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Heroes

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Being an Irishman, and enthusiastic rugby supporter, I, like many other rugby fans, was much vexed when our Irish rugby hero, Brian O’Driscoll, was dropped for the deciding Test for the British and Irish Lions versus Australia this summer.  This vexation was due somewhat to national pride, but more importantly, because he is one of my sporting heroes. This outpouring of emotion on the demotion of someone I’ve never met led me to contemplate the nature of heroism and heroes, how they affect us, and specifically how heroes can have a positive impact on urologists in this day and age of constant cynicism towards the noble deeds of others.

Heroism is defined as conduct as exhibited in fulfilling a high purpose or attaining a noble end. To this end, how does my rugby hero qualify? Is it his display of innate skills that thrill the crowd? Is it his professional attitude to the institution of his sport/profession? Is it his ability to overcome adversity for the good of his team?  (These are all attributes I see in my Urological heroes.)  Personally, I think back to moments where I realised that he had done things that I couldn’t even imagine being able to do, and just marvel at them.  Passing the ball to himself and ghosting past the opposition, scoring a length of the field try and being physically ill afterwards due to a pre-existing virus, being listed as ‘likely to play’ for the following week with a personal injury list of ‘concussion, torn hamstring and lacerated ear’. These are levels of physical and athletic prowess unattainable by most people.

 

But what of others that I would class as heroes? It is 50 years this June since the late John F. Kennedy made his famous speech in Berlin, immortalised by the phrase “Ich bin ein Berliner’.  However, his greatest segment is when he lists some of the positives that people were attributing to Communism at the time, and extolling his own personal opposition with the repeated statement ‘Let them come to Berlin!’  Watching the reaction of a group of Berliners to this speech 40 years after its occurrence, seeing them moved to tears by his reiteration of the support of the free world to the citizens of Berlin, this alone is enough to convince me of the heroism of this amazing, somewhat flawed, ever impressive man.

Heroism can also be displayed by people using their professional experience to reach extraordinary outcomes in the face of enormous adversity. Captain Chesley ‘Sully’ Sullenberg, who, after a complete engine failure on his commercial jet, in the space of 180 seconds, managed to control and ditch his plane on the Hudson River in New York, saving 155 souls. His wife, on being told that her husband had landed a multi-ton commercial jet in a river, with no harm to anyone, apparently replied laconically “Oh that sounds like Sully, alright”.

But how does this relate to urologists?  It is my personal belief that the ‘heroes’ we have in society today are not fit for purpose, vacuous celebrities of little consequence in general, and that we would all gain much by having a number of personal and professional heroes that we can use as an example when adversity, conflict, or difficult decisions face us as surgeons. Surgeons should, and often do, aim to attain a noble end. I have many heroes in Urology in particular, and often use their example, and sage-like advice in times of difficulty,

It is extremely easy to live life these days in a manner that loses sight of the wonder and awe with which we held medicine when young. It is easy to live life in a manner where much of it seems jaded and worn. It is easy to believe that there are things we cannot do, goals we cannot reach, achievements we cannot achieve. In these situations, having a hero, whose deeds seem somehow beyond what the rest of us can do, can give us a guide, an example to strive to emulate, attempt to equal, maybe even to surpass.  It is this aspect of heroism which can be utilised as something to be aspired to, for the betterment of all.

On a final note, I am often astounded by the heroism of my patients.  For these people to be able to face ill health, their own frailties and mortality and put their trust in us as surgeons, especially if we are recommending a new or unique form of treatment, is to display a level of trust that definitely puts them in the pantheon of heroes for me.  I believe we owe it to them to remain interested, invigorated and willing to sacrifice ourselves to emulate our heroes, for their benefit.  Heroes are great, everyone should have one!

 

David Bouchier-Hayes is Consultant Urologist and Robotic Surgeon Honoray Clinical Lecturer at the Galway Clinic, Doughiska, Co. Galway, Ireland. Follow him on Twitter @dbh44

Editorial: Regulatory T cells in renal cell carcinoma: additional fuel to the bonfire of debate

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In the developing immune system, all T cells are positively selected in the neonatal thymus for the ability to recognize self-antigens, the major histocompatibility complex (MHC) proteins. Thus, the mature T-cell repertoire is trained to ‘see’ foreign pathogens ‘complexed’ with those self-antigens (‘MHC-presentation’). Fundamentally, this requirement predisposes mammalian systems to the development of autoimmune diseases, as all T cells are self-reactive. That such diseases are the exception rather than the rule is attributable to a small population (∼2–5%) of circulating T cells, termed ‘regulatory T cells’ (Tregs), that suppress the activation and function of many other immune cells. The fine balance between Tregs and other pro-inflammatory cells is essential for maintaining self-tolerance while allowing immunological reactivity against danger signals such as foreign antigens (mostly pathogens) and malignant cells. Many pathogens co-evolving alongside the mammalian immune system have learned to ‘hijack’ this balance to propagate disease or to inhibit their own clearance, notably Leishmaniasis, malaria, tuberculosis, HIV, hepatitis C virus and Helicobacter pylori. In these scenarios, an excess of Tregs induced by the pathogens prevents their clearance and establishes infective chronicity.

Likewise, in malignant diseases, such as pancreatic and ovarian cancer, an excess of Tregs is thought to contribute to failure of the immune system to clear neoplastic cells. Whether the tumour environment appropriates the regulatory function of Tregs to propagate its own survival in a manner akin to infectious agents, or whether Tregs infiltrate larger tumours in which there is more chronic inflammation is unclear. Nevertheless, a correlation between higher Treg numbers and poorer outcomes is a common feature of malignancies. In this issue of the BJUI Polimeno et al. add evidence to the debate over whether Treg numbers in RCC are associated with worse outcomes. While previous publications both support (Cancer Immunol Immunother 2007, BJU Int 2009) and refute (Clin Cancer Res 2007) this assertion, the data presented by Polimeno et al. identify not only increased circulating Treg numbers in patients with RCC but also find an association betweenTreg numbers, especially those that express the naïve T-cell marker CD45RA, and both larger tumour load and worse prognosis. In the same dataset, as expected, the authors also find that a shorter disease-free survival was evident in patients with lower numbers of tumoricidal natural killer cells. In the serum, patients with RCC had higher concentrations of soluble factors involved in cell growth and movement, such as epidermal growth factor, hepatocyte growth factor, vascular endothelial growth factor and interferon γ-induced protein 10 (also known as CXCL10), and markers of active inflammation, such as interleukins 6 and 8.

These observations suggest several broad possibilities: (i) that the ‘Tregs’ identified in the tumour environment and circulation are not Tregs but are in fact other activated T cells that temporarily express the same surface markers as bona fide Tregs; (ii) that Tregs in the context of RCC are unable to control tumour-associated inflammation; (iii) that Tregs contribute to tumour survival by inhibiting clearance of neoplasms by other immune cells, resulting in chronic inflammation; and/or (iv) that Tregs are actively contributing to the inflammation by converting to pro-inflammatory phenotypes, as has been demonstrated by several groups. These possibilities can be differentiated by isolating Tregs from the tumour environment or local draining lymph nodes and testing their functional characteristics in vitro; however, the fact that CD45RA+ Tregs were independently associated with worse outcomes makes (i) and (ii) less likely, as such cells are less likely to be recently activated and are inherently less plastic than other populations of Tregs.

In our opinion, the clinical value of the data presented in this paper and those of others, even if the underlying biology is poorly understood, should next be determined in a prospective study to see whether the immunological ‘fingerprint’ in peripheral blood can correctly identify those patients who are more likely to do poorly, targeting them for closer monitoring and/or more aggressive therapy.

Behdad Afzali and Giovanna Lombardi
Medical Research Council Centre for Transplantation, King’s College London, King’s Health Partners, Guy’s Hospital, and National Institute for Health Research Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, Guy’s Hospital, London, UK

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Conference Report – ERUS 2013 – live surgery spectacular in Stockholm

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When it comes to live surgery meetings, one of the biggest and best of them all is the EAU Robotic Urology Section (ERUS) Congress (formerly the European Robotic Urology Symposium). The 10th edition of ERUS took place in Stockholm this week and continued the tradition of spectacular live robotic assisted surgery, along with scientific sessions dealing with issues around robotic assisted surgery. Following discussions with the EAU over the past two years, ERUS has now become an official section of the main EAU Organisation and future scientific and educational activity will be co-ordinated under that esteemed banner. In his welcoming address at this weeks meeting, EAU Secretary General and proud Swede Per-Anders Abrahamsson, warmly welcomed ERUS into the EAU family. He also highlighted the mission statement of ERUS, “to support science and education in the field of robotic urology”.

Over 750 delegates gathered from around the world (including a healthy delegation from Australia, South America and the USA), giving this meeting a truly global footprint. The programme featured 12 live surgical procedures performed by some of the world’s leading robotic surgeons and broadcast in full 3-D from Karolinska Hospital.

 

This meeting has showcased many advances in roboticsurgery over the past 10 years and this year was no exception. The audience seemed most interested in extended public lymph node dissection during radical cystectomy and prostatectomy, as well as intra-corporeal urinary diversion and complex partial nephrectomy. This year’s starring surgeons included Alex Mottrie, Peter Wiklund, Magnus Annerstedt, Geoff Coughlin, Hubert John, Aldo Bocciardi, Jean Palou, Carl Wijburg, Craig Rogers, Jim Porter, Tim Wilson, Vip Patel and Abi Hosseini. An outstanding line-up of surgeons from all over the world.

Of note, this Section has led the development of ethical guidelines around the conduct of live surgery and these have been fully endorsed by the EAU. We have previously blogged about this issue and I have blogged about my own experience of doing live surgery at ERUS 2012 in London.  As part of the live surgery ethical governance, Convener of ERUS 2012, Ben Challacombe (London), presented an update on the outcome of all patients who underwent live surgery as part of last years meeting.

The main scientific meeting was preceded by the Junior ERUS Section, the Nursing Course on Robotics, and five master classes led by experts and dealing with various aspects of robotic assisted surgery.  The Junior ERUS Prize was awarded to Khan et al who presented a poster on behalf of the International Robotic Curriculum Group entitled, “Towards a Standardised Training Curriculum in Robotic Surgery”. There were also a number of parallel meetings dealing with education and scientific activity within ERUS/EAU, in particular, the development of structured robotic training and a robotic surgery curriculum across Europe and beyond. The BJUI Editor in Chief Prokar Dasgupta, a well-known robotic surgery innovator and also an expert in simulation and education, is playing an active role coordinating development of this curriculum. European Urology Editor in Chief Jim Catto, was also present at ERUS 2013 and delivered a podium presentation outlining some of the exciting changes which the Platinum Journal will undertake once he takes over in January 2014. What is clear is that robotic surgery is an important part of the content for both of these leading journals.

Of course, this meeting has a particular reputation as being a friendly and sociable event (a point repeatedly mentioned by many of the Intercontinental visitors). The local organising committee pulled out all the stops with the official social events by hosting the welcome reception at the Stockholm City Hall, home of the famous Nobel Prize banquet each year. The gala dinner was in the spectacular Vasa Museum, surely one of the world’s most spectacular maritime museums.

We were treated to a tour of this spectacular, fully intact 17th century warship, followed by dinner in the shadow of this huge exhibit, notorious for capsising in Stockholm harbor only 15 minutes into her maiden voyage.

As we have seen at all major urology meetings this year, social media played a prominent role in expanding the reach of the meeting and in enabling engagement from within the audience and from around the world. The conference organisers placed a Twitter feed on the panellists monitors so that questions could be directed via Twitter to the expert panels and to the operating rooms.

 As if the spectacular multiple source 3-D display was not providing enough content, social media guru Carl Wijburg was busy tweeting “backstage” photos from Karolinska as he waited to perform a meticulous extended pelvic lymph node dissection.

 

 The final data from Symplur showed just how enthusiastically delegates from all over engaged with the meeting through Twitter.

 

Congratulations go to the organisers and scientific committee of #ERUS13 led by Alex Mottrie (Belgium), Peter Wiklund (Stockholm) and Magnus Annerstedt (Copenhagen) who did an outstanding job putting on this complex congress.

We are already looking forward to ERUS 2014 which takes place in beautiful Amsterdam from 17- 19th September 2014, led by Chair of the Local Organising Committee, Henk van der Poel. A must-attend for anyone interested in robotic surgery.

 

Declan Murphy BJUI Associate Editor

Follow Declan on Twitter @declangmurphy

 

Chemoprevention of Prostate Cancer – Is it justified?

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The September #urojc International Urology Journal Club discussion on twitter was based on the paper “Long-Term Survival of Participants in the Prostate Cancer Prevention Trial” published in the New England Journal of Medicine a few weeks earlier.

In 2003, the Prostate Cancer Prevention Trial (PCPT) proved what it set out to do. It significantly reduced the risk of PCa. Unfortunately, the champagne was never even taken off ice, as finasteride was also associated with an increased risk of high-grade prostate cancer. In June 2011, US FDA ordered the drug’s warning label to be updated to state that finasteride may increase the risk of high grade prostate cancer. As a primary prevention drug for PCa, despite many published, favorable subgroup analyses, finasteride was quite flaccid in the eyes of many urologists.

 

Now, ten years after the PCPT was published and with up to 18 years of follow-up, would these long-term results be the catalyst to force an FDA backflip? Or would the specter of erectile dysfunction rise? Amongst the first tweets that were fired (no prizes to guess who it was)

Tweeted link by @LoebStacy

 

To summarise, this post hoc analysis – that wasn’t pre-specified in the original protocol – analysed rates of survival among all original PCPT study participants including those with prostate cancer. Prostate cancer incidence amongst PCPT candidates was collected for an additional year after the original report and the Social Security Death Index was searched to assess survival status until 31st October 2011.

In all 18,880 men, PCa was diagnosed in 10.5% of the finasteride group and 14.9% of the placebo group (RR in finasteride group, 0.70; 95% CI, 0.65 to 0.76; P<0.001). Furthermore, 333 (3.5%) in the finasteride group and 286 (3.0%) in the placebo group had high-grade cancer (GS, 7 – 10, RR, 1.17; 95% CI, 1.00 to 1.37; P=0.05). Fifteen-year survival rates of 78.0% (finasteride) and 78.2%, (control) were reported in the men who died. Unadjusted hazard ratio for death in the finasteride group was not significant. Ten-year survival rates were 83.0% (finasteride) 80.9% (placebo) with low-grade PCa and 73.0% and 73.6%, respectively, with high-grade prostate cancer.

The authors as well as the #urojc community were quick to identify limitations.

 

 

Indeed, since information regarding the mode of death for patients who passed away was unavailable, PCa specific mortality could not be reported by this study. In amongst the discussion regarding limitations, it was important to see twitter etiquette observed.

There was some discussion on whether high grade “finasteride” prostate cancer was morphologically identical to “placebo” prostate cancer or different?

 But at the end of the day, it doesn’t matter how it is discussed, packaged or assembled…

 

In an underpowered study, not designed to look at PCa-specific mortality, there was always going to be conjecture as to the benefit of reducing low grade PCa by 30% (in an era of increased active surveillance) whilst giving 1 in every 200 men offered finasteride high grade PCa.

Erectile dysfunction was an ever present factor during our discussion, although was generally thought of as #firstworldproblems

At times, when drawing conclusions, our intellectual, verbatim-driven minds give way to pictorial clarity; in other words a picture tells a thousand words. I still wonder how many a tweet is worth… In my very humble opinion, my conclusions are

1) 5 ARIs decrease low grade PCa, but low grade PCa doesn’t necessarily equal death, so…

2) Primary prevention for PCa would need to be robust, 5ARIs are too far from the mark

 

3) I thought appropriately chosen patient with bothersome LUTS, a large prostate with elevated PSA (proved to be cancer free or low volume GS 6) should go green (I can already feel the holmium lasers, microwave emitters and diode beams aimed behind my head, but that is a conversation for another time…)

 

The king summed it up well I think,

This month’s prize has been generously donated by Urological Society of Australia and New Zealand, one full registration to USANZ ASM 2014 in Brisbane! There was a clear winner who was novel in tweeting an image that said it all.

Congratulations to Dr Todd Morgan!

 

A warm thank you is extended to all who participated in this month’s #urojc discussion. All of you are encouraged to participate in next month’s discussion starting on 4th-5th October depending on your time zone.

Analytics for for this month’s discussion:

 

 

Dr George Koufogiannis is an Australian Urology Trainee, currently based at Port Macquarie Hospital. @DrVasano78 Vasano = torment, 78 = 1978, the year I began to torment my mother, who gave me the nickname.

Urological oncology in the BJUI

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Urological oncology is increasingly multi-disciplinary, and hence competitive for high impact thought leadership. Innovation leading to paradigm changes may come from a number of different ideas and sources. Effective leadership in our specialty certainly requires technical innovations in surgical treatments, but also pivotal roles in improving the process of diagnosis, staging, patient counselling, multi-modal therapy, and ultimately evidence-based clinical guidelines. The ultimate end-result of innovation is a peer reviewed publication, and at the BJUI we wish to bring you nothing but the highest quality.

Our daily lives are increasingly busy with our varying mixtures of clinical work, teaching, administration, and research. How much time do we have to read a surgical journal? It is an important part of our learning, but we must be efficient to squeeze it into a busy day. Keeping this in mind, the Editorial Board is more selective than ever in the papers that make it into the BJUI. Each paper we accept needs to represent something valuable to the reader and to our science, such as a technical innovation, large study of a new method to fix an unmet need, multi-institutional validation trial, or updated guideline. For this to work, we need fair and efficient peer reviewers, and high quality submissions.

In this month’s BJUI, we see encouraging work from multiple talented authorship groups who address a plethora of unmet needs. These papers show the diversity of impact the Editorial team is looking for in BJUI urological oncology submissions.

Prostate cancer, of course, is a common topic for new submissions and subsequent citations. In the field of localised prostate cancer and PSA screening, the recent U.S. Preventive Services Task Force (USPSTF) report was critical of our diagnostic practice results in terms of biopsy related complications and, of course, negative (a.k.a. unnecessary, a term we should drop) biopsies. I must confess that I am still stuck in the tradition of the PSA/DRE as the key driver of my recommendation for a biopsy, and several informal ‘raise your hand’ polls at meetings have produced little movement when asked if anyone has adopted newer calculators that incorporate TRUS volume. Why not change? The numbers certainly seem reasonable: an area under the curve (AUC) of 0.71 for DRE/PSA and 0.77 for the risk calculator. You can even make a crude DRE-volume estimate and improve your odds – AUC of 0.73 without and 0.77 with DRE-volume. If that sounds of interest, then perhaps the study by Carlsson et al. in this issue may interest you with their biomarker panel of kallikreins that can do the same work as the combined clinical efforts and reach AUCs of 0.76 alone, or 0.792 if you still want to add the DRE and TRUS volume. I agree with the authors, that this is perhaps a simpler model, which may allow the physician and patient some time to have a look at their risk of a positive biopsy and make a decision, rather than the idea of the last minute TRUS volume that is supposed to put the brakes on a biopsy at a certain size. With further refinement, we can all learn new thresholds for biopsy that are better selected, and in the future should always be calculated as overall cancers detected/missed and high-grade cancers detected/missed.

In addition, the USPSTF criticised the toxicity of a biopsy, and drug-resistant sepsis is an increasing problem. Symons et al. present an instructive series of transperineal biopsies and results, and they seem to have solved the sepsis problem (0.2%), but must weigh the added cost of anaesthesia, physician time, and no obvious difference in bleeding/other minor complications. I am increasingly interested in re-utilising this technique, which previously was only for third-line saturation biopsies. If you are also convinced, Kuru et al. present a tour-de-force presentation of transperineal technique, terminology, and data collection for a multi-centre collaboration.

Finally, in a must-read special article, Carter expands upon the recent AUA guidelines on PSA screening that were intensely debated, especially the recommendations against routine screening in men aged <55 years. Guidelines are an interesting area of study, and can vary in outcome based upon who is on them and what methodology/objectives are selected. If the guideline is meant to be best clinical practice, than the personnel can certainly be influential. However, if the guideline is meant to emphasise evidence-based recommendations, then in theory, any panel of experts will arrive at a similar place. This is the essential message from Carter, that the revised guidelines are meant to reflect the evidence, and currently we do not have level 1 evidence that involved screening men aged <55 years.

Closing this month in ‘Urological Oncology’, Cindolo et al. report an accuracy/generalizability study of the Karakiewicz nomograms for cancer-specific survival with RCC. These articles are, of course, largely statistical exercises, but very necessary, as we define populations suitable for surgery only vs those in need of neoadjuvant/adjuvant inclusion. Wong et al. conclude the month with an innovative report on office-based laser ablation of non-muscle-invasive bladder cancer using local anaesthesia, mostly in an elderly population. The study protocol allowed photodynamic diagnosis, and includes a cost analysis. The results certainly support continued use in this population where we commonly wish to avoid the morbidity of repeat general anaesthetics.

John W. Davis, MD, FACS
Associate Editor, BJUI

Original publication of this editorial can be found at: doi: 10.1111/bju.12380. BJUI 2013; 112: 531–532.

Editorial: Salvaging failed radiation therapy: does the tumour location permit a less toxic approach?

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In the introduction to their manuscript in this issue of the BJUI, Meeks et al. outline a significant challenge for physicians managing prostate cancer: from the estimated 240 000 diagnosed annually (USA) to the 120 000 choosing radiation, to the 40 000 estimated biochemical failures in the first 5 years who may benefit from additional local therapy to avoid local and/or systemic progression. The basis of these calculations was from conventional beam radiation, and although we expect dose-escalation strategies to perform better, the ideal management strategy remains to be identified. Indeed, Zelefsky et al. showed that there was a higher risk of metastatic disease with external beam radiation therapy than with surgery for high-risk prostate cancer, although there was some confounding of the results due to the differences in salvage treatment. This confounding may be the key point: more acceptable salvage options may promote optimal local control and fewer progressions.

Certainly, the concern with salvage therapy after failed radiation is the toxicity, and the concept of achieving less urinary incontinence with cryotherapy or even focal cyrotherapy is attractive, as outlined by de Castro Abreu et al. in this issue. In their parallel cohorts of total and focal salvage cryotherapy, urinary incontinence occurred in three (13%) of the 25 salvage total and zero of the 25 salvage focal therapies, and there was only one fistula in either series. However, the cancer control outcomes are different among these non-randomised and non-comparable cohorts: 87% disease-free survival for patients with bilateral disease treated with total cryotherapy and 54% disease-free survival for patients with unilateral disease treated with focal cryotherapy. These comparisons are limited, but one could hypothesise that salvage total therapy has improved disease control over salvage focal therapy.

Returning to the Meeks et al. study, a cohort of 198 patients with biopsy confirmed radiation recurrence underwent a salvage prostatectomy at a single institution. Pre-treatment biopsies showed 48% and 13% Gleason sums 7 and 8–10, respectively, and multifocal location in 61% (92/151 patients). Salvage prostatectomies showed 56% advanced pathological stage and 35% Gleason 8–10, and multifocal location in 57%. In comparing specific biopsy locations to radical prostatectomy mapping, undetected cancers from biopsy ranged from 12% to 26%, and 58% upgrading. In patients with unilaterally localised biopsies, final pathology was unilateral in only half – a statistic that matches the PSA failure rate from focal therapy in the de Castro Abreu et al.’s study. The authors point to a non-radiated biopsy-to-prostatectomy study and by comparison conclude that the accuracy of biopsy in radiated prostates is actually greater, perhaps due to the smaller radiated gland. But let’s be clear – both groups had significant rates of multifocal disease and inaccuracies between biopsy and radical prostatectomy.

These two BJUI studies provide a developing agenda of what we know and do not know about salvage therapy for failed radiation:

  • Local failure after radiation selects patients who probably have significant disease in terms of volume, stage, and grade, and should not be confused with the over-detection of low-volume, low-grade disease seen in primary treatments for PSA-screened disease.
  • Salvage focal therapy for unilateral disease by biopsy may be less morbid but may be only 50% effective.
  • The link between metastatic progression and PSA failure after failed salvage focal therapy is unknown, and completion treatment of the other side could be studied.
  • The additive accuracy of post-radiation biopsy plus imaging is not established.
  • We are basing most of our treatment recommendations on tumour morphology (histopathology, location, size) and surrogates (PSA failure definitions) rather than biology and survival.
  • The current management of post-radiation local failure should consider total gland treatments as the standard and focal therapies as experimental.

John W. Davis and Seungtaek Choi*
Departments of Urology and *Radiation Oncology, UT MD Anderson Cancer Center, Houston, TX, USA

Article by Meeks et al.
Article by de Castro Abreu et al.

Editorial: Micro-PNL vs RIRS: dealer’s choice? The devil is in the details

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Advances in minimally invasive endourological techniques continue to provide the Urologist a myriad of options for the management of symptomatic renal calculi. Previously, shock wave lithotripsy (SWL) or standard percutaneous nephrolithotomy (PNL) were the only two endourological options available. Yet, limitations of these two ‘standard’ techniques result from hard or dependent stones (for SWL) or the potential of increased morbidity during the treatment of small renal calculi (for PNL). Now the introduction of smaller fibre-optic needle-scopes combined with laser stone fragmentation (micro-PNL or ‘microperc’) provides access to difficult-to-reach renal calculi with minimal patient morbidity. Moreover, newer flexible ureteroscopes, along with nitinol baskets and graspers (retrograde intra-renal surgery or ‘RIRS’) allow another minimally invasive option for hard-to-reach renal calculi.

In the present issue of BJUI, Sabnis et al. present a well performed, randomised, prospective trial comparing microperc to RIRS for the management of renal calculi of <1.5 cm in diameter. They determined that both procedures were essentially identical in their ability to remove small-to-moderate sized renal stones with minimal patient morbidity/complications. Yet, both of these procedures have inherent limitations that are unique to the instrumentation used for each technique. Microperc has limited applicability for stones located anteriorly within the kidney, while RIRS is an ideal technique to access symptomatic renal stones within an anterior calyx. RIRS may not be able to target lower pole calculi in those patients with an acute infundibular angle or stones in a calyceal diverticulum, whereas a microperc can be used to reach hard-to-access calculi.

One must accept that both of these innovative procedures are inefficient in their ability for removal of large volume stones and neither technique offers an efficient method of clearing multiple stone fragments. Ideally, both microperc and RIRS should only be used for small volume renal calculi.

I would offer that both procedures are safe and effective alternatives for the management of small renal calculi. Yet, we must be realistic in offering these techniques to our patients, pairing each procedure with the most appropriate situation. Even in 2013, large volume renal calculi are best managed by standard or mini-PNL, where devices such as ultrasonic lithotripsy or dual ultrasonic/pneumatic lithotripsy offer efficient methods of stone removal. SWL is still a reasonable option for the treatment of renal calculi of ≤1 cm in diameter.

Now RIRS and microperc can be added to the list of treatment options for managing symptomatic renal calculi. In patients with large renal calculi, along with multiple medical comorbidities or bleeding diatheses/on anti-coagulation, RIRS provides another, yet inefficient, alternative for stone removal, often requiring multiple procedures to clear the stone. In those situations where the flexible ureteroscope cannot target a renal calculus of <1.5 cm, microperc provides the option of accessing the calculus, yet offers no method of efficiently clearing stone fragments. If we set reasonable expectations for the use of these two minimally invasive endourological techniques, our patients will surely benefit.

Glenn M. Preminger
Duke University Medical Center, Durham, NC, USA

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Conference Report: Prostate Cancer World Congress 2013, Melbourne, Australia

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Melbourne played host to the Prostate Cancer World Congress last week. With over 1,000 delegates and a stellar International faculty comprising of 21 global leaders, it was no surprise that tweeters worldwide battled off sleep to keep up with the action.

 

 

 

 

Amidst a buzzing crowd, overlooking the iconic @MCG #pcwc13 President Tony Costello reminisced about the very first conference; 2 speakers, 27 delegates made up largely of residents only fourteen years ago. Undoubtedly the highlight of the conference was the release of ‘The Melbourne Consensus Statement on Prostate Cancer Testing’. This gathering of worldwide experts allowed for the ideal opportunity to generate a set of consensus statements with the goal of finally ending the confusion that exists with current guidelines and allow for early detection of prostate cancer. 

https://www.bjuinternational.com/bjui-blog/the-melbourne-consensus-statement-on-prostate-cancer-testing/

As well as major media coverage following the statements release #PCWC13 caused a stir virally around the globe. With tweeters from New Zealand, United Kingdom, Ireland, United States, Canada and all states and territories of Australia the success of #SoMe was a hot topic of discussion around the Convention Centre. Novel and newbie #SoMe users could not resist joining the frenzy of twitter traffic which grew in strength over the five days.

 

 

Dr Stacy Loeb kickstarts #PCWC live on @abc

The conference featured three main streams; Clinical Urology #CU, Translational Science #TS and Nurses & Allied Health #NAH, a programme which ensured the multidisciplinary team and all practitioners involved in prostate cancer care could learn and share expertise. Day 1 the tone was set at the moderated poster presentations by @DrHWoo who outlined some conference housekeeping rules ‘All phones on silent and everyone must be adequately tweeting!!’.

 

An exceptionally high standard of candidates left decision making difficult for poster judges; @DrDanielMoon and @DrHWoo. A clever addition to the #PCWC13 welcome package was the BJUI supplement containing all #CU abstracts, allowing delegates and faculty to gain further knowledge of each individual presentation.

 

That evening @AustProstate The Australian Prostate Cancer Research function and drinks allowed faculty to relax and mingle while receiving a warm welcome from Professor Rosemary Knight from the Dept. of Health, Canberra, Hon David Davis MP, Victorian Minister for Health and Hon Dr Andrew Southcott, Federal Shadow Spokesman for Health.

 

On Wednesday morning at the opening multidisciplinary plenary @SwannyQLD the Honourable Wayne Swan MP gave an emotional account of his personal battle with prostate cancer. His heartfelt story touched all those present, emphasising that underlying the scientific and clinical excellence of a conference of this magnitude remains the care of our patients.

 

@LoebStacy Assistant Professor of Urology and Population Health from NYU followed with a superb summation of ‘Practice-changing publications in prostate cancer this year’. Dr Loeb condensed a typically three hour session by herself and Dr. William J. Catalona into twenty minutes addressing the most prominent issues in prostate cancer, including ‘Nature V Nurture’, the fish oil debate, the FDA approval of Radium-223 and the PSA recommendations by USPSTF.

Prof Noel Clarke from the Christie Hospital in Manchester presented the inaugural BJUI Lecture “Breaking the Mould in Prostate Cancer Trials”, to a packed audience including clinicians and scientists.

On his fourth trip to Australia and attending the conference, Dr. Patrick C Walsh delivered the inaugural speech so named after the orator himself, a lecture which will continue to be an annual highlight of the APCC.  An insightful look at the progress in prostate cancer genetics, over the last two decades, from one of the fathers of Urology kickstarted #PCWC13.

 

#PCWC13 co- convenor A/Prof Declan Murphy released ‘The Melbourne Consensus statement ‘at 1pm sparking major national and global media attention.

 

https://www.heraldsun.com.au/lifestyle/health-fitness/prostate-cancer-test-should-be-taken-by-men-in-their-40s/story-fni0diac-1226692750214

https://www.theaustralian.com.au/news/breaking-news/prostate-experts-end-psa-test-confusion/story-fn3dxiwe-1226692802245

https://www.businessweek.com/news/2013-08-06/prostate-test-warrants-rational-use-as-cancer-gauge-doctors-say

The signatories outlined five major points with a view to clarifying the use of PSA testing and media representatives were given the chance to address pressing questions with @LoebStacy, @proftcostello, Dr. Walsh, Dr Catalona and Mr Murphy (@declangmurphy) at the press conference.

 

https://www.couriermail.com.au/lifestyle/health-fitness/prostate-cancer-test-should-be-taken-by-men-in-their-40s/story-fnihoylo-1226692750214
https://www.news.com.au/lifestyle/health-fitness/prostate-cancer-test-should-be-taken-by-men-in-their-40s/story-fneuzlbd-1226692750214
https://www.theaustralian.com.au/news/breaking-news/prostate-experts-end-psa-test-confusion/story-fn3dxiwe-1226692802245
https://au.news.yahoo.com/thewest/a/-/newshome/18405046/debate-reignites-on-prostate-screening/
https://www.medicalobserver.com.au/news/international-experts-support-psa-testing
https://www.bloomberg.com/news/2013-08-07/prostate-test-warrants-rational-use-doctors-say.html
https://localtoday.com.au/get-local/news/88156-prostate-experts-end-psa-test-confusion.html 
 
 

 

Late morning and afternoon on Wednesday was filled with an extensive range of sessions in all three streams, including discussion and developments on tumour imaging, therapies & biomarkers and management of sexual rehabilitation. A round table discussion on PSA testing and the ‘Melbourne Consensus Statement’ caused some heated debate with controversial questions from the audience. Cocktails in the exhibition centre followed, where delegates were given the opportunity to mingle with faculty and further discuss the monumental statement which has undoubtedly put Melbourne and Victoria on the map as a centre of Urological academia. Pharmaceutical and surgical sponsors showcased their latest innovations and enthusiasts were given the chance to practise skills robotic on the Da Vinci console. An eventful day drew to a close @MCEC with the announcement of the poster winners, generously sponsored by Ipsen Pharmaceuticals.

#CU- Survival disparities between Maoiri and non-Maoiri men with non-localised prostate cancer in New Zealand. Zuzana Obertova

#NAH-New prostate cancer diagnoses-improving timeliness of communication with patients General Practitioners. Sue Stanbridge

#TS-Engineering a High-Throughout Prostate Cancer Stem Cell Niche Mimic. Micael Doran

 

The BJUI were major supporters of this year’s PCWC and published all of the accepted abstracts in a special supplement (https://onlinelibrary.wiley.com/doi/10.1111/bju.2013.112.issue-s1/issuetoc)

 

 

 

 

Thursday flew into action bright and early with breakfast talks from Dr. Joseph Smith, Professor Paul Waring and an expert #NAH panel. A combined multidisciplinary plenary addressed risk stratification and imaging, with notable speakers including Dr Matt Cooperberg on the issues in treating localised prostate cancer and Dr Tom Aherling ‘The critical role of hypogonadism or low testosterone in prostate cancer’. Key topics addressed in sessions on Thursday included active surveillance, changes in treatment of options of metastatic prostate cancer and screening. Highlights included an excellent lecture on Radium 223 by Dr. Oliver Sartor, an anecdotal insight into the recent work of Dr. Niall Clarke and Dr. Monique Roobol addressed ‘The PRIAS project’. For those delegates that had thus far escaped the #SoMe excitement, a workshop to twitter with the times was provided and the evening closed with an extensive global perspective on prostate cancer.

An academic programme and faculty line-up that would surely struggle to be matched, was further enhanced by the splendour and uniqueness of Thursday evenings congress dinner. Guests enjoyed pre-dinner drinks and canapés while exploring the National Sports Museum before being treated with the rare honour of stepping out onto the ‘hallowed turf’ of the mighty MCG. As if we had not been spoiled enough, the Aussie experience continued upon entering the Members dining room where we got the chance to cuddle a Koala, pose with crocs and if one dared; to dangle a python around your neck! It had both young and more mature delegates jumping around like children. The magnificence of the location was conveyed further to guests by a fun fact quiz on @MCG. Main course was an Australian culinary delight, with accompanying national wines and a surreal view of Australia’s most spectacular sporting venue. Mark Holden had guests laughing while Catarina Torres ensured faculty and delegates of all ages put on their #dancingshoes.

Masterclasses on Friday in robotic-assisted surgery remains one of the most favoured aspects of the program with surgeons of all levels looking forward to hearing tips and techniques from #robotics worldwide leaders. The da Vinci Prostatectomy Masterclass was conveend by Dr Daniel Moon and Dr Geoff Coughlin. Key speakers included Dr Tom Aherling and Dr David Gillatt, between whom have experience of over 15,000 radical prostatectomies. Dr Aherling talked through a full length RARP case sharing advanced tricks, followed by Dr. James Borin’s discussion on the intricacies of UV anastomosis. Trainees enjoyed a more intimate opportunity to engage with experts such as @LoebStacy, @dr_coops, @JGrummet, @DrDanielMoon, @lawrentschuck in a master class engineered for budding future urologists. Knock off drinks took place that evening on the glistening Southbank as the success of #PCWC13 could hardly be disputed. A sunny Melbourne Saturday saw GPs provide a workshop for GPs to improve both their knowledge and management of men with prostate cancer both in terms of testing and treatment.

By the end of the week, data from symplur.com using the #pcwc13 hashtag showed just how imapct this year’s Congress had on social media.

The BJUI Social Media team were very pleased to be a part of this success.

It was my first Urology conference and as a medical student I was excited to have an opportunity to be in the same centre as such a stellar line-up of experts. In all honesty I was star-struck. As a member of the BJUI social media team I was tweeting until my thumbs ached but not only did this allow me to engage with @urotwitteraiti household names virally, in many cases it gave me a window to engage with them in person. #Surreal. A fact that surely emphasises the power of #SoMe and would quash any reservations of #tweeterdoubters.

#pcwc13 #RoaringSuccess

Follow the link to Australian Prostate Cancer Research to see highlights of all the action. https://www.facebook.com/media/set/?set=a.503695969711643.1073741827.232024796878763&type=1

Authors:
The BJUI Social Media Team at PCWC – Áine Goggins, Medical Student, Queens University Belfast and University of Melbourne; Dr Marni Basto, Peter MAccAllum Cancer Centre, Melbourne; Dr Sarah Wilkinson, Monash University, Melbourne.
@gogsains @DrMarniqueB @wilko3040

 

 

Is Gleason 6 really cancer?

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The recently published Viewpoint of the National Cancer Institute working group on “Overdiagnosis and Overtreatment in Cancer” by Esserman and colleagues [1] raises continued discussion as to whether some lesions currently classified as carcinomas should have the designation of “cancer” removed, based on low rates of progression, death, and other adverse outcomes. Pertinent to those interested in urology, a central example in the article is prostatic adenocarcinoma.

One simple answer to this question is that to a small extent, a subgroup of prostatic lesions has already been reclassified as not cancer: In current practice, needle biopsy or radical prostatectomy specimens with an overall Gleason score (GS) of 5 or less are now quite rare in current practice. This shift is due in part to modern updates to the Gleason grading system [2], under which many tumors now reach thresholds for GS6 or above. However, at least some lesions previously considered adenocarcinoma with a low overall GS would now be categorized as atypical adenomatous hyperplasia or adenosis in the era of immunohistochemistry for markers of prostatic basal cells. Nonetheless, the current and more controversial debate surrounds whether some (or all?) tumors currently classified as GS6 could be recategorized as not “cancer”.

Arguments against removing the cancer designation from some prostatic adenocarcinomas:

A major difficulty from the pathologic standpoint in adopting a non-cancer nomenclature for some tumors (such as GS6 adenocarcinomas) is that the Gleason pattern 3 component of a GS 3+3=6 tumor (small, round prostatic glands that lack a basal cell layer and infiltrate between benign glands) is for all intents and purposes identical to the Gleason pattern 3 component of a GS 3+4=7 or higher prostate cancer. These similarities are not limited exclusively to the microscopic appearance but also include a number of immunohistochemical and molecular features, as summarized in a recent article addressing this question [3]. Therefore, no pathologic features are as yet defined that ideally predict whether Gleason pattern 3 glands in a biopsy specimen represent a pure GS6 tumor or a component of higher-grade tumor in which the high-grade component is not represented. Not surprisingly, it is not unusual for tumors with GS6 on needle biopsy to be upgraded to GS7 at radical prostatectomy [3], particularly when a high tumor volume is present in the needle biopsy.

Gleason pattern 3 glands from a GS7 tumor, identical to those of a GS6 tumor.

To compare to other cancers with low risk of aggressive behavior, basal cell carcinoma and squamous cell carcinoma of the skin similarly show locally infiltrative properties, supporting their classification as carcinomas by a classical pathologic definition. Despite that the word “carcinoma” continues to be used for these tumors, most patients are not concerned that they have a life-threatening disease and these lesions are even excluded from the American Cancer Society statistics regarding cancers [4]. In the same way, Gleason pattern 3 glands exhibit infiltrative growth by extending between benign glands, invading nerves, and sometimes extending outside of the prostate. This difference in mindset regarding some types of “cancers” could be considered supportive evidence for the assertion in the recent Melbourne Consensus Statement that uncoupling prostate cancer diagnosis from intervention may be more appropriate than removing its “cancer” nomenclature.


This small GS6 adenocarcinoma was an incidental finding in a radical cystoprostatectomy specimen for bladder cancer but surprisingly extended into periprostatic fat via this focus of perineural invasion.

Supporting removal of the cancer designation from some prostatic adenocarcinomas:

A valid argument of the NCI Viewpoint is that a neoplasm should have a substantive rate of progression and patient death if it is to be considered a cancer. Likewise, others have questioned whether low-volume GS6 tumors fulfill other molecular and pathogenetic hallmarks of cancer, such as unlimited replicative potential and other features [5].

In general, benign and malignant neoplasms can be regarded as having some prototypical gross and microscopic pathologic characteristics, such as a circumscribed vs infiltrative growth and homogeneous vs pleomorphic cell population. However, differentiating benign from malignant lesions also relies heavily on parameters specific to the organ involved. Clear cell renal cell carcinoma, another genitourinary tract tumor, often does not possess these prototypical features of malignancy. Tumors often form a well-circumscribed mass without an “invasive” growth pattern and they often are composed of a uniform population of cells. However, based on known behavior of these tumors, their status as a malignancy is not in doubt. Conversely, renal oncocytoma is a benign neoplasm that shares some of these general features (a round mass composed of a homogeneous population of renal tubular cells). Occasionally oncocytomas appear infiltrative by extending into the perinephric fat or renal vein, yet their status as benign is also not the subject of debate. If some prostate cancers do not have a substantial likelihood of resulting in progression and death, they may not meet an important criterion for a diagnosis of cancer, despite that other features, such as infiltration of tissues, invasion of nerves, and loss of the basal cell layer are characteristic of a malignant neoplasm.

Since a diagnosis of GS6 by needle biopsy is not always predictive of a radical prostatectomy overall GS6, a major challenge to such an approach would be to determine where such a cutoff could be drawn between “cancer” and “not cancer” [5]. If based on tumor volume, it would be difficult to conceptualize that a small amount of GS6 glands would be regarded as a benign lesion, whereas a large amount of identical glands would represent a malignant lesion. Alternatively, the presence of Gleason pattern 4 could used as the point of differentiation (GS7 or above). In the endometrium, a disorganized proliferation of crowded glands with some cytologic features of cancer is regarded as complex atypical hyperplasia. Diagnosis of adenocarcinoma is then reserved for proliferations with a confluent growth of these glands, similar to the threshold for recognizing a component of cribriform glands as Gleason pattern 4. A limitation to such an approach, however, is that a substantial fraction of patients with a needle biopsy GS6 are upgraded to GS7 at radical prostatectomy, as discussed above. Likewise, the ability to treat and monitor GS6 adenocarcinoma nonsurgically is not quite analogous to that of endometrial hyperplasia.

Higher magnification of image 2 shows Gleason pattern 3 glands invading a nerve with ganglion cells.

Other points of discussion

The NCI Viewpoint also suggests that high-grade prostatic intraepithelial neoplasia (HGPIN) no longer be considered cancer or even neoplasia.  A comparison to ductal carcinoma in situ (DCIS) of the breast for this argument is somewhat flawed, as HGPIN neither contains the word “carcinoma” nor is justification for treatment in and of itself. Its status as a risk factor for a future cancer even remains debated. The proposal to remove “neoplasia” from HGPIN is also a confusing one, particularly as cervical cancer is noted as an example of the successful application of screening, in which “cervical intraepithelial neoplasia” is the preferred term for precancerous lesions. The authors suggest the designation “indolent lesions of epithelial origin” (IDLE) for cancers in this category to convey their low likelihood of aggressive behavior. However, would recognizing the status of these lesions as at least premalignant neoplasms be more appropriate?

Likely a typographical error in the Viewpoint is that the authors also cite reclassification of urothelial papilloma as papillary urothelial neoplasm of low malignant potential [1]. Since urothelial papilloma has never been considered a malignant neoplasm, the authors likely meant reclassifying “grade 1 urothelial carcinoma” to papillary urothelial neoplasm of low malignant potential.

References
[1]        Esserman LJ, Thompson IM, Reid B. Overdiagnosis and Overtreatment in Cancer: An Opportunity for Improvement. JAMA. 2013 Jul 29:

[2]        Epstein JI, Allsbrook WC, Jr., Amin MB, Egevad LL. The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol. 2005 Sep: 29:1228-42

[3]        Carter HB, Partin AW, Walsh PC, et al. Gleason score 6 adenocarcinoma: should it be labeled as cancer? J Clin Oncol. 2012 Dec 10: 30:4294-6

[4]        Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013 Jan: 63:11-30

[5]        Ahmed HU, Arya M, Freeman A, Emberton M. Do low-grade and low-volume prostate cancers bear the hallmarks of malignancy? Lancet Oncol. 2012 Nov: 13:e509-17

 

Sean Williamson is Senior Staff Pathologist in the Department of Pathology and Laboratory Medicine, Henry Ford Health System, Detroit MI, USA. @Williamson_SR

Editorial: Time to raise the bar in localised prostate cancer

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In this issue of BJUI, Ficarra et al. present the long-term (mean 81.3 months) follow-up of a case series of 183 men that underwent robot-assisted radical prostatectomy (RARP) at a single academic medical centre in Europe. To the authors’ credit, they report both cancer control and patient-reported outcomes, using well-known validated and reliable instruments to assess both urinary and sexual function. Like others before them, Ficarra et al. demonstrate that RARP is a safe and effective way to treat localised prostate cancer.

However, the question the study raises is not so much about the operation’s success rate but rather how success is defined in the first place. Throughout the prostate cancer literature, we have loosened definitions of successful urinary and sexual function to make RP more palatable to patients. In the present study, potency is effectively defined as a Sexual Health Inventory for Men (SHIM) score of >17 with or without the use of a phosphodiesterase type 5 (PDE5) inhibitor. Similarly, continence is defined as either no pad use or the use of a single pad ‘for security’. This approach certainly has face validity to us as clinicians. After all, PDE5 inhibitors are effective therapies for erectile dysfunction and the use of a single urinary liner certainly does not seem like a big deal. However, we need to consider this from the patient’s perspective. Both urinary pads and PDE5 inhibitors are costly to the patient and may represent an inconvenience and a potential embarrassment to many men. Is it really fair to tell men that they will be potent and/or continent after the operation, if they are going to require these additional interventions to achieve the desired state? I think not.

Going forward, we must set the bar higher if we are to be truly honest with our patients and optimise outcomes after RP. We must effectively ‘leave patients the way we found them’ with the critical difference being that they are now cancer-free. In other words, if a man was able to achieve an erection sufficient for intercourse preoperatively without the use of PDE5 inhibitors, he should only be considered potent postoperatively if he is in the same state, i.e. able to achieve an erection sufficient for intercourse without the use of a PDE5 inhibitor. The same holds true for urinary continence and the use of urinary liners. This will certainly make it more difficult to achieve the ‘trifecta’ but the reader should remember that the term is meant to imply ‘triple perfection’ and needing to use a PD5 inhibitor for sexual activity or having to wear a urinary pad, while acceptable to many patients, is certainly not perfect.

Some will say that I am insisting that the bar be set too high, that patients are willing to accept these reasonable but less than perfect definitions of success to be cured of their cancer. I acknowledge that there may be some validity to this argument in men with higher risk disease, where we know that cancer control and cure is necessary. However, I do not think the argument holds up in the case of men with low-risk disease, many of whom will never experience any symptoms of prostate cancer in their lifetimes and will not die of their disease if it were left untreated. In these patients, setting the bar higher would not only be more honest but it would probably increase the uptake of active surveillance and decrease overtreatment. In summary, while the use of more stringent definitions of success after RP may make our operations look ‘worse’, it will help our patients to set more realistic expectations, make more informed choices about treatment and ultimately to have better outcomes.

David F. Penson
Department of Urologic Surgery, Vanderbilt University, 2525 West End Avenue, Suite 1200, Nashville, TN, 37203, USA

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