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Divided by more than a common language

March 29, 2016/by Mike Wyllie

At its simplest, hypogonadism manifests as (abnormally) low testosterone levels, which require effective clinical intervention; however, there is little or no consensus on the definition, diagnosis and treatment of the condition. Indeed, at least in the USA, the issue of the (ab)use of testosterone replacement has been under the microscope because of a hypothesis, albeit flawed, linking it to increased cardiovascular risk. The need for consensus on the management of hypogonadism is increasing almost in front of our eyes as a result of the link with the metabolic dysfunction associated with the increase in diabetes and/or obesity in the general population. With this background, an international panel representing the disciplines involved in the management of hypogonadism was convened; the output of the group, in terms of definition and patient management, is reported in this month’s issue of BJUI [1].

Apparently, the need for effective intervention is more critical than one would necessarily assume. Not only is there a hypogonadism ‘epidemic’, linked to the fattening of our population, but there is no globally approved treatment for secondary hypogonadism (2HG) i.e. that form not associated with testicular failure. Epidemiologists warn that 2HG is in fact the predominant clinical representation, being roughly six times as common as primary hypogonadism.

The conclusions of the recent consensus panel are neither more nor less appropriate nor scholarly than those of other groups, e.g. the Endocrine Society, BAUS, AUA or SMSNA, but their value is as a timely reminder that unless there is clinical consensus on the disorder it is practically impossible to design regulatory authority-proof clinical trials to ensure drug approval. Ironically the most effective treatment strategy in many instances would be lifestyle intervention, but we all know how compliant men are when diet and exercise are recommended.

Returning to drug treatment, the panel does emphasize the critical importance of distinguishing between the different aetiologies of primary hypogonadism and 2HG. Although testosterone replacement therapy is usually appropriate in the treatment of primary hypogonadism, it may be inappropriate in the treatment of 2HG. Because of negative feedback in this situation testosterone replacement can reduce spermatogenesis and testicular function. This clinical phenomenon is exemplified by the phase III data from two clinical trials presented by Kim et al. [2] in this issue of BJUI. Compared with placebo, testosterone replacement produced substantial reductions in spermatogenesis and testicular function. Bearing in mind that many men with androgen deficiency may well wish to preserve fertility, testosterone replacement could therefore in fact be counterproductive. The trials by Kim et al. also showed that, by comparison, the selective, centrally active, oestrogen antagonist, enclomiphene, could normalize testosterone levels while maintaining testicular function and spermatogenesis.

In many ways, assuming eventual regulatory approval, enclomiphene could represent the optimum therapy for 2HG, preferably as an adjunct to lifestyle modification, i.e. dietary manipulation and exercise. Unfortunately, at least in the USA, the regulatory authority appear not to recognize 2HG as a condition that merits treatment. Pressure from the clinical community could influence this attitude.

Michael G. Wyllie, BJUI Consulting Editor, Sexual Medicine

Stratton House, Shenington, Banbury, Oxfordshire, UK

References

1 Dean J, Maggi M, de Boer J-B et al. Diagnosing secondary hypogonadism: important consequences for fertility and reversibility. BJU Int 2016; 117: 551–4

2 Kim ED, McCullough A, Kaminetsky J. Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone: restoration instead of replacement. BJU Int 2016; 117: 677–85

March #urojc: Radiotherapy for Prostate Cancer – Is it a gift that keeps on giving?

March 18, 2016/4 Comments/by Henry Woo

The International Urology Journal Club on Twitter is now well into its 4^th year. The subject for the March 2016 discussion was a paper published in the BMJ entitled “Second Malignancies after radiotherapy for prostate cancer: systematic review and meta-analysis”.

Lead and senior authors, Chris Wallis and Rob Nam were kind enough to make themselves available to participate in this discussion. Rob Nam made use of the #urojc guest twitter account.

The literature was searched using Medline and Embase and the method of review was the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analysis of Observational studies in Epidemiology (MOOSE) guidelines for reporting of this systematic review and meta-analysis.

Chris Wallis provided an excellent TL:DR summary with the following tweet.

It is well recognized that secondary malignancies following radiation exposure could take many years to become apparent.

The responses were fairly predictable but nevertheless an important point to explore.

Early in the discussion, there was also relevant reminder of the issue of differences in odds ratios and absolute risk. That said, consideration needs to be given to the ‘big ticket’ nature of secondary malignancy where even a small absolute risk drives a great deal of interest in this subject matter.

An interesting finding from the study was that the risk of secondary malignancy was less with brachytherapy compared with external beam radiation.

Further to this, is it possible that there could be a difference between HDR and seed brachytherapy? An interesting thought although not specifically covered in the paper.

A more controversial aspect to the discussion was whether the risk of secondary malignancy would justify screening or surveillance. The following exchange was worthy of note.

Whilst there is nothing in the way of documented guidelines or actual evidence to demonstrate a benefit of surveillance, it seems something worthy of consideration for future practice guidelines – in other words, recommendations one way or the other.

Rob Nam refers to a third paper on radiation outcomes in the context of previous surgery. This BJC paper, the Lancet Oncology paper (previous discussed at a #urojc in 2014) and now the current paper could cheekily be called the Nam Trilogy – make note that you heard this term here for the first time.

To what extent should we be counseling our patients on the risk of secondary malignancy if they are to undergo radiation for prostate cancer? Is this just another factor to encourage surgery over radiotherapy? Will there be no change in practice, particularly in the US where many lucrative radiation oncology services are actually owned by urological surgeon private practice groups?

The state of radiation oncology practice is different outside the US and my own personal thoughts on the matter are that the Nam Trilogy of papers will create a series of well cited ‘evidence’ that will further shift the weight of opinion towards surgery over radiotherapy as a primary treatment for localized prostate cancer.

Anybody who followed the March installment of the #urojc would have been impressed by the high level of interaction by the authors Chris Wallis and Rob Nam. A particular mention should be given to Sabin Motwani who as a radiation oncologist, provided valuable input to the discussion.

Please do join us for the April installment of the #urojc and I encourage you all to email, tweet or DM your suggestions for papers to be discussed. Please also, feel free to volunteer to write up a monthly summary for publication on the BJUI blogs. I would also like to acknowledge the contributions of Rustom Manecksha who was the winner of the 2016 BJUI SoMe Award for #urojc – a reflection to the quality of his participation and support for this online educational activity.

Henry Woo is an Associate Professor of Surgery at the Sydney Adventist Hospital Clinical School of the University of Sydney. He is the coordinator of the International Urology Journal Club on Twitter.

EAU 2016 Congress Day 3

March 18, 2016/1 Comment/by Kari Tikkinen

Das bringt mich weiter! While the sun was shining in Munich, the 3^rd day of the 31^st EAU Annual Congress continued with very well attended plenary and poster sessions. And that is no wonder because the EAU Scientific Committee had created such an attractive program, including amazing plenary sessions during the morning and a plethora of informative poster sessions in the afternoon.

Professor Hendrik Borgmann (@HendrikBorgmann) has already covered highlights of the opening days 1 and 2 of this year’s Congress in his BJUI blog. We will give you some highlights of Day 3 and highly recommend you to take a look on EAU congress website, Day 3, which has archived a huge amount of material to allow you to catch up on sessions you may have missed. Indeed, lots of webcasts are available!

We focused on non-oncology plenary morning sessions and oncology poster sessions afternoon. Here are some of our highlights:

SURGERY IN THE ELDERLY – As our urological patients become older and older, surgery for octogenarians, or even nonagenarians, is increasingly common. The morning session covered various aspects on diagnosis and treatment of benign prostatic hyperplasia and other urological conditions in the ageing patient.

Professor Cosimo De Nunzio began the morning with “Highlights” on lower urinary tract symptoms and prostatic disease presented during this year’s EAU congress. Also this year, as many as every third abstract was on either prostate cancer or prostatic hyperplasia.

Indeed, the plenary session on Day 3 also covered prostatic disease.

Professor Alexander Bachmann talked about surgery for BPO in the elderly. He pointed out that in elderly (high-risk) patients we do not need a complete anatomical tissue removal, we do not need a (very) long-term follow-up and that we do not need tissue for prostate cancer diagnosis. Instead, we need a safe and efficient operation with individual adaptation of the technique and preferably feasibility in an ambulatory setting or local anaesthesia.

Professor Bachmann further emphasized that it would be preferable if surgery for the elderly would be performed by experienced surgeons, and that age per se is not a reason to not operate. There are several new minimally invasive operations available, and especially for elderly less is often more.

HOW AND WHEN TO STOP ANTICOAGULATION – Managing perioperative thromboprophylaxis for patients who already receive anticoagulants remains a challenge. Associate professor Daniel Eberli and Professor Per Morten Sandset covered many of these aspects in their helpful presentations.

Dr. Eberli told us that bridging therapy (options for stopping or not stopping anticoagulation in the above figure) is eminence-based, as no papers exist showing benefits. He also presented data from the recent NEJM trial (BRIDGE study; see Table below), which showed that stopping anticoagulation without bridging was non-inferior to perioperative bridging for the prevention of arterial thromboembolism and decreased the risk of major bleeding.

Dr. Eberli gave us all a take home message to discuss and question our local bridging guidelines as new evidence is very likely not supporting them (concluding slide below).

Professor Sandset recommended that during the perioperative period only use aspirin in high-risk patients, that is, those with recent thrombotic event or extensive coronary heart disease. He also informed us that stopping antiplatelet therapy 5 days before surgery (figure below) is often the way to go, and agreed with Dr. Eberli regarding bridging therapy statements.

Professor Sandset also gave helpful information regarding use of direct oral anticoagulants (DOACs) in urological surgery:

There were numerous poster sessions available on Day 3, as usual, many of them on prostate cancer. We have selected some of the highlight abstracts presented.

PROSTATE CANCER – On Day 3, prostate cancer presentations dominated once again in a number of poster, abstract and thematic sessions but also kidney, bladder, testicular and penile cancer sessions, which provided new interesting data.

Molecular markers, genomic profiling and individualized risk and treatment assessments were presented and discussed in poster session 58, and summarized by Stacy Loeb (@LoebStacy). Further advances in prostate cancer biomarkers in prostate cancer were presented in poster session 84. These new tools are moving from bench to bedside and urologists can hopefully incorporate these new tools to cancer care sooner rather than later.

In sessions on prostate cancer diagnostics, more advanced risk profiling tools were highlighted. For instance, STHLM3 test combines history of the patient, clinical parameters, biochemical markers and genetic markers. It was presented earlier in the congress and on Day 3 further health, economic and clinical evaluations were presented in Thematic session 12. It is one example of the tests showing promising results to potentially decrease the number of prostate biopsies needed. Other similar risk profiling tools were also presented during the congress. In addition to PSA only, evaluation of the smart use of already available clinical and biochemical parameters and the combination of genetic markers may bring individualized risk assessment of prostate cancer to the next level.

In poster session 62 on Day 3, diagnostic proceedings in prostate cancer with co-morbidity evaluation, biopsy strategies and MRI imaging were presented. A combination of molecular markers and imaging may be the way to proceed in future. These aspects were covered nicely in Thematic session 12.

MRIs have been heavily integrated in prostate cancer diagnostics during recent years. Image guidance in prostate biopsies seem to be making a breakthrough in prostate cancer diagnostics. Targeted biopsies with cognitive or MRI-TRUS fusion imaging were shown to be the way to enhance the results and reliability of biopsies and cut down the number of biopsies. However, as biopsies are still needed in prostate cancer diagnostics, use of the pre-biopsy MRI protocols were suggested to be done only in clinical trial setting. Many aspects of MRI diagnostics of prostate cancer were elegantly summarized in Thematic session 11.

New sophisticated imaging technologies in addition to MRI were present in several sessions during the meeting. Diagnostic enhancement has been seen also in metastatic prostate cancer. PSMA-PET seems to be replacing choline-PET-TT in evaluation of relapsing and metastatic prostate cancer (e.g. Thematic session 10). More reliable diagnostics and imaging of prostate cancer are also enhancing the treatment decision and treatment choice of patients with local prostate cancer. Finding the right patients for the active surveillance protocols is also being helped with advanced diagnostics. Indeed, finding only patients who need treatment for prostate cancer should be the ultimate goal for enhanced diagnostics as discussed in poster sessions 66 and 75 on Day 3. There are also high expectations on focal therapy (e.g. poster session 66), which at the moment is still experimental but will likely be a real option for patients with low volume prostate cancer verified by imaging.

The role of quality of life evaluations and patient reported outcomes measured were heavily discussed during the congress in all treatment modalities of both local and advanced prostate cancer. Survivorship issues are an increasingly important issue when more effective treatments both in local and advanced prostate cancer are available.

In metastatic disease, the use of early chemotherapy in combination with hormonal treatment has been implemented very rapidly to clinical use after the results of the CHAARTED and STAMPEED studies. Further evaluation of early chemo in metastatic disease is still needed and the patient selection needs still clarification. Hormonal therapy still has a very marked role in metastatic prostate cancer and new advances can also be found in new strategies of using castration therapy as presented in poster session 67. Urologists should actively follow the changing landscape of the medical treatment of metastatic prostate cancer and be active in treatment planning and treatment of these patients. At the same time with poster session 62 novel drugs and new forms of isotope radiation therapy in castration resistant prostate cancer were discussed in poster session 61. These open new possibilities for potential treatments.

The clinical and scientific content of the program of the Day 3 was of a very high standard, and reflective of the breadth of contemporary research in many areas within urology. Besides this session, it was our pleasure to meet old and new urological friends worldwide. The annual EAU meeting remains a highly effective method of knowledge translation and provides the opportunity for collaboration between surgeon scientists and other researchers in the field. As always in big congresses, there are so many interesting sessions going on at the same time, that it is hard to pick up and follow everything you would like to. We hope that this report provides some memories and take home messages of the Day 3 to the readers of the BJUI and BJUI blogs.

We look forward to future BJUI and EAU happenings!

Kari Tikkinen

Urology resident, adjunct professor of clinical epidemiology

Helsinki University Hospital, Helsinki, Finland

@KariTikkinen

Mika Matikainen

Chief of urology, adjunct professor of urology

Helsinki University Hospital, Helsinki, Finland

Rehumanising

March 8, 2016/by Jim Duthie

We live in a dehumanizing world. Out of a need for efficiency, convenience, and reassurance, we both dehumanize and are dehumanized routinely in our commerce and relationships. We are not a three-dimensional human being of unique genetics and experience, forte and frailty, preferences and peculiarities to our bank, public library, or insurance company. Out of necessity, these structures diminish us to a number or barcode. We are grouped by age and demographic, measured by our internet clicks, targeted according to our income by corporations. To those profiting from our consumption our individuality is irrelevant; the big money is in exploiting groups. Whether you support a free Tibet does not concern the people selling cheeseburgers, unless enough people agree with you that some marketing leverage can be generated from this fact. In medical research we reduce people to “female between 40 and 75 years with chemotherapy naïve metastatic ovarian carcinoma”. Not “Julie, mother of three boys (one with cerebral palsy), who put up with her vague abdominal symptoms for too long because she was preoccupied by supporting her younger sister out of an abusive relationship”. While logistical limitations do not allow for the statisticians to enter into every individual story, we reassure ourselves that the depersonalized and homogenized data from these studies is for the greater good. Indeed, sometimes it just isn’t any of our business.

We can accept that on this macro level there are faceless amoral corporations that care only about how to alter our spending patterns, but on an interpersonal level we can be equally guilty of dehumanizing attitudes. Thanks to the heuristics developed by our ancestors, which I for one am grateful for, the human brain is very efficient at mentally grouping things under such headings as “dangerous” and “delicious”. This has allowed our continued survival. Having a general suspicion of things that looks like snakes means a reduced risk of envenomation. Being suspicious of strangers by default means that we are less likely to be on the back foot if someone pulls a spear on us. It would be nice to think that we have largely put this simplistic cognitive process behind us, but we tend to fall back on bad habits. Every time we mentally label a person we are trimming their humanity in order to fit them into a pre-existing cognitive category. When we think “young hoodlum”, “old codger”, “drug addict”, “liberal”, or “health nut”, we are in fact extracting what we deem to be the most salient point of person and making it the sum total of their identity. There is obviously expedient for us, as we continue to do it. It makes it easier to ignore the “derelict” on the street, and not feel too bad about the “foreigners” affected by natural disasters. Our bias is routinely exploited by our leaders, especially in times of war. We are not killing people very similar to ourselves, we are fighting “scum”, “heretics”, “commies”. While studying for a degree in psychology I came across a study that demonstrated that people attribute more negative characteristics to people groups if they are referred to by nouns rather than adjectives. People were more mistrustful of others described as “Poles” or “Jews”, rather than “Polish” or “Jewish”. The objective label nudges people into a category, with the adjective reminds us that these are complex individuals, who happen to have a given ethnicity or faith.

We have a reflexive discomfort at being dehumanized ourselves. We don’t like being treated like cattle by airlines or sports stadiums. We despise being written off as nothing more than the town we came from, the school we went to, the era we grew up in, or our gender. We know from personal experience that we are unique, and attribute value to this, at least in ourselves.

Surgery is dehumanizing. We take frightened people, anaesthetize them so that they cannot resist, and then disassemble them. The intention is to reassemble them in an improved way, but we are reducing people to a collection of organs and meat in a way that strips them of usual dignity. Until the Renaissance, disassembling the dead was considered too shameful to tolerate. Indeed, to begin with only executed criminals, considered sub-human (already dehumanized), were considered suitable candidates for anatomical dissection. It was too much to imagine a person opened up for the world to see their insides, their dignity stripped in an extreme form of nudity. I have already written about how not entering into the full experience of every human drama is what makes surgery a viable career (https://www.bjuinternational.com/bjui-blog/surgery-is-not-normal/), and I don’t think it is helpful to focus on the bigger picture beyond the operating theatre while focusing on the technical steps of an operation, but a few points are worth considering.

Firstly, those of us who have had human dissection as a part of our training tend to share a common experience. While in the thick of a dissection, occasionally rewarded with the discovery of a familiar structure, it is normal to forget that the prosection was once the residence of a functioning person. Typically it is the glimpse of a uniquely human feature; the face, feet, hands that triggers a moment of shock at what is going on. I still recall looking down to see that our cadaver had painted toenails. Instead of being a learning resource, it struck me that this woman had spent time days before her death, tending to her toenails fastidiously, unaware of what was to come. This placed her in a room in her home, at a time of day, perhaps before leaving to attend a social event. The full experience of her humanity was infinitely greater than the tutorial aid she had been reduced to. The strict procedures governing the use of human tissue made sense, lest we forget the gift of the donor.

One of the more moving experiences I have had in a hospital is watching Intensive Care nurses managing comatose patients. My observation is that these patients are treated more gently than necessary, and there is a constant one-way conversation from the nurses explaining that now, they are going to reposition the legs. They are going to brush teeth. They are adjusting the pillow. Calling the patient by their name, as their words fall on deaf ears. While logically this makes no difference to medical treatment, it protects the nurse from dehumanizing the patient, making them more than an oxygen trace on a screen.

Ultimately, the effort to re-humanize is what makes us fully human. The unconscious patient or cadaver is not affected by our attitude towards them, but we sacrifice our own humanity whenever we revert to applying broad heuristics to other people. A cat knows to be frightened of snakes, but it takes human intelligence and will to deliberately consider that a person is more than something to fear, ignore, or desire. It is an act of overcoming base instinct. When we apply the appropriate reverence for a person as we prepare them for surgery, care for them in their unconsciousness, our respectfully use their dead body to improve the treatment of future patients, we affirm our own humanity. It is more for us than for them.

Jim Duthie is a Urological Surgeon/Robotic Surgeon. Interested in Human Factors Engineering, training & error, and making people better through electronic means. Tauranga, New Zealand. @Jamesduthie1

STAMPEDE at the Dumball rally

March 5, 2016/2 Comments/by Simon Hughes

I’m sure I’m not the only one to board a long haul flight with the aim of catching up on a little CPD reading, only to be led astray by a series of films that later I’ll never admit to watching. Still they can be educational, as having stopped studying History at the age of 12 I’m ashamed to admit that without this educational medium I would never have been aware that the 16^th President of the United States spent his formative years hunting Vampires. So in January 2016 I boarded a 10-hour flight from London to Chennai equipped with the latest publication from the STAMPEDE Study, a Workshop Manual for the Hindustan Ambassador, and a sense of inevitability that I’d be watching Matt Damon land on Mars before we’d finished crossing Kent. Taking a car manual for in-flight entertainment was not a cunning plan to encourage my neighbouring passengers to change seats before I engaged them in conversation. I have an unread copy of Donald Trump’s 2009 tome “Think Like a Champion” that fulfils that role perfectly. The manual was my homework, as I was en route to join the Dumball Rally.

The Dumball Rally is a fancy-dress charity banger rally – that raises money for the Teenage Cancer Trust. Since its inception in 2006 (Amsterdam to Athens) it has raised over £650,000. This year the route was Chennai to Goa, via Kanyakumari (the Southern Tip of India), the Western Ghats, Cochin, and for our team a stapes-shuddering Rock Bar in Mysore. 37 Hindustan Ambassadors awaited us on the start-line, their fully enclosed monocoque chassis based on the Morris Oxford Series III that last rolled off the production line in Cowley in 1959 – just in case you’re thinking I didn’t read the manual.

As a Clinical Oncologist I’m admit to being in one of the more geek-orientated specialities. Who needs a PDE5-inhibitor when a graph depicting a Bragg Peak excites you? So as I read about the history of Hindustan Motors, and the inner workings of my Ambassador, I was struck by the commonality of their significant anniversaries with those of my chosen profession. Hindustan Motors was founded in 1942, the year after Charles Huggins published his seminal paper on Prostate Cancer. The Morris Oxford Series III began production in 1956, the same year that Hertz and Li first described the successful use of cytotoxic chemotherapy (methotrexate) to treat a solid tumour (Choriocarcinoma). The production of the Hindustan Ambassador began in 1958, the year Rosalind Franklin died. The final version of the Ambassador (the Avigo) began production in 2004, the same year Tak327 was published demonstrating a survival advantage for Docetaxel and prednisone in metastatic castrate-resistant prostate cancer. Who said altitude and wine don’t mix well?

The rally began on 10^th January 2016. Our team, dressed as Dick Dastardly and Muttley (wise outfit choices in greater than 30 degrees centigrade heat), were pitted against a range of other themed cars from a fire-engine (with wired-in power washer), a yellow-submarine (broadcasting “Beatles” songs), to the Jungle Book (which continuously grew with foliage collected from the roadside). The Rally results are summarised below, and compared with the results from the STAMPEDE Study (finally read on the return flight).

STAMPEDE is a study assessing the impact of intensifying initial treatment for locally advanced and metastatic prostate cancer. Its novel Multi-Arm Multi-Stage (MAMS) design may prove as important to future cancer care as the results generated by the study itself. Basically MAMs permits multiple different primary questions to be addressed simultaneously and sequentially over a far shorter time period, and with fewer subjects, than would be required to address the questions separately.

Median Overall Survival for the Standard of Care (SOC) arm of STAMPEDE was 71 months, which increased to 81 months with the addition of 6 cycles of Docetaxel Chemotherapy. There was no additional benefit with the use of Zoledronic acid (with or without Docetaxel). Looking at the subset with metastatic disease, Median Overall Survival increased from 45 months to 60 months with the addition of Docetaxel, demonstrating that this should now be standard of care in suitable patients with metastatic disease. Regarding the Median Overall Survival for the Dumball Rally, there were insufficient events (only 1 car had to be abandoned), and follow-up is too short (8 days) to report meaningful data.

Median Failure Free Survival (FFS) for the SOC arm of STAMPEDE was 20 months, which increased to 37 months with Docetaxel. The hazard ratios were similar for both metastatic and non-metastatic subsets. Again there was no additional benefit with the addition of Zolendronic acid. The median FFS for the Hindustan Ambassador was about 6 hours. The passenger seat and seat-belt broke in our car whilst exiting the car-park having just collected it; most cars over-heated daily (interestingly the electrics are located directly beneath the radiator overflow); one engine seized completely; and an axel broke on Dumball 1, the organiser’s car.

Grade 3 + adverse events reported within the first 6 months of the STAMPEDE Study increased from 17% in the SOC arm to 36% with the addition of Docetaxel. Despite this the chemotherapy was well tolerated, with most patients completing all 6 planned cycles with minimal changes in dose or scheduling. Regarding the Rally, ironically it coincided with India’s National Road Safety Week. Their slogan “Hurry leads to worry; Accident brings tears; Safety brings cheers” repeated Orwellian-style in my subconscious as we negotiated the Indian traffic. In India they drive on the left……and sometimes the right, the middle of the road, the pavement –in fact wherever they want! A gentle toot of the horn lets other road users know where they are, and it appears to be the driver’s responsibility to avoid anything in front of them – no matter how late it pulls out. But it works – and everything keeps moving with good humour and smiles. It wasn’t unusual to be horrendously cut-up, only for the “offending driver” to then stop, get out the car and come over for a friendly chat and a photo opportunity. As a result, there were minimal adverse events – other than putting on a few additional Kg in weight eating curry 3 times a day.

Work on next year’s Dumball Rally has already started – rumours are that it may involve Nepal. If anyone is interested in taking part, please look at their website: www.dumball.org

Simon Hughes is a Consultant Clinical Oncologist at Guy’s and St Thomas’, London

The Zika virus epidemic in the Americas

March 3, 2016/by Miguel Hernando Parra Avila

In May 2015, Brazil reported for the first time home-grown cases of Zika virus, since that moment the cases have increased dramatically and the infection caused by this virus has been spreading quickly to 22 other countries in the Caribbean, South and Central America. The spread of Zika in South America has been developing rapidly, pushing the WHO to declare the Zika epidemic as a Public Health Emergency of International Concern in February of 2016.

Zika virus was isolated accidentally for the first time from rhesus macaques in 1947, in the area known as Zika forest, located in Uganda; later, researchers observed that the virus could infect humans, but human infections have remained confined to Africa and Asia with few cases reported, until now when thousands of cases have been reported in South American countries since 2015.

Zika is an emerging mosquito borne virus, closely related to other important human viruses transmitted by mosquitoes like Yellow Fever, Dengue, and West Nile virus. The virus has a positive single strain of RNA genome, and belongs to the Flavivirus family. It is transmitted through the infected female mosquito Aedes spp bite, the same vector as Yellow Fever, Dengue, and recently Chinkungunya in the Americas. Distinct species of Aedes mosquitoes are related with the transmission of the virus; however, Aedes aegypti is the most common vector associated with the infection in humans. These mosquitoes are found in many countries in the Americas, a fact that have been contributing to introduction and spread of the virus inside the continent. Additionally, researchers have reported sexual, blood transfusions, and perinatal transmission.

The symptoms of the Zika infections are pretty similar to other mosquito-borne diseases that are circulating in the same geographical areas such as Dengue and Chinkungunya. These diseases are characterized by fever, headache, arthralgia, myalgia, rash, and conjunctivitis, making it difficult to make a differential diagnosis. Epidemiological data showed that until December of 2015, between 440,000 and 1.3 million of Zika cases were reported in Brazil. Additionally, data obtained from Health Ministry of Brazil also reported a significantly increasing number of microcephaly cases in areas infested with Zika, suggesting a possible relation between Zika and microcephaly. Recently, The New England Journal of Medicine reported the identification of Zika virus in fetal brain tissue obtained from a 32 weeks of gestation fetus with serious signs of microcephaly that was aborted after his mother had symptoms related with Zika some weeks after, supporting the idea that Zika virus could be associated with the development of microcephaly in the fetus. Sexual transmission of Zika has also been reported, but the information about it remains confused. Nevertheless, Zika virus has been isolated from semen.

Other neurological symptoms like Guillain-Barré syndrome have been associated with Zika infections. Reports obtained from outbreaks of Zika in French Polynesia in 2013, and Brazil in 2015, showed an increasing number of Guillain-Barré cases probably associated with Zika.

According with the epidemiological data, Colombia is the country second most affected by the Zika virus. Reports from Instituto Nacional de Salud (INS) showed that until January of 2016, 27,454 cases of Zika have been reported, no official data about increasing cases of microcephaly or Guillain-Barré related with Zika infection were observed.

With the 2016 Olympic games due to be held in Rio de Janeiro in August, the World will be watching how Brazil and other South American countries manage the spread of Zika virus in the coming months.

Miguel Hernando Parra Avila, Bact. MSc. PhD.

Posición Post Doctoral

Grupo BCEM (bcem.uniandes.edu.co)

Departamento de Ciencias Biológicas

Universidad de los Andes

Bogotá, Colombia

Where we are with screening and risk prediction for prostate cancer in 2016

February 22, 2016/by admin Z.9

The rate of PSA-based screening over the last 35 years can be compared with driving your car from the Netherlands to Italy. It starts with a rather ﬂat drive, perhaps a few hills in the Southern part of the Netherlands, which represents the rate of PSA screening in the late 1980s. Moving with high speed through Germany, one gradually climbs to higher altitudes, i.e. the rate of PSA testing in the 1990s. Then the high (but very difﬁcult to drive) summits and beautiful valleys of Switzerland are there, representing PSA testing practices in the new millennium and the decline in metastatic disease and related mortality [1]. Finally, we descend to Italy’s Po valley, comparable to PSA testing rates, especially in the USA after the recommendations of the USA Preventive Services Task Force [2,3].

The question is what will we do next? Will we take a left turn and slowly disappear into the sea like Venice? That is, returning to a situation where one out of two or three men died from their prostate cancer? [4] Or will we stop our car, look behind, see the beautiful landscape and return taking the Gotthard road tunnel, avoiding spillage of petrol (i.e. unnecessary PSA testing and potentially harmful prostate biopsies) and go straight to the valleys of Switzerland?

The ﬁrst option is obviously not the way to go. Unfortunately, the recommendation to stop the use of the PSA test as a screening tool is a direct consequence of the rapid and uncontrolled uptake of the test, often followed by a random biopsy resulting in over-diagnosis and subsequent overtreatment. However, there are ample tools available to turn this situation around and reduce the negative effects of prostate cancer screening [5,6].

An example of such an approach can be found in the publication of Poyet et al. [7] in this issue of BJUI. In this study, the investigators validated updated versions of two multivariate risk-prediction tools, i.e. prostate cancer risk calculators (RCs), in a cohort of 1996 men all biopsied (6-, 8- or 12-core random biopsy) on the basis of an elevated PSA level or abnormal DRE. The data showed that both RCs outperformed the PSA/ DRE-based strategy in reducing unnecessary testing, and in addition avoided over-diagnosis. As said, this approach is one of the many opportunities to reduce the negative aspects of PSA-based screening all summarised in the different guidelines [8]. Reading these guidelines, it soon becomes clear that it is known that repeatedly testing men with low PSA levels is useless. It is known that screening men with a limited life expectancy will only cause harm, and that simply repeating a prostate biopsy after a negative biopsy result (i.e. no prostate cancer detected) is not the way to go. And yet, this is what we see happening in daily clinical practice [9,10].

So, where are we with prostate cancer screening and risk prediction in 2016? We are in a situation that we know that we can reduce suffering and death from (metastatic) prostate cancer, with early detection and treatment, but that we have to selectively identify men that can actually beneﬁt. The latter is realistic if we start to implement the knowledge we have acquired over recent decades.

Monique J. Roobol

Department of Urology, Erasmus University Medical Center, Rotterdam, The Netherlands

References

1 Schroder FH, Hugosson J, Roobol MJ et al. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet 2014; 384: 2027–35

2 Moyer VA; U.S. Preventive Services Task Force. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012; 157: 120–34

3 Banerji JS, Wolff EM, Massman JD 3rd, Odem-Davis K, Porter CR, Corman JM. Prostate Needle Biopsy Outcomes in the Era of the U.S. Preventive Services Task Force Recommendation against Prostate Speciﬁc Antigen Based Screening. J Urol 2016; 195: 66–73

4 Hsing AW, Tsao L, Devesa SS. International trends and patterns of prostate cancer incidence and mortality. Int J Cancer 2000; 85: 60–7

5 Roobol MJ, Carlsson SV. Risk stratiﬁcation in prostate cancer screening. Nat Rev Urol 2013; 10: 38–48

6 Emberton M. Doubling our precision of risk stratiﬁcation in early prostate cancer: too good to be true? BJU Int 2016; 117: 8–9

7 Poyet C, Nieboer D, Bhindi B et al. Prostate cancer risk prediction using the novel versions of the European Randomised Study for Screening of Prostate Cancer (ERSPC) and Prostate Cancer Prevention Trial (PCPT) risk calculators: independent validation and comparison in a contemporary European cohort. BJU Int 2016; 117: 401–8

8 Loeb S. Guideline of guidelines: prostate cancer screening. BJU Int 2014; 114: 323–5

9 Nordstrom T, Aly M, Clements MS, Weibull CE , Adolfsson J, Gronberg H . Prostate-speciﬁc antigen (PSA) testing is prevalent and increasing in Stockholm County, Sweden, Despite no recommendations for PSA screening: results from a population-based study, 2003-2011. Eur Urol 2013; 63: 419–25

10 Drazer MW, Huo D, Eggener SE. National Prostate Cancer Screening Rates after the 2012 US Preventive Services Task Force recommendation discouraging prostate-speciﬁc antigen-based screening. J Clin Oncol 2015; 33: 2416– 23

Correction: The word “their” was added to this sentence to clarify its meaning: “That is, returning to a situation where one out of two or three men died from their prostate cancer? [4]”

RSM Winter Meeting in Saalbach, Austria

February 2, 2016/6 Comments/by Rebecca Tregunna

This year the urology section of the RSM held their annual winter meeting in Saalbach, Austria hosted by Tom McNicholas and Rik Bryan.

Kicking off the meeting was a state of the art lecture by Professor Shahrokh Shariat, Professor of Urology at the Medical University of Vienna who presented a convincing perspective on whether we should really be calling Gleason 3+3 disease “prostate cancer” due to the lack of hallmarks of cancer compared with Gleason four disease, and clinical data suggesting that Gleason 3+3 cancer does not metastasise. Education of patients to ensure compliance of active surveillance is surely key to ensuring that change in disease pattern or small volume higher Gleason grade disease is not missed. Interestingly from Dominic Hodgson’s experience in Portsmouth approximately 50% of patients with Gleason 3+3 disease on TRUS were upgraded to Gleason 3+4 on template biopsy, although these patients who went on to have more extensive biopsies did so due to other concerning parameters. SIN PIN keeps you connected to your loved ones around the world! All New Customers receive $1 FREE to try SIN PIN International Calling Service. Make High Quality International Calls to those who don’t have the SIN PIN App yet. Never go out of touch with the ones you care about most! SIN PIN keeps you connected! You can find here the free International calling app Ft Lauderdale FL.

The bladder and upper tract cancer session was also a highlight with Rik Bryan presenting data on the use of ‘Oncoscan’ to detect genomic profiles and aberrations in urinary DNA from cell free centrifuged urine. This however was not absolutely specific to bladder tumours as undiagnosed prostate cancer was also detected in one of the tested urine specimens.

The Bladder Path trial being set up by Professor Nick James was also discussed. This trial hopes to investigate the addition of MRI into the haematuria clinic pathway. TURBT in muscle invasive disease does not completely stage tumours and may lead to a delay in definitive treatment. There is no current evidence that debulking of tumour is necessary prior to radical treatment. This randomised controlled trial will review whether MRI as opposed to TURBT could be used for staging in likely muscle invasive tumours with the phase II and phase III aspects looking at time to definitive treatment and time to recurrence or progression.

Professor Karl-Dietrich Sievert from the Universitätsklinik für Urologie und Andrologie, Saltzburg demonstrated how his unit use Diffusion Tensor Imaging MRI to visualise white matter and plan for nerve sparing prostatectomy to preserve post-operative incontinence and erectile function. We also heard how Tim O’Brien has learned many of his lessons in complex renal cancer surgery the hard way, in an inspiring and candid talk.

For the benign urologists there were a plethora of sessions on male and female incontinence as well as male and female ejaculation! Matthew Bultitude and I (RT) debated on medical expulsive therapy for ureteric stones in the wake of the SUSPEND trial. Although the majority of the room seemed convinced of the lack of benefit for small ureteric stones, there appeared to be some doubt created by the regarding larger distal ureteric stones.

We also had a lot of interesting non-urological discussions. From Martin Mansell, Consultant Nephrologist we heard of the change in law since the Montgomery Judgment leading to the necessity for doctors when taking consent to inform patients of any risk no matter the likelihood of the risk occurring if that particular patient would attach significance to that risk. Mark Speakman pointed out that this may mean a change in the BAUS consent forms which many of us use to consent patients. We also heard of new educational tools such as MedShr from Asif Qasim, Consultant Cardiologist, which is an app serving as a platform to discuss complex cases with colleagues from around the world. BAUS President Mark Speakman presented the BJUI Knowledge tool which allows BAUS members to access interactive e-learning modules and log CPD activity.

2016 marked the 34th annual winter meeting for the urology section of the RSM and we paid tribute this year to Peter Worth who has been a regular attendee since the beginning. With a fantastic meeting already planned in Lake Tahoe for 2017 to mark the 35th year hosted by Professor Roger Kirby and Matthew Bultitude, I would encourage as many trainees and consultants to attend for both a rigorous transatlantic educational programme as well as a fantastic opportunity to meet new colleagues and, of course ski!

Rebecca Tregunna (ST4, Alexandra Hospital, Redditch (Worcestershire Acute Hospitals NHS Trust) – @rebeccatregunna

Dominic Hodgson (Consultant Urologist, Queen Alexandra Hospital, Portsmouth) – @hodgson_dominic

Importance of fundamental science as the cornerstone for translational research

January 24, 2016/by admin Z.9

Research headlines that attract the most publicity are those that show success in beneﬁtting patients, whether it is through new targeted drugs or new immunotherapies. Many funding bodies and charities have also changed their policy toward funding more translational research that has clear economic, clinical and patient beneﬁt. We must remember, however, that the innovations for these transformative publications and translational research projects are imbedded in our fundamental understanding of the molecular and cellular biology of disease investigated at the basic science level. These investigations are the cornerstone of translational research.

The BJUI has continued its tradition of publishing fundamental research with translational insight, and this is exempliﬁed in this month’s article by Liu et al. [1], which undertakes to explain the mechanistic and functional role of EZH2 in RCC. In this study the authors manipulate the expression of EZH2 by silencing it using short-hairpin EZH2, which targets the RNA. They also use a small molecule inhibitor of methyltransferase which has been shown to deplete the expression of EZH2. Both these approaches inhibit EZH2 expression, which was associated with reduced migration and invasion of the cancer cells, as assessed in in vitro models, as well as with slowing tumour growth and prolonging survival in an in vivo nude mouse model. These changes were mechanistically explained by a change in the mesenchymal epithelial transition phenotype of the tumour cells. The authors then went on to show that EZH2 is associated with E-cadherin suppression and poor survival in patients with RCC, demonstrating the translational importance of these ﬁndings.

This impo rtant fundamental and translational paper adds to the growing body of evidence that EZH2, which is a histone methyltransferase and regulator of gene expression, plays a key role in the development of a range of cancers including prostate, breast, lymphoma and colon [2].

The Translational Science section of the BJUI is looking for relevant and citable articles similar to the paper by Liu et al., which are imbedded in fundamental science and bring the concept into clinical investigation, either through its validation in clinical material or manipulation in clinically relevant in vivo model systems, and represent a clear translational step.

To facilitate our readers’ understanding and to familiarize them with often complicated and complex fundamental scientiﬁc concepts, in 2013 the BJUI introduced the ‘Science Made Simple’ review-type article section, in which various scientiﬁc concepts are explained so as to assist interactions between scientists and clinicians as they translate their ideas and ﬁndings into clinical utility.

References

1 Liu L, Xu Z, Zhong L et al. Enhancer of zeste homolog 2 (EZH2) promotes tumour cell migration and invasion via epigenetic repression of E-cadherin in renal cell carcinoma. BJU Int 2016; 117: 351–62

2 Simon JA, Lange CA. Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat Res 2008; 647: 21–9

R. William Watson, BJUI Consulting Editor, Translational Science

UCD School of Medicine and Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland

The British Association of Urological Surgeons nephrectomy audit for T1 renal tumours

December 18, 2015/2 Comments/by Prokar Dasgupta

It is hard to believe that 3 years have elapsed since my new team took over publishing the BJUI, aiming to make it ‘the most read surgical journal on the web’. Many of our readers believe that we have achieved that and a number of web statistics indicate that we are not far away. Complacency is not in our DNA and this year you will notice a number of subtle changes to www.bjui.org to make it even more attractive and user friendly. Of course we rely heavily on feedback from o ur authors and readers. The January 2016 issue includes our ‘Thank you to reviewers’ online, listing all 785 people who have reviewed for us in 2015. We just cannot achieve our high standards without you. Each reviewer is entitled to Continuing Professional Development (CPD) points as a recompense for the time they spend helping us select only the very best papers.

Last year, we published a fantastic selection of ‘Articles of the Month’. If you missed any, you can ﬁnd them collected together in our free online virtual issue (https://bit.ly/ZrWA6q). The end of 2015 was dominated by falling PSA testing and prostate cancer detection rates, as highlighted in David Penson’s editorial in JAMA [1]. In the UK and many other parts of the world we have already been through this. I remember during my training years that the majority of men presented with locally advanced or metastatic disease. And while we look towards ‘smart’ screening of high-risk groups, particularly those with a relevant family history of prostate and breast cancer, I urge you again to look at the summary table of our ‘Guideline of Guidelines’ by Loeb [2] on this thorny subject.

The BAUS has taken the lead on public reporting of surgical outcomes. The BJUI is proud to publish our nephrectomy audit [3], which has >6000 patients. Radical nephrectomy (RN) was performed mostly for T1b and partial nephrectomy (PN) for T1a tumours. Over 90% of RNs were minimally invasive – an established standard of care. Only 43% of PNs were minimally invasive of which one-third were robotic, with no obvious difference between the robotic and laparoscopic arms. As expected, the complication rates of PN were higher than RN. All of us as surgeons can learn a lot from large national datasets such as this and, more importantly, strive to improve continuously. I hope you enjoy reading this important paper and look forward to interacting with many of you in 2016.

References

1 Penson DF. The pendulum of prostate cancer screening. JAMA 2015; 314: 2031–3

2 Loeb S. Guideline of guidelines: prostate cancer screening. BJU Int 2014; 114: 323–5

3 Hadjipavlou M, Khan F, Fowler S et al. Partial vs radical nephrectomy for T1 renal tumours: an analysis from the British Association of Urological Surgeons Nephrectomy Audit. BJU Int 2015; 117: 62–71

Prokar Dasgupta, Editor-in-Chief, BJUI

King’s College London, Guy’s Hospital, London, UK