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Transarterial Embolisation of Angiomyolipomas – Not so Cut and Dry

May 29, 2015/by Anthony Noah

The month of May 2015 saw the International Urology Journal Club #urojc Twitter discussion move away from a cancer topic to a benign one. The discussion centred on the recent Journal of Urology paper entitled ‘Transarterial Embolization of Angiomyolipoma – A Systematic Review’. In this paper Murray et al presented a review of 524 cases of transarterial embolization (TAE) for AML in 31 studies (published between 1986 and 2013) with a mean follow up of 39 months.

The authors reported technical success of the procedure in 93.3% of cases with a mean AML size reduction of 3.4cm (38.3%). Post-procedural mortality was reported in 6.9% and unplanned repeat procedures in 20.9%.

The conversation kicked off on Sunday 3rd May at 22:00 (BST) with a flurry of tweets from around the world. Initially there were brief questions about the sample size and clarity of the results in the paper.

A few contributors were not convinced by the overall efficacy of embolisation in the study.

Post-procedure embolisation-related morbidity was reported in 6.9% of patients.

The suggestion of low morbidity moved the conversation away from the paper itself and on to the risks of AMLs if left untreated. The most significant risk of renal AML is bleeding.

There is also the important issue of misdiagnosis

Oesterling et al (1986) published a key paper suggesting that 82% of patients with symptoms had AMLs >4cm. This and other similar papers from the 1980s and 1990s form the basis of treatment protocols for renal AML. The lack of further literary knowledge regarding the natural history of AML became a key sticking point.

Cue the introduction of some more recent literature, suggestive that <2cm AMLs can be ignored (https://www.ncbi.nlm.nih.gov/m/pubmed/24837696/).

This caused further debate about the appropriate screening and management of AMLs. It became apparent that opinions on surveillance vary.

Growth is the important factor. Rate of growth is perhaps more important than actual size in small AMLs.

However there will be data published further supporting this approach to small AMLs.

Are we being overcautious?

Or are we shifting our anxieties to the patient?

There was the inevitable discussion of surgical treatment (partial nephrectomy preferred) instead of embolization. The reasoning for embolization versus surgery was sought out.

Partial nephrectomy allows for definitive treatment of the AML with preservation of renal function and acceptable complication rates.

Embolisation is less invasive without the risks of major surgery and so provides first line treatment for many.

Therefore local complication rates are important to consider, especially when considering nephron-sparing surgery.

CT angiography findings may aide in treatment choice if the vascular supply is amenable to a successful embolisation with minimal non-target embolisation.

Mammalian target of rapamycin (mTOR) is a protein which regulates cell growth, proliferation and survival. Everolimus, an oral mTOR inhibitor, has been shown to reduce the size and growth rate of Tuberous Sclerosis related AML.

As AMLs are benign tumours with significant potential complications, there may be wider variations in management protocols than would be seen with a malignant tumour. Perhaps patient preference, or urologist preference plays much more of a role in individual cases.

As always the debate was interesting and raised a number of key points. Discussion focussed more on overall issues around the management of angiomyolipoma following a brief discussion of the paper itself. The literature is lacking recent high level evidence for treatment of angiomyolipoma. Whilst most follow classical teaching of intervening in symptomatic and larger tumours (>4cm), there is wide variation in the follow up and surveillance of small tumours.

More recent data suggests smaller tumours may not require close follow up. Perhaps rate of growth, much like PSA dynamics in prostate cancer, is more important than the actual size of the tumour. There is also evidence lacking in the direct comparison of embolization versus nephron-sparing surgery for angiomyolipoma.

This draws to a conclusion the summary of the May #urojc summary blog. Please follow @iurojc on Twitter for updates and to get involved on the first Sunday/Monday of each month.

Anthony Noah

Urology Speciality Trainee, West Midlands, UK

Twitter: @antnoah

#AUA15 bursts to life in New Orleans

May 27, 2015/by Aine Goggins

Creole cuisine, bustling Bourbon street, beads and beignets and 16,000 urologists. #AUA15 has just drawn to a close in the birthplace of Jazz; New Orleans, Louisiana #NOLA. With 2,598 abstracts being presented, over 2,500 speakers and representation from more than 100 countries it was undoubtedly an educational and action packed five days.

This was my first AUA and while I knew it was going to be a big conference I was stunned by the size of it all. There were urologists everywhere, so much so that jiving to jazz on Frenchman became a game of ‘spot the urologist’ by the signature urology dance moves and stylish….ish dress code!!!! The scientific programme was so extensive it was difficult to find the time to attend all the sessions I wanted to. However, the committee deserve huge credit for developing the AUA2015 app and Daily news snippets that were available throughout the centre which made it easy to optimise your time at the meeting.

The French Quarter, NOLA

The conference got off to a heated beginning with the Crossfire: Controversies in Urology session sparking plenty of debate. Few topics have ignited as much argument as the question of focal ablation for prostate cancer and the discussion between Mark Emberton MD, UCL, London and Aaron E. Katz, MD,PhD, Winthrop University Hospital was no different. To call it a lively session is an understatement. The question of alpha blockers being sold over the counter for BPH was also discussed during this session. Although the drugs have proven safe over the last 25 years clinicians have concerns that the loss of patient contact as a result of this relabeling would causes a loss of control in the treatment of men with BPH.

Friday drew to a close with the urotwitterati enjoying the social media TweetUp encouraging newbie tweeters to get involved. It clearly worked because #AUA15 set a new record and almost trebled it’s tweeting volume since #AUA13.

Day two, Saturday saw the opening of the Science and Technology hall. A spectacle of testicular, penile devices and stalls I have never seen. I fear what one might have thought had they stumbled into the conference centre by accident!!

The @BJUIJournal #SoMe awards took place on Saturday evening. @DrHWoo deservedly bagged The Social Media Award 2015 for #UROJC. A well chosen venue there were no issues with Wifi for tweeting!!! Read the #SoMe blog for all award details

Enjoying the @BJUIjournal cult #SoMe awards

A personal favourite of mine at the conference was the 4th annual Residents Bowl which took place over three days; with residents engaging in a battle of the brains! Northeastern claimed the trophy in the end and team members on the winning side included this year’s BAUS representative @DerekHennessey.

BAUS, BJUI and USANZ came together on Sunday afternoon for a stellar line-up of speakers and topics. The session was well attended and speakers outlined the most recent data but more importantly shared the experience of techniques and outcomes in their centres and countries. I think this combined society session is a fantastic arena for all to both learn and educate each other on what is working best, where and why? The superb line up included Dan Moon, Jeremy Grummet, Henry Woo, Declan Murphy, David Nicol, Damien Bolton, Stephen Boorjian and Philip D. Stricker who all shared their clinical expertise.
BJUI Guest speaker Ben Challacombe discussed the evidence base for management of RCC by partial nephrectomy. Lower intraoperative complications and WIT were observed at their centre at Guy’s Hospital London, which is similarly reflected by low complication rates in the BAUS mandatory UK national nephrectomy audit. Professor Prokar Dasgupta started his up and down journey for the evidence supporting robotic cystectomy for TCC bladder by reminiscing on where it all began; kite-flying in India as a young boy.

Much anticipated CORAL trial found that 90 day complication rates and oncological control were comparable in ORC v LRC/RARC.

Finally the session closed with the presentation of the Coffey-Krane award to Gopa Iyer; Phase III Study of everolimus in metastatic urothelial cancer collected on Dr Gopa’s behalf by David Quinlan. This award is for trainees who are based in the Americas and judged by a panel as the best publication accepted to the BJUI.

Overall, some of the big points of the conference were the amendments to AUA guidelines including Castration-Resistant Prostate Cancer, which was updated from just last year. Perhaps, the most significant was the first ever draft of AUA Peyronie’s disease guidelines; outlining recommendations from medical therapy to surgery.

The huge rise in social media at urology conferences was demonstrated again by record-breaking figures via @symplur showing that the use of Twitter among the urology community continues to grow:

#AUA15 was both an educational and social experience. I had a blast, learned loads and also got to experience the culinary delights of Muffuletta and Gumbo, take the trolley up St. Charles to the Garden district and simply encounter the warmth and friendliness of both the Louisiana folk and the huge family of Urology. The AUA Scientific Committee deserve a huge congratulations on the success of a stimulating, enjoyable and extensive scientific programme. I know I heard echoes of ‘best AUA yet’ in my company.

Áine Goggins

Medical Student; Queens University Belfast, Ireland

@gogsains

The 3rd BJUI Social Media Awards – #AUA15 in New Orleans

May 27, 2015/by Declan Murphy

What a fun destination we had for the 3^rd Annual BJUI Awards! As you may know, we alternate the occasion of these awards between the annual congresses of the American Urological Association (AUA) and of the European Association of Urology (EAU). Our first awards ceremony took place at the AUA in San Diego in 2013, followed last year in Stockholm at the EAU. This year, we descended on New Orleans, Louisiana to join the 16,000 or so other delegates attending the AUA Annual Meeting and to enjoy all that the “Big Easy” had to offer. What a fun city; a true melting pot of food, music and culture all borne out of the eclectic French, American and African cultures on show. I think I met more key opinion leaders in the clubs on Frenchman Street than I did in some of the prostate cancer poster sessions!

You can read more about all that in our #AUA15 Conference Highlights blog, so on now to the Awards. The AUA Annual Meeting plays host to intense social media activity and it is fitting that the BJUI Social Media Awards gets to acknowledge the rapidly growing number of Uro-Twitterati in attendance. Over 100 of the most prominent tweeters turned up to the Ritz-Carlton to enjoy the hospitality of the BJUI and to hear who would be recognised in the 2015 BJUI Social Media Awards. Individuals and organisations were recognised across 16 categories including the top gong, The BJUI Social Media Award 2015, awarded to an individual, organization or innovation who has made an outstanding contribution to social media in urology in the preceding year. The 2013 Award was won by the outstanding Urology Match portal, followed in 2014 by Dr Stacy Loeb for her outstanding contributions. This year our Awards Committee consisted of members of the BJUI Editorial Board (Declan Murphy, Prokar Dasgupta, Matt Bultitude as well as BJUI Managing Editor Scott Millar whose team in London drive the content across our social platforms).

The full list of awardees, along with some examples of “best practice” in the urology social media sphere can be found on this Prezi. The winners are also listed here:

Most Read Blog@BJUI – “Are you ready to go to prison on a manslaughter charge?”. Accepted by Dr Ben Challacombe, on behalf of Prof Roger Kirby, London, UK
Most Commented Blog@BJUI – “Prof John Fitzpatrick – Life in the Fast Lane”. Accepted by Dr Ben Challacombe, on behalf of Prof Roger Kirby, London, UK
Best Blog Comment – Dr Brian Stork, Michigan, USA
Best BJUI Tube Video – Hospital volume and conditional 90 day post-cystectomy mortality. – accepted by Dr Angie Smith on behalf of Dr Matt Neilsen, North Carolina, USA.
Best Urology Conference for Social Media – SIU Annual Congress, Glasgow 2014. Accepted by Dr Sanjay Kulkarni on behalf of the SIU
Best Social Media Campaign – Dr Ben Davies, Pittsburgh, USA, for highlighting industry issues around BCG shortage
“Did You Really Tweet That” Award – Ben Davies, Pittsburgh, USA (three years running!)
Best Urology App – The Rotterdam Prostate Cancer Risk Calculator. Accepted by Dr Stacy Loeb on behalf of Dr Monique Roobol, ERSPC, Rotterdam, The Netherlands
Innovation Award 2015 – #eauguidelines. Accepted by EAU Guidelines panellists Dr Stacy Loeb and Dr Morgan Roupret, on behalf of Dr James N’Dow, Dr Maria Ribal, and the EAU Guidelines Committee.
#UroJC Award – David Canes, Boston, USA
Best Selfie – Morgan Rouprêt, Paris, France
Best Urology Facebook Site – European Association of Urology. Accepted by Dr Alex Kutikov, Digital Media Editor, European Urology
Best Urology Journal for Social Media – Nature Reviews Urology. Accepted by Editor-in-Chief, Annette Fenner
Best Urology Organisation – American Urological Association. Accepted by Taylor Titus, AUA Communications Office
The BJUI Social Media Award 2015 – International Urology Journal Club #urojc. Accepted by Dr Henry Woo, Sydney, Australia.

Most of the Award winners were present to collect their awards themselves, including the omnipresent Dr Henry Woo who received our top gong for his work on the very successful International Urology Journal Club #urojc. The #urojc now has over 3000 followers and its monthly, asynchronous 48hr global journal club has become a huge event. Many other specialties and #FOAMed resources have recognised #urojc and BJUI are delighted to publish a blog summarising each month’s discussions. Well done to Henry, Mike Leveridge and others in setting and maintaining this outstanding example of social media adding real value.

A special thanks to our outstanding BJUI team at BJUI in London, Scott Millar and Max Cobb, who manage our social media and website activity as well as the day-to-day running of our busy journal.

See you all in Munich for #EAU16 where we will present the 4^th BJUI Social Media Awards ceremony!

Declan Murphy

Associate Editor for Social Media at BJUI. Urologist in Melbourne, Australia

Follow Declan on Twitter @declangmurphy and BJUI @BJUIjournal

Editorial: Patients not p-values

May 27, 2015/by Jonathan Rees

A well powered study can attain statistical significance at a small effect size, but in real-life clinical practice, we do not routinely judge the success or failure of treatment based on the mean result for the hundreds of patients we have treated previously. Nor do we compare the response to treatment with what would have happened if we gave our patient a placebo; instead, clinical effectiveness is determined by the response of the individual patient seated across the desk in our clinic. In an ideal world, therefore, clinical significance, as well as statistical significance, should be built into study design and influence sample size and methodology in much the same way. In this way, we could attempt to assign objectivity to what is essentially a subjective metric: ‘did this treatment work for you?’

It is 25 years since the concept of ‘minimum clinically important difference’ (MCID) was first postulated [1] and almost 20 years since Barry et al. [2] applied this theory to LUTS and the IPSS in particular. MCID represents the smallest change as a result of treatment that is of clinical importance. In a measure such as blood pressure or diabetic control, this is the difference that makes a meaningful impact on complications, but in a quality-of-life field, such as measurement of urinary symptoms where we are predominantly treating the bother caused by the symptoms, the MCID is the smallest change that is noticeable to the patient. Barry et al. showed that a three-point improvement in IPSS is the minimum change required for a patient to notice a slight improvement in symptoms (five points correlating with a moderate improvement and eight points with marked improvement). For the IPSS quality-of-life item, the MCID is considered to be 0.5 points. This is based on two considerations: in other well studied questions with similar seven-point Likert scales, the MCIDs are usually ∼0.5, with the rule of thumb that the MCID is ∼0.5 of the standard deviation/one standard error of measurement. The 2010 National Institute for Health and Care Excellence LUTS in Men Guideline examined the concept of what constituted the MCID for flow rate changes; the evidence base is weak, but a change of 2 mL/s was taken as the MCID, based on the evidence available and expert opinion [3]. A change of three points in total IPSS, however, whilst noticeable, does not necessarily imply a significant improvement in overall or disease-specific quality of life. Furthermore, in a patient with severe symptoms, an improvement of three points may represent a much smaller change than in a patient with milder symptoms at baseline, and for this reason, an improvement in IPSS of ≥25% from baseline has also been proposed as a threshold for clinically meaningful improvement.

The study by Nickel et al. [4] is a rare example of an attempt to integrate the concept of MCID into LUTS trial reporting, analysing the proportion of men with LUTS/BPH, treated with tadalafil 5 mg once daily, who achieved a meaningful improvement in symptoms based on changes in both actual and percentage IPSS. This analysis again shows the power of placebo in LUTS treatment, with approximately half the patients in placebo arms of the four studies achieving the MCID on the IPSS. For those treated with tadalafil, a greater proportion achieved the MCID, with 71.1% seeing an improvement of ≥3 points on the IPSS, and 61.7% a ≥25% change in total IPSS. This benefit over placebo was greater when more demanding clinical thresholds were used, e.g. 50 or 75% improvement on IPSS.

It is encouraging to see a paper that reports clinical significance, but whilst of interest, the study is a post hoc analysis of four trials designed to test tadalafil vs tamsulosin or placebo, for licensing approval, and not a trial designed specifically to measure the clinical significance of changes in symptoms. It is a useful reminder to urologists, however, of the concept of MCID, which despite being well established is not widely known. MCID should be incorporated into the analysis of any results based on patient-reported outcomes [5] where the clinical significance of the results may not be immediately apparent to the clinician.

Read the full article

by Jonathan Rees

Backwell & Nailsea Medical Group, Nailsea, North Somerset, UK

References

1 Jaeschke R, Singer J, Guyatt G. Measurement of health status: ascertaining the minimally clinically important difference. Control Clin Trials 1989; 10: 407–41

2 Barry MJ, Williford WO, Chang Y et al. Benign prostatic hyperplasia speciﬁc health 30 status measures in clinical research: how much change in the American Urological 31 Association symptom index and the benign prostatic hyperplasia impact index is 32 perceptible to patients? J Urol 1995; 154: 1770–4

3 National Institute for Health and Clinical Excellence. The management of lower urinary tract symptoms in men. (Clinical Guideline 97.) 2010. https://guidance.nice.org.uk/CG97

4 Nickel JC, Brock GB, Herschorn S, Dickson R, Henneges C, Viktrup L. Proportion of tadalaﬁl-treated patients with clinically meaningful improvement in lower 1 urinary tract symptoms associated with benign prostatic hyperplasia – integrated data 2 from 1499 study participants. BJU Int 2015; 115: 815–21

5 McGlothin A, Lewis R. Minimal clinically important difference: deﬁning what really matters to patients. JAMA 2014; 312: 1342–3

Editorial: The impact of the surgical correction of Peyronie’s disease – a patient’s perspective

May 20, 2015/by David Ralph

Peyronie’s disease (PD) is an acquired benign connective tissue disorder of the tunica albuginea of the penis that leads to the formation of fibrous inelastic plaques. As a result of pain, worsening quality of erections, penile shortening and deformity, the quality of life of both the patient and their partner may be significantly affected, and this may lead to depression, low self-esteem and relationship difficulties [1].

At present, surgery represents the ‘gold standard’ treatment when PD is stable, and should be offered to guarantee a penis straight and rigid enough to allow penetrative intercourse.

The flow chart in the 2010 guidelines on PD indicates the type of surgery that should be offered according to the preoperative quality of the erection, degree of deformity and penile length, but patient perception of preoperative penile shortening is not taken into consideration [2]. Penile shortening does play an important part, however, with regard to postoperative patient satisfaction, as confirmed by Akin-Olugbade et al. [3], whose series of patients with PD reported the lowest satisfaction rates after penile prosthesis implantation.

According to the present series by Kueronya et al. [4], in which patient-perceived pre- and postoperative penile length loss in patients with PD was evaluated, 79.1% of patients perceived a degree of length loss attributable to PD, and a subjective loss of length of >2.5 cm translated into reduced ability with regard to sexual intercourse. In particular, patients who underwent penile prosthesis implantation reported more significant perceived shortening. This is not surprising, as patients with larger plaques, more severe forms of PD and fibrosis are more likely to have erectile dysfunction and ultimately to require a penile prosthesis implantation. Among patients who did not undergo penile prosthesis implantation, those requiring Nesbit plication reported less preoperative shortening than those requiring plaque incision and grafting, as the latter group presented with more severe deformities.

Further penile length loss caused by the surgical correction leads to bother to the patients, irrespective of the magnitude of the loss. The message from the present series by Kueronya et al. is that, to achieve higher postoperative satisfaction rates in this unfortunate cohort of patients, the choice of the type of surgery should take into consideration patient’s perceived preoperative penile shortening and not be based solely on the 2010 PD guidelines algorithm, because ultimately patients wish to obtain full restoration of the shape and size of penis they had before the onset of PD [2].

As patient’s perceived penile length plays such an important role in a patient’s postoperative satisfaction and because patients undergoing penile prosthesis implantation are those who have lost more length, length restoration should be offered simultaneously with penile prosthesis implantation [5, 6].

Kueronya et al. should be congratulated for their work, which is the first series evaluating patient’s perceived penile shortening and may represent a significant step towards the restoration of an adequate sex life in patients with PD.

Read the full article

Giulio Garaffa and David J. Ralph

St Peter’s Andrology and the Institute of Urology, University College London Hospitals, London, UK

References

1 Rosen R,Catania J, Lue T et al. Impact of Peyronie’s disease on sexual and psychosocial functioning: qualitative ﬁndings in patients and controls. J Sex Med 2008; 5: 1977–84

2 Ralph D, Gonzalez-Cadavid N , Mirone V et al. The management of Peyronie’s Disease: evidence-based 2010 guidelines. J Sex Med 2010; 7: 2359–74

3 Akin-Olugbade O, Parker M, Guhring P, Mulhall J. Determinants of patient satisfaction following penile prosthesis surgery. J Sex Med 2006; 3: 743–8

4 Kueronya V, Miernik A, Stupar S et al. International multicenter psychometric evaluation of patient reported outcome data for the treatment of Peyronie’s Disease. BJU Int 2015; 115: 822–8

5 Sansalone S, Garaffa G, Djinovic R et al. Simultaneous penile lengthening and penile prosthesis implantation in patients with Peyronie’s Disease, refractory erectile dysfunction and severe penile shortening. J Sex Med 2012; 9: 316–21

6 Egydio PH, Kuehhas FE, Sansalone S. Penile girth and length restoration in severe Peyronie’s Disease using circular and longitudinal grafts. BJU Int 2013; 111 (4 Pt B): E213–9

The Drugs Don’t Work

May 19, 2015/12 Comments/by Matthew Bultitude

For those pop enthusiasts amongst you, “The drugs don’t work” – the year was 1997; The band: The Verve. For those more urologically minded, you will immediately be thinking of the recent publication in the Lancet reporting on the use of tamsulosin and nifedipine vs. placebo for the medical expulsive therapy (MET) of ureteric stones. Current national (BAUS) and international (EAU guidelines) recommend the use of MET, usually with an alpha blocker – and often tamsulosin, and it has certainly become common practice in most Emergency and urology departments certainly across the UK and likely worldwide.

There have however always been doubts regarding the use of these with many small heterogenous studies with variable inclusion/exclusion criteria, various blinding protocols and suspicion of publication bias when only positive trials get published. Regardless, the clear outcome from the Hollingsworth meta-analysis was that both alpha blockers and calcium channel blockers are effective for helping stone passage and so they crept into routine clinical use. This trial should change all of that with headline results:

No change in spontaneous stone passage at 4 weeks for either drug vs. placebo or compared against each other
No difference when analysed by stone size or location
No difference in analgesic use or time to stone passage

Aren’t those all the reasons we prescribe them? The first question of course is whether this trial is accurate. It certainly is a large trial with 1167 patients, randomised to the three double-blind arms in 24 centres in the UK. The trial (like many modern studies) is described as pragmatic. This has pros and cons. The advantages are that it replicates real life clinical practice allowing for variations in decision making (e.g. follow-up imaging in this paper) thus making it generally applicable. The downside of course is the lack of precision that this can introduce with stone passage possibly being only patient reported, or based on ultrasound, plain x-ray, IVU or CT. I guess we have to decide which type of trial we prefer, although it would be very difficult to mandate CT follow-up, with concerns about radiation safety, in this trial if that isn’t part of routine practice. Thus maybe this study is actually applicable to the vast amount of units around the world.

Secondly did it include the right type of patient? Well the current guidelines suggest using MET for any stone measuring up to 1cm in any part of the ureter … and that is what this trial did. And this is thus a strength given that it didn’t just focus on the distal ureter. Thus the trial population seems reasonable. One possibility is that if MET only works in the distal ureter (as almost all the studies only look at this), this could this explain the negative findings. Sub-group analysis of this based on location or stone size seems to suggest not unless it was underpowered to show a difference for this cohort of patients.

Whilst the odds ratios (see table) seem clear, the Forest plot shows the breakdown of subgroup by sex, stone size and location. Whilst not statistically significant, this does suggest a trend towards favouring MET for lower ureteric stones.

Thirdly, is it possible this trial is wrong … a type II error ? Well of course anything is possible, and the trial may be criticised for the follow-up mentioned above. However it does seem to provide easily the best evidence to date. Thus why has the use of MET been allowed to become routine practice based on a number of small trials all introducing inherent bias which is then amplified when a meta-analysis is performed. I guess it was the best evidence around at the time although it makes you wonder how many other interventions there are that we currently use that are based on smallish trials, and would they actually stand up to the rigour of a well conducted big multicentre trial?

My last question is will this change practice again? Well it should, but with no alternative (except time, fluids and NSAID’s) to offer patients with ureteric stones and given that alpha blockers are usually well-tolerated, I wonder whether people will continue to prescribe MET for the foreseeable future. But if we believe in evidence based medicine, and we do, then surely we should no longer prescribe MET for ureteric stones which after all is an off-licence indication.

Finally congratulations must go to the NIHR and the research team for answering a very important clinical question. Was the whole ‘MET’ story a placebo effect all along … or to quote another less well known song title from The Verve, was it “All in the mind”? The conclusion from this excellent study has to be yes.

Conflict of interest: Acted as PI for Guy’s and St. Thomas’ Hospital for this trial recruiting patients although have no part of study design, data analysis or publication.

Matthew Bultitude

Consultant Urologist, Guy’s and St. Thomas’ Hospital

Associate Editor, BJUI

Editorial: Selecting the right α-blocker – is silodosin your best option?

May 13, 2015/by Hugo Lavigueur-Blouin

A significant proportion of aging men will have bothersome LUTS and will eventually seek help for this problem. Various medical therapies are available to help aleviate these symptoms. Amongst the various treatments, α-blockers are some of the most widely used drugs. Novara et al. [1] recently published a report on the efficacy and safety of silodosin in a pooled analysis of individual patient data from three registrational randomized controlled trials comparing silodosin and placebo in patients with LUTS. Their study contributes pertinent information to aid the clinician in determining which α-blocker is best suited for specific patients with LUTS.

In the current study, patients were subdivided into groups in order to better understand which patient would benefit most from the use of silodosin [2]. In addition, the article examines the safety of silodosin in these same distinct patient groups. With regard to efficacy, silodosin was significantly more effective than placebo in improving all IPSS-related variables and maximum urinary flow rate, regardless of the patient’s age. When comparing the efficacy of silodosin in different age groups, no difference was observed for any of the IPSS variables, whereas patients aged <65 years had a statistically significantly greater maximum urinary flow rate.

With regard to safety, silodosin was associated with a significantly higher adverse event (AE) rate compared with placebo. When comparing the safety of silodosin in patients aged <65 years and >65 years, the overall AE rate, ejaculatory dysfunction and discontinuation rate attributable to AEs were all higher in the younger age group. Interestingly, in patients with concomitant use of antihypertensive drugs, the use of silodosin was not associated with a higher risk of either dizziness or orthostatic hypotension.

In a previous study by the same authors, no clinically relevant or statistically significant differences with regard to diastolic blood pressure, systolic blood pressure or heart rate in patients taking silodosin as compared to placebo were found [3]; however, a minor statistically significant difference vs placebo was observed with tamsulosin. The present study by Novara et al. [2] further supports the belief that silodosin is a safe drug from a cardiovascular standpoint.

From a sexual standpoint, silodosin does not seem to perform as well. In the present study, patients in the silodosin group had significantly more adverse events as compared with the placebo group. Retrograde ejaculation was by far the most common side effect affecting 32.8% of patients aged <65 years vs 0.9% in the placebo group. Similarly, in a study by Chapple et al. [3], as many as 14.2% of patients in the silodosin treatment group had ejaculatory dysfunction, compared with 2.1 and 1.1% of patients in the tamsulosin and placebo treatment groups, respectively. Although the percentage of patients who discontinued treatment because of treatment-emergent AEs in the present study was small and not significantly different among all treatment groups, one might hypothesize that over a longer follow-up period, such a prevalent side effect could be responsible for a higher discontinuation rate. Consequently, it should be kept in mind that for patients desiring to maintain antegrade ejaculation, or who are bothered by treatment-onset ejaculatory dysfunction, especially younger patients, silodosin might not be the best treatment option. Furthermore, it should be recognized that some patients would potentially accept a reduction in treatment efficacy to preserve ejaculation [4].

With regard to clinical outcomes, few published papers comparing tamsulosin with silodosin are available [5, 6]. One article found no clinically significant difference between the two α-blockers [5] whereas the other, which was a post hoc analysis, found a marginal clinical benefit for silodosin over tamsulosin [4]. Unfortunately, head-to-head trials are not forthcoming, so it will not be possible to determine if one α-blocker is clinically better than the other. Furthermore, the present study, because it lacked an active control arm, did not compare silodosin with tamsulosin, which leaves something to be desired.

In conclusion, careful consideration should be given to specific patient characteristics such as age and comorbidities, along with personal preferences towards sexual function when offering patients α-blockers for treatment of LUTS.

Read the full article

Hugo Lavigueur-Blouin and Naeem Bhojani

Department of Urology, Centre Hospitalier de l’Universite de Montreal, Montreal, QC, Canada

References

1 Novara G, Chapple CR, Montorsi F. A pooled analysis of individual patient data from registrational trials of silodosin in the treatment of non-neurogenic male lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). BJU Int 2014; 114: 427–33

2 Novara G, Chapple CR, Montorsi F. Individual patient data from registrational trials of silodosin in the treatment of non-neurogenic male lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH): subgroup analyses of efﬁcacy and safety data. BJU Int 2015; 115: 802–4

3 Chapple CR, Montorsi F, Tammela TL et al. Silodosin therapy for lower urinary tract symptoms in men with suspected benign prostatic hyperplasia: results of an international, randomized, double-blind, placebo- and active-controlled clinical trial performed in Europe. Eur Urol 2011; 59: 342–52

4 Sturch P, Woo HH, McNicholas T, Muir G. Ejaculatory dysfunction after treatment for lower urinary tract symptoms: retrograde ejaculation or retrograde thinking? BJU Int 2014. doi: 10.1111/bju.12868

5 Montorsi F. Proﬁle of Silodosin. Eur Urol Suppl 2010; 9: 491–5

6 Novara G, Tubaro A, Sanseverino R et al. Systematic review and meta-analysis of randomized controlled trials evaluating silodosin in the treatment of non-neurogenic male lower urinary tract symptoms suggestive of benign prostatic enlargement. World J Urol 2013; 31: 997–1008

RSM Bladder Day

May 12, 2015/by Rebecca Tregunna

The urology section of the RSM left Wimpole Street and travelled up to sunny Queen Elizabeth Hospital in Birmingham on the 24th April to be educated in the ‘Management of Non-Muscle invasive and Muscle Invasive Bladder Cancer’. This meeting was organised in collaboration with Nick James and Rik Bryan at the Birmingham Warwick Uro-Oncology unit as the RSM looks to add to its regional programme of teaching days.

The meeting was well attended by both experts as well as trainees and we kicked off with John McGrath and a review of the evidence behind current haematuria investigations as well as the new NICE guidelines. Professor Charles Hutchinson from the University of Warwick then gave a detailed talk on pre-operative imaging in bladder cancer and this led to an interesting debate on the necessity of performing a full TURBT in cases of known muscle invasive disease if the patient will ultimately require a cystectomy. No consensus was reached although if definitely proceeding to cystectomy it is unlikely to be beneficial. If radiotherapy is considered then debulking is important.

Eva Comperat from the Service d’Anatomie and Cytologie Pathologiques du Pr Capron presented a fascinating histopathological perspective of bladder cancer and it was interesting to see that even amongst eminent pathologists there can be challenges in distinguishing pTa from pT1 disease with only 44% in one large study showing full agreement. The importance in reporting histological variants such as micropapillary or plasmocytoid was discussed due to the aggressive nature of these types and the need for more radical treatment. This was also re-iterated by Peter Rimington while discussing early cystectomy which should be offered to all suitable patients at high risk of progression according to EORTC tables, especially in young patients and in tumours which are multifocal, difficult to resect, have deep lamina propria or prostatic involvement and those with associated CIS.

A highlight for me was Professor John Kelly’s talk on the treatment option of hyperthermic Mitomycin C. HYMN Trial.

Data from the HYMN trial which looked at hyperthermic MMC vs. standard treatment in BCG failures was disappointing in that there was no difference in terms of disease free survival at 24 months. Outcomes were found to be worse in patients with CIS, but in patients with papillary disease, hyperthermic MMC had far more favourable results. This has led to the HIVEC I and HIVEC II trials currently recruiting in the UK and Spain looking at standard MMC vs. hyperthermic MMC in intermediate risk disease. It was also interesting to see new immunotherapy drugs currently in phase III trials which will hopefully be available in the near future.

Rik Bryan’s presentation on the evolving role of bio markers explained that the Bladder Cancer Diagnostic Programme had found that contrary to our beliefs, patients trust, and would rather accept certainty over burden and thus would rather continue with cystoscopic surveillance over bio-markers, unless the sensitivity of these bio-markers was over 99%. No such bio-marker has yet been found to be that accurate but current research into odor-readers, urinary dipsticks and DNA all look promising in terms of potential for both diagnosis and prognosis.

Both Nick James and Hugh Mostafid highlighted current research trials with the CALIBER RCT on chemo resection in recurrent low risk bladder cancer as well as the PHOTO trial looking at both clinical and cost effectiveness of photo-dynamic cystoscopy leading the way in terms of surgical trials currently recruiting. Nick also caused a stir on Twitter as he presented data showing a median survival advantage of more than a year between surgeons performing low or high volume of cystectomies annually. Surely we do not need more convincing evidence to centralise such surgery?

Reviewing bladder cancer from the oncologist’s perspective, Syed Hussein from the University of Liverpool explained that although there is a 6% overall survival benefit with neo-adjuvant chemotherapy there have been no RCT on MVAC vs gemcitabine/cisplatin regimes. Nick James’ talk on bladder preserving treatment added to this that synchronous chemoradiotherapy could be complementary to neo-adjuvant treatment and the addition of synchronous chemotherapy has been shown to provide a significant improvement in terms of loco regional control.

Vijay Ramani presented his series on salvage cystectomy with no significant difference in terms of complications for salvage vs. primary surgery as long as certain techniques were adopted such as division of ureters outside of the pelvis and using bowel at least 15-20cm proximal from the ileocaecal valve.

To complete the diverse and stimulating programme, Professor Peter Wiklund from the Karolinska University Hospital, Stockholm, presented a state of the art lecture on “Reconstruction rules! The robot has taken over?”. With discussion and impressive videos demonstrating intra-corporeal robotic neobladder reconstruction it was difficult not to be in awe of such an impressive series, with a 90% continence rate in males.

Overall it was fantastic to have the RSM in the West Midlands. Roger Plail has done much to reach out to those of us outside of London and I look forward to the Geoffrey Chisholm Prize Meeting and AGM on the 22nd May in Hastings. RSM President’s Day.

Rebecca Tregunna, Speciality Trainee, Burton Hospitals NHS Foundation Trust, West Midlands Deanery @RebeccaTregunna

What’s the Diagnosis?

May 8, 2015/by admin Z.9

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This image is taken from a recent BJUI paper (Bach et al, BJUI 2014).

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Editorial: TRP channel – a reality that still requires many years of scientific efforts

May 6, 2015/by Francisco Cruz

Seventeen years have elapsed since the capsaicin receptor was first cloned by Caterina et al. [1] and the excellent review with an unusual provocative title by Deruyver et al. [2] was written. The capsaicin channel, re-named transient receptor potential (TRP) vanilloid receptor subtype 1 (TRPV1), is now commonly referred to as the founding member of the TRP family, as it currently includes 28 related channels, a number difficult to foresee in those early years [3].

TRP channels have been extensively studied in the lower urinary tract (LUT) with the aim of clarifying their role in micturition control and in the generation of LUTS. It is well accepted that TRP receptors have neuronal and non-neuronal expression [3, 4]. TRPV1 is fundamental to bladder hyperactivity and pain associated with LUT inflammation [3], while TRPV4 may participate in the generation of the normal sensation to void [5]. Another group of TRP receptors may even participate in bladder oncogenesis, which seems to be a role of TRPV2 [3]. The main substance of all this information is not a myth; rather it represents a large body of very solid scientific data.

There are certainly still many obscure areas. The distribution of TRP receptors in the bladder is certainly one of them. However, I disagree that a substantial part of available technical and financial resources have been allocated to study this matter. One should not forget that other matters, like the role of many TRP channels for bladder function, remain elusive. Broadly speaking, in my opinion, future key studies should tackle three very relevant but still unclear points. The importance of most TRP channels for bladder function is difficult to predict at the moment [3]. Just as an example, TRPA1 and TRPM8, which are sensitive to cold temperatures, are expressed in the bladder. However, the bladder, as all internal organs, is conserved at very constant physiological temperatures, making it difficult to understand the relevance of cold receptors to its function. Then, we need to find what the endogenous agonists for TRP receptors are in the LUT. Anandamide has been largely explored as an endogenous agonist for TRPV1 in the bladder [6], a fruitful observation as drugs able to manipulate endogenous levels of anandamide are currently being explored in clinical trials. The same holds true for the other members of the TRP family. TRPA1 may respond to infections due to its capacity to react to hydrogen sulphide [3]. But for the large majority of the TRP family endogenous agonists remain unknown. Finally, TRP antagonists that are simultaneously effective and safe must be generated. Most available TRPV1 antagonists, produced to date, although able to control bladder dysfunction in models of cystitis and spinal cord injury [3], cause hyperthermia and have been associated with an enlargement of ischaemic areas of the heart after coronary artery obstruction [3]. TRPV4 antagonists look very promising for controlling frequency but a compound safe for human use is still eagerly awaited [2]. Eventually the combination of antagonists for more than one of these receptors may prove effective at very low doses, so low that they do not generate serious adverse effects [7].

In conclusion, TRP receptors are a reality that still needs an enormous amount of work and dedication before becoming therapeutically useful. And that may take more time than we anticipate at the moment.

Read the full article

Francisco Cruz

Department of Urology, Al. Hernani Monteiro, Porto, Portugal

References

1 Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997; 389: 816–24

2 Deruyver Y, Voets T, De Ridder D, Everaerts W. Transient receptor potential channel modulators as pharmacological treatments for lower urinary tract symptoms: myth or reality? BJU Int 2015; 115: 686–97

3 Avelino A, Charrua A, Frias B et al. Transient receptor potential channels in bladder function. Acta Physiol (Oxf) 2013; 207: 110–122

4 Birder LA, Kanai AJ, de Groat WC et al. Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells. Proc Natl Acad Sci U S A 2001; 98: 13396–401

5 Gevaert T, Vriens J, Segal A et al. Deletion of the transient receptor potential cation channel TRPV4 impairs murine bladder voiding. J Clin Invest 2007; 117: 3453–62

6 Dinis P, Charrua A, Avelino A et al. Anandamide-evoked activation of vanilloid receptor 1 contributes to the development of bladder hyperreﬂexia and nociceptive transmission to spinal dorsal horn neurons in cystitis. J Neurosci 2004; 24: 11253–63

7 Charrua A, Cruz C, Jansen K, Rozenberg B, Heesakkers J, Cruz F. Co- administration of transient receptor potential vanilloid 4 (TRPV4) and TRPV1 antagonists potentiates the effect of each drug in a rat model of cystitis. BJU Int 2014; [Epub ahead of print] doi: 10.1111/bju.12861