European Urology Today Vol. 32 - No. 3 – June/July 2020

European Urology Today Official newsletter of the European Association of Urology Is there a second, digital, me?

Systems medicine technologies in PCa care

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Dr. Charles Auffray

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Vol.32 No.3 - June/July 2020

Molecular pathology before systemic treatment: feasible?

Prof. Sven Perner

Special EAU20 Virtual Congress Edition

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A growing force amplifying the patient’s voice EPAG: empowering patients

“EAU20 will still provide state-of-the-art urological science” SCO chair Prof. Peter Albers offers insight into the conversion from a physical into a virtual EAU20

By Juul Seesing The EAU is on course for its first online-only Annual Congress: the EAU20 Virtual Congress and Theme Week. Coming up with a suitable scientific programme based on the physical EAU20 was a Herculean task for Scientific Congress Office (SCO) chair Prof. Peter Albers (Düsseldorf, DE) and his team. We spoke with him about the challenges they faced and how they arrived at a programme which still meets EAU20’s quality standards of being the place to be for the latest developments and clinical innovations in urology.

In light of the COVID-19 pandemic, the Board and Executive of the European Association of Urology communicated on 1 April 2020 that the 35th Annual EAU Congress would be converted from a physical congress into a virtual one. The safety of the congress participants and the healthcare community as a whole has the EAU’s highest priority. The EAU20 Virtual Congress is taking place from 17 to 19 July and will be followed by the EAU20 Theme Week from Monday to Sunday, 20-26 July. Prof. Albers takes us back to the early stages of the conversion: “It was an unprecedented situation. After the decision had been made to convert the congress into a virtual one, we first discussed the new format. We also looked around how other societies managed the problem; for instance, we had a conference call with the American Society of Clinical Oncology (ASCO), who had their meeting planned for the end of May.” “Taking that knowledge into consideration, there were different thoughts on how to best organise a virtual meeting. We agreed to cut down the programme of the plenary and thematic sessions to a three-day virtual meeting. The EAU decided to go ahead with a mixture of short lectures, pro/con discussions and question-and-answer sessions.”

“The virtual meeting should become a very vivid and interesting discussion event.”

“As we wanted the best abstracts to still be presented and discussed, we thereafter decided to present the ten best abstracts per track (topic) during a live event with moderators. As a result, we settled on a three-day EAU20 Virtual Congress followed by a seven-day EAU20 Theme Week. This result fulfils the main objective of the Annual EAU Congress to provide state-of-the-art urological science and education.”

Packed programme For the full packed programme of both the EAU20 Virtual Congress and Theme Week, which comprises hot topics in plenary sessions, interactive moderation, live panel discussions and much more, please see pages 24 and 25 of this issue.

Prof. Albers: “The programme shows that delegates of our virtual activities can still expect that we will be presenting the most important topics of EAU20 as initially envisioned. We have a rich mix of oncology and non-oncology sessions. We even

managed to arrange for the Game Changing sessions to feature a discussant as well, next to the presenter, to put the particular issue into perspective.”

“In the course of compiling the planning, we also shortened the time for lectures to leave more opportunity for discussion. The virtual meeting should become a very vivid and interesting discussion event. The online platform that we will be using will have a chat feature that allows all participants to submit their questions.”

“The decision what to include and not to include in the virtual scientific programme was made with the whole SCO. These were hard choices to make, and my colleagues helped a lot. A selection is always subjective, but we tried to reduce the content to the most interesting and/or controversial topics. I hope everyone will be satisfied with the programme.”

Prof. Peter Albers speaking at a previous edition of the Annual EAU Congress

Best abstracts The SCO designed the EAU20 Theme Week to broaden the scientific programme of the Virtual Congress and let delegates easily make a selection of their preferred topics. Combined with the selection of UROwebinars by the European School of Urology (see page 18), the Annual EAU Congress experience will be replicated as a not-to-be-missed multiday online event.

“The threshold for access to the latest and best in urological science has never been lower.”

The Theme Week consists of seven evening sessions, each day from 17:00 to 20:00 CET and with each day covering a different topic: Andrology, Imaging, Functional Urology, Bladder Cancer, Renal Cancer, Prostate Cancer and finally Urinary Stones.

Theme Week days start with a poster session, featuring ten two-minute presentations and discussion. The abstracts were specifically selected by the SCO for their quality and relevance. In that sense, the Theme Week is a digital continuation of the popular expert-guided Poster Tours that were a feature of recent Annual EAU Congresses.

Following each Poster Session, there will be an Industry Session with keynote speakers on products related to each theme. Each day ends with a half-hour Video Session comprising a selection of the best video presentations on the topic and a discussion.

Prof. Albers: “ASCO and other societies decided to completely shift to an on-demand programme of abstracts. We wanted the best abstracts to be discussed. Of course, we cannot organise a virtual abstract session in all aspects of urology, but we selected the most interesting and appealing topics with their best ten abstracts. In addition, all PowerPoint presentations and videos of the originally scheduled abstract presenters at the physical EAU20 will be available in the EAU20 Resource Centre on 1 July.”

The Annual EAU Congress experience will be replicated as a not-to-be-missed multiday online event

Good compromise The experience of chairing the SCO in preparation of an Annual EAU Congress was already unprecedented in itself for Prof. Albers, who started the job last year. “Although I would have loved to chair the SCO for a normal in-person Annual EAU Congress in my first year, I believe we have created a good compromise,” he says. “But I do hope that this will be the first and last completely virtual Annual EAU Congress. I love to meet my colleagues!”

Yet, Prof. Albers also points out a significant advantage of a virtual meeting. “It is easier to participate. It doesn’t matter where you are. You

can log in and out on our virtual platform whenever you want, and you can catch up on any sessions that you might have missed later. We have already started welcoming new delegates who were unable to attend EAU20 in Amsterdam but who can now take part in the Virtual Congress. The threshold for access to the latest and best in urological science has never been lower.”

The EAU20 Virtual Congress platform is going live on 17 July and will be online until 27 July. Delegates can obtain their accreditation credits via this platform. All content will be available on demand.

Please keep an eye on www.eau20.org for the latest information.

Reach for the original.

NGage

®

NITINOL STONE EXTRACTOR

This is a special EAU20 edition of European Urology Today. Due to the cancellation of EAU20 in Amsterdam, which would have taken place from 20 to 24 March 2020, the three EAU20 Congress Newsletters could not be disseminated among delegates. This 48-page EUT features all quality content that was intended for the original EAU20 Congress Newsletters, including all articles written by scheduled presenters.

MEDICAL

Some products may not be available in all markets. © COOK 12/2018

June/July 2020

URO-D44122-EN-F

EUT Congress News

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Non-conventional sperm analyses Beyond the WHO: New EAU Guidelines try to fill the gap Prof. Andrea Salonia Dept of Urology University Vita-Salute San Raffaele Milan (IT)

binding test20, acrosome reaction21, and sperm penetration test (heterologous, based on hamster oocytes devoid of the ZP)22. Nonetheless, the widespread diffusion and adoption of IVF-ICSI as a first-line treatment option led to a decline of the clinical importance of these tests.

Sperm DNA integrity Normal sperm chromatin structure is key for sperm fertilising ability23. The vast majority of sperm DNA is bound to protamine in a dense more compact state, protected from potential damage23. Although sperm The semen analysis (SA) in the male fertility work-up DNA damages may translate into decreased sperm has several goals. We use semen analysis in our quality in SA, conventional SA is not an adequate everyday clinical practice in order to estimate the tool for the assessment of sperm DNA integrity. The probability of natural conception of a subfertile origin of sperm DNA damage is multifactorial and couple1. Moreover, SA assists in the decision regarding mainly due to protamine deficiency, oxidative stress, assisted reproduction techniques, and influences and failure to repair DNA strand breaks23. To date, subsequent second-level fertility diagnostics2-4, published evidence suggests that sperm DNA with the ultimate goal of detecting possible damage, in particular increased DNA fragmentation, underlying causes (e.g. genetics, hypogonadism). results in reduced fertility potential24. The DNA fragmentation index (DFI) is the most frequently This is of major importance, not only for the used proxy measure of sperm DNA damage24. self-evident concept that an informative SA may open Expressed as percentage, DFI indicates the the door to possible treatment, but also because of proportion of sperm cells with detectable DNA the epidemiological connection between male damage25. It was initially shown that fecundability 5,6 declines as a function of the percentage of sperm reproductive health and general health status . This should be addressed by the urologist irrespective of with abnormal chromatin and becomes small when aberrant cells are > 40%26. It is debated what the success of any treatment of fertility issues.

7 represents the best DFI cut off for discriminating However, the WHO parameters of conventional semen analysis may have limited predictive value for infertile men, as well as for the selection of suitable candidates for assisted reproductive technologies the occurrence of spontaneous pregnancy in couples trying to achieve natural conception8,9. Whether this is (ART). As for IUI, the ORs for biochemical pregnancy, due to the high intra-individual variability of SA itself10 clinical pregnancy, and delivery were significantly or to the inherent lack of predictive power of lower for couples with DFI > 30% as compared with conventional semen parameters is not known. As a those with DFI < 30%27. Men with DFI > 30% show remark, up to 60% of male infertility cases remain significantly better results with ICSI than with IVF27. unexplained11,12. Several improvements have been However, there is no full consensus regarding these proposed in order to overcome this lack of appraisal thresholds24. regarding both paternal outcomes and cause identification.

Live birth rates In terms of live birth rates (LBR), a systematic review Total sperm motile count and meta-analysis found that IVF treatment in men A quite different modality to express sperm quality is with high sperm DNA fragmentation is associated the calculation of the total motile sperm count with lower LBR outcome compared to those with low (TMSC). It is obtained by multiplying the volume of the DNA fragmentation28. These results were confirmed in ejaculate (millilitres) by the sperm concentration a more recent meta-analysis29, which also focused the (millions per ml) and the proportion of A (fast forward attention on a key aspect: the type of assay used for progressive) and B (slow progressive) motile sperms the determination of sperm DNA damage determines divided by 100%13,14. There is no full consensus on the final results. whether TSMC values are more informative than conventional SA. A meta-analysis of 16 studies “IVF treatment in men with high showed that TMSC values between 0.8 × 106 and 6 5 × 10 has a prognostic value in couples undergoing sperm DNA fragmentation is IUI. A cohort study recently showed that prewash associated with lower LBR outcome TMSC had better correlation with spontaneous pregnancy rate compared to the WHO 2010 compared to those with low DNA classification system15. More specifically, three fragmentation.” prognostic groups were defined: couples with TMSC < 5, couples with TMSC between 5 and 20, and couples with a TMSC of more than 20 × 106 spermatozoa.

To date, there are at least four different assays for the determination of DFI30: salonia.andrea@ hsr.it

European Urology Today Editor-in-Chief Prof. M. Wirth, Dresden (DE) Section Editors Prof. T.E. Bjerklund Johansen, Oslo (NO) Mr. Ph. Cornford, Liverpool (GB) Prof. O. Hakenberg, Rostock (DE) Dr. D. Karsza, Budapest (HU) Prof. P. Meria, Paris (FR) Dr. G. Ploussard, Toulouse (FR) Prof. J. Rassweiler, Heilbronn (DE) Prof. O. Reich, Munich (DE) Dr. F. Sanguedolce, Barcelona (ES) Prof. S. Tekgül, Ankara (TR) Special Guest Editor Mr. J. Catto, Sheffield (GB) Founding Editor Prof. F. Debruyne, Nijmegen (NL) Editorial Team E. De Groot-Rivera, Arnhem (NL) L. Keizer, Arnhem (NL) H. Lurvink, Arnhem (NL) J. Seesing, Arnhem (NL) EUT Editorial Office PO Box 30016 6803 AA Arnhem The Netherlands T +31 (0)26 389 0680 F +31 (0)26 389 0674 EUT@uroweb.org Disclaimer No part of European Urology Today (EUT) may be reproduced without written permission from the Communication Office of the European Association of Urology (EAU). The comments of the reviewers are their own and not necessarily endorsed by the EAU or the Editorial Board. The EAU does not accept liability for the consequences of inaccurate statements or data. Despite of utmost care the EAU and their Communication Office cannot accept responsibility for errors or omissions.

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EUT Congress News

“The WHO parameters of conventional semen analysis may have limited the predictive value of the occurrence of spontaneous pregnancy in couples trying to achieve natural conception.”

Sperm function tests Sperm function tests (SFT) were developed as an attempt to overcome the limitations of conventional SA. These tests were originally conceived to predict the fertilisation potential of the male gamete in vitro, and most of them remained confined to the research setting by the WHO7. To date, none of them is recommended in the routine examination of the infertile male in the available guidelines3-16. Over time, SFT showed a fair capability in predicting pregnancy outcomes, in particular following IUI17.

However, most of these assays share unpractical disadvantages, the most important being their high demand in terms of disposable time18. The main clinical application of SFT turned out to be the direct submission of patients to intracytoplasmic sperm injection (ICSI) without spending time insisting on IUI in the case of unfavourable functional testing results16. As the name itself suggests, SFT recapitulates the biological events related to sperm-egg interaction, namely sperm capacitation, recognition and binding of the zona pellucida (ZP), acrosome reaction, and sperm penetration16. Such tests are known as capacitation test19, sperm ZP

• TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labelling) • COMET (single cell gel electrophoresis) • SCSA (sperm chromatin structure assay) • SCD (sperm chromatin dispersion) Overall, all these tests have a reasonable-to-good sensitivity30. For the TUNEL assay, SCD test, and Comet assay, meta-regression showed no differences in predictive value between IVF and ICSI30. During SCSA, meta-regression indicated that the predictive values for IVF and ICSI were different30. As current indications for the best setting and candidates for DFI are lacking, the new 2020 EAU Guidelines try to fill this gap.

References 1. Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile male: a committee opinion. Fertil Steril 2015;103:e18-25.

2. Ventimiglia E, Capogrosso P, Boeri L, Pederzoli F, Montorsi F, Salonia A, et al. When to Perform Karyotype Analysis in Infertile Men? Validation of the European Association of Urology Guidelines with the Proposal of a New Predictive Model. Eur Urol 2016:4–7. doi:10.1016/j. eururo.2016.06.015.

3. Jungwirth A, Vice-chair TD, Kopa Z, Krausz C, Minhas S, Tournaye H. EAU Guidelines on Male Infertility 2019.

4. Colpi GM, Francavilla S, Haidl G, Link K, Behre HM, Goulis DG, et al. European Academy of Andrology guideline Management of oligo-asthenoteratozoospermia. Andrology 2018;6:513–24. doi:10.1111/ andr.12502.

5. Eisenberg ML, Li S, Behr B, Pera RR, Cullen MR. Relationship between semen production and medical comorbidity. Fertil Steril 2015;103:66–71. doi:10.1016/j. fertnstert.2014.10.017.

6. 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. doi:10.1016/j.fertnstert.2015.04.020.

7. World Health Organisation. WHO laboratory manual for the Examination and processing of human semen. 5th ed. Geneva, Switzerland: 2010.

8. Guzick DS, Overstreet JW, Factor-Litvak P, Brazil CK, Nakajima ST, Coutifaris C, et al. Sperm morphology, motility, and concentration in fertile and infertile men. N Engl J Med 2001;345:1388–93. doi:10.1056/ NEJMoa003005.

9. Bonde JP, Ernst E, Jensen TK, Hjollund NH, Kolstad H, Henriksen TB, et al. Relation between semen quality and fertility: a population-based study of 430 first-pregnancy planners. Lancet (London, England) 1998;352:1172–7. doi:10.1016/S0140-6736(97)10514-1.

10. Leushuis E, Steeg JW Van Der, Steures P, Repping S, Bossuyt PMM, Mol BWJ, et al. Semen analysis and prediction of natural conception 2014;0:1–8. doi:10.1093/ humrep/deu082.

11. Punab M, Poolamets O, Paju P, Vihljajev V, Pomm K, Ladva R, et al. Causes of male infertility : a 9-year prospective monocentre study on 1737 patients with reduced total sperm counts 2017;32:18–31. doi:10.1093/ humrep/dew284.

12. Olesen IA, Andersson AM, Aksglaede L, Skakkebaek NE, Rajpert-de Meyts E, Joergensen N, et al. Clinical, genetic, biochemical, and testicular biopsy findings among 1,213 men evaluated for infertility. Fertil Steril 2017;107:74-82. e7. doi:10.1016/j.fertnstert.2016.09.015.

13. Smith KD, Rodriguez-Rigau LJ, Steinberger E. Relation between indices of semen analysis and pregnancy rate in infertile couples. Fertil Steril 1977;28:1314–9. doi:10.1016/ s0015-0282(16)42976-6.

14. Ayala C, Steinberger E, Smith DP. The influence of semen analysis parameters on the fertility potential of infertile couples. J Androl 1996;17:718–25.

15. Hamilton JAM, Cissen M, Brandes M, Smeenk JMJ, De Bruin JP, Kremer JAM, et al. Total motile sperm count: A better indicator for the severity of male factor infertility than the WHO sperm classification system.

Hum Reprod 2014;30:1110–21. doi:10.1093/humrep/ dev058.

16. Oehninger S, Ph D, Franken DR, Ph D, Ombelet W, Ph D. Sperm functional tests. Fertil Steril 2014;102:1528–33. doi:10.1016/j.fertnstert.2014.09.044.

17. Arslan M, Morshedi M, Arslan EO, Taylor S, Kanik A, Duran HE, et al. Predictive value of the hemizona assay for pregnancy outcome in patients undergoing controlled ovarian hyperstimulation with intrauterine insemination.

Fertil Steril 2006;85:1697–707. doi:10.1016/j. fertnstert.2005.11.054.

18. ESHRE. Consensus workshop on advanced diagnostic andrology techniques. ESHRE (European Society of Human Reproduction and Embryology) Andrology Special Interest Group. Hum Reprod 1996;11:1463–79.

19. Zaneveld LJ, De Jonge CJ, Anderson RA, Mack SR. Human sperm capacitation and the acrosome reaction. Hum Reprod 1991;6:1265–74. doi:10.1093/oxfordjournals. humrep.a137524.

20. Barros C, Gonzalez J, Herrera E, Bustos-Obregon E. Human sperm penetration into zona-free hamster oocytes as a test to evaluate the sperm fertilizing ability.

Andrologia 1979;11:197–210. doi:10.1111/j.1439-0272.1979. tb02186.x.

21. Cross NL, Meizel S. Methods for evaluating the acrosomal status of mammalian sperm. Biol Reprod 1989;41:635–41. doi:10.1095/biolreprod41.4.635.

22. Mao C, Grimes DA. The sperm penetration assay: can it discriminate between fertile and infertile men? Am J Obstet Gynecol 1988;159:279–86. doi:10.1016/s00029378(88)80068-1.

23. Erenpreiss J, Spano M, Erenpreisa J, Bungum M, Giwercman A. Sperm chromatin structure and male fertility: biological and clinical aspects. Asian J Androl 2006;8:11–29. doi:10.1111/j.1745-7262.2006.00112.x.

24. ASRM. The clinical utility of sperm DNA integrity testing: a guideline. Fertil Steril 2013;99:673–7. doi:10.1016/j. fertnstert.2012.12.049.

25. Lewis SEM. The place of sperm DNA fragmentation testing in current day fertility management. Middle East Fertil Soc J 2013;18:78–82. doi:https://doi.org/10.1016/j. mefs.2013.01.010.

26. Spano M, Bonde JP, Hjollund HI, Kolstad HA, Cordelli E, Leter G. Sperm chromatin damage impairs human fertility. The Danish First Pregnancy Planner Study Team.

Fertil Steril 2000;73:43–50. doi:10.1016/s00150282(99)00462-8.

Due to space constraints, the entire reference list can be made available to interested readers upon request by sending an email to communications@uroweb.org.

June/July 2020

The urologist as gatekeeper for men’s health Male infertility: A warning sign for overall health? between MFI and the development of metabolic abnormalities. Glazer et al. performed a large prospective trial including 39,516 subjects from the Danish national IVF dr.lucaboeri@ register to look at the gmail.com risk of further developing diabetes The infertile man may be a lucky man. This seems a mellitus (DM). They crazy opening statement, but I can explain. It is found that 1.6% of men common knowledge that infertility is a major health developed DM care problem that affects nearly 15% of all couples throughout follow-up. worldwide. A male factor (MFI) is recognised in about The risk was half of the cases. These data gain even more significantly higher for importance when we consider the evidence of an patients with intertwined link between MFI and the overall health Health comorbidities in infertile men oligospermia (HR 1.44; status.

95% CI:1.01-2.06), azoospermia (HR 2.10; In the last two decades, several studies have shown defects in DNA repair genes may be responsible for 95% CI:1.25-3.56), and aspermia (HR 3.20; 95% that infertile men are ‘less healthy’ individuals chronic oxidative stress causing semen alterations CI:1.00-10.31) compared to fertile men. compared to their fertile counterparts. Metabolic and and could at the same time be associated with several cardiovascular disorders, autoimmune diseases, A worse cardiovascular health profile has been cancer types. Microdeletions of the Y-chromosome are endocrinopathies, and tumours have been consistently frequently associated with MFI. Eisenberg et al., in a an established cause of MFI. And differential found to be more prevalent in infertile than fertile cohort of 9,387 men with available semen analysis, expression patterns of the Y chromosome genes have controls of comparable age. Even more crucial, large reported that hypertension, peripheral vascular been associated with PCa. Aberrant epigenetic events population studies suggested a higher overall diseases, cerebrovascular diseases, and non-ischemic affecting DNA hypo and hyper-methylation have been mortality risk for patients affected by MFI. Quantitative heart diseases were all associated with a significantly associated with decreased semen concentration, measures of the overall health status have recently higher rate of semen abnormality (any type). More morphology and motility, but similar mechanisms are been linked directly to seminal parameters alterations. importantly, the same authors compared data of known to be involved in the development of different 13,027 men having received an MFI diagnosis with types of cancer as well. Finally, shared risk factors However, the pathophysiological mechanisms 23,860 men tested for infertility and 79,099 such as smoking and obesity may contribute to the supporting the huge amount of evidences depicting vasectomised men. Infertile men showed significantly development of both infertility and cancer. infertile men as ‘less healthy’ are yet unidentified. So, higher risks of developing ischemic heart disease as compared to controls (HR 1.48; 95% CI:1.19-1.84) and why should we considered infertile men as ‘lucky’ if Hypotheses they carry such a burden of comorbidities? First, let’s vasectomised men (HR 1.20; 95% CI:1.09-1.32).

Two valid hypotheses support the correlation between explore the risky background of the infertile man.

MFI and chronic diseases.

Overall health, mortality, and male infertility Firstly, infertility and comorbidities may share Salonia et al. were among the first to investigate the Cancer and male factor infertility common pathophysiological factors (e.g. genetic association between MFI and overall men’s health.

Men with abnormal semen analyses have been alterations). Secondly, comorbidities may directly They used the Charlson Comorbidity Index (CCI) to associated with a greater incidence of testicular interfere with male reproductive function. Indeed, it is objectively quantify the burden of patients’ cancer, colorectal cancer, and melanoma than their well known that metabolic syndrome and diabetes counterparts in the general population. comorbidities. They showed that infertile men had mellitus have a detrimental impact on hormonal significantly higher CCI scores compared to control environment and semen quality. groups, thus depicting a lower overall health. These “Data depicts MFI as a proxy of were corroborated by subsequent studies A dysregulation of the hormonal environment may overall men’s health. So why should findings where sperm concentration was found to be inversely be a common path between cardiovascular disorders and MFI. Low testosterone levels have infertile men be considered lucky?” associated with increasing CCI score. Interestingly, longitudinal studies confirmed the association been widely associated with a higher risk of between comorbidities and MFI. Data from the In a multicentre study including 51,461 couples developing cardiovascular diseases, suggesting that recruited from 15 centres in California, Walsh et al.

Marketscan claim dataset showed that among 13,027 testicular failure could be responsible for cardiac assessed the incidence of testicular cancer among infertile men, the risk of developing subsequent alterations among infertile men. These data depict male partners and compared results with data from comorbidities was significantly higher compared to MFI as a proxy of overall men’s health. So why the SEER database. They showed that patients with 23,860 controls. The risks of cardiovascular disorders should infertile men be considered lucky?

MFI had a three-fold higher risk of testis cancer as and diabetes was significantly higher in infertile than compared to fertile men. More solid evidence comes fertile men.

Recently, Corona et al. proposed the concept of the from population-based cohort studies. Raman et al. impotent patient as a lucky man, because he has the linked 3,800 men with infertility and abnormal semen Overall mortality chance to undergo certain kinds of medical parameters to regional cancer registries in order to Male infertility has also been associated with overall examinations which may improve not only his sexual retrospectively assess the incidence of testicular mortality. A Danish population-based study analysed life but his health as well. cancers among patients with MFI. The authors found data from 43,277 men submitted to semen analysis a 20-fold higher risk of testicular cancer among evaluation between 1963-2001. The total mortality and Comprehensive medical assessment infertile men compared to the general population. cause-specific mortality of this cohort were compared Similarly, we believe that infertile men are lucky with data from an age-matched population. The because MFI should be considered as an ‘opportunity’ Debate authors reported that, among patients without for a comprehensive medical assessment to check for The association between MFI and subsequent risk of azoospermia, there was a decrease in the risk of comorbid conditions and to improve health status. developing prostate cancer is under debate. Walsh et mortality as the semen concentration increased up to This means that treating infertile men does not al., in a population-based study of 22,562 infertile 40 x 106/mL. Similarly, a decrease in mortality was revolve around mere reproduction, but should be men, reported that men with MFI were 2.6 times associated with better semen motility and focussed on general health status, since relevant more likely to develop a high-grade prostate cancer morphology. Causes of death included infectious comorbidities might influence not only his fertility, (PCa) than their age-matched controls. Similarly, diseases, cancer, cardiovascular disorders, respiratory but his life expectancy as well.

Eisenberg et al., in a large study including 76,083 diseases, and gastro-intestinal diseases. infertile men, reported a two-fold higher risk of PCa It is, therefore, fundamental to properly outline the compared to a control population. On the contrary, Eisenberg et al. further corroborated these findings. presence of coexisting diseases during the male others failed to find an association between MFI and In a cohort of 11,935 infertile men, they showed a infertility work-up, since these may turn out to be of an increased risk of PCa. significantly higher mortality rate associated with low fundamental importance in terms of etiologic semen volume, low sperm concentration, low sperm assessment, therapeutic choice, and paternity Apart from urogenital malignancies, other types of motility, and low total sperm count. Moreover, they outcomes. At the same time, clinicians should be cancer are associated with MFI. Eisenberg et al. used showed that men with two or more abnormal semen aware of the need to properly follow-up these commercial insurance claim data to compare a cohort parameters had a 2.3-fold higher risk of death, patients given their higher risk of developing cancer. of 76,000 infertile men with an age-matched control compared with those having normal semen.

The increasing knowledge and awareness of the group of 112,000 vasectomised men that were comorbidities-infertility interaction will provide presumed to be fertile. They found that patients with Reasons remain unclear precious insights in terms of patient care and future MFI showed a 49% higher risk of being subsequently Why are infertile men characterised by this huge therapeutic developments. diagnosed with any cancer as compared to fertile amount of comorbid conditions, you may ask. male thus considering melanoma, prostate, testis and In fact, the pathophysiological mechanism underlying Due to space constraints, the reference list can be bladder cancer, as well as haematological the association between MFI and lower overall health made available to interested readers upon request by malignancies. is not clear yet. Various theories have been proposed. sending an email to: communications@uroweb.org.

Luca Boeri Dept. of urology Policlinico of Milan Milan (IT)

Metabolic and cardiovascular diseases The impact of metabolic disorders (obesity, insulin resistance) on semen quality and male reproductive function has been widely investigated. Recent evidence has also highlighted the inverse relationship June/July 2020

Genetic and environmental factors have been implicated in the relationship between MFI and cancer. Mutations in the SRY gene on the Y-chromosome have been associated with both gonadal dysgenesis and testicular cancer. Similarly,

Friday 17 July 15.30 - 17.00: Thematic session 02 Men’s health 2020 Virtual room 2

“EAU20 will still provide state-of-the-art urological science”. . . . . . . . . . . . . . . . . . . . . 1 Non-conventional sperm analyses. . . . . . . . . . 2 The urologist as gatekeeper for men’s health. . . 3 Laser enucleation of the prostate: Tips and tricks. . . . . . . . . . . . . . . . . . . . . . . . 7 DNA repair gene mutations in prostate cancer. . . 8 Best Abstracts Non-Oncology: Ass. Prof. Yoshiyuki Akiyama. . . . . . . . . . . . . . 9 Imagine all the people… is there a second, digital, me?. . . . . . . . . . . . . . . . . . . . . . . . . . 11 Treatment of penile amputation. . . . . . . . . . . 12 Molecular pathology before systemic treatment: feasible? . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Frailty and cognitive assessment in MIBC patients. . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Burch colposuspension and pubovaginal sling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 The penile implant of the future. . . . . . . . . . . 17 ESU: UROwebinars programme. . . . . . . . . . . 18 Urethral stricture management: all current and emerging office-based technologies . . . . 19 EAUN: Improving follow-up care after nephrectomy . . . . . . . . . . . . . . . . . . . . . . . . 20 Has the paradigm of botulinum toxin A changed?. . . . . . . . . . . . . . . . . . . . . . . . . . . 21 AUS for stress urinary incontinence in women . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 EAU20 Virtual Congress and Theme Week programme. . . . . . . . . . . . . . . . . . . . . . 24-25 EAU RF section: PHOENIX update. . . . . . . . . . . . . . . . . . . . . 26 Development of predictive biomarkers for RCC . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 EAU RF announces PRIME Study: Prostate imaging using MRI +/- contrast enhancement. . . . . . . . . . . . . . . . . . . . . . . . 27 Best Abstracts Oncology: Prof. Allen C. Gao. . . 28 Limitations of PSMA based on prostate cancer biology. . . . . . . . . . . . . . . . . . . . . . . 29 Best Abstracts Non-Oncology: Dr. Yang Yang. . . 30 Tips and tricks in the removal of large abdominal masses. . . . . . . . . . . . . . . . . . . . 31 Persistence of OAB symptoms after prostate surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Endourology with limited armamentarium, where is the limit? . . . . . . . . . . . . . . . . . . . . 34 Robotic transgender vaginoplasty . . . . . . . . . 35 Best Abstracts Oncology: Dr. Paul Sargos and Dr. Igor Latorzeff . . . . . . . . . . . . . . . . . . 36 Microsurgical sperm recovery from the vas deferens . . . . . . . . . . . . . . . . . . . . . . . . 37 Definition of high-risk, BCG-non-responsive NMIBC. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 Best Abstracts Non-Oncology: Dr. Hiroki Ito. . . 41 New technology for urology: 7T MRI scanner . . 42 Incontinence after prostate treatment: AUA Guidelines update. . . . . . . . . . . . . . . . . 43 Sequencing urothelial carcinoma: “Just do it”. . . . . . . . . . . . . . . . . . . . . . . . . . 45

EAU PI section: Building bridges and connecting people . . . 46 A growing force amplifying the patient’s voice. . . . . . . . . . . . . . . . . . . . . . 47

EUT Congress News

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Award

VIRTUAL

17-26 July

EAU Willy Gregoir Medal M. Wirth

EAU Frans Debruyne Life Time Achievement Award H. M. Van WirthPoppel

Dresden, Germany

Leuven, Dresden,Belgium Germany

For a significant contribution to the development of the urological specialty in Europe

For contribution to the development of the urological Foraasignificant longstanding and important contribution to the specialty in Europe activities and development of the EAU

EAU Crystal Matula Award M. Tilki Wirth D. Dresden, Germany Hamburg, Germany For aasignificant the development of the urological For young contribution promisingtoEuropean urologist specialty in Europe

Supported by LABORIE

EAU Innovators in Urology Award J. Barentsz Nijmegen, The Netherlands For inventions and clinical contributions which have had a major impact on influencing the treatment and/or diagnosis of a urological disease

EAU Hans Marberger Award

EAU Prostate Cancer Research Award

A. Larcher

D. Osses

Milan, Italy

Rotterdam, The Netherlands

For the best European paper published on Minimally Invasive Surgery in Urology

For the best paper published on clinical or experimental studies in prostate cancer

The ERUS Curriculum for Robot-assisted Partial Nephrectomy: Structure Definition and Pilot Clinical Validation European Urology 75 (2019) 1023-1031 Supported by KARL STORZ SE & CO.KG

Results of Prostate Cancer Screening in a Unique Cohort at 19 yr of Follow-up European Urology 75 (2019) 374-377 Supported by the FRITZ H. SCHRÖDER FOUNDATION

EAU Ernest Desnos Prize M. Moran Tucson, United States of America For extraordinary contributions to the History of Urology

New EAU Honorary Members

European Urology® Awards

European Urology® Awards

For an important influence on European urology

Best Scientific Paper

Best Scientific Paper on Robotic Surgery

Genomic Drivers of Poor Prognosis and Enzalutamide Resistance in Metastatic Castration-resistant Prostate Cancer

Robot-assisted AMS-800 Artificial Urinary Sphincter Bladder Neck Implantation in Female Patients with Stress Urinary Incontinence

European Urology, Volume 76, Issue 5, Pages 562–571

European Urology, Volume 75, Issue 1, Pages 169–175

B. Peyronnet, G. Capon, O. Belas, A. Manunta, C. Allenet, J. Hascoet, J. Calves, M. Belas, P. Callerot, G. Robert, A. Descazeaud, G. Fournier (Rennes, Bordeaux, Le Mans, Brest, Limoges, France)

D. Castro Diaz

W. Chen, R. Aggarwal, L. Zhang, S. Zhao, G. Thomas, T. Beer, D. Quigley, A. Foye, D. Playdle, J. Huang, P. Lloyd, E. Lu, D. Sun, X. Guan, M. Rettig, M. Gleave, C. Evans, J. Youngren, L. True, P. Lara, V. Kothari, Z. Xia, K. Chi, R. Reiter, C. Maher, F. Feng, E. Small, J. Alumkal (San Francisco, New Haven, Ann Arbor, Portland, Durham, Los Angeles, Davis, Seattle, St. Louis, USA; Vancouver, Canada)

Tenerife, Span

Supported by ELSEVIER

W. Artibani Verona, Italy

Best Scientific Paper on Fundamental Research

R. Sylvester Brussels, Belgium

T. Tammela Tampere, Finland

L-P. Xie Hangzhou, China

Antifibrotic Synergy Between Phosphodiesterase Type 5 Inhibitors and Selective Oestrogen Receptor Modulators in Peyronie’s Disease Models

Prediction of High-grade Prostate Cancer Following Multiparametric Magnetic Resonance Imaging: Improving the Rotterdam European Randomized Study of Screening for Prostate Cancer Risk Calculators European Urology, Volume 75, Issue 2, Pages 310–318

M. Ilg, M. Mateus, W. Stebbeds, U. Milenkovic, N. Christopher, A. Muneer, M. Albersen, D. Ralph, S. Cellek (Chelmsford, Cranfield, London, United Kingdom; Leuven, Belgium)

A. Alberts, M. Roobol, J. Verbeek, I. Schoots, P. Chiu, D. Osses, J. Tijsterman, H. Beerlage, C. Mannaerts, L. Schimmöller, P. Albers, C. Arsov (Rotterdam, The Hague, Den Bosch, Amsterdam, The Netherlands; Dusseldorf, Germany)

Supported by ELSEVIER

Best Scientific Paper on Clinical Research

Supported by BOSTON SCIENTIFIC

Extended Versus Limited Lymph Node Dissection in Bladder Cancer Patients Undergoing Radical Cystectomy: Survival Results from a Prospective, Randomized Trial

Metastasis-directed Therapy in Treating Nodal Oligorecurrent Prostate Cancer: A Multi-institutional Analysis Comparing the Outcome and Toxicity of Stereotactic Body Radiotherapy and Elective Nodal Radiotherapy

European Urology, Volume 75, Issue 4, Pages 604–611

European Urology, Volume 76, Issue 6, Pages 732–739

J. Gschwend, M. Heck, J. Lehmann, H. Rübben, P. Albers, J. Wolff, D. Frohneberg, P. de Geeter, A. Heidenreich, T. Kälble, M. Stöckle, T. Schnöller, A. Stenzl, M. Müller, M. Truss, S. Roth, U-B. Liehr, J. Leißner, T. Bregenzer, M. Retz (Munich, Essen, Dusseldorf, Karlsruhe, Kassel, Cologne, Fulda, Homburg, Ulm, Tubingen, Ludwigshafen, Dortmund, Wuppertal, Magdeburg, Germany)

E. De Bleser, B. Jereczek-Fossa, D. Pasquier, T. Zilli, N. Van As, S. Siva, A. Fodor, P. Dirix, A. Gomez-Iturriaga, F. Trippa, B. Detti, G. Ingrosso, L. Triggiani, A. Bruni, F. Alongi, D. Reynders, G. De Meerleer, A. Surgo, K. Loukili, R. Miralbell, P. Silva, S. Chander, N. Di Muzio, E. Maranzano, G. Francolini, A. Lancia, A. Tree, C. Deantoni, E. Ponti, G. Marvaso, E. Goetghebeur, P. Ost (Ghent, Antwerp, Belgium; Milan, Terni, Firenze, Rome, Brescia, Modena, Verona, Pavia, Italy; Lille, France; Geneva, Switzerland; London, United Kingdom; Melbourne, Australia; Baracaldo, Spain)

Best Scientific Paper on Oncology A Systematic Review on the Role of Imaging in Early Recurrent Prostate Cancer European Urology Oncology 2 (2019) p47-76

P. De Visschere, C. Standaert, J. Fütterer, G. Villeirs, V. Panebianco, J. Walz, T. Maurer, B. Hadaschik, F. Lecouvet, G. Giannarini, S. Fanti (Ghent, Brussels, Belgium; Nijmegen, The Netherlands; Rome, Udine, Bologna, Italy; Marseille, France; Munich, Hamburg, Essen, Germany) Supported by ELSEVIER

EUT Congress News

Resident’s Corner Awards for the Best Scientific Paper by a Resident (2 awards)

European Urology, Volume 75, Issue 2, Pages 329–340

Supported by ELSEVIER

4

Supported by the VATTIKUTI FOUNDATION

Supported by BOSTON SCIENTIFIC

Platinum Awards P. Dasgupta, London, United Kingdom K. Fizazi, Villejuif, France S. Gillessen, Manchester, Untided Kingdom C. Moore, London, United Kingdom D. Murphy, Melbourne, Australia K. Plass, Arnhem, The Netherlands

June/July 2020

Gallery Best Papers published in Urological Literature Awards

Best Abstract Awards Oncology

Best Abstract Awards Non-Oncology

Best Paper on Fundamental Research

First Prize

First Prize

Single-cell transcriptomes from human kidneys reveal the cellular identity of renal tumors

Inhibition steroid sulfatase suppresses androgen signaling and improves response to enzalutamide

Novel model of micturition based on a multi-unit recordings of optogenetically-identified Barrington’s CRH neurons in mice

Science 361 (6402), 594-599 DOI: 10.1126/science.aat1699

Abstract No. PT090

Abstract No. 423

M. Young, T. Mitchell, F. Vieira Braga, M. Tran, B. Stewart, J. Ferdinand, G. Collord, R. Botting, D-M. Popescu, K. Loudon, R. Vento-Tormo, E. Stephenson, A. Cagan, S. Farndon, M. Del Castillo Velasco-Herrera, C. Guzzo, N. Richoz, L. Mamanova, T. Aho, J. Armitage, A. Riddick, I. Mushtaq, S. Farrell, D. Rampling, J. Nicholson, A. Filby, J. Burge, S. Lisgo, P. Maxwell, S. Lindsay, A. Warren, G. Stewart, N. Sebire, N. Coleman, M. Haniffa, S. Teichmann, M. Clatworthy, S. Behjati (Hinxton, Cambridge, London, Newcastle upon Tyne, United Kingdom)

A. Gao, M. Armstrong, C. Liu, L. Liu, J. Yang, W. Lou, P. Li, C. Evans (Sacramento, Columbus, USA; Chengdu, China)

H. Ito, A. Sales, M. Drake, A. Pickering (Kanagawa, Japan; Bristol, United Kingdom)

Second Prize

Second Prize

Late toxicity and quality of life from GETUG-AFU 22 study: A randomized phase II trial comparing 6 months of degarelix in combination with radiotherapy to radiotherapy alone for patients with detectable PSA after radical prostatectomy

Are glomerulations still a characteristic marker for interstitial cystitis/bladder pain syndrome? Biological evidences from global gene expression and comprehensive immunohistochemical quantification analyses

Best Paper on Clinical Research Treatment Outcome, Toxicity, and Predictive Factors for Radioligand Therapy with 177Lu-PSMA-I&T in Metastatic Castration-resistant Prostate Cancer European Urology 75 (2019) 920-926; https://doi.org/10.1016/ j.eururo.2018.11.016

M. Heck, R. Tauber, S. Schwaiger, M. Retz, C. D’Alessandria, T. Maurer, A. Gafita, H-J. Wester, J. Gschwend, W. Weber, M. Schwaiger, K. Knorr, M. Eiber (Munich, Germany)

Abstract No. 925

Abstract No. 285

P. Sargos, S. Guerif, J. Fraisse, E. Meyer, S. Supiot, E. Lagneau, E. Deniaud-Alexandre, P. Rochin, A. Benyoucef, L. Cartier, H. Hamidou, A. Hasbini, G. Crehange, P. Pommier, G. De Laroche, S. Pelissier, E. Gross, P. Fourneret, L. Salomon, I. Latorzeff (Bordeaux, Poitiers, Montpellier, Caen, Saint-Herblain, Dijon, La Roche-sur-Yon, Mougins, Rouen, Avignon, Angers, Brest, Lyon, St Priest en Jarez, Paris, Marseille, Chambery, Creteil, Toulouse, France)

Y. Akiyama, D. Maeda, H. Katoh, H. Kume, Y. Homma (Tokoyo, Osaka, Japan)

Third Prize Increased stromal components and prostatic fibrosis via altering the CYP19/Estrogen/GPER signaling in the early progression of BPH tissues of men ≤ 50 years old Abstract No. 640

Y. Yang, J. Lin, J. Zhang, Y. Tian, J. Jin (Beijing, China)

Best Abstracts by Residents-in-Urology Awards

Best Video Abstract Awards

Young Academic Urologists Awards

First Prize

First Prize

Best Paper by YAU

CDK12 expression profile and correlation with tumor associated immune cell infiltrates in prostate cancer

Innovations and technical variations in robot-assisted kidney transplantation: Results from the ERUS working group

Abstract No. 1122

V59

Impact of Three-dimensional Printing in Urology: State of the Art and Future Perspectives. A Systematic Review by ESUT-YAUWP Group.

M. Hupe, A. Offermann, C. Schreiber, A. Merseburger, S. Perner (Lubeck, Germany)

A. Gallioli, R. Boissier, A. Territo, R. Campi, G. Vignolini, M. Musquera, A. Alcaraz, K. Decaestecker, V. Tugcu, D. Vanacore, S. Serni, A. Breda (Barcelona, Spain; Ghent, Belgium; Istanbul, Turkey; Florence, Italy)

Second Prize Diagnostic test performance of ultrasound and cytology in upper tract cancer – results from the IDENTIFY study Abstract No. PT339

S. Khadhouri, K. Gallagher, T. Shah, K. Mackenzie, S. Moore, E. Zimmermann, E. Edison, M. Jefferies, M. Nielsen, J. Mcgrath, V. Kasivisvanathan, The BURST collaborative and IDENTIFY Study Group (Aberdeen, Edinburgh, London, Newcastle, Wrexham, Westonsuper-mare, Swansea, Exeter, United Kingdom; Chapel Hill, USA)

Third Prize Does biopsy approach affect histopathology grade concordance from biopsy to prostatectomy? An Australian analysis Abstract No. 54

L. Qu, T. Howard, C. Poyet, N. Davis, D. Bolton, M. Al-Shawi, G. Jack (Victoria, Australia)

Second Prize Double-face augmentation urethroplasty for bulbar urethral strictures-dorsal versus ventral approach: Technical implications and short-term outcomes V58

B. Enganti, M. Chiruvella, M. Bendigeri, S. Ghouse, D. Ragoori, P. Reddy, S. Pandya (Hyderabad, India)

European Urology 2019 Aug; 76(2): 209-221. doi: 10.1016/j.eururo.2019.04.044.

Epub 2019 May 18

G. Cacciamani, Z. Okhunov, A. Meneses, M. Rodriguez-Socarras, J. Rivas, F. Porpiglia, E. Liatsikos, D. Veneziano (Los Angeles, Irvine, USA; Sao Paulo, Brazil; Milan, Turin, Reggio Calabria, Italy; Madrid, Spain; Patras, Greece)

Best Abstract by YAU The IRON study: Investigation of Robot-assisted versus Open Nephron-sparing surgery Abstract No. 30

V57

A. Larcher, G. Rosiello, A. Minervini, A. Mari, F. Di Maida, K. Bensalah, B. Peyronnet, Z. Khene, R. Schiavina, A. Bianchi, A. Mottrie, G. De Naeyer, E. Mazzone, A. Antonelli, M. Furlan, K. Rha, A. Almujalhem, I. Derweesh, A. Bradshaw, J. Kaouk, G. Sawczyn, R. Bertolo, F. Montorsi, U. Capitanio (Milan, Florence, Bologna, Verona, Brescia, Italy; Rennes, France; Aalst, Belgium; Seoul, South-Korea; San Diego, Cleveland, USA)

D. Enikeev, M. Taratkin, E. Laukhtina, R. Sukhanov, A. Dymov, N. Sorokin, S. Shariat, P. Glybochko (Moscow, Russia; Vienna, Austria)

Best Reviewer YAU

Third Prize Safety and short-term oncological outcomes of thulium fiber laser en-bloc resection of non-muscle-invasive bladder cancer: A prospective non-randomized phase II trial

Reviewer for European Urology and Social Media Editor of Scandinavian Journal of Urology M. Fode, Herlev, Denmark

European Urological Scholarship Programme Awards EUSP Best Scholar Award - LAB Real-Time Measurement of Changes in Intra-Pelvic Pressure (IPP) and Intra-Pelvic Temperature (IPT) during Modern Upper Urinary Tract Endourologic Procedures Y. Noureldin, Benha, Egypt

ESUI Vision Award

ESTU René Küss Prize

Multiparametric Cystoscopy for Detection of Bladder Cancer Using Real-time Multispectral Imaging

The European experience in robot-assisted kidney transplantation: Learning curve

M. Kriegmair, J. Rother, B. Grychtol, M. Theuring, M. Ritter, C. Günes, M. Michel, N. Deliolanis, C. Bolenz (Mannheim, Bonn, Ulm, Germany)

Abstract No. 960

A. Gallioli, A. Territo, R. Boissier, R. Campi, G. Vignolini, M. Musquera, A. Alcaraz, K. Decaestecker, V. Tugcu, D. Vanacore, S. Serni, A. Breda (Barcelona, Florence, Italy; Ghent, Belgium; Istanbul, Turkey)

EUSP Best Scholar Award – Clinical Research Renal Transplantation & Urological Oncology R. Boissier, Marseille, France

June/July 2020

EUT Congress News

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21

Cutting-edge Science at Europeâ&#x20AC;&#x2122;s largest Urology Congress

Join us in Milan!

Abstract submission deadline: 1 November 2020

www.eau2021.org 6

EUT Congress News

June/July 2020

Laser enucleation of the prostate: Tips and tricks EEP is gaining momentum worldwide as the technique of choice for surgical treatment of BPH Dr. Fernando Gómez Sancha Institute for Advanced Surgery in Urology Clínica CEMTRO Madrid (ES)

fgomsan@gmail.com Renal transplantation (RT) is currently the best therapeutic option for patients with end-stage renal disease1. The mean age of patients undergoing RT has increased in recent years2. After the restoration of diuresis, LUTS become evident frequently and are responsible for patient bother. Bladder outlet obstruction can also jeopardize graft function.

Recently the role of newer endoscopic approaches, such as laser prostatectomy, has been explored for the treatment of these patients3. Endoscopic enucleation of the prostate (EEP) is gaining momentum worldwide as the technique of choice for surgical treatment of BPH, irrespective of energy source used. Holmium laser enucleation of the prostate is the best studied modality with high quality of published evidence. It is currently the most widely utilised energy source for EEP. More attractive There have been exciting developments both in technology as well as in surgical technique that can make this option even more attractive for BPH patients. Among the technical developments, the advent of fast morcellation is one of the most significant. The efficiency of morcellation has risen to average rates of 10-11 g/minute4. Another exciting development is the introduction of new pulse modulations such as the MOSES technology, which emits two consecutive pulses. The first pulse generates a cavitation bubble that ‘separates the water’ (as the biblical Moses did) to allow for the passage of Holmium laser photons through the bubble resulting in a farther reach of the energy. This results in improved cutting properties as well as enhanced haemostasis, and results in reduced surgical time7.

Developments since HoLEP Surgical techniques have also evolved since the original description of the HoLEP technique by Fraundorfer and Gilling5. The three-lobe technique has evolved over the years, reducing the number of incisions in the gland from 3 to 2, from 2 to 1. Recently incisionless techniques have been introduced, where the adenoma is dissected in one piece in a retrograde

fashion, as the en-bloc enucleation of the adenoma with early apical dissection technique6.

The advantages of the en-bloc approaches, as reported by different groups, are faster operation times, improved visibility throughout the procedure and easier localisation of the surgical plane. Also, it seems that this approach is easier to learn.

Not a simple procedure EEP is not a simple procedure, and there are some factors that are paramount for its success. First, it is a team effort; the surgeon cannot complete this operation alone. He needs everyone in the operating room to understand the procedure and to be able to help if necessary.

Enucleation phase Better visibility due to irrigation of a smaller space

Less bladder distension due to intracapsular work throughout the procedure Faster procedure

Better visibility due to improved hemostasis

Faster morcellation 11g/minute

Second, the right instruments are needed for this Better hemostasis due to MOSES technology procedure. High-quality telescopes allow for perfect visibility, as it is important to recognise the minute details of the right and wrong plane. A fast morcellator Figure 10: Advantages of improved technology and surgical technique in HoLEP is imperative as well as a good camera system.

The procedure starts with a careful urethroscopy and visualisation of the anatomy of the apex, recognising the position of the sphincter relative to the veru montanum. In very large glands, the apex pushes down the sphincter, and the veru is not a good landmark for the sphincter’s position. Careful entry into the bladder must be achieved avoiding excessive downward force of the scope as it can split the sphincter at 12 o’clock.

En-bloc enucleation The first step of en-bloc enucleation is to mark the limit between sphincter and apex by scoring the mucosa circumferentially with the laser fibre positioned at 6 o´clock (see figure 1). This will serve as a reference for the rest of the procedure and protect not only the sphincter but also its mucosal lining, which seems to be very important in providing immediate postoperative continence. This protection of the mucosa was neglected in traditional techniques.

This has influenced the occurrence of temporary postoperative stress incontinence after HoLEP, which probably subsides when the sphincter’s mucosa grows back after some weeks and is again able to provide the watertight sealing effect necessary for continence. There are other potential explanations for temporary postoperative stress incontinence. However, we have seen that the rate of this complication is minimal when this technique is followed, and the mucosal lining of the sphincter is present at the end of the procedure.

Initially, the attachments of the apex to the sphincter are cut clockwise from 3 to 9.

Figure 4: Detachment of the anterior attachments complete early apical liberation

Figure 5: Visibility during en-bloc enucleation is excellent due to the efficient irrigation of a small operative field

Entry into the plane Entry into the plane is achieved by using laser energy or a very gentle blunt push with the tip of the scope towards the side. Once both lateral planes are found posteriorly at the apex, the fibrous tissue cranial to the veru is cut to obtain a single posterior plane that is developed towards the bladder neck to generate some posterior space (see figure 2).

The standard position of the scope, where half the screen shows the adenoma and the other half shows the surgical capsule, is determined. The ‘line of attack’ is seen in the middle. This positioning will happen during the entire procedure. As the circumferential plane is being developed, it will change its orientation from horizontal when dissecting the posterior plane to vertical on the lateral plane. I prefer to keep the fibre at 12 o’clock throughout the procedure (see figure 3).

Anterior sphincter The attachments of the apex to the anterior sphincter are then cut. First, the adenoma must be cut to a depth of 5 mm, clockwise from 9 to 3. This detaches the anterior sphincter from the apex. Once this is done, the correct plane is sought and developed towards 12 o’clock from both sides. As the apex descends progressively, the fibres remaining at 12 o’clock are verticalized and can easily be cut to complete the apical detachment (see figure 4).

After this, the sphincter is safe, and the line of attack can be followed circumferentially to progressively develop the plane towards the bladder neck. The

Figure 7: Entry into the bladder. The view of vertical fibers is the unequivocal sign that the bladder entry point is reached

Figure 8: Completion of the en-bloc enucleation by cutting the 6 o’clock attachments and passage of the adenoma into the bladder

Figure 2: Liberation of the lower half of the sphincter

June/July 2020

Lower irrigation bags due to good visibility - less bladder distension intraoperatively

Less risk of postoperative temporary stress incontinence due to better preservation of sphincter’s mucosa

Figure 1: The limit between apex and mucosa is marked at the beginning of the procedure

Figure 3: Liberation of the posterior plane. Standard view throughout the enucleation phase

Morcellation phase

Figure 6: When the dissection angle opens, the laser fiber must point to the line of attack. When it closes, the laser fiber must point closer to the adenoma to avoid capsular perforation

Figure 9: Wrong (left) and right (right) position of the blade during morcellation. The lower corners allow to judge the distance to the bladder wall and to stop if the blade gets too close

visibility at this stage is usually perfect, as the operative field is very small and thus the irrigation very efficient (see figure 5). Haemostasis is carefully maintained ‘as we go’.

Shape of adenoma It is important to keep in mind the pseudospherical shape of the adenoma (see figure 6), as initially the angle of dissection is eccentric but as we reach the equator of the adenoma, it begins to become concentric. To develop the plane of the first half of the operation, the fibre must point towards the line of attack. In the second part, it must point a little more to the adenoma to allow for a safe dissection and avoid entry into the capsule.

The bladder is entered anteriorly, cranial to the anterior commissure, and this entry is facilitated by the finding of vertical fibres below the circular fibres of the bladder neck (see figure 7).

The bladder neck is cut circumferentially, and the adenoma is tilted into the bladder to facilitate the cutting of the remaining attachments at 6 o’clock (see figure 8). Haemostasis is perfected, and morcellation starts.

Safety measures The key safety measures for morcellation are good haemostasis and visibility and always keeping the bladder full. The tip of the morcellator must be introduced at least at 2 cm to allow vision of the bladder at both sides of the blade. It is a common mistake to keep the blades too close to the telescope.

Then the screen is filled with the image of the adenoma and no information of the position relative to the bladder wall. After morcellation, it is important to check that there are no remaining hidden fragments before withdrawing the instrument and inserting the catheter.

Postoperatively, the catheter is removed after a few hours, even if light haematuria is present. We wash the catheter thoroughly and deflate the balloon to wash the prostate fossa as well. 250-300 mL of saline is instilled before withdrawal, so the first void takes place immediately. We then administer 20 mg of furosemide iv if there is no contraindication to ensure that the patient will void 3-4 times before discharge.

Promising approach In RT patients, this approach of en-bloc enucleation with shorter operation times and less pressure in the bladder during the enucleation phase - with the efficient haemostasis provided by MOSES technology, is certainly very promising. The excellent effect of total de-obstruction provided by HoLEP will ensure a good recovery of the bladder function thanks to better emptying with less chance of residual urine and infection that could risk the survival of the graft.

For non-transplanted patients, HoLEP remains an excellent method for the total resolution of lower urinary tract symptoms. Recent refinements in surgical techniques6 and in surgical technology have made this procedure simpler to perform and learn. It is a very fast, most procedures can be performed in less than 1 hour, and very safe operation, with low incidence of complications and very low risk of temporary postoperative incontinence (see figure 10).

Due to space constraints, the reference list can be made available to interested readers upon request by sending an email to: communications@uroweb.org.

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DNA repair gene mutations in prostate cancer Effects on outcomes after primary and systemic therapy Ms. Elena Castro Hospital Universitario Virgen de la Victoria Madrid (ES)

ecastro@ext.cnio.es The high prevalence of genomic alterations involving DNA damage repair (DDR) genes in prostate cancer has only recently been recognised1-7.

In 2015, the Cancer Genome Atlas (TCGA) identified DDR alterations in 19% of the 333 primary tumours analysed5. At the same time, a report of the International Stand Up to Cancer/Prostate Cancer Foundation (SU2C-PCF) identified genomic alterations affecting DDR genes in 23% of the 150 metastatic biopsies studied1. However, the larger series of prostate cancer samples screened for DDR defects has been provided by the PROFOUND study8, a phase III study addressing the benefit of olaparib in mCRPC.A total of 2792 samples, including both primary tumour and metastatic biopsies, were successfully screened for aberrations in 15 genes involved in the homologous recombination (HR) pathway. Such alterations were identified in 28% of the samples analysed9, and confirmed BRCA2 as the most commonly altered DDR gene (8.7%) followed

by CDK12 (6.3%), ATM (5.9%), CHEK2 (1.2%) and BRCA1 (1%). Genomic events leading to a mismatch repair (MMR) deficiency have been observed in 3.1% of prostate cancer cases, mostly affecting MSH210.

Mutated genes One of the most important findings of the SU2C-PCF was the observation that in half of the samples with DDR defects, these alterations were already present in the germline. Unexpectedly, 8% of the mCRPC patients analysed by Robinson et al. were found to harbour a germline DDR mutation1. Later studies have confirmed these findings and established the prevalence of germline DDR in metastatic prostate cancer patients between 7.5 and 12%, depending on the number of genes analysed and the genetic background of the population studied2,7,11. BRCA2 is the most mutated gene (5-3%), although the prevalence of these alterations may vary among populations.

Despite the relatively high prevalence of germline and somatic DDR defects in prostate cancer, the clinical relevance of these alterations remains unclear. The only exception is germline BRCA2 mutation, which has been shown to be an independent prognostic factor for prostate cancer outcomes in different settings7,12-14.

“Interestingly, those patients who received chemotherapy before the ARSI had shorter PFS and CSS, suggesting that treatment sequence could be important in this setting.”

Germline BRCA mutation carriers The data currently available regarding the implications of germline and somatic DDR defects in early prostate cancer come from retrospective analyses. It is mostly focussed on germline BRCA mutation carriers. A report on the outcome of 1,211 men undergoing active surveillance that included 11 BRCA1, 11 BRCA2 and 5 ATM germline carriers has shown that tumours in BRCA2 carriers are more likely to present a tumour grade re-classification in subsequent biopsies. In this series, tumour staging upgrade incidence at 2, 5 and 10 years was 27%, 50% and 78% in BRCA2 carriers compared to 10%, 22% and 40% in non- carriers (p = 0.001)14. These results indicate that active surveillance may not be the appropriate management strategy for germline BRCA2 carriers with low-risk tumours.

Relevance of alterations Likewise, no conclusive data is available regarding the relevance of alterations in BRCA2 or other DDR genes in selecting curative treatment options. The only existing data comes from a retrospective study 8

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that analysed the outcomes of 1,200 patients with localised disease, including 18 BRCA1 and 49 BRCA2 carriers. In this series, BRCA1/2 carriers developed metastasis significantly earlier than non-carriers after radical treatment. Metastasis-free survival for those surgically treated was 89% and 67% in BRCA1/2 carries and 97% and 91% in non-carriers at 5 and 10 years, respectively (p = 0.024). The difference was even greater for those treated with radiotherapy, as only 57% and 39% of BRCA1/2 carriers were free from metastasis at 5 and 10 years, respectively, compared to 91% and 80% of non-carriers (p < 0.001)13. A direct comparison of the two groups was not performed because patients treated with radiotherapy (both carriers and non-carriers) presented with more advanced disease than men who were surgically treated. Therefore, it is not possible to conclude which of the two treatment options would be preferable for BRCA1/2 carriers.

“Active surveillance may not be the appropriate management strategy for germline BRCA2 carriers.”

Three retrospective studies The evidence regarding the clinical implications of DDR defects in advanced prostate cancer is conflicting. Three retrospective studies have assessed the role of germline DDR mutations in the outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) treated with androgen receptor signalling inhibitors (ARSi) and taxanes. In the first report, Annala et al.15 analysed 176 mCRPC patients, including 22 germline carriers (16 gBRCA2). They found that carriers treated with an ARSI as first-line therapy had shorter PFS than noncarriers (3.3 vs. 6.2 months, p = 0.01), even though they observed prolonged responses to ARSi in some carriers. Importantly, almost all carriers in this series had a ctDNA/cfDNA fraction > 35%, which is strongly correlated with poor responses and shorter OS16. Therefore, it is questionable whether the poor clinical outcomes of these patients may be related solely to their germline status or was affected by other confounding factors. In a second report, Antonarakis et al.17 analysed the clinical outcomes of 172 mCRPC patients, including 22 germline carriers (5 gBRCA2) who were treated with ARSI. In this study, carriers showed a statistically significant trend to longer PFS than non-carriers (15 vs. 10.8 months, p = 0.090). Interestingly, those patients who received chemotherapy before the ARSI, had shorter PFS and CSS, suggesting that treatment sequence could be important in this setting. The third report18 analysed the outcomes of 390 mCRPC patients included in the series published by Pritchard et al. describing the prevalence of germline DDR alterations2. This study included 60 germline DDR mutation carriers (37 in BRCA2). No significant differences in the responses to the administered therapies or in overall survival were observed. However, it should be noted that up to 47% of carriers in this series had received platinum salts and/or PARP inhibitors, which could have a confounding effect on the outcomes.

Treatment sequence PROREPAIR-B7 was the first prospective study designed to evaluate the impact of germline DDR mutations on the outcomes of mCRPC patients. 419 patients were analysed, including 68 germline carriers (14 gBRCA2). It is remarkable that in this cohort, in which none of the carriers received PARP inhibitors or platinum salts, CSS was halved in BRCA2 carriers compared with non-carriers (17.4 vs. 33.2 months, p = 0.027). The multivariate analyses identified gBRCA2 mutations as an independent prognostic factor for CSS in this setting (HR, 2.11;95% CI,1.06-4.18). Exploratory analyses in this cohort showed that gBRCA2 carriers had worse CSS when they received a taxane as first-line treatment followed by an ARSI (10.7 vs. 28.4 months, p < 0.001) than non-carriers. Conversely, there were no differences in CSS between gBRCA2 carriers and non-carriers treated with the ARSI-taxane sequence (24 vs. 31.2 months, p = 0.901). No differences in outcomes based on treatment sequence were observed in noncarriers. Further studies are required, to validate a potential role or germline BRCA2 status in tailoring treatment sequence.

Studies of PARP inhibitors in monotherapy for mCRPC PROFOUND

TRITON 2

TALAPRO 1

GALAHAD

Drug

Olaparib 300 mg bid

Rucaparib 600 mg bid

Talazoparib 1mg qd

Niraparib 300 mg qd

Study Design

Phase III

Phase II

Phase II

Phase II

Population

mCRPC Progression to ARSi

mCRPC Progression to ARSi and taxane

mCRPC Progression to ARSi and taxane

mCRPC Progression to ARSi and taxane

Primary objective

rPFS in pts with alterations in ATM, BRCA1, BRCA2

ORR and PSA response (≥50% decline) in pts with DDR alterations

ORR in patients with DDR alterations

ORR in patients with Bi-allelic BRCA1/2 alterations

Specimen tested

Tumor tissue Central

Plasma or tumor tissue Central/Local

Tumor Tissue Central/Local

Plasma Central

Test used

FoundationOne®

FoundationOne® FoundationACT® Local

FoundationOne®

Resolution-HRD®

Genes screened

ATM, BARD1,BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L

ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, RAD54L

Genomic alteration required

ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA,MLH1, MRE11A, NBN, PALB2, RAD51C,

Mono- Bi- allelic DDR alterations

A summary of the four clinical trials which address the benefit of PARP inhibitors in mCRPC

Synthetic lethality strategies The relatively high prevalence of alterations in DDR genes in advanced prostate cancer is a unique opportunity to take advantage of these defects by using synthetic lethality strategies. Platinum-based chemotherapy causes DNA cross-links that cannot be repaired easily when the HR pathway is impaired, leading to cell death. Platinum salts have not shown a significant benefit in unselected mCRPC patients and are not a standard of care for these patients unless a neuroendocrine differentiation has occurred19,20. However, this strategy has been proven successful to treat breast21,22 and ovarian23 cancer with pathogenic mutations in BRCA1 or BRCA2.

Several trials are testing platinum-based chemotherapy to treat prostate cancer with DDR defects, as retrospective analyses suggest a clear benefit for these patients24,25. Another strategy to treat DDR-deficient tumours is to exploit the synthetic lethal interaction between the inhibition of the poly ADP-ribose polymerase (PARP) and HR impairment. Several PARP inhibitors are at different stages of clinical development and they differ in their ability to bind PARP and to trap PARP-DNA complexes26.

PROFOUND trial PROFOUND8 has been the first randomised phase 3 biomarker-driven clinical trial in mCRPC patients. In this trial, HR-deficient mCRPC patients, who had progressed to prior ARSIs, were randomised 2:1 to receive olaparib 300 mg bid or the alternative ARSI according to the physician´s choice. The study showed a statistically significant benefit for rPFS in patients with BRCA2, BRCA1, and ATM alterations, with a median rPFS of 7.4 months in men treated with olaparib vs. 3.5 in those who received abiraterone or enzalutamide (p < 0.0001; HR 0.34 95% CI 0.25-0.47). Median Overall Survival in patients with BRCA2, BRCA1 and ATM alterations was 18.5 vs. 15.1 months in the control group (p=0.02). In an exploratory analysis to look at the gene-by-gene effect on rPFS, BRCA2 alterations seem to have the greatest predictive value of response to olaparib.

Preliminary results of two phase II trials (TRITON 227 and GALAHAD28) evaluating the efficacy of two other PARP inhibitors (rucaparib and niraparib, respectively) in heavily pre-treated mCRPC patients have also been reported. Both studies have enrolled patients with DDR defects, although the assays and the gene panels used to screen patients and decide their eligibility are different.

“Several trials are testing platinum-based chemotherapy to treat prostate cancer with DDR defects, as retrospective analyses suggest a clear benefit for these patients.”

Response rates Similar response rates have been reported in both trials for patients with germline BRCA1/2 mutations (44% TRITON2 and 40% in GALAHAD). Half of

ATM, BRCA1, BRCA2, BRIP1, CHEK2, FANCA, HDAC2, PALB2

Bi-allelic DDR alterations Elena Castro MD PhD

BRCA1/2 carriers also had a ≥ 50% decrease in PSA. Response rates were significantly lower for patients with DDR defects other than BRCA1/2, as only 15% and 9% of patients achieved an objective radiographic response in TRITON2 and GALAHAD, respectively. TRITON included patients with mono and bi-allelic BRCA1/2 alterations whilst only patients with bi-allelic defects were eligible for GALAHAD. However, in view of the reported response rates the impact of the zygosity on the response to PARP inhibitors is unclear, at least for mCRPC. The results of these studies will promptly change the current clinical practice. They will lead the way to a new first targeted therapy for men with advanced prostate cancer.

“The results of these studies will lead the way to a new first targeted therapy for men with advanced prostate cancer.”

Other therapeutic strategies, including anti PD-1, ATR, ATM and Chk inhibitors, are being explored to treat patients with DDR defects in genes other than BRCA2 that have shown limited benefit form treatment with PARP inhibitors.

References 1.

2.

3.

4.

Robinson, D., et al., Cell, 2015. 161(5): p. 1215-1228.

Pritchard, C.C., et al., N Engl J Med, 2016. 375(5): p. 443-53.

Abida, W., et al., JCO Precis Oncol, 2017. 2017.

Abida, W., et al., Proc Natl Acad Sci U S A, 2019. 116(23): p. 11428-11436.

5. Cancer Genome Atlas Research, N., Cell, 2015. 163(4): p.

1011-25.

6. Armenia, J., et al., Nat Genet, 2018. 50(5): p. 645-651.

7. Castro, E., et al., J Clin Oncol, 2019. 37(6): p. 490-503.

8. de Bono et al; N Engl J Med. 2020 Apr 28. doi: 10.1056/ NEJMoa1911440.

9. J.S. de Bono et al., Annals of Oncology, 2019. 30: p. v325-355.

10. Abida, W., et al., JAMA Oncol, 2018.

11. Nicolosi, P., et al., JAMA Oncol, 2019.

12. Castro, E., et al., J Clin Oncol, 2013. 31(14): p. 1748-57.

13. Castro, E., et al., Eur Urol, 2015. 68(2): p. 186-93.

14. Carter, H.B., et al., Eur Urol, 2019. 75(5): p. 743-749.

15. Annala, M., et al., Eur Urol, 2017. 72(1): p. 34-42.

16. Annala, M., et al., Cancer Discov, 2018. 8(4): p. 444-457.

17. Antonarakis, E.S., et al., Eur Urol, 2018. 74(2): p. 218-225.

18. Mateo, J., et al., Eur Urol, 2018. 73(5): p. 687-693.

19. Sternberg, C.N., et al.,. J Clin Oncol, 2009. 27(32): p.

5431-8.

20. Hager, S., et al., Ann Oncol, 2016. 27(6): p. 975-84.

21. Byrski, T., et al., J Clin Oncol, 2010. 28(3): p. 375-9.

22. von Minckwitz, G., et al., Lancet Oncol, 2014. 15(7): p. 747-56.

23. Yang, D., et al., JAMA, 2011. 306(14): p. 1557-65.

24. Pomerantz, M.M., et al., Cancer, 2017. 123(18): p.

3532-3539.

25. Cheng, H.H., et al., Eur Urol, 2016. 69(6): p. 992-5.

26. Murai, J., et al., Cancer Res, 2012. 72(21): p. 5588-99.

27. Abida W et al; Clin Cancer Res. 2020 Feb 21. doi: 10.1158/1078-0432.CCR-20-0394.

28. Smith, M.R., et al., Annals of Oncology, 2019.

30(Supplement_5).

June/July 2020

Best Abstracts

Glomerulations as marker for IC/BPS? Evidence from global gene expression and immunohistochemical analyses Ass. Prof. Yoshiyuki Akiyama Dept. of Urology Graduate School of Medicine University of Tokyo (JP) yakiyamauro-tky@ umin.ac.jp Ass. Prof. Yoshiyuki Akiyama is one of the authors of the abstract “Are glomerulations still characteristic marker for interstitial cystitis/ bladder pain syndrome? Biological evidences from global gene expression and comprehensive immunohistochemical quantification analyses,” which won the second prize in the EAU20 Best Abstract Awards Non-Oncology. This article reflects its highlights.

A Hunner lesion and glomerulations (mucosal bleeding after bladder overdistension) have been considered characteristic disease markers of interstitial cystitis/ bladder pain syndrome (IC/BPS) with and without Hunner lesions respectively and play a significant role in the diagnosis and classification of IC/BPS1,2.

Currently, IC/BPS without Hunner lesions with glomerulations is to be diagnosed as non-Hunner type IC in the East Asian guidelines or BPS type 2 in the International Society for the Study of Bladder Pain Syndrome (ESSIC) guidelines. IC/BPS with neither Hunner lesions nor glomerulations is to be designated as hypersensitive bladder or BPS type 1. In the past, some studies suggested that glomerulations could result from increased neovascularisation and abnormal capillary structure in the bladder mucosa, which might be associated with the pathophysiology of IC/BPS3. To date, IC/BPS without Hunner lesions with glomerulations is likely to be regarded as a disorder of the urinary bladder, with obvious pathology such as ‘bladder mucosal bleeding’4. Moreover, bladderdirected treatments such as intravesical therapies (lidocaine, heparin, hyaluronic acid, chondroitin sulphate, or botulinum toxin) or bladder hydrodistension have been applied to patients with IC/ BPS without Hunner lesions with glomerulations. Thus, the presence or absence of glomerulations plays a critical role in the diagnosis, classification, and clinical management of IC/BPS.

Unsupervised hierarchical clustering analysis using the DEGs was performed to overview the genomic landscape of IC/BPS with and without glomerulations and normal bladder. For histological analysis, we quantified subepithelial lymphoplasmacytic and mast cell infiltration, neovascularisation, and microvasculature by digital immunohistochemical enumeration of CD3, CD20, CD138, human mast cell tryptase, and vascular endothelial growth factor (VEGF)-positive cells as well as CD31-positive microvessels (defined as capillaries or small precapillary arterioles with an endothelial monolayer, an area of 10 to 314 mm2, and an average luminal diameter of 20 mm or less), using Tissue Studio® software (version 3.5, Definiens AG, Munich (DE)).

Consequently, the presence of glomerulations did not affect global gene expression or the degree of subepithelial lymphoplasmacytic and mast cell Figure 2A: Lymphoplasmacytic and mast cell densities infiltration, neovascularisation, and microvasculature.

IC/BPS patients lacking Hunner lesions showed a similar gene expression pattern to the controls, regardless of the presence or absence of glomerulations.

A total of 46 DEGs were detected in patients with glomerulations. The number was too small to yield reliable results in the pathway enrichment analysis.

Therefore, the presence of glomerulations could not be linked to any biological pathways (see figure 1). There were no differences in densities of lymphoplasmacytic and mast cells, VEGF-positive cells, and microvessels detected between patients with IC/BPS and controls, regardless of the presence or absence of glomerulations (see figure 2). These results indicate that glomerulations may be irrelevant to the subepithelial inflammation, neovascularisation, and microvasculature, suggesting that it may not be a pathognomonic feature of IC/BPS. Collectively, the results of this study could lead to the assumption that a proven, clinically relevant subtype of IC/BPS is the Hunner lesion subtype alone. The Hunner lesion subtype has a definite bladder aetiology and presents with bladder-centric symptoms. Moreover, patients with IC/BPS with Hunner lesions are likely to be responsive to bladder-directed treatments such as fulguration/resection of the lesions and intra-lesion steroid injection6.

Meanwhile, the non-Hunner lesion subtype (potentially regardless of the presence or absence of glomerulations) has little bladder aetiology and presents with widespread, systemic symptoms with a variety of comorbid diseases. This might explain why bladder-directed treatments have limited effects in patients with this subtype7,8,9. However, this study has the limitation of a small sample size, which may not be enough to draw any definitive conclusions.

Further biological analyses using larger samples should be warranted to verify the role of glomerulations in the diagnosis and aetiology of IC/ BPS.

In conclusion, the current study demonstrated that in IC/BPS without Hunner lesions the presence of glomerulations did not make a difference in global gene expression, densities of subepithelial Figure 1: The presence of glomerulations could not be linked to any biological pathways inflammatory infiltrates and microvessels, and degree of neovascularisation.

Glomerulations may not be a phenotypic feature of IC/ However, a recent meta-analysis study revealed that BPS. It may be about time to revisit the definition, there was no consistent relationship between glomerulations and the diagnosis of IC/BPS5. Moreover, diagnosis, and classification of IC/BPS. Proper glomerulations did not correlate with symptom severity subtyping and an accurate understanding of the and were found in patients without IC/BPS and healthy pathophysiology based on clinical and basic research findings is the only way to achieve better clinical subjects. In this study, we attempted to seek for management and future research progress. biological evidence of glomerulations that could shed light on this controversial matter by conducting systemic genomic and histological analyses in patients Due to space constraints, the reference list can be with IC/BPS with and without glomerulations. For made available to interested readers upon request by sending an email to: communications@uroweb.org. genomic analysis, we sequenced total RNA obtained from the bladder mucosal biopsies of 21 patients with IC/BPS without Hunner lesions, including with11 and Saturday 18 July 16.30-17.00: Poster Session without10 glomerulations, and 9 controls of normal bladder. We looked for differentially expressed genes Best abstract session: Non-oncology (DEGs) in order to identify significantly enriched genes Virtual room 2 and biological processes related to glomerulations.

June/July 2020

Figure 2B: Microvessel density and VEGF positivity

To all those working tirelessly in the fight against COVID-19,

Thank you.

You inspire us.

We’re committed to doing our part.

Visit BMS.com to learn about how we’re supporting our communities in Europe during these unprecedented times.

© 2020 Bristol-Myers Squibb Company.

All rights reserved.

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Every single day is about Changing tomorrow.

Each day we commit ourselves to answer the unmet needs of patients, building on our heritage in oncology, urology and transplant.

We follow the science and apply breakthrough research to further therapy areas including neuroscience, ophthalmology, nephrology, womenâ&#x20AC;&#x2122;s health, immunology and muscle diseases.

We are relentless in our mission to transform innovative science into value for our patients.

Find out more about us at: astellas.com/eu

Š April 2020 Astellas Pharma Europe Ltd. Date of preparation: April 2020 NON_2020_0027_APE

10

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June/July 2020

Imagine all the people… is there a second, digital, me?

PIONEERing big data and systems medicine technologies in prostate cancer research and care Dr. Charles Auffray European Institute for Systems Biology & Medicine (EISBM) Vourles (FR)

cauffray@eisbm.org Over the past two decades, advances in engineering and computer sciences have provided increasingly efficient and affordable access to high-dimensional functional genomics data as global measures of metabolomic, proteomic, transcriptomic, genomic, genetic, and epigenetic features. Their integration with biological, clinical, environmental, and lifestyle assessments using iterative statistical analyses, computational modelling, and experimental validation has enabled systems biology approaches, which started to transform biomedical research and clinical practice. This is triggering the transition from a reactive to a proactive practice of medicine, revolutionising how medicine is practised in the 21st century.1-10 The effective development of participatory, personalised, predictive, and preventive (P4) systems medicine was made possible by harmonisation of experimental and computational methods for data, information and knowledge collection, storage, analysis, integration, and sharing on a big data scale.

High-performance cloud computing infrastructures were used11, supporting ongoing community efforts of biologists, medical doctors, and computer scientists for the development of systems medicine disease maps using an advanced intelligence approach for multi-level representation of domain expert knowledge and experimental data in a human and machine readable format (figure 1).12-13

“By monitoring individuals over a long period of time, it becomes possible to provide them with actionable recommendations to maintain their state of health and well-being.”

Monitoring well-being In addition, the emergence of a wide variety of connected mobile devices has made it possible to also assess environmental and occupational exposures (e.g. nutrition, sleep, exercise, and stress) on a regular, real-time basis.14 The power of integrating these diverse types of data into a digital representation of a person has been demonstrated initially by two individuals who have managed to anticipate the occurrence of disease and take preventive measures to their benefit.15-16 An effective implementation of systems medicine has thus been made possible by scaling up the monitoring of well-being, health, and disease through the collection of billions of data points for increasing numbers of individuals who are healthy, at risk of developing disease, or in the course of disease development, with their active participation through social networks (figure 2).17-18 By monitoring individuals over a long period of time, it becomes possible to provide them with actionable recommendations to maintain their state of health

and well-being, detect early events indicative of a risk or a transition to disease, and enable improvement of their personalised management, treatment and cure (figure 3).19 The expectation is that expanding the monitoring from one to millions to billions of individuals over the next generation will trigger a reversal of the escalating costs of healthcare management, drug, and diagnostic development, providing the basis for a more cost-efficient and sustainable integrated health care system.20

“PIONEER has already identified critical evidence gaps in prostate cancer care through a detailed prioritisation exercise.”

Data security and training In this context, ensuring data security and compliance Figure 2: Monitoring well-being, health, and disease: collection of diverse data types from single individuals with personal data and privacy protection regulations, such as the European Union General Data Protection Regulation, is important. An active participation of all stakeholders, including researchers and clinicians in academy and industry, regulatory and funding bodies, individuals and patient organisations, and the multidisciplinary training of a new generation of scientists and medical doctors, has been recognised as essential components of this ongoing transformation.11,21-22 PIONEER partnership PIONEER will leverage these big data and systems medicine technologies. PIONEER (Prostate Cancer DIagnOsis and TreatmeNt Enhancement through the power of big data in EuRope) is a public-private partnership of 34 academic, industrial, legal, medical, and patient organisations from 9 countries across Europe, part of the Big Data for Better Outcomes Programme of the Innovative Medicines Initiative.

Since May 2018, it has been supported by the European Union and the European Federation of Pharmaceutical Industries and Associations, a support which it will receive for five years total.23 PIONEER has already identified critical evidence gaps in prostate cancer care through a detailed prioritisation exercise that involved all relevant stakeholders. The consortium is set up to leverage advanced big data management and systems medicine technologies within a shared computational platform. Its mission is to provide the high-quality evidence required to support improvement in prostate cancer management and care. This will be achieved through the standardisation and integration of existing sources of data from prostate cancer patients across different stages of the disease, in close collaboration with worldwide data providers. PIONEER thus aims to contribute to overcome the current underuse of effective treatments and overuse of ineffective treatments and to enhance the quality of health and social care delivered to each individual and all prostate cancer patients and their families, while serving as an exemplar project for the dissemination of the practice of systems medicine.

References 1. Auffray C, Chen Z, Hood L. (2009) Systems medicine: the future of medical genomics and healthcare. Genome Med. 1:29. PMID:19348689 2. Auffray et al. (2010) Chest 137:1410-1436. PMID:20525651 3. Hood L, Friend SH. (2011) Predictive, personalized, preventive, participative (P4) cancer medicine. Nat Rev Clin Oncol. 8:184-187. PMID:21364692 4. Hood L, Balling R, Auffray C. (2012) Revolutionizing medicine in the 21st century through systems approaches. Biotechnol J. 7:992-1001. PMID:22815171

Figure 1: Development of disease maps using the Systems Biology Graphical Notation for representation of data, information, and domain expert knowledge in a human and machine readable format; example of the AsthmaMap

June/July 2020

Figure 3: Monitoring well-being, health, and disease: integrated analyses to construct a digital representation of each person and deliver actionable recommendations to individuals and their care providers

5. Wheelock et al. (2013) Eur. Resp. J. 42:802-825.

PMID:23397306 6. Saqi M, Pellet J, Roznovat I, Mazein A, Ballereau S, De Meulder B, Auffray C. (2016) Systems medicine: the future of medical genomics, healthcare, and wellness. Methods Mol Biol. 1386:43-60.

PMID:26677178.

7. Auffray C. (2018) Interview with a thought leader on systems medicine. Syst. Med. 1:11-12.

8. De Meulder et al. (2018) A computational framework for complex disease stratification from multiple large-scale datasets. BMC Syst. Biol. 12:60. PMID:29843806 9. Auffray C et al. (2019) Ten years of Genome Medicine.

Genome Med. 11:7. PMID:30767786 10. Auffray C, Noble D, Nottale L, Turner P. (2020) Progress in integrative systems biology, physiology and medicine: towards a scale relative biology. Eur. Phys. J. A, 56:88.

11. Auffray C et al. (2016) Making sense of big data in health research: towards an EU action plan. Genome Med. 8:71.

PMID:27338147 12. Mazein et al. (2018) Systems medicine disease maps: community-driven comprehensive representation of disease mechanisms. NPJ Syst. Biol. Appl. 4:21.

PMID:29872544 13. Mazein et al. (2018) AsthmaMap. Clin. Exp. All. 48:916-918. PMID:30133857 14. Topol EJ. (2019) High-performance medicine: the convergence of human and artificial intelligence. Nat. Med. 25:44-56. PMID:30617339 15. Smarr L. (2012) Quantifying your body: a how-to guide from a systems biology perspective. Biotechnol. J.

7:980-991. PMID:22887886 16. Chen et al. (2012) Personal omics profiling reveals dynamic molecular and medical phenotypes. Cell 148:1293-1307. PMID:22424236 17. Hood L, Auffray C. (2013) Participatory medicine: a driving force for revolutionizing healthcare. Genome Med. 5:110.

PMID:24360023 18. Hood L, Price ND. (2014) Demystifying disease, democratizing health care. Sci. Transl. Med. 6:225ed5.

PMID:24574336 19. Price et al. (2017) A wellness study of 108 individuals using personal, dense, dynamic data clouds. Nat. Biotechnol. 35:747-756. PMID:28714965 20. Auffray et al. (2017) Viva Europa, a land of excellence in research and innovation for health and wellbeing. Prog.

Prev. Med. 2:e006.

21. Aarestrup et al. (2020) Towards a European health research and innovation cloud (HRIC). Genome Med. 12:18. PMID:32075696 22. Cesario A, Auffray C, Russo P, Hood L. (2014) P4 medicine needs P4 education. Curr. Pharm. Des. 20:6071-6072.

PMID:24641231 23. Omar MI et al. (2020) Introducing PIONEER: a project to harness big data in prostate cancer research. Nat. Rev. Urol., in press.

Sunday 19 July 16.10 - 17.00: Thematic session 10 New technology for urology Virtual room 2

EUT Congress News

11

Treatment of penile amputation Ingenuity and innovations lead to new techniques in challenging field Prof. Miroslav Djordjevic Belgrade Centre for Genitourinary Reconstructive Surgery Belgrade (RS) djordjevic@ uromiros.com Penile amputation is rare because the penis is well protected by its flexible anatomy and the bony pelvis.

The management of severe penile trauma can present a great challenge to the reconstructive urologist, since this injury often requires routine urological care mixed with ingenuity and innovations.

Traumatic amputation of the penis may be either partial or complete and can occur because of self-mutilation, vehicular trauma, power take-off accidents, child abuse, animal bites, gunshot wounds, or iatrogenic causes, such as excessive surgical excision during circumcision or correction of severe penile anomalies. This condition severely limits sexual function and seriously impairs the aesthetic appearance, affecting both the psycho-physical balance and social life of the patient. Regardless of the cause, the potential for devastating deformity as well as loss of length and function mandates that these patients receive expert attention immediately following stabilisation. There is no universal therapeutical management strategy due to the rarity and disparity of the trauma. Therefore, penile reconstructive surgery represents a special challenge for the genital reconstructive surgeon.

management includes reconstruction of missing parts and deficient areas with genital flaps and buccal mucosa grafts. Glans reconstruction using skin or mucosal grafts can be performed. Penile lengthening is recommended to restore length and is followed by penile shaft coverage with genital skin flaps or skin grafts. Urethral reconstruction includes simple closure, flap urethroplasty, or staged repair with buccal mucosa grafts.

More complex approaches In the absence of a native penis, reconstruction requires more complex approaches typically involving total phalloplasty with mixed aesthetic and functional outcomes. Reconstruction includes microvascular phalloplasty, multi-stage urethroplasty onto a vascular scrotal skin flap recipient site, and penile prosthesis placement. Corporal remnants are very useful for placement of either malleable or inflatable penile implants. Total phalloplasty should fulfil the following requirements: good volume of the neophallus enabling insertion of a prosthetic stiffener for successful sexual penetration and creation of a competent neourethra that will allow voiding in standing position. The procedure should involve a limited number of reproducible surgical stages.

Finally, the goals of surgery should be the creation of a sensitive and aesthetically acceptable phallus, with minimal scarring and without functional loss in the donor area.

Reimplantation Penile amputation, partial or total, requires complex reconstructive techniques including phalloplasty.

These injuries can be treated by immediate reimplantation if possible, with or without anastomosis of the vasculature, to restore erectile function. Reimplantation is the paramount treatment and should be attempted if the injury occurred within the prior 24 hours. Microsurgical replantation has been well established in the literature and was first performed at Massachusetts General Hospital (US) in 1977. Many cases and series have been reported in literature. However, most of these patients have had a native penis for replantation with good functional outcomes. If primary reattachment is not possible, then the remnants of the corpora cavernosa should be closed in a similar way as in partial penectomy. The urethral opening should be positioned in a good-viable segment of the penile stump for further reconstruction.

Delayed procedure Reconstruction of the penis after either partial or complete amputation is performed as a delayed procedure. Delayed management includes several options. In cases with partial amputation,

Figure 1: Partial penile amputation after failed hypospadias repair

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EUT Congress News

Figure 2: Lengthening of the corporal bodies

Free flaps Various free flaps have been used for total phalloplasty, such as radial forearm flap, latissimus dorsi flap, anterolateral tight flap, abdominal wall flaps, free deltoid flap, scapular free flap, sensate osteocutaneous free fibula flap, deep epigastric artery perforator flap, and dorsalis pedis flap. Since Chang and Hwang described their results for phalloplasty in cases after penile trauma, radial forearm free flap became the most used flap for phalloplasty worldwide. This technique yields a sensate neophallus with complete urethral lengthening at the same stage.

However, drawbacks of this technique include the small size and circumference of the neophallus, as well as visible donor site scar. The small volume of the neophallus sometimes presents a limitation for the insertion of two cylinders of the penile prostheses.

Multiple treatment options While a rare event, multiple treatment options have been documented in the literature. The main shortcoming may be the inability to define the true classification of this injury. The standard classification of penile trauma into avulsion, penetrating, and amputation injuries is general and insufficient to precisely describe all possible conditions. Thus, we consider it more appropriate to classify all injuries according to the involved penile entities and to organ injury scale of penile injury, as recommended by the American Association for the Surgery of Trauma1. They could be offering better understanding of this complex field, minimising the risk of treatment and improving the outcome.

Accordingly, penile amputation is classified as a

Grade IV (partial penectomy) or Grade V (total penectomy) injury.

Iatrogenic error Recently, we reviewed 13 patients who underwent single or multiple surgical procedures due to traumatic penile amputation2. We presented our experience with penile amputation injury in unusual cases and choice of treatment to emphasise special techniques that allow successful outcomes. The aetiologies for penile amputation in our group of patients are different than those seen in literature.

The largest number of amputations were caused by mutilation due to an iatrogenic error in circumcision and surgical repair of penile anomalies such as epispadias, hypospadias, and curvature. Although an emergency urological unit should commence, all cases in this series were referred several months or years after injury. So far, treatment algorithms for severe penile injury have not been defined to cover all possible options. Our goal in this reconstruction was to reconstruct a functional penis with presentable gross anatomical features. The mainstay of our approach in partial penile amputation injuries is to restore missing parts into a functional and aesthetically acceptable organ. Corporal advancement Figure 4: Outcome, one year later was very useful in a case of penile semi-amputation after hypospadias repair with good length achieved prosthesis can be exchanged for the malleable and the penile shaft covered by scrotal skin (see prosthesis later. Corporal remnants are recruited to Figures 1-4). support the proximal cylinders. If the crura are no longer serviceable, proximal cylinder tips can be fixed Flap advantages to the inferior pubic rami.

Even though radial forearm flap remains the gold standard in phalloplasty, we prefer the Penile transplantation musculocutaneous latissimus dorsi flap due to its New techniques in penile reconstructive surgery advantages. We have published our first results continue to improve. More clinical work must be with this technique in phallic reconstruction in boys done before most of us are fully comfortable with with epispadias, micropenis, and intersex using these techniques. Although optimum results of disorders3. Based on our experience in genderpenile restoration are increased aesthetic and affirming surgery, this flap presents an acceptable functional outcomes, achieving these goals using the choice for phalloplasty giving an excellent volume current available techniques is a great challenge. of the neophallus enabling feasible urethral Penile transplantation is another novel and exciting reconstruction and full penile prosthesis technique that could, in the future, provide another implantation. option for delayed phallic substitution. Since the first penile transplant was carried out in 2005, only one Moreover, the phallus can be constructed according penile allotransplantation has been performed. It to the size desired by the patient. Neophallus took place at the University of Stellenbosch (ZA) in retraction seems less likely with muscle-based December 2014, and the long-term results of this grafts than with fasciocutaneous forearm flaps, currently successful transplantation still have to be since well-vascularised muscle is less prone to described. Another three cases were done recently: contraction than connective tissue. Another at the Massachusetts General Hospital (US) in 2016, important advantage of the latissimus dorsi flap is a again in South Africa in 2017, and at the Johns cosmetically acceptable scar, in contrast to the Hopkins Hospital (US) in 2018. The four-year stigmatising visible scar left by the forearm flap follow-up of the Boston case confirmed complete phalloplasty. revascularisation and reinnervation of the penile allograft. The patient can have erections and Denervated graft intercourse with sensations that are normal for the Penile prosthesis implantation is technically easier penis glans. and better tolerated with the good volume muscular bed present in the latissimus flap. However, the obvious disadvantage is the inability of a denervated â&#x20AC;&#x153;There are no specific guidelines for graft to provide protective and erogenous sensitivity.

Implantation of a semi-rigid prosthesis is the treatment of penile amputation recommended three months after phalloplasty to injuries.â&#x20AC;? prevent phallic retraction. If desired, an inflatable No specific guidelines Finally, there are no specific guidelines for the treatment of penile amputation injuries since there are numerous variations on what constitutes an injured penis. Primary reconstruction should be reserved to and recommended for specialised trauma centres.

Iatrogenic penile amputation presents a special problem due to insufficient penile tissue and requires complex stage repair. The unifying rule for the successful management of penile amputation injuries is to individualise treatment with standard, creative, and innovative techniques. Future development of penile transplantation surgical techniques may play an important role in improving options for patients who suffer from penile amputation.

References

Figure 3: Penile shaft is reconstructed by scrotal skin flaps. New glans is created with skin graft

1. Mohr AM, Pham AM, Lavery RF, Sifri Z, Bargman V, Livingston DH. Management of trauma to the male external genitalia: the usefulness of American Association for the Surgery of Trauma organ injury scales. J Urol. 2003 Dec;170:2311-5.

2. Djordjevic ML, Bizic M, Stojanovic B, Joksic I, Bumbasirevic UV, Ducic S, Mugabe H, Krstic Z, Bumbasirevic MZ. Outcomes and special techniques for treatment of penile amputation injury. Injury. 2019;50 Suppl 5:S131-S136 3. Djordjevic ML, Bumbasirevic MZ, Vukovic PM, Sansalone S, Perovic SV. Musculocutaneous latissimus dorsi free transfer flap for total phalloplasty in children. J Pediatr Urol. 2006; 2:333-9.

June/July 2020

Molecular pathology before systemic treatment: feasible?

The value of novel prognostic and predictive biomarkers Prof. Sven Perner Institute of Pathology University Hospital Schleswig-Holstein Luebeck (DE) Research Center Borstel Leibniz Lung Center Borstel (DE) sven.perner@uksh.de

Prof. Verena Sailer Institute of Pathology University Hospital Schleswig-Holstein Luebeck (DE)

verena-wilbeth. sailer@uksh.de Prostate cancer is still the most common noncutaneous cancer in the world. The majority of patients is cured from the disease, but a subset of patients will progress to develop advanced and metastatic, ultimately castration-resistant disease1.

These patients will require systemic treatment to stop cancer progression and to improve quality of life.

Because high-throughput sequencing techniques have entered the molecular landscape of metastatic prostate cancer, we can start implementing precision oncology in the treatment of patients with advanced prostate cancer2. Identifying prognostic tumour characteristics as well as predictive biomarkers will help guide clinical management. Molecular pathology plays an important role in establishing these biomarkers in tumour tissue or liquid biopsy.

However, we should acknowledge that most patients are likely treated outside of large, mainly universitybased treatment centres specialising in urological oncology. Therefore, access to very novel and in general cost-intensive molecular studies may not always be available. We will hence focus on biomarkers that have the potential of being broadly implemented in everyday practice and on techniques that are already established. Reimbursement cannot be part of our considerations due to regional differences.

Immunohistochemistry The most used adjunct diagnostic method in virtually all pathology labs is immunohistochemistry.

Immunohistochemistry is a reliable method to visualise proteins on a cellular level. Both qualitative (is the protein expressed?) and (semi-) quantitative (how much of the protein is expressed and in which cellular compartment?) immunohistochemistry is available. The latter is especially important in the setting of predictive biomarkers, e.g. PD-L1- or HER2-expression on tumour cells.

“We focused on biomarkers that have the potential of being broadly implemented in everyday practice and on techniques that are already established.”

Another method commonly available in most pathology labs is fluorescence-in-situhybridization (FISH) to assess numeric or structural chromosomal alterations. It is commonly used in non-small-cell lung cancer (NSCLC) to detect therapeutic targets such as ALK or ROS1 rearrangements. Next-generation sequencing methods were pioneered in NSCLC as well. Most labs nowadays perform either in-house targeted sequencing or send their samples for sequencing to external collaboration partners. Whole-exome or whole-genome-sequencing is uncommon in daily practice. Liquid biopsies interrogating treatment resistance to EGFR-TKI are more widely implemented as well and may be adapted to serve the needs of prostate cancer patients. This is particularly the case in tumour heterogeneity that might not be sufficiently addressed by a biopsy of a single metastatic site2. Which pathways can therefore be interrogated before starting systemic treatment in patients with advanced and metastatic prostate cancer?

June/July 2020

AR pathway The androgen receptor (AR) pathway is the most altered pathway in prostate cancer with a variety of alterations such as AR amplification, mutation, and chromosomal rearrangements. AR overexpression and the presence of several splice variants is frequent in advanced and metastatic prostate cancer. AR aberrations detected in cell-free DNA via liquid biopsies can provide valuable information about resistance to androgen inhibitor therapy, such as enzalutamide and abiraterone3. Detection of the L702H mutation both in cell-free DNA and circulating tumour cells (CTCs) is associated with resistance to AR inhibitor drugs4,5. Linking the detection of the AR splice variant AR-V7 in CTCs to shorter progression free and overall survival has gained a lot of interest as predictive biomarker for abiraterone and enzalutamide therapy6,7. However, since some patients might still respond to abiraterone and/or enzalutamide, these tests have not been implemented in routine practice yet8.

PI3K-AKT-pathway Major alterations are also found in the PTEN-PI3KAKT-axis. Phosphatase and tensin homologue (PTEN) loss, mostly by deletion, is frequent in advanced prostate cancer and can be detected by immunohistochemistry or FISH analysis9,10. Loss of PTEN is found in up to 50% of CRPC. PTEN is a negative regulator of the PI3K-AKT-pathway and upon deletion, the PI3K-AKT-pathway is activated resulting in increased surrvival11. In CRPC samples, PTEN loss might be predictive of decreased response to abiraterone and of therapeutic response to PI3K inhibitor therapy11,12. However, given the intricate mechanism governing both the PI3K-AKT-pathway and the AR pathway and their crosstalk, a promising PI3K-inhibitor therapy for patients with advanced prostate cancer has not yet emerged11. PTEN loss is also a strong prognostic biomarker both in primary prostate cancer and in CRPC. In CRPC, PTEN loss is associated with shorter survival and shorter time on AR-inhibitor therapy13.

“Novel prognostic and predictive biomarkers keep emerging as we enhance our understanding of the molecular basis of advanced and metastatic prostate cancer.”

cell morphology. If a transformation occurred, a routine HE stain without necessity for further molecular analyses is enough. In small cell carcinoma, the Notch signalling pathway with overexpression of DLL3 is active. If small cell carcinoma is present, assessing protein expression of DLL3 might serve as a predictive biomarker for anti-DLL3-therapy18.

In conclusion, novel prognostic and predictive biomarkers keep emerging as we enhance our understanding of the molecular basis of advanced and metastatic prostate cancer. Most of these biomarkers could be implemented in routine

Neuroendocrine prostate cancer Lineage plasticity with transformation from an adenocarcinoma phenotype to a highly aggressive, AR-independent neuroendocrine phenotype via TP53 and RB1 alterations remains a clinical challenge8. If such a transformation is suspected, a metastatic biopsy might be indicated to rule out or confirm small

Due to space constraints, the reference list can be made available to interested readers upon request by sending an email to: communications@uroweb.org.

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DNA damage repair pathway Defects in the DNA damage repair (DDR) pathway are much more common than previously thought. In patients with advanced or metastatic prostate cancer, the frequency of germline DDR ranges between 11 and 15%14,15. Overall, the frequency of DDR is about 20-25% in CRPC2. Both germline and somatic DNA damage repair deficiencies are predictive of response to PARP-inhibitor therapy16.

Next-generation sequencing (NGS) to detect DDR is commonly available. It should be noted that pathogenic mutations in BRCA1/2 are spread widely across both genes and NGS interrogating DDR should also include genes such as ATM or CHEK2.

Defects in the DNA damage repair pathway have also been associated with exceptional response to platinum-based chemotherapy17. According to the 2017 advanced prostate cancer consensus conference (APCCC), BRCA1/2 and ATM mutations should be analysed and reported if a patient undergoes metastatic biopsy.

Repair genes Some patients harbour a defect in one of the mismatch repair genes (MSH2, MSH6, PMS2, MLH1), resulting in a hypermutated phenotype and microsatellite instability (MSI). Their disease may be amenable to immunotherapy. Pembrolizumab has been approved for patients harbouring a defect in the genes mentioned above, regardless of underlying histology. The MSI status can be easily assessed by immunohistochemistry and followed up by molecular studies, if immunohistochemistry detects a loss of the mismatch repair proteins2.

practice if requested by clinicians to guide patient management. For the time being, however, most of these predictive biomarkers are not sufficiently validated.

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Frailty and cognitive assessment in MIBC patients Growing need for multidisciplinary management of patients Prof. Yann Neuzillet Hôpital Foch, University of Versailles - Saint-Quentin-enYvelines Suresnes (FR) Dept. of Urology y.neuzillet@ hopital-foch.org Because the population in Europe is ageing, urologists have growing therapeutic concerns about muscle-invasive bladder cancer (MIBC) management.

Since the use of radical cystectomy and neoadjuvant chemotherapy treatments is supported by strong recommendations based on a rating system, we tend to apply these treatments to all patients, no matter how old they are.

However, there is a risk of both undertreatment and overtreatment when we offer the recommended treatment to elderly patients. Indeed, when we refuse this kind of management for elderly patients solely based on their chronological age, we run the risk of causing segregation between them; some may benefit from surgery. Furthermore, evidence regarding neoadjuvant chemotherapy is not applicable to elderly patients, since they have not been included in the studies.

“Cognitive assessment is crucial in order to improve postoperative outcome.”

Frailty These issues should be solved by assessing elderly patients in their totality and studying both the MIBC and its host features. Frailty is theoretically defined as a clinically recognised state of increased vulnerability, resulting from an age-associated decline in reserve

and function across multiple physiological systems.

This compromises the ability to cope with daily or acute stressors1. Cross-sectional studies suggest that about 7% of persons older than 65 years is frail and that the prevalence of frailty increases with age and may exceed 45% after the age of 852. When frailty of the elderly patient is taken into account, this radically changes both the therapeutic objectives to be achieved and the means to achieve them.

Multiparametric clinical tests There are tools available to assess frailty and cognition in patients diagnosed with MIBC. They consist of multiparametric clinical tests, which need both the clinician’s experience to apply the tests and the clinician’s availability, as these tests are very timeconsuming.

“The challenge for the urologist is to become the ‘orchestra conductor’ of this ‘care symphony’.”

However, cognitive assessment is crucial in order to improve the patient’s postoperative outcome.

Dementia, which is a multifactorial disease, is triggered by degenerative, vascular and psychiatric causes leading to both amnestic and non-amnestic mild cognitive impairments. The Mini-Mental State Examination (MMSE) and the Mini-Cog test aim to detect these cognitive impairments. The aim of their use is not only to diagnose a mental illness, but also to help prevent a confused state, which impairs postoperative outcome.

Functional and nutritional status Two other important issues are the patient’s functional and nutritional status. These are correlated to autonomy loss, complications of antineoplastic treatments and overall survival.

Their standardised assessment should lead to an improvement in thought rehabilitation and nutrition protocols.

It runs in the family Our family of journals — European Urology, European Urology Focus and European Urology Oncology, and European Urology Open Science — share a passion for urology, an unending commitment to patients, a dedication to multi-disciplinary science, and a continuous focus on quality. Our newest offspring European Urology Open Science is a broad-scope, gold open access journal.

All OA articles will be immediately and permanently accessible online-only for everyone to read, download, copy and distribute.

Figure 1: Aging acts like a prism, determining various health conditions in a heterogeneous population. Clinicians have to differentiate the robust patients, who can benefit from the standard treatments, from the frail patients, who could experience decompensation of their health condition and thus become dependent or disabled as a result of the same treatment.

Last but not least, comorbidity and consequent polymedication of patients should be assessed in order to both correct imbalanced diseases and reduce the risk of drug interactions. In this setting, clinical pharmacists may provide help in addition to the physicians and specialists who treat the patient’s diseases.

‘Care symphony’ In summary, frailty and cognitive assessment issues highlight the growing need for multidisciplinary management of patients diagnosed with MIBC in order to improve and adapt healthcare to our aging population even more. Frail patients who see a urologist may have more benefit from the support of physiotherapists, nutritionists, occupational therapists, etc. than from a single oncology healthcare pathway only combining a urological surgeon and a

medical oncologist. The challenge for the urologist is to become the ‘orchestra conductor’ of this ‘care symphony’.

“Frailty and cognitive assessment issues highlight the growing need for multidisciplinary management of patients diagnosed with MIBC.” References: 1. Xue QL. The frailty syndrome: definition and natural history. Clin Geriatr Med. 2011;27(1):1–15.

2. Theou O, Brothers TD, Peña FG, Mitnitski A, Rockwood K. Identifying common characteristics of frailty across seven scales. J Am Geriatr Soc. 2014;62(5):901–906.

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June/July 2020

Burch colposuspension and pubovaginal sling The perfect alternative for mid-urethral tapes?

Prof. Dirk De Ridder Dept. of Urology University Hospitals KU Leuven Leuven (BE)

dirk.deridder@ uzleuven.be In 2016, synthetic polypropylene meshes for vaginal prolapse repair was classified by the FDA as high-risk implants. In 2019, selling these products for prolapse repair was banned in the US. Many European countries followed and some have also included polypropylene slings for the treatment of stress incontinence. Scotland, for example, has banned synthetic slings for stress urinary incontinence.

For this reason, patients and doctors became more aware of the potential risks of synthetic slings. As a consequence, techniques using autologous material to improve the support of the urethra were rediscovered.

Burch colposuspension and pubovaginal fascia slings were commonly used as primary treatment for stress incontinence until 1998, the year the transvaginal tape of Dr. Ulmsten was commercialised. Nowadays these techniques are revisited and may be considered perfect alternatives for mid-urethral tapes. Synthetic mid-urethral tapes have had a bad press because of potential complications. However, reoperation rates at 5 years are quite low: 6 percent for retropubic tapes and up to 9 percent for transobturator tapes1. In a large American study, the reoperation rate for Burch colposuspension was 4.2 percent and for slings 6.7 percent2.

Burch colposuspension John Christopher Burch published his technique in 1961. It was a modification of the Marshall-MarchettiKrantz operation. Lifting the peri-vaginal tissue by suspending it on the Cooper’s ligament became known as the Burch colposuspension. Many modifications have been described. The technique has been adapted for laparoscopy and robotic surgery in recent years3.

quality. For use as primary treatment for uncomplicated stress incontinence, we need to go back to the older publications from the late 90s.

Synthetic slings Synthetic slings have been introduced in 1998, when the TVT sling was commercialised by Johnson & Johnson. Since then, the number of incontinence treatments has increased significantly. This means that many more women who were previously untreated or undertreated could not be offered a safe and quick procedure with good short-term and long-term outcomes. Modifications of the transvaginal tape include the transobturator tape, the single incision mini slings, and the adjustable synthetic slings.

Until today, the synthetic mid-urethral sling is still considered to be the gold standard for stress urinary incontinence surgical treatment in most countries. The EAU guidelines also clearly state that a mid-urethral sling should be offered to women with primary stress incontinence. The complications that arose with the use of synthetic mesh in the treatment of pelvic organ prolapse have elicited fear and uncertainties about the long-term fate of mid-urethral synthetic slings.

Most countries have invested in increasing the awareness about the potential risks among doctors and patients and have organised registries and/or close follow-up. Other countries have opted to ban selling and using of the synthetic material for vaginal pelvic organ repair as well as for stress urinary incontinence treatment.

“If Burch colposuspension and pubovaginal slings were to return as primary treatments, education and training programmes should be set up to ensure optimal care and surgical skills.”

Comparative studies on synthetic slings and Burch Studies which compare Burch suspension and synthetic slings as primary treatment for stress incontinence all show a better outcome for the At one year follow-up, success rates of 85-90 percent mid-urethral slings in objective and subjective cure are reported, while at 5 years the success rate drops to rates (82 percent vs 74 percent). The outcome is independent of the approach that was used for the 70 percent. Given its long history, complications are well known. Bleeding can occur in about 2 percent, Burch colposuspension: laparoscopic or open5. bladder injury has been reported in 0.4-9.6 percent, wound infections in 4-10.8 percent. Functional Comparative studies on synthetic slings and fascial problems such as immediate post-operative voiding slings dysfunction can occur in a percentage as high as 25 Fascial slings and synthetic mid-urethral slings have percent of the patients, with a need for intermittent been compared in several studies. Cohort studies with catheterisation varying between 0.7 and 7 percent. more than three years follow-up showed that Dyspareunia and pain are reported in 2 percent. synthetic slings had higher success rates than Specific to this kind of colposuspension is the risk of autologous slings in stress incontinence outcome. secondary enterocoele formation, which occurs in There was no difference in complication rate. about 12-17 percent of women.

However, obstructive voiding was more prevalent in the autologous sling group, leading to high rates of catheterisation or surgery to relieve the “The complications that arose with intermittent outflow obstruction5. Most studies, however, had a limited follow-up. the use of synthetic mesh in the

treatment of pelvic organ prolapse have elicited fear and uncertainties about the long-term fate of midurethral synthetic slings.”

Autologous sling Fascial slings have been used for the treatment of stress incontinence for many years. Goebel published his first report in 1910. McGuire and Blaivas promoted fascial slings, especially in the US, in the 90s. The fascia can be harvested from the rectus abdominus muscle or from the fascia lata. The results of these slings are also well known4. Reported success rates vary between 31 percent and 100 percent, while a cure rate of 85 percent is usually cited in review articles. Complications such as retention (5-20 percent) and de novo urgency (15-20 percent) are quite prevalent. Persisting voiding difficulties vary between 1.5 and 7.8 percent and de novo urgency incontinence is reported to be present in about 7 percent. There are certainly indications where fascial slings are the preferred primary option rather than synthetic slings: after urethral perforation, following fistula repair, following urethral diverticulum repair, and in chronic pelvic pain patients. As secondary procedure, fascial slings are used after the removal of a synthetic sling or in women with poor tissue June/July 2020

Comparative studies on fascial slings and Burch In 2007, an important prospective multicentre randomised clinical trial about surgical treatment for women with stress incontinence, comparing fascial sling and Burch colposuspension, by Albo et al. was published in the New England Journal of Medicine.

The study is referred to as the SISTEr trial. There was a significant difference in the primary outcomes for overall treatment success (47 percent vs 38 percent) and for the stress incontinence specific outcome (66 percent vs 49 percent), as well as for the treatment satisfaction (86 percent versus 78 percent), in favour of the sling procedure. Complications occurred in both groups: 30 percent in the sling group and 10 percent in the Burch group. Surgeries for voiding dysfunction were only performed in the sling group (6 percent)6.

So now what?

The available evidence from large studies, systematic reviews, and meta-analyses show that mid-urethral synthetic slings outperform the Burch colposuspension and pubovaginal autologous slings as treatment for primary stress urinary incontinence.

This is true for objective success as well as for subjective continence. There is also a significantly lower rate of storage LUTS with synthetic slings. Even though mesh exposure is a risk, it seems to be acceptable when compared to the outcomes of the alternatives.

This means that Burch colposuspension and pubovaginal slings are certainly not the perfect alternative for mid-urethral slings. Of course, good patient selection and proper training in different continence procedures is of utmost importance for a urologist who wants to perform continence surgery.

A recent survey amongst the members of the pelvic floor special interest group of the Flemish and Dutch Society for obstetrics and gynaecology and the Belgian association of urology showed that most physicians are convinced that Burch colposuspension will lead to more suture-related problems, an increased risk of prolapse, and de novo voiding problems when compared to mid-urethral slings7. They also felt that

chronic pain and dyspareunia would be more prevalent in the mid-urethral sling group. Most of the physicians involved in the questionnaire had less than 20 years of practice experience and were thus not familiar with the common use of Burch colposuspension or fascial slings. If Burch colposuspension and pubovaginal slings were to return as primary treatments, education and training programmes should be set up to ensure optimal care and surgical skills.

Due to space constraints, the reference list can be made available to interested readers upon request by sending an email to: communications@uroweb.org.

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EUT Congress News

15

ME 35th Annual European Association of Urology Virtual Congress (EAU)

INVITATION CURRENT SCIENTIFIC QUESTIONS INFLUENCING PATIENT MANAGEMENT IN ADVANCED PROSTATE CANCER

SCIENTIFIC COMMITTEE Bertrand Tombal, BELGIUM Laura-Maria Krabbe, GERMANY

FRIDAY 17 JULY 2020 14:30–15:30

FACULTY Boris Hadaschik, GERMANY Alexandre de la Taille, FRANCE Jochen Walz, FRANCE

EAU20 Virtual Congress You are invited to participate in the Janssen-sponsored satellite symposium entitled Current scientific questions influencing patient management in advanced prostate cancer, to be held on Friday 17 July 2020 at the EAU Virtual Congress 2020.

OVERALL LEARNING OBJECTIVES After attending this symposium, participants should be able to: • Describe the clinical benefits of earlier treatment of patients with metastatic hormone-sensitive prostate cancer (mHSPC) and non-metastatic castration-resistant prostate cancer (nmCRPC) and the consequences of disease progression • Discuss the impact of new data on treatment and management decisions for individual patients with mHSPC and nmCRPC

PROGRAM TIME

SESSION

FACULTY

14:30-14:35 Welcome and introduction

14:35–15:25

Bertrand Tombal

Current major questions influencing patient management Roundtable discussions around the following topics: • How do the major scientific questions in advanced prostate cancer shape clinical decision-making?

• Rethinking mHSPC: what do we need to debate?

• nmCRPC: a disease under discussion • Finding answers in the management of patients with advanced prostate cancer

15:25–15:30 Pressing thoughts and questions

Laura-Maria Krabbe, Bertrand Tombal, Boris Hadaschik, Alexandre de la Taille, Jochen Walz

Laura-Maria Krabbe

With the support of Janssen Pharmaceutical Companies of Johnson & Johnson in EMEA Janssen Pharmaceutica NV Turnhoutseweg 30 B-2340 Beerse, Belgium Date of preparation: May 2020 EM-29300 Copyright © 2020 Janssen Pharmaceutica NV

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EUT Congress News

June/July 2020

The penile implant of the future Future of implantology holds revolutionary potential for patient counselling in andrological disease Dr. Giorgio Ivan Russo Urology Section, Department of Surgery University of Catania (IT)

time. The simplicity of the surgical implant, the low rate of post-operative pain and the rapid resumption of sexual activity are the goals of the malleable prostheses. Surgery increasingly adapts itself to patients’ wishes.

Three-dimensional printing Furthermore, advancements in implantation may soon involve the use of three-dimensional Implantable penile prostheses - in inflatable or printing. 3D printing is a process malleable configurations - continue to be the surgical of building 3D objects from a standard of treatment for patients with moderate-to- digital file. The 3D printing severe erectile dysfunction or Peyronie’s disease with technology has been in use for severe penile curvature. Technological advances over 30 years in the automobile continue to progress, and surgery, especially in the and aeronautical industries. In field of andrology, needs special evolutions, both the medical field, the use of this from a functional and aesthetic point of view, and it technology was limited to 3D should suit the patient’s needs. Apart from purely printing of anatomical models for surgical needs, design needs also deserve attention. study purposes. However, recent The future of implantology must in fact combine advances in the development of specific design aspects with maximum functionality. new biodegradable materials have made 3D printing Patients’ perception technology in the medical and Patients’ perception of prostheses should be close to pharmaceutical field the truth but may reflect an overly simplistic view.

Figure 2: A patient with a severe corpora cavernosum fibrosis after the removal of the penile implant revolutionary2.

Therefore, the designer should seek to understand the baseline condition of palpability. Compressibility, Currently, additive manufacturing elastomeric behaviour, and consistency of modulus surgical procedure, we fail to become aware of what Whenever a new technology is used, costs remain a technology has wide applications in the clinical field from one phallic region to another should be major concern. The reported cost is variable. and is growing rapidly, thanks to the sustainability of the surgical outcome is.” “Moreover,” Dr. Cocci said, considered. The intention of the design regarding the costs and the personalisation of medicine. It has “we must take into account the psychological Following the initial cost of the 3D printer, the costs flaccid state is to preserve resting fullness and girth, implications deriving from such an intervention which of a 3D-printed model mainly depend on the revolutionised the healthcare system, allowing the while delivering elastomeric behaviours, density, and construction of biomedical models and customisation can often hinder the restoration of sexual function, amount of material used5 and the scale of mass that are as indiscernible from the natural production. The use of one colour and one material, of surgical patient aids. The most widespread clinical despite the resolution of the deformity.” anatomy as possible1. as well as large production numbers, could help applications include the creation of patientIn figure 2, we see a patient with a severe corpora make it cheaper6. customised prostheses, regeneration of biosynthetic cavernosum fibrosis after the removal of the penile tissues and organs, and the creation of anatomical “The Tactra™ Malleable Penile implant. The surgeon should expect a difficult penile models that can be used for pre or perioperative In conclusion, three-dimensional printing may show implant, the patient a severe shortening. However, simulations3. revolutionary potential for patient counselling and for Prosthesis represents an evolution thanks to the 3D reconstruction, surgeons will be able andrological disease. in the design of malleable penile to counsel the patient in a more efficient way. This Penile model technology could be applied to every type of penile References implants to offer the patient and his Interestingly, Renterghem et al. created a highdisease, even to Peyronie’s disease or penile cancer. fidelity, non-biohazardous, and cost-effective 1. Lund JJ. Biomedical engineering and erectile partner a more authentic, natural cadaveric penile model to simulate penile prosthetics restoration: design considerations for urologic surgery. The penile model was composed of a prosthetics. Asian J Androl 2019. doi:10.4103/aja. feeling erection.”

“Recent advances in the synthetic hydrogel tissue that mimics the aja_115_19. biomechanical properties of human tissue. The model development of new biodegradable 2. Liaw C-Y, Guvendiren M. Current and emerging Recently, Boston Scientific Corporation launched the was made using polyvinyl-alcohol (PVA) powder that applications of 3D printing in medicine. Biofabrication materials have made 3D printing Tactra™ Malleable Penile Prosthesis in the United was dissolved to create a viscous gel. It was used to 2017; 9: 024102. replicate all appropriate steps of inflatable penile States. The new penile prosthesis is the first 3. Ventola CL. Medical Applications for 3D Printing: technology in the medical and innovation in penile implants from Boston Scientific in prosthetic surgery: corporal exposure, corporal and Projected Uses. P T 2014; 39: 704–11. pharmaceutical field revolutionary.” 4. Current dilation, appropriate measurement, corporal closure, more than 10 years. It represents an evolution in the van Renterghem K, Ghazi A. 3D pelvic cadaver model: design of malleable penile implants to offer the reservoir placement, pump insertion, prosthesis a novel approach to surgical training for penile patient and his partner a more authentic, natural connections, and closure4.

Planning of surgical interventions implant surgery. Int J Impot Res 2019. doi:10.1038/ feeling erection.

We can also use 3D printing in the planning of s41443-019-0211-2.

5. Souzaki R, Kinoshita Y, Ieiri S, Kawakubo N, Obata S, Andrology Master surgical interventions in case of penile prosthesis Natural A pathway to another interesting application is the extrusion, due to the migration of the prosthesis with Jimbo T et al. Preoperative surgical simulation of The Tactra™ Penile Prosthesis utilises dual-layer study of deformity in patients affected by Peyronie’s subsequent perforations of the corpora cavernosa or laparoscopic adrenalectomy for neuroblastoma using silicone which feels natural and includes a Nitinol core disease. This application was shown for the first time due to the final hypo-dimensioning of the prosthesis a three-dimensional printed model based on

by Dr. Andrea Cocci (see photo) during the Andrology with curvature of the gland in the erection phase preoperative CT images. J Pediatr Surg 2015; 50: to optimise comfort, rigidity, and durability for effective penetration and concealment. The easy-toMaster, which was held in Florence on 5 and 6 (syndrome of ‘concorde’). In this case, preservation of 2112–5. use implant is manually lifted for intercourse and December 2019. the urethra and avoidance of iatrogenic lesions are 6. Cacciamani GE, Okhunov Z, Meneses AD, Rodriguezmanually pushed down when not in use (see figure 1). essential. This type of surgery must be as precise as Socarras ME, Rivas JG, Porpiglia F et al. Impact of In an interview, Dr. Cocci affirmed that “this possible. Therefore, 3D printing could improve Three-dimensional Printing in Urology: State of the It is interesting that Boston focuses on this new type innovation may also improve patient counselling and intervention outcomes and reduce complications, Art and Future Perspectives. A Systematic Review by compliance. If we only look at the description of the significantly improving the patient’s quality of life. of prosthesis, which was underestimated for a long ESUT-YAUWP Group. Eur Urol 2019; 76: 209–221. giorgioivan.russo@ unict.it

Figure 1: the Tactra™ Penile Prosthesis is manually lifted for intercourse and manually pushed down when not in use

June/July 2020

Dr. Andrea Cocci (right) and Dr. Giorgio Ivan Russo

EUT Congress News

17

VIRTUAL 17-19 July

#EAU20

Cutting-edge Science at Europe’s largest Urology Congress

UROwebinars of the ESU Recorded

Learn from the experts

Upcoming

Prostate cancer

Urolithiasis

Tuesday, 14 July

Monday, 27 July

Prostate cancer imaging and biopsy: When and how to use it Dr. J. Walz, Marseille (FR) Dr. G. Villeirs, Ghent (BE) Dr. I. Schoots, Rotterdam (NL)

Flexible ureterorenoscopy and retrograde intrarenal surgery:Instrumentation, technique, tips, tricks and indications Prof. O. Traxer, Paris (FR) Prof. M. Grasso, New York (USA) Prof. P.J.S. Osther, Fredericia (DK)

Urological surgery

Male LUTS

Surgical anatomy for laparoscopic and robotic-assisted radical prostatectomy and cystectomy Prof. J-U. Stolzenburg, Leipzig (DE) Mr. H.A.R. Qazi, London (GB) Ms. J. Cresswell, Middlesbrough (GB)

Management of BPO: From medical to surgical treatment, including setbacks and operative solutions (SOS) Mr. V.A.C. Ramani, Manchester (GB) Prof. S. Ahyai, Göttingen (DE) Dr. T.R.W. Herrmann, Frauenfeld (CH)

Thursday, 16 July

Monday, 30 July

Andrology Office management of male sexual dysfunction Mr. I. Eardley, Leeds (GB) Mr. D.J. Ralph, London (GB) Dr. J. Marcon, Munich (DE)

Infections

Prostate cancer

Dealing with the challenge of infection in urology in the COVID era Prof. F.M.E. Wagenlehner, Giessen (DE) Dr. Z. Tando du, London (GB) Dr. B. Köves, Budapest (HU)

Prostate cancer update: 2019-2020 Prof. F. Montorsi, Milan (IT) Prof. M. Graefen, Hamburg (DE)

EAUN - ESU

Paediatric urology

Penile prosthesis

Practical approach to paediatric urology Prof. J.M. Nijman, Groningen (NL) Prof. S. Tekgul, Ankara (TR) Mr. D.N. Wood, London (GB)

Prof. I. Moncada-Iribarren, Madrid (ES) Prof. M. Albersen, Leuven (BE) Ms. M. Lenaers, Hasselt (BE)

Urothelial tumours

Urolithiasis

Practical management of bladder cancer Prof. J.A. Witjes, Nijmegen (NL) Prof. B. Malavaud, Toulouse (FR)

Percutaneous nephrolithotripsy (PCNL) Prof. E. Liatsikos, Patras (GR) Prof. T. Knoll, Sindelfingen (DE) Dr. C.M. Scoffone, Turin (IT)

Please visit https://eaucongress.uroweb.org/ to find all webinar-related information, including a time schedule, where to register, and where to watch recorded webinars.

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18

EUT Congress News

June/July 2020

Urethral stricture management An overview of all relevant current and emerging office-based technologies Mr. Petros Tsafrakidis Consultant urologist NHS Fife, Victoria Hospital Kirkcaldy (GB)

Figure 5: The Optilume™ balloon delivering system

Figure 2: The UDC catheterisation system

petertsaf@yahoo.gr Urethral stricture is a worldwide prevalent condition that can lead to obstructive symptoms and even renal failure if left untreated. It is also linked to severe worldwide healthcare financial implications.

There is a socio-economic, age-related and anatomical relevance to the pathophysiology of urethral stricture disease (USD). The main causes of urethral strictures in the industrial countries are iatrogenic (35%) and idiopathic (circa 30%). Less common causes are blunt trauma, bacterial urethritis, and balanitis xerotica obliterans1. The prevalence in industrial countries is estimated at 0.9% of the general male population2. Urethral strictures are 2.6 times more prevalent in urban centres than in rural ones3.

Regardless of the cause, prevention of iatrogenic injuries, and more importantly, minimally invasive surgical management of urethral strictures are within the grasp of everyday office urology as numerous current and emerging procedures can be performed purely in an out-patient environment under local anaesthetic.

Figure 6: Balloon inflation in the bulbar urethra. The dilation process is fully controlled under endoscopic guidance (Courtesy of Optilume™ DCB) Figure 3: The catheter is passed over the guidewire into the bladder, bypassing the site of any LUT-GURS avoiding any urethral trauma or disruption of the anastomosis (Courtesy of Urethrotech UCD®)

medical and nursing staff training, the risk of urethral injury during catheter insertion is ever present.

Urethral catheterisation injury (UCI) may convert a relatively simple procedure into an emergency with long-term patient morbidity and significant financial burden to both patient and healthcare service. In extreme cases it leads to potentially fatal complications of urosepsis. Acute UCI complications Tests such as bleeding and false passage traditionally Diagnosis of USD is made through the identification of require catheterisation under cystoscopic vision or clinical symptomatology consistent with an obstructive suprapubic catheter insertion. This usually results in nature, a flow test pattern following a low peak unnecessary hospital admission and prolonged hospital stay. plateau, a flexible cystoscopy, a retrograde urethrogram and, finally, with the use of sonography.

All these tests can be carried out in an out-patient As a brief outline of financial implications, the cost (office) setting. Elaborating further on diagnostic of managing UCIs was €335,377 ($371,790) during a evaluation is not in the scope of this abstract.

6-month study period at two major hospitals in the UK. 81% (n = 30) sustained complications Clavien-Dindo grade 2 or greater and the additional Approximately 130 million catheters are placed length of hospital stay was 9.4 ± 10 (2-53) days. annually with an injury incidence of 1.3%, which is translated to more than 1,560,000 injuries worldwide. The cost of flexible cystoscopic catheterisation is However, the true incidence is difficult to establish in the absence of prospective studies and specific hospital codes and protocols recording difficult urethral catheterisations and urethral injury.

“Urethral strictures are 2.6 times more prevalent in urban centres than in rural ones.”

“Minimally invasive technologies can become a game changer for urological office practice.”

Urethral catheterisation injury Urethral catheterisation is one of the most commonly implicated procedures worldwide. Mainly, it is performed by trained nurses or junior doctors. Even though there has been large emphasis on junior

Figure 4: Hydrophilic S-Cook dilators

Figure 7: Endoscopic view after deflating the balloon and before removing it

estimated at €750 (£640) while the corresponding cost of inpatient suprapubic catheterisation is €790 (£676)4.

The TUC Safety Valve The Trans Urethral Catheterisation (TUC) Safety Valve, is an innovative technology aimed at eliminating the problem of inadvertent inflation of the urology catheter balloon in the urethra as it simply does not allow inflation of the balloon above a certain pressure. It uses an innovative safety pressure relief valve to indicate misplacement of the anchoring balloon, eliminating urethral damage.

The TUC Safety Valve can be used with any brand of catheter as it standardises the inflation speeds of the various branded catheters, allowing the balloons to open in a more controlled manner. A recent study (n = 100) demonstrated that the TUC valve had prevented urethral injury in 7% of the hospitalised patients (n = 7)5.

“UCI may convert a relatively simple procedure into an emergency.”

Urethrotech UCD® system The Urethrotech UCD® system developed at the University College Hospital (UCH) in London, UK, was designed to tackle the risk of urethral injury and formation of a false passage. The device was tested and audited in the trial with promising results and minimum complications rates in difficult catheterisations5.

The audit aimed to facilitate the spread of the NICE-approved innovation across the NHS in the UK and consolidate the evidence of health benefit and cost-effectiveness of the innovation.

Figure 1: Urinary-catheter “safety-valve” for preventing balloon-related urethral injuries during urethral catheterisation.

The safety-valve attaches distally to an existing commercial syringe and proximally to any commercial urinary catheter (A).

The flow restrictor prevents rapid inflation of the balloon, which can bypass the safety-valve (B)

June/July 2020

Hydrophilic S-Cook dilators The hydrophilic S-Cook dilators are an excellent and well-established addition to our armamentarium for the treatment of both anterior and posterior urethral strictures. The clinician can perform a urethral dilatation to a maximum diameter of 26f under local anaesthetic over a guide wire that can be inserted either blindly or through cystoscopic inspection.

Optilume™ Drug Coated Balloon Another very promising and innovative technology is the balloon-mediated infusion of paclitaxel within the scar tissue of the urethral stricture via a flexible cystoscope under local anaesthetic.

As shown in figure 5, 6, and 7, the Optilume™ Drug Coated Balloon (DCB) is a catheter with a tapered atraumatic tip. The distal end of the catheter has a semi-compliant inflatable balloon. The dynamiccompliant balloon expands at high pressure, expanding the lumen and creating micro-fissures in the tissue to a maximum diameter of 30F. Upon inflation, the coating releases paclitaxel directly into the fissured tissue. Paclitaxel is absorbed by the urothelium where it resides for approximately 30 days preventing cell proliferation and fibrotic scar tissue generation. The estimated study (ROBUST I, n = 50) completion date is December 2022.

In conclusion, minimally invasive but yet efficient devices and technologies for the prevention and treatment of urethral strictures can become a key player and a game changer for urological office practice at the dawn of the decade. However, additional data is required in order to determine the efficacy and sustainability of those treatments.

References 1. Urethral stricture: Aetiology, Investigation and Treatments. S Tritscher et al. Deutsches Arzteblatt International. 2013 Mar;110(13):220-226.

2. AUA Guidance on urethral stricture management.

3. Rourke KF, “The Epidemiology, Clinical Presentation, and Economic Burden of Urethral Stricture,” Brandes SB et al. (eds.), Advanced Male Urethral and Genital Reconstructive Surgery (2014), New York: Humana Press, pp.83-93.

4. A new urethral catheterisation device (UCD) to manage difficult urethral catheterisation S. Bugeja, K. Mistry, I. H. W. Yim, A. Tamimi, N. Roberts & A. R. Mundy World Journal of Urology volume 37, pages 595–600(2019).

5. Clinical Evaluation of a Safety-device to Prevent Urinary Catheter Inflation Related Injuries, Niall F. Davis, Eoghan M. Cunnane, Rory O’C Mooney, James C. Forde, and Michael T. Walsh Urology, Volume 115, May 2018, Pages 179-183. https://doi.org/10.1016/j.urology.2018.02.026.

EUT Congress News

19

Improving follow-up care after nephrectomy Experiences from a Dutch cancer institute Corinne Tillier, CNS, MANP Nurse Practitioner (ANP) Urology The Netherlands Cancer Institute Amsterdam (NL)

Table 2: Schedule Follow-up after nephrectomy- intermediate risk Nephrectomy: Intermediate risk Follow-up Consultation Laboratory test Imaging test

c.tillier@nki.nl Similar to worldwide trends, renal cell carcinoma (RCC) in the Netherlands comprises 2% of all malignancies1. The Netherlands Cancer Institute is a specialised institute where many cases of nephrectomies and partial nephrectomies are performed in localised and locally advanced RCC.

Send a letter to the GP

Year 1 4w 3m Urologist x x Clinical Nurse Specialist x (call) x x CT abdomen x CT lung x Ultrasound x

A personalised follow-up depending on risk of recurrence is linked with the digital file of the patient (Table 2). This means that all the requests for CT scans, ultrasounds and blood tests are computerised. The The follow-up after surgery was until 2014 done by urologist or the clinical nurse specialist has to fill at the urologists only. There were no common guidelines the time of the follow-up (for example month 42) and all the imaging tests and laboratory tests needed for for the follow-up. In 2014 we decided to develop a standardised follow-up after partial and total the next consultation are automatically included and nephrectomy where the clinical nurse specialist could scheduled (Table 3). If the patient develops metastasis play an important role. The goal was to have a during the follow-up, we end the follow-up in the standardised follow-up and to decrease the digital file and we refer the patient to the oncologist. consultations by urologists.

We evaluated that performing the follow-up alternating with urologist and a clinical nurse specialist could generate a decrease of the urologist’s consultations by about 58%. We decided to include the Leibovich prognosis score2 which is dependent of the risk of recurrence in order to perform an adapted/ personalised follow-up after partial or radical nephrectomy. The score takes into account the pathological T stage, nodal status, tumour size, nuclear grade and histological tumour necrosis. The Leibovich prognosis score gives a score ranging from 0 to 11 and is categorised into three groups dependent of the risk of recurrence after surgery: low- (0–2), intermediate- (3–5) or high-risk (≥6) groups (Table 1).

“The patient is very satisfied to have the opportunity to prepare her/his consultation, because in this way the patient will remember to ask a question to the urologist/clinical nurse specialist.”

We implemented a standardised follow-up according to the evidence based in August 2015. We divided the patients into three groups depending on the risk of recurrence after partial/radical nephrectomy (low, intermediate and high-risk groups). The follow-up is alternately done by the urologist and the clinical nurse specialist urology.

The follow-up after partial nephrectomy and nephrectomy is, respectively, five and nine years.

Four weeks after the surgery, the patient has a consultation with the urologist who explains the risk of recurrence and reviews with the patient the medical issues one month after surgery. The patient receives from the urologist an overview of the follow-up for the next years. A few days after the clinical nurse specialist calls the patient and asks if everything is clear. The nurse explains his/her role in the follow-up as the permanent contact person who is accessible for the patient when needed.

Table 1: Leibovich prognosis score after partial/ radical nephrectomy2 Characteristics Tumour

Dimension Lymph node status Fuhrman

Tumour necrosis

pT1a pT1b pT2 pT3-pT4 <10 cm >10 cm pNx/pN0 pN1-pN2 1-2 3 4 absent present

Points 0 2 3 4 0 1 0 2 0 1 3 0 1

“We evaluated that performing the follow-up alternating with urologist and a clinical nurse specialist could generate a decrease of the urologist’s consultations by about 58%.”

Preparing for the consultation (Self-Management) During the follow-up, the patient has the opportunity to prepare the consultation with the urologist or clinical nurse specialist. The patient can log-in through his patient portal (www.mijnavl.nl) and can ask questions or report physical/mental complaints after surgery. When the urologist/nurse clinical specialist prepares the consultation (a few days before), the questions/complaints appear in the patient’s digital file. The most common questions/ complaints are: Is my cancer hereditary? Is it normal that I am still very tired? Do I have to follow a special diet after nephrectomy? Can I live with one kidney without health problems?

The patient is very satisfied to have the opportunity to prepare her/his consultation because in this way the patient will remember to ask a question to the urologist/clinical nurse specialist. We have to admit that we are also very satisfied since it makes the consultation easier. We can already prepare the answers to the questions/complaints. We have evaluated the follow-up after partial or radical nephrectomy (one year after implementation). The patient expressed satisfaction on the following:

financial costs (less CT scans). The computerisation of the orders depending on the moment of the follow-up avoids unnecessary CT scans and allows a standardised follow-up. In case of local recurrence or metastasis during the follow-up, patients have to be discussed within a multidisciplinary team (MDT), no matter if the patient had a consultation with the urologist or the Advanced Nurse Practitioner before.

EUT Congress News

Year 4 42 m 48 m x x x x x x x x

Year 5 54 m 60 m x x x x x x x x

Year 7 Year 9 84 m 108 m x x x x x x x

x x x

References 1. Dutch Cancer Registration 2015: http://www. cijfersoverkanker.nl/selecties/Dataset_2/ img578bcb8073d2d 2. Leibovich BC, Blute ML, Cheville JC 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: 1663–71.

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“The personalised follow-up after partial and radical nephrectomy based on the Leibovich prognosis score is feasible.”

The urologist has fewer consultations after partial/ radical nephrectomy (for example 28% less consultations for low-risk after nephrectomy). We noticed that compared to the follow-up before the standardisation, we perform less CT scans. Moreover, the clinical nurse specialist appreciates providing counselling and support to the patients and is able to give the results of the CT scan or other exams.

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Year 3 30 m 36 m x x x x x x x x

Table 3: Example of computerised orders

• The alternating consultation urologist/clinical nurse specialist. They do not mind who is giving the results of CT Scans/ultrasounds/ laboratory results; • Receiving a schedule of the visits for the next five to nine years; • Having the same urologist/clinical nurse specialist; and • Having the opportunity to prepare the consultation.

Feasible scheme The personalised follow-up after partial and radical nephrectomy based on the Leibovich prognosis score is feasible, efficient and can be alternatively done by the urologist and the clinical nurse specialist. It saves consultation time for the urologist and also reduces

Year 2 6 m 9 m 12 m 18 m 24 m x x x x x x x x x x x x x x x x x x x

03.02.2020 11:05:13

June/July 2020

Has the paradigm of botulinum toxin A changed?

Efficacy and side effects of injections into the bladder wall for OAB Prof. Marcio Averbeck Committee Member, International Continence Society (ICS) Porto Alegre (BR)

a predominantly female population at short-term follow-up. Mohee et al. followed OAB patients after their first BTX-A injection and demonstrated that almost two-thirds of patients (61.3%) had discontinued therapy at 36 months, with a 63.8% discontinuation rate at 60 months. The main reasons for discontinuation were tolerability issues6.

Rahnama’i et al.7 evaluated the long-term compliance of BTX-A in a heterogeneous group of male patients who underwent intradetrusor injections between 2004 and 2010 at a single In science and philosophy, a paradigm is a distinct set centre. The mean follow-up was almost 6 years. 24 patients presented with idiopathic OAB (mean age of concepts or thought patterns, including theories, 67 years). Only 5 (21%) persistent on BTX-A therapy research methods, etc., which constitute legitimate in the long run. This is less than the rates reported contributions to a field. The use of botulinum toxin in the literature for idiopathic OAB treatment in certainly constitutes a legitimate contribution to the women. Most important factors for poor therapeutic approach of overactive bladder (OAB) compliance were insufficient effect patients. (n = 8) and adverse events (n = 10).

OAB is defined by the International Continence Society 2. Urinary retention has been reported in up to 30% (ICS), as ‘urinary urgency, usually accompanied by of patients increased daytime frequency and/or nocturia, with urinary incontinence (OAB-wet) or without (OAB-dry), According to a systematic review of the literature8, the need for IC at doses of 100 units (the on-label dosage in the absence of urinary tract infection or other for patients with idiopathic OAB) ranged from detectable disease.1’ This set of lower urinary tract 6.9–30%9,10. It should be noted, however, that the symptoms (LUTS), which affects 10.7% of the indication of catheterisation varied among the worldwide population2, usually leads to a great studies. Such differences between the definitions for negative impact on the quality of life of a significant urinary retention and the need for IC render part of the population3. For over 20 years – since the comparison among studies difficult. Regardless, term “overactive bladder syndrome” was first introduced to the urological community community - retention is transitory and dose-dependent. more than 5,000 articles have been published in specialty journals. marcioaverbeck@ gmail.com

According to the EAU guidelines on urinary incontinence, if dietary and fluid recommendations fail, patients should be offered either oral antimuscarinics and/or β-3 agonists. When medications fail, patients are considered for minimally invasive techniques such as intradetrusor botulinum toxin A (BTX-A), posterior tibial nerve stimulation (PTNS), or sacral neuromodulation (SNM). Despite recent advances in the medical treatment of OAB, non-compliance to oral antimuscarinics is still high4. According to a recently published study, the proportion of patients adherent to OAB medical therapy at 1 year varies between 15% and 44%.

Onabotulinum toxin A Onabotulinum toxin A (OnaBoNT-A) accounts for the largest number of scientific studies and was approved for the treatment of urgency urinary incontinence by the Food and Drug Administration (FDA) in 2013. Other botulinum toxins, such as abobotulinum toxin A and incobotulinum toxin A, were less frequently studied for bladder indication, so that their efficacy and safety are not well known.

In addition, their use is not provided on label for this indication5.

The efficacy and side effects of the treatment with OnaBoNT-A depend on the dose used.

The recommended dose for patients with idiopathic OAB is 100 U. The use of 150 U results in a discrete improvement of efficacy, but higher risks of urinary retention. Most studies evaluated the botulinum toxin injection into the body of the bladder, sparing the bladder trigone. Different protocols were used, including injections into 10-20 bladder sites with such dilution to inject 0.5-1.0 mL per site.

OnaBoNT-A injection should be performed deeply into the detrusor. Submucosal injection was less often evaluated and its results are not well known.

OnaBoNT-A injection can be performed with local/ general anaesthesia, sedation or spinal block.

The need for reinjections over time It is critical that patients are carefully educated about the risks and accept the possibility that they need bladder intermittent catheterisation (IC) in case of urinary retention. Patients should also be informed that the effects of the treatment diminish over time (mean duration of effects around 9 months) and that the vast majority will need reinjections.

There are several factors which should be carefully reviewed to explain why the paradigm of botulinum toxin A injection in the bladder wall for OAB may change soon: 1. Despite being effective, the adherence to BTX-A is low in the long run Although intradetrusor injection is an established treatment for OAB patients, most studies have evaluated efficacy and compliance to this treatment in June/July 2020

Figure 1: EAU guidelines on urinary incontinence: summary of evidence and recommendations for bladder wall injection of onabotulinum toxin A

“Despite being effective, the adherence to BTX-A is low in the long run.”

(Medtronic, Minneapolis, MN (US)) was the sole device on the market used to deliver sacral neuromodulation with demonstrable OAB therapeutic success rates as high as 83%15. Main downsides of SNM therapy include device-related adverse events, lack of magnetic resonance imaging (MRI) compatibility and need for surgical reintervention. Studies show that by 36 months of SNS therapy 11% of subjects require battery replacement due to depletion16. Therefore, development of new SNM technologies has concentrated on providing improvements to decrease device-related adverse events and surgical re-intervention.

More recently, the 2-year outcomes of the Rosetta trial have been published11. This was a multicentre, open-label, randomised extension trial (February 2012-July 2016) at 9 US medical centres involving 386 women with ≥ 6 urgency urinary incontinence episodes (UUIE) over 3 days, which were inadequately managed by oral medications.

Participants were clinical responders to treatment: ≥ 50% reduction in UUIE after sacral neuromodulation implant or 1 month post BTX-A injections. Over 24 months, 72% (115/159) of the BTX-A participants requested a second injection (median interval between first and second injection was 350 days). In this group, 101/115 (88%) had 200 U of which 6 (6%) required IC. Patients with a postvoid residual of more than 300 mL or more than 200 mL and symptoms of incomplete voiding were instructed to perform IC after treatment. Per protocol, participants requiring IC for > 6 weeks after initial BTX were dose-reduced. Specifically, 14/115 (12%) were dose-reduced from 200 U to 100 U, and 3/14 (21%) still required IC after 100 U. Median CIC duration across the nine participants was 29 days (interquartile range = 17–56 days).

New SNM devices / MRI compatibility Axonics Modulation Technologies has recently developed a new SNM device for the treatment of OAB. The device was approved in 2016 for the treatment of OAB in Europe and Canada and consists of a small volume rechargeable neurostimulator (60% smaller than the currently available Medtronic device) and a tined lead with four electrodes percutaneously inserted through the sacrum. The tined lead is subsequently connected to a pulse generator implanted in the upper buttock area. The implantable pulse generator battery is rechargeable with a 15-year lifetime in the body, which may obviate frequent IPG replacements. In addition, the device is current controlled: output voltage is automatically adjusted based on tissue impedance.

According to the manufacturer, this may provide more consistent therapy. An important consideration is the possibility of future MRI studies for the patient.

The FDA approved the Axonics r-SNM System for fullbody 1.5 Tesla MRI scans in September 2019. This differs from the recommendation for the standard Interstim-2 device, which is only approved for 1.5 T head MRI.

3. There are other effective options as third-line therapies for OAB Non-invasive and invasive electrostimulation techniques have been extensively studied in the treatment of lower urinary tract dysfunctions, including OAB.

Medtronic has received CE Mark approval for its InterStim Micro neurostimulator and InterStim SureScan MRI leads in January 2020. By making full-body MRI scans possible, the firm has increased accessibility to sacral neuromodulation (SNM) therapy for European patients. InterStim Micro is a rechargeable device, which offers sacral Percutaneous tibial nerve stimulation (PTNS) is a neuromodulation therapy for the treatment of minimally invasive office-based procedure, which has overactive bladder (OAB), faecal incontinence (FI) and been shown to be safe and effective in treating OAB non-obstructive urinary retention. InterStim Micro is symptoms12. The patients must be able to make said to be 80% smaller than the already existing frequent hospital/clinic visits to receive the therapy, recharge-free InterStim II neurostimulator. The making it time-consuming for the patient and costly SureScan leads, which will be used in both the for both the patient and healthcare system. Most PTNS InterStim Micro system and in future implants of the protocols suggest 12-weekly treatments followed by existing recharge-free InterStim II, are designed to less frequent treatments to sustain OAB symptomatic allow for full-body 1.5 and 3 Tesla MRI-conditional improvement. Heesakkers et al.13 have recently scans. Medtronic claims that it is the only firm in published a prospective multicentre study assessing Europe to provide patients with a choice between the safety and performance of the RENOVA system in rechargeable and recharge-free systems, which are the treatment of patients with OAB with or without both full-body MRI-conditional17. urgency incontinence Thirty-four of the 36 implanted subjects completed the study. At six-month follow-up, New advances in neuromodulation techniques may 71% experienced clinical improvement (based on impact on patients’ decision about third-line bladder diaries). therapeutic approaches to OAB. Sacral neuromodulation (SNM) is another established third-line treatment for refractory OAB. SNM electrically stimulates somatic afferent nerves in a sacral spinal root (usually S3) and sends signals to the central nervous system that may restore normal bladder function. Activation of somatic afferent nerves inhibits bladder sensory pathways and detrusor overactivity14. Until recently, Interstim®

4. Despite being a minimally invasive procedure, the need for bladder wall injections to deliver the medication is a barrier Bladder application of BTX-A requires a cystoscopic procedure with intradetrusor needle injection into 20 to 30 sites. The patient is under local anaesthesia or sedation. The avoidance of intradetrusor BoNT needle injections may potentially decrease the risk

of complications, such as haematuria, pain, large PVR and UTI. Because of the limited permeability of the bladder wall, OnaBoNT, which is a large molecule (approximately 150 kDa), has limited access to the submucosal nerve plexus when not injected with a needle.

Recently Chuang et al. demonstrated that bladder uptake of BoNT improved when the toxin was formulated with liposomes in a in an overactive bladder model in rats bladder model in rats18. Liposomes (lipid vesicles) have been extensively studied as a drug delivery platform for anticancer drugs, and several such products have received FDA approval. Liposomes have been previously studied as toxin carriers to enhance efficacy at lower doses. They rely on vesicle endocytosis for intravesical drug delivery19.

A multicentre, placebo-controlled study to assess the safety and efficacy of onaBoNT-A complexed with liposomes was performed in men and women with OAB20. This treatment successfully reduced urinary frequency and urgency; however, the treatment did not reduce UUI episodes. Furthermore, onaBoNT-A complexed with liposomes did not result in urinary retention. Risk of UTI was similar between placebo and treatment arms. We may conclude that instillation of onaBoNT-A complexed with liposomes successfully impairs afferent neurotransmission but not the efferent neurotransmission.

What the future holds for BTX-A is unknown. Feasible advances in clinical practice are still eagerly awaited by the international urological community and by patients suffering from OAB symptoms.

References 1. Haylen BT, de Ridder D, Freeman RM, Swift SE, Berghmans B, Lee J, Monga A, Petri E, Rizk D, Sand PK, Schaer GK An International Urogynecological Association (IUGA) / International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Neurourol Urodyn, 2010,29:4-20; International Urogynecology J, 2010,21:5-26 2. Irwin DE, Kopp ZS, Agatep B, Milsom I, Abrams P. Worldwide prevalence estimates of lower urinary tract symptoms, overactive bladder, urinary incontinence and bladder outlet obstruction. BJU Int. 2011;108:1132.1138. https://doi.org/10.1111/j.1464.410X.2010.09993.x 3. Int Braz J Urol. 2016 Mar-Apr;42(2):188-98. doi: 10.1590/ S1677-5538.IBJU.2015.0365. Overactive bladder - 18 years - Part I. Truzzi JC1, Gomes CM2, Bezerra CA3, Plata IM4, Campos J5, Garrido GL6, et al.

4. Real-world persistence and adherence to oral antimuscarinics and mirabegron in patients with overactive bladder (OAB): a systematic literature review.

Yeowell G, Smith P, Nazir J, Hakimi Z, Siddiqui E, Fatoye F. BMJ Open. 2018 Nov 21;8(11):e021889. doi: 10.1136/ bmjopen-2018-021889.

5. Int Braz J Urol. 2016 Mar-Apr;42(2):188-98. doi: 10.1590/ S1677-5538.IBJU.2015.0365. Overactive bladder - 18 years - Part I. Truzzi JC1, Gomes CM2, Bezerra CA3, Plata IM4, Campos J5, Garrido GL6, et al.

6. BJU Int. 2013 Jan;111(1):106-13. doi: 10.1111/j.1464410X.2012.11282.x. Epub 2012 Jun 6. Long-term outcome of the use of intravesical botulinum toxin for the treatment of overactive bladder (OAB). Mohee A1, Khan A, Harris N, Eardley I.

Due to space constraints, the entire reference list can be made available to interested readers upon request by sending an email to: communications@uroweb.org.

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June/July 2020 27.05.20 13:49

AUS for stress urinary incontinence in women Artificial urinary sphincter successfully reinforces urethral support Prof. Emmanuel Chartier-Kastler Academic Hospital Pitié-Salpétrière Sorbonne Université Paris (FR) emmanuel. chartier-kastler@ aphp.fr

Dr. Christine Reus Dept. of Molecular Medicine and Surgery Karolinska Institute Stockholm (SE)

reus0@me.com Is it time to reconsider our stance on female AUS in the 21st century?

Due to a paucity of evidence, the artificial urinary sphincter (AUS) is often considered a second-line surgical option for the treatment of female stress urinary incontinence (SUI) secondary to intrinsic sphincter deficiency (ISD) (EAU, ICS and AUA guidelines 2019). Consequently, the device has currently a non-reimbursed nor registered status for this specific indication in many countries1.

Additionally, synthetic mid-urethral slings (SMUS) have recently fallen out of favour. Therefore, the debate about the optimal timing and indication for AUS implantation in women has become a contemporary hot topic.

“The question is: what is the appropriate timing for repeat UI surgery, be it sling or AUS?” Today, more than ever, evidence-based quantitative and qualitative AUS evaluations are essential for adequate patient counselling. In this niche area, expert opinions still prevail and understanding the underlying mechanisms of female UI, careful history taking, thorough clinical examination and tailored investigations are the foundations for an adequate pre-AUS implantation assessment.

Physiopathology and pre-operative assessment of female SUI The two-fold mechanisms underlying female SUI, as postulated by Blaivas et al., involve an insufficient support of the bladder neck and urethra, known as urethral hypermobility, with (which is often the case) or without concomitant ISD2. These mechanisms will not only steer the choice of the surgical technique suitable for the patient but also, more importantly, determine the results.

Therefore, a thorough pre-operative work-up is paramount. Whilst a positive Marshall or submidurethal (SMU) tape test elicits urethral hypermobility on clinical examination, ISD is a more complex entity to exact due to the absence of international consensus on its definition, which is essentially based on amalgamated clinical examination, cystoscopy, and urodynamic findings.

Consequently, the following are pathognomic of ISD: clinically uncontrolled orthostatic urinary leakage, a maximum urethral closing pressure (MUCP) of < 40 cmH20 and/or a decreased Valsalva leak point pressure (VLPP) of < 60 cmH20 (VLPP) on urodynamic exploration.

Additionally, a partially or totally open urethral sphincter on video urodynamics (if available) or cystoscopy will complete the work-up. Le Normand and colleagues summarised that a combination of leakage on increased intra-abdominal pressure, urethral hypomobility, a negative Marshall/SMU test, and previously failed UI surgery are strongly suggestive of ISD3. These investigations are essential to guide the clinician in his/her choice for sling or AUS surgery.

Sling insertion or AUS implantation?

In the presence of urethral hypermobility (with or without intrinsic sphincter deficiency), the surgical June/July 2020

technique reinforcing urethral-support-using slings is more likely to yield successful outcomes4.

Conversely, ISD associated with a fixed urethra and/ or previously failed UI procedure - provided initial correct indication - is linked to poorer results when using slings. In this context, the AUS should be offered as a first line option5.

The question is: what is the appropriate timing for repeat UI surgery, be it sling or AUS? Indeed, sling re-insertion offered too early exposes patients to complications such as procedure failure, de novo overactive bladder, chronic pain, and erosions.

Offering the AUS too late, after multiple UI surgeries (as is often the case) results in high peri-operative complications as reported in the literature, namely bladder neck, vaginal, bladder, and even bowel injury.

“The ongoing SU-ACT trial will be the first prospective study of its kind analysing AUS implantation in a pure cohort of women.”

Furthermore, a 20-year-long follow-up cohort study of 344 patients, the largest to date, highlighted that the number of previous UI surgeries, neurogenic bladders, and concomitant augmentation enterocystoplasties was associated with lower AUS mechanical survival rates6. These findings support early AUS implantation rather than multiple UI procedures, however more data to confirm this assumption are required.

For all the reasons above, decision-making for AUS implantation still is largely based on expert opinion and clinical experience. It is therefore strongly recommended that such patients be referred to highly specialised centres, where proper counselling is offered to enable an informed decision, where high success and qualitative outcomes are weighed against high complication/revision rates7. AUS is the only device which has to be open in the voiding phase and automatically closed in the storage phase, however, its impact on the voiding phase is minimal, thus mimicking the physiological continence/voiding cycle as much as possible. This advantage must be discussed in case of known hypocontractile detrusor to avoid/prevent any need of self-catheterisation post-operatively.

AUS implantation: open or robotic approach?

The female AUS of today is a three-piece device composed of a cuff (sizes 6-9 cm) placed around the bladder neck, a reservoir located intra-abdominally (usually 61-70 cmH2O), and a pump in the labia majora (AMS800™, Boston Scientific (US)). The patient manually manipulates the pump prior to voiding in order to open the cuff. The main advantage of the device is that it offers good continence outcomes whilst preserving voiding function.

“Robotic female AUS surgery is still at its infancy and comparing both open and laparoscopic approaches requires a prospective study.”

Patients referred for AUS implantation are complex, having often undergone more than one UI surgery anteriorly. Moreover, the inherent technical challenges have led to the reluctance to envisage this option. AUS implantation is usually performed using the open technique, via an infra-umbilical laparotomy or a Pfannenstiel incision. Undoubtedly, dissection of the endopelvic fascia on either side of the proximal urethra, which extend to the connection with the anterior vaginal wall, is reserved for experienced surgeons. This step is rendered more difficult in scarred multi-operated pelvises, where the planes are no longer defined, leading to intra-operative bladder neck/bladder and vaginal injuries and eventually abortion of the procedure. Therefore, mastering of the dissection procedure requires a long learning curve (see photo 1). Recently, robotic AUS implantation has been the ‘new kid on the block’, exhibiting good results, with the advantage of a shorter incision, a decreased surgical morbidity, post-operative pain improvement and reduced convalescence duration8.

View of a cuff insertion around the bladder neck through an open route in women

Our institution performs this technique in a day surgery setting for selected patients, i.e. women with confirmed ISD without urethral hypermobility, with no prior UI surgery or in AUS revision cases. The results of a larger follow-up cohort study shall be published soon9. However, robotic female AUS surgery is still at its infancy and comparing both open and laparoscopic approaches requires a prospective study and more significant sample to be able to draw any conclusions10.

AUS outcomes Regardless, an overall continence rate defined as a ‘zero pad’ rate of 85.6% and mean device survival of 14.7 years have been reported. This is comparable to sling procedures for a similar patient group with anteriorly failed multiple UI procedures, among whom the ‘zero pad’ rate ranges between 42-86%.

High patient satisfaction rates are also published, although no validated questionnaires were used to assess quality of life, since PROMS were not used at the time of publication1. High continence rates come at the cost of significant complication rates, as illustrated in a recent systematic review: 6-44% revisions, 2-41% mechanical failures, 2-54% procedure adverse events and 2-27% explantations1,11.

Interestingly, in our experience many women would choose to undergo another AUS operation if needed and accept the odds of related complications rather than living with UI.

“In our experience, many women would choose to undergo another AUS operation if needed and accept the odds of related complications rather than living with UI.” Future perspectives In summary, the SMUS is a good option for SUI with urethral hypermobility. However, we must address the problem arising from multiple failed sling procedures and consequent functional sequelae.

The AUS on the other hand is a very valid surgical alternative for SUI secondary to ISD associated with fixed urethra, with or without prior unsuccessful UI procedures. Recommended as a second-line surgical therapy, the AUS should reasonably be considered in keeping with an adequate timeline, in order to optimise functional outcomes with a minimum of peri-operative adverse events. It would help if we were able to identify those selected cases that would benefit from an earlier AUS implantation within the current therapeutic algorithm in order to improve the patient’s quality of life.

Indeed, more prospective randomized clinical trials are needed, however, these are expensive. Paving the way for future evidence-based material on the subject, the ongoing SU-ACT trial (ClinicalTrials.gov, identifier: NCT02490917) comparing ACT™ balloon (Uromedica, USA) outcomes with the AMS 800™ will provide much needed information on SUI secondary to ISD. This will be the first prospective study of its kind analysing AUS implantation in a pure cohort of women. This study will strive to deliver guidance to the urologist in the matter of patient counselling prior to female AUS in tomorrow’s clinical setting.

Financial disclosures Emmanuel Chartier-Kastler is an honorarium speaker and training surgeon for Boston Scientific and a consultant for UroMems. Christine Reus has nothing to disclose.

References 1. Reus CR, Phé V, Dechartres A, Grilo NR, Chartier-Kastler EJ, Mozer PC. Performance and Safety of the Artificial Urinary Sphincter (AMS 800) for Non-neurogenic Women with Urinary Incontinence Secondary to Intrinsic Sphincter Deficiency: A Systematic Review. Eur Urol Focus [Internet]. 2018 Oct [cited 2018 Nov 20]; Available from: https://linkinghub.elsevier.com/retrieve/pii/ S240545691830302X 2. Blaivas JG, Olsson CA. Stress incontinence: classification and surgical approach. J Urol. 1988 Apr;139(4):727–31.

3. Cour F, Le Normand L, Lapray J-F, Hermieu J-F, Peyrat L, Yiou R, et al. Insuffisance sphinctérienne et incontinence urinaire de la femme. Prog En Urol [Internet]. 2015 Jun [cited 2018 Dec 23];25(8):437–54. Available from: https:// linkinghub.elsevier.com/retrieve/pii/S1166708715001037 4. English SF, Amundsen CL, McGuire EJ. Bladder neck competency at rest in women with incontinence. J Urol.

1999 Feb;161(2):578–80.

5. Haliloglu B, Karateke A, Coksuer H, Peker H, Cam C. The role of urethral hypermobility and intrinsic sphincteric deficiency on the outcome of transobturator tape procedure: a prospective study with 2-year follow-up. Int Urogynecology J [Internet]. 2010 Feb [cited 2018 Sep 1];21(2):173–8. Available from: http://link.springer. com/10.1007/s00192-009-1010-y 6. Costa P., Poinas G., Ben Naoum K., Bouzoubaa K., Wagner L., Soustelle L., et al. Long-term results of artificial urinary sphincter for women with type III Stress urinary incontinence. Eur Urol [Internet]. 2013;63(4):753– 8. Available from: http://www.embase.com/search/result s?subaction=viewrecord&from=export&id=L51925579 7. Chartier-Kastler E., Van Kerrebroeck P., Olianas R., Cosson M., Mandron E., Delorme E., et al. Artificial urinary sphincter (AMS 800) implantation for women with intrinsic sphincter deficiency: A technique for insiders? BJU Int [Internet]. 2011;107(10):1618–26.

Available from: http://www.embase.com/search/results? subaction=viewrecord&from=export&id=L361674168 8. Rouprêt M., Misraï V., Vaessen C., Cardot V., Cour F., Richard F., et al. Laparoscopic Approach for Artificial Urinary Sphincter Implantation in Women with Intrinsic Sphincter Deficiency Incontinence: A Single-Centre Preliminary Experience. Eur Urol [Internet].

2010;57(3):499–505. Available from: http://www.embase. com/search/results?subaction=viewrecord&from=export& id=L50471254 9. Chartier-Kastler E, Reus C. Are Slings Still the Gold Standard for Female Stress Urinary Incontinence? Eur Urol Focus. 2019 May;5(3):315–6.

10. Peyronnet B., Vincendeau S., Tondut L., Bensalah K., Damphousse M., Manunta A. Artificial urinary sphincter implantation in women with stress urinary incontinence: preliminary comparison of robot-assisted and open approaches. Int Urogynecol J Pelvic Floor Dysfunct [Internet]. 2016;27(3):475–81. Available from: http://www. embase.com/search/results?subaction=viewrecord&from =export&id=L606535471 11. Peyronnet B, O’Connor E, Khavari R, Capon G, Manunta A, Allue M, et al. AMS 800 Artificial urinary sphincter in female patients with stress urinary incontinence: A systematic review. Neurourol Urodyn [Internet]. 2019 Aug [cited 2020 Jan 24];38(S4). Available from: https:// onlinelibrary.wiley.com/doi/abs/10.1002/nau.23833

EUT Congress News

23

VIRTUAL 17-19 July

#EAU18

Cutting-edge Science at Europe’s largest Urology Congress

EAU20 Virtual Congress programme Friday, 17 July

17:00 - 18:30

08:20 - 08:30 Introduction Welcome to the EAU20 Virtual Congress

17:00 - 17:15

08:30 - 09:10 Game Changing Session 1 08:30 - 08:45 Continence following robotassisted (R-LRPE) and conventional laparoscopic radical prostatectomy (LRPE) - results of a prospective, randomized, multicenter, patient blinded study 08:45 - 08:50 Discussion, questions and answers 08:50 - 09:05 ProPSMA Study: A prospective randomised multi-centre study of PSMA-PET/CT imaging for staging high risk prostate cancer prior to curative-intent surgery or radiotherapy 09:05 - 09:10 Discussion, questions and answers 09:10 - 11:40

Plenary Session 1 Modern prostate cancer imaging in daily practice 09:10 - 09:20 Ultrasound in prostate cancer imaging: Dead or ready to get started?

09:20 - 10:10 Prostate biopsies 10:10 - 10:20 Screening strategy and active surveillance in 2020 10:20 - 10:45 Biochemical recurrence I 10:45 - 11:20 Biochemical recurrence II 11:20 - 11:30 A peek into the future: Artificial intelligence and prostate cancer imaging 11:30 - 11:40 Discussion, questions and answers 11:40 - 13:00

11:40 - 11:45 11:45 - 12:25 12:25 - 12:45 12:45 - 13:00 13:00 - 14:30 13:00 - 13:15 13:15 - 13:35 13:35 - 13:50 13:50 - 14:10 14:10 - 14:30

Thematic Session 1 Focal therapy for prostate cancer: Mid-term oncological outcomes and salvage radical prostatectomy Introduction to focal therapy Midterm oncological results of focal therapy Outcomes of salvage radical prostatectomy after focal therapy Discussion, questions and answers Plenary Session 2 New frontiers in infections New diagnostic techniques to overcome antibiotic resistance How to minimise infectious complications of prostate biopsies: A white paper Urosepsis: Hot data from the SERPENS study Infection control practices in patients at risk for multiresistant pathogens Live Discussion, questions and answers

14:30 - 15:30

Industry Session

15:30 - 17:00

Thematic Session 2 Men’s health 2020 The urologist as a gatekeeper for men’s health Case-based debate Preservation of quality of life in prostatic disease Discussion, questions and answers

15:30 - 16:00 16:00 - 16:55 16:55 - 17:00

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EUT Congress News

17:15 - 17:30 17:30 - 17:45

17:45 - 18:10

18:10 - 18:20 18:20 - 18:30

Thematic Session 3 Management of patients with CRPC in 2020 CRPC: Prediction of response to systemic treatment Imaging of CRPC - what is possible, what is necessary?

Molecular pathology before systemic treatment - what is feasible?

Case-based debate M0 CRPC: Androgen receptor targeted treatment (ARTA) The best sequence for M+ CRPC in 2020 Discussion, questions and answers

18:30 - 20:00 Thematic Session 4 Radioligand therapy in metastatic castration-resistant prostate cancer 18:30 - 18:45 Current and future radioligands (ligands and emitters) 18:45 - 19:00 Limitations of PSMA based on prostate cancer biology 19:00 - 19:15 Critical assessment of radioligand therapy 19:15 - 19:50 Case-based debate (PSMA)-targeted radioligand therapy: For which patients, which stages?

19:50 - 20:00 Discussion, questions and answers

Saturday, 18 July 08:30 - 09:05 Game Changing Session 2 08:30 - 08:45 Recurrence risk in patients with high grade non-muscle invasive bladder carcinoma in the Randomised Phase III Clinical Trial ‘NIMBUS’ stratified for EORTC and CUETO risk categories. A contemporary trend to less recurrences?

08:45 - 09:00 Results from the phase III study of nadofaregene firadenovec: Safety and efficacy in patients (pts) with high-grade, BCGunresponsive Non-Muscle Invasive Bladder Cancer (NMIBC) 09:00 - 09:05 Discussion, questions and answers 09:05 - 11:25

Plenary Session 3 Challenges across the spectrum of bladder cancer 09:05 - 09:15 Definition of very high-risk and refractory NMIBC 09:15 - 09:45 Early cystectomy in high-risk NMIBC: A standard?

09:45 - 10:00 Immunotherapy and beyond: New options for NMIBC 10:00 - 10:15 Urinary markers in low-grade NMIBC: Ready to stop cystoscopies?

10:15 - 10:30 Frailty and cognitive assessment in patients diagnosed with MIBC 10:30 - 10:45 Treatment options for elderly patients with muscle-invasive bladder cancer 10:45 - 11:00 Different bladder cancer genotypes: New treatment options

11:00 - 11:15

11:15 - 11:25 11:25 - 13:00

11:25 - 11:55 11:55 - 12:25 12:25 - 12:55 12:55 - 13:00 13:00 - 13:20 13:00 - 13:15

13:15 - 13:20 13:20 - 15:00

13:20 - 13:30

13:30 - 13:55

13:55 - 14:20

14:20 - 14:30

14:30 - 15:00

The future of personalised treatment: Test the tumour for a response Discussion, questions and answers

19:00 - 19:25

Thematic Session 5 Five things I wish I would have known earlier in my career: Lessons from the mentors Bladder Cancer Kidney Cancer Prostate Cancer Discussion, questions and answers

19:40 - 20:00 Best abstract session Oncology

Game changing Session 3 The real effect of prostate cancer treatment: EUPROMS study first patient driven quality of life study ever Discussion, questions and answers Plenary Session 4 Bladder dysfunction, storage symptoms and benign prostatic disease Basic neurological workup in a male LUTS patient: Keypoints for daily clinical practice Non-neurogenic OAB in a 60yr man with 60g prostate: First-line medical prescription Non-neurogenic OAB and proven obstuction, drugs don’t work Persistence of OAB symptoms after prostate surgery, despite good de-obstruction Minimally-invasive options for day case surgery

15:00 - 16:00 Industry Session 16:00 - 16:30 Thematic Session 6 Urinary reconstruction in (neuro)urology 16:00 - 16:30 Debate: What happens if Botox does not work in MS anymore?

16:30 - 17:00 17:00 - 18:10 17:00 - 17:20 17:20 - 17:30 17:30 - 17:50

17:50 - 18:00

18:00 - 18:10 18:10 - 19:40 18:10 - 18:25 18:25 - 19:00

Best abstract session Non-oncology Thematic Session 7 Immunotherapy and beyond Perioperative therapy for urothelial cancer Should we sequence all urothelial cancer patients?

Immunotherapy combinations for intermediate-poor risk mRCC Novel urothelial cancer treatment beyond PD-1/PD-L1 inhibition Discussion, questions and answers Thematic Session 8 Salvage LND prostate cancer Does early diagnosis help the patient?

Primary treatment of pelvic lymph node metastatic prostate cancer

19:25 - 19:40

Treatment of recurrent lymph node metastatic PCa Treatment of polymetastatic hormone sensitive prostate cancer

Sunday, 19 July 08:30 - 09:05 Game changing Session 4 08:30 - 08:45 A prospective randomized study of bicalutamide +/docetaxel for non metastatic prostate cancer with a rising PSA (SPCG-14) 08:45 - 09:00 Health-related quality-of-life (HRQoL) analysis from KEYNOTE-426: pembrolizumab (pembro) plus axitinib (axi) vs sunitinib for advanced renal cell carcinoma (RCC) 09:00 - 09:05 Discussion, questions and answers 09:05 - 11:35

Plenary Session 5 Nightmare on robotics 09:05 - 09:50 Mechanical failure of the robot during RARP: Should I have stopped?

09:50 - 10:35 Were you ready for this level of complexity? Robotic T3 RCC into the IVC 10:35 - 11:20 Was your team appropriately skilled? Bowel perforation during robotic radical cystectomy 11:20 - 11:35 Discussion, questions and answers 11:35 - 13:00 11:35 - 11:50 11:50 - 12:05 12:05 - 12:20 12:20 - 12:35 12:35 - 12:50 12:50 - 13:00 13:00 - 15:10 13:00 - 13:10

13:10 - 13:35

13:35 - 13:45 13:45 - 14:05

14:05 - 14:45 14:45 - 15:10

15:10 - 16:10

Thematic Session 9 Complications of renal surgery Complications of laparoscopic renal surgery Complications of robotic renal surgery Complications of retrograde intra-renal surgery Complications of renal transplantation Complications of open renal surgery Discussion, questions and answers Plenary Session 6 Stones: The role of innovation Temperature and intrarenal pressure during laser lithotripsy Perioperative Antibiotic Prophylaxis: When, how and how long?

How to minimise radiation exposure in endourology New technology in retrograde intrarenal surgery: Unnecessary luxury vs. measurable benefit Beyond holmium laser: New lithotripsy devices 1cm stone in the lower calyx plus 2cm upper ureteral stone with complete obstruction Industry Session June/July 2020

www.eau20.org www.eau20.org

#EAU20 #EAU20

EAU20Theme ThemeWeek Weekprogramme programme EAU20 16:10 - 17:00 Thematic Thematic Session 16:10 - 17:00 Session 10 10 New technology urology New technology forfor urology 16:10 - 16:30 Patterns Patterns computers 16:10 - 16:30 andand computers 16:30 - 16:55 Small Small devices, new materials 16:30 - 16:55 devices, new materials 16:55 - 17:00 Discussion, Discussion, questions 16:55 - 17:00 questions andand answers answers 17:00 - 19:00Plenary Plenary Session 17:00 - 19:00 Session 7 7 #Testis cancer surgical #Testis cancer andand surgical andrology andrology 17:00 - 17:10 TheThe current treatment algorythm 17:00 - 17:10 current treatment algorythm Peyronie’s disease: Is there forfor Peyronie’s disease: Is there a role surgery? stillstill a role forfor surgery?

17:10 - 17:25 “I wish “I wish never…”: 17:10 - 17:25 I’dI’d never…”: Complications how avoid Complications andand how to to avoid them in male genital them in male genital reconstructions reconstructions 17:25 - 17:35 Infertility Infertility testis 17:25 - 17:35 andand thethe riskrisk of of testis cancer: New molecular cancer: New molecular connections connections 17:35 - 17:50 Autologous Autologous testicular tissue 17:35 - 17:50 testicular tissue transplantation in young cancer transplantation in young cancer patients: How we? patients: How farfar areare we?

17:50 - 18:00 How How manage testicular 17:50 - 18:00 to to manage testicular microlithiasis microlithiasis andand CISCIS 18:00 - 18:15 TheThe new testis cancer biomarker 18:00 - 18:15 new testis cancer biomarker miRNA 371: Ready prime time? miRNA 371: Ready forfor prime time?

18:15 - 18:45 Twitter Twitter told robot 18:15 - 18:45 told meme thethe robot cancan dodo Small retroperitoneal masses it: it: Small retroperitoneal masses in in testis cancer, what is best?

Stage testis cancer, what is best?

Stage IIAIIA 18:45 - 19:00 Discussion, Discussion, questions 18:45 - 19:00 questions andand answers answers 19:00 - 20:00Thematic Thematic Session 19:00 - 20:00 Session 11 11 Controversies in renal cancer Controversies in renal cancer surgery surgery 19:00 - 19:20 Case Case based debate 19:00 - 19:20 based debate Organ preservation: Organ preservation: DoDo thethe benefi ts outweigh additional benefi ts outweigh additional risks? risks?

19:20 - 19:30 Open Open minimally invasive 19:20 - 19:30 vs.vs. minimally invasive partial nephrectomy: What is the partial nephrectomy: What is the evidence? evidence?

19:30 - 19:40 How How best approach large 19:30 - 19:40 to to best approach thethe large renal mass: Tips tricks renal mass: Tips andand tricks 19:40 - 20:00Case Case based debate 19:40 - 20:00 based debate Cytoreductive nephrectomy: Cytoreductive nephrectomy: What know?

What dodo wewe know?

Monday, Monday,20 20July July Andrology Andrology

Friday, Friday,24 24July July Renal RenalCancer Cancer

17:00 17:00 – 17:45 – 17:45Poster Poster Session Session 1 1 Andrology Andrology andand genital genital cancers: cancers: Novelties Novelties surrounding surrounding that that other other Corona Corona

17:00 17:00 – 17:45 – 17:45Poster Poster Session Session 5 5 Renal Renal cellcell carcinoma carcinoma

17:45 17:45 - 18:45 - 18:45Industry Industry Session Session 18:45 18:45 – 19:15 – 19:15Video Video Session Session 1 1 Challenges Challenges in andrology in andrology

Tuesday, Tuesday,2121July July Imaging Imaging

17:45 17:45 - 18:45 - 18:45Industry Industry Session Session 18:45 18:45 – 19:15 – 19:15Video Video Session Session 5 5 Emerging Emerging technologies technologies in partial in partial nephrectomy nephrectomy

Saturday, Saturday,25 25July July Prostate ProstateCancer Cancer

17:00 17:00 – 17:45 – 17:45Poster Poster Session Session 2 2 New New frontiers frontiers in urological in urological imaging imaging

17:00 17:00 – 17:45 – 17:45Poster Poster Session Session 6 6 Management Management of prostate of prostate cancers cancers – from – from screening screening to metastasis to metastasis

17:45 17:45 - 18:45 - 18:45Industry Industry Session Session

17:45 17:45 - 18:45 - 18:45Industry Industry Session Session

18:45 18:45 – 19:15 – 19:15Video Video Session Session 2 2 Clinical Clinical applications applications of novel of novel imaging imaging techniques techniques

18:45 18:45 – 19:15 – 19:15Video Video Session Session 6 6 Advances Advances in the in the treatment treatment of localised of localised prostate prostate cancer cancer

Wednesday, Wednesday,22 22July July Functional FunctionalUrology Urology

Sunday, Sunday,26 26July July Stones Stones

17:00 17:00 – 17:45 – 17:45Poster Poster Session Session 3 3 Surgical Surgical options options in functional in functional urology: urology: Shaping Shaping thethe future future

17:00 17:00 – 17:45 – 17:45Poster Poster Session Session 7 7 TheThe toptop 10% 10% - News - News onon stones stones

17:45 17:45 - 18:45 - 18:45Industry Industry Session Session 18:45 18:45 – 19:15 – 19:15Video Video Session Session 3 3 Advanced Advanced reconstructive reconstructive surgery surgery

17:45 17:45 - 18:45 - 18:45Industry Industry Session Session 18:45 18:45 – 19:15 – 19:15Video Video Session Session 7 7 3D3D guidance guidance forfor stone stone management management

Thursday, Thursday,23 23July July Bladder BladderCancer Cancer 17:00 17:00 – 17:45 – 17:45Poster Poster Session Session 4 4 Targeted Targeted treatment treatment andand personalised personalised management management of advanced of advanced bladder bladder cancer cancer 17:45 17:45 - 18:45 - 18:45Industry Industry Session Session

Theme ThemeWeek Week

18:45 18:45 – 19:45 – 19:45Video Video Session Session 4 4 Improving Improving outcomes outcomes in the in the treatment treatment of bladder of bladder cancer cancer

Please Please note note that that allall speakers, speakers, session session times, times, and and virtual virtual event event rooms rooms listed listed in in this this edition edition of of thethe EUT EUT areare subject subject to to change. change.

Please Please visit visit www.eau20.org www.eau20.org forfor thethe fullfull programme programme including including speakers, speakers, session session times, times, and and virtual virtual event event rooms. rooms.

20-26 20-26July July

Industry IndustrySessions Sessionssponsored sponsoredby: by: Friday, July Friday, 17 17 July Industry Session Janssen Industry Session by by Janssen

Wednesday, July Wednesday, 2222 July Industry Session Astellas Pharma Europe Industry Session by by Astellas Pharma Europe

Saturday, July Saturday, 18 18 July Industry Session Medscape supported Industry Session by by Medscape supported by by independent educational grant from Ferring anan independent educational grant from Ferring

Thursday, July Thursday, 2323 July Industry Session Astellas Pharma Europe Industry Session by by Astellas Pharma Europe

Sunday, July Sunday, 19 19 July Industry Session Astellas Pharma Europe Industry Session by by Astellas Pharma Europe - Endorsed APCCC Endorsed by by APCCC Monday, July Monday, 2020 July Industry Session Pharma a Vifor Pharma Group Industry Session by by OMOM Pharma SA,SA, a Vifor Pharma Group company company

Friday, July Friday, 2424 July Industry Session Intuitive Industry Session by by Intuitive Saturday, July Saturday, 2525 July Industry Session Sanofi Genzyme Industry Session by by Sanofi Genzyme Sunday, July Sunday, 2626 July Industry Session Lumenis Industry Session by by Lumenis

Tuesday, July Tuesday, 21 21 July Industry Session Medac GmbH Industry Session by by Medac GmbH

June/July 2020

EUT Congress News

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EAU Research Foundation: PHOENIX update Prospective registry for patients undergoing penile prosthesis implantation Christien Caris, MSc Clinical Project Manager EAU Research Foundation Arnhem (NL)

Questionnaire translation During the first investigator meeting, the study protocol was c.caris@uroweb.org presented and the attendees participated in Co-authors: Ass. Prof. Koen Van Renterghem and lively discussions. Various Dr. Federico Deho patient questionnaires, related to sexual function, treatment satisfaction, and In one of the previous EUT editions, we have quality of life, will be used in the registry. Since not all reported on the first Phoenix investigator meeting questionnaires are available in the required which took place at the occasion of the Annual EAU languages, they will be professionally translated Congress in Barcelona in 2019. Phoenix is a registry according to the international ISPOR guidelines (the entitled ‘Prospective Registry for patients Undergoing professional society for health economics and Penile Prosthesis Implantation for Male Erectile outcomes research), including forward and backward Dysfunction’. translation, as well as cognitive debriefing.

Penile prosthesis implants The aim of the registry is to collect prospective data from 1,000 patients with a penile prosthesis implant.

The plan is to collect data from all Penile Prosthesis Implants (PPI) that are used in daily urological practice, so all surgeons who implant these prostheses are welcome to participate!

Wanted: participating centres for registry We aim at including European centres who offer PPI to their patients with erectile dysfunction. High as well as low-volume centres can participate in order to get a good representation of daily clinical practice. In this registry we will collect pre-defined parameters related to this kind of surgery. All registered devices that are used as implant in daily urological practice should be included. No extra visits will be required to collect the data. Patients are seen on a regular basis according to standard clinical practice.

and guidelines can be further improved resulting in better care for this group of ED patients.

“Questionnaires will be professionally translated according to the international ISPOR guidelines.”

The Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questionnaire (patient and partner version) has been translated and is ready to be tested. The Quality of Life and Sexuality with Penile Prosthesis questionnaire (QoLSPP), which is only available in Italian, has been translated into English first. The English version will be used as a basis for translation into the other required languages.

Cognitive debriefing means testing the translated questionnaires on a small group of relevant patients in order to test alternative wording and to check understandability, interpretation, and cultural relevance of the translation. This testing will be done by means of patient and partner interviews.

Translations The wording of the English translation has been improved, in consultation with the Italian designers of the questionnaire, based on comments provided during the interviewer instruction meetings. After the improved English QoLSPP version is tested in patients, this version will be translated in all required languages. These translations will be tested locally (and modified where needed) by means of patient interviews. Validation of the translated questionnaires will be part of the Phoenix project.

Publications will be generated during the translation and validation process.

National coordinators The Phoenix national coordinators have identified a Furthermore, it should be possible to identify clinical person in their department to conduct these and surgical factors that correlate with patient interviews. Several meetings have taken place during outcome, surgical complications and mechanical which the interviewer was informed about the background of cognitive debriefing and instructed on reliability of the devices used in daily urological practice. With the results, treatment recommendations how to conduct the interviews.

Once all translated documents are available (in the second quarter of 2020), the EAU Research Foundation (EAU RF) can start this very interesting project. In parallel to the questionnaires translation process, the Phoenix project has already been submitted to several ethical committees, enabling a swift start.

This will enable us to create a synopsis on patient and partner satisfaction as well as assess the mechanical reliability of the different PPIs on the market. The final goal is to demonstrate that this therapeutic option is an excellent treatment for patients with refractory Erectile Dysfunction (ED) who did not respond to previous treatments.

Patient inclusion should be consecutive. The EAU RF has a list of interested European urologists from Belgium, Italy, Germany, Denmark, Serbia, Spain, the Netherlands, France, the United Kingdom, and Sweden. Quite some centres have already shown interest to set up such a registry and are willing to participate by contributing their patient data after receipt of the patient’s consent. However, additional centres are welcome.

Interested?

Should you be interested in participating in, or funding of this registry, please inform the EAU RF by sending an email to C.Caris@uroweb.org.

Principal Investigators: Dr. Koen Van Renterghem, Hasselt (BE) Dr. Federico Deho, Milano (IT) Organisation: EAU Research Foundation

Development of predictive biomarkers for RCC The EASE registry: Opportunity to define the natural history of small, biopsy-proven RCC Prof. Alessandro Volpe Chairman Dept. of Urology University of Eastern Piedmont Novara (IT) alessandro.volpe@ med.uniupo.it In collaboration with the EAU Research Foundation (EAU RF), Prof. Alessandro Volpe of the University of Eastern Piedmont in Novara, Italy, is coordinating a multinational prospective longitudinal study to collect data on patients with small, incidentally detected, histologically confirmed renal cell carcinomas (RCCs) undergoing active surveillance (AS). This observational registry is called the European Active Surveillance of Renal Cell Carcinoma (EASE) study.

AS is a reasonable strategy for the management of small renal tumours in patients with advanced age or significant comorbidities. The evidence on AS is mainly based on retrospective and single institutional studies with relatively short follow-up. Moreover, the assessment of the oncological outcomes in these series can be biased by the presence of benign tumours since histological confirmation of malignancy is only obtained in a proportion of cases.

choose the most suitable conservative or active management approach for the individual patient.

EASE will contribute to reaching this goal since serum, urine and tissue specimens will be stored at baseline and at the time of tumour progression, for the assessment of genomic and molecular predictors of fast growth and progression of small renal tumours.

“The EASE study has the potential to clearly define the oncological outcomes and the clinical role of AS for small RCCs.” Objectives The primary objective of EASE is to assess the overall survival of patients who are diagnosed with incidental, histologically (biopsy) confirmed, < 4 cm RCC and are managed conservatively with AS. Furthermore, we hope to demonstrate that overall survival in this population is not significantly different compared to the overall survival of the general population without RCC, with similar age and comorbidities.

EASE is the first multicentre prospective study on AS that only includes patients with histologically-proven RCC by percutaneous biopsy at enrolment. Therefore, the study has the potential to clearly define the oncological outcomes and the clinical role of AS for small RCCs.

The secondary objectives include the following: • Growth and progression rates of small renal tumours in AS • Cancer-specific and progression-free survival of renal tumours in AS • Identification of clinical and pathological predictors of fast growth rate and progression for small RCCs • Identification of serum, urine and tissue predictive markers of fast growth rate and progression of small RCCs.

With the expansion of treatment options for small renal masses, it is also increasingly important to identify reliable biomarkers that can differentiate tumours with varied aggressiveness and metastatic potential at diagnosis. This enables a urologist to

Patient population EASE will include a total of 400 patients with small, incidentally detected, histologically-confirmed RCCs. The study will collect data related to the oncological outcomes of the AS approach.

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EUT Congress News

Study procedures A percutaneous biopsy of the renal mass is performed in all cases to histologically confirm the diagnosis of RCC. Biopsies are carried out under local anaesthesia with ultrasound or CT guidance.

At baseline, information on demographics, medical history, tumour-related symptoms and performance status are collected. A physical examination is performed and blood and urine are collected.

Abdominal imaging is performed by contrastenhanced CT scan and MRI or, in case of contrast allergy or abnormal serum creatinine, by ultrasound.

All patients follow a standardised AS protocol.

Follow-up visits are scheduled three and six months after diagnosis, every six months up to three years and every year thereafter. A follow-up visit is also carried out at the time of progression when it occurs. Follow-up visits include medical history, physical examination and assessment of performance status, serial abdominal imaging and assessment of quality of life and anxiety by questionnaires.

“More than 80 institutions have shown interest in including patients in the EASE registry.”

Electronic Case Report Form Biopsy material at baseline and at the time of tumour progression, as well as, voided urine and blood samples at definite time points are collected and stored for assessment of predictive biomarkers. The translational analyses are collected by the Francis Crick Institute in London where a group of scientists led by Dr. Samra Turajlic is spearheading the research in this field.

Study status More than 80 institutions across Europe and some from other continents have shown interest in including patients in the EASE registry. Seventeen centres from Argentina, Austria, Finland, Iceland, Italy, Lithuania, the Netherlands, Spain, Turkey and the United Kingdom have already obtained ethics approval and started recruiting patients. Several other institutions will follow soon. Please join us. New sites are welcome!

If you are interested in participating, please contact the EAU Research Foundation via researchfoundation@uroweb.org.

Study team Principal Investigator: Alessandro Volpe (Email: ale.volpe@me.com) Associate Professor of Urology University of Eastern Piedmont, Novara (IT) Clinical Protocol Committee: • Alessandro Volpe • Axel Bex • Anders Bjartell • Umberto Capitanio • Grant Stewart • Wim Witjes Translational Protocol Committee: • Samra Turajlic • Egbert Oosterwjik • Grant Stewart • Alessandro Volpe EAU Research Foundation • Wim Witjes, Scientific and Clinical Research Director • Christien Caris, Clinical Project Manager • Joke van Egmond, Clinical Data Manager

The web-based database management system, Marvin, is used to collect patient data. The system is intuitive and easy to use.

June/July 2020

EAU Research Foundation announces PRIME Study Prostate imaging using MRI +/- contrast enhancement Dr. Veeru Kasivisvanathan University College London and UCLH PRIME Chief Investigator London (GB) veeru.kasi@ucl.ac.uk Twitter: @veerukasi We are looking for centres to take part in the PRIME Study. The study is brought to you by the team that delivered the PRECISION study.

Background Since the publication of PRECISION, MRI-FIRST, and a number of other high-profile studies, the EAU and other international guidelines panels now recommend performing multiparametric MRI in men when they first present with suspicion of prostate cancer. Meeting the new increased demand for MRI scans can be a challenge.

We aim to ensure that every man who needs an MRI has access to one. One method of achieving this is by streamlining the multiparametric MRI scan. There is uncertainty in whether the contrast sequences in the multiparametric MRI contribute significantly to the detection of clinically significant cancer and subsequent treatment decisions. The PIRADs committee have highlighted this as an important area of research.

“We aim to ensure that every man who needs an MRI has access to one.”

Dynamic contrast enhanced images A full multiparametric MRI (T2-weighted images (T2W), diffusion weighted images (DWI) and dynamic contrast enhanced images (DCE)) takes approximately 30 minutes. The DCE sequence takes around a third of this scan time. It requires a health practitioner to insert a cannula into the patient for gadolinium contrast administration and requires a doctor to be present in the event of contrast reaction. Recent data has raised questions over the long-term safety of the gadolinium contrast.

Removing the contrast sequence can increase the number of MRI scans performed in any given day, reduce costs (less medical staff need to be present) and reduce the need for use of contrast medium. This would make meeting the high demand of MRI scans now required in prostate cancer diagnosis much more feasible.

Aim The PRIME study aims to assess whether biparametric MRI (T2W & DWI) is non-inferior to multi-parametric MRI (T2W, DWI and DCE) in the diagnosis of clinically significant prostate cancer.

Limitations of some of the previous studies in this area were: • Small sample size, single institution retrospective studies • No true blinding of the radiologists reporting the biparametric MRI to the DCE sequence • Using an MRI scoring system that already assumes that DCE has no role in differentiating between who needs a biopsy and who does not • No MRI-targeted biopsies Sample size required: 500 patients Intended length of recruitment: 24 months from recruitment of the first patient Patient eligibility criteria Key Inclusion criteria: 1. Men at least 18 years of age referred with clinical suspicion of prostate cancer 2. Serum PSA ≤ 20 ng/ml 3. Able to provide written informed consent Key exclusion criteria: 1. Prior prostate biopsy or prostate MRI 2. Contraindication to MRI or prostate biopsy Study design PRIME is an international multi-centre prospective diagnostic test evaluation study. Men referred with clinical suspicion of prostate cancer based on raised prostate specific antigen (PSA) or abnormal digital rectal examination (DRE), who have had no prior biopsy, undergo mpMRI. The DCE sequence is blinded for the radiologist who reports the biparametric (bpMRI) first. After reporting the bpMRI, the DCE sequence is made available to the radiologist who reports the multi-parametric (mpMRI). The MRIs and lesions are scored on a 1-5 scale of suspicion for the likelihood that clinically significant cancer is present: 1. Very low (clinically significant cancer is highly unlikely to be present) 2. Low (clinically significant cancer is unlikely to be present) 3. Intermediate (the presence of clinically significant cancer is equivocal) 4. High (clinically significant cancer is likely to be present) 5. Very high (clinically significant cancer is highly likely to be present) Subsequent recommendations Men with non-suspicious MRI on bpMRI and mpMRI and low risk of cancer will be recommended to undergo PSA surveillance. Suspicious areas scoring 3, 4 or 5 on either bpMRI or mpMRI will undergo MRI-targeted biopsy using the information from the bpMRI and mpMRI to influence biopsy conduct.

Suspicious areas will be labelled with their location and whether they were suspicious on either bpMRI, mpMRI, or both sequences. Targeted biopsy cores will be stored separately from areas that were uniquely suspicious on DCE so that conclusions can be made

Members of the PRECISION team were awarded the 2019 BMJ Research Paper of the Year for the PRECISION study.

The same team will be delivering the PRIME Study

on whether the pathology was from suspicious areas on the bpMRI or mpMRI. In addition, systematic biopsies will be taken. The proportion of patients with clinically significant prostate cancer will be ascertained and compared between bpMRI and mpMRI. Treatment eligibility decisions without the DCE information will be made and once the clinicians are unblinded to the DCE sequence the impact that this information has on the treatment decision will also be evaluated.

Primary outcome The primary outcome is the proportion of men with clinically significant cancer detected (Gleason Grade ≥ 3+4) / Gleason grade group 2 or greater).

Key secondary outcomes: 1. Agreement between bpMRI and mpMRI in score of suspicion 2. Proportion of men with clinically insignificant cancer detected (Gleason grade 3+3 / Gleason grade group 1) 3. Proportion of men with significant cancer missed by bpMRI & mpMRI-targeted biopsies and detected by systematic biopsy MRI requirements: High-quality MRI

“Since the publication of PRECISION, MRI-FIRST, and a number of other high-profile studies, the EAU and other international guidelines panels now recommend performing multiparametric MRI in men.”

Biopsy requirements: Either visually targeted or software-assisted fusion targeted biopsies are permitted. Transperineal biopsy approach is the ideal standard.

Implications of study If bpMRI is non-inferior to mpMRI, then bpMRI will become the new standard of care for prostate cancer detection in men with suspicious MRIs. This will allow a greater capacity to deliver MRI scans so that every man who needs a scan will be able to get one. If, however, the DCE sequence in mpMRI

Figure 1: Simplified study scheme

June/July 2020

identifies a large proportion of significant cancer and significantly influences staging and treatment eligibility decisions, then mpMRI will be recommended as the standard of care.

Funding Veeru Kasivisvanathan is funded by a National Institute for Health Research Academic Clinical Lectureship. The PRIME study has been supported by an EAU Research Foundation Grant.

Participating sites will be paid for participation with per patient recruited payments.

Requirements for your centre to take part 1. Prompt communication and prompt completion of study eligibility forms 2. Good quality MRI imaging and experience in MRI-targeted biopsy 3. Either publications showing your detection rates of clinically significant prostate cancer by MRI-targeted biopsy or provide audit data for your detection rates from your last 100 MRItargeted biopsies 4. Willingness to work with the UCL team in advance of the study to optimise your imaging protocols before taking part in PRIME 5. Be able to obtain all local approvals and start recruiting patients within 6 months 6. Aim for recruitment of at least 50 patients in 12 months (4-5 patients per month) 7. Give the names of a dedicated named radiologist, urologist, and data entry contact responsible for successful delivery of the study at your site and copy them in the email expressing your interest (see next paragraph) If your centre meets these requirements and you are interested in taking part in PRIME, please email veeru.kasi@ucl.ac.uk, copy and paste the above requirements with specific confirmation that you can meet each one and answers to the above points where applicable.

The Trial Management Group includes: Chief Investigator: Dr. V. Kasivisvanathan UCL NCITA Trials Group: Dr. C. Brew-Graves, Prof. S. Punwani, Prof. C. Moore, Dr. P. Khetrapal Statistics by University of Birmingham Test Evaluation Research Group, Dr. Y. Takwoingi, Prof. J. Deeks EAU Research Foundation: Dr. W. Witjes, Ms. C. Caris, Prof. A. Bjartell Trial Network: PRECISION & START Consortium

The members of the START consortium, which consists of world experts in prostate cancer, who are also part of the group conducting the PRIME study

EUT Congress News

27

Best Abstracts

Targeting STS to overcome resistance in PCa cells Understanding mechanisms of resistance is essential to improve therapies Prof. Allen C. Gao Dept. of Urologic Surgery University of California, Davis Sacramento (US)

acgao@ucdavis.edu Prof. Allen Gao is one of the authors of the abstract “Inhibition steroid sulfatase suppresses androgen signaling and improves response to enzalutamide,” which won the EAU20 Best Abstract Award Oncology. This article reflects its highlights.

Most prostate cancer (PCa) patients who receive enzalutamide (enza) or abiraterone (abi) eventually develop drug resistance. Emerging clinical evidence showed the serum levels of steroids, particularly dehydroepiandrosterone sulphate (DHEAS) and the biologically active dehydroepiandrosterone (DHEA) catalysed by steroid sulfatase (STS), are still in the high range and may serve as an ample pool of precursors for androgen synthesis despite of abi treatment.

In this study, we determined the contribution of STS to treatment resistance and explored the potential of targeting STS overcoming resistance in PCa cells. We found that STS is overexpressed in castration-resistant prostate cancer (CRPC) patients and resistant cells.

Overexpression of STS increases intracrine androgen synthesis, cell proliferation, and confers resistance to enza and abi.

Inhibition of STS expression by specific siRNA suppresses PCa cell growth and androgen receptor (AR) signalling. Targeting STS activity by selected small-molecule inhibitors of STS (STSi) inhibits the STS activity and suppresses AR transcriptional activity, and the growth of resistant C4-2B and Vertebral-Cancer of the Prostate (VCaP) cells. In addition, STSi significantly suppresses resistant VCaP tumour growth and decreases the serum PSA levels. Furthermore, STSi enhances enzalutamide treatment in vitro and in vivo.

These studies suggest that STS plays a critical role in PCa proliferation. Targeting this enzyme could be a viable strategy in treating CRPC and improving the second generation anti-androgen therapy.

Mechanisms of resistance Targeting androgen signalling via androgen deprivation therapy (ADT) has been the mainstay of clinical interventions in PCa. While initially effective, most men experience only transient benefit from these interventions before developing CRPC, which is currently incurable.

Enza, abi, and most recently apalutamide (apal) and darolutamide (daro), the second-generation antiandrogen drugs are approved for the treatment of CRPC. Even though these treatments have initially shown their efficacy, resistance frequently occurs. This is the most common cause of treatment failure. Better understanding of the mechanisms that confer resistance is urgently needed to design more effective treatments in overcoming resistance and improving therapies.

While AR mutations, amplifications, and overexpression of its variants such as AR-V7 have been suggested to play important roles in promoting CRPC progression and induction of resistance to enza and abi therapy, the mechanisms associated with resistance to these treatments are still largely unknown.

Intratumoural androgen biosynthesis is well characterised as a mechanism of CRPC1-4. Many enzymes are involved in androgen synthesis, including STS. CYP17A1, another androgenic enzyme, can be inhibited by abi in clinical treatments5,6. However, androgen synthesis inhibition by abi is incomplete, suggesting sustained steroidogenesis in addition to CYP17A1 contributes to resistance7-9. STS may contribute to this sustained androgen production even in the presence of abi (see Figure 1).

DHEAS conversion to DHEA by STS DHEAS is present at plasma concentrations up to 500 times higher than testosterone and can potentially be 28

EUT Congress News

transported into PCa cells via organic anion transporters. Once into the cells, DHEAS can be desulphated via endogenous STS into DHEA. DHEA can then be used as a precursor to synthesise into testosterone (T) by hydroxysteroid dehydrogenases and into dihydrotestosterone (DHT) via 5α reductase.

STS is present in most of the PCa specimens10 and its expression is increased in CRPC. Therefore, conversion of circulated DHEAS to DHEA by STS is believed to be an alternative source of androgen which cannot be inhibited by abi. Thus, DHEA is a major source of tumour androgens for prostate cancer and DHEAS is the most abundant steroid in male circulation.

In PCa patients treated with the nonspecific CYP17A1 inhibitor, ketoconazole, or the specific CYP17A1 inhibitor, abi, significant circulating DHEAS concentrations were still present (~20 μg/dL, which is about 2000 times higher than castrate levels of testosterone), suggesting that DHEAS could act as a depot for further downstream androgen formation via desulphatation12. These clinical data suggest the importance for exploring STS inhibition to prevent DHEAS conversion to DHEA. STS inhibition Numerous STS inhibitors have been tested for potential activity both in animal and clinical studies in breast cancer17. However, while STS has been widely investigated in breast cancer, there are limited studies in PCa. We provided experimental evidence suggesting that STS is overexpressed in CRPC cells. Overexpression of STS increases cell growth and confers resistance to anti-androgens. In addition, we have identified several novel small-molecule STSi. Targeting STS activity with STSi inhibits STS activity, suppresses AR transcriptional activity, reduces the growth of resistant PCa cells, and enhances enzalutamide treatment in vitro and in vivo. These results suggest that STS plays a critical role in PCa progression and that targeting STS could be a viable strategy to treat CRPC.

Figure 1: Sustained androgen production by STS in the presence of abi

Regulation of Steroid Action by Sulfation and Desulfation.

Endocrine reviews 2015;36:526-63 12. Tamae D, Mostaghel E, Montgomery B, Nelson PS, Balk SP, Kantoff PW, et al. The DHEA-sulfate depot following P450c17 inhibition supports the case for AKR1C3 inhibition in high risk localized and advanced castration resistant prostate cancer. Chemico-biological interactions 2015;234:332-8 13. Purohit A, Foster PA. Steroid sulfatase inhibitors for estrogen- and androgen-dependent cancers. The Journal of endocrinology 2012;212:99-110 14. James MR, Skaar TC, Lee RY, MacPherson A, Zwiebel JA, Ahluwalia BS, et al. Constitutive expression of the steroid sulfatase gene supports the growth of MCF-7 human breast cancer cells in vitro and in vivo. Endocrinology

2001;142:1497-505 15. Utsumi T, Yoshimura N, Takeuchi S, Ando J, Maruta M, Maeda K, et al. Steroid sulfatase expression is an independent predictor of recurrence in human breast cancer. Cancer Res 1999;59:377-81

Due to space constraints, the entire reference list can be made available to interested readers upon request by sending an email to: communications@uroweb.org.

Saturday 18 July 19.40 - 20.00: Poster Session Best abstract session: Oncology Virtual room 1

Conclusions Overexpression of STS increases intracrine androgen synthesis and confers resistance to enza in CRPC cells.

Inhibition of this enzyme improves enza treatment.

References 1. Cai C, Chen S, Ng P, Bubley GJ, Nelson PS, Mostaghel EA, et al. Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is upregulated by treatment with CYP17A1 inhibitors.

Cancer Res 2011;71:6503-13 2. Ishizaki F, Nishiyama T, Kawasaki T, Miyashiro Y, Hara N, Takizawa I, et al. Androgen deprivation promotes intratumoral synthesis of dihydrotestosterone from androgen metabolites in prostate cancer. Scientific reports 2013;3:1528 3. Locke JA, Guns ES, Lubik AA, Adomat HH, Hendy SC, Wood CA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res 2008;68:6407-15 4. Mohler JL, Titus MA, Bai S, Kennerley BJ, Lih FB, Tomer KB, et al. Activation of the androgen receptor by intratumoral bioconversion of androstanediol to dihydrotestosterone in prostate cancer. Cancer research 2011;71:1486-96 5. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011;364:1995-2005 6. Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013;368:138-48 7. Chang KH, Li R, Kuri B, Lotan Y, Roehrborn CG, Liu J, et al.

A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer. Cell 2013;154:1074-84 8. Attard G, Reid AH, Auchus RJ, Hughes BA, Cassidy AM, Thompson E, et al. Clinical and biochemical consequences of CYP17A1 inhibition with abiraterone given with and without exogenous glucocorticoids in castrate men with advanced prostate cancer. J Clin Endocrinol Metab 2012;97:507-16 9. Li Z, Bishop AC, Alyamani M, Garcia JA, Dreicer R, Bunch D, et al. Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer. Nature 2015 10. Nakamura Y, Suzuki T, Fukuda T, Ito A, Endo M, Moriya T, et al. Steroid sulfatase and estrogen sulfotransferase in human prostate cancer. The Prostate 2006;66: 1005-12 11. Mueller JW, Gilligan LC, Idkowiak J, Arlt W, Foster PA. The

June/July 2020

Limitations of PSMA based on prostate cancer biology Can DDR biomarkers be used to guide PSMA-directed therapies?

A

B

C

Figure 113: (A) Bone and lymph node mCRPC biopsies from the same patient demonstrating significant heterogeneity between metastases. (B) Levels of mPSMA expression in patients with deleterious aberrations in genes involved in the DNA repair vs those without.

(C) Expression of mPSMA in matched mCRPC and CSPC in patients with detected deleterious DDR aberrations vs patients without DDR aberrations.

Dr. Pasquale Rescigno Institute of Cancer Research Royal Marsden Hospital London (GB) pasquale.rescigno@ icr.ac.uk Prostate-specific membrane antigen (PSMA) is a type II membrane protein. It is expressed in healthy prostate and kidney tissues, salivary glands, nervous system glia, and the small bowel jejunal brush border, but also in prostatic adenocarcinoma (PC)1-4.

The PSMA gene is located on the short arm of chromosome 11, a region uncommonly deleted in PC5.

The PSMA protein consists of 3 portions (external, transmembrane, and internal)6. It acts as a glutamatepreferring carboxy-peptidase7 and plays a role in the cellular uptake of folate and glutamate, which are key for the synthesis and repair of DNA. Interestingly, its expression seems to be inversely related to androgen levels8.

The first anti-PSMA antibody that was developed (mAb 7E11) can recognise and bind a PSMA intracellular and/or cytoplasmic epitope1. From a clinical perspective, more than 90% of metastatic castration-resistant PC (mCRPC) patients presented PSMA-positive lesions based on 68Ga-PSMA positron emission tomography/computed tomography (PET/CT) images9. The detection rate of relapse and occult metastatic disease is similarly high in patients with biochemical reoccurrence post-radical treatment and PSA > 2ng/L10. However, ~ 50% of mCRPC patients do not respond to PSMA radioligand therapy despite documented PSMA expression11,12.

Membranous PSMA protein expression In our recent work, we evaluated membranous PSMA (mPSMA) protein expression in mCRPC biopsies and, when available, the matching, same-patient, diagnostic, castration-sensitive prostate cancer (CSPC) biopsies by immunohistochemistry (IHC), using a mouse monoclonal Ab internally validated.

Membranous PSMA quantification for each sample was determined by a pathologist blinded to clinical and molecular data using modified H-scores. The overall percentage of mPSMA positivity across the entire stained tumour sample was determined, yielding a range from 0 to 30013.

Prognostic role of PSMA expression We first studied mPSMA expression levels in 38 CSPC PC diagnostic biopsies (median H-score 17.5 [0.0– 60.0]). While 16 (42%) patient samples had no detectable expression, the remaining 22 expressed PSMA, with a significant degree of interpatient and intrapatient heterogeneity in expression.

In our analyses, higher levels of mPSMA expression were associated with a higher Gleason grade (p = 0.04) and a worse overall survival (hazard ratio [95% CI]: H-score < 17.5 = 1.00 vs H-score > 17.5 = 2.97 [1.38–6.43]; p = 0.006).

June/July 2020

Expression of mPSMA protein demonstrates intraand interpatient heterogeneity Median mPSMA H-score was 55.0 (2.8–117.5) in 60 mCRPC samples. Importantly, 16 (27%) of these biopsies had no detectable expression of mPSMA. Interestingly, a comparison with matched, same patient CSPC tissue samples revealed that half of these samples with no mPSMA protein expression (8/16) were also negative for mPSMA expression at PC diagnosis.

Overall, 37 of the 44 mCRPC mPSMA+ samples (84%) demonstrated marked heterogeneity in expression.

This also depended on type of tissue biopsy analyzed, with liver metastases (n = 8) showing overall lower PSMA expression compared to bone (n = 25), lymphoid tissue (n = 22), or other sites (n = 5).

mRNA expression, and both BRCA2 mRNA expression (p < 0.001) and double-strand break repair (p < 0.001).

This would suggest that high PSMA expression in mCRPC is associated with BRCA2 loss and a reduction in homologous recombination dependent DNA repair.

Conclusions Taken together, these data indicate that a proportion of patients exhibit no detectable PSMA expression in their tumour biopsies at diagnosis, and this correlates with survival. Moreover, while mPSMA increases in mCRPC, a proportion of patients exhibit no detectable PSMA. When it is present, mPSMA expression exhibits intra and interpatient heterogeneity, with a potential impact on the clinical utility of PSMA theranostics.

Finally, we showed that deleterious DDR aberrations are associated with significantly higher mPSMA expression levels in mCRPC. Therefore, DDR biomarkers can potentially be used to guide PSMA-directed therapies.

Due to space constraints, the reference list can be made available to interested readers upon request by sending an email to: communications@uroweb.org Friday 17 July 18.30 - 20.00: Thematic session 04 Radioligand therapy in metastatic castrationresistant prostate cancer Virtual room 2

“mCRPC samples from patients harbouring DDR aberrations had significantly higher mPSMA expression than those without these aberrations.” mPSMA expression was heterogeneous within the same patient’s sample, with regions of PSMA-negative tumour cells segregated from regions of PSMA expressing cells, a number of which were > 2 mm apart, which is the maximal tissue penetrance of the beta particle emitter 177Lu used in current clinical trials.

Furthermore, heterogeneous mPSMA expression between metastases from the same patient was also observed (see figure 1A).

Expression of mPSMA protein in mCRPC and DNA repair In addition to this, considering that intratumour heterogeneity can be significantly increased by genomic instability14, we have also pursued next-generation sequencing (NGS) studies to investigate whether deleterious DNA damage repair (DDR) aberrations were associated with PSMA protein expression.

Overall, mCRPC samples from patients harbouring DDR aberrations had significantly higher (p = 0.016) mPSMA expression than those without these aberrations (DDR 87.5 [25.0–247.5] vs no DDR 20 [0.3–98.8]; difference in medians 60 [5.0–95.0].

More interestingly, when we compared the change in mPSMA protein expression between matched CSPC and mCRPC tissue samples, we observed that mPSMA expression increased significantly in mCRPC patients with detectable DDR aberrations (p = 0.02), but not in those without detectable DDR gene mutations (p = 0.19) (Coef = 35; 95% CI: 2–68; p = 0.04; see figure 1C).

“Deleterious DDR aberrations are associated with higher mPSMA expression levels” When we explored the association between PSMA expression and DNA repair using RNA-sequencing data (163 mCRPC transcriptomes data from SU2C/PCF cohort), we found an inverse correlation between PSMA

Recent Advances in the Treatment Landscape for the Patient With BCG Unresponsive NMIBC CPD SATURDAY, 18 JULY 2020 | 15:00 – 16:00 cet

MODERATOR Shahrokh F. Shariat, MD Professor and Chairman of Urology Medical University of Vienna Department of Urology and Comprehensive Cancer Center Vienna, Austria PANELISTS Marek Babjuk, MD, PhD Professor and Chairman Department of Urology Second Faculty of Medicine Charles University Motol University Hospital Prague, Czech Republic

Ashish M. Kamat, MD, MBBS Professor of Urology and Cancer Research The University of Texas MD Anderson Cancer Center Houston, Texas, United States Joan R. Palou, MD, PhD, FEBU, FRCS Chairman of the Urology Department Fundació Puigvert Autonomous University of Barcelona Barcelona, Spain

www.medscape.org/symposium/advances-nmibc THIS SATELLITE SYMPOSIUM IS IN CONJUNCTION WITH THE 35TH ANNUAL EAU CONGRESS.

Supported by an independent educational grant from Ferring Pharmaceuticals.

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Best Abstracts

BPH under 50: Increased stromal components and fibrosis Altering the CYP19/oestrogen/GPER signalling pathway in patients with early-progressed BPH Dr. Yang Yang Dept. of Urology Beijing Friendship Hospital, Capital Medical University Beijing (CN)

vttyoouyy@163.com Dr. Yang Yang is one of the authors of the abstract “Increased stromal components and prostatic fibrosis via altering the CYP19/Estrogen/ GPER signaling in the early progression of BPH tissues of men ≤ 50 years old,” which won the third prize in the EAU20 Best Abstract Awards Non-Oncology. This article reflects its highlights.

Specific study In this study, researchers enrolled the prostate specimens from three groups of patients: BPH patients ≤ 50 years old (defined as Early progressed BPH patients), ≥ 70 years old (defined as Elderly BPH patients) with end-stage clinical progression that need surgery treatment, and bladder cancer patients ≤ 50 years old who underwent cystoprostatectomy (Age-matched control group). They first attempted to explore the pathological characteristics of patients with early progressed BPH by comparing the pathological differences in prostate tissues among these three groups of patients. They found that the main histopathological characteristics of BPH tissues with early progressed BPH appear to be increased stromal components with higher ratios of stromal fibrosis, which was accompanied with higher myofibroblast accumulation and collagen deposition.

Difference in prostate stroma The question is: what causes the difference in Benign prostatic hyperplasia (BPH) is thought to occur prostate stroma? Further analysis of the specimens mostly in men older than 50 years. With the increase showed that aromatase (CYP19) was highly expressed of age, elderly men will gradually develop lower in the early progressed BPH tissues compared to the urinary tract symptoms due to BPH, and eventually other two groups, whereas SRD5A2 and androgen develop clinically advanced BPH that requires receptor were weakly expressed. The results medication and surgical intervention. Generally, this suggested that there is a switch from androgens to process takes about 10-20 years. oestrogens in the BPH tissues with accelerated progression. Interestingly, they noticed that the early However, researchers from China, Dr. Yang and progressed BPH group had higher BMI, which is Dr. Jin, found that a small number of BPH patients associated with high expression and activity of show rapid clinical progression of BPH under the aromatase as well as increased circulating oestrogen age of 50 and need medication or even surgical levels. To clarify which type of oestrogen receptors intervention.

(ERs) is involved in the oestrogen-promoted stromal cells proliferation and prostatic fibrosis of early Therefore, Dr. Yang and Dr. Jin believe that revealing progressed BPH patients, researchers examined the the causes of early onset in these BPH patients will expression of three types of ERs: ERα, ERβ, and G help to better understand the pathophysiology of protein-coupled oestrogen receptor (GPER) in the BPH occurrence and development. Moreover, it can prostate specimens. They found that only GPER provide drug targets for individualised treatment of expression in early progressed BPH group was BPH patients. higher than in the other two BPH groups.

GPER key factor?

In vitro data also revealed that oestrogen may not function through ERα or ERβ. However, the GPER could promote prostatic stromal cells’ proliferation and fibrosis, which indicates that GPER may be a key factor for the increased stromal components and fibrosis process of prostate in accelerated clinical progressive BPH patients. By further dissecting the mechanism of prostatic fibrosis regulation by oestrogen/GPER, the authors found that oestrogen could upregulate the protein level of HIF-1α through protecting its protein stability in prostatic stromal cells, which may consequently result in the fibrosis of prostatic stromal cells.

In addition, oestrogen/GPER can also activate EGFR/ ERK signalling to promote the proliferation of prostatic stromal cells. Therefore, mechanism dissection suggested the CYP19/oestrogen/GPER signalling pathway may be involved in the regulation of stromal cell proliferation and prostatic fibrosis that may accelerate the clinical progression of BPH patients.

“...prostatic fibrosis should be considered one of the pathobiological processes associated with accelerated clinical progression of BPH” Increased stromal components The overall results of this study provide the description of prostatic histopathological characteristics of early progressed BPH patients.

Dr. Yang and his team pointed out that the increased stromal components and prostatic fibrosis with higher myofibroblast accumulation and collagen deposition may be the key factors for the early clinical

progression of BPH/LUTS. The CYP19/oestrogen/GPER pathway modulates the EGFR/ERK and HIF-1α signalling, all of which have key roles on the proliferation and fibrogenesis of prostatic stromal cells in patients with accelerated clinical progression of BPH. Personalised medicine It has been reported that still more than 30% of patients suffer from BPH progression after the administration of 5ARIs and α-adrenergic blockers, which are the mainstays of current medical therapy to prevent BPH progression.

Therefore, the goals of BPH therapy are not only to alleviate bothersome LUTS but also to delay the clinical progression of BPH to optimise personalised management of BPH patients beyond the limitations of current medications. This study from Dr. Yang and Dr. Jin suggests that prostatic fibrosis should be considered one of the pathobiological processes associated with accelerated clinical progression of BPH, other than prostatic enlargement and smooth muscle contraction. The development of prostatic fibrosis enriches the pathophysiological mechanism of BPH/LUTS. Moreover, the findings reported here may provide personalised medicine with therapeutic targets for stromal hyperplasia with prostatic fibrosis. In the future, antifibrotic treatment by targeting the CYP19/oestrogen/GPER signalling pathway combined with current drugs may be efficacious in delaying the progression of BPH patients with prostatic fibrosis.

Saturday 18 July 16.30 - 17.00: Poster Session Best abstract session: Non-oncology Virtual room 2

1page-no-bleed.pdf 1 30/01/2020 12:46:47

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June/July 2020

Tips and tricks in the removal of large abdominal masses How to pass this test of your mental and physical resolve The renal artery is not divided at this point as exposure is better later in the operation. Ligation of the artery flush with the aorta also mitigates the problems that can arise from incomplete control due to early branching of the artery.

Mr. Tim O’Brien Consultant Urological Surgeon Guy’s and St Thomas’ Hospitals London (UK)

tsoburol@aol.com Urological surgery presents fascinating diverse challenges, not least in the anatomical size of those challenges, ranging from the micro-surgery of vasovasostomy to resection of 25 cm diameter kidney tumours or retroperitoneal nodes. Precision is required for both but precision of a very different nature. This talk sets out some principles for this macro-precision!

What is large?

There is no definition for what constitutes ‘very large’ and one principle to set out right at the start would be that size alone is an imperfect predictor of difficulty. A 20 cm diameter smooth walled renal cystic mass would generally be a far more straightforward proposition than a 12 cm mass with a blocked left renal vein and local infiltration of psoas and the tail of the pancreas. For the purpose of the talk and this article we will consider masses to be very large if for whatever reason they are being considered for open surgical removal.

Multiple skilled surgeons In a talk that majors on the technical, i.e. tips and tricks, I make no apology for the first lessons to be non-technical. They are critical. Planning is paramount. These are not solo operations or operations to be performed with junior assistance.

More than one skilled surgeon is required. In 2020, there are no straightforward ‘open’ procedures (all of those are done laparoscopic or robotic), so if it’s being done open, it is difficult. The requirement for multiple skilled surgeons is for 3 reasons. Firstly, the manoeuvring of the mass by the assistant to display anatomy and aid dissection is critical to that dissection and requires skill, judgement, and experience. In the operations in which I am the nominated lead, I will most often be that individual, i.e. the first assistant, because the display and the manoeuvring becomes the key role. Secondly, the most feared and most likely intra-operative complication is heavy bleeding. This is role and time critical, stressful, and requires experience to resolve successfully. Thirdly, the operations can be lengthy.

The maintenance of super-intense levels of concentration over 4-5 hours is well-nigh impossible.

Mental fatigue leading to impaired physical performance sets in. Sharing the load by generating an ‘ebb and a flow’ whereby surgeons take turns ‘facing the bowling’ really helps.

Teamwork A second key element of preparation relates to team.

Smooth effortless teamwork only comes with consistent periods of working together, and not all surgeons pair well together. Ryder cup captains know that not all pairings work and surgeons need to, too.

Figure 1: Obliteration of the left para-aortic space by lymph node and haematoma

Figure 2A: Incisions commonly in use: right-sided tumours

June/July 2020

Figure 2B: Incisions commonly in use: left-side tumours

Lower pole Peripheral dissection and dissection of lower pole is done with cautery on 40 w and releases the lateral peritoneal attachments. In right-sided dissection, division of the ligament of Treitz, mobilisation of the colon, and small bowel is done at this point. This exposes the ivc. Safe dissection is possible flush with the ivc’s anterior surface. With exposure of the great vessels to define the medial danger, exposure of the common iliac artery to define the inferior danger, and lateral peritoneal release, control and division of the gonadal vein and ureter is then possible. Care is required to avoid damage to the common iliac artery if the mass is very large and arising from the lower pole. These steps allow release of the inferior attachments and posterior dissection is undertaken very straightforwardly.

Upper pole For peripheral dissection and dissection of the upper pole, the splenic or hepatic flexure is released using diathermy and Liga clips to expose the upper pole Figure 2C: Incisions commonly in use: left-side tumours into ivc mass. Decisions at this point are needed about the need for full mobilisation of the right hepatic lobe or spleen and tail of pancreas. If bleeding from splenic Good assistants anticipate the next move, no capsular tears occurs, it can usually be controlled by questions or instructions need to be given. applications of pro-coagulants such as floseal. Deep tears may require splenectomy. The plane between Create a plan the pancreas and the adrenal is usually well A third final element of preparation relates to creating preserved. Infiltration of the tail of the pancreas can a plan. Review of the imaging is critical and needs to be managed by distal pancreatectomy and involve the surgical team and radiologists who splenectomy. The pancreas can be stapled or understand the surgical challenge. There is no place overseen with 3/0 prolene. The adrenal is taken en for bland generic radiological reports. This review bloc. Dissection of the mass off the diaphragm can be often relates to the status and management of the very difficult. It is best done with diathermy. Venous adjacent structures, numbers of renal arteries, state bleeding can be intense and is best sutured with 2/0 of the veins, collaterals, and proximity of iliac blood vicryl figure of 8 sutures. Safe dissection of the upper vessels. A key question is: are the adjacent structures pole requires exposure of the medial vascular compressed by the mass or infiltrated by it? These structures, aorta on left, and ivc on right. The key may be ‘game changing’ findings such as involvement supero-medial venous structure on the right is the of the SMA/coeliac trunk, direct infiltration of the liver, right adrenal vein which can bleed ferociously. It is or infiltration around the head of the pancreas/ best controlled by Liga clips and once divided duodenum. These are all rare but only by reviewing bleeding from other structures is rarely problematic. the imaging with radiologists who understand the surgical challenge will good decisions be made.

Mobilisation of the liver Large masses often invade the renal vein and/or ivc.

Embolisation Mobilisation of the liver allows exposure of 10 cm of Should the patient undergo embolisation of the mass ivc behind the liver. Two elements may be required. pre-procedure? Usually no, as early ligation of the Mobilisation of the caudate lobe off the front wall of renal artery is feasible in most cases. However, in the ivc requires control of small communicating veins situations where the renal artery is deep within a by fine ligatures or Liga clips (see figure 5a). If the nodal mass (see figure 1) and the renal vein is caudate lode is wrapped around the ivc this step can obstructed, then pre-procedure arterial embolisation can help reduce bleeding. In our unit, the patient is transferred to interventional radiology at 08.30 am and undergoes embolisation under general anaesthesia before transfer to the operating theatre at approximately 11.00 am for nephrectomy.

Embolisation under local anaesthesia is painful and embolisation in the days running up to a nephrectomy should be avoided as it can generate an inflammatory SIRS syndrome.

Incisions The operations are done supine. Incisions are chosen which guarantee good access. We favour reverse L and Mercedes incisions (see figure 2 a-c). Midline incisions restrict access laterally making it more difficult to dissect the right lobe of the liver or the splenic hilum / tail of pancreas. If patients have had pelvic surgery, then long midline incisions (with lateral extensions) can allow accurate dissection of pelvic adhesions to the small bowel. The Thompson abdominal retractor gives superb access to the upper abdomen (see figure 3).

Ligation of the renal artery This is the crucial first step in these operations as it minimises blood loss from the collaterals in the periphery of the dissection. It is best done flush with the aorta i.e. to the left of the inferior vena cava (ivc) for a right sided tumour (see figure 4). Dissection of the colon and reflection of the colon and the small bowel is unnecessary at this point. The 4th part of the duodenum is simply reflected to the right; off the anterior wall of the aorta, the dissection continues cephalad flush with anterior wall of the aorta -- and the left renal vein is identified. Dissection under this allows identification of the renal artery at its origin. In our hands, this step takes fifteen to twenty minutes and saves on average 1000 ml of blood loss per case.

Figure 3: The Thompson retractor exposing the upper abdomen

Figure 5A: Mobilisation of the liver: the caudate lobe

Figure 5B: Mobilisation of the liver: the right lobe

be very tricky. If tumour extends higher in the ivc or if the tumour mass invades the diaphragm or adrenal then full mobilisation of the right lobe of the liver is required (see figure 5b). Diathermy dissection suffices and major bleeding is rare as the bare area is dissected free. If bleeding from the liver is encountered then 4 steps may help: the application of the argon beam coagulator, floseal or other procoagulants, compression of liver lobes after further dissection, and suture ligation with prolene. A pringle manoeuvre can help reduce bleeding if visualisation is difficult. If bleeding continues, placement of a swab and compression for 10 minutes will often suffice.

Control and division of renal vessels We avoid ligation of the renal vein until we are sure we have controlled all the renal arterial supply.

Ligation of the renal vein with less than perfect arterial control can lead to bleeding that is ferocious and very difficult to control. A short right renal vein may mean control of the caval side is best achieved with a side-biter ‘mini satinsky’ allowing suture ligation of the ivc wall with 4/0 prolene. Standard triple ligation usually suffices on the left. A caution is that very large masses can weigh several kilograms and can avulse the renal vein from the ivc if the renal vein carries the whole weight of the mass. This has happened to us twice and is problematic. It is avoided by the assistant cradling the mass thus reducing tension on the vein and/or by leaving some fascial attachments to the mass in addition to the renal vein to share the weight of the mass.

Post-removal We slow down at this point. The nephrectomy bed after removal of a large mass is extensive and raw. It is the small volume bleeding from periadrenal, pericaval, or posterior abdominal wall veins that may result in a return to theatre for bleeding later that night. Liga clips and 4/0 prolene sutures are often needed to secure these veins reliably. Floseal and fibrillar gauze is used as a routine. The diaphragm needs careful attention.

Post-operation care All our patients are managed in high dependency areas post-procedure. Analgesia is provided by a pre-procedure single shot spinal block, a TAP block placed intraoperatively by the surgeon, a wound catheter and infusion of chirocaine, and PCA of morphine. Post-operative antibiotics are not given.

Subcutaneous prophylactic low molecular weight heparin is started the day after surgery. Skin clips are removed after 2 weeks.

Very large renal masses test the physical and mental resolve of the patient and the surgeon. Disasters are possible but should be rare. Using the techniques outlined above, our return to theatre rate for bleeding is 0.3%, and overall mortality rate is under 1%.

Figure 4: Early ligation of the right renal artery to the left of the ivc

Sunday 19 July 19.00 - 20.00: Thematic session 11 Controversies in renal cancer surgery Virtual room 2

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Join us for this virtual symposium:

EAU20 Theme Week: Renal Cancer Da Vinci for partial nephrectomy: Tips on technique and a pathway for day surgery Friday, 24 July 2020 · 17:45 - 18:45 (CET)

Virtual symposium as part of EAU20 Theme Week Don’t miss this opportunity to hear from three urologic surgeons about their experience with the da Vinci surgical system in renal surgery.

As a part of this virtual event, the panel surgeons will discuss the value of robotic-assisted surgery and its potential benefits for their patients. They will share data on the clinical and economic impact, same-day surgery for partial nephrectomy, video surgical tips, and advantages of adopting robotics into their practices.

MODERATOR

Mr Ben Challacombe, MS FRCS(Urol) Guy’s Hospital and King’s College London Mr. Challacombe will moderate the virtual session and share his thoughts on the value of continuing da Vinci surgery while hospitals manage in a COVID environment.

Robotic-assisted Partial Nephrectomy with da Vinci – inspirations to refine surgical techniques Dr. Georg Schön Clinic of Urology München-Planegg, Germany

The pathway to day-surgery for robotic-assisted partial nephrectomy Prof. Jean-Christophe Bernhard University Hospital Bordeaux, France

Dr. Schön will share the impact of da Vinci robotics surgery development for renal cancer over the years. He will cover the evolution of the complexity of tumors operated with nephron sparing surgery, sharing video tips on surgical techniques and approaches. He has demonstrated success in surgical and functional outcomes based on his more than ten years of experience with the da Vinci surgical systems and supporting a multitude of da Vinci teams across Europe.

Prof. Bernhard will discuss his journey with robotic-assisted surgery, focusing on his experience and the value for patients. He will explain the role of robotics within enhanced recovery programs for partial nephrectomy and the overall impact on the length of stay and cost comparisons. He has been doing day-case surgeries since 2016.

The views and opinions expressed in the material presented at the symposium are those of the authors (independent surgeons) based on their practice and personal experience performing surgery with the da Vinci surgical system. Their experience may or may not be reproducible, generalizable, and does not necessarily represent the opinion of Intuitive Surgical.

Financial disclosure Mr. Challacombe, Prof. Bernhard, and Dr. Schön, have received compensation from Intuitive for consulting and/or educational services.

Important safety information For important safety information, indications for use, risks, full cautions, and warnings, please refer to www.intuitive.com/safety.

The da Vinci X, da Vinci Xi and da Vinci Si Surgical Systems are class IIb medical devices. Refer to the instructions for use for further information. © 2020 Intuitive Surgical, Inc. All rights reserved. Product and brand names/logos are trademarks or registered trademarks of Intuitive Surgical or their respective owner.

See www.intuitive.com/trademarks

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Persistence of OAB symptoms after prostate surgery Preoperative OAB symptoms, preoperative detrusor overactivity, and older age are risk factors Ass. Prof. Malte Rieken alta uro AG Basel (CH)

m.rieken@ outlook.com Lower urinary tract symptoms (LUTS) are highly prevalent in men over 50 years and can be divided into storage, voiding, and post-micturition symptoms. As LUTS can severely impact quality of life, a treatment approach which takes the aetiology of the condition into account seems most promising. While LUTS have traditionally been related to bladder outlet obstruction (BOO) caused by benign prostatic enlargement (BPE), increasing evidence relates LUTS to bladder dysfunction, such as detrusor overactivity (DO) and/or overactive bladder syndrome (OAB). In this context, it is important to explore reasons as well as strategies for the management of patients suffering from persisting OAB symptoms following surgical deobstruction.

patients undergoing TURP, urinary NGF was associated with preoperative as well as postoperative OAB symptoms8. In addition, various other mechanisms, such as changes in detrusor muscle calcium-activated chloride channels activity, ischemic-induced variations in response to neurotransmitters of the urothelium and detrusor muscle, and the nitric oxide pathway may play a role in detrusor dysfunction following bladder outlet obstruction2.

“...a patient-centred and symptomfocussed approach is crucial” Risk factors behind persisting OAB symptoms Several studies were able to identify preoperative risk factors behind persisting OAB symptoms after prostate surgery.

In the study of Antunes et al., maximum cystometric capacity (MCC) of less than 250 ml preoperatively was associated with persisting DO. While DO persisted in 64% of patients with MCC less than 250 ml, in patients with MCC greater than 250 ml DO was observed in only 20% of men3. When combining low preoperative MCC with prevalence of DO amplitude > 40 cm H20 and early DO, the chance of persisting DO after TURP was 83.3%3.

These results are supported by another study on Overactive bladder syndrome is characterised by persisting OAB symptoms after TURP, which found that increased frequency and urinary urgency and can be accompanied by urge urinary incontinence. In contrast, the preoperative degree of initial storage symptoms on IPSS, small bladder capacity, impaired detrusor DO is defined as involuntary contractions of the contractility, and age were associated with persisting detrusor during the filling phase of the bladder and is observed during urodynamics. Importantly, only around OAB symptoms4. In contrast, a recent systematic review and meta-analysis showed that preoperative DO was 50% of patients with OAB show DO. In men with BPE, cystometric studies revealed DO in 50-75% of men and not associated with improvement of IPSS, QoL, Qmax and PVR after transurethral BPE surgery9. In a a meta-analysis demonstrated DO with a mean population-based cohort study on 4,887 men who prevalence of 60.2%1. The prevalence of DO is associated with grade of obstruction and increases from underwent TURP, the association of diabetes mellitus 51.4% in Schäfer class 0 to 83.3% in Schäfer class VI1. In and outcomes of TURP was analysed. Although the data do not contain any information on symptom addition, DO was also associated with increasing age. scores or urodynamic investigations, the higher rate of DM patients with continuing medication of antiOAB symptoms after BPO surgery muscarinics or alpha-blockers is suggestive of a When assessing the rate of OAB symptoms after BPO detrimental effect of DM on bladder function10. surgery, it is important to adhere to appropriate terminology. Early postoperative storage symptoms, which are often new in onset, are generally “In persisting cases of DO, summarised under the term ‘dysuria’ and are usually associated with postoperative wound healing, onabotulinum toxin A injections inflammation, and pain2. These are usually short-term should be taken into consideration.” (less than 3 months) and self-limiting. In contrast, patients with preoperative OAB and/or DO with Treatment strategies persisting OAB symptoms after persisting symptoms define a distinct clinical entity.

BPO surgery Evidence from trials is very limited in patients with Transurethral resection of the prostate (TURP) is the persisting OAB symptoms following transurethral most studied surgical treatment in men with OAB BPO-surgery. Ideally, a cohort of patients with symptoms. In a study with 46 patients undergoing TURP, DO was present in 26 (56%) men preoperatively. preoperative well-defined OAB symptoms or verified DO should be followed for a minimum of 6-12 months Of those 26 men, 16 (62%) had a resolution of DO to investigate any meaningful and persisting effect of while 10 (38%) were suffering from DO at 12 months postoperatively3. Postoperatively, DO did not develop in an intervention or medication. any patient who did not have DO preoperatively3.

A prospective randomised trial comparing the effect of Another study on 116 men analysed persisting OAB tamsulosin with the combination of tamsulosin and symptoms six months following TURP and found 33 solifenacin or no additional medication after TURP did (28%) men to have persisting symptoms4. not show any additional LUTS improvement during 8 weeks follow-up11. In another prospective randomised The persistence of DO has also been investigated in trial, tolterodine 2 mg twice daily lead to a significant patients undergoing HoLEP. In a prospective study in reduction of storage LUTS (assessed by IPSS subscores) 165 patients, symptoms and urodynamic parameters at 4 weeks after TURP compared to placebo12. This were analysed prior to and 6 months after HoLEP. The could mean that presurgical use of anti-muscarinics is rate of patients with DO decreased from 45% associated with the highest risk of continuing preoperatively to 36% after HoLEP5. In contrast, bladder compliance did not improve. Another study on medication following transurethral prostate surgery13.

Pelvic floor muscle exercises after TURP lead to a the effect of HoLEP on patients with DO found that at significantly higher reduction in storage LUTS (assessed 6-months follow-up, more patients in the DO group

by IPSS subscores) as compared to TURP alone14. were taking anti-muscarinics compared to patients 6 without preoperative DO (48% vs. 21%) .

Lack of evidence Given the lack of high-level evidence, a patient-centred Aetiology of OAB symptoms after BPO surgery and symptom-focussed approach is crucial for the The pathophysiology of DO in men with BPO remains to be fully elucidated. There is a hypothesis involving a management of persisting OAB symptoms. A thorough clinical assessment as well as urodynamic studies in three-stage model of BPO-induced bladder selected cases are cornerstones in establishing causes remodelling. It consists of: of persisting OAB symptoms. Anti-muscarinics and the β-3 agonist mirabegron can be used as oral 1. hypertrophy, characterised by an increase in medication2. Pelvic floor muscle exercises alone or in collagen production which may play a role in combination with medication may be of benefit. In decompensation of bladder function; 2. compensation, which is characterised by increased persisting cases of DO, onabotulinum toxin A injections detrusor contractility during the voiding phase and should be taken into consideration. often combined with DO; Conclusions 3. decompensation, which is characterised by The persistence of OAB symptoms after transurethral detrusor underactivity7. prostate surgery is a common clinical scenario. Bladder remodelling from chronic bladder outlet obstruction Neurotrophins may also play a relevant role in DO may lead to persisting bladder dysfunction after pathophysiology. Nerve growth factor (NGF) is a signalling protein produced by detrusor smooth muscle adequate de-obstruction. Preoperative predominant cells and bladder urothelial cells8. In a recent study on OAB symptoms, preoperative DO and older age have June/July 2020

been identified as risk factors. In case of persisting OAB symptoms, a thorough clinical investigation, including urodynamics in selected cases, should be performed to identify potential causes and select for adequate treatment. Pharmacotherapy with antimuscarinics or β-3 agonist, pelvic floor muscle exercises or onabotulinum toxin A injections may be used for treatment. Further studies are necessary to provide high-level evidence on the best treatment approach to improve quality of life in this heavily burdened cohort of patients.

References 1. Oelke M, Baard J, Wijkstra H, de la Rosette JJ, Jonas U, Hofner K. Age and bladder outlet obstruction are independently associated with detrusor overactivity in patients with benign prostatic hyperplasia. European urology. 2008;54:419-26.

2. Cornu JN, Grise P. Is benign prostatic obstruction surgery indicated for improving overactive bladder symptoms in men with lower urinary tract symptoms? Current opinion in urology. 2016;26:17-21.

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? The Journal of urology. 2015;193:2028-32.

4. Choi H, Kim JH, Shim JS, Park JY, Kang SH, Moon du G, et al. Prediction of persistent storage symptoms after transurethral resection of the prostate in patients with benign prostatic enlargement. Urologia internationalis.

2014;93:425-30.

5. Kwon O, Lee HE, Bae J, Oh JK, Oh SJ. Effect of holmium laser enucleation of prostate on overactive bladder symptoms and urodynamic parameters: a prospective study. Urology. 2014;83:581-5.

6. Jeong J, Lee HS, Cho WJ, Jung W, You HW, Kim TH, et al.

Effect of Detrusor Overactivity on Functional Outcomes After Holmium Laser Enucleation of the Prostate in Patients With Benign Prostatic Obstruction. Urology.

2015;86:133-8.

7. Bosch R, Abrams P, Averbeck MA, Finazzi Agro E, Gammie A, Marcelissen T, et al. Do functional changes occur in the bladder due to bladder outlet obstruction? - ICI-RS 2018.

Neurourology and urodynamics. 2019;38 Suppl 5:S56-S65.

8. Hu H, Zhang W, Liu X, Wang H, Fang Z, Liang C, et al.

Nerve Growth Factor Levels are Associated with Overactive Bladder Symptoms and Long-Term Treatment Outcome after Transurethral Resection of the Prostate in Patients with Benign Prostatic Hyperplasia. The Journal of urology.

2018;200:620-5.

9. Kim M, Jeong CW, Oh SJ. Effect of urodynamic preoperative detrusor overactivity on the outcomes of transurethral surgery in patients with male bladder outlet obstruction: a systematic review and meta-analysis. World journal of urology. 2019;37:529-38.

10. Lin YH, Hou CP, Chen TH, Juang HH, Chang PL, Yang PS, et al. Is diabetes mellitus associated with clinical outcomes in aging males treated with transurethral resection of prostate for bladder outlet obstruction: implications from Taiwan Nationwide Population-Based Cohort Study.

Clinical interventions in aging. 2017;12:535-41.

11. Shin YS, Zhang LT, You JH, Choi IS, Zhao C, Park JK. Efficacy and safety of tamsulosin hydrochloride 0.2 mg and combination of tamsulosin hydrochloride 0.2 mg plus solifenacin succinate 5 mg after transurethral resection of the prostate: a prospective, randomized controlled trial.

Clinical interventions in aging. 2016;11:1301-7.

12. Tehranchi A, Rezaei Y, Shojaee R. Tolterodine to relieve urinary symptoms following transurethral resection of the prostate: a double-blind placebo-controlled randomized clinical trial. Korean journal of urology. 2014;55:260-4.

13. Strope SA, Vetter J, Elliott S, Andriole GL, Olsen MA. Use of Medical Therapy and Success of Laser Surgery and Transurethral Resection of the Prostate for Benign Prostatic Hyperplasia. Urology. 2015;86:1115-22.

14. Hou CP, Chen TY, Chang CC, Lin YH, Chang PL, Chen CL, et al. Use of the SF-36 quality of life scale to assess the effect of pelvic floor muscle exercise on aging males who received transurethral prostate surgery. Clinical interventions in aging. 2013;8:667-73.

Saturday 18 July 13.20 - 15.00: Plenary session 04 Bladder dysfunction, storage symptoms and benign prostatic disease Virtual room 1

EAU Virtual Congress and Theme Week July 17-26, 2020

LIVE VIRTUAL INDUSTRY SESSION* Improving the management of recurrent cystitis in clinical practice: can we do more?

Join us online on Monday, July 20 from 17.45-18.45 CET!

SCIENTIFIC PROGRAMME Chairman: Prof. Dr. Florian Wagenlehner

Disease burden of recurrent cystitis: the importance of prompt diagnosis and risk identification

Prof. Dr. Tommaso Cai, Santa Chiara Regional Hospital, Trento, Italy

State of the art in the management of recurrent cystitis Prof. Dr. Gernot Bonkat, Alta-Uro AG, Basel, Switzerland Chair of the EAU guidelines on Urological Infections

The place of immunotherapy in the management of recurrent cystitis: an attractive option Prof. Dr. Florian Wagenlehner, Justus-Liebig University, Giessen, Germany

* The symposium will also be available on demand after the live session.

EUT Congress News

33

Endourology with limited armamentarium, where is the limit?

Essential material to perform percutaneous nephrolithotomy or ureteroscopy Dr. Juan Pablo Caballero Romeu General University Hospital Alicante Alicante (ES)

juanpablocaballero@ gmail.com The limit of endourology with limited armamentarium is marked by patient safety in the first place. Reducing the probability of serious complications and minimising minor complications are essential.

Technological form of surgery Endourology is an increasingly technological form of surgery with thinner instruments, with an increasingly flexible method due to the atraumatic approach, and with better outcomes. We love technology and small devices. We even finally have a robot to treat stones. We like all these devices and sometimes we forget that there is an even less invasive technique, the ESWL, a more efficient technique in many circumstances1.

Costs However, this technology makes the procedures more expensive. We will have to see whether the new materials make endourology more effective, but they really do increase costs. The use of disposable material can increase the cost of each ureteroscopy by 238 euros2. We also have to be aware that what is revealed during the congress or what is reflected in the EAU guidelines not only has consequences in Europe, which has many social and economic differences between the different regions, it also has consequences in other less developed countries. If we conclude that using the latest technology is essential for endourology, we are excluding not only many patients but also many professionals from a treatment with a minimally invasive approach.

Referral Avoiding bureaucracy that delays patient care could be in favour of, for instance, bringing medical attention to the patient at home owing to the added comfort for the patient and his family, avoidance of patients transfers, and associated costs.

An imaging study can differentiate between a simple case and a very difficult case.

In this case, we diagnosed a calyceal diverticulum

Problems referring a patient to another centre can be: • change of indications; • delays due to bureaucratic factors; • secondary social and economic consequences due to a longer distance between home and the hospital; • longer stent dwelling times; • urinary tract infections; • voiding symptoms associated with catheters; • patient anxiety; • difficult postoperative follow-up.

Good surgery planning If a patient is treated at a centre with limited armamentarium, an important first safety measure should be good surgery planning3. If it is necessary to make a correct case selection in each ureteroscopy or percutaneous nephrolithotomy with a limited armamentarium available, it should be more exquisite. It is essential to do an imaging study, often with contrast in the urinary tract to rule out situations that complicate the case. In the case of ureteroscopy, we should avoid cases in which the lithiasis is impacted. Impacted lithiasis may require the use of guidewires with different characteristics, with varying stiffness and tips to adapt to the patient’s anatomy.

The presence of large cavities both at the ureteral and renal level makes the use of flexible material necessary in the case of stone migration.

Part of the essential material to perform a ureteroscopy

Nephroscopes with a reduced caliber can be very useful, but they are not essential to perform percutaneous nephrolithotomies

Dr. Perez-Seoane. Some countries don’t even have a modern video system (Photo courtesy)

In the presence of an important ureteral dilation, stones can easily pass into the kidney

34

EUT Congress News

In this case we identified a large middle lobe that made ureteral access very difficult

Avoiding problems Strategies to avoid problems when you have a limited armamentarium: • adequate preoperative study with imaging tests to assess the characteristics of the urinary and musculoskeletal pathways surrounding organs and lithiasis (position, hardness, and volume); • preoperative urine culture; • pre-stenting in selected cases; • use of a small calibre ureteroscope (< 8 Fr.); • inform the patients about treatment options, patient expectations and preferences.

confirm the presence of a perforation of the urinary tract using contrast media. Some studies have shown that it is feasible to perform ureteroscopy without fluoroscopy with good results9. These studies are usually carried out in high-volume hospitals, so their results cannot be extrapolated to hospitals with a low volume of patients.

Size of ureteroscope tip The use of a ureteroscope with a tip < 8 Fr. reduces the damage that occurs to the urinary tract both in access to the ureter and during the ascent to the upper ureter10. The lower the distance between the wall of the ureter and the instruments, the greater the Endourologists may think that different tools are ESSENTIAL to perform a ureteroscopy: tools such as a risk of injury to the ureteral orifice, but especially the risk of ureteral avulsion, which may occur when the ureteroscope, a safety guidewire, a C-arm fluoroscope, a powerful laser, a stone retrieval basket, ureteroscope is removed. a flexible ureteroscope, an irrigation pump, or a Minimum material to perform a ureteroscopy: ureteral access sheath. The EAU guidelines (the 2019 version) determine that the standard ureteroscope tip • radio transparent table; should be < 8 Fr. The guidelines also consider the use • saline; • 7.5 / 9.5 Fr. ureteroscope or similar; of fluoroscopy mandatory. The use of a safety • reusable graspers for stone extraction; guidewire is recommended. Ureteral dilators may be • fragmentation system, preferably m 10 W available, but they are not essential. The use of an holmium laser; irrigation system is still controversial. Several studies • safety guidewire and work guidewire; compare the use of an irrigation pump or an • fluoroscopy and / or ultrasound;11 alternative system to improve the quality of vision.

• iodised contrast (except in allergic patients).

The efficiency of irrigation flow in gravity-based irrigation is significantly lower than when using an If a percutaneous nephrolithotomy is performed, alternative irrigation system14. Jefferson et al. did not find differences in surgeons’ satisfaction and surgical one may consider an ultrasound, a balloon dilator, a pneumatic lithotripter, different sizes of Amplatz outcomes comparing the use of hand pump infuser sheaths, or small nephroscopes in addition to the irrigation to an automated irrigation pump15. material mentioned above.

Repeated access Ureteral access sheaths (UAS) allow repeated access When performing PNL, we advise the use of a balloon to the kidney in a non-traumatic and repeated dilator to establish the percutaneous tract. It is a less manner. UAS also favour low intrarenal pressure traumatic dilation than when metal dilators are used.

Nevertheless, different studies, such as those published during the procedure, reducing the risk of urinary sepsis, but they are not without risk. Even so, they are by Hijazi et al. and by the Clinical Research Office of the not essential and there is a lack of data on whether Endourological Society, did not identify advantages of they increase the stone-free rate or reduce the use of balloon dilation over metal dilators12. complications in the short and long term4,5.

Size of nephroscope Stone retrieval devices are useful to increase the Regarding the size of the nephroscope, there is no stone-free rate at the end of the procedure but have robust evidence that smaller calibre is associated with not been shown to improve surgical results lower morbidity.13 6 significantly . The EAU guidelines state that the Minimum material to perform a percutaneous holmium laser is the standard fragmentation method, nephrolithotomy: although it also lists pneumatic and ultrasonic lithotripsy as effective. Today, there are lasers up to 120 • radio transparent table; • saline; W available, but in the past we resolved stones with a • fluoroscopy; 10 W Holmium laser in more than 90% of cases7.

• nephroscope; Safety • flexible cystoscope; The first element that ensures patient safety is the • metal dilators; safety guidewire; it facilitates the ureteral access • Amplatz sheath; and, in case of ureteral injury, we can place a • graspers for stone extraction; ureteral catheter more easily. Some studies have • pneumatic lithotripter; shown that it is possible to perform a ureteroscopy • iodised contrast (except in allergic patients). without a safety guidewire. A review of six studies

by Molina et al.8 in 2017 included 1,886 patients, and Each urology department must analyse and plan which material is available or what they can acquire. it did not show an increase in complications or You should also try to honestly analyse which residual stones in patients in whom no safety capabilities the team has to solve in the cases that are guidewire was employed. However, it does not seem advisable as a generalised practice. It should presented. It is also important to establish a fluid only be done by experienced endourologists who dialogue with the hospital to which complex cases are adequately measure the risk to which the patient is referred, so patients will arrive with the appropriate studies. This reduces the number of visits and exposed. transfers, and it reduces the time needed until a final resolution is found.

Fluoroscopy brings benefits and risks. The risk is exposure to ionizing radiation by the patient and the staff. The benefit is that anatomical data are obtained Due to space constraints, the reference list can be made available to interested readers upon request by and elements that are not under direct vision at the sending an email to: communications@uroweb.org. moment of operation are localised. It allows us to June/July 2020

Robotic transgender vaginoplasty How the technique represents an applicable, efficacious and safe reconstruction method Prof. Ervin Kocjancic Dept. of Urology University of Illinois Hospital and Health Sciences System Chicago (US)

ervkoc@gmail.com

Dr. Ömer Acar Dept. of Urology University of Illinois Hospital and Health Sciences System Chicago (US)

oacar@kuh.ku.edu.tr In 2014, the United States Department of Health and Human Services reversed its exclusion of transsexual surgical treatments from Medicare coverage after determining that it did not reflect the current understanding, scientific literature and standards of care for the treatment of gender dysphoria. Increased insurance coverage and advocacy efforts have improved health care access for transgender and gender nonconforming individuals which has resulted to more interest and utilisation of gender-confirming surgical procedures.

In the creation of a natural-looking, sensate and functional vagina, labia and mons pubis for transwomen, vaginoplasty represents a desirable surgical treatment for gender confirmation and several existing techniques. Even for experienced gender surgeons, vaginoplasty represents a technically challenging operation with a major complication rate of over 20%. Penile inversion vaginoplasty (PIV) may be complicated by neovaginal stenosis and inadequacy of neovaginal dimensions.

The first description of robotic assistance for vaginoplasty was published in 2008 with a case report of a sigmoid vaginoplasty in a cis-female with Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. Since then, additional cases have been described without bowel interposition as well as for use in gender-confirmation surgery.

diagnosed with MRKH syndrome or those who have underdeveloped vaginal canals due to disorders of sex development.

Operative steps The procedure starts with patient positioning and port placement. Our initial cases were performed with a multi-port fashion, similar to Jacoby et al.

But with the availability of the single port (SP) robot, we have transitioned to utilising this platform as our preferred approach for robotic vaginoplasty. The flexible camera can be brought closer to the operative field and deeper into the pelvis. There is a reduced risk of instrument collision, and only a single abdominal incision is required which potentially translates into better cosmesis.

For many surgeons, the dissection between rectum and bladder-prostate complex represents the most challenging part of vaginoplasty, especially when performed solely through the perineal approach.

This is particularly true in patients with relatively larger prostates; patients with prior prostate intervention (e.g. surgery, biopsy); or patients with a history of perianal/rectal inflammation, abscess or fistula.

With the combined perineal and robotic approach, the rectovesical/rectoprostatic dissection may be safer, as both teams guide each other intraoperatively towards the correct plane of dissection, minimising the risk of adjacent organ injury.

A horizontal incision at the level of the rectovesical junction is made. While paying attention to spare more posterior than anterior peritoneum, both flaps are undermined and released from their subperitoneal attachments.

The critical step is to harvest sufficient peritoneal tissue to cover the neovagina and to avoid tension along the base of the flaps to prevent devascularisation and dehiscence. The amount of peritoneum harvested depends on the dimension of the neovaginal space and the availability of tissue lining at the distal part of the neovagina. In MRKH patients, neovaginal lining can be composed almost completely of peritoneum, as the absence of a prostate gland facilitates dissection, deep pelvic transposition and suture fixation of peritoneal flaps.

Single port robotic-assisted vaginoplasty: Port configuration, patient positioning

neovaginal dimensions and to create a tensionfree neovaginal space. Vaginoplasty revisions where penile, scrotal and perineal skin have been used for the primary reconstruction mainly rely on extragenital tissue sources. In this setting, peritoneal flaps seem to be a very promising option. Their vascular supply, secretory capacity and hairless nature, potentially leading to improved lubrication during intercourse, lower risk of devascularisation and wound breakdown are important points in favour of their utility for vaginal reconstruction.

Peritoneum Gender dysphoria, vaginal hypoplasia (secondary to congenital disorders such as MRKH syndrome) and neovaginal stenosis (following primary gender-affirming vaginoplasty with penile skin inversion technique) represent the most common indications of robotic-assisted vaginoplasty with the peritoneal flap technique.

“Even for experienced gender surgeons, vaginoplasty represents a technically challenging operation with a major complication rate of over 20%.”

More recently, the largest available series consists of 41 patients. The series was described as using robotic assistance to mobilise peritoneal flaps to optimise neovaginal dimensions. The peritoneum has promising use in vaginal reconstruction due to its relative ease of harvest with the aid of robotic assistance, proximity to the target area, hairless nature, good vascular supply, secretory capacity and elasticity.

Skin flaps A window is created between perineal and pelvic dissection planes. After enlarging this fenestration by further lateral incisions, which may be done simultaneously by the perineal and robotic surgeons to identify the points of tension/ resistance, peritoneal flaps are sutured to either a penile skin flap, labial/vestibular flaps, or a tabularised full thickness skin graft. The graft used depends on whether one is performing vaginoplasty for gender confirmation, vaginal hypoplasia or shortened vaginal canal following.

“The combination of the robot and perineal approach enables more extensive and safer dissection of the neovaginal cavity together with more precise suturing of the peritoneal flaps.”

The dimensions of the resultant cavity can be measured by vaginal dilators. The dilator is secured at its maximal depth with a purse string suture to define the neovaginal apex. Further concentric purse string suture(s) are placed on the peritoneum to close the defect overlying the neovaginal apex. This step is important to prevent peritoneal fluid leakage and intestinal herniation through the neovaginal cavity.

With regard to cis-gender vaginoplasties, the robot-assisted peritoneal flap technique offers several advantages over pedicled bowel segmentbased vaginal reconstruction as it does not involve intestinal dissection, resection and anastomosis.

Therefore, the risk of potentially morbid complications associated with using the intestine can be avoided, as well as, a faster return to bowel function perioperatively.

Furthermore, constructing a neovagina that is proximally attached to the abdominal wall via peritoneal flaps theoretically eliminates the risk of neovaginal prolapse and the need to place “anti-prolapse” fixation stitches to pelvic bony/ ligamentous prominences which carry the risk of pudendal nerve injury. Lateral peritoneal defects are closed via running barbed sutures.

Moreover, common problems associated with intestinal neovaginas such as excessive mucus production, bleeding after intercourse, malodour and the anecdotal potential for developing diversion colitis, ulcerative colitis and cancer are theoretically non-existent in neovaginas lined with peritoneum.

Technical considerations Robot-assisted vaginoplasty with peritoneal flaps relies primarily on the initial technical description

by Davydov in 1969.

This procedure, which is ideally performed by a laparoscopic approach, includes dissection of the peritoneum from the pelvic sidewalls and the pouch of Douglas. These peritoneal flaps are then used to augment the inverted penile skin flap raised by the classical penile skin inversion technique. In case of insufficient neovaginal depth and width following primary gender-affirming vaginoplasty with the penile skin inversion technique, abdominal skin grafts may be used in addition to the peritoneal flaps.

This approach can also be employed to reconstruct the hypoplastic vaginas of cis-gender patients June/July 2020

Transgender patients who might benefit from this approach include those with a deficiency in the quality and quantity of peno-scrotal skin (i.e. history of circumcision, scrotal orchiectomy, etc.); those who cannot afford electrolysis or laser epilation involving the genital region; and those who have a history of prostate-related issues (e.g. biopsy, surgery, radiation, etc.).

Technical modifications Currently, PIV is the most frequently performed surgical procedure within the context of feminising gender-affirming genital reconstruction. A variety of technical modifications have been employed, incorporating scrotal, urethral and/or perineal tissue, to augment the penile skin flap and create deeper and wider neovaginas.

Conclusion The robotic-assisted Davydov technique represents a potentially applicable, efficacious and safe method of vaginal reconstruction. Application of the technique can augment the penile skin flap in primary gender-affirming vaginoplasty; correct neovaginal stenosis in redo feminising vaginoplasty; and reconstruct hypoplastic vaginal tissue in cis-gender patients.

In patients with deficient genital skin, additional tissue sources must be utilised to provide optimal

A faster recovery process, relative ease of mobilisation, deep pelvic transposition and

suturing of the peritoneal flaps with the aid of robots decreased the likelihood of bowel-related complications, are the main advantages of this approach.

The combination of the robot and perineal approach enables more extensive and safer dissection of the neovaginal cavity together with more precise suturing of the peritoneal flaps.

References 1. Berli JU, Knudson G, Fraser L, et al. What Surgeons Need to Know About Gender Confirmation Surgery When Providing Care for Transgender Individuals: A Review. JAMA Surg. 2017;152:394-400.

2. Falcone M, Timpano M, Ceruti C, et al. A Singlecenter Analysis on the Learning Curve of Male-toFemale Penoscrotal Vaginoplasty by Multiple Surgical Measures. Urology. 2017;99:234-239.

3. Jacoby A, Maliha S, Granieri MA, Dy G, BluebondLangner R, Zhao LC. Robotic Davydov Peritoneal Flap Vaginoplasty for Augmentation of Vaginal Depth in Feminizing Vaginoplasty. J Urol. 2019.

4. Kim C, Campbell B, Ferrer F. Robotic sigmoid vaginoplasty: a novel technique. Urology.

2008;72:847-849.

5. Pushkar P, Rawat SK, Chowdhary SK. Robotic approach to vaginal atresia repair in an adolescent girl. Urol Ann. 2015;7:396-398.

6. Kocjancic E, Acar O, Greenwald D, Dobbs R, Halgrimson W, Crivellaro S. V12-09 ROBOTICASSISTED VAGINAL RECONSTRUCTION WITH THE DAVYDOV TECHNIQUE. Journal of Urology.

2019;201:e1207-e1207.

7. Dy GW, Sun J, Granieri MA, Zhao LC. Reconstructive Management Pearls for the Transgender Patient. Curr Urol Rep. 2018;19:36.

8. Davydov SN. [Colpopoeisis from the peritoneum of the uterorectal space]. Akush Ginekol (Mosk).

1969;45:55-57.

9. Davies MC, Creighton SM. Vaginoplasty. Curr Opin Urol. 2007;17:415-418.

10. Ismail IS, Cutner AS, Creighton SM. Laparoscopic vaginoplasty: alternative techniques in vaginal reconstruction. BJOG. 2006;113:340-343.

11. Davydov SN, Zhvitiashvili OD. Formation of vagina (colpopoiesis) from peritoneum of Douglas pouch.

Acta Chir Plast. 1974;16:35-41.

12. Bizic MR, Stojanovic B, Djordjevic ML. Genital reconstruction for the transgendered individual. J Pediatr Urol. 2017;13:446-452.

13. Horbach SE, Bouman MB, Smit JM, Ozer M, Buncamper ME, Mullender MG. Outcome of Vaginoplasty in Male-to-Female Transgenders: A Systematic Review of Surgical Techniques. J Sex Med. 2015;12:1499-1512.

14. Selvaggi G, Ceulemans P, De Cuypere G, et al. Gender identity disorder: general overview and surgical treatment for vaginoplasty in male-to-female transsexuals. Plast Reconstr Surg. 2005;116:135e-145e.

15. Perovic SV, Stanojevic DS, Djordjevic ML. Vaginoplasty in male transsexuals using penile skin and a urethral flap. BJU Int. 2000;86:843-850.

16. Kocjancic E, Vigneswaran H, Sofer L, et al. V10-01 Novel Vaginoplasty Technique: Inversion Of Penile Skin And Use Of Scrotal Graft Without Sacrospinal Fixation. Journal Of Urology. 2018;199:E1072-E1072.

17. Acar O et al. Single Port and Multi-Port Approaches for Robotic Vaginoplasty with the Davydov Technique.

Urology. 2020;S0090-4295(20)30003-0.

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Best Abstracts

Late toxicity and quality of life - GETUG-AFU 22 study Salvage treatment for patients with detectable PSA after radical prostatectomy Dr. Paul Sargos Radiation oncologist Bergonié Institute Bordeaux (FR)

p.sargos@ bordeaux.unicancer.fr

Dr. Igor Latorzeff Radiation oncologist Clinique Pasteur Toulouse (FR)

ilatorzeff@ clinique-pasteur.com Dr. Paul Sargos and Dr. Igor Latorzeff are two of the authors of the abstract “Late toxicity and quality of life from GETUG-AFU 22 study: A randomized phase ii trial comparing 6 months of degarelix in combination with radiotherapy to radiotherapy alone for patients with detectable PSA after radical prostatectomy,” which won the second prize in the EAU20 Best Abstract Awards Oncology. This article reflects its highlights.

Radical prostatectomy (RP) can provide good long-term oncological outcomes in patients with localised prostate cancer (PCa)1. After RP, prostatespecific antigen (PSA) represents the cornerstone for follow-up of patients and it is expected to be undetectable within 6 weeks of RP.

Ploussard et al.2 showed that approximately 75% of patients with persistent PSA could present a biochemical recurrence. Moreover, persistent PSA represents a common finding early after RP (in 8.8% of cases) and is associated with worse oncological outcome after RP3. For patients with detectable PSA after radical prostatectomy, the GETUG-AFU 22 study, a multicentre randomised phase II trial, compared 6 months of degarelix in combination with radiotherapy (RT) to RT alone as a salvage treatment (NCT01994239).

The primary endpoint was event-free survival. During the EAU20 Virtual Congress, Dr. Paul Sargos, radiation oncologist at the Bergonié Institute in Bordeaux (FR), will present the toxicity (CTCAE V4.0) and quality of life (QLQ-C30 and PR-25) results.

In this study, patients with localised PCa, treated by RP, with a PSA level post-RP ≥ 0.2 ng/mL and ≤ 2 ng/ mL at randomisation and N0 M0 on imaging were included. The design of the study is presented in Figure 1.

In this study, 125 patients were included. Median PSA level was 0.3 ng/mL (0.09-1.82) post- RP and 0.6 ng/ mL (0.12-3.65) at randomisation. Median follow-up was 38 months (95% CI: 31.4-44.1). The French group

reported that, at 2 years, no difference in late genitourinary (GU) or gastrointestinal (GI) toxicity was observed between both arms (p = 0.145) (see Figure 2).

At 2 years, QoL was evaluated in 59% of patients in the RT arm and 77% in the RT+HT arm. Interestingly, no difference in QLQC-30 or QLQ-PR25 analysis was reported. This study highlights the good tolerance of post-operative radiotherapy. In this direction, the GETUG-AFU 16 study4 aimed to establish the effect of adding 6 months of androgen suppression at the time of salvage RT on biochemical outcome and overall survival in men with rising PSA following RP. In this positive trial, 3 (8%) of 366 patients had grade 3 or worse hot flushes and one patient had grade 3 or worse sweating in the RT plus goserelin group versus none of 372 patients in the RT alone group.

Late adverse event The most common late adverse events of grade 3 or worse were genitourinary events (29 [8%] in the RT alone group vs. 26 [7%] in the RT plus goserelin group), and sexual disorders (20 [5%] vs. 30 [8%]).

On the other hand, our study demonstrates that 6 months of degarelix did not affect patient’s toxicity and QoL at two years.

Figure 1: GETUG-AFU 22 trial design

Regarding efficacy, the 10 year results of the GETUGAFU 16 trial confirmed the benefits of androgen suppression plus RT as salvage treatment in patients with increasing PSA concentration after RP. Can these results be extrapolated to patients with persistent PSA after RP, the population explored in the GETUG-AFU 22 trial? Preisser et al. demonstrated in a multivariable analysis that persistent PSA remained an independent predictor for metastasis (HR: 3.59, p < 0.001), death (HR: 1.86, p < 0.001), and cancer-specific death (HR: 3.15, p < 0.001). Patients with persistent PSA after RP appear to have a survival benefit when they received salvage RT3. The results from the GETUG-AFU 22 study, evaluating efficacy, are expected in 2020 and will help clarify the appropriate approach of salvage RT with or without androgen suppression in this population of patients with detectable PSA after RP. Due to space constraints, the reference list can be made available to interested readers upon request by sending an email to: communications@uroweb.org.

Saturday 18 July 19.40-20.00: Poster Session Best abstract session: Oncology Virtual room 1

Figure 2: Late GI and GU toxicities at 2 years

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Microsurgical sperm recovery from the vas deferens Treatment of non-obstructed azoospermic men with advanced spermatogenesis Dr. Athanasios Zachariou University of Ioannina Ioannina (GR)

testis or even in the lumen of epididymis or the vas deferens.

zahariou@otenet.gr

In our department, preliminary clinical studies targeted to investigate whether living spermatozoa can be collected from the vas deferens from nonobstructed azoospermic men with testicular foci of spermatogenesis up to the spermatozoon stage.

Co-authors: Dr. Aris Kaltsas and Prof. Nikolaos Sofikitis

Recovery of spermatozoa Recovery of spermatozoa from the vas deferens in NOA men may allow carrying out the ICSI procedures without the development of hypogonadism or other complications in the male partner.

A significant percentage of non-obstructed azoospermic (NOA) men are positive for foci of advanced spermatogenesis in their seminiferous tubuli, even up to the spermatozoa stage1. Testicular spermatozoa can be recovered from the latter men using percutaneous testicular aspiration techniques2, non-magnified testicular single or multiple biopsy procedures3, or microsurgical testicular biopsy procedures4. The recovered haploid male gametes - either fresh or frozen - can be processed for injections into the oocytes of the female partner (Intracytoplasmic Sperm Injection, ICSI, procedures).

Ninety nine non-obstructed azoospermic men participated in our initial studies. Inclusion criteria for the recruitment of the participants were: a) absence of Y-chromosome deletions b) normal XY-karyotype c) absence of surgery in their genital tract in their medical history d) negative for genetic alterations to the CFTR gene.

However, all the above procedures have been associated with non-neglectable complications such as hypogonadism, development of hematoma, and fibrosis. It appears to be of great clinical importance to develop techniques to collect haploid male gametes from NOA men that are not accompanied by the above complications.

Microsurgical instruments Subinguinal incision was performed and the vas deferens was exposed and isolated in each participant. Then the anterior wall of the vas deferens was opened with microsurgical instruments. Then a paediatric venous catheter was inserted within the lumen of the opened vas deferens toward the direction of the epididymis. BWW-Hepes buffered medium (medium-commonly used in our laboratory and previously described7) was expelled through the catheter into the lumen of the vas deferens (VD) towards the direction of epididymis. Then the expelled medium was aspirated in the syringe attached to the venous catheter. The aspirated fluid was processed for microscopical observation. Then microsurgical testicular biopsy was performed.

It is known that a small subpopulation of nonobstructed azoospermic men occasionally produce semen samples that post-centrifugation demonstrate a few spermatozoa in the pellet5. In addition, in previous initial communications we6 have reported that a percentage of NOA men positive for foci of spermatogenesis up to the spermatozoon stage have spermatozoa in the rete

All the above men visited our facilities in order to participate in assisted reproductive technology programmes and aimed to father children.

A paediatric venous catheter (indicated by black arrows) was inserted in the lumen of the opened vas deferens toward the direction of the epididymis

Droplets of sedimented cells Thus, 99 NOA men underwent microscopical testicular biopsy and microsurgical aspiration of fluid from the VD. Testicular tissue was minced and evaluated for the presence of spermatozoa8,9. The testicular tissue material from each of the above men was washed three times with normal saline. Seminiferous tubules were then washed in Dulbeccoâ&#x20AC;&#x2122;s phosphate buffered saline containing 5.6 mm glucose and 5.8 mm sodium lactate (modified DPBS) and subsequently minced into small pieces. Samples were kept at 5 ÂşC constantly.

A dissecting microscope was used to facilitate mincing the tissue into small pieces in order to avoid cutting small blood vessels. The overall mincing process lasted 40-50 minutes. After mincing, the samples were filtered via a filter of 20-30 lm of pore size (the exact diameter of the pores had been measured via a confocal scanning laser microscope-computer assisted system). The filtrate was collected, centrifuged at 1000 g for 45 min, and sedimented cells were resuspended in modified DPBS (final sample). Droplets of sedimented cells were then observed via an inverted microscope (IX-70, Olympus, Tokyo (JP))-computer assisted system (Apple Computers

Inc., Cupertino (US)). Spermatozoa were identified in 33 men.

Maintenance of gametes All spermatozoa observed (looking through the prepared droplets of the final samples for longer than 90 min) were collected one by one via a pipette attached to the injecting arm of a micromanipulator and transferred and washed several times into drops of testicular sperm medium (TSM). Finally recovered spermatozoa were processed for cryopreservation.

Forty eight men were positive for testicular spermatozoa. Nine from the above 48 men were positive for spermatozoa in the lumen of VD. A percentage of NOA men equal to 48% or 9% are positive for testicular spermatozoa or VD spermatozoa respectively. Among NOA men positive for testicular spermatozoa, a percentage equal to 18% are positive for VD spermatozoa. Spermatozoa from the VD can be recovered from NOA men during the complications of testicular surgery.

Editorial Note: Due to space constraints, the reference list can be made available to interested readers upon request by sending an email to: communications@uroweb.org.

Introducing European Urology Open Science

We are pleased to announce the launch of European Urology Open Science, a member of the European Urology family of journals.

The journal is dedicated to the publication of high quality, innovative research that will benefit patients with urological conditions and will serve the world-wide community of urologists in academia and practice.

European Urology Open Science is a broad-scope, gold open access (OA) journal published on behalf of the European

Association of Urology (EAU) and the European Board of Urology (EBU). All OA articles will be immediately and permanently accessible online-only for everyone to read, download, copy and distribute.

Learn more about OA https://www.elsevier.com/journals/europeanurology-open-science/open-access-journal Submit your paper https://www.editorialmanager.com/euros

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Definition of high-risk, BCG-non-responsive NMIBC Importance of tumour characteristics and risk prognosis Prof. Marek Babjuk Dept. of Urology Faculty of Medicine Charles University, Prague (CZ)

babjuk@volny.cz Bladder cancer is the ninth most diagnosed cancer worldwide, and approximately 430,000 new cases were reported in 2012. In the European Union, the age-standardised incidence rate is 19.1 for men and 4.0 for women1. Approximately 75-85% of all patients with bladder cancer have mucosa-confined disease (stage Ta or stage carcinoma in situ (CIS) or submucosa (stage T1)). This group of tumours is referred to as non-muscle-invasive bladder cancer (NMIBC) as opposed to muscle-invasive disease staged as T2-T4.

NMIBC comprises tumours with extremely heterogeneous biological behaviour and natural history. After complete endoscopic resection, up to 80% of patients will develop tumour recurrence with 2-50% showing stage progression. At one end of the spectrum, low-grade Ta tumours show a high recurrence rate, but rarely represent a threat to the patient. At the other extreme, high-grade T1 tumours show high progression and death rates. The success of treatment for NMIBC depends on the biological characteristics of the tumour and on correctly selected and performed treatment.

Principles of NMIBC management The current recommendations for the management of NMIBC are summarised in the European Association of Urology (EAU) guidelines2. The philosophy is based on the following principles: • Effective tumour removal and reliable diagnosis achieved by complete transurethral resection (TURB). A complete resection, performed by either fractioned or en-bloc technique, is essential to achieve a good prognosis.

• Individual prediction of the risk of recurrence and progression, stratification into risk groups.

• Adjuvant treatment tailored according to individual risk of tumour recurrence and progression. The routinely used modalities are intravesical chemotherapy, bacillus CalmetteGuérin (BCG) immunotherapy, or, in high-risk patients, radical cystectomy.

• The follow-up based on cystoscopies and upper urinary tract investigation. The frequency and duration of both should reflect the individual patient’s degree of risk.

Prediction of tumour behaviour and risk stratification Prediction of the risk of disease recurrence and progression is crucial in the management of NMIBC. The best available clinical prognostic tool for patients with NMIBC is the European Organization for Research and Treatment of Cancer (EORTC) prognostic model and risk tables which were developed in 20063.

They are based on data from 2,596 patients diagnosed with TaT1 tumours who were randomised in seven EORTC trials. The system can predict both the short-term and long-term risks of recurrence and progression in individual patients. The scoring system is based on the six most significant clinical and pathological factors: • number of tumours • tumour size • prior recurrence rate • T-category • presence of concomitant CIS • tumour grade A similar model which predicts the risk of recurrence and progression in patients treated with BCG has been published by the Club Urológico Español de Tratamiento Oncológico (CUETO) (the Spanish Urological Oncology Group)4.

“The best available clinical prognostic tool for patients with NMIBC is the EORTC prognostic model and risk tables.”

For practical reasons and to allow treatment recommendations, the individual prognosis is translated into risk group stratification. Patients with NMIBC are separated into a low-risk, intermediaterisk and high-risk group (see table 1). This stratification is based on clinicopathologic parameters and considers the EORTC risk tables’ probabilities of recurrence and, especially, progression.

All necessary data to include patients in a risk group can be obtained from the patient history, cystoscopy, TURB, and histological evaluation of resected tissue.

This underlines the role of carefully and correctly performed diagnostic steps, particularly TURB.

Table 1: NMIBC risk groups stratification (2020 EAU Guidelines for NMIBC publication)

High-risk tumours

Table 2: Categories of unsuccessful treatment with intravesical BCG (2020 EAU Guidelines for NMIBC publication)

June/July 2020

Figure 1: Micropapillary variant of urothelial carcinoma

High-risk group In the high-risk group all patients with either T1 tumour, G3/HG, or CIS are included. Several TaG2/LG tumours with unfavourable features (multiple, large, and recurrent tumours) are also included. The risk of progression in high-risk tumours is significant (17-45% at 5 years according to EORTC tables), but even this group contains tumours with very heterogeneous behaviour. Although BCG intravesical instillations are a very effective therapy, about one third of high-risk tumours progress to muscleinvasive disease. About 11% of patients eventually die because of bladder cancer in spite of BCG5. All efforts should be aimed at identifying patients with unfavourable prognosis (= highest risk patients) as soon as possible.

“The definition of the highest risk subgroup attempts to identify tumours with the highest risk of progression. Immediate radical cystectomy should be recommended.”

The highest risk subgroup The definition of the highest risk subgroup attempts to identify tumours with the highest risk of progression, in whom conservative management with BCG is not sufficiently effective and immediate radical cystectomy should be recommended.

The highest risk group is comprised of the following patients: • Patients with the highest score according to the EORTC prognostic model3. These are patients with T1G3/HG tumours associated with concurrent bladder CIS, multiple and/or large T1G3/HG tumours and/or recurrent T1G3/HG. The risk of progression within five years in this population is 45% in EORTC model and 34% in CUETO model (BCG treated patients)3-6.

• Men with T1G3/HG tumour in the bladder associated with CIS in the prostatic urethra. In his paper from 2011, Palou demonstrated a 17.1% risk of progression and 12.3% risk of disease-related death among 146 patients with BCG-treated T1G3 bladder cancer. The associated CIS in prostatic urethra and female gender were the only independent predictors of the risk of recurrence, progression, and death from the disease7.

• Some variants of urothelial carcinoma, particularly micropapillary (see figure 1), plasmocytoid, and sarcomatoid, have a worse prognosis than pure high-grade urothelial carcinoma. These variants are observed predominantly in tumours with muscle invasion (T2-T4), they can, however, also appear in T1 disease. They relate to the high risk of understaging, but even if staged correctly, they have lower response rates after appropriate BCG instillations. In a high percentage of cases, they progress without radical surgery.8,9 Moreover, they may be underdiagnosed because of insufficient

quality of TURB specimen and an information gap between urologists and pathologists8.

• T1 tumours with lymphovascular invasion (LVI). LVI is detected in about 19% of TURB specimen. It is significantly associated with pathological upstaging, worse recurrence-free survival, progression-free survival, and disease-specific survival10.

BCG failures and BCG unresponsive tumours BCG is nowadays the most effective intravesical treatment for high-risk NMIBC. It is, however, very important to specify tumours that do not respond despite adequate BCG treatment and can progress in the near future. Non-muscle-invasive tumours presenting after BCG can be categorised into BCG-refractory, BCG-relapsing, BCG-unresponsive, and BCG-intolerance (see table 2). The definitions are based on stage and grade of persistent or recurrent lesion, on adequacy of previous BCG treatment, and on the interval after the last BCG instillation2.

The updated definition of BCG-unresponsive tumours was introduced recently to denote a subgroup of patients at higher risk of progression in whom further BCG most likely does not cure the patient11. This definition was developed in consultation with the FDA to allow for single-arm trials to provide primary evidence of effectiveness to support a marketing application since no effective therapy is available for BCG-unresponsive NMIBC.12 According to this analysis, patients who fit this definition are more likely to require salvage radical cystectomy (in 54.5%) and are less likely to remain without tumour recurrence (only 23%).13

“Molecular subtyping holds great promise in understanding the disease and in personalised therapeutics.”

Future trends The prognosis prediction and patient stratification is currently based on clinicopathological parameters, but this approach has several limitations. The factors considered are subject to interobserver variation; they cannot predict individual course of disease nor response to different treatment modalities.

Molecular subtyping holds great promise in understanding the disease and in personalised therapeutics. Although it is currently discussed mostly in association with muscle-invasive tumours, it will probably play a role in the future treatment of high-risk non-muscle-invasive tumours because of its biological similarities with invasive lesions.14,15 Due to space constraints, the reference list can be made available to interested readers upon request by sending an email to: communications@uroweb.org.

Saturday 18 July 09.05 - 11.25: Plenary session 03 Challenges across the spectrum of bladder cancer Virtual room 2

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Best Abstracts

Development of a novel micturition model in mice How does Barrington’s nucleus in the brainstem control micturition?

Dr. Hiroki Ito School of Physiology, Pharmacology and Neuroscience Faculty of Biomedical Sciences University of Bristol (UK) hiroki.ito@ bristol.ac.uk Dr. Hiroki Ito is one of the authors of the abstract “Novel model of micturition based on a multi-unit recordings of optogenetically-identified Barrington’s CRH neurons in mice,” which won the EAU20 Best Abstract Award Non-Oncology.

This article reflects its highlights.

It is a great honour for me to be offered such an opportunity at EAU20. I am a trainee Japanese urologist with an academic interest in bladder dysfunction. This was initiated with my PhD studies in the laboratory of the Department of Continence Medicine at the University of Tokyo (JP). These studies focussed on the functional physiology and pharmacology of bladder control, especially in relation to ageing in rodent models. When I came to the end of my PhD, I was looking for opportunities to develop my interests. I was so excited to find a postdoctoral position in Bristol (GB)! I could study the effect of phosphodiesterase type-5 inhibitors on lower urinary tract symptoms as part of an NIHfunded collaboration with the team of Mr. Tony Kanai in Pittsburgh (US). Thus, me, my wife, and our 1-year-old son all came to Bristol.

busy, but I also got interested in the neuroscience of bladder control (obviously influenced by Professor Drake and Pickering). This is a strange world for a clinical urologist, but I was keen on using some of the amazing new tools and methods to genetically target and control discrete populations of neurons, which were employed by other people in my research group.

Barrington’s nucleus We decided to try and investigate how Barrington’s nucleus in the brainstem controls micturition.

Therefore, we used optogenetics to selectively activate those neurons in vivo with light in a CRH-Cre mouse line. Thanks to the genetically modified mice, we could use a viral vector to express channelrhodopsin-2 in those neurons. We showed that these neurons could control bladder pressure and could sometimes produce a void but only when the bladder was filled.

This seemed to be a probabilistic process, which is not typically how a ‘command neuron’-controlled voiding should work.

“We succeeded in obtaining enough data to build a novel model of voiding that recapitulates many of the observed features of our data.”

Team effort To explore this further, we needed to engage in the most challenging part of these experiments: recording Barr-CRH firing activity from optogenetically identified neurons using multisite silicon probes. This was a team effort with my colleague Dr. Anna Sales (GB), who had developed the approach in our lab. I found that an inaccuracy of only a few microns at the probe site already made a huge difference in the recording, The PDE5i research went well, and I published several imposing tearful patience on us. However, we interesting papers1-3. I also developed the decerebrate succeeded in obtaining enough data to build a novel model of voiding that recapitulates many of the arterially perfused mouse preparation (DAPM). I was

STEPS Sessions To Evaluate ProgresS in the management of urological cancers

observed features of our data. This suggests that Barrington’s nucleus makes repeated inferences about the state of bladder fullness (by generating non-micturition contractions) and only generates the explosive void when the bladder is sufficiently full.

This is shown schematically in the figure.

isoform of alcohol dehydrogenase. And now, to put the cherry on the cake, I was awarded with the first prize for the Best Abstract (non-oncology). I would like to thank the EAU committee for being so broad-minded in their selection, my colleagues and friends in Bristol, and my family, who have been so supportive.

Personal and private success Due to space constraints, the reference list can be made available to interested readers upon request by My three years in Bristol brought me and my family a lot: extraordinary professors (Tony Pickering, Marcus sending an email to: communications@uroweb.org.

Drake, and Chris Fry, all GB), helpful lab mates with huge diversity, the profound world of neuroscience, lab Saturday 18 July 16.30 - 17.00: Poster Session meetings on the beautiful lawn (only in the short Best abstract session: Non-oncology summer), and my lovely daughter! We also learnt that trains do not always arrive on time and that British Virtual room 2 beer can be a challenge if you do not have the correct

Interactive, Insightful and Independent Education Learning from Experts in Onco-Urology Applications now open!

Applications now open!

Visit Ipsen booth E38 during EAU19 to learn more What is is STEPS? STEPS? STEPS, management of STEPS, or “Sessions To Evaluate ProgresS in the management urological programme specifically designed for recently recently urological cancers”, cancers”, is a programme specialised specialised onco-urologists onco-urologists who who want want to to learn directly from worldleading prostate, renal and and testis cancers.

The CMEleading experts expertsininbladder, bladder, prostate, renal testis cancers.

The accredited programme is a fundamental part of the EAU/ESOU strategic CME-accredited programme is a fundamental part of the EAU/ESOU partnership with Ipsen.

It isIpsen. founded our shared commitment to the strategic partnership with It ison founded on our shared commiteducation of young urologists. ment to the education of young urologists.

Bringing together a multinational group of medical professionals Bringing together a multinational group of medical professionals across several areas of expertise, and with different experiences, across several areas of expertise, and with different experiences, allows the Fellows to see a variety of new treatment possibilities. allows the fellows to see a variety of new treatment possibilities.

It can highlight the pitfalls and solutions provided by diverse It can highlight the pitfalls and solutions provided by diverse approaches. It also opens the door to creating international ties among approaches. It also opens the door to creating international ties medical practitioners, and a networking opportunity that can prove among medical practitioners, and a networking opportunity that can invaluable to the careers of young clinicians. prove invaluable to the careers of young clinicians.

“STEPS connects younger urologists from different countries – it’s very interactive with lots of new information and data discussed” STEPS fellow 2018

Since inaugural session in recognised 2011, more than To date,the 20 different internationally experts, 20 internationally recognised experts supported by the ESOU Board, have inspired have 158 supported the30ESOU Board to inspire almost is200 fellows from countries – and our objective to Fellows over 30 countries to further continue from supporting STEPS to help improve their the education in of onco-urology – and our objective management all patients with urological cancers.is to continue supporting STEPS to help improve the management all patients with urological cancers.

Who should of apply?

Recently specialised clinicians with a firm interest in Who should apply? the management of urological cancers, who: Recently specialised clinicians with a firm interest in - Can demonstrate support from their Head of the management of urological cancers, who: Department - Can demonstrate support from their Head of - Department Are keen to participate in ESOU and EAU programs - Are keen to participate in ESOU and EAU programs

Next STEPS event: Next event: Meet-the-Expert Session during the 18 17th Meeting of the EAU Section of Oncological Urology (ESOU) Saturday 2021 Saturday 13 18thth February January 2020 Gothenburg, Sweden Dublin, Ireland

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New technology for urology: 7T MRI scanner Data provides layout of body areas in somatotopic maps of human brain Dr. Wietske Van Der Zwaag Researcher Spinoza Centre for Neuroimaging Amsterdam (NL) w.vanderzwaag@ spinozacentre.nl 7T MRI is a game changer for MRI. The higher signal strength as a result of the stronger magnetic field can be used to generate higher resolution images. It also boosts sensitivity to the brain function, opening up the possibility of investigating the brain function in individuals rather than groups and the visualisation of very small functional units, such as the regions that control pelvic floor muscle contractions.

Magnetic resonance imaging (MRI) is a frequently used tool in the modern clinic. Ultra-high field (UHF) MRI systems, which contain a magnet with a field strength of 7 Tesla or higher (see figure 1), are relatively rare compared with the standard 1.5T or 3T systems mostly used in clinical practice.

Figure 2: Somatotopic digit map in the human cerebellum, data from an individual subject (van der Zwaag et al. 2013)

recently showed that by using UHF fMRI, this mapping changes can be observed in a very small number of can be done reliably in single subjects. patients, or even in a single individual, potentially allowing classification of treatment options (van Functional brain responses Waarde et al. 2015) or follow-up of treatment success.

Higher field strength First, we investigated the functional brain responses The most important advantage of higher field strength to a pelvic floor muscle contraction task in men References is the increase in signal-to-noise ratio (SNR), which (Groenendijk et al. 2020). In this study, we Es, Daniel M. van, Wietske van der Zwaag, and Tomas can be used in prostate imaging to better visualise Knapen. 2019. “Topographic Maps of Visual Space in the demonstrated that UHF fMRI can visualise the neural tumour growth, for example (Steensma et al. 2019). representations of the male pelvic floor in the whole Human Cerebellum.” Current Biology: CB 29 (10): An additional advantage of using UHF systems is the 1689-1694.e3. https://doi.org/10.1016/j.cub.2019.04.012. brain of a single subject. The subjects, all healthy much higher sensitivity to the changes observed volunteers, executed two motor tasks, one involving Groenendijk, Ilse M., Sven P. R. Luijten, Chris I. de Zeeuw, during functional MRI scans. The ‘BOLD signal,’ which consecutive pelvic floor muscle contractions (PFMC) Joan C. Holstege, Jeroen R. Scheepe, Wietske van der stands for Blood Oxygen Level Dependent signal, and a control task with tongue movements. The Zwaag, and Bertil F. M. Blok. 2020. “Whole Brain 7T-FMRI scales approximately linear with the magnetic field tongue forms a good reference area to map, because during Pelvic Floor Muscle Contraction in Male Subjects.” strength (van der Zwaag et al. 2009).

Neurourology and Urodynamics 39 (1): 382–92. https:// it is also part of the digestive tract; plus, the tongue is necessary for speaking and chewing; both highly doi.org/10.1002/nau.24218.

This means that a functional experiment looking at a 1 conditioned tasks, much like PFMC in daily life.

Luijten, Sven P.R., Ilse M. Groenendijk, Joan C. Holstege, Chris percent signal change at 3T can be expected to yield a I. De Zeeuw, Wietske van der Zwaag, and Bertil Blok.

2.3 percent signal change at 7T. In addition, that signal In the single subjects, responses to both tasks were 2020. “Single subject and group whole-brain fMRI change is measured with higher signal to noise ratio, visualised in the cortex, putamen, thalamus, and the mapping of male genital sensation at 7 Tesla”. Scientific leading to very greatly increased detection power. cerebellum. Activation was seen during PFMC in the Reports.

This can be traded for increased spatial resolution or superomedial and inferolateral primary motor cortex significantly reduced scan times. Hence, UHF has been (M1), supplementary motor area (SMA), insula, midcingulate gyrus (MCG), putamen, thalamus, and in a real game changer for cognitive neuroimaging, opening avenues to functionally imaging the columns the anterior and posterior lobes of the cerebellum.

During tongue movement, activation was seen in the and layers within our cortices (Polimeni et al. 2010; inferolateral M1, SMA, MCG, putamen, thalamus, and van der Zwaag et al. 2018) and imaging very small, functional units (van der Zwaag et al. 2013, see figure anterior and posterior lobes of the cerebellum.

Tongue activation was found in the proximity of, but 2), while also enabling reliable measures of brain not overlapping with, the PFMC activation. function within a very small number of subjects, or Connectivity analysis demonstrated differences in even a single subject (van Es, et al. 2019), which can neural networks involved in PFMC and tongue lead the way to measures of brain function in movement. individual patients.

“What makes Ultra High Field MRI so powerful is that changes in the somatotopic maps of the human brain can be observed even in a single individual, potentially allowing classification of treatment options.”

How does the urologist benefit from this new technology?

The human brain contains several organised representations of body parts, also known as homunculi. The one in the motor cortex is perhaps most widely known, but the somatosensory cortex and cerebellar cortices also contain full body representations. These body representations are of special interest, as they contain a representation of the pelvic floor and genital organs which can be mapped in functional MRI. Even the cerebellar body representations can be mapped in individual subjects as is illustrated in figure 2. In two related studies, we

Figure 1: A 7T MRI scanner

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Polimeni, Jonathan R., Bruce Fischl, Douglas N. Greve, and Lawrence L. Wald. 2010. “Laminar Analysis of 7T BOLD Using an Imposed Spatial Activation Pattern in Human V1.” NeuroImage 52 (4): 1334–46. https://doi. org/10.1016/j.neuroimage.2010.05.005.

Serino, Andrea, Michel Akselrod, Roy Salomon, Roberto Martuzzi, Maria Laura Blefari, Elisa Canzoneri, Giulio Rognini, et al. 2017. “Upper Limb Cortical Maps in Amputees with Targeted Muscle and Sensory Reinnervation.” Brain: A Journal of Neurology 140 (11): 2993–3011. https://doi.org/10.1093/brain/awx242.

Steensma, Bart R., Mariska Luttje, Ingmar J. Voogt, Dennis W. J. Klomp, Peter R. Luijten, Cornelis A. T. van den Berg, and Alexander J. E. Raaijmakers. 2019. “Comparing Signal-to-Noise Ratio for Prostate Imaging at 7T and 3T.” Journal of Magnetic Resonance Imaging: JMRI 49 (5): 1446–55. https://doi.org/10.1002/jmri.26527.

Waarde, J. A. van, H. S. Scholte, L. J. B. van Oudheusden, B. Verwey, D. Denys, and G. A. van Wingen. 2015. “A Functional MRI Marker May Predict the Outcome of Electroconvulsive Therapy in Severe and TreatmentResistant Depression.” Molecular Psychiatry 20 (5): 609–14. https://doi.org/10.1038/mp.2014.78.

Zwaag, Wietske van der, Pieter F. Buur, Alessio Fracasso, Tessa van Doesum, Kâmil Uludag, Maarten J. Versluis, and José P. Marques. 2018. “Distortion-Matched T1 Maps and Unbiased T1-Weighted Images as Anatomical Reference for High-Resolution FMRI.” NeuroImage 176: 41–55. https://doi.org/10.1016/j.neuroimage.2018.04.026.

Zwaag, Wietske van der, Susan Francis, Kay Head, Andrew Peters, Penny Gowland, Peter Morris, and Richard Bowtell. 2009. “FMRI at 1.5, 3 and 7 T: Characterising BOLD Signal Changes.” NeuroImage 47 (4): 1425–34. https://doi.org/10.1016/j.neuroimage.2009.05.015.

Zwaag, Wietske van der, Remy Kusters, Arthur Magill, Rolf Gruetter, Roberto Martuzzi, Olaf Blanke, and José P. Marques. 2013. “Digit Somatotopy in the Human Cerebellum: A 7T FMRI Study.” NeuroImage 67 (February): 354–62. https://doi.org/10.1016/j. neuroimage.2012.11.041.

Sunday 19 July 16:10 - 17:00: Thematic session 10 New technology for urology Virtual room 2

Genital sensation In the second study (Luijten et al. 2020), we investigated the brain responses of male genital sensation. We acquired high-resolution whole-brain neural representations of genital touch at both single subject and group level. Subjects underwent bilateral tactile stimulation of the penile shaft and, as a control, of the feet. Tactile stimulation of the penile shaft evoked significant activation in the primary and secondary somatosensory cortices (S1 & S2), ventral premotor cortex, posterior and anterior insula, posterior midcingulate gyrus, medial prefrontal cortex, thalamus, and cerebellum. Tactile stimulation Figure 3: Top view of the group analysis results of tactile stimulation (Luijten et al. 2020) of the feet evoked significant activations in S1, S2, posterior insula, thalamus, and cerebellum (see figure 3). Our results clearly indicate that the genitalia are represented in the hip region and not below the feet in S1 as depicted in the original sensory homunculus.

Furthermore, tactile genital input activates brain regions implicated in processing both discriminative and affective aspects of touch, whereas tactile input from the feet activates mostly discriminative regions.

Whole-body map Combining information from the two studies, we see that e.g. in the cerebellum, a whole-body map forms in the anterior lobe, where the penile shaft representation fits neatly on the line roughly from feet to tongue representation. Note that in the cerebellum, tactile and motor responses are expected to yield BOLD responses in the same locations and can hence be combined in a single map.

These data provide us with the layout of relevant body areas in the somatotopic maps of the human brain (see figure 4). Changes in these areas or their responsivity which may occur in clinical patients (Serino et al. 2017), can then be investigated. What Figure 4: The layout of relevant body areas in the somatotopic maps of the human brain makes Ultra High Field MRI so powerful is that these June/July 2020

Incontinence after prostate treatment: AUA Guidelines update American Urological Association publishes revised IPT guideline Prof. John Stoffel Dept. of Neurourology/Pelvic Reconstruction University of Michigan Ann Arbor (US) jstoffel@ med.umich.edu Urinary incontinence after prostate treatment (IPT) is a clinically significant complication and can cause a high degree of patient distress. It is one of the few urological diseases that is iatrogenic, mostly from surgical and/or radiation treatments for prostate cancer or, less commonly, after surgical management of benign prostatic hyperplasia (BPH).

Understanding the potentially changing nature of IPT is crucial both during recovery and during extended survivorship. Patients benefit from having clear expectations regarding the short, medium, and long term sequela of IPT. Practitioners also benefit from being able to assess which patient will likely experience further symptom recovery versus those that will not.

However, management of IPT can vary considerably among practitioners, particularly regarding surgical intervention. For example, figure 1 shows that between 2004 and 2010, endoscopic injection of a bulking agent was the most common treatment for IPT, followed by artificial urinary sphincter and male sling1.

Given the knowledge gap regarding natural history and disparate practice patterns, the American Urological Association (AUA), with support from the Society of Urodynamics/Female Pelvic Medicine/ Urogenital Reconstruction (SUFU), commissioned a guideline for IPT. Chaired by Dr. Jaspreet Sandu, a

Figure 3: Evaluation of IPT from the AUA IPT guideline2

12-member multi-disciplinary committee with expertise in urological oncology, reconstructive urology, physical therapy, and guideline methodology developed the IPT guideline using systematic review from the Mayo Clinic Evidence Based Practice Center. Literature was reviewed from a search performed by a research librarian between 2000 and 31 December 2018.

The AUA Incontinence After Prostate Therapy Guideline2 has 36 guideline statements separated into the following sections: pre-treatment recommendations to reduce risk of IPT, post-prostate treatment, evaluation of incontinence after prostate treatment, surgical treatment options, complications of IPT surgery, and special situations. Each guideline statement carries a recommendation (strong, moderate, conditional) based on whether the net benefit (or harm) is respectively substantial, moderate, or minimal. Strength of evidence is also presented for each guideline statement: a statement is graded from A (well-designed RCTs) to C (Observational Studies).

When minimal evidence is available but a component of clinical care is very widely agreed upon by urologists or other clinicians, the statement is labelled as a clinical principle. An expert opinion designation, achieved by consensus of the Panel based on clinical training and judgement, is similarly used to support a statement for which there is no published evidence.

For more information on the AUA guideline nomenclature, please see the unabridged guideline available through the AUA. Some highlights from the IPT guideline which will be presented at the EAU conference include:

Figure 1: Incontinence procedures reported by certifying US urologists as percentage of total number per years1

Figure 22: Continence recovery overtime after prostatectomy. RARP/RLP = robotic assisted/lap prostatectomy, RRP = open prostatectomy

June/July 2020

incontinence. The guideline recommends using appropriate testing, including urodynamics when necessary, to best understand the underlying bladder physiology and select appropriate treatment. The panel also recommended that cystoscopy should be performed prior to any surgical intervention to rule out any urethral or bladder pathology. An evaluation algorithm is included in the guideline (see figure 3).

Treatment options The IPT guideline recommends that an artificial urinary sphincter can be offered as treatment to men with any degree of refractory stress incontinence after prostate treatment. A male sling should be offered to patients with mild to moderate stress incontinence symptoms. Adjustable balloons can be offered to men with mild stress incontinence. In men who are status post-radiation therapy for prostate cancer, an artificial sphincter is preferred over a sling or adjustable balloons. The panel evaluated evidence regarding bulking agents and recommended that patients should be counselled that the efficacy is low in treating post-prostatectomy incontinence and that the cure rate is very low.

Complications after surgery/special situations These sections address complications that can occur after artificial urinary sphincter and slings. The panel reviewed artificial sphincter outcome data and noted that the failure rate is likely to increase over time and may reach 50% by 10 years after implantation.

Consequently, patients should be counselled that the artificial urinary sphincter will lose effectiveness over time. If a sphincter (or sling) erodes, the panel states as a clinical principle that the device should be surgically removed and preimplantation delayed as long as 3-6 months. If men have persistent bothersome incontinence after sling, an artificial sphincter is recommended as the next treatment option. However, the panel notes that experienced surgeons trained in replacement surgery may consider another sling as an alternative.

Pre-treatment The Pre-Treatment section focuses on managing expectations regarding the natural history of incontinence after prostate therapy. Patients should be informed of potential risk factors for urinary incontinence after prostatectomy, such as increased prostate size, advanced age, and shortened membranous urethral length on pre-treatment MRI. It is also important to discuss with patients prior to radical prostate surgery that it is not uncommon for men to experience some incontinence immediately after the catheter is removed. Symptoms generally improve over a period of 12 months, but some men may continue to experience incontinence. The guidelines recommend that men may be offered pelvic floor muscle exercises 3 to 4 weeks prior to surgery, Conclusions and although the effectiveness of these exercises is not Many men who undergo radical prostatectomy will definitively known, the benefit outweighs the risk. experience some stress incontinence symptoms after the procedure, as will some men treated with Post-prostate treatment radiation for prostate cancer or with outlet procedures The guideline notes that patients with significant for benign prostatic hyperplasia. This guideline seeks stress incontinence who show no improvement to help providers provide some expectations and post-prostate treatment may need to initiate treatment options for patients concerned about post treatment, including consideration for surgical treatment urinary symptoms. The full guideline is available through the American Urological Association procedures, starting at 6 months post-procedure rather than waiting for longer than 12 months. (www.auanet.org/guidelines).

The guideline notes that there is little evidence to suggest that patients have significant improvement References in continence after 12 months post-procedure 1. Poon SA, Silberstein JL, Savage C, et al Surgical practice which informed this guideline recommendation patterns for male urinary incontinence: analysis of case (see figure 2). logs from certifying American urologists. J Urol. 2012 Evaluation after prostate treatment When evaluating urinary symptoms, it is important to differentiate between urge incontinence and stress

Jul;188(1):205-10.

2. Sandhu JS, Breyer B, Comiter C, et al. Incontinence After Prostate Treatment. AUA/SUFU Guideline. J Urol. 2019 Aug; 202(2): 369-78

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Janssen’s clinical research commitment

Janssen’s commitment to research for patients with bladder and prostate cancer is why we are conducting multiple clinical trials in these areas.

Learn more about our trials and how you can refer a patient for possible participation.

Prostate Cancer (PC) Trials Localized PC: PROTEUS – NCT03767244

Bladder Cancer (BC) Trials Non-Muscle-Invasive BC: THOR-2 – NCT04172675

Metastatic PC: PREVALENCE – NCT03871816 GALAHAD – NCT02854436 QUEST – NCT03431350 MAGNITUDE – NCT03748641

Advanced BC: ANNAR – NCT03955913 NORSE – NCT03473743 THOR – NCT03390504

To refer a patient to a trial or for more information, please visit www.clinicaltrials.gov or contact: 001-844-434-4210 or JNJ.CT@sylogent.com

Janssen Research & Development, LLC Uro-Oncology Campaign-ENG02 Version 2.0, 14Jan2020 ©Janssen-Cilag B.V. - EM-25824 44 EUT Congress News Creation date: 14Jan2020

June/July 2020

Sequencing urothelial carcinoma: “Just do it” Despite challenges, NGS will dramatically improve urothelial carcinoma care Prof. Shahrokh F. Shariat Dept. of Urology Comprehensive Cancer Centre Medical University of Vienna (AT) sfshariat@gmail.com

Dr. Benjamin Pradere Dept. of Urology Comprehensive Cancer Centre Medical University of Vienna (AT) benjaminpradere@ gmail.com With the advent of personalised/precision medicine, we are closer in fulfilling our ethical oath now than ever before: to treat the right tumour in the right patients with the right therapy at the right time.

Modern medical decisions, practices, interventions and/or products can be tailored to the individual patient based on her/his predicted response or risk of disease. While the practice of customising patient treatment dates back to the time of Hippocrates, the advent of genomic-based diagnostic and informatics approaches that provide understanding of the molecular basis of disease have ushered in a new age of personalised/precision medicine.

Next-generation sequencing This revolution was powered by advances in next-generation sequencing (NGS) technologies, which have unveiled new dimensions in cancer biology. It is now more affordable to carry out large-scale NGS experiments with a reasonable turnaround time. This has led to a rapidly expanding body of pioneering research exploring the genomic landscape and molecular mechanisms of various cancer types.

Furthermore, genetic drivers (i.e. mutations that confer a selective growth advantage, thus promoting cancer development) were discovered, exemplified by the effort from large international sequencing initiatives such as The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC). This has generated vast amounts of data and identified numerous biomarkers and targets for patient stratification and therapeutics.

Although the translation of these findings into the clinic has been slow, in certain settings (including urothelial carcinoma) NGS is becoming a complementary diagnostic tool, guiding the decision making to achieve personalised/precision medicine.

While we are still managing UC based on the “one size fits all” strategy, new NGS-based opportunities to improve our daily clinical practice are arising. In this article, we will sketch four scenarios where a tangible benefit of NGS arises for our urothelial carcinoma patients.

Once diagnosed with Lynch Syndrome, patients have stringent protocols to diagnose other Lynch syndromeassociated malignancies earlier, as they often present with earlier, aggressive tumours (especially colon cancer).

In addition, epidemiologic data and molecular characterisation suggest bladder urothelial carcinoma and prostate cancer as unrecognised components of Lynch syndrome4,5.

Finally, Lynch syndrome related UTUCs harbour a disproportionally high rate of mutation in the tumour genome making their malignancy acutely sensitive to immune checkpoint blockade.

Sequencing for alterations in fibroblast growth factor receptors Advanced urothelial carcinoma is a highly heterogeneous entity with a varied response to standard therapies. This multiplicity is derived from mutations, mutation signatures, chromosomal loss, and disruption of molecular pathways, which ultimately affect tumour progression, recurrence, and responsiveness to intravesical and systemic chemotherapies. The emergence of NGS has enabled a comprehensive assessment of the genomic landscape underlying advanced urothelial carcinoma, uncovering prognostic and predictive biomarkers, as well as, new therapeutic targets.

Currently we have the proof that UTUC has a distinct mutational profile compared to urothelial bladder cancer, most notably higher prevalence of fibroblast growth factor receptor (FGFR)3 alterations and a dominant APOBEC-induced mutagenesis6. FGFR mediates cellular proliferation and angiogenesis through activation of downstream PI3K-AKT, PKC, and Ras/MAPK pathways.

“NGS has the potential to guide clinicians in tailoring treatment to dynamic genomic changes in individual tumours.”

In addition, UTUC has a T-cell depleted microenvironment and a low-tumour mutational burden, all of which may contribute to a less robust antitumour immune response. If FGFR3 coordinates the luminal-papillary and immune-depleted phenotypes in UTUC, its inhibition can potentially reverse the mechanisms underlying the immune depletion. This provides a rationale for why FGFR3 inhibition may be particularly suited for the treatment of UTUC. In advanced bladder urothelial carcinoma, FGFR activating mutations and fusions (FGFR3-TACC3) have been reported in 15-20% of patients7. This resulted in the current development of several agents targeting this pathway.

Erdafitinib, for example, is a pan-FGFR inhibitor that demonstrated encouraging efficacy with an objective response rate of 40% and a relatively tolerable toxicity profile in a phase II trial that includes patients with platinum-refractory metastatic bladder urothelial carcinoma harbouring FGFR2/3 mutations or fusions8.

Several other FGFR inhibitors are being tested in clinical trials based on FGFR mutations, fusions, and/ or mRNA overexpression.

Sequencing for Lynch syndrome Lynch syndrome is an autosomal dominant disorder defined by germline mutations in DNA mismatch repair (MMR) genes that predisposes individuals affected to certain malignancies. Upper tract urothelial carcinoma (UTUC) is, after colorectal and endometrial carcinoma, the third most common malignancy in Lynch syndrome1. Reflexive testing for MMR protein loss by immunohistochemistry is, however, only recommended for colorectal and endometrial cancers. With an estimated 10-15% of UTUC cases harbouring molecular alterations common to Lynch syndrome, UTUC is the urologic disease with the highest rate of germline mutations2,3.

Sequencing for alterations in DNA damage response pathways TCGA’s integrative genomic analysis of 412 patients with bladder urothelial carcinoma has demonstrated a high overall somatic tumour mutational burden (median 5.8/Mb) and the significant role of apolipoprotein B mRNA editing enzyme catalytic polypeptide (APOBEC) enzymes as key mutagenic drivers9. Somatic alterations (e.g. mutations, indels, copy number changes, fusions) were noted in several canonical pathways including TP53/cell cycle regulation (89%), RTK/RAS/PI(3)K signalling (71%), chromatin modification (52%) and DNA damage response (DDR) pathway (16%).

Since clinical criteria are too insensitive (< 30%) to detect Lynch syndrome-related UTUC, we believe that universal screening of UTUC should be performed in all patients using NGS, to evaluate for microsatellite instability (MSI) and detect mutations of MMR genes.

DDR genes sense DNA damage and promote the maintenance of genome integrity. Defects in one of the components of the DDR network lead to genomic instability, one of the hallmarks of cancer. Mutations of DDR genes such as BRCA1/2, ERCC2, ATM, FANCC or RAD51 are expected to have significant future

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therapeutic implications in urothelial carcinoma. For example, a mutation status of ERCC2, FANCC, ATM, and RB1 have been shown to predict response to neo-adjuvant platinum-based chemotherapies and to targeted therapies10. At the same time, DDR targeting represents an attractive therapeutic strategy especially effective in cells that already carry a DNA repair gene defect.

The paradigmatic example of DDR targeting is represented by the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib, approved as a single agent for treatment of breast and ovarian cancers harbouring BRCA1 or BRCA2 germline mutations, i.e. carrying defects in DNA repair by homologous recombination. Indeed, the presence of a loss of function mutation in a homologous recombinationrelated gene associated with pharmacological inhibition of a protein involved in a complementary DDR-pathway, such as PARP, leads to genomic instability and cell death.

Leveraging this putative synthetic lethality of PARP inhibition in urothelial carcinoma with deficient DDR genes has led to several trials investigating PARP inhibitors, either as monotherapy or in combination with anti-PD-1/L1 agents in advanced urothelial carcinoma.

The synergistic rationale for combining immune checkpoint with PARP inhibitors is that treatment with the latter increases the tumour mutational load, stimulates the immune recognition of the cancer cells, and upregulates PD-L1 expression.

Sequencing for molecular subtyping Over the last decade, molecular subtyping efforts from several teams have led to distinct or partially overlapping molecular classifications of advanced bladder urothelial carcinoma. The arising molecular subtypes based on these classifications have been shown to be clinically useful in predicting the likelihood of therapy response.

Recently, a comprehensive effort of assigning 1617 muscle-invasive bladder cancer (MIBC) transcriptomes according to published independent classification systems has led to a six-class consensus system successfully reconciling the distinct structures from each input molecular classification: luminal papillary (estimated prevalence: 24%), luminal non-specified (8%), luminal unstable (15%), stroma-rich (15%), basal/squamous (35%), and neuroendocrine-like (3%)11. These consensus classes differ regarding underlying oncogenic mechanisms, infiltration by immune and stromal cells, and histological and clinical characteristics, including outcomes.

This consensus system offers a robust framework that will enable testing and validation of predictive biomarkers in future prospective clinical trials.

Similar as in other malignancies, such as breast cancer, molecular subtyping promises to be an integral part of pathological evaluation and drives the subsequent clinical decision-making process.

“Further development of NGS requires real-time knowledge of genome alterations that can be used in clinical decision making.”

Boom in clinical trials The advances in NGS with emerging novel therapies that target-specific key molecules in cancer cells are leading to a long-awaited boom in urothelial carcinoma translational and clinical trials. This rapid pace research is strengthening the evidence for the applicability and value of sequencing in daily practice. Indeed, NGS has been instrumental in the development of novel biomarkers, either prognostic or predictive of response to specific therapies.

However, further development of this field requires real-time knowledge of genome alterations that can be used in clinical decision making. This requires a robust data infrastructure, continuous improvement in sequencing technology, development of analytical tools based on artificial intelligence, and ongoing biomarker-driven preclinical and clinical trials.

Because of the magnitude of sequencing data generated, the continuing development of advanced bioinformatics tools capable of handling these data efficiently in a timely manner is vital for NGS-centred

research and clinical implementation. Researchers and clinicians are now faced with a wide range of NGS techniques and platforms with no clear consensus guidelines, where the trade-offs between costs, accuracy, power and technical difficulties must be considered.

Heterogeneity Further complicating the implementation of genomic medicine is the fact that driver mutations can evolve during cancer growth. In addition to genomic evolution, tumours may also develop intertumoural and intratumour heterogeneity.

Intertumoural heterogeneity refers to differences in alterations of tumours at different sites, while intratumour heterogeneity refers to differences in alterations within a tumour. Both intertumoural and intratumour heterogeneity can further complicate the determination of relevant mutations, because it means that tissue for NGS must be obtained from relevant sites, as well as, at relevant times in the treatment course. This can result in repeated biopsies.

Additionally, metastatic sites such as bone and brain can be difficult to test.

Finally, when ordering genetic tests, we must ensure that the medical, psychological, and ethical consequences of the testing have been considered.

Specifically, since patient interest and awareness of genetic testing has increased with the advent of advertising campaigns12. Moreover, we must provide accurate interpretations of tests and ensure that risk information is clearly communicated to both patient and family.

Taken together, NGS has the potential to guide clinicians in tailoring treatment to dynamic genomic changes in individual tumours, thereby tangibly improving urothelial carcinoma care beyond what we can imagine today. We are just seeing the tip of the iceberg in this genomic revolution affecting urothelial carcinoma. The question is not if sequencing will be used in daily patient care, but when and how this will happen.

References 1. Mork M, Hubosky SG, Rouprêt M, Margulis V, Raman J, Lotan Y, et al. Lynch Syndrome: A Primer for Urologists and Panel Recommendations. J Urol. 2015 Jul;194(1):21–9.

2. Rouprêt M, Babjuk M, Compérat E, Zigeuner R, Sylvester RJ, Burger M, et al. European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2017 Update. Eur Urol. 2018;73(1):111–22.

3. Metcalfe MJ, Petros FG, Rao P, Mork ME, Xiao L, Broaddus RR, et al. Universal Point of Care Testing for Lynch Syndrome in Patients with Upper Tract Urothelial Carcinoma. J Urol. 2018;199(1):60–5.

4. Skeldon SC, Semotiuk K, Aronson M, Holter S, Gallinger S, Pollett A, et al. Patients with Lynch syndrome mismatch repair gene mutations are at higher risk for not only upper tract urothelial cancer but also bladder cancer. Eur Urol. 2013 Feb;63(2):379–85.

5. Das S, Salami SS, Spratt DE, Kaffenberger SD, Jacobs MF, Morgan TM. Bringing Prostate Cancer Germline Genetics into Clinical Practice. J Urol. 2019;202(2):223–30.

6. Robinson BD, Vlachostergios PJ, Bhinder B, Liu W, Li K, Moss TJ, et al. Upper tract urothelial carcinoma has a luminal-papillary T-cell depleted contexture and activated FGFR3 signaling. Nat Commun. 2019 05;10(1):2977.

7. di Martino E, Tomlinson DC, Williams SV, Knowles MA. A place for precision medicine in bladder cancer: targeting the FGFRs. Future Oncol Lond Engl. 2016 Oct;12(19): 2243–63.

8. Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, et al. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2019 25;381(4):338–48.

9. Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cherniack AD, et al. Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer. Cell.

2017 Oct 19;171(3):540-556.e25.

10. Tse J, Ghandour R, Singla N, Lotan Y. Molecular Predictors of Complete Response Following Neoadjuvant Chemotherapy in Urothelial Carcinoma of the Bladder and Upper Tracts. Int J Mol Sci. 2019 Feb 13;20(4).

Due to space constraints, the entire reference list can be made available to interested readers upon request by sending an email to communications@uroweb.org.

Saturday 18 July 09.05 - 11.25: Plenary session 03 Challenges across the spectrum of bladder cancer Virtual room 2

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Building bridges and connecting people An update of the EAU’s patient initiative after eight years Ms. Patricia Chang EAU Patient Information Website & Social Media Coordinator Arnhem (NL)

Silva (PT), Prof. Monique Roobol (NL), and Mr. André Deschamps (BE).

p.chang@ uroweb.org Co-authors: Ms. Esther Robijn, Ms. Andrea Scholten-Klausing

The Russian Society of Urology (RSU) has been involved in the Russian translations of EAU PI’s animated videos on tests, treatments and surgical procedures. Furthermore, we are excited that a number of our animated videos have also been translated into Lithuanian.

Since 2012, EAU Patient Information (EAU PI) has been the channel between healthcare professionals and patients by providing reliable and evidencebased urology information.

All our videos can be found on YouTube and our website. We will keep our audience up to date on new animated videos via Twitter (@EauPatient) and Facebook (@EAUPatientInformation).

Animated videos The production of animated videos that explain medical procedures and urological conditions remains one of EAU PI’s strongest assets.

Online information leaflets for patients On patients.uroweb.org, you can find our patient information leaflets about conditions, tests, and treatments in several European languages. Our NEW: PI logo information leaflets are free, downloadable and We are proud to present our new logo which has printable for your own use, to distribute to your been enhanced with a colourful icon that uses four patients, or simply to add to your waiting room colours of EAU PI’s corporate colour palette. The icon leaflets. We will continue to update and extend our is a symbol referring to our close collaboration with collection of information leaflets. Our latest leaflets stakeholders, such as patient organisations/ are entitled “PSA: Why should I get tested?”, which advocates and HCP’s in providing and improving is available in English and Dutch with a Portuguese urology-related healthcare education and patient translation on its way, and “Robotic surgery in information. urology”, which is available in English.

In this article, we would like to share with you EAU PI’s activities and some new exciting developments within the patient information initiative of the EAU.

Website makeover We invite you to come see our new look! EAU PI’s website (patients.uroweb.org) has had a makeover.

The homepage has been redesigned to make it more engaging. Tiles with overview pages linking to the various topics make navigating through the content easier and more user-friendly (see figure 1). On the English pages, each urological cancer and disease now shows a table of contents providing a clearer overview and allows for easier navigation.

Website development and its content is an ongoing activity for EAU PI. If you have visited our website and you have ideas for improvement, or any other comments, please let us know.

NEW: Coronavirus COVID-19 webpage EAU PI provides reliable and evidence-based information during the COVID-19 pandemic. To help contribute to trustworthy and valuable information, EAU PI has created a dedicated page on its website where reliable COVID-19 resources are listed. On this page, visitors can also find animated videos about the coronavirus in general, hospitalisation, and disease progression in twelve different languages: Arabic, Dutch, English, Flemish, French, German, Italian, Polish, Portuguese, Russian, Spanish, and Turkish.

With COVID-19 being at the centre of the world medical stage, we see that many urological cancer patients are worried about the consequences of COVID-19 on their treatment.

EAU PI is anticipating on this global need for accurate and trustworthy information and has started collecting frequently asked questions specific to COVID-19 and patients who have urological cancer. Via the FAQs page (patients. uroweb.org/faqs-about-covid-19) on the EAU PI website, you can submit your questions and those of your patients. A multidisciplinary team of experts will review all incoming questions on a weekly basis. We will publish answers to all these questions on our website and via our social media platforms. If you haven’t already done so, please explore this page to see how you best can help yourself, those around you, and your wider community.

NEW: Content about PSA testing We are excited to have included new content about PSA testing on our website. Visitors to our website can find answers to questions such as “What is PSA?”, “Who should get tested?”, and “I feel healthy, why should I be tested?” Additionally, the benefits, limitations and potential risks of PSA testing are described, and there is a free and downloadable PSA testing leaflet. We thank the following contributors: Dr. Selçuk Sarikaya (TR), Dr. Mark Behrendt (DE), Prof. Dr. Hendrik Van Poppel (BE), Mr. Phil Cornford (GB), Ms. Franziska Geese (DE), Prof. Nicolas Mottet (FR), Dr. Ricardo Pereira E 46

EUT Congress News

Figure 1: EAU PI’s homepage has been redesigned to make it more engaging

• Online subscription to European Urology Today (EUT), the official journal of the EAU which is published every two months • Online subscription to European Urology, the specialist journal in the field of urology and nephrology that publishes peer-reviewed original articles and topical reviews on a wide range of urological topics, published every month • Online subscription to European Urology Focus, published every two months • Online subscription to European Urology Oncology, the sister journal to European Urology and European Urology Focus, and the first official publication of the EAU fully devoted to the study of genitourinary malignancies • Online subscription to Urosource, the EAU learning library for urologists • Subscription to the EAU Newsletter sent only to members

information about urology conditions, tests, and This is a summary of EAU PI’s activities: treatments. The 2020 updates will be made available in June.

• Translations of urological topics and related content EAU PI newsletters • Continuous development of animated videos, The newly launched digital EAU PI prostate cancer next in line: newsletter focuses on patient groups’ activities, • Robot-assisted partial nephrectomy interesting webinars, up-and coming events and • Continuous updates of topics based on the EAU also features a patient summary section. The Guidelines specially formatted newsletter can be easily read • Continuous development of the website and shared using your mobile and other electronic • Continuous development of patient information devices so you can directly and instantly share leaflets information.

• Continuous new video additions to the EAU PI playlist on Youtube We will be sending out three separate quarterly • Continuous posts with patient-informationdigital newsletters each one dedicated to bladder, related content on social media (Twitter and kidney and prostate cancers. This is our opportunity Facebook) to provide patient groups, patients and other • Further improvement of patient-oriented stakeholders with quick and easy access to content information about some of the important work and • Quarterly mailings of online newsletters with activities in urology.

BCa-, PCa-, and RCC-related information • Further development of EPAG objectives and To receive our newsletters and be included in our activities network: send us your organisation’s contact details • Further development of EAU Patient Advocacy via: info.patientinformation@uroweb.org. activities • Stronger cooperation with patient organisations Search for new chairman through social media awareness campaigns and We are looking for a new chair to lead the EAU PI events department and its Working Group. The Working • Expansion of social media platforms with Group consists of members from different European Instagram account countries who represent the ESRU, YAU and the • Development of care pathways EAUN. If you are interested and would like to find • Development of webinars out more about this position, go to uroweb.org/ • Development of EAU Patient Journey App eau-launches-search-for-new-patient-information• Development of ESU Patient Advocates Education chairman/. courses and seminars

Patient advocates are eligible for membership if they work for a recognised patient advocacy group.

Additionally, they must provide their CV and a letter of recommendation from the patient advocacy group they represent. They can register at uroweb.org/ membership/.

The EAU PI Working Group is an expert team of healthcare professionals among whom are urologists, specialist nurses and a uropathologist.

This group develops new patient information materials, updates urology topics and explores new ways to further develop activities and initiatives.

Questions or interested?

If you would like to learn more about EAU PI and its activities, or if you have any suggestions to improve our patient information, please do not hesitate to contact us via e-mail at info.patientinformation@uroweb.org.

EAU Guidelines-based updates of urological topics The EAU PI Working Group has updated all 23 urological topics that can be found on EAU PI’s website (patients.uroweb.org). The annual topic updates are based on the EAU Guidelines. In this way, we maintain the most up-to-date scientific

The scope of EAU PI’s activities EAU PI’s horizon of core competencies and activities have expanded and will continue to expand given the close collaboration with patient organisations and other stakeholders in contributing to better and safer healthcare for patients.

Please feel free to visit our website (patients.uroweb.org), and to follow us on Twitter (@EauPatient) and Facebook (@EAUPatientInformation).

EAU Patient Advocate Membership (PAM) The EAU has implemented a new membership type within its membership environment: Patient Advocate Membership (PAM). Patient advocates can join an international community of over 18,000 urology experts sharing best practices, updates on treatments and drug development and much more.

The PAM has an annual fee of €25 and includes:

EAU PI’s animated videos in multiple languages: Benign Prostatic Enlargement (new) English Changing Stoma Bag English, German, Lithuanian, Russian Cystectomy English, Lithuanian, Russian Cystoscopy English, Lithuanian, Russian Double J-stent placement English, German, Lithuanian, Russian Drug treatment for Overactive Bladder English, Russian Erectile dysfunction as a comorbidity (new) English PCNL English, German, Lithuanian, Russian RARP (new) English Robot-assisted Cystectomy (new) English SWL English, Lithuanian, Russian TURBT English, German, Lithuanian, Russian URS Chinese, English, German, Lithuanian, Russian, Spanish, Turkish Urodynamic testing English, Russian June/July 2020

A growing force amplifying the patient’s voice EPAG and patient advocacy: Empowering patients to take co-responsibility Ms. Andrea ScholtenKlausing EAU Patient Information Assistant Arnhem (NL)

a.scholten@ uroweb.org Co-authors: Ms. Esther Robijn and Ms. Patricia Chang The European Association of Urology (EAU) raises the level of urological care through its educational and scientific programmes aimed at urology healthcare professionals (HCP’s) throughout Europe. Besides meeting the scientific and educational needs of HCP’s, it is EAU’s aim to be engaged in the field of patient advocacy.

Patient involvement and empowerment has become more and more important. Involving patients in the production and dissemination of guidelines and patient information and empowering patients to take co-responsibility for the management of their condition enhances medical outcomes and lowers costs. The aim is to design and deliver health services in a way that is inclusive and enables citizens to take responsibility for and control of their healthcare needs. Effectively, this is done by transferring knowledge, providing education, and by offering patient groups a platform from which they can voice their needs and wishes.

Collaboration with patient organisations The EAU aims to create a platform for urology patient groups and organisations to enable them to actively engage with us by bringing to the table the collective needs and interests of their patient community.

EAU Patient Advocacy Group (EPAG) In 2019, the EAU established the EAU Patient Advocacy Group (EPAG) to help disseminate knowledge to patient advocacy groups, patient organisations and caregivers. EPAG members are involved in the development of patient information produced by EAU Patient Information (EAU PI) as well as creating patient-oriented sessions at the annual EAU Congress.

Collaboration, to help us reach our goals in matters relating to the EU healthcare system and EU health legislation, is also a major factor in the establishment of EPAG. EPAG’s first assembly took place at the Annual EAU Congress in Barcelona, March 2019. EPAG consists of healthcare professionals and patient representatives from the following five patient organisations: ECPC The European Cancer Patient Coalition’s (ECPC) main objective is to “firmly establish [themselves] as the main voice of cancer patients in Europe and focus on activities that ensure patients play a leading role in the development of healthcare programmes in Europe.” In order to achieve this, ECPC develops three-year multi-annual strategies based on consultations with board members and reviews patient advocacy strategies and best practices.

Europa Uomo Europa Uomo (EUomo) is an advocacy movement representing and supporting 27 prostate cancer patients’ groups in European countries. Their headquarters is based in Antwerp, Belgium. EUomo recently carried out a prostate-cancer, quality-of-life study, surveying 3,000 men with prostate cancer. The study found that a “higher than expected number [of patients] are struggling with mental health, sexual and tiredness problems after treatment.”

EUomo had planned to announce the results of EUPROMS (Europa Uomo Patient Reported Outcomes Study) at the annual EAU Congress in Amsterdam. The results will now be presented at the EAU Virtual

The second EPAG assembly meeting during EMUC, November 2019, Vienna

Meeting, Saturday 18 July, 13.00-13.20 hours, virtual room 2.

Are you interested in finding out more about this study? At EUomo’s website, a detailed presentation about EUPROMS has been made available. Go to europa-uomo.org/news/quality-oflife-study-toheadline-at-major-meeting/.

WBCPC The World Bladder Cancer Patient Coalition (WBCPC) is a new organisation “founded on the premise of international multi-stakeholder collaboration to make a difference for people affected by bladder cancer.”

The WBCPC had its first Annual Meeting at EAU19 and hopes to continue this trend at the next EAU Annual Congress.

IKCC The International Kidney Cancer Coalition (IKCC) is an international network of patient organisations with a specific focus on kidney cancer. IKCC’s InfoHub provides a resource of information, graphics and materials about kidney cancer (ikcc.org/infohub/).

ECL The Association of European Cancer Leagues (ECL) is a non-profit, pan-European umbrella organisation of national and regional cancer societies. Located in Brussels, ECL provides an exclusive platform for members to collaborate with their international

peers, primarily in the areas of cancer prevention, tobacco control, access to medicines and patient support, and creates opportunities to advocate for these issues at the EU level.

Something new: Europa Uomo and new website EUomo just launched their new website which features new sections, content, and functionality. All text can be translated into your own language by using the “Translate” button at the top of each page.

Visit their website (europa-uomo.org) to get acquainted with their organisation.

EAU EPAG up-and-coming event At the 12th European Multidisciplinary Congress on Urological Cancers (EMUC20), experts from across and beyond Europe will examine the best practices and challenges in managing genitourinary (GU) malignancies. This leading congress in GU cancers for European medical specialists is set to take place from 12 to 15 November 2020 in Athens, making it the first Greek edition of EMUC. The EPAG will be meeting during this congress. This weekend is an opportunity for the EPAG to formally introduce new members, review current policies, discuss projects and developments as well as present new initiatives.

For more information on EMUC20 and the EPAG meeting, visit EMUC20.org.

T:270 mm S:257.3 mm

NOW ENROLLING The COSMIC-021 phase 1b study investigates cabozantinib and atezolizumab, either alone or in combination in solid tumors. The expansion phase of the trial includes 24 cohorts in 12 tumor types, including prostate, renal cell, and urothelial cell carcinoma. Patients must meet inclusion and exclusion criteria specific to each tumor cohort to be eligible for enrollment.

Learn more at COSMIC021.com.

Learn more at clinicaltrials.gov or contact Exelixis Medical Information at 1-888-EXELIXIS (1-888-393-5494). NCT03170960.

CABOZANTINIB, ATEZOLIZUMAB, AND THE COMBINATION OF CABOZANTINIB AND ATEZOLIZUMAB ARE NOT APPROVED FOR THE USES UNDER INVESTIGATION IN THIS TRIAL. SAFETY AND EFFICACY HAVE NOT BEEN ESTABLISHED. © 2020 Exelixis_COSMIC-021_EAU Newsletter_v1_07May2020

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T:194.3 mm

S:181.6 mm

This study is part of the COSMIC Trials Program evaluating cabozantinib, alone or in combination with immune checkpoint inhibitors, for the treatment of solid tumors.

In these unprecedented times we remain committed to advancing science in urology and pelvic health and helping you deliver the best care for your patients.

Find out how Boston Scientific supports you during the COVID-19 pandemic. bostonscientific.eu/EAU2020

This material is not intended for use in France.

URO-821501-AA Š 2020 Boston Scientific Corporation or its affiliates. All rights reserved.

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