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Thank you all for your overwhelming support of the new web and paper versions of the BJUI. For those who have missed it, please check out the web journal at: www.bjui.org.

We hope you had a relaxing holiday period – we certainly did and recharged our batteries. Despite this, the editorial team at the BJUI handled 76 articles between Christmas 2012 and New Year’s Day 2013; an average of 10 per day.

This is a reflection of the global popularity of the BJUI. We have papers coming in from all over the world from many different time zones. Furthermore, New Year celebrations in the West do not necessarily match others, such as the Chinese New Year or the Baisakhi in the Northern Indian subcontinent. The BJUI wants to continue receiving the best papers from our authors irrespective of where they are on this planet.

As a celebration of our truly global presence we are delighted to present content from around the world at www.bjui.org as articles, blogs and videos, and we invite you to post your comments on any or all of these.

The BJUI poll shows that our readers love the ‘article of the week’, which is available completely free to everyone, everywhere.

In this issue we highlight the role of tadalafil, not just in erectile dysfunction but also in ejaculatory and orgasmic dysfunction. This article provides Level 1 evidence and is accompanied by an editorial from Mike Wyllie, our expert in Sexual Medicine.

Please keep the conversations going on Twitter, Facebook and [email protected]. Your web journal needs you.

Prokar Dasgupta, Editor-in-Chief

Ashutosh Tewari, Editorial Board

Video of Ashutosh Tewari reading the Journal in New York

Editorial: Oncological outcomes: open vs robotic prostatectomy

John W. Davis and Prokar Dasgupta*

Departments of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA and *Guy’s Hospital, Kings College London, London, UK
e-mail: [email protected]

For men at significant risk of dying from untreated prostate cancer within reasonably estimated remaining life spans, which technique offers the best disease-free survival: open radical prostatectomy (RP) or robot-assisted RP (RARP)? The practice patterns in many countries suggest RARP, but many concerns have been raised about the RARP technique for high-risk disease, including positive surgical margin rates, adequate lymph node dissections (LNDs), and the learning curve. In this issue of the BJUI, Silberstein et al provide a convincing study, short of a randomised trial, that suggests that in experienced hands both techniques can be effective, and that surgeon experience had a stronger effect than technique. In contrast to large population-based studies, this study sought to take the learning curve and low-volume surgeon variables out of the equation by restricting the inclusion criteria to four high-volume surgeons from a single centre. The follow-up is short (one year), and may underestimate the true biochemical relapse rates, and needs follow-up study, but for now offers no difference in relapse rates nor pathological staging outcomes.

Beyond the comparative effectiveness research (CER), Silberstein et al also provide a valuable vision for prostate cancer surgeons using any standard technique. Several recent landmark studies on PSA screening, the Prostate cancer Intervention Versus Observation Trial (PIVOT), and comparisons of metastatic progression between RP and radiation, all indicate the need to shift our practice pattern towards active surveillance for lower risk patients (with or without adjunctive focal therapy, but the former still experimental in our view), and curative therapy for intermediate- to high-risk disease. Such a practice pattern is evident when you compare this study (2007–2010) with a similar effort from this institution (2003–2005) comparing RP with laparoscopic RP (LRP). In the former study, >55% had low-risk disease compared with <35% from the current study. As expected, the present study shows higher N1 stage (9%) and positive surgical margin rates (15%) than the former (7% and 11%, respectively). While erectile function recovery was not presented, the authors noted the familiar reality that patients demand nerve sparing whenever feasible, only 2% in this study had bilateral non-nervesparing and 91% had a combination of bilateral or partial nerve sparing. The number of LNs retrieved has increased from 12–13/case to 15–16, and the authors state that even with nomogram-based exclusion of mandatory pelvic LNDs with <2% risk of N1 staging, this modern cohort had a pelvic LND in 94% of cases, including external iliac, obturator, and hypogastric templates.

We fully concur with this practice pattern, and have recently provided a video-based illustration of how to learn the technique, and early experience showing an increase in median LN counts from eight to 16, and an increase in positive LNs from 7% to 18%. By risk group, our positive-LN rate was 3% for low risk, 9% for intermediate risk, and 39% for high risk. We certainly hope that future multi-institutional studies will no longer reflect what these authors found, in that RARP surgeons are five times more likely to omit pelvic LNDs than open, even for high-risk cancers.

Finally, Silberstein et al and related CER publications leave us the question, does each publication on CER in RP have to be comprehensive (i.e. oncological, functional, and morbidity) or can it focus on one question. Members of this authorship line have published the ‘trifecta’ (disease control, potency, and continence) and others the ‘pentafecta’ (the trifecta plus negative surgical margins and no complications). Indeed, Eastham and Scardino stated in an editorial that ‘data on cancer control, continence, or potency in isolation are not sufficient for decision making and that patients agreeing to RP should be informed of functional results in the context of cancer control’. We feel that the answer should be no, focused manuscripts have their merit and publication space/word limits create this reality. But we should not discount the sometimes surprising results when one institution using the same surgeons and methodologies publishes on the broader topic: the Touijer et al. paper discussed above found the same oncological equivalence between RP and LRP as this comparison of RP and RARP, but also included functional data showing significantly lower recovery of continence with LRP. Nevertheless, the recent body of work in the BJUI now provides a well-rounded picture of modern CER including oncological outcomes, complicationsrecovery of erectile dysfunction, continence and costs. We feel it is reasonable to conclude that patients should be counselled that RARP has potential benefits in terms of blood loss, hospital stay, and complications (at increased costs), but oncological and functional results are probably based upon surgeon experience.

Abbreviations

CER, comparative effectiveness research; LN(D), lymph node dissection; (RA)(L)RP, (robot-assisted) (laparoscopic) radical prostatectomy

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Editorial: Phosphodiesterase Inhibitors (PDEi) improve orgasm. The power of meta-analysis?

Ever since the potential utility of meta-analyses in the assessment of clinical data was brought to the notice of the urological community by Peter Boyle [1], they have been used increasingly. Indeed this approach to evaluation of drug effects has become de rigueur for healthcare providers and regulatory bodies. In particular, invaluable insight has been given into the benefit : risk ratios of drugs in BPH/LUTS and overactive bladder. Even to the extent, where sufficiently large databases have been made available, it has been possible to identify characteristics predictive of subpopulations of responders and non-responders [1].

The most recent example of the power of meta-analysis is the rigorous statistical dissection of the impact tadalafil on sexual function in erectile dysfunction (ED) by the Department of Urology atWeill Cornell published in BJUI [2]. As would be anticipated from previously published individual clinical trials, there was confirmation in this review of 3581 subjects in 17 placebo-controlled studies, of the positive effect of tadalafil (exemplifying the phosphodiesterase inhibitor [PDEi] class) on erectile function. It could perhaps be argued that with a clinical effect as large and clear-cut as that of PDEi in ED, the meta-analysis was superfluous. Only in situations where the clinical impact beyond that of placebo was of lower magnitude does it come to the fore, e.g. a-adrenoceptor antagonists in the treatment of LUTS [3]. However, at this point the following health warning should be issued, PDEi in the hands of the skilled meta-analysts and marketeers: caveat lector (let the reader beware).
Returning, however, to the material in hand, the analysis of the tadalafil data also shows unequivocally that there is an additional positive effect of the drug (and presumably the PDEi class) on orgasm and sexual satisfaction. These products and class attributes have often been alluded to with varying degrees of conviction, but this is the first time convincing evidence has been tabulated and documented.

Also described is the positive effect of tadalafil on co-morbid ejaculatory dysfunction (EjD) which, at first sight, would tend to provide supportive evidence for the off-label use of tadalafil and other PDEi in the treatment of premature ejaculation (PE). Although the words in the manuscript [3] fall short of advocating this practice, the inference is there for all to read and potentially be detailed astutely by the field-force.We now move into the ‘grey’ area between caveat lector and caveat emptor (let the buyer beware). EjD can mean different things to different men and can represent a continuum from premature to delayed or even anejaculation. Almost certainly most of the patients in the clinical trials analysed would not meet the definition of PE crafted by the International Society for Sexual Medicine (ISSM) [4], so little conclusion about the benefit to men with PE can be drawn.

Ironically, a meta-analysis on the impact of PDEi on men with unequivocal PE (or at least meet the ISSM definition) has just been published [5]. The conclusion was that there is no clinically or statistically significant improvement in PE with acute or chronic treatment with PDEi.

Although, at least in the case of ejaculatory function the conclusion of the two meta-analyses appear to be at variance, in actuality they are addressing different questions. It remains, that, although in the use of meta-analysis we have the means of creating a level playing field, we have to be careful to consider what questions are being asked, by whomand with what objective.

References
1 Boyle P, Gould AL, Roehrborn CG. Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: meta-analysis of randomized clinical trials. Urology 1996; 48: 398–405
2 Paduch DA, Bolyakov A, Polzer PK, Watts SD. Effects of 12 weeks of tadalafil treatment on ejaculatory and orgasmic dysfunction and sexual satisfaction in patients with mild to severe erectile dysfunction: integrated analysis of 17 placebo-controlled studies. BJU Int 2013; 111: 333–42
3 Boyle P, Robertson C, Manski R, Padley RJ, Roehrborn CG. Meta-analysis of randomized trials of terazosin in the treatment of benign prostatic hyperplasia. Urology 2001; 58: 717–22
4 McMahon CG, Althof S, Waldinger MD et al. International Society for Sexual Medicine Ad Hoc Committee for Definition of Premature Ejaculation. An evidence-based definition of lifelong premature ejaculation: report of the International Society for Sexual Medicine Ad Hoc Committee for the Definition of Premature Ejaculation. BJU Int 2008; 102: 338–50
5 Asimakopoulos AD, Miano R, Agrò EF, Vespasiani G, Spera E. Does current scientific and clinical evidence support the use of phosphodiesterase type 5 inhibitors for the treatment of premature ejaculation? A systematic review and meta-analysis. J Sex Med 2012; 9: 2404–16

Mike Wyllie
Plethora Solutions Ltd London, London, UK.
e-mail: [email protected]

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Editorial: The promise of EMT-associated biomarkers in a clinical setting

Emily A. Matuszak  and Natasha Kyprianou
Departments of Toxicology, Urology and Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA

Radical prostatectomy is among the most successful treatment modalities for patients exhibiting clinically localized prostate cancer. Despite this, roughly one-third of all radical prostatectomy patients will experience biochemical recurrence following prostatectomy. Curing prostate cancer requires a greater understanding of distinct biological events that differentiate prostate cancer from advanced life-threatening disease. Thus, a current challenge facing the clinical management of prostate cancer is the need for novel prognostic biomarkers capable of predicting biochemical recurrence to direct therapeutic interventions at earlier disease stages.

The oncogenic epithelial–mesenchymal transition (EMT) plays a critical role in metastatic prostate cancer progression [1]. EMTs engender coordinated molecular and genetic events which provoke phenotypic transformations that are indicative of the acquisition of mesenchymal characteristics which yield altered cellular behaviours [2]. Such altered behaviours may include but are not limited to enhanced migratory capability, increased invasive capacity, heightened resistance to apoptosis and conferred stem-like properties [3,4]. Conversion of an epithelial-derived prostate cancer cell to a more mesenchymal-like state has recently been implicated in prostate tumourigenesis as a mechanism facilitating the progression to metastatic castration-resistant disease [5].While alterations in the expression profiles of numerous EMT-associated transcriptional regulators and their molecular targets have served as biomarkers for studying EMT programmes, less is known about the contributions of EMTs in the emergence of treatment failure and tumour recurrence. Recently, EMT has been suggested to be a programme involved in metastatic disease progression that may also profoundly influence therapeutic outcomes amongst patients. Thus, it may be advantageous to develop predictors for risk assessment among prostate cancer patients that include specific EMT-associated markers in clinical evaluations.

Despite our current lack of knowledge regarding the clinicopathological significance of EMT, the potential value of an EMT marker signature as a prognostic indicator of biochemical recurrence among prostate cancer patients has emerged with some promise. Behnsawy et al. establish an initial path towards estimating the clinical value of assessing EMT marker levels in tandem with conventional clinicopathological prognostic factors in radical prostatectomy specimens from patients with organ confined prostate cancer, without any neoadjuvant therapy. Their evaluation follows a robust profile and results intriguingly reflect a pattern that may facilitate prediction of biochemical recurrence among patients. Using an exhaustive immunohistochemical analysis, the expression patterns of 13 EMT markers were evaluated in 197 radical prostatectomy specimens of which the expression levels of two EMT-associated markers, Twist and vimentin, were the most promising factors for such predictions.

The novel aspect and translational significance of this study are both reflected in the homogeneity of the patient population, in terms of localized organ confined disease. It represents an initial step towards recognizing an expression signature for specific EMT-associated factors in the therapeutic outcome of localized prostate cancer, but not disease progression. While the clinical impact of the reported findings may not be fully apparent, one may begin to speculate the promise of incorporating EMT-associated biomarkers in a clinical setting to facilitate diagnosis, prognosis and/or directing treatment strategies among patients. Primary endpoints of acquisition of an EMT phenotype following androgen axis targeting treatment must be clearly defined in the design of future clinical trials for the treatment of prostate cancer patients, with caution being given to selection of biopsy specimens vs radical prostatectomy specimens at an ‘optimal’ EMT window and in order to mitigate bias in tissue sampling resulting from long duration of therapeutic intervention. Control groups will provide valuable biological material to identify alternative mechanisms of treatment resistance (MAPK signalling). The statistical power in the relatively large cohort analysed enhances our confidence in considering the EMT landscape as an attractive platform for prediction of therapeutic response in future clinical trials. The concern, however, of whether improved prediction of biochemical recurrence by EMT profiling in pretreatment biopsies justifies its integration in the clinicopathological parameters (Gleason score, PSA) remains. Thus high expectations and much promise surround the pathological exploitation of EMT biomarkers (as signatures) in identifying profiles of tumour aggressiveness and providing a significant contribution in our quest towards the development of personalized therapies in prostate cancer patients with advanced disease.

References
1 Matuszak E, Kyprianou N. Androgen regulation of epithelial–mesenchymal transition in prostate tumorigenesis. Expert Rev Endo Metab 2011; 6: 469–82
2 Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial–mesenchymal transition in development and disease. Cell 2009; 139: 871–90
3 Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 2009; 9: 265–73
4 Kalluri R, Weinberg R. The basics of epithelial–mesenchymal transition. J Clin Invest 2009; 119: 1420–8
5 Tanaka H, Kono E, Tran CP et al. Monoclonal antibody targeting of N-cadherin inhibits prostate cancer growth, metastasis and castration resistance. Nat Med 2010; 16: 1414–20

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Editorial: Stent removal need not be painful

Matthew Bultitude

Matthew Bultitude
Urology Centre, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

Ureteric stents are undoubtedly a significant cause of morbidity while in situ [1].Whilst there are different options for removal, they are usually removed under local anaesthetic with the aid of a flexible cystoscope. This is an uncomfortable procedure and a proportion of patients seem to get fairly severe pain afterwards, which may be attributable to ureteric spasm. The pain after stent removal has not been well reported in the literature. In this issue of the BJUI we present a randomised controlled trial of a non-steroidal anti-inflammatory (NSAID) to dramatically reduce pain after stent removal.

This beautifully simple study by Tadros et al. [2] had simple aims: to determine the incidence of pain after stent removal and whether this could be reduced using a single oral dose of a NSAID given before the procedure. In a prospective randomised double-blind placebo controlled trial, the authors have shown a clear advantage to the use of active medication over placebo, such that the trial was stopped after an interim analysis. Using a visual analogue scale (VAS) the mean pain after stent removal was 2.7 in the NSAID group compared with 5.5 with placebo.More impressively the proportion of patients with severe pain (as defined as aVAS >=7) within 24 hours of stent removal was 0% vs. 55%. A corresponding reduction in narcotic use was seen (1.67 mg vs. 4.77 mg).

With increasing healthcare pressures on emergency departments and beds, and in the UK with financial penalties for re-admissions, this simple intervention has the potential to improve our own patients pain ratings and satisfaction and also reduce emergency consultations and even re-admissions. It should be noted that in this trial, there were two visits to the emergency department and one re-admission, all in the placebo group.

NSAIDs are thought to work through a number of mechanisms such as direct effect on pain pathways, reduced ureteric contractility and renal blood flow. This is thought to be a class effect for all NSAIDs. The drug used in this trial (rofecoxib) has subsequently been withdrawn from the market, although one would expect similar outcomes with other NSAID medications.

References
1 Joshi HB, Stainthorpe A, MacDonagh RP et al. Indwelling ureteral stents: evaluation of symptoms, quality of life and utility. J Urol 2003; 169: 1065–9
2 Tadros NN, Bland L, Legg E et al. A single dose of a non-steroidal anti-inflammatory drug (NSAID) prevents severe pain after ureteric stent removal: a prospective, randomised, double-blind, placebo-controlled trial. BJU Int 2013; 111: 116–20

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Editorial: Is botulinum toxin not the solution to OAB after all?

Dirk De Ridder
Department of Urology, University Hospital Leuven, Belgium

The article by Mohee et al. highlights a problem that is often neglected: the outomes we see in clinical trials do not predict the success of the therapy in real life. We know this from anticholinergics: the study results are good, but the performance in real life is much poorer. Only 20-40% will continue to take the medication.

For botulinum toxin in OAB it is surprising to see that even in experienced hands only 38.7% of patients continued with the treatment at 36 months. The reasons to abandon the treatment were retention, the need for CISC and urinary tract infections. Moreover, 8.6% of the patients had no response at all after the initial injection.

Of course infections could have been avoided by using prophylactic antibiotics, but the other issues remain. How to explain the primary failures? How to manage the risk of CISC?

Given the fact that most patients abandoned the treatment within the first 3 years, more research would be needed on how to increase the treatment adherence of the patients after the initial injection.

This challenging article also stresses the fact that in a time where only RCTs stand a good chance of being published in journals, good retrospective cohort studies can be extremely important too.

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Editorial: What have we learned from the Partin table update?

The controversies surrounding a physician’s best treatment strategy advice to an individual patient with clinically localized prostate cancer create a continuing need for advanced statistics. Historically, the Partin tables [1] were one of the first statistical tools that physicians and patients found readily usable. The tables have been updated and always focused on prediction of pathologic stage from standard clinical variables. The next commonly cited/used tool was the Kattan nomogram [2] that carried the prediction the next step to the endpoint of biochemical relapse. By 2008, Shariat et al catalogued over 100 predictive tools published from 1966 to 2007 on various endpoints of prostate cancer [3].

 

 

 

What have we learned from this update of the Partin tables?

  1. The pre-operative grade distribution has shifted up slightly with no change in prostatectomy grade/stage distribution. The authors discuss possible causes such as changes in interpreting the Gleason scoring system, shifts in selection for surgery away from lower grade patients, and a possible plateau in stage migration.
  2. The tables have split off Gleason 3+4, 4+3, 8, and 9–10, and found the latter significantly more aggressive, while Gleason 4+3 and 4+4 are more similar. Gleason 9–10 must have a pattern 5 component >5% and may therefore have more aggressive biology. On the other hand, two cases of prostate cancer may have identical volumes of 4 pattern, but if one adds additional 3 pattern, that additional tumour foci paradoxically lowers the sum to 7, but perhaps not the risk of non-organ confined stage.
  3. In the past, the tables were commonly used to predict pT3 stage, with possible change in management away from surgery as that risk increased. Clearly the literature on surgery for higher risk disease has matured, and augmented by the adjuvant/salvage radiation literature such that it is less likely to use the tables for this reason any more. On the other hand, prediction of N1 disease for the purpose of omitting a lymph node dissection remains a useful tool. In this update, using a <2% cut-off you would essentially omit all node dissections in Gleason 6 with PSA < 10 and cT1c/cT2a, while continuing with a dissection for any dominant Gleason 4 pattern. It is noteworthy that this experience was largely based upon standard templates, and those advocating extended templates will find these N1 rates too low. Indeed, when our center adopted the extended template using a robotic technique, the N1 rate for high-risk disease was 39% and 9% for intermediate risk [4]. Moving forward, what tools do we need to provide useful statistics to our patients? Updating old tools with more contemporary patient cohorts is certainly a worthy exercise. Multicentre study based tools will be required for endpoints such as positive surgical margins, quality of life, biochemical recurrence, and other endpoints that may be significantly affected by the experience of the treating physician. Beyond this, the next step should be adaptive nomograms that update in real time rather than en masse every 4–5 years [5].

John W. Davis
Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

References
1 Eifler JB, Feng Z, Lin BM et al. An updated prostate cancer staging nomogram (Partin tables) based on cases from 2006 to 2011. BJU Int 2013; 111: 26–33
2 Kattan MW, Eastham JA, Stapleton AM et al. A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst 1998; 90: 766–71
3 Shariat SF, Karakiewicz PI, Roehborn CG, Kattan MW. An updated catalog of prostate cancer predictive tools. Cancer 2008; 113: 3075–99
4 Davis JW, Shah JB, Achim M. Robot-assisted extended pelvic lymph node dissection (PLND) at the time of radical prostatectomy (RP): a video-based illustration of technique, results, and unmet patient selection needs. BJUI 2011; 108: 993–8
5 Vickers AJ, Fearn P, Scardino PT et al. Why can’t nomograms be more like Neflix? Urology 2010; 75: 511–3

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