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EUT Congress News
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31st Annual Congress of the European Association of Urology
Monday, 14 March 2016
Munich, 11-15 March 2016
Optimal PCa therapies remain elusive
The mess with the mesh
Experts tackle issues in prostate cancer diagnostics and treatment By Joel Vega
By Loek Keizer From new imaging technologies, managing high risk prostate cancer (PCa) to the challenges posed by new drugs that present alternatives to standard treatment regimens, PCa experts yesterday examined the various ways on how to offer optimal diagnostics and therapy to patients, particularly those with recurring disease.
“For the first time, we are establishing some firm rules for mesh use, which can only be a good thing for the safety of patients.” This was one of the hopeful conclusions of Prof. Stefano Salvatore (IT), gynaecologist and President of the European Association of Urogynaecology.
Chaired by Professors Manfred Wirth (DE) and Didier Jacqmin (FR), Plenary Session 2 presented three debates, three state-of-the-art lectures, and a case discussion which all addressed a manifold of treatment and diagnostic issues in prostate cancer. Despite the emergence of novel techniques, deeply-rooted practices do not disappear overnight and many speakers conceded it may take some time for doctors to move beyond their comfort zones.
Salvatore gave a well-received state-of-the-art lecture as part of Thematic Session 7 which had the theme “Challenges in incontinence treatment.” Salvatore summarised the problem with meshes: “Despite improving the anatomical outcome, particularly when we use them to repair what is commonly called cystocele, prolapse of the anterior vaginal wall. It brings a high rate of complications including pain: not just during sexual intercourse but also spontaneously. Also there is the case of infections, erosion, and exposure in the vaginal canal. Pain during sex can occur not just for women but for their partners as well. This has given rise to a new term: dyspareunia.”
“Of all the inhabitants on the planet, none is more resistant to change than humans. Except urologists, of course,” quipped Prof. Kurt Miller (DE) before moderating a debate on chemotherapy for hormone-naïve PCa patients. The first debate on the role of magnetic resonance imaging (MRI) drew mixed comments although there was agreement that MRI has a role in repeat biopsies. “The greatest benefit of pre-biopsy MRI is found in patients undergoing re-biopsies. Moreover, the main role of pre-biopsy MRI is to detect clinically significant prostate cancer and localize index lesion,” said Dr. Eduard Baco (NO).
Profs. Manfred Wirth (L) and Didier Jacqmin chair the session on prostate cancer
To the question regarding the role of pre-biopsy MRI, discussant and radiation-oncologist Prof. Harriet Thoeny (CH) was unequivocal as she confirmed MRI/TRUS fusion-guided biopsies detect more significant PCa with less cores and reduces the detection rate of low-risk cancers. She said the real question is how to keep the costs of MRI economically feasible.
Kurt Miller: “Of all the inhabitants on the planet, none is more resistant to change than humans. Except urologists, of course.”
On the chemotherapy debate, Prof. Nicolas Mottet (FR) strongly argued classical hormone therapy will remain with urologists but only if they adapt to changes and learn new tools. “Hormone therapy will not be lost for urologists provided we learn new drugs, recognize major
disease changes and be involved in all stages including advanced and final ones,” he said while adding a cautionary word: “A multi-disciplinary team is key for optimal patient care, and the one who knows will take the lead.”
Prof. Thorsten Schlomm (DE), in his state-of-the-art lecture on whether genomics can aid in identifying high-risk disease, said molecular features determine the speed of disease transition. “In the future we will create a molecular speedometer for each patient in order to precisely predict individual patient’s pprogress,” said Schlomm.
iPad overtakes the doctor A group of Australian doctors has prepared patients for surgery using iPads, and found that patients’ understanding was much better than after a face-to-face consultation. “Patients often find it difficult to understand the medical language used by doctors during face-to-face standard verbal communication, and they often feel intimidated by the interaction”, said lead researcher, Matthew Winter (Sydney, Australia), whose study was presented by his colleague at the Abstract Session. ”Often doctors work within busy practises and clinical environments with time limiting the quality of a consult and or verbal consent for a procedure. Patients often find it difficult to comprehend their planned procedure”, said Winter. The researchers designed a randomised controlled trial (RCT) to check the understanding of 88 patients facing surgery for acute renal colic (the abdominal Monday, 14 March 2016
The debate on the timing of radiotherapy after radical prostatectomy (RP) also drew sharp commentaries from debaters Prof. Thomas Wiegel (DE) who took up the view for radiationoncology against that of urologist Dr. Jeffrey Karnes (US). “Why only use one gun when you still have two?” said Wiegel as he insisted there is no overtreatment from adjuvant radiotherapy (aRT) after RP. Karnes remained steadfast that salvage radiotherapy is a better option since the core goal is to balance survival with adverse effects and costs. “High-level evidence is pending on aRT versus early salvage radiotherapy (eSRT). eSRT is a valid option. Our current evidence of aRT is ‘weak.’ eSRT provides similar survival but less exposure,” added Karnes.
“Taken all together, this brought a huge reaction against meshes from the patients themselves. There is also media pressure. Meshes can be helpful, but we don’t yet have the ideal material, and we currently have no certification for the surgeons who perform the procedure,” Salvatore explained. He said aside from proper patient selection, the units where this procedure should be performed should also be identified with preference to centres with a high workload and high number of cases. Recent attention to the dangers of mesh use (including reclassifications from the FDA from Class II to Class III, or high-risk) has reached a peak because complications aren’t immediately clear. “Patients can experience shrinkage of mesh, worsening of the condition of women. The increasing number of cases means more awareness of these problems, including two class-action lawsuits. This caused a revolution in the market: devices were withdrawn, whole industries shut down,” he said. The backlash to meshes is also driving reassessment and improvement in legislation, safety and technology. Salvatore: “The FDA is encouraging not just post-marketing surveillance but, even better, pre-market approval and appraisal. This means drawing up a safety and efficacy profile of any new device.”
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pain often caused by kidney stones). 45 of the patients discussed the forthcoming surgery with their doctor as normal, whereas 43 patients were given a video presentation with cartoon animation narrated by a doctor which could be viewed on tablets such as an iPad. The patients were then questioned on their understanding of the medical procedure and their satisfaction regarding the information delivery technique. After this they were switched, with those who had received face-to-face counseling receiving the video, and vice versa, followed by the same questionnaire. Patients were then asked to give their overall preference of information delivery. They found the use of the video increased understanding by 15.5% compared to direct consultation. Moreover, 71 patients (80.7%) preferred the video as against 17 (19.3%) who preferred the face-to-face meeting.
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Andrology update: Timing of PDE-5 inhibitors is key
Today’s Industry Sessions
Tackling ED and Peyronie’s Disease
Stone disease and QoL issues By Joel Vega
Industry session starting at 17:45 hrs Experts yesterday clarified issues on stone diagnosis, prevention and treatment and the recurring message among the speakers was the tendency of urologists to lumped together patients in one category despite the subtle- and yet crucial- differences in their disease and individual needs.
By Constance de Koning Unravelling the mysteries of male LUTS to aid individualised therapy ASTELLAS - Room 14b
The Andrology Update 2016 during Thematic Session 5 exclusively featured state-of-the-art lectures including one that highlighted erectile dysfunction (ED) treatment after radical prostatectomy (RP) and how to choose the right method for the right patient.
Chaired by Prof. Thomas Knoll (DE), Thematic Session 1 featured three state-of-the-art lectures that tackled basic research on stone formation, quality-of-life (QoL) issues, recommendations for metabolic evaluation and an update session in the form of a point-counterpoint debate. “Stone formation is complex and we need a deep understanding of issues such as metabolic evaluation,” said Knoll.
Despite excellent oncologic outcomes, RP is associated with disability functional impairments, such as urinary incontinence and ED. “Up to 70% of patients still experience postoperative ED, even when a bilateral nerve-sparing approach is performed. Also, younger patients have higher rates of ED than older patients,” said Dr. G. Gandaglia (IT). ED is multifactorial and psychological factors in particular, should not be ignored as they have a high impact. Treatment options are many of which PDE-5 inhibitors take centre stage, according to Gandaglia. He emphasized that penile rehabilitation - defined as the use of any intervention or combination with the goal of restoring erectile function (EF) pretreatment levels - should not be overlooked. Although some randomized controlled trials have been conducted with PDE-5 inhibitors, there are some concerns with regard to the timing of drug administration, short follow-up periods and selection criteria. Gandaglia: “A recent study showed that patients at intermediate risk of ED after surgery are the ones who benefit most from use of PDE-5 inhibitors and they are the ones that should be targeted.”
European Urology Today Editor-in-Chief Prof. M. Wirth, Dresden (DE) Section Editors Prof. T. E. Bjerklund Johansen, Oslo (NO) Mr. Ph. Cornford, Liverpool (GB) Prof. O. Hakenberg, Rostock (DE) 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)
Other options to treat ED are vacuum erection devices (“cost-effective compared to other treatments, suitable for use in combination with PDE-5 inhibitors”), and intracorporeal injection therapy which can be effective as second- line option for patients who failed to respond to oral treatment. Finally, penile prosthesis implantation is a third- line option after failure of less invasive treatments or non-compliance to conservative management. “They have a low rate of complications and implant failure,” Gandaglia said. “But the best timing – early versus delayed implantation - is still not clear.”
Traxer’s advice for stone formers include regular water consumption (2 to 2.5 litres per day), a limit on calcium and sodium intake, and for certain stone formers a restriction on oxalate and uric acid food intake.
Prof. Enrique Lledo-Garcia (ES) had a hard time disagreeing with his “opponent” Dr. Rajesh Ahlawat (IN) who had earlier outlined the benefits and potential of robotic procedures in kidney transplants. “We cannot stop the future,” Lledo-Garcia conceded.
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“Most surgical disciplines have moved to minimallyinvasive procedures, including urology, gynaecology, and general surgery. Why has it taken so long for the transplantation community to come with an alternative for open kidney transplantation? I think transplant surgeons have stayed away from the mainstream a little too long,” said Ahlawat.
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Advertising I. Moerkerken L. Schreuder
As part of Thematic Session 9, the two experts debated the merits of robot-assisted transplantation and Ahlawat began with an eloquent overview of the developments in the field in a video-filled presentation.
Four distinct innovations have made robotic surgery a viable option for transplant surgeons. The adoption of the RALP position as a standard removes the problem of varying approaches and the need to re-dock. The use of GelPOINT at the umbilicus for peritoneal access allows the surgeon to deliver ice slush and the graft. This keeps the temperature close to 20 degrees Celsius without affecting the rest of the body (a third innovation). And finally, by using the peritoneal flaps to fixate the graft, problems with torsion and subsequent biopsy difficulties are avoided. Ahlawat also showed the similarity of results of the IDEAL 2b/3 single-centre trial between robotic and
EUT Congress News
Prof. Oliver Traxer (FR) brought home the message that metabolic evaluation is often taken for granted by urologists but having a good grasp of the basics such as urine analysis and diet can make a big difference in preparing an effective treatment plan. According to Traxer, different types of stones require different types of approaches since a dietary advice for a patient with a uric acid stone may not necessarily fit a patient suffering from cystine stones. Traxer stressed the importance of taking a proper urine collection and also noted that a metabolism check-up is highly recommended for a calcium load test and bone density.
By Loek Keizer
Onsite Reporting and Editing Team J. Bloemberg L. Keizer C. de Koning T. Parkhill J. Vega
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Recommendations for surgery depend on the specific characteristics of the disease. Zacharakis emphasized that detailed consent is imperative as well as following published algorithms. Plication/ Nesbit is indicated for deformity < 60° and borderline ED. If the patient has a deformity > 60° and an experienced surgical team is available, then grafting is a treatment option. Patients with refractory ED and PD are eligible for prosthesis placement with manipulation.
“There are differences in perception, and people in the same situation will assess their quality of life based on economic, social, health, independence and other factors,” Monga said. He added that having an awareness of the patient’s viewpoint will enable urologists to better respond to issues such as pain symptoms, dietary needs and a drug plan that is appropriate.
Thematic Session 9 explores transplantation surgery techniques
Coordination and Editing J. Vega
No part of European Urology Today (EUT) may be reproduced without written permission from the Communication Office of the European Association of Urology (EAU). The comments of the reviewers are their own and not necessarily endorsed by the EAU or the Editorial Board. The EAU does not accept liability for the consequences of inaccurate statements or data. Despite of utmost care the EAU and their Communication Office cannot accept responsibility for errors or omissions.
Optimal management for Peyronie’s disease (PD) - which does not affect the patient solely on a physical level but perhaps even more psychologically - consists of various options, according to Dr. E. Zacharakis (GB). “There have been many oral treatments for PD, most of which are not effective, apart from pentoxifylline and L-Arginine/PDE-5 inhibitors. There is limited evidence that interferon and verapamil are effective, whereas the evidence for collagenase is Grade A/Level 1,” he said. Furthermore, topical treatment with verapamil gel is not recommended; topical energy treatment seems to have limited benefit whereas shock wave therapy has none.
Weighing the merits of robotic kidney transplants
Founding Editor Prof. F. Debruyne, Nijmegen (NL)
Disclaimer
Andrology session topics include the medical treatment for ED
Speaker Prof. Manoj Monga (US) of the American Urological Association (AUA) spoke on QoL and noted that patient’s perception of QoL differs than that of the doctor or healthcare professionals, a difference which, when misunderstood, can lead to inappropriate care.
Ahlawat outlines the steps of a robotically-assisted kidney transplant
open transplantation, regarding warm ischemia, cold ischemia and complications. Lledo-Garcia, on the other hand, summarized the well-known advantages of robotic surgery, such as: enhancement in surgeons’ control of the instruments and the ability to perform more intricate procedures; less post-operative pain, risk of infection, and blood loss for patients as well as a shorter hospital stay.
However, Lledo-Garcia insisted on continued evaluation of robotic surgery, particularly taking costs into account. “Robotic-assisted kidney transplantation seems to be technically feasible, at least in experienced hands, but it is not yet functionally or clinically superior to open surgery. It remains to be seen if it can match or exceed open surgery on a cost-basis,” he added. Monday, 14 March 2016
Setting standards in urological training Special Session addresses needs of young urologists By Constance de Koning Assessing the needs of young urologists and residents with regards to training and education was the focus of a special session that involved the Young Urologists Office (YUO). “This year, we celebrate the 25th anniversary of the European Society of Residents in Urology (ESRU) and one of its objectives has long been to develop a European urological curriculum ,” said Dr. Michiel Sedelaar (NL). The ESRU always had a close link with the European Board of Urology (EBU) and the European Association of Urology (EAU); since 2015, and ESRU is now fully incorporated in the YUO.
One of the main concerns about residents is that 40% of senior residents has never performed a major procedure. EBU and EAU are both concerned about the overall urological training, but objections against an overall curriculum are that Europe is a very divided continent, with different reimbursement systems, private and public health care and several new medication, diagnostics and new treatments not being available in all countries as well as profound cultural differences. “Training has changed enormously over the years, becoming so much more technical and urologists need to keep up with this change”, Sedelaar said. A large 2013 online survey showed the needs of the
young urologists are quite different from those of the residents. “Residents are looking for good theoretical education and hands-on training for basic urological procedures”, according to Sedelaar. “Young urologists desire hands-on training and exposure to advanced urological procedures.” He capped his talk by mentioning the European School of Urology (ESU) courses which do not only take place at the yearly EAU congress, but also at smaller regional and national meetings. At this year’s congress, there are 52 ESU courses and 70 HOT sessions. “In fact the 2016 HOT sessions sold-out faster than Adèle concert tickets!,” he added.
Congress news. . . . . . . . . . . . . . . . . . . . . . . . 1 Congress highlights . . . . . . . . . . . . . . . . . . 2/3 Urothelial Cancer: Point-Counterpoint . . . . . . 4 Molecular classification and treating urothelial carcinoma. . . . . . . . . . . . . 5 Female neobladder and continent urinary diversion . . . . . . . . . . . . . . . . . . . . . . 6 Ultra-mini PCNL. . . . . . . . . . . . . . . . . . . . . . . 7 ESU Course 38: Testicular cancer. . . . . . . . . . .9 Optimising ureteral stricture repair. . . . . . . . 10 Is Gleason 6 cancer?. . . . . . . . . . . . . . . . . . . . 11 Transurethral en-bloc resection of NMIBC. . . 13 Is there a diminishing role for a re-TUR in NMIBC?. . . . . . . . . . . . . . . . . . . . . 14 Asymptomatic microhematuria. . . . . . . . . . . 15 Endoscopic Combined IntraRenal Surgery. . . 16 Clinical consequences of PET signals after curative treatment . . . . . . . . . . . . . . . . 19 What are the limits of nephron sparing surgery?. . . . . . . . . . . . . . . . . . . . . 20 Prostatic Urethral Lift in treating BPO. . . . . . 23 Ureteral reflux after kidney transplant: How relevant is it. . . . . . . . . . . . . . . . . . . . . 26 EAUN: PCa survivors and mental health. . . . 27 Current status of androgen receptor research. . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
BEST BOOTH IPSEN wins the Best Booth Award at the Technical Exhibit. From left: A. Soares, J. Mallet, H. Arditti, C. Chapple, P. Cabri, M. Brassart, P. Hazenberg, M. Alinquant
Day 3 Award Gallery
First Video Prize: N. Doumerc (Toulouse, France)
Second Video Prize: R. Campi (Florence, Italy)
Third Video Prize: N-S. Vuong (Bordeaux, France)
First Prize Best Abstract by a Resident: M. Roumiguie (Toulouse, France)
Third Prize Best Abstract by a Resident: A. Fernando (London, United Kingdom)
European Urology Resident’s Corner Award: N. Fossati (Milan, Italy)
EUSP Best Scholar Award 2016: I. Lucca (Vienna, Austria)
ESTU René Küss Prize 2016: L. Peri Cusi (Barcelona, Spain)
ESUI Vision Award: M. Ritter (Mannheim, Germany) Sponsored by INVIVO CORPORATION
ESOU Achievement Award: W. Månsson (Malmö, Sweden) Big attendance for Thematic Session 5: the Andrology Update 2016
Monday, 14 March 2016
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Plenary Session 4, Urothelial Cancer: Point-Counterpoint Experts debate on a single installation of chemotherapy post-TURBT Prof. Richard Sylvester, ScD EAU Guidelines Office Board Brussels (BE)
Which patients with stage pTa-pT1 urothelial carcinoma of the bladder benefit from a single immediate instillation of chemotherapy after transurethral urethral resection? The EAU Non-muscle Invasive Bladder Cancer (NMIBC) Guidelines recommend a single immediate instillation of chemotherapy after complete transurethral resection (TURBT) in all low and intermediate risk pTa-pT1 patients1. The basis for this recommendation is a literature based meta-analysis of seven randomized controlled trials (RCTs) comparing a single immediate postoperative instillation of chemotherapy to TURBT alone. This meta-analysis, which included 1476 patients from these seven studies, concluded that a single immediate instillation of chemotherapy reduced the relative risk of recurrence after TURBT by 39%, odds ratio = 0.61, p < 0.0001. The number of patients needed to treat to prevent one recurrence was 8.52. In their guidelines, the American Urological Association also supported the use of an immediate postoperative instillation in patients with small volume, low-grade pTa tumors3. After the original publication of these guidelines, several additional RCTs assessing the efficacy of an immediate instillation were carried out, some of which questioned its efficacy, especially in intermediate risk patients4. One review even called for an immediate instillation to be abandoned5. In order to take into account these additional RCTs, two new literature based meta-analyses were undertaken; however they could not adequately answer the question of which patients benefited from an immediate instillation of chemotherapy after TURBT6-7. Because of the uncertainty concerning which patients benefit from the instillation, an immediate instillation of chemotherapy after TURBT is not universally used in day to day clinical practice. The main limitation of all of these meta-analyses was that they were not based on individual patient data. Thus time-to-recurrence, prognostic factor and subgroup analyses could not be carried out and it was not possible to accurately identify which patients benefited from the instillation. New systematic review and meta-analysis To finally answer the ongoing question of which patients benefit from a single immediate instillation of chemotherapy, a new systematic review and meta-analysis using individual patient data has been carried out8.
Time-to-first recurrence was the primary endpoint in several trials
risk of recurrence: HR = 0.65, 95% CI: 0.58 – 0.74, p < 0.001. The five year recurrence rates were 44.8% (95% CI: 41.6% – 48.0%) on a single instillation and 58.8% (95% CI: 55.7% – 61.9%) on TURBT alone. The number of patients needed to treat to prevent one recurrence within five years was seven eligible patients. There was no beneficial effect of an immediate instillation on the time-to-progression or on the duration of either overall or bladder cancer specific survival.
Bladder Tumor Intravesical Chemotherapy Prevents Non–Muscle-invasive Bladder Cancer Recurrences: An Updated Meta-analysis on 2548 Patients and Quality-ofEvidence Review. Eur Urol 2013;64:421-30. 8. Sylvester RJ, Oosterlinck W, Holmang S, et al. Systematic review and individual patient data meta-analysis of randomized trials comparing a single immediate instillation of chemotherapy after transurethral resection with transurethral resection alone in patients with stage pTa-pT1 urothelial carcinoma of the bladder: which
patients benefit from the instillation? Eur Urol 2016;69:231-44.
Tuesday, 15 March 8.00-13.10: Plenary Session 4, Urothelial Cancer EAU Guidelines Point-Counterpoint Session: Single installation of chemotherapy post TURBT: Statistically significant and also clinically significant?
Which patients benefit? However contrary to the previous literature- based meta-analyses, we were now able to precisely identify which patients benefited and which patients did not benefit from the immediate instillation. The results are summarized in the accompanying Forest plot. An immediate instillation did not reduce the risk of recurrence in patients with a prior recurrence rate of more than one recurrence per year or in patients with an EORTC recurrence risk score of five or more. If you want to know more details and what the impact of this meta-analysis is on the 2016 EAU NMIBC guidelines, then come to the EAU Guidelines Point-Counterpoint Session at 9:05 AM on the morning of Tuesday, 15 March, in Plenary Session 4 (Urothelial Carcinoma) of the 2016 31st Annual EAU Congress in Munich where the following question will be debated: Single instillation of chemotherapy post TURBT: statistically significant and also clinically significant? References 1. Babjuk M, Burger M, Zigeuner R et al. EAU Guidelines on
RCTs which compared TURBT alone to a single Non–Muscle-invasive Urothelial Carcinoma of the immediate instillation of chemotherapy after TURBT in Bladder: Update 2013. Eur Urol 2013; 64:639-653. patients with single or multiple, primary or recurrent 2. Sylvester R, Oosterlinck W, van der Meijden A. A single stage pTaT1 urothelial carcinoma of the bladder were immediate postoperative instillation of chemotherapy eligible. However, trials which allowed additional decreases the risk of recurrence in patients with stage Ta treatment prior to the first recurrence were not T1 bladder cancer: a meta-analysis of published results included. Time-to-first recurrence was the primary of randomized clinical trials. J Urol 2004; 171:2186–90. endpoint while time-to-progression and the duration 3. Hall MC, Chang SS, Dalbagni G et al. Guideline for the of both overall and bladder cancer specific survival management of nonmuscle invasive bladder cancer were secondary endpoints. (stages Ta, T1, and Tis): 2007 update. J Urol 2007; Thirteen RCTs published between 1985 and 2011 were eligible for inclusion. Individual patient data were obtained for all 2,278 eligible patients entered in 11 of these studies. 1,161 patients were randomized to TURBT alone and 1,117 to a single instillation after TURBT. Epirubicin was used in five studies, mitomycin C in four, pirarubicin in one and thiotepa in one study. A total of 1,128 (49.5%) of 2,278 patients recurred: 475 (42.5%) allocated to a single instillation and 653 (56.2%) to TURBT alone. As expected, the difference between treatments for the time- to-first recurrence was statistically significant in favor of an immediate instillation, with a reduction of 35% in the relative 4
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178:2314-30. 4. Gudjonsson S, Adell L, Merdasa F, et al. Should all patients with non muscle invasive bladder cancer receive early intravesical chemotherapy after transurethral resection? The results of a prospective randomized multicentre study. Eur Urol 2009;55: 773-80. 5. Holmang S. Early single-instillation chemotherapy has no real benefit and should be abandoned in non-muscle invasive bladder cancer. Eur Urol Suppl 2009;8:458-63. 6. Abern MR, Owusu RA, Anderson MR, Rampersaud EN; Inman BA. Perioperative Intravesical Chemotherapy in Non–Muscle-Invasive Bladder Cancer: A Systematic Review and Meta-Analysis. JNCCN 2013;11:477–484. 7. Perlis N, Zlotta AR, Beyene J, Finelli A, Fleshner NE, Kulkarni GS. Immediate Post–Transurethral Resection of
Monday, 14 March 2016
From new genetic classifications to direct treatment Molecular classification could be a step forward in refining chemotherapy for some patients Prof. Eva Compérat Dept. of Pathology, Hôpital La Pitié – Salpêtrière UPMC Paris VI Paris (FR)
The most important criterion for optimal cancer treatment is a correct classification of the tumour. During the last three years, several very important progresses have been made with a better definition of urothelial carcinoma (UC), especially from a molecular point of view. We start having a global understanding of UC, although many details are still not completely understood. In the current diagnosis of UC, histology is still the gold standard. The new WHO classification of ‘Tumours of the Urinary System and Male Genital Organs’ 2016 divides UC into two groups: the “Non-invasive UC” and the “Infiltrating UC.” Distinctions of low-grade and high-grade lesions still exist and G1-3 should not be employed any further. For the first time the WHO also gives a comment on the sub-staging of T1 tumours considering substaging as clinically relevant, but still no agreement exists about which method should be employed. The ICCR (International Collaboration on Cancer Reporting) suggests in their recommendations to use either depth of invasion in millimeters or total maximum dimension of invasive tumour in millimeters or pT1a/b (invasion above or beyond the muscularis mucosae). Furthermore, the classification makes a difference between tumours invading the detrusor muscle (T2) and the perivesical fat (T3) underlining the problems of histological distinction between pT2b and pT3a tumours, as the limits between the outer layer of the muscle and perivesical fat can be difficult to make. The classification also underlines the clear interest of recognizing variant histology as a predictor of more aggressive tumour behaviour. Some variants are known to be highly aggressive such as the plasmocytoid, the micropapillary, sarcomatoid and poorly differentiated UC. Nevertheless some entities are still under-recognized and underdiagnosed. One of the major problems of UC is the extremely heterogenous genetic profile. Major familiar syndromes like in other tumours are missing and UC is extremely exposure-dependent. Genetic evidence indicates at least two major pathways, one from urothelial proliferation of uncertain malignant potential (previously called hyperplasia) towards low grade non-invasive papillary UC and from dysplasia/atypia towards carcinoma in-situ towards high-grade invasive UC. A marked genetic difference exists between low-grade and high-grade tumours, but many supplementary pathways interfere in the development of UC.
Chromosomal alterations UC can be mono- or polyclonal, therefore mutlifocal or metachronous tumours can show both, either the same mutations, but also novel and differently acquired mutations. When taking a glimpse into the different genetic modifications of UC, several different pathways have been described. Chromosomal alterations, some of them known already for a while such as CDKN2A, RB1 or E2F3 have been reported; the spectrum of mutations is quite huge and recurrent mutations in genes such as TP53, FGFR3 or PIK3CA have been described. The Cancer Genome Atlas revealed 302 mutations, 204 segmental copy number alterations and on average 22 rearrangements per tumour. Recurrent driver mutations were found in 32 genes including cell cycle regulation genes, kinase signalling pathways and nine additional genes unknown up to this day. With lung cancers and melanomas, UC has the most frequent mutational rate. The FGFR3/RAF/RAS pathway regulates several genes that are important for the cell cycle. One quite well The range of mutations in UC is huge and recurrent known fusion gene is FGFR3-TACC3, which activates FGFR3, known to play a role especially in non-invasive low-grade tumours. group of tumours, which is particularly true, when regarding clinical behaviour of these tumours. Other pathways like the PI3K/AKT/mTor pathway, which controls processes in carcinogenesis such as Molecular sub-staging cell growth and proliferation or Notch, which is an In another recent paper they demonstrate that the important actor in the cell-cell communication also mRNA expression of progression biomarkers revealed play an important role in the bladder cancer a strong association with molecular subtype. The risk development. Up to now not too well known was of progression was low for urobasal tumours and the chromatin remodelling pathway. Changes in the important for genetically unstable and squamous cell chromatin structure lead to altered gene expression. carcinoma like bladder cancers. But there seem to be many further and not entirely understood steps in the bladder carcinogenesis. Risk factors for progression such as multi-focality, concomitant carcinoma in-situ, invasion depth, “When defining subgroups of lymphovascular invasion were seen globally only in bladder cancer on a molecular level, the two latter groups. Therefore the authors that in the T1 group molecular subwe can avoid treating patients with concluded staging seems to be of a major interest and helps to identify patient with more aggressive disease chemo-resistance.” (Patschan). Recent studies have made very important steps forward in the understanding of UC. Especially the group around Sjödahl could show distinct UC groups. They could, according to gene expression profiles distinguish five groups of UC. Urobasal A, Urobasal B, genomically unstable, infiltrated and squamous cell carcinoma like bladder cancers. Interestingly these tumours showed different cytokeratin signatures and keratinization-associated antigenes. They also display different mutations and FGFR3 gene expression signatures. Furthermore, distinct molecular subtypes show different cell adhesion gene signatures. The authors claimed in this paper that the tumour groups were completely pathology independent, but when analysing the subgroups, it is clearly shown that some groups such as Urobasal A contains in a major amount Ta and T1 tumours of low grade. The T1 group is described as a very heterogeneous
Choi et al demonstrated in a recent paper separate tumour groups according to luminal and basal subtypes, a concept which has already been explored in breast and head and neck cancers. They could show a link between histology and gene expression signatures. Basal tumours were enriched with sarcomatoid features and often had metastatic disease at presentation. These tumours also expressed high levels of epidermal growth factor receptor (EGFR) and several of its ligands. Another characteristic of the basal type group was expression of several cytokeratins, a finding which confirmed the results of the Sjödahl group. These data were especially true for basal tumours which invaded the detrusor muscle. The luminal group was rich with epithelial biomarkers such as E-Cadherin and showed high levels of FGFR3 mutations. There existed also an upregulation of the proliferator activator (PPAR) pathway and an upregulation of the estrogen receptor (ER) and its co-activator Trim-24. Choi et al also described a subgroup in the luminal tumours which they called “p53-like luminal muscle invasive bladder cancers.” This group could be distinguished from the luminal group by their expression of an active p53-associated gene expression signature. This expression was not associated with the presence of wild-type TP53. Interestingly, these UC also contained an active p16 gene signature.
chemotherapy is a current standard and also recommended in the EAU Guidelines for the treatment of patients with muscle invasive bladder cancer (MIBC). Chemo resistance Choi et al described in their paper a chemo resistance of all p53-like luminal MIBCs, but the cohort only contained seven patients. They then extended the cohort and confirmed the first findings. On the other hand, they demonstrated that luminal and basal types responded to in more than 50% to the neoadjuvant chemotherapy. Sjödahl et al had a different approach to the treatment of UC. They compared possible drugs with drug target genes. Their results showed gene expression of potential drug targets was associated with molecular sub-types, pathological stratification seemed to play a minor role. A recent publication of McConkey et al enrolled 60 patients in a neoadjuvant trial of four cycles of dose dense methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) associated with bevacizumab. The patients underwent gene expression profiling before the treatment in order to benefit from chemotherapy according to their “molecular” UC. Basal UC had improved survival compared to luminal and p53-like UC. In this study the p53-like luminal type also displayed chemo resistance and showed more aggressive disease with bone metastasis. The authors concluded that there exists a benefit to treat patients according to their genetic profile and in the sense of personalised medicine it could be interesting to treat only chemo-sensitive patients. References 1. WHO Classification of Tumours of the Urinary System and Male Genital Organs, 4th edition Patschan O, Sjödahl G, Chebil G, Lövgren K, Lauss M, Gudjonsson S, Kollberg P, Eriksson P, Aine M, Månsson W, Fernö M, Liedberg F, Höglund M.A Molecular Pathologic Framework for Risk Stratification of Stage T1 Urothelial Carcinoma. Eur Urol. 2015 Nov;68(5):824-32.
This pathway is also known to play a major role in the development of aggressive UC. The aims of characterising groups and subgroups are to find possible and optimal drug targets. The histological classification, still the gold standard, helps in decision-making such as BCG treatment or neoadjuvant chemotherapy and surgery.
Molecular sub-staging helps identify patients with more aggressive disease
Monday, 14 March 2016
The molecular classification could help us make a step forward to refine the chemotherapy in these patients. When defining subgroups of bladder cancer on a molecular level, we can avoid treating patients with chemo-resistance. Neoadjuvant cis-platin based
A molecular taxonomy for urothelial carcinoma. Sjödahl G, Lauss M, Lövgren K, Chebil G, Gudjonsson S, Veerla S, Patschan O, Aine M, Fernö M, Ringnér M, Månsson W, Liedberg F, Lindgren D, Höglund M. Clin Cancer Res. 2012 Jun 15;18(12):3377-86. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Choi W, Porten S, Kim S, Willis D, Plimack ER, HoffmanCensits J, Roth B, Cheng T, Tran M, Lee IL, Melquist J, Bondaruk J, Majewski T, Zhang S, Pretzsch S, Baggerly K, Siefker-Radtke A, Czerniak B, Dinney CP, McConkey DJ. Cancer Cell. 2014 Feb 10;25(2):152-65.
Tuesday, 15 March 08.00-13.10: Plenary Session 4, State-of-the-Art Lecture Urothelial cancer
EUT Congress News
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Female neobladder and continent urinary diversion Avoiding complications through operative measures Prof. Bedeir Ali-ElDein Urology Department Urology and Nephrology Center Mansoura University Mansoura (EG)
Orthotopic neobladder (ONB) is now becoming widely used in select women with carcinoma of the urinary bladder. A variety of functional, medical, and surgical complications may develop after ONB1-4. Among functional complications, total incontinence, nocturnal incontinence (NI) and chronic urinary retention (CUR) are the most important3,5,6. Similarly, pouch-vaginal fistula (PVF) and uretero-intestinal anastomotic stricture are among the major surgical complications4,7.
descent, and anchoring the vaginal stump3,5. After the vaginal stump was closed meticulously during radical cystectomy (RC), the medial ends of the round ligaments, preserved in the first part of the operation, were used to anchor the closed vaginal stump (Figure 1). In addition, the peritoneum covering the anterior rectal wall was sutured to the anterior aspect of the closed vaginal stump. Furthermore, a generous pedicled omental flap raised on the left or right gastroepiploic artery was fashioned and brought down to fill the empty pelvic cavity (Figure 2). The interposed pedicled omentum between the vaginal stump and neobladder will help prevent development of PFV. Also, it provides back support to the neobladder, especially during voiding, thus preventing the neocystourethral angle from becoming acute. After creation of the neobladder, its dome was suspended to the posterior aspect of the rectus abdominis.
On the other hand, other investigators reported that failure to preserve the autonomic nerves of the Few researches have investigated either the functional bladder neck and proximal urethra may be the cause or surgical complications following ONB in women of CUR6,10. The basis for this hypothesis is that many and proposed some clinical and technical measures patients develop urinary retention after extensive to avoid or decrease the incidence of such pelvic surgery; however, this may be most probably complications4-8. In addition, clinical data, results of due to peripheral bladder denervation rather than to imaging, and urodynamic tests can be used for the denervation of the urethra and sphincter. prediction, characterization, and treatment planning for continence and voiding problems after ONB in Moreover, autonomic denervation and urethral women5,6,9. transection in female dogs caused a 50% reduction of the proximal urethral pressure, but did not affect the In this newsletter, a short description of the technical mid- or distal urethra11. In addition, in women with modifications to avoid or minimize some functional CUR after ONB, treatment with alpha-blockers has and surgical complications after female ONB, namely been ineffective, thus questioning the role of excess total incontinence, NI, CUR, and PVF is made. sympathetic tone5,11,12. Nevertheless, currently we and other investigators stress that meticulous dissection in Clinical and technical measures to avoid the area between the bladder neck and proximal complications urethra anteriorly, and the anterior vaginal wall Clinical and technical measures, which can help posteriorly, as well as along the lateral wall of the minimize the functional complications after female vagina, is of utmost importance. Although there was ONB were described before4-8. These include significant decrease in the incidence of CUR after the pre-operative, operative, and post-operative above mentioned measures in our experience as well measures. as others, it still occurs and my develop as a new event after one year5,6. However, if CUR develops, Pre-operative measures clean self-intermittent catheterization (CIC) is a good Pre-operatively, proper selection of the women and effective treatment. with bladder cancer (BC) for ONB is mandatory. Women with history of stress urinary incontinence Measures to avoid total incontinence or SUI (SUI) or other forms of incontinence before Preservation of the rhabdosphincter is very important development of BC were excluded3,5. In addition, for post-operative continence in women undergoing women with a poor urethral pressure profile (UPP) ONB after RC1,10,11. This can be achieved by careful with a maximal urethral closure pressure (MUCP) dissection of the urethra and bladder neck, and of less than 30 cm H2O were considered transecting the urethra in the proximal, one cm distal unsuitable for ONB3. Furthermore, women with to the bladder neck. A good neobladder capacity by using enough intestinal length and fashioning a history of hysterectomy and/ or radical pelvic spherical configuration by detubularization is also surgery may be considered unsuitable for ONB, due to previous reports that suggested a positive very important. These measures and possibly the correlation between hysterectomy and poor preservation of as much as we can of the autonomic nerves help minimize the incidence of post-operative functional outcome6. total incontinence or SUI1-3,6,10. Operative measures Measures to avoid CUR Measures to avoid PVF Certain technical modifications were described to In our experience, certain surgical modifications have prevent CUR3,5. These modifications were based on been performed after the first 100 cases to avoid PVF7. the finding that CUR may result from a mechanical These modifications included meticulous closure of factor secondary to caudal and posterior neobladder the vaginal stump with embedding of its mucosa and displacement and increased acuteness of the dissection, and suturing of the peritoneum covering neocystourethral angle during voiding3,5,8. These the anterior rectal wall onto the closed vaginal stump. modifications aimed at providing a proper back In addition, a pedicled omental flap was interposed support to the neobladder, preventing its caudal between the vagina and the urethroileal anastomosis. In this study, between January 1995 and March 2010, 298 women (mean age, 52 years) underwent ONB after RC7. A standard RC was conducted in 283 patients and genitaliasparing cystectomy in 15. Eight PVF (2.7%) were diagnosed by voiding radiography of the pouch and preoperative endoscopy. After a mean follow-up of 146 months, the incidence of PVF was five of 100 (5%) before and three of 198 (1.5%) after the technical modifications. Figure 1: After the vaginal stump was closed meticulously during RC, the medial ends of the round ligaments (RL, arrows) were used to anchor the vaginal stump. In addition, the peritoneum covering the anterior rectal wall (ARW) was sutured to the anterior aspect of the closed vaginal stump. The symphysis pubis (SP) is seen and the urethra (U) is seen held with multiple sutures.
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EUT Congress News
Post-operative measures Strict follow-up is mandatory to pick up early complications and
prevent further deterioration, especially the deleterious effect of these complications on the upper tract (CUR) and on the social life of women (NI). Oncological and functional evaluation was described before4. Pelvi-abdominal CT scan or MRI was carried out annually, and when otherwise indicated to rule out oncological failure. Panendoscopy was done if the patient Figure 2: A generous pedicled omental flap was brought down to fill the empty pelvic cavity. The complained of bleeding urethra (U) is seen held with multiple sutures. per urethra or hematuria. Radioisotope bone scan was carried out, whenever needed. Functionally, and NI after the operation. The incidence of PVF has patients were interviewed about daytime and dramatically decreased after adoption of technical nighttime continence. Also, they were asked about modifications to avoid its occurrence. According to pouch emptying to a completion. We evaluated the the opinion of some investigators, uterus upper tract imaging by excretory urography or MRU preservation and attempted nerve-sparing during RC every year. Fluoroscopic voiding study with video and ONB have been associated with better functional recording was conducted. Pelvic floor MRI was also outcome. performed in some cases5. The role of urodynamic testing in the pre- and post-operative assessment in References our experience and others’ will be shortly detailed 1. Hautmann RE, Paiss T, de Petriconi R. The ileal here below. neobladder in women: 9 years of experience with 18 Genitalia sparing cystectomy Genitalia sparing cystectomy in women with BC is gaining increased interest. In a previous study, we reported on our early experience on 15 cases, in whom the inclusion criteria included stage (T2b N0 Mo or less), unifocal tumors away from the trigone, sexually active young women and internal genitalia free of tumor13. It was concluded that it is feasible in selected women. A good functional outcome and better sexual function together with the potential of keeping fertility were achieved. The oncological outcome was good. In addition, other investigators reported on similar experiences with favorable outcome6,14,15. Role of UPP and other urodynamic tests These can help predict some post-operative complications and detect them early to avoid further consequences6,9. In patients with women with NI after ONB, it has been stated that urodynamic testing can characterize the reasons for voiding and continence problems in most cases9. Pouch hyperactivity should be treated once diagnosed in these cases because it was shown to be the cause of NI in 50% of the cases and a good factor in response to treatment. We recommend urodynamic evaluation in women with abnormal voiding and continence after ONB. In addition, Gross et al (2015) stated that in the post-operative period, patients with incontinence and no post-void residue (PVR) had a shorter functional urethral length and a lower median maximal urethral closure pressure with a subsequently lower continence product compared with continent women without PVR6. Furthermore, patients with bilateral nerve sparing had the highest continence products6. Also, changes in the UPPs over time could explain the change of their women’s status either from spontaneous voiding to CUR or from incontinence to continence6. Take home message Some of the complications after RC and ONB in women can be avoided. These complications include CUR, total incontinence, NI, and PVF. We have provided strong evidence that CUR is mostly due to anatomical factors. Other investigators stated that lack of preservation of the autonomic nerves supplying the proximal urethra during RC may be the cause of CUR. Nevertheless, modifications to increase back support of the neobladder with ventral suspension near its dome and support the vaginal stump are recommended to avoid this complication. In addition, careful dissection of the area between the bladder neck and proximal urethra anteriorly and the anterior vaginal wall posteriorly as well as along the lateral wall of the vagina is of utmost importance. This careful dissection will help keep the integrity of the rhabdosphincter and possibly the autonomic nerves supplying the proximal urethra, and this may decrease the incidence of CUR, total incontinence,
patients. J Urol. 1996;155:76-81. 2. Stein JP, Grossfeld GD, Freeman JA, Esrig D, Ginsberg DA, Cote RJ, et al. Orthotopic lower urinary tract reconstruction in women using the Kock ileal neobladder: updated experience in 34 patients. J Urol. 1997;158:400-5. 3. Ali-El-Dein B, El-Sobky E, Hohenfellner M, Ghoneim MA. Orthotopic bladder substitution in women: functional evaluation. J Urol. 1999;161:1875-80. 4. Ali-El-Dein B, Shaaban AA, Abu-Eideh RH, El-Azab M, Ashamallah A and Ghoneim MA. Surgical complications following radical cystectomy and orthotopic neobladders in women. J Urol 2008; 180(1):206-10. 5. Ali-El-Dein B, Gomha MA and Ghoneim MA. Critical evaluation of the problem of chronic retention after orthotopic bladder substitution in women. J Urol 2002; 168: 587-92. 6. Gross T, Meierhans Ruf SD, Meissner C, Ochsner K, Studer UE. Orthotopic ileal bladder substitution in women: factors influencing urinary incontinence and hypercontinence. Eur Urol 2015;68(4):664–71. 7. Ali-El-Dein B, Ashamallah A. Vaginal Repair of Pouch-vaginal Fistula After Orthotopic Bladder Substitution in Women. Urology. 2013 Jan;81(1):198-203. 8. Puppo P, Introini C, Calvi P, et al. Prevention of chronic urinary retention in orthotopic bladder replacement in the female. Eur Urol. 2005;47:674-8. 9. Ali-El-Dein B, El-Hefnawy AS, Zahran M, Shaaban AA and Ghoneim MA. Urodynamic Characterization of Voiding and Continence Problems after Orthotopic Neobladders in Women. J Urol 2011; 185 (4):e458. 10. Stenzl A , Colleselli K , Poisel S , Feichtinger H , Pontasch H , Bartsch G . Rationale and technique of nerve sparing radical cystectomy before an orthotopic neobladder procedure in women . J. Urol. 1995;154:2044-9. 11. Ali-El-Dein B and Ghoneim MA. Effects of selective autonomic and pudendal denervation on the urethral function and development of retention in female dogs.J Urol. 2001, 166: 1549-54. 12. Skinner EC and Comiter CV. Can we improve the functional outcomes of orthotopic diversion in Women? Editorial to “ Gross T, Meierhans Ruf SD, Meissner C, Ochsner K, Studer UE. Orthotopic ileal bladder substitution in women: factors influencing urinary incontinence and hypercontinence. Eur Urol 2015;68(4):664–71.” Eur Urol. 2015; 68:672-3. 13. Ali-El-Dein B, Mosbah A, Osman Y, El-Tabey N, Abdel-latif M, Eraky I, Shaaban AA. Preservation of the internal genital organs during radical cystectomy in selected women with bladder cancer: A report on 15 cases with long term follow-up. EJSO 2013; 39: 358-64. 14. Horenblas S, Meinhardt W, Ijzerman W, Moonen LF. Sexuality preserving cystectomy and neobladder: initial results. J Urol 2001;166:837–40. 15. Koie T, Hatakeyama S, Yoneyama T, Hashimoto Y, Kamimura N, Ohyama C. Uterus-, fallopian tube-, ovary-, and vagina-sparing cystectomy followed by U-shaped ileal neobladder construction for female bladder cancer patients: oncological and functional outcomes. Urology. 2010;75:1499–503.
Monday 14 March 10.30-12.00: Thematic Session 16 Challenges in reconstructive urology
Monday, 14 March 2016
Ultra-mini PCNL Challenges in the removal of medium-sized lower pole stones Dr. Janak D. Desai Samved Hospital Dept. of Urology Ahmedabad (IN)
There is an increasing incidence of nephrolithiasis throughout the world. Rates of Extracorporeal Shock Wave Lithotripsy (ESWL) are falling and Retrograde Intrarenal Surgery (RIRS) increasing. The moderate sized stone of 10-20 mm is common and is technically suitable for all modalities of intervention including percutaneous nephrolithotomy (PCNL). Experienced urologists realise that it is not simply the stone size, but its position, associated anatomical abnormality, body habitus, comorbidity, patient demand and cost of treatment that determines the selection of the intervention. Although RIRS has a better safety profile, its stone clearance rate is inferior to that of PCNL, but although PCNL has good stone clearance rates it is associated with a significant risk of morbidity. Since most of the morbidities associated with PCNL are related to the size of tract, a reduction in tract size can lower the number of complications associated with it. Much of the morbidity associated with PCNL has been from the size of the tract. Reducing the tract size to 14-18F mini PCNL has been shown to reduce bleeding, analgesic requirements and length of stay, which is thought to be due to reduced dilatation giving rise to less tissue and renal trauma. With Ultra-Mini PCNL (UMP), the tract size is further reduced without compromising on the stone- free rates. The innovative aspects of UMP is the use of the a 3.5F telescope to allow good endoscopic visualisation as well as the use of the Venturi effect from the small channel within the sheath which creates turbulence within the collecting system forcing the small fragments out via the sheath when the inner sheath is removed.
There are still regions in the collecting system where the flexible ureteroscope still cannot access. Even with RIRS in a straight-forward moderate sized stone, there can be difficulty in accessing the ureter, deploying an access sheath, fully fragmenting and removing fragments all at one sitting. Procedure times can be prolonged and there can certainly be an element of fatigue in maintaining an optimal hand position for fragmentation. All these factors can result in less than optimal results with RIRS.
We believe the smaller tract size, fewer dilatation manoeuvres to access the stone and the use of miniaturised instruments are responsible for the small number of complications and minimal impact on haemoglobin concentration and serum creatinine. Anecdotally, the fluoroscopy time is reduced as there are less dilatations compared to conventional PCNL.
Comparisons Tubeless and stentless PCNL have previously been shown to be opiate-sparing and have reduced the Operative time length of stay in prospective randomised controlled Access to the kidney can be achieved from any pole. studies. A comparative prospective study by Knoll et The majority of the punctures were inter or lower al. demonstrated a reduced analgesic requirements pole due to the position of the index calculus and the as well as length of stay in mini-PCNL(18F) compared Many healthcare systems and, ultimately, patients relative safety of access. On occasion, where a perfect to PCNL. Similarly our combination of no themselves find it difficult to accept the fragility and end on papillary puncture is not possible, e.g. in cases nephrostomy, small diameter tract and 4mm skin high costs associated with RIRS and its associated of calyceal diverticula, completely obstructed calyceal incision probably all contributed to the reduced disposables. Ureteric access sheaths use is not calculi and anterior calyceal punctures, the smaller without risk and with potential for trauma. postoperative pain and length of stay. sized sheath of UMP is more forgiving and less likely Prospective evaluation has shown ureteric wall to result in bleeding and parenchymal damage. trauma in 46.5% of patients. UMP appears in this study to have a high stone-free rate together with a low complication The concern with any newer more minimally invasive rate and a comparable length of stay to RIRS. For Structuring or avulsion of the ureter although rare, will put the entire renal unit at risk. UMP does require procedure is whether the operative difficulty is the moderate sized stone it appears to offer very increased and, therefore, the time required to ureteric access but only with a 6F soft ureteric good outcomes. fragment and remove the calculi. The mean UMP catheter with no requirement of dilatation of the operating time of 53.7 ± 15.4 mins is comparable to ureter. Although there is a risk of haemorrhage, with 85% of the world’s 7 billion population are in the modern highly selective interventional techniques, the recent micro (4.85F) PCNL for ≤15mm calculi developing world, where healthcare systems and risk of complete renal unit loss is extremely low.
“UMP, as a technique, will not replace conventional 24-30F PCNL but will simply complement it. It is not suitable for large complex stones especially where there are matrix or “putty” stones.” The issue of stent symptoms from RIRS is no small matter and endo-urologists will be all too familiar with frequent patient grievances this causes, as well as the consternation of the forgotten encrusted stent. Meta-analysis has shown consistently that stents increased symptoms, cost and lowered quality of life, with further procedures or appointments required to facilitate removal. Although the majority of UMP patients have a ureteric catheter, this is removed at 12 to 24 hours as there is no mechanical trauma to the ureter, thus overcoming the limitations of RIRS.
Comparison of UMP with standard AMPLATZ
UMP relies on laser fragmentation and allows removal of fragments via an innovative designed sheath and irrigation system. The technique can be performed either supine or prone and there are longer sheaths for obese patients.
(51.6±18.5 mins), mini PCNL with 20F dilation for ≤15mm calculi (57.3 ±SD 14.5 mins) and conventional This prospective “real world” study demonstrates that 30F PCNL series by Resorlu in 140 patients with calculi UMP can achieve high stone-free rates (83%) in treating between 10 and 20mm (57.5 ± 22.1mins) . stones between 10-20 mm on CT-KUB follow-up. This rate is in line with other large published series of mini The operative time of UMP is comparable to other PCNL and PCNL. We have been strict in our definition of endourological techniques and we believe this to be “stone-free.” A further 15% of patients had 2 mm partly due to the good vision offered by the 17,000 residual fragments or less, which many similar studies pixel endoscope as well as use of the modern high have deemed as clinically insignificant. If followed up definition stack systems offering good lighting and by KUB X-ray or ultrasound, the majority of these would image quality. not have been detected. In addition, significant progress in this area has been UMP appears to be a safe procedure with a 5% achieved by improved engineering and manufacturing complication rate. The majority (80%) were lowprocesses allowing for smaller robust sheaths and grade as per Clavien-Dindo and were managed telescopes with levels of visualisation to which we are conservatively or with antibiotics. accustomed to in traditional percutaneous surgery.
Challenges Readers may question why we need this procedure, especially with the improvements in flexible ureterorenoscopy. RIRS is an excellent procedure, but is still challenging in difficult to reach calculi, i.e., acute calyceal angles, calyceal diverticula and in fragmenting larger lower pole stones.
These findings compare favourably with RIRS and appear significantly better than those reported for mini PCNL (26.9%) or standard PCNL (14.5%) or from a recent large meta-analysis (15.6%). There were no transfusions and patients had no clinically significant alteration in haemoglobin concentration or serum creatinine.
UMP has been previously demonstrated to be feasible and successfully used in small retrospective cohort studies. The ideal indication is a 10-20mm calculi and not the larger more complex calculi. Improvements in technology, engineering and manufacturing processes have enabled smaller robust reusable 3.5F telescopes and 11-13F sheaths with similar levels of visualisation that we are accustomed to in conventional PCNL surgery.
We were able to achieve an excellent (99%) intraoperative stone-free rate based on the image intensifier due to the ease by which the fragments are evacuated. Low pressure irrigation allows for good endoscopic vision. If bleeding was encountered, it was washed out using irrigation via the ureteric or the outer sheath. A 3F grasper was available to remove any debris, small stones or clots encountered. Although not required for our cohort, should progress or vision become difficult, UMP can be converted to a mini or conventional PCNL through the same tract. The relative lack of trauma and bleeding allows surgeons to confidently forego the nephrostomy tube. This makes a direct impact on length of stay and postoperative pain and discomfort. 79% of patients did not require a nephrostomy and 92% were stent-free on discharge. A stent was only placed (8%) if there were concerns regarding the integrity of the collecting system or if there were retained fragments or clots which may drain better after a short period with a stent in-situ.
ULTRA-MINI PCNL (UMP) set
Monday, 14 March 2016
operative recovery. Mean length of stay in our study was 1.6 ± 0.69 days. In effect, UMP appears to be levelling the playing field with RIRS in terms of length of stay.
The vast majority (91%) of patients required only oral analgesia postoperatively and therefore quick to mobilise. Intramuscular or patient-controlled anaesthesia was seldom required and which reflected in the reduced length of stay and routine post-
patients are exquisitely sensitive to the rising costs of modern surgery. A technique which is effective, minimally invasive and has few complications with relatively low costs would certainly be in demand.
“...UMP may be a valuable addition to the armamentarium of the endourologist.” UMP will always face resistance because of the need to puncture percutaneously. The skill of percutaneous access has a learning curve; as endo-urologists we need to continue to embrace learning, as well as teaching this skill. In some units, the skill will reside with the radiologist, but whoever performs the access, we should not be afraid of using the technique, if it is to achieve the best outcome for our patients. UMP, as a technique, will not replace conventional 24-30F PCNL but will simply complement it. It is not suitable for large complex stones especially where there are matrix or “putty” stones. UMP, however, may also have a role in reducing the invasiveness of multi-tract PCN where the risk of bleeding increases significantly. Innovation is important, but as with most surgeon scientists, we believe it is important to understand a technique and see where its strengths and limitations lie rather than advocate it blindly. Like most things in medicine, advances are incremental upgrades which require careful evaluation. Further multicentre studies are required but if confirmed, UMP may be a valuable addition to the armamentarium of the endourologist. 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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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. 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.
Monday, 14 March 2016
ESU Course 38: Testicular cancer Quality matters in residual resection of advanced testis cancer after chemotherapy Prof. Peter Albers Department of Urology Düsseldorf University Hospital Düsseldorf (DE)
Testicular germ cell tumors are potentially curative neoplasms even in cases of metastatic disease. In US, the number of newly diagnosed patients with testicular cancer in 2015 will be around 8,400 cases with a mortality of about 380 patients which corresponds to a cure rate of about 95%. With an incidence of about 10/100.000 in northern and central European countries, the absolute number of newly diagnosed patients (pts) with metastatic disease according to Eurocare 5 is about 1000-2000 pts in most of the large European countries. About half of them will end up with an indication to perform residual tumor resection (RTR) after successful chemotherapy. Correct classification and timing of surgery is crucial All patients before and after chemotherapy have to be staged very precisely, according to the International Germ Cell Cancer Collaborative Group (IGCCCG) classification system including markers after orchiectomy and with perfectly performed imaging studies. Important is an appropriate application of contrast medium in CT imaging with exact timing of contrast to be able to judge on the nodes around the renal hilum and great vessels as well as possible caval thrombosis. Usually, CT is preferred over MRI. FDG-PET is not indicated in the preoperative staging of non-seminoma after chemotherapy due to the lack of correct imaging of teratoma components. Even in seminoma after chemotherapy positive FDG-PET signals have to be handled with caution since in
about 50-60% these signals do not represent active residual seminoma but inflammation after chemotherapy. Surgery in those cases may be really related to a high complication rate without being indicated at all1. In all patients, RTR is an important addition to chemotherapy in order to cure patients. To delay or omit RTR has to have a very good explanation. The correct indication for RTR is every tumor residual > 1 cm in transverse CT diameter after chemotherapy in non-seminoma. Surgery should be performed as early as possible after chemotherapy (mostly three to four weeks) to avoid early marker progression from residual tumor which will eventually lead to salvage chemotherapy. This can be prevented by a perfectly performed chemotherapy with a low complication rate and thus a good chance to proceed with surgery in time. To delay surgery in patients that need it (“salvage residual tumor resection“) will lead to a significant drop in cancer-specific survival. So immediate RTR after chemotherapy is standard of care. Extent of surgery and additional procedures Traditionally, the extent of a retroperitoneal RTR included both sides of the great vessels (“bilateral approach“) in every patient following the borders of resection described by Donohue et al. in their pivotal paper on distribution of lymph node metastasis in testis cancer. Meanwhile, there is accumulating data to restrict the field of resection to the right or left template in patients with tumors < 5 cm and strictly unilateral metastasis before chemotherapy. This
Figure: Complete en-bloc resection of the tumor including the aorta with aortal grafting
approach benefits patients since antegrade ejaculation can be preserved in most cases. In more advanced cases, bilateral resection is still the standard of care. In those cases, additional procedures like nephrectomy, liver resections, caval resection with reconstruction, aortic replacement may be necessary in about 25-30% of patients2. This demands that this kind of surgery has to be performed in centers where vascular surgeons, liver surgeons are readily available because preoperatively most of the additional procedures are not predictable. Our group has published that vascular procedures are necessary in every fifth patient if the residual tumor is > 5 cm and the patients started chemotherapy as a poor or intermediate risk patient3. Complications of residual resections include lymphocele, deferred wound healing, bleeding and lesions of the ureter in the order of usually < 10% of
Table: Additional procedures in patients with good versus intermediate & poor prognosis Additional Procedures
“Good Prognosis”
“Intermediate and Poor Prognosis”
P-Value
Nephrectomy (%)
5.0
14.0
p=0.01
Vena Cava Resection (%)
3.3
19.3
p<0.001
Liver Resection (%)
1.7
12.3
p=0.05
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cases (Clavien IIIA and higher). Complications are correlated to the extent of resection, not necessarily to the volume of residual disease. The Indiana group has lately published a simple prognostic parameter to predict additional procedures and complications of RTR: prepoperative tumor size > 10 cm. But additional procedures and complications may also be anticipated in patients with significant tumor shrinkage after chemotherapy, usually having had chorio- or embryonal carcinoma where tumor shrinkage leads also to fibrosis to adjacent organs which then are hard to separate surgically4. To avoid unnecessary complications due to unexpected intraoperative scenarios, centralized surgery in a multidisciplinary surgical setting at least in patients with intermediate and poor prognosis before chemotherapy is warranted. References 1. Decoene J, Winter C, Albers P. False-positive fluorodeoxyglucose positron emission tomography results after chemotherapy in patients with metastatic seminoma. Urol Oncol. 2015 Jan;33(1):23.e15-21. doi: 10.1016/j.urolonc.2014.09.019. Epub 2014 Nov 4. 2. Stephenson AJ1, Tal R, Sheinfeld J. Adjunctive nephrectomy at post-chemotherapy retroperitoneal lymph node dissection for nonseminomatous germ cell testicular cancer. J Urol. 2006 Nov;176(5):1996-9. 3. Winter C, Pfister D, Busch J, et al. Residual Tumor Size and IGCCCG Risk Classification Predict Additional Vascular Procedures in Patients with Germ Cell Tumors and Residual Tumor Resection: A Multicenter Analysis of the German Testicular Cancer Study Group. Eur Urol. 2012 Feb;61(2):403-9. 4. Clint Cary,M.D.,M.P.H.*, TimothyA.Masterson,M.D., RichardBihrle,M.D.,Richard S.Foster,M.D. Contemporary trends in postchemotherapy retroperitoneal lymph node dissection: Additional procedures and perioperative complications; Urologic Oncology 2015, 33: 389.e15-21
Monday 14 March 12.00-14.00: ESU Course 38, Testicular Cancer
Bristol-Myers Squibb. Research that leads the way in Immuno-Oncology.
www.WCE2016.com
What if you could help the body’s own immune system combat cancer? Bristol-Myers Squibb is researching ways to make this possible. At Bristol-Myers Squibb, we’re committed to Immuno-Oncology (I-O), a rapidly evolving field that enlists the immune system in the fight against cancer. As we learn more about how cancer evades the immune system, the growing potential of Immuno-Oncology continues to drive our research efforts.
Held in conjunction with the South African Urological Association (SAUA) Meeting • November 8 – 9, 2016
LEADING THE WAY. © 2016 Bristol-Myers Squibb Company. All rights reserved. ONCDE16NP00128-01 01/16
Monday, 14 March 2016
104812 EAU Munich Advert 194.3x133.4mm v1.0 2016.01.13.indd 1
15/01/2016 12:29
EUT Congress News
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Optimising ureteral stricture repair Prof. Stephan Roth Department of Urology Pediatric Urology and Urogynecological Surgery University Witten / Herdecke Wuppertal (DE)
Co-Authors: Stephan Degener, Niki M. Dreger, Friedrich-Carl von Rundstedt Ureteral injuries can occur in patients who have had prior surgical procedures but most commonly are observed in the context of pelvic surgery such as a hysterectomy or vascular graft surgery in the retroperitoneal space. Other common causes of ureteral stricture formation include ischemia, trauma, periureteral fibrosis, radiation, malignancy, or congenital disorders. Urologist have a wide variety of tools at their disposal for a successful management including surgical reconstruction of the injured ureter. Palliative situation In cases of an extrinsic compression of the ureter from a malignant mass, indications for treatment should be considered very carefully. Exchangeable ureteral stents are considered to be the first option in the management of ureteral obstruction. Metallic mesh stents have been used with limited success due to epithelial hyperplasia and tumor eroding through the mesh. These stents are placed permanently and multiple problems limit the applicability of these stents. However, a recent study with a selfexpandable, double-layered and coated metallic mesh stents demonstrated a primary success rate of 65 % with follow-up of about one year6. Another possibility is a subcutaneous pyelovesical prosthetic bypass8. Different working groups suggest that the quality of life may be better for those patients than with conventional nephrostomy tubes. A real improvement is the so called “TwinsTechnique“ (Figure 1). Extensive compression may lead to obstruction of conventional double-J-stents. A trick to ensure the urinary flow is the insertion of two double-J-stents which increases the rigidity and reduces luminal compression. The rationale for the two stents is the idea of urine draining in the space
Figure 1
Figure 2
between the stents as well as through them9,17,26 (Figure 1). Definitive management Endourologic options Ureteral stent placement is the primary choice in the acute management of most ureteral strictures in particular intrinsic ureteral strictures. Whether minor ureteral contusions can be managed with temporary stent placement remains unclear. They may stricture later or break down after microvascular damage with consecutive ischemia. Long term management with ureteral stents may be an option in older patients with the caveat of a procedure required for the exchange every six to 12 months. The technique of a retrograde or antegrade ballon dilation is rarely definitive and usually requires repeated dilatations on a regular basis. Contraindications to this approach include an active infection or a stricture longer than 2 cm as dilatation alone will rarely be successful in this setting. Various reports suggested that results were better when the stricture was at the site of a prior anastomosis and of recent onset and length. In a literature review12 the authors reported success rates ranging from 50 % to 76%. Endoureterotomy with endoluminal ureteral incision can be performed using a cold knife22, a cutting electrode7 or a holmium laser. In all cases, the incision is made from the ureteral lumen out to the periureteral fat in a full-thickness fashion. Some authors found benefit in the injection of cortisone ureteroscopically after endoureterotomy28. Success rates seem to be variable. Knowles14 reported a 90% patency rate in the treatment of obliterated distal ureteral segments using cautery wire ballon incision at 36 months follow-up, but only demonstrated this in 10 patients. Surgical repair without intestinal segments A short defect involving the upper ureter or midureter is most appropriate for uretero-ureterostomy (end-to-end repair, Figure 2). This surgery must be meticulous and ureteral blood supply is tenuous. The injured ureters has to be carefully mobilized to prevent devascularization. Both ends are spatulated and the anastomosis must be tension-free and watertight and should be stented temporarily. Optical magnification using surgical loops is recommended. However, determination of whether enough ureteral mobility can be achieved to allow a tension-free anastomosis usually cannot be made until time of
Figure 4
Figure 5
surgery. The success rate for a tension-free, watertight reports documenting long-term outcome for a Psoas ureteroureterostomy is high and is reported to be hitch in adults. In a retrospective review of adult above 90%4. patients, no significant difference in the preservation of renal function or risk of stenosis was identified in The procedure of uretero-neo-cystostomy is used to the refluxive versus antirefluxive precedures24. It is repair distal ureteral injuries that occur so close to the unclear whether a nonrefluxive anastomosis decreases the risk of a pyelonephritis in an adult bladder that the bladder does not need to be mobilized, so it can reach the ureteral stump as done patient. Our own results10 support the principle of a in a Psoas hitch or a Boari procedure. refluxive reimplantation in the absence of long-term side effects while avoiding the risk of stenosis at the However, the mainstay in the treatment on injuries to site of the reimplantation. the lower third of the ureter is the Psoas BladderHitch. It is important to mobilize the bladder Transureterouretereostomy sufficiently by freeing its peritoneal attachments and With this technique the injured ureter is brought the anterior cystotomy should be created in an across the midline and anastomosed end-to-side into oblique or horizontal fashion to facilitate the non-injured ureter. It is rarely used because it displacement of the bladder toward the ipsilateral involves surgery on the healthy, contralateral ureter ureter. When the bladder dome is secured to the with the theoretical risk of converting unilateral psoas minor tendon or the psoas major muscle using ureteral injury into a bilateral (iatrogenic) ureteral several absorbable sutures, care should be taken to injury, but may be justified in some cases of distal avoid injury to the genitofemoral nerve and the ureteral injury where a bladder flap or hitch repair femoral nerve. Placing the stitch parallel to the nerve are not feasible. can decrease the risk of injury or strangulation of the nerve (according to Link). The success rate of the Free buccal or peritoneal graft (Figure 5) Psoas hitch procedure is over 85% in both adults and There is a paucity of published research work about children based on recent reports1. ureteral stricture reconstruction using buccal mucosa or peritoneal grafts3,15,19,21. Almost all described However, if the ureteral defect is too long to be longitudinal incision of the strictured ureteral bridged by bringing the bladder up in the Psoas hitch segment leaving behind a more or less vascularized procedure, it can be managed with a Boari flap ureteral strip which is augmented with the harvested (Figure 3). This can bridge ureteral defect of about graft. Thus, the ureteral wall defect is covered without 10-15 cm and a spiraled bladder flap can reach the a complete ureteral transsection. What seems renal pelvis in some circumstances. The base of the important is the additional wrapping of the flap should be at least 4 cm and the tip of the flap at reconstructed part with a patch of omentum. Pycha et least 3 cm in diameter to obtain a sufficient tensional. from Bozen reported most recently a series of 19 free tubularization. To minimize the risk of flap patients and 18 / 19 had a successful outcome after ischemia, the ratio of flap length to base width should augmentation with free peritoneal grafts21. not be greater than 3:1. The number of reported patients treated with a Boari flap is limited but the Surgical repair with intestinal segments results are good if a well-vascularized flap is used18. Incorporation of other tissues in ureteral repair is reserved for situations in which a defect cannot be bridged by other methods or the bladder is not Renal mobilization for descensus (Figure 4) This helpful idea was originally described by Popescu suitable for reconstruction. In such a scenario the ileal in 1964 and can provide additional length to bridge a interposition (Figure 6) has been demonstrated to be a satisfactory option for very complicated ureteral defect in the upper ureter or decrease tension on a reconstruction5,23. Sometimes bilateral ileal ureteral ureteral repair. Up to 8 cm of additional length may substitution (Figure 6) may be necessary by using a be gained using this technique. In such cases, the renal vessels, especially the renal vein, limit the exent longer segment that travels intraperitoneally from one kidney to the other and than to the bladder (“inverse to which the kidney can be mobilized. hockey shape“). Occasionally, a segment of colon may be more accessible than the ileum and is harvested Is antirefluxive reimplantation necessary? using the same surgical principles11 (Figure 7). There has been considerable controversy about the type of reimplantation in a ureteroneocystostomy: Different reports have shown that refluxive ileovesical antirefluxive versus refluxive. There are very few anastomosis is a reasonable approach as the intestinal peristalsis provides a valve-like effect5,13,27. A general contraindication to an ileal ureteral substitution are baseline renal insufficiency with a serum creatinine value greater than 2 mg /dl, bladder dysfunction or outlet obstruction, inflammatory bowel disease or radiation enteritis.
Figure 7
Figure 8
In some patients the reconstruction of an ileal ureter may not be a feasible option such as an insufficient length of ileum, extensive abdominal adhesions, comorbidities or renal insufficiency. In these situations transverse reconfigured colon segments may be used successfully to reconstruct extensive ureteral defects (Figures 8,9). The technique was first described by Pope & Koch20 and consists of a modified Yang-Monti principle29. A 3 to 4 cm colon segment is isolated, detubularized and reconfigured to create a long slim graft to bridge the defect. Because of the wide cross-sectional diameter of colon (compared with ileum) the length needed for reconfiguration is minimal (approximately 3 cm for a single and 6 cm for a double segment). The proximity of the colon to the ureter is of great advantage. The procedure can be performed in a retroperitoneal approach through a flank incision with only colonic isolation being intraperitoneal. Special attention must be given to the precarious blood supply of the isolated colon ring (Figures 8,9). Especially in obese patients the reconfiguration may be challenging. However, the proximity of the colon to the mid and upper ureter ensures that mobilization of the colon pedicle is minimized. Long-term results of this technique are very encouraging and thus this technique is quite often applied in our department16,25. NOTE: Interested readers can request for the complete reference list by sending an email to: communications@uroweb.org Monday 14 March 10.30-12.00: Thematic Session 16, Challenges in reconstructive urology
Figure 3
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EUT Congress News
Figure 6
Figure 9
Monday, 14 March 2016
Is Gleason 6 cancer? Identification of low-risk Gleason 7 Dr. Geert van Leenders Department of Pathology Erasmus MC, Rotterdam Rotterdam (NL)
The Gleason score has been the universal grading system for prostate cancer for half a century. In the late 1960s, Donald Gleason (1920-2008) developed his ‘classic’ grading system, which was solely based on the classification of tumor growth patterns and is unique in taking account of tumor heterogeneity. In 2005 the International Society of Urologic Pathology (ISUP) significantly modified the Gleason grading system. This modification resulted from alterations in clinical presentation and pathological diagnosis of prostate cancer in the preceding 40 years; in Gleason’s day prostate cancer was commonly discovered at a late stage or incidentally at transurethral resection for hyperplasia, since Prostate Specific Antigen (PSA) was only introduced in the late 1980s. Immunohisto-chemistry for basal cells was not included in the pathologic diagnosis of lesions suspicious for prostate cancer at that time. Many closely packed, slightly atypical glands originally classified as Gleason grade 1 or 2 probably represented atypical adenomatous hyperplasia since immunohistochemical staining for basal cells is a prerequisite for differentiating these lesions. In November 2014, the ISUP updated the Gleason grading system again with relatively minor changes in relation to the 2005 modification. With the modified Gleason grading system the criteria for diagnosing Gleason score 6 prostate cancer became more strict and uniform. As a result of the Gleason grade modification, almost half of ‘classic’ Gleason score 6 tumors on diagnostic biopsies are upgraded to ‘modified’ Gleason score 7. Since the introduction of the modified grading system, several studies have demonstrated very low (<1%), if any, metastatic potential of Gleason score 6 prostate cancer at radical prostatectomy. Considering the minimal chance of metastasis or disease-specific death, the question has been raised whether Gleason score 6 tumors should be considered ‘cancer’ at all.
It has been known for a long time that the Gleason score at biopsy is lower than the actual Gleason score at radical prostatectomy in up to 20% of cases. This could explain the potential for aggressive behavior of tumors with Gleason score 6 at biopsy. Finally, Gleason grading in daily practice is unfortunately subject to inter-observer variation. Distinguishing Gleason score 6 from Gleason score 7 with ill-formed and fused growth patterns can be particularly problematic, leading to false reassurance or overtreatment of prostate cancer patients. Pathologic Gleason grading is an important parameter for optimal treatment of individual prostate cancer patients. While many patients with Gleason score 6 prostate cancer are eligible for active surveillance, active treatment is generally preferred for Gleason score 7 tumors. Considering the excellent prognosis of Gleason score 6 prostate cancer, the question arises whether subpopulations with good prognosis can also be identified within the large cohort of Gleason score 7 prostate cancer patients.
Figure 2: Intraductal carcinoma of the prostate (IDC-P) is an aggressive prostate cancer feature. IDC-P is characterized by large cribriform proliferations of malignant epithelial cells within pre-existent prostate glands. Hematoxylin & Eosin, 200x
that Gleason score 6 and 7 prostate cancer on biopsy have statistically similar rates of post-operative biochemical recurrence and disease-specific death.
This group of Gleason score 7 cancers consists predominantly of ill-formed and fused malignant Microscopically Gleason score 3+4=7 is composed of glands, which are particularly associated with well-delineated malignant Gleason grade 3 glands inter-observer variability in prostate cancer grading. If and Gleason grade 4 epithelial structures which validated by other groups, these findings might well encompass a heterogeneous group of growth patterns affect future therapeutic strategies for prostate cancer. including so called ill-formed, fused, glomeruloid and Presence of invasive cribriform Gleason grade 4 cribriform structures. Recently, we and others have prostate cancer or IDC-P is indicative of aggressive shown that Gleason score 7 tumors with cribriform biological potential and should prompt active growth, representing 20% of tumors, have a treatment. On the other hand, Gleason score 3+4=7 significantly higher risk for biochemical recurrence prostate cancer patients without these features might and metastasis after prostatectomy and radiation therapy. In addition, expansion of prostate cancer within pre-existent glandular structures, called intraductal carcinoma of the prostate (IDC-P), has been shown to represent an adverse feature in disease outcome (Figure 2).
be candidates for active surveillance since their outcome is not statistically different from Gleason score 6 cancers. In conclusion, Gleason score 6 is prostate cancer but with low potential to metastasize. Invasive cribriform and intraductal carcinoma are aggressive prostate cancer features, which might affect therapeutic stratification of Gleason score 7 prostate cancer patients. Monday 14 March 10.30-12.00: Thematic Session 12, Questions in early diagnosis of prostate cancer
SATELLITE SYMPOSIUM
SUMMARY
Formally, IDC-P is an adjunct tumor characteristic, not being part of the Gleason grading system. Cribriform Gleason grade 4 prostate cancer and IDC-P are closely related; morphologically they can only be separated based on the presence (IDC-P) or absence (cribriform growth) of basal cells, and both lesions often co-exist. In a group of more than 1000 diagnostic biopsies, we have shown that presence of cribriform growth or IDC-P is an independent parameter for diseasespecific death in all Gleason score subpopulations.
Moving Forward in Urological Cancers Symposium Chair: Jacques Irani (France)
Prostate cancer and androgen deprivation therapies: What are the newest data?
Jacques Irani (France) Professor Irani discussed the latest data on the use of androgen-deprivation therapy (ADT) in prostate cancer, starting with a detailed analysis of the STAMPEDE study and exploring other studies demonstrating the advantages of introducing chemotherapy in combination with ADT earlier in the disease course. Professor Irani also discussed recent analyses of the relative benefits of continuous versus intermittent ADT in patients with metastatic prostate cancer and explained the differences between luteinizing hormone-releasing hormone agonists and antagonists with respect to prostate-specific antigen control and adverse events.
Since presence of invasive cribriform or intraductal carcinoma is indicative of aggressive tumor behavior, to what extent do Gleason score 3+4=7 prostate cancer patients without these features differ clinically from Gleason score 6? If patients with invasive cribriform growth and IDC-P are excluded, we found
Is androgen-deprivation therapy the backbone of advanced prostate cancer treatment?
Meeting held on Saturday March 12th
From a pathologic point of view, the answer to this question is straightforward: Gleason score 6 is cancer. Gleason score 6 shares pathognomic microscopic features with Gleason score 7 to 10 prostate cancer, such as infiltration between pre-existent benign glands, absence of basal cells, presence of prominent nucleoli and perineural invasion. In addition, extra-prostatic expansion and positive surgical margins occur in up to 20% of Gleason score 6 cancers at radical prostatectomy, and are associated with post-operative biochemical recurrence in 10% of cases (Figure 1).
Despite these arguments, it might still seem attractive to label Gleason score 6 not as cancer but as a lesion of low or indeterminate malignant potential. However, one should realize that the studies demonstrating excellent outcome of Gleason score 6 cancer all involved radical prostatectomy specimens with post-operative adjuvant therapy in case of recurrence. In contrast to Gleason score 6 at prostatectomy, 2% of patients with Gleason score 6 prostate cancer on diagnostic biopsy develop metastasis or die from disease.
Axel Merseburger (Germany) Professor Merseburger introduced the importance of continuing ADT throughout prostate cancer treatment, particularly in the castration-resistant setting. He discussed mechanisms of ADT resistance, concluding that combining ADT with agents targeting alternative pathways may be a valid approach to overcome this problem in castration-resistant prostate cancer. Professor Merseburger highlighted a number of studies on combination therapies and demonstrated the value of ADT as a backbone therapy throughout the course of disease.
Prostate cancer in China: From fundamental research to clinical practice
Liqun Zhou (China) Professor Zhou delivered an overview of the recent advances in prostate cancer care and research in China. He began by introducing the epidemiology of the disease in Chinese men, before moving on to discuss developments from fundamental research conducted in China. Professor Zhou highlighted new therapeutic targets and discussed the potential of new diagnostic and prognostic markers described by Chinese groups. He concluded that China will play a big part in the evolution of future prostate cancer care.
Photodynamic diagnosis of bladder cancer in a real world setting: Does it work outside of clinical trials? And can we manage high-risk patients better in real life?
Maximilian Burger (Germany)* Professor Burger presented data on photodynamic diagnosis in bladder cancer, highlighting the benefits of hexaminolevulinate (HAL) in transurethral resection of the bladder (TURB). He demonstrated the advantages of this technique in bladder cancer detection, resulting in delayed and reduced rates of recurrence. He provided a comparison of HAL–TURB in clinical trials and clinical practice, concluding that HAL–TURB is similarly effective in both settings.
TOPIC OF THE YEAR 2016
*The Innovators in Bladder Cancer “Bladder Cancer Topic of the Year” was voted on and the winner announced during the symposium. If you would like further details on the selected Topic of the Year, please visit the Ipsen booth (Booth D42, Hall B1).
Figure 1: Gleason score 6 prostate cancer glands with expansion into extra-prostatic fat tissue (pT3). Hematoxylin & Eosin, 200x
Monday, 14 March 2016
EUT Congress News
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Transurethral en-bloc resection of NMIBC Where is the evidence? Thomas RW Herrmann Vice chairman, Asst. Professor Dept. of Urology & Urological Oncology Hannover Medical School (MHH) Hannover (DE)
Co-Authors: Mathias Wolters (DE), Alexander Karl (DE), Mario W. Kramer (DE) Conventional transurethral resection of bladder tumors (TURBT) is the unmatched current standard for the diagnosis and treatment of bladder cancer regardless whether TURBT is performed in monopolar or bipolar fashion. However, there are some well know limitations: intravesical tumor fragmentation that may impede histopathological evaluation, possible tumor cell seeding and a rather high rate of under staging. Therefore, one of the key changes in the 2015 update of the guidelines on non-muscle invasive bladder cancer was the implementation of a new section on resection techniques with special focus on the significance of biopsy for bladder cancer pathology. For the last five years transurethral en-bloc resection of bladder tumors (ERBT) came into focus as it seems to possibly meet the demands of a more standardized treatment and to overcome some of the abovedescribed limitations.
complete resection and avoidance of cautery artefacts. ERBT summarizes all energy sources for en bloc. Today ERBT plus is only available with monopolar current (Hybridknife ™, ERBE, Tübingen, Germany) for incision and dissection and a hydrojet to inject saline solution into the interstitium of the submucosal and deeper tissue layers of the bladder, thereby expanding the thickness of the bladder wall. As in gastroenterological surgery, the proposed advantage is the prevention or reduction of perforation of the targeted tissue3,4,5. The authors of this overview have compiled two structured reviews in 2014 and 2015 exploring both data of laser (Holmium, Thulium, LBO [Lithium Borate]) and monopolar / bipolar approaches for ERBT with regard to effectivity and safety of the procedure5,6. This data analysis resulted in the conclusion that one of the mayor features of ERBT/ERBT plus represents a technique with low intraoperative and perioperative morbidity. One evident limitation is that complication reporting has not been done in a structured manner such as using Clavien-Dindo classification5. Another key feature as result of ERBT is excellent specimen quality, with regard to low thermocoagulatory artefacts and high and reproducible presentation of lamina muscularis propria (LMP) in the specimen8,5,6.
A specimen in one piece allows for description of margin status and architecture (T1 substratification). The latter one could be profitable for future risk stratification models. These findings are supported by the latest findings of the working group for En-Bloc The published literature of the past five years Resection of Urothelial carcinoma (EBURC) from suggests that the so called transurethral en-bloc 2015. A database from six centres could resection of bladder tumors (ERBT) has the potential demonstrate in 221 patients, independently of the to change the course of endoscopical surgical energy source used, a high presentation of LMP approach in the removal, diagnosis and assessment of (>97%) and thoroughly high specimen’s quality non-muscle-invasive bladder bancer (NMIBC) within [8] according to the current NMIBC quality the next decade2. Numerous different surgical guidelines criteria (LMP and complete resection). techniques are explored in the literature using This study also compared HF-ERBT (156 patients) different energy sources. In conclusion, all these and laser ERBT (65 patients) and found no clinical techniques can be broken down into two surgical relevant difference. The median surgical time was principles: ERBT (Figures 1 and 2), and ERBT plus 25 minutes. The only difference found was a (Figure 3) with additional measures2. significantly lower Hb-drop in the laser ERBT group (p = 0,0013). But the overall Hb-drop was Both approaches are similar to other surgical only about 0,38 g / dl. The overall complications en-bloc techniques: no touch, safety margin, rate reported was as low as 2,7%.
Figure 4: Specimen after Hybrid Knife resection
One of the critical issues of assessment of ERBT today is the short follow-up reported and the study quality in general. Prospective data collection or randomized controlled data are sparse. In our study, we could report a follow-up of 12 months in 148 patients. 33 (22,3%) had tumor recurrence with 63,6% were out-of-field8. But, no conclusion about the oncological advantage / disadvantage can be drawn so far from the existing literature5,6,8. These data are confirmed by the latest monocentric study from Hurle et al. (2016). ERBT has huge potentials, but many further challenges need to be addressed. What is a favourable location for ERBT, what are the basic requirements that allow for ERBT, which surgical skill set is appropriate? Who is eligible receiving ERBT? What to do with larger or solid tumors that cannot be extracted in one piece? Is a bag always required for tumor retrieval? What about reducing costs in NMIBC management? Two studies are currently under way that potentially find some answers to the questions raised: The “Hybrid-Blue” study comparing ERBT using the HybridKnife® with cTURBT. The results of this study are awaited by the end of 2016. Primary aim of this study is the assessment of the tumor regarding the depth of invasion as well as the resection status. Furthermore, residual tumor rates, recurrence rates and progression rates will be analyzed during one year of follow-up (Figure 4.) Furthermore, the EBRUC project (En Bloc Resection of Urothelial Cancer), originally derived from a European Association of Urology section of Uro-Technology (ESUT) project10. Phase 1 provides analyses based on retrospective data and is currently ongoing [8]. Phase 2 represents a European multi-institutional prospective, randomized study in which ERBT (lasers and electrical) will be compared to cTURBT. These two studies will give us some early answers to the questions, but the future of ERBT is open (for discussion). But one thing is for sure. ERBT addresses the quality issue of contemporary cTURBT quality and will inspire the surgical community to improve diagnosis and staging of NMIBC and MIBC. References
Figure 1A-D: Surgical principle of enbloc resection of bladder tumors (ERBT) from Kramer et al. World J Urol. 2015 Apr;33(4):571-9. (1)
Figure 2: EBRT en-bloc dissection with excision of t e inner layer of lamina muscularis propria. From Kramer et al. Minim Invasive Ther Allied Technol. 2014 Aug;23(4):206-13 (2)
Monday, 14 March 2016
1. Mario W. Kramer, Mathias Wolters, Thomas RW Herrmann.En bloc resection of bladder tumors – ready for prime time?. Eur Urol 2016. DOI: 10.1016/j. eururo.2016.01.004
Figure 3: EBRT plus. Hydro-injection plus monopolare en-bloc resection of NMIBC. From Kramer et al. Minim Invasive Ther Allied Technol. 2014 Aug;23(4):206-13 (2)
2. Karl A, Herrmann TR. En bloc resection of urothelial cancer within the urinary bladder: the upcoming gold standard? : Re: Kramer MW, Wolters M, Cash H, Jutzi S, Imkamp F, Kuczyk MA, Merseburger AS, Herrmann TR. Current evidence of transurethral Ho:YAG and Tm:YAG treatment of bladder cancer: update 2014. World J Urol. 2014 Jun 10. [Epub ahead of print]. doi: 10.1007/ s00345-014-1337-y. World J Urol. 2015 Apr;33(4):581-2. doi: 10.1007/s00345-015-1498-3. 3. Nagele U, Kugler M, Nicklas A, Merseburger AS, Walcher U, Mikuz G, Herrmann TR. Waterjet hydrodissection: first experiences and short-term outcomes of a novel approach to bladder tumor resection. World J Urol 29(4):423–427 4. Fritsche HM, Otto W, Eder F, Hofstadter F, Denzinger S, Chaussy CG, Stief C, Wieland WF, Burger M. Water-jetaided transurethral dissection of urothelial carcinoma: a prospective clinical study. J Endourol 2011 25(10): 1599–1603 5. Kramer MW, Abdelkawi IF, Wolters M, Bach T, Gross AJ, Nagele U, Conort P, Merseburger AS, Kuczyk MA, Herrmann TR. Current evidence for transurethral en bloc resection of non-muscle-invasive bladder cancer. Minim Invasive Ther Allied Technol. 2014 Aug;23(4):206-13 6. Kramer MW, Wolters M, Cash H, Jutzi S, Imkamp F, Kuczyk MA, Merseburger AS, Herrmann TR. Current evidence of transurethral Ho:YAG and Tm:YAG treatment of bladder cancer: update 2014. World J Urol. 2015 Apr;33(4):571-9.Fraundorfer MR, 7. Kramer MW, Abdelkawi IF, Wolters M, Bach T, Gross AJ, Nagele U, Conort P, Merseburger AS, Kuczyk MA, Herrmann TR. Current evidence for transurethral en bloc resection of non-muscle-invasive bladder cancer. Minim Invasive Ther Allied Technol. 2014 Aug;23(4):206-13 8. Kramer MW, Rassweiler JJ, Klein J, Martov A, Baykov N, Lusuardi L, Janetschek G, Hurle R, Wolters M, Abbas M, von Klot CA, Leitenberger A, Riedl M, Nagele U, Merseburger AS, Kuczyk MA, Babjuk M, Herrmann TR. En bloc resection of urothelium carcinoma of the bladder (EBRUC): a European multicenter study to compare safety, efficacy, and outcome of laser and electrical en bloc transurethral resection of bladder tumor. World J Urol. 2015 Apr 25. [Epub ahead of print] DOI 10.1007/ s00345-015-1568-6 9. Hurle R, Lazzeri M, Colombo P, NM Buffi, Morenghi E, Peschechera R, Castaldo L, Pasini L, Casale P, Seveso M, Zandediacomo S, taverna G, Benetti A, Lughezzani G, Fiorini G, Guazzoni G. “En Bloc” Resection of NMIBC: a Prospective Single Centre Study. Urology 2016. doi:10.1016/j.urology.2016.01.004. Available online 14 January 2016 10. Bach T, Muschter R, Herrmann TR, Knoll T, Scoffone CM, Laguna MP, Skolarikos A, Rischmann P, Janetschek G, De la Rosette JJ, Nagele U, Malavaud B, Breda A, Palou J, Bachmann A, Frede T, Geavlete P, Liatsikos E, Jichlinski P, Schwaibold HE, Chlosta P, Martov AG, Lapini A, Schmidbauer J, Djavan B, Stenzl A, Brausi M, Rassweiler JJ. Technical solutions to improve the management of non-muscle-invasive transitional cell carcinoma: summary of a European Association of Urology Section for Uro-Technology (ESUT) and Section for Uro-Oncology (ESOU) expert meeting and current and future perspectives. BJU Int. 2015 Jan;115(1):14-23 11. Guidelines on Non-muscle-invasive Bladder Cancer (Ta, T1 and CIS) M. Babjuk (Chair), A. Böhle, M. Burger, E. Compérat, E. Kaasinen, J. Palou, M. Rouprêt, B.W.G. van Rhijn, S. Shariat, R. Sylvester, R. Zigeuner
Monday 14 March 10.30-12.00: Thematic Session 13, NMIBC
EUT Congress News
13
Is there a diminishing role for a re-TUR in NMIBC? Quality of TUR: A crucial role in recurrence and progression issues References
collect proper tissue for PA investigation due to coagulation artifacts. The other way around is also true: beautiful specimens incorporating basal layer and detrusor muscle do not guarantee a complete resection of all tumor tissue.
Dr. Jorg Oddens Department of Urology Jeroen Bosch Hospital ´s-Hertogenbosch (NL)
Non Muscle Invasive bladder cancer (NMIBC) is histological diagnosed and treated at the same moment by resecting the initial tumor via the transurethral route (TUR). The pathological examination of the collected tissue is of importance to stage and grade the disease properly. This information is needed for an accurate treatment plan afterwards. First of all, the important distinction between NMIBC and muscle invasive bladder cancer can be made. In case of NMIBC, together with all collected information at the time of the TUR, the risk of recurrence or progression of the disease can be predicted. For this purpose, the EORTC risk tables take into account, besides stage and grade, the tumor diameter, the amount of tumors, the occurrence of carcinoma in situ (CIS) and whether the disease is primary or recurrent1. On the basis of this risk calculation, an advice on adjuvant treatment is based, according to the EAU guidelines on NMIBC2. In this respect, the T1 and Grade 3 tumors together with CIS are most prone to recur and progress, making the recognition of these stages and grades even more important compared to lower stages and grades. This makes adequate resection combined with accurate pathological examination a key process. But how adequate can we be at both these topics at the same time? A thorough electrical loop resection and fulguration of all vital tumor tissue can be very successful to treat the tumor without the capability to
In high-risk patients(T1 and/or G3), a resection within six weeks after the initial TUR is advised to restage the tumor2. In reports on re-TUR, residual tumor tissue was found in up to 50% of patients, suggesting that a complete TUR in these patients is difficult to achieve3,4, while upstaging to muscle invasive disease is described in even 30% of patients in some series5. But very recently, based on combined data of 2451 high-risk NMIBC patients from several centers, a retrospective analysis by Gontero et al. showed strong arguments to believe that after a good TUR, judged on the basis of finding detrusor muscle in the specimen, Diagram showing the T stages of bladder cancer (Photo: Cancer Research UK / Wikimedia Commons) a re-resection in case of T1 or G3 disease does not alter the outcome of the disease6. The quality of a resection, however, differs among centers. In patients with comparable characteristics treated in seven different EORTC studies, Brausi et al. showed a variation in recurrence rates at the first follow-up cystoscopy after surgery among the different centers, even after taking into account patient characteristics and the use of adjuvant intravesical chemotherapy. In patients with solitary tumors the best center had a three-month recurrence rate of 3.4%. In patients with multiple tumors the highest three-month recurrence rate was 45.8%. Some of these three-month recurrences could be true recurrences, but the majority of these lesions were considered to be tumors missed at the initial resection. In other words, the statistically significant difference could not be explained by factors other than differences in the quality of surgery7.
did not achieve the desired results: a complication rate of 16% was observed. After another two years continuing this teaching program, the complication rate diminished to 6.1%8,9. Other data about a structured and repeated course on the technical and oncological aspects of the TUR procedure by Brausi et al., showed an increase of quality: the three-month recurrence rate for both residents and staff members decreased significantly (from 8% to 3% for staff and from 28% to 16% for residents), while the presence of muscle in the specimen increased from 50% to 80% overall10.
Quality procedure: a crucial role A transurethral resection of a bladder tumor is an oncological procedure of which the quality is linked to chances of recurrence and progression in case of NMIBC. Introduction of training programs for TUR Knowing how to perform the TUR and teaching lead to better resections. A re-TUR is at least indicated someone else to do it are two different things. For this in high-risk patients without detrusor muscle present purpose, a complication based study was performed in the specimen, or in a recognized incomplete by Pycha et al. In 2003, after a two-year period, their resection, leading to a motivated selection of patients attempt to implement a structured training program for this procedure.
1. Sylvester RJ, van der Meijden APM, Oosterlinck W, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 2006; 49: 466–77. 2 Babjuk M , Böhle A, Burger M, et al. Guidelines on Non-muscle-invasive Bladder Cancer (Ta, T1 and CIS). EAU 2015. http://uroweb.org/guideline/non-muscleinvasive-bladder-cancer/ 3. Herr HW, Donat SM, Dalbagni G. Can restaging transurethral resection of T1 bladder cancer select patients for immediate cystectomy? J Urol. 2007 Jan;177:75-9 4. Schwaibold HE, Sivalingam S, May F, Hartung R. The value of a second transurethral resection for T1 bladder cancer. BJU Int. 2006 Jun;97:1199-201 5. Herr HW. The value of a second transurethral resection in evaluating patients with bladder tumors. J Urol. 1999 Jul;162:74-6. 6. Gontero P, Sylvester R, Pisano F, et al.The impact of re-transurethral resection on clinical outcomes in a large multicentre cohort of patients with T1 high-grade/Grade 3 bladder cancer treated with bacille Calmette-Guérin. BJU Int. 2015 Oct 15. [Epub ahead of print] 7. Brausi M, Collette L, Kurth K, et al. Variability in the recurrence rate at first follow-up cystoscopy after TUR in stage Ta T1 transitional cell carcinoma of the bladder: a combined analysis of seven EORTC studies. Eur Urol. 2002 May;41:523-31. 8. Pycha A, Palermo S. How to teach the teacher to teach the TUR-B. Int J Surg. 2007 Apr;5(2):81-5. 9. Pycha A, Lodde M, Lusuardi L, et al. Teaching transurethral resection of the bladder: still a challenge? Urology. 2003 Jul;62:46-8. 10. Brausi MA, Gavioli M, Peracchia G, et al. Dedicated teaching programs (DTP) can improve the quality of TUR of Non-muscle invasive bladder tumors (NMIBT): experience of a single institution. J Urol suppl 2008;179:615-616.
Monday 14 March 10.30-12.00: Thematic Session, NMIBC
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
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To characterise the safety and tolerability of ODM-201
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•
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Histologically or cytologically confirmed adenocarcinoma of prostate without neuroendocrine differentiation or small cell features.
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Progressive Castration-resistant prostate cancer (CRPC) with castrate level of serum testosterone.
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Prostate-specific antigen doubling time of ≤ 10 months and PSA > 2ng/ml at screening
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Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
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Blood counts at screening: haemoglobin ≥ 9.0 g/dl, absolute neutrophil count ≥ 1500/µl (1.5x109/L), platelet count ≥ 100,000/µl (100x109/L).
http://www.clinicaltrials.gov (NCT02200614) Bayer and the Bayer cross are registered trademarks of Bayer. © Bayer. (February) 2016. L.DE.COM.SM.02.2016.4369.
L.DE.COM.SM.02.2016.4369 ARAMIS ODM-201 2016 Ad v02.indd 1
EUT Congress News
Screening values of serum alanine aminotransferase (ALT) and/or aspartate transaminase (AST) ≤ 2.5 x upper limit of normal (ULN), total bilirubin ≤ 1.5 x ULN (except patients with a diagnosis of Gilbert’s disease), creatinine ≤ 2.0 x ULN.
Selected Exclusion Criteria:
Selected Inclusion Criteria:
For complete information please visit:
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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
Monday, 14 March 2016
L.DE.COM.SM.02.2016.4369 – ARAMIS ODM-201 Clinical Trial Ad – 1/2 Pg HORIZONTAL AD (270mm x 194.3mm)
Asymptomatic microhematuria Who really needs investigating and how? Prof. Bernd J. Schmitz-Dräger Urologie Schön Klinik Nürnberg Fürth Fürth (DE)
Co-Authors: Eva C. Kuckuck (DE), Christian G. Rass (DE) Assessment of patients with so-called asymptomatic microhematuria (aMh) has been a challenge to urologists for decades. Since aMh is an established risk factor of bladder cancer, urological assessment of aMh patients typically includes upper tract imaging, cystoscopy, urine analysis and urine cytology. These tests are expensive, may cause discomfort and anxiety to patients, and cystoscopy is invasive and related to side effects including infection, gross hematuria, bladder and urethral irritation. In order to reduce over diagnosis numerous guidelines have been developed to stratify and assess patients according to their individual risk.
In order to improve and facilitate risk stratification we recently developed a nomogram, which calculates the individual patient risk based upon personal risk factors15. Applying this nomogram to the same cohort of aMh patients reduced the work-up to 75% of patients without compromising sensitivity14. The use of molecular markers as a non-invasive urine test to detect bladder cancer and/or stratify patients with microhematuria based on risk for bladder cancer, could lead to a reduction of unnecessary cystoscopies, hence be of major impact onto current disease management. Several efforts in this direction have been undertaken, mostly evaluating FDA– approved bladder cancer markers. A meta-analysis of 13 studies published before 2002 on the use of NMP22, BTA, urinary and plasma carcinoembryonic antigen, FISH assay, cytokeratin tissue polypeptide-specific antigen, and urinary bladder cancer tumor marker test in screening patients with hematuria, suggested no clear benefit from marker use in either detecting or excluding bladder cancer16. However, several difficulties were encountered when performing this meta-analysis, related mainly to insufficient and heterogeneous reporting among the individual studies.
A recent review by the International Bladder Cancer Network (IBCN) demonstrates that these guidelines differ in several aspects, tend to be complex and are not validated1. In consequence it has been suggested that aMh guideline adherence is low among practicing physicians and urologists2.
“The likelihood that benign conditions as opposed to bladder cancer are the cause of aMh should impact the selection and the ranking of diagnostic interventions.”
Key issue in restricting urological work-up to patients at risk of suffering from urological diseases is validation of the diagnosis and exclusion of nephrological conditions. In order to validate the diagnosis a repetitive positive dipstick finding must be confirmed by microscopic sediment analysis. Patients with proteinuria and hemoglobinemia or patients with microscopically dysmorphic erythrocytes should be referred to nephrology.
More recently, Cha and coworkers retrospectively analyzed data from 1,182 consecutive subjects with newly diagnosed asymptomatic hematuria without a history of bladder cancer undergoing urologic evaluation at three centers17. All subjects underwent standard work-up including voided cytology, upper tract imaging, cystourethroscopy, and immunocytology (uCyt+/Immunocyte). Multivariable analysis was used to construct a nomogram.
In order to avoid over-diagnosis current guidelines eliminate patients with irrelevant causes for aMh such as UTI, menses, intense exercise, and recent urological procedures from further analysis3-9. In a second step, potential nephrological conditions are excluded. Finally, risk stratification is performed for those patients with assumed “urological” aMh. Due to the absence of level I evidence, recommendations on exclusion criteria, conditions for nephrology referral and risk definitions vary considerably. While several guidelines define a variety of risk factors, others use age as primary risk factor9.
Work-up yielded bladder cancer in 245 (20.7%) patients. Increasing age, smoking history, gross hematuria, cytology and immunocytology were independent predictors of bladder cancer presence (Table 2). Positive immunocytology was the strongest predictive factor and increased accuracy for predicting the presence of bladder cancer from 83.5 to 90.8%17.
The Swedish recommendations differ from all others as they do not recommend screening for or assessment of aMh patients10,11. It is argued that aMh is poorly predictive of cancers of the urinary tract. In addition, it is concluded that hemoglobin dipstick testing may not reliably detect early bladder cancer in high risk patients. Also for stone diagnosis the authors feel that microhematuria testing is not helpful. Nevertheless, it may be argued that aMh assessment will not only diagnose or rule out the presence of urothelial cancer or other malignancies but may also delineate other non-malignant conditions requiring therapeutic intervention (Tab. 1)12,13. A key problem of most guidelines is that risk stratification remains unsatisfactory as suggested by a recent simulation applying different guidelines to a cohort of 608 consecutive patients with aMh recruited at two different centers14. This simulation shows that application of major guidelines to this cohort would have excluded less than 10% of patients from further work-up.
Despite the retrospective character and the fact that also gross hematuria patients were included, this study as well as a previous analysis restricted to aMh patients18 suggest a potential use of immunocytology in the assessment of aMh patients. Despite contrasting findings in some other studies we feel that there is a growing body of evidence suggesting that molecular markers may have potential in stratifying patients with hematuria according to their risk of being diagnosed with bladder cancer. Several current guidelines provide varying recommendations for the follow-up of patients with persistent aMh3-5,7-9. As most patients with aMh after negative urological evaluation have a <1% risk of eventually developing bladder cancer even on long-term follow-up a repetition of urologic work-up is unwarranted unless patients present with new symptoms1. In contrast, patients with persistent aMh who are at high risk for urologic malignancy (e.g. age >50 years, smoking history, exposure to occupational carcinogens) may benefit from repeated examination. These patients should undergo repeated urologic evaluation as aMh may precede the diagnosis of bladder cancer by several years3.
Table 1: Relevant urological conditions underlying asymptomatic hematuria Non-Malignant Stones Strictures BPH Renal cysts Interstitial cystitis Developmental disorders (e.g. reflux, ureteropelvic junction obstruction, valves, ureterocele, horseshoe kidney, etc.) Viral diseases Anticoagulants Monday, 14 March 2016
Neoplasia Urothelial Cancer Renal Cancer Prostate cancer Infiltrating tumors (Colo-rectal, vagina, uterus) Endometriosis Benign Tumors (urethral polyps, papilloma, hemangioma) Metastases Rare malignancies (sarcoma, melanoma)
Table 2: Multivariate analysis of bladder cancer risk factors in 1,182 patients with newly diagnosed hematuria19 P-Value Immunocyt Cytology Hematuria Smoking Gender Age
<0.0001 <0.0001 0.014 <0.0001 0.894 <0.0001
Adjusted 95% C.I. for OR OR Lower Upper 18.257 11.804 28.236 2.923 1.805 4.733 1.634 1.103 2.422 3.664 2.425 5.534 0.968 0.595 1.573 1.029 1.013 1.045
Even after decades of research there is no generally accepted definition of aMh. Nevertheless, an adequate definition should be reliable and meaningful from a clinical point of view. Reliability is necessary to exclude laboratory errors and a temporary/unique condition. Repeat testing and sediment analysis to confirm the presence of erythrocytes appear to be essential to validate the diagnosis. It appears reasonable not to initiate further testing before confirmation. Amazingly, information concerning underlying conditions beyond bladder cancer is poor and controversial. This may be due to the fact that it is impossible to definitely determine the condition responsible for hematuria. It should be kept in mind that always the reason which is considered most likely responsible by the physician will be reported. For example, if two or more conditions are present potentially causative for hematuria (e.g. stone and stricture) the more likely condition will be reported although definitive proof is lacking. Currently, there is only weak evidence supporting aMh assessment with regard to early detection of bladder cancer. The high prevalence of bladder cancer as reported in some studies rather suggests a selection bias. Nevertheless, we believe aMh assessment of high risk patients is appropriate as it is done not solely for detection or exclusion of bladder cancer, but also for diagnosis of other conditions potentially requiring treatment. As medical or surgical treatment may be indicated based upon results from microhematuria assessment in up to one-third of all cases by13 it is remarkable that current aMh guidelines still focus on bladder cancer detection as the sole endpoint. The likelihood that benign conditions as opposed to bladder cancer are the cause of aMh should impact the selection and the ranking of diagnostic interventions. Most algorithms and guidelines place upper tract imaging before cystoscopy. The concept behind could be to start out with less invasive measures and, subsequently, continue with invasive procedures. However, it must be questioned if this sequence is logical. Looking at studies analyzing potential causes of microhematuria, upper tract conditions are rare12,13. Furthermore, several of these situations will be detected be renal ultrasound. Keeping this in mind, it might be reasonable to reserve UUT imaging (CT, MRI) to patients at risk after negative cystoscopy. Beyond health economic effects reduction of radiation exposure can be expected without compromising the diagnostic accuracy.
“Even after decades of research there is no generally accepted definition of aMh. Nevertheless, an adequate definition should be reliable and meaningful from a clinical point of view.” Another interesting question is whether urine markers (urine cytology, molecular markers) might play a role in the assessment of patients with aMh. Several guidelines reject a role for urine cytology3,6-8. Nevertheless, the high specificity of urine cytology and a reasonable sensitivity in diagnosis of high grade disease could be helpful in guiding further examinations. Studies addressing the relevance of molecular markers in assessment of patients with aMh are
infrequent. Although prospective validation is pending, including molecular markers in the diagnostic armamentarium might save a significant number of patients from further diagnostic interventions if the sole goal is to exclude the presence of urothelial cancer. Reviewing current guidelines, it is obvious that most prefer a dichotomous algorithm3,4,6-9,16. For several reasons it is debatable if this format is optimal. Complexity represents an important problem: depending on the given algorithm and the individual patient situation up to 10 branches/decisions must be taken. It is unlikely that such a complicated algorithm is applicable in routine practice. However, essential goal of guidelines should be to provide an effective and simple procedure. We therefore believe that nomograms/risk tables will eventually replace current guideline formats. References: 1. Schmitz-Dräger BJ, Kuckuck EC, Zuiverloon TCM, Zwarthoff E, Saltzman A, Srivastava A, Hudson MA, Seiler R, Todenhöfer T, Vlahou A, Grossman HB, Schoenberg M, Sanchez-Carbayo M, Brünn LA, van Rhijn B, Goebell PJ, Kamat AM, Roupret M, Shariat SF, Kiemeney LA. Microhematuria assessment – a comprehensive review of current guidelines. 2016, submitted 2. Elias K, Svatek RS, Gupta S, Ho R, Lotan Y. High-risk patients with hematuria are not evaluated according to guideline recommendations. Cancer. 2010; 116: 2954-9 3. Davis R, Jones JS, Barocas DA, Castle EP, Lang EK, Leveillee RJ, Messing EM, Miller SD, Peterson AC, Turk TM, Weitzel W; American Urological Association. Diagnosis, evaluation and follow-up of asymptomatic microhematuria (AMH) in adults: AUA guideline. J Urol. 2012 Dec;188(6 Suppl):2473-81 4. Wollin T, Laroche B, Psooy K. Canadian guidelines for the management of asymptomatic microscopic hematuria in adults. Can Urol Assoc J. 2009; 3: 77-80 5. Horie S, Ito S, Okada H, Kikuchi H, Narita I, Nishiyama T, Hasegawa T, Mikami H, Yamagata K, Yuno T, Muto S. Japanese guidelines of the management of hematuria 2013. Clin Exp Nephrol. 2014; 18: 679-89 6. Scottish Intercollegiate Guidelines Network (SIGN). 103: Diagnosis and management of chronic kidney disease. 2008. http://www.sign.ac.uk/pdf/sign103.pdf 7. Loo R, Whittaker J, Rabrenivich V. National practice recommendations for hematuria: how to evaluate in the absence of strong evidence? Perm J. 2009 Winter;13(1):37-46 8. Anderson J, Fawcett D, Feehally J, Goldberg L, Kelly J, MacTier R. Joint Consensus Statement on the Initial Assessment of Haematuria. BAUS 2008 9. Nederlandse Vereniging voor Urologie. Richtlijn Hematurie. 2010 10. Malmström PU. Time to abandon testing for microscopic haematuria in adults? BMJ. 2003 Apr 12;326(7393):813-5 11. Svensk urologisk förening (SUF) http://www.urologi.org/ sota/2002-123-38/2002-123-38.pdf. 2002 12. Yun EJ, Meng MV, Carroll PR. Evaluation of the patient with hematuria. Med Clin North Am. 2004; 88: 329-43 13. Schmitz-Dräger BJ, Tirsar L-A, Schwentner C, Hennenlotter J, Stenzl A, Mian C, Martini T, Lodde M, Cha EK, Shariat SF (2015) What is behind asymptomatic microhematuria? Comparison of 3 contemporary cohorts. In preparation 14. Kuckuck EC, Hennenlotter J, Brünn LA, Schwentner C, Stenzl A, Mian C, Rass C-G, Sahin S, Schmitz-Dräger BJ. Discriminative capacity of diagnostic algorithms and guidelines in the assessment of patients with asymptomatic microhematuria. In preparation 15. Cha EK, Tirsar L-A, Schwentner C, Hennenlotter J, Christos PJ, Stenzl A, Mian C, Lodde M, Pycha A, Shariat SF, Schmitz-Dräger BJ. Accurate risk assessment of patients with asymptomatic hematuria for the presence of bladder cancer. World J Urol. 2012; 30: 847-52 16. Rodgers M, Nixon J, Hempel S, Aho T, Kelly J, Neal D, Duffy S, Ritchie G, Kleijnen J, Westwood M. Diagnostic tests and algorithms used in the investigation of haematuria: systematic reviews and economic evaluation. Health Technol Assess. 2006; 10(18):iii-iv, xi-259 17. Cha EK, Tirsar L-A, Schwentner C, Christos PJ, Mian C, Hennenlotter J, Martini T, Stenzl A, Pycha A, Shariat SF, Schmitz-Dräger BJ. Immunocytology is a strong predictor of bladder cancer presence in patients with asymptomatic hematuria: A multicenter study. Eur Urol 2012; 61: 185-92 18. Schmitz-Dräger BJ, Beiche B, Tirsar L-A, Schmitz-Dräger C, Bismarck E, Ebert T. Immunocytology in the assessment of patients with asymptomatic microhematuria. Eur Urol 2007; 51: 1582-8
Tuesday 15 March 08.00-13.00: Plenary Session 4 Urothelial cancer
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15
Endoscopic Combined IntraRenal Surgery (ECIRS) Best option for a completely stone-free status with minimal punctures Prof. Cesare Marco Scoffone Department of Urology Cottolengo Hospital Turin (IT) a
b
c
d
e
Figure 3 - Endovision control of the needle puncture (a), guidewire insertion (b), fascial (c) and tract balloon dilation(d), Amplatz sheath application (e)
Combo, as recently renamed overseas) has been taken assists renal puncture (Figure 3a), guidewire over by many urologists, who reported improved PNL application (Figure 3b) (possibly inserted through and safety and efficacy. through from the percutaneous access to the external Dr. Cecilia Maria urethral meatus, creating the so-called kebab or Cracco Role of combined flexible nephroscopy skewered patient), tract dilation (Figure 3c-d) and Department of The advantages of the cooperation between rigid and Amplatz sheath insertion (Figure 3e), avoiding Urology flexible nephroscopy are intuitive. Actually Harris insufficient application or over advancement of the Cottolengo Hospital reported the percutaneous use of a fiberoptic various devices, thus, bleeding, fluid overload or Turin (IT) bronchoscope for stone removal already in 1975, but damage of the collecting system. after three decades all authors agreed that flexible nephroscopy offers the patient excellent one-step Later fURS may assist lithotripsy, avoid descent of stone-free rates independently from the presence of a stone fragments into the ureter, allow simultaneous difficult collecting system anatomy, and minimizes the treatment of stones in calyces parallel to the access morbidity of the multi-tract accesses needed in case tract, dislocate stones into more accessible calyces, The introduction of percutaneous nephrolithotomy of rigid-only PNL. treat stones impacted in infundibula, within calyceal (PNL) in the 1970s represented a real milestone in the diverticula, or in double districts. For all the The ancillary role of the flexible approach does not interventional treatment of large urolithiasis which aforementioned reasons, the standardized use of run out with the combined treatment of the was previously managed with invasive open renal intraoperative fURS reduces the need for multiple urolithiasis (with the use of the Holmium laser), but surgery. renal punctures and related morbidity. Finally, the remains essential at the end of the procedure, opportunity to explore all calyces, in collaboration Nonetheless, PNL - in spite of its effectiveness and allowing a careful check of all calyces for residual with the flexible nephroscope, and to retrieve/remove fragments, additionally sparing radiation exposure. mini-invasiveness - remained in the long-term escaped residual fragments, allow obtaining a restricted to referral urological centers, mainly maximally stone-free patient, minimizing radiation Diagnostic role of preliminary fURS because of its long learning curve and difficult-toexposure, thanks to the continuous visual control. When the ureter is compliant preliminary fURS manage complications. replaces the step of ureteral catheter application for Criticisms to the simultaneous use of fURS and PNL During the last decade PNL progressively underwent retrograde pyelography before starting PNL. It for treating large or complex urolithiasis represents a reliable and safe approach, allowing a substantial improvements in efficacy and safety, It has been noted that with ECIRS as the combination real-time anatomic evaluation of both urolithiasis and of PNL and fURS, the overall complication rates may thanks to the evolution of the access techniques, technology and miniaturization of the endoscopic collecting systems, possibly conditioning the strategic also finally be the sum of the respective complication instrumentation and related accessories, choices during PNL, including the change of indication rates. On the contrary, the combined use of fURS and intracorporeal lithotripsy devices and drainage from ECIRS to RIRS (Retrograde IntraRenal Surgery). PNL seems to produce a strong reduction of the management. In particular, the regular adjunct of overall complication rates because of the flexible nephroscopy to the traditional rigid First, fURS allows to assess the overall compliance of intraoperative synergy between the two approaches. percutaneous approach represented an essential step the ureter from the orifice to the uretero-pelvic forward in PNL evolution, reducing the need for junction, to rule out the presence of spasms or multiple tracts with related morbidity, and improving kinkings, to look for ureteral stones or strictures, the one-step stone-free rate of the procedure outcomes of previous surgeries, congenital independently from the collecting system anatomy. malformations. Subsequently, fURS completes the “static” anatomic information obtained from preoperative imaging studies (Figure 2a) with data on the “dynamic” intraoperative anatomy (Figure 2b) (elasticity and compliance of the involved calyces and infundibula after retrograde irrigation, mobility and hardness of the urolithiasis, possibility creating a sort of water path around the stone, degree of inflammation/infection within the collecting system, easy mucosal bleeding, discrimination between parenchymal calcifications or large Randall’s plaques Figure 1: Patient in the Galdakao-modified supine Valdivia position and stones). Based upon all these elements, the following choices of the best calyx of access, and technique and size of percutaneous tract dilation can PNL evolution and ECIRS be tailored onto the single clinical case and The modification of the traditional prone patient personalised from time to time. positioning was also part of PNL evolution. A variety of prone-modified, flank, supine and supine-modified Active role of intraoperative fURS positions have been proposed during the years in Presently, it is clear that PNL outcomes highly depend order to gain a diagnostic and working retrograde on the precision, refinement and accuracy of the renal access to the renal cavities, and obviate the access creation. Its optimization reduces the risk of anaesthesiological problems related to the prone bleeding, renal trauma, postoperative discomfort and position. The Galdakao-modified supine Valdivia urine leakage, and at the same time increases the position (Figure 1), combining the supine decubitus of possibility of a complete stone clearance. Image Valdivia with a modified lithotomy position of the guidance, augmented reality, fusion of different legs, fully satisfies both requirements and optimally imaging modalities, motion tracking systems and supports the Endoscopic Combined IntraRenal robotics are rapidly evolving and increasingly attract Surgery (ECIRS), an efficient combined antegrade and the attention of the urologic community; therefore, retrograde approach to the upper urinary tract for the one of the next steps in PNL development will be the treatment of large and/or complex urolithiasis with modernization of the renal puncture technique. both rigid and flexible endoscopes. Meanwhile, in the operating room we optimally use In the 1980s occasional cooperation between current tools at our disposal (fluoroscopy and retrograde and antegrade approaches for the ultrasound), integrating them with the Endovision treatment of reno-ureteral stones was attempted, assistance supplied by fURS. In the first place, fURS both blindly with the transcutaneous retrograde nephrostomy of Hawkins-Hunter and Lawson, and under vision in very particular clinical cases, with the patients in a modified prone position. Gaspar Ibarluzea was the very first urologist who started using flexible retrograde ureteroscopy (fURS) as an essential step of PNL rather than an occasional complementary tool. Initially obliged by very prosaic problems, he developed the innovative philosophy of the standardized cooperation between fURS and the a b rigid/flexible percutaneous approach to stone disease, along with the ergonomic Galdakao-modified supine Figure 2: a) Preoperative contrast CT and b) intraoperative retrograde pyelography, demonstrating the elasticity of the Valdivia position. His legacy led to intense debate infundibulum of the superior calyx during those years but nowadays ECIRS (or PNL
Another debated point of ECIRS is the economic issue, i.e., higher costs in terms of more equipment and repair costs and the need for a second surgeon. As to repair costs, it is important to underline that the role of the flexible ureteroscope is not always active, and more frequently functions as a visual aid to the percutaneous steps. Thus, the life of the instrument is not as much at risk as in RIRS. Additionally, the increased costs of ECIRS might well be balanced by indirect advantages (less complications, fewer blood transfusions, less and shorter hospital stays, fewer follow-up procedures). Innovative approach Based on our experience, ECIRS, being the standardized collaborative procedure of fURS and rigid/flexible PNL, is an innovative approach to the treatment of large and/or complex urolithiasis, aiming at the achievement of the maximal one-step stone-free rate with no major complications. Of course, the issue of costs will require further evaluation. In any case, ECIRS is a novel approach in PNL, contributing to its continuous development and fully exploiting the opportunities offered by new technologies. 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 Meeting of the EAU Section of Urolithiasis (EULIS)
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The Platinum Hour 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
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Clinical consequences of Figure PET1. Left signals after curative treatment obturator lymph nodal uptake at 11C-Choline PET/CT scan in a patients with New imaging modalities cannot be ignoredbiochemical but trialrecurrence results after areradical still awaited prostatectomy. Dr. Nazareno Suardi Department of Urology Vita-Salute University San Raffaele Milan (IT)
Despite the most recent advances in surgical as well as in the radiotherapic treatment in patients with organ-confined prostate cancer (PCa), up to 40% of them develop biochemical recurrence (BCR). Of them, only a minority will develop the clinical signs of PCa recurrence and eventually die of the disease. The challenge is to identify these patients promptly in order to choose the best salvage treatment for those at risk of progressing while saving the side effects of these treatments to those who will never need them.
recurrence, since lymph nodes represent the first site of PCa recurrence after curative treatment of organ-confined PCa. Salvage treatment Given the excellent sensitivity of 11C-Choline PET-CT scan in identifying nodal recurrence, in 2007 a salvage pelvic and/or retroperitoneal lymph node dissection (sLND) series relying on 25 patients was published. Despite the absence of robust data on the long-term results of such salvage approach, several groups continued with this experimental approach, and several series based on small patient numbers showed that sLND was able to achieve undetectable PSA (<0.2 ng/ml) in a significant number of patients with BCR and nodal evidence of recurrence. To date, a growing body of evidence shows that roughly 50% of patients with isolated nodal recurrence of PCa after initial curative treatment can achieve complete biochemical and clinical remission after sLND.
Age: 67 years PSA: 1,8 ng/ml 22 months after radical prostatectomy
Similarly, published data agree on the real intermediate-term outcome of these patients, showing that after an initial complete biochemical response the majority of these patients eventually develop BCR after a median time of two years. 1: Left obturator lymph nodal uptake at 11C-Choline PET/CT scan in a patients with biochemical recurrence after radical However, recurrencerecurrence-free is delayed in patients Figureclinical 2. Biochemical survival inFigure patients with complete PSA response (a) and withclinical complete response to surgery, and(b) theafter evidence recurrence-free survival salvageprostatectomy lymph node dissection. Therefore, standard therapies in patients with suggests that systemic therapies can be significantly aggressive recurrence of PCa are represented by delayed after this surgical salvage approach (Table 2). systemic therapies, such as hormonal deprivation. as well as in the most updated guidelines for patients However, after the introduction of more sophisticated with nodal recurrence of PCa after curative treatment. imaging modalities the paradigm is gradually changing. Furthermore, PSMA PET-CT scan represents a field in In particular, the introduction of 11C-Choline PET-CT continuous evolution, and the introduction of new scan leads to a very high sensitivity in the identification tracers can only improve the clinical results available of the site of recurrence after curative treatment in today. patients with BCR and low PSA value (Table 1). However, the lack of randomized studies suggests that Furthermore, with the rapid technological advances in more robust evidence should be available before this nuclear medicine research, a new set of tracers, approach is considered as standard practice. On the other hand, it is very difficult for clinicians to ignore especially based on the prostate specific membrane antigen (PSMA), have been developed with promising the excellent results of new imaging modalities. results, which seem able to correctly show the recurrence site and extent at very low PSA value (i.e. < At the moment, a well-designed prospective 1 ng/ml). randomized clinical trial is being carried out in Belgium, comparing the outcome of patients The results obtained with such imaging techniques submitted to lesion-targeted approach versus Figure 2: Biochemical recurrence-free survival in patients with complete PSA response (a) and clinical recurrence-free survival (b) standard hormonal therapy in patients with recurrent have naturally led to the characterization of a new patient population which shows limited extraprostatic after salvage lymph node dissection PCa (Clinicaltrials.gov identifier: NCT01558427). The recurrence with low PSA value (Figure 1). results of this study will help in identifying the best management strategy of these patients. As a natural consequence of these recent Meanwhile, radiation oncologists have suggested that In 2015, the series of patients with BCR and nodal Editorial Note: Due to space constraints we have technological advances in imaging modalities, some given the non-negligible morbidity of sLND, a recurrence of PCa with the longest follow-up clinicians have started to develop new treatment ommitted the reference list. Interested readers can (minimum of five years) was published, showing that radiotherapic approach to patients with nodal modalities targeting the exact sites of recurrence as email a request at communications@uroweb.org. with a median follow-up of 81 months, the eight-year recurrence of PCa might be used. Despite the lack of an alternative to standard systemic therapy as well as BCR-free rate was 23% in patients who achieved robust evidence of the newly introduced salvage in combination with standard systemic therapies. management options in improving cancer-specific Monday 14 March undetectable PSA after sLND. 10.30-12.00: Thematic Session 10 mortality-free survival and metastatic-free In particular, the first patient populations that were progression survival, these treatments are now PSMA-PET/CT for the diagnosis of PSA relapse More interesting, the eight-year clinical recurrenceaddressed were patients with BCR and isolated nodal free survival was 38% (Figure 2). considered in several institutions in clinical practice, The correct identification of the site of recurrence may be challenging, since historically no imaging modality was able to characterize the site and the extent of the recurrence, with conventional CT scan and bone scan having very low accuracy at low PSA value.
Table 1: Performance characteristics of positron emission tomography in detecting prostate cancer recurrence after definitive treatment.
Table 2: Studies including patients with lymph node recurrent prostate cancer and treated with salvage lymph node dissection.
Study
Year
Patients, n. Imaging type
Sensitivity, %
Specificity, %
Accuracy, %
De Jong et al.
2003
22
11C-Choline PET/CT scan
100
83.3
90.9
Study
Patients, PSA at n. sLND, ng/ ml (mean)
Picchio et al.
2003
100
11C-Choline PET/CT scan
80.0
93.3
86.0
Rinnab et al.
15
Scattoni et al.
2007
25
11C-Choline PET/CT scan
100.0
66.6
92.0
Winter et al.
6
Vees et al.
2007
11
18F-Choline PET/CT scan and 11C-acetate PET/CT scan
43.0
50.0
45.0
Martini et al.
8
Nodes Positive Complete removed, nodes, n. response, n. (mean) (mean) %
Mean BCR-free follow-up, survival, % mo.
Clinical recurrence-free survival, %
1.7
13.9
N.A.
N.A.
13.7
N.A.
N.A.
2.0
N.A.
N.A.
N.A.
24
N.A.
N.A.
1.6
11.6
1.0
N.A.
N.A.
N.A.
N.A.
Schilling et al. 10
10.9
7.1
2.8
N.A.
N.A.
N.A.
N.A.
Rinnab et al.
2007
50
11C-Choline PET/CT scan
94.8
36.3
82.0
Rigatti et al.
72
3.7
30.6
9.8
56.9
39.4
19 at 5 yrs
34 at 5 yrs
Reske et al.
2008
49
11C-Choline PET/CT scan
69.9
66.6
69.4
Jilg et al.
52
3.9
23.3
9.7
46
35.5
9 at 5 yrs
26 at 5 yrs
Husarik et al.
2008
23
11C-Choline PET/CT scan
100.0
0
78.0
Suardi et al.
59
3.9
29.5
8.9
59.3
81.1
29.4 at 5 yrs. 52 at 5 yrs
Schilling et al.
2008
10
11C-Choline PET/CT scan
100.0
0
70.0
Karnes et al.
52
2.2
23.8
5.3
57.7
20.9
45.5 at 3 yrs. 46.9 at 3 yrs.
Pelosi et al.
2008
56
18F-Choline PET/CT scan
82.7
96.2
89.2
Tilki et al.
58
9.8
18.6
6
22.4
39
0 at 5 yrs
Rinnab et al.
2008
15
11C-Choline PET/CT scan
100.0
0
60.0
Richter et al.
2010
73
18FDG and 11C-Choline PET/ CT scan
61.0
100.0
62.0
Giovacchini et al. 2010
358
11C-Choline PET/CT scan
85.0
93.0
89.0
Panebianco et al. 2012
84
18F-Choline PET/CT scan
83.0
63.0
81.0
Giovacchini et al. 2010
170
11C-Choline PET/CT scan
86.7
89.5
88.2
Bertagna et al.
2011
45
11C-Choline PET/CT scan
60.0
91.0
84.0
Castellucci et al.
2011
102
11C-Choline PET/CT scan
83.0
100.0
94.0
Casamassima et al.
25
5.7
N.A.
29
17% at 3 yrs.
Henniger et al.
2012
35
18F-Choline PET/CT scan
64.3
57.1
62.9
Wurschmidt et al.
16
1.8
N.A.
28
N.A.
Schillaci et al.
2012
49
18F-Choline PET/CT scan
91.7
100.0
93.9
75%
21.9
63.5% at 2.5 yrs.
Marzola et al.
2013
233
18F-Choline PET/CT scan
100.0
97.0
99.0
Kitajima et al.
2014
70
11C-Choline PET/CT scan
90.0
100.0
92.9
31
54.6%
Mamede et al.
2013
71
11C-Choline PET/CT scan
88.2
98.1
95.8
25
N.A.
Ceci et al.
2013
157
11C-Choline PET/CT scan
66.2
0
66.2
Detti et al.
30
14
13% (radiological)
12
53%
Tilki et al.
2013
56
18C-Choline PET/CT scan
39.7
95.8
82.1
Lèpinoy et al.
18
3.2
N.A.
20.9
61%
Monday, 14 March 2016
35.9 at 5 yrs
Table 3: Studies including patients with lymph node recurrent prostate cancer and treated with salvage radiation therapy. Study
Patients, n.
PSA at sLND, ng/ ml (mean)
Jereczek-Fossa et al.
16
1.8
Schick et al.
33
6.7
Decaestecker et al.
27
3.8
Complete response, Mean % follow-up, mo.
N.A.
Progression-free survival, %
EUT Congress News
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What are the limits of nephron sparing surgery? Partial nephrectomy boosted by technology but finding a balance is crucial for surgeons Dr. Mireia Musquera Hospital Clínic de Barcelona Barcelona (ES)
As previously mentioned, tumor size used to be a limiting factor for partial nephrectomy years ago, but has now evolved into the current treatment of choice for small renal masses and even for tumors < 7cm. Currently, even tumors larger than 7cm are now safely resected. In a recent paper published by Long et al, in 46 patients with renal tumors bigger than 7cm treated by partial nephrectomy, five and 10 years overall and RCC specific survival were 94.5% and 70.9%5.
Renal cell carcinoma (RCC) represents 3% of all adult malignancies. Its incidence has increased over the last decades, around 3.7% per year, probably because of the increase in abdominal imaging performed for other causes.
Influenced by tumor size and location, the concept of warm ischemia time has become important, because the more difficult the tumor is in terms of size, morphology and location, the longer the warm ischemia time. The 30-minute limit is well established in order to avoid irreversible damage to the kidney Most of the increased incidence is due to the detection function. When required, if extra-time is likely, cold of small renal masses (<4cm), but even nowadays ischemia should be considered. around a third of patients with RCC still present with metastatic disease. On the other hand in When we analyze results of partial nephrectomies, industrialized countries the incidence of comorbidities the achievement of the Trifecta (Warm ischemia time such as hypertension and diabetes has also increased <25, negative surgical margins and no complications) over the last decades, having a direct impact on the is very important. In a recent study analysing the development of chronic kidney disease (CKD), and Trifecta achievement in PN for tumors >7cm conveying a higher risk of cardiovascular diseases. compared to tumors between 4-7 were similar.
Figure 1: 65-year-old female with bilateral tumor (6.8 in the left side and 4,5 in the right)
Twenty years ago, the indication for a nephron sparing surgery (NSS) was limited to small renal masses and patients with impaired renal function. During these two decades, the tendency has been to reduce morbidity using minimal invasive techniques like laparoscopy, and to preserve renal function while maintaining good oncologic results; Partial nephrectomy (PN), using minimal or open techniques, have been adopted worldwide and are increasing in number. Currently, PN has become the standard of care for small renal masses (>4cm); in larger tumors (<7cm) even for tumors >7cm can be considered as an indication when technically feasible1. This increasing acceptance for partial nephrectomy in bigger tumors is related in part to the higher incidence of CKD in this population. Indeed around 25% of patients with RCC present with underlying CKD2. In initial studies, PN for small tumors <4cm demonstrated improved overall survival in comparison to radical nephrectomy3,4. PN in lesions measuring 4 to 7 cm compared to radical nephrectomy have equivalent recurrence-free, CSS and overall survival.
EUT Congress News
In experienced surgeon’s hands almost everything can be done, but the balance of surgical complications, complexity, renal function preservation and safety oncologic outcomes is very important. And the most important thing for surgeons is to know and set their own limits References 1. Alanee S1, Nutt M, Moore A, Holland B, Dynda D, Wilber A, El-Zawahry A. Partial nephrectomy for T2 renal masses: contemporary trends and oncologic efficacy. Int Urol Nephrol. 2015 Jun;47(6):945-50. doi: 10.1007/ s11255-015-0975-3. Epub 2015 Apr 12. 2. Russo P. End stage and chronic kidney disease: associations with renal cancer. Front Oncol. 2012 Apr 2;2:28. doi: 10.3389/fonc.2012.00028. eCollection 2012. 3. Thompson RH, Boorjian SA, Lohse CM, Leibovich BC, Kwon ED, Cheville JC, Blute ML. Radical nephrectomy for pT1a renal masses may be associated with decreased overall survival compared with partial nephrectomy. J Urol. 2008 Feb;179(2):468-71; discussion 472-3. 4. Huang WC1, Elkin EB, Levey AS, Jang TL, Russo P. Partial nephrectomy versus radical nephrectomy in patients with small renal tumors--is there a difference in mortality and
Monday 14 March 10.30-12.00: Thematic Session 19 Management of T1a-b renal masses
Lower RENAL score in series was significantly associated with the Trifecta achievement6.
“Partial nephrectomy in the setting of patients with metastatic disease also plays a role, albeit controversial, due to the importance of renal function preservation, especially in patients with solitary kidney.” Tumor size and location have been grouped in the morphometric scores systems such as the R.E.N.A.L. score, the P.A.D.U.A. score and C-index, in order to get a grasp on the feasibility and predict post-operative complications when planning surgery. When dealing with complex cases and especially a complex mass, options include nephrectomy, ex-vivo partial nephrectomy and auto-transplant.
Partial nephrectomy in the setting of patients with metastatic disease also plays a role, albeit controversial, due to the importance of renal function For larger tumors, PN has demonstrated feasibility preservation, especially in patients with solitary and oncologic safety in carefully selected patients, but kidney. Limited data are reported on that setting; those results remain controversial. Those results taken series of small number of patients reported better together with the fact that CKD and end stage renal cancer-specific survival rates in PN or equal cancerdisease (ESRD) impact on morbidity and mortality specific survival than radical nephrectomy7,8,9. suggest that PN should be considered the procedure of choice when feasible in renal tumors less than 7cm It is well known that RCC is more frequent in patients and in some cases of tumors larger than 7. It seems on dialysis and this higher incidence persists after that the tendency is to perform PN in more and more kidney transplantation. RCC may occur on native complex renal mass, with the major objective of kidneys and in the transplanted one. The treatment of preserving as much as possible renal function. So, in choice in a transplanted kidney should be the same this scenario which are the limits for a partial than in the general population; partial nephrectomy nephrectomy? should be considered as the first choice to maintain kidney function avoiding dialysis. Imaging techniques Nowadays, we have excellent imaging techniques In the literature several series have reported the (angioCT scan, with 3D reconstruction) that permit a results of partial nephrectomies in transplanted better anatomical pre-operative planning recognition kidneys, with good oncological and functional results. of the tumor and, consequently, a better surgical plan. In the future we also will get 3D impressions that New concepts could help these types of surgeries. Recently, new concepts have emerged like the enucleation of the tumor in complex renal mass. In a Surgeons have improved surgical abilities recent paper of 96 tumors treated by simple (laparoscopic and open) with better instrumentation enucleation, the authors described good results, and optics (3D vision) and the introduction of robotics; concluding that enucleation for highly complex renal at times it looks as if it is now possible to perform tumors is an effective treatment, with a potential key almost everything and the sky is the limit. role in NSS10.
20
Figure 2: CT scan after bilateral partial laparoscopic nephrectomy. Post-operative creatinine 1,49: Pathology: papillary renal cell carcinoma Furhman II
cardiovascular outcomes? J Urol. 2009 Jan;181(1):55-61; discussion 61-2. doi: 10.1016/j.juro.2008.09.017. Epub 2008 Nov 13. 5. Long CJ, Canter DJ, Kutikov A, Li T, Simhan J, Smaldone M, Teper E, Viterbo R, Boorjian SA, Chen DY, Greenberg RE, Uzzo RG Partial nephrectomy for renal masses ≥ 7 cm: technical, oncological and functional outcomes. BJU Int. 2012 May;109(10):1450-6. doi: 10.1111/j.1464-410X.2011.10608.x. Epub 2012 Jan 5. 6. Benoit T1, Nouhaud FX2, Roumiguié M2, Mérigot De Treigny O3, Thoulouzan M2, Doumerc N2, Bellec L3, Gamé X2, Rischmann P2, Soulié M2, Huyghe E2, Beauval JB2 Does a tumor size higher than 7cm impact partial nephrectomy outcomes for the treatment of renal cancer?. Prog Urol. 2015 Mar;25(3):138-44. doi: 10.1016/j. purol.2014.11.007. Epub 2014 Dec 31. 7. Krambeck AE, Leibovich BC, Lohse CM, Kwon ED, Zincke H, Blute ML. The role of nephron sparing surgery for metastatic (pM1) renal cell carcinoma. J Urol. 2006 Nov;176(5):1990-5; discussion 1995. 8. Capitanio U, Zini L, Perrotte P, Shariat SF, Jeldres C, Arjane P, Pharand D, Widmer H, Péloquin F, Montorsi F, Patard JJ, Karakiewicz PI. Cytoreductive partial nephrectomy does not undermine cancer control in metastatic renal cell carcinoma: a population-based study. Urology. 2008 Nov;72(5):1090-5. doi: 10.1016/j.urology.2008.06.059. Epub 2008 Sep 16. 9. Hellenthal NJ, Mansour AM, Hayn MH, Schwaab T. Is there a role for partial nephrectomy in patients with metastatic renal cell carcinoma? Urol Oncol. 2013 Jan;31(1):36-41. doi: 10.1016/j.urolonc.2010.08.026. Epub 2011 Mar 10. 10. Serni S1, Vittori G1, Frizzi J1, Mari A1, Siena G1, Lapini A1, Carini M1, Minervini A2. Simple enucleation for the treatment of highly complex renal tumors: Perioperative, functional and oncological results. Eur J Surg Oncol. 2015 Jul;41(7):934-40. doi: 10.1016/j.ejso.2015.02.019. Epub 2015 Apr 24.
Patients Information
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Official Scientific Journal Deutsche Gesellschaft für Urologie
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21
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. 22 EUT Congress News Monday, 14 March 2016 2016. Date of preparation: January EUHQ-P-162x-0116-122568
Prostatic Urethral Lift (PUL) Has PUL ushered in a new era in the treatment of Benign Prostatic Obstruction? Prof. Dr. Karl-Dietrich Sievert SALK University Clinic/Paracelsus Medical Private University Salzburg (AT)
In the early 1990’s urology saw a great shift in the care for men with lower urinary tract symptoms (LUTS) associated with benign prostatic obstruction (BPO). Since the commercial launches of tamsulosin and finasteride, millions of men have elected medical management over disobstructing intervention. Today it is estimated that 97% of BPO patients are managed with pharmacotherapy or watchful waiting1. As urologists we are pleased that so many patients are taken care of with relatively benign medication, but we have also seen a trend toward the delay of definitive disobstructing treatment.
What do the data show? Across published studies, PUL shows a consistent effect (Figure 2). Symptomatically, this effect is best described as rapid improvement in two weeks and acceptable durability to at least three years thus far6. By four weeks, it appears the PUL patient experiences the improvement he can expect at three years, approximately a 10-point IPSS improvement. Adverse events, such as hematuria, dysuria, urgency and pelvic discomfort are mild to moderate. Unlike the prior thermal ablation techniques, these adverse events typically resolve within two weeks, and patients return to normal activity between five and eight days. Post-operative catheterization rates have varied by study and healthcare system, but when tested, rates have been as low as 20%8. Thus, the minimally-invasive goal of rapid relief appears to be well in hand. Unlike TURP or laser procedures, PUL is not associated with sustained iatrogenic ejaculatory or erectile dysfunction7-11. Analysis of the LIFT randomized study showed not only a lack of de novo dysfunction but a significant improvement in ejaculatory function and ejaculatory bother score12. Erectile function was sustained and even showed modest yet statistical improvement in men entering the study with severe erectile dysfunction. As McVary et al point out, these improvements could be a result of improving LUTS without inducing harm12.
Figure 2: Consistent symptomatic improvement across studies. [Roehrborn et al. Can J Urol 2015; 22(3); 7772-7782]
Who is the PUL patient? The clinical studies to date have focused on men with moderate to severe BPO who are not in urinary retention. Mean age reflects BPO prevalence and ranged from 63 to 67 years. Prostate volume has averaged 45 to 51 cc, ranging from 16 to 149 cc7-11. As men delay the necessary definitive treatment with Roehrborn reported that, in the LIFT randomized years of palliative medication, we are finding an study, results showed no dependence on prostate increased prevalence of bladder dysfunction, volume up to the protocol maximum volume of 80 cc6. polypharmacy and cardiac comorbidities by the time a Quality of life (QOL) improvement after PUL follows It would appear that the maximum prostate volume man elects to undergo transurethral resection of the the same trajectory as IPSS with a two to three-point prostate (TURP) or its myriad alternatives2. This can for PUL may be more of an issue of health economics improvement over three years. Maximum urinary flow than efficacy. In prostates over 80 cc it may be that too result in complicated procedures with extended recovery periods, and it can minimize the therapeutic rate (Qmax) is only modestly improved when many implants are required to effectively open the compared to the superphysiologic flow rates achieved prostate to keep the procedure cost effective. impact of disobstruction. with TURP. PUL shows a reproducible 4 mL/sec Importantly, all studies have excluded an obstructive increase in Qmax. An intriguing finding of the BPH6 By 2000 a concerted attempt was underway to shift median lobe, though a multi-center study is currently randomized study is that, while TURP predictably disobstruction forward with the advent of thermal underway investigating a technique to address this ablation of the prostate. Today these techniques have showed a five-point greater IPSS drop and much anatomy [NCT02625545; clinicaltrials.gov]. Active greater flow rate improvement, these were not became less important, most likely due to the infection should be ruled out and a perioperative associated with a difference in QOL improvement prolonged period of increased irritative LUTS and course of antibiotic is prudent. when compared to PUL (Table 1)7. This would imply possible periodic retention during the weeks where thermal ablation biologically transformed to resorbed that, for some patients, if not many, the incremental “With the repeatability of results improvement TURP can afford them may not be worth or scarred tissue. the compromises they must make in sexual function across several studies to date, it Just like every other surgical treatment, TURP, the BPO and time-to-recovery. would appear that we now have a surgical gold standard, has its risks and complications, some of which have a great effect on treatment option that may indeed PUL TURP p-value the patient’s QoL. The primary risk of TURP is Change in IPSS -11.4 (8.4) -15.4 (6.8) 0.02 lead to a shift in care for men with sphincteric injury resulting in patients with stress Change in Qmax +4.0 (4.8) +13.7 (10.4) <0.001 urinary incontinence, which might require further BPO.” Change in QOL -2.8 (1.8) -3.1 (1.6) 0.8, NS surgical interventions. Further, the development of scar tissue in the bladder neck may lead to bladder outlet obstruction requiring repeated resections. In most patients retrograde ejaculations show as a consequence of TURP, which goes along with impairment of QOL/sexuality. In 2011 we saw the first reports of a new technique, the Prostatic Urethral Lift (PUL)5. Now five years later, the technique has been studied in two randomized studies and in seven open-label studies6-10. PUL’s uniquely rapid recovery and improvement, complete preservation of sexual function, and now, impressive durability may have ushered in a new era for BPO treatment, where we may indeed have an attractive offering that will allow our patients to undergo disobstruction prior to the downward spiral of bladder dysfunction. What is PUL? The Prostatic Urethral Lift creates a mechanical opening of the prostatic fossa by means of transprostatic implants that are installed transurethrally under cystoscopy (Figure 1). The urologist first compresses the prostate lobe with the delivery instrument and then essentially tacks the compressed tissue to the firm capsule. No tissue is destroyed or removed and for this reason, recovery is rapid and ejaculatory function is uniquely preserved.
Table 1: One year randomized results comparing the prostatic urethral lift (PUL) to transurethral resection (TURP) [mean (SD)]. While IPSS and Qmax are significantly different, this is not associated with a significant difference in the achieved quality of life (QOL) improvements. [Sonksen et al. Eur Urol 2015; 68; 643-652] At the 2016 EAU Congress we see the presentation of the four-year results from the LIFT randomized study and the two-year results from the BPH6 randomized study. While it will be important to see a continued, sustained effect from PUL, it is instructive to read how Roehborn sets PUL three-year durability into context6. By three years, PUL surgical retreatment (equally distributed between PUL revision and TURP/laser resection) was 10.7%. This contrasts greatly to the prior thermal ablation techniques, where three- year retreatment rates were 20% to 50%3,4.
At our center, we see a number of men who are already in chronic urinary retention. Nine out of 14 patients we treated had a transurethral catheter, and they were not approved by the anesthesiologist to undergo any kind of surgery. We treated those patients in local anesthesia with UroLift and eight of nine were able to void with decreasing residual volume over the initial month. Their IPSS dropped from pre-op to the first follow-up from a mean 23 [10-31] to 9 [14-2]. They were able to micturate after the transurethral catheter was removed with a mean flow of 12.7 [6-22]ml/s and decreasing residual of urine within the initial months to 42 [0-80]ml.
Many believe that freeing patients from chronic catheterization is the ultimate test for a BPO treatment. While the vast bibliography of studies has not focused on this population, our preliminary results appear encouraging. Importantly, bladder function should be taken into consideration when assessing results. Beside these encouraging results, In the BPH6 randomized study, one-year retreatment this gives these patients new QoL while reducing the for PUL and TURP were 7% and 6%, respectively7. If significant risk of urinary infections and longitudinal treatments for complications are included, the TURP cost of healthcare. Although we had one patient who follow on procedure rate increases to 14%. At present, was released with a catheter, we have to keep in with three and soon to be presented four-year mind that even with TURP, patients with a dystrophic follow-up, it would appear that PUL does not suffer bladder may not necessarily be helped with removal from the lack of durability seen with thermal ablation. of outlet obstruction. What is the new era for BPO? As healthcare systems sharpen their pencils to evaluate the cost effectiveness of care, it is important to point out that PUL is now recommended by the UK’s National Institute for Health and Care Excellence (NICE) as cost effective when compared to TURP13. This is not a claim that any prior minimally invasive treatment can make.
Figure 1: Prostatic Urethral Lift (PUL) showing (a) cystoscopy prior to treatment; (b) cystoscopy at end of procedure; (c) schematic of implant (I) locations, showing anterolateral location is far from dorsal venous complex (DV) and neurovascular bundles (NV) [Courtesy of NeoTract, Inc.].
Monday, 14 March 2016
With the repeatability of results across several studies to date, it would appear that we now have a treatment option that may indeed lead to a shift in care for men with BPO. At the SALK we see men electing a disobstructing procedure perhaps earlier
than they might otherwise have with our gold standard surgery. The main features that may indeed create this paradigm shift are that PUL: • Can be done minimally invasively (under only local anesthesia at our center); • Offers reliably rapid improvement without complications or iatrogenic sexual dysfunction; and • Shows a durability not seen in prior minimally invasive treatments. While these characteristics are certainly attractive to younger, healthier BPO patients, they are equally attractive for the patients with serious comorbidities for whom less anesthesia time, quicker recovery and lower risk of fluid shifts are important safety considerations. Now with preliminary evidence that PUL is effective in getting men off chronic urinary catheter, we believe this may indeed be the start of a new era in BPO care. References 1. Hutchinson A, Farmer R, Verhamme K et al. The efficacy of drugs for the treatment of LUTS/BPH. A study of 6 European countries. Eur Urol 2007; 51: 207-216. 2. Disantostefano R, Biddle A, Lavelle J. An evaluation of the economic costs and patient-related consequences of treatments for benign prostatic hyperplasia. BJUI 2006; 97:1007-1016. 3. Bouza C, Lopez T, Magro A et al. Systematic review and meta-analysis of transurethral needle ablation in symptomatic benign prostatic hyperplasia. BMC Urol 2006; 6:14. 4. Hoffman R, Monga M, Elliott S et al. Microwave thermotherapy for benign prostatic hyperplasia. Cochrane Database Syst Rev 2012; 9: CD004135. 5. Woo HH, Chin PT, McNicholas TA et al. Safety and feasibility of the prostatic urethral lift: a novel minimally invasive treatment for lower urinary tract symptoms (LUTS) secondary to benign prostatic hypertrophy (BPH). BJU Int 2011; 108: 82-88. 6. Roehrborn CG, Rukstalis DB, Barkin J et al. Three year results of the prostatic urethral L.I.F.T. study. Can J Urol 2015; 22(3); 7772-7782. 7. Sønksen J, Barber NJ, Speakman M et al. Prospective, Randomized, Multinational Study of Prostatic Urethral Lift Versus Transurethral Resection of the Prostate: 12-month Results from the BPH6 Study. Eur Urol 2015; 68; 643-652. 8. Shore N, Freedman S, Gange S et al. Prospective multi-center study elucidating patient experience after prostatic urethral lift. Can J Urology 2014; 21(1): 7094-7101. 9. Roehrborn CG, Gange SN, Shore ND, et al. Multi-Center randomized controlled blinded study of the prostatic urethral lift for the treatment of LUTS associated with prostate enlargement due to BPH: the L.I.F.T. study. J Urol 2013; 190: 2162-2167. 10. McNicholas TA, Woo HH, Chin PT et al. Minimally invasive Prostatic Urethral Lift: surgical technique and multinational study. Eur Urol 2013; 64: 292-299. 11. Chin PT, Bolton DM, Rashid JG et al. Prostatic Urethral Lift: Two-year results after treatment for lower urinary symptoms secondary to benign prostatic hyperplasia. Urology 2012; 79: 5-11. 12. McVary KT, Gange SN, Shore ND et al. Treatment of LUTS secondary to BPH while preserving sexual function: randomized controlled study of the prostatic urethral lift. J Sex Med 2014; 11: 279-287. 13. NICE MTG26. UroLift for treating LUTS of BPH. 2015. nice. org.uk/guidance/mtg26.
Saturday 12 March Meeting of the EAU Section of Genito-Urinary Reconstructive Surgeons (ESGURS)
EUT Congress News
23
NOW ENROLLING: A Clinical Research Study For Patients
Patient Population: • Chemo-naïve CRPC patients • Asymptomatic or mildly symptomatic • ≥ 2 bone metastases • No known brain metastasis or visceral metastasis • ECOG 0 or 1 Stratifications: • Geographical Regions (EU&NA&AUS vs Asia vs ROW) • Concurrent use of bisphosphonate or denosumab or none • Total ALP below 90U/L or not
1:1 Randomisation
with Castration Resistant Prostate Cancer Evaluating Radium-223 Dichloride in Combination with Abiraterone Primary endpoint • SSE-FS
• Radium-223 dichloride • abiraterone and prednisone/ prednisolone
• Matching placebo
Active Follow-up Active Follow-up without clinic visit with clinic visit • Phone call every • Clinic visit every 3 months until SSE 3 months until SSE, death or inability to travel or death
• abiraterone and prednisone/ prednisolone
Secondary endpoints • OS • Time to opiates • Time to pain • Time to chemo • rPFS • Safety
Long Term Follow Up • Phone call every 6 months until 7 years after the last dose of Radium-223 dichloride or death • To determine safety and OS
Primary Outcome Measures:
•
Asymptomatic or mildly symptomatic prostate cancer.
•
•
Medical or surgical castration with testosterone less than 50 ng/dL (1.7nmol/L).
•
Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1
Symptomatic skeletal event free survival (SSE-FS)
Secondary Outcome Measures: • • •
Overall Survival Time to opiate use, time to pain progression and time to cytotoxic chemotherapy Radiological progression free survival (rPFS)
Selected Inclusion Criteria: •
•
Prostate cancer progression documented by prostate specific antigen according to the Prostate Cancer Working Group 2 (PCWG2) criteria or radiological progression according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Two or more bone metastases on bone scan within 4 weeks prior to randomization with no lung, liver, other visceral and/or brain metastasis.
For complete information please visit:
http://www.clinicaltrials.gov (NCT02043678) Bayer and the Bayer cross are registered trademarks of Bayer. © Bayer. (February) 2016. L.DE.COM.SM.02.2016.4365.
Selected Exclusion Criteria: •
•
• •
Prior cytotoxic chemotherapy for the treatment of CRPC, including taxanes, mitoxantrone and estramustine History of visceral metastasis, or presence of visceral metastasis detected by screening imaging examinations Malignant lymphadenopathy exceeding 3 cm in short-axis diameter. Use of opiate analgesics for cancer-related pain, including codeine and dextropropoxyphene, currently or anytime during the 4- week period prior to randomization.
Trial Sponsor: Bayer HealthCare Pharmaceuticals, Inc. 100 Bayer Boulevard, PO Box 915, Whippany, NJ 07981 USA
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Monday, 14 March 2016
Check out the new nursing guidelines 2016 Available from 13 March at www.eaun.uroweb.org Or order a printed copy through eaun@uroweb.org
Evidence-based Guidelines for Best Practice in Urological Health Care
Male external catheters in adults Urinary catheter management Condom Catheter Urinary Sheath Penile Sheath
2016
Š 2008, Golgeon Group, Inc.
European Association of Urology Nurses
Publication of this booklet was made possible by an educational grant from Hollister Incorporated, Manfred Sauer GmbH and Wellspect Healthcare.
www.eaun.uroweb.org
New to the European Urology Family
Editor-in-Chief: J. Catto Editor: A. Briganti Associate Editors: G. Giannarini and T. Klatte
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Monday, 14 March 2016
EUT Congress News
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Renal transplantation Ureteral reflux: How relevant is it? Dr. Pedro Nunes Staff Urologist Department of Urology and Renal Transplantation Centro Hospitalar e Universitário de Coimbra Coimbra (PO)
Vesico-ureteral reflux (VUR) after renal transplantation is a common situation: it is diagnosed in 10% to 80% of the cases where an ureterovesical anastomosis is performed. In most cases VUR is asymptomatic and does not require any surgical procedure. Asymptomatic VUR does not compromise long-term function or survival of the transplant. In contrast, 3% of patients with VUR may be symptomatic and need some intervention1.In patients submitted to renal transplantation, VUR may be primary or secondary, either to the graft or native kidneys. The decision to perform a refluxing or a nonrefluxing ureteroneocystostomy at the time of transplant surgery is debatable. The ureteroneocystostomy should provide a watertight, tension-free, nonrefluxing anastomosis, permitting a free low-pressure passage of urine without obstruction. The incidence of VUR in kidney transplant recipients depends on the used technique: direct extravesical (50%), extravesical Lich-Gregoir (36%) and intravesical Leadbetter-Politano (13%)2,3. Reflux depends on the surgical technique and many transplant surgeons prefer to perform a wide patent ureteroneocystostomy rather risking a tunnelled anastomosis in order to reduce the rates of ureteral stricture. Some argue that creating an antirefluxing anastomosis may also sum technical difficulties and time to the procedure. Tunnel length at the time of transplantation is also very important. At least a 3 cm tunneling resulted in no reflux in a series of extravesical ureteric reimplantation during kidney transplants4. In a Lich-Gregoir ureteroneocystostomy with a short tunnelling VUR rates can reach an 80% while with the same technique but with a long (3-4 cm) tunnel VUR rates are no more than 10%. The EAU guidelines also recommended that the antireflux tunnel for the ureterovesical anastomosis should be 3 to 4 cm long.
In contrast to adults, ESRD is associated with functional or anatomical abnormalities of the lower urinary tract in approximately 25% of children. VUR in children predisposes to pyelonephritis (23–37 % vs. 0–5 % without VUR) and leads to graft dysfunction. Younger children and those with concomitant lower urinary tract dysfunction are at higher risk9.So, in the paediatric population with a much higher incidence of UTI and an increased incidence of lower urinary tract dysfunction a nonrefluxing anastomosis is preferred. Because of the potential morbidity of VUR in an immunocompromised patient, our longstanding practice has been to perform nonrefluxing reimplantation of the transplant ureter unless there is a compelling reason not to do so. Rates of post-transplant VUR have improved from 79 % in older series to 9 % and 19 %, with the development of more modern extravesical and intravesical techniques, respectively10. VUR in the renal transplant recipient becomes more prevalent with time and patients with lower urinary tract dysfunction generally present earlier with VUR. The true clinical significance of a refluxing anastomosis with respect to long-term graft function is controversial but some authors report graft function decline and premature graft loss among those with VUR. Diagnosing the presence of reflux in a transplant recipient can be challenging, but even more challenging can be the diagnosis of the importance of the reflux. We believe that a control VCUG is not required for every post-transplantation patient unless there is persistent reflux, kidney function deterioration, recurrent UTIs, unexplained hypertension or a known underlying lower urinary tract abnormality. In light of the finding that VUR incidence may change with time after surgery and considering that the ureteroneocystotomy continues to heal for at least six to eight weeks after transplantation, VUR identified very early after transplantation can disappear or reappear during subsequent follow-up11.
Transplant recipients presenting with recurrent pyelonephritis should undergo evaluation for VUR In a recent meta-analysis it was concluded that the only after two or three months post-transplant. available evidence favours an extravesical A period of watchful waiting and monitoring should ureteroneocystostomy for having a smaller amount of be the rule in the initial management of VUR in renal urological complications, but the presence of VUR was transplant patients. not evaluated in this study5. A well-performed graft ultrasound can point towards a VUR diagnosis if there is a collecting system After a lower urinary tract infection, there is an 80% chance of a febrile infection if VUR is present dilatation that resolves after emptying the bladder. comparing to 10% if it is absent. Febrile recurrent UTI Basic workup obligatory includes urinalysis, urine are associated with VUR and are a well-known risk culture, creatinine levels, VCUG. factor for kidney damage and premature graft loss, Another problem is secondary reflux originating from even in patients with normal lower urinary tract a dysfunctional lower urinary tract. A complete formal function, and this is particularly relevant in the immunosuppressed transplantation population6. urodynamic study should be considered if an underlying LUT dysfunction is suspected. High storage As in native renal units, the same scarring risk applies pressures from reduced bladder compliance and to kidney transplants subjected to recurrent UTIs and capacity may require augmentation cystoplasty and/or clean intermittent catheterization. VUR7. The long-term impact of VUR on renal transplant function, hypertension and pyelonephritis is unclear. Bladder outlet obstruction is a frequent cause of secondary reflux in men. Transurethral bladder outlet procedures have been shown to be safe and effective VUR in children in transplant recipients, even in the early postIn the adult population, there is insufficient data to operative period12. support universally performing a nonrefluxing anastomosis since the VUR rates can be as high as Managing transplant VUR The management of transplant VUR starts optimizing of the lower urinary tract dysfunction, which can imply the use of anticholinergics, botulinum toxin detrusor injection, indwelling catheter, intermittent catheterization, bladder augmentation or other targeted measures. Some advocate a trial of antibiotic prophylaxis or observation for a single UTI in transplant patients with low-grade reflux (grade I-III). Prophylaxis with probiotics, cranberry derived products and methionine has been tried with conflicting results in renal transplant recipients with recurring UTIs13,14. Figure 1: US showing an enlarged graft ureter and ureterovesical anastomosis in a case of VUR. This image disappeared after emptying the bladder.
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to around 80 % with a second injection. Effective correction rates of 90 % can be reached for low-grade VUR (I-II) in contrast to 31% in grades III-IV. A consistent reduction in the mean number of infections per year from 4.89 to 1.31 has been observed1,16,18.
86% but the rates of febrile UTIs are quite low (0,1-4,7%) and the presence of reflux does not directly affect graft function or survival8.
Recurrent infection and the diagnosis of high-grade VUR should, however, lead to surgical correction
Overall success is lower than in native kidney VUR due to the fibrosis at the anastomotic site and to the ectopic location of the neo-meatus that may both impair endoscopic needle approach and create increased orifice mobility. Due to its minimally invasive nature and low morbidity, endoscopic injection treatment with bulking agents can be proposed as the first line treatment for symptomatic VUR of a transplanted kidney regardless of reflux grade. References Figure 2: VCUG. Primary graft VUR in a 29 years old male recipient, with recurrent febrile UTIs, 24 months after a deceased donor kidney transplantation. Open graft ureter to native ureter anastomosis was successfully carried out.
trying to decrease the risk of pyelonephritis and protect against graft deterioration. It is known from large series of patients with primary VUR that, while repair of reflux will not decrease the future risk of UTI, it decreases febrile UTI frequency significantly compared with antibiotic prophylaxis and observation. The gold standard treatment for symptomatic VUR is open surgical correction with an 83% to 100% success rate. The options are a graft to native ureteroureterostomy or pyeloureterostomy or a redo transplant ureteric implant. Nevertheless, these procedures may be technically challenging and carries a significant 16% to 53% morbidity (obstruction, ureteral necrosis, urine leakage, infection and graft loss)1,15. Extravesical redo ureteric reimplantation with limited dissection of the anastomosis between the graft ureter and bladder is our favourite technique. Some surgeons advocate placing non-absorbable sutures during the transplant, at the anastomosis side on the detrusor so they can easily find it during an eventual revision surgery. For cases with very dilated graft ureters, some encourage a Politano–Leadbetter method of intra-extravesical reimplantation3. Neuhaus et al described a sub mucosal tunnel of less than 1 cm in all their cases of post-transplantation VUR. After increasing the length to no less than 3 cm they observed 100% VUR resolution at three to six-month follow-up4. Minimally invasive procedures There are no reports in the literature of surgical correction of VUR using a laparoscopic or robotic approach. Endoscopic treatment with subureteral injection of bulking agents is a minimally invasive procedure with low morbidity and high success rate: dextranomer/hyaluronic acid copolymer (Deflux) has been used to treat VUR in native kidneys since 1995. In 2007 the first results in transplant VUR were published. The reported success rates of the technique vary between 44 and 58 %, which may be improved
Figure 3: Retrograde cystography. Symptomatic secondary (low capacity bladder, high pressure voiding, outlet obstruction) VUR in 69 years old male, 22 years post-transplant. TURP was performed successfully correcting the VUR.
1. Akiki A, Boissier R, Delaporte V, Maurin C, Gaillet S, Karsenty G, et al. Endoscopic treatment of symptomatic vesicoureteral reflux after renal transplantation. J Urol. 2015;193:225-9. 2. Ostrowski M, Wlodarczyk Z, Wesolowski T, Gracz H, Sluzar T, Sienko J, et al. Influence of ureterovesical anastomosis technique on the incidence of vesicoureteral reflux in renal transplant recipients. Ann Transplant. 1999;4:54-8. 3. Dinckan A, Aliosmanoglu I, Kocak H, Gunseren F, Mesci A, Ertug Z, et al. Surgical correction of vesico-ureteric reflux for recurrent febrile urinary tract infections after kidney transplantation. BJU Int. 2013;112:E366-71. 4. Neuhaus TJ, Schwobel M, Schlumpf R, Offner G, Leumann E, Willi U. Pyelonephritis and vesicoureteral reflux after renal transplantation in young children. J Urol. 1997;157:1400-3. 5. Slagt IK, Klop KW, Ijzermans JN, Terkivatan T. Intravesical versus extravesical ureteroneocystostomy in kidney transplantation: a systematic review and meta-analysis. Transplantation. 2012;94:1179-84. 6. Dupont PJ, Psimenou E, Lord R, Buscombe JR, Hilson AJ, Sweny P. Late recurrent urinary tract infections may produce renal allograft scarring even in the absence of symptoms or vesicoureteric reflux. Transplantation. 2007;84:351-5. 7. Coulthard MG, Keir MJ. Reflux nephropathy in kidney transplants, demonstrated by dimercaptosuccinic acid scanning. Transplantation. 2006;82:205-10. 8. Lee S, Moon HH, Kim TS, Roh Y, Song S, Shin M, et al. Presence of vesicoureteral reflux in the graft kidney does not adversely affect long-term graft outcome in kidney transplant recipients. Transplant Proc. 2013;45:2984-7. 9. Routh JC, Yu RN, Kozinn SI, Nguyen HT, Borer JG. Urological complications and vesicoureteral reflux following pediatric kidney transplantation. J Urol. 2013;189:1071-6. 10. Krishnan A, Swana H, Mathias R, Baskin LS. Redo ureteroneocystostomy using an extravesical approach in pediatric renal transplant patients with reflux: a retrospective analysis and description of technique. J Urol. 2006;176:1582-7; discussion 7. 11. Margreiter M, Gyori GP, Bohmig GA, Trubel S, Muhlbacher F, Steininger R. Value of routine voiding cystourethrography after renal transplantation. Am J Transplant. 2013;13:130-5. 12. Duty BD, Barry JM. Diagnosis and management of ureteral complications following renal transplantation. Asian Journal of Urology. 2015;2:202-7. 13. Pagonas N, Horstrup J, Schmidt D, Benz P, Schindler R, Reinke P, et al. Prophylaxis of recurrent urinary tract infection after renal transplantation by cranberry juice and L-methionine. Transplant Proc. 2012;44:3017-21. 14. Schwenger EM, Tejani AM, Loewen PS. Probiotics for preventing urinary tract infections in adults and children. Cochrane Database Syst Rev. 2015;12:CD008772. 15. Kayler L, Kang D, Molmenti E, Howard R. Kidney transplant ureteroneocystostomy techniques and complications: review of the literature. Transplant Proc. 2010;42:1413-20. 16. Seifert HH, Mazzola B, Ruszat R, Muller A, Steiger J, Bachmann A, et al. Transurethral injection therapy with dextranomer/hyaluronic acid copolymer (Deflux) for treatment of secondary vesicoureteral reflux after renal transplantation. J Endourol. 2007;21:1357-60. 17. Pichler R, Buttazzoni A, Rehder P, Bartsch G, Steiner H, Oswald J. Endoscopic application of dextranomer/ hyaluronic acid copolymer in the treatment of vesico-ureteric reflux after renal transplantation. BJU Int. 2011;107:1967-72. 18. Yucel S, Akin Y, Celik O, Erdogru T, Baykara M. Endoscopic vesicoureteral reflux correction in transplanted kidneys: does injection technique matter? J Endourol. 2010;24:1661-4.
Saturday 12 March Meeting of the EAU Section of Transplantation Urology (ESTU)
Monday, 14 March 2016
Prostate cancer survivors and mental health Assessment and interventions on mental health of survivors are crucial to prevent depression Marie-Anne van Stam Dept. of Urology UMC Utrecht Cancer Center The Netherlands Cancer Institute Utrecht (NL)
Institute), we aimed to describe this target population and we further unraveled the long-term relation between prostate cancer and mental health. These general aims were divided in three research questions: 1. Are prostate cancer survivors more at risk for mental health problems than an age and sex matched reference group without prostate cancer?; 2. What are risk factors for mental health problems in prostate cancer survivors?; and 3. Do these risk factors differ from risk factors in the reference group?
Urinary bother; and 6. Less sexual satisfaction. Health professionals should pay extra attention to survivors with these characteristics or health problems. These men are at risk for developing mental health problems.
Lastly, we analyzed whether these risk factors in the ‘Prostate Cancer Survivors’ group differed To answer these three questions we composed two Co-Authors: J.L.H.R. Bosch, H.G. van der Poel, S. from the risk factors in the groups. The first group, ‘The prostate cancer Horenblas, N.K. Aaronson survivors’, consisted of 644 prostate cancer survivors. ‘Reference group’ (Question 3). The second group, ‘Reference group’, consisted of 644 Two differences between the Prostate cancer is the most prevalent diagnosed groups were observed. 1. In the men from the general population with a comparable cancer in men (American Cancer Society, 2015). About age but without a history of prostate cancer (Figure 1). ‘Reference group’ a higher age one in seven men will be diagnosed with prostate was a risk factor for mental cancer during his life. health problems. No association ‘Mental health’ is not something you can easily see. between mental health and age We used a standardized questionnaire, the Short Fortunately, the average life expectancy of patients Form (36) Health Survey to measure the quality of life was found in the prostate cancer newly diagnosed with prostate cancer is a decade or group. 2. A poor general health of the men in the study. This respondent-reported longer (Ferlay et al., 2010). According to the American survey contains a mental health scale (MHI-5). One was a stronger risk factor in the Cancer Society a ‘long-term cancer survivor’ is a prostate cancer group. can score between 0 and 100. A score of 52 points or person who is alive five years after being diagnosed less suggests severe depressive symptomatology with cancer. Therefore, the majority of patients with In summary, prostate cancer (Ware, Snow, Kosinski, & Gandek, 1993). prostate cancer will become long-term survivors. survivors are more at risk for The next step was to perform analyses to answer the mental health problems. Men diagnosed with prostate cancer have higher levels three research questions. First, we compared the Therefore, this study stresses the of anxiety, depression and suicide compared to an importance of ongoing mental health scores of ‘Prostate cancer survivors’ age- and gender comparable cohort from the general assessment and interventions with the ‘Reference group’ (Question 1, Figure 1). We population (Bennett & Badger, 2005; Mehnert, observed that our ‘Reference group’ had significantly focusing on the mental health of Lehmann, Graefen, Huland, & Koch, 2010). Ongoing better mental health scores compared to the ‘Prostate prostate cancer survivors assessment, identification, and psychological especially for men who have to Cancer survivors’ (difference of -6.52, p < 0.01). This interventions have been found successful in relieving cope with additional physical, means that in the ‘Prostate cancer survivors group’ distress for prostate cancer patients and survivors 14% of the men were suspected of having depressive economic and emotional disturbances. (Skolarus et al., 2014). Unfortunately, they are symptomatology. This was only 6% in the ‘Reference inconsistently available in prostate cancer survivorship- group’ (OR 0.41, 95% confidence interval 0.28-0.60). Mental health problems are not only a problem for care. These interventions are especially important for prostate cancer patients. Many other patients prostate cancer patients and survivors who are at high Secondly, we identified prostate cancer survivors who experience depressive symptoms possibly associated risk for mental health problems (the target population). were particularly at risk for mental health problems with the effects of a disease. However, possibilities to (Question 2, Figure 2). We observed six important risk help these patients (e.g. by referring to a mental Therefore, in our study (collaboration between UMC health professional) are often not well known by factors: 1. Being a widower; 2. A low socioeconomic Utrecht Cancer Center and The Netherlands Cancer health professionals. Thinking about the answer to status; 3. Poor general health; 4. Bodily pain; 5.
New EAU guidelines available online!
the following question might be the first step: What can you do in your professional setting when you suspect a patient of having mental health problems? Saturday 12 March Thematic Session 3, 17th International EAUN Meeting Perspectives in prostate cancer care
STEPS
Interactive Education with World Experts in Onco-Urology
Sessions To Evaluate ProgresS in the management of urological cancers
Pocket App free for EAU members only
Applications now open! Visit Ipsen at booth D42 to learn more What is STEPS?
European A ssociation of Urology
Guidelines 2016 edition
• A scientific case discussion session led by senior experts in urological cancers • Open to applications from recently specialised clinicians
Follow us #eauguidelines
• 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/
Monday, 14 March 2016
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Stebabiotech
Innovation
Low Risk Prostate Cancer
TOOKAD速 Minimally Invasive Focal Therapy
Available Soon A complementary approach to Active Surveillance
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.
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EFFICACY & QUALITY OF LIFE 28
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Cutting-edge Science at Europeâ&#x20AC;&#x2122;s largest Urology Congress
32nd Annual EAU Congress www.eau17.org
Monday, 14 March 2016
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Current status of androgen receptor research Predictive medicine can play a key role in managing PCa progression Prof. Dr. Zoran Culig Experimental Urology Department of Urology Medical University of Innsbruck Innsbruck (AT)
inhibit the transcription activation function in the N-terminal region of the AR. There have been only limited efforts in this area. In addition to targeting AR itself, researchers should also address the issue of its co-activators overexpressed in prostate cancer. These co-activators may interact either with the N-terminal region or ligand-bidning domain of the AR and some of them are overexpressed in prostate cancer. Coactivators are proteins with multiple functions. Coactivators such as p300 also regulate processes in cells which do not express the AR.
Investigations on androgen receptor (AR) in human prostate cancer are the focus of research interest for many years. It is clear that the androgen receptor is Specific functions of coactivators in modulation of expressed in tumor specimens obtained from patients proliferation, apoptosis, migration, and invasion have with castration therapy resistant disease. been described in the literature. Therefore, these coactivators are potential targets for novel therapies. In previous studies, it has been demonstrated that Small molecule inhibitors of coactivators have been long-term treatment with hydroxyflutamide or developed, however, most of their effects have been bicalutamide may lead to appearance of point assessed in vitro but not in vivo. Structural modifications mutations which yield promiscous androgen of these small molecules may be necessary in order to receptors. Activation of AR by steroids other than achieve a longer half-life and a better therapeutic effect. androgen and by AR antagonists is one of the mechanisms that contribute to cancer progression. Adaptive responses during endocrine therapy in Improvements in prostate cancer clinical treatment prostate cancer have been achieved with abiraterone acetate and There is no doubt that short-term androgen enzalutamide which either inhibit synthesis of withdrawal or blockade of the AR is useful in order to intracellular androgens or block ligand-binding cause a reduction of tumor volume. However, induced activation of the AR. However, mechanisms of long-term androgen ablation is associated with resistance to therapy with abiraterone and/or activation of several adaptive mechanisms, such as enzalutamide are still incompletely understood. AR amplification or enhanced stability of receptor mRNA or protein. The role of these adaptive In part, they are similar to those previously described mechanisms in facilitation of tumor progression is for hydroxyflutamide or bicalutamide. Specific frequently underinvestigated. For example, an mutations were discovered in patients treated with important anti-apoptotic oncogene Mcl-1 is frequently enzalutamide. One of the most important areas of up-regulated in prostate cancer and it has been research are truncated ARs which have been demonstrated that inhibition of its expression may described in tumors from patients with advanced occur as a result of androgenic treatment. prostate cancer. Full-length AR contains the N-terminal region, the DNA- and ligand-binding Consequently, culture of prostate cancer cells which are regions. Ligand-binding domain prevents activation of depleted of steroids leads to elevated expression of the receptor and expression of AR-inducible genes in Mcl-1. Mcl-1 is implicated in modulation of antithe absence of androgens. apoptotic signals of the pro-inflammatory cytokine interleukin-6 in prostate cancer. Mcl-1 is also expressed Following innovative work of Scott Dehm, Donald in stem cells in prostate cancer and these cells cannot Tindall and associates, several researchers were able be targeted with therapies that are currently being to demonstrate the presence of truncated AR which do available. Because of its up-regulation during not express a functional ligand-binding domain. These androgen ablation therapy, several options for receptors are constitutively active and could upimprovement of treatment may be discussed. For regulate androgen-regulated genes in the absence of example, an inhibitor of Mcl-1 may be used in therapy ligand. Interestingly, truncated AR have been in combination with abiraterone acetate or enzalutamide. This may be a rational approach for frequently detected in prostate cancer cells obtained from patients who received treatment with abiraterone improvement of prostate cancer therapy that is based acetate or second generation anti-androgens. on tumor biology. Although a higher frequency of constitutively active AR has been observed in individuals who failed therapy, these receptors are also detectable in earlier stages tumors. Truncated AR, therefore, have a growth advantage and their overexpression in various cancer cells results with accelerated proliferation and reduced apoptosis. Androgen receptor coactivators may be overexpressed in advanced disease On the basis of these findings, one can conclude that targeting solely ligand-binding domain of the AR is not sufficient in advanced prostate cancer. Research efforts should also be focused on novel ways to
Predictive medicine is an approach that is discussed more frequently in connection with analysis of alternative pathways (Photo: EAU Archive)
are very heterogenous and that it is particularly difficult to make a prediction which mechanisms are of particular importance in individual patients. The AR is involved in prostate cancer progression through interaction with coactivators, activation by other ligands and non-steroidal substances, and by structural alterations. The existence of truncated AR is one of the most important discoveries in urological oncology that helped us better understand resistance to therapy. Predictive medicine is an approach that is discussed more and more frequently in conjuction with analysis of alternative pathways involved in prostate cancer progression.
Further improvement in patients´ survival may be therefore achieved with a more appropriate use of biomarkers in prostate cancer. The number of publications with potential biomarkers is strongly increasing; however, there have been many issues with reproducibility of data which limit progress. Better description of study protocols, inclusion of standard operating procedures, and organization of consensus conferences may help achieve the goals to improve diagnostics and therapy for prostate cancer. Sunday 13 March Thematic Session 4: Resistance to novel endocrine therapy in prostate cancer
An example of another protein which is up-regulated during androgen ablation is an AR coactivator p300. P300 and its related molecule CBP have been shown to increase AR activity in the presence of androgens, anti-androgens, and non-steroidal regulators, such as interleukin-6. Its up-regulation in advanced prostate cancer indicates that additional approach with targeting a coactivator in addition to classic therapy should be worked out. Molecular mechanisms In conclusion, molecular mechanisms leading to lack of success of endocrine therapy in the long-term are in part understood. It seems that these mechanisms
Besides targeting AR, researchers should also address the issue of its co-activators overexpressed in prostate cancer
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Monday, 14 March 2016
ADVERTORIAL
Unique for RARP 3D Systems and Karolinska Training Centre (KTC) Collaborate to Develop Simulation Training Module Prostate cancer is the most common (non-skin) cancer in men. In the US, about 1 in 6 men will be diagnosed with prostate cancer. Radical Prostatectomy, the surgical removal of the entire prostate gland, is a common procedure for those with localized prostate cancer. According to The National Cancer Institute, 80% of radical prostatectomies in the United States are performed using minimally invasive robotic assisted approaches. This relatively new minimally invasive procedure is complicated, leading to a growing need for a comprehensive training solution on the robotic technology and procedural steps. 3D Systems’ RobotiX Mentor™ is a VR training simulator that provides surgeons of all expertise levels across diverse medical specialties with an opportunity to efficiently and effectively practice the skills required to perform robotic surgery. “Simulator training has the potential to decrease the learning curve for the acquisition of robotic skills. It can supplement the hands-on training clinical phase and can act as a bridge between preclinical training and
actual hands-on clinical training without jeopardizing the safety of patients” (Kumar et al., Current opinion in urology, 2015). 3D Systems and KTC are collaborating to develop a Robotic Assisted Radical Prostatectomy (RARP) full procedure training module for the RobotiX Mentor simulator. The module provides the trainee with the opportunity to practice prostatectomy in a virtual reality environment, and includes step-by-step procedural guidance, anatomy identification, video-based curriculum for the entire procedure, and performance metrics. “It is important to differentiate between basic and advanced simulation. Basic simulation develops skills on how to use the equipment safely and efficiently, whereas advanced simulation trains you on how to perform the actual surgical procedure”, said Justin Collins, MD, Research coordinator, Karolinska Institute. Karolinska University Hospital is one of the largest robotic training centers in Europe, with 3 Da Vinci Si’s. Over 600 robotic assisted radical
Peter Wiklund, MD, Professor of Urology, and Justin Collins, MD, Research Coordinator, Karolinska Institute
prostatectomies (RARP) and 120 Robotic assisted radical cystectomies (RARC) are performed at this center every year. They also run master classes in robotics and have access to the KTC, with an onsite dry lab and licensed wet-lab, where regular robotic courses are currently run.
The goal of this joint project is to provide a robotic training module for advanced simulation in RARP with construct and predictive validity. Simulation validation will be achieved by having surgical trainees (fellows) use the advanced simulation, after which their performance in complex multi-step robotic surgeries, starting with RARP, will be evaluated using various assessment tools. Peter Robotic Radical Prostatectomy Wiklund, MD, Professor of Urology, Karolinska Procedure (RARP) Simulation Institute, Pioneer in complex multi step surgery
noted that “Karolinska is pleased to be part of this exciting project to develop the first full procedure RARP simulation and curriculum. Advanced simulation has the potential to greatly impact robotic training in the future.” “3D Systems views the development of validated training in advanced simulation as an important step in the progression towards precision medicine, and are excited to partner with the KTC experts in robotic surgery in this project,” said Kevin McAlea, Executive Vice President & Chief Operating Officer, Healthcare, 3D Systems. Click for more information on the RobotiX Mentor” to the following link: http://simbionix.com/ simulators/robotix-mentor/
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Monday, 14 March 2016
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Nocturia: Control the cause. Restore the night.
EEP, L S E R MO BANCE R U T S I LESS D
DESMOPRESSIN ORAL LYOPHILISATE
Nocturnal polyuria occurs in the majority of patients with nocturia. 1 By causing the kidneys to produce less urine, Minirin® Melt significantly reduces nocturnal voids in patients 2 by selectively acting on vasopressin 2 receptors in the kidneys to concentrate urine. Abbreviated Prescribing Information: Prescribing information and indications may vary from country to country. Contact the local Ferring representative for country specific prescribing information. Prescribing active ingredient: Desmopressin acetate. Composition: 1 x 60 µg orally dissolving tablet contains 67 µg desmopressin acetate, corresponding to 60 µg desmopressin, 1 x 120 µg orally dissolving tablet contains 135 µg desmopressin acetate, corresponding to 120 µg desmopressin, 1 x 240 µg orally dissolving tablet contains 270 µg desmopressin acetate, corresponding to 240 µg desmopressin. Other components: Gelatine, mannitol (Ph.Eur.), citric acid. Applications: Treatment of primary nocturnal enuresis as part of an overall treatment concept, such as in the event of failure of other non-medication treatments or in the event of an indication for medication treatment, caused by nocturnal ADH deficiency; symptomatic treatment of nocturia (nocturnal urination at least twice a night) in adults, associated with nocturnal polyuria; trauma-related polyuria and polydipsia in the event of a temporary ADH deficiency of various origins; central diabetes insipidus. Contra-
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indications: Oversensitivity to desmopressin or one of the excipients of the medication, habitual or psychogenic polydipsia, polydipsia in alcoholics, known or suspected heart failure, states that require treatment with diuretics, known hyponatremia, kidney insufficiency with a creatinine clearance of less than 50 ml/min, inadequate ADH production syndrome, patients aged 65 years and over using desmopressin to treat nocturia. Pregnancy and lactation: Care should be taken when prescribing this medication to pregnant women and blood pressure monitoring is recommended. MINIRIN® should only be prescribed to pregnant women following a careful risk/benefit assessment. Studies on the breast milk of women who had received a high dose of 300 µg desmopressin indicated that the amounts of desmopressin that could be transferred to the child are too low to affect diuresis. Side effects: General: Treatment without simultaneous restriction of fluid intake may result in water retention/hyponatremia with or without concomitant warning signs and symptoms (headache, nausea/vomiting, increase in weight and, in serious cases, seizures, sometimes with somnolence and potentially lengthy periods of loss of consciousness). This particularly applies to small children under
Date of preparation: January 2016 MN/2505/2015/ECO
For the treatment of nocturia in adults associated with nocturnal polyuria 2 the age of one year or to elderly patients, depending on the general state of health. Primary nocturnal enuresis / central diabetes insipidus: Frequent: Headache, abdominal pain, nausea. Very rare: allergic skin reactions, general allergic reactions, hyponatremia, emotional disorders (children). Nocturia: Very frequent: Headache. Frequent: Hyponatremia, insomnia, dizziness, hypertension, nausea, abdominal pain, dry mouth, diarrhoea, frequent urination, tiredness, peripheral oedema, increase in weight. Dosage and other recommendations: See product characteristics. Presentations: MINIRIN ® 60 microgrammes lyophilisate for oral administration: 30/90 orally dissolving tablets, MINIRIN® 120 microgrammes lyophilisate for oral administration: 30/90 orally dissolving tablets, MINIRIN® 240 microgrammes lyophilisate for oral administration: 30/90 orally dissolving tablets. Date of information: December 2014. Only available on prescription. FERRING Arzneimittel GmbH, Fabrikstraße 7, 24103 Kiel, Tel.: 0431-5852-0, Fax: 0431-5852-74, E-mail: info-service@ferring.de. Reference: 1. Weiss et al. J Urol 2011;186:1358-1363 2. Minirin SmPC
Monday, 14 March 2016