EAU16 Congress Newsletter Sunday 13 March by European Association of Urology (EAU)

European Urology Today

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31st Annual Congress of the European Association of Urology

Sunday, 13 March 2016

Munich, 11-15 March 2016

Plenary debates: a critical look on standard therapies From functional urology to andrology, experts re-examine evidence By Loek Keizer Challenging established wisdom and standard therapies was the central theme in the first Plenary Session with EAU Guidelines Office chair Prof. James N’Dow (GB) underscoring the point that every urologists’ responsibility as a practitioner is to take each patient’s individual care needs into account. Non-adherence must of course be justifiable, only done with consent of the patient and strictly documented. The session was chaired by N’Dow and by Joan Palou (ES), Chairman of the European School of Urology (ESU) who both led the discussion and debates among the invited experts. Several speakers took a critical look at various issues such as managing ureteral stones using case discussions to trigger the exchange of insights and clinical experience. The session also featured the American Urological Association (AUA) Lecture on “Testosterone Therapy” with a personal narrative by Dr. Abraham Morgentaler (US). (See Page 3) Ureteral stone management and MET The first topic took up the opposing results of

the existing meta-analysis for the use of MET or medical expulsive therapy (benefit), and those of recent high-quality, double-blinded studies (no benefit, even harm) from the UK , Australia and the USA. The resulting dilemma for the EAU Guidelines offices was laid bare in the following discussion between Prof. Christian Seitz (AT), who defended the Guidelines’ standpoint, and Prof. Samuel McClinton (GB) who seriously challenged prior evidence and continued recommendation of MET with the use of alpha blockers. McClinton: “It’s largely a methodological problem: Is one good study good enough to overturn the meta-analysis of multiple weaker studies? Now it’s up to the EAU Guidelines to grade the evidence and re-evaluate earlier recommendations. Old evidence keeps alpha blockers in the Guidelines; another point is that as urologists we may have grown too comfortable in prescribing tamsulosin. I’m hopeful that the EAU Guidelines will be taking these new trials on board in the coming years.”

Chapple: ‘A streamlined, fully engaged EAU’ Rassweiler and Van Kerrebroeck elected

Session chairs Profs. Palou and N’Dow share a light moment at Plenary Session 1

Both McClinton and Seitz agreed that small stones (<5mm) have a high expulsion rate, and probably do not need the prescription of alpha blockers. However, the debate remained regarding their efficacy with larger stones, where further high-quality studies are required.

Seitz reiterated the recommendation will remain optional for larger stones in the foreseeable future. “We cannot recommend it any more for smaller stones or for pain relief medication. These new trials will naturally be assessed and incorporated in future updates of the EAU Guidelines.”

Live surgery at EAU16 By Constance de Koning The Live Surgery Session gave congress participants a glimpse of modern technology and their applications, and how these new procedures may impact current treatments.

By Joel Vega Organised by the EAU Section of Uro-Technology (ESUT), in cooperation with the EAU Robotic Urology Section (ERUS) and the EAU Section of Urolithiasis (EULIS), Session Chair Prof. Jens Rassweiler (DE) said the extensive and varied session consisted of a A big audience at the Live Surgery Session wide range of percutaneous, endo-urological, laparoscopic, and robotic-assisted procedures which techniques. 3D for instance, which has been around all featured the latest technologies. for a considerable time, has significantly improved in quality; the next step is now ultra HD,” he said. “Live surgery at EAU16 is a continuation of what we have done in 2015, as we have become more Regarding the future, Rassweiler is convinced this will experienced and acquired a routine with these new be a very exciting era due to new robots.

Challenges require a fully engaged and streamlined organization and the European Association of Urology (EAU) will need to restructure both its short and long-term strategies to keep up with modern demands and respond to the needs of its members and the urological community. “There are always challenges and we have a road ahead of us and this requires us to evaluate things, improve and restructure if we are to achieve our goals and stay fully on track,” said EAU Secretary General Prof. Chris Chapple (UK) yesterday during the General Assembly Meeting.

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Chapple also noted that economic pressures in the world have an impact on EAU activities which prompts the organisation to prioritise and invest on the most key and crucial projects that will ultimately serve its members and forward the cause of urology. EAU Treasurer Prof. Manfred Wirth (DE) also reiterated the call for investing on key projects which both he and Chapple said are needed to ensure the future of urology. These projects include educational training, research, meetings, publications and guidelines creation, among many others. Structuring the organization also leads to changes within the ranks of executive board members. During the meeting, Prof. Jens Rassweiler (DE) was elected as the new chairman of the EAU Section Office, while Prof. Philip Van Kerrebroeck (BE) took over from Dirk Schultheiss as the new chair of the EAU History Office. Prof. Hein Van Poppel (BE) was re-elected by majority vote as the Adjunct Secretary General for Education. Sunday, 13 March 2016

Voting at the General Assembly

The EAU will also actively pursue consistent contacts and engagement not only with other medical institutions but also politically such as the European Commission since it expects European-wide regulations to heavily impact on medical communities and professional associations. Guidelines creation, educational training and publications will remain top priorities of the association while contacts with national societies in Europe will be boosted in tandem with the EAU’s growing ties with international and regional urology groups based outside the region.

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On focus: Preventing infections

Today’s Industry Sessions

ESFFU-ESUI joint meeting stresses antibiotic stewardship

Industry sessions, all starting at 17:45 hrs

By Joel Vega

Understanding the many faces of mCRPC ASTELLAS - eURO Auditorium Changing the paradigm in flexible ureteroscopy BOSTON SCIENTIFIC - Room 1 Immuno-oncology: A hype or a potential new foundation for GU cancers? BRISTOL-MYERS SQUIBB - Room Paris Prostate cancer management – Selecting the right treatment for the right patient FERRING - Room London Understanding personalised medical management for BPH patients at risk of progression GLAXOSMITHKLINE - Room Stockholm

Prudent antibiotic use and the complexity of treating and managing “common” or frequently encountered urological infections were recurring themes or points of attention from the speakers at the joint meeting yesterday of the EAU Section of Female and Functional Urology (ESFFU) and the EAU Section of Infections in Urology (ESIU). “Antibiotic consumption is increasing since their introduction. In Europe, drug-resistant bacteria is the cause of 25,000 deaths annually,” said Dr. Vitaly Smelov (FR). In acute-care hospitals in the US, studies showed that 20% to 50% of antibiotics are unnecessary or inappropriate, and that in the case of urinary tract infections (UTIs), most hospital-acquired UTI strains are generally antibiotic-resistant, according to Smelov who spoke on the role of the micro biome in the development of urinary tract problems. Saying that “sterile urine” is a myth, Smelov noted that new technologies have detected a range of “non-culturable” bacteria in the urine.

Avanafil 2.00: The 2nd generation of PDE5-Is has begun THE MENARINI GROUP - Room Vienna Optimising care in patients over 65 with overactive bladder PFIZER INTERNATIONAL OPERATIONS - Room Madrid

“It’s high time to redefine UTIs and urinary tract disorders based on routine test findings only,” said Smelov. He also cautioned that new technology should not lead to increased use of antibiotics which only result to unwanted adverse events.

Speaker Bjorn Wullt (SE) emphasized the role of basic research as he highlighted that current science has now shifted its focus on the host and not only the bacteria. “It takes two to tango,” said Wullt. “Once upon a time, the bug was the focus. That’s history. The host susceptibility caused by genetic polymorphisms is now in the focus and we’re just beginning to understand this interplay,” he added. Wullt said that genetics are increasingly becoming important to map dysfunctions or genetic events in the host. For example, inflammation in pyelonephritis is extremely dependent on the balance in the inflammatory response, he explained whilst noting that conditions such as asymptomatic bacteriuria (ABU) provides a good example to explain host response down-regulation and tolerance which may be key to future treatments. Wolfgang Kummer (DE) lectured on the role of brush cells in the urinary tract, while Markus Drake (UK) gave a comprehensive overview of the management of UTIs in a neurogenic patient and how it differs from a non-neurogenic patient. Bela Köves (HU) spoke on the use of catheters and UTI and warned about inappropriate use of indwelling catheters. Among their take-home messages: Drake: “Neurogenic patients have changed LUT function, bladder care and medical interventions… The fundamentals of their management include the

Managing infections is a central theme in the joint ESFFU-ESUI meeting

identification of organisms and its sensitivities and the adequate duration courses of suitable antibiotics…” Köves: “Indwelling catheters should be placed only when they are indicated and 30% of initial urinary catheterizations are unjustified. It is also recommended to remove the catheter as soon as possible.”

Infections impact transplant outcomes Large differences in organ availability exists in Europe

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

By Constance de Koning Infections are a major cause of morbidity and mortality in recipients of kidney grafts, as was made clear by Prof. T. Fuller (DE) during the joint meeting of the EAU Section of Transplantation Urology (ESTU), the EAU Section of Infections in Urology (ESIU) and the EAU Section of Urolithiasis (EULIS)

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. S. Sarikaya, Ankara (TR)

Pre-transplant screening secures successful transplantation, but vigilance is indicated posttransplant as well. Infection such as cytomegalovirus (CMV) and Epstein-Barr-Virus (EBV) have a relatively high prevalence in this population, the risk being highest in case of a positive donor and a negative recipient.

Founding Editor Prof. F. Debruyne, Nijmegen (NL)

“A remarkable exception is hepatitis C virus (HCV) which is now a relative issue due to recent revolutionary developments in treatment. New agents can achieve sustained virological response (SVR) which can be as high as 100%. However, for end-stage renal disease (ESRD) patients, HCV is still a relevant problem where the number of years on dialysis are an

Coordination and Editing J. Vega Onsite Reporting and Editing Team J. Bloemberg L. Keizer C. de Koning T. Parkhill J. Vega

EUT Editorial Office PO Box 30016 6803 AA Arnhem The Netherlands T +31 (0)26 389 0680 F +31 (0)26 389 0674 communications@uroweb.org

The EAU Research Foundation (EAURF) yesterday presented updates on its registries, on-going and planned trials and urged researchers to join its various studies which aim to investigate prostate cancer, urological infections, kidney and bladder tumours and Benign Prostate Hyperplasia (BPH), among other issues.

Colophon

By Joel Vega

No part of European Urology Today (EUT) may be reproduced without written permission from the Communication Office of the European Association of Urology (EAU). The comments of the reviewers are their own and not necessarily endorsed by the EAU or the Editorial Board. The EAU does not accept liability for the consequences of inaccurate statements or data. Despite of utmost care the EAU and their Communication Office cannot accept responsibility for errors or omissions.

“We urge researchers across Europe to join and contribute to these registries as they form the basis of future research and provide insights to challenges we see in everyday clinical practice,” said EAURF chair Prof. Peter Mulders who chaired and moderated the special session. Among the results presented were from the EVOLUTION study led by Prof. Andrea Tubaro (IT). Tubaro gave details on the patient selection for the pharmacological treatment of Lower Urinary Tract Symptoms (LUTS) due to BPH. “The study collected real-life information on pharmacological management practices and outcomes

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Taking all of the above into account, Fuller concluded that improved prophylactic, diagnostic and treatment strategies have led to an improvement in long-term renal graft outcomes. “Screening and prophylaxis as well as meticulous post-transplant surveillance for infections should be the standard of care in renal transplant patients,” he said. Of a rather different nature – but nevertheless impacting on renal transplantation in total - are the significant country-to-country differences in kidney transplants rates. Different legal and social standards across Europe might be responsible for this phenomenon as was shown by a new Europe-wide survey. Within the EU, the number of kidney donors per country per head of population ranges from 3.3 deceased donors (per million) in the Russian Federation up to 35.7 for Spain. Dr. Díez-Nicolás (ES) explained this variation: “Basically, it depends on two factors: social sensitivity and legislation. Most organs

for transplantation are derived from brain dead donors, but each country manages organ availability differently. In Spain, each citizen is a potential donor unless they opt-out of the transplant scheme, whereas in Germany there is an ‘opt-in’ scheme. Furthermore, some countries also allow donation from living donors, or from donors whose hearts have stopped.” ESTU Chairman Prof. A.J. Figueiredo (PT) added: “Transplantation remains the most effective way of replacing kidney function. End-stage renal failure incidence is increasing steadily in all European countries and, notwithstanding the fact that efforts should primarily be put on prevention, transplantation activity also needs be promoted, as the demand clearly exceeds supply.” Figueiredo also said there are significant discrepancies in transplant activity among European countries, and the ones with lower rates of transplant per capita should look at the examples of the leaders. There are important differences where the transplanted organs come from, such as brain dead, non-heart beating and living donors.

EAURF: Ongoing studies, new trials and interim results

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independent risk factor for HCV infection,” Fuller emphasized.

treatment. Symptom persistence were also seen in 50% in the untreated group and 62% in the treated group. Regarding progression, this was seen in 16% in the untreated group and 17% in those who received treatment. “There were less symptom improvement with phytotherapeutics in the untreated group,” Tubaro said adding that there were significant differences in patient management among European countries. The five participating countries were France, Germany, Italy, Spain and the UK. Prof. Peter Mulders (R) during the EAURF Special Session

Also presenting their studies or planned trials during in men with LUTS/BPH. The primary aim was to gather the EAURF session were Prof. Marc-Oliver Grimm (DE) who spoke on the study involving optimizing adjuvant information on symptom persistence defined as IPSS greater than 8 at 24 months,” said Tubaro. treatment of intermediate/high-risk non-muscle invasive bladder cancer (NMIBC), Mark Emberton (UK) The data collected were from 2,175 men treated for regarding the ongoing PRECISION project which looks their LUTS/BPH, and the effects were evaluated on into the use of image guidance for prostate cancer symptoms, quality of life and sexual function. The men diagnosis, Dr. Alessandro Volpe (IT) who will be leading a study on the individual management of were grouped into those who received treatment and those who had no treatment. patients with incidental small renal masses, Prof. Erik Truls Bjerklund-Johansen (SE) who leads the GPIU In his concluding message, Tubaro said symptom study on antibiotic resistance in urinary tract infections improvements were seen in 70% in the untreated and Dr. R. Hamid on the patient selection for minimal invasive therapy of stress urinary incontinence. group of men and 42% in men who had received Sunday, 13 March 2016

Re-evaluating testosterone therapy Moving on from “feeding the hungry tumour” By Loek Keizer

Congress news. . . . . . . . . . . . . . . . . . . . . . . . 1 Congress highlights . . . . . . . . . . . . . . . . . . 2/3

conventional wisdom dictated that low testosterone protected against PCa.

“In the 1980s, testosterone was the devil when it came to prostate cancer. High testosterone levels were seen “From the early 1990s, I began performing sextant as feeding a hungry tumour, or even throwing prostate biopsies prior to testosterone therapy to rule gasoline on a bonfire.” out PCa. All men had low testosterone, PSA values below 4.0ng/ml. Cancers were nevertheless diagnosed These were the words of Dr. Abraham Morgentaler in 11 of the first 77 men, a similar cancer rate as men (US), the final speaker of Plenary Session 1, who chose with an elevated PSA,” he said. to give a first-hand account of his re-assessment of Nobel Prize-winning research that had become Morgentaler decided to examine the origin of the link conventional wisdom in the decades since. In his own between high testosterone levels and the onset of words: “Everything we once learned about prostate cancer, searching Harvard basements for testosterone is wrong.” Charles Huggins’ “Studies on Prostate Cancer,” published in Cancer Research in 1941. Huggins was Morgentaler chronicled his experiences of treating men awarded the Nobel Prize in 1966 for his research, with testosterone injections in 1988. The men were all which concluded that “cancer of the prostate is healthy, apart from low testosterone levels. Men activated by testosterone injections.” reported improved erections, libido and orgasms, with the added benefit of greater feelings of wellbeing and “But how strong was Huggins’ conclusion regarding mood. At the time, this defied standard practice, as the dangers of testosterone injections?” Morgentaler

Resistant prostate cancer. . . . . . . . . . . . . . . . 4 Prevention and management of biopsy complications . . . . . . . . . . . . . . . . . . . 5 Adjuvant radiotherapy after radical prostatectomy. . . . . . . . . . . . . . . . . . . . . . . . . 6 Genital covering convey subtle messages. . . . 7 Dr. Morgentaler, giving his presentation at Plenary Session 1

Complex congenital anomalies and transition of care . . . . . . . . . . . . . . . . . . . . . . 8

asked. “Only three men received testosterone injections for fourteen days, two men had results reported and one had been previously castrated and androgendeprived. His conclusion was based on one patient, treated for only 14 days.”

Optimal sequencing in treating neurogenic patients. . . . . . . . . . . . . . . . . . . . 9

Renewed research Morgentaler conducted fresh research into the link between PCa and testosterone levels. “For the first time since Huggins in 1941, did someone bother to look at what testosterone does to prostate cancer!”

Role of PET/CT in recurrent prostate cancer. . . 11 Getting acquainted with YAU . . . . . . . . . . . . 12 OAB and incontinence after prostate surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Regenerative medicine and the urinary bladder . . . . . . . . . . . . . . . . . . . . . . 14 The urine microbiome . . . . . . . . . . . . . . . . . 15 Adjuvant vs Early Salvage Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Laparoscopic living donor nephrectomy. . . . 19 Do we need specific workup for our stone patients?. . . . . . . . . . . . . . . . . . . . . . . 20 Towards a Urogenital European Reference Network. . . . . . . . . . . . . . . . . . . . 21 Robot and children: Special care . . . . . . . . . 22 Peyronies Disease: Conservative treatment. . . 23 Laparoscopic and robotic kidney transplantation. . . . . . . . . . . . . . . . . . . . . . . 24 Bladder neck closure in adolescents and adults . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Urological impact of schistosomiasis . . . . . . 27 Nocturia in females with Pelvic Organ Prolapse. . . . . . . . . . . . . . . . . . . . . . . 29 Management of stones. . . . . . . . . . . . . . . . 30

EAU Secretary General Prof. Chris Chapple formally opens yesterday the three-day Technical Exhibit which gathers under one roof the latest technological, research, pharmaceutical, learning and educational developments in urology, and medicine in general. Around 2,600 exhibitors registered with 167 exhibitor booths from around the world.

Herbal medicines in the management of renal stones. . . . . . . . . . . . . . . . . . . . . . . 31

Day 2 Award Gallery

Best Paper on Fundamental Research: P. Uvin and J. Franken (Leuven, Belgium)

Best Paper on Clinical Research: P. Black (Vancouver, Canada)

First Prize Best Abstract (Oncology): M. Roumiguie (Toulouse, France)

First Prize Best Abstract (Non-Oncology): U. Joensen (Copenhagen, Denmark)

Second Prize Best Abstract (Oncology) T. O’Brien on behalf of M. Stares (London, United Kingdom)

Second Prize Best Abstract (Non-Oncology): Handed over to Y. Igawa on behalf of K. Ichihara (Tokyo, Japan)

Third Prize Best Abstract (Oncology): S. Salami (Ann Arbor, United States of America)

Third Prize Best Abstract (Non-Oncology): L. Schneidewind (Greifswald Germany)

Best Scientific Paper Fundamental Research in European Urology: E. Efstathiou (Houston, United States of America) Sponsored by ELSEVIER

Best Scientific Paper Clinical Research in European Urology: P. Abrams (Bristol, Germany)

Best Scientific Paper in European Urology: N. Clarke on behalf of N. James (Coventry, United Kingdom) Sponsored by ELSEVIER

Best Scientific Paper on Robotic Surgery in European Urology: A. Volpe (Novara, Italy) Sponsored by VATTIKUTI FOUNDATION

Sunday, 13 March 2016

EUT Congress News

Resistant prostate cancer Truncated androgen receptor and intracrine androgen synthesis Prof. Allen C. Gao Department of Urology UC Davis Comprehensive Cancer Center University of California at Davis Sacramento California (USA) Several mechanisms facilitate the progression of hormone-sensitive prostate cancer to castrationresistant prostate cancer (CRPC). At present, the approved therapies for CRPC include systemic drugs (docetaxel and cabazitaxel) and agents that target androgen signaling, including enzalutamide and abiraterone. While up to 30% of patients have primary resistance to these treatments, each of these drugs confers a significant survival benefit for many. Over time, however, all patients inevitably develop resistance to treatment and their disease will continue to progress. Several key mechanisms have been identified that give rise to drug resistance. Expression of constitutively active variants of the androgen receptor, such as AR-V7, intracrine androgens and overexpression of androgen synthesis enzymes like AKR1C3, are just some of the many discovered mechanisms of drug resistance. Treatment strategies are being developed to target these pathways and reintroduce drug sensitivity. Niclosamide has been discovered to reduce AR-V7 activity and synergized to enzalutamide. Indomethacin has been explored to inhibit AKR1C3 activity and showed to be able to reverse resistance to enzalutamide. By better understanding the mechanisms by which drug resistance develops improved treatment strategies will be made possible. AR hyper-activation Castration-resistant prostate cancer (CRPC) is defined as progression of disease in the presence of castrate levels of circulating testosterone1,2. It is hallmarked by hyper-activation and/or overexpression of the AR resulting in the transcription of downstream target genes and tumor progression despite only castrate levels of androgen being present in the patient. Dysregulated mechanisms that contribute to the development of CRPC from hormone-sensitive prostate cancer have been extensively investigated and can be broken up into five general categories: AR amplification and mutation, AR co-activator and co-repressor modifications, aberrant activation and/ or post-translational modification, altered steroidogenesis, and AR splice variants. Each of these five broad classifications have the end result of increased AR activation whether due to increasing the amount of androgen, enhancing the response to existing androgen, sensitizing the AR to nonclassical ligands, allowing the AR to activate in the absence of ligand, or a myriad of other mechanisms3-7. Currently available treatments for the CRPC include next generation of antiandrogens such as enzalutamide and abiraterone which target AR activation either directly or indirectly (Figure 1). Sadly, primary resistance to these treatments is not uncommon. Up to one-third of patients receiving abiraterone and one-fourth of patients receiving enzalutamide fail to respond to initial treatment with these drugs8,9. Even patients who initially benefit from treatment develop drug resistance within 24 months of initial exposure. Enzalutamide Enzalutamide (Xtandi, ENZA, MDV-3100) functions by reducing AR activity as a competitive inhibitor of ligand binding to the AR. Additionally, it inhibits AR translocation to the nucleus, co-activator recruitment, AR binding to DNA and activation of AR target genes10. Enzalutamide has greater affinity for the AR compared to earlier anti-androgens, such as bicalutamide and flutamide, and is subsequently more effective than its predecessors. Data from the AFFIRM trial demonstrated that enzalutamide-treated CRPC patients who failed docetaxel treatment had nearly five months improved survival compared to placebo treated individuals9. Furthermore, the PREVAIL trial found the enzalutamide was also effective in pre-chemotherapy 4

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Figure 1: An overview of approved and experimental treatment strategies for CRPC targeting the androgen axis. Currently approved therapies are written in red while experimental therapies are in orange.

hormone-na誰ve prostate cancer patients11. Primary resistance to enzalutamide was observed in 25% of patients in the AFFIRM trial in whom progression occurred within three months of treatment and by 24 months, all patients had progressed in their disease despite enzalutamide therapy12. Enzalutamide resistance As cells develop enzalutamide resistance, several key dysregulated mechanisms have been brought to light. Among these are alterations in steroidogenesis, glucose metabolism, and autophagy. Specifically, Liu et al. observed enzalutamide-resistant prostate cancer cells had upregulated expression of androgen and its precursors including cholesterol, DHEA and progesterone. Additionally, this study found that genes involved in steroid biosynthesis were significantly over-expressed compared to enzalutamide-sensitive parental cells and that of these AKR1C3 proved to be of particular importance being as overexpression of this enzyme alone was sufficient to desensitize normally responsive cells to enzalutamide treatment13. Point mutations to the AR in the regions coding for the ligand-binding domain are also implicated in enzalutamide resistance and it is estimated that 10-30% of CRPC patients have AR mutations14. Many of these mutations result in gain-of-function that increase coactivator improvement, alter ligand specificity and affinity. Interestingly, some of these mutations instigate ligand-binding specificity to switch from agonist to antagonist activation. In particular, the Phe876Leu mutation in the AR has been associated with enzalutamide activating the AR; however further study into this mutation is required to determine clinical significance15,16. Other molecular pathways have also been tied to enzalutamide resistance. Studies have determined that overexpression of p52 confers enzalutamide resistance and that this may be due in part to changes in glucose metabolism and expression of AR splice variants, which will be discussed shortly17-19. Others have observed that constitutive Stat3 activation due to IL-6 overexpression also induces insensitivity to enzalutamide20. AR variants are truncated versions of the wild type AR and are often ligand-independent and constitutively active. AR variants may be generated by genome rearrangement and alternative splicing involving splicing factors such as hnRNPAs21,22. Generally, the C-terminal ligand-binding domain is the portion of the AR that is lost; however at least one variant is known to be truncated at the N-terminus resulting in a loss of the DNA binding domain23-27. The functional implications of AR variants are not yet fully understood, due in part to the lack of variant specific antibodies, and the role of these variants in CRPC is still being established. CWR22Rv1 cells have nearly equal expression of full length AR and AR variants;

however most CRPC cell lines exhibit AR variant expression at some level. Additionally, bone metastases have higher AR variant expression compared to hormone-sensitive prostate cancer and AR variant expression is associated with poorer prognosis and the development of CRPC28. Both abiraterone and enzalutamide resistance have been tied to expression AR splice variants19,29,30. Among the identified splice variants, variant 7 (AR-V7) in particular has been implicated in drug resistance. Antonarakis et al. demonstrated that AR-V7 expression in patients treated with enzalutamide or abiraterone correlated to a significantly lower PSA response, shorter progression-free and overall survival compared to men without AR-V731. No changes in PSA response or progression-free survival were observed in patients treated with docetaxel regardless of AR-V7 expression suggesting that AR-V7 positive patients may be less susceptible to primary taxane drug resistance32.

Furthermore, enzalutamide resistant C4-2B cells expressing AR-V7 displayed a significant dosedependent cytotoxic effect to niclosamide and when used in combination with enzalutamide had an additive response34. On top of its action as an AR-V7 inhibitor, niclosamide has been determined to improve enzalutamide sensitivity by modulating Stat3 activity by inhibiting its phosphorylation and reducing Stat3 target gene expression and abrogating recruitment of AR to the PSA promoter35. A recent study by Nadiminty et al. also tied AR-V7 downregulation to enzalutamide resensitization; by downregulating the splice factor hnRNPA1, they were able to decrease AR-V7 expression which sensitized resistant cells to enzalutamide treatment22. Another drug, ASC-J9, was found to degrade of both full length and AR-V3 by and associated with a decrease in CWR22Rv1 xenograft tumor growth36.

While AR-V7 lacks the ligand binding domain, it and other constitutively active variants of the AR retain the N-terminus. Drugs have been developed that target this region of the AR, including EPI and Overcoming enzalutamide resistance Proposed methods for reintroducing sensitivity to derivatives thereof, and these too have been enzalutamide include mediating dysregulated observed to inhibit prostate cancer cell growth. EPI is pathways and avoiding AR activation. Liu et al. found known to covalently bind the N-terminal domain of both AR and its variants and inhibit transcriptional that inhibition of AKR1C3 enzymatic activity with indomethacin, a nonsteroidal anti-inflammatory drug, activity. In vivo administration of EPI in prostate restored enzalutamide sensitivity in resistant prostate cancer xenograft models was observed to reduce cancer cells and suggests that targeting intracrine tumor growth37,38. 13 androgens improves enzalutamide therapy . In a separate study, enzalutamide sensitivity was also Niphatenones are another class of drugs that target restored by inhibiting Stat3 activity using both siRNA the N-terminal domain of the AR. While niphatenone and the Stat3 inhibitor AG490 resulting in increased treatment was found to inhibit transactivation of AR apoptosis and inhibition of prostate cancer cell and its variants, it was also observed to promote growth20. glutathione adduct formation and therefore may not be as viable for prostate cancer therapy as Others have demonstrated that cells can be realternatives39. sensitized to enzalutamide treatment when administered together with autophagy inhibitors: A complex disease co-treatment of resistant CRPC cells with CRPC is a complex disease characterized by enzalutamide and either metformin or clomipramine progression despite the availability of multiple had greater effect on reducing tumor volume currently approved therapies targeting different compared to enzalutamide alone in murine models33. pathways. Resistance to these drugs develops over This has led to the clinical trials investigating the time through a multitude of dysregulated pathways combinatory effects of metformin with enzalutamide and aberrant AR activation. Intense, ongoing research in CRPC patients. is dedicated to discerning these pathways and ways to target them to improve drug sensitivity. The more Targeting AR variant expression is effective at complete understanding of these mechanisms of resistance will enable the development of improved reintroducing drug sensitivity and decreasing CRPC tumor growth. The FDA approved anti-helminthic treatment strategies to overcome this resistance. drug, niclosamide, has been identified as an AR-V7 inhibitor via several mechanisms including increased Editorial Note: Due to space constraints we have AR-V7 protein degradation and reduced recruitment ommitted the reference list. Interested readers can of AR-V7 to promoter regions of target genes resulting email a request at communications@uroweb.org. in reduced transcriptional activity. The AR-V7 Sunday 13 March degradation induced by niclosamide was determined to be the result of proteasome-dependent pathways 10.30-12.00: Thematic Session 4 due to the fact that MG132, a 26S proteasome Resistance to novel endocrine therapy in inhibitor, reduced niclosamide-mediated inhibition of prostate cancer AR-V7 protein expression. Sunday, 13 March 2016

Prevention and management of biopsy complications An urgent need to revise prostate biopsy policy Dr. Tommaso Cai Department of Urology Santa Chiara Hospital Trento (IT)

Co-Author: Riccardo Bartoletti, Pisa (IT) Prostate biopsy is currently an essential procedure for prostate cancer diagnosis and the transrectal approach is most commonly used by European urologists1. Even if transrectal prostate biopsy (TR-PB) is generally considered a safe procedure, it may be accompanied by several clinical complications, like bleeding due to the biopsy trauma or, more frequently, infective complications ranging from asymptomatic bacteriuria to symptomatic urinary tract infections and sepsis2.

fluoroquinolone resistant organisms has become a true contemporary health emergency (Fig. 1). This condition is due both to the misuse and over-prescription of antibiotics and the limited research on new molecules with subsequent reduced number of new antibiotics in the pipelines of pharmaceutical companies6. Alternative strategies to reduce infective complications Several strategies have been proposed and evaluated to prevent infective complications after TR-PB, such as the following: 1) Risk assessment to select patients at higher risk for infective complications; 2) Microbiological sampling of the faecal flora prior to biopsy to identify resistance to specific agents; 3) Number of biopsy cores and the use of targetedimage fusion-guided biopsies; 4) Change of biopsy route (perineal approach); and 5) Alternative antibiotics with improved susceptibility to be used for prophylaxis.

rectal swab and urine culture and analysed the susceptibility to the most commonly used antibiotics10. Among 865 investigated patients, Escherichia coli was the most common isolate (80.9%) and accounted for 90.6% of ciprofloxacinresistant specimens while the rate of ciprofloxacinresistant coliforms in general was 19%10. Infectious complications occurred in 3.6% of patients and 48% of these patients had ciprofloxacin-resistant bacteria at pre-biopsy rectal swab investigation. Their findings strongly indicate that the increasing prevalence of infection rate after TR-PB is due to an increasing prevalence of ciprofloxacin-resistant E. coli in the rectal flora10. To note, consider that rectal swab would represent a substantial burden for clinical microbiology laboratories and might fail to detect ciprofloxacinsensitive isolates with borderline MICs. On the other hand, we have other aspects to consider such as the number of biopsy cores, the use of targeted, image fusion-guided biopsies and the change of biopsy route (perineal approach). Wagenlehner et al. identified the number of biopsy cores to be the only significant risk factor for symptomatic versus asymptomatic urinary tract infections after prostate biopsy3.

Among all reported complications after the procedure, in recent years we observed a higher rate of infective complications that remained the leading cause of hospital admission after procedure1-3. The higher rate of sepsis could be due to the emerging resistance to fluoroquinolones, in particular to ciprofloxacin3-4.

“Fosfomycin is a candidate alternative agent for antibiotic prophylaxis in TR-PB having shown elevated activity against MDR Gramnegative bacteria and favourable pharmacokinetic parameters...”

Today, the infective complications after TR-PB represent an important challenge for the urologist and a life-threatening risk for the patient, in particular, due to the increased rate of antibioticresistant bacteria. We need to focus our attention on the prevention of infective complications and find novel approaches and strategies.

First, we consider the risk assessment to select patients at higher risk for infective complications. Recently, Loeb et al. in a large cohort of patients who had undergone prostate biopsy showed that age, race, region, year, and Charlson comorbidity score are independent prognostic factors affecting the risk of hospitalization8.

This finding was confirmed by Dodds et al. who observed an increased rate of complications after prostate biopsy in a cohort of 2,080 consecutive patients from 2003 to 2010, pinpointing the number of biopsy cores as one of the main causes of patients’ hospitalization11. Moreover, Grummet et al. evaluated the rate of hospital re-admission for sepsis after transperineal biopsy, showing that the rate of hospital re-admission for infection was zero12. Furthermore, the international data suggested a negligible rate of sepsis with transperineal biopsy12.

Infective complications: Size of the problem Even if fluoroquinolones being the most prescribed drug for TR-PB prophylaxis, in line with European Association of Urology (EAU) guidelines5, the hospital admission rates due to complications following TR-PB have increased dramatically during the last 10 years3,6.

Moreover, men with prostate enlargement and diabetes had an increased risk of developing febrile complications after the procedure8. For these reasons, the assessment of comorbidity is important to identify patients at higher risk of infective complications.

Even if transrectal prostate biopsy is convenient, cheap and quick to perform, consider as an option the transperianeal approach to all patients in whom a high risk of infective complication has been confirmed.

Thus, there is an urgent need to identify patients at higher risk of infective complications!

Finally, the role of alternative antibiotics with improved susceptibility. As discussed above, an increasing ciprofloxacin resistance and creeping MICs call for a reassessment of the current recommendations on antibiotic prophylaxis2,6,13.

The recently published results of the Global Prevalence Study of Infections in Urology (GPIU) study showed a high rate of symptomatic urinary tract infections (5.2%) and a significant rate of hospitalization (3.1%)3. Interestingly, in the same study, Wagenlehner et al. reported that fluoroquinolones were administered to 98.2% of patients, in accordance with the EAU guidelines, but the resistance rate against fluoroquinolones was seen in 60% of all isolated bacterial strains3. Moreover, several studies showed that the higher risk of infection is due to an increase in ciprofloxacin resistance in Escherichia coli and hence a concomitant decrease in the efficacy of ciprofloxacin prophylaxis in patients undergoing TR-PB7. The recent increase of

Moreover, there is the importance of microbiological sampling of the faecal flora prior to biopsy to identify resistance to specific agents. Some researchers proposed doing rectal swab culture test before prostate biopsy to isolate and characterize fluoroquinolone-resistant organisms from patients’ native intestinal flora, in order to perform a targeted antibiotic prophylaxis9. Based on these evidences, Taylor evaluated the prevalence of ciprofloxacin-resistant bacteria in patients undergoing TR-PB and estimated the subsequent risk of infectious complications after prostate biopsy with peri-operative ciprofloxacin prophylaxis10. They collected a pre and post-biopsy

In particular, the rising resistance to fluoroquinolones, such as ciprofloxacin, is the most likely cause of the increasing prevalence of infectious complications after TR-PB; thus, novel approaches for antibacterial prophylaxis need to be designed and evaluated accordingly. Based on these suggestions, a valid option could be the use of antibiotics with a low profile of resistance, such as fosfomycin trometamol.

“...it is clear that prostate biopsy policy should be totally revised to obtain acceptable prospective results in terms of infective complications, costs saving and patient compliance.” Fosfomycin is a candidate alternative agent for antibiotic prophylaxis in TR-PB having shown elevated activity against MDR Gram-negative bacteria and favourable pharmacokinetic parameters, including an elevated penetration into prostatic tissue14-15. Recently, Wagenlehner argued that fosfomycin trometamol 3 g orally three hours before and 24 hours after, could be used as prophylaxis during traumatic endourological interventions and surgical procedures16. Moreover, these data have been confirmed by Lista et al. that showed as antibiotic prophylaxis with fosfomycin trometamol 3 g orally three hours before and 24 hours after in prostate biopsy is an alternative as effective and safe as ciprofloxacin (10 doses of 500 mg), which carries lower rates of resistance17. Further studies are, however, required to examine the role of fosfomycin trometamol in the antibiotic prophylaxis before prostate biopsy.

Figure 1: Antimicrobial resistance surveillance in Europe, 2013. Annual report of the European Antimicrobial Resistance Surveillance Network (EARS-Net). http://ecdc.europa.eu/en/publications/Publications/antimicrobial-resistance-surveillanceeurope-2013.pdf

Sunday, 13 March 2016

Take home messages In conclusion, from all these evidences it is clear that prostate biopsy policy should be totally revised to obtain acceptable prospective results in terms of infective complications, costs saving and patient

compliance. In everyday clinical practice, please take into account the following aspects: • A detailed evaluation of all risk factors for infectious complications (i.e., diabetes, previous use of antibiotics for UTIs); • Evaluation of all risk factors for harbouring resistant organisms (i.e., recent hospitalization, travel to certain geographical regions or antibiotic use); and • The role of alternative strategies for reducing the risk of infective complications. References 1. Chun FK, Epstein JI, Ficarra V, Freedland SJ, Montironi R, Montorsi F, Shariat SF, Schröder FH, Scattoni V. Optimizing performance and interpretation of prostate biopsy: a critical analysis of the literature. Eur Urol 2010;58:851–64. 2. Cai T, Verze P, Bartoletti R, Mirone V, Bjerklund Johansen TE. Infectious complications after prostate biopsy: Time to rethink our clinical practice. World J Clin Urol 2015 July 24; 4(2): 00-00 ISSN 2219-2816 (online). DOI: 10.5410/ wjcu.v4.i2.00. 3. Wagenlehner FM1, van Oostrum E, Tenke P, Tandogdu Z, Çek M, Grabe M, Wullt B, Pickard R, Naber KG, Pilatz A, Weidner W, Bjerklund-Johansen TE; GPIU investigators. Infective complications after prostate biopsy: outcome of the Global Prevalence Study of Infections in Urology (GPIU) 2010 and 2011, a prospective multinational multicentre prostate biopsy study. Eur Urol 2013;63(3):521-7. 4. Loeb S, van den Heuvel S, Zhu X, Bangma CH, Schröder FH, Roobol MJ. Infectious complications and hospital admissions after prostate biopsy in a European randomized trial. Eur Urol 2012;61(6):1110-4. 5. European Association of Urology Guidelines on Urological Infections. 2014. http://uroweb.org/ wp-content/uploads/19-Urological-infections_LR2.pdf 6. Bartoletti R, Cai T. Prostate biopsies should be performed according to a standard of care. Eur Urol 2013;63:528–9. 7. Carignan A, Roussy JF, Lapointe V, Valiquette L, Sabbagh R, Pépin J. Increasing risk of infectious complications after transrectal ultrasound-guided prostate biopsies: time to reassess antimicrobial prophylaxis? Eur Urol. 2012;62(3):453-9. 8. Loeb S, Carter HB, Berndt SI, Ricker W, Schaeffer EM. Complications after prostate biopsy: data from SEER-Medicare. J Urol 2011;186:1830–4. 9. Taylor AK, Zembower TR, Nadler RB, Scheetz MH, Cashy JP, Bowen D, Murphy AB, Dielubanza E, Schaeffer AJ. Targeted antimicrobial prophylaxis using rectal swab cultures in men undergoing transrectal ultrasound guided prostate biopsy is associated with reduced incidence of postoperative infectious complications and cost of care. J Urol 2012;187:1275–9. 10. Taylor S, Margolick J, Abughosh Z, Goldenberg SL, Lange D, Bowle WR, Bell R, Roscoe D, Machan L, Black P. Ciprofloxacin resistance in the faecal carriage of patients undergoing transrectal ultrasound guided prostate biopsy. BJU Int. 2013; 111:946-953. 11. Dodds PR, Boucher JD, Shield DE, Bernie JE, Batter SJ, Serels SR, Dodds JH. Are complications of transrectal ultrasound-guided biopsies of the prostate gland increasing? Conn Med 2011;75:453–7. 12. Grummet JP, Weerakoon M, Huang S, Lawrentschuk N, Frydenberg M, Moon DA, O’Reilly M, Murphy D. Sepsis and ‘superbugs’: should we favour the transperineal over the transrectal approach for prostate biopsy? BJU Int 2014;114(3):384-8. 13. Akduman B, Akduman D, Tokgöz H, Erol B, Türker T, Ayoglu F, Mungan NA. Long-term fluoroquinolone use before the prostate biopsy may increase the risk of sepsis caused by resistant microorganisms. Urology 2011;78:250–5. 14. Falagas ME, Kastoris AC, Kapaskelis AM, Karageorgopoulos DE. Fosfomycin for the treatment of multidrug-resistant, including extended-spectrum beta-lactamase producing, Enterobacteriaceae infections: a systematic review. Lancet Infect Dis 10: 43-50, 2010. 15. Mazzei T, Diacciati S. Pharmacological aspects of the antibiotics used for urological diagnostic procedures. J Chemother 2014;26 Suppl 1:S24-34. 16. Wagenlehner FM, Thomas PM, Naber KG. Fosfomycin trometamol (3,000 mg) in perioperative antibiotic prophylaxis of healthcare-associated infections after endourological interventions: a narrative review. Urol Int 2014;92(2):125-30. 17. Lista F, Redondo C, Meilán E, García-Tello A, Ramón de Fata F, Angulo JC. Efficacy and safety of fosfomycintrometamol in the prophylaxis for transrectal prostate biopsy. Prospective randomized comparison with ciprofloxacin. Actas Urol Esp. 2014 Jul-Aug;38(6):391-6.

Sunday 13 March 07.30-10.55: Plenary Session 2, Prostate Cancer

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Adjuvant radiotherapy after radical prostatectomy ART provides better biochemical relapse-free survival in selected patients Prof. Thomas Wiegel University Hospital Ulm Department of Radiation Oncology Ulm (DE)

Radical prostatectomy (RP) and radiation therapy are the two major first-line therapeutic options for patients with prostate cancer. The best results are achieved in patients with organ-confined disease. Recurrence of prostate cancer after RP has been associated with multiple factors including Gleason score, prostate-specific antigen (PSA) level before surgery, tumor stage, infiltration of the seminal vesicles or positive surgical margins. However, biochemical recurrence is a common event, even in patients with favorable prognostic factors. A PSA increase of ≥0.2 ng/mL is now widely used to define disease progression following RP. Such biochemical progression occurs in up to 50% of patients with pT3/4 tumors and up to 70% in pT3 patients with positive surgical margins and/or positive pelvic lymph nodes. The location, extent and number of positive surgical margins after RP are significant predictors of biochemical progression after RP. In their retrospective series of 7160 RP-patients, the investigators of the Cleveland Clinic/Ohio found 1501 patients with positive margins. The seven-year progression free probability was 60% in these patients, resulting in a hazard ratio for biochemical recurrence of 2.3 in the case of positive surgical margins compared with negative margins; the seven-year rate for patients with organ-confined tumors (pT2) and positive surgical margins was 24%. Vital tumor tissue has been found in biopsies form the urethrovesical anastomosis in 35% to 55% of all patients with rising PSA after RP without clinical correlates suggestive of recurrent tumor.

apparently worse results in bNED of the ARO study after five years, but long-term results are quite similar between the three trials. In the EORTC trial, when the data of patients with pT2 tumors and positive surgical margins were analyzed, there was a significant benefit of 10-year biochemical progression-free survival rate in the irradiated group (HR=0.41). However, these data come from a subgroup analysis and biochemical progression-free survival was not the primary end point of this study. Therefore, the results must be interpreted with caution. The possible benefit of radiotherapy must be weighed out carefully in consideration of potential late effects like erectile dysfunction. In the wait-and-see arm of the ARO 96-01 trial, subgroup analysis of R1-cases demonstrated continuously growing rates of progression in patients with additional unfavorable tumor characteristics, namely pT 3b/c and Gleason score 7-10 with 10-year bNED of 14% and 18%, respectively. Patients with these features can thus be treated with immediate post-RP radiotherapy without the risk of overtreatment. Adjuvant RT of pelvic lymph nodes? The three randomized trials included only patients with cN0 or pN0-disease. The effect of adjuvant RT in node-positive prostate cancer has not yet been prospectively assessed. A retrospective study by Da Pozzo et al. reported a significant positive impact of RT in combination with hormonal therapy (HT) in patients with nodal metastases treated with RP and pelvic lymph node dissection.

“Adjuvant radiotherapy provides improved biochemical relapsefree survival, and possibly overall survival for patients with a high-risk of recurrence after prostatectomy.” However, in this retrospective analysis, patients treated with adjuvant RT were affected by more aggressive disease. Therefore, no effect of ART on cancer-specific survival was demonstrated on univariate survival analyses. There was a significant gain in predictive accuracy when ART was included in multivariable models predicting biochemical recurrence-free and cancer-specific survival (gain: 3.3% and 3%, respectively; all p < 0.001).

While individual risk factors may characterize men with an increased risk of recurrence, the optimal management of these patients remains controversial. The treatment approaches under discussion are adjuvant radiation therapy (ART) in men with an undetectable PSA or observation followed by early salvage radiation therapy (SRT) in men with persisting or rising PSA after initially postoperative undetectable In a large retrospective series, Abdollah et al. assessed the effect of post-RP adjuvant treatment in values. The current contribution will focus on ART. node-positive prostate cancer patients. After surgery with elective lymph node dissection, the men received Randomized clinical trials either adjuvant HT alone (intended but not confirmed Three randomized phase III trials demonstrated an for lifelong, n=721) or HT plus ART (66.6-70.2 Gy to the approximately 20% absolute benefit for biochemical progression-free survival (bNED) after ART (60-64 Gy) prostate bed and 45-50.4 Gy to the pelvic lymph compared with a “wait and see” policy, mostly for pT3 nodes, n=386). The median follow up was 7.1 years. cN0 or pN0 tumors (Table 1). All three studies show a specific benefit from ART in the bNED of patients with Based on the pathologic T stage, Gleason score, number of positive lymph nodes and surgical margin positive margins. The impact of margin status on status, five risk-groups were defined. In the progression has been confirmed after central intermediate risk group, there was an overall survival pathological review of the EORTC and the ARO data. advantage from combined therapy of 6% and 18%, Also, men with a Gleason score ≤6 have a specific after five and eight years, respectively. In the high-risk profit from ART. group, the figures were 6% and 20%, respectively, in favor of ART plus HT compared with HT alone. Only in the SWOG trial, also overall survival was significantly improved by ART. It has been discussed that this effect was largely based on reduced rate of In multivariable analysis, two groups had a significant competing cause deaths in the ART-arm. benefit from additional ART, namely (1) patients with The three randomized studies have used different ≤2 positive lymph nodes, Gleason score 7-10, pT3b/ definitions of biochemical progression. SWOG: pT4 stage, or positive surgical margins; and (2) PSA >0.4 ng/ml, EORTC: PSA >0.2 ng/ml, ARO: patients with 3-4 positive lymph nodes irrespective of PSA >0.05 ng/ml. other features. Because of the retrospective nature of this series with no standardized definition of target Consequently, biochemical recurrences (a PSA increase out of the undetectable range) were detected volumes, radiation dose, and duration of HT, these results should be interpreted with caution. However, earlier in the EORTC and the ARO study. This lead to

Figure 1: Treatment plan for post-prostatectomy IMRT with RapidArc technique at the prostate bed

they provide support for this treatment in selected cases, while it remains to be validated in prospective clinical trials. Additional use of hormone therapy to ART It is now clearly established that the standard non-operative management for patients with locally advanced prostate adenocarcinoma includes long-term HT. Two cooperative group trials, RTOG 96-02 and EORTC 22961 have demonstrated an overall survival advantage if these patients, and specifically those with additional high-risk factors like Gleason score 8-10, are treated for two to three years with HT. It remains unknown whether men with high-risk, node-negative prostate adenocarcinoma initially treated with RP and pelvic lymph node dissection benefit from additional adjuvant HT. The primary rationales for the use of HT post-RP are to 1) improve local control by eradicating disease in a hypoxic scar that may be radioresistant; 2) address micrometastatic disease which may have spread to the lymph nodes or distant sites; 3) alter PSA kinetics in patients who will eventually relapse. Previous studies have indicated a potential benefit from combination therapy for men at high risk of recurrence. A secondary analysis of RTOG 85-31, a phase III trial comparing standard external beam RT plus immediate ADT versus RT alone for patients with non-bulky prostate cancer, found improved bNED in patients who received combination therapy as compared to men treated with RT alone.

Thompson et al. 2006;2009: 431 SWOG 8794 Bolla et al. 2005;2012: 1005 EORTC 22911 Wiegel et al. 2009;2014: 388 ARO 96-02 6

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Inclusion criteria

Randomization

Definition of PSA recurrence pT3 cN0 ± involved SM 60-64 Gy (n=214) vs. > 0.4 ng/ml wait and see (n=211) pT3 ± involved SM cN0; 60 Gy (n=502) vs. > 0.2 ng/ml pT2 + involved SM wait and see (n=503) pT3 ± involved SM pN0 60 Gy (n= 148) vs. > 0.05 ng/ml + PSA post-RP undetectable wait and see (n=159) confirmation

Side effects and toxicity The three randomized clinical trials discussed above included prospective collection of data on GI or GU toxicity in the two cohorts (ART vs. observation). However, in the EORTC and SWOG trials, radiation was based on 2-D treatment planning which did not enable normal tissue sparing to nowadays state-ofthe-art. In contrast, modern 3-D based radiation treatment techniques such as IMRT allow for minimization of dose to the rectum and bladder. In the German study, which utilized 3-D-based radiation treatment planning, the incidence of late grade 3 or higher adverse events was only 0.3%. One patient in the observation arm developed a urethral stricture, compared to two patients in the ART arm. Urinary incontinence was not assessed in this trial. SRT usually involves higher doses than ART: “At least 66 Gy” according to the EAU Guidelines and typically ≥70 Gy are prescribed. Since the introduction of IMRT at the Memorial Sloan-Kettering Cancer Center, New York, the routine dose there has been raised to 72 Gy. Compared with conventional 3D-CRT, GI-tract toxicity was lower, nonetheless. The five-year rates of grade ≥2 GI tract reactions were 1.9% with IMRT and 10.2% with conventional 3D-CRT, respectively.

However, toxicity to the GU tract could not be reduced (IMRT: 16.8%; 3D-CRT: 15.8%). Compared with ART at With a median follow-up of five years, the progression- 64-66 Gy, SRT may thus be connected with higher free survival for men treated with combination therapy rates of side effects. Also, delayed SRT at a PSA above was estimated to be 65% as compared to 42% for men 0.5 ng/ml reduces the chance of cure, significantly. treated with RT alone (p= 0.002). Depending on clinico-pathological risk factors, even Similar results were seen in a retrospective study lower PSA thresholds for the initiation of SRT have performed at Stanford University. Two further been proposed. Patients with post-RP persisting randomized trials into HT-RT combination therapy, PSA are likely to require additional aggressive RTOG-P-0011 and EORTC 22043, closed prematurely treatment. Thus, the question “post-RP because of poor recruitment. The ongoing RADICALS radiotherapy – immediate or early delayed” cannot trial will address the question of duration of HT be answered in one sentence. Both, ART and SRT combined with ART. are beneficial if given to optimally selceted patients at the right time. Radiation therapy techniques The advent of 3D-conformal RT and specifically of Improved biochemical relapse-free survival multi-leaf-collimation enabled a significant dose Adjuvant radiotherapy provides improved biochemical escalation and simultaneous shielding of critical relapse-free survival, and possibly overall survival for normal tissue. Since this stage of technical patients with a high-risk of recurrence after development, the prescribed dose has been 60-64 Gy prostatectomy. While thus only a minority of RP for ART after RP. patients benefit from ART, it seem clearly indicated for those with combined risk factors like R1 + pT3b/c or Today, intensity-modulated radiotherapy (IMRT) is the R1 + Gleason score 7-10. recommended treatment standard for prostate RT. IMRT and the more recent arc-techniques, aim to Additionally, selected patients with positive lymph optimize coverage of the tumor volume not only in nodes seem to profit from ART combined with HT terms of target contour but also in terms of thickness (level 2 evidence). Modern radiation therapy and they should further reduce normal tissue techniques like IMRT should be used, ideally with complication rates. Dose escalation up to 74 Gy has image guidance. Serious side effects are low, thus confirming the suitability of this therapeutic approach.

Table 1: Randomized clinical trials into adjuvant radiotherapy after radical prostatectomy Reference Trial

been carried out with adjuvant IMRT, but has not been adopted in routine to keep side effects at minimum. The standard dose is 64-66 Gy with these approaches.

Median follow up 152 mo. 127 mo. 112 mo.

Biochemical progression free survival 10 years: 53% vs. 30% p < 0.05 10 years: 60% vs. 41% p <0.0001 10 years: 56% vs. 35% p <0.0001

Overall survival 10 years: 74% vs. 66% p = 0.023 10 years: 76.9% vs. 80.7% p= 0.20 n.a.

However, it remains unknown whether early salvage radiation therapy initiated after a PSA failure is equivalent to ART. To this end, the results of the ongoing randomized clinical trials RADICALS, RAVES, and GETUG-17 that compare ART and SRT directly are still awaited. Sunday 13 March 7.30-10.55: Plenary Session 2 Prostate Cancer

Sunday, 13 March 2016

Covered, uncovered, discovered Genital covering across continents and time convey subtle messages Prof. Philip Van Kerrebroeck Urologist Member, EAU History Office

Since prehistory, men have covered their pubic area or their genitals with different forms of ‘cache-sexe’. In the anthropological literature a cache-sexe refers to a small garment, worn to cover the genitals, but also represents multiple symbols, and is (or rather was) present in all continents and in the majority of ethnic societies. As such, their use in tribal social groups with a common national or cultural tradition is a confirmation of interrelations between gender and class. In Western societies, however, the term cache-sexe turned to be applied to indicate what is used to cover something bothersome or blameworthy. This transition from the view on the cache-sexe within ethnic tribes to the one as used in Western society is indicative of the fate over time of the cache-sexe itself. Figure 2: Wearing a genital “codpiece” was popular in the 16th Century

Nevertheless, the philosophy behind the widespread culture of the cache-sexe can help us better understand male patients with problems related to the genital area that come to see a medical caregiver. It also can be useful to understand the traditions of the cache-sexe to overcome prejudices related to male genitals and their urological or non-urological use. A cache-sexe was already used by prehistoric Europeans, as indicated with the discovery of a golden penis cover found on a skeleton at the necropolis in Varna, Bulgaria (4600-4200 BC, Figure 1). Another prehistoric European, Ötzi the Iceman, a well-preserved natural mummy of a man who lived around 3,300 BCE, and who was found in September 1991 in the Ötztal Alps, was wearing a loincloth covering his genital area. Whether the use of this fabric was purely functional as a protection or also had a symbolic meaning is not known, but the rather sophisticated structure of the loincloth indicates the importance of this specific piece of clothing. The European cache-sexe further developed from rather primitive medieval ‘underwear’ to a sophisticated ‘codpiece’, that accentuates the male genital area, which was popular in the 16th century (Figure 2). During the Renaissance genital cover in the arts was ambiguous, as most artists discretely let foliage hide that area, while Michelangelo’s David is presented fully naked. However, when Queen Victoria of the British Empire came to unveil a copy of David in the South Kensington Museum (now the V&A), a specially

made plaster cast of a fig leaf, half a metre high, was placed in a strategic position to function as secondary cache-sexe. Ethnic cache-sexe In ethnic societies, worldwide, the tegument used as male cache-sexe varies from a simple loincloth to sophisticated forms of pubic or genital covers, made of different materials. Different types can be distinguished based on the extent of the body area covered. The ethnic cache-sexe varies from an abdominal ‘bark’ belt to hold a frontal piece of fabric (Figure 3) over more specific covers for the foreskin, the glans, the penis or the scrotum to the cache-sexe proper, covering the whole genital area. A cache-sexe can have different functions from basic protection against outside trauma to a ritual and symbolic role, sexual or non-sexual. The ethnic male cache-sexe can also be an indication of the status of the owner in the tribal hierarchy. The form, structure, decoration, and use of the male cache-sexe were often strictly controlled within the ethnic group, but could vary significantly between different clans. However, outside formal gatherings, the cache-sexe could be removed and the genital area uncovered, even in front of female counterparts, without feelings of shame. As such, the ethnic cache-sexe rarely is intended purely to cover or hide the view of the men’s genitalia, but rather proudly accentuates the male member or his pubic area. The penis cover or koteka, as indicated in New Guinea, is probably the best known example of male cache-sexe, as this form of male genital cover is still in use in some villages of the Central Highlands of Papua New-Guinea. However, for centuries the ethnic male cache-sexe was used worldwide, and was widely distributed in all continents. In NorthAmerica, indigenous men used a genital cover mostly limited to a more or less decorated loincloth.

Figure 1: Skeletal remains at the necropolis in Varna, Bulgaria (4600-4200 BC)

Sunday, 13 March 2016

The design or the decoration of these loincloths was often symbolic and influenced by shamanistic rituals. In South-America, a form of kynodesme closing off the foreskin was and still is commonly used in isolated tribes. However in some areas men rather covered their penis with a gourd or a woven penis sheath. Until the 1980s of last century very elegant penis covers were in use in some tribes in Central Africa. In South Africa, Zulu and Shona men used to wear woven glans covers. In the framework of a play of gender roles, Kapsiki women from North-West Cameroun wear a cache-sexe imitating an erect phallus! In Asia, men from Nagaland (North-East India) wear a very elaborated loincloth on which the genital area is accentuated with a metal disk (Figure 4).

Figure 3: Tribal man wearing an ethnic cache-sexe made of fabric

However, best known for a great variation in male cache-sexe is the South-West Pacific area including Aboriginal Australia. Aboriginal men from Kimberley (West-Australia) used to wear a pearl shell pubic cover, called Jakoli, decorated with intricate engraved motifs related to ancestral stories (Figure 5). On the island Malakula (North Vanuatu) men wrap their penis with a piece of bark cloth or tapa, called namba, and two competing tribes are called the Big Nambas and the small Nambas, for the size of their nambas. The whole island of New-Guinea is overwhelmed by a wealth of different male cachesexe in all kind of forms, colours and materials. Colonial restrictions Under colonial rule, often influenced by different religious concepts of decency, the cache-sexe as a form of primitive behaviour was eradicated, and replaced by more civilised and acceptable types of Western clothing. As a consequence, examples of the early forms of pubic and genital cover are scarce, even in ethnographic collections. After all, these cache-sexe were utensils, and were prone to wear and tear, to finally be abandoned or destroyed. Nevertheless, some explorers, and even missionaries, have collected examples of these artefacts and preserved them for us to be discovered. This allows us to have an idea of the large variety in materials, forms, decorations and even colours, used in the different types of male pubic and genital covers. Precious contemporary documents based on anthropological expeditions allow us to have an idea on the original use and role of the different ethnic male cache-sexe. During the 6th International Congress on the History of Urology on March 11, an overview will be given on the geographic distribution of the male cache-sexe. Furthermore, the symbolism and aesthetics will be discussed, and documented with unique illustrations. It will be concluded that the ethnic male cache-sexe and its use bears important messages not only for the modern urologist, but also for every human

Figure 5: Pubic cover made of engraved shell

being, male and female. Hence, everyone is welcome to the History Congress! Literature Heider K, Attributes and categories in the study of material culture. J. Roy. Anthr. Inst., 4;3, 1969. Ucko PJ, Penis sheaths: a comparative study. Proc. R. Antrop. Inst. 24-67,1969. Lagercrantz S, Penis sheaths and their distribution in Africa. Uppsala Universitet, 1976.

Friday 11 March 8.30-16.15: The 6th International Congress on the History of Urology

Figure 4: Indian tribesmen wear a loincloth accentuated with a frontal disk component

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Complex congenital anomalies and transition of care Multidisciplinary care plays a vital role for adolescent patients Prof. Dr. Wolfgang Rösch Chief and Director Pediatric Urology Clinic University of Regensburg Regensburg (DE)

Urogenital conditions requiring continued management from childhood into adolescence and adulthood are rare, but they can have major and lifelong implications for the respective patient. The advances in medical care over the last decades, now extends the life-span of some of these patients, who would not have survived into adulthood 50 years ago. This can now present a challenge to adult urologists, who may not have encountered these specific patients during their training in adult urology. The successful management of patients with such complex disorders requires a broad knowledge of pediatric as well as adult urology.

A high percentage of BEEC patients who underwent bladder neck repair without augmentation require subsequent additional bladder enlargement3. Furthermore, incorporation of bowel with bladder mucosa has been linked to increased risk of secondary malignancies. Adults with BEEC have a 17.5% risk of developing any malignancy, which is about 700 times greater than the normal population2. The highest risk for secondary malignancies after urinary diversion affects patients with ureterosigmoidostomies, regardless of technique. Similar to other centers, we recommend annual endoscopy screening, starting five years after such a reconstruction. Renal function Renal deterioration may be caused by reflux nephropathy, incomplete bladder/reservoir emptying or recurrent infections. Therefore, it is important to monitor upper tract morphology and renal function annually and life-long

Morphology and long-term function of the hips Up to now there is a lack of data on long-term hip function and orthopedic consequences in patients with BEEC. In contrast to the sparse long-term results after symphysis closure with osteotomy, we found no Currently such specialists are rare. Hence, there is an impairment of long-term hip morphology or function upcoming discussion, whether adolescent urology in adult and adolescent patients after symphyseal should be established as a separate sub-specialty in approximation without osteotomy in the newborn order to facilitate a smooth transition of these patients period (Figure 1)4. from pediatric care to an adult urology team, dedicated to their long-term care. Regular routine orthopedic investigation, especially X-ray controls or CT-scans, seem not to be necessary Currently either pediatric urologists cover this as long as developmental hip dysplasia has been assignment, or adult urologists must familiarize excluded or adequately treated in early childhood. themselves with the specific conditions, the problems they may encounter, and the special management “Besides the pediatric urologist, these patients require in order to live normal lives1. Using the bladder-exstrophy-epispadia-complex (BEEC) as an example, the possible issues will be pointed out in this article. Challenging cases The BEEC still represents the most challenging cases in the field of pediatric reconstructive surgery. During childhood the patients often undergo multiple reconstructive operations with the goal of achieving urinary continence, adequate sexual function and acceptable cosmesis.

this team must also comprise a pediatric orthopedic surgeon, a pediatrician; a pediatric psychologist experienced in urology, as well as experienced pediatric nurses and uro-therapists.”

Sexual function and fertility To adolescents, their body image, self-esteem, sexuality, sexual function and fertility are crucially The resilience of children with BEEC is tested to its important. Persistence of impairments disturbs the limits by numerous hospital stays and operations, regular development of body image and self-esteem physical and psychological challenges and and may create vulnerabilities up to psychosexual incontinence2. Nevertheless, adolescents who grew up dysfunction. with BEEC have an overwhelming desire to be treated as normal people and to become normal adults. Many Female BEEC patients can experience dyspareunia, achieve high levels of education and occupy a wide lack of clitoral sensation and urine leakage with range of employment scenarios. intercourse. Therefore, it is important to assess the integrity of the reconstruction, functional outcomes and cosmesis in adult life. To define a suitable routine assessment for adult patients with BEEC, it is essential to consider long-term follow-up data, which are still rare. Long-term development of bladder/urinary reservoir Irrespective of the type and timing of reconstruction, it is important to evaluate for a change in urinary continence by history, at least annually. Most often changes in continence indicate a change in bladder compliance, de novo detrusor overactivity, an increasing insufficiency of bladder neck or catheterizable stoma, or the presence of stones.

Additionally, there is a high incidence of pelvic organ prolapse throughout the women’s lifetime. In general, female patients are considered to have normal fertility due to normal internal genitalia, but more females than males with BEEC have an unfulfilled wish to have their own children2,5. In males, the most common reason for dissatisfaction is insufficient penile length and dorsal chordee. Concerning fertility, the results in the literature are inconsistent. Iatrogenic damage during initial repair or further reconstructions appears to be the reason for impaired fertility in most cases. The observation of comorbid testicular tumors in adult BEEC patients should prompt a preventive annual examination by ultrasound starting latest after puberty6. Also the young men should be reminded with every visit to perform selfexaminations once a month.

To adolescents, their body image, self-esteem, sexuality, sexual function and fertility are crucially important.

EUT Congress News

During childhood and adolescence, BEEC patients should be followed by a urologist or a pediatric urologist who feels comfortable with major reconstructive

Pain, sport activities, Harris Hip Score

passive range of hip flexion and extension

No complaints regarding hip, dorsal pain and knee pain

4 patients with exceeding normal strechted external hip rotation 2 patients with diminished internal flexed rotation

Median sport marks: 1,5 (1-3; 15 answers) Harris Hip Score between 100 and 90: excellent for all 17 exstrophy patients

No daily life impairment

No impairment during sport activities

Figure 1: Orthopedic results of 17 exstrophy patients (2 f, 15m; mean age 23.9 yrs.) after symphysis adaptation without osteotomy4

surgery and management of the possible long-term complications that may need intervention. As a consequence, support by a multidisciplinary team is mandatory, in order to help the affected individuals and their parents throughout childhood and adolescence. Besides the pediatric urologist, this team must also comprise a pediatric orthopedic surgeon, a pediatrician; a pediatric psychologist experienced in urology, as well as experienced pediatric nurses and uro-therapists. Current long-term outcome analysis now would allow judgment regarding the effects of treatment strategies implemented 20 to 30 years ago. A standardized follow-up programme as a result of long-term outcome studies will definitely help to improve the final results and therefore lifelong outcome success. Obviously, the requirement of multidisciplinary care does not end when childhood ends. With regard to the poorly described but widely accepted dynamic changes in continence and bladder function after childhood, as well as the emerging tremendous problems with sexuality and fertility in both sexes often encountered in that period, transition to an adult urological care with sufficient experience in this

particular field team is imperative for all patients with major congenital anomalies2,5. References 1. Woodhouse CRJ, Neild GH, Yu RN et al. Adult care of Children From Pediatric Urology. J Urol (2012) 187: 1164 2. Gupta AD, Gearhart JP Approach to the exstrophy patient In: Wood HM, Wood D (eds.) Transition and Lifelong Care in Congenital Urology. (2015) Springer International Publishing, Switzerland 3. Whittam B, Szymanski K, Misseri R et al. Long-Term Fate of the Bladder after Isolated Bladder Neck Procedure. J Pediatr Urol (2014) 10: 886 4. Kertai M, Rösch WH, Brandl R et al. Morphological and Functional Hip Long-Term Results after Exstrophy Repair. Eur J Pediatr Surg (2015) 7. DOI: 10.1055/s-0035-1564711; ISSN 0939-7248 5. Park W, Zwink N, Roesch W et al. Sexual function in adult patients with classic bladder exstrophy: A multicenter study. J Pediatr Urol (2015) 11 (3): 125 6. Ebert AK, Kliesch S, Neissner C et al. Testicular Tumors in Patients with Exstrophy-Epispadias-Complex. J Urol (2012) 188: 1300

Sunday, 13 March 10.30-12.00: Thematic Session 8, Paediatric Urology 2016

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Immuno-Oncology: A Hype or a Potential New Foundation for GU Cancers? Sunday, 13 March, 2016 | 17:45 – 19:15 Internationales Congress Center München Paris Room, Hall B2, Level 0 München, Germany Presentations Include: I-O in Bladder Cancer: A Question of Patient Selection? Marc-Oliver Grimm, MD, PhD University Hospital of Jena Jena, Germany

Redefining Treatment Expectations for Metastatic Renal Cell Carcinoma Laurence Albiges, MD, PhD Institut de Cancérologie Gustave Roussy Villejuif, France

I-O: A New Mode of Action Ignacio Duran, MD, PhD Hospital Universitario Virgen Del Rocio Madrid, Spain

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Sunday, 13 March 2016

Optimal sequencing in treating neurogenic patients Holistic approach, extensive urological assessment are needed for neurogenic patients Dr. John Heesakkers Department of Urology Radboud UMC Nijmegen Nijmegen (NL)

The assessment of neurogenic patients is different from other functional disorders. In the latter, quality of life is key and is the starting point. We ask our patients what the main problem or complaint is, why that is bothering them and why they come at this moment. After that we assess the amount of bother and the qualty of life and we perform the diagnostic work-up. This implies that we combine subjective elements (e.g. questionnaires and VAS scales) with objective or semi-objective findings like voiding diaries and urodynamic investigations. When the diagnosis has been made, we discuss with the patient what can be done. We discuss severity of the disease and findings, whether this can be treated or not, what the treatment options are and what the expected benefits and risks are. Afterwards the patient chooses the best treatment for him, based on well-informed consent.

“The main medical issues that neurogenic patients have to deal with are: kidney failure, urinary tract infection, bladder cancer, urolithiasis, proper bladder emptying, incontinence and sexual dysfunction.” In oncological diseases this is most often quite different. Someone comes with a suspected disease that can be based on imaging or some abnormal bloodtest. Often there are no complaints at all. A good example is prostate cancer or a small renal mass suspicious of kidney cancer. Diagnosis is made and staging is done as good as possible. Than the treatment options are discussed, including watchful waiting. A decision is made by the patient, also based on informed consent. However, the treatment options deal with getting rid of the cancer and survival. Hardly ever quality of life issues play a role, only when discussing the operating technique. The first intention and goal is to cure the cancer. With this in mind one can cut one’s penis or testicles without protest, because this serves the good cause. It is needless to say that cutting one penis or testicles most often does not improve quality of life and that some degree of subjective bother will be induced by the surgery. So this assessment is quite the oppostie from dealing only with functional problems. A gray area Dealing with neurogenic patients is something in between dealing with patients with oncological disorders and those patients with pure symptomatic bothersome disorders. There are many quality of life aspects in people suffering from neurogenic diseases. The degree of bother and the kind of bother is different from patient to patient and very much depending on the kind of neurogenic disease, the severity and the involvement of other organ systems outside the urogenital tract. However, the aspect that has to be assessed and that is on top of the list is the preservation of kidney function. Every urologists who sees neurogenic patient has listed this goal as top priority. The reason for this is mainly based on a publication from McGuire et al in 1981 (J Urol 1981:126:205-209). This was an observation in a small study with bifid spine patients. One of the conclusions was that the detrusor leak point pressure should not exceed 40 cm H2O in order te prevent kidney damage. Although this study is known and the conclusion is often consequently put in clinical practice, everyone who is involved realizes that the outcome might not be representative for every patient suffering from a neurogenic disease. Sunday, 13 March 2016

For clinical practice this means that there is variation in the risks for acquiring top priority disorders like kidney failure, that there is variation in types of neurogenic patients and that there is variation in bother. The rule however is: medical issues come first, quality of life comes second. In clinical practice, this mean that you have to assess the risk category your patient is in and that you have to look at the individual physical situation and also bother and wishes. The main medical issues that neurogenic patients have to deal with are: kidney failure, urinary tract infection, bladder cancer, urolithiasis, proper bladder emptying, incontinence and sexual dysfunction. Some of these also influence quality of life directly but others don’t. Medical conditions Some percentages, although there are many published, can be mentioned here to give some idea of what kind of risks we are talking about (See list in Table 1). Risk category The risk category a patient is in depend amongst others on: kind of neurogenic disease, onset of disease and duration of the neurogenic disorder. Another important factor is the urodynamic based classification of lower urinary tract behaviour, which was described very elegantly by Madersbacher (Madersbacher Paraplegia 1990;28(4):217-229). This handy classification looks at the behaviour of the bladder and the bladder outlet of the lower urinary tract during the long-lasting filling or storage phase and the relatively short voiding phase. If for instance patient A is known with an overactive detrusor in the filling phase and an overactive sphincter in the voiding phase, the risks of developing upper urinary tract disorders is higher than patient B with an overactive bladder and an underactive sphincter in the filling phase. The last situation means that the bladder outlet functions as a pressure relieve valve. When the pressure goes up because of detrusor overactivity, the bladder outlet opens and the intravesical pressure decreases. This causes incontinence but there is less risk of upper urinary tract deterioration. Therefore, patient A is in a different risk category compared to patient B. This has consequences for treatment as well as follow-up.

“In neurourology, personalized medicine is put into clinical practice already for ages to serve both the medical and personal needs of patients.” As mentioned before, the prevention of medical disorders comes first and quality of life comes second. For treatment, the rule is that one starts with non – invasive measures like life style intervention, physical therapy if appropriate, followed or accompanied by drug treatment. If that is not enough one can continue with minimally invasive or invasive treatments. The rules of thumb therefore are: 1. 2. 3. 4.

Medical risks come first; Quality of life issues come next; Assess the risk category your patient is in; Assess his personal situation regarding other organ systems (intellectual capacity, social environment, dexterity, transfer possibility, bowel behaviour); and

Quality of life aspects have to be carefully considered in treating patients suffering from neurogenic diseases

5. Define the individual treatment and sequence of treatments based on points 1 through 4. Sequencing of treatment As listed in the rules of thumb above, generally speaking there is some sequencing of treatment but this very much depends on the personal situation of the patient. An example will make clear why it is not possible to generalize rules of thumb, guidelines, efficacy measures etc. Suppose we have the next case: A neurogenic patient, suffering from incontinence, weelchairbound, she has good cerebral capacities and she lives in a good social environment within an optimal care-taking system. She works in an office. Urodynamic investigation reveals a cystometric capacity of 250 cc, detrusor overactivity starting at 100 ml of bladder filling. The detrusor pressures at DO (detrusor overactivity) go up to 100 cm H2O and last for about 30 seconds. Post-void residual is 50 ml. Compliance is slightly deteriorated. Kidney function is normal but renography shows that the efflux from the kidneys is slightly delayed. Some aspects are obvious for every urologist: 1. something needs to be done to prevent kidney damage. 2. The pressure in the bladder has to be lowered. Everyone will most likely agree that lifestye intervention will not be the solution. How about drugs? It is known that antimuscarinics will bring down the detrusor pressure (Stöhrer Spinal Cord 1999), but is it enough? We can try to find out what the effect is. However suppose that the patient is suffering from constipation, than this is perhaps not the first option.

Table 1 • Kidney deterioration

25,7 % (Spina Bifida)

• End stage renal disease

1,3 % (Spina Bifida) (Veenboer et al PLoS ONe 2012;7:e48399

• Urinary tract infection

22% (Spinal Cord Injury) (Cruz et al Eur Urol 2012)

• Bladder cancer

0,11% - 9,68% (Spinal Cord Injury) (Welk et al Spinal Cord 2013;51:516-521)

• Incontinence

25% (Dementia), 65% (Mental Retardation) 95% (High SCI)

• Bladder emptying disorders

26% (Lumbar Spine Disease) 83% (Lower Spinal Cord Injury) (EAU Guidelines Neurourology 2015)

• Sexual Dysfunction

85% (Cauda Equina) (Podnar et al J Neur Neurosurg Psychiatry 2002;73(6):715-720) 35-87% (MS) (de Seze, Game X, Prog Urol 2014;24(8):482-494

The next step would most likely be the intradetrusor application of botulinum toxin A injections. This will bring the detrusor pressure down with about 32 cm H2O (Cruz et al Eur Urol 2012), so we might give it a try. The risk for urinary retention is however 17% of this treatment, and this means that she runs the risk that she has to catheterize to empty her bladder. If she is a paraplegic spinal cord injury patient this will mean that she will need help to perform CIC and to make transfers. If she is paraplegic with good hand function she might perhaps be able to make transfers and perform CIC, but we also need to know whether this is possible in her working environment. Another situation is that if she is a MS patient neuromodulation could be tried because there are publications showing good results (Engeler BMC Urol 2015;23(15):105). And another important point is whether her age is 24 or 64 years. In the last situation a suprapubic catheter could be an option because we also know that with careful control risks for developing bladder cancer are most likely lower than in older days (Feifer, Corcos Neurourol Urodyn 208;27(6):475-479). This could perhaps be combined with anticholinergic instillation or botulinum toxin injections and careful control, which would be out of the question in a young 24-year-old patient.

“Dealing with neurogenic patients is something in between dealing with patients with oncological disorders and those patients with pure symptomatic bothersome disorders.” In conclusion we can say that it is very important to look at all aspects of a neurogenic patient and expand the urological assessment to most other organ systems and also to take the social situation into account when making a decision on treatment and the sequence of treatments. We can therefore conclude that in neurourology, personalized medicine is put into clinical practice already for a long time to serve both the medical and personal needs of patients. Sunday 13 March 10.30-12.00: Thematic Session 6, Neuro-urology

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ADVERTORIAL

The economic impact of bladder cancer Improved techniques for initial detection may decrease the economic burden Bladder cancer is the ninth most common cancer worldwide1, and among the most expensive to manage2. Leal et al. recently estimated the total costs of bladder cancer to be 4.9 billion euros in 2012 with healthcare accounting for 2.9 billion euros (59%) and representing 5% of total healthcare cancer costs across the EU3. The management of early stage bladder cancer therefore represents a potential target for major healthcare savings. Direct costs related to the management of nonmuscle-invasive bladder cancer (NMIBC) are driven by regular surveillance cystoscopies, frequent crosssectional imaging and repetitive transurethral resections of bladder tumours (TURB), and intravesical therapies4. Complete TURB is paramount to optimising oncological outcomes and minimising costs2. Mariappan et al. compared data from two prospective cohorts of patients who had either good-quality white light cystoscopy (GQ-WLC) TURB or blue-light cystoscopy (BLC) TURB. Figure: CIS lesion, blue-light vs. white-light, copyright: Professor Dirk Zaak, Traunstein, Germany Patients had early re-TURB within 6 weeks if they had high-risk disease while all other patients had follow-up cystoscopy at 3 months. The recurrence rate at first follow-up cystoscopy (including early re-TURB) was 30.9% (n = 155 patients) in the GQ-WLC group and 13.6% (n = 191 patients) in the blue-light cystoscopy group. Early recurrence after TURB is most often the result of missed lesions or inadequate resection at the time of the initial TURB, with tumour behaviour, rarely, being a confounding factor. It is by improving tumour detection and enhancing tumour clearance that BLC TURB is thought to effect its benefits5. For Ta/T1 tumours, Burger et al. in his meta-analysis demonstrated that one in four patients had at least one additional tumour detected by blue-light cystoscopy (BLC) that was missed with white-light cystoscopy (WLC) alone. Concerning carcinoma in situ (CIS), the odds of detection were 12.4 times higher with BLC than with WLC, with more than 25% of patients having CIS detected by BLC only6. In a recently published meta-analysis including more than 2,200 patients, Yuan and colleagues reported that the recurrence rate was significantly lower in the BLC group than in the WLC group (OR, 0.5; 95% CI, 0.4 - 0.62; p < 0.00001)7. In addition to improving patient outcomes, findings from several studies show BLC to be cost effective in the management of patients across a range of healthcare systems, even taking into account the need for upfront investment8,9,10. A health economic modelling indicates that the use of HAL to assist primary TURB is no more expensive than WLC alone and will result in improved QALYs and reduced costs over time11.

“Bladder cancer is one of the most expensive diseases and most of the expenses are due to the treatment of recurrent non-muscle-invasive bladder cancer. If we spend a lot of money for transurethral resection, we should try to aim at a reduction of these procedures - not only for the benefit of the patient but also to make the treatment more cost-effective. When we have to spend more on imaging to achieve this goal, these costs have to be weighed against the reduction of TURBs. Therefore, while it is absolutely important to put emphasis on the imaging, maybe the additional monitoring of biomarkers after a bladder cancer event will not only show up a recurrence, but also permit to stratify between low-risk and high-risk patients. This will show which patient may need an augment treatment, which will initiate costs and, sometimes, severe side effects in the patients. In conclusion, better imaging and biomarkers should reduce the number of recurrences and enable us to predict progression or non-progression, allowing us to make the right choice whether patients need an augment treatment or not.” Professor Arnulf Stenzl (Tuebingen, Germany) Recently published real world data (RWD) studies confirm previous trial results in daily clinical use At last year’s DGU (German Society of Urology) congress in Hamburg, Professor Maximilian Burger presented the results of a prospective noninterventional study (OPTIC III), investigating optimised photodynamic diagnosis for TURB12. 403 patients with suspected non-muscle-invasive bladder cancer, undergoing TURB in daily clinical

practice, were included by 30 German sites to assess additional detection of bladder cancer with PDDassisted TURB. It was shown that hexaminolevulinate (HAL)-guided cystoscopy identified a vital number of additional CIS lesions (+25%, p < 0.0001). Additionally, in 10.0% of patients with NMIBC, ≥1 positive lesions were detected with PDD only and 2.2% of NMIBC patients would have been missed with white-light cystoscopy alone. These results are in line with previously conducted randomised clinical trials demonstrating that HAL-guided cystoscopy significantly improves the detection of bladder cancer and provides a diagnostic benefit to patients with suspected NMIBC in daily clinical practice. Another study, published in the Scandinavian Journal of Urology earlier in 2015, concludes that fluorescence cystoscopy with PDD combined with immediate post- TURB chemoprophylaxis effectively reduced the recurrence risk and the number of follow-up TURB procedures under clinical routine conditions10. In total, 190 consecutive patients were enrolled over a 2-year period and followed as the intervention group; 216 patients treated over a 2-year period before introduction served as controls. The intervention group showed a 41% reduction in the risk of recurrence (hazard ratio 0.59, 95% CI 0.45 0.78), and median recurrence-free survival was extended from 13.6 months to 36.8 months. A saving of roughly every third TURB was demonstrated during follow-up. Compared with white light cystoscopy TURB, blue-light cystoscopy TURB + Mitomycin C (MMC) treatment achieved a cost saving of ~DKK1,500 (~€200) in the first year as a result of the 32% reduction in need for subsequent TURBs10.

Lykke et al. were able to confirm that patients with primary and recurrent disease, as well as those with low-risk tumours benefit from the treatment. The authors concluded that the procedure was costeffective, with savings realised through the reduced number of TURB procedures10. “Real world data largely reflect outcomes of most randomised controlled trials. And again the impact of PDD is there, but not equivocal across all risk groups of non-invasive bladder cancer. Improvement of visualisation is notable in high-risk cases, since CIS is significantly better detected using hexaminolaevulinic acid,” is the personal conclusion from Professor Maximilian Burger (Regensburg, Germany) for the available real-world-studies. References 1. Ploeg et al., World J Urol 2009; 27:289-93. 2. Sievert et al., World J Urol 2009; 27:295-300. 3. Leal et al., Eur Urol. 2015 Oct 24 [e-pub ahead of print]. 4. Johnson et al., Urol Clin N Am 42, 2015;235-52. 5. Mariappan et al., Urology. 2015 Aug; 86(2):327-31. 6. Burger et al., Eur Urol. 2013; 63:234-41. 7. Yuan et al., PLoS One. 2013 Sep 13;8(9):e741422013. 8. Malmstroem et al., Scand J Urol Nephrol. 2009;43(3):192-8. 9. Burger et al., Eur Urol. 2007 Jul;52(1):142-7. 10. Lykke et al., Scand J Urol. 2015 Jun;49(3):230-6. 11. Witjes et al., Eur Urol. 2014 Nov; 66(5):863-71. 12. Burger et al., Optimized photodynamic diagnosis for Transurethral Resection of the Bladder (TURB) in clinical practice - Results of the Non-Interventional Study (NIS) OPTIC III (V 38.8, DGU 2015).

Existing European guidelines and consensus statements on the use of PDD-guided cystoscopy in the diagnosis of non-muscle-invasive bladder cancer Bladder cancer guidelines

Settings

To guide initial bladder cancer resection and biopsy

Expert consensus statements on bladder cancer

EAU

ICUD-EAU

NICE

2015

2012

2015

European 2014

German

NORDIC

2008

2010

2012

In patients with positive urine cytology but negative white-light cystoscopy To aid diagnosis of CIS

To assess suspected recurrence

During follow-up of patients with high risk of recurrence (eg, high-grade T1, CIS, or multifocal lesions) During office-based examinations (with flexible cystoscopy)

(

) (

)

As a teaching tool

= recommended by the panel; ( ) = panel believes that there may be a role, but further research is required; BLC = blue-light cystoscopy; CIS = carcinoma in situ; EAU = European Association of Urology; ICUD = International Consultation on Urological Diseases. *In patients who are suspected of harbouring a high-grade tumour, for example, for biopsy guidance in patients with positive cytology or with a history of high-grade tumour. **In patients not previously staged with hexaminolevulinate-guided BLC. Adapted from: Babjuk et al. NMIBC Guideline 2015, NICE BC Guideline 2015, Witjes et al. 2014

EUT Congress News

While the number of active participants is constantly growing and, after a very fruitful year with the Topic of the Year (ToY) 2015 “Identification and management of NMIBC high-risk patients”, the Innovators in BC® will again present the “Bladder Cancer Topic of the Year” at this year’s EAU congress in Munich. Urologists and oncologists are invited to vote for the bladder cancer topic they believe should be further discussed and placed high on the agenda in 2016. Innovators in BC® (www.Innovators-in-BC.com) aims to change the way doctors and healthcare professionals view bladder cancer. The main objective of this platform is to provide sciencebased information in order to raise awareness of bladder cancer in general and to share information, experience and material with in-depth educational background. Its content has been compiled by medical professionals and is updated regularly by providing news about bladder cancer, summaries of congresses, current studies and publications. The website shares educational material for doctors, such as slide kits and patient cases. Moreover, improving early

detection and intervention cystoscopy and resection could reduce the risk of subsequent recurrence and progression, for the patients’ benefit. The potential of Innovators in BC® will increase with its number of users. As a “living tool”, urologists and oncologists are asked regularly to provide new content for the website and with that to raise more the interest of the audience. Innovators in BC® is a restricted area for medical practitioners only from Austria, Belgium, the Czech Republic, France (www.Innovators-in-BC.fr), Germany, the Netherlands, Spain and Switzerland, developed by IPSEN. Without any commercial purpose the platform aims to be neutral and independent.

Sunday, 13 March 2016

Role of PET/CT in recurrent prostate cancer How to optimize the use of imaging in the recurrent setting Dr. Stefano Fanti Service of Nuclear Medicine S. orsola-Malpighi Hospital University of Bologna Bologna (IT)

(PET/CT), proved its leading role for staging, restaging and evaluating the response to therapy in patients affected by several solid cancers and hematologic disease. However, 18F-FDG PET/CT showed a limited role for investigating PCa patients, demonstrating an acceptable feasibility only in patients with very aggressive disease (very high Gleason score).

11C-choline and/or 18F-choline PET/CT has proven to be a better diagnostic tool for restaging patients with PCa after BR when compared to conventional imaging. Choline is a substrate for phosphatedylcholine Co-Authors: Francesco Ceci (IT), Paolo Castellucci (IT), synthesis, which is the major phospholipid in the cell Riccardo Schiavina (IT) membrane. The use of Choline for PET/CT imaging of PC is based on up-regulation of the Choline Biochemical relapse (BR) is a common event after metabolism in tumour cells due to increased activity of primary therapy in prostate cancer (PCa) patients and the enzyme Choline kinase. In addition, Choline occurs in 20% to 30 % of patients after radical uptake is related to a membrane selective transporter, prostatectomy (RP) and in up to 60% after primary which is increased in PCa cells too. Choline can be external-beam radiotherapy (EBRT). labelled with 11C or 18F: the main difference between the two tracers is the earlier urinary appearance of the Nowadays, several tools evaluating clinical and 18F-Choline, probably due to incomplete tubular pathologic parameters such as PSA doubling time and re-uptake. This is particularly relevant in prostate velocity (namely, PSA kinetics), pathologic Gleason cancer diagnosis, staging and assessment of local score, pathologic stage (TNM) and lymph node relapse since sensitivity of the procedure in the pelvis invasion are available to assess the probability of can be reduced by the presence of radioactive urine in harbouring local vs. systemic recurrence after RP or the bladder. EBRT. Although these models are characterized by a relatively good accuracy in distinguishing between On the other hand, 11C has a half-life of 20 local and distant relapse, they are not able to provide minutes and it has to be used soon after precise and individual information about the site of production. These modalities allow for relapse (visceral vs. bone metastases, pelvic vs. extra differentiating between an early relapse limited to pelvic lesions) and/or the number of metastases. the pelvis and a systemic progression. Choline PET/CT may show the site of tumour recurrence in Clinicians are currently not able to target a single step examination, earlier than individualized salvage therapies according to the conventional imaging techniques and its detection information provided by nomograms only. Moreover, rate is related to different parameters, including it should be highlighted that conventional imaging, PSA and PSA kinetics. Interestingly, it has been that include computed tomography (CT), bone demonstrated that the administration of ADT in scintigraphy (BS) and magnetic resonance (MR), is castrate-resistant patients does not reduce the characterised by low sensitivity and not optimal sensitivity of this imaging procedure, allowing the specificity in the staging of recurrent PCa after detection of those lesions not responding to ADT. primary treatment. As a consequence, these patients are generally referred for salvage radiotherapy (S-RT) Impact on therapeutic management to the prostate bed vs. systemic androgen deprivation Choline PET/CT proved a significant impact, in therapy (ADT) when a local vs. systemic relapse is recurrent disease, on therapeutic management and suspected, respectively. on the clinical decision making process. This imaging procedure could be used for patients risk Nonetheless, it has been hypothesized that stratification according to their clinical and imaging metastases-directed therapy might play a role in the features, selecting those patients who are most management of these patients. Such an approach likely to respond and benefit from aggressive would be feasible only if all possible metastatic treatments such as S-RT or salvage pelvic lymphdeposits in the recurrent settings are accurately node dissection (S-PLND). Recently, different studies identified. For this reason, the correct knowledge of designed to investigate the importance of PET the number and site(s) of metastases would therefore imaging to guide therapies have been published. play a critical role. Choline PET/CT may be suggested before salvage therapies, particularly in patients showing fast PSA During the last decades, positron emission kinetics or PSA increasing levels despite on-going tomography (PET), with 18F-deoxy-glucose as ADT, considering the higher probability to detect radiotracer and using hybrid PET/CT tomographs positive findings outside the pelvis

These patients could be excluded from aggressive therapies due to the presence of distant metastases, avoiding futile aggressive treatment and preventing radiation-induced or surgery morbidity. Moreover, the detection of positive loco-regional LNs at PET/CT could have an impact on patient management performing S-RT in an extended PTV or an extended S-PLND. These studies emphasize the importance of PET imaging to guide therapies not only on the local recurrence, especially in case of LN relapse. Finally, in castrate-resistant PCa patients treated with different systemic therapies (including docetaxel, abiraterone and enzalutamide) choline PET/CT recently proved its feasibility for evaluating the response to therapy, assessing the eventual progression of the disease regardless of the serum PSA values. Nonetheless, choline PET/CT still shows a relatively low sensitivity, especially in patients with low PSA levels at the time of imaging. On the other hand, the optimal timing for salvage treatments to obtain the best chance of cure in case of PCa recurrence would be when the cancer burden is low, which corresponds to low PSA levels. In this context, the availability of a diagnostic test capable of differentiating between oligo and poly metastatic disease at recurrence could be crucial and would substantially impact on the clinical decisionmaking process.

PET/CT. These investigations reported also a higher tumour-to-background ratio for 68Ga-PSMA PET/CT for the detection of suspected PCa metastases when compared to choline PET/CT. Further studies published in literature in larger populations of recurrent PCa patients after radical therapy proved the high value of 68Ga-PSMA PET/CT to restage patients in case of BR, with very promising performance also at very low PSA levels. As a consequence, over the last few months an increasing interest on the potential use of this novel radiopharmaceutical tracer in the scientific community has been observed, particularly considering the high specificity of the radiotracer reported in literature (specificity >95%). No extensive validation However, despite these promising results, the results obtained by 68Ga-PSMA PET/CT in recurrent PCa have not been extensively validated with either histology (e.g. biopsy of the suspicious metastatic site) or with lesion-directed imaging provided with high specificity. This is important, since the performance characteristics of any novel imaging methodology should be validated and its performance characteristics supported by confirmatory assessments.

Unfortunately, this has not been systematically done in the available literature. This may have contributed to an artificial inflation of the sensitivity and Recently, a new molecular probe targeting the specificity of 68Ga-PSMA PET/CT reported in the prostate-specific membrane antigen (PSMA) has been literature. Therefore, despite high performance developed. PSMA is a membrane-bound enzyme with characteristics of this novel approach, there is a need significantly elevated expression in PCa cells in for improvement in sensitivity, thus decreasing the comparison to benign prostatic tissue. The localization number of false negative findings. This would help in of the catalytic site of PSMA in the extracellular optimizing the use of lesion-targeted approach in domain allowed for the development of small specific recurrent disease. inhibitors that are internalized after ligand binding. Preliminary studies demonstrated that 68Ga-PSMA Sunday 13 March (Glu-NH-CO-NH-Lys-(Ahx)-[68Ga(HBED-CC)]), an 10.30-12.00: Thematic Session 3 extracellular PSMA inhibitor for PET/CT imaging, is The changing landscape in the management of characterized by a significantly higher accuracy in the prostate cancer recurrence detection of early recurrence as compared to choline

SATELLITE SYMPOSIUM

SUMMARY

Moving Forward in Urological Cancers Symposium Chair: Jacques Irani (France)

Prostate cancer and androgen deprivation therapies: What are the newest data?

Jacques Irani (France) Professor Irani discussed the latest data on the use of androgen-deprivation therapy (ADT) in prostate cancer, starting with a detailed analysis of the STAMPEDE study and exploring other studies demonstrating the advantages of introducing chemotherapy in combination with ADT earlier in the disease course. Professor Irani also discussed recent analyses of the relative benefits of continuous versus intermittent ADT in patients with metastatic prostate cancer and explained the differences between luteinizing hormone-releasing hormone agonists and antagonists with respect to prostate-specific antigen control and adverse events.

Meeting held on Saturday March 12th

Is androgen-deprivation therapy the backbone of advanced prostate cancer treatment?

Axel Merseburger (Germany) Professor Merseburger introduced the importance of continuing ADT throughout prostate cancer treatment, particularly in the castration-resistant setting. He discussed mechanisms of ADT resistance, concluding that combining ADT with agents targeting alternative pathways may be a valid approach to overcome this problem in castration-resistant prostate cancer. Professor Merseburger highlighted a number of studies on combination therapies and demonstrated the value of ADT as a backbone therapy throughout the course of disease.

Prostate cancer in China: From fundamental research to clinical practice

Liqun Zhou (China) Professor Zhou delivered an overview of the recent advances in prostate cancer care and research in China. He began by introducing the epidemiology of the disease in Chinese men, before moving on to discuss developments from fundamental research conducted in China. Professor Zhou highlighted new therapeutic targets and discussed the potential of new diagnostic and prognostic markers described by Chinese groups. He concluded that China will play a big part in the evolution of future prostate cancer care.

Photodynamic diagnosis of bladder cancer in a real world setting: Does it work outside of clinical trials? And can we manage high-risk patients better in real life?

Maximilian Burger (Germany)* Professor Burger presented data on photodynamic diagnosis in bladder cancer, highlighting the benefits of hexaminolevulinate (HAL) in transurethral resection of the bladder (TURB). He demonstrated the advantages of this technique in bladder cancer detection, resulting in delayed and reduced rates of recurrence. He provided a comparison of HAL–TURB in clinical trials and clinical practice, concluding that HAL–TURB is similarly effective in both settings.

TOPIC OF THE YEAR 2016

*The Innovators in Bladder Cancer “Bladder Cancer Topic of the Year” was voted on and the winner announced during the symposium. If you would like further details on the selected Topic of the Year, please visit the Ipsen booth (Booth D42, Hall B1).

C-11 choline PET-CT scan of left pelvic lymph node in recurrent prostate cancer (Photo: Courtesy of Mayo Clinic)

Sunday, 13 March 2016

EUT Congress News

Getting acquainted with YAU YAU takes big strides, bold initiatives Prof. M. Selcuk Silay Chairman, Young Academic Urologists Chairman, Pediatric Urology Division Bezmialem University, Istanbul Istanbul (TR)

Endourology and Stone Disease, Men’s Health and Robotics 7. YAU have published 42 articles in PUBMED since the first day it was initiated in 2011? 8. YAU members prepared most of the EAU Patient Information? 9. YAU working groups meet twice a year to plan out their scientific work?

Despite a relatively newcomer, the Young Academic Urologists (YAU) is emerging to be one of the most dynamic groups in the EAU family.

10. Every year around five to 10 new members join the YAU groups and five to 10 members leave (due to age restriction, etc.) ?

Its members have actively pursued a varied programme and have taken many collaborative initiatives since the group was created six years ago.

11. Residents in urology can apply as a YAU Associate Member provided they fulfil the application criteria?

Some facts and figures about the YAU. Do you know that… 1. YAU consists of already renowned young urologists under the age of 40 from all over Europe? 2. The main objective of YAU is to conduct scientific work?

12. YAU members publish articles and announce activities in every regular issue of the European Urology Today newsletter? 13. The twitter address of YAU is: ‘@EAUYAUrology’? 14. Beyond their scientific collaborationm, YAU members also become good friends? 15. You are welcome to apply and join the YAU team?

3. There are currently 72 members of YAU from all over Europe? 4. Majority of the YAU members are also experts (journal editors, reviewers, speakers in EAU congresses, guideline panel members, EAU section members etc.) in their respective fields? 5. Each YAU group is represented in relevant EAU Sections? 6. There are eight scientific working groups of YAU? These are: Prostate Cancer, Renal Cancer, Urothelial Cancer, Functional Urology, Paediatrics,

YAU Board Meeting

We look forward to your applications. Teamwork is key to our success. But we are not only a team because we work together, we are a team because we trust, respect and care for each other! Come and join the YAU!

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Sunday, 13 March 2016

OAB and incontinence after prostate surgery What’s out, what’s in, what’s coming? Dr. Mauricio Plata Fundacion Santa Fe De Bogota Urology Department Bogota (CO)

Despite the fact that prostate cancer (PCa) incidence has decreased over the years after PSA introduction, PCa still represent 14% of all cancers. There is also a trend to lower cancer mortality, in part, related to early detection and the introduction of multiple treatment modalities that can improve survival. The rough estimated survival of PCa is 98.9% at five years and more than 94% at 10 years. The increased survival put the patient at risk of dealing with the sequela of treatment such as urinary incontinence, one of the most devastating conditions after prostatic surgery for benign and malignant disease. The rates of urinary incontinence are variable but up to now it seems there is no big difference regarding the way the procedure is performed, either open or laparoscopic/ robot-assisted. In the long-term, patients undergoing prostatectomy can have a urinary incontinence in a rate of about 18% at 15 years after surgery1. 5-10% of men with post-prostatectomy incontinence (PPI) are expected to be treated with surgery2. However, it is a common thought to blame the surgery as the sole cause of urinary incontinence, but there are multiple factors that play a role and are responsible for the huge disparity of presentation of urinary incontinence. The aging process itself increases incontinence rates after surgery or radiation therapy. The more a patient survives, the higher the chance of having urinary incontinence in the long-term3.

for three days because the amount of leakage can suggest the type of procedure that can work better7. Video/urodynamics is mandatory and can help identify detrusor underactivity, over activity, determine the degree of leakage and also be helpful in determining the degree of mobility of the bulbar urethra, and in selecting patients that can benefit any type of procedure such as a retroluminal sling. Cystoscopy is also important to check for sphincteric function and to rule out strictures. With this in mind, the decision-making process is more straightforward taking into account the severity of incontinence, the co-morbidities, the willingness to accept a second procedure after prostatic surgery, the adversity of the patient to have a prosthetic device, his own biases and our personal biases towards any procedure, especially those with whom we were trained or are more familiar. Despite all these facts, once the type of incontinence and the severity are identified it seems advisable to start dealing with the problem that is most bothersome in the first place.

“PPI is a growing challenge for the urologist who will face more cases as the life expectancy increases. It is our duty to deliver the best care for these patients.” Independent of the type of incontinence, there is evidence that suggests that pelvic floor rehabilitation after radical prostatectomy can improve outcomes but more, importantly, can reduce the time to gain continence in those patients who will recover it.

In a center of clinical care for prostate cáncer, it seems advisable to bring the physiotherapist into the team and include an educational session before surgery and standardized sessions of pelvic floor rehab after the surgical procedure which starts once the catheter is withdrawn. This will allow those patients who will recover continence by themselves less time to achieve Patients who have had prostatectomy can have a urinary incontinence risk of about 18% at 15 years after surgery. Photo: Getty Images this point8,9,10. If this is not the case, after a prudential No matter being continent after surgery, for the only but arbitrary timeframe of up to 12 months, the decision reason of getting older the chance to become of an invasive procedure has to be determined. incontinent is 11%4. In addition, not only incontinence over time13. Long-term follow-up have shown a there is evidence that urethral repair is better than related to sphincteric issues can be the cause of SUI surgery continence rate of about three in every four cases14. leaving the erosion for second healing regarding Surgical procedures are considered the long-term What is important is to realize that despite the fact all stricture formation. Transcorporal AUS is an excellent incontinence after surgery. Detrusor overactivity, diminished bladder capacity, impaired detrusor treatment for the majority of patients with moderate of the slings have level III evidence, some of them salvage approach for patients who have had prior cuff have longer follow-up and more patients treated and erosion. contractility and bladder outlet obstruction can lead to and severe Stress Urinary Incontinence (SUI). The urinary symptoms and urinary incontinence after history of SUI surgery after prostatectomy has a broad enrolled in clinical trials over the others. surgery5. variety of surgical procedures based on the theories PPI is a growing challenge for the urologist who will that were the trend at the time. The main principle of It is the physician’s own judgement based on the best face more cases as the life expectancy increases. It is any surgical procedure for incontinence is to gain evidence and experience which drives the selection of our duty to deliver the best care for these patients. There are several factors after surgery that can alter any type of sling in particular. One special bladder and outlet dynamics such as reduced bladder urinary continence without endangering the perfusion induced by long-term elevated intravesical micturition act with an acceptable rate of consideration is the patient who undergoes adjuvant References pressure, inflammation and fibrosis, surgery-linked complications. radiation therapy after surgery. There is some 1. Resnick MJ, Koyama T, Fan K-H, Albertsen PC, Goodman evidence that in those patients the outcome of a male altered bladder wall geometry, and partial surgical M, Hamilton AS, et al. Long-Term Functional Outcomes sling is compromised15. Current and past surgical procedures have failed in decentralization of the bladder which can also be after Treatment for Localized Prostate Cancer. N Engl J achieving a complete successful gain in urinary responsible for overactive bladder symptoms and Med. Massachusetts Medical Society; 2013 Jan impaired detrusor contractility caused by transient continence. This failure varies depending on the way AUS 30;368(5):436–45. bladder denervation. continence is measured; however, the failure rates Why is the AUS the gold standard despite the fact no 2. Kumar A1, Litt ER, Ballert KN, Nitti VW. Artificial urinary reflect in part the shortcomings in understanding the RCTs are available? The answer is simple. It passed sphincter versus male sling for post-prostatectomy pathophysiology of PPI. On the other hand, the added value of adjuvant incontinence--what do patients choose? J Urol. 2009 the test of time after more than 35 years of use. There radiation therapy to surgery in the patient with are few modifications of the original device since its Mar;181(3):1231-5 There are two procedures that have passed the test of introduction in the early 1970s, it has standardized non-locally advanced prostate cancer is offset by the 3. Kopp RP1, Marshall LM, Wang PY, Bauer DC, Barretthigher chance of urinary complications such as a time or there is a growing body of evidence in its and reproducible surgical technique, there are known Connor E, Parsons JK; Osteoporotic Fractures in Men combination of stress urinary incontinence and favor. The male sling and the artificial urinary complications (and the way to deal with them) and MrOS Research Group. The burden of urinary overactive bladder with the great dilemma of the best sphincter (AUS)11 male slings belong to three main incontinence and urinary bother among elderly prostate there is nothing yet better with regards outcomes. management choice for each one or for whom should categories: suburethral bone-anchored slings (no cancer survivors. Eur Urol. 2013 Oct;64(4):672-9. one start first6. Recent evidence has shown that the perineal 4. Naselli A1, Simone G, Papalia R, Gallucci M, Introini C, longer in use), Transobturator retroluminal slings approach may have some advantages over the Andreatta R, Puppo P. Late-onset incontinence in a (RTS) and adjustable slings. penoescrotal for primary and secondary procedures. cohort of radical prostatectomy patients. Int J Urol. 2011 Another factor that is important is the status of the When the sphincter fails, the need for a tándem cuff bladder before surgery. Little is known about the Jan;18(1):76-9 The mechanism of action of the retroluminal sling is relation of bladder quality and urinary symptoms is more frequent for the penoescrotal (10.0%) than for 5. Porena M1, Mearini E, Mearini L, Vianello A, Giannantoni hypothesized to rely more on repositioning of the after surgery. It sounds logical to believe that if the perineal (1.2%)16. Some patients can have a loose A. Voiding dysfunction after radical retropubic descended posterior and sphincteric urethra than on bladder deterioration ocurred because of long-term cuff instead of uretral atrophy and can benefit more prostatectomy: more than external urethral sphincter direct compression of the bulbar urethra12. Only men with cuff downsize and proximal relocation than a bladder outlet obstruction before surgery, the with adequate bladder neck and proximal urethral deficiency. Eur Urol. 2007 Jul;52(1):38-45. outcome of urinary symtoms after surgery can be mobility should be offered retroluminal sling surgery, tandem cuff. Tandem is associated with higher 6. Suardi N1, Gallina A2, Lista G2, Gandaglia G2, Abdollah compromised but the literature is poor in this matter. whereas those with an immobile proximal urethra erosion rates. The introduction in 2010 of the 3.5 cm. F2, Capitanio U2, Dell’Oglio P2, Nini A2, Salonia A2, would be more appropriately treated with a cuff had a favorable impact on continence Montorsi F2, Briganti A2. Impact of adjuvant radiation The best way to deal with this patients is in a compressive quadratic sling or AUS. outcomes17,18, however in irradiated patients or therapy on urinary continence recovery after radical multidisciplinary approach in a clinical care center, concomitant penile prosthesis surgery have been prostatectomy. Eur Urol. 2014 Mar;65(3):546-51 that is accountable for the total care for a medical The ideal candidate for a retroluminal sling is the identified as factors associated with a greater rate of condition and its complications; it is mission driven, patient who do not want a mechanical device, who erosion for the 3.5 cms cuff 19. Editorial Note: Due to space constraints the reference patient-centered and with standardized parameters. cannot use it, who is able to interrupt the urinary list has been shortened. Interested readers can This is translated in added value for patients. stream (residual sphincteric function), less tan 400 gr In the coming years, the higher life expectancy of the request for the complete list by sending an email to in 24-hour pad test and a normal bladder capacity prostate cancer survivors will confront the urologist to communications@uroweb.org. Diagnostic workup and compliance on urodynamics. more challenging cases, second procedures after The diagnostic workup must include a detailed history failed incontinence surgery and long-term failures Sunday 13 March of lower urinary tract symptoms with any validated A meta-analysis of male slings showed best results and complications. The half time failure for the AUS is 10.30-12.00: Thematic Session 7, Challenges in questionnaire, a bladder diary with and without clamp seen in studies in well selected men with mild to eight years in average. Mechanical failure can occur incontinence treatment to determine the real bladder capacity, A 24 pad test moderate incontinence with a trend to loss of efficacy as well as infection or late erosion. If this is the case, Sunday, 13 March 2016

EUT Congress News

Regenerative medicine and the urinary bladder Tissue engineering offers both challenges and opportunities Ramnath Subramaniam Consultant paediatric urologist Leeds Teaching Hospitals NHS Trust Leeds (UK)

Regenerative medicine involves a diverse areas of tissue engineering, stem cells and cloning with a common goals of “Replacing or regenerating human cells, tissues or organs, to restore or establish normal function”1. Regenerative medicine offers the possibility to replace old and damaged cells by genetically similar young and functional cells2. Tissue engineering follows the principles of cell transplantation, materials science and engineering to construct functional tissues and supplement or replace diseased and defective body parts3,4. Strategies for bladder tissue engineering Urinary bladder regeneration is the most heavily researched aspect of tissue engineering in urology4. However the optimal method has not yet been established. Most strategies involve the use of a scaffold or matrix to support development of new tissues. Scaffolds or matrix can be used simply as a graft alone depending then entirely upon the host to provide the ingredients to develop new tissue. Other researchers have seeded the grafts with cultured cells from the organ of interest to promote regeneration. As a rule, seeded constructs did much better than unseeded constructs as demonstrated by this study in a canine model of subtotal cystectomy where a synthetic polymer seeded with autologous urothelial and smooth muscle cells resulted in tissue formation similar to the native bladder5.

Reseeding scaffolds Urothelial tissue culture aims to produce cells that can be seeded onto areas of the bladder lacking in urothelium. Oberpenning et al6 used tissue engineering to create a functional canine de novo bladder. Autologous urothelial and smooth muscle cells (SMC) were passaged in vitro and then seeded on either side of a polymer in the shape of a bladder and transplanted over an area above the trigone. Their study claimed that capacity, compliance as well as histology of the neobladder was similar to the native tissue. This approach, re-seeding scaffolds with engineered urothelial cells and SMC, was translated into humans culminating in a publication in Lancet 20067 with much promise and media hype. This was indeed an impressive scientific and surgical achievement but early results were then reported on seven patients only, with two apparently lost to follow-up. It took a very long time with further follow-up data until Joseph et al from the same group presented results from a Tengion-sponsored phase II clinical trial8; the results were much less positive with less attention. The study concluded: “Our autologous cell seeded biodegradable scaffold did not improve bladder compliance or capacity, and our serious adverse events surpassed an acceptable safety standard”8 Composite cystoplasty This is a different strategy that our group has been working on for a considerable number of years. The idea is to propagate autologous urothelial cells in vitro and then transfer them onto a vascular smooth muscle substrate, which has been de-epithelialised. The main difference here is that only the urothelium needs to be engineered, and the smooth muscle tissue is borrowed from an existing preformed vascularised tissue in vivo9-11. By engineering the urothelium, we can avoid the detrimental effects of the intestinal epithelium and its consequences.

Alternative cell sources Researchers in tissue engineering continue to strive and look for cell sources with regenerative potential and those working on the urinary tract are no different. They are in search of readily available sources and outside the urologic organs, candidate cells from non-urologic tissue and stem cells have been considered. Buccal mucosa is one alternate non-urologic source that has been cultured successfully for use in the urethroplasty in particular. Research in stem cell technology is expanding and holds much promise to provide an endless source of non–diseased material for generation of specific cells or tissue as required for replacement and reconstruction. Epigenetic rejuvenation of diseased urothelium Despite considerable progress around the development of robust techniques to culture and differentiate urothelium from surgical samples of normal bladder, our most recent work has shown that the urothelium from abnormal (neuropathic and non-neuropathic) bladders has a compromised capacity for proliferation and differentiation in vitro12. The basis for this compromised phenotype is unknown, but poses a risk to translating composite enterocystoplasty into clinical practice. Our hypothesis is that the modification to the urothelium is epigenetic - caused by the diseased, chronically-inflamed environment of the bladder and we predict that drugs developed as epigenetic modifiers may be useful for reprogramming the urothelium from patients with diseased bladders. References: 1. Mason C, Dunnill P. A brief definition of regenerative medicine. Regen Med 2008;3:1–5. doi:10.2217/17460751.3.1.1. 2. Atala A, Murphy S. Regenerative medicine. JAMA 2015;313:1413–4. doi:10.2217/17460751.2.1.11. 3. Wezel F, Southgate J, Thomas DFM. Regenerative medicine and urology. BJU Int 2011;108:1046–65. doi:10.1111/j.1464-410X.2011.10206.x.

4. Roth CC, Kropp BP. Recent advances in urologic tissue engineering. Curr Urol Rep 2009;10:119–25. doi:10.1007/ s11934-009-0022-y. 5. Jayo MJ, Jain D, Ludlow JW, Payne R, Wagner BJ, McLorie G, et al. Long-term durability, tissue regeneration and neo-organ growth during skeletal maturation with a neo-bladder augmentation construct. Regen Med 2008;3:671–82. doi:10.2217/17460751.3.5.671. 6. Oberpenning F, Meng J, Yoo JJ, Atala a. De novo reconstitution of a functional mammalian urinary bladder by tissue engineering. Nat Biotechnol 1999;17:149–55. doi:10.1097/00005392-199909010-00130. 7. Atala A, Bauer SB, Soker S, Yoo JJ, Retik AB. Tissueengineered autologous bladders for patients needing cystoplasty. Lancet 2006;367:1241–6. doi:10.1016/ S0140-6736(06)68438-9. 8. Joseph DB, Borer JG, De Filippo RE, Hodges SJ, McLorie G a. Autologous cell seeded biodegradable scaffold for augmentation cystoplasty: Phase II study in children and adolescents with spina bifida. J Urol 2014;191:1389–94. doi:10.1016/j.juro.2013.10.103. 9. Turner A, Subramanian R, Thomas DFM, Hinley J, Abbas SK, Stahlschmidt J, et al. Transplantation of Autologous Differentiated Urothelium in an Experimental Model of Composite Cystoplasty. Eur Urol 2010;59:447–54. doi:10.1016/j.eururo.2010.12.004. 10. Turner AM, Subramaniam R, Thomas DFM, Southgate J. Generation of a Functional, Differentiated Porcine Urothelial Tissue In Vitro. Eur Urol 2008;54:1423–32. doi:10.1016/j.eururo.2008.03.068. 11. Subramaniam R, Turner AM, Abbas SK, Thomas DFM, Southgate J. Reconstructive Urology Seromuscular Grafts for Bladder Reconstruction: Extra-luminal Demucosalisation of the Bowel. URL 2012;80:1147–50. doi:10.1016/j.urology.2012.07.047. 12. Subramaniam R, Hinley J, Stahlschmidt J, Southgate J. Tissue engineering potential of urothelial cells from diseased bladders. J Urol 2011;186:2014–20. doi:10.1016/j. juro.2011.07.031.

Sunday 13 March 10.30-12.00: Thematic Session 8, Paediatric urology 2016

NOW ENROLLING: Efficacy and Safety Study of

ODM-201 in Men with High-risk Non-metastatic Castration-resistant Prostate Cancer (ARAMIS) Key eligibility criteria: • • • •

Castration resistant PC High risk non metastatic (MO) PSADT of ≤ 10 months PSA > 2ng/ml

2:1 Randomisation

ODM-201: ARAMIS Phase III Design

N~1,500

ODM-201 600mg bid Placebo

Primary endpoint:

• Metastasis-free survival (MFS)

Primary Objective •

To evaluate ODM-201 vs. placebo in prolonging metastasis-free survival (MFS) in patients with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC)

Secondary Objectives •

Overall survival (OS), Time to first symptomatic skeletal event (SSE), Time to initiation of first cytotoxic chemotherapy, Time to pain progression

•

To characterise the safety and tolerability of ODM-201

•

Histologically or cytologically confirmed adenocarcinoma of prostate without neuroendocrine differentiation or small cell features.

•

Progressive Castration-resistant prostate cancer (CRPC) with castrate level of serum testosterone.

•

Prostate-specific antigen doubling time of ≤ 10 months and PSA > 2ng/ml at screening

•

Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

•

Blood counts at screening: haemoglobin ≥ 9.0 g/dl, absolute neutrophil count ≥ 1500/µl (1.5x109/L), platelet count ≥ 100,000/µl (100x109/L).

http://www.clinicaltrials.gov (NCT02200614) Bayer and the Bayer cross are registered trademarks of Bayer. © Bayer. (February) 2016. L.DE.COM.SM.02.2016.4369.

L.DE.COM.SM.02.2016.4369 ARAMIS ODM-201 2016 Ad v02.indd 1

EUT Congress News

Screening values of serum alanine aminotransferase (ALT) and/or aspartate transaminase (AST) ≤ 2.5 x upper limit of normal (ULN), total bilirubin ≤ 1.5 x ULN (except patients with a diagnosis of Gilbert’s disease), creatinine ≤ 2.0 x ULN.

Selected Exclusion Criteria:

Selected Inclusion Criteria:

For complete information please visit:

•

History of metastatic disease or presence of detectable metastases Presence of pelvic lymph nodes < 2 cm in short axis below the aortic bifurcation is allowed. Acute toxicities of prior treatments and procedures not resolved to grade ≤ 1 or baseline before randomisation. Prior treatment with: second generation androgen receptor (AR) inhibitors, other investigational AR inhibitors, oral ketoconazole longer than for 28 days OR CYP17 enzyme inhibitor. Use of estrogens, 5-α reductase inhibitors or AR inhibitors (bicalutamide, flutamide, nilutamide, cyproterone acetate) within 28 days before randomisation. Prior chemotherapy or immunotherapy for prostate cancer except adjuvant/neoadjuvant treatment completed > 2 years before randomisation. Radiation therapy within 12 weeks before randomisation. Initiation of treatment with bisphosphonate or denosumab within 12 weeks before randomisation. Major surgery within 28 days before randomisation. Any of the following within 6 months before randomisation: stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft; congestive heart failure New York Heart Association (NYHA) Class III or IV. Uncontrolled hypertension. Gastrointestinal disorder or procedure which expects to interfere significantly with absorption of study treatment. ODM-201 is an investigational agent and is not approved by the FDA, EMA, or other health authorities. Trial Sponsor: Bayer HealthCare Pharmaceuticals, Inc. 100 Bayer Boulevard, PO Box 915, Whippany, NJ 07981 USA Orion Corporation, Orionintie 1, FI-02200 Espoo, Finland

2/12/16 11:59 AM

Sunday, 13 March 2016

L.DE.COM.SM.02.2016.4369 – ARAMIS ODM-201 Clinical Trial Ad – 1/2 Pg HORIZONTAL AD (270mm x 194.3mm)

The urine microbiome Relations to urinary tract infection, hormonal status, gender and age D.J. Kok Assistant Professor Erasmus MC Dept. of Urology Rotterdam (NL)

Co-Author: D.M. Maghdid, Erasmus MC, Rotterdam (NL) It has become clear that the urine bladder is not sterile. It contains a microbiome1. The bacterial species in this bladder microbiome often do not grow under routine urine culture conditions but can be identified under culture conditions that better resemble the bladder environment and by bacterial DNA analysis2.

coming for IVF treatment microbiome composition has been determined over a 30-week interval. In women who did not become pregnant microbiome composition was stable. In women who did become pregnant the composition drastically changed10. Mechanisms for long-term survival of a urine microbiome Next to simply having luck and staying behind in residual urine, bacteria can prolong their stay by adhesion to the bladder wall through biofilm formation, by invading urothelial cells or by being located inside crystalline material that is not excreted11-13. Further research into how to disturb these survival techniques may lead to new therapies for prevention of UTI.

Urine microbiome as a source for urinary tract infection When accepting that the bladder contains a microbiome, invasion of the urinary tract by a pathogen from an outside source is not the only mechanism by which urinary tract infection (UTI) may start. When the bladder microbiome contains Identification of bacterial presence using DNA potential causes of UTI, UTI may start when the enhancing techniques holds the risk of DNA false positive identifications due to multiplication of minor microbiome as a whole is given the chance to multiply as outlined above. In a study on 96 children contaminations that occurred during sample with and without a history of UTI and with or without collection. However, analysis of matched urine samples and samples taken from potential sources for problems of urinary tract function we found that for E coli, the most common cause of UTI, we could very contamination strongly supports the conclusion that the bacteria identified with such techniques in a urine accurately predict the risk of forming a new E coli UTI using the percentage of E coli in the microbiome14. sample do represent a true urine microbiome2. The existence of a urine microbiome has several implications: • It raises questions on the stability of that microbiome. • It raises questions on how this microbiome survives over time. • It changes the way we should look at the development of urinary tract infection. • It opens up the potential use of urine microbiome analysis as a diagnostic tool.

Stability of the urine microbiome size The doubling time of E coli in urine under laboratory conditions averages one hour3. If we accept that a microbiome exists permanently in the bladder there must be some mechanism to balance such growth of bacterial numbers in the microbiome given the fact that bacteriuria is not the normal condition for healthy people. A simple balancing mechanism could be the normal voiding cycle in which most of the urine is excreted regularly. When a person has a residual urine volume of 10 ml, the average for normal men4, containing 100 E coli/ml (a negative culture) and does not void for six hours the total E coli population size may reach 64000, after 10 hours this would be half a million. When urine volume in these periods increases to 0.5 liter this translates into 120 (stabilization) respectively 1000 E coli/ml (a ten-fold increase). After new rounds of delayed voiding and ten-fold increases the number of E coli reaches values connected to UTI symptoms. This simple model of microbiome dynamics shows that the normal habit of emptying the bladder almost completely four to six times per day may already stabilize the urine microbiome at a level that does not cause problems. Upon delayed voiding and/ or residue after voiding, the balance moves towards growth of bacterial numbers and potential problems. This mechanism clarifies why having residual urine in the bladder after voiding increases the risk for development of UTI5 and why vesicoureteral reflux would increase the risk for renal infection6. Both clinically proven risk factors make less sense when bladder urine would be sterile. It also explains the phenomenon of low bacterial count UTI in children7 and explains why for adult men with normal urinary tract function an increase of residual urine volume within the normal range correlates with positive urine cultures8. This mechanism stresses the importance of regular and complete voiding for prevention of UTI. In fact, frequency linked to UTI is a natural defense mechanism in this light. Stability of the urine microbiome composition Analysis of urine microbiome composition in males and females of different age groups shows that microbiome composition is gender specific. In women from the fertile age range the urine microbiome is dominated by Lactobacillus species. This Lactobacillus presence is low after birth, increases during puberty and decreases after menopause9. In boys Lactobacillus is largely absent except for newborns. In women Sunday, 13 March 2016

The reporter operated curve (ROC) for the prediction of a new E coli UTI from the percentage of E coli in the microbiome had an area under the curve of 0·86, asymptotic significance =0·000, 95% confidence interval 0·771-0·950. It should be stressed that this prediction is based on the relative presence of E coli expressed as percentage of the total microbiome not on the absolute number (the unit for urine culture). In the light of the doubling mechanism described above, absolute numbers may be more variable than the relative presence. Microbiome analysis as a diagnostic tool Using microbiome analysis for prediction of UTI risk would be one application. In the study on IVF patients we found another surprising application. The urine microbiome composition determined before treatment very accurately predicts the chance that a woman will become pregnant from IVF10. Our proposed explanation for this marker function is that the marker bacteria that we found prefer a urothelial environment that resembles the endometrial environment that the fertilized egg will encounter after transfer during IVF. In view of the rapid doubling times of bacteria this suggests that microbiomes might be used as sensitive, fast reacting sensors for the internal human environment. Declaration of interests DJ Kok and DM Maghdid are co-owners of a patent based on microbiome analysis: New method and kit for prediction success of in vitro fertilization, PCT/ NL2011/050563. References 1. Hilt EE, McKinley K, Pearce MM, et al. Urine is not sterile. J Clin Microbiol 2013; 52: 871–6 2. Wolfe AJ, Toh E, Shibata N, et al. Evidence of uncultivated bacteria in the adult female bladder. J Clin Microbiol 2012; 50: 1376–83. 3. Tong H, Heong S, Chang S. Effect of ingesting cranberry juice on bacterial growth in urine. Am J Health-Syst Pharm 2006; 63: 1417–9. 4. Kolman C, Girman CJ, Jacobson SJ, Lieber MM. Distribution of post-void residual urine volume in randomly selected men. J Urol 1999; 161: 122–127. 5. Merrick MV, Notghi A, Chalmers N, Wilkinson AG, Uttley WS. Long-term follow up to determine the prognostic value of imaging after urinary tract infections. Part 1: Reflux. Arch Dis Child 1995; 72: 388–392. 6. Puri P, Cascio S, Lakshmandass G, Colhoun E. Urinary tract infection and renal damage in sibling vesicoureteral reflux. J Urol 1998; 160: 1028–30. 7. Kanellopoulos TA Vassilakos PJ, Kantzis M, Ellina A, Kolonitsiou F, Papanastasiou DA. Low bacterial count urinary tract infections in infants and young children. Eur J Pediatr 2005; 164: 355–61. 8. Truzzi JCI, Almeida FMR, Nunes EC, Sadi MV. Residual urinary volume and urinary tract infection. When are they linked? J Urol 2008; 180: 182–185. 9. Maghdid DM, vd Hoek J, vd Toorn F, Scheepe JR, Wolffenbuttel KP, Abozaid YJ, Drexhage VR, Kok DJ. Gender specific composition of the urine microbiome. (submitted)

Identification of bacterial presence using DNA enhancing techniques holds the risk of false positive identifications but new studies show the value of this type of bacterial analysis (Photo: Monitor)

10. Maghdid DM, Laven JSE, Alnakshabandi AA, Beckers NGM, Mansoor IY, Steegers-Theunissen R, Kok DJ. Human urinary microbiome as predictor for the success of IVF. (submitted) 11. Mathoera RB, Kok DJ, Verduin CM, Nijman RJ. Pathological and therapeutic significance of cellular invasion by Proteus mirabilis in an enterocystoplasty infection stone model. Infect Immun 2002; 70: 7022–32 12. Anderson GG, Palermo JJ, Schilling JD, Roth R, Heuser J, Hultgren SJ. Intracellular bacterial biofilm-like pods in urinary tract infections. Science 2003; 301: 15–107. 13. Mulvey MA, Schilling JD, Hultgren SJ. Establishment of a

persisent Escherichia coli reservoir during the acute phase of a bladder infection. Infect Immun 2001; 69: 4572–79. 14. Maghdid DM, vd Hoek J, vd Toorn F, Scheepe JR, Wolffenbuttel KP, Abozaid YJ, Drexhage VR, Kok DJ. Prediction of Urinary Tract Infection from urine microbiome in children. (submitted)

Sunday 13 March 10.30 – 12.00: Thematic Session 8, Paediatric urology 2016

STEPS

Interactive Education with World Experts in Onco-Urology

Sessions To Evaluate ProgresS in the management of urological cancers

Applications now open! Visit Ipsen at booth D42 to learn more What is STEPS? • A scientific case discussion session led by senior experts in urological cancers • Open to applications from recently specialised clinicians • Developed by Professor Maurizio Brausi, Chairman of ESOU, and his fellow Board members

“The expert mentors key messages were so useful for my daily clinical activity.” Fouad Aoun, STEPS participant in 2016

• A CME accredited program • Runs annually at the EAU Section of Oncological Urology (ESOU) conference “A great learning opportunity, not only for fellows but also for us as experts.” Hendrik van Poppel, STEPS mentor in 2015

Who should apply? • Recently specialised clinicians with a firm interest in the management of urological cancers, who: - Have demonstrated support from their Head of Department - Are keen to participate in ESOU and EAU programs - Understand and speak English fluently

Find out more about STEPS: http://esou2015.uroweb.org/scientific-programme/steps/

EUT Congress News

Stebab Low Risk Prostate Cancer

速 TOOKAD Minimally Invasive Focal Therapy

Available Soon

A complementary approach to Active Surveillance

EFFICACY & QUALITY OF LIFE 16

EUT Congress News

Sunday, 13 March 2016

biotech

Innovation

Steba Biotech wishes to express its gratitude to all the urologists who have invested their effort and have supported the clinical development of TOOKAD速, a minimally invasive focal therapy, for the sole benefit of providing low risk prostate cancer patients an active treatment and optimal quality of life.

TOOKAD速 phase III randomized trial has been submitted to the EMA for marketing authorization. TOOKAD速 has already obtained its first marketing approval in Mexico.

G N I K A E R B

T C A R T S B A On Sunday March 13th, at 8 am,

during Plenary Session 2 Prostate Cancer (eURO Auditrium (Hall C, Level 0), Prof. Mark Emberton will present the

results of TOOKAD速 Randomized Phase 3 Clinical Trials, 413 patients, 47 centers, 10 countries Sunday, 13 March 2016

EUT Congress News

Adjuvant vs Early Salvage Radiation Therapy A truly fair comparison? Dr. Robert Jeffrey Karnes Mayo Clinic Dept. of Urology/ Urologic Oncology Rochester, Minnesota (USA)

Co-Author: Alessandro Morlacco One of the overarching paradigms in the contemporary management of prostate cancer is to balance oncologic control with treatment-related morbidity. In this context, post-radical prostatectomy radiation is commonly employed as secondary therapy to maximize local control and long-term oncologic outcomes, but represents a source of potential morbidity. Accordingly, clinicians often find themselves facing the following dilemma: “Which patients will benefit from upfront adjuvant radiation therapy (aRT), and which patients can be safely managed with observation followed by salvage radiation therapy in case of BCR (PSA>0.2 ng/mL)?” The definition of aRT is commonly accepted as RT given with an undetectable PSA postoperatively or <0.2 ng/mL. However, the timing of aRT is more variable: some administer aRT within the first three months after surgery (a definition frequently used in research), while others wait until urinary function has stabilized. In contrast, salvage radiotherapy (SRT) is the administration of RT in the setting of biochemical recurrence (BCR) in the absence of distant metastatic disease. “Early salvage” RT (eSRT) applies to sRT when administered at very low PSAs (e.g. first confirmed detectable PSA, or PSA ≤ 0.5 ng/ml). The optimal timing of postoperative RT is an unresolved issue to many. The greatest advantage of sRT is avoidance of overtreatment and associated cost and potential morbidity. Indeed, a substantial proportion of men with adverse pathologic characteristics will not recur after surgery: in the main randomized clinical trial comparing aRT vs initial observation, half of observed men were free of BCR at five years (i.e. potentially 50% overtreatment rate) and around one-third were free of BCR at 10 years (EORTC 22911) Accordingly, the concept of critically weighing immediate aRT vs expectant management with SRT at the time of biochemical recurrence is probably more commonly employed and explains the low utilization rate of aRT. The American Society for Radiation Oncology (ASTRO)1 and American Society of Clinical Oncology (ASCO)2 guidelines suggest ”discussing” aRT with men who have adverse pathologic features at radical prostatectomy (RP), including seminal vesicle invasion, positive surgical margins, or extraprostatic extension. The guidelines emphasize that patients should be informed of the potential reduction in the risk of BCR, local recurrence, and clinical progression, but also of the uncertain impact of aRT on metastasisfree and overall survival. The National Comprehensive Cancer Network (NCCN) guidelines3 provide similar recommendations, but add that observation after RP may be appropriate, that positive surgical margins should be considered more unfavorable when diffuse (>10 mm margin involvement or ≥3 sites of positivity), and that aRT be administered after recovery of urinary function. Finally, EAU guidelines4 explicitly list two options: immediate aRT and observation followed by SRT in the case of BCR, but before the PSA exceeds 0.5 ng/ml. Three landmark randomized trials provide the highest level of evidence for the guidelines discussed above yet do not provide clear evidence of a metastasis-free or survival benefit and only a mere impact on BCR. Started in 1992, EORTC 22911 compared immediate aRT (60 Gy) with initial observation in patients with pT2–3 N0 prostate cancer with at least one of the following adverse pathologic features: capsular perforation, positive surgical margins, or seminal vesicle invasion. The trial reported improved 10-year biochemical relapse-free survival (BRFS) with aRT (60.6% vs. 41.1% in the observation group), but overall survival (OS) did not differ significantly between the treatment arms5. The estimated NNT was 55.6 to prevent one death. 18

EUT Congress News

Subset analysis demonstrated that aRT significantly improved clinical progression-free survival in patients with pT2–3 R1 prostate cancer (HR 0,69), but not in those with pT3 R0 cancer. Furthermore, excess mortality was noted in patients aged 70 years or older who had aRT compared with same-age men who were in the observation arm which is probably explained by competing risks and unbalance. aRT vs eSRT Despite the valuable insights provided by this trial, it does not address the question above – that is, whether aRT is superior to eSRT. First, 29% of patients had a detectable PSA postoperatively upon study entry. Even more importantly, among the patients in the wait-and-see group, 16% with BCR-only didn’t undergo any active treatment, and of the 84% who went on to receive active treatment, only 56.4% underwent RT, while 22.9% received medical or surgical ADT. Thus, the actual SRT population was only a fraction of the entire BCR group. Furthermore, as the authors themselves noted, comparison of this trial’s results with the SWOG trial is difficult, as the EORTC trial reported a smaller treatment benefit than the SWOG trial6. No documented differences in selection of patients or study conduct were clearly evident between these trials, but both SWOG study groups fared worse in terms of OS, suggesting the potential role of other factors, such as variations in the quality of surgery or unrecognized selection patterns. In the SWOG 8794 trial6, inclusion criteria was similar. In this study, aRT significantly improved metastasis-free survival (71% vs. 61% at 10 year, with a median prolongation of 1.8 years, p = 0.016) and 10-year OS (74% vs. 66%). Here, too, an undetectable PSA after radical prostatectomy was not required, and more than 30% of patients had a detectable PSA after surgery6. This patient population appeared somewhat older with more higher grade disease. Another limitation is that there is sparse information regarding treatment at BCR: only one third of these patients received SRT, which precludes meaningful conclusions about the impact of SRT. The NNT to prevent one metastasis was 12.2 and 56 to prevent one death, at a median follow-up of 12.6 years. Finally, the ARO 96-02/AUO AP 09/05 trial was the only RCT to require an undetectable (< 0.1 ng/mL) PSA postoperatively. Thus, this trial was truly a comparison of aRT vs observation. Patients were included if they had adverse pathology at RP, regardless of surgical margin status. After a median follow-up of 112 months, the aRT group demonstrated a significant improvement in BCR rate (56% vs. 35, p = 0.0001)7 . At 10-years follow-up, neither metastasis-free survival nor OS were significantly improved by aRT, but the study was notably underpowered for these end points8. Again, little is known about treatment at the time of BCR. Collectively, the three RCTs provide evidence for aRT over initial observation for BCR, but they do not inform us regarding aRT versus sRT or eSRT for men with high-risk PCa. Moreover, the benefit of aRT over initial observation is unclear in men with pT3 RO disease. Accordingly, most of the present evidence regarding sRT comes from retrospective studies. A recent review by Pfizer et al9, which included10 retrospectives studies, examined eSRT. Although the authors did not directly compare sRT to aRT, they reported good long-term outcomes for sRT, with overall five-year BRFS of 71%. Furthermore, data from the only two retrospective studies adequately powered to compare aRT and sRT suggest comparable three-year BRFS in patient with high-risk features post RP10 and five-year

Graph from the study by Fossati et al, regarding long-term impact of adjuvant vs eSRT on clinical recurrence in pT3N0 Pca patients treated with radical prostatectomy

BRFS in pT3pN0 R0-R111. Notably, the overall analysis showed that five-year BRFS rates were significantly improved for patients who receive eSRT compared with patients treated with sRT when PSA values are >0.5 ng/ml. Additional evidence was provided by Briganti et al12, who examined 472 node-negative patients with BCR after RP and treated by eSRT (PSA <0.5 ng/ml) and reported a the five-year BCR-free survival rate was 73.4%. Accurate patient selection Accurate patient selection is critical when determining timing of sRT at BCR. A subsequent paper by the same group assessed the optimal timing for SRT in a cohort of 955 patients who experienced BCR after achieving a postoperatively undetectable PSA12. The authors observed that cancer control after eSRT was influenced by pretreatment PSA level, and this effect was more evident in men with at least two of the following pathologic features: pT3b/4 disease, pGS ≥ 8, and negative surgical margins. These results suggest that such men might benefit more from early SRT. In another study, Abdollah et al conducted a retrospective analysis of a single-center cohort of patients with adverse pathologic features (positive margins, extracapsular extension, seminal vesicle invasion, pT4 stage, nodal invasion) after RP.13 The authors reported that aRT did not improve OS in patients with only one adverse risk factor, but did significantly improve survival in patients with two or more of the following risk factors: pGS 8, stage pT3b/4, and positive lymph node count >1. In a recent multi-institutional study being presented during this EAU Congress (Fossati et al, “Long-Term Impact Of Adjuvant Versus Early Salvage Radiation Therapy On Clinical Recurrence In pT3N0 Prostate Cancer Patients Treated With Radical Prostatectomy: Results Of A Multi-Institutional Analysis”.), pT3N0 patients were identified with undetectable PSA after radical prostatectomy from seven tertiary referral centers in Europe and US and stratified them into two groups: aRT or observation followed by SRT at a PSA level >0.1 and <0.5 ng/ml. At 10-years follow-up, there was no difference in metastasis-free survival in patients who received timely eSRT compared with those who received aRT. There is relatively little high-level data regarding treatment related morbidity with aRT and sRT, and a direct comparison is almost impossible. Nevertheless, in a recent review by Gandaglia et al14, these two approaches appeared to have a similar risk of toxicity, an important consideration given that the advantage of sRT is to spare these effects in a relevant portion of patients. Refining patient selection for post-RP treatments is an important goal, and multiple tools have been described to predict the risk of recurrence after RP. Unfortunately, such tools were not specifically developed to determine who is going to benefit from postoperative therapy such as aRT compared with observation and eSRT, if needed. As such, they must be applied indirectly in this context. Nevertheless, clinically-based scores, like the CAPRA-S score15 and the Stephenson postoperative nomogram16, are widely used in post-prostatectomy decision-making. More recently, the use of a genomic classifier (GC) known as Decipher®,( GenomeDx) has been reported to better prognosticate or risk-stratify men in the post-RP setting. In work by Den et al17, the GC was applied to a population of post-RP irradiated patients with regard to risk of developing metastasis. The GC outperformed the CAPRA-S score in outcome prediction and, more importantly, identified patients who may benefit from aRT versus observation with eSRT.. In a two-group analysis, patients with low-level GC expression (<0.4) treated with either aRT or sRT have a comparable five-year risk of metastasis, while men with higher levels of GC (>0.6) have a significantly lower risk of metastasis if treated with aRT (80% hazard reduction in Cox models). This study, despite some limitations, suggests the possible use of a GC in personalizing the management of men with adverse pathology (pT3 or R1) PCa after RP. Also presented at this Congress will be follow-up studies using and further supporting the GC in the setting of postoperative RT entitled, “Efficacy of Early and Delayed Radiation in a Prostatectomy Cohort Adjusted for Genomic and Clinical Risk and Utilization of a GC for prediction of metastases following postoperative salvage radiation therapy.”

Ongoing RCTs Several randomized clinical trials specifically comparing aRT and sRT are currently ongoing. The results are eagerly waited, in the hope they can provide a definitive answer to our initial question. RADICALS RT, active in the UK, Canada, Denmark and Ireland is still recruiting patients (the target is 1250 pts for the mid-2016, with more than 1100 recruited as of October 2015). Another trial, GETUG 17, is expected to show initial results in 2022, while the RAVES trial should do so in 2021. Conversely, the EORTC 2204330041 trial was early terminated because of poor patient recruitment. There are still many unknowns regarding postoperative RT despite the timing issue (aRT vs observation with early sRT) such as dose, volume, and use of hormonal therapy. Adjuvant RT does appear to decrease the rate of postoperative BCR but this does not appear to be “enough” for clinicians to endorse to date. Until higher level evidence is available addressing aRT vs sRT, in an effort to balance cost, toxicity, and oncologic control, initially observing a man with adverse pathology at RP and performing a more risk-adjusted approach is acceptable. References: 1. Thompson, I. M. et al. ADJUVANT AND SALVAGE RADIOTHERAPY American Urological Association Radiotherapy after. Am. Urol. Assoc. Guidel. 1–45 (2013). at <https://www.astro.org/Clinical-Practice/Guidelines/ Genitourinary-Cancers.aspx> 2. Freedland, S. J. et al. Adjuvant and salvage radiotherapy after prostatectomy: American Society of Clinical Oncology clinical practice guideline endorsement. J. Clin. Oncol. 32, 3892–8 (2014). 3. NCCN 2015 Prostate Cancer Guidelines. at http://www. nccn.org/professionals/physician_gls/pdf/prostate.pdf. 4. EAU 2015 Prostate Cancer Guidelins at https://uroweb. org/guideline/prostate-cancer/. 5. Bolla, M. et al. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). Lancet (London, England) 380, 2018–27 (2012). 6. Thompson, I. M. et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J. Urol. 181, 956–62 (2009). 7. Wiegel, T. et al. Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative undetectable prostate-specific antigen: ARO 96-02/AUO AP 09/95. J. Clin. Oncol. 27, 2924–30 (2009). 8. Wiegel, T. et al. Adjuvant radiotherapy versus wait-andsee after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial. Eur. Urol. 66, 243–50 (2014). 9. Pfister, D. et al. Early Salvage Radiotherapy Following Radical Prostatectomy. Eur. Urol. 65, 1034–1043 (2014). 10. Ost, P., De Troyer, B., Fonteyne, V., Oosterlinck, W. & De Meerleer, G. A matched control analysis of adjuvant and salvage high-dose postoperative intensity-modulated radiotherapy for prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 80, 1316–22 (2011). 11. Briganti, A. et al. Early salvage radiation therapy does not compromise cancer control in patients with pT3N0 prostate cancer after radical prostatectomy: results of a match-controlled multi-institutional analysis. Eur. Urol. 62, 472–87 (2012). 12. Briganti, A. et al. Prediction of outcome following early salvage radiotherapy among patients with biochemical recurrence after radical prostatectomy. Eur. Urol. 66, 479–86 (2014). 13. Abdollah, F. et al. Selecting the Optimal Candidate for Adjuvant Radiotherapy After Radical Prostatectomy for Prostate Cancer : A Long-term Survival Analysis. Eur. Urol. 63, 998–1008 (2013). 14. Gandaglia, G. et al. The Role of Radiotherapy After Radical Prostatectomy in Patients with Prostate Cancer. Curr. Oncol. Rep. 17, 53 (2015). 15. Cooperberg, M. R., Hilton, J. F. & Carroll, P. R. The CAPRA-S score. Cancer 117, 5039–5046 (2011). 16. Stephenson, A. J. et al. Postoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy. J. Clin. Oncol. 23, 7005–12 (2005). 17. Den, R. B. et al. Genomic Classifier Identifies Men With Adverse Pathology After Radical Prostatectomy Who Benefit From Adjuvant Radiation Therapy. J. Clin. Oncol. 33, 944–951 (2015).

Sunday 13 March 07.30-10.55: Plenary Session 2, Prostate Cancer

Sunday, 13 March 2016

Laparoscopic living donor nephrectomy Safety issues: How to best secure the pedicle? Prof. Arnaldo José Figueiredo Hospitais da Universidade de Coimbra Urology & Transplantation Coimbra (PT)

Living donor nephrectomy (LDN) is the surgical procedure with the greatest responsibility any urologist can be faced with. “Safety first” is nowhere as fundamental as here. Even if all steps of the nephrectomy are to be addressed with equal care, the control of the pedicle is the one that encompasses the biggest danger. Transition from open surgery to laparoscopic/robotic surgery led to the abandon of what is considered the safest way to secure the artery, an oversewing suture1. Non-locking metallic clips, locking polymer clips (ex. Hem-o-Lok), staples (ex. Endo-GIA) and ligatures are all used, but none is 100% safe2. Following concerns raised by donor death reports in the US due to clip dislodgment, the Teleflex Company and the FDA decided to contraindicate the use of Hem-o-lok clips for ligation of the renal artery during laparoscopic LDN. However, without any perceivable explanation, there are no remarks regarding the use of Hem-o-Loks during all other nephrectomies. Given the existing controversy, and acknowledging that Hem-o-loks are widely used by urologists to control the renal pedicle during laparoscopic and robotic nephrectomies, the EAU Section of Transplantation (ESTU) conducted an online survey to inquire what urologists use to secure the artery during laparoscopic LDN. Furthermore, the occurrence of serious malfunction episodes and the participant’s perspective on the safety and legal aspects of Hem-o-Lok use in this context were also inquired.

We got answers from 252 surgeons actively involved in laparoscopic LDN, 70% of them from European centers. Hem-o-Lok was the most commonly used device during laparoscopic LDN (73% of responders, in 14% of cases in association with a metallic clip), while Endo-GIA was used by 13.9% of responders (Figure). This use of Hem-o-Loks occurs notwithstanding the fact that, when asked “Do you have any concerns with the legal aspect of the use of Hem-o-loks in the setting of laparoscopic LDN?” 43.5% responded affirmatively (responders included Hem-o-Lok non-users). Amongst those who did not use Hem-o-Loks, about 40% of indicated an Institutional directive as the explanation for that practice; the rest stated personal motives. The fact that 14% added a metallic clip to a Hem-o-Lok may be seen as a safeguard against potential legal implications of using it alone. The use of Hem-o-Loks was more common in nephrectomies for other reasons than living donation, with 85% of responders indicating they used it (in 10% of cases associated with metallic clips), while Endo-GIA was used by 8.6%. Dangerous device failures were experienced during laparoscopic LDN at least at one occasion by 28% of the responders. Endo-GIA failures were reported by 11.1% of participants, Hem-o-Lok failures by 9.6% and metallic clip failures by 4.8%. The overall reported incidence of dangerous failures during nephrectomies for other reasons was 31.5%, slightly more than during laparoscopic LDN. Endo-GIA was again the device that was most commonly reported as being involved (15.6% of responders), followed by the metallic clips (8.3%) and the Hem-o-Lok (5.4%). Noticeably, 29.6% of users of Endo-GIA stated they removed the triple staggered rows of staples from the donor kidney side during laparoscopic LDN, yet the failure rate was less reported in that setting than during other nephrectomies.

The ESTU survey shows that many urologists consider the Hem-o-Lok a safe option in laparoscopic LDN

is in agreement with the failures reported to the U.S. FDA Manufacturer and User Facility Device Experience database (MAUDE), where in the 92 complications identified between 1997 and 2007, 59 (64%), 21 (23%), and 12 (13%) were failures of endoscopic staplers, titanium clips, and locking clips, respectively3. In conformity with the low reported failure rates, only 7.4% of responders of the ESTU survey considered the Hem-o-Lok unsafe. Likewise, in a survey conducted among surgeons of the American Society of Transplant Surgeons, multiple locking hemostatic clips were given the highest safety rating among the techniques of arterial stump closure in laparoscopic donor nephrectomies, on par with oversewing and staplers1.

It stands out that the various renal artery-securing devices for laparoscopic LDN are generally safe, but Taking in consideration the relative use of each device, not exempt from malfunctions. According to the ESTU the reported failures rates indicate the Hem-o-Lok is survey, the majority of the urologists involved in the least involved in failures, while the Endo-GIA is laparoscopic LDN considers the Hem-o-Lok a safe the one that most users experience failures with. This alternative, experienced fewer failures with it than

with Endo-GIA, and keep using it regardless of the FDA directives. Surgeons must be aware of the potential failures they may encounter and be stringent in the way they use any each specific device in order to maximize safety. References 1. Friedman AL, et al: Fatal and nonfatal hemorrhagic complications of living kidney donation. Ann Surg 2006; 243: 126-30 2. Kurukkal SN: Techniques to secure the renal hilum in laparoscopic donor nephrectomy. World J Lap Surg 2012; 5: 21-26 3. Hsi RS, et al: Analysis of techniques to secure the renal hilum during laparoscopic donor nephrectomy: review of the FDA database. Urology 2009; 74: 142-7

Sunday 13 March 10.30-12.00: Thematic Session 9 Lessons from transplantation surgery applied to urology

NOW ENROLLING: A Clinical Research Study For Patients

Patient Population: • Chemo-naïve CRPC patients • Asymptomatic or mildly symptomatic • ≥ 2 bone metastases • No known brain metastasis or visceral metastasis • ECOG 0 or 1 Stratifications: • Geographical Regions (EU&NA&AUS vs Asia vs ROW) • Concurrent use of bisphosphonate or denosumab or none • Total ALP below 90U/L or not

1:1 Randomisation

with Castration Resistant Prostate Cancer Evaluating Radium-223 Dichloride in Combination with Abiraterone Primary endpoint • SSE-FS

• Radium-223 dichloride • abiraterone and prednisone/ prednisolone

• Matching placebo

Active Follow-up Active Follow-up without clinic visit with clinic visit • Phone call every • Clinic visit every 3 months until SSE 3 months until SSE, death or inability to travel or death

• abiraterone and prednisone/ prednisolone

Secondary endpoints • OS • Time to opiates • Time to pain • Time to chemo • rPFS • Safety

Long Term Follow Up • Phone call every 6 months until 7 years after the last dose of Radium-223 dichloride or death • To determine safety and OS

Primary Outcome Measures:

•

Asymptomatic or mildly symptomatic prostate cancer.

•

Medical or surgical castration with testosterone less than 50 ng/dL (1.7nmol/L).

•

Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1

Symptomatic skeletal event free survival (SSE-FS)

Secondary Outcome Measures: • • •

Overall Survival Time to opiate use, time to pain progression and time to cytotoxic chemotherapy Radiological progression free survival (rPFS)

Selected Inclusion Criteria: •

•

Prostate cancer progression documented by prostate specific antigen according to the Prostate Cancer Working Group 2 (PCWG2) criteria or radiological progression according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Two or more bone metastases on bone scan within 4 weeks prior to randomization with no lung, liver, other visceral and/or brain metastasis.

For complete information please visit:

http://www.clinicaltrials.gov (NCT02043678) Bayer and the Bayer cross are registered trademarks of Bayer. © Bayer. (February) 2016. L.DE.COM.SM.02.2016.4365.

Selected Exclusion Criteria: •

•

• •

Prior cytotoxic chemotherapy for the treatment of CRPC, including taxanes, mitoxantrone and estramustine History of visceral metastasis, or presence of visceral metastasis detected by screening imaging examinations Malignant lymphadenopathy exceeding 3 cm in short-axis diameter. Use of opiate analgesics for cancer-related pain, including codeine and dextropropoxyphene, currently or anytime during the 4- week period prior to randomization.

Trial Sponsor: Bayer HealthCare Pharmaceuticals, Inc. 100 Bayer Boulevard, PO Box 915, Whippany, NJ 07981 USA

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Sunday, 13 March 2016

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EUT Congress News

Do we need specific workup for our stone patients? A contrary view Prof. Thorsten Bach Head, Department of Urology Asklepios Hospital Harburg Hamburg (DE)

Treating patients with urinary stone disease is an essential part of daily urological practice and the majority of patients will ask their doctor about mechanisms and recommendations of preventing stone recurrence during the treatment course or as long as the impression of renal colic is still fresh. Not only to fulfil patients demands, but even more to identify patients at risk of disease recurrence and to prevent consecutive damage to the kidney, recent EAU guidelines recommend stepwise workup of all stone patients to allow categorization into a high- and low-risk group of recurrence. While low-risk stone formers may benefit from simple preventive measures like life-style advice and increased fluid intake, high-risk stone formers should, according to guideline recommendations, undergo metabolic stone workup and individual treatment to prevent recurrence. So far, so good. The premise of metabolic workup and identification of risk factors is based on the assumption, that the identification of individual risk factors will allow individualized and tailored preventive measures and treatment for the individual patient; However, to identify high-risk patients and give correct recommendations, it is important to know the mechanism which supports stone formation. This may be rather clear in patients with cystinuria or uric acid stones, leading to preventive measures that aim to reduce the risk of for example supersaturation of the urine, but more difficult, for example, in calcium oxalate stone formers, where the precise mechanism of stone formation is not yet understood completely. The whole principle of metabolic workup and preventive treatment is based on the assumption that tailored prevention of recurrence is first of all possible at all and the effects are not only gained by general changes in life-style and drinking habits. Furthermore, it is postulated, that only after a detailed metabolic evaluation it is possible to give personalized tailored recommendations, especially for high-risk patients. Last but not least, doctors expect their patients to follow the given recommendations to ensure treatment success, knowing that long-term compliance is the hardest part to achieve in prevention. So, what is the information needed to provide profound recommendations on preventive measures to these patients: 1. We need to identify risk factors, e.g. anatomical variants, concomitant diseases, basic laboratory values and urine testing. This information should be obtained during the initial visit of our patients and do not require metabolic workup posttreatment. 2. Stone composition: Without any question, stone composition is the most important information needed, to identify and stratify our patients into groups with low- or high-risk of recurrence. Therefore, it is without doubt, that every stone must be sent for analysis. But would this be enough information to give the patient preventive advice, or do we need more information at this point?

The recommendation: “drink better, eat better” may be more effective, than a complicated tailored approach (“drink that much, eat only this, take pills and measure your urine-pH”), which is not followed by the patients for a In this group of patients, there may be no need for longer time-course as we extensive metabolic workup, keeping in mind that the know. Of course, there are a majority of calcium stone formers without additional remaining number of high-risk risk factors will have – besides low volume of urine patients in whom basic - normal metabolic findings. So far only one evaluation and stone analysis randomized controlled trial of all was able to show may not be sufficient to improved outcome for tailored preventive measures identify the underlying cause based on urine analysis as compared to non-selective of stone formation and more treatment at all, and it remains unclear, if dietary sophisticated diagnostics is measures alone, pharmacological measurement alone “Drink better, eat better” may be more effective than a complicated tailored approach necessary, also to identify or combination of both is the method of choice for the to prevent stone recurrence other diseases like RTA or majority of these patients. hyperparathyroidism, where reveals that less than 5% of all patients with high-risk effective treatment is possible. Independently of a possible metabolic workup, most of recurrence will return for metabolic stone workup, patients will end up with the general advice of But for quite a number of our patients, besides some life-style adjustments and, most important, increased despite detailed recommendations. This low rate is confirmed by other groups, stating rates as low as exceptions, we simply do not have the quality of fluid intake. This may, again, question the need for 7.4% of high-risk patients receiving metabolic evidence in studies proving that evaluation and further metabolic workup and even more metabolic evaluation. So, probably we have to accept that treatment of abnormal urine values will positively and/or pharmacological treatment in this group, patients simply don´t want metabolic workup once influence stone recurrence. The patient examined exceeding regular urological surveillance, to identify they are free of complaints. Keeping this in mind, it collectively within these studies often is and - in the era of endourology - treat possible can be postulated that the compliance for any kind of inhomogeneous and conclusions to certain patient recurrence as soon as possible. metabolic treatment will be even lower, as shown by groups remain, at the most, difficult. Dauw et al, who found a six-month adherence of Finally, cost effectiveness of metabolic testing and So yes, the concept of metabolic testing and preventive treatment has to be kept in mind and must approximately 50% of all patients receiving medical preventive measures. prevention is tempting, but unless we have the results be discussed especially in this group of patients. of high quality studies, proving which preventive Chandhoke compared the cost of metabolic testing measure is the important trigger to reduce or even and medical intervention in 10 countries, including six In conclusion, general measures for prevention are easy to follow and increased fluid intake is the avoid recurrence, the best approach for prevention of European countries and showed that metabolic fundamental measure, independent of stone recurrence may be to keep it simple and straight and assessment and medical prevention was only cost invest time and energy in counselling the patient to effective in patients with at least one stone passage in composition. Therefore every patient should be counselled to follow them, although it is probably stay on board. every three years. Even more, Lotan et al., were able the hardest task for the urologist to keep patients to show, that simple measurements like dietary understanding and compliance high over the years. Sunday 13 March modifications without metabolic evaluation were With this, we will not tackle the underlying 10.30-12.00: Thematic Session 1, Quality of care for effective in reducing recurrence rates, accounting for pathology, but keeping treatment simple and patients with recurrent stone formation only 5% of the cost of directed metabolic evaluation straightforward. and treatment. lifetime, questioning the need for not only metabolic workup but also changes in lifestyle at all, as long as other risk factors are missing. But, even in patients, who may have formed at least two calcium stones, over 30% will stay free of recurrence within a 10-year interval.

Finding a balance Summing this up, metabolic evaluation and even more regular pharmacological treatment for calcium stone formers should be reserved to those with frequently recurring stones, restricted probably even those with psychological strain to ensure a high level of compliance during the treatment course. Of course, the risk of recurrence is considerably higher in patients with genetic defects like cystinuria or in patients with infectious or uric acid stones, where up to 85% percent of all patients will develop recurrence due to individual risk factors. And yes, it is a straightforward approach that complete metabolic workout has to be carried out, to identify underlying causes and severity of metabolic disorders to tailor individual treatment approaches for the individual patient. But although it sounds more than reasonable, that treating the underlying cause of stone formation will lead to reduced recurrence rates, it may be rather difficult to find the balance between treating the usual mixture of urinary abnormalities and tolerance of the preventive (medical) regimen to ensure patients compliance. Considering that only 50% of the patients, who decide to undergo metabolic evaluation and prevention, will stay with the recommendations, even during a short-term follow-up interval, the rational should be to treat the patient as simple as possible.

New EAU guidelines available online! Pocket App free for EAU members only

European A ssociation of Urology

Guidelines

2016 edition

However, how is the quality of evidence supporting the approach of metabolic evaluation and preventive measures anyway? In general it has to be stated that the level of evidence for tailored stone prevention Does the recommendation of preventive measures measures based on urine analysis in patients with require metabolic workup at all? uric acid stones, struvite and also cystine stones is The risk of recurrence varies not only from patient to rather low and good quality studies comparing the patient, but is also dependent on stone composition. efficacy of these measures versus general preventives Let us have a look at first-time calcium stone formers, measures is low. Even more, no data exists on the who count for the vast majority of all stone patients in effect of “active surveillance” on recurrence and early European states. On average, the 10-year recurrence endourological treatment in case of recurrence and in rate is approximately 50%. Even more, only 10 to 20% terms of preserving renal function, patient’s quality of of patients with recurrence will be symptomatic life and health economics, whether with or even during their recurrent stone episode and of those without general preventive measures. being symptomatic, only 50% will need intervention. Metabolic workup: Most patients simply don´t Keeping this in mind, means, that only two to five out want it! of 100 patients within this group of calcium stone Tackling the last issue of patients’ compliance, it has to be stated that compliance will decrease with every formers will need re-intervention during a 10-year day passing beyond the last episode of stone passage. course. This leads to a high number of patients, who will only have one symptomatic stone episode during Data of patients treated in our own department 20

EUT Congress News

Sunday, 13 March 2016

Towards a Urogenital European Reference Network A core mission of share, care and cure Michelle Battye EAU EU Policy Coordinator Sheffield (UK)

Imagine if the best specialists from across Europe could join their efforts to tackle complex or rare medical conditions that require highly specialised healthcare and a concentration of knowledge and resources. That’s the purpose of the European Reference Networks and it’s fast becoming a reality. Health systems in the European Union seek to provide high-quality, cost-effective care. This is particularly difficult in the case of conditions requiring a concentration of resources or expertise, and even more so with rare or low-prevalence complex diseases or conditions. Currently there is no formal platform at the EU level to construct partnerships on healthcare, although cross-border cooperation in healthcare within the EU has been increasing. With a new initiative called European Reference Networks (ERNs), a formal platform at EU level will be established to construct partnerships on healthcare and take advantage of potential synergies and economies of scale. The European Commission will launch a call for proposals for ERNs with different specialties in the first two weeks of March 2016; the call is well-timed with the Annual EAU Congress from 11 to 15 March in Munich. In fact, the European Commission will give a presentation on ERNs in a workshop on rare diseases on 14 March, which will be followed by a presentation on the EAU’s activity to engage with this important and pioneering European agenda.

ERNs are the next logical step in the framework of patient mobility and the difficulty for the 28 health systems of the EU to provide patients with rare or low prevalence complex diseases or conditions with the treatment they need in a cost effective way. The networks aim to support Europe-wide cooperation on highly specialised healthcare between providers and centres of expertise for patients with rare conditions, no matter where they are in Europe. By bringing together highly specialised healthcare providers in different Member States, patients will have access to the best possible expertise and care available in the EU, characterised by quality and equity. Besides improving high quality specialised care, ERNs will also lead to better sharing of knowledge and expertise allowing for the development of more evidence-based clinical tools and treatment.

• Collaborate closely with other centres of expertise and networks at national and international level. Criteria to be met by healthcare providers to participate in a Network include: • Patient empowerment and patient-centred care; • Organisational, management and business continuity of the healthcare provider; • Research and training capacity; • Exchange of expertise, information systems and eHealth tools; and • Expertise, good practice, quality, patient safety and evaluation. Members of a Network must also meet the following criteria specific to the scope of that particular Network:

The European Commission envisages a total of around 20 to 30 ERNs being established, which will inevitably • Competence, experience and outcomes of care, and involve the clustering of some disease areas (for • Specific human structural and equipment example, a ‘family’ of rare cancers may be grouped resources and organisation. together into a single network). Criteria and conditions To achieve this agenda is not without challenges. It is inevitably complex to involve healthcare professionals, health authorities (who must approve the participation of each individual healthcare provider), managers and patients in a joint project for the implementation of ERNs. Therefore, high-level criteria and conditions must be met to establish both a Network and for its Membership, such as the following: • Have knowledge and expertise to diagnose, follow-up and manage patients with evidence of good practice; • Follow a multi-disciplinary approach; • Offer a high level of expertise and have the capacity to produce good practice guidelines and to implement outcome measures and quality control; • Make a contribution to research; • Organise teaching and training activities; and

evidence-based clinical management of rare and complex urogenital diseases and conditions. This network will cover paediatric, highly specialised functional urogenital surgery and the latest state-ofthe art diagnosis treatment for patients with rare urogenital cancers. It will be a priority for the ERN on rare and complex urogenital diseases and conditions to maximise the speed and scale at which innovation in medical science and health technologies is incorporated into healthcare provision. The ERN will serve as a focal point for medical training and research, and for the dissemination of information to other countries and health systems with more limited resources. By utilising the already existing experience, knowledge and networks of the EAU, together we will exploit new technologies, innovate and translate new devices and ideas to market more quickly and thereby maximise economic impact and, most importantly, create more effective outcomes for our patients throughout all Member States.

Measurement against these final two criteria will be based on the evidence and consensus of the scientific, technical and professional communities. Rare and complex urogenital conditions In the field of rare and complex urogenital diseases and conditions, the EAU has taken the lead to bring together centres of expertise across Europe to create an ERN. The network will aim to disseminate state-of-the-art

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Sunday, 13 March 2016

EUT Congress News

Robot and children: Special care Prof. Mario De Gennaro Division of Urology Robotic Surgery and Urodynamics Ospedale Pediatrico Bambino Gesù Roma (IT)

Abdominal paediatric surgery Gastric fundoplication. Since the first case reported in 2001, several series demonstrated the feasibility, safety, and efficiency of robotic procedure with good results, even in children with neurological impairment and previous gastrostomy7.

Co-Authors: Giovanni Torino (IT), Matteo Ritrovato (IT), Giorgia Tedesco (IT), Massimiliano Raponi (IT)

Hepatobiliary surgery: Although the laparoscopic approach is possible, it is technically challenging even for many experts. Only sporadic publications have reported on robotic procedure attempts9,10. Particularly in biliary atresia repair there fewer adhesions may occur, with easier dissection for later liver transplantation.

Nowadays, with the use of robotic technologies becoming more widespread in medicine, its use or application have also inevitably expanded into many paediatric cases.

Cholecystectomy: Cholecystectomy is safe and efficacious, and it also allows a single-site robotic approach, inserting all instruments through one port11.

New applications have been developed with the following areas as examples: in rehabilitation such as in re-walking robotic instruments for paraplegic persons, mainly with incomplete and acquired paraplegia. In neurosurgery where neurosurgical procedures can be assisted by a robotic stereotactic neuro-navigation system.

Thoracic This first assessment of paediatric Robotic Assisted Thoracic Surgery (RATS) suggests that the most suitable procedures are mediastinal cyst excisions for children weighing more than 20 kg.

Robotic surgery Robot-assisted minimally invasive surgery has been one of the most recent major innovations introduced to pediatric surgeons.The “da Vinci®” surgical robot offers three-dimensional vision and articulated tips. Surgeons sit at a console which provides a stereoscopic view in the patient’s body. Innovation: Innovation is seldom adopted in a universal and rapid fashion, but adoption progressively occurs over time. In 1964 the renowned scientist Isaac Asimov broadly outlined his vision and said that ‘‘…robots will neither be common nor very good in2014, but they will be in existence.’’ Evolution: Current robotic technology is in a firstgeneration phase, defined by the various master– slave surgical system models. Future robotic and computer-assisted technology will become more advanced and better suited for the pediatric setting1,2. History and trends The first paediatric series of robotic-assisted laparoscopic surgery (RALS) was published in 20013. Since then, robotic surgery in children has expanded in multiple specialties including urology, general surgery, otolaryngology and orthopedic surgery. Robotic surgical daVinci instrument is not suited for small paediatric patients in its current form. Pediatric surgery in general is an ‘‘orphan’’ field for commercial scale innovation due to an unappealing market potential. As described by Peters, ‘‘…similar to children, new technologies do not spring forth in mature form but, rather, require time for development and refinement’’4. On safety, initial concerns regarding potential danger relating to electronic malfunction and system instability have been resolved, with no known reports of patient harm due to these factors. Comparison with laparoscopic procedures One argument against robotic surgery is that for procedures in which laparoscopy has already demonstrated benefits as compared with open surgery, robotic surgery may offer little additional benefit to the patient. On the contrary, procedures (such as antireflux ureteral re-implant), can capitalize on the advantages of the robot, while few cases are done laparoscopically. Dissection, static retraction, intra-corporeal suturing are rate-limiting steps for laparoscopic surgery, while robot-assisted surgery performs them well. Robotic surgery in paediatric specialties The spectrum of pathology encountered in paediatric surgery is shown by the wide range of rare operative indications. The more frequent procedures which are performed worldwide are Pyeloplasty (Figure 1) and Funduplication. Collectively, these procedures comprise an estimated 46% of the overall volume of robotic procedures performed in children5. Recent meta-analyses of comparative effectiveness literature has identified that clinical outcomes are either comparable or marginally superior to alternative techniques6.

EUT Congress News

Transoral Trans-oral Robotic Surgery in adults is being increasingly utilized for head and neck surgery, with less invasive and improved outcomes compared with traditional approaches. Robotic surgery in paediatric urology In a recent study the number of robotic surgeries performed over five years in 47 tertiary children hospitals increased by an average of 19.8% per year (P < 0.0001). The number of urologic robotic procedures performed grew by an average of 17.4% per year (P < 0.0001); while the growth rate for general surgery robotic procedures was not statistically significant (P = 0.87)14. Pyeloplasty In 2004 the first series of robot-assisted pyeloplasty was reported in 15 children, and nowadays there are consistent level 3-4 evidence confirming the feasibility, safety, and efficiency of robotic pyeloplasty (RP) in children. A metanalysis conducted in 2015, RP was associated with significantly shorter hospital stay when compared with OP, longer time, less estimated blood loss and postoperative analgesic agents15. According to US national database analysis, RP is the most frequent robotic procedure in children, with short-term success rates comparable with OP, which is still considered the gold standard16. Age/Infants: Initially RP was considered feasible in children older than six years. But recent series in infants showed safety even below one year, with 90% hydro improvement, one to two days of hospital stay and low postoperative complications17. Re-do pyeloplasty: Failed open pyeloplasty (5%), mainly due to crossing vessels are successfully treated by robotic redo procedures with 80-100% success rates18. Stenting: Laparoscopic pyeloplasty needs double-J stenting, requiring a second anesthesia, while many advocate unstented pyeloplasty19. Selected patients (especially without thin ureter and unfavorable crossing vessels) may undergo stentless pyeloplasty15. Ureteral reimplantation Due to the difficulty of the laparoscopic technique, robotic ureteral reimplantation could be the solution, using an extravesical20 or intravesical approach21. A Level 3 evidence compared robotic with open. The operative time was significantly longer in the robotic group (p< .001) for both approaches. The hospital stay was reduced in the robotic group for the intravesical approach (p=0.001) but not for the extravesical approach (p=1)22. Other urological procedures Nephrectomy: Robotic procedures for total nephrectomy are questionable, while robotic assistance is more valuable for partial nephrectomy.

Fig 1: A 3-years old boy undergoing anaesthesiological preparation for robot-assisted pyeloplasty procedure

Complex reconstructive surgery The robot is definitely more helpful than laparoscopy for complex reconstructive procedures. Augmentation cystoplasty: Laparoscopic bladder augmentation was not widely adopted due to its technical difficulty and increased operative time. The robot-assisted laparoscopic Ileocystoplasty with Mitrofanoff appendicovesicostomy is feasible, with operative time significantly longer compared with open but has a shorter length of stay. A series of 15 patients showed operative time significantly longer compared with open (623 vs 287 min; p < 0.01) but shorter length of stay (6 vs 8 d; p = 0.01). Costs The procedural breakdown and case volume of pediatric urology and general surgery differ with adult specialties. A recent analysis of cost for RAL prostatectomy in Australia found that 140 procedures per year are needed to get a positive balance for healthcare23. Nevertheless, there is great potential for next-generation surgical robotics, and trends in the literature and from national in-patient databases indicate that pediatric robot-assisted minimally invasive surgery continues to expand in terms of global adoption24,25.

Future perspectives It is hard to imagine a major technology that has evolved as far as robotic surgery only to be later abandoned. Thus, the use of robotic surgery in paediatrics is increasing particularly in the management of urologic conditions. Several prototype robots exclusively designed for pediatric use are already under development. Single-site robotic approach, already attempted in cholecystectomy in children, allows the insertion of all the instruments through one port. The software allows control of instruments in an intuitive fashion without the need for crossing hands. In conclusion, hospitals around the world continue to purchase new da Vinci_ Surgical Systems. One should be reminded of Buxton’s Law which says that ‘‘it is always too early until, unfortunately, it’s suddenly too late’’30.

A personal analysis of costs A working group of “Bambino Gesù” Children’s Hospital sought to compare the costs of RS with laparoscopic surgery (LS) and Fig. 2: An example of Break Even Point, that is the point at which revenues equal total open surgery (OS), also analyzing cost. In this particular scenario a total of 349 cases per year are required. its impact on hospital organization. Case mix of 176 procedures in (2-17 years old, >15 Kg, ASA ≤2) children Abbreviated References: were analyzed, performed during the 2012 with LS and Cundy TP, Harling L, Marcus HJ et al (2014) Meta analysis of OS and potentially transferable to RS. robot-assisted versus conventional laparoscopic A personal decision-oriented methodology (do-HTA) was adapted to assess safety, efficacy, cost, organizational impact26. Break Even Analysis (BEA) and Cost-minimization Analysis (Δ Contribution Margin) analyzed (fixed and variable) costs. The BEA suggested that for the different scenarios, the BEP ranged from 103 to 458 procedures/year (fFigure 2), but in paediatric urological surgery with a favorable scenario the BEP is obtained by 159 procedures/year27. Education and training in pediatric robotic surgery Pediatric urology is a low surgical volume subspecialty. The robotic surgery is known to have a steep learning curve, but someone estimated that 37 patients are needed for a surgeon to overcome the learning curve28.

Table 1: Most common robotic procedures among 1419 ones from 47 Tertiary Children’s Hospitals (20082013)- Mahida J Surg Res, 2015

fundoplication in children. J Pediatr Surg 49:646–652 Alqahtani A, Albassam A, Zamakhshary M et al (2010) Robot-assisted pediatric surgery: How far can we go? World J Surg 34:975–978 Mahida J, Cooper J Herz D (2015) Utilization and costs associated with robotic surgery in children J Surg Res 199:1 6 9- 76 Varda BK, Johnson EK, Clark C et al (2014) National trends of perioperative outcomes and costs for open, laparoscopic and robotic pediatric pyeloplasty. J Urol 191:1090–1095 Ritrovato M, Tedesco G, De Gennaro M (2015) A comparative cost analysis of robotic-assisted surgery (RS) versus laparoscopic surgery (LS) and open surgery (OS) in a paediatric hospital Abstr EAU Annual Congress, 2005 Tasian GE, Wiebe DJ, Casale P (2013) Learning curve of robotic assisted pyeloplasty for pediatric urology fellows. J Urol 190(4 Suppl):1622–1626

Editorial Note: Due to space constraints we have shortened the reference list. Interested readers can email a request at communications@uroweb.org. Sunday 13 March 10.30-12.00: Thematic Session 8, Pediatric Urology

Sunday, 13 March 2016

collagenase induces a tissue response that is more effective in those patients with early disease. This effect can be enhanced by a mechanotransduction response-induced therapy (a key ‘step’ in the remodeling phase) like modeling. A similar phenomenon occurs with PTT, which proves to be more effective in the AP. Taking into account these results, future perspectives probably will lie in the use of a combined or sequential therapy, including both CCh and PTT.

Peyronies Disease: Conservative treatment Hope for new promising options Dr. Juan I. MartínezSalamanca Hospital Universitario Puerta de HierroMajadahonda Universidad Autónoma de Madrid Madrid (ES)

Peyronie’s Disease (PD) is a chronic wound-healing disorder characterized by formation of fibrous inelastic scarring of the tunica albuginea following trauma of the penis and causing a variety of deformities, including curvature, shortening, narrowing and hinge defect. In most cases it is associated with a variable degree of erectile dysfunction (ED), which significantly affects the quality of life of the patient and his partner. In addition to physical symptoms, the psychological impact of PD should be considered. Studies show that many patients experience clinical depression, emotional and relationship difficulties, and poor self-esteem. Surgical therapy remains the gold standard for correcting erect penile deformity as a result of PD, and should be indicated in the chronic phase (at least six months of stable disease) and when penile curvature precludes intercourse. Non-surgical treatments already tested are vitamin E, potaba, tamoxifen, colchicine, carnitine and pentoxifiline. Intralesional injectable agents such as interferon, collagenase and verapamil, and more recently, electromotive therapy, iontophoresis, radiation therapy and traction therapy, have been studied. The majority were ineffective or not suitable for clinical use. Collagenase clostridium histolyticum (CCh) was first introduced nearly 20 years ago as a potential novel approach to treat Dupuytren disease. The first study describing the use of collagenase in PD was conducted by Gelbard in 1985 with 31 patients; it concluded that collagenase seemed to be effective in the treatment of PD. In 2010 the US Food and Drug Administration (FDA) approved Xiaflex (® Auxilium Pharmaceuticals, Inc, Malvern, PA) as an office-based nonsurgical treatment for adult patients with Dupuytren’s contracture with a palpable cord. In December 2013, the FDA approved Xyaflex as the first medicine to treat men with bothersome curvature of the penis (men who have a curvature of 30° or more and tangible scar tissue plaque in their penis), a condition known as Peyronie’s disease. The European Medicines Agency (EMA) did the same in June 2014.

The treatment of PD has been and continues to be largely surgical, although in selected patients nonsurgical alternatives appear to be useful to treat this disease. Clinical studies have shown that CCh is effective and safe when administered correctly, although long-term effects and results need further investigation, with large follow-up series. Comparison studies between collagenase and standard surgical treatment (plication or grafting) have not been conducted yet. As the financial costs of the treatment become more affordable (approximately 800 euros per dose), and the longterm effects better elucidated, CCh might be able to shift the current treatment paradigm.

two injections of CCh 0.58 mg (10,000 units) were given 24–78 hours apart. Subjects received up to three cycles at six-week intervals. Penile modeling consisted of a gentle stretching of the flaccid penis in the opposite direction to the curvature. The physician held the stretched position for 30 seconds, before allowing the penis to return to the non-modeled position for 30 seconds. This procedure was repeated three times. When designated, investigator modeling was applied 24–72 hours after the second injection of each cycle. Primary efficacy endpoints were the change from baseline in penile curvature and the change in total score for each PD-PRO domain score (a non-validated 15-question, disease-specific, patient reported outcome measure for quantifying the psychosexual impact, resulting from the physical and psychological symptoms of PD, in accordance with established scientific standards and guidance from the FDA to advance the research and understanding of PD), and International Index of Erectile Function (IIEF) score. Safety analysis was based on the adverse event (AE) incidence, and the change from baseline in laboratory values and vital signs.

deviation angle, plaque width and plaque length (LE 1b GR B).

38% Improvement

The preliminary experience of the use of CCh for the treatment of Dupuytren’s disease concludes that the application of continuous traction in Dupuytren’s contracture increases the activity of degradative enzymes. This initially leads to a loss of tensile strength and ultimately to solubilization. It is followed by an increase in newly synthesized collagen. This phenomenon is called mechanotransduction. The principle of mechanotransduction (a cellular process that translates mechanical stimuli into a chemical response that leads to activation of cell proliferation) has been applied to the use of penile traction therapy (PTT) in the nonsurgical treatment of PD.

Figure 2

consisting of two injections per cycle with a six-week interval between each cycle. One to three days later, penile plaque modeling was conducted.

The results showed a mean improvement in penile curvature (34% versus 18%; p < 0.0001) and in bother domain score (p < 0.0037) assessed using the After CCh treatment, significant mean improvements Peyronie’s Disease Questionnaire (PDQ; the first in penile curvature (29.7% versus 11%, p = 0.001) and validated PD-specific patient-reported measure of patient-reported outcome symptom bother scores psychosexual impact). Secondary endpoints were the (p = 0.004) were observed compared with placebo. percentage of global responders, PDQ psychological Subjects who underwent the modeling procedure and physical symptoms, IIEF overall satisfaction, showed a mean 32.4% improvement in penile percentage of composite responders (patients with curvature versus a mean 2.5% worsening in curvature 20% or greater improvement in penile curvature plus for the placebo group (p < 0.001). Subjects without an improvement in the PDQ PD bother score of 1 or modeling experienced a 27.1% mean improvement in greater), and plaque consistency. The post hoc penile curvature when treated with CCh, which did meta-analysis, which combined the study databases not statistically significantly differ from the 27.9% to improve statistical power, revealed statistical mean improvement observed for placebo. significance in all secondary endpoints except penile Subject 1106-7852 No significant differences in IIEF were observed. length and penile pain based on the multiple Baseline curvature deformity - 45° Efficacy and safety assessments were recorded over comparison algorithm. (See Table) 36 weeks, and AEs deformity were mostly mild or moderate End of study curvature - 28° (38% Improvement) AUX-CC-802 Photo Sub-Study (injection site bruising, edema, Subject rash, penile pain). Discussion FIGURE 1 No treatment-related serious AEs were reported. A number of medical therapies have been tried for FIGURE 2 the treatment of PD; unfortunately not many have Normal remodeling of collagen been subjected to double-blind drug testing. Peyronie’s Disease matrix following trauma/ inflammation and during growth However, data from controlled studies showing efficacy are limited for most historically available minimally invasive treatments. The FDA approval of CCh represents a renewed interest in the conservative management of PD. A key benefit of minimally Less Collagen Collagen Collagen Degradation invasive treatment is the improvement in PD signs, More Collagen Degradation Deposition Deposition [BOX such as penile curvature and psychosocial symptoms, BLUE, BOLD] with less morbidity than with surgery.

Data from studies are encouraging; also, in our preliminary experience, PTT was found to be safe and effective. Recently, our group published the results of a prospective, randomized and controlled trial to determine the efficacy of PTT on the conservative treatment of the acute phase (AP) of PD, A total of 55 patients underwent PTT for six months and were compared with 41 patients with AP of PD who did not receive active treatment (‘no intervention group’). After six months of treatment and a mean follow-up of nine months, we found a statistically significant decrease in the mean curvature, from 33° at baseline to 15° at six months and 13° at nine months, with a mean decrease of 20° (p < 0.05). Also, there was a significant increase in stretching penile length and flaccid girth (p = 0.03). Moreover, we identified predictors of treatment success: penile curvature greater than 45° at baseline, visual analogue scale score for penile pain greater than five, time from diagnosis less than three months, absence of plaque on the ultrasound study, and age under 45 years. EAU Guidelines acknowledge that penile traction devices and vacuum devices may reduce penile deformity and increase penile length (LE 2b GR C).

The three studies comparing the efficacy of CCh and penile modeling in the treatment of PD showed a statistically significant reduction in penile curvature in patients treated with CCh and modeling over CCh alone. These data suggest that modeling further decreases the restrictive effects of the plaque on tunica albuginea expansion during erection. However, these trials are often unclear as to whether the patients under evaluation include those in the early (acute) phase, the late fibrotic (stable) phase, or a Saturday 12 March Meeting of the EAU Section of Genito-Urinary Reconstructive Surgeons Figure10.15-15.45: 2 The European Association of Urology (EAU) Guidelines combination of patients of both phases. Treatment in (ESGURS) 2015 provided recommendations for the diagnosis and the early inflammatory phase can theoretically reduce [BOX ENDS] treatment of congenital and acquired PD penile the degree of inflammation and break the cycle of More recently, Gelbard and colleagues published the curvature. This should be focused on patients in the fibrin deposition and abnormal tissue remodeling . results of two phase III multicentre, prospective, early stage of the disease when symptoms are present Xiaflex is an injectable collagenase preparation randomized, double-blind and placebo controlled and the plaque is not densely fibrotic or calcified. Further evaluation regarding the effect of treatment in consisting of a predetermined mixture of two distinct studies (IMPRESS I and IMPRESS II) to determine the The role of conservative treatment in men with stable patients with PD in AP (< 12 months) should be collagenases that cleave collagen strands at different clinical efficacy and safety of intralesional CCh in or chronic disease has not been adequately defined. conducted. Because the duration of the disease is sites. AUX I (a class I Clostridium histolyticum subjects with PD. In both studies, the primary goal Under these directions, conservative management in significantly less in patients with low baseline collagenase) cleaves the terminal ends of collagen, was to assess the change in penile curvature. A total the acute PD phase is obtaining a progressively larger curvature severity, this suggests that earlier treatment and AUX II (a class II C. histolyticum collagenase) of 417 and 415 patients, respectively, were enrolled. consensus among experts. Moreover, the EAUmay be indicated to promote improved responses. cleaves internal sections of collagen. The main duration of PD history was 4.1 years. considered intralesional treatment with clostridium Even the pathophysiology of the disease continues to Patients received up to four cycles of 0.58 mg CCh, collagenase showed significant decreases in the A treatment course for Peyronie’s disease consists of a be the subject of discussion. It is clear that collagenase maximum of four treatment cycles. Each treatment induces a tissue response that is more effective in cycle consists of two Xiaflex injection procedures (in those patients with early disease. This effect can be Table 1: Summary results of randomized clinical trials. which Xiaflex is injected directly into the collagenenhanced by a mechanotransduction responsePHASE 2B IMPRESS I IMPRESS II containing structure of the penis) and one penile induced therapy (a key ‘step’ in the remodeling phase) CCh Placebo CCh Placebo CCh Placebo modeling procedure performed by the health care like modeling. A similar phenomenon occurs with PTT, # Subjects 111 36 199 104 202 107 professional. which proves to be more effective in the AP. Taking Change in SD penile -16,3+/-14,6 -5,4+/-13,8 -37,6 +/- 30,3 -21,3+/- 29,9 -30,5+/- 27,7 -15,2+/-28,7 into account these results, future perspectives probably will lie in the use of a combined or The safety and effectiveness of Xiaflex for the curvature (%). sequential therapy, including both CCh and PTT. treatment of Peyronie’s disease were established in p Value <0.001 0.001 0.0005 0.0059 two randomized double-blind, placebo-controlled Change in SD PDQ PD -3,3+/- 3.8 -2,0+/- 3,5 -2,4+/-3,6 -1,6+/-3,5 The treatment of PD has been and continues to be studies in 832 men with Peyronie’s disease with bother score largely surgical, although in selected patients penile curvature deformity of at least 30 degrees. p value 0.05 0.0451 0.0496 nonsurgical alternatives appear to be useful to treat Participants were given up to four treatment cycles of Change in +/- SD PDQ -3,2+/- 5,2 -1,6 +/- 4,5 -2,6+/-4,8 -1,0+/-4,8 this disease. Clinical studies have shown that CCh is Xiaflex or placebo and were then followed 52 weeks. PD symptom score effective and safe when administered correctly, Xiaflex treatment significantly reduced penile p value 0.026 0.034 although long-term effects and results need further curvature deformity and related bothersome effects Change in IIEF overall 1,0 +/- 2,6 0,5+/2,4 1,0 +/-2,3 0,3+/-2,4 investigation, with large follow-up series. Comparison compared with placebo. satisfaction studies between collagenase and standard surgical p value 0.08 0.11 treatment (plication or grafting) have not been Treatment outcomes conducted yet. As the financial costs of the treatment In 2012, Gelbard and colleagues reported the results of % of composite 50,6 25,4 42,3 30,6 become more affordable (approximately 800 euros per a phase IIb multicenter, prospective, randomized, responder dose), and the long-term effects better elucidated, CCh placebo-controlled study to determine the safety and p value <0.0001 <0.024 might be able to shift the current treatment paradigm. efficacy of CCh. Patient-reported outcome Change SD in penile 0,4+/-1,3 0,1+/-1,1 0,5+/-1,3 0,2+/-1,5 questionnaires were used. In this phase II study, a length (cm) total of 147 subjects with PD (27% of patients with a Saturday 12 March p value 0.63 0.024 history of PD < 12 months), stratified by degree of 10.15-15.45: Meeting of the EAU Section of Change in SD PDQ -5,1+/-5,2 -4,0+/-4,1 -3,8+/-5,9 -4,5+/-5,4 curvature (30–60° or >60°) were randomized into Genito-Urinary Reconstructive Surgeons penile pain four groups to receive CCh versus placebo (3:1), with (ESGURS) 0.79 0.69 or without plaque modeling (1:1). Per-treatment cycle, p value Sunday, 13 March 2016

Greenfield JM, et al. Urol Clin North Am. 2005;32:469-478.

EUT Congress News

Laparoscopic and robotic kidney transplantation Less morbidity, lower costs may help robotic KT become standard procedure in the future Feasibility of robotic KT in morbidly obese patients who have been refused open KT has been shown by Prof. Giulianotti group from Chicago2. With MIS benefits and low perioperative morbidity, robotic KT has the potential of becoming a standard KT procedure in the future once the cost of robotic procedure is brought down.

1. Slower return of renal functions post-operatively, with higher discharge serum creatinine, although the values were comparable at three months. Slower decline in the values could be attributed to longer re-warm ischemia periods (with gradual rise in temperature of intraperitoneally placed graft and longer anastomosis times during the learning curve);

Dr. Rajesh Ahlawat Medanta the Medicity Gurgaon (IN)

References 2. Varying techniques of ports and graft placements; Despite significant advances in medical management, the surgical technique of kidney transplantation (KT) with open procedure has remained unchanged since its inception. It is surprising since minimally invasive techniques have made significant inroads in all surgical spheres across the specialties including donor nephrectomy.

3. There were instances of torsion of intraperitoneally placed grafts around the pedicle with subsequent graft loss; and 4. Obtaining percutaneous graft biopsies from intraperitoneally placed grafts was unsafe, and required open surgical or laparoscopic assistance. There was, thus, the need to innovate a standardized robotic procedure for KT with regional hypothermia (to avoid ischemic insult), and fixation of graft at end of procedure (to enable percutaneous biopsies and prevent graft torsion).

A collaboration between Vattikuti Urology Institute at Henry Ford Hospital, Detroit, USA and Institute of Kidney and Urology at Medanta, India started exploring the possibility of robotic KT in early 2012 using IDEAL framework (acronym for steps of Innovation, Development, Exploration, Assessment and Long-term follow-up) of developing a safe surgical procedure as outlined by BALLIOL group1. With its 3-D vision, seven degrees of freedom of instruments, and capabilities to work at depth and in limited spaces, the robotic approach, theoretically, could achieve desired results. There were only three case reports of attempts at robotic KT in literature at that time.

A Phase 0 of preclinical simulation was added to IDEAL framework4, which established a safe procedure of intracoporeal cooling using ice slush without a significant drop in core body temperature using a radical prostatectomy model, and by fresh cadaver studies to choose the most practical of instruments and options. Procedures were monitored for safety and the learning curves using statistical methods during the learning phase5. Procedure is performed in the familiar patient’s position as in robotic radical prostatectomy, using similar ports position. A GelPOINT device at umbilicus incorporated the robotic lens and is used to deliver ice slush for intracorporeal cooling as well as placing the graft inside the peritoneal cavity for anastomosis.

Two case series of minimally invasive KT appeared in literature in 2013, one performed robotically (Giulianotti group from Chicago, USA)2 and another laparoscopically (Modi group from Ahemedabad, India)3. There was limited enthusiasm for laparoscopic KT due inherent limitation of instrumentation and After end-to-side vascular anastomosis of graft vision. Moreover, these reports could be criticized for: vessels to external iliac vessels, the graft is flipped in

Video still from a robotic renal transplant (Photo: European Urology Archives)

right iliac fossa to be fixed with premade peritoneal flaps to prevent its torsion and enable safe post-op percutaneous biopsies. Procedure is finished with ureterovesical anastomosis of the graft ureter to the recipient bladder. One hundred and fifty robotic KT have been performed by our group using the described procedure since January 2013. Prospective nonrandomized comparison of robotic KT procedure has been performed with open KTs being performed at the same centre6. The comparison of robotic and open KT cases with minimal follow-up of six months proves its feasibility and reproducibility. There are significant MIS benefits (pain score, analgesic requirement, blood loss, scar size), as expected, with no SSI morbidity or technical complication of arterial, venous and ureteric anastomoses. Short and long-term graft outcomes are equivalent to open KT (immediate postoperatively and till six months). Safe ultrasound guided percutaneous biopsies could be performed whenever indicated. There were no postoperative perigraft collection or lymphoceles in robotic group, probably a result of the graft’s intraperitoneal placement and the limited dissection needed during the robotic procedure. There was no graft loss.

1. McCulloch P, Altman DG, Campbell WB, et al. No surgical innovation without evaluation: the IDEAL recommendations. Lancet 2009; 374:1105-1112. 2. Oberholzer J, Giulianotti P, Danielson KK, Spaggiari M, Bejarano-Pineda L, Bianco F, et al. Minimally invasive robotic kidney transplantation for obese patients previously denied access to transplantation. Am J Transpl 2013;13:721-8. 3. Modi P, Pal B, Modi J, Singla S, Patel C, Patel R, et al. Retroperitoneoscopic living-donor nephrectomy and laparoscopic kidney transplantation: Experience of initial 72 cases. Transplantation 2013;95:100-5 4. Menon M, Abaza R, Sood A, Ahlawat R, Ghani KR, Jeong W, Kher V, Kumar RK, Bhandari M Robotic kidney transplantation with regional hypothermia: evolution of a novel procedure utilizing the IDEAL guidelines (IDEAL phase 0 and 1). Eur Urol. 2014 May;65(5):1001-9. 5. Sood A, Ghani KR, Ahlawat R, Modi P, Abaza R, Jeong W, Sammon JD, Diaz M, Kher V, Menon M, Bhandari M. Application of the statistical process control method for prospective patient safety monitoring during the learning phase: robotic kidney transplantation with regional hypothermia (IDEAL phase 2a-b). Eur Urol. 2014 Aug;66(2):371-8. 6. Sood A, Ghosh P, Jeong W, Khanna S, Das J, Bhandari M, Kher V, Ahlawat R, Menon M. Minimally invasive kidney transplantation: perioperative considerations and key 6-month outcomes. Transplantation. 2015 Feb;99(2):316-23.

Sunday 13 March 10.30-12.00: Thematic Session 9, Lessons from transplantation surgery applied to urology

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EUT Congress News

Sunday, 13 March 2016

Bladder neck closure in adolescents and adults Prof. Frank Van der Aa UZ Leuven Urology Department Leuven (BE)

When the decision to perform bladder neck closure in adults and/or adolescents is made, this is generally a next step in a long medical/surgical-urological history with poor functional results. The decision implies performing yet another surgical procedure with a reasonable risk for complications in this patient group. As this is a rare situation, pooled experience, knowledge of different techniques and adequate patient selection are the perquisites for success. The patient should be adequately counseled regarding the surgery, the risk of complications and the alternatives with their pro’ and con’s. Indications The “devastated outlet” in men and women is almost always iatrogenic. Men often have an oncological history (most typically prostate cancer surgery with or without bladder neck contracture and with or without previous irradiation). Women might also have an oncological history or most likely will have undergone multiple failed anti-incontinence procedures such as bulking agents, autologous or heterologous slings of colposuspensions. Underlying neurogenic bladder disease is the most common underlying disorder in adolescents. In female patients, a longstanding indwelling catheter can destroy the bladder neck and urethra. The total absence of the anterior aspect of the urethra renders “conservative” functional reconstruction impossible. Alternatives Alternatives of bladder neck closure with creation of a continent vesicostomy are an indwelling

catheter or urinary diversion. In cases of devastated outlet with severe incontinence, an indwelling catheter will not restore continence and thus, diversion will be the only alternative to bladder neck closure. Caveats Previous irradiation diminishes tissue quality due to obliterative endarteritis. Long standing neurogenic bladder disease or multiple previous bladder neck instrumentations can cause fibrosis. Both conditions treat the healing process after bladder neck closure and increase the risk of urinoma or vesico-cutaneous fistula formation. In these cases, diversion must be thoroughly considered as an alternative. If bladder neck closure is performed, omental interposition is mandatory in these cases. Overactive bladder disease (or neurogenic bladder) can be associated with detrusor overactivity. The presence of either one of these will increase the likelihood of postoperative intractable bladder contractions and the risk of urinoma or vesicocutaneous fistula formation. Bladder augmentation should be performed in these cases, to create a low pressure reservoir. This will also decrease incontinence rates at the level of the catheterizable stoma. The upper tract should be evaluated prior to surgery (kidney function/hydronephrosis). Patient counselling/informed decision Patients should be informed about possible failure. But also in case of “success,” lifelong intermittent catheterization will be the case. Many people will have some complications on the long run (bladder stones/mucus, catheterization difficulties which in case of closed bladder neck can create emergencies, incontinence through the catheterizable diversion, etc...). On the other hand, after a successful surgery, patients will be dry and confident about their continence. This will have an important positive impact on their social life and self-esteem. Using self-catheterisation, they will be in control of their own bladder.

EAU Patient Information on Bladder Cancer

Evidence There is no scientific evidence to support management decisions in this group of patients. Only case series have been published. It is unlikely that evidence will be produced in the future, seen the rare occurrence and the diverse nature of the underlying disorders. Expert opinion and pooled experience in tertiary referral centers will remain the level of knowledge. Validated symptom scores and quality of life questionnaires could increase our knowledge on this subject. We will present our experience together with an overview of the literature. Technique(s) Different techniques have been described, especially in the pediatric population. Briefly, the bladder is mobilized without damaging the vesical pedicles. If an augmentation is performed in the same time, approximately 20 cm of preterminal ileum is harvested, with an additional 4 cm if a Monti stoma will be used to create continent access to the bladder. The bowel continuity is restored. The 20 cm isolated preterminal ileum is opened antimesenterially and a spiral Monti is created from the small segment of ileum. When a well sized appendix is present, it is isolated on its vasculature and cut from the caecum using staplers. After preparation of the bowel segments, the bladder is transversally opened (clam shell). The bladder neck is identified. Both ureters are cannulated with 5 French feeding tubes. The urethra is dissected sharply and without diathermia and eventually transsected at the level of the bladder neck. The posterior wall of the bladder is mobilized by developing a plane between the bladder and Denonvilliers fascia or perivaginal tissue. The opening in the bladder neck is closed in two layers using slowly resorbable sutures. The suture line ends up by lying on the anterior surface. The urethra is closed with slowly resorbable sutures. Omental interposition is generally performed at this stage. Now the catheterizable stoma is inserted in the posterior bladder wall using an anti-incontinence technique (Lich-Grégoir). Subsequently the 20 cm isolated ileum is sutured onto the opened bladder to create a high volume, low pressure (acontractile) reservoir.

Outcomes Reported overall success rates for bladder neck closure in different populations using different techniques vary greatly from around 50 to 100%. Thus, outcomes are not universally good. Urinoma, fistula formation or urethral recanalization have been reported in 0 to 24% of cases. Although no scientific evidence exists, experience has learned that severe scarring and especially previous irradiation bears the risk of urinoma/fistula formation. A number of patients will require additional surgeries to achieve a functionally acceptable outcome. The majority of patients will achieve such a functionally acceptable outcome. A minority will end up with a urinary diversion. Bladder neck closure (with omental interposition, continent vesicoileostomy and bladder augmentation) is an effective technique to restore continence in a specific population of patients with “devastated outlet.” Patients that successfully underwent this surgery are continent and can have a normal, active life. The surgery is however not without complications, both on the short-term and on the long run. To avoid immediate complications, adequate patient selection and pooled experience is important. Patient need to be adequately counselled and urinary diversion should always be discussed as well. On the long run, most complications arise from the associated procedures (such as catheterizable vesicostomies). Sunday 13 March 10.30-12.00: Thematic Session, Challenges in incontinence treatment

ormation Patient Information Patient InPatient Information Patient Information ormation Patient Information Patient InPatient Information Patient Information ormation Patient Information Patient InPatient Information Patient Information ormation Patient Information Patient InTOPIC Patient Information PatientNEW Information Download at: ormation Patient Information Patient Inpatients.uroweb.org Patient Information Patient Information Sunday, 13 March 2016

Generally, the catheterizable stoma is best positioned in the umbilicus. At this place, the abdominal wall is at it thinnest, which is particularly interesting in obese patients. The bladder is drained for at least two weeks after the surgery and a cystography is performed to confirm the absence of any leakage at the level of the bladder neck closure prior to removing the bladder drainage.

www.WCE2016.com

Held in conjunction with the South African Urological Association (SAUA) Meeting • November 8 – 9, 2016

EUT Congress News

Today’s European Urology Events Chair – James Catto

Writing course

March 13th

How to write a manuscript and get it published in European Urology

Surgery in Motion March 13th

Chairs: J.Catto, A. Mottrie, H. Van der Poel

Platinum hour

• Why publishing (and publishing on European Urology) is important for you – C. Gratzke • Clinical research original article: How to write an article and get it published in European Urology – M.Cooperberg • Common problems and potential solutions – J. Catto • The importance of statistical design and analysis – D. Sjoberg • How to write a basic research article to be relevant for the readers of

• Robot-assisted radical cystectomy and urinary diversion: Technical recommendations from the Pasadena consensus panel – K.Chan • Robotic unclamped “Minimalmargin” partial nephrectomy: Ongoing refinement of the anatomic zero-ischemia concept – R. Satkunasivam • Robot-assisted simple prostatectomy for treatment of lower urinary tract symptoms secondary to benign prostatic enlargement: Surgical technique – Z.S. Dovey

European Urology – J. Cornu • How to write the perfect Twitter text – J. Catto • Surgery in Motion: How to combine the best possible manuscript and video for the Surgery in Motion Section – A. Mottrie • How to review a paper for European Urology – S.Boorjian Questions and answers – J. Catto To be held in room 12 from 8.30 to 11.30

• Robot-assisted, single-site, dismembered pyeloplasty for ureteropelvic junction obstruction with the New da Vinci platform: A stage 2a study – N. Buffi • Surgical tips and tricks during urethroplasty for bulbar urethral strictures focusing on accurate localisation of the stricture: Results from a tertiary centre – T.L.C. Kuo To be held in room 1 ICM, Level 0 from 10.30 to 12.30

We would like to invite you to attend the Platinum Hour drinks reception to meet and greet the Editors, Authors and Reviewers of The Platinum Journal. Please join us daily to toast the success of European Urology, “Your” Platinum Journal. To be held at the European Urology booth #A02. Daily from 16.00 to 18.00

March 12th - 14th

europeanurology.com 26

EUT Congress News

Sunday, 13 March 2016

Schistosomiasis - A deadly neglected tropical disease Urological impact of schistosomiasis Lawrence DrudgeCoates EAUN Chair London (GB)

Schistosomiasis, also known as bilharzia or “snail fever,” is a parasitic disease carried by fresh water snails infected with one of the five varieties of the parasite Schistosoma. Schistosomiasis infects 240 million people in as many as 78 countries, with approximately 90% of the burden occurring in Africa. Schistosomiasis ranks second only to malaria as the most common parasitic disease. Epidemiology There are two types of schistosomiasis, intestinal and urogenital, which are caused by five main species of schistosoma (Table 1). However, despite their different geographical nature, all species are contracted in the same way, through direct contact with infested fresh water. With respect to risk populations, schistosomiasis particularly affects agricultural and fishing populations. Women carrying out domestic chores in infested water, such as washing clothes, are also at

Treatment In the management of urogenital schistosomiasis, any individual with evidence of infection should be treated, as adult worms can live for many years and it is often difficult to distinguish between active and previous infection. Treatment should of course be prioritised based on presenting symptoms and medical need.

risk. In addition where there is inadequate access to safe drinking water and adequate sanitation, this only serves to amplify the problem. Interestingly, it is the migration to urban areas and the movement of refugees that is leading to the introduction of this disease to new areas. The resulting increase in population size and subsequent needs for power and water, have led to increased transmission. In addition, with the rise of tourism and travel, more people are travelling to countries with poor sanitation and a limited infrastructure. Therefore, an increased number of tourists are contracting schistosomiasis, often presenting with severe acute infections. Transmission to humans It is during contact with infected water that transmission to humans begins, when the larva or cercariae of the parasite are released into the water by freshwater snails, until they come into contact with an individual and penetrate the skin. Once inside the body, the larvae develop into male and female worms that pair up and live together in the blood vessels for years, with schistosoma haematobium travelling to the vesicle plexus (veins of the bladder). Female worms release thousands of eggs, about 50% of the eggs are excreted either in urine of faeces, but the rest become trapped in body tissues where they cause immune reactions and damage to organs. Urogenital schistosomiasis causes scarring and tearing of the bladder and kidneys, and can lead to bladder cancer. As a direct result of this infection process, squamous cell carcinoma (SCC) of the bladder remains the most common presentation of this type of bladder cancer.

Table 1: Schistosoma species and their geographical distribution Geographical distribution Intestinal schistosomiasis

Africa, the Middle East, the Caribbean, Brazil, Venezuela, Suriname, China, Indonesia, the Philippines, several districts of Cambodia, Lao

Urogenital schistosomiasis

Africa and the Middle East

Figure 1: The disease transmission cycle for schistosomiasis. This image is a work of the United States Department of Health and Human Services, taken or made as part of that person’s official duties. As a work of the US Federal Government, the image is in the public domain.

In infected individuals, urinating or defecate in freshwater, the excreted eggs migrate to snails where they eventually hatch and the whole cycle begins again (Figure 1). Symptoms Symptoms vary depending on the species of schistosoma worm involved and can include: • Initial itching and rash at infection site (“swimmer’s itch”) • Frequent, painful or bloody urine • Abdominal pain and bloody diarrhoea • Anaemia • Fever, chills and muscle aches • Inflammation and scarring of the bladder • Lymph node enlargement • Enlargement of the liver or spleen • Secondary blood disorders in cases of colon damage • Where infection persists, bladder cancer may develop • Children can develop anaemia, malnutrition and learning disabilities

• Biltricide (Praziquantel), an oral medication, has been shown to be effective against all forms of schistosomiasis and has few side-effects. It has low reported toxicity and no important long-term side-effects have been reported .Importantly its use in children and pregnant women is also considered to be safe. • Biltricide is given at a dose of 40 mg/kg for urogenital schistosomiasis, which causes dislodgement of the adult worms and in turn reduces the egg burden Importantly, education is required about risks of getting infected advising people not to swim, stand, wade or bathe in untreated water. Improved water and sanitation and breaking the lifecycle of the disease by encouraging the use of latrines and standpipes are also needed. From the perspective of a nurse assessment, considering a patient’s travel history or tracing their movements in any known areas of endemic disease are a key part of history-taking when presented with symptoms that may give rise to a suspicion of urogenital schistosomiasis. However, other conditions need to be excluded before an accurate diagnosis can be made. Schistosomiasis haematobium presents the greatest risk to the human urinary tract. Editorial Note: Due to space constraints we have ommitted the reference list. Interested readers can email a request at communications@uroweb.org. Sunday 13 March 15.45 – 16.45: 17th International EAUN Meeting Thematic Session: Rare cases and diseases in urology. State-of-the-art lecture: Schistosomiasis

Platinum Picture Perfect Please come to the European Urology booth #A02 and have your Platinum Postcard created and posted online. Daily from 10.00 to 18.00

europeanurology.com

Sunday, 13 March 2016

EUT Congress News

Superior prevention of SREs vs zoledronic 1 acid*

Find more about XGEVA® at stand D10, Hall B1

Skeletal-related events (SREs): pathological fracture, radiation to bone, spinal cord compression or surgery to bone, in adults with bone metastases from solid tumours. *Data from an integrated analysis of 3 randomized, identically designed phase III studies comparing XGEVA® with zoledronic acid for the prevention of SREs in patients with bone metastases from advanced breast cancer (n=2,046), castration-resistant prostate cancer (n=1,901), and other solid tumours (excluding breast and prostate cancer) or multiple myeloma (n=1,776). Endpoints included time to first SRE, time to first and subsequent (multiple) SRE, adverse events, time to disease progression and overall survival. XGEVA® was superior to zoledronic acid in delaying time to first on-study SRE by a median 8.21 months, reducing the risk of a first SRE by 17% (HR=0.83 [95% CI: 0.76–0.90]; p<0.001). Reference: 1. Lipton A, et al. Eur J Cancer. 2012;48:3082-3092.

XGEVA® (denosumab) Abbreviated Prescribing Information ▼This medicinal product is subject to additional monitoring. All suspected adverse reactions should be reported. Composition: Each vial contains 120mg of denosumab in 1.7ml of solution (70 mg/ml) (EU/1/11/703/001-3). Delivery form: Packaging as a single dose, three or four. Pharmacotherapeutic group: Drugs for the treatment of bone diseases - other drugs affecting bone structure and mineralisation, ATC code: M05BX04. Indications: Prevention of skeletal-related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with bone metastases from solid tumours. Treatment of adults and skeletally mature adolescents with giant cell tumour of bone that is unresectable or where surgical resection is likely to result in severe morbidity. Contraindications: Severe, untreated hypocalcaemia. Hypersensitivity to the active substance or to any of the excipients. Unhealed lesions from dental or oral surgery. Special Warnings and Precautions: Calcium and Vitamin D supplementation: Supplementation with calcium and vitamin D is required in all patients unless hypercalcaemia is present. Hypocalcaemia: Hypocalcaemia must be corrected prior to treatment. Hypocalcaemia can occur at any time during therapy with XGEVA. Monitoring of calcium levels should be conducted prior to the initial dose of XGEVA, within two weeks after the initial dose, or if suspected symptoms of hypocalcaemia occur. In the post-marketing setting, severe symptomatic hypocalcaemia (including fatal cases) has been reported, with most cases occurring in the first weeks of initiating therapy, but it can occur later. Renal impairment: Patients with severe renal impairment (creatinine clearance < 30 ml/min) or receiving dialysis are at greater risk of developing hypocalcaemia. The risk of developing hypocalcaemia and accompanying elevations in parathyroid hormone increases with increasing degree of renal impairment. Regular monitoring of calcium levels is especially important in these patients. Osteonecrosis of the jaw (ONJ): ONJ has been reported commonly in patients receiving XGEVA. The following risk factors should be considered when evaluating a patient’s risk of developing ONJ: potency of the medicinal product that inhibits bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy, cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking, concomitant therapies (corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to head and neck), poor oral hygiene, periodontal disease, poorly fitting dentures, pre-existing dental disease, and invasive dental procedures e.g. tooth extractions. The start of treatment/new treatment course should be delayed in patients with unhealed open soft tissue lesions in the mouth. A dental examination with preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with XGEVA. All patients should be encouraged to maintain good oral hygiene, receive routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling, or non-healing of sores or discharge during treatment with XGEVA. While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to XGEVA administration. Atypical femur fracture (AFF): AFF has been reported in patients receiving XGEVA. Discontinuation of XGEVA therapy in patients suspected to have an AFF should be considered pending evaluation of the patient based on an individual risk/benefit evaluation. Patients with growing skeletons: XGEVA is not recommended in patients with growing skeletons. Clinically significant hypercalcaemia has been reported in XGEVA-treated patients with growing skeletons weeks to months following treatment discontinuation. Warnings for excipients: Patients should be advised to report new or unusual thigh, hip, or groin pain. Patients presenting with such symptoms should be evaluated for an incomplete femoral fracture. Other: Patients receiving XGEVA should not be treated concomitantly with other denosumab-containing medicinal products (for osteoporosis indications) or bisphosphonates. Patients with rare hereditary problems of fructose intolerance should not use XGEVA. Adverse reactions: Very common: dyspnoea, diarrhoea, musculoskeletal pain. Common: Hypocalcaemia, hypophosphataemia, tooth extraction, hyperhidrosis, ONJ. Rare: Drug hypersensitivity, anaphylactic reaction, AFF. Amgen Europe B.V., Minervum 7061, NL-4817 ZK Breda, The Netherlands, tel. +31 (0) 76 5732500. For more information, see the registered product information. This product information is regularly updated. Detailed information on this medicine is available on the European Medicines Agency website: www.ema.europa.eu. Date of PI preparation: November 2015. 28 EUT Congress News 13 March 2016 2016. DateSunday, of preparation: January EUHQ-P-162x-0116-122568

Nocturia in females with Pelvic Organ Prolapse Nocturia and POP: A strong but underestimated link Prof. Antonella Giannantoni University of Perugia Department of Surgical and Biomedical Science, Urology and Andrology Clinic Perugia (IT)

Pelvic Organ prolapse (POP) includes anterior vaginal prolapse (cystocele), posterior vaginal prolapse (rectocele), apical or uterine prolapse, enterocele and perineal descent1. POP has been reported to affect 50% of the parous women, and the lifetime risk of undergoing a single operation for prolapse by age 80 is about 11 %. As the population ages, it is estimated that the rate of women seeking treatment for POP will double3. More than 50% of women with symptoms of POP report at least one symptom of another pelvic floor disorder: stress urinary incontinence, anal incontinence and/or overactive bladder (OAB). OAB, defined as urgency with or without urgency incontinence, usually with frequency and nocturia4, is frequently observed in patients affected by POP. OAB symptoms increase with age in both sexes, with 21% of women older than 70 years being affected by the condition. 88% of women affected by POP present with OAB symptoms2. As POP and OAB are frequently observed in the old female population, it is expected to find an association between the two conditions in the same patient. The close relationship between OAB/Lower Urinary Tract Symptoms (LUTS) and POP has rarely been explored, but it seems that having either incontinence or prolapse may be associated with an increased risk of developing the other condition5. Indeed, data from community and hospital-based studies show the prevalence of OAB symptoms is higher in patients affected by POP, although from these studies it is not possible to establish a causal relationship between the two conditions. Impact on QoL POP has also been shown to affect many aspects of a woman’s quality of life (QoL) including her social, psychological, physical, sexual, body image and overall wellbeing. A high prevalence of depression has been detected in women with POP5. Women seeking treatment for urogenital proplapse frequently present with nocturia, pelvic pain and bowel dysfunction perceived as their most bothersome symptoms. In a recent study, LUTS associated with POP, and particularly nocturia, have been found to increase the likelihood of poor sleep quality. Poor sleep quality and sleep deprivation have a negative impact on mood, cognitive health, immune function and cardiovascular health5. Several theories have been developed to explain the relationship between OAB and POP. A supersensitivity to neurotransmitters (i.e. acetylcholine) and a higher irritability of the detrusor muscle due to partial denervation of the obstructed bladder, and changes in spinal micturition reflexes after obstruction are usually considered as potential causative factors2. Indeed, several studies reported a lower maximum flow rates during voiding and a higher prevalence of detrusor overactivity (DO) in patients with POP than in those without the condition, although the prevalence of DO does not increase with the severity of POP. Furthermore, data from the literature do not show a clear association between the prevalence of OAB symptoms or DO and both stage and type of the prolapsed compartment, although in women with coexisting POP and OAB, an improvement in OAB symptoms after treatment of POP can be observed. In spite of these observations, presence and assessement of the type of nocturia in patients with POP and its eventual resolution after POP treatment have been rarely investigated. De Boar et al. investigated which factors predict the presence of OAB symptoms after surgery for POP and found that bothersome OAB symptoms decreased Sunday, 13 March 2016

after POP intervention7. Frequency and urgency were more likely to improve or disappear as compared to urge incontinence and nocturia. The authors argued that the presence of nocturia may be more dependent on external factors such as poor sleep and nocturnal polyuria, which are both unlikely to be influenced by the presence of a vaginal prolapse, and probably more related to cardiac condition7. In a previous study functional symptoms related to POP and the eventual anatomo-functional associations were investigated in 374 patients aged 65 years8. It was found that patients with stage 3-4 anterior vaginal prolapse suffered significantly more frequently of nocturia, voiding difficulties and occult stress urinary incontinence, while those with stage 3-4 rectocele suffered significantly more frequently of defecatory dysfunction. In another study examining the clinical and urodynamic characteristics of women with LUTS presenting various rates of cystocele, nocturia, urgency and urge incontinence, were found to be significantly associated with functional bladder capacity9. In this study no relationship has been demonstrated between the degree of cystocele and symptoms of the filling phase of the bladder, on the one hand, and urodynamic evidence of DO and incontinence on the other hand. When examining the results of anterior repair surgery of POP, it was found that this surgery was significantly effective in improving urgency, daytime frequency, incontinence, but no significant change in nocturia was observed one year after surgery. The authors did not give any explanation for this result.

“Presence and types of nocturia in women with POP should be more adequately investigated and assessed in future studies, in order to really improve such a bothersome condition...”

Kegel exercises diagram for POP, Photo By Gend27 (Own work) [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

7. de Boer TA, Kluivers KB, Withagen MI, et al. Predictive factors for overactive bladder symptoms after pelvic organ prolapse surgery. Int Urogynecol J. 2010; 21:1143-9. 8. Adjoussou SA, Bohoussou E, Bastide S, et al. Functional symptoms and associations of women with genital prolapse. Prog Urol 2014; 24:511-7. 9. Adot Zurbano JM, Salinas Casado J, Dambros M, et al. Filling phase abnomalities and cistocele. Arch Esp Urol. 2005; 58:309-15.

10. Okui N, Okui M, Horie S. Improvements in overactive bladder syndrome after polypropylene mesh surgery for cystocele. Aust N Z J Obstet Gynaecol. 2009; 49:226-31.

Sunday 13 March 10.30-12.00: Thematic Session 6, Neuro-urology

In our clinic, between January 2013 and December 2015, 83 women presenting with stage from II to IV POP, were examined for the evaluation of urinary symptoms and nocturia. Sixty-six % of these women complained of nocturia > 2 times/night, associated with poor sleep quality. It was observed that severe nocturia symptoms were associated with older age, more comobidities and more severe depressive symptoms. In about half of the cases a nocturnal polyuria condition was detected. We are now analyzing whether the surgical resolution of POP in these women can reduce the severity of nocturia while improving the quality of sleep.

Science at your fingertips

Presence and types of nocturia in women with POP should be more adequately investigated and assessed in future studies, in order to really improve such a bothersome condition which affects, together with other LUTS, a number of females with urogenital prolapse. References 1. Payne C, Brown J, Castro-Diaz D et al. In Abrams P, Cardozo L, Khoury S, Wein A editors. Chapter 23: research in Incontinence. 4th International consultation on Incontinence. Paris, July, 5-8 2008. 4th Edition. Health Publication Ltd; 2009. 2. Olsen AL, Smith VJ, Bergstrom JO, et al. Epidemiology of surgically managed pelvic organ prolapse and urinary incontinence. Obstet Gynecol. 1997; 89:501-6. 3. Luber KM, Boero S, Choe JY. The demographics of pelvic floor disorders: Current observations and future projections. Am J Obstet Gynecol 2001; 184: 1496-501. 4. Abrams P, Cardozo L, Fall et al. The standardisation of terminology of lower urinary tract function: Report from the standardisation sub-committee of the International Continence Society. Neurourol urodyn 2002; 21: 167-78. 5. Ghetti C, Lee M, Oliphant S, et al. Sleep quality in women seeking care for pelvic organ prolapse. Maturitas. 2015; 80:155-61. 6. Cartwright R, Kirby AC, Tikkinen KA et al. Systematic review and metaanalysis of genetic association studies of urinary symptoms and prolapse in women. Am J Obstet Gynecol, 2015; 212: 199-24.

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Management of stones Collaboration among stone and kidney specialists plays a crucial role Prof. Thomas Knoll Department of Urology Klinikum SindelfingenBöblingen University of Tuebingen Tuebingen (DE)

Co-Author: Kemal Sarica (Istanbul, TR) Urolithiasis is daily routine business for urologists. Incidence and prevalence are increasing almost worldwide. Various factors seem to be responsible for this trend, from life style changes, obesity and associated metabolic disorders to environmental changes such as rising global temperature. This observation illustrates that urologists got to focus on the whole process of renal stone formation. Cooperation with other disciplines such as nephrology are as much necessary as support by a dietician. However, the important underlying pathophysiology was forgotten (or never known?) by many urologists due to the enormous technological developments for interventional stone management. Open techniques are now limited to selected cases and minimalinvasive treatment modalities became standard of care. Extracorporeal shockwave lithotripsy (SWL) has been the treatment of choice for decades, but further optimization of ureteroscopy (URS) and percutaneous nephrolithotomy (PNL) has changed treatment patterns as shown in Figure 1. This shift towards more invasive endoscopic treatment might be triggered by the faster stone-free status, but the fascination of urologists for “more surgical” approaches could be a factor that should not be neglected. It is sobering that no generally accepted definition of the most important aspect of stone treatment, the

stone-free status, exists. Although stone-free rates (SFR) close to 100% are regularly reported, the methods for detection of residual fragments are very heterogeneous. Some urologists determine the SFR by intraoperative endoscopic inspection, others with conventional KUB. Several studies demonstrated the low correlation of such methods with postoperative computer tomography (CT) that regularly detects residuals in “stone-free patients.” Therefore non-enhanced CT should be considered the gold standard, at least in more complex cases and to report SFR in scientific projects. The term “clinically insignificant residual fragments (CIRF)” is questionable as it was shown that such “insignificant” fragments might lead to recurrent stone formation. Treatment success should therefore specify the rate of CIRF. Rigid and flexible URS became the treatment of choice for the majority of stones. The major innovations for URS were realized for flexible endoscopes, including the step from fiberoptic to digital systems. Interestingly, PNL – though being the most invasive procedure in the armamentarium of the endourologist – is increasingly used again. A reason for this development could be the availability of miniaturized systems. It might be assumed that the reduction of access tract diameter leads to a reduced complication rates, especially with respect to bleeding. Percutaneous approaches even for medium-sized stones can, therefore, be easier justified, although no good study has ever proven this advantage when compared to standard PNL with 26-30F. It has to be kept in mind that many different systems are summarized as mini-PNL, with the smallest (Micro) diameter of 5F up to 18-22F. Not only the size of the access sheath and the endoscope changes when using such systems, but other associated factors as well, such as the dilation or lithotripsy method. Good comparative studies are urgently needed to develop treatment algorithms helping to choose the right instrument.

Figure 1: Interventional stone treatment in Germany (Federal Statistical Office, Germany. PNL=Percutaneous nephrolithotomy, URS=Ureteroscopy, ESWL=Extracorporal shock wave lithotripsy).

But once again, stone removal is only one part of the game and in recurrent stone formers the treatment of the symptom is not the cause. Knowledge of the stone composition is mandatory for metabolic evaluation and prevention. An interesting new concept for detection of stone-free rate became possible with the availability of digital scopes. Several authors have reported a rather good correlation with endoscopic stone “analysis” based on the appearance and color of the stone and a later stone analysis. Although the precision of a laboratory stone analysis with X-ray diffraction or polarization microscopy, particularly for mixed compositions, will never be reached, such concepts might be a applicable when stone analysis is not possible. Research on stone metabolics focused mainly on urine analysis in the last 50 years. Although extensive studies have been performed, the most important advice for prevention of stone recurrence remains an

increased amount of fluid intake. The benefit of other dietary attempts is, mostly, not confirmed in systematic reviews and ever since citrate is the key medication to limit crystallization. However, findings like interstitial calcium phosphate formation as precursors of calcium oxalate stone formation illustrate that investigators have to think out of the box. New hypotheses and new methodology are required to make progress not only in stone surgery but in stone prevention as well. Only collaboration between different groups as urologists, nephrologists, nutrition experts and basic researchers – which is the concept of the EAU Section for Urolithiasis (EULIS) – will help us reach this aim. Saturday 12 March 10.15-14.00: Meeting of the EAU Section of Urolithiasis (EULIS)

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Sunday, 13 March 2016

Herbal medicines in the management of renal stones Systematic screening of herbal remedies is needed to validate their efficacy Prof. Robert Unwin Centre for Nephrology University College London London (UK)

Herbal remedies for renal stone disease have a long and ancient history, and this form of treatment remains popular with the general public and is often publicized in the media and on the Internet, but with little supporting information much of which is anedoctal. Despite our scientific progress in understanding drug design, formulation, and drug action, we still do not know which herbal medicines or mixtures actually work in clinical practice, what their mode of action is and whether it is novel; if there is one or more active ingredient and what it is, or if all such remedies are universally safe to prescribe. This subject warrants more serious attention and there is still a lot of work that needs to be done to properly exploit these traditional ‘cures’. Exactly how renal stones form continues to be a subject of ongoing speculation, despite the significant advances we have made in our understanding of many of the urinary components and external factors, including diet and lifestyle, and even genetics, that are strongly associated with the risk of stone formation and stone type, which are: low urine volume, increased excretion of calcium and oxalate, increased or decreased urine pH, decreased excretion of citrate and magnesium. However, as doctors (physicians or surgeons), we have very few, if any, medical treatments, preventive or otherwise, other than oral citrate, in the often forlorn hope that our patients will take it and that we can give sufficient to boost its excretion; thiazide diuretics to reduce calcium excretion, which is also ‘hit and miss’, if their dose-related metabolic and electrolyte side effects are to be avoided; xanthine oxidase inhibitors such as allopurinol or febuxostat for uric acid stones; and the more specific thiol-based chelators for those with cystinuria and cystine stones. Therefore, it is not surprising that many (desperate) patients ask about the value of various ‘herbal remedies’ that have been touted in the media or on the Internet as a ‘cure’ for kidney stones; but is there any evidence that they are of benefit and if so, what might the active ingredient(s) be? Systematic investigation A more systematic exploration and investigation of herbal remedies for treating renal stones not only has potential clinical value as preventive or adjunct medication, but also as a scientific endeavour to identify novel targets and pathways involved in the pathogenesis of stone formation. An innovative and relatively ‘high throughput’ screening approach has already been described in the fruit fly for calcium oxalate stone formation1, which could be followed up by isolating the active ingredient(s) and progressing to a clinical trial to show efficacy. Using the search terms ‘kidney stones’ and ‘herbal’ or ‘herbs’ in PubMed you will get a return of between 10 and 60 publications, respectively; however, the actual Table 1: Proposed ‘natural remedies’ for treating renal stones and their possible actions: • Arctostaphylos uva-ursi (urinary antiseptic) • Dandelion root (diuretic) • Kidney beans (diuretic) • Horsetail (diuretic) • Pomegranate (urinary antiseptic) • Celery seeds (diuretic) • Basil (diuretic and urinary antiseptic) • Nettle leaf tea (diuretic and urinary antiseptic) • Watermelon (diuretic and may promote citrate excretion) • Apple cider vinegar (diuretic, urinary antiseptic, and citrate source)

Sunday, 13 March 2016

number is surprisingly variable and uncertain, and seems relatively small, confused by what is defined as ‘herbal’, rather than a dietary component such as fruit or vegetables containing alkali, citrate and magnesium, and both the (changing) composition and indications for use of various herbal extracts, making it difficult to determine what might be of benefit and how. Many are so-called ‘natural remedies’ with scant information on their mode of action (See Table 1). However, it seems likely that many of these remedies may achieve their apparent success and popularity from a mild diuretic effect, for example, from caffeine (an adenosine receptor antagonist)2, or smooth muscle relaxation (also a potential effect of caffeine), similar to α-blockade, or provide alkali as citrate, or even act as mild urinary antiseptics3. Moreover, as a warning, many ‘over-the-counter’ health tonics or stimulants contain ‘ephedra’ or ephedrine, which can be a cause of renal stones4. That said almost all reports are based on in vitro assays of stone formation (crystal formation in artificial urine)5 or in animal models3,5, and almost exclusively for use in treating calcium oxalate stones, rather than any human data from the ‘gold-standard’ of a prospective double blind randomized controlled trial (RCT). RCTs have always been challenging to do for the treatment of nephrolithiasis, because its natural history is often unpredictable, compliance with treatment is generally poor (anything given more than once a day over the long-term), as well as the difficulty in blinding any medication; all this makes the choice of outcome and end-point, other than short-term changes in urine composition or long-term rates of stone recurrence, uncertain and costly. Indeed, Butterweck & Khan3, in their comprehensive review of herbal treatments for nephrolithiasis a few years ago, could find only 21 human trials, but all in healthy volunteers, and many testing citrus or cranberry juices that can affect citrate excretion and/ or urine pH. In fact, there are very few RCTs for medical treatment of renal stones, apart from thiazide diuretics, including indapamide, oral citrate, and allopurinol6. I could find four published and accessible randomized clinical trials, only one of which was double-blind. These looked at stone-free interval after lithotripsy7 and effect on urinary calcium excretion8 with Uriston; urine composition at six weeks and stone-free interval at one year with Cystone (See Table 2)9, and another lithotripsy study using biomarkers of oxidative damage to study the ‘protective’ effect of a popular Chinese herbal mixture for renal stones10. All except the Cystone study, the only double-blind study, claimed to show some benefit, but the numbers are small and duration short. Interestingly, Cystone has shown a positive effect in vitro to reduce calcium oxalate crystallization5, but this did not translate to any clinical efficacy in vivo. Table 2: Herbal preparations used to treat renal stones in published clinical trials: • Hibiscus sabdariffa (diuretic) • Phylantus niruri (Uriston®) (diuretic) (RCT – no blinding) • Orthosiphon grandiflorus (diuretic/uricosuric/caffeine-like) • Dolichos biflores • Andrographis paniculata • Sambucus nigra (diuretic) • Solidago virgaurea (diuretic) • Cystone® (herbal mixture with diuretic properties) (RCT – double blind) ® RCT

Registered trade mark Randomised Controlled Trial

Systematic approach to screening In summary and (this author’s) conclusion, looking through the published literature, which is often not in mainstream nephrological or urological journals, it is very difficult to chart a course and find any potentially useful herbal remedies that have been validated and properly tested in clinical trials, and at the same time be confident of avoiding any risk of toxicity from non-standardized or fully analyzed herbal preparations. We have a limited therapeutic armamentarium for renal stone disease and so it is not unreasonable to turn to herbal remedies as a

potential source of new and additional treatments. However, until we adopt a more systematic approach to screening these herbal remedies, identifying their active ingredients, understanding their mechanisms of action, and demonstrating efficacy in rigorously conducted clinical trials, any benefit will remain little more than hearsay, and we risk misleading our patients. How to encourage wider academic interest in understanding the pathophysiology of renal stone disease, as well as pharmaceutical interest in its treatment, is a key challenge for us.

Various types of Indonesian bottled jamu herbal medicines, Photo by dpinpin via Wikimedia Commons

References 1. Wu S-Y, Shen J-L, Man K-M, et al. An Emerging Translational Model to Screen Potential Medicinal Plants for Nephrolithiasis, an Independent Risk Factor for Chronic Kidney Disease. Evidence-Based Complementary and Alternative Medicine 2014; 2014: 1–7. 2. Ferraro PM, Taylor EN, Gambaro G, Curhan GC. Caffeine intake and the risk of kidney stones. Am J Clin Nutr 2014; 100: 1596–603. 3. Butterweck V, Khan S. Herbal Medicines in the Management of Urolithiasis: Alternative or Complementary? Planta Med 2009; 75: 1095–103. 4. Hoffman N, McGee SM, Hulbert JC. Resolution of ephedrine stones with dissolution therapy. Urology 2003; 61: 1035–2. 5. Rodgers AL, Webber D, Ramsout R, Gohel MDI. Herbal preparations affect the kinetic factors of calcium oxalate crystallization in synthetic urine: implications for kidney stone therapy. Urolithiasis 2014; 42: 221–5. 6. Sfoungaristos S, Gofrit ON, Yutkin V, Pode D, Duvdevani M. Prevention of renal stone disease recurrence. A systematic review of contemporary pharmaceutical options. Expert Opin Pharmacother 2015; 16: 1209–18.

7. Micali S, Sighinolfi MC, Celia A, et al. Can Phyllanthus niruri Affect the Efficacy of Extracorporeal Shock Wave Lithotripsy for Renal Stones? A Randomized, Prospective, Long-Term Study. The Journal of Urology 2006; 176: 1020–2. 8. Nishiura JL, Campos AH, Boim MA, Heilberg IP, Schor N. Phyllanthus niruri normalizes elevated urinary calcium levels in calcium stone forming (CSF) patients. Urol Res 2004; 32: 362–6. 9. Erickson SB, Vrtiska TJ, Lieske JC. Effect of CystoneÂ® on urinary composition and stone formation over a one year period. European Journal of Integrative Medicine 2011; 18: 863–7. 10. Sheng B, He D, Zhao J, Chen X, Nan X. The protective effects of the traditional Chinese herbs against renal damage induced by extracorporeal shock wave lithotripsy: a clinical study. Urol Res 2010; 39: 89–97.

Saturday 12 March 10.15-14.00: Meeting of the EAU Section of Urolithiasis (EULIS), Management of stones: How did the advancing technology, better evaluation and increased collaboration change our traditional approach?

ChM in Urology This two year part-time Master of Surgery programme in Urology, taught entirely online, supports learning for professional urology examinations [FRCS(Urol) and FEBU] and develops skills in academic urology. For further information contact chminfo@rcsed.ac.uk

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