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31st Annual Congress of the European Association of Urology
Saturday, 12 March 2016
Munich, 11-15 March 2016
Innovate and specialise: A challenge to urologists Awardees cite the role of flexibility and vision to break new grounds “The biggest challenge to urology is to shift from surgical to medical management,” said Artibani shortly before accepting the honour which he said “overwhelmed” him as he knew there are many other people who are more deserving. “ If I may advise young urologists, I would encourage them to sub-specialise in areas such as endourology and uro-oncology.”
J. Hosseini (IR), G. Janetschek (AT), M. Marberger (AT), K. Parsons (UK), Y. Sun (CN) and V. Tkachuk (RU). A remarkable moment was the standing ovation from the audience for Prof. Michael Marberger as he went up to the podium to receive his Honorary Member award.
One of the youngest awardees, Crystal Matula awardee Dr. Alberto Briganti noted the need for young urologists to focus on innovation while adhering to evidence-based practices. “Urology need to keep on the track of novel discoveries because that would significantly change our practice.” The Munich All-Stars deliver an elegant violin music
By Joel Vega Violin music from the four female performing artists of the Munich All-Stars greeted yesterday the Opening Ceremony audience of the 31st Annual EAU Congress in Munich with EAU Secretary General Chris Chapple welcoming participants to Europe’s largest annual urology event.
“Nothing would happen without being made to happen,” said Chapple as he cited the efforts of the urological community to sustain new developments and pursue contemporary challenges in medicine. Chapple’s words were echoed by some of the awardees with Prof. Walter Artibani, recipient of the EAU’s highest honour, the Willy Gregoir Award, underscoring the key role of adapting to modern challenges.
This year’s awardees are Prof. Teillac (FR) who received the EAU Frans Debruyne Life Time Achievement Award, Prof. J.M. Gil-Vernet Vila (ES) winner of the EAU Innovators in Urology Award, Dr. M. Gundeti (US) (EAU Hans Marberger Award), and J. Pencik (AT) winner of the EAU Prostate Cancer Research Award. The EAU also granted Honorary Member titles to former EAU Secretary General P-A. Abrahamsson (SE),
Prof. Chapple (R) hands over the Honorary Member award to Prof. Marberger
Multi-disciplinary care in PCa management 3rd ESO Prostate Cancer Observatory highlights collaborative work By Tom Parkhill Multidisciplinary care and the role of a comprehensive collaborative effort in managing prostate cancer was highlighted at the 3rd European School of Oncology (ESO) Prostate Cancer Observatory held yesterday which had “Innovation and Care in the Next 12 Months” as central theme.
Session co-chairs, Steven Joniau (BE) and Riccardo Valdagni (IT) spoke on the importance of providing a platform for a diverse group of experts specializing on prostate cancer.
“It’s only recently that patients with metastatic prostate cancer have become subjects for real, intensive, specialised treatment, and this is due to a couple of changes we have seen described here The session hall was filled to overflowing with today,” said Valdagni. “The first thing is that several delegates having to watch the proceedings on multi-disciplinary care is growing in all fields of the outside screen, the meeting attracted high interest cancer care, but especially in prostate treatment among opening day congress participants. The session we are seeing the involvement of teams of was led by a very distinguished group of scientists specialists: oncologists, radiologists, surgeons, and clinicians joining with patients to forecast what hormone specialists, and so on, all followed up by the trends would be in prostate treatment over the a much more comprehensive level of support care.” next 12 months.
Celebrating the history and culture of urology By Loek Keizer “Stimulating the study of history opens windows to the future,” was how Prof. Frans Debruyne eloquently opened the 6th International Congress on the History of Urology yesterday morning. It became clear over the course of the day-long congress that it celebrated not only the history, but also the culture of urology by highlighting its social and artistic aspects. Fifteen experts from five continents took part in the day-long scientific programme that explored the worldwide origins of urology. Over 200 delegates arrived in Munich earlier than usual to attend the Congress, which was organised by the EAU History Office and its international partners in conjunction Saturday, 12 March 2016
with the 31st Annual EAU Congress. Former EAU Secretary General Prof. Debruyne was its Honorary Congress President, with Prof. Dirk Schultheiss sharing ceremonial duties as Chairman of the EAU History Office.
“For example, the new PET-CT is changing the diagnostics of prostate cancer. And this has changed our strategic approach,” added Valdagni. “Metastatic prostate cancer is now becoming treatable, whereas previously patients with one or two metastatic tumours were almost considered inoperable. Joniau added: “Patient involvement is vitally important. There can be a tendency to run with the
Prof. Touijer speaks at the ESO Prostate Cancer Observatory
treatment, and we need patients to balance our enthusiasm and make sure that we keep site of the quality of life of the patient – to treat the patient, and not just the disease. Just because something is treatable doesn’t mean that treatment is obligatory. These changes will also involve an education process. It’s hard enough for specialists in the field to keep up with the remarkable changes we are seeing, but think how much more difficult for the average GP to take this on board.”
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Naturally, the congress included topics on the origins of certain procedures, biographies of known and unknown pioneers and even the prehistoric evidence of cultures of sexuality. (Continued Next Page)
“The second great advance is in imaging,” added Joniau. “We are now seeing new imaging modalities which are revolutionizing what we can see and what is treatable. The differences are startling. It’s a bit like going from an old black and white TV to a large screen 3-D full colour 4K screen – you just see more than we used to see.”
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EAU-CAU: ‘Hot’ urology topics
Today’s Industry Sessions
Lat-Am examines uro-onco issues
Industry sessions and workshops, all starting at 18:00 hrs Interpreting the value of OAB treatment ASTELLAS - eURO Auditorium How the microbiome is influenced by the therapy of urological diseases: Standard vs. alternative approaches? Workshop by BIONORICA SE - Room 11 State-of-the-art in intravesical GAGs therapy: From infection prevention to pain control IBSA INSTITUT BIOCHIMIQUE SA - Room 12 Moving forward in urological cancers IPSEN PHARMA - Room Paris Patient journeys through metastatic castrationresistant prostate cancer: A multidisciplinary team discussion JANSSEN PHARMACEUTICA NV - Room Madrid A Debate Workshop by LUMENIS - Room 13b Managing patients with NMIBC: Old disease – New ideas MEDAC - Room Vienna Evolving concepts in the management of male LUTS/BPH RECORDATI SPA - Room London
European Urology Today
By Joel Vega The Joint EAU-Confederacion Americana de Urologia (CAU) meeting tackled a range of so-called ‘hot’ urology issues with topics ranging from female stress urinary incontinence, imaging in prostate cancer, surgical techniques in bladder and kidney tumours to challenges in conducting randomized trials. EAU Sec. General Chris Chapple gave a state-of-the-art lecture on managing female Stress Urinary Incontinence (SUI) wherein he presented an overview of the medical and surgical options in recent years to manage SUI in female patients. He highlighted the need for surgeons to carefully look into the complications of surgical interventions.
Although it is not a surprise that chemotherapy works in PCa, it is rather startling that it took 50 years to realize this, Tombal pointed out. As the average response rate to hormone therapy is no more than one year combined with the heterogenity of the patients, there is a clear need for better treatment options. “It is only natural to put forward what works in castration resistant PCa (CRPC),” Tombal said. Chemotherapy has shown to be effective in patients with newly diagnosed PCa, showing major benefits which are unprecedented.
Coordination and Editing J. Vega Onsite Reporting and Editing Team J. Bloemberg L. Keizer C. de Koning T. Parkhill J. Vega
Ritter won the award for his study titled “The Uro Dyna-CT Enables Three-dimensional Planned Laser-guided Complex Punctures” published in the November 2015 edition of the European Urology. M. Ritter
“The ESUI Vision Award aims to highlight the most innovative imaging study published in urology during the last year. We are happy to encourage urology researcher and specialists in their endeavor to come up with innovations,” said ESUI Chair Dr. Jochen Walz. The study explores the feasibility of a 3D planned laser-guided approach for urological punctures using the Uro Dyna-CT. Ritter and his colleagues also showed a successful puncture in 24 out of 27 patients without any severe complications. The ESUI jury cited the study’s innovative imaging tool and its use in clinical practice by employing complex 3D navigational procedures. The technique has great potential for urology, according to the ESUI. Formally granted today during the ESUI meeting, the award was supported by an unrestricted grant of 1,500 euros from Invivo Corporation’ producer of UroNav. Previous Vision Award recipients were V. Pasoglou (2015), F. Cornelis (2014), F. Lecouvet (2013), F. Farag (2012) and A. Briganti (2011).
Concerns about toxicity are unnecessary as the effects are absolutely acceptable. “Anybody who is fit for chemotherapy should be informed about the results of the recent studies and the possibility early chemotherapy could offer to the individual patient,” explained Tombal. A quick real-life check revealed that the vast majority of attendees of this session was in favor of early inclusion of early chemotherapy in their practice. Asked regarding the timing on when early chemotherapy ideally would be introduced, Tombal emphasized that he would limit its use to patients with newly diagnosed metastatic PcA. Another step back into history before moving to the present day and beyond was examined by Dr. L. Albiges (Villejuif) who discussed immunotherapy in metastatic renal cell carcinoma (mRCC). She said that while overall survival (OS) now ranges between 8-43 months with a median of 23 months, there is still a
long way to go which might be aided by two new drugs - nivolumab and cabozantinib – for use in second and third lines. Nivolumab, which was already approved for lung cancer and melanoma, recently received approval for mRCC and has shown an OS of 25 months compared to 19.6 months with everolimus. “Most agents for mRCC are approved on the basis of progression free survival (PFS), whereas nivolumab clearly shows an OS benefit of more than 5 months”, said Albiges. She illustrated the effect of nivolumab by presenting a case of a mRCC patient who had disease progression despite sunitinib and sorafenib. The patient was enrolled in the aforementioned study comparing nivolumab and everolimus and received nivolumab 3 mg/kg every 2 weeks. “After 2 months of treatment, he was showing very nice results and achieved complete remission (CR) after 18 weeks which was still the case at 32 weeks”, she explained.
Full-day History Congress draws large audience
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What made the 6th International Congress unique was the often first-hand accounts given by veteran speakers like Prof. Claude Schulman (Brussels, BE), Mr. John Pryor (London, GB) and Prof. Christian Chaussy (Regensburg, DE). Their reflections on their experiences working with Willy Gregoir, in the burgeoning field of Andrology or on their own innovations in ESWL respectively made for an unforgettable afternoon. Organisers were also most pleased with the participation of speakers from as far away as Egypt, Argentina and China. Each presented unique insights from the medical history of their respective countries, in some cases decidedly longer histories than others. Also in attendance and chairing the session on Politics and Urology was another former EAU Secretary General: Prof. Per-Anders Abrahamsson. He made his return to the Annual EAU Congress after being succeeded by Prof. Chris Chapple in
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The EAU Section of Urological Imaging (ESUI) granted the sixth ESUI Vision Award to Manuel Ritter of the Department of Urology at the University Medical Center Mannhein in Germany.
Early PCa treatment and new mRCC options Prostate cancer (PCa) took center stage during the Joint Session of the European Association of Urology (EAU) and the Japanese Urological Association (JUE), and highlighting the topic was completely justified according to Prof. B. Tombal (BE) considering that despite intensive screening metastatic PCa is still a major problem.
Founding Editor Prof. F. Debruyne, Nijmegen (NL)
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Jens Rassweiler enumerated the benefits of the Avicenna Roboflex and said it improves ergonomy and provides more dexterity than the human hand. “Besides offering fine movement, the Roboflex is steerable at the console,” he said whilst noting the procedure may decrease costs by extending the lifetime of a flexible scope and reduces the number of second sessions. “I believe this is the future of flexible ureterorenoscopy,” said Rassweiler referring to the Avicenna Roboflex.
Mark Emberton discussed the issue of conducting randomized trials in prostate cancer research and spoke on the challenges often encountered by “Regarding the future, we can expect future surgical researchers. “We need a cheaper and more scalable procedures to be characterized by less material load method of randomization in surgery. And the cohort such as light or ultra-light mesh materials with embedded RCT has many desirable attributes. In its improved elasticity and larger pores,” Chapple said in ultimate form, it is a partnership between patient and a full session. healthcare personnel and designed to accumulate J. Angelo Cuesta discussed epigenetic and new markets knowledge efficiently,” said Emberton in his for personalized medicine and among his conclusions concluding remarks. are that in the future methylation signatures will be Jochen Walz examined the role of Magnetic Resonance useful in the follow-up and prediction of responses to different types of therapies. “Hypermethylation profiles Imaging in the diagnosing prostate cancer and its role can also predict prognosis in patients with cancer, but in repeat biopsies. “MRI increases the detection rate in most of the potential markers identified have not been the repeat biopsy setting, and also characterizes disease better with targeted biopsies. But validated yet in a clinical setting, prospectively,” he standardisation and quality assurance are key to said. render it useful,” said Walz. Joan Palou spoke on managing complications in The session was chaired by Prof. Hein van Poppel (BE) robot-assisted radical cystectomy (RARC). “Robotwho spoke on partial nephrectomy, and Professors assisted radical cystectomy is not bad and is probably better than open. For surgeons, RARC is also easier to Dávila Barrios (VE) and Villavencencio Mavrich (ES).
By Constance de Koning 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)
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.
learn than laparoscopic procedures since the surgeon is more relaxed than in open and laparoscopic procedures,” he added.
Urology Beyond Europe: Japan-EAU meeting tackles PCa treatment
Editor-in-Chief Prof. M. Wirth, Dresden (DE)
Disclaimer
Ritter receives Vision Award
Madrid last year. “I am happy to co-chair this session at the History Congress, now that I myself have become a person of history”, he quipped. The Politics and Urology session, the second of four, included Dr. Mike Moran, curator of the AUA’s William Didusch Center for Urologic History in Baltimore (US). His talk on the American Civil War delved into some 19th century urology-related procedures on the American battlefields, as well as touching upon the Historian’s plight of having to rely on centuries-old documentation which might not answer the modern-day questions. Away from the spotlights of hard science elsewhere at EAU16, many speakers told personal anecdotes and shared insights from their many decades of experience. Prof. Jerzy Gajewski (Halifax, CA) kept it light after his detailed history on the Canadian Urological Association, ending with a quote from Leo Tolstoy: “Historians are like deaf people who go on answering questions that no one has asked them.”
At its peak, over 200 delegates with different backgrounds attended the 6th International Congress on the History of Urology
Saturday, 12 March 2016
African urologists face chronic challenges EAU joint meetings with Africa and Iran yield insights By Tom Parkhill and Constance de Koning Pan African Urological Surgeons Association (PAUSA) represents urology in the whole African continent, which means addressing patient care in a vast range of settings and significantly different cultures. The EAU yesterday hosted a joint session with PAUSA, “Update on Uro-Oncology, functional, and reconstructive urology.” PAUSA was represented by their president, E. Oluwabunmi Olapade-Olaopa (Nigeria), who co-chaired with David Castro-Diaz (ES). In general the African medical environment is less cash-rich than in Europe or North America. Said Prof. Olapade-Olaopa, who works in Nigeria’s third largest city, Ibadan, as he described some of the practical issues his department faces. “In Ibadan we have the largest urology department in West Africa, with five consultants. But there are only 130 urologists in the whole of Nigeria, which has a population of 170 million. What this means is that small changes to procedures can make a huge difference to practice: little things do matter a lot, and
in our work we have to balance more advanced urology with practical and financial realities.”
for muscle invasive bladder cancer (MIBC) were extensively discussed.
Castro Diaz pointed out: “Prostate cancer seems to be more common in Africans than in Europeans in general. We also find that in Africans it tends to be more aggressive, so there have been arguments for screening. But for that you need to have the infrastructure to treat the increased number of cases, so at present it can’t really be justified.” He also quoted from Dr. A Takure’s (NG) talk on bladder cancer, pointing out how increasing industrialization and a dropping rate of schistosomiases had led to transitional cell bladder cancer rates increasing, while rates of squamous cell bladder cancer are dropping.
“The key variable driving surgical and postsurgical outcomes is the skill and experience of the surgeon or surgical team, regardless of whether or not robot assistance is used,” said Prof. Walter Artibani (IT), one of the speakers at the joint session. Regarding new surgical options, he mentioned that reports of complications after radical cystectomy (RC) and urinary reconstruction would benefit from using standardized criteria. They should also be assessed from the intraoperative period until at least three months postoperatively with a meticulous follow-up, including complications which occur outside of the home institution.
EAU Secretary General Chris Chapple, while reviewing the state of urethroplasty, took time to thank PAUSA and Prof. Olapade-Olaopa. “We’re really pleased with a good session, and we want to continue to develop good links with PAUSA.” Meanwhile, at the joint EAU- Iranian Urological Association (IUA) meeting, new treatment options in surgery, chemotherapy and trimodality therapy (TMT)
Differences between RARC and ORC are the rates of estimated blood loss (EBL) during surgery and the need for transfusions which are lower in RARC. Extended and highly extended robotic lymph node dissections (LNDs) are feasible and should be performed, even though they add to overall operative time. The same applies to nerve-sparing procedures - whether RARC or ORC - which may result in more favorable functional outcomes and should be pursued in appropriate patients.
Hospital costs of RARC appear to be significantly higher than for ORC, although a complete accounting of costs associated with these surgeries has not been completed. Therefore, well-controlled cost-effectiveness studies are urgently needed; the preferred method of cost analysis is quality-adjusted life expectancy in relation to With regards overall complication rates, robot-assisted total costs of treatment, and an incremental cost-effecradical cystectomy (RARC) and open radical cystectomy tiveness ratio is used as the key outcome measure. (ORC) are comparable in terms of overall complication rates, rates of positive surgical margins (PSMs), lymph When discussing chemotherapy, Artibani emphasized that the meta-analysis on adjuvant chemotherapy node yields (LNYs), and intermediate- term oncologic which featured randomized trials - faced a number of outcomes. Artibani: “The lack of longer term studies limitations, including various definitions of diseaselimits the ability to assess the cancer-specific free survival (DFS). outcomes following RARC at 10 year follow-up.”
Day 1 Awards Gallery
Prof. Chapple awards Prof. Artibani with the EAU Willy Gregoir Medal
Prof. Teillac receives the EAU Frans Debruyne Life Time Achievement Award
Prof. Gil-Vernet Vila receives the EAU Innovators in Urology Award from Prof. Chapple
Prof. Briganti receives the EAU Crystal Matula Award from Prof. Chapple and Mr. Ellacott from LABORIE
Congress news. . . . . . . . . . . . . . . . . . . . . . . . 1 Congress highlights . . . . . . . . . . . . . . . . . . 2/3 ESWL: A shocking change in urology . . . . . . . 4 Fluid intake and preventing recurrent urinary stones . . . . . . . . . . . . . . . . . . . . . . . . 5
Prof. Gundeti accepts the EAU Hans Marberger Award from Prof. Chapple and Mrs. Storz from KARL STORZ
Prof. Culig accepts the EAU Prostate Cancer Research Award on behalf of Prof. Pencik from Prof. Chapple and Prof. Schröder from FHS FOUNDATION
Prof. Chapple congratulates P-A. Abrahamsson with his EAU Honorary Membership
Primary hypospadias in adults: Tips and tricks . . . . . . . . . . . . . . . . . . . . . . . . 7 Pelvic floor disorders in women. . . . . . . . . . . 8 Percutaneous renal surgery . . . . . . . . . . . . . . 9 What do urologists expect from nephrologists?. . . . . . . . . . . . . . . . . . . . . . . . 11 Cryoablation for small renal mass . . . . . . . . 12 Urinary diversions and infective complications. . . . . . . . . . . . . . . . . . . . . . . . 13 Lower urinary tract function and urogenital infections. . . . . . . . . . . . . . . . . . . 14 Anterior urethra reconstruction: Tips and tricks . . . . . . . . . . . . . . . . . . . . . . . 15
Prof. Chapple congratulates J. Hosseini with his EAU Honorary Membership
Prof. Chapple congratulates G. Janetschek with his EAU Honorary Membership
Prof. Chapple congratulates M. Marberger with his EAU Honorary Membership
Medically induced stone passage: Are the EAU guidelines wrong. . . . . . . . . . . 18 Renal tumour biopsy: Is it really established. . . . . . . . . . . . . . . . . . 19 Treatment options for oligometastatic bladder cancer. . . . . . . . . . . . . . . . . . . . . . . 20 Neobladder formation . . . . . . . . . . . . . . . . . 22 Metastatic renal cell carcinoma . . . . . . . . . . 25 EAUN launches update of MEC guidelines. . . 27 The prehistoric penis . . . . . . . . . . . . . . . . . . 29 Kidney sparing surgery for Upper Tract Urothelial Cancer. . . . . . . . . . . . . . . . . . . . . 30
Prof. Chapple congratulates K. Parsons with his EAU Honorary Membership
Saturday, 12 March 2016
Prof. Chapple congratulates Y. Sun with his EAU Honorary Membership
Prof. Chapple congratulates V. Tkachuk with his EAU Honorary Membership
Percutaneous nephrolithotripsy can be effective in every case. . . . . . . . . . . . 31
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ESWL - a shocking change in urology The lasting impact of ESWL on open surgery for stone removal Prof. Christian G. Chaussy Professor of Urology University of Regensburg, Germany Clinical Professor of Urology Keck School of Medicine, USC, USA Strasslach (DE) Urolithiasis is – with a prevalence of 2% to 3 % - one of the most frequent diseases worldwide and in the industrialized countries the frequency is still growing. The introduction of Extracorporeal Shockwave Lithotripsy (ESWL), which is the fragmentation of urinary stones by extracorporeal means, has therefore become a medical milestone and a revolution in urology. Initial research for this method started 15 years before the first patient with kidney stone was treated on 7 February 1980. In airplane and aerospace technology, the interaction of shockwaves with solid bodies, such as the impact of raindrops or micrometeorites on flying objects, are of great interest in order to clarify the damage mechanisms on aircraft structures. To research these impacts, high speed projectiles, which produce shock waves that imitated micrometeorites, have been shot at a target. In following experiments with shock waves, created by high-speed water drops, it was proven that it was possible to destruct kidney stones. Shortly after, physicists of Dornier were able to fragment kidney stones in an open water bath, using shockwaves generated with a light-gas gun. The first experimental phase of researching the in vivo and in vitro effects of shockwaves was planned and conducted in 1974 by Ch. Chaussy, F. Eisenberger, B. Forssmann and W. Hepp. The idea was to destroy a kidney stone with just one extracorporeal shockwave exposure. What is important for the result was that the shock wave source, through its location in a semi-ellipsoid, allowed a certain shock wave concentration on the kidney stone. Generation of shockwaves through underwater spark discharge with water as the transmitter promised to provide the ideal acoustical interface into the human body. Irritating and harmful reflexions at the tissue entry point could practically be excluded. Positive results After the first positive results of generating and optimizing the focusing of shock waves in the water bath it was only a short time till the first Shock Wave Lithotripter was planned and built. It was possible to place experimental objects for in vitro or in vivo experiments, via membrane or water bath, in the device. In the water bath, kidney stones, placed in the focal area, could be fractured under sight and without any problems with one impact of high energy shock waves. The first ideas of the destruction mechanism had been developed. The main factors seemed to be the shear forces at the shock wave entrance point and the tear forces at the shock wave exit point, as well as the super imposition of tear and shear forces within the stone caused by focusing effects of the shock wave. Even after repeated shock wave exposure within the shock wave focus there was no negative impact on Erythrocytes or the proliferate process of mixed lymphocyte cultures. Beginning in 1975 the studies with small animals started. In these experiments, neither in eventerated organs nor in the water bath macroscopic or microscopic relevant pathological changes could be detected - even after multiple exposures. Exception was only the lung where severe tissue lesions were found because of the multiple air-tissue interface. This was somehow expected because of the different impedance levels in lung tissue. However, we learned that it was possible to avoid these lesions by interposition of protecting materials (i.e. Styrofoam). The main topic of further research was the fragmentation of urinary stones in dogs and their necessary localisation within the body. For these experiments freshly harvested human kidney stones were implanted in operatively dilated calyceal systems of dogs. Afterwards undisturbed urine flow was 4
EUT Congress News
restored. A further necessity in this stage of research was the solution of technical/material problems experienced with the underwater spark discharge and the reproducibility of shockwave generation.
Due to the previously mentioned difficulties of localisation with ultrasound we had to apply for the integration of an X-ray system for stone localisation. In a lab study it was possible to prove that with two independent, two-plane optical systems a three dimensional localisation was possible. Now, the necessary high financial support by the Ministry of Research and Technology was granted for the development of the TM4, Fig. 3: HM 1 in Munich: First worldwide ESWL treatment on Feb. 7th, 1980 an experimental device with integrated x-ray system. clinical results were accepted and published in Succeeding experiments Lancet. Interestingly, the AUA rejected a submitted Localisation with the integrated three-dimensional presentation about the results. However, one year x-ray system was reproducible; however after shock later, ESWL as a topic gained sufficient trust and was wave exposition there were larger not dischargeable accepted and another nine years later the AUA fragments scattered over the calyceal system. Only the presented Ch. Chaussy, F. Eisenberger and E. Schmiedt Fig. 1: Forssmann – Eisenberger – Chaussy (from left) at one of use of less energetic shockwaves with impulse series with the “Distinguished Contribution Award.” the first experimental devices of up to 500 single shots/sec led to a dischargeable fragment size. The energy dose for a complete Now it was possible to extend the indications to the fragmentation was surprisingly less than with the treatment of ureter and partial staghorn stones. A significant element for this optimization was the high energy method. Strain on the kidney either Contraindications, which are still valid today, have striation optic experiments to focus with brass through the shock wave or through scattered been defined. First treatments were performed in ITN; ellipsoids in different dimensions. This led to a more concrement particles was clearly reduced. With the fortunately, it soon became evident that peridural efficient shock wave generation for further animal new experimental setup the reproducible destruction anaesthesia was sufficient. In a first clinical study 206 experiments. Influence of tissue-caused attenuation of kidney stones in one or two sessions with patients were treated, under strict selection criteria, within the path of the shock wave was gained from consecutive spontaneous discharge was possible. with extra corporeal produced shock waves – later the experimental data, and the effect of the kinetic that year the method was named “ESWL” or energy of the fragments was determined from high An impediment of the kidney function through shock Extracorporeal Shock Wave Lithotripsy. speed pictures in order to exclude eventual damage wave exposition was excluded by nuclear-medical of the calyceal system. methods and repeated lab tests. Neither macroscopic The study showed that there were no serious observation nor histology of the organs from complications, neither through the treatment itself Diagnostic ultrasound experimental animals showed impairments that nor through the discharge of the debris. High expectations to improve the localisation of would hinder the further development of the method. Conservatively, treatable colic or pain was in some concrements were raised by the new diagnostic Results of these experimental series provided the cases caused by the fragment discharge. None of the ultrasound. In a new developed experimental setup a prerequisites which justified the human application. patients had to undergo emergency surgery. The new, further improved, shock wave generator was follow-ups, up to one year after ESWL, showed no tested and an ultrasound A-scan integrated in the At this point the development of the first clinical significant biochemical changes in blood or urine. ellipsoid. prototype of a lithotripter (HM1) started. Technical Nuclear isotope studies performed on these patients tests, as they are standard requirements nowadays, did not show any alterations of renal function after Because of problems with the ultrasound A-Scan, in were not performed at that time. Even though ESWL. Further clinical routine prompted the need for vivo fragmentation of concrements was only possible technical security experts tested the device, they did technological advances such as improvements in in exceptions, even after positive in vitro tests in the not take the responsibility and declined an expertise shock wave generation, optimisation of the X-ray water bath. Hence the funding ministry lost trust in for the HM1 regarding the security risk of the electrical system and adaptation of the patient support for the project and threatened to stop the support. spark gap with the patient immersed in the water possible emergency situations. These modifications bath; therefore the research team had to take full were tested in the HM1 and verified in the HM2. By chance and just in time for the shortly following responsibility for the clinical application. reviewer’s committee, it was possible to break On 20 May 1982 the first lithotripsy center was down an implanted kidney stone into several On 7 February 1980 Ch. Chaussy, B. Forssmann and D. launched in Munich under the supervision of Ch. fragments. This was the success urgently needed to Jocham treated worldwide the first patient suffering Chaussy at the Department of Urology (E.Schmiedt), gain further financial support. Also the localisation with the fourth recurrence of a renal pelvic stone. The University of Munich. With this set up fast and further through Ultrasound B-Scan with the - then treatment was performed in ITN. The stone was clinical evaluation of the extension of indications was available - compound scanners in an advanced successfully disintegrated into spontaneously possible. The data and success of ESWL sparked an experimental setup did not allow a definite dischargeable fragments. The follow-up showed the enormous interest in Germany and worldwide. In 1983 localisation of concrements, but it showed the passage of the fragments without any significant the second Lithotripsy Center was opened in Stuttgart organ boundaries. problems. During the first patient treatments (F. Eisenberger ) unexpected problems occurred through the induction Now it was at least possible to research the effects of of extrasystoles by shock waves. This phenomenon Clinics in the US systemic shock wave exposures with high energy was later avoided by the introduction of ECG A Food and Drug Administration (FDA) study, shock waves on kidney parenchyma in a series with triggering of the shock wave impulse. Until today the necessary for approval of ESWL in the US, was dogs without kidney stones. Histology showed neither induction of extrasystoles by shock waves is still not planned at six centers. In spite of the great interest systemic nor pathological side effects on the kidney or understood. displayed by radiologists, it was possible to keep the adjacent organs. However, stone fragmentation was procedure in the hands of urologists. The main reason still not possible because of localisation problems Gaining acceptance was that all principal investigators had to be trained with the then available ultrasound. Motivated by the first successful treatments we in Munich and the Munich urologists refused to train proceeded routinely. Already in December, the first radiologists. Stone destruction could only be achieved by a raster application of up to 20 high energy shockwaves in the The first device in the US was installed in February area where the concrement was suspected. With this 1984 in Indianapolis (D. Newman, J. Lingeman); five method, first in vivo stone destructions of implanted other clinics followed. The US FDA study was human stones through extracorporeal produced shock monitored by G. Drach. Due to the method’s success, waves were possible. In most cases the implanted the PMA was granted for general marketing already in stones were fragmented, however, larger not December 1984. This fast decision was mainly due to dischargeable pieces remained. the acceptance of the Munich data. These played a significant role because the results of the US study Accordingly, the principal possibility of the method were not published until two years later. was proven; but under consideration of the then available ultrasound guided localisation systems it In summary, the introduction of Extracorporeal Shock was still a long way until its clinical application. In Wave Lithotripsy has become a medical milestone and the meantime, method and available results were a revolution in urology worldwide. With the presented for the first time during a symposium in acceptance and propagation of ESWL, open surgical Meersburg with the attendance of the Secretary for removal of urinary stones lost its place in urology. Research and Technology. This was more for political than scientific reasons to show the Friday, 11 March feasibility of the method. Finally, the funding for the 08.30-16.15: The 6th International Congress on Fig. 2: TM4 – experimental Lithotripter with X-ray locating project by the Ministry of Research and Technology the History of Urology system proceeded. Saturday, 12 March 2016
Is any special beverage likely to matter apart from water? Adequate fluid intake is crucial in preventing recurrent urinary stone formation
The supersaturation of urine with the stone-forming salt is a prerequisite for the necessary precipitation. A high fluid intake increases urine volume and reduces the risk of stone formation by lowering urinary activity product ratio (supersaturation) of stone-forming constituents1.
The bicarbonate content of mineral water can replace alkalization therapy with potassium citrate and contribute to urine inhibitory power by increasing urinary pH and citrate excretion9,10. A study in healthy subjects under standardized conditions revealed a significant and persistent increase in 24h urinary pH from 6.10 to 6.59 and citrate excretion from 3.045 to 4.554 mmol/24h after the intake of a mineral water containing 3,388 mg/l bicarbonate (Figure 1)10. During intake of the bicarbonate-rich mineral water, urinary pH values were significantly higher in each urine fraction compared to the control fractions (Figure 2).
Urine volume A low urine volume is one of the most important risk factors for urinary stone formation. An adequate fluid intake is therefore an essential measure for the prevention of recurrent urinary stone formation, irrespective of stone composition. According to the Guidelines on Urolithiasis of the European Association of Urology (2015), the aim should be to obtain a 24h Figure 1: Urinary pH and citrate excretion before (control) and urine volume of at least 2.5 litres2. after receiving mineral water (M ± SEM; * P < 0.05) A randomized controlled trial in idiopathic calcium oxalate stone formers assigned participants either to increase fluid intake to maintain urine volume of greater than 2 l/d or to receive no treatment3. During the five-year follow-up period, patients in the intervention group had significantly higher urine volumes, a 50% lower recurrence rate, and a longer time to first recurrence. Data from large observational studies repeatedly confirmed the inverse relationship between high fluid intake and the risk of stone formation in both men and women4,5. A systematic review of 28 randomized controlled trials revealed that increased fluid intake substantially reduced the risk for recurrent calcium stones6. Urine pH and citrate excretion Urinary pH is an important factor that triggers the formation of various types of stones in the urinary tract. An acidic urinary pH affects the solubility of uric acid and cystine, and promotes crystallization of the stone-forming components. The solubility of uric acid and cystine increases with a pH above 6.5 and 7.5, respectively. The dissolution of uric acid stones can be attained by urine alkalization at a pH of 7.0 to 7.27.
Figure 2: Diurnal variation in urinary pH during a 24 h period before and after receiving mineral water (* P < 0.05)
A randomized cross-over study in healthy individuals examined the effect of a bicarbonate-rich mineral water compared to a potassium citrate preparation on urine composition9. The intake of 2 l/d of the mineral water containing 1,715 mg/l bicarbonate resulted in a significant increase in urinary pH from 6.06 to 6.68 and citrate excretion from 2.677 to 3.103 mmol/24h. The effect of the bicarbonate-rich mineral water on urinary pH and citrate excretion was similar to that of potassium citrate, which was administered in equimolar concentration with respect to the alkali load (Figure 3). A double-blind cross-over study in 34 recurrent calcium oxalate stone formers compared the effect of a bicarbonate-rich mineral water with a water low in bicarbonate on urinary pH. During intake of 1.5 l/d of the bicarbonate-rich mineral water, a significant increase in urinary pH from 5.9 to 6.7 was observed11.
be diluted with water before ingestion. Moreover, certain vegetable juices contain high oxalate concentrations18.
Adequate fluid intake A low urine volume is one of the most important risk factors for urinary stone formation. An adequate fluid intake, to achieve a urine volume of at least 2.5 l/24h, is the most important dietary measure for the prevention of recurrent urinary stone formation, irrespective of stone composition. Favourable changes in urine composition can be attained by special beverages. Beverage should be carefully selected. Although mineral water has been suggested to be a Studies on the association between soda consumption suitable beverage for urine dilution, the water and the risk of stone formation have likewise provided composition has to be taken into account. The conflicting results. Assessing the data from two cohort bicarbonate content of mineral water can replace trials, the intake of soda, including sugared cola, was alkalization therapy with potassium citrate and not associated with increased risk for stone contribute to urine inhibitory power by increasing urinary pH and citrate excretion. formation15,16 while results from three cohort studies revealed a higher risk of stone formation associated with consumption of sugar-sweetened cola14. The effect of fruit juices on urine composition is mainly determined by the presence of citrate. Citrus Recommendations for stone formers juices are rich sources of citrate. However, RCTs are A sufficient circadian fluid intake by suitable lacking and data from interventional and cohort beverages is one of the most effective nutritional studies on the effect of different types of fruit juices on measures irrespective of stone composition or the the risk of urinary stone formation are conflicting. cause of stone formation. An adequate urine dilution Caffeinated coffee, black and green teas are less is an important goal to reduce urinary supersaturation suitable for urine dilution. Alcoholic beverages, with lithogenic substances and to decrease the risk for including beer, and soft drinks, including cola, are stone formation. Depending on the environmental unsuitable for recurrence prevention of urolithiasis. temperature and the degree of physical activity, it is usually necessary to drink at least 2.5 l/day to achieve References the recommended 24h urine volume7. The fluid intake 1. Pak CYC, Sakhaee K, Crowther C, Brinkley L (1980) should be evenly distributed over the day. Evidence justifying a high fluid intake in treatment of It is particularly important to drink before going to bed at night to avoid increased urine concentration during the sleeping period. Patients with severe stone disease should be encouraged to have nocturia at least once per night. Patients exposed to chronic dehydration, caused by hot and/or dry environments, extensive physical activity or diarrhea, are recommended to replace extrarenal fluid losses.
Hypocitraturia is an important risk factor for calcium oxalate urolithiasis. The amount of urinary citrate is mainly influenced by variations in the fraction of reabsorption. Changes in acid-base balance are the major determinants of urinary excretion of citrate. Ingested citrate is absorbed in the intestine and nearly completely metabolized to bicarbonate, providing an alkali load, which in turn increases urinary pH and citrate excretion8. Thus, the effect of beverages on urinary pH and citrate excretion is mainly determined by the presence of bicarbonate and citrate, respectively. Fruit juices The effect of fruit juices is mainly determined by the presence of citrate. Citrus juices are rich sources of Mineral water citric acid and potassium. Dietary citrate is absorbed Although mineral water has been suggested to be a in the intestine and nearly completely metabolized to suitable beverage for urine dilution, the water bicarbonate. Bicarbonate can raise urinary pH and increase citrate excretion. Intracellular citrate is a Table 1: Recommendations for fluid intake17 central component of the Krebs cycle and provides the major part of the excreted citrate8. The amount of Neutral beverages urinary citrate is determined by reabsorption. • mineral water with low content of Approximately 65 to 90% of the citrate filtered by the bicarbonate, calcium and sulfate renal glomeruli is reabsorbed by the renal tubules. • tap water (cave: pay attention to sterility of Changes in acid-base homeostasis appear to be the drinking water) major physiologic determinant of proximale tubule • herbal tea, fruit tea, kidney tea, bladder tea reabsorption and urinary excretion of citrate. With • some fruit juices, e.g. apple juice alkali loads, urinary citrate excretion increases8. Alkalizing beverages However, data from observational and interventional • mineral water with high bicarbonate content studies on the effect of different types of fruit juices on (at least 1,500 mg HCO3ˉ/l) the risk of urinary stone formation are conflicting. The • citrus juices (e.g. orange, lemon, grapefruit inconsistent results could be explained by differences juice) in the populations and the dosing of potassium and citric acid. Analysis of the citric acid concentration of Unsuitable beverages various fruit juices revealed a higher citric acid • black tea, green tea content of lemon and lime juice, both from the fresh • caffeinated coffee (max. 500 ml/d) fruit and from juice concentrates, than orange juice • sugar-sweetened soft drinks, including cola from the fresh fruit and orange juice, grapefruit juice • alcoholic beverages, including beer and lemonade from ready-to-consume12. Saturday, 12 March 2016
Soft drinks, coffee and tea Since stone formers are advised to increase their intake of fluid, studies were undertaken to determine the effect of soft drink and coffee consumption on the risk of stone formation. However, data from clinical and epidemiological studies on the effect of different types of beverages on the risk of urinary stone formation are inconsistent. Whereas an interventional trial demonstrated an increased urinary calcium/ creatinine ratio and an elevated Tiselius risk index after caffeine loading13, a prospective study found that coffee consumption was associated with a lower risk of stone formation14.
The type of beverage should be carefully selected (Table 1). If the stone composition is unknown, neutral beverages should be preferred. Neutral beverages, that are fluids which dilute urine without affecting its composition, include tap water, mineral water with a low mineral content, fruit and herbal teas. Less suitable beverages are caffeinated coffee and black or green tea. Alcoholic beverages and sugar-sweetened soft drinks are unsuitable for stone formers. Fluids which additionally increase urinary pH and citrate excretion are bicarbonate-rich mineral water and citrus juices, for example orange and lemon juice. Neutral and alkalizing beverages are suitable for the recurrence prevention of the majority of urinary stones that are calcium oxalate, uric acid and cystine17. The calculation of the relative supersaturation of calcium oxalate suggests that bicarbonate-rich water can be an effective treatment option for the nutritional therapy of calcium oxalate stone disease (Figure 4). It should be emphasized that fruit juices have a considerable content of energy and should therefore
Figure 3: Urinary pH before (control) and after receiving mineral water or alkali citrate (M ± SEM; * P < 0.05) Figure 1
5
5
4
4
3
3
*
*
2
2
1
0
RS CaOx
The biomineralization process resulting in a urinary stone has a multifactorial origin in which genetic, constitutional factors, metabolic abnormalities as well as diet and lifestyle might act in concert.
composition has to be taken into account. Bicarbonate (HCO3ˉ) is a natural component of mineral water. Renal tubular H+ excretion is always coupled with the reabsorption of filtered HCO3ˉ. The ingestion of HCO3ˉ therefore increases buffering capacity of the organism and has a strong alkalizing effect.
RS CaOx
Prof. Dr. Roswitha Siener University Stone Centre Department of Urology University of Bonn Bonn (DE)
1
Control
Mineral Water
Control
Alkali Citrate
0
Figure 4: Relative supersaturation of calcium oxalate (RS CaOx) before (control) and after receiving mineral water or alkali citrate (M ± SEM; * P < 0.05)
nephrolithiasis. Ann Intern Med 93:36-39 2. Skolarikos A, Straub M, Knoll T, Sarica K, Seitz C, Petrik A, Türk C (2015) Metabolic evaluation and recurrence prevention for urinary stone patients: EAU Guidelines. Eur Urol 67: 750-763 3. Borghi L, Meschi T, Amato F, Briganti A, Novarini A, Giannini A (1996) Urinary volume, water and recurrences in idiopathic calcium nephrolithiasis: a 5-year randomized prospective study. J Urol 155: 839-843 4. Curhan GC, Willett WC, Knight EL, Stampfer MJ (2004) Dietary factors and the risk of incident kidney stones in younger women. Arch Intern Med 164: 885-891 5. Taylor EN, Stampfer MJ, Curhan GC (2004) Dietary factors and the risk of incident kidney stones in men: new insights after 14 years of follow-up. J Am Soc Nephrol 15: 3225-3232 6. Fink HA, Wilt TJ, Eidman KE, Garimella PS, MacDonald R, Rutks IR, Brasure M, Kane RL, Ouellette J, Monga M (2013) Medical management to prevent recurrent nephrolithiasis in adults: a systematic review for an American College of Physicians clinical guideline. Ann Intern Med 158:535-543 7. Hesse A, Tiselius HG, Siener R, Hoppe B (2009) Urinary stones: Diagnosis, treatment, and prevention of recurrence. Karger, Basel 8. Hamm LL, Hering-Smith KS (2002) Pathophysiology of hypocitraturic nephrolithiasis. Endocrinol Metab Clin N Am 31:885-893 9. Keßler T, Hesse A (2000) Cross-over study of the influence of bicarbonate-rich mineral water on urinary composition in comparison with sodium potassium citrate in healthy male subjects. Brit J Nutr 84: 865-871 10. Siener R, Jahnen A, Hesse A (2004) Influence of a mineral water rich in calcium, magnesium and bicarbonate on urine composition and the risk of calcium oxalate crystallization. Eur J Clin Nutr 58: 270-276 11. Karagülle O, Smorag U, Candir F, Gundermann G, Jonas U, Becker AJ, Gehrke A, Gutenbrunner C (2007) Clinical study on the effect of mineral waters containing bicarbonate on the risk of urinary stone formation in patients with multiepisodes of CaOx-urolithiasis. World J Urol 25:315-323 12. Penniston KL, Nakada SY, Holmes RP, Assimos DG (2008) Quantitative assessment of citric acid in lemon juice, lime juice, and commercially-available fruit juice products. J Endourol 22: 567-570 13. Massey LK, Sutton RAL (2004) Acute caffeine effects on urine composition and calcium kidney stone risk in calcium stone formers. J Urol 172: 555-558
Editorial Note: Due to space constraints the reference list has been shortened. Interested readers can request for the complete list by sending an email to communications@uroweb.org. 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?
EUT Congress News
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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
UK
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
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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. Join the 2016 BLADDER CANCER TOPIC OF THE YEAR ANNOUNCEMENT during the IPSEN symposium on Saturday, 12 March 2016 from 6:00–7:30 pm (Room: Paris) by: Professor Maximilian Burger, Regensburg, Germany 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.
Saturday, 12 March 2016
Primary hypospadias in adults: Tips and tricks Techniques for repair do not differ much between adults and children Prof. Dr. Piet Hoebeke Department of Urology Ghent University Hospital Gent (BE)
Dr. Anne-Françoise Spinoit Department of Urology Ghent University Hospital Gent (BE)
Adults presenting with primary non-operated hypospadias seeking surgical correction are rare. Indeed, hypospadias in adults is mostly encountered in older men presenting for Lower Urinary Tract symptoms mostly based on prostatic problems; however these men do not seek surgical correction of hypospadias. Most men asking for reconstruction of adult hypospadias present with minor or distal forms of hypospadias which were either not diagnosed or not corrected. In some rare studies incidence of distal hypospadias in adult men is more than 15 %1. Despite this rather high incidence, the number of manuscripts on adult primary hypospadias repair is rather low2,3. Most men with undiagnosed or untreated hypospadias probably do not seek correction as they probably do not find it necessary to correct a mild anomaly. A recent study analyzed how the penis should look according to lay persons4. The quite interesting results show that laypersons find the position and the shape of the meatus the least important in the aspect of the penis4. Very few studies are available in the literature about primary hypospadias correction in adults: Snodgrass compares outcome in adults and children operated by the same group of surgeons: their complication rate is similar in both groups, with 12.5% complications after primary repair2. This study demonstrates that proximal meatus and reoperation are risk factors for complications2. Pubertal stage, and thus adulthood were not identified as risk factors for complication2. In the study of Hensle the complication rate in a small group of patients with primary repair in adulthood is reported at 37.5 %, which is much higher than what is generally published for complication rates in children3. But this study analyzes a very small group of patients, thereby offering a very low evidence level3. Low-level studies Research on hypospadias repair in general is based on low-level studies6. Most studies are retrospective with short follow-up and non-objective measurements of functional and aesthetic outcome7. For primary repair in adults there is no evidence at all so the recommendations that follow are based on large experience and on literature about urethral reconstruction in adults. The main difference between children and adults presenting with hypospadias consists of changes that happen with puberty. Next to growth of the penis there is also the increased trophicity of the tissues based on increased vascularity with puberty and the more systematic spontaneous erectile function in adults, more specifically nocturnal erections. While better tissue quality should be in favor of wound healing, the nocturnal erections might interfere with good healing as tension is put on the reconstructed tissues. What do these findings imply on the operative technique? The techniques used in adults do not differ from those in children8.Tubulurarized incised plate urethroplasty (TIPU) which is nowadays most popular in children has been shown to be feasible in adults9.10. Other techniques described are meatal advancement and glanuloplasty (MAGPI) and Mathieu repair as well as Tiersch Duplay techniques like GAP-repair. Saturday, 12 March 2016
In a comparative study comparing outcome of urethroplasty after failed hypospadias repair compared to urethroplasty for stricture disease non-related to hypospadias repair, we found a tendency for more complications in hypospadias, however non-significant11. Surgical approaches What logically differs in the surgical approach of hypospadias between children and adults is the size of the suture material, the size of the catheter and the kind and duration of the dressing. For children it is known what is generally used12. Where in children sutures are resorbable and most often 6.0 monofilament or thinner, in adults rather 4.0 sutures are used like in most urethroplasty techniques. The suture material seems to have no result on the outcome and studies on suture size are nonexistent13,14. Catheter size in children is most often 10 French (Fr) where in adults 16 or 18 Fr is more frequently used. As for duration of catheter there is wide variation in children, going from no catheter to two weeks; this information is unknown in adults.
“...no final word is written on primary hypospadias repair in adults. It is common sense to accept that techniques for repair do not differ between adults and children...” Erections logically might interfere with healing and outcome. Prevention of erection has been studied but no single treatment has been found to be effective to prevent nocturnal erections in a postoperative setting15,16. The only way to limit the negative effects of erection on outcome is by using a good postoperative compressive dressing during the night. Where in children most often foam-based or tegaderm-based dressing are used, in adults more often a simple compressive penile dressing is used. In our center we try to keep the primary dressing for at least five days and encourage patients to use a compressive dressing during night for at least three weeks after surgery. In conclusion, no final word is written on primary hypospadias repair in adults. It is common sense to accept that techniques for repair do not differ between adults and children; however sutures, catheters and dressing need to be adapted to the size and the erectile activity of the adult penis. With the increased detection of genital anomalies at a younger age and the advent of microsurgical techniques, virtually most of hypospadias are nowadays diagnosed, and most of them are corrected. Primary adult hypospadias will probably therefore progressively vanish, at least in Western Europe.
Various types of hypospadias
8. Subramaniam R, Spinoit AF, Hoebeke P. Hypospadias repair: an overview of the actual techniques. Seminars in plastic surgery. 2011;25(3):206-12. 9. Adayener C, Akyol I. Distal hypospadias repair in adults: the results of 97 cases. Urologia internationalis. 2006;76(3):247-51. 10. Sharma G. Tubularized-incised plate urethroplasty in adults. BJU Int. 2005;95(3):374-6. 11. Lumen N, Hoebeke P, Deschepper E, Van Laecke E, De Caestecker K, Oosterlinck W. Urethroplasty for failed hypospadias repair: a matched cohort analysis. Journal of pediatric urology. 2011;7(2):170-3. 12. Springer A, Krois W, Horcher E. Trends in hypospadias surgery: results of a worldwide survey. Eur Urol. 2011;60(6):1184-9. Epub 2011/08/30. 13. Cimador M, Castagnetti M, Milazzo M, Sergio M, De Grazia E. Suture materials: do they affect fistula and stricture rates in flap urethroplasties? Urologia internationalis. 2004;73(4):320-4. Epub 2004/12/18.
14. Spinoit AF, Poelaert F, Van Praet C, Groen LA, Van Laecke E, Hoebeke P. Grade of hypospadias is the only factor predicting for re-intervention after primary hypospadias repair: a multivariate analysis from a cohort of 474 patients. J Pediatr Urol. 2015;11(2):70 e1-6. 15. Johansen LV, Kirkeby HJ, Kiil J. Prevention of erection after penile surgery. A double-blind trial of intracavernous noradrenaline versus placebo. Urol Res. 1989;17(6):393-5. 16. DeCastro BJ, Costabile RA, McMann LP, Peterson AC. Oral ketoconazole for prevention of postoperative penile erection: a placebo controlled, randomized, double-blind trial. J Urol. 2008;179(5):1930-2.
Saturday, 12 March 10.15-15.45: Meeting of the EAU Section of Genito-Urinary Reconstructive Surgeons (ESGURS), Uro-genital reconstructive surgery: Personal tips and tricks
UROLOGY CLEARLY DEFINED
References 1. Fichtner J, Filipas D, Mottrie AM, Voges GE, Hohenfellner R. Analysis of meatal location in 500 men: wide variation questions need for meatal advancement in all pediatric anterior hypospadias cases. J Urol. 1995;154(2 Pt 2):833-4. 2. Snodgrass W, Villanueva C, Bush N. Primary and reoperative hypospadias repair in adults--are results different than in children? J Urol. 2014;192(6):1730-3. 3. Hensle TW, Tennenbaum SY, Reiley EA, Pollard J. Hypospadias repair in adults: adventures and misadventures. J Urol. 2001;165(1):77-9. 4. Ruppen-Greeff NK, Weber DM, Gobet R, Landolt MA. What is a Good Looking Penis? How Women Rate the Penile Appearance of Men with Surgically Corrected Hypospadias. The journal of sexual medicine. 2015;12(8):1737-45. Epub 2015/07/21. 5. Bronselaer GA, Schober JM, Meyer-Bahlburg HF, T’Sjoen G, Vlietinck R, Hoebeke PB. Male circumcision decreases penile sensitivity as measured in a large cohort. BJU Int. 2013;111(5):820-7. Epub 2013/02/05. 6. Snodgrass W, Macedo A, Hoebeke P, Mouriquand PD. Hypospadias dilemmas: a round table. J Pediatr Urol. 2011;7(2):145-57. Epub 2011/01/18. 7. Spinoit AF, Poelaert F, Groen LA, Van Laecke E, Hoebeke P. Hypospadias repair at a tertiary care center: long-term followup is mandatory to determine the real complication rate. J Urol. 2013;189(6):2276-81. Epub 2013/01/12.
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Pelvic floor disorders in women Do we still need meshes for correction of pelvic organ prolapse? without mesh. They also stated that the benefit of mesh augmented anterior vaginal wall repair is anatomical and is not associated with Apart from the reinforcement of tissue repairs commercially available mesh kits offer the advantages better results as far as symptoms relief is of “easy” and “fast” repairs. concerned. The above The clearance of the first transvaginal surgical mesh mentioned FDA product designed for pelvic organ prolapse by the Food notifications provoked, as and Drug Administration (FDA) in 2004, was expected, different accompanied by a significant uptake of mesh reactions with some Dr. Konstantinos augmented repairs in the following years. Jonsson Funk urogynecologists Giannitsas et al.10 utilised adjudicated healthcare claims involving abandoning the use of Patras University mesh for POP in the USA from 2005 to 2010 and they mesh while others Hospital Department reported an overall significant increase in vaginal mesh continued using it in Figure 4 of Urology procedures from 36.7 to 60.8 per 100.000 person-years prolapse repairs13,14. Patras (GR) during the study period (Figure 1). What to do now? Reasons for not using a mesh The best way to face this situation of uncertainty is to The most important reason for not using a mesh for critically evaluate it. The first important thing to do is POP repair is complications: these complications can clearly differentiate between SUI and POP surgery and be related either to the procedure of placing the mesh between mesh positioned by the vaginal route and by Pelvic organ prolapse (POP) is an increasingly (such as injuries to the urinary tract, bowel or vessels the abdominal route. The FDA 2014 recommendation common female health problem1 which, when during trocar/introducer placement) or to the to move total vaginal mesh from low- to-moderate symptomatic, has a significant negative impact on all presence of the mesh itself. Among the latter, the risk class to high-risk class specifically excludes mesh aspects of daily life2. Treatment is commonly surgical3 most frequently reported are mesh exposure through when it is used for either stress urinary incontinence and should aim not only at restoring anatomy but the vagina (Figures 2-3), pain, infection and (SUI) or trans-abdominal POP repair such as also at alleviating symptoms, improving long-term dyspareunia. Vaginal scarring/shrinkage and sacrocolpopexy15. This does not imply that mesh used pelvic organ function. emotional problems are less frequently reported. The during sacrocolpopexy or for treatment of SUI is above conditions may require additional intervention devoid of complications but the risk is definitely including medical or surgical treatment and The etiology of POP is multifactorial. The end-result, lower12. nevertheless, is an inadequate pelvic organ support hospitalization. system. Emerging evidence suggests even a genetic Another important point is that although mesh linkage to supporting tissue defects in women with complications may be quite bothersome and difficult POP. The poor condition of these tissues at the time of to treat this is not the rule: about 35% of vaginal surgical intervention provides the rationale for the use mesh exposures are asymptomatic and are found of mesh to reinforce repairs. during follow-up clinical examinations, usually within the first months after surgery. This article will focus on recent evidence on the pros and cons of using synthetic meshes in POP repairs. One key in avoiding transvaginal mesh complications is patient selection after weighing benefits against Reasons for using a mesh risk for an individual patient. But what patientThe rationale behind the use of mesh is to enhance prolapse is the best candidate for mesh augmentation efficacy of prolapse repairs: improve anatomic repair? support and avoid recurrence. In a recent review of the literature Richter et al.4 found that native tissue It is reasonable to use mesh in cases of increased risk repair of the anterior vaginal compartment is Figure 2: Recurrent vaginal mesh exposures after TVM of prolapse recurrence. Factors associated with associated with more recurrent anatomic prolapse recurrence are age less than 60 years, prolapse stage and increased symptomatic bulging compared with 3 or 4, diabetes mellitus and recurrent prolapse16. If mesh is to be used how can the risk of mesh-related vaginal repair using polypropylene mesh. This finding is in agreement with the 2013 Cochrane review5 and is complications be minimised? Known risk factors for further supported by newly published evidence: in a mesh exposure are lack of experience of the surgeon, recent prospective randomised controlled trial6, delayed infection and injury to adjacent tissue17,18. women with stage III or IV anterior vaginal wall Based on the above observations a vaginal approach prolapse were randomised to anterior colporrhaphy with vaginal colposuspension or transvaginal mesh. to prolapse stage at least III, either primary or after recurrence following initial native tissue repair in a Vaginal mesh gave better two-year anatomical results young woman is the best indication of mesh augmentation. General, non-specific measures like than vaginal colposuspension. In another singlepreoperative obesity management, smoking center, randomised, interventional trial of posthysterectomy vaginal vault prolapse7, Prolift Total® cessation, and adequate diabetes control may be was compared to native tissue, unilateral vaginal helpful in reducing the risk for complications. The sacrospinous colpopexy with vaginal repair. On benefit of using local estrogen is unclear and clinical examination at one-year follow-up, only one prevention of perioperative infection with case of anatomical failure was observed in the Prolift Figure 3 prophylacting antibiotics a must, despite the lack of robust evidence to support it. group (3%) compared to 22 (65%) in the sacrospinous colpopexy group. Sometimes complications, especially exposure and After patient selection the choice of mesh to use is The above mentioned efficacy benefit is derived from shrinkage, can be devastating and require multiple, another important point. Unfortunately the ideal non-absorbable, synthetic mesh. In a randomised difficult operations to be managed. The initial uptake mesh has not been found yet. Most experts agree that in mesh augmented repairs in the years following controlled trial with 12 months follow-up8, anterior macroporous, low weight, (collagen coated) compartment pelvic organ prolapse using porcine 2004 was followed by such an important increase in polypropylene is the material of choice while small intestine submucosa did not confer additional complication reporting that lead to the 2008 FDA polyester, polyfilament, microporous, composite mesh benefit over a native tissue repair, both in terms of issue of a public health notification11 to inform should be avoided. anatomic and patient-reported outcomes. This is in physicians and patients of these adverse events. In the three years that followed, there was a five-fold accordance with and supported by previously The search for the ideal mesh is continuing and tissue published data: in a meta-analysis of 49 studies increase in the number reports associated with mesh engineered repair material (TERM) may be the future: for POP, prompting the FDA to adipose-derived stem cells could be combined with release a safety communication biodegradable scaffolds to create a TERM that is in 201112. Finally, in April 2014, suitable for SUI and POP treatment, hopefully the FDA proposed moving total reducing the risk of mesh related comlications19,20,21. vaginal mesh for POP from class II (low-risk to moderate-risk) to In summary, most scientific societies and the FDA class III (high-risk) (Figure 4). agree that the current situation can be overcome by paying attention to surgeon training, proper patient The FDA reports challenged the selection and detailed counselling of the patients. In rationale of using mesh: they the meantime, mesh kits should be subject to high stated that there is no evidence quality level I research in randomized controlled trials. that using mesh during transvaginal repair to support References the top of the vagina (apical 1. Wu JM, Hundley AF, Fulton RG, Myers ER. Forecasting the repair) or the back wall of the prevalence of pelvic floor disorders in U.S. Women: 2010 vagina (posterior repair) to 2050. Obstet Gynecol. 2009;114(6): 1278-83. provides any added benefit 2. Fritel X, Varnoux N, Zins M, Breart G, Ringa V. compared to traditional surgery Figure 1 Symptomatic pelvic organ prolapse at midlife, quality of Prof. Elisabetta Costantini University of Perugia Dept. of Urology Ospedale Santa Maria della Misericordia Perugia (IT)
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involving 4569 women9 non-absorbable synthetic mesh had a significantly lower objective prolapse recurrence compared to absorbable synthetic mesh and biological graft.
life, and risk factors. Obstet Gynecol. 2009;113(3): 609-16. 3. Olsen AL, Smith VJ, Bergstrom JO, Colling JC, Clark AL. Epidemiology of surgically managed pelvic organ prolapse and urinary incontinence. Obstet Gynecol. 1997;89(4): 501-6. 4. Richter LA, Carter C, Gutman RE. Current role of mesh in vaginal prolapse surgery. Curr Opin Obstet Gynecol. 2014;26(5): 409-14. 5. Maher C, Feiner B, Baessler K, Schmid C. Surgical management of pelvic organ prolapse in women. Cochrane Database Syst Rev. 2013 Apr 30;4:CD004014. 6. Lamblin G, Van-Nieuwenhuyse A, Chabert P, LebailCarval K, Moret S, Mellier G. A randomized controlled trial comparing anatomical and functional outcome between vaginal colposuspension and transvaginal mesh. Int Urogynecol J. 2014;25(7):961-70. 7. Svabik K, Martan A, Masata J, El-Haddad R, Hubka P. Comparison of vaginal mesh repair with sacrospinous vaginal colpopexy in the management of vaginal vault prolapse after hysterectomy in patients with levator ani avulsion: a randomized controlled trial. Ultrasound Obstet Gynecol. 2014;43(4):365-71. 8. Robert M, Girard I, Brennand E, Tang S, Birch C, Murphy M, Ross S. Absorbable mesh augmentation compared with no mesh for anterior prolapse: a randomized controlled trial. Obstet Gynecol. 2014;123(2 Pt 1):288-94. 9. Jia X, Glazener C, Mowatt G, MacLennan G, Bain C, Fraser C, Burr J. Efficacy and safety of using mesh or grafts in surgery for anterior and/or posterior vaginal wall prolapse: systematic review and meta-analysis. BJOG. 2008;115(11): 1350-61. 10. Jonsson Funk M, Edenfield AL, Pate V, Visco AG, Weidner AC, Wu JM. Trends in use of surgical mesh for pelvic organ prolapse. Am J Obstet Gynecol. 2013;208(1):79.e1-7. 11. US Food and Drug Administration. Public health notification: serious complications associated with transvaginal placement of surgical mesh in repair of pelvic organ prolapse and stress urinary incontinence [Issued 20 October 2008]. http://www.fda.gov/MedicalDevices/Safety/ AlertsandNotices/PublicHealthNotifications/ucm061976. htm 12. US Food and Drug Administration. FDA safety communication: update on serious complications associated with transvaginal placement of surgical mesh for pelvic organ prolapse. 13 July 13 2011 http://www.fda.gov/MedicalDevices/Safety/ AlertsandNotices/ucm262435.htm 13. Skoczylas LC, Turner LC, Wang L, Winger DG, Shepherd JP. Changes in prolapse surgery trends relative to FDA notifications regarding vaginal mesh. Int Urogynecol J. 2014;25(4): 471-7. 14. Condrea A, Netzer I, Ginath S, Eldor-Itskovitz J, Golan A, Lowenstein L. Is mesh becoming more popular? Dilemmas in urogynecology: a national survey. Obstet Gynecol Int. 2012;2012:672356. 15. Koski ME, Rovner ES. Implications of the FDA statement on transvaginal placement of mesh: the aftermath. Curr Urol Rep. 2014;15(2): 380. 16. Whiteside JL, Weber AM, Meyn LA, Walters MD. Risk factors for prolapse recurrence after vaginal repair. Am J Obstet Gynecol. 2004;191(5): 1533-8. 17. Wang AC, Lee LY, Lin CT, Chen JR. A histologic and immunohistochemical analysis of defective vaginal healing after continence taping procedures: a prospective case-controlled pilot study. Am J Obstet Gynecol. 2004;191(6): 1868-74.
Editorial Note: Due to space constraints the reference list has been shortened. Interested readers can request for a complete list at communications@uroweb.org. Friday, 11 March 13.15-15.45: Urology Beyond Europe, Joint Session of the EAU and the CaucasusCentral Asia
Saturday, 12 March 2016
Percutaneous Renal Surgery Prevention and management of complications during surgery and endourology Jorge GutierrezAceves Professor of Urology Director of Endourology and Stone Diseases Wake Forest School of Medicine North Carolina (USA)
Percutaneous nephrolithotomy (PCNL) has consolidated as the first treatment option for complex and large kidney stones. The European Association of Urology and the American Urological Association guidelines recommend PCNL as the first-line of treatment for staghorn renal stones; PCNL should also be strongly considered for renal stones 2 cm or larger and for complex intrarenal stones. Despite the widespread use of this procedure, this technique has to be considered an invasive procedure; the total complication rate of PCNL varies widely with reports between 15% and 83%. A proper preoperative patient evaluation is the first important step in the prevention of surgical complications. A complete understanding of the patient medical history and co-morbidities will help to make treatment decisions on each specific case. Diabetes, chronic kidney dysfunction, cardiopulmonary pathology, bleeding disorders, immunosuppression and obesity may be considered high risk factors for any endoscopic surgical intervention and surgeon should know what is the current status and present treatment for these conditions to plan accordingly.
bleeding, 2) complications related to kidney instrumentation: urothelium laceration, parenchyma perforation, UPJ stricture, arterio-venous fistula and 3) complications related to injury to adjacent organs: most frequently pleura or colon but also include injury to duodenum, liver or spleen. The most frequent surgical complication is bleeding necessitating transfusion. Data from contemporary series show an incidence of significant intra-operative bleeding between 1.4 and 7.2% (Table 1). The CROES (Clinical Research of the Endourology Society) PCNL Global Study report from 2011, the largest prospective database of patient treated with PCNL that include a registry of 5803 patient treated in 96 sites all over the world, shows a complication rate of 15%. Bleeding necessitating transfusion was the most frequent surgical complication and was reported in 5.7% of patients. Medical complications related to PCN renal surgery are divided in immediate or late complications. Fever, that can be present in up to a fourth of patients, is by far the most frequent early medical complication (Table 2). 0.4% to 4.7% of patients who develop urinary infection may evolve to a multi-organic failure and sepsis, a problem that should be addressed in a complete different way. Late medical complications include rare cases of hypertension or recurrent UTI frequently related to the persistence of residual kidney stones. Despite the overall incidence of complications related to PCN renal surgery, most of them can be considered low risk complications. CROES study reports that 11.1% of complications are Clavien grade I and less than 4% are Clavien grade IIIa or higher.
Figure 1: Patient with Fever PATIENT WITH FEVER Hemodynalically unstable?
NO
Response to a 500 cc IV crystalloid fluid challenge
Preoperative bacteriuria and / struvite stone disease
Bacteriologic Reevaluation
Close observation Continued IV antibiotics Adequate urinary drainage YES
Fever resolved?
•Patient can be discharged •Continue oral antibiotics for 6 days
NO
Clinical and laboratory reevaluation NO
SIRS
Adjust antibiotic therapy according to culture results
NO
YES, INSTABLE
YES
NO
YES
YES
SEPSIS/ SEVERE SEPSIS
SEPTIC SHOCK
•Aggressive fluid resuscitation •Invasive monitoring •Broad spectrum ab •Use of pressors •Assessment for lactic acidosis, renal, hepatic, pulmonary dysfunction; and coagulation disorders •Low dose of steroids •Maintain normal glucose •Recombinant activated protein C
ICU
Wake Forest Baptist Medical Center
Urinary infections are the most common complications related to stone interventions. As mentioned before, a full preoperative evaluation including midstream urine culture will be the first step to identify high-risk patients with the potential for infectious complications. Risk factors for infections related to the patients include diabetes mellitus, immunosuppression, chronic use of steroids, advanced age and poor nutritional status, limited renal and liver function, coexisting infections, obesity and prolonged hospitalization and probably female gender. Risk factors related to the urinary tract include anatomic abnormalities, voiding dysfunction, urinary obstruction and hydronephrosis, urinary diversion and indwelling catheters particularly nephrostomy tubes.
Once a patient develops urinary infection, the main goal is to prevent that the problem evolve to a septic or multi-organic failure problem. Fever below 101 F degrees that usually presents between 12 and 24 hours after surgery, generally it is not associated with hemodynamic changes and usually will not deserve further treatment different than oral antibiotics for five to seven days after surgery. When patient presents fever above 101 F degrees, physician needs to evaluate the patient’s hemodynamic status. If no hemodynamic changes are present, usually the patient only needs to stay on IV antibiotic and discontinue them 24 hours after patient remains afebrile. Patients who develop fever above 101 F and show evidence of hemodynamic changes, or patients with present hemodynamic changes without evidence of fever are the patients who can evolve to a real septic and multi-organic failure problem. These patients develop this condition usually during the first six to 12 hours after procedure; they do need a critical medical support including full monitoring in an intensive care unit, blood culture and urine re-culture, ventilation and hemodynamic support as needed. Urologist need to recognize his limitations and consult the medical team who can help in the treatment of theses acute condition. Critically ill septic patients, who delay their medical urgent care, may evolve to a fatal condition; mortality after septic shock may reach as high as 66%. An algorithm to manage infectious complications after PCN and endourological procedures can be seen in the figure.
During the presentation of this lecture, recommendations will be address on the management of the most frequent surgical and The history of the stone disease should include the medical complications. Following are some comments time elapsed between the initial diagnose and the on the treatment of the most frequent surgical en Patients with a positive culture must receive medical issues. stone treatment as well as the history of prior pre-operative antibiotics tailored to culture-specific interventions and instrumentations. All patients organisms. If a stone is associated with urinary MEDICAL should be evaluated with physical examination and Table 2: Medical ComplicationsCOMPLICATIONS obstruction, kidney should be initially decompressed laboratory test including midstream urine culture. placing a ureteral stent or a nephrostomy tube. If Urinary tract infection (UTI) is the most common urinary infection is related to urinary tract MEDICAL COMPLICATIONS colonization, culture specific antibiotics must be used complication related to stone interventions; therefore, adequate assessment of culture data as well as MEDICAL COMPLICATIONS Incidence % orally five to seven days before surgery and/or IV 24 hours pre-operative. Controversy still exists in the information on prior infectious events and antibiotic Fever 10.5-24 treatments is a fundamental part of the preoperative prophylactic use of pre-operative antibiotics before MEDICAL COMPLICATIONS Incidence % 0.5-4.7 Sepsis/multi-organic failure patient evaluation. Finally, a proper preoperative endourological interventions, especially in patients 10.5-24 evaluation should include a well-performed non-Fever with high risk factors for infection. There is enough Embolism 0.3-1 Sepsis/multi-organic failure 0.5-4.7 contrast CT to understand not only the stone evidence to support the use of prophylactic antibiotics Dead 0-1.1 characteristics and distribution inside the collecting in patients who undergo PCN surgery. When Embolism 0.3-1 system but also the kidney anatomy and the extrarenal pre-operative urine culture is negative, a single dose Dead 0-1.1 Skolarikos A., Current Opinionin Urology: 2008. 18: 229-234 anatomy to plan a safe approach to the stone. In order to prevent complications during PCN surgery of antibiotic appears to be as effective in preventing Seitz, C., Eur Urol: 2012. 61 (1): 146-58 post-operative infections as multiple doses, and endourological procedures, urologists should De la Rossette, CROES., J Endourol: 2011; 25 (1): 11-17 A., Current Opinionin Urology: 2008. 18: 229-234 A better understanding of the surgical technique have Skolarikos irrespective of antibiotic used. follow basic rules that include a proper preoperative Seitz, C., Eur Urol: 2012. 61 (1): 146-58 De la Rossette, CROES., J Endourol: 2011; 25 (1): 11-17 Wake Forest Baptist Medical Center led to a reduction in the morbidity related to the evaluation, identify preoperative risk factors and Risk factors for urinary infections related to the procedure and yielded overall stone-free rates up to patients with risk factors for urinary infections, have As addressed before, bleeding is the most frequent 90%. The cornerstone for the procedure is a safe intra-operative procedure include the number of in mind technical suggestions related to surgery, surgical complication. The initial and essential step percutaneous access to the kidney. Studies of the percutaneous tracts, operative time, volume of recognize the problem early enough when it presents, renal collecting system and vascular anatomy in to stop an intraoperative bleeding is to place the irrigation fluid, bleeding during surgery and purulent be aggressive with the treatment and ask for help human cadavers by Sampaio in early 1990s Amplatz sheath or the nephroscope inside the urine during surgery. Keeping a low intrarenal when needed. collecting system. To accomplish this, in cases where pressure below 30 mm hg, the use of diuretics at the contributed to establish the paradigm that the access to the collecting system should be through the fornix the stone is taking the complete cavity of the calix, beginning of irrigation time, the use intermittent Friday 11 March of the calyx and not through the infundibulum to fragmentation of the stone is needed before the suction, limiting the irrigation time, reducing the 09.30-13.00: Joint Session of the European reduce the risk of bleeding. These lessons resulted in sheath can be completely positioned into the calix. surgical time and a staged procedure are all measures Association of Urology (EAU) and the a significant reduction in morbidity and specifically This simple maneuver stops the bleeding in the great that may reduce the risk of infections during surgery, Confederación Americana de Urología (CAU) have decrease transfusion rates from 25% in early especially in patients with risk factors for infections. majority of cases allowing the surgeon to continue reports to 1-2% in most recent literature. with the procedure. If bleeding persists, placement of a nephrostomy tube will be the next step; again, the Complications of PCN renal surgery are divided in bleeding will stop in the vast majority of cases. In surgical and medical complications. Surgical case of persistent bleeding, placement of a Download the complications include: 1) complications related to the tamponed balloon catheter, emergent angiography renal access: intraoperative bleeding, post-operative with selective embolization or open surgical exploration will be the steps to follow, all of them very rarely needed. Continuous monitoring of the Table 1: Surgical Complications blood loss through urethral catheter or around the nephrostomy tube and patient full monitoring of The easiest way to navigate at EAU16 SURGICAL COMPLICATIONS blood pressure and vital signs are necessary during SURGICAL COMPLICATIONS with your smartphone or tablet! this process. Wake Forest Baptist Medical Center
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COMPLICATIONS PCNL COMPLICATIONS PCNL
Incidence % Incidence %
Significant intra-operative 1.4-7.2 Significant intra-operative bleeding bleeding
1.4-7.2
Peri-operative transfusion Peri-operative transfusion
0.4-17.5
0.4-17.5
Late bleeding Late bleeding
0.3-1.5
0.3-1.5
3.4
3.4
Intrathoracic Intrathoracic lesion lesion
0.1-3.1
0.1-3.1
Colon perforation Colon perforation
0.2-0.8
0.2-0.8
0-1.8
0-1.8
Renal pelvis perforation Renal pelvis perforation
Conversion to open surgery Conversion to open surgery
Skolarikos A., Current Opinionin Urology: 2008. 18: 229-234 Skolarikos A., Current Opinionin Urology: 2008. 18: 229-234 Seitz, C., Eur Urol: 2012. 61 (1): 146-58 Seitz, C., Eur Urol: 2012. 61 (1): 146-58 De la Rossette,De CROES., J Endourol: 2011; 25 (1): 11-17 la Rossette, CROES., J Endourol: 2011; 25 (1): 11-17
Wake Forest Baptist Medical Center Wake Forest Baptist Medical Center
Saturday, 12 March 2016
Management of late bleeding is a complete different history. Patient who presents a late bleeding typically initiate one week or more after surgery, common presentation is a sudden bleeding that usually stops when patient is placed on rest. This bleeding usually reactivates when the patient starts moving again. This is usually a non-acute, threatening bleeding and the case can be scheduled without rush for angiography and selective embolization, preferably when patient is presenting an active bleeding. Working with an experienced intervention radiologist, this procedure is usually successful with minor permanent damage to the ipsilateral renal function.
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Saturday, 12 March 2016
What do urologists expect from nephrologists? Dr. Noor Buchholz Consultant urologist Sobeh’s Vascular and Medical Center Dubai Health Care City Dubai (UAE)
Nephrologists and urologists have been working next to each other for a very long time. Yet, too often there seems to be a rivalry, almost a competition, as can be found in many places between physicians and surgeons. Naturally, given the different approaches to disease, their view of the world and even their “dialect” differ. This poses a barrier between the two specialties that often care for the same patients, the same organ, and the same pathophysiologies. This applies also to stone disease, which is often complex and caused by underlying co-morbidities that cannot be tackled by blasting the stone alone. Conveniently though for the urologists, developments in stone blasting technologies have made treatment very smooth and easy, leading to a neglect of the diagnosis of underlying causes. On the other hand, nephrologists show only a limited interest in stone disease amongst all the other renal pathologies to deal with. Yet, in complex stone disease collaboration and complementation between the two specialties is not only desirable, but crucial for the benefit of the patients. Often, the important question for the urologist to involve the nephrologist is not whether but when? Whereas there are guidelines for General Practitioners1,2, there are no such guidelines for urologists. In a recent study3, most primary care physician respondents were aware of the appropriate preventive measures for recurrent kidney stones. However, they did not appear to apply this knowledge effectively in clinical practice. Furthermore, a low response rate was a limitation of that study but may be reflective of a low interest in the topic. We may safely assume that the same can be said for urologists, and that they may not be always aware of the underlying complexities of stone disease. What do we expect from our colleagues nephrologists? We would like them to help us out in more complex and overlapping stone cases. We would like them to help us raise awareness of what they do and how they look at the “stone world”. And we would like to collaborate for the benefit of the patients. To start with, we have identified a few areas of interdisciplinary overlap of conditions frequently encountered in urological practice:
Kidney scars Another frequent finding in stone patients are kidney scars as identified on ultrasound, CT scan or renal scintigraphy. They are often incidental findings and should lead to questions about a history of renal childhood problems (i.e. vesico-ureteric reflux VUR), stones, infections, and renal surgeries4. Apart from the above-mentioned referral guidelines for eGFR changes, patients with renal scars should be referred to the nephrologist if there is also hypertension, proteinuria, or both. Kidney scars can sometimes be very painful. The involvement of a pain team may be indicated. Always remember that nephrectomy is not a painkiller!
Table 3: Lists conditions associated with a particularly high risk of stone recurrence Underlying condition Brushite stones Xanthine stones Dihydroxyadenine stones Cystine stones Infection stones Indinavir stones Single kidney Primary hyperparathyrodism Distal renal tubular acidosis (overt) Distal renal tubular acidosis (partial) Primary hyperoxaluria Secondary hyperoxaluria (bariatric surgery, inflammatory bowel disease, bowel resection, malabsorptive syndromes) Medullary sponge kidney Other forms of nephrocalcinosis (often associated with familial hypercalciuria conditions) Pyelo-ureteral or ureteral strictures Autosomal dominant polycystic kidney Anatomical abnormalities of the kidney and urinary tract (horseshoe kidney; ureterocele, vesico-ureteral reflux, etc.)
All of the above may occur in conjunction with stone disease. All can be direct or long-term results of stone disease. The urologist will usually exclude stone disease and/ or treat any stone. But provided the patient is stone-free and still has elevated CREA/ eGFR, hematuria or proteinuria, the pertinent questions urologists will have to ask themselves are: at what level of CREA/ eGFR should I refer to the nephrologist? At what point in time should I refer? And when is it not necessary to refer? Guidelines for General Practitioners in the UK1,2 may give answers to that but are of course not part of the urologists’ background reading. Very briefly, referrals can be split according to urgency:
Indeed, many chronic metabolic conditions associated with stone disease carry a risk of CKD or metabolic bone disease (MBD) Medullary sponge kidney (MSK) Many urologists will encounter regularly patients with MSK. The condition is however not very well-defined in their clinical practice, and cases where intraparenchymal calcifications have been shock-waved are frequent. It is important to reassure patients that MSK is a benign disease. Only 10% will develop CKD, but 10% will suffer in a lifetime from co-morbidities caused by passing stones and their treatments. In MSK, most stones will pass spontaneously. Surgery is rarely required.
are in the PCS6. Severe pain syndromes are possible. NC is a serious disease and patients should be prepared for eventual kidney transplantation early. Medical therapy is indicated: thiazides and salt restriction (hypercalciuria), pyridoxine (hyperoxaluria), citrate (RTA) and magnesium7. Surgery on single kidneys If it is necessary to perform surgery on a single kidney, patients should be always consented about the possibility of a nephrectomy and dialysis in case of complications. If the risk is high, it seems like a good idea to inform the nephrologist beforehand. In cases of ablative surgery, planning of dialysis is mandatory. The same will apply for stone surgery in a transplant kidney.
There is no specific therapy for MSK apart from excluding hypercalciuria and ensure a high drinking volume. A genetic screening may be advisable for family members with stones. In general, MSK can be managed by the urologists and there is no need for a nephrology referral.
The status quo All of the above highlights the need for a closer collaboration between urologists and nephrologists. In a recent survey of 523 urologists and nephrologists, 90% of urologists confirmed that they had access to a nephrology service, but only 52% thought that their Nephrocalcinosis nephrologists might have an interest in stone disease This stands in contrast with nephrocalcinosis (NC). NC at all. Only 20% had access to a dedicated stone can be caused by hyperoxaluria, hypercalciuria, renal clinic. 39% of urologists never refer patients to tubular acidosis (RTA), and papillary necrosis. Patients nephrology, 51% occasionally do so. with NC should always be managed by the nephrologist through a specialised metabolic stone We then continued with some simple clinical clinic. The role of the urologist is limited to treat questions which highlighted discrepancies between “break through” stones from time to time. Again, both specialties in clinical approaches and emphasis. there is the diagnostic dilemma to decide which Details of this survey will shortly be published stones are in the renal parenchyma, and which ones elsewhere.
Underlying condition Primary hyperparathyrodism Distal renal tubular acidosis (overt) Distal renal tubular acidosis (partial) Primary hyperoxaluria Secondary hyperoxaluria (bariatric surgery, inflammatory bowel disease, bowel resection, malabsorptive syndromes) Medullary sponge kidney Other forms of nephrocalcinosis (often associated with familial hypercalciuria conditions)
Risk CKD Moderate High Low Very high High
systemic yes possible possible yes yes
RSF yes yes yes yes yes
Risk MBD yes yes yes yes yes
Low High
possible
yes yes
yes yes
Legend: CKD = chronic kidney disease; RSF = recurrent stone formation; MBD = metabolic bone disease Table 2: lists the metabolic conditions associated with stone disease and a high risk of CKD Underlying condition Primary hyperoxaluria Autosomal dominant polycystic kidney Infection stones Single kidney Distal renal tubular acidosis (overt) Secondary hyperoxaluria (bariatric surgery, inflammatory bowel disease, bowel resection, malabsorptive syndromes) Other forms of nephrocalcinosis (often associated with familial hypercalciuria conditions) Anatomical abnormalities of the kidney and urinary tract (horseshoe kidney; ureterocele, vesico-ureteral reflux, etc.) Legend: CKD = chronic kidney disease; RSF = recurrent stone formation; MBD = metabolic bone disease Other forms of nephrocalcinosis (often associated with familial hypercalciuria conditions) Anatomical abnormalities of the kidney and urinary tract (horseshoe kidney; ureterocele, vesico-ureteral reflux, etc.)
Risk CKD Very high Very high High High High High
Systemic RSF yes yes yes possible yes
MBD Yes
1. Immediate referral in newly detected end-stage possible yes yes renal failure (RF) (eGFR < 15 mL/min/1.73 m2) yes yes yes 2. Urgent referral in newly detected stage 4 (unless known to be stable) or stable stage 5 chronic High possible yes yes kidney disease (CKD) 3. Routine referral in acute deterioration in kidney High yes function (defined as a fall of eGFR of >20% or rise of serum creatinine concentration of >30% from baseline), a falling eGFR (>15% fall over 12 months), or with a clinical suspicion of High possible yes yes atherosclerotic renal artery sclerosis (ARAS). 4. In proteinuria, refer if combined with moderate or High yes severe CKD (eGFR < 60ml/min). 5. In unexplained haematuria, refer if combined with hypertension or proteinuria or both. Legend: CKD = chronic kidney disease; RSF = recurrent stone formation; MBD = metabolic bone disease Saturday, 12 March 2016
Systemic
MBD
yes yes yes possible yes
RSF yes yes yes yes yes yes
yes possible possible yes yes
yes yes yes yes yes
yes yes yes yes yes
Metabolic stone disease Very few urologists are aware of the metabolic basis Low yes for stone disease in greater detail. Very few also have High possible yes an interest to evaluate patients metabolically for stone disease. For those who have an interest, patient care Moderate yes is best accomplished in a multidisciplinary stone clinic Very high yes with a nephrologist and ideally a nutritionist and a High yes life-style coach. However, for those not interested or not able to perform metabolic urolithiasis diagnostics, an early referral to a nephrologist with expertise in Legend: CKD = chronic kidney disease; RSF = recurrent stone formation; MBD = metabolic bone disease stone disease would be indicated.
Table 1: lists the conditions associated with stones and metabolic bone disease Rise of serum creatinine (CREA) and/ or decrease of estimated glomerular filtration rate (eGFR), unexplained hematuria, and proteinuria
Risk Moderate Low Low Moderate High Low High Moderate High Low Very high High
yes yes
Areas of overlap From the above it is clear that there is a lot of areas of overlap between urology and nephrology. It also becomes clear that the approach to stone disease comes from a very different angle. Nephrologists simply see stone disease with very different eyes. From the point of view of a urologist, closer collaboration would be desirable. Skills and specific knowledge of each specialty could nicely complement each other. To address these issues further, urologists and nephrologists with an interest in stone disease came together for the Consensus Conference for the Metabolic Diagnosis and Medical Prevention of Calcium Nephrolithiases and its Systemic Manifestations held in Rome (Italy) last March 2015. This elaborate group came up with the following consensus statement which rounds up nicely what was said earlier: I) Often, nephrology and urology are alternative rather than complimentary. There is no clear definition of roles in the non-surgical stone field. There is a need to expand the overall view of the whole stone field and for co-operation between the two specialities. II) Often, the general practitioner (GP) is the first point of contact for stone patients. The GP has a crucial role in triaging patients to urology or nephrology. The GP has a crucial role in excluding and treating in the follow-up underlying diseases associated with stone disease. III) a. Collaboration can be enhanced on a local level by Multidisciplinary Stone Meetings (MDT) and clear local protocols. b. There is a need for skills development including metabolic stone disease on all levels from joined local workshops to international meetings. c. There is a need to raise awareness for stone disease in general. This can be promoted by cross-talk sessions in each other’s meetings on all levels. d. Guidelines need to be developed to define areas of combined and complementary stone management. A score system could aid in decision making. e. Stone cross-talks and MDTs could be the driver for other joint uro-nephrological collaborations (i.e. chronic kidney disease after renal cancer surgery, malformations, UTI). This would promote joint continuity of care to the benefit of the patients. f. It would be useful to adapt and expand the joint guidelines and score tools for the use of GPs. g. Joint research into stone disease will further promote co-operation, enhance the knowledge base and lead to a better understanding of stone disease as such. Editorial Note: Due to space constraints we have ommitted the reference list. Interested readers can email a request at communications@uroweb.org. 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?
EUT Congress News
11
Cryoablation for small renal mass Selection criteria, complications, functional and oncologic outcomes Dr. Oscar Rodriguez Faba Department of UrologyF Fundació Puigvert Barcelona (ES)
Co-authors: Sabine Brookman-May(DE), GD Stewart (UK), Francesco Sanguedolce (UK)
experience of the surgeon, management of outcomes, duration of follow-up, and probable publication bias. Complication rates are comparable also with other needle ablative techniques4. The overall rate of complications with CA is relatively low, at 7.8–20%, with the majority being minor, while the rate of major complications across the literature is 0.8–9.5% for LCA and 0–7.5% for PCA4. In a recent meta-analysis comparing LCA with laparoscopic or robotic-assisted PN, Klatte et al. showed a lower risk of complications with LCA (RR 1.82), including urological (RR 1.99) and non-urological ones (RR 2.33)5.
disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) rates were reported in five series and ranged between 85% and 97%, 98.5 and 100%, and 85% and 97.8%, respectively. Follow-up varied between 20 and 97.9 months. Long-term (>5 years) follow-up outcomes are emerging only recently and involve series only with LCA (Table 1): Aron et al11 reported the results of 80 patients who underwent LCA, 55 of whom had biopsy-proven RCC. In the latter group of 55 patients, median follow-up was 93 months. Five patients (9%) had local recurrences, while six developed distant metastases (11%). The DFS, CSS, and OS rates were 81%, 92%, and 84% at five years and 78%, 83%, and 51% at 10 years, respectively.
The most common complication is discomfort at the insertion site of the CA probe (64%)6. Potential major complications include adjacent organ injury, collecting system injury, and fistula formation and haemorrhage Tanagho et al12 retrospectively reviewed the results in requiring transfusion. Haemorrhage has been linked 35 patients with biopsy-proven RCC among a cohort to tumour size, central tumour location, and use of a of 66 patients who underwent LCA and were followed However, many such lesions are benign and are greater number of probes. In a UK series of 147 up for an average of 76 months. DFS, CSS, and OS diagnosed in people over the age of 70 years or with patients, ablation of upper pole tumours was found to rates were 80%, 100%, and 72%. Six patients (17%) severe comorbidity. Moreover, most of them behave in be associated with a higher risk of complications, of experienced local recurrences. Interestingly, the an asymptomatic manner, with a growth rate of 3–4 which the most common was pneumothorax7. authors also reported that tumour size ≥2.6 cm was mm/year. Active surveillance is an option in these the only variable predictive of oncologic failure at Cox cases even though this may entail a degree of anxiety Other minor complications include urinary tract regression analysis. for patients and also increased costs. Partial infection, pneumonia, haematuria, and hematoma nephrectomy (PN) has become the standard therapy formation. A meta-analysis of case series has also Caputo et al. recently reported the series with the for T1a renal cell carcinoma (RCC)2. identified the following rarer complications8: longest follow-up, comprising 142 tumours treated with Genitofemoral nerve injury, cryoshock (a systemic LCA (mean tumour size = 2.4 cm)13. Histopathologic In this context, focal cryoablation (CA) is an response where free radicals are generated and result diagnosis of RCC had been confirmed upfront in 100 increasingly popular treatment option for SRMs in in multi-organ failure)9, respiratory failure, and lesions, and the mean follow-up in this group was 98.8 cases that are technically difficult from the surgical ureteropelvic junction obstruction. Evidence regarding months. The estimated DFS, CSS, and OS rates in point of view and in patients who present relative the ability of nephrometry scores (i.e., RENAL score, patients diagnosed with RCC were 86.5%, 96.8%, and contraindications to PN. The last version of the PADUA score, and C-index) to predict complications 79.1% at five years and 86.5%, 92.6%, and 53.8% at 10 European Association of Urology (EAU) guidelines on for both laparoscopic and percutaneous CA is years, respectively. The number of recurrences was not RCC specifically concluded, however, that due to the controversial, although on balance it appears that specified but they occurred at a mean of 27.6 months, low quality of available data, no recommendation can higher RENAL scores are associated with a higher rate with the latest recorded 53.3 months after ablation. be made on CA2. On the other hand, the American of complications7. Tumour size and location seem to Urological Association considers ablation techniques, be the best complication predicting tumour Functional outcomes including CA, as a third-line treatment option in characteristics; when combined with patient factors of Preservation of renal function is one of the main patients with cT1a tumours associated with major myocardial infarction and diabetes the (MC)2 score is objectives when treating patients with CA, especially comorbidities and increased surgical risk. the best predictive signature of complications in those with pre-existing chronic kidney disease following CA identified to date10. (CKD). Despite the selection bias introduced by Selection criteria including in CA protocols elderly patients (>70 years) When selecting the therapeutic option in patients with Oncologic outcomes with comorbidities and CKD, several studies have SRMs, there is a need to balance the treatment Assessment of oncologic outcomes after CA of SRMs is analyzed functional outcomes after CA. Kim et al benefit, the life expectancy, and the willingness of the currently hindered by the wide heterogeneity of investigated 263 patients comparing functional patient to undergo a particular treatment. Currently, reported data due to differences in inclusion criteria, outcomes of LCA and PCA [14]. While the two groups there is no overall consensus on the best patient and definition of treatment failure, and the techniques had a different duration of follow-up, the authors tumour selection criteria; nonetheless, some main adopted for ablation. However, the main limitation on found that LCA and PCA patients had a comparable indications can be outlined. appraisal of the oncologic results lies in the nature of decline in eGFR (LCA: 3.8±18.5 ml/min per 1.73 m2 at the reported series, which have all been retrospective 45.0±35.4 months; PCA: 6.6±17.1 ml/min per 1.73 m2 at Peripheral, enhancing, and well-circumscribed SRMs and have included small numbers of patients and 24.6±20 months. p=0.21). with a size ≤ 3cm represent ideal lesions for this short follow-up. treatment modality, especially in patients who would Likewise, CKD stage progression rates were similar benefit from nephron-sparing surgery but who are Among several reviews published in the past few between the LCA and PCA groups. Wehrenberg-Klee not ideal surgical candidates; larger tumours between years, the strongest and most up-to-date data have et al measured decline in renal function in patients 3-4 cm may also be treated with CA by combining been provided by two systematic reviews. In the first with CKD who underwent PCA [15] and found no multiple cryoprobes. Due to higher reported rates of of these, Klatte et al [5] performed a systematic significant difference in mean baseline eGFR prior to recurrence and treatment failure for CA, nephronreview comparing peri-operative and oncologic treatment and the values at one month (41.1 vs 41.4 sparing surgery still represents the gold standard for outcomes of LCA versus extirpative approaches (open/ ml/min per 1.73 m2) and one year (42.1 vs 44.4 ml/min younger and minimally comorbid patients with a life laparoscopic/robotic PN). Ten of the 13 selected per 1.73 m2). expectancy exceeding 15 years. CA is instead currently studies provided oncologic outcomes for a total of 475 predominantly offered as a reliable treatment option laparoscopic CA procedures. Functional outcomes have also been compared to older or frail patients and those with comorbidities between CA and other nephron-sparing procedures. such as diabetes, hypertension, or congestive cardiac The meta-analysis showed a 9.4% (n=45) rate of local Comparing PN and ablation techniques in patients failure. tumour progression and a 4.4% rate of distant with solitary kidney at three months, no differences metastases, with duration of follow-up ranging from were found either in post-treatment eGFR (50.3 vs CA may also represent the preferred treatment option six to 60.2 months. Unfortunately, due to the 49.3) or change in CKD stage. The same study also in certain specific subsets of patients, including those retrospective nature of the studies, the level of reported no significant differences in percentage with a history of von Hippel-Lindau disease, tuberous evidence provided by this systematic review is change in eGFR between RFA and CA16. Similarly, sclerosis, or other inheritable familial renal tumours: suboptimal (LE: 2b). In the second, more recent study, Mues et al, in a multi-institutional analysis comparing these patients are at higher risk of induction of renal Zargar et al4 performed a collaborative review on CA CA and PN, reported no differences in postoperative insufficiency by surgery owing to the recurrent nature for SRMs that included only high-volume series. eGFR changes between the two techniques17. of their diseases, and CA can be offered as a first-line treatment option that provides optimal preservation of Oncologic outcomes were identified in 11 nonIn conclusion, CA is associated with minimal decline renal function. Furthermore, CA may be indicated in comparative CA cohorts with a minimum sample of in postoperative renal function. The studies patients with SRMs in solitary or transplant kidneys. 100 laparoscopic or percutaneous CA procedures. The comparing different nephron-sparing techniques treatment failure rates were available for eight series indicate that the proportional decline in function may In addition, recent data from small single-institution be comparable for CA and PN. series suggest CA to be a safe and feasible option for and were reported to be between 0% and 13%. The the treatment of oligometastatic RCC as part of a multimodal approach3. Table 1: Long-term oncologic outcomes of CA Relative contraindications to CA are younger age, Technique No. of patients Age Size (cm) Compl. FU (mo.) DFS (%) CSS (%) OS (%) tumour size >4 cm, and hilar, intrarenal, and cystic (yr) (%) tumours. Tumour proximity to the collecting system 92 59.6 2.3 9.8 97.9 91 98.5 77.6 represents a relative contraindication due to the risk of Johnson LCA [6] (SD 0.94) (mean) ureteric strictures. The only absolute contraindication Aron LCA 80 (55 RCC 66 2.3 10 93 81 (5 years) 92 (5 years) 84 (5 years) is untreatable or irreversible coagulopathy. The extensive use of ultrasound and computed tomography (CT) in recent years has increased the incidental diagnosis of small renal masses (SRMs) by 60%1.
[11]
biopsy proven)
(0.9-5)
(median)
Tanagho LCA 66 (35 RCC 67 2.52 9.7 76 80 (6 years) 100 (6 years) 72 (6 years) Complications [12] biopsy proven) (2.3-2.8) (mean) The complications reported in association with both Caputo LCA 138(100 RCC 66.35 2.4 10.6 98.8 86.5/86.5 96.8/92.6 79.1/53.8 LCA and PCA are heterogeneous across multiple [13] biopsy proven) (SD 0.8) (mean) (5/10 years) (5/10 years) (5/10 years) studies in the literature4. This high variability across case series is suggested to be due to differences in (LCA, laparoscopic cryoablation; Compl, complication rate; FU, follow-up; DFS, disease-free survival; patient selection, baseline disease severity, technique, CSS, cancer-specific survival; OS, overall survival)
12
EUT Congress News
Conclusions Focal CA is an established minimally invasive technique for the treatment of SRMs. Due to the lack of robust evidence in the literature, it is indicated only in selected patients: available clinical, oncological and functional outcomes support indication of CA as safe and effective treatment options for patients who have relative contraindications to extirpative approaches. With the relatively high proportion of benign lesions, oncologic outcomes should be evaluated in patients with prior biopsy. In recent years the role of the percutaneous approach has been expanding because of its ability to reduce pain and length of hospitalization, the possibility of performing the procedure under sedation, and, finally, the fact that it is potentially more cost-effective. References 1. Silverman SG, Israel GM, Trinh QD: Incompletely characterized incidental renal masses: emerging data support conservative management. Radiology 2015, 275(1):28-42. 2. Ljungberg B, Bensalah K, Canfield S, Dabestani S, Hofmann F, Hora M, Kuczyk MA, Lam T, Marconi L, Merseburger AS et al: EAU guidelines on renal cell carcinoma: 2014 update. Eur Urol 2015, 67(5):913-924. 3. Welch BT, Callstrom MR, Morris JM, Kurup AN, Schmit GD, Weisbrod AJ, Lohse CM, Kohli M, Costello BA, Olivier KR et al: Feasibility and oncologic control after percutaneous image guided ablation of metastatic renal cell carcinoma. The Journal of urology 2014, 192(2):357-363. 4. Zargar H, Atwell TD, Cadeddu JA, de la Rosette JJ, Janetschek G, Kaouk JH, Matin SF, Polascik TJ, ZargarShoshtari K, Thompson RH: Cryoablation for Small Renal Masses: Selection Criteria, Complications, and Functional and Oncologic Results. Eur Urol 2015. 5. Klatte T, Shariat SF, Remzi M: Systematic review and meta-analysis of perioperative and oncologic outcomes of laparoscopic cryoablation versus laparoscopic partial nephrectomy for the treatment of small renal tumors. The Journal of urology 2014, 191(5):1209-1217. 6. Johnson DB, Solomon SB, Su LM, Matsumoto ED, Kavoussi LR, Nakada SY, Moon TD, Shingleton WB, Cadeddu JA: Defining the complications of cryoablation and radio frequency ablation of small renal tumors: a multiinstitutional review. The Journal of urology 2004, 172(3):874-877. 7. Breen DJ, Bryant TJ, Abbas A, Shepherd B, McGill N, Anderson JA, Lockyer RC, Hayes MC, George SL: Percutaneous cryoablation of renal tumours: outcomes from 171 tumours in 147 patients. BJU Int 2013, 112(6):758765. 8. El Dib R, Touma NJ, Kapoor A: Cryoablation vs radiofrequency ablation for the treatment of renal cell carcinoma: a meta-analysis of case series studies. BJU Int 2012, 110(4):510-516. 9. Rivoire M, De Cian F, Meeus P, Gignoux B, Frering B, Kaemmerlen P: Cryosurgery as a means to improve surgical treatment of patients with multiple unresectable liver metastases. Anticancer Res 2000, 20(5C):3785-3790. 10. Schmit GD, Schenck LA, Thompson RH, Boorjian SA, Kurup AN, Weisbrod AJ, Kor DJ, Callstrom MR, Atwell TD, Carter RE: Predicting renal cryoablation complications: new risk score based on tumor size and location and patient history. Radiology 2014, 272(3):903-910. 11. Aron M, Kamoi K, Remer E, Berger A, Desai M, Gill I: Laparoscopic renal cryoablation: 8-year, single surgeon outcomes. The Journal of urology 2010, 183(3):889-895. 12. Tanagho YS, Roytman TM, Bhayani SB, Kim EH, Benway BM, Gardner MW, Figenshau RS: Laparoscopic cryoablation of renal masses: single-center long-term experience. Urology 2012, 80(2):307-314. 13. Caputo PA, Ramirez D, Zargar H, Akca O, Silva HA, O’Malley C, Remer EM, Kaouk JH: Laparoscopic cryoablation for renal cell carcinoma: 100-month oncologic outcomes, a single institution’s experience. The Journal of urology 2015. 14. Kim EH, Tanagho YS, Saad NE, Bhayani SB, Figenshau RS: Comparison of laparoscopic and percutaneous cryoablation for treatment of renal masses. Urology 2014, 83(5):1081-1087. 15. Wehrenberg-Klee E, Clark TW, Malkowicz SB, Soulen MC, Wein AJ, Mondschein JI, Van Arsdalen K, Guzzo TJ, Stavropoulos SW: Impact on renal function of percutaneous thermal ablation of renal masses in patients with preexisting chronic kidney disease. J Vasc Interv Radiol 2012, 23(1):41-45.
Note: Interested readers can request for the complete references by sending an email to: communications@uroweb.org. Friday 11 March 13.15-15.45: Joint Session of the European Association of Urology (EAU) and the Société Internationale d’Urologie (SIU)
Saturday, 12 March 2016
Urinary diversions Treating infective complications Prof. Jørgen Bjerggaard Jensen Department of Urology Aarhus University Hospital & Hospital of West Jutland Aarhus (DK)
EAU members are kindly invited to the EAU Booth F40 to collect the following complimentary items: EAU Extended Guidelines The EAU Extended Urological Guidelines edition 2016.
2016 edition
Historia Urologia e Europaeae addressed to all series is to make known European urologists. Its aim is the ideas and predecessors, the work of and to help our us understa rent trends nd the curin the develop ment of our Unfortunately, speciality. the ancient Chinese treatises written in Sanskrit , Greek and ficult to find Latin are both , and difficult difto understa should, therefor nd, and e, be translate same applies d into English. to more recent The various languag books publishe d in es.
Most of the treatises produce the 17 th century, d before even the legenda gaps, mistakes ry ones, have scientific researchand inconsistencies. Modern ancient knowled allows us to re-evalu ate this ge and examine perspectives. it from new The History Office of the collaboration EAU in with internati onally based gists, historian urolos, conducts researchphilologists and other experts, , accumulates fascinating and shares information this in their tion, Historia Urologiae Europaeannual publicaae. “Remember the days of years of many old, conside generations, r the ask thy father, will shew thee; and he thy elders, and (Deuteronomy they will tell thee.” 32:7)
E 23
DE HISTO RIA
De Historia Urologiae Europaeae Vol. 23 This year marks the 23rd edition of De Historia Urologiae Europaeae, the EAU History Office’s annual edited volume of Europe’s urological history. Beside the regular contributors from the History Office, newcomers tackle a broad range of fascinating topics.
UROLOGIAE
European Associa tion of Urology 2016
VOLUME
23
EUROPAEAE
EDITED BY PROF. DR. DIRK SCHULT HEISS
Forbidden Fruit: Sex, Eroticism, Art by Johan J. Mattelaer Former EAU History Office Chairman Dr. Johan Mattelaer delves into the cultural aspects of urology and sexology once again in this new, attractively illustrated volume. Over the course of thirteen chapters Forbidden Fruit explores the depiction of the human body and eroticism in worldwide art.
Internationa l Consultation Medical Treatm on ent of Urolog ical Malign ancies Lisbon 2014
MEDICAL TREATME UROLOGICAL NT MALIGNA OF NCIES Editors: C.
Medical Treatment of Urological Malignancies; C. Stief, K. Fizazi, C. Evans The results of the 2014 EAU-ICUD International Consultation on the Medical Treatment of Urological Malignancies, held at the EMUC14, presented as a fully-updated volume on a e-card. An comprehensive 600-page single volume with chapters covering the medical treatment of systemic therapy for all common urological cancers.
Stief, K. Fizazi
, C. Evans
SYSTEM REQUIRE MENTS Windows • Intel Pentium 4 processor or higher • Microsoft Windows • 1 GB of available XP/Vista/7/8 RAM
E t CM nten -A d co EUcredite
USAGE Insert the CD-ROM
Treatment naturally includes antibiotics in the febrile or even septic patients. But thorough instruction, transluminal procedures, surgical repairs or even re-diversions should be part of the repertoire of the urologist treating these patients – or at least in his/ her mind so referral to highly specialized centres can be made on time. A review of the field with tips and tricks and examples of severe cases with need for surgery and rediversions will be presented in the full lecture. Saturday 12 March 10.15-14.00: Lower urinary tract function and urogenital infections. Joint meeting of the EAU Section of Female and Functional Urology (ESFFU) and the EAU Section of Infections in Urology (ESIU)
ac
Given the different, non-reservoir, structure of the ileal conduit compared to pouch and neobladders, infective
Guidelines
EAU Pocket Guidelines The Pocket Guidelines can be collected at JANSSEN PHARMACEUTICA NV. booth D44.
E EUROPAEA
Except for continent cutaneous reservoirs, practically all urinary diversions are constructed from ileum. This gives a very low intra-diversional colonization of urinary pathogens per se but not totally unneglectable. Contrary to this, colonization from crypts of the bowel may constitute serious problems in pouches constructed of colon. Re-diversion to an ileal conduit or construction of a continent reservoir made of ileum is a way to treat patients or avoid chronic colonization in patients with long-term diversions.
European Association of Urology
EAU members are kindly invited to collect the following complementary items:
UROLOGIA
Moreover, the construction of continent reservoirs and especially neobladders are still a preferred urinary diversion, if possible, in young patients with bladder cancer and in some patients undergoing urinary diversion for benign conditions. This highlights the need for the general urologist to be aware of diagnostic dilemmas and therapeutic adversities in these patients. Incidence, symptoms, and treatment naturally depends highly on the type of diversion; ileal conduit, cutaneous continent reservoir, or neobladder. But also on patient factors, reconstruction method, and segment of bowel used.
Bacteruria is present in the majority of asymptomatic patients with ileal conduit regardless of anamnesis with infection or not. This emphazises the need for restriction of antibiotics to patients with true symptoms to avoid resistant bacteria development. The general practitioner should be instructed in this to avoid the routine urinary culture after antibiotic treatment. Patients with neobladders and pouches constitute typically a diagnostic enigma and full investigation is warranted including functional, anatomical and bacteriological investigations. Thus, residual urine, reflux, stenosis, concrements, poor hygiene, bad habits, co-morbidities, emptying pressure etc. should be meticulously in all but the simplest patients to avoid accelerating conditions and resistant bacteria.
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Given the relative improved prognosis of muscle invasive bladder cancer when performing modern treatment including cystectomy and a more radical approach in high-risk non-muscle invasive bladder cancer, the number of patients having long-term urinary diversions is increasing.
complications are much rarer in this simple diversion. Most infections in ileal conduit patients are thus upper tract infection. The risk of this is, however, thought to increase by three-fold compared to similar persons with the normal bladder intact. Moreover, the risk of infection is increased in conduits with uretero-entero anastomotic strictures which in itself will compromise the renal function. This emphasizes the need for attention and acute treatment in febrile patients.
in the CD tray of your computer If the applicatio n does not start Windows • automatically: Click on “Start” • Click on “Run” in your windows bar • Type “D:\start. exe” and click (If D is the drive “OK” Macintosh • of your CD player) Double click the “Abstract s2015” • Double click on the file “index.ht icon on your desktop ml” For more informat European Associati ion: on of Urology PO Box 30016, 6803 AA Arnhem, T +31 (0)26 389 The Netherlan 0680, F +31 ds (0)26 389 eau@uroweb.org, www.uroweb.org 0674 ISBN/EAN 97890797 54694
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Lower urinary tract function and urogenital infections Is UTI in a neurogenic patient different from UTI in a non-neurogenic patient? Prof. Marcus J. Drake Senior Lecturer in Urology University of Bristol and Bristol Urological Institute Southmead Hospital Bristol (UK)
In addition to the disability resulting from neurological disease, affected patients often suffer considerable detrimental effects on their medical situation and quality of life as a result of predisposition to urinary tract infection (UTI). The risk results from the combination of a range of factors, any one of which is recognised as a potential influence. They include the risks of changed lower urinary tract function (failure of urine storage and voiding), use of catheters, multiple exposures to antibiotics, increased surgical interventions, renal dysfunction and possibly immune dysfunction. Consequently, the patient suffers increased exposure to pathogens, more pathogenic organisms, and reduced ability to deal with infection. A further aspect is the potential delay in presentation, as many patients become aware of early symptoms later in the process than neurologically intact individuals. The picture of the LUT dysfunction and its management changes over the years for individual patients, even with a supposedly stable neurological dysfunction such as spinal cord injury1. Consequently, the protracted nature of the risk over many years makes UTI sometimes a challenging issue. Many patients with neurological disease have abnormal lower urinary tract (LUT) function. Urine storage is impaired due to sphincter weakness and detrusor overactivity. Consequently, there is urine contamination of the perineum, leading to damage to the epithelium, colonisation with pathogenic organisms, colonisation of the urethra, and impairment of the anatomical barrier to bacterial penetration of the bladder. Impaired voiding leads to chronic incomplete emptying and reactive debris, potentially allowing a biofilm to form, and alteration in the urothelium. If catheterization is begun by patients with recurrent or chronic UTI and urinary retention, the incidence of infection usually decreases, and this may be due to better drainage of the infected urine “sump” and debris removal. In both storage and voiding phases, vesico-ureteric reflux (Figure 1) may permit bacteria-laden urine to gain access to the upper urinary tract. In male patients, there may be reflux of urine along the prostatic ducts. Reassuringly, extended longitudinal
follow-up showed that UTIs did not represent a risk factor for deterioration in renal function in spinal cord injury1. Managing LUT dysfunction Management of LUT dysfunction often requires catheterisation, with intermittent catheterisation (IC) forming a key part of management for many patients, and use of indwelling catheters commonly needed during particular events, such as surgery or a neurological deterioration. The rate of complications associated with catheterization in myelomeningocele treated with clean IC for a minimum of 10 years is actually relatively low2. Clean IC is considered acceptable practice in the majority, while sterile IC may sometimes be advocated. In both cases, the physical effect of placement of the foreign body into the LUT represents a bacterial challenge which needs to be overcome by natural defences. A systematic Cochrane review summarizing current evidence on the relationship between sterile single-use catheters or clean re-used catheters and the incidence of UTIs3 showed there is considerable variation in length of follow-up and definitions of UTI, and all the evaluated studies were underpowered. Consequently, there are no definitive studies illustrating that incidence of UTIs is affected by type of IC. Based on the current data, it is not possible to state that one catheter method is better than another. If symptomatic infections occur, improper CIC or misuse should be considered.
bacterial persistence through bacterial adherence and mucus production. Episodes of febrile UTI (4.8-9%) are seen in people with augmentation cystoplasty, and cases of late urosepsis have been reported7. For those patients receiving Onabotulinum-A intravesical therapy, UTIs are one of the main adverse effects8, and this may be a result of multiple injection-point breaches of the urothelium in the context of a colonised LUT. Most patients with neurological disease need courses of antibiotics more often than healthy individuals. These are not just for UTI, but also for chest infections (due to weakened respiratory muscles) and skin infections. This risks a selection pressure, predisposing to resistant and virulent organisms. Abnormal bowel function may also be a factor, since many patients require assisted defaecation and anal sphincter weakness, and consequently suffer perineal contamination. Individuals with neurological disease may not be accurate at determining whether they have a UTI based on their symptoms9. Delayed presentation is partly due to reduced sensation as a consequence of the neurological impairment. Warning signs and symptoms that warrant early further investigation include; fever, pain, hematuria, catheterization problems, clinical infections and signs of autonomic dysreflexia.
UTI management is not standardised and clinical practice suffers from a weak evidence base10. The principles of the UTI management are no different Colonisation of indwelling catheters (IDCs) is inevitable from the neurologically healthy population, meaning in a short period, regardless of any attempts to give identification of organism and its sensitivities, the catheter particular structural properties. It is adequate duration courses of suitable antibiotics, recognised from high quality research that routine use removal of infection sources (e.g. abscess drainage), of antimicrobial-impregnated catheters cannot be and prevention of recurrence (e.g. antibiotic supported4. IDCs are needed permanently in some prophylaxis and bladder stone removal). patients, and temporarily in many. Increased fluid intake is often advocated, but it is not Catheterisation and instrumentation is also essential certain that this approach is logical in someone with in diagnostic assessment. Symptomatic UTI after cystometry is not infrequent and antibiotic prophylaxis has been advocated5. Randomised controlled trials (RCTs) found prophylactic antibiotics can be effective in reducing bacteriologically proven UTI after invasive cystometry for all patients6. The use of prophylactic antibiotics in urodynamics reduces the risk of significant bacteriuria. Risk factor The presence of abnormal structures in the bladder is a considerable risk factor. Patients with neurogenic LUT dysfunction are at risk of forming bladder stones as a result of urodynamic dysfunction, infection, and perhaps the altered ionic content of urine (maybe including a raised urinary calcium level due to the less physically active lifestyle for someone with muscle weakness). Where bladder enlargement or continent diversion is undertaken, the presence of a bowel segment detrimentally influences the chance of
abnormal voiding function, since they will unavoidably have to catheterise more often. Cranberry supplements used to prevent UTIs in SCI do not show significant benefit over placebo11. Many clinicians advocate antibiotic prophylaxis for recurrent UTI. A weekly oral cyclic antibiotic regimen consisting of the alternate administration of an antibiotic once per week over a period of at least two years to prevent UTI in SCI adult patients, meant that symptomatic UTI dropped from 9.4 to 1.8 per patient-year12. A randomised trial of twice-daily bladder irrigation using one of three different solutions for eight weeks with sterile saline, acetic acid, or neomycin-polymyxin solution found no detectable effect on the degree of bacteriuria or pyuria13. Management remains a challenge Overall, UTI in a neurogenic patient is different from UTI in a non-neurogenic patient in the sense of increased risk factors for exposure, persistence, resistance and upper tract involvement. The principles of treatment do not differ, but response may be adversely affected. The complex nature of the overall clinical picture makes management potentially a greater challenge. The potential impairment of multiple organ systems is influential, even if the extent of impairment may be comparatively small. Ongoing bacterial challenge is inevitable, since IC or IDC is unavoidable for many. Thus, scrupulous attention to all aspects of LUT care is needed. Ongoing research is really needed to help improve this difficult situation. NOTE: Interested readers can request for the complete reference list by sending an email to: communications@uroweb.org Saturday 12 March 10.15-14.00: Joint meeting of the EAU Section of Female and Functional Urology (ESFFU) and the EAU Section of Infections in Urology (ESIU)
SATELLITE SYMPOSIUM
Moving Forward in Urological Cancers Saturday March 12th 2016 • 18:00-19:30 Paris room (Hall B2), Level 0, ICM
Symposium Chair: Jacques Irani (France)
Prostate cancer and androgen deprivation therapies: What are the newest data? Jacques Irani (France)
Is androgen-deprivation therapy the backbone of advanced prostate cancer treatment? Axel Merseburger (Germany)
Prostate cancer in China: From fundamental research to clinical practice Liqun Zhou (China)
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)* TOPIC OF THE YEAR
*The Innovators in Bladder Cancer “Bladder Cancer Topic of the Year” will be voted on, and the results announced at the end of this presentation.
2016
Figure 1: A male patient with neurological disease. After voiding, there is a post-void residual in the bladder, and vesico-ureteric reflux is seen (arrow) 14
EUT Congress News
Treatment of urological cancers has undergone a series of important advances in recent years. This symposium will discuss key developments in the fields of prostate and bladder cancer, including an overview of the most exciting new data. Androgen-deprivation therapy (ADT) is a well-established and effective treatment for prostate cancer, but there is still further progress to be made. Recent trials have demonstrated the value of early chemotherapy plus ADT in patients with metastatic disease – results that are likely to revolutionise future treatment. In addition, combining ADT with other recently approved therapies in castration-resistant prostate cancer may provide an opportunity for overcoming ADT resistance. The prostate cancer treatment landscape is also evolving outside of Europe. China, for example, has considerably increased investment in prostate cancer research over recent years, thereby contributing greatly to the literature on the treatment, diagnosis and genetics of the disease. Bladder cancer treatment has also seen a number of exciting new developments recently. For example, data from recent clinical studies have demonstrated that higher-quality transurethral resection of the bladder can be achieved using improved imaging techniques. However, are these results transferable to clinical practice?
Saturday, 12 March 2016
Anterior urethra reconstruction: Tips and tricks Penile urethra reconstruction remains a challenge with a high complication rate Dr. Guido Barbagli Centro Chirurgico Toscano Arezzo (IT)
Co-Authors: Sofia Balo (Arezzo, IT), Salvatore Sansalone (Rome, IT), Massimo Lazzeri (Milan, IT) Anterior urethra includes penile and bulbar tracts. We present here some tips and tricks we use in our practice in performing penile urethroplasty. We limited the scope of this article only to the reconstruction of the penile urethra, because in the Meeting of the EAU Section of Genito-Urinary Reconstructive Surgeons (ESGURS), the tips and tricks of the bulbar urethra reconstruction will be presented by Prof. Margit Fisch and we like to avoid any overlap presentation. Penile urethroplasty should be done in one or two-stage repair using skin flap or oral free graft from the mouth. The purpose of the tips and tricks we suggest here is to make one or two-stage penile urethra reconstruction, safe, effective and easily reproducible in the hands of any surgeons. Surgical repair technique Lichen sclerosus (LS), failed hypospadias repair (FHR), urethral instrumentation and catheter are the main causes of penile urethral strictures in developed countries1,2,3. Gonococcal urethritis remains the most frequent cause of stricture in developing countries but there also seems to be a trend of an increase of instrumentation and catheter-related strictures in these countries as well4. The surgical repair technique for a penile urethral stricture is mainly related to the stricture etiology, because LS and FHR strictures more frequently require a two-stage approach5,6. The repair of penile strictures should be done, whenever possible, using a one-stage procedure, saving the patient the noticeable changes in aesthetic penile appearance and the discomfort of an abnormal site of the external urinary meatus, necessitating to void in sitting position. There are two main questions still open in the literature about penile urethra reconstruction: in one-stage repair is it better to use a skin pedicled flap or an oral mucosa free graft?7. In two-stage repair, when and how should an oral mucosa graft be used? We present here, step by step, our revised and updated techniques of one-stage and two-stage penile urethroplasty using oral mucosa graft including the use of a new glue and a new approach for staged urethroplasty.
Patients with a history of FHR represent a challenging problem and, whenever possible, we need to offer the patient the opportunity to solve the stricture using a one-stage approach. Patients with FHR-related strictures associated with fistulae, scarred penile skin, chordee, abnormal meatus, small glans and deficiency of the dartos layer may require a two-stage approach5,6,8. Before planning any type of penile urethroplasty, it is mandatory to perform a retrograde and voiding urethrography and to make a calibration of the external urinary meatus by the progressive insertion of 10,12,14,16 F Nelaton catheters. Before the surgery it is very important to establish if the stricture involves the meatus and the navicularis tract. Surgical techniques One-stage penile urethroplasty using oral mucosal graft and glue Three days prior to surgery, the patient should begin using chlorhexidine for mouth cleansing twice a day. The day before surgery the patient receives intravenous prophylactic antibiotics. The patient is intubated through the nose, and two surgical teams work simultaneously, one harvesting the graft and one preparing the urethra. The oral mucosa is harvested from the cheek according to our standard technique9. The graft is harvested according to the stricture characteristics. The patient is placed in a simple supine position. A suture is placed in the glans to stretch the penis. In strictures involving the external urinary meatus and extending into the distal part of the penis, the penile urethra is approached by circular sub-coronal incision and penile degloving. In more proximal strictures the penile urethra is approached by a midline longitudinal incision of the penile skin or by perineal approach. We used, with some important changes, the technique described in 2001 by Asopa et al.10. The distal site of the stricture is identified by a Nelaton 16 F. catheter through the meatus. The urethra is longitudinally opened extending for 2 cm in the distal and proximal healthy urethra, and the urethral mucosal plate is longitudinally incised (Fig. 1A). The longitudinal incision of the urethral plate is transformed into a wide window (Fig. 1B). Two ml of glue (Glubran 2®) are injected onto the window of the urethral plate. The graft is moved over the glue bed and pressed using two small swabs for 45 seconds.
In one-stage penile urethroplasty is it better to use a skin flap or oral graft? The current literature does not offer any evidence for graft vs. flap and we believe that the choice should be based on stricture characteristics, surgeon background and preference5,6,7,10,12. In our experience, the use of oral graft to repair penile strictures using a one-stage technique provides a higher success rate compared to the use of penile skin flaps12. Figure 3: A: The skin incisions and the midline incision of the urethral plate are outlined. B: The incision of the urethral plate is transformed into a wide window. C: No quilted sutures are used to fix the graft. D: The urethra is closed over a Foley 12 F. silicone grooved catheter.
to the margins of the urethral plate and the new urinary meatus is located in the healthy urethral mucosa 2 cm proximally to the stricture (Fig 2B). A Foley 12 F silicone catheter is left in place for three days (Fig. 2C). A soft dressing is applied. An ice-bag is placed on the genital area for 24 hours to reduce pain and hematoma formation. Three days after surgery the dressing and catheter are removed and patients are discharged from the hospital. Every four months the patient is requested for a follow-up visit to perform uroflowmetry and a calibration of the new external urinary meatus by progressive insertion of 10,12,14,16 F Nelaton catheters. The clinical outcome is considered a failure when any postoperative instrumentation is required, including dilation. Uroflowmetry and urine cultures are repeated every four months in the first year and annually thereafter. When symptoms of decreased force of stream are present and uroflowmetry is less than 14 ml per second, the urethrography, urethral ultrasound and urethroscophy are repeated. Six months after the first stage the patient is evaluated for closure of the urethra by second-stage urethroplasty. Second-stage using oral mucosal graft and glue (Glubran 2®) The patient is intubated through the nose, allowing the mouth to be completely free, and two surgical teams work simultaneously, one harvesting the graft and one preparing the urethra. The oral mucosa is harvested from the cheek according to our standard technique9. The graft is harvested according to the stricture characteristics. The patient is placed in a simple supine position. A suture is placed in the glans to stretch the penis. Before starting the urethra reconstruction the new meatus is calibrated by progressive insertion of 10,12,14,16 F Nelaton catheters.
If the new meatus is well calibrated to 16 F. we begin the second stage. If the meatus don’t accept the 16 F. Nelaton catheter, we perform meatotomy and the second stage reconstruction is delayed for six more months. The lateral skin incisions and the midline incision of the urethral plate are outlined (Fig. 3A). Figure 2: A: The urethra is longitudinally opened. B: The skin Selection and pre-operative evaluation of patient margins are sutured to the margins of the urethral plate and the The urethral plate is fully longitudinally incised and The majority of patients presenting penile strictures the longitudinal incision of the urethral plate is new urinary meatus is located in the healthy urethral mucosa. transformed into a wide window (Fig. 3B). Two ml of due to urethral instrumentation or catheter are good C: A Foley 12 F. silicone grooved catheter is left in place. glue (Glubran 2®) are injected onto the window of the candidates for one-stage urethroplasty using oral urethral plate. The graft is moved over the glue bed mucosal graft. In patients with histological proven LS, and pressed using two small swabs for 45 seconds. presenting obliterative external urinary meatus No quilted sutures over the graft are used (Fig. 1C). No quilted sutures over the graft are used (Fig. 3C). associated with navicularis and distal penile A Foley 12 F. silicone grooved catheter is inserted. strictures, it is mandatory to have complete excision of The urethra is closed in a single layer over it using 5/0 A Foley 12 F. silicone grooved catheter is inserted. The urethra is closed in a single layer over it using 5/0 the diseased urethral segments and tissues which polyglactin sutures (Fig. 1D). The dartos fascia is polyglactin sutures (Fig. 3D). The dartos fascia is should be replaced with oral mucosa in a two-stage closed over the suture line. The penile skin is closed closed over the suture line. The penile skin is closed repair, because LS does not affect the oral mucosa5,6,8. meticulously and a soft dressing is applied. meticulously and a soft dressing is applied. Ice-bags are placed on the cheek and genital area for Ice-bags are placed on the cheek and genital area for 24 hours to reduce pain and hematoma formation. 24 hours to reduce pain and hematoma formation. Patients are discharged from the hospital three days Patients are discharged from the hospital three days after surgery and voiding cystourethrography is after surgery and voiding cystourethrography is performed two weeks later. The clinical outcome is performed two weeks later. The clinical outcome is considered a failure when any postoperative considered a failure when any postoperative instrumentation is required, including dilation. instrumentation is required, including dilation. Uroflowmetry and urine cultures are repeated every Uroflowmetry and urine cultures are repeated every four months in the first year and annually thereafter. four months in the first year and annually thereafter. When symptoms of decreased force of stream are When symptoms of decreased force of stream are present and uroflowmetry is less than 14 ml per present and uroflowmetry is less than 14 ml per second, the urethrography, urethral ultrasound and second, the urethrography, urethral ultrasound and urethroscophy are repeated. urethroscophy are repeated. Two-stage penile urethroplasty Discussion First-stage Using the techniques we present here, you will be Figure 1: A: The urethra is opened and the urethral plate is This technique was described by Johanson in 195311. able to repair the majority of penile strictures using a longitudinally incised. B: The incision of the urethral plate is The patient is placed in a simple supine position. A one-stage or two-stage techniques, excluding transformed into a wide window. C: No quilted sutures are suture is placed in the glans to stretch the penis. The used to fix the graft. D: The urethra is closed over a Foley 12 F. urethra is fully longitudinally opened along its ventral patients with LS requiring substitution urethroplasty silicone grooved catheter. surface (Fig. 2A). The penile skin margins are sutured with oral mucosa at the first stage.
Saturday, 12 March 2016
We prefer the use of an oral graft as the primary choice for one-stage penile urethroplasty and we choose to use a vascularized pedicled skin flap in failure redo-cases. The use of the graft entails a non-invasive surgery which better preserves all penile components (foreskin, dartos), greatly reducing the risk of complications (penile/glans torsion, hematoma, infection, skin necrosis, fistula, diverticulum). In two-stage repair, when and how should an oral mucosa graft be used? In patients with complex penile strictures related to LS or FHR the rationale for the use of two-stage repair using oral mucosa is well documented in the literature5,6,8,13,14. However, we have recently changed our practice. We use the oral mucosa at the first stage only in patients with LS. In any patient with complex penile stricture due to FHR requiring two-stage repair, we do not use the oral graft at the first stage. This is due to the fact that in our previous experience only 61% of patients who underwent staged procedure required two surgical steps for the final urethral reconstruction and 39% of cases required more than two steps for scarring and retraction of the transplanted graft requiring revision (Fig. 4)15.
Figure 4: Retraction of oral mucosal graft after first stage urethroplasty.
Andrich et al. reported that revisions are common with two-stage procedures and in approximately 50% of cases a two-stage repair will turn out in practice to be three stages8. In our experience the use of Johanson’s opening of the penile urethra at the first stage, without using any substitution of oral graft, appears to be more suitable for an anatomical reconstruction at the second stage using an oral Asopa’s graft inlay, and may avoid retraction and scarring of the graft requiring a high incidence of revision rates. Penile urethra reconstruction remains a challenging problem presenting high complications rate. The aim of our work is to simplify the surgical techniques and improve the success rate of any type of urethroplasty. Penile urethra reconstruction involves not only functional, but also aesthetic and sexual aspects, and outcome evaluations may differ greatly between the surgeon’s point of view and patient’s point of view. Conclusions Recently, we have greatly changed and improved our techniques for penile urethra reconstruction. Using the non-invasive techniques we presented here any surgeon will be able to repair the majority of simple (one-stage repair) or complex (two-stage repair) penile strictures. Note: Interested readers can request for the full reference list by sending an email to: communications@uroweb.org. Saturday 12 March 10.15-15.45: Meeting of the EAU Section of Genito-Urinary Reconstructive Surgeons (ESGURS) Uro-genital reconstructive surgery: Personal tips and tricks
EUT Congress News
15
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
Saturday, 12 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 Saturday, 12 March 2016
EUT Congress News
17
Challenging the evidence Medically induced stone passage: Are the EAU guidelines wrong? Prof. Christian Seitz Vice Chairman Department of Urology Medical University of Vienna Vienna (AT)
The term “evidence” in medicine is found for the first time shortly after the Scottish physician James Lind published the first ever clinical trial in 1753. His results definitively established the superiority of citrus fruits above all other treatments for scurvy. In 1793 “evidence” was mentioned in the publication “An attempt to improve the Evidence of Medicine” by the Scottish physician George Fordyce. Another Scottish physician marked the start of present international efforts in “evidence-based medicine” with the book “Effectiveness and Efficiency: Random Reflections on Health Services” published by Archie Cochrane in 1972. His work further contributed to an increasing acceptance of controlled studies and was recognized by naming the Cochrane Collaboration after him. Meanwhile, finding evidence and using that evidence to make clinical decisions has become routine. A cornerstone of evidence-based medicine (EBM) is the hierarchical system of classifying evidence known as the levels of evidence.
Levels
Types of evidence
1a
Evidence obtained from meta-analysis of randomized trials Evidence obtained from at least one randomized trial Evidence obtained from one well-designed controlled study without randomization Evidence obtained from at least one other type of well-designed quasi-experimental study Evidence obtained from well-designed nonexperimental studies, such as comparative studies, correlation studies and case reports Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities
1b 2a 2b
3
4
Grades Nature of recommendations A
Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomized trial Based on well-conducted clinical studies, but without randomized clinical trials Made despite the absence of directly applicable clinical studies of good quality
B C Table 11
comprising of small, predominantly single center trials. Hence, being prone to larger treatment effects than multicenter trials5. This is in agreement with Bellomo et al. reporting that positive results of single center trials could not be reproduced in multicenter settings6, suggesting that this should be considered when results of RCTs are interpreted5. With these limitations in mind MET was recommended by the EAU Urolithiasis Guidelines, having been aware that large, multicentric randomized clinical trials are needed to obtain reliable answers, thus confirming present evidence. Meta-analyses of small RCTs rather generate hypotheses for more reliable RCTs than providing the best possible evidence7. This emphasizes the need for high-quality trials with wide inclusion criteria. Consequently, to contribute to resolve uncertainty about MET the multi-centric, double blinded, placebo-controlled trials from Pickard et al.8 and Furyk et al.9 including 1136 and 403 patients, respectively were recently published. Pickard et al. reported that 80% of 379 participants in the placebo group did not need further intervention by four weeks, compared with 81% of 378 in the tamsulosin group and 80% of 379 in the nifedipine group. No difference was noted between active treatment and placebo (p=0,78), or between tamsulosin and nifedipine (p=0,77)8. Pickard et al. concluded that tamsulosin 0.4mg and nifedipine 30mg are not effective at decreasing the need for further treatment to achieve stone clearance in four weeks for patients with expectantly managed ureteric colic8. Furyk et al. conducted a randomized, double-blind, placebo-controlled, multicenter trial of adult participants with stones detected on computed tomography (CT)9. Patients were allocated to 0.4mg of tamsulosin or placebo daily for 28 days. Different to the study from Pickard et al in which the primary endpoint was the effectiveness in decreasing the need for further treatment primary outcomes were stone expulsion on CT at 28 days and time-to-stone expulsion8,9. These are important, methodologically sound trials, with robust means of concealment of allocated treatment challenging the evidence that MET is effective in the routine expectant management of ureteral stones. However, the study from Furyk et al. demonstrated 19.4% higher stone expulsion rates in stones >5mm compared to distal ureteral stones <5mm. Therefore, the authors concluded that in the subgroup with large stones (5 to 10 mm), tamsulosin did increase passage and should be considered9.
secondary outcomes assessed with surveys, which were not adequately powered and suffered from significantly decreased follow-up rates when compared with the primary outcome (62% vs. 97%)10. EAU Guidelines update 2016 Based on those two large RCTs, MET seems to be ineffective. However, although Furyk et al. found that treatment with tamsulosin did not affect overall stone passage there was an apparent trend to benefit in patients with large stones (>5 mm) with a difference of 19.4% (95% CI –39.2% to 0.3%; P=0.06). Stone passage in patients with small stones (<5mm) was almost identical in both groups with a difference of 1,1% (95% CI –9.3% to 7.6%; P=0.84) supporting previous reported evidence that small stones have a high probability of spontaneous expulsion independent of MET9. Although not primarily investigated, results of those recent trials raise doubts in the effectiveness of MET using alpha- or calcium channel blocker not only for ureteral stones and generated fragments but also for their capability of limiting pain. Therefore the 2016 EAU Guideline on Urolithiasis update acknowledges that there is evidence in a large number of small single center trials that MET accelerates spontaneous passage of ureteral stones and fragments generated with SWL, and limits pain. However, there is new evidence from multicentric high quality trials challenging that MET (tamsulosin and nifedipine) has no expulsive effect nor limits pain in patients with ureteral stones. Taking those recent multi-centric RCTs into consideration the new recommendation for MET, was changed from: “for MET α-blockers are recommended” to: “for MET α-blockers are an option and patients should be counseled regarding the lack of efficacy in a recent large multicentric trial, attendant risks of MET, including the associated drug side effects, and should be informed that it is administered off-label.”
Although RCTs are often assigned the highest level of evidence, not all RCTs are conducted properly and results should be handled carefully. Poorly conducted RCTs may report a negative result due to low power when in fact a real difference exists between treatment groups. To judge the quality of RCTs scales such as the Jadad scale have been developed. Quality The lack of urologic intervention in the study from assessment includes: randomization, blinding, a description of the randomization and blinding Pickard et al. is an imprecise surrogate marker for evaluating the true efficacy of MET for stone expulsion. process, description of the number of subjects who withdrew or drop out of the study; the confidence A more accurate assessment of true stone passage could have been provided with computed tomography intervals around study estimates; and a description of imaging. However, this would have resulted in the power analysis. However, taking only high quality RCTs into consideration based on e.g. the Jadad scale additional costs and radiation doses. Additionally, does not exclude bias caused by the nature of a small there were no significant differences in pain scales or single center RCT. number of rescue pain medication. These were
Medical Expulsive Therapy (MET) The 2015 EAU Guidelines on Urolithiasis reported an increased efficacy for medical expulsive therapy in distal ureteral stones based on high-quality metaanalyses published e.g. in Lancet 20062, European Urology 20093 and the Cochrane Database of Systematic Reviews 20144 including each over 690, 2400 and 5800 patients, respectively. Although results were encouraging for the use of alpha blockers or calcium channel blockers to facilitate stone expulsion of distal ureteral calculi smaller than 10mm, the included RCTs had a risk of publication bias and different degrees of heterogeneity.
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Additionally, treatment effects are likely to be overestimated. The influence of trial sample size on treatment effect estimates within meta-analyses has been assessed by Dechartres et al. Compared to meta-analyses with ≥ 1000 patients a 48% larger treatment effect was found in trials with less than 50 patients. Possible explanations for the association between trial sample size and treatment effects regardless of sample size could be reporting bias, whereas smaller studies are more prone to publication bias12. Another mechanism is the difference in methodological quality by sample size. The larger the sample size, the greater the heterogeneity in patient selection or implementing interventions12. Further work is required to investigate the phenomenon of large, high-quality trials showing smaller effect size than meta-analysis of several small, single center, lower-quality studies. Results of meta-analyses should be subjected to careful sensitivity analyses to test the robustness of the findings. The question raises whether all available evidence must be included in meta-analyses. To minimize publication bias trial registration should be a prerequisite of ethics committees in the approval of studies. Meta-analyses based on small, single center trials should be interpreted on principle with caution even if the pooled effect is statistically significant. If the overall results of RCTs show highly significant evidence of a worthwhile effect of treatment, but one large RCT indicates no benefit, then the appropriate question is whether there is good enough evidence that this treatment should be denied to these patients.
Limitations of RCTs and meta-analyses The question is whether to base treatment decisions References on meta-analyses comprising of single center, small, mainly low-quality trials favoring MET or on two large 1. Phillips B, Ball C, Sackett D, Badenoch D, Straus S, high-quality trials with a finding of no significant Haynes B, Dawes M: Oxford Centre for Evidence-based effect. What is the future role of small single center Medicine Levels of Evidence 1998 Updated by Jeremy RCTs on evidence-based medicine? Howick March 2009. In.; 2009.
However, it is important that readers do not assume that level 1a evidence is always the best choice for the research question, simply because outcome of a meta-analysis depends on the quality of RCTs included. It unlikely provides the same quality of results if its standards are less stringent.
The vast majority of trials included in those metaanalyses were found to be of low-to-moderate quality. Variability in trial design consisted of inadequate blinding, selection of patient populations with predominately small ureteral stones, differing inclusion criteria and outcome measurements,
Assuming that data included in a meta-analysis were stringent and of high-quality, significant information may still be lacking. Data on patient withdrawal after randomization or patients lost to follow-up may alter treatment efficacy. Publication bias is a serious often underestimated issue. As small trials are more likely to be affected by publication bias, larger trials have a higher probability to be published irrespective of clinical significance.
2. Hollingsworth JM, Rogers MA, Kaufman SR, Bradford TJ, Saint S, Wei JT, Hollenbeck BK: Medical therapy to facilitate urinary stone passage: a meta-analysis. Lancet 2006, 368(9542):1171-1179. 3. Seitz C, Liatsikos E, Porpiglia F, Tiselius HG, Zwergel U: Medical therapy to facilitate the passage of stones: what is the evidence? Eur Urol 2009, 56(3):455-471. 4. Campschroer T, Zhu Y, Duijvesz D, Grobbee DE, Lock MT: Alpha-blockers as medical expulsive therapy for ureteral stones. Cochrane Database Syst Rev 2014, 4:CD008509. 5. Dechartres A, Boutron I, Trinquart L, Charles P, Ravaud P: Single-center trials show larger treatment effects than multicenter trials: evidence from a meta-epidemiologic study. Ann Intern Med 2011, 155(1):39-51. 6. Bellomo R, Warrillow SJ, Reade MC: Why we should be wary of single-center trials. Crit Care Med 2009, 37(12):3114-3119. 7. Pogue J, Yusuf S: Overcoming the limitations of current meta-analysis of randomised controlled trials. Lancet 1998, 351(9095):47-52. 8. Pickard R, Starr K, MacLennan G, Lam T, Thomas R, Burr J, McPherson G, McDonald A, Anson K, N’Dow J et al: Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet 2015, 386(9991):341-349. 9. Furyk JS, Chu K, Banks C, Greenslade J, Keijzers G, Thom O, Torpie T, Dux C, Narula R: Distal Ureteric Stones and Tamsulosin: A Double-Blind, Placebo-Controlled, Randomized, Multicenter Trial. Ann Emerg Med 2016, 67(1):86-95.e82. 10. Gottlieb M, Nakitende D: Comparison of Tamsulosin, Nifedipine, and Placebo for Ureteric Colic. CJEM 2015:1-3. 11. Türk C, Knoll T, Petrik A, Sarica K, Skolarikos A, Straub M, Seitz C: EAU Guidelines on Urolithiasis. In.; 2015. 12. Dechartres A, Trinquart L, Boutron I, Ravaud P: Influence of trial sample size on treatment effect estimates: meta-epidemiological study. BMJ 2013, 346:f2304.
Saturday 12 March 8.30-10.15: Plenary Session 1 Evidence-based medicine vs common practice / Challenging the evidence Medically induced stone passage: Are the EAU guidelines wrong? Stones in kidney can move and block the ureter. Photo: Courtesy of Mayo Clinic
Saturday, 12 March 2016
Renal tumour biopsy: Is it really established? RTB gains momentum but limitations still exist Dr. Umberto Capitanio Unit of Urology, University Vita-Salute San Raffaele Scientific Institute Milan (IT)
Historically, the use of Renal Tumour Biopsies (RTBs) was limited by concerns about safety, collection of inadequate tissue for diagnosis, discordance with final pathology, and, most importantly, the lack of perceived impact on clinical management1. Although RTBs remain globally underutilized2, in the last years such approach has been newly proposed due to the increasing evidence showing that treatment of renal mass should be tailored according to each patient and tumour characteristics, and that surgery should be limited to those who can benefit the most3. Unfortunately, abdominal imaging still has – and probably will have - limited ability to characterize the histology and the biological aggressiveness of renal lesions1. In this setting, RTBs can integrate abdominal imaging for a better planning of patients’ management. For example, RTBs can be considered in incidentally detected small renal masses, to exclude the presence of a benign condition which can be just observed, even in the younger patients. Likewise, in elderly and sicker patients, RTBs can confirm the presence of a low-grade localized renal tumour, which can be treated with percutaneous cryoablation or radiofrequency4, avoiding major surgery.
Several molecular and genetic tissue markers have been investigated as potential prognosticators for RCC, including markers typically associated with renal cell carcinogenesis and progression (von Hippel-Lindau, hypoxia-induced factor 1 alpha, VEGF, CAIX, etc.) and markers that have been extensively described and investigated in other malignancies (p53, Ki67, CXCR3, CXCR4, matrix metalloproteinases 2 and 9, vimentin, survivin, etc.)2. The application of the upcoming translational findings to the tissue retrieved by RTB will provide adequate characterization of histology and natural history of renal masses. Safety concerns With respect to safety, RTB is nowadays well characterized. In particular, the routine use of a coaxial technique is strongly recommended and plays an important role in avoiding the risk of needle track seeding, which has not anymore been reported in the modern series1. Furthermore, the use of 18-gauge needles allows for good diagnostic results with limited risk of clinically significant bleeding. Reported complication rate is low (<9%), with anecdotal major complications (ClavienDindo≥3a: <0.2%, mainly percutaneous angioembolization)6. Having said that, is RTB really established? Although most of the historical concerns about RTBs have been clarified, some uncertainties remain, such as:
CT scan showing a small (intrarenal) mass of the right kidney. Percutaneous biopsy revealed the presence of renal oncocytoma
In a very interesting recent report, Richard and colleagues retrospectively reviewed the diagnostic performance of 529 patients who underwent RTBs at a single large-volume institution6. Richard et al. showed that in centres with appropriate experience, RTBs can be very reliable for the characterization of malignancy and histotype of renal tumours. The diagnostic yield of biopsies was 90%, reaching 94% when a repeat biopsy was performed after a failed one. Overall, 20% of RTBs harboured benign disease, avoiding the need for additional active treatment. Biopsy histology and nuclear grade were highly concordant with final pathology (93% and 94%, respectively)6. One of the most exciting aspects in the setting of RTBs is that translational research has been increasingly delivering novel insights in our ability to diagnose and characterize renal masses. Immunohistochemistry, cytogenetic analyses, and gene expression profiling have been historically applied on whole-tumour specimens. However, the assessment of molecular and genetic markers on adequate biopsy tissue is possible and can potentially provide important information before treatment decisions2. Saturday, 12 March 2016
In a recent report, Ball et al. quantified nuclear grade heterogeneity in small renal masses. Overall, 81% of the samples were heterogeneous, including 15 of 16 (93.8%) high-grade specimens. Median fraction of low-grade tissue in high-grade specimens was roughly 40%, meaning that the risk of under sampling high-grade tumours may not be insignificant when interpreting renal mass biopsy findings7.
d) Finally, it remains to be determined whether the efforts to limit unnecessary surgical indications by performing RTBs will lead to an effective decrease of surgery-related adverse events (for instance perioperative complications and long-term renal function) without jeopardizing cancer control11. RTB gains momentum In conclusion, RTB is gaining the momentum of a new renaissance: although many limitations still exist, the increasing knowledge about renal cancer genetic and molecular profiling is going to overcome these aspects and to further expand RTBs indication to better guide individual management of patients. Undoubtedly, many other efforts coming from the scientific community are still required to maximise patient management.
a) It is not clear whether the excellent outcomes of References RTBs in highly-experienced tertiary care institutions can be easily generalized to all centres 1. capitanio U, Montorsi F. Renal cancer. Lancet 2015. in the community setting. The current data proves doi:10.1016/S0140-6736(15)00046-X. that multidisciplinary and skilled teams of 2. Volpe A, Finelli A, Gill IS, Jewett MAS, Martignoni G, urologists, interventional radiologists, and Polascik TJ, et al. Rationale for percutaneous biopsy genitourinary pathologists are crucial to ensure and histologic characterisation of renal tumours. Eur high diagnostic yield and accuracy of biopsies1. Urol 2012;62:491–504. doi:10.1016/j. b) Further efforts are needed to standardize ideal biopsy patterns to maximize overall accuracy in cancer detection and characterization. There is currently agreement that 18-gauge needles are ideal for RTB, allowing a safe procedure and sufficient tissue for an accurate diagnosis in the majority of cases2 but the ideal number and location of biopsies for obtaining a diagnosis have not been clearly defined. Even an unflawed biopsy may sample only a small fraction of a renal mass.
Finally, in frail metastatic patients for whom cytoreductive nephrectomy cannot be recommended, RTBs enable the selection of the most suitable targeted therapy based on tumour histology3. Although these examples represent only a portion of all kidney cancer diagnoses, clinical decisions can be influenced by RTBs outcomes. By knowing the histology before removal, clinicians can look into the surgical indication, avoid the potential morbidity associated with an upfront invasive management, decide the correct timing and, finally, provide a precise informed consent to the patients5.
sampled and whether future evolutionary tumour branches might be predictable and ultimately targetable10.
The volume of a sample obtained per pass using an 18-gauge biopsy needle with an inner diameter of 0.04 cm and maximum core length of 2.2 cm is roughly 0.01 cm3. This means, for instance, that with two cores only 2% of a 1 cm tumour is sampled and the likelihood of missing a high-grade component when such a small sample is obtained is not insignificant7. Some authors have also proposed to combine fine needle aspiration biopsy and core biopsy during the same procedure, to increase the rate of diagnostic material8. It also needed to be determined how to address the issue of cystic renal masses, which can be characterized to significantly poorer diagnostic performance of biopsy9.
c) Even more importantly, further studies are warranted to clarify the issues of intratumour heterogeneity and inter-observer variability, especially in the assessment of tumour grade. The uncertainties regarding the risk of misdiagnosing hybrid tumours containing benign and malignant histology (mainly oncocytoma and chromophobe carcinoma) have been reduced recently by the finding that <3% of patients with solitary, sporadic, solid benign renal masses show concomitant malignant histology, and none harbour high-grade pathology9. However, understanding the degree of phenotypic and genotypic heterogeneity in a small renal mass may have implications for interpreting renal mass biopsy data and clinical decision.
Using multi-region exome sequencing, Gerlinger et al. demonstrated an impressive intratumour heterogeneity in somatic mutations and genomic copy number across multiple regions in primary tumours and metastatic lesions in renal cancer patients10. The regional isolation of tumour clades, together with extensive evidence of parallel evolution of tumour sub-clones, raised important questions regarding how such diseases can be optimally
eururo.2012.05.009. 3. Ljungberg B, Bensalah K, Canfield S, Dabestani S, Hofmann F, Hora M, et al. EAU Guidelines on Renal Cell Carcinoma: 2014 Update. Eur Urol 2015;67:913–24.
doi:10.1016/j.eururo.2015.01.005. 4. Zargar H, Atwell TD, Cadeddu JA, la Rosette de JJ, Janetschek G, Kaouk JH, et al. Cryoablation for Small Renal Masses: Selection Criteria, Complications, and Functional and Oncologic Results. Eur Urol 2015:1–13. doi:10.1016/j.eururo.2015.03.027. 5. Larcher A, Fossati N, Tian Z, Boehm K, Meskawi M, Valdivieso R, et al. Prediction of Complications Following Partial Nephrectomy: Implications for Ablative Techniques Candidates. Eur Urol 2015. doi:10.1016/j. eururo.2015.07.003. 6. Richard PO, Jewett MAS, Bhatt JR, Kachura JR, Evans AJ, Zlotta AR, et al. Renal Tumor Biopsy for Small Renal Masses: A Single-center 13-year Experience. Eur Urol 2015;68:1007–13. doi:10.1016/j.eururo.2015.04.004. 7. Ball MW, Bezerra SM, Gorin MA, Cowan M, Pavlovich CP, Pierorazio PM, et al. Grade heterogeneity in small renal masses: potential implications for renal mass biopsy. J Urol 2015;193:36–40. doi:10.1016/j.juro.2014.06.067. 8. Parks GE, Perkins LA, Zagoria RJ, Garvin AJ, Sirintrapun SJ, Geisinger KR. Benefits of a combined approach to sampling of renal neoplasms as demonstrated in a series of 351 cases. The American Journal of Surgical Pathology 2011;35:827–35. doi:10.1097/PAS.0b013e31821920c8. 9. Ginzburg S, Uzzo R, Al-Saleem T, Dulaimi E, Walton J, Corcoran A, et al. Coexisting Hybrid Malignancy in a Solitary Sporadic Solid Benign Renal Mass: Implications for Treating Patients Following Renal Biopsy. J Urol 2014;191:296–300. doi:10.1016/j. juro.2013.07.059. 10. Gerlinger M, Horswell S, Larkin J, Rowan AJ, Salm MP, Varela I, et al. Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nat Genet 2014;46:225–33. doi:10.1038/ ng.2891. 11. capitanio U, Volpe A. Renal Tumor Biopsy: More Dogma Belied. Eur Urol 2015;68:1014–5. doi:10.1016/j. eururo.2015.05.007.
Friday 11 March 13.15-15.45: Joint Session of the European Association of Urology (EAU) and the Société Internationale d’Urologie (SIU)
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
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Treatment options for oligometastatic bladder cancer Paolo Gontero Associate Professor of Urology Urology Unit, Department of Surgical Sciences Molinette Hospital, University of Studies of Torino Torino (IT) The word “oligometastatic” disease does not match any Medline search in the context of urothelial bladder cancer (UBC) and hence there is no definition available. Based on scanty literature reports addressing the potential curative role of multimodal therapies including surgical extirpation for limited disease outside the bladder (nodal and systemic), the following definition for oligometastatic UBC is herein proposed: any clinical evidence of urothelial disease outside the bladder involving either the lymph nodes (LNs) up to the retroperitoneum and/or “limited” metastatic deposits located in more distally LNs or visceral organs and potentially amenable for treatment with curative intent. The counterpart of oligometastatic UBC is represented by advanced and grossly or multiple (> 5) metastatic disease at presentation. These latter may potentially be rendered “oligometastatic” after systemic therapy (chemotherapy) and thus become potentially curable with surgical consolidation. European guidelines do not distinguish between clinical LN positive UBC and disease located in other system organs: both entities are defined as metastatic UBC to be treated primarily with cysplatin-containing combination chemotherapy. However they do acknowledge the existence of prognostic factors that may affect response and survival (Bajorin DF, 1999). Chiefly, patients with LNs metastases, good PS and adequate renal function may obtain excellent response rates with up to 20% achieving long-term disease-free survival (von der Maase H, 2005). Conversely, the presence of visceral metastases is an independent poor prognostic factor for survival (Bajorin DF, 1999). It is likely that the difference in aggressiveness between nodal metastases only and extranodal disease will also occur in the setting of oligometastatic disease. Postchemotherapy surgery after partial or complete response is mentioned as a potential contributor to long term disease-free survival (Witjes JA, 2015). The aim of this report is to address the current evidence of the available treatment options for “oligometastatic” bladder cancer (as per the definition above), the role of a multimodal therapeutic strategy and the future perspectives of this complex disease entity. Staging issues for oligometastatic bladder cancer Diagnostic accuracy in the detection of LN and visceral metastatic deposits is a prerequisite for a reliable evaluation of treatment efficacy. The American Joint Committee on Cancer 2010 TNM Staging System defines the extent of LN disease as follows: N1—single regional lymph node in the true pelvis, N2—multiple regional lymph nodes, N3— common iliac lymph node involvement, and M1—distant lymph nodes restricted to retroperitoneal space. CT, currently the gold standard staging procedure in UBC (McKibben MJ, 2015), or MRI, mostly base LN staging on the assessment of nodal status size. Hence sensitivities are low, ranging 48-87% due to inability to identify metastases in normal-sized nodes. Specificities are also low (64%) as nodal enlargement may be the result of benign pathology (Witjes JA, 2015). Similar considerations hold true also for visceral metastases. Up to 30% of UBC treated with cystectomy with curative intent will recur, in the majority of cases as systemic disease, meaning the presence of micrometastatic disease undetected at initial staging (Stein JP, 2001). Limitations of current staging modalities need to be taken into account when interpreting treatment response in metastatic UBC. New diagnostic tools that allow for assessment of metabolic activity of tissue such as PET CT or MR may improve restaging and evaluation of response to chemotherapy but needs further evaluation (McKibben MJ, 2015). In the 1980s, methotrexate, vinblastine, doxorubicin (Adriamycin) and cisplatin (M-VAC) was introduced as an effective chemotherapy regime for metastatic UBC, with an overall response rate of around 60% and a 20
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median survival period of 13-14 months. These data fared well with previous median survival rates rarely exceeding three to six months (Sternberg CN, 1988). Response rates in pelvic and retroperitoneal nodes have been reported to be superior compared to extranodal sites (65-75% vs 30% respectively) (Sternberg CN, 2001). Subsequently, a combination of gemcitabine and cisplatin (GC) was shown to be equally effective but less toxic and adopted as the new standard regime in advanced UBC (Von der Maase H, 2000).
thoracotomy for UBC. Since then few retrospective series (Table 2) have addressed the role of metastasectomy in UC. As expected, inclusion criteria lacked homogeneity. First, mixed series of UBC and upper tract UC were included. The number of metastatic deposits was generally limited (never exceeding five) as well as the number of metastatic sites (1-3), matching our definition of oligometastatic disease. Lungs were the most common visceral metastatic sites followed, albeit, a few patients with regional LN disease only were also included.
Despite relatively high response rates to first-line chemotherapy, durability of response remains inadequate. The overall five-year survival following cisplatin-containing combination chemotherapy is only approximately 10-20%, the upper threshold being represented by LN disease only (21% 5y CSS) compared to only 6.8% in patients with visceral metastases (von der Maase H, 2005). Furthermore, it has been estimated that as many as 50% of the patients with advanced or metastatic UC will not be candidates to receive cisplatin, generally due to impaired renal function or performance status (ECOG-PS≥2) (Galsky MD, 2011). In spite of the numerous efforts with several combinations of chemotherapy regimens, metastatic UBC remains today a lethal disease (Abida W, 2015; Bellmunt J, 2014).
Surgical consolidation generally aimed at complete resection with curative intent of metastatic deposits that responded to previous chemotherapy (Abe T, 2014; Lehmann J, 2009) or showed slow recurrence in the same site after previous response to chemotherapy (Siefker-Radtke A, J Urol 2004). However, there were few cases in each series that received surgery only. Finally, one study (Otto T, 2001) explored the role of surgical palliation in a series of chemo-refractory oligometastatic UBC. In general, median OS and five-year OS were in the range of 23-26 months and 30% respectively for the series where surgery was pursued with curative intent but dropped to disappointingly low levels of seven months and 0% respectively when aimed at symptoms palliation of non-responders to chemotherapy.
Surgery only in oligometastatic UBC Having chemotherapy long been established as the first-line treatment option for clinical LN positive or visceral UBC, there is hardly no series exploring the role of surgery alone in this patients category. The finding that pathological LN disease in a large chemo naïve series of clinical N0 muscle invasive UBC patients receiving cystectomy and LN dissection conferred a five-year recurrence-free and overall survival of only 33% and 26% respectively (Madersbacker S, 2003) suggests the inadequacy of surgery as monotherapy. Combined preoperative chemotherapy + surgery in UBC Introduction Herr et al were among the first to provide a clinical rationale to a multimodal approach that included surgery in a mixed series of 80 locally advanced UBC with or without nodal metastases deemed as “unresectable” at presentation (Dodd P, JCO 1999; Herr H, 2001). They showed an interesting 30%, five-year CSS rate for those rendered clinically disease-free by combining chemotherapy and surgery. Both a major response to chemotherapy and the addition of consolidating surgery appeared a prerequisite to predict survival since no patient failing a response to chemotherapy and only one out of 12 chemotherapy responders who refused surgery survived beyond five years. Notably, residual disease was documented at pathological specimen in up to a third of patients with an apparent complete clinical response to chemotherapy. A 20 to 40% rate of residual disease at surgery has also been reported in subsequent series with clinical LN positive disease deemed as chemotherapy complete responders (Table 1). Dimopoulos et al (1994) observed that in 58 consecutive metastatic UBC patients relapsing after prior response to chemotherapy, 74% of recurrent events occurred at the site of response, thus providing further rationale to the role of consolidating surgery. Outcomes of a multimodal approach combining chemotherapy and surgery are likely dependent upon the extent (oligometastatic versus multimetastatic) and the location of disease (LNs versus visceral metastases) (Svatek RS, 2009). Surgery for clinical pelvic or retroperitoneal LN-positive disease Table 1 reports the most representative series exploring the role of surgery after chemotherapy for clinical LN disease of the pelvis and/or retroperitoneum. Overall clinical response to chemotherapy and complete responses (CR) were generally documented in 80% and 35% of cases respectively, with no difference in response between regional LNs (N1-3) or retroperitoneal LNs (M1). Residual disease was usually documented in up to 30% of those exhibiting a clinical complete response. Overall median survival and five-year CSS ranged 15-25 months and 25-40% respectively, with M1 disease generally falling in the lower range. Both CR and pathological response to chemotherapy were frequently reported as independent predictors of outcomes with five-year CSS rates of 40 and 60%, respectively, in N1 disease. Metastasectomy (visceral/distant LNs) The concept of surgical resection of visceral metastases from urothelial cancers (UC) dates back 1982 when Cowles (1982) reported a five-year median survival in six patients who have undergone
Metastatic UBC remains a highly lethal disease. The breakthrough in survival achieved by cisplatin combinations is still inadequate: in spite of encouraging early response rates, the majority of patients will experience relapse of disseminated disease. Consolidating surgery following chemotherapy has been proposed in selected UBC harbouring oligometastatic disease in an attempt to reduce the risk of recurrence in the surgical field and potentially improve long-term survival. Several considerations support the rationale of chemo-surgery in the treatment of oligometastatic UBC: the finding of persistent disease during surgery even in complete responders to chemotherapy, the positive prognostic role of response to chemotherapy to subsequent surgical consolidation (achieving a 40-60% five-year CSS for LN disease), the virtual absence of relapse in the surgical field and finally the observation that some patients can be rendered long-term survivors. The available evidence suggests that overall one out of three patients with LN disease and/or limited visceral metastatic deposits can be alive at five years by chemosurgery.
Nonetheless, the beneficial effect on survival conferred in oligometastatic UBC by combining chemotherapy with surgery remains undetermined due to the virtual absence of comparable control groups (chemotherapy alone or surgery alone). Prospective randomised neoadjuvant studies in UBC showed a modest (around 5%) five years survival advantage over surgery (cystectomy) alone in invasive UBC. These results cannot be translated to oligometastatic disease since the vast majority of patients were non-metastatic, with only a minority (4%) harbouring clinically LN positive disease. The same considerations hold true for adjuvant chemotherapy whose role in prospective randomised cystectomy studies remain inconclusive. Some oligometastatic patients (Tables 1 and 2) underwent post-surgery chemotherapy outside a standardized protocol, mostly in a salvage rather than adjuvant setting, without any conclusion on its added beneficial role being possible. Similarly, the true benefit of surgical consolidation in the context of oligometastatic UBC in terms of survival remains speculative. Anecdotal reports of patients rendered long-term survivors with a combination of chemotherapy and surgery do not necessarily represent a proof of treatment efficacy. Claiming a survival advantage for surgery by comparing the CSS of a highly selected cohort of responders to chemotherapy with good performance status with that of unselected cohorts of metastatic UBC treated with chemotherapy only would be scientifically sound. What seems clear from the available evidence is that by combining chemotherapy and surgery a small yet consistent subgroup of oligometastatic UBC can be cured. The next logical step is to identify factors predicting optimal response to this treatment combination in the setting of a large retrospective series. This would be a prerequisite to set up a prospective study with standardized inclusion criteria aimed to explore the combination of surgery with systemic therapies, including the new promising immunotherapies for advanced UBC. Editorial Note: Due to space constraints we have ommitted the reference list. Interested readers can email a request at communications@uroweb.org. Saturday, 12 March 10.15-14.00: Joint meeting of the EAU Section of Urological Imaging (ESUI), the EAU Section of Uropathology (ESUP) and the EAU Section of Urological Research (ESUR)
Table 1: Studies addressing the role of preoperative chemotherapy + surgery in the treatment of clinical N+ bladder cancer Author Nieuwenh uijzen JA, J Urol 2005
N type of study 52 retrosp
De Vries RR, EJSO 2009
14 retrosp
Meijer RP, Urology 2014
149 retros
Ho PL, Urol Oncol 2015
55 retros
Clinical Stage
Staging modality
Chemo regimen
cN1 21% cN2 77% cN3 2%
-FNA 40% -Staging LND 60%
Neoadjuvant -MVAC -HD-MVAC
cM1 100%
cN1 36% cN2-3 42% cM1 22%
T1 16% T2> 84% cN1 29% cN2 9% cN3 15% cM1 47%
Clinical response to chemo CR 15/52 (29%) PR 29/52 (57%)
Extent of surgery LND up to the ureter in all patients Retroperitoneal LND only if clinically positive
Neoadjuvant (100%) - MVAC or HDMVAC - GCarbo
CR 5/14 (35%) PR 9/14 (65%)
Retroperitoneal LND + cystectomy
Imaging only 30% FNA 27% Staging LND 43%
Neoadjuvant (100%) - MVAC or HDMVAC - GC - GCarbo
CR 35% PR 48% SD 12% PD 5.4%
LND: Before 2000 – up to common iliac After 2000 – up to the aortic bifurcation
- CT (55/55) - CT guided FNA (33/55)
Neoadjuvant 92% CIS based, 60% MVAC 5 cycles 29% GC 6cy
84% CR or PR CR 38% PR 45% SD 9% PD 2%
FNA 85%
Discretion of surgeon.
Pathological response to chemo pCR 11/15 cCR pCR in 3/29 cPR
Clinical outcome
27% of residual disease in cCR pCR 4/14 (65%) 1/5 cCR had residual disease pCR 27% pPR 28% pSD 24% pPD 10% 38% of residual disease in cCR pT0 21% pN0 54% pN1 9% pN2 20% pN3 1.8% pM1 15%
- Median CSS 15.4m - 5y CSS 23% cCR: 42% cPR: 19% cSD: 0% - Median CSS 10m - No difference between pCR and pPR - 5y CSS: 24% - Median CSS 20 m - 5y CSS 29.2% cCR: 43% cN1: 42% cN2-3: 23% cM1: 23% -Median CSS 25.7m -5y CSS 40%: CR: 60% pN0: 66% pN1-3: 18% pM1: 0%
Independent Predictor of outcome Clinical CR to chemo (HR 8.0; CI: 2.427.0)
NA
Pathological response to chemo (p=0.002), but NOT clinical response to chemo - Clinical response to chemo - Pathological N category
Legend: FNA = fine needle aspiration; LND = lymph node dissection; GC = gemcitabine cisplatin; CR = complete responder, PR = partial responder; SD = stable disease; PD = progressive disease; suffix c = clinical; suffix p = pathological
Table 2: Studies addressing the role of preoperative chemotherapy + metastasectomy of oligometastatic visceral disease Author
N type of study 70 prosp phase II
Type of urothelial cancer UBC: 70
Metastatic sites
Pre-surgical treatment
LN: 68 Peritoneum: 10 Skin:3 Bone:8 Lung:21 Liver:8
Chemo 70/70
SiefkerRadtke A, J Urol 2004
31 retrosp
UBC: 24 UTUC: 7
-Lung: 24 -Distant nodes: 4 -Brain: 2
Surgery only:9 Chemo+surgery:22
Lehmann J, Eur Urol 2009
44 retrosp
UBC: 35 UTUC: 9
Surgery only:9 Surgery+chemo:13 Chemo+surgery:16 Chemo+surgery +chemo:6
Abe T, J Urol 2014
42 retrosp
UBC: 21 UTUC: 18
-Retroperiton nodes: 25 -Distant nodes:5 -Lung:8 -Bone:2 -Other sites:4 -Region LN:8 -DistantLN:12 -Lung:14 -Local recur:5 -Other sites:4
Otto T, Urology 2001
Surgery only:1 Chemo+surgery:34 Surgery+chemo:7
Selection criteria for surgery Refractory disease to chemo, symptoms palliation
Pathological response to chemo NA
Visceral met, responders to chemo, recurrence at the sole initial metastatic site Visceral metastases with curative intent
2/29 necrotic tissue
Single organ met, response to chemo, curative
Clinical outcome
-Median OS: 7m -2y OS: 19% - significant benefit on QoL only in symptomatic patients -Median OS: 23m -Median time to recurrence: 7m -5y OS: 33%
Independent Predictor of outcome Not defined
Not defined
pCR in 4/22 receiving neoadjuvant chemo
-Median OS: 27m -5y OS: 27% -5y CSS: 32% -5yPFS: 24%
Not identified
pCR: 12/34 with chemo before surgery
-Median OS: 26m -5y OS: 31%
Longer survival for solitary lung or LN metastases
Saturday, 12 March 2016
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.
©2016 Amgen Inc. All rights reserved. Amgen (Europe) GmbH, Dammstrasse 23, CH-6301 Zug, Switzerland.
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. Saturday, 12 March 2016 EUTofCongress 21 Date preparation:News January 2016. EUHQ-P-162x-0116-122568
Neobladder formation Personal tips and tricks Prof. Hassan AbolEnein Urology and Nephrology Center Mansoura University Mansoura (EG)
Urologic surgical operations and interventions are increasing year after year. Minimal invasive techniques are significantly expanding and replace a lot of open techniques; however the open surgery is still essential and may be the only approach in many indications. The section meetings during the Annual EAU Congress allow the interested urologists to address their personal needs and where they have a wider window of discussion, share knowledge and discuss what is new in the field. Every surgeon has some specific personal tricks which he developed himself or has acquired from long experience. We have a long history of more than 35 years of doing radical cystectomy and different kinds of urinary diversion techniques. We have learned and developed many tricks which make the procedure easier and achieve the highest rate of success with the least number of complications. The tricks start from the proper selection of cases and reviewing the check list before going to the operation theater, and this includes patient’s factors, tumor charactersitics, renal and ureteric indices, abdominal and bowel condition and, recently, the facilities and the experience of the surgeon and his team. The objectives of radical surgery are to clean the patient from his malignancy and provide him the maximum quality of life. Therefore, good radical surgery is required with adequate lymphadenectomy and removal of an average of 20 lymph nodes to obtain the best rate of survival; meanwhile careful
bites, six stay sutures using a double armed 3/0 absorbable monofilament stitch keeping the remaining working needle towards the urethral lumen side to be ready to pass to the neobladder neck from in-out and making the knot outside the anastomotic line.
The pouch is then closed using regular 4/0 absorbable monofilament stitches keeping in mind to invert the mucosa to avoid leakage or fistula formation. Attention should be on keeping the suture line of the bowel anastomosis away from the sutures of the pouch to avoid the poucho-enteric fistula (Figure 4).
Following removal of the cystoprostatectomy specimen, attention goes to preparation of a reliable neobladder made from ileum. Simulation of the selected ileal segment to reach the area of the urethral stump should be tried for proper choice of the segment to achieve a urethral anastomosis without tension.
Adequate closure of the reservoir is then tested by filling the neobladder with 100 to 150 ml of saline to make sure there are no major leak or suture defects. Two tube drains are left in both sides of the pelvis and kept under gravity drainage.
Back-light illumination behind the stretched mesentery would clearly identify the distribution of the mesenteric blood supply to the assigned ileal segment. Creation of mesenteric windows and use of the vascular sealing machine make the job much easier, adequate and faster (Figure 1). The isolated tubular ileal segment should be reconfigured into a spherical reservoir keeping in mind that each 10 cm long segment of the normal ileum will provide 100ml capacity of the spherical urinary reservoir at three to five months postoperatively. Detubularization and double folding of the ileal segment is mandatory to have a compliant low pressure high capacity reservoir. Using a straight needle with monofilament 4/0 absorbable stitches is very fast and of great help (Figures 2 and 3). A hole is created at the bottom of the most dependent area of the bottom of the reservoir and should have vascularized edges; this is easier achieved by reopening the continuity of the bottom suture line for 1-2 cms, admitting the tip of the index finger. The muscle layer only of the ileal wall at both edges of the created hole is incised, not including the mucosa as a sort of sphincterotomy. The mucosa of the created aperture should be everted by some stitches using a rapidly absorbed monofilament absorbable 4/0 sutures. The slit hole is then transformed into a circular opening mimicking the bladder neck to be adapted easily to the urethral stump. The anastomotic stricture following these tricks will be less than 1%.
Closure The fashioned spherical ileal reservoir is then closed except at the upper part, pushed down to the pelvis, the bridge of the table is then closed and the root of the mesentery is pushed gently towards the pelvis; then the pouch will reach the urethra easily. I never have difficulty to fix the pouch to the urethra Figure 1: Back illumination would facilitate isolation of an ileal sehment with in any of my patients. The pouch is intact vascular supply and the use of the vascular sealing machine anastomosed to the urethra using the pre-fixed urethral stay sutures and all needles that are inside should pass from in-out in a dissection at the apical area, nerve-sparing attempt parachute technique. During the time of bringing the and delicate handling of the tissues are among the pouch to the pelvis the nurse and the assistants necessary surgical steps. would apply some traction on the urethro-ileal stitches to avoid kinking or coiling within the Techniques anastomotic lumen. The six stitches are tied well and Breaking the bridge of the operative table, 20-30 the 22 F silicon well-lubricated catheter is gently degrees of Trendelnberg position would facilitate the surgery and provide more exposure of the deep pelvis inserted to the pouch and its tip is received by the tip of the index finger from within the pouch. The and the area of apical dissection. The cut urethral catheter balloon is then inflated by 10 cc of saline. stump should be mounted with a good full thickness
Figure 3: Voiding pouchourethrogram one-year post-operative, showing spherical reservoir dependent urethral anastomosis and the absence of reflux
The necessity to have a non-refluxive or an anti-refluxive uretero-ileal reimplantation technique is a matter of controversy; however, when the patient has a healthy and well vascularized long ureters, the kidneys will have some protection against reflux due to the adequate peristalsis of the ureters. Wide, well saptulated tension-free mucosa-to-mucosa stented anastomosis usually results in good outcome.
The small bowel should be rearranged gently and the greater omentum has to cover the bowel before closure of the abdominal wall. This would minimize the incidence of post-operative bowel obstruction and the risk of the adhesive ileus. The drains are then removed when drainage is minimal; the patient might be discharged from the hospital by the 6th or 7th post-operative day. Pouchostomy tube is removed on Day 12, and the urethral catheter after Day 15. Ascending pouchogram is not routinely required.
The left ureter should pass from left to right in all cases through a suitable wide opening in the mesocolon in a non-angulated smooth curve of the course to keep the ureter a retroperitoneal structure and to avoid its course in front and around the sigmoid, which may be bulky and redundant in many patients. This step should be performed before fashioning the reservoir. Two double J siliconized stents are kept, stenting the uretero-ileal anastomosis and to ensure good healing, minimizing urine leakage and to shorten the hospital stay. A multi-fenestrated tube of a soft silicon nature is left as a pouchostomy tube, coming through a stab in the pouch wall outside the abdominal wall. This will add extra safety on the pouch drainage and allow the mucous to be flushed by the nurse in the early post-operative period.
Figure 4: Avoid “kissing” the two suture lines to prevent the risk of pouchoenteric fistula
Saturday 12 March 10.15-15.45: Meeting of the EAU Section of Genito-Urinary Reconstructive Surgeons (ESGURS)
Register Now! www.WCE2016.com
Held in conjunction with the South African Urological Association (SAUA) Meeting • November 8 – 9, 2016 Figure 2: Detubularization and double folding are necessary to obtain a complaint reservoir
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Education Online
Test your knowledge in Hall B0, level 0
Improve your skills: e-learning at your own convenience
Guidelines E-Course Prostate Cancer (CME 3 credits) & Renal Cell Carcinoma Risk profile-oriented management of BPE/LUTS
(CME 1 credit)
Overactive bladder: onabotulinumtoxinA as treatment (CME 2 credits) Overactive bladder: mechanisms & management
(CME 1 credit)
uroweb.org/education
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
L.DE.COM.SM.02.2016.4365 ERA-223 2016 Ad v04.indd 1
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L.DE.COM.SM.02.2016.4365 – ERA-223 Clinical Trial Ad – 1/2 Pg HORIZONTAL AD (270mm x 194.3mm)
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Metastatic renal cell carcinoma A prospective multicenter biomarker identification trial for sunitinib in Japanese patients with mRCC Dr. Ryuichi Mizuno Keio University, School of Medicine Dept. of Urology Tokyo (JP)
Molecular targeted drugs, which interfere with proteins that play critical roles in tumor growth and progression, have significantly changed systemic therapy for metastatic renal cell carcinoma (mRCC) over the past 10 years. In clear-cell RCC, inactivation of the von Hippel–Lindau (VHL) tumor-suppressor gene results in the abnormal accumulation of hypoxia-inducible factor (HIF). The accumulated HIF translocates into the nucleus and induces vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), resulting in the dysregulation of cellular growth and angiogenesis1. Therefore, the biology of clear-cell RCC provides a strong rationale for targeting the VEGF pathway as a systemic treatment strategy for mRCC.
of improved PFS in patients treated with sunitinib. Secondary endpoints were PFS, overall survival (OS), the objective response rate (ORR), and clinical benefit rate (CBR). Analysis of serum angiogenic and inflammatory biomarkers Serum protein levels were analyzed for VEGF-C, soluble VEGF receptor (sVEGFR)-2, sVEGFR-3, hepcidin, basic fibroblast growth factor (bFGF), high-sensitivity C reactive protein (hs-CRP), interleukin (IL)-6, and IL-8 using validated enzymelinked immunosorbent assays. Analysis of immune cell subsets In immunological marker testing, the percentages of T helper type 1 (Th1) cells and T helper type 2 (Th2) cells as well as the Th1:Th2 cell ratio in peripheral blood were analyzed using a flow cytometric analysis. The percentages of regulatory T (Treg) cells and myeloidderived suppressor cells (MDSCs) were also analyzed.
risk of cancer mortality4. Thus, recent studies have focused on the relationship between low grade inflammation and cancer. In the present study, we demonstrated that hs-CRP, which detects low grade inflammation, also has prognostic value in mRCC. Furthermore, the results of the multivariate analysis suggest that hs-CRP and IL-8 independently predict prolonged PFS, which implies that, in addition to inflammation-based resistance reflected by hs-CRP, IL-8 signaling pathways also independently contribute to resistance to sunitinib. IL-8 is a potent pro-inflammatory factor that belongs to the chemokine receptor family. In addition to its inflammatory effects, IL-8 facilitates angiogenesis by promoting endothelium proliferation, survival, and MMP expression.
suppl.1: Table patient characteristics Table Patient1.characteristics characteristics Patients, no. Age, yr, median (range) Sex, no., male/female ECOG performance status, no. 0 1 2 MSKCC risk group favorable intermediate
90 65 (31 - 79) 71/19 77 11 2 21 69
cytokines and are involved in the M2 polarization of macrophages, which are important for mediating humoral immunity as well as Th2 responses.
In many malignancies including RCC, the activation of IL-8 production in RCC has been suggested to be Th1 enhances anti-tumor immune responses as related to the clinical aspects of RCC, such as opposed to the inhibitory effects of Th2 cells on host positive inflammatory reactions, hypervascularity, immunity. Therefore, patients with a higher and resistance to immunotherapy5. Moreover, Huang et al. reported that neutralizing antibodies to IL-8 percentage of Th1 cells or Th1/Th2 ratio at baseline Efficacy re-sensitized the angiogenic activity of RCC exhibit productive anti-cancer immune responses. In Four (4.6%) and 17 (19.6%) patients achieved a xenografts to sunitinib, implicating IL-8 as the these patients, sunitinib may affect cancer cells with complete response (CR) and partial response (PR), innate anticancer immunity synergistically. escape pathway used by tumors to overcome the respectively. Twenty-four (27.6%) patients presented effects of sunitinib in RCC6. Thus, it is not surprising with stable disease (SD) for more than six months, In summary, our results show that some angiogenic, whereas 42 patients (48.3%) showed PD or SD for less that high serum IL-8 levels predicted resistance to inflammatory, and immunological markers at sunitinib. than six months. Three patients were considered not baseline may predict responses to sunitinib therapy Inhibitors of the VEGF pathway, including assessable for efficacy. ORR (CR+PR) and CBR bevacizumab and tyrosine kinase inhibitors (TKIs) such (CR+PR+SD≥6Mo) were 24.2 and 51.8 %, respectively. Some immunological markers may predict responses and/or disease progression in patients with mRCC and low to intermediate risk. The predictive ability of each to sunitinib because RCC are known to possess as sorafenib, pazopanib, axitinib, and sunitinib, are Median PFS was 9.3 months (95% CI 6.5–13.1), and immunological features. In the present study, we marker is considerable, and these results have currently the standard agents used in the treatment of median OS was 35.3 months (95% CI 16.4–49.5). important implications for optimizing the care of also demonstrated potential relationships between mRCC. Sunitinib malate is an orally administered TKI mRCC patients. the baseline proportions of T cell subsets and that targets VEGF and PDGF receptors, KIT, FLT-3, Predictors of treatment responses responses to sunitinib in mRCC patients. T cells may colony stimulating factor-1 receptors, and RET. Among the angiogenic, inflammatory, and Note: Interested readers can request for the be classified as Th1, or Th2 cells, which are Sunitinib achieved better median progression-free immunological markers analyzed, baseline levels of antagonistic to each other. Th1 cells produce full reference list by sending an email to: survival (PFS) than interferon alpha in a large phase III IL-6, IL-8, hs-CRP, and MDSCs were significantly interferon-gamma, IL-2, tumor necrosis factor-alpha, communications@uroweb.org. study of treatment-naïve patients with mRCC2. higher in patients with progressive disease than in and CXCL10, and activate macrophages toward an M1 those with clinical benefits. However, no significant phenotype, further promoting cell-mediated Joint Session of the European Association of Sunitinib is approved multinationally for the differences were observed for the other markers. In Urology (EAU) and the Japanese Urological immunity through cytotoxic T lymphocyte activation treatment of mRCC, and is considered the standard for order to evaluate the accuracy of these markers in Association (JUA) first-line treatments. In clinical trials, up to 50% of predicting the lack of a response to sunitinib, the area as well as Th1 responses7. On the other hand, patients receiving sunitinib obtained clinical benefits under the ROC curve was calculated. The areas under Th2 cells produce IL-4, IL-5, IL-10, IL-13, and other in the form of either an objective response or disease the ROC curves of hs-CRP, IL-6, IL-8, and MDSCs were stabilization (31% and 48%, respectively, in a phase 0.603, 0.612, 0.591, and 0.558, respectively. III trial)2. However, some of the population has progressive disease (PD) at the first evaluation, Analysis of biomarkers possibly due to intrinsic resistance or other factors. In An analysis by the Cox regression model using the addition, even if an initial response to sunitinib is continuous value for each marker showed that obtained, the majority of tumors become resistant to baseline IL-8, hs-CRP, and %Th1 cells correlated with this TKI (acquired resistance), with most patients PFS in a univariate analysis. A multivariate analysis eventually succumbing to disease progression. identified these three markers: IL-8 (P = 0.0075, unit This Industry-Sponsored Symposium Is Presented by Bristol-Myers Squibb risk = 1.011), hs-CRP (P = 0.0470, unit risk = 1.00009), Although sunitinib is currently the first-line standard, and %Th1 cells (P = 0.0329, unit risk =0.960), as treatment decisions for mRCC are still based on clinical independent indices to predict PFS (Table 2). criteria. Several studies have suggested that the identification of biomarkers, which may predict Discussion responses to sunitinib, has the potential to avoid The present results strongly suggest that baseline unnecessary costs and adverse events. By linking hs-CRP and IL-8 are not only prognostic markers, but aspects of the biology of RCC, many investigators have also appear to predict good responses to sunitinib. explored the use of angiogenic factors as prognostic We also demonstrated that some immunological and predictive biomarkers in mRCC3; however, markers, such as MDSC and %Th1 cells, have the validated predictive molecular markers to identify potential to predict prognoses and responses. patients who may benefit from sunitinib are still Sunday, 13 March, 2016 | 17:45 – 19:15 lacking. The aim of this prospective study was to Elevated levels of CRP often correlate with advanced Internationales Congress Center München evaluate baseline immunological and inflammatory cancer. Furthermore, high pretreatment levels of Paris Room, Hall B2, Level 0 molecules, in addition to angiogenic markers, in order CRP often predict poor responses to systemic to predict responses to sunitinib in patients with mRCC. therapy in metastatic cancer patients, which München, Germany suggests that an underlying inflammatory Patients and methods mechanism plays a role in modulating resistance to Presentations Include: In this prospective multicenter study, 90 consecutive systemic therapy. The reasons for CRP elevations in patients with favorable or intermediate Memorial cancer patients are not clearly understood; however, I-O in Bladder Cancer: Sloan-Kettering Cancer Center (MSKCC) risk features several possible mechanisms have been suggested A Question of Patient Selection? were enrolled from 18 institutions between November to explain the relationship between cancer and high Marc-Oliver Grimm, MD, PhD 2009 and August 2012 (Table 1). Patients were eligible CRP levels. University Hospital of Jena for this trial if they were older than 18 years of age, Jena, Germany had an Eastern Cooperative Oncology Group One possible mechanism may be that tumor growth performance status of 0-2, a life expectancy of ≥12 causes inflammation around the tumor, thereby Redefining Treatment Expectations weeks, a histological diagnosis of predominantly clear increasing the serum level of CRP. Alternatively, for Metastatic Renal Cell Carcinoma cell mRCC, received no previous treatment or only one chronic inflammation, for which CRP is a marker, may Laurence Albiges, MD, PhD regimen of cytokine therapy, had measurable cause cancer progression. In addition, inflammatory Institut de Cancérologie Gustave Roussy metastatic disease, and adequate hematological, cytokines may facilitate cancer progression by Villejuif, France hepatic, renal, and cardiac functions. promoting the growth and proliferation of tumor cells I-O: A New Mode of Action and interrupting apoptosis. The IL-6 cytokine family is Ignacio Duran, MD, PhD Study design and treatment known to produce acute phase proteins, including Hospital Universitario Virgen Del Rocio Sunitinib was administered at a starting dose of 50 CRP, in hepatocytes. Since IL-6 is an autocrine growth Madrid, Spain mg in six-week cycles of four weeks on followed by factor in RCC, elevations in CRP levels may be caused two weeks off. Dose reductions were permitted based by IL-6 produced from RCC. on individual tolerability. Sunitinib was discontinued due to disease progression, unacceptable toxicity, or Among the large number of inflammatory markers, physicians’ discretion. Clinical assessments were hs-CRP, which detects CRP levels that are an order of conducted every four weeks during the treatment magnitude lower than traditional assays, is the most until week 24, and every six weeks thereafter. extensively studied biomarker of low grade Response assessments were performed after six inflammation, especially in cardiovascular diseases. ONCDE15NP08668-01-01 1/16 ©2016 Bristol-Myers Squibb Company weeks of the treatment. The primary endpoint of this More recently, hs-CRP elevations have been study was the identification of biomarkers predictive associated with cancer progression and an increased
Immuno-Oncology: A Hype or a Potential New Foundation for GU Cancers?
Saturday, 12 March 2016
BMNIGL16X056_EAU_Sympo_Congress_Ad_R02.indd 1
1/15/16 3:00 PM
EUT Congress News
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Today’s European Urology Events 1. Chair – J.W.F. Catto, Sheffield (UK)
Social Media Course
2. Social media for beginners – M.D. Cooperberg, San Francisco (US) 3. Why social media matters – D. Murphy, Melbourne (AU) 4. Using social media in medicine – A. Kutikov (US) 5. Examples of best practice – M.D. Cooperberg, San Francisco (US) 6. Trends and developments in social media – D. Murphy, Melbourne (AU) 7. www.europeanurology.com – A. Kutikov (US) To be held in room 13a from 11.00 to 14.00
March 12th
Come and see the Residents Corner Award winners accept their prize:
Residents’ Corner Awards
Efficacy of enzalutamide following abiraterone acetate in chemotherapy-naive metastatic castration-resistant prostate cancer patients Azad Arun, Bernhard J. Eigl, R. Nevin Murray, Christian Kollmannsberger and Kim N. Chi Volume 67 Issue 1, January 2015, Pages 23-29 Preoperative Prostate-specific Antigen Isoform p2PSA and Its Derivatives, %p2PSA and Prostate Health Index, Predict Pathologic Outcomes in Patients Undergoing Radical Prostatectomy for Prostate Cancer: Results from a Multicentric European Prospective Study Nicola Fossati, Nicolò Maria Buffi, Alexander Haese, Carsten Stephan, Alessandro Larcher, Thomas McNicholas, Alexandre de la Taille, Massimo Freschi, Giovanni Lughezzani, Alberto Abrate, Vittorio Bini, Joan Palou Redorta, Markus Graefen, Giorgio Guazzoni and Massimo Lazzeri Volume 68 Issue 1, July 2015, Pages 132-138
March 12th
Platinum hour
To be held in room Madrid at the end of the Resident Meeting Day (16.30)
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
Saturday, 12 March 2016
EAUN launches update of MEC guidelines Lack of information and training lead to underuse of adult male external catheters Susanne Vahr, CNS University Hospital of Copenhagen Rigshospitalet Copenhagen (DK)
The number of European incontinent men are likely similar to the Americans. Treatment and promotion of continence should be the primary aim, but for those men where this aim is not possible, a male external catheter (MEC) may be a good choice. In the U.S. the use of MEC has decreased steadily from a peak of 34.6% in 1972-1975 to a low of 1.5% in 2001-20052. This is in contrast to the number of men experiencing urinary incontinence and may be due to the fact that many nurses are unfamiliar with the various types of MEC and also its use. Therefore, the EAUN working group is pleased to present an evidence-based updated version of the 2008 guideline on Male external catheters in Munich at the 17th International EAUN Meeting.
European Association of Urology Nurses
The working process for this guideline was similar to the evidence-based guidelines issued in previous years, with a systematic literature search done in the summer of 2015. Two guideline group meetings and three video conferences were held. A blinded review was conducted with the participation of specialised nurses, urologists in various countries and a patient organisation representative.
T +31 (0)26 389 0680 F +31 (0)26 389 0674
Urinar y cat het er ma nag ement
eaun@uroweb.org www.eaun.uroweb.org
Condom Catheter Urinary Sheath Penile Sheath
2016
The written guidelines are made up of three parts. The first part is methodological and stated the building process used for writing the guidelines and the definitions of terms. The second and principal part is composed of chapters on the indications and contraindications with regards the use of male external catheters. These are followed by chapters describing the products and material, the principles of management and nursing interventions, complications, nurse and patient education. The third part is made up of documents describing the procedures, which help the nurse how to use the MEC in a step-by-step manner.
Male ex te rnal ca theter s in adul ts
PO Box 30016 6803 AA Arnhem The Netherlands
Inc.
Individuals who are incontinent may carry an emotional burden of shame and embarrassment in addition to the physical discomfort and disruption of their lives that occur with episodes of incontinence. In a study from the U.S. Department of Health and Human Services more than a quarter of noninstitutionalised American men aged 65 and older reported a urinary leakage1.
Evidence-based Guidel ines for Bes t Practice in Urolog ical Health Care
© 2008, Golgeon Group,
Bladder incontinence may be caused by conditions such as age-related changes in the lower urinary tract, urinary tract infection, and conditions not directly related to the genitourinary system, such as diabetes, cancer, stroke, cognitive impairment, and mobility impairment.
“The aim of these guidelines is to expand knowledge regarding MEC products and provide practical help in using them in order to prevent unintended harm to patients and to enhance compliance with using MECs.”
European Association of Urology Nurses
assessment, choice of MEC and educational issues. The guideline also highlights the need for more research in this nursing field.
European Association of Urology Nurses
supporting this independent guideline with an educational grant. References:
In writing this guideline we had the same challenge as with the other nursing guidelines in finding high-level evidence regarding the choice of MEC, frequency of changing the MEC and how to obtain a valid urine sample for culture from the MEC. Low-level evidence indicates that no higher level evidence was found in the literature, but this cannot be regarded as an indication of the importance of the recommendation for daily practice. This guideline has clear recommendations for patient
The guideline can be downloaded for free at http://nurses.uroweb.org/nurses/guidelines/ while the printed version can be ordered by sending an email at info@uroweb.org. National societies that would consider translating these guidelines can find the rules for translation on the EAUN guidelines webpage or send a request directly to the EAUN at eaun@uroweb.org. We would like to thank Coloplast, Hollister Incorporated and Manfred Sauer GmbH for
1. Prevalence of incontinence among older Americans, Vital and Health Statistics, Series 3, number 36, June 2014 2. Cameron AP et al: Bladder Management After Spinal Cord Injury in the United States 1972 to 2005. The journal of Urology, Vol. 184, 213-217, July 2010
Saturday 12 March 16.15 – 17.00: 17th EAUN International Meeting Thematic session 5, Guidelines presentation: Male External Catheters
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
•
Selected Exclusion Criteria: •
•
•
•
•
Selected Inclusion Criteria:
•
•
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).
For complete information please visit:
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
Saturday, 12 March 2016
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.
•
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
EUT Congress News
L.DE.COM.SM.02.2016.4369 – ARAMIS ODM-201 Clinical Trial Ad – 1/2 Pg HORIZONTAL AD (270mm x 194.3mm)
27
Guidelines Office Update New publications, panel members from the GO The last few months have been a hectic period for the Guidelines Office (GO) and its members with the newly published EAU Guidelines, collaborative projects with other EAU offices and internal changes. Below are some highlights of GO activities: EAU full text guidelines Don’t forget to pick up your copy of the newly published EAU Guidelines, free for EAU full members from the Congress Booth (F40).
European A ssocia tio
EAU PO Box 30016 6803 AA Arnhem The Nether lands
European A ssociatio n of Urolog y
n of U rolo gy
Guideline
2016 edition
A ssocia tio
s 2016 edition
• A Tool-Kit for Practicing Evidence Based Urology – Monday 14th 12.00-15.00
Euro on A ssociatiYou y will find the EAU Guidelines Office on Facebook of Urologand Twitter (#eauguidelines).
European
Guideline
EAU PO Box 30016 6803 AA Arnhem lands The Nether 389 0680 T +31 (0)26 389 0674 F +31 (0)26 uroweb.org guidelines@ .org www.uroweb es #eauguidelin
• What’s New in the 2016 Guidelines – Saturday 12 (Today) 12.00-15.00
GO Booth (alongside the Congress Booth) Please stop by the GO booth to meet the staff who will be happy to answer any questions you may have about the activities of the GO. A number of our very talented Guidelines Associates will also be available at the booth during the EAU16 congress to promote the Associates’ Programme. If you are interested in finding out more about GO activities, do come along. You can pick up at the booth a full programme of GO n pea co-ordinated events at EAU16.
s
EAU Members can pick up a free copy at the EAU Booth in the Exhibition, while stocks last.
Young doctors considering working with the Guidelines Office, in an Associate position supporting the various panels, would particularly find Monday’s course an interesting introduction to the methodology which underpins the Guidelines recommendations.
They can also be ordered online at http://www. uroweb.org/pulications/eau-guidelines/.
T +31 (0)26 389 0680 F +31 (0)26 389 0674 guidelines@ uroweb.org www.uroweb #eauguidelin .org es
Guidelines European School of Urology Courses A reminder that the GO is facilitating two European School of Urology Courses at EAU16:
s Guideline
gy n of U rolo
2016 edition
Guideline s 2016 edition
Back and front covers of the new EAU Guidelines
New Transplantation Panel The Guidelines Office is pleased to announce in 2015 the formation of a new working group, chaired by Dr. Alberto Breda, to address the EAU Guidelines on Renal Transplantation (RT). The Panel met for the first time in August 2015 to discuss the processes Dr. Alberto Breda involved in updating the previous RT guidelines. All panel members agreed the current text offers an excellent starting point, but that some sections require updating and expansion to cover new developments in renal transplantation.
Forbidden Fruit: Sex, Eroticism, Art A new book by Johan Mattelaer, available at EAU16 Former EAU History Office Chairman Dr. Johan Mattelaer delves into the cultural aspects of urology and sexology once again in this new, attractively illustrated volume. Over the course of thirteen chapters, Forbidden Fruit explores the depiction of the human body and eroticism in worldwide art.
ADVERTORIAL
New Compact SWL Solution for Urological Workstations STORZ MEDICAL presents a new versatile lithotripter: The MODULITH® SLK »intelect« Since more than 25 years STORZ MEDICAL is enhancing the technology of shock waves. With the new compact MODULITH® SLK »intelect« a lithotripter has been developed which can be perfectly adapted to different imaging modalities. The device features a fully motorized positioning of the therapy source making it easy to set up the lithotripter or to target stones in the urinary tract. The Companion for Urological Workstations X-ray workstations are an important part of equipment in urological departments. They can be used for diagnosis and interventional procedures. But they are often lacking in the possibility of performing instantly an SWL when a stone is detected in the KUB of a patient. This gap is now filled with the MODULITH® SLK »intelect«. It allows treating patients lying on the table of the workstation. There is no need to move them to a separate SWL room.
“The ideal SWL complement to urological workstations.” In this combination the superior image quality of the workstation’s X-ray can be used for localising the stone and in-line X-ray control of the therapy success during the treatment. After the therapy the lithotripter can easily be moved away from the urological workstation and be stored without using much space. The MODULITH® SLK »intelect« is the ideal complement to urological workstations like the PRIMERA ST360®. 28
EUT Congress News
LITHOTRACK® Navigation System LITHOTRACK® is an optical navigation system comfortably linking the MODULITH® SLK »intelect« to an urological workstation, C-arc or ultrasound device. The setup of the lithotripter in combination with an X-ray system and the focus adjustment during the therapy are assisted by this navigation system. Handheld ultrasound can be used to localise the stone in the kidney in the same way as for diagnostic scans. Once the stone is visualised, it only has to be marked in the ultrasound image and the automatic positioning system LITHOPOS® moves the shock wave focus on the stone for the treatment. The same smart function works with X-ray systems as well. The Lithotripsy Module for C-arcs The MODULITH® SLK »intelect« in its basic version can be combined with various surgical C-arcs and OR-tables with lateral cut-out. The motorised movements of the therapy source facilitate the focus alignment for a fixed therapy head position. In-line ultrasound can be used for targeting radiolucent stones. The MODULITH® SLK »intelect« can optionally be linked to C-arc and ultrasound device via the optical navigation system LITHOTRACK®. This version allows maximum flexibility in setup and use. No dedicated table is needed to perform a SWL, normal surgical OR-tables are sufficient. Smart Features The lithotripter can be folded easily to a space saving transport position for storage or transport. Safe and simple handling is ensured through the integrated brake which fixes the device securely for operations. The integrated focal gauge allows re-aligning the system or checking the focus alignment within seconds.
MODULITH® SLK »intelect«
Economic Solution The long service life of the proven shock wave components makes the investment economic and controllable. The smart control concept guarantees a short learning curve. Hospital owned C-arcs can be used without any mechanical modifications for localisation. Virtually no installation is necessary and setup is easy thanks to the small foot print of the device. The modular concept of the new MODULITH® SLK »intelect« allows easy future updates at any time. The lithotripter can be configured according to needs
and budget, from the economic solution without navigation up to a high-end setup with LITHOTRACK® navigation system. It can be used with C-arcs and urological workstations like the PRIMERA ST360®. The MODULITH® SLK »intelect« - Great flexibility has never been so compact.
Olaf Gleibe Product Manager Urology
Saturday, 12 March 2016
The prehistoric penis Paleolithic legacy: From genital decoration to penile mutilation Javier Angulo Professor of Urology Universidad Europea de Madrid Laureate Universities Hospital Universitario de Getafe Madrid (ES)
Although human depictions are, generally speaking, seldom seen in prehistory (before written language), female genital representations are relatively common motifs in prehistoric times all over the world, often preserved on cave walls and rock shelters. Not often seen or depicted, male genitals were also represented on cave wall art, both as isolated forms or as complete human male images, commonly known as ithyphallics. Moreover, female and male genitalia were sculptured on pieces obtained from excavations of archeological sites. These vulvar or phallic portable elements were etched (or carved) in stone, bone or antler. It should also be noted that humans and their genitals were also sometimes depicted as fine carvings in the decoration of bone fragments and small stones. The most antique representations in prehistory date from the Upper Paleolithic (approximately 40,00012,000 years B.P. [before present]) and were found in Western Europe, especially Iberia and France. However, wall art is a phenomenon present all over the world and both human figures and genital motives can be seen in every continent. Classically, anthropologists and Paleolithic art experts have related the erectile status depicted in prehistoric art to rituals of fertility, possibly influenced by male deities in Levant Neolithic (9,000-6,000 years B.P.) and also by Chalcolithic Atlantic culture (6,000-4,000 years B.P.) that transformed the landscape building megalithic tombs and setting menhirs with phallic shape in many places in Europe (Figure 1). In those late prehistoric times humans have ceased being hunter gatherers and settled in a territory. Their future depended on the fertility of the land, crops and animals. However, in more ancient times, during the Paleolithic period, the meaning of penile representations was much richer and more diverse. Penis: An optic clue A Paleolithic penis can be represented as part of a human or animal form and also as an isolated figure by itself. The size of the phallic representation seems an important issue. It is true that the phallus sometimes appears more important than the human form and is the optic clue that determines the representation as an outstanding part of the whole. However, the size of the penis is not always that exaggerated and sometimes the penis is represented but almost hidden to the eyes of the observer or timidly suggested. Human and animal erection captivated the artist’s minds and possibly implied virility and strength, not opposed to the feminine but to nature itself. Man or animal against nature or even better defined, the individual and its seeding or reproductive capacity against an adverse natural world, of which, paradoxically, the individual is also part of. Many ithyphallic men share animal and human characteristics; that is, they mixed details of different
animal species, according to what has been called anthropomorphic thinking which was characteristic of the Paleolithic mind. They are usually represented alone, not as part of a scene in very noticeable places in caves, and often referred to as sorcerers although there is no evidence of religious feeling behind these representations. In rarer examples these ithyphallics were a part of a composition of figures. In several of these, male erection is associated with serious danger or death. Erection could mean virility and strength, not fertility as in Neolithics, and I dare say not opposed to the feminine but to nature and the animal world. The link between erection and dangerous situations has been interpreted as a representation of the transition to death, possibly a shamanistic interpretation of the physiologic phenomenon of male orgasm linked to the loss of the soul. Among others we have some beautiful examples of this dreadful association in the Lascaux cave where a hunter lies dead on the ground in front of an eviscerated bison (Montignac, France) (Figure 2) or in the Addaura cave (Palermo, Sicily) where a group of men are about to be suffocated and surrounded by a group of executor dancers. Sometimes males and male genitals are represented close to females or female genitals, and these representations recall mating rituals. Even coital
These pieces show evidence of a culture that favored prepuce retraction. If Upper Paleolithic humans would have practiced circumcision, that would explain the scarcity of phallic representations that show phimosis. Also from a technical point of view, lithics had been developed to achieve clean cutting, and knowledge of the curative properties of ointments and creams made of natural elements could have facilitated the development of curative medical knowledge as well. Of course not all Paleolithic penises appear circumcised. On cave walls sometimes phimosis is evident in the depictions of some ithyphallics with sharpened or point-ending erectile phalluses (Murat, Gabillou, Tuc d’Audoubert, Les Trois-Frères, Les Combarelles, and as mentioned previously, in Lascaux and Addaura) an there is also an example with para-phimosis (Fronsac). However, the majority of Paleolithic penises on portable art do not show phimosis. One of the batons recovered from Roc-deMarcamps (Gironde, France) displays concentric lines on the preputial skin that covers the gland, possibly signaling the mark where to cut if circumcision was to be performed. Curiously, this is one of two portable art phalli represented with phimosis. The other example recovered in Fourneau-du-Diable (Dordogne, France) reveals partial preputial skin retraction.
Figure 2: The erect hunted hunter in Lascaux lies dead on the ground near an eviscerated bison (Montignac, France).
scenes are also depicted. These representations are more frequent between animals than humans. Possibly the oldest human intercourse were represented in Los Casares cave (Guadalajara, Spain) (Figure 3) and in a stone block detached from the Laussel shelter (Dordogne, France) (GravettianSolutrean, around 20,000 years B.P.). Other coital scenes which are absolutely naturalistic and, sexually speaking, diverse were represented in some stone blocks in the La Marche cave (Vienne, France) and in Enlène cave (Midi-Pyrénées, France) (Magdalenian, around 12,000 years B.P.). In some blocks from La Marche several scenes represent sex, but definitely not leading to reproduction. Also in Ribeira do Piscos (Foz Coa, Portugal) are thousands of Paleolithic representations which were produced in the open air on river banks and tributaries to the Douro river, also at Magdalenian time, where an ejaculating large size human figure was depicted with a prominent penis and its emission carved on a vertical rock. His mouth is open, with rays shining out or irradiating from his head, representing orgasm. In another very curious carving in open air at the Coa Valley, rear penetration with a condom was represented! However, it must be noted that this image is post-Paleolithic.
Figure 1: Outeiro menhir with phallic shape (Regengos de Monsaraz, Portugal).
Saturday, 12 March 2016
antler, bone, or stone have been recovered in the context of habitation from different excavations, most of them in France (Figure 4). All over Europe, other bone instruments of unknown use with prominent phallic decorations have also been found. This material was far from being waste itself, because it could have been used to make valuable spear points or pendants instead. Some believe they constitute dildos or domestic masturbating devices, but they could also have been used in rituals. The real meanings of these devices are totally unknown, but indicate that erection was important enough in these people’s minds to merit a depiction and preservation.
Ritualistic phallic forms Many portable art elements are batons on antler or bone and have the form and size of the penis. A collection of such instruments with phallic forms done with
However, we cannot ascertain that Paleolithic people practiced circumcision, but these observations favor a general culture of penile foreskin retraction, genital hygiene care and very likely the practice of circumcision. Although no specific ritual of circumcision has been represented in Paleolithic art, these data provide indirect evidence of its practice; possibly for decorative purpose or as a body mark, it may also have become fashionable.
Figure 3: Possibly the oldest coital scene represented in the Los Casares cave (Guadalajara, Spain).
been performed several thousand years earlier in Eastern Europe. It is therefore impossible to state the real origins of these peculiar prehistoric decorative rituals, but they could have taken place during a long time span between 38,000 to 11,000 years B.P. Among those prehistoric rituals of prepuce retraction, circumcision, sub-incision, dorsal cutting, piercing, tattooing and scarification, only circumcision has continued, possibly because this practice is not only fashionable but also useful. Other practices, the intention of which was also to segregate individuals from the collective and to a specific marked group, have outlived very occasionally and remain purely anecdotal and decorative, and mainly among marginal individuals. The same happens in modern primitives today; the roots behind body decoration were most probably spiritual, such as animist superstitions, based on a belief that ink and body art can protect the body from evil. Possibly, prehistoric tattooing and other forms of body decoration may have followed similar patterns of behavior. Genital decoration Otzi, the Neolithic man recovered from ice in the Alps gives definite proof that body tattoo was practiced in the final phases of European prehistory. Also during the metal ages, there is evidence of genital decoration in the warriors struggling in Vermelhosa (Foz Coa, Portugal) represented in a fine open air carving and also in the human representation in a stela from Badajoz (Spain) in the late Bronze age (3,200-2,700 years B.P.). These late prehistoric images represent penile infibulation, a form of penile mutilation that prevented warriors from losing their energy in penetration. This is another intervention in the penis, consisting of the insertion of a fibula that closes the preputial skin and interrupts male erection and intercourse. This same procedure has been performed
Body decoration There is archeological evidence that modern humans, and even Neanderthals, performed rituals of body decoration. Colors have been used as skin paint and make-up and hair dying were also applied. It should therefore not be surprising that some types of permanent corporal decorations may Figure 4: Paleolithic phallic instruments recovered from different excavations in France also have been performed. In fact, engravings with human representations and in some modern primitive beings in Asia, Africa and statuettes also provide evidence that body scars were America. considered aesthetical throughout the Upper Paleolithic. In conclusion, the representation of the penis throughout the different phases of prehistory is Phallic decoration with a series of dots and lines is amazingly varied and rich. Far from being a nasty explicitly represented in European Palaeolithic art for graffiti, the depiction of the phallus has captivated identification or ornamental purposes. Scars, holes prehistoric artists and is a very important graphical and marks appear intentionally and were made on motif that gives us many indirect clues on how our the surface of the penis. Therefore, circumcision, male antecessors behaved and thought. genital tattooing, piercing and scarification may have been decorative surgeries practiced during Paleolithic Friday 11 March times. Most of the archaeological evidences of 8.30-16.15: The 6th International Congress decorated phalli are Magdalenian elements that were on the History of Urology recovered in France, but these designs could have EUT Congress News
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Kidney sparing surgery for Upper Tract Urothelial Cancer selected patients with low-risk UTUC2,3. A recent Fig 3: Surgical treatment according to location and risk status. From the 2016 EAU guidelines on UTUC Fig 3. Surgical treatment according to location and risk status. From the 2016 EAU guidelines on UTUC meta-analysis from Yakoubi et al. identified only eight eligible studies comparing survival of UTUC patients UTUC treated with endoscopic urologic surgery versus RNU5. No significant difference was found in terms of overall survival and cancer-specific survival between the two populations. However, these results were largely limited by the quality of the studies included, thereby URETER KIDNEY not allowing definitive conclusions.
Prof. Shahrokh Shariat Department of Urology Medical University of Vienna Vienna General Hospital Vienna (AT)
Co-Author: Ilaria Lucca (AT) Staging is notoriously difficult in patients afflicted with upper tract urothelial carcinoma (UTUC) leading to a significant rate of overtreatment. Radical nephroureterectomy (RNU) with bladder cuff excision has been the standard treatment of non-metastatic UTUC patients for decades. Recently, however, the development of new technologies such flexible video-endoscopy and high-definition imaging together with a better understanding of UTUC biology and outcomes have opened new perspectives for individualized riskstratification and therapy. This together with the increased awareness of the detriments associated with loss of renal function at time of RNU has encouraged the quest for sparing the kidney as often as possible without increasing the patients’ oncologic risk. At the heart of this paradigm shift is what has been termed “personalized medicine”, that is the selection of the right patient for the right therapy at the right time. This has been one of the focus areas of the 2016 EAU Guidelines on UTUC. In order to select the right candidate for kidney sparing surgery (KSS), it is crucial to consider both patient and tumor characteristics. Computed tomography (CT) urography and endoscopic investigations including urinary cytology and tumor biopsy represent currently the best combination of tests to ensure accurate diagnosis and risk stratification of UTUC. Based on the obtained information, one can stratify the patients into low- and high-risk UTUC (Figure 1)1.
Segmental ureterectomy is an effective from of KSS that is likely to benefit patients with tumors located in the distal third of the ureter. These tumors are not limited to large low-risk UTUC not amenable to endoscopic management (i.e., technical limitation, size, ect…) but also well-selected high-risk, nonmetastatic UTUC (Figure 3)1. Klatte et al., for example, found no difference in cancer-specific survival between patients treated with segmental ureterectomy versus RNU (5 year rates of 83% [SE ±4%] versus 80% [SE ±4%], respectively)8. Important to both segmental ureterectomy and RNU is the complete removal of the bladder cuff. REF PMID: 24360665 and PMID:22579047
“Even in this rare disease, overtreatment needs to be avoided when possible to ensure the best possible outcomes for our patients.” One of the limitations of KSS is the increased rate of endoluminal and/or intravesical recurrence compared to RNU. Fajkovic et al., for example, found that endoluminal and intravesical recurrences were 61% and 39% for patients treated with flexible ureteroscopy versus 36% and 28% for those treated with a percutaneous approach, respectively6. However, most of these recurrences were low-risk and amenable to endoscopic management.
Several issues remain to be resolved to ensure optimal results with KSS. First is the indication, schemata and delivery method of endoluminal therapy (i.e., single dose and/or adjuvant chemo- and immune-therapy). Second, the utility and cost Patients with low-risk UTUC are the ideal candidates effectiveness of single dose postoperative intravesical for KSS such as flexible ureteroscopy, segmental Fig 1. Risk stratification of upper tract urothelial carcinoma. From the 2016 EAU guidelines on UTUC. ureterectomy and percutaneous endoscopy (Figure 2). therapy to prevent bladder recurrences.REF PMID: 21684068. Third, the indication and benefit for second All of these have shown to result to result in similar UTUC look ureteroscopy (four to eight weeks after the first oncological outcomes to RNU in appropriatelyFig 1: Risk stratification of upper tract urothelial carcinoma. From the 2016High-risk EAU guidelines on UTUC UTUC** Low-risk UTUC*
Fig 1. Risk stratification of upper tract urothelial carcinoma. From the 2016 EAU guidelines on UTUC.
- Unifocal disease - Tumour size < 1 cm - Low-grade cytology - Low-grade URS biopsy - No invasive aspect on MDCT-urography
UTUC
- Hydronephrosis - Tumour size > 1 cm - High-grade cytology - High-grade URS biopsy - Multifocal disease - Previous radical cystectomy for bladder cancer High-risk UTUC**
Low-risk UTUC*
- Hydronephrosis - Tumour size > 1 cm - High-grade cytology - High-grade URS biopsy - Multifocal disease - Previous radical cystectomy for bladder cancer
- Unifocal disease - Tumour size < 1 cm - Low-grade cytology - Low-grade URS biopsy - No invasive aspect on MDCT-urography
MID & PROXIMAL
Low risk
1. URS 2. Ureteroureterostomy
DISTAL
High risk
• •
CALYX
Low risk
RNU +/- LND
•
URS or distal ureterectomy
High risk
• •
RENAL PELVIS
Low risk
RNU or distal ureterectomy +/- LND
1. URS • +/- instillation 2. RNU*
High risk
• •
RNU +/- LND
Low risk
1.URS 2. Percutaneous
High risk
• •
RNU +/- LND
Explain 1. First treatment option 2. Secondary treatment option *in case not amendable to endoscopic management
ureteroscopy) in order to identify and treat additional tumors, and change strategy when necessary. Finally, the optimal risk-based follow-up of patients treated with KSS (i.e., need for accurate non-invasive follow-up method). In conclusion, KSS seems a safe approach in wellselected patients. While maintaining adequate local control, it has a lower immediate therapeutic burden and better functional outcome (i.e., renal function preservation) in an elderly multimorbid population with an already decreased glomerular filtration rate and performance status (PMID: 2346497). Further refinement of variables which could help us identify the ideal patient for KSS is needed. Technological progress such as narrow band imaging
and better understanding of the biology and natural history of cancers stemming from collaborative efforts hold the promise of ensuring the widespread implementation of this therapeutic paradigm shift. Even in this rare disease, overtreatment needs to be avoided when possible to ensure the best possible outcomes for our patients. Editorial Note: Due to space constraints, references (including those indicated as “PMID”) were omitted. Interested readers can email at communications@ uroweb.org for the complete list. Monday 14 March 10.30-12.00: Thematic Session 13, Non Muscle Invasive Bladder Cancer (NMIBC)
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
www.essqchm.rcsed.ac.uk
* All of these factors need to be present ** Any of these factors need to be present
Fig 2: Proposed for the management of localized UTUC. 2016EAU EAUguidelines guidelines on UTUC Fig 2.flowchart Proposed flowchart for the management of localized UTUC.From Fromthe the 2016 on UTUC.
* All of these factors need to be present ** Any of these factors need to be present
UTUC
Diagnostic evaluation: CTU, urinary cytology, cystoscopy
+/- Flexible ureteroscopy with biopsies
High-risk UTUC*
Low-risk UTUC
RNU
Kidney-sparing surgery: flexible ureteroscopy or segmental resection or percutaneous approach
Open
(select open in cT3, cN+)
Laparoscopic
Recurrence
Close and stringent follow-up
Single postoperative dose of intravesical chemotherapy
* In patients with solitary kidney, consider a more conservative approach
30
EUT Congress News
Saturday, 12 March 2016
PCNL: Optimal approaches Reducing morbidities is a key goal
www.esut16.org
ESUT16
Evangelos Liatsikos Associate Professor University of Patras Patras (GR)
5th Meeting of the EAU Section of Uro-Technology 8-10 July 2016, Athens, Greece
Percutaneous nephrolithotripsy (PCNL) represents the gold standard treatment option in the management of large, multiple and inferior calyx renal stones. Percutaneous track can offer a wide and direct access to the entire pelvicalyceal system as well as an antegrade access to the ureter and, as a result, all stone scenarios can be effectively managed by this approach.
But for the everyday adult case, what is the evidence of using minimally invasive PCNL? Current literature does not clearly answer the question whether a miniaturisation of PCNL systems is advantageous for the patient. High level of evidence on the subject is still lacking as very few prospective randomized controlled trials (RCT) are available on this topic.
The procedure offers the highest stone-free rates after the first treatment as compared to the other minimally invasive lithotripsy techniques (extracorporeal shock wave lithotripsy, retrograde intrarenal surgery - RIRS), with the cost of higher morbidity and a longer hospitalization.
According to EAU Guidelines, the efficacy of miniaturized systems seems to be high, but longer operation times apply and benefit compared to standard PNL for selected patients has yet to be demonstrated.
During the last decade PCNL has faced a barrage of technical refinements including miniaturization of its access, evolution of its instruments, ureteroscopic assistance, introduction of tubeless techniques and use of hemostatic agents, all of which aim to reducing the morbidity of the approach.
Longer operative times of minimally invasive PCNL are a result of inferior visualization, inability to retrieve big fragments with a grasper, need of lithotripsy into smaller pieces or stone dusting, as well as lack of active suction in the majority of small-track PCNL setups.
Among them, the trend to avoid or reduce postoperative percutaneous drainage and the miniaturization of PCNL instrumentation are the most prominent and largely accepted changes in practice.
There is some evidence that smaller tracts cause less bleeding complications, but further studies need to evaluate this issue, especially when longer operative time is a well established predictor of complications including bleeding and fever.
To tube or not to tube Percutaneous drainage in the immediate postoperative period following PCNL is a well-established safety measure of the procedure. Percutaneous nephrostomy allows monitoring of bleeding, ensures urine drainage during a short period, when clots and stone fragments might pass, tamponizes percutaneous track assisting hemostasis, allows a second look procedure, while establishing a low pressure system, reducing post-operative infectious complications and assisting healing when rupture of the pelvis is present. Despite the above-mentioned advantages, a wealth of data today support the safety of tubeless PCNL approaches in a selected set of cases given the employment of a tubeless approach (with or without an internal ureteral stent) reduces postoperative pain and increase patientâ&#x20AC;&#x2122;s covalence. Most common indications for a tubeless strategy are cases operated by a single puncture track, following an uncomplicated procedure for a moderate stone bulk, lasting <2hrs leading to a complete stone-free outcome with no evidence of significant bleeding at the end of the procedure. In addition, tubeless approach is contraindicated in cases of single kidney, infectious stones and after an upper calyceal puncture. Advocates against the approach question the feasibility of an everyday case to meet all these criteria at the same time, especially when PCNL is a procedure indicated mostly for large stone debulking and complicated cases, leaving less demanding stone scenarios to be favorably treated by retrograde approaches. While the debate on the ideal drainage strategy after PCNL is ongoing, the introduction of tubeless techniques in PCNL had a major impact in our everyday practice. It assisted on the identification of percutaneous drain as a factor associated with morbidity and has directed surgeons into trying to reduce the adverse effects of its use, by choosing smaller nephrostomies and reducing the time of postoperative draining. Miniaturization of PCNL instruments: Do we need that stuff? The body size of our patients differs, including children and those who are obese, tall and short. In addition, stone scenarios and anatomical variations are many. As a result, the recently introduced variation in available instrumentation including smaller scopes renders PCNL versatile to respond to any given scenario. Indeed, the use of mini-PCNL instruments in pediatric population is considered today a standard practice. Saturday, 12 March 2016
EAU Events are accredited by the EBU in compliance with the UEMS/EACCME regulations
Abstract submission deadline: 1 May 2016
Several investigators question whether miniaturization of PCNL instruments would expand the indications of PCNL into smaller stones. Indeed, the indications of mini-PCNL seem to partially overlap with those of RIRS. Can we do it better with mini PCNL vs RIRS? Meta-analyses on studies comparing PCNL (standard and mini) vs RIRS gives insight on this issue (eg. Eur Urol. 2015;67(1):125-37). Stone-free rates of standard PCNL are superior to RIRS, while stone-free rates of RIRS were compared favorably with the rates of mini-PCNL. In addition, complication rates following RIRS were significantly lower than PCNL (standard and mini). Based on the above, given the added morbidity and lower efficacy of MI-PCNL, RIRS should be preferred in small renal stones, while for larger stones standard PCNL should be considered standard treatment due to lower efficacy of mini-PCNL.
WEEK 2016 26-30 SEPTEMBER
As evidence on the subject is accumulating, it appears that minimally invasive PCNL can be ideally used in the setting of endoscopic combined intra-rarenal surgery. In the presence of ureteroscopic assistance, operative times are significantly reduced and as a result large-bore percutaneous accesses might not be that necessary. In addition, mini PCNL can be employed as a secondary track in complex cases requiring more than one access. Finally, mini PCNL seems the ideal approach in the case of small stones when RIRS is less likely to be effective (e.g. lower pole stone in complex calyceal anatomy, calyceal diverticula). An evolving field In conclusion, PCNL is a field constantly evolving by incorporating novel concepts in percutaneous approach. Whether adaptation of these does possess a benefit for the patient remains to be better documented in the future.
initiative of the European
Still, what has been already clear is that PCNL morbidity should not be taken for granted but can be reduced to a minimum. Due to the wide variation of available instrumentation, the time when PCNL was a single procedure has passed and surgeon should be ready to adopt his practice and instrumentation into the given case to obtain the optimum results with minimum morbidity
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Saturday 12 March 10.15-14.00: Meeting of the EAU Section of Urolithiasis (EULIS)
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Prostate cancer management: Selecting the right treatment for the right patient Scientific programme 17:45-17:55 Welcome and introduction An overview of the current prostate cancer treatment landscape Chair: Prof. Francesco Montorsi (Urologist) 17:55-18:15 How best to manage patients with advanced prostate cancer presenting with high burden metastatic disease Dr Michiel Sedelaar (Uro-oncologist) 18:15-18:35 Determining the right patients for neoadjuvant/adjuvant therapy Prof. Heather Payne (Radiation Oncologist) 18:35-18:55 What is the prevalence of CVD in patients with prostate cancer and how do we assess CV risk when deciding treatment strategy? Dr Alex Lyon (Cardiologist) 18:55-19:05 Managing treatment side effects through lifestyle changes: Empowering patients to take control Prof. Francesco Montorsi 19:05-19:15 Discussion summary and concluding remarks Prof. Francesco Montorsi
Sunday 13 March 2016 London Room, 17:45 - 19:15 ICM / Messe M端nchen, Germany FN/2271/2015/ECOa
32
EUT Congress News
Saturday, 12 March 2016