arrowheads), concerning for tumor invasion or bland thrombus. greyscale us (c) shows the mass (arrow) and the renal vein (arrowheads) to have similar echogenicity. ceus (d) shows tumor enhancement (arrow) that is contiguous with enhancing tissue in the renal vein (arrowheads), confirming venous invasion by tumor. b c d a lymph node staging is 83% to 88%[69]. both ct and mri are unable to differentiate enlarged, reactive nodes from metastatic lymph nodes or identify micrometastases in normal-sized lymph nodes[69,71]. a review showed that fdg pet had a sensitivity and specificity of 75% and 100%, respectively, for the detection of lymph node metastases in rcc[71] (figure 11). imaging in follow-up in rcc, 80% to 85% of tumor recurrence occurs within the first 3 years following surgery[69,72]. the incidence of local recurrence at the surgical bed following surgery for localized rcc is about 2%[69]. risk for tumor recurrence following surgery depends on the pathological size, stage, grade, and histologic subtype of the primary tumor[69]. pathological stage and grade of the primary tumor enable risk stratification of surgical candidates[57,61]. patients with positive surgical margin are considered to be in at least one higher level of risk category than that based upon their surgical specimen[61]. there is no consensus on the surveillance program following treatment. a risk-based postoperative surveillance schedule has been recommended by the aua[61] as well as eau[8]. contrast-enhanced ct or mri of the abdomen as well as chest imaging are suggested with each follow-up visit[61]. chest radiograph is table 1. t staging categories tx primary tumor cannot be assessed t1 t1a: ≤ 4 cm, limited to the kidney t1b: > 4 cm and ≤ 7 cm, limited to the kidney t2 t2a: > 7 cm and ≤ 10 cm, limited to the kidney t2b: > 10 cm, limited to the kidney t3 t3a: invades renal vein/branches, perirenal fat, renal sinus fat, or pelvicalyceal system t3b: extends into vena cava below the diaphragm t3c: extends into vena cava above the diaphragm or invades vena cava wall t4 invades beyond gerota’s fascia, including direct extension to adrenal gland amin mb and edge sb. ajcc cancer staging manual, 8th edition. springer nature switzerland ag; 2017.[57] 415siuj.org siuj • volume 3, number 6 • november 2022 imaging of renal cell carcinoma http://siuj.org figure 11. papillary renal cell carcinoma metastases on pet/ct 18f-fdg pet/ct shows focal uptake in the primary left upper pole papillary renal cell carcinoma and in metastatic lesions in the ribs, spine, pelvis, and retrocrural lymph nodes. physiologic activity is within the renal collecting system and bladder. coronal pet and ct fusion image is on the left, and coronal pet is on the right. recommended for those in low-risk and intermediate risk categories, and chest ct is recommended for those in high-risk and very high-risk categories[61]. us alternating with ct or mri may be considered in low-risk and intermediate-risk groups after the initial 2 years of follow-up after surgery or ablation, and in active surveillance of localized renal masses[61]. patients managed with ablative treatments are recommended to follow an intermediate-risk category surveillance schedule[61]. patients with relapse, stage iv disease, and surgically unresectable disease are recommended to undergo ct or mri every 6 to 16 weeks at the physician’s discretion and patient’s clinical status[9]. a detailed discussion of the imaging manifestations following ablation and systemic therapy with targeted agents, such as antiangiogenic agents and immunotherapy, is beyond the scope of this article. traditional evaluation of tumor size to determine therapy response may be inadequate in these settings. imaging findings supportive of favorable response include development of marked necrosis, decrease in tumor attenuation, and change in pattern of enhancement[73]. currently, aua recommends that pet/ct should not be routinely obtained but may be considered in select cases[61]. a meta-analysis showed that the pooled sensitivity and specificity were 86% and 88%, respectively, of 18f-fdg pet/ct for the detection of metastatic disease in rcc[74]. another study showed that pet/ct was comparable to ct for the detection of metastatic disease after surgery[75]. pet/ct may have prognostic benefit and can influence clinical decision. a study showed that positive pet/ct scan correlated with lower progression-free survival at 3 years and lower overall survival by 5 years, which affected management decision in 43% of patients[76]. another study showed that the high number of fdg-positive rcc metastases or metastases with high suvmax at baseline pet/ct were linked to shorter overall survival[77]. furthermore, the study showed that disease progression on pet/ct at 16 weeks after start of treatment correlated with decreased overall survival and progression-free survival. qualitative metrics, such as total lesion glycolysis and metabolic tumor volume, were also shown to be predictive of overall survival and progression-free survival[78,79]. 416 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org a summary of the currently recommended imaging modalities to be utilized according to the stage of the disease is included (table 2). imaging-assisted interventions renal mass biopsy, percutaneous tumor ablation, and intraoperative surgery can be assisted by realtime imaging. image-guided percutaneous renal mass biopsy has become more commonly performed and can be guided by us or ct. biopsy may help to avoid surgery by demonstrating benign pathology, or if showing malignancy can help guide management decision to surgery, ablation, or active surveillance. image-guided percutaneous thermal ablation of a renal mass is an alternative to surgery in select patients with localized tumors and can be potentially curative. intraoperative us can be utilized as an adjunct to assist surgery by increasing confidence in selection of the site of parenchymal transection, aid in evaluation of the relationship of the mass to renal vessels and renal collecting system, verify extent of inferior vena caval tumor, and aid in detection of additional lesions[80,81]. three-dimensional (3d) imaging technology, such as 3d printing model, augmented reality, and mixed reality technology, is a novel application of ct or mr imaging dataset to produce a visually concise representation of a renal tumor to improve its localization within the kidney and understand its relationship to relevant anatomical structures. three-dimensional printing models and augmented reality have been utilized for preoperative surgical planning in complex cases[82] and for patient counseling[83]. future directions a number of novel imaging techniques are being investigated to further characterize indeterminate renal masses including elastography, dual-energy spectral ct and perfusion ct, novel pet radiotracers, 99m technetium sestamibi, and the utility of radiomics with artificial intelligence[84,85]. advanced us techniques, such as elastography, are being studied for their potential to differentiate between benign and malignant renal masses[86]. advanced ct techniques, such as dual-energy spectral ct and perfusion ct, are being studied but their exact role in renal mass ct protocol is unclear. studies have shown mixed results in the ability of dual-energy spectral ct and perfusion ct to differentiate between benign and malignant renal masses[87], rcc subtypes[88], and rcc histologic grade[89]. the higher radiation dose penalty and more challenging technique of perfusion ct may limit the technique’s wider utility in comparison to dual-energy spectral ct[90]. novel pet radiotracers linked to specific proteins, such as prostate-specific membrane antigen (psma) and carbonic anhydrase ix (caix), are under current investigation for the evaluation of rcc. a systemic review showed that psma pet/ct has a potential role in staging, restaging, and predicting treatment response, but not for primary tumor evaluation[91]. it appears superior to fdg pet/ct for detection of local recurrence and bone metastases[92]. caix is a cell-surface antigen that is highly expressed in ccrcc but not found in other rcc subtypes or benign renal tissue (figure 12). girentuximab is an anti-caix monoclonal antibody. preliminary studies showed that 89zr-girentuximab pet/ct was able to differentiate between ccrcc and non-ccrcc[93], and improved detection of rcc metastases compared to ct alone or ct in combination with fdg pet/ct[94]. theragnostic applications directed at psma and caix are being explored[95]. 99m technetium sestamibi is a radiotracer that accumulates in mitochondria-rich cells, and is commonly utilized in myocardial and parathyroid scintigraphy. renal oncocytoma has high mitochondrial content compared to chrcc. a meta-analysis showed that 99m table 2. recommended imaging modalities for evaluation at each clinical stage of disease recommended imaging modality suspected renal mass us, ct, mri renal mass characterization ct, mri, us rcc staging ct, mri restaging post-treatment ct neurological symptoms mri, ct bone pain/increased alkaline phosphatase bone scintigraphy ct: computed tomography; mri: magnetic resonance imaging; rcc: renal cell carcinoma; us: ultrasound. 417siuj.org siuj • volume 3, number 6 • november 2022 imaging of renal cell carcinoma http://siuj.org technetium sestamibi scintigraphy had a pooled sensitivity and specificity of 92% and 88%, respectively, for detecting renal oncocytomas versus other renal lesions, and 89% and 67%, respectively, for detecting renal oncocytoma versus chrcc[96]. novel application of this radiotracer to further characterize indeterminate renal masses would allow for triage of suspected oncocytomas to active surveillance. radiomics with artificial intelligence is an emerging field that uses computational methods to extract quantitative metrics, such as shape, size, and texture, from any standard clinical image dataset, such as ct, mri or pet/ct, which can then be used to help differentiate between benign and malignant renal masses, predict nuclear grade, and evaluate gene expression profile[97]. preliminary studies have shown that radiomics allows for differentiation of benign from malignant renal masses with ct[98,99] and mri[100,101]. one ct study showed that sensitivity and accuracy were 85.8% and 74.4%, respectively, in differentiating ccrcc from oncocytoma[98]. another ct study of 127 patients with rcc showed a sensitivity, specificity, and accuracy of 89%, 92%, and 87%, respectively, for differentiating ccrcc from non-ccrcc, and 87%, 92%, and 78%, respectively, for differentiating prcc from chrcc[102]. a further ct study of 62 patients with prcc showed 84% accuracy in differentiating between type 1 and type 2 prcc[103]. an mri study found a sensitivity, specificity, and accuracy of 92%, 41%, and 70%, respectively, for distinguishing benign from malignant renal masses when utilizing deep learning algorithms[100]. studies have shown feasibility of radiomics to differentiate between low and high-grade rcc[104,105]. one study of 53 patients showed a sensitivity, specificity, and accuracy of 91.3%, 80.6%, and 85.1%, respectively, for predicting high-grade from low-grade clear cell rcc[106]. radiogenomic studies have shown that brca1associated protein 1 mutation is associated with ill-defined tumor margins and presence of calcification, and more commonly seen with higher grade rcc[107]. mutation of mucin 4 is found to be associated with exophytic tumor growth and reduced survival[107], while mutation of lysine demethylase 5c is found to be associated with renal vein invasion and reduced survival[108]. however, a systemic review of 57 studies found that translation of radiomics into clinical practice remains technically challenging owing to several factors including heterogeneous image acquisition protocols, reproducibility of radiomics signature, and big data sharing[109]. conclusion imaging plays a central role in the clinical detection, stag i ng, a nd fol low-up of pat ients w it h rcc . contemporary management of rcc has emphasized the role of imaging in the multidisciplinary care of these patients. 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mh, abele j, mcinnes mdf, low g. diagnostic accuracy of 99mtc-sestamibi spect/ct for detecting renal oncocytomas and other benign renal lesions: a systematic review and meta-analysis. abdom radiol (ny).2020;45:2532-2541. doi:10.1007/ s00261-020-02469-8. 97. suarez-ibarrola r, hein s, reis g, gratzke c, miernik a. current and future applications of machine and deep learning in urology: a review of the literature on urolithiasis, renal cell carcinoma, and bladder and prostate cancer. world j urol.2020;38:2329-2347. doi:10.1007/ s00345-019-03000-5. 98. coy h, hsieh k, wu w, nagarajan mb, young jr, douek ml, et al. deep learning and radiomics: the utility of google tensorflowtm inception in classifying clear cell renal cell carcinoma and oncocytoma on multiphasic ct. abdom radiol (ny).2019;44:2009-2020. doi:10.1007/ s00261-019-01929-0. 422 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org 99. yap fy, varghese ba, cen sy, hwang dh, lei x, desai b, et al. shape and texture-based radiomics signature on ct effectively discriminates benign from malignant renal masses. eur radiol.2021;31:1011-1021. doi:10.1007/s00330-020-07158-0. 100. xi il, zhao y, wang r, chang m, purkayastha s, chang k, et al. deep learning to distinguish benign from malignant renal lesions based on routine mr imaging. clin cancer res.2020;26:1944-1952. doi:10.1158/1078-0432.ccr-19-0374. 101. vendrami cl, mccarthy rj, villavicencio cp, miller fh. predicting common solid renal tumors using machine learning models of classification of radiologist-assessed magnetic resonance characteristics. abdom radiol (ny).2020;45:2797-2809. doi:10.1007/ s00261-020-02637-w. 102. zhang gmy, shi b, xue hd, ganeshan b, sun h, jin z y. can quantitative ct texture analysis be used to differentiate subtypes of renal cell carcinoma? clin radiol.2019;74:287-294. doi:10.1016/j. crad.2018.11.009. 103. duan c, li n, niu l, wang g, zhao j, liu f, et al. ct texture analysis for the differentiation of papillary renal cell carcinoma subtypes. abdom radiol (ny).2020;45:3860-3868. doi:10.1007/s00261-020-02588-2. 104. huhdanpaa h, hwang d, cen s, quinn b, nayyar m, zhang x, et al. ct prediction of the fuhrman grade of clear cell renal cell carcinoma (rcc): towards the development of computer-assisted diagnostic method. abdom imaging.2015;40:3168-174. doi:10.1007/s00261-015-0531-8. 105. shu j, wen d, xi y, xia y, cai z, xu w, et al. clear cell renal cell carcinoma: machine learning-based computed tomography radiomics analysis for the prediction of who/isup grade. eur j radiol.2019;121:108738. doi:10.1016/j.ejrad.2019.108738. 106. bektas ct, kocak b, yardimci ah, turkcanoglu mh, yucetas u, koca sb, et al. clear cell renal cell carcinoma: machine learning-based quantitative computed tomography texture analysis for prediction of fuhrman nuclear grade. eur radiol.2019;29:1153-1163. doi:10.1007/ s00330-018-5698-2. 107. shinagare ab, vikram r, jaffe c, akin o, kirby j, huang e, et al. radiogenomics of clear cell renal cell carcinoma: preliminary findings of the cancer genome atlas-renal cell carcinoma (tcga-rcc) imaging research group. abdom imaging.2015;40:1684-1692. doi:10.1007/ s00261-015-0386-z. 108. karlo ca, di paolo pl, chaim j, hakimi aa, ostrovnaya i, russo p, et al. radiogenomics of clear cell carcinoma: associations between ct imaging features and mutations. radiology.2014;270:464-471. doi:10.1148/radiol.13130663. 109. ursprung s, beer l, bruining a, woitek r, stewart gd, gallagher fa, et al. radiomics of computed tomography and magnetic resonance imaging in renal cell carcinoma – a systematic review and meta-analysis. eur radiol.2020;30:3558-3566. doi:10.1007/ s00330-020-06666-3. 423siuj.org siuj • volume 3, number 6 • november 2022 imaging of renal cell carcinoma http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information testosterone, lower urinary tract symptoms, bph, hypogonadism none declared. received on april 22, 2022 accepted on june 12, 2022 this article has been peer reviewed. soc int urol j. 2022;3(5):296–302 doi: 10.48083/pojq7964 relationship between serum testosterone and severity of lower urinary tract symptoms among malaysian men suzliza shukor, fam xeng inn, zulkifli md zainuddin department of surgery, faculty of medicine, hospital canselor tuanku mukhriz, universiti kebangsaan malaysia, kuala lumpur, malaysia abstract background lower urinary tract symptoms (luts) are commonly experienced among ageing males. the increasing prevalence of late-onset hypogonadism suggests a possible relationship between serum testosterone and severity of luts. this study examines the association between serum testosterone and severity of lower urinary tract symptoms among malaysian men, as reflected by the international prostate symptom score (ipss). method a total of 163 men with luts were enrolled in a cross-sectional study in hospital canselor tuanku mukhriz, malaysia. full examination, ipss, and serum total testosterone (tt) levels were evaluated. categorical and continuous correlations were analyzed using chi-square test and age-adjusted pearson’s partial correlation, respectively. result mean age was 66.25 (sd = 7.05), with mean serum tt of 16.74 nmol/l (sd = 6.32). twenty eight percent (n = 46) had low testosterone levels. severity of luts (mild, moderate, severe) was not found to be dependent on tt status (normal, low, severely low), (χ2 [4, n = 163] = 4.24, p = 0.37). weak negative correlations between total ipss and ipss storage sub-score with serum tt levels were exhibited respectively (r = −0.17, p < 0.05; r = −0.17, p < 0.05). conclusion among elderly malaysian men, severity of luts and tt status were not found to be associated, despite a weak negative correlation between ipss and serum testosterone levels. nonetheless, with a high prevalence of hypogonadal ageing men, further research regarding serum testosterone measurement among this population may be valuable as part of a multimodal approach to treatment. introduction lower urinary tract symptoms (luts) are common among men above 50 years of age in malaysia, with prevalence increasing at the rate of 8% per decade, so that up to 65.4% of men above 70 years of age are affected[1]. an age-related reduction in serum total testosterone is also frequently seen in this population and is viewed as one of the more important endocrine-related changes seen in ageing men[2,3]. while the relationship between ageing and serum testosterone and ageing with luts have been widely established, studies that looked into the relationship between serum testosterone and luts have not been consistently reported[4-8]. 296 siuj • volume 3, number 5 • september 2022 siuj.org original research https://orcid.org/0000-0002-2854-7521 mailto:suzliza.shukor%40gmail.com?subject=siuj https://orcid.org/0000-0002-1377-6436 http://siuj.org the importance of testosterone in the general well being of ageing men is readily acknowledged. nonetheless, especially among those who are diagnosed with late-onset hypogonadism with concomitant luts, limited studies are available that highlight the effects of testosterone in the development of luts, and whether it could potentially be a surrogate tool to predict luts severity, and thus subsequently assist in the management of luts among this population. in the present study, we aim to elicit the relationship between serum total testosterone levels and severity of luts among ageing men with luts in malaysia. we also aim to investigate the prevalence of hypogonadism among the different ethnic groups that make up the south east asian demographic, thus allowing better insight into the epidemiology and management of the condition among the population within this region. materials and methods the study involved multi-ethnic men aged 50 to 80 years who presented with urinary tract symptoms to the urology outpatient clinic at a tertiary teaching hospital in kuala lumpur between may 2021 and january 2022. clinical data were obtained, including age, body mass index, waist circumference, and medical history. we excluded from the study men with a history of malignancy, liver cirrhosis, or urinary tract infections, as well as those who were previously diagnosed with hypogonadism, those who were taking hormones, antiandrogen, antifungal medications, or any urological medications (including alpha-blocker, anticholinergics, 5-alpha-reductase inhibitors, and phosphodiesterase-5 inhibitors), those who were previously treated surgically for bph, and those who were diagnosed with other lower urinary tract problems such as urethral stricture. men with abnormal digital rectal examination or raised prostate specific antigen levels (> 4ng/ml) were also excluded from the study. lower urinary tract symptoms were assessed using the validated international prostate symptoms scoring (ipss) which comprises an 8-item questionnaire, in which the sum of the first 7 items yields an overall score ranging from 0 to 35. based on the ipss, luts severity is categorized as mild (0 to 7), moderate (8 to 18), or severe (more than 18) for categorical data analysis. the ipss storage sub-scores were assessed through items 2 (frequency), 4 (urgency), and 7 (nocturia) in the questionnaire, while ipss voiding sub-scores were assessed based on summing the outcome from item 1 (incomplete emptying), 3 (intermittency), 5 (weak stream), and 6 (straining). all participants underwent uroflowmetry testing, with a minimal voiding volume requirement of 150 ml. they also underwent transabdominal ultrasonography to assess prostate size (4mhz, canon aplio). blood measurement of serum total testosterone (tt) was done between 8:00 a.m. and 10:00 a.m. following an overnight fast to minimize the effects of diurnal variation on hormonal levels. based on the european association of urology (eau) guideline on diagnosing late-onset hypogonadism, we categorized serum total testosterone status as “severely low” at a level of 8 nmol/l or less, as “low” at between 8 and 12 nmol/l, and as “normal” at more than 12 nmol/l.[9] data analyses were done using spss sof tware (version 22.0, inc. chicago, us). continuous variables were presented as the mean ± standard deviation (sd) or median (interquartile range). categorical data were presented as numbers and percentages. categorical data on luts severity (“mild,” “moderate,” “severe”) and serum total testosterone status (“normal,” “low,” “severely low”) were analyzed using the chi-square test. statistical comparisons of continuous variables comprising the international prostate symptom score and serum testosterone levels were done using an age-adjusted pearson partial correlation coefficient to minimize the possible confounding effect of age on the outcome. a p-value of < 0.05 was considered significant. results a total of 163 men were enrolled in the study, with a mean age of 66.25 years (sd = 7.05). of these, 6 (0.04%) had mild luts, 112 (68.71%) had moderate luts while the remaining 45 (27.6%) had severe luts (table 1). the mean serum tt level was 16.74 nmol/l (sd = 6.32), and mean prostate volume was 43.25 cm3 (sd = 18.57). further patient characteristics are summarized in table 2 and table 3. based on serum total testosterone level, 4.91% of men (n = 8) were found to have severely low testosterone, 23.31% (n = 38) had low testosterone, and 71.78% (n = 117) had normal testosterone. of men from indian ethnicity (n = 14), 35.72% (n = 5) had a testosterone level of less than 12nmol/l. among chinese men, 29.76% (25/84) had low to severely low testosterone, and among malay men, 24.62% (16/65). abbreviations bph benign prostatic hyperplasia ipss international prostate symptoms scoring luts lower urinary tract symptoms trt testosterone replacement therapy tt total testosterone 297siuj.org siuj • volume 3, number 5 • september 2022 relationship between serum testosterone and severity of luts http://siuj.org as shown in table 4, categorical data analysis using the chi-square test revealed that severity of lower urinary tract symptoms is independent of the serum total testosterone status, χ2 (4, n = 163) = 4.24, p = 0.37). subsequent analysis based on the continuous variables using the pearson’s partial correlation following age-adjustment showed a negative correlation between total ipss and serum total testosterone level, although only a weak association was seen (r = −0.17, p < 0.05) (table 5). similarly, for the ipss storage sub-score, a weak correlation with serum total testosterone level was exhibited table 1. frequency table of severity of luts and serum total testosterone status severity of luts mild moderate severe total total testosterone normal 4 85 28 117 low 2 23 13 38 severely low 0 4 4 8 total 6 112 45 163 table 2. patient characteristics characteristic mean ±sd interquartile range age (years) 66.25 ± 7.05 61–72 bmi (kg/m2) 25.83 ± 3.69 23.2–27.95 waist circumference (cm) 89.09 ± 13.28 78–98 diabetes mellitus (%) 47 (28.83%) hypertension (%) 72 (44.17%) total testosterone (nmol/l) 16.74 ± 6.23 11.55–19.89 psa (ng/ml) 1.63 ± 1.08 0.8–2.31 prostate volume (cm3) 43.25 ± 18.57 32–50.5 total ipss 15.77 ± 5.67 11–19 ipss voiding sub-score 9.55 ± 3.97 6–8 ipss storage sub-score 7.22 ± 3.09 4.5–7 qmax (ml/s) 8.65 ± 2.04 2.35–10 post residual volume (ml) 33.15 ± 43.56 0–50 bmi: body mass index; psa: prostate specific antigen; ipss: international prostate symptom score; qmax: peak flow rate table 3. patient characteristics based on serum total testosterone status tt category normal (n = 117) low (n = 38) severely low (n = 8) characteristic mean ± sd age (years) 65.68 ± 6.79 67.14 ± 7.17 70.25 ± 9.35 bmi (kg/m2) 25 ± 3.26 27.46 ± 4.07 30.25 ± 1.62 waist circumference (cm) 86.45 ± 12.04 93.79 ± 14.43 105.38 ± 6.25 diabetes mellitus (%) 88 (75.21%) 25 (65.79%) 3 (37.5%) hypertension (%) 67 (57.26%) 19 (50%) 3 (37.5%) total testosterone (nmol/l) 19.35 ± 5.21 10.69 ± 2.53 7.27 ± 0.48 psa (ng/ml) 1.58 ± 1.08 1.71 ± 1.10 1.84 ± 1.11 prostate volume (cm3) 43.05 ± 19.15 42.68 ± 15.77 48.75 ± 23.53 total ipss 15.21 ± 5.94 16.87 ± 4.76 18.75 ± 4.20 ipss voiding sub-score 9.11 ± 3.85 10.13 ± 2.90 6.94 ± 3.20 ipss storage sub-score 6.94 ± 3.20 7.76 ± 2.66 8.63 ± 3.02 qmax (ml/s) 8.63 ± 3.02 8.63 ± 2.14 9.01 ± 2.45 post residual volume (ml) 33.28 ± 46.36 30.89 ± 33.36 41.88 ± 45.75 tt: total testosterone; bmi: body mass index; psa: prostate specific antigen; ipss: international prostate symptom score; qmax: peak flow rate 298 siuj • volume 3, number 5 • september 2022 siuj.org original research http://siuj.org (r = −0.17, p < 0.05). contrastingly, for the ipss voiding sub-score, no significant correlation was seen with the serum total testosterone level (r = −0.12, p = 0.07). discussion lower urinary tract symptoms (luts) are commonly seen among ageing males and largely attributed to benign prostatic hyperplasia (bph). the main etiologic factors that have been accepted to play a role in the pathogenesis of the condition are ageing and alterations in androgen levels[10,11]. serum testosterone levels gradually decrease after the age of 40, and it is during this period that the onset of bph usually occurs[3]. although it has been well established that serum testosterone and its metabolite, 5-alpha-dihydrotestosterone, is vital for prostate growth, the mechanism of increasing luts occurrence in the later stages of life despite the declining androgen levels remains unclear. xia et al. analyzed the correlations between prostate volume and serum testosterone level over a 4-year period and found a linear increase in prostate volume with the decrease in serum testosterone level, suggesting that prostate volume is not dependent on serum testosterone in the ageing male population[12]. until now, the persistence of conflicting views on the effect of prostate volume on luts shown in previous studies highlights the complex nature of bph and factors that may contribute to it[13,14]. our study found that the severity of luts, as categorized according to the ipss, and the serum tt status are independent of each other, which is consistent with previous studies reported by crawford et al. and liu et al.[4,6]. similarly, a cross-sectional study by schaztl et al. of 312 men above 40 years of age with untreated luts showed that hypogonadism had no impact on luts status and its clinical parameters, including ipss and uroflowmetry[15]. this finding is in keeping with the saturation hypothesis, which surmises that incremental increase in testosterone level does not cause further androgen-stimulated prostate tissue proliferation due to the saturation of the available androgen receptors on the gland[16]. interestingly, based on the continuous variable data analysis, we found negative correlations between serum total testosterone levels with total ipss and ipss storage sub-score, although only weak correlations were demonstrated. several possible mechanisms may explain the inverse association between testosterone and luts. the urethral and bladder epithelial cells have been found to contain a large amount of androgen receptors. one animal study showed that testosterone may have an effect in maintaining the pelvic ref lex activity of the autonomic nervous system, including the suppression of detrusor activity, which may play an important role in determining the severity of luts[17]. other postulation includes the effect of testosterone on nitric-oxide-mediated smooth muscle relaxation, which may result in the reduction of luts severity among those with a higher testosterone level[18]. additionally, testosterone may also have a physiologic role in the maintenance of the vasopressin level, thus affecting the ability of the kidneys to concentrate urine, thereby improving storage symptoms such as nocturia[19]. furthermore, testosterone has been demonstrated to enhance the anti-inflammatory effect in prostate, thus dampening the effect of chronic inflammatory process that has been postulated to be one of the major etiologies of luts/bph development[20]. similarly, the presence of metabolic syndrome, which is commonly seen among men with lower testosterone levels, may perpetuate this chronic inflammatory process, therefore further propagating the development of luts/bph among men in this population[20,21]. apart from lower urinary tract symptoms, the effects of low testosterone are diverse, encompassing mental, physical, and sexual functions. the prevalence of table 5. age-adjusted pearson partial correlations between ipss (total and sub-scores) and serum total testosterone level coefficient ipss -0.172* ipss-v -0.123 ipss-s -0.165* * p < 0.05, ** p < 0.01, *** p < 0.001 conditioned on variables: age ipss: international prostate symptom score; ipss-v: ipss voiding sub-score; ipss-s: ipss storage sub-score table 4. chi-square test of luts severity with serum total testosterone value df asymptotic significance (2-sided) pearson chi-square 4.243a 4 0.374 n of valid cases 163 a 4 cells (44.4%) have expected count less than 5. the minimum expected count is 0.29. 299siuj.org siuj • volume 3, number 5 • september 2022 relationship between serum testosterone and severity of luts http://siuj.org male hypogonadism in malaysia has been reported as being between 17.5 and 18.5% among the general population[22,23]. nonetheless, there is still a paucity of data available locally with regards to late-onset hy pogonadism among men with luts/bph. in our cohort, the prevalence of hypogonadism among ageing men in malaysia with luts was relatively high, accounting about 28%, with almost 5% having a severely low testosterone level. disparities were also seen in the distribution among the multi-ethnic communities, and men of indian ethnicity showed the highest preponderance of hypogonadism. plausible causes of the disparity would include differences in genetic and epigenetic makeup and in socioeconomic background, which require further investigation. its high prevalence indicates that thorough evaluation of ageing men presenting with luts, with or without late-onset hypogonadism syndrome, is vital as these symptoms are closely associated, regardless of testosterone level[24]. as the elderly population increases in malaysia, the incidence of lower urinary tract symptoms with concurrent hypogonadism needs to be adequately addressed by clinicians, and consideration should be given to testosterone replacement therapy (trt). in general, most guidelines still include precautions regarding trt in men with bph because of the belief it may aggravate the increase in prostate volume and thus hasten the progression of bph, despite studies showing that exogenous testosterone has no effect on prostate volume or prostate specific antigen in older hypogonadal men[25]. in a systematic review by cui et al. on 16 randomized controlled trials involving 1030 men, it was found that neither short-term nor long-term trt increased the risk of prostate growth among hypogonadal men, thereby suggesting its safety among men with luts/bph[26]. a 5-year prospective study by yassin et al. that examined 261 hypogonadal men with luts receiving trt found that trt was associated with a significant luts improvement of 13.4% in hypogonadal men, suggesting a potential beneficial effect of trt among this cohort[27]. kohn et al., in their meta-analysis of 14 clinical trials involving 2029 men receiving trt for late-onset hypogonadism, reported that ipss changes were similar among men with mild to moderate luts receiving trt versus placebo, indicating that trt treatment does not worsen luts among men with late-onset hypogonadism[28]. more recently, a systematic review by lee et. al of 12 clinical trials to investigate the relationship between trt and luts found that there was no significant worsening of luts following trt and concluded there was not sufficient evidence to support warnings that trt may worsen luts among men with hypogonadism[29]. the outcomes f rom our study high lighted t he complexity of the relationship between testosterone and the development of luts/bph. more extensive research is required to improve the management of luts among ageing men. several limitations to our study were noted. a correlation between the ipss and serum total testosterone levels was found, but there were only weak associations, and a larger sample size would strengthen the outcome of the study. as compared to a longitudinal study, the crosssectional study design prevents the ability to make causal inferences from the observed association. our study included only one sampling of serum total testosterone per participant, which may provide an imperfect evaluation that may be inf luenced by individual and analytical errors, and the study did not include free testosterone measurement. conclusion our study found no significant relationship between the severity of luts with total testosterone status, although a higher ipss, particularly those related to storage symptoms, was found to have a weak association with lower levels of serum total testosterone. among malaysian men with lower urinary tract symptoms, up to 28% may have concurrent testosterone deficiency, with males of indian ethnicity having the highest preponderance of hypogonadism. as a high prevalence of low testosterone is seen among this population, more research is needed to elucidate the role of serum testosterone measurement among ageing patients with luts and its implication to the clinical practice, so as to better optimize the multimodal approach to its management. further prospective research could include evaluating measurement of serum testosterone levels as possible biochemical predictor for luts progression and response to bph therapy. acknowledgements the study was performed in accordance with the ethical standards based in the 1964 declaration of helsinki and was approved by the local institutional ethics board (ukm ff-2021-082). special thanks to associate professor dr rozita hod for statistical consultation and consultant endocrinologist, associate professor dr norlaila mustafa for research input. 300 siuj • volume 3, number 5 • september 2022 siuj.org original research http://siuj.org references 1. teh gc, sahabudin rm, lim tc, chong wl, woo s, mohan m, et al. prevalence of symptomatic bpe among malaysian men aged 50 and above attending screening during prostate health awareness campaign. med j malaysia.2001 jun;56(2):186–195. 2. feldman ha, longcope c, derby ca, johannes cb, araujo ab, coviello ad, et al. age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the massachusetts male aging study. j clin endocrinol metab.2002 feb 1;87(2):589–598. 3. wu fcw, tajar a, beynon jm, pye sr, silman aj, finn jd, et al. identification of late-onset hypogonadism in middle-aged and elderly men. n engl j med.2010 jul 8;363(2):123–135. 4. crawford ed, poage w, nyhuis a, price da, dowsett sa, muram d. effects of testosterone level on lower urinary tract symptoms. am j mens health.2016 sep 1;10(5):440–442. 5. liao ch, chiang hs, yu hj. serum testosterone levels significantly correlate with nocturia in men aged 40-79 years. urology.2011 sep;78(3):631–635. 6. liu cc, huang sp, li wm, wang cj, chou yh, li cc, et al. relationship between serum testosterone and measures of benign prostatic hyperplasia in aging men. urology.2007 oct;70(4):677–680. 7. martin sa, haren mt, marshall vr, lange k, wittert ga, members of the florey adelaide male ageing study. prevalence and factors associated with uncomplicated storage and voiding lower urinary tract symptoms in community-dwelling australian men. world j urol.2011 apr;29(2):179–184. 8. shim js, kim jh, yoon ys, choi h, park jy, bae jh. serum testosterone levels are negatively correlated with international prostate symptom score and transitional prostate volume. low urin tract symptoms.2018 may;10(2):143–147. doi: 10.1111/luts.12150. epub 2016 nov 5 9. eau guideline. eau male sexual and reproductive health guidelines. edn. presented at the eau annual congress amsterdam 2022. isbn 978-94-92671-16-5. 10. berry sj, coffey ds, walsh pc, ewing ll. the development of human benign prostatic hyperplasia with age. j urol.1984 sep;132(3):474–479. 11. partin aw, oesterling je, epstein ji, horton r, walsh pc. influence of age and endocrine factors on the volume of benign prostatic hyperplasia. j urol.1991 feb;145(2):405–409. 12. xia bw, zhao sc, chen zp, chen c, liu ts, yang f, et al. relationship between serum total testosterone and prostate volume in aging men. sci 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physiology to clinical implications. eur urol.2014 jan;65(1):115-23. 17. yassin a a, el-sakka ai, saad f, gooren ljg. lower urinary-tract symptoms and testosterone in elderly men. world j urol.2008 aug;26(4):359–364. 18. smet pj, jonavicius j, marshall vr, de vente j. distribution of nitric oxide synthase-immunoreactive nerves and identification of the cellular targets of nitric oxide in guinea-pig and human urinary bladder by cgmp immunohistochemistry. neuroscience.1996 mar;71(2):337–348. 19. shigehara k, sugimoto k, konaka h, iijima m, fukushima m, maeda y, et al. androgen replacement therapy contributes to improving lower urinary tract symptoms in patients with hypogonadism and benign prostate hypertrophy: a randomised controlled study. aging male.2011 mar;14(1):53–58. 20. rastrelli g, vignozzi l, corona g, maggi m. testosterone and benign prostatic hyperplasia. sex med rev.2019 apr;7(2):259-271. 21. tsujimura a, miyagawa y, takezawa k, okuda h, fukuhara s, kiuchi h, et al. is low testosterone concentration a risk factor for metabolic syndrome in healthy middle-aged men? urology.2013 oct;82(4):814-819. 22. kang wh, siruhan m, shree vn, karupiah m, sukor n, kamaruddin na. prevalence of hypogonadism among male type 2 diabetes mellitus patients in pusat perubatan universiti kebangsaan malaysia. j asean fed endocr soc.2021 dec 5;36:12–12. 23. ho cc, singam p, hong ge, zainuddin zm. male sexual dysfunction in asia. asian j androl.2011 jul;13(4):537–542. 24. tsuru t, tsujimura a, mizushima k, kurosawa m, kure a, uesaka y, et al. international prostate symptom score and quality of life index for lower urinary tract symptoms are associated with aging males symptoms rating scale for late-onset hypogonadism symptoms. world j mens health.2022 jan 6. doi: 10.5534/wjmh.210171. 25. raynaud jp, gardette j, rollet j, legros jj. prostate-specific antigen (psa) concentrations in hypogonadal men during 6 years of transdermal testosterone treatment. bju int.2013 may;111(6):880–890. 301siuj.org siuj • volume 3, number 5 • september 2022 relationship between serum testosterone and severity of luts http://siuj.org 26. cui y, zhang y. the effect of androgen-replacement therapy on prostate growth: a systematic review and meta-analysis. eur urol.2013 nov;64(5):811-822. 27. yassin dj, el douaihy y, yassin aa, kashanian j, shabsigh r, hammerer pg. lower urinary tract symptoms improve with testosterone replacement therapy in men with late-onset hypogonadism: 5-year prospective, observational and longitudinal registry study. world j urol.2014 aug;32(4):1049–1054. 28. kohn tp, mata da, ramasamy r, lipshultz li. effects of testosterone replacement therapy on lower urinary tract symptoms: a systematic review and meta-analysis. eur urol.2016 jun;69(6):1083-1090. doi: 10.1016/j.eururo.2016.01.043. 29. lee mh, shin ys, kam sc. correlation between testosterone replacement treatment and lower urinary tract symptoms. int neurourol j. 2021 mar;25(1):12–22. 302 siuj • volume 3, number 5 • september 2022 siuj.org original research http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information social media, facebook, instagram, twitter, tiktok, medical student, medical education none declared. received on october 1, 2022 accepted on january 16, 2023 this article has been peer reviewed. soc int urol j. 2023;4(2):112–116 doi: 10.48083/jkkq6501 urology reach on social media: appealing to future potential applicants rachel e. kaufman,1 madeline snipes,1 catherine wallace,2 martha terris2 1 medical college of georgia, augusta, united states 2 department of urology, medical college of georgia, augusta, united states abstract objective on average, internet users aged 16 to 29 years spend 3 hours per day on social media platforms. previous research has identified social media as an important tool for prospective applicants in the age of virtual residency interviews, but no study to date has included tiktok as a social media platform of interest. tiktok is the fastestgrowing social network in the united states, and there were predictions it would reach 1.8 billion users by the end of 2022. this study seeks to understand the difference in reach of facebook, instagram, twitter, and tiktok to inform medical student engagement efforts. methods a binary (yes/no) poll was posted on mcg urology accounts on facebook, twitter, instagram, and tiktok. the poll asked the question “are you a medical student?” and was open for viewing and/or response on each platform for 24 hours. the number of total views and the number and percentage of respondents were recorded for each application. engagement was determined by the percentage of viewers who responded to the poll. results a total of 3038 views and 839 responses were collected from all social media platforms. tiktok had the highest number of views (1838) and responses (617) but low engagement (33.56%). the highest percentage of “yes” responses was on twitter (61%); however, twitter had the lowest engagement of 7.2%. results of a chi-square test showed that while the total raw number of medical students reached was highest on tiktok, of all those who engaged with the poll, there were statistically significantly more medical students on twitter (p < 0.0001). conclusions medical student outreach can be successfully conducted through social media. twitter allows for engagement with a statistically significantly larger proportion of medical students, and tiktok allows access to a grossly larger audience of medical students. urology residency programs should consider the utility of both twitter and tiktok for student outreach. introduction on average, internet users aged 16 to 29 years spend 3 hours per day on social media platforms. in the age of virtual interviews, many students have resorted to using social media to engage with residency programs, and in turn, programs have utilized social media as a recruiting tool. a study of general surgery applicants from the 2020–2021 cycle found that the majority of applicants utilized social media to inform and educate themselves about the programs they applied to[1]. in response to increased student engagement on social media, the number of general surgery residency social media accounts and usage of these accounts significantly increased in 2020, following the covid-19 pandemic[2,3]. similar trends were identified for orthopedic surgery, plastic surgery, otolaryngology, and integrated vascular surgery matches[4–7]. 112 siuj • volume 4, number 2 • march 2023 siuj.org original research mailto:rkaufman%40augusta.edu?subject=siuj http://siuj.org a study of urology applicants from the 2021 application cycle found that students applying to urology residency increasingly utilized twitter during the covid-19 pandemic. they also found that students who matched in urology were more likely to have a twitter account[8]. additionally, another study on the use of social media in the urology residency match found that the majority of applicants had an instagram account[9]. while heard et al. found that there was no relationship between the presence of applicants on social media and their urology match outcomes[10], a majority of applicants and program directors believed that social media use aided them in some way in the 2021 urology match process. aside from the match, urology is one of the leading specialties that has utilized social media such as twitter, instagram, facebook, and now tiktok as an opportunity for education of patients, students, and physicians. an analysis of urology residency program presence on social media found that 86% of urology residency programs have a twitter account, 39% have an instagram account, and 34% have a facebook account[11]. a study published in association with the european association of urology guidelines office dissemination committee analyzed the usage of hashtags and found that hashtags are a valuable tool in the urologic community for education and communication via social media content[12]. hashtags are topic indicators that facilitate content organization using a hash symbol (#) followed by a key word or phrase. if one searches for a particular hashtag on a social medial platform, only the content that contains that key word or phrase will populate. different social media platforms have variable user interfaces and utilize different algorithms to show users content on the application or website. however, across the four major platforms examined in this study, content creators may associate their posts with captions and/or hashtags, and new posts are algorithmically directed to users who have demonstrated interest in similar content. the facebook and instagram algorithms work similarly to display content on the platform in which posts from followed accounts are arranged in a non-chronological order on the main “home” page. the twitter algorithm displays posts chronologically and includes original posts and retweets from followed accounts as well as occasional posts labeled as “based on your likes.” these posts are identified via key word similarities and hashtags, #urosome, for example. the tiktok algorithm is constructed differently, as it primarily curates videos for users based on a combination of demonstrated interests through viewed and searched hashtags, likes, and comments. for example, a first-time user will open the application and see a random assortment of videos; however, based on the user’s engagement with videos, machine learning is able to identify user interests and present similar content on their “for you” page, which is the default interface on the application. tiktok is the fastest-growing social network in the united states, having grown more than 900% since january 2018, when the application had approximately 11 million monthly active users, to more than 100 million american monthly active users in august 2020, and predictions that it would reach 1.8 billion users by the end of 2022. of these 100 million monthly active users, 50 million are on the app every day, 41% of whom are between 16 and 24 years of age. the current landscape of literature about tiktok is primarily focused on content quality analysis. to our knowledge, no previous study has examined tiktok as a potential social medial platform for student outreach. materials and methods a binary (yes/no) poll was posted on mcg urology accounts on facebook, twitter, instagram, and tiktok. the native software on each of the platforms was utilized to conduct each poll. the poll asked the question “are you a medical student?” and was open for viewing and/or response on each platform for 24 hours on july 23, 2021. a 24-hour polling period was conducted to account for constraints of the native software across platforms, with instagram, facebook, and twitter only allowing for a 24-hour polling period during which a respondent can respond only once. the specific date was chosen arbitrarily, as there was no difference in follower activity between dates according to account analytics. the number of total views and the number and percentage of respondents were recorded for each application using the native analytics features on each of the platforms. at the time of the poll, the mcg urology twitter account had 4.8k followers, instagram had 1.6k followers, facebook had 1.5k followers, and tiktok had 48k followers. the difference in number of followers across platforms was accounted for by measuring engagement. engagement was determined by the percentage of those who viewed the poll who responded either “yes” or “no.” statistical analysis was conducted using spss software. the proportion of medical students’ “yes” responses were compared across social media platforms using the chi-square test (p < 0.01). demographic and geographic data of poll viewers were collected on tiktok only, as this was the only platform to release this data. demographic and geographic data of poll respondents could not be collected due to constraints of the social medial platforms. results a total of 3038 views and 839 responses were collected from facebook, twitter, instagram, and tiktok in the 113siuj.org siuj • volume 4, number 2 • march 2023 urology reach on social media: appealing to future potential applicants http://siuj.org 24-hour period during which the poll was open for viewing and response on each platform. facebook and instagram had the highest engagement compared to twitter and tiktok, with 45.5% and 55.4%, respectively. the poll on facebook had 156 total views and 71 total responses, representing 45.5% engagement with the poll (figure 1). instagram had a similar breakdown to facebook, with a total of 157 views and 87 total responses, representing 55.4 % engagement (figure 1). while the poll on twitter had the highest percentage of medical students at 61% (39), it also had the lowest engagement of 7.2%, representing 64 total votes of 887 views (figure 1). tiktok had the highest number of views (1838) and responses (617), with 35.98% engagement. on facebook, 53.52% of respondents (38) indicated that they were medical students (figure 2). of those who responded to the poll on instagram, 54.02% (47) indicated that they were medical students (figure 2). tiktok had lowest percentage of those who indicated that they were medical students, at 36%; however, although the proportion of those who responded “yes” to the poll on tiktok was the smallest, tiktok had the largest total number of medical students reached, at 222 students (figure 2). chi-square test results showed that while the total raw number of medical students reached was highest on tiktok, of all those who engaged with the poll, there were statistically significantly more medical students on twitter (p < 0.0001) (table 1). demographic and geographic data collected on tiktok showed that the majority of poll viewers, regardless of engagement or response, were 25 to 35 years old (figure  3), equally likely to be male (50%) or female (50%), and from the united states (63%). discussion while twitter has traditionally been used for medical student outreach, it had the lowest engagement and the lowest total medical students reached, though of all the students who engaged with the poll, there were statistically significantly more medical students on twitter compared to other social media platforms (p < 0.0001) (table 1). conversely, tiktok, which has been the least utilized social media platform by academic urolog y programs for outreach, had the smallest percentage of medical students respond, but it reached the largest total number of medical students compared to other social media platforms. the differences in the results can be explained by the different algorithms of the platforms, as instagram, twitter, and facebook have home pages that primarily show users posts from accounts that they have already figure 1. poll total views and responses (engagement) facebook 156 (45.51%) (55.41%) (7.22%) (35.98%) 157 71 87 64 887 617 1838 instagram twitter tiktok 2000 1800 1600 1400 1200 1000 800 600 400 200 0 views responses figure 2. “are you a medical student?” yes/no responses tiktok 222 395 700 600 500 400 300 200 100 0 yes no facebook 38 33 twitter 39 25 instagram 47 40 114 siuj • volume 4, number 2 • march 2023 siuj.org original research http://siuj.org followed. tiktok, however, uniquely directs users to the “for you” page that includes content from accounts that users may or may not follow but that are algorithmically tailored to their interests, according to their likes, comments, and searches. while most social media platforms do use machine learning to tailor content to users based on previously demonstrated interests, tiktok does so on its main user interface and to a greater extent. twitter and tiktok are both perhaps better able to tailor content to users based on hashtags. hashtags used as topic indicators on tiktok and twitter are able to demonstrate content to specific groups of users such as table 1. results of chi-square analysis cv outcome yes no row totals facebook 38 (29.28) [2.60] 33 (41.72) [1.82] 71 instagram 47 (35.88) [3.45] 40 (51.12) [2.42] 87 twitter 39 (26.39) [6.02] 25 (37.61) [4.23] 64 tiktok 222 (254.45) [4.14] 395 (362.55) [2.90] 617 column totals 364 493 839 (grand total) figure 3. age distribution of viewers on tiktok 23% 6% 11% 23% 37% 18-24 25-34 35-44 45-54 55 and up medical students. the more a user interacts with posts that contain a certain hashtag, the more they will see other posts that contain that hashtag or content that is similar. however, the audience reached on tiktok was larger than that on twitter. the fact that the tiktok main user interface focuses on all accounts rather than those accounts that users have deliberately followed may have contributed to the larger audience reached on tiktok. in contrast, the home page on twitter is less utilized to show users novel content and is more focused on accounts that users have followed. this could be the reason that those who engaged with the poll on twitter were statistically significantly more likely to be medical students, as studies have shown that twitter is the primary social media platform used by residency applicants during the match[8]. our study did have some important limitations. due to the nature of the degree of anonymity of users on social media, there was no ability to verify the accuracy of the responses or to run the poll for longer than 24 hours while ensuring only one response per person per poll. additionally, while the breakdown of followers of mcg urology accounts is similar to other institutions on facebook, instagram, and twitter, the mcg urology tiktok account has a significantly larger following on tiktok compared to the other social media platforms, and this may have contributed to the increased reach on tiktok. however, as there are so few urology residency programs on tiktok, it is difficult to assess as to whether the large number of followers on tiktok would be unique to mcg urology. perhaps there is a large audience on tiktok that could be reached by other programs. further research is necessary to determine the practical utility of tiktok for medical student outreach. conclusion although urologists are in high demand across the country, too many medical students are exposed to the field later than many other specialties due to lack of early curricular exposure[13]. social media may be an important remedy for this. an undecided medical student with accounts on each platform may follow a few academically focused accounts on twitter, facebook, and instagram, but their home page will primarily consist of tweets from accounts they follow or tweets that were liked, retweeted, or replied to by accounts that they already follow. however, on tiktok, if the student liked a tiktok from an account that had some connection to urology, they will be more likely to see content from a program that may not have noticed. additionally, previous research has consistently shown that social media is an invaluable asset in the residency application process for urology as well as other surgical specialties. while our analysis was consistent 115siuj.org siuj • volume 4, number 2 • march 2023 urology reach on social media: appealing to future potential applicants http://siuj.org with previous research that has shown that twitter has been the mainstay of social media engagement for residency recruitment, tiktok may be an emerging player in student outreach efforts. twitter and tiktok both have utility for medical student outreach: twitter allows for engagement with a statistically significantly larger proportion of medical students and tiktok allows access to a grossly larger audience of medical students. instagram and facebook may be falling out of favor by medical students for engagement with urology programs. with increasingly younger students entering medical education, urology residency programs should consider the utility of both twitter and tiktok for student outreach. references 1. fuller cc, deckey dg, brinkman jc, tummala sv, lu pg, mishra n, et al. general surgery residency applicants' perspective on social media as a recruiting tool. j surg educ.2022;79(6):1334–1341. doi: 10.1016/j. jsurg.2022.06.003. pmid: 35739022. 2. bludevich bm, fryer m, scott em, buettner h, davids js, lafemina j. patterns of general surgery residency social media use in the age of covid-19. j surg educ.2021;78(6):e218–e225. doi: 10.1016/j. jsurg.2021.04.017. pmid: 34016568; pmcid: pmc8635497. 3. fang ha, boudreau h bs, khan s, singh np, rais-bahrami s, king tw, et al. an evaluation of social media utilization by general surgery programs in the covid-19 era. am j surg.2021;222(5):937–943. doi: 10.1016/j.amjsurg.2021.04.014. pmid: 33906728; pmcid: pmc8629310. 4. bixby ec, danford nc, desai ss, paskey tl, levine wn. instagram use among orthopaedic surgery residency programs. j am acad orthop surg.2022;30(14):648–657. doi: 10.5435/jaaos-d-22-00089. pmid: 35472190. 5. chun m, girard a, zhang y, meyers a, roohani i, cook t, et al. what attributes make united states plastic surgery programs desirable? perspectives from medical students and residents. eplasty.2022;22:e3. pmid: 35958739; pmcid: pmc9350546. 6. patro a, landeen kc, stevens mn, cass nd, haynes ds. the digital dilemma: perspectives from otolaryngology residency applicants on social media. ann otol rhinol laryngol.2022;131(9):954–961. doi: 10.1177/00034894211050625. pmid: 34617461. 7. lagrone rb, singh np, nocera ap, rais-bahrami s, novak z, beck aw, et al. the use of social media and virtual opportunities by integrated vascular surger y residency programs during the covid-19 pandemic. vascular.2022:17085381221075 479. doi: 10.1177/17085381221075479. pmid: 35574934. 8. friedman bj, chen i, asantey k, loeb s, kim sp, malik rd, et al. twitter engagement of medical students applying to urology residency during covid-19: a mixed methods study. urology.2022;165:120–127. doi: 10.1016/j.urology.2021.11.046. pmid: 35063463. 9. carpinito gp, caldwell km, kenigsberg ap, ganesan v, khouri rk jr, kuprasertkul a, et al. twitter and instagram use in the urology residency application process. urology.2022;159:22–27. doi: 10.1016/j. urology.2021.08.046. pmid: 34637837. 10. heard jr, wyant wa, loeb s, marcovich r, dubin jm. perspectives of residency applicants and program directors on the role of social media in the 2021 urology residency match. urology.2022;164:68–73. doi: 10.1016/j.urology.2021.08.041. pmid: 34606880. 11. zaliznyak m, tsai k, gaither t w, wong r, duel b, hamilton z. analyzing the growth in social media proliferation in academic urology: associations between program ranking and social media footprint. can urol assoc j.2022 sept 30. doi: 10.5489/cuaj.8038. online ahead of print. pmid: 36218316. 12. teoh jy, bhatt nr, cucchiara v, garcia rojo e, pradere b, borgmann h, et al; european association of urology guidelines office dissemination committee. the power of hashtags in social media: lessons learnt from the urology tag ontology project. eur urol focus.2022;8(6):1565–1567. doi: 10.1016/j.euf.2022.05.002. pmid: 35668025. 13. slaughenhoupt b, ogunyemi o, giannopoulos m, sauder c, leverson g. an update on the current status of medical student urology education in the united states. urology.2014;84(4):743–747. doi: 10.1016/j. urology.2014.06.003. pmid: 25102786. 116 siuj • volume 4, number 2 • march 2023 siuj.org original research http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information renal cell carcinoma, venous tumor thrombus, inferior vena cava tumor thrombus none declared. received on july 14, 2022 accepted on september 14, 2022 this article has been peer reviewed. soc int urol j. 2022;3(6):451–463 doi: 10.48083/egwh6536 2022 wuof/siu international consultation on urological diseases: management of locally advanced renal cell carcinoma vsevolod b. matveev,1 sarah p. psutka,2 grant d. stewart,3 gennady bratslavsky,4 e. jason abel5 1 department of urology, n. n. blokhin national research institute of oncology, moscow, russia 2 university of washington medical center, seattle cancer care alliance, seattle, united states 3 department of surgery, university of cambridge, cambridge biomedical campus, cambridge, united kingdom 4 department of urology, suny upstate medical university, syracuse, new york, united states 5 departments of urology and radiology, university of wisconsin school of medicine and public health, madison, united states abstract renal cell carcinoma (rcc) has a natural tendency to invade the venous system with formation of a venous tumor thrombus in the renal vein, which can extend proximally into the inferior vena cava (ivc) and in some cases into the right atrium. the presence of venous involvement significantly worsens prognosis. despite recent advances in systemic therapies, surgery remains the most effective method of treatment and in the case of complete removal of all tumor, it provides satisfactory long-term survival and must be attempted whenever possible. several surgical techniques have been proposed, but all are associated with a high rate of perioperative complications and mortality. minimally invasive approaches are mainly applicable for less extended ivc thrombi, while open surgery remains the gold standard for this category of patients. most ivc thrombi can be managed without use of circulatory support by using different methods of ivc control depending on the thrombus level. however, use of cardiac bypass with or without deep hypothermic cardiac arrest is indicated in some patients with bulky intraatrial tumor thombi. in select patients presenting with ivc tumor thrombus and synchronous distant metastases, cytoreductive nephrectomy with ivc tumor thrombectomy may be considered with or without neoadjuvant systemic therapy. surgery for rcc with venous thrombus is complex and requires experienced multidisciplinary surgical, anesthesia, and critical care teams at high-volume centers to achieve the best outcomes. introduction venous tumor thrombus (vtt) involvement is identified in up to 10% of patients with rcc[1]. currently, surgery remains the only curative approach for m0 rcc with ivc invasion. while an open approach is most commonly utilized, there is growing interest regarding the role for minimally invasive approaches in appropriately selected patients; however, there is limited data regarding long-term outcomes regarding these approaches. in select patients presenting with ivc tumor thrombus and synchronous distant metastases, cytoreductive nephrectomy with ivc tumor thrombectomy may be considered with or without neoadjuvant systemic therapy. classification of vtt in renal cell carcinoma an unusual hallmark of rcc is its predilection for vascular invasion. the vtt can then form a cast of the main renal vein (pt3a) and extend proximally into the inferior vena cava (ivc; pt3b), in some cases extending into the right atrium of the heart (pt3c) or can invade directly from the venous lumen into the endothelium (pt3c)[2]. 451siuj.org siuj • volume 3, number 6 • november 2022 2022 wuof/siu international consultation on urological diseases mailto:vsevolodmatveev%40mail.ru?subject=siuj http://siuj.org recent estimates suggest that vtt is identified in approximately 1 in 10 patients with newly diagnosed rcc[3–12]. involvement of the right cardiac chambers is encountered in 1% of cases[13]. vtt is classically categorized according to the height or extent of the vtt, according to the mayo classification system[14] (table 1). the level of tumor thrombus is relevant not only from the perspective of oncologic prognosis but also in terms of anticipating surgical complexity and surgical planning[12]. other features of the vtt such as direct invasion of the tumor thrombus into the endothelium and presence of bland thrombus are associated with both increased surgical complexity[15,16] and inferior cancer-specific survival[17–19]. macroscopically, venous tumor thrombi can also be categorized according to their consistency, and may be described as either solid or friable, where friability has been associated with worse pathologic features and prognosis[20,21]. pathophysiology of tumor venous thrombosis and clinical manifestations of rcc with ivc tumor thrombus complete occlusion of the ivc by vtt or by proximal bland thrombus propagation has multiple potential physiologic consequences. ivc obstruction may result in lower-extremity edema, development of varicoceles, and pelvic pain from gonadal vein obstruction. reduced venous return to the right atrium (reduction in preload) may lead to hemodynamic instability, and altered mental status and death. other commonly reported symptoms may include fatigue, dizziness, weight loss, night sweats, anorexia, palpitations, diaphoresis, dizziness, and shortness of breath on exertion[22]. failure of the kidneys to have adequate venous drainage can result in progression of renal insufficiency. similarly, obstruction of the hepatic veins can lead to hepatic congestion, which presents with transaminitis, hepatic insufficiency, ascites, and budd-chiari syndrome[23–26]. up to 5% of patients with rcc and ivc tumor thrombus may present with pulmonary embolism[27–29]. finally, level iv ivc tumor thrombus that grows into the right atrium can cause atrioventricular blockage with acute heart failure and death. collateral venous return in the setting of ivc obstruction may include drainage via the azygos-hemiazygos circulation, vertebral pathways via prominent lumbar veins, collateralization of the portal-venous system, as well as via aberrant parasitic vessels or superficial/subcutaneous veins, as is observed in patients presenting with a “caput medusa”[30,31]. the degree of collateralization depends on the duration and extent of the ivc obstruction. diagnostic imaging and staging staging evaluation consists of cross-sectional imaging of the chest, abdomen, and pelvis to characterize the size of the primary tumor and assess for potential involvement of adjacent structures or distant metastases. crosssectional imaging provides critical details regarding the level of the thrombus, the presence or absence of ivc occlusions, the degree of venous collateralization, and the volume and location of association bland thrombus[22,32,33]. multiphase computed tomography (ct) and magnetic resonance imaging (mri) are acceptable staging imaging modalities. in patients with lower-extremity edema, a doppler ultrasound abbreviations io immuno-oncology therapy rcc renal cell carcinoma vtt venous tumor thrombus table 1. classification of vtt level in rcc: the mayo classification system14 level anatomic landmark 0 thrombus is limited to the segmental or main renal vein, detected clinically or during pathologic evaluation. i thrombus extends into the infradiaphragmatic ivc, within 2 cm of the renal vein ostium. ii thrombus extends into the infradiaphragmatic ivc, > 2 cm above the renal vein ostium but below the confluence of the hepatic veins. iii thrombus extends into the infradiaphragmatic ivc, above the confluence of the hepatic veins. iv thrombus extends above the diaphragm, and may involve the right atrium. ivc: inferior vena cava; rcc: renal cell carcinoma; vtt: venous tumor thrombus. 452 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org (us) is indicated to assess the venous patency of the lower extremities. also, in patients with neurological symptoms, head imaging (ct or mri) should be obtained to rule out brain metastases. venography is not currently utilized to evaluate for vtt due to its invasiveness and moderate risk for associated complications[34]. at the time of surgery, transesophageal echocardiography can provide real-time, additional information regarding the upper extent of the thrombus and involvement of the intraand supra-hepatic ivc, hepatic veins, and right atrium. it can also provide helpful information regarding the mobility of the thrombus[35]. neoadjuvant therapy before radical nephrectomy and thrombectomy there is no level i or ii evidence of presurgical systemic therapy in either nonmetastatic or metastatic rcc vtt. retrospective studies have been undertaken and these have focused on mixed groups of targeted therapies[36–39]: sunitinib[40,41], axitinib[42], and pazopanib[43]. naxiva is a phase 2 feasibility clinical trial (nct03494816) that was undertaken to determine the safety, efficacy, and effect of neoadjuvant axitinib on vtt[44]. drug and surgery-related adverse events were as expected, with clavien-dindo grade ≥3 complications observed in 11.8% (2 of 17) of patients. the trial provided initial evidence that vascular endothelial growth factor receptor tyrosine kinase inhibitors (vegfr tkis) can successfully downstage vtt (75% [15 of 20] with reduction in vtt length, 35.3% [7 of 20] with reduction in mayo level), leading to a reduction in the extent of surgery in 41.2% (7 of 17) of patients[44]. however, before this strategy can be considered for routine clinical practice, future randomized studies evaluating contemporary standard of care treatment combinations (immuno-oncology therapy [io]/io or io/tki) are needed. surgical technique of radical nephrectomy with ivc thrombectomy surgery in patients with level iii and iv vtt is generally performed through midline, chevron, or thoracoabdominal incision. to minimize the morbidity associated with a thoracoabdominal approach, radical nephrectomy and thrombectomy may be performed via midline abdominal approach, which can be used for all levels of vtt. regardless of the primary tumor laterality, the access to the retroperitoneum is achieved by incising the posterior peritoneum lateral to the ascending colon. the right colon is reflected medially, and the duodenum is kocherized to expose the anterior surface of the ivc and aorta. early ligation of the renal artery decreases the bleeding from venous collaterals and may permit for retraction of the cephalad most extent of the vtt. the mobilization of the kidney should be deferred until after complete vascular control is achieved. thrombectomy in patients with level i-iii tumor thrombus after ligation of the renal artery, the vena cava is completely dissected from the surrounding structures above and below the renal vein. rummel tourniquets or vascular clamps are placed around the infrarenal ivc, contralateral renal vein, and suprarenal ivc cephalad to the superior extent of the vtt. in patients with a subhepatic level ii vtt, several (2–4) accessory hepatic veins from the caudate lobe of the liver are ligated and divided. as a result of this maneuver, 3 to 5 cm of additional ivc is exposed. in the case of the right-sided primary, the right kidney is then completely mobilized outside gerota's fascia, leaving the kidney attached only by the renal vein. in the case of a left-sided tumor, the kidney is mobilized only after completion of thrombectomy. the tourniquets on infrarenal ivc, contralateral renal vein, and ivc above the upper extent of the thrombus are sequentially closed (figure 1a). the antero-lateral wall of the subhepatic vena cava is longitudinally incised, and the thrombus is extracted with blunt and sharp dissection from the vessel wall, followed by a circumferential excision of the ostium of the renal vein (figure 1b). after evaluating for remnant thrombus fragments adhering to the ivc intima, the defect of the ivc is closed with a 4–0 running vascular suture, the cavorraphy is backbled to avoid an air embolism, and the clamps are removed in the following order: (1) suprarenal ivc, (2) contralateral renal vein, (3) infrarenal ivc. the management of patients with level iii vtt requires mobilization of the liver, which allows for exposure of the intrahepatic and subdiaphragmatic segments of the ivc (figure 2a). resection of a level iii vtt can be safely performed in most of the cases without circulatory support[45,46]. ivc above the upper extent of the thrombus is controlled at the intrapericardial level by using the transdiaphragmatic approach. absence of tributaries makes circular mobilization of the intrapericardial part of the ivc significantly easier to perform compared with subdiaphragmatic circular mobilization. to accomplish a transdiaphragmatic ivc clamp, the diaphragm and underlying pericardium are incised above the ivc. incision of the pericardium on both sides of the intrapericardial ivc allows for passing a tourniquet around the intrapericardial ivc[47] (figure 2a). 453siuj.org siuj • volume 3, number 6 • november 2022 management of locally advanced renal cell carcinoma http://siuj.org alternatively, the pericardium can be separated from the incised diaphragm and left intact. the advantages of approaching the intrapericardial ivc through a diaphragmatic incision include simplicity, decreased surgical trauma, and the ability to perform the procedure by one surgical team using a strictly abdominal approach[46,47]. the hepatoduodenal ligament is isolated to control the hepatic circulation with a pringle maneuver. after closure of all tourniquets with a pringle maneuver, the ivc is incised at the retrohepatic level. widely opening the ivc at this level allows the surgeon to perform visual inspection of the ostium of the major and minor hepatic veins. following thrombectomy, the closure of the upper part of the cavotomy is started. as soon as the suture line reaches the subhepatic portion of the ivc, a satinsky clamp is placed above the last stitch, the tourniquet from the intrapericardial ivc and the satinsky clamp from the hepatoduodenal ligament are released, thereby restoring hepatic circulation and venous blood return to the right atrium. the rest of the procedure is similar to cases with level ii vtt. ideally, the thrombus is removed en bloc with the kidney (figure 2b). in patients with level iii vtt and left-sided primary, the tourniquets are placed on the right renal vein (or right renal artery), while the left renal vein is sutured and divided with a ta stapler prior to thrombectomy. contraindication for this approach includes partial left renal vein and ivc occlusion by a thin tumor thrombus, which may dislodge and cause pulmonary embolization. transection of the left renal vein in patients with fixed ivc thrombi is safe and allows for greater ivc mobility, provides good access to the left renal artery and aorta, and facilitates en bloc removal of the thrombus with the ostium and vtt-containing stump of the left renal vein. in cases where a level iii thrombus is free floating, the thrombus can be extracted via an infrahepatic-only cavotomy similar to patients with level ii vtt. thrombectomy in patients with supradiaphragmatic (level iv) tumor thrombus in general, the approaches used for supradiaphragmatic thrombectomy can be divided into those that use any type of circulatory support, and those that avoid it. no surgical method was shown to be superior for the excision of vtt. most patients with nonadherent intraatrial thrombus can be managed without circulatory support[45–47]. figure 1. radical nephrectomy with thrombectomy in ct3bn0m0 rcc of the right kidney with level iv tumor thrombus 1a tourniquets are closed on the infrarenal ivc and rrv; satinsky clamp is positioned above the thrombus. 1b ivc is incised, and tumor thrombus is visualized in the ivc lumen.ivc: inferior vena cava; lrv: left renal vein; rcc: renal cell carcinoma; rrv: right renal vein 454 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org from a practical point of view, level iv thrombi can be subdivided into intrapericardial and intraatrial vtt. the first steps of the procedures are the same for either case, and follow the techniques described above for patients with level iii tumor thrombi. in patients with intrapericardial thrombus only, there is no need for complete mobilization of the intrapericardial ivc. instead, only incisions of the pericardium on both sides of the intrapericardial ivc are performed for tourniquet placement. on the contrary, in the case of an intraatrial thrombus, the intrapericardial ivc needs to be completely mobilized so that it can be encircled at the cavoatrial junction. the diaphragm at the ivc hiatus must be completely mobilized from the ivc to widen the natural narrowing for safer extraction of the thrombus from the right atrium (figure 3a) the upper tourniquet on the intrapericardial ivc is left unclamped until the apex of the thrombus is removed from the heart. after all other tourniquets are sequentially clamped with a pringle maneuver, the incision of the retrohepatic ivc is continued up to the cavoatrial junction. the thrombus is gently mobilized from the retrohepatic ivc (figure 3b). if the head of the thrombus is mobile, the retrograde blood f low from the right atrium will evacuate the thrombus. if the thrombus is adherent to the vessel wall, the incision is extended on the intrapericardial ivc and the thrombus is resected from the intima of the intrapericardial ivc under direct visualization. in the case of a large head of the tumor thrombus, the incision may even be extended 5 to 10 mm on the right atrium wall (figure 4). as soon as the thrombus is evacuated from the right atrium and the intrapericardial ivc, the upper tourniquet is closed. the rest of the procedure progresses as described above for patients with level iii thrombus. the majority of cases with level iv thrombus can be managed without circulatory support unless the head of the thrombus is too bulky for removal without performing wide atriotomy. thrombi that have a long history of surveillance and those that shrank after preoperative systemic therapy may be adherent to the vessel wall. removal of the thrombus in these patients may be figure 2. radical nephrectomy with thrombectomy in ct3bn0m0 rcc of the right kidney with level iii tumor thrombus 2a mobilization of the liver. several short hepatic veins have been divided (green arrows). tourniquets have been applied to the infrarenal ivc, left renal vein, and intrapericardial ivc. 2b surgical specimen: kidney with the tumor thrombus en bloc. 455siuj.org siuj • volume 3, number 6 • november 2022 management of locally advanced renal cell carcinoma http://siuj.org associated with excessive blood loss. circulatory support in these circumstances helps to maintain hemodynamic stability. thrombectomy in patients with tumor ivc wall invasion and/or descending bland thrombosis vena cava resection is required in cases where the wall of the ivc is directly invaded by tumor. repairs of the ivc include primary repair by venorrhaphy, prosthetic and autologous patch repair, and circumferential complete ivc replacement. in the majority of cases, resection of the dilated part of ivc does not result in clinically significant ivc narrowing, and primary cavorraphy is preferred. indications for prosthetic repair include narrowing of ivc of > 50%. however, grafts expose patients to an increased risk for infection and thrombosis. therefore, the optimal management of the ivc after resection is controversial[47]. descending thrombosis in patients with rcc and vtt is quite frequent and occurs in 9.8% of patients[48]. bland infrarenal ivc thrombus carries the risk for embolization, and recurrence from residual tumor cells, which can be found in 16% at the margin of tumor and bland thrombus. ivc interruption or segmental resection is required in most of the cases. the infrarenal ivc can be safely resected without reconstruction below the level of the proximal bland thrombus or just above the ivc bifurcation without any consequences[46,48–50]. figure 3. radical nephrectomy with thrombectomy in ct3bn0m0 rcc of the left kidney with level ii tumor thrombus 3a. tourniquet on the intrapericardial ivc. 3b. the cephalad part of the thrombus is evacuated from the ivc lumen. ivc: inferior vena cava; rcc: renal cell carcinoma. 456 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org most authors indicate that lower-extremity edema after ligation of the ivc occurs rarely, is well tolerated, and resolves spontaneously[49,50]. the suprarenal ivc can be safely resected with ligation of the left renal vein in patients with right-sided rcc with vtt. the collateral venous return from the left kidney is sufficient to preserve normal renal function. thus, resection of the ivc en bloc with rightsided rcc and tumor thrombus from the level of the major hepatic veins to the level of ivc bifurcation (en bloc cavectomy) can be performed without reconstruction[20,48] (figure 5). in patients with left-sided rcc, the right renal vein must be spared to preserve adequate venous drainage from the kidney. minimally invasive radical nephrectomy and ivc thrombectomy since the first report of laparoscopic ivc thrombectomy in 2000, numerous studies have highlighted the feasibility of minimally invasive techniques[51–62]. most minimally invasive ivc thrombectomies have been performed on right-sided renal tumors[52]. some have advocated that in individuals with left-sided renal tumors, preoperative arterial embolization may be beneficial due to the limited access to the left renal artery while the patient is in the flank position with the right figure 4. radical nephrectomy with thrombectomy in ct3bn0m0 rcc of the right kidney with large intraatrial level iv tumor thrombus 4a. ct scan shows large intraatrial thrombus. 4b. surgical specimen: right kidney with tumor thrombus removed en bloc. 4c. suture line on the intrapericardial ivc ending at the cavoatrial junction. 457siuj.org siuj • volume 3, number 6 • november 2022 management of locally advanced renal cell carcinoma http://siuj.org side up[57]. regardless of the tumor laterality and the decision regarding embolization, the “thrombus first” approach is necessary: the ivc thrombectomy should be completed prior to nephrectomy. most surgeons performing minimally invasive ivc thrombectomies prefer a transperitoneal approach. applied in both pure laparoscopic and robot-assisted techniques, a transperitoneal approach may be used for thrombi associated with both rightand left-sided renal tumors[57,58]. regardless of the laterality of the renal mass, the patient is placed in the left lateral decubitus position with the right side up. a12-mm camera port is inserted with additional three or four ports placed in a paramedian or mid-clavicular vertical line. typically, one small port is placed at the sub-xiphoid region for liver retraction as well as an additional 12-mm assistant port[52,57,62,63]. the dissection is begun with an incision to the posterior peritoneum, followed by mobilization of the colon medially, duodenal kocherization, and exposure of the ivc and the renal vessels[51,52,61–66]. minimally invasive level 0-i-ii thrombectomy early arterial ligation may help to slightly reduce the size of the thrombus. ligation of the renal artery (with either an endo-gia stapler or hem-o-lok clips) may be performed at the hilum or in the interaortocaval space. for thrombi limited to the renal vein, the latter may become f lattened and allow for the thrombus to be “milked” away from the ivc. an interoperative us is helpful to identify of the extent of the thrombus[58,67]. for left-sided level i tumor thrombi, one should consider doing the surgery in the right lateral decubitus (if th e thrombus appears that it can be milked away from the ivc). for ivc thrombi projecting less than 2 cm into the ivc, dissection of the contralateral renal vein and preplacement of a vessel loop with a secured hem-o-lock clip (rummel tourniquet) for later identification and cinching is often performed[68]. simple use of laparoscopic bulldogs can be safely performed to cross-clamp the cava and contralateral vein[66]. figure 5. en bloc resection of the ivc with rcc and associated caval thrombus lrv ivc bifurcation main hepatic veins 5a. schema. 5b. surgical specimen: resected ivc with tumor thrombus en bloc with the kidney. resected ivc: pink arrow; tumor thrombus: blue arrow. ivc: inferior vena cava; lrv: left renal vein; rcc: renal cell carcinoma. 458 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org similar to level 0 thrombi, vtt exclusion with excision of a small ivc cuff surrounding the renal vein ostium may be employed via the laparoscopic satinsky clamp and vascular stapler[52,69]. for larger level i and level ii thrombi, the ivc must be cross-clamped and the right adrenal vein may require ligation. for right-sided thrombi, rummel tourniquets or the vascular bulldogs should be cinched in the following order: (1) infrarenal ivc, (2) left renal vein, and (3) suprarenal ivc. for left-sided thrombi, the right renal artery should also be controlled with a vascular bulldog to prevent right renal engorgement[62]. incision of the ivc is performed until the cephalad extent of the thrombus is delivered. the renal vein is circumferentially excised at the level of the ostium of the ivc. upon thrombus removal, irrigation of the ivc lumen with heparinized saline is performed[52,55,60,69]. closure of the ivc with 4–0 prolene sutures in a single layer allows for excellent hemostasis. minimally invasive level iii thrombectomy initially performed by bratslavsky and cheng in march of 2013 for an 11-cm ivc thrombus, this surgery remains technically demanding and dangerous[51]. incision of the right triangular ligament and cephalad retraction of the liver will expose the retrohepatic ivc. short hepatic veins from the caudate lobe can be ligated using laparoscopic clips[51,56]. rummel tourniquets are cinched in the same order as in cases of level ii thrombi. for left-sided thrombi, transecting the ipsilateral renal vein with an endo-gia vascular stapler is often employed, as the rest of the left renal vein will be removed with the specimen[57]. upon en bloc thrombus removal with the renal vein stump closure of the cavatomy is performed with restoration of blood flow via the ivc. the patient is then repositioned and the left nephrectomy is completed. results of surgical management of rcc with vtt invasion of the venous system by rcc has long been associated with a poor prognosis[70]. however, the ability to provide a durable cure for some rcc patients provided a rationale for aggressive surgical management[71]. a systematic review of surgery for rcc with ivc thrombus cited major perioperative complication rates as high as 70% and perioperative mortality rates ranging from 3% to 16%[72]. most data demonstrate increased mortality as thrombus height increases, with higher mortality observed in patients with ivc thrombus that extends above the diaphragm or above the hepatic conf luence of veins (neves/mayo level iii and iv)[14]. early mortality rates from notable studies range from 8% to 22%[8,11,12,73–76]. no difference in mortality was observed between centers or among patients treated with cardiopulmonary bypass, similar to later reports[73]. hospital volume and surgeon volumes are associated with early mortality[77–79]. patients with metastatic rcc have a significantly worse prognosis compared to locally advanced rcc, with a cumulative mortality of 32% in the 9 months following surgery for metastatic patients[80]. perioperative complications in population-level data, toren et al. estimated the overall complication rate to be 78% in 633 patients treated with nephrectomy and ivc thrombectomy, including a 37% rate of surgical complications[79]. similar overall rates of complications have been reported at large centers[72,81], with blute et al. demonstrating that 30-day complication rates varied from 9% to 30% stratifying from thrombus level 0 to iv[28]. commonly reported intraoperative complications include hemorrhage, injury of adjacent structures, and cardiac events[28]. tumor thrombus embolization is a feared complication that occurs in 1.5% of patients and is associated with a reported 75% risk for mortality[82]. early postoperative complications include hemorrhage requiring transfusion, venous thromboembolic events, cardiac events, pulmonary events, renal failure, and infectious complications. late complications may include lower-extremity edema, chronic renal insufficiency, and incisional hernia[28]. independent predictors of major complications include preoperative systemic symptoms (weight loss or fatigue) and thrombus level[83]. use of cardiac bypass or deep hypothermic cardiac arrest was not identified as a predictor of major complications in this study[83] or subsequent analyses[73]. complication rates are lower at higher-volume centers[77] and with more experienced surgeons[79]. oncologic outcomes managed expectantly, rcc with vtt is associated with a median survival of 5 months with increased risk for cancer-specific mortality observed with pt3b/c and metastatic disease[84]. in a population-based study of patients treated with nephrectomy and venous tumor thrombectomy, 1-year overall survival in patients with localized disease was 90%[85]. a 5-year, cancer-specific mortality in patients with rcc and vtt ranges from 40% to 60%[28,86–88]. prognostic factors associated with cancer-specific mortality include increasing level of vtt, nodal and systemic metastases, advanced fuhrman grade, non-clear cell histology, and increasing tumor size[10,81,82,86,89–91]. 459siuj.org siuj • volume 3, number 6 • november 2022 management of locally advanced renal cell carcinoma http://siuj.org conclusion renal cell carcinoma with venous thrombus provides a fascinating example of seemingly implausible tumor biology. although these aggressive tumors have acquired the ability to invade and shed tumor cells into the largest blood vessel in the human body, some patients do not develop metastatic disease and may be cured when treated with definitive, aggressive surgery resulting in complete extirpation. surgery for rcc with venous thrombus is complex and requires experienced multidisciplinary surgical, anesthesia, and critical care teams at high-volume centers to achieve ideal 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the société internationale d'urologie, canada. key words competing interests article information gonadotropin-releasing hormone, cardiovascular disease, myocardial infarction, androgen deprivation therapy, leuprolide, gonadotropin-releasing hormone agonist, androgen deprivation therapy antagonist laurence klotz has no competing interests to declare. stephen van komen and sanja dragnic are employees of and own stock in abbvie. william b. white has received personal fees for cardiovascular drug safety consulting (including data safety monitoring boards, cardiovascular endpoint committees, and data analysis) to abbvie, alnylam, astrazeneca, bristol-myers squibb, jazz, marius, mylan, takeda-millennium, and tersera. he also receives royalties from wolters kluwer as an editor of uptodate funding abbvie (north chicago, il) sponsored the editorial assistance for this review and approved the final version. no honoraria and payments were made for authorship. received on april 6, 2022 accepted on may 2, 2022 this article has been peer reviewed. soc int urol j. 2022;3(4):259–275 doi: 10.48083/ vdnp9678 259siuj.org siuj • volume 3, number 4 • july 2022 review impact of androgen deprivation therapy on cardiovascular outcomes in prostate cancer laurence klotz,1 stephen van komen,2 sanja dragnic,3 william b. white4 1 division of urology, sunnybrook health sciences centre, toronto, canada, 2abbvie, mettawa, united states 3abbvie, north chicago, united states 4calhoun cardiology center, university of connecticut school of medicine, farmington, united states abstract purpose substantial evidence indicates that men with prostate cancer are at an increased risk for cardiovascular disease, and medical and surgical androgen deprivation therapy is associated with further increased cardiovascular risk. there are conflicting reports of differences in cardiovascular safety between gonadotropin-releasing hormone (gnrh) agonists and antagonists. the purpose of this narrative review is to compare data on the cardiovascular risks and safety outcomes associated with different hormonal treatment options in prostate cancer patients and to provide guidance on how to manage the increased risk associated with the condition. methods a pubmed search was conducted for papers published in the last 15 years using the following mesh terms: “prostate neoplasms,” “gonadotropin-releasing hormone,” “androgen agonist,” “androgen antagonists,” “cardiovascular disease,” “epidemiology.” results evidence regarding the risk of cardiovascular events during treatment with gnrh agonists and antagonists is conflicting. some retrospective studies have shown that agonists are associated with a greater risk of cardiovascular disease and cardiovascular mortality and morbidity, and a similar risk with agonists and combined androgen blockade. some studies have reported that antagonists are associated with a decreased risk of cardiovascular mortality and morbidity compared with agonists. with respect to coronary heart disease, ischemic heart disease, myocardial infarction, stroke, or sudden cardiac death, current evidence has failed to demonstrate a significant difference between antagonists and agonists. cardiovascular risks in patients should be mitigated by regular monitoring of blood pressure, blood glucose, and lipids, as well as counseling patients to abstain from alcohol and improve their diet and exercise. statins, metformin, and aspirin should also be considered. conclusions t he ev idence for t he i ncreased cardiovascular risk of gnrh agonists over antagonists for androgen deprivation therapy is unclear. differences in methodology, population sizes, risk stratification, and outcomes between studies make direct comparisons problematic. the single prospective, randomized prostate cancer trial with a primary cardiovascular end point in men with pre-existing cardiovascular disease comparing gnrh agonist to antagonist was stopped early due to an interim futility analysis. the results are inconclusive. introduction the burden of prostate cancer (pca) is expected to increase owing to natural growth and aging of the global population[1]. because of the high incidenceto-mortality ratio of pca, cardiovascular (cv) disease (cvd) is the leading cause of death in these men[2,3]. aside from the high prevalence of slow-growing malignancy, there is substantial evidence that men with pca are at an increased risk for cvd because of comorbid risk factors[4,5]. an analysis of the surveillance, epidemiology and end results (seer) program of the us national cancer institute, a network of population-based incident tumor registries, showed that men with pca had a higher risk of cvd and cvd than the average us resident, after adjusting for age, race, and sex over the same period[4]. van hemelrijck et al. found that patients with pca on surveillance (n = 19 526) had an elevated standardized incidence ratio (sir) for all cvd subtypes (myocardial infarction [mi], arrhythmia, ischemic heart disease, heart failure, and stroke) compared with the general population[6]. the sir was greater in patients with no circulatory disease detected at baseline (range 1.15 to 1.49) for all subtypes except ischemic heart disease, which was more common in patients with circulatory disease at baseline. pca patients who have undergone surgical castration, or who are receiving medical androgen deprivation therapy (adt), are at particularly high risk for cvd[6]. a cross-sectional analysis of the united states veterans health administration population examined the association between cv risk factors in men with pca receiving adt versus those not receiving adt[7]. among the two-thirds of men who received cv risk factor assessments (blood pressure measurements, serum cholesterol levels, blood glucose levels), about half had ≥ 1 uncontrolled cv risk factor, and 30% of those were not receiving treatment for it. patients with pca who had a history of atherosclerotic cvd, whether taking adt or not, had about a 20% lower risk of having an untreated cv risk factor compared with those without a history of cvd or those who had no history of adt. patients on adt with no history of cvd had a 5% lower risk for an untreated cv risk factor compared with patients with a cvd history who were adt-naïve[7]. this ref lects the tendency for patients who have had a history of cvd to have more intensive management of their cv risk factors than those with no prior history. these data suggest that patients receiving adt are at risk for the unrecognized development of cvd or cv-related mortality. whether the association between adt and cvd is because of differential patient monitoring or because of adverse effects of adt (or both) remains an unanswered question. cv risks in men with pca are driven by a number of factors, including age (which might itself predict underlying health conditions), high-fat diet, visceral adiposity and low levels of high-density lipoprotein (hdl), pre-existing cv risk factors, and metabolic syndrome[2,8–10]. recently, there have been studies reporting differences in cv safety between gonadotropin-releasing hormone (gnrh) agonists and antagonists, with mixed results[11–14]. some studies report differences in cv safety between gnrh agonists and antagonists in patients with pre-existing cvd, whereas others show no differences. several mechanisms have been proposed to explain cv safety differences between gnrh agonists and antagonists, such as differences in follicle-stimulating hormone levels, and the interaction between the agonists and gnrh receptors in endothelial plaque macrophages. these hypothesis-generating explanations remain speculative. the only randomized prospective study with cv event endpoints was closed early after an interim analysis because of a very low probability that a difference would be observed between agonists and antagonists (futility analysis)[12]. the purpose of this review is to elucidate the data on the cv risks and safety outcomes associated with different adt options in patients with pca and to consider strategies for mitigation of their cv risk. abbreviations adt androgen deprivation therapy cvd cardiovascular disease gnrh gonadotropin-releasing hormone mi myocardial infarction pca prostate cancer sir standardized incidence ratio 260 siuj • volume 3, number 4 • july 2022 siuj.org review search method a search was conducted using pubmed, and articles published after 2006 were included in the initial search. this allowed for research published in the past 15 years to be eligible for inclusion in the literature review. the search method is shown in figure 1. after selection, 71 papers were included in this review. cv risks reported with adt a landmark population-based study by keating et al. (n = 73 196) using retrospective data obtained from the seer database demonstrated that gnrh agonists were associated with a significantly increased risk of coronary heart disease (chd), mi, and sudden cardiac death compared with adt-naïve adult men ≥ 66 years of age with local or regional pca. chd was defined as an inpatient admission with a primary or secondary diagnosis code of ischemic heart disease or mi. sudden cardiac death was defined as a primary or secondary diagnosis code of sudden death or life-threatening ventricular arrhy thmia. using cox proportional hazard models and accounting for patient and tumor characteristics, the adjusted hazard ratios (ahrs) were 1.16 (p < 0.001), 1.11 (p = 0.03), and 1.16 (p = 0.004) for chd, mi, and sudden cardiac mortality, respectively, when using a gnrh agonist. furthermore, patients given gnrh agonists showed a significantly increased risk of chd after only 1 to 4 months of treatment (ahr, 1.14; p = 0.007) compared with patients not receiving adt. this risk stayed elevated as treatment duration continued for 5 to 12 months (ahr, 1.19; p < 0.001), 13 to 14 months (ahr, 1.11; p = 0.04), and ≥ 25 months (ahr, 1.18; p = 0.001)[15]. these results led to a 2010 joint statement from the american urological association, the american society for radiation oncology, and the american heart association alerting clinicians to a potential relationship between adt and cvd risk[16]. the us labels for gnrh agonists were revised to add a safety statement stating that an increased risk of mi, sudden cardiac death, and stroke has been reported in association with use of gnrh analogs in men. the safety statements emphasize the importance of monitoring for the development of cvd and managing patients appropriately[17–20]. figure 1. literature search records identied through pubmed database searching the following mesh terms: prostate neoplasms, gonadotropin releasing hormone, androgen antagonists, androgen agonists, cardiovascular disease, epidemiology additional records identi�ed via in-text citations (n=23) records screened (n = 137) full-text articles assessed for eligibility (n=48) papers included in review (n=71) records excluded (n=89) publication year earlier than 2006 (n=34) no safety/cv data, abstract only, no gnrh agonist/antagonist-speci�c data (n=55) 261siuj.org siuj • volume 3, number 4 • july 2022 impact of androgen deprivation therapy on cardiovascular outcomes in prostate cancer quantifying the cv risk of adt and the importance of pre-existing cvd several studies suggest that patients with pre-existing cvd are particularly at risk from the cv effects of adt. gandaglia et al. found a 5-year cumulative cv mortality estimate of 14.8% in patients with metastatic pca receiving adt (ie, gnrh agonist and/or bilateral orchiectomy) with underlying cv risk factors versus 9.8% in those without baseline cv morbidities. of the 9596 men on adt, 31.8% had cv comorbidities (n = 3049) at baseline, and 1083 cv mortality events (11.3%) were recorded. pre-existing cvd is the strongest predictor of cv mortality risk and warrants maximizing cv risk factor control before initiating adt[21]. a similar observational study, also by gandaglia et al.[22] assessed the 10-year cumulative incidence rates of chd, mi, and cv mortality in patients with non-metastatic pca. after propensity score matching and stratifying patients according to treatment type, the study found that patients using gnrh agonists (n = 28 988) had significantly greater incidence (p < 0.001) of chd, mi, and cv mortality events of 26.9%, 16.6%, and 17.7%, respectively, compared with 25.1%, 14.8%, and 14.2%, respectively, for those not on adt (n = 29 984). a multivariable, competing-risks regression analysis of the score-matched gnrh agonist cohort identified a statistically significant (p < 0.001) rate increase in chd (ahr, 1.11), mi (ahr, 1.09), and cv mortality (ahr, 1.18)[22]. these rates parallel those seen in keating et al. (ahr, 1.16, 1.11, and 1.16, respectively) and reinforce the significance of adt-associated cv risks[15]. in contrast, a meta-analysis by zhao et al. in 2014 consisting of patients receiving adt (gnrh agonist, antiandrogens, orchiectomy, or a combination of 2 or more treatments) (n = 129 802) and non-adt users (n = 165 605) failed to find a significant relationship between adt and cvd development (17.8% and 16.0%, p = 0.06, respectively)[23]. they did, however, find a significant relationship between cvd and gnrh agonists taken alone (ahr, 1.19; p = 0.01) and gnrh agonists plus antiandrogens (ahr, 1.46; p = 0.04), but not with adt using antiandrogens alone (ahr, 0.95; p = 0.16). adt use was significantly associated with a rise in cv mortality (ahr, 1.17; p = 0.01) compared with non-adt use when the prevalence of cv mortality events was assessed (11.7% and 9.0%, respectively). gnrh agonists had a significantly higher risk of cv mortality compared with non-adt (ahr, 1.36; p = 0.004), although men on gnrh agonists plus antiandrogen or those who had undergone orchiectomy had an even higher risk (ahr, 1.44; p < 0.001 and ahr, 1.69; p = 0.03, respectively). although adt did not have a significant association with mi incidence (p = 0.14), it did show a positive relationship with the gnrh agonist subgroup (ahr, 1.20; p = 0.008). treatment with antiandrogens alone reduced the mi ahr to 0.88 (p = 0.002)[23]. nguyen et al. performed another meta-analysis (n = 2200) that compared patients with non-metastatic pca on gnrh agonists with those not on adt (n = 1941)[24]. in this meta-analysis, gnrh agonist was not associated with a significant increase in risk for cv mortality (n = 255 events; relative risk [rr], 0.93; p = 0.41). additional subgroup analyses of shortand long-term therapy, of supplemental therapy (ie, radiation), and of older age cohorts also failed to find an association between gnrh agonist use and a significant increase in cv mortality. the evidence regarding the cv risks of adt is thus inconclusive (table 1)[25,26]. various confounding factors have been proposed to explain the variability in these studies. these include (1) that adt is often used for patients who are not considered for curative treatment. men selected for adt are typically older or in worse overall health and thereby may have an increased risk of cv mortality, although an important exception is the use of adjuvant adt with radiation therapy; (2) the presence of unknown cvd risk factors in populations being studied is a potential confounder; and (3) patients with adt in clinical trials are more likely to be closely monitored (so more likely that cv issues are detected) and treated than those in the general population[27]. the aim of adt is to reduce serum testosterone levels to castrate levels (20 to 50 ng/dl); this promotes regression of the disease[28]. patients with testosterone levels of >20 ng/dl (> 0.7 nmol/l) over the first year of adt have a higher risk of dying, with an hr of 2.08 compared with those who have testosterone levels of < 20 ng/dl (< 0.7 nmol/l). for those whose level was > 50 ng/dl (> 1.7 nmol/l), the hr was higher still at 2.93[29]. cv risk with orchiectomy most studies of the effect of adt on cv health have grouped all patients receiving adt together, whether castration is surgical or medical. since all of these techniques achieve castrate levels of testosterone in most patients, the metabolic syndrome associated with adt occurs regardless of method. however, some pre-clinical and clinical data suggest that the cardiovascular effects of surgical castration are greater than with medical castration. in the hyperglycemic male apoe -/-:ins2 +/ akita mouse model, orchiectomy induced greater weight gain, higher bmi, and necrotic plaque at the aortic root compared with lhrh agonist and antagonist[30]. the clinical data are more equivocal. some studies that have addressed this question, but not all, have reported that men treated with surgical castration have a higher rate of cv disease than those treated with lhrh agonists[31–33]. 262 siuj • volume 3, number 4 • july 2022 siuj.org review table 1. summary of cv risk factors for patients receiving androgen deprivation therapy cv outcome adt effect gnrh agonista gnrh antagonist cabb references cvd, mace inconclusive • no difference between gnrh agonists and gnrh antagonists cardwell et al. (2020)[35] lopes et al. (2021)[12] wallach et al. (2021)[13] cvd, cv mortality and morbidity mixed • greatest risk with gnrh agonists among adt types (versus non-adt group) • unchanged to decrease in risk of cv mortality and morbidity (versus gnrh agonist group) • risk is similar between cab and gnrh agonists keating et al. (2006)[15] d’amico et al. (2008)[55] faris and smith (2010)[56] nguyen et al. (2011)[24] o’farrell et al. (2012)[57] zhao et al. (2014)[23] bosco et al. (2015)[58] lester and mason (2015)[59] zareba et al. (2016)[10] lopes et al. (2021)[12] wallach et al. (2021)[13] cvd, cv mortality and morbidity mixed • greatest risk with gnrh agonists among adt types (versus non-adt group) • unchanged to decrease in risk of cv mortality and morbidity (versus gnrh agonist group) • risk is similar between cab and gnrh agonists keating et al. (2006)[15] d’amico et al. (2008)[55] faris and smith (2010)[56] nguyen et al. (2011)[24] o’farrell et al. (2012)[57] zhao et al. (2014)[23] bosco et al. (2015)[58] lester and mason (2015)[59] zareba et al. (2016)[10] lopes et al. (2021)[12] wallach et al. (2021)[13] cad, ihd, and mi inconclusive increased risk (versus non-adt and non-prostate cancer groups) no significant difference in risk (versus gnrh agonist group) greater risk with cab compared with gnrh agonists faris and smith (2010)[56] scailteux et al. (2017)[34] lopes et al. (2021)[12] wallach et al. (2021)[13] cerebrovascular accidents inconclusive increased risk (versus non-adt and non-prostate cancer groups) no significant difference in risk (versus gnrh agonist group) no significant difference in risk (versus gnrh agonist and nonadt groups) keating et al. (2006)[15] meng et al. (2016)[60] scailteux et al. (2017)[34] sudden cardiac death inconclusive increased risk (versus non-adt group) no data available no significant difference in risk (versus non-adt group) keating et al. (2006)[15] faris and smith (2010)[56] adt: androgen deprivation therapy; cab: combined androgen blockade; cv: cardiovascular; cvd: cardiovascular disease; gnrh: gonadotropin-releasing hormone; ihd: ischemic heart disease; mace: major adverse cardiovascular event; mi: myocardial infarction. a some of the therapies evaluated in these studies were goserelin, histrelin, leuprorelin, and triptorelin. bcab: (gnrh agonist + antiandrogen) and antiandrogen (flutamide, bicalutamide, nilutamide). table adapted from gupta et al. 2018[61]. 263siuj.org siuj • volume 3, number 4 • july 2022 impact of androgen deprivation therapy on cardiovascular outcomes in prostate cancer cv risk with gnrh antagonists and agonists in addition to the general lack of clarity about the cvd risks of adt, there is an uncertainty as to whether the link between adt and cv events is primarily a function of the reduction in testosterone, or whether it is a specific effect related to the type of adt drug, specifically gnrh agonists versus antagonists[16,23]. the difference in cv risk associated with use of gnrh agonists and antagonists has been summarized in table 2. gnrh antagonists have been in clinical use since 2008 and have had a lower rate of use than their agonist counterparts. therefore, there are fewer data on their correlation with cvd. scailteux et al. performed a retrospective analysis of 2010 to 2013 french health reimbursement agency and french hospital discharge database data for adult men (≥ 18 years) with pca who were newly prescribed adt using a composite endpoint of “ischemic events” (mi or ischemic stroke, whichever came first after adt initiation). of the total studied population (n = 35 118), 71% of the patients received gnrh agonists versus 3.6% who received a gnrh antagonist. relative to gnrh antagonists, agonist use did not have a significantly higher mi risk profile (ahr, 1.17; 95% ci 0.48 to 2.86 antagonist versus agonist using cox proportional hazard model), nor an increased risk for ischemic stroke (ahr, 1.28; 95% ci 0.60 to 2.72 antagonist versus agonist). the overall mortality rate was the same for both agonists and antagonists (0.03 per 100 person-years), and incidence of ischemic events was lower for agonists (0.74 per 100 person-years) than for antagonists (0.87 per 100 person-years)[34]. albertsen et al.[14] measured cv mortality and cvd among patients using gnrh agonists (leuprolide or goserelin n = 837) and the antagonist degarelix (n = 1491) by table 2. study compilation of cv risk assessment with gnrh agonists and antagonists in men with prostate cancer study design cv results cv conclusions summary of cvd risk gnrh agonist versus gnrh antagonist/control reference observational study patients (n = 73 196) ≥66 years old first diagnosed with locoregional pca from 1992–1999 gnrh agonist use was associated with increased risk of the following: • cad: ahr, 1.16; p < 0.001 • mi: ahr, 1.11; p = 0.03 • scd: ahr, 1.16; p = 0.004 gnrh agonist use may be associated with an increased risk of cvd when compared to patients with untreated locoregional pca gnrh agonist > control keating et al. (2006)[15] retrospective study single institution, pooled data (n = 5077) from 1997 to 2006 of patients with pca clinical stage t1 to t3 n0 m0 agonist and antiandrogen use was not associated with an increased risk of cad (ahr, 1.04; p = 0.82). for those with cad-induced chf or mi, use was associated with an increased risk of all-cause mortality (ahr, 1.96; p = 0.04) no association with an increased risk of all-cause mortality in men with no comorbidity of cad, but was increased in those with cad morbidity inconclusive gnrh agonist = control nanda et al. (2009)[62] prospective study 1-year rct of leuprolide acetate versus degarelix (n = 504) the incidence of the most common event (ischemic heart disease) was lower in the degarelix group with 18 patients (4%) versus leuprolide group with 21 patients (10%) no significant differences were found in either treatment group. both have similar cv safety profiles inconclusive smith et al. (2010)[63] meta-analysis of randomized trials pooled patient data (n =141) from rcts from 1966 to 2011 of men with unfavorable-risk, non-metastatic pca cv mortality in patients receiving gnrh agonists versus control cohort (nonadt/delayed adt) was not significantly different (11% versus 11.2%; 95% ci, 8.3%–15.0%, respectively; rr, 0.93, p = 0.41) no association with gnrh agonist and increased risk of cvd inconclusive gnrh agonist = control nguyen et al. (2011)[24] retrospective study capsure registry patients (n = 7248) agonist showed 2-fold greater likelihood of cv mortality (hr, 1.94); however, patients treated with ww/as had >2-fold increased risk of cv mortality (hr, 2.46) patients matched on propensity to receive agonist did not show an association with cv mortality inconclusive gnrh agonist < ww/as punnen et al. (2011)[9] pooled data from prospective trials pooled analyses on cv incidence in patients (n = 1704) from 9 degarelix clinical trials cv events were 5.5 and 6.1 eventsa per 100 person-years, before and after degarelix treatment, respectively (hr, 1.10, p = 0.45). in men without established cvd, the event rate was numerically lower after the initiation of degarelix treatment (5.6 versus 4.3 per 100 person-years; hr, 0.77; p = 0.11) cvd rates were similar before and after degarelix treatment inconclusive gnrh antagonist = no gnrh antagonist treatment smith et al. (2011)[64] adt: androgen deprivation therapy; ahr: adjusted hazard ratio; cad: coronary artery disease; cv: cardiovascular; cvd: cardiovascular disease; gnrh: gonadotropin-releasing hormone; hf: heart failure; hr: hazard ratio; icd-10: international classification of diseases, 10th edition; mace: major adverse cardiovascular event; meddra: medical dictionary for regulatory activities; mi: myocardial infarction; pca: prostate cancer; rct: randomized controlled trial; scd: sudden cardiac death; ww/as: watchful waiting/active surveillance. acvd before and after degarelix initiation; belevated risks of arrhythmia (adjusted hr, 1.44; 95% ci 1.02 to 2.01) were observed only among patients with pre-existing cvd; cincludes gnrh agonists, gnrh antagonist (degarelix), oral antiandrogens, estrogens, and orchiectomy. 264 siuj • volume 3, number 4 • july 2022 siuj.org review table 2. study compilation of cv risk assessment with gnrh agonists and antagonists in men with prostate cancer study design cv results cv conclusions summary of cvd risk gnrh agonist versus gnrh antagonist/control reference observational study patients (n = 73 196) ≥66 years old first diagnosed with locoregional pca from 1992–1999 gnrh agonist use was associated with increased risk of the following: • cad: ahr, 1.16; p < 0.001 • mi: ahr, 1.11; p = 0.03 • scd: ahr, 1.16; p = 0.004 gnrh agonist use may be associated with an increased risk of cvd when compared to patients with untreated locoregional pca gnrh agonist > control keating et al. (2006)[15] retrospective study single institution, pooled data (n = 5077) from 1997 to 2006 of patients with pca clinical stage t1 to t3 n0 m0 agonist and antiandrogen use was not associated with an increased risk of cad (ahr, 1.04; p = 0.82). for those with cad-induced chf or mi, use was associated with an increased risk of all-cause mortality (ahr, 1.96; p = 0.04) no association with an increased risk of all-cause mortality in men with no comorbidity of cad, but was increased in those with cad morbidity inconclusive gnrh agonist = control nanda et al. (2009)[62] prospective study 1-year rct of leuprolide acetate versus degarelix (n = 504) the incidence of the most common event (ischemic heart disease) was lower in the degarelix group with 18 patients (4%) versus leuprolide group with 21 patients (10%) no significant differences were found in either treatment group. both have similar cv safety profiles inconclusive smith et al. (2010)[63] meta-analysis of randomized trials pooled patient data (n =141) from rcts from 1966 to 2011 of men with unfavorable-risk, non-metastatic pca cv mortality in patients receiving gnrh agonists versus control cohort (nonadt/delayed adt) was not significantly different (11% versus 11.2%; 95% ci, 8.3%–15.0%, respectively; rr, 0.93, p = 0.41) no association with gnrh agonist and increased risk of cvd inconclusive gnrh agonist = control nguyen et al. (2011)[24] retrospective study capsure registry patients (n = 7248) agonist showed 2-fold greater likelihood of cv mortality (hr, 1.94); however, patients treated with ww/as had >2-fold increased risk of cv mortality (hr, 2.46) patients matched on propensity to receive agonist did not show an association with cv mortality inconclusive gnrh agonist < ww/as punnen et al. (2011)[9] pooled data from prospective trials pooled analyses on cv incidence in patients (n = 1704) from 9 degarelix clinical trials cv events were 5.5 and 6.1 eventsa per 100 person-years, before and after degarelix treatment, respectively (hr, 1.10, p = 0.45). in men without established cvd, the event rate was numerically lower after the initiation of degarelix treatment (5.6 versus 4.3 per 100 person-years; hr, 0.77; p = 0.11) cvd rates were similar before and after degarelix treatment inconclusive gnrh antagonist = no gnrh antagonist treatment smith et al. (2011)[64] adt: androgen deprivation therapy; ahr: adjusted hazard ratio; cad: coronary artery disease; cv: cardiovascular; cvd: cardiovascular disease; gnrh: gonadotropin-releasing hormone; hf: heart failure; hr: hazard ratio; icd-10: international classification of diseases, 10th edition; mace: major adverse cardiovascular event; meddra: medical dictionary for regulatory activities; mi: myocardial infarction; pca: prostate cancer; rct: randomized controlled trial; scd: sudden cardiac death; ww/as: watchful waiting/active surveillance. acvd before and after degarelix initiation; belevated risks of arrhythmia (adjusted hr, 1.44; 95% ci 1.02 to 2.01) were observed only among patients with pre-existing cvd; cincludes gnrh agonists, gnrh antagonist (degarelix), oral antiandrogens, estrogens, and orchiectomy. continued on page 266 pooling data from 6 phase 3 prospective randomized trials (n = 2328). in men without pre-existing cvd, no differences in either the incidence of cardiac events or death form any cause was noted. in men with pre-existing cvd (n = 619), cox regression modeling revealed an rr reduction of 56% of cv event or death with use of degarelix compared with gnrh agonists within 1 year of therapy initiation (ahr, 0.44; p = 0.002). in contrast, in this post hoc analysis, there were no significant differences in the incidence of a non-fatal cardiac event or death identified in patients without pre-existing cv morbidities. follow-up was 1 year in 3 of the studies, and 3 months in the other 3. all of the recorded cv events occurred in the 3 longer studies of 12 months’ duration. importantly, these trials were not designed to evaluate cv risk, nor were the events adjudicated by clinical cv event reviewers for their veracity. the authors also stated that the quality of the study data was “subject to bias” (according to the cochrane collaboration’s tool) because both patients and study personnel were not blinded regarding which form of adt was administered. a retrospective database analysis by cardwell et al. compared the cvd risk rate of degarelix (n = 387) and gnrh agonists (including goserelin, leuprolide, triptorelin, and histrelin) use in men (n = 10 480) with newly diagnosed pca versus untreated patients receiving active surveillance or watchful waiting (n = 4903)[35]. using cox regression modeling, cardwell et al. determined that degarelix use had a 50% increased risk of cv events (71 events; ahr, 1.5; 95% ci, 1.2–1.9) compared with a 30% increased risk for gnrh agonists (2075 events; ahr, 1.3; 95% ci 1.2 to 1.4). gnrh agonists and degarelix continued to have an elevated cv event risk (20% to 50%) for both short-term (< 365 daily defined 265siuj.org siuj • volume 3, number 4 • july 2022 impact of androgen deprivation therapy on cardiovascular outcomes in prostate cancer table 2. study compilation of cv risk assessment with gnrh agonists and antagonists in men with prostate cancer study design cv results cv conclusions summary of cvd risk gnrh agonist versus gnrh antagonist/control reference pooled data from prospective randomized trials pooled patient data from 6 phase 3 prospective trials comparing gnrh agonists leuprolide or goserelin (n = 837) with antagonist degarelix (n = 1491) among patients with pre-existing cvd, the risk of cv events was significantly lower (56%) in the antagonist group versus the agonist group (hr, 0.44; p = 0.002). no difference in cv events for those without pre-existing cvd these data suggest a greater risk of cv events for those using agonist with pre-existing cvd in patients with non-metastatic pca gnrh agonist > gnrh antagonist albertsen et al. (2014)[14] pooled data from prospective randomized trials pooled patient data (n = 1925) from 5 trials in patients receiving degarelix and leuprolide or goserelin patients with underlying cvd at baseline (29.6%) showed a nonsignificant lower risk of death with degarelix versus gnrh agonist (hr, 0.40; p = 0.051) degarelix use may be associated with lower incidence of cvd in men with pre-existing cvd gnrh agonist > gnrh antagonist klotz et al. (2014)[65] meta-analysis of population-based observational studies 9 studies comparing gnrh agonists (n = 119 625) versus control (n = 150 975) in patients with locoregional and non-metastatic pca gnrh agonists were associated with an increased risk of cvd (hr, 1.19; p = 0.01) compared with control cohort receiving non-adt or ww/as adt is associated with a 10% increased cv risk. significantly increased risks of cv mortality were observed in gnrh cohorts gnrh agonist > control zhao et al. (2014)[23] prospective study large cohort (n = 7637) from healthcare records of patients who initially underwent active surveillance gnrh agonist was associated with an increased risk of hf (ahr, 1.81) in men without pre-existing cvdb gnrh agonist was associated with a greater risk of hf without any pre-existing cvd gnrh agonist > control haque et al. (2017)[66] prospective study (hero) randomized, open-label, phase 3 trial. compared patients with advanced pca (n = 930) who received relugolix (gnrh antagonist) or leuprolide (gnrh agonist) for 48 weeks the incidence of mace was 2.9% in the relugolix group and 6.2% in the leuprolide group (hr, 0.46) meddra query showed a lower risk of mace with relugolix over leuprolide. any-grade mace incidence was 2.9% for relugolix versus 6.2% for leuprolide. incidence of grade 3 or 4 mace was 1.3% for both relugolix and leuprolide. ischemic heart disease incidence was 4% for relugolix and 1.6% for leuprolide gnrh agonist > gnrh antagonist shore et al. (2020)[37] observational study utilized database to search icd-10 codes of patients with newly diagnosed pca with cv events (death or hospitalization due to cvd) (n = 20 216) adtc (includes gnrh agonists and antagonists) use had a 30% increase of cv events (ahr, 1.3; 95% ci 1.2–1.4). this reflected increases in cv events associated with gnrh agonists (ahr, 1.3) and degarelix (ahr, 1.5), but not bicalutamide monotherapy (ahr, 1.0) degarelix and gnrh agonists both increased risk of cv events inconclusive cardwell et al. (2020)[35] prospective study (pronounce) randomized, open-label, phase 3, assessor-blind, 12-month study in patients (n = 545) with advanced pca and atherosclerotic cvd treated with adt (degarelix or leuprolide) for 12 months. primary endpoint was time to occurrence of mace at 1 year primary endpoint: incidence of mace was 15 (5.5%) for degarelix group versus 11 (4.1%) for leuprolide (hr, 1.28; p = 0.53). composite endpoint of cv death, non-fatal mi, or non-fatal stroke occurred in 9 patients receiving degarelix and 7 receiving leuprolide (hr, 1.20; p = 0.71) no significant differences were found in either treatment group. both treatments have similar cv safety profiles inconclusive study terminated owing to futility lopes et al. (2021)[12] retrospective, propensity-matched cohort study designed to emulate the pronounce study. adult men with pca and cvd who initiated degarelix or leuprolide using deidentified administrative claims data. primary endpoint was time to first occurrence of mace primary efficacy outcome: incidence of mace was 10.18 per 100 personyears for degarelix group versus 8.6 per 100 person-years for leuprolide (hr, 1.18; p = 0.30). secondary endpoints: • death: 7.43 (degarelix) versus 4.99/100 person/y (leuprolide) (hr 1.48, p = 0.046) • mi: 2.18 per 100 person-years for degarelix versus 1.87 per 100 personyears for leuprolide (hr, 1.16; p = 0.66) • stroke: 1.72 per 100 person-years for degarelix versus 1.87 per 100 person-years for leuprolide (hr, 0.92; p = 0.81) • angina: < 11 events each for degarelix and leuprolide (hr, 1.36; p = 0.60) no significant differences were found in either treatment group no difference in mace wallach et al. (2021)[13] adt: androgen deprivation therapy; ahr: adjusted hazard ratio; cad: coronary artery disease; cv: cardiovascular; cvd: cardiovascular disease; gnrh: gonadotropin-releasing hormone; hf: heart failure; hr: hazard ratio; icd-10: international classification of diseases, 10th edition; mace: major adverse cardiovascular event; meddra: medical dictionary for regulatory activities; mi: myocardial infarction; pca: prostate cancer; rct: randomized controlled trial; scd: sudden cardiac death; ww/as: watchful waiting/active surveillance. acvd before and after degarelix initiation; belevated risks of arrhythmia (adjusted hr, 1.44; 95% ci 1.02 to 2.01) were observed only among patients with pre-existing cvd; cincludes gnrh agonists, gnrh antagonist (degarelix), oral antiandrogens, estrogens, and orchiectomy. , cont’d 266 siuj • volume 3, number 4 • july 2022 siuj.org review table 2. study compilation of cv risk assessment with gnrh agonists and antagonists in men with prostate cancer study design cv results cv conclusions summary of cvd risk gnrh agonist versus gnrh antagonist/control reference pooled data from prospective randomized trials pooled patient data from 6 phase 3 prospective trials comparing gnrh agonists leuprolide or goserelin (n = 837) with antagonist degarelix (n = 1491) among patients with pre-existing cvd, the risk of cv events was significantly lower (56%) in the antagonist group versus the agonist group (hr, 0.44; p = 0.002). no difference in cv events for those without pre-existing cvd these data suggest a greater risk of cv events for those using agonist with pre-existing cvd in patients with non-metastatic pca gnrh agonist > gnrh antagonist albertsen et al. (2014)[14] pooled data from prospective randomized trials pooled patient data (n = 1925) from 5 trials in patients receiving degarelix and leuprolide or goserelin patients with underlying cvd at baseline (29.6%) showed a nonsignificant lower risk of death with degarelix versus gnrh agonist (hr, 0.40; p = 0.051) degarelix use may be associated with lower incidence of cvd in men with pre-existing cvd gnrh agonist > gnrh antagonist klotz et al. (2014)[65] meta-analysis of population-based observational studies 9 studies comparing gnrh agonists (n = 119 625) versus control (n = 150 975) in patients with locoregional and non-metastatic pca gnrh agonists were associated with an increased risk of cvd (hr, 1.19; p = 0.01) compared with control cohort receiving non-adt or ww/as adt is associated with a 10% increased cv risk. significantly increased risks of cv mortality were observed in gnrh cohorts gnrh agonist > control zhao et al. (2014)[23] prospective study large cohort (n = 7637) from healthcare records of patients who initially underwent active surveillance gnrh agonist was associated with an increased risk of hf (ahr, 1.81) in men without pre-existing cvdb gnrh agonist was associated with a greater risk of hf without any pre-existing cvd gnrh agonist > control haque et al. (2017)[66] prospective study (hero) randomized, open-label, phase 3 trial. compared patients with advanced pca (n = 930) who received relugolix (gnrh antagonist) or leuprolide (gnrh agonist) for 48 weeks the incidence of mace was 2.9% in the relugolix group and 6.2% in the leuprolide group (hr, 0.46) meddra query showed a lower risk of mace with relugolix over leuprolide. any-grade mace incidence was 2.9% for relugolix versus 6.2% for leuprolide. incidence of grade 3 or 4 mace was 1.3% for both relugolix and leuprolide. ischemic heart disease incidence was 4% for relugolix and 1.6% for leuprolide gnrh agonist > gnrh antagonist shore et al. (2020)[37] observational study utilized database to search icd-10 codes of patients with newly diagnosed pca with cv events (death or hospitalization due to cvd) (n = 20 216) adtc (includes gnrh agonists and antagonists) use had a 30% increase of cv events (ahr, 1.3; 95% ci 1.2–1.4). this reflected increases in cv events associated with gnrh agonists (ahr, 1.3) and degarelix (ahr, 1.5), but not bicalutamide monotherapy (ahr, 1.0) degarelix and gnrh agonists both increased risk of cv events inconclusive cardwell et al. (2020)[35] prospective study (pronounce) randomized, open-label, phase 3, assessor-blind, 12-month study in patients (n = 545) with advanced pca and atherosclerotic cvd treated with adt (degarelix or leuprolide) for 12 months. primary endpoint was time to occurrence of mace at 1 year primary endpoint: incidence of mace was 15 (5.5%) for degarelix group versus 11 (4.1%) for leuprolide (hr, 1.28; p = 0.53). composite endpoint of cv death, non-fatal mi, or non-fatal stroke occurred in 9 patients receiving degarelix and 7 receiving leuprolide (hr, 1.20; p = 0.71) no significant differences were found in either treatment group. both treatments have similar cv safety profiles inconclusive study terminated owing to futility lopes et al. (2021)[12] retrospective, propensity-matched cohort study designed to emulate the pronounce study. adult men with pca and cvd who initiated degarelix or leuprolide using deidentified administrative claims data. primary endpoint was time to first occurrence of mace primary efficacy outcome: incidence of mace was 10.18 per 100 personyears for degarelix group versus 8.6 per 100 person-years for leuprolide (hr, 1.18; p = 0.30). secondary endpoints: • death: 7.43 (degarelix) versus 4.99/100 person/y (leuprolide) (hr 1.48, p = 0.046) • mi: 2.18 per 100 person-years for degarelix versus 1.87 per 100 personyears for leuprolide (hr, 1.16; p = 0.66) • stroke: 1.72 per 100 person-years for degarelix versus 1.87 per 100 person-years for leuprolide (hr, 0.92; p = 0.81) • angina: < 11 events each for degarelix and leuprolide (hr, 1.36; p = 0.60) no significant differences were found in either treatment group no difference in mace wallach et al. (2021)[13] adt: androgen deprivation therapy; ahr: adjusted hazard ratio; cad: coronary artery disease; cv: cardiovascular; cvd: cardiovascular disease; gnrh: gonadotropin-releasing hormone; hf: heart failure; hr: hazard ratio; icd-10: international classification of diseases, 10th edition; mace: major adverse cardiovascular event; meddra: medical dictionary for regulatory activities; mi: myocardial infarction; pca: prostate cancer; rct: randomized controlled trial; scd: sudden cardiac death; ww/as: watchful waiting/active surveillance. acvd before and after degarelix initiation; belevated risks of arrhythmia (adjusted hr, 1.44; 95% ci 1.02 to 2.01) were observed only among patients with pre-existing cvd; cincludes gnrh agonists, gnrh antagonist (degarelix), oral antiandrogens, estrogens, and orchiectomy. 267siuj.org siuj • volume 3, number 4 • july 2022 impact of androgen deprivation therapy on cardiovascular outcomes in prostate cancer doses) and long-term use (≥ 365 daily defined doses). further analysis revealed that gnrh agonist only use had a statistically significant risk increase of 20% for developing an mi (ahr, 1.2; 95% ci 1.0 to 1.5) relative to untreated patients. they also found that gnrh agonist use in patients with baseline cv morbidities had a 20% increased risk for a cv event (ahr, 1.2; 95% ci 1.0 to 1.3). both gnrh agonists (ahr, 1.3; 95% ci 1.2 to 1.5) and degarelix (ahr, 1.8; 95% ci 1.3 to 2.6), however, had an elevated risk for cv events in patients without baseline cv morbidities relative to untreated patients. a recent meta-analysis by ma et al. of 6 controlled studies (4 rcts and 2 controlled clinical trials) concluded that the risk of cvd was the same for gnrh agonists as for gnrh antagonists for patients with pca[36]. the prospective phase 3 hero trial (n = 930) by shore et al. compared the gnrh antagonist relugolix with the gnrh agonist leuprolide and identified a lower incidence of major adverse cv events (mace) in the relugolix cohort[37]. however, the study was not powered to make distinctions in cv events. the reporting of cv events was based on a descriptive analysis of the non-adjudicated adverse events. the incidence of ischemic heart disease was reported as 2.4% for relugolix compared with 1.6% for leuprolide. the reported any-grade mace incidence was 2.9% for relugolix versus 6.2% for leuprolide. importantly, the incidences of grade 3 or 4 maces were identical (1.3%)[37]. because the incidence of mace grades 3 and 4 were identical between the 2 treatments and there was no adjudication by blinded clinical event reviewers, the clinical relevance of the difference in the incidence of all mace events with relugolix compared with leuprolide should be treated with caution. the reported difference in mace did not lead to a difference in castration resistance-free survival in the subgroup of men with metastatic disease treated with relugolix versus those treated with leuprolide (74% versus 75% of men, respectively; hr, 1.03, p = 0.84). maces were defined as non-fatal mi, non-fatal stroke, and all-cause mortality[37]. the us food and drug administration have historically defined maces differently, as non-fatal mi, non-fatal stroke, and mortality due to cv causes when labeling traditional adt drugs and testosterone replacement therapies[38]. the hero study[37], however, defined maces differently from the keating et al.[15] study and other phase 3 hormonal drug trials, making direct comparisons challenging[39,40]. a limitation of most adt studies is that they were not designed, or statistically powered, to evaluate cardiac events. rather they were reported as adverse events and may not have been comprehensive[14]. directly comparing studies is also hindered by differences in methodology, risk stratification, and assessed outcomes. the cardwell et al. analysis comparing 6 studies acknowledged incomplete patient data sets (stage, gleason score, lifestyle) that may have confounded the results. medication adherence was determined via dispensing record, so actual adherence cannot be confirmed. additionally, patients receiving adt would have had increased monitoring and therefore there would have been an increased likelihood of cvd being identified[35]. in scailteux et al., the composite outcome of “ischemic events” (mi or ischemic stroke, whichever came first) does not account for clinical differences among subgroup analyses (eg, mi and stroke are considered equal), and no significant heterogeneity was observed across these subgroups[34] this approach may have its limitations because a direct study comparison cannot be performed[36]. the lopes et al. pronounce study was designed to determine whether there was a significant difference favoring gnrh antagonists versus agonists in patients with pre-existing cvd, as hypothesized from the retrospective albertsen et al. meta-analysis described previously[12]. it was the first prospective, randomized cv outcomes study of men with advanced pca receiving adt. unlike most other trials to date, including the hero trial, there was a clinical event classification committee, composed of a cardiologist, a neurologist, and an oncologist, whose purpose was to provide independent, blinded adjudication of maces throughout the trial, as is the common standard for cv outcomes trials. in addition, the investigators were required to ensure that a cardiologist was treating the enrolled participant so that their cvd treatment was optimized. the primary outcome was the time from randomization to first occurrence of centrally adjudicated mace. key secondary outcomes were the time to first occurrence of cv-related death, non-fatal mi, or non-fatal stroke; time to first occurrence of cv-related death; and time to first occurrence of mi. the study had markedly fewer than expected mace events. sixty-six mace events were required to reject the null hypothesis of equal hazard for degarelix and leuprolide. hence, the study was terminated early after the enrollment of 545 participants (61% of the planned 900) owing to futility. the total number of mace events recorded over 12 months was 26: 15 (5.5%) for degarelix, and 11 (4.1%) for leuprolide (p = 0.53). thus, even if completed with full accrual, the study likely would have had insufficient statistical power to compare the relative cv safety of the 2 treatments with precision. the number of events for the secondary outcomes was also very low, and there were no significant differences between treatments for any of these outcomes. a similar study by wallach et al. was designed to replicate the pronounce trial, but using retrospective data from health care insurance claims[13]. this study could not replicate many features of the original prospective trial, including the assurance of having 268 siuj • volume 3, number 4 • july 2022 siuj.org review cardiologist involvement and adjudicated events, but used proxy selection criteria and outcomes to try to replicate it as closely as possible. the results from this realworld study are supportive of those in pronounce. among propensity-matched patients (n = 2226), no significant difference was observed in the risk of maces (defined as a composite endpoint of death from any cause, mi, or stroke) between degarelix and leuprolide (10.18 versus 8.60 events per 100 person-years; hr, 1.18; p = 0.30). degarelix was associated with a higher risk of death from any cause (hr, 1.48; p = 0.046) but not of mi (hr, 1.16; p = 0.66), stroke (hr, 0.92.; p = 0.81), or angina (hr, 1.36; p = 0.60). in summary, the sole randomized, prospective cv outcome study did not demonstrate a difference in cv risk between gnrh agonists and antagonists. the event rate in this study was too low to provide sufficient power to identify a difference, and the evidence remains inconclusive. it is possible that the low event rate reflected the optimization of cv care provided to the patients in the trial. management of cv risks in men with pca who are receiving adt patients with pca who have undergone surgical castration, or are receiving medical adt, are at particularly high risk for cvd[6]. because of comorbid risk factors, men with pca have a higher risk of cvd even if they are not receiving adt[5,7], and those who have undergone surgical or medical castration with adt are at an even higher risk for cvd and cv mortality[6]. although many of the cv risks in men with pca can be mitigated by controlling the underlying comorbid risk factors, recent data indicate that many are not being controlled[7]. in the recent veterans health administration study, about half the population of men with pca who were receiving adt and who had been assessed had ≥ 1 uncontrolled cv risk factor, and almost one-third of those with important cv risk factors were not receiving treatment to control their cv risk factors, suggesting that pca patients receiving adt are not being adequately assessed or their underlying risk factors treated for cvd in accordance with the various consensus recommendations[7]. in addition to potentially undesirable side effects, such as decreased libido, impotence, decreased muscle mass, increased fat mass, anemia, fatigue, and osteoporosis, changes in patient body composition as a result of medical castration create the potential for more severe metabolic complications and cv morbidities. for instance, the increase of adipose tissue and body weight in patients receiving adt could be associated with rising insulin levels; insulin resistance; and an elevation in hdl, low-density lipoprotein (ldl), and triglycerides. these conditions predispose individuals to diabetes and cv events (figure 2)[41]. adt, by reducing androgen levels, is thought to reduce the androgen-mediated inhibition of stem cell differentiation into adipocytes, thereby increasing visceral and subcutaneous fat and decreasing lean body mass[42]. this is a factor that may increase obesity and fat mass, which also contribute to insulin resistance and metabolic syndrome[10]. adt may be associated with an increase in arterial wall thickness and endothelial dysfunction as a result of low testosterone levels; this change in vascular structure could promote atherosclerosis and could, eventually, lead to plaque rupture (figure 3)[41]. many associations have developed recommendations regarding assessment of baseline cvd in men initiating adt[43–47]. most guidelines offer generic advice. men with cv comorbidities are encouraged to discuss treatment options with their care providers[41]. risk mitigation strategies include an assessment of the patient’s cv health before the initiation of adt and during treatment; frequent monitoring of blood pressure, blood glucose levels, and lipid profile; diet and regular exercise; cessation of smoking; and reduction in alcohol consumption (figure 4). the american heart association (aha) recommends that adt users be treated with antihypertensive therapy to lower blood pressure to < 130/80 mmhg, as dictated by specific comorbidities, and with glucose-lowering therapies in prediabetic and diabetic individuals. the aha also recommends low-dose aspirin therapy and statin therapy to reduce serum ldl levels to < 100 mg/dl[16]. the national comprehensive cancer network also recommends that patients receiving adt should be treated with statins and undergo frequent screening and monitoring for metabolic and cv disorders[48]. in a large observational study (n = 87 346) of men with advanced pca being treated with adt, anderson-carter et al. showed that those taking statins had longer overall survival (median, 6.5 years versus 4.0 years; p < 0.001) and decreased death from cancer (5-year pca-specific survival [94.0% versus 87.3%; p < 0.001]) than those who were not statin users[49]. another study of patients starting adt showed that statin use was associated with reduced hrs for overall mortality and pca-specific mortality[50]. statins may exert their effect by competitively binding to the organic anionic transporter slco2b1, which decreases the level of dehydroepiandrosterone sulfate (a precursor of androgens such as dihydrotestosterone), thereby depriving the tumor of endogenous androgens[51]. interventional studies have also found potential benefits in the use of metformin combined with lifestyle changes in men receiving adt. the rationale for its use is based on its ability to reduce hyperinsulinemia and improve metabolic syndrome. a systematic review and meta-analysis of 30 cohort studies in patients with pca 269siuj.org siuj • volume 3, number 4 • july 2022 impact of androgen deprivation therapy on cardiovascular outcomes in prostate cancer (n = 1 660 795) concluded that metformin treatment improves overall survival (hr, 0.72; p = 0.001), pca-specific survival (hr, 0.78; p = 0.001), and recurrence-free survival (hr, 0.60; p = 0.001) compared with non-metformin treatment[52]. the risk reduction was also seen in those patients receiving adt who had an overall survival hr of 0.77 and a pca-specific survival of 0.72 (p < 0.00001 for both)[52,53]. metformin use has also led to improvements in abdominal girth in men with pca after 6 months of adt treatment compared with the control population (mean 0.58% reduction for metformin group versus 2.15% increase for the control), as well as in weight (3.19% decrease versus 2.18% increase), body mass index (3.15% decrease versus 2.10% increase), and systolic blood pressure (5.96% decrease versus 1.77% increase)[54]. conclusions men with pca have a higher risk for cvd than those without pca, and there is substantial evidence that adt increases this risk, although the evidence is not conclusive. in these men, cv history and the cv risk factors that may trigger a mace should be evaluated and steps taken to mitigate them. the published cv risk data for gnrh agonists and antagonists are inconsistent and ref lect different populations, sizes, and study designs. the only rigorous, prospective, randomized 270 siuj • volume 3, number 4 • july 2022 siuj.org review figure 2. interconnections between hypogonadism and cardiovascular risk factors on atherosclerosis development hypogonadism is associated with several risk factors of atherosclerosis (obesity, type 2 dm, dyslipidemia, and hypertension). imt is a known marker of early atherosclerosis. hypogonadism increases inflammation and affects endothelial function through other mechanisms of pathogenesis. low testosterone increases the risk of myocardial ischemia. erectile dysfunction is a symptom of hypogonadism, but also an end result of atherosclerosis and a predictor of coronary artery disease. red boxes = atherosclerotic risk factors; dark green boxes = potential side effects of either hypogonadism or atherosclerosis. cad: coronary artery disease; crp: c-reactive protein; dm: diabetes mellitus; epc: endothelial progenitor cell; imt: intima-media thickness; vcam: vascular cell adhesion molecule. reproduced with permission from fahed ac, gholmieh jm, azar st. int j endocrinol.2012;2012:793953)[67] imt hypogonadism hypertension dyslipidemia type ii dm obesity erectile dysfunction atherosclerosis cad myocardial ischemia inflammatory cytokines, crp, vascular endothelial factors, vcam, epcs trial comparing cv events for men with pre-existing cvd receiving a gnrh agonist or antagonist was inconclusive over the time period studied, and the study was discontinued owing to there being insufficient events to achieve adequate power. there is currently no prospective study that will resolve this issue. although the data are conf licting, both gnrh agonists and antagonists are associated with increased cvd and cv mortality, but no randomized controlled trial (versus pooled approaches) supports the hypothesis of a cv risk difference between gnrh agonists and antagonists. an important factor to mitigate potential adverse events associated with receiving adt is to promote patient awareness of the increased risk of cvd and to provide education on how to improve cv health. this includes careful monitoring and lowering of blood pressure, glucose levels, and total and ldl cholesterol levels by making appropriate lifestyle changes and by using statins for hyperlipidemia. however, the focus of cv risk in people with pca should be mitigation strategies with individualized treatment options addressed by experienced cardiologists or cardio-oncologists working with urologists and oncologists. acknowledgments editorial support was provided by connor hunter, pharmd, and robin smith, phd, of the curr y rockefeller group, llc (tarrytown, ny), and was funded by abbvie (north chicago, il). additional thanks go to gabriel krigsfeld, phd, of abbvie (mettawa, il), for providing support in the writing of the paper. 271siuj.org siuj • volume 3, number 4 • july 2022 impact of androgen deprivation therapy on cardiovascular outcomes in prostate cancer figure 3. clinical measurements and resultant mechanistic processes in the relation between hypogonadism and specific stages of atherosclerosis =increase; =decrease. bp: blood pressure; crp: c-reactive protein; cvd: cardiovascular disease; dm ii: type 2 diabetes mellitus; ed: erectile dysfunction; epc: endothelial progenitor cell; fmd: flow-mediated dilation; hdl: high-density lipoprotein; imt: intima-media thickness; ldl: low-density lipoprotein; mets: metabolic syndrome; tg: triglyceride; vcam: vascular cell adhesion molecule. reproduced with permission from fahed ac, gholmieh jm, azar st. int j endocrinol. 2012;2012:793953).[67] ruptured plaque mature plaque clinical measurements dyslipidemia obesity mets dm ii hypertension plaques on carotid duplex scan hypogonadism and atherosclerosis �fmd �crp �imt �st depression �exercise tolerance �cvd �ed �mortality �anginal episodes mechanisms lipid deposition endothelial dysfunction myocardial susceptibility to ischemia �ldl �tg �hdl �lipoprotien a �bp �epcs �vcam �vascular tone �anti-inflammatory cytokines insulin resistance �pro-inflammatory cytokines normal artery early plaque 272 siuj • volume 3, number 4 • july 2022 siuj.org review figure 4. cvd risk mitigation and recommended management for men receiving adt adt: androgen deprivation therapy; bp: blood pressure; css: cancer-specific survival; cvd: cardiovascular disease; hba1c: hemoglobin a1c; hdl: high-density lipoprotein; ldl: low-density lipoprotein; os: overall survival; psa: prostate-specific antigen; tg: triglyceride; ttp: time to progression. 1. rhee et al. 2015[27] 2. bhatia et al. 2016[8] 3. schmitz et al. 2010[68] 4. galvão et al. 2016[69] 4. anderson-carter et al. 2019[49] 5. hamilton et al. 2021[50] 6. saraei et al. 2019[70] 7. alghandour et al. 2020[71] 8. he et al. 2019[52] 9. harshman et al. 2015[51] measure regular blood pressure, weight, fasting glucose, and ipid profile levels at baseline1,2 lifestyle and dietary modifications1-3 treatment management • hypertension • chronic obstructive airway disease • renal impairment maintain optimal blood glucose level • aim for hba1c 7% smoking cessation minimize or avoid alcohol maintain lipid profilemaintain optimal blood pressure • bp <130/80 mm hg • ldl <100 mg/dl • hdl = 40 mg/dl or higher • tg <150 mg/dl • non-hdl cholesterol <130 mg/dl diet and exercise • refer to dietitian, exercise physiologist, or weight loss expert • 150 minutes/week moderate intensity, 75 min/week of vigorous exercise, resistance training frequent monitoring of blood pressure, blood glucose, lipid profile • history of myocardial infarction • history of cerebrovascular events • congestive heart failure • peripheral arterial disease assess patient awareness of signs and symptoms of cvd addition of statins may be beneficial4,5 • use of statin at the time of adt initiation signi cantly prolongs ttp • statin users had longer os, css and skeletal related events controlling for age, race, charlson comorbidity index, psa, and gleason score addition of metformin should be considered1–3,6–9 • reduces the damaging effects of adt physiologist, or weight loss expert • potentially lengthens time to progression when combined with adt • reduced weight gain, waist circumference, glucose, insulin levels consider 81 mg acetylsalicylic acid daily1,2 references 1. ferlay j, shin hr, bray f, forman d, mathers c, parkin dm. estimates of worldwide burden of cancer in 2008: globocan 2008. int j cancer.2010;127(12):2893-2917. doi:10.1002/ijc.25516 2. national cancer institute. cancer stat facts: prostate cancer. available at: https://seer.cancer.gov/statfacts/html/prost.html. accessed november 11, 2021. 3. siegel rl, miller kd, jemal a. cancer statistics, 2020. ca cancer j clin. 2020;70(1):7-30. doi:10.3322/caac.21590 4. sturgeon km, deng l, bluethmann sm, zhou s, trifiletti dm, jiang c, et al. a population-based study of cardiovascular disease mortality risk in us cancer patients. eur heart j.2019;40(48):3889-3897. doi:10.1093/eurheartj/ehz766 5. koene rj, prizment ae, 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circulationaha.115.012519 9. p u n n e n s, c o o p e r b e r g m r , s a d e t s k y n, c a r r o ll p r . androgen deprivation therapy and cardiovascular risk. j clin oncol.2011;29(26):3510-3516. doi:10.1200/jco.2011.35.1494 10. zareba p, duivenvoorden w, leong dp, pinthus jh. androgen deprivation therapy and cardiovascular disease: what is the linking mechanism? ther adv urol.2016;8(2):118-129. doi:10.1177/1756287215617872 11. ahmadi h, daneshmand s. androgen deprivation therapy for prostate cancer: long-term safety and patient outcomes. patient relat outcome meas.2014;5:63-70. doi:10.2147/prom.s52788. 12. lopes rd, higano cs, slovin sf, nelson aj, bigelow r, sørensen ps, et al. cardiovascular safety of degarelix versus leuprolide in patients with prostate cancer: the primary results of the pronounce randomized trial. circulation.2021;144(16):1295-1307. doi:10.1161/ circulationaha.121.056810 13. wallach jd, deng y, mccoy rg, dhruva ss, herrin j, berkowitz a, et al. real-world cardiovascular outcomes associated with degarelix vs leuprolide for prostate cancer treatment. jama netw open.2021;4(10):e2130587. doi:10.1001jamanetworkopen.2021.30587 14. albertsen pc, klotz l, tombal b, grady j, olesen tk, nilsson j. cardiovascular morbidity associated with gonadotropin releasing hormone agonists and an antagonist. eur urol.2014;65(3):565–573. doi:10.1016/j.eururo.2013.10.032 15. keating nl, o’malley aj, smith mr. diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. j clin oncol.2006;24(27):4448-4456. doi:10.1200/jco.2006.06.2497 16. levine gn, d’amico av, berger p, clark pe, eckel rh, keating nl, et al. androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the american heart association, american cancer society, and american urological association: endorsed by the american society for radiation oncology. ca cancer j clin.2010;60(3):194–201. doi:10.3322/caac.20061 17. abbvie inc. lupron-depot (leuprolide acetate for depot suspension): prescribing information full prescribing information. north chicago, il: abbvie, inc.; 2019. 18. foresee pharmaceuticals. camcevi (leuprolide) injectable emulsion, for subcutaneous use (prescribing information). https://w w w. accessdata.fda.gov/drugsatfda_docs/label/2021/211488s000lbl. pdf. accessed oct 10, 2021. 19. shore n, mincik i, deguenther m, student v jr, jievaltas m, patockova j, et al. a phase 3, open-label, multicenter study of a 6-month pre-mixed depot formulation of leuprolide mesylate in advanced prostate cancer patients. world j urol.2020;38(1):111-119. doi:10.1007/ s00345-019-02741-7 20. tolmar pharmaceuticals inc. eligard (leuprolide acetate) for injectable suspension, for subcutaneous use (prescribing information). https:// eligardhcp.com/sites/default/files/pdfs/eli_full_pi.pdf. accessed 13 july 2021. 21. gandaglia g, sun m, popa i, schiffmann j,trudeau v, shariat sf, et al. cardiovascular mortality in patients with metastatic prostate cancer exposed to androgen deprivation therapy: a population-based study. clin genitourin cancer.2015;13(3):e123-130. doi:10.1016/j. clgc.2014.12.003 22. gandaglia g, sun m, popa i, schiffmann j, abdollah f, trinh q-d, et al. the impact of androgen-deprivation therapy (adt) on the risk of cardiovascular (cv) events in patients with non-metastatic prostate cancer: a population-based study. bju int.2014;114(6b):e82-e89. doi:10.1111/bju.12732 23. zhao j, zhu s, sun l, meng f, zhao l, zhao y, et al. androgen deprivation therapy for prostate cancer is associated with cardiovascular morbidity and mortality: a meta-analysis of populationbased observational studies. plos one.2014;9(9):e107516. doi:10.1371/ journal.pone.0107516 24. nguyen pl, je y, schutz fa, hoffman ke, hu jc, parekh a, et al. association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials. jama.2011;306(21):2359-2366. doi:10.1001/jama.2011.1745 273siuj.org siuj • volume 3, number 4 • july 2022 impact of androgen deprivation therapy on cardiovascular outcomes in prostate cancer 25. melloni c, slovin sf, blemings a, goodman sg, evans cp, nilsson j, et al. cardiovascular safety of degarelix versus leuprolide for advanced prostate cancer. jacc cardiooncology.2020;2(1):70-81. doi:10.1016/j. jaccao.2020.01.004. 26. a trial comparing cardiovascular safet y of degarelix versus leuprolide in patients with advanced prostate cancer and cardiovascular disease (pronounce) (nct02663908). available at : ht t ps://clinic altrials.gov/c t 2 /show/ nc t 0 2 6 6 3 9 0 8 ? ter m =degarelix+leuprolide+acetate&cond=prostate+cancer&draw=2. accessed july 13, 2021. 27. rhee h, gunter jh, heathcote p, ho k, stricker p, corcoran nm, et al. adverse effects of androgen-deprivation therapy in prostate cancer and their management. bju int.2015;115(suppl 5):3-13. doi:10.1111/ bju.12964 28. huggins c, hodges cv. studies on prostatic cancer: ii. the effects of castration on advanced carcinoma of the prostate gland. arch surg.1941;43:209-223. 29. klotz l, o’callaghan c, ding k, toren p, dearnaley d, higano cs, et al. nadir testosterone within first year of androgen-deprivation therapy (adt) predicts for time to castration-resistant progression: a secondary analysis of the pr-7 trial of intermittent versus continuous adt. j clin oncol.2015;33(10):1151-1156. doi:10.1200/jco.2014.58.2973 30. duivenvoorden wcm, naeim m, hopmans sn, yousef s, werstuck gh, dason s, et al. protective effect of pharmacological castration on metabolic perturbations and cardiovascular disease in the hyperglycemic male apoe(-/-):ins2(+/akita) mouse model. prostate cancer prostatic dis.2021;24(2):389-397. doi:10.1038/ s41391-020-00288-y 31. chen dy, see lc, liu jr, chuang ck, pang st, hsieh ic, et al. risk of cardiovascular ischemic events after surgical castration and gonadotropin-releasing hormone agonist therapy for prostate cancer: a nationwide cohort study. j clin oncol.2017;35(32):3697-3705. doi:10.1200/jco.2016.71.4204 32. kan wc, hsieh kl, chen yc, ho ch, hong cs, chiang cy, et al. comparison of surgical or medical castration-related cardiotoxicity in patients with prostate cancer. j urol.2022;207(4):841-850. doi:10.1097/ju.0000000000002340 33. thomsen fb, sandin f, garmo h, lissbrant if, ahlgren g, van hemelrijck m, et al. gonadotropin-releasing hormone agonists, orchiectomy, and risk of cardiovascular disease: semi-ecologic, nationwide, population-based study. eur urol.2017;72(6):920-928. doi:10.1016/j. eururo.2017.06.036 34. scailteux lm, vincendeau s, balusson f, leclercq c, happe a, le nautout b, et al. androgen deprivation therapy and cardiovascular risk: no meaningful difference between gnrh antagonist and agonists-a nationwide population-based cohort study based on 2010-2013 french health insurance data. eur j cancer.2017;77:99-108. doi:10.1016/j. ejca.2017.03.002 35. cardwell cr, o’sullivan jm, jain s, harbinson m t, cook mb, hicks bm, et al. the risk of cardiovascular disease in pros t ate c ancer p atient s receiving androgen deprivation t her apies. epidemiology. 2 0 2 0; 31(3) :4 3 24 4 0. doi:10.10 9 7/ ede.0000000000001132 36. ma c, abeysekera ir, xu w, wang y, peng j, li h. comparing the risk of cardiovascular disease following gnrh agonist and gnrh antagonist therapy for patient with prostate cancer: a systematic review and meta-analysis. minerva urol nephrol.2021;73(3):276-282. doi:10.23736/s2724-6051.20.03756-x 37. shore nd, saad f, cookson ms, george dj, saltzstein dr, tutrone r, et al. oral relugolix for androgen-deprivation therapy in advanced prostate cancer. n engl j med.2020;382(23):2187-2196. doi:10.1056/ nejmoa2004325 38. chong wh. endocrinologic and metabolic drugs advisory committee meeting. presented at: fda advisory committee meeting; october 24-25, 2018; silver spring, md. 39. abbvie inc. androgel (testosterone gel 1% ). full prescribing 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part 1: screening, diagnosis, and local treatment with curative intent-update 2013. eur urol.2014;65(1):124-137. doi:10.1016/j. eururo.2013.09.046 45. heidenreich a, bastian pj, bellmunt j, bolla m, joniau s, van der kwast t, et al. eau guidelines on prostate cancer. part ii: treatment of advanced, relapsing, and castration-resistant prostate cancer. eur urol.2014;65(2):467-479. doi:10.1016/j.eururo.2013.11.002 46. mohler jl, antonarakis es, armstrong aj, d’amico av, davis bj, dorff t, et al. prostate cancer, version 2.2019, nccn clinical practice guidelines in oncology. j natl compr canc netw.2019;17(5):479-505. doi:10.6004/jnccn.2019.0023 47. morris mj, rumble rb, basch e, hotte sj, loblaw a, rathkopf d, et al. optimizing anticancer therapy in metastatic non-castrate prostate cancer: american society of clinical oncology clinical practice guideline. j clin oncol.2018;36(15):1521-1539. doi:10.1200/ jco.2018.78.0619 48. national comprehensive cancer network. nccn clinical practice guidelines version 2.2021 prostate cancer. https://www.nccn.org/ professionals/physician_gls/pdf/prostate.pdf. accessed 3 march 2021. 274 siuj • volume 3, number 4 • july 2022 siuj.org review 49. anderson-carter i, posielski n, liou ji, khemees ta, downs tm, abel ej, et al. the impact of statins in combination with androgen deprivation therapy in patients with advanced prostate cancer: a large observational study. urol oncol.2019;37(2):130-137. doi:10.1016/j. urolonc.2018.11.017 50. hamilton rj, ding k, crook jm, o’callaghan cj, higano cs, dearnaley dp, et al. the association between statin use and outcomes in patients initiating androgen deprivation therapy. eur urol.2021;79(4):446-452. doi:10.1016/j.eururo.2020.12.031 51. harshman lc, wang x, nakabayashi m, xie w, valenca l, werner l, et al. statin use at the time of initiation of androgen deprivation therapy and time to progression in patients with hormone-sensitive prostate cancer. jama oncol.2015;1(4):495-504. doi:10.1001/ jamaoncol.2015.0829 52. he k, hu h, ye s, wang h, cui r, yi l. the effect of metformin therapy on incidence and prognosis in prostate cancer: a systematic review and meta-analysis. sci rep.2019;9(1):2218. doi:10.1038/ s41598-018-38285-w 53. richards k a, liou ji, cryns vl, downs tm, abel ej, jarrard df. metformin use is associated with improved survival for patients with advanced prostate cancer on androgen deprivation therapy. j urol.2018;200(6):1256-1263. doi:10.1016/j.juro.2018.06.031 54. nobes jp, langley se, klopper t, russell-jones d, laing rw. a prospective, randomized pilot study evaluating the effects of metformin and lifestyle intervention on patients with prostate cancer receiving androgen deprivation therapy. bju int.2012;109(10):14951502. doi:10.1111/j.1464-410x.2011.10555.x 55. d’amico av, chen mh, renshaw a a, loffredo m, kantoff pw. androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. jama.2008;299(3):289-295. doi:10.1001/ jama.299.3.289 56. faris je, smith mr. metabolic sequelae associated with androgen deprivation therapy for prostate cancer. curr opin endocrinol diabetes obes 2010;17(3):240-246. doi:10.1097/med.0b013e3283391fd1 57. o’farrell s, garmo h, holmberg l, adolfsson j, stattin p, van hemelrijck m. risk and timing of cardiovascular disease after androgen-deprivation therapy in men with prostate cancer. j clin oncol.2015;33(11):1243-1251. doi:10.1200/jco.2014.59.1792. 58. bosco c, bosnyak z, malmberg a, adolfsson j, keating nl, van hemelrijck m. quantifying observational evidence for risk of fatal and nonfatal cardiovascular disease following androgen deprivation therapy for prostate cancer: a meta-analysis. eur urol.2015;68(3):386396. doi:10.1016/j.eururo.2014.11.039 59. lester jf, mason md. cardiovascular effects of hormone therapy for prostate cancer. drug healthc patient saf.2015;7:129-138. doi:10.2147/ dhps.s50549 60. meng f, zhu s, zhao j, vados l, wang l, zhao y, et al. stroke related to androgen deprivation therapy for prostate cancer: a meta-analysis and systematic review. bmc cancer.2016;16(1):180. doi:10.1186/ s12885-016-2221-5 61. d, lee chuy k, yang jc, bates m, lombardo m, steingart rm. cardiovascular and metabolic effects of androgen-deprivation therapy for prostate cancer. j oncol pract.2018;14(10):580-587. doi:10.1200/ jop.18.00178 62. nanda a, chen mh, braccioforte mh, moran bj, d’amico av. hormonal therapy use for prostate cancer and mortality in men with coronary artery disease-induced congestive heart failure or myocardial infarction. jama.2009;302(8):866-873. doi:10.1001/jama.2009.1137 63. smith mr, klotz l, persson be, olesen tk, wilde aa. cardiovascular safety of degarelix: results from a 12-month, comparative, randomized, open label, parallel group phase iii trial in patients with prostate cancer. j urol.2010;184(6):2313-2319. doi:10.1016/j.juro.2010.08.012 64. smith mr, klotz l, van der meulen e, colli e, tanko lb. gonadotropinreleasing hormone blockers and cardiovascular disease risk: analysis of prospective clinical trials of degarelix. j urol.2011;186(5):1835-1842. doi:10.1016/j.juro.2011.07.035 65. klotz l, miller k, crawford ed, shore n, tombal b, karup c, et al. disease control outcomes from analysis of pooled individual patient data from five comparative randomized clinical trials of degarelix versus luteinizing hormone-releasing hormone agonists. eur urol.2014;66(6):1101-1108. doi:10.1016/j.eururo.2013.12.063 66. haque r, ulcickasyood m, xu x, cassidy-bushrow ae, tsai h-t, keating nl, et al. cardiovascular disease risk and androgen deprivation therapy in patients with localized prostate cancer: a prospective cohort study. br j cancer.2017;117(8):1233-1240. doi:10.1038/bjc.2017.280 67. fahed ac, gholmieh jm, azar st. connecting the lines between hypogonadism and atherosclerosis. int j endocrinol.2012;2012:793953. doi:10.1155/2012/793953 68. schmitz kh, courneya ks, matthews c, demark-wahnefried w, galvão da, pinto bm, et al. american college of sports medicine roundtable on exercise guidelines for cancer survivors. med sci sports exerc.2010;42(7):1409-1426. doi:10.1249/mss.0b013e3181e0c112 69. galvão da, taaffe dr, spry n, gardiner ra, taylor r, risbridger gp, et al. enhancing active surveillance of prostate cancer: the potential of exercise medicine. nat rev urol.2016;13(5):258-265. doi:10.1038/ nrurol.2016.46 70. saraei p, asadi i, kakar ma, moradi-kor n. the beneficial effects of metformin on cancer prevention and therapy: a comprehensive review of recent advances. cancer manag res.2019;11:3295-3313. doi:10.2147/cmar.s200059 71. alghandour r, ebrahim ma, elshal am, ghobrial f, elzaafarany m, elbaiomy m. 617mo repurposing metformin as an anticancer drug: preliminary results of randomized controlled trial in advanced prostate cancer (mansmed). ann oncol.2020;31:s511. doi:10.1016/j. annonc.2020.08.876 275siuj.org siuj • volume 3, number 4 • july 2022 impact of androgen deprivation therapy on cardiovascular outcomes in prostate cancer this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information prostate neoplasms, cystectomy, pelvic exenteration, prostatectomy, salvage therapy none declared. received on january 8, 2022 accepted on february 26, 2022 this article has been peer reviewed. soc int urol j. 2022;3(3):163–183 doi: 10.48083/kgmi7850 163siuj.org siuj • volume 3, number 3 • may 2022 review the role of pelvic exenteration in the management of locally advanced prostate cancer ala’a farkouh,1 nassib abou heidar,2 ryan w. dobbs,3 ibrahim abu-gheida,4 muhammad bulbul,2 mohammed shahait1 1 department of surgery, king hussein cancer center, amman, jordan 2 american university of beirut medical center, beirut, lebanon 3 cook county health and hospitals system, chicago, united states 4 burjeel cancer institute, burjeel medical city, united arab emirates abstract locally advanced prostate cancer poses a clinical challenge for physicians. despite the established role of radiotherapy and androgen-deprivation therapy in these cases, some patients with locally advanced disease experience recurrent disease or persistent disease with debilitating local symptoms, such as intractable pain and urinary symptoms. in this narrative review, we sought to evaluate the role of exenterative surgery in the management of locally advanced prostate cancer. from our search, we found that total pelvic exenteration or cystoprostatectomy represents a viable therapeutic modality to manage prostate cancer directly invading the bladder, lower urinary tract symptoms, debilitating pain caused by locally advanced disease, and as salvage treatment after failure of primary treatment among other applications. reports on minimally invasive pelvic exenteration for prostate cancer were also retrieved, as this represents a feasible and effective treatment option for experienced clinicians. pelvic exenteration may be an effective tool for the treatment of locally advanced prostate cancer in the surgeon’s armamentarium; however, further studies are needed to establish its role in improving survival and overall patient outcomes. introduction while there is no single definition of locally advanced prostate cancer (lapca), it is generally understood to be disease extending beyond the prostatic capsule (t3 and t4 disease)[1–3]. the european association of urology (eau) defines locally advanced prostate cancer as clinical ct3–ct4 or disease with positive lymph nodes (cn1)[1]. this issue has become particularly pertinent in recent years as a shift towards lapca has been observed following the united states preventative task force recommendation against routine prostate cancer screening in 2012[4]. although there is no consensus among urologists, oncologists, and radiation oncologists on the management of lapca, the survival benefit of radiotherapy (rt) combined with androgen-deprivation therapy (adt) has been well established, and it has been consistently used for the treatment of lapca[5,6]. the role of surgery in the treatment of this condition is more controversial but has been an area of intense investigation in recent years. a meta-analysis demonstrated significant survival improvement with radical prostatectomy (rp) in lapca, and when rp was combined with adjuvant radiotherapy, survival rates were comparable to those seen with rt and adt[7]. the survival benefit of surgery for t4 disease in men aged < 50 years was described by hsiao et al., who suggested that rp should be offered to men in that age group as part of a multimodal treatment approach[8]. http://siuj.org https://orcid.org/0000-0002-0362-9109 https://orcid.org/0000-0003-3811-5543 https://orcid.org/0000-0003-1397-7307 https://orcid.org/0000-0003-2609-5629 kim et al. stressed the importance of local treatment of the primary tumor in t4 prostate cancer with surgery, rt, or a combination of both compared to systematic therapy with adt or chemotherapy, and reported 5-year survival rates of 57.8% for local therapy versus 33.2% for systematic therapy[9]. given the high rates of positive surgical margins, recurrence, and occult systemic metastasis in lapca, a combination of surgery with either adjuvant or neoadjuvant rt has been described in the literature as having improved outcomes[10]. bot hersome pelv ic sy mptoms a re f requent ly encountered in the management of patients lapca. for instance, up to two-thirds of men diagnosed with castrate-sensitive prostate cancer (cspc) experience pelvic symptoms, including perineal pain, lower urinary tract symptoms (luts), and urinary tract obstruction[11]. men dying of prostate cancer experience a high incidence of urological complications[12]. fifty percent of men dying of metastatic prostate cancer suffer from luts, 21% undergo lower urinary tract procedures, and 8% undergo upper urinary tract interventions[13]. in another report, 25% of prostate cancer patients who underwent palliative transurethral resection of the prostate required repeat turp after a mean duration of 11 months[14]. lapca can lead to chronic pelvic pain requiring opioid medications, as well as bladder outlet obstruction requiring catheterization or renal failure requiring urinary diversion or ureteral stenting. while these sequelae might not lead to increased cancer-specific mortality, they decrease the quality of life (qol) of affected patients[15]. pelvic exenteration is an extensive surgery that involves the removal of pelvic organs to treat pelvic malignancies[16]. it was first described by brunschwig in 1948 for the management of gynecological cancers[17]. currently, pelvic exenteration is most commonly performed for gynecological and locally advanced rectal tumors[18]. total pelvic exenteration involves removal of the bladder, reproductive organs, sigmoid colon, and rectum, and creation of diversions for urine and stool. variations include anterior pelvic exenteration, which spares the rectosigmoid, and posterior pelvic exenteration, which spares the bladder[19]. pelvic exenteration has also been described in the management of other pelvic tumors such as bladder cancer and pelvic sarcomas[20,21]. in this review, we aim to evaluate the role of cystoprostatectomy and pelvic exenteration in patients with lapca by highlighting the various indications, complications, and outcomes reported in published studies, and to identify gaps in the literature that may be a focus for future studies. methods this review is structured as a narrative review in accordance with the scale for the assessment of narrative review (sanra) criteria[22]. a comprehensive literature search was performed by 2 authors using pubmed from 1980 to 2021. the search string used was ([prostate cancer] and [pelvic exenteration] or [cystoprostatectomy] or [cysto-prostatectomy]). filters included only english language papers, human subjects, and the following types of articles: case reports, classical articles, clinical studies, clinical trials, clinical trial protocols, clinical trials, comparative studies, controlled clinical trials, guidelines, journal articles, meta-analyses, multicenter studies, observational studies, practice guidelines, randomized controlled trials, reviews, and systematic review papers. the articles yielded from the final search were first screened by title, then abstract, and finally by full text. articles on prostate sarcomas and non-adenocarcinoma tumors and articles on pelvic exenteration performed for non-prostate pelvic tumors were excluded. letters to the editor, opinions, abstracts, summaries, videos, and reports in non-english languages were excluded. finally, a manual search was conducted from the selected articles and search engines. the included articles were then evaluated to extract the following data: number of patients included, type of exenteration surgery, the indication for exenteration, neoadjuvant or adjuvant treatments, operative outcomes (blood loss, blood transfusions, length of surgery, hospital stay), complications (including 30-day morbidity and mortality when reported), r0 resection, follow-up and the reported long-term survival outcomes. results following our search criteria, 529 articles were extracted and screened by title; 473 papers were excluded. a total of 56 abstracts were screened, and 23 papers were excluded. thirty-three full-text articles were reviewed, of which 4 were excluded. five articles were retrieved by a manual search, yielding a total of 34 articles included abbreviations adt androgen-deprivation therapy crpc castrate-resistant prostate cancer lapca locally advanced prostate cancer luts lower urinary tract symptoms qol quality of life rp radical prostatectomy rt radiotherapy 164 siuj • volume 3, number 3 • may 2022 siuj.org review http://siuj.org in our results. the article screening process, the numbers included and excluded, and the reasons for exclusion are summarized in figure 1. in our review, pelvic exenteration for prostate cancer has been described in different settings based on different indications. the majority of retrospective studies reporting the indications, complications, and outcomes of pelvic exenteration for prostate cancer are summarized in table 1[23–42]. table 2[43–48] summarizes the reported cases of minimally invasive pelvic exenteration for prostate cancer, whether laparoscopic or robot-assisted. cystoprostatectomy for prostate cancer invading the bladder cystoprostatectomy can be performed to control luts in prostate cancer invading the bladder and has been described as a palliative treatment option for luts after failure of other treatments or as a primary treatment option for prostate cancer invading the bladder[49]. leibovici et al. demonstrated that palliative cystoprostatectomy alleviated luts in 68% of patients with prostate cancer invading the bladder, whether primary or recurrent after radiotherapy, and reported significant relief of all local pain and luts, as well as the need for palliative lower urinary tract procedures initial pubmed search after applying �lters n = 529 articles screening articles by title n = 56 articles remaining screening articles by abstract n = 33 articles remaining full-text article screening n = 29 articles remaining total number of articles included in narrative review n = 34 excluded articles (n = 4) • exenteration not done for prostate cancer (n = 2) • prostate carcinosarcoma case (n = 1) • summary article (n = 1) articles retrieved by manual search from other articles or search engines n = 5 figure 1. the flowchart summarizes the screening process for article inclusion in this narrative review. numbers of articles screened at each phase, the reasons for exclusion, and the final number of articles included are demonstrated in the flowchart. 165siuj.org siuj • volume 3, number 3 • may 2022 the role of pelvic exenteration in the management of locally advanced prostate cancer http://siuj.org table 1. summary of studies on pelvic exenteration (anterior or total) for locally advanced prostate cancer author (year) total number of patients exenteration type (number) indication (number) neoadjuvant treatment blood loss prbc transfusion surgery time hospital stay reported complications r0 resection follow-up secondary treatment reported outcomes mador et al. (1985) 7 radical prostatectomy (4) cystoprostatectomy (3) salvage surgery after local recurrence of prostate cancer after failure of radiotherapy with no metastasis (7) – nr mean 5.3 units mean 4.9h mean 10 days 30-day mortality 1/7 30-day morbidity 5/7 late post-op complications 2/7 nr – – 6/7 patients alive at 3–22 months post-op 1/7 developed metastasis 1 year after cp moul et al. (1991) 22 radical perineal prostatectomy (4) cystoprostatectomy with urinary diversion: ileal conduit (5), koch pouch (3) salvage surgery for recurrent prostate cancer after radiotherapy (12) – rpp: mean 800 ml cp: mean 3190 ml (cp) rpp: nr cp: mean 6 units rpp: mean 4h20min cp: mean 8h20min rpp: average 23 days cp: average 21.7 days rpp: 4/4 reported post-op complications, including wound infection, urosepsis, urine leak cp and koch pouch: 3/3 reported postop complications, including urinoma requiring urinary diversion, urosepsis, sbo, pneumonia cp and ileal conduit: no reported complications 5/12 (41.7%) mean 49 months – 4/12 no evidence of disease recurrence at follow-up 5/12 only elevated psa at follow-up failure rate of salvage surgery after radiotherapy is higher than standard radical prostatectomy for localized prostate cancer (control) but not statistically significant cystoprostatectomy with urinary diversion: ileal conduit (8), koch pouch (1) pelvic exenteration with colostomy and ileal conduit (1) locally advanced prostate cancer not amenable to standard radical prostatectomy (10) 5 of 10 patients received neoadjuvant treatment mean 2890 ml mean 7.3 units mean 8h nr 6/10 reported post-op complications including haemorrhage requiring re-exploration, sbo, presacral abscess, ileus, mi, rectal laceration 3/10 (30%) mean 59 months – 6/10 developed metastasis and required adt 1/10 no evidence of disease recurrence at follow-up 1/10 only elevated psa at follow-up cp had a significantly higher failure rate than standard radical prostatectomy controls zincke et al. (1992) 62 radical prostatectomy (32) cystoprostatectomy with ileal conduit (23) total pelvic exenteration (7) salvage surgery after radiation failure, no distant metastasis in all patients at time of surgery (62) 22 patients (35%) received hormonal treatment before surgery nr rp: median 1.5 units, range 0–20 cp: median 1 unit, range 0–12 tpe: median 4 units, range 3–6 rp: median 3.1h, range 1.5–5 cp: median 4.7h, range3-7.5 tpe: median 5.5h, range 3.9–8 rp: median 11.5 days, range 5–23 cp: median 12 days, range6–34 tpe median 20 days, range 12–45 rp: 30-day morbidity 10/32, 18/32 developed late complications cp: 30-day morbidity 10/23, 8/23 developed late complications tpe: 6/7 developed complications with a total of 16 reported complications and some patients experiencing several complications rp: 24/32 (75%) cp: 15/23 (65%) tpe: 4/7 (53%) – 17 patients (27%) received hormonal treatment after surgery overall 5-year survival rate: 68% rp group had survival advantage and less recurrence compared to exenteration groups (higher residual cancer rates) among the rp group, those who received adjuvant hormonal therapy had significantly less progression than those who did not a data reported on a total of 18 patients: 6 prostate and 12 bladder cancer b neoadjuvant and adjuvant treatments different between different institutions prbc: packed red blood cells; nr: not reported; postop: postoperative; cp: cystoprostatectomy; rpp: radical perineal prostatectomy; psa: prostate specific antigen; sbo: small bowel obstruction; mi: myocardial infarction; adt: androgen deprivation therapy; rp: radical prostatectomy; tpe: total pelvic exenteration; lar: low anterior resection; intra-op: intra-operative; pe: pulmonary embolus; plnd: pelvic lymph node dissection; tcc: transitional cell carcinoma; uti: urinary tract infection; dvt: deep vein thrombosis. 166 siuj • volume 3, number 3 • may 2022 siuj.org review http://siuj.org table 1. summary of studies on pelvic exenteration (anterior or total) for locally advanced prostate cancer author (year) total number of patients exenteration type (number) indication (number) neoadjuvant treatment blood loss prbc transfusion surgery time hospital stay reported complications r0 resection follow-up secondary treatment reported outcomes mador et al. (1985) 7 radical prostatectomy (4) cystoprostatectomy (3) salvage surgery after local recurrence of prostate cancer after failure of radiotherapy with no metastasis (7) – nr mean 5.3 units mean 4.9h mean 10 days 30-day mortality 1/7 30-day morbidity 5/7 late post-op complications 2/7 nr – – 6/7 patients alive at 3–22 months post-op 1/7 developed metastasis 1 year after cp moul et al. (1991) 22 radical perineal prostatectomy (4) cystoprostatectomy with urinary diversion: ileal conduit (5), koch pouch (3) salvage surgery for recurrent prostate cancer after radiotherapy (12) – rpp: mean 800 ml cp: mean 3190 ml (cp) rpp: nr cp: mean 6 units rpp: mean 4h20min cp: mean 8h20min rpp: average 23 days cp: average 21.7 days rpp: 4/4 reported post-op complications, including wound infection, urosepsis, urine leak cp and koch pouch: 3/3 reported postop complications, including urinoma requiring urinary diversion, urosepsis, sbo, pneumonia cp and ileal conduit: no reported complications 5/12 (41.7%) mean 49 months – 4/12 no evidence of disease recurrence at follow-up 5/12 only elevated psa at follow-up failure rate of salvage surgery after radiotherapy is higher than standard radical prostatectomy for localized prostate cancer (control) but not statistically significant cystoprostatectomy with urinary diversion: ileal conduit (8), koch pouch (1) pelvic exenteration with colostomy and ileal conduit (1) locally advanced prostate cancer not amenable to standard radical prostatectomy (10) 5 of 10 patients received neoadjuvant treatment mean 2890 ml mean 7.3 units mean 8h nr 6/10 reported post-op complications including haemorrhage requiring re-exploration, sbo, presacral abscess, ileus, mi, rectal laceration 3/10 (30%) mean 59 months – 6/10 developed metastasis and required adt 1/10 no evidence of disease recurrence at follow-up 1/10 only elevated psa at follow-up cp had a significantly higher failure rate than standard radical prostatectomy controls zincke et al. (1992) 62 radical prostatectomy (32) cystoprostatectomy with ileal conduit (23) total pelvic exenteration (7) salvage surgery after radiation failure, no distant metastasis in all patients at time of surgery (62) 22 patients (35%) received hormonal treatment before surgery nr rp: median 1.5 units, range 0–20 cp: median 1 unit, range 0–12 tpe: median 4 units, range 3–6 rp: median 3.1h, range 1.5–5 cp: median 4.7h, range3-7.5 tpe: median 5.5h, range 3.9–8 rp: median 11.5 days, range 5–23 cp: median 12 days, range6–34 tpe median 20 days, range 12–45 rp: 30-day morbidity 10/32, 18/32 developed late complications cp: 30-day morbidity 10/23, 8/23 developed late complications tpe: 6/7 developed complications with a total of 16 reported complications and some patients experiencing several complications rp: 24/32 (75%) cp: 15/23 (65%) tpe: 4/7 (53%) – 17 patients (27%) received hormonal treatment after surgery overall 5-year survival rate: 68% rp group had survival advantage and less recurrence compared to exenteration groups (higher residual cancer rates) among the rp group, those who received adjuvant hormonal therapy had significantly less progression than those who did not a data reported on a total of 18 patients: 6 prostate and 12 bladder cancer b neoadjuvant and adjuvant treatments different between different institutions prbc: packed red blood cells; nr: not reported; postop: postoperative; cp: cystoprostatectomy; rpp: radical perineal prostatectomy; psa: prostate specific antigen; sbo: small bowel obstruction; mi: myocardial infarction; adt: androgen deprivation therapy; rp: radical prostatectomy; tpe: total pelvic exenteration; lar: low anterior resection; intra-op: intra-operative; pe: pulmonary embolus; plnd: pelvic lymph node dissection; tcc: transitional cell carcinoma; uti: urinary tract infection; dvt: deep vein thrombosis. continued on page 168 167siuj.org siuj • volume 3, number 3 • may 2022 the role of pelvic exenteration in the management of locally advanced prostate cancer http://siuj.org table 1. summary of studies on pelvic exenteration (anterior or total) for locally advanced prostate cancer author (year) total number of patients exenteration type (number) indication (number) neoadjuvant treatment blood loss prbc transfusion surgery time hospital stay reported complications r0 resection follow-up secondary treatment reported outcomes ahlering et al. (1992) 34 prostatectomy (10) cystoprostatectomy with urinary diversion (22): ileal conduit (8), continent cutaneous diversions (14) cystoprostatectomy and lar (1) total pelvic exenteration (1) salvage surgery after failure of radiotherapy and no distant metastasis (34) – nr nr nr rp: mean 7.6 days, range 6–12 exenteration: mean 11 days, range 7–16 2 patients of the cystoprostatectomy group developed complications (ileus and sbo, requiring exploration and adhesolysis) nr mean 109 months post radiotherapy 27/34 (79%) received perioperative adjuvant hormonal therapy 24/34 alive without disease 2 have elevated psa 10/34 developed recurrence 7 of whom died from disease pontes et al. (1993) 43 prostatectomy (35) cystoprostatectomy (8) salvage surgery after failure of radiotherapy (43) 26 received hormonal surgery before or after surgery cp: nr cp: nr cp: nr cp: nr cp: 2 rectal perforations intra-op repaired primarily and 1 death from pe no significant late morbidity reported for those who underwent cp 13/43 (30.2%) range 1–10 years 26 received hormonal surgery before or after surgery 6/9 died from metastasis 34 were alive: • 10/34 no evidence of disease • 15/34 elevated psa • 4/34 too early to evaluate • 5/34 has metastasis no influence of hormonal therapy on survival was seen lerner et al. (1995) 132 radical prostatectomy (79–90%) cystoprostatectomy (38–29%) total pelvic exenteration (5–4%) plnd alone (10–7%) salvage surgery after failure of local radiotherapy and no distant metastasis, low co-morbidity and 10-year life expectancy (132) – nr rp: median 1 unit, range 0–22 cp: median 2 units, range 0–22 tpe: median 9.5 units, range 7–97 plnd: median 1 unit, range 0–2 nr rp: median 8 days, range 2–44 cp: median 12 days, range 8–34 tpe: median 20 days, range 12–45 plnd: median 8 days, range 5–15 rp: 35 (44%) complications reported cp: 12 (31.6%) complications reported tpe: 6 complications reported (some patients experienced more than one) plnd: 4 (40%) complications reported nr – 80 (61%) received adjuvant perioperative hormonal therapy generally, overall survival and cause-specific survival was significantly higher for the rp group compared to the exenteration groups (due to a higher proportion of patients with organ-confined disease as well as a higher proportion of non-aneuploid cancer in the rp group) adjuvant hormonal therapy was associated with higher progressionfree survival in patients with non-aneuploid tumors a data reported on a total of 18 patients: 6 prostate and 12 bladder cancer b neoadjuvant and adjuvant treatments different between different institutions prbc: packed red blood cells; nr: not reported; postop: postoperative; cp: cystoprostatectomy; rpp: radical perineal prostatectomy; psa: prostate specific antigen; sbo: small bowel obstruction; mi: myocardial infarction; adt: androgen deprivation therapy; rp: radical prostatectomy; tpe: total pelvic exenteration; lar: low anterior resection; intra-op: intra-operative; pe: pulmonary embolus; plnd: pelvic lymph node dissection; tcc: transitional cell carcinoma; uti: urinary tract infection; dvt: deep vein thrombosis. after surgery[42]. similarly, sato et al. reported effective control of luts in all patients who under went cystoprostatectomy as a primary treatment for lapca and found no significant difference in qol or overall survival compared with rp in those without bladder neck involvement; in fact, for patients who underwent cystoprostatectomy, the 10-year disease-free survival rate was 82%[39]. a recent report by yuan et al. described cystoprostatectomy as a therapeutic option that provides symptom control and has favorable outcomes in terms of survival and patient qol[33]. they included 27 patients with prostate cancer invading the bladder who had not received neoadjuvant treatment and had no distant metastases. all the patients underwent open or laparoscopic cystoprostatectomy with urinary diversion (ileal conduit or cutaneous ureterostomy) and extended pelvic lymph node dissection. all patients had luts before surgery, and all reported relief of urinary symptoms after the procedure. qol was also assessed using the functional assessment of cancer therapy, cont’d 168 siuj • volume 3, number 3 • may 2022 siuj.org review http://siuj.org prostate (fact-p) questionnaire, with the total score improving significantly at 6 months and one year after surgery compared with the preoperative score. survival outcomes were also reported with a 3-year prostate cancer-free survival of 77.8%, as all patients received adjuvant adt, with 9 patients also receiving rt and 3 receiving chemotherapy. these survival outcomes are comparable to those reported by kumazawa et al., who described a similar population of patients, among whom 11 (64.7%) received neoadjuvant adt and all received adjuvant adt and were found to have a 5-year cancerspecific survival of 87.1%[41]. cystoprostatectomy as a salvage option after failure of other therapies several authors have published the outcomes of salvage surgery after failure of rt for lapca with no distant metastasis[23,26–28,32,34]. cystoprostatectomy rather than prostatectomy was performed to alleviate luts, severe local symptoms, and complications after rt table 1. summary of studies on pelvic exenteration (anterior or total) for locally advanced prostate cancer author (year) total number of patients exenteration type (number) indication (number) neoadjuvant treatment blood loss prbc transfusion surgery time hospital stay reported complications r0 resection follow-up secondary treatment reported outcomes ahlering et al. (1992) 34 prostatectomy (10) cystoprostatectomy with urinary diversion (22): ileal conduit (8), continent cutaneous diversions (14) cystoprostatectomy and lar (1) total pelvic exenteration (1) salvage surgery after failure of radiotherapy and no distant metastasis (34) – nr nr nr rp: mean 7.6 days, range 6–12 exenteration: mean 11 days, range 7–16 2 patients of the cystoprostatectomy group developed complications (ileus and sbo, requiring exploration and adhesolysis) nr mean 109 months post radiotherapy 27/34 (79%) received perioperative adjuvant hormonal therapy 24/34 alive without disease 2 have elevated psa 10/34 developed recurrence 7 of whom died from disease pontes et al. (1993) 43 prostatectomy (35) cystoprostatectomy (8) salvage surgery after failure of radiotherapy (43) 26 received hormonal surgery before or after surgery cp: nr cp: nr cp: nr cp: nr cp: 2 rectal perforations intra-op repaired primarily and 1 death from pe no significant late morbidity reported for those who underwent cp 13/43 (30.2%) range 1–10 years 26 received hormonal surgery before or after surgery 6/9 died from metastasis 34 were alive: • 10/34 no evidence of disease • 15/34 elevated psa • 4/34 too early to evaluate • 5/34 has metastasis no influence of hormonal therapy on survival was seen lerner et al. (1995) 132 radical prostatectomy (79–90%) cystoprostatectomy (38–29%) total pelvic exenteration (5–4%) plnd alone (10–7%) salvage surgery after failure of local radiotherapy and no distant metastasis, low co-morbidity and 10-year life expectancy (132) – nr rp: median 1 unit, range 0–22 cp: median 2 units, range 0–22 tpe: median 9.5 units, range 7–97 plnd: median 1 unit, range 0–2 nr rp: median 8 days, range 2–44 cp: median 12 days, range 8–34 tpe: median 20 days, range 12–45 plnd: median 8 days, range 5–15 rp: 35 (44%) complications reported cp: 12 (31.6%) complications reported tpe: 6 complications reported (some patients experienced more than one) plnd: 4 (40%) complications reported nr – 80 (61%) received adjuvant perioperative hormonal therapy generally, overall survival and cause-specific survival was significantly higher for the rp group compared to the exenteration groups (due to a higher proportion of patients with organ-confined disease as well as a higher proportion of non-aneuploid cancer in the rp group) adjuvant hormonal therapy was associated with higher progressionfree survival in patients with non-aneuploid tumors a data reported on a total of 18 patients: 6 prostate and 12 bladder cancer b neoadjuvant and adjuvant treatments different between different institutions prbc: packed red blood cells; nr: not reported; postop: postoperative; cp: cystoprostatectomy; rpp: radical perineal prostatectomy; psa: prostate specific antigen; sbo: small bowel obstruction; mi: myocardial infarction; adt: androgen deprivation therapy; rp: radical prostatectomy; tpe: total pelvic exenteration; lar: low anterior resection; intra-op: intra-operative; pe: pulmonary embolus; plnd: pelvic lymph node dissection; tcc: transitional cell carcinoma; uti: urinary tract infection; dvt: deep vein thrombosis. continued on page 170 169siuj.org siuj • volume 3, number 3 • may 2022 the role of pelvic exenteration in the management of locally advanced prostate cancer http://siuj.org table 1. summary of studies on pelvic exenteration (anterior or total) for locally advanced prostate cancer author (year) total number of patients exenteration type (number) indication (number) neoadjuvant treatment blood loss prbc transfusion surgery time hospital stay reported complications r0 resection follow-up secondary treatment reported outcomes gheiler et al. (1997) 8 cystoprostatectomy with urinary diversion: ileal conduit (5), orthotopic neobladder (3) radio-recurrent prostate cancer with: severe fibrosis of bladder neck (2) small fibrotic bladder with severe incontinence (1) synchronous bladder tcc (2) severe incontinence due to injury of external urinary sphincter suspected invasion of prostate cancer into bladder neck ileal conduit: mean 1030 ml neobladder: mean 800 ml ileal conduit: mean 1.2 units neobladder: mean 1 unit nr ileal conduit: mean 10.6 days neobladder: mean 12.7 days ileal conduit: 1/5 complications (incisional hernia, required operative repair) neobladder: 30-day morbidity 2/3 (ileus, pyelonephritis), no late complications reported ileal conduit: 3/5 (60%) neobladder: 1/3 (33.3%) – – ileal conduit: 1/5 developed metastasis and died 1/5 developed psa rise after 12 months 2/5 had no detectable psa rise 1/5 received orchiectomy as he had psa rise before surgery neobladder: 3/3 patients developed psa increase at an average 22 months after surgery bochner et al. (1998)a 6 cystoprostatectomy and orthotopic neobladder (3) total pelvic exenteration with orthotopic neobladder (3) recurrent prostate cancer after radiotherapy (4) rectoprostatic fistula after radiotherapy (2) – mean 840 mla nr nr mean 9.9 days, range 8-13)a 30-day morbidity 3/18 (1 ileus and 2 pouch-related complications)a 3/18 pouch-related late complications reported, with 2 requiring repeat interventionsa nr median 28 monthsa – 67% reported good daytime continence and 57% reported good night time continencea izawa et al. (2000) 6 cystoprostatectomy with en bloc pubic symphysectomy (3) cystoprostatectomy (1) prostatectomy with bladder neck closure and continent catheterizable stoma (2) severe complications from salvage cryotherapy after failure of primary therapy for prostate cancer (6); including: gross hematuria, urinary incontinence, prostatopubic fistula, bladder outlet obstruction and osteitis pubis – nr nr mean 547 minutes, range 288–748 nr 2/6 reported complications (incisional hernia, wound infection) nr mean 59 months, range 54-67 – 5/6 were alive at last followup (death was not related to prostate cancer) at last follow-up 3/6 remained disease-free with no detectable psa levels sato et al. (2003) 15 cystoprostatectomy with urinary diversion: ileal conduit (5), rectal bladder (8), koch pouch (1), ureterocutaneostomy (1) prostate cancer invading the urinary bladder (15) surgical patients received neoadjuvant and/or adjuvant hormonal therapy nr nr nr nr nr nr – surgical patients received neoadjuvant and/or adjuvant hormonal therapy disease specific survival: 82% at 10 years (vs. 100% for prostatectomy vs. 74% for hormonal therapy) psa relapse-free survival: 51% at 5 years (vs. 65% for prostatectomy vs. 38% for hormonal therapy) a data reported on a total of 18 patients: 6 prostate and 12 bladder cancer b neoadjuvant and adjuvant treatments different between different institutions prbc: packed red blood cells; nr: not reported; postop: postoperative; cp: cystoprostatectomy; rpp: radical perineal prostatectomy; psa: prostate specific antigen; sbo: small bowel obstruction; mi: myocardial infarction; adt: androgen deprivation therapy; rp: radical prostatectomy; tpe: total pelvic exenteration; lar: low anterior resection; intra-op: intra-operative; pe: pulmonary embolus; plnd: pelvic lymph node dissection; tcc: transitional cell carcinoma; uti: urinary tract infection; dvt: deep vein thrombosis. , cont’d 170 siuj • volume 3, number 3 • may 2022 siuj.org review http://siuj.org table 1. summary of studies on pelvic exenteration (anterior or total) for locally advanced prostate cancer author (year) total number of patients exenteration type (number) indication (number) neoadjuvant treatment blood loss prbc transfusion surgery time hospital stay reported complications r0 resection follow-up secondary treatment reported outcomes gheiler et al. (1997) 8 cystoprostatectomy with urinary diversion: ileal conduit (5), orthotopic neobladder (3) radio-recurrent prostate cancer with: severe fibrosis of bladder neck (2) small fibrotic bladder with severe incontinence (1) synchronous bladder tcc (2) severe incontinence due to injury of external urinary sphincter suspected invasion of prostate cancer into bladder neck ileal conduit: mean 1030 ml neobladder: mean 800 ml ileal conduit: mean 1.2 units neobladder: mean 1 unit nr ileal conduit: mean 10.6 days neobladder: mean 12.7 days ileal conduit: 1/5 complications (incisional hernia, required operative repair) neobladder: 30-day morbidity 2/3 (ileus, pyelonephritis), no late complications reported ileal conduit: 3/5 (60%) neobladder: 1/3 (33.3%) – – ileal conduit: 1/5 developed metastasis and died 1/5 developed psa rise after 12 months 2/5 had no detectable psa rise 1/5 received orchiectomy as he had psa rise before surgery neobladder: 3/3 patients developed psa increase at an average 22 months after surgery bochner et al. (1998)a 6 cystoprostatectomy and orthotopic neobladder (3) total pelvic exenteration with orthotopic neobladder (3) recurrent prostate cancer after radiotherapy (4) rectoprostatic fistula after radiotherapy (2) – mean 840 mla nr nr mean 9.9 days, range 8-13)a 30-day morbidity 3/18 (1 ileus and 2 pouch-related complications)a 3/18 pouch-related late complications reported, with 2 requiring repeat interventionsa nr median 28 monthsa – 67% reported good daytime continence and 57% reported good night time continencea izawa et al. (2000) 6 cystoprostatectomy with en bloc pubic symphysectomy (3) cystoprostatectomy (1) prostatectomy with bladder neck closure and continent catheterizable stoma (2) severe complications from salvage cryotherapy after failure of primary therapy for prostate cancer (6); including: gross hematuria, urinary incontinence, prostatopubic fistula, bladder outlet obstruction and osteitis pubis – nr nr mean 547 minutes, range 288–748 nr 2/6 reported complications (incisional hernia, wound infection) nr mean 59 months, range 54-67 – 5/6 were alive at last followup (death was not related to prostate cancer) at last follow-up 3/6 remained disease-free with no detectable psa levels sato et al. (2003) 15 cystoprostatectomy with urinary diversion: ileal conduit (5), rectal bladder (8), koch pouch (1), ureterocutaneostomy (1) prostate cancer invading the urinary bladder (15) surgical patients received neoadjuvant and/or adjuvant hormonal therapy nr nr nr nr nr nr – surgical patients received neoadjuvant and/or adjuvant hormonal therapy disease specific survival: 82% at 10 years (vs. 100% for prostatectomy vs. 74% for hormonal therapy) psa relapse-free survival: 51% at 5 years (vs. 65% for prostatectomy vs. 38% for hormonal therapy) a data reported on a total of 18 patients: 6 prostate and 12 bladder cancer b neoadjuvant and adjuvant treatments different between different institutions prbc: packed red blood cells; nr: not reported; postop: postoperative; cp: cystoprostatectomy; rpp: radical perineal prostatectomy; psa: prostate specific antigen; sbo: small bowel obstruction; mi: myocardial infarction; adt: androgen deprivation therapy; rp: radical prostatectomy; tpe: total pelvic exenteration; lar: low anterior resection; intra-op: intra-operative; pe: pulmonary embolus; plnd: pelvic lymph node dissection; tcc: transitional cell carcinoma; uti: urinary tract infection; dvt: deep vein thrombosis. continued on page 172 171siuj.org siuj • volume 3, number 3 • may 2022 the role of pelvic exenteration in the management of locally advanced prostate cancer http://siuj.org table 1. summary of studies on pelvic exenteration (anterior or total) for locally advanced prostate cancer author (year) total number of patients exenteration type (number) indication (number) neoadjuvant treatment blood loss prbc transfusion surgery time hospital stay reported complications r0 resection follow-up secondary treatment reported outcomes kumazawa et al. (2009) 17 cystoprostatectomy with urinary diversion: ileal conduit (7), rectal neobladder (9), koch pouch (1) prostate cancer invading the urinary bladder without distant metastasis (17) 11 received neoadjuvant hormonal therapy nr nr nr nr 11/17 (64.7%) reported perioperative complications as follows: wound infection: 3 (17.6%) prolonged ileus: 6 (35.3%) pelvic abscess: 1 (5.9%) acute pyelonephritis: 1 (5.9%) nr all received adjuvant hormonal therapy projected 5-year psa recurrence-free survival rate: 62.2% 5-year cause-specific survival: 87.1% (no significant difference between pn0 and pn1) guo et al. (2009) 18 total pelvic exenteration recurrent prostate cancer invading the rectum causing intractable perineal pain after failure of initial therapy (18) – nr nr nr nr nr 8/18 (44.4%) – all received adjuvant hormonal therapy and 17/18 received adjuvant chemotherapy 9/18 (50%) died at a mean 18 months after surgery (range 2–69 months) 9/18 (50%) alive at a mean 15 months after surgery (range 3–34 months), but 4 developed metastasis spahn et al. (2017)b 62 cystoprostatectomy ct4 prostate cancer with bladder invasion as part of multimodal treatment (62) – b nr nr nr nr nr 29 (46.8%) mean 2.9 years – b clinical recurrence in 69.4% of patients at a median of 35 months estimated prostate cancerspecific survival: 44.5% at 5 years and 39.7% at 7 years estimated overall survival: 39.8% at 5 years and 32.4% at 7 years seminal vesicle invasion was found to be a strong predictor of cancerspecific survival yuan et al. (2019) 27 cystoprostatectomy with urinary diversion (ileal conduit or cutaneous ureterostomy) upfront surgery for prostate cancer invading the urinary bladder (27) none nr nr mean 258.8 mins nr 9/27 (33.3%) patients developed complications, including hydronephrosis, wound infection, dvt, uremia, ileus, arterioureteral fistula, classified as follows: clavien-dindo grade 1: 5 (18.5%) patients clavien-dindo grade 2: 2 (7.4%) patients clavien-dindo grade 3: 2 (7.4%) patients 25/27 (92.6%) mean 46.1 months, range 20–80 all received adjuvant hormonal therapy, some also received adjuvant radiation or chemotherapy overall survival: 100% at 1 year, 88.9% at 3 years clinical progression-free survival: 100% at 1 year, 77.8% at 3 years biochemical progressionfree survival: 92.6% at 1 year, 62.9% at 3 years a data reported on a total of 18 patients: 6 prostate and 12 bladder cancer b neoadjuvant and adjuvant treatments different between different institutions prbc: packed red blood cells; nr: not reported; postop: postoperative; cp: cystoprostatectomy; rpp: radical perineal prostatectomy; psa: prostate specific antigen; sbo: small bowel obstruction; mi: myocardial infarction; adt: androgen deprivation therapy; rp: radical prostatectomy; tpe: total pelvic exenteration; lar: low anterior resection; intra-op: intra-operative; pe: pulmonary embolus; plnd: pelvic lymph node dissection; tcc: transitional cell carcinoma; uti: urinary tract infection; dvt: deep vein thrombosis. , cont’d 172 siuj • volume 3, number 3 • may 2022 siuj.org review http://siuj.org table 1. summary of studies on pelvic exenteration (anterior or total) for locally advanced prostate cancer author (year) total number of patients exenteration type (number) indication (number) neoadjuvant treatment blood loss prbc transfusion surgery time hospital stay reported complications r0 resection follow-up secondary treatment reported outcomes kumazawa et al. (2009) 17 cystoprostatectomy with urinary diversion: ileal conduit (7), rectal neobladder (9), koch pouch (1) prostate cancer invading the urinary bladder without distant metastasis (17) 11 received neoadjuvant hormonal therapy nr nr nr nr 11/17 (64.7%) reported perioperative complications as follows: wound infection: 3 (17.6%) prolonged ileus: 6 (35.3%) pelvic abscess: 1 (5.9%) acute pyelonephritis: 1 (5.9%) nr all received adjuvant hormonal therapy projected 5-year psa recurrence-free survival rate: 62.2% 5-year cause-specific survival: 87.1% (no significant difference between pn0 and pn1) guo et al. (2009) 18 total pelvic exenteration recurrent prostate cancer invading the rectum causing intractable perineal pain after failure of initial therapy (18) – nr nr nr nr nr 8/18 (44.4%) – all received adjuvant hormonal therapy and 17/18 received adjuvant chemotherapy 9/18 (50%) died at a mean 18 months after surgery (range 2–69 months) 9/18 (50%) alive at a mean 15 months after surgery (range 3–34 months), but 4 developed metastasis spahn et al. (2017)b 62 cystoprostatectomy ct4 prostate cancer with bladder invasion as part of multimodal treatment (62) – b nr nr nr nr nr 29 (46.8%) mean 2.9 years – b clinical recurrence in 69.4% of patients at a median of 35 months estimated prostate cancerspecific survival: 44.5% at 5 years and 39.7% at 7 years estimated overall survival: 39.8% at 5 years and 32.4% at 7 years seminal vesicle invasion was found to be a strong predictor of cancerspecific survival yuan et al. (2019) 27 cystoprostatectomy with urinary diversion (ileal conduit or cutaneous ureterostomy) upfront surgery for prostate cancer invading the urinary bladder (27) none nr nr mean 258.8 mins nr 9/27 (33.3%) patients developed complications, including hydronephrosis, wound infection, dvt, uremia, ileus, arterioureteral fistula, classified as follows: clavien-dindo grade 1: 5 (18.5%) patients clavien-dindo grade 2: 2 (7.4%) patients clavien-dindo grade 3: 2 (7.4%) patients 25/27 (92.6%) mean 46.1 months, range 20–80 all received adjuvant hormonal therapy, some also received adjuvant radiation or chemotherapy overall survival: 100% at 1 year, 88.9% at 3 years clinical progression-free survival: 100% at 1 year, 77.8% at 3 years biochemical progressionfree survival: 92.6% at 1 year, 62.9% at 3 years a data reported on a total of 18 patients: 6 prostate and 12 bladder cancer b neoadjuvant and adjuvant treatments different between different institutions prbc: packed red blood cells; nr: not reported; postop: postoperative; cp: cystoprostatectomy; rpp: radical perineal prostatectomy; psa: prostate specific antigen; sbo: small bowel obstruction; mi: myocardial infarction; adt: androgen deprivation therapy; rp: radical prostatectomy; tpe: total pelvic exenteration; lar: low anterior resection; intra-op: intra-operative; pe: pulmonary embolus; plnd: pelvic lymph node dissection; tcc: transitional cell carcinoma; uti: urinary tract infection; dvt: deep vein thrombosis. continued on page 174 173siuj.org siuj • volume 3, number 3 • may 2022 the role of pelvic exenteration in the management of locally advanced prostate cancer http://siuj.org table 1. summary of studies on pelvic exenteration (anterior or total) for locally advanced prostate cancer author (year) total number of patients exenteration type (number) indication (number) neoadjuvant treatment blood loss prbc transfusion surgery time hospital stay reported complications r0 resection follow-up secondary treatment reported outcomes heidenreich et al. (2020) 103 radical prostatectomy (9, 8.7%) cystoprostatectomy (71, 68.8%) total (23, 22.4%) locally advanced crpc (84) or cspc (19) with symptomatic infiltration into bladder, rectum or pelvic floor despite previous therapy nr 14.6% required transfusions from date of admission till 90 days after surgery mean 271 minutes, range 210–292 mean 18.3 days, range 10–34 reported complications classified as follows: clavien-dindo grade 2: 30.6% of patients clavien-dindo grade 3: 11.3% of patients clavien-dindo grade 4: 8.1% of patients 71/103 (68.9%) mean 3.04 years – symptom-free survival: 89.2% at 1 year, 64.1% at 3 years overall survival: 92.2% at 1 year, 43.7% at 3 years surcel et al. (2020) 25 cystoprostatectomy (23) total pelvic exenteration (2) urinary diversion: ileal conduit (18), ureterocutaneostomy (6), mainz pouch (1) palliation of ct4 prostate cancer with local invasion and local symptoms in a majority of patients, regardless of distant metastasis (25) 13 (52%) upfront surgery and 12 (48%) after adt nr nr nr nr 11/25 (44%) patients developed perioperative complications, classified as follows: • clavien-dindo grades 1-3a: 7 (28%) patients • clavien-dindo grades 3b-4: 4 (16%) patients (required surgical revision: 1 colostomy, 1 complicated lymphocele, 2 ileus due to adhesions) 12/25 (48%) median follow-up 15 months, range 3–41 – 11/25 (44%) were alive at follow-up 8/25 died of prostate cancer 6/25 died of other causes median overall survival: 15 months no significant difference in survival between the group who received preoperative adt and the group that did not a data reported on a total of 18 patients: 6 prostate and 12 bladder cancer b neoadjuvant and adjuvant treatments different between different institutions prbc: packed red blood cells; nr: not reported; postop: postoperative; cp: cystoprostatectomy; rpp: radical perineal prostatectomy; psa: prostate specific antigen; sbo: small bowel obstruction; mi: myocardial infarction; adt: androgen deprivation therapy; rp: radical prostatectomy; tpe: total pelvic exenteration; lar: low anterior resection; intra-op: intra-operative; pe: pulmonary embolus; plnd: pelvic lymph node dissection; tcc: transitional cell carcinoma; uti: urinary tract infection; dvt: deep vein thrombosis. or if rp was not surgically feasible. data on primary therapy, adjuvant therapy, and survival outcomes have not been consistently reported among studies with vast heterogeneity. the studies are presented in table 1. exenteration surgery to control local symptoms direct invasion of prostate cancer into the surrounding tissues in locally advanced disease may result in symptoms such as significant perineal pain, luts, and urinary tract obstruction[50]. pelvic exenteration has been described for prostate cancer with rectal and perineal invasion, causing severe symptoms that are unresponsive to rt[51]. kamat et al. described the efficacy of total pelvic exenteration in the complete relief of perineal pain not responding to narcotics in 14 men with prostate cancer invading the rectum and having failed adt and rt with an average symptom-free interval of 14 months in 11 men[40]. pelvic exenteration can alleviate symptomatic local recurrence of prostate cancer after rp, which is not possible with adt and rt. in a small series, leibovici et al. reported that 4 patients underwent total pelvic exenteration and 1 patient underwent wide tumor resection after rp, concluding that salvage pelvic exenteration is feasible in wellselected patients[25]. guo et al. reported the outcomes of total pelvic exenteration after recurrent prostate cancer invading the rectum causing severe intractable perineal pain[36]. on the other hand, surcel et al. performed cystoprostatectomy or pelvic exenteration for ct4 prostate cancer with severe local symptoms, regardless of previous treatment or distant metastasis[30]. , cont’d 174 siuj • volume 3, number 3 • may 2022 siuj.org review http://siuj.org role of exenteration in castrate-resistant prostate cancer many patients with castrate-resistant prostate cancer (crpc) experience local symptoms, such as hematuria, upper tract obstruction, or rectal invasion. although the changes in the landscape of crpc treatment have led to improvements in the overall survival of these patients from multimodal treatment and advancements in systemic therapeutics, local symptoms still pose a burden to affected patients and are projected to increase in incidence given the improved life expectancy of patients with crpc[52,53]. in fact, approximately half of crpc patients experience cancer-related local symptoms in their final year of life, with up to 25% requiring upper or lower urinary tract surgical interventions for palliation[52,53]. as described earlier, invasion of the bladder or rectum may necessitate anterior or total pelvic exenteration even in patients with crpc; however, patients should be good surgical candidates with an expected survival of over 1 year[52,53]. recently, heidenreich et al. reviewed 103 patients with lapca, of whom 84 had castrate-resistant prostate cancer and underwent pelvic exenteration for symptom relief[37]. overall, 78.6% of patients were able to obtain complete relief of symptoms in their remaining lifetime. a total of 41.7% of men reported gross hematuria before surgery, whereas none reported hematuria after pelvic exenteration. a total of 55.3% of patients had upper urinary tract obstruction before surgery managed by endoluminal stenting or percutaneous nephrostomy, all of which were removed postoperatively, with only table 1. summary of studies on pelvic exenteration (anterior or total) for locally advanced prostate cancer author (year) total number of patients exenteration type (number) indication (number) neoadjuvant treatment blood loss prbc transfusion surgery time hospital stay reported complications r0 resection follow-up secondary treatment reported outcomes heidenreich et al. (2020) 103 radical prostatectomy (9, 8.7%) cystoprostatectomy (71, 68.8%) total (23, 22.4%) locally advanced crpc (84) or cspc (19) with symptomatic infiltration into bladder, rectum or pelvic floor despite previous therapy nr 14.6% required transfusions from date of admission till 90 days after surgery mean 271 minutes, range 210–292 mean 18.3 days, range 10–34 reported complications classified as follows: clavien-dindo grade 2: 30.6% of patients clavien-dindo grade 3: 11.3% of patients clavien-dindo grade 4: 8.1% of patients 71/103 (68.9%) mean 3.04 years – symptom-free survival: 89.2% at 1 year, 64.1% at 3 years overall survival: 92.2% at 1 year, 43.7% at 3 years surcel et al. (2020) 25 cystoprostatectomy (23) total pelvic exenteration (2) urinary diversion: ileal conduit (18), ureterocutaneostomy (6), mainz pouch (1) palliation of ct4 prostate cancer with local invasion and local symptoms in a majority of patients, regardless of distant metastasis (25) 13 (52%) upfront surgery and 12 (48%) after adt nr nr nr nr 11/25 (44%) patients developed perioperative complications, classified as follows: • clavien-dindo grades 1-3a: 7 (28%) patients • clavien-dindo grades 3b-4: 4 (16%) patients (required surgical revision: 1 colostomy, 1 complicated lymphocele, 2 ileus due to adhesions) 12/25 (48%) median follow-up 15 months, range 3–41 – 11/25 (44%) were alive at follow-up 8/25 died of prostate cancer 6/25 died of other causes median overall survival: 15 months no significant difference in survival between the group who received preoperative adt and the group that did not a data reported on a total of 18 patients: 6 prostate and 12 bladder cancer b neoadjuvant and adjuvant treatments different between different institutions prbc: packed red blood cells; nr: not reported; postop: postoperative; cp: cystoprostatectomy; rpp: radical perineal prostatectomy; psa: prostate specific antigen; sbo: small bowel obstruction; mi: myocardial infarction; adt: androgen deprivation therapy; rp: radical prostatectomy; tpe: total pelvic exenteration; lar: low anterior resection; intra-op: intra-operative; pe: pulmonary embolus; plnd: pelvic lymph node dissection; tcc: transitional cell carcinoma; uti: urinary tract infection; dvt: deep vein thrombosis. 175siuj.org siuj • volume 3, number 3 • may 2022 the role of pelvic exenteration in the management of locally advanced prostate cancer http://siuj.org table 2. reported cases of minimally invasive pelvic exenteration for prostate cancer, author (year) number of patients exenteration surgery indication blood loss prbc transfusion surgery time hospital stay reported complications r0 resection follow-up reported outcomes yang et al. (2015) 1 laparoscopic total pelvic exenteration with cutaneous ureterostomy and sigmoidostomy recurrent prostate sarcoma causing difficult defecation 600 ml nr 415 min 10 days no early complications uti after 6 months r0 achieved 12 months died of recurrence castillo et al. (2015)a 1 robotic pelvic exenteration, bilateral eplnd, en-bloc excision of bladder and rectum, urinary and fecal diversion using double-barrel wet colostomy crpc after radical prostatectomy + salvage radiation followed by adt, presenting with rectal recurrence. 600 ml nr 249 min 7 days nr nr 24 months 6 weeks later: decreased psa = 1.39 then treated with adt and chemotherapy 2 years later: good quality of life, psa = 2.37 winters et al. (2015) 3 robotic total pelvic exenteration with laparoscopic rectus flap local recurrence of high-risk prostate cancer with a large malignant rectourethral fistula biopsy revealed recurrent prostate cancer extending to the rectal side of this fistula. 800 ml 2 units 660 min 7 days, 1 day in icu 30-day morbidity: 1/3 (33.3%) – patient developed pelvic abscess and pyelonephritis 2/3 (66.6%) – all back to daily activities within 4–6 weeks prostate cancer treated with brachytherapy presented 6 years later with ct4 high-grade, squamous differentiated urothelial carcinoma involving the bladder neck, prostate, and perirectal tissues 500 ml 1 unit 600 min 8 days, 1 day in icu t4n2m0 rectal adenocarcinoma treated with chemotherapy, followed by ebrt with persistent mass involving the prostate, seminal vesicles, and bladder 350 ml nr 570 min 7 days, 1 day in icu maurice et al. (2017) 1 robotic total pelvic exenteration with intracorporeal sigmoid conduit and colostomy metastatic crpc with failed primary brachytherapy but good systemic response to chemotherapy and adt. psa continued to rise with an enlarging prostatic pelvic mass causing progressive local symptoms nr nr 324 min (total robotic time) 8 days dic (resolved by blood products), tia (no permanent disability) nr – died after 5 months due to metastatic disease but complete palliation of symptoms was achieved a first reported case of robotic pelvic exenteration uti: urinary tract infection; eplnd: extended pelvic lymph node dissection; crpr: castrate-resistant prostate cancer; adt: androgen deprivation therapy; psa: prostate-specific antigen; nr: not reported; prbc: packed red blood cells; icu: intensive care unit; ebrt: external beam radiotherapy; dic: disseminated intravascular coagulation; tia: transient ischemic attack; lar: low anterior resection; tpn: total parenteral nutrition; apr: abdomino-perineal resection. 176 siuj • volume 3, number 3 • may 2022 siuj.org review http://siuj.org table 2. reported cases of minimally invasive pelvic exenteration for prostate cancer, author (year) number of patients exenteration surgery indication blood loss prbc transfusion surgery time hospital stay reported complications r0 resection follow-up reported outcomes yang et al. (2015) 1 laparoscopic total pelvic exenteration with cutaneous ureterostomy and sigmoidostomy recurrent prostate sarcoma causing difficult defecation 600 ml nr 415 min 10 days no early complications uti after 6 months r0 achieved 12 months died of recurrence castillo et al. (2015)a 1 robotic pelvic exenteration, bilateral eplnd, en-bloc excision of bladder and rectum, urinary and fecal diversion using double-barrel wet colostomy crpc after radical prostatectomy + salvage radiation followed by adt, presenting with rectal recurrence. 600 ml nr 249 min 7 days nr nr 24 months 6 weeks later: decreased psa = 1.39 then treated with adt and chemotherapy 2 years later: good quality of life, psa = 2.37 winters et al. (2015) 3 robotic total pelvic exenteration with laparoscopic rectus flap local recurrence of high-risk prostate cancer with a large malignant rectourethral fistula biopsy revealed recurrent prostate cancer extending to the rectal side of this fistula. 800 ml 2 units 660 min 7 days, 1 day in icu 30-day morbidity: 1/3 (33.3%) – patient developed pelvic abscess and pyelonephritis 2/3 (66.6%) – all back to daily activities within 4–6 weeks prostate cancer treated with brachytherapy presented 6 years later with ct4 high-grade, squamous differentiated urothelial carcinoma involving the bladder neck, prostate, and perirectal tissues 500 ml 1 unit 600 min 8 days, 1 day in icu t4n2m0 rectal adenocarcinoma treated with chemotherapy, followed by ebrt with persistent mass involving the prostate, seminal vesicles, and bladder 350 ml nr 570 min 7 days, 1 day in icu maurice et al. (2017) 1 robotic total pelvic exenteration with intracorporeal sigmoid conduit and colostomy metastatic crpc with failed primary brachytherapy but good systemic response to chemotherapy and adt. psa continued to rise with an enlarging prostatic pelvic mass causing progressive local symptoms nr nr 324 min (total robotic time) 8 days dic (resolved by blood products), tia (no permanent disability) nr – died after 5 months due to metastatic disease but complete palliation of symptoms was achieved a first reported case of robotic pelvic exenteration uti: urinary tract infection; eplnd: extended pelvic lymph node dissection; crpr: castrate-resistant prostate cancer; adt: androgen deprivation therapy; psa: prostate-specific antigen; nr: not reported; prbc: packed red blood cells; icu: intensive care unit; ebrt: external beam radiotherapy; dic: disseminated intravascular coagulation; tia: transient ischemic attack; lar: low anterior resection; tpn: total parenteral nutrition; apr: abdomino-perineal resection. continued on page 178 177siuj.org siuj • volume 3, number 3 • may 2022 the role of pelvic exenteration in the management of locally advanced prostate cancer http://siuj.org table 2. reported cases of minimally invasive pelvic exenteration for prostate cancer, author (year) number of patients exenteration surgery indication blood loss prbc transfusion surgery time hospital stay reported complications r0 resection follow-up reported outcomes smith et al. (2020) 2 robotic lar + en-bloc prostatectomy locally advanced extracapsular prostate cancer after brachytherapy nr 2 units 480 min 15 days, 1 day in icu ileus (required tpn), atrial fibrillation r0 achieved 12 months no recurrence for both at 12 months follow-up robotic apr + en-bloc cystoprostatectomy + ileal conduit locally advanced extracapsular prostate cancer after ebrt with synchronous t1 rectal cancer nr 2 units 360 min 11 days, 1 day in icu nr r0 achieved peng et al. (2020) 1 robotic pelvic exenteration prostate cancer with extracapsular extension that had persistent abutment of rectal wall and pelvic floor involvement after chemoradiation nr nr nr nr nr r0 achieved – – a first reported case of robotic pelvic exenteration uti: urinary tract infection; eplnd: extended pelvic lymph node dissection; crpr: castrate-resistant prostate cancer; adt: androgen deprivation therapy; psa: prostate-specific antigen; nr: not reported; prbc: packed red blood cells; icu: intensive care unit; ebrt: external beam radiotherapy; dic: disseminated intravascular coagulation; tia: transient ischemic attack; lar: low anterior resection; tpn: total parenteral nutrition; apr: abdomino-perineal resection. 5.8% of patients requiring stenting later. the surgical procedures and patient outcomes are summarized in table 1. other reported indications for pelvic exenteration in prostate cancer cystoprostatectomy has been described in t he management of synchronous prostate and rectal cancer[54,55] and synchronous prostate and bladder cancer[56], as well as in the management of severe complications of salvage cryotherapy for prostate cancer[38]. discussion pelvic exenteration, whether total or anterior, has been performed for lapca, including crpc, and has been described for the following indications: prostate cancer invading the bladder; salvage surgery after failure of other treatments; control of local symptoms; and synchronous prostate, bladder, or rectal tumors. in addition to the potential survival benefits associated with surgical treatment, pelvic exenteration may provide additional symptomatic benefits that investigators have evaluated in several studies. the main limitation in assessing the impact of pelvic exenteration in lapca is the heterogeneity and limitations of the published studies. the majority of the studies have had small sample sizes and varied patient characteristics. data on previous therapies, neo-adjuvant treatments, and adjuvant treatments have not been consistently reported and have insufficient details. different survival parameters and follow-up durations have been reported. surgical procedures and techniques were different between studies; for example, different types of urinary diversion were used with all being feasible, but no data reported on the superiority of one over the other. not all studies have reported operative outcomes, including the need for blood transfusions and length of hospitalization. reporting of complications was not standardized among studies, with few using the clavien-dindo classification. comparisons made within the studies were also heterogeneous. for example, gheiler et al.[35] compared all outcomes after cystoprostatectomy based on the type of urinary diversion used; zincke et al.[34] and lerner at al.[26] compared the outcomes between different types of surgery performed as salvage treatment after radiotherapy; and ward et al.[32] reported the difference in need for blood transfusions and early complication rates in patients undergoing cystoprostatectomy based on the year of their surgery. finally, there are scarce reports on the outcomes of long-term follow-up, including the need for further urological interventions, number of readmissions, and objective assessment of qol. , cont’d 178 siuj • volume 3, number 3 • may 2022 siuj.org review http://siuj.org pelvic exenteration represents a major surgery that can lead to significant morbidity and that may harbor a perioperative mortality risk. the major complication rates reported in the literature range between 44% to 55%. the impact of minimally invasive surgery for pelvic exenteration in prostate cancer is still unclear, given the small number of cases reported. although there are no clear outcomes, a minimally invasive approach is possible, with few reported complications. most authors concluded that exenteration may be feasible for well-selected patients despite the increased operative risk. therefore, the decision to proceed should be tailored according to patient comorbidities, projected life expectancy, impact of symptoms on qol, and availability of experienced surgeons to perform these complex operations. lapca management remains a clinical challenge despite advances in systemic therapies over the past decade[57,58]. even though systemic agents as well as traditional adt have been successful in decreasing the progression and improving the survival of patients with advanced prostate cancer, they may not palliate or address the symptoms associated with the direct invasion of lapca. pelvic exenteration, on the other hand, may not be curative in locally advanced disease but may be associated with a durable disease response, particularly in combination with systemic treatments. the rationale for the use of cytoreductive surgery involves multiple postulations. decreasing the bulk of the disease would render systemic therapy more effective, since the same dosage is used against a smaller number of malignant cells. another theory is that surgical debulking decreases the number of cells that can undergo somatic mutations and become castrate-resistant in cases of prostate cancer[59,60]. another rationale is extrapolation from the concept of index lesions in prostate cancer and clonality, which is the scientific basis of prostate focal therapy[61]. exenteration would treat the index lesion, which would eventually lead to metastasis and castration resistance. the evidence for cytoreductive surgery in metastatic prostate cancer is not as robust but is an area of interest for many investigators. a study using the seer database showed that such patients who underwent local therapy had a survival benefit over those who did not receive local therapy[62]. another national cancer database study showed that cytoreductive prostatectomy and primary radiotherapy provide an overall survival benefit in metastatic prostate cancer[63]. however, these were retrospective database studies and did not provide robust evidence to change current practice guidelines or currently available systemic treatment options. recently, the stampede trial has shown a survival benefit of local radiation therapy in low-volume metastatic prostate cancer[64]. table 2. reported cases of minimally invasive pelvic exenteration for prostate cancer, author (year) number of patients exenteration surgery indication blood loss prbc transfusion surgery time hospital stay reported complications r0 resection follow-up reported outcomes smith et al. (2020) 2 robotic lar + en-bloc prostatectomy locally advanced extracapsular prostate cancer after brachytherapy nr 2 units 480 min 15 days, 1 day in icu ileus (required tpn), atrial fibrillation r0 achieved 12 months no recurrence for both at 12 months follow-up robotic apr + en-bloc cystoprostatectomy + ileal conduit locally advanced extracapsular prostate cancer after ebrt with synchronous t1 rectal cancer nr 2 units 360 min 11 days, 1 day in icu nr r0 achieved peng et al. (2020) 1 robotic pelvic exenteration prostate cancer with extracapsular extension that had persistent abutment of rectal wall and pelvic floor involvement after chemoradiation nr nr nr nr nr r0 achieved – – a first reported case of robotic pelvic exenteration uti: urinary tract infection; eplnd: extended pelvic lymph node dissection; crpr: castrate-resistant prostate cancer; adt: androgen deprivation therapy; psa: prostate-specific antigen; nr: not reported; prbc: packed red blood cells; icu: intensive care unit; ebrt: external beam radiotherapy; dic: disseminated intravascular coagulation; tia: transient ischemic attack; lar: low anterior resection; tpn: total parenteral nutrition; apr: abdomino-perineal resection. 179siuj.org siuj • volume 3, number 3 • may 2022 the role of pelvic exenteration in the management of locally advanced prostate cancer http://siuj.org while pelvic exenteration may provide an oncologic benefit for locally advanced or metastatic prostate cancer, a more compelling reason for surgical intervention is the control of local symptoms. however, there is no standardized quantifiable qol indicator because symptomatology is variable given the heterogeneous nature of this disease and its classification. future studies using validated qol questionnaires would help to address these questions in these patients[65]. recently, with the introduction of theranostics and the emerging widespread adoption of functional imaging studies such as positron emission tomography using prostate-specific membrane antigen (pet-psma), variations in clinical management are expected[66]. these would include surgical planning in cases of advanced disease requiring exenteration. the improvement in the perioperative and postoperative outcomes of salvage robot-assisted radical prostatectomy might open the door for better utilization of neoadjuvant rt for lapca[67,68]. the role of neoadjuvant rt is well established for several different types of malignancies and is considered the standard of care for some patients[69,70]. the rationale for its preoperative use in cases of prostate cancer is that rt induces longterm growth arrest in prostate cancer cells rather than acute apoptosis[71]. these cells would still be positive if present at the resection margin; however, a positive margin after neoadjuvant radiation therapy might indicate the presence of sterilized cancer cells that later die due to necrosis[71]. the role of neoadjuvant rt in prostate cancer has not been well studied, and neoadjuvant rt is not part of the standard of care for the management of patients with prostate cancer. carlson et al. reported their results on 18 patients who received neoadjuvant rt doses ranging from to 40 to 70 gy followed by radical prostatectomy 1 to 2 months afterwards, with minimal postoperative morbidity and 67% of patients metastasis-free at 5 years[72]. several phase i and phase ii trials of neoadjuvant rt followed by radical prostatectomy have confirmed the safety of the surgery with minimal side effects and improvement in biochemical progression-free survival[73]. this approach should be investigated in patients with lapca who might be good candidates for pelvic exenteration. conclusion pelvic exenteration can be offered to patients with lapca, whether for cure or for palliation of local symptoms; however, it is not a widely used management option. retrospective data indicated that pelvic exenteration may help alleviate local pain and luts and improve patient qol. however, the oncological benefits of such procedures have not been well established. furthermore, this extensive surgical treatment option is associated with high complication rates. there is an urgent need for prospective multicenter studies that use a standardized methodology to report complications, incorporate patient-reported outcomes, and examine novel endpoints such as the need for adjunct upper and lower urinary tract procedures and the need for hospitalization for 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2, supplement 1, july 2021 stacy loeb,a,* peter c. black,b,† alexander w. wyatt,c yaw a. nyame,d,e neal shore,f derya tilki,g,h elena castro,i matthew cooperberg,j veda giri,k maria j. ribal,l,m giovanni lughezzani,n,o rafael sánchez-salas,p caroline m. moore,q art rastinehad,r linda kerkmeijer,s hashim u. ahmed,t shusuke akamatsu,u alexandre de la taille,v martin gleave,b simon tanguayw,‡ adepartment of urology and population health, new york university school of medicine and the manhattan veterans affairs medical center, new york city, united states bdepartment of urologic sciences, university of british columbia, vancouver, canada cvancouver prostate centre, department of urologic sciences, university of british columbia, vancouver, canada ddepartment of urology, university of washington medical center, seattle, united states edivision of public health sciences, fred hutchinson cancer research center, seattle, united states fcarolina urologic research center, myrtle beach, united states gmartini-klinik prostate cancer center, hamburg, germany hdepartment of urology, university hospital hamburg-eppendorf, hamburg, germany ispanish national cancer research center, madrid, spain jschool of medicine, university of california, san francisco, united states ksidney kimmel cancer center, thomas jefferson university, philadelphia, united states luro-oncology unit, hospital clinic, university of barcelona, barcelona, spain meau guidelines office, arnhem, the netherlands ndepartment of biomedical sciences, humanitas university, pieve emanuele, italy odepartment of urology, humanitas clinical and research hospital – irccs, rozzano, italy pdepartment of urology, institut mutualiste montsouris, paris, france qdivision of surgical and interventional science, university college london, london, united kingdom rdepartment of urology, lenox hill hospital, northwell health, new york city, united states sdepartment of radiation oncology, radboud university medical center, nijmegen, the netherlands timperial prostate, department of surgery and cancer, imperial college london, london, united kingdom udepartment of urology, kyoto university graduate school of medicine, kyoto, japan vurology department, chu mondor, assistance publique des hôpitaux de paris, créteil, france wdivision of urology, mcgill university, montreal, canada *co-chair of the scientific programme committee (pca) †chair of the scientific programme committee ‡co-chair of the scientific programme committee (rcc) the bench-to-bedside uro-oncology gu cancer triad meeting was organized by the société internationale d’urologie and was held online on may 21st and 22nd, 2021. the session on prostate cancer (pca) took place on the morning of saturday, may 22nd, and was chaired by dr. stacy loeb (united states) and dr. peter c. black (canada). this session covered advances in the diagnosis and management of localized, locally advanced, and metastatic pca, as well as three case-based panel discussions on biomarkers, focal therapy, and systemic therapy in pca. additionally, the programme included presentations on the state of the art of liquid biopsy, covid-19 impact, and digital health in urologic oncology. the first talk was led by dr. alexander wyatt, who presented the state of the art of liquid biopsy in urologic oncology. in particular, he discussed the use of plasma circulating tumour dna (ctdna) as a biomarker in pca. plasma ctdna comprises short fragments of post-apoptotic tumour dna in the blood that are mixed with cell-free dna from noncancer cells, such as leukocytes. generally, ctdna abundance is associated with tumour burden and more advanced disease[1]. while several non-genomic biomarkers, such as serum prostate-specific antigen (psa), are already well-established in pca management, ctdna-based biomarkers may be particularly useful for predicting treatment efficacy, especially in the metastatic setting. the fraction of ctdna (as a proportion of total cellfree dna in plasma) is a strong prognostic factor for disease outcomes. in two randomized phase 2 trials, ctdna fraction correlated with overall survival (os), with patients exhibiting poorer survival outcomes with increasing ctdna fraction, independent of clinical prognostic factors[2,3]. in addition, changes in ctdna fraction during treatment may indicate not only response but also pending relapse in the metastatic castration-sensitive pca (mcspc) and metastatic castration-resistant pca (mcrpc) settings[3,4]. understanding the prognostic value of ctdna fraction may also help to guide treatment decisions. the ongoing open-label phase 2 protract trial aims to doi: 10.48083/zjlz6285 b2b: prostate cancer summary 31 b2b: prostate cancer summary provide insights on whether ctdna fraction can assist treatment selection for second-line androgen receptor pathway inhibitor (arpi) compared to taxane-based chemotherapy[5]. dr. wyatt emphasized the key differences between tumour tissue and plasma ctdna sequencing. sequencing of tumour tissue is only performed in samples with high tumour content (>20%) to lower the chance of false negatives. by contrast, the tumour content (ctdna fraction) of plasma cell-free dna samples cannot be discerned prior to sequencing and must instead be determined via bioinformatics after sequencing. importantly, the precise ctdna fraction dictates which tumour alterations can be identified. for example, practical limits of detection are around 1% ctdna for most somatic mutations, but can be as high as 20% for certain changes in copy number[4,6]. in a phase 2 clinical trial of the poly(adp-ribose) polymerase (parp) inhibitor rucaparib in mcrpc, brca alterations were identified in patient-matched tissue and plasma, with a relatively high concordance of 75%[7]. several homozygous brca2 copy number losses were not identified by plasma testing, likely due to insufficient ctdna fraction. dr. wyatt highlighted that around 25% of patients with mcrpc can have very low ctdna fraction, which means that testing results must be carefully interpreted to understand if low ctdna may prevent the detection of certain somatic alterations. just as tissue samples with low tumour content are triaged prior to sequencing, when using ctdna to detect the mutational status of genes of interest, it is important to triage samples that have low tumour content in the plasma. in a recently published study of 879 patients with metastatic pca, samples of only 635 patients had sufficient ctdna fraction to allow identification of both somatic and germline mutations[8]. importantly, however, this approach allowed the minimally invasive detection of homologous recombination repair (hrr) gene mutations, such as brca2, atm, and cdk12, in over 15% of patients. these mutations were identified across 94% of serial ctdna samples as well as in all available archival primary tissues, suggesting that dna repair gene status does not change over time in patients with metastatic pca. studies of ctdna in mcrpc are also revealing emerging biomarkers, such as the independently prognostic impact of tp53 mutations[2]. androgen receptor (ar) copy number amplification as a continuous variable shows promising results as a biomarker to influence treatment selection between chemotherapy and arpi[3,9]. the next steps for development of ctdna-based predictive biomarkers is to prove clinical utility. a prospective biomarker-driven phase 2 trial led by the canadian cancer trials group is aiming to address this need[10]. currently, over 425 patients with mcrpc have been screened in this trial, using ctdna to stratify treatment arms. during the q&a, dr. wyatt discussed why some cancers shed more ctdna than others. differences in tumour shedding are seen not only across different cancer types, but also within the same form of cancer. in pca, higher proliferative tumour burden is associated with increasing ctdna shedding, although there are clearly some underlying biological mechanisms that are not yet understood. next, dr. wyatt discussed future applications of ctdna biomarkers in earlier disease stages, which he believes is a logical approach, although challenging. as dr. wyatt pointed out, there are good biomarkers already available in earlier pca settings to determine minimal residual disease or even early diagnosis. he advised caution for rushing to implement any new ctdna-based biomarkers in this space to avoid the risk of overdiagnosing or overtreating. dr. wyatt then commented on differences in allelic percentages reported by commercially available tests. according to him, these differences are likely due to the sampling probability for rare variants in small volumes of blood. in general, the field is moving away from reporting very rare variants (allelic frequencies much lower than 1%) that may not be reflective of the cancer and instead represent other somatic clones in circulation. dr. wyatt also provided his insights on advances for ctdna on the horizon. he highlighted the potential for analysis of serial ctdna samples collected over time to understand mechanisms of disease evolution and progression[11]. 32 proceedings from the siu b2b uro-oncology: gu cancers triad • may 21–22, 2021 – siuj volume 2, supplement 1, july 2021 b2b: prostate cancer summary the next presentation was by dr. yaw nyame (united states), who discussed racial disparities in pca and a patient-centred research framework for addressing inequities in pca care and outcomes. a health disparity is defined as a higher burden of illness, injury, disability, or mortality experienced by one group relative to another. pca is a profound example of a cancer health disparity, particularly in the united states. disparities in pca reflect interactions between social, health, and biologic factors. for instance, the worst outcomes in pca in the united states are concentrated in counties in the southeastern united states[12] that form the historic cotton belt—a region where the highest production of cotton occurred in the 19th century. cotton production during this time period was a major economic trade in the united states and was associated with the slave trade. the cotton belt is also home to the highest proportion of men of african american ancestry in the country[13]. this example demonstrates the complexity of socio-geographic and economic factors. despite a 50% reduction in pca mortality in the united states since the introduction of psa screening in the late 1980s, black men have consistently demonstrated a two-fold greater risk of dying from the disease compared to men of all other races (generated with data from[14]). this disparity appears to be even higher among younger males, in which 40and 50-year-old black men are at an up to four-fold higher risk of dying from pca compared to white men[15]. similar trends appear to occur worldwide in regions with not only large populations of african american ancestry but also in areas of the developing world[16]. regarding pca natural history, black men are likely to develop pca at younger ages and are at higher risk of progression to metastatic disease by the time of diagnosis compared to the general population[17]. what are some of the drivers of disparity in pca outcomes? in the early 2000s, the world health organization (who) popularized the concept of social determinants of health, which include economic stability, neighbourhood and physical environment, education, access to food, the community and social context, and the healthcare system[18]. these determinants dictate healthcare utilization and patient outcomes. social determinants of equity (i.e., economic and structural barriers) inform how each social determinant of health impacts pca risk[19]. pca disparities, particularly in the united states, form what dr. nyame calls a “perfect storm”: it is a disease with higher incidence, in which a variety of social factors, structural and societal barriers, mistrust, and health system barriers further impact outcomes. how can racial disparities in pca be reduced? to answer this question, dr. nyame and colleagues have developed a conceptual model to help identify critical checkpoints in the pca journey that may improve patient outcomes. for example, the model demonstrates that pca screening can be a powerful tool that may lead to early detection and mortality reduction. in this setting, access to psa testing and biopsy may lead to distinct improvements in health inequities. as a patient progresses to treatment, there are multiple timepoints where differential utilization of care influences outcomes, including: access and quality of care, modifiable risks, and treatment preferences in the localized setting; quality of surveillance following definitive treatment; and access to salvage therapy and clinical trials if pca progresses. pca screening has an important benefit for mortality rate reduction. in a recent study, the benefit of psa screening was evaluated over a period of more than 24 years since patients had been randomized in clinical trials[20]. results demonstrated a positive impact of psa screening on pca mortality beyond 16 years, highlighting a particular benefit in young and healthier men. given that black men present with pca at a younger age and with more disparate outcomes, earlier screening may be particularly valuable in this patient population[21,22]. by contrast, the 2012 u.s. preventive services task force recommendation against routine psa testing led to a decrease in pca screening that was markedly seen among black men[23]. regarding definitive treatment, a recent multiple-cohort study analyzed data from the surveillance, epidemiology, and end results (seer), the veterans affairs health system, and the national cancer institute-sponsored radiation therapy oncology group[24]. results demonstrated that access to care b2b: prostate cancer summary 33 b2b: prostate cancer summary and standardized treatment, as seen in clinical trials, are associated with decreased disparities in pca outcomes among black men. in a cohort of men with high-risk pca, another study evaluating data from the cleveland clinic, johns hopkins institute, and md anderson cancer center showed no differences in outcomes with standardized treatment, regardless of ethnicity[25]. nevertheless, the rate of definitive treatment for pca is lower in black men compared to other ethnicities[26]. as highlighted by dr. nyame, even more troubling is the fact the black men are underrepresented in clinical trials, at roughly 3% of current practice-informing studies[27]. how can barriers to research participation and clinical care among black men be overcome? in the united states, people of african american ancestry have been the subject of medical experimentation without their consent throughout history[28]. the trauma in this population is transgenerational and shapes medical mistrust and cultural health beliefs. in addition, poor and minority populations were long considered “medical material” for training in the clinical practice, which poses a barrier to the participation of these individuals in contemporary clinical trials. in such a challenging context, what can be done to close the gap in pca racial disparities? dr. nyame believes the focus must be in building communities and empowering patients. a patient-centred research approach is paramount and should be founded on the principles of reciprocal relationships, cooperative learning, partnership, transparency, honesty, and trust[29]. this novel approach is crucial to reduce racial disparities in pca and other diseases. in the q&a session, dr. nyame expressed the need for appropriate representation to mediate effective communication between the medical community and patients. this is deeply affected by the underrepresentation of several populations in practice-informing clinical trials. dr. nyame discussed the role of the who and artificial intelligence (ai) in correcting health disparities. according to dr. nyame, the who has mobilized funds to help flight health disparities, particularly in developing countries where even access to psa testing may be scarce. with regards to ai, he advised caution, as many platforms use real-world data that may lead to biased results and increased disparity. next, dr. nyame explained how to assess the effectiveness of community-based research. in this case, dr. nyame relies on seer data and emphasized that the ultimate goal is to produce significant improvements in the mortality curves. lastly, dr. nyame discussed whether single-nucleotide polymorphism (snp) approaches are a legitimate tool for inferring race from genetic data. he believes that these approaches are beneficial and may ultimately help to demystify the association of pca risk and ethnicity. next, dr. neal shore (united states) presented the five pca practice-changing advances on the horizon, as emphasized by dr. shore, these advances require an understanding of genetic profiling not only to guide treatment decision-making, but also to better counsel patients regarding their own and their family’s risk of developing cancers. first, dr. shore discussed advances in overcoming ar resistance in pca. despite rapid and dramatic responses to androgen deprivation therapy (adt) as monotherapy or in combination with an arpi, all patients with pca eventually develop castration resistance[30]. some of the mechanisms underlying this process include ar alterations, such as ar gene or gene enhancer amplification, ar point mutations, and autocrine tumour androgen production[30]. currently, there are several strategies under investigation to overcome ar resistance and improve treatment outcomes. one of these strategies involves the use of proteolysis targeting chimera (protac) protein degraders to target ars by engaging the ubiquitin proteasome system (ups), which is used by cells to degrade proteins and maintain homeostasis. this approach was recently investigated in a phase 1 clinical trial and demonstrated promising results in patients with mcrpc for treatment with arv-110, a protac with high ar-degradation activity in preclinical models[31]. another strategy under investigation is targeting of the dna damage response (ddr) system with atr inhibitors to prevent replication of defective cells with tumourigenic potential[32]. this approach may prove particularly useful in patients with mcrpc who harbour atm mutations and are likely more susceptible to atr inhibition. the ezh2 pathway may also offer a novel therapeutic target in mcrpc, given its involvement in important aspects of cancer 34 proceedings from the siu b2b uro-oncology: gu cancers triad • may 21–22, 2021 – siuj volume 2, supplement 1, july 2021 b2b: prostate cancer summary genetics, acquired drug resistance, and regulation of anti-tumour immune response through gene silencing[33]. inhibition of ezh2 leads to the re-expression of silenced genes and shows potential for combination with arpis to overcome ar resistance. finally, another strategy under investigation is targeting the pi3k/akt pathway, which shows crosstalk with ar pathways. targeting both pathways with an akt inhibitor and arpi shows potential to increase antitumour activity, particularly in pca tumours with pten loss[34]. then, dr. shore detailed the potential of bispecific t-cell engager (bite®) immunotherapy in pca. bite is a novel class of therapeutic molecules that are able to activate an anti-tumour immune response by engaging the patient’s own t cells[35]. amg 160 is a bite molecule that selectively targets prostate-specific membrane antigen (psma), which is highly expressed in pca cells. in an ongoing phase 1 clinical trial, amg 160 showed tolerable efficacy in patients with mcrpc[36]. cytokine release syndrome (crs) was the most common adverse event (ae) observed, which is commonly associated with the mechanism of action of bite immunotherapy. the next practice-changing advance in pca relates to the use of psma positron emission tomography (pet) imaging, which has profound diagnostic and therapeutic implications due to its high expression in pca tumours and metastases. in the end of 2020, the u.s. food and drug administration (fda) approved 68ga psma-11 for pet imaging[37]. more recently, the positive results of the phase 3 condor trial[38] and the phase 2/3 osprey trial[39] have led that to the approval of a second psma pet agent, 18f-dcfpyl, in the united states. as these new imaging approaches become standard of care in the united states and other countries, it is critical that urologists understand how this additional information may influence treatment decision-making. as highlighted by dr. shore, one of practice-changing potentials of next-generation psma pet imaging is visualization of disease sites that can then be targeted with radiopharmaceutical agents. to date, 223ra is the only radiopharmaceutical approved in the mcrpc space[40], although it remains underutilized. a new generation of radiopharmaceuticals that couple the radioactive β-emitter 177lu to a psma-targeted molecule is underway and has showed promising results in the phase 3 vision trial[41,42]. important considerations that emerge with new theranostic approaches include not only understanding how these will fit in the current systemic therapy landscape but also how to optimally select patients for these new treatments. lastly, dr. shore discussed the potential of combining parp inhibitors with other agent classes, such as adt, to target pca cells. because the ar and the hrr pathways are interconnected, combining adt and parp inhibition may result in synthetic lethality, as suggested by preclinical studies[43]. a similar rationale may be applied not only to parp inhibitor combination with adt, but also with other therapies in mcrpc, such as chemotherapy, radionuclide therapies, and immune checkpoint inhibitors (icis), as well as akt and atr inhibitors (reviewed in [44]). during the q&a, dr. shore provided his insights on practice-changing advances coming to the localized pca setting. several patients with high-risk localized pca who present with grade 3 to 5 disease may relapse after radical prostatectomy or radiation therapy. in this setting, dr. shore emphasized the upcoming results of the phase 3 atlas trial, which has evaluated the role of radiation therapy in combination with adt or apalutamide in this patient population[45]. similar strategies in neoadjuvant and adjuvant strategies are also under investigation in patients who undergo radical prostatectomy. the pca session continued with a case-based panel on the use of germline vs. genomic biomarkers in pca management. the discussion was moderated by dr. derya tilki (germany), with input from dr. elena castro (spain), dr. matthew cooperberg (united states), and dr. veda giri (united states). the first case was a 74-year-old male who underwent prostatectomy. the final pathology revealed tumour with gleason score (gs) 3+4, pt3a stage, no lymph node involvement, and focal positive margin. at his 2-month follow-up, the patient was using less than one pad per day and had undetectable psa levels (<0.015 ng/ml). since the patient presented with adverse pathology, should any additional biomarkers be assessed? in the postoperative setting, genetic-based tests may provide b2b: prostate cancer summary 35 b2b: prostate cancer summary additional insight to guide follow-up and management decisions. the decipher® prostate cancer test is an option in this space and uses the expression of 22 selected rna markers to predict the risk of metastasis and cancer-specific mortality[46]. for the patient in this case, the decipher score was 0.67, just above the high-risk threshold. what is the role of genetic biomarkers in treatment decision-making in the adjuvant setting post-radical prostatectomy? in 2020, results of the phase 3 radicals-rt, getug-afu 17, and raves trials demonstrated no benefit between adjuvant radiotherapy and salvage radiotherapy for patients with localized pca following prostatectomy[47-49]. however, decipher score may guide management decisions in the presence of rising psa levels. in a retrospective analysis, patients with high decipher scores and differing psa levels had improved outcomes when treated with adjuvant radiotherapy. by contrast, no benefit was seen in patients with low postoperative decipher scores[50]. in addition, decipher presents a grid report, which provides predictive responses to different treatment approaches in presence of biochemical recurrence. a novel genomic signature approach based on 24 genes called portos is under investigation to also predict response to postoperative radiotherapy. in a matched retrospective study, men with high portos had better outcomes after receiving radiotherapy compared to those who did not. interestingly, the opposite was seen in patients with low portos[51]. at 6 months following radical prostatectomy, the patient presented with rising levels of psa at 0.13 ng/ ml. in this scenario, it may be beneficial to wait until the psa level rises to 0.2 ng/ml to proceed to any additional interventions, according to the artistic trials[52]. in addition, this patient may benefit from germline genetic testing, given the high-risk pca features. this decision could also be influence by the patient’s family history of cancer, which could lead to investigations for hereditary cancer syndrome. the second case was a 75-year-old male who progressed to metastatic pca. the patient was initially treated with robotic-assisted prostatectomy. rising psa levels were observed postoperatively, upon which a pet/computed tomography (ct) scan revealed lymph node metastasis. at this point, the patient started on adt, which led to psa decline. this patient meets the criteria for germline testing in the metastatic setting, according to several guidelines worldwide (summarized in [53]). another important factor highlighted in the guidelines is the family history of cancer. in the case, a pedigree revealed that the patient’s family had a history of breast and colon cancers, and also uncovered ashkenazi jewish ancestry on both sides of the family, which is an additional criterion for germline testing. what genes should be analyzed for germline mutations? according to the philadelphia consensus, a broad panel that includes genes associated with cancer predisposition syndrome is recommended for patients with advanced pca[54]. if this is not feasible, at least the presence of mutations in brca1, brca2, and mismatch repair genes should be investigated. alterations in these genes have implications for therapy selection, such as parp inhibitors and immunotherapy. additional genes may also be included, according to the patient’s personal or family history of cancers. the patient underwent germline testing with a multi-gene panel that revealed a pathogenic mutation in brca2. while such patients may respond to adt, they are at increased risk of progression and should be monitored closely. upon progression to mcrpc, patients with germline brca2 may experience significantly improved outcomes with parp inhibitor therapy, as seen in clinical trials with rucaparib[55] and olaparib[56]. in addition, the use of parp inhibitors is under evaluation as monotherapy or in combination with other therapies, such as adt, in earlier disease settings (reviewed in [57]). brca2 mutation status may also have implications for patients with early-stage pca, given the increased molecular risk of aggressive disease[58]. however, it is still unknown how brca2 and other germline mutation status may influence management during active surveillance. germline testing in patients with pca also provides insights on hereditary cancer syndromes. in the case, the brca2 mutation identified in the patient is also associated with an increased risk for hereditary breast and ovarian cancer (hboc) syndrome, as well 36 proceedings from the siu b2b uro-oncology: gu cancers triad • may 21–22, 2021 – siuj volume 2, supplement 1, july 2021 b2b: prostate cancer summary as additional cancer risks[54]. this is an important consideration not only for pca survivors but also their families. the patient in the case qualifies for brca2 cascade testing, which involves germline testing for a particular mutation in all direct relatives, such as children and siblings. given the patient’s ashkenazi jewish ancestry, cascade testing could also be offered to other family members. in addition, the pathogenic brca2 mutation uncovered through germline testing would lead to specific screening recommendations for pca, melanoma, breast, ovarian, and pancreatic cancers for the patient and his relatives. it is important to highlight that genetic counselling is critical both prior to and post germline testing to inform patients about the purpose of the test, the potential for uncovering hereditary cancer syndromes or additional cancer risks, as well as how test results may influence cancer screening and management for patients and their families[54]. the next presentation was by dr. maria j. ribal (spain), who discussed the impact of covid-19 in urologic oncology. with nearly 153 million people affected by the pandemic worldwide, this is an unprecedented situation in modern times that has had profound effects on different aspects of uro-oncological care. dr. ribal first focused on the impact on optimization of resources. at the beginning of the pandemic, all hospital resources were shifted to care for patients infected with sars-cov-2. this situation pushed physicians to best prioritize healthcare resources, which led to the publication of guidelines specific for rapid response in the covid-19 era. with that in mind, the european association of urology (eau) published guideline recommendations in april 2020 in an effort to guide management decisions and patient prioritization during the pandemic[59]. while the clinical evidence to build these guidelines was not high level, the analysis of data collected during the past 1.5 years will provide important insights on the real impact of not only delayed therapy, but, more importantly, delayed diagnosis. recently, the impact of delayed treatment was systematically reviewed in a series of retrospective studies[60]. the results demonstrated an association between cancer treatment delays and increased mortality that may have important implications following the covid-19 pandemic. to this end, an attractive strategy may be the establishment of covid-19–free surgical pathways, in which major perioperative facilities are not shared with patients with covid-19[61]. another challenge is determining the appropriate timing of surgery following sars-cov-2 infection. in a recent prospective study, reduced mortality risk was found in patients who had a least a 7-week delay for surgery following the infection[62]. further delays may be beneficial if covid-19 symptoms persist for over 7 weeks. in addition to the utilization of resources, another important aspect is the impact of covid-19 on patients with cancer who were undergoing active treatment. this is a controversial topic, as dr. ribal highlighted. while early reports suggested that cancer patients with covid-19 undergoing treatment were at an increased risk of mortality, another prospective study demonstrated that the risk was not greater compared to non-infected patients[63]. dr. ribal emphasized that best way to address this question is by acquiring data from clinical registries. some examples include the covid-19 and cancer consortium registry (ccc19)[64], the asco survey on covid-19 in oncology (asco) registry[65], and the esmo-cocare registry[66]. the current challenge is evaluating the impact of covid-19 vaccination on cancer. several societies and organizations, such as the european society of medical oncology (esmo)[67], the american society of clinical oncology (asco)[68], and the national comprehensive cancer network (nccn)[69], have provided statements encouraging the vaccination of patients with cancer, as long as components of the vaccine do not interfere with active treatments. the benefit of covid-19 vaccination may be even greater for patients who undergo surgery, as suggested by a modelling study. since vaccine numbers are limited, prioritizing patients undergoing surgery may not only support safe re-initiation of elective surgical services, but also reduce the incidence of postoperative pulmonary complications and the associated healthcare costs[70]. the social-distancing restrictions imposed by covid-19 had impor tant repercussions for the b2b: prostate cancer summary 37 b2b: prostate cancer summary development of telemedicine. this novel modality of health care will likely remain a mainstay of health systems and will require adequate training for physicians and patients alike in order to fully explore the benefits of this tool[71]. however, each patient with cancer is different and many may still require in person interactions with their healthcare providers[72]. going forward, the benefits of in-person interactions should be balanced with the continuing need for telemedicine. covid-19 also imposed barriers to medical research, including patient recruitment for clinical trials and access to hospital facilities to conduct investigations. for several ongoing trials in genitourinary cancers, the need for repeated in-person visits has precluded accrual. research-related personnel and resources have also been relocated to covid-related care and research[73]. the pandemic has also posed a burden on the mental and emotional well-being of physicians[74]. medical departments should be aware of this challenge and develop initiatives to prevent burnout among their healthcare teams. the pandemic will have a long-lasting impact on healthcare systems, particularly because of delayed diagnoses. in a recent population-based modelling study in the united kingdom, delayed diagnosis due to covid-19 was shown to result in increased 5-year mortality rates for breast, colorectal, and esophageal cancers[75]. in uro-oncology, the reduction in surgeries seen since the beginning of the pandemic will also put medical units under continuous stress to be able to absorb the growing demand[76]. dr. ribal encourages the medical community to collaborate during these challenging times and to learn from this experience to improve patient outcomes in years to come. in the q&a period, dr. ribal provided her perspective on how clinicians and researchers may overcome the obstacles in pca research and care experienced during the pandemic. while these have been challenging times, dr. ribal highlighted all the achievements of the past year, including the development of several vaccines, and the importance of worldwide collaboration. next, dr. giovanni lughezzani (italy) discussed recent developments in high-resolution ultrasound (us), focusing on an update on the 29mhz micro-us. dr. lughezzani started by providing an overview of the pca diagnostic pathway evolution. conventional us-based imaging is a cheap, largely available, and easy approach that is only used for systematic biopsies and rarely provides any information regarding the presence of pca. multiparametric magnetic resonance imaging (mpmri) represents an important improvement from conventional us for pca diagnosis. however, the use of mpmri-based imaging may be limited by its cost and availability, as well as the need for an expert radiologist to obtain the images and assist in targeted biopsies. high-resolution micro-us has the potential to bridge the gap between conventional us and mpmri. micro-us allows immediate visualization and real-time targeting of prostatic lesions without radiologic assistance, in addition to limiting the use of mpmri to essential cases only. novel micro-us operates at 29 mhz, a much higher frequency compared to conventional systems. this leads to a substantial improvement in resolution to visualize both the axial and lateral axes of the prostate. the micro-us technology allows the adoption of transperineal or transrectal biopsy strategies, and an mri fusion approach can also be incorporated to allow better targeting of lesions[77]. lesions identified by micro-us are characterized using the prostate risk identification protocol using micro-us (pri-mus). this protocol classifies lesions in real time, using a scale from 1 to 5, ranging from benign to features typically associated with higher risk of pca[78]. pri-mus has been validated by several studies, which have also shown that the protocol can be easily learned by urologists with previous experience with conventional us. what are the potential applications of micro-us in the clinical practice? in addition to faster diagnosis and no need for contrast injection, micro-us may potentially help to avoid biopsies in the presence of pri-mus 1 to 2 lesions. compared to conventional us, real-time micro-us resulted in an increased detection rate of approximately 12% in an early experience at the cleveland clinic[79]. in a prospective study of 320 patients, similar detection rates for clinically significant pca were found between micro-us and mpmri[80]. more recently, in a multicentre registry of 1,040 38 proceedings from the siu b2b uro-oncology: gu cancers triad • may 21–22, 2021 – siuj volume 2, supplement 1, july 2021 b2b: prostate cancer summary patients, the diagnostic performance of micro-us demonstrated comparable or higher sensitivity for clinically significant pca compared to mpmri[81]. micro-us may offer good visualization of target lesions. in a study of 144 prostatic lesions, 9% of lesions identified by mri but not by micro-us were negative for clinically significant pca at biopsy. by contrast, 11.8% of lesions identified only by micro-us but not by mri also had a positive pca diagnosis at biopsy[82]. in addition, in a single-institution study of 222 patients comparing different diagnostic strategies, micro-us–guided biopsy of mri targets was superior to a robotic mri fusion approach[83]. this suggests that a substantial proportion of mri targets may be visible and amenable for biopsy with micro-us. micro-us may also complement mri to improve the biopsy of target lesions. in a study of 194 patients who underwent transperineal biopsy with mpmriand micro-us–guided biopsy, micro-us identified 11% of additional lesions that were not detected by mpmri. this suggests that micro-us may add significant information to current mri approaches[84]. similarly, in another study, the combination of micro-us and mpmri was revealed as the best approach for the detection of clinically significant pca[85]. finally, micro-us also shows potential to provide local staging of pca. in a feasibility study of 54 patients scheduled for robotic-assisted radical prostatectomy, five risk factors were evaluated to predict the presence of extraprostatic extension (epe)[86]. this preliminary experience revealed a statistically significant association between the presence and the number of risk factors and pca epe. based on the evidence currently available, dr. lughezzani proposed an alternative micro-us–based pathway for the initial work-up of patients with suspected pca. the micro-us findings can be used to guide subsequent decisions, which span from targeted biopsy in patients with positive findings to a tailored clinical follow-up in those with a negative micro-us result. in patients with an inconclusive micro-us image, a complementary mpmri may be considered. during the q&a, dr. lughezzani discussed whether in the future some multiparametric features of mpmri could be incorporated to improve the current micro-us technology. micro-us is based on b mode images, which could potentially be improved with features such as doppler and elastography. dr. lughezzani also detailed the learning curve with the micro-us technology. he explained that a urologist experienced with conventional us may need between 40 to 50 cases to become comfortable with the technology. dr. lughezzani also highlighted that, in his personal experience, the learning curve is continuous and there is always opportunity for growth. next, dr. rafael sánchez-salas (france) led a casebased panel on focal therapy advances and applications in 2021. the discussion had input from dr. caroline moore (united kingdom), dr. art rastinehad (united states), dr. linda kerkmeijer (the netherlands), and dr. hashim ahmed (united kingdom). focal therapy offers the opportunity for achieving cancer control while preserving function in pca patients. some benefits associated with focal therapy include lower rates of incontinence requiring pads and frequent maintenance of natural erections without medication, following a day surgery procedure with short catheterization time. by contrast, patients undergoing focal therapy may need a second focal procedure (1 in 5 men) or radical treatment (1 in 15 men) after 5 years and require more stringent monitoring. the first case was a 52-year-old male with hypertensive cardiac myopathy who presented with a psa level of 6.9 ng/ml and a gs 3+4 upon biopsy. the patient underwent three treatment blocks of left focal high-intensity focused us (hifu) treatment, with excellent uchida changes. in his 12-month follow-up, the patient showed no signs of disease by imaging, a psa decrease to 1.9 ng/ml, no urinary symptoms, and natural erections. in a retrospective analysis of 1,032 patients treated with hifu, 63.4% had gs 3+4, 20% required a second focal treatment in 5 years, and 3.7% required radical treatment after 5 years[87]. when looking at predictors of need for retreatment, higher gs was associated with greater risk. in the study, a trend for reduced retreatment rates was observed over time in response to improved patient selection, imaging, and operator experience. b2b: prostate cancer summary 39 b2b: prostate cancer summary patient selection is essential for treatment decision-making with focal therapy. this approach is currently recommended for patients with psa levels <20 ng/ml, gs up to 7, life expectancy greater than 10 years, and any prostate volume[88]. a biopsy after 1 year is critical for evaluating treatment outcomes. in the second case, a 70-year-old male presented with gs 3+4 on transperineal mri-us fusion biopsy 3 years after initial investigations for pca. the patient was treated with gold nanoshell-localized photothermal ablation as part of a clinical pilot device study[89]. after infusion, the nanoshells penetrate the tumour, allowing tumour-specific ablation through heat following stimulation with infrared light at a specific wavelength. an mri performed 48 hours post-ablation revealed no signs of disease in the targeted area. in a single-arm, multicentre, phase 1/2 trial of 44 patients, treatment with gold nanoshells resulted in 48% psa decrease and 71.1% negative lesions at 12 months[90]. with improved patient selection, imaging, and treatment technologies, focal therapy may become the preferred management approach for intermediate-to-high-risk pca in the future. while focal therapies offer an attractive option to pca management, it is important to also consider the limitations. pca is a multifocal disease with several lesions that are not all detected, even with high-resolution mpmri[91]. focal therapies are also heterogenous, both in target volume definition as well as technique, which limits comparisons[92]. in addition, the lack of prospective clinical trials comparing focal therapies to radical treatment limits inferences with respect to differences in toxicity and risk of recurrence. currently, the eau-eanm-estro-esur-siog guidelines for local pca treatment recommend that focal therapies are only offered in the context of a clinical trial[93]. similar to other focal therapies, there have been promising results using focal radiotherapy approaches, such as focal brachytherapy and focal external-beam radiation therapy (ebrt)[94,95], although comparative trials against radical treatments are still missing. nevertheless, radical radiotherapy has seen much improvement in the past years, with advances in mriguided radiotherapy and ultra-hypofractionation that lead to better targeting of the tumour[96,97]. an important consideration is whether there may be an alternative approach to whole-gland or focal radiotherapy. the focal boost strategy was investigated in the randomized phase 3 flame trial, which compared standard whole-gland ebrt to an additional focal boost to the prostatic lesion seen on mpmri. patients in the focal boost arm experienced significantly greater biochemical disease-free survival (dfs) at 5 years (92% vs. 85%; hr=0.45 [95% ci 0.28–0.71; p<0.001), along with similar toxicity and health-related quality of life compared to standard ebrt[98]. in the phase 2 hypo-flame trial, a similar approach (but with a lower whole-gland dose) was taken to investigate the role of focal boost to hypofractionated stereotactic body radiotherapy (sbrt), which resulted in no severe acute toxicities 6 months after treatment[99]. longer follow-up is needed to evaluate the long-term effects of this novel approach. the last case was a male in his 70s with psa level of 6.4 ng/ml, gleason 4+4, and metastatic lesion in the right superior public ramus as seen by mri and subsequent bone scan and ct. the patient started treatment with adt and enzalutamide, which resulted in minor tumour reduction. he was then enrolled in the phase 2 atlanta trial, which is evaluating local treatments in men with newly diagnosed metastatic pca[100]. in the trial, the patient was randomized to receive hifu to the primary tumour and sbrt to treat the metastatic lesion. this ongoing trial will have a follow-up of at least 2 years and progression-free survival (pfs) as the primary endpoint. during the q&a, dr. moore discussed how tumour size may guide the decision between focal ablation and hemiablation. based on clinical data of over 1,000 patients, no differences were seen in cancer outcomes between the two approaches. she explained that her current practice is to treat focally, with a 5to 9-mm margin depending on tumour characteristics. then, dr. rastinehad discussed the use of novel us thermometry in focal therapy. this as a new imaging technique that improves real-time assessment of tumour ablation, although it is still in early stages of development. next, dr. kerkmeijer provided her insights on patient selection for focal treatment of oligometastases. she believes that there is variation in imaging and disease 40 proceedings from the siu b2b uro-oncology: gu cancers triad • may 21–22, 2021 – siuj volume 2, supplement 1, july 2021 b2b: prostate cancer summary staging across countries that influence the classification of oligometastatic disease. this ultimately influences patient selection for focal treatment. as she pointed out, an international trial evaluating patient selection would be beneficial. lastly, dr. ahmed summarized the key considerations for focal therapy. according to him, focal therapy is most advantageous for men with localized disease who require treatment. he cautioned that this approach is not an alternative to active surveillance and that urologists should always be cognizant of the impact of overtreatment. the pca session continued with a case-based panel on the adoption of systemic therapies by urologists. the discussion was led by dr. shusuke akamatsu (japan), with input from dr. alexandre de la taille (france), dr. martin gleave (canada), and dr. neal shore (united states). the first case was a 67-yearold male with high-risk pca who initially underwent radical prostatectomy and salvage radiation therapy. after starting adt, the patient recurred and presented with castration resistance. metastases were not observed by ct or bone scan and the patient had a psa doubling time (psadt) of 6 months. to guide next management decisions, it is important to first evaluate whether metastases are indeed not present. psma pet localizes cells expressing psma and has better specificity and sensitivity compared to conventional imaging to detect metastasis. recently, a study demonstrated that psma pet identified metastasis in 55% of patients despite negative conventional imaging[101], leading to important changes in clinical management. another important consideration is the psadt. patients with psadt <10 months are at an increased risk of developing bone metastasis[102]. if psma pet is negative for metastases, the patient in the case is an ideal candidate for treatment with an arpi, such as enzalutamide, apalutamide, or darolutamide. all three agents have shown benefit in prolonging metastasis-free survival in patients with nonmetastatic crpc (nmcrpc), with tolerable toxicity[103-105]. radiation therapy to the primary tumour is, for some authors, questionable[106], but no prospective data have yet been reported. if psma pet is positive, the number of metastatic lesions has important implications for treatment decision-making. in the presence of multiple metastases, arpi (abiraterone, enzalutamide, or apalutamide) or docetaxel-based chemotherapy may be considered. by contrast, there is much debate regarding the management of oligometastatic crpc. current guidelines are based on conventional imaging and recommend arpi as standard of care[107]. discussion of management decisions with the tumour board is advised. after the patient has started on a systemic therapy, psa levels should be monitored closely, and minor elevations may warrant subsequent imaging (either conventional imaging or psma pet) to assess for additional lesions. the second case was a 59-year-old male with high-volume mcspc with multiple bone metastases. the patient had no family history of prostate, breast, ovarian, or pancreatic cancer. he was initially treated with adt + abiraterone but progressed to mcrpc after 5 months, with additional metastasis on conventional imaging. at this stage, the management plan would include the participation of a medical oncologist to start the patient on docetaxel-based chemotherapy. enrolment in a clinical trial may also be considered. however, some biomarker advances on the horizon, such as the use of ctdna, may help to identify genomic alterations to improve patient stratification and guide treatment sequencing decisions[108]. for instance, patients who progress while receiving arpi may develop therapy-specific alterations in the ar that may alter their response to subsequent hormonal treatments[109]. these alterations may be mapped out with serial ctdna to guide management changes during treatment resistance and progression. ctdna may also help to identify other genomic alterations that have recently become therapeutic targets under investigation in pca. this is the case of pi3k inhibition with ipatasertib, which demonstrated prolonged radiographic pfs when combined with abiraterone in patients with pten loss in the ipatential150 trial[34]. other ongoing trials are aiming to refine optimal biomarker profiles to optimize benefit from dual ar/pi3k pathway inhibition. dna repair alterations may also help inform therapy selection. these alterations may confer resistance to initial adt and arpi[2,110], but may underly good response to parp inhibitors, as seen in the profound trial[111]. b2b: prostate cancer summary 41 b2b: prostate cancer summary the third case was a 74-year-old male with node-metastatic pca who received whole-pelvic radiation and adjuvant adt for 2 years until recurrence with multiple bone metastases and local tumour extension. subsequent treatment was composed first of adt + enzalutamide, and then docetaxel, until the patient developed resistance, along with an additional bone metastasis and bulky primary disease. in this setting, treatment with cabazitaxel may offer benefit, which is particularly supported by the prolonged median os observed in the card trial, following progression on docetaxel and an arpi[112]. future treatment options for patients in this disease setting may include novel radiopharmaceuticals. therap is a randomized phase 2 trial examining the role of 177lu psma-617 vs. cabazitaxel in patients with mcrpc who progressed after docetaxel therapy[113]. another study is the phase 3 vision trial, which compared 177lu psma-617 + standard of care to standard of care alone in patients with mcrpc and psma-positive metastasis[42]. recently, it was reported that the trial had met both primary endpoints, with significant improvements in os and radiographic pfs[41]. other emerging therapies targeting psma are currently under investigation. day 2 of the b2b gu cancers triad virtual meeting concluded with dr. stacy loeb (united states) presenting the state of the art in digital health in urologic oncology. the use of social media is expanding globally, with 4.2 billion users worldwide as of january 2021[114]. there has also been an expansion in the use of health apps, which is greatest in china, india, indonesia, and united states, according to a recent report[115]. not surprisingly, digital health may have an important role at different stages of the patient journey with urologic cancers, such as awareness and education, screening and diagnosis, treatment selection, treatment, and survivorship. at each of these stages, social media may have both a positive and a negative influence. on the positive side, social media messaging may improve awareness and education, which may lead to increased cancer screening or lifestyle changes in response to known risk factors. at the diagnosis stage, health apps may help to guide the patient’s decision to undergo biopsy. an example is the rotterdam prostate cancer risk calculator, a validated app that provides easy information about pca risk based on the patient’s psa level, prior imaging, biopsy, and other clinical data[116]. another app, currently under development in collaboration with dr. veda giri, is the helix webtool. this app assists with targeted family history collection and the decision-making about germline testing. it includes interactive features, as well as a series of educational modules on pca genetics. with regards to treatment selection, the virtual tumour board sessions promoted by the national cancer grid in india represent an example of a practical platform where centres can come together to discuss oncological management and to promote standardized care to patients[117]. more recently, twitter has become an essential platform to connect and engage the urological community worldwide. first introduced in 2018, the #urosome hashtag has had a positive impact in helping the identification of urological content, as well as improving community engagement on the social media platform[118]. social networks have also developed an expanded role for the dissemination of evidence-based medicine. some examples come from the eau, which has been using various social platforms, such as twitter, facebook, and linkedin, to disseminate clinical practice guidelines, thereby contributing to the adherence to evidence-based medicine[119,120]. with regards to delivery of care, the use of telemedicine has shown rapid growth among urologists and uro-oncologists, particularly during the covid-19 pandemic, when telemedicine use increased from 16% to 46%[121]. digital tools will also have an increasing importance for the future of uro-oncology. as shown in recent studies, trainees use video content on youtube as their preferred tool to learn surgical techniques[122] and many have reported using apps to access practice guidelines[123]. social media also has a positive role in survivorship. patients and their families have started to make use of the gofundme platform to address the financial toxicity associated with cancer care. facebook groups and online health communities may also be used by patients to obtain advice and support from others who may be going through a similar journey. apps may be very useful during survivorship care, such as seen 42 proceedings from the siu b2b uro-oncology: gu cancers triad • may 21–22, 2021 – siuj volume 2, supplement 1, july 2021 b2b: prostate cancer summary in patients who underwent radical prostatectomy, to help in recovery and symptom improvement[124,125]. digital networks and apps can also be used to help identify the unmet needs of patients, such as seen through whatsapp-based surveys[126] and social media surveillance[127] during the pandemic. despite the positive impact of social media and digital apps for physicians and patients, digital health may also lead to negative experiences. a particular concern is the spread of misinformative or inaccurate information through social networks. for instance, a study of the 10 most shared articles in uro-oncology on social media platforms revealed that one to seven out of those articles were misinformative or inaccurate[128]. perhaps even more concerning was the fact that those articles were also 28 times more likely to be shared than factual articles. regarding the quality of bladder cancer and pca content on youtube, studies have shown that many videos contain misinformative and/or poor quality content[129,130]. moreover, poor quality content had not only more views but also generally high engagement from viewers[130]. more recently, among the limited number of tiktok posts with objective pca information, 41% was classified as misinformative[131]. several advances to digital health are underway. given its increasing role in uro-oncology, it is important to consider the evolution of digital health while ensuring quality and equity. to this end, the discern criteria provide a helpful guide to assist the production of consumer health information[132]. with regards to diagnosis, novel ai-based digital solutions are under development and validation. for instance, ai-based algorithms have been demonstrated to accurately assess core needle biopsies and may have important applications in pathology laboratory procedures[133]. integration of big data may support improved risk stratification to guide treatment decision-making in pca. an example is pioneer, the european network of excellence for big data in pca, which combines data from 32 partners across nine countries to improve management decisions and optimize pca care[134]. lastly, the role of telemedicine and remote surgery will likely expand in the future, with alternative healthcare delivery models and better data transmission systems[135,136]. during the q&a, dr. loeb addressed how patients may respond to engagement among physicians on social media and which best practices should be considered. dr. loeb emphasized that physician participation is key to the dissemination of evidence-based data and dilution of the misinformation spread about urologic cancers on social media. for online communication, she stressed the importance of following professional guidelines, out of which she highlighted three that are specific to urology: the eau, the american urological association (aua), and the british journal of urology international (bjui). b2b: prostate cancer summary 43 b2b: prostate cancer summary abbreviations used in the text adt androgen deprivation therapy ae adverse event ai artificial intelligence ar androgen receptor arp androgen receptor pathway inhibitor asco american society of clinical oncology aua american urological association bite bispecific t-cell engager bjui british journal of urology international ccc19 covid-19 and cancer consortium ci confidence interval crs cytokine release syndrome ct computed tomography ctdna circulating tumour dna ddr dna damage response dfs disease-free survival eau european association of urology ebrt external-beam radiation therapy epe extraprostatic extension esmo european society of medical oncology fda u.s. food and drug administration gs gleason score hboc hereditary breast and ovarian cancer hifu high-intensity focused ultrasound hr hazard ratio hrr homologous recombination repair ici immune checkpoint inhibitor mcrpc metastatic castration-resistant prostate cancer mcspc metastatic castration-sensitive prostate cancer mpmri multiparametric magnetic resonance imaging nccn national comprehensive cancer network nmcrpc nonmetastatic castration-resistant prostate cancer os overall survival parp poly(adp-ribose) polymerase pca prostate cancer pet positron emission tomography pfs progression-free survival pri-mus prostate risk identification protocol using micro-ultrasound protac proteolysis targeting chimera psa prostate-specific antigen psadt prostate-specific antigen doubling time psma prostate-specific membrane antigen sbrt stereotactic body radiotherapy seer surveillance, epidemiology, and end results snp 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evidences from a systematic review of the literature. world journal of urology. 2020;38(10):2367-2376. doi:10.1007/s00345-019-02996-0 this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information youtube, kidney neoplasm, social media, misinformation, dissemination none declared. received on may 28, 2022 accepted on july 15, 2022 this article has been peer reviewed. soc int urol j. 2022;3(5):315–321 doi: 10.48083/hmug9514 a quality assessment of information available on renal cancer on youtube jeremy saad,1,2 ramesh shanmugasundaram,2 darius ashrafi,1,2 daniel gilbourd1,3 1 canberra urology department, canberra hospital, garran, australian capital territory, australia 2faculty of medicine, university of sydney, sydney, australia 3 faculty of medicine, australian national university, canberra, australia abstract objectives many people are turning to alternatives to the conventional doctor-patient relationship, such as webbased search engines and video forums for their health care information. we undertook this study to investigate the quality of videos and information on renal cancer available on the streaming platform youtube. methods we completed a search of youtube (www.youtube.com) in september 2021 with the term “kidney cancer.” the first 120 videos found which met the inclusion criteria (english speaking, duration greater than one minute, greater than 500 views, renal cancer addressed) were selected. we recorded information including duration, view count, likes, dislikes, comments, publisher, and author. the modified discern tool and global quality score (gqs) questionnaire were used to assess the quality of the included videos. the level of misinformation was assessed using a likert 5-point scale. descriptive statistics were used to analyse the collected data. a 2-sample t test was used to further analyse the quality assessment tool results before, during, and after 2016. results most videos were published during or after 2016 (63.3%), were predominantly created in north america (77.5%), and were presented by health care professionals (60%). the median length of the videos was 4.23 (1.01 to 65.55) minutes, and the median number of views was 3087 (514 to 228 152). the median number of likes and dislikes was 24 and 5, respectively. the median modified discern score was 3, the median gqs score was 3, and the grading for overall level of misinformation was moderate. conclusion the quality of information accessed from youtube on kidney cancer is of a low to moderate overall standard with significant levels of misinformation. youtube should not be used alone for educational purposes on renal cancer by patients or the public. it is best used in conjunction with information and advice from a medical practitioner and the health care system. introduction kidney cancer is the second most common urological cancer worldwide, with 430 000 new cases recorded per year[1,2]. studies have found that 9.8% to 15.1% of patients with renal cancers report a lack of appropriate information as a major source of frustration in their care[3]. increasingly, the internet has become a primary information source used by patients. a review of google trends shows there has been a 400% increase in the number of searches on kidney cancer-related terms over the last 12 months[4]. surveys have shown that approximately 8 out of 10 internet users have searched online about health topics, and 25% have watched an online video about health or medical 315siuj.org siuj • volume 3, number 5 • september 2022 review https://orcid.org/0000-0003-0293-2226 mailto:jeremyjsaad%40gmail.com?subject=siuj https://orcid.org/0000-0003-3869-4119 https://orcid.org/0000-0001-6466-5536 https://orcid.org/0000-0002-6736-4859 http://www.youtube.com http://siuj.org issues[5,6]. the video-sharing platform, youtube, is the most accessed streaming platform in the world with over 2 billion views per day[7]. youtube has shown to be a commonly used resource for patients seeking medical information, including on urological diseases[8–11]. we believe video platforms such as youtube can enable patients to develop an improved level of health literacy and a greater understanding of their health care needs. however, there has been no objective analysis of the accuracy of the information available. web-based resources have been shown to have variable levels of quality and accuracy when compared with guidelines[12–14]. as distinguishing informative videos from those with significant inaccuracies may be challenging for the lay person, it is important that clinicians be aware of the quality of content and veracity of the resources patients may be using. the objective of our study was to use validated instruments to analyse the quality of renal cancer information available to patients on youtube. methods search strategy the term “kidney cancer” was used to search youtube (www.youtube.com) in september 2021. google trends indicated this was the most frequently used search term relating to renal cancer during the preceding 12 months. the default search setting on youtube was used, which automatically sorts the videos by relevance. we included all videos that were in english, had over 500 views, and covered information on renal cancer. studies were excluded if t hey were duplicates, advertisements, instructional surgical videos, lacked audio, were not published in the english language, or did not contain information on renal cancer. the first 120 videos meeting these criteria were included in the study and saved to a “playlist” after the initial search. information was collected on various characteristics, including year of publication, place of publication by continent, number of views, length (minutes), number of likes (thumbs up), number of dislikes (thumbs down), number of comments, and quality of audio and visual (table 1). content characteristics were also recorded including subject, type of provider, author, and intended audience (table 2). video analysis two authors (j.s. r.s.) independently reviewed the 120 videos included for further analysis. if there was any discrepancy, a third author (d.a.) was consulted held the deciding vote. information on the accuracy of information was assessed on the basis of consistency with either the latest european association of urology or american urological association guidelines[15,16]. if a video contained information on alternative therapies, then a literature search was conducted to assess the most current information on the topic. quality analysis the quality analysis was completed using a modified discern tool[17], global quality score (gqs)[18] and misinformation tool which was assessed on a likert 5-point scale[19]. the modified discern tool is scored based on 5 questions with 1 point for each answer, as shown in table 3. with 1-2 points indicating low quality, 3 points indicating moderate quality and 4-5 points indicating high overall quality. this tool has been validated to assess the reliability of online resources and has been used in similar studies[20–22]. the gqs was based on a 5-point scale including poor quality (not useful for patients), generally poor quality (very limited use), moderate quality (somewhat useful), good quality (useful for patients), and excellent quality (very useful for patients). the gqs is used to better assess the quality of online resources and indicates usefulness of the information to the intended audience. misinformation was assessed using a 5-point likert scale. on this scale, a score of 1 point indicated good quality information with low levels of misinformation, and a score of 5 points indicated high levels of misinformation. the videos were also assessed for inclusion of commercial bias. this was table 1. video characteristics of 120 youtube videos on renal cancer parameter upload date, n (%) ≤ 2015 44 (36.6) ≥ 2016 76 (63.3) location, n (%) north america 93 (77.5) europe 16 (13.3) asia 8 (6.7) other 3 (2.5) length, median (range) 4.23 (1.01–65.55) (sd 14.597) views, median (range) 3087 (514–228 152) (sd 30474.88) number of likes, median (range) 24 (0–1408) (sd 167.879) number of dislikes, median (range) 5 (0–93) (sd 12.131) number of comments, median (range) 7 (0–210) (26.091) vpi (range) 21.78 (0–42.25) like ratio, % 21.78 (0–42.25) 316 siuj • volume 3, number 5 • september 2022 siuj.org review http://www.youtube.com http://siuj.org defined as a personal judgment in favour of a specific product or service of a commercial interest. the presence of disclosures or conflict of interest, either in the video or written description, was recorded. video popularity was assessed using the video power index (like ratio × view ratio [views per day ÷ 100]) and the like ratio (like ÷ (like + dislike) × 100). data analysis this study was completed with the use of descriptive statistics for analysis of outcomes and demographic variables. continuous variables were expressed as a mean, range, and standard deviation. categorical variables were expressed as a number and percentage. the 2-sample t test was used to assess the quality analysis and misinformation tools, and a p value of < 0.05 was considered statistically significant. results the youtube search for the term “kidney cancer” identified over 4000 videos. two hundred fifty videos were saved into a playlist for further review, and the first 120 that met the criteria were included in the study. the majority of included videos were published during or after 2016 (63.3%) and created in north america (77.5%); 13.3% were created in europe. the median length of the videos was 4.23 minutes (1.01 to 65.55), and the median number of views was 3087 (514 to 228 152). the median number of likes and dislikes was 24 and 5, respectively (table 1). the most common content category was “treatment” and an “overview of renal cancer” with 3 out of the 4 included criteria (anatomy, symptoms, diagnosis, and treatment). approximately 39% of the videos were created by hospitals or health clinics, 18% by health channels, and 18% by foundations or advocacy groups. most of the videos (60%) were presented by health professionals including doctors or nurses, 20% by patients, and 16% were animations. most of the videos were intended to be accessed by patients (62.4%) followed by the general public (37.5%) and then health care providers (14.7%). the modified discern indicated a high number of videos scoring as moderate quality of information with an overall median score of 3; 74.1% of all videos in the study were of moderate to high (≥ 3) reliability. however, a significant portion of the videos (25.9%) were of low or very low quality. the gqs tool indicated that 83.4% of the videos had moderate to excellent levels of quality; 24.2% of the videos scored as excellent for the content they provided. a proportion of the studies (16.6%) were table 3. modified discern evaluation tool for reliability and quality of renal cancer information on youtube modified discern tool (point per question if answered yes) 1. are the aims clear? 2. are reliable information sources used? 3. is the information balanced and unbiased? 4. are additional sources listed for patients? 5. are areas of uncertainty stated? table 2. content characteristics of 120 youtube videos on renal cancer subject, n (%) anatomy/disease 8 (6.7) symptoms 5 (4.2) diagnosis 12 (10) treatment 47 (39.2) overview 41 (34.2) alternative/future therapy 7 (5.8) type of provider, n (%) hospital/health clinic 47 (39.2) foundation/advocacy 18 (15) news outlet 5 (4.2) university 11 (9.2) health channel 18 (15) journal 5 (4.2) industry 11 (9.2) other/unknown 5 (4.2) author, n (%) doctor 72 (60) patient 20 (16.7) animation 16 (13.3) public figure 3 (2.5) other/unknown 9 (7.5) intended audience, n (%) general public 45 (37.5) health care providers 17 (14.2) patients 52 (62.4) unknown 6 (7.2) 317siuj.org siuj • volume 3, number 5 • september 2022 a quality assessment of information available on renal cancer on youtube http://siuj.org scored either poor or very poor for levels of information. misinformation was found in 49.7% of the videos analysed, and 22.5% contained moderate to high levels of misinformation. the other 50.3% were scored as having no misinformation. a subgroup analysis was done of videos published within the last 5 years compared with videos published prior to this period (pre and post 2016). the median scores for all the quality assessment tools were equal between the 2 groups including the modified discern (3), gqs (moderate) and misinformation scores (2). the gqs and misinformation tools were found to have statistically difference p values between the videos published in 2015 or before and those published during or after 2016. quality analysis information is shown in table 4 alongside the supplementary analysis comparing videos submitted in 2015 or before with those submitted during or after 2016. less than 6% of the videos had disclosures or coi documented, and 24.2% were deemed to have commercial bias (figure 1). discussion the aim of this present study was to analyse the quality of renal cancer information available to patients on the video-sharing platform youtube, using validated instruments. we found over 7000 videos relating to renal cancer on youtube. most of the included videos were created by medical organisations (39%) and were intended primarily for patient viewing (62.4%). to our knowledge, this is the first study to analyse the quality of renal cancer information available on youtube. readily available, good quality, unbiased medical information can be beneficial for patients who want to inform themselves about specific health conditions[23,24]. there are evidence-based videos on youtube that have been found to have highquality information when created or reviewed by a legitimate source[25]. however, many available videos and web-based sources have been shown to be of poor overall quality and to offer outdated advice that may detrimentally affect patient care and well-being[26–28]. at the same time, videos from high-quality sources such as universities and health care organisations are viewed less on social media and web-based browsers[29], further contributing to greater levels of misinformation accessible to patients and the public[30]. our analysis found that there was a significant proportion of videos with misinformation (49.2%). of these, 22.5% scored between moderate and extreme levels of misinformation. the overall level of quality was low to moderate, highlighted by the quality assessment tools used. on the modified discern questionnaire, the videos had a median score of 3 out of 5, indicating moderate quality of information. approximately one quarter of the overall total scored as having low levels of reliability. on the gqs, the videos had a median score of 3, indicating the information was somewhat useful to patients. however, 16.6% of the videos were found to have poor or generally poor information that would have minimal benefit for the viewer. quality analysis studies within the field of urology have found that information available to patients on youtube contains moderate to high levels of misinformation[31]. they also found that the included information was of low to moderate quality and reliability[32,33]. a contributing factor to the high levels of misinformation is the ongoing development of the medical field and our understanding of the conditions within it. a subgroup analysis was completed to review the quality of the information published from 2016 to 2021. a statistically significant difference was found when comparing the gqs and the level of misinformation with data table 4. quality and misinformation analysis tool total ≤2015 (44) ≥ 2016 (76) p value modified discern, n (%) 1 14 (11.7) 6 8 0.3777 2 17 (14.2) 8 9 3 42 (35) 14 28 4 28 (23.3) 10 18 5 19 (15.8) 6 13 median 3 3 3 global quality scale, n (%) poor 7 (5.8) 4 3 0.0426 generally poor 13 (10.8) 7 6 moderate 38 (31.7) 12 26 good 33 (27.5) 12 21 excellent 29 (24.2) 9 20 median moderate moderate moderate misinformation score, n (%) 1 61 (50.8) 20 41 0.0455 2 32 (26.7) 11 21 3 18 (15) 7 11 4 7 (5.8) 5 2 5 2 (1.7) 1 1 median 2 2 2 318 siuj • volume 3, number 5 • september 2022 siuj.org review http://siuj.org published before 2016. this can be attributed to the evolution of alternate therapies that may have been disproved or to changes in treatment methods, such as surgical intervention techniques or radiotherapy and chemotherapy[34,35]. the role of the doctor-patient relationship in educating patients on diagnostic and management options is important to the patient-centred care model. the concern with web-based resources is that the quality of information varies significantly, as does the level of health literary expected in the viewer. as the videos are not reviewed for quality, to increased levels of misinterpretation is both plausible and found to be common. only 34.2% of the included videos gave an overview of renal cancer, with many of the remaining studies missing key information such as symptoms, diagnosis, and treatment. the number of videos produced by health professionals is increasing. in our study, 60% were produced by health professionals, and 39.2% promoted the use of treatment methods. health professionals and patients are increasingly being used in videos (16.7%) to promote newer treatment options, including immunotherapy and robotic surgical options. the popularity of robotic surgery has led to an increase of the use of intraoperative images and videos. intraoperative scenes were included in 19% of videos made during or after 2016, compared with 12% of those made during or before 2015. only 29% of the videos on treatment discussed side effects or postoperative complications. the increasing use of youtube videos that focus on diagnostic methods or treatment options may have been influenced by commercial interests and the potential for gain. in this study only 5.8% of the videos included conflict of interest disclosures. videos on youtube with greater advertising and promotion of medical treatments have higher levels of popularity. we found that videos with commercial bias have a higher standard of audio-visual quality. loeb et al.[33] found that 17% of the youtube videos included in their study on bladder cancer showed commercial bias and reached 324 287 viewers. the comments sections of the videos were reviewed to gauge viewer response. overall, there was a low number of comments per video (median 5), which may indicate poor patient engagement. a significant portion (21%) of the publishers were found to have removed the ability of the public to comment. in 27% of the videos, the comments included patients/members of the public asking for health-related advice. in only one video did the publisher respond to the request and subsequently advised the person to discuss this concern further with a local health practitioner. the number of commenters asking for further clarification suggests the need for more access to reliable information. limitations the study is limited by multiple factors including the inclusion of only youtube videos. there are many webbased platforms for patients to use including other search engines such as google, which is the largest webbased search engine. further analysis is required to better understand the effectiveness of other search media engines. this study is also limited by design, this is a cross sectional study and youtube changes rapidly, which makes reproducing the information and study design challenging. conclusion the use of youtube as a readily available source of health information on renal cancer has yet to be evaluated thoroughly. the information on youtube assessed in this study was found to be low to moderate quality. there were significant levels of misinformation due to the ongoing development of treatment methods and understanding of the disease. youtube should not be the sole source of information on renal cancer for patients or the public, and is best used in conjunction with information and advice from a medical practitioner and the health care system. figure 1. review of disclosures and commercial bias no yes disclosure/coi commercial bias 113 (94.2%) 7 91 (75.8%) 29 319siuj.org siuj • volume 3, number 5 • september 2022 a quality assessment of information available on renal cancer on youtube http://siuj.org references 1. gray re, harris gt. renal cell carcinoma: diagnosis and management. am fam physician.2019;99(3):179-184 2. sung h, ferlay j, siegel rl, laversanne m, soerjomataram i, jemal a, et al. global cancer statistics 2020: globocan estimates of incidence and 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med.2020;8(3):408-413.10.1016/j.esxm.2020.05.007. 320 siuj • volume 3, number 5 • september 2022 siuj.org review https://trends.google.com/trends/explore?q=renal%20cancer&geo=au https://trends.google.com/trends/explore?q=renal%20cancer&geo=au https://www.pewresearch.org/internet/2011/05/12/the-social-life-of-health-information-2011/ https://www.pewresearch.org/internet/2011/05/12/the-social-life-of-health-information-2011/ https://doi.org/10.1111/nep.12397 https://doi.org/10.1111/nep.12397 http://siuj.org 28. pratsinis m, babst c, l angenauer j, schmid hp, piller a , neuenschwander a, et al. qualitative assessment of medical information on youtube: a multilingual comparison of common urological conditions. urol int.2021;105(9-10):757-763.10.1159/000517292. 29. bora k, das d, barman b, borah p. are internet videos useful sources of information during global public health emergencies? a case study of youtube videos during the 2015-16 zika virus pandemic. pathog glob health.2018;112(6):320-328.10.1080/20477724.2018.1507784. 30. leong ay, sanghera r, jhajj j, desai n, jammu bs, makowsky mj. is youtube useful as a source of health information for adults with type 2 diabetes? a south asian perspective. can j diabetes.2018;42(4):395-403.e4.10.1016/j.jcjd.2017.10.056. 31. loeb s, taylor j, borin jf, mihalcea r, perez-rosas v, byrne n, et al. fake news: spread of misinformation about urological conditions on social media. eur urol focus. 2020;6(3):4 374 39.10.1016/j. euf.2019.11.011. 32. loeb s, sengupta s, butaney m, macaluso jn jr., czarniecki sw, robbins r, et al. dissemination of misinformative and biased information about prostate cancer on youtube. eur urol.2019;75(4):5647.10.1016/j.eururo.2018.10.056. 33. loeb s, reines k, abu-salha y, french w, butaney m, macaluso jn jr., et al. quality of bladder cancer information on youtube. eur urol.2021;79(1):56-59.10.1016/j.eururo.2020.09.014. 34. ali s, ahn t, papa n, perera m, teloken p, coughlin g, et al. changing trends in surgical management of renal tumours from 2000 to 2016: a nationwide study of medicare claims data. anz j surg.2020;90(1-2):48-52.10.1111/ans.15385. 35. goebell pj, staehler m, müller l, nusch a, scheffler m, sauer a, et al. changes in treatment reality and survival of patients with advanced clear cell renal cell carcinoma analyses from the german clinical rcc-registry. clin genitourin cancer.2018;16(6):e1101-e15.10.1016/j. clgc.2018.06.006. 321siuj.org siuj • volume 3, number 5 • september 2022 a quality assessment of information available on renal cancer on youtube http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj.org siuj • volume 4, number 3 • may 2023 159 editorial fomo: a force to be contained in urology peter c. black editor-in-chief soc int urol j.2023;4(3):159–160 doi: 10.48083/ vbhx1902 i was at an international meeting of urologists and researchers in the past year when i heard the term fomo (“fear of missing out”) for the first time. the person using the term was dutch, so i of course had to verify that this was indeed a mainstream term in the english language. i quickly recognized that i had somehow missed what had become a common term in many circles (ie, i was living under a rock). the context of the fomo conversation was to describe how one urologist, who was not at this meeting, would almost certainly come to the next meeting because of his fomo. that concept immediately resonated with me—a term was being applied to something that i also routinely perceived. i started thinking: how does fomo shape our behaviour as practising urologists, especially in the academic setting? fomo as a term has risen in prominence in the current era of ubiquitous social media. it was first coined in 2004[1] and was adopted into the oxford dictionary in 2013[2]. it typically refers to the perception that one is missing out on activities that one observes on social media, and it drives an unquenchable desire to be connected on social media or in person2. as mark morford phrased it[3], fomo is “the overwhelming feeling that you are, right now, missing out on some miraculous experience that is quite possibly the coolest thing ever to happen to anyone ever.” in this context it is associated with sensations of apprehension, anxiety and even depression. the general concept of fomo, however, regardless of terminology, certainly pre-dated social media, and its implications go well beyond social media. it is also not by necessity linked to mental health concerns. as with my introduction to the term fomo, the obvious expression of fomo in urology relates to the insatiable desire to attend every meeting. social media allows us to get a glimpse into the proceedings of meetings that we cannot attend, which may in fact attenuate the sensation of missing out in this setting. going to meetings could be a full-time job if we let it—and indeed there are often overlapping meetings that would prevent us from going to all meetings, even if we dedicated all our time to it. it is worse if we are invited to speak at meetings, because the potential fomo is then compounded by the need to say “no”—another concept with which some of us struggle even more. itsn (inability to say no) should be another term in our field. is an excessive travel and meeting schedule the hallmark of someone with combined fomo and itsn? there is surely more to it, but these are contributing factors. i recently took a full month of vacation to travel through new zealand. it was a much appreciated, prolonged break, and it afforded me a good opportunity to come to terms with some fomo. not only did i miss one of the key bladder cancer meetings of the year, i also missed the european association of urology meeting in milan, a regional genitourinary cancer meeting, and two additional invitations to speak. to some degree, however, i enjoyed the opportunity to break the cycle, and i recognized that missing out some of the time is not such a bad thing. the biggest conference of the year—the annual meeting of the american urological association—is looming in the very near future, and i am again unable to attend because of on-call obligations. another hefty dose of fomo... we all have our own academic priorities and strategies for achieving these priorities, but there is a lesson to be learnt around fomo—and one to be passed on to trainees and young colleagues. we need to plan carefully and determine which meetings mean the most to our own development, whether we are attending a meeting to learn, to educate, to network, or to exercise a leadership role. hopefully we are not attending meetings regularly just for fear of missing out, or because we feel that others expect it of us. as they say in german, we cannot dance at all weddings (“man kann nicht auf allen hochzeiten tanzen”), and we sacrifice productivity in research and clinical practice, not to mention home life, if we succumb to the pressure and desire to attend every meeting. http://siuj.org fomo may sneak into other aspects of urology as well. for example, fellowship training after residency is intended for the acquisition of subspecialty skills, yet in the canadian environment it is pursued frequently by those headed to a community practice in general urology. there is a perception that fellowship is needed to obtain a job—but there is also an element of missing out for those who do not do a fellowship. fomo may also affect research. in bladder cancer, for example, almost all major researchers have gravitated to studying tumor immunology. it is undoubtedly a critically important field of research, but there is a definite sense that if you are not studying bladder cancer immunology you are missing out. a potential example in clinical care is the adoption of intravesical treatment with sequential gemcitabine and docetaxel. this has evolved as a references 1. mcginnis p. social theory at hbs: mcginnis' two fos. the harbus. 10 may 2004. available at: https://harbus.org/2004/social-theory-athbs-2749/. accessed april 25, 2023. 2. gupta m and sharma a. fear of missing out: a brief overview of origin, theoretical underpinnings and relationship with mental health. world j clin cases.2021 jul 6;9(19):4881-4889. doi: 10.12998/wjcc. v9.i19.4881. 3. morford m. oh my god you are so missing out. sf gate. 4 aug 2010. available at: https://w w w.sfgate.com/entertainment/morford/ article/oh-my-god-you-are-so-missing-out-2536241.php. accessed april 25, 2023. standard treatment for non-muscle invasive bladder cancer in north america even though the evidence to support its use is limited. the reasons for this are manifold, including especially the lack of efficacious and cost-effective alternatives, but there is also a sense that its use has been disseminated by something akin to a peer-pressure. if you are not offering gemcitabine/ docetaxel, you are missing out. overall, fomo can be a motivator for urologists to stay engaged in their clinical, research, and academic practices, but it can also lead to stress and burnout if not managed appropriately. it is critical for us all to recognize the force of fomo and prioritize own well-being to strike a balance between our academic pursuits and our personal and professional responsibilities. 160 siuj • volume 4, number 3 • may 2023 siuj.org editorial https://harbus.org/2004/social-theory-at-hbs-2749/ https://harbus.org/2004/social-theory-at-hbs-2749/ https://www.sfgate.com/entertainment/morford/article/oh-my-god-you-are-so-missing-out-2536241.php https://www.sfgate.com/entertainment/morford/article/oh-my-god-you-are-so-missing-out-2536241.php http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information urogenital malignancy, cannabis, marijuana none declared. received on july 31, 2022 accepted on september 12, 2022 this article has been peer reviewed. soc int urol j. 2023;4(1):51–64 doi: 10.48083/ndoj8638 urogenital malignancy and cannabis use: a narrative review alice thomson, aoife mcvey, brennan timm, damien bolton department of urology, austin health, heidelberg, victoria, australia abstract background cannabis is the most commonly used illicit drug worldwide. an increasing number of jurisdictions are legalising cannabis for both medicinal and recreational use. the changing cannabis market has resulted in both an increase in the number of people consuming these compounds, and an increase in the frequency and quantity of cannabis being used. endogenous and exogenous cannabinoids act on receptors across the entire body including the genitourinary system; however, there is a paucity of understanding of how cannabinoids affect genitourinary malignancy. objective to present a narrative review of the available literature detailing the relationship between cannabis and the incidence, diagnosis, and management of genitourinary malignancy. methods a comprehensive search was undertaken using the ovid medline, ovid embase, and cochrane central register of controlled trials (central) up to july 2021. studies included case reports, case series, casecontrol studies, and in vitro studies. results the search identified 40 studies in total: 8 described the relationship between cannabis and testicular carcinoma, 20 related to prostate cancer, 5 to bladder cancer, 5 to renal cancer, 1 to penile cancer, and 1 study examined testicular carcinoma, renal cell carcinoma, bladder cancer, and prostate cancer. conclusions cannabis use has been linked to an increased risk of developing testicular tumours, whilst the evidence for bladder cancer is mixed. there is no apparent increase in risk for prostate cancer, penile cancer, or renal cell carcinoma; however, this evidence was based on a very small number of patients. there remains a lack of understanding of the relationship between cannabis and genitourinary malignancy. with an expected increase in cannabis use, monitoring for testicular tumour plus efforts to further understand its effects upon the genitourinary tract will aid diagnosis and management. introduction cannabis has been used by human populations for thousands of years for multiple reasons, but more recently for its perceived medicinal benefits. the united nations world drug report 2021 estimates that cannabis is used by 4% of the global population between the ages of 15 and 64 years[1]. cannabis is permitted for medicinal and/or recreational use in many north american jurisdictions, and its increasing acceptance has resulted in an increase in the frequency and number of people seeking to use it[1]. the active compounds in cannabis are referred to as cannabinoids and the primary active molecule is δ9-tetrahydrocannabinol (thc)[2]. both exogenous and endogenous cannabinoids exert their effects in humans via 51siuj.org siuj • volume 4, number 1 • january 2023 review mailto:dralicethomson%40gmail.com?subject=siuj http://siuj.org 2 main receptors: cannabinoid receptor 1 (cb1) and cannabinoid receptor 2 (cb2)[2]. cb1 and cb2 are part of the g-protein-coupled receptor superfamily, which affects downstream signalling pathways. receptors are located all around the body, including within the male urogenital system. the use of cannabis has been advocated for the treatment of chronic pain, mental health disorders, chemotherapy-induced nausea, and cancer-related pain[3]. there have been many papers looking at quality of life effects of cannabis, but few measuring effects on disease process. genitourinary malignancies are a major global health challenge, and there has been an increase in their incidence over the past 30 years[4]. whilst prostate and bladder cancer generally affect older men, renal and testicular cancer typically affect younger men. each of these entities represent a challenge to public health globally, and multimodal strategies to minimise their risk and improve their management are required to ease their burden on health systems and societies[4]. given the increasing use of cannabis for both medical and recreational purposes, greater understanding is needed of the potential effect of cannabis on urogenital malignancies. the aim of this review is to establish the current evidence for cannabinoids as a risk for developing genitourinary malignancy, and to assess their use as an antineoplastic agent in urogenital malignancy. methods we intended to complete a systematic review of the effect of cannabis on the incidence of genitourinary malignancy and its use as an antineoplastic agent, with a meta-analysis if appropriate. however, there were insufficient results to permit a quantitative analysis of the outcomes. therefore, we completed a qualitative narrative review. search strategy a comprehensive search strategy was undertaken using the ovid medline, ovid embase, cochrane central register of controlled trials (central) from inception to present, google scholar (first 200 citations relevancy ranked); clinical trial registries; references of included studies up to july 1, 2020. the search was restricted to articles written in english. the following words and mesh terms were used: “cannabinoid,” “cannabidiol,” “cannabinol,” “dronabinol,” “cannabis,” “medical cannabis,” “(cannabi* or thc or tetrahydrocannabinol or dronabinol or hemp or bhang or marijuana or marihuana or hashish or hash or skunk or marinol or nabilone or cesamet or sativex or sinsemilla),” which were then crossed with any of the following terms “exp urogenital tract cancer,” “exp kidney cancer,” “([prostate or penis or penile or testicular or germ cell or urothelial or testis or ureteric or ureter or urinary or renal cell or kidney or bladder or genital tract] and [cancer or carcinoma or tumour or tumor or metastasis]).” studies included observational studies, such as case reports, case series, case-control studies and in vitro studies, and interventional studies such as randomised controlled trials and clinical trials. search terms were then used in other databases using medline parameters. we used the preferred reporting items for systematic reviews and metaanalysis (prisma) statement to report results. the review was prospectively registered on prospero 2020 crd42020195998. data extraction and screening sources were independently obtained and reviewed by 2 individual authors to determine eligibility based upon relevance. publications’ titles and abstracts were first reviewed for relevance to the topic. appropriate publications then underwent a full-text review. articles that passed this screening process were then included in the manuscript based on the full text. any disagreement was resolved by the corresponding author. the systematic review results are depicted in figure 1. results the search identified 40 studies in total. eight described the relationship between cannabis and testicular carcinoma, 5 related to renal cancer, 5 related to bladder cancer, one related to penile cancer, and 20 related to prostate cancer. one study examined testicular carcinoma, renal cell carcinoma, bladder cancer, and prostate cancer. studies could be broadly categorised into 2 groups: those examining the effect the consumption of cannabis has on the incidence of urogenital cancers, and those examining the effect of cannabis or cannabinoids on the diagnosis, treatment or follow-up of urogenital cancer. cannabis consumption is an independent risk factor for the development of non-seminomatous germ cell testicular tumours[5–8] (table 1). there is no compelling evidence that it affects β-hcg levels, although this has earlier been suggested in case reports, and therefore its use should not affect protocols for the post-treatment follow-up of these tumours[9,10]. abbreviations cb cannabinoid receptor hcg human chorionic gonadotropin rcc renal cell carcinoma tgct testicular germ cell tumours thc tetrahydrocannabinol uc urothelial carcinoma 52 siuj • volume 4, number 1 • january 2023 siuj.org review http://siuj.org figure 1. data extraction method records identi�ed (n = 542) records removed before screening: • duplicate records removed (n = 1) abstracts screened (n = 542) records excluded (n = 501) • irrelevant • non-english papers • abstract only available records excluded • based on relevance (n = 0)  reports sought for retrieval (n = 40) reports sought for retrieval (n = 40) studies included in review (n = 40)in cl ud ed s cr ee ni ng identi�cation of studies via databases and registers id en ti �c at io n one study examined the effect of cannabis consumption on prostate cancer and found there was no increased risk with its use[11], whilst a second found a decreased risk[8] (table 2). nineteen studies examined the effect of cannabinoids on prostate cancer cells and demonstrated pro-apoptotic properties, identifying a potential novel treatment pathway[12–30]. three studies indicated that cannabis appears to be protective against bladder cancer, and this was further strengthened by the results of 3 in vitro studies showing that cannabis had pro-apoptotic effects on bladder cancer cell lines[8,31–35] (table 3). there has been no relationship suggested between cannabis consumption and penile cancer[36] (table 4). one study has examined the relationship between renal cell carcinoma (rcc) and cannabis consumption and found a decreased risk[37]; however, in vitro studies demonstrated marked downregulation of cb1 compared with normal renal tissue, potentially defining a new diagnostic marker[38–42] (table 5). discussion testicular cancer testicular cancer is the most common cancer in young men, and for reasons not yet understood, the incidence is increasing in the western world[43]. a 2009 53siuj.org siuj • volume 4, number 1 • january 2023 urogenital malignancy and cannabis use: a narrative review http://siuj.org table 1. summary of studies on the relationship between cannabis and testicular cancers author (year) in vitro versus in vivo type of study level of evidence (sackett) number of participants risk or management exclusion criteria summary callaghan et al. (2017) in vivo cohort iii 49 343 risk severe mental or physical conditions no relationship between lifetime “ever” cannabis use and development of testicular cancer (ahr 1.42; 95% ci 0.83 to 2.45). significant association between heavy cannabis use (>50 times in lifetime) and incidence of testicular cancer (ahr 2.57; 95% ci 1.02 to 6.50) 2.5-fold increased risk. lacson  et al. (2012) in vivo casecontrol iii 455 risk   ever use of cannabis had a 2-fold increased risk (or 1.94; 95% ci 1.02 to 3.68) of tgct of any histological type compared to never use. trabert  et al. (2011) in vivo casecontrol iii 335 risk extragonadal germ cell tumours frequent users (>1 daily) were more likely to be diagnosed with tgcts compared with controls (or 2.2; 95% ci 1.0 to 5.1). frequent users (or 3.1; 95% ci 1.2 to 8.2) and longterm (>10 years) users (or 2.4; 95% ci 1.0 to 6.1) were significantly more likely to have non-seminoma diagnosis. daling  et al. (2009) in vivo casecontrol iii 369 risk choriocarcinoma tumours current cannabis users were more likely to be diagnosed with tgst (or 1.7; 95% ci 1.1 to 2.5) with association between non-seminoma/mixed histology tumors (or 2.3; 95% ci 1.3 to 4.0). age at first use (age <18 or 2.8 versus age ≥ 18 or 1.3) and frequency of use (daily or weekly or 3.0 versus less than once per week or 1.8) modified risk. huang et al. (2022) in vivo cohort iii 64 730 risk previous cannabis use increased the risk of testicular cancer (hr 1.12; 95% ci 0.49 to 2.52). this did not reach statistical significance. braunstein et al. (1985) in vivo cohort iv 16 treatment   cannabis does not affect serum hcg levels, δ9-thc in male pooled serum did not affect hcg radioimmunoassay. hogan et al. (1983) in vivo cohort iv 6 treatment   synthetic nabilone (cannabinoid similar in structure to l-a9 tetrahydrocannabinol) had no effect on hcg levels. garnick et al. (1980) in vivo cohort iv 2 treatment   following treatment of tgct, hcg was elevated in two regular cannabis smokers, however normalised following ceasing cannabis. 54 siuj • volume 4, number 1 • january 2023 siuj.org review http://siuj.org table 2. summary of studies on the relationship between cannabis and prostate cancers author (year) in vitro versus in vivo type of study level of evidence (sackett) number of participants risk versus management exclusion criteria summary sidney  et al. (1997) in vivo cohort iii 64 855 risk cancer diagnosis one year prior to aids/hiv diagnosis no association between prostate cancer risk between ever users or never users of cannabis (or 1.3; 95% ci 0.6 to 2.6). huang et al. (2022) in vivo cohort iii 151 945 risk previous cannabis use was protective for prostate cancer risk (hr 0.52; 95% ci 0.46 to 0.58). when adjusted for family history, hr 0.83; 95% ci 0.74 to 0.94). roberto et al. (2019) in vitro experimental study v treatment cannabinoid win significantly reduced prostate cancer cell proliferation, migration, invasion, induced apoptosis, and arrested cells in go/g1 phase in a dose-dependent manner. administration of win resulted in a reduction in the tumor growth rate compared to control in athymic mice (p < 0.05). morales et al. (2013) in vitro experimental v treatment cannabinoid chromenopyrazoledione derivative 4 (pm49), inhibits prostate lncap cell viability (ic50 ¼ 15 mm) through oxidative stress mechanism, pparg receptor and partially cb1 receptor. in in vivo treatment, derivative 4 at 2 mg/kg, blocks the growth of lncap tumors and reduces the growth of pc-3 tumors generated in mice. pietrovito et al. (2020) in vitro experimental v treatment cannabinoid win negatively affected caf-mediated cancer cells’ invasiveness and impaired activation and reactivity of cancer-associated fibroblasts (cafs). baram et al. (2019) in vitro experimental v treatment variability observed with differing cannabis compounds and extracts. δ9-trans-tetrahydrocannabinol (δ9-thc) did not produce the same effects as the whole cannabis extracts. differing cannabis extracts had differing effects dependant on specific prostate cancer cell line and extract’s composition. kosgodage et al. (2018) in vitro experimental v treatment cannabidiol significantly reduced exosome release in pc3 cancer cell lines. modulating effects were dose dependent (1 and 5 µm). evidence to suggest cannabidiol may be associated with changes in mitochondrial function, including modulation of stat3 and prohibitin expression, cbd can be used to sensitize cancer cells to chemotherapy. continued on page 56 55siuj.org siuj • volume 4, number 1 • january 2023 urogenital malignancy and cannabis use: a narrative review http://siuj.org table 2. summary of studies on the relationship between cannabis and prostate cancers author (year) in vitro versus in vivo type of study level of evidence (sackett) number of participants risk versus management exclusion criteria summary morell et al. (2016) in vitro experimental v treatment pi3k/akt/ampk may be an important axis modulating prostate cancer neuroendocrine differentiation. cannabinoid win was found to block pi3k/akt/ampk and therefore cannabinoids may have therapeutic potential against ne prostate. orellanaserradell et al. (2015) in vitro experimental v treatment cb1 and cb2 receptors are more highly expressed in higher gleason score prostate cancer cell lines. treatment of these cells with synthetic cannabinoid analogs produces a cell growth inhibitor effect via an apoptotic pathway which is dose-dependent and mediated via the cb1 receptor. depetrocellis et al. (2013) in vitro experimental v treatment cannabidiol was associated with downregulation of androgen receptors, p53 activation and elevation of reactive oxygen species. it was pro-apoptotic in prostate cancer cell lines and enhanced effects of docetaxel and bicalutamide against xenograft tumors and when given alone reduced tumor size in some cell lines. nithipatikom et al. (2012) in vitro experimental v treatment endocannabinoids through cb1 activation suppress migration of prostate cancer cells. sreevalsan et al. (2011) in vitro experimental v treatment cannabinoids were demonstrated to inhibit prostate cancer cell line growth and induced mrna expression of several phosphatases. of note the addition of a phosphatase inhibitor was shown to prevent apoptosis which suggests a potential a role of phosphatases cell death in prostate cancer cells with cannabinoids. nithipatikom et al. (2011) in vitro experimental v treatment there was observed dose-dependent inhibition of cell proliferation in prostate cancer cancer cells, in the presence of endocannabinoid hydrolysis inhibitors. brown et al. (2010) in vitro experimental v treatment through anti-proliferative effects certain omega-3 fatty acids may act as endocannabinoids in prostate cancer cell lines. , cont’d continued on page 57 56 siuj • volume 4, number 1 • january 2023 siuj.org review http://siuj.org population-based case-control study of 369 patients aged 18 to 44 found that men with testicular germ cell tumours (tgct) were almost twice as likely to be current cannabis smokers (or 1.7; 95% ci 1.1 to 2.5)[5]. when further stratified by histological type, there was a stronger association between non-seminomatous or mixed tumours (or 2.3; 95% ci 1.4 to 4.0). younger age at first use and frequency of use appear to increase risk table 2. summary of studies on the relationship between cannabis and prostate cancers author (year) in vitro versus in vivo type of study level of evidence (sackett) number of participants risk versus management exclusion criteria summary chung et al. (2009) in vitro experimental v treatment higher prostate cancer severity (gleason grade) was associated with higher tumor cb1 receptor immunoreactivity and lower disease specific survival in prostate tissue specimens. olea-herrero et al. (2009) in vitro experimental v treatment by decreasing prostate cancer epithelial cell proliferation cb2 agonists may have a role in the treatment of prostate cancer. olea-herrero et al. (2009) in vitro experimental v treatment   a synthetic cb2 agonist exerts antiproliferative effects in prostate cancer cells. treatment of mice with prostate xenograft tumors with a cb2 agonist resulted in significant reduction in tumor growth sarfaraz et al (2006) in vitro experimental v treatment   mixed cb1/cb2 agonists can cause the arrest of prostate cancer cells in the cell cycle and induction of apoptosis. sarfaraz et al. (2005) in vitro experimental v treatment   mixed cb1/cb2 agonists induced time and dose-dependent apoptosis, decreased protein and mrna expression of androgen receptors, reduction of intracellular protein and mrna expression of psa, and decreased psa level in prostate cancer cells. velasco et al. (2001) in vitro experimental v treatment   cannabinoid c1 receptor mediated δ9-tetrahydrocannabinol stimulation of nerve growth factor production in prostate cancer pc-3 cells. melck et al. (2000) in vitro experimental v   treatment   prostate cancer cell proliferation was inhibited by endogenous ligands of cannabinoid receptors when induced by exogenous prolactin. ruiz et al. (1999) in vitro experimental v   treatment   δ9-tetrahydrocannabinol demonstrated dose-dependent apoptotic effect on prostate cancer cells pc-3. , cont’d (age < 18 years [or 2.8] versus age ≥ 18 years [or 1.3]) as does daily or weekly use (or 3.0) versus less than once per week use (or 1.8)[5]. trabert et al. compared males diagnosed with tgct and male friend controls, finding that patients with tgct were more likely to be frequent cannabis users compared with controls (or 2.2; 95% ci 1.0 to 5.1). 57siuj.org siuj • volume 4, number 1 • january 2023 urogenital malignancy and cannabis use: a narrative review http://siuj.org additionally, they found that patients with nonseminoma were significantly more likely than controls to be frequent and long-term users (or 3.1; 95%ci 1.2 to 8.2 and pr 2.4 and 95% ci 1.0 to 6.1)[7]. a further population-based case-control study from 2012 including 163 patients with 269 age and ethnicity-matched controls demonstrated that compared with no thc use, previous thc use increased the risk of tgct (or 1.94; 95% ci 1.02 to 3.68). when stratified by histological sub-type, there was a specific association between non-seminoma and mixed histology tumours (or 2.42; 95% ci 1.08 to 2.42)[6]. table 3. summary of studies on the relationship between cannabis and bladder cancer author (year) in vitro versus in vivo type of study level of evidence (sackett) number of participants risk versus management exclusion criteria summary thomas  et al. (2015) in vivo cohort iii 84 170 risk   at 11 year follow up time cannabis use only (no tobacco use) was associated with a 45% reduction in bladder cancer incidence (hr 0.55; 95% ci, 0.31 to 1.00). chacko  et al. (2006) in vivo case-control iii 124 risk   in patients with urothelial carcinoma, cannabis use significantly correlated with tumor stage, grade, and number of recurrences suggesting possible increased risk of tcc. huang et al. (2022) in vivo cohort iii 151 945 risk previous use of cannabis was associated with a reduced risk of bladder cancer (hr 0.66; 95% ci 0.51 to 0.86). when adjusted for tobacco smoking and gender, hr 0.77; 95% ci 0.58 to 1.02. bettiga et al. (2017) in vitro experimental v   treatment   exposure to cannabinoid receptor cb2 agonists inhibited bladder cancer growth, down-modulated akt, induced caspase 3-activation and modified sl metabolism, overall leading to bladder cancer cell apoptosis. gasperi et al. (2015) in vitro experimental v   treatment   endocannabinoids can exacerbate proinflammatory status in human urothelial cell carcinoma cell lines by binding to cb1 and cb2 receptors and allowing t lymphocytes to adhere to treated cancer cells. cb1 inverse agonist decreases cancer proliferation by delaying cell cycle progression. yamada et al. (2010) in vitro experimental v   treatment   vanilloid receptor is more abundantly expressed in high-grade urothelial carcinoma cells, and administration of cannabidiol results in dose-dependent apoptosis via influx of calcium. a meta-analysis of the above studies found that for current, chronic, and frequent users, there is an association with the development of tgct, compared with those who have never used[44]. previous use of cannabis increased the odds of tgct development by 62% (or 1.62; 95% ci 1.13 to 2.31) and a use frequency of weekly or more appeared to double the odds of tgct development (or 1.92; 95% ci 1.35 to 2.72). duration of cannabis use (> 10 years versus never used) increased likelihood of tgct development (or 1.5; 95% ci 1.08 to 2.09)[44]. a cohort study by huang et al. has examined united kingdom biobank specimens of individuals with infor58 siuj • volume 4, number 1 • january 2023 siuj.org review http://siuj.org table 4. summary of studies on the relationship between cannabis and penile cancer author (year) in vitro versus in vivo type of study level of evidence (sackett) number of participants risk versus management exclusion criteria summary maden  et al. (1993) in vivo case-control iii 465 risk   use of cannabis was not significantly associated with risk of penile cancer (or 1.5, 95% ci 0.7 to 2.3). mation on cannabis use[8]. after examining 64 730 samples, it demonstrated a minimally increased risk of developing testicular carcinoma (hr 1.12; 95% ci 0.49 to 2.52), this was not statistically significant (p = 0.793). a cohort study of 49 343 swedish males born between 1949 and 1951 found that there was no evidence of a significant relationship between previous cannabis use and the subsequent development of testicular cancer (119 testicular cancer cases, adjusted hr 1.42; 95% ci 0.83 to 2.45)[45]. however, heavy cannabis use (> 50 times in a lifetime) was associated with an increased incidence of testicular cancer (hr 2.57; 95% ci 1.08 to 5.42)[45]. in a 2-patient case series by garnick et al. elevated serum β-hcg levels returned to normal following cessation of cannabis use[10]. as β-hcg is a tumour marker for some testicular cancers, its implications in follow-up were believed to be significant. two subsequent small series examining a combined 22 patients determined that thc did not affect β-hcg levels[10,46]. further investigation is warranted in this younger population where reported cannabis use rates are increasing. cannabis use appears to be an important risk factor for tgct. whilst research to date demonstrates an apparent effect on incidence, more should be done to understand the mechanism of action and to potentially generate novel targets for treatment. penile cancer penile cancer accounts for <  1% of cancers in men annually[43]. a 2003 single case-control study by maden et al. found no relationship between cannabis use and penile cancer[36]. at the time of this review there were no publications examining cannabis as a treatment arm for penile cancers. this highlights the need for further research and understanding in this area. prostate cancer prostate cancer is the second most commonly diagnosed cancer in men worldwide, accounting for approximately 15% of male cancer diagnoses each year[43]. only one observational study has examined the relationship between cannabis use and prostate cancer incidence. this retrospective study examined several different malignancies, and found that when adjusted for confounding factors, previous use of cannabis did not confer a higher risk of prostate cancer in comparison with non‐use (rr 1.3, 95% ci 0.6 to 2.6)[11]. huang et al. demonstrated a reduction in incidence with previous use of cannabis (hr 0.52; 95% ci 0.46 to 0.58), which was statistically significant (p < 0.001). when adjusted for family history, hr 0.83; 95% ci 0.74 to 0.94)[8]. a number of studies have examined cannabis and its derivatives, as well as cannabinoid receptors, as potential treatment targets for prostate cancer. synthetic cannabinoid win 55-212,2 (win) has been shown to reduce prostate cancer cell proliferation, migration, and invasion, and to induce apoptosis and arrest cells in go/g1 phase in a dose-dependent manner by acting as an agonist on receptors cb1 and cb2[15–22,27,29,30]. mechanistic studies revealed these effects were mediated through a pathway involving cell cycle regulators p27, cdk4, and prb[12,13,25,26,28]. however, it should be noted that in vitro studies demonstrated significant variability between differing cannabis compounds and extracts, with effects dependent on specific prostate cancer cell lines in addition to the extract’s composition[14,24]. there is currently a paucity of high-level evidence for the risks of cannabis use and potential for developing prostate cancer, although promising models for cannabinoids as a targeted treatment for prostate cancer do exist. bladder cancer urothelial carcinoma (uc) of the bladder is the tenth most commonly diagnosed cancer worldwide and the seventh most common in men[43]. a case-control study by chacko et al. (2006) of vietnam-era veterans found that 88.5% of participants with uc reported habitual use of cannabis, compared with 69.2% of agematched controls (p = 0.008)[32]. importantly, however, this study’s small sample size (n  =  124) could not be 59siuj.org siuj • volume 4, number 1 • january 2023 urogenital malignancy and cannabis use: a narrative review http://siuj.org adjusted to remove tobacco use — the most common risk factor for uc — as a confounder. the authors postulated that thc had a carcinogenic effect due to metabolites remaining in the urine for up to 60 hours post consumption, as opposed to 12 hours for nicotine metabolites. in a separate cohort study of 47 092 men examining those who used cannabis (41%), tobacco (57%), both (27%), or neither (29%), only tobacco use was associated table 5. summary of studies on the relationship between cannabis and renal cancer author (year) in vitro versus in vivo type of study level of evidence (sackett) number of participants risk versus management exclusion criteria summary taha et al. (2019) in vivo observational iv 42** • included patients with mmelanoma and mrcc. unclear how many had mrcc alone. treatment use of cannabis during immunotherapy (nivolumab) in mccrcc decreased treatment response rate and did not affect progression free or overall survival. huang et al. (2022) in vivo cohort iii 151 945 risk previous use of cannabis was associated with a reduced risk of rcc (hr 0.51 95% ci 0.35-0.76). when adjusted for gender, smoking status and bmi, hr 0.61 95% ci 0.40-0.93. wang et al. (2019) in vitro experimental v   treatment cannabinoid cb2 receptor expression is functionally related to cellular proliferation, migration, and cell cycle of rcc cells and therefore may have role in assessing therapeutic effects or target in rcc. larrinaga et al. (2013) in vitro experimental v   treatment cannabinoid cb1 receptor mrna was under-expressed by 12-fold in chromosomal renal cell carcinoma (chrcc) and variable expression in renal oncocytoma and therefore may have a role in differention of tumours. larrinaga et al. (2010) in vitro experimental v   treatment in ccrcc tumour tissue expression of mrna encoding cannabinoid cb1 receptor was observed with marked downregulation of cb1 protein in tumor tissue and nontumour tissue. cb2 receptor expression was negative in all cases. findings indicate implications of cannibinoids in kidney physiology. choi et al. (2008) in vitro experimental v   treatment the cytotoxicity of cannabidiol increased in a doseand time-dependent manner with growth inhibition to a mild-moderate degree in rencal renal cancer cells. with an increased risk of bladder cancer (hr 1.52; 95% ci 1.12 to 2.07)[31]. cannabis use was in fact associated with a 45% reduction in bladder cancer incidence (hr 0.55; 95% ci 0.21 to 1.00)[31]. in the study of united kingdom biobank specimens, bladder cancer risk was again reduced in the setting of previous cannabis use (hr 0.66;95% ci 0.51 to 0.86)[8]. when adjusted for tobacco smoking and sex, hr 0.77; 95% ci 0.58 to 1.02. however, current use of cannabis 60 siuj • volume 4, number 1 • january 2023 siuj.org review http://siuj.org seemed to be associated with an increased risk. this was difficult to interpret, as the investigators did not have access to the timing of use, and therefore may have been confounded by cannabis use in the setting of managing the symptoms of malignancy. a number of in vitro studies also have shown cannabinoids to be protective against uc. yamada et al. showed that villinoid receptors are expressed more in high grade uc. they also demonstrated a dose-dependent relationship between cannabis administration and apoptosis mediated by calcium influx, via villinoid receptors[35]. this was supported by another study examining the activation of cb2 in primary uc of the bladder, where it was found to lead to cell death[33]. these principles were further expanded upon by gasperi et al. (2015), who demonstrated that endocannabinoids create a pro-inflammatory state in human uc by binding to cb1 and cb2 receptors therefore decreasing cancer proliferation by delaying cell cycle progression[34]. there appears to be an apparent protective effect of thc against the development of bladder cancer. in view of the high proportion of thc users who concurrently use tobacco, care must be taken, however, in interpretation of any studies that do not stratify for these 2 variables. renal cancer renal cell carcinoma accounts for 3% of cancer diagnoses each year, and there has been an increase of 2% in cases each year over the past 20 years; however, mortality rates have remained stable or are decreasing[43]. the examination of biobank specimens by huang et al. was the first study to look at the association between cannabis and rcc[8]. they found that previous cannabis use has a significant inverse association with developing rcc (hr 0.52; 95% ci 0.35 to 0.76, p < 0.001). taha et al. (2019) performed an observational study of 42 patients with either metastatic rcc, non-small cell lung cancer or metastatic melanoma who were undergoing immunotherapy and found that in these patients, the use of cannabis reduced the response rate to treatment. however, cannabis did not affect the progression-free survival or overall survival[38]. it should be noted that the data from this study did not stratify patients based on cancer type and involved only small numbers. several in vitro studies have been performed to examine the effect of cannabis and its derivatives on receptors of rcc cell lines. choi et al. in 2008 reported that rcc cells exhibited mild-to-moderate dose and time-dependent growth inhibition in response to cannabidiol[42]. another study found that cb2 expression on clear cell rcc cells was functionally related to cellular proliferation, migration, and the cell cycle. expression of cb2 was up-regulated in rcc compared with normal surrounding tissue, and was an independent prognostic factor for patients, and therefore represents a potential therapeutic target[39]. conversely, cb1 was under-expressed in rcc tissue as compared with surrounding normal tissue. given the difficulty in establishing a clear differential diagnosis of rcc in clinical practice, expression of cb1 and cb2 represent a potential diagnostic tool for rcc[40]. ultimately, there is a lack of understanding of the effect of cannabis use on the incidence of rcc, however cb1 and cb2 present potential targets for diagnostic and therapeutic purposes. confounding effect of tobacco tobacco smoke is a known significant carcinogenic substance for the development of many cancers[47]. cannabis and tobacco use commonly occur together. it was estimated that 57.9% of cigarette smokers reported a lifetime history of cannabis use, but 90% of cannabis users reported a history of smoking cigarettes[48]. adjustment for tobacco cigarette smoking was reported in all but one of the studies that examined the incidence of genitourinar y ma lignancy. given their likely association, adjusting for tobacco cigarette smoking is both difficult and important, and should be considered as a key endeavour to ensure study validity in future research. effect of thc delivery the delivery of thc is changing. whilst previously cannabis was almost exclusively smoked, novel delivery methods are being explored by consumers, including vaping and oral intake, including capsules and liquid mucosal sprays, as well as being combined in food or liquid forms[49]. alternative delivery methods can alter both the amount of thc being delivered to a consumer and the potential contaminates that reach the body. although vaping is thought to avoid toxic components of smoking such as tar, there are still contaminates, including pesticides, heav y metals, and ammonia potentially acting as carcinogens. as the cannabis industry continues to grow, it will be critical for manufacturers to work towards minimising contaminants of the cultivation process, as well as to standardise the quality of products being delivered to consumers[49]. limitations this review highlighted several limitations in the available literature. studies that have examined the risk of genitourinary malignancy and cannabis use are observational in nature, with no high-level evidence available. also, there is a large variation in the number of patients included, with many studies having very few patients, making it difficult to generalise results to 61siuj.org siuj • volume 4, number 1 • january 2023 urogenital malignancy and cannabis use: a narrative review http://siuj.org the population. additionally, the studies that examine the use of cannabis in the diagnosis, treatment, and follow-up of genitourinary malignancy are still in the experimental phase, limiting their ability to be translated into practical use at this point. this review has several limitations. the search was conducted of the data bases ovid medline, ovid embase, cochrane central register of controlled trials (central) from inception to present, google scholar (first 200 citations relevancy ranked), and clinical trial registries. although it is unlikely, it is possible that other articles may have been identified if other databases had been searched. additionally, only articles published in english were included, meaning that some relevant studies may have been excluded. finally, given that no further papers were excluded following full text review, it remains possible that the abstract screening was too narrow and therefore some relevant papers may not have been included. future directions this review has highlighted the lack of evidence about the effect of cannabis on the risk and management of genitourinary malignancy. further studies that explore the effect of cannabis, including in different forms such as oils and edibles, should be designed to better understand this area. it may help clinicians to references 1. united nation office on drugs and crime. world drug report 20 21: cannabis and opioids [internet]. 20 21. available at: https://www.unodc.org/res/wdr2021/field/ wdr21_booklet_4.pdf https://www.unodc.org/res/wdr2021/field/wdr21_booklet_3.pdf. accessed december 9, 2022. 2. rossato m, pagano c, vettor r. the cannabinoid system and male reproductive functions. j neuroendocrinol.2008;20(suppl. 1):90–93. 3. australian institute of health and welfare. national drug strategy household survey 2019. canberra; 2020. 4. zi h, he sh, leng xy, xu xf, huang q, weng h, et al. global, regional, and national burden of kidney, bladder, and prostate cancers and their attributable risk factors, 1990–2019. mil med res.2021;8(1):1–15. doi. org/10.1186/s40779-021-00354-z 5. daling jr, doody dr, sun x, trabert bl, weiss ns, chen c, et al. association of marijuana use and the incidence of testicular germ cell tumors. cancer.2009;115(6):1215–1223. 6. lacson jca, carroll jd, tuazon e, castelao ej, bernstein l, cortessis vk. population-based case-control study of recreational drug use and testis cancer risk confirms an association between marijuana use and nonseminoma risk. cancer.2012;118(21):5374–5383. 7. trabert b, sigurdson aj, sweeney am, strom ss, mcglynn k a. marijuana use and testicular germ cell tumors. cancer.2011;117(4):848– 853. doi: 10.1111/j.1365-3016.2011.01210.x 8. huang j, huang d, ruan x, huang j, xu d, heavey s, et al. association between cannabis use with urological cancers: a population-based cohort study and a mendelian randomization study in the uk biobank. cancer med.2022 aug 17. doi: 10.1002/cam4.5132. online ahead of print. 9. garnick mb. spurious rise in human chorionic gonadotropin induced by marihuana in patients with testicular cancer. n engl j med.1980;303(20):1177. 10. braustein g, thompson r, gross s, soares j. marijuana use does not spuriously elevate serum human chorionic gonadotropin levels. urology.1985;25(6). 11. sidney s, quesenberry cp, friedman gd, tekawa is. marijuana use and cancer incidence (california, united states). cancer causes control.1997;8(5):722–728. doi: 10.1023/a:1018427320658. stratify patients’ risk of having malignancy given their history of cannabis use. additionally, it is important for the policymakers to understand the unintended consequences of the ingestion of these substances, as there remains a lack of evidence surrounding the harm of using cannabis. likewise, further understanding of the effects of cannabis on the diagnosis, management, and follow-up of genitourinary malignancy will be important for translation of this research into in vivo models and the development of practical uses for this information. conclusion with the increasing legalisation of cannabis for both recreational and medical uses, it is imperative to understand its effect upon the incidence of and potential use in the management of genitourinary malignancies. cannabis has been associated with both increased and decreased risk of different genitourinary malignancies. the use of cannabis and cannabinoids for the investigation, treatment, and follow-up of these malignancies is not fully understood. this review demonstrates the incomplete nature of evidence that exists in this area. further research is required to be able to understand and potentially harness the use of cannabis. 62 siuj • volume 4, number 1 • january 2023 siuj.org review https://www.unodc.org/res/wdr2021/field/wdr21_booklet_4.pdf https://www.unodc.org/res/wdr2021/field/wdr21_booklet_3.pdf http://siuj.org 12. roberto d, klotz lh, venkateswaran v. cannabinoid win 55,212-2 induces cell cycle arrest and apoptosis, and inhibits proliferation, migration, invasion, and tumor grow th in prostate cancer in a cannabinoid-receptor 2 dependent manner. prostate.2019 feb;79(2):151-159. doi: 10.1002/pros.23720. epub 2018 sep 21. 13. morales p, vara d, goméz-cañas m, zúñiga mc, olea-azar c, goya p, et al. synthetic cannabinoid quinones: preparation, in vitro antiproliferative effects and in vivo prostate antitumor activity. eur j med chem.2013;70:111–119. doi.org/10.1016/j.ejmech.2013.09.043 14. brown i, cascio mg, wahle kwj, smoum r, mechoulam r, ross ra, et al. cannabinoid receptor-dependent and -independent anti-proliferative effects of omega-3 ethanolamides in androgen receptor-positive and -negative prostate cancer cell lines. carcinogenesis.2010;31(9):1584–1591. 15. chung sc, hammarsten p, josefsson a, stattin p, granfors t, egevad l, et al. a high cannabinoid cb1 receptor immunoreactivity is associated with disease severity and outcome in prostate cancer. eur j cancer.2009;45(1):174–182. 16. olea-herrero n, vara d, malagarie-cazenave s, díaz-laviada i. inhibition of human tumour prostate pc-3 cell growth by cannabinoids r()-methanandamide and jwh-015: involvement of cb 2. br j cancer.2009;101(6):940–950. 17. olea-herrero n, vara d, malagarie-cazenave s, díaz-laviada i. the cannabinoid r()methanandamide induces il-6 secretion by prostate cancer pc3 cells. j immunotoxicol.2009;6(4):249–256. 18. sarfaraz s, afaq f, adhami vm, mukhtar h. cannabinoid receptor as a novel target for the treatment of prostate cancer. cancer res.2005;65(5):1635–1641. 19. sarfaraz s, afaq f, adhami vm, malik a, mukhtar h. cannabinoid receptor agonist-induced apoptosis of human prostate cancer cells lncap proceeds through sustained activation of erk1/2 leading to g 1 cell cycle arrest. j biol chem.2006;281(51):39480–36491. 20. velasco l, ruiz l, sánchez mg, díaz-laviada i. δ9-tetrahydrocannabinol increases ner ve grow th factor production by prostate pc-3 cells: involvement of cb1 cannabinoid receptor and raf-1. eur j biochem.2001;268(3):531–535. 21. melck d, de petrocellis l, orlando p, bisogno t, laezza c, bifulco m, et al. suppression of nerve growth factor trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human breast and prostate cancer cell proliferation. endocrinology.2000;141(1):118–126. 22. ruiz l, miguel a, díaz-laviada i. δ9-tetrahydrocannabinol induces apoptosis in human prostate pc-3 cells via a receptor-independent mechanism. febs lett.1999;458(3):400–404. 23. pietrovito l, iozzo m, bacci m, giannoni e, chiarugi p. treatment with cannabinoids as a promising approach for impairing fibroblast activation and prostate cancer progression. int j mol sci.2020;21(3):1–16. 24. baram l, peled e, berman p, yellin b, besser e, benami m, et al. the heterogeneity and complexity of cannabis extracts as antitumor agents. oncotarget.2019;10(41):4091–4106. 25. kosgodage us, mould r, henley ab, nunn a v., guy gw, thomas el, et al. cannabidiol (cbd) is a novel inhibitor for exosome and microvesicle (emv) release in cancer. front pharmacol.2018;9(aug):1–17. 26. morell c, bort a, vara d, ramos-torres a, rodríguez-henche n, díazlaviada i. the cannabinoid win 55,212-2 prevents neuroendocrine differentiation of lncap prostate cancer cells. prostate cancer prostatic dis.2016;19(3):248–257. 27. orellana-serradell o, poblete ce, sanchez c, castellón ea, gallegos i, huidobro c, et al. proapoptotic effect of endocannabinoids in prostate cancer cells. oncol rep.2015;33(4):1599–1608. 28. de petrocellis l, ligresti a, schiano moriello a, iappelli m, verde r, stott cg, et al. non-thc cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: pro-apoptotic effects and underlying mechanisms. br j pharmacol.2013;168(1):79–102. 29. nithipatikom k, gomez-granados ad, tang at, pfeiffer aw, williams cl, campbell wb. cannabinoid receptor type 1 (cb1) activation inhibits small gtpase rhoa activity and regulates motility of prostate carcinoma cells. endocrinology.2012;153(1):29–41. 30. sreevalsan s, joseph s, jutooru i, chadalapaka g, safe sh. induction of apoptosis by cannabinoids in prostate and colon cancer cells is phosphatase dependent. anticancer res.2011;31(11):3799–3807. 31. thomas a a, wallner lp, quinn vp, slezak j, van den eeden sk, chien gw, et al. association between cannabis use and the risk of bladder cancer: results from the california men’s health study. urology.2015;85(2):388–393. doi.org/10.1016/j.urology.2014.08.060 32. chacko ja, heiner jg, siu w, macy m, terris mk. association bet ween marijuana use and tr ansitional cell c ar cinoma. urology.2006;67(1):100–104. 33. bettiga a, aureli m, colciago g, murdica v, moschini m, lucianò r, et al. bladder cancer cell growth and motility implicate cannabinoid 2 receptor-mediated modifications of sphingolipids metabolism. sci rep.2017;7(february):1–11. doi.org/10.1038/srep42157 34. gasperi v, evangelista d, oddi s, florenzano f, chiurchiù v, avigliano l, et al. regulation of inflammation and proliferation of human bladder carcinoma cells by type-1 and type-2 cannabinoid receptors. life sci.2015;138:41–51. doi.org/10.1016/j.lfs.2014.09.031 35. yamada t, ueda t, shibata y, ikegami y, saito m, ishida y, et al. trpv2 activation induces apoptotic cell death in human t24 bladder cancer cells: a potential therapeutic target for bladder cancer. urology. 2010;76 (2):5 09.e1-5 09.e7. doi.org /10.1016/j. urology.2010.03.029 36. maden c, sherman kj, beckmann am, hislop tg, teh cz, ashley rl, et al. history of circumcision, medical conditions, and sexual activity and risk of penile cancer. j natl cancer inst.1993;85(1):19–24. 37. woythal n, arsenic r, kempkensteffen c, miller k, janssen jc, huang k, et al. immunohistochemical validation of psma expression measured by 68 ga-psma pet/ct in primary prostate cancer. j nucl med.2018;59(2):238–243. 63siuj.org siuj • volume 4, number 1 • january 2023 urogenital malignancy and cannabis use: a narrative review http://siuj.org 38. taha t, meiri d, talhamy s, wollner m, peer a, bar-sela g. cannabis impacts tumor response rate to nivolumab in patients with advanced malignancies. oncologist.2019;24(4):549–554. 39. wang j, xu y, zhu l, zou y, kong w, dong b, et al. cannabinoid receptor 2 as a novel target for promotion of renal cell carcinoma prognosis and progression. j cancer res clin oncol.2018;144(1):39–52. 40. larrinaga g, sanz b, blanco l, perez i, candenas ml, pinto fm, et al. cannabinoid cb1 receptor is expressed in chromophobe renal cell carcinoma and renal oncocytoma. clin biochem.2013;46(7–8):638–641. doi.org/10.1016/j.clinbiochem.2012.12.023 41. larrinaga g, varona a, perez i, sanz b, ufalde a, candenas ml, et al. expression of cannabinoid receptors in human kidney. histol histopathol.2010;25:1133–1138. 42. choi wh, park h do, baek sh, chu jp, kang mh, mi yj. cannabidiol induces cytotoxicity and cell death via apoptotic pathway in cancer cell lines. biomol ther.2008;16(2):87–94. 43. eau renal cell cancer guidelines. 2021. available at: https://uroweb. org/guidelines. accessed december 20, 2022. 44. gurney j, shaw c, stanley j, signal v, sarfati d. cannabis exposure and risk of testicular cancer: a systematic review and meta-analysis. bmc cancer.2015;15(1). doi.org/10.1186/s12885-015-1905-6 45. callaghan rc, allebeck p, akre o, mcglynn ka, sidorchuk a. cannabis use and incidence of testicular cancer: a 42-year follow-up of swedish men between 1970 and 2011. cancer epidemiol biomarkers prev.2017;26(11):1644–1652. 46. hogan p, sharpe m, smedley h, sikora k. cannabinoids and hcg levels in patients with testicular cancer. lancet.1983;1144. 47. gandini s, botteri e, iodice s, boniol m, lowenfels ab, maisonneuve p, et al. tobacco smoking and cancer: a meta-analysis. int j cancer.2008;122(1):155–164. 48. agrawal a, budney aj, lynskey mt. the co-occurring use and misuse of cannabis and tobacco: a review. addiction.2012;107(7):1221–1233. 49. dryburgh lm, bolan ns, grof cpl, galettis p, schneider j, lucas cj, et al. cannabis contaminants: sources, distribution, human toxicity and pharmacologic effects. br j clin pharmacol.2018;84(11):2468–2476. 64 siuj • volume 4, number 1 • january 2023 siuj.org review https://uroweb.org/guidelines https://uroweb.org/guidelines http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj.org siuj • volume 4, number 3 • may 2023 key words competing interests article information bladder cancer, nmibc, blue light cystoscopy none declared. received on november 15, 2022 accepted on december 24, 2022 this article has been peer reviewed. soc int urol j. 2023;4(3):223–225 doi: 10.48083/anxw6767 223 pro and con continued use and expansion of photodynamic turbt michael e. rezaee, max kates johns hopkins medical institutions, baltimore, united states doubt is not a pleasant condition, but certainty is an absurd one. – voltaire urology has been fraught with informing practice based on weak evidence, and when a randomized controlled trial comes along in our field, it should be applauded. but to applaud the completion of a trial does not mean to kneel at its altar. we should ask ourselves 2 questions of every clinical trial: (1) does the trial address an important question, and (2) was the trial designed and conducted in such a way to successfully answer the intended question. the photo trial, which was recently published in the new england journal of medicine evidence is a trial that successfully answers a question that is largely unimportant. among patients with intermediate-risk non-muscle invasive bladder cancer (nmibc) with low rates of both carcinoma in situ (cis) and adjuvant bacillus calmette-guérin (bcg) therapy, initial photodynamic transurethral resection of bladder tumor (turbt) did not perform any better than traditional white-light turbt in terms of 3-year disease recurrence in a large, multicenter, randomized trial[1]. as such, many urologists now wonder if photodynamic turbt should be abandoned, especially given the costs associated with this technology. the answer is no. in fact, we favor the continued use and expansion of photodynamic turbt in appropriate patients. the risk for disease recurrence in intermediate-risk nmibc ranges from 40% to 56% based on european organisation for research and treatment of cancer (eortc) estimates, while up to 75% to 80% of patients with high-risk disease will experience a recurrence[2]. as such, the photo trial enrolled patients with suspected intermediate or high-risk nimbc who were expected to have recurrences. however, study enrollment was based on tumor cystoscopic appearance (eg, flat velvety erythematous mucosal changes) or imaging characteristics (eg, tumor ≥ 3 cm), not pathology specimens. this resulted in 89 patients (16.5%) being automatically excluded from the trial due to having muscle-invasive bladder cancer (mibc) or no tumor at the time of turbt. in addition, 374 (88%) patients enrolled in the trial had eortc intermediate-risk disease (46% intermediate-risk by national institute for health and care excellence criteria[3]), while 32 (7.5%) had high-risk disease and 18 (4.2%) could not be classified. this enrollment design reduced the number of potential tumor recurrences (the main study outcome) that could have been observed in the trial by 1) enrolling patients who would never have a recurrence, and 2) primarily enrolling patients at only intermediate risk for recurrence. the authors explain that the primary implication of this limitation is a reduction in predefined study power from 90% to around 80%. however, we believe this enrollment methodology likely also shifted the population of interest away from patients who would benefit from photodynamic turbt the most. patients with high-risk nmibc experience the greatest benefit from photodynamic turbt, particularly those with cis[4,5]. photodynamic turbt has been shown to detect 32% more high-risk tumors compared to white-light turbt and 36% more cis lesions, specifically[6]. in fact, multiple studies have demonstrated the additive benefit of photodynamic turbt in detecting cis compared with white-light turbt[7,8]. unfortunately, only 32 (7.5%) and 51 (9.5%) patients enrolled in the photo trial had eortc high-risk nmibc and cis, respectively. thus, the results of the photo trial likely do not adequately represent the true potential benefit of photodynamic turbt in high-risk patients, for which the technology is most appropriate for. http://siuj.org another important limitation of the photo trial was the underutilization of adjuvant bcg, an intravesical therapy known to reduce tumor recurrences and progression in nmibc[9]. only 68 (16.0%) patients in the final analysis cohort received induction plus maintenance bcg and 35 (8.2%) received induction bcg alone. bcg use was particularly dismal among patients with high-risk disease, with only 14 patients receiving induction and 7 receiving maintenance. these utilization rates are concerning given the known oncological benefits of bcg in high-risk nmibc[2]. most importantly, these rates suggest that many patients did not receive standard of care for adjuvant intravesical therapy. it is therefore not surprising that although at 1 year there is separation of the recurrence-free survival curves favoring photodynamic turbt, by 3 years there was no difference. the fact that most patients in the trial were eortc intermediate-risk nmibc without cis means that the trial is studying a population with fewer recurrences, lower stakes for patients and providers, and less proven outcomes with use of photodynamic technology. in the small group of patients with eortc high-risk nmibc, the fact that a small fraction was treated with standardof-care intravesical therapy means that the trial merely demonstrates that untreated high-risk nmibc leads to recurrences. a recent meta-analysis of 12 randomized trials found that photodynamic turbt improved recurrence-free survival compared to white-light turbt at 2 years of follow-up[4]. the photo trial does not erase this prior evidence supporting the utility of photodynamic turbt. instead, it adds to a growing literature base abbreviations bcg bacillus calmette-guérin cis carcinoma in situ eortc organisation for research and treatment of cancer nmibc non-muscle invasive bladder cancer turbt transurethral resection of bladder tumor available to urologists to continue to improve the quality of care delivered to patients with bladder cancer. overall, nmibc care is highly nuanced with varying disease trajectories, surveillance strategies, and treatment options. the photo trial suggests that photodynamic turbt may have limited utility when used at the initial diagnosis of patients with intermediate-risk disease, but there are many patients and clinical scenarios that other studies have shown derive benefit from photodynamic turbt. our approach to the patient demands that we be nuanced in interpreting the trial’s findings. an example of this is the use of immediate postoperative intravesical chemotherapy in intermediate-risk nmibc. intermediate-risk patients with an eortc recurrence score ≥ 6 (e.g., multiple tumors, at least one ≥ 3 cm) do not benefit from postoperative intravesical chemotherapy. however, those with a score < 6 can experience up to a 35% reduction in recurrence risk[10]. despite not having any oncologic benefit in some intermediate-risk patients, postoperative intravesical chemotherapy is commonly pursued in all intermediate-risk patients because the potential benefit for some patients outweighs the risk in most patients. if 1 in 10 or 1 in 20 patients derives benefit from the introduction of a technology, then all it takes is a few interventions like that to impact a sizable portion of patients with bladder cancer. because the photo trial did not enroll many patients with cis or high-risk nmibc, it was not powered to identify these differences. based on the limitations of the photo trial, available prior research, and the nuances of bladder cancer care, we support the continued use and expansion of photodynamic turbt in nmibc. this technology should be used in patients with high-risk nmibc, especially those with cis. use in intermediate-risk disease is also likely justified for many patients, despite the trial results. based on our experience, we also believe there is significant utility for this technology in restaging turbts to identify cis, during mucosal mapping for partial cystectomy and trimodality therapy planning, and for assessing response to intravesical therapy. 224 siuj • volume 4, number 3 • may 2023 siuj.org pro and con http://siuj.org references 1. heer r, lewis r, vadiveloo t, yu g, mariappan p, cresswell j, et al. a randomized trial of photodynamic surgery in non–muscle-invasive bladder cancer. nejm evid.2022;1(10). doi: 10.1056/evidoa2200092. 2. babjuk m, burger m, capoun o, cohen d, compérat em, dominguez escrig jl, et al. european association of urology guidelines on non-muscle-invasive bladder cancer (ta, t1, and carcinoma in situ). eur urol.2022;81(1):75–94. doi: 10.1016/j.eururo.2021.08.010. pmid: 34511303. 3. woldu sl, bagrodia a, lotan y. guideline of guidelines: non-muscleinvasive bladder cancer. bju int.2017;119(3):371–380. doi: 10.1111/ bju.13760. pmid: 28058776; pmcid: pmc5315602. 4. veeratterapillay r, gravestock p, nambiar a, gupta a, aboumarzouk o, rai b, et al. time to turn on the blue lights: a systematic review and meta-analysis of photodynamic diagnosis for bladder cancer. eur urol open sci.2021;31:17–27. doi: 10.1016/j.euros.2021.06.011. pmid: 34467237; pmcid: pmc8385287. 5. lotan y, bivalacqua tj, downs t, huang w, jones j, kamat am, et al. blue light flexible cystoscopy with hexaminolevulinate in non-muscle-invasive bladder cancer: review of the clinical evidence and consensus statement on optimal use in the usa — update 2018. nat rev urol.2019;16(6):377–386. doi: 10.1038/s41585-019-0184-4. pmid: 31019310; pmcid: pmc7136177. 6. mowatt g, n’dow j, vale l, nabi g, boachie c, cook ja, et al.; aberdeen technology assessment review (tar) group. photodynamic diagnosis of bladder cancer compared with white light cystoscopy: systematic review and meta-analysis. int j technol assess health care.2011;27(1):3–10. doi: 10.1017/s0266462310001364. pmid: 21262078. 7. fradet y, grossman hb, gomella l, lerner s, cookson m, albala d, et al.; pc b302/01 study group. a comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of carcinoma in situ in patients with bladder cancer: a phase iii, multicenter study. j urol.2007;178(1):68–73. doi: 10.1016/j. juro.2007.03.028. pmid: 17499291. 8. schmidbauer j, witjes f, schmeller n, donat r, susani m, marberger m; hexvix pcb301/01 study group. improved detection of urothelial carcinoma in situ with hexaminolevulinate fluorescence cystoscopy. j urol.2004;171(1):135–138. doi: 10.1097/01.ju.0000100480.70769.0e. pmid: 14665861. 9. kamat am, flaig tw, grossman hb, konety b, lamm d, o’donnell ma, et al. expert consensus document: consensus statement on best practice management regarding the use of intravesical immunotherapy with bcg for bladder cancer. nat rev urol.2015;12(4):225–235. doi: 10.1038/nrurol.2015.58. pmid: 25800393. 10. sylvester rj, oosterlinck w, holmang s, sydes mr, bir tle a, gudjonsson s, et al. systematic review and individual patient data meta-analysis of randomized trials comparing a single immediate instillation of chemotherapy after transurethral resection with transurethral resection alone in patients with stage pta–pt1 urothelial carcinoma of the bladder: which patients benefit from the instillation? eur urol.2016;69(2):231–244. doi: 10.1016/j.eururo.2015.05.050. pmid: 26091833. 225siuj.org siuj • volume 4, number 3 • may 2023 continued use and expansion of photodynamic turbt http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. 81siuj.org siuj • volume 4, number 2 • march 2023 editorial the emerging role of social media in urology practice jeremy yuen-chun teoh social media editor, siuj philippe e. spiess deputy editor, siuj director of publications and icud initiatives, société internationale d’urologie soc int urol j.2023;4(2):81–83 doi: 10.48083/natn6247 in this modern era, social media has become an integral and inevitable part of our daily lives. it allows effective dissemination of knowledge and rapid communication across our global community. while social media certainly has its pitfalls, we can learn to use it effectively in our urological practice. this special issue on “social media in urology made easy” is dedicated to providing comprehensive and important information regarding the utility of social media and its potential implications in the future. twitter appears to be the preferred social media platform for knowledge dissemination among health care professionals. in the study by dr spencer bell et al., the authors report the results of a social media network analysis on twitter and note that there was a steady increase in twitter representation among academic urologists[1]. urologic oncology represents the largest cohort, but andrology and reconstructive urology represent the highest proportion of their respective subspecialties. this study provides important insight into the constitution of the target audience on this social media platform. apart from medical professionals, it is also important to understand whether social media platforms have a significant influence among medical students globally. the study by dr rachel kaufman et al. investigated the degree of reach and engagement across various social media platforms including facebook, twitter, instagram, and tiktok[2]. the authors found that twitter allows for engagement with a statistically significantly large proportion of medical students, and tiktok allows access to a numerically larger audience of medical students. this study provides information regarding the reach of urology on social media, which will be very helpful for effective education and information dissemination across undergraduate and post-graduate residency programs. “likes” is perhaps one of the most well-known metrics in determining how engaging one post or tweet is. however, apart from showing how trendy a post or tweet is, does it actually carry any important implications? in their paper, dr justin loloi et al. discuss the various effects of social media usage in terms of branding, education, networking, research, and enhanced recruitment efforts[3]. the authors also provide guidance for engaging in social media as a medical professional, and summarize the important principles regarding appropriate use of social media. the importance of social media engagement has been increasingly recognized by urology journals, but how social media presence correlates with traditional journal metrics such as scimago journal & country rank, h-index, and scopus citescore, is largely unknown[4-6]. in a study of traditional and social media metrics, dr wei zheng so and colleagues found that 54.2% of all urology journals had at least one form of social medial presence[7]. urology journals with social media presence had significantly higher traditional metric values than journals without social media presence. the study shows that urology journals can disseminate the findings of research studies effectively to the urological community via the social media platforms, and this in turn will improve citations in the long run. social media platforms are also increasingly used by urological societies. in the paper by dr nikita bhatt et al., the european association of urology guideline dissemination committee discusses the novel methods of social media dissemination, the importance of maintaining quality, ethics, and reliability in social media, and how societies can play an active role in this[8]. this paper provides important guidance on how societies can engage medical professionals and disseminate useful information to the urology community more effectively. the authors also highlight the importance of having an authoritative guideline on the use of social media. http://siuj.org mailto:jeremyteoh%40surgery.cuhk.edu.hk?subject=siuj mailto:deputyeditor%40siuj.org?subject=suij 82 siuj • volume 4, number 2 • march 2023 siuj.org editorial social media may also play a role in research work, such as cross-sectional surveys. conventionally, emails are often used to disseminate surveys. in this modern era, there is increasing use of social media platforms in survey dissemination. in their review paper, dr william ong et al. discuss tips and pitfalls in using social media platforms for survey dissemination[9]. the main advantages of social media-based surveys include convenience and f lexibility of survey design, relatively low cost, anonymity of responders, and the ability to reach a broader population across geographical boundaries; however, cautious measures must be adopted to avoid data duplication, disruption, and inaccuracy. crowdsource funding to obtain financial support for a project through public engagement is now widely used, and it may carry important implications in our field as well. dr kevin byrnes et al. discuss the concept of crowdfunding and the practicality of such applications, and describe the characteristics of successful campaigns[10]. apart from seeking funding opportunities, the concept of crowdsourcing can also be used in research projects to improve site engagement, disseminate research findings, and network with collaborators. certainly, the use of social media has major benefits in conducting research work from a global perspective. last but not least, we must be aware of the potential harm and concerns relating to social media. social media misinformation is a genuine problem across various urological conditions, and the study by dr chaoyong wang et al. showed that pelvic organ prolapse is no exception[11]. as pointed out by dr brian stork, we as urologists should refute inaccurate information when we see it, share medically correct information, and incorporate new technology into our practices[12]. for example, the urolog y care foundation has created condition-specific, qr-coded educational materials that can be readily accessed w it h sma r t phones[13]. we must sta nd aga i nst medical misinformation and make an effort to ensure dissemination of accurate information to our patients and the general public. this special issue provides comprehensive coverage across various aspects of social media, and we hope the information will be useful for our readers. siu journal also embraces the utility of social media, and we actively use our twitter account (@siu_urology) to disseminate the findings of the published papers to our audience. currently, we have over 1000 followers on the twitter platform, and we would like to solicit your help in driving our social media platforms. the siuj is a platinum open access journal, so the full text of all published articles can be viewed or downloaded without cost. please consider submitting your research papers to our journal, and we will ensure that your work is disseminated effectively to the urology community. http://siuj.org http://siuj.org https://twitter.com/siu_urology 83siuj.org siuj • volume 4, number 2 • march 2023 the emerging role of social media in urology practice references 1. bell sh, sun c, helstrom e, dubin jm, isali i, mishra k, et al. social media network analysis of academic urologists’ interaction within twitter microblogging environment. soc int urol j.2023;4(2):96–104. doi: 10.48083/ tkek6928 2. kaufman re, snipes m, wallace c, terris m. urology reach on social media: appealing to future potential applicants. soc int urol j. 2023;4(2):112–116. doi: 10.48083/jkkq6501 3. loloi j, bernstein ap, dubin jm. “likes” in social media: does it carr y any implications? soc int urol j.2023;4(2):105 –111. doi: 10.48083/ktol8925 4. scimago. available at: https://w w w.scimagojr.com/. accessed march 6, 2023. 5. clarivate. web of science: h-index information. h-index. available at: https://support.clarivate.com/scientificandacademicresearch/s/ ar ticle/ web-of-science-h-index-information?language= en_us. accessed march 6, 2023. 6. elsevier. the citescore™ metrics advantage. available at: https:// www.elsevier.com/solutions/scopus/how-scopus-works/metrics/ citescore. accessed march 6, 2023. 7. so wz, tiong hy, gauhar v, castellani d, teoh jyc. social media engagement for urology journals — a correlation analysis of traditional and social media metrics. soc int urol j.2023;4(2):88–95. doi: 10.48083/dmpr4183 8. bhat t nr, teoh jyc, cucchiara v, garcia rojo e, mercader c, pradere b, et al. novel methods of social media dissemination in urology. soc int urol j.2023;4(2):136–138. doi: 10.48083/rbaz4307 9. ong wlk, gauhar v, castellani d, teoh y tc. tips and pitfalls in using social media platforms for survey dissemination. soc int urol j. 2023;4(2):118–124. doi: 10.48083/perg3137 10. byrnes k, asif a, ng a, khadhouri s, bhatt n, kasivisvanathan v. crowdsource funding via social media platforms. soc int urol j. 2023;4(2):127–129. doi: 10.48083/rvjx1845 11. wang c, kang j, gerard e, loeb s, malik rd. harm related to social media misinformation on pelvic organ prolapse in youtube, instagram, and pinterest posts. soc int urol j.2023;4(2):131–135. doi: 10.48083/pgwg4918 12. s tor k b r. t he influenc e of so cial me dial influenc er s on urology information: where are all the urologists? soc int urol j.2023;4(2):125–126. doi: 10.48083/ngto5760 13. urology care foundation. available at: https://www.urologyhealth.org. accessed march 6, 2023. http://siuj.org https://www.scimagojr.com/ https://support.clarivate.com/scientificandacademicresearch/s/article/web-of-science-h-index-information?language=en_us https://support.clarivate.com/scientificandacademicresearch/s/article/web-of-science-h-index-information?language=en_us https://www.elsevier.com/solutions/scopus/how-scopus-works/metrics/citescore https://www.elsevier.com/solutions/scopus/how-scopus-works/metrics/citescore https://www.elsevier.com/solutions/scopus/how-scopus-works/metrics/citescore https://www.urologyhealth.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information bladder cancer, predictive biomarker, urine biomarker, tissue biomarker, circulating tumor dna, molecular subtype, immunohistochemistry none declared. received on september 28, 2021 accepted on december 4, 2021 this article has been peer reviewed. soc int urol j. 2022;3(4):245–257 doi: 10.48083/rvzv1144 245siuj.org siuj • volume 3, number 4 • july 2022 review predictive biomarkers in the management of bladder cancer: perspectives in an evolving therapeutic landscape patrick j. hensley,1 niyati lobo,1 kelly k. bree,1 wei shen tan,2 paolo gontero,3 stephen b. williams,4 charles c. guo,5 gianluca giannarini,6 lars dyrskjøt,7 ashish m. kamat1 1 department of urology, university of texas md anderson cancer center, houston, united states 2 department of urology, london north west university healthcare nhs trust, london, united kingdom 3 department of urology, città della salute e della scienza, molinette university hospital, turin, italy 4 division of urology, the university of texas medical branch at galveston, galveston, united states 5 department of pathology, university of texas md anderson cancer center, houston, united states 6 urology unit, santa maria della misericordia university hospital, udine, italy 7 department of molecular medicine, aarhus university hospital, aarhus, denmark abstract bladder cancer (bc) is a heterogeneous disease with prognosis and therapeutic strategies highly dependent on tumor grade and stage. predictive biomarkers of therapeutic response have been studied to guide selection of intravesical and/or systemic therapy. a predictive biomarker is measured before the start of treatment and provides information on the likelihood of response to a specific therapy.  many candidate predictive biomarkers for bc have been identified, but few have been rigorously validated or distinguished from simply having treatment-agnostic prognostic capacity. identifying predictive biomarkers tailored to therapeutic mechanism of action has considerable implications for the sequencing of therapies, as well as bladder preservation strategies in advanced disease states. we evaluate predictive tissue-based, urine-based, and serum-based biomarkers across the spectrum of non–muscle-invasive and muscle-invasive bc and preview predictive biomarkers for emerging targeted therapies. introduction biomarker development has undergone an evolution over the years, with increasing focus on predictive biomarkers in the field of bladder cancer. a predictive biomarker is measured before the start of treatment and provides information on the likelihood of response to a specific therapy. while many candidate predictive biomarkers for bladder cancer (bc) therapeutic response have been proposed, few have had their predictive value compared with non-treated cohorts to distinguish them from simply having prognostic capacity. predictive biomarkers have utility throughout the spectrum of disease in bc, from aiding diagnosis to guiding initial therapy selection, and even to prompting timely abandonment of ineffective treatment in lieu of definitive surgical management, radiotherapy, or other systemic therapy. our understanding of specific therapeutic mechanisms of action is key to designing predictive markers that offer insight into innate tumor biology and therapeutic susceptibility. measuring the predicted or elicited response to local or systemic therapies provides an opportunity to tailor biomarker development to specific therapies. in this narrative review, we discuss predictive bc tissue-based, urine-based, and serum-based markers (figure 1), identify current limitations and unmet needs, and define the evolution of biomarker development in the landscape of targeted therapies. we summarize the current state of predictive biomarkers for both nmibc and mibc using a non-systematic review of published literature and provide expert opinion on the accuracy and clinical applicability of emerging biomarkers. predictive tissue biomarkers non–muscle-invasive bladder cancer the most extensively studied tissue-based molecular ma rkers pred ic t ive of t herapeut ic response to intravesical therapy for non–muscle-invasive bc (nmibc) to date are p53 and ki67, both potent cell cycle regulators. dysregulation of the tumor suppressor p53 has been correlated with bc progression, but not recurrence, following bcg therapy[1–3]. however, a prospective study failed to validate p53 as a predictive biomarker[4]. ki67, a nuclear protein indicative of cell proliferation, has predictive ability for intravesical therapies. the expression of ki67 has been correlated with recurrence following bcg[5] and both recurrence and progression following intravesical chemotherapy[6]. table 1 summarizes other molecular biomarkers demonstrated to be predictive of bcg response. these include cell cycle regulators, apoptosis inhibitors, cell adhesion molecules, and proliferative markers[7]. the majority of these biomarkers have been evaluated only retrospectively in small single-center cohorts with non-standardized methods of measurement and without external validation, thus limiting our ability to derive definitive conclusions about their utility as predictive biomarkers. predictive biomarker panels have also been recently evaluated following intravesical bcg. a subgroup analysis of 2 large nordic randomized trials performed by malmström et al. analyzing expression of ezrin, ck20, and ki67 failed to show a correlation between biomarker expression and recurrence or progression following bcg therapy[8]. similarly, park et al. evaluated the altered expression of 7 potential biomarkers (p53, prb, pten, ki67, p27, fgfr3, and cd9) and found no predictive value for recurrence or progression among high-grade t1 tumors treated with bcg[9]. these conflicting data underscore the need for comprehensive validation studies. functional mutations in dna mismatch repair genes have also been implicated in predicting therapeutic response in bc. sanguedolce et al. demonstrated that mutl homologue 1(mlh1) was an independent predictor of progression-free survival among patients treated with adequate bcg[10]. in patients who received bcg, polymorphisms within dna repair pathways have been associated with recurrence-free survival (rfs)[11]. furthermore, tumor mutational burden has recently been shown to correlate with response to intravesical therapy[12]. these data were corroborated through a comprehensive gene analysis on index non–muscle invasive tumors, with increased mutational burden noted among high-grade nmibc[13]. specifically, arid1a mutations were predictive of shorter rfs in patients treated with bcg; however, no association was noted between rfs and other analyzed markers, including tp53, mdm2, erbb2, and fgfr3 following bcg therapy[13]. damrauer et al. recently performed rna-based profiling to identify a novel expression signature of an inflamed tumor microenvironment (tme) which was predictive of bcg response[14]. notably, molecular subtyping and immune checkpoint gene expression were not predictive of treatment response. however, a pre-treatment tme enriched with cd25+ regulatory t cells and tumor-associated macrophages and decreased abbreviations bc bladder cancer bcg bacillus calmette-guérin ctdna circulating tumor dna nac neoadjuvant chemotherapy nmibc non–muscle-invasive bladder cancer mibc muscle-invasive bladder cancer rfs recurrence-free survival tam tumor-associated macrophage tmb tumor mutational burden tme tissue microenvironment turbt transurethral resection of bladder tumor figure 1. biomarker source material and analysis for nmibc and mibc 246 siuj • volume 3, number 4 • july 2022 siuj.org review continued on page 248 247siuj.org siuj • volume 3, number 4 • july 2022 predictive biomarkers in the management of bladder cancer: perspectives in an evolving therapeutic landscape table 1. predictive urine biomarkers for bcg therapeutic response in patients with nmibc reference year marker study populationa number of patients detection method(s) results palou et al.[5] 2009 ezrin, ki67 hg t1 92 ihc low ezrin expression (< 20%) associated with increased progression among patients receiving induction bcg (p = 0.031) b differential expression of ki67 in patients with early recurrence following induction bcg (p = 0.015) b zachos et al.[83] 2009 telomerase reverse transcriptase (htert) hg t1 nmibc 30 ihc htert nucleolar staining in >75% of cells was associated with worse rfs following induction bcg (relative risk of recurrence 8.85 [95% ci 1.9–41.6])b cormio et al. [84] 2010 prb hg t1 27 ihc altered prb expression was predictor of recurrence (p = 0.037) and progression (p = 0.018) in patients treated with adequate bcgc alvarez-mugica et al.[85] 2010 myopodin methylation hg t1 nmibc 170 methylation analysis among patients treated with adequate bcg, myopodin methylation associated with increased recurrence rate (p = 0.011) and progression (p = 0.030)b shirotake et al.[86] 2011 angiotensin ii type 1 receptor (at1r) nmibc 79 ihc strong at1r expression associated with worse 1-year rfs following bcg(p = 0.0012)b lima et al.[87] 2013 sialyl-tn (stn), sialyl-6-t(s6t) high-risk nmibc 94 ihc high stn and s6t expression was associated with bcg response (p = 0.024 and p < 0.0001) and with increased rfs (p = 0.001)c sen et al.[88] 2014 nestin hg t1 63 ihc recurrence rates were higher in nestin(+) compared to nestin(-) among patients receiving induction bcg (60.6% versus 30%, p = 0.014)c cheng et al.[89] 2015 e2f4 nmibc 188 rna sequencing treatment with bcg in e2f4 score > 0 patients associated with improved progression-free survival (p = 0.06) raspollini et al.[90] 2016 p16, galectin-3, cd44, cd138, e-cadherin, survivin, hyal-1, topoisomerase-liα hg t1 (≤ 3cm) 92 ihc topo-2α predicted dfs (p = 0.029), surviving predicted pfs (p = 0.020), surviving and e-cad predicted os (p = 0.006, 0.030)b aall studies listed were analyses of retrospective cohorts. bmultivariate analysis. cunivariate analysis. density of th2-predominant cd4+ t cells was predictive of poor rfs following bcg therapy[15]. lim et al. also noted that tme-tissues from bcg-responders was enriched with active cd8+pd-1(-) t cells and non-regulatory cd4+foxp3(-) t cells, whereas the tmes of non-responders were characterized by increased levels of exhausted cd8+pd-1(+) t cells[16]. among patients with carcinoma in situ (cis) treated with induction bcg, lower tumor-associated macrophage (tam) density was associated with improved recurrence-free survival compared with those with higher tam density[17]. furthermore, when subsets of tams (m1 and m2) were analyzed, a low density of m1-tam and high density of m2-tam were predictors of worse disease-specific survival among patients treated with bcg[18]. other components of the complex immune response to bcg therapy that have been predictive of favorable treatment response include increased expression of major histocompatibility complex 1[19], low level of infiltration by tumor-infiltrating dendritic cells[20], and increased levels of natural killer cell receptor ligands[21]. taken together, these data indicate that the tme likely plays an important role in modulating the bcg therapeutic response and serves as a promising predictive biomarker target. while there is a paucity of investigation into predictive biomarkers for individual intravesical chemotherapeutic agents in nmibc, single-institution series suggest high foxm1 expression[22] and tumors with high proliferation index (as measured by ki67) achieve favorable responses to mitomycin c[6,23]. muscle-invasive bladder cancer cisplatin-based neoadjuvant chemotherapy (nac) before radical cystectomy confers an overall survival benef it for pat ients w it h m ibc[24]. genom ic interrogation revealed that a significant proportion of mibcs harbor mutations in dna damage repair (ddr) genes. ddr pathways play a critical role in the cellular 248 siuj • volume 3, number 4 • july 2022 siuj.org review , cont’d table 1. predictive urine biomarkers for bcg therapeutic response in patients with nmibc reference year marker study populationa number of patients detection method(s) results meeks et al.[12] 2016 cancerassociated gene panel high-risk nmibc 25 dna sequencing increased total mutational burden associated with io response between non-progressors, progressors and metastatic tumors (15, 10.1, 5.1 mutations/mb, respectively; p = 0.02)c pietzak et al.[13] 2017 arid1a nmibc 65 dna sequencing arid1a mutations associated with shorter rfs after bcg (hr 3.14, p = 0.002)b sanguedolce et al.[10] 2018 mlh1 hg t1 67 ihc mlh1 expression was an independent predictor of pfs among patients treated with adequate bcgb mano et al.[91] 2018 hsp 60 hsp 70 hsp 90 hg t1 54 ihc hsp70 associated with lower risk of recurrence (hr 0.29, p = 0.003) and progression (hr 0.33, p = 0.045), hsp 60 associated with higher risk of progression (hr 3.96, p = 0.012) among patients treated with at least induction bcgb shao et al.[92] 2021 next generation sequencing intermediate or high-risk nmibc 58 dna sequencing neb, fgfr1, and sdhc were independent predictors of recurrence following bcg (p = 0.001, p = 0.004, and p = 0.017, respectively)b aall studies listed were analyses of retrospective cohorts. bmultivariate analysis. cunivariate analysis. response to platinum-based chemotherapy, providing a rationale for their use as predictive biomarkers. ercc2 encodes a dna helicase that plays a central role in the nucleotide excision repair pathway, repairing dna cross-linking caused by genotoxic agents such as platinum chemotherapies. van allen et al. performed whole-exome sequencing on pre-treatment tumor and germline dna from 50 patients with mibc receiving cisplatin-based nac before cystectomy[25]. ercc2 was the only significantly mutated gene enriched in cisplatin-responders compared with non-responders. this finding was mechanistically confirmed in vitro, as expression of wild-type ercc2 in an ercc2-deficient bc cell line rescued cisplatin sensitivity. using an independent mibc cohort, liu et al. found ercc2 alterations in 8/20 responders to chemotherapy (40%) versus 2/28 non-responders (7%) (p = 0.010, or 8.3 [95% ci 1.4 to 91.4])[26]. in a subsequent phase ii trial of neoadjuvant dose-dense gemcitabine and cisplatin in patients with mibc, the presence of one or more alterations in a panel of 29 ddr genes, including ercc2, was associated with chemosensitivity (positive predictive value for <pt2n0 of 89%)[27]. in addition to ercc2, alterations in atm, rb1 and fancc have also been shown to be predictive of response to cisplatin-based nac[28]. plimack et al. showed that alteration in 1 or more of these 3 dna repair genes was able to predict pathologic complete response to nac. additionally, missense mutations in the receptor tyrosine kinase erbb2 (her2) were enriched in patients with a complete response to platinum-based nac (24% of complete responders compared with 0% in non-responders)[29]. as a result of these studies, several trials are investigating the ability of predictive markers to triage patients for bladder sparing after a favorable clinical response to cisplatin-based nac (table 2). recent studies, however, have found no correlation between ercc2 mutation status and treatment response[30,31], but have instead identified other ddr biomarkers associated with response (eg, brca2), highlighting a high level of tumor heterogeneity and inter-cohort variability. large-scale expression and sequencing analysis have subtyped bcs based on genomic rna expression or specific genomic alterations[32,33]. choi et al. reported that the basal subtype, with enriched expression of genes in the p63 pathway, responded favorably to neoadjuvant mvac; in contrast, patients with “p53-like tumors,” with activated wild-type p53 gene expression signatures, were consistently chemoresistant. these findings were largely recapitulated through tumor profiling of patients in a phase ii trial of dose-dense neoadjuvant mvac and bevacizumab before cystectomy in which patients with basal tumors exhibited favorable survival but similar pathologic response rates[34]. similarly, a large multicenter study that performed whole transcriptome profiling on transurethral resection of bladder tumor (turbt) specimens from 343 patients with mibc[35] concluded that patients with basal subtype tumors derived the most improvement in overall survival compared with those who had surgery alone, whereas patients with luminal tumors had similarly favorable outcomes irrespective of nac use. a multiomics approach to identifying molecular markers of cisplatin sensitivity in the neoadjuvant or first-line settings was recently reported[30]. contrary to the findings of the aforementioned reports, patients with basal/squamous gene expression subtypes responded poorly to cisplatin-based chemotherapy, while patients who had tumors with immune cell infiltration and high pd-1 protein expression exhibited a favorable therapeutic response. notable differences in cohort selection and primary outcomes measurements may account for differing conclusions on platinum-sensitivity of basal tumors[36]. while seiler et al.[35] primarily compared survival outcomes in a nac cohort with those of the tgca cohorts, managed with variable adjuvant chemotherapeutic regimens, taber et al.[30] measured therapeutic response through pathologic downstaging and response on imaging in nac and first-line metastatic patients, respectively. taken together, these data indicate that more research is needed in this setting to determine the predictive value of expression subtypes. the role of molecular subtypes as predictive biomarkers for response to neoadjuvant immunotherapy have also been assessed. in the pure-01 study evaluating the efficacy of neoadjuvant pembrolizumab, basal tumors had better response rates than non-basal tumors[37]. tumor immunophenotypes have also been correlated with response to the anti-pd-l1 agent atezolizumab[38]. favorable response was associated with the cd8+ t-cell phenotypes and high tumor mutational burden, while so-called “immune desert” tumors and those with high transforming growth factor β (tgfβ) signaling in the tme exhibited therapeutic resistance. despite promising results, molecular subtyping using whole transcriptome rna expression profiling has yet to be adopted into clinical practice. this is primarily due to the technical difficulty of handling and profiling rna as well as the lack of definitive evidence from clinical trials specifically designed for measuring biomarker accuracy. however, studies have suggested that immunohistochemistry, which already has clinical applications, may be used to classify bc into molecular subtypes, thus facilitating their use in clinical practice[39]. several pd-1/pd-l1 immune checkpoint inhibitors (ici) have been approved for cisplatin-ineligible patients and those with locally advanced or metastatic 249siuj.org siuj • volume 3, number 4 • july 2022 predictive biomarkers in the management of bladder cancer: perspectives in an evolving therapeutic landscape bc[40–46]. the indication has since expanded, with several groups investigating the use of pd-1/pd-l1 inhibitors in the neoadjuvant setting. in the pure-01 study, 50 patients with mibc received 3 cycles of the pd-1 inhibitor pembrolizumab followed by radical cystectomy[47]. pathologic complete response (pt0) was observed in 40% of pd-l1 positive patients (≥ 10% combined positive score) compared with only 16% of pd-l1 negative patients. furthermore, a greater pathologic response to pembrolizumab was seen in patients with higher tumor mutational burden (tmb >15 mutations/mb). in contrast to the pure-01 study and trials in the metastatic setting, the neoadjuvant abacus study of the pd-l1 inhibitor atezolizumab was unable to show a significant association between pd-l1 expression (either on tumor cells or infiltrating cells) and therapeutic response[48]. the lack of standardization of pd-l1 assessment, such as different antibodies, thresholds for pd-l1 positivity, and immune cell quantification, is likely to contribute to its limited predictive ability in bc. bandini et al. recently constructed a probability calculator incorporating 2 biomarkers (pd-l1 expression and tmb) and baseline clinical t stage to predict pathologic complete response after pembrolizumab[49]. this predictive model performed well with a concordance index of 0.77 (95% ci 0.68 to 0.86), highlighting the complexity of the tumor-immune interaction and utility of predictive biomarker panels compared with single markers alone. table 2. clinical trials investigating tissue-based biomarkers predictive of neoadjuvant therapy response in mibc nct trial name study population biomarker(s) under investigation intervention primary endpoints 02710734 risk enabled therapy after initiating neoadjuvant chemotherapy for bladder cancer (retain) ct2-3 n0 bladder cancer sequenced pre-nac turbt specimens for ddr mutations tur followed by accelerated mvaca; patients with complete clinical response and ddr mutation managed with bladder sparing, others treated with intravesical chemotherapy, radiation therapy or radical cystectomy metastasis-free survival (mfs) at 2 years 03609216 alliance a031701 ct2-3 n0 bladder cancer sequenced pre-nac turbt specimens for ddr mutations tur followed by gemcitabine/ cisplatin; patients with ddr mutation and pathologic response (≤yct1) managed with bladder sparing; others treated with chemoradiation or radical cystectomy event-free survival (mfs) at 3 years 03558087 hcrn gu 16-257 ct2-4 n0 bladder cancer sequenced pre-nac turbt specimens for ddr mutations and tumor mutational burden tur followed by gemcitabine/ cisplatin/nivolumab; patients with complete clinical response managed with bladder sparing and maintenance novilumab, others treated with radical cystectomy (1) complete clinical response rate (2) ability of complete clinical response to predict 2-year metastasis-free survival 02177695 swog 1314 ct2-4 n0 bladder cancer co-expression extrapolation (coxen) gene expression algorithm tur followed by neoadjuvant dosedose mvaca or gemcitabine/cisplatin prior to radical cystectomy assess whether coxen profile is (1) prognostic of pt0 rate or ≤pt1 at cystectomy and (2) a predictive factor between chemotherapy regimens amethotrexate, vinblastine, doxorubicin, cisplatin 250 siuj • volume 3, number 4 • july 2022 siuj.org review predictive urine biomarkers non–muscle-invasive bladder cancer urine is a uniquely qualified biomarker source material, as it is readily available, easily collected, and has direct tumor contact. urine-based biomarkers have been primarily studied for purposes of diagnosis and surveillance of bc, with relatively few having sufficient accuracy to predict therapeutic response. the true predictive biomarker capacity of the urine-based markers mentioned herein remain largely uncharacterized as many were studied exclusively in treated populations or measured as an elicited response after intravesical therapy. bcg has proven efficacy in reducing recurrence and progression in intermediate and high-risk non– muscle-invasive bc (nmibc)[50]. reliable biomarkers predictive of bcg therapeutic response could have tremendous implications in sequencing of therapy for nmibc. unfortunately, given the relative non-specific mechanism of action and elicited immune response by bcg, clinicopathologic factors such as tumor stage, grade, size, presence or absence of cis, tumor focality and recurrence history remain the most reliable predictors of bcg therapeutic response[51]. the rationale for several candidate preclinical biomarkers have employed the mechanism of bcg therapeutic response[52]. interleukin (il)-8 is one of the first cytokines with induced expression after bcg therapy. in a pilot study of 20 patients, high levels of il-8 expression measured 6 hours after bcg instillation had lower rates of recurrence and progression[53]. additionally, failure to induce expression of il-2 and il-18 after bcg has been associated with poor bcg therapeutic response[54]. because bcg immunogenicity is complex and non specific, single candidate markers alone may be unreliable predictive tools. the cytokine panel for response to intravesical therapy (cyprit) nomogram was generated from expression profiling of 9 inducible urinary cytokines (il-2, il-6, il-8, il-18, il-1ra, trail, ifn-γ, il-12[p70], and tnf-α) in 130 patients with nmibc at the md anderson cancer center using an enzymelinked immunosorbent assay (elisa) at baseline and at specified time points throughout bcg therapy[55]. this nomogram predicted the likelihood of recurrence with 85.5% accuracy. additionally, baseline levels of pro-tumorigenic cytokines were profiled pre-treatment. indeed, expression of il-8 in urine was associated with recurrence in bcg-treated patients, with patients who had higher baseline urinary il-8 levels experiencing a 4-fold increased risk of tumor recurrence[56]. interestingly, higher baseline levels of il-8 expression in peripheral blood leukocytes similarly correlated with disease recurrence, suggesting a role for this cytokine as a systemic marker for bcg immunogenicity and therapeutic response. contrasting these results to the aforementioned studies indicating that induced urinary il-8 expression after bcg instillation is a marker of disease recurrence and progression, these data highlight the complexity of baseline and elicited immune states, as well as the stability and kinetics of cytokine profiling, in determining their potential as predictive biomarkers. the oncuria urine-based assay measures the expression of cancer-associated markers in voided urine specimens[57]. using urine samples from the cyprit cohort, investigators found that pre-treatment concentrations of mmp9, vegfa, ca9, sdc1, pai1, apoe, a1at, ang, and mmp10 were increased in subjects with disease recurrence. a predictive model of treatment outcomes reached an area under the receiver operating curve of 0.89 (95% ci 0.80 to 0.99), with a test sensitivity of 81.8% and a specificity of 84.9%. while not specifically fda approved for this indication, the fluorescence in situ hybridisation (fish) assay, which detects aneuploidy in chromosomes 3, 7, and 17 and loss of the 9p21 locus in voided urine samples (urovysion), has been studied in the context of bcg therapeutic response. in a study of 37 patients primarily receiving bcg for nmibc, 100% of patients with a positive post-treatment urovysion fish developed tumor recurrence[58]. the predictive capacity of positive post-treatment urovysion was independently confirmed in several studies with variable adjuvant intravesical agents for nmibc[59–62]. a subset of “molecular bcg failure” patients based on mid-treatment persistence of a positive fish assay was subsequently defined. in a study of 126 patients, those with a positive fish test during therapy were 3 to 5 times more likely to develop recurrence and 5 to 13 times more likely to progress compared with patients with negative mid-treatment fish[63]. this was subsequently validated in an independent, multicenter trial where fish was predictive of recurrence and/or progression events at baseline (hr 2.59; 95% ci 1.42 to 4.73), before the sixth induction instillation (hr 1.94; 95% ci 1.04 to 3.59) and at 3-month follow-up (hr 3.22; 95% ci 1.65 to 6.27)[64]. defined as positive fish at 6 weeks and 3 months after induction bcg in the setting of a negative cystoscopic evaluation, this molecular failure denotes a group at high risk of stage progression if managed with further bcg therapy, and who should be considered for enrolment into clinical trials or timely cystectomy[65]. muscle-invasive bladder cancer there currently exist no urine-based biomarkers to reliably predict therapeutic response in mibc. however, broad genomic expression and mutational profiling of molecular targets of novel therapeutic agents, including 251siuj.org siuj • volume 3, number 4 • july 2022 predictive biomarkers in the management of bladder cancer: perspectives in an evolving therapeutic landscape monoclonal antibodies and antibody-drug conjugates, have emerging rationale. for example, uroseek is a urine-based molecular assay which detects alterations in 11 commonly mutated genes which are druggable targets: tert, fgfr3, pik3ca, tp53, hras, kras, erbb2, cdkn2a, met, mll, and vhl[66]. as sequencing technology becomes more refined, urine-based genetic material, including exfoliated tumor cells, cell-free dna, and exosomes may prove feasible sources for molecular subtyping and further predictive biomarker development for mibc. predictive serum biomarkers serum biomarkers for bc remain an area of active research. these liquid biopsy tests may have a role in cancer risk stratification, characterization of tumor molecular signatures, and predicting response to systemic treatment, as well as for cancer surveillance. to date, these tests have remained proof-of-concept in preclinical studies but have emerging clinical relevance to guide treatment decisions. circulating tumor cells (ctc) represent one of the first studied serum biomarkers. while they have a poor sensitivity of 35% for the detection of bc due to their scarcity in circulating blood, the presence of ctcs has been associated with higher histological stage, grade, lymph node involvement, and presence of metastatic disease[67,68]. in the pre-radical cystectomy setting, ctcs have been shown to predict poor oncological outcomes, independent of clinicopathological variables[69]. serum rna markers such as long non-coding rnas (incrnas) and micrornas (mirna) have been reported to have prognostic value. zhang et al. reported that high serum ubc1 expression was associated with lower nmibc rfs (p = 0.01) [70]. in a systematic review and meta-analysis of 26 studies, 6 mirna (mir-21, mir-143, mir-155, mir-214, and mir-222) were identified as being predictive of early disease recurrence and progression[71]. more recently, there have been rapid advancements in circulating tumor dna (ctdna). developments in deep-sequencing technology have allowed for the reliable identification of double strand dna fragments as small as 150 bp. birkenkamp-demtröder et al. developed personalized ctdna assays based on ngs of tumor tissue. they report that ctdna was present even in nmibc patients, and the presence of higher levels of ctdna was associated with subsequent disease progression and metastasis[72]. in patients undergoing radical cystectomy, ctdna predicted oncological outcomes in several settings[31]. patients positive for ctdna at diagnosis before nac had a higher 12-month recurrence rate (42% versus 0%)[31]. similarly, following nac, patients positive for ctdna had a higher rate of 12-month disease recurrence (75% versus 7%) than did ctdna negative patients[31]. additionally, in the surveillance setting, ctdna had a median lead time of 96 days over radiological imaging[31]. this lead time of ctdna detection before radiologic or symptomatic clinical detection is allowing investigators to define a “biochemical relapse” to guide timely initiation of first-line atezolizumab after rc in a clinical trial setting (nct04138628). the role of ctdna as a predictive biomarker for atezolizumab has also been reported in a study where patients with ctdna positivity had a significantly improved overall survival compared with the observational arm (hr: 0.59; 95% ci 0.41 to 0.79)[73]. unmet needs in biomarker development characteristics for the ideal biomarker predictive of therapeutic response vary considerably by disease stage. for nmibc, bcg is the gold standard intravesical treatment because of its efficacy, favorable cost, and tolerability. to date, biomarkers predictive of response to bcg have primarily focused on identifying early non-responders in an effort to transition them to off-label salvage intravesical chemotherapy options or timely radical cystectomy. however, in the era of bcg shortages and emerging intravesical and systemic therapies available in earlier disease states, we would benefit from predictive markers that could guide initial therapeutic response. with emphasis on bladder preserving strategies, it will become equally important to identify predictive biomarkers of salvage intravesical and systemic therapies after bcg failure. recent molecular classification of nmibc has correlated candidate molecular subtypes to innate sensitivity and resistance to bcg therapy, and provided therapeutic rationale for upfront use of fgfr inhibitors, icis, or intravesical chemotherapy[74]. lastly, favorable results have recently been reported in the phase iii trial of intravesical nadofaragene firadenovec (rad-ifna/ syn3) for bcg unresponsive nmibc[75]. these investigators are validating a serum-based adenoviral antibody titer assay to evaluate immunogenicity of the gene therapy and corresponding therapeutic response[76]. while guidelines support the role of nac before radical cystectomy for mibc, there remains a role for risk-stratified nac patient selection. clinicopathologic risk factors have been implemented in predicting response to cisplatin-based nac[77,78], but efforts are underway to profile tissue-based biomarkers for this purpose. the southwest oncology group (swog) 1314 trial prospectively profiled the ability of the coxen tissue-based genetic classifier to predict complete pathologic response to cisplatin-based nac (table 2)[79]. 252 siuj • volume 3, number 4 • july 2022 siuj.org review recently reported results indicate limited predictive capacity of the genomic classier for individual treatment response, underscoring the importance of prospective validation of predictive markers in the clinical trial setting. our group, among others, has also been involved in profiling immunohistochemical signatures in turbt specimens predictive of response to nac to improve appropriate stratification of patients for nac or upfront cystectomy[80,81]. lastly, biomarkers could significantly aid in the ability to accurately predict and assess a complete clinical response to nac in those electing for bladder perseveration, a concept with supporting clinical data[82] and currently being evaluated in 2 randomized trials (retain, alliance a031701; table 2). conclusions there are no currently fda-approved predictive biomarkers for therapies in bc–neither for nmibc nor for mibc. the lack of clinically available predictive biomarkers is likely multifactorial, including difficulties in profiling intratumoral heterogeneity and dynamic cellular processes (ie, epithelial-mesenchymal transition, cell growth and proliferation, immune response) as well as the lack of “fit for purpose” profiling of biomarkers with mechanistic rationale. the ever-evolving armamentarium of therapeutic options further emphasizes unique unmet needs for predictive biomarker development. by convention, we have relied on non-specific markers of therapeutic response to drugs with non-specific targets—ie, cytokine expression profiling as a litmus for induced immunogenicity after intravesical bcg or dna mismatch repair genetic alterations to predict response to cytotoxic chemotherapies. with the growth of novel therapeutic modalities with specific targets, including monoclonal antibodies, antibody-drug conjugates, and gene therapies, we expect that biomarkers which are highly specific 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nd, gomella lg, kamat am, et al. intravesical nadofaragene firadenovec gene therapy for bcg-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. lancet oncol.2021;22(1):107-117. 76. mitra ap nv, boorjian sa, alemozaffar m, konety br, shore nd, et al. anti-adenoviral antibody levels predict nadofaragene firadenovec response in bcg-unresponsive nmibc: results from a phase 3 trial. aua annual meeting, las vegas, nv2021. 77. culp sh, dickstein rj, grossman hb, pretzsch sm, por ten s, daneshmand s, et al. refining patient selection for neoadjuvant chemotherapy before radical cystectomy. j urol.2014;191(1):40-47. 78. hensley pj, bree kk, campbell mt, alhalabi o, kokorovic a, miest t, et al. progression of disease after bcg therapy: refining patient selection for neoadjuvant chemotherapy before radical cystectomy. j urol.2021 nov;206(5):1258-1267. doi: 10.1097/ju.0000000000001943. epub 2021 jun 29. 79. boxley p, plets m, flaig tw. review of swog s1314: lessons from a randomized phase ii study of co-expression extrapolation (coxen) with neoadjuvant chemotherapy for localized, muscle-invasive bladder cancer. bladder cancer.2020;6(2):123-129. 80. laukhtina e, pradere b, mori k, schuettfort vm, quhal f, mostafaei h, et al. catalog of prognostic tissue-based biomarkers in patients treated with neoadjuvant systemic therapy for urothelial carcinoma of the bladder: a systematic review. urol oncol.2021 mar;39(3):180190.  doi: 10.1016/j.urolonc.2020.12.019. epub 2021 jan 8. 81. hensley pj, kyprianou n, purdom ms, he d, dicarlo v, wang c, et al. predictive value of phenotypic signatures of bladder cancer response to cisplatin-based neoadjuvant chemotherapy. urol oncol.2019;37(9):572. e1-.e11. 82. mazza p, moran gw, li g, robins dj, matulay jt, herr hw, et al. conservative management following complete clinical response to neoadjuvant chemotherapy of muscle invasive bladder cancer: contemporar y outcomes of a multi-institutional cohor t study. j urol.2018;200(5):1005-1013. 83. zachos i, konstantinopoulos pa, vandoros gp, karamouzis mv, papatsoris ag, podimatas t, et al. predictive value of telomerase reverse transcriptase expression in patients with high risk superficial bladder cancer treated with adjuvant bcg immunotherapy. j cancer res clin oncol.2009;135(9):1169-1175. 84. cormio l, tolve i, annese p, saracino a, zamparese r, sanguedolce f, et al. altered p5 3 and prb expression is predictive of response to bcg treatment in t1g3 bladder cancer. anticancer res.2009;29(10):4201-4204. 256 siuj • volume 3, number 4 • july 2022 siuj.org review 85. alvarez-múgica m, cebrian v, fernández-gómez jm, fresno f, escaf s, sánchez-carbayo m. myopodin methylation is associated with clinical outcome in patients with t1g3 bladder cancer. j urol.2010;184(4):1507-1513. 86. shirotake s, miyajima a, kosaka t, tanaka n, maeda t, kikuchi e, et al. angiotensin ii type 1 receptor expression and microvessel density in human bladder cancer. urology.2011;77(4):1009.e19-.e25. 87. lima l, severino pf, silva m, miranda a, tavares a, pereira s, et al. response of high-risk of recurrence/progression bladder tumours expressing sialyl-tn and sialyl-6-t to bcg immunotherapy. br j cancer.2 013;109(8):2106-2114. 88. sen v, bozkurt o, demir o, tuna b, yorukoglu k, ellidokuz h, et al. prognostic significance of nestin expression in pt1 highgrade bladder urothelial carcinoma patients treated with intravesical bcg. asian pac j cancer prev.2014;15(24):10813-10817. 89. cheng c, varn fs, marsit cj. e2f4 program is predictive of progression and intravesical immunotherapy efficacy in bladder cancer. mol cancer res.2015;13(9):1316-1324. 90. raspollini mr, luque rj, menendez cl, bollito e, brunelli m, martignoni g, et al. t1 high-grade bladder carcinoma outcome: the role of p16, topoisomerase-iiα, survivin, and e-cadherin. hum pathol. 2016;57:78-84. 91. mano r, zilber s, di natale rg, kedar d, lifshitz da, yossepowitch o, et al. heat shock proteins 60 and 70 are associated with longterm outcome of t1-stage high-grade urothelial tumors of the bladder treated with intravesical bacillus calmette-guérin immunotherapy. urol oncol.2018;36(12):531.e9-.e17. 92. shao y, hu x, yang z, lia t, yang w, wu k, et al. prognostic factors of non-muscle invasive bladder cancer: a study based on next-generation sequencing. cancer cell int.2021;21(1):23. 257siuj.org siuj • volume 3, number 4 • july 2022 predictive biomarkers in the management of bladder cancer: perspectives in an evolving therapeutic landscape this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information benign prostatic hyperplasia, holmium, laser surgery, learning curve, mentoring see acknowledgements. received on june 23, 2022 accepted on july 31, 2022 this article has been peer reviewed. soc int urol j. 2023;4(1):11–18 doi: 10.48083/ujcr1584 implementing holep in an academic department with multiple surgeons in training: mentoring is the key for success clément klein,1,2 thibault marquette,3 grégoire capon,1,2 eric alezra,1,2 peggy blanc,1,2 vincent estrade,1,2 jean-christophe bernhard,1,2 franck bladou,1,2 grégoire robert1,2 1 department of urology, bordeaux pellegrin university hospital, bordeaux, france 2 department of health sciences, university of bordeaux, bordeaux, france 3 department of urology, centre hospitalier de dax côte d’argent, dax, france abstract objective holmium laser enucleation of the prostate (holep) has been recommended for the surgical management of benign prostatic hyperplasia (bph) in most of the international guidelines, regardless of prostatic volume. the main advantages reported by randomized clinical studies are reduced perioperative bleeding, catheterization time, and length of hospital stay, but this technique is also described as difficult to master with a steep learning curve. the objective of this study was to describe the clinical outcomes of holep in the real-life setting of an academic department with multiple operators with no previous experience. methods a retrospective observational study was conducted including all consecutive cases performed in our department from april 2012 to october 2020. over the study period, 31 different operators were involved. in april 2012, 2 surgeons were trained by an experienced urologist. the 29 others learned the technique progressively with the help of the first 2 surgeons (surgical mentoring). results a total of 1259 patients were included. preoperatively, the mean prostate volume and qmax were 82.3 g and 9.4 ml/s, respectively. the mean operative time was 79.7 min. the intraoperative complication rate was 5.6% (n = 71), with the need for conversion being 0.6%. postoperatively, the complication rate was 18.6% (n = 234). surgeon’s experience reduced the perioperative complication rates (p = 0.01), operative time (p < 0.001), and length of hospital stay (p < 0.001), but the difference in blood transfusion rate was statistically non-significant (p = 0.3). conclusions most of the 31 urologists in training were able to master holep progressively, with good functional outcomes and acceptable complication rates. supervision by trained urologists was critical for the safe dissemination of the technique in our department. introduction holmium laser enucleation of the prostate (holep) is recommended by the main international guidelines for the surgical management of benign prostatic hyperplasia (bph), regardless of prostate volume[1,2]. in addition to having been evaluated in several randomized controlled trials against monopolar transurethral resection of the prostate (mturp) and open prostatectomy (op), holep has been shown to provide long-term functional outcomes (flowmetric and quality of life data) that ensure the durability of the improvement in urinary symptoms. if the functional outcomes were more or less similar to those of mturp[3,4] or op[5,6], the main advantages of holep were reduced perioperative bleeding, catheterization time, and length of hospital stay[7,8]. for all these 11siuj.org siuj • volume 4, number 1 • january 2023 original research https://orcid.org/0000-0003-1839-5875 https://orcid.org/0000-0001-8564-1699 https://orcid.org/0000-0001-5249-8689 mailto:gregoire.robert%40chu-bordeaux.fr?subject=siuj http://siuj.org reasons, holep has become a recommended surgical alternative to turp and op, regardless of prostate size. however, its steep learning curve has considerably slowed the spread of this technique since it was first described in 1998[9]. the objective of this retrospective study was to describe the clinical outcomes of holep in the real-life setting of an academic department involving multiple operators who had no previous experience with holep and limited experience in endoscopic surgery. materials and methods study population a single-center retrospective observational study was performed with consecutive patients who underwent holep between april 2012 and october 2020 in a highvolume center (180 to 200 holep interventions per year). all procedures were performed by 31 different urologists. in april 2012, 2 surgeons were trained by an experienced urologist from another center and became expert surgeons in our academic hospital. then each year, 3 to 4 new surgeons have learned the technique progressively, with the mentorship of the first 2 trained surgeons over a period of 2 years. a surgeon was considered an expert when he or she had performed at least 50 successful procedures as defined in the study by robert et al.[10]: a combination of complete enucleation and morcellation, within less than 90 min, without any conversion to turp, with acceptable stress and difficulty. at the start, mentoring began with the observation of approximately 10 procedures carried out by an expert, followed by 10 holep performed by the trainee itself under the supervision of the expert surgeon. then, the trainee performed holep autonomously, starting with easy cases (prostate volume 50 g to 80 g, no anticoagulant therapy) and progressively undertaking more complicated cases. at the end of their 2-year training, the operators had performed between 20 and 40 procedures on their own. all included patients received oral and written information explaining the principles of the procedure and its main complications and provided consent for data collection and analysis. this study was approved by the local ethics committee before data extraction and analysis. holep: equipment, technique, and follow-up the procedure was performed in the operating room under general anesthesia or spinal anesthesia. the equipment used included a 100 w holmium:yag laser generator (lumenis), with a 550 m fiber, a 26 fr resectoscope, and a versacut morcellator (karl storz). the surgical technique of enucleation has evolved over the last 8 years from the original technique described by gilling in "two or three lobes"[11] to a so-called "en bloc" technique[12]. at the end of the surgery, a 2-way bladder catheter was placed with continuous saline irrigation for a few hours. the bladder catheter was usually removed the next morning in the urology department or at home if the patient was already discharged. postoperative follow-up also evolved over time. during the first 3 years, follow-up check-ups were scheduled at 3, 6, 12, and 24 months postoperatively. subsequently, follow-up was done only 3 months postoperatively. statistical analyses data analysis was performed using r software (version 4.0.0). the significance level was set at 0.05 for all statistical tests, and p-values were 2-sided. continuous variables were reported as means and standard deviations (sds) or medians and interquartile ranges (iqrs), whereas categorical variables were reported as frequencies and proportions. student t test and mannwhitney u test were used for continuous variables. the chi-square test and fisher exact test were used for categorical variables. results during the study period, 1174 patients were operated on by 31 different urologists. preoperative characteristics are described in table 1. the mean age was 70.7 ± 8.6 years. at the time of preoperative consultation, the rate of aur was 27.7% (n = 326), and 27.9% (n = 320) of the patients had an indwelling urinary catheter at the time of surgery. at the time of surgery, 78.9% of patients (n = 926) received at least 1 drug treatment indicated for lower urinary tract symptoms (luts), and a previous history of surgical treatment for luts/bph was retrieved in 49 (4.1%) patients. perioperative data are reported in table 2. the overall perioperative complication rate was 6%, and 8 (0.7%) procedures required conversion (7 to turp and 1 to abbreviations bph benign prostatic hyperplasia holep holmium laser enucleation of the prostate mturp monopolar transurethral resection of the prostate op open prostatectomy ui urinary incontinence 12 siuj • volume 4, number 1 • january 2023 siuj.org original research http://siuj.org op). a total of 330 patients (28.2%) had a day-case procedure (los < 12 h according to the french requirements for day-case procedures). regarding surgeon experience, the periand postoperative complication rates were lower in the hands of experienced surgeons (table 3 and supplementary online appendix s1). the same applies to the operative time, but not blood transfusion rates. regarding other factors that may influence perioperative outcomes, the perioperative complication rate was higher in patients on antiplatelet therapy. the operative time was higher among patients with prostatic weight ≥ 100 g, anticoagulant therapy, and preoperative urinary catheters. anticoagulant and antiplatelet therapy and preoperative urinary catheterization increased the postoperative complication rate. the blood transfusion rate was higher in patients with prostatic weight ≥  100  g, anticoagulant therapy and preoperative urinary cathfigure 1. evolution of functional outcomes between preoperative and 3, 6, 12, and 24-month follow-up visits ipss: international prostate symptom score; ipss-q8 : question 8 of the ipss; psa : prostate-specific antigen; qmax: maximum urinary flow rate; pvr: post-voiding residual urinary volume; iief-5: 5-items international index of erectile function; ns = p > 0.05; = p < 0.001; = p < 0.0001 0.0 2.5 5.0 7.5 10.0 12.5 ipss-q8ipss 0 10 20 30 40 50 3 mo nths 6 mo nths 12 m onth s 24 m onth s preo pera tive psa qmax 0 10 20 30 40 50 3 mo nths 6 mo nths 12 m onth s 24 m onth s preo pera tive 0 10 20 30 40 nsns nsns nsns nsns 3 mo nths 6 mo nths 12 m onth s 24 m onth s preo pera tive 3 mo nths 6 mo nths 12 m onth s 24 m onth s preo pera tive iief5 0 20 40 60 80 3 mo nths 6 mo nths 12 m onth s 24 m onth s preo pera tive pvr 0 200 600 400 800 3 mo nths 6 mo nths 12 m onth s 24 m onth s preo pera tive eterization. the los was higher in the anticoagulant, antiplatelet and urinary derivation catheter groups. concerning functional results (figure 1 and supplementary online appendix s2), there was a significant improvement in qmax (+14.2 ml/s) (p < 0.001) and ipss (-14 points) (p < 0.001) at 6 months. these results were maintained over time since the median ipss at 3 years was 4, an improvement of 15 points. regarding sexual function, the mean iief5 score at 6 months was 12 ± 8.2 and appeared to remain stable over time. the rate of urinary incontinence (stress and urgency) requiring protection was 11.6% at 3 months and 3.8% at 6 months. discussion as noted, several rcts have proven the superiority of holep over mturp and op regarding perioperative bleeding, duration of catheterization, and length of 13siuj.org siuj • volume 4, number 1 • january 2023 implementing holep in an academic department with multiple surgeons in training: mentoring is the key for success http://siuj.org http://siuj.org http://siuj.org http://siuj.org http://siuj.org table 1. preoperative characteristics of the study population preoperative data n = 1174 values age, years 1174 70.7 ± 8.6 bmi (kg/m2) 1081 26.3 ± 4.1 asa score 1113 2 [2–2] antiplatelet therapy 1174 310 (26.4) monotherapy 282 (90.9) bitherapy 28 (9) curative anticoagulant therapy 1174 141 (12) vitamin k antagonists 84 (60) new oral anti-coagulants 54 (38.6) low molecular weight heparins 2 (1.4) bph complications (≥ 1 complication) 1174 510 (43.4) aur 326 (27.7) infection 173 (14.7) bladder stones 27 (2.3) bph treatment (≥ 1 oral treatment) 926 (78.9) alpha blocker 1174 850 (91.6) 5ari 219 (23.6) phytotherapy 240 (25.8) pde5i 16 (1.7) monotherapy 496 (53.6) bitherapy 404 (43.6) tritherapy 26 (2.8) history of bph surgery 1174 49 (4.1) turp 28 (57.1) op 4 (8.1) greenlight 6 (12.2) holep 6 (12.2) pae 3 (6.1) urolift 2 (4.1) prostatic weight (g) 1056 84.5 ± 43.5 psa (ng/ml) 916 6.8 ± 9.4 qmax (ml /min) 635 9.5 ± 4.6 pvr (ml) 631 150.5 ± 188.4 ipss 626 19 [13–23] ipss question 8 699 5 [4–6] iief5 459 13.7 ± 8.3 indwelling urinary catheter at the time of surgery 1143 320 (27.9) values expressed as mean (sd), median [interquartile range] or n (%). bmi: body mass index; asa: american society of anesthesiologists; bph: benign prostatic hyperplasia; aur: acute urinary retention; pae: prostate artery embolization. table 2. perioperative characteristics of the study population perioperative outcomes n = 1174 values surgical technique 1174 1174 (100) complete prostatic enucleation hospitalization 1174 1174 (100) conventional 841 (71.8) day-case 330 (28.2) perioperative complications 1174 71 (6) capsular perforation 23 (32.4) bladder injury 15 (21.1) other (equipment failure. ureteral meat coagulation significant bleeding. negative input-output) 33 (46.5) conversion 1174 8 (0.7) turp 7 (87.5) op 1 (12.5) operative time (min) 1079 83.2 ± 40.9 irrigation (l) 882 27.6 ± 14.7 delivered energy (kj) 997 105.7 ± 63.6 resected weight (g) 1151 50.1 ± 36.6 postoperative outcomes n values postoperative complications 1174 227 (19.3) clavien-dindo 1–2 207 (91.2) clavien-dindo ≥ 3 20 (8.8) blood transfusion 1174 52 (4.4) postoperative lengths of hospital stay (excl. the day before surgery) 1148 1.6 ± 3.1 values expressed as mean (sd) or n (%). hospital stay, but its steep learning curve has slowed its widespread adoption over the last decade[6–8]. in our cohort, the mean los (1.6 nights after surgery) was similar to that reported in major meta-analyses of randomized clinical studies (1.1 to 2.4 nights after surgery)[3,7]. our results confirm that, in a nonselected patient population operated on by a high number of surgeons with or without experience in the technique, the reduction of hospital stay remains a clear advantage of the holep technique. nonetheless, we observed a significantly longer hospital stay for patients of inexperienced surgeons (2.1 versus 1 for experts; p  <  0.001) that was balanced by a high proportion of day-case surgeries (28.2%) performed mainly by expert surgeons. 14 siuj • volume 4, number 1 • january 2023 siuj.org original research http://siuj.org significant perioperative bleeding resulting in postoperative blood transfusions was observed in 4.4% of patients in our cohort. this transfusion rate is higher than the one reported in meta-analyses of randomized studies. indeed, in a meta-analysis of 4 randomized trials comparing holep to turp, tan et al. reported a 0% transfusion rate[3]. this difference may be explained by strict patient selection in rcts often excluding patients receiving anticoagulant therapy. the percentage of patients undergoing antiplatelet or anticoagulant therapy was not specified in this meta-analysis. in a recent multicenter study that investigated factors influencing perioperative blood loss after holep, the transfusion rate was 5%[13]. in this study, 26.4% and table 3. perioperative outcomes depending on surgical experience, prostatic weight, anticoagulant therapy, antiplatelet therapy and indwelling urinary catheter overall cohort surgeon experience expert vs in-training prostatic weight ≥ 100 g vs < 100 g anticoagulant therapy yes vs no antiplatelet therapy yes vs no indwelling urinary catheter yes vs no n = 1174 expert n = 511 p -valuea ≥ 100 g n = 313 p -valueb yes n = 141 p -valuec yes n = 310 p -valued yes n = 320 p -valuee perioperative complications 71 (6) 21 (4.2) 0.01 24 (7.6) 0.2 7 (5) 0.5 29 (9.3) 0.004 25 (7.8) 0.1 operative time (min) 83.2 ± 40.9 71.4 ± 34.3 < 0.001 103.9 ± 44.3 < 0.001 88.8 ± 42.8 0.03 81.3 ± 40.2 0.3 96.5 ± 45.5 < 0.001 resected weight (g) 50.1 ± 36.6 51.4 ± 35.8 0.2 83.4 ± 44.5 < 0.001 51.3 ± 34.8 0.7 44.6 ± 32.6 0.002 65.8 ± 46.9 < 0.001 resected percentage (%) 60.8 ± 25.4 62.4 ± 23.8 0.07 postoperative complications 227 (19.3) 82 (16) 0.01 65 (20.7) 0.5 42 (29.8) < 0.001 85 (27.4) < 0.001 97 (30.3) < 0.001 blood transfusion 52 (4.4) 19 (3.7) 0.3 23 (7.3) 0.001 15 (10.6) < 0.001 19 (6.1) 0.08 30 (9.3) < 0.001 length of hospital stay 1.6 ± 3.1 1 ± 2.4 < 0.001 1.5 ± 1.9 0.8 3.3 ± 6.8 < 0.001 1.8 ± 2.2 0.05 2.4 ± 4.6 < 0.001 values expressed as mean (sd), median [interquartile range] or n (%). a p-value vs. in training; b p-value vs. < 100g; c p-value vs. no anticoagulant; d p-value vs. no antiplatelet; e p-value vs. no indwelling catheter 12% of patients were on antiplatelet and anticoagulant therapy, respectively. these results are very close to ours, considering that we also included 25.9% and 11.5% of patients undergoing antiplatelet and anticoagulant therapy, respectively. regarding perioperative bleeding and transfusion rates, our results also confirm the safety of the holep technique performed by a high number of surgeons, with and without experience, in a non-selected population of patients. the short-term (3 to 6 months) and long-term (>  5  years) functional outcomes of holep have been widely described in the literature. meta-analyses comparing holep with turp or op found no difference between the techniques for flowmetric data (qmax and rpm) or ipss. 15siuj.org siuj • volume 4, number 1 • january 2023 implementing holep in an academic department with multiple surgeons in training: mentoring is the key for success http://siuj.org in our study, we observed a 14to 16-point decrease in ipss at 3 and 6 months, respectively. similarly, qmax was improved by 13.4 to 14.2 ml/s at 3 and 6 months, respectively. the holep technique performed by a high number of surgeons, with and without experience, in a non-selected population of patients produced results similar to those reported in meta-analyses. in rcts, the improvement in ipss varied between 16 and 20 points at 6-month follow-up, and qmax varied from 14 to 18 ml/s[14–16]. even when follow-up after 6 months was available for a minority of patients, the improvement in ipss remained stable over time in our cohort, with a median ipss of 4 at 3-year follow-up, similar to the score reported in other publications with longer follow-up periods[4,17,18]. urinary incontinence (ui) (stress or urgency) is the main functional complication described after holep, with a rate varying from 4% to 17% at 3 months[19–22] and from 4% to 5% at 6 months[20–22]. the definition of ui in our study was based on the international continence society (ics) definition: "the complaint of any involuntary loss of urine from the urethra"[23]. the results observed in our series at 3 months are slightly higher than those observed in the literature, with a ui rate of 22.9%. however, the results at 6 months (6.4%) are consistent with those described in the previously cited studies. there is a chance that the higher rate of ui at 3 months observed in our series could be explained by the high number of inexperienced surgeons involved, as the impact of the surgeon's experience on the rate of ui has been reported in several studies in recent years[21,22,24]. in a multicenter retrospective study including 39 surgeons and 1113 patients, shigemura et al. evaluated how surgeon experience affected outcomes including continence after holep[22]. the surgeon's experience (from 20 procedures) was associated with a significantly reduced the rate of ui at 3 months, as the more experienced surgeon paid more attention to the prostatic apex than an operator at the beginning of his or her training. this threshold is also described in the study of houssin et al., in which the ui rate at 3 months was significantly lower in multivariate analysis for surgeons who had performed 20 procedures[21]. similar results were reported in the prospective study by elshal et al., in which they reported the functional results and the various perioperative and remote complications of the first 313 holep procedures performed by 3 surgeons. the rate of ui at 3 months decreased significantly (8.7% vs. 23.3%) after the surgeon had completed 20 procedures[24]. in our experience, only 4 patients (0.3%) with persistent ui required surgical management. although these results should be interpreted with caution because of the limited data available and the relatively short follow-up (26 months), the literature review also shows a rate of surgical treatment for persistent ui under 1%[25]. one of the obstacles to the diffusion of the holep technique over the last decade was said to be its long and steep learning curve. it has been clearly demonstrated that holep requires significant experience and endoscopic skills, and the advantages of the technique increase with the experience of the surgeon[18,26]. our series also confirmed that the surgeon's experience plays a role in terms of perioperative results (perioperative complications, transfusion rate, and los) and in terms of remote functional results. however, even though results were better for expert surgeons, our cohort, with a high proportion of novice operators (< 30 surgeries) confirmed clinical results close to those published in rcts. conversion to mturp or op was necessary in only 0.7% of cases (n = 8), and major complications requiring re-intervention (clavien-dindo ≥ 3) were seen in only 20 patients (8.8%). structured mentoring and supervision by an expert surgeon were critical in our experience, as previously described by peter gilling. the inventor of the technique divided the learning curve in 2 phases: a "mentoring" phase and a consolidation phase[27]. the importance of support at the beginning of the experience has already been underlined in a previous publication by our group[10]. in a prospective multicenter observational study without structured mentoring during the early phase of the learning curve, we looked at the success of the procedures. successful completion was defined as enucleation and morcellation in less than 90 min without conversion to turp. one out of 3 surgeons included in this study dropped out before the twentieth procedure. the remaining surgeons were able to complete the procedure in only 44% of the cases according to the criteria mentioned above. apart from the biases linked to the retrospective nature of this work, its main limitation is the large number of patients lost to follow-up after the 6-month visit, which did not allow us to evaluate the long-term results of our cohort. the main strength of this study is the representativeness of the results in a non-selected population of patients with multiple surgeons (real-life setting) reflecting what could be expected when implementing the holep technique in other urology departments. 16 siuj • volume 4, number 1 • january 2023 siuj.org original research http://siuj.org references 1. professionals s-o. eau guidelines: management of non-neurogenic male luts. n.d. available at: https://uroweb.org/guideline/treatmentof-non-neurogenic-male-luts/#5. accessed 27 october 2019. 2. lebdai s, chevrot a, doizi s, pradère b, delongchamps nb, baumert h, et al. surgical and interventional management of benign prostatic obstruction: guidelines from the committee for male voiding disorders of the french urology association [article in french]. prog urol.2021;31(5):249–265. doi: 10.1016/j.purol.2020.12.006. 3. tan a, liao c, mo z, cao y. meta-analysis of holmium laser enucleation versus transurethral resection of the prostate for symptomatic prostatic obstruction. br j surg.2007;94(10):1201–1208. doi: 10.1002/ bjs.5916. 4. gilling pj, wilson lc, king cj, westenberg am, frampton cm, fraundorfer mr. long-term results of a randomized trial comparing holmium laser enucleation of the prostate and transurethral resection of the prostate: results at 7 years. bju int.2012;109(3):408–411. doi: 10.1111/j.1464-410x.2011.10359.x. 5. li m, qiu j, hou q, wang d, huang w, hu c, et al. endoscopic enucleation versus open prostatectomy for treating large benign prostatic hyperplasia: a meta-analysis of randomized controlled trials. schwentner c. ed. plos one.2015;10(3):e0121265. doi: 10.1371/ journal.pone.0121265. 6. lin y, wu x, xu a, ren r, zhou x, wen y, et al. transurethral enucleation of the prostate versus transvesical open prostatectomy for large benign prostatic hyperplasia: a systematic review and meta-analysis of randomized controlled trials. world j urol.2016;34(9):1207–1219. doi: 10.1007/s00345-015-1735-9. 7. tooher r, sutherland p, costello a, gilling p, rees g, maddern g, et al. a systematic review of holmium laser prostatectomy for benign prostatic hyperplasia. j urol.2004;171(5):1773–1781. doi: 10.1097/01. ju.0000113494.03668.6d. 8. duc al, gilling pj. holmium laser resection of the prostate. eur urol.1999;35(2):155–160. doi: 10.1159/000019836. 9. fraundorfer mr, gilling pj. holmium:yag laser enucleation of the prostate combined with mechanical morcellation: preliminary results. eur urol.1998;33(1):69–72. doi: 10.1159/000019535. 10. robert g, cornu j-n, fourmarier m, saussine c, descazeaud a, azzouzi a-r, et al. multicentre prospective evaluation of the learning curve of holmium laser enucleation of the prostate (holep). bju int.2016;117(3):495–499. doi: 10.1111/bju.13124. 11. gilling pj, cass cb, malcolm ar, fraundorfer mr. combination holmium and nd:yag laser ablation of the prostate: initial clinical experience. j endourol.1995;9(2):151–153. doi: 10.1089/end.1995.9.151. 12. mallet r, gamé x. énucléation prostatique au laser holmium (holep) « en bloc ». [ the en bloc holmium enucleation of the prostate: technique, tips and tricks]. prog urol.2017;27(4):f 71–f 74. doi: 10.1016/j.fpurol.2017.09.001. 13. romero-otero j, garcía-gonzález l, garcía-gómez b, justo-quintas j, garcía-rojo e, gonzález-padilla da, et al. factors influencing intraoperative blood loss in patients undergoing holmium laser enucleation of the prostate (holep) for benign prostatic hyperplasia: a large multicenter analysis. urology.2019;132:177–182. doi: 10.1016/j. urology.2019.06.024. 14. montorsi f, naspro r, salonia a, suardi n, briganti a, zanoni m, et al. holmium laser enucleation versus transurethral resection of the prostate: results from a 2-center prospective randomized trial in patients with obstructive benign prostatic hyperplasia. j urol.2008;179(5, suppl):s87–s90. doi: 10.1016/j.juro.2008.03.143. 15. vavassori i, valenti s, naspro r, vismara a, dell'acqua v, manzetti a, et al. three-year outcome following holmium laser enucleation of the prostate combined with mechanical morcellation in 330 consecutive patients. eur urol.2008;53(3):599–606. doi: 10.1016/j. eururo.2007.10.059. conclusion with 1174 patients and 31 urologists involved in a retrospective analysis of our experience, we were able to confirm that holep can be progressively mastered by most urologists in training over a 2-year period, with good functional outcomes and acceptable complication rates close to those reported in previously published rcts. in our experience, supervision of trainees by expert surgeons seemed to be critical for the safe adoption of the technique. acknowledgements author disclosure c. klein, t. marquette, g. capon, e. alezra, jc. bernhard, p. blanc, v. estrade, f. bladou : no competing interests. g. robert: holep proctor for edap/tms. author contributions c.k.: data collection, data analysis, article writing. t.m.: data collection, data analysis. g.c.: critical revision of the article for important intellectual content. e.a.: data collection. p.b: data collection. v.e: data collection. j.c.b.: critical revision of the article for important intellectual content. f.b: critical revision of the article for important intellectual content. g.r.: protocol development, data analysis, article writing. 17siuj.org siuj • volume 4, number 1 • january 2023 implementing holep in an academic department with multiple surgeons in training: mentoring is the key for success http://siuj.org 16. ahyai sa, lehrich k, kuntz rm. holmium laser enucleation versus transurethral resection of the prostate: 3-year follow-up results of a randomized clinical trial. eur urol.2007;52(5):1456–1464. doi: 10.1016/j.eururo.2007.04.053. 17. enikeev d, taratkin m, morozov a, singla n, gabdulina s, tarasov a, et al. long-term outcomes of holmium laser enucleation of the prostate: a 5-year single-center experience. j endourol.2020;34(10):1055–1063. doi: 10.1089/end.2020.0347. 18. elzayat ea, elhilali mm. holmium laser enucleation of the prostate (holep): long-term results, reoperation rate, and possible impact of the learning curve. eur urol.2007;52(5):1465–1472. doi: 10.1016/j. eururo.2007.04.074. 19. nam jk, kim hw, lee dh, han j-y, lee jz, park s-w. risk factors for transient urinary incontinence after holmium laser enucleation of the prostate. world j mens health.2015;33(2):88. doi: 10.5534/ wjmh.2015.33.2.88. 20. cho mc, park jh, jeong ms, yi j-s, ku jh, oh s-j, et al. predictor of de novo urinary incontinence following holmium laser enucleation of the prostate. neurourol urodyn.2011;30(7):1343–1349. doi: 10.1002/ nau.21050 21. houssin v, olivier j, brenier m, pierache a, lamiado m, mouton m, et al. predictive factors of urinary incontinence after holmium laser enucleation of the prostate: a multicentric evaluation. world j urol.2021 jan;39(1):143–148. doi: 10.1007/s00345-020-03169-0. epub 2020 mar 26. 22. shigemura k, yamamichi f, kitagawa k, yamashita m, oka y, tanaka h, et al. does surgeon experience affect operative time, adverse events and continence outcomes in holmium laser enucleation of the prostate? a review of more than 1,000 cases. j urol.2017;198(3):663–670. doi: 10.1016/j.juro.2017.04.087. 23. abrams p, andersson ke, birder l, brubaker l, cardozo l, chapple c, 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(1):213–240. doi: 10.1002/nau.20870. 24. elshal am, nabeeh h, eldemerdash y, mekkawy r, laymon m, el-assmy a, et al. prospective assessment of learning cur ve of holmium laser enucleation of the prostate for treatment of benign prostatic hyperplasia using a multidimensional approach. j urol.2017;197(4):1099–1107. doi: 10.1016/j.juro.2016.11.001. 25. elkoushy ma, elshal am, elhilali mm. reoperation after holmium laser enucleation of the prostate for management of benign prostatic hyperplasia: assessment of risk factors with time to event analysis. j endourol.2015;29(7):797–804. doi: 10.1089/end.2015.0060. 26. du c, jin x, bai f, qiu y. holmium laser enucleation of the prostate: the safety, efficacy, and learning experience in china. j endourol.2008;22(5):1031–1036. doi: 10.1089/end.2007.0262. 27. vincent mw, gilling pj. holep has come of age. world j urol.2015; 33(4):487–493. doi: 10.1007/s00345-014-1443-x. 18 siuj • volume 4, number 1 • january 2023 siuj.org original research http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information penile cancer, chemotherapy, radiotherapy, interdisciplinary communication none declared. patient consent: obtained. received on october 18, 2022 accepted on october 22, 2022 soc int urol j. 2023;4(2):150–152 doi: 10.48083/gvtl9492 complete response of primary penile tumor with induction paclitaxel, ifosfamide, and cisplatin (tip) chemotherapy logan zemp,1 jad chahoud,1 peter a. johnstone,2 philippe e. spiess1 1department of genitourinary oncology, h. lee moffitt cancer center & research institute, tampa, united states 2 department of radiation oncology, h. lee moffitt cancer center & research institute, tampa, united states the patient was a 53-year-old male who presented to moffitt cancer center with a fungating lesion of the ventral penis and scrotum which was biopsy proven to be well-differentiated squamous cell carcinoma, invasive into at least the lamina propria, and unknown human papillomavirus (hpv) (figure 1a). presentation was delayed because of lack of health insurance. the penile lesion was mobile and inguinal lymph node (iln) enlargement was not appreciated on physical examination. staging ct and mri imaging identified tumor effacement of the corpus spongiosum (figure 1b), no evidence of iln, pelvic, or distant metastases. the patient was counselled on radical penectomy due to concern for ≥ ct2 disease, but he adamantly refused penectomy despite guideline directed counselling[1]. the case was presented at multidisciplinary tumor board (mdt) who favored penectomy, but patient preference was considered, and wide local excision with suprapubic catheter placement and staged penile urethroplasty after a period of observation to ensure adequate local control was discussed and presented to the patient. he refused. additional mdt discussions led to recommendation for induction paclitaxel, ifosfamide, and cisplatin (tip) chemotherapy due to limited treatment options. the patient underwent 4 cycles of tip chemotherapy without major adverse events resulting in a complete response (figure 1c and 1d). the patient underwent 28 fractions of external beam radiation to the ilns. at most recent follow-up he has no evidence of disease. these clinical images document the complete response of a large primary penile tumor with tip chemotherapy alone and importance of multidisciplinary care. reference 1. clark pe, spiess pe, agarwal n, biagioli mc, eisenberger ma, greenberg re, et al. penile cancer: clinical practice guidelines in oncology. j natl compr canc netw.2013;11(5):594-615. 150 siuj • volume 4, number 2 • march 2023 siuj.org clinical picture https://orcid.org/0000-0002-7701-5070 mailto:logan.zemp%40moffitt.org?subject=siuj https://orcid.org/0000-0002-8435-0264 https://orcid.org/0000-0003-4221-9388 https://orcid.org/0000-0002-5723-1972 http://siuj.org initial presentation figure 1. representative photo of the penile lesion a) on initial presentation b) pre-treatment sagittal and axial mri demonstrating penile mass with effacement of the corpus spongiosum a b 151siuj.org siuj • volume 4, number 2 • march 2023 complete response of primary penile tumor with induction paclitaxel, ifosfamide, and cisplatin (tip) chemotherapy http://siuj.org status post tip chemo c) penile lesion status post 3 cycles paclitaxel, ifosfamide, and cisplatin (tip) chemotherapy d) post-treatment mri images with resolution of primary penile tumor c d 152 siuj • volume 4, number 2 • march 2023 siuj.org clinical picture http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj • volume 4, number 3 • may 2023 siuj.org key words competing interests article information prostatic neoplasm, needle biopsy, neoplasm metastasis, prostate-specific antigen, early detection of cancer see acknowledgements. patient consent: obtained. received on october 28, 2022 accepted on november 6, 2022 soc int urol j. 2023;4(3):232–233 doi: 10.48083/zhvj6978 232 clinical picture the prostate problem you can’t put your finger on the normal way: a case of perineal prostate cancer post transperineal prostate biopsy kevin yinkit zhuo,1,2 james kovacic,1,2amanda chung,1,2,3 thomas eade,3,4 venu chalasani,1,2,3 1 department of urology, royal north shore hospital, sydney, australia 2 north shore urology research group, sydney, australia 3 university of sydney, sydney, australia 4 radiation oncology department, northern sydney cancer centre, royal north shore hospital, sydney, australia transperineal biopsy needle-tract tumour seeding is a rare complication, with sparse published literature[1].  we describe the management of metastatic prostate cancer secondary to transperineal biopsy needle-tract seeding. an 80-year-old male presented with an otherwise asymptomatic, hard perineal mass that had progressively enlarged over a few months. the patient’s urological history included prostate adenocarcinoma of the right prostatic apex, prostatic urethra, and lymph nodes (isup-grade 4 [4 + 4 = 8], pirads-5, psa-level 2.7µg/l), diagnosed via transperineal biopsy and turp 3 years prior. his prostate cancer was definitively managed with turp, adt, and radiotherapy with a post-treatment psa-level of 0.05µg/l. on pelvic examination, a perineal 2cm fixed lump was palpable. pelvic-mri demonstrated a 20mm irregular mass in the perineal fat immediately below the penile base (figure 1a). repeat psa-level was 6.0µg/l. subsequent psma pet-scan revealed a psma-avid lesion in the perineal midline, consistent with prostatic neoplasm metastasis without other metastatic disease (figure 1b). cystoscopy showed no obvious urinary-tract cancer recurrence. the patient’s case was discussed in a multi-disciplinary team meeting and excision was recommended. the patient then underwent a wide-local excision, requiring partial resection of bulbar-spongiosum (figure 1c). histopathology revealed a complete excision of his prostate adenocarcinoma metastasis, with post-excision psa-levels of 0.12µg/l. no adjuvant therapies were given. needle-tract seeding following transperineal prostate biopsy is rare and should not preclude patients from undergoing biopsies. this case highlights the need for patient follow-up after cancer treatment and exemplifies the practicality of psma pet-scans if there is evidence of rising psa-levels after definitive prostate cancer treatment. acknowledgements competing interests: dr amanda chung: proctor for medtronic and boston scientific. the other authors have no competing interests. reference 1. volanis d, neal de, warren ay, gnanapragasam vj. incidence of needle-tract seeding following prostate biopsy for suspected cancer: a review of the literature. bju int.2015 may;115(5):698-704. http://siuj.org mailto:k.zhuo2%40gmail.com?subject=siuj siuj.org siuj • volume 4, number 3 • may 2023 figure 1a. pelvic-mri. mass in perineal fat abutting fascia around inferior corpora spongiosis. figure 1b. psmapet (ongoing resolving right prostatic posterolateral peripheral zone and equivocal left pre-sacral node uptake. new psma-avid lesion in the perineal midline (suv-max 21.7) figure 1c. intraoperative image demonstrating perineal metastatic lesion abutting bulbospongiosus. the urethra, however, was clear of disease. 1c1b1a psmaavid lesion abutting fascia around inferior corpora spongiosis in perinael midline lesion bulbospongiosus 233 the prostate problem you can’t put your finger on the normal way: a case of perineal prostate cancer post transperineal prostate biopsy http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj.org siuj • volume 4, number 2 • march 2023 michael rochford is well known throughout the urological world for many reasons and could be regarded as a “renaissance man” of urology. his urological knowledge is more than impressive, but it is his dedication to the nurturing of the discipline of urology and of his colleagues and students, combined with his humanity and care for “community,” that truly makes him a giant in urology. michael obtained his medical degree at the university of sydney, graduating in 1961. he subsequently obtained surgical fellowships from the royal college of surgeons (frcs) in 1966, and then his urological fellowship from the royal australasian college of surgeons (fracs) in 1972. michael spent time working at the whittington hospital, with sir eric riches at the middlesex (royal marsden) hospital, and with dennis poole-wilson at the christie and salford royal hospitals, where he gained great experience in the surgical treatment of kidney and bladder cancers. upon returning to australia from the united kingdom, he was appointed consultant urological surgeon at nepean hospital, sydney in 1969, and then consultant urologist at the liverpool hospital, sydney in 1971. from 1972 onward, he served as medical officer (group captain) to the raaf, including formal appointment as command consultant urologist at 3-raaf hospital, richmond, from 1972 to 1992. this formal outline of his professional appointments does not reflect, in any way, the actual impact and significance of michael’s influence and contribution to those institutions in sydney. at the time of his appointment, both hospitals were community or district hospitals to which michael brought a level of urological expertise much higher than either institution previously had available. both hospitals were situated in the western part of sydney and were relatively under-serviced. michael was instrumental in upgrading the level of service provided, as well as in attracting better-qualified surgeons and starting training programs in urology. today, both hospitals are major teaching hospitals in sydney, with urology departments sought after for both training appointments and senior consulting urology posts. michael rochford was an active mentor of dr michael rochford, a giant in urology many urologists who are in practice today (including myself)—he guided the path of many to urology training, espousing breadth as well as depth of training, and placing a good deal of emphasis on common sense. the last trait he thinks is far too rare in modern surgery and urology! the urological society of australasia (the name of the urological society of australia & new zealand at the time) was also a beneficiary of michael rochford’s expertise. he served on the executive for many years and was honorary treasurer from 1983 to 1988. he was chairman of the australasian urological foundation michael rochford, sydney, australia william j. lynch department of urology, macquarie university, sydney, australia soc int urol j. 2023;4(2):145–147 145 giants in urology http://siuj.org from its inception in 1995 until 2022, directing its progress and continuation with great success. the urological society of australasia (usa) was formalized as a body in 1937, and immediately began its association with the siu. at that time, the australasian section of the siu was limited to 10 members—8 from australia and 2 from new zealand. as early as 1940, the usa was requesting the quota be increased—this did occur slowly over subsequent years. at that time, siu meetings were held every 3 years, mostly in europe, with french as the dominant language and simultaneous translation a typical feature—although obviously an increasing financial burden for the society. the siu has undergone substantial changes since those days, and michael was a very significant conduit for evolution within the siu. the 1991 siu meeting was held in seville, and a very enthusiastic group led by bruce pearson (chair), michael rochford, and david golovsky lobbied for the 1994 meeting to be held in sydney. the executive of the siu voted in its favour, and that decision would be the first step in a series of changes that, in one sense, could be regarded as an “avalanche of evolution,” although some undoubtedly perceived it as revolution. the siu meeting in seville heralded another momentous change for the siu, as the meeting’s official language was changed from french to english, with the local organizing committee having the discretion as to what translations were available. unfortunately, bruce pearson passed away unexpectedly in 1992 leaving michael and david golovsky to jointly run the meeting. the “chair” of the australasian section president was left vacant in his honour. until that time, to attend an siu meeting, a delegate had to be seconded by an existing siu member. michael and david lobbied successfully to have this restriction lifted, allowing invitation to the meeting to be extended to all urologists, which, of course, remains the situation to this day. more than 2700 delegates attended the siu meeting in 1994 in sydney, demonstrating that people were prepared to travel great distances to a good meeting. michael rochford was predominantly responsible for obtaining sponsorship for the meeting, which highlighted that an siu meeting could be financially successful. that significant inf lux of funds allowed the establishment of the siu secretariat office in montreal, which was the start of the “professionalization” of the organization and the progressive changes that formed the siu of 2023. michael then started a long association with the executive/board of directors of the siu. he became chairman of the congress and established strong and long-standing relationships with industry and other professional organizations. early in his role as chairman of congress, he and the committee faced logistical challenges, but michael’s diplomacy and his organizational skills were instrumental in overcoming all difficulties, and he was always quick to give credit to local organizing committees. of course, michael continued with the organization to become appointed president of the siu in 2002 in the stockholms stadshus, the hall where the nobel banquets are held, and his own memorable “presidential” meeting was held in hawaii in 2004. there are many stories that could be told about rochford/siu exploits around the world, and there are undoubtedly even more than will never be told. i think it could be a very educational evening to give michael that extra whisky and get him to tell some of those tales, but alas his discretion is legendary, and i fear i will go wanting! philosophically, michael saw a far-reaching role for the siu, and with some like-minded fellow members guided the organization to a wider and more expansive role than it had originally performed. this, of course, was made possible by the new-found financial stability afforded to the siu by the sydney meeting, followed by the montreal meeting in 1997. education, training, and access were the areas michael rochford saw as the backbone of the siu, and how the siu could have an identity of its own that was quite distinct from that of national societies and associations. much of the rochford “vision” has come to fruition in our present, modern siu. • meetings—he pushed for an annual meeting (as opposed to the original triennial meeting) so as to keep the siu in the mind’s eye of urologists and current to potential sponsors. after a period of biennial meetings, we now have an annual meeting. • journal—he also thought the siu needed a journal and, together with mostafa elhilali, initiated the original collaboration with urology, which has, of course, now evolved to the siu journal. • scholarships—the scholarship scheme was an idea that fitted his concept of what defines the siu perfectly and he did everything he could, through his various positions in the siu, to help establish this endeavour. joe thuroff, of course, was the long-time chair and a huge driving force behind this initiative. • training—michael long held the belief that the most effective method of helping upgrade skills was to assist individual urologists within their local environment. he was always extremely proud of the support the siu provided to centres in kilimanjaro, mozambique, and wad madani. 146 siuj • volume 4, number 2 • march 2023 siuj.org giants in urology http://siuj.org this short summary of michael rochford’s contribution to the siu is certainly not comprehensive, but hopefully it gives a perspective on his contribution to the organization’s evolution. those who might only have heard of him have some idea of the vision, philosophical bent, and imagination of the man who helped shape the siu as we now know it, as well as his drive and financial skills that helped make it possible. he is one half of the “dynamic duo” that directed and facilitated the emergence of the modern siu. michael is enjoying his well-earned retirement, although lamenting he does not get to play as much golf as he would like (by the way, he was depressingly good at that too). there are many who would consider it an honour to follow in michael’s footsteps—myself most definitely included in that category. 147siuj.org siuj • volume 4, number 2 • march 2023 michael rochford, sydney, australia http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information prostate biopsy, targeted prostate biopsy, fusion prostate biopsy, cognitive prostate biopsy, prostate cancer none declared. received on september 8, 2022 accepted on january 3, 2023 this article has been peer reviewed. soc int urol j. 2023;4(2):142–144 doi: 10.48083/ryrf4858 fusion biopsy, not cognitive, is the new gold standard alessandro marquis, giancarlo marra, paolo gontero azienda ospedaliera universitaria città della salute e della scienza, university of turin, department of surgical sciences, division of urology, turin, italy abstract to date, although some benefits resulting from a software-guided technique are undeniable, no clear superiority of fusion over cognitive targeted biopsy (cog-tb) has been supported by strong evidence. we discuss potential causes of trials failing to show the superiority of fusion tb (fus-tb) and highlight its advantages over the cognitive approach. one possible reason why current literature showed contradictory evidence in supporting fus-tb may be the lack of high-quality well-designed trials. indeed, most of the studies addressing this issue have considerable limitations, such as underpowering, small sample size, lack of randomization, and poor generalizability. a second reason may be the inclusion in the majority of trials of a wide spectrum of mri-lesions, a scenario in which the benefits of fus-tb may be less evident. in fact, some of the few studies considering smaller targets demonstrated higher accuracy for the fus technique. as concerns the advantages of fus-tb, the opportunity offered by some fusion systems of storing information useful for planning and/or follow-up active surveillance, focal therapy, and radical prostatectomy, as well as a reported faster learning curve, are strong points supporting the fusion approach. in conclusion, the potential advantages when targeting smaller lesions together with the storage capability to guide patient management after the biopsy and an easier learning curve may make the fus approach the more appropriate technique for performing tb. commentary when mri is positive, current guidelines strongly recommend a prostate biopsy combining systematic (sb) and targeted (tb) cores[1]. the mri target can be sampled through a cognitive guidance, a us/mri fusion software or, less frequently, a direct in-bore guidance[2]. to date, there is no strong evidence to support the superiority of either one of these methodologies. however, when comparing the fusion and the cognitive approaches, it is undeniable that fusion has some advantages. we discuss potential reasons that trials fail to show clinically significant differences and highlight some advantages of a software over a cognitive-based tb. evidence from trials is contradictory some rcts may have failed in capturing clinical benefits of the fusion over the cog-tb while others did not highlight significant advantages. overall, all these studies suffer from considerable limitations. notably, the future trial, which included 665 men with prior negative sb to undergo fusion versus cognitive versus in-bore tb, reported a higher clinically significant prostate cancer (pca) detection rate for the fusion than the cognitive group, although not reaching statistical significance (34.2% versus 33.3%, p > 0.9)[3]. however, the primary endpoint resulted clearly underpowered with only 79 and 78 patients randomized for fus and cog respectively versus 152 per group originally planned in the sample size calculation. furthermore, only men with prior negative sb were included thus making the results not generalizable to all patients with pca suspicion based on mri findings. 142 siuj • volume 4, number 2 • march 2023 siuj.org pro and con: fusion biopsy http://siuj.org the pairedcap study is a paired cohort trial which included 248 biopsy naïve patients undergoing 12 sb followed, in sequence, by 3-cores cog-tb and 3-cores fus-tb[4]. the cspca detection rate of fus-tb was 7% higher than that of cog-tb (54.0% versus 46.8%) and similar difference was shown also at the per-core analysis (38.1% versus 33.3%). although the trial was not powered to detect differences in the detection rate between the 2 techniques, these findings may support a potential advantage of fus-tb even in the biopsy naïve population. a more recent rct investigated the diagnostic yield of fusion versus cog-tb in 199 men, all biopsy naïve and randomized head-to-head[5]. the study was powered with 200 patients under the authors’ assumption of a 15% higher detection rate for fus-tb. the results confirmed the hypothesised advantage of fus: both the overall and cspca detection rates were significantly higher in the fusion than in the cognitive group (44.4% versus 31.0%, p = 0.035 and 33.3% versus 19.0%, p = 0.016, respectively). the average positive cores number was also higher in the fusion arm (13% versus 8%, p = 0.045). notably, the authors acknowledged in the discussion that in order to prove a 5% advantage of fusion over cog-tb (as current literature data seem to show), a total of 1776 patients would be needed, a number that exceeds the accrual of any available trial so far conducted and confirming that solid evidence in this respect is still lacking. size of mri lesion this may be another reason why some studies failed in showing clinically significant differences in favour of fus-tb. it is reasonable that larger targets are likely to be more easily sampled using cog-tb, while with smaller lesions, fus-tb may have significant advantages. existing evidence has shown a high grade of targeting precision for the fus system, with accuracy of 99% for lesions ≥ 6 mm and of 96% for 5 mm lesions. smaller targets are less likely to be adequately sampled using only 1 targeted bioptic core (61% for 3 mm lesion), but the probability increases to 94% with 3 cores[6]. therefore, fusion software is likely able to ensure levels of precision seldom achieved for small lesions in a cognitive setting. mean target size usually detected at mri is 12 mm (iqr 8 to 15 mm)[7]; therefore, it is not surprising that in the majority of the main trials comparing fusion and cog-tb, mean lesion size ranged from 11 to 14 mm [3–5,8], more than double the minimum detection threshold of mri. in this “wide-lesion” scenario, fus-tb benefits may be less evident. the profus trial analysed the fusion versus cog-tb diagnostic accuracy in a cohort with a slightly lower average size lesion (9 mm [iqr 7 to 13 mm]) and found a borderline significance in favour of fus-tb in terms of per-target cspca detection rate (20.3% versus 15.1%, p = 0.052). smaller target diameter was identified as one of the most influential factors for cancer detection in the fusion group, further supporting the view that fus-tb provides the greatest impact when targeting smaller lesions that may be difficult to sample using cog-tb[8]. importantly, previous retrospective series observed a significant advantage for fus-tb with a magnitude of effect that was larger in lesions below 1 cm (fus-tb 64.0% versus 40% cog-tb, where targets ≤ 10 mm were 52% versus 21%, respectively)[9]. fus-tb is more informative some fusion systems allow exact recording of the location of positive cores, which is key in the era of precision pca diagnostics and treatment when planning future management. this has implications for (1) a more accurate follow-up biopsy during active surveillance; (2) a more precise delivery and then follow-up of focal therapy; (3) radical prostatectomy planning[8]. fusion may be easier to learn a higher operator expertise may be required to achieve comparable outcomes with a cognitive approach. stabile et al. retrospectively evaluated both the detection rate and its improvement in 244 men during the learning curve[10]. there was no clear increase in detection of cspca overall (58% versus 45% p  =  0.07) but the detection of cspca on a per-target analysis was higher with fus-tb (57% versus 36%, p = 0.002). interestingly, not only the fusion technolog y but also operator expertise was an independent predictor of cancer detection. in addition, the cog-tb learning curve was steeper, and the number of procedures needed to reach the plateau lower for fus-tb. conclusion while current evidence does not strongly support the superiority of fusion over cognitive tb, it seems plausible that fus-tb is more accurate in targeting smaller lesions. major trials have generally been underpowered and have yielded contradictory evidence; however, most have included large lesions, while the advantages of fus-tb are likely more evident for smaller targets. the learning curve may also be shorter for fusion compared with cog-tb. in the era of precision medicine, advantages that are not clinically measurable, including storage capability to guide patient management after the biopsy, should also be considered. 143siuj.org siuj • volume 4, number 2 • march 2023 fusion biopsy, not cognitive, is the new gold standard http://siuj.org references 1. mottet n, van den bergh rcn, briers e, de santis m, gillesen s, grummet j, et al. eau guidelines on prostate cancer 2022. 2. yamada y, ukimura o, kaneko m, matsugasumi t, fujihara a vourganti s, et al. moving away from systematic biopsies: image‑guided prostate biopsy (in‑bore biopsy, cognitive fusion biopsy, mrus fusion biopsy)—literature review. world j urol.2021;39:677–686. https:// doi.org/10.1007/s00345‑020‑03366‑x. 3. wegelin o, exterkate l, van der leest m, kummer ja, vreuls w, de bruin pc, et al. the future trial: a multicenter randomised controlled trial on target biopsy techniques based on magnetic resonance imaging in the diagnosis of prostate cancer in patients with prior negative biopsies. eur urol.2018;75(4): 582‑590. https://doi.org/10.1016/j. eururo.2018.11.040. 4. elkhoury ff, felker er, kwan l, sisk ae, merdie d, natarajan s, et al. comparison of targeted vs systematic prostate biopsy in men who are biopsy naive: the prospective assessment of image registration in the diagnosis of prostate cancer (pairedcap) study 2019. https:// doi.org/10.1001/jamasurg.2019.1734. 5. izadpanahi m‑h, elahian a, gholipour f, khorrami m‑h, zargham m, mehrdad ms, et al. diagnostic yield of fusion magnetic resonance‑ guided prostate biopsy versus cognitive‑guided biopsy in biopsy‑naive patients: a head‑to‑head randomized controlled trial 2021. prostate cancer prostatic dis.2021;24:1103–1109. https://doi.org/10.1038/ s41391‑021‑00366‑9https://doi.org/10.1038/s41391‑021‑00366‑9. 6. wegelin o, henken kr, somford dm, breuking fam, bosch rj, van swol cfp, et al. an ex vivo phantom validation study of an mri‑transrectal ultrasound fusion device for targeted prostate biopsy. j endourol.2016 jun;30(6):685‑691.doi: 10.1089/end.2015.0864. epub 2016 mar 16. 7. kasivisvanathan v, rannikko as, borghi m, panebianco v, mynderse l a, vaarala mh, et al.;precision study group collaborators. mri‑targeted or standard biopsy for prostate‑cancer diagnosis. n engl j med.2018 may 10;378(19):1767‑1777. doi: 10.1056/nejmoa1801993. epub 2018 mar 18. 8. wysock js, rosenkrantz ab, huang wc, stifelman md, lepor h, deng f, et al. a prospective, blinded comparison of magnetic resonance (mr) imaging – ultrasound fusion and visual estimation in the performance of mr‑targeted prostate biopsy: the profus trial. eur urol.2014 aug;66(2):343‑351. doi: 10.1016/j.eururo.2013.10.048. epub 2013 nov 8. 9. oderda m, faletti r, battisti g, dalmasso e, falcone m, marra g, et al. prostate cancer detection rate with koelis fusion biopsies versus cognitive biopsies: a comparative study. urol int.2016;97(2):230‑237. doi: 10.1159/000445524. epub 2016 jun 4. 10. stabile a, dell'oglio p, gandaglia g, fossati n, scattoni v, maga t, et al. not all multiparametric magnetic resonance imaging – targeted biopsies are equal: the impact of the type of approach and operator expertise on the detection of clinically significant prostate cancer. eur urol oncol.2018 jun;1(2):120‑128. doi: 10.1016/j.euo.2018.02.002. epub 2018 may 15.2018;1. 144 siuj • volume 4, number 2 • march 2023 siuj.org pro and con: fusion biopsy http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj.org siuj • volume 4, number 3 • may 2023 talent hits a target no one else can hit; genius hits a target no one else can see. — arthur schopenhauer born in akron, ohio on february 13, 1938, the second of four children, patrick craig walsh always wanted to be a doctor, and he took lessons from the dominican nuns who taught him through high school, from his uncle (an amateur naturalist), and from his experiences as a paperboy (getting the newspapers dry, on the porch, on time!) to nurture and sustain his dream of using the gifts he had been given to help his fellow man. he completed his undergraduate and medical school studies at case western reserve, where he met peg, the love of his life. from there, the young couple moved on to surgical residency at the peter bent brigham hospital, pivoting from an initial trajectory towards neurosurgery to urology, under the mentorship of francis moore. he then headed west for urology training at ucla with willard goodwin and joseph kaufman, after which he was expected to return, under the wing of the elliot r. cutler professor, to lead urology at the brigham. walsh became fascinated by the explosion in molecular biology and spent two years in the research laboratory, during residency at ucla and following residency, at ut southwestern, with jean wilson, where they characterized the 5-alpha-reductase deficiency syndrome. he spent two years between residency and utsw as a urologist at the san diego naval hospital. there, for the first time, he began performing radical retropubic prostatectomies, an operation he had not done as a resident at ucla, where only the perineal approach was employed because goodwin had trained under hugh young at the brady. in 1974, at the age of 36, he assumed role of the david hall mcconnell professor and director of the brady urological institute at johns hopkins. when he arrived at hopkins in the mid-1970s, the status quo for men with prostate cancer was dismal, with approximately 50% dying of the disease within 15 years. at the time, radiation therapy was in its infancy, and few men accepted surgery, given risks of life-threatening bleeding, 25% total incontinence, and 100% impotence. he attacked these problems, using the operating room as an anatomy lab, first in 1977 developing his technique dr patrick craig walsh for controlling bleeding from the dorsal vein complex, opening the door to subsequent technical innovations. that year, he heard from a patient—and believed—that he was fully potent within a year following prostatectomy, challenging the accepted dogma of the time that the cavernous nerves ran through the prostate. as he has shared with countless audiences over the years, “if you want to make an important discovery, listen to your patients.” he attended his first meeting of the american association of genitourinary surgeons that year and met pieter donker, the chair at leiden. four years later, in 1981, walsh visited donker in leiden, where they patrick craig walsh, baltimore, united states matthew e. nielsen the john sloan rhodes and john flint rhodes distinguished professor and chair department of urology, university of north carolina school of medicine soc int urol j. 2023;4(3):229–230 doi: 10.48083/ncpl9196 229 giants in urology http://siuj.org discovered the location of the cavernous nerves during a fetal dissection, on walsh’s 43rd birthday. one year later, walsh observed that the location of these microscopic nerves could be identified in the operating room by their constant association with the capsular arteries and veins of the prostate; the neurovascular bundle of walsh[1]. using this observation, on april 26, 1982, he performed the first purposeful nerve-sparing radical prostatectomy on a 52-year-old man, who reported 7 months later that he was potent. the patient died 35 years later, free of cancer, and having lived a normal life. these discoveries led to the advent of safer surgery for prostate cancer, which, combined with psa screening to identify more men with curable disease in the 1990s, contributed to radical declines in prostate cancer morbidity and mortality in the united states and around the world. he has shared this story in greater detail to help others “understand how important discoveries can be made—a simple act of kindness to a lonely old man [dr donker], followed four years later by trying to understand what he was doing now that he was retired. never underestimate what you can learn from others”[2]. in addition to his pioneering anatomical discoveries leading to surgical innovations, walsh made major contributions to the basic understanding of benign and malignant neoplasms of the prostate, and led seminal work characterizing hereditary prostate cancer. he was editor-in-chief of campbell’s textbook of urology (subsequently renamed campbell-walsh urology) for a quarter century, and served on the editorial board of the new england journal of medicine for 15 years. he is the recipient of countless international honors and awards, including the charles kettering medal from the general motors cancer research foundation, the king faisal international prize in medicine, national physician of the year for clinical excellence from america’s top doctors, the francis amory prize by the american academy of arts and sciences, and multiple awards from the american urological association: the gold cystoscope, triennial eugene fuller, hugh hampton young, ramon guiteras, and honorary membership. his best-selling books, the prostate: a guide for men and the women who love them, and dr. patrick walsh’s guide to surviving prostate cancer have been translated into multiple languages and published internationally. along the way, he inspired, mentored, and developed countless leaders in the field, with 23 brady residents going on to become chairs of urology at major programs around the united states. in addition, for decades, he hosted young urologists from all over the world to work in the research laboratories at hopkins and serve a year as the junior resident on his service, learning his surgical techniques and unique and personal approaches to patient care. complementing his tremendous work ethic, imaginative approach to discovery, and commitment to excellence in every dimension, he maintains a catalogue of captivating, sometimes moving, and exceptionally hilarious jokes and stories, delivered with a style befitting “the raconteur of the operating room,” as he was described by garrison keillor. though no longer operating, he continues to see patients on fridays at the hopkins clinic, modeling his embodiment of francis peabody’s dictum that “the secret of the care of the patient is caring for the patient” with rotating medical students. a man of deep faith, humanity, and humility, his service to others extends far beyond his patients and mentees. since june 2013, he has served as a lay minister for people incarcerated in the chesapeake detention center federal prison, an imposing supermax prison dating back to 1807, which he and many others working at hopkins drive past on their way to the hospital. his reflections on this work are incredibly inspiring; among all of his accomplishments, he describes this as one of the most rewarding experiences in his life. patrick c. walsh lives by example the words of our lady of fatima—“the doctors who love their patients are the ones to whom god gives the greater power to heal their patients.” the dimensions of his genius and heart know no bounds, and our specialty, our patients, and any of us who have had the golden opportunity to walk alongside him, are left so much better than he found us. references 1. stedman’s medical dictionary. 27th ed. thomas lathrop stedman. baltimore: lippincott williams & wilkins, 2000. 2. walsh p c. t he dis cover y of t he c aver nous ner ves and development of nerve sparing radical retropubic prostatectomy. j urol.2007;177:1632– 1635. 230 siuj • volume 4, number 3 • may 2023 siuj.org giants in urology http://siuj.org 186 siuj • volume 3, number 3 • may 2022 siuj.org clinical picture this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information covid-19, bilateral spermatic vein, thrombosis conflict of interest: none declared. patient consent: obtained. received on december 9, 2021 accepted on december 11, 2021 soc int urol j.2021;3(3):186 doi: 10.48083/lmlq3196 bilateral spermatic vein thrombosis following covid-19 infection alfin okullo,1 philip crispin,2,3 daniel gilbourd1,3 1 department of surgery, the canberra hospital, canberra, australia 2 department of haematology, the canberra hospital, canberra, australia 3 australian national university, canberra, australia a 35-year-old male attended the emergency department complaining of bilateral inguinoscrotal pain. two weeks prior to presentation, he had been diagnosed with coronavirus disease-2019 (covid-19). on day 11 following covid-19 diagnosis he developed bilateral groin pain. the patient’s scrotal examination was remarkable for clinical grade 3 varicoceles, a finding he reported as new. there was moderate bilateral inguinal tenderness but no hernias. his blood tests showed a raised platelet count of 426 x109/l (normal:150 to 400), white cell count of 9.7 x 109/l (4 to 11) and haemoglobin of 146g/l. jak2 v617f was not detected. an inguinoscrotal ultrasound demonstrated absence of f low in his spermatic veins bilatera lly, with echogenic materia l w it hin the vessel lumen consistent with spermatic vein thrombosis (figure 1). a ct abdomen demons t r ate d a n i nc ident a l 18mm right renal angiomyolipoma. the patient was dis charged with a 3-month course of rivaroxaban. at a follow-up call one month later, his pain had resolved. bilateral spermatic vein thrombosis is a rare diagnosis with this being only the third case reported. all previous reported cases were associated with an underlying coagulation disorder and were managed with a course of anticoagulant therapy. in our patient, the likely predisposing factor was covid-19 infection. myeloproliferative neoplasia was considered; however, the resolution of the mild thrombocytosis and negative jak2 study were not supportive. covid-19 is associated with a pro-thrombotic state postulated to arise from the high pro-inf lammatory cytokine levels. increased platelet activation and reactive hyperfibrinogenemia contribute to the prothrombotic state. guidelines on the management of spermatic vein thrombosis a re lack i ng. in view of the symptoms, embolic risk a nd t he transient nature of the thrombotic risk factor, our patient was treated with a course of 15mg rivaroxaban twice daily for 3 weeks, and then 20mg daily for a total of 3 months. figure 1. http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information renal cell carcinoma, stage shift, rcc screening tools, risk-stratified screening none declared. received on july 15, 2022 accepted on september 20, 2022 this article has been peer reviewed. soc int urol j. 2022;3(6):371–385 doi: 10.48083/xbcx3386 2022 wuof/siu international consultation on urological diseases: kidney cancer screening and epidemiology sabrina h. rossi,1 hajime tanaka,2 juliet a. usher-smith,3 jean-christophe bernhard,4 yasuhisa fujii,2 grant d. stewart1 1 department of surgery, university of cambridge school of clinical medicine, cambridge biomedical campus, cambridge, united kingdom 2 department of urology, tokyo medical and dental university graduate school, tokyo, japan 3 the primary care unit, department of public health and primary care, university of cambridge school of clinical medicine, cambridge biomedical campus, cambridge, united kingdom 4 hôpital pellegrin chu de bordeaux, université de bordeaux, bordeaux, france abstract the incidence of renal cell carcinoma (rcc) has risen worldwide over the past few decades, and this has been associated with a stage shift. survival outcomes of rcc depend largely on the stage at diagnosis. although overall mortality has stabilized or declined in most countries, survival remains poor in late-stage disease, suggesting early detection may improve overall survival outcomes. a number of potential candidate screening tools have been considered (including urinary dipstick, bloodand urine-based biomarkers, ultrasound, and computed tomography [ct]), though it may be that a combination of these approaches may be optimal. ultimately, the sensitivity and specificity of the chosen screening tool will determine the rate of false positives and false negatives, which must be minimized. one of the key challenges is the relatively low prevalence of the disease, which might be overcome by performing risk-stratified screening or screening for more than one condition (such as combined lung and kidney cancer screening). both approaches have been shown to be acceptable to the general public, and they may maximize the efficiency of screening while reducing harms. indeed, quantifying benefits and harms of screening is key (including the impact on overdiagnosis and quality of life). whether screening for rcc will lead to a stage shift and the impact on survival are the decisive missing pieces of information that will determine whether the screening program might be adopted into clinical practice (along with feasibility, acceptability, and cost-effectiveness). epidemiology and risk factors for rcc incidence and risk factors renal cell carcinoma (rcc) rcc is the 9th most frequently diagnosed cancer in men and the 14th most common in women globally, accounting for 2.2% of all new cancer diagnoses (table 1)[1]. the incidence of rcc demonstrates geographic variability (figure 1)[2,3]. the international agency for research on cancer (iarc), established in 1965 by the world health assembly, provides comprehensive information on global cancer epidemiology by aggregating data from 343 population-based cancer registries in 65 countries[4]. the registry data is currently available online at the global cancer observatory as the globocan database[2]. according to the globocan 2020 report, the agestandardized incidence of kidney cancer is highest in northern america, followed by europe, oceania, latin america and the caribbean, asia, and africa (figure 1). the incidence of rcc has generally increased over time in both sexes, and is predicted to continue to rise over the next 15 years, although there is some variability across countries[2,3]. 371siuj.org siuj • volume 3, number 6 • november 2022 2022 wuof/siu international consultation on urological diseases https://orcid.org/0000-0001-7048-7158 mailto:sr725%40cam.ac.uk?subject=siuj http://siuj.org the geographic distribution and rising incidence of rcc have been partially attributed to variation in risk factors for the disease as well as differences in healthcare delivery systems, as detailed below[5–7]. a number of modifiable and nonmodifiable risk factors for rcc have been identified (table 2). the aging population and rising prevalence of certain risk factors (such as obesity, hypertension, and diabetes) contribute to increasing rates of the disease[5–7]. in addition, increased incidental detection reflects the widespread use of abdominal imaging. for example, in the united states, it is estimated that 43% of individuals aged 65–85 years on medicare undergo either thoracic or abdominal computed tomography (ct) in a 5-year period, and for every 1000 ct scans performed there are 4 additional nephrectomies[8]. additionally, 2 studies have shown a statistically significant increase in the number of renal cancers detected among newly insured patients secondary to widening access to care through expansion of healthcare insurance[9,10]. incidental detection has also contributed to a stage shift (i.e., detection of disease at an earlier stage), which was noted until the mid-2000s and has subsequently stabilized[11–13]. clinical stage i tumors accounted for 43% of all kidney cancers diagnosed in 1993; the percentage increased to 57% in 2004[11] and leveled off around 70% after 2007, although the size of localized tumors continued to decline[12]. overall, between 1993 and 2004, 50.6%, 26.7%, and 22.7% of kidney cancer patients were diagnosed with stage i, stage ii or iii, and stage iv, respectively[11]. in contrast, between 2004 and 2015, 70.3%, 10.5%, 8.3%, and 11.0% of patients were diagnosed with stage i (including 47.5% stage ia and 22.8% stage ib), stage ii, stage iii, and stage iv, respectively, highlighting a significant increase of stage i as well as a decrease of stage iv rcc[12]. mortality the crude mortality rate of kidney cancer was 13th in men and 14th in women (table 1; figure 2)[1]. europe has the highest age-standardized mortality rate, followed by northern america/oceania, latin america and the caribbean, asia, and africa (figure 2). the agestandardized rate and the cumulative risk for kidney cancer death have been stabilizing in many countries, and have declined particularly in europe and northern america during the past one to 2 decades in both sexes[2,14]. survival outcomes of rcc depend largely on the stage at diagnosis. the most recent report based on the national cancer database in the united states showed that the 5-year survival rate was 93%, 70%, and 13% in patients with localized, regional, and distant rcc, respectively[15]. in this report, the mortality data were collected by the national center for health statistics[15]. similar survival outcomes were also observed in the united kingdom; 5-year survival was 87% in stage i compared to 12% in stage iv rcc[16]. the decline in kidney cancer mortality may, therefore, be related to earlier diagnosis, as well as improved treatment strategies and recent advances in systemic therapy[12,17]. population screening rationale for screening the relatively large proportion of patients with rcc who are diagnosed at a late, advanced, or metastatic stage due to the absence of symptoms and the poor survival in this group are the main drivers for the need to improve the early detection of rcc. initiatives to raise public awareness of hematuria have not been successful in improving detection of rcc[18], suggesting that a more systematic identification approach may be necessary. screening for rcc has the potential to improve survival outcomes by enabling earlier diagnosis and treatment[19,20]. no randomized controlled trials (rcts) of screening for rcc have been performed and due to insufficient evidence, international urology and oncology associations have yet to publish guidelines on this topic[21–27]. screening and early detection of rcc have been identified as a key research priority in 3 independent priority-setting initiatives[28–31], and patient groups have been vocal in their desire to champion this agenda[32]. the “sojourn time,” also known as the “preclinical period,” refers to the length of time during which an individual with rcc has not yet received a diagnosis, and would therefore benefit from early detection via screening. cancers with very short or very long sojourn times are not ideal screening candidates. imaging studies have suggested the sojourn time for rcc is between 3.7 and 5.8 years[33]. scelo et al. demonstrated raised kidney injury molecule-1 (kim-1) plasma levels up to 5 years prior to rcc abbreviations aaa abdominal aortic aneurysm asr age-standardized rate auc area under the curve bmi body mass index ccrcc clear cell renal cell carcinoma chrcc chromophobe renal cell carcinoma ct computed tomography ctdna circulating tumor dna kim-1 kidney injury molecule-1 nv nonvisible rcc renal cell carcinoma rct randomized controlled trial srms small renal masses 372 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org table 1. age-standardized rate and cumulative risk of kidney cancer incidence and mortality (globocan 2020 report)[1] incidence mortality asr, per 100 000a cumulative risk, %b asr, per 100 000a cumulative risk, %b worldwide male 6.1 1.45 2.5 0.81 female 3.2 0.76 1.2 0.39 both sexes 4.6 1.06 1.8 0.57 europe male 13.1 2.78 4.5 1.41 female 6.4 1.36 1.7 0.58 both sexes 9.5 1.96 2.9 0.91 northern america male 16.1 3.23 3.0 0.95 female 8.6 1.69 1.3 0.45 both sexes 12.2 2.39 2.1 0.67 latin america and the caribbean male 6.3 1.37 2.8 0.79 female 3.3 0.74 1.3 0.37 both sexes 4.7 1.02 2.0 0.55 oceania male 12.4 2.83 3.0 1.05 female 5.4 1.27 1.3 0.51 both sexes 8.8 2.00 2.1 0.75 asia male 3.8 0.89 2.0 0.61 female 1.9 0.45 0.90 0.30 both sexes 2.8 0.65 1.4 0.44 africa male 2.1 0.48 1.4 0.43 female 1.5 0.24 0.98 0.21 both sexes 1.8 0.34 1.2 0.30 asr: age-standardized rate. athe age-standardized rate (asr) was adjusted to the world standard population. bthe cumulative risk was the probability of kidney cancer development or death in a lifetime defined as 0–74 years. source: reprinted from globocan 2020 report, global cancer observatory, cancer today. ferlay j, ervik m, lam f, et al., eds. age-standardized rate and cumulative risk of kidney cancer incidence and mortality. world health organization, international agency for research on cancer, copyright 2022 [1]. 373siuj.org siuj • volume 3, number 6 • november 2022 kidney cancer screening and epidemiology http://siuj.org figure 1. age-standardized rate of kidney cancer incidence figure 2. age-standardized rate of kidney cancer mortality source: reprinted from globocan 2020 report, global cancer observatory, cancer today. ferlay j, ervik m, lam f, et al., eds. age-standardized rate of kidney cancer incidence. world health organization, international agency for research on cancer, copyright 2022[1]. source: reprinted from globocan 2020 report, global cancer observatory, cancer today. ferlay j, ervik m, lam f, et al., eds. age-standardized rate of kidney cancer incidence. world health organization, international agency for research on cancer, copyright 2022[1]. 374 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org table 2. modifiable and nonmodifiable risk factors for rcc risk factor relative risks (rrs) and comments modifiable factors smoking established risk factor for rcc[34–37] rr 1.31 (95% ci, 1.22–1.40) for smokers versus nonsmokers[34] obesity established risk factor for rcc[35,37–39] rr 1.77 (95% ci, 1.68–1.87) for obesity (bmi ≥ 30) versus a normal bmi[39] hypertension established risk factor for rcc[37] rr 1.70 (95% ci, 1.30–2.22) for patients with hypertension vs. those without hypertension[37] meta-analysis reported 67% increased risk in patients with hypertension[40] diabetes controversial whether diabetes is an independent risk factor for rcc due to potential confounders (smoking, obesity, and hypertension)[7,41] diet meat: potential risk factor for rcc; may be partially related to the carcinogens formed in the cooking process[42,43] fruit and vegetables: may be protective (particularly for cruciferous vegetables)[44,45] alcohol: may be protective; an inverse relationship between moderate alcohol intake (< 60 g/day) and rcc risk is reported[46,47] occupation trichloroethylene: may modestly increase the risks of several cancers including rcc[48–50]. toxicity is officially acknowledged by the environmental protection agency in the united states drug exposure acetaminophen and nsaids other than aspirin: significantly associated with an increased incidence of kidney cancer[51] aspirin: no increase in rcc incidence[51] nonmodifiable factors age rcc incidence increases with age[14] global crude incidence, per 100 000 = 4.3 in 40–49 years, 10.8 in 50–59 years, 20.3 in 60–69 years, and 29.6 in 70–79 years[1] sex rcc incidence shows 2:1 male predominance across the world[1] (table 1) may be related to various confounders including modifiable risk factors of rcc (smoking, obesity, or hypertension) as well as intrinsic biological variances race racial disparities between black and caucasian has been highlighted asrs of kidney cancer incidence in black vs. white individuals, per 100 000 = 16.4 vs. 13.5 in males and 8.1 vs. 7.0 in females[2] asrs of kidney cancer incidence in black vs. white individuals, per 100 000 = 16.4 vs. 13.5 in males and 8.1 vs. 7.0 in females[2] family history rr 2.2-fold when patients have rcc history in any-degree relatives[52] rr 4.3-fold when patients have rcc history in first-degree relatives[52] asr: age-standardized rate; bmi: body mass index; ci: confidence interval; nsaid: nonsteroidal anti-inflammatory drug; rcc: renal cell carcinoma. 375siuj.org siuj • volume 3, number 6 • november 2022 kidney cancer screening and epidemiology http://siuj.org diagnosis[53], which is in keeping with the estimated sojourn time. taken together, these studies suggest that there is a length of time during which asymptomatic patients might benefit from screening interventions. any screening program for rcc, however, must be evaluated with the wilson and jungner criteria in mind[54], to minimize risks to the general population while maximizing benefits for individuals. the wilson and jungner criteria serve as guiding principles and a framework to evaluate potential screening programs and assess their utility and feasibility within the existing health service[54]. screening modality a successful screening strategy relies on a screening tool that is accurate, reliable, acceptable to the public, and scalable (i.e., can be rolled out on a population level by the existing health service). a number of screening approaches have been considered, each with advantages and disadvantages, although the ideal screening tool has yet to be identified. urinary tests urinary tests represent an ideal tool due to their noninvasive nature, ease of collection and storage, and acceptability by the general public[55]. this strategy could involve either a point-of-care test (such as dipstick for hematuria) or laboratory test (urinary biomarkers). dipstick tests are cheap, readily available, and require minimal training; however, color changes may be open to subjective interpretation. nonvisible (nv) hematuria is defined as blood in the urine detected by urinary dipstick or microscopy, which is not visible to the naked eye (as opposed to visible hematuria, which is macroscopic)[63]. the main concerns are the nonspecific nature of nv hematuria for rcc, the high number of incidental findings, and the unacceptably high rate of false positives and false negatives[20,64]. therefore, screening for rcc based around dipstick-detected nv hematuria is not currently recommended (though there may be benefits for bladder cancer detection)[65]. the vast majority of patients diagnosed with rcc will not have hematuria, meaning there would be a large number of false negatives. the prevalence of hematuria in rcc is 35% (prevalence 17.5% visible and 17.5% nonvisible hematuria), compared to 94% in bladder and ureter urothelial cancers[66]. the prevalence of nv hematuria may be as high as 20% to 30% in the general population[64,67]; however, < 1% of individuals with nv hematuria are found to have rcc and 5% are found to have bladder cancer[63]. conversely, urinary dipstick may identify a large number of nonmalignant urological diseases that are associated with nv hematuria (including renal stones, cysts, etc.) as well as medical diseases associated with proteinuria or glycosuria (renal disease, diabetes, infection, etc). the high volume of individuals requiring further investigation and the high number of incidental findings preclude this as a costeffective screening strategy for rcc. urinar y biomarkers would represent the ideal screening tool; however, to date none are validated or approved for use in clinical practice[68]. a number of different analytes have been considered, including urinary proteins, cell-free tumor dna, micrornas, and exosomes. perhaps the most well-studied group is urinary proteins, including aquaporin-1, perilipin-2, carbonic anhydrase-9, raf-kinase inhibitory protein, nuclear matrix protein-22, 14–3–3 protein β/α, and neutrophil gelatinase-associated lipocalin[68]. aquaporin-1 and perilipin-2 have been evaluated in a prospective study of 720 patients undergoing screening ct, 80 healthy controls, and 19 patients with rcc. in this cohort, these 2 biomarkers used in combination achieved an area under the curve (auc) of > 0.99 for rcc[69]. although these 2 proteins may be good markers for clear cell renal cell carcinoma (ccrcc) and papillary renal cell carcinoma (prcc), levels are low or negative in chromophobe renal cell carcinoma (chrcc), meaning that screening would miss these cancers[19]. further prospective validation in an independent cohort is warranted. blood tests blood-based tests represent anot her potentia l ly useful option due their relative public acceptability and presumed relatively low cost. analytes similar to those identified in urine may be used, such as proteins, circulating tumor dna (ctdna), micrornas, and exosomes. kim-1 is a glycoprotein that reflects injury to the proximal convoluted tubule of the kidney (from which ccrcc and prcc are derived). kim-1 blood levels may be elevated 5 years prior to a diagnosis of rcc[53]. one of the main disadvantages is the low specificity of kim-1 (levels may be elevated in kidney injury). furthermore, kim-1 levels are not elevated in patients with renal tumors derived from the distal nephron (e.g., chrcc and collecting duct rcc), limiting applicability as a screening tool. cancer screening using ctdna has recently received significant media attention and has entered large-scale validation studies[70–72]. a number of studies have been published evaluating ctdna for the simultaneous detection of multiple cancer subtypes with the aim of pan-cancer screening[70,73–75]. although initial reports evaluating mutations[76] and methylation patterns[74] in ctdna suggested that patients with rcc may have lower levels of ctdna than those with other malignancies, more recent reports evaluating dna methylation appear more promising[77]. nuzzo et al.[77] evaluated ctdna methylation using cell-free methylated dna immunoprecipitation and high-throughput sequencing (cfmedip–seq) in a case-control study. the 376 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org study cohort included 99 ctdna samples from patients with rcc (of which 33% were from patients with stage i–ii disease), 21 samples from patients with stage iv bladder cancer, and 28 healthy controls. the overall auc for the detection of rcc was 0.99, suggesting ctdna may be detected in patients with rcc across the spectrum of disease severity, raising the possibility that in future this could potentially be used to enable earlier disease detection. unfortunately, thus far, neither urinenor bloodbased biomarkers have achieved sufficient sensitivity and specificity required for implementation in clinical practice. further research on minimally invasive biomarkers as a screening tool, in prospective cohorts, is warranted. ultrasound ultrasound is perhaps the most well-studied screening method for rcc, with a number of observational studies published in the 1990s and early 2000s[78–85]. the main drawback is that accuracy is dependent on operator experience, anatomical factors (including obesity and overlying bowel gas), and lesion size. there is a potential for false negatives, as ultrasound can detect 85% to 100% tumors > 3 cm in size, but only 67% to 82% of tumors of 2–3 cm in size[86,87]. advantages of ultrasound include the relative acceptability by the general public, as it is pain-free and noninvasive (compared to blood tests). ultrasound is widely available, does not involve ionizing radiation, and is relatively inexpensive compared to ct. furthermore, focused renal ultrasound may be performed, imaging the kidneys alone rather than the entire abdomen, therefore reducing the time and cost of the scan and avoiding incidental detection of indeterminate lesions in other abdominal organs, which may require additional investigation with associated costs. another potential advantage is the opportunity to combine screening for renal cancer with the existing abdominal aortic aneurysm (aaa) screening program, currently underway in a number of countries[88–90]. a combined approach would reduce the overall cost of the screening intervention and maximize cost-effectiveness, although currently aaa is only recommended for men and not women. to the best of our knowledge, malaeb et al.[85] is the first and only study to explore the combined screening of rcc and aaa, demonstrating this is a feasible approach that is well tolerated by patients. although this study is promising, none of the ultrasound studies were randomized in nature, meaning the impact of the intervention on survival remains unknown. computed tomography use of ct has increased in recent decades due to technological advances (enabling increased resolution, reduced scanning times, and lower radiation dose), increasing availabilit y and reducing costs[8,91]. contrast-enhanced ct is the gold-standard diagnostic imaging technique to evaluate small renal masses in patients with suspected rcc (e.g., if a mass is identified on ultrasound or there is visible hematuria). contrast uptake can enable the differentiation between benign and malignant disease, and visualization of tumor and vessel anatomy that can guide operative management approaches. however, the utility of contrast-enhanced ct as a screening tool in the general population is limited by the use of contrast (which may be nephrotoxic), the relatively high radiation dose, and cost, particularly given the low prevalence of rcc. however, low-dose unenhanced ct has the advantage of providing less radiation dose and no contrast. whole-body ct has been proposed as a potential screening tool for the combined detection of multiple malignant and nonmalignant diseases (e.g., abdominal cancers, aaa, etc.). although a number of studies have been performed, the main drawback of performing whole-body scans is the high number of incidental findings, false positives, and findings of unknown clinical potential. for example, millor et al.[92] reviewed 6516 whole-body screening cts (which included unenhanced chest ct, enhanced abdominal ct, cardiovascular, and bone assessments). fewer than 2% of individuals had normal scans, meaning that > 98% had to undergo further investigations with significant costs, burden to the health service, and anxiety for the individual. only 1.5% of individuals were found to have a malignancy (35 of 96 were rcc). as a result, whole-body ct to screen for kidney cancer as a standalone test in an unselected population is unlikely to be a cost-effective strategy at present[93], though in future automated interpretation of imaging features using machine learning may increase the accuracy and feasibility of this strategy[95]. an alternative approach is to add low-dose noncontrast abdominal ct scans to the low-dose unenhanced chest ct scans currently being investigated for lung cancer screening. the yorkshire kidney screening trial (nct05005195), currently underway, is a novel study and the first to evaluate the added benefit of screening for rcc by extending the low-dose chest ct to image the kidneys in 55–80-year-old smokers and ex-smokers undergoing lung cancer screening enrolled in the yorkshire lung screening trial[95]. it is postulated that combined lung and kidney cancer screening may maximize cancer detection rates while reducing costs. screening population the ideal population to whom screening for rcc should be offered is unknown. meta-analyses have estimated that screening 1000 individuals using ultrasound would identify between 1 and 2 patients with rcc[78], while using ct would identify between 1 and 3 (the pooled 377siuj.org siuj • volume 3, number 6 • november 2022 kidney cancer screening and epidemiology http://siuj.org prevalence of rcc is 0.17% (95% ci 0.09–0.27%) and 0.21% (95% ci, 0.14–0.28%) in ultrasound and ct respectively)[33,78]. one of the main challenges is the relatively low prevalence of rcc. indeed, a health economic analysis of screening for rcc using ultrasound identified prevalence of rcc as the greatest determinant of cost-effectiveness[96]. risk-stratified screening may enable more efficient identification of rcc, focusing on high-risk individuals and therefore maximizing benefits while reducing costs and harms for those at low risk. a systematic review of risk-prediction models for rcc[97] identified 11 models that report performance measures and could potentially be used. fewer than 20% (2 of 11) had been validated in an external population, highlighting one of the limitations of current models. the most commonly included factors were sex, age, smoking status, body mass index (bmi), and hypertension, which is consistent with the known data on risk factors for rcc. however, none of these risk factors are specific for rcc. only one study considered genetic risk (i.e., single-nucleotide polymorphisms) and biomarker studies were characterized by a high risk of bias. the models identified in the systematic review were externally validated in > 450 000 participants within the uk biobank cohort[98]. five models had reasonable calibration and discrimination, with an area under the receiver operating characteristic curve between 0.61 and 0.72. all the models performed less well in women, compared to men. additionally, although the models were better at identifying individuals at high risk for rcc than age and sex alone, the improvement was small. risk-prediction models for rcc based on genetic factors performed poorly compared to the best genetic risk models for other cancers, suggesting more research on this topic is needed[99]. future incorporation of biomarkers into risk scores could improve performance. screening implementation and public acceptability if screening is demonstrated to improve disease-specific survival, it is crucial to consider implementation within the existing healthcare delivery system. the cost of screening is not limited to the intervention itself, but includes the associated costs of investigating incidental findings and the cost of treatment of diagnosed conditions. the cost-effectiveness of any screening intervention needs to be demonstrated prior to the screening program being accepted into clinical practice. other important considerations are in regard to program delivery, including optimal screening location (e.g., primary care, secondary care, screening vans in public spaces), training an adequate workforce to deliver screening (e.g., ultrasound delivered by technicians vs. sonographers), and quality control (e.g., audit for laboratories undertaking biomarker work or facilities offering imaging). public acceptability of the program will also be key to ensure high attendance rates. a survey has shown that members of the general public would be “very likely” or “likely” to undergo each of the following screening tests: urine test, 94%; blood test, 90%; ultrasound, 90%; low-dose ct, 79%; and low-dose ct offered as part of lung screening, 95%[55]. in addition, 83% reported that tailoring the starting age of rcc screening based on a risk score incorporating phenotypic or genetic risk was acceptable, and 85% reported they would be more likely to attend screening if the risk score suggested they were high risk[100]. the high anticipated intention to attend screening and positive attitudes toward risk-stratified screening are promising. unknown benefits and harms although screening could have many potential benefits, there are still many unknowns that require further research (table 3). importantly, it is unclear whether screening would lead to increased rcc diagnoses (including a stage shift) in view of the high rates of incidental detection. crucially, it is unknown whether screening leads to a survival benefit. another main challenge relates to increased detection of small renal masses (srms, defined as < 4 cm in diameter), which are difficult to characterize and therefore may lead to false positives or overdiagnosis of indolent lesions (table 4). ultimately, being able to clearly determine which srms require further investigation or treatment and developing pathways for the management of patients with srms based on competing risks are essential before any rcc population-based screening program can be implemented. as screening is offered to a large number of asymptomatic individuals in order to detect only a small number of cancers, it is crucial to understand any quality of life (qol) detriment associated with screening itself. none of the observational studies evaluating ultrasound screening for rcc assessed the impact on qol[19]. there are a number of ways in which screening can cause harm (table 4)[101–103]. these include physical harm, resulting from both the screening test and/ or follow-up procedures; psychological harm, including increases in anxiety; treatment burden, including from subsequent invasive procedures and overdiagnosis; financial costs associated with travel and time off work to attend appointments and potential loss of earnings; social harm, resulting from social stigma or missing out on other activities; and dissatisfaction with health care. 378 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org future directions in summary, the incidence of rcc has risen worldwide over the past few decades, and this has been associated with a stage shift. survival outcomes of rcc depend largely on the stage at diagnosis. although overall mortality has stabilized or declined in most countries, survival remains poor in late-stage disease, meaning that early detection could improve overall survival outcomes. a number of potential candidate screening tools are currently being investigated, though it may be that a combination of these approaches may be optimal. ultimately, the sensitivity and specificity of the chosen screening tool will determine the rate of false positives and false negatives, which must be minimized. one of the key challenges is the relatively low prevalence of the disease, which might be overcome by performing risk-stratified screening or screening for more than one condition (such as combined lung and kidney cancer screening). both approaches have been shown to be acceptable to the general public, and they may maximize the efficiency of screening while reducing harms. whether screening for rcc will lead to a stage shift and the impact on survival are the decisive missing pieces of information that will determine whether the screening program might be adopted into clinical practice (along with feasibility, acceptability, and cost-effectiveness). table 3. research questions that remain to be addressed unknowns comments, challenges, and future direction the ideal screening modality is unknown. • ideally a two-step approach would be adopted (such as for colorectal cancer screening), where an initial noninvasive test (e.g., urinary test) would be followed by a second, more advanced test (e.g., imaging). the ideal screening population is unknown. • the main challenge is the low prevalence of rcc, meaning that a large number of healthy individuals would have to be screened to identify only a small number of cases. • risk-prediction models may identify individuals at high risk, therefore maximizing costeffectiveness. however, existing models have a relatively low accuracy and are based on nonspecific risk factors. unknown whether screening for kidney cancer will translate into a survival benefit beyond length and lead time bias. • no randomized controlled trials (rcts) have been performed to date. • ultimately, an rct would be needed to demonstrate a survival benefit; however, due to the low prevalence of rcc, this would necessitate hundreds of thousands of participants with longterm follow-up, which is prohibitive. unknown whether screening will lead to increased detection and a stage shift (i.e., earlier detection) given high volume of abdominal imaging for other complaints and widespread incidental detection. • it is estimated that 43% of individuals aged 65–85 years on medicare in the united states undergo either a ct chest or ct abdomen over a 5-year period[8], meaning that it is unclear whether these individuals may benefit from further screening. unclear when to start screening and how often to screen. • no premalignant lesion has been identified for rcc. • thus far, studies have evaluated screening for rcc at a single time point rather than regular intervals[19]. potential harms of screening and the impact on quality of life have not yet been fully quantified. • see table 4. unclear whether screening could be implemented in the current health service. • once the screening modality has been selected, further data will be needed on costeffectiveness (based on a trial), feasibility, public acceptability, and potential uptake. adapted from rossi sh, t. klatte j, usher-smith j, stewart gd. epidemiology and screening for renal cancer. world j urol.2018;36(9):1341–1353. doi:10.1007/s00345-018-2286-7, under the creative commons license. 379siuj.org siuj • volume 3, number 6 • november 2022 kidney cancer screening and epidemiology http://siuj.org table 4. potential harms of screening for rcc the following potential harms may depend on the screening modality that is ultimately chosen potential harms comment false negatives • false negatives are associated with real harms and anxiety to the individual. • may erode public trust in the screening program and negatively affect attendance if the test is perceived to be inaccurate. false positives • unfortunately, it is not possible to accurately differentiate benign from malignant srms using contrastenhanced ct, the gold standard imaging investigation[97,98]. • renal biopsy is often under-utilised due to inadequate service provision, lack of expertise or low perceived clinical benefit. biopsy is non-diagnostic in ~10% of cases[99] and it can be particularly difficult to distinguish oncocytoma from eosinophilic variants of chrcc and ccrcc. • a meta-analysis demonstrated approximately 25% of renal biopsies reported as oncocytoma are found to be malignant following excision[100]. erring on the side of caution, patients with srm are often offered surgery and as a result, approximately 20%-30% are found to have benign disease post-operatively, meaning they underwent unnecessary surgery, with associated morbidity and potential long-term effects on renal function[101,102]. overdiagnosis and overtreatment of renal tumors that would not affect survival • it is not possible to distinguish aggressive from indolent srms, meaning that screening could identify a large number of individuals with srms who would not benefit from treatment. • increasing the use of active surveillance (which has been shown to be noninferior to primary intervention) especially in patients with comorbidities who may have a limited life expectancy, could reduce overtreatment[62]. • recently, a growing number of observational studies are being performed that are increasing our understanding of the natural history of disease[62]. incidental findings • high cost of further investigations. • may have indeterminate clinical potential and result in increased patient anxiety. • however, imaging-based screening may identify additional conditions (such as other abdominal cancers or aaa) that could benefit patients. anxiety and worry • resulting from both the screening test and/or follow-up procedures. aaa: abdominal aortic aneurysm; ccrcc: clear cell renal cell carcinoma; chrcc; chromophobe renal cell carcinoma; ct: computed tomography; srms: small renal masses. 380 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org references 1. ferlay j, colombet m, soerjomataram i, parkin dm, piñeros m, znaor a, et al. global cancer observatory, cancer today. international agency for research on cancer.2020. available at https://gco.iarc. fr/today. accessed september 22, 2022. 2. ervik m, lam f, laversanne m, ferlay j, bray f. global cancer observatory, cancer over time. international agency for research on cancer.2020. available at: 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randomised controlled trial to evaluate invitation to community-based low-dose ct screening for lung cancer versus usual care in a targeted population at risk. bmj open.2020;10(9):e037075. doi: 10.1136/ bmjopen-2020-037075 96. rossi sh, klatte t, usher-smith ja, fife k, welsh sj, dabestani s, et al. a decision analysis evaluating screening for kidney cancer using focused renal ultrasound. eur urol focus.2021 mar;7(2):407-419. doi: 10.1016/j.euf.2019.09.002. epub 2019 sep 14. 97. harrison h, thompson re, lin z, rossi sh, stewart gd, griffin sj, et al. risk prediction models for kidney cancer: a systematic review. eur urol focus.2021 nov;7(6):1380-1390. doi: 10.1016/j.euf.2020.06.024. epub 2020 jul 14 98. harrison h, pennells l, wood a, rossi sh, stewart gd, griffin sj, et al. validation and public health modelling of risk prediction models for kidney cancer using the uk biobank. bju int.2022 apr;129(4):498-511. doi: 10.1111/bju.15598. epub 2021 oct 7. 384 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/abdominal-aortic-aneurysm-screening https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/abdominal-aortic-aneurysm-screening https://www.nhs.uk/conditions/abdominal-aortic-aneurysm-screening/ https://www.nhs.uk/conditions/abdominal-aortic-aneurysm-screening/ http://siuj.org 99. harrison h, li n, saunders cl, rossi sh, dennis j, griffin sj, et al. the current state of genetic risk models for the development of kidney cancer: a review and validation. bju int.2022 apr 22. doi: 10.1111/ bju.15752. online ahead of print. 100. usher-smith ja, harvey-kelly llw, rossi sh, harrison h, griffin sj, stewart gd. acceptability and potential impact on uptake of using different risk stratification approaches to determine eligibility for screening: a population-based sur vey. health expect.2021 apr;24(2):341-351. doi: 10.1111/hex.13175. epub 2020 dec 2. 101. heleno b, thomsen mf, rodrigues ds, jorgensen kj, brodersen j. quantification of harms in cancer screening trials: literature review. bmj.2013;347:f5334. doi: https://doi.org/10.1136/bmj.f5334 102. harris rp, sheridan sl, lewis cl, barclay c, vu mb, kistler ce, et al. the harms of screening: a proposed taxonomy and application to lung cancer screening. jama intern med.2014 feb 1;174(2):281-5. doi: 10.1001/jamainternmed.2013.12745 103. korenstein d, chimonas s, barrow b, keyhani s, troy a, lipitzsnyderman a. development of a conceptual map of negative consequences for patients of overuse of medical tests and treatments. jama intern med. 2018;178(10):1401-1407. doi: 10.1001/ jamainternmed.2018.3573jamainternmed.2018.3573 385siuj.org siuj • volume 3, number 6 • november 2022 kidney cancer screening and epidemiology http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information renal cell carcinoma, stereotactic ablative radiotherapy, thermal ablation, microwave ablation, stereotactic ablative radiotherapy, sabr, radiofrequency ablation, rfa none declared. received on august 1, 2022 accepted on august 27, 2022 this article has been peer reviewed. soc int urol j. 2022;3(6):437–449 doi: 10.48083/ueml5802 2022 wuof/siu international consultation on urological diseases: ablative therapies for localized primary renal cell carcinoma muhammad ali, 1,2 vanessa acosta ruiz,3 sarah p. psutka,4 david liu,5,6,7 shankar siva,1,2 1 department of radiation oncology, peter maccallum cancer centre, melbourne, australia 2 sir peter maccallum department of oncology, university of melbourne, melbourne, australia 3 department of surgical sciences, radiology, uppsala, sweden 4 department of urology, university of washington, seattle cancer care alliance, washington, united states 5 department of radiology, faculty of medicine, university of british columbia, vancouver, canada 6 school of biomedical engineering, faculty of applied sciences, university of british columbia, vancouver, canada 7 department of interventional radiology, miller school of medicine, university of miami, miami, united states abstract surgery with either partial or radical nephrectomy remains the standard of care for localized primary renal cell carcinoma (rcc). however, most rccs are detected in an older age group, and some may have multiple comorbidities that preclude surgery. thermal ablation (ta) with radiofrequency ablation (rfa), cryoablation (ca), or microwave ablation (mwa) is considered an alternative to extirpative surgical procedures for select patients with small renal tumors. there is more than 90% post-ablation local control in carefully selected patients with reported complication rates of less than 10%. most thermal ablation require only a single procedure. more recently, stereotactic ablative body radiotherapy (sabr) has emerged as an attractive noninvasive treatment modality for elderly patients with comorbidities and localized rcc. it has shown more than 90% local control rates for both small and relatively larger tumors (> 4 cm). modest post-sabr renal function decline has been observed. despite most patients presenting with mild or moderate chronic kidney disease there is less than a 5% chance of progression to end-stage renal disease. this article aims to summarize the key evidence and ablative treatment’s optimal patient selection, efficacy, and toxicity. introduction surgery is the standard of care for primary localized renal cell carcinoma (rcc); however, many patients in this population have comorbidities that render them at high risk for complications from both anesthesia and surgery. moreover, partial (pn) or radical nephrectomy (rn) is associated with a potential risk for long-term impairment of renal function and chronic kidney disease (ckd)[1–3]. in patients where surgery is contraindicated, active surveillance (as) is commonly used, particularly in patients with multiple comorbidities, tumor size of less than 2 cm, and tumor growth kinetics of less than 5 mm/year[4]. for patients with small renal masses (srms) who are not considered good candidates for surgery or have declined surgery and are not candidate for as, thermal ablation (ta) has been endorsed by multiple international guidelines as a safe and effective alternative[5,6]. more recently, stereotactic ablative radiotherapy (sabr), a form of hypofractionated radiation, has emerged as an alternative noninvasive treatment option for patients who are not suitable for surgery. the european society of medical oncology (esmo) guidelines have endorsed sabr as a treatment option for patients considered unsuitable or who have declined other treatment options[6]. the 2022 national comprehensive cancer network (nccn) version 1.0 kidney cancer guidelines state, “sabr may be considered for medically inoperable patients with stage i kidney cancer (category 2b) [and patients] with stage ii/iii kidney cancer (category 3)”[7]. 437siuj.org siuj • volume 3, number 6 • november 2022 2022 wuof/siu international consultation on urological diseases mailto:muhammad.ali%40petermac.org?subject= http://siuj.org the aim of this article is to review the role of ablative therapies (ta/sabr) for localized primary kidney cancer. it will also report and summarize each modality’s optimal patient selection, efficacy, and toxicity. thermal ablation ta refers to the local application of thermal energy to a tumor[8]. when ta is applied to a renal tumor, the thermal energy is delivered directly into the tumor via an antenna or probe inserted through an imageguided percutaneous approach or surgically via an open or laparoscopic approach. renal tumors can be ablated via application of extreme heat (radiofrequency [rfa], microwave [mwa]) or cooling ablation (ca); the advantages and disadvantages of each system are summarized in table 1. small (t1) localized renal tumors are well suited for ablation because of their rounded shape and relative isolation from temperature-sensitive structures in the retroperitoneum[9]. given the in situ nature of the treatment, evaluation of treatment efficacy relies on continued surveillance via computed tomography (ct) or magnetic resonance imaging (mri). indications and patient selection historically, ta has been reserved for patients who are considered poor surgical candidates due to renal insufficiency or a high burden of comorbid conditions. international guidelines now support consideration of ta in treating patients with a renal tumor of < 3 cm as a primary treatment[10–12]. ta is also considered an effective treatment for patients with a solitary kidney, renal insufficiency, multiple tumors, or hereditary tumors. ablation is the treatment of choice in patients with compromised renal function where dialysis and/or nephrectomy are not desired[10,12]. percutaneous ta has the advantage of avoiding the temporary vascular clamping, which is required during pn[13,14]. also, the sphere-shaped ablation zone can be adjusted to minimize unnecessary damage to the normal renal parenchyma. an appropriate patient selection for ta can generate oncologic outcomes comparable to those of nephron-sparing surgery, with the added benefit of better preservation of renal function[15–18]. technical considerations the effect of ablative therapies varies across tumors. tumor size is one of the most important factors; rfa and mwa have excellent outcomes for masses of < 3 cm. masses measuring 3 to 4 cm or larger may need repeated treatment or multiple probes[19–22]. microwave ablation should theoretically be able to treat larger tumors efficiently given the physics behind the abbreviations as active surveillance ca cooling ablation ckd chronic kidney disease css cancer-specific survival ct computed tomography irock international radiosurgery oncology consortium for kidney mri magnetic resonance imaging mwa microwave ablation pn partial nephrectomy rcc renal cell carcinoma rfa radiofrequency ablation rn radical nephrectomy sabr stereotactic ablative radiotherapy smrs small renal masses ta thermal ablation table 1. advantages and disadvantages between ablative technologies advantages disadvantages rfa • most used system, more studies are available • short treatment time (12–30 min ablation time) • treatment of maximum 3 cm tumors • more affected by heat sink effect • rf current may be redirected to high electrolyte content of urine mwa • achieves larger ablation zones than rfa • quicker than rfa (5–8 min ablation time) • less affected by heat sink effect • newer system; needs further validation but principles of thermal coagulation same as rfa • more painful than rfa ca • can treat larger tumors (> 4 cm) • can treat central tumors • real-time monitoring of ice ball (however not reflective of the zone of cell death) • requires several probes; increased risk for postprocedural hemorrhage • argon (and possibly helium) canister required • time-consuming (30–40 min ablation time) ca: cooling ablation; mwa: microwave ablation; rfa: radiofrequency ablation. 438 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org larger active heating zone. although t1b tumors have been treated with secondary efficacy rates of up to 95%, current reports are limited by small samples (the largest series included 56 patients)[23–25]. high-output centers have reported good tumor control with single-session treatment for larger tumors using ca[26,27]. however, the upper size limit at which complete ablation can be expected remains to be defined. moreover, larger tumors also have an increased risk for hemorrhage with ta modalities. centrally located tumors are at increased risk for treatment failure as proximity to the larger hilar vessels washes out the extreme temperature gradients generated during ablation procedures, which is necessary for cell death[19,28]. ca appears to provide better oncologic outcomes for centrally located tumors than rfa[29,30]. rfa for central tumors is associated with low rate of complications but with severe sequelae, such as ureteropelvic junction obstruction, urinoma, and proximal ureteral stricture[31,32]. the early reports of ca appear to show that ca safe, with fewer complications than those reported with rfa[30,33]. the insulative properties of the surrounding retroperitoneal fat and the greater distance to large hilar vessels render exophytic tumors easier to ablate in a single session[19,20]. endophytic tumors are surrounded by renal parenchyma, through which temperature gradients may dissipate more rapidly, resulting in increased risk for treatment failure[34,35]. hydrodissection via saline instillation and intentional patient positioning can increase the distance between adjacent structures and the tumor target[34] (figure 1). retrograde pyeloperfusion can be similarly used to protect the ureter and ureteropelvic junction from thermal injury, with resultant risk for perforation, urine leak, and/or subsequent stricture[34]. renal tumor scoring systems can aid preprocedural planning and tumor selection[36,37]. a 43-year-old woman with prior history of von hippel-lindau syndrome and polycystic kidneys was treated for a 2.6-cm exophytic tumor in the lower pole of the left kidney. on the day of the procedure, the tumor (arrow) is seen in contact with the psoas muscle when the patient is examined in the prone position (a). two mwa probes are inserted in the tumor (blue arrows) and through a spinal needle (yellow arrow) (b), carbon dioxide (c, arrow) is insufflated, and the tumor is displaced from the psoas muscle (c, d). figure 1. example of a patient requiring tissue displacement prior to ablation a b c d 439siuj.org siuj • volume 3, number 6 • november 2022 ablative therapies for localized primary renal cell carcinoma http://siuj.org to summarize, a small (< 3 cm) exophytic tumor, with a minimum of 1 cm distance from the adjacent anatomic structures represents ideal morphologic characteristics for tumor ablation. preprocedural planning before ta, patient evaluation should include relevant comorbidities, risk factors for rcc, familial history of hereditary rcc syndromes, and blood workup including coagulative profile and renal function[38]. the american urological association/ society of urologic oncology (aua/suo) guidelines recommend renal mass biopsy prior to ta to characterize the tumor histolog y, subsequently informing posttreatment surveillance[10]. percutaneous ablation can be performed under either general anesthesia or conscious sedation. image-guided percutaneous techniques are preferred over laparoscopic approaches due to a lower risk for associated complications, shorter hospitalization and operative times, reduced morbidity, reduced opioid analgesic requirement, and faster recovery time[15,16,39–41]. preprocedural imaging aims to evaluate the feasibility of ablation, access site, the number of probes needed, the tumor’s location relative to other structures, and the need for any ancillary procedures[42,43]. ct is most commonly the modality of choice for both procedural planning and probe placement at the time of treatment. mri can be used but is more expensive and technically demanding. ultrasound alone allows for direct monitoring during probe placement; however, it may be limited in its ability to visualize adjacent structures, and thus is commonly used in combination with ct[43,44]. periand post-procedural complications ta is considered a safe procedure with very few complications (7.4%) compared to surgery (11%)[15]. the incidence of significant complications after ta is lower than following surgery (2.3% vs. 5%)[15,45]. complications during ablation of renal tumors include the following: 1. post-ablation syndrome: a transient and self-limiting constellation of symptoms experienced following ta characterized by fever, nausea, vomiting, and malaise. larger volumes of necrosis may prolong symptoms. fewer than 10% of patients experience the full spectrum of symptoms, while 60% report flu-like symptoms within the first 10 days following ablation[46]. 2. bleeding: most commonly, ta-associated bleeding is minor (6%), while massive hemorrhage requiring transfusion is extremely rare (< 1% of cases) [19,43,47]. some tumors may require pretreatment embolization, most often in the context of highly complex tumors[43,47,48]. 3. hematuria: this is a rare side effect of ta (0.5–1%) that generally spontaneously resolves within 12 to 24 hours of treatment[43]. if hematuria persists, thermal damage to the pelvicalyceal system should table 2. long-term cohort studies of percutaneous thermal ablation of t1 renal tumors author, year of publication study type tumor sizea (cm) no. patients median follow-up (years) lc (%) css dfs andrews et al. (2019)[17] r t1 367 median rfa 1.9 cm ca 2.8 cm 367 rfa 7.5 ca 6.3 rfa 95.9% ca 95.9% rfa 96% ca 100% nr psutka et al. (2012)[18] r t1a 143 t1b 42 median 3 cm 185 6.43 t1a 96.1% t1b 91.9% nr t1a 91.5% t1b 74.5% georgiades et al. (2014)[48] p t1a 115 t1b 19 median 2.8 cm 134 5 97% 100% nr yu et al. (2021)[88] r t1a 275 t1b 48 mean 2.9 cm 323 5.1 t1a 98.1% t1b 88.7% t1a 95.9 % t1b 91.4% t1a 85.2% t1b 69.1% amedian or mean. ca: cooling ablation; css: cancer-specific survival; dfs: disease-free survival; lc: local control; nr: not reported; p: prospective; r: retrospective; rfa: radiofrequency ablation. 440 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org be suspected. in the case of hydronephrosis due to clot obstruction, placement of a ureteric stent and/or manual irrigation of the bladder may be necessary. 4. ureteric/collecting system injury: this complication is associated with treatment of central tumors. although rare (1%–3% of cases[43]), injury can result in ureteric strictures, urine leak, urinoma, or formation of a urinary fistula[40,43,47], which may present in a delayed fashion (weeks to months following treatment). 5. neuropraxia: nerve injury (1%–3%) can occur following ablation of tumors close to the psoas muscle, or intercostal or lumbar nerves[43]. one study found that nerve injury resolved in 90% of affected patients within 6 months of treatment[47]. other rare complications include bowel perforation[43], infection[43,49], pneumothorax, skin burn or freeze at the site of entry, and tumor seeding along the entry site[9,41,47]. evidence synthesis local tumor control current literature suggests that careful patient and tumor selection can result in the successful ablation of nearly all renal tumors, with low recurrence rates over short and intermediate follow-up. to date, however, ta has not been compared against surgery in a randomized controlled trial. the available (retrospective) data is limited by selection bias, institutional practices, and local expertise, impacting generalizability of ta across centers, providers, and patients. the sum of the comparative efficacy data suggests comparable oncologic and safety outcomes between ta and radical or partial nephrectomy for t1a disease[50]. the largest-cohort studies of the long-term oncologic results following ablation are reported in table 2. comparative studies in a retrospective review of 1424 rcc patients (367 treated with rfa or ca; 1055 with pn), there was no difference in the clinical outcome of t1a disease, with 5-year css of 96%, 100%, and 99% for rfa, ca, and pn, respectively. however, a higher death rate from rcc was observed for ca compared to pn in this subset. for 376 ct1b patients, 5-year css was lower for ca compared to pn (91% vs. 98%, respectively). despite the limitations associated with the retrospective analysis design and risk of selection bias, the authors concluded that any clinically significant difference between ablation and pn of ct1a tumors was unlikely but encouraged further research regarding the oncologic efficacy of ca for ct1b tumors[17]. in a systematic review and meta-analysis of 107 studies, pierorazio et al. compared the effectiveness of as, ta, and rn or pn for t1 tumors. they reported an increased incidence of local recurrence following a single ablation session but no difference when secondary ablations were considered. ta was associated with less perioperative morbidity and complications compared to pn. there was no difference in the css across the different management options[50]. katsanos et al. reported similar findings as well[15]. selection bias is likely to contribute to some of these findings; for example, surgery is often favored for healthier patients and ablation for patients with a high burden of comorbidity or limited projected life expectancy. however, current data suggests that ta can be considered a practical alternate approach to surgery in small t1a tumors, and sometimes for larger tumors in patients unsuitable for or at higher risk from partial nephrectomy. several groups report a significantly lower cost for ablation (up to a third) than for surgery[51–53]. these cost-savings are the short procedure time, outpatient nature, limited ancillary perioperative costs, and lower complication rate[51,52]. theoretically, when considering the occasional need for retreatment post-ta, ta may contribute to additional expense due to further treatments. some data support that radiofrequency ablation is still less expensive than nephron-sparing surgery[54]. however, the authors concluded that future studies are necessary before using the analysis for policy-level decision-making. furthermore, the analysis was limited to short-term cost-effectiveness. stereotactic ablative radiotherapy (sabr) preclinical studies on mouse models with implanted human rcc cell lines and in vitro cell culture indicate that the entrenched dogma of radioresistance of rcc may not be relevant in the era of high doses per fraction, which can be safely delivered with the advent of sabr[55,56]. these reports were reinforced by excellent local control (lc) rates using sabr in patients with extracranial metastatic rcc[57]. since then, multiple retrospectives and prospective phase 1 and 3 studies have demonstrated the feasibility, safety, and efficacy of sabr[58–73]. the results of selected published studies are summarized in table 3. patient selection for sabr current published studies have evaluated the safety and efficacy of sabr in patients with localized rcc who are inoperable, those who refuse surgery, and those with baseline ckd and high risk for renal replacement therapy with pn or rn. sabr has the advantage of being a noninvasive treatment that does not require anesthesia or sedation. therefore, it may be a more suitable option for older and/or more frail patients, 441siuj.org siuj • volume 3, number 6 • november 2022 ablative therapies for localized primary renal cell carcinoma http://siuj.org table 3. summary of selective studies evaluating sabr for the treatment of primary renal cell carcinoma author, year of publication study type tumor sizea (cm) no. patients dose (gy)/ fraction lc (%) median follow-up (mo) grelier et al. (2021)[71] r 4.0 23 35/5–7 96 22 grubb et al. (2021)[68] p 3.7 11 48/3 54/3 60/3 90 34.3 tetar et al.(2020) [69] r 5.6 36 40/5 95.2 16.4 siva et al. ( 2020)[70] r 4.9 95 — 97.1 32.4 correa et al. (2019)[80] ma 4.6 372 — 97.2 28 siva et al. (2017)[61] p 4.8 33 26/1 42/3 100 24 chang et al. (2016)[59] r 4.0 16 30–40/6 100 19 sun et al. (2016)[66] r 3.9 40 21–48/3 92.7 na ponsky et al. (2015)[65] p 57.9 (median tumor volume) 19 24–48/4 no evidence of local progression in 15 evaluable patients 14 staehler et al.(2015)[62] p — 40 25/1 96 28 amedian or mean. cm: centimeter; gy: gray; lc: local control; ma: meta-analyses; mo: months; na: not available; p: prospective; r: retrospective. 442 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org table 4. suggested sabr dose constraints. adapted from irock consensus statement, siva s et al. future oncol. 2016;12(5):637-645[78] organ at risk 1 fraction 3 fractions 5 fractions spinal cord < 1 ml to 8 gy < 0.03 ml to 12 gy < 0.03 ml to 18 gy max 22.2 gy < 0.5 ml to 23 gy < 0.03 ml to 27.5 gy small bowel < 20 ml to 14 gy full circumference < 12.5 gy prv, d0.03 ml < 26 gy < 10 ml to 11.4 gy < 1 ml to 24 gy prv, d0.03 ml < 30 gy < 5 ml to 20 gy max 30 gy stomach < 10 ml to 11 gy < 5 ml to 22.5 gy < 10 ml to 16.5 gy 5 ml to < 22.5 gy max 30 gy < 5 ml to 18 gy max 30 gy large bowel prv, d1.5 ml< 26 gy prv, d1.5 ml < 42 gy 20 ml to < 24 gy max 38 gy < 20 ml to 25 gy chest wall n/a < 700 ml to 30 gy < 70 ml to 37 gy skin max 24 gy < 10 ml to 30 gy < 10 ml to 15 gy < 0.03 ml to 30 gy liver n/a < 700 ml to 15 gy v17 < 66% < 700 ml to 15 gy heart 15 ml to < 16 gy max 27.9 gy < 15 ml to 32 gy max 38 gy contralateral kidney alara alara v10 < 33% alara ipsilateral kidney alara: minimize volume receiving > 50% isodose alara: minimize volume receiving > 50% isodose alara: minimize volume receiving > 50% isodose alara: amount of radiation dose is as low as reasonably achievable; irock: international radiosurgery oncology consortium for kidney; n/a: not applicable; prv: planning organ at risk volume. 443siuj.org siuj • volume 3, number 6 • november 2022 ablative therapies for localized primary renal cell carcinoma http://siuj.org those requiring ongoing anticoagulation, or those with multiple competing comorbidities that would place them at unacceptably high risk from anesthesia, surgery, or ta. furthermore, sabr has the added advantage of having minimal impact on quality of life, which reverted to baseline at subsequent follow-up in a study in older and frail patients[74]. the treatment options are limited for patients with tumors measuring ≥4 cm in maximal diameter, who are not surgical candidates. ta is not suitable for patients with t1b rcc due to the increased risk for local recurrence and complications[5,6]. in this subset of patients with t1b disease, sabr has shown excellent outcomes and can be an attractive approach[69,70]. treatment of rcc in a patient with a solitary kidney is a challenging clinical scenario. pn, if feasible, remains the standard of care for renal masses in patients with a solitary kidney. however, ablative treatments are a good alternative for patients where pn is not possible due to tumor location or size. in challenging scenarios with rcc in a single kidney where other nephron-sparing approaches (pn, ta) are not technically or medically feasible, sabr has shown excellent tumor-related outcomes while avoiding the lifelong need for dialysis[58,75]. technical consideration different treatment units are used to deliver sabr to primary rcc[61,62,65,69,73]. irrespective of the treatment system used, respiratory motion management is essential for treatment planning and delivery, due to the motion of kidneys with respiration[76]. the most commonly used technique in linear accelerator-based treatment is the internal target volume (itv) concept, where a thin-cut 4-dimensional ct (4d-ct) is obtained during simulation. respiratory gating or tumor tracking using implanted fiducial markers may be used to allow for a reduction in itv, and this is usually incorporated into the delivery of sabr using cyberknife. a typical linear accelerator-based sabr plan is shown in figure 2. target volumes for sabr are defined as per the international commission on radiation units and measurements report (icru) 91[77], which has been suggested previously by the international radiosurgery oncology consortium for kidney (irock) consensus statement as well[78]. similarly, the irock group recommended organs at risk (oars) with acceptable dose constraints, adapted and summarized in table  4[78]. the irock consensus statement recommended 25–26 gy, 35–45 gy, and 40–50 gy in 1, 3, and 5 fractions, respectively[78]. clinical evidence for sabr in localized primary rcc multiple prospective and retrospective studies have reported encouraging results with sabr in patients with localized rcc. in the largest reported prospective case-control study, staehler et al. treated 40 patients with renal masses who were anticipated to require dialysis if they underwent nephrectomy with a single fraction of 25 gy[62]. after a median follow-up of 28 months, the authors reported an lc of 96%, with a minimal decline in renal function. in a prospective phase 1 trial (fastrack) of 33 patients with a median tumor size of 4.8 cm (range, 2.1–7.9), freedom from local progression, distant progression, and overall survival (os) at 2 years were 100%, 89%, and 92%, respectively[61]. treatmentrelated grade 1–2 toxicities (flank pain, fatigue, nausea, vomiting, diarrhea) occurred in 26 of 33 patients (78%), and grade 3 fatigue occurred in only one patient. while early results of prospective studies are promising, these studies have some inherent limitations: (1) the small number of patients treated, (2) the lack of longterm follow-up, and (3) the varying dose fractionation schemes. in a pooled analysis involving 223 patients with a mean tumor size of 4.4 cm, the irock group reported lc, cancer-specific survival (css), and progression-free figure 2. axial (left), coronal (middle), and sagittal sections (right) showing highly conformal radiation dose distribution with a typical sabr plan 444 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org survival (pfs) rates of 97.8%, 91.9%, and 65.4% at 4 years[79]. in another series of 95 patients with ct1b (> 4 cm tumor size) localized rcc treated with sabr, siva et al. (2020) reported css, os, and pfs rates of 96.1%, 83.7%, and 81.0% at 2 years and 91.4%, 69.2%, and 64.9% at 4 years, respectively[70]. at 4 years, local, distant, and any failure rates were 2.9%, 11.1%, and 12.1%, respectively. a systematic review and meta-analyses published in 2019 involving 372 patients with localized rcc (median size, 4.6 cm) involving 26 studies (11 of which were prospective) reported that the random effect estimates for lc were 97.2% with sabr[80]. the grade 1, 2, and 3–4 toxicity rates were 37.5%, 8.8%, and 1.5% (95% ci, 0–4.3%), respectively. prospective studies have used a range of dose fractionation regimens. the prospective dose-escalation studies evaluated doses ranging from 21 to 60 gy in 3 fractions[68,81,82] and 24 to 48 gy in 4 fractions[65]. they showed dose escalation to 60 gy in 3 and 48 gy in 4 fractions without dose-limiting toxicity. the ongoing phase 2 study trog 15.03 (fastrack ii) evaluates 26 gy in 1 fraction for tumors of ≤ 4 cm and 42 gy in 3 fractions for tumors of > 4 cm in size[83]. response evaluation currently, the interpretation of post-sabr response and identification of characteristics that coincide with treatment response or recurrence remain a key challenge. lc post-sabr is currently measured using the response evaluation criteria in solid tumors (recist) by either ct or mri. currently, lack of growth and subsequent slow regression in size is thought to represent a successful response to treatment. given that small rccs are associated with slow growth kinetics, radiographic responses following sabr are also attenuated. in a study of 40 patients, sun et al. reported an average regression of 0.37 cm in the maximum dimension of rcc per year[66]. unlike ta, where the absence of contrast enhancement post-procedure assesses the response, there are no significant changes in contrast enhancement after sabr[66]. early results of functional mri (fmri) have shown some promise in detecting early response to sabr[84]; however, further exploration is warranted to validate the role of fmri in characterizing the efficacy of sabr. routine post-sabr biopsy should be considered experimental. in a recent prospective study involving 11 patients with dose escalation to 60 gy in 3 fractions, 5 of 5 posttreatment biopsies in the expansion cohort were positive by hematoxylin and eosin staining[68]. however, there was no radiological progression in subsequent follow-up. moreover, staining of ki-67, a nuclear protein associated with cell proliferation, was negative in the post-biopsy samples, confirming that cell viability on microscopy does not necessarily indicate ongoing active cell proliferation. renal function post-sabr given that many patients with rcc are at risk for longterm ckd following treatment, concerns exist regarding the impact of sabr on renal function. the published literature demonstrates a mild to moderate decrease in baseline renal function following sabr. in the irock pooled analysis of 223 patients (mean tumor size, 4.4 cm) treated with renal sabr, the average glomerular filtration rate (gfr) decreased by ~5.5 ml/minute after sabr, with 6 patients requiring dialysis[79]. similarly, a systematic review and meta-analyses involving 372 patients showed a post-sabr gfr change of -7.7ml/ min from baseline[80]. though the renal function decline is subclinical in published studies, patients with ckd 4–5 at baseline undergoing sabr should be counseled regarding esrd risk following treatment and the potential need for renal replacement therapy[59]. future perspectives one ongoing, prospective, randomized pilot trial (nct03811665) compares sabr with rfa to manage sr ms. however, there are a lways cha llenges in completing large, randomized trials comparing different interventional modalities. one way to counteract these difficulties can be to conduct comparative studies using existing datasets and establish prospective registries. considering encouraging results with a combination of sabr and mwa in patients with larger (> 5 cm) rccs[85], an ongoing prospective clinical trial is exploring the safety and efficacy of this combination in patients with rccs of > 4 cm (nct02782715). evidence supports that sabr and ta also have potent immunomodulatory effects[86,87]. it will be interesting to combine ablative treatments, sabr or ta, with immunotherapies to optimize immune response to improve long-term outcomes. one trial (nct05024318) assesses sabr with or without pembrolizumab in patients with t1b-t3, n0 or n1, 0 or low-volume m1 rcc before nephrectomy. take-home messages • patients with a newly diagnosed, localized renal mass should undergo a detailed assessment, including history focusing on comorbidity burden, physical examination, renal function assessment, and appropriate comprehensive tumor staging imaging. in patients considering ta or sabr, renal mass biopsy is recommended to characterize the histology of the tumor. 445siuj.org siuj • volume 3, number 6 • november 2022 ablative therapies for localized primary renal cell carcinoma http://siuj.org • each case should be discussed in a multidisciplinary team meeting consisting of a urologist, interventional radiologist, and radiation oncologist, including a central imaging review. • ablative treatments, including ta or sabr, can be considered in patients at high risk for adverse outcomes following surgery who decline surgery and in whom as is not optimal. local expertise should be considered for decision-making. • srms less than 4 cm (ideally < 3 cm), predominantly exophytic and distant to the renal hilum, should be considered for ta preferentially to sabr. • tumors measuring more than 4 cm (ideally > 3 cm), predominantly endophytic and centrally located, could be considered preferentially for sabr over ta. • ongoing imaging at regular specified intervals is essential to monitor the treatment outcome. acknowledgments muhammad ali is a phd candidate who is supported through an australian government 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kurup an, callstrom mr, weisbrod aj, et al. percutaneous cryoablation of stage t1b renal cell carcinoma: technique considerations, safety, and local tumor control. j vasc interv radiol.2015;26(6):792-799. 25. chen y, wu x, zhou j, zhang j, huang j, huang y, et al. thermal ablation assisted laparoscopic partial nephrectomy for clinical t1b renal tumors. minim invasive ther allied technol.2022;31(2):179-184. 26. atwell td, farrell ma, leibovich bc, callstrom mr, chow gk, blute ml, et al. percutaneous renal cryoablation: experience treating 115 tumors. j urol.2008;179(6):2136-2140; discussion 40-1. 27. breen dj, bryant tj, abbas a, shepherd b, mcgill n, anderson ja, et al. percutaneous cryoablation of renal tumours: outcomes from 171 tumours in 147 patients. bju int.2013;112(6):758-765. 28. acosta ruiz v, lonnemark m, brekkan e, dahlman p, wernroth l, magnusson a. predictive factors for complete renal tumor ablation using rfa. acta radiol.2016;57(7):886-893. 29. hinshaw jl , lubner mg, ziemlewic z tj, fred t. l ee j, brace cl . percutaneous tumor ablation tools: microwave, radiofrequency, or cryoablation–what should you use and why? radiographics.2014;34(5):1344-1362. 30. rosenberg md, kim cy, tsivian m, suberlak mn, sopko dr, polascik tj, et al. percutaneous cr yoablation of renal lesions with radiographic ice ball involvement of the renal sinus: analysis of hemorrhagic and collecting system complications. ajr am j roentgenol.2011;196(4):935-939. 31. johnson db, saboorian mh, duchene da, ogan k, cadeddu ja. nephrectomy after radiofrequency ablation-induced ureteropelvic junction obstruction: potential complication and long-term assessment of ablation adequacy. urology.2003;62(2):351-352. 32. johnson db, solomon sb, su lm, matsumoto ed, kavoussi lr, nakada sy, et al. defining the complications of cryoablation and radio frequency ablation of small renal tumors: a multi-institutional review. j urol.2004;172(3):874-877. 33. warlick ca, lima gc, allaf me, varkarakis i, permpongkosol s, schaeffer em, et al. clinical sequelae of radiographic iceball involvement of collecting system during computed tomography-guided percutaneous renal tumor cryoablation. urology.2006;67(5):918-922. 34. schmit gd, kurup an, weisbrod aj, thompson rh, boorjian sa, wass ct, et al. ablate: a renal ablation planning algorithm. ajr am j roentgenol.2014;202(4):894-903. 35. tsivian m, lyne jc, mayes jm, mouraviev v, kimura m, polascik tj. tumor size and endophytic growth pattern affect recurrence rates after laparoscopic renal cryoablation. urology.2010;75(2):307-310. 36. kutikov a , uz zo rg. t he r.e.n. a .l. nephrometr y score: a comprehensive standardized system for quantitating renal tumor size, location and depth. j urol.2009;182(3):844-853. 37. gahan jc, richter md, seideman ca, trimmer c, chan d, weaver m, et al. the performance of a modified renal nephrometr y score in predicting renal mass radiofrequency ablation success. urology.2015;85(1):125-129. 38. higgins lj, hong k. renal ablation techniques: state of the art. ajr am j roentgenol.2015;205(4):735-741. 39. finley ds, beck s, box g, chu w, deane l, vajgr t dj, et al. percutaneous and laparoscopic cryoablation of small renal masses. j urol.2008;180(2):492-498; discussion 8. 40. hui gc, tuncali k, tatli s, morrison pr, silverman sg. comparison of percutaneous and surgical approaches to renal tumor ablation: metaanalysis of effectiveness and complication rates. j vasc interv radiol.2008;19(9):1311-1320. 41. acosta ruiz v, ladjevardi s, brekkan e, haggman m, lonnemark m, wernroth l, et al. periprocedural outcome after laparoscopic partial nephrectomy versus radiofrequency ablation for t1 renal tumors: a modified r.e.n.a.l nephrometry score adjusted comparison. acta radiol.2019;60(2):260-268. 42. ahmed m, solbiati l, brace cl, breen dj, callstrom mr, charboneau jw, et al. image-guided tumor ablation: standardization of terminology and reporting criteria-a 10-year update. j vasc interv radiol.2014;25(11):1691-1705 e4. 43. krokidis me, orsi f, katsanos k, helmberger t, adam a. cirse guidelines on percutaneous ablation of small renal cell carcinoma. cardiovasc intervent radiol.2017;40(2):177-191. 44. andersson m, hashimi f, lyrdal d, lundstam s, hellstrom m. improved outcome with combined us/ct guidance as compared to us guidance in percutaneous radiofrequency ablation of small renal masses. acta radiol.2015;56(12):1519-1526. 45. dai y, covarrubias d, uppot r, arellano rs. image-guided percutaneous radiofrequency ablation of central renal cell carcinoma: assessment of clinical efficacy and safety in 31 tumors. j vasc interv radiol.2017;28(12):1643-1650. 447siuj.org siuj • volume 3, number 6 • november 2022 ablative therapies for localized primary renal cell carcinoma http://siuj.org 46. zhong j, bambrook j, bhambra b, smith j, cartledge j, ralph c, et al. incidence of post-ablation syndrome following image-guided percutaneous cryoablation of renal cell carcinoma: a prospective study. cardiovasc intervent radiol.2018;41(2):270-276. 47. atwell td, carter re, schmit gd, carr cm, boorjian sa, curry tb, et al. complications following 573 percutaneous renal radiofrequency and cryoablation procedures. j vasc interv radiol.2012;23(1):48-54. 48. georgiades cs, rodriguez r. efficacy and safety of percutaneous cr yoablation for stage 1a /b renal cell carcinoma: results of a prospective, single-arm, 5-year study. cardiovasc intervent radiol. 2014;37(6):1494-1499. 49. crawford d, vansonnenberg e, kang p. infectious outcomes from renal tumor ablation: prophylactic antibiotics or not? cardiovasc intervent radiol.2018;41(10):1573-1578. 50. pierorazio pm, johnson mh, patel hd, sozio sm, sharma r, iyoha e, et al. management of renal masses and localized renal cancer: systematic review and meta-analysis. j urol.2016;196(4):989-999. 51. castle sm, gorbatiy v, avallone ma, eldefrawy a, caulton de, leveillee rj. cost comparison of nephron-sparing treatments for ct1a renal masses. urologic oncology: seminars and original investigations. 2013;31(7):1327-1332. 52. larcher a, sun m, dell’oglio p, trudeau v, boehm k, schiffmann j, et al. mortality, morbidity and healthcare expenditures after local tumour ablation or partial nephrectomy for t1a kidney cancer. eur j surg oncol.2017;43(4):815-822. 53. wang y, chen y w, leow jj, levy ac, chang sl, gelpi fh. costeffectiveness of management options for small renal mass: a systematic review. am j clin oncol.2016;39(5):484-490. 54. pandharipande pv, gervais da, mueller pr, hur c, gazelle gs. radiofrequency ablation versus nephron-sparing surger y for small unilateral renal cell carcinoma: cost-effectiveness analysis. radiology.2008;248(1):169-178. 55. ning s, trisler k, wessels bw, knox sj. radiobiologic studies of radioimmunotherapy and external beam radiotherapy in vitro and in vivo in human renal cell carcinoma xenografts. cancer. 1997;80(12 suppl):2519-2528. 56. walsh l, stanfield jl, cho lc, chang ch, forster k, kabbani w, et al. efficacy of ablative high-dose-per-fraction radiation for implanted human renal cell cancer in a nude mouse model. eur urol.2006;50(4):795-800; discussion 57. kothari g, foroudi f, gill s, corcoran nm, siva s. outcomes of stereotactic radiotherapy for cranial and extracranial metastatic renal cell carcinoma: a systematic review. acta oncol.2015;54(2):148-157. 58. svedman c, karlsson k, rutkowska e, sandström p, blomgren h, lax i, et al. stereotactic body radiotherapy of primary and metastatic renal lesions for patients with only one functioning kidney. acta oncol.2008;47(8):1578-1583. 59. chang jh, cheung p, erler d, sonier m, korol r, chu w. stereotactic ablative body radiotherapy for primar y renal cell carcinoma in non-surgical candidates: initial clinical experience. clin oncol (r coll radiol).2016;28(9):e109-114. 60. lo ch, huang w y, chao hl, lin kt, jen ym. novel application of stereotactic ablative radiotherapy using cyberknife® for early-stage renal cell carcinoma in patients with pre-existing chronic kidney disease: initial clinical experiences. oncol lett.2014;8(1):355-360. 61. siva s, pham d, kron t, bressel m, lam j, tan th, et al. stereotactic ablative body radiotherapy for inoperable primary kidney cancer: a prospective clinical trial. bju int.2017;120(5):623-630. 62. staehler m, bader m, schlenker b, casuscelli j, karl a, roosen a, et al. single fraction radiosurgery for the treatment of renal tumors. j urol.2015;193(3):771-775. 63. svedman c, sandström p, pisa p, blomgren h, lax i, kälkner km, et al. a prospective phase ii trial of using extracranial stereotactic radiotherapy in primary and metastatic renal cell carcinoma. acta oncol.2006;45(7):870-875. 64. pham d, thompson a, kron t, foroudi f, kolsky ms, devereux t, et al. stereotactic ablative body radiation therapy for primary kidney cancer: a 3-dimensional conformal technique associated with low rates of early toxicity. int j radiat oncol biol phys.2014;90(5):1061-1068. 65. ponsky l, lo ss, zhang y, schluchter m, liu y, patel r, et al. phase i dose-escalation study of stereotactic body radiotherapy (sbrt) for poor surgical candidates with localized renal cell carcinoma. radiother oncol.2015;117(1):183-187. 66. sun mr, brook a, powell mf, kaliannan k, wagner a a, kaplan id, et al. effect of stereotactic body radiotherapy on the growth kinetics and enhancement pattern of primary renal tumors. ajr am j roentgenol.2016;206(3):544-553. 67. kaidar-person o, price a, schreiber e, zagar tm, chen rc. stereotactic body radiotherapy for large primar y renal cell carcinoma. clin genitourin cancer.2017;15(5):e851-e854. 68. grubb wr, ponsky l, lo ss, kharouta m, traughber b, sandstrom k, et al. final results of a dose escalation protocol of stereotactic body radiotherapy for poor surgical candidates with localized renal cell carcinoma. radiother oncol.2021;155:138-143. 69. tetar su, bohoudi o, senan s, palacios ma, oei ss, wel amv, et al. the role of daily adaptive stereotactic mr-guided radiotherapy for renal cell cancer. cancers (basel).2020;12(10). 70. siva s, correa rjm, warner a, staehler m, ellis rj, ponsky l, et al. stereotactic ablative radiotherapy for ≥t1b primary renal cell carcinoma: a repor t from the international radiosurger y oncology consortium for kidney (irock). int j radiat oncol biol phys.2020;108(4):941-949. 448 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org 71. grelier l, baboudjian m, gondran-tellier b, couderc al, mcmanus r, deville jl, et al. stereotactic body radiotherapy for frail patients with primary renal cell carcinoma: preliminary results after 4 years of experience. cancers (basel).2021;13(13). 72. senger c, conti a, kluge a, pasemann d, kufeld m, acker g, et al. robotic stereotactic ablative radiotherapy for renal cell carcinoma in patients with impaired renal function. bmc urol.2019;19(1):96. 73. nomiya t, tsuji h, hirasawa n, kato h, kamada t, mizoe j, et al. carbon ion radiation therapy for primary renal cell carcinoma: initial clinical experience. int j radiat oncol biol phys.2008;72(3):828-833. 74. swaminath a, cheung p, glicksman rm, donovan ek, niglas m, vesprini d, et al. patient-reported quality of life following stereotactic body radiation therapy for primary kidney cancer results from a prospective cohort study. clin oncol (r coll radiol).2021;33(7):468-475. 75. correa rjm, louie av, staehler m, warner a, gandhidasan s, ponsky l, et al. stereotactic radiotherapy as a treatment option for renal tumors in the solitary kidney: a multicenter analysis from the irock. j urol.2019;201(6):1097-1104. 76. siva s, pham d, gill s, bressel m, dang k, devereux t, et al. an analysis of respiratory induced kidney motion on four-dimensional computed tomography and its implications for stereotactic kidney radiotherapy. radiat oncol.2013;8:248. 77. wilke l, andratschke n, blanck o, brunner tb, combs se, grosu al, et al. icru report 91 on prescribing, recording, and reporting of stereotactic treatments with small photon beams : statement from the degro/dgmp working group stereotactic radiotherapy and radiosurgery. strahlenther onkol.2019;195(3):193-198. 78. siva s, ellis rj, ponsky l, teh bs, mahadevan a, muacevic a, et al. consensus statement from the international radiosurgery oncology consortium for kidney for primary renal cell carcinoma. future oncol.2016;12(5):637-645. 79. siva s, louie av, warner a, muacevic a, gandhidasan s, ponsky l, et al. pooled analysis of stereotactic ablative radiotherapy for primary renal cell carcinoma: a report from the international radiosurgery oncology consortium for kidney (irock). cancer.2018;124(5):934-942. 80. correa rjm, louie av, zaorsky ng, lehrer ej, ellis r, ponsky l, et al. the emerging role of stereotactic ablative radiotherapy for primary renal cell carcinoma: a systematic review and meta-analysis. eur urol focus.2019;5(6):958-969. 81. kaplan i, redrosa i, martin c, collins c, wagner a. results of a phase i dose escalation study of stereotactic radiosurgery for primary renal tumors. int j radiat oncol biol phys.2010;78(3):s191. 82. mcbride s, wagner a, kaplan i. a phase 1 dose-escalation study of robotic radiosurgery in inoperable primary renal cell carcinoma. int j radiat oncol biol phys.2013;87(2):s84. 83. siva s, chesson b, bressel m, pryor d, higgs b, reynolds hm, et al. trog 15.03 phase ii clinical trial of focal ablative stereotactic radiosurger y for cancers of the kidney-fastr ack ii. bmc cancer.2018;18(1):1-10. 84. reynolds hm, parameswaran bk, finnegan me, roettger d, lau e, kron t, et al. diffusion weighted and dynamic contrast enhanced mri as an imaging biomarker for stereotactic ablative body radiotherapy (sabr) of primary renal cell carcinoma. plos one.2018;13(8):e0202387. 85. blitzer gc, wojcieszynski a, abel ej, best s, lee ft, jr., hinshaw jl, et al. combining stereotactic body radiotherapy and microwave ablation appears safe and feasible for renal cell carcinoma in an early series. clin genitourin cancer.2021;19(5):e313-e318. 86. chow j, hoffend nc, abrams si, schwaab t, singh ak, muhitch jb. radiation induces dynamic changes to the t cell repertoire in renal cell carcinoma patients. proc natl acad sci u s a. 2020;117(38):23721-23729. 87. chu kf, dupuy de. thermal ablation of tumours: biological mechanisms and advances in therapy. nat rev cancer.2014;14(3):199-208. 88. yu j, wang h, cheng zg, liu fy, li qy, he gz, et al. a multicenter 10-year oncologic outcome of ultrasound-guided percutaneous microwave ablation of clinical t1 renal cell carcinoma: will it stand the test of time? eur radiol.2021. 449siuj.org siuj • volume 3, number 6 • november 2022 ablative therapies for localized primary renal cell carcinoma http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information conferences, conflict of interest, urology, disclosure slides, guidelines none declared. funding: none received on february 16, 2022 accepted on march 30, 2022 this article has been peer reviewed. soc int urol j. 2022;3(4):276–279 doi: 10.48083/spql8302 276 siuj • volume 3, number 4 • july 2022 siuj.org brief communication the value of conflicts of interest disclosures in oral presentations at major urological conferences anique le roux,1 naji j. touma2 1 school of medicine, queen’s university, kingston, canada 2 department of urology, queen’s university, kingston, canada abstract the objective of this study is to assess the value of disclosure slide reporting at major urology conferences. in total, 557 speakers were evaluated from the conferences of the canadian urology association (n = 36), american urology association (n = 160), and european association of urology (n = 361) in 2020. overall, 49.0% of speakers had no disclosure slide. among speakers presenting a disclosure slide, the median number of conflicts was 5, median time spent on the slide was 4.4 seconds, and 34.8% gave context to disclosures. overall disclosure slide reporting seems inconsistent, and given how little time is spent on them and the lack of contextualization, their value is unclear. collaboration between physicians and pharmaceutical or device companies can result in worthy advancement in research, education, and clinical care. however, such interactions invariably result in real or perceived conflicts of interest (cois). short of prohibition, disclosure is a critical aspect of managing cois. scientific meetings are an important vehicle of continuing medical education (cme). an oral presentation at such meetings, especially national or international ones, is a prestigious perch that confers on the speaker a level of endorsement from the association of their academic credibility. in addition, commercial sponsorship at such meetings is substantial, leading to concerns that sponsors may have undue influence over program content and speakers[1]. therefore, it is in the interests of both the speaker and the meeting organizers to have full and transparent disclosures to allay concerns of bias. at scientific meetings, these disclosures often take the form of a slide at the outset of a presentation, laying out the possible conflicts and their nature. there have been several reports outlining the inadequacies of disclosure slides in cme events[2–5], but none in urological conferences. in urology, there has been some concerns of inadequate disclosures among guideline authors[6]. the hypothesis of this study is that disclosure slides at major urology conferences are displayed for too short a time and without providing an adequate context of the nature of cois, rendering a proper evaluation of bias impossible. with the advent of the covid-19 pandemic, major conferences switched to a virtual format in 2020. we prospectively evaluated oral presentations from the two major urological conferences occurring in 2020: the european association of urology (eau) conference, held 17–19 july, and the american urologic association (aua) annual meeting, held 26–27 june, as well as the national meeting of the canadian urological association (cua), held 22–26 june. the sessions evaluated included all plenary sessions, state of the art lectures, debates, panels, and surgical technique demonstrations. we excluded the various poster sessions. a single investigator recorded all disclosure slides and extracted information on coi presentations. primary data points evaluated were inclusion of a disclosure slide, number of conflicts listed, time spent on the disclosure slide, types of conflicts described and contextualization of disclosure slide. the context parameters were “said nothing,” “vague,” or “context.” speakers were categorized as vague if they said only “these are my disclosures.” anything they said beyond that, even simply reading out the coi, http://siuj.org https://orcid.org/0000-0001-9072-5440 https://orcid.org/0000-0002-1030-1689 mailto:njtouma%40gmail.com?subject=siuj was categorized as providing context. secondary end points included frequency of disclosure and number of conflicts per urologic subspecialty. a comparison between the different conferences was carried out to look for meaningful differences in disclosure slide reporting with a pearson chi-square analysis. in total, 557 speakers were evaluated from the cua (n = 36), aua (n = 160), and eau (n = 361). overall, 49% of speakers had no disclosure slide. among speakers presenting a disclosure slide, the median number of conflicts was 5 (iqr 2–11), median time spent on the slide was 4.38 seconds (iqr 2.76–6.25) and the median word count was 20 (iqr 13–34). among the speakers with a disclosure slide, 34.8% provided context, 50% were vague, and 15.2% said nothing. the types of conflict listed are shown in figure 1. the aua had the highest rate of speakers without disclosure slides (61.9%), followed by the cua (44.4%) and the eau (43.8%) (p = 0.001). speakers presenting on oncology topics were the most likely to offer a disclosure slide, and they had the highest median number of coi (figure 2). the median number of conf licts for each subspecialty topic was 8 (iqr 3–17) for oncology, 4 (iqr 2–5.75) for endourology, 3.5 (iqr 2–8) for reconstructive surgery, 3 (iqr 2.5–10) for andrology, 1 (iqr 1) for transplant, and 3 (iqr 1–7) for other topics. reporting of disclosure slides across conferences and specialties is inconsistent, ranging from 42.2% to 87%[3,7,8], which is in keeping with the findings of the current study (51%). the reasons for this broad range are multifactorial, but conference guidelines play a significant role. even amongst a relatively homogeneous group of urologists, disclosure slide reporting was lower for the aua than for the eau and the cua. ju et al. found similar discrepancies in reporting by spine surgeons depending on the conference[9]. common reasons for not disclosing were that presenters believed their presentation topic was unrelated to their payment or that they had misunderstood the disclosure guidelines[8]. for instance, disclosure reporting dropped from 79.3% when the payment was related to the topic of presentation to 50% when it was unrelated[8]. to resolve this confusion, some have proposed that conferences should develop a standardized guideline for disclosure slide reporting, similar to the form developed by the international council of medical journal editors, a group that figure 1. types of conflicts listed as a proportion of the total presentations 10 20 30 40 50 consultants advisory board speaker bureau/ honoraria other research studies/funding pi travel grants academic relations clinical trials research grant patent employed by government founder stocks 0 percentage of conflicts listed in presentations 277siuj.org siuj • volume 3, number 4 • july 2022 the value of conflicts of interest disclosures in oral presentations at major urological conferences http://siuj.org aims to provide a standardized document for reporting conflicts of interests for peer reviewed journals[10]. among speakers who did present coi, very little time was spent on disclosure slides. similar findings have been reported in other studies, with time spent ranging from 2 to 5 seconds[1-3,6]. the average reading speed of an individual is 3.8 words per second[11]. with 4.4 seconds as the median time spent per slide and a median word count of 20, the average reader would not have enough time to accurately read the slide. the value of presenting a disclosure slide comes into question when not enough time is allotted for the reader to accurately interpret it. even with the broadest definition, only 34.8% of presenters with a disclosure slide gave context and explained their disclosures to the audience. the inclusion of the disclosure slide appears mostly performative with questionable additional value. one explanation for this could be the constraints on the time allowed for presentations. a proposed solution would be to exclude disclosure slide time from the overall presentation time, thereby allowing researchers to fully explain coi[2]. in conclusion, there was low reporting of coi across major urology conferences in 2020. even when coi is reported, too little time is spent on disclosure slides, and so few are contextualized that their value is questionable. standardization of disclosure reporting across conferences with clear expectations and enforcements may help alleviate the problem. further, coi reporting could be excluded from the allotted presentation time, and/or a qr code could be provided to enable attendees to obtain more detailed information about coi. figure 2. percentage of disclosure slide presentation by subspecialty topic 0 10 20 30 40 50 60 presentations presenting disclosure slides (%) su bs pe ci al ite s endourology/mis oncology reconstructive surgery pedriatrics andrology and bph transplants others 278 siuj • volume 3, number 4 • july 2022 siuj.org brief communication http://siuj.org references 1. rothman d, mcdonald w, berkowitz c, chimonas s, deangelis c, hale r, et al. professional medical associations and their relationships with industry: a proposal for controlling conflict of interest. jama.2009; 301:1367–1372. doi: 10.1001/jama.2009.407 2. sassoon a, trousdale r. podium disclosures at the 2012 a aos meeting: an exercise in going through the motions. j bone joint surg am.2013;95:e51. doi: 10.2106/jbjs.l.00905 3. van lieshout c, tijdink j, smulders y. conflict of interest disclosure slides at the european society of cardiology congress 2016 in rome: are they displayed long enough to assess their content? a cross-sectional study. bmj open.2018;8:e023534. doi: 10.1136/ bmjopen-2018-023534 4. grey a, avenell a, dalbeth n, stewart f, bolland mj. reporting of conflicts of interest in oral presentations at medical conferences: a delegate -b ased prosp e c tive obser vational s t ud y. bmj open.2017;7:e017–019. doi: 10.1136/bmjopen-2017-017019 5. ahmed a, yoo s, mehta s, holliday e, deville c, vapiwala n, wilson l, jagsi r, prasad v, thomas c jr. meaningful and accurate disclosure of conflict of interest at the astro national meeting: a need for reassessment of current policies. j oncol pract.2018;14:e692–698. doi: 10.1200/jop.18.00121 6. carlisle a, bowers a, wayant c, meyer c, vassar m. financial conflicts of interest among authors of urology clinical practice guidelines. eur urol.2018 sep;74(3):348–354. doi: 10.1016/j.eururo.2018.04.023 7. ramm o, brubaker l. conflicts-of-interest disclosures at the 2010 augs scientific meeting. female pelvic med reconstr surg.2012; 18:79–81. doi: 10.1097/spv.0b013e3182436643 8. okike k, kocher m, wei e, mehlman c, bhandari, m. accuracy of conflict-of-interest disclosures reported by physicians. n engl j med.2009;361:1466–1474. doi: 10.1056/nejmsa0807160 9. ju b, miller c, whang p, grauer j. quantifying the variability of financial disclosure information reported by authors presenting at annual spine conferences. spine j.2011;11:1–8. doi: 10.1016/j.spinee.2010.08.022 10. international committee of medical journal editors. disclosure of interest. available at: https://www.icmje.org/disclosure-of-interest/. accessed may 26, 2022. 11. boothby a, wang r, cetnar j, prasad v. effect of the american society of clinical oncology’s conflict of interest policy on information overload. jama oncol.2016;2:1653–1654. doi: 10.1001/jamaoncol.2016.2706 279siuj.org siuj • volume 3, number 4 • july 2022 the value of conflicts of interest disclosures in oral presentations at major urological conferences http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information social media, misinformation, harm, pelvic organ prolapse none declared. received on, october 4, 2022 accepted on, november 26, 2022 this article has been peer reviewed. soc int urol j. 2023;4(2):131–135 doi: 10.48083/pgwg4918 harm related to social media misinformation on pelvic organ prolapse in youtube, instagram, and pinterest posts chaoyang wang,1 juhye kang,1 emily gerard,1 stacy loeb,2 rena d. malik1 1 department of urology at the university of maryland school of medicine, baltimore, united states 2 department of urology at nyu langone health, new york city, united states abstract social media can improve patient education but may pose risks due to misinformation. there is no consensus on categorizing types of misinformation and harm. this study aimed to categorize and quantify misinformation and resultant harm from posts on youtube, pinterest, and instagram on pelvic organ prolapse (pop), a prevalent benign condition that impacts quality of life. we conducted a descriptive study of 300 posts presented in these platforms in 2019. using fisher exact test, we show a significant difference in the distribution of misinformation between social media platforms. harmful posts were most frequently present on pinterest, leading to harmful inaction and economic harm. introduction in the united states, 8 in 10 internet users search for healthcare information online, a majority using social media[1]. a recent study examining misinformation in online cancer resources concluded that 32.5% of these articles contained misinformation and the majority were deemed harmful[2]. while misinformation about malignancies can pose significant health risks, it remains unclear whether misinformation about prevalent benign conditions such as pelvic organ prolapse (pop) leads to harm. with growing numbers of social media platforms, instruments to categorize diverse social media posts regarding the type of misinformation and potential harm may be challenging to implement due to the vastly different content format and length presented in these platforms. therefore, a streamlined classification of the type and nature of health-related misinformation compatible across multiple networks is needed. pop is a benign condition that impacts quality of life with a prevalence as high as 50% of women, with 12% electing for surgical correction[3]. we previously identified the presence of “low to moderate quality” information in 74.1% of posts on pelvic organ prolapse on pinterest, youtube, and instagram[4]. we investigated 3 prominent social media platforms (youtube, pinterest, and instagram) for pop posts to categorize the quantity and types of misinformation represented, as well as the degree and type of potential harm resulting from exposure to misinformation about this benign condition. 131siuj.org siuj • volume 4, number 2 • march 2023 brief communication mailto:chaoyang.wang%40som.umaryland.edu?subject=siuj http://siuj.org materials and methods we conducted a descriptive study in october 2021 that was exempt by the university of maryland internal review board (irb). relevant youtube videos and pinterest and instagram posts were identified by searching for “pelvic organ prolapse” on youtube and pinterest and “#pelvicorganprolapse” on instagram in september 2019. these platforms were chosen because they are among the top 15 most used social media platforms and have a proprietary search engine to identify relevant and publicly available pelvic organ prolapse posts. the first 100 posts on each platform were analyzed for quality, understandability, actionability, and misinformation as detailed by our previous study[4]. misinformation was assessed using a likert scale from 1 (no misinformation) to 5 (high misinformation). we reviewed posts with misinformation scores ≥ 2 for type and amount of misinformation, and the type of resultant harm[2].  to measure harmfulness, reviewers used a likert scale from 1 (certainly not harmful) to 5 (certainly harmful). harm was defined as harmful inaction (encouragement to forgo standard of care), economic harm (money spent on ineffective treatments), harmful action (toxic effects of the suggested test or treatment), and harmful interaction (medical interactions with curative therapies). type of misinformation was defined based on prior work: fabricated content (a completely false statement), misleading content (misleading use of content to frame an issue), imposter content (genuine sources impersonated with false sources), manipulative content (genuine information or imagery manipulated to deceive), false connection (headlines, visuals, or captions that do not support the content), and false context (genuine content shared with false contextual information)[5]. each social media post was reviewed by at least 2 reviewers. disagreements were reviewed until consensus was achieved. descriptive statistics were calculated as the number of observations and percentages. data were analyzed using fisher exact test and examined for associations between the categorical variables of interest: social media platform, quantity of misinformation, and harmfulness of medical claims. p-values < 0.05 were significant. results of 300 total posts including 100 posts per platform, 82 posts were identified as misinformative comprising 18 youtube videos, 24 pinterest posts, and 40 instagram posts. instagram and pinterest had a greater proportion of posts that contained “mostly false” claims, whereas youtube had a greater proportion of videos with “mostly true” claims. “mostly false” and “false” medical claims regarding pop were identified in 10 of 82 (12.2%) of the posts (0% youtube videos, 15% instagram posts, and 17% pinterest posts). social media misinformation about pop most frequently arises from fabricated content (4 of 10), false connection (5 of 10), or misleading content (6 of 10). for example, one video included chemotherapy and radiation as a nonsurgical treatment option for pop (fabricated content) and another post misrepresented an article published in the journal nature to claim that starvation and dysbiosis were prominent risk factors for pop (false connection). of 82 misinformative posts, 8.5% were found to be “probably harmful” (6% youtube videos, 3% instagram posts, and 21% pinterest posts). among these 7 posts, harmful inaction (5 of 7 posts) and economic harm (5 of 7 posts) were the most common types of harm, suggesting that harmful misinformation may result in delays of care and/or more expensive alternative routes of treatment (table 1). for example, one post advertised silicone pads and guaranteed symptom improvement without scientific evidence (economic harm). others encouraged their audience to forgo assessment by a doctor and pursue a pelvic floor physiotherapist instead (harmful inaction). regarding the reach of these 7 “probably harmful” posts, 5 of these posts came from pinterest, with a modest reach of around 1000 to 4000 followers. the 1 instagram post by a health blogger had the greatest reach with over 100 000 followers, and the 1 youtube post by a doctor in bangalore had the lowest reach with fewer than 200 subscribers and 400 views (table 1). discussion in this novel investigation assessing the categor y and quantity of misinformation and resultant harm regarding pop on youtube, pinterest, and instagram, our data show a significant difference in distribution of m isi n for mat ion across plat for ms , a nd t hat misinformative posts regarding a benign condition can also result in harm, most frequently harmful inaction and economic harm and most frequently in pinterest posts and least frequently in youtube posts. these findings are congruent with a previous study by morra et al. who found that youtube is considered a reliable source of information on bladder pain syndrome, with more than 70% of videos receiving good or excellent global quality scores and more than 80% having no misinformation[6]. limitations of the study are that the data were gathered from a small subset of posts and may not be generalizable to all medical-related content across 132 siuj • volume 4, number 2 • march 2023 siuj.org brief communication http://siuj.org all social media platforms. further limitations include the subjective nature of scoring and the selection of just 3 of dozens of social media platforms. while our methodology attempted to standardize review using multiple reviewers, subjectivity is naturally introduced when using nonbinary metrics for harm, where it is not possible to track which consumers of media pursued specif ic treatments and whet her resu ltant harm ensued. furthermore, while youtube, instagram, and pinterest are among the top 15 social media platforms used globally, facebook, the social media platform with the greatest number of daily and monthly users, was not included in our study because of the private nature of many pages and accounts that limited analysis of this magnitude. conclusion the rise of social media as a prominent source of healthcare information has outpaced research on its reliability and safety. our research demonstrates the potential harms of various types of misinformation, even in a benign condition that impacts quality of life. uniquely, our data help further categorize and quantify the specific type of misinformation across multiple social media platforms and sets the groundwork for analyzing the reach and impact of these posts. these data can help guide larger-scale policy changes, such as mandatory textual warnings underneath misinformative health posts, and help providers tailor medical education to best communicate patient diagnoses and treatment options. references 1. ventola cl. social media and health care professionals: benefits, risks, and best practices. pt. 2014;39(7):491–520. pmid: 25083128; pmcid: pmc4103576. 2. johnson sb, parsons m, dorff t, moran ms, ward jh, cohen sa, et al. cancer misinformation and harmful information on facebook and other social media: a brief report. j natl cancer inst.2022;114(7):1036–1039. doi: 10.1093/jnci/djab141. pmid: 34291289; pmcid: pmc9275772. 3. barber md, maher c. epidemiology and outcome assessment of pelvic organ prolapse. int urogynecol j.2013;24(11):1783–1790. doi: 10.1007/ s00192-013-2169-9. pmid: 24142054. 4. pace l a , herber t as, malik rd. characteristics of pelvic organ prolapse content available on social media. neurourol urodyn.2021;40(5):1165 –1174. doi: 10.1002/nau.24673. pmid: 33834557. 5. wardle c, derakhshan h. information disorder: toward an interdisciplinary framework for research and policy making. council of europe report dgi (2017)09. available at: https://rm.coe.int/ information-disorder-toward-an-interdisciplinary-framework-forresearc/168076277c. accessed january 29, 2023. 6. morra s, collà ruvolo c, napolitano l, la rocca r, celentano g, califano g, et al. youtubetm as a source of information on bladder pain syndrome: a contemporar y analysis. neurourol urodyn. 2022;41(1):237–24 5. doi: 10.10 02 /nau.24 8 02. pmid: 34559920. 133siuj.org siuj • volume 4, number 2 • march 2023 harm related to social media misinformation on pelvic organ prolapse in youtube, instagram, and pinterest posts http://siuj.org table 1. descriptive data for posts identified “probably harmful” medical claims regarding pop in your opinion, are the medical claims within the social media post/video accurate? which section, if applicable, contained the misinformation? what was misinformative about the post? how would you categorize the medical claims made? how would you categorize the type of harm caused by the medical claims? do you think there was purposeful intent by the creator to cause harm? number of likes or pins number of views publisher type speaker type number of followers or subscribers pinterest mostly false caption, title, hyperlink advertises silicone pad product (not evidence based) fabricated content harmful inaction likely intentional 54 commercial media/ industry industry 991 misleading content economic harm mostly false image, hyperlink advertised book that proposes cure to urinary incontinence with kegel exercises misleading content harmful inaction likely intentional commercial media/industry industry 1100 false context economic harm mostly false hyperlink claims that ob gyn doctors are not trained to diagnose pelvic floor dysfunction or prolapse and that pursuing ob gyn evaluation is not the best course of action fabricated content harmful inaction likely intentional consumer/ patient health blogger 4100 misleading content manipulated content economic harm false context mostly false image, caption, title, hyperlink claims that starvation and dysbiosis are prominent risk factors for pop using out-ofcontext nature article findings misleading content harmful inaction uncertain if harm was intentional consumer/ patient health blogger 4100 manipulated content false connection economic harm false context mixture of both true and false hyperlinked website to post claims that tight hip flexors could cause pelvic discomfort fabricated content economic harm likely intentional consumer/ patient physical therapist 2 manipulated content youtube mixture of both true and false video claims that radiation and chemotherapy are nonsurgical options to treat pop fabricated content harmful action likely intentional 0 421 doctor doctor 196harmful interactions economic harm instagram mixture of both true and false caption advertises electronic pelvic stimulator product (not evidence based) fabricated content harmful action likely intentional 839 health/wellness group health blogger 111 000 harmful inactionmisleading content manipulated content economic harm pop: pelvic organ prolapse. 134 siuj • volume 4, number 2 • march 2023 siuj.org brief communication http://siuj.org table 1. descriptive data for posts identified “probably harmful” medical claims regarding pop in your opinion, are the medical claims within the social media post/video accurate? which section, if applicable, contained the misinformation? what was misinformative about the post? how would you categorize the medical claims made? how would you categorize the type of harm caused by the medical claims? do you think there was purposeful intent by the creator to cause harm? number of likes or pins number of views publisher type speaker type number of followers or subscribers pinterest mostly false caption, title, hyperlink advertises silicone pad product (not evidence based) fabricated content harmful inaction likely intentional 54 commercial media/ industry industry 991 misleading content economic harm mostly false image, hyperlink advertised book that proposes cure to urinary incontinence with kegel exercises misleading content harmful inaction likely intentional commercial media/industry industry 1100 false context economic harm mostly false hyperlink claims that ob gyn doctors are not trained to diagnose pelvic floor dysfunction or prolapse and that pursuing ob gyn evaluation is not the best course of action fabricated content harmful inaction likely intentional consumer/ patient health blogger 4100 misleading content manipulated content economic harm false context mostly false image, caption, title, hyperlink claims that starvation and dysbiosis are prominent risk factors for pop using out-ofcontext nature article findings misleading content harmful inaction uncertain if harm was intentional consumer/ patient health blogger 4100 manipulated content false connection economic harm false context mixture of both true and false hyperlinked website to post claims that tight hip flexors could cause pelvic discomfort fabricated content economic harm likely intentional consumer/ patient physical therapist 2 manipulated content youtube mixture of both true and false video claims that radiation and chemotherapy are nonsurgical options to treat pop fabricated content harmful action likely intentional 0 421 doctor doctor 196harmful interactions economic harm instagram mixture of both true and false caption advertises electronic pelvic stimulator product (not evidence based) fabricated content harmful action likely intentional 839 health/wellness group health blogger 111 000 harmful inactionmisleading content manipulated content economic harm pop: pelvic organ prolapse. 135siuj.org siuj • volume 4, number 2 • march 2023 harm related to social media misinformation on pelvic organ prolapse in youtube, instagram, and pinterest posts http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information case series, cystinuria, renal stones, mutations, south africa, genetics none declared. received on july 24, 2022 accepted on october 18, 2022 this article has been peer reviewed. soc int urol j. 2023;4(3):165–170 doi: 10.48083/srpf1472 165siuj.org siuj • volume 4, number 3 • may 2023 original research a case series of cystinuric stone formers in western cape, south africa: slc3a1 or slc7a9 mutations and phenotype lisa-ann kaestner,1 john lazarus,1 azola salukazana,1 elmi muller,2 karl-heinz jehle3 1 division of urology, university of cape town, cape town, south africa 2 faculty of health sciences, university of stellenbosch, cape town, south africa 3 cape urology, vincent palotti hospital, cape town, south africa abstract objective to describe the genetic mutations and phenotype in the first african series of patients with cystinuria. methods patients with cystinuria were recruited from a specialist metabolic renal stone clinic in cape town, south africa, for dna sequencing to detect mutations in slc3a1 and slc7a9. chart reviews and patient interviews were conducted to record demographics, previous medical history, family history, stone-specific history, age at first presentation, cystinuria complications, urine cystine:creatinine ratio, stone analysis, and serum creatinine. results nine patients were included: 3 male patients and 6 female patients. the mean age (± sd) of patients was 33.43 ± 19.96 years. the median age (± iqr) at initial diagnosis of cystinuria was 16 ± 18 years, but the age ranged from 2 to 66 years. three of 9 patients included (33.3%) had chronic kidney disease (ckd); however, none were receiving dialysis. most patients initially presented with a staghorn calculus (4/9; 44.4%). the mean serum creatinine (± sd) was 84 ± 38 µmol/l. the mean urine cystine (± sd) was 2083 ± 1249 nmol/mg creatinine. eight patients had mutations in the slc3a1 gene; 1 had mutations in both slc3a1 and slc7a9. of the patients with only slc3a1 mutations, 1 patient was homozygous and the rest were compound heterozygotes (two different mutations identified in the same gene). four patients had a pathogenic variant in addition to an “uncertain significance” variant in slc3a1. there were 9 mutations (5 pathogenic and 4 “unknown significance”) in slc3a1 and 1 mutation in slc7a9. two of these were novel mutations. conclusion this “first in africa” series of cystinuria patients showed marked heterogeneity in both phenotype and genotype, with a predominance of slc3a1 mutations. this heterogeneity is similar to that reported in international cohorts. introduction cystinuria is a rare genetic disorder that causes a defect in the transporter of dibasic amino acids across membranes in the proximal renal tubule[1,2]. affected patients have a defect in the reabsorption of filtered dibasic amino acids and therefore excrete large amounts of cystine, arginine, lysine, and ornithine in their urine. cystine is poorly soluble at physiological urine ph and crystallizes in the urinary tract, causing recurrent cystine renal calculi[1,3]. as the other amino acids (arginine, lysine, and ornithine) are more soluble in urine, there are no adverse clinical consequences of high urinary excretion. the dibasic amino acid transporter is a heterodimer composed of 2 subunits (encoded by slc3a1 and slc7a9) joined by a disulphide bridge[4,5]. there is a high prevalence of mutations in either subunit gene, or more rarely, http://siuj.org mailto:lisalisa%40live.co.za?subject=siuj both genes. biallelic mutations of slc3a1 are classified as type a cystinuria. slc3a1, located on chromosome 2, encodes the heavy subunit of the dibasic amino acid transporter, and inheritance is autosomal recessive with 100% penetrance[6,7]. heterozygotes do not have an elevated risk for nephrolithiasis, and urinary excretion of cystine is usually within the normal range. some patients with duplications of exons 5–9 of slc3a1 may however excrete increased levels of urinary cystine and form cystine stones[8]. biallelic mutations of slc7a9 are classified as type b cystinuria. slc7a9 is located on chromosome 19 and encodes the light subunit of the amino acid transporter[6]. heterozygotes may excrete increased levels of cystine and rarely form stones. type b cystinuria therefore has either an autosomal recessive inheritance pattern or is autosomal dominant with incomplete penetrance[7,8]. bigenetic mutations of both slc3a1 and slc7a9 rarely occur and are referred to as type ab cystinuria. although cystinuria is a rare condition, patients develop stones at a young age and have an extremely high stone recurrence rate and a high risk for the development of chronic kidney disease[8–10]. there are population-dependent variations in the proportion of type a and b genotypes, with an equal distribution in the american population and a higher preponderance of type a genotype in the united kingdom, france, and eastern europe. there is a preponderance of type b genotype in cystinuria patients in spain[11]. according to the human gene mutation database, there are 257 slc3a1 and 170 slc7a9 mutations identified[12]. it is uncertain whether cystinuria patients in south africa carry known mutations noted in other countries or whether novel mutations exist in our population. although outcomes have been reported to be worse in male patients, clinical phenotype-genotype correlations have not been reported. outcomes and management for both type a or b cystinuria are similar[1]. there are no publications reporting on cystinuria patients in south africa, therefore nothing is known about the local prevalence, pathology, or genetics of cystinuria. knowledge of the local mutations in south africa could contribute to the development of a sanger sequencing technique for the most common local mutations to provide a cost-effective locally accessible test. considering south africa’s colonial history, a “founder effect” mutation was considered possible, and therefore a predominant slc3a1 or slc7a9 mutation was expected. this study aims to describe the genetic mutations and clinical phenotype (age at presentation, number of stone episodes, number of stone procedures) in the first south african cohort of patients with cystinuria. methods our unit is a general metabolic stone clinic at a tertiary referral center, groote schuur hospital in cape town, south africa. patients are followed up every 3 months, every 6 months, or annually depending on their renal stone type and clinical status. quantitative urinary amino acid measurement is done for all patients diagnosed with cystinuria on stone analysis or if clinical factors raise suspicion for cystinuria. patients with cystinuria based on either stone analysis or elevated urine cystine excretion were identified from an existing stone registry (r003/2018) and were invited to participate. all patients with confirmed cystinuria who were willing to consent were included. a single saliva sample or 2-cheek swabs were collected between september 2021 and december 2021 using a standard test kit provided by invitae laboratories for dna sequencing. samples were packaged and shipped to invitae laboratories. genomic dna was enriched using a hybridization protocol and sequenced using illumina technology focusing on the coding exons and flanking intronic sequences. copy number variations (deletions and duplications of exons) were assessed using invitae laboratories in-house algorithm to determine copy number at each target by comparing read depth for each target in the proband sequence with mean readdepth and read-depth distribution from a set of clinical samples. in cases where a copy number variation was identified, multiplex ligation-dependent probe amplification (mlpa) was done to confirm the variant. chart reviews and patient interviews were done to record patient demographics (age, gender), patient medical history (other illnesses, treatments for cystinuria), family history (relatives with calculi, relatives with “kidney problems,” relatives with known cystinuria, consanguinity), stone-specific history (type, location, age at first presentation, current stones), complications of cystinuria (renal failure, nephrectomy, chronic kidney disease, dialysis), previous investigations (24-hour urine collection, urine cystine:creatinine ratio, stone analysis), number of lifetime stone events, and number of stone procedures. patient weight and height were also measured. continuous data was expressed with the appropriate measures of central tendency. categorical data was reported as percentages and proportions. ibm® spss version 27 was used for all analyses. this protocol was reviewed by uct human research ethics committee (hrec ref: 215/2021). all patients completed informed consent before participation in the study. 166 siuj • volume 4, number 3 • may 2023 siuj.org original research http://siuj.org results of the 12 patients identified for possible inclusion in the study, 9 patients were included; 1 patient died of renal failure at the age of 83 years a month prior to the initiation of this study, 1 patient could not be traced, and 1 patient declined to participate. the mean age (± sd) of patients was 33.43 ± 19.96 years. three male patients and 6 female patients were included. the median age (± iqr) at initial diagnosis of cystinuria was 16 ± 18 years, but the age ranged from 2 to 66 years. three of 9 patients included (33.3%) had chronic kidney disease (ckd); however, none were receiving dialysis. the number of previous stone procedures per patient was difficult to assess, as 2 patients reported “too many to remember.” as both received treatment at multiple sites, the exact number of previous procedures could not be identified for either of these patients. for the other 7 patients, the number of stone episodes varied from 1 to 7 and the number of procedures from 3 to 7. most patients initially presented with a staghorn calculus (4/9; 44.4%). none of the patients reported consanguinity. one patient reported a cousin with renal calculi since infancy, but the diagnosis of cystinuria could not be confirmed in this relative. one patient reported a brother known with cystinuria and recurrent renal calculi since teenage years; however, he declined to participate in the study (table 1). table 1. clinical features of cystinuria patients case bmi (kg/m2) age (years) gender affected relatives age at diagnosis (years) ckd initial presentation number of stones number of stone procedures 1 28.6 71 female no 66 yes staghorn 2 7 2 19.5 33 female no 14 yes staghorn innumerable innumerable 3 20.4 16 female yes cousin 16 no staghorn 1 3 4 33.7 47 female no 19 no staghorn innumerable innumerable 5 25.1 39 male no 24 yes lower pole stone 6 3 6 20.8 42 female no 6 no passing small stones 5 3 7 19.1 14 male no 2 no bladder stone 7 7 8 29.3 34 female yes brother 20 no bladder stone 4 5 9 9.1* 5 male no 2 no bladder stone 2 2 *this case is a child. bmi: body mass index; ckd: chronic kidney disease. the mean serum creatinine (± sd) was 84 ± 38 µmol/l. the mean urine cystine (± sd) was 2083 ± 1249 nmol/mg creatinine; however, results were only available for 6 patients. one result was reported as “very high.” it is unclear why it was not reported as a numerical value. as the result was in keeping with the clinical picture and a stone analysis confirmed cystine nephrolithiasis, urine cystine measurement was not repeated for this patient. eight patients had mutations in the slc3a1 gene; 1 patient had mutations in both slc3a1 and slc7a9. of the patients with only slc3a1 mutations, 1 patient was homozygous and the rest were compound heterozygotes (two different mutations identified in the same gene). four patients had two pathogenic mutations in slc3a1, and 3 patients had a pathogenic variant in addition to an “uncertain significance” variant in slc3a1 (table 2). there were 5 pathogenic variants identified in slc3a and 4 variants of “uncertain significance” reported. the most common mutations in slc3a1 was c.638c>g (p.pro213arg) in 5/9 (55.5%) patients. the second most common was duplication of exons 5–9 (copy number = 3) seen in 4/9 (44.4%) patients (figure 1) the slc3a1 variant c.638c>g (p.pro213arg) was reclassified from “uncertain significance” to “pathogenic” by invitae laboratories during the course of this study. 167siuj.org siuj • volume 4, number 3 • may 2023 a case series of cystinuric stone formers in western cape, south africa: slc3a1 or slc7a9 mutations and phenotype http://siuj.org table 2. biochemical and molecular features of cystinuria patients cases biochemical molecular cystine nmol /mg creatinine creatinine µmol/l slc3a1 1 2816 121 gain (exons 5–9), copy number = 3 c.638c>g (p.pro213arg) heterozygous both pathogenic 2 986 106 c.1400t>c(p.met467thr); c.1366c>a(p.arg456ser) pathogenic uncertain significance 3 4278 68 c.1012-3a>g (intronic), heterozygous c.638c>g (p.pro213arg), heterozygous uncertain significance pathogenic 4 1291 83 c.1400t>c (p.met467thr), homozygous pathogenic 5 not available 155 gains (exons 5–9), copy = 3 deletion (exons 2–3), heterozygous both pathogenic 6 not available 64 gain (exons 5–9), copy number = 3 c.808c>t(p.arg270*), heterozygous both pathogenic 7* 1359 52 c.638c>g(p.pro213arg), heterozygous c.762c>g(p.asn254lys), heterozygous pathogenic uncertain significance 8 1773 85 gain (exons 5–9), number = 3 c.638c>g (p.pro213arg) heterozygous both pathogenic 9 “very high” 25 c.638c>g (p.pro213arg), heterozygous c.1237c>g (p.leu413val) heterozygous pathogenic uncertain significance * this patient had additional mutation in slc7a9: c.1402c>t (p.pro468ser), heterozygous. uncertain significance. 168 siuj • volume 4, number 3 • may 2023 siuj.org original research http://siuj.org although most of the mutations identified were either present in population databases or had been previously observed in other individuals with cystinuria who submitted samples to invitae laboratories for genotyping, there were two novel mutations identified. the novel mutation c.762c>a (p.asn254lys) in slc3a1 and c.1402c>t(p.pro468ser) in slc7a9 were both identified in the same patient who also had another known pathogenic mutation in slc3a1 (table 2). discussion this is the first single-population study of genetic mutations in cystinuria patients in africa. there was marked heterogeneity in both genotype and phenotype, as has been described in other populations[5,6,8,10,13]. we have reported two novel mutations, one each in slc3a1 and slc7a9 in a single patient (case 7). although both novel mutations are of unknown significance, the patient also has a heterozygous pathogenic mutation of slc3a1 and a clear clinical history of recurrent cystine calculi since infancy. it is therefore likely that one or both mutations are pathogenic and that the patient is a double compound heterozygote. three patients (cases 2,3,9) with slc3a1 mutations were compound heterozygotes with one pathogenic mutation and one “unknown significance” mutation. considering the clear cystinuria phenotype (based on recurrent cystine renal stones and elevated urine cystine excretion) in all 3 cases, the mutations classed as “uncertain significance” are extremely likely to be pathogenic. a pathogenic mutation of slc3a1 [c.638c>g (p.pro213arg)], not present in population databases, was the most common mutation reported in this series. 1 2 3 54 6 ex5–9 gain c.638c>g (p.pro213arg) c.762c>a(p.asn254lys) c.808c>t (p.arg270*) c1012-3a>g (inotronic) c 13 66c> a(p .arg456ser) c.1400t > c(p.met467thr) ex2–3 del c.1237c>g (p. leu413val) 0 frequency there were 9 mutations (5 pathogenic and 4 “unknown significance”) in slc3a1 and 1 in slc7a9. two of these were novel mutations. the predominance of slc3a1 mutations in this population is similar to that of populations from the united kingdom, france, and eastern europe[11,13]. the exon 5–9 duplication in slc3a1, which was one of the most common mutations in this cohort (4/9; 44.4%), was the most common mutation encountered in a large uk series (24/88; 27%)[13]. considering that south africa was a former english and dutch colony, we postulated that a single founder gene could be identified in this series. no predominant founder gene could be identified. although there was an overwhelming predominance of slc3a1 mutations, there were many different types of slc3a1 mutations and most of the participants were compound heterozygotes. this study was limited by the small number of patients included and the incomplete urine cystine results for the group. these limitations restricted the potential for genotype-phenotype correlations in the series. no other patients could be identified for recruitment at three other state-funded healthcare services, both within the region and beyond. limited access to renal stone analysis and metabolic renal stone services in the region could lead to underdiagnosis of cystinuria in south africa and on the rest of the continent. the lack of inclusion of family members for genotyping and phenotyping in cases of variants of unknown significance limited the assessment of variant significance to clinicopathological correlation alone. in the future, recruitment of patients from privately funded healthcare services and founding a national or african registry for rare stone diseases could enable broader recruitment for a large-scale south african or african study. this would facilitate collaboration and data sharing with international groups to allow for pooling of cohorts to glean further insights into this rare condition. conclusion this “first in africa” series of cystinuria patients showed marked heterogeneity in both phenotype and genotype with a predominance of slc3a1 mutations. the heterogeneity in genetics and clinical features seems similar to findings reported in populations in europe with cystinuria. acknowledgements funding: the study was funded by the south african urology association and division of urology, university of cape town research fund. figure 1. slc3a1 mutations 169siuj.org siuj • volume 4, number 3 • may 2023 a case series of cystinuric stone formers in western cape, south africa: slc3a1 or slc7a9 mutations and phenotype http://siuj.org references 1. thomas k, wong k, withington j, bultitude m, doherty a. cystinuria-a urologist's perspective. nat rev urol.2014;11(5):270–277. doi: 10.1038/ nrurol.2014.51. pmid: 24662732. 2. daga s, palit v, forster ja, biyani cs, joyce ad, dimitrova ab. an update on evaluation and management in cystinuria. urology.2021;149:70–75. doi: 10.1016/j.urology.2020.12.025. pmid: 33421442. 3. servais a, thomas k, dello strologo l, sayer ja, bekri s, bertholetthomas a, et al.; metabolic nephropathy workgroup of the european reference network for rare kidney diseases (erknet) and eurogen. cystinuria: clinical practice recommendation. kidney int.2021;99(1):48– 58. doi: 10.1016/j.kint.2020.06.035. pmid: 32918941. 4. lahme s, bichler kh, eggermann t, lang f. genomic and functional investigations of mutations of the slc3a1 gene in cystinuria. urol int.2002;69(3):207–211. doi: 10.1159/000063940. pmid: 12372889. 5. obaid a, nashabat m, al fakeeh k, al qahtani at, alfadhel m. delineation of cystinuria in saudi arabia: a case series. bmc nephrol.2017;18(1):50. doi: 10.1186/s12882-017-0469-x. pmid: 28166740; pmcid: pmc5292799. 6. skopková z, hrabincová e, stástná s, kozák l, adam t. molecular genetic analysis of slc3a1 and slc7a9 genes in czech and slovak cystinuric patients. ann hum genet.2005;69(pt 5):501–507. doi: 10.1111/j.1529-8817.2005.00185.x. pmid: 16138908. 7. vasudevan v, samson p, smith ad, okeke z. the genetic framework for development of nephrolithiasis. asian j urol.2017;4(1):18–26. doi: 10.1016/j.ajur.2016.11.003. pmid: 29264202; pmcid: pmc5730897. 8. d'ambrosio v, capolongo g, goldfarb d, gambaro g, ferraro pm. cystinuria: an update on pathophysiology, genetics, and clinical management. pediatr nephrol.2022;37(8):1705–1711.doi: 10.1007/ s00467-021-05342-y. pmid: 34812923. 9. knoll t, zöllner a, wendt-nordahl g, michel ms, alken p. cystinuria in childhood and adolescence: recommendations for diagnosis, treatment, and follow-up. pediatr nephrol.2005;20(1):19–24. doi: 10.1007/s00467-004-1663-1. pmid: 15602663. 10. rhodes hl, yarram-smith l, rice sj, tabaksert a, edwards n, hartley a, et al. clinical and genetic analysis of patients with cystinuria in the united kingdom. clin j am soc nephrol.2015;10(7):1235–1245. doi: 10.2215/cjn.10981114. pmid: 25964309; pmcid: pmc4491297. 11. sahota a, tischfield ja, goldfarb ds, ward md, hu l. cystinuria: genetic aspects, mouse models, and a new approach to therapy. urolithiasis.2019;47(1):57–66. doi: 10.1007/s00240-018-1101-7. pmid: 30515543; pmcid: pmc6592844. 12. hgmd® professional. the human gene mutation database 2021.3 available at: https://digitalinsights.qiagen.com/news/blog/clinical/ hgmd-fall-2021/. accessed march 28, 2023. 13. wong ka, mein r, wass m, flinter f, pardy c, bultitude m, et al. the genetic diversity of cystinuria in a uk population of patients. bju int. 2015;116(1):109–116. doi: 10.1111/bju.12894. pmid: 25109415. 170 siuj • volume 4, number 3 • may 2023 siuj.org original research https://digitalinsights.qiagen.com/news/blog/clinical/hgmd-fall-2021/ https://digitalinsights.qiagen.com/news/blog/clinical/hgmd-fall-2021/ http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj.org siuj • volume 4, number 3 • may 2023 key words competing interests article information prostatectomy, prostate cancer, urinary incontinence, pelvic floor, muscle contraction none declared. received on october 1, 2022 accepted on november 28, 2022 this article has been peer reviewed. soc int urol j. 2023;4(3):203–210 doi: 10.48083/nsov8979 203 original research pelvic floor muscle function and its relationship with post-prostatectomy incontinence cecile t. pham,1 manish i. patel,1,2 sean f. mungovan3,4 1 specialty of surgery, faculty of medicine and health, university of sydney, camperdown, new south wales, australia 2 department of urology, westmead private hospital, westmead, new south wales, australia 3 westmead private physiotherapy services, westmead, new south wales, australia 4 the clinical research institute, westmead, new south wales, australia abstract objectives post-prostatectomy incontinence (ppi) is a common condition, but the underlying mechanisms are not completely understood. transperineal ultrasound (tpus) assessment of voluntary pelvic floor muscle (pfm) function may be associated with ppi. this study investigates the relationship between ppi and preand postoperative displacement of anatomical landmarks related to pfm function. methods this was a prospective longitudinal cohort study of 40 patients undergoing robotic-assisted radical prostatectomy (rarp) by a high-volume single surgeon. all patients underwent pfm training preand postoperatively. tpus was used to obtain sagittal images of pelvic structures during maximal voluntary pfm contractions: (1) preoperatively, (2) 3 weeks postoperatively, and (3) 6 weeks postoperatively. tpus images were analyzed to calculate displacement of anatomical landmarks associated with activation of striated urethral sphincter (sus), bulbocavernosus muscle (bc), and puborectalis muscle (pr). continence was assessed at 3 and 6 weeks postoperatively, defined as use of ≤ 1 pad/day. the relationship of continence to the displacement of sus, bc, and pr was analyzed. results sus, bc, and pr displacement decreased significantly 3 weeks postoperatively (p = 0.042, p = 0.002, p < 0.001, respectively). continent men exhibited significantly greater sus displacement (median, 5.13 mm) than incontinent men (median, 3.90 mm) 3 weeks postoperatively (p = 0.029). between 3 and 6 weeks following rarp, there was significant increase in sus, bc, and pr displacement (p = 0.003, p = 0.030, p < 0.001, respectively). conclusions a significant decrease in pfm function occurs following rarp, with a subsequent recovery of postoperative pfm function between 3 and 6 weeks post-procedure in men who undergo pfm training. sus activation was significantly greater in continent patients compared to incontinent patients at 3 weeks following rarp. introduction post-prostatectomy incontinence (ppi) is a predictable consequence following radical prostatectomy. the incidence of ppi has been reported to occur in 59% to 63% of patients in the first 6 weeks following surgery[1–3]. the severity of ppi and the variation in the recovery of continence give rise to a significant clinical management issue. despite the high incidence of ppi, the etiology of ppi and the variable time course for recovery are not well understood. http://siuj.org https://orcid.org/0000-0002-5954-565x https://orcid.org/0000-0003-1409-9171 mailto:manish.patel%40sydney.edu.au?subject=siuj https://orcid.org/0000-0002-9949-2409 ppi typically occurs when urethral closure pressure is exceeded by bladder pressure. inadequate urethral sphincter function (insufficiency) can lead to a reduction in urethral pressure and incomplete sphincter closure[4–8]. urethral pressure can increase with voluntary contraction of the muscles that comprise the pelvic floor, including, the striated urethral sphincter (sus), the bulbocavernosus muscle (bc), and the puborectalis muscle (pr)[9]. contraction of the sus results in dorsal displacement of the membranous urethra; bc contraction causes compression of the urethra at the bulb of the penis; and pr contraction results in ventrocaudal motion of the urethra to compress the urethra against the pubic symphysis[10–13]. activation of the sus, bc, and pr results in the displacement of anatomical landmarks including posterior displacement of the mid-urethra (in the case of sus), anterior displacement of the bulb of the penis (bc), and anterior-superior displacement of the anorectal junction (pr)[11,12]. using noninvasive transperineal ultrasound (tpus) imaging, activation of the sus, bc, and pr can be reliably measured and has been validated against electromyography (emg) recordings[14,15]. the assessment of pfm function using tpus prior to and following radical prostatectomy provides the opportunity to better understand the role of pfm function in continence recovery[16–19]. to date, the time course of preand postoperative activation of the sus, bc, and pr and the association with return to continence have not been well described. therefore, the aim of this study was to investigate the relationship between ppi and displacement of anatomical landmarks related to pfm activation before and at 3 and 6 weeks following robot-assisted radical prostatectomy (rarp). abbreviations bc bulbocavernosus muscle bmi body mass index icc intraclass correlation coefficient iciq-ui sf international consultation on incontinence questionnaire–urinary incontinence short form iqr interquartile range pfm pelvic floor muscle ppi post-prostatectomy incontinence pr puborectalis muscle psa prostate-specific antigen rarp robotic-assisted radical prostatectomy sus striated urethral sphincter tpus transperineal ultrasound materials and methods participant selection this prospective longitudinal cohort study included patients who underwent rarp performed by a highvolume surgeon at a metropolitan center. consecutive patients were prospectively recruited during an initial consultation prior to rarp between february and november 2019. patients with a history of pad usage, pelvic surgery, or pelvic radiotherapy and patients who were unable to attend all physiotherapy consultations were excluded. this study was approved by the western sydney local health district human research ethics committee (eth02769) and all patients gave written informed consent. experimental protocol at the time of recruitment, each patient’s demographic information, including age, body mass index (bmi), a nd prost ate c a ncer cha rac ter ist ic s (prost atespecif ic antigen [psa] and histopatholog y) were collected. the patients were referred to a men’s health continence physiotherapist 1 month before r arp for the prescription of a preoperative pfm training program[20]. the international consultation on incontinence questionnaire–urinary incontinence short form (iciq-ui sf) was completed preoperatively. postoper at ively, pat ient s were re v iewed by a physiotherapist at 3 and 6 weeks following rarp. during these postoperative continence reviews, daily pad usage was recorded, and an individualized pfm training program was prescribed[20]. pelvic floor muscle training patients underwent a progressive individualized 6-week preand postoperative pfm training program that focussed on the activation and training of the sus[13]. tpus was used to teach voluntary pfm activation and to provide visual biofeedback feedback to the patient and physiotherapist to maximize sus activation[11,17]. tpus assessment all patients underwent tpus imaging upon completion of the preoperative pfm training program and within 1 week of surgery and at 3 and 6 weeks postoperatively. tpus was performed by 2 experienced physiotherapists using a philips iu22 ultrasound machine (philips healthcare; australia) in greyscale cine-loop format. at each review (preoperatively, and 3 and 6 weeks postoperatively), with each patient in a standing position, a curved array ultrasound transducer (7.0 mhz) was aligned on the perineum in the midsagittal plane so that the pubic symphysis, urethra, penile bulb, and anorectal angle were visible[11–13]. following a standardized verbal instruction: “contract your pelvic floor muscles as strongly as you can and hold,” tpus data were recorded 204 siuj • volume 4, number 3 • may 2023 siuj.org original research http://siuj.org while the patients performed 2 sustained maximal voluntary pfm contractions with a 10-second rest interval between the 2 contractions. tpus analysis inteleviewer digital imaging and communications in medicine (dicom) viewer software (intelerad medical systems inc.; montreal, canada) was used to analyze single-image frames from the cine-loop tpus data. the displacement of anatomical landmarks from the resting to the contracted position included posterior displacement of the mid-urethra (sus), anterior displacement of the bulb of the penis (bc), and anteriorsuperior displacement of the anorectal junction (pr) [11,12]. the mean displacement of the 2 sus, bc, and pr voluntary pfm contractions was used for the analysis of pfm function. a random subset of the data (10 participants) was reanalyzed after 3 weeks by the same assessor to determine the test-retest reliability of the tpus image analyses of the sus, bc, and pr displacement measurements at each time point. statistical analysis the median and interquartile range (iqr) were used to describe continuous variables. preand postoperative sus, bc, and pr displacement were compared using a one-way repeated measures analysis of variance (a nova). pat ients were categor i z ed based on their continence status at 3 and 6 weeks following rarp, defined as use of ≤ 1 pad daily. sus, bc, and pr displacement measurements were compared as continuous variables using a mann-whitney u test between continent and incontinent patients. testretest reliability was determined using the intraclass correlation coefficient (icc) with a 2-way mixed model for absolute agreement. icc values were interpreted as poor (< 0.5), moderate (0.5 to 0.75), good (0.75 to 0.9), and excellent (> 0.9)[21]. p-values < 0.05 were considered statistically significant. ibm spss statistics version 28 (ibm, armonk, united states) was used for the statistical analysis. results in this study, 52 consecutive patients were recruited, with 12 patients lost to follow-up. a total of 40 patients completed all experimental protocol procedures and were included in the analysis. the patients’ demographic, clinical, and operative characteristics are summarized in table 1. while 5 patients had a preoperative iciq-ui sf score > 0 (range, 3–8), they reported no symptoms of stress urinary incontinence or pad usage. these patients all reported episodes of urge urinary incontinence occurring less than once per week, with the iciq-ui sf score predominately determined by question 5 on the iciq-ui: “overall, how much does leaking urine interfere with your everyday life?”. excluding these table 1. demographic, clinical, and operative characteristics characteristic age (median, iqr) 66 (60–72) bmi (kg/m2) (median, iqr) 28.2 (26.4–32) psa (ng/ml) (median, iqr) 7 (4.3–9.2) prostate weight (g) (median, iqr) 35 (30–50) isup grade, n (%) 2 21 (52.5) 3 12 (30) 4 2 (5) 5 5 (12.5) clinical stage, n (%) t2 16 (40) t3 24 (60) d’amico risk group, n (%) intermediate 16 (40) high 24 (60) nerve-sparing procedure, n (%) not performed 2 (5) unilateral 13 (32.5) bilateral 25 (62.5) bmi: body mass index; iqr: interquartile range; isup: international society of urological pathology; psa: prostate-specific antigen. 5 patients from the analysis did not change the results of our investigation. the return to continence rate following rarp was 70% (n  =  28) at 3 weeks and 95% (n  =  38) at 6 weeks postoperatively. at 3 weeks following rarp, there was a significant decrease in sus, bc, and pr displacement (table 2). between 3 and 6 weeks following rarp, there was a significant increase in sus, bc, and pr displacement (table 2). at 6 weeks following rarp, there was no significant difference between preoperative and postoperative sus and bc displacement but there was significantly less pr displacement (p < 0.001) (table 2). continent patients (n = 28) had significantly greater sus displacement (median, 5.1 mm) compared to patients who were incontinent (n  =  12) (median, 205siuj.org siuj • volume 4, number 3 • may 2023 pelvic floor muscle function and its relationship with post-prostatectomy incontinence http://siuj.org table 2. pelvic floor muscle displacement prior to and 3 and 6 weeks following rarp displacement (median, iqr) (mm) p-value preoperative 3 weeks preoperative 6 weeks preoperative preoperative vs. 3 weeks preoperative vs. 6 weeks 3 weeks vs. 6 weeks sus 5.7 (4.0–7.3) 4.6 (3.4–6.6) 5.7 (4.3–7.9) 0.042 1.00 0.003 bc 5.3 (3.8–7.0) 3.8 (2.4–5.4) 4.4 (3.7–5.7) 0.002 0.24 0.030 pr 6.2 (3.8–7.9) 2.9 (2.0–5.0) 4.2 (3.3–6.4) < 0.001 < 0.001 <. 0001 bc: bulbocavernosus muscle; iqr: interquartile range; pr: puborectalis muscle; rarp: robotic-assisted radical prostatectomy; sus: striated urethral sphincter. table 3. postoperative pelvic floor muscle displacement in continent and incontinent men at 3 and 6 weeks following rarp displacement (median, iqr) (mm) p-value all participants continent (pad number ≤ 1) incontinent (pad number > 1) sus 3 weeks 4.6 (3.4–6.6) 5.1 (3.9–6.8) 3.9 (2.5–4.6) 0.029 6 weeks 5.7 (4.3–7.9) 5.7 (4.2–7.9) 6.4 (5.4–7.4) 0.34 bc 3 weeks 3.8 (2.4–5.4) 4.0 (2.7–5.6) 2.8 (2.1–4.3) 0.13 6 weeks 4.4 (3.7–5.7) 4.4 (3.6–5.6) 5.5 (4.3–6.7) 0.26 pr 3 weeks 2.9 (2.0–5.0) 3.1 (1.9–5.1) 2.9 (2.0–4.2) 0.59 6 weeks 4.2 (3.3–6.4) 4.2 (3.2–6.4) 4.3 (3.3–5.2) 0.78 bc: bulbocavernosus muscle; iqr: interquartile range; pr: puborectalis muscle; rarp: robotic-assisted radical prostatectomy; sus: striated urethral sphincter. figure 1. pelvic floor muscle displacement in continent and incontinent men 3 weeks following rarp. (a) sus, (b) bc, and (c) pr b c di sp la ce m en t ( m m ) continence status continent incontinent 10 8 6 4 2 0 p = .13 a su s di sp la ce m en t ( m m ) continence status continent incontinent 10 8 6 4 2 0 p = .029 b pr d is pl ac em en t ( m m ) continence status continent incontinent 10 8 6 4 2 0 p = .59 c 206 siuj • volume 4, number 3 • may 2023 siuj.org original research http://siuj.org 3.9 mm) (p = 0.029) at 3 weeks following rarp (table 3, figure 1). continent patients had greater median bc and pr displacement than incontinent patients 3 weeks postoperatively; however, this did not reach statistical significance (p = 0.13 and 0.59, respectively) (table 3, figure 1). at 3 weeks following rarp, there were no significant differences in age (p = 0.99), bmi (p = 0.83), prostate weight (p = 0.94), tumor volume (p = 0.072), or nerve-sparing status (p = 0.50) between continent and incontinent men. at 6 weeks following surgery, there was no significant difference between sus, bc, and pr displacement between continent (n = 38) and incontinent men (n = 2). there was good test-retest reliability of pfm displacement measures, with icc ranging from 0.86 to 0.99 (p < 0.001) (table 4). discussion our study investigated preand postoperative voluntary pfm function and ppi at 3 and 6 weeks following rarp. tpus was used to measure displacement of anatomical landmarks that are associated with pfm activation. our primary findings were (1) a significant decrease in pfm function at 3 weeks following rarp, (2) a significant increase in postoperative pfm function between weeks 3 and 6, and (3) sus activation was significantly greater in continent patients compared to incontinent patients at 3 weeks following rarp. the preand postoperative tpus assessment of pfm function and its relationship with return to continence adds new knowledge to our understanding of the etiology and clinical management of ppi. table 4. test-retest reliability coefficients for pelvic floor muscle displacement measures icc 95% ci p-value preoperative 0.88 0.52–0.97 < 0.001 sus 3 weeks 0.99 0.95–0.98 < 0.001 6 weeks 0.93 0.77–0.98 < 0.001 preoperative 0.97 0.79–0.99 < 0.001 bc 3 weeks 0.95 0.80–0.99 < 0.001 6 weeks 0.86 0.52–0.96 < 0.001 preoperative 0.96 0.66–0.99 < 0.001 pr 3 weeks 0.93 0.74–0.98 < 0.001 6 weeks 0.89 0.51–0.98 < 0.001 bc: bulbocavernosus muscle; ci: confidence interval; icc: intraclass correlation coefficient; pr: puborectalis muscle; sus: striated urethral sphincter. tpus is a noninvasive and accessible imaging modality that can provide clinicians with the ability to reliably assess pfm function prior to and following rarp, and thereby assess the effects of rarp and pfm training on continence recovery. milios et al. (2019) demonstrated that pfm training results in an improvement in the speed and endurance of pfm contractions postoperatively. men who did not undergo pfm training had greater 24-hour pad weights; however, the authors did not correlate pfm function with continence status[16]. there is a paucity of knowledge in the literature regarding preand postoperative pfm function, with only a handful of studies comparing pfm between time points. colarieti et al. (2022) demonstrated the feasibility and technique of tpus assessment of men prior to and following rarp but similarly did not correlate pfm function with continence status[17]. stafford et al. (2022) investigated sus, bc, and pr function at 2 weeks preand postoperatively in men who had undergone pfm training. sus activation was significantly greater in continent men[18]. we also observed a significant difference in sus activation between continent and incontinent patients at 3 weeks following rarp. we used pad number as an objective measure of continence. the daily number of pads is widely used in clinical practice and has been correlated with 24-hour pad weight[22,23]. our preand postoperative tpus assessment of pfm function provides further evidence that sus activation may contribute to early continence recovery. ppi occurs when urethral pressure is less than bladder pressure, which can occur due to urethral sphincter insufficiency following radical prostatectomy[24]. urodynamic inves207siuj.org siuj • volume 4, number 3 • may 2023 pelvic floor muscle function and its relationship with post-prostatectomy incontinence http://siuj.org tigations before and after radical prostatectomy report on the importance of urethral sphincter closure and the capacity of the sus to increase urethral pressure[4–8]. the sus forms a muscular coat in an omega-shaped loop that surrounds the entire length of the membranous urethra[25]. activation of the sus following radical prostatectomy is important for increasing urethral pressure due to removal of the prostatic urethra containing smooth muscle[26]. our longitudinal study design incorporated standardized preand postoperative (3 and 6 weeks) tpus assessments of pfm function at uniform time points. while we identified a decrease in pfm function at 3 weeks following rarp, sus and bc activation had returned to preoperative levels at 6 weeks, with a 95% continence recovery rate. this provides novel insight into the pattern of perioperative pfm function. it is important to consider the surgical factors that may contribute to the reduction in pfm function in the early postoperative period, including trauma during prostate resection and temporary disruption to the sphincteric innervation (neuropraxia)[27]. the mechanisms underlying recovery of pfm function are likely to include minimal intraoperative trauma to sus and bc fibers, full postoperative recovery of any neuropraxia, and the targeted pfm training program. by targeting and training the sus rather than the pr and the anal sphincter, we reasoned that the pfm training program would have a direct effect on increasing urethral pressure and therefore an earlier return to continence. we hypothesize that the effects of the preand postoperative pfm training were able to be maximized due to optimal surgical and postoperative recovery factors. however, we did not include a control group of patients that underwent rarp and were not given comprehensive pfm training. hence, we are unable to draw conclusions regarding whether the pfm training or intraoperative or postoperative recovery factors were responsible for recovery of pfm function at postoperative 6 weeks. future randomized controlled trials will help to determine how these factors contribute to continence recovery[28]. furthermore, there was less pr displacement at 6 weeks following surgery, which is consistent with recent studies[18,19]. this reduction in pr displacement may be due to either reduced pr activation or reduced capacity for pr displacement postoperatively. pr displacement may be affected by intraoperative disruption of pelvic fascial structures, including denonvilliers’ fascia, periprostatic fascia, endopelvic fascia, and puboprostatic ligaments[27]. there is emerging evidence that high-volume centers and greater surgeon experience with an annual surgical case load of greater than 50 cases results in improved ppi recovery time[29,30]. furthermore, the increasing use of robotic surgery and improvements in surgical technique have accelerated continence recovery following radical prostatectomy[3]. hence, variation among surgeons and techniques must be considered when conducting comparative analysis of factors influencing ppi rates, and efforts should be made to decrease the heterogeneity of the study cohort. we attempted to minimize possible confounding factors of surgical expertise and technique by limiting our series to participants who underwent rarp by a single high-volume robotic surgeon. meanwhile, previous studies have reported differing surgical approaches and techniques[10,16,18] and unspecified number and expertise of surgeons[10,17–19]. our study has several limitations. while a single surgeon series was chosen to reduce the confounding effect of surgeon experience and differing surgical technique, it may not be representative of a broader rarp population. a larger, multicenter study with high-volume surgeons should be considered to confirm our findings. furthermore, all patients in our study underwent a pfm training program, hence, our findings can be applied only to men who have had pfm training, particularly a program targeted for sus activation. there was a 23% loss to follow-up, as these patients did not return to complete their postoperative pfm training program. the postoperative training program may have been bothersome for patients to attend. it is unclear whether return of continence status contributed to why these patients did not complete the postoperative pfm training program. our study focuses on the early postoperative period, as 95% of participants had ≤ 1 pad usage daily at postoperative 6 weeks. while we demonstrated that sus activation is important in early postoperative continence control, we cannot comment on the importance of sus activation in long-term follow-up. a longer study period would be useful in providing more longitudinal data on long-term ppi rates and whether pfm function continues to increase in continent patients following rarp. conclusions a significant decrease in pfm function occurs following r arp, with a subsequent significant recovery of postoperative pfm function between 3 and 6 weeks in men who undergo a pfm training program. sus activation was significantly greater in continent patients compared to incontinent patients at 3 weeks following rarp. acknowledgements funding statement: this was an investigatorinitiated study that was supported by funding from westmead private physiotherapy services and the clinical research institute. 208 siuj • volume 4, number 3 • may 2023 siuj.org original research http://siuj.org ethics approval statement: the study was approved by the western sydney local health district human research ethics committee (eth02769). patient consent statement: informed written consent was provided by each participant. author contributions: c.p. was involved in investigation, data curation, data analysis, and writing and reviewing of the manuscript. m.p. was involved in project conceptualization, supervision, and writing and reviewing of the manuscript. s.m. was involved in project conceptualization, supervision, investigation, data curation, 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ashton-miller ja, constantinou ce, hodges pw. a new method to quantify male pelvic floor displacement from 2d transperineal ultrasound images. urology.2013;81(3):685 – 689. doi: 10.1016/j.urology.2012.11.034. pmid: 23332998; pmcid: pmc4123322. 13. hodges pw, stafford re, hall l, neumann p, morrison s, frawley h, et al. reconsideration of pelvic floor muscle training to prevent and treat incontinence after radical prostatectomy. urol oncol.2020;38(5):354– 371. doi: 10.1016/j.urolonc.2019.12.007. pmid: 31882228. 14. stafford re, coughlin g, lutton nj, hodges pw. validity of estimation of pelvic floor muscle activity from transperineal ultrasound imaging in men. plos one.2015;10(12):e014 4342. doi: 10.1371/journal. pone.0144342. pmid: 26642347; pmcid: pmc4671687. 15. cowley d, stafford re, hodges pw. the repeatability of measurements of male pelvic floor anatomy and function made from transperineal ultrasound images of healthy men and those before and after prostatectomy. neurourol urodyn.2021;40(6):1539–1549. doi: 10.1002/ nau.24701. pmid: 34130355. 16. milios je, ackland tr, green dj. pelvic floor muscle training in radical prostatectomy: a randomized controlled trial of the impacts on pelvic floor muscle function and urinary incontinence. bmc urol.2019;19(1).116. doi: 10.1186/s12894-019-0546-5. pmid: 31729959; pmcid: pmc6858748. 17. colarieti a, shaida n, thiruchelvam n, barrett t. transperineal ultrasound before and after prostatectomy: technical approach and description. j ultrasound med.2022;41(12):3125–3135. doi: 10.1002/ jum.16064. pmid: 35866181; pmcid: pmc9796877. 209siuj.org siuj • volume 4, number 3 • may 2023 pelvic floor muscle function and its relationship with post-prostatectomy incontinence http://siuj.org 18. stafford re, doorbar-baptist s, hodges pw. the relationship between preand postprostatectomy measures of pelvic floor muscle function and development of early incontinence after surgery. neurourol urodyn.2022;41(8):1722–1730. doi: 10.1002/nau.25034. pmid: 36066088; pmcid: pmc9826381. 19. cowley d, stafford re, hodges pw. the influence of prostatectomy and body position on location and displacement of pelvic landmarks with pelvic floor muscle contraction. neurourol urodyn.2021;41(1):203–210. doi: 10.1002/nau.24794. pmid: 34529870. 20. mungovan sf, carlsson sv, gass gc, graham pl, sandhu js, akin o, et al. preoperative exercise inter ventions to optimize continence outcomes following radical prostatectomy. nat rev urol.2021;18(5):259–281. doi: 10.1038/s41585-021-00445-5. pmid: 33833445; pmcid: pmc8030653. 21. koo tk, li my. a guideline of selecting and reporting intraclass correlation coef ficients for reliabilit y research. j chiropr med.2016;15(2):155 –163. doi: 10.1016/j.jcm.2016.02.012. pmid: 27330520; pmcid: pmc4913118. 22. nitti v, mourtzinos a, brucker bm; sufu pad test study group. correlation of patient perception of pad use with objective degree of incontinence measured by pad test in men with post-prostatectomy incontinence: the sufu pad test study. j urol.2014;192(3):836–842. doi: 10.1016/j.juro.2014.03.031. pmid: 24650425. 23. pham ct, patel mi, mungovan sf. pad weight, pad number and incontinence-related patient-reported outcome measures after radical prostatectomy. soc int urol j.2022;3(3):124 –130. doi: 10.48083/10.48083/tiwq1657. 24. kalejaiye o, vij m, drake mj. classification of stress urinar y incontinence. world j urol.2015;33(9):1215 –1220. doi: 10.1007/ s00345-015-1617-1. pmid: 26108731. 25. strasser h, frauscher f, helweg g, colleselli k, reissigl a, bartsch g. transurethral ultrasound: evaluation of anatomy and function of the rhabdosphincter of the male urethra. j urol.1998;159(1):100–104; discussion 104–105. doi: 10.1016/s0022-5347(01)64025-4. pmid: 9400446. 26. walz j, epstein ji, ganzer r, graefen m, guazzoni g, kaouk j, et al. a critical analysis of the current knowledge of surgical anatomy of the prostate related to optimisation of cancer control and preservation of continence and erection in candidates for radical prostatectomy: an update. eur urol.2016;70(2):301–311. doi: 10.1016/j. eururo.2016.01.026. pmid: 26850969. 27. heesakkers j, farag f, bauer rm, sandhu j, de ridder d, stenzl a. pathophysiology and contributing factors in postprostatectomy incontinence: a review. eur urol.2017;71(6):936–944. doi: 10.1016/j. eururo.2016.09.031. pmid: 27720536. 28. hodges p, stafford r, coughlin gd, kasza j, ashton-miller j, cameron ap, et al. efficacy of a personalised pelvic floor muscle training programme on urinary incontinence after radical prostatectomy (matchup): protocol for a randomised controlled trial. bmj open.2019;9(5):e028288. doi: 10.1136/bmjopen-2018-028288. pmid: 31061057; pmcid: pmc6502040. 29. haese a, knipper s, isbarn h, heinzer h, tilki d, salomon g, et al. a comparative study of robot-assisted and open radical prostatectomy in 10 790 men treated by highly trained surgeons for both procedures. bju int.2019;123(6):1031–1040. doi: 10.1111/bju.14760. pmid: 30927303. 30. trieu d, ju ie, chang sb, mungovan sf, patel mi. surgeon case volume and continence recovery following radical prostatectomy: a systematic review. anz j surg.2020;91(4):521–529. doi: 10.1111/ans.16491. pmid: 33319438. 210 siuj • volume 4, number 3 • may 2023 siuj.org original research http://siuj.org 155siuj.org siuj • volume 4, number 3 • may 2023 volume 4, number 3 | may 2023 issn 2563-6499 10.48083/aglr3780 editorial office info@siuj.org tel: 514-875-5665 ext. 26 siuj.org managing editor jane fairbanks jane.fairbanks@siu-urology.org the siuj is published 6 times a year by the société internationale d'urologie (siu). it is the official peer-reviewed publication of the siu but retains editorial independence. the siuj is circulated to urologists, urology residents, family medicine specialists, family medicine residents, general practitioners, nurses, medical libraries, and hospital and university departments of 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adam, mbbch south africa wayne lam, mbbs hong kong sar fahad alyami, mbbs saudi arabia sang dong lee, md korea mohsen azli, md algeria medina ndoye, md senegal erdem canda, md türkiye andrea necchi, md italy yao-chi chuang, md taiwan dedan opondo, mbchb kenya archil chkhotua, md georgia karima oualla, md morocco renu eapen, mbbs australia lourdes guerrios rivera, md puerto rico agus rizal ardy hariandy hamid, md indonesia mohammed shahait, md jordan thomas herrmann, md switzerland khurram siddiqui, mbbs oman christopher ho chee kong, md malaysia yaya sow, md senegal theocharis karaolides, md cyprus chuan-liang xu, md china abdol mohammad kajbafzadeh, md iran the société internationale d’urologie (siu). the society’s mission is to enable urologists in all nations, through international cooperation in education and research, to apply the highest standards of urological care to their patients. the siu is a major international platform for sustainable urological education and collaborative 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advertising advisory board. http://siuj.org mailto:susie.petrusa%40siu-urology.org?subject=siuj mailto:susie.petrusa%40siu-urology.org?subject=siuj mailto:info%40studiosamdesign.com%20?subject=siuj mailto:info%40studiosamdesign.com%20?subject=siuj mailto:info%40aikitech.ca?subject=siuj this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information frailty, bladder cancer, turbt, postoperative complications, risk assessment none declared. received on august 15, 2022 accepted on october 22, 2022 soc int urol j. 2023;4(3):187–194 doi: 10.48083/nqef6409 187siuj.org siuj • volume 4, number 3 • may 2023 original research a prospective evaluation of different frailty indices in patients undergoing transurethral resection of bladder tumor neebal abunaser,1 adnan elachkar,2 mohamad k. abou chaar,1 ali ababneh,1 sattam a. halaseh,1 ala’a farkouh,1 ramiz abo-hijleh,3 awni d. shahait,4 samer salah,5 mohammed shahait1 1 surgery department, king hussein cancer center, amman, jordan 2 surgery department, american university of beirut medical center, beirut, lebanon 3 radiation oncology department, king hussein cancer center, amman, jordan 4 surgery department, wayne state university, michigan, united states 5 medical department, king hussein cancer center, amman, jordan abstract background most studies investigating the relationship between preoperative frailty and postoperative outcomes among bladder cancer patients only assess frailty retrospectively in patients who have undergone radical cystectomy. transurethral resection of bladder tumor (turbt) is a commonly performed procedure in outpatient settings for a large number of bladder cancer patients. the prevalence of frailty among bladder cancer patients and its impact on postoperative complications and mortality are not well studied. methods to assess the prevalence of frailty among bladder cancer patients planned for turbt at a tertiary cancer center using the modified frailty index (mfi) and risk analysis index (rai) and further assess the impact of these indices on 30-day postoperative complications and mortality rates. results between may 2020 and march 2021, 343 consecutive patients were enrolled. the mean age of the cohort was 64.8 ± 13.1 years, 86.6% were male, and 82% had non–muscle-invasive bladder cancer (nmibc). the majority of the cohort (92%) was found to have low american society of anesthesiologists (asa) score class (i + ii), while 35.3% were labeled as frail using mfi 2+, and 32.1% based on rai (iii, iv). the 30-day readmission, postoperative complications, and mortality rates in this cohort were 3.8%, 2.3%, and 6.6%, respectively. rai was a better indicator of mortality compared to mfi. as such, patients with low rai score (i, ii) had 0.054 odds for 30-day mortality compared to the patients with high rai score (iii, iv) (or 0.054; ci 95%, 0.004 to 0.784; p = 0.033). conclusion frailty, as measured by risk analysis index, is an independent predictor of early mortality in patients undergoing turbt. preoperative frailty assessment may improve risk stratification and patient counseling prior to surgery. introduction frailty, a state of decreased homeostatic reserve, is characterized by dysregulation across multiple physiologic and molecular pathways, and a limited ability to compensate for and recover from stressors. it is particularly relevant to the perioperative period, during which patients are subject to high levels of stress and inflammation. surgery is a major stressor, and current preoperative evaluation methods fail to assess the physiological reserve of patients with the same chronological age. frailty has been shown to be an independent predictor of prolonged length of stay in hospital and increased postoperative complications[1]. frailty is an age-independent index, which is more prevalent in elderly due to an increase in comorbidities and functional decline. the routine implementation of a frailty assessment could provide a more comprehensive and individualized perioperative risk stratification[1–4]. http://siuj.org mailto:mshahait%40yahoo.com?subject=siuj.org most studies investigating the relationship between preoperative frailty and postoperative outcome only assess frailty retrospectively, and the actual benefit from a routine frailty assessment followed by an individualized treatment plan is lacking[5–7]. in muscle-invasive bladder cancer (mibc), fried frailty criteria (ffc) including grip strength, gait speed, exhaustion, physical activity, and shrinking was predictive of highgrade complications in patients undergoing radical cystectomy. performance status, tumor size, and extent of resection are perioperative factors associated with postoperative complications and mortality in patients undergoing transurethral resection of bladder tumor (turbt)[8]. the prevalence of frailty varies widely between different cohorts, yet frailty is one of the most significant factors affecting outcomes. modified frailty index (mfi) and risk analysis index (rai) are frailty assessment scores that involve 11 and 15 items, respectively, which include important factors such as functional status, chronic obstructive pulmonary disease (copd), and recent pneumonia as well as activities of daily living. both indices have been used previously to predict mm, but they have never been assessed prospectively in patients undergoing turbt[8–10]. in this study we aim to assess the prevalence of frailty among bladder cancer patients planned for staging and restaging turbt using mfi and rai, and assess the impact of frailty indices on 30-day postoperative complications and mortality[8]. methods this is a prospective observational study of bladder cancer patients planned for staging and restaging turbt at a tertiary cancer center that seeks to assess t he preva lence of frailt y preoperatively and its relationship to 30-day postoperative complications and mortality rates. between may 2020 and march 2021, 343 bladder cancer patients who were planned for staging turbt abbreviations asa american society of anesthesiologists auc area under the curve ci confidence interval mfi modified frailty index mibc muscle-invasive bladder cancer nmibc non–muscle-invasive bladder cancer os overall survival rai risk analysis index roc receiver operating characteristic turbt transurethral resection of bladder tumor or restaging turbt were identified. we prospectively collected mfi and rai for those patients with bladder cancer who were planned for staging and restaging turbt and collected the 30-day postoperative complications and mortality rates after the planned procedure. all patients were mandated to have a negative covid-19 pcr test result 24 hours before the surgery. participants were enrolled before the surgical intervention. during the encounter, a member of the treatment team filled out the required information for the frailty scale. patients received a unique identifier number that was maintained in our research database in a secure, encrypted, password-locked file and on an institutionally secured and managed device. 30-day postoperative complications and mortality were collected prospectively from the hospital administrative database. the database is linked to the national population census, and any death incident is captured without specific cause of death. as part of the routine follow-up for outpatient procedures in our institution, all patients receive calls on days 1, 7, and 28 post-discharge, any events such as admission in another facility, or intervention usually documented in the patients’ chart. the mfi was proposed and validated by chimukangara et al., and the following variables were included: copd or recent pneumonia, congestive heart failure, functional status (not independent), hypertension requiring medications, and diabetes mellitus. this was an abridged version of the 11-item mfi. the score is calculated by the number of listed comorbidities, and it’s categorized as 0, 1, and 2+. the higher the score, the sicker the patient[9]. rai assessment is based on 15-item survey relying on patients’ reporting and includes 4 items to evaluate activities of daily living and other 11 variables, which overall predicts 6-month mortality based on analysis of minimum data set mortality risk index-revised. the score is classified into 4 groups: class i: ≤ 15; class ii: 16–25; class iii: 26–35; and class iv: ≥ 36[10]. univariate analyses were performed using the chi-square and unpaired student t test for categorical and continuous variables, respectively. a receiver operating characteristic (roc) curve was generated with a 95% confidence interval (ci) for the area under the curve (auc). multivariate logistic regression analysis adjusting for preoperative variables was performed to identify predictors of mortality. univariate cox regression analysis was performed to identify correlation between mfi, rai, and stage of cancer with overall survival (os). kaplan-meier survival was utilized to determine os and stage-specific survival. a p-value < 0.05 was considered statistically significant. all analyses were performed using spss (ibm corp. released 2017. ibm spss statistics for windows, version 25.0. 188 siuj • volume 4, number 3 • may 2023 siuj.org original research http://siuj.org armonk, new  york: ibm corp.). this study was approved by the institutional review board at king hussein cancer center, amman, jordan (protocol number: 20-khcc-43). results in total, 343 bladder cancer patients participated in the study. the mean age of the cohort was 64.8 ± 13.1 years, 86.6% were male, and 87.5% had non–muscle-invasive bladder cancer (nmibc). of the cohort, 92% were found to have low american society of anesthesiologists (asa) class (i + ii). overall, 60.9% of the patients had stage 0 disease, 21.9% had stage 1, and only 5.8% had metastatic disease. preoperatively, among the 343 patients, 129 (37.6%) received intravesical treatment with either bacillus calmette-guérin (bcg) or chemotherapy such as mitomycin. patients with mibc were more likely to have a higher asa class, were more frail based on both rai and mfi scores, and had lower preoperative hemoglobin and preoperative albumin levels. all these factors might explain why these patients had a higher mortality rate compared to nmibc (table 1). tables 2 and 3 display the prevalence of frailty, and operative and postoperative outcomes using the mfi and rai, respectively. while 35.3% of the patients were labeled as frail using mfi 2+, 32.1% were labeled frail based on rai (iii, iv). the 30-day readmission, postoperative complications, and overall mortality rates in the entire cohort were 3.8%, 2.3%, and 6.6%, respectively. table 4 summarizes the recorded complications in our cohort. rai was a better indicator of the mortality compared to mfi (auc, 0.832; p = 0.049; and auc, 0.672; p = 0.063, respectively), as shown in figure 1. rai at a cutoff of 26.5 has 81.0% sensitivity and 57.8% specificity in predicting post-turbt mortality identified by roc. as such, patients with a low rai score (i, ii) had 0.054 odds for mortality compared to patients with a high rai score (iii, iv) (95% ci, 0.004–0.784; p = 0.033), using logistic regression analysis. as illustrated in figure 2, kaplan-meier curve shows os difference between different cancer stages and invasiveness. similarly, figures 3 and 4 show kaplanmeier curves for os by mfi and rai classifications. cox regression analysis showed that mibc status had a hazard ratio (hr) of 0.051 (95% ci 0.013 to 0.202; p < 0.001), and other factors such as mfi and rai did not have a significant impact on os. discussion in this study, using both r ai and mfi to assess the relationship between preoperative frailty and table 1. patients' characteristics, and operative and postoperative outcomes based on muscular invasiveness n (%) non–muscleinvasive bladder cancer 300 (87.5%) muscle-invasive bladder cancer 43 (12.5%) gender male 260 (86.7%) 37 (86.0%) female 40 (13.3%) 6 (14.0%) age, mean ± sd (years) 64.8 ± 13.1 64.7 ± 14.1 bmi, mean ± sd (kg/m2) 28.9 ± 5.3 27.2 ± 5.5 asa class i + ii 281 (93.7%) 35 (81.4%) ≥ iii 19 (6.3%) 8 (18.6%) previous intravesical treatment 109 (36.3%) 20 (46.5%) re-turbt 109 (36.3%) 20 (46.5%) previous radiotherapy 0 (0.0%) 2 (4.7%) 30-day complications 8 (2.7%) 0 (0.0%) all-cause mortality 4 (1.4%) 17 (40.5%) readmission 10 (3.3%) 3 (7.0%) rai i (1–15) 1 (0.3%) 0 (0.0%) ii (16–25) 216 (72.0%) 16 (37.2%) iii (26–35) 55 (18.3%) 5 (11.6%) iv (≥36) 28 (9.3%) 22 (51.2%) mfi 0 114 (38.0%) 9 (20.9%) 1 82 (27.3%) 17 (39.5%) +2 104 (34.7%) 17 (39.5%) preoperative hemoglobin, mean ± sd (g/dl) 14.9 ± 8.1 12.8 ± 1.6 hypoalbuminemia (<3.5 g/dl) 4 (1.3%) 6 (14.0%) ebl, mean ± sd (ml) 9.4 ± 34.9 26.5 ± 46.3 asa: american society of anesthesiologists; bmi: body mass index; ebl: estimated blood loss; mfi: modified frailty index; rai: risk analysis index; sd: standard deviation; turbt: transurethral resection of bladder tumor. 189siuj.org siuj • volume 4, number 3 • may 2023 a prospective evaluation of different frailty indices in patients undergoing transurethral resection of bladder tumor http://siuj.org table 2. patients' characteristics, and operative and postoperative outcomes of the different 5-item mfi n (%) all 343 mfi = 0 123 (35.9%) mfi = 1 99 (28.9%) mfi ≥ 2+ 121 (35.3%) p-value gender 0.451 male 297 (86.6%) 109 (31.8%) 87 (25.4%) 101 (29.4%) female 46 (13.4%) 14 (4.1%) 12 (3.5%) 20 (5.8%) age, mean ± sd (years) 64.8 ± 13.1 59.1 ± 10.1 64.9 ± 11.5 70.6 ± 9.1 0.034 bmi, mean ± sd (kg/m2) 28.7 ± 5.3 28.0 ± 5.8 28.9 ± 5.1 29.3 ± 5.0 0.165 asa class <0.001 i + ii 316 (92.1%) 123 (35.9%) 91 (26.5%) 102 (29.7%) ≥ iii 27 (7.9%) 0 (0.0%) 8 (2.3%) 19 (5.5%) clinical cancer stage 0.089 0 209 (60.9%) 78 (22.7%) 63 (18.4%) 68 (19.8%) i 75 (21.9%) 30 (8.7%) 18 (5.2%) 27 (7.9%) ii 21 (6.1%) 3 (0.9%) 11 (3.2%) 7 (2.0%) iii 2 (0.6%) 1 (0.3%) 1 (0.3%) 0 (0.0%) iv 20 (5.8%) 5 (1.5%) 5 (1.5%) 10 (2.9%) previous intravesical treatment 129 (37.6%) 45 (13.1%) 37 (10.8%) 47 (13.7%) 0.934 previous radiotherapy 2 (0.6%) 0 (0.0%) 0 (0.0%) 2 (0.6%) 0.158 30-day complications 8 (2.3%) 6 (1.7%) 0 (0.0%) 2 (0.6%) 0.047 all-cause mortality 21 (6.6%) 4 (1.3%) 3 (0.9%) 14 (4.4%) 0.009 readmission 13 (3.8%) 6 (1.7%) 4 (1.2%) 3 (0.9%) 0.611 rai <0.001 i (1–15) 1 (0.3%) 1 (0.3%) 0 (0.0%) 0 (0.0%) ii (16–25) 232 (67.6%) 116 (33.8%) 69 (20.1%) 47 (13.7%) iii (26–35) 60 (17.5%) 5 (1.5%) 21 (6.1%) 34 (9.9%) iv (≥ 36) 50 (14.6%) 1 (0.3%) 9 (2.6%) 40 (11.7%) preoperative hemoglobin, mean ± sd (g/dl) 14.6 ± 7.7 14.8 ± 1.8 15.6 ± 13.9 13.6 ± 1.8 0.147 hypoalbuminemia (<3.5 g/dl) 10 (2.9%) 2 (0.6%) 3 (0.9%) 5 (1.5%) 0.507 ebl, mean ± sd (ml) 11.5 ± 36.2 9.7 ± 29.5 11.9 ± 21.8 12.8 ± 49.5 0.792 asa: american society of anesthesiologists; bmi: body mass index; ebl: estimated blood loss; mfi: modified frailty index; rai: risk analysis index; sd: standard deviation. 190 siuj • volume 4, number 3 • may 2023 siuj.org original research http://siuj.org postoperative outcomes among bladder cancer patients who underwent staging and restaging turbt, our results revealed that although mfi labeled a higher percentage of patients as frail in comparison to rai, rai was better in predicting mortality rates post-turbt. however, frailty as assessed by rai and mfi was not a predictor of overall survival. frailty index is used as a predictor of postoperative mortality. previous studies have found an association between high mfi and postoperative complications and mortality in patients with mibc, as patients with table 3. patients' characteristics, and operative and postoperative outcomes of the different rai classes n (%) all i (0–15) 1 (0.3%) ii (15–25) 232 (67.6%) iii (26–35) 60 (17.5%) iv (> 35) 50 (14.6%) p-value gender 0.085 male 297 (86.6%) 0 (0.0%) 201 (58.6%) 53 (15.5%) 43 (12.5%) female 46 (13.4%) 1 (0.3%) 31 (9.0%) 7 (2.0%) 7 (2.0%) age, mean ± sd (years) 64.8 ± 13.1 33.0 ± 0.0 60.8 ± 41.2 74.6 ± 6.2 72.3 ± 14.4 0.012 bmi, mean ± sd (kg/m2) 28.7 ± 5.3 28.1 ± 0.0 29.2 ± 5.4 26.8 ± 5.4 28.7 ± 5.3 0.034 asa class 0.001 i + ii 316 (92.1%) 1 (0.3%) 222 (64.7%) 53(15.5%) 40 (11.7%) ≥ iii 27 (7.9%) 0 (0.0%) 10 (2.9%) 7 (2.0%) 10 (2.9%) clinical cancer stage <0.001 0 209 (60.9%) 1 (0.3%) 152 (44.3%) 36 (10.5%) 20 (5.8%) i 75 (21.9%) 0 (0.0%) 53 (15.5%) 15 (4.4%) 7 (2.0%) ii 21 (6.1%) 0 (0.0%) 10 (2.9%) 3 (0.9%) 8 (2.3%) iii 2 (0.6%) 0 (0.0%) 0 (0.0%) 1 (0.3%) 1 (0.3%) iv 20 (5.8%) 0 (0.0%) 6 (1.7%) 1 (0.3%) 13 (3.8%) previous intravesical treatment 129 (37.6%) 0 (0.0%) 92 (26.8%) 18 (5.2%) 19 (5.5%) 0.475 previous radiotherapy 2 (0.6%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 2 (0.6%) 0.008 30-day complications 8 (2.3%) 0 (0.0%) 6 (1.7%) 1 (0.3%) 1 (0.3%) 0.973 all-cause mortality 21 (6.6%) 0 (0.0%) 4 (1.3%) 3 (0.9%) 14 (4.4%) <0.001 readmission 13 (3.8%) 0 (0.0%) 9 (2.6%) 3 (0.9%)1 1 (0.3%) 0.611 preoperative hemoglobin, mean ± sd (g/dl) 14.6 ± 7.7 11.0 ± 0.0 15.3 ± 9.1 13.6 ± 1.7 12.9 ± 2.0 0.115 hypoalbuminemia (<3.5 g/dl) 10 (2.9%) 0 (0.0%) 0 (0.0%) 3 (0.9%) 7 (2.0%) <0.001 ebl, mean ± sd (ml) 11.5 ± 36.2 5.0 ± 0.0 10.6 ± 38.5 9.4 ± 15.2 18.2 ± 42.7 0.550 asa: american society of anesthesiologists; bmi: body mass index; ebl: estimated blood loss; mfi: modified frailty index; rai: risk analysis index; sd: standard deviation. table 4. postoperative complications n (%) overall rate 8 (2.3) urine retention 2 (0.6) pneumonia 1 (0.3) hematuria 2 (0.6) urinary tract infection 1 (0.3) 191siuj.org siuj • volume 4, number 3 • may 2023 a prospective evaluation of different frailty indices in patients undergoing transurethral resection of bladder tumor http://siuj.org figure 1. receiver operating characteristic (roc) curves for risk analysis index (rai) with an area under curve (auc) = 0.832, p = 0.049, and modified frailty index (mfi) with auc = 0.672, p = 0.063. figure 4. kaplan-meier curve for overall survival for bladder cancer by risk analysis index (rai) classification (i-iv); log-rank test for survival was significant (p < 0.001). mean follow-up period (months): rai class 1, 6.7; class 2, 30.5; class 3, 29.3; class 4, 30.7. figure 3. kaplan-meier curve for overall survival for bladder cancer by modified frailty index (mfi) classification; log-rank test for survival was significant (p = 0.001). mean follow-up period (months): mfi 0, 30.7; mfi 1, 26.9; mfi +2, 32.7. figure 2. kaplan-meier curve for overall survival for bladder cancer by invasiveness and stage; log-rank test for survival was significant (p < 0.001). mean follow-up period (months): nmibc, 31.1; mibc, 21.3; stage iv, 25.6; unknown, 38.2. mibc: muscle-invasive bladder cancer; nmibc: non–muscle-invasive bladder cancer. pa tie nt s a liv e (% ) follow-up period (months) 1.0 0.8 0.6 0.4 0.2 0.0 50.00 100.00 150.00 200.00 250.00.00 cancer stages nmibc mibc (stage ii+iii) stage iv unknown stage roc curve 1 speci�city se ns iti vi ty 1.0 0.8 0.6 0.4 0.2 0.0 0.2 0.4 0.6 0.8 1.0 0.0 source of curve rai mfi reference line 1.0 0.8 0.6 0.4 0.2 0.0 50.00 100.00 150.00 200.00 250.00.00 mfi 0 1 +2 pa tie nt s a liv e (% ) follow-up period (months) 1.0 0.8 0.6 0.4 0.2 0.0 50.00 100.00 150.00 200.00 250.00.00 rai i ii iviii pa tie nt s a liv e (% ) follow-up period (months) 192 siuj • volume 4, number 3 • may 2023 siuj.org original research http://siuj.org clavien-dindo grade ≥ 3 at 30 and 90 days postoperatively had significantly higher mfi compared to patients with clavien-dindo grade < 3—odds ratio of mfi for serious complications within 30 days was 1.5 (95% ci 1.1 to 2.1; p = 0.010) and for 90 days was 1.5 (95% ci 1.1 to 2.1; p = 0.008)[9]. another study that assessed frailty among 2679 bladder cancer patients who underwent radical cystectomy concluded that mfi can identify those patients at greatest risk for severe complications and mortality. when stratified at a cutoff of mfi > 2, the overall complication rate was not different (61.7% vs. 58.3%; p = 0.1), but mfi ≥ 2 group had a significantly higher rate of clavien-dindo grade 4 or 5 complications (14.6% vs. 8.3%; p < 0.001) and overall mortality rate (3.5% vs. 1.8%; p = 0.01) in the 30-day postoperative period[11–13]. our results in the context of turbt are consistent with these prior studies in the context of radical cystectomy. however, because of the low number of complications in our turbt cohort, there was no association between frailty and postoperative complications. our study showed that the prevalence of frailty in patients with mibc was higher than in patients with nmibc, hence the higher mortality rate after turbt. therefore, a different workflow for turbt in patients with suspicious mibc might be needed, where a senior urologist might be involved early on in these cases intraoperatively and define the goal of the procedure, which may involve resection of minimum tissue to establish diagnosis, without resecting the whole intravesical tumor, or considering computed tomography (ct)-guided biopsy to establish diagnosis[14]. recently, there has been heightened interest in incorporating magnetic resonance imaging (mri) in the staging of bladder cancer, as such preliminary data from the bladderpath trial showed that it might be feasible to direct patients with possible mibc to multiparametric mri (mpmri) for staging instead of turbt[15]. it is noteworthy that the 30-day overall mortality rate in our cohort was higher than the observed rate in the national surgical quality improvement program database[16]. this might be explained by several factors such as our institutional database being able to capture death more accurately than complications and readmissions to other hospitals and the fact that large numbers of patients in this cohort were operated during the first wave of covid-19. there are few studies in the literature that use frailty indices prospectively in perioperative planning and management, and even fewer studies examining bladder cancer surgical therapies specifically[3–5]. this is the first prospective study that examined the prevalence of frailty in bladder cancer patients who underwent turbt and used two different tools to assess frailty. in this study, rai was better than mfi in predicting 30-day mortality rates post-turbt. preoperative counseling of bladder cancer patients before turbt usually entails the anticipated oncological outcomes, procedural comorbidities, as well as the need for second-look turbt in high-grade tumors or in instances of inadequate pathology for complete staging[17]. however, surgeons might face challenges using tools such as different postoperative risk calculators, as these calculators use complex formulas requiring extensive clinical history documentation that might limit their applicability during clinical encounters. on the other hand, the rai score is a simple tool that can be rapidly computed by urologists without delaying the patient encounter[18]. there are several limitations to our study including a small sample size and lack of data on tumor size and characteristics. complications were collected prospectively using our institutional database; however, we cannot exclude the possibility that other complications were missed, as some patients may have sought urgent help in other centers. the low number of complications observed in this cohort affected to the ability to study the correlation between frailty and postoperative complications. other frailty measures such as hand grip using manometry were not used in this study due logistical and funding issues. in addition, this data was collected during the first wave of the covid-19 pandemic, and we cannot exclude the influence of covid-19 on the mortality rate. finally, we cannot exclude referral bias to our center. in order to better predict complication rates, larger, well-designed multicenter studies are needed to prospectively examine the efficacy of frailty indices preoperatively in diverse patient categories and for different therapies. nevertheless, despite these limitations, our study represents a robust cross-sectional analysis that correlates preoperative frailty to important 30-day postoperative outcomes conclusion frailty, as measured by risk analysis index, is an independent predictor of adverse early mortality in patients undergoing turbt. preoperative frailty assessment may improve risk stratification and patient counseling prior to surgery. 193siuj.org siuj • volume 4, number 3 • may 2023 a prospective evaluation of different frailty indices in patients undergoing transurethral resection of bladder tumor http://siuj.org references 1. amrock lg, deiner s. the implication of frailty on preoperative risk assessment. curr opin 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mortality in revision hip and knee arthroplasty. j arthroplasty.2019;34(7):1412–1416. doi: 10.1016/j.arth.2019.02.060. pmid: 30930155. 6. wahl ts, graham la, hawn mt, richman j, hollis rh, jones ce, et al. association of the modified frailty index with 30-day surgical readmission. jama surg.2017;152(8):749 –757. doi: 10.1001/ jamasurg.2017.1025. pmid: 28467535; pmcid: pmc5710500. 7. rothenberg ka, stern jr, george el, trickey aw, morris am, hall de, et al. association of frailty and postoperative complications with unplanned readmissions after elective outpatient surgery. jama netw open.2019;2(5):e194330. doi: 10.1001/jamanetworkopen.2019.4330. pmid: 31125103; pmcid: pmc6632151. 8. burg ml , clifford tg, bazargani st, lin-brande m, miranda g, cai j, et al. frailty as a predictor of complications after radical cystectomy: a prospective study of various preoperative assessments. in: urologic oncology: seminars and original investigations. elsevier ; 2019:40–47. 9. chimukangara m, helm mc, frelich mj, bosler me, rein le, szabo a, et al. a 5-item frailty index based on nsqip data correlates with outcomes following paraesophageal hernia repair. surg endosc.2017;31(6):2509–2519. doi: 10.1007/s00464-016-5253-7. pmid: 27699515; pmcid: pmc5378684. 10. 1hall de, arya s, schmid kk, blaser c, carlson ma, bailey tl, et al. development and initial validation of the risk analysis index for measuring frailty in surgical populations. jama surg.2017;152(2):175– 182. doi: 10.1001/jamasurg.2016.4202. pmid: 27893030; pmcid: pmc7140150. 11. shinall mc jr, arya s, youk a, varley p, shah r, massarweh nn, et al. association of preoperative patient frailty and operative stress with postoperative mortality. jama surg.2020;155(1):e194620. doi: 10.1001/jamasurg.2019.4620. pmid: 31721994; pmcid: pmc6865246. 12. voskamp mjh, vermeer m, molijn gj, cornel eb. the usefulness of the modified frailty index for muscle-invasive bladder cancer patients treated with radical cystectomy. curr 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morbidit y of transurethral resection of bladder tumor: implications for quality improvement. urology.2019:125:131–137. doi: 10.1016/j.urology.2018.10.027. pmid: 30366045. 17. ferro m, vartolomei md, cantiello f, lucarelli g, di stasi sm, hurle r, et al. high-grade t1 on re-transurethral resection after initial highgrade t1 confers worse oncological outcomes: results of a multiinstitutional study. urol int.2018;101(1):7–15. doi: 10.1159/000490765. pmid: 29975950. 18. shahait m, labban m, dobbs rw, cheaib jg, lee di, tamim h, et al. a 5-item frailty index for predicting morbidity and mortality after radical prostatectomy: an analysis of the american college of surgeons national surgical quality improvement program database j endourol.2021;35(4):483–489. doi: 10.1089/end.2020.0597. pmid: 32935596. 194 siuj • volume 4, number 3 • may 2023 siuj.org original research http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj.org siuj • volume 4, number 1 • january 2023 rudolf hohenfellner, or rudy, as he is called by all his friends around the world, grew up in austria, where, at the age of 16, he had the terrible experience of being conscripted for the last years of world war ii. he studied medicine in vienna and started his training in the legendary vienna surgery, established by the famous theodor billroth, and then specialized in urology. during residency, he already showed a strong curiosity for external input and traveled to paris to work with urologists like rené küss and roger couvelaire and to munich to learn the new technique of transurethral resection of the prostate from wolfgang mauermayer and ferdinand may. it was not until 1962 that the first academic chair of urology was created in vienna under the direction of richard übelhör, where rudy worked as a senior physician until 1964. he then moved to the urological university clinic in homburg/saar as junior faculty to professor c.e. alken, the doyen of german urology and then the only chair of urology in germany. at t hat time, urolog y as a specia lt y was usua lly under the difficult umbrella of general surgery, and the establishment of urology at german universities started from homburg/saar. rudy then moved to the newly created urologic chair at johannes gutenberg university in mainz in 1967 and retained this position for almost 30 years until his retirement in 1996, turning down various other chairmanships including in vienna and zurich. under his leadership, mainz quickly became the premier address for excellent clinical surgical urological education in germany. rudy always saw the art and craft of operative urology as the central building block for the successful advancement of our specialty. he traveled the world in search of new directions and advances in urology and found many friendly colleagues who subsequently came to mainz as visiting professors to share their knowledge with us. the clinic had a clear international focus: staff meetings, grand rounds, dr. rudolf hohenfellner, a giant in urology laboratory years for residents abroad, mostly in the united  states, and journal clubs. this at a time when medical training was otherwise rather antiquated and boring. rudy introduced 3-day assessment centers for new residents, probably before the term was even invented, and in these 3 days, the applicants not only got to know the clinic, residents, and faculty, but rudy with his enormous knowledge of human nature got a feel for whether the newcomer would fit into the team at mainz. we as his students especially remember rudy's annual return from the meeting of the gusurgeons, which gave us new ideas, inspiration, and work that he distributed among his fellow staff members as projects. he truly and selflessly enjoyed it when he saw co-workers rise and prove themselves at international congresses and thus also increase the reputation of mainz urology. rudy delegated responsibility to his staff very early on. he was indeed a mentor and enabler in the best rudolf hohenfellner, chairman, department of urology, johannes gutenberg university, mainz, germany, 1967 to 1996 jan fichtner,1 margit fisch2 1 klinik für urologie, johanniter krankenhaus oberhausen, germany 2 university medical centre eppendorf, university of hamburg, hamburg, germany soc int urol j. 2023;4(1):67–68 doi: 10.48083/htgy4912 67 giants in urology http://siuj.org sense, stepping back himself to further the careers of others. he was extraordinarily successful with this method: more than 50 chair positions were filled from mainz under his aegis. “the mainzers” were not always viewed positively from the outside, but sometimes with envy and resentment, not only because they were lucky enough to work at this excellent instituion, but also because they were sometimes endowed with a certain arrogance. this culminated in difficult situations in the operating room when rudy had the austrian song “schickeria” played, the lyrics go something like this: “it must be something special, they don’t let people like you and me in, everyone plays a superstar, and sip champagne at the bar…” nothing was a problem for rudy, and he even enjoyed swimming against the tide. this willingness, along with creativity and drive for innovation enabled the achievement of milestones in mainz urology, such as the development of percutaneous nephrolithotomy, the lithostar for extracorporeal shock-wave lithotripsy, the mainz pouch for orthotopic and heterotopic urinary diversion, the introduction of nephron-sparing surgery, and the introduction of buccal mucosa for urethral reconstruction. rudy was president of both the german society of urology and the siu, and he received numerous awards and prizes and was pleased with each one, but the most joyful thing for him in his humble way was to see one of his colleagues succeed. rudy also liked to push the limits in his private life: serious mountaineering, heliskiing, flying, and traveling all over the world. rudy was never about luxury here, but about frontier experiences, and he would trade a luxury hotel for a lonely mountain cabin any day. now in his early nineties, he participates actively in the evolution of his much-loved urology. mountaineers have a saying that the look back to the conquered summit in the evening twilight is the most beautiful thing and we wish rudy many more years to enjoy this. 68 siuj • volume 4, number 1 • january 2023 siuj.org giants in urology http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information social media, some, urosome, academic metrics, urology none declared. received on october 2, 2022 accepted on november 26, 2022 this article has been peer reviewed. soc int urol j. 2023;4(2):88–95 doi: 10.48083/dmpr4183 social media engagement for urology journals — a correlation analysis of traditional and social media metrics wei zheng so,1 ho yee tiong,2 vineet gauhar,3 daniele castellani,4 jeremy yuen-chun teoh5 1 yong loo lin school of medicine, national university of singapore, singapore 2 department of urology, national university hospital, singapore 3 department of urology, ng teng fong general hospital, singapore 4 urology unit, azienda ospedaliero-universitaria ospedali riuniti di ancona, università politecnica delle marche, ancona, italy 5 s.h. ho urology centre, department of surgery, the chinese university of hong kong, hong kong, china abstract introduction the growing adoption of social media (some) by the scientific community has cemented the role of some in information dissemination and engagement of academic work. the objective of this study is to evaluate the relationship between traditional and alternative some metrics of urology journals. methods urology journals listed on the scimago journal & country rank (sjr) electronic portal were selected and data pertaining to traditional metrics were collected. official some platforms of eligible journals were identified and indicators of online activity were recorded. correlations between traditional metrics (sjr, h-index, and scopus citescore) and social metrics were performed via spearman rank-order correlation. results of 107 journals, 54.2% of journals had at least one form of some presence. the median sjr (0.535 versus 0.334, p = 0.005), h-index (34 versus 20, p = 0.001), and scopus citescore (3.25 versus 2.20, p = 0.014) were significantly higher among journals with some networks. all 3 traditional indicators demonstrated strong global correlations with various twitter-based metrics (rs = 0.428 to 0.571). in particular, some journals with more than 3000 citations in the previous 3 years also displayed very strong correlations between all 3 traditional metrics and alternative social metrics (rs = 0.714 to 0.821). conclusions journals with some presence had significantly higher traditional metric values (sjr, h-index, and citescore) compared to journals without some presence. strong, positive correlations between citation-based and alternative social metrics were also observed. alternative social metrics may be harnessed as supplemental indicators of a journal’s scientific impact. introduction today’s currency of communication has largely turned digital in nature after the advent of social media (some) heralded a paradigm shift in human interaction. some, broadly defined as any internet-based web application that empowers real-time electronic communication between users, transcends geographical boundaries and enables instant dissemination of information across the online community. within the realms of health care communication, some has been said to enhance both intraand inter-professional interactions, promote health literacy and education, establish peer support, and design a constructive space for healthy discourse about healthcare practices[1]. 88 siuj • volume 4, number 2 • march 2023 siuj.org original research https://orcid.org/0000-0002-2303-0750 mailto:soweizhengs%40gmail.com?subject=siuj https://orcid.org/0000-0003-0077-7904 https://orcid.org/0000-0002-3740-7141 https://orcid.org/0000-0001-7354-9190 https://orcid.org/0000-0002-9361-2342 http://siuj.org traditionally, the impact of surgical research has always been quantitatively measured with bibliometrics. it takes into consideration numbers and indices that are objectively easier to compare as opposed to qualitative inputs[2]. examples include impact factor (if) [3] based on the science citation index, the scimago journal ranking indicator (sjr)[4], h-index[5], and scopus citescore[6,7]. unfortunately, these parameters are purely academic and fail to consider the social influence of articles across a wider audience. in addition, the accruement of article citations requires time, purporting a “lag time” before a journal’s impact may be accurately assessed[8,9]. in attempts to circumvent these limitations, newer counterparts such as alternative metrics (also known as altmetrics)[10] have been established to specifically track the online presence of a research article across various some platforms, culminating in an algorithmically derived figure that reflects the overall weight of article mentions online. a prior study evaluated whether article altmetric scores correlated with urological journal if and citation counts in 2013 and 2016 respectively, concluding weak correlations between newer and traditional metrics[11]. since then, some adoption within urology has accelerated by leaps and bounds, with over 53% of journals harboring some form of online presence. of the 4 major social networking platforms (twitter, facebook, instagram, youtube), it is worth noting that twitter has drawn the greatest extent of attention and participation of the scientific community, establishing itself as the most active platform for academic discourse[12,13]. our study aims to analyze the use of some by urological journals, hypothesizing that there is a significant correlation between traditional journal (sjr, h-index, and scopus citescore) and some platform metrics while placing a relatively greater emphasis on twitter-based indicators. methods data collection we included all urolog y journals indexed in the elect ronic por ta l scimago journa l & cou nt r y r a n k ( ht t ps://w w w.sci magojr.com /jou r na l ra n k . php?area=2700&categor y=2748)[4]. scimago is a research group affiliated with consejo superior de investigaciones científicas [csic], of the universities from granada, extremadura, carlos iii (madrid), and abbreviations ip impact factor sjr scimago journal ranking indicator some social media alcala de henares. the rankings consider region or country of origin, subject area (27 major thematic areas), and subject category (309 specific subject categories). data are retrieved from over 34 100 titles from more than 5000 international publishers across 239 countries. the sjr score of each journal is unique compared to if, in that it is independent of self-citations, includes noncitable documents such as commentaries and letters to the editor as part of calculating the total number of documents published by a journal, and has a relatively larger geographic and language coverage[14]. moreover, it utilizes the reputable pagerank algorithm, which is famously incorporated by google search engine into its web search[15]. sjr uses it for the assessment of citation quality. the rankings are publicly retrievable alongside other specified indicators for each journal. data from all journals filtered under the subset “medicine” and search term “urology” were collected. the following variables were recorded from the scimago database— sjr index, h-index, latest impact factor (2021), scopus citescore, total number of articles published in the previous 3 years, total citations in the previous 3 years, quartile, open access rights, and region of publication (europe, north america, asia, latin america, africa, and others). referencing the same list, some presence of journals on any of the 4 main social networking platforms (twitter, facebook, instagram, youtube) was evaluated. the following indicators were obtained: date of social media account creation; total number of followers; number of tweets (twitter); number of videos, subscribers, and views (youtube); and number of publications (instagram). the results were time adjusted by considering the duration of account presence on social media to accurately determine audience growth. to ensure that the some accounts sourced were valid and official, only links provided on the official page of the journal were used. some accounts of journal publishing groups were excluded from analysis. data procurement and collection were performed on september 14, 2022. statistical analysis the shapiro-wilk test was used to determine normality of data points. parametric continuous variables were presented as mean ± standard deviation (sd). nonparametric continuous variables were reported as median and range. chi-square tests (or fisher exact test, wherever applicable) were used to compare categorical variables. the mann-whitney u test was used to compare nonparametric continuous variables. relationships between traditional academic (sjr, h-index, and citescore) and alternative some metrics were investigated using spearman rank-order correlation coefficient, using the coefficient of determination (rs) as a measure of the goodness of fit. subgroup correlations were performed wherever appropriate. 89siuj.org siuj • volume 4, number 2 • march 2023 social media engagement for urology journals — a correlation analysis of traditional and social media metrics https://www.scimagojr.com/journalrank.php?area=2700&category=2748 https://www.scimagojr.com/journalrank.php?area=2700&category=2748 http://siuj.org the strength of bivariate correlations was interpreted according to ranges defined by dancey and reidy[16]: rs ≥ 0.70 (very strong), rs 0.40 to 0.69 (strong), rs 0.30 to 0.39 (moderate), rs 0.20 to 0.29 (weak), rs 0.01 to 0.19 (no or negligible). statistical significance in this study was determined as p < 0.05. all reported p-values were 2-sided, and analyses were performed with spss version 26.0 (ibm corp., armonk, ny). journal characteristics a total of 107 urology journals sourced from the scimago journal & country rank portal were included for analysis (supplementary table s1). fifty-eight journals (54.2%) had social media presence on at least 1 major social networking site. when traditional academic metrics were compared across journals with and without some networks, the median sjr (0.535 versus 0.334, p = 0.005), h-index (34 versus 20, p  =  0.001), and scopus citescore (3.25 versus 2.20, p = 0.014) were significantly higher among journals with online presence (table 1). across quartiles, there were significantly more quartile-1 journals within the social media group compared with those without social media (36.2% versus 12.2%, p = 0.002). a significantly higher proportion of journals with some presence had more than 3000 citations over the previous 3 years compared to journals without social networks (12.1% versus 0%, p = 0.021). across both groups, most journal publishers were based in europe and north america. otherwise, there were no other notable differences in baseline characteristics, such as the number of open access journals. table 2 depicts the baseline information of journals with social media presence. fifty-four of 58 journals had a social media account on twitter; 59.3% of them had table 1. traditional academic metrics of journals journals with social media networks journals without social media networks p-value (n = 58) (n = 49) sjr (median, iqr) 0.535 (0.255–0.859) 0.334 (0.127–0.610) 0.005 h-index (median, iqr) 34 (18–75.3) 20 (9–33.5) 0.001 scopus citescore (median, iqr) 3.25 (1.35–5.43) 2.20 (0.3–4.30) 0.014 quartile, n (%) 0.002 q1 21 (36.2) 6 (12.2) q2 12 (20.7) 15 (30.6) q3 17 (29.3) 9 (18.4) q4 8 (13.8) 19 (38.8) open access, n (%) 26 (44.8) 22 (44.9) > 0.05 region of publication 0.196 europe 30 (51.7) 23 (46.9) north america 18 (31) 12 (24.5) asia 4 (6.9) 10 (20.4) latin america 2 (3.4) 0 (0) africa 0 (0) 1 (2) others 4 (6.9) 3 (6.1) number of publications in the previous 3 years, n (%) 0.101 < 250 26 (44.8) 32 (65.3) 250–500 16 (27.6) 10 (20.4) > 500 16 (27.6) 7 (14.3) number of citations in the previous 3 years, n (%) 0.021 < 1000 40 (69) 42 (85.7) 1000–3000 11 (19) 7 (14.3) > 3000 7 (12.1) 0 (0) 90 siuj • volume 4, number 2 • march 2023 siuj.org original research http://siuj.org http://siuj.org at least 1000 followers, accruing a median count of 295 followers per year. the median number of tweets generated across these journals was 797 tweets. twenty-six of 58 journals had a presence on facebook, 7 of 58 journals were present on youtube, and 9 of 58 journals had an instagram account. to encompass a holistic correlation between metrics, our analysis focused mainly on twitterand facebook-derived data. this is in view of the disproportionately low presence of journals on the remainder of the some platforms. journals with some presence and a publisher base in europe observed significantly stronger correlations between their traditional and social metrics (table 3). the sjr indicator demonstrated strong global correlations with various alternative social metrics, such as number of twitter followers (rs  =  0.538), number of twitter followers per year (rs  =  0.503), number of tweets (rs = 0.520), and number of facebook followers (rs = 0.438). in particular, quartile-1 journals (rs = 0.702) and journals with more than 3000 citations (rs = 0.713) demonstrated very strong correlations between sjr and number of twitter followers. likewise, h-index correlated strongly with various social media metrics such as the number of twitter followers (rs = 0.571), number of twitter followers per year (rs = 0.570), and number of tweets (rs = 0.506). journals with more than 500 publications in the previous 3 years displayed relatively strong correlations between h-index and number of twitter followers (rs  =  0.625), number of twitter followers per year (rs  =  0.518), and number of tweets (rs = 0.749). journals with more than 3000 citations in the previous 3 years also displayed very strong correlations between h-index and number of twitter followers (rs  =  0.821) / number of tweets (rs = 0.893). citescore metrics also correlated strongly with various alternative social metrics, such as number of twitter followers (rs  =  0.487), number of twitter followers per year (rs = 0.428), number of tweets (rs = 0.474), and number of facebook followers (rs  =  0.405). journals with more than 500 publications in the previous 3 years displayed relatively strong correlations between citescore and number of twitter followers (rs = 0.578), while journals with more than 3000 citations in the previous 3 years displayed very strong correlations between citescore and number of twitter followers (rs = 0.714) / number of tweets (rs = 0.750). discussion some has revolutionized the way we communicate on a day-to-day basis and interact both professionally and academically. the use of some by the urology community has increased drastically during the past few years[17]. in the present study, we evaluated the correlation between traditional index metrics and some platforms among scimago-indexed urology journals. interestingly, we not only uncovered the prominence of some usage by urological journals but also provided updated insights regarding the utility of some in research dissemination. in addition, we demonstrated that journals with some presence had significantly higher traditional metric values (sjr, h-index, and citescore) compared to journals without some presence. strong, positive correlations between citation-based and alternative social metrics were also observed. the omnipresent world wide web has not only reshaped how information is shared across the internet but also paved a new way for communication by introducing social networking platforms whose hallmarks table 2. journal activity on social media twitter journals on twitter, n (%) 54 (50) number of tweets (median, iqr) 797.5 (145.75–1605.75) number of followers, n (%) < 1000 22 (40.7) 1000–3000 17 (31.5) > 3000 15 (27.8) number of followers/year (median, iqr) 295.55 (122.35–699.66) facebook journals on facebook, n (%) 26 (24.3) number of followers, n (%) < 1000 12 (46.2) 1000–3000 8 (30.8) > 3000 6 (23.1) number of followers/year (median, iqr) 1094 (271.25–2946) youtube journals on youtube, n (%) 7 (6.5) number of views (median, iqr) 285,103 (2124–4,560,263) number of subscribers/year (median, iqr) 347.27 (3.4–946.15) instagram journals on instagram, n (%) 9 (8.4) number of posts (median, iqr) 215 (77.5–346 number of followers/year (median, iqr) 153 (76.94–506.96) 91siuj.org siuj • volume 4, number 2 • march 2023 social media engagement for urology journals — a correlation analysis of traditional and social media metrics http://siuj.org table 3. correlation between traditional and alternative social media metrics sjr number of followers (twitter) number of followers/ year (twitter) number of tweets number of followers (facebook) overall correlation 0.538* 0.503* 0.520* 0.438* q1 (n = 27) 0.702* 0.360 0.413 0.267 region europe 0.613* 0.621* 0.539* 0.349 north america 0.527* 0.427 0.467 0.306 number of publications in the previous 3 years < 250 0.287 0.280 0.263 0.264 > 500 0.624* 0.394 0.479 0.571 number of citations in the previous 3 years, n (%) < 1000 0.058 0.063 0.133 0.087 > 3000 0.714* 0.393 0.750 0.400 h-index number of followers (twitter) number of followers/ year (twitter) number of tweets number of followers (facebook) overall correlation 0.571* 0.570* 0.506* 0.495* q1 (n = 27) 0.431 0.420 0.445* 0.498 region europe 0.517* 0.557* 0.494* 0.410 north america 0.488* 0.495* 0.437 -0.108 number of publications in the previous 3 years < 250 0.407 0.405 0.082 0.174 > 500 0.625* 0.518* 0.749* 0.167 number of citations in the previous 3 years, n (%) < 1000 0.290 0.279 0.159 0.098 > 3000 0.821* 0.536 0.893* -0.400 citescore number of followers (twitter) number of followers/ year (twitter) number of tweets number of followers (facebook) overall correlation 0.487* 0.428* 0.474* 0.405* q1 (n = 27) 0.603* 0.347 0.451* 0.249 region europe 0.559* 0.557* 0.516* 0.169 north america 0.526* 0.449 0.507* 0.319 number of publications in the previous 3 years < 250 0.226 0.197 0.208 0.273 > 500 0.578* 0.474 0.468 0.571 number of citations in the previous 3 years, n (%) < 1000 0.018 0.036 0.109 0.012 > 3000 0.714* 0.393 0.750* 0.400 *statistical significance attained at p < 0.05. 92 siuj • volume 4, number 2 • march 2023 siuj.org original research http://siuj.org are of the ability to provide a common yet integrated space where users can interact with the community and like-minded members of the society on personal and professional levels. it was found that 74% of urologists engage in some form of some presence[18] and this has paved the way for consistent scientific discussion. this finding is potentiated by the highly accessible and portable nature of some, where convenience and time efficacy are optimized. instantaneous procurement of information is made possible in the context of a urologist’s hectic schedule, enabling bite-sized but relevant pieces of research to be tailored to an individual’s social feed. some has provided an equally constructive platform akin to that of a physical journal club, but with all the virtual benefits—maintaining the same extent of productive discourse about a research topic through mentions and tweets[19]. in the same vein, the inception of #urosome in december 2018, a twitter hashtag specific to urology, as well as a dedicated account (@so_ uro), has revolutionized the social landscape of urology as never before[17,20]. initially set up to promote public awareness of urological conditions and professional academic discussions, the community has culminated in international, multicenter collaborations on research work[21,22]. with official guidelines already in place to regulate some use by professionals[23], much is eagerly awaited by the #urosome working group to further expand its outreach. the potential of some has also been tapped into by other fields in medicine, such as surgery[12], radiology[24], otolaryngology[25], pulmonology[26], and pediatric surgery[27]. the recurring theme in these studies that similarly evaluated the utility of alternative social metrics is that some indicators should be harnessed as adjuncts alongside traditional metrics to holistically evaluate academic impact. a randomized study by luc et al.[28] evaluated the impact of tweets on thoracic surgery research articles and found that articles that were tweeted on attained significantly greater increase in citation scores at 1 year (tweeted +3.1 ± 2.4 versus non-tweeted +0.7 ± 1.3, p < 0.001). moreover, exposure to a larger number of twitter followers was determined to be an independent predictor of citation count. all these collectively contribute to the plausibility of some platforms as reliable media of scholarly activity, allowing journals to build a wider academic audience and be exposed to peer recognition as well. twitter has evolved as a primary player for information dissemination in research. it prides itself as being a platform that allows for information to be shared in multiple modes: text, photographs, videos, and weblinks, and in the most compact form possible (≤ 140 characters). such content flexibility has given rise to creative outlets for circulating research findings and achieving outreach. infographics and videographics are revolutionary new ways in which information is shared on some platforms such as twitter and have been shown not only to attract attention to the topic they advocate but also to display an artistic flair. this captivates readership and encourages interactive discussion about the topic[29,30]. on the other hand, the development of conference-specific hashtags (#siu22, eau22, #aua22, #baus22) has also served as a surrogate marker of outreach beyond physical means, augmenting the conference experience for a wider audience. for instance, the american urological association’s annual meeting in 2013 garnered more than 8.6 million impressions and 4663 tweets in total across the peri-conference period[31], enhancing publicity for the subsequent year’s meeting. our study is not devoid of limitations. we excluded correlations with impact factors derived from journal citation reports, as if has certain inherent disadvantages that preclude holistic representation of all journals[32]. more robust counterpart metrics such as the sjr indicator consider self-citation articles and include a wider geographical and language scope. despite establishing a strong association between traditional and alternative social metrics, causality cannot be identified—the impact of research dissemination on some remains controversial, with a mixed bag of opinions regarding its academic utility. a relevant caveat of note here is the need to distinguish between journals that are highly cited versus those that are highly active on some. although there is a strong positive correlation between the 2, it is imperative for academics to discern the difference between these 2 groups, for they are not directly interchangeable. a journal that receives significant some growth may not necessarily translate to direct academic impact—some outreach is primarily aimed at instantaneous, bite-sized, and palatable dissemination of article content. while it does increase the viewership of said journal article, it does not always encourage greater citation counts. this can be for reasons as simple as only garnering a minority of their target academic audience interested in the same topic. for instance, hayon et al. concluded that citation counts are positively associated with the number of citations an article accrues only after 3 years in publication[33]. in fact, a novel “twitter impact factor” derived from some metrics of urology journals was also trialled to determine its correlation with the traditional impact factor[34]. however, on the other hand, established alternative metrics such as the altmetric score have failed to demonstrate strong correlations with article citation counts within urological literature[11]. other confounding factors such as financial capacity can determine how dedicated the parent publisher of the journal is in promoting some engagement. journals with respectable traditional metrics may have more resources to begin with for publicity, which 93siuj.org siuj • volume 4, number 2 • march 2023 social media engagement for urology journals — a correlation analysis of traditional and social media metrics http://siuj.org can substantially affect the extent of outreach compared to low-impact journals. future prospective studies are necessary to elucidate any underlying causal relationships between these variables. conclusions our study clearly demonstrates that journals with social media presence have significantly higher values of traditional metrics than those without, and these metrics (sjr, h-index, and scopus citescore) correlate well with journal activity on some platforms such as twitter. given the immediacy of some metrics, indicators of some presence should be actively considered as an adjunct to traditional measurements of scientific impact, generating information on both shortand long-term journal outreach and publicity[35]. author contributions all named authors have contributed significantly to the conceptualization, conduct, and writing of the paper. all authors have seen and approved the final version of the manuscript being submitted. all authors have fulfilled the committee on publication ethics (cope) requirements for authorship. references 1. moorhead sa, hazlett de, harrison l, carroll jk, irwin a, hoving c. a new dimension of health care: systematic review of the uses, benefits, and limitations of social media for health communication. j med internet res.2013;15(4):e85. doi: 10.2196/jmir.1933. pmid: 23615206; pmcid: pmc3636326. 2. bornmann l, leydesdorff l. scientometrics in a changing research landscape: bibliometrics has become an integral part of research quality evaluation and has been changing the practice of research. embo rep.2014;15(12):1228–1232. doi: 10.15252/embr.201439608. pmid: 25389037; 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in a t weet? op timizing so cial me dia impr es sions. bjui compass. 2022;3 (6):4 0 8 – 4 09. doi: 10.10 02 / bco2.18 0. pmid: 36267205; pmcid: pmc9579883. 31. wilkinson s, basto my, perovic g, murphy d, lawrentschuk n, murphy dg. the social media revolution is changing the conference experience: analytics and trends from eight international meetings. bju int.2015;115(5):839–846. doi: 10.1111/bju.12910. pmid: 25130687. 32. ranjan ck. bibliometric indices of scientific journals: time to overcome the obsession and think beyond the impact factor. med j armed forces india.2017;73(2):175–177. doi: 10.1016/j.mjafi.2017.03.008. pmid: 28924319; pmcid: pmc5592267. 33. hayon s, tripathi h, stormont im, dunne mm, naslund mj, siddiqui mm. twitter mentions and academic citations in the urologic literature. urology.2019;123:28–33. doi: 10.1016/j.urology.2018.08.041. pmid: 30278190. 34. cardona-grau d, sorokin i, leinwand g, welliver c. introducing the twitter impact factor: an objective measure of urology’s academic impact on twitter. eur urol focus.2016;2(4):412–417. doi: 10.1016/j. euf.2016.03.006. pmid: 28723474. 35. bellote mc, santamaria ht, pelayo-nieto m, es hp, gadzhiev n, gudaru k. social media in the urology practice | opinion: yes. int braz j urol.2019;45(5):877–881. doi: 10.1590/s1677-5538.ibju.2019.05.03. pmid: 31626516; pmcid: pmc6844359. 95siuj.org siuj • volume 4, number 2 • march 2023 social media engagement for urology journals — a correlation analysis of traditional and social media metrics http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj • volume 4, number 3 • may 2023 siuj.org key words competing interests article information targeted biopsy, prostate cancer, multiparametric mri, fusion biopsy none declared. received on october 15, 2022 accepted on october 22, 2022 this article has been peer reviewed. soc int urol j. 2023;4(3):226–227 doi: 10.48083/ltml9783 226 pro and con the end of photodynamic surgery for bladder cancer has arrived benjamin davies department of urology, university of pittsburgh medical center health system, pittsburgh, united states the photo study was a real-world—or “pragmatic” in the proper diction of the uk investigators—prospective randomized controlled trial (rct) to evaluate bladder cancer recurrence rates with over 3 years of follow-up. this is the longest rct performed on this technology published. it was extraordinarily vigorous—even for the high standards of any rct. there was central randomization with concealed allocation, blinding of personnel and outcome assessors, low rates of attrition, and a pre-published analytics plan. critically, the funding was governmental not pharmaceutical. the control arm and study arm were equally balanced. this study did allow for the appropriate use of postoperative intravesical therapy and adjuvant treatment, all of which were equally balanced in both arms. a real-world trial has shown—without any doubt at all—that the use of photodynamic diagnosis (pdd) for the express purpose of preventing recurrence after the initial diagnosis of bladder cancer is unhelpful. this negative result should not be a surprise. urologists only have to recall the original randomized trial that formed the basis for the approval of pdd at the fda to remind themselves this technology was always borderline[1]. in the final phase 3 trial, pdd met only one of its prespecified endpoints and failed to achieve superiority in comparison for follow-up recurrence rates. the proportion of the pdd group patients detected (16%) did exceed the prespecified 10% threshold, however. supporting documentation at the time (study 304), which did randomize to white light versus pdd, did not show a reduction in recurrence. the fda advisory committee voted 9 to 8 in favor of sufficient risk to benefit for using pdd. a “slow-clap” approval if there ever was one. after the photo study has been disseminated, studied, and dissected—we should see an international steep decline in the pro forma use of pdd for the purposes of preventing bladder cancer recurrence. why? it doesn’t work. in countries such as the united states where pharmaceutical representatives foot the bill for the lion’s share of postgraduate education, pdd use will likely plod along buttressed by conflicted experts. in the united kingdom, home of the photo study and where general adherence to evidence-based medicine can happen, pdd use will peter out and be used in select cases only. physicians do not consider one study to inform their practice. instead, physicians should consider all the highvalue studies packaged into a meta-analysis. urologists should therefore appreciate the work of maisch et al.[2], who in 2021 (prior to photo) performed a rigorous systematic review of all studies on pdd and recurrence rates. those authors downgraded the certainty of evidence by two levels according to the grading of recommendations assessment, development and evaluation (grade) framework. they found there was significant unexplained heterogeneity in the data on pdd and recurrence. if the photo trial was added, according to heer et al. [3], and the analysis was restricted to only robust trials with a priori protocols—the entirety of all pdd rct studies would result in a nonsignificant result. pdd just cannot get a break. there are many reports in the literature that pdd provides superior diagnostic capabilities in the setting of carcinoma in situ (cis), a point the pdd lobbyists will surely cling to. those reports—while numerous and retrospective— have heterogeneous patient characteristics and study design[4]. now, we have the clear cover of a modern real-world http://siuj.org rct, which was enriched with 12.9% of the pdd group versus 11.1% of the wl group, with cis, showing no clear difference in recurrence rates. modern high-definition cystoscopy, unavailable in the original rct but available to all currently, is one obvious reason pdd crumbled in this non-pharmaceutically sponsored photo trial. the real-world addition of intravesical therapy and re-resection of tumors also undoubtedly contributed. all told, payors and national health services should restrict this expensive technology immediately. thomas jefferson was fond of saying, “he who knows nothing is closer to the truth than he whose mind is filled with falsehoods and errors.” time to shed the errors and realize the truth: pdd is past its prime and high-definition optics has come to the fore. references 1. grossman hb, stenzl a, fradet y, mynderse l a, kriegmair m, witjes ja, et al. long-term decrease in bladder cancer recurrence with hexaminolevulinate enabled fluorescence cystoscopy. j urol.2012;188(1):58–62. doi: 10.1016/j.juro.2012.03.007. pmid: 22583635; pmcid: pmc3372634. 2. maisch p, koziarz a, vajgrt j, narayan v, kim mh, dahm p. blue versus white light for transurethral resection of non-muscle invasive bladder cancer. cochrane database syst rev.2021;12(12):cd013776. doi: 10.1002/14651858.cd013776.pub2. pmid: 34850382; pmcid: pmc8632646. 3. heer r, lewis r, vadiveloo t, yu g, mariappan p, cresswell j, et al. a randomized trial of photodynamic surgery in non–muscle-invasive bladder cancer. nejm evid.2022;1(10). doi: 10.1056/evidoa2200092. 4. veeratterapillay r, gravestock p, nambiar a, gupta a, aboumarzouk o, rai b, et al. time to turn on the blue lights: a systematic review and meta-analysis of photodynamic diagnosis for bladder cancer. eur urol open sci.2021;31:17–27. doi: 10.1016/j.euros.2021.06.011. pmid: 34467237; pmcid: pmc8385287.b renal cell carcinomas in patients with comorbidities. jpn j radiol. 2021;39(12):1213–1222. doi: 10.1007/ s11604-021-01168-8. pmid: 34228240. 227siuj.org siuj • volume 4, number 3 • may 2023 the end of photodynamic surgery for bladder cancer has arrived http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj • volume 4, number 4 • july 2023 siuj.org for instance, the nice (uk) and aua (us) guidelines endorse prostate therapy with rezūm as an alternative treatment option for patients with moderate to severe luts and a prostate volume of 30 to 80 ml[5,6]. however, the european association of urology guidelines consider the current evidence to support the efficacy of rezūm to be weak [7]. these discrepancies between guidelines, as confusing as they may be, must be part of patient counseling and consenting, and resulting patient anxiety must be addressed in an emphatic and appropriate manner [8]. in the uae, there is a recent trend towards rezūm for patients with mild luts and large prostates >  80 ml, in which the evidence base given the above seems at least doubtful. these are just two examples, and it goes without saying that this ongoing dilemma has unduly strained the references 1. world health organization. world health organization country cooperation strategy at a glance: united arab emirates. available at: accessed september 16, 2022. 2. smedley bd, butler as, bristow lr (eds). in the nation’s compelling interest: ensuring diversit y in the healthcare work force. 2004;washington, dc: institute of medicine. doi: 10.17226/10885. 3. bedoll d, van zanten m, mckinley d. global trends in medical education accreditation. hum resour health.2021;19(70): (2021). https://doi. org/10.1186/s12960-021-00588-x 4. dordoni p, remmers s, valdagni r, bellardita l, de luca l, badenchini f, et al. cross-cultural differences in men on active surveillance anxiety: a longitudinal comparison between italian and dutch patients from the prostate cancer research international active surveillance study. bmc urol.2022 jul 18;22(1):110. doi: 10.1186/s12894-022-01062-z. 5. burnett al, nehra a, breau rh, culkin dj, faraday mm, hakim ls, et al. erectile dysfunction: aua guideline. j urol.2018 sep;200(3):633641. doi: 10.1016/j.juro.2018.05.004. 6. national institute for health care and excellence. steam treatment recommended for men with an enlarged prostate.2020 june 24. available at: https://www.nice.org.uk/news/article/steam-treatmentrecommended-for-men-with-an-enlarged-prostate. accessed june 29, 2023. 7. malde s, umbach r, wheeler jr, lytvyn l, cornu jn, gacci m, et al. a systematic review of patients’ values, preferences, and expectations for the diagnosis and treatment of male lower urinary tract symptoms. eur urol.2021 jun 1;79(6):796-809. doi: 10.1016/j.eururo.2020.12.019. 8. avins al. when clinical practice guidelines meet the black box. arch intern med.2010 jun 28;170(12):1013-1014. doi: 10.1001/ archinternmed.2010.185. trust of patients in the medical profession. consequently, “doctor shopping” where patients see several specialists for the same problem within a short time is not unusual. similarly, health insurers tend not to trust the judgement of doctors and require that the providers answer questions—generally indicating lack of understanding--before approving a treatment. it is not unusual that the insurance requests and pays for an abdominal x-ray to prove the presence of a jj stent before approving jj removal. on a more positive note, the above factors are being addressed. the local regulatory bodies are aware of the problem and are adopting time-tested models from europe and the us, and the system will eventually incentivize and support good medical practice and clinical governance. 245siuj.org siuj • volume 4, number 4 • july 2023244 the dilemma of multiculturalism and multinationalism in medical practiceurology around the world the dilemma of multiculturalism and multinationalism in medical practice noor buchholz,1,2 mohammed shahait2 1 u-merge scientific office, athens, greece 2 consultant urological surgeon, dubai, united arab emirates doi: 10.48083/gahf2202 soc int urol j. 2023;4(4):244–245 the united arab emirates (uae) has made significant progress in expanding health insurance coverage to its population in recent years. the government has implemented various policies to ensure all residents have access to health care. a report by the dubai health authority (dha) in 2020 estimated that around 98% of the population in dubai had some form of at least basic health insurance coverage. depending on the insurance policy, access to specific health care providers may be limited and there may be some out-of-pocket expenses for the individual, such as copays or deductibles. for emirati citizens, however, quality health care is completely free of charge[1]. the uae is a very diverse country with a population consisting of a minority of emirati citizens and a majority of expatriates from all over the world and from all walks of life. the country’s health care system reflects this diversity, with doctors from many different cultural and educational backgrounds and nationalities practicing in the uae in all medical specialties[1]. on one hand, this diversity of medical practitioners in the uae certainly reflects the country’s commitment to providing world-class health care services to its residents and visitors. with a highly skilled diverse and well-equipped workforce, the uae’s health care system can offer a wide range of state-of-the-art medical services and treatments[1]. on the other hand, however, although this diversity of doctors undoubtedly enriches health care, bringing a variety of perspectives and experiences to patient care, there is less positive side[2]. unfortunately, medical education and regulation of medical practice is not universally standardized with respect to the doctor–patient relationship and communication, ethics, clinical governance, best practice, regulatory control, and continued medical education throughout a doctor’s career[3]. in a multicultural, multi-ethnic, and multinational society like the one in the uae, physicians may have varying approaches to patient care based on their sociocultural background, medico-social education, and communication and ethical training. all physicians in the uae will be faced with a multitude of patients from different sociocultural backgrounds with varying expectations and communication skills that will not necessarily match those the doctors were trained in and are used to[1]. therefore, they must develop a set of skills and bedside manners to deal with a variety of patients, and to understand and address their unique needs and concerns. in our specialty, this diversity in patients’ backgrounds, cultures, and treatment expectations plays an important role in shaping the practices of urologists in the uae. sociocultural factors have been demonstrated to affect the anxiety level among patients on active surveillance (as) for low grade prostate cancer, which is directly linked to patients opting for radical treatment options where as could be indicated [4]. these factors must be taken into account and sensitive counseling must be offered with a view to obtaining informed consent for the best course of treatment. patients can give fully informed consent only if they understand the doctor and the doctor understands them and their concerns. this might partially explain the large number of prostate cancer patients in the uae who are eligible for as but opt instead for surgical treatment. in addition to a financial aspect that might favor surgical treatments, unaddressed patient anxiety may be a factor here. national availability of medical devices has to be approved by both the emirates authority for standardization and metrology (esma) and the ministry of health authority prevention (mohap). however, their local availability is widely market-driven and dependent on the expertise of the providing health care professional. apart from these factors, it also depends on which internationally recognized guidelines the provider chooses to follow. http://siuj.org https://apps.who.int/iris/rest/bitstreams/609627/retrieve https://apps.who.int/iris/rest/bitstreams/609627/retrieve http://siuj.org mailto:mshahait%40yahoo.com?subject=siuj this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj.org siuj • volume 4, number 3 • may 2023 key words competing interests article information ileal conduit, urinary diversion, bricker, wallace, hybrid, stricture, retrospective none declared. received on june 6, 2022 accepted on january 22, 2023 this article has been peer reviewed. soc int urol j. 2023;4(3):171–179 doi: 10.48083/szdp5651 171 original research hybrid ureteroenteric anastomosis is associated with lower stricture rates in ileal conduit urinary diversion zein alhamdani,1 kirby r. qin,1 vidyasagar chinni,1 scott donellan,2 damien bolton,1 marlon perera,1 dixon woon1 1 department of surgery, university of melbourne, austin health, heidelberg, victoria, australia 2 monash health, melbourne, victoria, australia abstract background anatomic complications of the ureteroenteric anastomosis in ileal conduit (ic) cause significant morbidity in patients post-cystectomy and cystoprostatectomy. the bricker technique has a perceived disadvantage of increased risk for stricture, whereas the wallace technique runs the risk for ureteral malignancy affecting both ureteric ends, and bilateral ureteric obstruction from a stone lodged at the anastomosis. we aimed to evaluate the safety, efficacy, and stricture rate of a novel hybrid ureteroenteric anastomosis technique. we compared these outcomes to the bricker and wallace anastomosis techniques for ic urinary diversion (icud). methods we performed a retrospective chart review of patients who had undergone icud after cystectomy for bladder cancer from 2011 to 2016. patients were categorized into groups undergoing the bricker, wallace, and hybrid ureteroanastomosic techniques. strictures were identified during clinical follow-up or hospital presentations with complications. results we identified 68 patients suitable for inclusion. they were separated by bricker, wallace, and hybrid anastomosis techniques, with 19 (27.9%), 20 (29.4%), and 29 (42.6%) patients, respectively. ureteroenteric anastomotic strictures occurred in 9 patients (5 bricker, 3 wallace, 1 hybrid). this difference in stricture rates for bricker versus hybrid (26.3% vs. 3.4%; or, 10 [95% ci, 1.1 to 121.1]; p = 0.02) was significant but was comparable for wallace versus hybrid (15.0% vs. 3.4%; or, 4.9 [0.7 to 66.0]; p = 0.15) and for bricker versus wallace (26.3% vs. 15.0%; or, 2 [0.4 to 8.6]; p = 0.87). 15 patients (51%) in the hybrid group required oral antibiotics for a symptomatic urinary tract infection compared with 4 (21%) with bricker and 8 (40%) with wallace (p = 0.10). median post-cystectomy follow-up and stricture formation time were 16 months (iqr, 4–36) and 9 months (7–32), respectively. conclusion the hybrid technique is a safe and efficacious alternative to the bricker and wallace anastomoses. it carries with it a risk for urinary tract infection that is eclipsed by substantially lowered rates of ureteric strictures requiring intervention while maintaining the advantage of separating the two ureters. introduction ileal conduit is the commonest form of urinary diversion after radical cystectomy[1,2]. it has acceptable complication rates and reasonable postoperative quality of life, and the technique is relatively accessible by many urologists[3–7]. despite the lower rates of morbidity compared to alternative types of urinary diversion, complications do occur. http://siuj.org mailto:dixon.woon%40gmail.com?subject=siuj a source of morbidity in ileal urinary diversion is associated with anatomical complications of the ureteroenteric anastomosis[8–10]. in general, there are three types of refluxing anastomoses of the ureter to the ileal conduit used in contemporary practice[11,12]. the bricker anastomosis is categorized when the distal end of each ureter is anastomosed to the anti-mesenteric side of the proximal ileal conduit[13]. conversely, the wallace anastomosis is performed by anastomosing both distal ureters together to form one ureteric plate, which is then anastomosed to the proximal luminal end of the ileal conduit[14]. the third is a hybrid technique, where the left ureter undergoes an end-to-end anastomosis akin to the wallace technique but with a single ureter, and the right ureter is anastomosed to the side of the ileal conduit in a fashion consistent with the bricker technique. the wallace technique is thought to have a lower stricture rate compared to the bricker technique[15]; however, it is criticized to have a risk for bilateral renal obstruction with recurrence of disease or an obstruction stone with a theoretical risk of spreading the urothelial cancer to the contralateral side[16,17]. the hybrid technique may retain the benefits of the lower stricture rates in the left ureter while eliminating the risks of joining the two ureters. the pathophysiology of benign strictures is thought to be due to periureteral fibrosis secondary to ischemia or urine leakage at the anastomotic site[18]. ureteric stricture is more common in the left ureter, thought to be due to the additional mobilization and tension of the left ureter[16–18]. the incidence of strictures is quite variable, ranging from 1.9%[19] to as high as 25.3%[15], with the median time to diagnosis anywhere from 7 to 25 months[18]. it is plausible that differences in rates for strictures exist between anastomotic techniques due to variation in distal ureteric vascular supply and anastomotic tension. in this study, we aim to evaluate the safety, efficacy, and stricture rate for the hybrid method compared to the bricker and wallace methods performed at the institution. it is important to evaluate the incidence of stricture formation, as there is significant morbidity attached to the management of strictures. materials and methods after institutional ethical approval, we performed a retrospective study where data was collected through a abbreviations iv intravenous uti urinary tract infection retrospective chart review. we identified patients who had undergone ileal conduit urinary diversion after radical cystectomy and radical cystoprostatectomy for bladder cancer from 2011 to 2016. by australian standards, our institution is considered a moderatevolume tertiary center, performing approximately 15 radical cystectomies per year. at our institution, cystectomy is performed primarily by five consultant urological surgeons, with a fellow or a senior level resident as first assistant. urinary diversion may be completed by a consultant, fellow, or senior registrar under supervision. in general, most of the ileal conduit formations are performed by fellows or senior registrars in training. in our series, the decision of which anastomotic technique (bricker, wallace, or hybrid) to use was based on surgeon preference. a schematic highlighting the anatomic differences between the bricker, wallace, and hybrid techniques are highlighted in figure 1. prior to the formation of the ureteroenteric anastomosis, the segment of terminal ileum and ureteric mobilization techniques were standard irrespective of the anastomotic technique. the distal ureters were tension free, well vascularized, and generously spatulated at a minimum of 1.5 cm. for the bricker anastomosis, two small enterotomies were created on the proximal segment of the ileal conduit, free from the mesentery[13]. anastomosis was performed with two continuous absorbable sutures, typically 5–0 monocryl or 5–0 pds (ethicon, raritan, new jersey, usa). for the wallace anastomoses, the medial borders of the left and right spatulated ureter were sutured adjacently with absorbable suture[14]. anastomosis with the two ureters and the proximal lumen of the ileal conduit was performed with absorbable suture as above. finally, for the hybrid technique, the ileum was selected and isolated the same way as for the other two methods. the proximal lumen of the ileal conduit was opened in its entire diameter. the left ureter was mobilized in the usual fashion and tunnelled through the retro-mesocolon space created. it was spatulated to match the diameter of the ileum and anastomosed end to end with the proximal lumen of the ileal conduit using continuous absorbable sutures. all anastomoses were performed using the reconstructive principals in addition to ureteral stents and peri-conduit surgical drains. if concern existed over excessive tension or the viability of the distal ureter or conduit—this was addressed intraoperatively based on surgeon discretion. postoperative management was based on surgeon discretion. we collected data pertaining to age, gender, staging of the disease, and history of chemotherapy, radiotherapy, and neoadjuvant chemotherapy. all of our cases were discussed at a multidisciplinary team meeting involving senior urologists, medical oncologists, and 172 siuj • volume 4, number 3 • may 2023 siuj.org original research http://siuj.org radiation oncologists at our institution. cisplatin-based neoadjuvant chemotherapy was the standard of practice; patients with contraindications or personal choices against this regimen could receive gemcitabine and carboplatin instead, or no neoadjuvant chemotherapy. patients with a solitary kidney were excluded. all men had a radical cystoprostatectomy, and all women had a radical cystectomy. we recorded the following perioperative, intraoperative, and postoperative factors: operative time, estimated blood loss (ebl), postoperative transfusion rate, length of stay (los), postoperative complications, and the characteristic of ureteric strictures that required intervention. patients were monitored in the outpatient clinic or in hospital if they required readmission. ureteroenteric stricture was diagnosed in routine follow-up in outpatient clinics, which included a ct intravenous pyelogram at 3 months, then every 6 months after that for the first 2 years and yearly until the fifth year or at hospital if requiring admission. patients were excluded from subsequent analysis if key demographic information or outcome measures were missing, or if there was a history of or required postoperative salvage radiotherapy to the abdomen or pelvis. for missing data, the related data was removed. statistical analysis categorical variables were displayed as frequency (percentage) and compared using the chi-square test. when three-group chi-square yielded a p-value ≤ 0.10, a post-hoc bonferroni correction was performed to compare individual subgroups using the fisher exact test. continuous variables were treated as nonparametric (due to the small sample size), displayed as median (interquartile range [iqr]), and compared using the kruskal-wallis test. the kaplan-meier method was used to assess anastomotic stricture incidence after figure 1. schematic highlighting anatomic configurations of bricker, wallace, and hybrid anastomoses. hybrid anastomosis end-to-end anastomosis of the left ureter, end-to-side anastomosis of the right ureter to the ileal conduit. wallace anastomosis end-to-end anastomosis of a joint uretic plate to ileal conduit. bricker anastomosis end-to-end anastomosis of each individual ureter to the ileal conduit. surgery; time-to-event curves were compared using the log-rank test. analysis was performed using graphpad prism v9.0 (la jolla, california, usa) and statabe v17.0 (college station, texas, usa). p-values < 0.05 were considered statistically significant. results between 2011 and 2016, a total of 71 patients had radical cystectomy (or cystoprostatectomy) and ileal conduit diversion for bladder cancer. three patients had a solitary kidney and, thus, underwent a single bricker anastomosis, and therefore were excluded. of the remaining 68 patients, 19 patients (28%) underwent a bricker anastomosis, 20 (29%) underwent a wallace anastomosis, and 29 (42%) underwent the hybrid anastomosis. the demographics of the 68 patients are shown in table 1. overall cohorts were comparable with respect to age, gender, and tumor staging between patients receiving bricker, wallace, or hybrid anastomosis. in the wallace subgroup of 20 patients, 2 (10%) had a history of radiotherapy to the head and neck and breast while the other subgroups had none. most early postoperative complications did not differ between the groups. there were no significant differences in ebl, los, transfusion rate, ileus, electrolyte disturbance, acute kidney injury, or readmission within 30 days between the bricker, wallace, and hybrid techniques (table 2). the incidence of symptomatic urinary tract infection (uti) requiring oral antibiotics was higher in the hybrid group compared to bricker (52% vs. 21%; or, 4.0 [1.0 to 12.9]; p = 0.04) but similar compared to wallace (52% vs. 40%; p = 0.56). in comparison, there was no statistically significant difference in the 8 patients who developed urosepsis requiring intravenous (iv) antibiotics, of whom 1/19 was in the bricker group (5%), 4/20 in the wallace group (20%), and 3/29 in the hybrid group (10%) (p = 0.34) (table 3). 173siuj.org siuj • volume 4, number 3 • may 2023 hybrid ureteroenteric anastomosis is associated with lower stricture rates in ileal conduit urinary diversion http://siuj.org the clavien-dindo classification demonstrated that the rate of grade 2 complications was higher in the hybrid group compared to bricker and wallace (62% vs. 31% vs. 50%, respectively); however, the hybrid group had less grade 3a and 3b complications (10% vs. 21% vs. 15%, respectively). grade 4a complications were found only in the bricker subgroup (10%). there were only grade 4a complications in the bricker subgroup (10%)—there were no grade 4b or 5 complications. (table 4) overall, ureteral stricture needing intervention developed in 9 patients (13%). no patients developed bilateral ureteric stricture. in patients undergoing bricker anastomosis, ureteral stricture developed in 5/19 patients (28%); 3 strictures in the left and 2 in the right. with the wallace anastomosis, 3/20 patients (15%) developed stricture; all in the left ureter. of the 29 patients who had the hybrid anastomosis, 1 patient (3%) developed stricture in the right ureter (chi square, p = 0.07). median post-cystectomy follow-up and stricture formation time were 16 months (iqr, 4 to36) and 9 months (7 to 32), respectively. using the kaplan-meier method, the estimated stricture-free survival in the hybrid group at 1, 3, and 5 table 1. summary of patient demographics characteristics total bricker wallace hybrid sample size (%) 68 (100) 19 (27.9) 20 (29.4) 29 (42.6) age (iqr) 68 (62–73) 67 (63–74) 67.5 (61.5–71) 69 (61–73) male 55 (80.9) 18 (94.7) 13 (65) 24 (82.8) staging, pt (%) tx 3 (4.4) 0 (0) 1 (5.0) 2 (6.9) t0 9 (13.20 1 (5.3) 1 (5.0) 7 (24.1) tcis 5 (7) 1 (5.3) 1 (5.0) 3 (10.3) t1 8 (11.8) 2 (10.5) 4 (20.0) 2 (6.9) t2 17 (25) 8 (42.1) 3 (15.0) 6 (20.7) t3 19 (27.9) 5 (26.3) 7 (35.0) 7 (24.1) t4 7 (10.3) 2 (10.5) 3 (15.0) 2 (6.9) history of radiotherapy not involving the abdomen and pelvis (%) 0 (0) 0 (0) 2 (10.0) 0 (0) neoadjuvant chemotherapy (%) 7 (10.3) 1 (5.2) 2 (10.0) 4 (13.8) years was 100%, 100%, and 80%, respectively (figure 2). in the bricker subgroup, the estimated 1-, 3-, and 5-year stricture-free survival rate was 100%, 75%, and 20%, respectively. for the wallace subgroup, the estimated 1-, 3-, and 5-year stricture-free survival rate was 92.5, 82%, and 65%, respectively. estimated stricture-free survival differed significantly across anastomotic technique (log-rank test, p = 0.02). strictures were predominantly located in the left ureter (66.7%; p = 0.32). all of the 9 patients with strictures underwent successful endoscopic treatment, 7 as retrograde stent with dilation and 2 as anterograde stent with dilation. none of the patients underwent open repair or conservative treatment. no significant differences in stricture rates were identified when stratified by patient age and t staging status. the difference in stricture rates for bricker versus hybrid (26.3% vs. 3.4%; or, 10 [95% ci 1.1 to 121.1]; p = 0.02) was significant but were comparable for wallace versus hybrid (15.0% vs. 3.4%; or, 4.9 [0.7 to 66.0]; p = 0.15) and for bricker versus wallace (26.3% vs. 15.0%; or, 2 [0.4 to8.6]; p = 0.87). the median time to diagnosis was 15 (iqr, 8 to 37) months for the 5 patients in the bricker subgroup, 7 (7 to 8) months in the wallace group, and 32 months for the 1 patient in the hybrid subgroup. discussion the bricker and wallace techniques are the two most common forms of ureteroenteric anastomosis for urinary diversion post-radical cystectomy[19]. the choice between these two techniques is based mostly on surgeon preference. both have their perceived disadvantages, which are cumulatively listed as increased log-rank p = 0.21 0% 25% 50% 75% 100% st ric tu re in ci de nc e (% ) 29 18 16 12 7 4 3 3 1 0hybrid 20 11 8 7 4 3 3 2 0 0wallace 19 14 11 9 2 1 0 0 0 0bricker number at risk 0 10 20 30 40 50 60 70 80 90 months after surgery bricker wallace hybrid figure 2. anastomotic stricture formation 174 siuj • volume 4, number 3 • may 2023 siuj.org original research http://siuj.org stricture rates, chance for bilateral renal obstruction due to kidney stones or recurrence of disease, and theoretical risk for transfer of urothelial carcinoma to the contralateral side[11]. here we report the rates of a hybrid technique that aims to eliminate some of the risks while retaining the benefits from both techniques. our hybrid technique maintains distance between the ureteric orifice, eliminating the risk for bilateral renal obstruction due to kidney stones or disease, and theoretically retains the reduced risk in stricture formation. in addition, it is easier to discriminate the two ureters with retrograde conduitoscopy, as the right ureter is an end-to-side anastomosis and the left ureter is an end-to-end anastomosis, which also facilitates easier endoscopic access for surveillance. the practice of anastomosing a spatulated left ureter to the end of the conduit may have been performed in some institutions across the world; however, this is the first study to evaluate the safety and stricture rates of such an approach. table 2. reteroenteric stricture details outcome total bricker wallace hybrid p-value sample size (%) 68 (100) 19 (27.9) 20 (29.4) 29 (42.6) number of ureteric strictures requiring intervention 9 5 (26.3) 3 (15.0) 1 (3.4) 0.07* b vs. w: 0.87 b vs. h: 0.02 w vs. h: 0.15 time from cystectomy to stricture formation (months), median (iqr) 9 (7–32) 15 (5.5–45.5) 7 (7–9) 32 0.46 left:right 6:3 3:2 3:0 0:1 type of interventions nephrostomy/antegrade stent/dilatation 2 1 1 0 retrograde stent/dilatation 7 4 2 1 indication infected obstructed kidney 1 1 0 0 aki 1 0 1 0 worsening hydronephrosis 4 2 2 0 recurrent uti 1 0 0 1 ureteric stone 1 1 0 0 aki; acute kidney disease; uti, urinary tract infection. *chi-square test p-value ≤ 0.10, bonferroni correction performed with fisher exact test. the overall stricture rate in our series was 13.2% and showed a propensity for the left ureter (66.7%; p = 0.32). this is comparable to the literature where the reported incidence of strictures ranges from 1.9% to 25.3%[15,19] and corroborates the tendency for strictures to form in the left ureter[12,16,18]. at our institution, there was a notable difference in stricture formation between all three techniques. overall, it appeared that the hybrid anastomosis had substantially lower rates of stricture formation when compared to the bricker and wallace anastomoses performed at this site, with bricker being the highest. the review only included four studies due to a paucity of studies in the literature, and as such, it is difficult to comment on the true rate of stricture formation with the bricker or the wallace anastomosis. this is illustrated by cristoph et al.[15] in their analysis of 137 patients, with reported stricture rates of 25.3% of patients (roughly 12.9% of ureters) with the bricker technique and 7.7% of patients (roughly 3.9% of ureters) with the wallace technique, highlighting the variability in 175siuj.org siuj • volume 4, number 3 • may 2023 hybrid ureteroenteric anastomosis is associated with lower stricture rates in ileal conduit urinary diversion http://siuj.org incidence of stricture formation. in a study by large et al.[20], the stricture rate per ureter was 8.5% and 12.7% in the interrupted and running anastomosis groups, respectively. perhaps our stricture rates can be further improved by switching from running to interrupted suturing. table 3. summary of perioperative outcomes perioperative outcomes total bricker wallace hybrid p-value sample size (%) 68 (100) 19 (27.9) 20 (29.4) 29 (42.6) operative time (min), median (iqr) 317.5 (270–390) 390 (330–420) 315 (300–360) 300 (270–360) 0.01 blood lost (ml), median (iqr) 700 (500–1100) 500 (375–950) 900 (725–1750) 700 (400–1000) 0.55 length of stay (days), median (iqr) 13.1 (9.0–16.9) 13.9 (10.2–15.75) 12.6 (9.1–15.4) 13.1 (7.4–19.1) 0.62 postoperative complications (%) ileus 35 11 (57.9) 11 (55.0) 13 (44.8) 0.63 electrolyte disturbance 25 6 (31.6) 8 (40.0) 11(37.9) 0.85 acute kidney injury 18 7 (36.8) 4 (20.0) 7 (24.1) 0.46 uti 27 4 (21.0) 8 (40.0) 15 (51.7) 0.10* b vs. w: 0.30 b vs. h: 0.04 w vs. h: 0.56 urosepsis 8 1 (5.3) 4 (20.0) 3 (10.3) 0.34 pelvic collection 9 1 (5.3) 5 (25.0) 3 (10.3) 0.16 urine leak 5 0 (0) 3 (15.0) 2 (7.0) 0.20 postoperative transfusion 36 (100) 8 (22.2) 12 (33.3) 16 (44.4) 0.51 readmission within 30 days 13 (100) 4 (30.8) 4 (30.8) 5 (17.2) 0.94 reoperation within 30 days 1 (100) 0 0 1 (100) 0.51 post-cystectomy follow-up (months), median (iqr) 16 (4–36) 19 (4–33.8) 12 (6.3–36) 26 (3–41) 0.99 *chi-square test p-value ≤ 0.10, bonferroni correction performed with fisher exact test. the left ureter has a higher risk of developing a stricture in the bricker and wallace techniques, most likely due to ischemia from mobilizing it more than the right side in order to create a “tunnel” through the retrosigmoid mesocolon. we believe that the hybrid technique has a lower risk of developing a stricture in the left ureter, 176 siuj • volume 4, number 3 • may 2023 siuj.org original research http://siuj.org as there is less mobilization required to make an end-toend anastomosis as compared to the bricker technique, and also with the wallace technique a ureteric plate is required to be made between the two ureters. the right ureter undergoes a side-to-end anastomosis and is thought to be less susceptible to stricture formation, as it must travel less and undergoes less mechanical compression compared to the left ureter[18]. the anastomosis of the right ureter in our technique is essentially a bricker end-to-side refluxing anastomosis, therefore the stricture formation rates should be comparable to the rates found with bricker anastomosis with the right ureter. intraoperative and perioperative outcomes were a prime consideration in our study. we found that there was no statistically significant difference in perioperative morbidity between the subgroups, excluding operation time and urinary tract infections not requiring iv antibiotics. the hybrid group had a lower operation table 4. outcomes classified by clavien-dindo classification and comprehensive complication index clavien-dindo classification bricker wallace hybrid grade 1 3 1 3 grade 2 6 10 18 grade 3a 1 0 0 grade 3b 3 3 3 grade 4a 2 0 0 grade 4b 0 0 0 grade 5 0 0 0 comprehensive complication index 0–20 3 1 3 20–40 10 12 19 40–60 2 1 1 60+ 0 0 1 time (p < 0.01); however, it posed an additional risk for urinary tract infections requiring only oral antibiotics in our cohort (p < 0.04). while lower operation times will inevitably have a positive effect on patient outcomes, it is hard to quantify this against recent studies in the literature, as only robotic studies comparing bricker and wallace anastomoses recorded their operating time, which were invariably longer than the open approach[21,22]. the increased incidence of urinary tract infection is of concern with the hybrid approach. the expected incidence is not reported in the literature, but when compared to the other two approaches at our institution, it was clear that more patients with the hybrid approach developed a urinary tract infection. we are unsure of the exact reason why there were more episodes of acute uti in the hybrid group. one speculation is that the proximal end of the ileal conduit potentially can migrate through the retro-mesocolon space. as the retro-mesocolon space is usually narrow, it might cause urine trapping in the proximal ileal conduit and increase the risk for uti due to urine stasis. if this is the culprit, making the retro-mesocolon space larger may prevent urine trapping. fortunately, these urinary tract infections were treated with oral antibiotics only, and as such, it appears favorable to undergo the hybrid technique despite the risk. this is further supported by other perioperative outcomes, as it is apparent that there are no statistically significant differences between each technique, including the incidence of urosepsis requiring iv antibiotics. thereby, it can be said that the hybrid technique appears to be as safe and efficacious as the other two techniques, with the benefit of lower stricture rates that required intervention. postoperative follow-up in this cohort is believed to be adequate to detect most events of strictures in our patients; however, patients were not followed up for a uniform length. the median time to stricture formation in our cohort was 9 months (iqr 7 to 32), with 2 cases who presented at 32 and 37 months, postoperatively. this is mostly in line with the current literature where most strictures are thought to present within the first 2 years after surgery, though strictures have been reported at up to 40 months postoperatively[18]. reporting the time to stricture formation is paramount in evaluating the extent of strictures in this cohort of patients, as the assumed stricture rate could be falsely lower than the actual rate. a criticism of davis’ meta-analysis[19] is that 3 of the 4 studies had a follow-up duration of less than 2 years. despite most of the strictures presenting before then, a more complete view of time to stricture duration is obtained from longer follow-up. our study being retrospective and single center implies that it is susceptible to selection bias. as the operations were performed at a tertiary referring public teaching hospital, cases were performed by one of five 177siuj.org siuj • volume 4, number 3 • may 2023 hybrid ureteroenteric anastomosis is associated with lower stricture rates in ileal conduit urinary diversion http://siuj.org consultant surgeons supervising urology fellows and trainees. the decision on the choice of the three techniques was based on individual surgeon or fellow preferences. we were not able to ascertain the degree of involvement each consultant had intraoperatively based on chart review. therefore, this study isn’t able to separate surgeon technique from anastomotic technique, which could impact the results. it is worth mentioning that that the hybrid technique was started by the most junior urologist on the team, hence it is unlikely, though possible, that lack of experience alone has contributed to the difference in outcomes including an increase in urinary tract infections. this study is also limited by the small sample size for all three techniques, which is a potential reflection of the findings being due to chance. a further larger prospective study would help address the limitations in this current study. there were no significant differences between patient demographics besides an obvious predilection for male patients across all subgroups that mirrors the incidence of bladder cancer in the population[23]. conclusion in our single-center, retrospective, cohort study, it appears that the hybrid technique is a potentially safe and efficacious alternative to the bricker and wallace anastomoses. it carries with it a risk for urinary tract infection that is eclipsed by the substantially lowered rates of ureteric strictures requiring intervention while also maintaining the advantage of keeping the two ureters separate. this technique could lower the morbidity attached to stricture formation post–urinary diversion for many patients post-radical cystectomy; however, its role will need to be established by further prospective studies comparing the bricker, wallace, and hybrid anastomotic techniques. acknowledgements funding: marlon perera is sponsored by the australianamerica fulbright commission administered through a 2021–2022 fulbright future scholarship funded by the kinghorn foundation. 178 siuj • volume 4, number 3 • may 2023 siuj.org original research http://siuj.org reference 1. khalilullah sa, tranggono u, hendri az, danarto r. comparing the outcome of ileal conduit and transuretero-cutaneostomy urinary diversion after radical cystectomy: a retrospective cohort study. afr j urol.2021;27(1):59. doi: 10.1186/s12301-021-00163-9. 2. almassi n, bochner bh. ileal conduit or orthotopic neobladder: selection and contemporary patterns of use. curr opin urol.2020;30(3):415–420. doi: 10.1097/mou.0000000000000738. pmid: 32141937; pmcid: pmc8261790. 3. li z, liu z, yao k, qin z, han h, li y, et al. an improved ileal conduit surgery for bladder cancer with fewer complications. cancer commun (lond). 2019;39(1):19. doi: 10.1186/s40880-019-0366-8. pmid: 30999948; pmcid: pmc6471754. 4. gore jl, saigal cs, hanley jm, schonlau m, litwin ms, urologic diseases in america p. variations in 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ficarra v, giannarini g, crestani a, palumbo v, rossanese m, valotto c, et al. retrosigmoid versus traditional ileal conduit for urinary diversion after radical cystectomy. eur urol.2019;75(2):294–299. doi: 10.1016/j. eururo.2018.06.023. pmid: 30091420. 10. khalil el-sa. long term complications following ileal conduit urinar y diversion af ter radical cystectomy. j egypt natl canc inst.2010;22(1):13–18. pmid: 21503002. 11. evangelidis a, lee ek, karellas me, thrasher jb, holzbeierlein jm. evaluation of ureterointestinal anastomosis: wallace vs bricker. j urol.2006;175(5):1755–1758; discussion 1758. doi: 10.1016/s00225347(05)01020-7. pmid: 16600750. 12. kouba e, sands m, lentz a, wallen e, pruthi rs. a comparison of the bricker versus wallace ureteroileal anastomosis in patients undergoing urinary diversion for bladder cancer. j urol.2007;178(3 pt 1):945–948; discussion 948–949. doi: 10.1016/j.juro.2007.05.030. pmid: 17632159. 13. bricker em. bladder substitution after pelvic 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radical cystectomy for bladder cancer: options, patient selection, and outcomes. bju int.2014;113(1):11–23. doi: 10.1111/bju.12121. pmid: 24330062. 18. lobo n, dupré s, sahai a, thurairaja r, khan ms. getting out of a tight spot: an overview of ureteroenteric anastomotic strictures. nat rev urol.2016;13(8):447–455. doi: 10.1038/nrurol.2016.104. pmid: 27349367. 19. davis nf, burke jp, mcdermott t, flynn r, manecksha rp, thornhill ja. bricker versus wallace anastomosis: a meta-analysis of ureteroenteric stricture rates after ileal conduit urinary diversion. can urol assoc j. 2015;9(5–6):e284–e290. doi: 10.5489/cuaj.2692. pmid: 26029296; pmcid: pmc4439225. 20. large mc, cohn ja, kiriluk kj, dangle p, richards ka, smith nd, et al. the impact of running versus interrupted anastomosis on ureterointestinal stricture rate af ter radical cystectomy. j urol.2013;190(3):923–927. doi: 10.1016/j.juro.2013.02.091. pmid: 23454159. 21. desai mm, gill is, de castro abreu al, hosseini a, nyberg t, adding c, et al. robotic intracorporeal orthotopic neobladder during radical cystectomy in 132 patients. j urol.2014;192(6):1734–1740. doi: 10.1016/j.juro.2014.06.087. pmid: 25016136. 22. rehman j, sangalli mn, guru k, de naeyer g, schatteman p, carpentier p, et al. total intracorporeal robot-assisted laparoscopic ileal conduit (bricker) urinary diversion: technique and outcomes. can j urol.2011;18(1):5548–5556. pmid: 21333051. 23. horstmann m, witthuhn r, falk m, stenzl a. gender-specific differences in bladder cancer: a retrospective analysis. gend med.2008;5(4):385–394. doi: 10.1016/j.genm.2008.11.002. pmid: 19108811. 179siuj.org siuj • volume 4, number 3 • may 2023 hybrid ureteroenteric anastomosis is associated with lower stricture rates in ileal conduit urinary diversion http://siuj.org 157siuj.org siuj • volume 4, number 3 • may 2023 table of contents editorial fomo: a force to be contained in urology 159 peter c. black urology around the world trends towards sub-specialization in urology: what about morocco? 162 jihad el anzaoui, abdelghani ammani, jalal eddine el ammari,my hassan farih research a case series of cystinuric stone formers in western cape, south africa: slc3a1 or slc7a9 mutations and phenotype 165 lisa-ann kaestner, john lazarus, azola salukazana, elmi muller, karl-heinz jehle hybrid ureteroenteric anastomosis is associated with lower stricture rates in ileal conduit urinary diversion spencer 171 zein alhamdani, kirby r. qin, vidyasagar chinni, scott donellan, damien bolton, marlon perera, dixon woon ageand population-adjusted trends in inpatient surgical management of vaginal prolapse, rectal prolapse, and concurrent vaginal and rectal prolapse surgery 180 justina tam, hannah g. koenig, celine r. soriano, alvaro lucioni, jennifer a. kaplan, kathleen c. kobashi, vlad v. simianu, una j. lee a prospective evaluation of different frailty indices in patients undergoing transurethral resection of bladder tumor 187 neebal abunaser, adnan elachkar, mohamad k. abou chaar, ali ababneh, sattam a. halaseh, ala’a farkouh, ramiz abo-hijleh, awni d. shahait, samer salah, mohammed shahait augmentation cystoplasty: experience in the developing world 195 naveed ahmed mahar, mohsin mustafa memon, farag mohsen saleh aboali, shireen piyarali, harris hassan qureshi, sara rasheed kalwar, murli lal pelvic floor muscle function and its relationship with post-prostatectomy incontinence 203 cecile t. pham, manish i. patel, sean f. mungovan http://siuj.org 158 siuj • volume 4, number 3 • may 2023 siuj.org table of contents, cont'd review role of cryoablation for the treatment of ct1b kidney lesions: outcomes of a systematic review 211 adnan el-achkar, mustafa khader, ala’a farkouh, joelle hassanieh, bhaskar somani, mohammed shahait pro and con continued use and expansion of photodynamic turbt 223 michael e. rezaee, max kates the end of photodynamic surgery for bladder cancer has arrived 226 benjamin davies giants in urology patrick c. walsh, baltimore, united states 229 matthew e. nielsen clinical picture glans ischemia after circumcision 231 anna black, ryan paterson the prostate problem you can’t put your finger on the normal way: a case of perineal prostate cancer post transperineal prostate biopsy 232 kevin yinkit zhuo, james kovacic, amanda chung, thomas eade, venu chalasani http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information prostate cancer, commercial airline pilots, incidence, mortality none declared. received on september 1, 2021 accepted on january 23, 2022 this article has been peer reviewed. soc int urol j. 2022;3(3):145–162 doi: 10.48083/pdkf1241 145siuj.org siuj • volume 3, number 3 • may 2022 review incidence and mortality of prostate cancer in commercial airline cockpit crew: systematic review and meta-analysis hadia khanani,1 george mcclintock,1 hilary fernando,1 gillian heller,2 rebecca asher,2 cindy garcia,1 david p. smith,3 ian getley,4 nariman ahmadi,1 norbert doeuk,1 scott leslie,1 niruban thanigasalam,1 henry h. woo1 1 department of uro-oncology, chris o’brien lifehouse, camperdown, australia 2 national health and medical research council clinical trials centre, university of sydney, sydney, australia 3 daffodil centre, the university of sydney, a joint venture with cancer council new south wales, sydney, australia school of public health and preventative medicine, monash university, melbourne, australia menzies health institute queensland, griffith university, australia 4 pcaire inc, australia 5 college of health and medicine, australian national university, wahroonga, australia. san prostate centre of excellence, sydney adventist hospital, wahroonga, australia abstract commercial airline cockpit crew (ccc) are potentially exposed to occupational risk factors that may have detrimental health effects. however, available literature on prostate cancer (pca) as a health outcome is conflicted. therefore, this review of cohort studies aims to evaluate the incidence of and mortality from pca in ccc based on studies published to date. pubmed, medline, embase and scopus were searched from 1946 to april 2021. cohort studies reporting standardized incidence ratios (sir) and/or standardized mortality ratios (smr) of pca in ccc were included. military, cabin crew and service personnel data were excluded. independent data extraction was conducted, and study quality assessed. standardized ratios were pooled using a fixed effects model and expressed with 95% confidence intervals. 75 studies were assessed for eligibility from which 6 involving 129 374 licensed ccc were included in the final analysis: two reported incidence only, 1 incidence and mortality and 3 reported mortalities only. the pooled sir for pca in ccc was 1.41 (95% ci 1.17 to 1.71) with moderate heterogeneity (i2 = 53%) however, the pooled smr was not statistically significant (1.08; 95% ci 0.94 to 1.24) also with moderate heterogeneity (i2 = 70%). the available evidence shows that ccc are at a higher risk of developing pca but there is no evidence to suggest a similarly higher risk of death from the disease. the effect of early detection through psa testing in this cohort is unclear. occupational exposure to radiation and sleep disturbance may play a role, but clear evidence of additional risk is lacking. our review indicates that most evidence is dated and to confidently assess contemporary health outcomes of ccc, further research is required. introduction commercial airline cockpit crew (ccc) usually includes captains (pilot in command), co-pilots (first officer) and flight engineers with variations in number depending on type of aircraft and route[1]. this is an occupational cohort who undergo strict medical surveillance and are often regarded as healthier than the general population[2]. although a healthy worker effect exists among pilots[3,4], their unique work environment exposes them to several risk factors including exposure to electromagnetic fields, ionizing radiation of cosmic origin, disruptions of circadian rhythm, and noise pollution[5], ultimately raising their risk of poorer outcomes in several physical and mental health parameters[6–8,9]. http://siuj.org https://orcid.org/0000-0003-2101-8261 https://orcid.org/0000-0002-6992-8013 https://orcid.org/0000-0003-3647-8658 https://orcid.org/0000-0003-1270-1499 https://orcid.org/0000-0003-2502-4693 https://orcid.org/0000-0002-5787-2964 https://orcid.org/0000-0002-1474-3214 https://orcid.org/0000-0001-5864-1044 https://orcid.org/0000-0001-8727-5952 https://orcid.org/0000-0003-4322-2984 https://orcid.org/0000-0001-9848-969x https://orcid.org/0000-0002-6438-8732 https://orcid.org/0000-0003-4099-0339 mailto:henry.woo%40lh.org.au?subject=siuj in 1990, t he internat iona l com mission on radiological protection recommended that natural background radiation exposure be included as an occupational hazard for aircrew[10], and since then, various reports[5,9,11–21] have described the incidence and mortality risks of cancer in pilot cohorts. in summary, decreased mortality from cardiovascular and respiratory diseases was reported in some cohorts[5,11,13,14] as well as all cancer deaths[13,15,16,18,20,21] when compared with mortality in the general population. malignant melanoma has been consistently associated with high incidence[12,13,22–26] and mortality ratios[5,13,14]. prostate cancer ranks second in incidence after lung cancer and fifth in mortality rates in males globally[27]. to our knowledge, no studies have exclusively investigated pca in ccc. however, data on prostate cancer risks have been reported in studies documenting outcomes from multiple disease types that report conflicting results associated with incidence and mortality rates of pca. from these, 6 studies have reported increased incidence[12,13,25–29], 2 reported no significant association[23,26] and one[30] reported a lower incidence of pca compared with background population rates. similar contradictory evidence is available in mortality studies, with data reporting lower[9], unchanged[14,16,17,21,31,32], and higher[5,13,33] mortality rates of pca in ccc relative to population statistics. several commentaries[7], meta-analyses[34,35], and reviews[36] have reported cancer risks in f light personnel, with data for cockpit crew, f light attendants, and military personnel generally analyzed separately. these studies report for all cancer types, except one study[37] that focused exclusively on pca in pilots. raslau et al. in the review and meta-analysis reported a higher incidence of pca (rr 1.20; 95% ci 1.08 to 1.33) in pilots compared with the general population, but mortality was not significantly elevated (rr 1.20; 95% ci 0.91 to 1.60). after initial retraction[38], the revised version[37] was criticised[39] for omission of eligible studies[5,9,12,21] and re-inclusion of military data[40]. given the inconclusive nature of literature in this area and the previously retracted and criticised review, a new analysis is required. this study, therefore, in addition to correcting past errors, aimed to provide a systematic review and meta-analysis of data exclusively focusing on pca in ccc. materials and methods this systemat ic rev iew a nd meta-a na lysis was undertaken in accordance with the preferred reporting items for systematic reviews and meta-analyses (pr isma) statement recommendations[41]. two independent investigators (h.f. and h.k.) conducted the literature search, study selection, and data extraction, and resolved any discrepancies through discussion. selection criteria studies that fit the following criteria were included in the meta-analysis: (1) published studies only, (2) original population data, (3) cohort study design, (4) investigating ccc only, (5) pca as either one of the outcomes or the only outcome reported, (6) reporting in terms of standardized incidence ratios (sir) or standardized mortality ratios (smr) and their 95% confidence intervals (ci) only or studies containing sufficient data for calculation of these parameters, (7) reporting 2 or more cases of prostate cancer in either incidence or mortality occurrences and (8) written in any language. all studies that investigated military, cabin crew, f light attendants and other personnel not designated as an occupation undertaken inside the cockpit were excluded. latest studies that were investigative extensions of previous data cohorts were selected to avoid data duplication. literature search and data sources eligible cohort studies in any language published on pubmed, medline, embase and scopus from inception up to april 2021 were searched using the search strategies outlined in appendix 1. commercial aircraft pilot, navigator, and flight engineer data were included as ccc, and military and helicopter pilots, flight/cabin attendant and service personnel data were excluded. flight attendant cohorts that reported cancer incidence[24,42] and mortality[43,44] collectively analyzed 5 times as many females as males; most of the population were younger than 50 years, and they had a much shorter work period than pilots. they were therefore excluded. military and helicopter pilots fly different routes and at different altitudes[29] from commercial cockpit crew and so were also excluded from the analysis. the titles and abstracts of all identified articles were reviewed by 2 investigators independently, and disagreements and ambiguities resolved by discussion. the reference lists of identified studies and previous systematic reviews were manually examined for additional studabbreviations ccc commercial airline cockpit crew pca prostate cancer psa prostate specific antigen sir standardized incidence ratio smr standardized mortality ratio 146 siuj • volume 3, number 3 • may 2022 siuj.org review http://siuj.org ies of interest. reports in which the data were duplicated were identified, and only the most recent cohorts were included. the abbreviation “ccc” and the words “pilots” and “cockpit crew” are used interchangeably throughout the paper. data extraction and quality assessment a standardized data extraction form was used by 2 independent researchers. the following relevant information was extracted from each study: author, year of publication, study outcome (incidence, mortality, or both), title of paper, country, population size of cohort, duration of study, mean age at conclusion, newcastle– ottawa scale (nos)[45] score, risk factors assessed (years of employment, cumulative radiation dose in µsv or msv, cumulative block hours and high altitude long-haul or short-haul flights), observed and expected number of pca cases, sir or smr, and 95% confidence intervals. the quality of the papers included in the review was assessed using the newcastle–ottawa scale (nos) developed by wells et al.[45]. the nos is tailored to the design type and allows assessment the validity of results in the presence of selection, reporting, and confounding biases. it uses 3 domains for assessment: selection, comparability, and outcome. stars were added in each domain, with the totals signifying “good,” “fair,” or “poor” quality. details of each item can be found on the website (www.ohri.ca/programs/clinical_epidemiology/ oxford.asp). data synthesis and statistical analysis the outcomes of interest were standardized incidence rat ios (sir) a nd sta nda rdized mor ta lit y rat ios (smr). for each study, the observed and expected numbers were extracted. this allowed the calculation of the standardized ratios (sr) and corresponding confidence intervals to be consistent across studies. the sr was calculated as observed/expected and then log-transformed. the standard error of the log(sr) was calculated using 1/sqrt(observed) and confidence intervals constructed on the log-scale and exponentiated. this ensured that all estimates would be positive. a fixed effects meta-analysis was used to calculate the pooled standardized ratios across studies. the i2 statistic was calculated to investigate the extent of heterogeneity across studies. heterogeneity was considered low for i2 values between 25% and 50%, moderate for 50% to 75%, and high for >75%. r software (version 4.0.2) was used for computation of the estimates and construction of forest plots packages, with packages meta[46] and metaphor[47]. publication bias could not be assessed as the study included fewer than 10 studies[48]. results literature search and study selection figure 1 shows the literature search and study selection process. we identified 3100 records by key word search, and hand searching elicited 17 further studies. after screening, 75 remaining full-text articles were assessed for eligibility of which 6 were included in the review: 2 studies reported incidence only, 3 reported mortality only, and 1 reported both for pca. from the large number of studies excluded, 30 were tabulated with reasons for ex clusion and selected data characteristics (0and supplementary table s1b). methodological evaluation of studies: identification of systematic bias the nos components and total scores are shown against each study in table 1. the 1996 study by band et al.[13] was assessed for incidence and mortality outcomes separately. the median total score was 6, and only 2 studies scored a total of 7, indicating an overall good quality of studies and no manuscripts with a high risk of bias. total scores and thus quality of the studies tended to be less prone to bias if they were published more recently. incidence of prostate cancer among ccc: meta-analysis results table 2 and figure 2 summarize the results of the metaanalysis of 3 studies reporting incidence of pca. the pooled analysis resulted in a psir of 1.41 (95% ci 1.17 to 1.71) suggesting that observed rates were significantly higher than expected. the pooled results were of moderate heterogeneity (i2= 53%). an exploration of sources and subsequently a pooled analysis of subgroups and risk factors was not possible because of heterogeneity and lack of sufficient and consistent data in individual cohorts. studies by band et al.[12,13] did not include a risk factor analysis, leaving only one[25] from the included incidence studies attempting to analyze cosmic radiation and circadian disruptions as risk factors of pca by calculating relative risk estimates. they did so by approximating radiation exposure with block hours on short-haul flights and hormone disturbances with block hours on long-haul flights. mortality of prostate cancer among ccc: meta-analysis results the summary of results of the meta-analysis of the 4 mortality studies are shown in table 3 and figure 3. the analysis resulted a psmr of 1.08 (95% ci 0.94 to 1.24), suggesting that observed mortality rates were not significantly different to the rate expected in the general population with moderate heterogeneity (i2=70%). the 1990[12] study by band et al. was excluded from the mortality analysis because only 1 death from pca 147siuj.org siuj • volume 3, number 3 • may 2022 incidence and mortality of prostate cancer in commercial airline cockpit crew: systematic review and meta-analysis http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp http://siuj.org was observed. from the included studies, only 2[5,21] reported a risk factor analysis (discussed below); however, it is noteworthy that yong et al.[21] reported standardized rate ratios of duration of employment and cumulative cosmic radiation dose with mortality, but no data on pca were available. lack of risk factor analysis from other included studies prevented a multivariable analysis with mortality data as well. discussion this systematic review and meta-analysis summarizes available literature pertaining to incidence and mortality rates of pca in ccc. these results may support the hypothesis that prostate cancer risks in ccc ref lect a combination of screening, sociodemographic, and environmental factors that increase the risk of diagnosis but have no effect on the risk of death from prostate cancer. however, because of substantial heterogeneity among studies and an overall small sample size, we believe these results should be interpreted with caution. the most plausible drivers of the observed increased incidence of pca in ccc appear to be occupational risk factors discussed in detail below. however, it is also worth noting that over the last 2 decades the rise of prostate specific antigen (psa) testing in many developed countries has led to dramatic increases in the incidence rates of pca via diagnosis of sub-clinical disease[49]. although in most developed countries, psa testing is figure 1. flow diagram of literature search and study selection for meta-analysis of prostate cancer in commercial airline cockpit crew/pilots. records identi�ed through search of medline, pubmed, embase and scopus (n = 3100) in cl ud ed s cr ee ni ng id en ti �c at io n el ig ib il it y additional records identi�ed through manual search (n = 17) records after duplicates removed (n = 2852) records screened (n = 2852) records excluded (n = 2777) full-text articles assessed for eligibility (n =75) studies included in meta-analysis (n= 6) incidence and mortality of prostate cancer (n = 1) mortality of prostate cancer (n = 3) incidence of prostate cancer (n = 2) full-text articles excluded, with reasons:air force data / military data / cabin crew data / no data on outcome of interest / no data on prostate cancer / duplicated data cohorts (n = 69) 148 siuj • volume 3, number 3 • may 2022 siuj.org review http://siuj.org not mandated as part of the medical certification process for ccc[50–52], ccc are more likely to be tested for psa upon inquiry of reported lower urinary tract symptoms as they undergo more regularly scheduled and concentrated medical surveillance[2] than males in the general population. the results of this meta-analysis are likely also affected by increased use of psa testing in ccc, which results in the detection of more localised pca compared to the general population. ccc typically have higher incomes and psa testing with subsequent follow-up of abnormal results is performed more frequently in men with higher incomes[53]. despite increased incidence, mortality from pca was unchanged as compared with the general population. higher socioeconomic status and better baseline health could be factors in this observation, especially given the general long life expectancy of men diagnosed with pca. the data related to the impact of psa testing and early diagnosis of pca is controversial, with current literature suggesting it does not affect overall mortality[54], which would be consistent with these results. exposure to ionizing radiation of cosmic origin pca is not frequently included in the list of neoplasms attributable to ionizing radiation[55], largely due to the lack of sensitivity of the prostate to ionizing radiation, but also due to the latency period of radiation induced solid tumours being decades[56] and pca being among the slower growing solid tumours. supporting this theory, studies investigating radiologists and other medical radiation workers have shown no increase in incidence[57] or mortality[58] rates of pca. in contrast to this, studies after the 1986 chernobyl incident show an increase in the incidence of pca in regions surrounding the area of the accident[56,59]. the large release of radioactive material from the incident[60] makes it less relevant to pilots; however, findings of radiation induced incidence rates of pca in pilots show similarly conflicting results. the study of nordic pilots[25] quantified cumulative radiation exposure by converting aircraft specific block hours to effective doses. block hours are industry-standard measure of aircraft use and are defined as the time elapsed between closure of aircraft doors before departure and opening of these doors at the arrival gate following landing of the aircraft. the same study used the number of block hours on long-haul aircrafts to estimate circadian hormonal disruption among pilots as well. a statistically significant increase of pca was observed in exposure category ≥ 20 msv, rr 9.13; 95% ci 1.11 to 74.9 in men age < 60 years as compared with older ages in the same category of exposure (rr 1.08; 95% ci 0.55 to 2.12). similarly, gudmundsdóttir et al.[26] reported a statistically significant risk ratio of 2.57 (95% ci 1.18 to 5.56) in icelandic pilots exposed to > 25msv of ionizing radiation of cosmic origin compared with pilots who were not. these values could possibly be related to greater levels of uv radiation at the poles than at the equator. the association between prostate cancer and radiation exposure remains uncertain. according to available literature it seems unlikely that development of prostate cancer at an early age would be associated with ionizing radiation as no studies have been able to establish a causal link between the two[25]. adding to this evidence is the 20-year-old norwegian study[23] that reported an inconsistent trend in sir values as ionizing radiation exposure increased from 0msv to >20msv with a statistically non-significant elevated sir of 1.8 (95% ci 0.7 to 4.0) for pilots exposed to >20msv of ionizing radiation. overall mortality data show moderate but higher heterogeneity than incidence data, but information on measurement of risk factors is less conflicted, with the majority of studies showing no significant difference, although with heterogeneity in measurement methodology. a mortality analysis of pca cases exposed to >25 msv cumulative effective dose of cosmic radiation reported in a german publication[32] reported low and non-significant mortality and risk ratios (smr 0.92; 95% ci 0.00 to 37.69, rr 0.94; 95% ci, 0.18 to 4.79). a large european cohort study (escape)[61] attempted a risk factor analysis of cosmic radiation and mortality rates in pilots. pca was placed in the category of non-radiation related neoplasms[62,63] but smrs of pca with increasing doses of radiation were not reported individually. mortality studies that quantify years of employment[16,31] or number of block hours since attaining a license[15] as proxies for radiation exposure have reported no statistically significant mortality ratios of pca. an extension[5] of the escape[61] study cohort with addition of pilots from greece and united kingdom, analyzed years of employment as proxy for cumulative radiation exposure. this large study, included in this review, also reported no consistent change in smrs in proportion to increasing years of employment. it is important to keep in mind that this study was an extension of previously reported cohorts hence similar results were to be expected. further research into occupations frequently exposed to radiation is warranted for clarification of the relationship between radiation and prostate cancer. exposure to electromagnetic fields and disruption of circadian rhythm although not fully understood, the incidence of pca has been suspected to be linked with exposure to magnetic fields, which, it has been suggested, may lead to alteration in pineal function, subsequently causing reduction in levels of the pineal hormone, melatonin[33]. melatonin is associated with the sleep–wake cycle and maintenance 149siuj.org siuj • volume 3, number 3 • may 2022 incidence and mortality of prostate cancer in commercial airline cockpit crew: systematic review and meta-analysis http://siuj.org table 1. characteristics of six studies included in the meta-analysis of prostate cancer among pilots study author (year) sample size study period country/ region observed expected sir (95% ci) mean age at conclusion risk factors considered quality score categories total quality score* selection comparability outcome band et al. (1990) 891 1950–1988 canada 6 3.9 1.54 (0.69–3.43) 49.9 not available 6 fair band et al. (1996) 2680 1950–1992 canada 34 18.2 1.87 (1.34–2.62) 50.5 not available 6 fair pukkala et al. (2003) 10 051 1946–1997 (denmark from 1946, finland up to 1996, iceland from 1937, norway 1946–1994, sweden 1957–1994) nordic countries 64 52.9 1.21 (0.93–1.54) not available cumulative block hours, cumulative radiation dose 7 good band et al. (1996) 2680 1950–1992 canada 7 4.62 1.52 (0.72–3.19) 50.5 not available 6 fair cashman et al. (2007) 72 972 1980–2002 united states 4 10.9 0.37 (0.10–0.94) 43.09 not available 6 fair yong et al. (2014) 5964 1953–2008 united states (panam) 77 not available 0.90 (0.71–1.12) not available duration of employment, cumulative radiation dose 6 good hammer et al. (2014) 36 816 1957–1999 (denmark 1960–1996, finland 1971–1997, germany, greece, iceland 1960–1997, italy 1965–1996, norway 1962–1994, sweden 1957–1994, united kingdom 1989–1999) europe / united states† 114 119.99 1.23 (1.03–1.47) 53.3 duration of employment as proxy for radiation exposure 7 good *assessed by the newcastle-ottawa scale45 †united states was part of the cohort but data on pilots was not available or analysed (cabin crew data analysed only) 150 siuj • volume 3, number 3 • may 2022 siuj.org review http://siuj.org table 1. characteristics of six studies included in the meta-analysis of prostate cancer among pilots study author (year) sample size study period country/ region observed expected sir (95% ci) mean age at conclusion risk factors considered quality score categories total quality score* selection comparability outcome band et al. (1990) 891 1950–1988 canada 6 3.9 1.54 (0.69–3.43) 49.9 not available 6 fair band et al. (1996) 2680 1950–1992 canada 34 18.2 1.87 (1.34–2.62) 50.5 not available 6 fair pukkala et al. (2003) 10 051 1946–1997 (denmark from 1946, finland up to 1996, iceland from 1937, norway 1946–1994, sweden 1957–1994) nordic countries 64 52.9 1.21 (0.93–1.54) not available cumulative block hours, cumulative radiation dose 7 good band et al. (1996) 2680 1950–1992 canada 7 4.62 1.52 (0.72–3.19) 50.5 not available 6 fair cashman et al. (2007) 72 972 1980–2002 united states 4 10.9 0.37 (0.10–0.94) 43.09 not available 6 fair yong et al. (2014) 5964 1953–2008 united states (panam) 77 not available 0.90 (0.71–1.12) not available duration of employment, cumulative radiation dose 6 good hammer et al. (2014) 36 816 1957–1999 (denmark 1960–1996, finland 1971–1997, germany, greece, iceland 1960–1997, italy 1965–1996, norway 1962–1994, sweden 1957–1994, united kingdom 1989–1999) europe / united states† 114 119.99 1.23 (1.03–1.47) 53.3 duration of employment as proxy for radiation exposure 7 good *assessed by the newcastle-ottawa scale45 †united states was part of the cohort but data on pilots was not available or analysed (cabin crew data analysed only) 151siuj.org siuj • volume 3, number 3 • may 2022 incidence and mortality of prostate cancer in commercial airline cockpit crew: systematic review and meta-analysis http://siuj.org of circadian rhythm, and it may have a protective effect against prostate cancer[64]. magnetic field exposure in commercial aircraft has been measured in a prior study[65] and was concluded to be substantially higher than that of a home or a typical office environment. most studies used block hours as approximate values for amount of magnetic field exposure and hormonal disruption[21,25]. the nordic study[25] reported increased risk associated with a greater number of longhaul hours in men > 60 years of age as the strongest flying-related variable studied in the context of prostate cancer. the possibility that circadian disruptions have a role in causing hormone-related neoplasms cannot therefore be entirely excluded. however, a precise association or disassociation between jet lag and development of hormone-related cancers could not be established. gudmundsdóttir et al.[26] observed similar results of higher incidence rates of pca in pilots with >10 000 cumulative air hours (rr 2.61; 95% ci 1.22 to 5.60). in contrast, however, an incidence study[29] not included in the meta-analysis (supplementary table s1a and supplementary table s1b) reported no significant increase in the incidence of pca in relation to block hours (sir 1.28; 95% ci 0.73 to 2.08 for >10 000 block hours). similarly, the norwegian pilot cohort[23] reported a statistically non-significant sir of 1.1 (95% ci 0.6 to 1.9) among pilots who flew >10 000 block hours. the same year, in their study on icelandic pilots, raffnson et al.[28] attempted to evaluate the possible association between cancer risk and circadian rhythm disturbance but reported only incidence rates of malignant melanoma and all-cancer risk. an extension of this cohort[26] could not differentiate between pilots who had flown to north america and those who had flown within europe, as all icelandic pilots had flown both ways and so were unable to report cases of pca in pilots on long-haul versus short-haul flights. although long-haul flights suppress melatonin and, as hypothesized, might be expected to be associated with higher incidence rates of pca, a study of british airways pilots[14] (excluded from the review because of inclusion of helicopter crew data) reported a statistically non-significant relative risk of pca (rr 2.47; 95% ci 0.83 to 7.65) for short-haul compared with long-haul flights. in an attempt to resolve ambiguities in this area, a recent review[66] reported that neither short sleep (rr 0.99; 95% ci 0.91 to 1.07) nor long sleep (rr 0.88; 95% ci 0.75 to 1.04) was associated with pca in the general population, and long sleep may have a protective effect on pca; however, specific pilot cohorts were not investigated. available evidence has again proven to be inconsistent in arriving at a conclusion on the association of circadian abnormalities and pca necessitating deeper investigation into the subject. figure 2. study year sir 95% ci weight band et al. 1990 0.5 1 2 3.5 1.54 (0.69–3.43) 5.8% band et al. 1996 1.87 (1.34–2.62) 32.7% pukkala et al. 2003 1.21 (0.95–1.55) 61.5% 1.41 (1.17–1.71) 100% table 2. included incidence studies with observed and expected number of prostate cancer cases, individual and calculated sir, weightage, and calculated heterogeneity. sir, standardised incidence ratio study author (year) observed expected sir (95% ci) weight, % band et al. (1990) 6 3.9 1.5400 (0.6919–3.4279) 5.8 band et al. (1996) 34 18.16 1.8700 (1.3362–2.6171) 32.7 pukkala et al (2003) 64 52.9 1.2100 (0.9471–1.5459) 61.5 overall i2 = 53% 1.4146 [1.1673–1.7144] 100.0 152 siuj • volume 3, number 3 • may 2022 siuj.org review http://siuj.org other considerations the pilot population investigated to date has reported a mean age at conclusion of 41.7 to 50.5 years in incidence and 43.1 to 53.3 years in mortality studies. it is important to note that the japanese study[11] recorded a mean age of 45.9±13.6 years at conclusion of follow-up, indicating pca cases contributing to the reported allcancer mortality could possibly be non-existent because of the very low incidence of prostate cancer in younger men[67]. as older age is a well-established risk factor for pca, it can be deduced that studies on ccc reflecting the mean age group mentioned above may be reporting an underestimation of true risk of the disease. the strengths of this review lie in its exhaustive search and strict selection criteria for accurate representation of disease outcome and the inclusion of only ccc. including data related to military pilots and cabin crew can often be misleading, especially when risk factors such as ionizing radiation exposure and circadian rhythm are being explored concomitantly, because of the differences in aircraft and route selection and flight altitudes between the 2 categories of pilot[29]. although a sub-group analysis was not performed because of heterogenous exposure assessments in different studies, a streamlined sample approach aims to increase the credibility of this review. an important limitation of our review was the inability of search terms to produce important studies that were instead discovered by manual searching of references by both researchers. the large north american study[9] eligible for the meta-analysis, as well as some that were later excluded, were not initially identified via the online database search. it is noteworthy that the recent review by raslau et al.[37] did not include this study, perhaps due to the same reason. quality assessment of each study was conducted by both researchers independently, using the nos[45] that has proven to be useful in multiple similar systematic reviews[68,69]. the quality of 2 out of 3 incidence studies was “fair,” only one was “good” and none were “poor.” it was noted that studies with lower population samples were of ‘fair’ quality and also reported higher incidence rates than the ‘good’ quality study. this phenomenon of likelihood of publishing studies with lower sample sizes and positive associations has been previously described by researchers[70]. additionally, studies with fair quality were also older (published in the 1990s) than the ‘good’ quality study (published in 2003)[25]. in comparison to incidence cohorts, half of the mortality studies were of “fair” quality, and the other half were of “good” quality (none were of “poor” quality). it is noteworthy that the study with the largest sample table 3. included mortality studies with observed and expected number of deaths due to prostate cancer, individual and calculated smr, weightage and calculated heterogeneity. smr, standardised mortality ratio study author (year) observed expected smr (95% ci) weight, % band et al. (1996) 7 4.62 1.5200 (0.7246–3.1884] 3.4 cashman et al. (2007) 4 10.9 0.3700 [0.1389–0.9858] 1.9 hammer et al.(2014) 114 119.99 1.2300 [1.0285–1.4710] 57.7 yong et al. (2014) 77 not available 0.9000 [0.7198–1.1252] 37.0 overall i2 = 70% 1.0783 [0.9413–1.2353] 100 figure 3. study year smr 95% ci weight band et al. 1996 0.50.1 1 2 3.5 1.52 (0.72–3.19) 3.4% cashman et al. 2007 0.37 (0.14–0.99) 1.9% hammer et al. 2014 1.23 (1.03–1.47) 57.7% yong et al. 2014 0.90 (0.72–1.13) 37.0% 1.08 (0.94–1.24) 100% 153siuj.org siuj • volume 3, number 3 • may 2022 incidence and mortality of prostate cancer in commercial airline cockpit crew: systematic review and meta-analysis http://siuj.org of pilots (n = 72 972)[9] scored a total of 6 on the nos and was of “fair” quality. it also reported a markedly decreased mortality rate of pca among pilots, the lowest among all mortality studies, as well as in comparison to the pooled smr (1.08; 95% ci 0.94 to 1.24). although risk of potential bias is known to decrease with a higher sample size, this study is not only an exception but is also outnumbered by other included studies in this review that support results of low or unchanged mortality rates among pilots in comparison to the general population. the 1996 publication by band et al.[13] favours the theory of increased risk of bias associated with a smaller sample size and positive associations as it reported the highest mortality rate among all studies. we a re awa re of t he latest 2017 st udy by gudmundsdóttir et al.[26]. however, after consideration by the authors, it was concluded that this study should be excluded for a number of reasons. firstly, the 2003 study by pukkala et al. was a multinational cohort[25], inclusion of which would allow examination of a larger sample size, whereas the 2017[26] study by gudmundsdóttir et al. investigated only icelandic pilots. secondly, the latter study added only 47 new pilots to the initial icelandic sample in the pukkala et al. study, resulting in 83.6% data duplication (n = 239[25] and n = 286[26]). furthermore, it cannot be confirmed that differences in observed cases of pca from the 2003 study were in fact, observed cases in the added number of pilots. to demonstrate that results remain unchanged even with inclusion of this study, an analysis was performed with adjustment of sample sizes between the 2 studies to prevent data duplication (supplementary figure s1a). supplementary figure s1b shows pooled sir results (meta-sir 1.39; 95% ci 1.16 to 1.67 with i2 = 35.9%). it is evident that results remain largely unchanged. conclusions this systematic review of all available evidence suggests that compared with the general population, commercial airline cockpit crew have an increased risk of developing pca; however, there was no evidence of elevated risk of death from this disease. caution is suggested in interpretation of results, as most evidence is dated, results are inconclusive, and because of significant data duplication, the sample size for assessment of outcomes is ultimately small. the risk of developing pca as a result of exposure to ionizing radiation and circadian disruptions 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i n d m e d . 2 0 0 0 ; 3 8 ( 5 ) : 5 4 8 – 5 5 4 . d o i : 10.1002/1097-0274(200011)38:5<548::aid-ajim7>3.0.co;2-h. 66. liu r, wu s, zhang b, guo m, zhang y. the association between sleep duration and prostate cancer: a systematic review and meta-analysis. medicine.2020;99(28):e21180-e. doi: 10.1097/md.0000000000021180 67. bell kjl, del mar c, wright g, dickinson j, glasziou p. prevalence of incidental prostate cancer: a systematic review of autopsy studies. int j cancer.2015;137(7):1749–1757. doi: 10.1002/ijc.29538. epub 2015 apr 21. 68. geng q, zhang qe, wang f, zheng w, ng ch, ungvari gs, et al. comparison of comorbid depression bet ween irritable bowel syndrome and inflammatory bowel disease: a meta-analysis of comparative studies. j affect disord.2018;237:37–46. doi: 10.1016/j. jad.2018.04.111. epub 2018 may 4. 69. he x, yang k, wang h, chen x, wu h, yao l, et al. expression and clinical significance of survivin in ovarian cancer: a meta-analysis. plos one.2018;13(5):e0194463-e. published online 2018 may 24. doi: 10.1371/journal.pone.0194463 70. rivera-izquierdo m, martínez-ruiz v, castillo-ruiz em, manzanedanavío m, pérez-gómez b, jiménez-moleón jj. shift work and prostate cancer: an updated systematic review and meta-analysis. int j environ res public health.2020;17(4):1345. published online 2020 feb 19. doi: 10.3390/ijerph17041345 157siuj.org siuj • volume 3, number 3 • may 2022 incidence and mortality of prostate cancer in commercial airline cockpit crew: systematic review and meta-analysis https://www.casa.gov.au/information-dame-dao-co-and-medical-specialists/publication/designated-aviation-medical-examiners-handbook https://www.casa.gov.au/information-dame-dao-co-and-medical-specialists/publication/designated-aviation-medical-examiners-handbook https://www.casa.gov.au/information-dame-dao-co-and-medical-specialists/publication/designated-aviation-medical-examiners-handbook http://siuj.org supplementary table s1a. incidence studies excluded during eligibility assessment for the final meta-analysis, with characteristics and reasons for exclusion study sample size study duration observed expected standardized ratio mean age at conclusion country/ region reason(s) for exclusion prostate cancer incidence data: standardized incidence ratio (sir) 1 haldorsen et al. (2000) 3701 1946–1994 25 25 1.00 (0.68–1.48) not reported norway duplicated data cohort in pukkala et al. (2003) 2 gudmundsdottir et al. (2017) 286 1955–2015 15 11.8 1.27 (0.71– 2.10) not reported iceland duplicated data cohort in pukkala et al. (2003) 3 rafnsson et al. (2000) 265 1955–1997 4 2.84 1.41 (0.53– 3.76) not reported iceland duplicated data cohort in pukkala et al. (2003) 4 hammar et al. (2002) 1490 1961–1997 18 14.5 1.24 (0.78–1.97) not reported sweden duplicated data cohort in pukkala et al. (2003) 5 dos santos de silva et al. (2013) 15 867 1989–1999 not reported not reported 1.10 (0.96–1.26) not reported united kingdom duplicated data cohort in hammer et al. (2014) 6 gundestrup et al. (1999) 3790 1921–1995 3 (jet) 3 (non-jet) 3.97 (jet) 3.59 (non-jet) 0.8 (0.2–2.2) for both 41.65 years denmark duplicated data cohort in pukkala et al. (2002) 7 milanov et al. (1999) 34 1964–1994 not reported not reported not reported not reported republic of bulgaria no statistical data on prostate cancer reported 8 nicholas et al. (2001) 6533 1970–1998 65 not reported 0.7 (0.59–0.84) not reported united states, canada investigated cancer incidence by questionnaire (self-reported disease outcomes)–different methodology could give inconsistent results 9 pukkala et al. (2002) 10 032 1946–1997 (denmark from 1946, finland up to 1996, norway 1946–1994, sweden 1957–1994 iceland 1955–1997 64 52.9 1.21 (0.93–1.54) not reported nordic countries duplicate data cohort in pukkala et al. (2003) 10 pukkala et al. (2012) 1559 1947–1997 (finland 1947–1993, iceland 1947–1997, norway 1950–1994, sweden 1957–1994) 24 21.7 1.11 (0.71–1.65) not reported finland, iceland, norway, sweden cabin crew data 11 rogers et al. (2011) 106 418 1987–2008 not reported not reported not reported mean age at diagnosis ~ 50 years united states exclusively air force / military data, comparative study, calculates hazard ratio 158 siuj • volume 3, number 3 • may 2022 siuj.org review http://siuj.org supplementary table s1a. incidence studies excluded during eligibility assessment for the final meta-analysis, with characteristics and reasons for exclusion study sample size study duration observed expected standardized ratio mean age at conclusion country/ region reason(s) for exclusion prostate cancer incidence data: standardized incidence ratio (sir) 1 haldorsen et al. (2000) 3701 1946–1994 25 25 1.00 (0.68–1.48) not reported norway duplicated data cohort in pukkala et al. (2003) 2 gudmundsdottir et al. (2017) 286 1955–2015 15 11.8 1.27 (0.71– 2.10) not reported iceland duplicated data cohort in pukkala et al. (2003) 3 rafnsson et al. (2000) 265 1955–1997 4 2.84 1.41 (0.53– 3.76) not reported iceland duplicated data cohort in pukkala et al. (2003) 4 hammar et al. (2002) 1490 1961–1997 18 14.5 1.24 (0.78–1.97) not reported sweden duplicated data cohort in pukkala et al. (2003) 5 dos santos de silva et al. (2013) 15 867 1989–1999 not reported not reported 1.10 (0.96–1.26) not reported united kingdom duplicated data cohort in hammer et al. (2014) 6 gundestrup et al. (1999) 3790 1921–1995 3 (jet) 3 (non-jet) 3.97 (jet) 3.59 (non-jet) 0.8 (0.2–2.2) for both 41.65 years denmark duplicated data cohort in pukkala et al. (2002) 7 milanov et al. (1999) 34 1964–1994 not reported not reported not reported not reported republic of bulgaria no statistical data on prostate cancer reported 8 nicholas et al. (2001) 6533 1970–1998 65 not reported 0.7 (0.59–0.84) not reported united states, canada investigated cancer incidence by questionnaire (self-reported disease outcomes)–different methodology could give inconsistent results 9 pukkala et al. (2002) 10 032 1946–1997 (denmark from 1946, finland up to 1996, norway 1946–1994, sweden 1957–1994 iceland 1955–1997 64 52.9 1.21 (0.93–1.54) not reported nordic countries duplicate data cohort in pukkala et al. (2003) 10 pukkala et al. (2012) 1559 1947–1997 (finland 1947–1993, iceland 1947–1997, norway 1950–1994, sweden 1957–1994) 24 21.7 1.11 (0.71–1.65) not reported finland, iceland, norway, sweden cabin crew data 11 rogers et al. (2011) 106 418 1987–2008 not reported not reported not reported mean age at diagnosis ~ 50 years united states exclusively air force / military data, comparative study, calculates hazard ratio 159siuj.org siuj • volume 3, number 3 • may 2022 incidence and mortality of prostate cancer in commercial airline cockpit crew: systematic review and meta-analysis http://siuj.org supplementary table s1b. mortality studies excluded during eligibility assessment for the final meta-analysis, with characteristics and reasons for exclusion study sample size study duration observed expected standardized ratio mean age at conclusion country/ region reason(s) for exclusion 1 salisbury et al. (1991) 402 1950–1984 not reported not reported not reported not reported canada discusses proportional mortality rates, unable to pool in to standardized mortality data 2 irvine & davies (1992) 411 1966–1989 not reported not reported not reported not reported united kingdom helicopter pilots included and discusses proportional mortality rates, unable to pool in to standardized mortality data 3 kaji et al. (1993) 2327 1952–1988 not reported not reported not reported 45.9 ± 13.6 years japan no statistical data on prostate cancer 4 nicholas et al. (1998) 1538 1984–1991 38 27.56 1.38 (1.00–1.90) not reported usa discusses proportional mortality rates, unable to pool in to standardized mortality data 5 haldorsen et al. (2002) 3707 1946–1994 not reported not reported not reported not reported norway helicopter pilots included, duplicated data cohort in hammer et al. (2014) and no statistical data on prostate cancer. 6 irvine & davies (1999) 6209 1950–1992 15 13.48 111.3 (62.3–183.5) not reported united kingdom includes helicopter pilot data as well 7 ballard et al. (2002) 3022 1965–1996 4 3.76 1.06 (0.40–2.82) not reported italy duplicated data cohort in hammer et al. (2014) 8 zeeb et al. (2002) (cockpit crew) 6061 1953–1997 8.7 6.9 1.26 (0.53–2.59) not reported germany duplicated data cohort in blettner et al. (2003) 9 zeeb et al. (2003) (cabin crew/ att -endants) 11 079 1946–1997 (denmark 1947–1996) (finland 1947–1992) (germany 1953–1997) (greece 1946–1997) (iceland 1955–1997) (italy 1965–1995) (norway 1950–1994) (sweden 1957–1994) 5.2 4.8 1.09 (0.35–2.68) not reported europe cabin crew data, no mention of separate data for pilots/cockpit crew 10 zeeb et al. (2010) (cockpit crew) 6017 1953–2003 11 not reported 0.96 (0.42–1.91) not reported germany extended (+6 years) follow up after 2003 study – no new cohort members added hence duplicated data cohort in blettner et al. (2003) 11 blettner et al. (2003) 27 797 1921–1997 (denmark 1946–1996) (finland 1921–1997) (germany 1953–1997) (greece 1946–1997) (iceland 1935–1997) (italy 1965–1995) (norway1946–1994) (sweden 1957–1994) (united kingdom 1950–1997) 54 60.1 0.94 (0.72–1.23) not reported europe duplicated data cohort in hammer et al. (2014) 12 hammer et al. (2012) 6006 1960–2004 11.9* 12.4 0.96 (0.36–2.53) 51.5 years germany duplicated data cohort in hammer et al. (2014) 13 dreger et al. (2020) 6006 1960–2014 24 27.5 0.93 (0.54–1.51) 59.8 years germany only german data and extended follow-up (to 2014) of the same cohort from hammer et al. 2014. cumulative smr of all countries only in 2014 study 14 langner et al. (2004) 19 184 (escape) 1921–1997 not reported not reported not reported not reported europe duplicated data cohort in hammer et al. (2014) and no statistical data on prostate cancer 15 stavola et al. (2012) 15 881 1989–1999 not reported not reported not reported not reported united kingdom duplicated data cohort in dos santos de silva et al. (2013) and no statistical data on prostate cancer 16 krstev et al. (1998) 60 878 1984–1993 not reported not reported not reported not reported united states discusses mortality odds ratio—unable to pool in to standardized mortality data, case–control study 17 linnersjö et al. (2011) 1478 1957–1994 not reported not reported not reported not reported sweden no statistical data on prostate cancer 18 blettner et al. (2002) 4185 1953–1997 not reported not reported not reported not reported germany cabin crew / attendant data 19 paridou et al. (2003) 2678 1960–1997 not reported not reported not reported not reported greece no statistical data on prostate cancer 160 siuj • volume 3, number 3 • may 2022 siuj.org review http://siuj.org supplementary table s1b. mortality studies excluded during eligibility assessment for the final meta-analysis, with characteristics and reasons for exclusion study sample size study duration observed expected standardized ratio mean age at conclusion country/ region reason(s) for exclusion 1 salisbury et al. (1991) 402 1950–1984 not reported not reported not reported not reported canada discusses proportional mortality rates, unable to pool in to standardized mortality data 2 irvine & davies (1992) 411 1966–1989 not reported not reported not reported not reported united kingdom helicopter pilots included and discusses proportional mortality rates, unable to pool in to standardized mortality data 3 kaji et al. (1993) 2327 1952–1988 not reported not reported not reported 45.9 ± 13.6 years japan no statistical data on prostate cancer 4 nicholas et al. (1998) 1538 1984–1991 38 27.56 1.38 (1.00–1.90) not reported usa discusses proportional mortality rates, unable to pool in to standardized mortality data 5 haldorsen et al. (2002) 3707 1946–1994 not reported not reported not reported not reported norway helicopter pilots included, duplicated data cohort in hammer et al. (2014) and no statistical data on prostate cancer. 6 irvine & davies (1999) 6209 1950–1992 15 13.48 111.3 (62.3–183.5) not reported united kingdom includes helicopter pilot data as well 7 ballard et al. (2002) 3022 1965–1996 4 3.76 1.06 (0.40–2.82) not reported italy duplicated data cohort in hammer et al. (2014) 8 zeeb et al. (2002) (cockpit crew) 6061 1953–1997 8.7 6.9 1.26 (0.53–2.59) not reported germany duplicated data cohort in blettner et al. (2003) 9 zeeb et al. (2003) (cabin crew/ att -endants) 11 079 1946–1997 (denmark 1947–1996) (finland 1947–1992) (germany 1953–1997) (greece 1946–1997) (iceland 1955–1997) (italy 1965–1995) (norway 1950–1994) (sweden 1957–1994) 5.2 4.8 1.09 (0.35–2.68) not reported europe cabin crew data, no mention of separate data for pilots/cockpit crew 10 zeeb et al. (2010) (cockpit crew) 6017 1953–2003 11 not reported 0.96 (0.42–1.91) not reported germany extended (+6 years) follow up after 2003 study – no new cohort members added hence duplicated data cohort in blettner et al. (2003) 11 blettner et al. (2003) 27 797 1921–1997 (denmark 1946–1996) (finland 1921–1997) (germany 1953–1997) (greece 1946–1997) (iceland 1935–1997) (italy 1965–1995) (norway1946–1994) (sweden 1957–1994) (united kingdom 1950–1997) 54 60.1 0.94 (0.72–1.23) not reported europe duplicated data cohort in hammer et al. (2014) 12 hammer et al. (2012) 6006 1960–2004 11.9* 12.4 0.96 (0.36–2.53) 51.5 years germany duplicated data cohort in hammer et al. (2014) 13 dreger et al. (2020) 6006 1960–2014 24 27.5 0.93 (0.54–1.51) 59.8 years germany only german data and extended follow-up (to 2014) of the same cohort from hammer et al. 2014. cumulative smr of all countries only in 2014 study 14 langner et al. (2004) 19 184 (escape) 1921–1997 not reported not reported not reported not reported europe duplicated data cohort in hammer et al. (2014) and no statistical data on prostate cancer 15 stavola et al. (2012) 15 881 1989–1999 not reported not reported not reported not reported united kingdom duplicated data cohort in dos santos de silva et al. (2013) and no statistical data on prostate cancer 16 krstev et al. (1998) 60 878 1984–1993 not reported not reported not reported not reported united states discusses mortality odds ratio—unable to pool in to standardized mortality data, case–control study 17 linnersjö et al. (2011) 1478 1957–1994 not reported not reported not reported not reported sweden no statistical data on prostate cancer 18 blettner et al. (2002) 4185 1953–1997 not reported not reported not reported not reported germany cabin crew / attendant data 19 paridou et al. (2003) 2678 1960–1997 not reported not reported not reported not reported greece no statistical data on prostate cancer 161siuj.org siuj • volume 3, number 3 • may 2022 incidence and mortality of prostate cancer in commercial airline cockpit crew: systematic review and meta-analysis http://siuj.org supplementary figure s1b. pooled sir results with inclusion of latest study study year or 95% ci weight band et al. 1990 0.5 1 2 3.5 1.54 (0.69–3.43) 5.4% band et al. 1996 1.87 (1.34–2.62) 30.4% pukkala et al. 2003 1.21 (0.95–1.55) 56.5% ggudmundsdóttir et al. 2017 1.12 (0.58–2.17) 7.8% i2 = 35.9% 1.39 (1.16–1.67) 100% supplementary figure s1a. adjustmentof sample size between 2 studies study original totals number overlapping number deducted pukkala et al. total 10032 239 120 observed 64 0.77 expected 52.9 0.63 gudmundsdóttir et al. total 286 239 119 observed 15 6.24 expected 11.8 4.91 162 siuj • volume 3, number 3 • may 2022 siuj.org review http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information larcg,latin america, renal cell carcinoma, international collaboration none declared. received on june 7, 2022 accepted on september 5, 2022 this article has been peer reviewed. soc int urol j. 2023;4(1):27–33 doi: 10.48083/gwsk7789 the larcg latin american renal cancer group: achievements in support, teaching, research, collaboration, and advocacy stenio de cássio zequi,1,2,3 francisco rodriguez-covarrubias,4 ignacio pablo tobia,5 alberto jurado,5 anamaria autran gomez,6 luiz meza-montoya,7 walter henriques da costa,1,2 alejandro nolazco,8 thiago camelo mourao,9 diego abreu10 1 department of urology a.c. camargo cancer center, são paulo, brazil 2 national institute for science and technology in oncogenomics and therapeutic innovation, a.c. camargo cancer center, são paulo, brazil 3 graduate school-urology-escola paulista de medicina-universidade federal de são paulo 4 instituto nacional de ciencias médicas y nutrición salvador zubirán, mexico city, mexico 5 hospital italiano, buenos aires, argentina 6 lyx institute of urology. madrid, spain 7 instituto nacional de enfermedades neoplásicas, lima, peru 8 hospital británico, buenos aires, argentina 9 graduate school-antonio prudente foundation, a.c. camargo cancer center 10 hospital pasteur, montevideo, uruguay abstract the latin american renal cancer group (larcg) was founded in 2013. this is a non-profit collaborative group designed to foster scientific knowledge in all areas of kidney cancer, and to establish international cooperation among well-recognized oncologic institutions. since its creation, larcg has reported data from latin america to the scientific community and has promoted accredited information and advocacy principles for patients, lay people, and medical colleagues. currently, it consists of 44 centers in 7 latin american countries and spain. in this paper, we report our achievements in assistance, teaching, research, and advocacy, and we discuss the successful international collaborations. introduction we created the larcg (latin american renal cancer group) in 2013 to address the paucity of renal cell carcinoma (rcc) data in latin america when compared with north america and europe and to address the differences between the regions with respect to ethnic composition and health care systems[1]. larcg is a non-profit collaborative group designed to foster scientific knowledge in all areas of kidney cancer, to produce high-quality scientific information, to establish international cooperation with well-recognized oncological institutions, to report data from latin america to the scientific community, and to promote accredited information and advocacy principles to patients, lay people, and medical colleagues. since its creation, larcg has grown and incorporated more centers, expanding its activities in several scenarios, in ways unusual for latin america. in this manuscript, we aimed to report our achievements, divided by subtopics, discussing our future activities. creation, expansion, and economical support of the group and our database the larcg group was created by urologists, under the guidance of a specific statute. our board has scientific, ethics, and economic committees. in each participating institution, larcg is led by a local urologist, who invites other urologists, pathologists, medical oncologists, and radiologists to integrate their institutional departments into 27siuj.org siuj • volume 4, number 1 • january 2023 original research mailto:steniozequi%40gmail.com?subject= http://siuj.org larcg’s branches of pathological anatomy, medical oncology, and imaging, respectively[1]. soon after our foundation in 2014, we invited selected key opinion leaders from recognized high-quality urologic oncology centers in central and south america, and spain. within a few weeks, 26 centers had joined the group. retrospectively, we developed a comprehensive encrypted database containing more than 150 variables, with demographic, clinical, and pathological information, therapeutic modalities, and oncological and functional outcomes of 4502 rcc patients from 22 latin american and 2 spanish institutions. in november 2014, we presented the results of our survival analysis of 4238 patients at the plenary session of the confederación americana de urologia meeting in punta del este, uruguay[1,2]. between 2014 and 2016, the group expanded to its current composition (44 centers from argentina, brazil, bolivia, chile, mexico, peru, spain, and uruguay). at the same time, we developed a bilingual (english/spanish) website (available at https://larcg.org)[3]. during 2014, data of patients treated since 1980 were retrospectively entered by each participating institution. subsequently, information was received about patients treated until 2016, resulting in more than 6000 cases. the inclusion criteria for participation in the larcg group were first, to accept the invitation, with the commitment to send the required information and the promise to follow our statute rules. we sought to enhance the quality of our database, removing the repeated cases, searching information for missing values, and starting the development of a free, secure, and encrypted database in the research electronic data capture (red cap) (vanderbilt university) [4]. only centers that adhered to these security database policies were accepted. in the third—and current—phase, launched in 2020, we have received new cases from chile, and we are also accepting prospective information. concurrently, we are updating the original database, requiring follow-up information from each center, and encouraging them to include new cases. the chronological flow presenting the expansion of our database and the diagram of its current structure are represented in figures 1 and 2, respectively. in may 2015, we presented our epidemiological data and administrative information at the swog fall meeting in san francisco, california. this was a key event to increase our networking with urologic oncology leaders, resulting in some scientific collaborations[1,5]. up to 2014, we had no sponsorship from industry, and all efforts to create the larcg were voluntary (unpaid). in 2016, the larcg project was classified as a strategic initiative by the a.c. camargo cancer center (acccc), brazil, and encompassed in a comprehensive project entitled incito-inote (instituto nacional de ciência e tecnologia em oncogenômica e inovação terapêutica) (national institute for therapeutic innovation and oncogenetics), founded by several official governmental and private brazilian funding agencies, which support cancer research in that hospital[6]. the funds provided by the incito/inote project have covered the costs of our basic and translational investigations, as well as the acquisition of immunohistochemistry reagents, biomolecular analyses, and laboratory supplies. additionally, we received funds from incito/inote for the maintenance of our website, for the payment of audiovisual resources used during the larcg annual meetings at american urological association meetings[3,7]. these funds also covered travel expenses to bring international speakers to our brazilian events, promoted by acccc. these funds are in place until 2023, when new applications will be made to the official funding agencies. other meetings were promoted by the larcg group. they occurred at hospital pasteur (montevideo, uruguay) and hospital británico (buenos aires, argentina), and an advocacy event took place in mexico city, funded by asociación ale[1]. these meetings were supported by each regional promoter center. the kidney cancer association supported the expenses of the authors d.a. and s.c.z. at the 17th and the 18th kidney cancer symposiums, respectively[8]. in 2021, the uruguayan larcg team established the larcg foundation in that country. it is a non-profit virtual organization that received economic resources from the pharmaceutical industry (roche company) to cover database maintenance and the data managers’ salaries. this regional foundation receives donations for scientific initiatives through our website[3]. abbreviations acccc a.c. camargo cancer center asa american society of anesthesiologists ccrcc clear cell rcc epo erythropoietin ihc immunohistochemical larcg latin american renal cancer group os overall survival rcc renal cell carcinoma ren renin 28 siuj • volume 4, number 1 • january 2023 siuj.org original research https://larcg.org http://siuj.org finally, we reiterate that the larcg members have received no salaries or professional fees for any of their activities. in collaborative studies among the centers, each center must cover its expenses. research prognostic factors: clinical markers in the search of prognostic clinical markers in rcc, we evaluated patients with localized or locally advanced rcc, and patients with metastatic disease, reporting the prognostic factors in patients from latin america. in a survival analysis of 5670 patients with non-metastatic disease, using a multiple data imputation method to compensate for the effect of missing values, we demonstrated that the american society of anesthesiologists (asa) classification ≥ 3 and the perirenal fat invasion, aside from other well-known factors, were independent predictors for worse overall survival (os). perirenal fat invasion and microvascular invasion were adverse prognostic factors for cancer-specific survival (css)[9]. in 2010, we published a study showing that patients with asa classification ≥  3 presented more symptomatic tumors, higher nuclear grade, and larger lesions, besides of 10 times more metastasis than asa 1, and the double those asa 2. in the multivariable analysis, asa classification was an independent predictor of os for the whole cohort, and css for the patients with non-metastatic rcc[10]. the asa classification takes account the comorbidities of the patients, which is not incorporated in the most used performance status classification in oncology. as rcc is a metabolic disease[11], it seems logical that comorbidities could influence the outcomes of rcc patients. additionally, asa classification is a classification recognized worldwide that can be validated in many institutions, without the potential biases related to the assistant surgeons. in a series of 1523 small renal masses, we reported that asa ≥ 3, bilateral tumors, and extracapsular invasion were adverse independent prognostic factors for disease recurrence and metastases. in this study, patients ≥ 65 had a better 10-year os if they underwent partial nephrectomy rather than radical nephrectomy[12]. with respect to age, these results are in accordance with those of the mexican larcg team, which evaluated 410 patients who underwent surgery. they demonstrated that patients > 75 years presented outcomes similar to those of their younger counterparts[13]. according to these series, we can verify that latin american coun2020–22 after the covid-19 pandemic: new data acquisition, and update of data in each center are in the progress 2015–2017 2nd round 44 centers / 8 countries n = 6132 valid cases for survival analysis; n = 4508 may 2015 2nd round of invitations to the centers november 2014 1st round 24 centers / 5 countries n = 4502 valid cases for survival analysis; n = 3819 excel/spss �le database excel/spss �le database 2019 – 2020 accreditation of the centers in the new database may 2019 development of ecrf (electronic case report form)/redcap review of data quality, and data manager contracting 2018 convocations for migration to a secure, high-quality database january 2014 1st round of invitations six-month deadline to input the dataset may 2013 larcg foundation database creation brazil/uruguay with dozens of variables figure 1. chronological diagram for the expansion of the larcg database 29siuj.org siuj • volume 4, number 1 • january 2023 the larcg latin american renal cancer group: achievements in support, teaching, research, collaboration, and advocacy http://siuj.org tries are progressively increasing their rates of minimally invasive nephron-sparing surgeries, resulting in inherent benefits, such as reduced length of hospital stay, reduced bleeding and transfusion rates, and reduced pain or use of analgesics, as well as an earlier return to daily routine. in an argentinian series of 293 patients, the concomitant invasion of perirenal fat and renal sinus invasion was associated with an unfavorable setting for pt3a tumors. this is associated with higher mortality rates, venous involvement, and metastatic progression[14]. this study suggests a need for a subdivision of t3 stage, indicating that the concomitant fat and venous invasion present an ominous prognosis in comparison with any of these factors in isolation[15]. recently, the uruguayan larcg team, in collaboration with several recognized global experts in rcc, published their prognostic score in 530 de novo metastatic patients. it was a unique database, since 511 patients underwent nephrectomy, probably consisting of those in the more favorable risk group. in this series, the asa classification ≥ 3, perirenal fat invasion, and more than 2 metastatic lesions were associated with poor 5-year os and css. the authors presented a prognostic score, ranging from 0 to 3 points, being: 0 point: favorable group; 1 point: intermediary group; and 2 or 3 points: unfavorable group, which achieved the following median survivals: not reached, 33 months, and 14 months, respectively. in this population, patients with bone metastases, particularly those with non-vertebral lesions had better os. these data deserve further investigation[16]. validating the asa classification, perirenal fat invasion, and bone metastases as prognostic factors in other populations would be interesting and valuable, in order to extend resources in these areas. 2020–2022 return to each center of their original databases and request for correction, updating, and expansion of the data may 2019 development of ecrf (electronic case report form/ redcap larcg database of�ce & central database master administrators institutional database administrators updated and corrected original dataset imputation of new cases larcg centers immunochemistry markers a project called larcg 001 was launched, encompassing the analyses of several potential immunohistochemical (ihc) markers associated with “endocrine kidney enzymes” and with chromatin remodeling genes. we demonstrated that the low ihc expression of erythropoietin (epo) was an independent adverse prognostic factor for os and disease-free survival (dfs) in 220 patients with localized or locally advanced rcc (all histological types included)[17]. furthermore, the lack of renin (ren) expression was an independent prognostic factor for dfs, with almost 3 times more recurrences than those expressing ren. this study analyzed 498 patients with non-metastatic clear cell rcc (ccrcc), in collaboration with the university of california davis (ucd)[18]. in both studies, low expression of epo or r en was associated with unfavorable pathological features, such as higher tnm stages, higher nuclear grades, and larger lesions. the area of renal endocrine markers in rcc has been insufficiently studied enough and could open a new route of research. we are currently analyzing the concomitant expression of ren, epo, and cathepsin d, an alternative renin-angiotensin pathway activator, in more than 700 patients (data not published). motivated by the new era of check-point inhibitors in rcc, we investigated the prognostic role of the ihc expression of the check-point markers (pd-l1 and pd-1) in collaboration with lee moffitt cancer center (tampa, fl). in a series of 1017 patients with non-metastatic ccrcc (follow-up data available in 738 cases), the higher expression of these markers was associated with higher tumor stages, intratumoral necrosis, and lymph-vascular invasion. in a multivariable analysis, the expression of pd-l1 was associated with double the cancer-specific mortality compared with pd-l1-negative cases. we hypothesized that this marker could aid in stratifyfigure 2. flowchart of the current structure of the larcg database 30 siuj • volume 4, number 1 • january 2023 siuj.org original research http://siuj.org ing high-risk patients for adjuvant treatment or selecting candidates for immunotherapy[19]. regarding chromatin remodeling genes, our previous studies revealed that bap-1 and pbrm-1 were strong predictors of unfavorable outcomes in localized or locally advanced ccrcc. in a conjugated analysis of 441 patients with non-metastatic ccrcc, the concomitant low expression of bap-1 and pbrm-1 was associated with higher mortality rates and double the number of recurrences when compared with patients presenting both or only one of the markers expressed[20]. additionally, in 2019, we reported that the low ihc expression of bap-1 and pbrm-1 in 124 metastatic samples was an unfavorable feature for patients who underwent metastasectomy. in this study, the low expression of bap-1 was independently associated with 60% higher mortality and 93% more recurrences. on the other hand, the isolated prbm-1 immunostaining status did not influence the outcomes in the multivariate analysis[21]. in a retrospective review of 662 patients with primary or metastatic ccrcc, the low expression of setd-2, another chromatin remodeling gene, was associated with higher cancer mortality and recurrence[22]. finally, the negative expression of ezrin, an epithelial-mesenchymal transition marker, was associated with poor survival rates in a series of 567 patients with localized or locally advanced ccrcc[23]. intending to conclude the larcg 001 project, we will analyze the ihc expression of pten, and we need to validate the nitric oxide synthase 3 (nos-3) expression. in a limited series of 110 patients with diverse rcc histologies, high expression of nos-3 was associated with unfavorable pathological features worse, os in univariate analysis (58.1% versus 79.4%; p = 0.033)[24]. translational research: international collaboration groups regarding translational research, we developed a patient-derived xenograft (pdx) project performed in immunodeficient mice at acccc in collaboration with ucd. we were able to reproduce the anatomopathological and genetic features of the original tumors in 27% of the cases. a more intense gene expression was evidenced, probably due to the intratumoral heterogeneity or the immunodeficiency in the animal models. the most impressive was the resemblance of venous thrombus in 5 consecutive generations originated from one animal[25]. these pdx models can be an opportunity for testing future drugs or planning adjuvant treatment in patients with advanced disease. once this technique is standardized, we can deliver it in other larcg centers in the future. recently, acccc (são paulo), hospital pasteur (montevideo), and hospital italiano (buenos aires) sent more than 1500 dna aliquots from rcc patients, and 700 dna aliquots from healthy control samples, in collaboration with the continuation of the genome wide association study project from the american national cancer institute (nci), part of the national institutes of health. this international multicenter collaborative research encompasses the most recognized institutions in the rcc scenario around the world[26]. in this study, there were dedicated funds to each larcg participating institutions provided by the nci to this project. in support of continuing medical education and best practices, there was cooperation between larcg and the latin american cooperative oncology group (lacog), promoting expert meetings in 2019 that resulted in 2 manuscripts with recommendations for the best surgical and systemic management[27,28]. an update meeting was held in the second half of 2022. multicentric prospective studies larcg has developed a multicenter prospective study, led by hospital italiano from buenos aires. they are investigating the 10-year outcomes of patients in active surveillance with small renal masses, including those who refused surgical or percutaneous treatments. this trial was initiated in 2018, and currently has more than 140 enrolled patients[3]. teaching one of the larcg scopes is to offer the opportunity for international observerships in worldwide recognized institutions to young colleagues (urologists or medical oncologists). since 2017, there has been an agreement (residents & young doctors rotation program) between the larcg and the department of medical oncology and therapeutics research from city of hope comprehensive cancer center, in duarte, headed by professor sumanta kumar pal[29]. yearly, 4 young colleagues (2 urologists and 2 medical oncologists) from acccc and other larcg centers are selected for a 2-month rotation program at the city of hope. the covid-19 pandemic interrupted the program in 2020. according to this agreement, the travel expenses are supported by the californian cancer center. during this period, the observers can participate in clinic activities, become familiar with the routine of clinical trials, participate on tumor boards, participate in inpatient visits, and collaborate on the preparation of scientific manuscripts. this is a unique opportunity to get world class knowledge in rcc and in the clinical management of urological malignancies. six brazilian and 2 argentinian young professionals have benefited from this program. we hope to promote similar educational initiatives for our members in the future. 31siuj.org siuj • volume 4, number 1 • january 2023 the larcg latin american renal cancer group: achievements in support, teaching, research, collaboration, and advocacy http://siuj.org advocacy in latin american, oncology patients are not commonly well-informed about treatments and their implications. however, in the face of regional socioeconomic limitations and disparities, some educational and advocacy initiatives are necessary. as a result, the international kidney cancer coalition (ikcc) contacted the larcg to foster advocacy with kidney cancer patients in latin america between 2017 and 2018[30]. immediately, we organized several meetings in mexico, involving patients, associations, medical experts, the press, and lawyers. they debated aspects of the inequities in health assistance and the limited access to some medications or procedures. there was an exchange of information among 48 rcc patients’ organizations from all continents. larcg has contributed to the dissemination of information to lay people about kidney cancer risk factors, symptoms, and treatments. the group’s other task is to demystify clinical trials in this population, clarifying for them that participation in a clinical trial may be an opportunity to collaborate with scientific development and to receive the best available therapeutic options. meetings have also occurred in são paulo and lisbon, and a recent report was published regarding these meetings[31]. additionally, we published a study revealing that uninsured patients with metastatic disease in brazil receive fewer secondor third-line therapies, or even receive less effective therapies in comparison with insured or private patients. this was based on a survey using a commercial database with more than 4000 patients[32]. in other evaluation with 273 patients with metastatic disease at a tertiary center, we demonstrated that uninsured patients have more advanced disease, worse performance status, and are less likely than insured patients to undergo nephrectomy or systemic therapies[33]. since 2017, ikcc has promoted the annual world k id ney ca ncer day (w kcd), w it h awa reness campaigns, surveys, educational brochures, and websites in 14 languages. each year, the wkcd promotes provocative debates for questions associated with the daily life of the patients, many of which are underreported. larcg has actively participated in the wkcd, and launched the 2019 campaign in latin america. again in june, the ikcc and larcg joined together again for the 2022 wkcd, whose theme was “we must discuss therapeutic options”[34]. conclusion larcg was intended to enhance knowledge of and promote information about rcc. in few years, we have furthered the support, research, teaching, and advocacy for professionals and patients involved with this malignancy. expanding our network and establishing further collaborations will result in our partners maintaining higher levels of education and technical proficiency, and will benefit latin american patients affected by kidney malignancies. clinical trial development is in our 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costa wh, bezerra sm, da cunha iw, nobre jqc, brazão es jr, et al. prognostic impact of loss of setd2 in clear cell renal cell carcinoma. clin genitourin cancer.2021;19(4):339-345. doi: 10.1016/j.clgc.2021.03.003. 23. ferrari mvo, da costa wh, matushita mam, meduna rr, brazao es jr, bezerra sm, et al. immunohistochemical negative expression of ezrin predicts poor prognosis in clear cell renal cell carcinoma. urol oncol.2020;38(3):75.e1-75.e7. doi: 10.1016/j.urolonc.2019.09.011. 24. cássio zequi sd, fregnani jh, favaretto rl, costa wh, madeira campos rs, fonseca fp, et al. the impact of immunohistochemical expression of nitric oxide synthases on clinical and pathological features of renal cell carcinoma. world j urol.2013;31(5):1197-203. doi: 10.1007/s00345-012-0878-1. 25. beserra, ao, estevan ec, bezerra sm, torrezan gt, ikegami a, dellê h, et al. patient-derived renal cell carcinoma xenografts capture tumor genetic profiles and aggressive behaviors. kidney cancer.2022;6(1):11-22. doi: 10.3233/kca-210011. 26. scelo g, purdue mp, brown km, johansson m, wang z, eckel-passow je, et al. genome-wide association study identifies multiple risk loci for renal cell carcinoma. nat commun.2017;8:15724. doi: 10.1038/ ncomms15724. 27. de cássio zequi s, da costa wh, korkes f, dos reis rb, busato wfs, matheus we, et al. renal cell cancer treatment: an expert panel recommendation from the latin american cooperative group-genitourinary and the latin american renal cancer group: focus on surgery. ther adv urol.2019;11:1756287219872324. doi: 10.1177/1756287219872324. 28. soares a, monteiro fsm, maluf fc, bastos da, jardim dl, sasse ad, et al. advanced renal cell carcinoma (rcc) management: an expert panel recommendation from the latin american cooperative oncology group (lacog) and the latin american renal cancer group (larcg). j cancer res clin oncol.2020;146(7):1829-1845. doi: 10.1007/ s00432-020-03236-4. 29. city of hope comprehensive cancer center website. available at: https://www.cityofhope.org/academics. accessed may 30, 2022. 30. the international kidney cancer coalition (ikcc) website. available at: https://ikcc.org. accessed may 30, 2022. 31. herrera-caceres jo, ajaj r, leão r, barello s, rodriguez-covarrubias f, zequi sc, et al. patient-centered care can be improved by joint meetings between cancer patient group leaders and health care providers. patient educ couns.2022;105(3):786-787. doi: 10.1016/j. pec.2021.07.023. 32. bergerot pg, bergerot cd, dizman n, zequi s, fay a, dara y, et al. assessment of treatment patterns for metastatic renal cell carcinoma in brazil. j glob oncol.2018;4:1-8. doi: 10.1200/jgo.17.00113. 33. leite lm, bergerot pg, dettino ala, r ja júnior, zequi sc, formiga mndc. influence of treatment access on survival of metastatic renal cell carcinoma in brazilian cancer center. int braz j urol.2021;47(3):566573. doi: 10.1590/s1677-5538.ibju.2020.0443. 34. world kidney cancer day 2022. the international kidney cancer coalition (ikcc). available at: https://www.worldkidneycancerday. org. accessed may 28, 2022. 33siuj.org siuj • volume 4, number 1 • january 2023 the larcg latin american renal cancer group: achievements in support, teaching, research, collaboration, and advocacy https://ikcc.org https://www.worldkidneycancerday.org https://www.worldkidneycancerday.org http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj.org siuj • volume 4, number 3 • may 2023 key words competing interests article information male circumcision, postoperative complications, ischemia none declared. patient consent: obtained. received on december 13, 2022 accepted on december 15, 2022 soc int urol j. 2023;4(3):231 doi: 10.48083/ecnt1039 231 clinical picture a 28-year-old otherwise healthy male underwent an uncomplicated circumcision under general anaesthetic supplemented with a ring and dorsal nerve block of the injected 15 ml of 0.25% plain bupivacaine. the skin and mucosal collars were reapproximated with simple 4-0 vicryl rapide sutures, and the penis was loosely wrapped with vaseline gauze, and 2-inch kling gauze. the patient was discharged uneventfully from the recovery room. approximately 6 hours after surgery, the patient returned to the emergency room as the exposed glans penis appeared black and felt firm. the penile dressings were immediately removed. examination revealed a cool, black glans with an abrupt transition distal to where the dressings had been applied (figure 1). the glans softened after dressing removal and the suture line was not restrictive. there was decreased sensation to the entire penis but no pain. the patient was voiding normally. our clinical impression was the unusual event of ischemia of the glans secondary to venous congestion from a tight dressing. with all dressings removed, the patient was admitted to hospital for observation with ancillary measures of one 50 mg dose of intravenous hydrocortisone as well as prophylactic cefazolin and commencement of aspirin 325 mg daily. upon reassessment the subsequent morning, the glans had re-perfused with patches of pink colouration interrupted by purple discolouration. distal penile sensation had improved. the patient was discharged home on aspirin 325 mg and prophylactic cephalexin for 7 days. on the 5th postoperative day the reperfusion continued to improve, and by the 12th day there were only a few scattered areas of purple discolouration. four months postoperatively, the patient had made a full recovery with a good cosmetic result and no voiding or erectile dysfunction. glans ischemia after circumcision anna black, ryan paterson department of urologic science, university of british columbia, vancouver, canada figure 1. discolouration and reperfusion of the glans penis after circumcision. images of the glans are shown on postoperative day (pod) 0, 1, and 5. the arrow indicates the distal margin of the dressing that was applied after circumcision and removed upon admission to the er. pod 0 pod 1 pod 5 http://siuj.org mailto:annabla%40student.ubc.ca?subject=siuj this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj.org siuj • volume 4, number 4 • july 2023 key words competing interests article information arteriovenous malformation, urethrorrhagia, catheter injury, haematuria, penile avm none declared. patient consent: obtained. received on december 14, 2022 accepted on january 18, 2023 this article has been peer reviewed. soc int urol j. 2023;4(4):347–348 doi: 10.48083/fjoa1305 347 clinical picture novel finding of lower genital tract arteriovenous malformation leading to massive urethral bleed paul kim, james kovacic, ankur dhar, andrew r.h. shepherd royal north shore hospital, department of urology, st leonards, australia a 68-year-old male was referred for management of transfusion-dependent haematuria after traumatic self-removal of indwelling catheter with inflated balloon. haematuria recurred intermittently around and within catheter lumen and was exacerbated after each trial of void. cystoscopy revealed urethral bleeding refractory to endoscopic coagulation. ct-angiogram demonstrated contrast extravasation in the left corpus spongiosum, suggestive of penile arteriovenous malformation (avm) (figure 1a). endovascular embolisation of the avm with gelfoam from the left internal pudendal artery (figure 1b) was performed because of ongoing transfusion-dependent haematuria. postprocedurally there was immediate resolution of haematuria, and the patient underwent successful trial of void. at a 9-month follow-up, there was no recurrence of haematuria, no priapism or de novo erectile dysfunction, and no palpable penile lumps. avms of the lower male genital tract are rare, with only a few case reports published[1]. whilst the majority are paediatric cases of the scrotum and glans penis[2] they can also be acquired from traumatic catheter manipulation[3]. endoscopic intervention is often the first-line therapy, but it is rarely successful, and an endovascular or open approach is usually required[1]. the endovascular approach carries a risk of erectile dysfunction if the internal pudendal artery is compromised; however, favourable outcomes were identified in a small series of 10 patients[4]. in contrast, open approaches have been favoured in those with atraumatic aetiologies for their avms[2]. in this case, a minimally invasive approach has had a favourable outcome in a rare pathology with no standard treatment guidelines. references 1. white jt, baverstock rj. eruption of blood: arteriovenous malformation of the penile urethra. can urol assoc j.2017;11(1–2):e32–e34. 2. houston n, raghavan rs, asghar am, morales-lópez ra, metro mj. management of symptomatic adult penile urethral arteriovenous malformation. urol case rep.2021;38:101738. 3. francesco p, milena c, antonio b, francesco g, fabio c, antonio c, et al. a singular case of massive urethrorrhagia solved by transarterial embolization. egypt j radiol nucl med.2020;51(1):1–7 4. park hw, her sh, park bh, et al. correlation between internal pudendal artery stenosis and erectile dysfunction in patients with suspected coronary artery disease. plos one.2019 nov 12;14(11), e0225179. https://doi.org/10.1371/journal. pone.0225179. http://siuj.org mailto:paul.kim4%40health.nsw.gov.au?subject=siuj figure 1a. ct mesenteric angiogram: coronal view in arterial phase demonstrating contrast leak into corpus spongiosum on the left-hand side figure 1b. coronal view from pre-embolisation angiography highlighting region of hypervascularity at base of the penis on the left side from the left internal pudendal artery 348 siuj • volume 4, number 4 • july 2023 siuj.org clinical picture http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj.org siuj • volume 4, number 4 • july 2023 march 2023 marked the 50th year from the first i nt r ave sic a l bac i l lu s c a l me t te – guér i n (bcg) instillation in a patient with bladder cancer, and this was celebrated at the 4th annual bladder cancer forum, held in kingston, canada. a major highlight of this meeting was a special lecture (https://www.cua. org/program/16937) by dr alvaro morales in which he shared his personal perspectives on the 50 years of bcg in bladder cancer with scientists, trainees, and urologists from across north america. bcg immunotherapy remains the gold standard treatment for non-muscle invasive bladder cancer (nmibc). this groundbreaking treatment strategy was introduced to the treatment of patients with nmibc by dr alvaro morales, a urologist at the kingston general hospital, queen’s university. following the initial successes and failures of bcg immunotherapy in large, randomized clinical trials across multiple cancer types, alvaro morales, was enthusiastic about bringing this treatment approach for patients with nmibc in early 1970s. alvaro was born and raised in colombia. after obtaining his undergraduate medical training from the javeriana university in bogota, he moved to the united states and undertook post-graduate training in surgery in washington dc and boston. he continued with further training in toronto, kingston, and aberdeen, and then completed a fellowship at the laboratory of immunodiagnosis at the national cancer institute in bethesda md. it was during his training in the united states that alvaro became interested in the anti-tumor effects of bcg. in 1972, alvaro was appointed as a faculty member in the department of urology at the kingston general hospital, queen’s university, by andrew bruce. alvaro’s inspiration for bringing bcg to bladder cancer treatment was the 5 principles underlying the anti-tumor efficacy of bcg established by zbar and colleagues in the late 1960s[1-3]: (1) limited size of the tumor, (2) the ability to mount an immune response to mycobacterial antigens, (3) presence of sufficient number of viable bacteria in the preparation, (4) contact between dr alvaro morales bcg bacteria and cancer cells, and (5) development of immune response against tumor-associated antigens. according to alvaro, each of these 5 features perfectly aligned with the desirable local environment present in the bladder of intermediate and high-risk patients with nmibc. bcg was brought to canada in 1925 by armand frappier, at the university of montreal, to conduct research on tuberculosis[4]. alvaro was aware of the population-based observational study by frappier’s group in which children receiving bcg vaccine experienced 50% reduction in leukemia incidence[5]. this study prompted alvaro to access lyophilized bcg from the frappier institute for a clinical trial that he initiated in 1973 at the kingston general hospital, canada, in which 9 patients were enrolled. he developed a bcg treatment schedule primarily based on immunological principles as well as the initial packaging of the vaccine vials by frappier institute. these 9 patients did not experience recurrence after receiving treatment with 6 intravesical weekly doses of bcg. following the first alvaro morales, kingston, canada madhuri koti, d. robert siemens cancer research institute, queen’s university, kingston, canada soc int urol j. 2023;4(4):341–342 doi: 10.48083/amjg5367 343 giants in urology http://siuj.org https://www.cua.org/program/16937 https://www.cua.org/program/16937 publication by alvaro morales on the success of bcg immunotherapy in 1976[6], this treatment approach was validated in 2 large, randomized trials sponsored by the american national cancer institute[7], approved by the fda for treatment of carcinoma in situ, and adopted by urologists across the world. of note, alvaro faced a few initial challenges in securing funding to initiate this first bcg trial in patients with nmibc. his application to obtain funding support from the medical research council of canada was rejected with feedback that this treatment approach is a “throwback to the stone age of immunology.” the first bcg trial was later supported by the cancer institute of new york. this success was followed by additional funding from the ontario cancer treatment and research foundation for the subsequent remarkably efficacious trial on patients with carcinoma in situ, for which no other treatment besides cystectomy was then available[6]. donald lamm with investigators from the south west oncology group, further developed the 3-week maintenance schedule that was added to the initially established induction schedule of 6 weekly doses[8]. after close to 5 decades of continuous success, bcg remains to be matched or surpassed by any novel therapeutic. in a recent publication, in addition to highlighting the major milestones in improving response to bcg, alvaro shared the letter written to him by the daughter of professor camille guérin, thanking him for developing this treatment for bladder cancer after she had received 24 instillations for her own treatment of nmibc[9]. in 1982, alvaro morales became the head of the department of urology and continued in this position until 1997. he served as the president of the canadian urologica l association in 1993–1994. following retirement from clinical practice alvaro established the center for applied urologic research at queen’s university in 2004. for his seminal contributions in the field of urology, he received several awards including the cua lifetime achievement award in 1999, yamanouchi (renamed the mostafa elhilali) award from the société internationale d’urologie (2002), the william b coley medal from the cancer research institute of new york (1992), the hugh hampton young award of the aua and the colombian order of merit. in 2011, alvaro morales was appointed to the order of canada, the highest accolade for canadians who make extraordinary contributions to the nation. eventually he developed other related interests that included endocrinological aspects of male aging and the effect of androgens in prostate cancer. alvaro has published over 340 papers and 2 books on his areas of interest. alvaro’s peers and colleagues describe him as a humble leader and a role model for several of his trainees and surgeon scientists. undoubtedly, this giant in urology has made one of the most significant contributions in the treatment of patients with bladder cancer. references 1. zbar b, tanaka t. immunotherapy of cancer: regression of tumors af ter intralesional injection of living mycobacterium bovis. science.1971;172:271–273. doi:10.1126/science.172.3980.271 2. bast rc, jr, zbar b, borsos t, rapp hj. bcg and cancer (first of two parts). n engl j med.1974; 290:1413-1420. doi:10.1056/ nejm197406202902506. 3. bast rc, jr, zbar b, borsos t, rapp hj. bcg and cancer. n engl j med.1974;290:1458–1469, doi:10.1056/nejm197406272902605. 4. frappier a, guy r. the use of bcg. can med assoc j.1949;61:18–24. 5. davignon l, robillard p, lemonde p, frappier a. b.c.g. vaccination and leukemia mor t alit y. lan cet.19 70 ; 2: 6 3 8 . doi:10.1016 / s0140-6736(70)91402-9. 6. morales a , eidinger d, bruce aw. intracavit ar y b acillus calmette-guerin in the treatment of superficial bladder tumors. j urol.1976;116:180–183. doi:10.1016/s0022-5347(17)58737-6. 7. lamm dl, thor de, harris sc, reyna ja, stogdill vd, radwin hm. bacillus calmette-guerin immunotherapy of superficial bladder cancer. j urol. 124:38–40. doi:10.1016/s0022-5347(17)55282-9. 8. lamm dl. optimal bcg treatment of superficial bladder cancer as defined by american trials. eur urol.1992;21 (suppl 2):12–16, doi:10.1159/000474915. 9. lamm dl, morales a a. bcg success stor y: from prevention o f t u b e r c ulo sis t o o p t im al blad der c an c er t r e a t m e n t . vaccine.2021;39:7308–7318. doi:10.1016/j.vaccine.2021.08.026. 344 siuj • volume 4, number 4 • july 2023 siuj.org giants in urology http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information social media-based surveys, health care, survey fraud, survey dissemination none declared. received on october 10, 2022 accepted on december 10, 2022 this article has been peer reviewed. soc int urol j. 2023;4(2):118–124 doi: 10.48083/perg3137 tips and pitfalls in using social media platforms for survey dissemination william ong lay keat,1 vineet gauhar,2 daniele castellani,3 jeremy yuen-chun teoh4 1 department of urology, penang general hospital, penang, malaysia 2 department of urology, ng teng fong general hospital, nuhs, singapore 3 urology unit, azienda ospedaliero universitaria delle marche, università politecnica delle marche, ancona, italy 4 s.h. ho urology centre, department of surgery, the chinese university of hong kong, hong kong, china abstract introduction social media has become a prevalent platform for survey dissemination, despite the paucity of literature on this topic. the purpose of this paper is to outline the benefits and drawbacks of and best practices for social media-based surveys. methods we performed a scoping review of this topic and explored different strategies commonly employed for conducting efficient health care surveys via social media platforms. results the main advantages of social media-based surveys are the convenience and flexibility of survey design, their relatively low cost, the anonymity of responders, and the ability to reach a broader population of responders across geographical boundaries. several measures can be adopted to avoid issues inherent in this approach, such as data disruption and response duplication, as well as to enhance ethical behaviors and consent compliance. we discuss limitations associated with unclear distribution of survey respondents and outline survey fraud as a major impediment to the online propagation of surveys on various social media platforms. discussion the use of social media to disseminate surveys on various medical specialty topics has garnered global participation, particularly during the covid-19 pandemic. ethical codes of conduct emphasize the need for professionalism and truthfulness, and disclosure of potential conflicts of interest on the part of respondents, and high-quality survey research on the part of researchers. conclusion we advocate for the novel use of social media to promote large and diverse health care surveys. additional studies should further explore the use of emerging social media platforms for survey dissemination and their impact on health care research. introduction surveys represent a study design commonly used in health care research. they are simple to perform and aim to collect impartial information from a population of interest. traditional survey recruitment strategies, such as inperson interviews, postal mail, and telephone calls, are indeed time-consuming and labor intensive[1,2]. during the covid-19 pandemic, the world witnessed a dramatic surge in daily use of social media for communicating electronically[3]. the world health organization (who) implementation of social distancing policies and public health measures made onsite, in-person health care research a challenging endeavor[4]. 118 siuj • volume 4, number 2 • march 2023 siuj.org review https://orcid.org/0000-0002-3048-1170 https://orcid.org/0000-0002-3740-7141 https://orcid.org/0000-0001-7354-9190 https://orcid.org/0000-0002-9361-2342 mailto:jeremyteoh%40surgery.cuhk.edu.hk?subject=siuj http://siuj.org social media acts as an electronic communication online platform that enables its users to instantly share thoughts, information, and personal content. according to datareportal 2022, there are already 4.62 billion people around the world using social media, with individuals spending on average approximately 2 hours and 27 minutes each day communicating on social media platforms[5]. health care professionals are increasingly using social media channels, such as facebook, youtube, twitter, instagram, tiktok, and linkedin, as well as streaming audio applications, such as spotify and podcast, to reach a vast audience[6]. emerging as one of the rapidly expanding online tools, social media has been adopted by many health care specialties, including medicine and urology[7]. we have observed an exponential rise in the number of publications on urological subjects through analysis of social media over the past decade. with impactful knowledge exchange and educational information provision, social media offers an opportunity for clinicians worldwide to connect with their peers and exchange knowledge and best practices in real time or near real time. for example, twitter allows its users to compose brief 140-character messages and share them almost instantly with only a few clicks[8]. this not only reduces the amount of time spent waiting for a small group of in-person discussions but also allows medical professionals to reach more people across more geographical areas. instagram, for example, is one of the tools used most frequently by the who to aid in disseminating health information and educational messages[9]. jason frank, md, from the royal college of physicians and surgeons of canada has stated, “within the next decade, you won’t be able to be a successful scholar without having some activities on social media,” emphasizing the implications of social media within our modern technological era[8]. as a result, the use of social media as a recruitment technique for surveys has become prevalent and has garnered tremendous popularity in recent years. in the present study, we explore and evaluate best practices and pitfalls of survey distribution via social media platforms. methods literature review with the potential to effectively solicit the distinctive experience of health professionals, surveys distributed on social media have salient implications for researchers. the benefits of social media-based surveys include enhanced recruitment and increased anonymity, which may be advantageous when conducting research. at present, there are no clear recommendations for using social media to circulate health care surveys. we performed a scoping review on this topic and searched for key words and mesh terms, including (urology) and (survey) and (social media). we determined that most data are qualitative in nature, therefore, we presented the results in narrative format. conflicts of online methodologies email-based surveys containing the survey within the body of the email or as an attachment are sent by email directly to target participants, who are invited to complete the questionnaire and email it back to the researchers. while email-based survey responses may be slightly better distributed among the population of interest, the response rate of this traditional survey distribution is sometimes very low. in a project approved by the university of miami and conducted by dubin et al. in 2020, a total of 4519 surveys were emailed to urologists worldwide but only 537 (11.9%) responses from 29 countries were received[10]. this low response rate raises doubt on whether email invitation is the preferred method of survey dissemination. in contrast to traditional surveying methods, social media-based surveys entail the use of a well-designed online software system for posting the survey on the selected social media platform, through which participants can submit their responses. the data are captured immediately by the online software[6,11]—a feature that may allow for more accurate measurement of attrition, which is nearly impossible with email-based surveys. furthermore, networking on social media, largely driven by capital, fosters more social connections than email invitations. instead of relying on passive delayed interaction via email, social media platforms offer instantaneous and active engagement with the targeted audience. platforms such as twitter, facebook, and instagram provide their users with insights on content engagement, and as such, survey analytics metrics can be used to recognize patterns of engagement and improve outcomes[12]. social media-based surveys, by offering versatility and affording great utility, have opened a new approach for conducting surveys—what may be coined by some as a social network survey strategy. tips and tricks, strength of social mediabased surveys design flexibility, cost-effectiveness, convenience, and real-time access complex health care surveys can be constructed fast and with ease using common survey-building software technologies such as surveymonkey, google forms, jotform, and typeform. the layout and question-andanswer options can be created without hassle. once the survey has been created, it can be uploaded onto the social media platform and shared effortlessly, within seconds, on tablets, desktop computers, and smartphones. the ease of use of smartphones has contributed to the ever-increasing share of respondents participating in social media-based surveys via their 119siuj.org siuj • volume 4, number 2 • march 2023 tips and pitfalls in using social media platforms for survey dissemination http://siuj.org mobile devices from anywhere and at any time[13]. additiona l ly, adver tising sur veys on t he socia l media sites to garner more participation is relatively inexpensive compared with advertisements on print newspapers or billboards and pop-ups and banners on websites[14]. surveys on social media platforms prove to be a low-cost alternative for researchers seeking to create posts that can be tailored to the study population. another benefit of disseminating surveys in this manner is that respondents can complete the survey at a time that is most convenient for them. survey responses are stored automatically by the software system, allowing investigators access to the results through any mobilefriendly device. in turn, this renders the data analysis process seamless. anonymity email responses might reveal respondents’ identity and in conventional in-person interviews, it is even possible that interviewers can inf luence responses. the anonymity of social media-based surveys may be appealing to both researchers and participants, leading the latter to perhaps feel more secure and to have fewer inhibitions in truthfully answering the questions. the majority of survey respondents tend to answer “socially or emotionally sensitive” questions more honestly on online platforms because they know their responses are confidential. this also helps to mitigate the desirability bias, a potential drawback in research. in addition, online social media-based surveys are better utilized in recruitment of marginalized, hardto-access lesbian, gay, bisexual, transgender, and queer (lgbtq) young individuals, who may prefer a relatively safe and anonymous atmosphere over faceto-face interactions[15]. it has been documented in the literature that anonymized social media-based surveys are successful in procuring in-depth data from this population[16], which might not otherwise be possible through face-to-face interviews. distribution and sampling the link to the survey is typically publicized and shared or re-shared by both researchers and participants alike on social media channels, allowing for increased survey exposure and hence more likelihood for participation[6]. researchers are usually not able to determine who has engaged in the survey because they don’t have a master list of intended respondents. nonetheless, this methodology often generates convenience samples, encouraging recruitment through viewers’ engagement with the survey. it is of the utmost importance that researchers obser ve basic online etiquette while studying online communities. spamming, excessive contacting, or reposting the survey repeatedly on social media platforms should be avoided. in addition, survey participants should be reminded that they are expected to answer all the survey questions truthfully and to the best of their abilities. surveys may include preliminary screening questions that do not rely excessively on advertisement during recruitment. the main study objective, general information, and intended audience should all be clearly mentioned at the outset of the survey. it is quintessential to ensure the sampling method can gather a representative sample of the targeted population for a given survey. careful consideration should be given to the survey recruitment approach. today, as most health care professional bodies and organizations have social media profiles, it would not be difficult to reach out and recruit them for survey research. for instance, researchers can use social media to recruit a target population via facebook groups or facebook pages. also, the ability for social media users to repost content promotes an exponential rate of engagement, which can culminate in the snowball sampling phenomenon[17,18]. this type of chain referral helps ensure surveys are posted regularly and multiply simultaneously. this is not observed in the case of survey by email distribution. additionally, social media may offer multiple interactive formats that can incorporate audiovisual content and valuable resources[19]. another potential of social media-based surveys is that by accurately estimating the numbers of social media connections or followers as the denominator, the results of polls may likely be predicted. the use of “hashtags” may also substantially increase the number of people who can engage and complete the survey[20]. broader outreach and better response while the identity of respondents in social mediadriven surveys stays concealed, the intent is to reach a broader audience where social media is ubiquitous for maximizing survey outcomes. the availability of the internet and widespread use of social media across continents and many countries allow for overcoming geographical barriers.  a recent publication by the urosome team titled “a global survey of the impact of covid-19 on urological ser vices” described the significant impact the pandemic has had on the urology community[21]. the twitter platform was used to garner urologists from several continents to address covid-19–related urology issues. the survey questionnaire was distributed primarily to urology health care professionals via urosome twitter. the authors received an overwhelming response from a total of 1004 participants from asia, the united states, europe, africa, australia, and new zealand. this social media-based survey, which delivered high-quality scientific content in a short period of time, was a good example of timely global collaborative outcomes fostered by urologists[20,22]. 120 siuj • volume 4, number 2 • march 2023 siuj.org review http://siuj.org incentivisation has been used for survey participation and can vary from as simple as providing visibility to selected authors to monetary rewards including coupons and lucky-draw chances in commercially sponsored surveys to promote active participation and minimize dropouts[23,24]. in another recent global survey led by tan et al. on the psychological health of surgeons during covid-19, a variety of urls to the same survey were generated and sent to the participants who wished to promote the survey within their network[25]. once the participants ascertained a target number of completed respondents, which were tracked by surveymonkey, they were listed as pubmed-indexed collaborators to the study. this would eventually be reflected in the active responses by the survey software to determine the efficacy of their promotion. offering this type of co-authorship opportunity could optimize the reach of the social network and improve respondents’ engagement with the survey. preventing duplication a potential drawback of social media-based surveys concerns duplicate responses. it is possible that the same respondent might participate in a specific survey more than once. to mitigate this, surveys may limit survey participation of each individual to only one ip address. like other online survey software systems, surveymonkey and google forms have the ability to collect ip addresses. once the survey responses have been obtained from a specific ip address, that address is then blocked from further participating in the survey[26]. however, this method may raise concerns regarding compromising the anonymity of the respondents. measures to avoid missing data in contrast to the traditional in-person approach or telephone survey, surveys on social media have the potential downside of respondents intentionally or inadvertently opting not to answer (ie, sk ip) intricate questions. to avoid this, the survey software employs logic and skip patterns to generate questions that participants are required to answer[27] before proceeding to the next question. if the question remains unanswered, it will be marked, and participants will receive an automatic reminder to answer the question and proceed to complete the survey within a stipulated time. to prevent invalid responses, surveys may include “do not know” or “others” as a response option. ethics and consent all standard elements of the consent process should be adhered to in online investigations, including the provision of information about the research inquiry and clarification of the procedures in place to safeguard confidentiality, anonymity, and privacy. an introduction to the survey, including the survey’s purpose and eligibility of the respondents, should be listed on the landing page of the survey, prior to the first question. survey participants are presumed to have read and understood said statements and given their implied consent prior to proceeding to answer the questions[28,29]. anyone who does not wish to participate in the questionnaire is expected not to proceed to the next page. alternatively, the survey landing page can be designed with a button “i agree to participate” that respondents must click in order to proceed to the questions. pitfalls of social media-based surveys while the recruitment of survey participants using social media sounds impressive, the distribution of participants across different sites cannot be clearly determined. this is partly due to the limiting factors of not adopting sponsored advertising, resulting in limited sampling and respondent availability. variations in digital and technology capabilities may impact the representativeness of the sampling population and hence the generalizability of the results. certain rural populations are inevitably deprived of access to the internet, resulting in a lower response rate to social media-based surveys. however, with health care professionals' contemporary active online social media involvement, this pitfall is nearly trivial. survey fraud is one of the greatest obstacles when it comes to the online propagation of social media. many concerns exist regarding the methodological quality and equivalence, access challenges, and technological drawbacks of social media-based approaches. as dissemination of health care surveys via social media is in its infancy, the lack of regulatory guidance is cause for concern[7]. additionally, it is challenging to accurately measure nonresponse and attrition rates among social media users. the number of respondents who view the research opportunity but choose not to participate cannot be accurately determined. concerns also exist regarding anonymity and data security (for example, secure online transmission and storage of participant data) and digital delivery difficulties[30]. today, the sheer number of surveys conducted on social media platforms runs the risk of producing survey fatigue[31]. the truthfulness of the survey responses can be called into question, as respondents may rush through the surveys, particularly for lengthy or complex surveys. undeniably, in certain circumstances, the respondents may not provide truthful responses but rather respond solely for promised reward for survey completion. however, survey questions can be framed in different ways to assess participants’ deception and random responses[32]. another limitation is the poten121siuj.org siuj • volume 4, number 2 • march 2023 tips and pitfalls in using social media platforms for survey dissemination http://siuj.org tial bias influencing respondents through the design of the response options and how they are presented in the survey. last but not least, the absence of trained interviewers to address participants’ questions or doubts may potentially lead to less reliable data. discussion future directions social media has been adopted by many medical specialties, facilitating health care survey distribution. use of social media-based sur veys has increased due to social distancing measures brought on by the covid-19 pandemic, and as a result, has provided great opportunities for global participation. commercial software products are user friendly and designed to create questions and their answer options seamlessly. social media platforms should exercise caution to identify prospects with a strong interest in the survey topic. multiple social media platforms can be used to establish a more diversified sample to reduce sample composition bias. to define the target populations, an operational definition of the intended population should be developed to encourage the effective recruitment of respondents. demographic variables including age, gender, geographic location, and specialty field of interest should be explicated. additionally, the intended sample population should be taken into consideration when structuring the survey questions. questions should be written in an appropriate tone, use standard terminologies, and be clear and concise. excessively long surveys with complex and multistep questions should be avoided, as they promote attrition and poor survey completion compliance. contributing to participation dropout are factors such as an excessive number of qualitative questions, surveys with multistep questions, questions without the option to opt out or to decline answering, and an inaccessible survey interface[33,34]. it is incumbent upon survey researchers to identify the best data model in order to determine the variables needed to prevent survey response inconsistency and redundancy. conceptual modeling would enable obtaining data directly, without the need for any manipulation. “third-party guarantee of the survey” can be provided to increase credibility and perceived legitimacy[35]. to allay fears and concerns regarding the use of social media platforms, the european association of urology (eau), the american urologic association (aua), and other organizations have established recommendations and guidelines for the appropriate use of social media for communication among the urologic community[36]. ethical codes of conduct impart the need for professionalism and veracity, disclosure of any conflict of interest, good quality of survey research, and protection of confidentiality. the formation of a social media committee and stakeholders ensures the delivery of guidelines in urology to foster good social media practices[37]. professional standards for online conduct should be incorporated into social media education as the use of social media continues to proliferate in urological settings and beyond. conclusion our paper examined the efficacy and feasibility of social media as a survey dissemination tool among health care professionals. researchers may find it useful to create study-specific social media accounts to interact with their study population through various accessible online social media platforms. while recognizing the limitations of social media-based surveys, we must move forward and overcome obstacles inherent with this approach. as the saying goes, “a court ought not to be affected by the weather of the day, but will be by the climate of the era.” given that the widespread use of technology and social media has grown in popularity over the past few years, we advocate the novel use of social media platforms for promoting large and diverse survey participation. we also encourage additional studies to further explore the use of emerging social media 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siuj • volume 4, number 4 • july 2023 siuj.org key words competing interests article information ctdna, cfdna, plasma, gu tumors, liquid biopsy none declared. received on november 23, 2022 accepted on april 26, 2023 this article has been peer reviewed. soc int urol j. 2023;4(4):338–340 doi: 10.48083/xttp6351 in non-muscle-invasive bladder cancer, ctdna from plasma was reported to predict disease recurrence, with a high concordance of somatic variants with tumor dna[7]. molecular profiling of prostate cancer using urine and blood revealed a significant association between mutation allele frequencies in plasma and patients with metastatic prostate cancer[8]. additionally, while urine exhibited more mutations compared to blood, the number of mutations was not found to be associated with clinical characteristics of prostate cancer patients. however, studies have shown that urine cfdna may be a better source than plasma for early detection of and predicting treatment response in bladder cancer [9–11]. in patients with bladder cancer, urinary ctdna exhibited a high concordance rate with tumor dna compared to plasma ctdna[12], highlighting the importance of urine as a surrogate source of ctdna for diagnosis, disease monitoring, and personalized medicine. the major challenges associated with using liquid biopsies for ctdna detection include gaps in technology development, issues with clinical research methodologies, and the optimal integration into the clinical workflow[13]. the origin of ctdna circulating in biofluids can vary across tissue sources[14], hence, the best source of ctdna for a particular cancer depends heavily on the tissue of origin. while plasma has been the most universally accessible, extensively studied, and technologically advanced source for ctdna detection, the challenge for ctdna detection in plasma is low ctdna abbreviations cfdna cell-free dna ctdna circulating tumor dna gu genitourinary content (low ctdna/cf dna ratio). in recent years, urine has shown promising results over plasma as a major source of ctdna for diagnosis and monitoring of some gu cancers, especially bladder cancer. compared to plasma, urine is a completely noninvasive source of ctdna, characterized by ease of sampling, a high ratio of ctdna/cfdna, and high sensitivity for renal cell and urothelial carcinomas due to proximity to the tumors. however, large volume requirements of urine pose challenges for sample storage. additionally, ctdna yield may depend on time since the previous void, with glomerular filtration potentially limiting transrenal ctdna content[15,16]. seminal fluid may provide a prostate-specific source of cfdna for prostate cancer, allowing for noninvasive longitudinal sampling at multiple time points. seminal fluid has demonstrated reduced dnase activity[17] and high dna concentrations[18]. however, collecting seminal fluid can be challenging after surgical removal of the key organ and/or during ongoing androgen deprivation therapy. despite some theoretical benefits, urinary and seminal fluid ctdna assays are less developed than plasma-based ctdna alternatives. challenges associated with the clinical application of non-plasma–based ctdna detection include the lack of commercial availability and difficulties in the standardizing pre-analytical factors. overall, plasma remains the more validated source for clinical applications of liquid biopsies in most gu tumors, although urinary ctdna assays may substitute for plasma assays in bladder cancer. acknowledgments this work was supported by the national institute of health [r01ca212097 and r01ca250018 to l.w.] and by the h. lee moffitt cancer center & research institute. 339siuj.org siuj • volume 4, number 4 • july 2023338 benefits of plasma over other body fluids for circulating tumor dna detection in genitourinary tumorspro and con — liquid biopsy benefits of plasma over other body fluids for circulating tumor dna detection in genitourinary tumors manishkumar s. patel, liang wang department of tumor biology, h. lee moffitt cancer center and research institute, tampa, united states liquid biopsies have been established as remarkable alternatives to conventional biopsies because of their numerous benefits, including early-stage cancer detection, monitoring disease progression, and predicting treatment response and survival through a minimally invasive approach[1]. cell-free dna (cfdna) consists of short dna fragments (peak size = 167 bp) released into the bloodstream or other body fluids after cell apoptosis, carrying genome-wide dna from parent cells. among cfdna, circulating tumor dna (ctdna) is derived from tumor cells and can be analyzed from various sources, including blood, urine, saliva, pleural effusions, and cerebrospinal fluid (csf). plasma-based ctdna analysis has shown advantages over other biofluids, thanks to standardized blood collection and plasma isolation techniques. targeted therapies require continuous monitoring and quick analysis of evolving tumor profiles using minimally invasive methods. early cancer diagnosis and early detection of disease recurrence also require easily accessible material for genomic analysis, making the detection of ctdna in body fluids crucial in this process. generally, ctdna constitutes < 0.01% to 10% of the total cfdna, a low yield, necessitating sensitive assays for its detection. challenges such as hidden micrometastasis, low dna-shedding tumors, and the influence of different biological variables like mucinous histology contribute to false negatives. all these factors make the detection of ctdna in body fluids a significant challenge for clinical applications. although plasma is widely used for ctdna analysis, serum and other body fluids are also significant components of large biorepositories. a recent study demonstrated that variant allele frequency was reduced by approximately half in serum when compared to plasma samples[2]. serum contains higher levels of non-tumor cfdna, primarily due to leukocyte lysis during serum preparation. this can adversely affect the detection of mutations in ctdna, especially the ones with low allele fraction mutations[2]. overall, plasma minimizes ctdna dilution and enhances the sensitivity of ctdna analysis compared to serum. for genitourinary (gu) tumors such as prostate, bladder, and renal cancers, the major sources of ctdna are plasma, urine, and seminal fluid. however, blood-based ctdna analysis is well established for clinical implementation due to routine blood collection as part of clinical management of patients. plasma-derived ctdna enables the identification of prognostic, predictive, and response biomarkers in prostate cancer[3]. in a recent study, investigators reported an epigenetic classification of renal cell carcinoma (rcc) in patients across all stages of the disease[4]. the study demonstrated that urine-based classification was less accurate than plasma; however, technical and computational optimization could improve urine-based analysis. another study demonstrated that plasma ctdna can be used for predicting treatment response in metastatic castration-resistant prostate cancer[5]. in metastatic urothelial carcinoma, mutation concordance between plasma ctdna and matched tumor tissue was found to be 83.4%([6]. http://siuj.org http://siuj.org mailto:liang.wang%40moffitt.org?subject=siuj references 1. alix-panabières c, pantel k. liquid biopsy: from discovery to clinical application. cancer discov.2021;11(4):858–873. doi: 10.1158/21598290.cd-20-1311. pmid: 33811121. 2. pittella-silva f, chin ym, chan ht, nagayama s, miyauchi e, low sk, et al. plasma or serum: which is preferable for mutation detection in liquid biopsy? clin chem.2020;66(7):946–957. doi: 10.1093/clinchem/ hvaa103. pmid: 32516802. 3. de mattos-arruda l, mayor r, ng cky, weigelt b, martínez-ricarte f, torrejon d, et al. cerebrospinal fluid-derived circulating tumour dna better represents the genomic alterations 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carcinoma using plasma and urine cellfree dna methylomes. nat med.2020;26(7):1041–1043. doi: 10.1038/ s41591-020-0933-1. pmid: 32572266; pmcid: pmc8288043. 8. conteduca v, wetterskog d, scarpi e, romanel a, gurioli g, jayaram a, et al. plasma tumour dna as an early indicator of treatment response in metastatic castration-resistant prostate cancer. br j cancer.2020;123(6):982–987. doi: 10.1038/s41416-020-0969-5. pmid: 32669676; pmcid: pmc7492429. 9. vandekerkhove g, lavoie jm, annala m, murtha aj, sundahl n, walz s, et al. plasma ctdna is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer. nat commun.2021;12(1):184. doi: 10.1038/s41467-020-20493-6. pmid: 33420073; pmcid: pmc7794518. 10. zhang j, dai d, tian j, li l, bai j, xu y, et al. circulating tumor dna analyses predict disease recurrence in non-muscle-invasive bladder cancer. front oncol.2021;11 :657483. doi: 10.3389/fonc.2021.657483. pmid: 33996580; pmcid: pmc8114939. 11. chen g, jia g, chao f, xie f, zhang y, hou c, et al. urineand bloodbased molecular profiling of human prostate cancer. front oncol. 2022;12:759791. doi: 10.3389/fonc.2022.759791. pmid: 35402245; pmcid: pmc8984469. 12. chauhan ps, shiang a, alahi i, sundby rt, feng w, gungoren b, et al. urine cell-free dna multi-omics to detect mrd and predict survival in bladder cancer patients. npj precis oncol.2023;7(1):6. doi: 10.1038/ s41698-022-00345-w. pmid: 36658307; pmcid: pmc9852243. 13. patel km, van der vos ke, smith cg, mouliere f, tsui d, morris j, et al. association of plasma and urinary mutant dna with clinical outcomes in muscle invasive bladder cancer. sci rep.2017;7(1):5554. doi: 10.1038/s4159801705623-3. pmid: 28717136; pmcid: pmc5514073. 14. springer su, chen ch, rodriguez pena mdc, li l, douville c, wang y, et al. non-invasive detection of urothelial cancer through the analysis of driver gene mutations and aneuploidy. elife.2018;7:e32143. doi: 10.7554/elife.32143. pmid: 29557778; pmcid: pmc5860864. 15. zhang r, zang j, xie f, zhang y, wang y, jing y, et al. urinary molecular pathology for patients with newly diagnosed urothelial bladder cancer. j urol.2021;206(4):873–884. doi: 10.1097/ju.0000000000001878. pmid: 34061567. 16. ignatiadis m, sledge gw, jeffrey ss. liquid biopsy enters the clinic implementation issues and future challenges. nat rev clin oncol.2021;18(5):297–312. doi: 10.1038/s41571-020-00457-x. pmid: 33473219. 17. moss j, magenheim j, neiman d, zemmour h, loyfer n, korach a, et al. comprehensive human cell-type methylation atlas reveals origins of circulating cell-free dna in health and disease. nat commun.2018;9(1):5068. doi: 10.1038/s41467-018-07466-6. pmid: 30498206; pmcid: pmc6265251. 18. augustus e, van casteren k, sorber l, van dam p, roeyen g, peeters m, et al. the art of obtaining a high yield of cell-free dna from urine. plos one.2020 ;15(4):e0231058. doi: 10.1371/journal.pone.0231058. pmid: 32251424; pmcid: pmc7135229. 19. yao w, mei c, nan x, hui l. evaluation and comparison of in vitro degradation kinetics of dna in serum, urine and saliva: a qualitative study. gene.2016;590(1):142–148. doi: 10.1016/j.gene.2016.06.033. pmid: 27317895. 20. singer r, sagiv m, allalouf d, levinsky h, servadio c. deoxyribonuclease activity in human seminal fluid. arch androl.1983;10(2):169–172. doi: 10.3109/01485018308987559. pmid: 6860038. 21. ponti g, maccaferri m, micali s, manfredini m, milandri r, bianchi g, et al. seminal cell free dna concentration levels discriminate between prostate cancer and benign prostatic hyperplasia. anticancer res.2018;38(9):5121–5125. doi: 10.21873/anticanres.12833. pmid: 30194158. 340 siuj • volume 4, number 4 • july 2023 siuj.org pro and con — liquid biopsy http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information content, engagement, social media, twitter, urology none declared. received on october 20, 2022 accepted on january 16, 2023 this article has been peer reviewed. soc int urol j. 2023;4(2):105–111 doi: 10.48083/ktol8925 “likes” in social media: does it carry any implications? justin loloi,justin loloi,11* ari p. bernstein, ari p. bernstein,2* justin m. dubinjustin m. dubin3 1 department of urology, montefiore medical center, albert einstein college of medicine, bronx, united states 2 department of urology, nyu langone health, new york, united states 3 memorial healthcare system, aventura, united states *contributed equally as co-first authors. abstract social media usage has drastically increased in recent years. in particular, social media usage among medical providers has become commonplace. it may offer a variety of benefits in the medical arena, with respect to information dissemination, health promotion, and education. however, the implications of social media usage and engagement remain to be seen. this narrative review aimed to describe and highlight the effects of social media usage and engagement and to provide guidance for engaging in social media as a medical professional. our review demonstrates that active social media engagement unequivocally affords the urologist with meaningful opportunities for selfpromotion, branding, education, networking, research, and enhanced recruitment efforts, but this engagement comes with the risk for burdensome exposure to misinformation and harassment. we encourage adherence with american urological association/european association of urology (aua/eau) social media best practices and provide our own recommendations for social media engagement. introduction social media (some) represents a dynamic and interactive technology-based communication interface that has dramatically impacted virtually every aspect of society, including the field of medicine. specifically, some in healthcare has been utilized in a variety of ways, including promoting institutional branding and maintaining or improving both peer-to-peer and patient-to-clinician interactions[1]. there are several modalities of some platforms, including wikipedia, social networking sites such as facebook, media-sharing venues such as youtube, and microblogging platforms such as twitter[2], all of which are ubiquitous and used worldwide. more recently, video-sharing platforms such as instagram and tiktok have gained increasing recognition in the realm of medical knowledge acquisition and distribution[3]. among its many potential roles, some has become a significant tool for disseminating medical information and eliciting health promotion and education[4]. possibly the best example of the widespread use of some for information dissemination is the role some played during the covid-19 pandemic, where people relied on fast and effective platforms to seek, search, share, and distribute health-related information[5]. indeed, many people rely on these platforms to consume information; in 2015, it was estimated that more than 60% of the entire us adult population utilized the internet and subsequently, more than 70% of users endorsed seeking medical information online[6]. the field of urology has readily adopted and incorporated some into their practices. with the majority of both training and practicing urologists actively engaging in some platforms, there has been increasing interest in the roles 105siuj.org siuj • volume 4, number 2 • march 2023 original research mailto:jdubin50%40gmail.com?subject=siuj http://siuj.org and potential consequences of some usage[7,8]. some usage itself is not to be confused with some engagement, which is the measurement of how people interact with a some creator’s account and content. engagement metrics include likes, comments, favorites, clicks, mentions, shares, and other engagement actions based on the specific platform. some engagement is essential in measuring whether a creator’s content is resonating with their audience. for some influencers, high engagement often translates into sponsorships and financial success. but when it comes to medical professionals, what is the significance of some engagement? is being on some enough or should medical professionals be encouraged to be more active on platforms instead of just “lurking”? in this narrative review, we investigate the implications of some usage and engagement and provide recommendations for engaging in some as a medical professional. social media and research content creation on some prov ides users w it h significant opportunities at the personal, professional, and institutional levels. from a research perspective, some utilization can improve paper citation rates. eysenbach demonstrated a statistically significant positive correlation between tweets and citations[9]. furthermore, highly tweeted articles (those in the top 25th percentile with respect to tweets) were approximately 11 times more likely to be top-cited articles[9]. with this information, the author concluded that some metrics such as tweets can be used by scholars and institutions to not only monitor the impact of their research but also as a filter to direct users to highly impactful works. interestingly, this relationship between twitter presence and academic citations has garnered substantial support. a study by ozkent et al. showed a significant relationship between increased number of tweets about an article and the article’s increased number of citations[10], again suggesting the utility of twitter in disseminating academic and scholarly work. in a systematic review aimed to describe the varying tactics and strategies employed by medical journals to both engage with their readers and spread their research, erskine et al. concluded that promotion via twitter may improve a variety of metrics such as article dissemination, article readership, and citations, which may ultimately result in higher-impact work. in response to these data, several key strategies were adopted by medical journals to increase public attention to scholarly work; these include tweeting the link and title of their published articles, including infographics, having podcasts, and hosting monthly virtual journal clubs[11]. it appears that study authors should not only have a twitter account to keep up with the most recent literature but also be tweeting about their work to best capture audiences and maximize research impact. despite this data, it is not entirely clear whether more content engagement by consumers yields a greater impact. while further research is needed, there remains an overall positive sentiment on the utilization of some in this manner. social media and self-promotion some can play a role in the promotion of one’s practice, institution, or brand. when looking at the twitter engagement of over 340 medical residency training programs, it was noted that accounts that were tweeting more often had significantly more followers than those with fewer tweets (240 followers vs. 107 followers, respectively). furthermore, the authors found that all types of content engagement with twitter (such as likes, tweets, retweets, and comments) was associated with a larger following[12]. in surveying physicians who endorsed utilizing some (eg, facebook, youtube, blogs), campbell et al. revealed that participants highlighted some utility in branding, marketing, and networking[13]. additional survey data has substantiated that branding represents a common reason for physicians to adopt some[14]. as evidenced by our plastic surgery colleagues, a beneficial means of incorporating some into practice is by offering the public a glimpse into the life and practice of a surgeon; by creating an instagram account and categorizing a portion of the content as “private life,” a significant number of likes, clicks, and new followers were obtained when compared to posts designated as “scientific”[15]. thus, the personalization and access to a provider’s daily life may attract a large some following and enable enhanced branding and marketing opportunities. from a professional standpoint, creating some accounts may improve one’s chances of academic promotion or tenure. as some continues to be implemented into medicine, programs may consider developing and implementing institution-specific protocols describing an explicit set of guidelines delineating the types of some activities and presence that may be considered for career advancement[16]. criteria for some-based scholarship in health professions education have already been suggested; a consensus of 52 health abbreviations aua american urological association eau european association of urology smd social media disorder some social media 106 siuj • volume 4, number 2 • march 2023 siuj.org original research http://siuj.org professional educators from 20 organizations in four countries defined four key criteria for designation as some-based scholarship, including originality, advancing the field, content being saved in more permanent states and disseminated among formal channels, and providing the community the ability to comment on and provide feedback in order to elicit discussion[17]. in evaluating 98 studies that assessed the use and benefits of engaging in some for health communication, moorhead et al. described several key overarching benefits. namely, increased interactions with others, increased accessibility to information, peer social support, and the potential to influence health policy[4]. truly, some engagement— not just usage—has shown to help advance the careers of medical professionals in more ways than one. social media and education some can also facilitate medical education. cheston et al. performed a systematic review aiming to gauge the use of some in medical education in order to ascertain how educational interventions affect a host of factors such as satisfaction, knowledge, attitudes, and skills of physicians and physicians in training. they found that the incorporation of some tools into educational pursuits was associated with increased knowledge, skillset, and attitude. some tools (eg, blogs, youtube videos, twitter, and facebook posts) were particularly effective in promoting learner engagement, eliciting feedback, and fostering collaboration and professional development[18]. a considerably useful role for some use in education resides in the education of residents. after introducing twitter as a tool to facilitate education, the smart-me study showed that 38 of 40 (95%) residents felt that some could be useful as a medical education medium. interestingly, even prior to the intervention, 77% of participants were already using some for educational purposes[19]. within the realm of urology, some use has evolved to encompass multiple areas including acquiring urologic knowledge and conference participation[20]. in reviewing a european survey assessing the perceived role of some in acquiring urology-related knowledge, 63% of participants rated some as having a moderate-to-high impact on knowledge acquisition[21]. supporting the importance of some for urology residency, dubin et al. highlighted that more than 99% of urology trainees utilized some and 67.6% felt it was important to have some presence during residency[8]. furthermore, as it pertains to urology, social media may allow for virtual mentorship and dissemination of clinical practices and techniques, particularly for challenging procedures that may have a steep learning curve such as laser enucleation of the prostate[22]. from a research perspective, informational graphics may serve as powerful tools for advertising and information dissemination[23]. these were especially relevant during the covid-19 pandemic, which had a profound impact on urological care[24]. thus, with virtually all residents on and engaging in some, it is imperative that urological training programs and associations continue to adopt new approaches toward educating trainees via some. social media and the match the implications of enhanced content engagement are far-reaching beyond the obvious effects on education and research. in the field of urology specifically, the impact of united states residency applicant engagement with residency programs on platforms such as twitter and instagram have been shown to inf luence match statistics. with the covid-19 pandemic fueling an increased dependence on a virtual interview process, applicants are challenged with an inability to engage with residency programs directly in person. in lieu of in-person interactions, some has provided both programs and applicants a unique opportunity to learn about and engage with one another. a recent study by manning et al. revealed this interesting shift in content focus on twitter within the urological community following covid-19. their trigram (three-word combination) analysis of academic urology program tweets demonstrated a major shift toward recruitment and education, with a focus on utilizing some for recruitment efforts in the match process[25]. but beyond focusing content efforts on recruitment and the match, does some engagement impact the match results itself? heard et al. surveyed both residency applicants and program directors during the 2021 applicant season regarding their perspectives on some and its role in the residency match process. approximately 76% of applicants and 77% of program directors who were surveyed claimed to use some in the residency match process, with the vast majority of activity occurring on twitter[26]. while the majority (66%) of applicants followed their matched residency program on twitter prior to matching, few had direct content engagement with matched program accounts prior to the match. nonetheless, 66% of program directors felt their program’s some presence provided some benefit to the match, and 60% of applicants felt they gained better insight into residency programs from their some activity. importantly, no observed link between some usage and match outcomes was found[26]. despite observing no direct effect of some activity on match outcomes, when questioned about specific circumstances, 15% of program directors in the above study noted that an applicant’s some activity helped their chances of matching, whereas 12% noted that an applicant’s activity hurt their chances, suggesting a 107siuj.org siuj • volume 4, number 2 • march 2023 “likes” in social media: does it carry any implications? http://siuj.org meaningful influence of some activity on a more individual basis[26]. carpinito et al. similarly found that applicants to a single urology resident program utilized some as a means of information gathering, though increased content generation and engagement did not impact match outcomes to that specific institution[27]. however, friedman et al. also evaluated applicants to urology residency during the 2021 cycle and found that matched students were significantly more likely to have twitter accounts (59% matched vs. 28% unmatched, p = 0.02), and that matched students were more likely to have twitter accounts with more followers[28]. a study by bukavina et al. also supported the idea that increased applicant some engagement was associated with better match outcomes: among 250-matched and 45-unmatched urology applicants, matched applicants had higher numbers of twitter followers and overall tweet likes. having more followers, individual tweet likes, and total number of tweets increased overall odds of matching. notably, all matched applicants followed their matched program on twitter[29]. some appears to play an important and evolving role on the part of both applicants and programs as the virtual application cycle becomes the norm, though direct effects of content engagement remain to be elucidated. negative implications of social media some has many clear benefits, but its use can also have negative implications. social media disorder (smd) is a condition characterized by a behavioral addiction to some, diagnosed in subjects meeting five or more of the nine criteria on the validated social media disorder scale (preoccupation, tolerance, withdrawal, persistence, escape, problems, deception, displacement, and conf lict)[30]. in two studies, dubin et al. found that 6.1% of practicing urologists and 11.3% of urology trainees met criteria for smd[7,8]. many aspects of smd align with those involved in physician burnout. burnout rates among urologists are one highest in all medical subspecialties[31,32]. it is possible, therefore, that increases in some use could be associated with physician burnout. with a growing emphasis on the identification and prevention of physician burnout, a better understanding of some and its contribution to burnout development will be imperative. another concerning finding in one of the studies was that 17.7% of practicing urologists reported online harassment by other physicians, highlighting issues with professional conduct by physicians on some platforms[7]. these concerns were further warranted, as both studies by dubin et al. revealed that the majority of urology attendings and trainees have never reviewed professional guidelines on the appropriate use of some. it is clear that despite ubiquitous use of some by urologists, there exists great need and potential for formal interventions geared toward educating urologists on best practices in some use. social media and medical misinformation content engagement on some platforms and its apparent benefits across a multitude of medical specialties is not entirely without its challenges. medical misinformation is rampant, and there are no current standards to which users must adhere when sharing health-related content. studies have consistently shown poor overall quality of information regarding various urological conditions across youtube, tiktok, and instagram, with calls for the medical community to conduct collaborative efforts to enhance overall quality of information[33–36]. increased content engagement inherently comes with increased reach and perceived influence on the part of users, and therefore efforts to address misinformation are pivotal in the hopes of preventing the propagation of medically false information or inaccurate claims. engaging content filled with inaccuracies may be viewed as truthful simply by measure of popularity, a problem inherent to some that must remain at the forefront of any campaign to address misinformation. in the following section we provide recommendations for some engagement as well as suggestions for managing medical misinformation online. recommendations for social media engagement while having a some presence as a medical professional has been controversial in the past, it has now become clear that the potential benefits of utilizing some outweigh the potential pitfalls (figure 1). the risks, figure 1. potential benefits of social media engagement education research residency recruitment networking information dissemination personal and institutional branding/promotion social media 108 siuj • volume 4, number 2 • march 2023 siuj.org original research http://siuj.org however, are still potentially significant, and it is imperative that urologists who choose to engage in some be thoughtful of their online activities. despite both the american urological association (aua) and the european association of urology (eau) providing some best-practice guidelines, the majority of urology trainees and attendings have not reviewed either[7,8]. thus, we recommend that any urologist active on some platforms familiarize themselves with these guidelines to optimize their some experience. since the start of the covid-19 pandemic, medical information and misinformation online has become a growing concern among medical professionals. current research has confirmed fears of the promotion of misinformation through some platforms such as tiktok, instagram, and youtube[33–36]. in an attempt to address medical misinformation, urologists and other physicians have begun to focus their some efforts on discounting inaccurate information online while endorsing more medically accurate information. this kind of online engagement can potentially result in unwelcome consequences including harassment and, understandably, can defer many urologists from actively addressing medical misinformation on some. while not all urologists may feel compelled to dispute medical misinformation online, we think it is essential that every physician understand the ways in which they can best provide patients with accurate information both online and offline (figure 2). urologists interested in actively addressing medical misinformation on some should engage in manners that align with the aua/eau best practices. it is importfigure 2. recommendations for engaging in social media review aua & eau best practice guidelines on some endorse medically accurate information be prepared to address medical misinformation online invest in quality educational tools on some recommendations for engagement in social media ant to provide accurate, thoughtful commentary on the medical information and, if possible, limit personal commentary on the accounts/people providing the misinformation, as providing personal commentary can distract from the message and encourage further harassment. other ways in which the urological community can continue to expose medical misinformation is by continuing to invest in good online educational tools for patients interested in researching their health. the urology care foundation website is an excellent tool that provides accurate and easily digestible information for patients[37]. the creation of youtube channels by many urologists through which they provide medically accurate information has also become a popular and important tool for patient education. urologists should continue to support and promote these websites to patients both online and offline. although some is a valuable tool for medical information, the best way to provide medically accurate information remains through direct patient engagement. medical information is personal and private. by creating a safe environment and talking with their patients, physicians give themselves the best opportunity to address any patient concerns or questions about medical misinformation. conclusions through significant research efforts as well as the events following the covid-19 pandemic, prior questions regarding the value and sustainability of some in medicine have been answered: social media in medicine is here to stay. some is used by virtually all training and attending urologists and provides its users with various personal and professional opportunities. 109siuj.org siuj • volume 4, number 2 • march 2023 “likes” in social media: does it carry any implications? http://siuj.org simply having a some account is much different than actively engaging on the platforms and although both provide benefits, there is growing literature supporting that increased some engagement provides users with increased benefits. increasing engagement may come with risks and so we urge all urologists on some to familiarize themselves with the aua/eau social media best practices. despite the continuing pressure and clear benefits of being present on some, urologists should not feel compelled to be online. some engagement often requires time and resources, and with the already established high rates of burnout among urologists, urologists should engage in some only if they are interested. references 1. grajales fj 3rd, sheps s, ho k, novak-lauscher h, eysenbach g. social media: a review and tutorial of applications in medicine and health care. j med internet res.2014;16(2):e13. doi: 10.2196/jmir.2912. pmid: 24518354; pmcid: pmc3936280. 2. giustini d, ali 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sindhani m, kutikov a, et al. growth of the twitter presence of academic urology training programs and its catalysis by the covid-19 pandemic. eur urol.2021;80(2):261– 263. doi: 10.1016/j.eururo.2021.05.002. pmid: 34006446; pmcid: pmc8556659. 26. heard jr, wyant wa, loeb s, marcovich r, dubin jm. perspectives of residency applicants and program directors on the role of social media in the 2021 urology residency match. urology.2022;164:68–73. doi: 10.1016/j.urology.2021.08.041. pmid: 34606880. 27. carpinito gp, caldwell km, kenigsberg ap, ganesan v, khouri rk jr, kuprasertkul a, et al. twitter and instagram use in the urology residency application process. urology.2022;159:22–27. doi: 10.1016/j. urology.2021.08.046. pmid: 34637837. 28. friedman bj, chen i, asantey k, loeb s, kim sp, malik rd, et al. twitter engagement of medical students applying to urology residency during covid-19: a mixed methods study. urology.2022;165:120–127. doi: 10.1016/j.urology.2021.11.046. pmid: 35063463. 29. bukavina l, dubin j, isali i, calaway a, mortach s, loeb s, et al. twitter footprint and the match in the covid-19 era: understanding the relationship between applicant online activity and residency match success. urol pract. 2022;9 (4):331– 339. doi: 10.1097/ upj.0000000000000306. 30. van den eijnden rj, lemmens js, valkenburg pm. the social media disorder scale. comput human behav.2016;61:478–487. doi: 10.1016/j. chb.2016.03.038. 31. nauheim j, north ac. an updated review on physician burnout in urology. urol clin north am.2021;48(2):173–178. doi: 10.1016/j. ucl.2021.01.003. pmid: 33795050. 32. north ac, mckenna ph, fang r, sener a, mcneil bk, franc-guimond j, et al. burnout in urology: findings from the 2016 aua annual census. urol pract.2018;5(6):489–494. doi: 10.1016/j.urpr.2017.11.004. 33. babar m, loloi j, patel rd, singh s, azhar u, maria p, et al. crosssectional and comparative analysis of videos on erectile dysfunction treatment on youtube and tiktok. andrologia.2022;54(5):e14392. doi: 10.1111/and.14392. pmid: 35122283. 34. xu aj, myrie a, taylor ji, matulewicz r, gao t, pérez-rosas v, et al. instagram and prostate cancer: using validated instruments to assess the quality of information on social media. prostate cancer prostatic dis.2022;25(4):791–793. doi: 10.1038/s41391-021-00473-7. pmid: 34853412. 35. xu aj, taylor j, gao t, mihalcea r, perez-rosas v, loeb s. tiktok and prostate cancer: misinformation and quality of information using validated questionnaires. bju int.2021;128(4):435–437. doi: 10.1111/ bju.15403. pmid: 33811424 36. toprak t, yilmaz m, ramazanoglu ma, verit a, schlager d, miernik a. youtube is inadequate as an information source on delayed ejaculation. int j impot res.202223:1–6. doi: 10.1038/s41443-022-00559-3. pmid: 35318458; pmcid: pmc8940583. 37. urology care foundation. available at: https://www.urologyhealth. org/. accessed january 30, 2023. 111siuj.org siuj • volume 4, number 2 • march 2023 “likes” in social media: does it carry any implications? http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information prostatic neoplasms, prostatectomy, risk factors, adjuvant radiotherapy, salvage therapy none declared. received on june 13, 2022 accepted on august 8, 2022 this article has been peer reviewed. soc int urol j. 2023;4(1):40–50 doi: 10.48083/msvk1934 salvage versus adjuvant radiation therapy following radical prostatectomy in localised prostate cancer: a war without a winner lara rodriguez-sanchez,1 petr macek,1 camille lanz,1 qusay mandoorah,1 nuno dias,1,2 gianmarco colandrea,1,3 fernando p. secin,4 amandeep m. arora,5 rafael sanchez-salas,6 xavier cathelineau1 1 department of urology, institut mutualiste montsouris, université paris-descartes, paris, france 2 department of urology, são joão hospital and university center, porto, portugal 3 unit of urology, division of experimental oncology, uri urological research institute, irccs san raffaele scientific institute, vita-salute san raffaele university, milan, italy 4 discipline of urology, university of buenos aires school of medicine, buenos aires, argentina 5 division of urology, department of surgical oncology, tata memorial hospital, homi bhabha national institute, mumbai, india 6 department of surgery, division of urology, mcgill university health center, montreal, canada abstract objective to review current literature regarding the efficacy of adjuvant radiation therapy (art) and salvage radiation therapy (srt) following radical prostatectomy (rp) in patients with undetectable postoperative prostatespecific antigen (psa) levels and high-risk features of prostate cancer (pca) recurrence. methods seven randomized controlled trials focused on the use of art compared with either observation or srt after rp that had been published in pubmed up to may 2022 were reviewed. results the use of art following rp has been the treatment of choice over the past decade. three rcts comparing art with early srt show that srt given as soon as biochemical recurrence (bcr) is detected is not inferior to art while it offers the opportunity to avoid overtreatment and potential rt-related side effects. a meta-analysis summarizing the results from these trials supports these findings. conclusions early srt may be suggested as the standard of care for patients with pca and high-risk features for disease recurrence following rp. nevertheless, further investigations are needed to identify those patients who will benefit from art, particularly, in case of lymph node involvement. moreover, some patients might avoid srt despite reaching detectable postoperative serum psa levels. introduction because of its complexity and heterogeneity, prostate cancer (pca) management at any disease stage is under constant debate[1–3], and the use of adjuvant radiation therapy (art) following radical prostatectomy (rp) to address risk factors for disease recurrence has been questioned in recent years[4]. while earlier randomized controlled trials (rcts) showed a biochemical recurrence (bcr)-free survival benefit with art, a meta-analysis published in 2020 has shown no event-free survival benefit compared with salvage rt [5–9]. nevertheless, the impact of each of the risk factors and their combination on recurrence remain under debate[10]. in this respect, the last european association of urology (eau) guidelines, published in 2022, propose art be offered to a select group of patients: (a) patients without lymph node involvement but adverse pathology such as international society of urologic pathologists (isup) grade group 4–5 and pt3 with or without positive margins and, 40 siuj • volume 4, number 1 • january 2023 siuj.org review http://siuj.org (b) patients with lymph node metastasized pca with > 2 nodes involved[11]. in this review, we discuss the rcts evaluating art and salvage radiation therapy (srt) for patients treated with rp who had high-risk features for disease recurrence. methods we searched rcts and meta-analyses published up to may 2022, using the following terms: “adjuvant radiotherapy, prostatectomy,” salvage radiotherapy, prostatectomy,” and “postoperative radiotherapy, prostatic neoplasm.” articles not written in english were excluded. conference abstracts that did not provide enough information, case reports, review articles, and editorial comments were also excluded from review. seven rcts focused on the use of art compared with either observation or srt after rp were included in our review. results available evidence approximately 25% of men will experience recurrence of their cancer following rp for localised pca[10]. art has been the treatment of choice since the publication of 3 rcts over the past decade: the swog 8794[6], the european organisation for research and treatment of cancer (eortc 22911)[7], and the german cancer society (aro 96–02/auo ap 09/95)[8] trials, with their last results published in 2009, 2012, and 2014, respectively. the swog 8794 trial[6] (table 1) was the first randomized study to support the use of art in patients with unfavourable pathologic features (pt3 disease or positive surgical margins). thomson et al. proved that the use of art leads to better oncologic outcomes in abbreviations adt androgen-deprivation therapy art adjuvant radiation therapy bcr biochemical recurrence ct computed tomography mfs metastasis-free survival os overall survival pca prostate cancer pet positron emission tomography pfs progression-free survival psadt psa doubling time rct randomized controlled trial rp radical prostatectomy srt salvage radiation therapy terms of metastasis-free survival (mfs) and overall survival (os). nevertheless, it is important to note that the patients enrolled were randomized to art or observation instead of srt. hence, not every patient with bcr received timely srt. accordingly, the median serum psa level at the time of srt in the case of psa-only relapse was 0.75 ng/dl, and 37% of patients receiving srt had already experienced objective cancer recurrence. in addition, 33% of patients included in this trial did not have undetectable postoperative psa levels. similarly, bolla et al.[7] (table 1) randomized 1005 patients with pt3 disease or positive surgical margins following rp to art or a wait-and-see/obser vation policy. according to the swog 8794 trial, art improved biochemical progression-free survival (pfs) and local control compared with observation. unfortunately, half of the patients in the wait-and-see arm experienced only bcr (defined as an increase in psa concentration > 0.2 ng/dl after the lowest postoperative value was measured), but only 14.5% of them received srt. thus, at least 30% of patients with bcr after surgery did not receive srt as the first active salvage therapy. in addition, although pre-srt psa values were not reported, the median psa value before any type of active salvage treatment was 1.7 ng/dl, and 14 patients received srt despite a psa level that had not reached a nadir below 0.2 ng/ml after rp. the aro 96–02/auo ap 09/95[8] study (table 1) included only patients with undetectable postoperative serum psa levels. the results of this study also favoured art. art reduced the risk of progression (biochemical progression, local or distant clinical recurrence, or death from any cause) by 49%. in any case, no patient enrolled in the wait-and-see arm received additional treatment, so we cannot deduce whether the use of srt could have decreased the differences between study arms. following this, many retrospective studies were reported that focused on the effect of srt given to those patients with unfavourable clinical and pathologic features[10]. aiming to shed light on this topic, tao et al.[10] published a systematic review and meta-analysis that included 15 studies published between 2002 and 2018 comparing the prognosis of art and srt. it must be noted that this review did not include the above 3 rcts as those rcts compared art with observation, while the review focused on art versus srt. therefore, all studies considered for analysis were retrospective. according to this meta-analysis, the use of art following rp reduces the risk of bcr and 5-year overall mortality, although no benefit from art was demonstrated in terms of patient survival at 10 years from rp. importantly, (a) all patients considered had received either art or srt, which means that all patients included in the srt group had developed bcr, which 41siuj.org siuj • volume 4, number 1 • january 2023 salvage versus adjuvant radiation therapy following radical prostatectomy in localised prostate cancer: a war without a winner http://siuj.org in turn may imply a greater predisposition to unfavourable disease, and (b) no improvement in bcr in the art arm was observed when only early srt (defined as srt given at psa levels < 0.5 ng/dl) was considered. finally, a finnish trial published in july 2019 (table 1) randomized 250 patients with pt2 disease and positive margins or pt3a disease (irrespective of margin status) to art or observation[9]. art prolonged bcr-free survival compared with rp alone, but (a) the increase in psa levels before receiving srt was counted as an event, while nearly three-quarters of patients achieved psa remission after srt; (b) 29% of patients in the observation group whose disease progressed locally did not receive srt; and (c) the median psa level at srt was 0.7 ng/ml (range, 0.42 to 8.2). in short, the above-mentioned studies support the use of art when it is compared with observation or salvage radiotherapy, but they do not provide adequate outcome information about early srt. in this vein, several retrospective studies have suggested that early initiation of srt will not compromise cancer control but rather reduce the overtreatment that is associated with art[12–15]. in 2020, a meta-analysis showed that srt results may not differ from art results if the postoperative serum psa value is below 0.2 ng/ml at the time of treatment[5]. consequently, it has recently been disputed whether the use of srt as soon as psa values reach a detectable level may have an important impact when srt is compared with art. new investigations and findings at present, srt is recommended when the postoperative serum psa value is ≤  0.5  ng/ml[13,16]. it has been observed, however, that 5-year freedom from bcr after srt was 71% for those patients with a pre-srt psa level ≤ 0.2 ng/ml, 63% for those with a psa of 0.21 to 0.50  ng/ml, 54% for those with a psa value between 0.51 and 1.0 ng/ml, and 37% for those with a psa value ≥ 2.0 ng/ml[17]. hence, the timing of srt may alter its effectiveness[18]. three rcts — radicals-rt, raves, and getug afu-17 — were aimed at answering a hitherto unresolved dilemma: “what is the best timing for postoperative rt?”[19–21] (table 1). in this case, patients were randomized to art or observation followed by srt when the psa level was ≥  0.2  ng/dl[19,20] or even ≥  0.1  ng/dl[21]. a collaborative and prospectively designed systematic review and meta-analysis that included these 3 trials suggested that art does not improve event-free survival in men with localised or locally advanced pca compared with srt. five-year event-free survival in art and srt were 89% and 88%, respectively[5]. of interest, more than half of the patients included in the srt group did not meet the bcr criteria avoiding overtreatment and potential rt-related-side effects, including sexual, urinary, and bowel dysfunctions[5,22]. the radicals-rt, raves, and getugafu-17 trials[19–21] revealed that rt toxicity was more common among patients randomized to art compared with srt. grade 1 to 2 events were about twice as prevalent in the art group; grade 3 to 4 events were uncommon in both groups. data from these rcts support the notion that early srt avoids overtreatment without compromising the oncologic outcome. therefore, it seems reasonable to adopt this approach as the standard of care following rp for localised prostate cancer. nevertheless, can we generalise it to all patients? should we give special consideration to the different risk factors for recurrence and their combination? will the development of biomarkers and imaging techniques allow us to identify the best timing for rt after surgery? discussion accurate risk of recurrence estimation extracapsular extension, seminal vesicle invasion, positive surgical margins, high gleason score, and lymph node involvement are the main independent predictors of bcr[10,23,24]. however, the increasing use of genomic biomarkers to identify both germline and somatic variations may provide a more precise assessment of patients at risk of recurrence[25,26]. the heterogeneity of pca, with variable responses to treatment, is probably related to the molecular heterogeneity of this disease, which in turn is closely related to its genetic profile. thus, germline testing together with molecular profiling or tumour genomic profiling may lead us to understand more about the biology of the tumour, and distinguish pca with indolent behaviour from those cases with a lethal course[27]. approximately 5% of patients with localised pca harbour germline variations[28,29], such as brca2, and atm variations that are associated with both pca susceptibility and higher risk of aggressive disease[28]. in this regard, brca1/2 carriers with localised pca have a 16% increased absolute risk of developing metastases[30]. therefore, the identification of these variations may have a role in the management of patients at risk of bcr after rp. somatic changes in dna repair genes are found in nearly 10% of pca tumours confined to the prostate gland[31]. spratt et al. evaluated a 22-marker genomic classifier (gc; database of genomic variation and phenotype in humans using ensembl resources [decipher], sanger institute) to predict metastasis through a metanalysis of 5 studies. the authors proved that gc was an independent predictor of metastases. likewise, the 5-year cumulative incidence of metastasis was 2.4% for patients with a low gc score but 15.2% for patients 42 siuj • volume 4, number 1 • january 2023 siuj.org review http://siuj.org table 1. adjuvant radiation therapy randomized controlled trials swog 8794[6] eortc 22911[7] aro 9602[8] fp/finrog 0301[9] getug afu 17[19] radicals rt[21] raves[20] publication 2009 2012 2014 2019 2020 2020 2020 number of patients 425 1005 307 250 424 1396 333 randomisation art group: 214 observation group: 211 art group: 502 observation group: 503 art group: 148 observation group: 159 art group: 126 observation group: 124 art group: 212 srt group: 212 art group: 697 srt group: 699 art group: 166 srt group: 167 inclusion criteria extracapsular extension and/or svi and/or r1 n0m0 any postoperative psa pt2–3 with at least one of the following risk factors: capsular perforation svi r1 n0m0 any postoperative psa pt3–4 /r1–0 n0m0 postoperative psa <0.1 ng/dl pt2/r1 or pt3a/ r0-1 n0m0 postoperative psa < 0.5 ng/dl ≥ pt3/r1 n0m0 postoperative psa ≤ 0.1 ng/dl ≥ pt3 and/or preoperative psa ≥ 10ng/ml and/or gleason-score ≥ 7 and/or r1 n0/1m0 (5% pn1) postoperative psa ≤ 0.1 ng/dl pt3 or r1 n0m0 postoperative psa ≤ 0.2 ng/dl primary outcome mfs bcr-free survival pfs (bcr, clinical recurrence, or death) bcr-free survival event-free survival (disease relapse, bcr or death) freedom from distant metastases freedom from biochemical progression median follow-up (years) art group: 12.7 observation group: 12.5 10.6 art group: 9.25 observation group: 9.4 art group: 9.3 observation group: 8.6 6.25 4.1 6.1 ht added to srt/art not defined not defined not defined not defined 6 months of ht together with art and srt (all patients included in the trial) randomization to 0 vs 6 months vs 24 months of ht together with art and srt (some patients included in the trial) no rt dose 60–64gy 60gy 60gy 66.6gy 66gy 66gy or 52.5gy 64gy use of srt in the observation group 33% 31% — 30% 54% 33% 50% psa: prostate specific antigen; ht: hormonotherapy; bcr: biochemical recurrence; srt: salvage radiotherapy; art: adjuvant radiotherapy; svi: seminal vesicle invasion; r1: positive surgical margins; mfs: metastasis-free survival; pfs: progression-free survival; os: overall survival. *all patients in the observation group who received srt continued on page 44 43siuj.org siuj • volume 4, number 1 • january 2023 salvage versus adjuvant radiation therapy following radical prostatectomy in localised prostate cancer: a war without a winner http://siuj.org table 1. adjuvant radiation therapy randomized controlled trials swog 8794[6] eortc 22911[7] aro 9602[8] fp/finrog 0301[9] getug afu 17[19] radicals rt[21] raves[20] early or late srt late (median psa 1 ng/dl*) unknown (median psa unknown) — late (median psa 0.7 ng/dl*) early (median psa 0.24 ng/dl) early (median psa 0.2 ng/dl) early (median psa 0.2 ng/dl) 5-year eventfree survival art group: 92% srt group: 90% hr 0.81 [95% ci 0.48–1.36], p = 0.42 5-year bcr-free survival art group: 85% srt group: 88% hr 1.10 [95% ci 0.81–1.49], p = 0.56 art group: 86% srt group: 87% hr 1.12 [95% ci 0.65–1.90], p = 0.15 10-year pfs art group: 56% observation group: 35% hr: 0.51 [95% ci 0.37–0.70], p < 0.0001 10-year bcr art group: 53% observation group: 30% hr 0.43 [95% ci 0.31–0.58], p < 0.001 art group: 60.6% observation group: 41.1% hr 0.49 [95% ci 0·41–0·59], p < 0.0001 art group: 82% observation group: 61% hr 0.26 [95% ci 0.14–0.48], p < 0.001 10-year mfs art group: 71% observation group: 61% hr 0.71 [95% ci 0.54–0.94], p = 0.016 art group: 76.5% observation group: 71.3% art group: 98% observation group: 96% hr 0.49 [95% ci 0.09-2.68], p = 0.4 10-year os art group: 74% observation group: 66% hr 0.72 [95% ci 0.55–0.96], p = 0.023 art group: 60.6% observation group: 41.1% hr 0.49 [95% ci 0·41–0·59], p < 0.0001 art group: 92% observation group: 87% hr 0.69 [95% ci 0.29–1.60], p = 0.4 psa: prostate specific antigen; ht: hormonotherapy; bcr: biochemical recurrence; srt: salvage radiotherapy; art: adjuvant radiotherapy; svi: seminal vesicle invasion; r1: positive surgical margins; mfs: metastasis-free survival; pfs: progression-free survival; os: overall survival. *all patients in the observation group who received srt , cont’d 44 siuj • volume 4, number 1 • january 2023 siuj.org review http://siuj.org with high-risk gc scores[32]. later, marascio et al. explored the clinical benefit of decision-making based on decipher cg testing after rp. this prospective observational study revealed that patients with high gc risk who received art had a 2-year cumulative incidence of psa recurrence 8 times lower than those who did not. how should patients with very high-risk features and a combination of high-risk features and undetectable postoperative serum psa levels be treated? subgroup analysis in the artistic meta-analysis was limited by the low event rate, while the effect of rt timing could not be properly evaluated in patients with high-risk features for bcr such as seminal vesicle involvement (20% of patient enrolled), gleason score ≥ 8 (15% of patients enrolled) or node-positive disease (3% of patients enrolled)[5]. hence, there are still doubts about how to manage those patients with undetectable postoperative psa levels together with high-risk features, such as node-positive disease, gleason score > 8, and/or pt3b disease or higher[4]. in addition, investigators in the eortc 22911 trial determined that patients with 2 risk factors (eg, pt3a-b plus positive surgical margins) tended to have a greater risk of bcr and death if they received art compared with those who presented with a single risk factor[7]. no combination of adverse pathologic features was evaluated in the artistic meta-analysis[5], preventing us from knowing which is the best management option for these patients. particularly controversial has been the management of pathologically node-positive pca patients given the prognostic variability according to the number of affected nodes and tumour characteristics. in this regard, abdollah et al. suggested that patients with highrisk features for bcr (pathological stage > t3a and/or positive surgical margins together with gleason score 7 to 10) may benefit from art even when the number of lymph nodes involved is lower than 3[33,34]. in a systematic review of 26 studies published in 2018, only one propensity score-matched study provided information about the effectiveness of initial observation and srt versus art in the pn1 pca setting[34,35]. the study proved a benefit in terms of 4-year mfs for those patients receiving art regardless of disease characteristic[35]. recently, tilki et al., showed that art may be better when compared to srt. moreover, the benefit seems to be directly related to the number of lymph nodes affected. therefore, art might be avoided when ≤  3 positive lymph nodes are found (notably if at least 12 lymph nodes are sampled) but the impact that combination of positive lymph nodes with other risk factors for bcr may have on oncological outcomes was not explored[36]. in summary, rcts will be needed to determine the benefit of art in positive lymph node pca patients. until then, the use of art should be always considered in this group of patients, especially if more than 2 lymph nodes are involved and/or other risk factors for bcr are associated. impact of novel imaging techniques on treatment the detection rate of different imaging modalities is determined by psa level. thus, the lower the psa value, the lower the possibility of identifying locoregional or distant disease[37,38]. the decision to initiate art after rp should be made when serum psa values are < 0.5 ng /ml (or ideally < 0.2 ng/ml); therefore, the use of sensitive and accurate imaging techniques is of special interest. choline-based positron emission tomography (pet)/computed tomography (ct) detection rate is 30% when the serum psa level is ≤ 1 ng/ml after rp, while the corresponding detection rate is 60% for gallium 68 prostate-specific membrane antigen (68ga-psma) pet/ ct. furthermore, when serum psa is below 0.2 ng/ml the estimated detection rate for 68ga-psma) pet/ct is 40%[38,39]. pet imaging with 68ga-psma ligand was approved on december 1, 2020, by the us food and drug administration to detect pca recurrence after rp[40]. a meta-a na lysis of 15 st ud ies showed t hat 68ga-psma pet results after rp influenced the type and characteristics of treatment. the number of patients who received an increased dose or target volume of srt rose after 68ga-psma pet[41]. similar results were presented at asco 2022. armstrong et al. randomized 193 patients who experienced bcr to undergo any conventional imaging or 68ga-psma-11 pet/ct scan prior to srt (median psa before srt of 0.3 ng/ ml). seventy-one percent of major changes, defined as change of androgen-deprivation therapy (adt) duration ≥ 3 months, change of standard rt volumes, target volume delineation beyond standard rt field, simultaneous-integrated boost beyond standard rt fields, and initiation of advanced systemic therapy, were psma related[42]. pending final results of the radiation therapy oncology group (rtog) 0534 spport trial, which explores the effect of adt with or without pelvic lymph node treatment added to the prostate bed together with srt[43], novel imaging techniques may be useful in identifying patients who may benefit from whole-pelvis srt, although its association with improved oncologic outcomes is not yet known[44]. rt technique rt techniques in pca have advanced significantly in the past decades. for example, intensity-modulated rt 45siuj.org siuj • volume 4, number 1 • january 2023 salvage versus adjuvant radiation therapy following radical prostatectomy in localised prostate cancer: a war without a winner http://siuj.org (imrt) is now the gold standard for external beam rt (ebrt)[5]. although the benefit of dose escalation to 78 gy or higher for definitive localised pca rt is well known, its effect in the postoperative setting is still in doubt. a systematic review and meta-analysis of 71  retrospective studies demonstrated a proportional gain in bcr-free survival of 2% per incremental gy when escalating srt > 70 gy was given. a randomized phase 3 study that randomized patients with bcr following rp to either 64-gy or 70-gy srt showed that dose escalation had a minor impact on quality of life but led to significant worsening of urinary symptoms[45]. thus, neither national comprehensive cancer network (nccn) nor eau guidelines specify the appropriate dose to be administered and recommend doses of at least 66 gy up to 72 gy[11,46]. stereotactic body rt (sbrt) that accurately delivers a high radiation dose to an extracranial target in 1 or a few treatment fractions (extreme hypofractionation)[47] has been suggested as a safe procedure for patients with bcr and detectable local recurrence. although further investigations are needed, this emerging treatment option for isolated relapse may reduce the undesirable side effects of rt without compromising oncologic outcomes[48]. none of the studies included in the artistic meta-analysis administered rt doses higher than 66 gy or used hypofractionation techniques. therefore, new advances in rt may still improve oncologic outcomes following srt. timing and duration of adt with srt the optimal duration of adt together with srt is uncertain. the rtog 9601 trial supports the addition of 2 years of daily bicalutamide 150 mg to srt because a benefit in os at 10-year follow-up was observed (16% reduction in risk of death)[49]. similarly, the results of the getug-afu 16 trial, which randomized 743 patients to srt alone or srt plus 6 months of quarterly goserelin, confirmed that the addition of adt led to a 27% reduced risk of metastasis[50]. fossati et al. retrospectively explored the impact of adt duration on oncologic outcomes following srt and concluded that patients with more than one risk factor (≥ pt3b, isup > 3, or psa level at srt > 0.5 ng/ml) may benefit from long-term adt, whereas patients with a single risk factor may receive < 12 months of adt without compromising oncological outcomes. patients without any risk factors did not show a significant benefit from concomitant adt[51]. irrespective of the study arm, some patients enrolled in the radicals trial were randomized to 0 versus 6 versus 12 months of adt, but results regarding adt effect are still unknown[21]. likewise, the ongoing lobster tria l investigates whet her prolonging the duration of adt from 6 to 24 months improves oncologic outcomes. result from these 2 rcts will allow us to define the most appropriate treatment time for patients receiving srt. several ongoing rcts are evaluating the role of new androgen receptor pathway targeting agents in combination with srt. for instance, the salv-enza trial[52] compares srt plus placebo with srt plus enzalutamide, while the steel trial[53] compares srt plus standard adt with srt plus standard adt plus enzalutamide. the carlha-2 trial is exploring the effect of adding apalutamide to srt and standard adt[54]. finally, the formula-509 trial is studying the addition of apalutamide, abiraterone, and prednisone to srt plus standard adt[55]. benefit of srt in cases of bcr lastly, which patients would truly benefit from srt in the case of bcr? beyond reporting the role of art in the presence of high-risk features for bcr, the swog 8794[6],eortc 22911[7], aro 96–02/auo ap 09/95[8], and finnish[9] trials provided information about the natural history of pca. they revealed that median mfs and clinical pfs rates were > 10 years even among men included in the observation arm. these findings raise the question of whether all patients with bcr would benefit from srt and suggest that some patients with bcr following rp who receive srt may be overtreated. for instance, pak et al. retrospectively analysed 817 patients with bcr after rp. patients were categorised into 3 groups according to time from rp to bcr: an early group (median bcr-free survival of 8.5 months), an intermediate group (median bcr-free survival of 17.5 months), and a late group (median bcr-free survival of 70 months). the authors found that 8-year distant mfs and 8-year css were significantly better among patients receiving early srt (with or without adt) than among those receiving adt alone in cases of early bcr, but no differences were found in cases of late bcr. because patients included in the early bcr group had worse clinical and oncologic characteristics, such as higher nccn risk group, preoperative psa >  20  ng/ ml, gleason score 9 to 10, and pt3b-stage disease, more challenging tumour biology may explain these results. nevertheless, not all studies published to date support time from rp to bcr as an independent risk factor for worse oncologic outcomes[56,57]. although psa doubling time (psadt) is not always associated with short bcr-free survival, it has been noted that these variables are interconnected[56]. thirtysix retrospective studies evaluating prognostic factors in patients with bcr following rp that were included in a systematic review and subsequent meta-analysis showed a significant relationship between shorter psadt and higher risk of distant metastasis, pca-specific mortality, 46 siuj • volume 4, number 1 • january 2023 siuj.org review http://siuj.org and overall mortality, whereas bcr-free survival was also related to pca-specific mortality and overall mortality. in contrast, after psadt, pca gleason score based on prostatectomy histology report was recognized as a second factor more strongly associated with worse oncologic outcomes following rp as a primary treatment. based on these findings and the hypothesis that not all patients with bcr benefit from salvage treatment, the eau proposed a new bcr risk stratification that suggested that eau low-risk bcr patients after rp (psadt >  1 year and pathologic gleason score <  8) might avoid salvage treatment[57]. nevertheless, a recent validation showed that srt was highly protective, with maximum effect in early delivery[58]. therefore, risk group stratification after bcr remains inaccurate, and more research is needed to develop a molecular approach. so far, only retrospective studies have been published regarding this topic. when the art versus srt debate comes to an end, selecting those patients who may benefit from srt seems to be the next step. in this regard, rcts are of the utmost importance for shedding light on the hypotheses retrospective studies have raised[59,60]. conclusions early srt may be suggested as the standard of care for patients with pca with high-risk features and undetectable postoperative psa. nevertheless, some aspects, such as the duration of adt with srt as well as a more accurate stratification of patients at risk of clinical progression, require further investigation. therefore, some patients with undetectable psa following rp may benefit from art, while other patients can avoid srt despite reaching serum psa levels above 0.2 ng/ml. in conclusion, only improving patient selection for art or srt will lead to peace. references 1. gillessen s, attard g, beer tm, beltran h, bjartell a, bossi a, et al. management of patients with advanced prostate cancer: report of the advanced prostate cancer consensus conference 2019. eur urol.2020;77(4):508–547. doi:10.1016/j.eururo.2020.01.012. 2. aizawa r, takayama k, nakamura k, inoue t, yamasaki t, kobayashi t, et al. ten-year outcomes of high-dose intensity-modulated radiation therapy for nonmetastatic prostate cancer with unfavorable risk: early initiation of salvage 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androgen deprivation therapy in men with localised prostate cancer after radical prostatectomy (getug-afu 17): a randomised, phase 3 trial. lancet oncol.2020;21(10):1341-1352. doi:10.1016/ s1470–2045(20)30454-x. 20. kneebone a, fraser-browne c, duchesne gm, fisher r, frydenberg m, herschtal a, et al. adjuvant radiotherapy versus early salvage radiotherapy following radical prostatectomy (trog 08.03/anzup raves): a randomised, controlled, phase 3, non-inferiority trial. lancet oncol.2020;21(10):1331-1340. doi:10.1016/s1470–2045(20)30456–3. 21. parker cc, clarke nw, cook ad, kynaston hg, petersen pm, catton c, et al. timing of radiotherapy after radical prostatectomy (radicals-rt): a randomised, controlled phase 3 trial. lancet.2020; 396(10260):1413-1421. doi:10.1016/s0140–6736(20)31553–1. 22. huelster hl, laviana a a, joyce dd, huang l-c, zhao z, koyama t, hoffman ke, et al. radiotherapy after radical prostatectomy: effect of timing of postprostatectomy radiation on functional outcomes. urol oncol.2020;38(12):930.e23–930.e32. doi:10.1016/j. urolonc.2020.06.022. 23. chapin bf, nguyen jn, achim mf, navai n, williams sb, prokhorova in, et al. positive margin length and highest gleason grade of tumor at the margin predict for biochemical recurrence after radical prostatectomy in patients with organ-confined prostate cancer. prostate cancer prostatic dis.2018;21(2):221-227. doi:10.1038/s41391–017–0019–4. 24. bernstein an, shoag je, golan r, halpern ja, schaeffer em, hsu wc, et al. contemporary incidence and outcomes of prostate cancer lymph node metastases. j urol.2018 jun;199(6):1510–1517. doi: 10.1016/j. juro.2017.12.048. epub 2017 dec 26. pmid: 29288121; pmcid: pmc6530582. 25. nguyen pl, shin h, yousefi k, thompson dj, hornberger j, hyatt as, et al. impact of a genomic classifier of metastatic risk on postprostatectomy treatment recommendations by radiation oncologists and urologists. urology.2015;86(1):35-40. doi:10.1016/j. urology.2015.04.004. 26. marascio j, spratt de, zhang j, trabulsi ej, le t, sedzorme ws, et al. prospective study to define the clinical utility and benefit of decipher testing in men following prostatectomy. prostate cancer prostatic dis.2020;23(2):295-302. doi:10.1038/s41391–019–0185–7. 27. messina c, cattrini c, soldato d, vallome g, caffo o, castro e, et al. brca mutations in prostate cancer: prognostic and predictive implications. j oncol.2020:4986365. doi:10.1155/2020/4986365. 28. giri vn, knudsen ke, kelly wk, cheng hh, cooney k a, cookson ms, et al. implementation of germline testing for prostate cancer: philadelphia prostate cancer consensus conference 2019. j clin oncol.2020;38(24):2798-2811. doi:10.1200/jco.20.00046. 29. borque-fernando a, espílez r, miramar d, corbatón d, rodríguez a, castro e, et al. genetic counselling in prostate cancer: how to implement it in daily clinical practice? asesoramiento genético en cáncer de próstata: ¿cómo implementarlo en la práctica clínica diaria? actas urol esp.2021;45(1):8–20. doi:10.1016/j.acuro.2020.08.009. 30. castro e, goh c, olmos d, saunders e, leongamornlert d, tymrakiewicz m, et al. germline brca mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. j clin oncol.2013;31(14):1748-1757. doi:10.1200/ jco.2012.43.1882. 31. marshall ch, fu w, wang h, baras as, lotan tl, antonarakis es. prevalence of dna repair gene mutations in localized prostate cancer according to clinical and pathologic features: association of gleason score and tumor stage. prostate cancer prostatic dis.2019;22(1):59-65. doi:10.1038/s41391–018–0086–1. 32. spratt de, yousefi k, deheshi s, ross ae, den rb, schaeffer em, et al. individual patient-level meta-analysis of the performance of the decipher genomic classifier in high-risk men after prostatectomy to predict development of metastatic disease. j clin oncol.2017 jun 20;35(18):1991–1998. doi: 10.1200/jco.2016.70.2811. 33. abdollah f, karnes rj, suardi n, cozzarini c, gandaglia g, fossati n, et al. impact of adjuvant radiotherapy on survival of patients with nodepositive prostate cancer. j clin oncol.2014 dec 10;32(35):3939–47. doi: 10.1200/jco.2013.54.7893. 48 siuj • volume 4, number 1 • january 2023 siuj.org review http://siuj.org 34. marra g, valerio m, heidegger i, tsaur i, mathieu r, ceci f, et al. management of patients with node-positive prostate cancer at radical prostatectomy and pelvic lymph node dissection: a systematic review. eur urol oncol.2020 oct;3(5):565–581. doi: 10.1016/j.euo.2020.08.005. 35. tilki d, preisser f, tennstedt p, tober p, mandel p, schlomm t, et al. adjuvant radiation therapy is associated with better oncological outcome compared with salvage radiation therapy in patients with pn1 prostate cancer treated with radical prostatectomy. bju int.2017 may;119(5):717–723. doi: 10.1111/bju.13679. 36. tilki d, chen mh, wu j, huland h, graefen m, d’amico av. adjuvant versus early salvage radiation therapy after radical prostatectomy for pn1 prostate cancer and the risk of death. j clin oncol.2022 jul 10;40(20):2186–2192. doi: 10.1200/jco.21.02800. 37. krause bj, souvatzoglou m, tuncel m, herrmann k, buck ak, praus c, et al. the detection rate of [11c]choline-pet/ct depends on the serum psa-value in patients with biochemical recurrence of prostate cancer. eur j nucl med mol imaging.2008;35(1):18–23. doi:10.1007/ s00259–007–0581–4. 38. perera m, papa n, christidis d, wetherell d, hofman ms, murphy dg, et al. sensitivity, specificity, and predictors of positive 68ga-prostatespecific membrane antigen positron emission tomography in advanced prostate cancer: a systematic review and meta-analysis. eur urol.2016;70(6):926–937. doi:10.1016/j.eururo.2016.06.021. 39. treglia g, pereira mestre r, ferrari m, bosetti dg, pascale m, et al. radiolabelled choline versus psma pet/ct in prostate cancer restaging: a meta-analysis. am j nucl med mol imaging.2019; 9(2):127–139. 40. fda approves first psma-targeted pet imaging drug for men with prostate cancer. news release. us food and drug administration. december 1, 2020. available at: https://www.fda.gov/news-events/ press-announcements/fda-approves-first-psma-targeted-petimaging-drug-men-prostate-cancer. accessed june 1, 2022. 41. han s, woo s, kim yj, suh ch. impact of 68ga-psma pet on the management of patients with prostate cancer: a systematic review and meta-analysis. eur urol.2018;74 (2):179-190. doi:10.1016/j. eururo.2018.03.030. 42. armstrong wr, kishan au, booker km fendler wp, hope ta, nickols ng, et al. impact of psma pet/ct on prostate cancer salvage radiotherapy management: results from the prospective randomized phase 3 trial [psma srt nct03582774]. j clin oncol.2022;40(16suppl):5028–5028. doi: 10.1200/jco.2022.40.16_suppl.5028. 43. national library of medicine (u.s.). (2007, december). prostate radiation therapy or short-term androgen deprivation therapy and pelvic lymph node radiation therapy with or without prostate radiation therapy in treating patients with a rising prostate specific antigen (psa) after surgery for prostate cancer. identifier nct00567580. https://clinicaltrials.gov/ct2/show/nct00567580. 44. sachdev s, carroll p, sandler h, nguyen pn, wafford e, auffenberg g, et al. assessment of postprostatectomy radiotherapy as adjuvant or salvage therapy in patients with prostate cancer: a systematic review. jama oncol.2020 nov 1;6(11):1793–1800. doi: 10.1001/ jamaoncol.2020.2832. 45. ghadjar p, hayoz s, bernhard j, zwhalen dr, hölscher t, gut p, et al. acute toxicity and quality of life after dose-intensified salvage radiation therapy for biochemically recurrent prostate cancer after prostatectomy: first results of the randomized trial sakk 09/10. j clin oncol.2015;33(35):4158–4166. doi:10.1200/jco.2015.63.3529. 46. nccn clinical practice guidelines in oncology (nccn guidelines®) prostate cancer version 4.2022 — may 10, 2022. available at http://www.nccn.org/professionals/physician_gls/pdf/bone.pdf. 47. guckenberger m, andratschke n, alheit h, holy r, noustakis c, nestle u, et al; deutschen gesellschaft für radioonkologie (degro). definition of stereotactic body radiotherapy: principles and practice for the treatment of stage i non-small cell lung cancer. strahlenther onkol.2014;190(1):26-33. doi:10.1007/s00066–013–0450-y. 48. francolini g, jereczek-fossa ba, di cataldo v, simontacchi g, marvaso g, zerella ma, et al. stereotactic radiotherapy for prostate bed recurrence after prostatectomy, a multicentric series. bju int.2020;125(3):417–425. doi:10.1111/bju.14924. 49. shipley wu, seiferheld w, lukka hr, major pp, heney nm, grignon dj, et al; nrg oncology rtog. radiation with or without antiandrogen therapy in recurrent prostate cancer. n engl j med.2017;376(5):417– 428. doi:10.1056/nejmoa1607529. 50. carrie c, magné n, burban-provost p, sargos p, latorzeff i, lagrange j-l, et al. short-term androgen deprivation therapy combined with radiotherapy as salvage treatment after radical prostatectomy for prostate cancer (getug-afu 16): a 112-month follow-up of a phase 3, randomised trial. lancet oncol.2019;20(12):1740–1749. doi:10.1016/ s1470–2045(19)30486–3. 51. fossati n, robesti d, karnes rj, soligo m, boorjian sa, bossi a, et al. assessing the role and optimal duration of hormonal treatment in association with salvage radiation therapy after radical prostatectomy: results from a multi-institutional study. eur urol.2019 oct;76(4):443– 449. doi: 10.1016/j.eururo.2019.02.004. 52. kapoor r, deek mp, mcintyre r, raman n, kummerlowe m, chen i, et al. a phase ii randomized placebo-controlled double-blind study of salvage radiation therapy plus placebo versus srt plus enzalutamide with high-risk psa-recurrent prostate cancer after radical prostatectomy (salv-enza). bmc cancer.2019;19(1):572. doi:10.1186/s12885–019–5805-z. 53. posadas em, gay ha, pugh sl, morgan tm, yu jb, lechpammer s, et al. rtog 3506 (steel): a study of salvage radiotherapy with or without enzalutamide in recurrent prostate cancer following surgery. j clin oncol. published online may 25, 2020. doi:10.1200/jco.2020.38.15_ suppl.tps5601. 54. national library of medicine (u.s.) (2019, november). combined apalutamide, radiotherapy, and lhrh agonist in prostate cancer patients after prostatectomy (carlha-2). identifier nct04181203. https://clinicaltrials.gov/ct2/show/nct04181203 55. national library of medicine (u.s.) (2017 may). randomized phase ii study of salvage xrt + adt +/abiraterone and apalutamide for rising psa after rp (formula-509). identifier nct03141671. https:// clinicaltrials.gov/ct2/show/nct03141671 49siuj.org siuj • volume 4, number 1 • january 2023 salvage versus adjuvant radiation therapy following radical prostatectomy in localised prostate cancer: a war without a winner https://www.fda.gov/news-events/press-announcements/fda-approves-first-psma-targeted-pet-imaging-drug-men-prostate-cancer https://www.fda.gov/news-events/press-announcements/fda-approves-first-psma-targeted-pet-imaging-drug-men-prostate-cancer https://www.fda.gov/news-events/press-announcements/fda-approves-first-psma-targeted-pet-imaging-drug-men-prostate-cancer https://clinicaltrials.gov/ct2/show/nct00567580 http://www.nccn.org/professionals/physician_gls/pdf/bone.pd https://clinicaltrials.gov/ct2/show/nct04181203 https://clinicaltrials.gov/ct2/show/nct03141671 https://clinicaltrials.gov/ct2/show/nct03141671 http://siuj.org 56. pak s, you d, jeong ig, kim ys, hong jh, kim c-s, et al. time to biochemical relapse after radical prostatectomy and efficacy of salvage radiotherapy in patients with prostate cancer. int j clin oncol.2019;24(10):1238–1246. doi:10.1007/s10147–019–01463–5. 57. van den broeck t, van den bergh rcn, arfi n, gross t, moris l, briers e, et al. prognostic value of biochemical recurrence following treatment with curative intent for prostate cancer: a systematic review. eur urol.2019;75(6):967–987. doi:10.1016/j.eururo.2018.10.011. 58. tilki d, preisser f, graefen m, huland h, pompe rs. external validation of the european association of urology biochemical recurrence risk groups to predict metastasis and mortality after radical prostatectomy in a european cohort. eur urol.2019;75(6):896-900. doi:10.1016/j. eururo.2019.03.016. 59. collins r, bow man l , l andray m, peto r. t he magic of randomization versus the myth of real-world evidence. new engl j med.2020;382(7):674–678. doi:10.1056/nejmsb1901642. 60. trabulsi ej, valicenti rk, hanlon al, pisansky tm, sandler hm, kuban da, et al. a multi-institutional matched-control analysis of adjuvant and salvage postoperative radiation therapy for pt3–4n0 prostate cancer. urology.2008;72(6):1298 –1302; discussion 1302–1304. doi:10.1016/j.urology.2008.05.057. 50 siuj • volume 4, number 1 • january 2023 siuj.org review http://siuj.org double trouble! rare complete duplication of the entire urinary tract with dual neurogenic bladders necessitating dual intermittent catheterization sanjay sinha, lavina matai department of urology, apollo hospital, hyderabad, india we report a striking duplication of the entire urinary collecting system in an 18-year-old male with 2 renal pelves and 2 ureters on either side, along with a complete duplication of the bladder and urethra. the patient had previously undergone surgical inter ventions for lipomeningomyelocele, anorectal malformation, rectovesica l f istu la, a nd vesica l ca lcu lus (right hemibladder). on videourodynamics, the hemibladders showed poor compliance, altered bladder morphology, gross secondary vesicoureteral reflux with acontractlity, and large post-void residual volumes. the patient’s profound urinary incontinence resolved with daily administration of solifenacin 5mg and (double) clean intermittent catheterization through both the urethrae. serum creatinine was 1.1mg/dl, down from a peak of 1.45mg/dl, and the severe hydronephrosis has shown some improvement. figure 1 shows the first mri image of complete urinary tract duplication demonstrating 2 renal pelves and 2 ureters on either side, 2 hemibladders (sagittal duplication) and 2 complete urethrae. bilateral reflux into the lower moiety can be seen on dual urethrocystogram via both the urethrae. the glans showed 2 welldeveloped urethral meatuses with an intervening bridge of tissue consistent with effman type iii (complete) duplication[1]. the extraordinary rarity of this condition can be attributed to different embryological origins of various parts of the urinary tract. the condition encountered would require coincidental splitting of the urethral plate, the urogenital sinus, and both ureteric buds, as well as compatibility with survival[2]. while double ureter is encountered in about 1% of the population, the other 2 conditions have been reported only in sporadic case reports[2]. to the best of our knowledge, there are no reports of all these abnormalities occurring in the same individual. this is also perhaps the first report of dual intermittent catheterization to empty 2 lower urinary tracts. figure 1. mri, dual urethrocystogram and clinical photograph of the glans. 1a. mri shows 2 renal pelves and 2 ureters (rlu right lower moiety ureter, ruu right upper moiety ureter, llu left lower moiety ureter, luu left upper moiety ureter), the bladder split sagittally into 2 hemibladders (rhb right hemibladder, lhb left hemibladder) and complete duplication of the urethra (ru urethra draining the right hemibladder, lu urethra draining the left hemibladder). 1b. retrograde urethrocystogram done via both the urethrae. the left hemibladder was placed somewhat cranial to the right one with reflux into bilateral lower ureters. 1c. clinical photograph showing the 2 well-developed urethrae with an intervening bridge of tissue (arrow). references 1. effmann el, lebowitz rl, colodny ah. duplication of the urethra. radiology. 1976;119:179-185. 2. baskin ls, cunha g. embryology of the human genitourinary tract. in: par tin aw, dmochowski rr, kavoussi lr, peters ca, eds. campbell-walsh-wein urology. 12th edition. philadelphia, pa: elsevier 2020; 305-340. key words conflict of interest article information complete duplication of urethra, complete duplication of urinary bladder, neurogenic bladder, complete duplication of urinary tract none declared. patient consent: obtained. received on september 6, 2020 accepted on october 7, 2020 soc int urol j. 2021;2(1):72 72 siuj • volume 2, number 1 • january 2020 siuj.org clinical picture mailto:drsanjaysinha%40hotmail.com?subject=siuj http://www.siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. 77siuj.org siuj • volume 2, number 2 • march 2021 the société internationale d'urologie journal striving for global representation peter black, editor-in-chief  soc int urol j.2021;2(2):77–78 doi: 10.48083/ vzqd4051 the third issue of the société internationale d’urologie journal hits many of the highlights of what we are trying to achieve with our fledgling journal. the truly global character and special f lavor of the siuj are coming to the fore. this in turn is ref lective of the mission of the larger siu “to enable urologists in all nations, through international cooperation in education and research, to apply the highest standards of urological care to their patients.” we are a society of all urologists in all countries in the world, not limited by specific geographical or subspecialty boundaries. it is therefore critical that the pages of our journal represent broad global reach. the most obvious example of this is christian agbo’s contribution to “urology around the world,” which attests to the trials and tribulations of stone management in nasarawa state  in north central nigeria[1]. there is a clear sentiment in this article that dr agbo would like to be offering his patients more, as he strives to improve access to advanced technologies in a resource-poor setting. at the same time, those of us in resource-rich environments may contemplate our excesses in comparison to the limitations in nigeria, and be reminded of our duty to use our resources responsibly, and to consider the environmental impact and sustainability of our practices. we also need to be thinking about how we can develop clinical practice guidelines that can be applied beyond the borders of the wealthiest countries, as outlined in the last issue of the siuj by german patino et al.[2]. the collaborative work of joyce baard et a l. exemplifies global collaboration in research through the siu network of urologists[3]. we are particularly proud to publish this first project of ucare, the research arm of the siu. the paper reports results derived from a prospective registry of ureteral stent insertion after ureteroscopy. the registry captured patients from 50 centers in many different countries, ranging from saudi arabia to south africa, and from iran to malaysia and indonesia. the project reinforced connections between various national urological societies and the siu. this paper ref lects the power of global research cooperation and provides a uniquely international perspective on this common urologic procedure. it fulfills the siu’s objective to foster cooperation between urologists from all parts of the world despite differences in material conditions, professional concerns, and political views. ibrahem ismail samaha et al. report the results of a prospective randomized trial comparing a traditional transvesical approach for vesicovaginal fistula repair to a novel, potentially less invasive extravesical approach[4]. this type of surgery is particularly important in many regions of the world that make up key constituencies of the siu, so we are especially proud that the first randomized controlled trial to be published in the siuj is on such a pertinent topic in global surgery. education is front and center in the siu mission, and it is therefore only apt that jessica delong and ramón virasaro describe in the pages of the siuj a curriculum that has been established for genitourinary reconstructive surgery in the dominican republic[5]. wit h buy-in f rom a l l major sta keholders, t his curriculum has been launched successfully, and the first trainees have completed the program. this project has implications for global surgical training beyond the caribbean, as it provides a model that is transferable to other health care settings. as we continue to build the foundation of a new journal representing 10 000 siu members from over 130 countries worldwide, we strive to provide a vehicle for optimal communication of scientific information. our global reach helps distinguish us in the crowded field of urologic journals. http://www.siuj.org mailto:editorinchief%40siuj.org?subject=siuj 78 siuj • volume 2, number 2 • march 2021 siuj.org editorial references 1. agbo c. open surgery for urinary stones in a resource poor setting: a look at dalhatu araf specialist hospital, lafia, nigeria. soc int urol j.2021;2(2):79–81.doi: 10.48083/kfqz6048. 2. patino g, ndoye m, thomas hs, cohen aj, mmonu na, chu ce, et al. use of urology-based clinical practice guidelines in international settings. soc int urol j.2021;2(1):10–17. doi: 10.48083/qvxe4949. 3. dasgupta r, ong ta, lim j, rajandram r, gao x, hakim l, et al. a global perspective of stenting after ureteroscopy: an observational multicenter cohor t study. soc int urol j.2021;2(2):96 –105.doi: 10.48083/hrls8587. 4. samaha i, taha km, elbabouly i, ali m. novel extravesical versus transvesical technique for abdominal repair of vesicovaginal fistula. soc int urol j.2021;2(2):113–119.doi: 10.48083/ tvyu2515. 5. delong j, virasaro r. genitourinar y reconstructive surger y curriculum and postgraduate training program development in the caribbean. soc int urol j.2021;2(2):106 –112.doi: 10.48083/ rord8326. http://www.siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj.org siuj • volume 4, number 4 • july 2023 241 editorial liquid biopsies in genitourinary malignancies roger li1,2 guest editor 1 department of genitourinary oncology, h. lee moffitt cancer center, tampa, united states 2 department of immunology, h. lee moffitt cancer center, tampa, united states soc int urol j.2023;4(4):241–242 doi: 10.48083/grqw4595 measurement of extracellular circulating tumor dna (ctdna) in various body fluids and secretions represents a non-invasive method to capture a molecular snapshot of the systemic tumor burden in patients with various stages of cancer. at the same time, deep insights regarding the cancer’s molecular characteristics may be gleaned from comprehensive ctdna profiling to understand the mechanisms driving cancer progression and response to treatment, amongst other important clinical questions that may alter management strategies. given these advantages, it is easy to see why these novel diagnostic tests have engendered such great excitement in oncology practices. in the management of genitourinary tumors, the use of ctdna is further boosted by its accessibility: these tumors are in close proximity to the urinary tract, and it is postulated that higher levels of tumor-associated cfdna can be isolated directly from genitourinary secretions enabling more accurate detection and tracking of the disease. notwithstanding, there are many challenges present in the detection and interpretation of the results gathered in the context of genitourinary cancers. first, there is a wide array of techniques for identifying and measuring cfdna from malignancies, some involving tumor-informed methods, others relying on panel-testing of commonly occurring genomic alterations detected in cancer. optimization and customization of these methods are necessary for each of the genitourinary malignancies. additionally, specific challenges abound for various tumor types. kidney cancer is notorious for shedding low levels of ctdna, making systemic detection difficult. for prostate and germ cell tumors, the diagnostic accuracy of ctdna-based liquid biopsies needs to exceed the accuracy of established, timetested, non-invasive biomarkers widely available today. in urothelial carcinoma, although the detection of urinebased ctdna holds promise, technical challenges, such as distinguishing false positives from pre-existing mutations within normal urothelium, need to be resolved to arrive at a reliable testing modality. with the burgeoning genomic sequencing technology platforms enabling ever more affordable testing, data points are increasingly being gathered to address many of the outstanding issues hindering wide implementation of this technology. in this issue of the siuj, we summarize the most up-to-date knowledge regarding the use of ctdna in the management of prostate, urothelial, renal cell, and germ cell tumors[1–4]. we also explore whether urine or plasma is the ideal fluid for liquid biopsies to reflect the systemic tumor burden and molecular characteristics[5,6]. in addition, this issue features results of an original study using urinary ctdna to stage patients with muscle invasive bladder cancer at the time of radical cystectomy[7]. these reports will introduce this important novel platform and its capabilities, point out several unmet challenges, and help readers imagine a new era of precision medicine powered by molecular diagnostics. acknowledgements research support: predicine; veracyte; cg oncology; valar labs. clinical trial protocol committee: cg oncology. scientific advisor/consultant: bms, merck, fergene, arquer diagnostics, urogen pharma, lucence, cg oncology. http://siuj.org mailto:roger.li%40moffitt.org?subject=siuj references 1. kostos l, fettke h, kwan em, azad aa. utility and clinical application of circulating tumor dna (ctdna) in advanced prostate cancer. soc int urol j.2023;4(4):273–286. 2. dyrskjøt l. urine-based cell-free dna tests in urothelial cancer: additional value for clinical decision-making? soc int urol j.2023;4(4):341–342. 3. yip w, hakimi aa. circulating tumor dna (ctdna) in kidney cancer. soc int urol j.2023;4(4):287–292. 4. dolendo i, cox s, puri d, bagrodia a. the role of circulating tumor dna and cell-free dna in the management of germ cell tumors. soc int urol j.2023;4(4):293–300. 5. patel ms, wang l. benefits of plasma over other body fluids for circulating tumor dna detection in genitourinary tumors. soc int urol j.2023;4(4):338–340. 6. shiang a, nawaf c, chauhan ps, chaudhuri aa, smith zl, agarwal g. urinary tumor dna-based diagnosis and surveillance for nonmuscleinvasive bladder cancer. soc int urol j.2023;4(4):301–308. 7. murthy pb, gould b, davaro f, du p, camperlengo l, naidu s, rose k, gilbert sm, spiess p, sexton w, grass gd, jain r, wang x, meeks jj, necchi a, cheng l, jia s, li r. utilizing cell-free urinary and plasma tumor dna to predict pathologic stage at radical cystectomy. soc int urol j.2023;4(4):247–256. 242 siuj • volume 4, number 4 • july 2023 siuj.org editorial http://siuj.org 3siuj.org siuj • volume 1, number 1 • october 2020 the société internationale d'urologie journal going global peter black, editor-in-chief soc int urol j. 2020;1(1):3 the siu journal has officially arrived! we are proud to present volume 1, issue 1—the starting point for all journals, big and small. for the siuj this is the first step on the road to becoming part of the global urologic fabric, delivering high quality urologic research to an audience around the world. the siu has a long history of partnering with some of the key urologic journals, including bju international, urology, and, most recently, the world journal of urology. these have always been valuable collaborations. in recent years, however, the siu has experienced enormous growth, and, with over 10 000 members currently, the time has come to launch our own journal that we can tailor to the needs of our truly global membership. although the publishing space for urologic journals has become increasingly crowded, the growing number of good quality publications from around the world accommodates this expansion. we hope to reflect the character and spirit of the siu in the journal, and to attract both readers and authors from across the global urologic community, starting with but not limited to our own membership. we will introduce regular features such as “urology around the world” to showcase global urologic practices and experiences. we have structured our editorial board to be representative of all regions of the world, and have introduced regional editors specifically to champion the siuj in their respective regions—but also to champion their regions in the make-up of the siuj. we aim to be nimble and responsive so that we can adapt to the changing needs of our members. we want our members to value the siuj, and to identify the siuj as their own. we believe that the combined energy invested by the members of the editorial board is central to creating a successful journal. a critical feature of the siuj is open access. this open access will come at no cost to members, and only a nominal cost to non-member authors in a way that encourages non-members to sign up for membership. we are sending a very clear signal with this policy. we want universal access to the content of siuj, which is especially important for urologists in the developing world. open access also increases the reach and impact of articles, which is the ultimate goal of academic publishing and serves the needs of the authors. furthermore, all the hard work of the urologists and other health care providers who are writing and reviewing the manuscripts submitted to the siuj will benefit the urologic community and not the coffers of the publisher. with this in mind, we will institute rigorous peer review at the highest standards. we are particularly pleased in our first issue of the siuj to be able to offer a series of review articles on stateof-the art use of biomarkers in urologic oncology. these articles are summaries of full chapters written for the 1st international consultation on urologic disease (icud) world urologic oncology forum (wuof) consultation consultation on molecular biomarkers in urologic oncology, led by yair lotan, nathan lawrentschuk, and jack schalken, that will be published later this year. please join me and the entire siuj editorial team in embracing our new journal and making it a lasting success! http://www.siuj.org mailto:pblack%40mail.ubc.ca%20?subject=siuj this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information renal cancer, familial, genetics, syndrome, vhl, hlrcc, bhd, tsc, shd, bap1 none declared. received on july 25, 2022 accepted on september 19, 2022 this article has been peer reviewed. soc int urol j. 2022;3(6):397–406 doi: 10.48083/cbto5325 2022 wuof/siu international consultation on urological diseases: hereditary renal cell carcinoma syndromes jodi k. maranchie,1 brian m. shuch,2 gennady bratslavsky,3 eamonn r. maher4 1department of urology, university of pittsburgh and upmc, pittsburgh, united states 2 department of urology, university of california los angeles, los angeles, united states 3 department of urology, state university of new york (suny) upstate medical university, syracuse, united states 4 department of medical genetics, university of cambridge and cambridge university hospitals nhs foundation trust, cambridge, united kingdom abstract a number of germline syndromes that predispose affected individuals to develop renal cancer have been described, each with unique manifestations, histopathology, and tumor behavior. patients tend to present with early onset and/or multifocal tumors. familiarity with these syndromes helps to identify at-risk patients and recommend genetic screening. early detection is essential to direct appropriate cancer surveillance protocols for patients and other family members and care strategies that preserve lifelong renal function while minimizing risk of death from metastatic cancer. introduction hereditary syndromes represent 5% to 8% of all renal cell carcinomas (rccs)[1]. it is important for urologists to recognize and solicit their features. early detection facilitates appropriate cancer surveillance protocols and appropriate surgical planning[2], and helps identify other family members at risk. positive family history, early age of onset, or multifocal tumor should trigger consideration for referral for genetic counseling and screening. von hippel-lindau disease (vhl) vhl is caused by inheritance of one inactivated copy of the vhl tumor suppressor gene (tsg), located on chromosome 3 (3p25–26)[3]. inheritance is autosomal dominant, occurring in 1 in 35 000 births, with estimated prevalence in the united states of 7000 to 8000 people. affected patients develop renal cancer and cysts, pheochromocytomas or paragangliomas, central nervous system (cns) hemangioblastomas of the brain or spine, retinal angiomas, neuroendocrine tumors or cysts of the pancreas, and endolymphatic sac tumors of the inner ear or papillary cystadenomas of the epididymis or broad ligament[4]. rccs in vhl are uniformly clear cell histology (ccrcc). tumors are multifocal and early onset, and some patients require a first rcc intervention in their 20s[5]. due to its multiorgan nature of vhl, vhl patients are optimally managed by a multidisciplinary team managing routine retinal and cns examination and imaging as well as adrenal and pancreatic functional testing. cancer surveillance with abdominal ultrasound or cross-sectional imaging is recommended biannually starting at age 8. magnetic resonance imaging (mri) is preferred, when possible, to minimize risks for repeated radiation exposure. to prevent potentially lethal complications, pheochromocytoma must be excluded or managed prior to renal surgery. 397siuj.org siuj • volume 3, number 6 • november 2022 2022 wuof/siu international consultation on urological diseases mailto:maranchiejk%40upmc.edu?subject=siuj http://siuj.org historically, rcc was the leading cause of death in vhl. though rcc resection can decrease risk for metastases, bilateral nephrectomy profoundly limits quality and quantity of life. to preserve renal function, a conservative approach of active surveillance until the largest renal tumor reaches 3 cm, followed by nephron-sparing surgery to remove all tumors from that kidney was established[6–8]. the safety of this “3 cm rule” for prevention of metastatic disease in vhl patients has been confirmed[9]. more than 80% of vhl patients will develop a recurrent de novo renal tumor within 10 years of resection[10]. the “3 cm rule” can be applied again to trigger a second[11] or even a third or fourth nephron-sparing surgery[12]. alternatively, cutaneous ablation using radiofrequency, cryotherapy, or microwave therapy has been reported in select patients with comparable functional and oncologic outcomes[13,14]. in 2021, the oral hypoxia-inducible factor 2α (hif-2α) inhibitor belzutifan[15] was approved by the united states food and drug administration (fda) for systemic management of vhl associated rcc, cns, or pancreatic tumors based on a 97% rcc response rate at 21 months. belzutifan is generally well tolerated, with the most frequent side effects being anemia and fatigue[15]. birt-hogg-dubé syndrome (bhd) bhd is an autosomal dominant, familial syndrome[16 –18] caused by inactivating mutations of folliculin (flcn)[19,20]. manifestations include cutaneous fibrofolliculomas (hair follicle tumors) or trichodiscomas. present in at least 70% of patients by 40 years, these benign skin lesions are raised white papules on the nose and malar region and less commonly on the neck, ears, forehead, or trunk. pulmonary cysts occur in about 80% and may rupture, with a 30% lifetime risk for spontaneous pneumothorax[21]. all individuals with pathogenic flcn variants should be considered at risk for developing rcc regardless of family history[19]. lifetime risk for rcc is 25% to 30%, presenting as early as 20 years, with mean age at diagnosis of 50 years[21,22]. the most characteristic bhd histopat holog y is a hy br id ch romophobe/oncoc y t ic pat ter n, but chromophobe, clear cell, and papillary rcc have all been described[22,23]. other potential manifestations include colorectal polyps and cancer, thyroid cancer, and melanoma, though these have not yet been confirmed. colonoscopy is indicated if there is a family history of colorectal cancer[24]. affected or at-risk individuals should begin surveillance for rcc with annual mri at 20 years. ultrasonography can be used if mri is unavailable or not tolerated. when a solid renal lesion is detected, it is managed using the “3 cm rule,” followed by nephron-sparing surgery or ablation[23]. although mouse and cell-based models of flcn inactivation demonstrate mammalian target of rapamycin (mtor) pathway activation[25], a clinical trial of mtor inhibition with topical rapamycin for fibrofolliculomas did not demonstrate therapeutic efficacy[26] and additional study is required. hereditary leiomyomatosis and renal cell carcinoma (hlrcc) hlrcc was f irst described 50 years ago as the autosomal dominant familial reed ’s syndrome of cutaneous leiomyomas[27]. recognition of associated uterine leiomyomas and rcc led to the designation of hlrcc[28]. in 2002, fumarate hydratase (fh) was identified as the causal tsg[29]. hlrcc was initially thought to be a rare disease with high penetrance, but recent data suggests that hlrcc may have an incidence as high as 1 in 1000[30] with highly variable penetrance[31,32]. cutaneous leiomyomas are observed in 50% to 80% as raised skin papules that may be painful. uterine leiomyomas are reported in 30% to 80%. though benign, they can present with heavy vaginal bleeding and early hysterectomy. fh-deficient rcc occurs in 10% to 20% and is notoriously aggressive, with early progression to metastatic disease[31–33]. median age of onset is 36 to 40 years (range, 11–90 years)[17,34] and 7% present under the age of 20. if not detected by screening, rcc presents with symptoms from advanced disease (figure 1)[33,35]. to date, most rccs have been unifocal. however, with screening and effective early treatment, metachronous tumors have now been reported. fh-deficient rcc histology is variable and includes type 2 papillary, collecting duct, abbreviations aml angiomyolipoma bap1-tpds bap1 tumor predisposition syndrome bhd birt-hogg-dubé syndrome ccrcc clear cell renal cell carcinoma cns central nervous system cs cowden syndrome ct computed tomography esc rcc eosinophilic solid cystic rcc fh fumarate hydratase hlrcc hereditary leiomyomatosis and renal cell carcinoma mri magnetic resonance imaging mtor mammalian target of rapamycin phts pten hamartoma tumor syndrome rcc renal cell carcinoma tsc tuberous sclerosis complex tsg tumor suppressor gene vhl von hippel-lindau disease 398 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org or tubulocystic morphology[32,35], frequently with two or more growth patterns, and pleiomorphic eosinophilic nucleoli surrounded by a clear halo[32]. once a germline fh mutation is identified, all firstdegree relatives should be tested—ideally prior to age 10. any patient with multiple cutaneous leiomyomas, early-onset fibroids, or non-clear cell rcc by the age of 46 should also be considered for testing[36–38]. current management strategy for fh-deficient rcc is early detection with immediate intervention. annual crosssectional imaging with mri (preferred) or computed tomography (ct) is necessary, as renal ultrasound can easily miss a small papillary tumor. fluorodeoxyglucose positron emission tomography (fdg-pet) imaging may be useful due to the increased metabolic activity of fh-deficient rcc[39]. tumors may demonstrate solid and cystic elements and are frequently infiltrative in appearance[40]. once detected, prompt excision with clear margins is required regardless of tumor size. the “3 cm rule” does not apply to hlrcc, and nephronsparing surgery should be performed only if a negative margin is reasonably possible. regional retroperitoneal recurrences are common, and consideration should be given to regional node dissection even if the nodes are clinically negative[40]. efficacy of available systemic therapy for disseminated hlrcc is limited. national comprehensive cancer network (nccn) guidelines currently recommend bevacizumab plus erlotinib as first-line therapy based on response rates of 70%, with a median progression-free survival (pfs) of 21 months[41]. outcomes with other tyrosine kinase inhibitors have been variable. one series reported promising partial response rates approaching 50% for sunitinib or cabozantinib[42], but others found that most patients progressed within 6 months[43]. checkpoint inhibitors have similarly figure 1. gross inspection of a radical nephrectomy specimen showing hereditary leiomyomatosis and renal cell carcinoma (hlrcc) with an infiltrative tumor appearance 399siuj.org siuj • volume 3, number 6 • november 2022 hereditary renal cell carcinoma syndromes http://siuj.org shown mixed outcomes, with reports ranging from no response to complete response[44]. an ongoing trial (nct03914742) is investigating whether dna damage repair inhibitors may have therapeutic benefit[45]. hereditary papillary renal cell carcinoma (hprc) hprc is a rare autosomal dominant disease (incidence 1 in 500 000)[46], caused by germline-activating mutations of the met proto-oncogene (chromosome 7). met in turn activates multiple signaling pathways to promote rcc proliferation and survival[47]. hprcs are typically multifocal and indolent with an international society of urologic pathologists (isup) grade 1 or 2. they demonstrate predominantly papillary/tubulopapillary features with type 1 papillary histology[46], though concurrent ccrcc has been reported[47,48]. the median age of tumor presentation is 41 years[1] with earliest onset at 30 years. penetrance approaches 100% by the age of 80. advanced hprc tumors may present with the classic triad of flank pain, hematuria, and an abdominal mass or, rarely, with lung metastasis[49,50]. no nonrenal manifestations of hprc have been observed. genetic screening should be considered for any individual who has a known family history of hprc or who develops type 1 papillary rcc prior to age 45 or multifocal papillary tumors[51]. testing requires bidirectional dna sequencing. to date, all identified mutations reside in 4 of 21 met exons[47,52–54]. because papillary tumors are frequently isoechoic and missed by ultrasound, routine cross-sectional imaging with ct or mri is recommended every 2 years[55,56]. tumors are characteristically hypovascular with enhancement of 10–30 hounsfield units. management of rcc follows the “3 cm rule,” with nephron-sparing surgery as in vhl[55]. good preservation of renal function is documented for partial nephrectomy even with more than 20 tumors[57]. several agents targeting the met pathway have been studied for potential efficacy against hprc[47]. foretinib, a multikinase inhibitor of met, vefgr2, ron, axl, and tie-2 receptors, showed responses in 50% of patients with germline hprc[52]. other met-targeting agents including cabozantinib are being explored[58], potentially opening new therapeutic options for these patients. tuberous sclerosis complex (tsc) tsc is a multiorgan syndrome with autosomal dominant inheritance. estimated incidence is 1 in 6 000 to 10 000 new births. although penetrance in tsc is over 95%, there is significant variability in the disease phenotype, including rare cases with no overt manifestations[59]. dermatologic (facial angiofibromas, hypomelanotic macules, fibrous cephalic plaques, shagreen patches, and ungual fibromas) and cns manifestations (cognitive/ behavioral impairment or structural issues leading to epilepsy or nodules of the ventricular walls) present in 90% in early childhood[60]. renal manifestations include angiomyolipomas (amls) in nearly 70% and rcc in 2% to 4%[61]. a pathogenic alteration can be found in the genes for tsc (tsc1-hamartin and tsc2tuberin) in approximately 80% with both somatic and germline mosaicism described[62]. up to 50% are de novo alterations[63]. tsc2 germline defects are associated with greater disease burden and severity than tsc1[64]. amls (mesenchymal tumors of the pecoma family) are typically bilateral and multifocal. they develop in late childhood at a median age of 16.9 years[65]. bulky amls may merge, making it difficult to distinguish clear boundaries between lesions. the majority are benign, consisting of vascular, smooth muscle, and fatty elements. a rare but important variant, epithelioid aml, is composed of epithelioid cells with minimal to no fat. epithelioid amls may grow rapidly and are more prone to necrosis and hemorrhage and progression, with distant metastases observed in up to 33% in multiple series (figure 2). screening recommendations include baseline abdominal imaging with ct or mri at diagnosis and then every 1 to 3 years[66]. amls are usually easily identified by the presence of macroscopic fat, though fat-poor lesions may require confirmatory biopsy. ultrasound does not adequately assess tumor size or presence of fat. contrast-enhanced mri should be coordinated with brain mri whenever possible to minimize number of procedures under sedation. with prospective surveillance, more than 80% of tsc amls are identified prior to onset of symptoms or hemorrhage[65]. they can be safely observed until they reach 4 cm, at which time embolization or resection is indicated. epithelioid variants should be considered for earlier resection given their risk for malignant behavior. alternatively, everolimus is approved for the medical management of aml and has also shown efficacy in the setting of metastatic epithelioid aml[67]. tsc rccs occur at a median age of 28 years (range, 7– 59)[61]. perhaps due to routine surveillance imaging, the majority are small (median size, 2.9 cm), incidental[61], and localized. nearly 50% are multifocal[61,68]. our understanding of tsc rcc has evolved as more cases have been reported. initially, histology was believed to be similar to sporadic rcc, including ccrcc[63] molecularly distinct from vhl[69]. in recent years, common morphologic patterns have emerged including chromophobe and hybrid oncocy tic/chromophobe tumors (hoct), rcc with smooth muscle stroma (also known as renal angiomyoadenomatous tumors), and eosinophilic unclassified variants[61,68]. notably, the latter are reminiscent of sporadic eosinophilic solid 400 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org cystic rcc (esc rcc), which harbors somatic mtor/ tsc mutations. there are limited data to suggest that tsc rcc should be treated differently than other forms of rcc. however, renal preservation should be prioritized with use of partial nephrectomy or ablation when feasible. pten hamartoma tumor syndrome (phts) phts is a spectrum of autosomal dominant disorders caused by germline mutations in the pten tsg. the best recognized form is cowden syndrome (cs), but others include bannayan-riley-ruvalcaba syndrome (brrs), proteus-like syndrome, and macrocephaly with autism and/or learning disability. major manifestations of cs include mucocutaneous papillomatous papules and trichilemmomas, macrocephaly, multinodular goiter, follicular adenomas of the thyroid, and increased lifetime risks for breast (>80%), nonmedullary thyroid (~35%), and endometrial cancers (~30%)[70,71]. rcc, most commonly papillary and chromophobe subtypes, occurs in 15% to 24%, with median age at diagnosis of 50 years[70,72,73]. cs rcc is usually unilateral[73], with reported age at onset as early as 20 years. at least one manifestation of cs will be evident in 90% by age 30 years[74]. when clinical diagnostic criteria for cowden syndrome are met[74], diagnosis of phts is confirmed by germline testing for a pten pathogenic variant[75]. pten is now included on many multigene cancer testing panels. a positive test should trigger testing of at-risk relatives. comprehensive phts surveillance protocols are recommended starting at age 18 years[74,76]. for women, annual mammography or breast mri starts at age 30 years and endometrial cancer screening at age 35 years. prophylactic mastectomy may be offered. annual thyroid examinations and biannual dermatologic assessments begin at time of diagnosis and regular colonoscopy at 35 years. biannual rcc screening is started at 20 years[77]. treatment of phts rcc is the same as for sporadic rcc, and available data suggest that the “3 cm rule” can be applied. bap1 tumor predisposition syndrome (bap1-tpds) bap1-tpds is an autosomal dominant, multiorgan cancer syndrome caused by germline loss or mutation of bap1, which is located on 3p21.1 and frequently codeleted with vhl in ccrcc[78]. bap1 codes for ubiquitin carboxyl-terminal hydrolase bap1, a nuclear deubiquitinating enzy me involved in chromatin remodeling and repair of double-stranded dna breaks[79]. the prevalence of germline bap1-tpds is unknown, but it is estimated to represent 1% to 1.5% of all ccrccs and nearly 20% of patients who develop both rcc and uveal melanoma[80]. nonrenal bap1tpds manifestations include pigmented skin lesions (bap1-inactivated melanocytic tumors), aggressive uveal melanoma with high risk for metastasis and poor survival, and early-onset malignant mesothelioma (mm) of the pleura or peritoneum[81]. less commonly, c ut a ne ou s me l a nom a , b a s a l c e l l c a rc i nom a , meningioma, cholangiocarcinoma, and breast cancer are observed. penetrance is variable but high, with at least one tumor observed in nearly 90% of affected individuals[81]. rcc occurs in 10% of bap1-tpds patients and is often bilateral and multifocal[55,82]. tumors are predominantly ccrcc, though papillary and chromophobe have been reported[55,81]. median age at onset is 47 years. bap1-tpds rcc is typically high grade with poor clinical outcome, and the “3 cm rule” may not be appropriate. close surveillance of affected individuals with early excision is recommended until the syndrome is better characterized[82]. figure 2. epithelioid variant angiomyolipoma (aml) in a patient with tuberous sclerosis complex (tsc) who had failed two attempts at angioembolization of large vessel (coil seen) 401siuj.org siuj • volume 3, number 6 • november 2022 hereditary renal cell carcinoma syndromes http://siuj.org genetic consultation and screening should be offered to any individual with a personal or family history of two or more bap1-tpds tumors[83], with testing of at-risk relatives if positive. current guidelines for affected individuals require annual fundus and full body dermatologic examination annually starting at 2 years, mri of the brain every other year starting at age 18, and mri of the chest, abdomen, pelvis, and breast every other year starting at age 30 with annual mammography starting at age 40[84]. once a renal tumor is identified, however, annual abdominal imaging is advised due to the documented rapid growth rate of bap1-tpds rcc[85]. succinate dehydrogenase (sdh) deficient rcc sdh-deficient rcc is a rare autosomal dominant syndrome caused by germline mutations of the succinate dehydrogenase complex (sdha: 5p15.33; sdhb: 1p36.13; sdhc: 1q23.3; and sdhd: 11q23)[86]. in addition to early-onset rcc, affected individuals may develop paragangliomas (commonly of the head and neck), pheochromocytoma, wild-type (negative for mut ations of t he kit and pd gfra genes) gast rointest ina l stromal tumor (gist), and, less commonly, prolactin-secreting pituitary adenoma[55,82]. renal masses may be multifocal and bilateral and are morphologically distinct from other rccs[87]. germline sdh defects can be detected in up to 15% of all pheochromocytomas and paragangliomas and 1% to 1.5% of all rccs[55,88]. sdh is a complex enzyme composed of four subunits: sdha, sdhb, sdhc, and sdhd. it is often referred to as mitochondrial complex ii and is anchored on the inner mitochondrial membrane where it participates in both the krebs cycle (oxidation of succinate to fumarate) and the electron transport chain[89]. loss of sdh function leads to accumulation of succinate and a metabolic shift to aerobic glycolysis[82]. most cases of sdh-deficient rcc involve germline mutations of sdhb, though all subunits have been reported[55]. sdh-deficient rccs are tan to brown with well-circumscribed “pushing” margins[90]. cystic features are common. tumors have a distinctive histologic appearance of cuboidal cells with inconspicuous nucleoli arranged in nests or tubules, with eosinophilic cytoplasm containing vacuoles and cytoplasmic inclusions[55,86]. although the majority are low grade, high-grade sdh-deficient rccs are aggressive[86,91] and known for early metastasis[82]. at-risk individuals should be screened annually with abdominal mri or ct. the “3 cm rule” does not apply, and prompt excision regardless of size is recommended using nephron-sparing surgery where possible. hereditary hyperparathyroidism jaw tumor syndrome (hpt-jt) hpt-jt is a syndrome of parathyroid adenoma and cancer, benign ossifying fibromas of the jawbone, and renal and uterine cancers. it commonly presents as early-onset primary hyperparathyroidism, with an estimated penetrance of 65% by age 50[92]. inheritance is autosomal dominant and conferred by germline mutations of the cdc73 gene, which encodes the nuclear protein parafibromin. renal manifestations include renal cysts and tumors, with both ccrcc and wilm’s tumor reported[93]. though there are currently no consensus guidelines, renal screening by abdominal ultrasound every 5 years has been recommended for atrisk individuals[55]. conclusion hereditary rcc syndromes are a diverse group with varying penetrance, histology, and clinical behavior. although hereditary rccs are uncommon, most urologists will encounter them, and it is important to remain vigilant, take an appropriately detailed history, make use of genetic counselors when indicated, and select a surveillance and management strategy that addresses the tumor biology and lifelong risk for recurrence. 402 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases 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vlachodimitropoulos d, katsoulas n, kyriazis id, liatsikos en, et al. sdh-deficient renal cell carcinoma: a case repor t associated with a novel germline mutation. clin case rep.2021;9(10):e04605. 90. wilczek y, sachdeva a, turner h, veeratterapillay r. sdh-deficient renal cell carcinoma: a clinicopathological analysis highlighting the role of genetic counselling. ann r coll surg engl.2021;103(1):e20-e2. 91. kuroda n, yorita k, nagasaki m, harada y, ohe c, jeruc j, et al. review of succinate dehydrogenase-deficient renal cell carcinoma with focus on clinical and pathobiological aspects. pol j pathol.2016;67(1):3-7. 92. van der tuin k, tops cmj, adank ma, cobben jm, hamdy nat, jongmans mc, et al. cdc73-related disorders: clinical manifestations and case detection in primary hyperparathyroidism. j clin endocrinol metab.2017;102(12):4534-4540. 93. iacobone m, carnaille b, palaz zo ff, vriens m. hereditar y hyperparathyroidism-a consensus repor t of the european society of endocrine surgeons (eses). langenbecks arch surg. 2015;400(8):867-886. 406 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information renal cell carcinoma, treatment-related adverse events, vascular endothelial growth factor receptor tyrosine kinase inhibitors, mtor inhibitors, immune checkpoint inhibitors none declared. received on august 1, 2022 accepted on september 21, 2022 this article has been peer reviewed. soc int urol j. 2022;3(6):485–499 doi: 10.48083/syab9165 2022 wuof/siu international consultation on urological diseases: management of toxicity and side effects of systemic therapy for renal cell carcinoma kate young,1 andreas m. schmitt,1,2 deborah mukherji,3 lavinia spain,4 manuela schmidinger,5 lisa m. pickering1 1 renal and skin unit, royal marsden nhs foundation trust, london, united kingdom 2 department of clinical research, university hospital basel, basel, switzerland. 3 department of medical oncology, american university of beirut, lebanon; department of medical oncology, clemenceau medical center dubai, united arab emirates 4 department of medical oncology, peter maccallum cancer centre, melbourne, australia; department of medical oncology, eastern health, melbourne, australia; eastern health clinical school, monash university, melbourne, australia 5 department of urology, medical university of vienna, vienna, austria abstract standard approved systemic treatment options for the management of renal cancer have entirely transformed in the last 15 years and now comprise molecularly targeted therapies against the vascular endothelial growth factor receptor (vegfr) and the mammalian target of rapamycin (mtor) as well as immune checkpoint inhibitors. these agents may be used alone as monotherapies but increasingly are used in various combinations. the associated important improvements in cancer control and survival have therefore been accompanied by a range of new toxicities. good management of these toxicities is important for patient safety and quality of life, and also to optimize patients’ opportunity to continue with and therefore benefit from these therapies. the most common toxicities associated with vegfr tyrosine kinase inhibitors are fatigue, skin rashes, gastrointestinal, stomatitis, hypertension and other cardiovascular toxicities, and hematological and endocrine dysfunction. common side effects of mtor inhibitors include asthenia, stomatitis, skin rashes, pneumonitis, metabolic changes and infections. checkpoint inhibitors can lead to toxicities of any organ system with those seen most frequently including dermatologic, gastrointestinal and hepatic, endocrine, musculoskeletal, and pulmonary, whilst renal, hematological, ophthalmic, cardiac and neurological toxicities are seen less often. in general terms, toxicity management should start preemptively with patient education and may also include a combination of supportive approaches, dose reduction, schedule alteration, treatment interruption and occasionally treatment cessation. treatment of individual toxicities is dependent on the likely causative agent and is guided by its grade or severity. specific recommendations for management are discussed in this chapter. introduction since the mid-2000s, the introduction of new systemic therapies has transformed the management of renal cell carcinoma (rcc). vascular endothelial growth factor receptor (vegfr) tyrosine kinase inhibitors (tkis), mammalian target of rapamycin (mtor) inhibitors (mtoris), and most recently immune checkpoint inhibitors (cpis) have led to dramatically improved outcomes in advanced disease. in the past 5 years, several studies have demonstrated improved survival for the combination of cpis and tkis or the combination of the 2 cpi agents nivolumab and ipilimumab compared to first-line therapy with single-agent tkis, and these combinations are now established as standard of care[1–4]. the cpi pembrolizumab is also now approved as adjuvant therapy following 484siuj.org siuj • volume 3, number 6 • november 2022 2022 wuof/siu international consultation on urological diseases https://orcid.org/0000-0002-9500-2046 https://orcid.org/0000-0002-9568-8164 https://orcid.org/0000-0002-0192-5828 https://orcid.org/0000-0002-2567-2749 https://orcid.org/0000-0002-7579-340x http://siuj.org resection of high-risk localized disease, or following nephrectomy and full resection of all metastatic lesions[5]. however, alongside their beneficial effects, these agents can cause a range of toxicities. optimal management of such side effects is required to ensure safe treatment, manageable quality of life, and optimal drug delivery. general principles of rcc toxicity management prior to initiating systemic therapy for rcc, the patient’s current fitness, medical history and comorbidities, and concurrent medications should be considered. this allows for identification of patients at greater risk for toxicity and can trigger targeted pretreatment investigations, such as evaluation of cardiac, endocrine, gastrointestinal, or respiratory status. it may also highlight use of cy tochrome p450 3a4 (cyp3a4) enzyme inducers or inhibitors that will interact with the planned rcc treatment[6]. when toxicities arise, they should be graded according to the common terminology criteria for adverse events (ctcae)[7] in conjunction with guidelines for immune-related adverse events (iraes) to help select optimal management strategies. these include treatment interruption, dose or schedule modification, or occasionally treatment cessation, each of which has a role to play according to the severity or “grade” of the toxicity. early recognition and intervention aids optimal management of treatment-related adverse events (traes). support and education for patients, general physicians, and oncologists therefore minimizes the risks associated with these treatments. this is particularly important in the first few months after treatment initiation, but ongoing vigilance is required throughout, especially for cpi-induced toxicities, which can emerge late into, or even after, treatment. toxicity of vegfr tkis vegfr tk is including a x it inib, caboza nt inib, lenvatinib, pazopanib, sorafenib, sunitinib, and tivozanib are highly effective treatments for advanced rcc, with approvals by the united states food and drug administration (fda) both as single agents and in combination with cpis or mtor inhibitors. collectively, these agents have led to a marked improvement in sur vival compared with the “pre-tki” era[8–14]. vegfr tkis have varying potency and selectivity for vegfrs and other tyrosine kinase receptors including platelet-derived growth factor receptor (pdgf), met, and c-kit, which contributes to differences in their toxicity and clinical profiles. most patients experience some side effects, with trae rates for all-grade toxicity > 98% in the registration clinical trials and grade ≥3 toxicity in 10% to 15% of patients. dose interruptions were reported in 19% to 40% of patients, dose reductions in 14% to 46%, and treatment discontinuation in 4% to 21%. the most common traes reported in registration trials are skin, gastrointestinal, stomatitis, hypertension, hematological abnormalities, fatigue, and endocrine dysfunction (table 1). management of vegfr tki–associated toxicities general principles of managing vegfr tki–induced toxicities involve supportive interventions, treatment interruption, dose reduction and, particularly with sunitinib, schedule modification, with occasional treatment discontinuation. grade 1 and 2 toxicities can often be managed with supportive approaches in the first instance but may benefit from temporary treatment interruption. for treatment-related toxicities grade ≥ 3, treatment interruption is usually required, other than for some laboratory abnormalities. subsequent dose reduction or schedule modification may be needed. most vegfr tkis are administered on a continuous dosing schedule. sunitinib, however, is routinely administered on a dosing schedule that incorporates treatment-free periods: its approved starting dose and schedule is 50 mg daily for 4 weeks followed by a 2-week treatment break (4/2). several nonrandomized studies[15–17] and the prospective surf study[18] have shown that the alternate schedule of 2 weeks continuous dosing followed by a 1-week treatment break (2/1) reduces toxicity with no apparent compromise to efficacy. this schedule is not recommended at initiation of sunitinib but can be a useful switch option for therapy management. in selected cases in clinical practice, similar dosing regimens or "drug holidays” can be used for the management of toxicity associated with other vegfr tkis[19,20]. recognized guidelines for vegfr tki–driven toxicities should be followed where available. however, unlike abbreviations cpi immune checkpoint inhibitor ctcae common terminology criteria for adverse event ctla-4cytotoxic t-lymphocyte antigen 4 irae immune-related adverse event mrcc metastatic renal cell carcinoma mtor mammalian target of rapamycin mtori mammalian target of rapamycin inhibitor pd-1 programmed cell death 1 receptor rcc renal cell carcinoma trae treatment-related adverse event vegfr vascular endothelial growth factor receptor 485 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org table 1. safety outcomes reported in pivotal clinical trials of vascular endothelial growth factor receptor tyrosine kinase inhibitors in metastatic renal cell carcinoma sunitinib first line nct00083889 n = 375 17215529[13] pazopanib first or second line, nct00334282 n = 290 20100962[11] tivozanib first or second line nct01030783 n = 260 24019545[12] cabozantinib first line nct01835158 n = 78 28199818[10] axitinib first line nct00835978 n = 192 nct00920816[19] lenvatinib second line nct01136733 n = 52 26482279[9] trae leading to discontinuation in % 8 nr 4 21 4 death due to trae — n (%) nr 4 (1) nr 3 (4) none adverse event in % all grade 3/4 all grade 3/4 all grade 3/4 all grade 3/4 all grade 3/4 all grade 3/4 diarrhea 53 5 52 4 23 2 72 10 50 9 71 12 fatigue 51 7 19 2 19 5 86 6 33 5 50 8 nausea 44 3 26 < 1 12 < 1 32 3 20 1 62 8 stomatitis 25 1 – – 11 < 1 36 5 – – 25 2 hypertension 24 8 40 4 44 27 81 28 49 13 48 17 vomiting 24 4 21 2 – – – – – – 38 4 hand-foot syndrome 20 5 – – 14 2 42 8 26 7 15 0 anorexia – – 22 2 18 3 47 5 – – 48 6 back pain – – – – 14 3 – – 21 0 decreased appetite – – – – 10 < 1 – – 29 2 58 4 lower respiratory tract infection – – – – – – – – – – 8 8 laboratory abnormality neutropenia 72 11 34 1 11 2 15 0 – – – – thrombocytopenia 65 8 32 1 18 < 1 40 1 – – – – lymphopenia 60 12 31 4 – – – – – – – – leukopenia 60 5 0 0 – – 12 0 – – – – ast increase 52 2 53 8 37 2 62 3 – – – – increased lipase 52 13 – – 46 11 – – – – – – alt increase 46 3 53 12 28 1 55 5 – – – – hyponatremia – – 31 5 – – – – – – – proteinuria 3 – – – 72 3 – – – – 31 19 hypothyroidism – – – – – – – – – – 37 2 all adverse events grade 3 or worse that occurred in at least 5% of patients in one of the trials are reported. alt: alanine transaminase; ast: aspartate transaminase; nr: not reported in cited publication; trae: treatment-related adverse event. 486siuj.org siuj • volume 3, number 6 • november 2022 management of toxicity and side effects of systemic therapy for renal cell carcinoma http://siuj.org for toxicities associated with immune cpis, there are no regularly updated consensus guidelines, and recommendations are primarily derived from clinical expertise. practical recommendations for common vegfr tki–associated toxicities are summarized in table 2. a related and important point concerns hypertension as a potential biomarker for efficacy, best demonstrated with axitinib. it has been shown that blood pressure rise is somewhat correlated with axitinib serum concentration and that correct axitinib dose titration, including dose increase according to its approval, is associated with improved response to treatment[19]. toxicity of mtor inhibitors the mtoris temsirolimus and everolimus are usually well tolerated, with low rates of grade 3 and 4 adverse events[21–24]. common side effects include asthenia, stomatitis, skin rashes, pulmonary toxicity, metabolic changes particularly hyperglycemia and hyperlipidemia, table 2. management recommendations for key toxicities associated with vegfr tyrosine kinase inhibitors toxicity management recommendations hypertension almost all patients commencing these medications experience a dose-dependent elevation in blood pressure. pretreatment evaluation and treatment of blood pressure and cardiovascular risk essential as treatment-related reduction in lvef correlates with baseline risk. blood pressure should be monitored regularly with initiation of antihypertensive therapy ≥140/90 mmhg according to clinical practice guidelines. nondihydropyridine calcium-channel blockers that inhibit cpy3a4 (verapamil, diltiazem) should be avoided[25]. fatigue fatigue is common and often multifactorial. monitoring for and treatment of anemia, hypothyroidism, cardiac dysfunction, diarrhea, hypophosphatemia, and low testosterone levels in males can be of help. dose reduction may be required if fatigue persists despite correcting these factors. aerobic exercise reduces fatigue in fit patients. diarrhea dietary adjustment (brat diet: bananas rice, applesauce, toast) and increase in fluid intake. loperamide or pancreatic enzyme supplementation can also be considered in specific cases. diarrhea / emerging data probiotics have been shown to reduce the severity of chemotherapy-induced diarrhea; however; have not specifically been evaluated in tki-induced diarrhea[25]. fecal microbiota transplantation has recently shown promising results for the treatment of tki-induced diarrhea[27]. hand-foot syndrome preventative advice includes avoiding unnecessary friction/removing hyperkeratosis prior to treatment and avoiding excessively hot water. for erythema (grade 1), recommend self-care plus moisturizing creams and 20% to 40% urea creams. pain (grade 2) requires dose interruption/modification with addition of clobetasol 0.05% ointment/topical or systemic analgesia as required[28]. other dermatologic effects including skin and hair color changes are relatively common, thus patients should be counseled accordingly. stomatitis stomatitis may result in a significant reduction in food intake and qol. good oral hygiene. oral rinses (saline, sodium bicarbonate, or nonalcoholic mouthwash) can be used for mucosal erythema (grade 1). for grade ≥ 2 mucositis requiring dose interruption/modification; topical anesthetics, mucosal coating agents, and/or benzydamine hcl may be administered as needed for pain[29] hypothyroidism tsh should be measured at baseline and monitored during treatment at least every 3 cycles. replacement with thyroxine should be considered for patients with tsh above 10 iu/ml[30] lvef: left ventricular ejection fraction; qol: quality of life; tsh: thyroxine stimulating hormone; vegfr: vascular endothelial growth factor receptor. 487 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org and infections[31]. as for vegfr tki–related toxicities, the general principles of managing the side effects from mtoris are to consider treatment interruption, dose reduction, and use of supportive therapies, as well as treatment cessation for grade 3 and 4 toxicities[32]. key recommendations are summarized in table 3. toxicity of immune checkpoint inhibitors immune cpis are a well-established component of treatment for advanced renal cell carcinoma and now are also approved in the adjuvant setting[2,5,33,34]. while cpis are well tolerated by many patients, immune checkpoint blockade is associated with a unique collection of iraes. these iraes behave differently than the more predictable toxicities oncologists are accustomed to managing with chemotherapy or targeted therapies, occurring any time between initiation of treatment to many months after treatment cessation. mechanism, spectrum, and frequency of cpi-associated toxicities mechanisms of immune-related adverse events the exact mechanisms responsible for the development of iraes are not fully understood. the immune checkpoint proteins cytotoxic t-lymphocyte antigen 4 (ctla-4) and programmed cell death 1 receptor (pd-1) play important roles in immune homeostasis and selftolerance, acting to suppress t-cell function. ctla-4 signaling reduces t-cell proliferation early in the immune response, and pd-1 signaling inhibits activated table 3. management recommendations for key toxicities of mtor inhibitors toxicity management recommendations stomatitis one of the most common traes, presenting with an aphthous stomatitis different from cytotoxic induced mucositis[35,36]. grade 1: modified diet and alcohol-free mouthwash may alleviate symptoms. grade ≥ 2: treatment should be interrupted and can be restarted at full (grade 2) or reduced (grade 3) dose. grade 4: treatment should be discontinued permanently in most cases. investigation to rule out herpes and fungal infection may be helpful[37]. skin rash usually papulopustular/maculopapular, can be pruritic. avoid heavy sun exposure. grade 1 (covering < 10% bsa) and grade 2 (covering > 10% to < 30% bsa) toxicity can be managed with topical moisturizers and steroids. grade 3 toxicity (covering > 30% bsa) may require dose interruption and treatment with low-dose systemic steroids (eg, 10–20 mg prednisolone). noninfectious pneumonitis characterized by noninfectious, nonmalignant pulmonary inflammatory infiltrates[21,38]. if preexisting pulmonal morbidity, consider baseline luft. grade 1 (radiological findings only): clinical follow-up sufficient. grade 2 (cough, sob, no oxygen requirement): workup for other causes of symptoms including chest imaging. grade 3 (interference with adl or oxygen requirement): interrupt treatment and start steroids (prednisolone 0.75–1 mg/kg). treatment can be restarted with a reduced dose. grade 4 (life-threatening pneumonitis): start treatment with intravenous steroids (eg, methylprednisolone 2–5 mg/kg). discontinue treatment permanently. workup including bal is recommended. endocrine: hyperglycemia hyperlipidemia hypophosphatemia common, educate patients regarding symptoms of hyperglycemia, measure and correct according to standard guidelines[39–41]. grade 2 and 3 hyperglycemia (glucose > 8.9 mmol/l): treat according to guidelines, focus on avoiding symptomatic hyperand hypoglycemia. infections increased risk (candidiasis, pneumonia, invasive fungal infections, and infection reactivation). if high risk, hepatitis and hiv serology and prior tb exposure should be checked and active infection treated. adls: activities of daily living; bal: bronchoalveolar lavage; bsa: body surface area; luft: lung function test; mtor: mammalian target of rapamycin; sob: shortness of breath; traes: treatment-related adverse events. 488siuj.org siuj • volume 3, number 6 • november 2022 management of toxicity and side effects of systemic therapy for renal cell carcinoma http://siuj.org t cells in peripheral tissues[42]. while inhibiting these pathways enables the immune system to recognize and attack the patient’s cancer, inf lammation of normal tissues through the production of cytokines, autoreactive t cells, and autoantibodies may occur, resulting in iraes[43,44]. range of immune-related adverse events the spectrum of iraes experienced depends on whether the cpi is used in combination or alone and according to the malignancy being treated, alongside yet poorly understood host factors such as an individual’s genetics, epigenetics, and microbiome. overall, dermatological, gastrointestinal, endocrinological, musculoskeletal, and pu lmonar y iraes are more common, w it h renal, hematological, ophthalmological, cardiac, and neurological iraes seen more rarely[45,46]. iraes have a variable and wide range of onset, although typically dermatitis and colitis present early, followed by hepatitis and endocrinopathies, with pneumonitis and nephritis presenting later[47,48]. fatal iraes are fortunately rare, with reported rates ranging from 0.36% with anti–pd-1 antibodies to 1.23% in combination with ctla4[49]. given the increasing use of cpis in the treatment of solid cancers in general, and in renal cancer in particular, an absolute increase in iraes and also the occurrence of rare iraes are to be expected in these patients[50]. the frequency and severity of iraes do not appear to be dose-dependent and there is no role for dose reduction following cpi toxicity. immune-related adverse events in rcc landmark clinical trials demonstrate that small percentages of patients experience grade 3 or 4 toxicities, with overall benefits for health-related quality of life[51-53] (table 4). check mate 025 investigated nivolumab versus everolimus as secondor subsequentline treatment in patients with advanced rcc[33], check mate 214 investigated the combination of nivolumab and ipilimumab versus sunitinib in the firstline treatment of patients with advanced rcc[2], and keynote-564 investigated adjuvant pembrolizumab versus placebo following nephrectomy[2]. tr aes leading to discontinuation of cpi occurred in between 8% to 22% of patients in these trials, as outlined in table 4. management of cpi-associated toxicities general principles for management of immunerelated adverse events the management of iraes in patients with rcc is the same as in other solid tumors, and detailed guidelines are available from european society for medical oncolog y (esmo), american society of clinical oncology (asco), society for immunotherapy of cancer (sitc), and the national comprehensive cancer network (nccn)[46,54-56]. the guidelines have been developed based on consensus opinion from specialist physicians and oncologists, are regularly updated, and are strongly recommended to guide management of specific toxicities. the overarching principle of management is to control the inflammation that has precipitated the irae. management is directed by the severity of the irae and typically involves prompt immunosuppression with corticosteroids, treatment interruption, with hospita lization and specia list management in more serious cases. corticosteroids and corticosteroid-sparing agents in immune-related adverse events in general, for ctcae grade 1 iraes, corticosteroids are not required, and immunotherapy may be continued[46]. for grade 2 iraes, oral prednisone (or equivalent) may be considered, starting at 0.5–1 mg/kg daily, increasing to 2 mg/kg daily if required. for grade ≥3 iraes, oral prednisone at 1–2 mg/kg daily, or equivalent intravenous methylprednisolone, is commenced. immunotherapy is paused until the irae has resolved to grade 1 or less and steroids have been weaned, usually over 4 to 6 weeks. in severe or refractory cases, or where steroid sparing is desirable, other immunomodulatory agents may be considered. these agents may have specific immune targets such as tnfα (infliximab), il-6 (tocilizumab), or α4 integrin (vedolizumab), or be nonselective, such as mycophenolate mofetil[57]. in such cases, liaising with specialist physicians is of paramount importance. restarting immunotherapy treatment may be considered on a case-by-case basis after a grade 3 irae, but immunotherapy is discontinued after grade 4 iraes. most iraes are reversible with steroid treatment, but endocrinopathies, especially hypothyroidism and diabetes, may require lifelong hormone replacement, although these rarely require steroid treatment[58,59]. rcc outcomes in patients who experience immune-related adverse events although the development of iraes is not required to benefit from cpi, there are some data, including in rcc, to suggest that patients who experience iraes have better outcomes, particularly with anti–pd-1 and anti– pd-l1 treatment[60-65]. high-dose steroid treatment is not thought to impact outcomes negatively, although there are conf licting reports in the literature, and patients receiving high-dose corticosteroids at baseline do appear to experience inferior outcomes[43,61] immunosuppression with steroids may be associated with side effects including hyperglycemia, weight gain, hypertension, edema, gastritis, anxiety, adrenal insufficiency, osteoporosis, glaucoma, proximal muscle weakness, and opportunistic infections[43]. supportive 489 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org table 4. safety outcomes reported in pivotal registration clinical trials of immune checkpoint inhibitors in renal cell carcinoma nivolumab mrcc, second or later line, checkmate 025, nct01668784 n = 406[33] nivolumab & ipilimumab mrcc, first line, checkmate 214, nct02231749, n = 547[2,52] pembrolizumab adjuvant setting, keynote-564, nct03142334 n = 488[5] trae leading to discontinuation in % 8 22 21 death due to trae— n (%) none 8 (1) 2 (< 1) toxicity in % all grade 3/4 all grade 3/4 all grade 3/4 any 79 19 93 46 79 19 fatigue 33 2 37 4 30 1 pruritis 14 0 28 < 1 23 < 1 nausea 14 < 1 20 1 16 < 1 diarrhea 12 1 27 4 25 2 reduced appetite 12 < 1 14 1 rash 10 < 1 22 1 20 1 cough 9 0 –* – 16 0 dyspnea 7 1 – –* – – pneumonitis 4 1 – –* – – hypothyroidism – – 16 < 1 21 < 1 asthenia – – 13 1 10 < 1 vomiting – – 11 < 1 – – arthralgia – – – – 22 < 1 headache – – – – 14 0 hyperthyroidism – – – – 12 < 1 increased creatinine – – – – 10 < 1 *while cough, dyspnea, and pneumonitis were not reported, in the combination arm of the checkmate 214 study, 1 patient died from pneumonitis, 1 with pneumonia, 1 with immune-mediated bronchitis, and 1 with lung infection. mrcc: metastatic renal cell carcinoma; nr: not reported in paper; trae: treatment-related adverse event. 490siuj.org siuj • volume 3, number 6 • november 2022 management of toxicity and side effects of systemic therapy for renal cell carcinoma http://siuj.org therapies must therefore be considered for all patients on steroids, including gastric protection, calcium and vitamin d, and pneumocystis pneumonia prophylaxis, particularly for patients requiring a longer course. toxicities of combination vegfr tki/cpi regimens regimens that combine a vegfr tki with a cpi have become a standard of care in first-line therapy of advanced rcc due to improved cancer outcomes c omp a re d w it h t k i monot her apy[1,4 , 6 6 , 6 8]. collectively, these regimens are regarded as having acceptable safety profiles with manageable toxicity. given the impressive cancer control conferred by these regimens, patients are often on treatment for many months or years, thus good toxicity management is of great importance for durable good quality of life. spectrum and frequency of toxicities with tki/cpi combination regimens t he reg ist r at ion t r ia ls of approved t k i /cpi combinations have repor ted a variet y of safet y endpoints and toxicities, each compared with sunitinib monotherapy. although there are differences across both the trial populations and the toxicity measures reported, the data illustrate the acceptable tolerability of each of the regimens in trial populations (table 5). the rate of of grade ≥3 traes reported with the tki/ cpi combinations in registration studies was 57% to 72% (compared with 51% to 59% for the comparator sunitinib in these trials). across all trials, the most frequently occurring traes were consistently hypertension, raised transaminases, and diarrhea. discontinuation of at least one of the agents due to traes occurred in 15% to 37% of patients and discontinuation of both in 3% to 13%. management of toxicities associated with tki/cpi combination regimens optimal management of the toxicities from tki/cpi combination regimens requires appreciation of the expected range of side effects of each agent. however, there is additional complexity because some toxicities may be caused by both tkis and cpis. this requires an approach for identifying the more likely cause. the common and serious toxicities resulting from vegfr tkis and cpis are described above. toxicity caused by vegfr tkis most commonly manifests in the first few weeks following treatment initiation, whereas toxicities caused by immune cpis can start acutely or many months into treatment. however, there is considerable variation at the individual patient level, and the toxicity profiles do overlap considerably, therefore despite best efforts, reliable attribution can be challenging. points to consider include: 1. vegfr tkis have considerably shorter half-lives than cpis. axitinib has the shortest half-life at 2.5–6 hours, those of lenvatinib and cabozantinib are 28 hours and 100–120 hours, respectively. the half-lives of both pembrolizumab and nivolumab are around 26 days. thus, vegfr tki–driven toxicity, especially from axitinib, typically starts to improve within a few days of treatment interruption, including when used in an axitinib plus cpi combination[69]. 2. in some cases, directed investigation may help to differentiate the cause, assess impact and severity, and guide management such as sigmoidoscopy and biopsy for evaluation of colitis; assessment of the pituitary fossa by magnetic resonance imaging (mri) for hypophysitis; and cardiac mri to identify immune-mediated myocarditis. toxicities should be managed in accordance with the strategies described earlier in this article, including treatment interruption, dose reduction (for tkis but not cpis), and treatment discontinuation when indicated. as a general principle, grade 1 and 2 toxicities may not require any intervention other than supportive therapies and monitoring. grade 3 and higher toxicities usually require at least temporary treatment interruption. when treatment interruption of a tki/cpi regimen is required and there is uncertainty about the cause, the following pragmatic approach is suggested: • first stop the tki. improvement in toxicity should be seen within a few days if the toxicity is tki related. • if there is no improvement after 5 to 7 days, or less for axitinib, interruption of the cpi and initiation of steroids should be considered following a recognized irae guideline. • consider immediate interruption of both agents for severe, clinically significant toxicities. • continue to use appropriate supportive measures according to the toxicity. • ongoing regular assessment is required until improvement or resolution with vigilance for reemergence during steroid wean or following further treatment. toxicities of novel therapeutic approaches ongoing clinical trials are investigating new agents and combinations that will require attention to their tolerability and emergent toxicities. cosmic-313 (nct03937219) is a fully recruited, randomized trial assessing the triplet combination of cabozantinib plus ipilimumab and nivolumab in 840 patients with intermediateand poor-risk advanced rcc[70]. while there should be scrutiny of the tolerability of this triplet regimen, it has been successfully delivered in 491 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org a pan-genitourinary phase 1b trial with acceptable tolerability[71]. the hy poxia-inducible factor (hif)-2α inhibitor belzutifan was approved by the fda in 2021 for the treatment of von hippel-lindau (vhl)-associated metastatic renal cell carcinoma (mrcc)[72], and its role in sporadic mrcc is being evaluated in a phase 3 trial after promising initial results (nct04195750)[73]. belzutifan is relatively well tolerated, although grade ≥ 3 aes were reported in 25% of patients and included grade ≥ 3 anemia (related to inhibition of the erythropoietin gene) a nd hy pox ia , t hu s mon itor i ng for a nd management of these toxicities is essential[72] including blood transfusion and/or the use of erythropoietinstimulating agents[74]. patient selection and toxicity prediction good patient selection is an important tool in ensuring the optima l ba lance of eff icacy with acceptable toxicity and quality of life. the toxicities associated with treatment of rcc are not insignificant, leading to discontinuation of vegfr tki therapy in 12% to 24%[75,76], combination nivolumab plus ipilimumab in 22%[2,52], and tki/cpi combinations in 6% to11%[1,4,66,68]. therefore, understanding predictors of toxicity is an important focus of research. most research in this field to date has evaluated clinical and genomic predictors of toxicity to vegfr tki therapy with low body surface area, older age, and female gender identified as possible clinical predictors[77]. several studies have focused on the role of singlenucleotide polymorphisms (snps) in genes related to pharmacodynamic properties of vegfr tkis[78–80]. while research has not yet yielded practice-influencing results, it is hoped that large collaborative projects such as the eurotarget cohort[81], incorporating analysis of genomic, transcriptomic, and clinical parameters, will produce clinically useful information. currently, there are no defined biomarkers that predict toxicity to immune cpis, although it is apparent that some patients are at greater risk of experiencing iraes[45,49]. historically, patients thought to be at higher risk for iraes have been excluded from clinical trials, so data are lacking, but as real-world experience grows, multidisciplinary strategies for managing such patients are evolving. patients with chronic viral infections such as hepatitis and hiv, mild-to-moderate organ dysfunction, autoimmune disease, and even transplant recipients have been successfully treated with cpis in some circumstances, although a personalized discussion regarding potential risks and benefits is important[60]. there is growing interest in the role of the gut microbiome in modulating both the efficacy and toxicity of cpi therapy. in patients with advanced melanoma who received ipilimumab plus nivolumab, enrichment with bacteroides intestinalis and intestinibacter bartlettii was seen in patients who developed grade ≥3 adverse events versus those who did not[82]. investigation of this field continues, including in mrcc. in the future, as doublet, and potentially triplet, combination regimens are increasingly used, effective strategies to manage toxicity will be needed to transfer clinical trial regimens to more diverse real-world patient populations. genomic approaches may offer the possibility of refining treatment selection for patients according to expected toxicity profiles. however, at present, there are no robust or validated genomic predictors, therefore selection is reliant on traditional measures of performance status and comorbidities. summary toxicity management is an essential component of effective cancer control. in the past 15 years, considerable experience has been gained in the management of the side effects of molecularly targeted therapies, with strategies including dose modification, schedule modification, switching between agents, and use of supportive therapies. immune checkpoint inhibitors are also now used widely in treatment of mrcc. this advance has necessitated rcc oncologists to develop an understanding of a new range of toxicities and become familiar with new strategies and algorithms that have evolved to manage iraes, including use of corticosteroids and steroid-sparing agents, as well as increasing involvement of other organor systemspecific specialists. combination regimens of cpis and vegfr tkis are now increasingly used, but careful management can balance treatment delivery with tolerable side effects. it is hoped that ongoing research will identify robust means of prospectively identifying those at increased risk for treatment-related toxicities to allow for improved therapy selection at an individual level. 492siuj.org siuj • volume 3, number 6 • november 2022 management of toxicity and side effects of systemic therapy for renal cell carcinoma http://siuj.org table 5. safety outcomes reported in pivotal clinical trials for the combinations of tyrosine kinase inhibitors and immune checkpoint inhibitors in first line metastatic renal cell carcinoma and occurred in at least 15% of patients who received the vegfr tki / cpi combination axitinib + pembrolizumab first line, keynote-426, nct02853331, n = 429[4] axitinib + avelumab first line, javelin renal-101, nct02684006, n = 442[67] cabozantinib + nivolumab first line, checkmate 9er, nct03141177 n = 322[1] lenvatinib + pembrolizumab first line, clear, nct02811861 n = 355[3] treatment discontinuation for trae in % both drugs either 8 26 8 nr 3 15 13 37 treatment-related deaths— n (%) 4 (< 1) 3 (< 1) 1 (< 1) 4 (1) toxicity in % all grades grade 3/4 all grades grade 3/4 all grades grade 3/4 all grades grade 3/4 any 96 63 100 71 100 61 100 82 diarrhea 54 9 62 7 64 7 61 10 hypertension 45 22 50 26 35 13 55 30 fatigue 39 3 42 4 32 3 40 4 hypothyroidism 35 < 1 25 < 1 34 < 1 47 1 decreased appetite 30 3 26 2 28 2 40 4 hand–foot syndrome 28 5 33 6 40 8 29 4 nausea 29 1 34 1 27 1 36 3 alt increased 27 13 17 6 28 5 12 4 ast increased 26 7 15 4 25 3 11 3 dysphonia 25 < 1 31 1 17 < 1 30 0 cough 21 < 1 23 < 1 17 0 20 0 constipation 20 0 18 0 12 1 25 1 arthralgia 18 1 20 1 18 < 1 28 1 weight decreased 18 3 20 3 11 1 30 8 proteinuria 18 3 – – 10 3 30 8 dyspnea 16 2 20 3 – – 15 3 table 5 shows the safety outcomes that were reported in the referenced pivotal trials and occurred in at least 15% of patients who received the vegfr tki / cpi combination. alt: alanine transaminase; ast: aspartate transaminase; cpi: immune checkpoint inhibitor; trae: treatment-related adverse event; vegfr tki: vascular endothelial growth factor receptor tyrosine kinase inhibitor. continued on page 494 493 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org table 5. safety outcomes reported in pivotal clinical trials for the combinations of tyrosine kinase inhibitors and immune checkpoint inhibitors in first line metastatic renal cell carcinoma and occurred in at least 15% of patients who received the vegfr tki / cpi combination axitinib + pembrolizumab first line, keynote-426, nct02853331, n = 429[4] axitinib + avelumab first line, javelin renal-101, nct02684006, n = 442[67] cabozantinib + nivolumab first line, checkmate 9er, nct03141177 n = 322[1] lenvatinib + pembrolizumab first line, clear, nct02811861 n = 355[3] treatment discontinuation for trae in % both drugs either 8 26 8 nr 3 15 13 37 treatment-related deaths— n (%) 4 (< 1) 3 (< 1) 1 (< 1) 4 (1) toxicity in % all grades grade 3/4 all grades grade 3/4 all grades grade 3/4 all grades grade 3/4 stomatitis 16 1 24 2 17 3 35 2 headache 16 1 21 < 1 16 0 23 1 vomiting 15 < 1 18 1 17 2 26 3 asthenia 15 3 15 3 22 < 1 22 5 pruritis 15 < 1 14 0 19 < 1 17 < 1 rash 14 < 1 14 1 22 2 27 4 back pain 13 1 18 1 18 2 17 1 mucosal inflammation 13 1 14 1 21 1 – – pyrexia 13 0 13 0 12 1 15 1 abdominal pain 11 1 14 1 16 2 2 2 dysgeusia 11 < 1 13 0 24 0 12 < 1 increased lipase – – – – 17 6 18 13 hyponatremia – – – – 16 9 – – increased amylase – – – – 15 3 18 9 table 5 shows the safety outcomes that were reported in the referenced pivotal trials and occurred in at least 15% of patients who received the vegfr tki / cpi combination. alt: alanine transaminase; ast: 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immunother cancer.2019 apr 3;7(1):99. doi: 10.1186/ s40425-019-0579-z 67. martini dj, hamieh l, mckay rr, harshman lc, brandao r, norton ck, et al. durable clinical benefit in metastatic renal cell carcinoma patients who discontinue pd-1/pd-l1 therapy for immune-related adverse events. cancer immunol res.2018 apr 1;6(4):402–408. doi: 10.1158/2326-6066.cir-17-0220 68. motzer r, alekseev b, rha sy, porta c, eto m, powles t, et al. lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. n engl j med.2021 apr 8;384(14):1289–1300. 69. choueiri tk, motzer rj, rini bi, et al. updated efficacy results from the javelin renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. ann oncol.2020;31(8):1030-1039. doi:10.1016/j.annonc.2020.04.010 70. motzer rj, penkov k, haanen j, rini b, albiges l, campbell mt, et al. avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. n engl j med.2019 mar 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25;385(22):2036–2046. 75. choueiri tk, bauer tm, papadopoulos kp, plimack er, merchan jr, mcdermott df, et al. inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis. nat med.2021 may 1;27(5):802–805. 76. aapro m, beguin y, bokemeyer c, dicato m, gascón p, glaspy j, et al. management of anaemia and iron deficiency in patients with cancer: esmo clinical practice guidelines. ann oncol.2018;29(suppl 4):iv96-iv110. doi: 10.1093/annonc/mdx758 497 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org 77. motzer rj, hutson te, cella d, reeves j, hawkins r, guo j, et al. pazopanib versus sunitinib in metastatic renal-cell carcinoma. n engl j med.2013 aug 22;369(8):722–731. 78. choueiri tk, hessel c, halabi s, sanford b, michaelson md, hahn o, et al. cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (alliance a031203 cabosun randomised trial): progression-free survival by independent review and overall survival update. eur j cancer.2018 may 1;94:115–125. 79. van der veldt aam, boven e, helgason hh, van wouwe m, berkhof j, de gast g, et al. predictive factors for severe toxicity of sunitinib in unselected patients with advanced renal cell cancer. br j cancer.2008 jul 22;99(2):259–265. 80. diekstra mhm, swen jj, boven e, castellano d, gelderblom h, mathijssen rhj, et al. cyp3a5 and abcb1 polymorphisms as predictors for sunitinib outcome in metastatic renal cell carcinoma. eur urol.2015 oct 1;68(4):621–629. 81. de velasco g, gray kp, hamieh l, urun y, carol ha, fay ap, et al. pharmacogenomic markers of targeted therapy toxicity in patients with metastatic renal cell carcinoma. eur urol focus.2016 dec 15;2(6):633–639. 82. diekstra mh, belaustegui a, swen jj, boven e, castellano d, gelderblom h, et al. sunitinib-induced hypertension in cyp3a4 rs4646437 a-allele carriers with metastatic renal cell carcinoma. pharmacogenomics.2017 jan 1;17(1):42–46. doi: 10.1038/tpj.2015.100 83. van der zanden lfm, vermeulen sh, oskarsdottir a, maurits jsf, diekstra mhm, ambert v, et al. description of the eurotarget cohort: a european collaborative project on targeted therapy in renal cell cancer—geneticand tumor-related biomarkers for response and toxicity. urol oncol.2017 aug 1;35(8):529.e9-529.e16. 84. andrews mc, duong cpm, gopalakrishnan v, iebba v, chen ws, derosa l, et al. gut microbiota signatures are associated with toxicity to combined ctla-4 and pd-1 blockade. nat med.2021 aug 1;27(8):1432–1441. orcid ids kate young: 0000-0002-9500-2046, andreas m. schmitt: 0000-0002-9568-8164 deborah mukherji: 0000-0002-0192-5828 manuela schmidinger: 0000-0002-2567-2749 lisa m. pickering: 0000-0002-7579 -340x 498siuj.org siuj • volume 3, number 6 • november 2022 management of toxicity and side effects of systemic therapy for renal cell carcinoma https://orcid.org/0000-0002-9500-2046 http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj.org siuj • volume 4, number 4 • july 2023 key words competing interests article information ureterocele, pregnancy, prolapse none declared. patient consent: obtained. received on october 25, 2022 accepted on october 29, 2022 this article has been peer reviewed. soc int urol j. 2023;4(4):345–346 doi: 10.48083/ckyn3688 345 clinical picture a diagnostic dilemma identifies a rare case of a prolapsed ureterocele in pregnancy james kovacic,1 ankur dhar,1 andrew r.h. shepherd,2 amanda chung1 1 royal north shore hospital, department of urology, st leonards, australia 2 the university of adelaide school of medicine, adelaide, australia a 37-year-old woman at 30 weeks’ gestation presented to the emergency department by ambulance because of vaginal bleeding, urinary retention, mild left flank pain, and a tender mass that had developed at her vaginal introitus that day. she had a significant background of a left-sided 3 cm ureterocele diagnosed on prenatal imaging, but was otherwise medically well. examination identified a large, tender, blue-tinged cystic mass protruding from the vaginal introitus (figure 1), which was initially thought to represent amniotic membranes. obstetric review was undertaken; however, on speculum examination, the cervix remained closed with no evidence of vaginal bleeding. an indwelling catheter was inserted because of urinary retention with persistence of urine soaking her pad following insertion, despite appropriate placement. blood tests demonstrated normal biochemistry and inflammatory markers. urine microscopy and culture was negative for micro-organisms. following discussion with the urology service, provisional diagnosis of a prolapsed ureterocele was made, and endoscopic management was decided, given symptomatic retention. the patient was provided a spinal anaesthetic and placed into lithotomy and lateral wedge position. flexible cystoscopy was performed before and after reduction of the mass to ascertain anatomical features (figure 2). on manual reduction of the mass and rigid cystoscopy, a large cystic structure was protruding from the expected site of the left ureteric orifice, consistent with an inflamed ureterocele. endoscopic resection of the ureterocele was undertaken to reveal a single open ureteric orifice. histopathology identified the expected result of a ureterocele. postoperatively, the patient was monitored overnight prior to discharge home the following day, with outpatient urology follow-up planned. acknowledgements case presented in affiliation with the division of surgery and anaesthesia, department of urology, royal north shore hospital. with thanks to the royal north shore hospital staff involved with this case. disclosure statement dr amanda chung is a proctor for boston scientific and medtronic. http://siuj.org mailto:james.kovacic%40health.nsw.gov.au?subject=siuj figure 1. prolapsed ureterocele at vaginal introitus figure 2. flexible cystoscopy with retroflexed view of ureterocele 346 siuj • volume 4, number 4 • july 2023 siuj.org clinical picture http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj.org siuj • volume 4, number 4 • july 2023 key words competing interests article information orchidectomy, testis, testicular torsion, rural health none declared. received on december 20, 2022 accepted on february 19, 2023 this article has been peer reviewed. soc int urol j. 2023;4(4):257–264 doi: 10.48083/ wkfe4169 257 original research testicular torsion: an analysis of rural geography and socioeconomic status kevin tree,1,2 benjamin charles buckland,2,3 roy huynh,1,4 sris baskaranathan,1 dean fisher,1 balasubramaniam indrajit1,4 1 department of surgery, dubbo base hospital, new south wales, australia 2 university of newcastle, new south wales, australia 3 central coast local health district, new south wales, australia 4 university of sydney, new south wales, australia abstract objectives testicular torsion is a time-critical, organ-threatening diagnosis requiring prompt surgical intervention for successful salvage of the organ. in australia, 28% of individuals live in rural and remote areas and face barriers to health care such as greater distance, lower socioeconomic status, (ses), and limited health infrastructure. we hypothesize that these barriers would delay intervention and access to surgical care, and lead to higher orchidectomy rates. objectives a 12-year retrospective audit was conducted at a large rural referral center in australia, focusing on patients undergoing scrotal exploration for testicular torsion. primary outcomes were orchidectomy rate, time to operation, and ultrasound (us) and their relationship with patient distance, ses, age, and peripheral hospital attendance. data on ses for geographic postcodes was obtained from the australian government socio-economic indexes for areas 2016. statistical analysis was performed using ibm spss statistics software, and a p value < 0.05 was considered significant. results the study involved 107 patients, of whom 46% had left-sided pathology. the median age of the patients was 14 years. median ses was in the 37% to 41% centile range, median distance from travelled was 62 kilometers, and median time to operation from triage was 194 minutes. of the patients, 34 attended a peripheral hospital. no significant risk factors for orchidectomy were identified. us was used in 65% of cases, with torsion detected in 50% of those cases, and orchidectomy performed in 11 patients. us had a sensitivity of 86.1% and specificity of 52.9%. conclusion despite significant differences in geographical distance, ses, age, and access to health care, patients in rural and remote areas of australia experienced equivalent outcomes in testicular torsion management. testicular torsion was safely managed at a central referral center using a peripheral hospital catchment in rural and remote areas of australia, despite significant time delays due to greater distance or lower ses. introduction testicular torsion is a medical emergency, requiring prompt surgical intervention within 6 hours to salvage the affected organ[1]. international guidelines such as those from the european association of urology (eau) and british association of urological surgeons (baus) endorse urgent scrotal exploration as the mainstay of treatment[2,3]. in australia, 7 million people (28% of the population) live in rural and remote areas, with higher health morbidity and mortality due to poor access and use of primary health care services compared with metropolitan areas[4]. socioeconomic status (ses) plays a crucial role in determining health outcomes, and rural geography is a risk factor for low ses[5–7]. http://siuj.org mailto:kevintree0%40gmail.com?subject=siuj https://orcid.org/0000-0002-0354-0024 https://orcid.org/0000-0001-7125-6423 statistical analysis ibm spss statistics version 28[12] and microsoft excel were used for statistical analysis. the shapiro-wilk test was performed, along with data histogram, to determine normality. independent t tests + chi-square tests were performed to compare baseline characteristics with normal distribution, and the non-parametric mannwhitney test was performed if the data distribution was not normal. univariate regression and bivariate pearson correlation were performed to compare outcomes of subgroups for dichotomous and continuous data, respectively. multivariate regression was performed when significant results were found in the univariate regression to correct for potentia l confounding variables. a p value of < 0.05 was considered statistically significant. results patient characteristics during the study period, 145 patients were identified, but only 107 were included in the analysis due to 38 patients having incomplete data or meeting the exclusion criteria. the most common reason for exclusion was cryptorchidism. median age was 14 years, with 46% presenting with left-side symptoms (table 1). all patients were from rural areas under the modified monash model mm3-7. torsion was present in 50% of cases, with left-sided torsion observed in 49%. orchidectomy was performed in 12 patients, with median age of 13.5 years, and 83% of the cases were left sided. the degree of torsion was documented in 18 patients, and all 3 patients who underwent orchidectomy had rotation greater than 360 degrees. of the 54 patients without torsion, 12 (22.2%) patients had torsion of the appendix testis and 10 (18.5%) had epididymitis. no cases of repeat scrotal exploration were identified. the median time to operation was 194 minutes from triage, but it was significantly longer (335 minutes) in patients who attended a peripheral health service. upon arrival to emergency department of the operating hospital, median time between decision to operate and the actual operation was 32 minutes (interquartile range [iqr], 35 minutes). in patients with testicular torsion, no significant association was found between time from triage to operation and orchidectomy rate (odds ratio table 1. baseline characteristics all patients peripheral hospital attendance non-peripheral hospital attendance p value patients 107 34 73 age, years, median (iqr) 14 (8) 13.5 (9) 14 (9) 0.237 side of pathology left, n (%) 49 (46) 21 (62) 28 (38) 0.024 right, n (%) 58 (54) 13 (38) 45 (62) side in torsion 53 20 33 left, n (%) 26 (49) 13 (65) 13 (39) 0.071 right, n (%) 27 (51) 7 (35) 20 (61) distance, km, median (iqr) 62 (60) 122 (121) 11 (74) < 0.001 ses irsd, percentile, median (iqr) 39 (27) 17 (32) 40 (11) < 0.001 irsad, percentile, median (iqr) 37 (18) 22 (29) 38 (10) < 0.001 ier, percentile, median (iqr) 38 (14) 29 (9) 38 (3) <0.001 ieo, percentile, median (iqr) 41 (21) 21 (39.25) 41 (10.5) 0.044 time to surgery from triage, minutes, median (iqr) 194 (220.5) 335 (191.25) 194 (223) <0.001 ultrasound performed, n (%) 70 (65) 23 (68) 47 (64) 0.741 torsion present, n (%) 53 (50) 20 (59) 33 (45) 0.19 orchidectomy, n (%) 12 (11) 3 (9) 9 (12) 0.593 ieo: index of education and occupation; ier: index of economic resources; iqr: interquartile range; irsad: index of relative socio-economic advantage and disadvantage; irsd: index of relative socio-economic disadvantage; km: kilometers; ses socioeconomic status. the royal australasian college of surgeons (racs) position statement on acute scrotal pain endorses the accreditation of general surgeons, pediatric surgeons, and urologists to manage and operate on suspected testicular torsion without transferring the patient[8]. however, rural and remote communities often lack adequate infrastructure or available surgeons, which can necessitate patient transfer and lead to potential delays to surgery and thus reduction in organ viability. the aim of this study was to examine the management of testicular torsion in rural areas and its relationship to distance, ses, or peripheral hospital attendance. secondary outcomes included access to sonography and diagnostic accuracy in testicular torsion. we hypothesize that delays in surgical intervention due to increased distance from rural areas, hospital transfers, and reduced access to health care infrastructure would result in higher orchidectomy rates. method a retrospective audit was performed at dubbo base hospital, a large rural referral center in new south wales, australia, from october 2010 to february 2022. the hospital has a 24-hour on-call surgical service, access to operating theaters and anesthesia, and 24hour on-call availability of ultrasonography and sonographers. electronic medical records from the cerner application were used to identify patients of all ages who underwent scrotal exploration as a theater event. baseline demographic information, residential postcode, time from triage to operation, age, laterality, ultrasonography usage, diagnosis at operation, and operative details were recorded. patients with cryptorchidism, malignancy, and neonatal patients were excluded from the study. socioeconomic status socioeconomic status (ses) data was obtained from the publicly available australian bureau of statistics: socio-economic indexes for areas 2016 (seifa)[9]. abbreviations ieo index of education and occupation ier index of economic resources iqr interquartile range irsad index of relative socio-economic advantage and disadvantage irsd index of relative socio-economic disadvantage seifa socio-economic indexes for areas ses socioeconomic status us ultrasound four categories of ses were assessed: index of relative socio-economic disadvantage (irsd), index of relative socio-economic advantage and disadvantage (irsad), index of education and occupation (ieo), and index of economic resources (ier). seifa 2016 ranks postcodes according to variables of both advantage and disadvantage including income, education, employment, housing, disability, and access to infrastructure. postcodes are assigned a national centile, with 1 indicating the lowest ses and 100 indicating the highest. peripheral hospital attendance and distance the distance from the treating hospital was determined using google maps, considering road travel distance as all inter-hospital transfers were conducted by road transport. the distance was calculated from the center of the patient’s residential postcode to represent the patient’s local environmental resource and access to infrastructure[10]. dubbo base hospital serves as a catchment for over 20 multipurpose health services or peripheral hospitals, all located outside the dubbo base hospital’s postcode. peripheral hospitals did not have access to us but had a registered nurse or doctor available for clinical assessment. they also lacked an operating theater or surgeon. the time to operation was calculated from time of the first triage at the attending health center within the catchment to the start of operation. rural geographical classification was determined using the australian government modified monash model[11], which categorizes based on geographic remoteness and town size from mm1 (highest) to mm7 (lowest). primary outcome primary outcome was to determine the association between socioeconomic status, road distance, or peripheral hospital attendance and orchidectomy rate. patients with intraoperative findings of testicular torsion were considered true positive. orchidectomy was performed when intraoperative assessment deemed the testicle non-viable despite re-assessment after de-torsion and a minimum 15 minutes of warming. orchidopexy was performed for viable testes according to the burstbaus consensus guideline[2]. secondary outcome secondar y outcomes included an assessment of ultrasonography usage and its sensitivity, specificity, positive predictive value, negative predictive value, and accuracy in a rural setting. ultrasonography was performed with color doppler, and a positive finding was considered low or absent blood flow, with suspicious findings considered positive. furthermore, an assessment was performed to determine whether ses, distance, or peripheral hospital attendance influenced use of ultrasonography. 259258 siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org original research testicular torsion: an analysis of rural geography and socioeconomic status http://siuj.org http://siuj.org patients who underwent orchidectomy, 9 patients had preoperative ultrasonography, which correctly diagnosed the testicular torsion in all cases. patients who underwent ultrasonography had significantly longer time to operation (349 minutes; standard deviation [sd], 348.8 minutes) compared to those without ultrasonography (176 minutes; sd, 131.5 minutes; p = 0.005), but there was no significant difference in the orchidectomy rate (p = 0.464). discussion in australia from 2020 to 2021, 1830 scrotal explorations were performed, as reported by the australian institute of health and welfare[13], an incidence of 1 per 50 000 in a population of 25.74 million in 2021. australia has a population density of 3.3 people per square kilometer[14], primarily due to population sparsity in rural and remote areas, where 7 million (28%) of australians live. the combination of geographic isolation and a rare pathology exacerbate the timecritical challenge of managing testicular torsion. the limited accessibility to healthcare infrastructure due to geographic distance acts as a major obstacle to achieving positive outcomes. testicular torsion is a medical emergency that necessitates prompt surgical intervention, with the duration of symptoms being the primary predictor in the success of salvage procedures[15]. we hypothesized that barriers to healthcare such as geographical distance, peripheral hospital attendance, and low ses could delay intervention and increase orchidectomy rates. prompt surgical intervention plays a crucial role in reducing morbidity and mortality in emergency surgery[16], with patients residing in rural areas showing an association with equivocal or worse outcomes[17], particularly among transferred patients. geographical remoteness is significantly correlated with lower ses, and ses itself is associated with worse outcomes in emergency surgery even when corrected for remoteness[18], suggesting that ses is the predominant risk factor for morbidity. in australia, some patients who reside in rural or remote communities will elect to have surgical care closer to their homes despite being informed about the higher risks for morbidity and mortality[19]. as a result, the core curriculum for both urology and general surgery trainees in australia includes the competence to assess and perform scrotal explorations for testicular torsion at a patient’s initial presentation, regardless of their geographical location, without the need for transfer[8]. limited literature exists on the impact of geographical location on testicular torsion outcomes from a distance and ses perspective, and the study findings are heterogeneous. a national study in korea comparing metropolitan and rural provinces demonstrated no significant difference in incidence or orchidectomy rates based on geographic region or ses[20]. the authors choi et al. hypothesized that this is due to the ease of accessibility of public healthcare services in a relatively small country of 100 210 square kilometers. however, this contrasts the findings of the current study, conducted at a rural referral center with a catchment of 250 000 square kilometers. a study in the united states conducted by overholt et al.[21] demonstrated higher orchidectomy rates in patients who required transfer from peripheral health services, but did not find a significant correlation with distance or time delay. the authors acknowledged their study’s small sample size at only 23 patients, rendering the study underpowered and the findings nonsignificant. in contrast, our study, with a larger sample size (n = 107) and despite having patients who were geographically more distant (median 62 km vs. mean 38.3 km), did not find a significantly increased orchidectomy rate despite significantly longer time to operation. the australian health care system, publicly funded by medicare, relies on healthcare networks in rural areas, involving a catchment of multipurpose health services connected to a large rural referral hospital. this system ensures access to a 24-hour virtual doctor service at peripheral sites and facilitates inter-hospital transfers to a rural referral hospital where a surgeon is available on call 24 hours a day. this timely access to clinical assessment allows for prompt review and escalation, thereby alleviating disparities in rural and remote health care, in both surgical and medical care, to ensure patients from lower socioeconomic backgrounds receive optimal care. these initiatives by the australian government are part of the stronger rural health strategy[22], which aims to offset disadvantages related to access to and delivery of health care in rural and remote areas. this may explain why significant findings were found only in the ses category of irsd, which measures variables related only to disadvantage, while irsad, ieo, and ier, which measure variables of advantage, such as higher education level, higher income brackets, and certain occupations, could mitigate or compensate for disadvantage. ultrasonography has seen increasing use for the assessment of possible testicular torsion, despite guideline recommendations that testicular torsion is a clinical diagnosis[8]. the diagnostic ability of sonography for testicular torsion in adults has shown a sensitivity of 86% and specificity 95%[23]. these results are aligned with our study findings, with a similar sensitivity but a much lower specificity. the low specificity could be due to a high false-positive rate, as “suspicious” findings were coded as positive, leading to scrotal exploration in all cases. there are numerous decision-making tools available, such as the twist score in all ages[24,25], reporting a high sensitivity of 98.4% to 100% in low-risk patients and safely ruling out testicular torsion prior to [or], 0.999; p  =  0.584). age was not associated with increased orchidectomy rate, ultrasound use, or time to operation (table 2). peripheral hospital attendance and distance of the total patients, 34 (31.8%) attended a peripheral hospital, with median age of 13.5 years. the majority of these patients (62%) had left-sided pathology, in contrast to those with non-peripheral hospital attendance, with 62% exhibiting right-sided pathology. however, no significant difference in laterality was identified (p  =  0.071) in patients with diagnosis of torsion. the median distance from hospital was 122 kilometers (km) for patients attending a peripheral hospital, which was significantly further than that for non-peripheral hospital patients. additionally, the time to operation was significantly longer for peripheral hospital attendees, at 335 minutes, compared to non-peripheral hospital attendees, at 194 minutes. there was no significant difference in torsion rate (59%) and orchidectomy rate (9%) between these 2 patient groups (p = 0.19 and p  =  0.593, respectively). increased distance from the hospital was not a significant risk factor for orchidectomy or ultrasonography use (table 2). similarly, peripheral hospital attendance was also not a significant risk factor for orchidectomy or ultrasonography use (table 2). however, increased distance was significantly associated with increased time to operation (p < 0.001). socioeconomic status the median irsd was 39, irsad was 37, ieo was 38, and ieo was 41, with all patients falling within the lower 50% of australia’s national ses bracket. patients table 2. regression analysis for risk factors orchidectomy ultrasound use time to operation or 95% ci p value or 95% ci p value pearson correlation coefficient 95% ci p value distance 1.001 0.996–1.006 0.665 1.001 0.997–1.004 0.671 0.474 0.313–0.609 < 0.001 age 1.008 0.95–1.07 0.787 1.022 0.977–1.067 0.341 0.033 -0.157–0.222 0.732 irsd 0.994 0.955–1.033 0.748 0.991 0.964–1.018 0.5 -0.199 0.374–0.009 0.040 irsad 0.996 0.953–1.04 0.853 0.989 0.96–1.019 0.483 -0.169 -0.347–0.022 0.082 ier 1.006 0.971–1.043 0.743 0.993 0.97–1.017 0.584 -0.178 -0.356–0.012 0.067 ieo 1.012 0.957–1.07 0.676 0.981 0.944–1.019 0.32 -0.065 -0.251–0.127 0.508 peripheral hospital attendance 0.688 0.174–2.722 0.594 1.157 0.488–2.743 0.741 1.004 1.001–1.006 0.002 ci: confidence interval; ieo: index of education and occupation; ier: index of economic resources; irsad: index of relative socio-economic advantage and disadvantage; irsd: index of relative socio-economic disadvantage; or: odds ratio. table 3. ultrasonography diagnosis sensitivity 86.1% specificity 52.9% positive predictive value 66% negative predictive value 78.3% accuracy 70% who attended peripheral hospitals had a significantly lower median irsd, irsad, ier, and ieo compared to those who presented directly—(irsd 17 vs. 40, respectively), irsad (22 vs. 38, respectively), ier (29 vs. 38, respectively), and ieo (21 vs. 41, respectively). of those patients who presented directly, 46 lived in the same suburb as the operating hospital. no significant association was identified between the 4 ses categories and orchidectomy rate or ultrasound use. irsd, a measure of only ses disadvantage, correlated with increased time to operation (p = 0.04); however, irsad, ier, and ieo did not show a significant correlation. ultrasonography u ltrasound was per formed in 65% of pat ients preoperatively, with a sensitivity of 86.1%, specificity of 52.9%, positive predictive value of 66%, negative predictive value of 78.3%, and accuracy 70% (table 3). five patients had false-negative ultrasound results, and 16 patients had false-positive results. of the 12 261260 siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org original research testicular torsion: an analysis of rural geography and socioeconomic status http://siuj.org http://siuj.org references 1. mellick lb, sinex je, gibson rw, mears k. a systematic review of testicle sur vival time af ter a torsion event. pediatr emerg care.2019;35(12):821–825. doi: 10.1097/pec.0000000000001287. pmid: 28953100 2. clement kd, light a, asif a, chan vw, khadhouri s, shah tt, et al.; fix-it collaborators. a burst-baus consensus document for best practice in the conduct of scrotal exploration for suspected testicular torsion: the finding consensus for orchidopexy in torsion (fix-it) study. bju int.2022;130(5):662–670. 3. radmayr c, bogaert g, dogan h, kocvara r, nijman j, stein r, editors. eau guidelines on paediatric urology. eau guidelines, edition presented at the annual eau congress barcelona; 2019: eau. 4. australian government. australian institute of health and welfare (aihw). welfare aioha. rural and remote health. july 2, 2022. accessed june 9, 2023. ht tps://w w w.aihw.gov.au/repor ts/ rural-remote-australians/rural-and-remote-health 5. blumenthal sj, kagen j. the effects of socioeconomic status on health in rural and urban america. jama.2002;287(1):109. pmid: 11754719. 6. beard jr, tomaska n, earnest a, summerhayes r, morgan g. influence of socioeconomic and cultural factors on rural health. aust j rural health.2009;17(1):10–15. doi: 10.1111/j.1440-1584.2008.01030.x. pmid: 19161494. 7. shahar s, vanoh d, mat ludin af, singh dk a, hamid ta. factors associated with poor socioeconomic status among malaysian older adults: an analysis according to urban and rural settings. bmc public health.2019;19(suppl 4):549. doi: 10.1186/s12889-019-6866-2. pmid: 31196023; pmcid: pmc6565532. 8. royal australian college of surgeons. raco. acute scrotal pain and suspected testicular torsion guidelines (2018). accessed june 9, 2023. https://www.surgeons.org/en/about-racs/position-papers/ acute-scrotal-pain-and-suspected-testicular-torsion-guidelines-2018 9. australian government. australian bureau of statistics. socioeconomic indexes for areas (seifa). accessed june 9, 2023. https:// www.abs.gov.au/websitedbs/censushome.nsf/home/seifa 10. alexandrescu r, o’brien sj, lyons ra, lecky fe; trauma audit and research network. a proposed approach in defining population-based rates of major injury from a trauma registry dataset: delineation of hospital catchment areas (i). bmc health serv res.2008;8:80. doi: 10.1186/1472-6963-8-80. pmid: 18402693; pmcid: pmc2365946. 11. australian government. department of health and aged care. care dohaa. modified monash model 2021. accessed june 9, 2023. https://www.health.gov.au/topics/rural-health-workforce/ classifications/mmm 12. ibm® spss® statistics for windows. accessed june 9, 2023. https:// www.ibm.com/spss. version 28.0. 13. australian government. australian institute of health and welfare (aihw). procedures data cubes. july 8, 2022. accessed june 9, 2023. https://www.aihw.gov.au/reports/hospitals/procedures-data-cubes 14. australian government. australian bureau of statistics – september 2022. national, state and territory population. march 16, 2023. accessed june 9, 2023. https://www.abs.gov.au/statistics/people/ population/national-state-and-territory-population/latest-release 15. zvizdic z, aganovic a, milisic e, jonuzi a, zvizdic d, vranic s. duration of symptoms is the only predictor of testicular salvage following testicular torsion in children: a case-control study. am j emerg med.2021;41:197–200. doi: 10.1016/j.ajem.2020.11.023. pmid: 33221112. 16. meschino mt, giles ae, rice tj, saddik m, doumouras ag, nenshi r, et al. operative timing is associated with increased morbidity and mortality in patients undergoing emergency general surgery: a multisite study of emergency general services in a single academic network. can j surg.2020;63(4):e321–e328. doi: 10.1503/cjs.012919. pmid: 32644317; pmcid: pmc7458678. 17. wohlgemut jm, ramsay g, bekheit m, scott nw, watson ajm, jansen jo. emergency general surgery: impact of distance and rurality on mortality. bjs open.2022;6(2):zrac032. doi: 10.1093/bjsopen/ zrac032. pmid: 35466374; pmcid: pmc9035437. 18. de jager e, chaudhary ma, rahim f, jarman mp, uribe-leitz t, havens jm, et al. the impact of income on emergency general surgery outcomes in urban and rural areas. j surg res.2020;245:629–635. doi: 10.1016/j.jss.2019.08.010. pmid: 31522036. 19. stewart gd, long g, tulloh br. surgical service centralisation in australia versus choice and quality of life for rural patients. med j aust.2006;185(3):162–163. doi: 10.5694/j.1326-5377.2006.tb00507.x. pmid: 16893360. 20. choi jb, han kh, lee y, ha us, cho kj, kim jc, et al. the incidence of testicular torsion and testicular salvage rate in korea over 10 years: a nationwide population-based study. investig clin urol.2022;63(4):448– 4 5 4. doi: 10.4111/ icu.20 2 2012 2. pmid: 35 670 0 0 8; pmcid: pmc9262487. 21. overholt t, jessop m, barnard j, al-omar o. pediatric testicular torsion: does patient transfer affect time to intervention or surgical outcomes at a rural tertiary care center? bmc urol. 2019;19(1):39. doi: 10.1186/s12894-019-0473-5. pmid: 31101044; pmcid: pmc6525388. 22. australian government. department of health. care dohaa. stronger rural health strategy: improved access to australian trained general practitioners. 2021. accessed june 9, 2023. https:// a g e d c a r e . r o y al c o m mis sio n .g o v. au /s y s t e m / f ile s / 2 0 2 0 0 6 / cth.0001.1001.0585.pdf 23. ota k, fukui k, oba k, shimoda a, oka m, ota k, et al. the role of ultrasound imaging in adult patients with testicular torsion: a systematic review and meta-analysis. j med ultrason (2001).2019;46(3):325–334. doi: 10.1007/s10396-019-00937-3. pmid: 30847624. 24. barbosa jaba, de freitas pfs, carvalho sad, coelho aq, yorioka maw, pereira mwa, et al. validation of the twist score for testicular torsion in adults. int urol nephrol.2021;53(1):7-11. doi: 10.1007/s11255020-02618-4. pmid: 32844355. ultrasonography. thus, we recommend reserving sonography for patients falling into the medium-risk groups as an adjunct to support clinician suspicion, and we suggest incorporating other scoring systems as decision-making adjuncts. it is widely advocated in the literature that ultrasound should not delay scrotal exploration in high-risk patients due to increased rate of non-viable testes due to in-hospital time delays[26]. however, in our study, we found much lower orchidectomy rates overall compared to the literature, despite there being significant in-hospital delays[26], indicating a potential underpowering to assess the relationship between ultrasonography and orchidectomy. therefore, we agree with contemporary guidelines and advocate for scrotal exploration based on clinical findings, as ultrasonography nearly doubled the time to definitive management in this study. a limitation of this study is the inability to analyze the correlation between orchidectomy rates and symptom onset or degree of torsion due to incomplete and heterogeneous documentation, prohibiting accurate data collection. the literature establishes that symptom onset followed by torsion rotation is the predominant established risk factor[27,28] and when symptom onset is < 24 hours, hospital transfer has been shown to significantly increase orchidectomy rates[29]. however, in this study, we found no significant increase in orchidectomy rates associated with in-hospital delay to theaters, likely because the majority of patients underwent surgery within 4 hours of presentation. no manual de-torsion was performed and thus its role could not be assessed. furthermore, the absence of network guidelines or protocols resulted in inconsistency in clinician decision-making, with a mix of registered nurses, general practitioners, general surgeons, and urologists making assessments and determining the need for transfer and surgery. in particular, this could explain the high rate of ultrasonography usage, but no significant differences in ultrasonography use were identified between peripheral and non-peripheral hospitals. the orchidectomy rate in this study for patients with torsion was 22.6%, which is lower than the rates described in the literature, which can rise up to 39%[27]. this difference suggests that the analysis may have been underpowered to appropriately assess orchidectomy and its relationship with the variables described. we recommend future multicenter studies with sufficient samples sizes to further examine the relationships described in this study. due to incomplete or unavailable data, follow-up was not assessed, predominantly due to barriers in rural health care, including limited patient access to health care follow-up or incomplete assessments performed by non-surgical healthcare providers at peripheral health sites. conclusion in conclusion, our findings indicate that for patients residing in rural-remote areas of australia, geographical distance, ses, age, and peripheral hospital attendance were not significant risk factors for orchidectomy rate. despite significant time delays associated with peripheral hospital attendance, geographic remoteness, and low ses, we suggest that testicular torsion can be managed safely in rural health care settings, particularly within a rural referral center with a peripheral hospital catchment. future multicenter, prospective studies examining symptom onset and clinical decision-making rules, such as twist score, should be performed in rural health care settings to assess the diagnostic accuracy and the role and safety of ultrasonography in the management of this organ-threatening condition. acknowledgments the research protocol (pid01054/eth00931/ste01878) was approved by the greater western human ethics research committee as a negligible/low-risk project. the data were retrospectively collected and de-identified, eliminating the need for informed consent from each patient. this study did not involve any trials or animal experiments. the authors would like to disclose that they have not received any grant support and they declare no conf licts of interest. all the authors have reviewed and agree upon the content of the manuscript. the manuscript has not been previously published and it is not under consideration elsewhere. 263262 siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org original research testicular torsion: an analysis of rural geography and socioeconomic status https://www.aihw.gov.au/reports/rural-remote-australians/rural-and-remote-health https://www.aihw.gov.au/reports/rural-remote-australians/rural-and-remote-health https://www.surgeons.org/en/about-racs/position-papers/acute-scrotal-pain-and-suspected-testicular-torsion-guidelines-2018 https://www.surgeons.org/en/about-racs/position-papers/acute-scrotal-pain-and-suspected-testicular-torsion-guidelines-2018 https://www.abs.gov.au/websitedbs/censushome.nsf/home/seifa https://www.abs.gov.au/websitedbs/censushome.nsf/home/seifa https://www.health.gov.au/topics/rural-health-workforce/classifications/mmm https://www.health.gov.au/topics/rural-health-workforce/classifications/mmm https://www.aihw.gov.au/reports/hospitals/procedures-data-cubes https://www.abs.gov.au/statistics/people/population/national-state-and-territory-population/latest-release https://www.abs.gov.au/statistics/people/population/national-state-and-territory-population/latest-release http://siuj.org http://siuj.org 25. qin kr, qu lg. diagnosing with a twist: systematic review and metaanalysis of a testicular torsion risk score. j urol.2022;208(1):62–70. doi: 10.1097/ju.0000000000002496. pmid: 35238603. 26. wright hg, wright hj. ultrasound use in suspected testicular torsion: an association with delay to theatre and increased intraoperative finding of non-viable testicle. n z med j.2021;134(1542):50–55. pmid: 34531583. 27. macdonald c, kronfli r, carachi r, o’toole s. a systematic review and meta-analysis revealing realistic outcomes following paediatric torsion of testes. j pediatr urol.2018;14(6):503–509. doi: 10.1016/j. jpurol.2018.09.017. pmid: 30404723. 28. howe as, vasudevan v, kongnyuy m, rychik k, thomas la, matuskova m, et al. degree of twisting and duration of symptoms are prognostic factors of testis salvage during episodes of testicular torsion. transl androl urol.2017;6(6):1159–1166. doi: 10.21037/tau.2017.09.10. pmid: 29354505; pmcid: pmc5760391. 29. kwenda ep, locke ra, demarco rt, bayne ce. impact of hospital transfer on testicular torsion outcomes: a systematic review and meta-analysis. j pediatr urol.2021;17(3):293.e1–293.e8. doi: 10.1016/j. jpurol.2021.01.038. pmid: 33610457. 264 siuj • volume 4, number 4 • july 2023 siuj.org original research http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj.org siuj • volume 4, number 4 • july 2023 key words competing interests article information testicular cancer, germ cell tumors, cell-free dna, circulating tumor dna, liquid biopsy none declared. received on december 7, 2022 accepted on may 13, 2023 this article has been peer reviewed. soc int urol j. 2023;4(4):287–292 doi: 10.48083/ipco3495 293 review — liquid biopsy the role of circulating tumor dna and cell-free dna in the management of germ cell tumors: a narrative review isabella dolendo,1 shanice cox,2 dhruv puri,1 aditya bagrodia1,3 1department of urology, uc san diego school of medicine, la jolla, united states 2 department of urology, burnett school of medicine at texas christian university, fort worth, united states 3 department of urology, university of texas southwestern medical center, dallas, united states abstract liquid biopsy has demonstrated success as a diagnostic, prognostic, and therapy response monitoring tool in various cancers and could represent a rapid and minimally invasive alternative or complementary test for testicular germ cell tumors (gcts). this article aims to review the current state of the research into circulating tumor dna (ctdna) and cell-free dna (cfdna) in testicular gcts. studies have confirmed the presence of ctdna and cfdna can be identified in peripheral blood samples of patients with testicular gcts. further research has attempted to optimize the methods for ctdna detection in plasma to improve the sensitivity of these tests; however, a single method with high sensitivity and reliability has yet to be established. previous studies have employes different methods for detecting cfdna, including spectrophotometry, capillary electrophoresis, quantitative polymerase chain reaction (pcr), reverse transcription-polymerase chain reaction (rt-pcr), and whole genome sequencing. these studies have various elements of cfdna examined such as total cfdna quantity, methylation patterns, and specific mutations. additional studies have investigated the efficacy of cfdna detection in combination with other tests including mirna analysis. the application of cfdna as a biomarker has been rapidly expanding in several malignancies. however, there is a relative paucity of research on the clinical utility of cfdna in testicular cancer, and many questions remain about the significance and feasibility of this biomarker in gcts. cell-free dna shows promise as a biomarker to enhance detection and disease monitoring in testicular cancer, but robust studies are needed to develop an optimal and reproducible method for cfdna detection in order to determine its clinical application in testicular cancer. introduction the diagnostic evaluation of testicular cancer typically involves serum tumor markers including alpha-fetoprotein (afp), human chorionic gonadotropin (hcg), and lactate dehydrogenase (ldh)[1]. however, these markers are elevated in only about 40% of patients with testicular cancer[2]. testicular biopsy is typically avoided because of the associated risk for tumor cell seedling and altered patterns of metastases[3]. to overcome these limitations, liquid biopsy has emerged as a recent development, providing a rapid, accurate, and noninvasive alternative to tissue biopsy and radical orchiectomy[4]. http://siuj.org mailto:bagrodia%40health.ucsd.edu?subject=siuj is considered to be tumor specific and uniquely identifiable, and its analysis can provide insights into disease burden and progression. of the various cfdna characteristics, cf dna methylation and mutation analysis hold the most promise as cancer biomarkers[11]. several studies have identified cf dna in plasma samples of testicular cancer patients. ellinger et al. collected serum samples from patients with seminomas or nonseminomas and from healthy patients and isolated the cfdna[1]. the investigators used rt-pcr to examine beta-actin dna fragments (106 bp, 193 bp, and 384 bp) and found these fragments to be significantly increased in patients with testicular germ cell tumors (tgcts) compared to disease-free controls. boublikova et al. investigated total cf dna using spectrophotometry, capillary electrophoresis, and quantitative polymerase chain reaction (qpcr) in the peripheral plasma of patients with tgcts and controls[12]. they found that patients with tgcts had significantly higher total cfdna compared to controls. studies have shown ctcs can also be detected in the peripheral samples of patients with tgcts. bokemeyer et al. detected ctcs in apheresis samples from 58% of patients with metastatic tgcts undergoing high-dose chemotherapy and peripheral blood stem-cell (pbsc) transplantation[13]. fan et al. detected beta-hcg mrna in apheresis products using pcr[14], suggesting the presence of a significant number of ctcs or cell-free dna rather than tumor cells. all patients with circulating mrna exhibited elevated serum betahcg levels, whereas only 46% of patients without circulating mrna tested positive for betahcg. the findings also revealed a correlation between positive pcr results and higher serum betahcg levels at diagnosis[14]. similarly, in a study by hautkappe et al., all patients with circulating betahcg or afp mrna had elevated serum betahcg levels, while only 40% of patients with negative pcr results had positive serum betahcg[15]. a study conducted by hildebrandt et al. demonstrated that reverse transcription-polymerase chain reaction (rt-pcr) targeting germ cell alkaline phosphatase is highly sensitive in detecting residual gct cells in peripheral blood. this method enabled the detection of one tumor cell in at least 106 mononuclear cells[16]. yuasa et al. also used rt-pcr to detect malignant cells in the bloodstream by measuring the expression of afp in the peripheral blood of patients with advanced stage testicular cancer. they found that this assay could detect a single cancer cell in 106 peripheral blood stem cells[17]. further advancements in research have led to the development of techniques that enhance the detectability of ctdna and ctcs in gcts. nastały et al. developed a new assay using a label-free enrichment technique based on the physical properties of tumor cells. by using table 1. list of testicular cancer mesh entry terms and cell-free dna–related search terms used to identify relevant literature in the cochrane review and pubmed databases testicular cancer mesh entry terms cell-free dna–related search terms testicular neoplasm neoplasm, testicular testicular tumors neoplasms, testis neoplasm, testis testis neoplasm testis neoplasms testicular tumor tumor, testicular tumors, testicular neoplasms, testicular cancer of testis testis cancer cancer, testis cancers, testis testis cancers cancer of the testes cancer of the testis testicular cancer cancer, testicular cancers, testicular testicular cancers tumor of rete testis rete testis tumor rete testis tumors testis tumor, rete testis tumors, rete biopsies, liquid biopsy, liquid liquid biopsies cell-free nucleic acids nucleic acids, cell-free circulating cell-free nucleic acid circulating cell-free nucleic acid circulating nucleic acids acids, circulating nucleic nucleic acids, circulating cell-free nucleic acid cell-free nucleic acid nucleic acid, cell-free circulating cell-free nucleic acids circulating cell-free nucleic acids circulating nucleic acid acid, circulating nucleic nucleic acid, circulating cell-free dna cell-free dna dna, cell-free cfdna cirdna cell-free deoxyribonucleic acid acid, cell-free deoxyribonucleic cell-free deoxyribonucleic acid deoxyribonucleic acid, cell-free circulating dna dna, circulating cell-free rna cell-free rna rna, cell-free cfrna cirrna cell-free ribonucleic acid acid, cell-free ribonucleic cell-free ribonucleic acid ribonucleic acid, cell-free circulating rna rna, circulating dna, circulating tumor tumor dna, circulating cell-free tumor dna cell-free tumor dna dna, cell-free tumor tumor dna, cell-free cfdna: cell-free dna; cirrna: circulating tumor dna; mesh: medical subject heading. liquid biopsy involves the extraction and analysis of biological samples, such as blood, urine, or saliva. unlike tissue biopsy, which provides information confined to a specific region and fails to capture complex tumor heterogeneity, liquid biopsy isolates and analyzes tumor-derived or tumor-associated components that circulate in the bloodstream: circulating tumor cells (ctcs), circulating leukocytes, and tumor-derived circulating nucleic acids, such as cell-free dna (cfdna), circulating tumor dna (ctdna), microrna (mirna), and noncoding rna. this enables longitudinal monitoring of cancer progression[4]. cell-free dna refers to fragmented dna in the noncellular component of blood. circulating tumor dna consists of dna fragments of 150 to 200 base pairs (bp) released into the peripheral blood from cancerous cells as a result of apoptosis, necrosis, or secretion[5]. the presence of tumor-specific genetic and epigenetic alterations in ctdna makes ctdna a promising biomarker. the concentration of ctdna in blood plasma varies among cancer patients based on the type, location, and stage of the cancer and is typically low. the detection of somatic mutations, frequently single base-pair changes, copy number variations, or chromosomal rearrangements in ctdna shows promise for early cancer diagnosis, tumor dynamics assessment, minimal residual disease identification, and therapy monitoring. cell-free dna isolated from cancer patients can be used for various downstream applications, such as the investigation of mutations, copy number variations, gene fusions, and dna methylation using various methods including sequencingor pcr-based approaches. ctdna analysis can potentially overcome tumor heterogeneity, which may not be captured by tissue sampling. currently, there are 3 fda-approved liquid biopsy tests: 2 cf dna-based tests (cobas egfr mutation test v2 and epi procolon) and one ctc-based test (cellsearch)[5]. numerous ongoing clinical trials are employing cf dna analysis in urologic malignancies. mutations in fibroblast growth factor receptor-3 (fgfr3) in cf dna were monitored in patients with advanced urothelial carcinoma undergoing treatment with an fgfr antagonist[6]. patients with a decrease in mutations in cf dna were found to correlate with a greater decrease in tumor size. additionally, analysis of fgfr3 mutations in cf dna were shown to predict disease progression ahead of imaging with computerized tomography (ct) scans. cfdna has also been used in a study on a programmed death-ligand 1 (pd-l1) inhibitor in urothelial cancer by powles et al.[7]. those authors found a correlation between mutations found in ctdna with mutations found in tumor dna, suggesting a role for plasma-based biomarker screening in predicting immunotherapy response[7]. cell-free and circulating tumor dna are currently being used in clinical trials for urothelial carcinomas. for example, huang et al. are recruiting for a study using ctdna and urine tumor dna as biomarkers for minimal residual disease and upper urinary tract urothelial carcinoma recurrence[8]. van der heijden et al. are monitoring ctdna during follow-up of patients with urothelial carcinoma treated with ipilimumab and nivolumab[9]. lolkema and van der veldt are collecting ctdna as part of their study on biomarkers in patients with advanced urothelial cancer treated with pembrolizumab[10]. in this paper, we review the current state of research into liquid biopsies in gcts. methods a narrative review was conducted on september 24, 2022, by searching the pubmed and cochrane review databases without any limitation on the date range. articles addressing cf dna and ctdna in testicular cancer were included in the review. the search terms used included all medical subject heading (mesh) entry terms for testicular cancer and cell-free dna– related terms (table 1). relevant articles were also identified through the references of the included articles. all types of studies related to ctdna and cf dna in testicular cancer were included. duplicate articles were excluded. three reviewers (i.d., s.c., d.p.) independently screened the articles for inclusion. any discrepancies were discussed to determine the final inclusion. circulating tumor dna and cell-free dna in testicular cancer testicular cf dna is thought to result from apoptosis during spermatogenesis. this can occur in both physiological and pathological conditions, including ma lignancy. in the case of ma lignancy, cf dna abbreviations afp alpha-fetoprotein bp base pairs ctcs circulating tumor cells cfdna cell-free dna ctdna circulating tumor dna gcts germ cell tumors hcg human chorionic gonadotropin ldh lactate dehydrogenase mirna microrna pcr polymerase chain reaction qpcr quantitative polymerase chain reaction rt-pcr reverse transcription-polymerase chain reaction tgcts testicular germ cell tumors 295294 siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org review — liquid biopsy the role of circulating tumor dna and cell-free dna in the management of germ cell tumors: a narrative review http://siuj.org http://siuj.org mutations. tsui et al. identified cf dna mutations in plasma samples and employed whole genome sequencing to estimate the cfdna tumor fraction[24]. by using cf-impact, a tumor test capable of detecting genomic alterations in specific cancer-related genes, the researchers found somatic mutations in 60% of samples from patients with tgcts (n = 118). for the remaining samples without detected alterations and low tumor fraction, a more sensitive but less comprehensive test, msk-access, was used for re-analysis. this latter test showed 14 additional samples with somatic mutations. whole exome sequencing was then performed for samples without detected alterations but high tumor fraction, leading to the identification of 5 more samples with somatic mutations. in total, 90 of 118 samples (79%) exhibited somatic mutations across all 3 methods. overall, this study showed that cfdna tumor fraction can guide further testing for somatic mutations in cfdna to maximize mutation identification. moreover, the identification of specific mutations has the potential to inform the selection of precision medicine treatments. the prognostic implications of the presence of cfdna and ctdna in gcts remain unclear. ellinger et al. found that levels of cell-free mtdna did not correlate with disease severity, including tumor stage or lymphovascular invasion, and bokemeyer et al. showed that the presence of ctcs in transplanted pbsc apheresis products did not affect overall survival[13,23]. on the other hand, hautkappe et al. demonstrated that 41.2% of patients with stage iic/iii gcts had detectable mrna of either afp or betahcg compared to only 23.5% of patients with stage i disease[15]. in a clinical trial conducted by reid et al., cell-free dna is being investigated to determine whether cfdna is detectable in the plasma of patients with platinum refractory/resistant gcts. the researchers are further analyzing patients with detectable cf dna for changes in cfdna that are associated with clinical resistance to platinum (nct0398087)[25]. the clinical management of tgct has experienced limited progress in recent decades in integrating molecular diagnostic and prognostic tools into targeted therapies for affected patients[26]. total cfdna and changes in cfdna levels have been shown to be associated with specific treatment responses, prognoses, and survival rates in various tumors including lung, pancreatic, colorectal, and other malignancies. while the utility of cfdna in gcts remains uncertain, circulating mir-371a-3p has recently captured attention as a robust biomarker with significant potential to address clinical gaps in gct management. in 2011, murray and colleagues reported detectable serum mir-371a-3p in a 4-year-old boy with disseminated yolk sac tumor[27]. subsequent to this, a large body of literature has consistently illustrated the utility of mir-371a-3p in differentiating gcts from controls[28]. in the largest report to date, dieckmann et al. analyzed a cohort of 616 gct patients and found that mir-371a-3p exhibited a sensitivity of 90.1% and specificity of 94% for the diagnosis of gct[29]. mir-371a-3p also demonstrated a sensitivity of 83% and specificity of 96% for identifying relapses, indicating its expanded clinical utility beyond diagnosis[29]. the predictive capability of mir-371a-3p for identifying relapses has been substantiated by nappi et al. and lafin et al.[30,31]. leão et al. expanded on previous work by demonstrating that mir-371a-3p could also detect residual viable gct after chemotherapy, with an area under the curve of 0.874, and with levels declining in response to treatment[32]. apar t from identif y ing teratomas, mir-371a-3p shows potential as an important adjunct in the clinical management of gcts. currently, 2 clinical trials (nct04914026, nct04435756) are exploring the role of mir-371 in the management of gcts[33,34]. discussion the utility of circulating tumor dna and cell-free dna as diagnostic, prognostic, and therapeutic markers has been well-documented in various cancers. while the application of cf dna as a biomarker has been rapidly expanding in several malignancies, relatively little research exists on the clinical utility of cfdna in testicular cancer, leaving many questions unanswered about the significance and feasibility of this biomarker in tgcts. studies have demonstrated the presence of ctdna and cfdna in peripheral blood samples of patients with tgcts. efforts have been made to optimize the methods for ctdna detection in plasma to enhance the sensitivity of these tests; however, a single method with high sensitivity and reliability has yet to be established. previous studies have employed diverse methods for detecting cfdna, including spectrophotometry, capillary electrophoresis, qpcr, rt-pcr, and whole genome sequencing. these studies have also examined various aspects of cf dna, such as total cf dna quantity, methylation patterns, and specific mutations (table 2). some studies have evaluated the efficacy of cf dna detection in combination with other tests including mirna analysis. many questions remain about the implementation of cfdna and ctdna in the clinical setting. to achieve the clinical validity and utility of liquid biopsy tests, it is necessary to assess the analytical validity of these tests, and then conduct prospective studies using the protocols that resulted in analytical validity. analytical validity encompasses the accuracy, sensitivity, specificity, and robustness of the liquid biopsy test and relies on pre-analytical variables and protocols used for sample keratins 8, 18, and 19, and epcam as epithelial cell markers and sall4 andoct3/4 as germ cell markers, they achieved the detection of ctcs in 17.5% of peripheral blood samples from testicular cancer patients, compared to only an 11.5% detection rate using the cellsearch assay[18]. ruf et al. demonstrated the detection of ctcs through alkaline phosphatase enzymatic activity and the use of anti-keratin, anti-epcam, and anti-sall4 antibodies in immunocytochemistry[19]. taken together, these studies highlight the wide variety of tests developed to measure cf dna and ctdna in the peripheral samples of patients with tgcts. however, the inability to designate a single test as the gold testing standard hinders comparison of cfdna and ctdna levels in tgct patients across different studies. the variation in testing methods poses a significant challenge in establishing clinical application of cfdna and ctdna in testicular cancer care. clinical utility of circulating tumor dna and cell-free dna in testicular cancer circulating tumor and cell-free dna offer multiple clinical applications in the context of testicular cancer, showing promise as diagnostic and prognostic tools. various detection methods have been described in the literature. for example, ellinger et al. used rtpcr to isolate beta-actin dna fragments in cf dna, achieving a sensitivity of 84% and specificity of 97% in distinguishing patients with gcts from healthy controls[1]. even among patients with normal ranges of serum tumor markers, cfdna exhibited a sensitivity of 84% and specificity of 97%, suggesting its potential utility as a biomarker for gcts, particularly in those patients who do not have elevations in other serum tumor markers[1]. investigations have also focused on total cfdna and its 2 main fragments (360 bp and 180 bp) as targets for detection. boublikova et al. used spectrophotometry, capillary electrophoresis, and qpcr to identify total cfdna and found that the quantity of cfdna does not offer a clear threshold to distinguish between tgct patients and controls, thus limiting the sensitivity of this marker. however, they found that longer cf dna fragments (360 bp) were present in 58% of patients with tgcts but absent in controls[12], suggesting that targeting longer cfdna fragments instead of total cfdna may be a viable approach. further studies involving larger samples are necessary to establish an acceptable cutoff value. methylation patterns in serum samples of patients with tgcts have also shown promise as a biomarker. lobo et al. evaluated hypermethylated rassf1a in cfdna as a diagnostic marker for testicular gcts[20]. rassf1a is a tumor suppressor gene that exhibits inactivation in many cancers. promoter hypermethylation of rassf1a has been a useful marker in several solid malignancies and has also been detected in tissue samples of tgcts[20]. to quantify hypermethylated rassf1a, lobo et al. used a novel droplet digital pcr method to analyze 102 serum samples from patients with gcts and 29 samples from healthy young adult men[20]. they found that hypermethylated rassf1a exhibited a sensitivity of 86.7%, surpassing the 65.5% sensitivity of afp and hcg markers. they also found that combining hypermethylated rassf1a with mir-371a-3p, a reliable microrna biomarker for tgcts, exhibited a sensitivity and specificity of 100%. this study identified a cfdna target with high sensitivity and specificity, particularly in combination with a microrna marker. ellinger et al. also examined hypermethylation at rassf1a, as well as methylation at apc, gstp1, ptgs2, p14(arf), and p16(ink)[21] using rt-pcr to evaluate samples from 73 patients with tgcts and 35 individuals without disease. they found significantly higher rates of hypermethylation in the patients with testicular cancer across all examined gene sites. when combining multiple gene sites, the test achieved a sensitivity of 67% and specificity of 97%, surpassing the 58% sensitivity of conventional biomarkers (afp, hcg, plap, ldh). in patients with normal laboratory results, the hypermethylation pattern test demonstrated a sensitivity of 97%, indicating its potential as a set of methylation markers particularly useful for identifying disease in patients with normal laboratory markers. kawakami et al. identified another potential cfdna biomarker, the 5’ end of the xist gene expressed in male germ cells[22]. this gene has been found to be hypomethylated in tgcts. the investigators analyzed plasma samples from 24 patients with tgcts and 24 controls and found 64% of patients with tgcts had detectable unmethylated signals compared to none of the control samples. the presence of unmethylated signals was more common in patients with metastatic tumors (88%) compared to patients with nonmetastatic tumors (53%). further research is needed to improve the sensitivity of tests for this marker and establish unmethylated xist fragments as a diagnostic tool for tgct. ellinger et al. also investigated circulating cell-free mitochondrial dna in the serum of patients with seminoma and nonseminomas and found that cell-free mtdna exhibited a sensitivity of 59.6% and 94.3%, respectively, in identifying patients with gcts[23]. for patients without elevated serum tumor markers, cell-free mitochondrial dna demonstrated a sensitivity of 64.5% and specificity of 91.4%. studies have investigated the use of the cell-free dna tumor fraction and the identification of somatic 297296 siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org review — liquid biopsy the role of circulating tumor dna and cell-free dna in the management of germ cell tumors: a narrative review http://siuj.org http://siuj.org references 1. ellinger j, wittkamp v, albers p, perabo fge, mueller sc, von ruecker a, et al. cell-free circulating dna: diagnostic value in patients with testicular germ cell cancer. j urol.2009;181(1):363–371. doi: 10.1016/j. juro.2008.08.118. pmid: 19010497. 2. trigo jm, tabernero jm, paz-ares l, garcía-llano jl, mora j, lianes p, et al. tumor markers at the time of recurrence in patients with germ cell tumors. cancer.2000;88(1):162–168. doi: 10.1002/(sici)10970142(20000101)88:1<162::aid-cncr22>3.0.co;2-v. pmid: 10618619. 3. lobo j, gillis ajm, jerónimo c, henrique r, looijenga lhj. human germ cell tumors are developmental cancers: impact of epigenetics on pathobiology and clinic. int j mol 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med.2020;72:100828. doi: 10.1016/j.mam.2019.10.005. pmid: 31711714. 8. pal sk, rosenberg je, hoffman-censits jh, berger r, quinn di, galsky md, et al. efficacy of bgj398, a fibroblast growth factor receptor 1–3 inhibitor, in patients with previously treated advanced urothelial carcinoma with fgfr3 alterations. cancer discov.2018;8(7):812– 821. doi: 10.1158/2159-8290.cd-18-0229. pmid: 29848605 pmcid: pmc6716598. 9. powles t, carroll d, chowdhury s, gravis g, joly f, carles j, et al. an adaptive, biomarker-directed platform study of durvalumab in combination with targeted therapies in advanced urothelial cancer. nat med.2021;27(5):793–801. doi: 10.1038/s41591-021-01317-6. pmid: 33941921. 10. renji hospital. circulating tumour dna and urine tumor dna detection of minimal residual disease in locally advanced upper tract urothelial carcinoma with radical nephroureterectomy: a cohort study. cinicaltrials.gov identifier nct05595408. updated november 2, 2022. accessed march 6, 2023. https://clinicaltrials.gov/ ct2/show/nct05595408. 11. the netherlands cancer institute. phase 1b study to assess safety and efficacy of neo-adjuvant bladder urothelial carcinoma combination-immunotherapy (nabucco). cinicaltrials.gov identifier nct03387761. updated april 28, 2022. accessed march 6, 2023. https://clinicaltrials.gov/ct2/show/nct03387761 12. lolkema mpjk; erasmus medical center. biomarker discovery study to identify patients with advanced urothelial cancer benefitting from pembrolizumab treatment. cinicaltrials.gov identifier nct03263039. updated august 20, 2021. accessed march 6, 2023. https:// clinicaltrials.gov/ct2/show/nct03263039 13. krasic j, skara l, bojanac ak, ulamec m, jezek d, kulis t, et al. the utility of cfdna in tgct patient management: a systematic review. ther adv med oncol.2022;14:17588359221090365. doi: 10.1177/17588359221090365. pmid: 35656387; pmcid: pmc9152191. 14. boublikova l, kramarzova ks, zwyrtkova m, bakardjieva-mihaylova v, stuchly j, rosova b, et al. the clinical value of circulating free tumor dna in testicular germ cell tumor patients. urol oncol.2022;40(9):412. e15–412.e24. doi: 10.1016/j.urolonc.2022.04.021. pmid: 35729018. 15. bokemeyer c, gillis aj, pompe k, mayer f, metzner b, schleucher n, et al. clinical impact of germ cell tumor cells in apheresis products of patients receiving high-dose chemotherapy. j clin oncol.2001;19(12):3029–3036. doi: 10.1200/jco.2001.19.12.3029. pmid: 11408498. 16. fan y, einhorn l, saxman s, katz b, abonour r, cornetta k. detection of germ cell tumor cells in apheresis products using polymerase chain reaction. clin cancer res.1998;4(1):93–98. pmid: 9516957. 17. hautkappe al, lu m, mueller h, bex a, harstrick a, roggendorf m, et al. detection of germ-cell tumor cells in the peripheral blood by nested reverse transcription-polymerase chain reaction for α-fetoproteinmessenger rna and ß human chorionic gonadotropin-messenger rna1. cancer res.2000;60(12):3170–3174. pmid: 10866307. 18. hildebrandt mo, bläser f, beyer j, siegert w, mapara my, huhn d, et al. detection of tumor cells in peripheral blood samples from patients with germ cell tumors using immunocytochemical and reverse transcriptase-polymerase chain reaction techniques. bone marrow transplant.1998;22(8):771–775. doi: 10.1038/sj.bmt.1701416. pmid: 9827974. 19. yuasa t, yoshiki t, tanaka t, isono t, okada y. detection of circulating testicular cancer cells in peripheral blood. cancer lett.1999;143(1):57– 62. doi: 10.1016/s0304-3835(99)00194-9. pmid: 10465338. 20. nastał y p, ruf c, becker p, bednarz-knoll n, stoupiec m, kavsur r, et al. circulating tumor cells in patients with testicular germ cell tumors. clin cancer res.2014;20(14):3830–3841. doi: 10.1158/1078-0432. ccr-13-2819. pmid: 24634372. 21. ruf c, nastał y p, becker p, isbarn h, honecker f, pantel k, et al. 703 circulating tumor cells can be detected in patients with testicular germ cell tumors. j urol.2013;189(4s):e289. doi: 10.1016/j.juro.2013.02.261. preparation and biomarker detection[35]. pre-analytical variables are factors not associated with the disease that can impact the integrity of the bodily fluids or biomarkers present therein and hence inf luence the analysis results. these variables can have a technical, biological, or environmental origin. the impact of pre-analytical variables is based on the biomarker and nature of the bodily fluid studied and should be thoroughly assessed for each newly developed liquid biopsy test[36,37]. standard operating procedures for the complete workflow of liquid biopsy tests are critical for advancing their clinical implementation[5]. despite the success of cf dna in multiple cancers, particularly lung and colon cancers, only 3 liquid biopsy tests have received fda approval. the lack of table 2. summary of studies included in this narrative review highlighting the various detection methods and targets study detection method target bokemeyer et al.[13] rt-pcr betahcg, fibronectin (edb variant), egfr, cd44 (v8 to 10 variant), germ cell and placental alkaline phosphatase, human endogenous retrovirus type k (env and gag), and xist boublikova et al.[12] spectrophotometry, capillary electrophoresis, qpcr total cfdna and its 2 main fragments (360 bp and 180 bp) ellinger et al.[23] rt-pcr cell-free mitochondrial dna ellinger et al.[1] rt-pcr 106 bp, 193 bp, and a 384 bp beta-actin dna fragment ellinger et al.[21] rt-pcr hypermethylation at rassf1a; methylation at apc, gstp1, ptgs2, p14(arf), and p16(ink) fan et al.[14] pcr betahcg mrna hautkappe et al.[15] rt-pcr betahcg mrna, afp mrna hildebrandt et al.[16] rt-pcr germ cell alkaline phosphatase kawakami et al.[22] pcr methylation of 5’ end of the xist gene lobo et al.[20] droplet digital pcr hypermethylated rassf1a nastał y et al.[18] label-free enrichment technique, immunocytochemical staining germ cell tumor (anti-sall4, anti-oct3/4) and epithelial cell–specific (antikeratin, anti-epcam) antibodies ruf et al.[19] immunocytochemistry anti-keratin, anti-epcam, and anti-sall4 antibodies tsui et al.[24] cf-impact, msk-access, whole genome sequencing cfdna tumor fraction and somatic mutations yuasa et al.[17] rt-pcr afp cfdna: cell-free dna; mrna: messenger rna; pcr: polymerase chain reaction; rt-pcr: transcription-polymerase chain reaction. reproducibility in preclinical research may contribute to this poor clearance rate by the fda. future directions may focus on developing standardized methods for measuring cf dna in plasma to ensure reliable results that provide clinical value. standardization efforts may also help establish cutoff values for screening and prognostic purposes. addressing the challenges of cf dna detection, such as the low quantities of cfdna in plasma and its rapid clearance of cfdna to circulation, is crucial for the successful implementation of standardized methods. cell-free dna holds promise as a biomarker to enhance detection and disease monitoring in testicular cancer, but robust studies are needed to establish an optimal and reproducible method for cfdna detection before determining its clinical application in the context of testicular cancer. 299298 siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org review — liquid biopsy the role of circulating tumor dna and cell-free dna in the management of germ cell tumors: a narrative review http://siuj.org http://siuj.org 22. lobo j, van zogchel lmj, nuru mg, gillis ajm, van der schoot ce, tytgat gam, et al. combining hypermethylated rassf1a detection using ddpcr with mir-371a-3p testing: an improved panel of liquid biopsy biomarkers for testicular germ cell tumor patients. cancers (basel).2021;13(20):5228. doi: 10.3390/cancers13205228. pmid: 34680375; pmcid: pmc8534014. 23. ellinger j, albers p, perabo fg, müller sc, von ruecker a, bastian pj. cpg island hypermethylation of cell-free circulating serum dna in patients with testicular cancer. j urol.2009;182(1):324–329. doi: 10.1016/j.juro.2009.02.106. pmid: 19447423. 24. kawakami t, okamoto k, ogawa o, okada y. xist unmethylated dna fragments in male-derived plasma as a tumour marker for testicular cancer. lancet.2004;363(9402):40–42. doi: 10.1016/s01406736(03)15170-7. pmid: 14723995. 25. ellinger j, albers p, müller sc, von ruecker a, bastian pj. circulating mitochondrial dna in the serum of patients with testicular germ cell cancer as a novel noninvasive diagnostic biomarker. bju int.2009 jul;104(1):48–52. doi: 10.1111/j.1464-410x.2008.08289.x. pmid: 19154496. 26. tsui dwy, cheng ml, shady m, yang jl, stephens d, won h, et al. tumor fraction-guided cell-free dna profiling in metastatic solid tumor patients. genome med.2021;13:96. doi: 10.1186/s13073-021-00898-8. pmid: 34059130; pmcid: pmc8165771. 27. royal marsden nhs foundation trust. exploratory study of molecular characterization in patients with metastatic germ cell tumours refractor y/resistant to platinum treatment. cinicaltrials.gov identifier nct03980587. updated june 10, 2019. accessed june 11, 2023. https://clinicaltrials.gov/ct2/show/nct03980587 28. lavoie jm, kollmannsberger ck. current management of disseminated germ cell tumors. urol clin north am.2019;46(3):377–388. doi: 10.1016/j.ucl.2019.04.003. pmid: 31277732. 29. murray mj, halsall dj, hook ce, williams dm, nicholson jc, coleman n. identification of micrornas from the mir-371~373 and mir-302 clusters as potential serum biomarkers of malignant germ cell tumors. am j clin pathol.2011;135(1):119–125. doi: 10.1309/ ajcpoe11keyzcjht. pmid: 21173133. 30. gillis ajm, rijlaarsdam ma, eini r, dorssers lcj, biermann k, murray mj, et al. targeted serum mirna (tsmir) test for diagnosis and followup of (testicular) germ cell cancer patients: a proof of principle. mol oncol.2013;7(6):1083–1092. doi: 10.1016/j.molonc.2013.08.002. pmid: 24012110; pmcid: pmc5528443. 31. dieckmann kp, radtke a, geczi l, matthies c, anheuser p, eckardt u, et al. serum levels of microrna-371a-3p (m371 test) as a new biomarker of testicular germ cell tumors: results of a prospective multicentric study. j clin oncol.2019;37(16):1412–1423. doi: 10.1200/jco.18.01480. pmid: 30875280; pmcid: pmc6544462. 32. nappi l, thi m, lum a, huntsman d, eigl bj, martin c, et al. developing a highly specific biomarker for germ cell malignancies: plasma mir371 expression across the germ cell malignancy spectrum. j clin oncol.2019;37(33):3090–3098. doi: 10.1200/jco.18.02057. pmid: 31553692; pmcid: pmc7351323. 33. lafin jt, singla n, woldu sl, lotan y, lewis cm, majmudar k, et al. serum microrna-371a-3p levels predict viable germ cell tumor in chemotherapy-naïve patients undergoing retroperitoneal lymph node dissection. eur urol.2020;77(2):290 –292. doi: 10.1016/j. eururo.2019.10.005. pmid: 31699528; pmcid: pmc7756387. 34. leão r, van agthoven t, figueiredo a, jewett mas, fadaak k, sweet j, et al. serum mirna predicts viable disease after chemotherapy in patients with testicular nonseminoma germ cell tumor. j urol.2018;200(1):126–135. doi: 10.1016/j.juro.2018.02.068. pmid: 29474847. 35. haukeland university hospital. microrna as markers in testicular cancer. clinicaltrials.gov identifier nct04914026. updated august 8, 2022. accessed june 11, 2023. https://clinicaltrials.gov/ct2/show/ nct04914026?cond=nct04914026 36. swog cancer research network. a study of mirna 371 in patients with germ cell tumors. clinicaltrials.gov identifier nct04435756. updated june 9, 2023. accessed june 11, 2023. https://clinicaltrials. gov/ct2/show/nct04435756 37. merker jd, oxnard gr, compton c, diehn m, hurley p, lazar aj, et al. circulating tumor dna analysis in patients with cancer: american society of clinical oncology and college of american pathologists joint review. j clin oncol.2018;36(16):1631–1641. doi: 10.1200/ jco.2017.76.8671. pmid: 29504847. 38. fleischhacker m, schmidt b. pre-analytical issues in liquid biopsy – where do we stand? j lab med.2020;44(3):117–142. doi: 10.1515/ labmed-2019-0167. 39. ellervik c, vaught j. preanalytical variables affecting the integrity of human biospecimens in biobanking. clin chem.2015;61(7):914–934. doi: 10.1373/clinchem.2014.228783. pmid: 25979952. 300 siuj • volume 4, number 4 • july 2023 siuj.org review — liquid biopsy http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj.org siuj • volume 4, number 4 • july 2023 key words competing interests article information pyeloplasty, laparoscopy, minimally invasive surgical procedures, open surgery, pelvicoureteric junction obstruction none declared. received on november 16, 2022 accepted on february 19, 2023 this article has been peer reviewed. soc int urol j. 2023;4(4):309–320 doi: 10.48083/ilkv8446 309 review laparoscopic versus open pyeloplasty for pelvicoureteric junction obstruction: a systematic review and meta-analysis benjamin charles buckland,1,3* kevin tree,2 harry narroway,4 sean heywood,3 tharindu senanayake,5 marcus handmer3 1 the university of sydney, school of public health, sydney, australia 2 urology department, dubbo base hospital, dubbo, australia 3 urology department, john hunter hospital, newcastle, australia 4 department of surgery, gosford hospital, gosford, australia 5 department of surgery, john hunter hospital, newcastle, australia abstract objectives to compare outcomes of laparoscopic versus open pyeloplasty for the management of pelvicoureteric junction obstruction (pujo) using a systematic review and meta-analysis. in september 2022, electronic database searches were conducted using the cochrane library, the cochrane central register of controlled trials, embase, medline, clinical trial registries, and relevant conferences to identify relevant abstracts and presentations. methods prospective randomized controlled trials comparing laparoscopic to open pyeloplasty for pujo were included in the review. there were no restrictions on date or language. all populations were included. the authors performed data extraction and risk of bias assessment using the risk of bias tool. meta-analysis was performed using revman software. results six prospective randomized controlled trials involving 335 participants were included in the analysis. six studies included data on the failure rate, with a slight favouring of open pyeloplasty compared to laparoscopic pyeloplasty, although this was not statistically significant (odds ratio [or], 1.39; 95% confidence interval [ci] 0.50 to 3.83). five studies compared operative time, with open pyeloplasty found to have shorter times across all studies (mean difference [md], 54.97 minutes; 95% ci 47.08 to 62.85). based on 5 studies, laparoscopic pyeloplasty has a shorter hospital stay (md, 4.12 days; 95% ci 3.64 to 4.59). two studies compared postoperative analgesia requirements, showing a lower diclofenac requirement in the laparoscopic group (md, 330.08 mg; 95% ci 298.05 to 362.11 mg). one study compared blood loss intraoperatively and found no significant difference between the groups (md, 8.52 ml; 95% ci -2.49 to 19.53). based on 4 studies, laparoscopic pyeloplasty may result in slightly higher complication rates postoperatively (or, 1.49; 95% ci 0.53 to 4.18); however, there was no statistically significant difference. no subgroup analyses were conducted. conclusions limited, low-quality evidence from small-scale trials suggests that laparoscopic pyeloplasty has improved outcomes in terms of shorter hospital stays and reduced postoperative pain compared to open pyeloplasty. open pyeloplasty, on the other hand, had a shorter operative time. failure rate, complication rate, and blood loss were comparable between the 2 approaches. http://siuj.org https://orcid.org/0000-0002-0354-0024 extraction form to independently extract the following information. any discrepancies not resolved between the 2 authors were adjudicated with the help of a third author (h.n.). this review included all studies, regardless of whether they reported the outcomes of interest. the primary outcome assessed was the failure of pyeloplasty, while the secondary outcomes were length of stay, analgesia requirement, length of operation, estimated blood loss, surgical complications, and cosmetic appearance. in addition to these outcomes of interest, data on various other variables was sought, including study design, protocol, country/context, language, dates of study, inclusion criteria of participants, exclusion criteria of participants, number of participants per group, experimental and control intervention, and funding source. study risk of bias assessment two authors (b.b. and s.h.) independently conducted a risk of bias assessment using the cochrane risk of bias tool (rob 1.0)[13]. each author evaluated the criteria listed below as low risk, unclear risk, or high risk. any discrepancies in judgment between the authors (b.b. and s.h.) were discussed and resolved, and a third author (t.s.) was introduced to adjudicate on any differences that remained unresolved. criteria assessed: • random sequence generation (selection bias) • allocation concealment (selection bias) • blinding of participants and personnel (performance bias) • blinding of outcome assessment (detection bias) • incomplete outcome data (attrition bias) • selective reporting (reporting bias) • other sources of bias we evaluated selection bias on a trial-by-trial basis by examining the methods of randomization and allocation concealment. similarly, we assessed performance bias on a trial-by-trial basis by examining the methods used to blind participants and personnel to the intervention received. for each outcome within each trial, we assessed outcome and reporting bias. we then categorized the outcomes into objective (not susceptible to detection bias) and subjective (susceptible to detection bias). we planned to perform a primary analysis using only the studies with a low risk of bias and then a sensitivity analysis. effect measures and synthesis methods we reported continuous outcome data measures as mean differences (mds) with 95% confidence intervals (95% ci) and dichotomous outcome measures as a risk ratio (rr) with 95% ci. given the difference in populations, paediatric and adult populations were synthesized separately. we summarized the data using a random effects model and interpreted the results by considering the whole distribution of effects in the random‐effects meta‐ analyses. additionally, our statistical analyses followed the guidelines outlined the  cochrane handbook for systematic reviews of interventions. for dichotomous outcomes, we used the mantel‐haenszel method; for continuous outcomes, we used the inverse variance method. we used review manager 5 (revman 5) software to perform all the analyses. missing data: we had planned to contact the study authors for any missing data and intended to use an intention-to-treat analysis. however, no missing data were reported, and thus no imputation was necessary by the authors. statistical heterogeneity: we assessed heterogeneity both graphically, by interpreting forest plots, and statistically using the i2 statistic. a value of i2 over 75% indicated significant heterogeneity between studies. subgroup analysis: no subgroup analysis was planned. certainty assessment the employed the grade approach to assess the quality of evidence generated by this systematic review. the grade guideline development tool was used to make the summary of findings table. results the initial search strategy identified 1561 records from electronic databases, with an additional 8 records were identified from conference abstracts and 22 from citation searching of other sources (figure 1). after removing duplicates, we screened 1168 records, excluding 1010 based on the title and abstract screening. we screened 158 full articles for suitability. of these, 119 were excluded due to incorrect study type and 34 were excluded due to wrong intervention. we included 5 studies based on eligibility criteria and identified an additional study (garg 2014[14]) through other searching methods. study characteristics the baseline characteristics and demographics of participants are included in table 1. risk of bias assessment please refer to figures 2, and 3, as well as the study characteristics section. the completed risk of bias tool can be found in online appendix 1. introduction pelvicoureteric junction obstruction (pujo) is a common cause of hydronephrosis in children and adults. the prevalence of this condition has risen recently due to the increased efficacy and hence widespread use of antenatal screening. approximately one in 1000 newborns has pujo, with a male predominance (2:1)[1]. pujo is most frequently caused by a stenotic segment of the ureter at the pelvicoureteric junction (puj), creating a functional obstruction. less common causes of pelvicoureteric junction obstruction include crossing vessels, fibrosis, anatomical variants, and fibroepithelial polyps[2]. in adults, acquired stenosis of the puj can be caused by upper tract infections, stones, trauma (such as instrumentation), or ischemia and can culminate in reactive fibrosis and an annular stricture. upon presentation, symptoms typically include flank or abdominal pain due to increased pressure within the kidney, which can lead to kidney damage[3]. in approximately 60% to 70% of cases, patients do not require surgical management, with hydronephrosis resolving spontaneously[4]. however, patients who experience significant symptoms or impairment in renal function may require surgical management. open pyeloplasty (op) is considered the gold standard of treatment for symptomatic pujo[5]. however, there has been a trend toward minimally invasive techniques with advancements in technology. minimally invasive procedures such as robot-assisted laparoscopic pyeloplasty (lp) can theoretically improve efficiency and effectiveness[6]. these may include a reduced risk for significant bleeding, smaller incisions, decreased pain, improved cosmetic outcomes, lower risk for postoperative infections, and shorter hospital stays[7]. a study reported an increase in the use of minimally invasive pyeloplasty from 2.4% to 55.3% of all pyeloplasty procedures conducted between 1998 and 2009[8]. despite the increasing popularity of laparoscopic approaches, there is a lack of high-quality evidence directly comparing op to lp. systematic reviews have been conducted comparing different laparoscopic approaches to pyeloplasty[9], lp versus op in children[10], or lp versus robotic-assisted lp in infants[11], or have predominantly included retrospective studies[12]. to date, there has not been a systematic review of prospective studies comparing lp to op. this systematic review aims to identify and analyze randomized controlled trials (rcts) to assess the use of laparoscopic pyeloplasty in patients of all ages with pujo. methods eligibility criteria we included all prospective rcts and excluded all other study designs. we evaluated laparoscopic pyeloplasty compared to open pyeloplasty in children and adults with a diagnosis of pulo who had not previously received any surgical management. information sources in july 2022, we conducted electronic searches of the cochrane library and the cochrane central register of controlled trials, medline, and embase ovid (see online appendix 1 for search strategy), with no restrictions on date or language. we reviewed trials registries for unpublished studies, including the australia and new zealand clinical trials registry, international clinical trials registry (world health organization), and clinicaltrials.gov. additionally, we reached out to experts in urology to identify critical studies and ongoing research. we searched for abstracts presented at the european association of urology (eau) annual meetings, the british association of urological surgeons (baus), and the american urological association (aua) between 2019 and 2021. we conducted a manual search of the reference lists of included studies to identify any additional research. selection process two authors (b.b. and t.s.) reviewed all identified studies using rayyan, a software program designed to screen potential studies. all studies identified in the search strategy were screened by title and abstract. two review authors (b.b. and t.s.) independently conducted a thorough evaluation of the full text of all potentially relevant studies and categorized them as excluded, included, ongoing, or awaiting classification. the authors documented reasons for excluding specific studies. in the case of any discrepancies between the authors, a third author (h.n.) was involved to discuss and adjudicate any inconsistencies. this process is highlighted in the prisma flow diagram. a cohen’s unweighted kappa score of 0.92 was calculated, indicating strong agreement between the reviewers and hence strong inter-rater reliability. data collection process/items one author (b.b.) developed a dedicated data extraction form. two authors (b.b. and s.h.) used this data abbreviations ci confidence interval lp laparoscopic pyeloplasty md mean difference op open pyeloplasty pujo pelvicoureteric junction obstruction rcts randomized controlled trials rr risk ratio 311310 siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org review laparoscopic versus open pyeloplasty for pelvicoureteric junction obstruction: a systematic review and meta-analysis http://suij.org http://siuj.org http://siuj.org risk of bias in 5 studies, resulting in overall high risk. in one study (gatti 2017[16]), the operating surgeon completed all follow-up, leading to high risk of bias. incomplete outcome data no studies reported incomplete data, indicating low risk of bias for all 6 studies. selective reporting no studies included a published protocol. all outcomes appeared to be reported appropriately and logically as rcts. given that there was no protocol to compare, all 6 studies were judged as unclear risk of bias. other potential bias no studies included any disclaimer or declaration regarding conflicts of interest or funding. publication bias no publication bias was observed. a funnel plot was not feasible due to the low number of included studies. results of synthesis primary outcome—failure rate all 6 studies included data on the failure rate of pyeloplasty (total, 304: lp, 148; op, 156) (figure 4). however, there were no events in srinivas[17], making the risk ratio not estimable. in the adult population, lp likely results in no greater risk for failure compared to op (rr, 1.23; 95% ci 0.32 to 4.72). there was no statical heterogeneity (i2=0%) among the included studies. similar results were seen in the paediatric population (rr, 1.44; 95% ci 0.25 to 8.24). secondary outcomes operative time: five studies included data on operative time (total, 304: lp, 148; op, 156) (figure 5). in adults, figure 2. risk of bias graph: review authors’ judgments about each risk of bias item presented as percentage across all included studies. random sequence generation (selection bias) allocation concealment (selection bias) blinding of participants and personnel (performance bias) blinding of outcome assessment (detection bias) incomplete outcome data (attrition bias) selective reporting (reporting bias) other bias 0% 25% 50% 75% 100% low risk of bias unclear risk of bias high risk of bias figure 3. risk of bias summary: review authors’ judgments about each risk of bias item for each included study. bansal 2011 garg 2014 gatti 2017 mohammed 2017 ravish 2007 srinivas 2011 ra nd om s eq ue nc e ge ne ra tio n (s el ec tio n bi as ) a llo ca tio n co nc ea lm en t ( se le ct io n bi as ) bl in di ng o f p ar tic ip an ts a nd p er so nn el (p er fo rm an ce b ia s) bl in di ng o f o ut co m e as se ss m en t ( de te ct io n bi as ) in co m pl et e ou tc om e da ta (a tt rit io n bi as ) se le ct iv e re po rt in g (re po rt in g bi as ) o th er b ia s allocation random sequence generation four studies did not report the method of randomization used. one study (garg 2014[14]) reported an adequate ra ndomization met hod. anot her study (rav ish 2007[15]) reported using alternative allocation, putting it at a high risk of bias. allocation concealment five studies were rated as unclear risk of bias because of insufficient information. the study by ravish et al. was figure 1. study flow diagram additional records identi�ed through other sources (n = 30) records after duplicates removed (n = 1168) records screened (n = 1168) records excluded (n = 1010) full-text articles assessed for eligibility (n = 158)) full-text articles excluded, with reasons (n = 152) incorrect study type (n = 119) incorrect intervention (n = 34) studies included in qualitative synthesis (n = 6) s cr ee ni ng el ig ib il it y identi�cation of studies via databases and registers id en ti �c at io n in cl ud ed studies included in quantitative synthesis (meta-analysis) (n = 6) records identi�ed through database searching (n = 1561) rated at a high risk of selection bias because of a poor randomization technique. blinding blinding of participants and personnel we judged all 6 studies at high risk of bias due to the nature of the intervention. blinding of outcome assessment objective outcomes were assessed as being low risk of bias, while subjective outcomes were assessed as high 313312 siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org review laparoscopic versus open pyeloplasty for pelvicoureteric junction obstruction: a systematic review and meta-analysis http://siuj.org http://siuj.org table 1. baseline characteristics study name bansal et al.[21] garg et al.[14] gatti et al.[16] mohammed et al.[22] ravish et al.[15] srinivas et al.[17] lp op lp op lp op lp op lp op lp op age (median in years) 31.64 29.58 27.27 23.47 6.8 7.6 nr nr 31.64 29.58 20.42 22.83 left sided % 42.90% 47.10% 70% 56.70% 66% 69% nr nr 42.90% 47.10% 53.33% 46.60% gender (male %) 60.70% 58.80% 50% 56.70% nr nr nr nr 60.70% 58.80% 73.30% 73.30% bmi (kg/m2) ± sd nr nr nr nr nr nr 28.4 ± 3.25 30.4 ± 3.5 nr nr nr nr sample size 62 60 98 55 29 30 intervention (number) laparoscopic pyeloplasty (n = 28) laparoscopic pyeloplasty (n = 30) laparoscopic pyeloplasty (n = 50) laparoscopic pyeloplasty (n = 25) laparoscopic pyeloplasty (n = 28) laparoscopic pyeloplasty (n = 15) control (number) open pyeloplasty (n = 34) open pyeloplasty (n = 30) open pyeloplasty (n = 48) open pyeloplasty (n = 30) open pyeloplasty (n = 34) open pyeloplasty (n = 15) follow-up 33–34 months 3 months 16 weeks 12 months 3 months 3 months study design prospective rct prospective rct prospective rct prospective rct prospective rct prospective rct protocol no no no no no no country/context india/single centre india/single centre usa/not reported germany/not reported india/single centre india/single centre language english english english english english english dates of study 2004–2007 august 2011 – july 2013 2005–2014 august 2010 – august 2014 2004-2007 april 2004 – march 2005 inclusion criteria of participants symptomatic or worsening renal function, radiographic evidence of pujo diagnosis of pujo pujo, under 18 years of age indications for surgery overweight/obese (bmi > 25 kg/m2) pujo symptomatic or worsening renal function radiographic evidence of pujo primary pujo including symptomatic and asymptomatic patients exclusion criteria of participants no information reported <18 years of age renal function <15% coagulopathy spinal deformity cardiopulmonary compromise refusal of randomization previous pyeloplasty no information reported no information reported secondary pujo urinary tract infection redo pyeloplasty’s contraindications to surgery or laparoscopic surgery long segment pujo demographics (lp vs op) median age in years – 31.64 vs 29.58 male sex (%) – 60.7% vs 58.8% left-sided operation (%) – 42.9% vs 47.1% median age in years – 27.27 vs 23.47 male sex (%) – 50% vs 56.7% left-sided operation (%) – 70% vs 56.7% median age in years – 6.8 vs 7.6 male sex (%) – no information left-sided operation (%) – 66% vs 69% mean hydronephrosis grade – 3.5 vs 3.5 mean bmi (kg/m2) 28.4 ± 3.25 vs 30.4 ± 3.5 median age in years 31.64 vs 29.58 male sex (%) – 60.7% vs 58.8% left-sided operation (%) – 42.9% vs 47.1% median age in years – 20.42 vs 22.83 male sex (%) – 73.3% vs 73.3% left-sided operation (%) – 53.33% vs 46.6% experimental intervention laparoscopic pyeloplasty (n = 28) laparoscopic pyeloplasty (n = 30) laparoscopic pyeloplasty (n = 50) laparoscopic pyeloplasty (n = 25) laparoscopic pyeloplasty (n = 28) laparoscopic pyeloplasty (n = 15) control intervention open pyeloplasty (n = 34) open pyeloplasty (n = 30) open pyeloplasty (n = 48) open pyeloplasty (n =30) open pyeloplasty (n = 34) open pyeloplasty (n = 15) primary outcome success of procedure success of procedure success of procedure success of procedure success of procedure postoperative pain score definition of successful pyeloplasty no recurrence of pujo or conversion to op intraoperatively recurrence of pujo postoperatively no information recurrence of pujo on mag 3 scan at 3 months recurrence of pujo on follow up imaging no information secondary outcome operation time analgesic requirement length of hospital stay operation time analgesic requirement length of hospital stay estimated blood loss mean hb drop postoperatively success rate day of drain removal post operatively cost analysis length of operation length of stay analgesic use operation time analgesic requirement length of hospital stay haemoglobin loss operation time analgesic requirement length of hospital stay postoperative functionality score funding no information no information no information no information no information no information no information declaration of conflict of interests no information no information no information no information no information no information lp: laparoscopic pyeloplasty, op: open pyeloplasty. 315314 siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org review laparoscopic versus open pyeloplasty for pelvicoureteric junction obstruction: a systematic review and meta-analysis http://siuj.org http://siuj.org data to short-term outcomes. long-term outcomes are important for choosing a surgical approach in all populations, however. a key finding of this systematic review is the lack of high-quality studies endorsing the use of laparoscopic pyeloplasty over open pyeloplasty. lp likely results in little to no difference in failure rate, complication rate, intraoperative blood loss, or shortterm pain in both adult and paediatric populations. figure 6. forest plot for length of stay (days) figure 7. forest plot for complications figure 8. forest plot for postoperative diclofenac use (mg) the laparoscopic approach likely has shorter hospital stays, decreased analgesic requirements, and improved pain at 7 days postoperatively. lp likely has longer operative times compared to op. the results of this systematic review highlight that the key clinical benefits of using a laparoscopic technique are a shorter length of stay and improved pain compared to op. however, there is no significant difference in failure rates or complications between the 2 techniques. as such, patients can be counselled that lp may slightly lp likely results in a longer operative time of 66 minutes compared to op (md, 66.48 minutes; 95% ci 19.54 to 113.41). there is significant statistical heterogeneity (i2=96%). there was a smaller difference in the paediatric population of 17 minutes (md, 17.00; 95% ci 3.04 to 30.96). length of stay: five studies included data on length of stay (total, 304: lp, 148; op, 156) (figure 6). lp likely reduces hospital stay by 3 days in adults (md, -3.55; 95% ci -1.52 to -5.58). there is substantial statistical heterogeneity (i2=92%). there was no difference in the paediatric group (md, -0.10; 95% ci -4.58 to 4.37). complications: four studies included data on complications (total, 269: lp, 123; op, 126) (figure 7). lp likely results in no difference in complication rates in adults (rr, 1.24; 95% ci 0.48 to 3.23). there is no significant statistical heterogeneity (i2= 0%). similar results were seen in children (rr, 2.88; 95% ci 0.12 to 69.07). analgesia requirements: two studies included data on this analgesia requirements (total, 122: lp, 58; op, 64) (figure 8). lp is likely to have a lower analgesia postoperative requirement (md, -364.66; 95% ci -776.90 to 47.58). there is significant statistical heterogeneity (i2=99%). blood loss: one study included data on blood loss (total, 60: lp, 30; op, 30) (figure 9). lp likely results in little to no difference in blood loss (in millilitres) (md, 8.52 ml; 95% ci -2.49 to 19.53). there was no data on blood loss for the paediatric population. cosmetic outcome: no studies included data on cosmetic outcome. no subgroup analysis or sensitivity analysis was performed. summary of findings is shown in table 2. discussion key findings the review is based of 6 randomized controlled trials, all of which had relatively small sample sizes and events rates. additionally, most studies had a relatively short follow-up period of 3 months, which limits the figure 4. forest plot for failure rate in laparoscopic versus open pyeloplasty figure 5. forest plot for operative time (minutes) 317316 siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org review laparoscopic versus open pyeloplasty for pelvicoureteric junction obstruction: a systematic review and meta-analysis http://siuj.org http://siuj.org improve recovery times and postoperative pain, but there is no significant difference in outcomes of either failure rates or complications. lp and op are equivalent in these outcomes in both populations. comparison with existing knowledge previous systematic reviews comparing laparoscopic to open pyeloplasty have included only retrospective studies[12], focused on specific populations such as children[10], or compared other approaches such as robotic-assisted or retroperitoneal approaches[9,11]. mei et al. had similar results in the paediatric population, with lp having shorted hospital stays without an increased risk for complications or failure of the pyeloplasty[10]. huang et al. reported a shorter hospital stay and lower complication rate with lp compared to op in children[18]. strengths and limitations this review employed a broad search strateg y of numerous data sources to search for rcts regardless of publication status and language. despite this, there is a possibility of missing published studies in a language other than english, studies published in non‐indexed journals, or studies not yet published. this study only included randomized controlled trials, the gold-standard study type for an intervention such as lp compared to op. the quality of evidence was consistently downgraded for all studies included in this review due to the studies’ intrinsic limitations. given the surgical nature of the intervention, these studies are prone to selection bias from poor allocation concealment and lack of blinding[19]. overall, all studies included in this review are at high risk of bias, and the results should be interpreted with caution. an ongoing challenge in assessing new or evolving surgical techniques is accounting for user experience and the surgical learning curve[20]. surgical outcomes are dependent on the experience of the surgeon, the number of procedures performed, and the centre’s experience. other specific factors that may affect outcomes for pyeloplasty include stent and drain placement, which were not assessed. thus, this review cannot account for any of these factors, which may influence outcomes. implication for practice this systematic review highlights the minor benefits offered by laparoscopic pyeloplasty. in practice, these minor benefits are unlikely to outweigh the surgeon’s preference of approach based on their training, experience, and available resources. however, it emphasizes the importance of urologists in training to learn the laparoscopic approach for pyeloplasty. implication for research overall, this review has shown that lp may have some minor advantages over op, but the evidence is of low quality. further research could focus on larger sample sizes, with longer-term follow-up of participants. with the introduction of robotically assisted pyeloplasty, this approach could also be investigated with large rcts. references 1. morris rk, kilby md. congenital urinary tract obstruction. best pract res clin obstet gynaecol.2008;22(1):97–122. doi: 10.1016/j. bpobgyn.2007.08.007. pmid: 17904905. 2. woodward m, frank d. postnatal management of antenatal hydronephrosis. bju int.2002; 89(2):149–156. doi: 10.1046/j.14644096.2001.woodward.2578.x. pmid: 11849184. 3. gonzález r, schimke cm. ureteropelvic junction obstruction in infants and children. pediatr clin north am.2001;48(6):1505–1518. doi: 10.1016/s0031-3955(05)70388-6. pmid: 11732127. 4. chertin b, pollack a, koulikov d, rabinowitz r, hain d, hadas-halpren i, et al. conservative treatment of ureteropelvic junction obstruction in children with antenatal diagnosis of hydronephrosis: lessons learned after 16 years of follow-up. eur urol.2006;49(4):734–738. doi: 10.1016/j.eururo.2006.01.046. pmid: 16504374. 5. anderson jc; hynes w. retrocaval ureter; a case diagnosed pre-operatively and treated successfully by a plastic operation. br j urol.1949;21(3):209–214. doi: 10.1111/j.1464-410x.1949.tb10773.x. pmid: 18148283. 6. carr bm, lyon ja, romeiser j, 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meta-analysis. j endourol.2011;25(5):727–736. doi: 10.1089/end.2010.0544. pmid: 21476861. figure 9. forest plot for blood loss (ml) table 2. summary of findings: laparoscopic pyeloplasty compared to open pyeloplasty for pelvicoureteric junction obstruction outcomes anticipated absolute effects* (95% ci) relative effect (95% ci) no of participants (studies) certainty of the evidence (grade) comments risk with open pyeloplasty risk with laparoscopic pyeloplasty failure rate 38 per 1000 50 per 1000 (17 to 146) rr 1.31 (0.45 to 3.79) 304 (6 rcts) moderate operative time md 56 minutes more (13.88 more to 98.91 more) — 304 (5 rcts) moderate length of stay md 3.18 days fewer (5.13 fewer to 1.24 fewer) — 304 (5 rcts) moderate complications 48 per 1000 63 per 1000 (25 to 159) rr 1.33 (0.53 to 3.33) 249 (4 rcts) moderate analgesia requirement (postoperative diclofenac requirement) md 364.66 mg lower (776.9 lower to 47.58 higher) — 122 (2 rcts) low blood loss md 8.52 mls higher (2.49 lower to 19.53 higher) — 60 (1 rct) low *the risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% ci). ci: confidence interval; md: mean difference; rr: risk ratio grade working group grades of evidence high certainty: we are very confident that the true effect lies close to that of the estimate of the effect. moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. 319318 siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org review laparoscopic versus open pyeloplasty for pelvicoureteric junction obstruction: a systematic review and meta-analysis http://siuj.org http://siuj.org 11. chandrasekharam v vs, babu r. a systematic review and metaanalysis of conventional laparoscopic versus robot-assisted laparoscopic pyeloplasty in infants. j pediatr urol.2021;17(4):502–510. doi: 10.1016/j.jpurol.2021.03.009. pmid: 33812779. 12. uhlig a, uhlig j, trojan l, hinterthaner m, von hammerstein-equord a, strauss a. surgical approaches for treatment of ureteropelvic junction obstruction a systematic review and network meta-analysis. bmc urol.2019;19(1):112. doi: 10.1186/s12894-019-0544-7. pmid: 31711468; pmcid: pmc6849262. 13. sterne jac, savović j, page mj, elbers rg, blencowe ns, boutron i, et al. rob 2: a revised tool for assessing risk of bias in randomised trials. bmj.2019;366:l4898. doi: 10.1136/bmj.l4898. pmid: 31462531. 14. garg m, singh v, sinha rj, sankhwar sn. prospective randomized comparison of retroperitoneoscopic vs open pyeloplast y with minimal incision: subjective and objective assessment in adults. urology.2014;83(4):805 –811. doi: 10.1016/j.urology.2013.11.024. pmid: 24485998. 15. ravish ir, nerli rb, reddy mn, amarkhed ss. laparoscopic pyeloplasty compared with open pyeloplast y in children. j endourol.2007 aug;21(8):897-902. doi: 10.1089/end.2006.0411. pmid: 17867949 clinical trial. 16. gat ti jm, amstutz sp, bowlin pr, stephany ha, murphy jp. laparoscopic vs open pyeloplasty in children: results of a randomized, prospective, controlled trial. j urol.2017 mar;197(3 pt 1):792-797. doi: 10.1016/j.juro.2016.10.056. epub 2016 oct 17. 17. srinivas kk, uppin iv, nerle rb. a prospective randomized controlled trial complains open pyeloplasty and laparoscopic pyeloplasty for ureteropelvic junction obstruction (upjo): subjective outcome. j clin diagn res.2011;5(8):1601–1605. 18. huang y, wu y, shan w, zeng l, huang l. an updated meta-analysis of laparoscopic versus open pyeloplasty for ureteropelvic junction obstruction in children. int j clin exp med.2015;8(4):4922–4931. pmid: 26131065; pmcid: pmc4483847. 19. mcculloch p, taylor i, sasako m, lovett b, griffin d. randomised trials in surgery: problems and possible solutions. bmj.2002;324(7351):1448– 1451. doi: 10.1136/bmj.324.7351.1448. pmid: 12065273; pmcid: pmc1123389. 20. dahm p. envisioning an ideal future for urological innovation. bju int.2016;117(3):387–388. doi: 10.1111/bju.13129. pmid: 25810303. 21. bansal p, gupta a, mongha r, narayan s, das rk, bera m, chakraborty sc, kundu ak. laparoscopic versus open pyeloplasty: comparison of two surgical approachesa single centre experience of three years. indian j surg. 2011 aug;73(4):264-7. doi: 10.1007/s12262-011-0237-2. epub 2011 apr 26. pmid: 22851839; pmcid: pmc3144340. 22. mohamed he, el-asmar km, hassan ta , elshafei ea, soliman mh, allam am. feasibility, safety and effectiveness of laparoscopic transperitoneal pyeloplasty in children: ain shams university early experience. ann pediatr surg.2022;18(26). https://doi.org/10.1186/ s43159-022-00164-5 320 siuj • volume 4, number 4 • july 2023 siuj.org review http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information adjuvant therapy, neoadjuvant therapy, vascular endothelial growth factor receptor tyrosine kinase inhibitor, immune checkpoint inhibitor, renal cell carcinoma see ”acknowledgments” for details. received on july 15, 2022 accepted on september 9, 2022 this article has been peer reviewed. soc int urol j. 2022;3(6):465–477 doi: 10.48083/ vsqg7437 2022 wuof/siu international consultation on urological diseases: neoadjuvant and adjuvant therapy for renal cell carcinoma naomi b. haas,1 jeffrey shevach,1 ian d. davis,2 tim eisen,3 marine gross-goupil,4 anil kapoor,5 viraj a. master,6,7 christopher w. ryan,8 manuela schmidinger9 1abramson cancer center, perelman school of medicine, university of pennsylvania, philadelphia, united states 2 monash university eastern health clinical school, melbourne, australia 3 university of cambridge, cambridge, united kingdom 4 département d‘oncologie médicale, hôpital saint andré, chu de bordeaux, bordeaux, france 5 mcmaster university, hamilton, canada 6 department of urology, emory university school of medicine, atlanta, united states 7 winship cancer institute of emory university, atlanta, united states 8 oregon health and science university, knight cancer institute, portland, united states 9 department of urology, medical university of vienna, vienna, austria abstract patients undergoing definitive surgery or ablative techniques for nonmetastatic kidney cancer have varying degrees of risk of recurrent disease post procedure. the ultimate goal of “adjuvant therapy” is to reduce the incidence of recurrent disease, and to cure more patients. we summarize the current state of perioperative therapy for kidney cancer and explore future directions to develop optimal adjuvant strategies. we define risk and risk of recurrence post-definitive therapy, describe the controversies surrounding the trial landscape of adjuvant vascular endothelial growth factor receptor tyrosine kinase inhibitors and immune checkpoint inhibitors. we review data on neoadjuvant therapy before advanced kidney cancer resection. radiologic, ethnic, economic, and geographic considerations with respect to adjuvant therapy are highlighted, as well as adjuvant therapy issues especially pertinent to patients, future directions in adjuvant trial design specifically targeted to biomarkers and patient selection, and sequencing of treatment after adjuvant therapy in those patients with recurrence. introduction patients undergoing definitive surgery or ablative techniques for nonmetastatic kidney cancer have varying degrees of risk for recurrent disease post-procedure. the ultimate goal of “adjuvant therapy” is to reduce the incidence of recurrent disease, and to cure more patients. this review summarizes the current state of perioperative therapy for kidney cancer and explores future directions to develop optimal adjuvant strategies. we define risk and risk for recurrence post-definitive therapy and describe the adjuvant trials landscape of adjuvant vascular endothelial growth factor receptor tyrosine kinase inhibitor (vegfrtki) trials and immune checkpoint inhibitor (io) trials. we review data on neoadjuvant therapy before advanced kidney cancer resection. radiologic, ethnic, economic, and geographic considerations with regard to adjuvant therapy are highlighted. also covered are adjuvant therapy issues especially pertinent to patients, future directions in adjuvant trial design specifically targeted to biomarkers and patient selection, and sequencing of treatment after adjuvant therapy in those patients with recurrence. 464siuj.org siuj • volume 3, number 6 • november 2022 2022 wuof/siu international consultation on urological diseases mailto:naomi.haas%40pennmedicine.upenn.edu?subject=siuj http://siuj.org siuj typewritten text siuj typewritten text defining risk risk for disease recurrence post-nephrectomy for renal cell cancer depends largely on the characteristics of the primary tumor. this risk can mainly be stratified based on stage and grade of the cancer. patients with larger tumors and higher grade are at increased risk for recurrence after nephrectomy. risk for recurrence for high-risk patients is greatest early (0–3 years) postnephrectomy and plateaus after 4 to 5 years[1]. some predictive models that have been used for survival outcomes post-nephrectomy for renal cell carcinoma (rcc) including the uiss (university of california la integrated staging system)[2], ssign (stage, size, grade, necrosis)[3], karakiewicz nomogram[4], grant (grade, age, node, and tumor)[5,6], and leibovich[7,8]. the criteria used to determine risk in these staging systems can be found in table 1. based on these predictive models, in general, patients with resected stage t3 or higher, and high-grade tumors, are at the highest risk for recurrent disease, and are most likely to benefit from an adjuvant agent that would decrease their risk for recurrence and improve overall survival (os). patients at lower risk (t1 and t2a disease) receiving adjuvant therapy for the most part may be overtreated, as the risk for recurrence is less than 20%. the patient population that would likely benefit the most from adjuvant therapy are those with resected metastases, as demonstrated in keynote-564[9]. unanswered questions in adjuvant therapy include its role in non-clear cell histology. non-clear cell histologies can have higher risk for recurrence, but are often excluded in adjuvant trials, including the recent landmark keynote-564 adjuvant pembrolizumab trial, which required a clear cell component[9]. abbreviations dfs disease-free survival fda united states food and drug administration grant grade, age, node, and tumor io immune checkpoint inhibitor iraes immune-related adverse events os overall survival rcc renal cell carcinoma rfs recurrence-free survival ssign stage, size, grade, necrosis uiss university of california la integrated staging system vegf vascular endothelial growth factor vegfr-tki vascular endothelial growth factor receptor tyrosine kinase inhibitor table 1. predictive models for renal cell carcinoma recurrence and survival risk stratification criteria used 5-year cancer-specific survival low risk intermediate risk high risk uiss[2] t-stage, fuhrman grade, ecog 91.1% 80.4% 54.7% ssign[3] tnm stage, tumor size, fuhrman grade, tumor necrosis 0–2 points 97.1% 3–4 points 89.8% 5–6 points 74.1% 7–9 points 38.6% 10+ points 19.2% grant a[5,6] age, pt-stage, pn-stage, fuhrman grade 0 or 1 risk factors 2 risk factors 3 or 4 risk factors 86%–94% 76% 16%–46% karakiewicz[4] tnm stage, fuhrman grade, tumor size n/a leibovich[7,8] t-stage, n-stage, tumor size, fuhrman grade, tumor necrosis n/a a 5-year survival outcome for grant score is overall survival. ecog: eastern cooperative oncology group; grant: grade, age, node, and tumor; ssign: stage, size, grade, necrosis; m: metastatic stage; n: node; t: tumor; uiss: ucla integrated staging system. 465 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org adjuvant therapy trials in renal cell carcinoma cytokine era: several adjuvant trials with cytokines or other biologics have been previously completed, and summarized elsewhere, and are outside the scope of this review[10]. adjuvant trials with targeted agents the rationale for testing agents targeting the angiogenic pathway in the adjuvant setting is based on multiple observations showing that vascular endothelial growth factor (vegf) is involved in the pathogenesis of metastasis[11]. five placebo-controlled, adjuvant, phase 3 studies investigated the benefit of targeted therapy with vegfr-tkis versus placebo (table 2)[12–16]. the primary endpoint in all trials was disease-free survival (dfs); however, patient populations and study designs varied between the trials, with differing agents and duration of therapy. of these, only s-trac[14], which enrolled the highest risk group (pt3 and higher) demonstrated an improvement in dfs with sunitinib compared with placebo. patients assigned to sunitinib had a significantly improved dfs (6.8 years; 95% ci, 5.8–not reached) when compared to patients in the placebo arm (5.6 years; 95% ci, 3.8–6.6), though in an updated analysis, there was no difference in os[17]. notably, the assure[13] trial did not identify a significant difference between adjuvant sunitinib versus placebo with respect to dfs. the differences in patient population may have accounted for the differences in results between s-trac and assure. only patients with clear cell histology were eligible for table 2. adjuvant trials with targeted agents in rcc trial n histology patient characteristics treatment arms (vs. placebo) duration endpoint results s-trac[14] 615 clear cell high-risk rcc patients according to uiss sunitinib 1 year dfs hr, 0.76 95% ci, 0.59–0.98 (p = 0.03) assure[13] 1943 clear cell non-clear cell nonmetastatic rcc; disease stage ii–iv selected by uiss sunitinib/ sorafenib 1 year dfs hr, 1.02 (sunitinib) 97.5% ci, 0.85–1.23 (p =0.80) hr, 0.97 (sorafenib) 97.5% ci, 0.80–1.17 (p = 0.72) sorce[12] 1656 clear cell non-clear cell patients with leibovich highand intermediate-risk resected rcc sorafenib sorafenib 1 year 3 years dfs hr, 0.94 (1 year sorafenib) 95% ci, 0.77–1.14 (p = 0.51) hr, 1.01 (3 years sorafenib) 95% ci, 0.83–1.23 (p = 0.95) everest[20] 1537 clear cell non-clear cell pathological stage intermediate or very highrisk rcc patients with full or partial nephrectomy everolimus 9 cycles rfs hr, 0.85 95% ci, 0.72–1.00 (p = 0.0246)a protect[16] 1540 clear cell patients with moderately high or high risk after nephrectomy of localized or locally advanced rcc by ajcc tnm v.2010 pazopanib 1 year dfs hr, 0.86 95% ci, 0.70–1.06 (p = 0.17) atlas[15] 700 clear cell high-risk, nonmetastatic rcc with nephrectomy by ajcc tnm v.2010 axitinib 3 years dfs hr, 0.87 95% ci, 0.66–1.15 (p = 0.32) aone-sided p value, not statistically significant (threshold for significance set at 0.022). ajcc tnm: american joint commission on cancer tumor, node, metastasis staging system; ci: confidence interval; dfs: disease-free survival; hr: hazard ratio; rcc: renal cell carcinoma; rfs: recurrence-free survival; uiss: ucla integrated staging system. 466siuj.org siuj • volume 3, number 6 • november 2022 neoadjuvant and adjuvant therapy for renal cell carcinoma http://siuj.org s-trac, while clear cell histology accounted for only 80% of patients in assure. additionally, the higher risk (tumor stage 3 or higher) of patients in s-trac may have also led to differences in study outcomes. it should be noted, however, that in a post-hoc analysis of a subpopulation subject to the s-trac inclusion criteria, dfs was similar between all 3 arms[18]. while this analysis was underpowered to statistically detect a difference between sunitinib and placebo, there was no obvious trend in favor of active treatment. it is also possible that differences in trial conduct between s-trac and assure, such as disease imaging intervals (earlier and more frequent in s-trac), may have contributed to the observed differences in dfs, but they would not have impact on os. while there were differences in outcome of the individual vegfr-tki studies, a meta-analysis of adjuvant vegfr-tki trials for patients with rcc did identify a dfs benefit (hr, 0.84; 95% ci, 0.76–0.93)[19]. however, table 3. ongoing or completed adjuvant trials with immune checkpoint inhibitors in rcc trial n histology patient characteristics treatment arms duration (months) endpoint result keynote-546 nct03142334[9,58] 994 clear cell pt2, g4/sarcomatoid, n0 or pt3, g3-4, n0 or pt4, any g, n0 or ptany, any g, n1 or m1 resected pembrolizumab 12 dfs hr, 0.63 95% ci, 0.50–0.80 rampart nct03288532[59] 1750 clear cell non-clear cell leibovich 3–11 durvalumab + tremelimumab 12 dfs os pending checkmate-914 nct03138512[24] 1628 clear cell +/ sarcomatoid differentiation pt2a,g3/4, n0 or pt2b, any g, n0 or pt3, any g, n0 or pt4, any g, n0 or ptany, any g, n1 nivolumab + ipilimumab 24 dfs pendinga immotion010[23] 778 clear cell non-clear cell with sarcomatoid differentiation pt2, g4, or pt3a, g3-4 or pt3b, any g or ptany, any g, n1 or m1 resected atezolizumab 12 dfs pendinga prosper[37] adjuvant/ neoadjuvant 804 clear cell non-clear cell >ct2an0m0 or ctanyn1m0 nivolumab 1 neoadjuvant 9 adjuvant rfs pending litespark-022 1600 clear cell pt2, g4/sarcomatoid, n0 or pt3, any g, n0 or pt4, any g, n0 or ptany, any g, n1 or m1 resected pembrolizumab ± belzutifan 12 dfs pending apresentations of checkmate-914 (arm a), immotion-010, and prosper (ea8143) at european society of medical oncology meeting 2022 reported negative results. ci: confidence interval; dfs: disease-free survival; hr: hazard ratio; g: tumor grade; n: nodal stage; m: metastatic stage; os: overall survival; pt: pathologic t-stage; rfs: recurrence-free survival. 467 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org the meta-analysis did not identify an os benefit (nor have any of the individual trials), and due to the lack of a proven os benefit, coupled with the high rates of unacceptable toxicity and dropout from the treatment arms of the vegfr-tki trials, adjuvant therapy with sunitinib has not achieved widespread adoption, even in countries where sunitinib is approved for adjuvant therapy in rcc. everest is a randomized, placebo-controlled, phase 3 trial of everolimus versus placebo for 54 weeks in patients with clear and non-clear cell rcc after nephrectomy or partial nephrectomy[20]. a total of 1545 patients with pathological stage intermediateor high-risk status were enrolled. the primary endpoint of the trial was recurrence-free survival (rfs), and with median follow-up of 76 months, there was improvement in the everolimus arm that did not reach statistical significance (hr, 0.85; 95% ci, 0.72–1.00). adjuvant trials with immune checkpoint inhibitors immune checkpoint inhibitors (ios) targeting the programmed cell death protein 1 (pd-1) pathway, or the cytotoxic t lymphocyte-associated protein 4 (ctla-4) pathway have revolutionized the treatment of metastatic rcc. their role in the adjuvant setting is currently under investigation in multiple clinical trials (table 3), with one phase 3 trial—keynote-564—having published results so far. keynote-564[9] is a randomized, double-blind, placebo-controlled, phase 3 trial testing the role of the pd-1 inhibitor pembrolizumab in patients with intermediate-high-risk, high-risk, or m1–no evidence of disease (ned) status including intermediate-risk (pt2, grade 4, n0m0 or pt3, any grade, n0, m0), high-risk (pt4, any grade, any n, m0 or any pt, any grade, n+, m0), and also patients who had undergone complete resection of metastasis (m1), within a year of primary surgery. patients (n=994) were randomized to receive either pembrolizumab or placebo every 3 weeks for 1 year. the primary endpoint was investigator-assessed dfs, with os as a secondary endpoint. after a median follow-up of 30.1 months, the dfs rate at 30 months was 75.2% and 65.5% for pembrolizumab and placebo, respectively (hr, 0.63; 95% ci, 0.50–0.80)[21]. os data is not mature. the authors reported grades 3+4 treatment-related adverse events (aes) for pembrolizumab and placebo in 18.9% and 1.2%, respectively, with no treatment-related deaths. in the pembrolizumab group, 22% of patients discontinued treatment due to aes. based on these findings, pembrolizumab has received united states food and drug administration (fda) and european medicines agency (ema) approval as an adjuvant treatment in patients with rcc and high risk for relapse. while data has not yet been presented, recent press releases indicate that adjuvant atezolizumab (immotion010) and ipilimumab and nivolumab combination therapy (checkmate-914) have not demonstrated benefit in the adjuvant setting[22–25]. once full results are published, comparisons in trial design and patient selection will need to be carefully examined to determine why the results are inconsistent with keynote-564. additional trials evaluating the utility of adjuvant ios are ongoing (table 3). neoadjuvant therapy in rcc the standard-of-care management of nonmetastatic disease remains surgical resection. just as combination tki and immunotherapy combinations have come to dominate the frontline metastatic space, so too are investigators attempting to capitalize on the synergy of these agents in the neoadjuvant setting[26–33]. a summary of ongoing trials investigating immunotherapy in the preoperative setting is found in table 4. neoadjuvant therapy may have several potential advantages over adjuvant therapy: first, it may decrease tumor burden and improve surgical outcomes, allowing for nephron-sparing surgery in select cases, converting unresectable tumors to resectable, and decreasing venous involvement, thereby facilitating ease of surgery. second, response of the primary tumor to therapy can predict long-term outcomes to a particular therapy, potentially allowing for adaptive adjuvant therapy trials. also, neoadjuvant studies allow for collection of molecular correlative data from peripheral blood as well as paired biopsy and resection specimens to aid in response evaluation. lastly, the in situ tumor may provide increased priming of the immune system compared with micrometastatic disease, leading to a more robust immune response[34,35]. the application of immunotherapy in the neoadjuvant setting is early. two small phase 2 studies have demonstrated that neoadjuvant nivolumab prior to nephrectomy was safe and feasible, without delay to nephrectomy after receiving at least one dose of nivolumab[36,37]. the phase 3 study of neoadjuvant nivolumab, prosper rcc (nct03055013), is the only phase 3 trial investigating preoperative immunotherapy versus observation, with results pending at the european society medical oncology (esmo)[38]. perioperative durvalumab (anti–pd-l1) with or without tremelimumab (anti–ctla-4) was investigated in a multicohort phase 1b trial evaluating combined io[39]. there were no treatment-related delays or complications of surgery although the addition of tremelimumab was associated with excess immune-related aes (iraes) and the study was suspended. 468siuj.org siuj • volume 3, number 6 • november 2022 neoadjuvant and adjuvant therapy for renal cell carcinoma http://siuj.org rare instances of iraes delaying surgery, include at least one grade 4 ae, which underscores the need for biologic markers of patient susceptibility to iraes [36,39–42]. notably, there was no signal regarding surgical complications across the above studies of neoadjuvant immunotherapy. these data, combined with retrospective data, suggest that io is safe to continue through surgery without interruption[43]. additionally, while patients are less likely to have an ae with immunotherapy in the adjuvant setting, these aes can be debilitating and permanent, requiring long-term immunosuppression, whereas the aes seen with vegfr inhibition typically resolve with drug cessation. regulatory issues uptake of new therapies into routine clinical practice is based on published peer-reviewed evidence, influenced by international guidelines and recommendations, and tailored to the needs of each specific patient based on their circumstances and comorbidities. the “real-world” table 4. ongoing clinical trials investigating neoadjuvant therapy (± adjuvant component) in locally advanced or metastatic (with planned cytoreductive nephrectomy) rcc immunotherapy or immunotherapy combinations nct trial # phase arm drug dose nct04393350 2 single lenvatinib and pembrolizumab len:18 mg daily pembro: 200 mg q3w nct03680521 2 single sitravatinib and nivolumab sitravatinib: oral capsule daily nivolumab: 24 mg iv q2w nct04385654 2 single toripalimab and axitinib toripalimab: 240 mg iv q3w axitinib: 5 mg po bid nct04118855 2 single toripalimab and axitinib toripalimab: 240 mg iv q3w axitinib: 5 mg po bid nct04995016 pandora 2 single pembrolizumab and axitinib pembrolizumab: 200 mg q3w axitinib: 5 mg po bid nct05024318 napster 2 randomized sabr (arm 1) vs. pembrolizumab and sabr (arm 2) arm 1: sabr: 42 gy in 3 fractions arm 2: pembrolizumab 200 mg q3w x 3 cycles with sabr administered after cycle 1 nct03341845 neoavax 2 single axitinib and avelumab axitinib: 5mg bid avelumab: 10mg/kg q2w nct04028245 sparc-1 2 single spartalizumab and canakinumab spartalizumab: 400 mg q4w canakinumab: 300 mg q4w nct03055013 prosper rcc 3 randomized perioperative nivolumab vs. observation nivolumab: 480 mg every 14 days x 1 neoadjuvant cycle and up to 9 cycles adjuvantly nct04322955 cyto-kik 2 single preoperative nivolumab and cabozantinib nivolumab: 480 mg every 4 weeks cabozantinib: 40 mg daily aor deemed unresectable by surgeon. bclear cell must be predominant histology ( > 50%). cbegins 2 weeks prior to nivolumab. dclear cell component. eincluding rhabdoid and sarcomatoid differentiation. ffeasibility if > 85% proceed. gfirst 3 to 6 subjects will hold cabozantinib for 3 weeks prior to surgery; if safe, all others will hold for only 2 weeks prior. 469 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org table 4. ongoing clinical trials investigating neoadjuvant therapy (± adjuvant component) in locally advanced or metastatic (with planned cytoreductive nephrectomy) rcc immunotherapy or immunotherapy combinations nct trial # phase arm drug dose nct04393350 2 single lenvatinib and pembrolizumab len:18 mg daily pembro: 200 mg q3w nct03680521 2 single sitravatinib and nivolumab sitravatinib: oral capsule daily nivolumab: 24 mg iv q2w nct04385654 2 single toripalimab and axitinib toripalimab: 240 mg iv q3w axitinib: 5 mg po bid nct04118855 2 single toripalimab and axitinib toripalimab: 240 mg iv q3w axitinib: 5 mg po bid nct04995016 pandora 2 single pembrolizumab and axitinib pembrolizumab: 200 mg q3w axitinib: 5 mg po bid nct05024318 napster 2 randomized sabr (arm 1) vs. pembrolizumab and sabr (arm 2) arm 1: sabr: 42 gy in 3 fractions arm 2: pembrolizumab 200 mg q3w x 3 cycles with sabr administered after cycle 1 nct03341845 neoavax 2 single axitinib and avelumab axitinib: 5mg bid avelumab: 10mg/kg q2w nct04028245 sparc-1 2 single spartalizumab and canakinumab spartalizumab: 400 mg q4w canakinumab: 300 mg q4w nct03055013 prosper rcc 3 randomized perioperative nivolumab vs. observation nivolumab: 480 mg every 14 days x 1 neoadjuvant cycle and up to 9 cycles adjuvantly nct04322955 cyto-kik 2 single preoperative nivolumab and cabozantinib nivolumab: 480 mg every 4 weeks cabozantinib: 40 mg daily aor deemed unresectable by surgeon. bclear cell must be predominant histology ( > 50%). cbegins 2 weeks prior to nivolumab. dclear cell component. eincluding rhabdoid and sarcomatoid differentiation. ffeasibility if > 85% proceed. gfirst 3 to 6 subjects will hold cabozantinib for 3 weeks prior to surgery; if safe, all others will hold for only 2 weeks prior. access to and uptake of new therapies is inf luenced primarily by what is approved and, more importantly, reimbursed in each region or available to those with financial resources. the impact of heterogeneous regulatory approval processes was clearly illustrated with sunitinib. while sunitinib was granted approval as adjuvant therapy for patients with risk for rcc recurrence by the united states fda, counterparts in the european union and united kingdom did not grant approval for an adjuvant indication. additionally, the kidney cancer research network of canada issued a consensus statement that did not support the use of vegfr-tki in the adjuvant setting following a systematic review and meta-analysis of trials in this space[44]. in november 2021, the fda approved adjuvant pembrolizumab for patients who are at intermediate-high or high risk for recurrence after surgery based on the keynote-564 study results using investigator-assessed dfs as the major efficacy outcome[9]. the review of the pembrolizumab submission was duration goal n stage histology primary endpoint status 12 weeks 17 ≥ct3nx or t any n+a ccb orr recruiting sitravatinib: 6–8 weeksc nivolumab: 4–6 weeks 25 locally advanced rcc cc orr and point in treatment course of orr active, not recruiting 6 weeks 40 ct ≥ 2 or cn+ non-cc mpr, pcr, pnr not yet recruiting up to 12 weeks 30 t2-3, n0, m0 cc orr not yet recruiting 12 weeks 18 ≥t3nx or t any n+f ccd mpr not yet recruiting 9 weeks 26 t1b-3, n0-1, m0 or low volume m1 planned for nephrectomy cce mpr not yet recruiting 12 weeks 40 “nonmetastatic, completely resectable primary tumor of intermediate to high risk” cc rate of partial response results: 30% partial response rate 8 weeks 14 ≥ ct2nx or ctanyn1 ccb % of patients who proceed to radical nephrectomyf not yet recruiting 7-28 days preoperative, up to 9 months post-operatively 766 ≥ ct2nx or ctanyn1 any efs completed up to 12 weeksg 45 metastatic ccb cr rate recruiting cc: clear cell; efs: event-free survival; gy: gray; len: lenvatinib; m: metastatic stage; mpr: major pathologic response; n: nodal stage; orr: objective response rate; pcr: pathologic complete response; pembro: pembrolizumab; pnr: pathologic nodal response; rcc: renal cell carcinoma; sabr: stereotactic ablative radiotherapy; t: tumor stage. 470siuj.org siuj • volume 3, number 6 • november 2022 neoadjuvant and adjuvant therapy for renal cell carcinoma http://siuj.org also conducted under project orbis, which facilitates concurrent review of oncology products among international partners, allowing for simultaneous decisions in all countries. the australian therapeutic goods administration, health canada, and swissmedic participated in this review. the approval of pembrolizumab redemonstrated the fda’s acceptance of dfs as a regulatory endpoint for adjuvant rcc trials. in the uk, the appraisal of pembrolizumab in the adjuvant setting has started, the ema has approved, and publication of the results from the national institute for health and care excellence (nice) are pending[45]. issues important to patients adjuvant and neoadjuvant therapy adjuvant therapy given after curative intent therapy can be likened to life insurance: “a bet you do not want to win.” a life insurance policy is essentially saying to a company, “i bet i die,” and the company saying, “we bet you don’t.” a decision to undertake adjuvant therapy employs similar thinking. patients with no apparent residual disease will be offered adjuvant therapy to reduce their theoretical risk for recurrence and death from cancer. most patients who receive adjuvant therapy cannot benefit from it, and are therefore only exposed to possible harms, which is evident in the high discontinuation rate seen in the above adjuvant studies. however, it may be possible to increase the proportion of patients who may benefit through careful patient selection. conversely, neoadjuvant therapy is “a bet you want to win”—an investment in treatment now, while cancer is still detectable, to try to improve outcomes from definitive treatment such as surgery. currently for patients with renal cell cancer, this approach is nearly always in the context of a clinical trial, as its benefit is unproven. patient preferences clinicians and patients often have different goals for treatment and expectations of outcomes. a patient preference substudy in the sorce clinical trial[12] used a validated questionnaire aiming to understand what degree of improvement in survival would be judged by participants and investigators as sufficient to justify their participation and potential side effects from treatment with sorafenib[46]. investigators judged that larger survival benefits were required than their patients to make adjuvant treatment worthwhile[46,47]. patients and clinicians also perceive and report adverse events differently. clinician assessment through the nci common terminology criteria for adverse events (ctcae) is not always concordant with patient-reported outcomes (pro)[48]. owing to the differences between patient and clinician perspectives, it is imperative to work with community partners in the design of adjuvant clinical trials in rcc to ensure the outcomes align with community expectations and needs[49]. unmet needs the most obvious unmet need in the context of clinical trials for rcc is for effective therapies. none of the trials so far have demonstrated a survival advantage, including the data with pembrolizumab in keynote-564[9]. it is therefore reasonable to advise patients that the standard of care remains observation, with access to life-prolonging therapies in the event of relapse. patients want better treatments and outcomes with quicker results[50–53], and they want trials that examine and report the patient experience. these are all considerations for future trial designs but also apply to everyday treatment decision-making. future directions several issues need to be considered when designing clinical trials of adjuvant therapy in rcc. statistical designs for the trials there is equipoise in arguments for randomized control trials (rcts) versus multi-arm multistage (mams) designs for adjuvant trials. rcts are preferred in industry and ask well-defined controlled questions. this approach gives confidence that the trial will be delivered in the projected timescale and the simple design is easy for patients and physicians to understand. mams trials are ideal for academic consortia and can ask multiple questions simultaneously and in sequence and adapt to new data. rapid advancements in prostate cancer have been made using this approach via stampede and in kidney cancer via rampart. this model allows adaptions that include adding arms, dropping arms, and changing control arms in light of new data. although initially less attractive for commercial support, this approach, which demonstrated speed and quality of data at low cost, could be compelling. trial endpoints the aim of adjuvant treatment is to improve the cure rate or at least to prolong healthy life. os remains the gold standard but in event-driven trials, this will either take a long time (generally 3 to 4 years to accrue and 3 to 7 years for maturity) or will require very large numbers of patients. this massively increases costs and slows potential progress. moreover, there is expenditure of patients who may not need therapy and perhaps undertreatment of very high-risk patients. thus, dfs has become a de facto approach and was an accepted endpoint for s-trac and keynote-564. however, in a recent meta-analysis encompassing 13 studies and more than 6400 patients treated with adjuvant therapies for rcc, correlation between 5-year dfs and os rates was modest, suggesting dfs is not a good surrogate 471 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org marker of os[54]. these results underline the difficulty of choosing the good primary objective in designing an adjuvant clinical trial in rcc. essential requirements for future trials include cost-effectiveness: need for innovation in therapies to reduce health care costs, including the medium (such as oral checkpoint inhibitors instead of intravenous), the duration of therapy, and access to care. finally, quality of life remains underappreciated: the diarrhea and dysgeusia and fatigue experienced from vegfr-tkis continue to have poor remedy, and the autoimmune side effects from immunotherapy can be permanent. the risk/ benefit ratio for adjuvant therapy must outweigh that of reserving treatment only for metastatic disease. biomarkers needed contemporar y metastatic clear cell cancer tria l designs have failed to address whether both io and antiangiogenic therapy are necessary for individual patients. both pure antiangiogenic trials and pure io monotherapy trials have been applied to the adjuvant setting with continued uncertainty as to whom would benefit from adjuvant therapy or neoadjuvant therapy and for how long. with the availability of molecular signatures, which could improve prognostication, there is opportunity to design smarter trials. transcriptomics, which appear to indicate sensitivity or resistance of some metastatic renal cancers to io or antiangiogenic therapy[55], need validation and could be used to select treatments when indicated, or could be used in the development of adaptive, biomarker-driven basket trials similar to i-spy2 in breast cancer (nct01042379). the prosper trial is undergoing such analysis retrospectively. specimens from the assure trial are undergoing whole-exome rna sequencing, which likely will provide further insight into which patients are more likely to relapse and have worse prognosis. furthermore, analysis of kidney injury molecule-1 (kim-1) from blood correlates with detection of recurrence[56] and plasma dna methylation immunoprecipitation analysis are being retrospectively validated to predict recurrence in this population[57]. if validated, these tools could be applied to future trials to guide patient populations to be offered or spared adjuvant therapy. sequencing of treatments postadjuvant therapy the new approval and future use of io adjuvant therapy in some patients affects the design of first-line metastatic renal cancer trials. the timing of relapse may be important, as it is untested whether patients who relapse while receiving adjuvant therapy might still benefit from vegfr-tki monotherapy or vegfr-tki /io or io/io. furthermore, should patients who relapse 6 months after io therapy be considered differently than those who relapse later post-therapy? for now, these are unanswered questions. the application of molecular typing becomes essential in this era, and tools such as kim-1, dna methylation, or circulating tumor dna (ctdna) if sensitive enough, could be used for cancer screening, as is in process in grail[58], to identify earlier cancers and thereby obviate the use of adjuvant therapy in many patients. conclusions while io shows promise for the adjuvant treatment of high-risk clear cell rcc, there is still much to learn from ongoing clinical trials and longer follow-up data in this space, and the lessons learned from adjuvant targeted therapy trials must now be applied to this era. we must await and properly weigh os data from trials of adjuvant io, and we should strive to identify readily scalable biomarkers that can be used to hone patient selection criteria in future prospective therapeutic trials. 472siuj.org siuj • volume 3, number 6 • november 2022 neoadjuvant and adjuvant therapy for renal cell carcinoma http://siuj.org acknowledgments n. haas: participation on a data safety monitoring board or advisory board: merck; eisai, exilexis, aveo, roche (all paid to me). leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: co-chair genitourinary committee ecog-acrin, member nci gu steering committee, ecog-acrin representative to nci renal task force. funding: dod kidney cancer consortium. j. shevach: t32hg009495 funding support. i. davis: participation on a data safety monitoring board or advisory board: ipsen; eisai, bms, merck/ pfizer avelumab, aztrazeneca io (all advisory boards unpaid; honoraria paid directly to anzup). leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: director and board chair, anzup cancer trials group (unpaid). other financial or non-financial interests: institutional payments to support kidney cancer trials: anzup cancer trials group, msd, astrazeneca, exelixis, merck, pfizer, eisai. t. eisen: employment: astrazeneca (to march 2020); employment as vp oncology early clinical dev roche (from march 2020); employment as vp gu oncology late clin dev astrazeneca research support. stock options astrazeneca and roche. leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: macmillan cancer support trustee for 10 years to 2021; cambridge university health partners non-executive director travel support to genitourinary symposiums asco 2020 roche. m. gross-goupil: participation on a data safety monitoring board or advisory board: msd, bms, pfizer, ipsen. leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: member of the getug. support for attending meetings and/or travel: msd, ipsen, bms, pfizer. a. kapoor: participation on a data safety monitoring board or advisory board: ipsen, eisai, merck, bms, janssen, bayer, abbvie (advisory boards). leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: chair, kidney cancer research network of canada (kcrnc). stock options: verity pharma. v. master: participation on a data safety monitoring board or advisory board: merck, pfizer, bms, exilexis. support for attending meetings and/or travel: american college of surgeons. c. ryan: grants or contracts from any entity: ayala, bristol meyer squibb, daiichi-sankyo, deciphera, exelixis, genentech, novartis, karyopharm, merck, nektar, pfizer, xynomic, shasqi, monopar, boehringer ingelheim, ptc therapeutics, trillium therapeutic (to my institution for all). consulting fees: exelixis (all payments to me) aveo, daiichi, sankyo, synox, bristol meyer squibb, astra zeneca, janssen. m. schmidinger: consulting fees and honoraria: bms, msd, ipsen, exelixis, eisai. support for attending meetings and/or travel: msd ipsen bms. participation on a data safety monitoring board or advisory board: bms msd, ipsen, eisai. 473 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org references 1. chamie k, donin nm, klöpfer p, bevan p, fall b, wilhelm o, et al. adjuvant weekly girentuximab following nephrectomy for high-risk renal cell carcinoma: the ariser randomized clinical trial. jama oncol.2017;3(7):913-920. 2. zisman a, pantuck aj, dorey f, said jw, shvarts o, quintana d, et al. improved prognostication of renal cell carcinoma using an integrated staging system. j clin oncol.2001;19(6):1649-1657. 3. frank i, blute ml, cheville jc, lohse cm, weaver al, zincke h. an outcome prediction model for patients with clear cell renal cell carcinoma treated with radical nephrectomy based on tumor stage, size, grade and necrosis: the ssign score. j urol. 2002;168(6):2395-2400. 4. karakiewicz pi, briganti a, chun fkh, trinh q-d, perrotte p, ficarra v, et al. multi-institutional validation of a new renal cancer–specific survival nomogram. j clin oncol.2007;25(11):1316-1322. 5. buti s, puligandla m, bersanelli m, dipaola rs, manola j, taguchi s, et al. validation of a new prognostic model to easily predict outcome in renal cell carcinoma: the grant score applied to the assure trial population. ann oncol.2017;28(11):2747-2753. 6. buti s, karakiewicz pi, bersanelli m, capitanio u, tian z, cortellini a, et al. validation of the grade, age, nodes and tumor (grant) score within the surveillance epidemiology and end results (seer) database: a new tool to predict survival in surgically treated renal cell carcinoma patients. sci rep.2019;9(1):13218. 7. leibovich bc, blute ml, cheville jc, lohse cm, frank i, kwon ed, et al. prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. cancer.2003;97(7):1663-1671. 8. leibovich bc, cheville jc, lohse cm, zincke h, frank i, kwon ed, et al. a scoring algorithm to predict survival for patients with metastatic clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. j urol.2005;174(5):1759-1763; discussion 63. 9. choueiri tk, tomczak p, park sh, venugopal b, ferguson t, chang yh, et al. adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. n engl j med.2021;385(8):683-694. 10. dizman n, adashek jj, hsu j, bergerot pg, bergerot cd, pal sk. adjuvant treatment in renal cell carcinoma. clin adv hematol oncol.2018;16(8):555-563. 11. weis s, cui j, barnes l, cheresh d. endothelial barrier disruption by vegf-mediated src activity potentiates tumor cell extravasation and metastasis. j cell biol.2004;167(2):223-229. 12. eisen t, frangou e, oza b, ritchie aws, smith b, kaplan r, et al. adjuvant sorafenib for renal cell carcinoma at intermediate or high risk of relapse: results from the sorce randomized phase iii intergroup trial. j clin oncol.2020;38(34):4064-4075. 13. haas nb, manola j, uzzo rg, flaherty kt, wood cg, kane c, et al. adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ecog-acrin e2805): a double-blind, placebo-controlled, randomised, phase 3 trial. lancet.2016;387(10032):2008-2016. 14. ravaud a, motzer rj, pandha hs, george dj, pantuck aj, patel a, et al. adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. n engl j med.2016;375(23):2246-2254. 15. gross-goupil m, kwon tg, eto m, ye d, miyake h, seo si, et al. a xitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase iii, randomized atlas trial. ann oncol.2018;29(12):2371-2378. 16. motzer rj, haas nb, donskov f, gross-goupil m, varlamov s, kopyltsov e, et al. randomized phase iii trial of adjuvant pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma. j clin oncol.2017;35(35):3916-3923. 17. motzer rj, ravaud a, patard jj, pandha hs, george dj, patel a, et al. adjuvant sunitinib for high-risk renal cell carcinoma after nephrectomy: subgroup analyses and updated overall survival results. eur urol.2018;73(1):62-68. 18. haas nb, manola j, dutcher jp, flaherty kt, uzzo rg, atkins mb, et al. adjuvant treatment for high-risk clear cell renal cancer: updated results of a high-risk subset of the assure randomized trial. jama oncol.2017;3(9):1249-1252. 19. massari f, di nunno v, mollica v, graham j, gatto l, heng d. adjuvant t yrosine kinase inhibitors in treatment of renal cell carcinoma: a meta-analysis of available clinical trials. clin genitourin cancer.2019;17(2):e339-e44. 20. ryan cw, tangen c, heath ei, stein mn, meng m, alva as, et al. e verest: everolimus for renal cancer ensuing surgical therapy—a phase iii study (swog s0931, nct01120249). j clin oncol.2022;40(17_suppl):lba4500-lba. 21. powles t, tomczak p, park sh, venugopal b, ferguson t, symeonides sn, et al. pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma (keynote-564): 30-month follow-up analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. lancet oncol.2022;23(9):1133-1144. 22. bristol myers squibb. (2022, july 29). bristol myers squibb provides update on checkmate -914 trial evaluating opdivo (nivolumab) plus yervoy (ipilimumab) as adjuvant treatment of localized renal cell carcinoma [press release]. https://news.bms.com/news/ details/2022/bristol-myers-squibb-provides-update-on-checkmate-914-trial-evaluating-opdivo-nivolumab-plus-yervoy-ipilimumab-asadjuvant-treatment-of-localized-renal-cell-carcinoma/default.aspx. 23. uzzo r, bex a, rini bi, albiges l, suarez c, donaldson f, et al. a phase iii study of atezolizumab (atezo) vs placebo as adjuvant therapy in renal cell carcinoma (rcc) patients (pts) at high risk of recurrence following resection (immotion010). j clin oncol.2017;35(15_suppl):tps4598-tps. 24. bex a, russo p, tomita y, grünwald v, ramirez l-m, mchenry bm, et al. a phase iii, randomized, placebo-controlled trial of nivolumab or nivolumab plus ipilimumab in patients with localized renal cell carcinoma at high-risk of relapse after radical or partial nephrectomy (checkmate 914). j clin oncol.2020;38(15_suppl):tps5099-tps. 474siuj.org siuj • volume 3, number 6 • november 2022 neoadjuvant and adjuvant therapy for renal cell carcinoma https://news.bms.com/news/details/2022/bristol-myers-squibb-provides-update-on-checkmate--914-trial-evaluating-opdivo-nivolumab-plus-yervoy-ipilimumab-as-adjuvant-treatment-of-localized-renal-cell-carcinoma/default.aspx https://news.bms.com/news/details/2022/bristol-myers-squibb-provides-update-on-checkmate--914-trial-evaluating-opdivo-nivolumab-plus-yervoy-ipilimumab-as-adjuvant-treatment-of-localized-renal-cell-carcinoma/default.aspx https://news.bms.com/news/details/2022/bristol-myers-squibb-provides-update-on-checkmate--914-trial-evaluating-opdivo-nivolumab-plus-yervoy-ipilimumab-as-adjuvant-treatment-of-localized-renal-cell-carcinoma/default.aspx https://news.bms.com/news/details/2022/bristol-myers-squibb-provides-update-on-checkmate--914-trial-evaluating-opdivo-nivolumab-plus-yervoy-ipilimumab-as-adjuvant-treatment-of-localized-renal-cell-carcinoma/default.aspx http://siuj.org 25. oza b, frangou e, smith b, bryant h, kaplan r, choodari-oskooei b, et al. rampart: a phase iii multi-arm multi-stage trial of adjuvant checkpoint inhibitors in patients with resected primary renal cell carcinoma (rcc) at high or intermediate risk of relapse. contemp clin trials.2021;108:106482. 26. motzer r, choueiri tk. lenvatinib plus pembrolizumab for renal cell carcinoma. reply. n engl j med.2021;385(3):287. 27. rini bi, plimack er, stus v, gafanov r, hawkins r, nosov d, et al. pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for metastatic renal cell carcinoma (mrcc): outcomes in the combined imdc intermediate/poor risk and sarcomatoid subgroups of the phase 3 keynote-426 study. j clin oncol.2019;37(15_suppl):4500-. 28. powles t, plimack er, soulières d, waddell t, stus v, gafanov r, et al. pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (keynote-426): extended follow-up from a randomised, open-label, phase 3 trial. lancet oncol.2020;21(12):1563-1573. 29. albiges l, rini bi, haanen jbag, motzer rj, kollmannsberger ck, negrier s, et al. 908pd primary renal tumour shrinkage in patients (pts) who did not undergo upfront cytoreductive nephrectomy (ucn): subgroup analysis from the phase iii javelin renal 101 trial of firstline avelumab + axitinib (a + ax) vs sunitinib (s) for advanced renal cell carcinoma (arcc). ann oncol.2019;30:v359-v60. 30. choueiri tk, powles t, burotto m, escudier b, bourlon mt, zurawski b, et al. nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. n engl j med.2021;384(9):829-841. 31. motzer rj, penkov k, haanen j, rini b, albiges l, campbell mt, et al. avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. n engl j med.2019;380(12):1103-1115. 32. dallos m, aggen dh, ager c, obradovic a, easterlin ca, hawley j, et al. the sparc-1 trial: a phase i study of neoadjuvant combination interleukin-1 beta and pd-1 blockade in localized clear cell renal cell carcinoma. j clin oncol.2021;39(6_suppl):tps373-tps. 33. wang dy, salem j-e, cohen jv, chandra s, menzer c, ye f, et al. fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. jama oncol.2018;4(12):1721-1728. 34. topalian sl, taube jm, pardoll dm. neoadjuvant checkpoint blockade for cancer immunotherapy. science.2020;367(6477). 35. krishnamoorthy m, lenehan jg, maleki vareki s. neoadjuvant immunot her ap y for high risk , rese c t able malignancies: scientific rationale and clinical challenges. j natl cancer inst.2021;113(7):823-832. 36. gorin ma, patel hd, rowe sp, hahn nm, hammers hj, pons a, et al. neoadjuvant nivolumab in patients with high-risk nonmetastatic renal cell carcinoma. eur urol oncol.2021. 37. carlo mi, attalla k, mazaheri y, gupta s, yildirim o, murray sj, et al. phase ii study of neoadjuvant nivolumab in patients with locally advanced clear cell renal cell carcinoma undergoing nephrectomy. eur urol.2022;81(6):570-573. 38. harshman lc, puligandla m, haas nb, allaf m, drake cg, mcdermott df, et al. prosper: a phase iii randomized study comparing perioperative nivolumab (nivo) versus observation in patients with localized renal cell carcinoma (rcc) undergoing nephrectomy (ecogacrin 8143). j clin oncol.2019;37(7_suppl):tps684-tps. 39. ornstein mc, zabell j, wood ls, hobbs b, devonshire s, martin a, et al. a phase ib trial of neoadjuvant/adjuvant durvalumab +/ tremelimumab in locally advanced renal cell carcinoma (rcc). j clin oncol.2020;38(15_suppl):5021-. 40. carlo mi, attalla k, patil s, murray sj, chen y-b, kotecha r, et al. a pilot study of preoperative nivolumab in high-risk nonmetastatic renal cell carcinoma. j clin oncol.2021;39(6_suppl):323-. 41. forde pm, chaft je, smith kn, anagnostou v, cottrell tr, hellmann md, et al. neoadjuvant pd-1 blockade in resectable lung cancer. n engl j med.2018;378(21):1976-1986. 42. schmid p, cortes j, pusztai l, mcarthur h, kümmel s, bergh j, et al. pembrolizumab for early triple-negative breast cancer. n engl j med.2020;382(9):810-821. 43. elias aw, kasi pm, stauffer ja, thiel dd, colibaseanu dt, mody k, et al. the feasibility and safety of surgery in patients receiving immune checkpoint inhibitors: a retrospective study. front oncol.2017;7:121-. 44. karakiewicz pi, zaffuto e, kapoor a, basappa ns, bjarnason ga, blais n, et al. kidney cancer research network of canada consensus statement on the role of adjuvant therapy after nephrectomy for highrisk, non-metastatic renal cell carcinoma: a comprehensive analysis of the literature and meta-analysis of randomized controlled trials. can urol assoc j.2018;12(6):173-180. 45. national institute for health and care excellence. pembrolizumab for adjuvant treatment of renal cell carcinoma [id3810]. in development [gid-ta10693]. expected publication date: september 28, 2022. available at: https://www.nice.org.uk/guidance/indevelopment/ gid-ta10693. accessed june 17, 2022. 46. lawrence nj, martin a, davis id, troon s, sengupta s, hovey e, et al. what survival benefits are needed to make adjuvant sorafenib worthwhile after resection of intermediateor high-risk renal cell carcinoma? clinical investigators‘ preferences in the sorce trial. kidney cancer.2018;2(2):123-131. 47. blinman pl, davis id, martin a, troon s, sengupta s, hovey e, et al. patients‘ preferences for adjuvant sorafenib after resection of renal cell carcinoma in the sorce trial: what makes it worthwhile? ann oncol.2018;29(2):370-376. 48. atkinson tm, ryan sj, bennett av, stover am, saracino rm, rogak lj, et al. the association between clinician-based common terminology criteria for adverse events (ctcae) and patientrepor ted outcomes (pro): a systematic review. support care cancer.2016;24(8):3669-3676. 49. battle d, jonasch e, hammers hj, derweesh i, george dj, bex a, et al. patients perspectives on adjuvant therapy in renal cell carcinoma. j clin oncol.2018;36(6_suppl):644-. 475 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases https://www.nice.org.uk/guidance/indevelopment/gid-ta10693 https://www.nice.org.uk/guidance/indevelopment/gid-ta10693 http://siuj.org 50. cruz rivera s, mcmullan c, jones l, kyte d, slade a, calvert m. the impact of patient-reported outcome data from clinical trials: perspectives from international stakeholders. j patient rep outcomes.2020;4(1):51. 51. kadam ra. informed consent process: a step further towards making it meaningful! perspect clin res.2017;8(3):107-112. 52. mercieca-bebber r, king mt, calvert mj, stockler mr, friedlander m. the importance of patient-reported outcomes in clinical trials and strategies for future optimization. patient relat outcome meas.2018;9:353-367. 53. zeps n, northcott n, weekes l. opportunities for econsent to enhance consumer engagement in clinical trials. med j aust.2020;213(6):260262 e1. 54. harshman lc, xie w, moreira rb, bossé d, ruiz ares gj, sweeney cj, et al. evaluation of disease-free survival as an intermediate metric of overall survival in patients with localized renal cell carcinoma: a trial-level meta-analysis. cancer.2018;124(5):925-933. 55. motzer rj, banchereau r, hamidi h, powles t, mcdermott d, atkins mb, et al. molecular subsets in renal cancer determine outcome to checkpoint and angiogenesis blockade. cancer cell.2020;38(6):803817 e4. 56. xu w, puligandla m, halbert b, haas nb, flaherty kt, uzzo rg, et al. plasma kim-1 is associated with recurrence risk after nephrectomy for localized renal cell carcinoma: a trial of the ecog-acrin research group (e2805). clin cancer res.2021;27(12):3397-3403. 57. nuzzo pv, berchuck je, korthauer k, spisak s, nassar ah, abou alaiwi s, et al. detection of renal cell carcinoma using plasma and urine cellfree dna methylomes. nat med.2020;26(7):1041-1043. 58. liu mc og, klein ea, swanton c, seiden mv. sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free dna. ann oncol.2020;31:745-759. 476siuj.org siuj • volume 3, number 6 • november 2022 neoadjuvant and adjuvant therapy for renal cell carcinoma http://siuj.org clinical utility of bladder cancer biomarkers laura-maria krabbe,1 georgios gakis,2 yair lotan3 1 the university of muenster medical center, germany, 2 university hospital of würzburg, germany, 3 the university of texas southwestern medical center, united states abstract each year, there are an estimated 550 000 diagnoses of bladder cancer worldwide, and almost 200 000 deaths from bladder cancer. the need for frequent follow-up, including invasive procedures like cystoscopy, repetitive procedures like transurethral resection of bladder tumors and intravesical instillation therapy in non-muscle invasive stages, as well as systemic treatment with or without radical local treatment in advanced stages, makes bladder cancer one of the most expensive cancers to treat. prognostic and predictive biomarkers have the potential to fundamentally change bladder cancer treatment algorithms, which may result in improved patient comfort and oncological outcomes and may also decrease the socioeconomic burden of the disease. intense research has resulted in the recent approval by the u. s. food and drug administration of the first agent for this disease that targets a specific mutation (fibroblastgrowth factor receptor). yet, many areas of bladder cancer diagnosis and treatment have remained unchanged for decades, and this is only in part due to their therapeutic success. in order to integrate biomarkers into clinical practice patterns, specific considerations for the different disease stages and settings should be kept in mind. especially in the setting of screening, work-up of hematuria, as well as surveillance of patients with non-muscle invasive bladder cancer, (urine-)biomarkers may prove useful. they must, however, demonstrate a high enough sensitivity to pick up a cancer diagnosis or recurrence, allow easy handling (preferably a point-of-care setting) and adequate cost–benefit relationships, while also providing additional information to a full work-up. a biomarker to identify patients with muscle invasive bladder cancer who are in need of—and likely to respond to—neoadjuvant therapy would be very useful. in later disease, early detection of recurrence or progression, as well as biomarkers guiding treatment decisions between the available systemic agents, will be paramount for improved patient care. introduction there are about 550 000 new diagnoses of bladder cancer each year, and it was responsible for almost 200 000 deaths worldwide in 2018 [1]. the need for frequent follow-up, including invasive procedures like cystoscopy, repetitive procedures like transurethral resection of bladder tumors and intravesical instillation therapy in non-muscle invasive stages, as well as systemic treatment with or without radical local treatment in advanced stages, makes bladder cancer one of the most expensive cancers to treat [2]. prognostic and predictive biomarkers have the potential to fundamentally change bladder cancer treatment algorithms, which may improve patient comfort and oncological outcomes, as well as decreasing the socioeconomic burden of the disease. the u. s. food and drug administration has recently approved the first agent for this disease that targets a specific mutation [3]. yet, many aspects of bladder cancer diagnosis and treatment have remained unchanged for decades, and this is due only in part to their therapeutic success. in order to integrate biomarkers into clinical practice patterns, specific considerations for the different disease stages and settings should be kept in mind. key words competing interests article information biomarkers, bladder cancer, muscle invasive bladder cancer, non-muscle invasive bladder cancer, neoadjuvant therapy, hematuria, cystoscopy, risk stratification, clinical decision-making none declared. received on july 14,  2020 accepted on august 3,  2020 soc int urol j 2020; 1(1): 62–67 62 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation mailto:laura-maria.krabbe%40ukmuenster.de?subject=siuj http://www.siuj.org 63 abbreviations bcg bacillus calmette-guérin mibc muscle invasive bladder cancer nmibc non-muscle invasive bladder cancer nac neoadjuvant chemotherapy nlst national lung screening trial npv negative predictive value pd-l1 programmed death receptor ligand 1 plco prostate, lung, colorectal and ovarian cancer screening trial  ppv positive predictive value rc radical cystectomy considerations for biomarkers for bladder cancer screening because of the low incidence of bladder cancer in the general population (and even in high-risk populations), there is currently no recommendation for bladder cancer screening [4]. in general, for screening purposes in daily routine, a point-of-care test on a dichotomous basis could be performed easily in the ambulatory setting and should provide an initial risk assessment which could be used to tailor the need for further clinical investigation. urine is obviously the most promising resource for such a test. on the one hand, a urine-based biomarker test requires a high sensitivity and negative predictive value (npv) to ensure people at risk are not missed. on the other hand, given the low incidence, the test also needs a high specificity and positive predictive value (ppv) to prevent unnecessary (invasive) evaluation that would occur because of false positive results. in addition, given its application of a urine marker as a screening tool, the costs for test analysis should be low and not greatly exceed the usual costs for standard diagnostic work-up of bladder cancer. finally, an earlier detection after test analysis should ideally demonstrate a significant improvement in oncological outcomes. as it seems to be difficult to demonstrate an overall survival benefit in the general—or even high-risk—population, a reduction of rates of invasive disease may serve as a surrogate parameter since there are known significant differences in survival between non-muscle invasive bladder cancer (nmibc) and muscle invasive bladder cancer (mibc). most current urine markers have a ppv that is too low to justify their use in screening since the number of unnecessary evaluations will far exceed the finding of cancer. targeted screening of very high-risk populations may result in a high enough cancer incidence, but prospective studies will be necessary to demonstrate a survival benefit or at least a reduction of muscle invasive disease. it is known that male sex, older age, and duration and intensity of smoking are associated with higher risk of bladder cancer. a study evaluating these factors and incidence of bladder cancer in the prostate, lung, colorectal and ovarian (plco) cancer screening trial  and the national lung screening trial (nlst) found that in men older than 70 years with smoking exposure of ≥ 30 pack-years, incidence rates were as high as 11.92 (plco) and 5.23 (nlst) per 1000 person-years [5]. there is not a strong association between family history and bladder cancer. however, in the presence of distinct single-nucleotide polymorphisms that are associated with a significant risk for bladder cancer, screening for bladder cancer may be justified. upper tract urothelial carcinoma develops in up to 28% of patients with known lynch syndrome. these patients may be candidates for screening and routine urine analysis, as well as possible further evaluation using the american urological association guideline of ≥ 3 red blood cells per high power field [6]. patients with  lynch  syndrome who develop upper tract disease usually present at a younger age, with a higher female preponderance and a predisposition to bilaterality. diagnosis in patients with hematuria patients with hematuria have a markedly increased risk of having bladder cancer (gross 10% to 40%, depending on other risk factors, or microscopic  2% to  5%) and therefore need further clinical work-up [7,8]. this work-up consists of cystoscopy with cytology, as well as contrast-enhanced imaging of the upper urinary tract [4]. these procedures are costly, invasive, or uncomfortable. therefore it would be desirable to replace them with a biomarker test to spare patients who do not need a full evaluation. again, urine seems to be the most promising medium for a biomarker test in such a scenario. large efforts have been undertaken to stratify risk in patients with hematuria based on demographic and clinical factors as well as various genetic and protein markers [4]. dichotomous or semiquantitative tests indicating the individual risk for bladder cancer seem suitable to guide clinicians towards or against further testing. as with screening, a high sensitivity and npv is needed to ensure a tumor is not missed. a high specificity and ppv are also desirable to prevent unnecessary evaluations for false positive test results, but are less important than in screening, given the lower number of these “quasi”pre-screened patients and related costs. since the rate of cancer in patients with hematuria greatly exceeds the rate in screening cohorts, identifying high-risk patients who always need evaluation is important. several studies have found that the cancer yield increases with gross hematuria, male sex, and increasing age [9,10]. unfortunately, many patients with high-risk disease are not adequately evaluated [11-13]. while the incidence of urothelial carinoma in patients siuj.org siuj • volume 1, number 1 • october 2020 clinical utility of bladder cancer biomarkers http://www.siuj.org 64 with gross hematuria already justifies evaluation, risk stratification to select patients for work-up might benefit patients with microscopic hematuria. the goal for markers could be to improve risk stratification of patients so that higher risk patients get evaluation, but there is also identification of which lower risk patients need to be evaluated and which patients may be safely monitored without invasive testing [14,15]. a prospective randomized trial is currently open that randomizes patients based on clinical risk and marker status (nct03988309). patients in the control arm will have standard evaluation while those in the marker arm will have a clinical risk stratification, so patients with low clinical risk and a negative marker will not have cystoscopy but follow-up only, but those with a positive marker or higher risk based on clinical factors will undergo a standard evaluation with cystoscopy. further studies of this type will be necessary to change guideline recommendations. surveillance of patients with non-muscle invasive bladder cancer when patients are diagnosed with lowto intermediaterisk nmibc, the follow-up course is usually associated with frequent cystoscopies to rule out recurrent or progressive disease, especially in those undergoing intravesical instillation therapy. these examinations are cumbersome to many patients and are associated with significant costs. therefore, investigators have focused on biomarkers to accurately detect t he presence or absence of a recurrence as an alterative to invasive diagnostic procedures. given the low risk of progression in lowto intermediate-risk nmibc, (<15% at 5 years), but high risk of recurrence, the goals for a biomarker need to be considered. a biomarker with a high specificity will reduce the number of cystoscopies performed because of false positive findings, but if sensitivity is not high, it may miss recurrences [16]. this may be acceptable in order to reduce the number of cystoscopies since low-grade recurrences are unlikely to progress. as an alternative, some investigators have proposed alternating cystoscopy with a marker. this is more practical, as most markers have a better sensitivity for high-grade disease and would therefore be more likely to catch the rare case of a low-grade tumor that progresses. furthermore, periodic cystoscopy would assure patients and urologists that even if a marker missed a low-grade recurrence then the cancer would be detected at subsequent evaluation. the urofollow study, for example, was developed as a prospective randomized trial to compare routine cystoscopy with a urine markerguided, noninvasive follow-up of patients with pta g1–2/low-grade nmibc [17]. on the other hand, patients with a history of highrisk bladder cancer have the highest risk of recurrence (50% at 5 years) [16]. therefore, a useful biomarker test must have a high sensitivity and npv in order not to miss any high-grade recurrence which may result in progression to muscle-invasive stages. this could even come at the cost of lower test specificity. ideally a marker would be able to detect cancers missed by white light cystoscopy, which is known to miss some high-grade cancers, especially carcinoma in situ [18]. unfortunately, urine marker studies have not been designed to assess whether a patient with a normal cystoscopy and positive marker have a true positive or false positive finding. it is therefore not clear what steps should be taken if a marker assay is positive in this scenario. molecular markers could also aid in clinical decisionmaking for patients with nmibc in predicting response to intravesical therapy. adding a biomarker test to a standard work-up may identify patients who are unlikely to benefit from bcg bacillus calmette-guérin and require early radical treatment. nonetheless, this issue is difficult to address in clinical trials, as bladder cancer is a heterogeneous disease, and the intravesical therapies used are non-specific to a distinct molecular target for which testing would be possible. therefore, predicting response to intravesical therapy will remain challenging in the future. this is also complicated by the fact that immunotherapy with bcg and also chemoinstillation induce inf lammatory changes, which can sometimes impair the diagnosis of a tumor recurrence or influence test results. however, adding a biomarker test to a standard work-up may identify patients unlikely to benefit from bcg, who might require more radical treatment, early [19]. furthermore, markers may be able to select populations at higher risk for enrollment in clinical trials [20]. biomarkers with muscle invasive bladder cancer in mibc, there are several distinct needs that could be addressed by biomarkers. patients with ajcc stages 2 and 3 disease have variable rates of recurrence and progression. furthermore, approximately  40% of patients are understaged [21]. there is level 1 evidence for use of neoadjuvant chemotherapy (nac), but it is underused because of concerns about toxicity and a relatively small survival benefit [22]. there is a greater benefit to nac in patients who have non-organ confined disease, so identifying patients likely to have micrometastatic disease would be valuable. since there is also variable response to nac, a marker to identify likely responders would be important to prevent toxic treatments being given to patients unlikely to benefit from them. several possible biomarkers have been described, including mutations in dna repair genes  atm, rb1, siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation http://www.siuj.org 65 and fancc, [23] mutations in excision repair crosscomplementation group  2 (ercc2) gene, [24,25] protein biomarkers, [26] and rna subtyping of bladder cancer [27,28]. furthermore, while cystectomy is the main treatment for mibc, trimodality therapy is a reasonable alternative in some patients, and predicting responsiveness to this type of treatment would be valuable. in patients who do not get nac, there is a role for adjuvant therapy in patients with non-organ confined disease [29]. in addition, proponents of an adjuvant approach argue that there is a considerable risk of overtreatment w it h nac , since histopat hologica l risk factors determined in radical cystectomy (rc) specimens have a much stronger correlation to survival than histological parameters obtained by transurethral resection of bladder tumors [30,31]. pathological complete or partial response (downstaging to non-muscle invasive tumor stages) after nac is reported in 40% to 50% of the patients and associated with excellent survival [32]. on the contrary, the majority of patients will exhibit persistent muscle-invasive disease (≥ ypt2) after rc, which is associated with poor outcomes [32]. a predictive biomarker in this setting should be capable of identifying patients in need of systemic treatment and those whose tumors are sensitive to systemic treatment (maybe in future even indicate which treatment). given the high degree of intratumoral heterogeneity of mibc [33], biomarker expression levels should be homogenous within the tumor lesion to reliably predict response. ideally, a biomarker assessed in the transurethral resection specimen should have a higher sensitivity than specificity to prevent undertreatment of mibc patients. by contrast, a high specificity but low sensitivity may result in the underuse of neoadjuvant treatment, but this may be alleviated if an effective adjuvant treatment is available that is safe even in patients with comorbidities (eg, impaired renal function). the currently available histopathological parameters (ie, tumor and nodal stage) can be considered accurate enough to determine the necessity of adjuvant treatment in case of lack of a downstaging effect after neoadjuvant therapy; however, a biomarker might help in determining the most appropriate treatments in the future [34]. prediction of response in the adjuvant setting after failure of a neoadjuvant approach ideally requires a biomarker with an even higher specificity than the (primary) neoadjuvant setting, because the group of ≥ ypt2  patients after rc exhibit a very dismal prognosis [32]. for patients with a locally advanced tumor after rc who have not received previous neoadjuvant therapy, there might be benefit in a prognostic biomarker indicating which patients will experience recurrence and which will not, as well as a predictive biomarker of which treatment might be associated with the best response. metastatic bladder cancer in the metastatic cancer/disease, predictive biomarkers are urgently needed to determine which tumor will likely respond to which treatment, as this will help ensure patients in this very aggressive disease state are not receiving ineffective therapies. these biomarkers will likely be bloodor tissue-based. ideally, biomarkers should be assessable sequentially via blood draw so the patient does not have to undergo multiple biopsies and the biomarker provides an accurate representation of tumor characteristics, given that tumors, but especially metastases, evolve over time. groundwork on t he s e f ront s ha s b e en done by genom ic characterization of bladder tumors; there are, however, very few validated biomarkers. biomarkers to predict response to therapy are critical. there is already an approved targeted therapy for metastatic bladder cancer targeting fibroblastgrowth factor receptor mutations [35]. the role for biomarkers such as programmed death receptor ligand 1 (pd-l1) to predict response to checkpoint inhibitors is controversial but necessary in certain cases. in firstline cisplatin-ineligible patients who are eligible for carboplatin, the use of pd-l1  inhibitors is currently approved only after pd-l1  testing, whereas in the second-line, data from a randomized trial support the use of for example pembrolizumab in an unscreened population of platinum-pretreated patients [36,37]. given the low response rates in both settings (25% complete and partial remissions), it will be important to combine pd-l1 inhibitors with other targeting agents to improve response. nonetheless, in the future, it can be expected that the decision to use singleor multiagent targeted therapy in any line of systemic therapy will be based on marker expression. given the high mutational burden and heterogeneity of response to treatment in metastasized tumors, the critical question is whether the tissue obtained at primary diagnosis can accurately reflect the tumor biology after multiple lines of systemic treatment. therefore, the implementation of robust biomarkers in the different metastatic settings will require first a better understanding of the biological processes during progression of metastatic disease. this will require well-designed biopsy studies to systematically assess alterations in tumor biology during the process of metastasis formation. siuj.org siuj • volume 1, number 1 • october 2020 clinical utility of bladder cancer biomarkers http://www.siuj.org 66 conclusion there are many areas in bladder cancer where biomarkers can have an important role in improving clinical decision-making. the current information from stage and grade of disease is insufficient to adequately stage or predict outcomes for most patients. biomarkers have the potential to shed light onto clinical behavior of tumors to allow a personalized approach to care. there is also a potential for improved understanding of the biology of the disease to determine which patients need more intensive therapy and which therapies to use. references 1. burger m, catto jw, dalbagni g, et al., epidemiology and risk factors of urothelial bladder cancer. eur urol 2013; 63:  234–241. 2. elias k, svatek rs, gupta s, et al., high-risk patients with hematuria are not evaluated according to guideline recommendations. cancer 2010; 116: 2954–2959. 3. garg t, pinheiro lc, atoria cl, et al., gender disparities in hematuria evaluation and bladder cancer diagnosis: a population based analysis. j urol 2014; 192: 1072–1077. 4. ghandour r, freifeld y, singla n, lotan y. evaluation of hematuria in a large public health care system. bladder cancer 2019; 5:  119–129. 5. lotan y, svatek rs, krabbe lm, et al., prospective ex ternal validation of a bladder cancer detection model. j urol  2014; 192: 1343–1348. 6. lotan y, capitanio u, shariat sf, et al., impact of clinical factors, including a point-of-care nuclear matrix protein-22  assay and cytology, on bladder cancer detection. bju int 2009; 103: 1368–1374. 7. sylvester rj, van der meijden ap, oosterlinck w, et al., predicting recurrence and progression in individual patients with stage ta t1  bladder cancer using eortc risk tables: a combined analysis of  2596  patients from seven eortc trials. eur urol  2006; 49: 466–465; discussion 475–467. 8. benderska-soder n, hovanec j, pesch b, et al., toward noninvasive follow-up of low-risk bladder cancer—rationale and concept of the urofollow trial. urol oncol 2020. 9. daneshmand s, patel s, lotan y, et al., efficacy and safety of blue light flexible cystoscopy with hexaminolevulinate in the surveillance of bladder cancer: a phase iii, comparative, multicenter study. j urol 2018; 199: 1158–1165. 10. kamat am, willis dl, dickstein rj, et al., novel fluorescence in situ hybridization-based definition of bacille calmette-guerin (bcg) failure for use in enhancing recruitment into clinical trials of intravesical therapies. bju int 2016; 117:  754–760. 11. lotan y, inman ba, davis lg, et al., evaluation of the fluorescence in situ hybridization test to predict recurrence and/or progression of disease after bacillus calmette-guerin for primary high grade nonmuscle invasive bladder cancer: results from a prospective multicenter trial. j urol 2019; 202:  920–926. 12. shariat sf, palapat tu gs, karakiewicz pi, et al., discrepancy between clinical and pathologic stage: impact on prognosis after radical cystectomy. eur urol 2007; 51: 137–149; discussion 149–151. 13. alfred witjes j, lebret t, comperat em, et al., updated 2016 eau guidelines on muscle-invasive and metastatic bladder cancer. eur urol 2017; 71:  462–475. 14. plimack er, dunbrack rl, brennan ta, et al., defects in dna repair genes predict response to neoadjuvant cisplatin-based chemotherapy in muscle-invasive bladder cancer. eur urol  2015; 68:  959–967. 15. liu d, plimack er, hoffman-censits j, et al., clinical validation of chemotherapy response biomarker ercc2  in muscle-invasive urothelial bladder carcinoma. jama oncol 2016; 2: 1094–1096. 16. van allen em, mouw kw, kim p, et al., somatic ercc2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma. cancer discov 2014; 4: 1140–1153. 17. b ar as a s, gandhi n, munari e, et al., identific ation and validation of protein biomarkers of response to neoadjuvant platinum chemotherapy in muscle invasive urothelial carcinoma. plos one 2015; 10: e0131245. 18. choi w, por ten s, kim s, et al., identification of distinct basal and luminal subt ypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. cancer cell 2014; 25:  152–165. 19. seiler r, ashab ha, erho n, et al., impact of molecular subtypes in muscle-invasive bladder cancer on predicting response and survival after neoadjuvant chemotherapy. eur urol 2017. 20. advanced bladder cancer meta-analysis c. adjuvant chemotherapy in invasive bladder cancer: a systematic review and metaanalysis of individual patient data advanced bladder cancer (abc) meta-analysis collaboration. eur urol  2005; 48: 189–199; discussion 199–201. 21. gakis g, efstathiou j, lerner sp, et al., icud-e au international consultation on bladder cancer  2012: radical cystectomy and bladder preservation for muscle-invasive urothelial carcinoma of the bladder. eur urol 2013; 63:  45–57. 22. kukreja jb, porten s, golla v, et al., absence of tumor on repeat transurethral resection of bladder tumor does not predict final pathologic t0  stage in bladder cancer treated with radical cystectomy. eur urol focus 2018; 4:  720–724. 23. zargar h, zargar-shoshtari k, lotan y, et al., final pathological stage after neoadjuvant chemotherapy and radical cystectomy for bladder cancer-does pt0  predict better survival than pta/ tis/ t1? j urol 2016; 195:  886–893. siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation http://www.siuj.org 67 24. da costa jb, gibb e a, nykopp tk, et al., molecular tumor heterogeneit y in muscle invasive bladder cancer: biomarkers, subtypes, and implications for therapy. urol oncol 2018. 25. witjes ja, babjuk m, bellmunt j, et al., e au-esmo consensus st atements on the management of ad vanced and variant bladder cancer-an international collaborative multistakeholder effort(dagger): under the auspices of the eau-esmo guidelines committees. eur urol 2019. 26. loriot y, necchi a, park sh, et al., erdafitinib in locally advanced or metastatic urothelial carcinoma. n engl j med 2019; 381:  338–348. 27. balar av, castellano d, o’donnell ph, et al., first-line pembrolizumab in cisplatin -ineligible p atient s wit h lo c ally ad vanced and unresectable or metastatic urothelial cancer (ke ynote-052): a multicentre, single-arm, phase  2  study. lancet oncol  2017; 18: 1483–1492. 28. bellmunt j, de wit r, vaughn dj, et al., pembrolizumab as s e c o n d lin e t h e r ap y f o r a d v an c e d ur o t h elial c ar cin o m a. n engl j med 2017; 376: 1015–1026. siuj.org siuj • volume 1, number 1 • october 2020 clinical utility of bladder cancer biomarkers http://www.siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj.org siuj • volume 4, number 4 • july 2023 key words competing interests article information bladder cancer, urine, biomarker, cfdna none declared. received on december 23, 2022 accepted on april 4, 2023 this article has been peer reviewed. soc int urol j. 2023;4(4):341–342 doi: 10.48083/sblr8004 341 pro and con — liquid biopsy urine-based cell-free dna tests in urothelial cancer: additional value for clinical decision-making? lars dyrskjøt 1 department of molecular medicine, aarhus university hospital, aarhus, denmark 2 department of clinical medicine, aarhus university, aarhus, denmark liquid biopsy analyses encompass a wide range of materials and analytes derived from tumors. although blood tests are commonly used for liquid biopsy analysis, other fluids like urine, saliva, stool, and cerebrospinal fluid may also be used and provide novel insights into specific cancer types[1]. analysis of tumor-specific cell-free dna (cfdna) in blood has emerged as a strong biomarker, particularly for the detection of minimal residual disease and metastatic relapse in various cancers, including bladder cancer[2]. ongoing clinical intervention trials are currently ongoing— such as imvigor011 (nct04660344) and tombola (nct04138628)—to determine the clinical benefit of bloodbased tests. for patients with bladder cancer, urine analysis has been performed for decades for the diagnosis and detection of recurrence, particularly in the non-muscle invasive bladder cancer (nmibc) setting. urine studies conducted in nmibc patients are typically based on urine pellets, as these pellets harbor the cancer cells shed directly into the urine. however, despite the superior performance of biomarker tests over cytology, none have been recommended as replacements or supports for cystoscopy. historically, most research in this area has focused mainly on cancer type–specific biomarkers, which often exhibit low sensitivity and specificity for clinical decision-making. additionally, the highly accurate detection of a few molecules of patient-specific alterations requires use of novel technologies and analysis protocols developed over the past decade. studies applying sensitive methods like next-generation sequencing (ngs) and droplet digital pcr (ddpcr) for urine analysis have demonstrated promising results for recurrence detection in the early-stage setting. dudley et al. used a 311 kb custom panel (460 gene regions) sequencing method (ucapp-seq) to analyze urine tumor dna in 118 patients with nmibc. they detected urine tumor dna in 91% of patients who experienced recurrence in the surveillance setting, with a positive lead time in 92% of cases[3]. in another study, ward et al. applied deep-targeted sequencing of mutations in 23 genes and demonstrated a sensitivity of 87% and specificity of 85% in 165 hematuria patients diagnosed with bladder cancer. moreover, in the surveillance setting of nmibc patients, the test showed a sensitivity of 86% and specificity of 63%[4]. while patient-specific tests for nmibc surveillance may further increase sensitivity, they can significantly increase costs because of the increased workload associated with designing patient-specific assays. the reported lower specificity of these tests may also result from an increased sensitivity compared to cystoscopy, as evidenced by the increased risk for disease relapse often associated with “false-positive” tests in this setting. new randomized clinical trials are needed that incorporate sensitive technologies to determine whether cystoscopies can be omitted in certain cases during disease surveillance. in this setting, it is also important to acknowledge that the gold standard (cystoscopy) is not 100% sensitive[5]. renal clearance of plasma cfdna into the urine[6] is another important aspect to consider. this means that the cf dna detected in cell-free urine (supernatant) harbors biological signals from both tumor cells in the bladder and from dna cleared from plasma. however, in the nonmetastatic setting, the dna fractions originating from plasma may be small compared to contributions from apoptotic cells in the bladder. previous studies on cf dna have shown that mutated dna is present in urine at elevated levels years before the diagnosis of disease progression and metastasis[7,8]. in muscle-invasive bladder cancer (mibc), urine samples have shown promise in detecting residual disease prior to radical cystectomy, with mutated cfdna levels correlating to clinical outcomes[8,9]. http://siuj.org mailto:lars%40clin.au.dk?subject=siuj siuj • volume 4, number 4 • july 2023 siuj.org references 1. corcoran rb, chabner ba. application of cell-free dna analysis to cancer treatment. n engl j med.2018;379(18):1754–1765. doi: 10.1056/nejmra1706174. pmid: 30380390. 2. christensen e, birkenkamp-demtröder k, sethi h, shchegrova s, salari r, nordentoft i, et al. early detection of metastatic relapse and monitoring of therapeutic efficacy by ultra-deep sequencing of plasma cell-free dna in patients with urothelial bladder carcinoma. j clin oncol.2019;37(18):1547–1557. doi: 10.1200/jco.18.02052. pmid: 31059311. 3. dudley jc, schroers-martin j, lazzareschi dv, shi w y, chen sb, esfahani ms, et al. detection and surveillance of bladder cancer using urine tumor dna. cancer discov.2019;9(4):500 –509. doi: 10.115 8/ 215 9 8 2 9 0.cd -18 0 8 25. p mid: 3 05 78 35 7; p mcid: pmc6467650. 4. ward dg, baxter l, ott s, gordon ns, wang j, patel p, et al. highly sensitive and specific detection of bladder cancer via targeted ultradeep sequencing of urinary dna. eur urol oncol.2023;6(1):67–75. doi: 10.1016/j.euo.2022.03.005. 5. grossman hb, gomella l, fradet y, morales a, presti j, ritenour c, et al. a phase iii, multicenter comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of superficial papillary lesions in patients with bladder cancer. j urol.2007;178(1):62– 67. doi: 10.1016/j.juro.2007.03.034. pmid: 17499283. 6. botezatu i, serdyuk o, potapova g, shelepov v, alechina r, molyaka y, et al. genetic analysis of dna excreted in urine: a new approach for detecting specific genomic dna sequences from cells dying in an organism. clin chem.2000;46(8 pt 1):1078–1084. pmid: 10926886. 7. birkenkamp-demtröder k, nordentoft i, christensen e, høyer s, reinert t, vang s, et al. genomic alterations in liquid biopsies from patients with bladder cancer. eur urol.2016;70(1):75–82. doi: 10.1016/j. eururo.2016.01.007. pmid: 26803478. 8. christensen e, birkenkamp-demtröder k, nordentoft i, høyer s, van der keur k, van kessel k, et al. liquid biopsy analysis of fgfr3 and pik3ca hotspot mutations for disease surveillance in bladder cancer. eur urol.2017;71(6):961–969. doi: 10.1016/j.eururo.2016.12.016. pmid: 28069289. 9. chauhan ps, chen k, babbra rk, feng w, pejovic n, nallicheri a, et al. urine tumor dna detection of minimal residual disease in muscle-invasive bladder cancer treated with curative-intent radical cystectomy: a cohort study. plos med.2021;18(8):e1003732. doi: 10.1371/journal.pmed.1003732. pmid: 34 464379; pmcid: pmc8407541. 10. christensen e, nordentoft i, birkenkamp-demtröder k, elbæk sk, lindskrog sv, taber a, et al. cell-free urine and plasma dna mutational analysis predicts neoadjuvant chemotherapy response and outcome in patients with muscle-invasive bladder cancer. clin cancer res.2023;29(8):1582–1591. doi: 10.1158/1078-0432.ccr-22-3250. in a recent study conducted by my team, we performed paired urine and plasma analysis on 92 patients before, during, and after neoadjuvant chemotherapy (nac) to assess the value of urine-based analyses in nac response and outcome, as well as to evaluate the synergistic effects of urine and plasma analysis[10]. urine and plasma samples were prospectively collected for cfdna analysis using standardized protocols to optimize the analysis. we found that detection of mutated cfdna in urine and plasma prior to cystectomy was significantly associated with lower response rates and poor survival. furthermore, the dynamics of mutated cf dna in urine and plasma during nac was also associated with response and outcome. a combined analysis showed that patients with non-detectable mutated cfdna in urine or plasma exhibited very good outcomes compared to patients with detectable cf dna in both sample types. this suggests abbreviations cfdna cell-free dna nac neoadjuvant chemotherapy nmibc non-muscle invasive bladder cancer that a combination of measurements for residual disease in the bladder (urine) and systemic disease (plasma) may hold clinical relevance; however, larger studies are needed. it should be noted that although standardized protocols for urine procurement were applied, significant variation in urine-based results were observed, with sensitivities ranging from 70% to 80% in samples with known residual tumors. this underscores one of the main challenges with urine-based analysis: the concentration of biological signals may fluctuate significantly and may thus be difficult to control. more controlled methods for standardizing this should be evaluated. ultimately, when validated in larger studies, the combined approach of urine and plasma analysis may guide treatment decisions regarding neoadjuvant therapy response, continuation of treatment, and the potential application of bladder-sparing approaches. overall, urine-based analyses hold potential benefits for bladder cancer patients—both in early-stage disease for disease surveillance and in advanced stages for monitoring treatment efficacy and guiding treatment decisions. however, as highlighted in this commentary, several limitations must be addressed in new studies before these tests can become clinically useful. 342 pro and con — liquid biopsy http://siuj.org use of urology-based clinical practice guidelines in international settings german patino,*1,2 medina ndoye,*1,3 hannah s. thomas,*1,4 andrew j. cohen,5 nnenaya a. mmonu,1 carissa e. chu,1 benjamin n. breyer, 1,6 *authors contributed equally 1department of urology, university of california san francisco, united states 2 hospital san ignacio, bogotá, colombia 3 hôpital général de grand yoff, dakar, senegal 4 university of edinburgh school of medicine, edinburgh, united kingdom5 the brady urological institute at johns hopkins, baltimore, united states 6 department of biostatistics and epidemiology, university of california san francisco, united states abstract objective clinical practice guidelines (cpgs) serve as frameworks to unify diagnostic criteria and guide clinical decision-making. there is a paucity of literature surrounding the uptake of cpgs in urology practice settings with varied levels of resources worldwide. this study aims to evaluate reported use of cpgs within the context of international urology practice, identify local barriers to uptake, and evaluate the role of stakeholders in the cpgdevelopment process. methods this was an international, multi-center, cross-sectional study. an online survey collecting variables pertaining to the use of cpgs was distributed to attending/consultant urologists in latin america, africa, and china. statistical analysis was conducted using r software. result a total of 249 practicing urologists from 28 countries completed the survey. the majority of participants were males, aged 36 to 45, and practiced in a non-academic setting. ninety-three percent of urologists used cpgs in their everyday clinical practice, and 43% believed cpgs were very important to medical decision-making. however, barriers such as the lack of adaptability or applicability of cpgs to local settings were mentioned by 29% and 24% of participants, respectively. urologists believed scientific associations (81%), national urology boards (68%), and ministries of health (56%), were important stakeholders to consult to foster the development of local cpgs. conclusions globally, cpgs are widely used tools for clinical practice. however, there are concerns about the adaptability and applicability of cpgs to settings that may lack the resources to implement their recommendations. efforts should be directed towards incorporating scientific and medical stakeholders into the review and adaptation of urology cpgs to suit the unique features of local health care systems. key words competing interests article information urology, cpg, guidelines, global health, barriers none declared. received on: august 4, 2020 accepted on: october 12, 2020 soc int urol j. 2021;2(1):10–17 10 siuj • volume 2, number 1 • january 2021 siuj.org original research mailto:benjamin.breyer%40ucsf.edu?subject=siuj http://www.siuj.org introduction with the large volume of clinical research, it is cha l leng i ng for prac t it ioners to i ndependent ly synthesize and review scientific literature to ascertain proper ev idence-based care[1]. clinica l practice guidelines (cpgs) are tools used to identify, evaluate, and synthesize recent data and high-quality evidence to assist clinicians in providing evidence-based and outcome-based medicine[2,3]. developing cpgs mandates multi-professional collaboration through systematic, independent, and transparent methods to produce appropriate quality criteria. when implemented effectively, cpgs have been shown to improve the standardization of medical services, raise the quality of care, promote patient safety, and achieve optimal cost-effectiveness[4]. however, while cpgs are largely considered valuable tools to improve processes of care, associations between adherence to cpgs and patientrelated outcomes remain variable[5–7]. to guide clinical decision-making in urology, cpgs have been developed by major north american and european professional urology organizations such as the american urological association (aua) and european association of urology (eau). in the us, approximately 95% of urologists reported using the aua cpgs in regular clinical decision-making[8]. figures are more variable in european cohorts where italian urologists’ adherence to non-oncologic urology cpgs ranged from 45% to 88%[9], while croatian urologists’ compliance with eau recommendations ranged from 8% to 100%[10]. more specifically, cpg uptake varies when consulting for pathology and symptom-specific cases such as benign prostatic hyperplasia[11], bladder cancer[12] and asymptomatic hematuria[13]. younger age and academic practice settings have been found to be associated with greater cpg adherence[8,9]. the uptake of cpgs has not been extensively measured within urology settings of varied resource-levels. it has been hypothesized that cpgs may be valuable tools in lowand middle-income countries (lmics), where resource constraints limit the development of cpgs suitable to local sociocultural and economic contexts. cited barriers to cpg implementation in lmics include inadequate facilities for clinical practice advised by cpgs and comprehensibility of information within cpgs[14]. multidisciplinary literature has found that cpg implementation in lmics is often best achieved when coupled with educational programming and adaptation by local experts[15,16]. through an online survey, this study aimed to evaluate clinical decision-making factors and reported use of urology cpgs produced by professional urology organizations, and national and institutional cpgs. moreover, we sought to understand the key barriers to individual providers’ use of such cpgs. finally, in an attempt to improve cpg development and better serve international urology practice, we evaluated the importance of key stakeholders. methods study design and participants this was a n internat iona l, mu lt i-center crosssectional study. an online survey eliciting urologist demographics and use of and attitudes towards cpgs was disseminated, using means appropriate to the target region. in latin america, the survey was disseminated to consultant urologists through the email server of several national societies. similarly, prospective participants in china were invited to complete the survey through the chinese urological association. in africa, however, participants were more likely to respond if the survey was disseminated through local clinicians and contacts known to a member of the study team. all participants were invited to complete the study through a formalized letter from the research team from the university of california, san francisco, which included the survey link. in cases of non-response, a follow-up link was provided one month later. eligible participants were identified as consultant urologists practicing in an international setting. trainees and residents were not recruited. study variables a 17-question survey with consent was built through research electronic data capture (redcap) and offered in english, spanish, french, and chinese (suppl.) [17]. demographic variables such as provider age, sex, and years of practice were collected. knowledge about daily clinical decision-making, knowledge of cpgs, and access to relevant sources of scientific information was sought. the 5-point likert scale was used to elicit provider perspectives on the role of cpgs in clinical decision-making. finally, barriers to cpg uptake were investigated, along with provider perspectives on key stakeholders necessary for future cpg development. statistical analysis descriptive analyses were conducted using excel pivot tables. through r studio, chi-square tests of independence were used to approximate statistical significance. abbreviations aua american urological association cpg clinical practice guideline eau european association of urology 11siuj.org siuj • volume 2, number 1 • january 2021 use of urology-based clinical practice guidelines in international settings http://siuj.org ethics this study was forma lly approved t hrough t he institutional review board (irb) within university of california san francisco (#18-25978). the study was classed as minimal risk and received exempt irb status. results demographics a total of 249 participants, representing 28 different countries, completed the survey (table 1). twenty countries were in africa, 7 in latin america and 1 in asia (china). the majority of participants who reported demographic characteristics were men (92.8%, 192/207) aged 36 to 45 years old (38.6%, 95/246). most participants trained in their home country (70.1%, 143/204), and reported they were now practicing in a non-academic setting (community, national hospital, or private practice) (64.9%, 135/208). seventy-three urologists considered themselves to be working in an academic environment (35.1%, 73/208). a total of 34.6% had practiced for 1 to 5 years (72/208), and 32.2% for 16 or more years (67/208). overall, 33.7% of sampled urologists were practicing in latin america (84/249), 31.3% in africa (78/249), and 18.5% (46/249) in china. baseline factors contributing to clinical decision-making and access to cpgs a total of 43% (107/249) of responding urologists rated cpgs to be very important during their decisionmaking process, while 25.3% (63/249) greatly valued the role of scientific publications. similarly, experience and habits, expert opinion, and medical training were table 1. demographics of study participants participants africa n (%) latin america n (%) china n (%) totals n (%) p -value age 25–35 36–45 46–55 56–65 ≥ 66 28 (26.4) 51 (48.1) 15 (14.2) 9 (8.5) 3 (2.83) 30 (31.6) 29 (30.5) 15 (15.8) 15 (15.8) 6 (6.3 12 (26) 15 (33) 16 (35) 2 (4) 0 (0) 70 (28.5) 95 (38.6) 46 (18.7) 26 (10.6) 9 (3.7) 0.0058 gender male female 72 (86.7) 11 (13.3) 72 (86.7) 11 (13.3) 44 (97) 1 (3) 192 (92.8) 15 (7.2) 0.023 place of training home country other countries 36 (45.6) 43 (54.4) 62 (77.5) 18 (22.5) 45 (100) 0 (0) 143 (70.1) 61 (29.9) <0.001 years of practice 1–5 6–10 11–15 ≥ 16 38 (48.1) 17 (21.5) 11 (13.9) 13 (16.5) 25 (29.8) 19 (22.6) 8 (9.5) 32 (38) 9 (20) 3 (6) 11 (24) 22 (48) 72 (34.6) 39 (18.8) 30 (14.4) 67 (32.2) <0.001 type of practice academic community hospital national hospital private practice 53 (67.1) 2 (2.5) 16 (20.3) 8 (10.1) 8 (9.5) 24 (28.6) 26 (31) 26 (31) 12 (26) 0 (0) 32 (71) 1 (3) 73 (35.1) 26 (12.5) 74 (35.6) 35 (16.8) <0.001 respondents were in the following countries. in africa: algeria, liberia, nigeria, zambia, senegal, kenya, mali, niger, madagascar, gabon, togo, ivory coast, cameroon, mauritania, burkina faso, guinea, morocco, benin, republic of the congo, and democratic republic of the congo. in latin america: brazil, bolivia, uruguay, paraguay, colombia, argentina, mexico. in asia: china. 12 siuj • volume 2, number 1 • january 2021 siuj.org original research http://siuj.org considered to be very important by 20.5% (51/249), 13.7% (34/249), and 23.7% (59/249) of participants, respectively. in terms of relevant scientific resources, 30.5% (76/249) of participants greatly valued metaanalyses for consultation during medical decisionmaking, while 25.7% (64/249) emphasized randomized control trials. ten percent (24/249) of participants believed systematic reviews were important to consider, along with case reports (6%, 15/249), and case series (5.2%, 13/249). the majority of participants confirmed they were able to access the internet from their home (69.5%, 173/249), mobile phone (73.5%, 183/249), or local hospital (61.4%, 153/249). some participants reported difficulty accessing cpgs through institutional (26.5%, 66/249) or personal memberships (23.7%, 59/249). less than half felt cpgs were easily accessible through open access options (38.2%, 95/249). use of urology cpgs in international settings overall, 92.6% (225/243) of urologists reported using some form of cpgs in their daily clinical practice (table 2). of those who used cpgs, the majority were based at either a national hospital (30.5%, 69/226) or an academic center (28.8%, 65/226). in africa, 87.4% (90/103) of urologists who responded used cpgs in daily practice, along with 96.8% (92/95) in latin america and 95.6% (43/45) in china. the most commonly used cpgs were those from the eau, as most clinicians reported using them “always” or “frequently” (63.9%, 159/249) (table 3). both cpgs produced by the aua and the clinician’s national urology association were used mostly “frequently” or “sometimes,” capturing 80% (199/249) and 58% (144/249) of clinicians, respectively, in these categories. in comparison, respondents indicated that they used the joint consultations released by the société internationale d ’urologie and the international consultation on urologic diseases “never” or “sometimes” (70.7%, 176/249), closely followed by guidelines published by the clinician’s local institution (57%, 142/249). of participating clinicians, 51% (127/249), reported sometimes consulting “other” cpg sources as well. reported barriers to cpg use among participants, the principal cited barrier to the use of cpgs in everyday practice was the perceived lack of adaptability of the existing cpgs (29.2%, table 2. reported use of cpgs across international settings of practice and participant beliefs regarding individual stakeholders’ responsibility in the development of cpgs participants africa n (%) latin america n (%) china n (%) totals n (%) p -value use of cpg yes no 90 (87.4) 13 (12.6) 92 (96.8) 3 (3.2) 43 (95.6) 2 (4.0) 225 (92.6) 18 (7.4) 0.0279 type of stakeholder scientific association 81 (76.4) 85 (89.5) 34 (75) 200 (81.3) 0.0331 ministry of health 55 (51.9) 63 (66.3) 19 (42) 137 (55.7) 0.0160 board of urology 73 (68.9) 69 (72.6) 26 (57) 168 (68.3) 0.2081 non-profit organization, n (%) 15 (14.2) 11 (11.6) 5 (10) 31 (12.6) 0.8138 pharmaceutical industry 20 (18.9) 5 (5.3) 2 (4) 27 (11) 0.0026 health care provider 44 (41.5) 31 (32.6) 5 (10) 80 (32.5) 0.0013 insurance company 8 (7.5) 9 (9.5) 1 (2) 18 (7.3) 0.3039 proportions equate to the number of participants who indicated “yes” to the importance of this stakeholder in the cpg-development process. 13siuj.org siuj • volume 2, number 1 • january 2021 use of urology-based clinical practice guidelines in international settings http://siuj.org 35/120) (figure  1). secondarily, participants felt that international cpgs were not applicable to their country (24.2%, 29/120) or relevant for the health and/or financial status of their patients (16.7%, 20/120). open responses from a few participants reported barriers such as cost, time, expertise, and equipment limitations. stakeholder responsibility for the development of urology cpgs overall, scientif ic associations, national urolog y boards, and ministries of health were believed to be important stakeholders for local cpg development, by 81.3% (200/246), 68.3% (168/246), and 55.7% (137/246) of participants, respectively (table 2). seen as less important to the cpg-development process were insurance companies (7.3%, 18/246) and members of the pharmaceutical industry (11%, 27/246). discussion this study affirmed that cpgs for urology are widely used in many countries. urologists who reported uptake of cpgs are primarily based in national hospitals or academic centers, and consult the eau, aua, and the cpgs of their own national urology associations. ongoing barriers to cpg use in international urology practices relate to the lack of adaptability and relevant, everyday application. in creating cpgs that better serve urologists in resource-variable countries, participants believe that scientific associations, ministries of health, and national urology associations should be involved as key stakeholders. to our knowledge, this study is the first assessment of cpg use among urologists in resource-variable settings. cpgs are effective tools for crafting evidencebased clinical environments, with the avoidance of inappropriate treatment[4]. however, recommendations that are clinically effective may not necessarily reflect the realities of local constraints; therefore, cost-effectiveness must be considered as well[18]. the world health organization affirms that cpgs must have explicit aims and ultimately be targeted to the users themselves[19]. accredited cpgs are a valuable tool for urologists worldwide, although lack of resources often limits their proper implementation and therefore their usefulness. this study sur veyed a broad range of urologists operating in health care systems of varied capacities around the world. in latin america, recent studies have noted increased use of the grade criteria for cpg development; however, there is a paucity of guidelines for relevant, regional pathology[20]. similarly, in china, where traditional remedies represent 40% of health care provision, complementary medicine principles may be integrated into the framework of medical cpgs[21,22]. finally, at least one study of cpgs across africa has indicated that standards of evidence are distinctly different, signaling the need for greater regional crosscollaboration to produce high-quality recommendations [23]. these examples suggest that despite the similar reported use of urology cpgs in latin america, africa, and china, these results do not necessarily ref lect generalizable knowledge within each distinct region. ninety-three percent of urologists reported consulted international cpgs during daily clinical decisionmaking; however, they may not derive the full benefits or the same benefits as urologists in high-resource countries, because the cpgs may lack applicability lack of adaptability international not applicable patient condition not easy language barriers other 0 5 10 15 20 25 30 35 n um be r o f p ar tic ip an ts reported barriers to uptake of clinical practice guidelines a52 fig1 figure 1. reported barriers to uptake of clinical practice guidelines 14 siuj • volume 2, number 1 • january 2021 siuj.org original research http://siuj.org and acceptability in different environments. existing cpgs may remain “eurocentric,” reflecting the ideals, principles, and knowledge of only a segment of urologists globally. therefore, strengthening cpg development at the national level may be crucial. conversely, the development of cpgs is costly, time-consuming, and laborious and may not be a national priority amidst resource-constrained health systems. one recommended strategy for cpgs in resource-variable settings has been the direct adaptation of existing, international cpgs. in south africa, local practitioners were commissioned to revise international cpgs, with a view to applicability to south african clinical practice[24]. challenged by factors such as funding and human resources, the case analysis spotlighted a gap in research knowledge and critical appraisal among team members[24]. additional studies suggest that while urologists desire to practice evidence-based urology, they may not feel they have the necessary appraisal skills to conduct a comprehensive scientific analysis[25]. with this in mind, parallel development of research training and capacity-building should be considered when looking to craft local cpgs. finally, equitable access to resources is essential to close the loop and deliver cpgs to local practitioners. though this access is not universal, our study found that providers are generally able to access the internet through various means. in africa, participants indicated that internet access for telemedicine is generally available in urban areas, but that access is unreliable in rural regions[26]. however, even in the presence of internet, access to academic literature is variable. in our study, less than half of respondents reported the ability to access open access cpgs with ease. academic financial barriers such as rising subscription costs and evolving publishing restrictions limit global clinicians’ access to sound clinical evidence[27]. in the face of these challenges, some hail open access as a potential solution to mitigate inequities[27]. authors from low-resource countries may not be able to afford the fees for open access publication, so studies that might be particularly relevant to practice in the region may be subscriptiononly and therefore unavailable[28]. therefore, while promoting and crafting cpgs that are relevant to local contexts is crucial, the academic community at large must consider how best to support dissemination of this knowledge. core urology organizations such as the eau and aua make their guidelines available free of charge, as models of equitable publishing. however, the majority of our respondents who used cpgs worked at large national hospitals or academic facilities, highlighting an additional, important opportunity to engage providers in non-academic settings. while our study highlights a known gap in the literature, it has limitations. although we were able to determine that practitioners appear to be aware of cpgs and/or have the desire to use them, our analysis did not capture the scale and nuance of their use. an exploration of provider perspectives through a mixed-method approach might provide a better understanding of the integration of cpgs in urology practices in resource variable areas. moreover, the authors recognize that table 3. proportion of reported frequency of cpg for each type of cpg stakeholders’ responsibility in the development of cpgs international cpg reported frequency of cpg use never n (%) sometimes n (%) frequently n (%) always n (%) aua 8 (3.2) 78 (31.3) 121 (48.6) 15 (6.0) eau 4 (1.6) 59 (23.7) 115 (46.2) 44 (17.7) siu-icud consultation 66 (26.5) 110 (44.2) 40 (16.1) 4 (1.6) national urology association 44 (17.7) 74 (29.7) 70 (28.1) 30 (12.0) local institution 62 (24.9) 80 (32.1) 56 (22.5) 19 (7.6) other 52 (20.9) 127 (51.0) 25 (10.0) 8 (3.2) aua: american urological association, eau: european association of urology, siu: société internationale d’urologie, icud: international consultation on urologic disorders. “other” refers to other forms of cpgs not captured in the above categories. 15siuj.org siuj • volume 2, number 1 • january 2021 use of urology-based clinical practice guidelines in international settings http://siuj.org sampled participants may not necessarily represent generalizable, continent-level findings. urologists’ perspectives were largely compiled through a nonprobable, convenience sampling method, particularly among providers in africa. the global health literature acknowledges this approach as a strategy for collecting data from hard-to-reach populations, such as isolated urologists operating in regions with limited professional contacts[29,30]. overall, we believe this study is an important step towards capturing the practice habits of urologists in these situations. conclusions among our international cohort of urologists, reported rates of cpg use were high, indicating widespread awareness of their utility. however, the actual relevance and application of north american and european cpgs in everyday clinical practice is less clear, highlighting barriers to large-scale dissemination and subsequent promotion of evidence-based urology practice globally. therefore, the development of locally relevant cpgs, either through the creation of new guidelines or the modification of existing ones, should be a priority for stakeholders in health care systems. an effort to promote international cooperation is essential to help build, adapt, and implement cpgs congruent with the epidemiological and socioeconomic context of a country’s needs. references 1. sackett dl, rosenberg wm, gray ja, haynes rb, richardson ws. evidence based medicine: what it is and what it isn’t. bmj. 1996; 312:71. https://doi.org/10.1136/bmj.312.7023. 2. kredo t, bernhardsson s, machingaidze s, young t, louw q, ochodo e, et al. guide to clinical practice guidelines: the current state of play. int j qual health care. 2016; 28(1): 122–128. doi: 10.1093/ intqhc/mzv115. 3. 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american urological association membership. j urol. 2009; 181(2):767-77. doi: 10.1016/j.juro.2008.10.031. epub 2008 dec 16. 26. fraser hsf, mcgrath sjd. information technology and telemedicine in sub-saharan africa. bmj. 2000;321(7259):465-466. doi:10.1136/ bmj.321.7259.465. 27. chan l, arunachalam s, kirsop b. open access: a giant leap towards bridging health inequities. bull world health organ. 2009;87(8):631635. doi:10.2471/blt.09.064659. 28. smith e, haustein s, mongeon p, shu f, ridde v, larivière v. knowledge sharing in global health research the impact, uptake and cost of open access to scholarly literature. health res policy syst. 2017;15(1):1-10. doi:10.1186/s12961-017-0235-3. 29. shaghaghi a, bhopal rs, sheikh a. approaches to recruiting “hardto-reach” populations into re-search: a review of the literature. health promot perspect. 2011;1(2):86-94. doi:10.5681/hpp.2011.009. 30. valerio ma, rodriguez n, winkler p, lopez j, dennison m, liang y, et al. comparing two sampling methods to engage hard-to-reach communities in research priority setting. bmc med res methodol. 2016;16(1):1-11. doi:10.1186/s12874-016-0242-z. 17siuj.org siuj • volume 2, number 1 • january 2021 use of urology-based clinical practice guidelines in international settings http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. key words competing interests article information small renal mass, active surveillance, management strategies, kidney cancer none declared. received on september 25, 2022 accepted on october 4, 2022 this article has been peer reviewed. soc int urol j. 2022;3(6):424–436 doi: 10.48083/oses5540 2022 wuof/siu international consultation on urological diseases: active surveillance for small renal masses eric c. kauffman,1 mark w. ball,2 ravi barod,3 umberto capitanio,4 antonio finelli,5 m. carmen mir,6 brian shuch,7 marc c. smaldone,8 maxine g.b. tran,9 phillip m. pierorazio10 1 department of urology, roswell park comprehensive cancer center, buffalo, united states 2 urologic oncology branch, center for cancer research, national cancer institute, national institutes of health, bethesda, united states 3 specialist centre for kidney cancer, royal free hospital, london, united kingdom 4 unit of urology, division of experimental oncology, urological research institute (uri), irccs ospedale san raffaele, milan, italy 5 division of urology, department of surgery, princess margaret cancer centre, university health network and the university of toronto, toronto, canada 6 department of urology, fundación instituto valenciano oncologia, valencia, spain 7 department of urology, university of california los angeles, los angeles, united states 8 division of urology and urologic oncology, department of surgical oncology, fox chase cancer center, philadelphia, united states 9 university college london division of surgery and interventional science and the specialist centre for kidney cancer at the royal free london hospital, united kingdom 10division of urology, department of surgery, university of pennsylvania, penn medicine, philadelphia, united states abstract with greater awareness of indolence underlying small renal masses (srm ≤ 4 cm) and the morbidity of invasive treatment, active surveillance for srm patients is being increasingly utilized on an international level. this synopsis summarizes the 2022 review and expert opinion recommendations provided to the international consultation of urological diseases (icud) by 10 urologists from high-volume active surveillance practices at international centers. topics reviewed include srm biology and clinical behavior, current national and international guidelines for active surveillance of srm patients, active surveillance utilization patterns and barriers to implementation, outcomes and limitations of the active surveillance literature, criteria for active surveillance patient selection, protocols for active surveillance management including frequency/modality of imaging and the role of renal tumor biopsy, triggers for delayed intervention during active surveillance including tumor factors and patient factors, and pathological outcomes of delayed intervention. we conclude that despite limitations of the current literature, active surveillance is a safe initial management strategy for many srm patients. the slow growth and low metastatic potential of srms, combined with no evidence to suggest oncologic compromise with delay to treatment, should provide confidence to both patients and providers who are considering active surveillance. future research for prioritization should include characterization of long-term active surveillance outcomes including rates of metastasis and delayed intervention, standardization of objective tumor progression criteria for triggering delayed intervention, and further delineation of the role for active surveillance in young and healthy patients. introduction small renal masses (srm) are renal cortical neoplasms ≤ 4 cm comprising benign tumors and renal cell carcinomas (rcc) with rare metastatic potential[1]. with greater use of cross-sectional abdominal imaging there has been a significant stage migration towards incidental srm detection[2,3]. conversely, rcc mortality has remained stable, establishing a concern for overtreatment of srm patients and a rationale for active surveillance (as). 424 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases mailto:eric.kauffman%40roswellpark.org?subject=siuj http://siuj.org as is semantically distinct from watchful waiting (observation) and includes intention for curative delayed intervention (di) if necessary, whereas watchful waiting/ observation involves only palliative treatment and concedes metastasis when cancer-specific mortality is unlikely[4]. heterogenous and indolent srm biology srm encompass a variety of benign and malignant histologic subtypes with different genomic and genetic landscapes. benign tumors represent 20%–40% of srm[5–8]. malignant srm are commonly low-grade and low-stage rcc, with high-grade and/or pt3 tumors accounting for only 10%–25% of surgical cases[5,7]. regardless of histolog y, sr m rarely metastasize or become lethal. risk of death from non-cancer causes is higher in almost all categories of patient age, comorbidity, and tumor size among patients with ct1 tumors[9]. analysis of tumor genomics and genetics by the tcga and tracerx next-generation sequencing initiatives indicate that ct1a rcc typically has low genetic diversity and chromosomal complexity, which may explain indolent clinical behavior[10–12]. this biology, termed the vhl mono driver subtype, is characterized by limited genetic branching without additional driver mutations, tumor size < 45 mm, and excellent long-term survival, often requiring decades to acquire mutations conducive to metastatic potential[11,12]. guideline support c om mon ly u sed g u idel i ne s for sr m pat ient ma nagement include t hose from t he america n urological association (aua), european association of urology (eau), national comprehensive cancer network (nccn), american society of clinical oncology (asco) and european society of medical oncology (esmo). there is general agreement that expectant management (as or watchful waiting/ observation) is an option in patients with comorbidities or limited life expectancy (le), and preferred whenever the anticipated risk of intervention outweighs the oncological benefits of treatment. however, patient selection criteria, role of renal tumor biopsy (rtb), modality/frequency of imaging, and triggers for di all lack strong consensus recommendations. current aua[13,14] and nccn[15] guidelines each make conditional recommendations to consider as with potential for di as a first-line management option in patients with a srm < 2 cm, regardless of age or health, and in patients with a larger srm when cystic or with significant comorbidity. eau and asco support rtb to guide as scanning frequency and/or initial patient selection, while aua and esmo recommend consideration of rtb in select cases for additional risk stratification[16–18]. there is general agreement for initial repeat imaging within 3–6 months. specific patient-related and tumor-related factors favoring expectant management versus intervention are endorsed by the aua (table 1). however, many patients fall into a gray zone within this dichotomous scheme, and integration of additional factors is needed, as is attention to clinical scenarios in which contrasting factors are simultaneously present. current utilization and barriers as utilization has remained relatively static over the past 20 years. seer and ncdb population registries in the united states indicate that as utilization rates for srms remain < 10%[19,20]. in contrast, use of both partial nephrectomy and thermal ablation has increased over this period, including in older patients[21]. there are currently no population-based studies of as utilization in other countries. recent reports of high as utilization at some centers shed new light on potential barriers to broader as utilization. roswell park cancer center reported that almost all (> 95%) new srm patients seen over 5 years elected as management, regardless of patient age or health[22], while music registry analyses reported considerably variable as utilization across regional academic and private practices despite similar patient and tumor features[23]. hence, factors related to the provider and health care setting, rather than to the patient, appear most important in driving current as utilization. provider-related differences may reflect variable awareness and/or certainty in interpreting the current evidence in support of as. limitations of active surveillance literature historically, as was supported by only retrospective series, and the vast majority of reports are still subject to inherent retrospective design biases[24,25]. definitions and protocols regarding as were historically not well established, including substantial contamination with observation patients that potentially exaggerated metastasis rates, with di deferral being typical upon srm progression[26]. reports are further confounded abbreviations as active surveillance di delayed intervention gr growth rate le life expectancy rcc renal cell carcinomas rtb renal tumor biopsy srm small renal masses 425siuj.org siuj • volume 3, number 6 • november 2022 active surveillance for small renal masses http://siuj.org by variable inclusion of low complexity cysts (eg, bosnia k i-iii) without radiographic evidence of tumor, heterogeneous criteria for di, and questionable reliability of follow-up to capture all metastatic and/or dying patients. rarity of srm metastasis and cancerspecific death has challenged statistical comparisons to immediate treatment in both retrospective and prospective as cohorts, and surrogates for clinical progression such as growth rate (gr) have unclear relevance to these gold-standard outcomes. it is possible if not likely that a subset of as “failures,” particularly those with early metastasis (< 6–12 months), would not have benefited from immediate treatment[20,27]. finally, follow-up for most as studies remains relatively short (t y pica lly median 24–36 months), leav ing uncertainty regarding the long-term sustainability and safety. more prospective series with long-term follow-up using pre-defined objective criteria for selecting patients and triggering di are needed. summation of recent active surveillance literature despite its limitations, the summation of published literature indicates that as is a safe initial management strategy for many srm patients. a 2018 systematic review of as series from mir et al. concluded relatively slow linear growth rates (median 0.37 cm/year overall, 0.22 cm/year for sr ms), and low metastasis and cancer-specific survival rates[28]. these conclusions are supported by more recent prospectively managed cohorts using as protocols, differing in nuances of their prospective as pathways but collectively providing strong support for oncologic safety. one of the largest registries is an american multi-institutional prospective cohort study comparing the outcomes of srm patients undergoing as versus primary intervention, the delayed intervention and surveillance for small renal masses (dissrm) registry. initiated in 2009, dissrm at last report included 495 as patients with median followup of 3.3 years and a third of patients followed for > 5 years[29]. the 5-year progression-free survival in the as group was 67% and was driven largely by either rapid gr or patient preference. the 7-year cancer-specific survival (css) with as was 100% and not significantly different from other management strategies (98.8% for partial nephrectomy)[25,30]. oncological safety of as was similarly observed among carefully selected srm patients < 60 years old[31]. the dissrm registry has also provided data regarding gr variability over time, the minimal utility of routine chest imaging, and comparative outcomes for patient quality of life during as versus other management strategies[25,32–34]. the prospective renal cell cancer consortium of canada recently highlighted histology specific gr outcomes, with an overall average of 2–3mm/year during a median follow-up of 5.8 years[27,35]. rtb was encouraged at enrollment, and papillary type 1 renal cell carcinomas (rcc) demonstrated a significantly more indolent course than clear cell rcc, which had higher table 1. patient and tumor-related factors favoring active surveillance versus intervention according to the aua guidelines patient-related factors tumor factors favor active surveillance/ expectant management elderly life expectancy < 5 years high comorbidities excessive perioperative risk poor functional status marginal renal function patient preference to avoid treatment risks tumor size < 3cm tumor growth < 5mm/year non-infiltrative on imaging low complexity favorable histology (if rtb performed) favor intervention young life expectancy > 5 years low comorbidity acceptable perioperative risk good functional status anticipate adequate renal function following intervention patient preference for treatment tumor size > 3cm tumor growth > 5mm/year infiltrative on imaging high complexity unfavorable histology (if rtb performed) 426 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org gr and progression rates[35]. gr was variable within an individual patient, and rapidly growing tumors were frequently stable on subsequent imaging, suggesting value to a confirmatory scan. the 5-year progressionfree survival was 54%, driven mainly by elevated gr (82% of patients). only a minority (36%) of 136 patients with biopsy-proven rcc remained on as at 5 years, and 35% of nephrectomy di patients had high-grade pathology, suggesting enrichment for adverse pathology (see also delayed intervention pathology, below). six rcc patients (4%, all clear cell subtype) developed metastasis and 29 (21%) died, including 3 (2%) cancerrelated deaths. these long-term outcomes mirror those of malignant srm surgical series, and support the potential long-term durability of as in a subset of rtbconfirmed rcc patients. fox chase cancer center has a long histor y of investigating as for srms. in the most recent update, 544 lesions in 457 patients over a median 67 months indicated that 80% of srms will grow slowly or not at all, approximately 40% will undergo intervention at 5 years, and cancer-specific mortality is 1%[36]. data from this cohort support the safety of di in srm patients and, as for dissrm and the canadian registry, indicates rapid gr is associated with higher rates of intervention. in a recent cohort series of “universal ” as from roswell park cancer center, a ll non-hereditar y srm patients seen by one urologist over a 5-year period were recommended as if they lacked tumor progression criteria at presentation, which amounted to > 95% of consecutive new srm patients[22]. tumor progression criteria used for triggering immediate or delayed treatment were pre-defined as longest tumor diameter (ltd) > 4 cm, gr > 5 mm/year for ltd ≤  3  cm or  >  3  mm/year for ltd > 3 cm, unfavorable rtb histology, ct3a stage, or srm-related symptoms. patients meeting any criterion were recommended treatment if le was > 15 years, observation if le was < 5 years, and continued as versus di if le was 5–15 years. most patients tolerated as, with only 1 patient (1%) crossing over to treatment due to non-tumor factors (anxiety). of 128 patients, 75% remained di-free at 3 years, and none developed metastasis, which further supports as safety. selecting patients for active surveillance while national and international consensus guidelines recommend as patient selection based on tumor size, life expectancy, and comorbidities, very few strict size/age/comorbidity cut-offs exist[14,15,33]. tumor and patient factors to guide as patient selection are summarized below. tumor factors tumor size there is general consensus for ltd to guide as patient selection, as the strongest known clinical predictor of srm malignant histology, adverse pathology, and metastatic potential[5–8,34]. metastasis rates approach 0% for ltd < 2 cm, ~1% for < 3 cm, 2%–3% for < 4 cm, and increase exponentially for >  4  cm[9,37–43]. currently, aua and nccn recommend consideration of as independent of hea lt h in pat ients w it h ltd < 2 cm, while other guidelines are noncommittal regarding an ltd threshold. while < 2 cm is the most ideal for as patient selection, we believe the current literature supports adequate oncologic safety to consider as for patients with ltd up to 4 cm. however, more careful selection and/or monitoring (see below, active surveillance protocols / renal mass imaging; and triggers for delayed intervention / growth rate) should be considered for patients with ltd 3–4 cm due to the non-negligible metastatic risk at this size. benign or unfavorable renal tumor biopsy histology rtb can aid srm risk stratification by: (1) identifying benign neoplastic histology (renal oncocy toma or angiomyolipoma, aml); or (2) revealing unfavorable rcc histolog y[17,22,27,44]. r isk of spontaneous hemorrhage observed with larger aml appears to be insignificant among srms[45]. historically, rtb differentiation of oncocytoma from rcc (particularly chromophobe rcc) was challenged by histologic overlap necessitating diagnostic extirpation, but more reliable rtb diagnosis has evolved with immunohistochemistry panels that include the oncocytoma/chromophobespecif ic biomarker, cd117, and rcc biomarkers lacking in oncocytoma (eg, ck7, caix, amacr, vimentin); in addition to radiologic approaches that corroborate oncocytoma diagnosis, such as sestamibi scan and ct-based contrast enhancement measurement (tumor:cortex peak early enhancement ratio, or “peer” score)[45–50]. oncologic and functional safety of as for oncocytomas is generally supported but requires more long-term study[51–54]. srm patients with rtb favoring oncocytoma are ideal as candidates, given the indolence of oncocytic srms regardless of malignant vs. benign etiology[55]. in contrast, unfavorable rtb histology (nuclear grade > 3, papillary type 2 rcc, translocation rcc, unclassif ied/indeterminable rcc subty pes) may challenge as candidacy, although additional study is needed since even adverse histology may have outstanding outcomes among srm patients[28]. the value of histologic subtyping among favorable rcc histologies (eg, low-grade clear cell vs. papillary type 1 vs. chromophobe) remains unclear, although canadian 427siuj.org siuj • volume 3, number 6 • november 2022 active surveillance for small renal masses http://siuj.org registry investigators observed metastases exclusively with the clear cell subtype, while zero growth occurred more often among non-clear cell subtypes[35]. cysts predominantly cystic tumors (bosniak iii-iv) are associated with more favorable pathology and prognosis compared to solid tumors of the same size, including only rare metastatic potential[56,57]. moreover, as for bosniak iii lesions of all sizes and smaller bosniak iv lesions is associated with particularly excellent oncologic outcomes. accordingly, there is general consensus that bosniak iii-iv srms comprise an ideal patient subset for as consideration. patient factors age and life expectancy other cause mortality outweighs the risk of cancerspecific mortality for most srm patients, particularly in elderly, but also regardless of age, comorbidity, tumor size or initial management strategy elected[43,58–60]. dissrm and other registries support that patients >70 years old and those with competing risks of mortality (particularly cardiovascular disease)[60] are most likely to benefit from and remain on as[43,61,62]. specific le thresholds have not been routinely addressed. among patients with le <5 years, aggressive treatment (predominantly with surgery) has no known benefit but remains common, highlighting a need to better incorporate le into treatment decision-making[63]. ageand sex-adjusted le calculators are available (e.g., https://www.ssa.gov/oact/population/longevity.html), but methods to adjust based on comorbidities and frailty are not well standardized[64,65]. a health-adjusted renal mass-specific calculator was recently published by psutka et al. including dissrm registry patients (https://small-renal-mass-risk-calculator.fredhutch. org)[43]. as in young, healthy patients remains controversial, given the historical presumption that tumors would eventually grow and require intervention. however, dissrm registry analysis recently showed that a significant proportion of younger patients (< 60 years old) have a durable absence of significant growth, with 70% remaining on as after 5 years and metastasisfree[31]. similarly, a 72% rate of as continuation beyond 5 years was reported in roswell park cancer center’s recently updated experience of as recommended to over 200 consecutive progression-free srm patients without age-related or health-related selection bias, which yielded a relatively young and healthy as cohort[66]. as is thus likely to be safe for young, healthy patients with srms who wish to avoid immediate treatment, but counseling should mention the uncertainty of long-term (> 10 year) outcomes including di rates. renal function any intervention on a renal unit will adversely affect the estimated glomerular filtration rate, with nephronsparing approaches generally incurring ipsilateral loss of 10%–20%[21]. as is the only available management option that may not affect the natural history of chronic kidney disease progression[21,25,67]. given associated risks for cardiac morbidity and other cause mortality[68], patients at risk for end-stage renal disease upon treatment are ideal candidates for as[43]. patients who already have end-stage renal disease may or may not require treatment to be eligible for renal transplant, depending on center-specific requirements[69]. illness uncertainty/anxiety illness uncertainty and anxiety have historically played a major role in as patient selection. the impact of the healthcare setting and provider on illness uncertainty is increasingly apparent. with the roswell park experience in which nearly all newly presenting srm patients were recommended as, there was surprisingly wide acceptance of as enrollment after informed counseling (95% as, 1% immediate treatment, 4% unknown), including 100% as election among patients with follow-up at roswell park[22]. a structured as program, consultation with a rcc expert/specialist, and availability of rtb histology may all influence illness uncertainty and as enrollment. active surveillance protocols as protocols include periodic renal mass imaging, renal function monitoring, and periodic staging for metastatic progression, with or without adjunct use of rtb[70]. meaningful comparisons of protocols have been challenged by the rarity of srm metastasis or cancer-specific mortality outcomes to evaluate protocol efficacy[21]. in the absence of level 1 evidence, prospective cohort studies with rigorous patient and clinician adherence to meticulously defined eligibility criteria and strict surveillance schedules are critical to determining optimal surveillance protocols. renal mass imaging: timing, frequency and modality most prospective protocols use multiphasic crosssectional imaging initially, with a long-term goal for ultrasound of more indolent masses to minimize radiation and contrast exposures[22,30,35]. all major studies to date include initial short-term surveillance, typically within 3–6 months to rule out very rapid growth, and subsequently follow patients at intervals extending from 6–12 months[22,27,30,36]. the next iteration of nuanced imaging may involve intervals based on initial tumor size, as, for example, the 428 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases https://small-renal-mass-risk-calculator.fredhutch.org https://small-renal-mass-risk-calculator.fredhutch.org http://siuj.org roswell park protocol recommends an initial 3-month versus 6-month scan for tumors > 3 cm versus < 3 cm, respectively[22]. renal function and metastatic evaluation renal functional tests including a serum creatinine should occur at least annually[13,16]. baseline chest imaging to rule out pulmonary metastasis is recommended[37]. however, the utility of subsequent chest monitoring is questionable, given the metastatic risk approaches 0% in the absence of significant srm growth[20]; and there are definite psychologic, medical and financial harms to incidental pulmonary findings. approximately 20% of chest imaging tests evaluated in the dissrm registry were abnormal, of which most were non-actionable (no metastases)[34]. annual chest imaging can likely be omitted or at least reduced in frequency unless there is (1) an abnormality on baseline imaging, (2) significant srm growth, or (3) plans for di[70]. renal tumor biopsy rtb utilization has increased over the past decade because of systematic reviews and meta-analyses supporting a high diagnostic rate and excellent safety profile[71,72]. this evolution in practice is evident from a dissrm study showing an increase in rtb utilization over the past decade from 5% to 20%, while other contemporary as cohorts surpass 50%[22,27,32]. while guideline committee recommendations vary, there is growing consensus that rtb can be useful to risk-stratify for as but is not a requisite. there is also growing consensus to reserve rtb for srms with ltd >2 cm, given that smaller sizes have negligible oncologic risk and lower technical success rates[4,7,22]. some programs, such as at roswell park and in bologna, italy, additionally endorse rtb in smaller (< 2 cm) tumors whenever there is a rapid gr (> 5 mm/year) to rule out benign tumor histology before di conversion[22,73]. while some as centers such as the canadian registry and roswell park endorse routine rtb for as guidance (i.e, > 50% of patients)[22,35], other contemporary as programs use rtb more selectively based on variable patientand program-specific thresholds (8%–24% of patients)[29,36,74,75]. in the dissrm registry, patients are not routinely biopsied at enrollment, but rtb is recommended for gr >5mm/year or upon surpassing patient-specific ltd size thresholds (2, 3, or 4 cm)[29]. triggers for delayed intervention di should be triggered during as by any change that causes the oncologic risk to exceed the treatment risk[4,15–17]. this guiding principle mirrors that for initial as selection, but utilizes growth kinetics and potentially new histology information obtained during as to further improve risk stratification[22]. as with as patient selection, di triggers are divided into tumor factors and patient factors. recent maturation of oncologic safety data has fostered patient and physician comfort with as, and di cases are increasingly triggered by tumor factors rather than patient factors/anxiety. nevertheless, patient factors remain impactful and drive high variability between different as programs in contemporary di rates (11%–50%)[22,27,35,36,74–82]. tumor factors / progression criteria for intervention tumor factors for di have been referred to as progression criteria for intervention (pci), so as to differentiate from classic clinical progression (i.e. stage, grade, death), since the former may not include the latter[22]. pci generally fall within 5 categories (acronym: “glass”): (1) gr; (2) ltd; (3) adverse/unfavorable biopsy histology; (4) stage/infiltration; (5) symptoms/signs. based on both incidence and consensus level, gr and ltd are considered major pci, whereas other glass pci categories are minor. only few centers use minor pci, with roswell park observing < 3% versus 30% of patients meeting minor pci versus major pci, respectively[22]. greater pci standardization has been challenged by inconsistent usage of prospectively defined objective pci thresholds[22,27,35,74–81], as nonspecific subjective tumor thresholds are still commonly reported (eg, “fast” or “significant” growth, “radiological progression,” “change in srm’s features,” etc.)[73,75–77]. this heterogeneity drives high variability in reported pci rates (9%–30%)[22,27,75]. growth rate rapid gr is the most commonly used pci in contemporary as series[22,35,73–75,78,80,82], and also the most common di trigger when used with other pci[22,35]. numerous retrospective studies support gr association with rcc grade[22,74,83–86] metastatic potential[20,75,77,79,80,82,86], and an association between rapid gr and clear cell rcc histology is also reported[35]. however, prospective validation of these associations is still needed[52,75]. a systematic review of early as series identified a median gr of 6.5 mm/year among metastatic patients compared with 2.5 mm/year in non-metastatic patients[20], and the vast majority of the > 30 as patient metastases reported to date have had a primary tumor gr > 5 mm/year[29,35,75,77,79,80,82]. however, most of these patients were not followed with prospectively applied pci and had quite large primary tumors (> 6 cm) at metastasis, and validation in srm cohorts managed with timely di conversion is needed[36,78]. nevertheless, there is consensus, including from asco and aua to use gr of > 5 mm/ year to trigger di[4,15,17]. studies prospectively using gr > 5 mm/year suggest that 13%–18% of patients meet this threshold during as[22,56,74,78]. tumor size429siuj.org siuj • volume 3, number 6 • november 2022 active surveillance for small renal masses http://siuj.org stratified gr thresholds may have future utility. for example, roswell park prospectively uses gr > 5 mm/ year for ltd ≤ 3 cm, but gr > 3 mm/year for ltd > 3 cm, based on (1) increased/non-negligible srm metastatic risk beyond 3 cm; (2) historical reports of srm metastasis with gr < 5 mm/year but not < 3 mm/ year; and (3) high likelihood that a srm > 3 cm with gr > 3 mm/year will progress based on ltd > 4 cm within 1–3 years anyway[22]. an alternative to linear gr is volumetric growth or doubling rate, as used by the canadian rcc consortium and university of texas southwestern medical center[27,35,80]. however, caution with this approach must be exercised, since minute linear changes in very small srms (including those attributable to artifact/inter-observer variability) can yield volumetric doubling, while relatively fast linear growth (eg, ~6–8 mm/year) may fail to meet the volumetric doubling threshold for tumors > 4 cm. longest tumor diameter in a systematic review of early as series including over 800 patients, 89% (16/18) of metastatic patients had ltd > 4 cm at metastasis versus 0% (0/18) having ltd < 3 cm[20]. contemporary as series similarly support a negligible metastatic rate when <3cm, and a very low metastatic rate for ltd 3–4 cm, with most metastases occurring when > 4 cm[29,56,76,78,80,81,83]. accordingly, there is strong general consensus for ltd usage as a pci[4,16,17,87], with 4 cm being the most commonly used threshold. ltd > 4 cm triggered or helped trigger 25% and 50% of di cases in the canadian and roswell park cohorts, respectively[22,35]. a > 3 cm ltd cutoff for treatment is endorsed by current aua guidelines, but its reported use is uncommon[4,29,77]. one rationale for using ltd > 3 cm is its association with higher rates of eventual di[22,29,31]. nevertheless, a 3 cm threshold likely overtreats many patients, particularly those with slow growth (< 3 mm/year) for whom metastasis rates appear to approach zero and long-term di avoidance may be possible. adverse/unfavorable biopsy histology although the prevalence and diagnostic sensitivity of rtb for adverse histology in srms is low, diagnostic specificity is high. accordingly, any patient with rtb favoring high-grade rcc and/or a more aggressive subtype should be counseled on potentially higher risks with as continuation, given the higher metastatic risk in surgical series. stage/infiltration clinical upstaging from ct1a to ct3a is an independent prognostic variable for metastasis but is a rare event in most as series. only one patient (1%) in the roswell cohort developed ct3a disease (progressing also by both gr and ltd)[22]. similarly, canadian investigators reported one (1%) patient with di triggered by tumor thrombus[75]. regardless of rarity, detection of ct3a upstaging should trigger di consideration due to a potentially higher metastatic risk. symptoms/signs tumor-related symptoms or signs such as gross hematuria, retroperitoneal bleeding, or paraneoplastic effects are well described for rcc but exceedingly rare in the srm population. accordingly, the vast majority of srms remain asymptomatic during as[22,75]. in over 500 patients to date, the dissrm registry has yet to encounter gross hematuria attributable to a renal mass[29]. three (18%) patients in a prospective canadian study and one (1%) patient in the roswell park cohort developed gross hematuria, although a renal source is unclear. for symptom development during as, the first action should be to rule out other sources. patient factors with the exception of a few recent as series in which di was almost entirely driven by pci[22,35,73], di cases in contemporary as reports are still commonly, if not mostly, performed because of patient factors without pci development[7,27,74,76,82,88]. patient preference/anxiety patient preference due to anxiety or disease uncertainty is the most common patient factor triggering di. this is clearly demonstrated in the dissrm and canadian prospective registries where approximately 50% or more of patients who crossover to di do so without tumor pci development[27,76,78,82,88]. illness uncertainty predicts general quality of life, cancer-specific quality of life, and distress which can all impact the success of as[89]. interestingly, mental health scores improve over time in patients in a structured as program such as dissrm[33]. the increasingly apparent role of the provider and health care setting in influencing as program acceptance was discussed above. only rarely did as patients convert to di because of anxiety without pci development in the roswell park (1%) and italian (4%) cohorts, supporting this role[22,73]. given the impact of illness uncertainty during as[89], di conversion may be reduced by empowering the patient upfront with details regarding the very low gr (e.g., average 2–3 mm/year), planned use of pci thresholds, and negligible expected metastasis rates during pci freedom. the dissrm registry demonstrates that patients experience improving mental health domains while they are in structured as programs, indicating reductions in anxiety and illness uncertainty[33]. life expectancy le must be carefully considered before di conversion, since impending metastasis may not increase mortality risk when life expectancy is limited (eg, < 5 years)[90]. 430 siuj • volume 3, number 6 • november 2022 siuj.org 2022 wuof/siu international consultation on urological diseases http://siuj.org in young hea lthy indiv idua ls, pci development should serve as an absolute indication for di, whereas as continuation or observation conversion may be appropriate in elderly patients and/or patients with comorbidities despite pci development. improved patient health or resolution of an acute health issue during as may increase le and change the risk-benefit ratio towards treatment[82]. more recent cohorts, like that at roswell park, have integrated pci triggers with le calculations to guide decision-making regarding di conversion[22]. other patient factors other patient factors triggering di are uncommon. the need for unrelated additional surgery is reported as a di trigger[91], but, other than renal transplantation, is generally not endorsed. concern for losing a window to perform nephron-sparing treatment may raise consideration for early di, but the vast majority of di cases in contemporary as reports have been amenable to nephron-sparing, suggesting no compromise in renal preservation[22,35,73,74,76–80,88]. rarely, as patients may develop end-stage renal disease that requires resection to qualify for renal transplantation eligibility, depending on center requirements[70,79]. finally, concern regarding patient non-compliance may be an under-utilized reason for di conversion, given that many metastasis cases during as have been attributed to poor patient adherence to as protocols[20,79]. delayed intervention pathology most as series demonstrate a similar albeit slightly higher rate of malignancy at di (80%–100%) compared to surgical srm series[8,22,27,36,73,78,82]. avoidance of benign resections appears to correlate with degree of rtb usage, with the canadian consortium and roswell park each achieving a 0% benign di resection rate while using routine rtb to identify benign tumors non-surgically[6,22,27,73,78]. high nuclear grade or pt3 upstaging is uncommon in resected srm series and as series, comprising ~5% and 10%–20% of cases, respectively[78,86,92–96]. in contrast, roswell park recently reported very high rates (62%) of any adverse pathology at di surgeries, which may relate to keeping 99% of patients on as until pre-defined tumor pci development, potentially enriching di resections for higher risk tumors[22]. these investigators also found a rapid gr to be associated with higher adverse pathology rates, similar to many retrospective series. however a di cohort study from the dissrm registry observed low rates of adverse pathology and zero metastases, regardless of gr[78]. the clinical impact of adverse pathology at di remains unclear since resected srm patients have an excellent prognosis regardless of pathology. on the horizon a variety of technologic advances under active study have the potential to propel the as field forward. these approaches include the use of novel tumor biopsy-based biomarkers, blood-based biomarkers (e.g., circulating tumor cells/dna), and urine-based biomarkers, which may improve prognostic accuracy over conventional imaging and biopsy histology. radiomics guided by automated volumetry and/or artificial intelligence may also further refine current as strategies. summary despite limitations in the current literature, as appears to be a safe initial management strategy for many srm patients. the indolent clinical growth and low metastatic potential of srms, combined with no evidence to suggest oncologic compromise with delays to treatment, should provide confidence to both patients and providers who are considering as. future research in as patients should prioritize characterization of long-term rates of metastasis and di, standardization of objective tumor progression criteria for triggering di, and defining the role of as in young and healthy patients. 431siuj.org siuj • volume 3, number 6 • november 2022 active surveillance for small renal masses http://siuj.org references 1. gill is, aron m, gervais da, jewett mas. clinical practice. small renal mass. n engl j med.2010;362(7):624-634. doi:10.1056/ nejmcp0910041 2. kane cj, mallin k, ritchey j, cooperberg mr, carroll pr. renal cell cancer stage migration: analysis of the national cancer data base. cancer.2008;113(1):78-83. doi:10.1002/cncr.23518 3. patel hd, gupta m, joice ga, srivastava a, alam r, allaf me, et al. clinical stage migration and survival for renal cell carcinoma in the united states. 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this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj.org siuj • volume 4, number 3 • may 2023 key words competing interests article information clavien-dindo classification system, augmentation cystoplasty, ileocystoplasty none declared. received on august 24, 2022 accepted on october 16, 2022 this article has been peer reviewed. soc int urol j. 2022;4(3):195–202 doi: 10.48083/hcfx2060 195 original research augmentation cystoplasty: experience in the developing world naveed ahmed mahar,1 mohsin mustafa memon,1 farag mohsen saleh aboali,1 shireen piyarali,1 harris hassan qureshi,1 sara rasheed kalwar,1 murli lal1 1 department of urology, sindh institute of urology and transplantation, pakistan abstract objective to assess functional outcomes and classify postoperative complications of augmentation cystoplasty by the clavien-dindo classification system. methods a total of 197 adult patients undergoing augmentation cystoplasty between january 2016 and december 2020 at the department of urology, sindh institute of urology and transplantation (siut), were included in the study after obtaining approval from the ethics review committee. patients’ records were reviewed for assessment of complications up to 3 months of follow-up. functional outcomes were assessed by comparing preoperative video urodynamics study (vuds) findings with follow-up vuds findings at 1 year. ibm spss v23 was used to record and analyze all the complications, treatments, and preand postoperative vuds data. results of the 197 patients included in this study, 127 (64.5%) were male and 70 (35.5%) were female. the mean age of the patients was 38.4 ± 9.92 years. eighty-seven patients (44.2%) remained complication-free, 64 patients (32.5%) had grade i-ii complications, 44 patients (22.3%) had grade iii and iv complications, and only 2 patients (1%) had grade v complications. stomal stenosis was the most frequent complication, occurring in 14.7% of patients, followed by renal function deterioration and high-grade fever, each noted in 13.7% of patients. mean preoperative bladder capacity was 144.3 ± 63.09 ml, mean preoperative filling pressure was 43.34 ± 26.92 cm3 h2o, while mean postoperative bladder capacity was 460.83 ± 70.69 ml and mean postoperative filling pressure was 7.47 ± 5.79 cm3 h2o. conclusion augmentation cystoplasty can increase bladder capacity and improve bladder function. because of the potential for complications, it is essential to carefully choose patients for surgery and provide proper preoperative counseling. additionally, it is crucial to give proactive postoperative care. introduction the bladder, aided by pelvic floor muscles, the external urethral sphincter, and the bladder neck, plays a crucial role in continence and releasing urine through the urethra[1,2]. on average, the bladder holds 400 ml of urine[3,4]. the best course of treatment for bladder dysfunction depends on the degree of discomfort and the risk for upper tract injury. the most common treatment for incomplete bladder emptying is intermittent self-catheterization, while antimuscarinic medications are used to treat storage dysfunction. neuromodulation and intradetrusor injections of botulinum toxin are 2 intriguing alternatives[5]. augmentation cystoplasty (ac) is a complex and uncommon urological procedure used to treat refractory bladder dysfunction. the goal of ac is to provide adequate urine storage and continence, to prevent upper tract injury from http://siuj.org high pressure, and to improve bladder compliance in patients with low-capacity, high-pressure, or poorly compliant bladder[6]. tizzoni and von mikulicz were the first to describe augmentation cystoplasty in dogs and humans, respectively[7,8]. but the procedure wasn’t used very often until the 1950s, when couvelaire popularized its use for treatment of the tiny, contracted bladder from genitourinary tuberculous (tb)[9]. patients undergoing ac may encounter one or more complications, like with any other surgical procedure. fever, pain, sepsis, wound infection, anastomotic leak, and a decline in electrolytes and renal function are some of the short-term complications linked to ac. stomal stenosis, the necessity for further surgery, metabolic consequences, stone formation, declining renal function, and recurring infections are examples of long-term consequences. the majority of these complications are attributed to the complexity of surgery and the absorptive nature of the bowel mucosa[10,11]. outcomes are measured using 2 main parameters: complication rate and improvement in overall functional capacity and compliance with follow-up video urodynamic study (vuds). benefits and complications associated with augmentation cystoplasty are well documented, but data from our region is scarce. a systematic method was previously lacking for evaluating morbidity and mortality in the immediate postoperative period. the clavien-dindo classification system is now used around the world as a standard tool to classify and calculate the rates of complications after surgery[12]. in this study, we examine early (within 3 months) postoperative complications using the clavien-dindo classification system and functional outcomes in terms of improvement in vuds after ileocystoplasty with or without a catheterizable channel. methods this obser vationa l study was conducted at t he department of urology, sindh institute of urology and transplantation (siut), following permission of the institutional ethics review committee (erc reference number: siut-erc-2021/a-344). the medical records abbreviations ac augmentation cystoplasty cic clean intermittent catheterization cisc clean intermittent self-catheterization vuds video urodynamics study of all 197 adult patients undergoing augmentation cystoplasty between january 2016 and december 2020 were evaluated. in contrast to the 181 (91.9%) patients who received concurrent mitrofanoff procedure, only 16 (8.1%) patients (who did not consent to mitrofanoff and agreed to clean intermittent self-catheterization [cisc] per urethra) underwent augmentation cystoplasty alone. before surgery, extensive preoperative diagnostic workup was carried out. initial workup included detailed history, physical examination, bladder diary, ultrasound kidney ureter and bladder preand postvoid, blood urea and nitrogen, uroflowmetry (ufm), and voiding cystourethrogram (vcug). acid fast bacillus urine smear and genexpert were performed in patients suspected of having genitourinary (gu) tuberculosis (tb). vuds was performed in all patients with bladder dysfunction, except for thimble bladder on vcug or genitourinary fistulae. augmentation cystoplasty was performed in patients with refractory bladder dysfunction who had either small capacity, high pressure (posing risk for upper tract), and/or reduced compliance on vuds. patients with gu tuberculosis and extremely small capacity (thimble bladder) were also subjected to augmentation cystoplasty after completion of anti-tuberculosis treatment. patients with deranged renal function were first kept on continuous drainage with either suprapubic catheterization or urethral drainage. if renal function improved to within normal range, then augmentation cystoplasty was performed straightaway. a ll those patients with refractor y bladder dysfunction in whom renal function did not improve below 2.5 mg/dl on continuous drainage were counseled to increase awareness of potential postoperative risk for rapid renal function deterioration and renal insufficiency subsequently requiring renal replacement therapy or transplant. patients who did not wish for future renal transplant and serum creatinine was more than 2.5 mg/dl were kept on conservative therapy with anticholinergics and cisc every 2 to 3 hours or suprapubic catheterization. a multidisciplinary approach was adopted involv ing a neurologist, psychologist, and nephrologist (where required). each patient received thorough counseling regarding the entire procedure with the help of audiovisuals. patients were admitted the day before surgery, and a prophylaxis regimen of broad-spectrum antibiotics was started at admission. no patient received vigorous preoperative bowel preparation. patients were advised to consume clear liquids for 24 hours with overnight fasting prior to surgery. all patients underwent ileocystoplasty. an ileal segment of 25 to 60 cm depending upon the preoperative bladder capacity assessed by cystometry and video urodynamics was harvested with intact blood supply 20 cm proximal to the ileocecal junction (figure 1). the ileal segment was then detubularized over the anti-mesenteric border to create an ileal plate (figure 2). the plate was 196 siuj • volume 4, number 3 • may 2023 siuj.org original research http://siu.org then configured into either a “u” or “w” configuration to anastomose with the already opened (bivalve) bladder with polydioxanone suture 3/0 (figures 3 and 4). for the mitrofanoff procedure, we utilized the patient’s appendix (appendicovesicostomy) (figure 5). the monti procedure (figure 6) was performed if the appendix was not healthy, short in length, or had a narrow lumen preventing the 14-french catheter to be negotiated. all mitrofanoff procedures were done by creating a submucosal tunnel figure 1. selected part of the ileum being harvested along with the mesentery figure 2. ileal plate after detubularization into the bladder wall (figure  7) according to paquin’s law and exteriorized at mcburney’s point by vqz plasty (figure 8). following surgery, each patient remained in hospital for at least 5 days. the drain was removed on the third postoperative day (pod) once the drain output was down to 0 to 50 ml per 24 hours. the patient was followed figure 3. “u” configuration of the ileal plate figure 4. anastomosis of the ileal plate with the bivalved urinary bladder 197siuj.org siuj • volume 4, number 3 • may 2023 augmentation cystoplasty: experience in the developing world http://siuj.org up for 3 months with regular physical examination, serum electrolytes, serum creatinine, and urine analysis where indicated. on the 7th pod, the foley catheter was removed and on the 14th pod, the mitrofanoff tube was removed, and the patient was trained for cisc. on day 21, the suprapubic catheter was removed after clamping for a few days until the patient was fully trained for cisc, figure 5. healthy appendix with good length and adequate blood supply for appendicovesicostomy figure 8. vqz plasty final result figure 7. appendicovesicostomy by creating a submucosal tunnel in the bladder wall figure 6. the monti procedure. (a) both ileal plates are anastomosed at the short limb to form a long plate; (b) the ileal plate is tabularized over a 16-french catheter to form a tube for the mitrofanoff procedure a b which was performed every 3 hours in daytime with nighttime continuous drainage for next 3 months. after 3 months, the patient then followed every 6 months with advice to perform regular cic every 3 to 4 hours and a bladder wash once a week. repeat follow-up vuds of each patient was performed at 1 year to compare functional outcomes. a predesigned proforma was used 198 siuj • volume 4, number 3 • may 2023 siuj.org original research http://siu.org to record patient information such as age, sex, diagnosis, preoperative vuds findings, procedure performed, and postoperative vuds findings. the number and frequency of complications encountered within the first 3 months as well as the treatment provided were recorded in the proforma. for data analysis, ibm spss v23.0 was used. for categorical variables, frequencies were computed, but for continuous variables, the mean and standard deviation were calculated. the chi-square test was used to stratify effects modifiers. p-values below 0.05 were considered significant. results of the 197 patients included in this study, 127 (64.5%) were male and 70 (35.5%) were female. the mean age of the patients was 38.4 ± 9.92 years (table 1). of the 197 patients, 128 (65%) had a diagnosis of neurogenic bladder, mostly secondary to spinal pathology. in 45 patients (22.8%), the definitive cause of bladder dysfunction could not be established (table 2). a total of 181 patients (91.9%)underwent mitrofanoff formation along with ileocystoplasty, and 16 (8.1%) had ileocystoplasty alone. no patient with augmentation cystoplasty without mitrofanoff experienced bladder rupture. of the 197 patients, 87 (44.2%) remained complication-free; the majority, 64 (32.5%), had complications of grade i-ii requiring observation and pharmacological management. grade iii complications were observed in 38 (19.3%) patients requiring intervention, 24 (12.2%) without general anesthesia and 14 (7.1%) under general anesthesia. of the 8 patients who suffered more severe complications, 6 (3%) had grade iv complications, and 2 (1%) had grade v complications and succumbed to death due to multiorgan failure secondary to sepsis and peritonitis (tables 3 and 4). stomal stenosis (14.7%) was the most frequent complication, followed by renal function deterioration and high-grade fever (13.7% each) (table 4). most of the decline in renal function was seen in patients who had a low glomerular filtration rate before surgery. preoperative vuds was performed in 196 patients and 1 patient had genitourinary fistulae and urodynamic study was not possible. mean preoperative bladder capacity was 144.3 ± 63.09 ml and mean preoperative filling pressure was 43.34 ± 26.92 cm3 h2o, while mean postoperative bladder capacity was 460.83 ± 70.69 ml with mean postoperative filling pressure of 7.47 ± 5.79 cm3 h2o (table 1). of the 197 patients, 185 (94.4%) patients had reduced compliance preoperatively, while 11 (5.6%) patients had normal compliance. postoperatively, normal compliance was observed in 195 (99%) patients. table 1. descriptive statistics of age, preoperative and postoperative creatinine (mg/dl), and preand postoperative vuds findings n minimum maximum mean sd age 197 18 60 38.40 9.927 preoperative serum creatinine 197 0.30 6.00 1.4620 0.73751 postoperative serum creatinine 197 0.10 7.00 1.3930 0.93390 preoperative filling pressure 196 6 185 43.51 26.883 preoperative capacity 196 25 400 144.44 63.231 preoperative pdet at qmax 196 0 100 20.74 18.057 preoperative flow rate 196 0 23 5.50 4.303 postoperative filling pressure 197 0 54 7.47 5.795 postoperative capacity 197 283 690 460.83 70.609 postoperative pdet at qmax 197 0 61 7.07 6.745 postoperative flow rate 197 0 19 3.17 3.028 199siuj.org siuj • volume 4, number 3 • may 2023 augmentation cystoplasty: experience in the developing world http://siuj.org complication rate stratified by age and sex yielded no statistically significant association (p  =  1.00 and p = 0.393, respectively). discussion augmentation cystoplasty is a surgical procedure intended to increase bladder capacity and retention of larger volumes of urine without a significant increase in intravesical pressure or urinary leakage[13]. the goal of these procedures is to improve the patient’s long-term health and quality of life. before the advent of clean intermittent catheterization (cic), which subsequently decreased morbidit y, especia lly when used with anticholinergic drugs, quality of life was low. due to lack of detrusor contractility, augmented bladders cannot empty on their own, hence nearly every patient needs cic through a newly formed mitrofanoff or the urethra. it is crucial to conduct a multidisciplinary preoperative examination to ascertain the patient’s motivation and capability for clean intermittent self-catheterization, as doing so helps to avoid serious problems, especially in the early postoperative period. the majority of patients are hesitant to perform cic through the urethra, so with ac they also need a mitrofanoff procedure[14]. following surgery, most patients need basic care. third space loss emphasizes the significance of f luid electrolyte control. between 10 ml and 30 ml of saline is used to irrigate the bladder a minimum of 3 times daily in order to flush out mucus and maintain tube table 3. frequency of complications based on the clavien-dindo classification complication grade frequency, n percentage none 87 44.2 grade i 42 21.3 grade ii 22 11.2 grade iiia 24 12.2 grade iiib 14 7.1 grade iva 4 2.0 grade ivb 2 1.0 grade v 2 1.0 total 197 100.0 table 4. frequency of postoperative complications complication frequency, n percentage fever 27 13.7 urinary leak/bladder perforation 7 3.6 bowel anastomotic leak 1 0.5 ileus 16 8.1 drain dislodgement 2 1.0 sepsis 9 4.6 intra-abdominal bleeding 1 0.5 wound site bleeding 0 0 deterioration of renal functions 27 13.7 electrolyte imbalance 13 6.6 dislodgement of splints/catheters 9 4.6 surgical site infection (ssi) 21 10.7 wound dehiscence 3 1.5 urinary tract infection 25 12.7 stomal stenosis 29 14.7 incisional hernia 2 1.0 per urethral incontinence 4 2.0 stomal incontinence 2 1.0 death 2 1.0 patency. after 2 to 3 weeks, if no extravasation is seen on a cystogram, the foley catheter can be removed. until the patient is comfortable with the technique of cic, the suprapubic tube remains in place. particularly in the first few months, daily irrigation to remove mucus is crucial. studies of electrolytes, creatinine, and blood urea and nitrogen should be conducted at regular intervals[15]. the incidence of postoperative complications is used as a measure of surgical quality, but there is no consensus on what constitutes a complication and how severe it is, making it difficult to compare outcomes[16]. the majority of reports have evaluated postoperative complications using a non-standardized system and have not accounted for the severity of complications. 200 siuj • volume 4, number 3 • may 2023 siuj.org original research http://siu.org there have been uses of terms like “minor,” “moderate,” and “severe,” but they are arbitrary, unreliable, and frequently defined differently by each author[17]. the clavien-dindo classification (cdc) is a standardized system for the registration of surgical complications that has received international validation and acceptance. the cdc system’s key feature is that the degree of a complication’s severity is determined by the kind of therapy needed to manage the complication[18]. in some studies, the number of complications after augmentation enterocystoplasty was as high as 20% to 22%, and the number of deaths was between 0% and 3.2%[19]. the complication rate in our study was 35%, with the majority of complications being self-limiting and requiring no to minimal intervention. more severe complications were observed in patients who had low glomerular filtration rate before surgery. the most common early effects[19,20] are prolonged postoperative ileus, temporary urinary fistula (0.4% to 4%), wound infection (5% to 6.4%), bleeding that requires further intervention (0% to 3%), and thrombo-embolic problems (1% to 3%). in our study, stomal stenosis (14.7%) requiring endoscopic dilatation or surgical revision remained the most frequently observed complications, followed by fever (13.7%) and a rise in serum creatinine (13.7%). deterioration of renal function and electrolyte imbalance were usually transient and managed pharmacologically. a few patients required hemodialysis. in a study conducted at siut, the infection at the surgical site was reported as the most frequent complication of a catheterizable channel[14]. patients with neurogenic bladder are more likely to experience perforation, and it is generally believed that the perforation location is at the anastomotic suture line between the bowel segment and native bladder[21,22]. in a study in 2016, investigators retrospectively evaluated postoperative complications according to the clavien-dindo classification and found wound infection in 42% of patients, wound dehiscence in 28%, and urinary leakage in 14%. all were grade i-iii according to clavien-dindo classification. no major grade iv or v complications were observed[23]. in another study, the mortality rate from ac was reported to be 0% to 3.2%[24]. the mortality rate in our study was 1% (2 patients). the main limitations of our study are lack of knowledge about the patient’s quality of life after augmentation cystoplasty and the long-term risk for complications. this study opens the door for more research into these areas in the future. conclusion augmentation cystoplasty has proved to be quite versat i le for i ncrea si ng bladder c apacit y a nd enhancing bladder function in patients. unfortunately, augmentation enterocystoplasty is associated with various complications. hence, selecting patients for the procedure and providing them with adequate preoperative counseling are crucial, as is provisioning of proactive postoperative care following surgery. acknowledgements the authors thank dr syed arslan shah and dr muhammad nasurullah for help with data acquisition. references 1. chapple cr, roehrborn cg. a shifted paradigm for the further understanding, evaluation, and treatment of lower urinary tract symptoms in men: focus on the bladder. eur urol.2006;49(4):651–658. doi: 10.1016/j.eururo.2006.02.018. pmid: 16530611. 2. lukacz es, sampselle c, gray m, macdiarmid s, rosenberg m, ellsworth p, et al. a healthy bladder: a consensus statement. int j clin pract.2011;65(10):1026–1036. doi: 10.1111/j.1742-1241.2011.02763.x. pmid: 21923844; pmcid: pmc3206217. 3. manack a, motsko sp, haag-molkenteller c, dmochowski rr, goehring el jr, nguyen-khoa ba, et al. epidemiology and 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visceral defects. studies from the laboratories of the department of surgery, columbia university. 1920;3. 202 siuj • volume 4, number 3 • may 2023 siuj.org original research http://siu.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj • volume 4, number 3 • may 2023 siuj.org key words competing interests article information concurrent surgery, rectal prolapse, vaginal prolapse, multidisciplinary care none declared. received on july 19, 2022 accepted on october 18, 2022 this article has been peer reviewed. soc int urol j. 2023;4(3):180–186 doi: 10.48083/kupv7345 180 original research ageand population-adjusted trends in inpatient surgical management of vaginal prolapse, rectal prolapse, and concurrent vaginal and rectal prolapse surgery justina tam,1 hannah g. koenig,2 celine r. soriano,3 alvaro lucioni,1 jennifer a. kaplan,3 kathleen c. kobashi,1,* vlad v. simianu, 3 una j. lee1 1 section of urology and renal transplantation, virginia mason medical center, seattle, united states 2 research and academics, virginia mason medical center, seattle, united states 3 department of surgery, virginia mason medical center, seattle, united states * present address: department of urology, houston methodist, houston, united states previous presentation: this study was previously presented at the society of urodynamics female pelvic medicine and urogenital reconstruction (sufu) 2021 virtual winter meeting as a non-moderated poster and the abstract was published in the sufu 2021 abstracts issue of neurourology and urodynamics: tam j, soriano c, koeniga h, lucioni a, kaplan j, kobashi k, et al. age and population adjusted trends in inpatient surgical management of vaginal prolapse, rectal prolapse, and concurrent vaginal and rectal prolapse surgery in washington state. neurourol urodyn.2021;40:s229–s229. abstract objective to report ageand population-adjusted trends in the prevalence of inpatient vaginal prolapse (vp), rectal prolapse (rp), and concurrent vp/rp surgical procedures in women in washington state over a 12-year period. methods the comprehensive hospital abstract reporting system, an inpatient claims database, was queried for female patients aged 20 years or older with a diagnosis of vp and/or rp and associated surgical procedures from 2008 to 2019. rates for female patients were adjusted by age and population based on census results. results between 2008 and 2019, inpatient admissions for concurrent vp/rp surgery remained stable, with adjusted rates ranging from 1.42 to 3.38 per 100 000, with a majority performed in patients < 80 years old. the populationadjusted rate of inpatient rp repairs remained stable at 3.12 to 5.14 per 100 000. the population-adjusted rate of inpatient vp repairs decreased dramatically, from 81.79 to 6.96 per 100 000. conclusions the rate of inpatient rp and combined rp/vp surgical procedures was low and remained stable, while inpatient vp surgical repairs decreased substantially. since the dataset is limited to inpatient surgery, this trend may reflect a shift to outpatient settings for vp surgeries. nationally in the united states, there has been a trend toward multidisciplinary surgical management of concurrent vp/rp. however, this same trend does not appear to be reflected in washington state, suggesting that nationwide trends may not be reflective of trends within each state. further study is needed to understand how and why local trends in the management concurrent vp/rp may differ from national trends, and potentially improve concurrent vp/rp management using multidisciplinary approaches. introduction vaginal (vp) and rectal prolapse (rp) in women share a common pathophysiology and similar surgical approaches. the incidence of concomitant uterine/vp with rp is variable and has been reported to be ~38% in some analyses[1]. http://siuj.org https://orcid.org/0000-0002-1069-0901 https://orcid.org/0000-0003-2215-0301 https://orcid.org/0000-0003-0440-9439 https://orcid.org/0000-0002-9188-677x https://orcid.org/0000-0002-5668-251x https://orcid.org/0000-0003-1255-0221 https://orcid.org/0000-0003-1128-5083 mailto:una.lee%40virginiamason.org?subject=siuj siuj.org siuj • volume 4, number 3 • may 2023 both vp and rp occur more commonly in women over the age of 65 years[2,3], and traditionally have been treated as separate entities. however, there has been a trend toward a multidisciplinary approach, with concomitant procedures being performed by colorectal surgeons and urologists or g y necologists[1,4,5]. multidisciplinary approaches have been demonstrated to be safe and efficacious[1] and may improve surgical outcomes and patient symptoms[4,6–9]. prior work has demonstrated that the national rate of multidisciplinary repair in women diagnosed with vp and rp increased from 0.7% in 2003 to 1.9% in 2017[5]. however, a more detailed analysis of these trends on a statewide level has not been reported. the objective of this study is to report ageand population-adjusted trends in the prevalence of inpatient vp, rp, and concurrent vp/rp surgical procedures in women in washington state over a contemporary 12-year period. materials and methods the comprehensive hospital abstract reporting system (chars), a washington state administrative inpatient claims database that captures all inpatient hospitalizations from all hospitals in the state, and includes data such as age, sex, zip code, diagnosis and procedure codes, billing codes, and procedure dates, regardless of insurance type, was queried for female patients 20 years of age or older with both a diagnosis of vp and/or r p and associated vp and/or r p surgical procedures from 2008 to 2019. the chars data dictionary is publicly available at https://www. doh.wa.gov/ and includes diagnosis and procedural codes based on the ninth revision of the international classification of diseases (icd-9) and icd-10 for admissions. the chars database does not utilize current procedural terminology (cpt®) codes. using the international classification of diseases ninth and tenth edition (icd-9 and icd-10) codes, women ≥ 20 years of age with vp and/or rp diagnosis codes were identified (appendix 1). icd procedural codes for vp and rp operations were used to identify patients who had undergone treatment for prolapse (appendix 1). surgical procedures that were performed on the same date were considered concurrent, while those with different dates were considered staged. demographic characteristics and rates of concurrent surgica l repair were analyzed. rates were adjusted by age, and population of women, based on washington state census results for 2008 to 2019 using the direct method. the study was submitted for institutional review board (irb) review and was found to not constitute human subjects research and did not require irb approval. results query of the chars database identified 17 840 female inpatient admissions with a diagnosis of vp and/or rp who had also undergone a vp and/or rp procedure. of those, 15 279 (85.6%) underwent vp-only and 918 (5.1%) underwent combined vp/rp repair. the majority of women identified in our query were < 80 years old, 52.03% were identified as white, and 4.83% of the population were identified as minority groups (table 1). notably, there was no information provided on ethnicity in the database for 43.14% of the population. seventy-five percent of all vp-only, rp-only, or concurrent vp/rp inpatient surgeries were performed in the 7 most populated washington state counties. the majority of all combined vp/rp procedures were performed in 10 facilities in a single county (king county, which includes the seattle metropolitan area). the majority of patients identified in the query were residents of 5 counties (table 2), and 75% of patients lived within 20 miles of their treating facilities. among the top 15 centers performing vp and/or rp prolapse surgery, 2 centers were noted to have patient populations composed of nearly 95% of patients who resided less than 20 miles away (figure 1). between 2008 and 2019, inpatient admissions for concurrent vp/rp surgery remained stable, with adjusted rates ranging from 1.42 to 3.38 per 100 000 women (figure 2), and 95% of combined procedures were performed in patients < 80 years old. the adjusted rate of inpatient rp-only repairs also remained stable, 3.12 to 5.14 per 100 000 women, with 82% being performed in women < 80 years old. the adjusted rate of inpatient vp-only repairs decreased markedly, from 81.79 per 100 000 women in 2008 to 6.96 per 100 000 women in 2019, with 94% of these surgeries being performed in women < 80 years old. discussion prior work has demonstrated that there has been a nationw ide trend of increasing utilization of multidisciplinary approaches toward treating vp/ rp concurrently, increasing from 0.7% of all surgeries performed for rectal prolapse or pelvic organ prolapse in 2003 to 1.9% in 2017[5]. however, the same trend for concurrent vp/rp surgery has not been clearly identified in washington state. these data suggest that despite a nationwide trend toward multidisciplinary abbreviations chars comprehensive hospital abstract reporting system icd international classification of diseases irb institutional review board rp rectal prolapse vp vaginal prolapse 181 trends in vaginal and rectal prolapse surgery http://siuj.org https://www.doh.wa.gov/ https://www.doh.wa.gov/ http://siuj.org http://siuj.org siuj • volume 4, number 3 • may 2023 siuj.org approaches, this trend may not be occurring at similar rates in each state. additionally, the previously reported rates[5] were not adjusted for population, age, or gender, which may affect the ability to compare the results. although there was a significant nationwide increase in the number of concurrent vp/rp procedures, whether this increase is due to a growing and aging population with a higher incidence for pelvic organ prolapse has not been well studied. the procedure rates described herein were obtained using the chars database, which collects recordlevel information on inpatient and observation-patient community hospital stays. while limited to administrative data, this database has the advantage of capturing all procedures performed provided that the patient was hospitalized, regardless of insurance status. we acknowledge the limitations of using this inpatient statewide database. however, the information captured adds to our knowledge of trends in the utilization of concurrent rp/vp surgery overall. although some studies with small patient cohorts have suggested that rectal prolapse procedures such as laparoscopic rectopexy may be feasibly performed as outpatient procedures[10–13], the majority of rp surgeries are performed as inpatient procedures and concurrent vp/rp surgeries are therefore captured in this dataset, allowing for analysis of trends in this procedure. however, vp surgery can be performed either in an inpatient or outpatient setting, depending on many factors. the reporting of only inpatient vp surgeries is a limitation that prevents an accurate analysis of broader trends in vp and its procedures. we acknowledge this limitation as it relates to the capture of all vaginal prolapse surgeries. the focus of this study is concurrent vp/rp surgery, which is captured in this dataset. between 2008 and 2019, the rate of inpatient vp surgery decreased substantially in washington state from 81.79 per 100 000 women in 2008 to 6.96 per 100 000 women in 2019. previously published literature has demonstrated an increasing utilization of outpatient urologic procedures[14], suggesting that this trend could represent an increase in utilization of outpatient vp surgeries or a true decrease in vp surgery over time. the shift of surgery from inpatient to outpatient possitable 1. demographics by prolapse type for female inpatient admissions 2008–2019 in washington state prolapse type total prolapse n = 17 840 vaginal and rectal combination n = 918 vaginal only n = 15 279 rectal only n = 1643 n % n % n % n % age group < 50 years 4078 22.86 266 28.98 3485 22.81 327 19.90 50–64 years 6421 35.99 355 38.67 5557 36.37 509 30.98 65–79 years 6025 33.77 250 27.23 5270 34.49 505 30.74 80+ years 1316 7.38 47 5.12 967 6.33 302 18.38 ethnicity* american indian/alaskan native 78 0.44 2 0.22 62 0.41 14 0.85 asian 209 1.17 15 1.63 167 1.09 27 1.64 black/african american 98 0.55 7 0.76 78 0.51 13 0.79 hispanic origin 435 2.44 13 1.42 395 2.59 27 1.64 native hawaiian/pacific islander 40 0.22 0 0.00 36 0.24 4 0.24 white 9283 52.03 582 63.40 7561 49.49 1140 69.39 excluded/not provided 7697 43.14 299 32.57 6980 45.68 418 25.44 *all ethnicity categories/labels taken directly from the comprehensive hospital abstract reporting system database. 182 original research http://siuj.org siuj.org siuj • volume 4, number 3 • may 2023 table 2. female inpatient admissions for top 15 facility counties and residential counties by prolapse type facility county of care total prolapse (n = 17 840) combination vaginal and rectal prolapse (n = 918) vaginal only (n = 15 278) rectal only (n = 1643) county (n*) ads. % county (n*) ads. % county (n*) ads. % county (n*) ads. % king (17) 6136 34.39 king (10) 808 88.02 king (17) 4487 29.37 king (12) 841 51.19 spokane (4) 1965 11.01 spokane (4) 53 5.77 spokane (4) 1656 10.84 spokane (4) 256 15.58 pierce (5) 1590 8.91 pierce (4) 35 3.81 pierce (5) 1381 9.04 pierce (5) 174 10.59 snohomish (4) 1290 7.23 snohomish (2) 9 0.98 snohomish (4) 1211 7.93 snohomish (3) 70 4.26 benton (3) 887 4.97 benton (1) 6 0.65 benton (3) 815 5.33 benton (3) 66 4.02 yakima (4) 761 4.27 kitsap (1) 4 0.44 yakima (4) 755 4.94 thurston (2) 54 3.29 clark (2) 759 4.25 chelan (1) 1 0.11 clark (2) 747 4.89 kitsap (1) 41 2.50 whatcom (1) 538 3.02 clark (1) 1 0.11 whatcom (1) 516 3.38 chelan (1) 29 1.77 kitsap (1) 482 2.70 thurston (1) 1 0.11 kitsap (1) 437 2.86 skagit (2) 28 1.70 cowlitz (1) 414 2.32 cowlitz (1) 402 2.63 whatcom (1) 22 1.34 thurston (2) 399 2.24 clallam (1) 370 2.42 cowlitz (1) 12 0.73 clallam (1) 380 2.13 thurston (2) 344 2.25 clark (2) 11 0.67 skagit (3) 361 2.02 walla walla (2) 339 2.22 clallam (1) 10 0.61 walla walla (2) 342 1.92 skagit (3) 333 2.18 whitman (2) 8 0.49 grays harbor (1) 302 1.69 greys harbor (1) 301 1.97 jefferson (1) 7 0.43 patient residential county total prolapse (n = 17 840) combination vaginal and rectal prolapse (n = 918) vaginal only (n = 15 278) rectal only (n = 1643) county ads. % county ads. % county ads. % county ads. % king 6136 34.39 king 356 38.78 king 2919 19.10 king 841 51.19 spokane 1965 11.01 snohomish 311 33.88 snohomish 1762 11.53 spokane 256 15.58 pierce 1590 8.91 spokane 30 3.27 pierce 1322 8.65 pierce 174 10.59 snohomish 1290 7.23 pierce 28 3.05 spokane 1265 8.28 snohomish 70 4.26 benton 887 4.97 kitsap 23 2.51 yakima 794 5.20 benton 66 4.02 yakima 761 4.27 thurston 19 2.07 clark 656 4.29 thurston 54 3.29 clark 759 4.25 island 15 1.63 benton 653 4.27 kitsap 41 2.50 whatcom 538 3.02 skagit 14 1.53 whatcom 603 3.95 chelan 29 1.77 kitsap 482 2.70 whatcom 13 1.42 kitsap 589 3.85 skagit 28 1.70 cowlitz 414 2.32 clallam 11 1.20 clallam 432 2.83 whatcom 22 1.34 thurston 399 2.24 yakima 11 1.20 thurston 397 2.60 cowlitz 12 0.73 clallam 380 2.13 benton 9 0.98 cowlitz 363 2.38 clark 11 0.67 skagit 361 2.02 mason 6 0.65 grays harbor 330 2.16 clallam 10 0.61 walla walla 342 1.92 kittitas 5 0.54 skagit 279 1.83 whitman 8 0.49 grays harbor 302 1.69 kootenai (idaho) 5 0.54 franklin 228 1.49 jefferson 7 0.43 note: percentages calculated out of total prolapse type sample. *denotes number of facilities within that county. ads.: admissions. 183 trends in vaginal and rectal prolapse surgery http://siuj.org siuj • volume 4, number 3 • may 2023 siuj.org bly reflects the us health care system’s shift toward more cost-effective outpatient settings and insurance reimbursement patterns[15]. the prevalence of vp has been found to vary across racial groups[16,17], and racial disparities have been identified in women undergoing pelvic organ prolapse surgery[18]. for this reason, we were interested in evaluating the trends in multidisciplinary approaches in treating prolapse across racial groups. low rates of vp and/or rp surgery have been noted in minority groups[16,17]. however, this observation could not be clearly assessed using the chars database, as racial information was not provided for 43.14% of the patient population. the majority of all inpatient vp-only, rp-only, and concurrent vp/rp surgeries were performed in the most populated counties in washington state, and the majority of patients lived within a 20-mile radius of their treating facilities. indeed, in 2 facilities, the patient population was nearly entirely composed of patients who resided less than 20 miles away (figure 1). it should also be noted that the distances described here are straightline distances and may not be an accurate reflection of the time or actual distance required to travel to treatment centers, particularly in washington state, where patients may need to utilize ferry services in order to reach the more densely populated regions where highfigure 1. proportion of patients receiving care locally (within 20 miles) at top 15 washington state facilities from 2008 to 2019 by average annual volume of vaginal prolapse, rectal prolapse, or concurrent vaginal and rectal prolapse surgeries. centers sorted in descending order of average number of prolapse procedures per year for each center. figure 2. female inpatient prolapse procedures by prolapse type for washington state from 2008 to 2019. total prolapse is combined total of vaginal, rectal, and concurrent vaginal and rectal prolapse surgeries. de-identi�ed treatment centers, by number of prolapses per year 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% a 110 b 100 c 93 d 81 e 74 f 58 g 57 h 50 i 48 j 48 k 45 l 42 m 41 n 40 o 39 local non-local n um be r o f p ro la ps e pr oc ed ur es p er fo rm ed year of inpatient admission total* prolapse vaginal prolapse only rectal prolapse only rectal and vaginal prolapse 3500 3000 2500 2000 1500 1000 500 0 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 184 original research http://siuj.org siuj.org siuj • volume 4, number 3 • may 2023 er-volume facilities are located. patients electing surgical management are more likely to travel farther, as do patients travelling from areas with fewer women and older people[19,20]. distance travelled to reach care may be a barrier to patient care, and longer distances travelled have been associated with later presentation to care, and greater likelihood of planning surgery at presentation[19]. there may be a multitude of reasons for this, including patients electing treatments that require fewer follow-ups due to the long distances required for follow-up, lack of available services in less-populated counties, or patients who have failed conservative therapies at facilities closer to their homes. overall, our study showed that vp and/or rp surgical care was concentrated in the most populated areas of washington state. additional limitations of this database include the lack of recorded clinical variables, including outcomes, complications, recurrence, and patient-specific variables such as degree of prolapse or comorbid diseases. these results may not be generalizable, as the data are specific to washington state. strengths of the analysis include the ability to adjust surgery rates by gender, state population, and age. in addition, all patients undergoing inpatient vp-only, rp-only, and concurrent vp/rp procedures in washington state are included, and not limited by insurance status. national trends have shown an increase in utilization of concurrent vp/rp surgery. to assess this trend on a more local level, these procedures were examined in washington state over a 12-year time period and were found to have remained stable. the reasons for this cannot be clearly identified using the chars database. future directions may include investigations into contributing factors that may play a role in increasing awareness of the prevalence of concurrent vp and rp as well as supporting integrated and collaborative treatment for women with concurrent vp and rp. conclusion the rates of inpatient rp and combined vp/rp surgical procedures between 2008 and 2019 were low and remained stable in washington state. inpatient vp surgical repairs decreased from 81 to 6 per 100 000 women over the same time period, which may represent an increase in outpatient vp procedures. although previously published data suggest that a multidisciplinary approach to vp and rp is increasing nationwide, the trend seen here does not seem to reflect the same increase, suggesting that nationwide trends may not be reflective of local trends within each state. further study is needed to understand how and why local trends in the management concurrent vp/rp may differ from national trends, and potentially improve concurrent vp/rp management using multidisciplinary approaches. acknowledgements we thank virginia m. green, phd, for editorial assistance. financial disclosure no funding or other financial support was received. ethics statement the institutional review board of benaroya research institute at virginia mason determined that this study did not constitute human subjects research and thus this study did not require irb approval. 185 trends in vaginal and rectal prolapse surgery http://siuj.org siuj • volume 4, number 3 • may 2023 siuj.org references 1. geltzeiler cb, birnbaum eh, silviera ml, mutch mg, vetter j, wise pe, et al. combined rectopexy and sacrocolpopexy is safe for correction of pelvic organ prolapse. int j colorectal dis.2018;33(10):1453–1459. doi: 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lonergan,1 samuel l. washington iii,2 maxwell v. meng,1 renu eapen3 1 department of urology, helen diller family comprehensive cancer center, university of california, san francisco, united states, 2 department of epidemiology & biostatistics, university of california, san francisco, united states 3 department of genitourinary oncology, peter maccallum cancer centre, melbourne, australia abstract the clinical course of localized prostate cancer varies widely, from indolent disease unlikely to need treatment to aggressive disease requiring intensive, multimodal therapy. traditionally, treatment decisions have been based on clinical and pathologic factors, including serum prostate specific antigen (psa), clinical stage, and gleason score. however, these factors have limited ability to describe the underlying tumor biology. tissue-based genomic tests have emerged as a promising tool to more accurately characterize prostate cancer biology and predict clinical course. using prostate cancer tissue obtained at pre-treatment biopsy or radical prostatectomy, these tests exploit the expression of specific genes involved in key biological pathways and, as a result, have the potential to aid clinical decision-making. the current review summarizes available data describing the clinical use of 5 commercially available tissue-based genomic assays in a number of clinical scenarios. introduction over the last decade, numerous tissue-based genomic classifiers have been developed, providing additional diagnostic, prognostic, and predictive information in the management of prostate cancer (pca). using prostate tissue obtained at pre-treatment biopsy or radical prostatectomy, these tests exploit expression of specific genes involved in key biological pathways. gene expression profiling therefore has the potential to aid clinical decision-making. in this review, we summarize 5 commercially available tissue-based genomic classifiers and summarize the currently available data on their use in a number of clinical scenarios (table 1). confirmmdx description of assay confirmmdx (mdxhealth, irvine, united states) for prostate cancer is an epigenetic assay, which uses multiplex methylation-specific polymerase chain reaction (pcr) to measure the epigenetic status of the pca-associated genes gstp1, apc, and rassf1 in residual cancer-negative prostate biopsy tissue samples [1]. prediction of cancer after negative biopsy the diagnostic performance of confirmmdx for predicting cancer on subsequent biopsies after an initial negative biopsy has been assessed in 2 retrospective studies: (1) methylation analysis to locate occult cancer (matloc) [2] and (2) detection of cancer using methylated events in negative tissue (document) [3]. the matloc study generated a model with the methylation levels of the 3 genes and clinical parameters (age, psa, dre, initial biopsy pathology) in 483 men from the united kingdom and belgium. the studies found that this model resulted in a negative predictive value (npv) of 90% [2]. the document validation cohort of 350 men from 5 centers across the key words competing interests article information prostate cancer, genomic testing, pathology, biopsy, prostatectomy, active surveillance none declared. received on july 2, 2020 accepted on september 8, 2020 soc int urol j. 2020;1(1):23–29 http://www.siuj.org mailto:renu.eapen%40petermac.org?subject=siuj 24 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation united states found similar results in which the model incorporating the methylation levels had an npv of 88% [3]. the validity of the assay has also been assessed in a cohort of 211 african american men from 7 centers in the united states, in which methylation status had a npv of 94.2% for the detection of gleason score ≥ 7 cancer on repeat biopsy [4]. however, prospective validation studies have yet to be performed for this assay, and its performance compared with other biomarkers in men with a prior negative biopsy remains to be determined. oncotype dx genomic prostate score (gps) description of assay oncotype dx genomic prostate score (genomic health, inc., redwood city, united states) consists of a panel of 12 pca-related genes representing 4 distinct biological pathways (androgen signaling, cellular organization, stromal response, and cellular organization) relative to 5 reference genes, based on measured rna expression levels by reverse transcriptase-pcr [5]. prediction of disease progression in active surveillance the gps score was developed to determine the likelihood of adverse pathology in men undergoing immediate radical prostatectomy. although they were developed in the surgical context, studies have also shown that the gps correlates with disease progression in men on active surveillance (as), and the current national comprehensive cancer network (nccn) [6] and american association of clinical oncolog y (asco) [7] guidelines recommend considering such genomic tests for men qualifying for as in situations in which the assay results are likely to impact clinical decision-making. in the first such study in an as cohort of 271 men who had gps testing, 144 experienced biopsy upgrading, and gps was associated with an increased risk of upgrading [8]. a further study from the same as cohort assessed the ability of gps to predict adverse pathology (ap) as well as the risk of biochemical recurrence (bcr) after radical prostatectomy (rp). in 215 men on as who underwent delayed rp, gps was associated with an increased risk of adverse pathology at rp and bcr [9]. gps as a predictor of ap at rp has recently been reported in the multicenter canary prostate active surveillance study (pass) cohort [10]. overall, 101 men on as underwent rp after a median of 2.1 years, and 52 men were found to have ap. gps was significantly associated with ap when adjusted for diagnostic gleason score, but not when also adjusted for psa density [10]. although this was a prospective multicenter as cohort study with a defined as protocol using tissue from original diagnostic biopsy tissue, the sample size for the ap endpoint was small and further validation is warranted. the university of california san francisco (ucsf) as cohort has also reported the value of serial gps testing in the context of as [11]. in 111 men on as who underwent serial gps testing, the gps at first biopsy was associated with an upgrade at second biopsy; however, the second gps was not [11]. a further study in 1031 men from the ucsf cohort found that a composite score of 3 tissue genomic markers (including gps) predicted biopsy reclassification at first surveillance biopsy and up to 3 years after enrollment but was not associated with reclassification at 5 and 10 years [12]. these early validation studies of gps in the context of as are limited by their retrospective nature and the potential selection bias of those who underwent genomics testing as part of treatment. a recently published study of a cohort of 296 men with very low-risk (37.8% ) or low-risk (62.2%) disease who underwent gps testing found that gps score did not differ significantly across quartiles of disease volume (defined as percent of positive cores, number of cores with > 50% involvement, largest involvement of any single core, and psa density) [13]. however, the median likelihood of favorable pathology at rp was statistically different between volume quartiles. seven of the 105 men (6.3%) with very low-risk disease were reclassified to low-risk, and 13 of 181 (7.2%) with lowrisk disease were reclassified to intermediate-risk. on univariate analysis, disease volume did not correlate with reclassification on gps testing [13]. a further study to clarify the clinical utility of gps in determining eligibility for as found that no men with nccn very low-risk disease were reclassified [14]. in this cohort, nearly one-third of men with lowor intermediate-risk abbreviations ap adverse pathology as active surveillance bcr biochemical recurrence capra cancer of the prostate risk assessment ccp cell cycle progression ccr cell cycle risk dre digital rectal examination gps genomic prostate score nccn national comprehensive cancer network npv negative predictive value pca prostate cancer pcr polymerase chain reaction rp radical prostatectomy http://www.siuj.org 25siuj.org siuj • volume 1, number 1 • october 2020 the clinical applications of tissue biomarkers in prostate cancer disease were reclassified, but management decisions did not always reflect the change [14]. thus, gps provides additional risk stratification for patients, but is likely best reserved for patients whose clinical risk does not indicate a clear clinical recommendation for or against definitive treatment. prediction of adverse pathology at surgery the panel of genes used in gps was initially identified from 732 candidate genes selected through a metaanalysis of publicly available microarray datasets, based on the ability to predict cancer-specific mortality across multiple foci of cancer within rp specimens. it has been validated for predicting ap on rp specimens using biopsy specimens [15]. gps has a lso been validated prospectively as an independent predictor of ap at rp [16]. on multivariable analysis in models that included clinical variables (psa, clinical stage, and biopsy grade), gps was a significant predictor of ap at rp in both intermediate-risk and favorable table 1. summary of tissue genomic biomarkers used in prostate cancer genomic test tissue source clinical requirements marker measurement reported outcomes confirmmdx negative biopsy tissue prior negative biopsy, no asap dna methylation (gstp1, apc, rassf1, actb ) • any cancer [2,3] • gleason score ≥ 7 [4] oncotype dx gps positive biopsy tissue gleason 3+3 or 3+4, nccn very low to intermediate risk rna (17 gene expression: azgp1, fam13c, klk2, srd5a2, flnc, gsn, gstm2, tpm2, bgn, col1a1, sfrp4, tpx2, arf1, atp5e, cltc, gps1, pgk1) • adverse pathology at rp (gleason ≥ 4+3 or ≥ pt3a) [8,15,16] • metastasis after rp [17] • prostate cancer-specific death after rp [17] • biopsy upgrade on active surveillance [8,11] • adverse pathology at rp while on as [10] promark positive biopsy tissue gleason 3+3 or 3+4 protein (derl1, cul2, smad4, pdss2, hspa9, fus, ps6, ybox1) • unfavorable pathology at rp (gleason ≥ 3+4 or ≥ pt3a), pn1, pm1 [18,20] prolaris positive biopsy tissue or rp none rna (46 gene expression: 31 cell cycle progression genes, 15 housekeeping genes) • biochemical recurrence after rp [21,23–25] • prostate cancer-specific death after rp [22] • selection for active surveillance [22] • metastasis after rp [23] • risk stratification [25] • metastasis after definitive treatment [27] decipher positive biopsy tissue or rp none rna (22 gene expression: nfib, nusap1, zwilch, ano7, pcat-32, ube2c, camk2n1, mybpc1, pbx1, thbs2, eppk1, iqgap3, lasp1, pcdh7, rabgap1, glyatl1p4, s1pr4, tnfrsf19, tsbp, 3 rna markers not associated with genes) • metastasis after rp [28-32] • prostate cancer-specific death after rp [28] • biochemical recurrence after rp [29] • prostate cancer-specific death after rp [33,34] • adverse pathology at rp [35,36] http://www.siuj.org 26 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation intermediate-risk groups. the auc of the adverse pathology predictive model was 0.726 when combining capra and gps versus 0.633 with capra alone [16]. this study confirms prior validations that employed a prospective–retrospective design in men who underwent immediate rp. prediction of post-operative outcomes in a retrospective cohort study of 279 men treated with rp from 1995 to 2010 for localized prostate cancer spanning low to high nccn risk groups, gps from biopsy tissue was found to be independently associated with bcr, metastasis, and death after adjusting for capra score and nccn risk category [17]. the c-index for pca metastasis at 10 years increased from 0.65 for capra alone to 0.73 with the addition of gps. for prostate cancer death, a similar increase of 0.78 to 0.84 was found with the addition of gps to capra [17]. however, it is unclear what impact gps has on clinical decisions, particularly as models in the study were not adjusted for receipt of any adjuvant post-rp treatment. promark description of assay proma rk (meta ma rk genet ics, inc., wa lt ha m, united states) is a test that uses quantitative tissue proteomics [18] to generate a risk score from the levels of 8 target proteins, derived from a candidate biomarker study [19], for men with gleason score 3+3 and 3+4 cancer on biopsy tissue. the score gives the probability of having ap at rp. prediction of adverse pathology following surgery a clinical prognostic risk model was developed in 381 patients with biopsy and rp specimens and then validated in a separate cohort of 276 patients, assessing their proteomic panel risk against nccn risk category and d’amico classification [20]. in the validation cohort, the authors reported an auc for predicting ap at rp for the proteomic panel alone was 0.68 compared with the nccn model of 0.69 and d’amico model of 0.65. however, when the proteomic panel was added to both the nccn and d’amico models, the aucs increased to 0.75. additionally, when the authors used clinical cutoffs for the protein panel combined with nccn risk categories, they reported the positive predictive value for favorable pathology was 82% for nccn intermediaterisk, 82% for low-risk, and 95% for very low-risk. finally, a decision curve analysis was performed that found a net benefit with the addition of the protein panel for patients in nccn intermediateand high-risk groups, which may change treatment decision-making [20]. however, for patients with lower clinical risk disease, the promark proteomic panel may be more suitable to reassure and confirm that men are indeed low risk. to date, the promark genomic panel has been validated only for predicting ap at rp. although ap is associated with an overall less favorable prognosis, no study to date has validated promark for predicting survival or post-treatment disease recurrence. prolaris description of assay prolaris (myriad genetics, inc., salt lake city, united states) is a panel that measures the rna expression levels of 31 genes involved in cell cycle progression (ccp) relative to the expression of 15 housekeeping genes in cancerous tissue [21]. identification of men suitable for active surveillance a model combining ccp scores and clinical parameters, termed cell cycle risk (ccr) score, has been developed and applied to the identification of men with low-risk disease who are appropriate for as. in a validation cohort of 585 men conservatively managed with ccr scores below the threshold, the predicted mean 10-year pca mortality was 2.7%, and the ccr significantly dichotomized lowand high-risk disease. the potential clinical benefit of selecting men for as using the ccr score was evaluated in a sequential, unselected cohort of 19 215 men. the proportion of men identified as candidates was substantially higher when the ccr score was used than when clinicopathologic features alone were used, while the mean 10-year predicted pca mortality risks remained identical (1.9% versus 2.0%) [22]. however, the validation cohort in this study was composed of men who deferred curative therapy and were therefore not a “true” as cohort as there was minimal scheduled surveillance in the absence of symptoms of clinical progression. prediction of post-operative outcomes the ccp score has also been assessed on biopsy specimens of men who later underwent definitive treatment. in a cohort of 582 men who were treated with rp, biopsy ccp scores were significantly associated with bcr and metastases on multivariable analyses; it should be noted that only 2% of men developed metastases [23]. the ccp score was not significantly associated with clinical variables in any models, suggesting that it provides additional predictive information beyond traditional clinical parameters. however, the prognostic value of ccp was not directly compared with any established clinical risk calculators. in a further study using the same cohort, the ccp score provided additional prognostic value for bcr after rp in men with nccn low-risk disease beyond the capra score, with 35% of men with high ccp score experiencing bcr at 5 years. the c-index was 0.56 for the capra score alone and 0.66 for capra combined with ccp score. http://www.siuj.org 27siuj.org siuj • volume 1, number 1 • october 2020 the clinical applications of tissue biomarkers in prostate cancer a decision curve analysis which found that the ccp score provided net clinical benefit beyond capra [24]. therefore, using only pre-treatment data, the ccp score allows for prognostic stratification within the low-risk category, and this information could inform decision-making regarding as and local treatments in certain patients. use in risk prediction in addition to biopsy tissue, the ccp score has also been derived from rp tissue to prognosticate and stratify according to risk of bcr. in a study of 413 men who underwent rp, ccp score was able to effectively stratify patients within capra-s risk groups [25]. regardless of capra-s risk group, men with a very low ccp score did not experience cancer recurrence within 5 years of rp, whereas recurrence was almost 50% in men with a high ccp score. in the overall recurrence predictive model, the c-index of capra-s alone was 0.73 and increased to 0.77 with the addition of the ccp score. therefore, the ccp score provides some additional prognostic information, beyond pathologic factors, on the risk of bcr following rp. this additional information may aid decision-making regarding adjuvant treatments. risk stratification is often more challenging in certain cohorts such as african american men, for whom non-clinical social determinants of health may influence receipt of treatment and ultimate oncologic outcomes [26]. in a retrospective cohort of 767 men of whom 281 (37%) were african american, the ccp score was a significant predictor of metastatic disease on multivariable analysis including clinical parameters; however, there was no interaction with ancestry or treatment [27]. of note, ancestry was self-reported, and this may have introduced error thereby limiting the generalizability of the conclusions, as population-based genetic heterogeneity was not addressed. decipher description of assay the decipher genomic classifier (decipher biosciences, san diego, united states) is a genomic assay based on a full transcriptome microarray, including both protein coding and non-coding rna, and measures rna expression levels from 22 genes that were initially selected from 1.4 million candidate rna probes [28]. prediction of post-operative outcomes decipher was initia l ly va lidated for predicting metastases in a cohort of 545 patients who underwent rp at the mayo clinic, of whom 213 subsequently developed metastases. decipher has been further validated in multiple studies for predicting outcomes after rp [28]. in a study of 85 men who developed bcr following rp, decipher predicted metastases with an auc of 0.82, and in modeling with clinicopathologic variables, decipher was the only significant predictor of metastasis [29]. in a larger cohort of 260 men with intermediateand high-risk disease at the time of rp who did not receive adjuvant treatment, decipher added prognostic accuracy to the capra-s for estimating metastatic disease at 10 years. the c-index of decipher and capra-s alone was 0.76 and 0.77, respectively; when decipher and capra-s were combined, the c-index improved to 0.87. the greater net benefit of the combination was also confirmed with decision curve analysis [30]. a similar finding was observed in a cohort of 169 men that included 15 who had metastatic progression within 5 years of rp. in multivariable analysis, after adjusting for clinical risk factors, decipher predicted metastases and also had the highest c-index (0.77), compared with capra-s and stephenson nomogram, as well as a panel of previously reported, unrelated prostate cancer biomarkers [31]. use in risk stratification decipher has also been assessed in determining risk in men with a persistently detectable psa after rp, as a subset of these patients likely harbor metastatic disease. in a cohort of 477 men who underwent rp at 3 academic centers, 150 had an immediately detectable post-operative psa. the 5-year metastasis rate was 0.90% for decipher low/intermediate and 18% for decipher high-risk [32]. on multivariable analysis, only decipher high-risk, detectable psa, and lymph node invasion remained prognostic factors for metastasis [32]. the sample size of men with a detectable psa post-rp in this study may have limited the power to detect differences in various prognostic variables. decipher has also been shown to prognosticate prostate cancer death. combining capr a-s and decipher predicted prostate cancer death at 5 years after rp in 185 men with high-risk disease. the combination of capra-s and decipher had greater clinical benefit on decision curve analysis (dca) than either alone [33]. supporting this finding, a multicenter study of 561 men with adverse pathologic features at rp, the combination of decipher and capra-s improved the prediction of to 10-year prostate cancer death following rp (c-index 0.73) compared with either test alone (c-index 0.73 for each) [34]. dca also confirmed the net benefit of decipher combined with capra-s for 10-year prostate cancer mortality [34]. decipher has also been applied to prostate biopsies from patients to predict ap at rp [35]. in a retrospective multicenter cohort of 266 men with nccn very low-, lowand favorable intermediate-risk pca, decipher from diagnostic biopsies was an independent predictor of ap at rp. this study did not have long-term follow-up to evaluate survival outcomes, and the sample http://www.siuj.org 28 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation size and low number of events did not allow decipher to be assessed in the individual nccn risk (eg, favorable intermediate only) groups. a further study using this cohort also found that nccn favorable intermediaterisk disease with decipher low or intermediate score was not associated with significantly higher odds of ap compared to very low-risk/low-risk disease [36]. taken together, these studies demonstrate that the decipher has a prognostic value for both metastatic disease and pca mortality following rp. this can potentially assist patients and clinicians in decisionma k ing around adjuvant therapy—if a patient’s decipher risk for metastasis and prostate cancer death is low, then he could potentially forgo adjuvant treatments, even if his pathological characteristics are less favorable. emerging tissue biomarkers a benefit of the technology from genomedx, is the ability to study other rna expression signatures, which may be associated with outcomes beyond the scope of the original gene expression panel. retrospectively, genomedx has used their technolog y to identif y signatures related to other treatment modalities such as radiation, androgen deprivation therapy, and chemotherapy sensitivity. zhao et al. identified a 24-gene molecular signature that predicts patient response to adjuvant radiotherapy following radical prostatectomy. the gene signature, termed t he post-operative radiation therapy outcomes score (portos) was identified from patients included in 1 of 5 published studies of men with prostate cancer who had radical prostatectomy (with or without post-operative radiotherapy) and had gene expression analysis of the tumor, with long-term follow-up and for whom complete clinicopathological data were available. the authors demonstrated that in those patients who had a high portos score, those who had radiotherapy had a lower 10 year metastases rate than those who did not (5% versus 63%, hr 0.12, p < 0.001) [37]. portos remains to be validated prospectively, and its association with rt sensitivity has been shown only in post-rp patients. therefore, further investigation is required to validate the gene panel prospectively and in the setting of rt for primary treatment of prostate cancer. future challenges and directions many of the growing number of tissue-based genomic tests are clinically validated to improve on clinical parameters alone by more accurately determining prognosis and specific oncologic outcomes. however, whether a genomic test may be predictive of a clinically significant response to a particular management strategy is a more complex question. many of the genomic tests outlined have been shown to predict multiple endpoints, including ap, bcr, metastasis-free survival, and/or cancer-specific mortality, but one endpoint is not a surrogate for another. the temporal associations of many tissue genomic tests and outcomes remain obscure, but there are current prospective trials designed to address this issue. tissue-based genomic tests have the potential to optimize the care for men with prostate cancer, but determining the optimal genomic test for each patient to ensure the best outcome requires continued study. references 1. van neste l., bigley j, toll a, et al. a tissue biopsy-based epigenetic multiplex pcr assay for prostate cancer detection. bmc urol. 2012;12:16. 2. stewar t gd, van neste l, delvenne p, et al., clinical utilit y of an epigenetic assay to detect occult prostate cancer in histopathologically negative biopsies: results of the matloc study. j urol. 2013; 189(3):1110-6. 3. partin aw, van neste l, klein ea, et al. clinical validation of an epigenetic assay to predict negative histopathological results in repeat prostate biopsies. j urol. 2014;192(4):1081-7. 4. waterhouse rl jr, van neste l, moses k a, et al. evaluation of an epigenetic assay for predicting repeat prostate biopsy outcome in african american men. urology. 2019;128:62-65. 5. knezevic d, goddard ad, natraj n, et al. analytical validation of the oncotype dx prostate cancer assay a clinical rt-pcr assay optimized for prostate needle biopsies. bmc genomics. 2013;14: 690. 6. mohler jl, antonarakis es, armstrong aj, et al. prostate cancer, version 2.2019, nccn clinical practice guidelines in oncology. j natl compr canc netw. 2019;17(5):479-505. 7. eggener se, rumble rb, armstrong aj, et al. molecular biomarkers in localized prostate cancer: asco guideline. j clin oncol. 2020;38(13):1474-1494. 8. kornberg z, cowan je, westphalen ac, et al. genomic prostate score, pi-rads version 2 and progression in men with prostate cancer on active surveillance. j urol. 2019;201(2): 300-307. 9. kor nberg z , cooper berg mr, cowan je, et al. a 17gene genomic prostate score as a predictor of adverse pathology for men on active sur veillance. j urol. 2019; 202(4):702-709. doi: 101097ju0000000000000290 10. lin dw, zheng y, mckenney jk, et al. 17-gene genomic prostate score test results in the canary prostate active surveillance study (pass) cohort. j clin oncol. 2020: 10;38(14):1549-1557. doi: 10.1200/ jco.19.02267 http://www.siuj.org 29siuj.org siuj • volume 1, number 1 • october 2020 the clinical applications of tissue biomarkers in prostate cancer 11. cedars be, washington sl 3rd, cowan je, et al. stabilit y of a 17-gene genomic prostate score in serial testing of men on active surveillance of early stage prostate cancer. j urol. 2020(4):696-701. doi: 10.1097/ju.0000000000000271 12. l oner gan p e , washing ton sl 3r d, c ow an je , et al. risk factors for biopsy reclassification over time in men on active sur veillance for early stage prostate cancer. j urol. 20 20: 101097ju0000000000001186. 13. nyame ya, grimberg dc, greene dj, et al. genomic scores are independent of disease volume in men with favorable risk prostate cancer: implications for choosing men for active surveillance. j urol. 2018;199(2):438-444. 14. gaffney c, golan r, cantu md, et al. the clinical utility of the genomic prostate score in men with very low to intermediate risk prostate cancer. j urol. 2019; 202(1): 96-101. 15. klein ea, cooperberg mr, magi-galluzzi c, et al. a 17-gene assay to predict prostate cancer aggressiveness in the context of gleason grade heterogeneity, tumor multifocality, and biopsy undersampling. eur urol. 2014; 66(3):550-60. 16. eggener s, karsh li, richardson t, et al. a 17-gene panel for prediction of adverse prostate cancer pathologic features: prospective clinical validation and utility. urology. 2019;126:76-82. 17. van den eeden sk, lu r, zhang n, et al. a biopsy-based 17-gene genomic prostate score as a predictor of metastases and prostate cancer death in surgically treated men with clinically localized disease. eur urol. 2018;73(1):129-138. 18. shipitsin m, small c, giladi e, et al. automated quantitative multiplex immunofluorescence in situ imaging identifies phospho-s6 and phospho-pras40 as predictive protein biomarkers for prostate cancer lethality. proteome sci. 2014; 12:40. 19. shipitsin m, small c, choudhury s, et al. identification of proteomic biomarkers predicting prostate cancer aggressiveness and lethality despite biopsy-sampling error. br j cancer. 2014;111(6): 1201-12. 20. blume-jensen p, berman dm, rimm dl, et al. development and clinical validation of an in situ biopsy-based multimarker assay for risk stratification in prostate cancer. clin cancer res. 2015; 21(11):2591-600. 21. cuzick j, swanson gp, fisher g, et al. prognostic value of an rna expression signature derived from cell cycle proliferation genes in patients with prostate cancer: a retrospective study. lancet oncol. 2011;12(3):245-55. 22. lin dw, crawford ed, keane t, et al. identification of men with low-risk biopsy-confirmed prostate cancer as candidates for active surveillance. urol oncol. 2018;36(6):310 e7-310 e13. 23. bishoff jt, et al. prognostic utility of the cell cycle progression score generated from biopsy in men treated with prostatectomy. j urol. 2014;192(2):409-14. 24. tosoian jj, chappidi mr, bishoff jt, et al. prognostic utility of biopsy-derived cell cycle progression score in patients with national comprehensive cancer network low-risk prostate cancer undergoing radical prostatectomy: implications for treatment guidance. bju int. 2017; 120(6):808-814. 25. cooperberg mr, simko jp, cowan je, et al. validation of a cell-cycle progression gene panel to improve risk stratification in a c o n t e mp o r ar y p r o s t a t e c t o m y c o h o r t . j clin o n col. 2013;31(11):1428-34. 26. kagawa-singer m, valdez dadia a, yu mc, et al. cancer, culture, and health disparities: time to char t a new course? ca cancer j clin. 2010; 60(1):12-39. 27. canter dj, reid j, latsis m, et al. comparison of the prognostic utility of the cell cycle progression score for predicting clinical outcomes in african american and non-african american men with localized prostate cancer. eur urol. 2019;75(3):515-522. 28. erho n, crisan a, vergara ia, et al. discovery and validation of a prostate cancer genomic classifier that predicts early metastasis following radical prostatectomy. plos one. 2013;8(6):e66855. 29. ross ae, feng fy, ghadessi m, et al. a genomic classifier predicting metastatic disease progression in men with biochemical recurrence after prostatectomy. prostate cancer prostatic dis. 2014; 17(1):64-9. 30. ross ae, johnson mh, yousefi k, et al. tissue-based genomics augments post-prostatectomy risk stratification in a natural histor y cohor t of intermediateand high-risk men. eur urol. 2016;69(1):157-65. 31. klein ea, yousefi k, haddad z, et al. a genomic classifier improves prediction of metastatic disease within 5 years after surgery in node -negative high-risk prost ate cancer patients managed by radical prostatectomy without adjuvant therapy. eur urol. 2015;67(4):778-86. 32. sprat t de, dai dly, den rb, et al. per formance of a prostate cancer genomic classifier in predicting metastasis in men with prostate-specific antigen persistence postprostatectomy. eur urol. 2018;74(1):107-114. 33. cooperberg mr, davicioni e, anamaria crisan a, et al. combined value of validated clinical and genomic risk stratification tools for predicting prostate cancer mortality in a high-risk prostatectomy cohort. eur urol. 2015;67(2):326-33. 34. karnes rj, choeurng v, ross ae, et al. validation of a genomic risk classifier to predict prostate cancer-specific mortality in men with adverse pathologic features. eur urol. 2018;73(2):168-175. 35. kim hl, li p, huang h-c, et al. validation of the decipher test for predicting adverse pathology in candidates for prostate cancer active sur veillance. prostate cancer prostatic dis. 2019; 22(3):399-405. 36. herlemann a, huang h-c, alam r, et al. decipher identifies men with otherwise clinically favorable-intermediate risk disease who may not be good candidates for active surveillance. prostate cancer prostatic dis. 2020;23(1):136-143. doi: 10.1038/s41391-019-0167-9 37. zhao sg, chang sl, spratt de, et al. development and validation of a 24-gene predictor of response to postoperative radiotherapy in prostate cancer: a matched, retrospective analysis. lancet oncol 2016;17(11):1612-1620. http://www.siuj.org west africa sub-regional training and skills transfer: experience at the genitourinary division of the korle bu teaching hospital, accra, ghana abdullahi khalid  institute of urology and nephrology, usmanu danfodiyo university and usmanu danfodiyo university teaching hospital, sokoto, nigeria soc int urol j. 2021;2(1):7–9 figure 1. department of surgery, korle bu teaching hospital introduction surgical training in the west africa sub-regional countries produces specialist surgeons in most surgical disciplines, including urology, to ensure that people of the sub-region—and sometimes beyond—have access to surgical services. the training is conducted at tertiary health facilities accredited by the national and sub-regional postgraduate colleges. the countries in the sub-region established their national postgraduate colleges in addition to the subregional postgraduate college known as the west african college of surgeons. surgical trainees are at liberty to select the college of their choice in the course of training. the training involves a series of surgical clinical rotations of stipulated duration, with some variation between the national and west african postgraduate college, but with essentially similar course content. urological training requires a minimum of 5 to 6 years to complete depending on the postgraduate college[1]. during senior residency rotation trainees are encouraged to undertake postings outside their training centre to enhance knowledge and skills acquisition and transfer. 7siuj.org siuj • volume 2, number 1 • january 2021 urology around the world mailto:kalabduka%40gmail.com?subject=siuj http://www.siuj.org although this paper is intended to offer insights into the surgical training in west africa, it should be noted that this is primarily an account of my own 3-month clinical rotation as a trainee from sokoto, in the north west region of nigeria, at the korle bu teaching hospital, accra, ghana. the training facility korle bu teaching hospital, in accra, ghana, was established in 1923[2]. it is one of the major tertiary health facilities in ghana and the third biggest referral centre in africa, with 2000 beds, 21 clinical and diagnostic departments, and 3 centres of excellence (the national cardiothoracic centre, the national reconstructive plastic surgery and burns centre, and the national centre for radiotherapy and nuclear medicine)[2]. it is a postgraduate training centre in both surgical and medical subspecialties, and strives to become the “preferred centre of excellence and innovation for specialist care provision, training, research and advocacy in ghana and west africa”[2]. in addition to training urologists, the genitourinary division of the department of surgery (figure 1) also provides urological care for the people of greater accra region—a population of 4 010 054 people[1]. patients from other parts of the country—and even from other west africa sub-regional countries—occasionally receive treatment here because the concentration of a wide spectrum of specialists and the better facilities and equipment allow the provision of advanced care. the area’s network of rivers and dams, including the volta river and the akosombo dam, mean that waterborne diseases, including bilharziasis and its chronic sequelae, such as bladder cancer, ureteric strictures, and upper tract stones, are seen in relatively high numbers, as are other common urologica l diseases such as benign prostatic enlargement and urethral strictures. therefore, urologist trainees who rotate through this facility are exposed to a myriad of reconstructive, endourologic, laparoscopic, and other procedures. there is a need to introduce robotic urologic services to boost trainees’ exposure and keep the training institution on a par with similar facilities elsewhere in the world. meeting this challenge—and many others in health care—will require further government, philanthropic, and donor agency support. institutional structure and clinical rotation the trainee urologists are privileged to be taught by all the consultants in the division, many of whom are renowned in the sub-region and internationally. during my time there, whether in the theatre, on the ward, in the clinic, or even in the corridors of the hospital, they seized every opportunity to teach both individuals and groups, and they were always aware of and responsive to the academic needs of their trainees. in my experience, the trainees also freely shared knowledge and experience among their fellows. all of which ensured trainees acquired a wealth of relevant knowledge and skills within a relatively short period, making this an excellent clinical rotation. benefits the theatre sessions included procedures that the trainee urologists were seeing or participating in for the first time. even when procedures were more familiar, the volume of cases was far greater than we would have encountered at smaller centres. watching the precision and gentleness of tissue handling by some trainers during reconstructive urological procedures was an added advantage. trainees also benefitted greatly from attending a 1-day didactic and hands-on course on acute trauma operative management using live animals (figure 2), as well as a week-long workshop on percutaneous nephrolithotomy. social aspect even with such a busy schedule, trainees did have time on alternate weekends to tour the city of accra— in my case, with the aid of a reasonable and reliable figure 2. during the acute trauma operative management course 8 siuj • volume 2, number 1 • january 2021 siuj.org urology around the world http://siuj.org commercial taxi driver. particularly memorable were the outings to 2 historic sites: black star square, also known as independence square, and kwame nkrumah memorial park[4]. final word and recommendations ideally, the west africa health community and specialist training colleges should identify facilities of excellence that can be incorporated in the training rotations to achieve skilled specialists and clinicians to serve the west africa sub-region. support from governmental, non-governmental, and donor agencies will be needed to support these facilities as they work towards the further development of urological specialists in the sub-region. acknowledgements i wish to thank dr moyijo maishanu for his useful contribution to this work. i am also most grateful to my trainers, especially professor ismail arzika mungadi, professor jacob ndas legbo, dr abdullahi abdulwahabahmed, dr abubakar umar, and the entire management team of usmanu danfodiyo teaching hospital, sokoto, nigeria, for their unflinching support of my training. i sincerely appreciate the urology team at the korle bu teaching hospital, with special mention of dr james edward mensah, head of the genitourinary division, professor george klufio, mr samuel gepi-attee, and dr mathew y. kyei. references 1. shehu bb. faculty of surgery training programmes and curricula. west african college of surgeons: 64. http://www.wacscoac.org/ downloads/surgery%20curriculum. accessed october 24, 2020. 2. korle bu teaching hospital: a brief history. https://kbth.gov.gh/ brief-history. accessed december 6, 2020. 3. phc national analytical report 2010. https://statsghana.gov.gh/ gssmain/fileupload/pressrelease. accessed december 6, 2020. 4. visit ghana tourism authority. https://visitghana.com/attractions/. accessed december 17, 2020. 9siuj.org siuj • volume 2, number 1 • january 2021 west africa sub-regional training and skills transfer http://www.wacscoac.org/downloads/surgery%20curriculum http://www.wacscoac.org/downloads/surgery%20curriculum https://kbth.gov.gh/brief-history https://kbth.gov.gh/brief-history https://statsghana.gov.gh/gssmain/fileupload/pressrelease https://statsghana.gov.gh/gssmain/fileupload/pressrelease https://visitghana.com/attractions/i http://siuj.org classification of molecular biomarkers ankeet shah, dominic c. grimberg, brant a. inman duke cancer institute, division of urology, duke university medical center, durham, united states abstract a “biomarker” is any measurable characteristic that indicates the presence or absence of disease or the biological response to a stimulus, typically an exposure or intervention. the fda-nih biomarker working group has produced a document called biomarkers, endpoints and other tools (best), which defines 7 categories of biomarkers according to their clinical usage: susceptibility and risk, diagnostic, monitoring, prognostic, predictive, pharmacodynamic and treatment response, and safety. we approach the classification of biomarkers in 2 additional ways: their bodily source and their measurement type. in the context of their use in genitourinary malignancy, we also consider factors that influence their use and reliability in clinical and research applications. introduction a “biomarker” is any measurable characteristic that indicates the presence or absence of disease or the biological response to a stimulus, typically an exposure or intervention. the fda-nih biomarker working group has defined 7 categories of biomarkers according to their clinical usage: susceptibility and risk, diagnostic, monitoring, prognostic, predictive, pharmacodynamic and treatment response, and safety. we approach the classification of biomarkers in 2 additional ways: their bodily source and their measurement type. in the context of their use in genitourinary malignancy, we also consider factors that influence their use and reliability in clinical and research applications. biomarkers by source blood blood and its various components represent a valuable source for a wide variety of molecular biomarkers. although direct sampling of cells in solid tumours of urologic oncology is not accomplished with peripheral blood draws, circulating tumour cells, as well as cell-free circulating dna, can be used for genomic biomarkers [1,2]. proteomics, lipidomics, and metabolomics in oncology are growing fields that can also be applied to blood samples for additional biomarker evaluation [3]. the means used to obtain blood are less invasive than those used to obtain tissue and some biofluids, and many patients with urologic malignancies are likely to undergo blood draws for standard care. blood is largely composed of water but also contains erythrocytes, leukocytes, platelets, fibrinogen and other clotting factors, proteins including albumins and globulins, glucose, and electrolytes. importantly, these components may limit the assessment of a given analyte if the blood is not processed appropriately [4,5]. it is also challenging to control the variation of individual components that make up blood that can occur in disease states such as dehydration, infection, or malignancy [3,4,6]. to prevent degradation, blood and blood fractions have traditionally been cryopreserved in aliquots to limit the damage to target analytes caused by thawing and re-freezing within the specimen. a major critique of this approach is that the cost associated with cryopreservation can be significant [7,8]. alternative methods of storage that aim to decrease costs tied to cryopreservation include drying with newer methods such as lyophilization and isothermal vitrification; however, these methods are not yet standardized [9,10]. for low molecular-weight protein, drying on silica key words competing interests article information biomarker, nucleic acids, cryopreservation, tissue fixation, body fluids, tissues, urologic oncology none declared. received on june 30, 2020 accepted on august 1, 2020 soc int urol j. 2020; 1(1):8–15 8 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation mailto:brant.inman%40duke.edu?subject=siuj http://www.siuj.org chips is feasible but does not protect specimens at higher temperatures. dried blood spots using a paper system to evaporate water and contain blood components are useful in settings where access to cooling is limited for initial specimen handling. however, dbs requires controlled storage conditions, and certain analytes are more susceptible to oxidative damage. novel techniques for safeguarding blood components remain an area of exploration [10]. serum and plasma although whole blood has many uses for biomarker assessment, certain measurement modalities require sample refinement to optimize detection of a particular analyte. to this end, separating the cellular fraction out from the liquid portion of blood facilitates spectroscopybased analysis with less interference from blood cells. the liquid fraction of blood can be isolated as either serum or plasma. plasma is stored in a way that prevents coagulation and clot formation. various clotting factors, fibrinogen, and platelets are maintained in suspension in plasma. serum, on the other hand, is allowed to clot over 30 minutes before use and can give a cleaner sample when interference from platelets and other contaminants is undesirable. there are trade-offs of the 2 forms [4,11], and the liquid fraction used should be individualized to the analyte of interest [12]. cellular fractions cellular components of blood are also used in a variety of biomarkers. for example, a high neutrophil to lymphocyte ratio has been found to be a poor prognostic marker of systemic inf lammation and to correspond to worse outcomes in a variety of malignancies [13,14], while anemia and thrombocy topenia are used in risk stratification for renal cell carcinoma [15] and may broadly correlate with late stage tumours [16]. isolation of cellular fractions may be achieved by centrifugation and separation by size or using advanced spectroscopy [17,18]. cellular fractions are less subject to coagulation when blood is stored as plasma. reassessment of cellular biomarkers from blood samples may be facilitated with such specimens, although the anticoagulant or freezing technique used may affect the viability of cells [19,20]. flow cytometry and other immunological techniques can be used to characterize the cellular components of blood to a high degree of precision using fluorescent antibody labelling [21]. urine among t he least invasive liquid biomarkers to obtain, urine also has the advantage of a simpler constituent matrix than other biofluids. urine is more thermodynamically stable than other biof luids and generally requires less processing for preservation. also, in the case of urinary tract facing malignancies, an opportunity exists to capture tumour cells and their biochemical by-products. urinary extracellular vesicles containing a wide variety of molecular biomarker classes have also been discovered. a vast majority of the molecular biomarker classes are identifiable in urine. not all patients are able to supply urine for analysis, depending on their renal function or disease state. when urine can be provided, it is subject to variations in composition and ph, which can have varying effects on any given class of biomarker. uniquely, urine is also subject to contamination by the urinary microbiome, which can make interpretation of the source of particular analytes challenging [22-25]. ejaculate and prostatic secretions of particular relevance to prostate cancer are prostatic biof luids, which capture analytes more effectively than other sources [26]. of course, an intact prostate and ejaculatory pathway is required for procuring these specimens. the post-prostatic massage urine is a proxy for capturing prostatic secretions, and so this particular biofluid is also subject to the constraints of urinary specimens noted above. there are different social acceptability thresholds for semen and prostatic secretions, compared to other biofluids, making these secretions more procedurally intensive to collect. recent efforts have shown the ability to collect rna, dna, proteins, and other molecular biomarkers from these biof luids [26–30]. few data exist on storage considerations of prostatic secretions, a lt hough cryopreservation of seminal ejaculate is a standard practice in fertility scenarios [2,27,30]. tissue arguably, tissue is the most invasive specimen type to obtain, and using tissue has additional costs for procurement, processing, and storage. in urologic oncology, though, tissue samples are often already obtained during routine clinical practice and may be used to identify biomarkers that guide treatment or provide prognostic information [31,32]. the full range of molecular biomarkers can be obtained from tissue samples, including more direct measurement of immune parameters at the tumour site (eg, tumourinfiltrating leukocytes), which influences endogenous abbreviations dna deoxyribonucleic acid dnase deoxyribonuclease ffpe formalin-fixed, paraffin-embedded rna ribonucleic acid rnase ribonuclease 9siuj.org siuj • volume 1, number 1 • october 2020 classification of molecular biomarkers http://www.siuj.org immune response to tumour as well as chemotherapy and immunotherapy efficacy [33,34]. a major advantage of tissue specimens is the inherent ease with which the signal-to-noise ratio can be optimized in evaluating molecular biomarkers derived from tumours or tumour microenvironments. depending on the biomarker of interest, a sample may be “enriched ” to exclude normal tissue and prioritize tumour tissue for analysis (eg, laser capture microdissection). recently, efforts have been made to standardize the manner in which tissue samples for various types of tumours, are delineated from surrounding stroma on histopathologic analysis with the intent of decreasing inter-observer variability of certain biomarker assessments [35]. l i ke ot her s ou rc e s of bioma rkers , t i s sue based biomarkers are subject to degradation and contamination. this is particularly true in fresh frozen tissue samples, in which tissue will be subject to predictable ischemic changes in the ex vivo state, such as apoptosis and in situ coagulation until freezing occurs. the timeliness of such processing would affect the accuracy and quality of biomarker analysis across a range of analytes, including more sensitive proteins [36]. formalin-fixed, paraffin-embedded (ffpe) samples increase the longevity of the specimen regardless of storage temperature. however, residual paraffin (even after appropriate treatment) can contaminate the analysis of such a preserved sample [36]. there are tradeoffs of additional processing considerations for ffpe samples obtained for clinical evaluation. these may be associated with different contaminants or constraints in methodology for evaluation, and are discussed in more detail below [37,38]. biomarkers by type genomic biomarkers the european medicines agency, in concert with the international council for harmonisation of technical requirements for pharmaceuticals for human use, has defined a genomic biomarker as “a measurable dna and/or rna characteristic that is an indicator of normal biologic processes, pathogenic processes, and/or response to therapeutic or other interventions”[39]. factors affecting genomic biomarkers a lthough dna and r na are genera lly reliable biomarkers, there are some commonly encountered situations in biospecimen collection that occur in clinical medicine that can affect nucleic acid quantity and quality and impact their accuracy as biomarkers. a few of these conditions are described here. pre-fixation time: pre-fixation time is the duration of time between obtaining the biopsy or surgical specimen and its preservation. as the tissue samples removed are ischemic during this interval, several important biologic processes occur in the tissue that can affect nucleic acids. rna, in particular, is susceptible to the effects of this “cold” (ie, <37 °c) ischemia. changes that are seen during cold ischemia include increased expression (quantity) of rna molecules from hypoxia response genes (eg, hypoxia-inducible factor 1α [hif1α]); digestion and loss of rna molecules with short half-lives; and broad rna degradation and reduction in quality, starting at about 5 to 6 hours at room temperature [40]. in general, the shorter the time from patient to preservation (preservative or freezing), the better. formalin: formalin fixation is a common method used to preserve biological tissue samples that have been obtained surgically or by biopsy, and subsequent paraffin-embedding allows for the cutting of thin slices for histological examination. ffpe samples are abundant and represent the standard method of clinical tissue preservation in most hospitals. formalin has several effects on dna that affect dna quality, including dna denaturation and cross-linking with cytosine residues [41]. as a result of these and other effects on dna, formalin induces artificial mutations at a rate of approximately 1 mutation per 500 base pairs. rna shares these formalin effects, but it is also affected by formalin in other ways which impede reverse transcription [41, 42]. factors that increase the formalininduced artificial mutation rate include increasing formaldehyde concentration, increasing temperature, increasing duration of fixation, and decreasing ph [41]. tissue nucleases: deoxyribonucleases (dnases) and ribonucleases (rnases) are tissue nucleases that digest dna and rna, respectively. rna molecules are particularly susceptible to degradation by rnases, and for this reason, rnase inhibition is part of most rna extraction protocols. dnase is felt to be an important contributor to dna degradation in ffpe tissue samples [43]. storage conditions: the age of the ffpe sample and storage temperature can have an impact on nucleic acid quality [44]. in general, storage at −20°c is better than room temperature, and shorter duration of storage is better. dna dna has many attributes that make it an excellent biomarker. first, dna tends to be a very stable molecule—a biological requirement, as it directs the replication of all human cells—and is consequently 10 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation http://www.siuj.org affected less by environmental conditions than many other molecules. second, many characteristics are measurable in dna, including single-nucleotide variants (formerly single-nucleotide polymorphisms), v a r i a bi l it y of s hor t re p e at e d s e g me nt s (e g , m icros atel l ite s), epigenet ic mod i f ic at ions (eg , methylation), haplotypes, deletion mutations, insertion mutations, copy number variations, and cytogenetic variations (eg, translocations, duplications, deletions, or inversions). one important distinction with dna is the difference between germline changes and somatic changes. germline dna is the complement of genes that an individual is born with and can pass on to future progeny. generally, blood leukocytes are used as the source for germline dna, but there are scenarios (eg, leukemia) where this is not ideal, and buccal swabs, saliva, or other normal tissue are used. most evidence suggests that buccal swabs and saliva yield similar dna quality to blood leukocytes, although quantity is usually less [45,46]. germline dna alterations can inform the presence of an inherited tumour syndrome (eg, von hippel-lindau disease), a susceptibility to exposures (eg, glutat hione-s-transferase [gstm1] nu ll and n-acetyltransferase 2 [nat2] slow acetylator increase the risk for bladder cancer), an ability to metabolize drugs, and a susceptibility to developing certain diseases or adverse events associated with treatment. somatic dna refers to dna col lected from an affected tissue or organ, usually a tumour, and ref lects a change that occurred in the dna after conception. somatic alterations are not passed on to children. somatic alterations are useful for predicting responsiveness to treatment (eg, microsatellite instability and programmed death 1 ligand 1 [pd-l1] response), determining prognosis, and diagnosing the presence or absence of disease. rna rna is the transmitter of genetic information coded in the dna and is therefore a significantly more dynamic molecule than dna. rna quantity and composition change significantly from tissue to tissue under normal physiologic conditions. characteristics that are measured in rna include sequences, splicing, expression levels, and subtype (eg, mirna). as alluded to above, while rna is a more responsive molecule and, perhaps, a better reflector of genetic activity within a particular tissue, it is also substantially less stable and is affected by a larger number of environmental conditions than dna. there are numerous types of rna molecules and they are generally classified as the following: (a) those involved in protein synthesis, (b) those involved in rna modification, and (c) those whose function is mainly regulatory [47]. a non-exhaustive summary of the main types of rna is shown in table 1. protein proteins are the workhorses of the cell and are often highly dysregulated in disease states. proteins can be isolated from nearly all biofluids but, like all analytes, they are also subject to degradation and alteration. human blood and urine contain proteases that cleave proteins into smaller peptides, which can be cleaved by peptidases into even smaller pieces [48]. interestingly, the pattern of cleavage can be used as a signature to identify certain cancers [49]. adding protease inhibitors to biospecimens can help reduce artifactual changes in proteins caused by enzymatic degradation, although these additions can also affect downstream applications. urine can be a particularly challenging source for protein biomarkers because of dramatic changes in ph (ranges from 4 to 8), the influence of hydration status on protein concentration, and proteolysis that occurs during storage in the bladder [50]. about 30% of urinary proteins are derived from glomerular filtration and 70% from the renal tubules and urothelium, so the urine protein pool is a mix of systemic and local–regional sources [51]. protein-based biomarkers have generally been focused on the quantification of a particular protein or isoform. however, assessment of post-translational modifications is also important. post-translational modif ications that can important to biomarkers include phosphorylation, methylation, glycosylation, ubiquitination, acetylation, and lipidation [52]. glycans the attachment of carbohydrates to molecules, such as proteins and lipids—a process known as glycosylation— is common, occurring in > 50% of human proteins [53]. several important glycoproteins have been found to be good biomarkers in urology, including α-fetoprotein, prostate-specif ic antigen, and human chorionic gonadotropin. there are different forms of protein glycosylation, including n-linked (glycan attached to the nitrogen of asparagine) and o-linked (glycan attached to the oxygen of threonine and serine). tumours may show differences in the amount, size, and type of glycosylation when compared with normal tissue. for example, n-linked glycans tend to become larger and more branched, whereas o-linked glycans tend to be truncated and expose underlying peptide epitopes. other glycans can be important biomarkers, too. for example, glycolipids (glycans bound to lipid molecules) and glycosaminoglycans (mucopolysaccharides) have been studied as biomarkers. 11siuj.org siuj • volume 1, number 1 • october 2020 classification of molecular biomarkers http://www.siuj.org table 1. main types of rna protein synthesis type function messenger (mrna) • transcription of the information contained in dna exons (recipe for a protein) • subject to alternative splicing, which creates different protein isoforms ribosomal (rrna) • primary constituent of the ribosomes, where mrna is translated into protein • most abundant rna in cells (about 80%) transfer (trna) • carries an amino acid matching the mrna to the ribosome, required for translation rna modification type function small nuclear (snrna) • processing and splicing of mrna in the nuclear spliceosome small nucleolar (snorna) • involved in methylation and pseudouridylation of rrna and trna ribonuclease p • riboenzyme (enzyme made of rna) that cleaves rna ribonuclease mrp • riboenzyme that processes rrna in the nucleus regulatory type function micro (mirna) • single stranded rna, 22 bp length, interferes with other rnas small interfering (sirna) • double stranded rna, 20–25 bp length, interferes with other rnas long non-coding (lncrna) • single stranded rna, >200 bp length, interferes with other rnas short hairpin (shrna) • artificial rna molecule designed to inhibit other rnas, has a tight hairpin turn structure antisense (asrna) • single stranded rna complementary to a mrna to which it binds and inhibits lipids lipids are key molecules in cellular metabolism and are a critical structural component in the biological membranes that wrap all human cells. lipids are different from other biomolecules in that they are soluble in organic solvents, which is an important processing step in lipid analysis and characterization [54]. lipids are subdivided into 8 classes, each of which has had some biological role described in cancer biology: fatty acyls, glycerophospholipids, glycerolipids, sphingolipids, sterol lipids, prenol lipids, saccharolipids, and polyketides [55]. mass spectroscopy and related techniques are the main tools used for profiling biological lipids. imaging although it may not seem intuitive, imaging can also serve as a biomarker [56,57]. examples of widely available imaging-based biomarkers include basic radiological lesion characteristics (eg, size, shape, location), lesion density (computed tomography), lesion echogenicit y (u lt rasou nd), lesion sig na l intensity (magnetic resonance imaging), and contrast enhancement. the response evaluation criteria in solid tumors (recist) criteria for evaluating tumour response to therapy is a radiological biomarker that is commonly used in clinical trials [58,59]. functional molecular imaging has been further developed, whereby specific molecular features are studied using novel radiological ligands. for example, in positron emission tomography (pet) imaging, functional biomarkers are being explored to improve the detection of cancer, including, 18f-fluorodeoxyglucose (18f-fdg), carbon 11 choline (11c-choline), 68gallium prostate-specific membrane antigen (68ga-psma), and numerous others. 12 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation http://www.siuj.org in other cases, theranostic imaging is being pursued whereby a molecular target is imaged in a patient in vivo before the administration of a targeted agent against that molecular target [60]. pathology the histological evaluation of tissue samples (or blood smears) is not only a routine clinical component of cancer care but also an important source of clinical biomarkers. many standard descriptors of tissue morphology can be quantified and used as biomarkers. common examples in genitourinary oncology include tumour grade, presence of lymphovascular invasion, presence of mitoses, and histological tumour type and subtype. more recently, digital imaging has allowed for a new era of digital pathology, in which pattern recognition and artificial intelligence software tools can be used to characterize tissue sections with increasingly precise and reproducible methods [61,62]. it is highly likely that in the future digital pathology tools will form the backbone of the analysis of most tissue sections. conclusions biomarkers can be obtained and characterized from a highly diverse set of biological sources of measurement. there is no clear optimal biomarker, and each has inherent strengths and f laws. the future will likely consist of a collation of large networks of biomarkers that are merged computationally to provide a consensus picture of the pathological process that is occurring in the patient. this will undoubtedly require new informatic and artificial intelligence tools but will also lead to a new era of precision medicine. references 1. vandekerkhove g, struss wj, annala m, et al. circulating tumor dna abundance and potential utilit y in de novo metastatic prostate cancer. eur urol. 2019;75 (4):667-75. doi: 10.1016/j. eururo.2018.12.042 2. how kit a , nielsen hm, tos t j. dn a met hylation b ased biomarkers: practical 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effect of fixatives and tissue processing on the content and integrity of nucleic acids. am j pathol. 2002;161(6):1961-71. doi: 10.1016/s0002-9440(10)64472-0. 42. evers dl, fowler cb, cunningham br, mason jt, o’lear y tj. the ef fect of formaldehyde fixation on rna: optimization of formaldehyde adduct removal. j mol diagn. 2011;13(3):282-8. doi: 10.1016/j.jmoldx.2011.01.010 43. tokuda y, nakamura t, satonaka k, et al. fundamental study on the mechanism of dna degradation in tissues fixed in formaldehyde. j clin pathol. 1990;43(9):748-51. doi: 10.1136/jcp.43.9.748 14 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-15-establish-definitions-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data_en.pdf 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collection of blood, saliva, and buccal cell samples in a pilot study on the danish nurse cohort: comparison of the response rate and quality of genomic dna. cancer epidemiol biomarkers prev. 2007;16(10):20726. doi: 10.1158/1055-9965.epi-07-0611 47. xi x, li t, huang y, et al. rna biomarkers: frontier of precision medicine for cancer. noncoding rna . 2017;3(1):9. doi: 10.3390/ ncrna3010009 48. kushnir mm. are samples in your freezer still good for biomarker discover y? am j clin pathol. 2013;140(3):287-8. doi: 10.1309/ ajcpfzyy7bbkk9je 49. villanueva j, shaffer dr, philip j, chaparro ca, erdjument-bromage h, olshen ab, et al. differential exoprotease activities confer tumorspecific serum peptidome patterns. j clin invest. 2006;116(1):27184. doi: 10.1172/jci26022 50. thomas ce, sexton w, benson k, sutphen r, koomen j. urine collection and processing for protein biomarker discover y and quantification. cancer epidemiol biomarkers prev. 2010;19(4):9539. doi: 10.1158/1055-9965.epi-10-0069 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2017;189:13-29. doi: 10.1016/j. trsl.2017.06.006 56. white paper on imaging biomarkers. insights imaging. 2010;1(2): 42-5. doi: 10.1007/s13244-010-0025-8 57. medical imaging in personalised medicine: a white paper of the research committee of the european society of radiology (esr). insights imaging. 2011;2(6):621-30. doi: 10.1007/s13244-011-0125-0 58. schwar t z lh, litiere s, de vries e, et al. recist 1.1-update and clarification: from the recist commit tee. eur j cancer. 2016;62:132-7 doi: 10.1016/j.ejca.2016.03.081. 59. seymour l, bogaerts j, perrone a, et al. irecist: guidelines for response criteria for use in trials testing immunotherapeutics. lancet oncol. 2017;18(3):e143-e52. doi: 10.1016/s1470-2045(17)30074-8 60. turner jh. an introduction to the clinical practice of theranostics in oncology. br j radiol. 2018;91(1091):20180440. doi: 10.1259/ bjr.20180440 61. janowczyk a, madabhushi a. deep learning for digital pathology image analysis: a comprehensive tutorial with selected use cases. j pathol inform. 2016;7:29. doi: 10.4103/2153-3539.186902 62. janowcz yk a, zuo r, gilmore h, feldman m, madabhushi a. histoqc: an open-source quality control tool for digital pathology slides. jco cli n cancer inform. 2019;3:1-7. doi: 10.1200/cci.18.00157 15siuj.org siuj • volume 1, number 1 • october 2020 classification of molecular biomarkers http://www.siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. genitourinary reconstructive surgery curriculum and postgraduate training program development in the caribbean jessica delong,  ramón virasoro department of urology, eastern virginia medical school, norfolk, united states, devine-jordan center for reconstructive surgery and pelvic health, department of urology, virginia beach, united states abstract objectives to describe the development of a genitourinary reconstructive fellowship curriculum and the establishment of the first genitourinary reconstructive and pelvic floor postgraduate training program in the caribbean. methods in an effort to respond to the need for specialty-trained reconstructive urologists in the dominican republic, we developed an18-month fellowship program to train local surgeons. the process began with creation of a curriculum and partnership with in-country physicians, societies, hospitals, and government officials. we sought accreditation via a well-established local university, and fellowship candidates were selected. a database was maintained to track outcomes. subjective and objective reviews were performed of the fellows. results the first fellow graduated in 2018, the second in 2020, and the third is currently in training. the curriculum was created and implemented. the fellowship has been successfully integrated into the health system, and the fellows performed 199 and 235 cases, respectively, during the program, completing all rotations successfully. they have been appointed to the national health system. both graduates are now docents in the program and in the public system. additional staff including radiologists, radiology technicians, nurses, urology residents (both dominican and american), urology attendings, operating room staff, and anesthesia residents were trained as a result of the program. conclusions to our knowledge, this is the first fellowship of its kind in the caribbean. a novel curriculum was created and implemented, and the first 2 fellows have successfully completed all rotations. this training model may be transferable to additional sites. introduction global health and global surgery have gained significant interest and momentum over the last decade[1,2]. many surgical programs across the united states have implemented a global surgery rotation that highlights the growing interest of american surgical residents in this arena[2–7]. the global health community is committed to furthering surgical care and improving outcomes to reduce health inequities[8]; the lancet commission on global surgery and other reports have helped to spur this movement[9–11]. key words competing interests article information global surgery, reconstructive surgery, curriculum development, surgical training, surgical education none declared. received on november 13, 2020 accepted on january 15, 2021 soc int urol j. 2021;2(2):106–112 doi: https://10.48083/rord8326 106 siuj • volume 2, number 2 • march 2021 siuj.org original research mailto:jessicadelong%40gmail.com?subject=siuj https://10.48083/rord8326 http://www.siuj.org over 5 billion people lack access to adequate surgical and anesthesia care across the globe, the majority in lowand middle-income countries (lmics)[12–14]. this inequity is far-reaching and it has been shown that a significant percentage of the global disease burden is due to surgical conditions: the world health organization (who) reports 11%, and some contemporary estimates are as high as 30%[11–13,15,16]. this uptrend of surgical burden will likely continue as the world continues to industrialize. rose and colleagues estimated nearly 34 million urologic procedures were needed in 2010, based on the who global health estimate of disease by category[10]. cogent, compelling arguments have been made by many authors showing how surgical care is an integral part of global health, forming a necessary cog in the network that establishes a strong health system[17]. the need for access to reliable anesthesia and surgery is ubiquitous across countries in all stages of development, as well as across a spectrum of disease states[14]. there are multiple barriers to sustainable surgical programming abroad. finances, time constraints, and local leadership are all often cited[1,4,6]. in order to overcome these obstacles, regional and international investment is important. a local champion should be identified, and any proposed program needs to be able to adapt to the regional environment. the majority of published literature revolves around surgical rotations and fellowships that are based in united states programs, prov iding shor t-term rotations in a sustainable environment abroad[1,12,18]. multi-institutional and multinational co-operations lead to valuable learning experiences and benefits for all participants[4,5] although some of these advantages may be intangibles such as broadening cultural experience, satisfying altruistic desires or learning about different health care systems, many are concrete. these may include adapting surgical technique, participating in publishing research, and building surgical capacity. we present our innovative model for surgical education in a resource-poor setting to address a specific need identified by the local community. materials and methods in 2013, the authors began weeklong mission trips to the dominican republic (dr) in conjunction with physicians for peace, a united states-based non-profit organization. each year a minimum of 2 trips were taken to treat adult men with urethral stricture disease, the prevalence and severity of which are high in the dr. over this time the dominican urologists recognized a compelling need for fellowship-trained reconstructive surgeons, and the idea for a formal program was born. a basic needs assessment was performed during these mission trips and appropriate centralized hospital facilities were identified. a pre-established checklist or survey was not used, but consensus was developed among key stakeholders within the hospitals and residency programs. essential infrastructure required to support fellowship-level surgical training was identified, including ability to sterilize surgical equipment, availability of basic instruments, and radiology services, as well as anesthesia equipment. the authors set up a partnership among the following entities: a non-profit organization in the united states (physicians for peace), a local prestigious university (universidad autónoma de santo domingo), and a medical school in the united states (eastern virginia medical school) by the authors. a memorandum of understanding was signed by all parties, and the strengths of each of these organizations, along with other local and international partners, were brought together to form the fellowship. the first fellow was selected via a longitudinal evaluation spanning 2 years of biannual mission trips, and multiple candidates were considered throughout the country. subsequent fellows were selected via a nationwide selection process with interviews with the authors. the program is designed for recently graduated urology attendings in the dr who show both an interest in and an aptitude for reconstructive urology. he or she must be fluent in english and in spanish, able and willing to travel, and motivated to help engender positive change in surgical education. the curriculum was designed by the authors around established norms for reconstructive urology (supplemental material, curricular plan, available online), although no formal curriculum yet exists w it hin our internationa l societ y, genitourinar y reconstructive surgeons. the fellowship has been an on-the-ground pilot test for the curriculum and has gone through several iterations since its inception. as there was no existing curriculum within genitourinary reconstructive surgeons, the authors wrote the curriculum based on their expertise in the field as well as with curriculum development. the ministerio de educación superior (mescyt), the highest office of education in the dr, established standards that were followed within the plan for the fellowship. via a cooperation between mescyt and uasd, the current version of the curriculum and overall fellowship plan was incorporated. the fellow works within the national health system sistema nacional de salud, as well as within the private system. funding for the first fellow was provided through local and international organizations, as well as through the fellow’s billing for services within the private sector. for subsequent fellows, the authors secured a salary through the ministry of health. 107siuj.org siuj • volume 2, number 2 • march 2021 genitourinary reconstructive surgery curriculum and postgraduate training program development in the caribbean http://www.siuj.org a redcap database was created and maintained to track surgical and perioperative data. the fellows were evaluated during their training and input their cases into a log. results the needs assessment revealed that there were no fellowship-trained reconstructive urologic surgeons, but a high burden of care due to pathology that could be treated by such a provider. at the major partner hospital, hospital moscoso puello in santo domingo, facilities were adequate to perform the required surgeries, although some basic urologic equipment was lacking. via partnerships and publicity generated from the inception of the fellowship, several key equipment items were donated, including a flexible cystoscope and stirrups for patient positioning. over the fellowship period, key advances in anesthesia care have also been made. the curriculum was developed to meet the specific criteria requested by local partners at the dominican urological society and uasd and was designed around 4 major areas. it is to our knowledge the first formally developed curriculum for a fellowship in reconstructive urologic surgery (table 1). it is meant to be a learning resource, adaptable to the needs of each fellow as well as the needs of the area. the fellowship is accredited by the uasd, and the fellow graduates with a diplomate in reconstructive urology after 18 months of training. the first fellow graduated in july 2018, and the second in february 2020, and the third was onboarded in march 2020. the fel lows were eva luated subject ively a nd objectively during each segment of training in the following categories: patient care, surgical skill, and research/academic achievement. both graduated fellows received “highly satisfactory” or “satisfactory” ratings when evaluated by faculty. the first graduate performed 199 reconstructive urologic operations, the second 235. these included male urethral reconstruction, procedures related to incontinence and sexua l hea lt h, and genita l reconstruction, as well as female and general urology cases (table 2). both fellows rotated externally through eastern virginia medical school as well as centers of excellence in chile and argentina for a total of 6 months. the fellow was able to participate in surgical care, conferences and patient care. regular trips were taken by the authors and other collaborators to the dr to aid in training and consistent telemedicine classes were undertaken to facilitate didactic learning. at a minimum, biweekly conferences were held every 2 weeks. su rg ica l a nd per ioperat ive data, as wel l as complication rates and follow-up are being collected via an institutional redcap database. the first graduated fellow logged 18 urethroplasties in his first postgraduate year, and 56 the following year. additional data regarding etiology, case type, and follow-up were also recorded (table 3). discussion to our k nowledge, t his is t he f irst published genitourinar y reconstructive surger y fel lowship curriculum and is the first formal genitourinary reconstructive training program in the caribbean. the success of this program is predicated upon the interest and enthusiasm of our local partners in the dr. these local champions help to support the program on a daily basis. as cited in their work, riviello and colleagues point to key components of a successful program: relationships, mutual learning, local advocates, local needs superseding those of the visiting institution, research, and a mu ltidisciplinar y approach[19]. the authors also recognize these pillars and others, cultivating the relationships with the urological societies and residencies, appreciating the value of education and training, and maintaining openness to collaboration. this degree program provides the fellow with previously nonexistent resources: access to a network of international surgeons, opportunities to publish and present both nationally and internationally, and a support network to continue program building. it allows for appropriate training and education while providing longitudinal follow-up for patients, facets that have been identified as important to provision of surgical care[20]. the lack of specialty care is ref lective of the overall surgical health of the country; it is a privilege to be able to develop a fellowship program when the need for basic surgical care is still unmet in many areas. t here a re mu lt iple ex a mple s of long-ter m relationships between academic medical centers and programs in lmics[19,20] wherein partnerships have been forged to try to address this need. universities such as vanderbilt and harvard have successfully created sustainable training for not only surgeons but also anesthesia providers and nursing staff. sustainable development, capacity building, and programming are needed, particularly in resource-poor settings, in order to provide long-term solutions[20,21]. the initial needs assessment is very important as this will determine suitability of the site for a specialty training program and define care gaps; several tools have been developed to assess surgical need[22,23]. surgeons overseas developed ways to document baseline surgical capacity in lmics. among them is a survey intended 108 siuj • volume 2, number 2 • march 2021 siuj.org original research http://www.siuj.org table 1. fellowship modules a) diagnostic evaluation module 1 • history and physical specific to the specialty module 3 • urologic endoscopy, urodynamic studies: techniques and interpretation of studies module 2 • radiography, computed tomography, mri, ultrasound, doppler: techniques and interpretation of studies b) decision making module 4 • relevant anatomy review, review of operative equipment for genitourinary reconstructive surgery module 6 • morbidity and mortality, case presentations module 5 • interactive case reviews with discussion uasd sponsored course in bioethics (required for master’s degree) c) surgical techniques module 7 • anterior urethral reconstruction: trauma, iatrogenic and inflammatory module 11 • male sexual dysfunction • penile revascularization • penile prosthesis implantation module 8 • posterior urethral reconstruction • congenital (posterior urethral valves) • acquired (trauma, iatrogenic) module 12 • pelvic floor disorders • pelvic organ prolapse • urinary fistula • urethral erosion in patients with neurogenic bladder module 9 • penile and external genitalia reconstruction • correction of congenital and acquired curvature • correction of buried penis, genital lymphedema and hidradenitis suppurativa • correction of sequelae due to fournier gangrene and burns module 13 • utilization of intestinal segments • augmentation cystoplasty • continent urinary diversion • incontinent urinary diversion • ureteral reconstruction module 10 • urinary incontinence in the male and the female • injection of suburethral bulking agents • autologous and synthetic slings • artificial urinary sphincter • bladder neck closure, perineal approach and abdominal approach module 14 • hypospadias • tubularization of the urethral plate • reconstruction with flaps • reconstruction with grafts • management of chordee to detect care gaps. divided into sections for personnel, infrastructure, procedures, equipment, and supplies, it has been used to provide an index showing surgical capacity. the program in the dr grew from many years of ongoing surgical missions and a formal assessment using one of these established tools was not performed; this is a shortcoming of our work. the central public hospital moscoso puello is able to serve as a support hub and referral center for surrounding catchment area in the dr, a concept suggested by the who global surgery consortium 2030[14]. building specia lt y capacit y here helps surrounding facilities as well. we continue to meet challenges in some areas where certain equipment remains unavailable. 109siuj.org siuj • volume 2, number 2 • march 2021 genitourinary reconstructive surgery curriculum and postgraduate training program development in the caribbean http://www.siuj.org our collaborative model minimizes cultural and linguistic misunderstandings that can create gaps in care. it allows for an interchange of information that all involved parties find valuable and helps to build a successful system of surgical care. this systemsbased approach requires large-scale efforts from administrators, local champions, and government/ ministry of health representatives, as well as financial engagement. as stated by paul farmer and jim kim, “to do surgery properly requires a significant investment in infrastructure and training as well as a steady supply of consumables”[24]. surgery is not simple, nor easy, and it does not bear immediate fruits as a vaccination campaign might. many different approaches exist for monitoring and evaluation of these programs. first there is evaluation within the program–competencies for the fellow, presentations given, papers published. we employed a basic, reproducible evaluation form that was completed by faculty involved in training the fellows. equally important is the impact regionally: patients treated, staff trained, complication rates, and infrastructure change. various authors have set up schema to measure both need and impact, some with the idea of the creation of national registries to help track surgical encounters in lmics[10]. continued program evaluation and outputs analysis both internally with the fellowship as well as externally need to be completed. this program is in its infancy, so long-term data are not available. there is a need to continue to develop programming, as well as to finetune outputs. a redcap database is maintained to track patient outcomes. although there have been challenges in culling these data, we can report that the first graduated fellow completed a total of 74 urethroplasties in his first 2 years post training. data were not available for 17 patients (22.3%), but it is of note that a large number of patients developed stricture following placement of urethral catheter for other indications (28, 37.8%). interestingly 14 of these patients (18.9%) had failed prior interventions, consistent with the known prior poor success rates. follow-up was poorly recorded, and is a shortcoming in our work thus far. this program is part of a cooperative movement to promote surgical care as an integral part of global health. there are disparities in surgical care, largely based on finances available in the region: weiser and colleagues reported in 2008 that 30% of the world’s population receives 73.6% of the surgical care, with the poorest third undergoing only 3% to 5% of all surgical procedures[16]. conditions that require surgica l table 3. initial outcomes data: fellow 1 n % urethroplasties performed (74) postgraduate year 1 (2018) 18 – postgraduate year 2 (2019) 56 – stricture etiology foley trauma 28 37.8 iatrogenic 10 13.5 trauma 7 9.5 lichen sclerosus 2 2.7 infection 1 1.4 idiopathic/data not available 17 22.3 failed prior surgical intervention 14* 18.9* surgery performed excision, primary anastomosis 18 24.3 oral mucosa graft 28 37.8 perineal urethrostomy 5 6.8 dviu/dilation 3 4.1 data not available 20 27 results doing well at 2 years (qmax >20) 12 16.2 postoperative infection, resolved 2 2.7 wound dehiscence, resolved 1 1.4 stricture recurrence 2 2.7 no data available 57 77 * 5 of these also had known initial etiology and are listed separately, does not add to 100 table 2. fellowship cases fellow 1 fellow 2 case type n n urethral reconstruction 96 126 male incontinence 5 5 male sexual health 8 13 genital reconstruction 4 2 urinary diversion or ureteral reconstruction 2 10 female reconstruction 23 16 general 61 63 total cases 199 235 110 siuj • volume 2, number 2 • march 2021 siuj.org original research http://www.siuj.org intervention or remediation account for up to 15% of total disability adjusted life years[24]. while these data highlight the poor access to any procedure, specialty care is also severely lacking. this study has many limitations. data collection is incomplete and lacks certain outcome metrics. much of the impact is challenging to measure in the short term, such as public health initiatives, and is an active area of interest for the authors. as saluja and colleagues underline, research in academic global surgery needs to have rigorous standards[25]. we are working to improve our understanding of the local and regional impact of this program. future work will focus on the surgical outcomes, complications, and regional impact of the program. this intent of this study was to describe the fellowship itself. we met with many challenges in the execution of this fellowship. the curriculum and overall fellowship plan have undergone many iterations. during the first fellow’s training, it was challenging to implement and maintain a schedule for didactic lectures. the process was more streamlined with the second and third fellows, and all requirements have now been satisfied. bureaucracy within the institutions of higher learning led to frequent delays. there have also been many successes: the curriculum was approved, and the fellows were appointed to the national health system (securing a position within the public sector). after the graduation of the first fellow, uasd took over patronage of the fellowship. this is perhaps the greatest sign of sustainability: that the local institution has now assumed the main role as sponsor. the goal of this fellowship is to improve urologic specialty care in the dominican republic. as the fellowship continues to mature, we hope to standardize urologic training in country, show sustainability, and strive for accreditation via the accreditation council of graduate medical education. future plans include expanding the program to other regional applicants as we form a center of excellence. conclusions a comprehensive genitourinary reconstructive surgery curriculum was developed and accredited by the prestigious new world university. concomitantly, the first formal training program in genitourinary reconstructive surgery and pelvic floor in the caribbean was established. success can be achieved only when there is partnership with local colleagues, and there is much work yet to be done. acknowledgments the authors would like to thank physicians for peace for their support, and dr charles horton, jr, for providing this opportunity. the guidance and mentorship of dr anulfo lopez was invaluable. they would like to thank dr merycarla pichardo for her support and sponsorship of the program in the dominican republic. they would like to particularly thank the docents of the program in chile and argentina, dr reynaldo gomez, dr leandro capiel, and dr carlos giudice for their dedication and teaching within the program. they owe a debt of gratitude to ms carmen baxley, surgical technician, for her unparalleled commitment to help those in need. this program would not have been possible without the support and care provided by dr ezequiel ferrara, anesthesiologist. author contributions dr virasoro and dr delong contributed equally to this work in program creation, management, and manuscript preparation. 111siuj.org siuj • volume 2, number 2 • march 2021 genitourinary reconstructive surgery curriculum and postgraduate training program development in the caribbean http://www.siuj.org references 1. zhang lp, silverberg d, divino cm, marin m. building a sustainable global surgery program in an academic 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surgery in reaching the un millennium development goals. plos med. 2008;5(8):e182. doi:10.1371/journal.pmed.0050182. 18. yao c a , taro t b, w ipfli hl , ly s, gillenwater j t, c os t a ma, et al. the tsao fellowship in global health: a model for international fellowships in a surgery residency. j craniofac surg. 2016;27(2):282–285. 19. riviello r, ozgediz d, hsia ry, azzie g, newton m, tarpley j. role of collaborative academic partnerships in surgical training, education, and provision. world j surg. 2010; 34:459–465. 20. aarabi s, smithers c, louis fils mm, godson jl, pierre jh, mukherjee j, et al. global surgery fellowship: a model for surgical care and education in resource-poor countries. j pediatr surg. 2015; 50:1772–1775. 21. roa l, jumbam dt, makasa e, meara jg. global surgery and the sustainable development goals.  br j surg. 2019;106(2):e44‐e52. doi:10.1002/bjs.11044 22. 22. kushner, adam l. operation health: surgical care in the developing world. johns hopkins university press, 2015. 23. blair kj, paladino l, shaw pl, shapiro mb, nwomeh bc, swaroop m. surgical and trauma care in lowand middle-income countries: a review of capacit y assessments. j surg research. 2017; 210:139–151. 24. farmer pe, kim jy. surgery and global health: a view from beyond the or. world j surg. 2008; 32(4):533–536. 25. saluja s, nwomeh b, finlayson srg, holterman a l , jawa rs, jayarman s, et al. guide to research in academic global surgery: a statement of the society of university surgeons global academic surger y committee. surgery. 2017; doi.org/10.1016/j. surg.2017.10.013. 112 siuj • volume 2, number 2 • march 2021 siuj.org original research http://dx.doi.org/10.1016/j.jsurg.2017.06.031 http://dx.doi.org/10.1016/j.jsurg.2017.06.031 http://www.siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. urology amidst the war on covid-19 bishoy hanna,1,2 stuart jackson,1,3 harry narroway,3,4 amanda chung2,5,6 1 nepean urology research group, nepean hospital, kingswood, australia 2 north shore urology research group, st leonards, australia 3 university of sydney, camperdown, australia 4 central coast local health district, gosford hospital, gosford, australia 5 department of urology, macquarie university hospital, macquarie university, australia 6 department of urology, university of sydney, concord repatriation general hospital, concord, australia abstract objectives we sought to review the impact of the covid-19 pandemic on the practice of urology internationally, with particular focus on the australian response. methods a literature search of pubmed was conducted using search terms “urology,” “coronavirus,” “covid-19,” and “surgery.” this generated 165 articles. the abstracts were reviewed for relevance, and 33 articles were selected, reviewed in depth, and information synthesised along with relevant government, surgical college, and urological society policy documents. results extensive health care changes have been implemented worldwide to curb infection rates. elective surgery cancellations have been widely mandated to curb infection rates with mixed success. whilst demand on hospital resources was reduced by up to 80%, the estimated cost to clear the surgical backlog in the uk has reached £100 million. strict perioperative precautions have also been employed with mandatory personal protective equipment for all surgical staff and guidelines fast tracked for safe aerosol-generating procedures. attempts to reduce exposure to patients and health care workers resulted in compromised operative time, blood loss, and length of hospital stay, with potential increased risk of shortand long-term complications. systemic changes to education and training have also been made. clinically, the cancellation of training examinations and a freeze on rotations and elective surgery restrictions have blunted surgical experience and teaching. the effect has rippled through junior doctor positions, with uncertainty remaining for training positions in 2021. conclusions the covid-19 pandemic is the greatest current challenge facing health care worldwide. amidst elective surgery restrictions, novel preoperative testing procedures and intraoperative precautions, providing safe and appropriate urological care is a major challenge. this review was derived entirely from expert opinion articles. further research into the virus is needed to bring the world safely through the pandemic, and post-pandemic recovery will likely be the next challenge. introduction the first reported cases of coronavirus disease 2019 (covid-19), which is caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2), originated in wuhan city, hubei province, china in december 2019[1]. the virus spread rapidly around the world and was declared a pandemic by the world health organisation (who) on march 11, 2020. at that time there were 118 000 cases in 114 countries with 4291 lives lost[2]. the exponential nature of the infection meant that by february 2021, there were 104.4 million reports cases worldwide with 2.3 million deaths[3]. figure 1 shows the growth in covid-19 deaths to the time of writing. key words competing interests article information urology, covid-19, coronavirus, pandemic none declared. received on september 27, 2020 accepted on february 8, 2021 soc int urol j. 2021;2(2):120–128 doi: https://10.48083/oobf6912 120 siuj • volume 2, number 2 • march 2021 siuj.org review mailto:bishoy.hanna%40icloud.com?subject=siuj https://10.48083/oobf6912 http://www.siuj.org the impact of t his pandemic is w idespread. internationally, governments face the challenge of imposing lockdowns, social distancing measures, personal protective equipment laws, and health care resource allocation to curb infection rates. given the unprecedented nature of the pandemic, policies are often guided by expert opinion in the absence of highlevel evidence base with potentially enormous economic consequences. measures have had varied success worldwide. health care administration is at the forefront of the covid-19 response. consequently, the global urological community grapples with maintaining patient safety by balancing potential delays in diagnosis and treatment of urological conditions against risks of covid-19 exposure and additional stress on health care resources. table 1 outlines the deferral protocols for urological surgeries at the height of pandemic restrictions. so far, the response has been relatively successful in australia and new zealand, with 10 and 4 covid-19 deaths per 1 million people respectively; however, australians are acutely aware that the covid-19 pandemic is far from over as one of the australian states, victoria, is coming out of a “second wave” of the infection. at the time of writing of this article, by way of comparison, the statistics abroad are 475 deaths per million in the united states of america, and 230 deaths per million in europe[3]. as the covid-19 pandemic is still active, the impact of policy measures on urological disease will not be apparent until the post-pandemic recovery period. this article describes the changes in urological practice in australia during the covid-19 pandemic in the context of the international response. methods a literature search of pubmed was conducted using search terms “urology,” “coronavirus,” “covid-19,” and “surgery.” this generated 165 articles. the abstracts were reviewed for relevance to the topic of this article, and 33 articles were selected, reviewed in depth, and information synthesised along with relevant government, surgical college, and urological society policy documents for the writing of this article. results and discussion elective surgery cancellations on march 26, 2020, all elective surgery in australia, with the exception of category a (within 30 days) and urgent category b (within 90 days), was suspended in an attempt to prepare for a covid-19 related surge in demand for health care resources[4]. this was swiftly followed by the urological society of australia and new zealand (usanz) guidelines for urological prioritisation[5]. the board encouraged shared decision-making with patients and consideration for individual hospital/health district/ country/state and territory health care resources. surgical guidelines are summarised in table 1. these guidelines were intended to provide urologists and their patients with a framework of priority. they empowered the decision to operate where appropriate given the risk of multiple contacts, whilst reassuring patients of the urological safety to defer. a recent systematic review compared 15 guidelines and recommendations for urology care during the pandemic[6]. the european association of urology (eau) was the only other international urological group to publish urological guidelines on practice during the pandemic, with all other guidelines being single expert opinion[7]. a comparison of the usanz and eau guidelines is summarised in table 1. the guidelines reflect not only the existing differences between australian and european urological practices but also the varied impact of the pandemic in these regions. for example, the australian guidelines did not figure 1. 121siuj.org siuj • volume 2, number 2 • march 2021 urology amidst the war on covid-19 http://www.siuj.org table 1. summary of the usanz and eau guidelines for urological prioritisation during the covid-19 pandemic condition operation consider proceeding with surgery consider deferral of surgery testicular cancer usanz • inguinal orchidectomy as planned • rplnd for progressive mass post chemotherapy eau • inguinal orchidectomy in 1-2 days • rplnd for progressive mass post chemotherapy within <6 weeks • stage ≥ iib seminoma or nsgct treat within <24 hours usanz • slowly growing mature teratoma eau • stage 1 seminoma for as renal cancer transplant usanz • rcc >7cm as planned • rcc complicated by venous thrombus as planned • upper tract ucc as planned eau • t3 within <6 weeks • high grade ucc within <6 weeks usanz • immunotherapy/chemotherapy with delayed cytoreductive nephrectomy in metastatic rcc setting eau • renal mass <4cm defer by 6 months • t1b-t2 rcc within 3 months • low risk ucc up to 3 months • cadaveric renal transplant up to 3–4 months (case by case discussion) • living donor up to 6 months prostate cancer usanz • high risk (select gleason 8–10) as planned eau • high risk post radiation within 3 months with immediate neoadjuvant adt usanz • intermediate and some high-risk cancers with initial adt and deferred definitive treatment • low risk with active surveillance eau • low risk postpone for 6–12 month and as defer for 6 months • intermediate risk to after pandemic • high risk treat within 3 months or postpone until after pandemic (anxious patient or n1 disease, consider adt and ebrt as alternative) bladder cancer usanz • surveillance ce +/turbt for high-risk nmibc only (cis and g3t1) eau • grade >ct1 treat within 6 weeks • mibc treat within 3 months (consider omitting neoadjuvant chemo in t2/t3 disease) • metastatic within 6 weeks (adjuvant chemotherapy if n+) usanz • neoadjuvant chemotherapy and delayed cystectomy for mibc (after discussion with medical oncology) eau • low grade surveillance defer by 6 months • high grade surveillance by 3 months • refractory cis by up to 3 months • mibc if palliative consider only radiation and chemotherapy adt: androgen deprivation therapy; as: active surveillance; ce: cystoscopy; cis: carcinoma in situ; idc: indwelling catheter; isc: intermittent self-catheterisation; mibc: muscle invasive bladder cancer; mri: magnetic resonance imaging; nmibc: non-muscle invasive bladder cancer; nsgct: non-seminomatous germ cell tumour; pirads: prostate imaging-reporting and data system; rcc: renal cell carcinoma; rplnd: retroperitoneal lymph node dissection; turbt: transurethral resection of bladder tumour. continued on page 123 122 siuj • volume 2, number 2 • march 2021 siuj.org review http://www.siuj.org table 1. summary of the usanz and eau guidelines for urological prioritisation during the covid-19 pandemic condition operation consider proceeding with surgery consider deferral of surgery macroscopic haematuria usanz • diagnostic ce if abnormal radiology or cytology eau • clot retention then within 24 hours usanz • diagnostic ce if normal investigations (delay for 1–2 months) eau • diagnostic ce up to 6 weeks if not in retention prostate biopsies usanz • pirads 4/5 on mri eau • mri showing locally advanced or highly symptomatic usanz • pirads <4 on mri • protocol based as evaluation eau • until after pandemic without mri or not suspicious for locally advanced/highly symptomatic turp usanz • chronic or acute urinary retention not suitable for idc or isc usanz • idc or isc where possible eau • idc or isc and postpone for 6 months endourology usanz • symptomatic stones as planned • obstructed or infected kidney as planned • stent in situ as planned eau • obstructed or infective kidney as planned usanz • non-obstructing ureteric or renal stones eau • non-obstructing renal stones for >6 months • non-obstructing ureteric stones for 3–4 months (manage renal colic with pain relief, avoiding nsaids where possible) • stent in situ for >6 months (after pandemic) scrotal usanz • torsion as planned eau • torsion as planned trauma usanz • penile as planned • urethral as planned eau • penile as planned adt: androgen deprivation therapy; as: active surveillance; ce: cystoscopy; cis: carcinoma in situ; idc: indwelling catheter; isc: intermittent self-catheterisation; mibc: muscle invasive bladder cancer; mri: magnetic resonance imaging; nmibc: non-muscle invasive bladder cancer; nsgct: non-seminomatous germ cell tumour; pirads: prostate imaging-reporting and data system; rcc: renal cell carcinoma; rplnd: retroperitoneal lymph node dissection; turbt: transurethral resection of bladder tumour. , cont’d 123siuj.org siuj • volume 2, number 2 • march 2021 urology amidst the war on covid-19 http://www.siuj.org recommend deferring endourological procedures for patients with ureteric stents in situ as the eau guidelines suggested. as europe is the second most affected continent, with 230 covid-19 deaths per million people compared with australia’s 10 per million, the differences in guidelines reflect the differing degree of health care resource demand. from tuesday, 28 april 2020, elective surgery restrictions were eased in australia. however, with a substantial second wave of covid-19 cases in victoria towards the end of june, elective surgery restrictions were reintroduced on thursday, 16 july 2020. with large fluctuations in case numbers, further reviews into scope of elective operating are likely before the recovery from the pandemic can begin. additionally, the future challenge of post-covid waitlist reduction and health impacts from ongoing untreated disease is not fully realised. one study modelled the proportion of elective surgery that would be cancelled or postponed during the 12 weeks of peak disruption[8]. they found that a global total of 2.95 million urological surgeries will be postponed during this period. in the united kingdom for example, based on an average cost of £4000 per operation, it would cost over £2 billion to clear the backlog. additional considerations such as costs of complicated disease progression, deaths due to untreated disease, and a differently structured health care system are other post-covid surgical challenges yet to be completely quantified. operative covid precautions once the decision is made that it is safe and appropriate to operate, operative measures are implemented to further optimise safety and mitigate infection risk. preoperative workup the royal australasian college of surgeons (racs) has published a rapid rev iew of literature and recom mend at ions for preoperat ive cov i d -19 assessment[9]. if high-risk features (viral symptoms and high-risk contacts) are identified on history, patients are recommended to have reverse transcription-polymerase chain reaction (rt-pcr) test to diagnose sars-cov-2, and in patients over the age of 70 years, a ct scan of the chest is also recommended. the rt-pcr test is 80% to 100% sensitive compared with the 60% to 70% sensitivity of nasopharyngeal and oropharyngeal testing[10]. racs recommends that surgery required within 24 hours in high-risk patients should proceed, with surgical staff wearing full personal protective equipment and taking appropriate intraoperative precautions, especially for potential aerosol-generating procedures (agps). the patient is then to be isolated postoperatively and tested for sars-cov-2 infection when possible. racs does not endorse testing asymptomatic patients with no high-risk features before surgery. this is mirrored by the american centers for disease control[11]. however, given that 5% to 80% of covid-19 patients are asymptomatic carriers, one systematic review article recommends testing all preoperative patients if the testing capacity is available[12]. recommendations for preoperative testing will be dictated by local health care providers and testing resources, turnaround time, and acuity of procedure must be balanced with the theoretical risk of an asymptomatic carrier exposing theatre staff to the virus. safe minimally invasive surgery several studies analysing viral shedding have not detected sars-cov-2 in urine[13–15]. however, one chinese study detected sars-cov-2 rna in the urine of 4 covid-19 patients requiring hospitalisation out of a total of 58 patients in the cohort[16]. viral particles have also been demonstrated in covid-19 patient blood samples[17]. consequently, non-urgent cystoscopies should be deferred and extra caution taken to minimise trauma during procedures. one american review on operative adjustments during the pandemic suggests the use of disposable ureteroscopes to further reduce the risk of contamination[12]. given the highest risk of aerosolization is during intubation and extubation, the anaesthesia patient safety foundation has further recommended that when possible, ureteric stents should be inserted under sedation[18]. during the pandemic, and particularly within areas of high case numbers and stretched health care resources, added consideration of nephrostomy tubes in the acute setting is also advised. however, this remains contentious. the american society of anaesthesiologists states that laryngeal mask airway may actually increase the risk of aerosolization of sars-cov-2 in the setting of high airway pressures and leakage around the mask[19]. furthermore, although monitored anaesthesia care avoids intubation and extubation, it could potentially require the anaesthesia provider to be closer to the patient’s airway and be a potentially greater risk if there is any issue requiring manual bagging or unplanned intubation. the society acknowledges that, because there is a lack of validated studies, this is expert opinion rather than practice guidelines. agps can generate bioaerosols that contain viral materials, which should be considered a potential source of disease transmission[20]. racs recommends using lower energy ablation devices, where possible, to produce fewer or no surgical plumes thus mitigating risk. all bioaerosols should be trapped and treated as biohazards. for laparoscopic procedures, the pneumoperitoneum should be maintained at a lower pressure to reduce the risk of gas leak. on desufflation, gas should be vented via an appropriate filter and capture device. despite a lack of firm evidence to prove sars-cov-2 particle 124 siuj • volume 2, number 2 • march 2021 siuj.org review http://www.siuj.org transmission through aerosolization, international guidelines also suggest similar precautionary measures. a review of the international guidelines into agps during the pandemic suggested steps to reduce the risk of aerosolization during release of pneumoperitoneum and diathermy until more information is available[12]. most guidelines suggest frequent suctioning of smoke in the pneumoperitoneum, avoidance of air leaks around ports and during instrument transfers, and care in removing ports, especially when pneumoperitoneum is still established. other techniques to consider include using balloon ports or trocars that can be secured to avoid pneumoperitoneum leaking at the port sites. ultimately, the choice of procedure should not compromise the patient outcomes. therefore, laparoscopy and robotics must be used when indicated. the surgeon should carefully weigh the pros and cons of each approach. in addition to reducing the exposure of the patient and health care workers, operating time, blood loss, length of hospital stay, and risk of shortand long-term complications should be considered. use of telehealth telemedicine allows the provision of health care remotely using electronic communication tools[21]. telehealth is aimed at helping protect health care professionals, their staff, and patients from unnecessary risk of infection by minimising contacts. large international prospective studies comparing telehealth with traditional face-to-face consultations have shown clinical equivalency, safety, and acceptable patient satisfaction in both prostate cancer and endourology settings[22,23]. although these benefits have been well established, barriers include the reluctance of patients— particularly the elderly—to use the technology, costeffectiveness, and security of communication links regarding personal (including health) data[24]. as a result, australia has been slow to embrace telehealth with uptake mainly restricted to remote communities for certain medical specialties such as nephrology. telehealth has been largely underused by urologists in australia. however, to facilitate continued safe health care, the australian government has fast tracked the use of telehealth by providing clinicians with subsidised telehealth equipment from 13 march[24]. similar provisions have been made in the united kingdom[25]. this allows clinicians to claim for consultations made via telehealth, which was previously not a widely available option. ethical considerations need to be made for delivering cancer diagnoses remotely, and judicious individualised patient care is paramount. the absence of cancer specialist nurses and increased isolation may worsen the impact of a cancer diagnosis delivered via telehealth. however, as the medical industry adapts to the pandemic, telehealth may persist and become routine practice because it is convenient, it allows increased access to regional patients, and it has proven efficacy. with increasing use, streamlined platforms will no doubt become available. furthermore, particularly within australia, virtual departmental meetings, multidisciplinary team meetings, and morbidity and mortality meetings offer similar benefits and are becoming increasingly popular. education and training the covid-19 pandemic has had a significant impact on national and international urological education and training. the usanz annual scientific meeting and all individual state meetings have been cancelled in australia along with the american urological association annual meeting. other international meetings such as the european association of urology congress and the société internationale d’urologie congress have moved to virtual platforms. with research resources shifted to covid-19, specifically vaccination development, the slowing of urological development is inevitable. clinically, the cancellation of training examinations, freeze on rotations, and elective surgery restrictions have blunted surgical experience and teaching. the effect has rippled through all training doctor positions from clinical medical student to advanced trainee, and uncertainty remains with respect to training positions for future years. similar disruptions have been observed in the uk and singapore, with all undergraduate clinical rounds being cancelled and all teaching activities (for residents and undergraduates) switched to the online platforms[26]. this will not only impact trainee clinical development but also increase junior doctor stress and burnout. with social distancing laws and community lockdowns increasing individual isolation, the added employment uncertainty raises significant concern for the mental health of junior doctors. australian rural experience australia is an expansive country, with 29% of the population living in rural or remote regions[27]. these areas are often hundreds of kilometres from metropolitan centres and are therefore reliant on under-resourced health care services. after the country weathered the largest bushfire disaster regional australia has ever experienced, covid-19 posed an additional challenge to communities that were just starting to recover. regional and remote urological care in australia is largely self-sufficient with transfer to larger centres generally reserved for critical deterioration or where multiple subspecialty services are required. many of these communities rely on f ly-in/f ly-out urologists, who also provide emergency surgical support whilst 125siuj.org siuj • volume 2, number 2 • march 2021 urology amidst the war on covid-19 http://www.siuj.org on site. as a result of elective surgical cancellations, urologists were f lying in more sparingly. emergency urological procedures were therefore being attended to by resident general surgeons or required atypical metropolitan transfer. this has led to increased time to definitive treatment such as scrotal exploration in the event of suspected torsion, and to greater reliance on interventional radiology for acute renal decompression in the event of obstructive uropathy. furthermore, all australians have exhibited more restrained health care practices. for example, data from the cancer council have shown that there were 14 4 982 fewer mammograms and 4 4 3 935 fewer cervical screening tests between january and june 2020, and 144 379 fewer bowel screening tests returned from january to july, compared with previous years[28]. similarly, patients are presenting later with haematuria, and t hose on active sur veillance for urologica l cancers are more likely to delay routine surveillance appointments to avoid contacts. this challenge is exaggerated in regional and remote communities, particularly amongst indigenous australians, where follow-up procedures and compliance are already fragile. however, as a result of geographical isolation, these areas were largely unaffected by covid-19, with infection rates very low and early travel restrictions preventing spread of the virus from metropolitan areas. most rural urological services have since returned to routine practice, with the pandemic highlighting the longstanding health care inequalities in these regions and challenging policy makers to provide solutions. conclusions the covid-19 pandemic is the greatest current cha llenge facing hea lth care worldwide. amidst elective surgery restrictions, novel preoperative testing procedures, and intraoperative precautions, providing safe and appropriate urological care is a major challenge. australia is fortunate to have successfully contained the pandemic and therefore to have had minimal disruptions. this can be attributed to fostering strong clinician-patient partnerships with the use of telehealth and swiftly implementing policies and procedures to minimise the risk of surgery on pandemic progression to provide optimal urological care. invariably, urological academic and clinical development is challenging during the pandemic and insight into mental health challenges for frontline workers needs to be considered and managed. this review was entirely derived from expert opinion articles, and further research into the virus including promising vaccination programs will be key to bringing the world safely through the pandemic with post-pandemic recovery likely being the next challenge. 126 siuj • volume 2, number 2 • march 2021 siuj.org review http://www.siuj.org references 1. what you need to know about coronavirus (covid-19): australian government; 2020 available at: https://www.health.gov.au/news/ health-alerts/novel-coronavirus-2019-ncov-health-alert/what-youneed-to-know-about-coronavirus-covid-19. accessed february 9, 2021. 2. world health organisation (who) director-general’s opening remarks at the media briefing on covid-19 11 march 2020. available at: https://www.who.int/dg/speeches/detail/who-director-general-sopening-remarks-at-the-media-briefing-on-covid-19---11-march-2020. accessed february 9, 2021. 3. coronavirus disease (covid-19) 2020. available at: https://www.who. 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https://www.aihw.gov.au/reports/rural-remote-australians/rural-remote-health https://www.aihw.gov.au/reports/cancer-screening/cancer-screening-and-covid-19-in-australia https://www.aihw.gov.au/reports/cancer-screening/cancer-screening-and-covid-19-in-australia http://www.siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj.org siuj • volume 4, number 4 • july 2023 key words competing interests article information bladder cancer, minimal residual disease, next generation sequencing, cell-free dna, circulating tumor dna, urinary tumor dna none declared. received on may 11, 2023 accepted on july 1, 2023 this article has been peer reviewed. soc int urol j. 2023;4(4):247–256 doi: 10.48083/ wjmb7232 247 original research — liquid biopsy utilizing cell-free urinary and plasma tumor dna to predict pathologic stage at radical cystectomy prithvi b. murthy,1 billie gould,2 facundo davaro,1 pan du,2 lucia camperlengo,1 shreyas naidu,1 kyle rose,1 scott m. gilbert,1 philippe e. spiess,1 wade sexton,1 g. daniel grass,3 rohit jain,1 xuefeng wang,4 joshua j. meeks,5 andrea necchi,6,7 liang cheng,8 shidong jia,2 roger li1 1 department of genitourinary oncology, moffitt cancer center, tampa, united states 2 predicine, hayward, united states 3 department of radiation oncology, moffitt cancer center, tampa, united states 4 department of biostatistics and bioinformatics, moffitt cancer center, tampa, united states 5 department of urology, northwestern university, feinberg school of medicine, chicago, united states 6 irccs san raffaele hospital and scientific institute, milan, italy 7 vita-salute san raffaele university, milan, italy 8 department of pathology and laboratory medicine, brown university, providence, united states abstract objective to assess the ability of cell-free urinary and plasma tumor dna (cfdna) to predict pathologic stage at radical cystectomy for patients with clinical muscle-invasive bladder cancer. methods a total of 25 patients with clinical muscle-invasive bladder cancer were enrolled before undergoing radical cystectomy. blood and urine were collected before surgery. the 600-gene predicineatlas panel was used to sequence blood buffy-coat germline dna, plasma cfdna, and urine cfdna samples. low-pass whole genome sequencing was performed on plasmaand urine-derived cfdna. cfdna tumor fraction (tf), genome-wide copy number burden (cnb), and estimated tumor mutational burden (tmb) were measured in both plasma and urine samples and their correlation with pathologic t-stage was examined. results three of 25 plasma samples had insufficient cfdna. in 22 of 22 plasma samples and 24 of 25 urine samples, at least one nonsynonymous somatic variant was detected. across the cohort, 44% of plasma variants were concordant with paired urine variants. the mean number of variants did not differ between noninvasive (< pt1/pn0) and invasive disease (≥ pt1 or n+) for both plasma (8 vs. 9.5 variants; p = 0.85) and urine (33.7 vs. 30 variants; p = 0.45). a strong correlation was observed between urine tf and urine cnb score within patients (rv = 0.92). plasma tf (r  = 0.38), urine tf (r  =  0.21), and urine cnb score (r  =  0.16) exhibited positive correlations with pt stage. patients with carcinoma in situ (cis) had higher mean urine tf and cnb scores ( p = 0.07 and p = 0.05, respectively). plasma tf and cnb score did not correlate with the presence of cis. conclusions combining plasmaand urine-based cfdna analysis may help identify patients with residual disease at radical, although we were unable to predict pathologic t-stage based on these metrics.the presence of cis may contribute to greater urinary cnb and tf levels. considering cis in the analysis may improve the ability to correlate tumor metrics with pathologic stage. low-pass whole genome sequencing–derived urinary cnb correlates strongly with urinary tf and may provide a less resource-intensive method for future longitudinal disease monitoring. http://siuj.org mailto:prithvi.murthy%40moffitt.org?subject=siuj 250 ng of gdna, 5–30 ng of plasma cfdna, and up to 30 ng urinary cf dna from urine supernatant were used for next-generation sequencing (ngs) library preparation, panel-based hybridization, and enrichment prior to 150-bp paired-end sequencing on the illumina novaseq 6000 platform (illumina, san diego, california, us). the plasma samples were sequenced using the 600gene clia-validated predicineatlas panel assay. the urine samples were sequenced using the predicinewes+ whole-exome panel, which includes approximately 20 000 genes and encompasses all regions present in the atlas panel genes. in this study, we compared variants in atlas panel genes only. in parallel, both plasma and urine samples were sequenced using low-pass (1–3x) whole genome sequencing (wgs). analyses of ngs data the data was analyzed using the predicine deepsea analysis pipeline, which begins with the raw sequencing data (bcl files) and produces the final variant calls. brief ly, the pipeline first performs adapter trimming, barcode checking, and correction, followed by paired fastq read alignment to the human reference genome build hg19 using the bwa software package. candidate variants, consisting of point mutations, small insertions, and deletions, are identified across the targeted regions covered in the panel. variant calling and annotation candidate variants with low base quality, mapping scores, and other quality metrics are filtered as part of the deepsea pipeline. sequencing and polymerase chain reaction (pcr) errors are also corrected using a previously described algorithm[11]. white-list variant annotations are applied to genomic regions that are found to be mutated at high frequency in cancer datasets from the catalogue of somatic mutations in cancer (cosmic), the cancer genome atlas (tcga), and internal predicine samples. in general, a variant identified in cfdna is considered a somatic mutation only if (1) at least three distinct fragments—at least one of the fragments with double-strand support; i.e. the mutation is observed on both dna strands—contain the mutation; and (2) the mutant allele frequency is higher than 0.25%, or 0.1% for white-list mutations—ie, mutations are observed at high frequency across different cancer types in public cancer databases; and (3) the ctdna variant–containing fragments are significantly over-represented compared to the matched pbmc sample, as determined by a fisher exact test (p value < 0.01 and odds ratio > 3). non-white– list variants with high variant frequency (> 30%) are considered suspicious germline variants. gene-level copy number variants are reported for both urine and plasma at clia-validated thresholds: copy number ≥ 2.18 (gain) or ≤ 1.85 (loss)[12,13]. candidate somatic mutations were annotated for their effect on protein-coding genes as well as probable pathogenicity using the clinvar database and annotation tool varsome[14]. intronic and silent changes were excluded from our analyses, while missense mutations, nonsense mutations, frameshifts, or splice site alterations were retained. we also excluded common germline variants annotated in the 1000 genomes, exac, gnomad, and kaviar databases with a population allele frequency > 0.5%. finally, chip variants were identified by comparing them with matched pbmc samples. variants in common chip genes (dnmt3a, tet2, asxl1, jak2, and ppm1d) were called chip mutations if there were supporting mutated fragments in matched pbmc samples. likely chip mutations were called for variants in genes such as tp53, atm, chek2, sf3b1, etc., which often share mutations in both chip and solid tumors, if there were supporting mutated fragments in matched pbmc samples and the fisher exact test was not statistically significant. copy number alterations and copy number burden copy number variation was first estimated at the gene level using the ngs panel data. the in-house pipeline calculates the on-target unique fragment coverage based on consensus bam files, which are first corrected for gc bias and then adjusted for probe-level bias (estimated from a pooled reference). each adjusted coverage profile is self-normalized (assuming diploid status of each sample) and then compared against correspondingly adjusted coverages from a group of normal reference samples to estimate the significance of each copy number variant. to call an amplification or deletion of a gene, we required the absolute z-score and copy number change to pass minimum thresholds. we measured genome-wide copy number burden with predicinecnb[15]. this score represents a comprehensive genome-wide measure of copy number variation adapted from the previously developed ichorcna method. to calculate the cnb score, the ichorcna algorithm was applied to gc and mappability-normalized reads to estimate plasma and urine copy number variations using a hidden markov model (hmm)[16]. first, we measured segment level (1 mb) copy number deviation as the log2 ratio of the normalized reads between a sample and normal plasma background (or used a normal gdna background for urine cnb). then, we quantified arm-level cnv deviation as the average of segment cnvs across each chromosome arm. our method also accounts for local cfdna fragment-size distributions. finally, we calculated sample-level copy number burden (cnb score) as the sum of absolute z-score of arm-level cnv deviation, where a higher cnb score indicates a greater absolute cnv abnormality compared to the normal background. introduction survival following radical cystectomy (rc) for urothelial carcinoma of the bladder is strongly influenced by the pathologic t-stage and the presence of lymph node metastasis[1,2]. patients with non–organ-confined disease or lymph node involvement have nearly 50% lower survival rates at 5 years. the ability to predict minimal residual disease has profound implications for patient management, especially considering that more than 60% of patients who are pt0 on transurethral resection before radical cystectomy harbor residual disease[3]. individuals with complete response or minima l residua l disease following neoadjuvant chemotherapy may opt for bladder-sparing therapies, while those with more aggressive disease may be counseled to receive additional cycles of chemotherapy or undergo prompt surgical resection. cell-free circulating tumor dna in the plasma (ctdna) and urine (utdna) are emerging as promising biomarkers for identifying the presence of bladder cancer, predicting pathologic complete response (pcr), detecting disease recurrence following rc, and assessing response to adjuvant immunotherapy[4–9]. though significant inroads have been made to maximize clinical utility, neither ctdna nor utdna has been shown to predict pathologic t-stage following rc. instead, binary outcomes related to the presence or absence of ct/utdna have been associated with survival following radical cystectomy[6,8]. in this study, we employed ultra-lowpass whole genome sequencing and ultra-deep–targeted sequencing of both utdna and ctdna to investigate the potential of these biomarkers for predicting pathologic stage prior to rc. materials and methods after obtaining institutional review board (irb) approval (mcc 21616), we prospectively enrolled 25 patients diagnosed with muscle-invasive bladder cancer (mibc) at h. lee moffitt cancer center between november 2021 and august 2022, prior to their radical cystectomy. patients with prior history of upper tract urothelial carcinoma or non-urothelial bladder cancer were not eligible for enrollment. a previous history of nonmuscle-invasive bladder cancer, with or without history of intravesical treatment, was not an exclusion criterion. all patients provided written informed consent and the study was approved by the institutional review board. treatment and surveillance followed accepted national guidelines. the multidisciplinary treatment team made recommendations regarding the omission of neoadjuvant chemotherapy, the performance of template-based lymphadenectomy, and the administration of adjuvant treatment. boardcertified genitourinary pathology specialists reviewed the pathologic specimens. postsurgical surveillance consisted of cross-sectional imaging, urine cytology, and laboratory assessment every 3 to 6 months. peripheral blood (10 ml) was collected in edta-containing tubes (streck cell-free dna bct, la vista, nebraska, us) 1 to 2 hours prior to surgery. within 2 hours of collection, whole blood underwent a 2-step centrifugation at 1600g for 10 minutes, followed by 320g for 10 minutes at 10 °c. plasma, buffy coat, and cell pellets were stored at –80 °c. urine was collected in a sterile container, with a minimum of 25 ml and a maximum of 45 ml immediately transferred into a 50-ml conical tube. within 15 minutes of collection, 5 ml of streck urine preserve was added. the capped specimen was gently inverted 10 times, followed by centrifugation at 3200g for 10 minutes at 25 °c. the supernatant was transferred without disturbing the cell pellet and frozen at –80 °c. dna extraction germline dna (gdna), and plasma cfdna derived from peripheral blood mononuclear cells (pbmcs) were extracted using a combination of established proprietary kits and in-house column-based methods, as previously described[10]. plasma and urinary cfdnas were extracted using a bead-based extraction protocol. twenty-three of 25 patients had adequate preoperative plasma samples for cfdna extraction. the quantity and quality of purified cfdna were assessed using a qubit fluorimeter (thermofisher scientific, waltham, massachusetts, us) and bioanalyzer 2100 (agilent technologies, california, us). for cfdna samples with significant genomic contamination from peripheral blood cells, a bead-based size selection was performed to remove large genomic fragments (ampure xp beads, beckman coulter, california, us). after quality assessment and quantification, up to abbreviations cnvs copy number variants cfdna cell-free dna ctdna circulating tumor dna gdna germline dna maf mutant allele fraction mibc muscle-invasive bladder cancer nac neoadjuvant chemotherapy ngs next-generation sequencing pbmcs peripheral blood mononuclear cells rc radical cystectomy snvs single nucleotide variants tf tumor fraction tmb tumor mutational burden utdna urinary tumor dna wgs whole genome sequencing 249248 siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org original research utilizing cell-free urinary and plasma tumor dna to predict pathologic stage at radical cystectomy http://siuj.org http://siuj.org variations in cfdna metrics based on tumor stage and presence of cis we assessed the cfdna tumor fraction (tf), genomewide cnb score, and estimated tmb using both plasma and urine samples. tf, determined based on observed mafs in the panel, had a mean of 3.5% (range, 0.66%– 11.5%) in plasma and a mean of 14.2% (range, 0%– 71.0%) in urine. genome-wide cnb score, determined based on copy number variation across the genome using low-pass sequencing, was also higher in the urine (mean, 7.6; range, 5.3–11.4), versus plasma (mean, 4.8; range, 3.6–7.3). there was a positive correlation between tumor fraction and cnb score calculated from plasma and urine (online supplementary figure 1). a strong correlation was also observed between urine tumor fraction and urine cnb score within patients (r = 0.92). using these metrics, we assessed the correlation between preoperative ut/ctdna burden and pathologic t-stage identified in the rc specimen. plasma and urine tf showed weak correlations with t-stage (figure 3a, r = 0.38 and 0.21, respectively). urine cnb score also showed a positive correlation with t-stage (figure 3b, r  =  0.16). the number of variants observed in plasma and subsequently the estimated plasma tmb showed the greatest difference between the group of 3 patients with noninvasive disease and the 22 patients with invasive disease, although the difference did not reach statistical significance (ptmb, 0.7 vs. 3.4, p  =  0.12, figure 1. online supplementary table 3). similarly, neither urineor plasma-derived cnb score nor tumor fraction could distinguish between noninvasive and invasive disease in this small group. despite the study lacking statistical power to evaluate the accuracy of combining metrics for predicting the presence of invasive vs. noninvasive disease in this cohort of patients, we noted that several patients with fewer than 5 variants detected in plasma still had a high urinary cnb score (online supplementary figure 2). thus, a combined approach using both plasma variant detection and urinary low-pass sequencing to determine cnb score might be useful for early detection of mibc. it is important to note that utdna metrics were strongly influenced by the presence of cis. both urine mean tf and cnb score were higher in patients with pure or concomitant cis (figures 4 a and b, p = 0.07 and p = 0.05, respectively). the correlations remained statistically significant or marginally significant while controlling for pathologic t-stage within cis/non-cis groups (multivariate regression coef = 0.63, p = 0.047 and coef  =  4.8, p  =  0.08, respectively). in contrast, plasma tf and cnb score did not exhibit significant correlations with the presence of cis. discussion deep sequencing of utdna and ctdna is increasingly used to help determine minimal residual disease in gene fusions dna rearrangement was detected by identifying the alignment break points based on the bam files before consensus filtering. suspicious alignments were filtered based on repeat regions, local entropy calculation, and similarity between reference and alternative alignments. to report a dna fusion, larger than 3 unique alignments (at least one of them double stranded) were required. tumor fraction the ctdna fraction was estimated based on the mutant allele fraction of autosomal somatic mutations, as described prev iously[17]. brief ly, under t he conservative assumption that each snv may have loss of heterozygosity, the mutant allele fraction (maf) and ctdna fraction are related as maf  =  (ctdna * 1) / [(1 – ctdna) * 2 + ctdna *1], and so ctdna = 2 / ((1 / maf) + 1). somatic mutations in genes with a detectable copy number gain were omitted from ctdna fraction estimation, thus only a subset of samples could have the ctdna fraction accurately estimated from mutation data. tmb score estimation bloodand urine-based tumor mutational burden (tmb) was defined as the number of somatic coding snvs, including synonymous and nonsynonymous va ria nts, w it hin pa nel ta rget reg ions. because tmb estimation considers all variants (including synonymous), higher variant call specificity is required. more stringent cutoffs were used for variant calls, and only variants with allele frequency ≥ 0.35% were used in score calculation. the tmb score was normalized by the total effective targeted panel size within the coding region. samples with the maximum somatic allelic frequency (msaf) < 0.7% were excluded from tmb estimation. outcomes and statistical analyses the primary objective was to investigate the ability of preoperative plasma and urine to predict pathologic disease stage at cystectomy. all differences between patient group means were tested using a wilcoxon test. correlations between tumor burden metrics and pathologic t-stage rank were measured using the spearman correlation coefficient. multivariate models to predict cis were fitted to the entire dataset using binomial logistic regression with pathologic tumor stage as a covariate. all tests were conducted in r version 4.3.0. results cohort clinicopathologic features and specimen analysis a total of 25 patients with clinically muscle-invasive bladder cancer underwent rc with curative intent (online supplementary table 1). all but 2 patients were diagnosed with mibc based on transurethral resection of bladder tumor. two patients with t1 disease on transurethral resection had cross-sectional imaging concerning for muscle invasion and were considered to have clinical mibc. nine received neoadjuvant chemotherapy (nac) followed by rc, and 16 underwent upfront rc. all surgical procedures were performed at a single institution. prior to surgery, both urine and plasma were collected from each patient on the day of rc. all 25 urine samples underwent quality control, and all of them passed urinary cell-free dna extraction quality control. however, 3 plasma samples failed the quality control test. of these, 2 plasma samples had low sample collection volume (< 2 ml), resulting in low cfdna extraction yields and the third sample had low sequencing depth, likely due to sample degradation. the plasma samples that passed the quality checks were subjected to sequencing across regions in the predicineatlas 600 gene targeted cancer panel using 150 bp paired end reads. plasma samples were sequenced at an average target depth of 31 000x and an average unique fragment coverage of 3454 fragments (n  =  22 patients). urine samples were sequenced at an average depth of 14 000x and an average unique fragment coverage of 3077 fragments (n = 25 patients). overall, we detected at least one nonsynonymous somatic variant in all plasma samples and 24 of 25 urine samples. across the cohort, we detected 656 non-synonymous single nucleotide variants (snvs) and indels, 377 genelevel copy number variants (cnvs), and 5 fusion mutations (online supplementary table 2). plasma samples exhibited a median of 5 snvs/indels (range, 1–36) and 1 cnv (range, 0–7). in contrast, patient urine samples showed a median of 17 snvs/indels (range, 0–77) and a median of < 1 cnv (range, 0–54). for concordant variants, the mutant allele frequency (maf) was almost always higher in urine than in plasma (figure 1a). overall, 44% of plasma variants were concordant with paired urinary variants (figure 1b). seven nonconcordant plasma variants and 44 nonconcordant urine mutations occurred within white-list genes (ie, genes mutated at high frequency across cancer types). concordance between plasmaand urine-derived variants ranged between 0% to 70% within patients (figure 1c). we observed somatic alterations in several genes previously associated with bladder cancer (figure 2)[18]. the most common mutations occurred in tert promoter (59%), kmt2d (59%), tp53 (55%), arid1a (45%), and kdm6a (41%). we also observed frequent mutations in genes associated with mibc, such as egfr (28%), rb1 (27%), erbb2 (27%), atm (20%), and fgfr3 (12%) (online supplementary table 2). overall, there was no significant difference in the mean number of variants between patients with noninvasive (< pt1/pn0) and invasive (≥ pt1 or n+) disease for both plasma (8 vs. 9.5 variants; p = 0.85) and urine (33.7 vs 30 variants; p = 0.45). 251250 siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org original research utilizing cell-free urinary and plasma tumor dna to predict pathologic stage at radical cystectomy http://siuj.org http://siuj.org http://siuj.org http://siuj.org http://siuj.org http://siuj.org http://siuj.org http://siuj.org nac followed by rc[8]. the researchers employed a tumor-informed approach to select 50 somatic variants per patient from transurethral resection specimens to create a custom sequencing panel. cfdna positivity was established by comparing patient-specific variants to all nonpatient-specific variants, and cfdna levels were monitored throughout the nac course using mean variant allele frequency. while the investigators were able to predict treatment response to nac based on utdna and ctdna clearance, they did not identify a significant figure 3. correlation between mean variant allele frequency of the samples collected after nac but prior to rc and pathologic stage at rc. in our study, 6 of 9 patients treated with nac showed a decrease in urinary tumor fraction post-treatment (median change in tf, –1.3%, data not shown). yet, neither urinary tumor fraction nor cnb levels could distinguish between noninvasive and invasive disease. future studies should focus on the specific alterations more frequently found in noninvasive versus invasive bladder cancer to improve disease staging. various bladder cancer settings[5,6,8,9,19]. significant advances in next-generation sequencing technologies and the integration of genome-wide tumor dna metrics have improved the ability to predict pathologic complete response to neoadjuvant chemotherapy and estimate survival after rc[6]. however, the accurate prediction of pathologic t-stage using quantitative cfdna metrics has not yet been demonstrated. consistent with previous studies, urine-derived cfdna exhibited a larger spectrum of unique tumor-derived alterations and higher mean mutant allele figure 2. frequency compared to plasma-derived cf dna[19]. furthermore, we obser ved a positive correlation between tumor fraction and cnb score derived from both utdna and ctdna with increasing pathologic t-stage. however, in this pilot study, we were unable to accurately predict the presence of invasive versus noninvasive residual disease before cystectomy. to examine the role of cfdna in predicting response to nac, christensen et al. used a custom next-generation sequencing panel to longitudinally assess urine and plasma samples on a cohort of 92 patients undergoing a b 253252 siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org original research utilizing cell-free urinary and plasma tumor dna to predict pathologic stage at radical cystectomy http://siuj.org http://siuj.org cohort received neoadjuvant chemotherapy, which may have an unknown impact on sample variant makeup. in this study, we lacked the power to test multivariate models, but we did find several non-concordant mutations between plasma and urine in white-list cancer-associated genes, highlighting the utility of mutational profiling using both urine and plasma. future work incorporating larger datasets is needed to reassess the value of combining cf dna and clinical features to predict the presence of invasive versus noninvasive disease. additionally, further studies should explore incorporating the sequencing of personalized markers derived from initial tumor tissue biopsy with the panel genes used in this study. conclusions we observed a positive correlation between both utdna and ctdna metrics with increasing pathologic t-stage in patients who underwent radical cystectomy. specifically, patients with cis on final pathology exhibited higher urinary copy number burden and tumor fraction. future assessments that control for the presence of cis may improve the ability to correlate cfdna metrics with pathologic staging. the observed changes in urinary tumor burden in response to treatment, along with optimized plasmaand urine-based cf dna metrics, may help to identify patients who are candidates for bladder preservation. the use of combined plasmaand urine-based liquid biopsy techniques holds promise in the early detection of mibc and the measurement of minimal residual disease during treatment. references 1. madersbacher s, hochreiter w, burkhard f, thalmann gn, danuser h, markwalder r, et al. radical cystectomy for bladder cancer today–a homogeneous series without neoadjuvant therapy. j clin oncol.2003;21(4):690–696. doi: 10.1200/jco.2003.05.101. pmid: 12586807. 2. stein jp, lieskovsky g, cote r, groshen s, feng ac, boyd s, et al. radical cystectomy in the treatment of invasive bladder cancer: longterm results in 1,054 patients. j clin oncol.2001;19(3)666–675. doi: 10.1200/jco.2001.19.3.666. pmid: 11157016. 3. bree kk, kokorovic a, westerman me, hensley pj, brooks na, qiao w, et al. repeat transurethral resection of muscle-invasive bladder cancer prior to radical cystectomy is prognostic but not therapeutic. j urol.2023;209(1):140–149. doi: 10.1097/ju.0000000000003015. pmid: 36250944. 4. ward dg, baxter l, ott s, gordon ns, wang j, patel p, et al.; bladderpath trial management group. highly sensitive and specific detection of bladder cancer via targeted ultra-deep sequencing of urinary dna. eur urol oncol.2023;6(1):67–75. doi: 10.1016/j. euo.2022.03.005. pmid: 35410825. 5. dudley jc, schroers-martin j, lazzareschi dv, shi w y, chen sb, esfahani ms, et al. detection and surveillance of bladder cancer using urine tumor dna. cancer discov.2019;9(4):500 –509. doi: 10.115 8/ 215 9 8 2 9 0.cd -18 0 8 25. p mid: 3 05 78 35 7; p mcid: pmc6467650. 6. chauhan ps, shiang a, alahi i, sundby rt, feng w, gungoren b, et al. urine cell-free dna multi-omics to detect mrd and predict survival in bladder cancer patients. np j precis oncol.2023;7(1):1–6. doi: 10.1038/ s41698-022-00345-w. pmid: 36658307; pmcid: pmc9852243. 7. powles t, assaf zj, davarpanah n, banchereau r, szabados be, yuen kc, et al. ctdna guiding adjuvant immunotherapy in urothelial carcinoma. nature.2021;595(7867):432–437. doi: 10.1038/s41586021-03642-9. pmid: 34135506. 8. christensen e, nordentoft i, birkenkamp-demtröder k, elbæk sk, lindskrog sv, taber a, et al. cell-free urineand plasma dna mutational analysis predicts neoadjuvant chemotherapy response and outcome in patients with muscle invasive bladder cancer. clin cancer res.2023;29(8):1582–1591. doi: 10.1158/1078-0432.ccr-22-3250. pmid: 36780195; pmcid: pmc10102843. 9. rose km, huelster hl, meeks jj, faltas bm, sonpavde gp, lerner sp, et al. circulating and urinary tumour dna in urothelial carcinoma  upper tract, lower tract and metastatic disease. nat rev urol.2023 march 28. doi: 10.1038/s41585-023-00725-2. pmid: 36977797. online ahead of print. 10. nese n, gupta r, bui mht, amin mb. carcinoma in situ of the urinary bladder: review of clinicopathologic characteristics with an emphasis on aspects related to molecular diagnostic techniques and prognosis. j natl compr canc netw.2009;7(1):48–57. doi: 10.6004/ jnccn.2009.0004. pmid: 19176205. moreover, we found a strong, direct association between cnb score calculated from low-pass wgs and panel-derived tumor fraction within the urine. cnb has been used as an alternative strategy for ctdna analysis because of its low cost and high sensitivity, even when plasma tumor fraction is low[20,21]. in a study aiming to predict minimal residual disease using utdna, chauhan and colleagues developed a random forest model incorporating copy number burden–derived tumor fraction from ultra-low-pass wgs, whole-exome–derived estimates of variant allele frequency, and inferred tumor mutational burden from all non-silent mutations[6]. survival estimates derived from this model aligned with progression-free and overall survival estimates stratified by pathologic complete response, helping to establish the utility of cnb-based analyses of liquid biopsy data. importantly, we observed that the presence of cis was associated with higher urine cnb scores and tf levels. cis is a well-described high-grade urothelial lesion characterized by cellular discohesion among other features[10]. due to the propensity of cis for exfoliation and shedding, the sensitivity of detecting cis compared to other noninvasive high-grade urothelial tumors is higher using both urine-based conventional cytology and f luorescence in situ hybridization assays[22–24]. our results support these findings and demonstrate higher concentrations of tumor-derived cf dna in the urine supernatant in the context of cis. as the disease burden of cis cannot be reliably estimated due to difficulty with cystoscopic identification, utdna may serve as an indirect measure of disease burden and treatment response. in addition, utdna may serve as a more reliable source for genomic studies of cis, as tissue-based studies have been notoriously difficult because of sample size limitations and the inability to comprehensively capture tumor heterogeneity. as cis has become an important component in therapeutic trials for nonmuscle-invasive bladder cancer, a reliable utdna test that correlates with tumor burden and treatment response may also serve as a molecular endpoint for future clinical trials[25]. further investigations of the utdna profile associated with cis are urgently needed. our assessment is limited by small sample size and the use of a single preoperative time point for urine and plasma sampling. in addition, a subset of our patient figure 4. a b 255254 siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org original research utilizing cell-free urinary and plasma tumor dna to predict pathologic stage at radical cystectomy http://siuj.org http://siuj.org 11. newman am, lovejoy af, klass dm, kurtz dm, chabon jj, scherer f, et al. integrated digital error suppression for improved detection of circulating tumor dna. nat biotechnol.2016;34(5):547–555. doi: 10.1038/nbt.3520. pmid: 27018799; pmcid: pmc4907374. 12. yu l, lopez g, rassa j, wang y, basavanhally t, browne a, et al. direct comparison of circulating tumor dna sequencing assays with targeted large gene panels. plos one.2022;17(4):e0266889. doi: 10.1371/ journal.pone.0266889. pmid: 35482763; pmcid: pmc9049497. 13. predicine | advancing precision cancer therapies. predicineatlastm. accessed june 22, 2023. https://www.predicine.com/solutions overview/atlas/ 14. kopanos c, tsiolkas v, kouris a, chapple ce, albarca aguilera m, meyer r, et al. varsome: the human genomic variant search engine. bioinformatics.2019;35(11):1978–1980. doi: 10.1093/bioinformatics/ bty897. pmid: 30376034; pmcid: pmc6546127. 15. davis aa, luo j, zheng t, et al. genomic complexity predicts resistance to endocrine therapy and cdk4/6 inhibition in hormone receptor– positive (hr+)/her2-negative metastatic breast cancer. clin cancer res.2023;29(9):1719–1729. doi: 10.1158/1078-0432.ccr-22-2177. pmid: 36693175; pmcid: pmc10150240. 16. adalsteinsson va, ha g, freeman ss, choudhury ad, stover dg, parsons ha, et al. scalable whole-exome sequencing of cell-free dna reveals high concordance with metastatic tumors. nat commun.2017;8(1):1324. doi: 10.1038/s41467-017-00965-y. pmid: 29109393; pmcid: pmc5673918. 17. newman am, bratman sv, to j, wynne jf, eclov nc, modlin la, et al. an ultrasensitive method for quantitating circulating tumor dna with broad patient coverage. nat med.2014;20(5):548–554. doi: 10.1038/ nm.3519. pmid: 24705333; pmcid: pmc4016134. 18. rober tson ag, kim j, al-a hmadie h, bellmunt j, guo g, cherniack ad, et al.; tcga research network. comprehensive molecular characterization of muscle-invasive bladder cancer. cell.2017;171(3):540–556.e25. doi: 10.1016/j.cell.2017.09.007. pmid: 28988769; pmcid: pmc5687509. 19. zhang r, zang j, xie f, zhang y, wang y, jing y, et al. urinary molecular pathology for patients with newly diagnosed urothelial bladder cancer. j urol.2021;206(4):873–884. doi: 10.1097/ju.0000000000001878. pmid: 34061567. 20. lee dh, yoon h, park s, kim js, ahn yh, kwon k, et al. urinary exosomal and cell-free dna detects somatic mutation and copy number alteration in urothelial carcinoma of bladder. sci rep.2018;8(1):14707. doi: 10.1038/s41598-018-32900-6. pmid: 30279572; pmcid: pmc6168539. 21. molparia b, nichani e, torkamani a. assessment of circulating copy number variant detection for cancer screening. plos one.2017;12(7):e0180647. doi: 10.1371/journal.pone.0180647. pmid: 28686671; pmcid: pmc5501586. 22. halling kc, king w, sokolova ia, meyer rg, burkhardt hm, halling ac, et al. a comparison of cytology and fluorescence in situ hybridization for the detection of urothelial carcinoma. j urol.2000;164(5):1768– 1775. pmid: 11025767. 23. owens cl, epstein ji. significance of denuded urothelium in papillary urothelial lesions. am j surg pathol.2007;31(2):298 –303. doi: 10.1097/01.pas.0000213333.02240.d0. pmid: 17255776. 24. levi aw, potter sr, schoenberg mp, epstein ji. clinical significance of denuded urothelium in bladder biopsy. j urol.2001;166(2):457–460. pmid: 11458047. 25. kamat am, sylvester rj, böhle a, palou j, lamm dl, brausi m, et al. definitions, end points, and clinical trial designs for non-muscleinvasive bladder cancer: recommendations from the international bladder cancer group. j clin oncol.2016;34(16):1935–1944. doi: 10.1200/jco.2015.64.4070. pmid: 26811532; pmcid: pmc5321095. 256 siuj • volume 4, number 4 • july 2023 siuj.org original research https://www.predicine.com/solutions-overview/atlas/ https://www.predicine.com/solutions-overview/atlas/ http://siuj.org 39siuj.org siuj • volume 1, number 1 • october 2020 molecular biomarkers in urologic oncology: icud-wuof consultation circulating tumour dna as a biomarker source in metastatic prostate cancer gillian vandekerkhove, alexander w. wyatt vancouver prostate centre, department of urologic sciences, university of british columbia, vancouver, canada abstract tumour molecular features are increasingly linked to treatment response and patient prognosis in advanced prostate cancer. plasma cell-free circulating tumour dna (ctdna) isolated from a minimally invasive blood draw offers a convenient source of tumour material to develop clinical biomarkers. importantly, the burden of ctdna in the blood has strong prognostic implications at different points during the natural history of metastatic progression. in prostate cancer, the identification of somatic profiles from ctdna requires a broad next-generation sequencing approach because of the low mutation rate and frequent structural rearrangements. nevertheless, comparison of genomic profiles between liquid and tissue biopsies has demonstrated that ctdna is a surrogate for tumour tissue in the metastatic setting. our understanding of resistance to androgen receptor (ar) directed therapies has been significantly augmented by the frequent detection of ar gene amplifications, mutations, and structural rearrangements via liquid biopsy. furthermore, early studies suggest that distinct molecular subtypes derived from ctdna profiling can help determine the optimal therapeutic regimen for an individual patient and enable real-time monitoring for therapy response and resistance. indeed, in clinical trials targeting the dna damage repair pathway in prostate cancer, ctdna-based assessment of dna repair status is already under evaluation as a predictive biomarker. recent advances in the study of circulating dna fragments now make it possible to interrogate aspects of the epigenome. in this review, we describe the various applications of plasma ctdna in metastatic prostate cancer, including its potential role as a clinically informative liquid biomarker. etiology of cell-free dna upon cell death, genomic dna fragments can diffuse into sur-rounding bodily fluids. the most familiar source of cellfree dna (cfdna) is peripheral blood, but it can also be purified from urine, sputum, cerebrospinal fluid, and ascites. in healthy individuals, the cfdna in each fluid is derived from cell types in the immediate neighbourhood. therefore, in blood plasma, most cfdna originates from hematopoietic cells [1,2]. with conventional extraction methodology, blood from healthy individuals yields about five nanograms of cf dna (approximately 750 diploid genomes) per milliliter of double-spun plasma [3]. plasma cfdna has a periodic 167 base pair fragment pattern consistent with apoptotic processing, representing the intervals at which caspase-activated dnase cleaves dna [4]. the presence of high molecular weight dna in processed plasma is indicative of pre-analytic failure; proper collection, storage, and processing of plasma cfdna is crucial to downstream success [5]. injury and disease can alter the etiology of cf dna [1,6,7]. in cancer patients, genomes from tumour cells undergoing apoptosis can be shed into body fluids. these tumour-derived cfdna fragments are termed circulating tumour dna (ctdna), and they can be detected against a backdrop of cfdna from benign cells using assays to identify somatic alterations or epigenetic marks. the half-life of cfdna is typically measured in hours but varies by the enzymatic activity in each body fluid [8]. moreover, the kidneys, liver, and spleen all clear cfdna fragments in circulating blood. this rapid turnover means that detection of ctdna in blood represents a real-time cancer biopsy. key words competing interests article information circulating tumour dna, cell-free nucleic acids, prostatic neoplasms, castrationresistant, liquid biopsy, recombinational dna repair, dna mismatch repair, androgen antagonists, biomarkers alexander wyatt reports personal fees from astrazeneca, grants and personal fees from jannsen, personal fees from bayer, outside the submitted work. gillian vandekerkhove reports no competing interests. received on june 25, 2020 accepted on september 8, 2020 soc int urol j. 2020;1(1):39–48 http://www.siuj.org mailto:awyatt%40prostatecentre.com?subject=siuj 40 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation abbreviations ar -gsrs androgen receptor genomic structural rearrangements cfdna cell-free dna ctdna circulating tumour dna hrr homologous recombination repair mcrpc metastatic castration-resistant prostate cancer mmrd mismatch repair deficiency parp poly (adp-ribose) polymerase pca prostate cancer wgs whole-genome sequencing approaches for cell-free circulating tumour dna analysis in cancer patients, the proportion of cf dna that is tumour-derived (ie, the ctdna fraction) is highly variable [9]. this variability cannot be easily estimated without profiling purified cf dna, and represents the major technical challenge for ctdna detection and characterization. assays must be highly sensitive to detect the possibility of rare ctdna fragments diluted in hundreds to thousands of normal cfdna fragments [10]. polymerase chain reaction-based approaches to detect or characterize ctdna rely on either prior knowledge of tumour genotype (eg, from whole-exome sequencing of the matched primary tumour) or the plausible presence of recurrent hotspot mutations. unfortunately, with the possible exceptions of the ar and spop genes, prostate cancer (pca) does not harbour highly recurrent hotspot mutations with obvious clinical relevance [11,12], thus broader approaches are required to capture the frequent genomic structural rearrangements and copy number changes [13]. at present, most clinical research using ctdna in pca has applied targeted next-generation sequencing approaches that capture a limited number of exons for a set of cancer-related genes [14]. because of the lower cost, targeted sequencing is preferable to conventional whole-exome or genome approaches. for tumour tissuebased analysis, sequencing coverage of 30x to 100x is adequate to characterize the somatic genome [15,16]. however, ideal sequencing depths for ctdna are typically above 1000x and often considerably higher [10]. this can be expensive, and hence the selection of genes or regions for cf dna sequencing is a delicate balance between cost, genome coverage, and desired detection sensitivity. most commercial assays cover several ubiquitous cancer genes that are relevant for pca, such as tp53, myc, and brca2. however, important pca genes that are not always present in historical pan-cancer approaches include spop, foxa1, and cdk12 [13]. the selection of regions to sequence within each gene must also be carefully considered; inclusion of intronic and untranslated regions can enable identification of structural rearrangements and gene deletions. in pca, pten, rb1, msh2, foxa1, and ar are often disrupted by structural rearrangements affecting introns [15,17– 20]. some of these genes can also be perturbed by partial or entire locus deletions. from an assay design perspective, comprehensive detection of structural rearrangement breakpoints requires probes tiled across introns. inclusion of introns (often spanning kilobases) in targeted sequencing assays can significantly increase the cost of ctdna profiling. the ctdna fraction of a sample determines the type of somatic alterations that can be detected. advances in library preparation techniques (eg, duplex unique molecular identifiers) and bioinformatic approaches (eg, digital error suppression) enable somatic mutation identification at ~0.1% frequency [21,22]. however, mat hematica l limits regarding t he detection of copy number changes cannot be easily overcome by technological improvements. for example, the detection of entire chromosome arm deletions typically requires a ctdna fraction of at least 5% (rare outside of progressing metastatic disease) when using reasonably cost-effective targeted sequencing approaches [23]. ctdna purity must be even higher to enable detection of focal deletions. in pca, several focal copy number changes have clear clinical relevance (eg, deletions affecting pten, msh2, brca2) [24]. therefore, cf dna assays should report ctdna fraction and discriminate between a true negative result (ie, tumour wild type status) and the inability to detect a change due to low tumour dna purity. i n re s e a rch s e t t i ngs , pc a c f dna s a mple s have been subjected to whole-exome or wholegenome sequenci ng [18, 23, 25, 26]. w hole-exome sequencing is genera l ly cost-justif iable only in samples with ctdna fractions above 20% to 40%, but in such scenarios can provide a snapshot of somat ic mutat ions a nd copy nu mber cha nges. deep whole-genome sequencing (wgs) of cf dna is not fea sible out side bespoke a na lyses, but low-pass wgs is a cost-effective alternative that has shown promise for wide uptake [27]. with this method, the entire genome is sequenced at a shallow depth, normally less than 1x. low-pass wgs can provide an estimate of ctdna fraction (although typically not below 3% to 5%) and yields a low resolution genome-wide copy number profile. since no targeted capture steps are required, it is cheap and quick to perform, and software packages for data analysis are publicly available [27]. however, low-pass wgs does not inform on somatic mutations, complex structural rearrangements, or focal copy number changes. furthermore, the continual improvement of modular capture assays and targeted designs incorporating genome-wide targets means http://www.siuj.org 41siuj.org siuj • volume 1, number 1 • october 2020 circulating tumour dna as a biomarker source in metastatic prostate cancer that it is possible to incorporate a backbone for wholegenome copy number profiling (eg, leveraging germline single nucleotide polymorphisms) into modern targeted sequencing assays. idea lly, deep sequencing of plasma cf dna is accompanied by sequencing of matched leukocytes as a germline surrogate. in addition to identifying pathogenic germline alterations affecting genes such as brca2 and tp53 [28], leukocyte sequencing also allows resolution of somatic mutations in cf dna related to clonal hematopoiesis of indeterminate potential rather than cancer [17,29]. in summation, these factors significantly impact the detection sensitivity of each cf dna profiling approach, and can lead to divergence in the results when comparing commercials tests with one another or with research assays [13,30,31]. mutations with low variant allele fractions are particularly unreliable, which is likely due to clonal hematopoiesis and somatic expansions. end users must be aware of the limits of detection for their chosen assay. ultimately, there is no single ctdna testing approach that can inform on all possible scenarios in prostate cancer, and therefore, the choice should be governed by the scientific or clinical question of the investigator. circulating tumour dna abundance as a prognostic biomarker t h e a b u n d a n c e o f c t dna i s a p o t e nt i a l l y clinically impactful variable, even without further characterization of molecular subtype. in metastatic castration-resistant prostate cancer (mcrpc), plasma ctdna abundance is associated with clinical measures of disease burden such as prostate-specific antigen level and the presence of visceral metastatic lesions [23,26,32– 34]. accordingly, high ctdna fractions are associated with poor overall survival and short progression-free survival in mcrpc patients treated with standard of care [23,32,35–37]. the converse is also true: low or undetectable ctdna appears to be a marker of good prognosis [23]. importantly, ctdna fraction in mcrpc appears to provide independent prognostic information to standard clinical factors, suggesting that assays of ctdna abundance could become part of prognostic models [23,37]. since ctdna abundance is closely related to the volume of proliferative disease, effective therapy has a rapid impact, and therefore blood collection before treatment or at clinical progression is recommended to maximize the chance of sufficient ctdna for genomic characterization [17,37,38]. in metastatic castrationsensitive pca, one week of androgen-deprivation therapy can reduce ctdna fractions by 10-fold [38]. in mcrpc, declines in ctdna are associated with prostate-specific antigen responses to abiraterone or enzalutamide, and patients with a rising ctdna fraction while on treatment are at greater risk of progression [26,39–41]. the detection of changes in ctdna fraction during treatment is a potential surrogate biomarker of response and should be explored in prospective biomarker trials. relationship of circulating tumour dna to tumour tissue biopsy tumour molecular features derived from liquid biopsies are typically expected to align with those from tissuebased analyses. in a study of 45 patients with mcrpc, deep targeted sequencing of same-day metastatic tissue biopsies and plasma cf dna collections demonstrated high concorda nce for t y pica l pca driver gene alterations such as tp53 mutation, ar amplification, spop mutation, and pten deletion [42]. in a parallel study, copy number profiles were highly concordant when applying low-pass wgs to mcrpc patientmatched tissue and ctdna [43]. more recently, high tissue-ctdna concordance for driver gene alterations has been reported in de novo metastatic castratesensitive pca [38], and even among genomically or pathologically distinct patient subsets such as those with somatic mismatch repair defects or neuroendocrine features [18,25]. collectively, the similarity between patient-matched tissue and ctdna is consistent with the findings from rapid autopsy studies in which the vast majority of truncal driver alterations were conserved across metastatic sites [44,45]. nevertheless, subclonal or late-arising alterations associated with acquired treatment resistance (eg, ar amplification or mutation), and neutral passenger mutations, are likely to vary between metastatic lesions and therefore between a single biopsy site and ctdna. dna damage repair defects as prognostic and predictive biomarkers dna damage repair defects are common in pca, particularly in metastatic disease [46,47], but their precise prognostic relevance is contingent on a number of factors. for example, there are several distinct dna repair pathways and hundreds of individual genes with different degrees of involvement. alterations in each pathway and even gene can have drastically different downstream genomic and clinical effects in addition to the specific class of alteration observed. the most commonly affected dna repair gene in mcrpc is brca2, which is altered at the germline and/or somatic level in ~10% of patients [15,48,49]. biallelic brca2 defects result in compromised ability to repair double-strand dna breaks and reliance on http://www.siuj.org 42 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation alternative repair pathways that are more error-prone in this context [50]. since monoallelic brca2 deletion is common in pca, allelic status is key to reporting pathogenicity. in mcrpc with high ctdna fractions, loss of heterozygosity across deleterious germline brca2 mutations is evident in ctdna, suggesting that cf dna sequencing could identify patients with functional brca2 loss [51]. it is plausible that broad cfdna sequencing will also be able to identify genomic signatures of defective homologous recombination repair (hrr), as has been demonstrated by tumour tissue sequencing [52,53]. prospective and retrospective studies have suggested that brca2 defects detected via leukocyte and cf dna sequencing associate with poor mcrpc outcomes in the context of ar-targeted therapy [23,37,51,54]. an association between plasma ctdna dna repair defects and poor outcomes has also been obser ved in metastatic castrationsensitive disease [37]. however, these associations appear variable across patient cohorts and were not confirmed in some retrospective studies using tumour tissue [55,56]. regard less, mcr pc wit h bia llelic brca2 defects are vulnerable to therapies exploiting defective hrr, such as platinum chemotherapy or poly (adp-ribose) polymerase (parp) inhibitors [57–62]. since a large minority of mcrpc have low levels of ctdna, practitioners must understand the context of a ‘negative’ result when using liquid biopsies to screen for hrr defects. if there is no evidence for ctdna in the sample, then the tumour may still carry somatic hrr alterations, and tissue testing should be pursued. most dna repair defects appear to be truncal to the metastatic lineage, so reflex testing of either archival primary tissue or metastatic biopsy is appropriate [18,63]. in pca, ot her hr r genes such as brca1, palb2, and rad51 are altered at frequencies below 1% [24,48,64]. it is plausible that affected mcrpc tumours are vulnerable to parp inhibitors, but to date no clinical trials have been powered to address this question. conversely, atm and cdk12 mutations are prevalent in mcrpc, but their direct association with hrr is tenuous, with unique implications for parp inhibitor response. cdk12 mutations are linked to a distinct tandem duplicator phenotype and poor prognosis with standard of care treatments [65–69]. in cdk12-mutant mcrpc, parp inhibitor response rates have been low, regardless of patient selection via liquid or tissue biopsy. the frequent tandem duplications in cdk12-mutant tumours may result in an elevated neoa nt igen burden a nd sensit iv it y to i mmu ne checkpoint blockade, but this hypothesis is untested in clinical trials [67,68]. conversely, atm mutations have not been linked to a genomic phenotype. the prognosis of mcrpc with atm mutations is unclear, but as with cdk12, response rates to parp inhibitors appear to be reduced in comparison to brca2 [62]. currently, prospective plasma ctdna sequencing is under evaluation in several phase ii/iii parp inhibitor clinical trials in mcrpc, and upon regulatory approval is likely to be key for patient biomarker screening. the largest hurdle to be overcome for reliance on plasma ctdna screening is the detection of brca2 biallelic deletions, which (unlike atm and cdk12) are recurrent in mcrpc. dna mismatch repair defects are present in 3% to 5% of mcrpc [18,24]. msh2 and msh6 alterations predominate and can take the form of complex structural rearrangements, thus complicating detection strategies [70]. like hrr-deficient tumours, those with mismatch repair deficiency (mmrd) display distinctive mutationa l signatures, including hy permutation (c > t transitions, particularly in the ncg trinucleotide context) and microsatellite instability. mmrd signatures can be detected in plasma ctdna from patients with mcrpc [17,18,71]. although high tumour mutational burden is not exclusive to mmrd etiology, in pca there are no other common causes of hypermutation, and assays assessing mutational burden in ctdna can be used [18]. patients with mmrd mcrpc may respond to immune checkpoint inhibitors [72]. in the context of dna repair defects and parp inhibitors, serial sampling can enable resistance me c h a n i s m id e nt i f ic at ion . brc a 2 re ve r s ion mutations can be detected in plasma ctdna at clinical progression on platinum chemotherapy or parp inhibitors [13,40,73–77]. plasma cf dna sequencing identifies a greater diversity of brca2 reversion mutations than biopsy of a single metastatic site [73]. it is plausible that regular plasma cfdna screening could detect emerging brca2 reversion mutations prior to clinical progression, offering opportunities for earlier interventions. ar mutations, amplifications, and genomic structural rearrangements missense mutations in the ar ligand-binding domain can alter ligand affinity and drive therapy resistance and/or indicate potential vulnerabilities. overall, ar mutations are found in ~10% of ctdna-positive mcrpc, but few point mutations are widely recurrent, principally l702h, w742l/c, h875y and t878a [23,32,33,39,78]. ar w742l/c mutations are a resistance mechanism to bicalutamide and are frequently identified in the plasma ctdna of bicalutamide treated patients. nextgeneration ar-targeted therapies have activity against ar w742l/c, meaning that its detection via liquid biopsy may predict durable responses to enzalutamide and abiraterone [23,39]. ar t878a and l702h tend to arise after therapy, permitting agonism of the ar by http://www.siuj.org 43siuj.org siuj • volume 1, number 1 • october 2020 circulating tumour dna as a biomarker source in metastatic prostate cancer progesterones and glucocorticoids, respectively [32,33]. while detection of these alterations in plasma cf dna is linked to poor outcomes, switching to different artargeted therapies or steroid regimens may be effective in some scenarios [79]. ar copy number gain is the most frequent category of ar gene alteration in mcrpc, enabling tumours to adapt to low androgen levels during treatment [15]. ar copy gain in plasma cf dna has been associated with shorter progression-free survival and overall survival in mcrpc patients treated with ar-targeted therapy [23,32,37,39,80–84]. however, measuring ar copy gain in plasma cfdna is complicated by variability in ctdna abundance between mcr pc patients. resolving a single extra ar gene copy requires a ctdna fraction of approximately 20%, whereas the signal from 8 ar copies can be detected at a ctdna fraction of only 5% [23]. in reality, ar gain is not binary, but rather a continuous variable capturing increasing ar copies, and an ar copy dose-effect relationship with patient prognosis is plausible in the advanced-disease setting [23]. interestingly, plasma ar copy gain ris not associated with poor outcomes in mcrpc patients treated with taxane chemotherapy, suggesting an opportunity for a predictive biomarker [85]. ar copy gain acquisition requires a series of structural rearrangements affecting the ar locus. genomic breakpoints falling within the ar itself are termed ar-gsrs (genomic structural rearrangements). some ar-gsrs result in a transcript coding for a truncated ligand-binding domain, similar in concept to the splice variant arv7 but usually distinct in nucleic acid sequence [86,87]. while the downstream consequences are challenging to predict from dna breakpoints alone, in vitro studies have suggested that select ar-gsrs give rise to constitutively active ar proteins and drive therapy-resistant phenotypes. ar-gsrs can be detected via ctdna sequencing of ar introns, and are linked to primary resistance to ar-targeted therapies [23,88]. the presence of ar-gsrs is positively correlated with ar copy number [86,89], and ar-gsrs appear to be more abundant in patients with late-stage disease than initial mcrpc progression [17]. other common genomic alterations as potential biomarkers the tumour suppressor tp53 is altered in over 50% of mcrpc [12,48]. tp53 alterations detected in plasma cf dna are linked to worse overall survival and poor response to ar-targeted therapy [23,79,89], independent of ctdna fraction and clinical prognostic factors [23]. pca lacking the tumour suppressor triumvirate of tp53, rb1, and pten are generally clinically aggressive and primed for lineage plasticity and rapid adaptation to therapy-induced bottlenecks [90,91]. potentially aggressive disease variants can be identified at an early stage through the detection of tp53, rb1, and pten alterations in ctdna [37]. conversely, spop mutations appear to be a good prognostic factor when identified in either ctdna or tissue [23,92]. pten deletion is the most common pi3k pathway alteration in mcrpc [48]. other alterations affect this pathway, including activating missense mutations in akt1 and pik3ca in 6% of patients [93]. tumours with pi3k alterations may be reliant on pi3k signalling for survival and therefore represent a therapeutic vulnerability. pten deletion appears to be a biomarker for selecting patients most likely to respond to pi3k pathway inhibition [94]. consequently, the pan-akt inhibitor ipatasertib is under evaluation in a phase iii clinical trial in mcrpc patients with pten defects (nct03072238). it is unclear whether other pi3k signalling pathway alterations will be relevant for ipatasertib response if the drug is approved. however, a recent ctdna-based study suggested that patients with somatic truncal hotspot mutations in akt1 or pik3ca are reliant on the pathway and may have strong responses to ipatasertib [93]. non-genomic information available in cell-free dna in addition to genomic alteration status, ctdna profiling can inform on aspects of the epigenome. nucleosomes protect cf dna from degradation by circulating nucleases, and their positioning can be inferred from whole-genome mapping of cfdna fragments. patterns of nucleosome spacing indicate tissue of origin and were crucial in demonstrating that plasma cfdna is largely derived from hematopoietic cells [1]. in addition, plasma cf dna fragmentation patterns vary between cancer patients and healthy individuals, indicating diagnostic potential [2]. lastly, the non-random fragmentation pattern of ctdna means that even transcription factor activity and gene expression can be inferred from wholegenome cfdna sequencing [95,96]. epigenetic marks, such as cytosine methylation, are tissueand cancer-specific features present on cfdna/ ctdna fragments [97,98]. therefore, tissue of origin can also be predicted through methylation profiling of cfdna [7,99]. importantly, the number of cell typespecific methylation marks in a tumour cell vastly outnumbers the somatic mutation count. therefore, plasma cf dna methylation assays have potential for greater ctdna detection sensitivity than assays reliant on capturing somatic mutations, especially in the context of early cancer diagnosis [97,98]. detection of prostate lineage methylation marks on cf dna can provide an accurate measure of ctdna fraction and http://www.siuj.org 44 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation even resolve patients with ar copy gain [100]. finally, a recent study demonstrated that in a subset of mcrpc patients with high ctdna fractions, simultaneous whole-exome sequencing and whole-genome bisulfite sequencing can identify neuroendocrine pca [25]. future directions true clinical translation of recent ctdna correlative research will require prospective clinical trials. in the context of dna repair and parp inhibition, cf dna analysis is part of patient screening protocols in several ongoing phase ii/iii trials [61]. the innovative probio clinical trial (nct03903835) is an outcome-adaptive, multi-arm, platform trial testing the utility of liquid biopsies to tailor treatment decisions in mcrpc [101]. the initial arms in this trial will test prognostic and predictive biomarkers for many of the current standard of care therapies such as abiraterone and cabazitaxel. pc-bets (nct03385655; also known as ind234) is another multi-arm umbrella trial, but set in a later stage than probio, testing investigative agents such as adavosertib, darolutamide, palbociclib, and ipatasertib. ctdna fraction as a potential biomarker is also being prospectively tested in the phase ii protract trial (nct04015622). in protr act, mcrpc patients who have progressed on abiraterone are randomized to physician’s choice of enzalutamide or docetaxel, or a biomarker-driven stratification based on pre-treatment ctdna fraction. the results from these and similar trials will be crucial for moving cf dna profiling towards routine clinical use in mcrpc. beyond prospective validation, there are several other hurdles that must be overcome before ctdna analysis will become part of standard clinical care. with the sensitivity of current technology, liquid biopsy will remain uninformative for somatic alterations in those patients with minuscule plasma ctdna levels, meaning that tumour tissue testing must remain part of the molecular diagnostics paradigm. teaching practitioners how to interpret liquid biopsy results will be key to development of workf lows that optimally use both ctdna and tissue testing at appropriate times during pca progression. furthermore, the current range of commercially available ctdna tests are not tailored for pca, and most of the translational studies described in this review leveraged bespoke research-based sequencing approaches that cannot be implemented in a large clinical system. therefore, the development of clinical-grade liquid biopsy assays that are specific for the unique genomic features of pca will help speed the uptake of ctdna testing in the real world. references 1. snyder mw, kircher m, hill aj, daza 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conteduca v, jayaram a, romero-laorden n, et al. plasma androgen receptor and docetaxel for metastatic castration-resistant prostate cancer. eur urol. 2019 mar;75 (3):36 8 –73. doi.org /10.1016/ j. eururo.2018.09.049 86. li y, yang r, henzler cm, et al. diverse gene rearrangements mediate resistance to androgen receptor inhibitors in metastatic prostate cancer. clin cancer res. 2020 apr 15;26(8):1965–76. http:// dx.doi.org/10.1158/1078-0432.ccr-19-3023 87. henzler c, li y, yang r, et al. truncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer. nat commun. 2016 nov 29;7:13668. doi. org/10.1038/ncomms13668 88. de laere b, van dam p-j, whitington t, et al. comprehensive profiling of the androgen receptor in liquid biopsies from castrationresist ant prost ate cancer reveals novel intra-ar struc tural variation and splice variant expression patterns. eur urol. 2017 aug;72(2):192–200. doi.org/10.1016/j.eururo.2017.01.011 89. de laere b, rajan p, grönberg h, dirix l, lindberg j; core-arvctc and probio investigators. androgen receptor burden and poor response to abiraterone or enzalutamide in tp53 wild-type metastatic castration-resistant prostate cancer. jama oncol. 2019 jul 1;5(7):1060–2.doi.org/10.1001/jamaoncol.2019.0869 90. beltran h, hruszkew ycz a, scher hi, et al. the role of lineage plasticit y in prostate cancer therapy resistance. clin cancer res. 2019 dec 1;25 (23):6916 –24. doi.org/10.115 8/10780 4 32. ccr-19-1423 91. hamid aa, gray kp, shaw g, et al. compound genomic alterations of tp53, pten, and rb1 tumor suppressors in localized and metastatic prostate cancer. eur urol. 2019 jul;76(1):89–97. doi.org/10.1016/j. eururo.2018.11.045 92. boysen g, rodrigues dn, rescigno p, et al. spop-mutated/ chd1-deleted lethal prostate cancer and abiraterone sensitivity. clin cancer res. 2018 nov 15;24(22):5585–93. doi.org/10.1158/10780432.ccr-18-0937 93. herberts c, murtha aj, fu s, et al. activating akt1 and 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sequencing of plasma cell-free dna for cancer detection and classific ation. ann oncol. 2 018 jun 1;2 9 (6):14 4 5 – 5 3. doi. org/10.1093/annonc/mdy119 98. shen sy, singhania r, fehringer g, et al. sensitive tumour detection and classification using plasma cell-free dna methylomes. nature. 2018 nov;563(7732):579–83. doi.org/10.1038/s41586-018-0703-0 99. sun k, jiang p, chan kca, et al. plasma dna tissue mapping by genome-wide methylation sequencing for noninvasive prenatal, cancer, and transplantation assessments. proc natl acad sci u s a. 2015 oct 6;112(40):e5503–12. doi.org/10.1073/pnas.1508736112 100. wu a, cremaschi p, wetterskog d, et al. genome-wide plasma dna methylation features of metastatic prostate cancer. j clin invest. 2020 apr 1;130(4):1991–2000. doi.org/10.1172/jci130887 101. lindberg j, de laere b, crippa a, eklund m, grönberg h. probio: an outcome-adaptive, multi-arm, open-label, multiple assignment randomised controlled biomarker-driven trial in patients with metastatic castration-resistant prostate cancer. ann oncol. 2019;30:354. doi.org/10.1093/annonc/mdz248.053 http://www.siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj.org siuj • volume 4, number 4 • july 2023 key words competing interests article information liquid biopsy, circulating tumor dna, prostate cancer, personalized medicine, next-generation sequencing none declared. received on december 3, 2022 accepted on june 10, 2023 this article has been peer reviewed. soc int urol j. 2023;4(4):273–286 doi: 10.48083/rfsh8912 273 review — liquid biopsy utility and clinical application of circulating tumor dna (ctdna) in advanced prostate cancer louise kostos,1,2 heidi fettke,2,3 edmond m. kwan,4,5 arun a. azad1,2 1department of medical oncology, peter maccallum cancer centre, melbourne, australia 2sir peter maccallum department of oncology, university of melbourne, melbourne, australia 3cancer research division, peter maccallum cancer centre, melbourne, australia 4vancouver prostate centre, department of urologic sciences, the university of british columbia, vancouver, canada 5bc cancer, vancouver centre, vancouver, canada abstract the treatment landscape for metastatic prostate cancer has undergone significant changes in recent years. the availability of next-generation imaging techniques and the emergence of novel therapies have led to earlier and more aggressive treatment approaches for patients. however, despite these advancements, drug resistance and progression to castration-resistant disease remain inevitable. understanding the molecular landscape of advanced prostate cancer lies at the forefront of being able to deliver personalized therapies and more robustly risk-stratify patients, when combined with clinical factors. advanced prostate cancer is characterized by interand intratumoral heterogeneity, posing challenges in comprehensively analyzing the genomic tumor profile using a solitary tissue sample. additionally, the disease often manifests as bone-predominant metastatic tumors, making biopsies impractical in many cases. moreover, archival tissue samples from a prostatectomy specimen may not accurately represent the current state of the tumor. to overcome these limitations, liquid biopsies using plasma samples have emerged as a minimally invasive surrogate approach to obtain real-time information on the genomic tumor profile. growing evidence confirms the excellent concordance of liquid biopsies with tissue samples, making them an attractive alternative to traditional tissue biopsies. these assays can provide predictive and prognostic information that may enhance patient discussions and influence treatment decisions. this review focuses on the evolution and utility of circulating tumor-derived dna (ctdna) liquid biopsy assays in metastatic prostate cancer. background despite recent treatment advances, metastatic prostate cancer (mpc) continues to be a leading global cause of cancerrelated death in men worldwide, with a 5-year survival rate below 30%[1–3]. the treatment landscape for advanced disease has become increasingly complex over the past decade, with the availability of multiple systemic therapies such as taxanes, androgen receptor pathway inhibitors (arpis), poly (adp-ribose) polymerase inhibitors (parpi), and targeted radioligand therapy. each of these therapies is administered alongside androgen deprivation therapy (adt). there is an emphasis on early treatment intensification with the introduction of these therapies as doublet and even triplet regimens for metastatic hormone-sensitive prostate cancer (mhspc)[4,5]. while some clinical subgroups achieve a clear survival benefit from these approaches, not all patients benefit from treatment intensification. lingering questions remain regarding the optimal timing of treatment intensification or de-intensification, the ideal duration of treatment, and the optimal sequencing of available therapies. therefore, there is an urgent need for novel predictive and prognostic biomarkers to assist with risk stratification and inform treatment decisions. to address this critical unmet need, it is crucial to prioritize the elucidation of the molecular landscape of advanced prostate cancer and apply it at an individual patient level. in this context, there is the continuous development of http://siuj.org tools for comprehensive molecular tumor profiling to guide treatment selection and sequencing. currently, the gold standard approach for molecular biomarker assessment is analysis of tumor tissue[6]. however, collecting adequate tumor tissue in mpc, which often develops with bone lesions and deep abdominal lymph nodes, is not always feasible, with invasive biopsies often associated with significant procedural morbidities and low-quality samples that preclude serial, multisite biopsies[7–9]. moreover, characterizing molecular changes during therapy and upon disease progression is challenging, potentially leading to the oversight of resistance-conferring or novel clinically actionable clones[10]. this is especially important considering that the lethal clone involved in metastatic dissemination may not originate from the dominant foci of the primary prostate tumor[11]. liquid biopsy approaches to molecular tumor characterization have gained attention as attractive surrogates for tumor biopsy in advanced prostate cancer over the past decade. liquid biopsies commonly detect biomarkers such as circulating tumor cells (ctcs), cell-free dna (cf dna) or rna (cf rna), proteins, and extracellular vesicles[12]. among these, plasma cfdna has garnered the most interest because of its ease of sampling and established isolation and preparation protocols. the proportion of tumor-derived cf dna is referred to as circulating tumor dna (ctdna), and although it is found in all fluid compartments of the body, it is best characterized from plasma. furthermore, its short halflife (minutes to hours) and the ability to simultaneously profile both local and distant sites make it an ideal substrate for providing a comprehensive “snapshot” of the tumor[13–15]. the current landscape of ctdna in prostate cancer since the initial discovery of the connection between cancer and cfdna in 1994, the field of ctdna analysis in oncology has rapidly expanded, with fda-approved commercia l assays a nd compa nion diagnost ics becoming standard-of-practice for genomic profiling in many cancer types[13,16,17]. in 2015, azad et al. published the earliest clinical research involving genomic analysis of plasma ctdna in advanced prostate cancer. the authors successfully identified somatic androgen receptor (ar) point mutations and focal copy number gains using targeted next-generation sequencing (ngs) and array comparative genomic hybridization, respectively[18]. furthermore, they reported an association between plasma-detectable ar alterations and primary resistance to the arpi enzalutamide, providing evidence that ctdna can be exploited to identify and understand contemporary biomarkers. subsequent studies have shown that in mpc, ctdna is a high-fidelity substitute for solid tumor tissue-derived dna and is capable of not only recapitulating the somatic landscape of a tumor but also identifying clinically relevant driver alterations missed by a single metastatic biopsy[10,19–21]. additionally, through serial sampling before and during treatment, ctdna has the potential to monitor tumor progression, provide prognostic information, and thus dictate tailored treatment plans[22,23]. the investigation of ctdna biomarkers to prognosticate mpc and predict response to targeted therapies has become widespread, with liquid biopsy collection often incorporated into clinical trial design[24–27]. technical considerations for ctdna analysis as ctdna gains significance in guiding precision-based care for men with mpc, a myriad of approaches and technological platforms is being employed (table  1). understanding which approach will provide the most robust data for a particular research question is crucial to translating ctdna assays into the clinic. advanced prostate cancer can be detected in 60% to 90% of patient plasma samples, with the ctdna fraction varying widely among patients[10,21,28]. consequently, high assay sensitivity is essential to avoid excluding patients from data analysis and minimize false-negative results t hat may compromise biomarker identif ication. currently, ctdna analysis techniques can be broadly categorized as candidate gene approaches (for < 10 loci) and high-throughput approaches[13]. low-throughput candidate gene approaches such as digital droplet polymerase chain reaction (pcr) assays, have the highest sensitivity, enabling the detection of somatic mutations below 0.002% allelic frequency[29,30]. these approaches are valuable for monitoring treatment resistance and minimal residual disease when the targets are already known. high-throughput techniques such as ngs provide an unbiased approach to genomic analysis and are the preferred method for identifying mechanisms of treatment resistance and novel genomic biomarkers[31]. however, they are typically less sensitive and more expensive than candidate gene approaches. recent advances in ngs technology, however, such as the inclusion of molecular barcoding, patient-specific custom panels, and significant cost reductions for shortread sequencing have enabled the detection of somatic alterations below 0.5% allelic frequency[32]. these improvements also allow for the detection of focal copy number abnormalities, which are crucial for examining the landscape of mpc. previously, the prostate cancer genome was thought to be associated with few focal chromosomal gains or losses, but it is now clear that focal copy number alterations, such as focal deletions in pten or focal ar amplifications, play an integral role in tumor evolution and disease progression[33]. in addition to these pre-analytical assay decisions, the selection and design of the bioinformatics workflow used to profile ctdna are crucial. mpc is typically characterized by high levels of copy number abnormalities, structural rearrangements, and genomic heterogeneity among lesions[34,35]. therefore, a comprehensive approach capable of detecting point mutations, structural variants, copy number variants, and low-frequency subclonal somatic mutations is necessary for robust profiling of the prostate cancer genome. application of ctdna in metastatic castration-resistant prostate cancer most genomic studies have been conducted in patients with metastatic castration-resistant prostate cancer (mcrpc), initially using tissue samples and more recently incorporating plasma cf dna analysis. liquid biopsies exhibit excellent concordance with tissue samples and represent an attractive alternative to molecular profiling of the tumor[10,15]. as a peripheral blood sample contains ctdna from multiple sites, this liquid biopsy approach has the added benefit abbreviations adt androgen deprivation therapy ar androgen receptor arpi androgen receptor pathway inhibitor cfdna cell-free dna cnvs copy number variants ctdna circulating tumor dna ddr dna damage response and repair hrr homologous recombination repair ici immune checkpoint inhibitor ihc immunohistochemistry mcrpc metastatic castration-resistant prostate cancer mhspc metastatic hormone-sensitive prostate cancer mpc metastatic prostate cancer msi microsatellite instability ngs next-generation sequencing os overall survival parpi poly (adp-ribose) polymerase inhibitors pcr polymerase chain reaction pfs progression-free survival psa prostate-specific antigen snvs single nucleotide variants svs structural variants tmb tumor mutational burden of capturing interand intratumoral heterogeneity, thereby offering valuable insights to inform treatment decisions that would otherwise be missed in a single-site metastatic biopsy. the potential clinical applications of ctdna in mcrpc are outlined below (figure 1). pretreatment ctdna fraction and profile for prognostication the prognostic value of pretreatment ctdna levels has been firmly established in mcrpc, showing that higher ctdna fraction is associated with shorter progressionfree survival (pfs) and overall survival (os) regardless of treatment received[10,18,47]. in a study evaluating 202 patients with mcrpc receiving first-line treatment with the arpis enzalutamide or abiraterone acetate, a high ctdna fraction (> 30%) was associated not only with increased tumor burden (as indicated by elevated plasma levels of prostate-specific antigen [psa], lactate dehydrogenase [ldh], and alkaline phosphatase [alp]) but also with poor response to treatment even after adjusting for established clinical prognostic factors[48]. similarly, a high baseline ctdna fraction prior to taxane chemotherapy was associated with shorter radiographic pfs and os, independent of other prognostic variables[49]. furthermore, specific genomic abnormalities detected in ctdna have prognostic i mpl icat ions for t reat ment outcomes. pat ients treated with abiraterone acetate or enzalutamide who had baseline aberrations in tumor suppressor genes (tp53, rb1, or pten) exhibited worse survival outcomes compared to those who tested negative at baseline or showed undetectable levels by cycle 2 of treatment[47,48,50,51]. therefore, a high pretreatment ctdna fraction and the presence of tumor suppressor aberrations can facilitate informed discussions with patients about their treatment options and expected outcomes and potentially support a more aggressive approach to systemic therapy. longitudinal monitoring of treatment response trad it iona l ly, seria l ser u m psa measu rements have been used to monitor response to treatment in mcrpc. however, psa has limitations, as radiographic progression can occur in the absence of a psa rise, and heavily pretreated patients with ar-independent disease may have no or low levels of psa, making interpretation of potential response challenging[52,53]. serial ctdna assays offer an alternative method for treatment monitoring. an early reduction in cf dna concentration or fraction (within the first 9 weeks) has been associated with longer pfs and os in patients with mcrpc patients treated with taxanes, arpis, and parp inhibitors[54–57]. this finding was maintained even after adjusting for known clinical risk factors. similarly, a lack of response or persistent rise in ctdna fraction has been associated with shorter pfs[57]. 275274 siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org review — liquid biopsy utility and clinical application of circulating tumor dna (ctdna) in advanced prostate cancer http://siuj.org http://siuj.org sample. germline alterations can usually be detected through simultaneous analysis of leucocyte samples extracted from the buffy coat of peripheral blood after centrifugation. determination of hrr status not only informs whether the patient can benefit from a parp inhibitor but also predicts a favorable response to platinum chemotherapy[71]. it is important to note that clonal hematopoiesis of indeterminate potential involving dna repair genes may lead to false-positive results, and therefore ctdna samples should be accompanied by a whole blood control to exclude such variants[72]. prostate cancers with pten loss are more sensitive to akt inhibition, as demonstrated by the radiographic pfs benefit when combining the akt inhibitor ipatasertib with abiraterone acetate for patients with mcrpc and pten loss identified through tumor immunohistochemistry[73]. pten loss is also predictive of a poor response to abiraterone acetate while retaining sensitivity to docetaxel[74,75]. the prevalence of pten loss through cf dna assay is comparable to that found in tissue, potentially eliminating the need for archival tissue or a fresh biopsy[76]. prostate cancer is typically considered immunogenically “cold” due to minimal t-cell infiltrates failing to generate a significant peripheral antitumor response, with limited benefit from immune checkpoint inhibitor (ici) therapy in unselected cohorts[77–79]. however, a subset of prostate cancer exhibits an immunogenic phenotype that may benefit from such therapy. early detection of treatment resistance analysis of genomic alterations in patients with mcrpc has identified both primary and acquired mutations associated with treatment resistance. with the increasing integration of arpis earlier on in the mpc disease course, resistance and the development of aggressive neuroendocrine prostate cancer may become more prevalent[52,58]. therefore, it is crucial to use ctdna biopsies to investigate markers of arpi resistance. the presence and magnitude of ar gene amplification have been associated with shorter pfs and os[48,59–61]. some ar short variants are more frequently detected in liquid biopsy samples than in tissue biopsies, making ctdna an ideal tool for early detection of treatment-resistant clones[21]. this discordance between plasma and tissue is likely due to intratumoral heterogeneity in ar gene expression[62] and the ability of liquid biopsies to integrate genomic information from multiple metastatic sites. ctdna may also be used to predict resistance to parpi by detecting acquired brca reversion mutations, which are also more frequently detected in liquid biopsy samples compared to tissue and are thought to predict a poor response to parpi[21,63]. however, a recent analysis of patients with brca-mutant mcrpc enrolled in the triton2 trial suggests this may not be the case, as patients who developed a brca reversion mutation while receiving rucaparib experienced better treatment outcomes[64]. in addition to detecting specific genomic aberrations, dynamic changes in ctdna levels during table 1. general comparison of ctdna analysis platforms used in advanced prostate cancer approach detection method genomic elements tested limit of detection (vaf) variant types detected estimated turnaround time cost volume of plasma required strengths limitations clinical uses references high-throughput wgs entire genome 5%–10% snvs, indels, cnvs, svs, fusions, rearrangements 4–6 weeks high 10–20 ml provides comprehensive genomic information, no prior knowledge of loci required high cost, time-consuming, requires complex bioinformatic analysis comprehensive genomic profiling, identification of rare or novel alterations [36–39] wes exons 5%–10% 3–4 weeks moderate 10–20 ml focuses on protein-coding regions of the genome, no prior knowledge of gene required high cost, time-consuming, misses noncoding regions, requires bioinformatic analysis identification of novel targets and mechanisms of treatment resistance [39–42] targeted ngs panel of genes/regions 1%–5% 2–3 weeks moderate 5–10 ml cost-effective and allows focused analysis, high sensitivity high-cost, requires bioinformatic analysis, limited to selected targets, some methods cannot detect cnvs or svs targeted profiling, and monitoring of known alterations, i.e., mrd detection [39,42–44] candidate gene digital pcr specific mutations ≤ 0.01% snvs, indels, known mutations 1–2 weeks low 1–5 ml cost-effective, highly sensitive and precise detection of mutations limited to known mutations and loci detection of specific mutations for treatment allocation, monitoring treatment response [39,45,46] conventional pcr specific genes/regions < 1%–5% 1–2 weeks low 1–5 ml cost-effective and allows targeted analysis, no bioinformatic analysis required limited to known targets, most methods only detect snvs targeted mutation analysis [39] cnvs: copy number variants; ctdna: circulating tumor dna; indel: insertion/deletion; mrd: minimal residual disease; ngs: next-generation sequencing; pcr: polymerase chain reaction; snvs: single nucleotide variants; svs: structural variants; vaf: variant allele frequency; wes: whole exome sequencing; wgs: whole genome sequencing. therapy are also valuable for early detection of a lack of treatment response or the development of progressive disease. early reductions in plasma ctdna levels from baseline have been observed in patients prior to clinical determinants of treatment response[65], while persistent detectable ctdna have been associated with worse outcomes[47,49,66]. facilitating selection of personalized treatment one of the most important advantages of ctdna analysis is the ability to identify potentially actionable genomic aberrat ions, enabl i ng t he del iver y of personalized treatment plans (table 2). detecting ar gene amplifications from the outset may assist clinicians in providing tailored treatment plans, potentially favoring taxane chemotherapy due to the known resistance to arpis[67]. with the introduction of parpi such as olaparib and rucaparib for patients with homologous recombination repair (hrr) gene mutations[68,69], guidelines now recommend testing all patients with mcrpc for somatic and germline pathogenic hrr aberrations, including brca1 and brca2[70]. typically, this testing is conducted on tissue samples, which often suffer from compromised dna quality as they are archival pretreatment samples. however, ctdna analysis provides an easily accessible alternative for hrr status testing, showing excellent concordance with tissue samples for hrr-related gene mutations[21,56], although this depends on tumor content (ie, ctdna fraction) in the biomarkers detectable in cfdna assays can help identify these patients and provide a rationale for treatment. a recent analysis found that patients with mcrpc and a tumor mutational burden (tmb) of greater than 10 mutations per megabase respond better to ici therapy than chemotherapy[80]. similarly, patients with mcrpc whose tumors harbor cdk12 mutations[81,82] and high microsatellite instability (msi)[83] have shown vulnerability to ici therapy. both cdk12 mutations and msi can be detected using plasma ctdna platforms, showing high concordance with matched tissue samples[84,85]. somatic mutations in genes responsible for regulating the wnt signaling pathway are found in up to 20% of patients with mcrpc[43,86]. activating mutations in the wnt pathway, such as ctnnb1, are associated with resistance to arpi, and ctnnb1 mutations occur more frequently in mcrpc cfdna samples that have progressed on enzalutamide[50,87]. consequently, the wnt pathway has become an attractive target for therapeutic intervention, leading to extensive preclinical research into wnt pathway inhibitors[88]. despite the interest and development of several novel agents, wnt-pathway–directed therapies are yet to be approved for clinical use. finally, the transition to ar-independent mpc is driven by lineage plasticity and can result in neuroendocrine differentiation. confirming neuroendocrine features requires a repeat biopsy, which can be challenging due to tumor heterogeneity and the associated morbidity of metastatic biopsies. neuroendocrine 277276 siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org review — liquid biopsy utility and clinical application of circulating tumor dna (ctdna) in advanced prostate cancer http://siuj.org http://siuj.org of tumor suppressor gene alterations in tissue samples is associated with early relapse and worse outcomes[95,96]. in plasma samples, baseline alterations in dna damage response and repair (ddr) genes and loss-of-function alterations in tp53 are likewise associated with poorer pfs and os[35]. untreated mhspc patients with somatic ddr mutations had significantly shorter os and a shorter time to adt failure[35], while the presence of germline ddr alterations predicted shorter time to developing castration-resistant disease[98,99]. such findings can assist clinicians with risk stratification and deciding when to intensify upfront treatment for patients with mhspc. patients with poor prognostic factors present at baseline, such as a high ctdna fraction and/or ddr or tumor suppressor alterations, may be considered for a more aggressive treatment regimen or enrolment in clinical trials. conversely, the absence of detectable ctdna at baseline or the absence prostate cancer is enriched with tumor suppressor gene alterations (such as tp53, pten, rb1), heralding an aggressive disease phenotype resistant to standard therapeutic approaches[89,90]. cf dna methylation assays matched with tissue samples have shown high concordance for identifying neuroendocrine features, potentially serving as a future surrogate for tissue biopsies in cases where neuroendocrine transformation is suspected. ctdna analysis is now being integrated into clinical trials, both as a supplementary test conducted alongside treatment and, more recently, as a means of determining treatment. there are two ongoing biomarker-directed clinical trials (probio and pc-bets) using ctdna analysis to guide treatment allocation in mcrpc[91–93]. metastatic hormone-sensitive prostate cancer the benefits of ctdna in mhspc are less established compared with mcrpc, primarily because of the table 2. examples of the clinical significance of specific ctdna findings in advanced prostate cancer disease setting ctdna finding clinical significance mhspc baseline ctdna fraction • higher pretreatment ctdna fraction is predictive of adt failure, shorter metastasis-free survival and os[35,94]. baseline tumor suppressor gene alterations • associated with early relapse and worse survival outcomes[95,96]. • abiraterone acetate + adt less effective compared to patients without tumor suppressor gene alterations[97]. baseline ddr alterations • somatic ddr mutation associated with shorter pfs and os[35]. • germline ddr alterations predictive of a shorter time to developing castration-resistant disease[98,99]. baseline ar aberrations • any ar aberration was associated with poor os compared to patients without detectable ar alterations[100]. spop mutation • predictive of a favorable response to arpis and improved survival outcomes[101,102]. mcrpc ctdna fraction • higher ctdna fraction correlates with shorter pfs as well as os regardless of treatment received[10,13,47–49]. • an early reduction in cfdna concentration or ctdna fraction associated with longer pfs and os[54–57,103]. • a lack of response or continued rise in ctdna fraction has been associated with shorter pfs[47,49,57,66]. baseline tumor suppressor gene alterations • patients treated with arpis had worse survival outcomes compared to those without tumor suppressor gene alterations at baseline, or who reverted to undetectable by cycle 2 of treatment[47,48,50,51]. ar amplification • the presence, as well as magnitude, of ar gene amplification, has been associated with shorter pfs as well as os[48,59–61]. hrr alterations • presence of hrr mutation/s predicts sensitivity to parpi as well as platinum chemotherapy[71]. ctnnb1 mutation • wnt pathway activating mutations (such as ctnnb1) are associated with resistance to arpi[50,87]. pten loss • prostate cancers with pten loss on ihc are more sensitive to akt inhibition[73]. pten loss is also predictive for poor response to abiraterone acetate, while sensitivity to docetaxel is retained[74,75]. cdk12 mutation, high-msi, high tmb • a tmb of > 10 mutations per megabase[80], cdk12 mutations[81,82] and high msi[83] predict sensitivity to ici therapy. ar: androgen receptor; arpi: androgen receptor pathway inhibitor; ctdna: circulating tumor dna; ddr: dna damage response and repair; hrr: homologous recombination repair; ihc: immunohistochemistry; mcrpc: metastatic castration-resistant prostate cancer; mhspc: metastatic hormone-sensitive prostate cancer; msi: microsatellite instability; os: overall survival; pfs: progression-free survival; tmb: tumor mutational burden. ar: androgen receptor; ctdna: circulating tumor dna; ngs: next-generation sequencing. “created with biorender.com”. reproduced with permission. figure 1. advantages, limitations, and clinical applications of ctdna in advanced prostate cancer lower cf dna yield and ctdna fraction observed in lower-volume, less heavily pretreated disease and due to decreases in the abundance of ctdna in plasma following administration of adt[35]. ctdna as a prognostic tool to guide upfront treatment intensification kohli et al. demonstrated that baseline ctdna fraction also holds prognostic value in mhspc, with higher pretreatment ctdna fractions predicting shorter os. the combination of ctdna fraction, volume of disease, and serum alp levels was also more prognostic of survival than clinical factors alone, with low-volume metastatic disease and low ctdna fraction associated with the longest os[35]. a higher ctdna fraction was also predictive of adt failure and shorter metastasisfree survival[35,94]. additionally, several prognostic genomic aberrations exist in mhspc, and ctdna analysis is a useful method for identifying them (see table 2). the presence 279278 siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org review — liquid biopsy utility and clinical application of circulating tumor dna (ctdna) in advanced prostate cancer http://siuj.org http://siuj.org references 1. siegel rl, miller kd, fuchs he, jemal a. cancer statistics, 2021. 2021;71(1):7–33. doi: 10.3322/caac.21654. pmid: 33433946. 2. h, ferlay j, siegel rl, laversanne m, soerjomataram i, jemal a, et al. global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin.2021;71(3):209–249. doi: 10.3322/caac.21660. pmid: 33538338. 3. rebello rj, oing c, knudsen ke, loeb s, johnson dc, reiter 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chi kn, barnicle a, sibilla c, lai z, corcoran c, williams ja, et al. concordance of brca1, brca2 (brca), and atm mutations identified in matched tumor tissue and circulating tumor dna (ctdna) in men with metastatic castration-resistant prostate cancer (mcrpc) screened in the profound study. j clin oncol.2021;39(6_suppl):26. doi: 10.1200/jco.2021.39.6_suppl.26. 20. dong x, zheng t, zhang m, dai c, wang l, wang l, et al. circulating cell-free dna-based detection of tumor suppressor gene copy number loss and its clinical implication in metastatic prostate cancer. front oncol.2021;11:720727. doi: 10.3389/fonc.2021.720727. pmid: 34504797; pmcid: pmc8422845. 21. tukachinsky h, madison rw, chung jh, gjoerup ov, severson ea, dennis l, et al. genomic analysis of circulating tumor dna in 3,334 patients with advanced prostate cancer identifies targetable brca alterations and ar resistance mechanisms. clin cancer res.2021;27(11):3094–3105. doi: 10.1158/1078-0432.ccr-20-4805. pmid: 33558422; pmcid: pmc9295199. 22. geeurickx e, hendrix a. targets, pitfalls and reference materials for liquid biopsy tests in cancer diagnostics. mol aspects med.2020;72:100828. doi: 10.1016/j.mam.2019.10.005. pmid: 31711714. of poor prognostic aberrations may potentially spare the patient from unnecessary treatment toxicity. however, prospective data evaluating ctdna as a prognostic tool to guide treatment decisions in mhspc (alongside clinical parameters) is needed before ctdna can be adopted into mainstream practice. genomic aberrations to guide the choice of systemic therapy in metastatic hormonesensitive prostate cancer baseline tumor suppressor gene a lterations are associated with worse outcomes with ar pis in mhspc[97]. furthermore, the phase 3 titan trial, where patients received apalutamide or placebo in combination with adt for mhspc, found that any ar aberration combined with detectable ctdna at baseline is associated with poor os[100]. in such cases, the addition of docetaxel as part of triplet therapy may be particularly important. conversely, an spop mutation, which occurs in approximately 5% of patients with mhspc, predicts a favourable response to arpis and improved survival outcomes[101]. challenges and limitations of ctdna profiling one significant limitation of ctdna profiling in prostate cancer is the variability in ctdna shed into the plasma, potentially resulting in undetectable plasma tumor content. unfortunately, up to half of mpc patients have low plasma tumor fraction (< 20%), and the dynamics of ctdna release mechanisms and relative contributions from different lesions are still not fully understood[59,76]. these samples pose challenges, as the high background signal can hinder the sensitive and specific detection of copy number variants, the identification of loss of heterozygosity (either by copy-loss or copy-neutral mechanisms), and the filtering of non-neoplastic somatic mutations arising from hematopoietic stem cells[72]. it is unlikely that ctdna biopsies will completely replace genomic analysis of solid tissue, especially in earlierdisease stages where tumor burden is lower. additional approaches such as methylation or tumor-informed sequencing are required to overcome the limitations of low ctdna fraction. incorporating ctdna with current conventional methods will significantly advance our understanding of the biological processes underlying treatment resistance and response. indeed, recent studies on parp inhibitors in mcrpc have combined ctdna analysis with tumor tissue testing to detect hrr alterations[104,105]. continued advancements in dna processing, sequencing technologies, and downstream bioinformatics ana lysis w ill enable the increasing integration of ctdna into precisiononcology initiatives for mpc. however, due to the substantial infrastructural, technological, and financial requirements of ctdna analysis, particularly for high-throughput assays, global access to ctdna platforms at both the research and clinical levels is still limited. furthermore, there is considerable lack of harmonization in the post-analytical stage, further complicating the implementation of ctdna assays into the clinic (figure 1). significant efforts are still required to establish best practices for variant interpretation and reporting[106,107]. these considerations must be addressed before widespread clinical implementation of ctdna profiling in mpc can occur. conclusion the increasing complexity of optimal treatment selection and sequencing in mpc is compounded by the integration of multiple novel therapies. clinicians urgently need the ability to molecularly profile patients to gain predictive and prognostic insights that will guide treatment decisions. the high concordance between ctdna and tumor tissue samples, combined with its minimally invasive and easily accessible nature, makes ctdna a highly attractive alternative to tissue biopsy for assessing a tumor’s molecular profile. by employing serial 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10.1158/1078-0432.ccr-22-0931. pmid: 36043882; pmcid: pmc9811161. 106. taavitsainen s, annala m, ledet e, beja k, miller pj, moses m, et al. evaluation of commercial circulating tumor dna test in metastatic prostate cancer. jco precis oncol.2019;3:po.19.00014. doi: 10.1200/ po.19.00014. pmid: 32914020; pmcid: pmc7446428. 107. kwan em, wyatt aw, chi kn. towards clinical implementation of circulating tumor dna in metastatic prostate cancer: opportunities for integration and pitfalls to interpretation. front oncol.2022;12:1054497. doi: 10.3 389/fonc.2022.105 4 4 97. pmid: 36 4 39 4 51; pmcid: pmc9685669. 286 siuj • volume 4, number 4 • july 2023 siuj.org review — liquid biopsy http://siuj.org tissue-based immunohistochemical markers for diagnosis and classification of renal cell carcinoma liang g. qu,1,2 vaisnavi thirugnanasundralingam,3 damien bolton,1,2 antonio finelli,4 nathan lawrentschuk2,3,5,6 1 department of urology, austin health, heidelberg, australia, 2 department of surgery, university of melbourne, australia, 3 department of urology, royal melbourne hospital, melbourne, australia, 4 division of surgical oncology, princess margaret hospital, university health network, university of toronto, canada, 5 department of surgical oncology, peter maccallum cancer centre, melbourne, australia, 6 ej whitten prostate cancer research centre, epworth healthcare, melbourne, australia abstract the development and description of renal cell carcinoma (rcc) subtypes has led to an increase in demand for tissue biomarkers. this has implications not only in informing diagnosis, but also in guiding treatment selection and in prognostication. although historically, many immunohistochemical (ihc) stains have been widely characterized for rcc subtypes, challenges may arise in interpreting these results. these may include variations in tumor classification, specimen collection and processing, and ihc techniques. in light of the reclassification of rcc subtypes in 2016, there remains a requirement for a comprehensive outline of tissue biomarkers that may be used to differentiate between rcc subtypes and distinguish these from other non-renal neoplasms. in this review, concise summaries of the commonest rcc subtypes, including clear cell, papillary, and chromophobe rcc, have been provided. important differences have been highlighted between chromophobe rcc and renal oncocytomas. an overview of the current landscape of tissue biomarkers in other rcc subtypes has also been explored, revealing the variable staining results reported for some markers, whilst highlighting the essential markers for diagnosis in other subtypes. introduction classifying renal cell carcinoma (rcc) into its various subtypes relies on a range of diagnostic techniques. these involve the analysis of anatomical, morphological, immunohistochemical (ihc), and molecular characteristics. ihc tissue biomarkers have maintained a useful role in aiding the diagnosis and subtyping of rcc [1]. in addition, tissue biomarkers may aid in the differentiation of non-renal neoplasms or metastatic disease. its other uses include prognostication, as well as guidance of treatment selection [2,3]. advances have been made in ihc staining for rcc classification; however, challenges arise in the subtyping of rcc. substantial staining heterogeneity exists across and within tumor subtypes [4]. variations in processing may lead to inconsistencies in reported immunoreactivity or staining patterns [4]. ongoing revision of the classification of renal cell tumors (table 1) by the world health organization and international society of urological pathology creates difficulty in interpreting older literature [5,6]. there is increasing demand for smaller volume samples to be analyzed, as diagnostic biopsies are performed more frequently. although some of the described markers may not yet be commonly encountered in daily clinical practice, ihc staining remains useful in indicating the presence or absence of such markers, and in relaying quantitative information such as staining extent. key words competing interests article information tissue-based markers, immunohistochemistry, renal cell carcinoma, cancer subtyping. none declared. received on june 23, 2020 accepted on august 3, 2020 soc int urol j. 2020;1(1):68–76 68 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation mailto:liang.qu%40austin.org.au?subject=siuj http://www.siuj.org this review provides an update on the current landscape of tissue biomarkers for the diagnosis and classification of common rcc subtypes. clear cell rcc clear cell rcc (ccrcc) is responsible for approximately 75% of diagnosed rccs [5]. its staining profile has been widely characterized; however, markers are still being described that may aid differentiation of ccrcc from other subtypes (table 2). carbonic anhydrase 9 (caix), a transmembrane protein responsible for co2 transfer, stains along membranous non-necrotic areas [7,8]. a transmembrane mucin protein, epithelial membrane antigen (ema), may also be present in up to 85% of specimens [9,10]. human kidney injury molecule-1 (hkim-1) is a type 1 transmembrane glycoprotein found in injured proximal tubules [11]. this marker can be expressed in ccrccs but may also be found in other clear cell carcinomas of the ovaries or endometrium. cy tokeratin (ck) staining in ccrcc may vary depending on the antibody used and the specific ck studied. immunoreactivity in 60% of ccrcc specimens may be achieved for ck8 using cam 5.2 antibody [12]. ccrcc does not typically stain for ck7 [8]. ck19 antibody may result in infrequent immunoreactivity in 20% of specimens [13]. broad spectrum ck (panc y tokerat i n) may be detec ted usi ng a e1/a e3 antibodies [14]. ccrccs are not immunoreactive to 34βe12, an antibody for high molecular weight ck (hmwck) [13]. vimentin, an intermediate filament protein found in mesenchymal cells, may be detected in 87% of specimens [15,16]. lectins, carbohydrate-binding proteins, may also be used as markers in rcc. table 1. the who/isup classification of renal cell tumors, 2016 the classification of renal cell tumors as described by world health organization and international society for urological pathology, in 2016. renal cell tumors clear cell rcc multilocular cystic renal neoplasm of low malignant potential papillary rcc hereditary leiomyomatosis and renal cell carcinoma-associated rcc chromophobe rcc collecting duct carcinoma renal medullary carcinoma microphthalmia-associated transcription family translocation rcc succinate dehydrogenase-deficient rcc mucinous tubular and spindle cell carcinoma tubulocystic rcc acquired cystic disease-associated rcc clear cell papillary rcc rcc, unclassified papillary adenoma renal oncocytoma previously, galectin-1 (51%) and galectin-3 (78%) have been detected in ccrcc [17]. it is important to note that a number of mark ers produce negative immunoreactivity in ccrcc. alphamethylacyl coenzyme a racemase (amacr), an enzyme found in peroxisomes and mitochondria involved in fatty acid oxidation, does not typically stain in ccrcc tissue [8]. there is usually minimal immunoreactivity for parvalbumin, a calcium-binding albumin protein, and similar negative staining for claudin 7, 8, and cd117 [16,18-21]. e-cadherin is also ty pically not expressed, although may be detectable in tumors of higher grade [10,22,23]. kidney-specif ic cadherin (ksp-cadherin), detectable in the distal convoluted tubules, can be expressed in moderate intensity in some specimens (30%) [20]. brca1-associated protein 1 (bap1), a protein with deubiquitinase properties, expresses nuclear staining in up to 81% of ccrccs; wherein a loss of expression may be associated with higher grade of disease [24]. sensitive but non-specific markers may prove useful in confirming rccs, especially in determining the origin of metastatic deposits. rcc marker (rccm), an abbreviations amacr alpha-methylacyl coenzyme a racemase bap1 brca1-associated protein 1 caix carbonic anhydrase 9 ccrcc clear cell rcc cd10 cluster differential marker 10 chrcc chromophobe rcc ck cytokeratin ema epithelial membrane antigen hkim-1 human kidney injury molecule-1 hmwck high molecular weight ck ihc immunohistochemical mit microphthalmia-associated transcription rcc renal cell carcinoma rccm rcc marker ro renal oncocytoma 69siuj.org siuj • volume 1, number 1 • october 2020 tissue-based immunohistochemical markers for diagnosis and classification of renal cell carcinoma http://www.siuj.org antibody directed at the brush border of the proximal tubule, is present in 85% of ccrcc specimens [25]. however, it may also be detected in 27% of non-renal carcinoma specimens, including müllerian-derived tumors with clear cell morphology, rendering it a non-specific marker for rcc [26]. similarly, cluster differential marker 10 (cd10), is expressed in 94% of ccrcc specimens but may be detectable in many nonrenal tumors [27]. ccrcc may appear similar to chromophobe rcc (chrcc) because of their shared clear and eosinophilic morphology. to minimize the number of markers used to differentiate tumor subtypes, a suggested panel of ihc markers should include vimentin, rccm, caix, ksp-cadherin, cd117, and parvalbumin. papillary rcc papillary rcc (prcc) is the second most common rcc subtype, representing 15% of diagnosed rccs [5]. prccs demonstrate diffuse immunoreactivity to ae1/ ae3 antibody and cam 5.2 antibody, no reactivity to 34βe12, and strong membranous staining for ck7 [28]. roughly 90% of prccs will express some ck19 on staining [13]. other markers that are immunoreactive include amacr, vimentin, rccm, ema, hkim-1 and cd10 [11,25,27,29-31]. e-cadherin expression has been inconsistently described, likely because of variations in tumor grade or type, and in technique and processing [22]. specimens were more likely to express e-cadherin if they were higher grade or if they were type 2 prcc [22]. prccs do not express ksp-cadherin [20]. importantly, prcc table 2. summary of immunohistochemical markers for common renal cell tumor subtypes a summary of the commonly described immunohistochemical markers and their expression is listed for clear cell rcc, papillary rcc, chromophobe rcc, and renal oncocytoma. immunohistochemical marker ccrcc prcc chrcc renal oncocytoma pan-cytokeratin (ae1/ae3) + + + variable ck7 − type 1: + type 2: − + − ck8/ck18 (cam 5.2) + + + + ck19 − + − − hmwck (34βe12) − − − − ema + + + + e-cadherin − variable + + ksp-cadherin − − + + caix + − − − amacr − + − − vimentin + + − − parvalbumin − variable + + c-kit/cd117 − − + + cd10 + + − − rccm + + − − hkim-1 + + − − caveolin-1 + + + − s100a1 + + − + + ≥ 50% staining; − < 50% staining. 70 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation http://www.siuj.org usually do not stain for caix, though some specimens may be weakly immunoreactive near necrotic areas [8]. there is variable staining for parvalbumin but typically negative staining for cd117 [16,19,32]. reported data for membranous staining of claudin 7 range from 28% to 78% of prccs [33,34]. claudin 8 does not stain well in prccs in roughly 14% of specimens [34]. up to 83% may express galectin-1, whilst less than 6% of prcc stain for galectin-3 [17]. bap1 is reported to be expressed across all prcc specimens [24]. to assist with classifying a rcc with papillary features, a marker panel should consist of ck7, amacr, cd10, rccm, tfe3, and cd57 [30,35]. chromophobe rcc chromophobe rcc (chrcc) represents up to 11% of diagnosed rccs [7]. chrcc specimens are typically immunoreactive to cam 5.2 antibody, ae1/ae3 antibody, as well as ck7 [7]. chrcc do not usually express ck19 or hmwck [13]. ty pic a l ly, ch rcc s sta i n posit ive for em a, e-cadherin, and ksp-cadherin [10,20,22,36]. chrccs are immunoreactive for parvalbumin and cd117 in most specimens [16,37]. chrccs may also demonstrate immunoreactivity for tight junction proteins, claudin 7 (91%), and less frequently, claudin 8 (27%) [21,34]. these tumor subtypes highly express galectin-1 (100%), as well as galectin-3 (63%) [17]. bap1 may be expressed in up to 77% of specimens [24]. rh family c glycoprotein (rhcg) as a membranous stain, is homogeneously expressed across chrcc specimens [38]. it is also expressed in renal oncocytomas, although staining patterns may differ in comparison [38]. long noncoding rna linc01187 has also been studied. chrcc specimens demonstrate widespread expression of linc01187 using rna in situ hybridization, although this may also be identified in renal oncocytomas [38]. chrccs do not express vimentin, although specimens may stain positive in sarcomatoid areas [7,15,39]. caix, hkim-1, cd10, rccm and amacr are also not typically expressed in chrccs [7,11,27,29]. renal oncocytoma renal oncocy tomas (ros) remain challenging to diagnose because they share morphological and ihc features with chrcc. the ihc profile of ros consist of variable immunoreactivity to ae1/ae3 antibody (49%) and ck19 (40%), while no expression is demonstrated for hmwck [13]. ros may stain for cam 5.2 antibody [40]. ros can also be immunoreactive for parvalbumin, cd117, e-cadherin, and sometimes ema (52%) [10,16,36,37]. they may express ksp-cadherin in up to 76% of specimens [20]. there can be membranous staining for claudin 7 in 55% and mixed pattern expression of claudin 8 in 92% of specimens [21,33,34]. it is important to note that ros stain negative for vimentin, amacr, caix, cd10, and rccm [27,29,30,39,41]. limited staining has been reported for hkim-111. several markers to distinguish between ros and chrccs have been investigated. ros typically stain negative for hale’s colloidal iron stain; however, variability in processing and technique has affected the interpretability and reproducibility of this staining technique [10]. ck7 staining may demonstrate focal positivity in ros, which is in contrast to the diffuse staining observed in chrccs [39]. s100a1, a calciumbinding protein, demonstrates consistent and diffuse cytoplasmic staining in ros compared with chrcc, in which the positive staining rate for s100a1 is considerably lower [42]. caveolin-1, a scaffolding protein, which was originally described as demonstrating expression in chrcc and not in ros, has since been reported with variable expression and staining pattern, likely due to inconsistencies among subtypes [39,43-45]. additional markers are currently being explored. amylase α1a, a salivar y-ty pe digestive enzyme, produces 100% staining in ro specimens, compared with only 13% of chrccs [46]. wnt-5a, involved in tumor development, similarly produces 100% staining in ro specimens while only 16% of chrccs may stain positive [47]. fxyd2, a marker coding for a subunit of a distal tubule na/k atpase, stains in 17% of ros, compared with 96% in chrccs [48]. ankyrin-repeated protein with a proline-rich region, a muscle protein, was present in 86% of ros, compared with 0% in chrcc specimens [49]. cd63, a glycoprotein investigated for differential staining patterns, produces apical/ polar staining in 94% of ros, which is in contrast to the diffuse staining pattern observed in 96% of chrccs [50]. transforming growth factor β1, a cytokine, demonstrates predominantly cytoplasmic staining in ros, while producing membranous staining in chrcc specimens [51]. other novel markers include foxi1, a transcription factor identified in intercalated cells (positive in ros) [52], ela, a ligand of apelin receptor (positive in ros) [52], caspase 3, a protease involved in apoptosis (positive in chrccs) [53], nuclear expression of leptin (in ros) [54], loss of rb1 (in chrccs) [55], and nuclear staining of tyrosine kinase erbb4 [55]. 71siuj.org siuj • volume 1, number 1 • october 2020 tissue-based immunohistochemical markers for diagnosis and classification of renal cell carcinoma http://www.siuj.org other rcc subtypes in clear cell papillary rcc (ccprcc), there is diffuse positive cytoplasmic immunoreactivity for ck7. in addition, there can be a diffuse membranous expression of caix as in ccrcc; however, a unique “cup-like” pattern may be identified on basolateral tumor cells [8]. amacr is not usually expressed in ccprcc. there can be variable expression for hmwck using 34βe12 antibody [7]. in contrast to ccrccs, this subtype is negative for cd10 and positive for ck7. unlike prcc, this subtype is negative for amacr and cd10. microphthalmia-associated transcription (mit) family translocation carcinomas warrant careful discrimination from their morphologically similar counterparts, namely ccrcc and prcc, because of the differences in disease outcome, prognosis, and management [56]. mit family translocation carcinomas do not express cks or ema but do express cd10 and rccm. although the primary diagnostic modality is a fluorescence in situ hybridization assay, ihc markers may be used to distinguish mit family translocation rccs [57]. translocation rccs involving chromosome xp11.2 are negative for ck7 and caix, but positive for amacr [29]. a specific ihc marker, tfe3, may be used to identify this transcription factor that is overexpressed in this particular translocation [8]. a similar translocation-related marker, tfeb, may be used to distinguish cells affected by a translocation at chromosome 6p21 [58]. in relation to both chromosomal loci, an additional marker, cathepsin-k, may also be overexpressed and detectable in both xp11.2 and 6p21 translocation tumors. cathepsin-k is expressed in tfeb translocation rccs, and in up to 60% of tfe3 rccs [59,60]. ihc markers can be used as a supportive aid to diagnosis, but must be cautiously supplemented by other diagnostic tools, because of the occurrence of false positive and false negative results [61]. acquired cystic disease-associated rccs are slowgrowing tumors that occur within cysts. these tumors can occur multi-focally and bilaterally [14,62]. their diagnosis can of ten be made according to their characteristic morphological features; however, ihc markers may assist with diagnosis. this particular subtype of rcc is often immunoreactive to amacr, ae1/ae3 antibody, cam 5.2 antibody, vimentin, cd10, and rccm. they have been reported to demonstrate variable expression for caix and ck7 [62,63]. tubulocystic rccs, although similar to prccs morphologically, may be distinguished using ihc markers. these tumors stain positive for ck7, cd10, pax2, pax8, and diffusely for amacr [29]. in a study of 3 tubulocystic rcc specimens, all 3 cases stained positive for ck19, as well as vimentin, while being negative for hmwck [15]. ihc markers for succinate dehydrogenase-deficient rccs have been characterized in limited reports. these tumors have variable ck expression but have positivity for pax8, ema, and ksp-cadherin. typically, these tumors stain negative for vimentin, cd117, rccm, and caix [64,65]. these tumors require a loss of the sdhb gene, which codes a subunit for succinate dehydrogenase enzyme [64]. a negative stain for sdhb can be useful to confirm this diagnosis. it is important to differentiate collecting duct carcinomas from urothelial carcinomas. these tumors stain positive for ck5/6, ck7, ck8, ck19, as well as for hmwck [15] and are immunoreactive for vimentin, pax2, and pax8 [10,15]. they usually stain negative for cd10. in addition to pax8, urothelial markers p63 and gata3 may be used to rule out a urothelial tumor [30]. renal medullary carcinoma is closely related to collecting duct carcinomas and may be identified in individuals with sickle cell trait or anemia [66,67]. this subtype demonstrates immunoreactivity for ck7 and ae1/ae3 antibody but not to 34βe12 [15]. there is variable ema expression. these tumors stain positive for pax2 and pax8. smarcb1, a nuclear transcriptional regulator, can be used to distinguish renal medullary carcinoma from collecting duct carcinoma [68]. another transcription factor, oct3/4, can be used as a marker to distinguish this tumor from urothelial or collecting duct carcinomas [69]. multilocular cystic renal cell neoplasms of low malignant potential demonstrate ihc features that are identical to those found in low-grade ccrccs. this subtype is immunoreactive to cam 5.2 antibody, ema, ck7, caix, and pax2 [70,71]. variable expression has been reported for cd10 [70,71]. histologically, hereditary leiomyomatosis renal cell carcinoma-associated rcc (hlrcc) was historically reported as being similar to type 2 prcc or collecting duct carcinomas. in these tumors, there can be positive staining for ck7, cam 5.2 antibody, and cd10. the stroma is negative for cd117. loss of the fumarate hydratase gene is specific for hlrcc [72]. because of increasing fumarate, ihc staining may result from accumulating s-(2-succinyl cysteine) (s2c), where strong nuclear and cytoplasmic expression has been described. s2c can, however, be found in type 2 prccs [72]. mucinous tubular and spindle cell carcinoma (mtscc) displays several ihc similarities to prcc, despite being genetically dissimilar. these tumors are immunoreactive for amacr, ck7, pax2, e-cadherin and ema, but stain negative for rccm, 34βe12, and cd117 [15,73,74]. there can be variable staining for vimentin [15]. mtscc differs from prcc, with a lower 72 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation http://www.siuj.org level of staining for cd10 (15% versus 100%) [73]. reports have also described the in situ hybridization expression of vstm2a. vstm2a is expressed in moderate to high levels in mstcc, with a reported diagnostic area under receiver operating characteristics curve of 99.2% [75]. other tissue markers other useful markers may help distinguish rcc from non-renal cell tumor origins. pax2 and pax8 are transcription factors implicated in kidney and müllerian organ development [30,76]. pax2 and pax8 are usually expressed and found diffusely in normal kidney tissue; however, they are also present in up to 90% of renal neoplasms. pax2 differs from pax8 in that it is not usually expressed in ros or chrccs. in addition, urothelial carcinomas do not express pax2 or pax8, thereby demonstrating their utility in determining tumor origin [77]. gata3, an endothelial cell transcription factor, is a marker for urothelial carcinoma that consistently stains negative in rcc specimens [78]. ca-125, a marker classically associated with ovarian cancer, may also be used as a negative marker for rccs, distinguishing them from other tumors of clear cell morphology [26]. ck20 is a useful negative marker for ruling out renal cell neoplasms [30]. most rccs typically stain negative for ck20, with the exception of previously reported eosinophilic solid cystic rccs [79]. these may be useful in ruling out other ck20+ tumors, such as urothelial, ovarian, or colorectal carcinomas. other markers useful in work-up for ruling out non-renal neoplasms include rccm, cd10, vimentin and cks. add it iona l t is sue-ba sed ma rkers a re bei ng investigated, as guided by the recent advances in the study of rcc genomic alterations. commonly reported altered genes for ccrcc include vhl, pbrm1, and setd2 [80]. prcc may demonstrate met mutation, while chrcc may exhibit tp53 or pten mutations [81]. some genomic alterations may also aid differentiation of chrcc and ro [81]. although genomic alterations have largely been studied using next-generation sequencing techniques, some have been adapted to ihc. vhl, a tumor suppressor gene, is commonly inactivated in both hereditary and sporadic ccrccs [82]. the ihc detection of its gene product is expressed in up to 90% of primary renal tumors and 86% of metastatic rcc specimens [83]. however, it may also be identified in non-renal tumors such as clear cell carcinomas of the ovary or uterus [83]. pbrm1 has also been studied as an ihc marker; however, its application is mainly to aid prognostication. a loss of pbrm1 expression is associated with late tumor stage and poor differentiation [84]. similarly, ihc setd2 expression has been identified in metastatic rcc, and demonstrates utility in determining likely prognostic outcomes [85]. future studies should continue to investigate the adaptation of altered gene products to the field of diagnostic tissue markers. conclusion the characterization of rcc subtypes using tissue biomarkers must undergo ongoing review as new markers and techniques are developed and described. ihc staining remains a useful method to subtype rccs and to distinguish them from non-renal tumors, especially in small tissue volume specimens, such as in metastatic tissue biopsies. more study is required to further characterize the subtypes of rcc to further delineate them and improve the accuracy of diagnosis, treatment, and prognostication. references 1. williamson 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damayanti np, budka ja, khella hwz, et al. therapeutic targeting of tfe3/irs-1/pi3k/mtor axis in translocation renal cell carcinoma. clin cancer res. 2018;24(23):5977-89. 57. green wm, yonescu r, morsberger l, et al. utilization of a tfe3 break-apart fish assay in a renal tumor consultation service. am j surg pathol. 2013;37(8):1150-63. 58. davis ij, hsi bl, arroyo jd, et al. cloning of an alpha-tfeb fusion in renal tumors harboring the t(6;11)(p21;q13) chromosome translocation. proc natl acad sci u s a. 2003;100(10):6051-6. 59. martignoni g, bonetti f, chilosi m, et al. cathepsin k expression in the spectrum of perivascular epithelioid cell (pec) lesions of the kidney. mod pathol. 2012;25(1):100-11. 60. martignoni g, pea m, gobbo s, et al. cathepsin-k immunoreactivity distinguishes mitf/ tfe family renal translocation carcinomas from other renal carcinomas. mod pathol. 2009;22(8):1016-22. 61. calio a, segala d, munari e, brunelli m, martignoni g. mit family translocation renal cell carcinoma: from the early descriptions to the current knowledge. cancers (basel). 2019;11(8). 62. przybycin cg, harper hl, reynolds jp, et al. acquired cystic diseaseassociated renal cell carcinoma (acd-rcc): a multiinstitutional study of 4 0 cases with clinical follow-up. am j surg pathol. 2018;42(9):1156-65. 63. foshat m, eyzaguirre e. acquired cystic disease-associated renal cell carcinoma: review of pathogenesis, morphology, ancillary tests, and clinical features. arch pathol lab med. 2017;141(4):600-6. 64. gill aj, hes o, papathomas t, et al. succinate dehydrogenase (sdh)-deficient renal carcinoma: a morphologically distinct entity: a clinicopathologic series of 36 tumors from 27 patients. am j surg pathol. 2014;38(12):1588-602. 65. williamson sr, eble jn, amin mb, et al. succinate dehydrogenasedeficient renal cell carcinoma: detailed characterization of 11 tumors defining a unique subtype of renal cell carcinoma. mod pathol. 2015;28(1):80-94. 66. algaba f, akaza h, lopez-beltran a, et al. current pathology keys of renal cell carcinoma. eur urol. 2011;60(4):634-43. 67. yang xj, sugimura j, tretiakova ms, et al. gene expression profiling of renal medullary carcinoma: potential clinical relevance. cancer. 2004;100(5):976-85. 68. ohe c, smith sc, sirohi d, et al. reappraisal of morphologic differences between renal medullary carcinoma, collecting duct carcinoma, and fumarate hydratase-deficient renal cell carcinoma. am j surg pathol. 2018;42(3):279-92. 69. rao p, tannir nm, tamboli p. e xpression of oct3/4 in renal medullary carcinoma represents a potential diagnostic pitfall. am j surg pathol. 2012;36(4):583-8. 70. murshed k a, akhtar m, ben-gashir m. multilocular cystic renal neoplasm of low malignant potential extending into the perinephric adipose tissue. hum pathol. 2019;17:200305. 71. williamson sr, halat s, eble jn, et al. multilocular cystic renal cell carcinoma: similarities and dif ferences in immunoprofile compared with clear cell renal cell carcinoma. am j surg pathol. 2012;36(10):1425-33. 75siuj.org siuj • volume 1, number 1 • october 2020 tissue-based immunohistochemical markers for diagnosis and classification of renal cell carcinoma http://www.siuj.org 72. chen yb, brannon ar, toubaji a, et al. hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cancer: recognition of the syndrome by pathologic features and the utility of detecting aberrant succination by immunohistochemistry. am j surg pathol. 2014;38(5):627-37. 73. paner gp, srigley jr, radhakrishnan a, et al. immunohistochemical analy sis of mucinous t ubular and spindle c ell c ar cinoma and papillar y renal cell carcinoma of the kidney: significant immunophenotypic overlap warrants diagnostic caution. am j surg pathol. 2006;30(1):13-9. 74. nathany s, monappa v. mucinous tubular and spindle cell carcinoma: a review of histopathology and clinical and prognostic implications. arch pathol lab med. 2020;144(1):115-8. 75. wang l, zhang y, chen y-b, et al. vstm2a overexpression is a sensitive and specific biomarker for mucinous tubular and spindle cell carcinoma (mtscc) of the kidney. am j surg pathol. 2018;42(12):1571-84. 76. ozcan a, de la roza g, ro jy, shen ss, truong ld. pa x2 and pa x8 expression in primary and metastatic renal tumors: a comprehensive comparison. arch pathol lab med. 2012;136(12):1541-51. 77. albadine r, schultz l, illei p, et al. pa x8 (+)/p63 (-) immunostaining pat tern in renal collecting duct carcinoma (cdc): a useful immunoprofile in the differential diagnosis of cdc versus urothelial carcinoma of upper urinary tract. am j surg pathol. 2010;34(7):965-9. 78. mohammed kh, siddiqui mt, cohen c. gata3 immunohistochemical ex p r e s sion in in v asi v e ur o t helial c ar cinom a. urol o n col. 2016;34(10):432 e9e13. 79. trpkov k, abou-ouf h, hes o, et al. eosinophilic solid and cystic renal cell carcinoma (esc rcc): further morphologic and molecular characterization of esc rcc as a distinct entity. am j surg pathol. 2017;41(10):1299-308. 80. de velasco g, wankowicz sa, madison r, et al. targeted genomic landscape of metastases compared to primary tumours in clear cell metastatic renal cell carcinoma. br j cancer. 2018;118(9):1238-42. 81. durinck s, stawiski ew, pavía-jiménez a, et al. spectrum of diverse genomic alterations define non–clear cell renal carcinoma subtypes. nat genet. 2015;47(1):13. 82. kaelin wg. molecular basis of the vhl hereditary cancer syndrome. nat rev cancer. 2002;2(9):673-82. 83. lin f, shi j, liu h, et al. immunohistochemical detection of the von hippel-lindau gene product (pvhl) in human tissues and tumors: a useful marker for metastatic renal cell carcinoma and clear cell carcinoma of the ovar y and uterus. am j clin pathol. 2008;129(4):592-605. 84. paw łowski r, mühl sm, sulser t, krek w, moch h, schraml p. loss of pbrm1 expression is associated with renal cell carcinoma progression. int j cancer. 2013;132(2):e11-e7. 85. wang j, liu l, qu y, et al. prognostic value of setd2 expression in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors. j urol. 2016;196(5):1363-70. 76 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation http://www.siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj.org siuj • volume 4, number 3 • may 2023 key words competing interests article information cryoablation, kidney tumor, renal cell carcinoma, partial nephrectomy none declared. received on december 21, 2022 accepted on january 31, 2023 this article has been peer reviewed. soc int urol j. 2022;4(3):211–222 doi: 10.48083/imbm6087 role of cryoablation for the treatment of ct1b kidney lesions: outcomes of a systematic review adnan el-achkar,1 mustafa khader,2 ala’a farkouh,2 joelle hassanieh,1 bhaskar somani,3 mohammed shahait2 1 department of surgery, division of urology, american university of beirut medical center, beirut, lebanon 2 department of surgery, king hussein cancer center, amman, jordan 3 department of urology, university hospital southampton, southampton, united kingdom abstract introduction the american urological association (aua) and the european association of urology (eau) currently recommend partial nephrectomy (pn) over ablation for ct1b lesions. however, recent series have shown comparable outcomes for cryoablation (ca) when compared to pn, making it an appealing alternative for a select group of patients. the objective of this manuscript is to assess treatment outcomes and complications of ca for ct1b lesions. methods using preferred reporting items for systematic reviews and meta-analyses (prisma) guidelines, a comprehensive search was done on medline and cochrane library electronic databases identifying studies that reported on outcomes and complications of ca for kidney tumors. inclusion criteria included ct1b lesions between 4 cm and 7 cm, excluding treatment of other sizes. results a total of 347 patients with ct1b lesions identified on imaging underwent percutaneous or laparoscopic ca. the average age was > 65 years, the median size of lesions and renal score ranged between 4.3–4.8 cm and 8–9, respectively. the majority of patients had a charlson comorbidity index (cci) of 2, and median follow-up ranged between 13 months and 95 months. across all the series, primary and secondary success rates were between 84%–98% and 92%–98%, respectively. the local recurrence ranged from 2.8% to 27%. for patients with documented rcc on biopsy, the 5-year overall survival (os), cancer-specific survival (css), recurrence-free survival (rfs), and metastasis-free survival (mfs) ranged from 56%–91%, 85%–100%, 70%–96.4%, and 90%–96%, respectively. the major complication rate (clavien-dindo iii-v) was low, at 6.2%. conclusion with promising survival outcomes and low complication rates perioperatively, ca is acceptable in a select group of patients with t1b renal tumors, including those who are older, have multiple comorbidities, or have relative or absolute contraindication to surgery. introduction the increased use of medical imaging over the past decades, especially computerized tomography (ct) scans, has increased the detection of renal masses including renal cell carcinoma (rcc)[1]. partial nephrectomy remains the gold standard for treatment of ct1 lesions[2]. the currently available treatment modalities for ct1 tumors include radical nephrectomy, partial nephrectomy, and ablative therapy. 211 review http://siuj.org abbreviations aua american urological association ca cryoablation cci charlson comorbidity index css cancer-specific survival eau european association of urology mfs metastasis-free survival nos newcastle ottawa scale os overall survival pn partial nephrectomy prisma preferred reporting items for systematic reviews and meta-analyses rcc renal cell carcinoma rct randomized controlled trial rfs recurrence-free survival while the use of ablative therapy such as ca has become more widely accepted and is endorsed in treatment guidelines with comparable outcomes to partial nephrectomy (pn) for tumors classified as ct1a (less than 4 cm)[3,4], the data on its efficacy and long-term outcomes remains controversial for tumors classified as ct1b (between 4 cm and 7 cm)[5–8]. radical or partial nephrectomy is the preferred treatment modality for ct1b lesions[8]. nevertheless, for patients with ct1b tumors with multiple comorbidities, those who are unfit for general anesthesia, or those who have concomitant underlying chronic kidney disease, secondary therapies such as cryoablation could prove useful in the urologist armamentarium. for this reason, practitioners have recently extended the use of ca to a select group of patients with ct1b lesions. generally, cryoablation for large tumors whether performed percutaneously or laparoscopically has been associated with higher risk for recurrence and complications[9,10]. recent data for ct1b tumors is clinically promising; however, most of the series are single-center series with a limited number of patients, making it difficult to appreciate ca efficacy in this select group of patients. the goal of this paper is to compile the data on cryoablation therapy for ct1b tumors. specifically, we report outcomes such as primary success, need for repeat ablation, local recurrence, complications, and survival data. methods this systematic review was conducted according to the recommended preferred reporting items for systematic reviews and meta-analyses (prisma) check list guidelines[11] (online supplementary tables 1 and 2). a computer-assisted systematic literature search of the medline and cochrane library electronic databases was performed (latest search february 23, 2022) to identify eligible studies reporting on the outcomes and complications following cryoablation of kidney tumors. the key word combinations used were as follows: ([“cryotherapy” {mesh terms} or [“cryosurgery”{mesh terms} or “cryoablation* or cr yosurger y* or cryotherapy ”{all fields including title abstract and keywords}]) and (“kidney neoplasms ”[mesh terms] or “kidney next [cancer* or tumor*])”(all fields including title, abstract, keywords) or “ renal next (cancer* or tumor*)”(all fields including title, abstract, key words). the latter was specifically used in the cochrane library. google scholar was additionally checked for the most relevant articles. study selection and risk of bias duplicates were filtered by endnote x9. following the exclusion of ineligible articles by title and abstract revision, relevant articles underwent full-text review. the exclusion criteria were set on the following bases: articles not published in english, articles entailing basic science research and conducted on non-human species, letters to the editor, case reports, series with heterogeneous cohort encompassing lesions sizes of < 4 cm and > 7 cm, series lacking required data to be extracted, and lastly series with fewer than 5 treated patients. study selection was performed separately by 2 reviewers (j.h. and a.e.) and disagreement was resolved with the input of a third author (m.s.). the same was done for data extraction. eligibility assessment was based on the title or abstract and on full-text review if appropriate. articles were eligible for this systematic review if they documented either in the title or abstract the sequel of the cryoablation of kidney tumors. article inclusion criteria involved the following: original research, randomized controlled trials (rcts) or observational studies, published in the past 20 years, systematic reviews, and cohort studies with a minimum of 5 patients. the authors included clinical ct1b lesions, which might also encompass benign lesions as well such as oncocytoma. the database searches yielded 1018 articles. using the aforementioned inclusion and exclusion criteria and following abstract review, a total of 904 articles were excluded. the 144 remaining papers were analyzed by 2 independent researchers using an inclusion criterion of only ct1b tumors (size of the tumor between 4 cm and 7 cm) and all other sizes were excluded. this led to the exclusion of 120 articles after full-text screen. articles with the same set of patients were excluded. finally, 14 articles were excluded during data extraction due to inadequate data for the review, therefore, yielding 10 papers for this review (figure 1). 212 siuj • volume 4, number 3 • may 2023 siuj.org review http://siuj.org pubmed, medline (ovid), cochrane library 1964–2021 1018 citation(s) 1018 non-duplicate citations screened inclusion criteria percutaneous or laparoscopic cryoablation nephrectomy and radioablation were excluded criteria applied 144 articles retrieved 10 articles included 904 articles excluded after title/abstract screen 120 articles excluded after full text screen 14 articles excluded during data extraction inclusion criteria applied was ct1b lesions (size 4–7 cm) exclusion criteria applied tumor size less than 4 cm or more than 7 cm primary success was defined as no contrast enhancement observed in imaging at the 3-month follow-up examination after cryoablation session. persistence was defined as persistent positive enhancement on ct scan at 3-month follow-up. if there was a contrast-enhancing lesion at 3 months, usually a repeat cryoablation was done, and it was not considered recurrence but rather incomplete treatment or early post-treatment changes. secondary success was defined as no contrast enhancement after repeat cryoablation at 3 months. local recurrence or progression was defined as new contrast enhancement within the ablation zone on ct after local eradication of all tumor cells using imaging criteria[12]. deaths from non-rcc causes were censored in the assessment of cancer-specific survival (css). css, metastasis-free survival (mfs) and recurrence-free survival (rfs) were assessed only for patients with proven rcc. the newcastle ottawa scale (nos) was used to assess the quality of the cohort studies included. as for the case series, the proposed tool of murad et al. (2018) was used[13]. the rating was done by 2 authors (a.e. and m.s.). final decision was reached following consensus with the third author (j.h.). a score of 7 of 9 and 5 of 6 was considered indicative of a high-quality study for each tool, respectively. for the item assessing adequate long-term follow-up for nos, a cut-off of 60 months was set a priori and adequacy of follow-up to 50% in the first 4 years. for the murad et al. (2018) tool, items 5 and 6 were removed, as they are relevant to cases of adverse drug events. an adequate long-term follow-up for case series was a cut-off of 3 years[13]. results after reviewing the literature using the prisma guidelines, 10 studies were included in this review (figure 1). the sample size ranged from 23 to 52 patients, with a total of 347 patients. the average age was between 67 and 77 years. the median tumor size ranged from 4.3  cm to 4.8 cm, as only ct1b tumors were assessed, with a median renal score of 8 to 9. in 2 of the 10 cohorts, patients also had a biopsy taken during the procedure, figure 1. prisma diagram: the search strategy and the number of articles included and excluded in the systematic review 213siuj.org siuj • volume 4, number 3 • may 2023 role of cryoablation for the treatment of ct1b kidney lesions: outcomes of a systematic review http://siuj.org table 1. patient and tumor demographics in all studies study study sample inclusion criteria exclusion criteria cryoablation method median tumor size (cm) mean age sex m/f bmi mean ± sd or median (iqr) cci/ ecog/asa tumor complexity: renal score or descriptive (endophytic, exophytic, central, etc.) timing of biopsy biopsy results atwell et al. (2015)[42] n = 46 biopsy-proven rcc none mentioned pc 4.8 73 28/11 not mentioned cci: mean 3 ± 2 median 2 central: 34/46 exophytic: 10/46 intraparenchymal: 2/46 preop 44 rcc 2 rcc unclassified caputo et al. (2017)[21] n = 31 renal imaging not mentioned 25 lp 6 pc 4.3 68 25/6 30.6 (26.3–37.4) median cci (iqr) 6 (5–7) median 8 (6–9) preop 17 ccc 1 prcc 4 rcc unclassified hebbadj et al. (2018)[6] n = 27 biopsy-proven rcc coagulation disorder pc 4.8 72.3 15/12 not mentioned n/a median 8 (7–9) 12/27 (44.4%) ss 15/27 (55.6%) preop 25 ccc 1 chromophobe 1 oncocytoma hasegawa et al. (2018)[36] n = 23 biopsy-proven rcc hereditary rcc multiple tumors pc 4.6 66.5 11/12 not mentioned ecog=0 (61%) ecog =1–4 (39%) central: 1 (4%) non-central:22 (96%) preop 14 ccc 1 papillary 1 chromophobe rembeyo et al. (2020)[43] n = 55 renal mass on imaging n0m0 multiple, bilateral and metastatic rcc asa > 4 pc 4.6 72 37/18 27.0 (24.0-29.0) cci: low:13 intermediate:10 high: 32 renal: (4–6)à 12 (21.8%) (7–9)à24 (41.6%) (10–12)à19 (34.6%) preop 44 malignant 39 ccc 2 prcc gunn et al. (2019)[44] n = 37 biopsy-proven rcc none mentioned pc 4.73 66.5 22/15 34.8 ± 8.8 cci mean: 7.1 ± 2.4 median 9 (7–10) 23 (62%) preop biopsy 12 ccc 5 prcc 6 rcc unclassified grange et al. (2019) [45] n = 23 biopsy-proven rcc none mentioned pc 4.56 74.9 17/6 not mentioned cci mean: 4.1 ± 1.9 mean 8.1 ± 1.8 preop 17 ccc 4 prcc 2 chromophobe andrews et al. (2019)[17] n = 52 renal mass on imaging extrarenal spread pc 4.8 77 (69.5–83) 35/11 not mentioned cci median (iqr): 2 (1–4) not mentioned both 35 rcc: 24 ccc 4 prcc 7 rcc unclassified 16 benign 1 unknown bhagavatula et al. (2020)[46] n = 25 suspicious mass on renal imaging lack of pathology, multiple and prior rcc pc not mentioned, all tumors ablated between 4–7 cm 68 not mentioned not mentioned not mentioned not mentioned preop not specified for ct1b shimizu et al. (2021)[47] n = 28 biopsy-proven rcc/ and renal mass image metastasis or vascular invasion pc 4.6 73.9 22/6 not mentioned cci median (iqr): 6 (2–9) median 9 (5–11) preop 17 ccc 1 papillary 1 unknown 9 no biopsy bmi: body mass index; ccc: clear cell carcinoma; cci: charlson comorbidity index; ecog: eastern cooperative oncology group; iqr: interquartile range; lp: laparoscopic; n/a: not assessed; pc: percutaneous; pn: partial nephrectomy; prcc: papillary renal cell carcinoma; rcc: renal cell carcinoma; rn: radical nephrectomy. while in the other series this was done preoperatively. additionally, 5 series used embolization concurrently or preoperatively with cryoablation, and a total of 48 patients underwent embolization concomitantly during the ca procedure. of the 10 studies, 7 used percutaneous ca, 1 used laparoscopic ca, and 1 used a mixture of both methods (table 1). the primary and secondary success rate was high at 84%–98% and 92%–100%, respectively. most cohorts had a median of 5 probes to ablate the tumor. the median follow-up time ranged from 13 months to 95 months. during follow-up for patients with biopsy-proven rcc, the local recurrence ranged from 2.8% to 27%. the 5-year os, css, rfs/progression 214 siuj • volume 4, number 3 • may 2023 siuj.org review http://siuj.org free survival (pfs), and mfs ranged from 56%–91%, 85%–100%, 70%–96.4%, and 90%–96%, respectively (table 2). nine studies reported complications using the claviendindo classification system. a total of 74 (23%) complications were reported, with a higher complication rate of grade iii–iv noted in 6.2%. the majority of complications (73%) were grade i–ii, with 20.2% grade iii, and 6.75% grade iv. no grade v complications were encountered (table 3). nine studies included were considered high quality, with a mean nos score of 7.8 (standard deviation [sd], table 1. patient and tumor demographics in all studies study study sample inclusion criteria exclusion criteria cryoablation method median tumor size (cm) mean age sex m/f bmi mean ± sd or median (iqr) cci/ ecog/asa tumor complexity: renal score or descriptive (endophytic, exophytic, central, etc.) timing of biopsy biopsy results atwell et al. (2015)[42] n = 46 biopsy-proven rcc none mentioned pc 4.8 73 28/11 not mentioned cci: mean 3 ± 2 median 2 central: 34/46 exophytic: 10/46 intraparenchymal: 2/46 preop 44 rcc 2 rcc unclassified caputo et al. (2017)[21] n = 31 renal imaging not mentioned 25 lp 6 pc 4.3 68 25/6 30.6 (26.3–37.4) median cci (iqr) 6 (5–7) median 8 (6–9) preop 17 ccc 1 prcc 4 rcc unclassified hebbadj et al. (2018)[6] n = 27 biopsy-proven rcc coagulation disorder pc 4.8 72.3 15/12 not mentioned n/a median 8 (7–9) 12/27 (44.4%) ss 15/27 (55.6%) preop 25 ccc 1 chromophobe 1 oncocytoma hasegawa et al. (2018)[36] n = 23 biopsy-proven rcc hereditary rcc multiple tumors pc 4.6 66.5 11/12 not mentioned ecog=0 (61%) ecog =1–4 (39%) central: 1 (4%) non-central:22 (96%) preop 14 ccc 1 papillary 1 chromophobe rembeyo et al. (2020)[43] n = 55 renal mass on imaging n0m0 multiple, bilateral and metastatic rcc asa > 4 pc 4.6 72 37/18 27.0 (24.0-29.0) cci: low:13 intermediate:10 high: 32 renal: (4–6)à 12 (21.8%) (7–9)à24 (41.6%) (10–12)à19 (34.6%) preop 44 malignant 39 ccc 2 prcc gunn et al. (2019)[44] n = 37 biopsy-proven rcc none mentioned pc 4.73 66.5 22/15 34.8 ± 8.8 cci mean: 7.1 ± 2.4 median 9 (7–10) 23 (62%) preop biopsy 12 ccc 5 prcc 6 rcc unclassified grange et al. (2019) [45] n = 23 biopsy-proven rcc none mentioned pc 4.56 74.9 17/6 not mentioned cci mean: 4.1 ± 1.9 mean 8.1 ± 1.8 preop 17 ccc 4 prcc 2 chromophobe andrews et al. (2019)[17] n = 52 renal mass on imaging extrarenal spread pc 4.8 77 (69.5–83) 35/11 not mentioned cci median (iqr): 2 (1–4) not mentioned both 35 rcc: 24 ccc 4 prcc 7 rcc unclassified 16 benign 1 unknown bhagavatula et al. (2020)[46] n = 25 suspicious mass on renal imaging lack of pathology, multiple and prior rcc pc not mentioned, all tumors ablated between 4–7 cm 68 not mentioned not mentioned not mentioned not mentioned preop not specified for ct1b shimizu et al. (2021)[47] n = 28 biopsy-proven rcc/ and renal mass image metastasis or vascular invasion pc 4.6 73.9 22/6 not mentioned cci median (iqr): 6 (2–9) median 9 (5–11) preop 17 ccc 1 papillary 1 unknown 9 no biopsy bmi: body mass index; ccc: clear cell carcinoma; cci: charlson comorbidity index; ecog: eastern cooperative oncology group; iqr: interquartile range; lp: laparoscopic; n/a: not assessed; pc: percutaneous; pn: partial nephrectomy; prcc: papillary renal cell carcinoma; rcc: renal cell carcinoma; rn: radical nephrectomy. 215siuj.org siuj • volume 4, number 3 • may 2023 role of cryoablation for the treatment of ct1b kidney lesions: outcomes of a systematic review http://siuj.org table 2. outcomes of cryoablation including need for embolization, repeat cryotherapy, recurrence, metastasis, and salvage treatment study primary success secondary success rate number of intraop embolization done number of probes used repeat cryoablation vs. other modality (after technique failures) median follow-up (months) local recurrences type of salvage treatment progression to metastasis death os css rfs/ pfs mfs atwell et al. (2015)[42] 45/46 (98%) 98% 7 not mentioned 1 rn 24 1/36 (2.8%) 1 rn 2/36 (6%) 2 5-yr 94% 5y 94% 5-yr 96.4% 5-yr 94% caputo et al. (2017)[21] 27/31 (87%) 93.5% 0 median 2 2 rca 2 observed 13 5 (16%) 1 rn, 2 rca not assessed 1 crd 5 all-cause mortality 5-yr 60% 5-yr 85% 5-yr 70% – hebbadj et al. (2018)[6] 3/27 (88%) 92.5% 0 mean (range) 5.3 (3–9) 1 pn, 1 rca 20.0 3 (11.1%) 1 pn 2 active surveillance 1 1 crd 3-yr 96% 3-yr 95.7% 3-yr 97% 3-yr 96% hasegawa et al. (2018)[36] 1/23 (96%) 100% 13/23 patients (56.5%) (preop) median (range) 4 (3–5) 1 rca 23.0 2 (9%) active surveillance 2/21 (9%) 3 all-cause mortality 5-yr 82% 5-yr 100% 5-yr 91% 5-yr 91% rembeyo et al. (2020)[43] 9/55 (84%) 98% 0 mean 5 9 rca 19.9 12 (27%) [total 12] 5 rca 2 monitoring 1 pn 2 rn 0 2 crd 1 all-cause mortality 2-yr 93% 2-yr 95% 2-yr 72% 2-yr 93% gunn et al. (2019)[44] 4/37 (88%) 92% 3 (preop) median (range) 3 (1–7) 4 rca 25.1 8 (21.6%) 1 chemo, 1 rn after second cryotherapy attempt not assessed 1 3-yr 77.6% 3-yr 100% 3-yr 62.6% – grange at al. (2019)[45] 3/23 (86.3%) 100% 0 mean ± sd 4.9 ± 1.3 3 rca 13.9 2 (8.7%) 1 rn 1/23 (4%) 1 crd 2-yr 85.7% 2-yr 81.8% – andrews et al. (2019)[17] not assessed not assessed 7 not mentioned 72 3/48 (6.3%) 2/35 (6%) 2 5-yr 56% 5-yr 91% 5-yr 92.7% 5-yr 90% bhagavatula et al. (2020)[46] 2/25 (92%) 99% range (1–7) 2 rca 95 2 (8%) 2 rca 1 5-yr 91% 5-yr 95% 5-yr 85% 5-yr 96% shimizu et al. (2021)[47] 1/28 (96.4%) 100% 18 5.0 ± 1.5 1 rca 42 2 (7.1%) 2 rca 2/18 (11%) 3 deaths 5-yr 79.1% 5-yr 96% 5-yr 92.7% 5-yr 93% crd: cancer-related death; css: cancer-specific survival; mfs: metastasis-free survival; n/a: not assessed; os: overall survival; pfs: progression-free survival; pn: partial nephrectomy; rca: repeat cryoablation; rn: radical nephrectomy. 1.3) for the cohort arm. one cohort study was considered fair, and all the case series were of high quality. there were no rcts on the subject. (supplemental tables 1 and 2). discussion there are multiple treatment options available for ct1b renal tumors including radical nephrectomy, partial nephrectomy, cryoablation, radiofrequency ablation, or active surveillance. the selection of a personalized treatment option is based on many variables including but not limited to patient characteristics, patient preference, and aggressiveness of the tumor at hand. the european association of urology (eau), american urological association (aua), and national comprehensive ca ncer net work (nccn) g u ideli nes cu rrent ly recommend partial nephrectomy for ct1b tumors when pn is deemed feasible by the surgeon[14–16]. ca is proposed as an alternative to pn in ct1a patients with comparable outcomes. however, its role in ct1b remains controversial. historically, it has been considered only in patients with contraindications to surgery, those who are unfit for surgery, or those who refuse surgery[17]. in this systematic review, we reported the patient and 216 siuj • volume 4, number 3 • may 2023 siuj.org review http://siuj.org tumor characteristics of laparoscopic or percutaneous (image-guided) ca for such tumors, and the outcomes and complications of each series. our review consists of 10 cohorts where the authors recruited a total of 347 patients who underwent ca for their ct1b renal tumor. it is important to highlight that the demographic of the cohorts consists of an older and more comorbid group of patients. the average age ranges from 66.5 years to 75 years. the majority of patients had a charlson comorbidity index (cci) of ≥ 2. on the other hand, a large series on patients undergoing pn for ct1b kidney tumors showed that patients had an average age of 59 years, and the majority had a cci of 0–1[18,19]. despite being an older and a more comorbid cohort, the 5-year os, css, and rfs across all the cohorts ranged from 56%–91%, 85%–100%, 70%–96.4%, respectively. only a few patients (28/295; 9.5%) required repeated cryotherapy for recurrence at 3 months for incomplete treatment or technical failure, or for an unspecified reason. 23 of the 28 patients had repeat cryoablation, with an excellent primary and secondary success rate of > 90% and > 95%, respectively. in addition, the risk for metastasis was low, with 5-year mfs ranging from 90% table 2. outcomes of cryoablation including need for embolization, repeat cryotherapy, recurrence, metastasis, and salvage treatment study primary success secondary success rate number of intraop embolization done number of probes used repeat cryoablation vs. other modality (after technique failures) median follow-up (months) local recurrences type of salvage treatment progression to metastasis death os css rfs/ pfs mfs atwell et al. (2015)[42] 45/46 (98%) 98% 7 not mentioned 1 rn 24 1/36 (2.8%) 1 rn 2/36 (6%) 2 5-yr 94% 5y 94% 5-yr 96.4% 5-yr 94% caputo et al. (2017)[21] 27/31 (87%) 93.5% 0 median 2 2 rca 2 observed 13 5 (16%) 1 rn, 2 rca not assessed 1 crd 5 all-cause mortality 5-yr 60% 5-yr 85% 5-yr 70% – hebbadj et al. (2018)[6] 3/27 (88%) 92.5% 0 mean (range) 5.3 (3–9) 1 pn, 1 rca 20.0 3 (11.1%) 1 pn 2 active surveillance 1 1 crd 3-yr 96% 3-yr 95.7% 3-yr 97% 3-yr 96% hasegawa et al. (2018)[36] 1/23 (96%) 100% 13/23 patients (56.5%) (preop) median (range) 4 (3–5) 1 rca 23.0 2 (9%) active surveillance 2/21 (9%) 3 all-cause mortality 5-yr 82% 5-yr 100% 5-yr 91% 5-yr 91% rembeyo et al. (2020)[43] 9/55 (84%) 98% 0 mean 5 9 rca 19.9 12 (27%) [total 12] 5 rca 2 monitoring 1 pn 2 rn 0 2 crd 1 all-cause mortality 2-yr 93% 2-yr 95% 2-yr 72% 2-yr 93% gunn et al. (2019)[44] 4/37 (88%) 92% 3 (preop) median (range) 3 (1–7) 4 rca 25.1 8 (21.6%) 1 chemo, 1 rn after second cryotherapy attempt not assessed 1 3-yr 77.6% 3-yr 100% 3-yr 62.6% – grange at al. (2019)[45] 3/23 (86.3%) 100% 0 mean ± sd 4.9 ± 1.3 3 rca 13.9 2 (8.7%) 1 rn 1/23 (4%) 1 crd 2-yr 85.7% 2-yr 81.8% – andrews et al. (2019)[17] not assessed not assessed 7 not mentioned 72 3/48 (6.3%) 2/35 (6%) 2 5-yr 56% 5-yr 91% 5-yr 92.7% 5-yr 90% bhagavatula et al. (2020)[46] 2/25 (92%) 99% range (1–7) 2 rca 95 2 (8%) 2 rca 1 5-yr 91% 5-yr 95% 5-yr 85% 5-yr 96% shimizu et al. (2021)[47] 1/28 (96.4%) 100% 18 5.0 ± 1.5 1 rca 42 2 (7.1%) 2 rca 2/18 (11%) 3 deaths 5-yr 79.1% 5-yr 96% 5-yr 92.7% 5-yr 93% crd: cancer-related death; css: cancer-specific survival; mfs: metastasis-free survival; n/a: not assessed; os: overall survival; pfs: progression-free survival; pn: partial nephrectomy; rca: repeat cryoablation; rn: radical nephrectomy. 217siuj.org siuj • volume 4, number 3 • may 2023 role of cryoablation for the treatment of ct1b kidney lesions: outcomes of a systematic review http://siuj.org to 96%. the data at hand shows that cryotherapy may be a valid alternative to partial or radical nephrectomy for a select group of patients with encouraging oncological outcomes. only small, single-center retrospective studies have been published in the literature that compare the efficacy of ablation therapies (cryoablation or radiofrequency) compared to their surgical counterparts (partial nephrectomy or radical nephrectomy) in this group of patients (ct1b)[20]. caputo et al. published a matched analysis of 62 patients comparing partial nephrectomy to cryoablation in the treatment of t1b tumors and they found no significant difference in both overall mortality (p  =  0.155) or cancer-specific mortality (p = 0.48) between the 2 studied samples[21]. in another cohort, thompson et al. compared long-term outcomes of cryoablation to partial nephrectomy in t1b tumors. those authors retrospectively followed 376 patients from the mayo clinic tumor registry, 14% (n = 52) underwent cryoablation and 86% (n = 324) underwent partial nephrectomy. the median follow-up in that study was 6 years and 8.7 years, respectively, for each of the 2 groups. the authors found no significant difference between both groups in relation to local recurrence, metastases, and death of patients from their tumor. in addition, 5-year cancer-free survival was 91% for the cryotherapy group and 98% for the partial nephrectomy group[5,17]. while some found comparable survival data between both techniques, others have found a higher odds of survival when comparing ca to pn after propensity matching (hazard ratio [hr], 2.74; 95% ci 1.611–4.66; p < 0.001). however, this study didn’t account for tumor complexity using nephrometry score and had a clear selection bias between those treated with pn and those with cryoablation. two of the major concerns for cryoablation remain the local tumor control rate and the local recurrence rate[6,22]. one series by gunn et al. had the highest recurrence rate at 21%; however, this cohort had the highest mean body mass index (bmi) (34.8 ± 8.8), mean cci (7.1 ± 2.4), and median renal score 9 (range, 7–10) of all the patients[23]. higher bmi and higher tumor complexity are additional predictors of recurrence, as seen by caputo et al., who found significant differences in the rate of local recurrence at 1-year follow-up (p = 0.019), with recurrence rates significantly higher for the cryoablation group compared to pn. predictor of recurrence included tumor size, bmi > 30, and endophytic lesions[24]. while tumor complexity is a clear predictor of recurrence[25–28], the effect of bmi on recurrence and success remains controversial, with some series showing no effect of bmi or obesity on survival and recurrence[29,30]. across all series, only 12.1% of the subjects (n = 42) experienced local tumor recurrence, with progression to metastasis only ranging from 4% to 11%. it is important to note that these comparative series have shortterm follow-up, with a median follow-up time between 13 months and 31.6 months. recent data after long-term table 3. complications using the clavien-dindo classification system across all studies* study number of complications grade i grade ii grade iii grade iv grade v atwell et al. (2015)[42] 8 1 3 3 1 0 caputo et al. (2017)[21] 7 1 5 0 1 0 hebbadj et al. (2018)[6] 13 9 1 2 1 0 hasegawa et al. (2018)[36] 2 0 0 2 0 0 rembeyo et al. (2020)[43] 13 12 1 0 0 0 gunn et al. (2019)[44] 17 11 1 4 1 0 grange et al. (2019)[45] 5 4 1 0 0 0 andrews et al. (2019)[17] 8 1 3 3 1 0 bhagavatula et al. (2020)[46] _ _ _ _ _ 0 shimizu et al. (2021)[47] 1 0 0 1 0 0 total 74 39 15 15 5 0 *not considering hematuria for > 24 hours as a complication and allowing 2 asymptomatic hematomas. 218 siuj • volume 4, number 3 • may 2023 siuj.org review http://siuj.org follow-up have shown no difference in 5-year local recurrence-free survival between cryoablation and pn (91.6% vs. 92.7%; hr, 1.46; p  =  0.6)[17]. one reason could be the late recurrence of patients who underwent pn. with regard to postoperative complications, grade iii and above complications were low, at 6.2% across all the series. when comparing ca to pn, caputo et al. (2017) showed a higher incidence of postoperative complications with pn (pn 42% vs. ca 23%; p = 0.10)[21]. a recent systematic review showed a significant increase in postoperative complication of pn compared to ca (or, 2.97; 95% ci, 2.13–4.14; p < 0.001)[29]. cryoablation can be performed either laparoscopically or percutaneously, and this review included both these techniques. the majority of the procedures were done percutaneously; however, some institutions do still use the laparoscopic approach[21,31]. multiple studies have been published comparing outcomes of both techniques. while some series have shown similar complication rates, and similar os, css, and rfs between percutaneous and laparoscopic cryoablation[24], a meta-analysis has shown that percutaneous cryoablation (pca) had shorter hospital stay and laparoscopic cryoablation (lca) had lower incidence of perirenal hematoma. pca is favored for older patients and those with posterior tumors[32]. one final aspect of ca to be raised is the timing of renal mass biopsy (rmb), and whether to do it concomitantly or in a separate session prior to ablation. each institution has a different protocol, hence some of the series had rmb before the procedure while others concomitantly during the ablation procedure. the eau guidelines recommend a percutaneous renal biopsy done prior to ablation therapy rather than concomitantly because biopsy reduces the number of unnecessary ablations of benign lesions, where historically 32% to 45 % of patients undergoing ablation therapy had benign lesions[33–35]. in addition, oncological outcome of patients might differ based on the rcc subtypes detected on biopsy, which will help in better patient counseling and on the best treatment course[36]. comparing the 2 ablative methods (cryoablation vs. radiofrequency), the literature is especially lacking in studies for ct1b lesions. only one published study, performed by hasegawa et al., compared the efficacy of the 2 ablative methods in 46 patients with t1b stage rcc. those authors found that the 5-year os rates were similar between cryoablation and radiofrequency ablation (82% vs. 78%, respectively; p = 0.82), and the 5-year rcc-related survival rate was 100% for both groups[37]. cryoablation is preferentially used in centrally located lesions, for tumors between 3 cm and 7 cm, and for those near the ureter[34,38]. for now, radiofrequency ablation remains reserved for tumors smaller than 3 cm[38]. the eau guideline panel proposal still limits ablative therapy to lesions between 3 cm and 7 cm in patients where surgery is not feasible or contraindicated[40]. long-term oncological effectiveness about cryoablations remains hard to ascertain, as these series are not without limitations. these series are mostly retrospective, observational studies with short-term follow-up. no prospective rct exists that compares outcomes of pn to ca for ct1b kidney tumor. even matching was poor in some comparative series that compared ca and pn. moreover, these series have small sample sizes, and the authors fail to mention the reason for cryoablations or the criteria used to treat these patients with ca, both of which are causes of a selection bias. in addition, the median lesion size ranges from 4.3 cm to 4.8 cm. while this size range falls within the range of ct1b tumors (4 cm to 7 cm), it targets a subset of patients within that group, and these findings may not be generalizable to the larger population of ct1b. currently, there is no consensus on the number and size of probes that are used in the ablative techniques, and this causes some variability between treating centers. lastly, some centers elected to do preoperative or intraoperative embolization of tumor prior to cryoablation. embolization can decrease complications such as hemorrhage and renal collecting system injury in large tumors without affecting renal function. however, its definitive effect on recurrence rate and survival remains to be determined[41,42]. conclusion while partial nephrectomy remains the preferred method to treat ct1b kidney tumors, cryoablation is a feasible alternative with good survival and recurrencefree survival outcomes. cryoablation for t1b tumors might be considered in a select group of patients—those who are older, have multiple comorbidities, or cannot tolerate surgery. it can also serve as a suitable alternative for patients who refuse surgery. acknowledgments availability of data and material all data generated or analyzed during this study are included in this article and its supplementary material files. further enquiries can be directed to the corresponding author. authors contributions m. shahait and a. el-achkar conceived the study and its design; 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versus cryoablation for t1b renal cell carcinoma: a multi-center study. jpn j radiol.2018;36(9):551–558. doi: 10.1007/s11604-018-0756-x. pmid: 29968201. 38. schmit gd, atwell td, leibovich bc, callstrom mr, kurup an, woodrum da, et al. percutaneous cryoablation of anterior renal masses: technique, efficacy, and safety. ajr am j roentgenol. 2010;195(6):1418–1422. doi: 10.2214/ajr.09.3530. pmid: 21098204. 39. zondervan pj, buijs m, de bruin dm, van delden om, van lienden kp. available ablation energies to treat ct1 renal cell cancer: emerging technologies. world j urol.2019;37(3):445–455. doi: 10.1007/s00345018-2546-6. pmid: 30448873; pmcid: pmc6424924. 40. capitanio u, bedke j, albiges l, volpe a, giles rh, hora m, et al. a renewal of the tnm staging system for patients with renal cancer to comply with current decision-making: proposal from the european association of urology guidelines panel. eur urol.2023;83(1):3–5. doi: 10.1016/j.eururo.2022.09.026. pmid: 36253306. 41. harmon ts, matteo j, meyer te, kee-sampson j. pre-cryoablation embolization of renal tumors: decreasing probes and saving loads. cureus. 2018;10 (12):e3676. doi: 10.7759/cureus.3676. pmid: 30761229; pmcid: pmc6367110. 42. miller jm, julien p, wachsman a, van allan rj, friedman ml. the role of embolization in reducing the complications of cryoablation in renal cell carcinoma. clin radiol.2014;69(10):1045–1049. doi: 10.1016/j. crad.2014.05.110. pmid: 25037148. 221siuj.org siuj • volume 4, number 3 • may 2023 role of cryoablation for the treatment of ct1b kidney lesions: outcomes of a systematic review http://siuj.org 43. atwell td, vlaminck jj, boorjian sa, kurup an, callstrom mr, weisbrod aj, et al. percutaneous cryoablation of stage t1b renal cell carcinoma: technique considerations, safety, and local tumor control. j vasc interv radiol.2015;26(6):792–799. doi: 10.1016/j.jvir.2015.02.010. pmid: 25824313. 44. rembeyo g, correas jm, jantzen r, audenet f, dariane c, delavaud c, et al. percutaneous ablation versus robotic partial nephrectomy in the treatment of ct1b renal tumors: oncologic and functional outcomes of a propensity score-weighted analysis. clin genitourin cancer. 2020;18(2):138–147. doi: 10.1016/j.clgc.2019.10.006. pmid: 31982346. 45. grange r, tradi f, izaaryene j, daidj n, brunelle s, walz j, et al. computed tomography-guided percutaneous cryoablation of t1b renal tumors: safety, functional and oncological outcomes. int j hyperthermia. 2019;36(1):1065–1071. doi: 10.1080/02656736.2019.1675913. pmid: 31648584. 46. bhagavatula sk, tuncali k, shyn pb, levesque vm, chang sl, silverman sg. percutaneous ctand mri-guided cr yoablation of ct1 renal cell carcinoma: intermediateto long-term outcomes in 307 patients. radiology. 2020;296(3):687– 695. doi: 10.1148/ radiol.2020200149. pmid: 32633677. 47. shimizu k, enoki k, kameoka y, motohashi k, yanagisawa t, miki j, et al. image-guided percutaneous cr yoablation of t1b renal cell carcinomas in patients with comorbidities. jpn j radiol. 2021;39(12):1213–1222. doi: 10.1007/s11604-021-01168-8. pmid: 34228240. 222 siuj • volume 4, number 3 • may 2023 siuj.org review http://siuj.org 6 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation personalized medicine in urologic oncology yair lotan,1 jack schalken,2 nathan lawrentschuk,3,4 1 department of urology, university of texas southwestern medical center dallas, united states, 2 department of urology, radboud university medical center, nijmegen, the netherlands, 3 department of surgical oncology, peter maccallum cancer centre, melbourne, australia, 4 department of urology, royal melbourne hospital, australia soc int urol j. 2020;1(1):6–7 in an ideal world, the diagnosis and treatment of disease would be non-invasive and precise. biologic testing would be performed using easily available samples such as blood, urine, sputum, and skin swab, which would provide information regarding the cause of a disease as well as prognosis and optimal treatment. although in some areas there has been progress toward these goals, in others, significant work must still be done before molecular markers can be incorporated into common practice. in 2019, the société internationale d’urologie (siu), the international consultation on urological diseases (icud) and the world urologic oncology forum (wuof) convened key opinion leaders from around the world to review the current use of molecular markers for the diagnosis and management of urologic malignancies, as well as developments in research. this special edition of the siuj presents a summary of their work. an ideal marker would fulfill strict criteria demonstrating that it provides clinical benefit, information that is independent from other clinical factors, cost-effectiveness, and reproducibility, and would be comprehensively validated. the pathway to incorporate molecular markers should be standardized, similar to that required for approval of medications. a marker should pass through several phases, as outlined by melissa assel and andrew vickers [1], in which it is tested against the clinical question that it is supposed to answer and should then be validated in multicenter prospective cohorts. many markers do not survive the initial phase of discovery and evaluation in small retrospective cohorts. this phase, while exciting, is subject to risk of bias and overfitting. if a marker is developed that shows promise, the next phase of evaluation should involve validation in independent cohorts. finally, a test of clinical utility should be performed on a prospective cohort in which the marker is evaluated for its ability to change clinical management to the benefit of the patient. in this issue of the siuj, ankeet shah and colleagues discuss the sources from which most molecular biomarkers are obtained and the considerations that are associated with each [2]. blood-based markers have had major impact in the management of testis and prostate cancer. diagnosis and management of testis cancer includes the use of alpha-fetoprotein and beta-hcg. these markers help in differentiating histology and can guide use of chemotherapy, but they have limitations related to sensitivity and specificity. aditya bagrodia and colleagues examine the role of these markers and new promising markers, especially mirna, in the management of testicular germ cell tumors [3]. prostate specific antigen, in contrast, was developed for surveillance of patients with prostate cancer but has been incorporated into screening programs. the use of psa for screening has resulted in decades of controversy, since evaluation of the impact of prostate cancer screening on survival occurred many years after widespread utilization of the marker for this purpose [4]. renu eapen and colleagues examine serum-based markers that have been developed with the intention of overcoming some of the limitations of psa [5]. gillian vandekerkhove and alexander wyatt focus specifically on the development of circulating tumor dna as a clinically useful biomarker for prostate cancer [6]. urine-based markers have had the biggest impact in the management of bladder cancer. urine cytology have been incorporated into guidelines despite poor sensitivity for low-grade cancer and moderate sensitivity for high-grade disease. other urine markers have not been adopted because of failure to fulfill stringent criteria of performance. in this issue of the siuj, tilman todenhöfer and colleagues review the performance of currently available urine-based tumor markers for bladder cancer detection [7], and laura-maria krabbe et al. give an overview of the clinical utility of these markers [8]. similarly, for prostate cancer there are attempts to improve detection using urinary biomarkers, and these are reviewed by renu eapen and colleagues [5]. the utility of tissue-based markers is limited by the accessibility of tissue. nonetheless, in specific clinical scenarios where tissue is readily available, tissue markers can be invaluable. peter lonergan and colleagues [9] report on exciting developments in tissue biomarkers for prostate cancer, while liang qu and colleagues discuss the utility of tissue markers for diagnosis and classification of renal cell carcinoma [10]. http://www.siuj.org mailto:yair.lotan%40utsouthwestern.edu?subject=siuj 7siuj.org siuj • volume 1, number 1 • october 2020 personalized medicine in urologic oncology the emphasis on achieving a high standard of evidence before incorporating markers into clinical practice has merit [1]. it is particularly important because of the risk associated with false positive results, which often lead to unnecessary testing and anxiety. furthermore, these tests may contribute significantly to the cost of health care, a worldwide concern. some biomarkers have been adopted without sufficient evidence of effectiveness, resulting in controversy. the cancer genome atlas, which molecularly characterized over 11 000 cancers [11], has provided important new information regarding urologic cancers, that is now being used to characterize tumor behavior, prognosis, and response to therapy. this program, along with advances in next-generation sequencing will advance the goals of personalized medicine, and significant effort is needed to interpret this information using bioinformatics and to validate its utility in clinical care. multiple new clinical trials are based on targeting specific mutations or enriching the patient population for the expression of immunological markers such as pdl1. understanding the significance of these molecular alterations and how to use them to guide therapy will likely take years; performing trials is critical. patients with metastatic disease, especially urothelial cancer, have a short life expectancy and do not have the luxury of being treated with multiple therapies in an attempt to find one that works. thus, using molecular tests with predictive value to identify early the treatment with the highest likelihood of response may make a major difference for these individuals. rapid advances in our understanding of cancer biolog y are providing multiple opportunities to develop and validate molecular markers that will have a profound impact on patient management. the papers in this special issue of the siuj present information on currently available and potential future markers. for patients, researchers, and providers seek ing to incorporate markers into practice, it is important to evaluate how well the markers perform overall and whether they can provide a tool that improves patients’ care. references 1. assel m, vickers a j. siu -icud consult ation on molecular biomarkers in urological oncology: clinical development of biomarkers. soc int urol j. 2020;1(1):16–22. 2. shah a, grimberg dc, inman ba. siu-icud consultation on molecular biomarkers in urological oncology: classification of molecular biomarkers. soc int urol j. 2020;1(1):8–15. 3. bagrodia a, daneshmand s, cheng l, amatruda j, murray m, lafin jt. siu-icud consultation on molecular biomarkers in urological oncology: the past and future of biomarkers in testicular germ cell tumors. soc int urol j. 2020;1(1):77–84. 4. plco project team, gohagan jk, prorok pc, hayes rb, kramer b-s. the prostate, lung, colorectal and ovarian (plco) cancer screening trial of the national cancer institute: history, organization, and status. control clin trials. 2000;21(6):251s-272s. ht tps://doi. org/10.1016/s0197-2456(00)00097-0 5. eapen r, lonergan pe, bagguley d, ong s, condon b, meng mv. siu-icud consultation on molecular biomarkers in urological oncology: the clinical applications of serum and urinary biomarkers in prostate cancer soc int urol j. 2020;1(1):30–38. 6. vandekerkhove g, wyatt aw. siu-icud consultation on molecular biomarkers in urological oncology: circulating tumour dna as a biomarker source in metastatic prostate cancer. soc int urol j. 2020;1(1):39–48. 7. todenhöfer t, lodde m, van kessel k, pichler r, vlahou a, lotan y. siu-icud consultation on molecular biomarkers in urological oncology: urinar y-based markers for bladder cancer detection. soc int urol j. 2020;1(1):49–61. 8. krabbe l-m, gakis g, lotan y. siu-icud consultation on molecular biomarkers in urological oncology: clinical utility of bladder cancer biomarkers. soc int urol j. 2020;1(1):62–67. 9. lonergan pe, washington sl iii, meng mv, eapen r. siu-icud consultation on molecular biomarkers in urological oncology: the clinical applications of tissue biomarkers in prostate cancer. soc int urol j. 2020;1(1):23–29. 10. qu l, thirugnanasundralingam v, bolton d, finelli a, lawrentschuk n. consultation on molecular biomarkers in urological oncology: tissue-based immunohistochemical markers for diagnosis and classification of renal cell carcinoma soc int urol j. 2020;1(1):68–76. 11. the cancer genome atlas. the national cancer institute. available f r om: h t t p s: // w w w.c an c er.gov/ab ou tn ci/or ganiz a tion /c c g / research/structural-genomics/tcga. accessed august 27, 2020. http://www.siuj.org https://doi.org/10.1016/s0197-2456(00)00097-0 https://doi.org/10.1016/s0197-2456(00)00097-0 https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga age-related mental health consequences of covid-19: a global perspective jean de la rosette,1 pilar laguna,1 guohua zeng,2 patrick coloby,3 adrián momesso,4 raed a. azhar,5 piotr chłosta,6 john heesakkers,7 nicolae crisan,8 leticia ruiz,9,10,11 damien bolton,12 reynaldo gómez,13 laurence klotz,14 sanjay kulkarni,15 simon tanguay,16 stavros gravas17; and on behalf of the société internationale d’urologie (siu) board of directors 1 department of urology, faculty of medicine, istanbul medipol university, istanbul, turkey 2 department of urology and guangdong key laboratory of urology, the first affiliated hospital of guangzhou medical university, guangzhou, china 3 department of urology, centre hospitalier rené dubos, pontoise, france 4 department of urology, centro diagnóstico urológico, buenos aires, argentina 5 department of urology, king abdulaziz university, jeddah, saudi arabia 6 department of urology, jagiellonian university medical college, krakow, poland 7 unit of functional urology and neurourology, department of urology, radboud umc, nijmegen, the netherlands 8 department of urology, iuliu ha ieganu university of medicine and pharmacy, clinical municipal hospital, cluj-napoca, romania 9 the panama clinic, panama city, panama 10 department of urology, hospital punta pacífica, pacífica salud, panama city, panama 11 hospital nacional, panama city, panama 12 department of urology, austin health, melbourne, australia 13 department of urology, universidad andrés bello, hospital del trabajador, santiago, chile 14 division of urology, sunnybrook health sciences centre, toronto, canada 15 kulkarni reconstructive urology center, pune, india 16 division of urology, department of surgery, mcgill university, montreal, canada. 17 department of urology, faculty of medicine, school of health sciences, university of thessaly, larissa, greece abstract purpose the société internationale d’urologie (siu) conducted a survey to determine whether the pandemic has harmed the mental health of practicing urologists worldwide. methods members of the executive board of the siu designed a self-selected survey consisting of multiplechoice questions about the safety and mental health of urologists during the covid-19 pandemic. the survey was disseminated by email to siu members worldwide. result a total of 3448 siu members from 109 countries responded to the survey, which sought to determine the extent of mental health symptoms, including depression, anxiety, insomnia, and distress—experienced during the covid-19 pandemic. overall, 21% of urologists who responded reported that their mental health was very challenged, with 58% indicating increased stress levels, and 15% indicating greatly increased stress levels. older urologists were less likely to report any of the negative mental health symptom queried (ie, delirium [rs = −0.06, p = 0.001], psychosis [rs = −0.04, p = 0.019], anxiety [rs = −0.09, p < 0.001], depression [rs = −0.08, p <0.001], distress [rs = −0.07, p < 0.001]), except insomnia (p > 0.20). furthermore, 29% of urologists indicated they were afraid to go to work, while 53% reported being afraid to go home to their families after work. conclusions in this worldwide survey of practicing urologists, more than half of the participants reported an increase in insomnia, distress, and other psychological symptoms as they managed patients during the covid-19 pandemic, although half of respondents did not experience any mental health symptoms. institutions should provide psychological coping resources to all health care staff, not only for the front-line workers during the pandemic. introduction data have begun to emerge about the ongoing pandemic’s psychological impacts on the front-line health care workers who have faced severe and unprecedented stressors in providing patient care[1–7]. as the novel coronavirus disease 2019 (covid-19) outbreak began in late 2019, leading health organizations rushed to provide resources to help frontline health care workers cope with the psychological stress, basing their response on experiences with the 2003 severe acute respiratory syndrome (sars) epidemic and the ebola epidemic (2013–2016), among others[8–16]. key words competing interests article information mental health, urologists, coronavirus covid-19, pandemic, global health, psychological symptoms none declared. received on september 23, 2020 accepted on november 21, 2020 soc int urol j. 2021;2(1):25–31 25siuj.org siuj • volume 2, number 1 • january 2021 original research mailto:j.j.delarosette%40gmail.com?subject=siuj http://www.siuj.org covid-19 has altered the way in which health care workers currently practice medicine and deliver care, regardless of specialty or discipline. from the curtailment of routine and elective care to the intensification of protective protocols to the redeployment of non-specialist physicians to assist with direct care of covid-19 patients, the practice of medicine in the first months of 2020 differs substantially from late 2019 norms. urologists (one of the affected groups of medical specialists) typically divide their time between patient consultations and surgery. they are not on the front line as emergency responders. however, because of increased staffing needs during the pandemic, some urologists and physicians in other second-line specialties have been redeployed to the emergency departments or covid-19 tents to assist with triage of presumed covid-19 patients, as well as to covid-19 in-patient units and to intensive care units to manage critically ill patients. as the clinical demands faced by health care practitioners have changed, so have the challenges of maintaining mental health equilibrium during an uncertain time. thus, the mental health of all medical workers, including those outside the emergency medicine and critica l care disciplines, warrants evaluation during the pandemic. in this survey, the société internationale d’urologie (siu) aimed to capture the mental health challenges urologists are facing and to determine if these challenges vary by region, gender, or age groups. methods members of the executive board of the siu designed the survey on safety and mental health. this was a selfselected survey comprising multiple-choice questions about respondents’ demographics, as well as concerns related to contracting covid-19 and the provision by health care institutions of personal protective equipment (ppe); information about how to protect staff and patients from covid-19; and tools/support for managing increased stress. the full survey has been published, and issues related to ppe have been addressed separately[17]. this analysis deals with participants’ reports of concerns and stresses related to covid-19, and the support they received from their institutions. the survey was opened on april 16, 2020, and closed on may 1, 2020. it was administered online using the aventri platform (connecticut, us). distribution of the survey took place via email, using names on the siu enews mailing distribution list (15 252 contacts). the survey included the reasons why it was being conducted and the importance of participation. no compensation was offered for its completion. all responses were anonymous. to facilitate analysis of the impact of covid-19 on health care settings as it spread from east to west, respondents were grouped into the following regions: east/southeast asia and nearby regions, west/southwest asia and nearby regions, europe, africa, north america, and south america. the list of countries included in each region has been published elsewhere[17]. information about age and gender was also analyzed to determine the impact of these parameters on mental health. statistical analysis strategy continuous variables were analyzed using omnibus one-way anovas, with follow-up pairwise tests that were bonferroni-corrected for multiple comparisons. categorical questions were analyzed using omnibus pearson chi-square tests, with a follow-up examination of the adjusted standardized residuals, which were also bonferroni-corrected for multiple comparisons. data were analyzed by respondent age (selected from the following 4 categories: <40, 40–50, 51–60, >60), gender, and geographical region. age was analyzed using spearman rank-order correlations (rs). results the siu has a central office located in montreal, canada, and is governed by an international board of directors, with representatives in all continents. the siu currently has 10 018 members in 131 countries. a total of 3488 participants took the survey and the background demographics have been published elsewhere[17]. overall, 21% of urologists reported that their mental health and that of their colleagues was very challenged during this pandemic, with 58% indicating that their stress levels increased, and 15% indicating their stress levels greatly increased (figure 1). while urologists reported feeling appreciated as doctors involved in treating patients during the covid-19 pandemic (median score, 7; range, 0–10), they reported that their mental health has been challenged significantly during the pandemic (median score, 6; range, 0–10). in total, 29% of urologists reported that they were afraid to go to work and 53% reported that they were afraid to go home to their families after work. urologists’ greatest reported fear relating to their work was infecting their families (57%), with 17% reporting fear that they might infect themselves (figure 2). in addition, 14% of urologists reported that their biggest fear was that their ability to provide patient care would be compromised, and 10% reported that their biggest fear was that their institutions would not be able to handle the patient load. 26 siuj • volume 2, number 1 • january 2021 siuj.org original research http://siuj.org many urologists reported that the challenge to their mental health may have resulted in symptoms of insomnia (21%), distress (17%), physical exhaustion (14%), severe anxiety (11%), depression (11%), psychosis (1.6%), posttraumatic stress disorder (ptsd) (1%), or delirium (1%). more than half (53%) the respondents reported experiencing no symptoms due to stress from covd-19 (figure 3). overall, 84% of urologists reported that they know how to protect themselves, and 74.5% said they were getting enough time off work to be healthy and recharge. in total, only 27% of urologists reported receiving psychological or emotional coping tools or suggestions from their institutions (figure 4). among urologists who reported receiving these tools, 61% indicated they were provided with the option of meeting with mental health professionals, 33% reported receiving handouts on mental health, and 25% reported having access to workshops. in addition, 10% reported being required to meet with a mental health professional. also, among urologists who reported receiving psychological or emotional coping tools, 53% received only one such tool, while 24% received 2 and 22% received 3 or more. only 22% of respondents indicated there was a team member, such as a nurse, psychosocial worker, or community social worker, trained to provide support to the health care team (figure 4). among the 78% who reported not receiving such support, 53% thought it would be helpful to have it. analyses were performed by gender, region, and age. the analysis of gender and geographical region did not yield clinically relevant results. age differences older urologists reported feeling more appreciated than younger urologists as doctors involved in treating patients during covid-19 (rs = 0.11, p < 0.001). they were less likely than younger urologists to report that their own mental health and that of their colleagues was challenged during this pandemic (rs = −0.08, p < 0.001). older urologists were also less likely than younger urologists to report fear of going to work (rs = −0.04, p  = 0.025) or going home after work (rs = −0.16, p < 0.001). they also reported experiencing less avoidance by their family or community (rs = −0.10, p < 0.001), were more likely than younger urologists to report being most afraid that they would become infected (rs = 0.11, p < 0.001), and less likely to report being most afraid that members of their family would become infected (rs = −0.15, p < 0.001). every negative mental health symptom queried (except insomnia [p > 0.20]) was less common in older urologists: delirium (rs = −0.06, p = 0.001), psychosis (rs = −0.04, p = 0.019), anxiety (rs = −0.09, p < 0.001), figure 1. impact of covid-19 on stress level, by age (survey question 22) fig 1 a79x figure 1. impact of covid-19 on stress level, by age (survey question 22) 55.52 58.60 58.29 61.59 57.88 0 10 20 30 40 50 60 70 80 90 100 greatly increased increased same decreased pr op or tio n of re sp on de nt s % degree of change in stress 16.89 13.48 14.27 12.60 14.71 22.82 23.80 25.27 23.74 23.58 4.78 4.11 2.17 2.24 3.76 <40 40–50 51–60 >60 total 27siuj.org siuj • volume 2, number 1 • january 2021 age-related mental health consequences of covid-19: a global perspective http://www.siuj.org figure 3. experience of symptoms due to covid-19 (survey question 24) figure 2. biggest fears about covid-19, by age (survey question 23) fig 3 a79 figure 3. q24: experience of symptoms due to covid-19 10.9 21.3 delirium psychosis severe anxiety depression insomnia symptom distress physical exhaustion ptsd none abbreviation: ptsd, posttraumatic stress disorder 11.4 0.8 1.6 16.5 1.1 14.0 53.4 0 10 20 30 40 50 60 70 80 90 100 pr op or tio n of re sp on de nt s % fig 1 a79x figure 1. impact of covid-19 on stress level, by age (survey question 22) 64.09 59.27 49.59 42.48 56.54 becoming infected member of family becoming infected fear of going to work fear of going home degree of change in stress 13.34 14.82 18.07 27.24 16.74 31.71 29.70 25.78 29.49 29.09 62.59 52.72 43.73 43.49 52.98 <40 40–50 51–60 >60 total 0 10 20 30 40 50 60 70 80 90 100 pr op or tio n of re sp on de nt s % 28 siuj • volume 2, number 1 • january 2021 siuj.org original research http://siuj.org depression (rs = −0.08, p < 0.001), distress (rs = −0.07, p < 0.001), ptsd (rs = −0.04, p = 0.025), and physical exhaustion (rs = −0.10, p < 0.001). older urologists were less likely to report such outcomes overall (rs = −0.14, p < 0.001), but they were more likely to report having no symptoms (rs = 0.12, p < 0.001). older urologists were more likely than younger urologists to report feeling that they knew how to protect themselves at work from becoming infected with covid-19 (rs = 0.08, p < 0.001), and were more likely to report getting enough time off work to recover and recharge (rs = 0.09, p < 0.001). older urologists were also less likely to report sleeping at their institutions (rs  = −0.24, p < 0.001). older urologists were not more likely than younger urologists to report that their institutions provided them with psychological or emotional coping tools (p > 0.25) or to report that there was someone on their team trained to provide psychosocial support (rs = 0.03, p = 0.065). among urologists who said that there was no such person on their team, older urologists were less likely than younger urologists to say that such a person would be helpful (rs = −0.10, p < 0.001). discussion recent evidence suggests that covid-19 has taken its toll on the mental and physical health of physicians and related health professionals, as well as on the general population[1-7]. this survey addressed the impact of the covid-19 pandemic on the mental well-being of urologists, who typically do not work with infected patients. nonetheless, physical or mental symptoms due to covid-19 were reported by nearly half of urologists. despite their lack of front-line exposure to covid-19 patients, urologists reported overall high rates of negative mental health and well-being outcomes. almost one-third reported that they were afraid to go to work, while more than half reported that they were afraid to go home to their families after work. these findings may be explained by the fact that health care workers are fighting an invisible and virulent enemy in high-risk settings. a continuous and seemingly endless number of covid-19 patients have been treated by urologists during the past months, which has relentlessly challenged the boundaries of their own mental and physical limits. with limited short-term perspective on the one hand, and lack of ppe and mental health support on the other, it comes as no surprise that the challenges we are facing are similar to those encountered during earlier pandemics such as sars; however, the impact of the covid-19 pandemic is novel. during the past decade(s), health care systems have evolved, with the figure 4. ability/support received to address fears about covid-19, by age (survey question 25) fig 1 a79x figure 4. ability/support received to address fears about covid-19, by age (survey question 25) 71.83 78.30 79.16 83.55 76.95 0 10 20 30 40 50 60 70 80 90 100 know how to protect oneself getting enough time off work hospital provides coping tools hospital provides psychosocial support pr op or tio n of re sp on de nt s % knowledge/support to address covid-19 fears 82.88 86.82 88.90 86.33 25.97 26.25 28.35 26.77 27.55 20.73 22.70 23.74 24.24 22.43 <40 40–50 51–60 >60 total 89.94 29siuj.org siuj • volume 2, number 1 • january 2021 age-related mental health consequences of covid-19: a global perspective http://www.siuj.org training of physicians occurring under strict working directives and hours-of-service limits. an increasing number of physicians are working fewer hours per week and giving greater importance to their quality of life rather than making work their priority. while we did not observe any striking differences in mental health impact by region or gender, we observed significant differences in various mental health domains among age groups. older urologists reported that their mental health and that of their colleagues was less challenged during this pandemic than the mental health of younger urologists, and they were less likely than younger urologists to be afraid to go to work or afraid they would infect their family when they returned home. on the other hand, older urologists were more likely to be concerned about becoming infected themselves. given that their age makes them more vulnerable, this is a reasonable reaction. although we did not observe high proportions of reports of severe negative mental health outcomes, such as delirium, psychosis, or ptsd, there were relatively high rates of reported anxiety, depression, insomnia, and distress. all symptoms except insomnia were more likely to be reported by younger urologists. older urologists were also more likely than their younger counterparts to report having no mental health symptoms at all. this analysis offers the prospect of constructing a profile of the most psychologically vulnerable. this would be difficult within the present dataset. while the initial analysis suggested that single urologists showed several worse mental health outcomes than those with partners, after controlling for age, the social environment factor no longer emerged as an independent predictor. only age was predictive. older urologists reported feeling more appreciated than younger urologists, and they were less likely than younger urologists to indicate that their mental health and that of colleagues was challenged during this pandemic. despite the challenges that urologists face in terms of their mental health and well-being, they reported that they were not receiving adequate coping tools from their institutions. only 22% had a team member trained to provide psychosocial support and 53% of those who did not have such support reported that it would be helpful. both patients and health care professionals have been affected by the psychosocial consequences of the covid-19 crisis[1-7]. several groups have been working on specific guidelines for mental health services for the covid-19 outbreak, but their efforts may not have reached non-front-line health care professionals. the greater impact on the psychological functioning of younger doctors warrants further exploration. the effectiveness of this approach has been demonstrated among health care workers in china, where early intervention decreased the prevalence of insomnia in front-line professions within a short time period [18]. in addition, during the previous sars outbreak, health care workers with higher levels of trust in equipment or infection-control initiatives showed lower levels of emotional exhaustion and mental problems[19]. the present survey provides a global snapshot of a group of medical specialists who are partly involved in handling and treating covid-19-infected patients. adverse psychological effects were common, and adequate support was rare. we propose that large-scale epidemiological surveys be conducted to help examine the prevalence of mental health problems associated with the covid-19 pandemic in different subpopulations, including health care workers. we hope that these findings may be shared with our colleagues in psychology/psychiatry to benefit further research and address the growing problem in mental health issues during the pandemic. these are extraordinary times demanding extraordinary actions. we believe that health care workers need and are entitled to adequate work-related psychosocial supports from their institutions. we conclude by quoting greenberg et al.: “there is a pressing need to ensure that the tasks ahead do not cause long-lasting damage to health care staff. they will be the heroes of the day, but we will need them for tomorrow”[7]. there are several limitations to this survey. first, the questionnaire itself was not validated, as we aimed to capture the data rapidly during the initial stages of the pandemic. this survey is limited by its selfselected nature. the survey was restricted to urologists, because of the composition of siu membership. the participation by region of urologists in africa and south america was low, as was the participation of women (11.4%). unfortunately, the subdivision of regions was decided at the time of the survey preparation and did not directly correspond to the who regional classification, so it was not possible to compare the pandemic load by region with the who data[8]. in addition, we did not find any significant differences in outcome by region. the survey’s strength is that it provides a global snapshot of the mental health conditions in a significant sample size (3488 participants). it seems apparent from the survey that there is a worldwide need for further resources to address the adverse mental health effects of the pandemic on urologists and other health care workers. 30 siuj • volume 2, number 1 • january 2021 siuj.org original research http://siuj.org conclusions urologists face substantial struggles with respect to their mental health and well-being during the covid-19 pandemic, and many are not offered adequate coping tools or support from their institutions. older urologists reported better mental health and well-being outcomes than younger urologists. acknowledgments the authors would like to acknowledge support from the siu central office, including merveille de souza, carrie thompson, melissa st-onge, susie petrusa, and christine albino, for editorial support; and the contributions of darcy lewis and alison palkhivala for medical writing support, and michael barlev for statistical support. references 1. lai j, ma s, wang y, cai z, hu j, wei n, et al. factors associated with mental health outcomes among health care workers exposed to coronavirus disease 2019. jama netw open. 2020;3(3):e203976. doi:10.1001/jamanetworkopen.2020.3976. 2. galea s, merchant rm, lurie n. the mental health consequences of covid-19 and physical distancing: the need for prevention and early intervention. jama intern med. 2020 jun 1;180(6):817-818. online ahead of print, april 2020. doi:10.1001/jamainternmed.2020.1562. 3. pappa s, ntella v, giannakas t, giannakoulis vg, papoutsi e, katsaounou p. prevalence of depression, anxiety, and insomnia among health care workers during the covid-19 pandemic: a systematic review and meta-analysis. brain behav immun. 2020 may 8;s0889-1591(20):30845-x. online ahead of print. doi:10.1016/j. bbi.2020.05.026. 4. felice c, di tanna g, zanus g, grossi u. impact of covid-19 outbreak on health care workers in italy: results from a national e-survey. j community health. 2020 may 22;1-9. online ahead of print. doi:10.1007/s10900-020-00845-5. 5. abbasi j. prioritizing physician mental health as covid-19 marches on. jama. 2020 jun 9;323(22):2235-2236. online ahead of print, 2020 may 20. doi:10.1001/jama.2020.5205 doi 6. liu q, luo d, haase je, guo q, wang xq, liu s, et al. the experience of health-care providers during the covid-19 crisis in china: a qualitative study. lancet glob health. 2020;8(6):e790 – e798. doi:10.1016/s2214-109x(20)30204-7. 7. greenberg n, docherty m, gnanapragasam s, wessely s. managing mental health challenges faced by health care workers during covid-19 pandemic. bmj. 2020;368:m1211. published online march 26, 2020. doi:10.1136/bmj.m1211. 8. world health organization. mental health and psychosocial considerations during the covid-19 outbreak. world health organization; march 18, 2020. available at: https://www.who.int/ docs/default-source/coronaviruse/mental-health-considerations. pdf?sfvrsn=6d3578af_10. accessed may 26, 2020. 9. american medical association. managing mental health during covid-19. american medical association; april 24, 2020. available at: ht tps://w w w.ama-assn.org /delivering-care/public-health/ managing-mental-health-during-covid-19. accessed may 26, 2020. 10. smith m w, smith p w, k ratochvil c j, schwedhelm s. t he psychosocial challenges of caring for patient s with ebola virus disease. health secur. 2017;15 (1):10 4 –109. doi:10.1089/ hs.2016.0068 11. lu yc, shu bc, chang y y, lung f w. the mental health of hospital workers dealing with severe acute respiratory syndrome. psychother psychosom. 2006;75(6):370-375. doi:10.1159/000095443. 12. lancee wj, maunder rg, goldbloom ds; coauthors for the impact of sars study. prevalence of psychiatric disorders among toronto hospital workers one to t wo years af ter the sars outbreak. psychiatr serv. 2008 jan;59(1):91-95. doi:10.1176/ps.2008.59.1.91. 13. mcalonan gm, lee am, cheung v, cheung c, tsang kwt, sham pc, et al. immediate and sustained psychological impact of an emerging infectious disease outbreak on health care workers. can j psychiatry. 2007 apr;52(4):241-247. doi:10.1177/070674370705200406. 14. bai ym, lin cc, lin cy, chen jy, chue cm, choup. survey of stress reactions among health care workers involved with the sars outbreak. psychiatr serv. 2004 sep;55(9):1055-1057. doi:10.1176/ appi.ps.55.9.1055. 15. lee sm, kang ws, cho ar, kim t, park jk. psychological impact of the 2015 mers outbreak on hospital workers and quarantined hemodialysis p atient s. compr psychiatry. 2 018;8 7:12 3 -12 7. doi:10.1016/j.comppsych.2018.10.003. 16. maunder r, hunter j, vincent l, bennett j, peladeau n, leszcz m, et al. the immediate psychological and occupational impact of the 20 0 3 sa rs outbreak in a teaching hospital. cmaj. 2003;168:1245-1251. 17. de la rosette j, laguna p, álvarez-maestro m, eto m, mochtar ca, albayrak s, et al. cross-continental comparison of safet y and protection measures amongst urologists during covid-19. int j urol. 2020;27(11):981–989. online ahead of print, aug 8, 2020. doi:10.1111/iju.14340. 18. xiang y t, jin y, cheung t. joint international collaboration to combat mental health challenges during the coronavirus disease 2019 pandemic. jama psychiatry. 2020 oct 1;77(10):989-990. online april 10, 2020. doi:10.1001/jamapsychiatry.2020.1057. 19. marjanovic z , greenglass er, c of fey s. t he relevance of psychosocial variables and working conditions in predicting nurses’ coping strategies during the sars crisis: an online questionnaire sur vey. int j nurs stud. 2007 aug;4 4(6):991-998. doi:10.1016/j. ijnurstu.2006.02.012. 31siuj.org siuj • volume 2, number 1 • january 2021 age-related mental health consequences of covid-19: a global perspective https://www.who.int/docs/default-source/coronaviruse/mental-health-considerations.pdf?sfvrsn=6d3578af_10 https://www.who.int/docs/default-source/coronaviruse/mental-health-considerations.pdf?sfvrsn=6d3578af_10 https://www.who.int/docs/default-source/coronaviruse/mental-health-considerations.pdf?sfvrsn=6d3578af_10 https://www.who.int/docs/default-source/coronaviruse/mental-health-considerations.pdf?sfvrsn=6d3578af_10. accessed may 26, 2020 https://www.who.int/docs/default-source/coronaviruse/mental-health-considerations.pdf?sfvrsn=6d3578af_10. accessed may 26, 2020 http://www.siuj.org frequency of metabolic abnormalities in pakistani children with renal stones muhammad tanveer sajid,1 muhammad rafiq zafar,1 qurat-ul-ain mustafa,2 rabia abbas,3 sohail raziq,1 khurram mansoor1 1 armed forces institute of urology, rawalpindi, pakistan 2 army medical college, rawalpindi, pakistan 3 pak emirates military hospital, rawalpindi, pakistan abstract objective to determine the frequency of various metabolic abnormalities in children with urinary lithiasis. methods this cross-sectional study was conducted at the armed forces institute of urology, rawalpindi, from 30 january 2017 to 1 february 2020. a total of 1355 children who were aged 4 to 14 years and who had renal stones were included, while those with urinary tract infections, posterior urethral valve, pelvi-ureteric junction obstruction, reflux disease, and chronic renal failure were excluded. twenty-four-hour urine samples were analyzed for urinary uric acid, calcium, oxalate, citrate, and magnesium. demographics and metabolic abnormalities—hypercalciuria, hyperoxaluria, hypocitraturia, hyperuricosuria, and hypomagnesuria—were noted and analyzed. results the study analysis included 1355 patients. low urine volume was observed in 465 (34.3%) of the patients. three hundred nine patients (22.8%) had metabolic abnormalities, the most common being hypocitraturia (184, 59.5%) followed by hypercalciuria (136, 44%) and hypomagnesuria (126, 40.8%). mean age of presentation, disease duration, recurrent bilateral stones were found significantly different in those having metabolic abnormalities (7.81±2.25 versus 8.76±2.50 p < 0.001, 7.73±1.50 versus 8.43±1.54 p < 0.001, 19.4 versus 2.4% p < 0.001 respectively). no significant difference was found in frequency of abnormal urinary metabolic parameters between boys and girls (p > 0.05) or, upon data stratification, on the basis of disease duration, stone laterality, and recurrence. conclusions metabolic abnormalities were found in 22.8% % of children presenting with urinary lithiasis. the most frequent abnormality observed was hypocitraturia followed by hypercalciuria and hypomagnesuria. early identification helps manage such patients appropriately, mitigating long-term sequelae. introduction there has been a sharp rise in urinary lithiasis in the pediatric population over the past couple of decades, probably due to global warming and the widespread westernization of diet, which has led to the obesity pandemic, as well as other environmental factors[1]. although the true incidence is not known, it is estimated that 6% to 10% of children are affected. although the lifetime risk varies widely among nations, metabolic disorders are found in in approximately 40% to 50% of children with urolithiasis[2]. the disease is endemic in pakistan, turkey, and saudi arabia, as well as in some south asian and african countries. hot climate, poverty, paucity of clean water, and malnourishment are contributing factors[3]. urinary stones are typically classified by their location or by their chemical composition. pediatric urolithiasis is a multifactorial disease, rightly considered by many as a symptom of underlying abnormality, either metabolic or anatomical, having poorly understood etiopathogenesis[4]. supersaturation-crystallization is the most widely accepted theory. most patients present with non-specific symptoms. late presentation is a norm leading to significant key words competing interests article information child, calcium oxalate, crystallization, hypercalciuria, lithiasis, magnesium, uric acid, urinalysis none declared. received on july 22, 2020 accepted on september 28, 2020 soc int urol j. 2021;2(1):18–24 18 siuj • volume 2, number 1 • january 2021 siuj.org original research mailto:muhammadtanveersajid%40gmail.com?subject=siuj http://www.siuj.org delay in the diagnosis. ultrasonography is the preferred preliminary investigation, as it is non-invasive, easily available, and repeatable[5]. thorough metabolic evaluation of all children who have renal stones is the linchpin if morbidity and long-term renal complications are to be prevented. moreover, stone disease carries a high probability of recurrence among children, necessitating early identification of those at risk, prophylaxis, and lifestyle modifications. the 24-hour urine screening test is the most important tool in the diagnostic workup of children presenting with urinary lithiasis[6]. in adults, treatment options include watchful waiting, extracorporeal shock wave lithotripsy, ureterorenoscopy, percutaneous nephrolithotomy, and open removal. in children, however, extracorporeal shock wave lithotripsy and minimal invasive procedures utilizing smaller diameter scopes are preferred[7]. prophylactic treatment to prevent recurrence depends upon identification of metabolic abnormalities among those at risk. studies conducted worldwide have found a very high incidence of metabolic abnormalities when children presenting with nephrolithiasis were subjected to metabolic screening[8]. in recent years, several studies have studied metabolic evaluation of stone formers, but most deal with adult populations compounded by presence of limited local data having small sample size and absence of 24-hour urinary metabolic screening[9]. in this context, the current study aims to assess the frequency of metabolic abnormalities among local children presenting with urolithiasis. this is intended to help clinicians design management protocols that incorporate urine metabolic screening as an integral part, with a view to preventing stone recurrence. methods this descriptive cross-sectional study was conducted at the department of urology and renal transplantation, afiu rawalpindi pakistan, a quaternary care state-ofthe-art facility, from 30 january 2017 to 1 february 2020. approval was provided by the hospital’s ethical review board (certificate # uro-adm-trg-1/irb/2017/106), an independently organized body adhering to the guidelines of the declaration of helsinki, the who, and the international council on harmonization and good practice (ich-gcp). over a 3-year period, a non-probability consecutive sampling technique was used to enroll 1355 patients who met the inclusion criteria (children of both sexes, aged 4 to 14 years, with a confirmed diagnosis of renal stones), while those who had pujo, urinary tract infections, puv, vesicoureteral reflux, inadequate 24-hour urine samples, and crf were excluded. written informed consent was obtained from the patients and their guardians as deemed appropriate. all urine samples were obtained from the patients, without dietary restrictions, once lithiasis and/or associated uti had been treated. clean plastic bottles having 10 ml of 6m hydrochloric acid as preservative were used to collect 24-hour urine samples, and additional samples were collected without preservative to measure uric acid. collection adequacy was verified by urine creatinine excretion rate. urinary calcium, magnesium, citrate, oxa late, and uric acid were determined by a calorimetric method with advia 1800 clinical chemistry system (siemens medical solutions, malvern, us), while ph was measured by the mission expert urinalysis reagent strips (acon laboratories inc., san diego, us). presence or absence of metabolic abnorma lities ie, hy perca lciuria, hy peroxa luria, hypocitraturia, hyperuricosuria and hypomagnesuria (as per operational definition), as well as demographic details (age, sex, residence, educational status, bmi, urine volume, duration of symptoms, clinical presentation, family history of urolithiasis, stone laterality, and stone recurrence) were recorded on a specially designed proforma. stone recurrence was defined as symptomatic stone recurrence diagnosed on ultrasound or ct scan a minimum 30 days after complete clearance of stones. the following values were used to define abnormalities on 24-hour urine: creatinine (12 to 30mg/ kg), hypocitraturia (< 365mg/1.73m2 for boys and < 310mg/1.73m2 for girls), hypercalciuria (> 4mg/kg), hyperoxaluria (> 45mg/1.73m2), hypomagnesuria (< 1.2mg/kg), hyperuricosuria (> 9.3mg/kg) and low urine volume (< 1ml/kg/hr × 24hrs). statistical analysis was done using ibm spss statistics for windows, version 24.0. (armonk, ny: ibm corp). descriptive statistics were used to calculate means ±standard deviation for quantitative variables, while frequencies with percentage were calculated for qualitative variables, significance being determined by student t test and chi-square test, respectively. effect modifiers like age, sex, duration of disease, stone laterality, and recurrence were controlled by stratification. post-stratification chi-square was applied to determine the effect on metabolic abnormalities. p ≤ 0.05 was considered significant. results the study analysis included 1355 patients (75.7% of total 1789 reported; 434 (24.3%) excluded) with mean age 8.54±2.47 years, and male to female ratio 1.25:1. low urine volume was found in 465 (34.3%) of the patients. three hundred nine patients (22.8%) were found to have metabolic abnormalities. mean age of presentation was significantly younger in those having metabolic abnormalities (7.8±2.3 versus 8.8±2.5; p < 0.001), and more male than female 19siuj.org siuj • volume 2, number 1 • january 2021 frequency of metabolic abnormalities in pakistani children with renal stones http://siuj.org patients were affected with metabolic derangements (1.6:1 versus 1.2:1; p <0.01). disease duration and bmi were significantly lower in patients with metabolic abnormalities (p < 0.001), who also exhibited frequent bilateral recurrent stones and positive family history (in all cases, the difference was statistically significant, p < 0.001) (table 1). in the 309 patients with metabolic abnormalities, hypocitraturia (184, 59.5%) was the most common der a ngement , fol lowe d by hy poc a lc iu r ia a nd hypomagnesuria (table 2). when broken down by each type of metabolic abnormality individually, there was no statistically significant difference between subgroups of children stratified by sex, disease duration (± 6 months), stone laterality (right, left, or bilateral) and presence or absence of recurrence (table 3). discussion urinary lithiasis in pediatric populations is relatively rare but increasing steadily across the globe[1]. several factors can predispose children to nephrolithiasis, notably metabolic and genitourinary abnormalities[4]. recurrence is a hallmark of childhood stone disease, imposing considerable morbidity and cost[6]. the current study was conducted to determine the frequency of metabolic derangement among local children presenting with renal stones. our results show concordance with national as well as international literature, albeit with a different study population. in a study by rizvi et al.[10], the m: f  ratio was 2.7:1, the mean age was 7.1±3.8 years, and patients and malnutrition in their patients. metabolic evaluation was performed in 1892 children, revealing hypovolemia, hypocitraturia, and hyperoxaluria. our findings were similar with respect to age, nutritional status, and low urine volume, and hypocitraturia being the most common abnormality, but not with respect to sex distribution. however, in keeping with our findings, other studies have reported a male preponderance in children with metabolic abnormalities[3,11]. children in our study who had metabolic abnormalities were younger, had earlier presentation, presented more frequently with bilateral stones, and were more likely to have positive family history. there is wide variation in the reported frequency of metabolic abnormality (33% to 93% of children with renal stones), depending upon geographical region of the study. issler et al.[8] in their review carried in the uk found a frequency of 34%, similar to our findings, while studies by elmecai et al. in turkey[12] and gajengi et al. in india[13] reported 83.2% and 64%, respectively. similarly, bilge et al.[14] in their study analyzed children aged 16.8 ± 14.9 months and found metabolic abnormalities in 17.8% of cases, hypercalciuria being the most common (88.9%). barata et al.[15] in a retrospective analysis of children with nephrolithiasis in brazil reported a 13.6% frequency of metabolic abnormality. the most frequent disorders found were hypercalciuria, hyperuricosuria, and hypocitraturia. frequency was 22.8% in this study. the higher frequency may be due to a hot, humid climate, and, in keeping with the international literature, bilateral and recurrent stones were associated with positive family history. however, in contrast to our results, obesity rather than malnutrition was associated with metabolic abnormality as also indicated by bandari et al.[16]. ethnic and geographic differences may account for the variations in the reported prevalence of abnormalities in children with metabolic disorder. elmecai et al.[12] studied 143 preschool children a nd fou nd hy per uricosuria a nd hy pocit raturia to be most frequent disorders (24.5% and 23.8% respectively). they also found that 16.8% of patients had multiple metabolic abnormalities. in a study of 100 iranian children with urolithiasis, sadeghi et al.[17] reported hypocitraturia (64%) to be most common abnormality followed by hypercalciuria (56%), while velásquez-forero et al.[18] found hypocitraturia in 70%, hypomagnesuria in 42%, and hypercalciuria in 37% of mexican children evaluated. van dervoort et al.[19] similarly observed hypocitraturia to be the most commonly identified metabolic abnormality in a us population, present in 52% of the children, but rellum et al. found hypercalciuria to be most common in a dutch cohort, present in 47%[20]. our results revealed hypocitraturia in 59.5% children, hypocalciuria in 44%, and hypomagnesuria in 40.8%, while 14.6% had hyperuricosuria, and hyperoxaluria was present in 9.4%, which is consistent with the findings of previous reports[6,21]. however, in contrast to our findings, copelovitch et al.[22] reported hypercalciuria in 30% to 50% of the cases, and nasseri et al.[23], and amancio et al.[24] reported hyperuricosuria as a frequent metabolic change. similarly, isler et al.[8] reported hypercalciuria in 52%, hyperoxaluria in 21%, and cystinuria in 22%, while 27% also had bilateral stones. children with metabolic abnormalities in the current study had bilateral stones in 19.4% of cases compared to 2.6% in children without metabolic abnormalities (p <  0.001). a statistically significant relation was revealed among bilateral, recurrent stones, and family history in our study, underscoring the importance of metabolic assessment in children, as early identification allows targeted treatment which mitigates recurrence among those with longer life expectancy. as ours is a referral institute with a wide catchment area, our cohort of the represent all socioeconomic strata of the society, thus allowing generalization of the results. 20 siuj • volume 2, number 1 • january 2021 siuj.org original research http://siuj.org table 1. demographic features of children presenting with renal stones (n=1355) demographic variable patients without metabolic abnormalities (n=1046) patients with metabolic abnormalities (n= 309) p value age of the patient (mean±sd) 8.8±2.5 7.8±2.3 <0.001 gender distribution (m:f) 563:483 191:118 0.013 bmi (kg/m2) 16.3±1.3 15.6±1.5 <0.001 disease duration (months) 8.4±1.5 7.7±1.5 <0.001 urine volume (ml /kg) normal 686(65.6) 204(66.1) 0.89 low 360(34.4) 105(33.9) residence (n %) 0.36urban 515(49.2) 143(46.3) rural 531(50.8) 156(53.7) educational status (n %) 0.19 not attending school 180(17.2) 53(17.2) attending school 670(64.1) 184(59.5) disconnected education 196(18.7) 72(23.3) recurrent stones (n %) <0.001yes 114(10.9) 108(35) no 932(89.1) 201(65) family counselling (n %) 0.13yes 728(69.6) 229(74.1) no 318(30.4) 80(25.9) stone laterality (n %) <0.001 right 490(46.8) 116(37.5) left 529(50.6) 133(43) bilateral 27(2.6) 60(19.4) family history urolithiasis (n %) <0.001yes 94(9) 116(37.5) no 952(91) 193(62.5) clinical presentation (n %) 0.93 incidental 88(8.4) 25(8.1) abdominal/flank pain 260(24.9) 73(23.6) urinary tract infection 434(41.5) 130(42.1) hematuria 154(14.7) 49(15.9) vomiting 52(5) 15(4.9) enuresis 37(3.5) 08(2.6) urgency 21(2) 09(2.9) 21siuj.org siuj • volume 2, number 1 • january 2021 frequency of metabolic abnormalities in pakistani children with renal stones http://siuj.org more recent studies conducted in china[25] and the uk[26] found hypocitraturia and cystinuria to be the most common abnormalities. cystinuria has a reported frequency of 2% to 8%. our study did not report this abnormality as our institution does not have the capacity to test for it. different dietary habits and hereditary factors might influence differences in urine chemistry results explaining variegated pattern of frequencies world over. stone analysis was performed in various studies across the globe finding calcium oxalate and phosphate among 77% to 86 % of the patients[9,20], however such details were not reported in the studied patients so the type of stone cannot be commented upon. no significant difference was found in the frequency of abnormal urinary metabolic parameters between boys and girls (p > 0.05), which is consistent with results of elmaci et al.[12]. similarly, we did not find any difference in metabolic abnormalities with respect to age, laterality, and recurrence. our data showed significantly lower table 2. frequency of various metabolic abnormalities among children diagnosed with metabolic abnormalities metabolic disorder frequency (n %) yes no hypocitraturia 184(59.5) 125(40.5) hypercalciuria 136(44) 173(56) hypomagnesuria 126(40.8) 183(59.2) hyperuricosuria 45(14.6) 264(85.4) hyperoxaluria 29(9.4) 280(90.6) table 3. data stratification with respect to disease duration, stone laterality and recurrence in children having metabolic abnormalities (n=309) variable hypocitraturia (n %) p value hypercalciuria (n %) p value hypomagnesuria (n %) p value hyperuricosuria (n %) p value hyperuricosuria (n %) p value yes no yes no yes no yes no yes no disease duration <06 months 37(12) 25(8) 0.79 28(9) 34(11) 0.79 27(9) 35(11) 0.25 09(3) 53(17) 0.47 06(2) 56(18) 0.07 >06 months 147(48) 100(32) 0.84 108(35) 139(45) 0.91 99(32) 148(50) 0.82 36(11) 211(68) 0.75 23(7) 224(72) 0.66 stone laterality right 71(23) 45(15) 0.19 60(19) 56(18) 0.95 41(13) 75(24) 0.44 14(4) 102(33) 0.06 11(4) 105(34) 0.35 left 80(26) 53(17) 0.16 46(14) 87(28) 0.71 62(20) 71(23) 0.35 23(7) 110(36) 0.48 10(3) 123(40) 0.21 bilateral 33(11) 27(9) 0.45 30(10) 30(10) 0.77 23(7) 37(12) 0.44 08(3) 52(17) 0.65 08(3) 52(17) 0.65 stone recurrence yes 67(22) 41(13) 0.32 54(17) 54(17) 0.84 46(15) 62(20) 0.16 0.91 09(3) 99(32) 0.68 no 84(27) 117(38) 0.52 82(26) 119(38) 0.90 80(26) 121(39) 0.05 0.38 20(6) 181(59) 0.26 22 siuj • volume 2, number 1 • january 2021 siuj.org original research http://siuj.org table 3. data stratification with respect to disease duration, stone laterality and recurrence in children having metabolic abnormalities (n=309) variable hypocitraturia (n %) p value hypercalciuria (n %) p value hypomagnesuria (n %) p value hyperuricosuria (n %) p value hyperuricosuria (n %) p value yes no yes no yes no yes no yes no disease duration <06 months 37(12) 25(8) 0.79 28(9) 34(11) 0.79 27(9) 35(11) 0.25 09(3) 53(17) 0.47 06(2) 56(18) 0.07 >06 months 147(48) 100(32) 0.84 108(35) 139(45) 0.91 99(32) 148(50) 0.82 36(11) 211(68) 0.75 23(7) 224(72) 0.66 stone laterality right 71(23) 45(15) 0.19 60(19) 56(18) 0.95 41(13) 75(24) 0.44 14(4) 102(33) 0.06 11(4) 105(34) 0.35 left 80(26) 53(17) 0.16 46(14) 87(28) 0.71 62(20) 71(23) 0.35 23(7) 110(36) 0.48 10(3) 123(40) 0.21 bilateral 33(11) 27(9) 0.45 30(10) 30(10) 0.77 23(7) 37(12) 0.44 08(3) 52(17) 0.65 08(3) 52(17) 0.65 stone recurrence yes 67(22) 41(13) 0.32 54(17) 54(17) 0.84 46(15) 62(20) 0.16 0.91 09(3) 99(32) 0.68 no 84(27) 117(38) 0.52 82(26) 119(38) 0.90 80(26) 121(39) 0.05 0.38 20(6) 181(59) 0.26 bmi in those having metabolic abnormalities similar to findings of isler et al.[8]. nevertheless, quoted literature is divided on whether obesity or malnutrition contributes to stone formation. the reason for lower bmi in our patients is malnutrition, which is prevalent in this part of the world. the reported frequency of positive family history varies. amancio et al.[24] reported positive family history in 85% of patients, and barata et al.[15] in 61.3%. in the present study, 37.5% of the analyzed patients reported positive family history, recurrent stones were present in 35%, and bilateral stones in 19.4% of those having metabolic abnormalities. the findings are similar to those of ferraro et al.[27] and others. this fact points towards importance of metabolic evaluation in children presenting with nephrolithiasis so that appropriate strategy may be instituted to prevent relapse or recurrence. major clinical features were found to be similar in both groups of patients studied (p > 0.05). in our study, the most common presenting feature was uti, followed by flank or abdominal pain and hematuria. these results are consistent with those of other studies[13,28,29]. both visible and non-visible hematuria were relatively uncommon in our study compared w it h ot her reports[15,19]. these findings point to the close relation between uti and stone disease and to the previously noted importance of screening children presenting with recurrent uti. however, 24-hour urine collection in children is not always easy. parents, as well as children, need to be educated on the importance of these samples, which will help in timely identification and treatment of underlying abnormality. if 24-hour collection is not feasible, spot urine analysis can provide a useful alternative. limitations of the study the results of the present study should be interpreted with caution as it involved subjects from a single center and had a short follow-up. further, there was no availability of cysteine analysis at our laboratory, which limited our ability to draw epidemiological conclusions about cystinuria. moreover, neither metabolic screening of blood nor stone analysis was included, missing a critical aspect of stone disease in children. our results cannot be extrapolated with certainty to the global pediatric population because of significant geographical and environmental variations and because our data are not population based. conclusion metabolic abnormalities were found in 22.8% of children presenting with urinar y lithiasis. hy pocitraturia and hypercalciuria are the most frequently observed metabolic abnormalities observed in our series. children having metabolic abnormalities depicted frequent bilateral recurrent stones, underscoring the importance of 24-hour urine metabolic screening. references 1. geraghty rm, proietti s, traxer o, archer m, somani bk. worldwide impact of warmer seasons on the incidence of renal colic and kidney stone disease: evidence from a systematic review of literature. j endourol. 2017;31(8):729-35. doi:10.1089/end.2017.0123 2. alfandary h, haskin o, davidovits m, pleniceanu o, leiba a, dagan a. increasing prevalence of nephrolithiasis in association with increased body mass index in children: a population-based study. j urol. 2018; 199(4):1044-49. doi: 10.1016/j.juro.2017.10.023. epub 2017 oct 20. 3. jobs k, rakowska m, paturej a. urolithiasis in the pediatric population— current opinion on epidemiology, pathophysiology, diagnostic evaluation and treatment. dev period med. 2018; 22:201–8. 4. wollin da, kaplan ag, preminger gm, ferraro pm, nouvenne a, tasca a, et al. defining metabolic activity of nephrolithiasis— appropriate evaluation and follow-up of stone formers. asian j urol. 2018; 5:235e242. doi: 10.1016/j.ajur.2018.06.007 5. morrison jc, kawal t, batavia jp, srinivasan ak. use of ultrasound in pediatric renal stone diagnosis and surgery. currurol rep. 2017; 18:22-8. 6. bowen dk, tasian ge. pediatric stone disease. urol clin north am. 2018; 45:539–50. doi:10.1016/j.ucl.2018.06.002 23siuj.org siuj • volume 2, number 1 • january 2021 frequency of metabolic abnormalities in pakistani children with renal stones http://siuj.org 7. grivas n, thomas k, drake t, donaldson j, neisius a, petřík a, et al. imaging modalities and treatment of paediatric upper tract urolithiasis: a systematic review and update on behalf of the eau urolithiasis guidelines panel. j pediat urol. 2020 jul 4. doi: 10.1016/j.jpurol.2020.07.003 8. issler n, dufek s, kleta r, bockenhauer d, smeulders n, hoff w v. epidemiology of paediatric renal stone disease: a 22-year single center experience in the uk. bmc nephrol. 2017; 18:136. doi:10.1186/s12882-017-0505-x. 9. imran k, zafar mn, fatima n, ozair u, sultan s, rizvi sa. chemical composition of stones in paediatric urolithiasis. j ayub med coll abbottabad. 2017: 29:630–4. 10. rizvi sah, sultan s, zafar mn, ahmed b, faiq sm, hossain kz, et al. evaluation of children with urolithiasis. indian j urol. 2007; 23(4): 420–7. doi:10.4103/0970-1591.36717. 11. sas dj, becton lj, tutman j, lindsay la, wahlquist ah. clinical, demographic, and laborator y characteristics of children with nephrolithiasis. urolithiasis. 2016;4 4 (3):241–24 6. doi:10.1007/ s00240-015-0827-8. 12. elmaci am, ece a, akin f. clinical characteristics and metabolic abnormalities in preschool-age children with urolithiasis in southeast anatolia. j pediatr urol. 2013; 10:495–499. 13. g aje n gi a k r , wa g as k ar v g, tan w a w ar h v, m h as k e s, patwawardhan sk. metabolic evaluation in paediatric urolithiasis: a 4-year open prospective study. j clin diagn res. 2016; 10(2):04-06. 14. bilge i, yilmaz a, kayiran sm, emre s, kadioglu a, yekeler e, sucu a, sirin a. clinical importance of renal calyceal microlithiasis in children. pediatr int. 2013;55(6):731-6. 15. barata cb, valete cos. clinical-epidemiological profile of 106 pediatric patients with urolithiasis in rio de janeiro, brazil. rev paul pediatr. 2018; 36(3):261–267. doi:10.1590/1984-0462/;2018;36;3;00009. 16. bandari j, dangle pp, lyon td, lee a, schneck fx, cannon gm, et al. 24-hour urinary parameters in overweight or obese children with urolithiasis. j urol. 2016; 196:526-30. 17. sadeghi s, fazeli f, zarifi e. clinical characteristics and metabolic abnormalities in pediatric urolithiasis in south east iran (zahedan). j ped nephrol. 2015;3(4):149-54. 18. velásquez-forero f, esparza e, salas a, medeiros m, toussaint g, llach f. risk factors evaluation for urolithiasis among children. bol med hosp infant mex. 2 016;73:2 2 8 -3 6. doi:10.1016/ j. bmhimx.2016.05.006. 19. vandervoort k, wiesen j, frank r, et al. urolithiasis in pediatric patients: a single center study of incidence, clinical presentation and outcome. j urol. 2007; 177:2300-5. 20. rellum dm, feitz wf, van herwaarden ae, schreuder mf. pediatric urolithiasis in a non-endemic country: a single center experience from the netherlands. j pediatr urol. 2014;10:155–161. 21. jobs k, rakowska m, paturej a. urolithiasis in the pediatric population– current opinion on epidemiology, pathophysiology, dia g n o s t i c e v alu a t io n a n d t r e a t m e n t . d ev pe rio d m e d . 2018;22(2):201-208. 22. copelovitch l. urolithiasis in children–medical approach. paediatr clin north am. 2012:59(4); 881-96. doi:10.1016/j.pcl.2012.05.009 23. naseri m, varasteh a r, alamdaran sa . met abolic factors associated with urinary calculi in children. iran j kidney dis. 2010; 4:32-8. 24. a mancio l , f edriz zi m, bresolin nl , penido mg. pediatric urolithiasis: experience at a tertiary care pediatric hospital. j bras nefrol. 2016; 38:90-8. 25. yang d, tiselius h, lan c, chen d, chen k, ou l, et al. metabolic disturbances in chinese children with urolithiasis: a single center repor t. urolithiasis. 2017;45 (3):285 -290. doi: 10.1007/ s00240-016-0910-9. 26. coward rj, peters cj, duffy pg, et al. epidemiology of paediatric renal stone disease in the uk. arch dis child. 2003;88:962–965. 27. ferraro pm, arrabal-polo má, capasso g, croppi e, cupisti a, ernandez t, et al. a preliminary survey of practice patterns across several european kidney stone centers and a call for action in developing shared practice. urolithiasis. 2019 jun; 47(3):219-224. doi: 10.1007/s00240-019-01119-z. epub 2019 mar 8. 28. gouru vr, pogula vr, vaddi sp, manne v, byram r, kadiyala ls. metabolic evaluation of children with urolithiasis. urol ann. 2018; 10(1):94–99. doi:10.4103/ua.ua _98_17. 29. lekhlifia ze, laziri f, samihb m, hidac m, bouabdillahc y, souilmi fz. epidemiological characteristics of childhood urolithiasis in morocco. afr j urol. 2016; 22(2):92-5. doi:10.1016/j.afju.2016.01.009. 24 siuj • volume 2, number 1 • january 2021 siuj.org original research http://siuj.org promising biomarkers in renal cell carcinoma jada kapoor,1 francesco claps,2,3 m. carmen mir,2 joseph ischia,1,4 1 department of urology, austin health, melbourne, australia, 2 department of urology, fundacion instituto valenciano oncologia, valencia, spain, 3 department of urology, university of trieste, hospital of cattinara, trieste, italy, 4 department of surgery, university of melbourne, australia abstract renal cell carcinoma (rcc) incidence has been increasing in recent years, and it now represents the sixth most common cancer diagnosis in men and the tenth in women. although this is partly due to increased detection of incidental small renal masses on unrelated imaging, advanced rcc continues to be diagnosed in a significant portion of patients, with more than 15% presenting with distant metastases. biomarkers can be a cost-effective tool to identify high-risk patients and institute appropriate individualised therapies. while the literature in this field is nascent, this paper focuses on several biomarkers that have been extensively investigated in the diagnosis and prognosis of rcc, as well as in predicting its response to treatments, particularly the newer immuno-oncology drugs. introduction renal cell carcinoma (rcc) is a heterogeneous disease with a relatively unpredictable natural history. there are few reliable markers to distinguish between indolent and aggressive lesions at the time of diagnosis, predict relapse, and guide treatment decisions in the management of rcc. biomarkers have long been anticipated to deliver on the promise of precision medicine, and thus lead to better patient care and lower health care costs[1]. they are defined as “objectively measurable indicators of normal biological processes, pathogenic processes or pharmacologic responses to therapeutic intervention”[2]. diagnostic biomarkers can allow for an early detection and classification of cancer. prognostic biomarkers can inform clinicians about the natural course of an individual cancer and guide their decision of whom to treat, and how aggressively to treat. predictive biomarkers assess the probability of a patient benefiting from a particular treatment. despite significant advances in our knowledge of rcc at a molecular level, there are no validated biomarkers for this disease. an array of serum, urine, and tissue-based biomarkers have been described, but each has its own practical limitations. profiling complex fluids, such as serum and urine, requires awareness of the effect of other circulating proteases and nucleases on marker signals, as well as pre-fractionation strategies, given the vast difference in orders of magnitude in protein concentrations[3]. on the other hand, tumour heterogeneity may limit the utility of tissue-based markers[4]. this paper summarises the current status of the most widely studied molecular and genetic biomarkers in rcc. it is only a broad overview, and detailed description of individual markers should be sought in the referenced literature. while the recent advances in proteomics and metabolomics are likely to provide a more nuanced understanding of this disease in the future, their discussion is outside the scope of this paper. key words competing interests article information biomarkers, kidney cancer, diagnosis, prognosis none declared. received on june 13, 2020 accepted on december 6, 2020 soc int urol j. 2021;2(1):43–52 43siuj.org siuj • volume 2, number 1 • january 2021 molecular biomarkers in urologic oncology: icud-wuof consultation mailto:jjischia%40unimelb.edu.au?subject=siuj http://www.siuj.org diagnostic biomarkers improved characterisation of small renal masses is required to avoid surgical intervention in those with benign or indolent lesions and treat those with high metastatic potential in a timely manner. given the high level of discordance in pathological subtyping as seen in non-clear cell rcc cases[5,6] or biopsy specimens[7], a diagnostic biomarker would be particularly useful. carbonic anhydrase ix (caix) caix is a downstream effector of hif-1a and is thought to play a role in regulating intracellular and extracellular ph in tumour cells. it is highly expressed in 95% of clear cell rcc (ccrcc), compared with minimal expression in oncocytomas, chromophobe, and papillary rcc[8–10]. caix is also expressed in other tumours, including carcinomas of lung, breast, uterus, oesophagus, and brain, as well as in normal gastric mucosa[11]. while this somewhat limits the use of caix as a diagnostic marker for metastatic disease, there is ongoing enthusiasm for its utility in characterisation of the small renal mass. several clinical trials have demonstrated the possibility of improving the performance of positron emission tomography/ computed tomography (pet/ct) by using radio-labelled girentuximab, a chimeric monoclonal antibody against caix. redect, a phase iii open-label multi-centre trial, assessed the diagnostic accuracy of 124i-girentuximab pet/ct in 195 patients undergoing nephrectomy and reported a sensitivity of 86.2% and specificity of 85.9% in non-invasively identifying ccrcc. sensitivity was higher in tumours >2cm, and the overall positive predictive value was 94.4%, obviating the need for an invasive biopsy in these cases[12]. gene expression profiling gene expression arrays have been created to differentiate between rcc subtypes and identify the aggressiveness and metastatic potential of tumours. multiple studies have correlated the genetic expression profile of different types and grades of rcc with their morphological classification[13–15]. analysis of these signatures from early stage ccrcc have also informed us of additional pathways in tumourigenesis, including the downregulation of transcription factors required for normal renal development, such as gata3, tfcp2l1, tfap2b, and dmrt2. other studies have identified a panel of up to 34 genes that is predictive of tumour aggression, and may function as a biomarker in the future[16]. urinary biomarkers urine is an easily accessed source for biomarkers. profiling studies have identified 2 promising proteins originating from the proximal tubule, aquaporin 1 and adipophilin, that may be shed in urine and have diagnostic potential. initial results indicate that both proteins are significantly elevated in urine from patients with rcc compared with healthy controls, declining to control levels following nephrectomy[17,18]. nuclear matrix protein 22 (nmp22), an accepted urothelial cancer marker, was found to also be significantly elevated in urine samples from patients with rcc in a few studies conducted more than 15 years ago; however, there have been no further reports since[19–21]. other markers, eg, kidney injury molecule-1 (kim-1), neutrophil gelatinise-associated lipocalin (ngal), and matrix metalloproteinases (mmps) have been inadequate in differentiating renal malignancy[22,23]. tissue biomarkers there is a wide panel of antibodies that are currently used for diagnostic purposes, including ck7, cd10, pax 2, pax 8, vimentin, and alpha-methylacyl-coa (amacr) [24]. because of the particular difficulty in differentiating between benign and malignant eosinophilic tumours, a number of additional biomarkers have been studied to better characterise chromophobe rcc and oncocytoma such as hale’s colloidal iron, several cadherins, and bca2[25]. additional analysis of distinct chromosomal aberrations, such as tfe3 and tfeb, is now established for translocation-associated rccs. composite biomarkers the optimal future biomarker will likely be a panel of biomarkers utilising the strengths of those mentioned above. one such biomarker is the composite 3-marker panel of nicotinamide n-methyltransferase (nnmt), l-plastin (lcp1), and non-metastatic cell 1 protein (nm23a) that was evaluated in a cohort study of 189 patients, and further validated in 100 patients. plasma levels of nnmt, lcp1, and nm23a were significantly elevated in patients with kidney cancer. this composite assay had a positive predictive value of 87.2%, and a negative predictive value of 97% for diagnosis of renal cell carcinoma[26]. a recent validation of this assay was conducted in 9 centres with 1042 individuals, resulting in similar findings: the diagnostic sensitivity and specificity were 0.871 and 0.894, respectively, and the resulting area under curve of receiver operating characteristic was 0.917[27]. abbreviations caix carbonic anhydrase ix crp c-reactive protein rcc renal cell carcinoma vegf vascular endothelial growth factor 44 siuj • volume 2, number 1 • january 2021 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation http://siuj.org prognostic biomarkers accurate prognostic markers are the cornerstone of cancer management, and are indispensable in patient counselling, determining need for adjuvant therapies, and developing appropriate surveillance strategies. currently, at least 8 prognostic nomograms are frequently utilised for predicting the risk of relapse and survival in rcc[28–32]. however, recent prospective validation of these models, using data from the assure trial, showed a more substantial decrease in each of their prognostic abilities than previously reported in retrospective external validation studies[33]. most models only marginally outperformed standard staging, and all had a c-index below 0.7[34]. the search for more precise prognostic markers therefore continues. routine blood markers serum ldh, calcium, and haemoglobin have been widely reported to have independent prognostic significance in metastatic disease and are included in several nomograms[35,36]. several studies have reported that c-reactive protein (crp) is a strong predictor of metastasis and overall mortality after nephrectomy for localised rcc[37–41]. immunohistochemical studies have also demonstrated significant intratumoural production of crp which can be correlated with survival outcomes[42,43]. interestingly, after adjusting for tumour staining, preoperative serum crp was not a significant predictor of overall survival (os) (p = 0.741) in one of these studies[43]. thrombocytosis, another marker of the inflammatory milieu, is also an adverse prognostic factor in many cancers, including rcc [44–46]. however, in a predictive model comprising tnm stage, age, fuhrman grade, histological subtype, and preoperative haemoglobin, thrombocytosis did not add any meaningful value, with a predictive accuracy gain of 0.3% only[47]. i nc re a sed per ipher a l blood or i nt r at u mou r a l neutrophils is also associated with poor survival[48–52]. furthermore, a number of studies have demonstrated that a higher blood neutrophil/lymphocyte ratio (nlr) portends a poorer prognosis[53–55]. nlr is emerging as a prognostic factor in several other cancers, and is thought to represent an impaired cell-mediated immune response due to systemic inflammation[56]. changes in coagulation pathways are also wellrecognised in malignancy. cohort studies have reported significantly higher concentrations of plasma fibrinogen and d-dimer in patients with metastatic disease, and identified independent association with reduced cancerspecific survival (css) and os[57–59]. the vhl, hif, and vegf axis mutation of the vhl gene has been associated with a longer progression-free survival (pfs) and css in ccrcc in some studies[60,61]; however, this was not reproduced in other analyses[62–64]. similarly, analyses of elevated hif-1a levels and survival have varied, with some studies demonstrating favourable prognosis, and others associating it with worse outcomes[65,66]. increased vascular endothelial growth factor (vegf) concentration has consistently been associated with worse tumour stage and grade, necrosis, microvessel invasion, and css[67,68]. however, given that vegf is contained within platelets and released on clotting, falsely elevated results due to contamination of plasma with platelets or coagulation due to delays in processing the sample can occur, compromising its clinical applicability[69]. caix is one of the hif target genes, and is associated with tumour growth, aggressive phenotype, and poor prognosis in most cancers[70–72]. in contrast, high caix expression is associated with a better prognosis in rcc in several studies[73–76]. in a larger study, however, caix expression was not an independent prognostic factor, after adjusting for the effect of nuclear grade, sarcomatoid differentiation, and tumour necrosis[11]. these findings were further validated at the 5-year follow-up of this study[77]. immunologic markers the b7 family of immune regulatory ligands produce co-stimulatory or co-inhibitory t-cell signals, and therefore have been identified as promising prognostic biomarkers. b7-h1 functions as a negative regulator of immunity, and its over-expression is independently associated with significantly increased progression to metastatic disease (rr 3.46; p < 0.001) and cancerspecific mortality (rr 3.92; p < 0.001)[78, 79]. b7-h4 and, less strongly, b7-h3 have also been implicated as adverse prognostic factors[80, 81]. non-invasive immunoassays for the soluble forms of the b7 family are being developed with promising early results[82]. given the immunogenic nature of rcc, pathologic specimens harbour a high number of tumourinfiltrating lymphocy tes (tils). their prognostic significance is not established because of inconsistent findings on various multivariate analyses to date[83–85]. markers of cell proliferation and apoptosis various nuclear proteins that regulate cell growth, proliferation, and apoptosis are established as prognostic markers in other cancers. some of these are also very promising in rcc, as summarised in table 1[86–99]. 45siuj.org siuj • volume 2, number 1 • january 2021 promising biomarkers in renal cell carcinoma http://siuj.org the cell cycle progression (ccp) score is an rna expression assay that measures the activity of 31 genes involved in cellular proliferation, which has been widely validated for use in prostate cancer. most recently, its prognostic utility has also been demonstrated in predicting recurrence and mortality in a cohort of 565 rcc patients undergoing nephrectomy[100]. in another study from the same authors, a higher ccp score on renal mass biopsy was correlated with adverse pathology on surgery, suggesting its clinical value in risk-stratifying patients being considered for active surveillance of small renal masses[101]. utility of biomarkers in prognostic models incorporation of molecular markers into existing prognostic models, as well as combining markers to create molecular signatures of the disease, will certainly be of greater utility than any single marker. a prognostic model using p53, caix, gelsolin, and vimentin, combined with metastatic status, t-stage and ecog (eastern cooperative oncology group) performance status was 79% accurate in a cohort of 318 patients[102]. in another study of 634 patients, the integration of bioscore, which is based on expression of ki-67, survivin and b7-h1, with the uiss and ssign models improved the prognostic accuracy of the models by 4.5% and 1.6% respectively. furthermore, patients with high bioscores were noted to be 5 times more likely to die from rcc (hr 5.03; p <0.001)[103]. lastly, the prognostic value of multi-gene assays, such as clearcode-34 and 16-gene signature, has been reported to be greater than the established predictive models, and has now been validated in at least one prospective cohort. there are certainly caveats around tumour heterogeneity and misclassification due to sample bias; however, the results so far have been encouraging[104–107]. predictive biomarkers the therapeutic landscape in metastatic rcc has transformed in the past decade with the introduction of targeted and immuno-oncology treatments. identifying markers that can reliably predict the response to specific treatments is essential to optimise patient management. this section focuses on predictive markers for these contemporary treatments. immune checkpoint inhibitors immunohistochemical expression of pd-l1 is the most studied marker in this realm. studies to date have not established its independent predictive value. in all prospective trials, pd-l1 expression has been associated with worse prognosis, but not with response to checkpoint inhibitors[108–110]. biological and table 1. markers of cell proliferation and apoptosis as prognostic biomarkers prognostic biomarker role supporting literature refence insulin-like growth factor ii mrnabinding protein 3 (imp3) oncofoetal rnabinding protein; cell proliferation and invasion expression associated with significantly worse outcomes, >1400 patients total in 3 major studies • 5-year os 27% vs 82%, p < 0.0001 • os hr 1.42, p = 0.024; risk of distant metastases hr 4.71, p < 0.001 • risk of metastases specifically in chromophobe or papillary rcc hr 13.45, p < 0.001 86 87 88 89 ki-67 cell proliferation marker poor prognosis in many cancers, including rcc hr 2.18 and 2.50 for css in 741 tumours with and without necrosis respectively expression correlates with increasing stage and grade only independent predictor of rcc recurrence, in a study of several markers (caix, crp, hif) in 216 patients; hr 3.73 90 91 92 93 94 survivin member of the inhibitor of apoptosis protein (iap) family overexpressed in almost all human cancers, including rcc worse css, hr 2.4, p < 0.001; and pfs, hr 1.9, p 0.02 confirmed in several retrospective studies 95–98 p53 induces apoptosis when dna damaged over-expression is noted in 70% of papillary, 27% of chromophobe and 12% of clear cell tumours. prognostic significance not yet established. 99 46 siuj • volume 2, number 1 • january 2021 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation http://siuj.org logistical challenges in using pd-l1 as a biomarker have been well described, including intratumoural heterogeneity, discordant expression in primary and secondary sites, dynamic expression, and variation in immunohistochemical assays[111]. biomarker analysis from trial javelin-101 was recently published, and included a 26-gene expression signature and mutations and polymorphisms based on whole exome sequencing, in addition to pd-l1 expression[112]. pd-l1 expression was not predictive of response to avelumab. as in previous studies, tumour mutational burden did not demonstrate any significant predictive value[113]. several genetic mutations and the 26-gene signature were implicated in predicting treatment response; however, these findings need to be further validated. likewise, the phase ii immotion-150 trial demonstrated the utility of gene expression signatures, ref lecting angiogenesis and effector t-cell response, in predicting response to atezolizumab. a high angiogenic signature was associated with improved response rate and pfs in patients treated with sunitinib, and patients with high effector t-cell signature had better responses to icb. these findings were subsequently confirmed by the phase iii immotion-151 trial[114]. other predictive markers under investigation include tumour-infiltrating lymphocytes, mutation signatures and microsatellite instability, hla classification, tgf-b expression, pd-l2, ctla-4, mutational or neoantigen burden, and commensal gut microbiome[115,116]. vegf-related therapies vhl mutation status failed to show any predictive value in various studies[117,118]. however, downstream effectors of angiogenesis have shown some promise. high il-6 concentration is associated with improved pfs benefit from pazopanib compared with placebo, as well as improved os benefit from bevacizumab plus ifn-a compared with ifn-a alone[119,120]. the results for baseline levels of vegf-a, vegf receptor 2 and 3, hif-1a and 2a and caix have been variable and inconsistent. similar limitations were seen in analysis of other markers such as osteopontin, mmp, tissue inhibitor of metalloproteinase i (timp-i), tnf-related apoptosisinducing ligand (trail), and nlr[121,122]. the role of pd-l1 status was evaluated in 2 recent trials comparing the efficacy of cabozantinib to everolimus (meteor), and sunitinib (cabosun). although pdl1 expression was associated with shorter pfs and os in both studies, it was not predictive for response to either treatment[123,124]. limitations a major barrier to translating research findings to clinically applicable tools has been a lack of standardisation in study methodologies and small sample sizes lacking statistical power to demonstrate any meaningful correlation. a shift to collaborative efforts of large research networks involving industry and scientific experts in prospective trials, instead of the traditional model of small laboratory-based retrospective studies, is hoped to yield higher quality data and provide us with an exciting and unprecedented opportunity for the discovery and large-scale validation of reliable, precise and cost-effective rcc biomarkers. conclusion volumes of literature have been published on numerous promising diagnostic, prognostic and predictive rcc biomarkers. none of these have yet been established for routine clinical use in management of this heterogeneous disease. references 1. davis jc, furstenthal l, desai aa, norris t, sutaria s, fleming e, et 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burden (tmb) to immunotherapy response in met as t atic renal cell c ar cinoma (mrc c). j clin oncol. 2018;36(6_suppl):662–662. 114. rini bi, huseni m, atkins mb, mcdermott df, powles tb, escudier b, et al. lba31molecular correlates dif ferentiate response to atezolizumab (atezo) + bevacizumab (bev) vs sunitinib (sun): results from a phase iii study (immotion151) in untreated metastatic renal cell carcinoma (mrcc). ann oncol. 2018;29(suppl_8). 115. gibney gt, weiner lm, atkins mb. predictive biomarkers for che ck p oin t inhibit orb as e d immunot her ap y. lan cet oncol. 2016;17(12):e542–e51. 116. havel jj, chowell d, chan ta . t he evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. nat rev cancer. 2019;19(3):133–50. 51siuj.org siuj • volume 2, number 1 • january 2021 promising biomarkers in renal cell carcinoma http://siuj.org 117. choueiri tk, vaziri sa, jaeger e, elson p, wood l, bhalla ip, et al. von hippel-lindau gene status and response to vascular endothelial growth factor targeted therapy for metastatic clear cell renal cell carcinoma. j urol. 2008;180(3):860–5; discussion 5–6. 118. choueiri tk, fay ap, gagnon r, lin y, bahamon b, brown v, et al. the role of aberrant vhl/hif pathway elements in predicting clinical outcome to pazopanib therapy in patients with metastatic clear-cell renal cell carcinoma. clin cancer res. 2013;19(18):5218–26. 119. tran ht, liu y, zurita aj, lin y, baker-neblett kl, martin am, et al. prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials. lancet oncol. 2012;13(8):827–37. 120. nixon ab, halabi s, shterev i, starr m, brady jc, dutcher jp, et al. identification of predictive biomarkers of overall survival (os) in patients (pts) with advanced renal cell carcinoma (rcc) treated with interferon alpha (i) with or without bevacizumab (b): results from calgb 90206 (alliance). j clin oncol. 2013;31(15_suppl):4520. doi: 10.1200/jco.2013.31.15_suppl.4520 121. funakoshi t, lee ch, hsieh jj. a systematic review of predictive and prognostic biomarkers for vegf-targeted therapy in renal cell carcinoma. cancer treat rev. 2014;40(4):533–47. 122. winer ag, motzer rj, hakimi a a. prognostic biomarkers for response to vascular endothelial growth factor-targeted therapy for renal cell carcinoma. urol clin north am. 2016;43(1):95–104. 123. choueiri tk, escudier b, powles t, mainwaring pn, rini bi, donskov f, et al. cabozantinib versus everolimus in advanced renal-cell carcinoma. n engl j med. 2015;373(19):1814–23. 124. choueiri tk, halabi s, sanford bl, hahn o, michaelson md, walsh mk, et al. cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the alliance a031203 cabosun trial. j clin oncol. 2017;35(6):591–7. 52 siuj • volume 2, number 1 • january 2021 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj.org siuj • volume 4, number 4 • july 2023 key words competing interests article information bladder cancer, population registry, epidemiology, medical insurance, trends none declared. received on january 25, 2023 accepted on april 5, 2023 this article has been peer reviewed. soc int urol j. 2023;4(4):265–272 doi: 10.48083/znki7577 265 original research public policies and type of insurance are associated with the burden of bladder cancer – related inpatient health care in chile: a two-decade analysis ignacio eltit,1 joaquín cristi,1 iris delgado,2 paula huerta,1 sergio fuentes,1 alberto bustamante,1,3 mario i. fernández3,4 1 facultad de medicina clínica alemana universidad del desarrollo, santiago, chile 2 centro de epidemiología y políticas de salud, facultad de medicina clínica alemana universidad del desarrollo, santiago, chile 3 servicio de urología, clínica alemana de santiago, chile 4 centro de genética y genómica, facultad de medicina clínica alemana universidad del desarrollo, santiago, chile abstract objective to quantify changes in the burden of bladder cancer (bc) inpatient health care in chile between 2001 and 2019, focusing on the impact of public policies and the type of medical insurance (public or private) held by patients. methods we retrospectively collected national data on hospital discharges and calculated raw and adjusted hospitalization rates for the period of 2001 to 2019 categorized by sex and age. additionally, we analyzed length of hospital stays, outcomes of surgical interventions, and discharge conditions based on the type of medical insurance — public: fonasa; private: isapre. we also evaluated the impact of public policies such as the ges (“garantías explícitas en salud”) program, which ensures opportunities and access to medical attention, financial protection, and quality of care for a subset of diseases. results a total of 34 100 hospital discharges were analyzed. most patients were men (71%), and median age was 69 years. of the patients, 91.3% had some kind of medical insurance, either private or public. within this subset, 71.3% had public medical insurance (fonasa) and 23.2% had private medical insurance (isapre). patients on fonasa had significantly higher levels of overall surgery-related mortality (0.83% vs. 0.2%) and significantly longer median hospital stays (4 days vs. 2 days) compared to patients on isapre. following the implementation of the ges program in 2013, we observed an increase in transurethral resections and a reduction in radical cystectomies among publicly insured patients. conclusions the type of medical insurance has a significant impact on the burden of bc-related inpatient health care in chile, reflecting a significant disparity in terms of health care. the implementation of public policies such as the ges program can play a key role in reducing this gap between public and private medical insurance systems, especially in underdeveloped countries. introduction bladder cancer (bc) is the seventh most common malignancy worldwide, with a global incidence of 7.4/100 000[1]. incidence rates of bc are higher in high-income countries, particularly among men and associated with age. the main risk factor for bc is tobacco use, accounting for 50% to 60% of cases[2]. previous studies have demonstrated that socioeconomic status, ethnicity, and health coverage are independent prognostic factors of clinical outcomes for the common malignancies, including bc (cie-10 – c67)[3,4]. among these factors, health coverage is particularly http://siuj.org mailto:mariofernandez%40udd.cl?subject=siuj siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org regression software, v.4.6.0.0 statistical research and applications branch, national cancer institute, us, 2018). this test quantifies the annual percentage change (apc) adjusted by autocorrelation, with a statistical significance set at p < 0.05. all patient information was obtained and handled using encrypted codes for id, strictly adhering to the privacy regulations and use of sensitive data (chilean act #19628). results a total of 29 724 hospital discharges with bc as the primary diagnosis were recorded during the period from 2001 to 2019. as expected, most patients (71%; n = 21 113) were men, with a median of 69 years. the age range for 90% of patients (10th to 90th percentile) in this sample fell between 51 and 83 years. almost half of them (45.9%; n  =  13 635) underwent surgery. additionally, 86.1% of the patients (n  =  25 606) had some type of medical insurance, either public or private. among this subset, 75.8% were hospital discharges of patients with fonasa (public insurance, n  =  19 403), while 24.2% were isapres (private insurance, n = 6203). over the study period, we observed a steady increase of overall hospital discharges, along with changes in their distribution according to insurance type. interestingly, the proportion of isapre users increased from 17.3% in the period from 2001 to 2003 to 23.9% in the period from 2017 to 2019. table 1 and figure 1 summarize the number of annual discharges and the changes in discharge rates by insurance type over time, respectively. regarding clinical outcomes, the overall inpatient mortality rate was 3.7%. when analyzed by insurance type, the mortality rate was higher among fonasa patients (4.4%; 95% ci 4.0 to 4.8]) compared with isapre patients (2.7%; 95% ci 2.2 to 3.2; p  <  0.001). however, we observed a significant decrease in inpatient mortality for fonasa patients (-1.74% apc) over the period from 2001 to 2019 (figure 2). additionally, table 1. annual hospital discharges, population, and crude hospital discharge rates per 100 000 hospital discharges (n) population (n) crude hospital discharge rates fonasa crude hospital discharge rates isapreyear fonasa (public) isapre (private) total fonasa (public) isapre (private) 2001 791 12 803 10 156 364 2 940 795 7.7 0.4 2002 673 152 825 10 327 218 2 828 228 6.5 5.3 2003 871 317 1188 10 580 090 2 729 088 8.2 11.6 2004 808 346 1154 10 910 702 2 678 432 7.4 12.9 2005 846 325 1174 11 120 094 2 660 338 7.6 12.2 2006 811 225 1036 11 479 384 2 684 554 7 8.3 2007 777 161 938 11 740 688 2 776 912 6.6 5.7 2008 714 223 937 12 248 257 2 780 396 5.8 8 2009 759 259 1018 12 504 226 2 776 572 6 9.3 2010 748 271 1019 12 731 506 2 825 618 5.8 9.5 2011 801 227 1028 13 202 753 2 925 973 6 7.7 2012 1015 313 1328 13 377 082 3 064 719 7.5 10.2 2013 1058 413 1471 13 451 188 3 206 312 7.8 12.8 2014 1146 448 1594 13 468 265 3 308 927 8.5 13.5 2015 1338 475 1813 13 256 173 3 410 487 10 13.9 2016 1309 489 1798 13 598 639 3 427 665 9.6 14.2 2017 1414 467 1881 13 926 475 3 393 662 10.1 13.7 2018 1734 569 2303 14 242 655 3 404 896 12.1 16.7 2019 1790 511 2301 14 841 577 3 431 126 12 14.9 total 19 403 6203 25 606 relevant due to the high costs associated with bc diagnosis, treatment, and follow-up[5]. populationbased studies conducted in the united states (us) have revealed that the type of medical insurance can partially explain differences in bc patient survival[6]. indeed, us-based studies report lower overall survival and cancer-specific survival in bc patients without medical insurance or with public medical insurance[7]. in chile, the health care system uses a mixed model that consists of a public medical insurance fund (fonasa: “fondo nacional de salud ”) and private medical insurance providers (collectively called isapres: “instituciones de salud previsional”). according to official figures from 2018, fonasa covers 78% of the chilean population whereas isapres provides coverage for 18%. both insurance systems are regulated by the chilean ministry of health (minsal). the remaining 4% is covered by the armed forces and other specific insurance providers[9]. to date, private and public medical insurance systems operate independently, without formal coordination[10]. in 2005, chile implemented the explicit guarantees in health (“garantías explícitas en salud”; ges). this system ensures timely access to quality health care for a prioritized set of diseases. since ges was introduced, it is mandatory to report the diseases incorporated into this system. bc was incorporated into the ges program in 2013, guaranteeing the staging, treatment, and follow-up for this disease. when a primary care physician suspects bc, the ges system is activated, setting the time frame by which health providers must deliver care (up to 30 days for staging and up to 45 days for treatment). the ges program also provides financial coverage for both private and publicly insured patients[11,12]. the objective of our study was to quantify changes in the burden of bc inpatient health care in chile between 2001 and 2019, aiming to assess the impact of public policies and the type of medical insurance (public or private) held by patients. methods this descriptive population-based study analyzed hospital discharges related to bc between 2001 and 2019. the publicly available databases were obtained from the department of health statistics (deis) at the minsal. the collected variables included individual/ patient identification number (id), sex, age, type of medical insurance, year, and condition at discharge (alive or deceased), length of hospital stay (in days), surgical intervention (yes or no), and type of surgery. all patients with diagnoses belonging to the icd-10 c67 classification were identified. we only included the hospital discharges of fonasa (public insurance) and isapre (private insurance), which represented 95% of the total of individuals with health care coverage[9]. hospital discharge rates were calculated as annual discharge rate per 100 000, with a confidence interval (ci) of 95% and categorized by type of insurance. the overall rate was calculated by dividing the total number of annual bc discharges by the estimated total population obtained from the ine-celade and the 2017 national census. to calculate the rate according to type of medical insurance, we divided the total of discharges for each type of insurance by the total population of individuals with private and public medical insurance (isapre and fonasa, respectively). these calculations were based on data obtained from national surveys and administrative bulletins. the primary outcome of this study was to analyze the changes in the burden of bc inpatient health care in chile from 2001 to 2019, according to type of insurance and relative to the implementation of the ges program. the secondary outcomes were inpatient mortality and length of stay of bc patients according to type of insurance for the aforementioned period. the hospitalization burden was estimated using the annual bed-days, obtained by multiplying the number of days of hospital stays by the absolute frequency for each year and categorized by the type of insurance. to avoid registration bias of this variable, we excluded outliers (0.2% of outliers when considering length of stay < 100 days). differences in length of stay (days) were calculated as annual median and overall values by insurance type and type of bc surgery, and they were compared over time using 3-year periods (triennial). given the incorporation of bc into the ges program in 2013, we considered the period from 2001 to 2012 as the pre-ges period and the period from 2013 to 2020 as post-ges period. for perioperative and overall hospital mortality, we only included bc-related surgical interventions (associated with treatment). the evolution of overall inpatient mortality over time by insurance type was analyzed using a joinpoint regression model (joinpoint abbreviations bc bladder cancer ci confidence interval fonasa fondo nacional de salud ges garantías explícitas en salud; explicit guarantees in health id identification number isapres instituciones de salud previsional tur transurethral resection turbt transurethral resection of bladder tumor us united states 267266 original research public policies and type of insurance are associated with the burden of bladder cancer – related inpatient health care in chile http://siuj.org http://siuj.org siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org table 2. mean length of hospital stay (days) by medical insurance type. type of medical insurance fonasa (public) isapre (private) surgery mean mean radical cystectomy 23* 15 tur 6* 3 *p < 0.001 by anova (fonasa vs. isapre). tur: transurethral resection. *p < 0.05. apc: annual percentage change; jp: joinpoint regression model\*p < 0.05. apc: annual percentage change; jp: joinpoint regression model. figure 2. annual inpatient mortality by medical insurance type during the period of 2001–2019 in pa tie nt m or ta lit y % 10 8 6 4 2 0 20 01 20 02 20 03 20 04 20 05 20 06 20 07 20 08 20 09 20 10 20 11 20 12 20 13 20 14 20 15 20 16 20 17 20 18 20 19 year jp fonasa, apc: -1.74* fonasa (public) isapre (private) jp isapre, apc: 7.33 3000 2500 2000 1500 1000 500 0 n um be r o f s ur ge rie s fonasa (public) tur radical cystectomy n um be r o f s ur ge rie s isapre (private) triennium 2004–2006 2007–2009 2010–2012 2014–2016 2017–2019 2004–2006 2007–2009 2010–2012 2014–2016 2017–2019 tur radical cystectomy 0 500 1000 1500 2000 2500 3000 bc: bladder cancer; tur: transurethral resection. figure 3. trends in bc-related surgeries by medical insurance type during the period of 2001–2019. among fonasa patients observed in our study, regardless of surgery. notably, we observed a trend toward lower mortality rates following the incorporation of bc into the ges program in 2013, particularly among fonasa patients. this was accompanied by an increase in the number of turbts and a reduction in the proportion of radical cystectomies within the same subset of fonasa patients. these results are aligned with international reports. in 2010, the us congress approved the expansion of the medicaid program under the affordable care act (aca), which delivered health care coverage to inpatient mortality for patients undergoing bc-related surgical interventions was 0.6% compared to 6.5% for those not undergoing surgery (p < 0.001). after adjusting for insurance type, the overall postoperative mortality rate for bc patients was 0.8% for fonasa (public) patients and 0.2% isapre (private) patients (p < 0.001). among patients undergoing surgery, we observed a significant increase in transurethral resection of bladder tumors (turbts) and radical cystectomies over time in newly diagnosed cases, particularly following the introduction of the ges program. the total number of these procedures reached up to 2289 in the period from 2017 to 2019. this trend persisted after adjusting for type of insurance (figure 3). median values for hospital stay also differed according to insurance, with a median of 4 days for fonasa patients and 2 days for isapre patients. table 2 compares length of hospital stays by type of surgery, showing significantly longer stays for patients with public insurance across almost all types of surgery. finally, figure 4 shows a sustained increase in annual hospital bed-days over time, starting in 2010, particularly for fonasa patients. discussion to our k nowledge, this study provides the f irst descriptive analysis of the burden of bc-related hospital discharges in chile, while examining the impact of medical insurance and public policies such as the ges program. furthermore, we found a significant association between the type of medical insurance and bc clinical outcomes. most chileans are enrolled in fonasa (public medical insurance), and only a fraction uses private health coverage (isapre). however, the number of isapre users has progressively increased in recent years. our study found that the incorporation of bc into the ges program in 2013 was associated with an increase in the number of hospital discharges and bed-days. we also found a doubling in the number of turbts over the 2001–2019 period. while our findings indicate higher mortality rates among fonasa patients, these rates decreased over time, particularly after the incorporation of bc into the ges program, suggesting a positive effect of this public policy. patients undergoing bc-related surgery exhibited lower inpatient mortality compared with those without surgery, regardless of their medical insurance. however, our results also highlight the contrasting realities of the public and the private health care systems in chile. a previous study by castillo-laborde et al. showed that fonasa mainly serves the elderly and lower-tomid–income individuals. the public medical insurance provides coverage for a large proportion of the chilean population, including a high proportion of women and individuals with a higher prevalence of risk factors [10], which may explain the higher inpatient mortality rates cr ud e ho sp ita l d is ch ar ge ra te (p er 1 00 0 00 ) 20 18 16 14 12 10 8 6 4 2 0 20 01 20 02 20 03 20 04 20 05 20 06 20 07 20 08 20 09 20 10 20 11 20 12 20 13 20 14 20 15 20 16 20 17 20 18 20 19 year cr isapre (private) cr fonasa (public) cr: crude rate. figure 1. annual hospital discharge rates by medical insurance type during the period of 2001–2019. rates per 100 000 in fonasa and isapre patients 269268 original research public policies and type of insurance are associated with the burden of bladder cancer – related inpatient health care in chile http://siuj.org http://siuj.org siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org latin america, given the presence of similar (mixed) health care systems and comparable socioeconomic conditions. conclusions our study identified a significant increase in bc-related surgical interventions and admissions over the period from 2001 to 2019. this increase was more pronounced following the incorporation of bc into the ges program, which aimed to ensure access to health care for cancer patients. however, our findings highlight that there are significant differences in the burden bc admissions according to type of medical insurance (public versus private), ref lecting a significant disparity in terms of references 1. sung h, ferlay j, siegel rl, laversanne m, soerjomataram i, jemal a, et al. global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin.2021;71(3):209–249. doi: 10.3322/caac.21660. pmid: 33538338. 2. saginala k, barsouk a, aluru js, rawla p, padala sa, barsouk a. epidemiology of bladder cancer. med sci (basel).2020;8(1):15. doi: 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[article in spanish] salud publica mex.2011;53(suppl 2):s132– s143. pmid: 21877079. 10. castillo-laborde c, aguilera-sanhueza x, hirmas-adauy m, matute i, delgado-becerra i, nájera-de ferrari m, et al. health insurance scheme performance and effects on health and health inequalities in chile. medicc review. 2017;19(2–3):57–64. available at: http://www. redalyc.org/articulo.oa?id=437552190010 accessed june 15, 2023. 11. ministerio de salud. servicios de salud par de g en sl no. 19. 966. (2004). ley 19966. published september 3, 2004. available at: https:// www.bcn.cl/leychile/navegar?idnorma=229834 accessed march 14, 2022. 12. ministerio de salud. decreto n°4 aprueba garantías explícitas en salud del régimen general de garantías en salud. published februar y 22, 2013. available at: https://w w w.bcn.cl/leychile/ navegar?idnorma=1049111. accessed march 14, 2022. 13. kim u, koroukian s, statler a, rose j. the effect of medicaid expansion among adults from low-income communities on stage at diagnosis in those with screening-amenable cancers. cancer.2020;126(18):4209–4219. doi: 10.1002/cncr.32895. pmid: 32627180; pmcid: pmc8571714. 14. clegg lx, reichman me, miller ba, hankey bf, singh gk, lin yd, et al. impact of socioeconomic status on cancer incidence and stage at diagnosis: selected findings from the surveillance, epidemiology, and end results: national longitudinal mortality study. cancer causes control.2009;20(4):417–435. doi: 10.1007/s10552-008-9256-0. pmid: 19002764; pmcid: pmc2711979. health care. the implementation of public policies such as the ges program may help to reduce this gap between public and private health care systems. acknowledgements funding statement this research was funded by anid anillo act210079. author contributions all authors contributed to the study conception, design, and analysis. ignacio eltit and mario fernández wrote the first draft of the manuscript and all authors commented on previous versions of the manuscript. all authors read and approved the final manuscript. low-income individuals. consequently, cancer patients diagnosed after the expansion exhibited 15% less probability of having metastatic disease compared with patients diagnosed before the expansion, suggesting a major impact of health care coverage on the outcomes in low-income communities[14]. uninsured individuals in the us have been reported to have a 2-fold risk of being diagnosed with metastatic bc and a 60% higher risk of being diagnosed with locally advanced bc compared with individuals enrolled in medicaid[13]. regarding inpatient mortality by type of surgery, we observed a marked increase in mortality associated with radical cystectomies in fonasa patients compared with isapre patients, particularly in the period from 2017 to 2019 (2.9% vs. 0.4%). while this difference aligns with the length of stay based on insurance type, it is based on a multifactorial phenomenon that must be further investigated, including more detailed local data. studies in the us indicate that individuals without health care coverage tend to ignore their symptoms and are less likely to seek medical attention because they mistrust the health system[15]. on the other hand, a lack of social support or means of transportation, along with other cultural behaviors (such as of physicians) further contribute to delayed treatments[16]. timely treatments and medical care are also affected by the availability of medical providers, especially in remote or rural areas[17]. all these factors contribute to late diagnoses and the emergence of more comorbidities in patients, leading to longer hospital stay and potentially increased inpatient mortality burden. another relevant issue to discuss is the cost of bc treatments and management, which impact health care systems. in the us, annual bc-related costs were estimated at approximately us $4000 million in 2010 and projected to reach us $5000 million in 2020[18]. worldwide studies have consistently reported elevated costs associated with advanced-stage bc mainly because of the aggressive therapies patients undergo. moreover, non–muscle-invasive tumors usually involve even higher costs due to extended treatments and follow-up schedules[19]. our study revealed longer hospital stays for fonasa patients who underwent turbt compared to isapre patients (4 vs. 2 bed-days). additionally, hospital discharge rates increased over time in both fonasa and isapre patients, imposing a major economic burden on the public system, which accounted for 76.1% of the total discharges during the 2017–2019 period. it is important to acknowledge the imitations of our study, including potential registration bias leading to missing data for certain variables in our database, such as performance status, other comorbidities, tumor stage, and postoperative care. approximately 14% of patients did not have registered medical insurance between 2001 and 2019. additionally, some registries lacked associated ids, preventing assessment of whether they represented new cases or readmissions of the same patient. furthermore, we were unable to obtain clinical details for all patients, and some hospital stays may have been misdiagnosed as bc. finally, our analyses were limited to chilean patients, making it difficult to extrapolate these findings to other countries. however, these results may reflect the situation of low-income countries within figure 4. annual length of hospital stay by medical insurance type during the period of 2001–2019 le ng th o f h os pi ta l s ta y 20000 15000 10000 5000 0 20 01 20 02 20 03 20 04 20 05 20 06 20 07 20 08 20 09 20 10 20 11 20 12 20 13 20 14 20 15 20 16 20 17 20 18 20 19 year fonasa (public) total isapre (private) 271270 original research public policies and type of insurance are associated with the burden of bladder cancer – related inpatient health care in chile http://siuj.org http://siuj.org siuj • volume 4, number 4 • july 2023 siuj.org 15. lillie-blanton m, brodie m, rowland d, altman d, mcintosh m. race, ethnicity, and the health care system: public perceptions and experiences. med care res rev.2000;57(suppl 1):218–235. doi: 10.1177/1077558700057001s10. pmid: 11092164. 16. neale av, tilley bc, vernon sw. marital status, delay in seeking treatment and sur vival from breast cancer. soc sci med.1986;23(3)305–312. doi: 10.1016/0277-9536(86)90352-7. pmid: 3764489. 17. kane gc, grever mr, kennedy ji, kuzma ma, saltzman ar, wiernik ph, et al. the anticipated physician shortage: meeting the nation’s need for physician services. am j med.2009;122(12):1156–1162. doi: 10.1016/j.amjmed.2009.07.010. pmid: 19958898. 18. yeung c, dinh t, lee j. the health economics of bladder c anc er : an up dat e d r ev ie w of t he publishe d lit er at ur e. pharmacoeconomics.2014;32(11):1093–1104. doi: 10.1007/s40273014-0194-2. pmid: 25056838. 19. sloan fa, yashkin ap, akushevich i, inman ba. the cost to medicare of bladder cancer care. eur urol oncol.2020;3(4):515–522. doi: 10.1016/j. euo.2019.01.015. pmid: 31412015. 272 original research http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj.org siuj • volume 4, number 4 • july 2023 key words competing interests article information bladder cancer, nonmuscle-invasive bladder cancer, nmibc, liquid biopsy, urine tumor dna none declared. received on april 26, 2023 accepted on july 2, 2023 this article has been peer reviewed. soc int urol j. 2023;4(4):301–307 doi: 10.48083/eabm2528 301 review — liquid biopsy urinary tumor dna-based diagnosis and surveillance for nonmuscle-invasive bladder cancer—current landscape and future directions alexander shiang,1,2,* cayce nawaf,1,3,* pradeep s. chauhan,2 aadel a. chaudhuri,2,3,4,5,6 zachary l. smith1,3 gautum agarwal7 1 division of urology, department of surgery, washington university school of medicine, st. louis, united states 2 division of cancer biology, department of radiation oncology, washington university school of medicine, st. louis, united states 3 siteman cancer center, barnes jewish hospital and washington university school of medicine, st. louis, united states 4 department of computer science and engineering, washington university in st. louis, st. louis, united states 5 department of biomedical engineering, washington university in st. louis, st. louis, united states 6 department of genetics, washington university school of medicine, st. louis, united states 7 division of urology, david pratt cancer center, mercy hospital, st. louis, united states * these authors contributed equally to this work. abstract bladder cancer has a significant impact on patients, in terms of both morbidity and financial burden. this is especially true for patients with nonmuscle-invasive bladder cancer, who undergo long-term surveillance via cystoscopy and imaging, resulting in significant costs and risks. to address this issue, urinary tumor dna analysis, or “urinary liquid biopsy,” has emerged as a potential solution to reduce the testing burden and mitigate many of the costs and risks. over time, urinary tumor dna analysis has undergone several refinements. however, existing fda-approved urinary biomarker assays currently lack the sensitivity and specificity to significantly impact clinical decisionmaking. subsequent iterations of these technologies have attempted to bridge this gap by improving their diagnostic accuracy, and ultimately, clinical utility. here, we discuss the current role as well as future directions of urinary tumor dna analysis for the detection and long-term surveillance of nonmuscle-invasive bladder cancer. introduction each year, there are over 500 000 new cases of bladder cancer diagnosed worldwide[1]. this places a substantial burden on patients, with estimated annual costs exceeding $100 000 per patient[2–4]. consequently, the development of efficient and cost-effective methods for early disease detection is of the utmost importance. in current practice, diagnostic workup typically involves a combination of urinalysis, cytology, cystoscopy, and imaging[5]. these tests are also used in the surveillance setting after patients have local treatment with transurethral resection of bladder tumor (turbt). cystoscopy, in particular, is associated with increased costs of care and exposes patients to potential discomfort and risks for infection and other complications[6,7]. compliance with invasive testing can also be an issue for patients, leading to increased rates of progression and recurrence. additionally, cytology comes with significant limitations in the form of low sensitivity[8]. previous meta-analyses have demonstrated overall sensitivities ranging from 30% to 40%, with higher-grade disease associated with greater sensitivity. because of this, surveillance of nonmuscle-invasive bladder cancer (nmibc) beyond cystoscopy poses great challenges. http://siuj.org mailto:aadel%40wustl.edu?subject=siuj mailto:smithzl%40wustl.edu?subject=siuj mailto:gautum.agarwal%40mercy.net?subject=siuj sequencing–based hybrid capture assay[14]. ucapp-seq captures single nucleotide variants (snvs), insertions and deletions, and copy number alterations in genomic regions known to harbor common driver mutations for bladder cancer. the panel was based on data published from the cancer genome atlas (tcga)[15]. in total, it assays regions encompassing more than 450 genes and was predicted to identify a median of 7 mutations per bladder cancer patient. similarly to springer et al., dudley et al. tested ucappseq in both detection and surveillance cohorts. the researchers employed both tumor-informed and tumor-naive profiling approaches to each group. in the detection cohort, the majority of which exhibited stage pta (74%) with low-grade disease (54%), their tumor-naive approach achieved a sensitivity of 83% with a specificity of 97%. in comparison, cytology alone had a sensitivity of only 14% and specificity of 100%. as expected, their tumor-informed approach reached an even greater sensitivity of 93% with a specificity of 96%. however, it is important to note that this approach requires prior tumor and germline sequencing, making it less suitable for disease detection. in their surveillance cohort of patients who had previously received local bladder cancer treatment, their tumor-naive approach successfully detected disease recurrence in 84% of patients compared with only 38% for cytology. when cytology and cystoscopy were combined, only 53% of patients who had recurrence were detected, significantly lower than the 84% detected by ucapp-seq positivity alone (p = 0.0057). uromark (feber et al.) feber et al. developed uromark, a bisulphite urine sediment sequencing assay, and performed a proofof-concept investigation[16]. this 150-loci multiplex assay was developed using 86 muscle-invasive bladder cancer (mibc) patients and 30 healthy controls. it was subsequently validated with an independent cohort consisting of 167 bladder cancer (bc) patients and 274 healthy controls. the assay itself performed robustly with a sensitivity of 98%, a specificity of 97%, and a negative predictive value (npv) of 97% for detecting primary bc. future investigations will focus on accurately diagnosing patients presenting with hematuria within a clinical context. xiao et al. xiao et al. continue to advance the diagnostic landscape of nmibc[17]. they devised a study to comprehensively characterize the entire dna methylation landscape of bladder cancer to determine the relevant biomarkers for the diagnosis of non-invasive bladder cancer. in this multicenter, prospective cohort study, the researchers collected 304 samples from 224 donors and performed genome-wide bisulphite sequencing for dna methylation signature discovery. they developed a targeted sequence assay for bladder cancer–specific dna methylation signatures to distinguish tumor tissue from normal urine or mibc from nmibc. independent validation was performed by doubleblinded targeted sequencing of urine samples to determine the clinical diagnosis and prognostic value of dna methylation-based classification models. the study measured the concordance between pathology results and urinary tumor dna (utdna) methylation, genomic mutations, and other state-of-the-art diagnostic methods. the assay showed positivity in 60 of 60 patients (100%) found to have high-grade bladder cancer on initial tur bt. additionally, 21 of 57 patients (37%) with a positive dna methylation signal experienced disease progression. a subset of these patients had negative pathology results on initial turbt but were later found to harbor bladder cancer on subsequent turbt. this result further highlights the potential of utdna for early diagnosis before visible tumors are present. strandgaard et al. strandgaard et al. retrospectively analyzed 156 nmibc patients who had received bacillus calmette-guérin (bcg) treatment[18]. in all patients, urine samples were available for analysis both before and after treatment with bcg. the researchers analyzed the samples for the presence of 92 immuno-oncology–related proteins using the olink target 96 immuno-oncology assay (olink; uppsala, sweden). they also performed deeptargeted sequencing of tumor-specif ic mutations in urine cf dna with 3 different ngs panels (twist bioscience; san francisco, us). the researchers found significantly higher tumor dna (tdna) levels in the urine of the post-bcg recurrence group, but no difference was observed in tdna levels for the pre-bcg samples. notably, the exhaustion status defined by cd8 t-cells in tumor was found to be significantly associated with tdna levels in both the preand post-bcg urine samples. they also reported that patients with tdna clearance after bcg treatment has significantly better recurrence-free survival than patients without clearance. additionally, the investigators identified several genes related to cell division and immune function that were upregulated in patients who subsequently developed high-grade recurrence after bcg treatment. they were then able to assign scores based on these genes to predict the likelihood for tumor recurrence. these exciting new urine biomarkers allow for real-time assessment of a patient’s response to standard-of-care treatment, there has been growing interest in the application of urinary liquid-biopsy–based assays for the detection and surveillance of nmibc. because it is a readily available biofluid, urine has received most of this interest. urine allows for the potential detection of both genetic material released directly from tumor cells and malignant cells exfoliated into the urine[9]. there are currently severa l fda-approved urinar y biomarker assays for the detection and surveillance of bladder cancer such as immunocyt, nmp22, urovysion, bta, and cxbladder[10]. however, these tests exhibit low sensitivities and specificities, leading to poor utilization by providers within clinical contexts (table 1). while the first-generation urine-based assays did not meet the required performance levels for clinical applications, further efforts have focused on developing tests with improved sensitivities and specificities. these tests aim to be non-invasive, reproducible, and capable of not only detecting initial disease but also serving as a marker for treatment response and disease recurrence, providing real-time information on a patient’s disease status. ideally, these tests should predict the presence or absence of both low-grade and more invasive disease. such improvements would aid greatly in alleviating the morbidity and economic hardship associated with frequent clinic visits, imaging, and cystoscopy surveillance. currently, plasma circulating tumor dna (ctdna) tests are used in the invasive and metastatic settings, as well as for monitoring response to immunotherapy[11,12]. the application of urinary tumor dna (utdna) in a purely non-invasive setting has not yet been established. therefore, multiple trials are exploring utdna analysis and attempting to characterize tumor biopsy specimens on a molecular basis to improve prognostication and personalize treatment options. here, we will highlight an array of exciting past and ongoing investigations related to utdna analysis for nmibc, which we consider to be at the forefront of the field. completed studies/trials uroseek (springer et al.) the first generation of urinary tumor dna assays faced significant limitations in both sensitivity and specificity, particularly regarding the detection of lowgrade tumors. springer et al. attempted to address this issue through a combinatorial approach that involved the development of uroseek[13]. uroseek combined 3 separate tests (10 gene multiplex, tert singleplex, and aneuploidy) to detect mutations in 11 different genes and copy number changes on 39 chromosome arms. uroseek positivity was defined as a positive result in any one of these 3 tests, yielding a large increase in the assay’s sensitivity. patients were divided into 3 cohorts: a detection cohort, a surveillance cohort of those with confirmed bladder cancer, and a surveillance cohort of those with confirmed upper tract urothelial carcinoma. the detection cohort consisted primarily of patients who had presented with microscopic hematuria. it is important to emphasize that hematuria, either microscopic or gross, represents the most common initial presentation for bladder cancer. therefore, the author’s detection group represents a realistic clinical application of their assay within a diagnostic context. within this group, uroseek demonstrated a sensitivity of 83% and specificity of 99.5% for detecting bladder cancer. when combined with cytology, the sensitivity increased to 95%. the authors estimated the cost of this uroseekcytology combination to be one-third of the cost of cystoscopy alone. in the surveillance cohort, uroseek was able to detect recurrence with a sensitivity of 68% and specificity of 80%. on average, uroseek positivity preceded the clinical diagnosis of recurrence by 7 months. ucapp-seq (dudley et al.) after the publication of the initial results from uroseek, dudley et al. attempted to streamline the process further by developing ucapp-seq (utdna cancer personalized profiling by deep sequencing), a novel high-throughput table 1. reported sensitivity and specificity of commercially available urine-based assays for detecting bladder cancer nmp22 bta urovysion immunocyt cxbladder uromark sensitivity 0.69 0.65 0.63 0.78 0.82 0.98 specificity 0.77 0.74 0.87 0.78 0.85 0.97 company alere polymedco vysis scimedex pacific edge ucl cancer center 303302 siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org review — liquid biopsy urinary tumor dna-based diagnosis and surveillance for nonmuscle-invasive bladder cancer—current landscape and future directions http://siuj.org http://siuj.org turn, will allow patients with negative results to be safely spared from the financial burden and risks associated with routine cystoscopy. by mitigating morbidity and costs associated with excess cystoscopy, streamlined and efficient personalized care can be delivered[2,3]. despite early upfront costs, tailored genomic approaches have the potential for alleviating long-term financial strain[24]. a study by gordon et al. estimated average costs of $300 for targeted panels and $3000 for whole genome sequencing[25]. these costs could easily be offset by the reduced need for computed tomography (ct) scans and surveillance cystoscopies through the integration of genomic assays. specifically, these management strategies have been previously modeled to yield cost reductions of up to 9% in low-, intermediate-, and high-risk bladder cancer patients[26]. when developing and evaluating these assays, an important consideration is whether urine sediment or supernatant should be used, as tumor dna can be found in both. the dna present in the supernatant is known as cell-free (cfdna) and is thought to contain a higher proportion of tumor dna compared with sediment[27–29]. however, a consensus has yet to be reached on which fraction is optimal. figure 1. a schematic illustrating the potential role for liquid biopsy in both the diagnosis and surveillance of nmibc. this would allow for reductions in the quantity of ct and cystoscopy required for management. ct: computed tomography; turbt: transurethral resection of bladder tumor; nmibc: non-muscle-invasive bladder cancer. another potential avenue for expansion involves the application of personalized biomarkers derived from a patient’s original turbt sample. this approach could greatly benefit surveillance settings, as demonstrated by studies such as dudley et al., which showed key improvements in assay sensitivities when using tumor-informed analyses instead of tumor-naive analyses. further development of tissue registries and investigations of genomic concordance between urine cfdna and tissue samples will enable urine-based assays to play an expanded role in guiding clinical management and disease prognostication. currently, radical cystectomy is a common management strategy for many patients with high-risk, treatment-refractor y nmibc[30,31]. improvements in urine-based assays can allow for upfront risk stratification and identification of these high-risk patients. this would enable the option of early tumor-informed cystectomy for patients predicted to harbor high-risk nmibc. the presence of micrometastatic disease represents an additional risk for these patients. while not discussed in this paper, the supplementation of preexisting plasma-based assays could aid in early diagnosis and treatment[32]. enabling a more personalized approach to patient care. ongoing studies/trials assessment of the concordance of genomic alterations between urine and tissue in highrisk nmibc patients (trial id: nct03563443) this study from france aims to investigate whether analyzing urine cell-free tumor dna can predict relapse in high-risk nmibc. the eligibility criteria will be patients with high-risk bcg-naive nmibc who are set to undergo treatment with bcg. urine samples will be collected at various intervals, including before their initial bcg treatment, and at each subsequent instillation. tumor samples will be collected upon initial turbt and in the event of relapse. the primary outcome will be the agreement rate between urine cfdna and tumor tissue mutation profile, focusing on the concordance rate between mutations identified in the tumor. the secondary outcome will be to evaluate the prognostic value of tumor mutational burden (tmb), which will be calculated in the urine cfdna for each patient. this study also aims to compare the nmibc cohort to an mibc cohort, which will have urine samples collected at each routine clinic visit and have their cf dna analyzed against their initial diagnosis at turbt. genomic imprinting testing for diagnosis of bladder cancer (trial id: nct03563443) in recent years, increased attention has been devoted toward investigating epigenetic changes such as loss of imprinting (loi) within cancer cells. these changes have been demonstrated to play key roles in cancer mechanisms such as the development of resistance to chemotherapy and radiotherapy[19]. a novel approach investigating these mechanisms, lisenid, is being developed by lisen imprinting diagnostics company (wilmington, us). specifically, this trial aims to broadly investigate tumor loi patterns to establish a predictive and diagnostic urine-based bladder cancer loi panel. because of their ubiquitous nature, epigenetic changes such as loi can aid in potentially overcomes issues related to tumor heterogeneity when relying solely on mutational methodologies. furthermore, data has suggested that loi often precedes many morphological changes within tumor cells, potentially expanding the window for their detection and enhancing the sensitivity of urine-based testing for nmibc. previous studies integrating mutational and methylation changes have demonstrated significant improvements in disease detection and surveillance[20–22]. for example, a study by cheng et al. combined copy number variant and methylation analyses to improve the sensitivity of detecting nmibc to 91.9%[22]. when applied only to low-grade tumors, the sensitivity remained relatively robust at 84.2%, indicating a substantial improvement from the first-generation tests described above. the performance of cancer risk genes in the necessity of secondary turbt (trial id: nct05112523) patients with a bladder mass undergo standard-of-care turbt for tissue diagnosis ± postoperative intravesical treatment. if the patient is deemed to have nmibc, depending on the stage and the grade, repeat turbt is often recommended, or is considered standard-ofcare. however, there are currently some patients who do not need an additional procedure, which would reduce overtreatment, patient morbidity, and healthcare costs. this study seeks to investigate whether a urine biomarker can detect residual bladder tumor lesions and thus predict who will need repeat turbt before further treatment. genetron uro v1 is a non-invasive urinary liquid-biopsy assay for assessing the risk for uroepithelial tumor using dna extracted from urinary pellets. the investigators will perform this test on patients’ urine samples before patients undergo a secondary turbt and compare the test results with the final pathologic results. these findings will help to predict the need for secondary turbt in high-risk nmibc patients and establish correlations with patient recurrence-free survival and overall survival. discussion and future directions relying solely on pathologic analysis of bladder cancer specimens has been demonstrated to be surprisingly unreliable. in a study conducted by luchey et al., dedicated genitourinary pathologists re-reviewed 1191 bladder cancer biopsy specimens and found that nearly 30% of them resulted in a change in pathology[23]. this significant level of interobserver discordance can lead to suboptimal patient care by providing treatments that do not ref lect the true pathologic stage. urine-based biomarkers have the potential to supplement clinical workflows by allowing for more precise risk stratification and staging of bladder cancer patients (figure 1, created in biorender). however, these modalities are not perfect, and there lies a great deal of heterogeneity based on methodology used and thresholds placed on the assays themselves. future directions in this field involve integration of promising novel methylation-based approaches with preexisting single nucleotide variant and copy number– based assays. the aim of these combinatorial techniques will be to maximize the sensitivity of detecting nmibc for both diagnostic and surveillance purposes. this, in 305304 siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org review — liquid biopsy urinary tumor dna-based diagnosis and surveillance for nonmuscle-invasive bladder cancer—current landscape and future directions http://siuj.org http://siuj.org 20. chen x, zhang j, ruan w, huang m, wang c, wang h, et al. urine dna 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jl, buckley d, fu r, gustafson k, griffin jc, et al. urinary biomarkers for diagnosis of bladder cancer: a systematic review and meta-analysis. ann intern med.2015;163(12):922–931. doi: 10.7326/ m15-0997. pmid: 26501851. conclusion the current landscape of urine tumor-based testing for nmibc shows promise and tremendous potential for future improvement and growth. clinical applications, in both diagnostic and surveillance contexts, will enable providers to offer personalized, precision treatments and management strategies. reducing the risk and financial toxicity associated with unnecessary cystoscopies will result in more efficient delivery of care, benefiting both patients and their providers. 11. christensen e, birkenkamp-demtröder k, sethi h, shchegrova s, salari r, nordentoft i, et al. early detection of metastatic relapse and monitoring of therapeutic efficacy by ultra-deep sequencing of plasma cell-free dna in patients with urothelial bladder carcinoma. j clin oncol.2019;37(18):1547–1557. doi: 10.1200/jco.18.02052. pmid: 31059311. 12. birkenkamp-demtröder k, christensen e, nordentoft i, knudsen m, taber a, høyer s, et al. monitoring treatment response and metastatic relapse in advanced bladder cancer by liquid biopsy analysis. eur urol.2018;73(4):535–540. doi: 10.1016/j.eururo.2017.09.011. pmid: 28958829. 13. springer su, chen ch, rodriguez pena mdc, li l, douville c, wang y, et al. non-invasive detection of urothelial cancer through the analysis of driver gene mutations and aneuploidy. elife.2018;7:e32143. doi: 10.7554/elife.32143. pmid: 29557778; pmcid: pmc5860864. 14. dudley jc, schroers-martin j, lazzareschi dv, shi w y, chen sb, esfahani ms, et al. detection and surveillance of bladder cancer using urine tumor dna. cancer discov.2019;9(4):500 –509. doi: 10.115 8/ 215 9 8 2 9 0.cd -18 0 8 25. p mid: 3 05 78 35 7; p mcid: pmc6467650. 15. c ancer genome atlas research net work . comprehensive molecular characterization of urothelial bladder carcinoma. nature.2014;507(7492):315–322. doi: 10.1038/nature12965. pmid: 24476821; pmcid: pmc3962515. 16. feber a, dhami p, dong l, de winter p, tan ws, martínez-fernández m, et al. uromark-a urinary biomarker assay for the detection of bladder cancer. clin epigenetics.2017;9:8. doi: 10.1186/s13148-016-0303-5. pmid: 28163793; pmcid: pmc5282868. 17. xiao y, ju l, qian k, jin w, wang g, zhao y, et al. non-invasive diagnosis and sur veillance of bladder cancer with driver and passenger dna methylation in a prospective cohort study. clin transl med.2022;12(8):e1008. doi: 10.1002/ctm2.1008. pmid: 35968916; pmcid: pmc9377153. 18. strandgaard t, lindskrog sv, nordentoft i, christensen e, birkenkampdemtröder k, andreasen tg, et al. elevated t-cell exhaustion and urinary tumor dna levels are associated with bacillus calmetteguérin failure in patients with non-muscle-invasive bladder cancer. eur urol.2022;82(6):646–656. doi: 10.1016/j.eururo.2022.09.008. pmid: 36210217. 19. zhao x, liu x, wang g, wen x, zhang x, hoffman ar, et al. loss of insulin-like growth factor ii imprinting is a hallmark associated with enhanced chemo/radiotherapy resistance in cancer stem cells. oncotarget.2016;7(32):51349–51364. doi: 10.18632/oncotarget.9784. pmid: 27275535; pmcid: pmc5239480. 307306 siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org review — liquid biopsy urinary tumor dna-based diagnosis and surveillance for nonmuscle-invasive bladder cancer—current landscape and future directions http://siuj.org http://siuj.org bladder cancer tissue-based biomarkers francesco soria,1 marta sanchez-carbayo,2 natalya benderska-söder,3 bernd j. schmidz-dräger,3,4 stefania zamboni,5 marco moschini,6 anirban p. mitra,7 yair lotan8 1 division of urology, department of surgical sciences, torino school of medicine, torino, italy 2 translational oncology laboratory, lucio lascaray research center, university of the basque country, vitoria-gasteiz, spain 3 urologie 24, nuremberg, germany 4 department of urology and pediatric urology, friedrich-alexander university, erlangen, germany 5 urology unit, asst spedali civili, brescia, italy; department of medical and surgical specialties, radiological science and public health, university of brescia, italy 6 klinik für urologie, luzerner kantonsspital, lucerne, switzerland 7institute of urology, university of southern california, los angeles, united states 8 department of urology, university of texas southwestern medical center, dallas, united states abstract this review aims to provide a practical update regarding the current role of tissue-based biomarkers in bladder cancer. their prognostic and predictive role both in non-muscle-invasive (nmibc) and in muscle-invasive disease (mibc) has been reviewed with particular focus to their use in clinical practice. in summary, the literature on the prediction of disease recurrence in nmibc is inconclusive, and there is little information on prediction of response to intravesical bacillus calmette-guérin (bcg). concerning disease progression, external prospective validation studies suggest that fgfr3 mutation status and gene signatures may improve models that are based only on clinicopathologic information. in mibc, tissue-based biomarkers are increasingly important, since they may predict the response to systemic chemotherapy and immunotherapy. in particular, the advent of molecular characterization promises to revolutionize the paradigm of decision-making in the treatment of mibc. molecular subtyping has been shown to improve the prediction of pathological stage at rc and to predict the response to systemic chemotherapy and immunotherapy. however, external and prospective validations are warranted to confirm these preliminary findings. several different tissue-based biomarkers such as pd-1/pd-l1 expression, tumor mutational burden, and the analysis of tumor microenvironment, may in future play a role in selecting patients for systemic immunotherapy. however, to date, no pretreatment recommendations can be definitively made on the basis of any molecular predictors. in conclusion, despite the potential of tissue-based biomarkers, their use in bladder cancer should be limited to experimental settings. introduction in recent years, there have been significant innovations in the treatment of bladder cancer (bca). while most treatments are standardized, we are transitioning from the era of “one size fits all” into the era of “precision medicine,” in which treatments are personalized and tailored according to the particular characteristics of each patient and tumor. biomarkers play an undeniable role in this setting, allowing patient risk stratification, predicting response to treatments, and paving the way for targeted therapies. in this non-systematic review, the technical aspects of tissuebased biomarkers, as well as their current role in terms of clinical utility, both in non-muscle invasive (nmibc) and muscle-invasive bladder cancer (mibc), are reviewed. key words competing interests article information bladder cancer, tissue-based biomarkers, prognosis, prediction, immunotherapy none declared. received on july 16, 2020 accepted on october 18, 2020 soc int urol j. 2021;2(1):53–71 53siuj.org siuj • volume 2, number 1 • january 2021 molecular biomarkers in urologic oncology: icud-wuof consultation mailto:soria.fra%40gmail.com?subject=siuj http://www.siuj.org technical aspects of tissue-based biomarkers in bladder cancer several technical aspects should be considered when work ing with tissue specimens. first, there are important differences between using fresh, frozen, or formalin-fixed material. the use of fresh or fresh-frozen tissue, for example, enriches the quality of rna-derived material as compared with formalin-fixed tissue[1]. conversely, dna is usually more stable, and unless long nucleic acids are required, dna of sufficient quality for analysis can be obtained for the majority of the pcrbased methods in fresh, fresh-frozen, or formalin-fixed material. second, it is critical to consider that bca is extremely heterogeneous. this is particularly evident in mibc, in which tissue heterogeneity might be extremely high, with differential ratios between tumor and stromal cells among paraffin blocks, leading to very different results if microdissection is not performed. this may lead to significant differences when staining sections from different blocks. however, even when microdissection is performed, intratumoral heterogeneity may currently play a role in limiting the use of tissue-based biomarkers in bca. third, sample handling is very important to preserve the quality of the specimen. in frozen material, it is important that freezing is performed within 30 minutes of the specimen’s removal. when working with paraffinembedded tumors it is important that specimens are maintained no longer than 24 hours in formalin for fixation and that blocks are well orientated to be cut within that time[2,3]. finally, the use of controls is mandatory. a comparison with normal urothelium should always be performed in any experiment at the dna, rna, or protein level[4]. this is not always possible for bca because of the field effect of carcinogenesis so adjacent “normal” may be best alternative control. tissue-based biomarkers in non-muscle invasive bladder cancer in general, prognostic information for patients with nmibc is highly desirable, because guidance for further treatment and follow-up is urgently needed. so far, this information relies exclusively on clinicopathological parameters[5–8]. since there is a broad range of recurrence and progression rates even when applying european association of urology (eau) or american urology association (aua) risk stratification, there is need to refine prediction of rates to help inform treatment and surveillance decisions. key prognostic biomarkers for disease recurrence and progression in nmibc are listed in table 1 and are briefly described below. prognostic markers for disease recurrence the p53 tumor suppressor gene is probably the first molecular alteration that has been extensively studied, but there have been conf licting results regarding association with prognosis[9–14]. using p53 as a single marker has issues due to multiple cell cycle regulators that may have overlapping roles. considering the biological diversity of nmibc along with its intratumoral heterogeneity, the research focus in tissue marker research has shifted from the investigation of single alterations to consideration of combined alterations, including gene classifiers for discrimination between recurrent and non-recurrent nmibc, with promising results[13,15–17]. nevertheless, a large international retrospective validation study including 404 patients investigating a 26-gene signature found no association with tumor recurrence[18]. fgfr3 mutations have been correlated with the prognosis of patients with nmibc. a retrospective multicentre study investigated the prognostic potential of fgfr3 status and 3 molecular markers (mib-1, p53, and p27kip1) showed that the combination of fgfr3 and mib-1 was able to independently predict disease recurrence[12]. more recently, dysregulation of several mirnas has been suggested to predict tumor recurrence[19–21]; however, validation and prospective assessment are lacking. in summary, the role of molecular markers in the prognostication of disease recurrence in nmibc seems limited, not only for technical reasons but also because clinical parameters (eg, multiplicity, tumor size, incomplete tur) have a substantial effect on this event and mitigate the impact of biomarkers[12]. furthermore, most patients with nmibc, especially those with highrisk disease, undergo treatment, and response to therapy will impact the likelihood of recurrence significantly. abbreviations aua american urological association bca bladder cancer csm cancer-specific mortality eau european association of urology mibc muscle invasive disease nac neoadjuvant chemotherapy nmibc non-muscle invasive bladder cancer rc radical cystectomy 54 siuj • volume 2, number 1 • january 2021 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation http://siuj.org table 1. prognostic biomarkers in non-muscle invasive bladder cancer molecular pathway biomarker(s) method n results year reference cell cycle regulation rb ihc 74 no association with progression 1996 96 p21 ihc 207 no association with progression 2000 97 244 no association with recurrence 1999 98 p27 ihc 61 no association with recurrence and progression 2013 99 ki-76 ihc 61 no association with recurrence and progression 2013 99 cell death pathways p53 ihc 69 overexpression predicts disease progression 1995 9 ihc 104 overexpression predicts disease recurrence 1997 10 ihc 286 overexpression alone predicts disease progression, but not in combination with fgfr3 mutation 2003 12 ihc 83 overexpression predicts disease recurrence and progression 2007 13 rtpcr 105 no prognostic value 2007 14 bcl-2 ihc 100 no association with recurrence 1998 100 ihc 93 no association with recurrence 2000 101 cell growth signaling fgfr3 rtpcr 286 mutation associated with higher recurrence-free and progression-free survival 2003 12 erbb2 (her2) ihc 88 association with recurrence and progression 2015 102 rtpcr 141 association with recurrence and progression 2015 103 rtpcr 34 association with progression 2017 104 survivin ihc 233 association with progression 2016 105 115 association with recurrence and progression 2015 106 283 association with progression and survival 2012 107 angiogenesis markers vegf ihc 185 no association with recurrence 1999 108 140 no association with recurrence and progression 2005 109 hif-1 α ihc 140 no association with recurrence and progression 2005 109 immune markers pd-l1 rtpcr 296 association with recurrence, progression, and survival 2018 110 ihc: immunohistochemistry 55siuj.org siuj • volume 2, number 1 • january 2021 bladder cancer tissue-based biomarkers http://siuj.org prognostic markers for disease progression progression of disease is defined as a recurrence with a worsening stage or grade of disease. p53 alteration is one of the first and certainly most frequently studied markers in this context. most of these studies, including a combined analysis of 23 studies[22], reported a correlation between p53 overexpression and tumor progression. however, as p53 alterations are closely related to tumor grade, stage, and other molecular changes, the independent prognostic value of this parameter remains a matter of controversy[11–13]. immunohistochemical p53 overexpression has also been tested in combination with other alterations, frequently related to cell cycle regulation. in one prospective study every patient with high-grade nmibc underwent immunohistochemical staining for 5 biomarkers (p21, p27, p53, ki-67, and cyclin e1) no differences were found in progression or survival based on the number of altered markers[23]. a molecular grading based on the combination of fgfr3 mutation together with mib-1 expression is significantly associated with disease progression. a large prospective study of 1239 patients from the same group demonstrated that molecular grading based on fgfr3 mutational status and methylation of gata2 was able to improve the eau nmibc risk score in predicting tumor progression[24]. the development of gene classifiers and subtyping using microarrays is another option for combining molecular information[25,26]. in a large prospective scandinavian-based trial of 1224 patients, dyrskjøt et al. demonstrated that the results of a 12-gene real-time qualitative pcr assay yielded independent prognostic information on tumor progression[27]. nevertheless, with a 66% sensitivity and specificity to predict tumor progression as a stand-alone assay, it becomes obvious that, at this stage, information obtained by molecular markers is not sufficient and needs to be integrated with established clinicopathologic variables. predictive markers for response to intravesical therapy various tissue-based biomarkers have been evaluated for prediction of response to intravesical bacillus calmetteguérin (bcg) therapy. to date, the best evidence comes from a validation study based on 2 nordic multicenter trials comparing treatment with bcg and other intravesical adjuvant therapies[28]. in this report, ezrin, ck20, and ki-67 have been analyzed in a tissue microarray: unfortunately, none of the variables correlated with disease recurrence, and only tumor multifocality was associated with disease progression. several studies demonstrated a clinical utility in combining gene expression signatures with clinicopathologic features[29]. pietzak et al. demonstrated that patients with nmibc had a high prevalence of alterations to dna damage repair genes and that mutations in arid1a are associated with an increased risk of recurrence following bcg therapy[30]. moreover, total mutational burden has been associated with disease progression in a small retrospective study of 25 patients treated with bcg[31]. following the advent of immunotherapy with checkpoint inhibitors also in the nmi setting (recently, according to the results of the keynote-057 trial[32], the use of pembrolizumab in patients with bcgunresponsive cis has been approved by the fda), the role of potential immune markers (ie, pd-1 and pd-l1 mrna expression) to predict response to bcg has been investigated with promising results. however, it should be underlined that these findings need to be externally validated before they could be considered for clinical practice. finally, in the context of immunological markers, pichler et al. studied the association between recurrence-free survival and the count of cd4, gata3, tumor-associated macrophages, tregs, and t-bet+ t cells in the malignant tissue samples prior to bcg therapy[33]. they found that cd4+ and gata3+ t cells were predictors of prolonged recurrence-free survival, while the predictors of shorter recurrence-free survival were tams, tregs, and t-bet+ t cells. tissue-based biomarkers in muscle invasive bladder cancer prediction of oncological outcomes the standard treatment for patients with mibc is radical cystectomy (rc) with neoadjuvant chemotherapy (nac). however, despite the administration of adequate therapy and the recent development of new treatment strategies such as trimodal therapy (tmt) or targeted t herapies, mibc remains an aggressive disease characterized by a generally unfavorable prognosis [34,35]. there are significant challenges in accurately staging the disease and insufficient ability using clinical/ pathological factors alone to predict recurrence and progression, and an inability to predict response to systemic therapies and radiotherapy. the consequence is that many patients are either undertreated, overtreated, or given therapies that are unlikely to benefit the patient. understanding the molecular pathology and biology of bca could be useful to improve patients’ stratification and decision-making. recently, several reports have focused their attention on molecular biomarkers as 56 siuj • volume 2, number 1 • january 2021 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation http://siuj.org diagnostic and prognostic tools in mibc, although their application in clinical practice remains, to date, unclear. prediction of disease stage at radical cystectomy an accurate prediction of disease stage at diagnosis is of fundamental importance to risk-stratification and to select patients for neoadjuvant systemic therapies. understaging disease after initial turbt is over 40% despite examination under anesthesia and cross sectional imaging[36]. as such improving staging at diagnosis is important to appropriately treat patients. several tissue-based biomarkers have been investigated for this purpose and have been integrated into predictive models. mitra et al. firstly developed a pre-cystectomy decision model to predict pathological upstaging and oncological outcomes in ct2 patients undergoing rc[37]. this model was based on clinicopathologic variables such as the preoperative presence of hydronephrosis, evidence of deep muscolaris propria invasion and lvi as well as tumor growth pattern and count. subsequently, shariat et al. tested the accuracy of a preoperative panel of tissue-based biomarkers (p53, p21, p27, ki67, and cyclin e1); the number of altered biomarkers was able to predict t-stage upstaging but not tand/or n-stage upstaging; however, the accuracy of the model in the prediction of the t-stage upstaging was low (62%)[38]. recently, a genomic subtyping classifier was used to evaluate pathological upstaging in a multi-institutional cohort of patients with ct1-t2 bca treated with rc[39]. luminal tumors showed a lower rate of upstaging to non-organ confined disease compared to non-luminal ones (34% versus 51%). pending external validation, molecular characterization promises to transform the paradigm of bca risk-stratification, thus paving the way to an even more personalized approach. prediction of oncological outcomes after radical cystectomy alone there has been an interest in predicting the likelihood of recurrence in patients who underwent rc alone. these patients may benefit from adjuvant therapies such as chemotherapy[40] and multiple trials are evaluating the value of adjuvant checkpoint inhibitors. key biomarkers evaluated for prediction of oncological outcomes are listed in table 2. currently, p53 is the most studied prognostic biomarker in patients treated with rc, with conflicting results reported in the literature. in patients with bca confined to the bladder, p53 has been associated with progression and survival, independently of tumor grade, stage, and lymph node status[41]. human epidermal growth factor receptor 2 (her2) is a tyrosine kinase transmembrane receptor involved in cycle cell regulation and cell proliferation. its overexpression was associated with adverse pathological features at rc but its relationship with long-term oncological outcomes remains controversial[42,43]. the retinoblastoma protein (r b1) is a tumor suppressor gene, which acts as a negative regulator of cell cycle progression and has been proved to be dysregulated in several cancers. the loss of rb1 expression is an adverse prognostic biomarker in mibc[44,45]. inactivating rb1 mutation results in a lower expression of fgfr3 levels and is associated with worse cancerspecific mortality (csm)[46]. survivin, an inhibitor of apoptosis, was found to be associated with disease recurrence (hr 1.7, p = 0.04), csm (hr 1.7, p = 0.03), and all-cause mortality (hr 1.7, p = 0.04) in 222 consecutive patients treated with rc after accounting for the effects of standard prognosticators[47]. these results have been externally validated and survivin status has been incorporated in a nomogram for the prediction of outcomes in patients with pt1-3n0m0 disease: the addition of survivin improved the accuracy of the model over standard clinicopathologic features for prediction of disease recurrence and csm. despite these findings, the role of these biomarkers in clinical practice as single markers remains limited, mainly due to their unsatisfactory accuracy. models based on the assessment of multiple markers (p53, p21, rb, cyclin e1, and p27) showed higher predictive accuracy compared to those based on single markers [48–50]. a prospective study of 216 patients treated with rc who underwent immunohistochemical staining for p53, p21, p27, cyclin e1, and ki-67 found that in a multivariable model adjusting for the effects of standard prognosticators, only lvi and number of altered biomarkers were independent predictors of recurrence and csm[51]. as a lready before mentioned, bca molecular characterization is acquiring increasing importance in the prediction of prognosis in patients with mibc. recently, a consensus classification has been provided. compared to luminal papillary tumors that were taken as reference, luminal non-specified and stromarich tumors showed similar outcomes while luminal unstable, basal/squamous, and neuroendocrine-like subtypes were associated with worse survival, with the latter representing the class with the worst prognosis (hr 2.18, p < 0.05). moreover, this classification, besides providing a promising tool for risk-stratification, suggests possible therapeutic implications such as those related to targeted therapies, thereby representing a milestone for mibc classification. 57siuj.org siuj • volume 2, number 1 • january 2021 bladder cancer tissue-based biomarkers http://siuj.org prediction of response to neoadjuvant chemotherapy key biomarkers investigated for prediction of response to nac are listed in table 3. cisplatin acts as an alkylating agent and interferes with dna replication and gene transcription. this dna-damage is repaired by 2 pathways: the first includes brca1, brca2, and rads51 genes while the second involves the nucleotide excision repair ner, and includes several genes such as ercc1-5, cdk7, ddb1-2, xpa. alteration of these pathways has been suggested to affect the response to cisplatin-based chemotherapy. the breast cancer susceptibility gene 1 (brca1) modulates chemoresistance encoding a nuclear protein that responds to dna damage with several different mechanisms. patients with low/intermediate brca1 levels were found to have a significantly higher pathological response at rc compared to patients with high brca1 levels (66% versus 22%, p = 0.01)[52]. the excision repair cross-complementing 1 (ercc1) is involved in dna repair and dna recombination: it was found associated with cisplatin resistance different tumors[53–55], whereas its role in bca remains debated[56]. genomic alterations in the dna repairassociated genes atm, rb1, and fancc were found to be predictors of response (87% sensitivity, 100% specificity) and better os after mvac chemotherapy for table 2. prognostic biomarkers after radical cystectomy alone in muscle-invasive bladder cancer molecular pathway biomarker(s) method n results year reference cell cycle regulation rb ihc 38 association with cancer-specific mortality 2012 45 p21 ihc 692 association with disease recurrence and cancer-specific mortality 2010 111 cell death pathways p53 ihc 692 association with disease recurrence and cancer-specific mortality 2010 112 ihc 243 association with disease recurrence and cancer-specific mortality 1994 41 erbb2 (her2) ihc 354 no association with oncological outcomes 2010 42 ihc 198 association with disease recurrence and cancer-specific mortality 2016 43 survivin ihc 222 association with disease recurrence and overall mortality 2007 47 angiogenesis markers vegf ihc 286 association with cancer-specific mortality 2007 113 markers of tumor cell invasion e-cadherin ihc 25 association with survival 1993 114 mmps ihc 54 association with disease recurrence 2003 115 molecular markers luminal unstable transcriptome analysis 1750 association with worse survival compared to luminal papillary subtype 2019 61basal/squamous neuroendocrine-like ihc: immunohistochemistry 58 siuj • volume 2, number 1 • january 2021 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation http://siuj.org mibc[57,58]. regarding the ability of p53 mutation to predict response to nac, conflicting results have been reported[58,59]. recent studies evaluated the role of molecular profiles for decision-making and counseling of patients treated with nac and rc. while there is some evidence that different tumor subtypes (basal, luminal, p53-like) are associated with different patterns of response to nac [60], in the recently developed international consensus about the molecular classification of mibc[61] no significant association between the consensus classes and oncologic outcomes in patients treated with nac was found. prediction of response to systemic chemotherapy several cell cycle regulators and markers of proliferation have been evaluated as predictors of chemotherapy response[62,63]. alongside this, a combination of regulatory rnas and transcription factors has shown to be predictive in metastatic bca patients treated with cisplatin-based therapy[64]. however, there is yet to be a clinically validated role for them as predictive markers. the most promising class of predictive markers thus far for chemotherapeutic response is represented by those involved in dna damage detection and repair (ie, brca-1, brca-2, rad51, par, parp1, ercc1, ercc2, and rr m1). in a study of patients with advanced or metastatic urothelial cancer receiving platinum-based palliative chemotherapy, 341 genes including 34 dna damage response (ddr)-associated genes were evaluated[65]. patients with ddr gene alterations had significantly longer progression-free and os than patients with wild-type ddr genes. in the setting of advanced urothelial carcinoma, overexpression of ercc1, rad51, and par has been correlated with worse survival for patients treated with first-line platinum combination chemotherapy[66,67]. aberrations of growth factors and their associated tyrosine kinase receptors can result in an abnormal increase in the rate of transduction of growth signals, thereby leading to uncontrolled cellular proliferation and tumor formation. such kinases are the targets of several new systemic therapies in oncology. several tyrosine kinase inhibitors have been tried in bca including lapatinib (inhibits egfr and her2/neu pathways), and pazopanib (inhibits fgf, pdgf, and vegf pathways). while these drugs appear to have limited activity in bca, the possibility of biomarker enrichment for response has been assessed with mixed results[68–72]. table 3. biomarkers associated with response to neoadjuvant chemotherapy molecular pathway biomarker(s) method drug(s) n results year reference cellular efflux ctr1 ihc cis 47 association with pathologic response 2016 116 cell death pathways p53 ihc mvac 111 association with survival 1995 59 ihc mvac 44 does not predict pathologic response 2014 58 bcl-2 ihc cis + radiotherapy 51 low levels associated with better prognosis 2000 117 dna repair brca-1 rtpcr cis 57 low/intermediate levels predict pathologic response 2011 52 ercc1 ihc cis 38 does not predict pathologic response but predicts survival 2013 118 ercc2 rtpcr cis 50 predicts pathologic response 2014 119 molecular markers basal subtype transcriptome analysis cis 343 association with better survival 2019 120 mvac: methotrexate, vinblastine, doxorubicin, cisplatin, cis: cisplatin-based, ihc: immunohistochemistry 59siuj.org siuj • volume 2, number 1 • january 2021 bladder cancer tissue-based biomarkers http://siuj.org several other factors have been assessed for their ability to predict chemotherapy response, including immunological markers[73], germline and somatic dna mutations[74,75], as well as drug transport genes[62,76]. several of these factors are summarized in table 4. prediction of response to systemic immunotherapy the advent of systemic immunot herapy in t he management of advanced bca represents a quantum leap over the last few years, especially in patients refractory to cisplatin-based therapies. several immune checkpoint inhibitors have shown promising activity, including agents targeting pd-1 receptor and its ligand pd-l1, and cytotoxic t-lymphocyte antigen 4 (ctla4). while these developments are promising, a majority of patients still do not respond to treatment[77–84], resulting in a significant financial burden and potential treatment-related side effects. this highlights the need for appropriate biomarkers to aid in selecting patients who are most likely to benefit from checkpoint targeting therapy. while several biomarkers have been explored table 4. biomarkers associated with systemic chemotherapy and immunotherapy response molecular pathway biomarker(s) method drug(s) n results year reference cell cycle and proliferation cyclin d1 ihc cis 63 overexpression predicts better chemo response 2016 63 ccdn1 fish cis 63 does not predict chemo response 2016 63 ki-67 ihc cmv, mvac 99 does not predict chemo response 1998 62 mirnas rtpcr mvac, gc 83 increased mir-21, mir-372 and e2f1 associated with chemo response and survival 2013 64 cell death pathways p53 ihc mc, mec cmv, mvac 83 overexpression predicts improved survival in chemoresistant patients 1999 121 ihc cmv, mvac 99 does not predict chemo response 1998 62 ihc cisca, mvac 25 overexpression associated with worse response 1998 122 ihc mvac 114 does not predict chemo response (phase iii rct) 2011 123 bcl-2 ihc cis 51 low expression predicts better response to chemoradiation 2000 117 ihc cisca, mvac 25 overexpression associated with worse response 1998 122 mvac: methotrexate, vinblastine, doxorubicin, cisplatin, mc: methotrexate, cisplatin, cmv: cisplatin, methotrexate, vinblastine mvec: methotrexate, vinblastine, epirubicin, cisplatin, mec: methotrexate, epirubicin, cisplatin, gc: gemcitabine, cisplatin gct: gemcitabine, cisplatin, paclitaxel, cis: cisplatin, cisca: cisplatin, doxorubicin, cyclophosphamide, ihc: immunohistochemistry continued on page 61 60 siuj • volume 2, number 1 • january 2021 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation http://siuj.org in the context of these clinical trials, no pretreatment recommendations can be definitively made at this point based on any molecular predictors, since a significant proportion of patients do respond to treatment despite testing negative for a biomarker. nevertheless, biomarker-based selection for immunotherapy remains an area of active interest that is likely to further develop in the years to come. pd-l1 ex pression has been associated w it h higher tumor grade, worse outcomes, and decreased postoperative survival[85,86]. in the imvigor210 trial, a higher pd-l1 expression score was associated with a higher response rate[77]. in contrast, the checkmate 275 trial showed meaningful responses to nivolumab, irrespective of pd-l1 expression levels[78]. lack of standardized testing and evaluation of pd-l1 may be partia lly responsible for these discrepancies. additionally, pd-l1 expression has been variously assessed: on tumor-infiltrating immune cells in the imvigor210 trial[77], on tumor cells in the checkmate 275 trial[78], and on both tumor cells and immune cells in the durvalumab trial[84]. furthermore, there are variations in percentage cutoffs used to define the high and low expression. finally, pd-l1 expression is continued on page 62 table 4. biomarkers associated with systemic chemotherapy and immunotherapy response molecular pathway biomarker(s) method drug(s) n results year reference dna repair brca-1 ihc cis 104 does not predict chemo response 2015 66 rtpcr gc, gct 57 does not predict chemo response 2007 67 brca-2 ihc cis 104 does not predict chemo response 2015 66 rad51 ihc cis 104 overexpression associated with worse survival 2015 66 par ihc cis 104 overexpression associated with worse survival 2015 66 parp1 ihc cis 104 does not predict chemo response 2015 66 ercc1 ihc cis 104 overexpression associated with worse survival 2015 66 rtpcr gc, gct 57 overexpression associated with worse survival 2007 67 rrm1 rtpcr gc, gct 57 does not predict chemo response 2007 67 drug resistance mdr1 rtpcr mvec 108 overexpression associated with inferior outcome 2010 76 p-glycoprotein (mdr1) ihc cmv, mvac 99 does not predict chemo response 1998 62 caveolin-1 rtpcr gc, gct 57 does not predict chemo response 2007 67 mvac: methotrexate, vinblastine, doxorubicin, cisplatin, mc: methotrexate, cisplatin, cmv: cisplatin, methotrexate, vinblastine mvec: methotrexate, vinblastine, epirubicin, cisplatin, mec: methotrexate, epirubicin, cisplatin, gc: gemcitabine, cisplatin gct: gemcitabine, cisplatin, paclitaxel, cis: cisplatin, cisca: cisplatin, doxorubicin, cyclophosphamide, ihc: immunohistochemistry , cont’d 61siuj.org siuj • volume 2, number 1 • january 2021 bladder cancer tissue-based biomarkers http://siuj.org dynamic, and a single biopsy is unlikely to provide a complete assessment of status for the entire duration of disease. therefore, evaluation of the predictive value of pd-l1 positivity is difficult, and correlations with response to treatment or survival vary between trials. despite these discrepancies, both pembrolizumab and atezolizumab are approved by the fda and the ema for first-line treatment in cisplatin-ineligible patients only in case of positive pd-l1 status on the basis of unpublished results from ongoing phase  ii trials. patients with negative pd-l1 expression should be treated with chemotherapy-based combinations. exploratory analyses from the cisplatin pre-treated arm of the imvigor210 trial showed that molecular subtypes were independently associated with response to atezolizumab treatment[77]. pd-l1 immune cell prevalence was highly enriched in the basal subtype versus the luminal subtype (60% versus 23%, p < 0.001). response to atezolizumab occurred in all subtypes but was significantly higher in luminal cluster ii than in other subtypes[77]. conversely, in checkmate 275, the basal-1 subtype had the highest proportion of continued on page 63 table 4. biomarkers associated with systemic chemotherapy and immunotherapy response molecular pathway biomarker(s) method drug(s) n results year reference cell growth signaling fgfr3 wes pazopanib 3 mutation associated with partial response 2016 68 erbb2 (her2) wes pazopanib 3 mutation associated with better response 2016 68 ihc lapatinib 116 does not predict chemo response 2017 69 ihc lapatinib 34 does not predict chemo response 2009 70 her1 ihc lapatinib 116 does not predict chemo response 2017 69 egfr ihc lapatinib 34 overexpression associated with response 2009 70 vegf serum sunitinib 26 does not predict chemo response 2014 71 serum, ihc pazopanib 18 does not predict chemo response 2013 72 hif1 ihc pazopanib 18 does not predict chemo response 2013 72 dna markers germline snps microarray cabazitaxel 45 snps predicted chemo response and toxicity 2016 74 microarray cis 210 snps predicted chemo response 2013 75 immune markers il-8 luminex xmap sunitinib 38 underexpression associated with better time to progression 2011 73 other metallothionein ihc cmv, mvac 99 overexpression associated with worse survival 1998 62 mvac: methotrexate, vinblastine, doxorubicin, cisplatin, mc: methotrexate, cisplatin, cmv: cisplatin, methotrexate, vinblastine mvec: methotrexate, vinblastine, epirubicin, cisplatin, mec: methotrexate, epirubicin, cisplatin, gc: gemcitabine, cisplatin gct: gemcitabine, cisplatin, paclitaxel, cis: cisplatin, cisca: cisplatin, doxorubicin, cyclophosphamide, ihc: immunohistochemistry , cont’d 62 siuj • volume 2, number 1 • january 2021 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation http://siuj.org table 4. biomarkers associated with systemic chemotherapy and immunotherapy response molecular pathway biomarker(s) method drug(s) n results year reference immune markers pd-l1 ihc atezolizumab 310 overexpression associated with increased response to systemic immunotherapy 2016 77 ihc nivolumab 265 does not predict response to systemic immunotherapy 2017 78 ihc pembrolizumab 114 overexpression associated with increased response to neoadjuvant immunotherapy 2020 86 molecular markers luminal cluster ii transcriptome analysis atezolizumab 310 better response compared to other subtypes 2016 77 basal-1 transcriptome analysis nivolumab 265 better response compared to other subtypes 2017 78 mvac: methotrexate, vinblastine, doxorubicin, cisplatin, mc: methotrexate, cisplatin, cmv: cisplatin, methotrexate, vinblastine mvec: methotrexate, vinblastine, epirubicin, cisplatin, mec: methotrexate, epirubicin, cisplatin, gc: gemcitabine, cisplatin gct: gemcitabine, cisplatin, paclitaxel, cis: cisplatin, cisca: cisplatin, doxorubicin, cyclophosphamide, ihc: immunohistochemistry , cont’d responders[78]. these discrepancies may be partially attributable to the fact that both trials allowed biopsy specimens from the primary tumor, lymph nodes, or metastatic lesions for subtyping, which may lead to inaccurate tumor classif ication. until further details emerge, molecular classification may not be a reproducible predictive biomarker for immunotherapy. the role of neoadjuvant therapy with checkpoint inhibitors is also gaining interest. the pure-01 study evaluated the activity of preoperative pembrolizumab (nct02736266) administered in t2-4an0m0 mibc patients[87]. in total, 114 patients were enrolled, and the pt0 rate was 37% (95% ci 28 to 46) while pt ≤ 1 rate was 55% (95% ci 46 to 65). on multivariable analysis, tumor mutationa l burden and pd-l1 combined positive score were associated with both the pt0 and the pt ≤  1 response, regardless of tumor histology. a separate study using rna sequencing found that the immune190 signature was significant for complete response on multivariable logistic regression analyses in pure-01, but not in a cohort of patients who underwent nac and rc[88]. hallmark signatures for interferon gamma (ifnγ; or 1.11, p = 0.004) and ifnα response (or 1.07, p = 0.006) were also associated with complete response for pure-01, but not for nac (ifnγ: or 0.99, p = 0.9 and ifnα: or 0.99, p = 0.8). basal subtypes (across classifications) with higher immune190 scores showed 100% 2-year progression-free survival after pembrolizumab therapy. high mutational load may be associated with better response to immunotherapy[77]. however, there is currently no standardized definition of mutation burden relative to the depth of sequencing performed. targeted sequencing panels may also not adequately cover gene fusions, truncations, and translocations. further, germline variants may not be silenced by informatics techniques that f ilter common germline singlenucleotide polymorphisms. these challenges currently limit the use of tumor mutational burden as a predictive biomarker for immunotherapy. finally, the tumor microenvironment may play a role in predicting response to therapy[89]. checkmate 275 found that the highest cxcl9 or cxcl10 expression was observed in nivolumab responders[78]. the same findings were reported by analyzing the cohort of cisplatin-pretreated patients of the imvigor210 trial[77]. immune markers investigated for the prediction of response to systemic immunotherapy are summarized in table 4. 63siuj.org siuj • volume 2, number 1 • january 2021 bladder cancer tissue-based biomarkers http://siuj.org table 5. biomarkers associated with radiotherapy response molecular pathway biomarker(s) chemoradiation regimen n results year reference cell proliferation ki-67 rt 59.4 gy + cisplatin 70 higher ki-67 associated with higher cr 2000 124 rt 40 gy + cisplatin 94 higher ki-67 associated with higher cr 2015 125 rt 40.5 gy (median) + cisplatin 62 no association with response 2004 126 cell death pathways apoptotic index rt 59.4 gy + cisplatin 70 higher index associated with higher cr 2000 124 bax/bcl-2 ratio rt 40.5 gy (median) + cisplatin 62 higher ratio associated with higher cr 2004 126 dna repair ercc1 rt 40-66 gy + cisplatin or nedaplatin 22 expression loss associated with higher cr 2011 127 ercc1, xrcc1 rt 48.6 gy (median) + cisplatin 157 positive expression associated with improved survival 2013 128 mre11 rt 55 gy 179 high expression associated with improved survival 2010 129 ddr alterations rt or chemoradiation 48 presence of alterations associated with trend to improved recurrence-free survival 2016 130 cell growth signaling erbb2 rt 40 gy + cisplatin + other agents 55 positivity associated with lower cr 2005 131 rt 40 gy + cisplatin 119 positivity associated with lower cr 2014 132 rt 64.8 gy + paclitaxel with (group 1: erbb2+) or without trastuzumab (group 2: erbb2-) 66 cr rates, 72% for group 1 and 68% for group 2 2017 133 other molecular subtype rt 40 gy + cisplatin 118 cr rates, 52%/45%/15% for gu/scc-like/ urobasal 2018 134 hsp60 rt 40 gy + cisplatin 54 positivity associated with better response 2007 135 rt: radiotherapy, cr: complete response, ddr: dna damage response, gu: genomically unstable, scc: squamous cell cancer 64 siuj • volume 2, number 1 • january 2021 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation http://siuj.org prediction of response to radiotherapy in t he moder n era, rad iot herapy is genera l ly administered in the context of organ preservation therapy in bca. with careful patient selection, tmt yields oncological outcomes and quality of life comparable to rc in mibc[90–92]. however, those who do not achieve complete response may undergo salvage cystectomy, with unfavorable oncological outcomes[93,94]. it is therefore imperative to carefully select patients who may be the optimal candidates for tmt. several studies have looked at biomarkers that can predict response to tmt; the logic for evaluation of these biomarkers is generally based on their ability to predict response to the radiotherapy aspect of tmt. severa l dif ferent biomarkers such as cellu lar proliferation markers (ie, ki-67), cell cycle regulators (ie, p53, bcl-2, bax, bad), cell growth factors (ie, her2/ neu), and dna damage repairs genes have been studied for this purpose. however, because of conflicting results between studies or lack of external validations, none of these markers is currently available for clinical practice. important biomarkers that are predictive of response to radiotherapy in the context of tmt are listed in table 5. tissue-based biomarkers and target therapies biomarkers are important not only because of their ability to predict outcomes or response to therapy but also, and more importantly, because they could act as potential targets for biomarkers-directed therapies. this is the case of erdafitinib, the first fda-approved oral pan-fibroblast growth factor receptor (fgfr) kinase inhibitor that binds to 4 fgfrs (fgfr-1 to -4), leading to decreased cell signaling and cellular apoptosis. the efficacy of erdafitinib (balversa) has been tested in 99 patients with advanced or metastatic urothelial cancer progressing after at least one cycle of chemotherapy with fgfr2 or fgfr3 alterations[95]. the overall response was 40%, with 3% of patients experiencing complete response and 37% experiencing partial response. of note, response was observed also in patients previously treated with systemic immunotherapy (response rate of 59% in this subgroup of patients). following these promising results, fgfr3 inhibitors (eg, infigratinib) are currently under investigation in the adjuvant setting after rc (eudract 2019-003248-63). conclusions reviewing the literature on the utility of tissuebased biomarkers in bca through the last 2 decades, it appears obvious that the focus of research has moved from immunohistochemical analysis and tumor-related phenotypic changes to the analysis of genetic alterations. furthermore, a trend towards marker combinations and genetic classifiers, mostly combining these findings with clinical parameters, is observed. in summary, the literature on the prediction of disease recurrence in nmibc is inconclusive, and little information is available for prediction of response to intravesical bcg. concerning disease progression, external prospective validation studies suggest that mutational fgfr3 status and gene signatures may improve models on the basis of clinicopathologic information. in mibc, tissue-based biomarkers are increasing their importance since they may predict the response to systemic chemotherapy and immunotherapy. the advent of molecular characterization carries the promise to revolutionize the paradigm of decision-making in the treatment of mibc, 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permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. a global perspective of stenting after ureteroscopy: an observational multicenter cohort study ranan dasgupta,1 teng aik ong,2 jasmine lim,2 retnagowri rajandram,2 xiaofeng gao,3 lukman hakim,4 patrick mburugu,5 rohit ajmera,6 emrah yuruk,7 yeong-shiau pu,8 petrisor geavlete,9 raed a. azhar,10 shingai mutambirwa,11 joyce baard 12 1 imperial urology, imperial college healthcare nhs trust, charing cross hospital, london, united kingdom 2 department of surgery, faculty of medicine, university of malaya, kuala lumpur, malaysia 3 department of urology, changhai hospital, second military medical university, shanghai, china 4 department of urology, airlangga university, dr soetomo hospital, surabaya, indonesia 5 department of urology, kenyatta national hospital, nairobi, kenya 6 jawahar lal nehru (jln) medical college, rajasthan, india 7 department of urology, bağcılar training and research hospital, . istanbul, turkey 8 department of urology, college of medicine, national taiwan university, taipei, taiwan 9 department of urology, saint john emergency clinical hospital, bucharest, romania 10 department of urology, king abdulaziz university, jeddah, saudi arabia 11 department of nuclear medicine, sefako makgatho university, pretoria, south africa 12 department of urology, amsterdam umc, university of amsterdam, the netherlands abstract objectives with an increasing number of patients undergoing ureteroscopic surgery worldwide for stone disease, and the concomitant pressures on health care resources, we aimed to review global patterns for ureteric stenting following ureteroscopy. with a centralized electronic database, a longitudinal cohort study was designed to help define the indications for stenting, type of drainage, and methods of stent removal. methods this multicenter study was conducted prospectively, with centralized data acquisition by ucare (research arm of the société internationale d'urologie), and registered at clinicaltrials.gov (nct03567421). along with baseline demographic data, details were entered for stone imaging characteristics, intraoperative information, including urine culture, and exit strategy for stent removal. an independent audit was undertaken to sample the accuracy of data entered across the sites. results in total, 2544 patients were included from 50 centers in 15 countries. there were 1969 patients with ureteric stones, and 942 with renal stones. while 41% ureteric stones were distal (median length 10mm), 52% renal stones were in the lower pole (median diameter 11 mm). the majority of patients (68.8%) were given antibiotics at induction; 20.6% were “pre-stented” before the ureteroscopy, and a high percentage were stented following ureteroscopy (91%). the majority of the stents (85.1%) were polyurethane, mean duration of stent after surgery was 27 days, and 80% of stent removals were undertaken in the operating room. conclusion this is one of the largest prospective global cohort studies, reflecting widespread usage of stenting, despite emerging evidence to the contrary. stent removals may also be modified with time, as the pressure on health care resources mounts. introduction globally, the past decade has witnessed the increasing trend towards ureterorenoscopic treatment of stone disease[1–3]. these procedures may involve use of semi-rigid or flexible instruments, and either digital or fiber optic technology. the miniaturization of the scopes, along with the availability of tools (laser fibers, guidewires, baskets), has led to ureterorenoscopy (urs) overtaking extracorporeal shockwave lithotripsy (eswl) in terms of numbers of key words competing interests article information ureteral stent, urolithiasis, ureteroscopy, stent none declared. received on october 2, 2020 accepted on december 1, 2020 soc int urol j. 2021;2(2):96–105 doi: https://10.48083/hrls8587 96 siuj • volume 2, number 2 • march 2021 siuj.org original research mailto:joyce.baard%40siu-urology.org?subject=siuj clinicaltrials.gov https://10.48083/hrls8587 http://www.siuj.org procedures for upper tract stone disease[4]. it is accepted that patients will sometimes need a ureteric stent at the end of a urs procedure, although debate remains about the indications for this[5]. the use of a stent has associated morbidity and is often the aspect of a urs procedure that a patient remembers most vividly. w hi le dif ferent g uidelines and rev iews have attempted to offer broad outlines on the appropriate use of stents, there remains much variation in practice with respect to their usage. data from 11 885 urs procedures in the clinical research office of the endourological society (croes) study gave an insight into the frequency of use of stents (84.1% for all procedures, 60% after ureteric stone treatment, 80% after renal stone treatment), highlighting the need for further detail on the indications and features of these stent insertions[6]. the importance of this common aspect of stone treatment, with implications for health care costs and delivery worldwide, led to the current longitudinal cohort study with centra lized independent data acquisition, allowing us to analyze the practice patterns across the globe and address the key questions of indication for stent insertion, the type and duration of drainage, and patterns for stent removal techniques. methods this is a prospective multicenter observational longitudinal cohort study of patients with ureteric or renal stones treated by ureterorenoscopy. the study was executed by ucare, the office of research of the société internationale d’urologie (siu). to meet the inclusion criteria, patients had to be ≥18 years old, able to give written consent, and suitable for treatment of a ureteric or renal stone by ureteroscopy. the estimated enrollment for this registry was at least 30 patients from 50 participating centers worldwide. all participating centers obtained ethical approval or a waiver from their local institutional review board (irb). patient data were anonymized, stored in a centralized database, and audited at the conclusion of the study period. this study was registered at clinicaltrials.gov (nct03567421) on june 25, 2018. study assessments: data entry was undertaken at 3 timepoints: t1 (baseline, on the day of the urs), t2a (day of stent removal for stented patients) or t2b (first outpatient clinic, for unstented patients). the study scheme is outlined in figure 1. the data collected were baseline characteristics: age, gender, american society of anesthesiologists physical status classification system (asa i-iv), body mass index, urinary tract infection (uti), prior stent use, previous stone treatment, and other morbidity. stone characteristics: location, number of stones, largest dimension (stone burden, surface area = length × width × 0.25 × 3.14159). abbreviations asa american society of anesthesiologists eswl extracorporeal shockwave lithotripsy iqr interquartile range pcnl percutaneous nephrolithotomy siu société internationale d’urologie uas ureteral access sheath urs ureteroscopy ureterorenoscopy uti urinary tract infection patient selection 1. aged ≥ 18 years old with a ureter or renal stone 2. plan for ureteroscopic (urs) treatment day of surgery (t1) postoperative visit (t2) stented patients non-stented patients day of stent removal (t2a) day of first outpatient clinic (t2b) post-urs data collected: baseline characteristics, stone characteristics, intraoperative data and exit strategy (stending status) data collected: stent removal setting and postoperative details data collected: postoperative details figure 1. study scheme 97siuj.org siuj • volume 2, number 2 • march 2021 a global perspective of stenting after ureteroscopy: an observational multicenter cohort study http://www.siuj.org intraoperative information: use of antibiotics, use of anesthesia, whether pre-stented (and indication for pre-stenting), need for ureteric dilatation, whether semi-rigid and/or flexible ureteroscopy, use of ureteral access sheath (uas), type of lithotripsy energy, duration of surgery (defined as from passage of transurethral instruments to insertion of stent or ureteric drainage catheter), stone-free status assessed endoscopically. exit strategy: ureteric drainage (stent or ureter catheter), type of stent, indication, and indwelling time. stent removal: actual indwelling time, type of anesthesia for stent removal. data are presented as descriptive information, reporting mean (with standard deviation) or median (i nterqua r t i le ra nge) for nor ma l ly d ist r ibuted and skewed (continuous) variables, respectively. dichotomous or categorial numbers are reported as absolute numbers or as percentages. results the study was launched on june 1, 2018, and data collected until end of august 2019. a total of 2544 patients were included from 50 centers from 15 countries (figure 2 and appendix 1 for an overview of participating centers). appendix 1. participating research centres figure 2. inclusion per country 0 8 41 42 48 65 91 102 179 186 202 224 493 855 united states iraq greece saudi arabia kenya iran romania india indonesia taiwan malaysia china turkey 200 400 600 800700500300100 900 3 5 south korea south africa baseline characteristics of a total of 2544 patients, 2540 with complete case records were included. baseline characteristics at inclusion are described in table 1. our cohort had a mean age of 49.0 years (range 18 to 93 years), 64.3% were male, and the majority had an asa classification 1 (51.5%) or asa 2 (40.4%). diabetes mellitus (13.9%) and previous urinary tract infection (16%) were frequently reported comorbidities. of the 671 patients (26.4% of total) who had undergone previous stone surgery, 362 (53.9%) had experience of previous ureteroscopy, 272 (40.5%) previous eswl, and 114 (17.0%) pcnl. renal anomalies were infrequent (3.6%), and only 36 patients had a solitary functioning kidney. stone characteristics in total, 1969 stones were reported in the ureter and 942 stones in the renal system. the distribution of ureteric and renal stone location is shown in figure 3. ureteric stones were most often located in the distal ureter (40.8%), and just over half of the renal stones (52.1%) were in the lower pole. the median stone burden for ureteral stones was 47.1 mm3 (iqr 27.5 to 75.4) with a median length of 11.0 mm (iqr 7.0 to 12.0) and median width 6 mm (iqr 5.0 to 8.0). the renal stones in this cohort were larger with a median stone burden of 66.0 mm3 (iqr 28.4 to 117.8) with a median length of 10.0 mm (iqr 7.1 to 15.0) and median width 8.0 mm (iqr 5.0 to 10.0). intraoperative details of those patients given antibiotics, the majority (68.8%) were administered a prophylactic dose, whereas 30.8% had a therapeutic course after the procedure. just over 20.6% (n = 524) had a stent inserted before the definitive ureteroscopy procedure. reasons for these stent insertions included tight ureter (16.2%) and ureteric narrowing/stenosis (17.2%). interestingly, the main indication for pre-stenting was the surgeons’ preference (23.3%). the median indwelling time in these patients was 30 days (iqr 20 to 60 days). 98 siuj • volume 2, number 2 • march 2021 siuj.org original research http://www.siuj.org in 81.7% of procedures, a semi-rigid ureteroscope was used; the dimensions of semi-rigid ureteroscopes used ranged from 4.5fr to 13fr, with the commonest being 6 to 8 fr as expected. in 30.8% a flexible ureteroscope was used, mainly fiber optic (66.2%). the variety of instruments together with the other intraoperative details are shown in table 2 and figure 4. in 27.9% of procedures a uas was used. in almost half of these cases, the preferred uas was sized 12 or 14 fr (47.7%). in the majority of cases (76%), laser stone fragmentation was used, and in 24%, pneumatic lithotripsy was used. stent details in the vast majority (n = 2332; 91.3%) of the 2429 patients undergoing insertion of a ureteric drainage tube, a double j stent was used, rather than a ureteric stent. the reasons for stent insertion were concern about ureteric edema (54.9%), lengthy procedure (4.9%), difficult access (5.3%), residual stones (23.6%), use of a uas (15.8%), ureteric stricture (12.6%) or lesion (12.0%), solitary kidney (1.0%), or surgical preference (29.8%). the majority were polyurethane (85.1%%) versus silicone (6.1%) or other (5.1%) materials. whereas 759 patients (31.2%) had a multi-length stent, the remaining 1668 had a specific size; the commonest being 24cm (18%), 26cm (43.5%) or 28cm (32.5%). the most commonly used double j stent diameters were 6 fr (54.5%) and 4.7 fr (34.9%). in terms of stent removal, with median duration being 27 days (iqr 15.0 to 37.0), the majority were undertaken in the operating room (80.0%), with very few favoring self-removal by string (1.9%) and a few opting for removal in the office setting (19.9%). the operating room removals were mostly by rigid cystoscopy (61.6%), followed by ureteroscopy (25.1%) and flexible cystoscopy (13.3%) discussion the morbidity associated with ureteric stenting is the aspect of stone treatment that patients tend to remember most vividly. yet there remains a well-documented wide variation in practice. a recent systematic cochrane review found it difficult to make firm conclusions about the practice because of what the authors described as moderate to low “certainty of evidence.” indeed, the review confirmed that there is no agreed-upon definition of an “uncomplicated” ureteroscopy. this being a global issue, we aimed to analyze this practice in an inter-continenta l study, w it h prospective data acquisition, and identify stenting patterns and preferences across the world[5]. this study allows some key conclusions, namely the types of stenting, duration of stent, antibiotic usage, and differences in management table 1. demographics variable n (%) patients included 2544 gender male 1635 (64.3) female 904 (35.5) na 5 (0.2) age mean (range) 49.0 (18.0–93.0) bmi median (iqr) 25.5 (23.3-28.4) asa i 1310 (51.5) ii 1026 (40.3) iii 188 (7.4) iv 11 (0.4) v 1 (0.0) na 8 (0.3) medical history oab 31 (1.2) uti 406 (16.0) dm 353 (13.9) chronic prednisolone use 27 (1.1) upj stenosis 42 (1.7) longstanding immobilization 17 (0.7) previous surgery upj-plasty 19 (0.7) stone treatment 671 (26.4) eswl 272 (40.5) urs 362 (53.9) pcnl 114 (17.0) other 49 (7.3) ureter dilatation 131 (5.1) other urological surgery 113 (4.4) renal anomaly 91 (3.6) ectopic kidney 4 (4.4) horseshoe kidney 10 (11.0) solitary kidney 36 (39.6) other 41 (45.1) asa: american society of anesthesiologists; bmi: body mass index; dm: diabetes mellitus; eswl: extracorporeal shockwave lithotripsy; na: not available/specified; oab: overactive bladder; oac: oral anticoagulation; pcnl: percutaneous nephrolithotomy; upj: ureteropelvic junction; uti: urinary tract infection; urs: ureteroscopy. 99siuj.org siuj • volume 2, number 2 • march 2021 a global perspective of stenting after ureteroscopy: an observational multicenter cohort study http://www.siuj.org for proximal stones. these findings are of relevance both for urologists and for those responsible for delivery of health care systems, and for the design of elective and emergency pathways. with the benefit of a central online database, records were uploaded prospectively by the host centers in real time, and data entries could thus be audited both during and at the conclusion of the study period. over 2500 records were thus collated, of which 10% were sampled for verification and validation of data entry. the global distribution is shown in figure 2 and appendix 1, highlighting the geographical spread of the centers contributing information to this study, with representation from asia, the middle east, europe, and africa. this covers a range of health care systems, thus reducing any bias related to financial remuneration, for instance. the high rate of ureteric stenting after ureteroscopy in this global cohort study (2331/2540; 91.8%) is in line with previous reports, with the commonest justification being concern about ureteric edema leading to pain and/ or obstruction[6]. although various guidelines have proposed that uncomplicated ureteroscopy can avoid routine stenting post-urs, there remains uncertainty about the zone that lies between “complicated” and “uncomplicated,” and this is ref lected in the high stenting rates worldwide[2,3,7–10]. the consistent high rates, regardless of country as per our study, suggest that this is a universal clinical concern and is unrelated to health care system. nevertheless, almost 40% of the cases were for distal stones, and therefore one might expect a slightly lower propensity for stenting in these cases, compared with the 35% proximal stones for which a stent may be somewhat expected. it is possible to speculate that the reason for this high rate of stenting for distal stones is related to the concern about the higher rate of hospital readmission for unstented patients post-urs. however, this is not captured in the dataset as “surgical preference,” which is listed as the reason in only 30.0% of cases. while there would undoubtedly be overlap with those reporting ureteric edema as the cause, one would expect “surgical preference” to be higher if listed. the high proportion of stent removals that were undertaken in the operating room, as opposed to the office, was somewhat surprising, especially with the widespread availability of f lexible cystoscopy and indeed a novel cystoscope with the grasper inbuilt[11]. furthermore, the number of stents-on-string was surprisingly low, and this may be further developed, particularly following the coronavirus pandemic and the move to reducing unnecessary hospital visits. there remains uncertainty about the optimal timing for such stent removal—24 to 48 hours, > 72 hours, etc—and this relates to the questions about duration of ureteric edema after ureteroscopy. indeed, this is likely to be one of the factors that drives surgical preference for stenting. the pilot study by paul et al., although it had a small sample size and retrospective design, suggested a higher proportion of postoperative issues for those with stent removal on day 3 versus on day 7[12]. this study also found that almost 50% of patients preferred to avoid stent-on-string removal. again, this is an area that warrants review through a validated patient reported outcome measure. whether a local anesthetic office-based stent removal, or stent-on-string removal, it will be interesting to review whether the effects of the pandemic change the current global practice patterns. table 2. intraoperative details variable n (%) antibiotic regimen prophylactic 1749 (68.8) therapeutic 784 (30.8) pre-stented 524 (20.6) reason for pre-stentinga surgeons’ preference 122 (23.3) tight ureter 85 (16.2) ureter stenosis 90 (17.2) solitary kidney 17 (3.2) otherb 264 (50.4) indwelling time when pre-stented (days), median (iqr) 30.0 (20.0–60.0) ureter dilatation performed 208 (8.2) uas 710 (27.9) 10/12 226 (31.8) 11/13 85 (12.0) 12/14 339 (47.7) other 60 (8.5) type lithotripter laser 1929 (75.8) pneumatic 608 (4.3) ballistic 25 (0.1) other 83 (3.3) duration surgery (min), median (iqr) 45.0 (30.0-60.0) impacted stone 924 (36.3) stone free 13 (0.5) uas: ureteral access sheath, a multiple answers possible, b including obstructing stone. 100 siuj • volume 2, number 2 • march 2021 siuj.org original research http://www.siuj.org ureter proximal distal upper pole interpolar lower pole renal renal pelvis upjmid 8,8 29,3 52,1 26 21,4 40,8 24,1 38,1 ureter proximal distal upper pole interpolar lower pole renal renal pelvis upjmid 8,8 29,3 52,1 26 21,4 40,8 24,1 38,1 one of the key questions for ureteroscopic stone treatment is whether primary urs is feasible or whether a period of pre-stenting is required. this is likely to differ between the treatment of ureteric stones (in which the majority, though not all, of even proximal stones may be accessible at the initial procedure) and renal stones (in which safe practice, even with availability of access sheaths, may preclude reaching a stone in the case of a tight ureter). our relatively low figure of 20.6% prestented patients is consistent with other reports: 11.9% preoperative placement for ureteric stones, 36.4% for renal stones[13]. this likely reflects the fact that most upper tracts are accessible by the miniaturization of the technology (with use of access sheaths and flexible ureterorenoscopes) but that some ureters will naturally remain too tight to permit safe retrograde passage without a period of passive dilation. this figure may also help with decision-making when the alternatives of eswl and pcnl may be considered in terms of stonefree rates and choice of primary procedure. with the increasing recognition of mini-pcnl, the boundaries between urs and pcnl for renal stones have shifted over the past decade. a further area of variability in practice is the prophylactic use of antibiotics and the prescription of antibiotics following the procedure. it remains fairly standard to use antibiotics at the time of urs, with approximately 2/3 giving a dose at induction, though a relatively high proportion (almost 1/3) continued a course of antibiotics after the procedure. while the latter practice would certainly be advisable when there may be a risk of ongoing infection (eg, recent preoperative uti, colonized stent, neuropat hic patients, etc), the unquestionable global problem of antimicrobial resistance should lead to more judicious use of antibiotics. this should be reflected in guidelines, which have generally deferred to “local practice,” with the lack of high-quality evidence being cited as a reason for the lack of a universal standard[2,3,7,8]. of course, the other challenge is establishing the optimal type and dose of antibiotic (eg, an aminoglycoside, a penicillin, a cephalosporin, a quinolone, or a combination). urinary tract infections, hematuria, and stent-related symptoms are known postoperative problems associated with both the procedure as with stenting and may also be related to the duration of stenting. whether reducing this stent indwell time (eg, by greater use of stent-onstring) would impact on the postoperative uti rate, further research into optimal ureteric drainage would ideally incorporate such infection data. in a global study such as this, one would expect to observe variations in the use of uas; with 710 cases (27.9%) using this, this figure is broadly as expected, especially for the number of proximal ureteric and renal stones. the proliferation of endourology expertise and technology would appear to have translated into use of this disposable. although a higher rate would be expected in a renal stone rather than a ureteric stone study alone, the current figure illustrates familiarity with these sheaths globally; the relatively similar numbers for the 10/12 fr size (31.8%) and 12/14 fr (47.7%) may reflect local availability and experience. this may well also have an impact on stenting, as some who favor use of access figure 3. stone location ureter n = 1969 renal n = 942 101siuj.org siuj • volume 2, number 2 • march 2021 a global perspective of stenting after ureteroscopy: an observational multicenter cohort study http://www.siuj.org sheath may argue for the benefits of stenting due to theoretical issues about edema associated with uas. limitations of this study include those of any study in which the data entry is by the individual center, but it has 2 advantages over other studies of practice (eg, online surveys, snapshot audits): (1) the centralized database was hosted by an independent organization, and (2) realtime entry meant that recall bias could be minimized, while the completion of datasets was maximized, and spurious or outlying data could be followed up. data quality was assessed by an appointed audit committee, who were able to interrogate 10% of all cases, and confirmation of consent, imaging, and patholog y reports were all accessed, and operative details were also verified. this process revealed that some centers kept original data in print form while others had moved to electronic data, and some used a combination. while the questionnaire was designed in english, the consent process relied on translation locally, and the governance of informed consent relied on robust local institutional review board approval at each center. finally, the listing of stent indication under “surgeon preference” was a broad variable without any qualitative description (ie, how this differed from concern about edema, residual fragments, etc). conclusion this large multicenter cohort study reflects the current practice of stenting following ureteroscopy for stone disease and reveals widespread use of stenting despite an increase in suggestions that for certain cases, this morbid aspect of the surgery can be avoided. where stents are used, the practice of stent-on-string remains underused, again reflecting current surgical preference. future studies should address the indications for stenting in greater detail and help improve stent-related morbidity in the future acknowledgments the authors would like to thank the following for their help. research council representatives: rui chen, chinese urological association; prodromos philippou, cyprus urological association; yasser farahat, emirates urological society; selcuk guven, eurasian urooncological association; bernhard ralla, german society of residents in urology; athanasios papatsoris, hellenic urological association; lukman hakim, indonesian urological association; moha mmad hadi radfar, iranian urologica l association; yoshihiko tomita, japanese urological association; patrick mburugu, kenya association of urological surgeons; jae young park, korean urological association; teng aik ong, malaysian urological association; paul villanti, movember foundation; raed a. azhar, saudi urological association; andré van der merwe, south african urological association; yeongshiau pu, taiwan urological association. audit committee members (for patient data audit): yigit akin, samuel yee. siu central office (for study coordination and database management): christine albino, brittany scarfo. figure 4. instrumentation (%) semirigid scope < 6 8 9 >9 1,3 3,5 22,1 27,9 6 22,1 7 23,1 flexible scope digital fiberoptic singleuse other 21,3 66,2 10,6 2,3 102 siuj • volume 2, number 2 • march 2021 siuj.org original research http://www.siuj.org this research study would not have been possible without the support from the société internationale d’urologie. we would like to thank the study team and all the research investigators who participated in the enrollment of patients for this study. see appendix 1 for a complete list of participating centers. author contributions ranan dasgupta: drafting of the manuscript, acquisition of data, reviewing of the manuscript. teng aik ong, jasmine lim, xiaofeng gao, lukman hakim, patrick mburugu, rohit ajmera, emrah yuruk, yeong-shiau pu, petrisor geavlete, raed a. azhar, shingai mutambirwa: acquisition of data, critical revision of the manuscript for important intellectual content joyce baard: study concept and design, critical revision of the manuscript for important intellectual content source of funding: this registry is funded by the société internationale d’urologie (siu), 1155 robert-bourassa blvd, suite 1012, montréal, québec, canada. ethics approval: regional medical research ethics committee, institutional review board (irb) or a waiver for consent was obtained at each participating center prior to subject enrollment. references 1. raheem oa, khandwala ys, sur rl, ghani kr, denstedt jd. burden of urolithiasis: trends in prevalence, treatments, and costs. eur urol focus. 2017;3(1):18–26. http://dx.doi.org/10.1016/j.euf.2017.04.001. 2. türk c, neisius a, petřík a, seitz c, thomas k, skolarikos a. eau guidelines on urolithiasis 2020. eau guidelines. 2020 ed. 2020; presented. 3. cloutier j, anson k, giusti g, grasso m, kamphuis g, lahme s, et al. update of the icud-siu consultation on stone technology behind ureteroscopy. world j urol. 2017;35(9):1353–9. 4. seklehner s, laudano ma, jamzadeh a, del pizzo jj, chughtai b, lee rk. trends and inequalities in the surgical management of ureteric calculi in the usa. bju int. 2014 mar;113(3):476–483. doi: 10.1111/bju.12372. epub 2013 nov 21. pmid: 24053734. 5. ordonez m, hwang ec, borofsky m, bakker cj, gandhi s, dahm p. ureteral stent versus no ureteral stent for ureteroscopy in the management of renal and ureteral calculi: a cochrane review. can urol assoc j. 2020;14(2):61–8. 6. de al rosette j, denstedt j, geavlete p, keeley f, matsuda t, pearle m, et al.; croes urs study group. the clinical research office of the endourological society ureteroscopy global study: indications, complications, and outcomes in 11,885 patients. j endourol. 2014;28(2):131–9. pmid: 24147820 doi: 10.1089/end.2013.0436 7. assimos d, krambeck a, miller nl, monga m, murad mh, nelson cp, et al. surgical management of stones: american urological association/endourological societ y guideline, part i. j urol. 2016;196(4):1153–60. http://dx.doi.org/10.1016/j.jur0.2016.05.090. 8. assimos d, krambeck a, miller nl, monga m, murad mh, nelson cp, et al. surgical management of stones: american urological association/endourological societ y guideline, part ii. j urol. 2016;196(4):1161–9. http://dx.doi.org/10.1016/j.jur0.2016.05.091. 9. e xcellence c. nice guideline – renal and ureteric stones: assessment and management: nice (2019) renal and ureteric stones: assessment and management. bju int. 2019;123(2):220–232. 10. haleblian g, kijvikai k, de la rosette j, preminger g. ureteral stenting and urinary stone management: a systematic review. j urol. 2008;179(2):424–430. 11. doizi s, kamphuis g, giusti g, palmero jl, patterson jm, proietti s, et al. first clinical evaluation of a new single-use flexible cystoscope dedicated to doublej stent removal (isirist m): a european prospective multicenter study. world j urol. 2017;35(8):1269–75. 12. paul cj, brooks na, ghareeb gm, tracy cr. pilot study to determine optimal stent duration following ureteroscopy: three versus seven days. curr urol. 2018;11(2):97–102. 13. assimos d, crisci a, culkin d, xue w, roelofs a, duvdevani m, et al. preoperative jj stent placement in ureteric and renal stone treatment: results from the clinical research of fice of endourological society (croes) ureteroscopy (urs) global study. bju int. 2016;117(4):648–654. 103siuj.org siuj • volume 2, number 2 • march 2021 a global perspective of stenting after ureteroscopy: an observational multicenter cohort study http://dx.doi.org/10.1016/j.euf.2017.04.001 http://dx.doi.org/10.1016/j.euf.2017.04.001 http://www.siuj.org appendix 1. participating research centres institute country principal investigator 1. shanghai changhai hospital, second military medical university china yinghao sun 2. ningbo first hospital, the affiliated hospital of ningbo university china yue cheng 3. the first affiliated hospital of guangzhou medical university and g uangdong key laboratory of urology china guohua zeng 4. renji hospital, school of medicine, shanghai jiao tong university china wei xue 5. tongji hospital, tongji medical college, huazhong university of science and technology china lei cui 6. guangdong second provincial general hospital, the third clinical medical college of southern medical university. china guosheng yang 7. sismanoglio general hospital greece athanasios papatsoris 8. aretaieion academic hospital greece athanasios dellis 9. aristotle university, 1st department of urology, thessaloniki greece anastasios anastasiadis 10. university of crete, department of urology greece charalampos mamoulakis 11. university hospital of larissa, department of urology greece stavros gravas 12. jawahar lal nehru (jln) medical college india rohit ajmera 13. kulkarni reconstructive urology center india sanjay kulkarni 14. sanglah hospital, department of urology, udayana university indonesia kadek budi santosa 15. sardjito hospital, gadjah mada university, department of urology, jogjakarta indonesia indrawarman soeroharjo 16. cipto mangunkusumo hospital, department of urology, university of indonesia indonesia nur rasyid 17. dr. soetomo hospital, department of urology, airlangga university indonesia johan renaldo 18. hasan sadikin hospital, department of urology, padjajaran university indonesia safendra siregar 19. saiful anwar hospital, department of urology, brawijaya university indonesia taufiq nur budaya 20. shahid beheshti hospital, hamadan university of medical sciences iran seyed habibollah mousavibahar 21. university of basra college of medicine, department of urology iraq murtadha almusafer 22. pandya memorial hospital kenya sundeep chavda 23. university of malaya medical centre malaysia teng aik ong 24. selayang hospital malaysia rohan malek 25. sarawak general hospital malaysia guan chou teh continued on page 105 104 siuj • volume 2, number 2 • march 2021 siuj.org original research http://www.siuj.org appendix 1. participating research centres institute country principal investigator 26. kuala lumpur hospital malaysia vijayan manogran 27. serdang hospital malaysia saiful azli 28. st. john clinical hospital of emergency, department of urology romania petrisor geavlete 29. international medical center saudi arabia raed a. azhar 30. king abdulaziz university saudi arabia raed a. azhar 31. prince sultan military medical city scientific research center saudi arabia ali obied 32. sefako makgatho health sciences university south africa shingai mutambirwa 33. smg-snu boramae medical center south korea sung yong cho 34. national taiwan university hospital, department of urology taiwan yeong-shiau pu 35. en chu kong hospital, department of urology taiwan chung-cheng wang 36. cardinal tien hospital, department of urology taiwan hsu-che huang 37. kaohsiung veterans general hospital, division of urology, department of surgery taiwan chia-cheng yu 38. university of health sciences, dept of urology, bagcilar hospital turkey emrah yuruk 39. 9 eylul university, department of urology turkey guven aslan 40. gazi university school of medicine, department of urology, ankara turkey bora küpeli 41. baskent university, faculty of medicine, department of urology turkey m. ilteris tekin 42. hacettepe university, department of urology, ankara turkey cenk y. bilen 43. istanbul medipol university, department of urology turkey selcuk guven 44. cerrahpasa school of medicine, istanbul university turkey bulent onal 45. necmettin erbakan university, meram medical school turkey mehmet balasar 46. university of çukurova, department of urology, adana turkey ibrahim atilla aridogan 47. konya meram education & research hospital turkey mahmud zahid ünlü 48. bulent ecevit university, department of urology turkey n. aydin mungan 49. selcuk university selcuklu medical school turkey mehmet kaynar 50. university of minnesota, department of urology united states michael borofsky , cont’d 105siuj.org siuj • volume 2, number 2 • march 2021 a global perspective of stenting after ureteroscopy: an observational multicenter cohort study http://www.siuj.org 4 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation australia’s two-tier health care system united against covid-19 bishoy hanna,1,2,3 amanda chung4,5,6,7,8 1 north shore urology research group, st leonards, australia, 2 nepean urology research group, kingswood, australia, 3 northern sydney local health district, st leonards, australia 4 department of urology, macquarie university hospital, macquarie university, australia, 5 the university of sydney, concord repatriation general hospital, department of urology, concord, australia, 6department of urology, royal north shore hospital, st leonards, australia, 7department of urology, northern beaches hospital, frenchs forest, australia, 8department of urology, sydney adventist hospital, wahroonga, australia soc int urol j. 2020;1(1):4–5 introduction the coronavirus disease 2019 (covid-19) pandemic has had and continues to have an unprecedented impact on health care systems worldwide. the australian system has yet to be truly tested by the pandemic, as rapid implementation of public health measures has curbed infection rates. australia’s 2-tier health care has allowed sufficient staffing, equipment, and beds to continue providing acute health care in the face of an exceptional and extreme demand. no health system is perfect and, although australia’s has some wonderful attributes that make it the envy of many other countries, it faces a number of important challenges. this paper describes how australia’s health care structure has adapted to respond to the covid-19 crisis, examines the challenges involved and the lessons learned, and explores how this environmental pressure could lead to systemic adaptations. the australian health care system australia has a 2-tier system, public and private. the public system, medicare, is funded by the federal government and is available for australian citizens and permanent residents. two percent of taxable income with up to a 1.5% surcharge on high earners funds this component, which accounts for approximately 67% of total health care costs [1]. australian health care in 2017– 2018 cost $170 billion, which is 9.6% of gross domestic product, slightly above the organisation of economic co-operation and development average [1]. however, the health cost to gdp ratio in australia remains behind those of the united states, canada, new zealand, and the united kingdom. public health care in australia is subject to limited resources, leading to acute health care prioritization and waitlisting for non-urgent care. the general practitioner (gp) determines the medical treatment required, making referrals to public clinics before specialist care can be sought and treatment initiated. this all takes time and is only the beginning of the wait. if the referral is accepted, the patient is put on an outpatient wait list to see a specialist. wait time is determined by acuity. if a problem is urgent, it will be attended to within 30 days of being added to the wait list, not from initial gp attendance. semi-urgent conditions have a wait time of 90 days, and non-urgent problems wait up to 365 days. patients with semi-urgent conditions wait 90 days, and those with non-urgent problems wait up to 365 days. these are targets: waits may be longer or shorter, depending on individual public hospitals. the patient with an urgent bladder mass might not be assessed for 30 days, and the cataract keeping someone from reading or driving might not be removed for up to a year. a parallel and optional private system puts patients in control, allowing them choice of treating physician, time to treatment, and location. australian private insurance is market-based. consumers purchase a policy with an assigned premium that suits their individual needs. this policy predominantly covers the cost of admission and health care provision in private hospitals. these facilities are completely separate from government built and run public hospitals. private hospitals are owned and operated by independent companies, providing ser vices partially medicare funded and partially privately sourced, with insurance providing capped hospital excesses. until very recently, public and private health care provision have, for the most part, remained separate. united against a common enemy the austra lian hea lt h care system has evolved over many years to become the world-class service provider it is today. however, its strength in providing multifaceted tailored health care for a broad range of societal situations has led to bureaucratic rigidity. as the technological world exponentially expands, many australian hospitals remain without even a universal electronic medical records system. the system is cluttered with several competing agendas and litigious fears to the detriment of efficient health care delivery. http://www.siuj.org mailto:amandashujun.chung%40gmail.com?subject=siuj 5siuj.org siuj • volume 1, number 1 • october 2020 australia’s two-tier health care system united against covid-19 however, on april 1, 2020, a joint media release stated the australian government would partner with the private hospital sector to help fight the covid-19 pandemic [2]. overnight, the entire structure of australian health care provision was rearranged to aid the pandemic effort. private hospitals were commissioned to service public category 1 elective surgeries and facilitate the transfer of public ward and icu patients to private facilities. not only did this secure an immediate 30 000 private hospital beds and 105 000 skilled workers but it also significantly increased the supply of in-demand consumables such as personal protective equipment (ppe), ensuring public hospitals were adequately buffered to weather the covid-19 storm. medical administration collaborated with clinicians and ground staff to put these measures swiftly into action with immediate results. it is as if the viral enemy at the door galvanised a sense of united toil to overcome the barriers of bureaucratic delay [3]. the pandemic has become a catalyst for health care development. a more f lexible system, welding together public and private systems for optimal health care provision is merely the beginning of pandemicinitiated improvements. the advent of telehealth and videoconferencing has increased access for rural and remote patients and facilitated multidisciplinar y discussion and management. working from home has seen creativity and innovation replace the pretence of productivity imposed by the “clock in, clock out” mentality. efficient technological advances, ranging from safe aerosol-generating procedures to vaccination programs, have shown development can be rapid in the face of adversity. unification of public and private sectors was symbolic of a broader unification of politician, clinician, allied health, and administration to implement effective and efficient health care. conclusion australia’s distinct 2-tier health care system has afforded inherent reserve to allow for immediate pandemic-proof reform. unifying the systems to respond to a common adversary has enabled developments in health care provision that would not have been possible had they remained separate. if the australian system is to remain adaptable and innovative, this unified model must survive beyond the pandemic. references 1. aihw. australian institute of health and welfare: australia’s health 2018. australia’s health series no. 16: aus 221; 2018. 2. department of health australian government partnership with private health sector secures 30,000 hospital beds and 105,000 nurses and staff, to help fight covid-19 pandemic 2020. april 1, 2020. available from: https://w w w.health.gov.au/ministers/ the-hon-greg-hunt-mp/media/australian-government-partnershipwith-private-health-sector-secures-30 0 0 0 -hospital-beds-and10 5 0 0 0 nur s e s a n d s t a f f-t o h elp -f ig h tc o v id -19 p a n d e mic . accessed september 16, 2020. 3. khadra m. new normal post-covid-19: nepean’s experience. med j aust. august 10, 2020. http://www.siuj.org https://www.health.gov.au/ministers/the-hon-greg-hunt-mp/media/australian-government-partnership-with-private-health-sector-secures-30000-hospital-beds-and-105000-nurses-and-staff-to-help-fight-covid-19-pandemic https://www.health.gov.au/ministers/the-hon-greg-hunt-mp/media/australian-government-partnership-with-private-health-sector-secures-30000-hospital-beds-and-105000-nurses-and-staff-to-help-fight-covid-19-pandemic https://www.health.gov.au/ministers/the-hon-greg-hunt-mp/media/australian-government-partnership-with-private-health-sector-secures-30000-hospital-beds-and-105000-nurses-and-staff-to-help-fight-covid-19-pandemic https://www.health.gov.au/ministers/the-hon-greg-hunt-mp/media/australian-government-partnership-with-private-health-sector-secures-30000-hospital-beds-and-105000-nurses-and-staff-to-help-fight-covid-19-pandemic novel expanding renal cell carcinoma biomarkers francesco claps,1,2 m. carmen mir1 1 department of urology, fundacion instituto valenciano oncología, valencia, spain 2 department of urology, university of trieste, hospital of cattinara, trieste, italy abstract identification of reliable molecular biomarkers that can complement clinical practice represents a fascinating challenge in any cancer field. renal tumors are usually asymptomatic and incidentally identified during imaging studies undertaken for unrelated causes. however, in 25% to 30% of patients the first diagnosis is accompanied by symptoms and associated with distant metastasis. thus, early diagnosis may reduce the risk of disease progression also avoiding side effects of inadequate treatments. moreover, the ability to categorize patients' risk of recurrence after radical treatment, or even predict benefit from a target therapy, represents a compelling challenge. here we review the current state-of-the-art on rcc biomarkers, particularly focusing on the new approaches of genomics, liquid biopsy, proteomics, and metabolomics. introduction renal cell carcinoma (rcc) is the third most common urological cancer in the united states, with an estimated 44 120 new cases in 2019[1]. clear-cell renal cell carcinoma (ccrcc) is the most frequent subtype, accounting for approximately 75% to 80% of these tumors, and is responsible for the majority of kidney cancer deaths[2]. in this narrative review we present the current state-of-the-art on diagnostic and prognostic rcc biomarkers, particularly focusing on the new approaches of genomics, liquid biopsy, proteomics, and metabolomics. a medline/pubmed search was performed using individual or/and different combinations of terms including “renal cell carcinoma,” “biomarker,” “diagnosis,” “prognosis,” and “survival.” only papers with the title and abstract in the english language were screened for eligibility. the full text of included papers was analyzed. biomarkers in early detection and diagnosis recent advances in diagnostic techniques have increased early ccrcc detection. mortality rates, however, remain steady[3]. imaging studies are still unable to differentiate histology, and renal mass biopsy has a 10% to 20% nondiagnostic rate[4]. therefore, it is highly desirable to have novel and reliable biomarkers suitable for rcc screening and early detection, ensuring that the benefits of new technologies are fully realised (table 1). circulating cell-free dna liquid biopsy assays, such as circulating tumor cells (ctcs) or circulating cell-free dna (cf dna), constitute promising and less invasive techniques that can overcome the limits related to conventional diagnostic methods[5]. cfdna consist mostly of double-stranded molecules that circulate as nucleoprotein complexes[6]. hauser et al. evaluated cfdna from patients with rcc and from healthy individuals using quantitative real-time polymerase chain reaction (pcr). two primer sets amplifying a sequence of the actin-beta gene (actb) were used: actb-106 detects fragmented cf dna that results from apoptosis, and actb-384 detects long dna fragments released by necrosis. in this analysis, dna fragments were significantly increased in rcc patients compared to healthy controls[7]. lu et al. evaluated cfdna extracted from plasma of healthy controls and 229 ccrcc patients at stages m0 and m1. the 306 base pairs fragment was lower in rcc patients than in controls. since cfdna fragment sizes are indicators of the integrity of cfdna molecules, the authors showed that the ratio of longer to shorter cfdna key words competing interests article information renal cell carcinoma, biomarker, diagnosis, prognosis, survival none declared. received on july 16, 2020 accepted on september 8, 2020 soc int urol j. 2021;2(1):32–42 32 siuj • volume 2, number 1 • january 2021 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation mailto:mirmare%40yahoo.es?subject=siuj http://www.siuj.org fragments was significantly improved in patients staged as m0 compared with those as m1 subgroup[8]. on plasma cf dna, yamamoto et al. showed that median levels of cf dna and median size of fragments from rcc patients were significantly greater than those from controls. an optimal cut-off value of 2876 copies/ml was identified[9]. nuzzo et al. performed cell-free methylated dna immunoprecipitation and high-throughput sequencing (cf medip-seq). cf medip-seq is an enrichmentbased method to comprehensively interrogate cf dna methylation profile extracted from plasma and urine. the authors identified differentially methylated regions and selected the top rated between case and control samples. samples from rcc patients were assigned a higher median methylation score than those from controls. furthermore, the lowest methylation scores in rcc patients came from patients with small tumors. thus the authors reported an accurate classification of patients across all stages of rcc in plasma cfdna (auc 0.99) and demonstrated the validity of this assay using urine cfdna (auc 0.86)[10]. the abundance and relative fragmentation of cfdna in blood can be a universal marker for rcc7 yet the precise cfdna metrics that are most clinically relevant remain controversial. study results reported to date are limited by heterogeneity with respect to clinical stage, tumor pathology, blood sample processing, and methods of cfdna analysis. circulating tumor cells ctcs are cells that have been shed into the vasculature or lymphatics from a primary tumor. the detection and analysis of ctcs can assist in determining patient prognosis and personalized treatments, as well as initial diagnostic and monitoring procedures. moreover, ctcs are particularly suited to interrogate functional heterogeneity by combining genetic and transcriptomic assessment of single ctc[11] or by transcriptome and epigenome analysis[12]. it is difficult to assess the diagnostic value of ctcs in rcc due to the use of different methods of ctc collection and identification across studies[13]. the different techniques include epithelial or non-epithelial marker-dependent isolation, reverse transcription pcrbased methods, and morphologicaland cell size-based methods[14]. moreover, rcc cancer cells are inclined to the loss of their epithelial antigens through epithelialto-mesenchymal transition, in which morphological transformation leads to acquisition of mesenchymal features[15]. other surface markers have been developed to select rcc cancer cells in the blood (eg, caix). adding this new set of cell surface markers including caix and cd147 to the conventional detection of ctcs through epithelial markers, such as the epithelial cell adhesion molecule (epcam), has shown better results[16]. the role of micrornas micrornas (mirs) are implicated in the regulation of processes such as proliferation, migration, invasion, and apoptosis, and are readily detectable in tissues and bodily fluids[17]. wulfken et al. reported that the level of mir-1233 was significantly increased in patients with rcc compared with healthy controls. thus, mir-1233 levels were investigated in an independent cohort confirming a higher mean value in rcc patients[18]. zhao et al. found that mir-210 levels were higher in primary rcc tissues than in normal tissue. furthermore, the serum level of mir-210 was significantly decreased in patients 7 days after nephrectomy; consequently, a potential combined role in early detection and monitoring after radical treatment could be proposed[19]. iwamoto et al. confirmed at the serum level that the expression of mir-210 was significantly higher in rcc patients than in healthy controls[20]. in addition, a meta-analysis conducted by chen et al. that included 7 studies, 570 rcc patients, and 415 healthy controls showed pooled sensitivity, specificity, and diagnostic or to predict rcc of 74%, 76%, and 8.81, respectively[21]. chen et al. evaluated the expression levels of mir129-3p and mir-129-5p in 69 cases of paired renal tumors, healthy tissues, and conventional rcc cell lines. mir-129-3p and mir-129-5p are 2 mature products of mir-129-2 known for its anti-tumor effects in various malignancies. they showed that mir-129-3p, but not mir-129-5p, was widely attenuated in human ccrcc, and chrcc, yielding a 73.5% accuracy in discriminating ccrcc from normal tissues. the relative mir-129-3p expression significantly differed between malignant and benign kidney tumors[22]. in a prospective cohort, yadav et al. found that use of serum mir-34a, mir-141, and mir-1233 was able abbreviations actb actin-beta gene ccrcc clear-cell renal cell carcinoma css cancer-specific survival ctcs circulating tumor cells cfdna circulating cell-free dna mirs micrornas os overall survival pcr polymerase chain reaction pfs progression-free survival rcc renal cell carcinoma 33siuj.org siuj • volume 2, number 1 • january 2021 novel expanding renal cell carcinoma biomarkers to diagnose ccrcc with a sensitivity of 80.76%, 75%, and 93.33%, and specificity of 80%, 73.33%, and 100%, respectively, when tumor pathologic was used as the reference. moreover, a combined approach using a panel of 2 serum mirs (mir-141 and mir-1233), allowed a diagnosis of ccrcc with 100% sensitivity and 73.3% specificity[23]. recently, zhang et al. investigated whether mirnas in serum exosomes can serve as biomarkers in ccrcc. their findings showed that the expression levels of exosomal mir-210 and mir-1233 were significantly higher in rcc patients than in healthy individuals (both p < 0.01). roc analysis demonstrated that exosomal expression levels distinguished rcc patients from healthy individuals with 70% sensitivity and 62.2% specificity for mir-210, and 81% sensitivity and 76% specificity for mir-1233[24]. metabolites as novel biomarkers of rcc metabolomic approaches have shown promising results in oncology, with the recognition of metabolic reprogramming as a hallmark of cancer. globally, rcc metabolic signature of the tumor microenvironment is characterized by alterations in metabolites associated with energy metabolism, especially those involved in glycolysis, amino acid metabolism, and fatty acid catabolism pathways, which are essential for cell growth and proliferation[25]. kim et al. first evaluated the utility of urine metabolomics analysis for metabolomic profiling. the authors identified a total of 212 molecules able to differentiate rcc presence. the rate of correct classification was 88%[26]. ganti et al. showed differential urinary concentrations of several acylcarnitines as a surrogate of rcc status and grade, with most acylcarnitines being increased in rcc patients’ urine. furthermore, urinary acylcarnitines were increased in a grade-dependent fashion in rcc patients and likely emanated from the tumor tissues. acylcarnitines have both cytotoxicity and immune modulatory properties and thus may play a role in decreasing the inf lammatory response and providing a mechanism by which these cells are able to evade immune surveillance[27]. in the same field, niziol et al. showed that hydroxybutyrylcarnitine, decanoylcarnitine, propanoylcarnitine, carnitine, dodecanoylcarnitine, and norepinephrine sulfate were found in much higher concentrations in both rcc tissues (compared with the paired normal tissue) and urine of cancer patients (compared with urine of control subjects)[28]. proteomics analysis proteomics offers a useful platform to study the complex molecular events of tumorigenesis. upregulation in the glycolytic f lux is a common pathway in cancer. therefore, using isobaric tags for relative and absolute quantitation (itraq) white et al. identified 55 proteins significantly dysregulated in rcc. dysregulation of alpha-enolase (eno1), l-lactate dehydrogenase a chain (ldha), heatshock protein beta-1, known as hsp27, mitochondrial (hspe1) was confirmed in 2 independent sets of patients by western blot and immu nohistochemist r y (ihc). the ex pressions of ahnak, eno1, and hsp27 were found to be significantly elevated in ccrcc compared with matched normal tissues. whereas hspe1 was significantly downregulated in rcc patients[29]. zhang et al. recently found 16 significantly upregulated and 14 significantly downregulated in early-stage rcc compared with healthy controls. serum heat shock cognate 71 (hsc71) was highly elevated in the rcc group compared with control group[30]. kim et al. showed that rcc upregulated proteins were nicotinamide-n-methyltransferase (nnmt), secretagogin (scgn), l-plastin, human neuron specific enolase (hnse), nonmetastatic cell 1 (nm23a), ferritin light chain (ftl), and thioredoxin peroxidase (kim2010). nnmt was the most commonly upregulated protein over all types of rcc, especially in comparison with normal tissues. scgn was elevated in ccrcc samples but not in papillary, chromophobe, or normal tissue, while nm23a showed the same behavior, although the magnitude of changes was smaller than in the first 2 molecules[31]. prognostic biomarkers although most biomarkers for early detection and diagnosis remain at an early stage, more advances have been made with prognostic biomarkers for rcc. to date, few biomarkers have been taken beyond single studies, thus none are yet ready for routine clinical practice. furthermore, emerging and promising approaches can serve as new platform in which novel potential biomarkers can be found. following any type of surgical treatment of rcc, there is a need for risk stratification aiming to enable personalized outcome prediction. the major endpoints evaluated and predicted using prognostic biomarkers across the studies referred to in the following sections of this paper are disease/ progression/recurrence-free survival (d/p/rfs), overall and cancer-specific survival (os, css), and correlations with clinicopathological features that might influence the prognosis among these patients[32] (table 2). cfdna one of the most promising uses of liquid biopsy is to determine the risk of recurrence after curative treatment. wan et al. measured plasma levels of cfdna before and after surgery for localized disease. mean preoperative level of plasma cf dna in patients who developed recurrent disease was significantly higher than in those 34 siuj • volume 2, number 1 • january 2021 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation http://siuj.org with localized disease or controls[33]. analyzing the genomic and mitochondrial cf dna concentrations, lu et a l. developed 2 models that incorporated clinicopathological features to specific expression patterns among cf dna fragments. particularly, app gene, the alu sequences, and the mitochondrial dna fragments showing significant correlation in terms of os and rfs[8]. in terms of quantitative measurement, table 1. novel potential candidates biomarkers in diagnosis and early detection of renal cell carcinoma biomarker source trend correlation/use reference cfdna plasma serum increased  rcc and mrcc detection, association with histotype, monitoring after curative surgery hauser et al. (2010)[7] de martino et al. (2012)[51] lu et al. (2016)[8] yamamoto et al. (2018)[9] nuzzo et al. (2020)[10] ctcs blood increased  rcc detection and monitoring allard et al. (2004)[52] li et al. (2005)[53] liu et al. (2016)[16] broncy et al. (2018)[54] mirna mir-1233 serum increased  rcc detection wulfken et al. (2011)[18] zhang et al (2018)[24] yadav et al. (2017)[23] mir-451 serum decreased  rcc detection redova et al. (2012)[55] mir-378 serum increased  rcc detection redova et al. (2012)[55] mir-21 tissue increased  rcc detection, differential diagnosis between ccrcc, prcc and chrcc and oncocytoma faragalla et al. (2012)[56] mir-15a tissue urine both increased  rcc detection, differential diagnosis between malignant and benign renal tumors von brandestain et al. (2012)[57] mir-210 tissue urine serum increased  increased  increased  rcc detection and disease monitoring after local treatment zhao et al. (2013)[19] iwamoto et al. (2014)[20] zhang et al. (2018)[24] chen et al. (2018)[21] mir-129-3p tissue decreased  rcc detection, differential diagnosis between malignant and benign renal tumors chen et al. (2014)[22] mir-34a serum decreased  rcc detection yadav et al. (2017)[23] mir-141 serum decreased  rcc detection yadav et al. (2017)[23] abbreviations: cfdna, cell-free dna; ccrcc, clear-cell renal cell carcinoma; chrcc, chromophobe renal cell carcinoma; ctcs, circulating tumor cells; eno1, alpha-enolase; finc, fibronectin-1; hsc71, heat shock cognate 71; hspe1, heat shock protein family e member 1; mirna, microrna; mrcc, metastatic renal cell carcinoma; nnmt, nicotinamide n-methyltransferase; prcc, papillary renal cell carcinoma; rcc, renal cell carcinoma; s100a8, s100 calcium-binding protein a8; s100a9, s100 calcium-binding protein a9; tu m2-pk, tumor m2-pk. continued on page 36 35siuj.org siuj • volume 2, number 1 • january 2021 novel expanding renal cell carcinoma biomarkers yamamoto et al. divided their cohort into 2 subgroups according to the length of cf dna fragments. their resu lts showed t hat cf dna f ragment size was significantly associated with progression-free survival (pfs). although cf dna fragmentation correlated with poorer outcomes, cf dna plasma levels were not associated with any of survival outcomes[9]. evaluating plasma circulating tumor dna (ctdna) as a subset of cfdna, bacon et al. reported that only 33% of patients had detectable ctdna. among ctdna-positive patients the most commonly mutated genes were vhl, bap1, and pbrm1. moreover, ctdna-positive patients had shorter os and pfs on first-line therapy[34]. ctcs identification an initial experience using a rt-pcr assay to detect ctcs in peripheral blood of patients at different stages of rcc reported a different rate of positivity on localized and metastatic rcc (mrcc)[35]. developing a new set of cell surface markers including caix and cd147, liu et al. showed a significant association of ctc number/ ctc expression status of vimentin, with disease progression[16]. wang et al. investigated the relationship of dynamic changes of ctcs and beclin-1 expression of ctcs and rcc prognosis. ctcs were divided into epithelial, mesenchymal, and mixed phenotype-based surface biomarkers. for the metastatic group, the number of mixed ctcs at 12 months was significantly higher than mixed preoperatively and 6 months ctcs. of note, the number of preoperative beclin-1 positive ctcs was significantly higher in the metastatic group. thus, variation trend of ctcs and beclin-1 expressive ctcs was significantly associated with the onset of metastatic disease[36]. moreover, in a prospective cohort of 60 patients who underwent surgical treatment with curative intent, haga et al. evaluated ctcs drawn from a peripheral artery collected just before and immediately after surgery. the authors showed that open table 1. novel potential candidates biomarkers in diagnosis and early detection of renal cell carcinoma biomarker source trend correlation/use reference metabolomics and proteomics acetylcarnitines urine tissue increased  rcc detection, grade-dependent behavior ganti et al. (2012)[27] niziol et al. (2018)[28] tu m2-pk plasma increased  rcc and mrcc detection roigas et al. (2001)[58] weinberger et al. (2007)[59] ahnak tissue increased  rcc detection white et al. (2014)[29] eno1 tissue increased  rcc detection white et al. (2014)[29] hspe1 tissue decreased  rcc detection white et al. (2014)[29] nnmt tissue increased  rcc detection kim et al. (2010)[31] hsc71 serum increased  rcc detection zhang y et al. (2015)[30] s100a8 serum increased  rcc detection zhang l et al. (2015)[60] zhang l et al. (2016)[61] s100a9 serum increased  rcc detection zhang l et al. (2015)[60] zhang l et al. (2016)[61] finc plasma increased  rcc detection yokomizo et al. (2011)[62] abbreviations: cfdna, cell-free dna; ccrcc, clear-cell renal cell carcinoma; chrcc, chromophobe renal cell carcinoma; ctcs, circulating tumor cells; eno1, alpha-enolase; finc, fibronectin-1; hsc71, heat shock cognate 71; hspe1, heat shock protein family e member 1; mirna, microrna; mrcc, metastatic renal cell carcinoma; nnmt, nicotinamide n-methyltransferase; prcc, papillary renal cell carcinoma; rcc, renal cell carcinoma; s100a8, s100 calcium-binding protein a8; s100a9, s100 calcium-binding protein a9; tu m2-pk, tumor m2-pk. , cont’d 36 siuj • volume 2, number 1 • january 2021 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation http://siuj.org table 2. novel potential candidate biomarkers in prognosis of renal cell carcinoma biomarker source outcomes correlated reference ctcs peripheral blood rfs, os bluemke et al. (2009) [63] liu et al. (2016) [16] wang et al. (2019) [36] beclin-1-positive ctcs peripheral blood rfs wang et al. (2019) [36] cfdna plasma rfs, os de martino et al. (2011) [51] wan et al. (2013) [33] lu et al. (2016) [8] yamamoto et al. (2018) [9] bacon et al. (2020) [34] mirna mir-378 serum dfs, clinical stage fedorko et al. (2015) [64] mir-221 serum os, csm, lymphovascular invasion teixeira et al. (2014) [65] vergo et al. (2014) [66] mir-150 serum dss, clinical stage chanudet et al. (2017) [67] mir-451 serum clinical stage redova et al. (2012) [68] mir-21 tumor tissue css, os, dfs, clinical stage, tumor grade, tumor size faragalla et al. (2012) [56] tang et al. (2015) [38] vergho et al. (2014) [69] vergho et al. (2014) [66] mir-126 tumor tissue dfs, css, os vergho et al. (2014) [69] vergho et al. (2014) [66] khella et al. (2015) [70] mir-106b tumor tissue pfs slaby et al. (2010) [71] mir-27a-3p tumor tissue pfs nakata et al. (2015) [72] mir-210 tumor tissue css tang et al. (2015) [38] mir-141 tumor tissue css tang et al. (2015) [38] mir-200c tumor tissue css tang et al. (2015) [38] mir-429 tumor tissue css tang et al. (2015) [38] mir-486 tumor tissue csm, clinical stage goto et al. (2013) [73] mir-23b tumor tissue os ishihara et al. (2014)[74] abbreviations: cfdna, cell-free dna; csm, cancer-specific mortality; css, cancer-specific survival; ctcs, circulating tumor cells; dfs, disease-free survival; gapdh, glyceraldehyde 3-phosphate dehydrogenase; os, overall survival; pfs, progression-free survival; pkm2, pyruvate kinase-muscle-2; rcc, renal cell carcinoma; rfs, recurrence-free survival; s100a8, s100 calcium-binding protein a8; tk1, thymidine kinase 1; tu m2-pk, tumor m2-p continued on page 38 37siuj.org siuj • volume 2, number 1 • january 2021 novel expanding renal cell carcinoma biomarkers nephrectomy resulted in a significantly greater number of postoperative ctcs. at multivariate level that the surgical approach was significantly correlated with the number of postoperative ctcs (p = 0.016) and the perioperative change in ctcs (p = 0.01). thus, especially after open surgery more cancer cells can be expelled into the bloodstream, suggesting a careful follow-up for these patients[37]. mirna in a comprehensive meta-analysis of 29 published studies reporting mirna signatures in rcc, tang et al. identified a robust meta-signature of mirnas as a prognostic biomarker. they reported that high expression of mir-21, mir-210, and low expression of mir-141, mir-200c, and mir-429 were associated with worse css following rcc resection[38]. similarly, table 2. novel potential candidate biomarkers in prognosis of renal cell carcinoma biomarker source outcomes correlated reference mir-27b tumor tissue os ishihara et al. (2014)[74] lnc-znf180-2 tumor tissue pfs, css, os, clinical stage ellinger et al. (2015)[40] lnc-nbat-1 tumor tissue os xue et al. (2015) [75] metabolomics creatine tumor tissue advanced tumor stages (t3-4) gato et al. (2012) [42] glutamate tumor tissue advanced tumor stages (t3-4) gato et al. (2012) [42] glutamine tumor tissue advanced tumor stages (t3-4) gato et al. (2012) [42] gapdh tumor tissue high grade wettersten et al. (2015) [43] enolase-2 tumor tissue high grade wettersten et al. (2015) [43] pkm2 tumor tissue high grade wettersten et al. (2015) [43] l-lactate tumor tissue high grade wettersten et al. (2015) [43] glutathione tumor tissue advanced stages hakimi et al. (2016) [44] tum2-pk serum rfs nisman et al. (2010) [76] gayed et al. (2015) [77] tk1 serum rfs nisman et al. (2010) [76] cathepsin d urine os vasudev et al. (2009) [78] s100a8 tissue dfs, tumor grade, stage an et al. (2019) [79] abbreviations: cfdna, cell-free dna; csm, cancer-specific mortality; css, cancer-specific survival; ctcs, circulating tumor cells; dfs, disease-free survival; gapdh, glyceraldehyde 3-phosphate dehydrogenase; os, overall survival; pfs, progression-free survival; pkm2, pyruvate kinase-muscle-2; rcc, renal cell carcinoma; rfs, recurrence-free survival; s100a8, s100 calcium-binding protein a8; tk1, thymidine kinase 1; tu m2-pk, tumor m2-p , cont’d 38 siuj • volume 2, number 1 • january 2021 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation http://siuj.org gu et al. conducted a meta-analysis of 27 published studies and found that elevated expression of mir-21, mir-1260b, mir-210, mir-100, mir-125b, mir-221, mir630, and mir-497 was associated with a poor prognosis in rcc patients. conversely, decreased expression of mir-106b, mir-99a, mir-1826, mir-215, mir-217, mir187, mir-129–3p, mir-23b, mir-27b, and mir-126 was associated with a worse prognosis. importantly, the results from this meta-analysis confirmed that elevated mir-21 expression was associated with shorter os, css, and dfs. the decreased expression of mir-126 was associated with shorter css, os, and dfs[39]. also, results were promising in a study by ellinger et al. regarding specific circulating long non-coding (lnc) rnas, defined as rna transcripts longer than 200 nucleotides that are not transcribed into a protein. the authors next validated the expression profile of 6 lncrnas transcripts (lnc-aco1625, lnc-cyp4a22-2/3, lnc-peak1.1-1, lnc-pcyox1l , lnc-vcan-1, lncznf180-2) with potential prognostic interest. a significant increase of lnc-znf180-2 expression in advanced rcc tissue compared with localized rcc was observed. furthermore, lnc-znf180-2 expression levels were an independent predictor of pfs, css, and os[40]. qu et al. built a model named rcclnc4 based on 4 lncrnas to improve postoperative risk stratification after radical treatment. stratifying patients into highrisk versus low-risk groups in terms of clinical outcomes, rcclnc4 remained as an independent prognostic factor, achieving a higher accuracy than clinical staging systems like tnm and ssign score[41]. prognostic value of metabolomic approaches analyzing tumors and their matched tissue, gao et al. studied the metabolomic rcc profile. creatine, glutamate, and glutamine were found at higher concentrations in tissues of tumors at t3-4 stages[42]. the glycolysis-relevant metabolites are significantly increased in high-grade disease, suggesting that glucose metabolism is more prominent with increasing tumor grade. consequently, glyceraldehyde 3-phosphate dehydrogenase, enolase 2, and py ruvate k inasemuscle-2 are increased in tumor tissue as compared with normal tissues. l-lactate follows the same tendency in a grade-dependent manner. also levels of carnitine and acyl/acetyl-carnitines were associated with grade, suggesting how the combination of these metabolites can predict the biological aggressiveness of rcc and thus influence its prognosis[43]. a study by hakemi et al. showed increased levels of glutathione were also grade and stage-dependent[44]. thus, the upregulation of antioxidant capacity in adaptation to intrinsic oxidative stress is indeed a common event in rcc, especially in the advanced stages[45]. epigenetic and dna methylation biomarkers epigenetic variations play an important role in renal carcinogenesis and progression. dna methylation is defined as a covalent addition of a methyl group to cytosines that precede a guanosine which are mainly clustered as cpg islands in the promoter region of genes bringing a functional silencing[46]. furthermore, dna methylation alterations are often shown to be associated with clinicopathological features and rcc patient survival or both[47]. cpg island methylation markers ref lect tumor biology, allowing the identification of patients with “high epigenetic risk” who can benefit from tailored management to improve sur v iva l outcomes. in a recent systematic review, joosten et al. described 9 genes (sfrp1, bnc1, grem1, rassf1a, pcdh8, scube3, gata5, lad1, and nefh), associated with patient survival. their prognostic value was indepen dently validated in other studies[48]. to develop a 5-cpgbased assay for ccrcc prognosis, a panel composed by methylation of pitx1, foxe3, twf2, rin1, and ehbp1l, was validated in 3 independent sets from china, the united states, and the cancer genome atlas (tcga) database. stratifying patients into 2 groups from this 5-cpg panel, wei et al. defined lowand highrisk categories. an important correlation between the high-risk group and poorer os[49] was demonstrated. with the same endpoint, chen et al. identified 7 specific prognosis-subgroups based on the dna methylation spectrum of rcc from the tcga database. the specific dna methylation patterns ref lected differentially in the clinical index, including tnm classification, pathological grade, clinical stage, and age. in addition, 437 cpgs corresponding to 477 genes of 151 samples were identified as specific hyper/hypomethylation sites for each specific subgroup. the authors then constructed a bayesian classifier to determine the function of the prognosis prediction model, with 437 specific cpg sites as characters (auc 0.95)[50]. conclusions ca ncer biomarkers have shif ted treat ment a nd management of patients with many cancer types. a lt hough “persona lized ” medicine is becoming more common in our daily practice, none of the rcc biomarkers discussed are in routine clinical use. metabolomics and proteomics studies have shown excellent potential in terms of diagnostic accuracy, but research in these areas still appears to be hypothesisgenerating. most of publications mentioned above aimed to understand tumor biology due to the high heterogenicity of rcc. 39siuj.org siuj • volume 2, number 1 • january 2021 novel expanding renal cell carcinoma biomarkers circulating biomarkers have 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carcinoma. j urol. 2014; 192:1822–30. 75. xue s, li q-w, che j-p, guo y, yang f-q, zheng j-h. decreased expression of long non-coding rna nbat-1 is associated with poor prognosis in patients with clear cell renal cell carcinoma. int j clin exp pathol. 2015; 8:3765–74. 76. nisman b, yutkin v, nechushtan h, gofrit on, peretz t, gronowitz s, et al. circulating tumor m2 pyruvate kinase and thymidine kinase 1 are potential predictors for disease recurrence in renal cell carcinoma after nephrectomy. urology. 2010; 76:513.e1-6. 77. gayed ba, gillen j, christie a, peña-llopis s, xie x-j, yan j, et al. prospective evaluation of plasma levels of angpt2, tum2pk, and vegf in patients with renal cell carcinoma. bmc urol. 2015; 15:24. 78. vasudev ns, sim s, cairns da, ferguson re, craven ra, stanley a, et al. pre-operative urinar y cathepsin d is associated with survival in patients with renal cell carcinoma. br j cancer. 2009; 101:1175–82. 79. an hj, koh hm, song dh. s100a8 expression may have a prognostic value in ccrcc reflecting tnm staging and fuhrman nuclear grade. anticancer res. 2019; 39:4681–5. 42 siuj • volume 2, number 1 • january 2021 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation http://siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj.org siuj • volume 4, number 4 • july 2023 key words competing interests article information renal cell carcinoma, biomarkers, ctdna none declared. received on march 14, 2023 accepted on april 26, 2023 this article has been peer reviewed. soc int urol j. 2023;4(4):287–292 doi: 10.48083/jesk5072 287 review — liquid biopsy circulating tumor dna (ctdna) in kidney cancer: a narrative review wesley yip, a. ari hakimi memorial sloan kettering cancer center, new york, united states abstract circulating tumor dna (ctdna) has been investigated as a potential noninvasive biomarker for disease prognostication, monitoring, and treatment selection in various tumor types, including renal cell carcinoma (rcc). in this narrative review, we explore the current methods of ctdna analysis and the use of ctdna in both localized and metastatic rcc, focusing on plasma and urine samples. additionally, we discuss several ongoing as well as upcoming clinical trials that incorporate ctdna analyses into their study designs and outcomes. despite the exciting potential of ctdna in rcc, current assays still face significant limitations in sensitivity and detection limits. introduction kidney cancer ranks as the sixth most common cancer in men and the ninth most common in women[1]. although most cases of renal cell carcinoma (rcc) present with localized disease, 25% to 50% of these patients eventually develop metastases[2]. approximately 30% have metastatic disease at initial presentation[3]. survival outcomes differ significantly between localized and metastatic disease, with overall survival ranging from 6 months to 5 years in the latter group[4]. given these discrepant outcomes, accurate risk-stratification and disease prognostication are crucial for appropriate management. the memorial sloan kettering cancer center (mskcc)[5] and international metastatic rcc database consortium (imdc)[6] models are commonly used prognostic tools in the metastatic setting and were developed from retrospective studies examining clinical and laboratory factors in patients treated with systemic therapy. however, with an increasing number of investigations on the molecular landscape of rcc[7], these factors are not included in classic prognostic models. moreover, while a multitude of therapeutic options are now available for advanced disease, there is minimal guidance for treatment selection. circulating tumor dna (ctdna) has emerged as a noninvasive method that can potentially influence both the diagnosis and treatment of rcc, offering an alternative or complement to tissue biopsies[8]. liquid biopsies can be performed serially over the course of treatment and may better represent the tumor profile as a whole, compared to a single biopsy section, which can be limited by spatial heterogeneity within tumors[9,10]. a proposal exists to potentially incorporate ctdna detection into standard tnm staging[11]. in this review, we discuss the current methods of ctdna evaluation, the use of ctdna in localized and metastatic settings, and future directions in urine-based studies and clinical trial correlatives. ctdna overview human blood contains various materials, including cell-free nucleic acids (dna and rna), proteins, cells, and exosomes, which can be measured as a “liquid biopsy.” these materials can originate from both benign and malignant sources, but the rapid turnover of malignant cells and the shedding of viable tumor cells from the tumor itself may increase the detection of these circulating tumor cells[12]. the half-life of ctdna in the circulation is approximately http://siuj.org mailto:hakimia%40mskcc.org?subject=siuj siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org patients had genomic alterations, with a median of one (interquartile range [iqr], 0-3) alteration per patient. the most frequent alterations included tp53, vhl, egfr, nf1, and arid1a. patients receiving targeted therapy following first-line treatment had a higher mutation frequency compared to those who had firstline therapy alone, particularly for tp53, vhl, egfr, nf1, and pik3ca[25]. notably, the frequency of several of these alterations was much higher than in prior tissue-based studies, such as the cancer genome atlas (tcga), although this may be due to a lower proportion of advanced disease in the tcga cohort. however, mutations in several significant genes[26], such as pbrm1, bap1, and kdm5c, were not included in the guardant360 panel. there may also be an association between ctdna and rcc tumor burden. in a study of 34 patients with metastatic rcc, detectable ctdna was found to be associated with a higher sum of longest diameter of measurable lesions, a surrogate for tumor burden[27]. a similar finding was reported in the study by kim et al., where a statistically significant correlation (p = 0.048) was found between ctdna and tumor burden based on primary tumor diameter on ct scans at the time of diagnosis[23]. concordance with tissue-based genomic profiling was investigated by kotecha et al. the study evaluated the cell-free dna profiles of 110 patients with metastatic rcc compared to tumor tissue using established panel-based assays (cfdna-impact[28] and msk-impact[29], respectively). tissue testing revealed 554 genomic alterations overall, of which 60% were from primary tumors and 40% from metastatic sites. the median number of genomic alterations per patient was 4, and all patients had at least one alteration. the most commonly identified alterations included vhl, pbrm1, setd2, bap1, and tp53. however, only 24 alterations were detected in 7 of 110 patients (6%) using standard thresholds. in a repeat analysis using expanded detection thresholds, the authors found 210 alterations in 74 of 110 patients (67%), predominantly in vhl, pbrm1, and tp53. the median time between tissue and blood analysis was 23 months (iqr 14 to 48)[30]. the time elapsed between assays may be important, as determined by zengin et al. in their study of 839 patients with advanced rcc and ctdna testing, the authors found that 112 patients also had tissue-based genomic alterations assessed by either a targeted ngs panel (foundationone or tempus xt) or whole-exome sequencing. ctdna assessment revealed at least one genomic alteration in 72% of patients, with tp53, vhl, and tert being the most frequently mutated genes. tissue samples showed that vhl, pbrm1, and setd2 were the most commonly mutated genes. of note, several commonly mutated genes in tissue samples were not 2 hours, compared with 16 minutes for nonmalignant cell-free dna[13,14]. in an initial study evaluating cell-free dna detection in rcc, 35 patients with rcc (all stages) were compared with 54 healthy controls. the study used quantitative real-time polymerase chain reaction (pcr) with two primer sets targeting a sequence of the actin-beta gene (actb). one primer set amplified both short and long dna fragments (actb106), while the other set amplified only long dna fragments (actb-384). actb-106 levels represented dna of apoptotic origin, whereas actb-384 levels indicated dna from nonapoptotic cells. the study found that median actb-106 levels were two times higher and actb-384 levels were three times higher in rcc patients compared to healthy controls[15]. several assays are available for assessing ctdna, which typically target a small number of variants or aim for broad coverage[16]. targeted assays can be useful for detecting specific variants associated with drug response and often use pcr, while broad coverage assays can detect large numbers of variants across multiple genes and typically use next-generation sequencing (ngs). it is crucial to draw blood samples into cell stabilization or edta tubes and process them within 6 hours of collection to avoid lysis of white blood cells and subsequent ctdna dilution by normal leukocyte dna[17]. ngs methods do not require prior knowledge of molecular mutations but are most expensive, time-consuming, and prone to false positives from sequencing artifacts. however, they are also more sensitive than pcr and can be more efficient by running multiple tests[18]. in addition, ngs may be better suited for assessing tumor mutational burden (tmb) compared to candidate gene analysis[19]. clinical applications—localized as cpg island hypermethylation has been found widely in cancer cells, hauser et al. investigated hypermethylation in cell-free dna in 8 genes (apc, gstp1, arf, p16, rar-b, rassf1, timp3, and ptgs2) known to be involved in rcc development and progression. thirtyfive patients with organ-confined rcc were compared to 54 healthy controls, and at least one gene was found to be methylated within serum cell-free dna in 30 of 35 patients. most genes were more frequently methylated in rcc patients than in the controls, with the exception of p16 and timp3. combining the analysis of multiple abbreviations cfdna cell-free dna nac neoadjuvant chemotherapy nmibc non-muscle invasive bladder cancer genes increased diagnostic sensitivity[20]. thus, cpg island hypermethylation could potentially have a role in the initial diagnosis of rcc. in another study examining cell-free dna methylation profiling, nuzzo et al. used a cell-free methylated dna immunoprecipitation and high-throughput sequencing (cfmedip-seq) assay with high sensitivity in both localized and metastatic disease across a range of tumor types[21]. the authors analyzed 148 samples, of which 99 were rcc (88 clear cell, 11 papillary), 21 were bladder cancer, and 28 were from healthy controls. of the rcc samples, 69 were derived from plasma, with 23 of these from patients with stage i-ii disease. the investigators identified differentially methylated regions between patient groups and constructed a classifier based on the top 300 regions to assign a methylation score. they found that 97% of rcc samples had a higher median methylation score compared to control samples. while localized cases exhibited the lowest methylation scores, there was no statistically significant association between stage and methylation score (p = 0.09)[22]. in a study using a targeted deep sequencing platform, kim et al. profiled genetic alterations from plasma and tumor tissue samples from 20 patients with rcc (10 localized, 10 metastatic) who underwent nephrectomy. plasma samples exhibited variants in 40% of localized samples and 50% of metastatic samples, while tissue samples showed variants in 80% of localized samples and 70% of metastatic samples. the mutation patterns did not differ significantly between localized and metastatic samples. however, the investigators found that 53% of patients with mutations in tumor tissue had corresponding mutations in plasma samples across the entire cohort. of the patients with metastatic disease, this concordance percentage was 71%, with the most common mutations occurring in vhl, pbrm1, and kdm5c. patients with rcc demonstrated a higher median value of cell-free dna compared to healthy controls (p < 0.03), but ctdna levels could not differentiate between localized and metastatic disease[23]. wan et al. evaluated 92 patients with clear cell rcc and measured plasma cell-free dna levels before and after surgery using quantitative pcr. they found that patients with metastatic disease had significantly higher pretreatment levels than those with localized disease. moreover, of patients with localized disease, those who experienced recurrence had higher pretreatment levels compared to those without recurrence[24]. clinical applications—advanced pal et al. conducted a study involving 220 patients with advanced rcc who underwent ctdna assessment using the guardant360 platform, which encompasses 73 cancer-related genes. the authors found that 79% of assessed in the ctdna panels (eg, pbrm1, setd2, and kdm5c). in patients with gene mutations detected in both ctdna and tissue, 34% of the alterations in tissue were also found in ctdna. the percentage increased to 51% when samples were collected within 6 months of each other and further increased to 61% when collected within 3 months of each other[31]. ctdna may find utility in disease monitoring and prognostication, as demonstrated in a study of 53 patients with clear cell rcc from the osaka university hospital. thirty-nine of these patients had metastatic disease, of which 13 were untreated at the time of ctdna analysis. the study investigators found that changes in mutant allele frequency of ctdna closely mirrored the overall tumor burden over the course of treatment. moreover, patients with short fragment sizes of cell-free dna and/or positive ctdna had a worse response to tyrosine kinase inhibitors compared to those with long fragment sizes and/or negative ctdna. the size of cellfree dna fragment size and ctdna status showed a statistically significant correlation with cancer-specific survival but not progression-free survival[32]. the potential of ctdna to predict tumor response to treatment is of particular interest, but limited data is available. a small study that followed 4 patients who received ipilimumab/nivolumab for metastatic rcc found that 3 patients had detectable ctdna levels prior to treatment. two of these patients had decreased ctdna levels, along with a partial response to immune checkpoint inhibition. one of these patients with a partial response had a tp53 mutation, and the other had mtor and arid1a mutations. the remaining patient, who progressed during treatment, had increased levels of ctdna over the course of therapy, with mutations in tp53, vhl, and pik3ca[23]. the authors suggest that ctdna may have efficacy as an early predictor of immune checkpoint blockade response, although the study’s small size limits its conclusions. future directions several groups are exploring the possibility of assessing ctdna through urine, providing an even less invasive form of liquid biopsy. in a multicenter study involving 91 patients with renal tumors of all stages, urine samples were collected from 37 patients prior to surgery. the study found low overall ctdna detection in plasma at 28% using an untargeted assay, which improved only to 55% with a targeted method. ctdna was detected in urine in only 22% of patients. while plasma ctdna detection correlated with lesion size and/ or tumor thrombus, urine ctdna detection did not. however, the study suggests that ctdna results may overcome intratumoral heterogeneity in patients with detectable ctdna in either plasma or urine[33]. 289288 review — liquid biopsy circulating tumor dna (ctdna) in kidney cancer: a narrative review http://siuj.org http://siuj.org siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org conclusion ctdna holds promise as a noninvasive biomarker for disease prognostication, monitoring, and treatment selection. it may also provide valuable insights into changes in tumor profiles over time and overcome intratumoral heterogeneity. however, improvements in assay design are needed to increase sensitivity and detection limits. prospective evaluation of ctdna is being investigated through correlative studies in ongoing and upcoming clinical trials. in the study by nuzzo et al., cf medip-seq was performed on 30 urine samples from patients with rcc, with the majority of patients being at stage i– ii (67%). when comparing the urine cell-free dna in these patients to healthy controls, the authors found a mean area under receiver operating characteristic curve of 0.86 (95% ci 0.83 to 0.89). although these results are not as accurate as those from plasma, the authors believe that the assay performance can be enhanced by enriching for tumor-derived dna and incorporating tumor methylation data into the analysis[22]. clinical trials completed nct02960906: the biomarker driven trial with nivolu mab a nd ipi limu mab or vegfr tk i in naïve metastatic kidney cancer (bionikk) was a randomized phase 2 study involving 202 patients with treatment-naïve metastatic rcc who received nivolumab, ipilimumab/nivolumab, or tki based on molecular subgroups. among the exploratory outcome measures, the study aimed to determine whether the mutation and methylation status of ctdna can be correlated with the clinical evolution and progressionfree survival rates. the primary endpoint of investigatorassessed objective response rates per molecular/ treatment group has been reported, while the results of the exploratory analyses, including ctdna, are planned for future publication[34]. nct03469713: in the phase 2 study of nivolumab and stereotactic body radiotherapy in patients with metastatic rcc (nives), 69 patients were enrolled and received nivolumab for at least 6 months with 30 gy of radiation in 3 consecutive fractions (10 gy per fraction) to a metastatic site. a planned exploratory analysis is evaluating jak1, jak2, and b2m mutations in ctdna from plasma samples, as these may be associated with acquired resistance to checkpoint inhibition. similar to the bionikk trial, the primary outcomes of the nives trial have been published[35], but the ctdna data are eagerly awaited. recruiting nct05059444: guardant health is currently recruiting approximately 1000 patients with a wide range of cancer types including rcc to their observation of residual cancer with liquid biopsy evaluation (oracle) study to determine whether their guardant reveal assay can be used for detecting recurrences of early-stage solid tumors. the study is recruiting patients with highrisk rcc, defined as grade 3–4 and stage ii-iv who are being treated with curative intent. patients with limited/resectable distant metastases are also eligible for inclusion. nct04295174: the kidstage observational study conducted by odense university hospital has completed patient recruitment. the study uses positron emission tomography/computed tomography (pet/ct) and ctdna for monitoring tumor burden and disease progression in patients with rcc of any stage. the primary outcomes include investigating the utility of ctdna for disease monitoring and whether dual time point fluorodeoxyglucose (fdg) pet/ct can be used for staging. the goal of 70 patients recruited has been met, and with a study timeframe of 3 years, the results are expected soon. nct03786796: the orchid phase 2 study of olaparib plans to enroll 20 patients with metastatic rcc harboring specific dna repair gene mutations who have received prior treatment with either an immune checkpoint inhibitor or anti-vegf therapy. the primary outcome measure is objective response or stable disease at 6 months, and ctdna reversion mutations at clinical progression will also be evaluated. nct05329532: the phase 1/2 study of the modi-1/ modi-1v vaccine (modify) is recruiting patients with triple negative breast cancer, human papillomavirus– negative head and neck squamous cell carcinoma, highgrade serous ovarian carcinoma, or rcc and evaluating treatment as monotherapy and in combination with immune checkpoint inhibitor therapy. ctdna will be measured throughout the study and up to 12 weeks after the final treatment dose. nct04609293: an observational study in china aims to evaluate the efficacy of combination therapy with camrelizumab, apatinib, and hypofractionated radiotherapy in patients with locally advanced, metastatic, or recurrent rcc. secondary outcome measures include ctdna analysis and whole exome sequencing of the primary tumor 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riediger al, et al. comprehensive characterization of cell-free tumor dna in plasma and urine of patients with renal tumors. genome med.2020;12(1):23. doi: 10.1186/s13073020 00723-8. pmid: 32111235; pmcid: pmc7048087. 34. vano ya, elaidi r, bennamoun m, chevreau c, borchiellini d, pannier d, et al. nivolumab, nivolumab-ipilimumab, and vegfrtyrosine kinase inhibitors as first-line treatment for metastatic clear-cell renal cell carcinoma (bionikk): a biomarker-driven, open-label, non-comparative, randomised, phase 2 trial.  lancet oncol.2022;23(5):612–624. doi: 10.1016/s1470-2045(22)00128-0. pmid: 35390339. 35. masini c, iotti c, de giorgi u, bellia rs, buti s, salaroli f, et al. nivolumab in combination with stereotactic body radiotherapy in pretreated patients with metastatic renal cell carcinoma. results of the phase ii nives study. eur urol.2022;81(3):274–282. doi: 10.1016/j. eururo.2021.09.016. pmid: 34602312. 292 review — liquid biopsy http://siuj.org 30 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation key words competing interests article information biomarkers, non-invasive, serum, urine, prediction none declared. received on july 1, 2020 accepted on august 16, 2020 soc int urol j. 2020;1(1):30–38 the clinical applications of serum and urinary biomarkers in prostate cancer renu s. eapen,1 peter e. lonergan,2 dominic bagguley,3 sean ong,3 ben condon,3 nathan lawrentschuk,1,3,4,5 maxwell v. meng2 1 department of genitourinary oncology, peter maccallum cancer centre, melbourne, australia, 2 department of urology, helen diller family comprehensive cancer center, university of california, san francisco, united states, 3 ej whitten prostate cancer research centre at epworth, melbourne, australia, 4 department of surgery, university of melbourne, australia, 5 department of urology, royal melbourne hospital, australia abstract at every stage of the prostate cancer journey from screening and diagnosis to management of advanced disease, patients and clinicians face dilemmas and decisions that can impact long-term outcomes. although traditional risk stratification in prostate cancer is based on serum prostate specific antigen, clinical stage and gleason score, in recent years, biomarkers have been developed that may be useful in several clinical scenarios. biomarkers that can accurately predict an individual patient’s risk, prognosis, and response to specific treatments could lead to improvements in decision-making and clinical care. although there is evidence to support the use of biomarkers to guide management decisions, the optimal scenario in which to use them, how to interpret the results, and how to incorporate those results into clinical decision-making can be confusing. nevertheless, in the era of personalized and precision medicine, it is important for clinicians to be aware of what tests are available, what clinical questions they seek to answer, and what limitations they have. this review focuses on the serum and urine biomarkers for the management of prostate cancer that have been under intense investigation in recent years. introduction prostate cancer (pca) is a heterogenous disease with a highly variable clinical course and behavior. traditional risk stratification of pca has been based on standard clinical parameters such as prostate specific antigen, clinical stage, and biopsy gleason scores. following the widespread use of psa testing, the pendulum swung towards overdiagnosis of clinically insignificant pca and the subsequent overtreatment with its associated morbidity [1]. traditional models and nomograms, although allowing risk stratification of patients to a certain degree, do not allow accurate prediction of outcomes for an individual patient with pca, leading to potential undertreatment of high-risk disease [2,3]. because of these limitations, leading to discordant care, many areas of uro-oncology have recognized the need for the development of reliable biomarkers to aid decision-making in various challenging clinical contexts. finding the “ideal” biomarker that can accurately predict a patient’s individual risk and improve on existing, validated risk stratification tools has become an area of intense research interest in the last decade. biomarkers can be classified according to the source (eg, serum, urine, or tissue) (table 1) or the clinical decision juncture at which they are used (figure 1). in this 2-part summary, we review commercially available blood, urine and tissue-based biomarkers and summarize the currently available data on their use in a variety of clinical scenarios. the first section will focus on the serum and urinary pca biomarkers. blood and urine sources have the advantage of being non-invasive, easily attainable, and convenient for patients and physicians. the subsequent article will focus on tissue-based biomarkers [4]. http://www.siuj.org mailto:renu.eapen%40petermac.org?subject=siuj 31siuj.org siuj • volume 1, number 1 • october 2020 the clinical applications of serum and urinary biomarkers in prostate cancer serum biomarkers prostate specific antigen measurement of serum psa is the most widely used test to aid in the detection of early prostate cancer, despite its well-known limitations, including high false-positive rates, poor specificity for prostate cancer, which lead to over diagnosis. psa is not tumor specific as it is secreted by both benign and malignant prostatic tissue. therefore, apart from pca, many benign processes such as inflammation, benign prostatic hyperplasia (bph), and trauma may lead to increased psa values. psa gained fda approval for pca screening in 1994 after it was shown to have higher sensitivity than prostatic acid phosphatase (pap) in the detection of prostate cancer [5]. historically, a serum psa level above 4 ng/ml was the accepted cutoff to predict the potential presence of prostate cancer [6]. however, it has since been recognized that 20% of patients diagnosed with prostate cancer have a psa lower than 4 ng/ml [7,8]. furthermore, it has been reported that when using a psa threshold of 4 ng/ml, the specificity in detecting pca is only 12.8%, leading to high false-positive rates and unnecessary biopsies [9]. to enable better discrimination between pca and bph, the measurement of the ratio of free to total psa was proposed as a more accurate indicator, and many studies have demonstrated its usefulness [10-13]. in a large prospective multicenter clinical trial of 773 patients with psa levels between 2 and 10 ng/ml, it was shown that a percent free psa (%fpsa) cutoff of 25% detected 95% of cancers and avoided 20% of unnecessary biopsies, with minimal loss in sensitivity [14]. a multivariable analysis showed %f psa to be an independent predictor of prostate cancer (or 3.2, 95% ci 2.5 to 4.1; p < 0.001) and more significant than total psa (tpsa). generally, the lower the %fpsa, the higher the risk of cancer. however, prostate volume has been found to have an influence on %f psa. stephan et al. reported diagnostic value of %f psa in patients with prostate volume < 40cm3, but advised caution in using %f psa in those with larger glands [15]. other psa metrics have also been employed to enhance the diagnostic and predictive capacity of psa. these include psa density (psad), psa doubling time (psadt), and psa velocity (psav). psa density is a quotient of serum psa and prostate volume and may be a means of distinguishing between bph and pca [16]. a higher psad may not only indicate the presence of pca but may also reflect the aggressiveness of the cancer. studies have shown a correlation between higher psad and adverse pca prognostic features [17]. a high psav and a shorter psadt, especially in the setting of post-treatment biochemical recurrence (bcr), are associated with an increased risk of castration resistance, metastases, and cancer-specific and overall mortality [18]. prostate health index (phi) prostate health index (beckman coulter inc., brea, us) combines 3 quantitative kallikrein immunoassays— t psa, %f psa, a nd [-2]propsa (p2psa)—v ia a mathematical algorithm into a single score. the phi received fda approval in 2012 and is indicated as an adjunct to tpsa in men aged over 50 years with tpsa between 4 and 10 ng/ml and non-suspicious digital rectal examination (dre) findings. numerous validation studies have addressed the clinical utility of phi. a prospective multi-institutional trial enrolled 892 men with no history of pca, normal dre, and tpsa of 2 to 19 ng/ml, and found that within this range of psa, at a sensitivity of 80% to 95%, the specificity and area under the curve (auc) of phi exceeded those of psa and %fpsa [19]. similarly, stephan et al. evaluated 1362 patients with tpsa of 1.6 to 8.0 ng/ml who underwent systematic biopsy with ≥ 10 cores, and showed that phi (auc = 0.74) outperformed %p2psa (auc = 0.72), p2psa (auc = 0.63), %f psa (auc = 0.61), and tpsa (auc = 0.56) in predicting pca [20]. furthermore, these large series have demonstrated the advantage of phi over %fpsa in distinguishing between high-grade disease (gleason score ≥ 4 + 3) and low-grade disease or negative biopsies [19,20]. catalona et al. showed that an increasing phi was associated with a 4.7-fold increased risk of pca and 1.6-fold increase in higher-grade disease. other prospective studies have indicated the ability of phi to detect aggressive (gleason score ≥ 7) cancer with higher specificity than tpsa and %fpsa in biopsy naïve men, reducing the need for unnecessary biopsies [21]. the utility of phi in detecting clinically significant prostate cancer (cspca) was evaluated by tosoian and colleagues, who reported that the median phi density abbreviations %fpsa percent free psa bph benign prostatic hyperplasia cspca clinically significant prostate cancer dre digital rectal examination epi exodx prostate intelliscore hoxc6 homeobox c6 pap prostatic acid phosphatase pca prostate cancer psad psa density psadt psa doubling time psav psa velocity soc standard of care tpsa total psa http://www.siuj.org 32 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation (based on prostate volume) was higher for those with cspca (1.21) than for those with clinically insignificant pca (0.70) and negative biopsies (0.53) with p < 0.001. using a threshold of 0.43, phi density was 97.9% sensitive and 38% specific for cspca and 100% sensitive for gleason ≥7 disease [22]. the authors concluded that discriminative ability of phi density (auc = 0.84) for cspca was higher than phi, psa, psad, %f psa, and prostate volume (auc 0.52 to 0.79). up to 38% of biopsies could be avoided while missing only 2% of cspca [22]. another advantage of phi over %fpsa is the lack of influence of patient age and prostate volume [19]. a recent study has evaluated the impact of phi on clinical decision-making. in an observational study of 500 men, white et al. found that those who received a phi test had a significantly lower biopsy rate compared to the control group (36.4% versus 60.3%; p < 0.001). the phi test purportedly impacted physicians’ management plans, including the decision to defer biopsies when table 1. commercially available biomarkers that are fda and clinical laboratory improvements amendments (clia) approved biomarker molecular markers tested serum prostate specific antigen (psa)* psa prostate health index (phi)* beckman coulter inc, united states tpsa, %fpsa, p2psa 4k score opko lab, united states tpsa, fpsa, intact psa, hk2 urine progensa prostate cancer antigen 3 (pca3)* hologic, united states pca3 exodx prostate (intelliscore) exosome diagnostics inc, united states pca3, erg michigan prostate score (mips), united states tmprss2-erg mrna, pca3 select mdx mdx health, united states hoxc6, dlx1 tissue confirm mdx mdxhealth, united states dna methylation (gstp1, apc, rassf1, actb) oncotype dx genomic health, united states rna (17 gene expression) promark metamark genetics, united states 8 proteins prolaris* myriad genetics, united states rna (46 gene expression) decipher genome dx biosciences, united states rna (22 gene expression) * fda-approved biomarkers http://www.siuj.org 33siuj.org siuj • volume 1, number 1 • october 2020 the clinical applications of serum and urinary biomarkers in prostate cancer phi score was low and to perform biopsies when the phi score was intermediate or high [23]. similarly, the prospective comparative analysis of 345 men by tosoian et al. demonstrated that phi testing reduced the rate of biopsy procedures whilst the detection of higher-grade cancers remained unchanged [24]. another potential application of the phi score is the integration into a multivariable model with mu lt i-pa ra met r ic mag net ic resona nce i mag i ng (mpmri). gnanapragasam et al. found that adding phi to mpmri improved the prediction of overall and cspca (auc 0.71 and 0.75) compared with mpmri or psa alone (auc 0.64 and 0.69) [24]. in determining whether to re-biopsy men with a negative mpmri, phi performed better than psa and psad in identifying cspca. with a phi threshold of > 35, 42% of men avoided biopsy while missing only one of 21 significant cancers [25]. 4k score the 4k score (opko health, miami, us) comprises a panel of 4 kallikrein (4k) markers including tpsa, %f psa, intact psa, and human kallikrein 2 (hk2) and combines clinical variables (age, dre findings, and previous biopsy status) into a model to predict the likelihood of having cspca (gleason score ≥ 7) on prostate biopsy. it may have value in reducing unnecessary prostate biopsies [25]. the merit of the 4k score in the pre-biopsy setting has been extensively evaluated, particularly in europe and the us [26–34]. vickers et al. reported on 2914 men in the european randomized study of screening for prostate cancer (erspc) who underwent prostate biopsy for psa ≥ 3ng/ml, in which pca was diagnosed in 28% of men [30]. incorporating the 4k score with psa and age significantly improved predictive accuracy with (auc 0.78 versus 0.70) and without (auc 0.76 versus 0.64) dre results (p < 0.001). for every 1000 men, the addition of the 4k score would reduce the number of unnecessary biopsies by 513, albeit with the tradeoff that 12% of cspca would be missed [30]. a smaller series of 262 men showed similar results, with the 4k score having greater diagnostic accuracy than “base” clinical models incorporating psa, age, and dre findings only, with auc increases from 0.63 to 0.78 in pca prediction and 0.77 to 0.87 for prediction of high-grade pca [27]. parek h et a l. prospectively evaluated the diagnostic performance of the 4k score in 1012 men undergoing biopsy without restrictions on the indication for biopsy. clinically significant pca (gleason ≥ 7) was found in 23% of patients in this cohort [31]. the 4k score outperformed the pcpt risk calculator 2.0 (auc 0.82 versus 0.74; p < 0.001) in detecting cspca and would have reduced the number of unnecessary biopsies by 58%. in a large representative cohort study of 40379 men from sweden, stattin et al. studied the 4k score for its ability to predict the risk of distant metastases [32]. using a risk stratification approach to prostate biopsy using psa and 4k score, they found that in patients with psa ≥ 3 ng/ml, the risk of distant metastases at 5, 10, 15, and 20 years would be greater for the high-risk group with 4k ≥ 7.5% (2.4%, 5.6%, 9.9%, and 16.4%) than for the low-risk group with 4k < 7.5% (0%, 0.2%, 1%, and 1.8%) [32]. in men with previously negative prostate biopsy but persistently elevated psa, 4k score was found to have superior predictive capacity for high-grade cancers while minimizing unnecessary biopsies [32]. the 4k score showed higher discriminatory accuracy than psa and dre alone (auc 0.68 versus 0.58, p < 0.001) in detecting pca on repeat biopsy. for the prediction of high-grade (gleason ≥ 7) pca, the 4k score outperformed clinical factors alone (auc 0.87 versus 0.76. p = 0.003). using a 4k risk threshold of 15%, 712 repeat biopsies could potentially be avoided for every 1000 men, with only 3 of the 53 missed cancer diagnoses having a gleason score ≥ 7 [32]. a comparison of 4k score and phi in a populatedbased cohort study of 531 men with psa 3 to 15 ng/ml showed their predictive values to be similar in predicting any pca (auc 0.69 for 4k, auc 0.70 for phi), as well as high-grade pca (auc = 71.8 for 4k, auc = 71.1 for phi) [33]. compared with a base model of age and psa, screening / pre-1st biopsy psa 4k score phi pca3 select mdx mips exodx previous negative biopsy / pre-2nd biopsy 4k score phi pca3 figure 1. serum and urinary biomarkers according to their clinical applications http://www.siuj.org 34 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation both 4k and phi had higher auc (p < 0.001). using high-grade pca risk thresholds of 10% for 4k and 39 for phi, 29% of biopsies could potentially be avoided with the caveat that 10% of high-grade cancers could be missed [33]. although there is little evidence to support their use in primary screening, both phi and 4k scores are mentioned by the european association of urology (eau), american association of urology (aua), and national comprehensive cancer network (nccn) as potential markers that may be used to risk stratify patients in the early detection of pca. their benefits of predicting risk of high-grade pca and reducing unnecessary biopsies in men with psa from 2 to 10 ng/ ml is recognized, as is their superiority over %fpsa [35]. urinary biomarkers progensa prostate cancer antigen 3 (pca3) pca3 (hologic, marlborough, us) is a non-coding large chain rna that is highly overexpressed in the majority of malignant prostate tissue compared with benign prostate tissue [36,37]. the progensa pca3 gene assay measures pca3 mrna concentrations in the first void urine collected after dre [38]. in 2012, the fda approved the use of pca3 to facilitate the decisionmaking process to re-biopsy men with a previous negative biopsy. multiple studies have evaluated the clinical utility of pca3 in the early detection of pca and as a prognostic marker in the active surveillance of patients with low-risk pca [39–41]. a key european multicenter prospective study by haese et al. correlated pca3 scores of 463 men with previous negative prostate biopsies to the repeat biopsy outcomes, with a higher pca3 score associated with a greater probability of a positive repeat biopsy [39]. men who had a pca3 score ≥ 35 had a 39% chance of having a positive biopsy compared with 22% in men with a pca3 score < 35 (p < 0.001). the mean pca3 score was significantly higher in men with a positive biopsy than in those with a negative biopsy (63.8 versus 35.5; p < 0.001). furthermore, a pca3 threshold of 35 provided greater diagnostic accuracy than a comparable %fpsa cutoff of 25%. pca3 was found to be independent of tpsa, prostate volume, and patient age [39]. in a retrospective analysis of 13 men, wu et al. reported that use of a pca3 score threshold of 25 yielded sensitivity and specificity of 0.67 and 0.64, respectively [42]. although pca3 was found to be independently associated with pca (auc 0.64) in multivariable analyses, the highest diagnostic accuracy was derived from a model comprising pca3, psad, psa, dre, and trus findings (auc 0.82) [42]. a prospective validation trial by wei et al. included 859 psa-screened patients undergoing initial biopsy and repeat biopsy after prior negative biopsy [41]. the authors demonstrated a positive predictive value (ppv) of 80% for pca3 > 60 at initial biopsy and a negative predictive value (npv) of 88% for pca3 < 20 at repeat biopsy. their findings supported the use of pca3 in reducing unnecessary biopsies in men with a prior negative biopsy and concluded that for initial biopsy, a pca3 > 60 significantly increases the probability of cancer detection [41]. in another european prospective multicenter study of 516 men, de la taille et al. observed that the mean pca3 score was higher in those men with a positive versus negative biopsy (69.6 versus 31.0; p < 0.001) and higher in men with cspca. pca3 scores > 35 had the highest diagnostic accuracy with sensitivity of 64% and specificity of 76%. pca3 score was independent of age, total psa and prostate volume and outperformed total psa, psad, and %fpsa [43]. the ability of pca3 to predict tumor volume and select low-risk patients for active surveillance was prospectively evaluated by ploussard et al. who reported that pca3 scores strongly correlated with tumor volume [44]. a pca3 score > 25 was associated with a 3-fold increase in risk of cspca. on multivariate analysis, a pca3 score > 25 was a predictive factor for tumor volume > 0.5cm3 (or 5.4; p = 0.01) and for significant cancer (or 12.7, p = 0.003), suggesting its use as a tool in selecting better candidates for active surveillance [44]. nakanishi et al. also found a significant association between pca3 and tumor volume, with pca3 being particularly useful in identifying low tumor volume < 0.5 ml (auc 0.757) [45]. as pca3 is the only urinary biomarker with fda approval, the various guidelines do mention its use to risk stratify patients after a previous negative biopsy and to determine the need for a repeat biopsy. however, it is not recommended as a primary screening tool, and no threshold for the pca3 score has been defined to guide decision-making. exodx prostate intelliscore (epi) the exodx prostate intelliscore (exosome diagnostics, waltham, us) is a newer, novel urine exosome gene expression assay used to predict the risk of pca on biopsy. exosomes are 1 of 2 types of microvesicles found in prostate secretions [46]. exosomes may be secreted by both normal and malignant tissues, but elevated exosome secretions have been found in malignant biof luids such as the urine of patients with pca. exosomes contain a portion of the parent cell cytoplasm containing proteins and rna that closely resemble the http://www.siuj.org 35siuj.org siuj • volume 1, number 1 • october 2020 the clinical applications of serum and urinary biomarkers in prostate cancer cell of origin [47]. exosomes lack ribosomal rna but are rich in mrna, which acts as a unique genetic footprint of specific tumor cells and may give information about the specific tumor genotype that underlies the varying phenotypes that are seen in a heterogenous disease like pca. exosomes isolated from post dre urine contain pca3 and erg (erythroblastosis virus e26 oncogene homologues) [47]. the epi test has the advantage of not requiring a pre-collection dre, making it non-invasive and more convenient. the test uses an algorithm independent of clinical variables to provide a risk score, with 15.6 being the threshold discriminating between high-grade and low-grade pca [48]. mckiernan et al. compared the performance of epi with biopsy outcomes in men with psa ranging from 2 to 20 ng/ml, then went on to validate the prognostic score [49]. they found that incorporating epi into the standard of care (soc) improved the discrimination of high-grade disease from low-grade or benign disease. validation in 519 patients showed the superior performance of epi plus soc (auc 0.73) over soc alone (auc 0.63) in predicting high-grade disease (p < 0.001). using an epi cutoff score of 15.6, the authors concluded that 27% of biopsies could have been avoided, missing 5% of high-risk cancers [49]. a recent prospective randomized study by tutrone et al. examined the clinical utility and the impact of epi score on decision-making in men presenting for initial prostate biopsy with psa 2 to 10 ng/ml [48]. a total of 1094 patients and 72 urologists were involved in the study. sixty-eight percent of urologists were influenced by the epi score in their decision to recommend or defer a biopsy, the main reason for noncompliance with epi results being a rising psa. eighty-seven percent of patients with a positive epi score were recommended to proceed to biopsy, leading to the detection of 30% more high-grade pca than in the control arm. on the other hand, 63% of patients with a negative epi score were recommended to defer prostate biopsy, and the authors estimated that 49% fewer high-grade cancers were missed because of biopsy deferral compared with soc [48]. the latest nccn guidelines do mention epi as a potential investigative marker, but it is not currently incorporated into mainstream practice. mi prostate score (mips) the mips assay was developed at the university of michigan rogel cancer centre. it is a urine multiplex analysis that combines psa with 2 pca specif ic biomarkers: pca3 and an rna marker that is found only when tmprss2 and erg abnormally fuse. erg is an et transcription factor that is overexpressed in 57% of prostate cancers [50]. in more than 90% of cases that overexpressed erg, there was found to be fusion with tmprss2. tmprss2-erg (t2-erg) fusion is thought be a strong indicator of pca. in a trial of 48 patients undergoing prostate biopsy, salami et al. found an association between the presence of t2-erg and pca (or 12.02, p < 0.001) [51]. although pca3 had higher sensitivity (93%), t2-erg had the highest specificity (87%) in predicting pca. t2-erg also had better discriminative ability (auc 0.77) compared with pca3 (auc 0.65) and serum psa (auc 0.72). combining all 3 factors into a multivariable algorithm improved the auc for cancer prediction to 0.88 with specificity of 90% and sensitivity of 80%, better than any individual marker alone [51]. laxman et al. showed that compared with pca3 alone (auc 0.662), t2-erg in combination with pca3 and a multiplex panel of urinary transcripts (auc 0.758) improved the early detection of pca [52]. a validation trial in 1225 patients by tomlins et al. assessed the ability of the multivariable mips model incorporating psa, pca3 and t2-erg in predicting pca and high-grade pca on biopsy [53]. the authors showed that models incorporating t2-erg had higher auc than psa in predicting any (0.693 versus 0.585) and high-grade (0.729 versus 0.651) pca. the mips model incorporating t2-erg outperformed other models incorporating only pca3 and psa in the detection of pca (p < 0.001) [53]. the mips is currently an investigational tool within nccn guidelines and currently not routinely used in mainstream practice. select mdx select mdx (mdx health, irvine, us) is a post dre urine-based gene assay risk score that aims to predict a patient’s risk of high-grade pca. the algorithm measures the mrna signatures of 2 genes implicated in prostate carcinogenesis—homeobox c6 (hoxc6) and distal-less homeobox 1 (dlx1)—and combines these with clinical factors such as age, family history, previous negative biopsies, and dre. leyten et al. initially described a 3-gene urinary panel including hoxc6 and dlx1 that was shown to have additional value over serum psa and pca3 in the detection of pca and reducing the risk of overtreatment [54]. van neste et al. developed a model incorporating hoxc6 and dlx1 on a cohort of 519 patients and subsequently validated the risk score in an independent cohort of 386 patients in two prospective multicenter studies [55]. the authors identified the mrna signature risk score in combination with psad and previous negative biopsies to be the most significant factors with an overall auc approaching 0.90 (95% ci 0.85 to 0.95). another model adding dre as a risk factor http://www.siuj.org 36 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation was also tested with an auc of 0.86. when compared with the pcptrc and pca3, this model could reduce unnecessary biopsies by 53% with a npv of 98% for gleason ≥ 7 disease [55]. correlating select mdx with mpmri results, a retrospective obser vational study of 172 patients reported a positive association between the risk score and the final pi-rads grade [56]. median select mdx scores were higher in patients with a suspicious lesion on mpmri than in those with a negative mpmri (p < 0.01). select mdx was also shown to have some value in predicting the mpmri result with auc of 0.83 compared with psa (auc 0.66) and pca3 (auc 0.65). the cost effectiveness of select mdx compared with soc was evaluated by dijkstra et al., who concluded that the judicious use of select mdx to reduce the overdiagnosis and overtreatment of men with pca and psa > 3ng/ml could lead to reduction in costs and gains in quality adjusted life years [57]. conclusions a myriad of serum and urinary biomarkers have emerged with the goal of improving decision-making processes in the early diagnosis of localized pca. although a few have gained fda approval, most are investigational and not used routinely in clinical practice. biomarkers must add value beyond existing multivariable models to be cost-eff icient and of overall benefit. therefore, at this time, they must be used judiciously in the management of patients with suspected and known pca. references 1. cooperberg mr, carroll pr. trends in management for patients with localized prostate cancer, 1990-2013. jama. 2015;314(1):80-2. doi: 10.1001/jama.2015.6036 2. wang s-y, cowan je, cint cary k, et al. limited ability of existing nomograms to predict outcomes in men undergoing active surveillance for prostate cancer. bju int. 2014; 114(6b):e18-e24. doi.org/10.1111/bju.12554 3. kretschmer a, tilki d. biomarkers in prostate cancer — current clinical utility and future perspectives. crit rev oncol hematol. 2017;120:180-193. doi: 10.1016/j.critrevonc.2017.11.007 4. lonergan pe, washington sl iii, meng mv, eapen r. siu-icud consultation on molecular biomarkers in urological oncology: the clinical applications of tissue biomarkers in prostate cancer. soc int urol j. 2020;1(1):30–38. 5. stamey ta, yang 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prostate. 2017;77(14):1401-1407. doi: 10.1002/pros.23401 57. dijkstra s, govers tm, hendriks rj, et al. cost-effectiveness of a new urinary biomarker-based risk score compared to standard of care in prostate cancer diagnostics a decision analytical model. bju int. 2017;120(5):659-665. doi: 10.1111/bju.13861 http://www.siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2023 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. siuj.org siuj • volume 4, number 4 • july 2023 key words competing interests article information urinary bladder neoplasms, diagnosis, spectroscopy, raman spectroscopy, infrared spectroscopy none declared. received on january 15, 2023 accepted on march 17, 2023 this article has been peer reviewed. soc int urol j. 2023;4(4):321–334 doi: 10.48083/nczw3015 321 review point-of-care diagnosis of bladder cancer with vibrational spectroscopy: a systematic review arthur yim,1,5 matthew alberto,1 varun sharma,2,3 bayden wood,4 jaishankar raman3 lih-ming wong,1 joseph ischia,1 damien bolton1 1department of urology, austin health, australia 2department of surgery, the university of melbourne, australia 3department of cardiac surgery, austin health, australia 4centre for biospectroscopy, school of chemistry, monash university, australia 5young urology researchers organisation (yuro), melbourne, australia abstract introduction vibrational spectroscopy (vs) is a new and rapidly evolving technology in cancer diagnostics. originating from analytical chemistry, vs evaluates vibrations of nuclei to produce a unique “biological fingerprint.” while multiple studies have been published on this technology and physician awareness has increased, no systematic review has evaluated the role of vs in bladder cancer (bca) tissue diagnosis. methods to conduct this systematic review, we searched the medline, embase, and cochrane databases for studies that used raman spectroscopy (rs), surface-enhanced rs (sers), infrared spectroscopy (ir) or near-infrared spectroscopy (nirs) to analyze human bca specimens. studies using animal tissue or liquid biopsies were excluded. we synthesized the evidence by comparing modalities, study design, data analysis techniques, and diagnostic accuracy. the quality of evidence was evaluated by the quadas-2 tool. results out of 362 results, 20 studies met our inclusion criteria. there has been growing interest in vs use in bca, with 50% of the studies published in the past 5 years. rs was the most commonly used modality (65%), followed by ir (20%) and sers (10%). only one study compared rs to ir (5%). the mean sample size was 44 patients (range, 6–214). to date, there have been only 2 in vivo studies, with the remaining ex vivo studies performed with large variation in tissue preparation, data analysis, and reporting. advancements in fiber optic probes and machine-learning data analysis techniques, and increased computational power have improved diagnostic accuracy up to 98% sensitivity and 100% specificity. conclusions vs shows high potential for bca diagnosis, but there is a need for uniform reporting methods and studies with adequate sample sizes to validate the models. rs has shown promising results, with ongoing improvements in fiber optic probes allowing its integration into conventional cystoscopes. while no single vs modality has proven to be perfect, a multimodal approach is likely required to establish its value in clinical practice. introduction challenges in bladder cancer diagnosis bladder cancer (bca) is among the 10 most common cancer types worldwide, with approximately 550 000 new cases annually[1]. the recurrence and progression rates vary greatly, based on factors such as tumour grading, size, depth of invasion, and presence of carcinoma in situ (cis). at 5 years, the recurrence rates range from 31% to 78% and the progression rates range from 1% to 45%[2]. the stage of cancer is the most important prognostic factor, highlighting http://siuj.org https://orcid.org/0000-0003-2045-1231 https://orcid.org/0000-0003-3722-7754 https://orcid.org/0000-0002-5008-4113 https://orcid.org/0000-0003-3581-447x https://orcid.org/0000-0002-7691-4779 https://orcid.org/0000-0003-0490-7876 https://orcid.org/0000-0001-7177-3631 https://orcid.org/0000-0002-5145-6783 mailto:damienmbolton%40gmail.com?subject=siuj the importance of techniques for accurately and efficiently diagnosing bca stage in controlling disease progression. the current gold standard diagnostic method is white-light cystoscopy, followed by biopsies or transurethral resection of bladder tumour (turbt) for histopathological examination. while white-light cystoscopy is reliable for papillary tumours, it has limitations in detecting flat carcinomas such as cis, dysplasia, and multifocal lesions. integrated findings from 2 fluorescence cystoscopy registration studies revealed that only 38% of cis lesions[3] and 71% of cis cases were detected using white-light cystoscopy[3,4]. although newer optical techniques such as fluorescence and narrow-band imaging can improve tumour visualization, they do not contribute to histopathologic diagnosis[5]. thus, repeated biopsies are often performed, a procedure that not only is costly but also does not provide real-time point-of-care diagnosis. delays in diagnosis and treatment may lead to increased morbidity and mortality, particularly for high-risk invasive bca. a more rapid and cost-effective diagnostic method would potentially enhance management of bca patients. vibrational spectroscopy spectroscopy has attracted attention in cancer diagnosis in recent years. originating from analytical chemistry, vibrational spectroscopy (vs) is a powerful technique that measures the vibrational energy of molecules[6]. the 3 most common techniques used in cancer detection are infrared (ir), raman (rs), and near-infrared (nir) spectroscopy. the key characteristics, advantages, and limitations of each technique are summarized in table 1[7]. abbreviations ann artificial neural network auc area under the curve bca bladder cancer cis carcinoma in situ ffpe formalin-fixed paraffin-embedded ft-ir fourier transform infrared ir infrared nirs near-infrared spectroscopy pca principal component analysis qcl quantum-cascade laser quadas-2 quality assessment of diagnostic accuracy studies rs raman spectroscopy sers surface-enhanced raman scattering turbt transurethral resection of bladder tumour vs vibrational spectroscopy such as protein/lipid ratio, tumour characteristics, and immune cell interactions, encompassing a multimarker approach to cancer diagnostics[13]. in recent years, proof-of-concept studies in breast, colon, skin, and bladder cancers have demonstrated that vs can be employed as a label-free, non-destructive, and non-invasive approach to specimen analysis, facilitating the identification of specific “spectral biomarkers”[14]. objective of this review despite the increasing literature and public awareness into the role of vs in bca tissue diagnosis, no systematic review has covered the topic. this review aims to • provide a historical overview of the development of vs in bca diagnosis. • compare the 3 most common vs techniques—ir, rs, and nirs. • assess the feasibility and diagnostic accuracy of studies. • identify future areas of research based on the current literature. table 1. overview and comparison of the three common vibrational spectroscopy methods used in tissue analysis mid-ir nir raman basis method of detection mid-infrared light absorption using polychromic light source near-infrared light absorption using polychromic light source inelastic light scattering using monochromic laser excitation wavenumber 400–4000 cm-1 4000–10 000 cm-1 50–4000 cm-1 wavelength 2500–25 000 nm 1000–2500 nm 2500–20 0000 nm sampling methods sample interface historically complicated straightforward point-and-shoot, versatile straightforward point-and-shoot sample preparation complex minimal minimal penetration of glass / quartz / plastic no yes yes probes probes fragile fiber optic probe compatible fiber optic probe compatible sample size area 1–2 mm up to several cm 0.3–1 mm depth < 15 µm < 1 mm to several mm surface spectra from bulk material possible sensitivity water high medium low coloured samples no issue no issue susceptible to fluorescence specificity chemical high medium high observed bands fundamentals—narrow combinations and overtones— overlapping fundamentals—narrow ir: infrared; nir: near-infrared ir absorption spectroscopy relies on the absorption of mid-ir radiation by the sample, where molecules absorb specific frequencies of light based on their unique structure. this allows for identification and quantification of the molecular compound in a sample. the exact frequency required to excite a molecular vibration depends on the mass of the atoms involved in the vibration and the type of chemical bonds between these atoms, which can be influenced by a molecule’s structure and chemical microenvironment[8]. rs is a complementary method based on inelastic light scattering. in this method, the sample is illuminated with monochromatic laser light, and the interactions between molecules and photons leads to the scattering of light. the energy of the scattered light reflects the molecular composition of the sample[8]. rs offers several advantages over ir spectroscopy, including less interference from water and glass, less sample preparation, and higher spatial resolution. however, rs is inherently weaker and requires longer spectral scanning times to achieve an adequate signal-to-noise ratio. another significant limitation of rs is the presence of strong fluorescent signals, particularly in the analysis of organic tissues, dramatically reducing its specificity and hampering its clinical translation. surface-enhanced raman scattering (sers) spectroscopy is the newest technique that aims to overcome the limitations of conventional rs. sers uses plasmonic substrates, such as silver or gold colloids, to amplify the raman signal of molecules adsorbed onto the metal surface[9]. this technique holds great potential in identifying bca in liquid biopsies such as urine or serum, but its use in tissue is still emerging[10]. compared with its counterparts, mid-ir and rs, near-infrared (nir) spectroscopy has received less historical research attention. contrary to the mid-ir region, which relies on distinct fundamental absorption bands, the nir region contains overlapping overtone and combination bands that have lower intensity and reduced specificity[11]. however, recent advancements in quantum mechanical calculations and computational power have greatly expanded the use of nir in modern analytical applications[12]. nir offers advantages such as easier sample handling, low cost, greater sample penetration, and rapid acquisition times. all 3 techniques—ir, rs, and nirs—can analyze biological tissues, which comprise the superposition of biochemical components such as dna, proteins, lipids, and carbohydrates. vs can capture the unique “biological fingerprint” of the entire sample under analysis, rather than focusing on single elements like cell morphology in histopathology or tumour dna in assays. vs has the potential to evaluate the entire phenotypic response of the host, including tissue changes methods this review was performed in accordance with the prisma 2020 statement[15]. it was registered with the international prospective register of systematic reviews (prospero #crd42022349369), where the protocol and search strategy are available. eligibility criteria a summary of eligibility criteria for this review, fol low i ng t he pic o f r a me work (popu l at ion, inter vention, comparison, outcome) is detailed in  table 2. studies of humans with  either ex vivo  or in vivo vibrational spectral analysis of bladder tissue for the detection of cancer were included. there were no demographic restrictions. tissue samples required analysis by vs in a laboratory or operating theatre for inclusion. types of vs considered included rs, nirs, and ir spectroscopy. histopathology was required as the reference standard. publications reporting any diagnostic capability of vs were included. there were no restrictions on language or publication date. studies involving animal tissue, pooled cells, tissue markers, or liquid biopsies were excluded. only peer-reviewed 323322 siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org review point-of-care diagnosis of bladder cancer with vibrational spectroscopy: a systematic review http://siuj.org http://siuj.org articles were considered, with review articles, opinion papers, and commentaries excluded. search strategy an online electronic database search was undertaken using the platforms of medline, embase, and cochrane library. the search encompassed the entire database content. the initial search employed broad mesh terms including “urinary bladder neoplasms/” and (spectrum analysis, raman or spectroscopy, nearinfrared/ or spectrophotometry, infrared/)while also extracting key terminology/key words from reviews and a sample of potentially relevant primary data studies. a gold test set of relevant studies was used to ensure the search terms retrieved all of the gold test set. the results of the literature search were downloaded into endnote x9 software (clarivate analytics, london, uk) and exact article duplicates were removed using the duplicate tool in that software program. subsequently, a reference review of identified articles and reviews was conducted to identif y any additional relevant articles. grey literature was searched via guidelines from the european association of urology (eau), american urological association (aua), and national institute for health and care excellence (nice) and ongoing clinical trials through clinicaltrials.gov, the isrctn registry, and the world health organization international clinical trials registry platform (ictrp) portal. the authors of trials were contacted for preliminary or unpublished results for potential inclusion in the review. full search strategy and results are provided in online appendix 1. selection process following completion of the search, all identified citations were uploaded into covidence systematic review software (veritas health innovation, melbourne, australia) and duplicates were removed. the screening results a total of 363 articles were identified through literature search, of which 263 were excluded on screening. of 29 full-text articles assessed for eligibility, 20 were included in this review (figure 1). characteristics of the included studies table 3 provides a summary of the characteristics of the included studies, while table 4 contains a summary of all data collected. there has been a growing interest in spectroscopy and bca since the publication of the first study in 2004, with 10 of 20 studies published in the past 5 years. the most commonly used modality was rs figure 1. prisma 2020 diagram of study selection records removed before screening: duplicate records removed (n = 71) records screened (n = 292) records excluded (n = 263) reports not retrieved (n = 1)  reports sought for retrieval (n = 29) reports excluded: wrong study design (n = 3) wrong tumour type (n = 3) wrong intervention (n = 1) conference poster (n = 1) reports assessed for eligibility (n = 28) studies included in review (n = 20) s cr ee ni ng identi�cation of studies via databases and registers id en ti �c at io n in cl ud ed records identi�ed from: databases (n = 362) medline (n = 160) embase (n = 200) cochrane (n = 2) registers (n = 1) table 2. criteria for studies included in this systematic review inclusion criteria population human bladder cancer tissue investigation vibrational spectroscopy modalities: 1. raman (rs) 2. fourier transform infrared (ft-ir) 3. near-infrared (nirs) control histopathology outcomes quantitative: diagnostic accuracy, sample size, scan time, and excitation laser wavelength qualitative: study design and limitations, tissue preparation, algorithm for analysis, and the pathological groups compared setting intraoperative, bedside, or laboratory (65%), followed by ir (20%), and sers (10%). no studies using nirs were found. two comparator studies were included. one compared ft-ir and rs on the same bladder specimens[17], while another compared a novel superficial rs fiber optic probe with a non-superficial probe[18]. sample sizes of the studies were low, with a mean of 44 patients (range, 6–214). only 2 studies were conducted in vivo[18,19], while the remaining studies were ex vivo (n = 18). there was considerable variation in tissue preparation methods, including snap-freezing bladder specimens post-turbt and subsequently thawing (40%), for inclusion was conducted in 2 phases. the first phase involved screening titles and abstracts from the initial search results. the second phase involved reviewing full-text articles based on the previously stated inclusion criteria. both phases of screening were conducted by 2 independent reviewers (a.y. and m.a.). in cases of unresolved disagreements, a third senior reviewer (d.b.) acted as an adjudicator. the same approach was used to screen all grey literature sources. data collection process two reviewers (a.y. and m.a.) independently conducted data extraction onto a predefined extraction sheet. the extracted data were cross-checked independently. the primary outcome measures extracted for assessing the effectiveness of a diagnostic modality included quantitative measures of accuracy such as sensitivity, specif icity, overall accuracy, and area under the curve (auc) values. secondary outcome measures encompassed bot h qua nt itat ive a nd qua litat ive data covering study design and limitations, tissue preparation, scan time, excitation laser wavelength, data analysis technique, and comparison of pathological groups. if multiple data analysis techniques were evaluated within a study, the data described are based on the most effective technique used. when data were presented for both a training set and test/crossvalidation set, the data from the test set are presented, as it reflects the performance of the test in clinical practice most closely. study risk of bias assessment two reviewers independently assessed each eligible study using the quality assessment of diagnostic accuracy studies (quadas-2) tool[16]. any areas of conflict between the 2 reviewers were resolved through arbitration involving a third reviewer (d.b.), if necessary. 325324 siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org review point-of-care diagnosis of bladder cancer with vibrational spectroscopy: a systematic review http://siuj.org http://siuj.org immediate analysis of fresh specimens post-turbt (30%), or placing specimens into formalin that was variably reversed before spectral scanning (30%). regarding data analysis techniques, principal component fed linear discriminant analysis (pca-lda) was the most commonly used technique (45%). other analysis methods included support vector machines, partial least squares linear discriminant analysis, cluster-averaged spectra, ordinary least squares regression, principal component analysis, and artificial neural networks. the quantitative measures of accuracy varied greatly across studies. while not all studies reported sensitivity and specificity, some chose to report overall accuracy and auc. additionally, 25% of the studies provided only descriptive analysis of tissue constituents such as proteins, lipids, dna, collagen, and cholesterol. comparing the performance of spectroscopic techniques quantitative measures of diagnostic accuracy, such as sensitivity and specificity, were reported in 12 of 14 studies that used rs. the remaining 2 studies reported descriptive analysis of tissue constituents instead of accuracy[17,20]. diagnostic endpoints varied significantly across studies, depending on the histopathological categories chosen for analysis. for example, 90% of the studies compared benign to malignant tissues, while 30% compared low-grade with high-grade urothelial cancer. this variability made direct comparisons between studies difficult. overall, the sensitivity and specificity for detecting malignancy ranged from 71% to 97% and from 72% to 100%, respectively. in contrast, only 1 of 5 ft-ir studies reported on accuracy. hughes et al. (2013) used support vector machines to achieve a class accuracy of 98% to 99% when distinguishing conventional urothelial cancer from rare subvariants. they did not compare with benign tissues[21]. pezzei et al. (2013) used ft-ir microscopic imaging with tissue microarray technology to correlate with stained histological bca tissue sections, opening up new possibilities for spectroscopic analyses and exploration of the molecular changes associated with histopathological morphology[22]. the remaining 3 ft-ir studies reported only on concentrations of tissue constituents. two studies with markedly different study designs used sers. the first study, conducted by jin et al. (2019), compared luminal and basal-like subtypes of bca and reported an overall accuracy of 94%[23]. that study used 50 snap-frozen specimens without any benign controls. in a subsequent study, zacharovas et al. (2022) applied sers to freshly excised bladder tissue and extracellular fluid. their 3-group algorithm achieved a sensitivity of figure 2. quality assessment of diagnostic accuracy studies (quadas-2) analysis of the included studies study risk of bias applicability concerns patient selection index test reference standard flow and timing patient selection index test reference standard crow et al., 2004 low low low low low low low crow et al., 2005 high high low high low low low de jong et al., 2006 high low low unclear high high low stone et al., 2007 high low low unclear low high low draga et al., 2010 low high high high low low low ahmed et al., 2010 unclear high low unclear high high low barman et al., 2012 low low low low low low low ai-musletet al., 2012 unclear low low unclear high high low pezzeiet al., 2013 high high low high high high low hugheset al., 2013 high high low unclear high high low chenet al., 2018 low low low low low low low jinet al., 2019 high high unclear unclear high high unclear pavlovet al., 2019 low low unclear low low low unclear yousifet al., 2020 high high low low low high low placzeket al., 2020 low low high high low low low corderoet al., 2020 low low high high low low low morselliet al., 2021 low low low high low high low zacharovas et al. (2022)[10] low high low high low high low stomp-agenantet al., 2022 high high low high high low low taieb et al., 2022 high high low high high high low table 3. characteristics of studies included in the systematic review characteristic studies n (%) period of publication 2004–2009 5 (25) 2010–2016 7 (35) 2017–2022 10 (50) spectroscopy modality raman 14 (65) ft-ir 5 (20) sers 2 (10) raman & ft-ir 1 (5) nirs 0 (0) sample size < 20 6 (30) 20–50 10 (50) 50 4 (20) tissue preparation in vivo 2 (10) ex vivo: frozen 8 (40) ex vivo: fresh 6 (30) ex vivo: formalin 6 (30) data analysis technique pca-lda 9 (45) pca-svm 2 (10) pls-lda 2 (10) pca 2 (10) ols 1 (5) pca-ann 1 (5) constituents only 5 (25) histopathological categories compared benign vs. cancer 18 (90) grade characterization 6 (30) stage characterization 3 (15) subtype characterization 2 (10) ann: artificial neural networks; cas: cluster-averaged spectra; ft-ir: fourier transform infrared; lda: linear discriminant analysis; nirs: near-infrared spectroscopy; ols: ordinary least squares regression; pca: principal component analysis; pls: partial least squares; sers: surfaceenhanced raman spectroscopy; svm: support vector machines. flow and timing reference standard index test patient selection q u a d a s2 d om ai n 0% 20% 40% 60% 80% 100% proportion of studies with low, high or unclean risk of bias 0% 20% 40% 60% 80% 100% proportion of studies with low, high or unclean concerns regarding applicability low high unclear 327326 siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org review point-of-care diagnosis of bladder cancer with vibrational spectroscopy: a systematic review http://siuj.org http://siuj.org table 4. summary of all data collected for the included studies study/ year country patients/ specimens malignant/ control tissue preparation spectroscopy modality/ mean scan time laser wavelength data analysis technique histopathological categories compared diagnostic endpoint sensitivity / specificity accuracy / other crow et al. (2004)[24] united kingdom 72/75 3/22 ex vivo—snap-frozen post-turbt raman / 10 sec 830 nm pca-lda • (i) normal, (ii) cystitis, (iii) malignant • (i) low grade, (ii) high grade • (i) pta, (ii) pt1, (iii) pt2 91% / 98% 93% / 98% 96% / 96% n/a crow et al. (2005)[40] united kingdom 24/29 10/19 ex vivo—snap-frozen post-turbt raman, fibreoptic probe / 5–30 sec 785 nm pca-lda • (i) benign, (ii) malignant 79% / 89% accuracy 84% de jong et al. (2006)[41] netherlands 15/15 9/6 ex vivo –snap-frozen post-turbt raman map / 20 sec 845 nm pca-lda cas • (i) benign, (ii) malignant 94% / 92% accuracy 98% stone et al. (2007)[20] united kingdom 24/73 41/32 ex vivo—snap-frozen post-turbt raman / 20 sec 830 nm ols • (i) benign, (ii) malignant n/a constituents: actin, collagen, choline, triolein, dna, cholesterol draga et al. (2010)[19] the netherlands 38/63 23/29 in vivo—live tissue prior to turbt raman and pdd / 1–5 sec 785 nm pca-lda • (i) normal, (ii) cystitis, (iii) malignant • (i) normal, (ii) cancer • (i) normal, (ii) pta, (iii) pt1 + pt2 71% / 87% 85% / 79% 58% / 76% n/a ahmed et al. (2010)[17] sudan 7/14 4/0 ex vivo—formalin, dried, grinded, kbr additive raman and ft-ir / scan time n/a 1064 nm constituents only • (i) benign, (ii) malignant n/a constituents: proteins, lipids, nucleic acids barman et al. (2012)[25] united kingdom 14/28 14/14 ex vivo—fresh post-turbt raman,confocal probe / 5 sec 785 nm pca-lda • (i) benign, (ii) malignant 86% / 100% accuracy 93% auc 0.91 al-muslet et al. (2012)[42] sudan 11/22 11/11 ex vivo—formalin, dried, grinded, kbr additive ft-ir / scan time n/a n/a constituents only • (i) benign, (ii) malignant n/a constituents: proteins, lipids, nucleic acids pezzei et al. (2013)[22] austria 214 214/0 ex vivo—formalin, dried ft-ir micro-spectroscopy / scan time n/a n/a pca • (i) benign, (ii) malignant n/a n/a hughes et al. (2013)[21] united kingdom 6/6 6/0 ex vivo—reversal of ffpe tissue ft-ir micro-spectroscopy / scan time n/a n/a pca-svm • rare subvariants only: (i) conventional urothelial cancer, (ii) micro-papillary, (iii) stroma, (iv) lymphocyte-rich, (v) clear cell, (vi) lipoid n/a accuracy 98% chen et al. (2018)[26] china 10/32 21/11 ex vivo—snap-frozen in liquid nitrogen raman, fiber optic probe / 1 sec 785 nm pca-ann • (i) normal, (ii) low grade, (iii) high grade 90% / 98% lg 98% / 96% hg accuracy 93% jin et al. (2019)[23] china 50 50/0 ex vivo—snap-frozen sers / 10 sec 633 nm pca-lda two subtypes: • (i) luminal, (ii) basal-like n/a accuracy 94% auc 97 pavlov et al. (2016)[43] russia 22 22/13 ex vivo—fresh post-turbt raman / scan time n/a 785 nm pca-lda • (i) benign, (ii) malignant 97% / 96% n/a yousif et al. (2020)[44] iraq 46/46 23/23 ex vivo—formalin atr-ft-ir / scan time n/a n/a constituents only • (i) benign, (ii) malignant n/a constituents: proteins, lipids, collagen placzek et al. (2020)[27] denmark 44/119 53/66 ex vivo—fresh or snap-frozen raman and oct / scan time n/a 785 nm pls-lda • (i) benign, (ii) malignant • (i) low grade, (ii) high grade 95% / 88% 81% / 61% n/a cordero et al. (2020)[35] denmark 28/67 37/11 ex vivo—fresh or snap-frozen raman, fiber optic mapping / 3 sec 785 nm pls-lda • (i) benign, (ii) malignant • (i) low grade, (ii) high grade 92% / 93% 85% / 83% accuracy 92% accuracy 84% morselli et al. (2021)[28] italy 114/169 40/129 ex vivo—fresh post-turbt raman, fiber optic & fluorescence & reflectance / scan time n/a 785 nm pca-lda • (i) benign, (ii) malignant • (i) low grade, (ii) high grade • (i) pta, (ii) pt1 • (i) pta, (ii) pt2 • (i) pt1, (ii) pt2 77% / 72% 73% / 65% 65% / 71% 81% / 81% 75% / 76% accuracy 77% zacharovas et al. (2022)[10] lithuania 30/58 25/28 ex vivo—fresh post-turbt sers /5 min 1064 nm pca • (i) normal, (ii) cystitis, (iii) malignant 85% / 97% n/a stomp-agenant et al. (2022)[18] the netherlands 75/117 51/66 in vivo—live tissue prior to turbt raman fiber optic, superficial vs normal probe / 0.5 sec 785 nm pca-lda • (i) benign, (ii) malignant • (i) normal, (ii) low grade, (iii) high grade 90% / 87% superficial probe 80% / 85% normal probe auc 0.95 superficial probe auc 0.80 normal probe taieb et al. (2022)[45] israel unknown unknown ex vivo—reversal of ffpe tissue raman mapping / 60 sec 561 nm pca-svm • (i) benign, (ii) malignant 84% / 88% n/a ann: artificial neural networks; atr: attenuated total reflection; auc: area under the curve; cas: cluster-averaged spectra; ffpe: formalin-fixed paraffin-embedded; ft-ir: fourier transform infrared; hg: high grade; lda: linear discriminant analysis; lg: low grade; n/a: not available; nirs: near-infrared spectroscopy; ols: ordinary least squares regression; pca: principal component analysis; pdd: photodynamic diagnosis; pls: partial least squares; sers: surface-enhanced raman spectroscopy; svm: support vector machines; turbt: transurethral resection of bladder tumour. 329328 siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org review point-of-care diagnosis of bladder cancer with vibrational spectroscopy: a systematic review http://siuj.org http://siuj.org multimodal approach improved accuracy up to 90%[28], the additional time and resource expenditure is significant, limiting this approach in a clinical setting. comparison of vs techniques in the context of bca diagnosis, rs has received the most attention in recent years. a systematic review of 9 original studies conducted between 2004 and 2015 demonstrated an impressive pooled diagnostic sensitivity of 94% and specificity of 92%[29]. however, the studies included in this meta-analysis were highly heterogeneous in terms of sample type, instrument used, excitation wavelength, and algorithm for analysis. some studies used snap-frozen or formalin-fixed paraffinembedded (ffpe) tissue, while others used cell lines, peripheral blood, or urine. there has been great interest in using rs to analyze urine samples for molecular signatures associated with bca to develop a truly non-invasive screening test. huttanus et al. (2020) developed an rs-based chemometric urinalysis (rametrix) as a direct method for screening urine samples. using a model built with 22 principal components, bca was detected with 82.4% sensitivity and 79.5% specificity[30]. the reduced accuracy of this label-free method could be attributed to the diversity of urine composition, concentration, and ph[31]. with the surface enhancement provided by sers, greater diagnostic accuracy could be achieved, as demonstrated a recent study by hu et al. (2021) with 100% sensitivity and 98.85% specificity[32]. ft-ir analysis of bladder washings has also been proposed as a sensitive, rapid, non-destructive, and operator-independent analytical diagnostic method for bca compared with traditional urine cytology. in a study by gok et al. (2016), bladder washings were analyzed from 136 patients, demonstrating a sensitivity of 100% but modest specificity of 73.5%. interestingly, traditional urine cytology had a sensitivity of only 45% on the same specimens in this study[33]. the combination of ft-ir with microscopy has also led to the development of ir imaging. studies have demonstrated accuracies > 90% compared with immunohistochemical (ihc) diagnostics by pathologists[34]. however, clinical translation of this powerful integrated technique has been hindered by long measuring times and complex ft-ir setup requiring liquid nitrogen cooling. quantum-cascade laser (qcl)-based microscopes have shown promise in overcoming these limitations, enabling ir imaging to be performed within minutes. kuepper et al. (2018) demonstrated that qcl-based ir imaging could identify colorectal cancer in the same time frame as a frozen thin section diagnosis by pathologists, boasting a sensitivity of 96% and specificity of 100%[34]. limitations of evidence and review process despite the high levels of diagnostic accuracy achieved with vs recently, this review has identified several limitations that indicate the need for further work before the clinical use of vs as a minimally invasive tool for cancer investigation. the inclusion criteria of this review did not impose limitations on sample size to provide a broader overview of all available literature on vs. as a result, one-third of studies included had fewer than 20 participants, offering a low level of evidence with significant heterogeneity in study design. furthermore, variation in tissue sample preparation techniques, pathological grouping, and data analysis make direct comparison between studies difficult. this prevents any meaningful pooling of results through meta-analysis to obtain statistical estimates of overall diagnostic accuracies. the reporting methods of the included studies were inconsistent and often incomplete. while many studies often reported sensitivity and specificity, they often omitted reporting accuracy and auc, or vice versa. only 1 study reported all 4 of measures of accuracy[25]. the use of the term “optimal” sensitivity in some studies raises concerns about reporting bias, as the authors may have been selecting the best results for reporting. concerningly, none of the studies provided complete data for all key areas of diagnostic accuracy: true and false positivity and negativity, sensitivity, specificity, and positive and negative predictive values. it is paramount to publish larger studies that comprehensively report these values to further evaluate spectroscopy. implications on clinical practice and challenges for future research while many of the studies included in this review analyzed ex vivo bladder specimens, the true potential of non-invasive vs lies in its application in a real-time in vivo setting. this will undoubtedly depend upon the development and optimization of fiber optic probes that can be introduced via the urologist’s everyday cystoscope. this trend is already evident in the studies included in this review, with 4 of the 5 studies published in the past 5 years using a fiber optic probe[18,26,28,35]. another major challenge is the presence of f luids such as urine or glycine, which can interfere with the spectroscopic signal and reduce specificity. more in vivo research is needed to evaluate the feasibility of vs in the operating theatre. the results of a phase 1 trial by hermann et al. are awaited (clinicaltrials.gov identifier: nct05124106), as the study utilizes fiber optic probes to take rs measurements inside the bladder of 30 patients. it is noteworthy that no studies using nirs to analyze bca were included in this review, despite the successful use of this technique in evaluating prostate cancer, breast cancer, and cardiac fibrosis specimens[36–38]. 85% and specificity of 97% in distinguishing malignancy from cystitis and normal tissue[10]. quality assessment and risk of bias all articles were evaluated for risk of bias and concerns regarding applicability using the quadas-2 quality assessment tool (figure 2). up to 45% and 50% of the studies showed a high risk of bias regarding patient selection and index test, respectively. this was predominantly due to non-random patient selection and knowledge of reference standard results prior to interpreting the index test. discussion evolution of spectroscopy in clinical practice since the first ex vivo rs study by crow et al. (2004) using frozen tissue (figure 3), significant technological advancements in optoelectronics, computationa l capacity, and machine-learning data analysis techniques have facilitated rapid and real-time applications[24]. in the first in vivo study, draga et al. (2010) introduced a fiber optic probe with a 2.1-mm external diameter via a cystoscope to acquire rs measurements immediately before turbt[19]. their algorithm achieved a sensitivity of 85% and a modest specificity of 79% in distinguishing bca from normal tissue, thus highlighting the challenges in clinical translation for rs. subsequent rs studies have implemented hardware and software improvements to optimize diagnostic accuracy. barman et al. (2012) introduced a confocal fiber optic probe that limited sampling to 300 μm. figure 3. figures from the first ex vivo raman spectroscopy study by crow et al. (2004) using frozen tissue. a) the mean raman spectra measured for each of the pathological groups. b) scatter plots of the scores of linear discriminant function 1 vs. 2 showing clustering in the eight-group algorithm. c) the prediction power of the eight-group diagnostic algorithm demonstrating a sensitivity and specificity of 93% and 98%, respectively. (reproduced with permission.[24]) adeno: adenocarcinoma; a.u.: absorption units; cis: carcinoma in situ; cyst: cystitis; ldf; linear discriminant function; sq: squamous; tcc: transitional cell carcinoma. by suppressing spectral information from deeper tissue layers beyond the region of interest, diagnostic accuracy improved to 86% sensitivity and 100% specificity[25]. following a similar principle of shallow tissue sampling, stomp-agenant et al. (2022) developed a superficial fiber optic probe with a measuring depth of 200 μm. this significantly reduced the signal-to-noise ratio compared to a regular probe, improving accuracy to 90% sensitivity and 87% specificity[18]. in add it ion to t he ha rdwa re i mprovements described, advancements in computational capacity and machine-learning data analysis techniques continue to enhance the diagnostic accuracy of spectroscopy. chen et al. (2018), analyzed 32 snap-frozen bladder specimens using a fiber optic probe, similar to previous studies, but combined pca with artificial neural network (ann) modelling to achieve a sensitivity of 98% and specificity of 96% in detecting high-grade bca. ann is a powerful, self-adaptive, and data-driven pattern recognition method capable of capturing non-linear characteristics of the data[26]. after comparing ann with other popular classifications methods such as linear discriminant analysis (lda) or support vector machines (svm) in dozens of studies, the authors noted that ann constantly outperformed other techniques. while no single spectroscopy technique has proven to be perfect, a multimodal approach is likely to be required. rs has been combined with a concurrent diagnostic method in 3 studies, including photodynamic diagnosis[19], optical coherence tomography[27], and f luorescence and diffuse ref lectance[28]. although a 331330 siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org review point-of-care diagnosis of bladder cancer with vibrational spectroscopy: a systematic review http://siuj.org http://siuj.org references 1. richters a, aben kkh, kiemeney lalm. the global burden of urinary bladder cancer: an update. world j urol.2020;38(8):1895 –1904. doi: 10.1007/s00345-019-0298 4 4. pmid: 31676912; pmcid: pmc7363726. 2. sylvester rj, van der meijden apm, oosterlinck w, et al. predicting recurrence and progression in individual patients with stage ta t1 bladder cancer using eortc risk tables: a combined analysis of 2596 patients from seven eortc trials. eur urol.2006;49(3):466– 477; discussion 475 – 477. doi: 10.1016/j.eururo.2005.12.031. pmid: 16442208. 3. jocham d, witjes f, wagner s, zeylemaker b, van moorselaar j, grimm mo, et al. improved detection and treatment of bladder cancer using hexaminolevulinate imaging: a prospective, phase iii multicenter study. j urol.2005;174(3):862–866; discussion 866. doi: 10.1097/01. 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n71. pmid: 33782057; pmcid: pmc8005924. 16. whiting pf, rutjes aws, westwood me, mallett s, deeks jj, reitsma jb, et al.; quadas-2 group. quadas-2: a revised tool for the quality assessment of diagnostic accuracy studies. ann intern med.2011;155(8):529–536. doi: 10.7326/0003-4819-155-8201110180-00009. pmid: 22007046. 17. ahmed eg, al-muslet na, ahmed mm, moharam m, musaad w. the use of fourier infrared spectroscopy and laser-raman spectroscopy in bladder malignancy diagnosis, a comparative study. appl phys res.2010;2(1):108–117. 18. stomp-agenant m, van dijk t, r. onur a, grimbergen m, van melick h, jonges t, et al. in vivo raman spectroscopy for bladder cancer detection using a superficial raman probe compared to a nonsuperficial raman probe. j biophotonics.2022;15(6):e202100354. doi: 10.1002/jbio.202100354. pmid: 35233990. 19. draga rop, grimbergen mcm, vijverberg plm, van swol cf, jonges tg, kummer ja, et al. in vivo bladder cancer diagnosis by highvolume raman spectroscopy. anal chem.2010;82(14):5993–5999. doi: 10.1021/ac100448p. pmid: 20524627. 20. stone n, hart prieto mc, crow p, uff j, ritchie aw. the use of raman spectroscopy to provide an estimation of the gross biochemistry associated with urological pathologies. anal bioanal chem.2007;387(5):1657–1668. doi: 10.1007/s00216-006-0937-9. pmid: 17123068. 21. hughes c, iqbal-wahid j, brown m, shanks jh, eustace a, denley h, et al. ftir microspectroscopy of selected rare diverse sub-variants of carcinoma of the urinary bladder. j biophotonics.2013;6(1):73–87. doi: 10.1002/jbio.201200126. pmid: 23125109. 22. pezzei c, brunner a, bonn gk, huck cw. fourier transform infrared imaging analysis in discrimination studies of bladder cancer. analyst.2013;138(19):5719–5725. doi: 10.1039/c3an01101a. pmid: 23897512. recent improvements in machine-learning analytical techniques have led to substantial progress in research and industry[11,12]. nirs has the potential to provide real-time molecular data, analogous to handheld ultrasound devices, with low computational requirements (6 kb per spectrum), making it possible to be performed on mobile devices in line with the evolution toward ambulatory and personalized care[38]. compared to the aforementioned techniques, nirs spectra can be obtained from greater sample thickness, allowing for easier sample handling, and it is fast without the need for a laser, unlike rs. additionally, near-infrared light penetrates deeper into human tissues, causing less photodamage and safer tissue probing[39]. considering that nirs and rs provide complementary information when analyzing the same sample, combining the 2 techniques in a multimodal approach could potentially further enhance diagnostic accuracy. with ongoing advancements in spectroscopy technology, machine-learning analytical techniques, and multimodal approaches to improve accuracy, vs offers several potential advantages over standard histopathology: rapid, label-free, and operator independent. when used in conjunction with fiber optic probes in endoscopy, it may help reduce cases of incomplete tumour resection and lower the risk for recurrence. it can serve as a tool to aid clinical decision-making in real time, providing a quick and safe assessment of stage and grade, allowing urologists to reduce overor under-treatment of bca. in an increasingly frail population with rising anticoagulant use, these improvements could reduce adverse events related to surgery and expedite the staging and grading of urothelial cancer of the bladder. conclusions although vs is a mature technology in analytical chemistry, its use in medical diagnostics is still in its infancy. recent advances in technology and computing power and reductions in equipment costs and size have facilitated a shift in focus from the laboratory to the bedside. as fiber optic probes for spectroscopy become commercially available, their use in combination with a conventional cystoscope opens up the exciting possibility for real-time diagnostic imaging of bca. rs has demonstrated high levels of diagnostic accuracy, which continue to improve with advancements in sers. however, studies are small and highly heterogeneous. larger spectroscopy studies with robust reporting methods and a multimodal approach are needed to assess not only the overall diagnostic accuracies but also the optimal utilization of this emerging technology. ongoing research into modalities such as sers and nirs holds great promise, making spectroscopy an exciting and dynamic field in urological diagnostics with the potential to enhance intraoperative decisionmaking. 333332 siuj.org siuj • volume 4, number 4 • july 2023siuj • volume 4, number 4 • july 2023 siuj.org review point-of-care diagnosis of bladder cancer with vibrational spectroscopy: a systematic review http://siuj.org http://siuj.org 23. jin d, wang x, fu b, li t, chen n, chen z, et al. raman spectroscopy of luminal subtype and basal subtype muscle invasive bladder cancer. int j clin exp med.2019;12(5):5447–5453. 24. crow p, uff js, farmer ja, wright mp, stone n. the use of raman spectroscopy to identify and characterize transitional cell carcinoma in vitro. bju int.200 4;93(9):1232–1236. doi: 10.1111/j.14 6 4 410x.2004.04852.x. pmid: 15180613. 25. barman i, dingari nc, singh gp, kumar r, lang s, nabi g. selective sampling using confocal raman spectroscopy provides enhanced specificit y for urinar y bladder cancer diagnosis. anal bioanal chem.2012;404(10):3091–3099. doi: 10.1007/s00216-012-6424-6. pmid: 23052868. 26. chen h, li x, broderick n, liu y, zhou y, han j, et al. identification and characterization of bladder cancer by low-resolution fiber-optic raman spectroscopy. j biophotonics.2018;11(9):e201800016. doi: 10.1002/ jbio.201800016. pmid: 29797794. 27. placzek f, cordero bautista e, kretschmer s, wurster lm, knorr f, gonzález-cerdas g, et al. morpho-molecular ex vivo detection and grading of non-muscle-invasive bladder cancer using forward imaging probe based multimodal optical coherence tomography and raman spectroscopy. analyst.2020;145(4):1445–1456. doi: 10.1039/ c9an01911a. pmid: 31867582. 28. morselli s, baria e, cicchi r, liaci a, sebastianelli a, nesi g, et al. the feasibility of multimodal fiber optic spectroscopy analysis in bladder cancer detection, grading, and staging. urologia.2021;88(4):306–314. doi: 10.1177/03915603211007018. pmid: 33789562. 29. jin h, lin t, han p, yao y, zheng d, hao j, et al. efficacy of raman spectroscopy in the diagnosis of bladder cancer: a systematic review and meta-analysis. medicine (baltimore).2019;98(47):e18066. doi: 10.1097/md.0000000000018066. pmid: 31764837; pmcid: pmc6882629. 30. huttanus hm, vu t, guruli g, tracey a, carswell w, said n, et al. raman chemometric urinalysis (rametrix) as a screen for bladder cancer. plos one.2020;15(8):e0237070. doi: 10.1371/journal.pone.0237070. pmid: 32822394; pmcid: pmc7446794. 31. liu z, zhang p, wang h, zheng b, sun l, zhang d, et al. raman spectrumbased diagnosis strategy for bladder tumor. urol int.2022;106(2):109– 115. doi: 10.1159/000518877. pmid: 34515249. 32. hu d, xu x, zhao z, li c, tian y, liu q, et al. detecting urine metabolites of bladder cancer by sur face-enhanced raman spectroscopy. spectrochim acta a mol biomol spectrosc.2021;247:119108. doi: 10.1016/j.saa.2020.119108. pmid: 33161263. 33. gok s, aydin oz, sural ys, zorlu f, bayol u, severcan f. bladder cancer diagnosis from bladder wash by fourier transform infrared spectroscopy as a novel test for tumor recurrence. j biophotonics.2016;9(9):967–975. doi: 10.1002/jbio.201500322. pmid: 27041149. 34. kuepper c, kallenbach-thieltges a, juet te h, tannapfel a, großerueschkamp f, gerwert k. quantum cascade laser-based infrared microscopy for label-free and automated cancer classification in tissue sections. sci rep.2018;8(1):7717. doi: 10.1038/s41598-01826098-w. pmid: 29769696; pmcid: pmc5955970. 35. cordero e, rüger j, marti d, mondol as, hasselager t, mogensen k, et al. bladder tissue characterization using probe-based raman spectroscopy: evaluation of tissue heterogeneity and influence on the model prediction. j biophotonics.2020;13(2):e201960025. doi: 10.1002/jbio.201960025. pmid: 31617683; pmcid: pmc7065650. 36. ali jh, wang wb, zevallos m, alfano rr. near infrared spectroscopy and imaging to probe differences in water content in normal and cancer human prostate tissues. technol cancer res treat.2004;3(5):491–497. doi: 10.1177/153303460400300510. pmid: 15453814. 37. gu y, chen wr, xia m, jeong sw, liu h. effect of photothermal therapy on breast tumor vascular contents: noninvasive monitoring by nearinfrared spectroscopy. photochem photobiol.2005;81(4):1002–1009. doi: 10.1562/2004-09-05-ra-305. pmid: 15807632. 38. adegoke ja, gassner c, sharma vj, patel sk, jackett l, afara io, et al. near-infrared spectroscopic characterization of cardiac and renal fibrosis in fixed and fresh rat tissue. anal sens.2023;3(1):e202200030. doi: 10.1002/anse.202200030. 39. wu s, but t h-j. near-infrared-sensitive materials based on upconverting nanoparticles. adv mater.2016;28(6):1208–1226. doi: 10.1002/adma.201502843. pmid: 26389516. 40. crow p, molckovsky a, stone n, uff j, wilson b, wongkeesong l m . a s s e s s m e n t o f f i b e r o p t i c n e a ri n f r a r e d r a m a n spectroscopy for diagnosis of bladder and prostate cancer. urology.2005;65(6):1126–1130. doi: 10.1016/j.urology.2004.12.058. pmid: 15913721. 41. de jong bwd, bakker schut tc, maquelin k, van der kwast t, bangma ch, kok dj, et al. discrimination between nontumor bladder tissue and tumor by raman spectroscopy. anal chem.2006;78(22):7761–7769. doi: 10.1021/ac061417b. pmid: 17105169. 42. al-muslet na, ali ee. spectroscopic analysis of bladder cancer tissues using fourier transform infrared spectroscopy. j appl spectrosc.2012;79(1):139–142. 43. pavlov v, bilyalov a, gilmanova r, yakupov rr, et al. the use of intelligent data processing techniques of raman spectroscopy for the diagnosis of malignant tumors. bashkortostan med j.2016;13. 44. yousif es, abdulkareem dt, enad alboaisa ns, mohammad ej. detection of urinary bladder cancer by (atr-f tir) spectroscopy. system rev pharm.2020;11(12):1932–1937. 45. taieb a, berkovic g, haifler m, cheshnovsk y o, shaked nt. classification of tissue biopsies by raman spectroscopy guided by quantitative phase imaging and its application to bladder cancer. j biophotonics.2022;15(8):e202200009. doi: 10.1002/jbio.202200009. pmid: 354887 334 siuj • volume 4, number 4 • july 2023 siuj.org review http://siuj.org 77siuj.org siuj • volume 1, number 1 • october 2020 molecular biomarkers in urologic oncology: icud-wuof consultation the past and future of biomarkers in testicular germ cell tumors aditya bagrodia,1 siamak daneshmand,2 liang cheng,3 james amatruda,4 matthew murray,5,6 john t. lafin1 1 department of urology, university of texas southwestern medical center, united states, 2 department of urology, university of southern california, keck school of medicine, united states, 3 department of pathology, indiana university school of medicine, united states, 4 cancer and blood disease institute, children’s hospital los angeles, departments of pediatrics and medicine, keck school of medicine, university of southern california, united states, 5 department of pathology, university of cambridge, united kingdom, 6 department of pediatric hematology and oncology, cambridge university hospitals nhs foundation trust, cambridge, united kingdom abstract testicular germ cell tumor (gct) is the most common malignancy in 18to 40-year-old men. unlike most other cancers, gct is frequently curable even when metastatic. these tumors can be classified histologically into seminoma and non-seminoma, which determines treatment. therefore, successful treatment requires accurate diagnosis, classification, and monitoring. serum tumor markers, including lactate dehydrogenase, α-fetoprotein, and β-human chorionic gonadotropin, aid in the classification and staging of gcts. these markers therefore play a critical role in the decision-making process when managing gct patients. however, there exist many scenarios in which these markers fail to perform adequately. this is particularly true in the case of seminoma, where only 10% to 15% will have elevated serum tumor markers. non-specific elevation of these markers is also a common occurrence, complicating the interpretation of borderline positive results, particularly in follow-up. to bridge this gap in performance, next generation biomarkers are being investigated. in this review, we consider the role of conventional serum tumor markers in gct management and discuss recent advances in the next generation of biomarkers, with a focus on circulating micrornas. we discuss the value that circulating micrornas could bring as an addition to currently used markers, as well as potential weaknesses, in gct management. introduction testicular germ cell tumor (gct) is the most common solid tumor in 18to 40-year-old men, and accounts for more life-years lost than any other non-pediatric malignancy [1]. gcts are histologically classified as seminoma or non-seminomatous gct (nsgct). seminomas retain pluripotency markers and genotypically resemble primordial germ cells, their presumed cell of origin. nsgct can be further subdivided based on differentiation into embryonic germ layers (teratoma), toward extraembryonic elements (choriocarcinoma, yolk sac tumor) or early embryonic elements (embryonal carcinoma) [2]. these classifications are not mutually exclusive: approximately 15% of nsgct also contain seminomatous elements [3]. identification of these elements is critical to determining optimal clinical management. serum tumor markers (stms) can help to identify the presence of gct, as well as the presence of particular components. conventionally, 3 stms have been used to monitor gct: lactate dehydrogenase (ldh), α-fetoprotein (afp), and β-human chorionic gonadotropin (β-hcg). stms are particularly useful in nsgct, 60% to 85% of which secrete detectable stms (table 1). however, these markers are less helpful in seminoma, in which only 10% to key words competing interests article information testis cancer, germ cell tumor, microrna, teratoma, serum biomarker, serum tumor markers none declared. received on june 26, 2020 accepted on august 15, 2020 soc int urol j. 2020;1(1):77–84 http://www.siuj.org mailto:aditya.bagrodia%40utsouthwestern.edu?subject=siuj 78 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation 15% of cases have elevated markers, and afp is absent by definition [4]. further, markers often are normal in the case of early recurrence or low tumor burden, and non-specific processes may cause them to be elevated. despite these limitations, stms have proven integral in the diagnosis and monitoring of gcts. this is evidenced by the current staging system including an s-stage classification, indicating the presence of these markers [5]. although current markers play a critical role in the management of gcts, there are numerous scenarios where they fail to provide adequate information. perhaps most glaringly, 10% to 50% of men presenting with clinical stage i disease (any t, n0m0s0) with normal stms post-orchiectomy will harbor occult disease [6]. up to 30% of patients with clinical stage ii disease (t any n1m0s0-1) will ultimately be found to have pathologic n0 disease [7]. there is currently no way to identify these patients at point of care. in this review, we discuss currently used conventional stms in the context of gct diagnosis and management. we also examine the next generation of gct markers, particularly circulating micrornas (mirnas, mir), which hold promise to fill the critical gaps left by currently conventional stms [6]. conventional serum tumor markers lactate dehydrogenase lactate dehydrogenase (ldh) is a ubiquitously expressed enzyme in all cells that reversibly converts lactate to pyruvate [8]. circulating ldh levels are associated with high cell turnover, and the level may be elevated in non-gct malignancies, including lymphoma and renal cell carcinoma. elevated ldh has also been reported in the case of cell lysis or injury, such as rheumatologic disorders, myocardial infarction, and other muscular disease [8]. therefore, ldh is the least gct-specific of the 3 conventional stms. this problem is exacerbated by the fact that the enzymatic activity assay used to detect ldh varies considerably across laboratories. in part because of this variation, the precise half-life of ldh is unknown, but it is on the order of days, not hours [9]. despite low specificity, ldh has relatively high sensitivity compared with other stms: it is elevated in 40% to 60% of gcts and may be the only positive marker in the case of seminoma, where as few as 30% of patients will have ldh elevation [8]. α-fetoprotein afp is composed of an α-globulin molecule and carbohydrate moiety [9]. afp is normally produced by the fetal yolk sac and liver, and therefore post-pubertal serum levels are generally low (<12 ng/ml) [9,10]. a chemiluminescent sandwich enzyme assay is typically used to detect it, which may have different upper limits of normal parameters across laboratories [9]. the halflife of afp is estimated at 5 to 7 days [8]. afp is produced in most yolk sac tumors and can also be detected in some patients with embryonal carcinoma or teratoma elements. composition of the teratomatous element may play a role in afp levels; in pure teratoma specimens, afp may be produced by gastrointestinal or hepatic elements in the tumor [9]. afp level is related to clinical stage in nsgct, with patients with stage i disease showing afp elevation in 10% to 20% of cases before orchiectomy, and patients with metastatic disease showing elevation in 40% to 60% of cases [8]. elevated afp levels preclude a diagnosis of seminoma by definition [8]. even if pathologic examination of the orchiectomy specimen reveals seminoma exclusively, very high levels of afp indicate the presence also of an element of nsgct. in exceptional cases afp may be elevated in patients with seminoma with hepatic metastases when liver regeneration is occurring [11]. minimal or non-specific afp elevations must be considered with caution when attempting to classify such cases. several reports exist of marginal afp elevation (generally < 20 ng/ml) in cases of pure seminoma [12]. false positive afp levels are often associated with certain liver conditions, including chronic liver disease, hereditary ataxia telangiectasia, hepatocellular carcinoma, or with a history of gastric or hepatic surgery [13]. other potential scenarios include lung or gastrointestinal cancers, including colon, stomach, and pancreatic cancers [8]. additionally, liver damage due to systemic therapy, alcoholism, or viral infection may lead to erroneously high afp levels [14]. therefore, absent other indications of gct, it is recommended that patients with mildly elevated but stable afp be managed by surveillance [10]. abbreviations afp α-fetoprotein ß-hcg ß-human chorionic gonadotropin gcnis germ cell neoplasia in situ gct germ cell tumor igcccg international germ cell cancer collaborative group ldh lactate dehydrogenase mirna, mirmicrorna nsgct non-seminomatous germ cell tumor rplnd retroperitoneal lymph node dissection stm serum tumor marker http://www.siuj.org 79siuj.org siuj • volume 1, number 1 • october 2020 the past and future of biomarkers in testicular germ cell tumors β-human chorionic gonadotropin hu m a n c hor ion ic gon a dot ropi n ( hc g) i s a heterodimeric glycoprotein, composed of an αand a β-subunit. generally, both the α-β heterodimer and the free β-subunit are measured and combined into total hcg, referred to as β-hcg [9]. β-hcg is generally measured with a double antibody immunometric assay, with normal levels determined as < 2 iu/l [8]. elevated β-hcg is found in both seminoma and nsgct and is the most commonly elevated stm in adult gct patients. approximately 15% to 20% of seminoma cases will have elevated β-hcg due to the presence of syncytiotrophoblast cells [8]. although elevated β-hcg levels are associated with tumor bulk, there is no known association between β-hcg levels and risk of metastasis following orchiectomy in patients with stage i disease. β-hcg is also not incorporated into international germ cell cancer collaborative group (igcccg) risk stratification for patients with pure seminoma [5]. approx imately 10% to 20% of patients w it h stage i nsgct w i l l have elevations in β-hcg before orchiectomy [8]. up to 40% of patients with disseminated disease will display elevated β-hcg levels. however, β-hcg is detectable in a subtype-specific manner; although β-hcg can be present in patients with embryonal carcinoma, β-hcg levels are greatest in patients with significant portions of choriocarcinoma. in contrast to seminoma, the igcccg risk stratification criteria include β-hcg as an important prognostic factor for nsgct [5]. although β-hcg is the most frequently elevated stm in gct, its specif icity remains a concern. hypogonadism is a particular confounding factor, as it can occur following orchiectomy [8]. hypogonadism leads to a compensatory increase in hcg from the pituitar y gland. additionally, hy pogonadism can cause an increase in levels of luteinizing hormone (lh), which has an identical αsubunit and similar β-subunit to hcg. this can lead to a cross-reaction in the β-hcg assay and erroneous results, although most β-hcg assays no longer cross-react with lh. additional potentially confounding factors include marijuana use, tumor lysis pursuant to chemotherapy, and the presence of heterophile antibodies [15,16]. other cancer types, including lymphoma, leukemia, and neuroendocrine tumors, are also known to produce detectable β-hcg, but generally not to the high levels that can occur in some patients with gcts (>10 000 iu/l) [15]. serum micrornas as biomarkers in testicular gcts conventional stms play an essential role in the diagnosis and monitoring of patients with gcts. however, as outlined above, they are hampered in part by histological considerations and limited performance characteristics [6]. gct-specific serum micrornas (mirna, mir-) [17–20] have emerged over the past decade as highly accurate tools for monitoring gct patients, outperforming conventional stms [9,21]. the measurement of these mirnas may significantly change the way that gct patients are diagnosed and treated. micror nas are short, non-coding r nas that control gene expression in a target-specific manner [6]. although longer rna strands are notorious for being very labile, mirna are remarkably stable, and have been proposed as markers in other cancer types [22,23]. in 2006, voorhoeve et al. described overexpression of mir-372 and -373 in gct tissues and cell lines, and table 1. histology-specific serum afp and β-hcg levels [9] histologic subtype afp β-hcg seminoma – ± embryonal carcinoma ± ± choriocarcinoma – ++ yolk sac tumor ++ – teratoma ± – ++: strongly positive levels; – : negative levels; ± : marker may be negative or moderately positive. adapted from murray mj, huddart ra, coleman n.[9] with permission of springer nature. http://www.siuj.org 80 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation hypothesized that these mirnas acted as oncogenes by inhibition of p53 signaling via lats2 suppression [24]. a body of work following this study has since demonstrated overexpression of 8 mirnas in malignant gct tissues, all from the mir-371~373 and mir-302/367 clusters [25,26]. this expression pattern was absent in teratoma, but otherwise occurred regardless of histology, site of origin, or sex or age of the patient. critically, these results were the first to demonstrate a universal molecular abnormality of this disease. in the next seminal study in this arena, murray and colleagues demonstrated that through the use of a highly sensitive qpcr-based assay, including a pre-amplification step, these malignant gct-specific mirnas were elevated in the serum of a gct patient compared with a pool of normal controls [27]. the levels were also found to be informative of treatment response and disease status on follow-up. these results triggered an avalanche of investigations concerning the performance and potentia l inclusion of the serum mirna test in routine clinical diagnosis and management for patients with gcts. screening there are few data available to assess whether gctassociated mirnas are useful in screening for the development of invasive gct. however, there may be some utility of serum mirnas in the case of screening at-risk patients for the presence of germ cell neoplasia in situ (gcnis), the presumed precursor lesion of postpubertal gcts. novotny et al. reported overexpression of gct-associated mirnas in gcnis tissue compared with normal adult testis controls [28]. an initial study suggested that serum mirnas do not detect gcnis, but a subsequent study indicated that up to 50% of patients with gcnis lacking frank gct have elevated serum mirnas [29,30]. importantly, these studies were conducted in a small number of patients and further validation is required in this setting. pre-orchiectomy a solid testicular mass detected by physical examination or sonography is initially considered a malignancy. these techniques can overlook non-malignant causes of a testicular mass, and therefore stms may play an important role here. conventional stms may not be informative in this context, particularly in seminoma, where only 10% to 15% of cases show elevated markers [4]. the superior sensitivity of circulating mirnas over conventional stms could therefore be valuable in the pre-orchiectomy setting. this setting is where the utility of circulating mirnas has so far been best described (table 2). in 2013, gillis et al. examined serum mirna expression in 80 gct patients, in non-cancer controls, and in patients with non-gct testicular masses [31]. using magnetic bead purification but no pre-amplification step, this study identified that a 4-member panel (mir-371a-3p, mir372-3p, mir-373-3p and mir-367-3p) outperformed a full panel that included mir-302a~d from the mir302/367 cluster, refining the necessary targets for an informative test. the test performance was acceptable, with 98% sensitivity and 48.3% specificity, although without the pre-amplification step [28], specificity was necessarily low in order to retain high sensitivity. the test was negative for non-gct testicular masses and returned to normal in post-orchiectomy stage i gct patients. this revised 4-member panel would set the basis for future studies. these results were confirmed in an expanded cohort by van agthoven and looijenga in 2017 [29]. magnetic bead purification was used in combination with the standard pre-amplification step to examine a 3-member panel lacking mir-372-3p in 250 gct patients, 60 non-gct patients, and 104 healthy male controls. performance improved as expected, with a 90% sensitivity and 91% specificity in the combined panel. importantly, this study aligned with previous and subsequent reports that serum mirna does not detect pure teratoma [32–34]. more recently, attempts have been made to reduce the 4-member panel further, while maintaining sensitivity. in 2017, dieckmann et al. compared the performance of circulating mir-371a-3p to the full 4-member panel, using a column-based extraction and standard pre-amplification. this study reported comparable performance between mir-371a-3p alone and the full panel (92% sensitivity, 85% specificity) [34]. following this report, dieckmann et al. used the same method to examine mir-371a-3p exclusively in 616 gct patients and 258 controls, the largest cohort yet [35]. this study reported 90% sensitivity and 94% specificity in viable gct, a return to normal levels following orchiectomy in the majority of stage i patients, and no detectable circulating mir-371a-3p in pure teratoma. no long-term follow-up data were available to determine the clinical significance of persistently elevated serum mir-371a3p levels post-orchiectomy in clinical stage i patients, which is an outcome measure in current clinical trials (see below) [20]. the refinement of target selection and methods in the context of pre-orchiectomy has resulted in a mirnabased test that significantly outperforms conventional stms. although these methods have begun to converge to a single standard of normalization and quantification, further work is required. these refined methods are now being used in other scenarios, some examples of which follow. http://www.siuj.org 81siuj.org siuj • volume 1, number 1 • october 2020 the past and future of biomarkers in testicular germ cell tumors identification of occult metastases in patients with early stage i/stage i disease from 10% to 50% of patients with clinical stage i viable gct, normal conventional stms, and no radiographic evidence of metastasis will ultimately relapse [6]. it is extremely challenging to identify which of these patients harbor occult disease, as diagnostic tools are limited. further, 85% to 90% of stage ia nsgct patients will be cured by orchiectomy alone; surveillance is preferred in these patients to prevent overtreatment, but the potential for metastases currently cannot easily be ruled out [36]. patients with occult disease would be better served if they were to receive a single cycle of bep or primary retroperitoneal lymph node dissection (rplnd), as both are associated with excellent outcomes [37]. additionally, early identification of occult metastatic seminoma could permit earlier, less intensive treatment. circulating mirna levels are associated with tumor mass, raising potential concerns about whether they reach detectable levels in the case of radiographically occult metastases [34]. recent studies provide evidence that circulating mirna levels are detectable even when current identification strategies fail. nappi et al. reported that mir-371a-3p levels in plasma accurately predicted relapse in all cases in their small cohort [38]. lafin et al. demonstrated that serum mir-371a-3p accurately detected minimal residual pathologically confirmed viable gct at primary rplnd [39]. in this 24-patient cohort with normal conventional stms, mir371a-3p showed a 100% sensitivity and 92% specificity, demonstrating the value of circulating mirnas in this setting. these studies and others suggest that circulating mirnas may help avoid overtreatment of the 20% to 30% of stage iia, marker negative patients that are ultimately devoid of occult disease on histology [7,40]. additionally, because low circulating mirna levels immediately before chemotherapy are associated with complete response, this tool may in the future aid clinicians deciding between obser vation and further treatment [36]. similarly, this principle might be extended to patients who have received primary rplnd and who are being considered for surveillance or adjuvant chemotherapy. response to treatment in patients with disseminated disease the utility of circulating mirnas in the context of chemotherapy is an area of active study. dieckmann et al. found in patients with stage ii/iii gct that serum mirna levels both tracked treatment response during chemotherapy and, in 2 cases, suggested resistance [35]. seventy out of 118 patients with systemic disease exhibited a decrease in serum mir-371a-3p levels after the first cycle of chemotherapy. as a group, stage ii patients exhibited no further statistically significant reduction after the first cycle, while stage iii patients ex hibited no further reduction af ter the second cycle. the 2 patients in this cohort who experienced disease progression and ultimately died showed rising circulating mir-371a-3p levels. mego et al. examined plasma mirna levels in 180 patients with metastatic gct treated with systemic therapy and found that mirna levels were associated with igcccg risk group and response [41]. patients with primary metastatic or relapsed gct will receive induction chemotherapy, and those without radiographically complete response will receive a postchemotherapy rplnd [41]. this surgery is currently the only accurate method to determine if residual masses harbor teratoma or viable gct. it is also the only way table 2. performance characteristics of serum pre-orchiectomy gct-associated mirnas for prediction of gct on final orchiectomy histopathology. reference sensitivity, % specificity, % ppv, % npv, % auc gillis et al. [27] 98 48.3 nr np 0.96 van agthoven and looijenga [26] 90 91 94 7 0.962 dieckmann et al. [31] 90.1 94 97.2 82.7 0.966 auc: area under the curve; gct: germ cell tumor; npv: negative predictive value; ppv: positive predictive value. http://www.siuj.org 82 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation to treat teratoma and can contribute to therapeutic management in patients with chemo-resistant viable gct [42,43]. however, approximately 50% of patients receiving this operation will harbor only fibrosis/ necrosis, meaning 50% of the patients who undergo this operation will have done so unnecessarily. leão et al. examined circulating mirna at post-chemotherapy rplnd and found that mir-371a-3p exhibited the best performance to detect residual viable gct, but did not find any discriminatory capacity for the presence of pure teratoma [44]. a recent report from tcga expression data suggested that teratoma and yolk sac tumor tissue express high levels of mir-375 [45]; however, lafin et al. did not find any discriminatory capacity of this circulating mirna in 3 teratoma-only patients at rplnd [39]. additional studies have confirmed these negative results in larger cohorts [42,43]. surveillance circulating mirnas represent a powerful tool capable of changing the way gct patients are monitored. because this assay cannot detect pure teratoma, the likelihood of teratoma formation must always be kept in mind. the development of teratoma is an extremely rare occurrence in patients with pure seminoma, and in this arena, circulating mirnas may in future supplant axial imaging and conventional stms. for patients with nsgct, teratoma formation must remain a consideration and warrants ongoing infrequent axial imaging. in this setting, circulating mirnas may offer a complementary test, permitting a reduction in the number of axial scans required for surveillance [6]. conclusions conventional stms play a critical role in the current diagnosis, treatment, and monitoring of patients with gct. unfortunately, their performance is limited in many situations by false positives and low sensitivity. this limitation extends from diagnosis, through treatment and into surveillance, impacting decisionmaking across the spectrum of patient care. the promise of circulating mirnas as an addition to these markers is supported by a growing body of literature [17–20, 27,29,35]. inclusion of circulating mirnas alongside conventional stms could aid in identification of false positives, such as in a case report describing elevated afp levels pursuant to liver regeneration [12]. two large clinical trials (agct1531 [nct03067181] and swog-s1823) are further studying the role of mirna in patients with gcts. despite generally excellent performance of circulating mirnas, limitations remain. first, a standard method of collection, normalization, and quantification must be devised to reduce variation across laboratories and enable large-scale validation. second, identification of pure teratoma by circulating biomarkers remains an elusive target. differentiation of pure teratoma from viable gct is an unmet clinical need; recommendation of surgery or chemotherapy will often depend on segregating the two. despite t hese modest limitations, circu lating mirnas have the potential to change the way that gct cases are managed, aiding clinicians in decision-making to provide greater benefit to their patients. references 1. siegel rl, miller kd, jemal a. cancer statistics, 2016. ca cancer j clin. 2016;66(1):7-30. doi: 10.3322/caac.21332 2. woldu sl , a matruda jf, b agrodia a . testicular ger m cell tumor genomics. curr opin urol. 2017;27(1):41-7. doi: 10.1097/ mou.0000000000000347 3. woodward pj, looijenga lhj, oosterhuis j w, mcleod dg. pathology and genetics of tumors of the urinary system and male genital organs. lyon 2004. 4. barlow lj, badalato gm, mckiernan jm. serum tumor markers in the evaluation of male germ cell tumors. nat rev urol. 2010;7(11):610-7. doi: 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micrornas mir-371-3 in serum as diagnostic tools in the management of testicular germ cell tumours. br j cancer. 2012;107:1754. doi: 10.1038/bjc.2012.469 33. murray mj, bell e, raby kl, et al. a pipeline to quantify serum and cerebrospinal fluid micrornas for diagnosis and detection of relapse in paediatric malignant germ-cell tumours. br j cancer. 2016;114(2):151-62. doi: 10.1038/bjc.2015.429 34. dieckmann kp, radtke a, spiekermann m, et al. serum levels of microrna mir-371a-3p: a sensitive and specific new biomarker for germ cell tumours. eur urol. 2017;71(2):213-20. doi: 10.1016/j. eururo.2016.07.029 35. dieckmann kp, radtke a, geczi l, et al. serum levels of microrna371a-3p (m371 test) as a new biomarker of testicular germ cell tumors: results of a prospective multicentric study. j clin oncol. 2019;37(16):1412-23. doi: 10.1200/jco.18.01480 36. nayan m, jewett ma, hosni a, et al. conditional risk of relapse in sur veillance for clinical stage i testicular cancer. eur urol. 2017;71(1):120-7. doi: 10.1016/j.eururo.2016.07.013 37. huddart ra, reid am. adjuvant therapy for stage ib germ cell tumors: one versus two cycles of bep. adv urol. 2018;2018:8781698. doi: 10.1155/2018/8781698 38. nappi l, thi m, lum a, et al. developing a highly specific biomarker for germ cell malignancies: plasma mir371 expression across the germ cell malignancy spectrum. j clin oncol. 2019;37(33):3090-8. doi: 10.1200/jco.18.02057 39. lafin jt, singla n, woldu sl, et al. serum microrna-371a-3p levels predict viable germ cell tumor in chemotherapy-naïve patients undergoing retroperitoneal lymph node dissection. eur urol. 2020;77(2):290-2. doi: 10.1016/j.eururo.2019.10.005 http://www.siuj.org 84 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation 40. rosas plaza x, van agthoven t, meijer c, et al. mir-371a-3p, mir-373-3p and mir-367-3p as serum biomarkers in metastatic testicular germ cell cancers before, during and after chemotherapy. cells. 2019;8(10). doi: 10.3390/cells8101221 41. mego m, van agthoven t, gronesova p, et al. clinical utilit y of plasma mir-371a-3p in germ cell tumors. j cell mol med. 2019;23(2):1128-36. doi: 10.1111/jcmm.14013 42. leão r, nayan m, punjani n, et al. a new model to predict benign histology in residual retroperitoneal masses after chemotherapy in nonseminoma. eur urol focus. 2018;4(6):995-1001. doi: 10.1016/j. euf.2018.01.015 43. woldu sl, moore ja, ci b, et al. practice patterns and impact of postchemotherapy retroperitoneal lymph node dissection on testicular cancer outcomes. eur urol oncol. 2018;1(3):242-51. doi: 10.1016/j.euo.2018.04.005 44. leão r, van agthoven t, figueiredo a, et al. serum mirna predicts viable disease af ter chemotherapy in patients with testicular nonseminoma germ cell tumor. j urol. 2018;200(1):126-35. doi: 10.1016/j.juro.2018.02.068 45. shen h, shih j, holler n dp, e t al. in t e gr at e d mole cular char ac terization of tes ticular ger m cell tumor s. cell rep. 2018;23(11):3392-406. doi: 10.1016/j.celrep.2018.05.039 http://www.siuj.org this is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 the authors. société internationale d'urologie journal, published by the société internationale d'urologie, canada. can incomplete metastasectomy impact renal cell carcinoma outcomes? a propensity score matching analysis from a prospective multicenter collaboration alice dragomir,*1 charles hesswani,*1 gautier marcq,1 alan i. so,2 christian kollmannsberger,2 naveen s. basappa,3 adrian fairey,3 anil kapoor,4 aly-khan a. lalani,4 antonio finelli,5 lori a. wood,6 daniel y.c. heng,7 georg bjarnason,8 rodney h. breau,9 luke t. lavallée,9 denis soulières,10 darrel drachenberg,11 frédéric pouliot,12 simon tanguay 1 *co-first authors 1 mcgill university, montreal, canada 2 department of urologic sciences, university of british columbia, vancouver, canada 3 cross cancer institute, university of alberta, edmonton, canada 4 juravinski cancer centre, mcmaster university, hamilton, canada 5 princess margaret cancer centre, university of toronto, toronto, canada 6 queen elizabeth ii health sciences centre, halifax, canada 7 tom baker cancer centre, university of calgary, calgary, canada 8 odette cancer centre, sunnybrook health sciences centre, toronto, canada 9 ottawa hospital cancer center, ottawa, canada 10 centre hospitalier de l’université de montréal, montreal, canada 11 university of manitoba, winnipeg, canada 12 centre hospitalier universitaire de québec, université laval, quebec, canada abstract objectives to evaluate the role of incomplete metastasectomy (im) for patients with metastatic renal cell carcinoma (mrcc) on overall survival (os) and time to introduction of first-line systemic therapy. methods patients diagnosed with mrcc between january 2011 and april 2019 in 16 centers were selected from the canadian kidney cancer information system database. we included mrcc patients who had prior nephrectomy and had received an im (resection of at least 1 metastasis) or no metastasectomy (nm). a propensity score matching was performed to minimize selection bias. cox proportional hazards analysis was used to assess the impact of the metastasectomy while adjusting for potential confounders. os was assessed by kaplan-meier analysis. results a total of 138 patients with mrcc underwent im, while 1221 patients did not. on multivariate analysis, im did not improve os (hazard ratio [hr] 0.96, 95% ci 0.63 to 1.45, p = 0.836) however, subgroup analyses revealed im improved os compared with nm when lungs were the only site involved (median time to os not reached versus 66 months, respectively; p = 0.014). additionally, lung metastasectomy delayed the systemic therapy compared with nm (median 41 and 13 months, respectively, p = 0.014). im of endocrine organs (thyroid, pancreas, adrenals) or bone metastases did not impact os. conclusion the role of im for mrcc is limited. incomplete resection of lung metastases was associated with improved os and delayed time to introduction of systemic therapy when lungs were the sole location of metastatic disease. despite case-matching, unknown unadjusted confounders may explain the relationship between im and survival in this analysis. key words competing interests article information kidney neoplasms, incomplete metastasectomy, neoplasm metastasis, clear-cell metastatic renal cell carcinoma, systemic therapy none declared. received on september 27, 2020 accepted on january 2, 2021 soc int urol j. 2021;2(2):82–95 doi: https://doi.10.48083/ wqfr32352 correction: this article was amended on march 19, 2021, to correct errors in author names. 82 siuj • volume 2, number 2 • march 2021 siuj.org original research mailto:simon.tanguay%40mcgill.ca?subject=siuj https://doi.10.48083/wqfr32352 http://www.siuj.org introduction in 2020, kidney cancer was estimated to be the sixth most common neoplasm in canadian men and the eighth most common in canadian women[1]. renal cell carcinoma (rcc) is metastatic at diagnosis in 15% of cases, and metastasis will occur after diagnosis in up to 30% of patients[2]. despite the advent of systemic therapies and immunotherapies, drug resistance remains a major therapeutic challenge in treating metastatic rcc. since current systemic therapy does not offer complete response in most patients with metastatic disease, surgical resection of metastases can be used to improve survival. most studies have compared complete metastasectomy (cm) w it h incomplete or no metastasectomy, and demonstrated a significant improvement in overall survival (os) [3,4]. a recent systematic review pooling 8 studies and 2267 patients demonstrated an improved os in patients undergoing cm when compared with those who had incomplete metastasectomy (im) or no metastasectomy (nm) (os 36.5 to 142 months for cm and 8.5 to 27 months for im/nm)[5]. similarly, a recent single institution retrospective cohort study comparing patients undergoing cm with those who had im/nm demonstrated a significantly improved os (at 2 years 81% versus 53%, p < 0.001)[6]. few studies have compared the outcomes of im patients with those of nm patients. the few available studies have been discorda nt a nd/or published before the era of tyrosine k inase inhibitors and immunotherapy[7–9]. all were single-center studies with limited power to allow extrapolation and clear recommendations for daily practice. multicenter studies comparing im with nm are lacking. the present study was conducted to assess os and time to first-line systemic therapy of im in patients with metastatic rcc (mrcc) when compared to patients who did not receive metastasectomy in a large prospective multicenter database using propensity score matching. methods patient demographics and clinical and pathological data were collected from the canadian kidney cancer information system (ckcis) database, a prospective multicenter collaboration of 16 institutions in 6 canadian provinces. baseline information was obtained from patient surveys and the medical record and included age, sex, date of rcc and mrcc diagnosis, date of nephrectomy, comorbidities, and the location and number of metastases. cm was defined as surgical resection of all visible metastases, while im was defined as resection of some, but not all, of the radiographically visible metastases. im was performed without curative intent. if this information was missing, the no evidence of disease status of the patient post-metastasectomy was used to classify patients between the im and the cm groups. complete versus incomplete resection was specified by patient’s medical records. if the patient underwent subsequent metastasectomy at different dates, the cm versus im status was defined on the first metastasectomy. the indication for the metastasectomy and the reason for incomplete surgical resection were not available. research ethics board approval was obtained at each individual participating center. medical records of patients diagnosed with mrcc who underwent radical or partial nephrectomy between january 2011 and april 2019 were reviewed. patients receiving a cm were excluded and were reported separately[10]. histopathological evaluation of the nephrectomy specimen was used to diagnose rcc. the date of diagnosis of a first metastasis confirmed by imaging was labeled as the index date. the analysis ranged from the index date to the end of follow-up, defined as the earliest date between the last patient visit, the date of death, or the end of study period (april 31, 2019). clinical characteristics including sex, age, number and location of metastases, metastasectomy sites, pathological stage, clear cell histology, synchronicity, comorbid it ies (d iabetes mel litus, hy per tension, dyslipidemia, cardiovascular disease, smoking status, and obesit y), charlson comorbidit y index score (excluding the solid tumors) and time from rcc diagnosis until metastasis were identified at the index date. “endocrine” metastasis was defined as a metastasis at one of the following sites: adrenal glands, pancreas, and thyroid. the use of systemic therapy and radiation therapy was assessed at the index date and during follow-up. a propensity score method was used to determinate the predicted probability of receiving an im based on clinical characteristics evaluated at index date including age (< 65 years versus ≥ 65), sites and number of metastasis (1 versus ≥ 2), synchronous disease abbreviations cm complete metastasectomy hr hazard ratio im incomplete metastasectomy iqr interquartile range mrcc metastatic renal cell carcinoma nm no metastasectomy os overall survival rcc renal cell carcinoma 83siuj.org siuj • volume 2, number 2 • march 2021 can incomplete metastasectomy impact renal cell carcinoma outcomes? http://www.siuj.org (yes versus no) and clear cell histology (yes versus no). for each patient, a propensity score and its quintiles were obtained. in order to reduce selection bias, patients receiving im were matched with patients who had not received a metastasectomy. up to 4 patients were randomly selected for each patient with im. the date of im or the date of selection was defined as the matching date. the matching was performed for (1) the propensity score quintiles (ie, probability of receiving an im), (2) the status of the systemic treatment at the time of matching (yes versus no), (3) time between the first metastasis and the rcc diagnosis (< 3 months, 3 months to < 6 months, 6 months to < 1 year, 1 year to < 2 years, and ≥ 2 years), and (4) an equivalent duration of follow-up between index date and the matching date. clinical and demographic characteristics between im group and nm group were performed using t test for continuous variables and chi-square test for categorical variables. individual propensity scores of im were obtained using a multivariate logistic regression model based on variables enumerated in the section above. overall survival was calculated from matching date to death from any cause. kaplan-meier curve analysis was performed to estimate os since matching date in the matched cohort, with log-rank test to compare the im and nm groups. similarly, the time to introduction of systemic therapy during follow-up was assessed in im and nm groups. the cox proportional hazards regression model was used in the matched cohort to evaluate the association between im and overall survival by adjusting for different covariables that were not used for matching. these included sex, age 65 and older (yes versus no), sites and number of sites of metastasis and clear cell carcinoma versus other histology. the use of systemic treatment and the use of radiation therapy were also included as time-dependent factors. a second cox model was performed by adding an additional factor, the charlson comorbidity index (0 or 1 versus > 1). to assess differences between im and nm by metastatic sites we performed several stratified analyses. kaplan-meier curve analyses were performed (1) to estimate os since matching date and (2) to estimate time to introduction of systemic therapy during follow-up, in the matched cohort, with log-rank test to compare the im and nm groups by metastatic site (lung, lymph nodes, bones, and endocrine). patients with brain and liver metastasis were included in the multiple sites analysis but were not considered from the individual sites analyses because of the low number of patients in these groups. finally, kaplan-meier curve was performed to assess the os among patients receiving im by metastasectomy sites. all statistical tests were 2-sided, with a p < 0.05 considered significant. all analyses were performed using sass (version 9; sas institute, cary, north carolina). results during the study period, the ckcis cohort included 8936 patients diagnosed with rcc (figure 1); 6223 patients did not develop metastasis and were therefore excluded from the analysis. patients without prior nephrectomy (336 patients) or who had received a cm (266 patients) were also excluded from the cohort. our final cohort consisted of 1367 patients: 146 of these patients underwent an im, and 1221 patients did not undergo any form of metastasectomy (figure 1). t he demog r aph ic s a nd c l i n ic opat holog ic a l characteristics of the cohort before propensity score matching were summarized in supplementary table s1. one hundred thirty-eight patients who underwent an im were matched with 522 patients with nm based on usage of systemic therapy before selection or date of im, delay between primary tumor diagnosis and first metastasis, and propensity score quintiles (table  1). 8,936 patients with con�rmed rcc histology 6,223 did not have metastatic disease 2,713 rcc patients with a diagnosis of metastasis 760 patients diagnosed before jan 1, 2011 1,953 prospective mrcc 417 patients had a metastasectomy 151 incomplete metastasectomy 266 complete metastasectomy study cohort: 1,367 patients having had prior nephrectomy 146 patients with incomplete metastasectomy 1,221 patients with no metastasectomy 1,536 mrcc patients did not undergo metastasectomy figure 1: flowchart diagram. rcc: renal cell carcinoma. mrcc: metastatic renal cell carcinoma figure 1. flowchart 84 siuj • volume 2, number 2 • march 2021 siuj.org original research http://www.siuj.org table 1. patient demographics, matched cohort incomplete metastasectomy no metastasectomy (matched with incomplete) p value no. patients 138 522 median age at diagnosis (iqr) 63.5 (56–69) 65 (57–72) 0.1496 a over 65 years old at mrcc diagnosis,% 43.5 51.2 0.109 male, % 79.0 73.6 0.193 female, % 21.0 26.4 median follow-up, months (iqr) 26 (16–54) 26 (12–42) 0.058 a time between primary tumor to metastasis, median (iqr) (months) 14.9 (0–60) 14.3 (1–48) 0.376 a over 1 year from primary tumor to metastasis, % 59.2 52.9 0.981 time between the index dateb and the time of matchingc date, median (iqr) (months) propensity score quintiles first 72.5 74.1 0.558second 24.6 24.3 third 2.9 1.5 pathological t-stage at diagnosis, % t1 25.4 31.7 0.002 t2 16.7 15.5 t3 45.7 48.9 t4 5.8 2.5 tx 6.5 1.4 clear cell rcc (yes vs no), % 84.8 82.8 0.579 synchronous metastasis (yes vs no), % 39.9 40.2 0.936 metachronous metastasis (yes vs no), % 60.1 59.8 had a nephrectomy (yes vs no), % 100 100 – number of organ sites with metastasis 1 71.0 82.4 0.003 ≥ 2 29.0 17.6 first-line systemic treatment prior to matching datec (%) 16.7 15.7 0.784 a wilcoxon two-sample test for medians. b index date: the date of the first metastasis. c matching date: the date of incomplete metastasectomy or the date of selection. d patients with multiple locations were counted in all specific locations. e fisher exact text. continued on page 86 85siuj.org siuj • volume 2, number 2 • march 2021 can incomplete metastasectomy impact renal cell carcinoma outcomes? http://www.siuj.org all the variables used in the matching were balanced after matching the im group and their respective nm patients. after matching, several other features remained or were balanced between the 2 groups, such as age over 65 years, sex, more than 1 year from primary tumor diagnosis and usage of systemic therapy during follow-up (table  1). a significant difference persisted among the pathological stages at diagnosis between each group. the im group had a higher percentage of pt2, pt4 and ptx, while the nm group had increased pt1 and pt3 disease (p = 0.002). more patients received radiation treatment in the im group than in the nm group (56.0 versus 42%, p = 0.036). the number of organs involved by metastasis was also significantly different. in the im group, 71% of patients had a single organ with metastases compared with 82.4% of patients in the nm group (p =  0.003). more patients in the im group had hypertension (p < 0.001), diabetes mellitus (p< 0.001), dyslipidemia (p = 0.031), and history of smoking (p < 0.001). one-third (33.3%) of patients in the im had a charlson comorbidity index score over 1 compared with 50.7% of patients in the nm group (p = 0.004) (table 1). the median os was similar between the im group and their matched nm group (58 months iqr 22 to “not reached” [nr]) versus 47 months iqr (18 to nr); p = 0.878), respectively (figure 2a). at 12 months, 81.2% table 1. patient demographics, matched cohort incomplete metastasectomy no metastasectomy (matched with incomplete) p value sites of metastasis,d % lung 41.3 44.6 0.483 bones 26.8 26.6 0.965 liver 8.7 6.1 0.283 brain 5.1 2.3 0.083 endocrine 15.9 0.04 systemic treatment during follow-up, % first-line (ref: yes) 71.1 63.4 0.068 second-line (ref: yes) 33.0 31.7 0.763 radiation treatment at index date and during follow-up (ref: yes), % 56.0 42.0 0.004 comorbidities, % hypertension (ref: yes) 55.1 35.6 <0.0001 diabetes (ref: yes) 29.0 13.4 <0.0001 hypercholesterolemia (ref: yes) 23.9 13.6 0.003 coronary artery disease 8.0 9.0 0.703 cardiovascular disease 11.6 8.1 0.190 smoker (ref: yes) 4.4 0 <0.0001e obesity (ref: yes) 3.6 3.3 0.831e charlson score index, % (n = 624) 0 or 1 66.7 49.3 0.0004 more than 1 33.3 50.7 a wilcoxon two-sample test for medians. b index date: the date of the first metastasis. c matching date: the date of incomplete metastasectomy or the date of selection. d patients with multiple locations were counted in all specific locations. e fisher exact text. , cont’d 86 siuj • volume 2, number 2 • march 2021 siuj.org original research http://www.siuj.org of patients were still alive in the im group, and 86.2% in its matched nm group. the 5-year os was 48.7% versus 42.5%, respectively (figure 2a). regarding the time to introduction of systemic therapy, no significant difference was observed between the im and the nm group (p = 0.327) (figure 2b). the multivariate analysis revealed that performing an im was not associated with a survival advantage compared with nm (hazard ratio [hr] 0.96, 95% ci 0.63 to 1.45, p  =  0.836) (table 2). clear cell histology was not found to be an independent factor associated with a decreased risk of mortality compared with other histology (hr 0.63, 95% ci 0.38 to 1.041, p  =  0.071). when including the charlson comorbidity index in the multivariate analysis, the risk of mortality related to an im remained similar (hr 1.05, 95% ci 0.0.69 to 0.1.60) (data not shown). having a charlson comorbidity score of 0 or 1 versus more than 1, was not associated with a reduced risk of death (hr 0.89, 95%ci 0.56 to 1.41). stratified analyses by site of metastasis revealed that im in patients with only lung metastases, led to improved os (median os not reached versus 66 months in the nm group) (2-year os 82% versus 68%, 5-year os 82% versus 50%, respectively) (p  =  0.026) (figure  3a). im of bone or endocrine lesions did not show a significant difference in survival compared with nm (p = 0.849 and p = 0.388, respectively), while im of lymph nodes showed a decreased os compared with nm (median os 14 months versus nr) (2-year os 44.4% versus 73.8%) (figure 3a). im of liver and brain lesions was not assessed because of the low number of events at these sites. furthermore, analysis performed for the time to systemic treatment initiation revealed that only im in patients with lung metastasis resulted in a delayed initiation of systemic therapy (median of 41 months (95% ci 14 to 57) compared with 13 months (95% ci 7 to 35) in nm patients) (p = 0.026) (figure 3b). no significant difference was found for bone, lymph node or endocrine metastasectomy (p = 0.063, p = 0.149 and p = 0.701, respectively) (figure 3b). while there was no difference in os observed between the im and nm groups all organ sites combined, the os differed among im sites (supplementary figure 1a). among patients with an im, those with lung lesions had better survival (2-year os of 86%; 5-year os of 86%) (median not reached) when compared with patients who had bone, lymph node, and endocrine metastasis (2-year os 62%, 44% and 76.8%; 5-year os 35%, na and 57.6%, respectively) (medians 41 months (iqr 11 to 65), 14 months (iqr 8 to nr), and 61 months (iqr 46 to nr), respectively) (p = 0.004) (supplementary figure 1a). subgroup analysis of im patients with a single organ site involved by metastasis yielded a significant difference between groups (p = 0.003) the im of lung lesions had the higher delay to first-line systemic therapy initiation when compared to bone, lymph node, and endocrine metastasectomy (supplementary figure 1b). the median time to systemic therapy initiation was 39 months (iqr 14 to 57) compared with 5 months (iqr 3 to 19), 8 months (iqr 3 to na), and 15 months (iqr 6 to 57), respectively. discussion the role of im on overall survival in mrcc patients, as part of a multimodal treatment approach, is limited. im continues to be performed, however, mainly for palliative reasons. also, im and stereotactic body radiation therapy are being increasingly used for figure 2.figure 2a. overall survival for patients with im vs nm all organ sites combined (matched cohort) figure 2b. overall survival for patients with im vs nm all organ sites combined (matched cohort) 87siuj.org siuj • volume 2, number 2 • march 2021 can incomplete metastasectomy impact renal cell carcinoma outcomes? http://www.siuj.org oligoprogression. in our cohort, 10.7% of patients underwent an im, a rate comparable to those found in other studies (range 9% to 19%)[7,11–13]. the median age of patients at the time of metastasis is also similar to that in other studies (61 to 65 years old)[14,15]. in addition, our analysis consisted of primarily clear cell histology (84.8%), which is similar to the findings of previous studies (80% to 93.8%)[7,16,17]. after matching, most clinicopathologic characteristics were similar between the 2 groups, with the exception of pathological t-stage, number of organ sites involved by metastasis, and comorbidities. more patients had 2 and more organ sites involved by metastasis in the im than the nm. additionally, patients having undergone im had more comorbidities than nm patients; however, charlson score favored the im group. this finding may reflect the existence of poorly controlled or more severe comorbidities in the nm group, resulting in healthier patients being selected for surgery. however, when adjusting for the charlson comorbidity index, the hr of im versus nm remained the same, and this was not found to be an independent factor associated to the survival in this population. our survival analysis showed that there was no significant difference in os among patients who had undergone im compared with those who had not (p = 0.8). our results are comparable to those of other studies in which im had no os advantage over nm. as stated before, you et al. reported comparable os medians of 29.6 versus 23.5 months ([95% ci 15.4 to 43.8 months], and [95% ci 18.9 to 28.1 months], respectively) for im and nm, respectively[12]. in addition, yu and colleagues also reported in a singlecenter retrospective study of patients undergoing im, table 2. cox regression model incomplete metastasectomy versus no metastasectomy variables univariate hr (95%ci) p value multivariate hr (95%ci) p value n (metastasectomy vs. no metastasectomy) 138 vs. 522 – 138 vs. 522 – had a metastasectomy 1.03 (0.71–1.51) 0.868 0.96 (0.63–1.45) 0.836 male (ref: female) 0.90 (0.62–1.31) 0.580 0.92 (0.62–1.38) 0.686 systemic therapy during follow-up (time-dependent variable) (ref: yes) 0.87 (0.57–1.35) 0.545 0.91 (0.56–1.46) 0.685 age (ref: ≥ 65 years) 1.42 (1.01–2.00) 0.044 1.39 (0.96–2.02) 0.079 clear cell renal cell carcinoma (ref: yes) 0.62 (0.39–0.97) 0.038 0.63 (0.38–1.04) 0.071 bones metastasis (ref: yes) 1.76 (0.88–3.54) 0.110 1.58 (0.67–3.77) 0.299 liver metastasis (ref: yes) 1.18 (0.60–2.32) 0.634 1.59 (0.70–3.62) 0.2699 lung metastasis (ref: yes) 1.12 (0.73–1.71) 0.616 1.52 (0.84–2.73) 0.165 brain metastasis (ref: yes) 0.98 (0.22–4.36) 0.977 0.84 (0.15–4.68) 0.8399 lymph node metastasis (ref: yes) 1.41 (0.75–2.65) 0.281 1.72 (0.86–3.41) 0.0.124 endocrine metastasis (ref: yes) 1.24 (0.61–2.50) 0.554 1.40 (0.66–2.98) 0.381 more than 1 location of tumor (ref: 1 location) 1.22 (0.80–1.84) 0.359 0.79 (0.39–1.60) 0.513 radiation therapy (time-dependent variable) (ref: yes) 1.51 (1.01–2.25) 0.05 1.49 (0.96–2.3) 0.076 ref: reference. 88 siuj • volume 2, number 2 • march 2021 siuj.org original research http://www.siuj.org similar os among im and nm with median os of 16 months versus 22 months (95% ci 9.5 to 22.5 and 17.6 to 26.4, respectively)[7]. in contrast, our recent study using the ckcis database found a significant improvement in os all-sites combined when cm was compared to nm (median os 82 months [95% ci 80 to nr] versus 66 months [95% ci 60 to nr], respectively [p = 0.001])[10]. although no difference in survival was shown among all metastasectomy sites combined, the risk of death among different im sites is not similar. patients with lung and endocrine im experienced longer survival rates than those with bone and lymph node im. however, in our subgroup analyses comparing each site to their matched nm, only lung im was associated with better os. in fact, lung im had a 5-year os of 82% compared with 50.4% without surgical resection. these results are similar to what was previously reported in the literature for cm (range 75% to 83.3%)[18,19]. site-specific survival analyses were not conducted in previous studies evaluating im[7,8,12]. from what is reported in the literature, lymph nodes, both regional and distant, represent 15% of sites of metastatic recurrences of rcc[20]. in our study, survival was worsened in patients with incomplete lymphadenectomy when compared with patients without surgical resection (p  =  0.024). yet this finding should be interpreted with caution, as this analysis is likely underpowered to assess the role of im on lymph node metastasis since only 9 patients received an incomplete resection of lymph nodes, and no multivariate analysis was possible. additionally, lymphadenectomy is often done in conjunction with organ metastasectomy. our study confirmed that there is no benefit for os when single or multiple metastatic sites are incompletely resected. therefore, the role of lymphadenectomy is limited and should not be part of a multi-site im. analysis of liver and brain im was inadequate because of the small number of cases present in our registry (8.7% and 5.1%, respectively). as for figure 3a. overall survival for patients with im vs nm all organ sites combined (matched cohort) 89siuj.org siuj • volume 2, number 2 • march 2021 can incomplete metastasectomy impact renal cell carcinoma outcomes? http://www.siuj.org endocrine im, our results confirmed the absence of survival benefits (p = 0.388). kavolius et al. previously demonstrated that among patients undergoing cm, those with isolated endocrine disease (pancreas, adrenal, ovary, thyroid, and salivary gland) exhibited the most favorable prognosis with a 5-year os of 63%[9]. however, the benefit was only in patients who received a cm and not in those who had an im or nm. this study is the first to demonstrate significantly delayed mean time to introduction of first-line systemic therapy (28 months delay in this study) compared with nm. therefore, when lung lesions represent the only site of metastasis, there may be a benefit of partial resection of metastasis on survival and time to systemic therapy. given that lungs are the most common organ site for metastasis in renal cell carcinoma, one can speculate that the indication for metastasectomy included a higher proportion of patients with oligoprogression when compared with other sites[21]. metastasectomy at other organ sites, such as bone or brain metastasectomy, may have been performed at a higher proportion for palliative measures such as for pathological fractures or seizures. unfortunately, it is impossible to confirm this hypothesis through the ckcis database, which constitutes a limitation of our study. while stereotactic body radiation therapy is mainly used in the contemporary era, surgery may represent one treatment modality for such lesions. it is important to note that patients undergoing im had a higher burden of metastasis and more comorbidities than patients without surgical resection, and despite this, a survival benefit was still evident in subgroup analyses. incomplete metastasectomy could not be categorized according to the extent of metastasis resected due to the unavailability of this information. the main limitation of our study arises from its retrospective nature. also a selection bias may have figure 3b. time to first line systemic treatment for patients with im vs nm by metastatic location (matched cohort) 90 siuj • volume 2, number 2 • march 2021 siuj.org original research http://www.siuj.org occurred with respect to the patient’s characteristics. indeed, patients with a worse general condition may have been deemed unfit for surgery and were selected in the nm group. we performed a propensity score analysis along with matching analysis to address this limitation. propensity score estimation was carried for variables such as age, sites and number of metastases, disease synchronicity, and histology, and each patient undergoing incomplete surgical resection was matched with up to 4 patients among those who did not have a metastasectomy for variables deemed associated with treatment choice, including prior use of systemic therapy. this analysis allowed us to balance these clinicopathologic variables and drastically limit selection bias. with the exception of the number organs involved by metastasis, all were balanced in the final cohort. interestingly, patients in the im group had a higher percentage of patients with 2 or more organ sites involved than did the nm group. additionally, patients in the im group had a higher rate of hypertension, diabetes, and hypercholesterolemia, and were more likely to be smokers. therefore, despite having more comorbidities and a higher disease burden, a significant improvement in os and delay to introduction of systemic therapy was obtained for lung im. unfortunately, no multivariate analysis was possible because of the limited number of patients in the analysis stratified by metastasis location. our results show potential benefits of im for lung metastasis only, compared with nm; however, our multivariate analysis found that having a lung metastasis was not a predictive factor for os when compared with other metastasis location. furthermore, a better survival was observed for patients receiving im for lung metastasis only in comparison with im for other single metastasis locations such as endocrine, lymph nodes, and bones. again, the small number of patients in each group made impossible a multivariate analysis or another alternative method, ie, matching strategy. another limitation is the lack of quality of life (qol) assessment post-metastasectomy. im may negatively affect patient’s qol, especially when performed in a nonpalliative setting. future comparative trials for different modalities for metastasectomy such as stereotactic body radiation therapy versus surgery versus cryotherapy may shed more light on not only potential survival benefits of one modality compared with the other, but also on improvement in patients’ qol. lastly, the patients’ list of medications was unavailable. some medications, such as metformin or angiotensin converting enzyme inhibitors, may alter survival in metastatic renal cell carcinoma patients[22,23]. one of the main strengths of our analysis is the multicenter prospective registry: our study included 138 patients treated in 16 different hospitals across the country, making this study one of the largest studies on im. conclusion our study indicates that the benefit of im on os for mrcc patients is limited. incomplete resection of lung metastasis shows a potential improvement in os and delayed time to introduction of systemic therapy when lungs are the sole location of metastatic disease. outside this indication, im is not associated with a survival benefit, but may have a role in select patients for symptom relief or palliation. in addition, survival of patients receiving im varies depending on the metastasectomy site, with the highest value observed for singular lung metastasis. although groups were matched by propensity score on important measured covariates, some unmeasured confounders may have existed and may have impacted the survival benefit of lung im in this analysis. future randomized controlled trials are required to shed more light onto the role of im. 91siuj.org siuj • volume 2, number 2 • march 2021 can incomplete metastasectomy impact renal cell carcinoma outcomes? http://www.siuj.org references 1. siegel rl, miller kd, jemal a. cancer statistics, 2020. ca cancer j clin.2020;70(1):7–30. 2. tajzler c, tanguay s, mallick r, ahrens b, ly tl, breau rh, et al. determining generalizability of the canadian kidney cancer information system (ckcis) to the entire canadian kidney cancer population. can urol assoc j.2020;14(10). doi: 10.5489/cuaj.6716 3. breau rh, blute ml. surgery for renal cell carcinoma metastases. curr opin urol.2010;20(5):375–81. 4. dabestani s, marconi l, hofmann f, stewart f, lam tb, canfield se, et al. local treatments for metastases of renal cell carcinoma: a systematic review. lancet oncol.2014;15(12):e549–e61. 5. zaid hb, parker wp, safdar ns, gershman b, erwin pj, murad mh, et al. outcomes following complete surgical metastasectomy for patients with metastatic renal cell carcinoma: a systematic review and meta-analysis. j urol.2017;197(1):44–9. 6. lyon td, thompson rh, shah ph, lohse cm, boorjian sa, costello ba, et al. complete surgical metastasectomy of renal cell carcinoma in the post-cytokine era. j urol.2020;203(2):275–82. 7. yu x, wang b, li x, lin g, zhang c, yang y, et al. the significance of metastasectomy in patients with metastatic renal cell carcinoma in the era of targeted therapy. biomed res int. published online 2015;oct. doi: 10.1155/2015/176373 8. orlova r, borisov p, karlov pa, shkolnik m. efficacy of incomplete metastasectomy with targeted therapy in patients with metastatic renal cell carcinoma. am soc clin oncol. 2016;34(15 suppl). doi: 10.1200/jco.2016.34.15_suppl.e16117 9. kavolius jp, mastorakos dp, pavlovich c, russo p, bur t me, brady ms. resection of metastatic renal cell carcinoma. j clin oncol.1998;16(6):2261–6. 10. dragomir a, nazha s, wood la, rendon ra, finelli a, hansen a, et al. outcomes of complete metastasectomy in metastatic renal cell carcinoma patients: the canadian kidney cancer information system experience. urol oncol.2020;38(10):799.e1–799.e10. doi: 10.1016/j.urolonc.2020.07.021. 11. alt al, boorjian sa, lohse cm, costello ba, leibovich bc, blute ml. survival after complete surgical resection of multiple metastases from renal cell carcinoma. cancer.2011;117(13):2873–82. 12. you d, lee c, jeong ig, song c, lee j-l, hong b, et al. impact of metastasectomy on prognosis in patients treated with targeted therapy for metastatic renal cell carcinoma. j cancer res clin oncol.2016;142(11):2331–8. 13. vogl u, zehetgruber h, dominkus m, hejna m, zielinski c, haitel a, et al. prognostic factors in metastatic renal cell carcinoma: met ast asec tomy as independent prognostic variable. br j cancer.2006;95(6):691–8. 14. assouad j, petkova b, berna p, dujon a, foucault c, riquet m. renal cell carcinoma lung metastases surgery: pathologic findings and prognostic factors. ann thorac surg.2007;84(4):1114–20. 15. hofmann h-s, neef h, krohe k, andreev p, silber r-e. prognostic factors and survival after pulmonary resection of metastatic renal cell carcinoma. eur urol.2005;48(1):77–82. 16. escudier b, porta c, schmidinger m, rioux-leclercq n, bex a, khoo v, et al. renal cell carcinoma: esmo clinical practice guidelines for diagnosis, treatment and follow-up. ann oncol.2016;27(suppl. 5):v58–v68. 17. naito s, kinoshita h, kondo t, shinohara n, kasahara t, saito k, et al. prognostic factors of patients with metastatic renal cell carcinoma with removed metastases: a multicenter study of 556 patients. urology.2013;82(4):846–51. 18. meacci e, nachira d, congedo mt, porziella v, chiappetta m, ferretti g, et al. lung metastasectomy following kidney tumors: outcomes and prognostic factors from a single-center experience. j thorac dis.2017;9(suppl 12):s1267. doi: 10.21037/jtd.2017.05.04 19. chen f, fujinaga t, shoji t, miyahara r, bando t, okubo k, et al. pulmonar y resection for metastasis from renal cell carcinoma. interactive cardiovascular and thoracic surgery. interact cardiovasc thorac surg.2008;7(5):825–8. doi: 10.1510/icvts.2008.181065. 20. eggener se, yossepowitch o, kundu s, motzer rj, russo p. risk score and metastasectomy independently impact prognosis of patients with recurrent renal cell carcinoma. j urol.2008;180(3):873–8. doi: 10.21037/atm.2019.11.139 21. bianchi m, sun m, jeldres c, shariat s, trinh q-d, briganti a, et al. distribution of metastatic sites in renal cell carcinoma: a population-based analysis. ann oncol.2012;23(4):973 – 80. doi: 10.1093/annonc/mdr362. 22. h amie h l , m ck a y r r, l in x , m o r eir a r b, sim an t o v r, choueiri tk. ef fect of metformin use on sur vival outcomes in patients with metastatic renal cell carcinoma. clin genitourin cancer.2017;15(2):221–9. doi: 10.1016/j.clgc.2016.06.017. 23. derosa l, izzedine h, albiges l, escudier b. hyper tension and angiotensin system inhibitors in patients with metastatic renal cell carcinoma. oncol rev.2016;10(2):298. doi: 10.4081/oncol.2016.298 92 siuj • volume 2, number 2 • march 2021 siuj.org original research http://www.siuj.org continued on page 94 supplementary table s1. patient characteristics, unmatched cohort variable incomplete metastasectomy no metastasectomy p value no. patients 146 1221 median age at diagnosis (iqr) 63.5 (56–69) 64 (56–72) 0.002a over 65 years old at diagnosis (yes vs no), % 42.5 48.7 0.152 male, % 78.8 73.5 0.167 female, % 21.2 26.5 median follow-up, months (iqr) 26.5 (16–54) 19 (9–36) <0.0001a time from primary tumor to metastasis, median, months (iqr)a 13.0 (0–56) 4.8 (0–22) <0.0001a over 1 year from primary tumor to metastasis, % 50.7 33.3 <0.001 pathological t-stage, % t1 24.7 16.5 0.0004 t2 15.8 12.7 t3 48.0 62.4 t4 5.5 6.6 tx 6.2 1.9 clear cell rcc (ref: yes), % 83.6 81.1 0.467 synchronous metastasis (ref: yes), % 39.0 44.9 0.179 metachronous metastasis (ref: yes), % 61.0 55.1 had a nephrectomy (ref: yes), % 100 100 – location of metastasectomyb, % lung 19.9 – – bone 29.5 – – liver 2.7 – – brain 14.4 – – lymph node 10.3 – – endocrine 13.0 – – number of organs with metastasis, % a wilcoxon rank-sum test. b patients with multiple locations were counted in all specific locations; the total can exceed 100%. c fisher exact text. 93siuj.org siuj • volume 2, number 2 • march 2021 can incomplete metastasectomy impact renal cell carcinoma outcomes? http://www.siuj.org supplementary table s1. patient characteristics, unmatched cohort variable incomplete metastasectomy no metastasectomy p value 1 72.6 68.4 0.299 ≥ 2 27.4 31.6 metastasis locationb, % lung 39.0 54.7 0.0003 bones 27.4 15.7 0.0004 liver 8.2 9.8 0.554c brain 7.5 1.5 <0.0001c lymph nodes 16.4 27.9 0.003 endocrine 15.1 13.3 0.55c systemic treatment during follow-up, % first-line 71.2 73.5 0.565 second-line 33.7 30.1 0.456 radiation therapy at index date and during follow-up, % 57.5 36.3 <0.0001 number of metastasectomy, % 1 82.2 – 0.587 ≥ 2 17.8 – comorbidities, % hypertension (ref: yes) 54.1 52.0 0.631 diabetes (ref: yes) 28.1 21.5 0.069 hypercholesterolemia (ref: yes) 24.0 19.7 0.219 coronary artery disease (ref: yes) 7.5 10.7 0.243 cardiovascular disease (ref: yes) 11.0 9.3 0.506 smoker (ref: yes) 4.8 4.1 0.689c obesity (ref: yes) 3.4 3.8 0.836c charlson score index, % n = 1374 0 or 1 67.7 50.2 0.0001 more than 1 32.3 49.8 propensity score quintiles first 69.2 87.5 <0.0001 second 25.3 11.6 third 5.5 0.9 fourth – – a wilcoxon rank-sum test. b patients with multiple locations were counted in all specific locations; the total can exceed 100%. c fisher exact text. , cont’d 94 siuj • volume 2, number 2 • march 2021 siuj.org original research http://www.siuj.org 1.0 0.8 0.6 0.4 0.2 0.0 0 glandular ln bones lung 22 9 24 31 23 15 5 17 18 12 2 10 15 9 0 9 11 7 7 8 5 3 3 2 2 1 0 0 + censored logrank p = 0.0263 su rv iv al p ro ba bi lit y 20 40 60 60 metastasectomy site time (months) endocrine ln bones lung 1.0 0.8 0.6 0.4 0.2 0.0 0 glandular ln bones lung 22 9 24 31 23 7 3 12 12 3 2 6 12 2 0 4 6 1 4 3 1 3 2 0 0 0 + censored su rv iv al p ro ba bi lit y 20 40 60 60 metastasectomy site time to 1st targeted treatment (months) endocrine ln bones lung logrank p = 0.0032 supplementary figure 1a. overall survival for patients with im by metastasectomy site supplementary figure 1b. time to first line systemic treatment for patients with im by metastasectomy 95siuj.org siuj • volume 2, number 2 • march 2021 can incomplete metastasectomy impact renal cell carcinoma outcomes? http://www.siuj.org _goback 49siuj.org siuj • volume 1, number 1 • october 2020 molecular biomarkers in urologic oncology: icud-wuof consultation urinary-based markers for bladder cancer detection tilman todenhöfer,1,2 michele lodde,3 kim van kessel,4 renate pichler,5 antonia vlahou,6 yair lotan7 1 studienpraxis urology, clinical trial unit, germany, 2 medical school, university of tuebingen, germany, 3 centre hospitalier universitaire de québec research centre, université laval, québec, canada, 4 erasmus mc cancer institute, rotterdam, the netherlands, 5 department of urology, medical university innsbruck, austria, 6 biomedical research foundation, academy of athens, greece, 7 department of urology, university of texas southwestern medical center, dallas, united states abstract background the use of urine markers for diagnosis and surveillance has been a topic of broad interest and ongoing controversies in the management of patients with bladder cancer. there has been a constant quest for markers that demonstrate clinical utility. aim in the framework of the international consultation on urological diseases 2019 on molecular biomarkers in urologic oncology, a comprehensive review of literature on urinary biomarkers for bladder cancer has been performed. results currently available urinary markers include protein-based markers, rna-based markers, and dna-based markers. the introduction of high-throughput analysis technologies provides the opportunity to assess multiple parameters within a short period of time, which is of interest for rna-based, dna-based, and protein-based marker systems. a comprehensive analysis of molecular alterations in urine samples of bladder cancer patients may be of interest not only for diagnosis and surveillance but also for non-invasive longitudinal assessment of molecular, potentially therapy-relevant, alterations. however, most systems lack prospective validation within well-designed trials and have not been broadly implemented in daily clinical practice. conclusions because of limited data from prospective trials, the routine use of any urine marker except cytology is not considered as standard of care in international guidelines. there is an urgent need for prospective trials of urine markers to answer specific clinical questions. introduction a diagnosis of bladder cancer (bc) is routinely made by cystoscopy followed by biopsy of suspicious lesions [1,2]. cystoscopy represents the most important component of surveillance of bc. however, as white light cystoscopy may miss tumors and may be associated with discomfort for the patient, there has been a constant interest in the discovery of urine markers for use in diagnosis and surveillance of bc patients [3,4]. a marker with reasonable performance may be of interest in different clinical scenarios. these scenarios include the use of urine markers for patients with symptoms suggestive of bc (such as hematuria) and urine marker based surveillance (eg, with adaptation of cystoscopy intervals according to urine marker results) [5]. so far, the majority of studies performed in this field have shown that an increased sensitivity of non-cytology urine markers, compared with cytology, is often associated with limited specificity and that various factors (eg, infection and hematuria) frequently encountered in the patient population that is of interest for these markers may limit the diagnostic accuracy. a decreased specificity is also the key words competing interests article information urine, biomarkers, surveillance, screening, hematuria, urothelial carcinoma dr lotan reports grants from mdxhealth, grants from pacific edge, grants from cepheid, grants from decipher biosciences, personal fees from nucleix, personal fees from photocure, personal fees from merck, personal fees from astrazeneca, personal fees from fergene, during the conduct of the study. the remaining authors report no competing interests. received on july 7, 2020 accepted on july 29, 2020 soc int urol j. 2020;1(1):49–61 http://www.siuj.org mailto:todenhoefer%40studienurologie.de?subject=siuj 50 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation main limitation of approaches based on a combined use of various markers to increase sensitivity. the current review summarizes data and potential applications of different types of urine markers, including cell-based markers, rna markers, dna markers, and protein markers. new technologies allowing quick and broad molecular analyses have been implemented in the context of urine markers to gain more information on tumor-associated alterations within a short period of time. these high-throughput technologies have a high potential of reaching some of the goals that have been set in the context of urinary diagnosis in bc. cell-based bladder markers severa l cel l-based urine markers are avai lable, including conventional urinary cytology, immunocyt/ ucyt + (scimedx, denville, us), f luorescence in situ hybridization (fish) urovysion (abbott molecular, des plaines, us) and cell detect (zetiq technologies ltd., tel aviv, israel) (table 1). urine cytology remains the gold standard and the only urine marker that is recommended by the european association of urolog y (eau) and the american urological association (aua) [1,2] for the diagnosis and surveillance of high-grade bc (in combination with cystoscopy). overall, the reported sensitivity ranges from 20% to 97.3%; specificity ranges from 74% to 99.5% [6–8]. urine  cytology  has an excellent specificity with few false-positive cases for high-grade bladder cancer (hgbc) and carcinoma in situ (specificity 83% to 99%) [1,9]. historically, urine cytology had a high sensitivity for hg disease, but more contemporary series reported sensitivity for cytology at 40.8% and 54.3% for hg [10,11]. furthermore, a low sensitivity in low-grade tumors represents a main downside of conventional cytology; therefore, it is not used to replace cystoscopy. immunocytology (immunocyt [ucyt+], scimedx, us) is based on immunoassays for detection of tumorassociated cell-based antigens. the global sensitivity of immunocytology ranges between 78% and 90% and is higher than that of cytology, especially for low-grade cancers, whereas its specificity has been reported as 68% to 87% and therefore tends to be lower than that of cytology [12–14] (table 2). immunocyt/ucyt+ in patients whose cytology was atypical has been frequently discussed as a reflex test to avoid cystoscopy in patients with low-grade cancer since the test has a npv of 83.7% [1,15]. nevertheless, immunocyt/ucyt+ has been recently removed from the market. fluorescence in situ hybridization (multi-target multicolor fish – urovysion) (abbott molecular, us) allows the detection of chromosomal abnormalities that are frequently observed in malignant urothelial cells (gains in chromosomes 3, 7, 17 or deletions of chromosome 9). these assays have been shown to be more sensitive than cytology in detecting bc at the cost of a lower specificity. sensitivity ranges from 50% to 88% and specificity from 78% to 92% [12–14], depending on table 1. summary of commercially available cell-basedt urinary markers marker / test marker / test description fda status immunocyt /ucyt+ scimedx, us immunocytochemical assay for detection of expression of carcinoembryonic antigen and bc-associated mucins approved for follow-up; recently removed from the market urovysion abbott molecular, us multicolor fish assay for detection of numerical aberrations of chromosomes 3, 7, 17 and locus 9p21 approved for diagnosis and follow-up cell detect zetiq technologies, israel platform technology comprising a proprietary plant extract and 3 dyes that enables color discrimination between malignant (red) and benign (green) cells based on specific metabolic alterations exclusive to the tumor not approved abbreviations aua american urological association bc bladder cancer bcg bacillus calmette-guérin eau european association of urology fish fluorescence in situ hybridization hgbc high-grade bladder cancer mirna microrna nmibc non-muscle invasive bladder cancer nmp22 nuclear matrix protein 22 tert telomerase reverse transcriptase http://www.siuj.org 51siuj.org siuj • volume 1, number 1 • october 2020 urinary-based markers for bladder cancer detection the bc prevalence in the cohort of the study (table 3) and also on the criteria of positive tests. fish sensitivity was reported to be twice as high as cytology for nonmuscle invasive bladder cancer (nmibc) (50.9% versus 29.8%) [16,17] and triple (73% versus 24%) when scoring criteria have been modified. notably the scoring algorithm of the manufacturer was developed for voided urine but was modified for bladder washings [17,18]. in patients with atypical cytology or indeterminate cystoscopy, urovysion may help to identify those who would need further evaluation since 2 prospective studies found a higher likelihood of cancer in patients with positive markers with a reasonable positive predictive value [19,20]. this role has been included in the aua guidelines as a potential use of urine markers. there is evidence from various sources that anticipatory false-positive results exist. patients with positive fish but no visible tumor in cystoscopy were reported to be at increased risk for recurrence and progression [21,22]. persisting positive fish during bacillus calmetteguérin (bcg) immunotherapy increased the risk of recurrence and progression [23]. recently, 2 multicenter prospective studies confirmed the predictive value of fish in detecting recurrence and progression in hgbc treated with bcg [10,25]. a positive fish at initiation or completion of bcg is associated with 3-fold higher rate of recurrence but results in individual patients vary, which makes it challenging to make clinical decisions on the basis of fish results [26]. the platform celldetect (zetiq technologies, israel) uses a proprietary plant extract and 3 dyes that enable color discrimination between malignant (red) and benign (green) cells on the basis of specific metabolic alterations associated with bc. in a multicenter validation study, the test reached a sensitivity of 84% (table 3) (78% for detecting lg nmibc). the specificity was 84% in patients undergoing sur veillance by cystoscopy [24]. dna-based markers various types of dna alterations can occur in bc, such as mutations, copy number alterations, and genomic rearrangements. in general, bc is known to have a high mutational burden [27,28]. until now, none of the dna-based urine assays that are based on detection of mutations have been fda approved for use in clinic. prospective validation of most urine assays is still awaited. some of the most frequently found dna mutations in bc include mutations in the fgfr3, ras, pik3ca, and tert genes. approximately two-thirds of nmibcs have activating fgfr3 mutations. the number of table 2. performance characteristics of cell-based urine markers study patients n studies included n context sensitivity % specificity % patients with tumor n immuno-cytology chou et al. [13] 1876 7 primary diagnosis 85 (78–90) 83 (77–87) 401 mowatt et al. [14] 4199 10 mixed 84 (77–91) 75 (68–83) na schmitz drager et al. [12] 4899 20 mixed 81 (median) 75 (median) 1252 urovysion chou et al. [13] 651 2 primary diagnosis 73 (50–88) 95 (87–98) 144 mowatt et al. [14] 3321 14 mixed 76 (65–8) 85 (78–92) na schmitzdrager et al. [12] 2852 21 mixed 72 (median) 80 (median) 792 cell detect davis et al. [24] 217 1 surveillance 84 84 96 http://www.siuj.org 52 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation table 3. performance of assays that are based on detection of dna alterations assay parameters author year technique patients n population sens % spec % mutation: fgfr3, pik3ca, ras methylation: 41 cpg islands in 23 genes microsatellite: 12 different primers zuiverloon et al. 36] 2013 snapshot analysis methylation specific multiplex ligationdependent probe amplification 136 surveillance • fgfr3 49 66 • cytology 56 57 • fgfr3 + cytology 76 42 • fgfr3 + microsatellite 71 44 • fgfr3 + methylation 75 22 surveillance, patients stratified by inclusion tumor • fgfr3 66 50 • fgfr3 + pik3ca + ras 71 63 • microsatellite 67 40 • fgfr3 + microsatellite 82 82 • methylation 68 42 • fgfr3 + methylation 75 22 mutation: fgfr3 methylation: otx1, onecut2, osr1 kandimalla et al. [37] 2013 snapshot analysis 301 surveillance • methylation only 74 90 • combined 79 77 mutation: fgfr3 methylation: hs3st2, slit2, septin9 clinical parameters: age, smoking status roprech et al. [38] 2016 allele specific pcr quantitative multiplexmethylation specific pcr 167/158 • hematuria 97 84 • surveillance 90 65 mutation: tert, fgfr3 methylation: sall3, onecut2, ccna1, bcl2, eomes, vim dahmcke et al. [39] 2016 droplet digital polymerase chain reaction (ddpcr) 475 hematuria • all 97 77 • tert 82 84 • fgfr3 41 98 • sall3 68 97 • onecut2 78 94 • ccna1 67 97 • bcl2 63 98 • eomes 46 97 • vim 76 96 • tert, fgfr3, onecut2, ccna1 97 80 continued on page 53 http://www.siuj.org 53siuj.org siuj • volume 1, number 1 • october 2020 urinary-based markers for bladder cancer detection table 3. performance of assays that are based on detection of dna alterations assay parameters author year technique patients n population sens % spec % mutation: fgfr3, tert methylation: otx1 beukers et al. [40] 2017 snapshot analysis 977 surveillance • previous high grade 72 55 • previous low grade 57 59 mutation: fgfr3, tert, hras methylation: otx1, onecut2, twist1 clinical parameter: age van kessel et al. [41] 2016 snapshot analysis methylation-specific polymerase chain reaction (msp) 154 hematuria 97 83 mutation: fgfr3, tert, hras methylation: otx1, onecut2, twist1 clinical parameter: age van kessel et al. [42] 2017 snapshot analysis methylation-specific polymerase chain reaction (msp) 200 hematuria 93 86 mutations in 11 genes copy number changes on chromosome 39 cytology springer et al. [43] 2018 multiplex pcr singleplex pcr aneuploidy assays 570 primary diagnosis • 10 genes combined 68 nr • tert 57 nr • aneuploidy 46 nr • uroseek (assays combined) 83 93 cytology • uroseek + cytology 43 100 • utuc 95 93 • 10 genes combined • tert 64 nr • aneuploidy 29 nr • uroseek (assays combined) 39 nr surveillance 75 nr • 10 genes combined 52 nr • tert 57 nr • aneuploidy 28 nr • uroseek (assays combined) 68 80 • cytology 25 100 • uroseek + cytology 71 82 panel of 15 methylation markers (epicheck bladder) witjes et al. [44] 2018 quantitative multiplexmethylation specific pcr 440 surveillance 68.2 88.0 , cont’d activating mutations is much lower in mibc [29], (only <15% of tumors have fgfr3 mutations); however, > 40% of mibcs overexpress fgfr3 [30]. tumors with an fgfr3 mutation grow slowly and are less likely than fgfr3 wild-type tumors to progress to mibc [30–33]. several hotspot mutations in the fgfr3 gene have been identified as oncogenic. in general, mutations in the kras gene are most frequent in cancer. for instance, kras is mutated in 90% of pancreatic cancers and 45% of colorectal cancers [34]. in bc, hras is the most commonly mutated ras gene: hras mutations are present in approximately 5% of bladder tumors [27]. http://www.siuj.org 54 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation further, approximately 20% of bc tumors harbor a mutation in the pik3ca gene [27]. pi3k can be activated by rtks, or via crosstalk via the rtk-ras-mapk pathway. finally, mutations in the telomerase reverse transcriptase (tert) gene are frequent in bc: >70% of bladder tumors harbor a tert promotor mutation [35]. the presence of a tert mutation has been found to be more frequent in tumors that also harbored fgfr3 mutations; however, it was not associated with stage or grade of the tumors [35]. overall, significant overlap between different mutations occurs. epigenetic studies, such as genome-wide methylation ana lyses, have identif ied severa l genes t hat are significantly hypermethylated in bc cells compared with normal urothelial cells [45]. methylation of several genes was found to be useful for the diagnosis of bc, with some markers being highly specific for bc. gene hypermethylation has also been proposed in predicting disease progression [46,47]. the epicheck platform (nucleix, israel) has been designed for detection of dna methylation changes associated with bc in a panel of 15 biomarkers. the test has been validated in several studies that included mainly patients who were under surveillance for nmibc [39,40]. other assays that were validated in several cohorts have been designed to combine the analysis of both bc-relevant dna gene methylations and mutations [42,49]. assay results and clinical parameters (type of hematuria) have been incorporated in multivariate models to obtain optimal performance. in the literature, various dna-based urinary markers have been developed. for most of these, prospective validation is still lacking. the urine-based markers suggested in the literature can be subdivided into markers used for detection of primary tumors (eg, in a patient with hematuria) and markers used for detection of recurrent tumors (eg, patient previously treated for bc). furthermore, markers based on cell pellet dna exist, as well as cell-free dna-based markers table 3. provides an overview of studies that combine various dna marker assays. rna-based markers a high number of rna-based urinary gene panels are being validated, with the aim of improving diagnostic accuracy in bc without decreasing specificity [3]. t hree messenger r na (mr na)-based u rina r y biomarkers (cxbladder assay [pacific edge diagnostics, us], genexpert bc [cepheid, us], and taqman array, [thermofisher, us]) and various microrna (mirna)-based urinary targets (eg, members of the mirna-200 family and mirna-145) are currently tested in clinical trials for bc detection or surveillance. in detail, 5 published studies [50–53] on different clinical scenarios (detection of bc in risk population, and sur veillance for recurrent bc) consistent ly confirmed promising diagnostic performances with a high sensitivity (even in lg tumors on surveillance) and npv of the cxbladder assay at the expense of a lower specificity than cytology. for bc screening and detection, the cxbladder has the potential to reduce the frequency of diagnostic and invasive procedures in patients presenting with hematuria; however, further prospective validation studies are necessary. the genexpertbc test has shown 83% to 100% sensitivity for hg tumors and up to 77% sensitivity for lg tumors, and overall sensitivity ranged between 46.2% and 84%. whereas the specificity in the bc detection population was very high (90% to 95%), in homogeneous data specificity was confirmed for bc surveillance (77% to 91%) [11,54–56].the training and validation study analyzing the diagnostic accuracy of a specific 12 + 2 gene set (taqman array) panel on bladder washings and voided urine samples showed consistently high sensitivities and specificities in bc detection (sensitivity: 70%, 80%, and 98%; specificity: 86%, 96%, and 99%) and for discrimination between lg and hg tumors (sensitivity: 75% to 79%; specificity: 75% to 92%) [50,51]. these findings were confirmed in a prospective, blinded multicenter trial [59]. an overview of the diagnostic performance characteristics of the 3 mrna-based urine assays for detection/surveillance of bc is shown in table 4. moreover, mir nas may become bioma rkers for bc detection and sur veillance in the future. nevertheless, identified mirna signatures were found to be heterogenous in published studies, with few trials confirming their results by independent validation cohorts, resulting in a low degree of reproducibility in the clinical setting. most trials included only a small number of patients (n = 47 to 207) [60,61]. another controversial issue that is discussed controversially is the feasibility of implementation and application of different analytical platforms and bioinformatics in the clinical setting [62]. in summar y, r na-based urinar y markers are characterized by ease of handling, their brief hands-on sample preparation time, technical instrument systems that automate and integrate all complex pcr processes, and high-qua lit y standards including in-sample quality controls [55]. one of the major limitations of the application of rna-based urinary techniques is the difficulty in obtaining sufficient quantity of “highquality” rna from voided urine compared with bladder washings. studies using bladder washings and optimized specimen collection and handling may achieve results that are not attainable in real world practice [57,63]. it has been shown that bladder washing samples yielded higher amounts of better rna-quality than voided urine http://www.siuj.org 55siuj.org siuj • volume 1, number 1 • october 2020 urinary-based markers for bladder cancer detection table 4. diagnostic performance characteristics of mrna-based urine markers for detection/surveillance of bc study study design indication patients n sn % sn for hg tumors % sp % npv % cxbladder o’sullivan et al. [51] marker-comparison study, prospective microhematuria 485 82 97 85 lotan et al. [53] marker-comparison study, prospective bc surveillance 803 91 97 – 96 g + p index kavalieris et al. [50] cohort, prospective microand macrohematuria 695/ (mah) 45 (mih) 95 45 98 kavalieris et al. [52] cohort, prospective bc surveillance 763 93 97 – 97 genexpert bc van valenberg et al. [11] marker-comparison study, prospective bc detection + surveillance 239 (surveillance)/ 508 (detection) 74 83 80 (surveillance) 95 (detection) 93 wallace et al. [54] cohort, prospective bc detection, surveillance 484 (training cohort) + 450 (validation cohort) 73 – 90 (hematuria) 77 (surveillance) – pichler et al. [55] marker-comparison study, prospective bc surveillance 140 84 100 91 93 d’elia et al. [56] marker-comparison study, prospective bc surveillance 230 46.2 85.7 77 83 taqman array (12 +2 gene panel) mengual et al. [57] cohort, prospective bc detection 341/235 (control) 98 100 99 95 mengual et al. [58) case–control study bc detection 207 (independent set)/ 404 (training set) 80 – 86 – ribal et al. [59] cohort, prospective bc detection 525 81.5 – 91.3 – bc: bladder cancer; hg: high grade; mah: macrohematuria; mih: microhematuria; npv: negative predictive value; sn: sensitivity; sp: specificity. http://www.siuj.org 56 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation samples [57]. another limitation is the fact that there is a wide variability in the cost of rna-based urine tests. for widespread use in the future, these tests should be available at reasonable cost. another challenge of rnabased urinary markers in preanalytics is the mrna instability, resulting in an advantage for commercial test systems (working with rna-stabilizing tubes) compared with single urinary mrna targets (caix or survivin). standardized processes are indispensable for rna analysis. according to the current eau and aua guidelines, rna-based urinary biomarkers cannot be recommended for screening, detection of bc in patients with microscopic hematuria, or bc surveillance [2,64]. protein markers in comparison with other-omics, the proteome can be directly linked to a phenotype, and hence represents a rich source of biomarkers and therapeutic targets (the latter, however, typically not in urine). on the downside, the extensive complexity and large dynamic range of protein components of a biological sample (in the case of urine, spanning at least 6 orders of magnitude) raise technical challenges, regularly encountered to some extent in proteome analysis and addressed, via the application of high-resolution mass spectrometry-based methodologies [67]. a large number of proteins have been reported in association with bc phenotypes, for disease prognosis or treatment prediction [68–71]. of the most widely studied, nuclear matrix protein 22 (nmp22), quantified by the point-of-care nmp22 bladderchek, and the nmp22 elisa immunoassay (alere/abbott), has received approval by the fda for application in bc surveillance (both tests) and detection of the disease in high-risk or symptomatic populations (for the nmp22 bladderchek test only). similarly, the bta trak immunoassay-based and bta stat pointof-care tests (polymedco), detecting the complement factor h and complement factor h-related protein, have also been granted fda approval for use in bc diagnosis and surveillance. meta-analyses of existing studies demonstrate that the performance for both approved markers varies widely among the studies (ranging for the sensitivities and specificities from 47% to > 90%) [65,68–72] (table 5). the reported sensitivities are higher than those of cytology in the detection of lowgrade disease, but hematuria, infections, presence of stones or instrumentation are frequent confounders, compromising the specificity of the assays [73]. besides the abovementioned fda-approved tests, several additional exploratory protein biomarkers have been reported in primary diagnosis, and in cancer detection during surveillance and/or monitoring of treatment response. among the most frequently reported are proteins of the extracellular and the nuclear matrix, apolipoproteins (apolipoprotein a-i, apolipoprotein a-ii, apolipoprotein e) and other plasma proteins (alpha table 5. overall performance rates of fda approved urinary protein markers, based on the most recent available metaanalyses protein marker reference context sample size sensitivity specificity nmp22 (nuclear matrix protein 22) chou et al. [4] primary diagnosis n=1313 for elisa; n=1816 for poc 67 (elisa) 47 (poc) 84 (elisa) 93 (poc) mowatt et al. [65] diagnosis of primary and prevalent cancer n=10119 -elisa and poc 68 (overall) 79 (overall) bta (complement factor h-related protein and complement factor h) chou et al. [4] diagnosis of primary cancer n=1021 (poc) 76 78 guo et al. [66] diagnosis of primary and prevalent cancer n=3175 (poc) 67 75 poc: point of care assay http://www.siuj.org 57siuj.org siuj • volume 1, number 1 • october 2020 urinary-based markers for bladder cancer detection 1 anti-trypsin, heparin cofactor ii), including angiogenic factors (such as angiogenin, vascular endothelial growth factor a-vegfa), as well as inflammatory factors (such as interleukins 2, 6, 8, 10, tnfα) [68,70]. commercially available assays for the measurement of some of these proteins have been established; these include the ubc rapid, (idl biotech ab) or cyfra 21-1 (cisbio international) tests measuring cytokeratin fragments— mainly of cytokeratins 8 and 18 for the former [74] and cytokeratin 19 for the latter [75]—or adxbladder, (arquer diagnostics ltd), quantifying the levels of the mini-chromosome maintenance-mcm 5 protein [76], having being tested mainly in diagnostic contexts of use and, as essentially with all tests, exhibiting better performance in advanced than in early grade and stage tumors. applications in disease prognosis have also been described, including the recent examples of the shed ectodomains of epithelial cell adhesion molecule (epcam) and hepatocy te growth factor activator inhibitor-1 (ha-1), exhibiting a prognostic value for disease-specific death (in the range of 2 times increased risk at increased marker levels) in nmibc [77]; or various interleukins (such as il12, trail, tnfα) in response to bcg treatment [78]. a clear consensus is emerging that combination of individual protein markers with clinicopathological information [79,80] in biomarker panels or multiparametric classifiers results in increased accuracy rates. examples include the cyprit (cytokine panel for response to intravesical therapy) measuring the levels of 9 cytokines, as a predictor of response to bcg treatment in intermediateand high-risk nmibc [78]; or the simultaneous quantification of matrix metalloproteases and plasma proteins v ia elisa-based assays in diagnostic contexts of use [68,81] (table 6). in addition, peptides mainly originating from extracellular matrix proteins (collagens, fibrinogen) but also plasma proteins quantified simultaneously via mass spectrometry-based assays and combined to a classifier (diapat) have shown diagnostic value in disease primary detection and surveillance [82]. collectively, several urinary protein markers in association with bc phenoty pes and prognostic/ predictive contexts of use have been reported. proper prospective validation is pending to define their added value (stand-alone or in combination) in disease management. technology advancements allowing the simultaneous detection of marker panels provide a solid basis for future work in this direction. clinical considerations for use of urinary molecular markers in context of bc the various marker tests differ regarding their potential applications in the diagnosis and surveillance of bc. whereas fish, immunocytology, and nmp22 have long been considered the most valuable alternatives to cytology, other dnaand rna-based assays have drawn broad attention within the last 10 years. with the advent of high-throughput analysis technologies there is the hope that performing multiple analyses in parallel with high resolution will improve the detection rate. many of these test systems provide information on dna, rna, and protein levels. in the future, such information can be helpful not only in the detection of bc but also for the non-invasive monitoring of disease. one potential indication that has been investigated in the context of the urovysion is the monitoring of patients treated with bcg. because of the high risk of recurrence in these patients, a marker that provides evidence of response or failure of treatment would be of high value to prevent delay of cystectomy in patients who table 6. exploratory marker panels for protein-based bc detection protein marker reference context sample size sensitivity, % specificity, % cytokine panel (9 cytokines; cyprit) kamat et al. [78] nmibc prediction of recurrence n=130 80 77.4 10 protein panel (meso scale diagnostic) shimizu et al. [81] diagnosis of primary cancer n=200 85 81 ce-ms peptide panel (diapat) frantzi et al. [82] diagnosis of primary and prevalent cancer (test set n=481) n=481 (test set) 91 (primary) 87 (prevalent) 68 (primary) 51(prevalent) http://www.siuj.org 58 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation do not respond to bcg. the high level of complexity of new marker combination panels is associated with various challenges. one main challenge of any combination marker panel that is developed with the goal of achieving a high sensitivity will be to avoid falsepositive test results, which has been a major issue in the development of many markers that have been discussed as potential alternatives for cytology. any marker or test system that is supposed to be broadly implemented in clinical practice requires prospective clinical trials to address the value of the test in the relevant clinical context. case–control studies provide preliminary information on test characteristics but will not be sufficient for a broad clinical use. a common study design used for va lidation of promising markers is to ana lyze urine samples prospectively from patients undergoing cystoscopy because of suspicion of bc. one of the primary goals of urine biomarkers in this context is to replace cystoscopy, but the cohorts studied are typically too heterogenous with respect to the indication for evaluation (gross hematuria, microscopic hematuria, or irritative voiding symptoms), so that the study results are not adequate to change practice. moreover, many studies include both patients undergoing primary diagnostic workup and those under surveillance. such heterogeneity potentially explains the considerable differences of test performances between different validation studies. to avoid such heterogeneity of patient groups, it makes sense to test the potential of urine markers in specific clinical settings. both clinicians and companies should make every effort to validate an assay in a prospective trial designed in cooperation with guideline panels and key opinion leaders. one example of a prospective trial that has been set up in a specific setting with a specific hypothesis is the urofollow trial [83]. in this trial, patients with low grade nmibc are randomized to receive standard of care surveillance using cystoscopy versus regular measurement of urine markers (including cytology and urovysion), with cystoscopies performed only in the case of a positive marker or clinical signs of recurrence. the hypothesis of the trial is that a urinary marker-based follow-up is non-inferior to a cystoscopybased follow-up with respect to detection of recurrence and progression. another clinical trial (nct03988309) is randomizing patients to a marker-based approach using cxbladder versus a standard evaluation for patients with hematuria. the goal of the trial is to determine if a risk-based approach with the addition of a marker is superior to cystoscopy for all patients. such specific study designs will not only allow a better understanding of the performance of an assay but also provide data on the potential use of a specific test. conclusions changing current clinical practice in bladder cancer workup is a very ambitious goal for any biomarker. there is currently no urinary marker available for which there is sufficient evidence to indicate it may change our current diagnostic workup, which includes cystoscopy and cytology. new markers should be considered for a use in more specific indications and clinical settings to allow the setup of properly designed trials. references 1. babjuk m, burger m, comperat em, et al. european association of urology guidelines on non-muscle-invasive bc (tat1 and carcinoma in situ) 2019 update. eur urol. 2019;76(5):639–57. 2. chang ss, boorjian sa, chou r, et al. diagnosis and treatment of non mus cle inv asi ve b c: aua / suo guideline. j ur ol. 2016;196(4):1021–9. 3. maas m, bedke j, stenzl a, todenhofer t. can urinary biomarkers replace cystoscopy? 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valenberg f, hiar am, wallace e, et al. prospective validation of an mrna-based urine test for surveillance of patients with bc. eur urol. 2019;75(5):853–60. 12. schmitz-drager bj, droller m, lokeshwar vb, et al. molecular markers for bc screening, early diagnosis, and surveillance: the who/icud consensus. urol int. 2015;94(1):1–24. 13. chou r, gore jl, buckley d, et al. urinary biomarkers for diagnosis of bc: a systematic review and meta-analysis. ann intern med. 2015;163(12):922–31. http://www.siuj.org 59siuj.org siuj • volume 1, number 1 • october 2020 urinary-based markers for bladder cancer detection 14. mowatt g, zhu s, kilonzo m, et al. systematic review of the clinical effectiveness and cost-effectiveness of photodynamic diagnosis and urine biomarkers (fish, immunocy t, nmp22) and cy tology for the detection and follow-up of bc. health technol assess. 2010;14(4):1–331, iii–iv. 15. odisho ay, berry ab, ahmad ae, cooperberg mr, carroll pr, konety br. reflex immunocyt testing for the diagnosis of bc in patients with atypical urine cytology. eur urol. 2013;63(5):936–40. 16. bubendor f l , grilli b, sauter g, mihatsch m j, gasser tc, dalquen p. multiprobe fish for enhanced detection of bc in voided urine specimens and bladder washings. am j clin pathol. 2001;116(1):79–86. 17. bubendorf l, grilli b. urovysion multiprobe fish in urinary cytology. methods mol med. 2004;97:117–31. 18. zellweger t, benz g, cathomas g, mihatsch m j, sulser t, gasser tc, et al. multi-target fluorescence in situ hybridization in bladder washings for prediction of recurrent bc. int j cancer. 2006;119(7):1660–5. 19. schlomer bj, ho r, sagalowsky a, ashfaq r, lotan y. prospective validation of the clinical usefulness of reflex fluorescence in situ hybridization assay in patients with at ypical cy tology for the detection of urothelial carcinoma of the bladder. j urol. 2010;183(1):62–7. 20. lotan y, bensalah k, ruddell t, shariat sf, sagalowsky ai, ashfaq r. prospective evaluation of the clinical usefulness of reflex fluorescence in situ hybridization assay in patients with atypical cytology for the detection of urothelial carcinoma of the bladder. j urol. 2008;179(6):2164–9. 21. seideman c, canter d, kim p, et al. multicenter evaluation of the role of urovysion fish assay in surveillance of patients with bc: does fish positivit y anticipate recurrence? world j urol. 2015;33(9):1309–13. 22. gopalakrishna a, fantony jj, longo ta, et al. anticipatory positive urine tests for bc. ann surg oncol. 2017;24(6):1747–53. 23. kamat am, dickstein rj, messetti f, et al. use of fluorescence in situ hybridization to predict response to bacillus calmet teguerin therapy for bc: results of a prospective trial. j urol. 2012;187(3):862–7. 24. davis n, shtabsky a, lew s, et al. a novel urine-based assay for bc diagnosis: multi-institutional validation study. eur urol focus. 2018;4(3):388–94. 25. liem e, oddens jr, vernooij rwm, et al. the role of fluorescence in situ hybridization for predicting recurrence af ter adjuvant bacillus calmette-guerin in patients with intermediate and high risk nonmuscle invasive bc: a systematic review and meta-analysis of individual patient data. j urol. 2020;203(2):283–91. 26. lotan y, inman ba, davis lg, et al. evaluation of the fluorescence in situ hybridization test to predict recurrence and/or progression of disease after bacillus calmette-guerin for primary high grade nonmuscle invasive bc: results from a prospective multicenter trial. j urol. 2019;202(5):920–6. 27. robertson ag, kim j, al-ahmadie h, et al. comprehensive molecular characterization of muscle-invasive bc. cell. 2017;171(3):540–56 e25. 28. cancer genome atlas research n. comprehensive molecular char ac t eriz ation of ur ot helial bladder c ar cinoma. nat ur e. 2014;507(7492):315–22. 29. van rhijn bw, zuiverloon tc, vis an, et al. molecular grade (fgfr3/mib-1) and eortc risk scores are predictive in primar y non-muscle-invasive bc. eur urol. 2010;58(3):433–41. 30. tomlinson dc, baldo o, harnden p, knowles ma. fgfr3 protein expression and its relationship to mutation status and prognostic variables in bc. j pathol. 2007;213(1):91–8. 31. hernandez s, lopez-knowles e, lloreta j, et al. prospective study of fgfr3 mutations as a prognostic factor in nonmuscle invasive urothelial bladder carcinomas. j clin oncol. 2006;24(22):3664–71. 32. van rhijn bw, vis an, van der kwast th, et al. molecular grading of urothelial cell carcinoma with fibroblast growth factor receptor 3 and mib-1 is superior to pathologic grade for the prediction of clinical outcome. j clin oncol. 2003;21(10):1912–21. 33. burger m, van der aa mn, van oers jm, et al. prediction of progression of non-muscle-invasive bc by who 1973 and 2004 grading and by fgfr3 mutation status: a prospective study. eur urol. 2008;54(4):835–43. 34. downward j. targeting ras signalling pathways in cancer therapy. nat rev cancer. 2003;3(1):11–22. 35. allor y y, beukers w, sagrera a , et al. telomerase reverse transcriptase promoter mutations in bc: high frequency across stages, detection in urine, and lack of association with outcome. eur urol. 2014;65(2):360–6. 36. zuiverloon tc, beukers w, van der keur k a, et al. combinations of urinar y biomarkers for sur veillance of patients with incident nonmuscle invasive bc: the european fp7 uromol project. j urol. 2013;189(5):1945–51. 37. kandimalla r, masius r, beukers w, et al. a 3-plex methylation assay combined with the fgfr3 mutation assay sensitively detects recurrent bc in voided urine. clin cancer res. 2013;19(17):4760–9. 38. roperch jp, grandchamp b, desgrandchamps f, et al. promoter hypermethylation of hs3st2, septin9 and slit2 combined with fgfr3 mutations as a sensitive/specific urinary assay for diagnosis and sur veillance in patients with low or high-risk non-muscleinvasive bc. bmc cancer. 2016;16:704. 39. dahmcke cm, steven ke, larsen lk, et al. a prospective blinded evaluation of urine dna testing for detec tion of urothelial bladder carcinoma in patients with gross hematuria. eur urol. 2016;70(6):916–9. 40. beukers w, van der keur k a, kandimalla r, et al. fgfr3, tert and otx1 as a urinary biomarker combination for surveillance of patients with bc in a large prospective multicenter study. j urol. 2017;197(6):1410–8. 41. van kessel ke, van neste l, lurkin i, zwarthoff ec, van criekinge w. evaluation of an epigenetic profile for the detection of bc in patients with hematuria. j urol. 2016;195(3):601–7. 42. van kessel ke, beukers w, lurkin i, et al. validation of a dna methylation-mutation urine assay to select patients with hematuria for cystoscopy. j urol. 2017;197(3 pt 1):590–5. http://www.siuj.org 60 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation 43. springer su, chen ch, rodriguez pena mdc, et al. non-invasive detection of urothelial cancer through the analysis of driver gene mutations and aneuploidy. elife. 2018;7:e3214 3  doi:  10.7554/ elife.32143 44. witjes ja, morote j, cornel eb, et al. performance of the bladder epicheck methylation test for patients under sur veillance for non-muscle-invasive bc: results of a multicenter, prospective, blinded clinical trial. eur urol oncol. 2018;1(4):307–13. 45. kandimalla r, van tilborg a a, kompier lc, et al. genome-wide analysis of cpg island methylation in bc identified tbx2, tbx3, gata 2, and zic4 as pta-specific prognostic markers. eur urol. 2012;61(6):1245–56. 46. beukers w, kandimalla r, masius rg, et al. stratification based on methylation of tbx2 and tbx3 into three molecular grades predicts progression in patients with pta-bc. mod pathol. 2015;28(4):515–22. 47. van kessel kem, van der keur k a, dyrskjot l, et al. molecular markers increase precision of the european association of urology non-muscle-invasive bc progression risk groups. clin cancer res. 2018;24(7):1586–93. 48. d’andrea d, soria f, zehetmayer s, et al. diagnostic accuracy, clinical utility and influence on decision-making of a methylation urine biomarker test in the surveillance of non-muscle-invasive bc. bju int. 2019;123(6):959–67. 49. van kessel kem, de jong jj, ziel-van der made acj, et al. a urine based genomic assay to triage patients with hematuria for cystoscopy. j urol. 2020;204(1):50–7. 50. kavalieris l, o’sullivan pj, suttie jm, et al. a segregation index combining phenotypic (clinical characteristics) and genotypic (gene expression) biomarkers from a urine sample to triage out patients presenting with hematuria who have a low probability of urothelial carcinoma. bmc urol. 2015;15:23. 51. o’sullivan p, sharples k, dalphin m, et al. a multigene urine test for the detection and stratification of bc in patients presenting with hematuria. j urol. 2012;188(3):741–7. 52. kavalieris l , o’sullivan p, frampton c, et al. per for mance characteristics of a multigene urine biomarker test for monitoring for recurrent urothelial carcinoma in a multicenter study. j urol. 2017;197(6):1419–26. 53. lotan y, o’sullivan p, raman jd, et al. clinical comparison of noninvasive urine tests for ruling out recurrent urothelial carcinoma. urol oncol. 2017;35(8):531 e15– e22. 54. wallace e, higuchi r, satya m, et al. development of a 90-minute integrated noninvasive urinar y assay for bc detection. j urol. 2018;199(3):655–62. 55. pichler r, fritz j, tulchiner g, et al. increased accuracy of a novel mrna-based urine test for bc sur veillance. b ju int. 2018;121(1):29–37. 56. elia cd, pycha a, folchini dm, et al. diagnostic predictive value of xper t bc monitor in the follow-up of patients af fected by non-muscle invasive bc. j clin pathol. 2019;72(2):140–4. 57. mengual l, burset m, ribal mj, et al. gene expression signature in urine for diagnosing and assessing aggressiveness of bladder urothelial carcinoma. clin cancer res. 2010;16(9):2624–33. 58. mengual l, ribal mj, lozano jj, et al. validation study of a noninvasive urine test for diagnosis and prognosis assessment of bc: evidence for improved models. j urol. 2014;191(1):261–9. 59. ribal mj, mengual l, lozano jj, et al. gene expression test for the non-invasive diagnosis of bc: a prospective, blinded, international and multicenter validation study. eur j cancer. 2016;54:131–8. 60. sapre n, macint yre g, clarkson m, et al. a urinar y microrna signature can predict the presence of bladder urothelial carcinoma in patients undergoing surveillance. br j cancer. 2016;114(4):454–62. 61. yun sj, jeong p, kim w t, et al. cell-free micrornas in urine as diagnostic and prognostic biomarkers of bc. int j oncol. 2012;41(5):1871–8. 62. backes c, meese e, keller a. specific mirna disease biomarkers in blood, serum and plasma: challenges and prospects. mol diagn ther. 2016;20(6):509–18. 63. klatte t, shariat sf. novel urinary markers for detection of bc–are we failing? j urol. 2014;191(1):9–10. 64. babjuk m, bohle a, burger m, et al. eau guidelines on non-muscleinvasive urothelial carcinoma of the bladder: update 2016. eur urol. 2017;71(3):447–61. 65. mowatt g, zhu s, kilonzo m, et al. systematic review of the clinical effectiveness and cost-effectiveness of photodynamic diagnosis and urine biomarkers (fish, immunocy t, nmp22) and cy tology for the detection and follow-up of bc. health technol assess. 2010;14(4):1–331. 66. guo a, wang x, gao l, shi j, sun c, wan z. bladder tumour antigen (bta stat) test compared to the urine cytology in the diagnosis of bc: a meta-analysis. can urol assoc j. 2014;8:e347–52. 67. aebersold r, mann m. mass-spectrometric exploration of proteome structure and function. nature. 2016;537(7620):347–55. 68. frantzi m, vlahou a. ten years of proteomics in bc: progress and future directions. bc. 2017;3:1–18. 69. zuiverloon tcm, de jong fc, theodorescu d. clinical decision making in sur veillance of non-muscle-invasive bc: the evolving roles of urinary cytology and molecular markers. oncology (williston park). 2017;31(12):855–62. 70. d’costa jj, goldsmith jc, wilson js, br yan rt, ward dg. a systematic review of the diagnostic and prognostic value of urinary protein biomarkers in urothelial bc. bladder cancer. 2016;2:301–17. 71. sathianathen nj, butaney m, weight cj, kumar r, konety br. urinar y biomarkers in the evaluation of primar y hematuria: a s y s t ematic r e v ie w and me t a anal y sis. bladder c an c er. 2018;4:353–63. 72. schmitz-drager bj, droller m, lokeshwar vb, et al. molecular markers for bc screening, early diagnosis, and surveillance: the who/icud consensus. urol int. 2015;94(1):1–24. 73. todenhofer t, hennenlotter j, kuhs u, et al. influence of urinary tract instrumentation and inflammation on the performance of urine markers for the detection of bc. urology. 2012;79:620–4. 74. st yrke j, henriksson h, ljungberg b, et al. evaluation of the diagnostic accuracy of ubc((r)) rapid in bc: a swedish multicentre study. scand j urol. 2017;51(4):293–300. http://www.siuj.org 61siuj.org siuj • volume 1, number 1 • october 2020 urinary-based markers for bladder cancer detection 75. hu an g y l , c h an j, yan w, z an g d, q in q , d en g a m . diagnostic accuracy of cy tokeratin-19 fragment (cyfr a 21-1) for bc: a systematic review and meta-analysis. tumor biol. 2015;36(5):3137–45. 76. dudderidge t, stockley j, nabi g, et al. a novel, non-invasive test enabling bc detection in urine sediment of patients presenting with haematuria-a prospective multicentre performance evaluation of adxbladder. eur urol oncol. 2020;3(1):42–6. 77. snell kie, ward dg, gordon ns, et al. e xploring the roles of urinary hai-1, epcam & egfr in bc prognosis & risk stratification. oncotarget. 2018;9(38):25244–53. 78. kamat am, li r, o’donnell ma, et al. predicting response to intravesical bacillus calmette-guérin immunotherapy: are we there yet? a systematic review. eur urol. 2018;73(5):738–48. 79. lotan y, svatek rs, krabbe lm, xylinas e, klatte t, shariat sf. prospective external validation of a bc detection model. j urol. 2014;192:1343–8. 80. todenhofer t, hennenlotter j, esser m, et al. combined application of cytology and molecular urine markers to improve the detection of urothelial carcinoma. cancer cytopathol. 2013;121(5):252–60. 81. shimizu y, furuya h, br yant greenwood p, et al. a multiplex immunoassay for the non-invasive detection of bc. j transl med. 2016;14(1):1–9. 82. frantzi m, van kessel ke, zwarthoff ec, et al. development and validation of urine-based peptide biomarker panels for detecting bc in a multi-center study. clin cancer res. 2016;22:4077–86. 83. benderska-soder n, hovanec j, pesch b, et al. toward noninvasive follow-up of low-risk bc -rationale and concept of the urofollow trial. urol oncol. 2020. http://www.siuj.org key words competing interests article information biomarkers, prediction modeling, prostate cancer, clinical utility, decision analysis, discrimination, calibration, net benefit dr vickers reports grants from national institutes of health during the conduct of the study; personal fees from opko outside the submitted work. in addition, dr vickers has a patent arctic partners issued. dr assel reports grants from national institutes of health during the conduct of the study. received on june 30, 2020 accepted on august 7, 2020 soc int urol j. 2020;1(1):16–22 biomarker evaluation and clinical development melissa assel, andrew j. vickers department of epidemiology and biostatistics, memorial sloan kettering cancer center, new york, united states abstract most candidate biomarkers are never adopted into clinical practice. the likelihood that a biomarker with good predictive properties will be incorporated into urologic decision-making and will improve patient care can be enhanced by following established principles of biomarker development. studies should follow the remark guidelines, should have clinically relevant outcomes, and should evaluate the biomarker on the same patients to whom the biomarker would be applied in practice. it is also important to recognize that biomarker research is comparative: the question is not whether a biomarker provides information, but whether it provides better information than is already available. continuous biomarkers should not be categorized above or below a fixed cutpoint: risk prediction allows for individualization of care. the risk predictions must be calibrated, that is, close to a patient’s true risk, and decision analysis is required to determine whether using the biomarker in clinical practice would change decisions and improve outcomes. finally, impact studies are needed to evaluate how use of the biomarker in the real world affects outcomes. introduction biomarkers are used either to assess the risk of a current diagnostic state, such as having biopsy-detectable cancer, or to predict the risk of a future event, such as prostate cancer death. in the former case, the biomarker gives the clinician information at less cost, risk, and inconvenience than the diagnostic test; in the latter case, it provides an estimate of probability for occurrence of a future outcome in an individual patient. in this paper, we review methodologic considerations for biomarker development using serum biomarkers in prostate cancer as an example. we do not discuss how biomarkers are discovered or how they can best be measured accurately and reproducibly. we start from early phase studies in humans evaluating the association between the biomarker and the outcome, and move to the later phase trials (ie, impact studies) examining the effects of the biomarker when used in the clinic. to be used most effectively, biomarkers need to be integrated into other information available to the clinician, such as a patient’s age or the stage of the tumor. this can be done informally by “clinical judgment,” using cutpoints and clinical rules, or by using a prediction model. in the case of psa for prostate cancer early detection, an early approach was to use the clinical rule of “psa > 4 or positive digital rectal examination (dre).” this subsequently evolved to the more informal clinical judgment approach, in which the urologist considers the age of the patient, the recent clinical history (such as symptoms of benign prostate disease) and the dre, as well as the absolute level of psa. in the last 10 to 15 years, there has been a move to statistical methods of risk prediction. using statistical models such as the “pcpt risk calculator [1]” or the “pbcg model [2],” the urologist enters clinical data about the patient age, race, dre, family history, and history of prior negative biopsy, as well as the level of psa, and obtains a percentage risk of high-grade cancer. the advantage of prediction models is that they give more accurate predictions than either informal clinical jud g ment—nu merou s st ud ies have demonst rated t hat computer models out per for m cl i n icia ns [3–5]—or the risk groupings used for clinical prediction rules [6–9]. moreover, use of prediction models allows greater individualization of care. a man who is older, has comorbidities, or is averse to medical procedures, but has a psa 16 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation mailto:vickersa%40mskcc.org?subject=siuj http://www.siuj.org abbreviations auc area under the curve dre digital rectal examination epca early prostate cancer antigen pcpt prostate cancer prevention trial pcptrc prostate cancer risk calculator roc receiver operating characteristic epca early prostate cancer antigen level just above 4 might reasonably ask whether his psa warrants a biopsy; comparably, a man anxious about prostate cancer who has a psa just below 4 might want reassurance that his risk is indeed low. it is only by using predicted probabilities that urologists can have a rational conversation about risk that takes into account patient preferences and characteristics. statistical methods for building models are described at length in various publications and are not further discussed here [10]. instead, we focus on approaches to assess the predictiveness of a biomarker in 2 different scenarios: when the biomarker is used independently and when it is incorporated into a prediction model. can the biomarker predict the outcome of interest? choose the right outcome the appropriate clinical endpoint for a biomarker is sometimes more complex that it appears. well-known studies such as the practical collaboration have developed polygenic risk scores for the endpoint of incident prostate cancer [11]. but incident prostate cancer is not synonymous with cancer-related mortality or morbidity. the central problem of prostate cancer early detection is overdiagnosis, reflecting that cancers are diagnosed that would never cause symptoms during the course of the patient’s natural life. it is thus not as useful to know a man’s risk of a prostate cancer diagnosis as it is to know the risk of prostate cancer metastasis or death: a man at high risk of prostate cancer death might want to consider screening to find a cancer early before it spreads; it is not at all clear what a man should do if he is at higher risk of prostate cancer. biomarkers or models that predict the risk of any grade cancer on prostate biopsy can be subject to a similar criticism: we want to find cancers that we would consider treating (eg, grade 2 or higher disease); we do not need to know about the risk of all cancers, including grade group 1 disease, the most appropriate management strategy for which is to order a second biopsy. naturally, the ideal endpoint for any biomarker to predict is cancer-specific morbidity (ie, metastasis) or mortality. given that such endpoints may occur 10 or 20 years after diagnosis, this is challenging and has been attempted only for a handful of prostate cancer biomarkers, including the 4kscore [12,13], the decipher score [14], and, of course, psa [15,16]. does the biomarker distinguish between samples of clearly distinguishable patients? investigators can test whether biomarker levels differ in clearly distinguishable groups of people. these studies can be performed relatively quickly as samples can be obtained from patients on the basis of an outcome status already achieved as opposed to following a cohort of patients prospectively until the outcome of interest occurs, or waiting to accrue patients undergoing a procedure such as biopsy. for example, in the now retracted epca study, levels of epca in men with prostate cancer were compared with those in healthy men, healthy women, and patients with other diseases, such as liver cancer or benign lung disease. diagnostic accuracy should instead be assessed using a sample representative of the population, as shown in table 1. in scenarios a and b, we have a biomarker with high sensitivity and specificity (both 90%) for advanced disease, but unable to distinguish localized disease (sensitivity and specificity of 50%). scenario a represents a sample with an equal number of patients in each disease group, in which the sensitivity and specificity in the entire population for detecting cancer is 70%. however, if the distribution of patients were more ref lective of the population, as in scenario b, the sensitivity and specificity drop to 58% and 63%, respectively. is the biomarker associated with the outcome in patients the biomarker would be applied to in practice? just as drugs are studied in the patients who would receive the drug were it shown to be effective, biomarkers should be studied in the patients to whom they would be applied in practice. the development of free-to-total psa ratio is a good example of a marker that moved from research on convenience samples to the target population of men considering biopsy. first, christensson et al. demonstrated an association between the ratio of a psa isoform, free psa, and the total amount of psa in serum (free-to-total psa ratio) is significantly lower among men with prostate cancer than in men with benign prostate hyperplasia [18]. catalona et al. then determined that free-to-total psa can enhance the specificity of prostate cancer screening by confirming that the association of free-to-total psa 17siuj.org siuj • volume 1, number 1 • october 2020 biomarker evaluation and clinical development http://www.siuj.org and prostate cancer on biopsy remains significant among men with total psa values of 4.1 to 10 ng/ml indicated for prostate biopsy in clinical practice [19]. how well does the biomarker predict the outcome of interest compared to information available to the clinician? a useful biomarker should make additional information available to the clinician. in the catalona et al. example above, measurement of free-to-total psa ratio added information about prostate cancer risk over and above total psa and dre [19]. assessments of discrimination or clinical utility (explained in detail below) can be used to compare the performance of a new biomarker with the performance of an existing model or existing biomarker. alternatively, a biomarker can be combined with other clinical factors by building a prediction model. for example, klein et al. assess the added value of the genomic prostate score by demonstrating that it is significantly associated with the risk of adverse pathology on multivariable logistic regression analysis when added to model containing standard clinical predictors (age, psa, clinical stage, and biopsy) or established prediction models, including cancer of the prostate risk assessment score [20] and the national comprehensive cancer network risk groupings [21]. assessing predictiveness discrimination the area under the receiver operating characteristic curve (auc), also referred to as the concordance statistic (or c index), is commonly used to assess discrimination: the probability that a randomly selected patient with the disease will have higher predicted probability of having the disease according to the test compared to a randomly selected subject without the disease [22-24]. when comparing the discrimination of different models or biomarkers, investigators are encouraged to report the difference in discrimination along with 95% confidence intervals. approaches to assess whether there is a significant difference in discrimination depend on whether the models being compared are “nested.” a nested model is created when, for example, a new biomarker is added to an existing model, for instance, when the 2 models are psa, dre, and age versus psa, dre, age, and free-to-total-ratio. a comparison of 2 existing models, such as the pcpt and the pbcg model, would be non-nested. in these cases, the delong test can be used to test for a difference in discrimination [25]. when models are nested, the p-value from the wald test corresponding to the biomarker should be reported, the delong test being invalid [26,27]. calibration to be clinically useful, a prediction model must not only be able to discriminate between patients with and without the disease but also provide an accurate risk prediction. the degree to which predictions are in agreement with the observed outcomes is known as calibration [28]. a calibration plot visualizes the agreement between model predictions on the x-axis and the actual outcome on the y-axis. this is typically done by splitting the data into equal sized groups of increasing predicted probabilities (deciles) and plot the mean of the observed outcome by the decile of prediction [23]. see figure 1 for an example of a calibration plot. a model with poor calibration in ranges of table 1. two hypothetical studies that sample from individuals without disease, with benign disease, with localized disease, or with advanced cancer* cancer (advanced or localized) no cancer (no disease or benign condition) scenario a biomarker positive (90% x 250) + (50% x 250) = 350 (true positives) (10% x 250) + (50% x 250) = 150 (false positives) biomarker negative (10% x 250) + (50% x 250) = 150 (false negatives) (90% x 250) + (50% x 250) = 350 (true negatives) total 500 500 scenario b biomarker positive (90% x 50) + (50% x 200) = 145 (true positives) (10% x 250) + (50% x 500) = 275 (false positives) biomarker negative (10% x 50) + (50% x 200) = 105 (false negatives) (90% x 250) + (50% x 500) = 475 (true negatives) total 250 750 18 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation http://www.siuj.org probabi lities in which treat ment decisions ca n reasonably differ is likely to be of limited clinical value, even if discrimination is excellent: it is difficult to make a good decision if information about patient risk is wrong. some biomarkers, such as the prostate health index [29] and exodx prostate intelliscore, provide a score, and decisions are made by comparing the score with a proposed cutpoint but these scores do not represent risk of disease. therefore, it is not possible to assess calibration in the traditional sense, although investigators can report the probability of the outcome above and below the previously proposed cutpoints to assess clinical value. clinical utility a new biomarker is of value only if its use leads to improvement in patient outcome via a change in treatment decision patterns. a full assessment of the prognostic value of a biomarker or model must incorporate clinical consequences of the resulting decisions made. table 2 shows a hypothetical study of 1000 men with elevated psa levels. risk of cancer on biopsy was calculated on the basis of a prediction model including a new biomarker. this shows that 300 men had high-grade cancer and that among the 510 men with a predicted risk of 10% or greater (our threshold to indicate biopsy) cancer was detected in 210 of these men (table 2). the clinical consequences shown in table 2 indicate that to determine whether it is better to biopsy all men or to use the statistical model and biopsy those with a 10% risk of high-grade cancer, we need to consider whether it is worth missing 90 cancers to avoid 490 biopsies. in some cases, the results will be fairly obvious: if, for instance, there were only 10 high-grade cancers missed for a reduction of 490 biopsies, the value of the biomarker would be apparent. when results are not immediately clear, decision analysis can be of value. one of the simplest approaches, and the most widely used according to the urologic literature, is “net benefit,” which incorporates the consequences of clinical decisions of a prediction model or biomarker in the analysis [30]. net benefit incorporates both discrimination (auc) and calibration, making it an ideal statistic for comparing prognostic value [31]. a key aspect of net benefit is that the level of risk at which a patient opts to undergo a biopsy is informative of how a figure 1. a calibration plot for a model predicting the risk of high-grade prostate cancer on prostate biopsy. the dots show the average risk (and 95% ci) of patients divided into 10 groups of increasing risk. the dots and dashed regression line fall above the 45-degree line for good calibration, demonstrating that patients had higher risk than that predicted by the model. this is particularly a problem for risks around 10%, the sort of risk at which a patient might opt for prostate biopsy. such a calibration plot would raise questions about whether the model should be used to inform prostate biopsy decision-making. 0 20 40 60 80 100 o bs er ve d ri sk (% ) 0 20 40 60 80 100 predicted risk (%) 19siuj.org siuj • volume 1, number 1 • october 2020 biomarker evaluation and clinical development http://www.siuj.org table 2. hypothetical results of a biomarker study for prostate biopsy illustrating clinical consequences and decision analysis. strategy biopsied biopsy avoided high-grade cancers caught high-grade cancers missed unnecessary biopsies net benefit biopsy all men with elevated psa ied 1000 0 300 0 700 300 – (700 x — ) = 2220.100.90 biopsy all men with elevated psa 510 490 210 90 300 210 – (300 x — ) = 1770.100.90 patient weighs the relative harms of a false-positive (an unnecessary biopsy with risks of side-effects including infectious complications and hospitalization) versus a false-negative (missing or delaying the detection of a high-grade cancer) result. this level of risk is termed threshold probability [30]. the threshold probability chosen in table 2 was 10%, corresponding to odds of 10:90, implying that missing a cancer is 9 times worse than performing an unnecessary biopsy [32]. a threshold of 10% corresponds to a “number-neededto-test” of 1/10% = 10, meaning that 10 men need to be biopsied to find 1 cancer [32,33]. applying this 9:1 ratio to the study results gives the findings in table 2, where it can be seen that the biomarker is actually harmful. even though the marker has reasonable sensitivity and specificity (~70% and ~60%), too many high-grade cancers are missed for the decrease in unnecessary biopsy achieved [34]. one obvious issue is that the threshold can vary between patients or doctors: a patient worried about cancer might opt of a threshold of 6%, whereas one nervous about medical procedures might demand a 15% risk before considering biopsy. in decision curve analysis, the threshold probability is varied over a reasonable range and net benefit plotted against threshold probability [30]. by visualizing the decision curve, one can readily ascertain whether one strategy or model is optimal for across the full range of threshold probabilities of interest. for more on decision curves, which are very widely used in urology research, a selection of further reading is available at www.decisioncurveanalysis.org. impact studies decision analytic techniques provide hypothetical assessments of clinical consequences. impact studies assess the real-world consequences of a new biomarker or model-based strategy. for example, an impact study might assess whether the results of the biomarker translated to changes in decisions. for instance, a typical study of the 4kscore would conclude that, hypothetically, were doctors to use the 4kscore to make biopsy decisions based on a cut-off of 10%, then the biopsy rates would fall by about 50%. in a study designed to determine what happens in actual practice, konety et al. reported a 65% reduction in prostate biopsies in men receiving the 4kscore [35]. however, not all impact studies are consistent with clinical biomarker studies: white et al. found that use of the phi in practice led to a very large decrease in the capture of high-grade cancers, with an approximate 30% risk of high-grade cancer amongst men who avoided biopsy [36]. impact studies are also undertaken because some endpoints are not entirely predictable from clinical research. early research on psa did find that it detected prostate cancer at an early stage, but it was unclear if prostate cancer screening regimens based on psa led to reductions in mortality. the european randomized study of screening for prostate cancer followed men for 16 years and demonstrated a reduction in mortality with psa screening, and can therefore be considered an impact study [37,38]. study design issues the r em ar k g uidelines discuss study design considerations at length [39]. for instance, one key point is that assessors of the outcome should be blinded from the biomarker status. another key concept is that of internal versus external validation. interval validation occurs when a multivariable regression model is developed or a new cutpoint for a biomarker is selected and evaluated for performance on the same dataset. when a prediction model or biomarker cutpoint is developed and assessed on the same dataset estimates of performance are over-optimistic, a phenomenon known as overfitting [40,41]. harrell et al. describe methods for obtaining optimism-corrected internal assessments of performance including data splitting, cross validation, and bootstrapping [42]. external validation not only solves the problem of overoptimism but evaluates genuine differences between 20 siuj • volume 1, number 1 • october 2020 siuj.org molecular biomarkers in urologic oncology: icud-wuof consultation http://www.decisioncurveanalysis.org http://www.siuj.org cohorts. a model predicting recurrence after radical prostatectomy, for instance, may be affected by surgeon skill—less skilled surgeons having higher recurrence rates—or by differences in pathologic grading. an excellent practical example of external validation was a study showing that the risk of prostate cancer among chinese men with a given psa had been shown to be lower than for european men, the most likely explanation being that chinese men have higher rates of benign disease. this true difference between cohorts will mean that prediction models using psa will likely have poor properties when applied in china [43]. recommendations in this paper, we have outlined the evaluation of prostate cancer biomarkers. our key “take-aways” can be summa rized as follows: 1. biomarkers should predict risk rather than be categorized as being above or below a fixed cutpoint: risk prediction allows individualization of care. 2. choose a clinically relevant outcome: many endpoints commonly used in biomarker studies, such as incident prostate cancer or advanced surgical pathology, are problematic. 3. evaluate the biomarker on the patients to whom the biomarker would be applied in practice. 4. follow the remark guidelines for the conduct and reporting of biomarker studies. 5. biomarker research is comparative: the question is not whether a biomarker provides us with information, but whether it provides us better information than we already have, from clinical features or a currently used biomarker. 6. report discrimination, calibration, and net benefit: a biomarker must be able to discriminate better than existing predictors, but risk predictions must be close to a patient’s true risk; decision analysis is required to determine whether using the biomarker in clinical practice would change decisions and whether doing so would improve outcomes. 7. conduct impact studies: evaluate how use of the biomarker in the real world affects outcomes. conclusions it has often been noted that biomarker research has a poor track record of getting biomarkers into clinical practice. following established principles of biomarker development increases the chances that a biomarker with good predictive properties will be incorporated into urologic decision-making and ultimately improve patient care. references 1. thompson im, ankerst dp, chi c, et al. assessing prostate cancer risk: results from the prostate cancer prevention trial. j ntl cancer inst. 2006;98(8):529-34. 2. ankerst dp, straubinger j, selig k, et al. a contemporary prostate biopsy risk calculator based on multiple heterogeneous cohorts. eur urol. 2018;74(2):197-203. 3. kattan mw, yu c, 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