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Editorial: Fesoterodine is superior to extended-release tolterodine for OAB

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The treatment of overactive bladder (OAB) is still based on antimuscarinics, although the recent introduction of β3 agonists and botulinum toxin A has opened a window of new opportunities, the range of which is yet to be defined.

The clinical development of fesoterodine has taken the Urological community by surprise and raised levels of expectation. From a pharmacological standpoint fesoterodine is just a ‘smart drug’ because it is the pro-drug of 5-hydroxymethyl tolterodine (5-HMT) the active metabolite of tolterodine that is metabolised into 5-HMT by cytochrome P450 (CYP) enzymes, the activity of which is known to suffer significant genetic variability. Fesoterodine is transformed into 5-HMT by nonspecific esterase pathways. Pharmacokinetic studies of fesoterodine have shown highly predictable plasma levels of the 5-HMT after fesoterodine administration. Whether or not the better bioavailability offered by the esterase-related activation pathway translates into a larger clinic benefit for our patients with OAB was initially unclear. A phase II study showed a good safety profile and suggested that two different doses of fesoterodine could be proposed with a good balance between efficacy and adverse events. Results of the pivotal phase III study confirmed how the two different doses: 4 and 8 mg, tended to separate with a larger benefit observed with the larger dose, although a slightly larger incidence of adverse events was observed. As long as the comparison between 4 and 8 mg of fesoterodine was not part of the pre-planned analysis, the results of thepost hoc analysis had to be confirmed in a properly design prospective randomised trial.

The assumption that a higher drug dose brings a larger therapeutic effect is very often just wishful thinking and clinical pharmacology has often disproved such a belief. What is instead clear, from the paper of David Ginsberg et al., which pools data from two randomised trials (BJU Int 2010, BJU Int 2011), is that the flexible dosage available with fesoterodine brings a clinically relevant advantage in our daily practice.

The question is whether there is a real need for dose flexibility in the management of OAB. After a couple of decades in this area, I strongly believe that flexible dosing is crucial, in general, and even more so in functional urology. This is in fact an area where storage and voiding function needs to be rebalanced; a too weak or too strong effect may easily lead to a therapeutic failure. Reaching the right balance between therapeutic effect and adverse events is crucial while using antimuscarinics. If 40% of patients who withdraw from anticholinergic medications do so because of insufficient benefit, another large proportion (22%) discontinues treatment because of side-effects.

The question in real-life practice, provided treatment should be initiated with a 4 mg dose because of regulatory issues, is whether the dose should be upgraded and when, should this be left to the individual patient’s decision or should it be guided by the treating physician? There is no ‘golden’ rule and in my opinion is a matter of patient expectations. Most patients expect drugs to cure the conditions they are prescribed for, although we know this is rarely the case. When patients are properly informed about the effect of antimuscarinics treatment they will often choose their goal, some patients will look for reducing OAB symptoms while avoiding dry mouth and constipation as much as possible, others will want to become dry and accept higher levels of adverse events. Furthermore, because of body distribution, different doses of drugs may be required in a 45 kg lady and in a 90 kg man, although this may depend on the drug bioavailability at the target organ. The same applies to patients with normal detrusor contractility and patients with a weak bladder, such as patients with multiple sclerosis. The ‘one dose fits all’ approach does not seem to be the way to go.

The larger therapeutic effect achieved in the 8 mg fesoterodine group is obtained at the expense of almost doubling the incidence of dry mouth (from 15% to 28%), although the increase in the constipation rate is just 1%. Whether or not the observed differential improvement between tolterodine 4 mg and fesoterodine 8 mg is clinically relevant is matter for discussion for the investigators but looking at the parallel improvement in all patients reported outcomes, the difference seems to be of importance from the patient perspective.

The therapeutic area of storage disorders, e.g. OAB, is experiencing a number of paradigm changes, including the availability of flexible dosing of antimuscarinics, β3 agonists and botulinum toxin A. What once used to be a neglected area of functional urology is now an exciting area of basic and clinical research.

Andrea Tubaro and Cosimo De Nunzio*
Urology Unit, Department of Clinical and Molecular Medicine, Faculty of Health Sciences, Sapienza University, and *Urology Unit, Sant’Andrea Hospital, Rome, Italy

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Editorial: Accepting the positive results of unconventional methods

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It is sometimes difficult to accept the results of a study based on a concept that is unfamiliar, involves unknown physiological mechanisms, or shows results that defy rational explanation. Remote ischaemic preconditioning (RIPC) is probably not a familiar topic to most urologists and, admittedly, was not familiar to this reviewer until now. Yet the authors, based on animal models and clinical data from non-urological literature, conducted a prospective, surgeon and patient ‘blinded’, randomised controlled trial to evaluate the potential benefit of RIPC in minimising ischaemic damage. By most available factors affecting postoperative renal function (warm ischaemia time, tumour complexity as measured by Preoperative Aspects and Dimensions Used for an Anatomical [PADUA] scores, preoperative renal function, tumour stage, etc.), no difference existed between the control and study groups. The authors found that patients undergoing RIPC had a lower change in estimated GFR (eGFR) at 1 month and appeared to have less ischaemic damage based on urinary marker levels (retinol binding protein) and functional imaging parameters. Unfortunately, the short-term benefit of RIPC did not translate to improvements over a longer period, with no differences at 6 months or in absolute eGFR between the two groups.

The authors should be congratulated for conducting such an elegant trial, unfamiliar and unconventional as the concept may be. Strengths of this study include its randomised ‘blinded’ design, correlation with metabolite, urinary marker and imaging findings, 6-month follow-up, and due diligence for assessing most pre-analytic factors. Limitations include the absence of data on residual functioning renal parenchyma, which arguably is the single best predictor of function in an operated kidney; additionally, this population with outstandingly good renal function (≈120 mL/min/1.73 m2 in both groups) with very few comorbidities (<5–10% incidence of hypertension and diabetes) may not translate equally to the less healthy, more renally impaired Western population. The results may appear to be underwhelming, but I agree with the authors that further study is needed, and in particular for the Western population. The major impact from this reviewer’s perspective is for the patient with baseline renal compromise, whose risk for short- and long-term ischaemic renal injury is greater, and who could most benefit from a simple protective measure. Should we now enter unfamiliar territory and accept that the results of a randomised, ‘blinded’, prospective trial of a simple but unconventional method provide sufficient justification for testing this strategy in a higher risk population?

Surena F. Matin
Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Editorial: Equivalent outcomes for monopolar and bipolar TURP; but are we overlooking the potential for improvement in sexual function after surgery?

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Both BPH and sexual function (SF) have a major impact on quality of life in older men. Sexual dysfunction is a complex process encompassing both erectile and ejaculatory dysfunction, as well as reduced libido and difficulty achieving orgasm. Whilst retrograde ejaculation is an almost inevitable consequence of TURP, the evidence that TURP causes erectile dysfunction is conflicting. This is probably attributable, at least in part, to a lack of high-quality historical data. Studies now show that LUTS is a risk factor for sexual dysfunction, and we are becoming increasingly aware of the relationship that exists between LUTS, depression and sexual dysfunction.

Given the favourable safety profile of bipolar TURP (b-TURP), it is perhaps a surprise that this latest study from Mamoukalis et al. has failed to demonstrate any difference in outcomes with regard to the deterioration in SF after surgery. The authors should be praised for their attempts to examine in fine detail (using the International Index of Erectile Function [IIEF]-15 in this case) any potential differences between b-TURP and monopolar TURP (m-TURP).

The design of the bipolar system is such that tissue is removed at a lower temperature and therefore the likelihood of damage to surrounding tissues and nerves is reduced. Several randomized trials have compared b-TURP with m-TURP, but only a small number have looked specifically at sexual variables in a randomized setting. This multicentre study by Mamoukalis et al. randomized 279 men to one of the two resection techniques, looking specifically at overall SF quantified by the IIEF-15. No differences were detected in any aspect of SF; erectile function (EF) improved in 26.4% of patients in the m-TURP group compared with 19.6% in the b-TURP group, and remained stable in 60.9 and 60.8% of patients, respectively. A deterioration in EF was apparent in 12.7% of the m-TURP group compared with 19.6% of the b-TURP group (P = 0.323). These results mirror those of a similar randomized study by Akman et al. comparing a quasi-bipolar system with m-TURP. They demonstrated equivalence for all measured variables except for operating time and a 1.4% incidence of TUR syndrome in the m-TURP group. In their study, the EF domain of the IIEF-15 was measured before and after surgery. EF worsened in 17% of men, improved in 28.2% and was unchanged in 54.8%. A comparative evaluation of EF was performed in a sub-group of 188 sexually active non-catheterized men of whom 18.2% developed de novo erectile dysfunction.

The explanation for the equivalent outcomes is unclear and further investigation is required. Does the failure of bipolar TURP to demonstrate a benefit with regard to SF leave the door open for the competing minimally invasive laser technologies? The overall impact of the holmium laser compared with that of TURP appears to be equivalent, with a mean of 7.5 and 7.7% of patients reporting decreased erectile function, and 7.1 and 6.2% of patients reporting increased function after each surgery. From the data available thus far, it would also appear that photoselective vaporization of the prostate similarly has no overall deleterious impact on SF when compared with TURP in a randomized trial. Further randomized data are pending and are of course of great importance if we are to understand better how the procedures we perform for symptomatic BPH affect our patients. As technological advances are made the hope is that the ‘damaging’ effects of BPH surgery on overall SF (particularly EF) will reduce further, but it may indeed be that we are searching for small margins when our attention might be better focused on maximizing the likelihood of a positive outcome, facilitated by considering the preoperative status (general health as well as urinary and sexual function), aided by the use of validated questionnaires. A better appreciation and understanding of the factors that may increase the risk of ED after surgery (age, diabetes, metabolic syndrome, obesity, cardiovascular disease and psychological factors) will enable us to manage expectations more effectively. A shorter hospital stay with minimal postoperative discomfort and an early return to normal activities, coupled with good symptomatic improvement in the longer term can only serve to be of benefit with regard to improving SF outcomes.

One recent study reporting both the short-, medium- and long-term effects of TURP on SF highlighted the high incidence of LUTS before treatment with 57% overall reporting ED before surgery. Those with severe LUTS were much more likely to have significant sexual dysfunction before surgery. This study also demonstrated a 15% improvement in pre-existing ED which was related to the improvement in LUTS after TURP.

On reflection, therefore, it would seem reasonable to conclude from the evidence presented that, although retrograde ejaculation frequently occurs after outflow surgery, erectile function is as likely to improve as it is to deteriorate. By focusing on the specific patient characteristics for each individual case before surgery it is possible we can improve the proportion of patients achieving a favourable outcome. When counselling patients before surgery regarding SF we should therefore remember to include the potential benefits as well as the risks. Furthermore, for those patients particularly anxious about the possibility of worsening SF, a ‘lesser’ surgical procedure, which might not achieve a transurethral resection-like cavity should perhaps be considered as a compromise. However, a surgical alternative which is not equivalent to TURP may indeed reduce the likelihood of improving erectile function, given the interrelationship that appears to exist between LUTS and SF.

Richard Hindley
Department of Urology, Hampshire Hospitals NHS Foundation Trust, Basingstoke, Hampshire, UK.

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Editorial: Impact of ERSPC study on PSA testing in the Netherlands

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General practitioner (GP)’s view on screening for prostate cancer in the Netherlands: the impact of a randomized trial

I am grateful to be given the opportunity to provide an editorial comment on a so-far unique publication investigating the impact of results of the European Randomized study of Screening for Prostate Cancer (ERSPC) on the attitude of Dutch GPs in requesting a serum determination of PSA in men aged >40 years. Access to data from one of the major health insurance companies and the structure and data acquisition of regional laboratories in the Netherlands provided an opportunity to carry out the project. This included the differentiation of age groups, of primary as opposed to repeat PSA testing and, in the case of the hospital database, of repeat PSA testing within 1 year, which provided the opportunity to address the primary goal of the study: the evaluation of the difference in primary PSA testing rates as well as follow-up testing before and after the 2009 publication of interim data from the ERSPC study. The fact that a Dutch translation of this publication and a recommendation by the Dutch Association of General Practitioners (Nederlands Huisartsen Genootschap, NHG) were mailed at the same time and the fact that GP guidelines had not been changed since 2005 in the Netherlands provided an important basis for the reported study.

Two different databases were used and PSA testing was evaluated 1 year before and 1 year after March 2009 (excluding the month March 2009). An overview of the data acquisition and results is given in Table 1. In brief, the data based on insurance claims show a significant decrease in PSA use before and after the 2009 publication. This decrease was less pronounced or not seen at all in men aged 70–80 or >80 years. The study selectively identified men in the ERSPC region of Rotterdam after exclusion of those assigned for re-testing in the screening arm. In line with earlier investigations, the PSA testing rate in the Rotterdam region was considerably higher then in the rest of the Netherlands. This effect was blamed on increased awareness and possibly on the motivation of men randomized into the control group of the study. The so-called ‘hospital database’ refers to a regional GP laboratory. It remains unexplained why only 2098 men of the total of 9766 men who were identified as having undergone primary PSA testing (Tables 1 and 2 in the study) were included in the analysis. These data show that there was no overall difference in testing before and after the ERSPC publication, but the proportion of re-testing decreased significantly between the two periods.

Table 1: Data acquisition and results.

Several comments can be made on this study. First, information provided on the insurance claims database allows an estimate of the proportion of men in whom PSA is evaluated (123 996/715 000 = 17.3%) and of those who undergo primary PSA testing for early diagnostic purposes (66 848/715 000 = 9.4%). The overall figure contrasts sharply with the results of a study by the Central Bureau of Statistics in the Netherlands, published in 2006. The study shows PSA use of 30–40% for the age groups 60–70 years or older.

Second, as the authors acknowledge, the differentiation between primary PSA tests for the purpose of early diagnosis and for other purposes may not be entirely reliable; however, the bias resulting from possibly incorrect assumptions is likely to be small.

Third, the sub-analysis of data coming from the Rotterdam region is likely to show the impact of greater awareness resulting from written informed consent before randomization and the effect of randomization into a control group. The data confirm an earlier evaluation of this subject (reference 7 in Van der Meer et al.) and at the same time provide a rough estimate of the level of contamination which may take place in the ERSPC study, Rotterdam region.

Fourth, it is interesting to see how age and previous PSA values influence the request for repeat PSA studies. It is counterintuitive (Table 3 in Van der Meer et al.) that even in the critical PSA range 4–10 ng/mL a significant decrease of PSA use within 1 year was seen. The multivariate analysis shows that study period before and after 2009, PSA categories and age groups are all significantly related to the decrease of PSA re-testing within 1 year.

Finally, as one of the initiators of the ERSPC study, I should like to refer to two important follow-up publications (Schröder et al., Heijnsdijk et al.) that point to the over-diagnosis and over-treatment of prostate cancer as the main reasons why the almost 30% reduction in prostate cancer mortality in screened men cannot (yet) be used for establishing population-based screening. For these reasons, the authors fully agree with the viewpoint of the Dutch GP Association and the recommendation against routine use of PSA-driven screening for prostate cancer; however, as pointed out in the last sentences of their paper instruments are now available to decrease over-diagnosis and the rate of unnecessary biopsies. In addition to that, it should be realized that men who are well informed and wish to be tested for prostate cancer cannot be refused PSA testing. To assist this process, the International Society of Urology (SIU) and the international movement ‘Movember’ have recently made available on their websites a validated decision aid for men who wish to be tested, their GPs and their treating urologists.

Fritz H. Schröder
Erasmus Medical Center, Rotterdam, The Netherlands.

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Editorial: Botulinum toxin-A for overactive bladder: formulations, dosing and clean intermittent catheterisation

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The article by Ravindra et al., in this issue of the BJUI, tries to address an important question of comparing the 2 commonest types of botulinum toxin-A (BTX-A), Ona- and AbobotulinumtoxinA. In their institution they changed from OnbotulinumtoxinA to AbobotulinumtoxinA and thus compared results of their different case series for patients with overactive bladder syndrome. Very few studies have tried to address this issue for botulinum toxin-A use in the urinary tract and to my knowledge there are no head to head studies. The authors found the 2 types of BTX-A equivalent in terms of voiding diary parameters, ICIQ questionnaires, patient reported global satisfaction and duration of effect but noted a significant difference for clean intermittent self catheterisation (CISC) rates (23% OnabotulinutoxinA vs 42% AbobotulinumtoxinA). The dose used for OnabotuliumtoxinA was 200 IU and for AbobotulinumtoxinA was 500 IU initially and then later 300 IU. One must bear in mind some important considerations which limit the impact of the result. Namely the non-randomised, retrospective nature of the study and the fact that the study was not designed or powered to assess the BTX-A formulations in this way. The primary endpoint in this case was a patient reported satisfaction measure indicating that 85% had ‘better’ or ‘much better’ symptoms which I think is a fair reflection in my experience. Furthermore there were significant gaps in data acquisition particularly for voiding diary, PVR and ICIQ data which again is not that uncommon in retrospective studies. No urodynamic data was included which I think may also have been interesting to look at when assessing outcomes and CISC rates.

None the less the study generates some interesting discussion about the formulations, optimal dosing and the dosing equivalence. The study is one of the first to report on the use of AbobotulinumtoxinA at 300 IU as most studies utilised 500 IU. In view of the move to lower doses of OnabotulinumtoxinA to treat refractory OAB of 100–150 IU, this dose seems appropriate. Evidence from a large dose ranging RCT using OnabotulinumtoxinA suggests no further efficacy beyond doses of 150 IU but an increase in voiding dysfunction. Interestingly CISC rates are still high at 300 IU in this study. A recent systematic review tried to assess the 2 formulations in aspects of BTX-A use for various lower urinary tract dysfunction. Due to the heterogenousity of the studies, a lack of standardised or high quality data a direct comparison between the 2 was not formally possible. It was noted that OnabotulinumtoxinA has been studied more extensively compared to AbobotulinumtoxinA and with both formulations CISC rates could be high at the doses used in this study (OnabotulinumtoxinA 43%; AbobotulinumtoxinA 35%). Assessing the compound muscle action potential of the extensor digitorum brevis muscle in healthy volunteers has suggested an AbobotulinumtoxinA to OnabotulinumtoxinA ratio of 1.57:1 (95% confidence interval: 0.77–3.20 units) with the data indicating that a dose-equivalence ratio of 3:1 was just within statistical error limits but ratios over 3:1 were too high. The same author following a review of the literature in treatments outside the urinary tract suggest a ratio of 2–2.5:1 maybe the most appropriate. An animal model of spinal cord injury and neurogenic detrusor overactivity to compare the 2 formulations has recently been published. The minimal effective dose of Abo- and OnabotulinumtoxinA was found to be 10 IU and 7.5 IU, respectively, for significant changes in cystometry.

When should CISC be instigated? Practice seems to vary considerably and thus results difficult to compare. Many clinicians will base CISC decisions on a cut off, typically 100–200 mL or on whether patients are symptomatic with their PVR. Chapple has suggested >40% of the functional capacity as a significant PVR and this to me seems entirely logical. Future studies should consider this as an endpoint regarding CISC.

At present, the decision as to which formulation is used in clinical practice is often based on local pharmacy regulation and financial considerations. Licensing is undoubtedly going to have a significant influence on this practice. OnabotulinumtoxinA is now licensed for use in many parts of the world to treat neurogenic detrsuor overactivity and has recently been approved by the FDA in the USA to treat refractory OAB. At the time of writing this editorial, no formulation is currently approved for refractory OAB in the UK.

Arun Sahai
Consultant Urologist & Honorary Senior Lecturer, Department of Urology, Guy’s Hospital MRC Centre for Transplantation, King’s College London, King’s Health Partners

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Why I care about social media – and why you should too

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I was born in the ‘Eighties’. I was a teenager when the Internet first became accessible to the general public and a medical student when Facebook was launched in 2004. It seems improbable and surreal that my time spent ‘liking’ and ‘poking’ Facebook posts from college acquaintances would someday be of any use to my career and research. Indeed, ‘I was there’ at the very beginnings of social media, but I had little idea of what it would become.

The social media revolution started in the early millennium, with the emergence of blogs: microsites consisting of topical entries usually displayed in reverse chronological order. Blogs, such as Deadspin or Gizmodo, became pillars of the new era, breaking news at an unprecedented pace and gaining millions of page views by the second. Meanwhile, the print media were slow to adopt a digital strategy, often branding the aforementioned websites as ‘hacks’ or ‘teenagers with a lack of journalistic integrity’. Almost simultaneously, a website called Wikipedia was launched on 15 January 2001 by Jimmy Wales and Larry Sanger, a ‘social’ alternative to bulky reference books, such as the Encyclopaedia Britannica. Fleetingly, Wikipedia rose to fame and grew at an exponential rate, drawing along a significant chunk of web traffic. It caught idlers with such haste that some felt the need to ban the website from classrooms. Oh my, have things changed. In September 2010, Arthur Sulzberger Jr, Chairman and publisher of The New York Times, announced that the prestigious journal would cease to exist in print, sometime in the not-so-far future. In related news, the Chicago-based company behind the Britannica announced that it would stop printing the revered reference encyclopaedia after >200 years in press.

The adoption of new technology in any and every field follows a simple bell curve, as described in a sociological model by Joe Bohlen et al. at Iowa State University. The hypothesis indicates that the first group of individuals to use a new product is called ‘innovators’, followed by ‘early adopters’. The early and late majorities follow these, and the last group to ultimately adopt a product is called ‘laggards’. ‘Medicine’ as a collective crowd is usually the laggard. On one hand, it is reasonable and understandable that a field with such enormous responsibilities be as meticulous and practical in the process of adopting new drugs, technologies or paradigms. It is entirely within the realm of comprehension that a new drug must succeed at many stages of testing to show unequivocal safety and efficacy before being accepted into medical practice. Yet, on the other hand, most would safely agree that institution, tradition and dogma dominate the world of medicine, and most notoriously in surgical sub-specialties. Not unlike our most recent history in adopting robotic surgery, met initially with ferocious and apocalyptic discontent, many contemporary leaders in our field display excessive scepticism towards social media, even when its dissemination is widespread through all echelons of society. In an era where wars and revolutions are being fought over Twitter, and where the likelihood of experiencing an influenza pandemic can be accurately predicted based on relevant social media buzz, I am not sure what doctors are waiting for to accept social media for what it is – an inevitable revolution in how we communicate.

As many of you ponder whether or not to embrace social media, there is good evidence that medicine has finally absorbed the latest innovation. I could cite many factual titbits to demonstrate that this is in fact true. I could provide propensity-matched-instrumental-variable-adjusted analyses to show its benefits. Yet, wise men once said that stories, not statistics, drive change: here are some stories of how social media has already transformed our field.

The ‘uro-twitterverse’ is now a rich and engaging planet of its own. Since November 2012, >100, I am not making the numbers up, users engage in a monthly Urology journal club on Twitter, enhanced by the presence of the lead investigator of the study open for discussion. Even the most prestigious of first-tier Ivy League institutions would not be able to attract lead authors to attend every single journal club, even less to convince a pool of key opinion leaders from around the world to comment and critique these studies.

Every day, I know that I can turn to my fellow ‘Twitterati’ to ask a hard clinical question. Should I perform a lymph node dissection in this patient with prostate cancer? What is the value of positron-emission tomography-CT to assess recurrence in a patient with bladder cancer? What is the recommended evaluation for a patient with suspected interstitial cystitis? Across 24 standard time zones, I know that an answer is a couple of seconds away. Somewhere in the world, a knowledgeable authority is answering my tweet, either while reading the morning news at breakfast, between two major cases in the operating theatre, or checking the Internet right before going to sleep. Having Twitter on my smartphone is a click away from being at a grand rounds talk, with everyone – from Benjamin Davies to Stacy Loeb – in attendance.

Every year, physicians travel thousands of miles to attend medical conferences. Many academics converge at these meetings with the hope of building relationships with potential collaborators. Twitter has brought the academic world under a single digital roof. Most of my research collaborators are on Twitter. I exchange direct messages with them every day to discuss research, grant and collaborative opportunities. I met several of my peers and collaborators on Twitter before actually gathering in person. In fact, many have questioned the need for so-called ‘formal’ medical conferences in the new digital era. While I am not ready to cancel my annual trip to the AUA and the European Association of Urology meetings – especially when they are being held at exotic destinations, such as San Diego and Milan, these social phenomena suggest that change is inevitable.

As much as we like the world we are accustomed to living in, there is little doubt that scientific journals, professional societies, and medical institutions need to adapt to this growing revolution. And, as regrettably experienced by traditional portals, e.g. the print media, those who do not will struggle to remain relevant. Of course, there are caveats to social media. How do we set boundaries between patient care and personal endeavours? Regardless of these issues, society has dreamt forever of the open and free opportunities provided by social media. The world cannot wait.

At BJUI, we are using social media, especially Twitter and Facebook, to highlight the most important international studies published in the journal, e.g. July’s ‘Article of the Month’ from Taiwan comparing tract creation using plasma vaporization with balloon dilatation in percutaneous nephrolithotomy.

Quoc-Dien Trinh
BJUI Associate Editor Health Services Research,
Department of Surgery and Center for Surgery and Public Health, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

 

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Editorial: PCNL tract creation: think plasma vaporization

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Surgical planning and access are important factors for successful stone-free outcomes in patients undergoing percutaneous nephrolithotomy (PCNL); however, PCNL has a high risk of haemorrhagic complications (reported transfusion rates of up to 12%), which curtail surgery and result in suboptimum outcomes. Access to the pelvicalyceal system remains the major risk for bleeding, often associated with an off-set tract, splitting of the infundibulum/pelvis and/or angulated sheath, and requiring inordinate torque. The ideal tract dilatation method is still being debated, with differing reports on operating time and blood loss (Urol Int 2003, BJU Int 2005, J Endourol 2008, J Endourol 2011).

The present study evaluates a new method for percutaneous renal access, reporting a shorter operating time, a lower drop in haemoglobin levels and a shorter hospital stay, with no patient requiring transfusion. A patient selection bias might exist, which would explain the low complication rate. Also, the vaporization bubbles and the bleeding could result in difficult views, requiring a high level of expertise in plasma vaporization. The authors did not observe peri-nephric space fluid extravasation or dislodging of the single safety wire. Despite the promising outcome, the reproducibility of this technique remains to be seen, but this is a promising account of reducing bleeding and operating times and maintaining better visualization in PCNL.

Joe Philip
Department of Urology, Southmead Hospital, Westbury-on Trym, and University of Bristol, Bristol, UK

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Editorial: Laparoscopic and robotic approach to staging nodes in penile cancer

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In recent years, efforts to reduce morbidity from lymphadenectomy for penile cancer were based on surgical procedures to reduce the area of lymph node dissection. The proposition of extensive video-endoscopic inguinal lymphadenectomy, a technique still experimental, is to reduce the morbidity of conventional surgery without affecting the maximum chance of oncological control of locoregional disease. Therefore the initiative of using the help of a robot to facilitate the implementation of this procedure is very welcome.

The authors present an excellent study on their initial experience with robotic assisted video-endoscopic inguinal lymphadenectomy (RAVEIL). I understand that for better comparison of the dissection area with open surgery these authors have opted to use an additional incision in the inguinal fold. However this area is the least vascularized area of the field of dissection because the lymph nodes are resected above and below this additional incision. It would be better to make an incision at the upper limit of the dissection. This approach was used in open surgery with low complication rates. The rate of necrosis (10%) and wound breakdown (10%) seems high for a minimally invasive approach. Possibly, when no additional incision is used to complement the procedure these rates will become lower.

Antonio A. Ornellas
Hospital Mario Kröeff, RJ, Brazil, and Department of Urology, Brazilian National Cancer Institute, RJ, Brazil

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Editorial: A step toward simplicity

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Although effective, current treatments of stress urinary incontinence (SUI) can be viewed as palliatives, as they do not regenerate the normal function of the urethral sphincter. Cell therapy pretends to do so.

Mesenchymal-derived stem cells, isolated from bone marrow, striated muscle or fat have been investigated. Transurethral injection of striated muscle-derived stem cells (MDSCs) has been the most studied technique in human. Although results were encouraging, the need for pre-implantation cell expansion to provide a sufficient amount of cells has two major drawbacks. First, the need for a complex long and expensive process of cell biology to treat a patient precludes diffusion of such a technique. Secondly, cell culture and manipulation are known to affect survival and myogenic potential of MDSCs.

After they first demonstrated in pigs, that an autologous graft of a striated muscle piece around the urethra resulted in degeneration of mature myocytes and an activation of satellite cells, which differentiated in well-oriented myotubes with synapses and contractility, for the first time, Yiou et al. report in BJUI clinical data on striated muscle cells used as a source of stem cells to repair the urethral sphincter without cell expansion in a ‘one-time’ procedure.

The step is remarkable and is a step toward simplicity. It has to be kept in mind that SUI pathophysiology does not only suppose a damaged muscle. Denervation is another mechanism as suggested by the observation of longer activation latency in the urethral sphincter before stress, cough or sneeze in incontinent female patients without neurological disease. Urethral fibrosis is implicated in post-prostatectomy SUI or after urethral complication of a first anti-incontinence procedure.

There is still need for an extensive and subtler understanding of the mechanisms leading to different forms of SUI. Cell therapy will find its specific indications among these different forms of SUI. Combined cell therapy approaches (muscle based, fat based and other) may be the way to regenerate the whole function of the urethral sphincter.

 

Gilles Karsenty*†
*Aix-Marseille University, and †Department of Urology and Kidney Transplantation, La Conception Hospital, Marseille, France

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Editorial: Multiparametric MRI in active surveillance – time to rethink our current strategy?

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Active surveillance for low-risk prostate cancer is gaining increasing acceptance. Indeed, many would argue that it is now the primary management strategy for men who have little to gain from radical therapy but who may incur some harms. However, active surveillance is far from a perfect pathway. First, many men and their physicians find it unacceptable to not treat a known cancer. Second, the burden of follow-up with clinical examinations and serum PSA testing on both men and healthcare systems is far from cost-neutral. Third, the need for repeat transrectal biopsies, which many advocate, carries harms of complications and the difficulties of inaccuracy. Fourth, there is some concern that the window of curability may be lost when men eventually go on to have radical therapy, although overall and disease-specific survival is in fact reassuringly high in the medium term.

Mullins et al. have attempted to address some of these issues by evaluating the role of multi-parametric MRI (mpMRI) in men followed using active surveillance. The results, albeit preliminary, are very encouraging. The ability of mpMRI to exclude clinically significant prostate cancer found on repeat biopsies reflects those results we have seen from other groups (J Urol 2012, BJU Int 2011). Further, they show that the presence of a lesion on mpMRI more often predicts reclassification on repeat biopsy. This has been supported by others who have demonstrated that the inclusion of mpMRI findings into a nomogram was able to predict clinically insignificant prostate cancer better than models without imaging. Mullins et al. have been appropriately guarded about their own results and point out the weaknesses of their cohort in an open manner so readers can judge the external validity of their findings; however, the significance of these results for the urological community cannot be underestimated, particularly as they point us in the direction of important research questions and clinical trials that need to be formulated to give us the answers we need to improve patient care.

There is an increasing body of evidence pointing to TRUS-guided prostate biopsy as being one of the major problems in the current prostate cancer pathway. As a test, it is both inaccurate, unreliable and has harms. It is inaccurate because about one-third of men with low-risk disease have grade or burden reclassification when a better test (template biopsy) is used. It is unreliable because the status of ‘cancer’ and ‘no cancer’ fluctuates from one biopsy to the next. It is harmful not only because it can cause complications (bleeding, sepsis and pain), but also because it detects clinically insignificant disease the treatment of which the man gains little benefit from. So, the problems with active surveillance do not stem from the fact that surveillance per se is flawed, but rather from its heavy reliance on a deeply flawed diagnostic test.

So, what are the key questions for the field of active surveillance that require a coordinated effort to deliver in a timely fashion? First, could the use of mpMRI before biopsy avoid unnecessary diagnosis of clinically insignificant prostate cancer? Second, if low grade and low-volume lesions were found on an accurate biopsy (template mapping and/or MRI-targeted), could we re-designate these lesions as something other than ‘cancer’? Combined, these two changes could in effect, make active surveillance unnecessary. Third, if mpMRI has a predilection for detecting clinically significant lesions, should the presence of a lesion on imaging lead to a man being excluded from active surveillance? Thus, should all men who are considering active surveillance undergo mpMRI and possibly template mapping biopsies? Fourth, can repeat mpMRI, as opposed to repeat transrectal biopsy, detect disease progression in men on active surveillance, and how is progression defined on imaging? Fifth, is the tissue-preserving strategy of focal therapy an alternative for men suitable for active surveillance or an alternative for those men with intermediate- and high-risk disease who stand to benefit from treatment but wish to minimise the harms of treatment?

It is clear that amongst all of these elements of research we will need to embed health economics to ensure that novel strategies are both clinically and cost-effective. Nonetheless, these are exciting times for those of us who work to innovate in clinical practice and research and improve the care of men with localised prostate cancer.

 

Hashim U. Ahmed
MRC Clinician Scientist and Clinical Lecturer in Urology, Division of Surgery and Interventional Science, University College London, London, UK

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