Year: 2015

Capsaicin, resiniferatoxin and botulinum toxin-A – a trip down memory lane

May 31, 2015/1 Comment/by Prokar Dasgupta

Over 20 years ago, I went to work at Queen Square, the Mecca of Neurology, as Medical Research Council fellow to Prof. Clare Fowler, an international expert in the neurogenic bladder. She has now retired leaving a lasting legacy, which features in this edition of the BJUI.

I clearly remember my first meeting with Vijay Ramani (now Consultant Urologist in Manchester) and Dirk De Ridder (Associate Editor, BJUI), which led to a collaborative paper on the effects of capsaicin in refractory neurogenic detrusor overactivity (NDO) [1]. While we were busy studying suburothelial nerves in NDO, with many hours of computerised image analysis, a seminal paper describing the ‘capsaicin receptor’ appeared in Nature [2]. This was my first encounter with transient receptor potential (TRP) channels. They continue to excite urologists and neurologists alike as potential therapeutic targets in overactive and painful bladders [3].

Just like semisynthetic capsaicin, derived from chillies, which acted through TRP receptors, TRPV1 antagonists are effective but have numerous side-effects including hyperthermia. No surprises here But there are other subtypes, such as TRPV4 and TRPM8, which are generating a lot of interest in the field of drug discovery.

Life, of course, moved on. Capsaicin never received a license for NDO and was followed by resiniferatoxin (RTX), which also made a rapid exit as it adhered to the plastic bags that it was dispensed in as a solution. Botulinum toxin-A turned out to be the game changer [4]. After extensive trials and safety studies, it has changed the lives of many millions with incontinence secondary to DO, who have failed most other first-line treatments. It has a licence for clinical use and the science behind its mechanism of action has led to many fascinating discoveries.

So, are TRP inhibitors the next big thing in functional urology? After 20 years of fundamental research, they certainly have the potential. As with most eureka moments in translational research, only time will tell.

References

1 De Ridder D, Chandiramani V, Dasgupta P, Van Poppel H, Baert L, Fowler CJ. Intravesical capsaicin as a treatment for refractory detrusor hyperreﬂexia: a dual center study with long-term followup. J Urol 1997; 158: 2087–92

2 Caterina MJ, Rosen TA, Tominaga M, Brake AJ, Julius D. A capsaicin- receptor homologue with a high threshold for noxious heat. Nature 1999; 398: 436–41

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

4 Sahai A, Dowson C, Khan MS, Dasgupta P. Improvement in quality of life after botulinum toxin-A injections for idiopathic detrusor overactivity: results from a randomized double-blind placebo-controlled trial. BJU Int 2009; 103: 1509–15

Prokar Dasgupta @prokarurol

Editor-in-Chief, BJUI

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

What’s the Diagnosis?

May 27, 2015/by admin Z.9

Test yourself against our experts with our weekly quiz. You can type your answers here if you want to compare with our answers.

This image is from Thomsen et al. (BJUI 2015).

No such quiz/survey/poll

#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

Article of the Week: Evaluating the proportion of tadalafil-treated patients with clinical improvement in LUTS associated with BPH

May 27, 2015/by admin Z.9

Every Week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Dr. Jonathan Rees, discussing the paper.

If you only have time to read one article this week, it should be this one.

Proportion of tadalafil-treated patients with clinically meaningful improvement in lower urinary tract symptoms associated with benign prostatic hyperplasia – integrated data from 1499 study participants

John Curtis Nickel, Gerald B. Brock*, Sender Herschorn†, Ruth Dickson‡, Carsten Henneges§ and Lars Viktrup¶

Department of Urology, Queen’s University, Kingston, *University of Western Ontario, London, †Division of Urology, University of Toronto, ‡Eli Lilly Canada Inc., Toronto, ON, Canada, §Lilly Deutschland GmbH, Bad Homburg, Germany, and ¶Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA

Read the full article

OBJECTIVES

To evaluate the proportion of patients achieving clinically meaningful improvement of lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH-LUTS) with tadalafil using two definitions of response.

PATIENTS AND METHODS

Post hoc integrated analysis of four placebo-controlled studies in men (aged ≥45 years; International Prostate Symptom Score [IPSS] of ≥13; maximum urinary flow rate [Q_max] of ≥4 to ≤15 mL/s) with BPH-LUTS randomised to tadalafil 5 mg (752 patients) or placebo (747) for 12 weeks after a 4-week placebo run-in. Responders were defined as having a total IPSS improvement of ≥3 points or ≥25% from randomisation to endpoint (Week 12). Response status was calculated per patient, and relative benefit and odds ratio (OR) with 95% confidence interval (CI) of tadalafil vs placebo was calculated using a logistic Generalised Mixed Model for Repeated Measures.

RESULTS

Tadalafil 5 mg once daily resulted in a significantly greater proportion of patients achieving a ≥3-point IPSS improvement (71.1% and 56.0% for tadalafil and placebo patients, respectively [OR 1.9, 95% CI 1.5, 2.4; P < 0.001]) and achieving a ≥25% improvement in total IPSS randomisation to endpoint (61.7% and 45.5% for tadalafil and placebo patients, respectively [OR 2.0, 95% CI 1.6, 2.5; P < 0.001]).

CONCLUSIONS

About two-thirds of tadalafil-treated patients achieve a clinically meaningful improvement in BPH-LUTS symptoms, based on two different definitions of responder status.

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

Video: Patients not p-values

May 27, 2015/by admin Z.9