EUT Congress News - Saturday 16 March 2019 by European Association of Urology (EAU)

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EAU19 Congress News

F tu irst rd ay Edit 16 ion M ar ch

34th Annual Congress of the European Association of Urology Barcelona, 15-19 March 2019

EAU19 honours innovators and notable contributions Congress officially commences in Barcelona By Jen Tidman and Erika de Groot The vocal prowess of “Carmen”, the name of the lead in the iconic opera by French composer Georges Bizet, echoed throughout the auditorium and kick-started the opening of the EAU19 Congress. At the Opening Ceremony, EAU Secretary General Prof. Christopher Chapple (GB) welcomed delegates who came from different parts of the world. Prof. Chapple also emphasised the need for well-trained urological nurses and the importance of the cooperation between the EAU and the European Association of Urology Nurses (EAUN). Distinguished recipients of this year’s Honorary Memberships were recognised at the ceremony: Prof. Dr. Yuri Alyaev (RU), Prof. Dr. Michael Droller (US), Prof. Hartwig Huland (DE), Prof. Michael Jewett (CA), and Prof. Dr. Jørgen Nordling (DK). Two of these renowned beneficiaries expressed their gratitude for their patients. Prof. Huland said, “My advice to those who want to pursue academic urology, learn from your patients. What we’ve learned from the patients

that we’ve treated will benefit the next generation of patients.” Prof. Jewett stated, “I would like to thank the patients that I’ve looked after for what they’ve taught me. I’m now pursuing the study of engaging patients and activating them in their care which, I believe if it were a drug would be a ‘blockbuster drug’ that will impact on overall survival of these cancer specialties.”

The Opening Ceremony also highlighted this year’s awardees: Prof. Freddie Hamdy (GB) was recipient of EAU’s top honour, the Willy Gregoir Medal. He said, “One of my passions is to develop academic careers. I discovered early that success follows seed and soil. There are amazing seeds in our training community but they will only succeed if they are embedded in fertile soil. It is therefore our responsibility to provide this environment to our department.”

Other notable awardees included current EAU Adjunct Secretary General – Science, Prof. Dr. Francesco Montorsi (IT), who accepted the EAU Frans Debruyne Lifetime Achievement Award; Dr. Maarten Albersen (BE) who won the EAU Crystal Matula Award; Dr. Giuseppe Simone (IT) who received the EAU Hans Marberger Award; and Prof. Peter Alken (DE), who was recipient of The Innovator in Urology Award. The EAU Ernest Desnos Prize was granted to medical company, KARL STORZ SE & Co. KG, for extraordinary contributions to the field of urological history. Dr. Sybill Storz (DE), daughter of company founder Mr. Karl Storz accepted the accolade. The last awardee of the evening, Dr. Veeru Kasivisvanathan (GB) shared “To all of you out there who dream of doing something, keep working at it because anything is possible.” Dr. Kasivisvanathan received the EAU Prostate Cancer Research Award. The final acts of “Carmen” marked a festive conclusion of the ceremony, which was followed by the EAU Networking Reception.

The 34th Annual EAU Congress officially started to the sound of Bizet’s Carmen

ESO Observatory features forecasts in PCa management A multidisciplinary take on what to expect in the coming year By Erika de Groot The “6th ESO Prostate Cancer Observatory: Innovations and care in the next 12 months” showcased predictions by experts from diverse fields in prostate cancer (PCa) treatment. Chaired by Prof. Dr. Jeroen Van Moorselaar (NL) and Mr. John Dowling (IE), the session was introduced with the lecture “The urologist’s perspective on focal therapy”. Prof. Dr. Roman Ganzer (DE) discussed ongoing trials with results to look forward to, such as the multicentre study “MRI/US Fusion Imaging and Biopsy in Combination with Nanoparticle Directed Focal Therapy for Ablation of Prostate Tissue”; the Partial prostate Ablation versus Radical prosTatectomy (PART) study; and the Robotic Surgery After Focal Therapy (RAFT) trial. In his presentation “The urologist’s perspective on surgery”, Prof. Markus Graefen (DE) made several

predictions: the role of radical prostatectomy (RP) as the first line treatment option in advanced PCa will increase; neoadjuvant androgen-deprivation therapy (ADT) might need reconsideration; cytoreductive RP will become routine; and salvage RP after failure of focal therapy will be further explored. According to Dr. Roderick Van Den Bergh (NL), active surveillance (AS) should be the standard option, reduction in the variation in the AS use is needed, and AS should be standard part of screening policies. In his lecture “The urologist’s perspective on active surveillance”, he stated, “We need to also focus on the timing of treatment, not only its avoidance. We need wider inclusion, targeted biopsy risk stratification, and a personalised approach.” Dr. Olivier Rouvière (FR) recommended magnetic resonance imaging (MRI) before any prostate biopsy. In his presentation “The imaging specialist’s perspective on MRI”, he predicted that risk stratification will be used to determine who should undergo a biopsy after MRI and that the role of systematic biopsy will gradually decrease. In addition, Dr. Rouvière forecast that obtaining a substantial number of targeted cores from each lesion will remain necessary due to the imprecision of the MR/US fusion methods, and that certification of radiologists and the use of quantitative MRI will improve the reproducibility of interpretations. In his lecture “The pathologist’s perspective”, Prof. Dr. Ferran Algaba (ES) shared his insights on accurate pathology wherein not all pattern 4, pT2a, pT3a, and positive margins are the same. He also recommended the inclusion of simple molecular pathology, as easy molecular markers can help some patients. Prof. Algaba added that in terms of reproducible pathology, the aim is to improve the pathology image base for standardisation.

Prof. Ganz discussing ongoing trials at the ESO PCa Observatory

Saturday, 16 March 2019

According to Dr. Alberto Bossi (FR), genes are crucial in patient profiling. During his presentation “The radiation oncologist’s perspective” he said, “The [treatment] landscape is ready to use genetic profiling

for daily decision-making for patients undergoing radiotherapy.” In her lecture “The medical oncologist’s perspective”, Prof. Silke Gillessen Sommer (GB) shared her expectations for the next two years. Androgen receptor (AR)-antagonists will be a new option in addition to androgen-deprivation therapy (ADT) for metastatic castration-sensitive PCa. In non-metastatic castrationresistant prostate cancer (nmCRPC), treatment with AR-antagonists will be standard for the majority of patients with a short PSA doubling time (PSADT). For mCRPC, precision medicine will become a reality. However, the costs and availability of the abovementioned drugs will be an issue.

During his presentation, “The andrologist’s perspective”, Dr. Maarten Albersen (BE) anticipated more AS is for improvement of preservation of sexual function in 2019; and more hypofractionation without increased sexual side effects. He added that there would be an increased awareness of and lower threshold in offering therapy for sexual dysfunction. On behalf of Mr. André Deschamps (BE), Mr. Dowling discussed the three pillars in PSA screening in the lecture “The patient’s perspective”: patient awareness, PSA-led screening with risk stratifications and parameters, and treatment should be carried out in multidisciplinary centres.

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A Chinese view on Oncology and Andrology By Patricia Chang Congress news . . . . . . . . . . . . . . . . . . . . . . . . 1 Congress highlights . . . . . . . . . . . . . . . . . 2-3 Post-biospy infections . . . . . . . . . . . . . . . . . 5 Stem cell therapy in ED . . . . . . . . . . . . . . . . 6 Herbal treatment for renal stones . . . . . . . . 7 SCO: Interview with Prof. Culig . . . . . . . . . . 8 Treating late-onset hypogonadism . . . . . . . 9 Beyond BCG in NMIBC . . . . . . . . . . . . . . . 10 The EASE registry . . . . . . . . . . . . . . . . . . . . 11 Organ-sparing surgery in penile cancer . . 12 Male infertility . . . . . . . . . . . . . . . . . . . . . . 13 Improving the bladder diary . . . . . . . . . . . 15 Genetics in bladder cancer . . . . . . . . . . . . 16 New ESGURS chairman . . . . . . . . . . . . . . . 17 ESU’s educational aspirations . . . . . . . . . . 18 Molecular aspects of BCa in the young patient . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Urolithiasis as a systemic disorder . . . . . . 21 EAUN19: 20th Anniversary meeting . . . . . . 22

Professors James N’Dow (GB), Yeong-Shiau (TW) and Li-Qun Zhou (CN) were delighted to chair the Joint Session of the EAU and the World Chinese Urologists, providing Chinese-speaking urologists with a stage to discuss a wide range of topics. Three oncological topics were highlighted: 1. advancing the diagnosis techniques for urological cancer in order to improve treatment outcomes, 2. Chinese urological cancer registries, and 3. the need for patient engagement in urological cancer care. In terms of cancer diagnosis, Dr. See Tong Pang (TW) noted that current conventional approaches all have limitations in detecting genitourinary cancers. In PCa, PSA is used as a screening tool, but causes several problems, e.g. false positive and false negative percentages, and in BCa, cytology is used as a screening tool, but lacks the sensitivity to detect cancer. The same poor sensitivity is seen in kidney cancer detection. The genomic background of cancer can play a more differentiating role taking into account a new diagnostic strategy based on nanotechnology with biomarkers. The development of a CMX biochip is a novel way of

increasing detection sensitivity up to 80%, which can reduce unnecessary biopsies and may lead to accurate, rapid, non-invasive and low-cost detection methods. A colleague of Dr. Ren Shancheng (CN) delivered his contribution on registries. There are nine consortiums in China covering a wide range of oncological publications and data. The shared database includes over 20,000 cases and contains clinical guidelines. China’s vastness provides a unique opportunity to study different kinds of

cancers and the final data will improve the care of Chinese patients. The need for patient engagement is important in developing guidelines, according to Ms Karin Plass (NL), EAU Guidelines Office Manager. Organisations such as the EMA, FDA, and NHS have set up full patient engagement programmes. Having patients as partners in healthcare may result in better patient outcomes and improved quality and safety. Patients want valid and trustworthy information from reliable sources such as EAU Patient Information and the EMA. In the field of andrology, two speakers got to the stage: Prof. Chen Yu (TW) on “Penile Augmentation: The role of urologists in Taiwan”, and Mr. Suks Sukhbinder Minhas (GB) on “Penile curvature surgery: European perspectives”.

Discussion at the EAU-World Chinese Urologists Joint Session covered topics including oncology and penile curvature

Prof. Chen Yu (TW) discussed rare cases where genetic and hormonal problems can cause a condition called micropenis; an erect penis of less than 7 cm. In Taiwan, penile augmentation is mostly performed by plastic surgeons who are well-trained in managing penile tissues using high-tech methods such as Da Vinci robotic Xi surgical systems.

Spain’s urology was shaped by its empire History Specialty Session highlights Spanish contributions to early urology

Innovations in functional urology . . . . . . . 23 Perioperative systemic immunotherapy 24-25

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Section Editors Prof. T. E. Bjerklund Johansen, Oslo (NO) Mr. Ph. Cornford, Liverpool (GB) Prof. O. Hakenberg, Rostock (DE) Prof. P. Meria, Paris (FR) Dr. G. Ploussard, Paris (FR) Prof. J. Rassweiler, Heilbronn (DE) Prof. O. Reich, Munich (DE) Dr. F. Sanguedolce, London (GB) Dr. Z. Zotter, Budapest (HU)

The EAU History Office typically organises a session at every EAU Annual Congress highlighting the history of urology in the host country. Last year saw an extensive session on Danish urology, and in 2017 the History Office collaborated with BAUS in London. This year, the session was chaired by EAU History Office Chairman Prof. Philip Van Kerrebroeck (NL) and Dr. Luis Fariña-Péres (ES).

Founding Editor Prof. F. Debruyne, Nijmegen (NL) Onsite Reporting and Editing E. de Groot L. Keizer J. Tidman P. Chang

Renaissance Spain and Urology Prof. Remigio Vela Navarette (ES) spoke about the birth of urology in renaissance Europe, in particular the Spanish contributions in the 16th century. Vela Navarette felt that Spanish achievements in early urology have been historically overlooked, for instance

Marketing Communication J. Bloemberg M. van Gurp L. Stuart-Young Advertising M. van der Krieke F. Strating

By Jen Tidman The Young Academic Urologists (YAU) “are the current backbone of research within the EAU,” said Arnulf Stenzl (DE), Chairman of the Scientific Congress Office, at the YAU Session on Friday afternoon. “The scientific content of this meeting is based on the work of young academics and YAU members,” he said, noting that 82% of the group’s members are presenting at EAU19. “The EAU needs you, and what we can give you in return is something as a base for your research, your networking, and success in your career.” Giving an overview of the scientific activities of the YAU, Chairman Selçuk Silay (TR) said it had been a record-breaking year for its members, with 44 publications, four meetings and eight hands-on courses, as well as a special session and 48 accepted abstracts at the EAU annual congress.

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One Spanish renaissance ‘proto-urologist’ is Andreas Vesalius (1514-1564), the so-called ‘prince of anatomy’ and personal doctor of Charles V and Philip II. Several Spanish anatomists were active in Paris at the time. A lesser-known contemporary of Vesalius was Andres Laguna (1499-1559), author of Anatomical Method (1535). This work describes horseshoe kidney and ileocecal valve. Juan Valverde de Amusco (c 1525-1587 published anatomical work in Rome in 1556. His illustrations (and even a portrait painting of him) are often confused with Vesalius. Valverde described the prostate as a “spherical mass of meat”.

Spanish innovators Prof. Javier Angulo Cuesta (ES) explored the life of renowned Cuban-born urologist Joaquín María Albarrán (1860-1912), particularly how he was influenced by Spain, and how in turn he impacted Spanish urology. Albarran was orphaned at an early age and taken to Spain for his studies. After becoming one of Europe’s foremost urologists, he influenced dozens of followers in the Spanish and French medical world. Dr. José Maria Gil-Vernet Sedo (ES) spoke on his grandfather Salvador’s work in the 1940s, particularly his publication of Patologia Urogenital (1944), a hugely influential and beautifully illustrated volume. The role of the medical illustrator (particularly with regard to Spanish urology) is further highlighted in Dr. Luis Farina’s chapter in De Historia Urologiae Europaeae Vol. 26, available for all EAU members at the Membership booth from Saturday morning.

Over a period of several decades in the 16th and 17th centuries, descriptions can be found in Spanish medical sources of prostatism, stone treatment, and particularly and uniquely, New World remedies. Spanish doctors and scientists studied chocolate, cacao and cantarida (“Spanish fly”) as aphrodisiacs. The New World also brought (urological) disease, and Spanish doctors pioneered the description and treatment of syphilis, which originated in Hispaniola and reached Europe through Barcelona(!) and Naples.

Prof. Vela Navarette during his talk on Renaissance Spain

A record-breaking year of scientific achievements

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in Ernest Desnos’s influential History of Urology (1914), which makes no mention at all of Spanish developments in the field. In the discussion that followed his presentation, he attributed this to a climate of French nationalism surrounding the First World War.

YAU: ‘the backbone of EAU research’

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Spain has greatly contributed to the field of urology, through its scholars, surgeons and innovators, the audience learned at the EAU History Office’s Special Session on Friday afternoon. Particularly striking is the role that Spain’s former empire played in the development of Spanish urology: from previously unknown diseases and herbs that reached Spain from the New World to the LatinAmerican urologists who trained and worked in Spain, reaching great new heights. The tale of Spanish urology is inextricably linked with Spain’s history of overseas conquest.

Editor-in-Chief Prof. M. Wirth, Dresden (DE)

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By Loek Keizer

Silay encouraged young academics to attend the speciality session “Leadership and the EAU” and the ESU course “Improving your communication and presentation skills” on Monday at EAU19, as well as the forthcoming YAU19 meeting in Vienna. This year is the second consecutive year that a YAU member has won the EAU Crystal Matula award, with Maarten Albersen (BE) scooping 2019’s prize after Silay’s success in 2018. He is also one of two recipients of an EAU Research Foundation (EAU-RF) seeding grant awarded to support original research by a junior investigator. During the YAU session Albersen presented on how he developed this successful research bid, in order to help other young academics applying for the next round. He highlighted the importance of demonstrating innovativeness and the potential for larger-scale

funding, as well as personal motivation and knowledge. Anders Bjartell (SE), Chairman of the EAU-RF, echoed this when commenting on the quality, feasibility and potential impact of two research proposals presented by YAU members Maria Carmen Mir Maresma (ES), Paolo Capogrosso (IT) and Paolo Verze (IT). “The most interesting thing for a reviewer is what is in the design, what is going to be done, and whether it is possible,” he said. “Look at the Guidelines, the need, and the real-world data.” The YAU awards were also presented during this session: Fabio Castiglione (GB) was named as reviewer of the year; Bernhard Haid (AT) accepted the award for the best paper published in 2018 by a YAU group; and Panagiotis Kallidonis (GR) accepted the award for best poster presented at EAU19 by a YAU group. Saturday, 16 March 2019

EAU-USANZ delivers updates in the region

Welcome to EAU19!

Reshaping the workforce, reassignment surgery updates By Erika de Groot

surgical procedures currently offered in the region.

Female-to-male (FTM) gender reassignment surgery and the practice patterns of female urologists in Australia and New Zealand were examined during the Joint Session of the European Association of Urology (EAU) and the Urological Society of Australia and New Zealand (USANZ). This Urology Beyond Europe session was chaired by Prof. Peter Heathcote (AU) and Prof. Manfred Wirth (DE).

In the first two years of practice, a total of 17 patients have undergone procedures: 13 RAP, 2 ALT, 1 PP and 1 Meta. However, not all patients went through all stages. Complications, functional outcomes, and measures on patient-reported outcome were assessed.

In her lecture, “Practice patterns of female urologists in Australia and New Zealand: Do we need to know?”, Dr. Lydia Johns Putra (AU) disclosed that more women in Australia and New Zealand are joining the urology workforce. She added that on average, they are younger than their male counterparts and are mainly general urologists.

A total of 54% patients had complete sensation of the phallus, and 46% had near completion. 60% reported penile implant use, with 100% adequate implant rigidity.

Female urologists do not take as much time off and intend to retire aged between 60 and 69. Dr. Putra also stated they are more likely to have children but fewer children per individual; work shorter hours; and are more likely to subspecialise compared to female urologists in the United States. FTM surgery “We have successfully established an expert service for gender reassignment surgery in Brisbane, Australia,” said Dr. Hans Goossen (AU) during his presentation “Female to male gender reassignment surgery Australia: Early experience and outcome”. Metoidioplasty (also known as Meta), Radial Artery Forearm Flap (RAP), Antero-Lateral Thigh Flap (ALT) and Pubic Phalliplasty (PP) are

Dr. Goossen stated that complication rates appear similar to the reported literature; no complete loss of phallus, no major complications of donor sites, and no cardiovascular events. Goossen added that overall patient satisfaction in terms of phallus cosmesis is high (54% rated excellent and 46% good) and that the majority of patients rated scrotum cosmesis as excellent (22%), good (67%) and average (11%). Patients also reported excellent and good urine flow (60% and 10% respectively). A total of 54% patients had complete sensation of the phallus, and 46% had near completion. 60% reported penile implant use, with 100% adequate implant rigidity. Patients’ gender dysphoria was resolved in 31%, with the other 69% reporting great improvement.

Dr. Lydia Johns Putra speaking at EAU19 on Friday, discussing the practice patterns of female urologists in Australia and New Zealand. On average, female urologists are younger than their male counterparts

Day 1 Awards Gallery

C. Chapple awards F. Hamdy with the EAU Willy Gregoir Medal

F. Montorsi receives the EAU Frans Debruyne Life Time Achievement Award from C. Chapple and F. Debruyne

Mrs S. Storz receives the EAU Ernest Desnos Prize from C. Chapple

M. Albersen receives the EAU Crystal Matula Award from C. Chapple and H. Fürstenberg from LABORIE

G. Simone receives the EAU Hans Marberger Award from C. Chapple and E. Dourver from KARL STORZ

V. Kasivisvanathan accepts the EAU Prostate Cancer Research Award from C. Chapple and F. Schröder from the FHS Foundation

P. Alken receives the EAU Innovators in Urology Award by C. Chapple

C. Chapple congratulates Y. Alyaev with his EAU Honorary Membership

C. Chapple congratulates M. Droller with his EAU Honorary Membership

C. Chapple congratulates H. Huland with his EAU Honorary Membership

M. Jewett was awarded an EAU Honorary Membership

C. Chapple congratulates J. Nordling with his EAU Honorary Membership

Saturday, 16 March 2019

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Post-biopsy infections: Better be prepared! Standards and recommendations for antibiotic prophylaxis in transrectal prostate biopsy Gernot Bonkat Chairman Guidelines Panel on Urogenital Infections CEO and Head Physician alta uro AG, Basel (CH)

A transrectal prostate biopsy is frequently performed to obtain tissue for the histological diagnosis of prostate cancer. The procedure is indicated by an abnormal digital rectal examination of the prostate, an elevated prostate specific antigen (PSA) or suspicious findings in multiparametric magnetic resonance imaging (mpMRI). This short review discusses the most promising antimicrobial strategies to reduce infectious complications in men undergoing prostate biopsy. It is estimated that more than 1 million men over 65 years have had a prostate biopsy as part of the Medicare programme in the United States in 2003, with an annual prevalence of about 1,600/100,000 men at risk1. The National Health Service (NHS) in Great Britain recorded 49,495 men as having had a prostate biopsy in 2015, giving a biopsy prevalence of 500/100,000 men at risk per year2. Post-biopsy infections Most prostate biopsies are transrectal ultrasound guided (transrectal ultrasound; TRUS)3. Thus, biopsy needles can be accurately placed in the prostate under local anaesthetic with ultrasound image guidance and a systematic sequence of tissue samples taken for examination4. Each biopsy core requires a separate entry and passage of the needle and generally a single needle is repeatedly used to obtain a set of biopsies from each individual. Needle placement into the prostate from the bowel bears a high risk of introducing micro-organisms in tissue layers, urinary system or blood stream. This may cause infectious complications, ranging from mild prostate inflammation to life-threatening urosepsis. However, the risk varies between cohorts and according to definitions of infection. While infectious complications were only rarely reported in the past, recent evidence indicates increasing rates of post-biopsy infections. A Canadian study reported an increase from 1% in 1996 to 4.1% in 2005 and a mortality in one men out of 1000 following prostate biopsy5. A recent well-controlled study found a 7% rate of microbiologically proven infection6. Two major strategies Two major strategies could reduce risk of infection after prostate biopsies: I) administration of antimicrobial drugs and II) technical modifications. The most frequently used strategy is administration of an antimicrobial prophylaxis. The rationale is that a sufficient concentration of an antimicrobial drug should be present in the prostate during biopsy. That way, survival of bacteria implanted by the biopsy needle is limited and clinical infection is inhibited. Another antimicrobial intervention is washing the rectal wall with antiseptics, such as povidone iodine, prior to biopsy to reduce bacterial contamination of the needle entry point. Antimicrobial prophylaxis Antimicrobial prophylaxis to reduce infectious complications was evaluated for the first time in a randomised study published in 19799. Many more studies followed and were comprehensively analysed in a Cochrane review in 20118. For all investigated parameters (bacteriuria, bacteraemia, urinary tract infection, fever, hospitalisation) the antimicrobial prophylaxis was superior compared to the control/ placebo groups (in all cases p < 0.05). In 2015, another updated systematic review and meta-analysis was published, including nine trials analysing antibiotics versus placebo/no treatment. The authors showed the clinical benefit of antimicrobial prophylaxis compared to control/no prophylaxis regarding the primary endpoints bacteriuria, bacteraemia, fever, UTI, and hospitalisation (in all cases p < 0.05)9. Interestingly, the rate of adverse events due to antimicrobial prophylaxis was not increased in the antimicrobial intervention group (p = 0.63)8. Thus, antibiotic prophylaxis is currently the gold standard worldwide3. Saturday, 16 March 2019

Duration of antimicrobial prophylaxis The duration of antimicrobial prophylaxis is a matter of debate. The currently available RCTs include single shots, one-day, three-day, five-day and seven-day regimes. The Cochrane analysis of 2011 compared a three-day regimen with a single shot/one-day prophylaxis. In all analysed endpoints no significant differences were detected (for all p > 0.05), only postoperative bacteriuria was reduced in the three-day intervention (p = 0.01)8. However, the Cochrane analysis from 2011 excluded studies with patients at risk for infective complications (e.g. indwelling catheters, diabetes etc.) and mixed up a single shot prophylaxis without full 24-hour duration of action and full one-day regimens. In an updated meta-analysis from 2015, again, no substantial differences between longcourse versus short-course treatments were detected regarding the clinical outcomes fever, urinary tract infection and hospitalisation (in all cases p > 0.05)9. To summarise, future metaanalyses will have to include studies with patients being at risk for infectious complications to represent the real clinical situation. Augmented antimicrobial prophylaxis A combination of multiple antibiotics was proposed to overcome increased infectious complications caused by antibiotic resistance. Most studies report infectious complications in a retrospective arm and compare the data with a prospective arm recorded after the introduction of a combination therapy. A metaanalysis published in 2,016 identified three RCTs with 659 patients and five case-control studies with 3,404 patients on this issue10. Similar to the Cochrane review of Zani et al.8 patients with heart disease, prosthesis, pre-biopsy bacteriuria and indwelling catheters were excluded. The authors evaluated bacteriuria, bacteraemia, fever, UTI, hospitalisation and drug-resistant bacteria isolated in urine and blood. All seven endpoints significantly favoured the augmented antimicrobial use (in all cases p < 0.05). The authors concluded that the addition of an antimicrobial agent to the basic antimicrobial prophylaxis can contribute to the reduction in severe infection and drug resistance. They point out that this might be beneficial for high risk patients, although they were excluded in these studies. In addition, it has to be considered that the casecontrol studies usually compare data from a retrospective cohort (with usually high infection rates) with a prospective arm recorded after the introduction of an intervention using a combination therapy. Thus, a significant bias is present. Four different antimicrobials The augmented prophylaxis can take bizarre dimensions: In the most recent study performed in Iran, the authors randomised 450 patient to a combination of four different antimicrobials (ceftriaxone plus amikacin plus ciprofloxacin plus metronidazole) or the standard prophylaxis being ciprofloxacin plus metronidazole11. The incidence of infectious complications in the intervention group was reported to be significantly lower than that in the control group (4.6% versus 0.9%, p = 0.017). However, the long-term complications regarding the development of antimicrobial resistance must be considered. Choice of antimicrobial class Several studies investigated the most suitable antibiotic for prophylaxis in men undergoing prostate biopsy. Due to their valuable pharmacokinetic properties in prostatic tissue, fluoroquinolones have been widely evaluated. However, in the analysis of available RCTs no antibiotic class was shown to be clearly superior. This was also shown in the Cochrane review by Zani et al.8. Specifically, the fluoroquinolones have been in discussion in recent years because of increasing fluoroquinolone resistance in the faecal flora.

with subsequent bacterial culture for pre-biopsy 8. Zani, E.L., O.A. Clark, and N. Rodrigues Netto, Jr., screening could offer individual targeted antimicrobial Antibiotic prophylaxis for transrectal prostate biopsy. therapy. Recently, a systematic review was performed Cochrane Database Syst Rev, 2011(5): p. CD006576. 9. Yang, L., et al., Prophylactic Antibiotics in Prostate on this issue and included 15 studies (only one RCT) Biopsy: A Meta-Analysis Based on Randomized with 12,320 patients16. Targeted antibiotic prophylaxis resulted in significantly less infectious complications Controlled Trials. Surg Infect (Larchmt), 2015. 16(6): p. (0.81%) compared with standard antibiotic 733-47. prophylaxis (3.40%). This translates into an estimated 10. Yang, L., et al., The augmented prophylactic antibiotic number needed to treat of 39 with targeted antibiotic could be more efficacious in patients undergoing prophylaxis compared to standard antimicrobial transrectal prostate biopsy: a systematic review and prophylaxis to prevent one post-biopsy infection16. meta-analysis. International Urology and Nephrology, The authors further concluded that fluoroquinolone resistance drives the higher rates of infectious complications in the standard antimicrobial prophylaxis group16. Up to now, a total of three RCTs have been published involving 1,337 patients17-19. While in two studies infectious complications occurred only in the standard prophylaxis group18-19, the third study showed an equal distribution of infectious complications17. Of note, the later study demonstrated an unusually high rate of infectious complications with a sepsis rate of 5.2% among all groups. To give a final recommendation, a meta-analysis of the available RCTs is mandatory. Conclusion The available data only show that antimicrobial prophylaxis is of significant advantage to reduce infectious complications following prostate biopsy. The augmented and targeted antimicrobial prophylaxis shows some potential, but needs further validation. References 1. Loeb, S., et al., Complications after prostate biopsy: data from SEER-Medicare. J Urol, 2011. 186(5): p. 1830-4. 2. Health, U.D.o., 2015. 3. Wagenlehner, F.M.E., et al., Infective complications after prostate biopsy: Outcome of the Global Prevalence Study of Infections in Urology (GPIU) 2010 and 2011, A prospective multinational multicentre prostate biopsy study. European Urology, 2013. 63(3): p. 521-527. 4. Hodge, K.K., J.E. McNeal, and T.A. Stamey, Ultrasound guided transrectal core biopsies of the palpably abnormal prostate. J Urol, 1989. 142(1): p. 66-70. 5. Pilatz, A., et al., Acute epididymitis revisited: impact of molecular diagnostics on etiology and contemporary guideline recommendations. Eur Urol, 2015. 68(3): p. 428-35. 6. Yang, L., et al., Antibiotics may not decrease prostatespecific antigen levels or prevent unnecessary prostate biopsy in patients with moderately increased prostatespecific antigen levels: A meta-analysis. Urol Oncol, 2015. 33(5): p. 201 e17-24. 7. Ruebush, I.T.K., J.H. McConville, and F.M. Calia, A double-blind study of trimethoprim-sulfamethoxazole prophylaxis in patients having transrectal needle biopsy of the prostate. Journal of Urology, 1979. 122(4): p. 492-494.

Saturday 16 March 10.00-14.00: Joint Meeting of the EAU Section of Infections in Urology (ESIU) and the EAU Section of Urological Imaging; Prepare for the future: Prevent, detect, strike back!

EAU Education Online presents:

EAU Guidelines E-Courses How well do you know the EAU Guidelines? The e-courses feature questions formulated by experts in the field, reviewed by the EAU Guidelines Office and the Young Urologists Office. Primary Urethral Carcinoma

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NMIBC (Non-Muscle Invasive Bladder Cancer)

Thromboprophylaxis

Currently, fosfomycin is in focus as a good alternative. However, from the three available RCTs only one RCT showed a significant reduction of infectious complications compared to standard prophylaxis with fluoroquinolones12-14. Nevertheless, a recent metaanalysis which included those three RCTs and two retrospective cohorts reported significantly lower infectious complications in the fosfomycin cohort compared to the fluoroquinolone based prophylaxis (RR = 0.20, 95% CI: 0.58 - 5.23, p = 0.00001)15. Targeted antimicrobial prophylaxis Considering the increase in fluoroquinolone resistance in faecal isolates, the use of a rectal swab

2016. 48(8): p. 1197-1207. 11. Izadpanahi, M.H., et al., Addition of Ceftriaxone and Amikacin to a Ciprofloxacin plus Metronidazole Regimen for Preventing Infectious Complications of Transrectal Ultrasound-Guided Prostate Biopsy: A Randomized Controlled Trial. Adv Urol, 2017. 2017: p. 4635386. 12. Fahmy, A.M., et al., Fosfomycin antimicrobial prophylaxis for transrectal ultrasound-guided biopsy of the prostate: A prospective randomised study. Arab J Urol, 2016. 14(3): p. 228-33. 13. Lista, F., et al., Efficacy and safety of fosfomycintrometamol in the prophylaxis for transrectal prostate biopsy. Prospective randomized comparison with ciprofloxacin. Actas Urologicas Espanolas, 2014. 38(6): p. 391-6. 14. Sen, V., et al., The use of prophylactic single-dose fosfomycin in patients who undergo transrectal ultrasound-guided prostate biopsy: A prospective, randomized, and controlled clinical study. Canadian Urological Association Journal, 2015. 9(11-12): p. E863-7. 15. Noreikaite, J., et al., Fosfomycin vs. quinolone-based antibiotic prophylaxis for transrectal ultrasound-guided biopsy of the prostate: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis, 2018. 16. Scott, S., et al., The effectiveness of targeted relative to empiric prophylaxis on infectious complications after transrectal ultrasound-guided prostate biopsy: a meta-analysis. World J Urol, 2018. 17. Elshal, A.M., et al., Chemoprophylaxis during transrectal prostate needle biopsy: critical analysis through randomized clinical trial. World J Urol, 2018. 18. Fahmy, A., et al., Optimizing prophylactic antibiotic regimen in patients admitted for transrectal ultrasoundguided prostate biopsies: A prospective randomized study. Prostate Int, 2016. 4(3): p. 113-7. 19. Ozgur, A., et al., Prevalence of antibiotic resistance in fecal flora before transrectal ultrasound-guided prostate biopsy and the clinical impact of targeted antibiotic prophylaxis. Arch Esp Urol, 2017. 70(10): p. 852-858.

Urolithiasis

Menâ&#x20AC;&#x2122;s Health

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Stem cell therapies in erectile dysfunction: Is it too early? Trials show that regenerative cell-based therapy for erectile dysfunction is probably safe Maarten Albersen, MD, PhD (FEBU) Dept. of Urology University Hospitals Leuven (BE) Dept. of development and regeneration KU Leuven (BE)

Uros Milenkovic, MD Dept. of Urology University Hospitals Leuven (BE) Dept. of development and regeneration KU Leuven (BE)

Erectile dysfunction (ED) is defined as the inability to attain and maintain erection of the penis sufficient to permit satisfactory sexual activity. This disease most commonly affects men from 40 years of age with a clear age-associated increase in prevalence. There is a large number of disorders known to contribute to the development of ED, including but not limited to diabetes, hypogonadism, metabolic syndrome, cardiovascular disease, cigarette smoking, pelvic neurovascular injury, and local disorders, such as Peyronie’s disease. The condition may have significant negative impact on quality of life of both the patients and their partners.

differentiated daughter cell. In ‘stochastic differentiation’ one father cell divides into two differentiated cells, while another father cell divides into two exact copies of itself in order to maintain the population of stem cells. Differentiation into more specialised cell types, e.g. smooth muscle cell, endothelial cell, or neuron was initially thought to serve as a replacement of defected or apoptotic cells in stem cell therapy (the “building block theory”). More recently, however, various types of stem cells have been shown to influence the environment into which they are transplanted in a paracrine fashion (the “paracrine theory”), and the principle of engraftment and differentiation has been questioned. Stem cell types reported in ED animal research mainly include adipose tissue-derived SCs (ADSCs), bone marrow-derived SCs (BMSCs), and muscle derived SCs (MDSCs), although there are rare reports on the use of embryonic stem cells. Theoretically, these cells can differentiate into all cell types of the mesodermal origin, including muscle, fat and bones, although extra-linear differentiation has been shown in-vitro3.

“Available treatment armamentarium solely provide symptom relief”

Iatrogenic trauma of the neurovascular bundle as result of radical prostatectomy (RP) is a frequent cause of ED. This complication remains frequent despite a refinement of nerve-sparing operative techniques including the introduction of robotassisted laparoscopy. Post-prostatectomy erectile dysfunction remains difficult to treat due to the lack of bio-available NO. Furthermore, as detailed above, Understanding the molecular aspects of ED PDE5i typically do not work well in this group of pathogenesis has successfully resulted in widespread patients5. The initial studies on stem cell application use of phosphodiesterase type 5 inhibitors (PDE5i). As for ED have investigated early post-cavernous nerve these drugs interfere with the nitric oxide (NO) – cyclic injury applications of stem cells, most often guanosine monophosphate (cGMP) pathway, an intact intracavernous, in rat models. The first report on stem NO supply from the nerves and endothelium is cell application was published in 2004 by Bochinski et needed to guarantee the efficacy of these agents. al. form the Lue laboratory in San Francisco (US)6. Several prevalent diseases reduce the bio-availability of NO and men with these underlying pathologies, What we have learned from a series of animal studies such as diabetes, commonly don’t respond as well to by diverse groups worldwide, is that stem cells PDE5i as patient without these comorbidities. improve functional recovery of ED in the setting of Available pharmacological treatments are effective in cavernous nerve injury, and that stem cell recruitment about 60% of patients and mostly well tolerated, but to the injured nerves and ganglia is important3 in some patients usage is limited by the frequent (See Figure 1). It is currently believed that stem cells occurrence of bothersome side effects, such as release local factors which can act trophic, headache, dyspepsia and muscular pains. immunomodulatory, antifibrotic or as stimulants or inhibitors of other biological processes. Hence, Loss of spontaneity mesenchymal stem cells are often referred to as an Most of these treatments take the spontaneity out of sex “injury-drugstore”7. Therapeutic application of SC has as it needs to be planned accordingly and this may feel also been investigated in chronic disease animal unnatural to some patients and their partners. Patients models of ED including aging, diabetes mellitus and experiencing treatment failure or adverse events now hyperlipidaemia. In chronic ED the mechanism of face no other choice than to resort to more invasive action is presumed to be by engraftment and options such as intracavernous injection, vacuum transdifferentiation, which differs from the paracrine devices and finally penile prosthesis implantation. action seen in acute disease models such as CNI. However, the evidence supporting this notion often Besides these well-known limitations to the currently relies on rather poor methodology3. available treatment armamentarium, these modalities are solely providing symptom relief and do not Stem cell therapy: too early, too risky? provide a permanent improvement of the condition or To come back to the initial question whether stem cell an increase in spontaneous erections by targeting the therapies in ED are too early or too risky, the answer underlying pathophysiological processes1. Notably is quite easy. Too early yes, too risky likely not. A however, in a 1998 study published at the time of variety of stem cell sources can be used for the marketing of the first available PDE5 inhibitor treatment of degenerative diseases and injury. So far, only bone marrow stem cells and adipose stromal sildenafil, the highest rank measure of treatment vascular fraction have been tested in ED clinical trials. success in terms of importance for ED patients was ’cure’2. A cure for ED resulting in spontaneous Bone marrow aspiration yield BMSCs for injection unassisted intercourse entices research into novel either after culture or uncultured as whole mononuclear fraction, of which 83 per 1 × 106 cells are regenerative treatment methods, and besides low-intensity shock wave application and platelet-rich mesenchymal stem cells (MSC). ADSCs from adipose plasma (both of which will be discussed in the tissue are easily harvested, either as a component of abstract sessions at this year’s Annual EAU Congress), the so-called ’stromal vascular fraction’ (stem cells in stem cell therapy is one of these options currently fat residue in the perivascular niche) of the adipose explored3,4. While a wealth of animal data have been tissue, containing around 560 MSC per 1 × 106 cells, or gathered over the last 15 years, human data are still as a purified stem cell population after successive scarce while in commercial clinics, autologous stem culturing. Adipose tissue is easily harvested in large cell transplantations are already offered at high cost amounts without major adverse events, and this can for this indication. Therefore the question arises: is it be done under local anaesthesia by liposuction. still too early or too risky to treat patients suffering Harvested fat tissue or lipoaspirate is processed from ED with stem cell therapy? mechanically and incubated with collagenase to remove the extracellular matrix. Mature adipocytes Stem cell therapy are separated by centrifugation, and pelleted SVF cells Stem cells are defined by their capability for selfisolated, which can then be re-injected in the patient renewal and differentiation into more specialised cell or used for isolation and expansion of ADSC. To date, types. The self-renewal trait means offspring from four published trials have been conducted in human patients. Bahk et al. performed a single arm phase 1 repeated division remains undifferentiated, and thus sustains a stem cell pool at the niche where these trial administrating umbilical cord stem cells in 7 stem cells are derived from. In ‘asymmetric division’ a diabetic patients awaiting penile implant, and 6/7 parent cell divides into an exact copy and one more showed improved erectile function8. In 2016, Haahr et 6

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Presence of adipose-derived stem cells (ADSC) at the rat major pelvic ganglion (MPG) 7 d after cavernous-nerve crush (as a model for post-radical prostatectomy erectile dysfunction) and intracavernous injection with 5-ethynyl-2-deoxyuridine (EdU)–labeled ADSC. S-100 protein was used to stain for nerve fibers, EdU staining for ADSC, and DAPI for nuclear staining. This image shows that even though stem cells where injected in the penis, they can be detected at the site of the injury several days after injection, and illustrates their migratory capacity.

al. treated 17 patients post-radical prostatectomy with intracavernous injection of adipose tissue derived regenerative cells and concluded that 6 months after injection, 8 (47%) men recovered their erectile function and were able to accomplish sexual intercourse9. All these men had also regained continence, which therefore may be a predictor for stem cell response or a proxy for nerve-sparing status. Overall, the IIEF-5 score gain was in the range of 10 points. In an update paper, this effect was sustained at 12 months10. Interestingly, in this study no effects were seen at 1 month post-injection which argues against placebo effect and pro induction/stimulation of regenerative processes. Rene Yiou and colleagues used intracavernous injection of bone marrow mononuclear cells in post-radical prostatectomy patients suffering from ED in the INSTIN phase ½ trial which included dose-finding. They concluded that erectile function was statistically significantly improved after 6 months in the patients given 1×109 cells, with IIEF-EF domain scores 18±8.3 vs 3.7±4.1 (baseline)11. No serious side effects occurred after a mean follow-up of 62.1 months in the first 12 patients, and no elevated risk for prostate cancer recurrences were seen12. Al Demour et al. contributed to the literature with a single arm phase 1 trial published in 2018, in which 4 diabetic ED patients experienced no side effects but an IIEF-EF improvement of about 12 points after intracavernous injection of autologous bone marrow derived mesenchymal stem cells13. All patients on placebo While these are all phase 1 open label non-controlled trails, the authors made claims on efficacy in all instances. This is troublesome as 1. a large proportion of these patients was prone to experience spontaneous ED improvement (inclusion relatively short after nerve sparing radical prostatectomy) and 2. placebo effect can be very prominent in ED research. To illustrate this, De Araujo and co-workers designed a prospective, controlled, single-blind, parallel-group study with 123 patients with ED: all patients got placebo treatment. Even though patients were aware of this, they experienced an average IIEF-EF score increase of 4 points14. The important lesson to learn from these data is that ED patients under active treatment in a study setting are likely to experience an improvement in their IIEF scores. Hence, single-arm studies and open label non-controlled trails are to be viewed as hypothesis generating and should not be included in an evidence review aimed at making practice recommendations or guidelines. In all studies that have been reported, side effects have been limited to minor side effects, such as mild pain or bruising at the site of harvesting (adipose tissue or bone marrow) or at the site of injection (penis). No recurrences of prostate cancer have been seen in patients following stem cell injections. Hence, the conclusion that we can draw today is that regenerative cell-based therapy for erectile dysfunction is probably safe and may be functionally beneficial. Data of phase 2 trials are underway to confirm these data in small RCTs, after which phase 3 trials are expected. Until we have the data from these trials, we cannot recommend this treatment in any of our ED patients, except for those included in trials.

References 1. Fode M, Hatzichristodoulou G, Serefoglu EC, Verze P, Albersen M. Low-intensity shockwave therapy for erectile dysfunction: is the evidence strong enough? Nat Rev Urol 2017;14:593–606. doi:10.1038/nrurol.2017.119. 2. Hanson-Divers C, Jackson SE, Lue TF, Crawford SY, Rosen RC. Health outcomes variables important to patients in the treatment of erectile dysfunction. J Urol 1998;159:1541–7. doi:10.1097/00005392-199805000-00037. 3. Soebadi MA, Milenkovic U, Weyne E, Castiglione F, Albersen M. Stem Cells in Male Sexual Dysfunction: Are We Getting Somewhere? - PubMed - NCBI. Sexual Medicine Reviews 2017;5:222–35. doi:10.1016/j. sxmr.2016.11.002. 4. Milenkovic U, Albersen M, Castiglione F. The mechanisms and potential of stem cell therapy for penile fibrosis. Nat Rev Urol 2018;214:199. doi:10.1038/s41585-018-0109-7. 5. Albersen M, Shindel AW, Mwamukonda KB, Lue TF. The future is today: emerging drugs for the treatment of erectile dysfunction. Expert Opin Emerging Drugs 2010;15:467–80. doi:10.1517/14728214.2010.480973. 6. Bochinski D, Lin GT, Nunes L, Carrion R, Rahman N, Lin C-S, et al. The effect of neural embryonic stem cell therapy in a rat model of cavernosal nerve injury. BJU Int 2004;94:904–9. doi:10.1111/j.1464-410X.2003.05057.x. 7. Caplan AI, Correa D. The MSC: An Injury Drugstore. Cell Stem Cell 2011;9:11–5. doi:10.1016/j.stem.2011.06.008. 8. Bahk JY, Jung JH, Han H, Min SK, Lee YS. Treatment of diabetic impotence with umbilical cord blood stem cell intracavernosal transplant: preliminary report of 7 cases. Exp Clin Transplant 2010;8:150–60. 9. Haahr MK, Jensen CH, Toyserkani NM, Andersen DC, Damkier P, Sørensen JA, et al. Safety and Potential Effect of a Single Intracavernous Injection of Autologous Adipose-Derived Regenerative Cells in Patients with Erectile Dysfunc... - PubMed - NCBI. EBioMedicine 2016;5:204–10. doi:10.1016/j.ebiom.2016.01.024. 10. Haahr MK, Harken Jensen C, Toyserkani NM, Andersen DC, Damkier P, Sørensen JA, et al. A 12-Month Follow-up After a Single Intracavernous Injection of Autologous Adipose-Derived Regenerative Cells in Patients with Erectile Dysfunction Following Radical Prostatectomy: An Open-Label Phase I Clinical Trial. Urology 2018;121:203. e6–203.e13. doi:10.1016/j.urology.2018.06.018. 11. Yiou R, Hamidou L, Birebent B, Bitari D, Lecorvoisier P, Contremoulins I, et al. Safety of Intracavernous Bone Marrow-Mononuclear Cells for Postradical Prostatectomy Erectile Dysfunction: An Open Dose-Escalation Pilot Study. - PubMed - NCBI. Eur Urol 2016;69:988–91. 12. Yiou R, Hamidou L, Birebent B, Bitari D, Le Corvoisier P, Contremoulins I, et al. Intracavernous Injections of Bone Marrow Mononucleated Cells for Postradical Prostatectomy Erectile Dysfunction: Final Results of the INSTIN Clinical Trial. Eur Urol Focus 2017;3:643–5. doi:10.1016/j.euf.2017.06.009. 13. Demour Al S, Jafar H, Adwan S, AlSharif A, Alhawari H, Alrabadi A, et al. Safety and Potential Therapeutic Effect of Two Intracavernous Autologous Bone Marrow Derived Mesenchymal Stem Cells injections in Diabetic Patients with Erectile Dysfunction: An Open Label Phase I Clinical Trial. Urol Int 2018;101:358–65. doi:10.1159/000492120. 14. De Araujo AC, Da Silva FG, Salvi F, Awad MC, Da Silva EA, Damião R. The management of erectile dysfunction with placebo only: does it work? - PubMed - NCBI. J Sex Med 2009;6:3440–8. oi:10.1111/j.1743-6109.2009.01496.x.

Saturday 16 March 10.00-14.00: Meeting of the EAU Section of Andrological Urology (ESAU) New medical and surgical options in andrological treatment: From molecular biology to surgery and from philosophy to ethics

Saturday, 16 March 2019

Herbal treatments for renal stones: Myth or fact? Mr. Samih Al-Hayek Cambridge University Hospitals, Cambridge (UK)

Urolithiasis is a common condition with an overall prevalence of 10.6% in men and 7.1% in women1 and a lifetime risk of about 13% in men and 7% in women in Western countries2. Acute presentation with pain (colic) peaks in young and middle-aged active people affecting their work and costing billions. It is a recurring problem with risk of 35-50% of having another episode in 5 years and 80% in 10 years. Medical treatment of stones There have been significant advances in diagnosing urinary tract stones with improved imaging and in their treatment. The various energy sources (LASER, ultrasound, pneumatic...), allowed us to use a wide range of minimally invasive treatment interventions including Extracorporeal Shockwave Lithotripsy (ESWL), ureteroscopy (optic and digital including robotic), standard, mini and ultra-mini percutaneous nephrolithotomy (PCNL).

“However, we only have limited options to treat stones with medical therapy and even less options for primary or secondary prevention.” We have reasonable knowledge about the pathophysiology and the theories behind the formation of crystals leading to the formation of stones, including genetic factors. However, we do not seem to be able to intervene medically to interrupt the formation cycle and avoid the final product (stones). Currently, we use potassium citrate to alkaline the urine - which mainly helps the dissolution and prevention of uric acid stones, to a much lesser degree, calcium oxalate but the dosage, duration and actual effect are not standardised. Thiazides can help to reduce the excretion of calcium in urine and allopurinol can reduce urate, but compliance is poor and overall outcome is variable. Is herbal therapy the answer? Those who have experienced renal colic once do not want to go through the same pain again. They seek advice on how to prevent stones, but urologists have limited options to offer. Patients find dietary advice difficult to follow and get frustrated when we keep advising them to increase fluid intake. Desperate to find a solution, they search the internet that is full of magic herbal ‘cure’ options for dissolving existing stones and stopping them from coming back. The options vary from something as simple as fruits and vegetables and natural products to more complex formulated tablets. But do they really provide ‘cure’ and are they safe to use?

Name of the Plant

Berberis vulgaris

Abutilon indicum

Daucus carota Linn.

Homonoia riparia Lour.

Plantago major L.

Bergenia ligulata

Achyranthes aspera

Dichrostachys cinerea

Ichnoccarpus frutescens L.

Ricinus communis Linn.

Beta vulgaris

Achyranthes indica Linn.

Dolichous biflorus

Lantana camara Linn.

Rotula aquatica Lour.

Boerhaavia diffusa

Aegle marmelose L.Corr.

Eleusine coracana Gaertn.

Lawsonia inermis Linn.

Solanum Indicum Linn.

Bryophyllum pinnatum

Aerva lanata

Equisetum debile Roxb.

Macrotyloma uniflorum Lam. Tinospora cordifolia Willd.(L.)

Bonnaya reprtans Spreng.

Amaranthus caudatus

Ficus carica L.

Melia azedarach L.

Tribulus terrestris L.

Cassia fistula L.

Amaranthus spinosus

Gomphrena celosioides Mart.

Mentha piperita L.

Xanthium strumarium L.

Centella asiatica (Linn.)

Amni visnaga Lam

Grewia flavescens A. Juss.

Musa paradisica Linn.

Cucumis sativus L.

Argemone maxicana

Herniaria hirsute Linn.

Ocimum sanctum

Cyanodon dactylon

Asperagus racemosus Willd.

Table 1: list of some herbs used for treating urolithiasis (courtesy of Dr. A. Trinchieri, IT) clinical studies in healthy volunteers at that point were studies to test citrus or cranberry juices which affect citrate excretion. A more recent systematic review by Elena Monti et al in 20154 has screened 541 articles and only 16 studies were eligible for inclusion. There was a significant degree of bias, heterogeneity and poor level of evidence with a small number of participants and a short study period. Most of the studies did not specify the stone composition, the imaging modality for follow-up, comparison data or clear randomisation method. Another review by Russel et al5 for the herbal remedies used in India and China also indicated that there are some products with reported efficacy, but the evidence is not strong enough to establish their use routinely. The results of those limited studies and reviews are summarised below: Effect on urine: • Calcium: Agropyrum repens and Wu-Ling-san had no significant effect on calcium excretion compared to placebo • Urate: the above herbal therapies also showed no significant effect on urate excretion • Oxalate: 1 out of 6 studies reported on intergroup differences and Agropyrum repens had no significant effect Effect on stone size: • Crataeva magna plus Musa paradisiaca versus placebo: • 33.04% reduction in size was documented in the active arm, versus a 5.13% increase in the placebo arm if original stones were less than 10 mm (p = 0.017) • In the large stone group (over 10 mm), no significant inter-arm differences in size reduction were found • A study comparing Orthosiphon grandiflorus infusions with citrate evaluated the rate of stone size reduction per year (ROSRPY) at different time points up to 18 months. No significant differences were found between treatment arms at any point • Celosia argentea, a putative litholytic agent, was found to reduce stone size to a greater extent than citrate, after 6 months of therapy (-2.57 mm versus -1.82 mm, respectively; p < 0.05)

Effect on stone number: • In an open-label study comparing Phyllantus niruri with no treatment in post-lithotripsy patients, 90.6% of patients treated with the plant Possible mechanisms of action extract were free of lower caliceal stones (without It is not clear how most herbal therapies work. Some residual fragments), compared to 70% of control of them play an antiseptic, diuretic role. Others could patients. The difference was statistically have anti-spasmodic or muscle relaxant effects. The significant (p = 0.03). Treatment did not perform available products (see table 1) are usually a mixture significantly better than no treatment in patients of several extracts, making it difficult to know what the affected by upper or middle caliceal calculi active component is. The lack of a standardised • Didymocarpus pedicellata (DP) combined with method of cultivating the plant and the process used another herb (Cystone). Pooled analysis showed for extracting the molecules could affect the active that the DP preparation was superior to placebo in component. Herbal products may not affect the inducing size reduction (mean difference: urinary risk factors (exertion of calcium, oxalate, urate, DP preparation, 4.93 mm lower; p = 0.02) and citrate) but might have a direct effect on the process of total clearance but there was no effect on crystallisation. D. Styraciflium was reported recently to excretion of calcium or oxalate (which was shown prevent oxidative renal cell injury and might serve as a in vitro). The study had a small patient number potential anti-urolithic drug. Herbs can also affect the and short duration matrix of the stone, renal parenchyma and urine transition through the nephrons but unfortunately no Compared to citrate: one knows. In 151 participants (75 in the phytotherapy arm, 76 in the citrate arm), Dolichus biflorus, Saxifraga ligulata, What is the available evidence? Crataeva nurvala, Celosia argentea, and other When looking for products sold freely on the internet, components were compared to citrate as a single the majority claim high success with positive feedback agent. Data were obtained after 3 months of therapy. and no side effects. They don’t provide details on The citrate group showed a significantly higher supportive data or clinical trials. If found, the evidence decrease in stone size by 0.42 mm (p < 0.0001). Citrate is based on observational in vitro studies, using cell has significantly reduced the excretion of urate cultures or animal models. A small number of clinical compared to herbal products (p < 0.0003) with no trials have taken place in humans. A review by difference in calcium and oxalate excretion between Butterweck and Khan in 20093 indicated that the only the arms. Saturday, 16 March 2019

Phyllanthus niruri L.

Side effects A few studies did not mention anything about possible side effects. Eight studies reported no adverse events or side effects, nor any complaints from treated patients. One study reported nausea, giddiness, epigastric pain. Those taking citrate, reported fatigue and loss of appetite in 26% patients with no complaints in the herbal agent arm (no statistics available). In the Singh 2011 study, citrate induced upper GI disturbances with no adverse events were recorded in the cohort treated with herbal. In the Premgamone 2009 study on the effect of Orthosiphon grandiflorus (OG), placebo showed significantly higher adverse effects after 14 days of therapy (treatment arm 2.8% patients, placebo arm 17.5% patients with adverse events; p = 0.03). In the Shekar Kumaran and Patki trial, vomiting, gastric irritation and dyspepsia were recorded in three different patients belonging to the group treated with the DP preparation. Conclusion There is a large number of advertised herbal products that claim to be a cure for urolithiasis patients by dissolving existing stones or preventing new ones in the future. There is no clear supportive scientific evidence for many of those products. The mode of action, the active component, the way of extraction are not clear and the dose and duration of treatment are not standardised or validated. There are some clinical trials that included small numbers of participants over a short duration, but they are of low quality, have a high level of heterogeneity and risk of bias.

“There is an unmet demand for medical therapy to help dissolve stones and prevent recurrences. Herbal products might have a potentially promising role.”

The herbal products did not seem to have any effect on calcium, oxalate or urate exertion in the urine. Herbal formulations containing Didymocarpus pedicellata (DP) combined with other herbal agents were superior to placebo in inducing size reduction and total clearance of renal and ureteral stones, whereas pooled analysis of three studies with low quality of evidence showed that citrate treatment was able to decrease the mean stone size and urate excretion more than phytotherapy. There is an unmet demand for medical therapy to help dissolve stones and prevent recurrences. Herbal products might have a potentially promising role. However, in the current format it is not safe to endorse the available products until large wellstructured studies look into their efficacy and safety. These studies are urgently needed to help guide our desperate stone patients. References 1. Charles D. Scales Jr., Alexandria C. Smith, Janet M. Hanley, Christopher S. Saigal, Urologic Diseases in America Project. Prevalence of kidney stones in the United States. Eur Urol. 2012;62:160-5 2. Pearle MS, Calhoun EA, Curhan GC; Urologic Diseases of America Project. Urologic diseases in America project: urolithiasis. J Urol. 2005; 173:848-57 3. Butterweck V, Khan S. Herbal Medicines in the Management of Urolithiasis: Alternative or Complementary? Planta Med 2009; 75: 1095–103. 4. Elena Monti, Alberto Trinchieri, Vittorio Magri, Anne Cleves, Gianpaolo Perletti. Herbal medicines for urinary stone treatment- a systematic review. Archivio Italiano di Urologia e Andrologia 38 2016; 88, 1 5. Kasote DM, Jagtap SD, Thapa D, Khyade MS, Russell WR. Herbal remedies for urinary stones used in India and China: A review. J Ethnopharmacol. 2017 May 5;203:55-68

Rest of references available on request Saturday 16 March 10.00-14.00: Meeting of the EAU Section of Urolithiasis (EULIS) Management of urinary stones: Where are we in 2019?

13-15 February 2020, Berlin, Germany

Application deadline: 1 November 2019

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From the EAU Scientific Congress Office

Culig: “Important to invest more in experimental urology” Newly-appointed Professor of Experimental Urology reflects on achievements of SCO Prof. Zoran Culig (Innsbruck, AT) is a long-serving member of the Scientific Congress Office (SCO), advising on abstract selection and the design of the scientific programme for the EAU’s Annual Congress since 2012. He was recently promoted to Professor of Experimental Urology at Innsbruck Medical University, one of four people to hold this position in Europe.

“For instance, during the Congress in London (EAU17), the experts who represented different fields gave wonderful presentations and showed all of us how urological research should be developed.”

“In my view, the Scientific Congress Office is primarily responsible for preparing the program of the Annual Congress. For this purpose, there are two meetings during the year. During the first meeting, plenary and thematic sessions are discussed. The second meeting, closer to the congress is more important for selection of abstracts.”

“With considerable progress in worldwide scientific research, the EAU’s Scientific Congress Office could, in my opinion, become involved in more activities in future. Scientific policy in Europe could also be discussed during the committee’s meetings, especially if we consider the fact that in the United States there is much more money for multi-institutional collaborations. Unfortunately, we do not see the same Prof. Zoran Culig (right) trend in Europe and joint projects between urological researchers from different nations is very difficult at present. The SCO could potentially help facilitate this.” publications in oncology, pathology, and endocrinology journals but also to some prestigious Experimental Urology awards.” Starting on January 1st, Prof. Culig was appointed Professor of Experimental Urology at Innsbruck From his new academic position, Prof. Culig is looking University. Prof. Culig was appointed based on his to increase the involvement of urology researchers at previous work in urological research, covering a earlier stages of drug development: variety of topics. “I strongly believe that basic and translational “The main part of my earlier research was devoted to researchers have to be involved in studies on possible studies on therapy-resistant prostate cancer, in drug resistance at earlier stages of drug development. particular to endocrine therapy and chemotherapy It should be clear to all participants in the process resistance. With my team, I was able to demonstrate that we have many targets in urological oncology and the critical role of cytokines and their suppressors in many potential novel drugs. However, the results of prostate carcinogenesis and progression. We also pre-clinical research are sometimes not considered in investigated novel pathways related to oncogenic role specific discussions and novel trials. With the help of of androgen receptor in advanced prostate cancer.” the EAU, our research in that field may become more visible, also for clinical cancer therapy.” “My team and I have developed original models for prostate cancer resistance, some of which are used by Prof. Culig is one of four Professors of Experimental many colleagues in Europe, North America and Asia. Urology in Europe and considers his appointment a This research led me not only to a large number of significant honour.

Prof. Culig joined the SCO at the invitation of then-EAU Secretary General Prof. Abrahamsson and SCO Chairman Prof. Stenzl. “I cover a large number of basic and translational research topics, in particular those in prostate, urothelial and renal oncology.” “For a while, I was both chairman of the EAU Section of Urological Research (ESUR, now chaired by Prof. Kerstin Junker) and a member of the SCO. This was a very challenging time period with many meetings and tasks to be done for the European Association of Urology.” Looking back on seven years on the SCO, Prof. Culig is particularly proud of the level that the congress’s thematic sessions on urological oncology reached. “From feedback received from urologists and urology-related scientists, I am pleased to hear that we brought thematic sessions in urological oncology to a very high level. I liked discussions between basic and clinical scientists in which we addressed key issues of therapy resistance, such as cellular stemness.”

As urology and specifically urological research continues to evolve, Prof. Culig considers the time ripe for a shifting role of the SCO:

“I am very grateful to Professor Wolfgang Fleischhacker, Rector of Innsbruck Medical University and his Vice Rectors for selecting me for the professorship. It will give us more stability to improve plans for future research and to coordinate research activity, submissions of grant applications and publications.” “My goal is to keep a relatively high number of academic positions in the field of Experimental Urology in Innsbruck and to offer new opportunities for career development. In particular, a stay abroad for outgoing PhD researchers will be arranged. Other professorships have been established in the Netherlands, United Kingdom and Finland, and all of these positions are important to provide appropriate research environment in Europe. “Because of a high prevalence of urological cancers in Europe, it may be very important to invest more in experimental urology professorships in other countries.”

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Saturday, 16 March 2019

Is there evidence on how to treat late-onset hypogonadism? The main causes are obesity, inactivity and chronic diseases Prof. G.R. Dohle Dept. of urology Erasmus MC Rotterdam (NL)

Male hypogonadism is a condition characterised by symptoms and low testosterone levels. It can occur early in life and cause congenital malformations of the male genitalia (cryptorchidism, hypospadias, short anogenital distance), delayed puberty and male undervirilisation in adult life. With age, testosterone levels decline. In some men this results in late onset hypogonadism (LOH). Symptomatic male hypogonadism occurs in 2 to 5% of men above 50 years of age1.

Symptoms With age testosterone will decline with 0.5 to 1.5% per year2. Also, Sex Hormone Binding Globulin (SHBG) will increase with age. As a consequence, bioavailable (free) testosterone will reduce further. This may cause symptoms of low testosterone, but at least half of the men with low testosterone are without hypogonadal symptoms. Furthermore, symptoms associated with male hypogonadism also occur in men with normal testosterone. Table 1 highlights the symptoms of late onset hypogonadism. Common symptoms of men with low testosterone are sexual dysfunction, loss of vigour, frailty, insomnia, unexplained anaemia, cognitive dysfunction and depression. Only sexual symptoms have a significant association with low testosterone, other symptoms are less specific. Symptoms of testosterone deficiency are also depending on individual androgen sensitivity: some men may need more testosterone than others. Testosterone deficiency is common in men with obesity, chronic diseases, men with low-trauma fractures, low sperm count, testicular dysfunction and small testes. In these men testosterone measurement can be considered. Current guidelines, however, advise against routine screening for hypogonadism in ageing men.

In contrast to testosterone therapy for congenital forms of male hypogonadism, testosterone treatment in ageing men is controversial, because of unclear indications for replacement and potential risks in older men. Ageing men develop low testosterone levels mainly due to overweight, inactivity and chronic “Restrict the diagnosis of testosterone diseases. The first advice for these patients is to deficiency to men with persistent improve their lifestyle: exercise, reduce weight and manage comorbidities as well as possible. This may symptoms suggesting hypogonadism” result in normalisation of testosterone levels and Source: EAU guidelines on male hypogonadism 2017 reduce associated health risks, such as type 2 diabetes mellitus and cardiovascular diseases. Indications for therapy A low testosterone level is considered a biomarker for The aim of testosterone therapy (TT) is to treat symptoms associated with low testosterone and to an impaired general health status and is associated improve quality of life in hypogonadal men. with obesity, metabolic syndrome, an increased risk Randomised controlled trials (RCTs) on testosterone for cardiovascular diseases and sexual dysfunction. therapy have raised doubts about the indications for Treatment of these health problems seems more the treatment of low testosterone in ageing men. important than just testosterone replacement. A recent series of RCTs have provided insight into the Furthermore, weight reduction will increase true indications for TT in ageing men: sexual testosterone levels, decrease the risks for type 2 symptoms, such as erectile dysfunction and loss of diabetes mellitus, cardiovascular incidents and libido and sexual satisfaction, all improve with TT3,4. sudden death. For patients with type 2 diabetes mellitus and erectile dysfunction this was only the case in men with “Testosterone treatment may improve testosterone levels < 8mmol/L.

symptoms, but many hypogonadal men have a chronic illness and are obese. Weight reduction, lifestyle modification and good treatment of comorbidities can increase testosterone and reduce associated risks for diabetes and cardiovascular diseases”

Source: EAU guidelines on male hypogonadism 2017

Table 2: Contra-indications for testosterone therapy according to the Endocrine Society guidelines (from reference 5) • Active prostate cancer, PSA > 4,0 ng/ml • Elevated haematocrit • Untreated severe obstructive sleep apnoea • Uncontrolled heart failure

Clinical symptoms and signs suggestive of androgen deficiency: Reduced testis volume Male-factor infertility Decreased body hair Gynaecomastia Decrease in lean body mass and muscle strength Visceral obesity Metabolic syndrome Insulin resistance and type 2 diabetes mellitus Decrease in bone mineral density (osteoporosis) with low trauma fractures Mild anaemia Sexual symptoms: Reduced sexual desire and sexual activity Erectile dysfunction Fewer and diminished nocturnal erections Cognitive and psychovegetative symptoms: Hot flushes Changes in mood, fatigue and anger Sleep disturbances Depression Diminished cognitive function Saturday, 16 March 2019

Formulation

Administration

Advantages

Disadvantages

Testosterone undecanoate

Intramuscular; one injection every ten to fourteen weeks

Steady-state testosterone levels without fluctuation

Long-acting preparation that cannot allow drug withdrawal in case of onset of side-effects

Transdermal testosterone

Gel; daily application

Steady-state testosterone level without fluctuation

Risk of interpersonal transfer

Gels and injections are the mostly prescribed applications (see table 3). The aim is to restore testosterone to physiological levels. Guidelines advice to start with a short-acting application first to observe improvement of symptoms and monitor side effects. Risk of testosterone treatment Testosterone treatment is associated with some potential risk factors: an increase of red blood cells and an elevation of prostate specific antigen (PSA) may occur. The consequences of these laboratory observations are unclear, but erythrocytosis may result in an increased risk for thrombosis and an elevation of PSA indicate prostate growth and a higher chance of developing prostate cancer. Current RCTs, however, are too small and follow-up is too short to estimate the associated risk of developing thrombosis and prostate cancer under TT. Observational studies do not indicate a higher risk for thrombosis or prostate cancer in men undergoing TT, but monitoring haematocrit and PSA remains advisable. Contraindications for TT are locally advanced and metastatic prostate cancer. Also, men with an active wish for children should not use testosterone, since it inhibits spermatogenesis.

“Do not use testosterone therapy in patients with male infertility and active child wish since it may suppress spermatogenesis”

“There is no substantive evidence that testosterone treatment, when supplemented to the normal physiological range, is related to the development of major adverse cardiovascular events” Source: EAU guidelines on male hypogonadism 2017 Key points 1. The main causes of male hypogonadism are obesity, inactivity and chronic diseases 2. Sexual symptoms in ageing men are most predictive for low testosterone 3. Life style changes are the first-line therapy for the treatment of late onset hypogonadism: lose weight, become active, treat comorbidities as good as possible. This may normalise testosterone levels and reduce associated health risks, such as type 2 diabetes mellitus and cardiovascular diseases. 4. Indications for screening and treatment of LOH are multiple symptoms of hypogonadism, sexual symptoms, and to a lesser extent loss of vigour and depressive symptoms. 5. Men on testosterone treatment should be regularly evaluated for prostate health, erythrocytosis and cardiovascular symptoms.

Source: EAU guidelines on male hypogonadism 2017 Key references

• Severe lower urinary tract symptoms

Table 1: symptoms of late onset male hypogonadism (from reference 1)

Table 3: Commonly used preparations for testosterone replacement therapy

• Myocardial infarction or stroke within the last 6 months • Thrombophilia

In contrast, one RCT comparing phosphodiesterase-5 inhibitors (PDE5i) with PDE5i and TT did not show an additional benefit of TT over PDE5i alone5. Men with erectile dysfunction can first be treated with a PDE5i, since this is an effective treatment with little side effects. In case of poor response to PDE5i testosterone is measured and, if low, TT is added. It will take at least 3 months of TT before improvement of sexual function will occur. Other symptoms that may improve under TT are walking distance, mood, depressive symptoms, anaemia, and bone density, but all to a very modest degree. TT did not improve vitality and cognition in recent RCTs.

“Treatment should be restricted to adult men with low testosterone and consistent and preferably multiple signs and symptoms of hypogonadism following unsuccessful treatment of obesity and comorbidities”

Cardiovascular risks Hypogonadal men have an increased risk of obesity and cardiovascular events. This relationship could be explained by a poorer health condition in men with low testosterone. However, also men with congenital forms of hypogonadism, such as Klinefelter patients, have an increased risk for obesity and associated health problems. A randomised trial indicated that TT may result in a higher risk of cardiovascular incidents, especially in men over 65 years of age. Also, in one study TT was associated with an increase in coronary artery plaque volume. Large retrospective and observational studies could not confirm these observations: meta-analyses of observational and randomised studies do not show an increased risk for major cardiovascular events (MACE) in men undergoing TT7. Also, The European Medicines Agency (EMA) concluded that there is no consistent evidence of an increased risk of coronary heart disease associated with TT in hypogonadal men8. Still, men with uncontrolled cardiovascular disease should first consult a cardiologist before starting TT, since it may result in heart failure in these men. Monitoring of men treated with testosterone consists of clinical assessment, haematocrit (not exceeding 0.54), PSA (not exceeding 4.0 ng/ml) and testosterone levels maintained within the mid-normal healthy range.

Conclusions Reversing obesity is The Key Factor

1. Dohle GR, et al. EAU guidelines on male hypogonadism, 2017 edition 2. Kaufman, J.M., et al. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev, 2005. 26: 833. 3. Snyder, P.J., et al. Effects of Testosterone Treatment in Older Men. N Engl J Med, 2016. 374: 611.. 4. Wu FC, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med 2010 363(2): p. 123-35. 5. Spitzer M, et al. Effect of testosterone replacement on response to sildenafil citrate in men with erectile dysfunction: a parallel, randomized trial. Ann Intern Med. 2012 20;157(10):681-91. 6. Bhasin S, et.al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab, 2018, 103(5):1715–1744 7. Corona, G., et al. Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis. Expert Opin Drug Saf, 2014. 13: 1327. 8. European Medicines Agency. No consistent evidence of an increased risk of heart problems with testosterone medicines. Available at: www.ema.europa.eu/docs. Accessed 10 January 2018.

Key points The main causes of adult onset male hypogonadism are obesity and chronic diseases: testosterone is a biomarker for male health Losing weight and improving lifestyle are the most important goals in managing male hypogonadism, since this will increase testosterone and reduce the chance of cardiovascular incidents and type 2 diabetes.

Source: EAU guidelines on male hypogonadism 2017 Several applications of testosterone are available for TT, including oral preparations, transdermal gels and intramuscular injections. Comparative studies of different applications are not available.

Sexual symptoms are most predictive for male hypogonadism and are currently the main indication for testosterone therapy.

EUT Congress News

Beyond BCG in non-muscle invasive bladder cancer Overview of non-muscle invasive bladder cancer treatments over the past decade Prof. Ashish M. Kamat Professor of Urologic Oncology (Surgery) University of Texas MD Anderson Cancer Center (US) akamat@ mdanderson.org

Justin T. Matulay Urologic Oncology Fellow University of Texas MD Anderson Cancer Center (US) jtmatulay@ mdanderson.org Intravesical administration of bacillus CalmettéGuerin (BCG) has been the cornerstone of management for non-muscle invasive bladder cancer (NMIBC), the 10th most common malignancy worldwide1, for nearly half a century since the original work performed by Alvaro Morales in the 1970s2. To this day it remains first-line intravesical therapy for intermediate and high-risk NMIBC with proven efficacy over other agents in direct head-tohead comparisons. Despite its status as the most effective immunotherapeutic drug in oncology, BCG has well-known limitations and drawbacks. The randomised controlled trials demonstrating the superiority of BCG do so with regard to tumour recurrence and progression but results on survival outcomes are less robust. Additionally, in order to derive these benefits BCG must be given as maintenance therapy for 1 to 3 years, which some urologists find hard to do despite evidence that, most patients can complete a full course of 3 year maintenance3. Failure of BCG therapy, either because of intolerability or lack of efficacy, leaves the patient in the precarious position of choosing between radical cystectomy (RC) and bladder preservation strategies with varying efficacy. Those patients with high-grade carcinoma in situ (CIS) and/or T1 disease face a risk of progression to life-threatening muscle-invasive bladder cancer (MIBC) that is over 50%. What follows is a review of the current options for BCG failure, including clinical trials and experimental therapies, as well as potential alternatives and adjuvants for the treatment-naïve patient (see Table). Risk Stratification There is a wide spectrum of NMIBC, ranging from small, low-grade papillary tumours to T1 tumours widely invading the lamina propria and subepithelial lymphatics. Risk stratification is paramount in determining whether or not an individual patient should be offered BCG therapy with the goal of minimising toxicity for those at lowest risk of progression while maximising efficacy in higher risk disease. Certain clinicopathological characteristics – high volume T1, T1 with CIS, persistent T1, lymphovascular invasion and/or variant histology – denote a very high-risk subgroup that may benefit from an immediate RC, in spite of the morbidity and impact on quality of life4,5. These special circumstances aside, the urologist is more likely to be seeking alternatives to BCG therapy following therapeutic failure. Definition The term ‘BCG failure’ has taken on several different meanings throughout the years, leading to a heterogeneous cohort of patients with this designation included in clinical trials studying BCG alternatives. On the advice of experts such as the Group at ASCO GU and the International Bladder Cancer Group (IBCG), the Federal Drug Administration of the United States has adopted a unified definition of BCG failure. An important new subgroup consists of the ‘BCG unresponsive’ tumours, where further BCG instillations are unlikely to prove beneficial6. In this population, radical cystectomy is the only proven salvage therapy, and as such, patients entering clinical trials should not be offered a placebo treatment as a control arm, thus making single-arm studies acceptable7. 10

EUT Congress News

Intravesical Chemotherapy Intravesical chemotherapy is the most frequently studied option in BCG failure; the only FDA-approved drug is valrubicin (Valstar®) but it has minimal efficacy. Other agents include gemcitabine, docetaxel, paclitaxel, cabazitaxel, cisplatin and combination therapies. In small, early phase trials, initial response rates with single agents are often very good (over 50%), however, after 1 year of therapy, durable responses range from only 16 to 40%7. The combinations hold more promise: intravesical gemcitabine/docetaxel has demonstrated good durability – 34% freedom from HG recurrence at 2 years8. Triple therapy with cabazitaxel/gemcitabine/ cisplatin has also been reported9. Our practice, at the time of writing, is to offer combination intravesical chemotherapy with gemcitabine and docetaxel to patients with BCG unresponsive disease who refuse radical cystectomy and are not candidates for clinical trials. Nanoparticles can be loaded with specific drugs to increase delivery to the urothelium over the solubilised drug alone. Albumin-bound nanoparticles loaded with paclitaxel and delivered intravesically had an initial CR rate of 36%, although only 18% remained disease-free after 3 years10. Docetaxel (NCT02982395) and rapamycin (NCT02009332) loaded nanoparticles are being studied in early phase human trials.

Table 1: Alternatives and adjuvants for BCG-unresponsive non-muscle invasive bladder cancer

Radiofrequency-induced chemohyperthermia Radiofrequency-induced chemohyperthermia (CHT) with mitomycin C (MMC) has shown benefits over MMC alone in an open-label RCT as initial treatment for intermediate and high-risk NMIBC patients (2-year RFS 82.9% versus 42.5%, p < 0.01)11. However, when compared to BCG in another RCT, there was no statistically significant difference in the 2-year RFS endpoint between CHT and BCG (78.1% versus 64.8%, p = 0.08), each given with 1 year of maintenance therapy12. Limited data exist for CHT in the setting of truly BCG unresponsive disease, but in a post-hoc analysis from a prospective study of CHT, 55 BCG unresponsive patients were observed to have 1-year RFS of 47% and a median disease-free interval of 17.7 months13.

more robustly to intravesical BCG exposure if the patient is first exposed systemically to an intradermal BCG vaccine. Specially designed vaccines containing tumour-specific proteins purported to increase the immune response of the tumour microenvironment have been studied in trials in combination with intravesical BCG. PANVAC (containing viral transgenes for CEA and MUC-1 plus co-stimulatory molecules)19 and HS-410 (containing heat shock proteins)20 have both reported data showing an enhanced immune response in tumour tissue. A genetically modified BCG vaccine, VPM1002, shows increased immunogenicity and is being studied in a phase I/II study. The vaccine Ty21a has been in use for several decades against typhoid and is now being studied clinically as an intravesical alternative to BCG (NCT03421236).

Intravesical Chemotherapy Mitomycin C Gemcitabine + Docetaxel Cabazitaxel + Gemcitabine + Cisplatinum

Gene Therapy CG0070 (oncolytic adenovirus) Instiladrin (rAd-IFN/Syn3) Inodiftagene vixteplasmid (BC-819)

Immunotherapy Atezolizumab Durvalumab Nivolumab Pembrolizumab ALT-801 ALT-803 Intradermal priming with BCG Interferon-alpha Indoleamine 2,3-dioxygenase 1 Lenalidomide M. phlei cell wall–nuclei acid complex

Nanoparticle Encapsulation Docetaxel (polymeric micelles) Paclitaxel (nanoparticle albumin bound) Rapamycin (nanoparticle albumin bound)

Chemohyperthermia + Intravesical Chemotherapy Combat® Synergo® Chemoradiation (Trimodal Therapy)

Immunotherapeutic Agents The immune checkpoint inhibitors with demonstrated efficacy in metastatic bladder cancer are being studied in BCG unresponsive NMIBC. Thus far, only the KEYNOTE-057 phase II trial has reported interim Interferon-alpha results at ESMO in 2018. Here, the PD-1 inhibitor Interferon-alpha (IFN- ) has been studied as pembrolizumab (Keytruda®) was studied in BCG monotherapy or in conjunction with BCG. The only unresponsive patients with CIS (+/- Ta or T1)21. Out of randomised controlled trial comparing BCG plus 103 patients 31% had a durable complete response IFN- combo therapy to BCG alone for BCG-naïve with a median follow-up of 14 months, without any patients found the combination to be non-superior14. progressions to MIBC or metastasis. These results led When used in the setting of BCG failure, IFN- may to initiation of a phase III trial comparing the be useful when added to repeat BCG induction combination of systemic pembro plus intravesical BCG therapy. The best salvage responses appear to occur to re-induction with BCG alone (KEYNOTE-676; NCT in patients whose diseases were initially responsive to 03711032). The side effect profile of systemic BCG but then developed a late (> 1 year) recurrence. immunotherapy is certainly acceptable for metastatic Gene therapy with rAd-interferon- /Syn3 patients, but the potential for serious events, even (Instiladrin®) uses an adenoviral vector to deliver the death, exists. Thus, this means that pursuing this IFN- gene to the urothelial cell where it can be treatment strategy for NMIBC requires a certain incorporated into the genome and natively expressed. element of caution, although this can be weighed Single-arm phase II data are encouraging (35% RFS against the 2-5% mortality risk of RC, the current at 1 year) and a phase III trial is currently underway15. standard therapy for BCG failures. Other immune checkpoint agents targeting the programmed death-1 Other gene-based therapies pathway (anti-PD-L1/PD-1 antibodies) are also being Other gene-based therapies in development include studied in phase I, II, and III trials including those which target cancer cells via defective signalling atezolizumab (NCT02792192; NCT02844816), pathways to deliver oncolytic adenovirus (e.g. nivolumab (NCT03519256), and durvalumab CG0070)16. A multicentre, phase II trial of CG0070 (NCT03258593; NCT03528694). These may be used demonstrated a 47% complete response rate at 6 alone or in combination with BCG, radiotherapy or months but no long-term data is available at this other agents such as indoleamine 2,3-diogenase 1 time17. Another gene therapy that is being studied is (IDO1) inhibitors. BC-819 (Indoiftagene vixteplasmid), a recombinant dsDNA plasmid that delivers diphtheria toxin-A (DTA), Lenalidomide, ALT-801 and ALT-803 are non-PD-1 and has shown 33% CR rate for previously treated based immunotherapies under investigation for use in intermediate risk NMIBC in a phase IIb study NMIBC. Lenalidomide, derived from thalidomide, is (NCT00595088). Oportuzumab monatox (vicinium) an oral medication with direct tumouricidal, consists of Pseudomonas exotoxin linked to an antiangiogenic and immunomodulatory effects, which anti-EpCAM antibody, which helps to target neoplastic may prove useful as an adjuvant to BCG therapy cells due to EpCAM overexpression typically found in (NCT01373294)22. ALT-801 is a recombinant fusion high-grade NMIBC. The substance has made it to protein comprised of IL-2 linked to a T-cell receptor phase III trials with a 42% CR rate for CIS patients at against cell surface p53 tumour antigen with phase I the preliminary 3-month time point (NCT02449239)18. data in combination with gemcitabine for patients The fibroblast growth factor receptor 3 (FGFR3) is failing BCG (NCT01625260). The immune stimulant overexpressed in a large proportion of NMIBC and IL-15 is closely related to IL-2 and has been turned into FGFR3-inhibitors, including BGJ398, are being tested an IL-15/IL-15R complex protein (ALT-803) as an for efficacy in high-risk disease (NCT02657486). agonist of endogenous CD8+ cells with a potential for enhanced BCG responsiveness (NCT03022825)23. Use of BCG adjuvants Enhancing the immune response through the use of Trimodal Therapy BCG adjuvants is another strategy. The phase III SWOG A potential role for chemoradiation in NMIBC is being S1602 trial for BCG-naive patients is based on the idea studied by the Radiation Therapy Oncology Group that the immune system can be primed to respond which has recently completed enrolment for a phase II

“BCG has well-known limitations and drawbacks.”

Targeted Therapy BGJ398 (FGFR3 inhibitor) Vincinium (oportuzumab monatox, VB4-845) Vaccine PANVAC Vesigneurtacel-L (HS-410) VPM1002BC Ty21a Other Electromotive drug administration Photodynamic therapy

study (RTOG 0926; NCT00981656) of HG T1 disease that has not responded to at least one BCG induction course. Additionally, photodynamic therapy (PDT) with newer, improved sensitising agents are being studied in early clinical trials in Canada. Conclusion The landscape for treatment of NMIBC has evolved rapidly over the past decade with the recognition of the need to move beyond BCG, not only to salvage patients who fail BCG therapy but also for who cannot tolerate it. Notably, the recent spurt in agents has been spurred not only by better understanding of the mechanisms that affect resistance to BCG therapy but also because of unified definitions of the different post-BCG disease states. Approaches using combination chemotherapy regimens, improved drug delivery, gene manipulation and immunotherapy all hold promise for the future of bladder preservation in this patient population. This is even more relevant as we currently are facing a worldwide shortage of BCG. Editorial Note: Due to space constraints the reference list has been shortened. Interested readers can email at communications@uroweb.org to request for the full list. References 1. Bray, F., et al., Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018. 2. Morales, A., D. Eidinger, and A.W. Bruce, Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol, 1976. 116(2): p. 180-3. 3. Oddens, J., et al., Final Results of an EORTC-GU Cancers Group Randomized Study of Maintenance Bacillus Calmette-Guérin in Intermediate- and High-risk Ta, T1 Papillary Carcinoma of the Urinary Bladder: One-third Dose Versus Full Dose and 1 Year Versus 3 Years of Maintenance. European Urology, 2013. 63: p. 462-472. 4. Babjuk, M., et al., EAU Guidelines on Non-Muscleinvasive Urothelial Carcinoma of the Bladder: Update 2016. Eur Urol, 2017. 71(3): p. 447-461. 5. Denzinger, S., et al., Early versus deferred cystectomy for initial high-risk pT1G3 urothelial carcinoma of the bladder: do risk factors define feasibility of bladdersparing approach? Eur Urol, 2008. 53(1): p. 146-52. 6. Kamat, A.M., et al., Definitions, End Points, and Clinical Trial Designs for Non-Muscle-Invasive Bladder Cancer: Recommendations From the International Bladder Cancer Group. J Clin Oncol, 2016. 34(16): p. 1935-44. 7. Kamat, A.M., et al., BCG-unresponsive non-muscleinvasive bladder cancer: recommendations from the IBCG. Nat Rev Urol, 2017. 14(4): p. 244-255. 8. Milbar, N., et al., Oncological Outcomes of Sequential Intravesical Gemcitabine and Docetaxel in Patients with Non-Muscle Invasive Bladder Cancer. Bladder Cancer, 2017. 3(4): p. 293-303. 9. DeCastro, G.J., et al., A phase I trial for the use of intravesical cabazitaxel, gemcitabine, and cisplatin (CGC) in the treatment of BCG-refractory nonmuscle invasive urothelial carcinoma of the bladder. Journal of Clinical Oncology, 2017. 35(6_suppl): p. 313-313.

Saturday 16 March 08.15-10.00: Plenary Session 1 Bladder cancer in the young patient: Unique aspects

Saturday, 16 March 2019

EASE registry: Opportunity to define natural history of RCCs Pursues development of predictive biomarkers Prof. Alessandro Volpe Ass. Professor of Urology University of Eastern Piedmont Novara (IT) ale.volpe@me.com In collaboration with the EAU Research Foundation, 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) who are managed with active surveillance (AS). This observational registry is called European Active Surveillance of Renal Cell Carcinoma (EASE) study. On Sunday March 17 at 9 am, during the annual EAU congress in Barcelona, an investigator meeting will take place to present the status of the study to urologists from the institutions that have already joined the project or would like to participate. Rationale 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 was obtained only in a proportion of cases. EASE is the first multicentre prospective study on AS that includes only patients with histologically proven RCC by percutaneous biopsy at enrolment and has therefore the potential to clearly define the oncological outcomes and the clinical role of this conservative approach for 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 different aggressiveness and metastatic potential at diagnosis, thereby enabling the urologist to choose the most suitable conservative or active management approach for the individual patient. EASE will contribute to reach 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. 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 and to demonstrate that overall survival in this population is not significantly different compared to the overall survival of the general population without RCC and with similar age and comorbidities; The secondary objectives are: • the growth rate and progression rate of small renal tumours in AS; • the cancer-specific and progression-free survival of renal tumours in AS; • the identification of clinical and pathological predictors of fast growth rate and progression for small RCCs; • the identification of serum, urine and tissue predictive markers of fast growth rate and progression of small RCCs.

RCC. Biopsies are carried out under local anaesthesia with ultrasound or CT guidance. At baseline, information is collected on demographics, medical history, tumour-related symptoms and performance status. A physical examination is performed and blood and urine is collected. Abdominal imaging is performed by contrast-enhanced 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 yearly 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 quality of life and anxiety by dedicated questionnaires. 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 centralised at the Francis Crick Institute in London, where a group of scientists led by Dr. S. Turajlic is leading the research in this field. Electronic Case Report Form The web-based database management system Marvin is used for collection of patient data. The system is intuitive and easy to use.

Study status More than 65 institutions across Europe and some Patient population from other continents have shown interest to include A total of 400 patients with small, incidentally patients in the EASE registry. Seventeen centres from detected, histologically confirmed RCCs will be included and data related to the oncological outcomes Italy, the Netherlands, Spain, Austria, Finland, Iceland, Lithuania, Turkey and Argentina already obtained of the AS approach will be collected. ethics approval and started recruiting patients. Several institutions in the United Kingdom will join Study procedures A percutaneous biopsy of the renal mass is performed soon. Other countries will follow shortly. Please join us. New sites are welcome! in all cases to histologically confirm the diagnosis of

If you are interested to participate, please contact the EAU Research Foundation on researchfoundation@ uroweb.org Study team Principal Investigator: Alessandro Volpe, email address: ale.volpe@me.com Associate Professor of Urology University of Eastern Piedmont Novara, Italy 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

Sunday 17 March: 09.00: EAU RF EASE Study Investigators Meeting Room 8.19 (Blue Area) Fira Gran Via

Platinum Picture Perfect Please come to the European Urology booth #L04 and have your Platinum Postcard created and posted online. Daily from 10.00 to 18.00

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Saturday, 16 March 2019

EUT Congress News

Penile cancer: Organ-sparing surgery Preservation of penile length and improved cosmetic outcomes are the standard of care Mr Asif Muneer Consultant Urological Surgeon and Andrologist, Associate Professor, Male Genital Cancer Centre NIHR Biomedical Research Centre, University College London Hospital, London, UK

Penile Preserving Procedures The type of penile preserving procedure will depend on the size and site of the lesion as well as the degree of local invasion. Since the majority of primary lesions are located on the glans penis or prepuce, the corporal bodies and penile shaft skin can be preserved. The advances in imaging techniques using penile MRI with an artificial erection allows surgical planning (see Figure 1). By performing pre-operative penile imaging, the degree of infiltration into the corpus spongiosum or into the tips of the corpus cavernosum can be assessed.

Primary penile cancer is a rare male genital malignancy in Western Europe and North America, accounting for approximately 0,2-0,6% of all malignancies. However, in parts of South-America, Asia and Africa, penile cancer can comprise 1-2% of all malignancies. Histologically the majority of these lesions are squamous cell carcinoma (SCC) which represent over 95% of all penile cancer cases.

Management of small glans and foreskin lesions 1. Circumcision ± wide local excision Approximately 30% of lesions are limited to the foreskin or may extend onto a small area of the glans penis. Undertaking a circumcision with a wide local excision of any extension of tumour onto the glans is safe, provided that additional biopsies are taken of the base of the tumour to Although there are specific risk factors such as ensure that there is a tumour free margin. Lesions uncircumcision, tobacco use, exposure to ultraviolet located on the edge of the glans corona can be Fig. 2: Glansectomy procedure demonstrating dissection under Bucks’ fascia and ligation of dorsal neurovascular bundle therapy (PUVA), poor hygiene, we now accept that the excised and the defect covered with preputial or two principle drivers of the oncogenic pathway are penile shaft skin advancement flap. Larger areas the presence of high-risk HPV infection (HPV subtypes with residual pre-malignant disease can be 16 and 18) or the presence of lichen sclerosus. excised and covered with a split skin graft with a progression-free survival of 81% between (distal corporectomy) can be offered which still (described below) as a partial glans resurfacing allows preservation of the penile length. To 5 and 10 years. However, brachytherapy is also Centralisation of penile cancer services in Europe procedure. associated with a penile necrosis rate of 0 to ensure clear oncological margins, intraoperative The management of rare cancers has increasingly 26%, and meatal stenosis rate of 9 to 45%. EBRT frozen sections of the distal urethra and the tips been centralised in some European countries. The NKI 2. Alternative techniques for small lesions on the is associated with a 5-year amputation-free of the corporal bodies can be analysed to ensure in Amsterdam (NL) has led the way in centralising glans penis survival rate is about 43% and local control rates tumour-free margins. penile cancer services. In the UK the implementation Over the years dermatological techniques used to amount to 62% at 5 years. For EBRT, necrosis has of a national policy called IOG for urological cancers manage skin cancer have been applied to been observed in 1 to 3% of the cases and meatal A split thickness skin graft (STSG) can be used to published in 2002 led to the establishment of penile manage penile lesions. Mohs’ micrographic stenosis in 7 to 28% of cases. reconstruct a neoglans (see Figure 2). The STSG cancer supraregional networks, which have to cover a surgery (MMS) is a technique used to excise small covers the exposed tips of the corpus cavernosum minimum population of 4 million and manage at least low grade lesions. However, the local recurrence Collaboration between European Networks and provides a better cosmetic outcome 25 cases per annum. rates are high and the technique has not been The recent development of the European Reference compared to techniques which bring the penile widely adopted as the disfigurement with larger Networks for rare disease which includes the shaft skin forward and sutured directly to the One of the benefits of the centralisation of penile lesions results in poor cosmetic outcomes. eUROGEN rare tumour group has now provided an urethra. cancer services has undoubtedly been the opportunity for European centres to develop acceptance that penile preserving surgery should, Laser therapy consists of laser dissection and/or collaborations across education, research and 2. Partial Penectomy where possible, be offered to all patients as laser ablation using carbon dioxide (CO2) laser or Although partial penectomy has been performed development of penile cancer services and standard management for the primary penile a Neodymium(Nd)-YAG laser, when a 3-10 mm multidisciplinary teams. An online clinical platform for distal penile cancers invading into the corpus lesion. Previously in centres where very few penile tissue penetration depth is required. Again local allows discussion of clinical cases between ERN cavernosum, traditionally the penile shaft skin is cancers were seen, men would be offered either a recurrence rates are higher compared to surgical centres such that the management for patients is used for primary closure and results in a poor circumcision for preputial lesions, partial excision with one multi-centre study reporting a standardised throughout the centres. cosmetic outcome. Preoperative planning using penectomy for distal penile lesions or large glans 58.3% local recurrence rate. MRI can allow larger lesions which are just lesions and a total penectomy for more extensive Conclusion invading into the distal corpus cavernosum to be lesions based on the historical acceptance that a 2 Management of PeIN and superficial Ta/T1 lesions of managed by performing a glansectomy and distal Penile preserving surgical options have become cm clearance margin was required. the glans penis standard for patients presenting with penile cancer. corporectomy, which minimises the amount of 1. Topical agents Although different techniques have been used in penile shaft removed. Again a neoglans can be This arbitrary 2 cm margin has been challenged in Premalignant disease diagnosed as PeIN III can reconstructed using a STSG. A modification of the published retrospective series from multiple European a number of studies which have shown that much be managed by performing a circumcision centres, the outcomes have been consistent in that technique has recently been described to allow smaller margins are now acceptable. Although the followed by application of either topical urethral centralisation combined with a STSG and local recurrence rates are higher than for partial or local recurrence rate is higher, long-term follow-up chemotherapy (topical 5-FU) or immunotherapy total penectomy. However this does not affect the again provides an excellent cosmetic result. indicates that the overall cancer specific survival is (topical imiquimod). It is important to take a long-term prognosis for patients, provided that the Recurrence rates for larger cT2/3 tumours where unaffected if patients present with a local biopsy of any suspicious areas following a recurrent lesions are removed. Pre-operative surgical margins are less than 10 mm are between 18% recurrence. circumcision in order to ensure that there is no planning now utilises penile MRI with the and 20% and therefore close post-operative invasive component which is unlikely to respond reassurance that lesions are not infiltrating into surveillance is required. A significant loss in penile length following a partial to topical treatment. deeper structures. Even traditional partial penectomy or total penectomy would inevitably result in an techniques have been modified to allow preservation 3. Radiotherapy inability to have penetrative sexual intercourse or void 2. Glans resurfacing of penile length and improve cosmetics. Radiotherapy is used rather infrequently for the standing up. Add to this the loss of the patients’ In cases where PeIN lesions fail to respond to treatment of penile cancer; both brachytherapy masculinity and patient’s self-esteem and we can topical treatments, the glans epithelium and Saturday 16 March and external beam radiotherapy (EBRT) are the appreciate the devastating psychological as well as sub-epithelial tissue can be excised. The resulting 10.15-15.45: Meeting of the EAU Section of main options. negative body image effects of this as a result of this defect can be covered with a split thickness skin Genito-Urinary Reconstructive Surgeons (ESGURS) surgical intervention. graft (STSG) with an excellent cosmetic and Genito-urinary reconstruction in 2019 For brachytherapy, an amputation-free survival of functional outcome. Either part of the glans around 73% at 8 to 10 years has been reported, The EAU, NCCN and ESMO guidelines all recommend epithelium can be excised (partial glans that organ-sparing treatment should be offered when resurfacing) or a total glans resurfacing oncologically safe. The EAU guidelines also state that procedure can be performed when the affected ’the aims in the treatment of the primary tumour are area on the glans is more extensive. The complete tumour removal with as much organ procedure is also useful for superficial tumours preservation as possible, without compromising provided that separate biopsies of the base of the oncological control’. lesion are performed to ensure that there is no deeper invasion into the corpus spongiosum (upstaging to pT2 disease) in which case there is a high chance of local recurrence and a glansectomy can be offered. Management of T2 glans lesions and T3 lesions invading distal corpus cavernosum 1. Glansectomy and split skin graft Lesions affecting the glans corona and more than 50% of the glans may be suitable for a hemiglansectomy with the penile skin brought up to the residual glans margin. The preservation of the perimeatal area allows patients to void without spraying.

Fig. 1: Penile MRI demonstrating cancer limited to the glans penis with no infiltration into the distal corpus cavernosum

EUT Congress News

In cases where there are larger lesions affecting the glans penis or distal urethral lesions infiltrating into the glans penis, a total glansectomy is the preferred option. In cT3 cases where there is tunical involvement, a glansectomy with resection of the tips of the corpora cavernosa Fig. 3: Following removal of the glans penis a STSG from the upper thigh can be used to reconstruct the neoglans Saturday, 16 March 2019

Male infertility: An indicator of male health status? An intriguing hypothesis Prof. Andrea Salonia Division of Experimental Oncology/Unit of Urology University Vita-Salute San Raffaele Milan (IT)

The hypothesis that men with male factor infertility may have a lower general health status has been widely corroborated throughout the last few years. As a matter of fact, the relationship between health status and male fertility is a closely intertwined one, since several conditions known to negatively impact men’s health have been repeatedly associated with impaired reproductive functioning. This implies a wide range of alterations going beyond the well-known 20-fold increased risk of testicular cancer described in men with abnormal semen analyses1,2. Colorectal cancer, melanoma and prostate cancer3,4 along with a higher rate of certain noncancerous disorders5 seem to be associated with male infertility. Urogenital and systemic infections6, autoimmune diseases7, endocrinopathies and metabolic disorders8, as well as chronic kidney and liver disorders9,10 have all been alleged, and often confirmed, factors known to detrimentally influence fertility. Mortality decreased as sperm concentration increased General health status has been inquired in several ways in infertile men, with specific outcomes differently varying according to the analysed study, ranging from life expectancy up to general health related indexes and isolated comorbidities. First reports by Jensen et al.11 found that mortality decreased as the sperm concentration increased up to a threshold of 40 million/ml; moreover, mortality decreased in a dose-response manner as the percentages of motile and morphologically normal spermatozoa and semen volume increased. Likewise, Bonde et al.12 also reported an increase in the probability of conception with increasing sperm concentration up to the same threshold of 40 million/ ml, thus eliciting a direct association between fecundity and general health status. Comorbidity index Dealing with life expectancy in infertile and, therefore, usually young men may be simultaneously intriguing and way too speculative. In this regard, existing comorbidities indexes would be somehow better fitted in the subfertile population. Recently Eisenberg et al.13, observed that by stratifying their large cohort of infertile men using the Charlson Comorbidity Index (CCI), differences in all measured semen parameters were identifiable. Men with diseases of the endocrine, circulatory or genitourinary systems, or skin diseases all showed significantly higher rates of semen abnormalities. Notably, the CCI estimates overall disease burden giving an appraisal

of the related mortality risk14. These results were later confirmed15 considering semen parameters, further adding interesting insights in terms of hormonal values: infertile and less healthy patients were found to have lower testosterone and higher follicle stimulating hormone values; moreover, patients with sperm concentration lower than 45.6 million/ml were at higher risk of having comorbidities. Though being somehow reductive, the use of comorbidities indexes gives an appraisal of the general health status as compared with the analysis of a single subset of comorbidities. Overall, this is of major importance when dealing with young men, where the comorbidity burden is seen as more familiar as compared to the idea of life expectancy. Possible links between low general health status and male infertility Several authors attempted to explain the relationship between health status and male infertility. Recently, Ventimiglia et al.15 hypothesised two different mechanisms to explain the coexistence of infertility and comorbidities: the existence of a common mechanism promoting both infertility and a particular subset of associated pathological conditions; and comorbidities directly interfering with male reproductive function (see Figure 1). Considering the first mechanism, substantial evidence suggests that men with reproductive health disorders may lack certain regulatory genes, predisposing them not only to abnormal spermatogenesis but also to abnormal control mechanisms for cell division and, hence, an increased probability of cancer1-4. To this regard, many DNA repair genes previously identified in cancer syndromes have been found to regulate key processes in gamete production16. Polymorphism as risk factor For instance, a single nucleotide polymorphism in the Lynch syndrome gene MLH1, involved in mismatch repair pathway, was reported as a risk factor in men with azoospermia and oligozoospermia17. Moreover, this single nucleotide polymorphism was associated with increased DNA fragmentation in men with normal sperm concentration as well17. A common mechanism underlying germ cell defects and cancer appears particularly discernible in azoospermic men4. Preclinical data from a mouse model lacking DNA repair gene ERCC1 confirms this association18. To this regard, the case of cryptorchidism is glaring; undescended testis is associated with impaired fertility and is a major risk factor for testicular cancer. Postnatal germ-cell development deteriorates in the undescended testis after the first year with the consequent risk of infertility increasing with age19. Moreover, the relative risk of testicular cancer among these patients doubles if orchiopexy is performed after reaching 13 years of age20. Apart from the genetic background alleged to partially link cryptorchidism to both testicular cancer and infertility [16], data showing an association between delayed orchiopexy and an increased rate of cancer/infertility clearly suggest a major role for ‘local environmental factors’ as well.

Comorbidities with detrimental effect Alternatively, it may be the case that comorbidities have a detrimental effect on male reproductive function. Many of the conditions found in our cohort, which are known to impact reproductive function, are extremely common in the male general population. Up to 39% of the adult population in the USA has criteria suggestive of metabolic syndrome (MetS)21; comparable rates were observed in the Italian population22. Similarly, high rates have been observed for dysmetabolic conditions, such as MetS and obesity23, diabetes24 and hypertension25. Although hormonal homeostatic changes (i.e. higher rates of hypogonadism) brought on by MetS (and obesity per se) have been widely reported and accepted26-28, the effects on semen parameters are still inconclusive28,29. Similar findings are reported for diabetes29; indeed, though not univocal, both altered semen parameters and markers of spermatogenesis have been documented in diabetic men29. Although the majority of these potential detrimental factors have been analysed separately, the current data support the idea of a common pathophysiology pathway in which they act together to perturb overall reproductive health. In this context, an excess of peripheral adipose tissue results in increased tT to E2 aromatization, which eventually leads to secondary hypogonadism and reproductive axis derangement30. Moreover, oxidative stress at the level of the testicular microenvironment may result in decreased spermatogenesis and increased sperm damage31, with several other factors being strongly involved in this complex scenario as well7. Notably, all the aforementioned conditions are included in the CCI score or are considered closely related risks. Among other CCI determining diseases, autoimmune and liver diseases are known for their possible impact on male reproductive function8,9,13. In conclusion, the importance of comorbidities in the male reproductive setting is gaining more and more attention and relevance. Therefore, it is fundamental to properly outline the presence of coexisting diseases during the male infertility work-up, since it may reveal of utter importance in terms of etiologic assessment, therapeutic choice and paternity outcomes. References 1. Raman JD, Nobert CF, Goldstein M. Increased incidence of testicular cancer in men presenting with infertility and abnormal semen analysis. J Urol 2005; 174:1819 – 1822. 2. Walsh TJ, Schembri M, Turek PJ, et al. Increased risk of high-grade prostate cancer among infertile men. Cancer 2010; 116:2140–2147. 3. Eisenberg ML, Betts P, Herder D, et al. Increased risk of cancer among azoospermic men. Fertil Steril 2013; 100:681 – 685. 4. Salonia A, Matloob R, Gallina A, et al. Are infertile men less healthy than fertile men? Results of a prospective case-control survey. Eur Urol 2009; 56:1025 – 1031. 5. Pellati D, Mylonakis I, Bertoloni G, et al. Genital tract infections and infertility. Eur J Obstet Gynecol Reprod Biol 2008; 140:3–11. 6. Carp HJ, Selmi C, Shoenfeld Y. The autoimmune bases of

Figure 1. Relationship between health status and reproductive function

infertility and pregnancy loss. J Autoimmun 2012; 38:J266–J274. 7. Michalakis K, Mintziori G, Kaprara A, et al. The complex interaction between obesity, metabolic syndrome and reproductive axis: a narrative review. Metabolism 2013; 62:457–478. 8. Hofny ER, Ali ME, Taha EA, et al. Semen and hormonal parameters in men with chronic hepatitis C infection. Fertil Steril 2011; 95:2557 – 2559. 9. Iglesias P, Carrero JJ, Dez JJ. Gonadal dysfunction in men with chronic kidney disease clinical features, prognostic implications and therapeutic options. J Nephrol 2012; 25:31 – 42. 10. World Health Organization web chapter on couple’s infertility. http://www.who.int/topics/infertility/en/. [Accessed 31 December 2018] 11. Jensen TK, Jacobsen R, Christensen K, et al. Good semen quality and life expectancy: a cohort study of 43,277 men. Am J Epidemiol 2009; 170:559– 565. 12. Bonde JP, Ernst E, Jensen TK, et al. Relation between semen quality and fertility: a population-based study of 430 first-pregnancy planners. Lancet 1998; 352:1172–1177. 13. Eisenberg ML, Li S, Behr B, et al. Relationship between semen production and medical comorbidity. Fertil Steril 2015; 103:66 – 71. 14. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40:373–383. 15. Ventimiglia E, Capogrosso P, Boeri L, et al. Infertility as a proxy of general male health: results of a cross-sectional survey. Fertil Steril 2015; 104:48–55. 16. Matzuk MM, Lamb DJ. The biology of infertility: research advances and clinical challenges. Nat Med 2008; 14:1197 – 1213. 17. Ji G, Long Y, Zhou Y, Huang C, et al. Common variants in mismatch repair genes associated with increased risk of sperm DNA damage and male infertility. BMC 2012; 10:49. 18. Paul C, Povey JE, Lawrence NJ, et al. Deletion of genes implicated in protecting the integrity of male germ cells has differential effects on the incidence of DNA breaks and germ cell loss. PLoS One 2007; 2:e989. 19. Huff DS, Fenig DM, Canning DA, et al. Abnormal germ cell development in cryptorchidism. Horm Res 2001; 55:11 – 17. 20. Pettersson A, Richiardi L, Nordenskjold A, et al. Age at surgery for undescended testis and risk of testicular cancer. N Engl J Med 2007; 356:1835– 1841. 21. Golden SH, Robinson KA, Saldanha I, et al. Clinical review: Prevalence and incidence of endocrine and metabolic disorders in the United States: a comprehensive review. J Clin Endocrinol Metab 2009; 94:1853– 1878. 22. Miccoli R, Bianchi C, Odoguardi L, et al. Prevalence of the metabolic syndrome among Italian adults according to ATP III definition. Nutr Metab Cardiovasc Dis 2005; 15:250 – 254. 23. Corona G, Lee DM, Forti G, et al. Age-related changes in general and sexual health in middle-aged and older men: results from the European Male Ageing Study (EMAS). J Sex Med 2010; 7:1362 – 1380. 24. Wild S, Roglic G, Green A, et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004; 27:1047– 1053. 25. Wolf-Maier K, Cooper RS, Banegas JR, et al. Hypertension prevalence and blood pressure levels in 6 European countries, Canada, and the United States. JAMA 2003; 289:2363 – 2369. 26. MacDonald AA, Herbison GP, Showell M, Farquhar CM. The impact of body mass index on semen parameters and reproductive hormones in human males: a systematic review with meta-analysis. Hum Reprod Update 2010; 16:293 – 311. 27. Lotti F, Corona G, Degli Innocenti S, et al. Seminal, ultrasound and psycho- biological parameters correlate with metabolic syndrome in male members of infertile couples. Andrology 2013; 1:229 – 239. 28. Leisegang K, Udodong A, Bouic PJ, Henkel RR. Effect of the metabolic syndrome on male reproductive function: a case-controlled pilot study. Andrologia 2014; 46:167 – 176. 29. La Vignera S, Condorelli R, Vicari E, et al. Diabetes mellitus and sperm parameters. J Androl 2012; 33:145 – 153. 30. Aggerholm AS, Thulstrup AM, Toft G, et al. Is overweight a risk factor for reduced semen quality and altered serum sex hormone profile? Fertil Steril 2008; 90:619 – 626. 31. Hammoud AO, Gibson M, Peterson CM, et al. Impact of male obesity on infertility: a critical review of the current literature. Fertil Steril 2008; 90:897–904.

Saturday, 16 March 2019

EUT Congress News

Today’s European Urology Events How to write the introduction and methods

ESU Writing Course Part 1

March 16th 8.30 – 10.30 Green Room 16

Aims and objectives: Understand how to construct a well written introduction and methods section for your manuscript. Learn how to work through examples of good and bad practices, and understand key points when writing. Obtain insight from editors on what they expect to see. • To understand what makes a good introduction • To understand what makes a good methods section • To improve understanding of systematic reviews and meta-analysis • To learn from experienced editors • Interactive working groups and question and answer sections during the course

1. Welcome Jim Catto, Sheffield (GB) 2. Writing the introduction Matthew Cooperberg, San Francisco (US) 3. How to write the methods section Maarten Albersen, Leuven (BE) 4. Key features for a systematic review Giacomo Novara, Padova (IT) 5. What to look for in the statistics section Daniel Sjoberg, New York (US)

How to write results and discussion

ESU Writing Course Part 2

March 16th 12:00 – 14:00 Green Room 16

Residents’ Corner Awards

March 16th

Aims and objectives: Learn the best way to draft the results and discussion section of a scientific paper. Understand how to work through examples of good and bad practices, to find the key points of the manuscript. Obtain insight from editors on what they expect to see. • To understand what makes a good results section and how to best present your data • To understand what makes a good discussion • To learn from experienced editors • Interactive working groups and question and answer sections during the course

1. Welcome Jim Catto, Sheffield (GB) 2. Choosing and presenting your statistical analysis Daniel Sjoberg, New York (US) 3. How to write the results section Richard Lee, New York (US) 4. Writing the discussion section Paul Nguyen, Boston (US) 5. What the editor looks for when reviewing the results and discussion Laurence Albiges, Villejuif (FR)

Resident’s Corner Award for the Best Scientific Paper published in European Urology® by a resident Prospective Implementation of Enhanced Recovery After Surgery Protocols to Radical Cystectomy Karl H. Pang, Ruth Groves, Suresh Venugopal, Aidan P. Noon, James W.F. Catto European Urology, Vol. 73, Issue 3, p363–371 Substitution Urethroplasty with Closure Versus Nonclosure of the Buccal Mucosa Graft Harvest Site: A Randomized Controlled Trial with a Detailed Analysis of Oral Pain and Morbidity Armin Soave, Roland Dahlem, Hans O. Pinnschmidt, Michael Rink, Jessica Langetepe, Oliver Engel, Luis A. Kluth, Birte Loechelt, Philip Reiss, Sascha A. Ahyai, Margit Fisch European Urology, Vol. 73, Issue 6, p910–922

16.15 Green Room 2

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Saturday, 16 March 2019

Can we improve the bladder diary? A lecture on behalf of the Japanese Continence Society (JCS) Dr. Satoru Takahashi Dept. of Urology Nihon University School of Medicine Tokyo (JP)

The data obtained from bladder diaries are important for decisions with regard to the treatment strategy and identification of the pathophysiology. Functional bladder capacities are crucial to choose drugs, and voiding intervals are useful information for timed/ prompted voiding and life-style interventions. Nocturnal polyuria may mostly be a cause of nocturia in elderly patients. However, recording the urinary diaries, especially bladder diaries, is a considerable effort for patients and caregivers, and sometimes is difficult in elderly with cognitive impairment.

“...the sigmoid function is effective for grasping the urine storage and voiding pattern and excluding artefactual errors in the continuous measurement of the intravesical urine volume.”

Es#mated intravesical urine volume [ ml ]

Urinary diaries are commonly used, recommended tools in the management of patients with lower urinary tract symptoms (LUTS), especially frequency, incontinence and nocturia. The International Continence Society (ICS) has defined the following three types of urinary diary on the basis of the recorded parameters: micturition charts, frequencyvolume charts and bladder diaries1. Bladder diaries record a full option of the parameters; the times of micturition and voided volumes, as well as other information, such as incontinence episodes, pad usage, fluid intake, and degree of urgency for at least 24 hours.

Es#mated intravesical urine volume [ ml ]

Figure 3

Time [ min ]

Figure 3: The sigmoid function is effective for grasping the urine storage and voiding pattern and excluding artefactual errors in the ultrasound measurement of the intravesical urine volume. The figure shows different curve patterns.

volume. Recently, a Japanese group has developed an ultrasound-assisted prompted voiding (USAPV) care programme for the management of urinary incontinence in elderly individuals; care workers regularly monitor the intravesical urinary volume of elderly individuals via ultrasonography, and prompt to void when the volume reaches the pre-fixed optimal value. In a randomised clinical trial, they found that the change in daytime urine loss was statistically greater in the USAPV (median, −80.0 g) than in the conventional prompted voiding (CPV) (median, −9.0 g; p = .018) group2. The care burden scale score of caregivers was unchanged in the USAPV group (p = .59) but significantly worsened in the CPV group (p = .010) after the intervention. These findings suggested that USAPV is efficacious and feasible for managing urinary incontinence in nursing homes. In order to further promote the feasibility and utility of measuring the intravesical urine volume with portable ultrasound devices, a new device for bladder volume ultrasound (Lilium -200; Lilium Otsuka Co., Ltd., Tokyo, Japan) has been developed. It can quickly scan the intravesical urine volume and shows a good correlation between its estimated intravesical urine volumes and actual voided urine volumes (see Figure 1). The Lilium -200 can also continuously monitor

Portable ultrasound devices In this decade, portable ultrasound devices have been developed to measure the intravesical urine

the urine volume before and after voiding, which enables to automatically create the bladder diaries (see Figure 2). However, an artefactual error during body movement remains the most confounding matter in the automatically recording voiding diaries (see Figure 1). Novel method to display urine storage Recently, we proposed a novel method for displaying the urine storage and voiding pattern on an approximate curve, which is created with estimated intravesical urine volumes measured every minute with the portable ultrasound device. Quadratic function and sigmoid function were used for approximation, and examination was performed in subjects with different micturition intervals. From these results, the sigmoid function is effective for grasping the urine storage and voiding pattern and excluding artefactual errors in the continuous measurement of the intravesical urine volume (see Figure 3).

In my lecture for the Japanese Continence Society, I will present a recent advancement and possibilities of further innovations of the bladder diary. References 1. Lucas MG, Bosch RJL, Burkhard FC, et al. EAU guidelines on assessment and nonsurgical management of urinary incontinence. Eur Urol, 2012;62:1130–42. 2. Suzuki M, Miyazaki H, Kamei J, et al. Ultrasound-assisted prompted voiding care for managing urinary incontinence in nursing homes: A randomized clinical trial. Neurourol Urodyn. 2019 Jan 8. doi: 10.1002/ nau.23913. [Epub ahead of print].

Saturday 16 March 10.15-14.00: Meeting of the EAU Section of Female and Functional Urology (ESFFU) Innovative surgical procedures in functional urology

Figure 1

400

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3 - 6 September 2019

500

y = 0,8335x + 31,391 R² = 0,71945

Es#mated intravesical urine volumes

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actual voided urine volumes

400

y = 0,7823x + 46,146 R² = 0,50631

Leading Continence Research and Education

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actual voided urine volumes

Call for Abstracts: 1 March - 1 April 2019

Figure 1: Relationship between estimated intravesical urine volumes measured with Lilium® -200; Lilium Otsuka Co., Ltd., Kanagawa, Japan and actual voided urine volumes. A: Data obtained from measurement at rest, B: Data obtained from measurement during routine daily living.

Figure 2

Es#mated intravesical urine volumes

No. of voiding/24h; 10 (day;me 9, nigh?me 1) Maximum bladder capacity; 404ml Mean voided volume; 260ml Mean postvoid residual; 33ml

450 400 350 300 250 200 150 100 50 0

Total urine volume/24h; 2,503ml Nocturnal urine volume; 428ml Nocturnal polyuria index; 17%

International Continence Society 49th Annual Meeting

www.ics.org/2019

#me Figure 2. Continuous monitoring of the intravesical urine volume during storage and voiding phases with Lilium -200 (41-year-old female). • indicates actual voiding. – indicates automatic adjustment.

Saturday, 16 March 2019

EUT Congress News

Genetics in bladder cancer Most genetic changes are somatic mutations developed during life Susanne Osanto Dept. Of Medical Oncology Leiden University Medical Center Leiden (NL)

Molecular subtypes Molecular subtypes have been shown to be associated with different survival outcomes and responses to chemotherapeutic and biological therapies, underscoring their clinical relevance for future bladder cancer clinical management (McConkey and Choi, 2018; Chandrasekar et al., 2018; Matulay and Kamat, 2018).

S.Osanto@lumc.nl

Sequencing technology allowed discovery of somatic mutations in individual tumours with a large variation in mutation burden between and within tumour types, ranging from 10s to 1000s of mutations/tumour (Lawrence et al., 2013 and Alexandrov et al., 2013). Bladder cancer ranks third in highest prevalence of tumour mutational burden (TMB). Somatic mutations potentially result in an increased neo-antigen burden. The more mutations, antigens and neo-antigens a patient has, the more likely they will respond to immunotherapy.

Cristina Alvarez Gómez de Segura Dept. Of Medical Oncology Leiden University Medical Center Leiden (NL)

clinicopathological features. Class 1 tumours included non-invasive papillary tumours with the highest expression levels of early cell cycle genes. Class 2 included a higher number of pT1 and high-grade cases and were characterised by epithelialmesenchymal transition and APOBEC mutational signatures. Class 2 tumours had a much higher chance of progressing to muscle-invading disease than class 1 NMIBCs. Class 3 expressed a basal-like gene expression signature that corresponds with class 2, with a higher risk of progression to MIBC. The GS1 group of Hurst et al. was very similar to the UROMOL class 1 of Hedegaard, while GS2 was more similar to UROMOL class 2. Such classifications may aid in clinical decision making and future studies should address the question whether GS2/UROMOL class 2 tumours would be treated more aggressively than GS1/URMOL class 1 tumours. Clinical trials test whether FGFR3 targeted of mTOR targeted therapies are more successful in patients with alterations in these genes/pathways.

Fig. 1: Tumour stage (T) and subtypes

based chemotherapy. Choi et al. (2014) demonstrated that half of the basal tumours were sensitive to neo-adjuvant therapy.

Subtype profiles Basal/squamous-like tumours are predominantly found in females and are also characterised by a high Molecular biomarkers in bladder cancer level of immune infiltration and tumour PDL-1 The use of new molecular profiling technologies led expression, biomarkers of epithelial to mesenchymal to the discovery of potential bladder cancer molecular MIBC Genetics Bladder cancer (BC) is one of the most common Histological variants are now classified at molecular transition and epidermal growth factor receptor biomarkers. The assessment of a single molecular cancers worldwide ranking 13th in annual cancer biomarker may not adequately reflect tumour biology level to better establish clinical approaches. Although (EGFR). For neuronal subtypes (5%) similar to mortality (Antoni et al. 2017; Cumberbatch et al. 2018) or provide proper stratification due to the complexity each study varies in classification, nomenclature and neuroendocrine cancers, etoposide plus cisplatinwith a high prevalence in industrialised countries identification of different number of subtypes, there based therapy is advocated. The last subtype called of molecular alterations and multi-step pathways. (Ferlay et al., 2012; Cumberbatch et al. 2018). are also similarities (Choi et al., 2017; McConkey et al., luminal-papillary (35%) has been characterised as Possible combinations are necessary to identify Environmental occupational carcinogens, dietary 2014; Chandrasekar et al., 2018). Current low tumour stage, enriched with papillary features optimal treatment strategies (Krabbe et al., 2018; factors, and tobacco smoking are important classifications from 2 to 6 subtypes have been and with better overall survival. Its frequent activating Yousef and Gabril, 2018). attributable risk factors, next to metabolic syndrome identified for MIBC using next-generation sequencing, FGFR3 mutations also suggests its progression to and Schistosoma infection (Cumberbatch et al. 2016, particularly RNA-expression profiling. muscle-invasive cancers. This subtype profile NMIBC genetics 2018). In the majority of cases there is no family suggested early cystectomy treatment and little added There is growing interest in the genomics of NMIBC. history and most genetic changes are somatic A consensus classification similar to that used for clinical benefit observed with neo-adjuvant therapy. TMB is much lower in NMIBC than in MIBC, and mutations in bladder cells developed during lifetime breast cancer, with among other things luminal and mutations are mediated by the APOBEC family of (Knowles and Hurst, 2015; Zhang and Zhang, 2015; basal subtypes, reflecting degrees of tumour Several groups are investigating DNA damage repair enzymes early in tumour development. Non-invasive Cumberbatch et al. 2018). aggressiveness and sensitivity to chemotherapy, has (DDR) defects as a hotspot for chemotherapy low-grade urothelial carcinoma is characterised by loss of heterozygosity of chromosomes (chromosome been developed for MIBC. The groups from University response. If the patient’s tumour shows alterations in Pathological subtypes of North Carolina and Curie Institute clustered 262 a DDR pathway, it is more likely to respond to 9 being the most common), frequent mutations of More than 90% of cases of BC originate from the and 383 high-grade MIBC tumours in 2 subgroups, chemotherapy. DDR defects also seem to be a pathway and driver genes, such as FGFR3, PIK3CA inner surface lining of the bladder. Other histological and STAG2, and infrequent p53 mutations at luminal and basal-like, similar to breast cancer predictor of response to immunotherapy, perhaps via types include squamous cell carcinoma, small-cell (Rebouissou et al., 2014; Damrauer et al., 2014). a high total TMB. DDR abnormalities are found across molecular level. Activating fibroblast growth factor carcinoma, micropapillary and adenocarcinoma the urothelial bladder cancer spectrum. ERCC2 and receptor 3 (FGFR3) mutations are detected in 70-80% (Knowles and Hurst, 2015). Traditionally, there is a The three MIBC molecular subtypes obtained from 130 ATM are the most common DDR abnormalities. Many of non-invasive urothelial carcinoma compared to distinction between non-muscle invasive papillary samples (Choi et al., 2014) from MD Anderson Cancer alterations are of unknown significance and further 10-20% of invasive tumours. Furthermore, activated bladder cancer (NMIBC) and muscle-invasive bladder FGFR3 triggers the downstream PI3K pathway. Centre and the four subtypes using 129 samples by characterisation is needed to develop the most cancer (MIBC) based on cellular appearance, depth of the Cancer Genome Atlas (TGCA, 2014) started appropriate treatment approaches. invasion and clinical behaviour. A two-pathway model On the other hand, muscle-invasive bladder cancer providing biological insight and relationship with explains the development of NMIBC and non-papillary with dysplasia or CIS lesions is also characterised by disease outcomes. Genomics in upper tract urothelial carcinoma (UTUC) (solid) MIBC (Audenet et al. 2018; Chandrasekar et al. loss of heterozygosity of chromosome 9, but shows UTUC has traditionally been considered to be like 2018; Matulay et al. 2018; Sanli et al. 2017). More detailed classification urothelial bladder cancer tumours, since both stem significant genetic instability and more complex More recent studies from Lund University (Sjödahl et from the transitional lining of the urinary tract. UTUCs chromosomal changes, with alterations in three NMIBC versus MIBC treatment approach and clinical tumour suppressors: TP53, RB1 and PTEN (Yousef and al., 2017) and TGCA network (Robertson et al., 2017; are more rare tumours and so far poorly investigated, outcome Choi et al. 2017) showed a more detailed classification precluding a good comparison. Moss et al., (2017) Gabril, 2018; Chandrasekar et al, 2018; Sanli et al, Current treatment management is based on with 5 subtypes. TGCA network re-evaluated their reported that although UTUC shares many genomic 2018). presentations as NMIBC or MIBC. Approximately 75% previous work in a final cohort of 408 MIBCs alterations and gene expression profiles with bladder of patients with newly diagnosed bladder cancer identifying 5 subtypes, namely Luminal papillary/ urothelial carcinoma, novel mutations and four “In the majority of cases there present with NMIBC, 25% with MIBC. Most NMIBC UroA, luminal infiltrated/p-53-like, luminal/GU, basal expression subtypes are present with unique patients will not succumb to the often indolent cancer is no family history.” squamous and neuronal/neuroendocrine subtypes. molecular profiles. Sequencing of DNA demonstrated that does carry a risk of local recurrences. These 5 subtypes were partially overlapping with that DNA repair and chromatin-modifying genes play Recurrences occur in 50-70% of cases, with only their 2014 classification into 4 subtypes (TGCA 2014). a critical role. Expression analyses confirmed the Using chromosomal, protein, gene expression and 10-20% of cases progressing to MIBC (Babjuk et al., A recent review of the same group shows a sixth additional critical role of FGFR3 in both low- and mutational analyses, 2 subgroups - GS1 with few 2017). Patients undergo frequent intravesicle basal subtype (TCGA cluster IV/claudin-low/ high-grade tumours. The study result suggests a chromosomal abnormalities and a high frequency of treatments and lifelong cystoscopic monitoring. mesenchymal-like) (McConkey and Choi, 2018). The rational therapeutic target, along with immune mutations in chromatin remodelling genes and GS2, NMIBC is associated with inconvenience, morbidity, Lund group concluded that 5 tumour phenotypes checkpoint therapies for a subset of patients with the with loss of chromosome 9q, a higher mutation rate and decreased patient QoL and poses a high could be observed – urothelial-like, genomically most adverse molecular and clinical features. and upregulation of mammalian target of rapamycin health-economic burden. unstable, basal/SCC like, mesenchymal-like and small complex 1 (mTORC1) - were distinguished (Hurst et cell/neuroendocrine-like. These 5 Lund-subtypes have Conclusion al., 2016). GS2 tumours had generally more aggressive overlaps with the TGCA classification. Additional The MIBC standard of care is radical cystectomy with Recent genomic analyses, including large-scale, malignancies, more high-grade tumours and a worse subtypes may emerge as larger cohort of bladder perioperative cisplatin-based combination next-generation sequencing collaborations such as recurrence free survival. Both GS1 and GS2 had many cancer variants are profiled. chemotherapy, but renal insufficiency may preclude The Cancer Genome Atlas, have revealed that the the use of cisplatin-based combination chemotherapy tumours with activating mutations of fibroblast classification of urothelial carcinoma is much more growth factor receptor 3 (FGFR3) and primarily in non-metastatic and metastatic MIBC. Novel Tumour subtype allocation have been related to complex than the classification into NMIBC and MIBC, inactivating mutations of KDM6A (a chromatin immunotherapy with checkpoint is effective in a clinical outcomes but the correlation between bladder which has been used for many years. There are at remodelling demethylase). proportion of chemo-resistant and treatment-naïve subtypes and genomic alterations is not clear yet least five MIBC-subtypes with different biological bladder cancer patients. The often poor outcome of (Audenet et al., 2018). So far, and taking into account behaviour, sensitivity to chemotherapy and clinical Gene expression analysis mMIBC poses an unmet need for better predicting TCGA and Lund groups subtypes, the luminal outcome, underscoring the complexity and Hedegaard et al. (2016) primarily used gene sensitivity to chemotherapy, immunotherapy or any infiltrated/p53-like subtype (19%) is predicted to heterogeneity of bladder cancer. Molecular subtyping expression analysis in a much larger set of tumours show little response to neo-adjuvant chemotherapy new form of targeted therapy. has led to new insights and concepts for treatment (including more high grade tumours) and but does show response to immune checkpointapproaches targeting driver pathways. Genomic Molecular taxonomy of bladder cancer: classification distinguished 3 molecular subtypes (UROMOL classes inhibitors. There are no recommended therapies for classification and identification of driver pathways has 1-3) with different progression-free survival and luminal/GU subtype (6%). Its genomic characteristics led to novel clinical trials and may evolve into truly based on molecular structure suggest chemotherapy sensibility, but the available Cancer genome studies may provide insight into the personalised-medicine approaches to all urothelial data are not clear. origin of tumours and provide a handle for improved carcinoma patients. Ultimately, such targeted personalised treatment approaches, even for therapies will lead to improved treatment outcomes Several studies into neo-adjuvant sensitivity, prevention and early detection of cancer, and may and an improved bladder cancer survival rate. molecular target therapy and immune checkpoint contribute to reduced cancer morbidity and mortality. inhibitors to which GU tumours seem to be sensitive Recent genomic analyses using next-generation Saturday 16 March 10:15 – 15:00 are currently ongoing. Additionally, luminal tumours sequencing technologies and genome-wide Joint meeting of the EAU Section of Oncological have more frequent ERBB2 mutations, which could be molecular expression profiling demonstrated a more Urology (ESOU), the EAU Robotic Urology Section candidates to ERBB-targeting drugs. Similar to complex classification of urothelial carcinoma than (ERUS), the EAU Section of Uro-Technology basal-like breast cancer, basal/squamous tumours what has been the traditional histopathological and (ESUT) and with the ECCO, EORTC GUCG, ESMO, (Lund SSC-like and UroB) and TGCA neuronal clinical dichotomy of NMIBC and MIBC. These studies ESSO, ESTRO and EUOG subtypes were aggressive and associated with confirmed the separation of disease into NMIBC and New modalities in diagnosis and treatment in advanced stage and metastatic disease and shorter MIBC with different mutational pathways. oncology survival in the absence of neo-adjuvant cisplatinFig. 2: Histopathology images of Urothelial carcinoma 16

EUT Congress News

Saturday, 16 March 2019

ESGURS Welcomes new chairman David Ralph reveals ambitions for EAU’s reconstructive section The EAU Section of Genitourinary Reconstructive Surgeons will have a new chairman from EAU19 on. Prof. David Ralph (London, GB) was elected to follow Dr. Rados Djinovic (Belgrade, RS) at a vote held at an ESGURS board meeting during ELUTS18. Prof. Ralph has been a member of ESGURS since its creation as the ESMGS in 1994 before it became an EAU Section in 2001. He has been on the ESGURS Board since 2016, previously serving as an EAU Section of Andrological Urology (ESAU) board member for eight years. As a consultant urologist and Professor of Urology at University College London Hospitals, Prof. Ralph is an expert in male reconstructive urology, particularly ED and penile disorders and gender assignment issues. He is currently president of the Sexual Advice Association, and previously held positions as President of the European Society for Sexual Medicine, Chair of the International Consultation of Sexual Medicine and board member of the European Society of Andrological Urology. Prof. Ralph has been an EAU member for more than 25 years, and also served the European School of Urology as a faculty member at several events. We asked him about his field and the future of the EAU’s reconstructive Section: What do you see as the biggest developments and challenges in genitourinary reconstructive surgery? Recently, the field has started making use of robotic surgery, mainly for bladder and upper tract procedures. This replaces traditional large open procedures. Robotics are of course also widely used for prostate surgery, offering better post-operative morbidity and fewer unwanted late effects.

Prof. Ralph (right) is an extremely experienced reconstructive surgeon with a long history of association with ESGURS and the EAU. Here he is pictured here chairing a session during ELUTS18 in Milan together with Prof. Carlo Bettocchi (centre)

to grow new urethras in the lab? Are penile and bladder transplantation becoming feasible? What is the role of ESGURS in the wider “reconstructive landscape”? What is the role of its chairman?

The Section’s, and indeed the chairman’s role is to bring together and integrate all areas of genital reconstruction. Furthermore, it is essential for us to bring the younger generation of urological surgeons into our specialty. My main aim is to increase the membership and to explore We are all reconstructive surgeons: we can be a victim the possibility of a publication dedicated to our field. of our own success by pioneering stem cell therapy and transplantation, ultimately replacing the What are your priorities for ESGURS in the coming operations that we currently perform. Will we be able years?

We currently have two section meetings per year. I would like us to have specific prospective projects: multi-centre, involving the leaders in the field. We must lead in the establishment of medical guidelines in our area of expertise as we have the key opinion leaders in our Section. I would also like to see ESGURS publish certain standards of care. The current surgical masterclasses all over Europe need to be identified and coordinated through ESGURS. We could establish certificates of competence for certain operations or conditions. The section needs to become more democratic, its bylaws revisited and members having more of a

say. Finally, I believe that the industry should be encouraged to participate in our activities. Do you have any words for the ESGURS section (and the readers of European Urology Today) on the occasion of you taking over from Dr. Djinovic? Dr. Djinovic has served us proudly! Our meetings have grown significantly under his leadership. We’ve enjoyed very high attendance figures at our section meetings held during the EAU Annual Congress. Rados has always been fair and let all players have a chance to promote new ideas and exciting research. We thank him for his and wish him well for the future.

Innovators in Bladder Cancer website Launching in March 2019! The Innovators in BC website is a science-based, international forum providing the latest scientific and clinical information to urologists, oncologists and uro-oncologists managing BC.

Innovators in BC aims to provide an accessible scientific resource to facilitate: • sharing up-to-date information in the field • assisting the optimisation of daily clinical practice • supporting peer-to-peer learning by facilitating the sharing of content

To register for access, please visit the Ipsen Booth: E38 in Hall 8.1

Hot topics

Congress highlights

Knowledge modules

Guidelines

Publication summaries

Useful dates and links

HEX-ES-000005 l February 2019

Saturday, 16 March 2019

EUT Congress News

ESU’s educational aspirations for urologists grow Objectives, current activities and the benefits against burnout Dr. Joan Palou ESU Chairman Fundació Puigvert Barcelona (ES)

jpalou@ fundacio-puigvert.es Good urological education stems from purposeful guidance of highly-experienced experts. It is also the product of accumulated reliable, evidence-based information. And we at the European School of Urology (ESU) aim in bolstering patient care and daily clinical practice. As American lawyer and civil rights activist, Marian Wright Edelman, once said “Education is improving the lives of others and for leaving your community and world better than you found it.”

Participant hones her laparoscopic skills at a programme in Singapore

For two decades now, the ESU has been fully committed to offer prime training to young and experienced urologists. We develop and refine our educational activities to parallel the expanding field of urology. We tailor these activities to provide urologists diverse learning possibilities and to meet their professional needs. Being a urologist is an amalgamation of two specialties: the medical aspect (requiring knowledge on metabolism, stones, infections, endocrine pathways in infertility, and medical oncological treatments to name a few) and the surgical aspect. We aim for complete coverage of these aspects (in a urological sense), and more innovative formats for our educational activities. Our other objective is designing a Pan-European postgraduate education consisting of unbiased, high-quality curriculum provided by European and non-European experts. What we do now Our ESU courses and Hands-on Training courses are integrated into the scientific programmes of international events and EAU’s own meetings and congresses. For immersion into specific topics, we offer masterclasses that include live and/or semi-live surgeries with updates from renowned field experts. To expand the capabilities of young, promising urologists, we established the new URO Berlin Skills Teaching and Training (UROBESTT) which recently took place in February. And we also encourage urological residents who are in their final year to participate at our European Urology Residents Education Programme (EUREP). Since EUREP’s inception in 2003, about 5,700 delegates from 44 countries in and beyond Europe have participated in this highly-acclaimed programme. To give urologists from all over the world access to reliable resources online, we also offer webinars to address current treatments and controversies in various urological subspecialties, and e-courses to provide current updates. In 2018 alone, 2,000

STEPS Sessions To Evaluate luate ProgresS Progres in the management of o urological cancers

participants registered for seven webinars, and 1,646 new users signed up for the 12 e-courses.

EAU Edu Platform

The online learning platform for GU cancers

Together with the EAU and its scientific journal, European Urology, we revived and upgraded the EAU Edu platform. It features accurate, topic-related content which BLADDER CANCER KIDNEY CANCER PROSTATE CANCER ranges from the latest uroonco.uroweb.org scientific articles, videos, e-courses, webinars and valuable insights of key The first EAU Edu platform, UROONCO, covers prostate, kidney, and bladder cancers opinion leaders on new urology developments and 2011, burnout among urologists increased despite meeting highlights (both EAU and non-EAU; both European and non-European). UROONCO is the first work-hour limits. EAU Edu platform that covers prostate, kidney, and Research results of the 2018 study “Prevalence of and bladder cancers; and has received 5,000 unique site visits since its launch in early December. Predictive Factors for Burnout Among French Urologists in Training” by Dr. Jérôme Gas (FR), et al. showed that More dynamic activities are in development as we on top of a well-balanced lifestyle (e.g. having a pastime, sex life), the feeling of being well-trained is speak and more expansive urology updates will be a strong protective factor against burnout of young made available soon. urologists in training. Therefore, good urological Good training counters burnout education also improves how they manage the stress Burnout is defined by the World Health Organisation and the demands that this profession entails. And in as “a feeling of intense exhaustion, loss of control and turn, good education positively affects their inability to achieve concrete results at work”. Since performance and the welfare of their patients. Powered by

We at the ESU not only aim for the further advancement of the field but most significantly, reinforce and enhance the abilities and well-being of urologists. Urologists can look forward to many training opportunities via the ESU. That is for certain. To know more about the ESU, feel free to explore www.uroweb.org/education/. You can also drop by the ESU Booth found in the Green Area during the congress for exclusive updates and sneak preview of what’s to come. ESU Course during EAU18 in Copenhagen

Interactive, Insightful and Independent Education Learning from Experts in Onco-Urology Applications now open! Visit Ipsen booth E38 during EAU19 to learn more

What is STEPS? STEPS, or “Sessions To Evaluate ProgresS in the management of urological cancers”, is a programme specifically designed for recently specialised onco-urologists who want to learn directly from worldleading experts in bladder, prostate, renal and testis cancers. The CME-accredited programme is a fundamental part of the EAU/ESOU strategic partnership with Ipsen. It is founded on our shared commitment to the education of young urologists. Bringing together a multinational group of medical professionals across several areas of expertise, and with different experiences, allows the fellows to see a variety of new treatment possibilities. It can highlight the pitfalls and solutions provided by diverse approaches. It also opens the door to creating international ties among medical practitioners, and a networking opportunity that can 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

To date, 20 different internationally recognised experts, supported by the ESOU Board, have inspired 158 fellows from 30 countries – and our objective is to continue supporting STEPS to help improve the management of all patients with urological cancers. Who should apply? Recently specialised clinicians with a firm interest in the management of urological cancers, who: - Can demonstrate support from their Head of Department

Next event: Meet-the-Expert Session during the 17th Meeting of the EAU Section of Oncological Urology (ESOU) Saturday 18th January 2020 Dublin, Ireland

- Are keen to participate in ESOU and EAU programs - Understand and speak English fluently “Within STEPS I really like the enthusiasm of the delegates and the interaction I can have with them as an expert” Peter Mulders, STEPS mentor 2018

Find out more about STEPS from the ESOU website: http://uroweb.org/section/esou/information/

TRI-ALL-000551

EUT Congress News

The STEPS programme is supported by Ipsen.

Saturday, 16 March 2019

Your overview of ESU courses and HOT courses at EAU19 Found below is a great selection of popular ESU courses and Hands-on Training (HOT) courses classified according to topics. Mark your calendars for tomorrow, 16 March. Get ready to increase your knowledge and hone your skills. Topics Adrenals General urology

Infections Kidney transplantation Paediatric urology

Penile and testicular cancer Prostate cancer

Renal tumours Trauma Urolithiasis Urologic surgery Urothelial tumours Topics Diagnostics and follow-up

Functional urology Endoscopy

ESU Courses ESU Course 9: Adrenals for urologists ESU Course 1: How to write the introduction and methods ESU Course 8: How to write results and discussion ESU Course 12: Guideline updates and controversies: Incontinence, Bladder / Paediatric stones and Male LUTS ESU Course 15: Dealing with the challenge of infection in urology ESU Course 2: Renal transplantation: Technical aspects, diagnosis and management of early and late urological complications ESU Course 10: Paediatric urology for the adult urologist. Congenital problems of the urinary tract: Obstruction and reflux and long-term outcome ESU Course 14: Paediatric urology for the adult urologist. Congenital disorders of the external genitalia, DSD and long-term outcome ESU Course 4: Testicular cancer ESU Course 7: Prostate biopsy - Tips and tricks ESU Course 11: Robot-assisted laparoscopic prostatectomy ESU Course 13: Prostate cancer screening and active surveillance - Where are we now? ESU Course 17: Retropubic radical prostatectomy - Tips, tricks and pitfalls ESU Course 3: Treatment of small renal masses ESU Course 16: Urinary tract and genital trauma ESU Course 5: Metabolic workup and non-surgical management of urinary stone disease ESU Course 6: Prosthetic surgery in urology ESU Course 19: Lymphadenectomy in urological malignancies ESU Course 18: Practical management of non-muscle invasive bladder cancer (NMIBC) HOT Courses HOT 07: ESU/ESFFU Hands-on Training Course in Urodynamics HOT 08: ESU/ESFFU Hands-on Training Course in Urodynamics HOT 09: ESU/ESUT/ESUI Hands-on Training Course in MRI Fusion biopsy HOT 10: ESU/ESUT/ESUI Hands-on Training Course in MRI Fusion biopsy HOT 16: ESU/ESFFU Hands-on Training Course in Sacral neuromodulation HOT 17: ESU/ESFFU Hands-on Training Course in Sacral neuromodulation HOT 01: ESU/ESUT/EULIS Hands-on Training Course in Endoscopic stone treatment - step 1 HOT 02: ESU/ESUT/EULIS Hands-on Training Course in Endoscopic stone treatment - step 2 HOT 03: ESU/ESUT/EULIS Hands-on Training Course in Endoscopic stone treatment - step 3 HOT 04: ESTs1 Exam HOT 05: ESTs1 Exam HOT 06: ESTs1 Exam

Speakers A.S. Gözen (DE) J.W.F. Catto (GB) J.W.F. Catto (GB) A.K. Nambiar (GB) F.M.E. Wagenlehner (DE) F.J. Burgos Revilla (ES)

Time 10:45 - 13:45 08:30 - 10:30 12:00 - 14:00 11:00 - 14:00 14:30 - 17:30 08:30 - 10:30

Rooms Green room 15 Green room 16 Green room 16 Green room 21 Green room 14 Green room 15

J.M. Nijman (NL)

11:00 - 14:00

Green room 14

G. Bogaert (BE)

14:30 - 17:30

Green room 15

P. Albers (DE) P. Hammerer (DE) P-T. Piéchaud (FR) A.R. Zlotta (CA) O.Hakenberg (DE) P. Gontero (IT) N.D. Kitrey (IL) T. Tailly (BE) A. Muneer (GB) A. Mattei (CH) J.A. Witjes (NL) Speakers G. Van Koeveringe (NL) G. Van Koeveringe (NL) L. Budäus (DE) L. Budäus (DE) H. Hashim (GB) H. Hashim (GB)

08:30 - 10:30 08:30 - 10:30 11:00 - 14:00 14:30 - 17:30 14:30 - 17:30 08:30 - 10:30 14:30 - 17:30 08:30 - 10:30 08:30 - 10:30 14:30 - 17:30 14:30 - 17:30 Time 09:30 - 12:30 13:00 - 16:00 14:00 - 16:00 16:00 - 18:00 13:00 - 15:00 15:30 - 17:30 09:30 - 10:30 11:00 - 12:00 12:30 - 13:30 13:45 - 14:30 14:30 - 15:15 15:15 - 16:00

Green room 13 Green room 23 Green room 13 Green room 16 Green room 21 Green room 14 Green room 13 Green room 21 Green room 22 Green room 23 Green room 22 Rooms Green Room 7 Green Room 7 Green Room 8 Green Room 8 Green Room 7 Green Room 7 Green Room 6 Green Room 6 Green Room 6 Green Room 6 Green Room 6 Green Room 6

TP 62 2.0 01/2019/A-E

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Saturday, 16 March 2019

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•

not only somatic but also germline mutations

•

genetic counseling

•

association with Lynch syndrome and subsequent testing with

Molecular aspects of bladder cancer in the young patient immunohistochemistry

How genomic alterations are particularly of relevance for younger bladder cancer patients Prof. Roland Seiler Dept. of Urology University Hospital Bern (CH)

Development of high-throughput technologies, such as next generation, sanger sequencing or microarrays, have permitted investigation of the molecular landscapes underpinning human malignancy. In recent years, a range of groups and consortia, including ‘The Cancer Genome Atlas’ (TCGA), have leveraged these techniques and exerted tremendous effort to study large cohorts of patients with bladder cancer. The resulting molecular characterisations have provided important insights into recurrent genomic and transcriptomic alterations present in bladder cancer and dramatically improved our understanding of disease biology. We now have at our fingertips a vast array of multimodal data representing the epigenetic, genomic, transcriptomic and proteomic features of bladder cancer. These data levels give insight into different biological aspects and allow to answer different scientifical questions. Methods for analysis and interpretation may be different depending on the scientific purpose. These differences in interpretation and analysis might be of particular relevance to young patients. Bladder cancer is strongly related to age and is therefore a typical disease of the elderly. Indeed, the average age at diagnosis is approximately 73 years. However, almost all large cohorts include patients below the age of 50 or 40 years. Urothelial bladder cancer in childhood is extremely rare but has been described in rare cases as young as 10 years old. While the above mentioned efforts have been undertaken to improve the understanding of the biology of bladder cancer in general, particularly in young patients, investigations should include other aspects as well. The following paragraphs will describe molecular aspects of bladder cancer in the young patients. Genomic alterations are described first, because they may be most relevant in this particular context.

“...genetic counselling should be considered in patients with bladder cancer below the age of 50 years.” Classification and impact of genomic alterations in cancer Permanent alterations in DNA are termed mutations and in cancer there are two broad categories: germline versus somatic mutations. Germline mutations are present in germ cells and can be transmitted to descendants. Some germline mutations are linked to cancer predisposition. The most famous example is Angelina Jolie, who carries a germline mutation in a gene called BRCA1. This gene helps coordinate DNA damage repair: an important mechanism for maintaining DNA integrity throughout life. Germline mutations in BRCA1 are strongly associated with the development of breast cancer, and presumably contributed to Angelina Jolie’s decision to undergo preventive bilateral mastectomy. In contrast, somatic mutations are mutations that are acquired during cancer development and evolution. Therefore, somatic mutations are not present in germ and non-cancerous cells. To acknowledge and resolve these two categories of mutation, good scientific practice for genomic DNA sequencing in cancer research typically includes two specimens for analysis: cancerous tissue as well as non-malignant tissue. The latter aids considerably in so-called ‘normalisation’ of the individual cancer tissue genome but also ensures more accurate characterisation of somatic mutations. The spectrum of somatic mutations can then be used to describe the evolution, molecular subtype and potential therapeutic vulnerabilities in the given tumour. Genomic alterations of bladder cancer in the young patient In the context of a young bladder cancer patient, early data suggest some somatic mutations are less common (e.g. mutations in TP53 and RB1) while 20

EUT Congress News

others seem to be more prevalent (e.g. HRAS). However, this concerns unpublished data obtained from the bladder cancer TCGA database, which included only 8 patients below the age of 45 years.

Figure 1

In daily clinical practice, one observes clustering of bladder cancer in families. However, one of the main risk factors of bladder cancer is exposure to carcinogens. Therefore, clustering of bladder cancer in families may mainly be related to similar environmental exposures. Hereditary bladder cancer is rare but has not yet been investigated in detail. One can hypothesise that some germline mutations may also have caused bladder cancer in the few described young patients. However, there is only scarce knowledge and the published data has caveats: the researcher used targeted sequencing, only focusing on a handful of genes. This approach may not allow a non-biased discovery of germline mutations that are Figure 1 associated with bladder cancer. Furthermore, this aspect has neither been investigated in the context of young patients nor in the context of ethnic backgrounds and races. In parallel to findings from e.g. breast cancer, it may not be surprising that the few reports also described the presence of germline mutations in the DNA damage repair pathway in bladder cancer patients. A more comprehensive analysis of germline mutations in bladder cancer is needed to understand their role in the development of bladder cancer. These investigations need to focus on associations of germline mutations and bladder cancer. On the other hand, as seen in other hereditary cancers, they need to investigate if the gene with a known germline mutation is affected by a second somatic mutation that may potentiate its cancer driving impact. Transcriptomic alterations in bladder cancer and young patients The understanding of transcriptomics in bladder cancer was dramatically improved by the discovery of molecular subtypes. Based on gene expression or transcriptomics, bladder cancers can be clustered into different groups, so called molecular subtypes. Different subtyping methods have been described that became more and more confusing for non-specialists. Groups that are involved in molecular subtyping undertook a great effort and consensus was reached on 6 molecular subtypes. Interestingly, when comparing these subtypes and patient age, it is noticeable that all bladder cancers of patients below 43 years showed a Luminal papillary subtype (see Figure 1). However, again the bladder cancer TCGA dataset was not designed to investigate transcriptomics in young bladder cancer patients and more comprehensive characterisation is needed. Recommendations for clinical practice There are currently no guidelines and recommendations for genetic counselling in bladder cancer. This is likely because of the lack of evidence, the fact that it often arises in older patients and is mainly related to exposure to carcinogens. However, until more evidence is available, it may be reasonable to follow recommendations from other cancer types. Referral to genetic counselling should be considered in patients with: •

•

to develop colorectal, endometrial, ovarian and gastric cancer. Screening of these organ systems should be considered too. Genetic counselling When referring a patient for genetic counselling, one should be aware of potential consequences. Due to the fact that germline mutations can be transmitted to descendants and be present in several other family members, detection of such a germline mutation in the referred patient may also affect his/her family members. Importantly, in cancer types with known hereditary components (e.g. breast cancer), the lack of detection of such a germline mutation does not reduce the risk for relatives of the patient conferred by a family history of cancer. These issues should be discussed with the patient prior to referral. Early data seem to show that germline mutations in DNA damage and mismatch repair are associated with bladder cancer. However, one can neither recommend a specific follow-up

schedule including cystoscopies or cytology nor surgical procedures such as cystectomy based on the current evidence. Take home messages: In patients with bladder cancer below the age of 50 years consider: •

not only somatic but also germline mutations

•

genetic counselling

•

association with Lynch syndrome and subsequent testing with immunohistochemistry

Sat 16 March 08.15-10.00: Plenary Session 1 Bladder cancer in the young patient: Unique aspects

What is the SIU?

THE SIU is

130

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THE SIU is

10,000 MEMBERS and counting.

cancer at the age below 50 years (in some cancer types this threshold is different, e.g. diffuse gastric cancer, leukaemia, sarcoma and cancer in children) synchronous or metachronous cancer (Cave: recommendation for colorectal, breast and endometrial cancer, may not be adopted directly to bladder cancer) three or more cases of breast, ovarian, pancreatic and/or aggressive prostate cancer in close relatives, including the patient. In this recommendation, bladder cancer is not listed but could be taken into account.

Urothelial carcinoma of the upper urinary tract is more frequent in patients with Lynch syndrome that is caused by mutations in mismatch repair genes (MLH1, MSH2, MSH6 or PMS2). Therefore, it is can be considered to search for defects in mismatch repair in patients with urothelial carcinoma of the upper urinary tract. In bladder cancer patients below the age of 50 years, it seems to be reasonable to screen for Lynch syndrome as well. It can be diagnosed by DNA sequencing or by immunohistochemistry for MLH1, MSH2, MSH6 and PMS2. The expression of at least one of these four proteins is absent in 83% of tumours from patients with Lynch syndrome. Finally, patients with Lynch syndrome have an increased risk

Come and visit us at booth E50 to learn more about SIU and our latest programmes and activities.

www.siu-urology.org

Saturday, 16 March 2019

Urolithiasis as a systemic disorder: What are the hypotheses? New pathogenic mechanism ‘endothelial cell hypothesis’ in calcium oxalate stone disease Prof. Kemal Sarica Chairman of EULIS Dept. of Urology Kafkas University Kars (TR)

The pathophysiological mechanisms of calcium oxalate stone formation are still to be elucidated. Published data so far showed that elevated urinary oxalate levels on one hand will induce renal tubular cell toxicity where a pre-existing renal epithelial cell injury preferably in proximal part of the tubes is essential for crystal attachment. On the other hand hyperoxaluria may cause crystal formation and deposition in the presence of injured renal tubular epithelium1-3. Although supersaturation is the main driving force for crystallisation, some basic research studies have also clearly pointed out that hyperoxaluria and subsequent crystal formation are not the sole prerequisites for this process. Although some investigators reported that oxalate and/or CaOx crystals have direct toxic effects on renal tubular cells, others suggested the crystal–cell interaction process as the crucial mechanism for renal tubular epithelial cell injury which is thought to be mediated by increased free radical production2-9. Vascular factors Although crystal-cell interaction was found to be responsible for tubular injury related crystal deposition, vascular factors have gained more importance in the formation of renal stones in recent years. The least popular one of these is intravascular phenomenon as proposed by Low and Stoller3. They proposed that stones form within the vasa recta of renal papillae. Injury to vasculature results in atherosclerotic-like lesions and the eventual calcification erodes the papillary duct and serves as a nidus. Although subsequent studies could not verify them10, in our recently published original study we were able to show that the renal epithelial cell injury is also under the control of vascular endothelial cells. Our results partly support this hypothesis where the correct order of events might be oxalate elevation in intravascular area, resulting in endothelial dysfunction first and eventually renal epithelial cell injury and death upon which facilitated crystal attachment occurs. Endothelial cell hypothesis In relation to this hypothesis we were able to show that hyperoxaluria induces asymmetrical dimethyl arginine (ADMA) expression which is a marker of endothelial dysfunction in renal tissue of ethylene glycol administered rats11. To support our hypothesis further, in another, later study we aimed to demonstrate this critical interaction between renal vascular endothelial (HUVEC) and renal tubular epithelial cells (RPTEC) in a direct manner by using co-cell culture system. Our data have clearly shown the decreased renal tubular cell viability after co-incubation of RPTECs with HUVECs and pretreatment with PDTC which antagonises ADMA and prevented the formation and extent of renal tubular cell death with restoration of endothelial cell function12. These findings did further confirm the results of our first study which focused on the ‘interaction between renal vascular endothelial and tubular epithelial cells’ resulting in renal tubular cell injury originating from endothelial cell dysfunction. Both of our studies put forward a new understanding, ‘endothelial cell hypothesis’ in stone formation. These findings were also partly supported by other authors. Ilbey and his co-workers13 showed that administration of PDTC to hyperoxaluria induced rats prevented crystallisation in renal tubules by decreasing oxidative stress in renal tissue. Although they claimed the findings to be the result of direct action of PDTC on renal tubular oxidant stress, their findings are actually in parallel with and supportive to our study mentioned above. In this study again, the authors did not demonstrate tubular cell death, although they attributed the protective role of PDTC to the prevention of hyperoxaluria-induced peroxidative damage to renal tubular cells. Related to their findings, induction of renal tissue iNOS expression is supposed to be by p38-MAPK whose expression was increased with ethylene glycol administration. Since p38-MAPK activity was shown Saturday, 16 March 2019

to be stimulated by vascular endothelial growth factor receptor-2 activation14 and vascular endothelial growth factor gene polymorphism has been found to be associated with calcium oxalate stone disease15, it can be postulated here that ethylene glycol-induced elevation of plasma oxalate levels initially affects the vascular endothelium and activates VEGF which eventually induces p38-MAPK and then iNOS expression and causes NO production. Similar data were reported by Huang et al.16: excessive CaOx crystal accumulation was shown to enhance endothelial NOS (eNOS), iNOS, and NAD(P)H oxidase protein expression in the kidney. Increased superoxide formation was thought to be derived from NAD(P)H oxidase and uncoupled eNOS, and increased nitrotyrosine formation from iNOS and ED1-positive cells that gathered around the CaOx crystals. Co-treatment with L-NAME reduced renal oxidative nitrosative stress and tubular damage. Renal tubular cell death This study again confirms that CaOx stone formation is a cumulative result of endothelial dysfunction. It states that increased ROS production was a result of NAD(P)H oxidase activation by calcium oxalate crystals and resulting eNOS uncoupling further amplifies oxidative stress in kidneys. The results of our study mentioned above are in accordance with these findings and prove that hyperoxaluria-induced endothelial cell dysfunction plays a crucial role in renal tubular cell death. Endothelial cells not only play role in pathological processes, but also regulate some physiological mechanisms. Proximal tubule epithelial cells are in close contact with the renal capillaries. Vascular endothelial cells have been shown to regulate proximal tubule epithelial cell function especially sodium transport through NOS-dependent upregulation of cGMP in these cells17. Additionally, the endothelium of the peritubular capillaries have been shown to affect proximal tubule acidification, probably via stimulation of Na?/H? exchanger and endothelium- derived nitric oxide (EDNO) which has been thought to play important role in this function18. Confirmatory results were reported by Wang et al.19 who found that nitric oxide regulates HCO3- and Na? transport by a cGMP-mediated mechanism in the kidney proximal tubule. Based on all these demonstrated facts we may claim that if physiological transport mechanisms are under the control of vascular endothelial cells, any pathological condition affecting endothelial function should have direct effects on renal tubule function. The above-mentioned hyperoxaluria-induced changes in our published study do further support this critical relationship. Urolithiasis and systemic disorders The possible association of urolithiasis with certain systemic disorders such as obesity, hypertension, hyperlipidaemia and metabolic syndrome (all of which are characterised by systemic endothelial dysfunction)20-25 does further support our ‘endothelial cell dysfunction’ theory in the formation of renal stones from the ‘clinical’ point of view. Most of these studies demonstrate increased ROS in these conditions. Disturbed endothelial function is supposed to be the result of oxidative stress induced by high lipids, blood pressure or glucose. In our previously published study, we have shown that hyperoxaluria causes systemic endothelial dysfunction as ADMA levels were found to be increased in hyperoxaluric rats11. Since hyperoxaluria is the result of excess oxalate in the blood stream, an initial event could be systemic endothelial dysfunction in this cascade. All of these studies indicate that urolithiasis is not a disease restricted only to the kidneys but is part of a systemic disorder or may be a separate syndrome. Oxalate-induced death of renal tubular epithelial cells exhibits predominantly the features of apoptosis26. Oxalate-induced free radical production is the offender of this process. Increase in the rate of apoptosis with co-incubation of RPTECs with HUVECs indicates that apoptosis of renal tubular epithelial cells could be mediated by endothelial cells. As mentioned above again, our previously published data clearly showed that pretreatment with PDTC will preserve endothelial cell function and prevent tubular apoptotic changes indicating the possible direct role of endothelial cells in stone formation.

‘endothelial cell hypothesis’ in CaOx stone formation. The findings which may be obtained with this project will help understand ‘systemic underlying causes of calcium oxalate stone disease’ better and result in treatment strategies that target endothelial cell preservation which may help in the prevention and/or management of stone disease. References 1. Verkoelen CF, van der Boom BG (1998) Increased calcium oxalate monohydrate crystal binding to injured renal tubular epithelial cells in culture. Am J Physiol 274:F958 2. Scheid C, Koul H, Hill WA et al (1996) Oxalate toxicity in LLCPK1 cells: role of free radicals. Kidney Int 49(2):413. 3. Low RK, Stoller ML (1997) Endoscopic mapping of renal papillae for Randall’s plaques in patients with urinary stone disease. J Urol 158(6):2062 4. Khan SR, Byer KJ, Thamilselvan S et al (1999) Crystal–cell interaction and apoptosis in oxalate-associated injury of renal epithelial cells. J Am Soc Nephrol 10(Suppl 14):S457 5. Verkoelen CF, van der Boom BG (1998) Increased calcium oxalate monohydrate crystal binding to injured renal tubular epithelial cells in culture. Am J Physiol 274:F958 6. Sarica K, Yagci F, Bakir K et al (2001) Renal tubular injury induced by hyperoxaluria: evaluation of apoptotic changes. Urol Res 29(1):34 7. Sarica,K.,Erbagcı,A.,Yagci,F., Bakır,K.,Erturhan,S.,Uçak,R.: Limitation of apoptotic changes in renal tubular cell injury induced by hyperoxaluria. Urol.Res.; 32:271-277, 2004. 8. Tanriverdi O., Telci D., Aydin M., Ekici ID, Miroglu C., Sarica K., “Hyperoxaluria induced tubular ischemia: the effects of verapamil and vitamin E on apoptotic changes with an emphasis on renal papilla in rat model” Urol Res. 2012 Feb;40(1):17-25. 9. Horuz R, Göktas C, Çetinel CA, Akça O, Aydın H, Ekici ID, Albayrak S, Sarıca K. : The role of TNF-associated cytokines in renal tubular cell apoptosis induced by hyperoxaluria. Urolithiasis. 2013 Jun;41(3):197-203. 10. Evan A, Lingeman J, Coe FL et al (2006) Randall’s plaque: pathogenesis and role in calcium oxalate nephrolithiasis. Kidney Int 69(8):1313. 11. Aydin H, Yencilek F, Mutlu N et al (2010) Ethylene glycol induced hyperoxaluria increases plasma and renal tissue asymmetrical dimethylarginine in rats: a new pathogenetic link in hyperoxaluria induced disorders. J Urol 183(2):759. 12. Sarıca K, Aydin H, Yencilek F, Telci D, Yilmaz B. Human umbilical vein endothelial cells accelerate oxalateinduced apoptosis of human renal proximal tubule epithelial cells in co-culture system which is prevented by pyrrolidine dithiocarbamate.Urol Res. Oct;40(5):4616.; 2012. 13. Ilbey YO, Ozbek E, Sims¸ek A et al (2010) Pyrrolidine dithiocarbamate treatment prevents ethylene glycolinduced urolithiasis through inhibition of NF-jB and

p38-MAPK signaling pathways in rat kidney. Arch Ital Urol Androl 82(2):87 14. Gee E, Milkiewicz M, Haas TL (2010) p38 MAPK activity is stimulated by vascular endothelial growth factor receptor 2 activation and is essential for shear stress-induced angiogenesis. J Cell Physiol 222(1):120 15. Chen WC, Chen HY, Wu HC et al (2003) Vascular endothelial growth factor gene polymorphism is associated with calcium oxalate stone disease. Urol Res 31(3):218 16. Huang HS, Ma MC, Chen J (2008) Chronic L-arginine administration increases oxidative and nitrosative stress in rat hyperoxaluric kidneys and excessive crystal deposition. Am J Physiol Renal Physiol 295(2):F388 17. Linas SL, Repine JE (1999) Endothelial cells regulate proximal tubule epithelial cell sodium transport. Kidney Int 55(4):1251. 18. Amorena C, Castro AF (1997) Control of proximal tubule acidification by the endothelium of the peritubular capillaries. Am J Physiol 272(2 Pt 2):R691 19. Wang T (1997) Nitric oxide regulates HCO3- and Na? Transport by a cGMP-mediated mechanism in the kidney proximal tubule. Am J Physiol 272(2 Pt 2):F242 20. Taylor EN, Stampfer MJ, Curhan GC (2005) Obesity, weight gain, and the risk of kidney stones. JAMA 293:455 21. Zimmerer T, Weiss C, Hammes HP et al (2009) Evaluation of urolithiasis: a link between stone formation and diabetes mellitus? Urol Int 82(3):350 22. Obligado SH, Goldfarb DS (2008) The association of nephrolithiasis with hypertension and obesity: a review. Am J Hypertens 21(3):257 23. West B, Luke A, Durazo-Arvizu RA et al (2008) Metabolic syndrome and self-reported history of kidney stones: the National Health and Nutrition Examination Survey (NHANES III) 1988–1994. Am J Kidney Dis 51(5):741 24. Celik A, Davutoglu V, Sarica K, Erturhan S, Ozer O, Sari I, Yilmaz M, Baltaci Y, Akcay M, Al B, Yuce M, Yilmaz N.:Relationship between renal stone formation, mitral annular calcification and bone resorption markers.Ann Saudi Med.;Jul-Aug;30(4):301-5; 2010. 25. Aydin H, Yencilek F, Erihan IB, Okan B, Sarica K.: Increased 10-year cardiovascular disease and mortality risk scores in asymptomatic patients with calcium oxalate urolithiasis.Urol Res.;Dec;39(6):451-8.,2011. 26. Miller C, Kennington L, Cooney R et al (2000) Oxalate toxicity in renal epithelial cells: characteristics of apoptosis and necrosis. Toxicol Appl Pharmacol 162:132

Saturday 16 March 10.00-14.00: Meeting of the EAU Section of Urolithiasis (EULIS) Management of urinary stones: Where are we in 2019?

www.eulis19.org

EULIS19 5th Meeting of the EAU Section of Urolithiasis 3-5 October 2019, Milan, Italy An application has been made to the EACCME® for CME accreditation of this event

Call for Abstracts Deadline 5 June 2019

In summary, published limited data in the literature and our results indicate a new pathogenic mechanism EUT Congress News

Anniversary 20th EAUN Meeting Strong international bonds highlighted in Joint Sessions with AEEU, ECET and ANZUNS Corinne Tillier Chair EAUN Scientific Congress Office Amsterdam (NL)

c.tillier@eaun.org Some of the readers may remember the first urology nurses conference in Brussels, Belgium, where around 68 nurses joined in session room Cinedoc, April 2000. Despite some problems with the projectors on the second day, this first meeting was such a success that it was decided to continue this initiative in the next year and form a group of organisers.

Rita Willener presenting in Stockholm in 2009

At the request of Ronny Pieters, on 7 September 2000 a meeting was organised by the EAU to discuss the start of a nurses’ committee. Ronny Pieters (BE), Martin Beynon (UK), Maria Ascension Crespo Garcia (ES), Rita Willener (CH), Thea De Laat (NL) attended, as well as two professors from Switzerland, Prof. Fiona Burkhard (CH) and Prof. Hans-Jürg Leisinger (CH), and the Secretary General and founder of the EAU, Prof. Frans Debruyne, as well as EAU Executive Manager Operational Affairs Jacqueline Roelofswaard.

proposed a programme on Testicular and Prostate cancer, Cystoscopy and Nurses training in various countries. At the third meeting in February in Birmingham in 2002, nurse participants from all over Europe got to know each other better at the ‘Healthcare Professionals Dance Evening’ in Tiger Tiger, the same party destination that was unknowingly selected by the EAUN Board 15 years later in London! Ronny Pieters chaired the EAUN until 2004, when Aase Grundal (DK) took over (she chaired from 2004-2006). After a short co-chairmanship by Ronny Pieters and Jerome Marley until 2007, the following chairs were installed at the annual meeting: Bente Thoft Jensen (DK, 2007-2011), Kate Fitzpatrick (IE, 2011-2014), Lawrence Drudge-Coates (UK, 2014-2016) Stefano Terzoni (IT, 2016-2018). The current chair is Susanne Vahr Lauridsen (DK, 2018-2020), who will hand over the baton to Paula Allchorne (UK) to chair the EAUN from 2020 until 2022.

The committee that decided to initiate an annual meeting for urology nurses in Brussels in April 2000

At the conference in March 2005 the very first EAUN guidelines were introduced, entitled “Urethral Catheterization, Section 1: Male Catheterization”, of what now is a series of 11 guidelines. The first Nurses Panel consisted of Martin Beynon (UK), Thea De Laat (NL), Jessica Greenwood (UK), Toine Van Opstal (NL), Eva Lindblom (SE) and Eija Luotonen Emblem (NO). Many other important guidelines for urology nurses followed, continuously keeping up with the developments in the scientific process of developing guidelines. The series currently counts 7 topics which are regularly reviewed. In 2014 the EAUN Board decided that the important task of composing the Scientific Programme of the annual EAUN meeting should be left to a committee of experienced scientifically trained nurses, which would enable the board to increase their efforts to develop educational activities and accreditation specifically for the members and build on the international relations.

16-18 March 2019, Barcelona Looking back it cannot be missed that there is one person who has been at the heart of all these developments. This, and the joyous occasion of celebrating the 20th annual meeting here in Barcelona, is the reason the EAUN Board has established a lifetime achievement award to be awarded yearly to an exceptional EAUN member. The award is named after its initiator: Mr. Ronny Pieters (BE). The award will be handed over for the first time at the Plenary Opening Session this morning at 9.00 AM. Don’t miss it!

Ronny Pieters handing over the award to A. Bäärnhielm in 2009

The first Scientific Congress Office (SCO) counted several members with a long and strong relation with the EAUN: Rita Willener (CH), Lisette Van De Bilt (NL), Bente Thoft Jensen (DK), Jerome Marley (IE) and was chaired by Stefano Terzoni (IT), EAUN Board Member, and they have set the tone for a more complete, and more attractive programme with a high scientific level.

Saturday 16 March 09.00-10.00: Plenary Session 1 at the 20th International EAUN Meeting: From 20th century nursing into the 21st century

UROGENITAL CANCER TREATMENT AT A GLANCE PA S T, P R E S E N T A N D F U T U R E

34TH ANNUAL EAU CONGRESS, BARCELONA AN IPSEN SPONSORED SATELLITE SYMPOSIUM

Jerome Marley chairing in 2009

C H AI R E D BY P R O FE S S O R L U I S M A R TÍ N E Z - P I Ñ E I R O ( S PA I N )

At the EAU Congress in Geneva in 2001 the first board of the EAUN was installed, of course with Ronny Pieters as the first Chair, and as first board members: Martin Beynon (UK), Fiona Burkhard (CH), Maria Ascension Crespo Garcia (ES), Thea De Laat (NL), Helén Marklund Bau (SE), Thomas Stöcker (DE), Rita Willener (CH). For the Geneva nurses’ meeting an abstract session and an excellent programme were composed, also thanks to a Swiss nurses and doctors group who

S AT U R D AY 1 6 M A R C H , 1 8 : 0 0 - 1 9 : 3 0 GREEN AREA, ROOM 3

Helén Marklund Bau receives a prize in Milan in 2008

18:00–18:05

Chairperson’s welcome and introduction

Professor Luis Martínez-Piñeiro

18:05–18:30

Challenging paradigms in advanced prostate cancer: A new era

Dr María Ribal

18:30–18:55

The changing landscape in advanced Renal Cell Cancer management

Professor Marc Oliver Grimm

18:55–19:20

Blue light flexible cystoscopy: Improving the patient experience

Professor Yair Lotan

19:20–19:30

Summary and close

Professor Luis Martínez-Piñeiro

The landscape of urogenital cancer treatment is constantly developing through the generation of new clinical data. This symposium will take a journey from the past through to the present with a view of what the near future holds for prostate, renal and bladder cancers.

and immunotherapies, and how this could potentially improve patient outcomes. Recent data is investigating how patient characteristics can impact a physician’s approach to treatment sequencing and selection.

Treatments for prostate cancer have continually evolved to improve patient outcomes. Lately, there has been clinical interest in systemic therapies, using androgen deprivation therapies (ADT) as a backbone for combination therapies in the management of patients with prostate cancer.

Finally, clinical evidence from trials using blue-light flexible cystoscopy (BLFC) have demonstrated the consistent performance of photodynamic diagnosis in the outpatient setting and its positive impact on the patient experience. The main challenge now is how this technique can be integrated into urological services across Europe.

For advanced renal cell carcinoma (aRCC), there is a growing body of evidence exploring the use of a combined treatment approach with tyrosine kinase inhibitors (TKIs)

The faculty welcome you to join them for this engaging and insightful symposium navigating the landscape of urogenital cancer treatment.

CBZ-ALL-001429 FEBRUARY 2019

The 3rd International EAUN Meeting took place in 2002 in Birmingham

EUT Congress News

Saturday, 16 March 2019

Innovative surgical procedures in functional urology Are synthetic slings for female stress urinary incontinence coming to an end? David Castro Díaz Department of Urology. Hospital Universitario de Canarias. Universidad de La Laguna (ES)

Surgical management of female stress urinary incontinence (SUI) has evolved within the last two decades implementing synthetic mid-urethral slings (MUS) which became the standard procedure. In fact, MUS have replaced the traditional Burch colposuspension and the autologous fascia sling, becoming the most commonly used procedure for the management of SUI around the world. In the search for a better outcome and simplicity, many techniques were initially adopted to be later abandoned because of either safety or efficacy issues. Moreover, few devices were introduced into the market to be later also abandoned due to poor long-term durability as well as complications1. Just to mention a few, we might recall the Kelly plication or anterior repair approach, the Marshall-Marchetti Krantz procedure, also known as cystourethropexy, several needle suspensions techniques, Raz’s procedures, the UroVive self-detachable balloon system, the Vesica percutaneous bladder neck stabilization, the bone anchoring AMS, the in-fast™ minimally invasive pubovaginal sling, the AMS Mainstay for bone anchoring, etc. Consequently, Burch colposuspension and autologous facial sling became the most commonly used procedures for the management of stress urinary incontinence until the introduction of synthetic MUS.

“Although colposuspension is related with later development of prolapse, it has been associated with high rates of objective and subjective long-term cure.” Cure rates and morbidity Although colposuspension is related with later development of prolapse, of either middle or posterior compartment2, it has been associated with high rates of objective and subjective long-term cure. Studies have shown that after 5 years, 70% of women continued dry3. Laparoscopic colposuspension is associated with similar cure rate of SUI, when performed in the same manner but with a lower risk of complication and shorter hospital stay4. The autologous fascial sling has been considered as to provide a similar cure rate of SUI, when compared with colposuspension but with a higher risk of post-operative complications, particularly bladder outlet obstruction, need for self-catheterization, etc.5,6. In recent years a modification of the traditional pubovaginal, a shorter sling (sling on a string), has been used based on a needle suspension technique in a more minimally invasive manner, placed loosely at the mid-urethra, although long term outcome data are needed in order to widely adopt this technique7. However, in a direct comparison of autologous fascial sling with colposuspension, in a controlled randomised trial, the autologous fascial sling showed a significantly higher cure rate but with higher morbidity, including urgency incontinence, voiding dysfunction and urinary tract infections8. Improved management of SUI The introduction of the tension-free vaginal tape (TVT) in 1998, transfigured the management of SUI worldwide. The main reason for this change was that TVT demonstrated to be an efficacious and minimally invasive procedure, that could even be carried out under an outpatient basis causing less postoperative pain and morbidity. This success stimulated the development and manufacturing of many similar commercial slings. Complications were mostly related to inexperienced and incorrect trocar positioning and placement of the tape causing serious injury to the bladder, bowel or vessels warranting the need of intraoperative cystoscopy. In order to reduce the risk of a retropubic pass of the trocar, the need of cystoscopy and to simplify the procedure, a trans-obturator approach (TOT) to Saturday, 16 March 2019

implant a MUS was introduced later becoming very commonly used9,10. As it is a minimally invasive procedure it can also be performed on outpatient or day case surgery. Several studies have demonstrated its efficacy and a very low rate of complications. When comparing TOT this with the retropubic TVT, both techniques show similar efficacy and safety11. Moreover, several systematic reviews and metaanalysis of randomised controlled trials have shown comparable or even higher cure rate for a synthetic mid-urethral sling, when compared with colposuspension. In addition, the operative time is shorter, and the rate of voiding dysfunction is lower with MUS when compared with colposuspension12. The raise of mid-urethral tapes As a consequence of the benefits of MUS, when compared with colposuspension and autologous fascial slings, mid-urethral tapes became the procedure of choice for the management of female stress urinary incontinence worldwide. Due to the success of mid-urethral synthetic slings, the use of mesh implants was extended to the management of pelvic organ prolapse (POP) and implemented in daily practice. The rational basis for this approach was that traditional POP surgery had a high recurrence rate, which could be lowered using a synthetic transvaginal mesh (TVM). However, due to the high complication rate of POP meshes, patient complains and legal issues become very common. On the other hand, in a multicentre randomised controlled trial, comparing traditional repair versus synthetic mesh and biological grafts in more than one thousand women, with two years follow-up, it was observed that neither synthetic or biological TVM provided any additional benefit over traditional native tissues POP repair. Furthermore, although there were no differences regarding serious adverse events, dyspareunia or recurrences, one in eight of women in the synthetic mesh group needed to undergo reoperations for management of mesh complications13. The FAD released safety communications on the use of TVM and significant development in regulations, medico-legal issues and statements from scientific societies warned of the actual risk of using meshes for POP repair. As a consequence of a growing number of legal claims, some companies manufacturing synthetic meshes decided to withdraw their products from the market. Although most legal claims involved synthetic slings for SUI, social and patients concern started after the FDA communication on TVM for POP. Nevertheless, several systematic reviews, evaluating efficacy, complications and re-intervention rates of MUS, have demonstrated similar or even higher objective cure rate of MUS when compared with colposuspension. Furthermore, MUS are associated with shorter operating time, less postoperative de novo voiding issues or overactive bladder symptoms (14). Although MUS were initially implemented without enough evidence, this procedure is clearly the most extensively investigated technique for surgical management of SUI in women. Moreover, MUS offer a good safety profile, as concluded in a recent Cochrane review14. The social, legal and economic impact of all of these controversies have led authorities to ban the use of implant mesh in several countries in order to prevent patients from possible damage of synthetic materials for SUI and POP. As a result, physicians

and scientific societies raised concern because such constraint will prevent women from having the current best surgical option for the management for SUI. Scientific societies elaborated guidelines for the indications of its use in patients with POP, limiting the use of meshes only to complex cases with recurrent prolapse in specialist referral centres15. Differences from synthetic meshes for POP and SUI were highlighted as there are clear differences particularly regarding surface extension which is obviously smaller for midurethral tapes and larger for TVM. Recommendations for mesh implants Because the safety of mesh implants has been brought into question by thousands of women around the world, mesh implants have been banned in several countries including Australia, New Zeeland and the UK. The National Institute of Clinical Excellence (NICE) recommends the use of surgical mesh for SUI or POP only after all other surgical options have failed. NICE also recommends “the use of mesh implants for stress urinary incontinence only as last resort”. NICE suggested that “suspension of the use of mesh in England should remain in place until the national database for registering operations and complications was up and running and when all operations could be performed by specialist surgeons based at specialist treatment centres”16.

“The EAU guidelines continue recommending MUS and other procedures highlighting the need to properly inform patients on possible side effects and complications.” NICE also warns on the need to properly inform women undergoing surgery for SUI or POP, of possible risk and benefits of the procedure. A close follow-up of patients was also suggested. Some authorities have recommended that mesh should be just a third line option therapy and be offered only after medical and other surgeries failed. While most of us would agree on this statement regarding POP, it is clear that most of the surgeons involved in the management of SUI, would recommend the use of mid-urethral synthetic slings because of its efficacy, safety and simplicity when compared with Burch colposuspension or autologous sling. Nevertheless, as the long-term outcome is not completely known, database and national registries should be implemented and to achieve this it is clearly needed the support from authorities as our main aim is to obtain the best benefit for our patients. A recent join consensus group by the European Association of Urology and the European Urogynaecology Association concluded that “When considering surgery for SUI, it is essential to evaluate the available options, which may include synthetic mid-urethral slings (MUSs) using PP tapes, bulking agents, colposuspension, and autologous sling surgery. The use of synthetic MUSs for surgical treatment of SUI in both male and female patients has good efficacy and acceptable morbidity. Synthetic mesh for POP should be used only in complex cases with recurrent prolapse in the same compartment and restricted to those surgeons with

Surgical treatment of female SUI EAU Recommendations

appropriate training who are working in multidisciplinary referral centres”15. Furthermore, the EAU guidelines continue recommending MUS and other procedures highlighting the need to properly inform patients on possible side effects and complications17. The banning of MUS would change the current practice for the management of SUI in such a way that would compel surgeons to use old techniques, that have been proved to have less efficacy and safety, and sufferers would be prevented from receiving the best evidence base surgical management. Consequently, synthetic slings for the management of stress urinary incontinence have not come to an end, but as a consequence of the media and social impact, this controversy may possibly change our current practice as many patients might be reluctant to undergo a synthetic sling placement for the management of this bothersome and costly condition. References 1. Glazener CM, Cooper K. Bladder neck needle suspension for urinary incontinence in women. Cochrane Database Syst Rev 2014;12: CD003636. 2. Maher C, Feiner B, Baessler K, Christmann-Schmid C, Haya N, Brown J. Surgery for women with anterior compartment prolapse. Cochrane Database Syst Rev 2016;11:CD004014. 3. Lapitan MCM, Cody JD. Open retropubic colposuspension for urinary incontinence in women. Cochrane Database Syst Rev 2016;2:CD002912 4. Dean N, Ellis G, Wilson PD, Herbison GP. Laparoscopic colposuspension for urinary incontinence in women. Cochrane Database Syst Rev 2006;3:CD002239. 5. Rehman H, Bezerra CC, Bruschini H, Cody JD. Traditional suburethral sling operations for urinary incontinence in women. Cochrane Database Syst Rev 2011;1:CD001754. 6. Albo ME, Richter HE, Brubaker L, et al. Burch colposuspension versus fascial sling to reduce urinary stress incontinence. N Engl J Med 2007;356:2143–55. 7. Khan N, Abboudi H, Khan MS, Dasgupta P, Ahmed K. Measuring the surgical ‘‘learning curve’’: methods, variables and competency. BJU Int 2014;113:504–8. 8. Albo ME, Richter HE, Brubaker L, et al. Burch colposuspension versus fascial sling to reduce urinary stress incontinence. N Engl J Med 2007;356:2143–55. 9. Delorme E1, Droupy S, de Tayrac R, Delmas V.Eur Urol. 2004 Feb;45(2):203-7.Transobturator tape (Uratape): a new minimally-invasive procedure to treat female urinary incontinence. Eur Urol, 2004 10. Novel Surgical Technique for theTreatment of Female Stress Urinary Incontinence: Transobturator Vaginal Tape Inside-Out. Jean de Leval*. European Urology 44 (2003) 724–730 11. Leone Roberti Maggiore U1,2, Finazzi Agrò E3, Soligo M4, Li Marzi V5, Digesu A6, Serati M7. Int Urogynecol J. 2017 Aug;28(8):1119-1130. doi: 10.1007/s00192-0173275-x. Epub 2017 Feb 17. Long-term outcomes of TOT and TVT procedures for the treatment of female stress urinary incontinence: a systematic review and meta-analysis. 12. Fusco F, Abdel-Fattah M, Chapple CR, Creta M, La Falce S, Waltregny D, Novara G. Eur Urol. 2017 Oct;72(4):567591. doi: 10.1016/j.eururo.2017.04.026. Epub 2017 May 4. Review. 13. Glazener CM, Breeman S, Elders A, et al. Mesh, graft, or standard repair for women having primary transvaginal anterior or posterior compartment prolapse surgery: two parallel-group, multicentre, randomised, controlled trials (PROSPECT). Lancet 2017;389:381–92 14. Ford AA, Rogerson L, Cody JD, Ogah J. Mid-urethral sling operations for stress urinary incontinence in women. Cochrane Database Syst Rev. 2015;CD006375. https://doi.org/10.1002/14651858.CD006375.pub3 15. Chapple CR, Cruz F, Deffieux X et all. Consensus Statement of the European Urology Association and the European Urogynaecological Association on the Use of Implanted Materials for Treating Pelvic Organ Prolapse and Stress Urinary Incontinence. Eur Urol http://dx.doi. org/10.1016/j.eururo.2017.03.048 16. Kmietowicxz Z.Use mes implants for stress urinary incontinence only as last resort, says NICE. BMJ 2018. DOI:10.1136/bmj.k4242 (Publishes 9 October 2018) 17. Burkhard F, Bosch JLHR, Cruz F et al. European Association of Urology. Guidelines on Urinary Incontinence 2018

Saturday 16 March 10.15-14.00: Meeting of the EAU Section of Female and Functional Urology (ESFFU) Innovative surgical procedures in functional urology

EUT Congress News

Perioperative systemic immunotherapy Where are we heading in muscle invasive bladder cancer? Test new therapies Radical cystectomy in Europe usually occurs 6 to 8 weeks after MIBC diagnosis, and this time frame offers a unique opportunity to test new therapies preoperatively. Pathological downstaging to non– muscle-invasive disease or pathological complete response (pT0) to neoadjuvant chemotherapy is a well-recognised biomarker of improved overall survival (OS) and can be offered as a suitable endpoint for phase II neoadjuvant trials12,13.

Dr. Andrea Necchi Dept. of Medical Oncology Milan (IT)

The PURE-01 study was designed to obtain biomarker results and assess the efficacy of single-agent pembrolizumab in patients with MIBC, regardless of cisplatin eligibility14. In this study, patients with T2-3bN0M0 MIBC received three courses of 200 mg pembrolizumab every 3 weeks, preceding radical cystectomy. Pembrolizumab exhibited a 42% pT0 among 50 treated patients and was safely administered. Immune-related adverse events have been reported, but they did not delay the planned surgery and postsurgical complications were similar to those reported in the most recent literature related to either open or robot-assisted procedures.

After decades of therapeutic stagnation in the field of urothelial carcinoma (UC), the introduction of new agents targeting the PD-1 and PD-L1 axis has revolutionised the way we currently manage locally advanced or metastatic UC1-6. These improvements have meant a significant shift in the way we conceive the treatment of early stage bladder UC thus far. The evolving standard of care Based on their documented activity in UC, coupled with the optimal toxicity profile, immune checkpoint inhibitors yield the best features for use in earlier disease stages (e.g. muscle-invasive bladder cancer (MIBC) in nonmetastatic UC). By recapitulating the therapeutic model proposed for early-stage non– small cell lung cancer or melanoma7,8, integrating short courses of immunotherapy before radical cystectomy in MIBC is poised to make a significant impact in MIBC management. In fact, although the recommended standard of care for MIBC in patients who are eligible to receive cisplatin is neoadjuvant chemotherapy followed by radical cystectomy, the real-world adherence to this standard therapy is poor, with less than 25% of patients ultimately accessing multimodality treatment9. Additionally, about 50% of the total amount of patients with UC are considered ineligible to receive cisplatin based on their renal function, performance status and comorbidities, and a subset of patients refuse to receive any chemotherapy10. And although neoadjuvant chemotherapy is active, residual high-risk disease (i.e. pT2 or higher) is still present in more than 50% of patients and represents a poor prognostic factor11. Finally, for the patients who cannot receive cisplatin, there is no standard neoadjuvant therapy.

Pembrolizumab (PURE-01) Pembrolizumab (PANDORE) Atezolizumab Atezolizumab Avelumab (BL-AIR) Atezolizumab (ABACUS) Nivolumab/urelumab Nivolumab/ipilimumab (NABUCCO) Durvalumab/tremelimumab vs. chemotherapy (DUTRENEO) Durvalumab/tremelimumab (NITIMIB) Durvalumab/tremelimumab Nivolumab ± ipilimumab (CA209-9DJ) Durvalumab + olaparib (NEODURVARIB)

Country

Eligibility

Cisplatin Eligibility Italy T2-3aN0M0 Yes France T2-4N0 or Nx No South Korea T2-4aN0M0 N/A United States T<2, T2-4N0M0 No United States T2-4aN0M0 No Europe T2-4aN0M0 No Immune Combination Therapy United States T2-4aN0M0 No Netherlands T3-4N0 or N+ No

EUT Congress News

Trial Identifier

Status

NCT02736266 NCT03212651 NCT03577132 NCT02451423 NCT03498196 NCT02662309

Has results Enrolling Enrolling Enrolling Enrolling Has results

NCT02845323 NCT03387761

Enrolling Enrolling

Spain

T2-4N0 or N1

Yes

NCT03472274

Enrolling

Switzerland

T2-4N0 or N+

NCT03234153

Enrolling

MDACC MSKCC

T2-4aN0M0 T2-4aN0M0

No No

NCT02812420 NCT03520491

Enrolling Enrolling

Spain

T2-4aN0M0

NCT03534492

Enrolling

NCT03294304

Enrolling

NCT03674424

Enrolling

NCT02690558

Enrolling

NCT02365766

Has results

NCT03558087

Enrolling

NCT03661320

Enrolling

NCT03732677

Enrolling

NCT03549715

Not yet enrolling

Chemo-immunotherapy Combinations Nivolumab + gemcitabine/ United States T2-4aN0M0 Yes cisplatin (BLASST-1) Avelumab (AURA) ± Belgium T2-4N0 or N+ Yes/No chemotherapy Pembrolizumab + gemcitabine/ United States T2-4N0 or Nx Yes cisplatin Pembrolizumab + gemcitabine/ Indiana University T2-4aN0M0 Yes cisplatin Nivolumab + gemcitabine/ Hoosier Cancer T2-4aN0M0 Yes cisplatin Research Network Multicentre T2-4aN0M0 Yes Chemotherapy vs. international chemotherapy + nivolumab, ± BMS-986205 (CA017-078) Chemotherapy vs. Multicentre T2-4aN0M0 Yes chemotherapy + durvalumab international Durvalumab + tremelimumab French multicentre T2-4aN0-1M0 Yes + dose-dense MVAC (NEMIO)

Finally, the preliminary findings of a phase 1b/2 trial of pembrolizumab plus gemcitabine and cisplatin showed an encouraging pathologic downstaging proportion of approximately 60%17.

Current challenges However, several important issues necessitate additional data to confirm such a therapeutic strategy as the new standard. Firstly, the patient selection still needs to be optimised. Whether cisplatin eligibility is needed to select patients for new neoadjuvant therapies is a question of In particular, no differences in terms of intra-, perinoteworthy importance, and it is linked to the role and postoperative complications were recorded of PD-L1 expression. Although the PURE-01 study compared with patients from the same centre demonstrated that the strategy of treating all undergoing radical cystectomy and not receiving patients is feasible, it should be noted that, among pembrolizumab. Similarly, intraoperative performance patients with advanced UC, the safety alert on (e.g. number of removed lymph nodes, soft tissue decreased survival with pembrolizumab and surgical margins and operating time) was not atezolizumab in patients who are eligible to receive compromised by neoadjuvant immunotherapy. cisplatin with low PD-L1 expression from Notably, PD-L1 expression (defined as combined IMvigor130 and KEYNOTE-361 studies resulted in an positive score ≥ 10% with the 22C3 antibody) and FDA update of drug labels. Therefore, caution is high tumour mutational burden (TMB; assessed with needed when avoiding standard cisplatin-based the FoundationOne assay) predicted for enriched chemotherapy, and thorough patient information is pathologic responses. necessary prior to including patients in such trials. A summary of the ongoing neoadjuvant PURE-01 trial immunotherapy trials, including key information on At last year’s Annual EAU Congress, updated patient selection, is provided in Table 1. results from the PURE-01 trial have been presented, including the preliminary analysis of Secondly, long-term follow-up is lacking in most survival. Of note, pembrolizumab confirmed to be immunotherapy trials and, most importantly, no effective both in terms of relapse-free survival data so far indicate RFS and OS improvement in the (RFS) and overall survival (OS), also in those postoperative setting among patients who received patients who did not respond at the pathologic neoadjuvant immunotherapy. Most noteworthy, the level15. value of pathological response after neoadjuvant single-agent checkpoint inhibitors is unknown.

Table 1: Summary of the clinical trials of neoadjuvant immunotherapy recruiting patients with muscleinvasive bladder cancer Single-Agent Therapy

The results of another window-of-opportunity trial have been presented, allowing for the administration of two courses of neoadjuvant atezolizumab in patients with cisplatin-ineligible MIBC. In this study, a pT0 was observed in 40% of patients with PD-L1–positive disease (evaluated on tumour microenvironment with the anti–PD-L1 antibody SP142) compared with only 16% in the PD-L1–negative cohort16. In both investigatorinitiated neoadjuvant trials, treatment produced major pathologic responses indicating that the side effects of chemotherapy can be reliably avoided when using single-agent immunotherapy.

Role of biomarkers These limitations highlight the role of the biomarkers associated with enriched pathologic responses. Besides the value of PD-L1 expression, analyses of matched pre- and post-therapy tumour samples in the PURE-01 and ABACUS studies revealed that strong immune-mediated mechanisms of adaptive resistance may develop during neoadjuvant immunotherapy administration and may contribute to the lack of tumour regression from radical cystectomy, despite a concurrent promotion of adaptive immunity. In addition, TMB emerged as potentially the biomarker most robustly associated with the activity of pembrolizumab.

Interestingly, some of the biomarkers predictive for neoadjuvant chemotherapy activity are also reported with neoadjuvant immunotherapy use. DNA damage response and repair (DDR) gene alterations, for example, have been associated with both dose-dense neoadjuvant gemcitabine/cisplatin and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy, although they emerged as a surrogate of TMB in the PURE-01 study17,18. Similarly, the basal phenotype of The Cancer Genome Atlas classification was linked to the greatest benefit achieved with neoadjuvant chemotherapy, and its immune infiltrate features also portend response probabilities with checkpoint inhibitor use19. All these premises warrant confirmatory studies with a randomised design. The potential of combination immunotherapy Of note, the dynamic expression of several negative regulators of the immune response from the PURE-01 study also suggests that combination immunotherapeutic approaches may further enhance the pathological response. Also, the few ‘drugable’ gene alterations that were lost or newly identified in cystectomy specimens support the need for reassessing post-immunotherapy tissue before screening the patients for trials with targeted agents. Among the new drug combination strategies, emerging data point at the potential of poorer response to anti–PD-L1 therapy in patients with FGFR aberration–positive disease. The response to checkpoint inhibitors is largely dependent on an existing antitumour T-cell response, including sufficient T-cell infiltration in the tumour microenvironment. However, not all UC exhibits high T-cell infiltration. Similarly, differential responses to immunotherapies have been observed in UC based on bladder cancer molecular subtype and the underlying immune landscape of these subtypes. Luminal 1 tumours are reported to be enriched for FGFR3 mutations and lacking in immune marker expression and immune cell infiltrate20. The luminal 1 subtype showed the lowest response rate to the anti–PD-L1 inhibitors atezolizumab and nivolumab compared with other bladder cancer subtypes2,21. Therefore, combination strategies of immune checkpoint inhibitors with agents targeting FGFR alterations yield the potential to overcome the limitations of PD-L1 expression, and clinical trials are planned in the neoadjuvant setting. Optimising clinical trial design Looking at the possible developments of clinical trials in MIBC, there is an ongoing debate regarding the identification of the optimal trial design for studies aimed at confirming the role of neoadjuvant immune checkpoint inhibitors and setting new standards. Such a natural evolution would imply the comparison of standard chemotherapy plus immunotherapy with chemotherapy alone in a 1:1 randomised design. Pending the results of large phase III trials that are recruiting patients in first-line metastatic setting (IMvigor130, KEYNOTE-361, and CheckMate 901), mature results with neoadjuvant combination chemo-immunotherapy in MIBC are pending.

14-17 November 14-17 November 2019, Vienna, 2019,Austria Vienna, Austria

Implementing Implementing multidisciplinary multidisciplinary strategiesstrategies in genito-urinary in genito-urinary cancers cancers 11th European 11th European Multidisciplinary Multidisciplinary CongressCongress on Urological on Urological Cancers Cancers In conjunctionInwith conjunction the with the • 8th Meeting• of8th theMeeting EAU Section of theofEAU Urological SectionImaging of Urological (ESUI) Imaging (ESUI) • European School • European of Urology School (ESU) of Urology (ESU) • EMUC Symposium • EMUConSymposium Genitourinary on Genitourinary Pathology andPathology and Molecular Diagnostics Molecular(ESUP) Diagnostics (ESUP)

www.emuc19.org www.emuc19.org Saturday, 16 March 2019

Chemotherapy combination strategy Yet there are some perplexities in pursuing the chemotherapy combination strategy: platinum-based combinations do not address the chemotherapyineligible population or those who refuse to receive any chemotherapy preoperatively, pushing clinicians to the old limitations of chemotherapy delivery in these patients. Also, adding chemotherapy may substantially prolong the total duration of neoadjuvant therapy compared with the short courses that were allowed with single-agent immunotherapy. The postoperative phase of these studies is still under debate, as the optimal use of adjuvant checkpoint inhibitors based on the quality of pathologic response in largely unknown. Finally, the optimal trade-off between the optimal therapeutic regimen and use of PD-L1 biomarker is still unaccounted for. In the PURE-01 study, among the patients who expressed PD-L1 the pathologic downstaging rate was 65.7%, higher than the 60.0% achieved by adding standard chemotherapy to pembrolizumab, although heterogeneity in patient populations should be accounted for. Based on the available results, the population of patients harbouring a high PD-L1 expressing tumour coupled with high TMB feature (â&#x2030;Ľ 20 mutations/mb) are most suited for a single-agent neoadjuvant checkpoint inhibitor regardless of their cisplatin eligibility. Adjuvant Immunotherapy Trials Although most of the findings achieved in the neoadjuvant context came from small academic studies, large phase III trials are recruiting patients with a high-risk disease postoperatively to receive adjuvant immune checkpoint inhibitors (NCT02632409, NCT03244384, NCT02450331). Indeed, the possibility to administer well-tolerated compounds in this context yields the potential to overcome the limitations of chemotherapy delivery, mainly related to the impossibility of timely administration of treatment after radical cystectomy because of the length of postoperative recovery. The adjuvant immunotherapy studies share similar inclusion criteria, mainly represented by pT3-4 and/or pN+ residual disease in patients who have already received neoadjuvant chemotherapy or who are ineligible to receive adjuvant cisplatin-based chemotherapy. If, on one hand, it is likely that such

studies will set new standard therapies in MIBC, on the other hand it is important to outline that the overall improvement in outcome is more likely to come from the integration of pre- and postoperative strategies, which is being planned in the next phase III trial (NCT03661320). Conclusion In conclusion, the revolutionary road of immunotherapy in UC that started in 2016 with atezolizumab studies has now produced the first outcomes in the nonmetastatic clinical stages. In MIBC in particular, there is potential for a revitalised multidisciplinary collaboration that allows patients with organ-confined disease to receive potent systemic therapies, with the aim of improving long-term outcomes, quality of life, patient adherence to treatment, and, likely, the proportion of bladders spared after curative treatment. References: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

Rosenberg JE, et al. Lancet. 2016;387:1909-20. Sharma P, et al. Lancet Oncol. 2017;18:312-22. Bellmunt J, et al. N Engl J Med. 2017;376:1015-26. Powles T, et al. JAMA Oncol. 2017;3:e172411. Patel MR, et al. Lancet Oncol. 2018;19:51-64. Bellmunt J, et al. J Clin Oncol. 2018;36 (suppl; abstr 410). Forde PM, et al. N Engl J Med. 2018;378:1976-86. Amaria RN, et al. Nature Med 2018;24:1649-1654. Burger M, et al. Eur Urol. 2012;61:1070-1. Galsky MD, et al. J Clin Oncol. 2011;29:2432-8. Bhindi B, et al. Eur Urol. 2017;72:660-4. Chism DD, et al. Oncologist. 2013;18:933-40. Sonpavde G, et al. Cancer. 2009;115:4104-9. Necchi A, et al. J Clin Oncol. doi: 10.1200/JCO.18.01148. [Epub ahead of print]. 15. Necchi A, et al. EAU 2018 (abstract 1122). 16. Powles T, et al. J Clin Oncol. 2018;36 (suppl; abstr 4506). 17. Holmes C, et al. ESMO 2018 congress (LBA 33). 18. Plimack ER, et al. Eur Urol. 2015;68:959-67. 19. Iyer G, et al. J Clin Oncol. 2018;36:1949-56. 20. Seiler R, et al. Eur Urol. 2017;72:544-54. 21. Robertson AG, et al. Cell. 2017;19:171:540-56.e25. 22. Rosenberg JE, et al. Lancet. 2016;387:1909-20.

Saturday 16 March 08.15-10.00: Plenary Session 1 Bladder cancer in the young patient: Unique aspects

URO 88 1.0 01/2019/A-E

me and o c e s a le P 26 t Booth D a s u it is v

The New Flexible Video-Cystoscope HD-VIEW The highest demands by definition BRILLIANT Camera chip in High-Definition yy EASY Atraumatic tip for gentle insertion yy FAST Suction valve for rapid bladder draining yy

KARL STORZ SE & Co. KG, Dr.-Karl-Storz-StraĂ&#x;e 34, 78532 Tuttlingen/Germany, www.karlstorz.com

Saturday, 16 March 2019

EUT Congress News

ABU DHABI, UAE

Held in conjunction with:

ENDOUROLOGICAL SOCIETY

Join us in the spectacular city of Abu Dhabi, UAE, for the 37th World Congress of Endourology, the world’s foremost meeting dedicated to minimally invasive urologic surgery. Assembling today’s global leaders in endourology, WCE 2019 will provide unparalleled opportunities to expand your education, enhance your skills and exchange ideas.

HELP PEOPLE AFFECTED BY ERECTILE DYSFUNCTION (ED) FIND THEIR BEST TREATMENT SOLUTION SHARE EDTREATMENTS.COM WITH YOUR ED PATIENTS.

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ESUT20 7th Meeting of the EAU Section of Uro-Technology in conjunction with the German Working Groups of Endourology, Laparoscopy and Robotic Assisted Surgery

VISIT US AT BOOTH #H26

EDTreatments.com ED-Behandlungen.de ED-Behandelingen.nl Trattamentodisfunzioneerettile.it Tratamientosdisfuncionerectil.es

Incl. Live Surgery

23-24 January 2020, Leipzig, Germany

www.esut20.org Arbeitskreis Endourologie

EUT Congress News

Saturday, 16 March 2019

EAU 2019 Industry Session

P.R.China

New Frontiers

Pioneer and promoter of PCNL with total X-ray free technique; Over 20,000 cases of ultrasonic-guided PCNL for personal up to now

in the Management of nmCRPC 16 March 2019, 18:00-19:30 Green Room 12, Fira Gran Via. Prof. Jianxing Li

Barcelona, Spain

Director of Urology Department of Beijing Tsinghua Changgung Hospital Proposer of Direct Visualized Access Technology (DVA), Inventor of Needle-perc and Jianxing Scope Winner of Red Star Original Design Award (Top Award of Chinese Industrial Design)

CHAIR AND PRESENTER: Karim Fizazi, MD, PhD University of Paris Sud, Institut Gustave Roussy, Villejuif, France

Needle-perc Ⅰ

PRESENTER: Bertrand Tombal, MD, PhD Cliniques Universitaires Saint-Luc, Brussels, Belgium

AGENDA 18:00–18:05

18:05–18:35

18:35–19:05

Needle-perc Ⅱ

Visualized Puncture & in Situ Dilation

Visualized Puncture

Needle-perc Ⅲ Visualized Puncture & in Situ Dilation & Sheath Placement

Introduction Karim Fizazi, MD, PhD

Needle-perc Series based on Direct Visualized Access (DVA) Technology

The Role of Emerging Agents in the Treatment of nmCRPC Karim Fizazi, MD, PhD

Jian Xing Scope

The Importance of Quality of Survival in the Evolving nmCRPC Landscape Bertrand Tombal, MD, PhD

19:05–19:25

Panel Discussion and Q&A Karim Fizazi, MD, PhD; Bertrand Tombal, MD, PhD

19:25–19:30

Closing Karim Fizazi, MD, PhD; Bertrand Tombal, MD, PhD

Disposable Digital RigiFlex Percutaneous Nephroscope

Welcome to booth J39 E-mail: info@youcaretech.com www.youcaretech.com All products are granted with patent.

MA-DAR-ES-0003-1 01-2019 MA-DAR-ALL-0014-1

9112 BAY EAU EAU133.4x194.3 Advertisement WITH Agenda 03.indd 1

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01/02/2019 15:12

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䤀倀 Saturday, 16 March 2019

䨀漀椀渀甀猀昀漀爀琀眀漀搀愀礀猀漀昀搀椀猀挀甀猀猀椀漀渀愀渀搀栀愀渀搀猀ⴀ漀渀琀爀愀椀渀椀渀最愀琀琀栀攀䤀洀瀀攀爀椀愀氀䌀漀氀氀攀最攀䰀漀渀搀漀渀匀漀甀琀栀䬀攀渀猀椀渀最琀漀渀挀愀洀瀀甀猀䐀愀礀伀渀攀

䐀愀礀吀眀漀

倀爀漀猀琀愀琀攀䌀愀渀挀攀爀䐀椀愀最渀漀猀琀椀挀猀㨀䴀刀䤀䘀漀甀渀搀愀琀椀漀渀猀漀昀倀爀漀猀琀愀琀攀䴀刀䤀倀䤀刀䄀䐀匀 ☀ 䰀䤀䬀䔀刀吀䌀愀猀攀刀攀瘀椀攀眀匀攀猀猀椀漀渀

䘀漀挀愀氀吀栀攀爀愀瀀礀㨀倀愀琀椀攀渀琀匀攀氀攀挀琀椀漀渀䐀攀ǻ渀椀渀最愀䘀愀瘀漀甀爀愀戀氀攀刀椀猀欀䜀爀漀甀瀀䘀漀挀愀氀吀栀攀爀愀瀀礀椀渀䠀椀最栀刀椀猀欀倀愀琀椀攀渀琀猀

倀爀漀猀琀愀琀攀䌀愀渀挀攀爀䐀椀愀最渀漀猀琀椀挀猀㨀䈀椀漀瀀猀礀䘀爀漀洀吀爀愀渀猀爀攀挀琀愀氀琀漀吀爀愀渀猀瀀攀爀椀渀攀愀氀吀栀攀吀栀攀嘀愀氀甀攀漀昀匀礀猀琀攀洀椀挀吀攀洀瀀氀愀琀攀䈀椀漀瀀猀椀攀猀䌀漀渀琀爀漀瘀攀爀猀椀攀猀椀渀匀礀猀琀攀洀椀挀吀愀爀最攀琀攀搀䈀椀漀瀀猀椀攀猀

䌀漀洀洀甀渀椀挀愀琀椀漀渀椀渀琀栀攀䌀氀椀渀椀挀㨀䘀漀挀愀氀吀栀攀爀愀瀀礀瘀猀⸀ 圀栀漀氀攀䜀氀愀渀搀䠀愀渀搀猀ⴀ漀渀眀椀琀栀䴀刀䤀Ⰰ 䈀椀漀瀀猀礀 ☀ 䘀漀挀愀氀吀栀攀爀愀瀀礀

䌀愀渀倀爀漀猀琀愀琀攀唀氀琀爀愀猀漀甀渀搀䌀漀洀瀀攀琀攀眀椀琀栀䴀刀䤀㼀

匀礀洀瀀漀猀椀甀洀䘀漀挀愀氀䠀䤀䘀唀

匀礀洀瀀漀猀椀甀洀䘀漀挀愀氀䌀爀礀漀琀栀攀爀愀瀀礀

䐀攀戀愀琀攀㨀圀栀椀挀栀倀愀琀椀攀渀琀猀匀栀漀甀氀搀刀攀挀椀攀瘀攀匀愀氀瘀愀最攀䘀漀挀愀氀吀栀攀爀愀瀀礀㼀

䘀漀挀愀氀吀栀攀爀愀瀀礀䴀䐀吀䌀愀猀攀ⴀ䈀愀猀攀搀匀攀猀猀椀漀渀

䠀愀渀搀猀ⴀ漀渀眀椀琀栀䴀刀䤀Ⰰ 䈀椀漀瀀猀礀 ☀ 䘀漀挀愀氀吀栀攀爀愀瀀礀

刀攀最椀猀琀攀爀漀渀氀椀渀攀䀀眀眀眀⸀昀琀洀愀猀琀攀爀挀氀愀猀猀⸀挀漀洀

㔀ⴀ㘀䄀瀀爀椀氀㈀㄀㤀 EUT Congress News

Experience innovation in fURS and PCNL.

fURS

PCNL

NaviGuide™ Percutaneous Access Needle

LithoVue Empower™ Retrieval Deployment Device

Swiss LithoClast® Trilogy Lithotripter

LithoVue™ Single-use Digital Flexible Ureteroscope

See all of our innovative solutions and PCNL augmented reality at booth #H26

Do not miss the live cases on Saturday 16 March in eURO Auditorium 1 13:51 - 14:04 LithoVue Single-Use Ureteroscopic Lithotripsy E. Emiliani, Barcelona (ES)

15:47 - 16:05 Percutaneous Nephrolithotripsy D.A. Pérez Fentes, Santiago de Compostela (ES)

CAUTION: The law restricts these devices to sale by or on the order of a physician. Indications, contraindications, warnings and instructions for use can be found in the product labelling supplied with each device. Information for use only in countries with applicable health authority registrations. This material not intended for use in France. Products shown for INFORMATION purposes only and may not be approved or for sale in certain countries. Please check availability with your local sales representative or customer service. All images are the property of Boston Scientific. All trademarks are the property of their respective owners.

EUT Congress News

Saturday, 16 March 2019