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Editorial: Prostate cancer families – predicting disease before and after the radical

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In this issue of BJUI, Borque et al. discuss a subject that is now very close to my heart. Aged 48 years, I am 6 weeks post radical prostatectomy for a Gleason 3 + 4 prostate adenocarcinoma measuring ~2 mL in volume, with a PSA level of 2.54 ng/mL. Histology reassures me it is organ confined and seminal vesicle negative. My father and his brother both died aged 63 years of Gleason 10 prostate cancer and my brother is awaiting his radical prostatectomy in a few weeks. I have two sons, one of whom has asked me when he should be tested. Any prognostic information is going to help me advise my family.

In all, 85% of prostate cancers appear to be sporadic. The incidence of all prostate cancers is 1 in 8500 under the age of 40 years, rising to 1 in 15 at 60–69 years and 1 in 8 after that. The lifetime risk in the UK for all men is 8–10%.

The genetics of prostate cancer are confused by case clustering; the family members of men with a prostate cancer diagnosis seek out early advice from their physician resulting in detection of some clinically questionable cancers and an apparent higher incidence in certain families. These families do not necessarily have genetically determined prostate cancer.

The lifetime risk is altered dramatically by having two or more first-degree relatives with a diagnosis of prostate cancer; if the disease in the relative is identified before the age of 65 years the risk is increased further. Bratt suggests the risk rises from 15 to 20% when a single first-degree relative is diagnosed aged < 60 years. Zeegers et al., in a meta-analysis, have shown that diagnosing prostate cancer in a relative aged < 65 years increases the relative risk of having prostate cancer by 3.3, and having two first-degree relatives increases the relative risk by a factor of 5.1.

Analysis of a huge database from Sweden including data on 182 000 fathers and 3700 sons with prostate cancer suggest a standardised incidence ratio of 9.4 in men with a father and brother diagnosed with prostate cancer, with further analysis also showing unsurprisingly that the risk increases as an individual ages. Some true ‘prostate cancer families’ have been identified. These families have three or more relatives with prostate cancer often associated with a diagnosis at a young age, possibly with an increased tendency to an aggressive
phenotype; my uncle was 18 months from diagnosis to death from his disease, my father 4 years. In these families, the relative risk in male family members is 3.39 in those where the diagnosis of identified sufferers was made aged > 65 years, and 7.33 where the diagnosis is in men aged < 65 years. These risks which effectively give a lifetime risk in the individual of 45–50% are associated with carriage of a gene identified as increasing the prostate cancer risk. The best identified of these genes is the BRCA2 (breast cancer type 2 susceptibility protein) gene, which is associated with an increased risk of other cancers including breast, ovarian, gallbladder and pancreatic cancer, as well as malignant melanoma. This gene, carried in 1% of
Ashkenazi Jewish families, is associated with prostate cancer families in this population.

Now my prostate has been removed, I need to determine my chance of treatment failure. It would be interesting to know whether my genes and my single nucleotide polymorphisms (SNPs), which have almost certainly been responsible for me developing prostate cancer, can also predict my chance of developing early biochemical recurrence (EBCR) and the possibility of needing further treatment. In the Borque et al. article, I would appear on the first model (Fig. 1) to have a chance of ECBR of between 1 and 5%. This risk, according to this study, could increase to up to 30%, if I was to have four SNPs associated with prostate cancer (Fig. 2). Furthermore, we need to know whether identification of SNPs is any better than other possible predictors of EBCR and disease progression, such as the identification of lymphovascular invasion and tumour volume in the final specimen and the presence of extraprostatic extension, data not included in this study. Incidentally, I had no evidence of lymphovascular invasion.

The authors identify that this study needs repeating, particularly in a more ethnically diverse group (this study included Caucasian origin as an entry criterion), and we await longer term data to see how SNPs predict metastasis and prostate cancer-related death.

Jonathan M. Glass
Department of Urology, Guys & St Thomas’ Hospital Trust, London, UK

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Who let the Dogs Out?

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Or

Let’s Paws for a Second!

Or

Lets paws for a second before we all start howling about nothing!

 

Recently while driving to a Day Surgery list at Heatherwood hospital in Ascot, I happened to listen to BBC Radio 4. There was a report regarding high accuracy for the detection of stomach cancer by a simple breath test. This reminded me of a study published some time ago in European Urology on the ability of a dog to detect prostate cancer by smelling a sample of urine. For a skeptic like me, reading that article in the platinum journal had indeed brought a sarcastic chuckle. Pondering over the paper and the report on the radio, it just dawned on to me as to why I would instantly believe a high-tech nanosensor detecting stomach cancer but not a mortal Belgian Malinois shepherd! This formed my basis of my blog.

It is well known that when someone is afflicted by a disease or cancer, there is a change that occurs in the internal milieu. In the vast majority, before this change can be manifested clinically, there is definite change seen biochemically.  There is emerging evidence that volatile organic compounds (VOC) that are exhaled either in the breath or in bodily fluids can indicate these changes reflecting the underlying pathology.  This is where the humble mongrel comes into play. Olfactory bulb in dogs is forty times bigger than of humans relative to total brain size. Having 125 to 220 million smell-sensitive receptors, their olfactory sense is up to one hundred thousand to one million times more sensitive than a human’s. So, there may be some sense and science in the paper that I had initially chuckled at. The earliest report is a letter to the Lancet reporting the diagnosis of melanoma made after the dog sniffed at a suspicious mole of its owner. Since then, there have been several reports on the ability for the trained dogs to detect various cancers and chronic illness, urological diseases. One of the earliest attempts to detect prostate cancer can be dated back to 2002. Further attempts were made to initiate trials in 2003 but no published results on Medline were found. Earliest published paper can be traced back to 2008, wherein the study did not support the concept of dogs being able to detect prostate cancer. This was recently challenged by the article by Cornu J et al that revealed a sensitivity and specificity of 91% for biopsy proven prostate cancer! In fact, one of the three patients who was wrongly classified as prostate cancer, was found to have cancer on a re-biopsy! The potential VOC that may be found in the urine of a patient with prostate cancer can be found in this letter to the editor. Indeed, to carry out more research, “Medical Detection Dogs” is aiming to recruit prostate cancer patients within the UK!

One would obviously think that if we can diagnose prostate cancer, why not bladder cancer? This is precisely what led to a “proof of principle” study headed by Carolyn Willis and findings were published in the BMJ. The dogs had a mean success rate of 41%, compared with 14% expected by chance alone. Multivariate analysis suggested that the dogs’ capacity to recognise a characteristic bladder cancer odour was independent of other chemical aspects of the urine detectable by urinalysis. What was astonishing about this study was on one occasion during training, all dogs unequivocally indicated as positive a sample from a participant recruited as a control on the basis of negative cystoscopy and ultrasonography. The consultant responsible for the patient was sufficiently concerned to bring forward further tests, and transitional cell carcinoma of the right kidney was discovered! The same group further reported specificity that ranged from 92% for urine samples obtained from healthy, young volunteers down to 56% for those taken from older patients with non-cancerous urological disease.

More trials are being carried out for detection of cancers affecting the lung, breast, ovary, bowel and others, a review of which can be found in this article. We may need to wait for a few more years to find out whether we are dealing with real science or we are going in circles like the dog chasing its own tail!

On the lighter note, if you hear an old male dog bark for no apparent reason, think prostate cancer!! Dog is the only other mammal that can be afflicted by prostate cancer and fortunately the doggie world will not be affected by the USPSTF recommendations, as canine prostate cancers do not secrete PSA!

Amrith Rao is a Consultant Urological Surgeon at Wexham Park Hospital, Wexham, UK

Tweet: @urorao

 

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No Classical Music In My Operating Room Please

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For as long as I have been operating independently, music has been an essential part of my operating theatre environment. If there is no music playing in the background, it is to me as if there is a missing component of the “time out” check list that is carried out by surgical teams prior to each procedure.

For many years, I was trapped in the 70s and 80s with my choice of music. Bowie, Stones, R.E.M. and Pink Floyd were some of the artists that were on high rotation. It provided education to the growing numbers of nurses and medical students who had never heard of classic albums such as Dark Side of the Moon. These days I am lucky to find a medical student who can volunteer the names of the four Beatles – I don’t even bother asking if they know anything about Pete Best who was ousted in favour of Ringo. Sometimes they almost believe my suggestion that the next Pope will be named John Paul George Ringo I, which of course is a perfectly reasonable suggestion. The music played in my theatre therefore actually has an important educative role that makes up for parenting deficiencies with the failure to teach their children about classic rock acts of the 70s and 80s.

 

Over the past couple of years, I have been encouraged to explore contemporary music, which has led to a change in the music played in my operating theatre to performers such as the XX, The Vaccines, First Aid Kit, The Hives, Regina Spektor, Mumford & Sons and Laura Marling just to name a few. This has been a positive move in that I not only have come to appreciate some of the great new music that will one day become classic material, but it also receives a high approval rating from other staff within the operating room. I do admit that I have the latest David Bowie album on order in the vinyl format though an EBay seller.

Why am I telling you all about this? This month, a systematic review by authors Moris and Linos was published in the journal Surgical Endoscopy entitled Music meets surgery: two sides to the art of “healing”. Using fairly limited search terms, a literature search identified 28 relevant articles that were included for review. These papers covered a mix of subject matter including effects of music in the operating theatres on patients, surgeons and theatre staff.

As a surgeon, I will leave discussion of effects of music on patients to our anaesthetic colleagues and it is for them to debate whether there is any beneficial effect of music on induction and upon waking up. Our interaction with music occurs when the patient is asleep so our interest as surgeons lies primarily with its effects on ourselves and other members of staff in the operating room.

Having your anaethetist ‘on board’ with your attitude to music is essential. In the private sector, this is unlikely to be an issue given that you will generally choose to work with somebody who has some compatibility with your own personal tastes. The public sector can at times be challenging where the anaesthetist feels equally entitled and at times more entitled to determine the choice of music or even absence of music in the operating room– this requires tactful negotiation. The principle reason I tend to back off from a fight over this type of issue is that I hate going into an operation feeling cranky. The only time I may make a stand is when classical music is being played – the swings between the calms and storms of some pieces are a little too stressful for my liking.

So what do operating room staff prefer to listen to? Only a couple studies examined this but the bottom line is that classical music is not a clear majority choice – in one study it was favoured amongst 1.2% of respondents and in another it was 45%, they prefer to listen to a type of music that’s a bit more fun . With the latter, my personal inclination is that they were asking non-urologists who are no way as cool as urologists in general. My thoughts, as you may have gathered, are to drop the ‘al’ and choose classic music over classical music.

 

Summary of relevant studies extracted from Table 1 of the Moris study published in Surgical Endoscopy.

 

I am not sure I entirely agree with one conclusion of the review, which states: “With regard to its effect on surgical staff, music is thought to be distracting, reducing the staff’s ability to cooperate and coordinate”. Only one retrospective study is insufficient to reach the general conclusion about the effects of music on staff in operating theatres. My admittedly biased perspective has been in total agreement with the second conclusion that states “From a surgeon’s point of view, music facilitates achievement of higher speed and accuracy of task performance.”

 

Henry Woo is an Associate Professor of Surgery at the Sydney Adventist Hospital Clinical School of the University of Sydney in Australia. He has been appointed as the inaugural BJUI CME Editor. He is currently the coordinator of the International Urology Journal Club on Twitter. Follow him on Twitter @DrHWoo

 

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Editorial: Robot-assisted radical prostatectomy: getting your ducks in a row!

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Robot-assisted radical prostatectomy (RARP) has become the technique of choice for clinically localised prostate cancer. However, marked inter-surgeon heterogeneity and an obvious lack of standardisation exist for the indications and technique of the procedure. In this issue of the BJUI, Ficarra et al. conducted a multinational survey seeking opinion from 145 robotic surgeons about individual practices during RARP. These opinions can be compared against the benchmark set by the Pasadena Consensus and can help gauge the impact of its recommendations.

Responses from 116 (79.4%) invited surgeons were analysed. The authors acknowledge the limited participation of non-European surgeons (17.1%), which may limit validity and application of its results at a global level. Most surgeons were in consensus with the Pasadena recommendations for transperitoneal access (88%), antegrade approach (76%) and bladder neck preservation (77%). The opinions on cautery use for the seminal vesicle/vas deferens dissection (51% athermal; 21% bipolar), athermal nerve-sparing approach (90%) and the use of the running suture technique for urethrovesical anastomosis (96.6%) were also in agreement.

Despite wide surgeon and institutional variability regarding the definition of bladder neck preservation and its role in the return of urinary continence, most preferred to preserve the bladder neck. This may pose difficulty in the interpretation of the results in view of the ambiguity about the definition and technique adopted under the term ‘bladder neck preservation’ (Eur Urol, BJU Int).

Most of the participating surgeons were using anterolateral prostatic fascia dissection (Veil of Aphrodite) towards preserving the cavernous nerves by using an athermal approach. Over the last decade the evolution of robot-assisted surgery, with excellent three-dimensional visualisation, depth perception, and EndoWrist® technology has made working in the confines of the pelvis both ubiquitous and a desired skill.

The present study found that 33% of surgeons omitted the internal iliac lymph nodes (LNs) and removed only obturator, with or without the external iliac LNs. The Pasadena Consensus recommends a template that includes the internal iliac, external iliac and obturator LNs. Mattei et al. in an attempt to map primary prostatic lymphatic ‘landing’ zones found that after performing a standard limited LN dissection (dorsal to and along the external iliac vein; medially along the obturator nerve) only 38% of LNs were removed. They recommended a template that retrieves LNs extending up to the ureteric crossing of the common iliac vessels. Meanwhile, Menon et al. evaluated the role of only internal iliac LN dissection (limited) in patients with a low probability of nodal disease (Partin table prediction 0–1%), and surprisingly found positive LNs in the internal iliac/obturator region 13.7 times more often than in the external iliac/obturator region. One of the issues that could be addressed in future surveys would be to evaluate how surgeons view and adapt to changes in the proposed LN template. The Pasadena Consensus further recommends considering performing LN dissection for the low-risk category based on the D’Amico risk stratification. The surgeon’s indications for pelvic LN dissection were not addressed in this survey.

Despite significant studies, including two randomised controlled trials (RCTs), published in the peer-reviewed literature reporting minimal advantage for early recovery of urinary continence with posterior reconstruction, a significant number of the surveyed surgeons still preferred to perform it. Responses to other questions about the posterior/anterior reconstruction also showed marked variability reflecting the controversial opinion about the value of these surgical steps.

On the other hand, future surveys should gather opinions about the role of RARP for high-risk disease, standardised evaluation of surgical complications; while addressing continence and potency status along with methods of their measurement. These topics were already addressed in the Pasadena Consensus and obtaining opinions of surgeons will further provide insight as to how surgeons adapt to the ever-changing advances in this field.

Over the last decade RARP has gained acceptance despite the absence of high-quality RCTs in robot-assisted surgery. The Pasadena Consensus was meant to meet the need for uniformity and this study educates us on how the surgeons really perform ‘in the trenches’. Until further evidence is available, surgeon experience and institutional volume will remain the main force driving the use of these surgical techniques and their outcomes.

Ahmed A. Aboumohamed and Khurshid A. Guru
Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA

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Editorial: The importance of citrate in patients with calcium stones and loss of bone mineral density

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Stone disease and osteopaenia are both common conditions, and reduced bone mineral density (BMD) is an increasingly recognized complication in stone formers; indeed, in a previous paper in BJUI, Arrabal-Polo et al. reported that patients with recurrent stones have lower BMD compared with controls or patients with just a single episode of urolithiasis.

Although the exact pathogenesis of bone loss in stone disease is yet to be determined, the conceptually obvious relationship with hypercalciuria is well documented. In the present study, Arrabal-Polo et al. emphasise that hypocitraturia is also associated with reduced BMD. Furthermore, they found a higher calcium : citrate ratio in patients with a cumulative maximum stone diameter > 20 mm, or in those with frequent recurrences than in controls, and found that this correlated with higher levels of β-crosslaps, consistent with increased bone resorption in these patients.

We commented in our previous editorial that metabolic abnormalities should be sought in recurrent stone formers, and managed in a multi-disciplinary setting. In addition to dietary advice, options for treatment include bisphosphonates (which inhibit bone resorption, and are commonly used in osteoporosis), thiazide diuretics (which reduce calcium excretion and can increase BMD) and potassium citrate (which acts as an alkalinizing agent mitigating the bone restorative effect of acidosis). This approach is supported by recent data in medullary sponge kidneys, in which hypercalciuria and hypocitraturia were commonly detected in association with reduced BMD. Patients who were treated with potassium citrate were found to have increased urinary pH citrate levels, and an improvement in their BMD.

In the present article, Arrabal-Polo et al. suggest using a calcium : citrate ratio of 0.25 for predicting the risk of future recurrent stone formation, but this value could equally be used to predict the risk of patients having reduced BMD and the complications that may follow. Either way, their findings strengthen the argument for metabolic screening of recurrent stone formers, and for an assessment of these patients’ BMD. Patients can then be appropriately treated with a thiazide diuretic, potassium citrate, or a bisphosphonate, either singly or in combination, according to the abnormalities detected and their progress on treatment.

Daron Smith
Stone and Endourology Unit, University College Hospital, London, UK

Chris Laing
UCL Centre for Nephrology, Royal Free Hospital London, London, UK

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Tiger Testes

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Although I enjoyed reading Jim Duthie’s Blog Post ‘Surgery Isn’t Normal’, I would argue that no profession, particularly those constituting a high degree of specialization, are normal. Let me set the scene from a research scientist’s perspective…

It was late on a Tuesday night three years ago, and being a poor PhD student at the time (PhD scholarships pay below poverty level), I was completing my part-time work in the histology department to help make the rent. My research laboratory specialises in diseases of the prostate; however, the laboratory next to ours – for which I was currently performing histology work – specialises in germ cell development and male fertility. Most of their work is focused on the human species, however, one of their projects was looking into the fertility of rare or endangered species to help prevent their extinction. As such, they had an ethics agreement with the Melbourne Zoo which gave them access to the reproductive organs of any endangered species that passed away. So there I was on my microtome sectioning the testes of a recently deceased Bengal tiger.

For anyone who works in pathology, the temperature and hydration of tissue to be sectioned must stay within a tight range in order to obtain perfect 5-µM thick sections that can then be stained for analysis. Too hot and your tissue will crumple, too cold and the sections will curl over on themselves, whilst over-hydrated tissues will swell out of the paraffin wax, and under-hydrated tissues break when they meet the microtome’s blade. These tiger testes were getting a little too warm for my liking, so I placed them on ice and left the room to grab myself a beverage from the hospital cafe – cutting testes is thirsty work!

To my dismay when I arrived back at the hospital laboratory my access card would not let me in the room. It was late, no one was around in the histology department, and I was now getting worried about the time these testes had been sitting in water on ice, so I headed for the hospital security. As I stood there explaining to a ICORP Security guard that I urgently needed to get into the histology department on level 3 as my tiger testes were getting too cold and may over hydrate, I too had the realisation of how abnormal this must seem. And yet, the very things that may make my job seem abnormal to an outsider are the very things I love most about my role. Every day is different, and I get exposed to new and exciting research projects that really make a difference to the world and people in it.

This particular job has also come in handy in some unexpected situations. When I caught a man trying to steal the hubcaps off my tyres I was able to tell him, “I may look harmless, but I cut testes for a living,” and so my hubcaps remain…

Dr Sarah Wilkinson is a post-doctoral research fellow at Monash University, Melbourne. She is interested in how the prostate tumour microenvironment can be targeted as a therapeutic treatment for prostate cancer.

Twitter: @wilko3040

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A Tale of Four Prostates

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There was a time when doctors were reluctant to tell patients the truth about a diagnosis of cancer, and even more unwilling to discuss any illness from which they themselves suffered.  John Anderson broke the mould last year when he made a public announcement about his newly diagnosed liver metastases, which subsequently turned out to be the result of secondary spread of adenocarcinoma of the prostate.

John was President Elect of the British Association of Urological Surgeons (BAUS) at the time, so sadly had to resign his presidency (the best president we never had!) and subsequently his trusteeship of the Prostate Cancer UK charity. John’s energy and drive are legendary, he is a true surgeon’s surgeon. The stoicism and determination that he has displayed throughout a year in which he has received hormonal treatment, followed by chemotherapy, is awe-inspiring.

My admiration for John, in addition to my own recent diagnosis of localised prostate cancer, requiring robot-assisted radical prostatectomy (https://moreintelligentlife.co.uk/content/ideas/simon-garfield/prof-roger-kirby) led me to approach Sean Vesey and Damian Hanbury, whom I knew were similarly afflicted by a disease that carries a 1 in 9 lifetime risk. It occurred to me that there was a great deal to be gained from frank disclosure and discussion, as opposed to treating this problem as some dark, furtive secret. Women suffering from breast cancer are generally much more open about their problem and consequently receive much more support from friends, relatives and others who have been touched by the disease. This empowers them to make the difficult but smarter choices about their health by opting in to breast cancer treatment. Men need this kind of social encouragement and support so that we can be within reach to them as well.

The result was a publication entitled “a Tale of Four Prostates” in the upcoming issue of Trends in Urology and Men’s Health (www.trendsinurology.com) and a short accompanying video.

In this John, Damian and myself discuss the impact of our respective diagnoses and treatment. We sincerely hope that, by being frank, honest and transparent about our own situation, we can help other patients to help themselves by seeking advice and treatment earlier, and by sharing information about their diagnosis with others in order to mobilize support from their family and friends.

 

Sadly, John Anderson has since died. You can read an obituary by Roger Kirby here. 

 

 

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