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West Coast Urology: Highlights from the AUA 2016 in San Diego… Part 2

May 12, 2016/1 Comment/by Jonathan Makanjuola

By Ben Challacombe (@benchallacombe) and Jonathan Makanjuola (@jonmakurology)

The AUA meeting was starting to hot up with the anticipation of the Crossfire sessions, PSA screening and the MET debate that appeared to rumble on. We attended the MUSIC (Michigan Urological Surgery Improvement Collaborative) session. It is a fantastic physician led program including >200 urologists, which aims to improve the quality of care for men with urological diseases. It is a forum for urologists across Michigan, USA to come together to collect clinical data, share best practices and implement evidence based quality improvement activities. One of their projects is crowd reviewing of RALP by international experts for quality of the nerve spare in order to improve surgical outcomes.

The MET debate continues to cause controversy. In the UK there has been almost uniform abandonment of the use of tamsulosin for ureteric stones following The Lancet SUSPEND RCT.

The MET crossfire debate was eagerly awaited. The debate was led by James N’Dow (@NDowJames) arguing against and Philipp Dahm (@EBMUrology) in favour of MET. Many have criticised the SUSPEND paper for lack of CT confirmation of stone passage. Dr Matlaga (@BrianMatlaga) stated that comparing previous studies of MET to SUSPEND is like comparing apples to oranges due to different outcome measures. He recommended urologists continue MET until more data is published. More conflicting statements were made suggesting that MET is effective in all patients especially for large stones in the ureter. The AUA guidelines update was released and stated that MET can be offered for distal ureteric stones less than 10mm.

In a packed Endourology video session there were many high quality video presentations. One such video was a demonstration of the robotic management for a missed JJ ureteric stent. Khurshid Ghani (@peepeeDoctor) presented a video demonstrating the pop-corning and pop-dusting technique with a 100w laser machine.

One of the highlights of the Sunday was the panel discussion plenary session, Screening for Prostate Cancer: Past, Present and Future. In a packed auditorium Stacy Loeb (@LoebStacy), gave an excellent overview of PSA screening with present techniques including phi, 4K and targeted biopsies. Freddie Hamdy looked into the crystal ball and gave a talk on future directions of PSA testing and three important research questions that still needed to be answered. Dr. Catalona presented the data on PSA screening and the impact of the PLCO trial. He argued that due to inaccurate reporting, national organisations should restore PSA screening as he felt it saved lives.

There was a twitter competition for residents and fellows requiring participants to tweet an answer to a previously tweeted question including the hashtag #scopesmart and #aua16. The prize was Apple Watch. Some of the questions asked included; who performed the 1st fURS? And what is the depth of penetration of the Holmium laser?

UK trainees picked up the prizes on the first two days.

The British Association of Urological Surgeons (BAUS) / BJU International (BJUI) / Urological Society of Australia and New Zealand (USANZ) session was a real highlight of day three of the AUA meeting. There were high quality talks from opinion leaders in their sub specialities. Freddie Hamdy from Oxford University outlined early thoughts from the protecT study and the likely direction of travel for management of clinically localised prostate cancer. Prof Emberton (@EmbertonMark) summarised the current evidence for the role of MRI in prostate cancer diagnosis including his thoughts on the on going PROMIS trial. Hashim Ahmed was asked if HIFU was ready for the primetime and bought us up to speed with the latest evidence.

The eagerly awaited RCT comparing open prostatectomy vs RALP by the Brisbane group was summarised with regards to study design and inclusion criteria. It is due for publication on the 18th May 2016 so there was a restriction of presenting results. Dr Coughlin left the audience wanting more despite Prof. Dasgupta’s best effort to get a sneak preview of the results! We learnt from BAUS president Mark Speakman (@Parabolics) about the UK effort to improve the quality of national outcomes database for a number of index urological procedures.

Oliver Wiseman (@OJWiseman) gave us a flavour of outcomes from the BAUS national PCNL database and how they are trying drive up standards to improve patient care. A paediatric surgery update was given by Dr Gundeti. The outcomes of another trial comparing open vs laparoscopic vs RALP was presented. There was no difference in outcomes between the treatment modalities but Prof. Fydenburg summarised by saying that the surgeon was more important determinant of outcome than the tool. Stacy Loeb closed the meeting with an excellent overview of the use of twitter in Urology, followed by a drinks reception.

It was not all about stones and robots. The results of the Refractory Overactive Bladder: Sacral NEuromodulation vs. BoTulinum Toxin Assessment (ROSETTA) trial results were presented. Botox came out on top against neuromodulation in urgency urinary incontinence episodes over 6 months, as well as other lower urinary tract symptoms.

The late breaking abstract session presented by Stacy Loeb highlighted a paper suggesting a 56% reduction in high-grade prostate cancer for men on long term testosterone. This was a controversial abstract and generated a lot of discussion on social media.

It has been an excellent meeting in San Diego and we caught up with old and met new friends. It was nice to meet urologists from across the globe with differing priorities and pressures. There was a good British, Irish and Australian contingent flying the flag for their respective countries. It was another record-breaking year for the #AUA16 on twitter. It surpassed the stats for #AUA15 with over 30M impressions, 16,659 tweets 2,377 participants. See you all in Boston for AUA 2017.

West Coast Urology : Highlights from the AUA 2016 in San Diego… Part 1

May 10, 2016/3 Comments/by Ben Challacombe

By Ben Challacombe (@benchallacombe) and Jonathan Makanjuola (@jonmakurology)

The 2016 AUA returned to the beautiful city of San Diego set on the shores of the Pacific in an excellent conference centre located in the centre of the town adjacent to the Gaslamp district. For a change the wifi was excellent and allowed enhanced levels of social media interaction and urological discussion. Opening these interactions were 2 key sessions which provoked much debate. Firstly the announcement that after over 10 years of trying the FDA has approved HIFU treatment although it seemed to get there through a slightly “de novo” pathway. Apparently the FDA approved it as an ablation tools but not for prostate cancer.

Although not directly approved for use in prostate cancer, that is exactly what it is going to be used for. A packed house saw a debate with evidence from both sides. Dr Nathan Lawrentschuk promoted the 4 Ds of HIFU. His key point was that 56/101 had a post treatment biopsy of which 51 where biopsy positive!

The second big session focussed on the AUA/SAR consensus statement document on prostate cancer diagnostics. This recommended a “High Quality” MRI should be strongly considered if patient has a rising PSA with a previous negative biopsy, has persistent clinical suspicion for prostate cancer or is undergoing a repeat biopsy. There was no mention of MRI for all at the pre-biopsy stage which many had hoped for and only 2 lines on trans-perineal biopsy as an option. This is of course related to health resources and the outpatient office-based nature of most USA urologists.

A welcome innovation was the Crossfire Sessions which pitted 2 well known advocates of one treatment against 2 with the opposite views. It was hardly debating of the Oxbridge variety but none the less did provoke some useful discussions. Topics included radical prostatectomy vs radiotherapy, endoscopic vs nephro-ureterectomy management of upper tract TCC, and enucleation at partial nephrectomy vs formal resection. Standing room only at the back of the halls but no real audience interaction or voting which was a shame.

The session which really woke everyone up was Rene Sotalo’s wonderful complication horror show. Bleeding, bleeding and more bleeding in a variety of ways. How would you handle this he asked? Pray I thought! But this and similar sessions clearly show the benefits of recording all cases and reviewing these DVDs if something goes wrong. The cause of some complications were only identified by review of the intra-operative tapes. Some clinical titbits learn’t included using only a horizontal incision for the camera port at RARP to reduce hernias and turning off pneumocompression stockings if there is a major venous injury to prevent excessive venous bleeding.

From a SoME perspective there was both good and bad. One poster showed that 40% of graduating US residents had publicly accessible unprofessional content on social media. Food for thought at the consultant interview no doubt, but on the other side SoMe ranks third in the acquisition of urological knowledge (and climbing…). One hack produced this tweeting guideline for all to reflect on.

Prof Prokar Dasgupta had the honour of presenting the widely anticipated session on emerging robotic technology . At last there appears to be some real competition to Intuitive’s dominance on the way. There are at least 3 credible robotic systems on the way. He finished with an intriguing slide on Dr Google being the most powerful doctor in the world!

Despite Europe and Asia moving towards the use of PMSA PET , the USA is not moving in this direction due to reimbursement issues if the PMSA molecule.

There was a lot of interest in a packed auditorium to see live surgery for a single use disposable fURS “Lithovue” with some reporting superior vision , optics and deflection.

There were some sceptics amongst the stone community with the environmental impact and cost effectiveness a concern.

With the popular Gaslamp district a stones throw away many delegates went after the conference for a meal and drinks. The local baseball team San Diego Padres was a popular destination with may watching baseball for the 1st time whist others had gone for a run along the harbour and even caught a sighting of some seals!

RE: Opportunity of widening the resort to multiparametric MRI/transrectal ultrasound fusion imaging-guided prostate cancer brachytherapy

May 9, 2016/by admin Z.9

Sir,

Thank you for your interest in our article regarding whole-gland brachytherapy to the prostate for prostate cancer (1). Your letter is highlighting the expanding role of brachytherapy to that of focal therapy (2). We agree that multiparametric magnetic resonance imaging (mpMRI) scans have expanded the ability to localise tumours and indeed that they may be useful in carefully selected men wishing to undergo focal therapy. However, other advances such as the use of fiducial markers and spacers have also allowed better dosimetry and for a reduction in side effects (3). The safety and performance of brachytherapy in whole gland treatment means we should have faith in it as a modality to destroy cancer on the focal therapy setting. There are new trials being developed with focal brachytherapy and we look forward to the results in the coming years.

References

Chao MW, Grimm P, Yaxley J, Jagavkar R, Ng M, Lawrentschuk N. Brachytherapy: state-of-the-art radiotherapy in prostate cancer. BJU Int 2015; 116(S3): 80-8. doi: 10.1111/bju.13252.

Nguyen PL, Trachtenberg J, Polascik TJ. The role of focal therapy in the management of localised prostate cancer: a systematic review. Eur Urol. 2014 Oct;66(4):732-51. doi: 10.1016/j.eururo.2013.05.048. Epub 2013 Jun 6. Review.

Ng M1, Brown E, Williams A, Chao M, Lawrentschuk N, Chee R. BJU Int. 2014 Mar;113 Suppl 2:13-20. doi: 10.1111/bju.12624. Fiducial markers and spacers in prostate radiotherapy: current applications.

Letter to the Editor

Opportunity of widening the resort to multiparametric MRI/transrectal ultrasound fusion imaging-guided prostate cancer brachytherapy

Sir,

I have recently read, with high interest, the review article “Brachytherapy: state-of-the-art radiotherapy in prostate cancer”, by Chao et al.[1]. The authors made extremely clear the advanced technologies of computerized treatment planning and imaging-guided delivery modalities to reach a tailored ablative prostate tumor target dose by resorting to either low-dose-rate (LDR) or high-dose-rate (HDR) different brachytherapy procedures as regards three basic – low, intermediate, high – disease risk classificative conditions.

It is today proven that focal instrumental procedures inside the prostate gland – from biopsy to various prostate cancer focused ablative strategies, among which laser interstitial thermal therapy and particularly the prostate cancer brachytherapy – might require the resort to proper software digital overlay-mediated fusion of both beforehand multiparametric magnetic resonance imaging (mpMRI) scans and later real-time transrectal 3D ultrasound findings. Like this, indeed, intriguing developments in software modelling techniques have led to reach, by a mpMRI-ultrasound image fusion approach, more accurate targeted prostate cancer biopsies than those by transrectal ultrasound imaging alone achieved [2,3].

If the transperineal focal laser prostate tumor ablation usually occurs only with the guidance of mpMRI (T2-weighted, diffusion-weighted, dynamic contrast material) [4], as regards the prostate cancer brachytherapy, instead, it is more and more timely, for just targeting the tumor “index-dominant lesion”, the resort to mpMRI/transrectal real-time ultrasound fusion imaging. Quite recently, mpMRI/real-time transrectal ultrasound software-mediated digital co-registration has allowed to properly carry-out, in patients suffering from intermediate/high risk prostate carcinoma with mpMRI visible “index- dominant” intraprostatic nodule, the HDR ¹⁹² Ir transperineal temporary implant-brachytherapy as accurate partial prostate radiation dose escalation supplemental to hypofractionated external beam radiotherapy [5,6].

Given the interesting, even rare, reports on this subject, it would be advisable to widen the resort to the above-outlined mpMRI/transrectal ultrasound fusion imaging-guided prostate cancer brachytherapy, particularly for a suitably targeted dominant tumor nodule detection/ablation.

Contardo Alberti

L D of Surgical Semeiotics, University of Parma, Parma, Italy

References

1 Chao MW, Grimm P, Yaxley J, Jagavkar R, Ng M, Lawrentschuk N. Brachytherapy: state-of-the-art radiotherapy in prostate cancer. BJU Int 2015; 116(S3): 80-8. doi: 10.1111/bju.13252.

2 Shoji S, Hiraiwa S, Endo J, Hashida K, Tomonaga T, Nakano M et al. Manually controlled targeted prostate biopsy with real-time fusion imaging of multiparametric magnetic resonance imaging and stransrectal ulrasound :an early experience. Int J Urol 2015; 22(2): 173-8. doi: 10.1111/iju.12643.

3 Marks L, Young S, Natarajan S. MRI-ultrasound fusion for guidance of targeted prostate biopsy. Curr Opin Urol 2013; 23(1): 43-50. doi: 10.1097/MOU.0b013e32835ad3ee.

4 Woodrum DA, Kawashima A, Gorny KR, Mynderse LA. Magnetic resonance-guided thermal therapy for localized and recurrent prostate cancer. Magn Reson Imaging Clin N Am.2015; 23(4): 607-19. doi:10.1016/j.mric.2015.05.014

5 Bubley GJ, Bloch BN, Vazquez C, Genega E, Holupka E, Rofsky N, Kaplan I. Accuracy of endorectal magnetic resonance/transrectal ultrasound fusion for detection of prostate cancer during brachytherapy. Urology 2013;81(6): 1284-9. doi: 10.1016/j.urology.2012.12.051.

6 Gomez-Iturriaga A, Casquero F, Urresola A, Ezquerro A, Lopez JI, Espinosa JM et al. Dose escalation to dominant intraprostatic lesions with MRI-transrectal ultrasound fusion high-dode-rate prostate brachytherapy. Radiother Oncol 2016 Feb 15. doi: 10.1016/j.radonc.2016.02.004 (Epub ahead of print).

Article of the Week: FH as a risk factor for PCa

April 13, 2016/by admin Z.9

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

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

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

A positive family history as a risk factor for prostate cancer in a population-based study with organised prostate-specific antigen screening: results of the Swiss European Randomised Study of Screening for Prostate Cancer (ERSPC, Aarau)

Marco Randazzo*,†, Alexander Muller*, Sigrid Carlsson‡,§, Daniel Eberli*, Andreas

Huber¶, Rainer Grobholz**, Lukas Manka††, Ashkan Mortezavi*, Tullio Sulser*, Franz Recker† and Maciej Kwiatkowski†,††

*Department of Urology, University Hospital Zurich, Zurich, †Department of Urology, Cantonal Hospital Aarau, Aarau, Switzerland, ‡Department of Surgery (Urology Service), Memorial Sloan Kettering Cancer Center, New York, NY, USA, §Department of Urology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden, ¶Department of Laboratory Medicine, **Department of Pathology, Cantonal Hospital Aarau, Aarau, Switzerland, and ††Department of Urology, Academic Hospital Braunschweig, Braunschweig, Germany

Read the full article

Objective

To assess the value of a positive family history (FH) as a risk factor for prostate cancer incidence and grade among men undergoing organised prostate-specific antigen (PSA) screening in a population-based study.

Subjects and Methods

The study cohort comprised all attendees of the Swiss arm of the European Randomised Study of Screening for Prostate Cancer (ERSPC) with systematic PSA level tests every 4 years. Men reporting first-degree relative(s) diagnosed with prostate cancer were considered to have a positive FH. Biopsy was exclusively PSA triggered at a PSA level threshold of 3 ng/mL. The primary endpoint was prostate cancer diagnosis. Kaplan–Meier and Cox regression analyses were used.

Results

Of 4 932 attendees with a median (interquartile range, IQR) age of 60.9 (57.6–65.1) years, 334 (6.8%) reported a positive FH. The median (IQR) follow-up duration was 11.6 (10.3–13.3) years. Cumulative prostate cancer incidence was 60/334 (18%, positive FH) and 550/4 598 (12%, negative FH) [odds ratio 1.6, 95% confidence interval (CI) 1.2–2.2, P = 0.001). In both groups, most prostate cancer diagnosed was low grade. There were no significant differences in PSA level at diagnosis, biopsy Gleason score or Gleason score on pathological specimen among men who underwent radical prostatectomy between both groups. On multivariable analysis, age (hazard ratio [HR] 1.04, 95% CI 1.02–1.06), baseline PSA level (HR 1.13, 95% CI 1.12–1.14), and FH (HR 1.6, 95% CI 1.24–2.14) were independent predictors for overall prostate cancer incidence (all P < 0.001). Only baseline PSA level (HR 1.14, 95% CI 1.12–1.16, P < 0.001) was an independent predictor of Gleason score ≥7 prostate cancer on prostate biopsy. The proportion of interval prostate cancer diagnosed in-between the screening rounds was not significantly different.

Conclusion

Irrespective of the FH status, the current PSA-based screening setting detects the majority of aggressive prostate cancers and missed only a minority of interval cancers with a 4-year screening algorithm. Our results suggest that men with a positive FH are at increased risk of low-grade but not aggressive prostate cancer.

Editorial: To PSA or not to PSA?

April 13, 2016/2 Comments/by Brian Helfand

Family history (FH) has long been known to increase a man’s risk of developing prostate cancer (PCa); there is an approximately twofold increased risk with an affected father and a threefold increased risk with an affected brother [1]. Furthermore, FH may increase the risk of more aggressive disease for family members, although results of studies in the PSA screening era have been inconsistent [2, 3]. Using FH as a risk factor, the present analysis of the Swiss arm of the European Randomized Study of Screening for Prostate Cancer (ERSPC) conducted by Randazzo et al. [4] sought to determine whether men with a positive FH of PCa, followed up by PSA screening every 4 years, would have a higher risk of having more aggressive disease.

As expected, the present results show that a significantly higher proportion of men with a FH were diagnosed with PCa compared with those with a negative FH; however, there was no difference in the frequency of more aggressive disease amongst men with a FH, therefore, while FH information can be used to identify men at highest risk of PCa, it does not appear to identify those who are most likely to harbour clinically significant disease.

One reason that a positive FH may not be associated with aggressiveness in the present study is that it has been previously established that PSA screening is associated with a migration towards lower grade and stage disease. It may not be surprising, therefore, that the PSA screened arm may have less aggressive disease. What we ultimately want to understand is whether unscreened men with a FH present with more aggressive disease. This question may have been better addressed by comparing those with a positive FH undergoing screening with those with a positive FH not undergoing screening. Previous studies conducted in this fashion suggested a difference in PCa mortality among men with a positive FH [5]. Unfortunately, these data were not available in the ERSPC. Future studies that continue to evaluate this question may elucidate whether FH predisposes to more aggressive disease.

Another factor that may have impeded the results of the present study is that men aged <55 years were not included in ERSPC. It is possible that FH predisposes to more aggressive cancers earlier in life, in men as young as 40 years. There is evidence that relative risk and risk for early-onset disease increases when a father or brother is diagnosed at a younger age, <60 years [6]. Future studies incorporating this younger cohort of men should therefore be conducted.

Until it has been clarified whether men with a positive FH of PCa are at risk of more aggressive disease, PSA screening strategies that begin at young ages should be used. In this fashion, it will be possible to selectively test populations of men at highest risk of developing PCa. Once these men have been screened, clinicians will be able to distinguish men with aggressive disease from those with more indolent disease. We believe that this shifts the focus to a different question: to treat or not to treat? Future research should continue to focus on methods of identifying those men who will go on to develop aggressive disease. Until then, men with low grade disease should continue to be followed by active surveillance [3].

Read the full article

Christina G. Selkirk* and Brian T. Helfand†

*Center for Medical Genetics, Department of Medicine, NorthShore University Health System, and †John and Carol Walter Center for Urological Health, Department of Surgery, NorthShor e University HealthSystem, Chicago, IL, USA

References

1 Kicinski M, Vangronsveld J, Nawrot TS. An epidemiological reappraisal of the familial aggregation of prostate cancer: a meta-analysis. PLoS One 2011; 6: e27130

2 Kupelian PA, Kupelian VA, Witte JS, Macklis R, Klein EA. Family history of prostate cancer in patients with localized prostate cancer: an independent predictor of treatment outcome. JCO 1997; 15: 1478–80

3 Selkirk CG, Wang CH, Lapin B, Helfand BT. Family history of prostate cancer in men being followed by active surveillance does not increase risk of being diagnosed with high-grade disease. Urology 2015; 85: 742–7

4 Randazzo M, Muller A, Carlsson S et al. A positive family history as a risk factor for prostate cancer in a population-based study with organised prostate-speciﬁc antigen screening: results of the Swiss European Randomised Study of Screening for Prostate Cancer (ERSPC, Aarau). BJU Int 2016; 117: 576–83

5 Liss MA, Chen H, Hemal S et al. Impact of family history on prostate cancer mortality in white men undergoing prostate speciﬁc antigen based screening. J Urol 2015; 193: 75–9

6 Madersbacher S, Alcaraz A, Emberton M et al. The inﬂuence of family history on prostate cancer risk: implications for clinical management. BJUI 2011; 107: 716–21

Article of the Week: Immunocytochemical expression of ERG in urine identifies prostate cancer

March 30, 2016/by admin Z.9

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

Immunocytochemical detection of ERG expression in exfoliated urinary cells identifies with high specificity patients with prostate cancer

Raj P. Pal*†, Roger C. Kockelbergh†, John Howard Pringl e*, Lara Cresswell‡, Roger

Hew§, John P. Dormer§, Colin Cooper¶, John Kilian Mellon†, Julian G. Barwell** and Edward J. Hollox**

*Department of Cancer Studies and Molecular Medicine, University of Leicester, †Department of Urology, ‡Department of Cytogenetics, §Department of Cellular Pathology, University Hospitals of Leicester NHS Trust, Leicester, ¶Department of Cancer Genetics, University of East Anglia, Norwich, and **Department of Genetics, University of Leicester, Leicester, UK

Read the full article

Objectives

To evaluate the immunocytochemical detection of ERG protein in exfoliated cells as a means of identifying patients with prostate cancer (PCa) before prostate biopsy.

Materials and Methods

Urine samples (30 mL) were collected after digital rectal examination (DRE) from 159 patients with an elevated age-specific prostate-specific antigen (PSA) and/or an abnormal DRE who underwent prostate biopsy. In all cases, exfoliated urinary cells from half of the urine sample underwent immunocytochemical assessment for ERG protein expression. Exfoliated cells in the remaining half underwent assessment ofTMPRSS2:ERG status using either nested reverse-transcriptase (RT)-PCR (151 cases) or fluorescence in situ hybridization (FISH; eight cases). Corresponding tissue samples were evaluated using FISH to determine chromosomal gene fusion tissue status and immunohistochemistry (IHC) to determine ERG protein expression. Results were correlated with clinicopathological variables.

Results

The sensitivity and specificity of urinary ERG immunocytochemistry (ICC) for PCa were 22.7 and 100%, respectively. ERG ICC results correlated with advanced tumour grade, stage and higher serum PSA. In comparison, urine TMPRSS2:ERG transcript analysis had 27% sensitivity and 98% specificity for PCa detection. On tissue IHC, ERG staining was highly specific for PCa. In all, 52% of cancers harboured foci of ERG staining; however, only 46% of cancers that were found to have ERG overexpression were positive on urine ICC. The ERG ICC results showed strong concordance with urinary RT-PCR and FISH, and tissue IHC and FISH.

Conclusion

This is the first study to show that cytological gene fusion detection using ICC is feasible and identifies patients with adverse disease markers. ERG ICC was highly specific, but this technique was less sensitive than RT-PCR.

Editorial: New possibilities for urinary molecular diagnostics

March 30, 2016/by Zoran Culig

Fusion of androgen-driven serine protease transmembrane protease (TMPRSS) and oncogenic erythroblast transformation-specific-related gene (ERG) genes is a specific alteration in human prostate cancer and many studies have been performed in order to analyse its role as a biomarker or, even more interestingly, as a tumour promoter [1]. Recently, Nguyen et al. [1] demonstrated that ERG activates the Yes-associated protein 1 (YAP1) transcriptional programme thus inducing prostate carcinogenesis. YAP is a transcriptional coactivator involved in regulation of many biological processes. Thus, there is increasing evidence showing that ERG is causally involved in prostate cancer development. Since the original publication by Tomlins et al. [2], in which the gene fusion was discovered, researchers have addressed numerous scientific questions in order to reveal importance of the TMPRSS:ERG fusion in prostate cancer. This is particularly important because several other proteins have been proposed as prostate tumour markers; however, many of them cannot be used in clinical practice. The reasons for that are related to differences in sampling of tissues and methodologies. Thus, biomarker research will in future probably be restructured on the basis of standardisation of experimental procedures. Biomarker research work related to the TMPRSS:ERG fusion appears to be more advanced. In addition to tissue diagnostics, studies on detection of ERG may be performed in urine as evidenced in the paper by Pal et al. [3]. Moreover, the authors for the first time show that exfoliated urinary cells can be used to identify patients with prostate cancer by detection of positive ERG samples. The authors used nested PCR and urinary immunocytochemistry and fluorescence in situ hybridisation in this study. As the TMPRSS:ERG fusion is detectable in ≈50% of prostate cancer specimens, the data presented in the study published in this issue of BJUI are of considerable interest.

Combining the use of TMPRSS:ERG detection and other markers in urine should further improve diagnostics of prostate cancer. Another tumour marker, prostate cancer antigen 3 (PCA3), is frequently used in prostate cancer diagnostics. In urine, TMPRSS:ERG urinary transcript detection is superior to PSA and PCA3 for identifying patients with cancer [4]. The results support data recently published according to which the determination of urine TMPRSS2:ERG together with PCA3 may be used for a more individualised prostate cancer risk assessment [5].

As the authors state in the paper [3], differences between results of some marker studies on TMPRSS:ERG detection may be a consequence of the appearance of less common isoforms, which are not detectable by all assays.

In summary, Pal et al. [3] show for the first time that patients with prostate cancer could be identified by immunocytochemistry on the basis of detection of ERG in exfoliated urine cells. In addition, the authors [3] also show that the appearance of ERG in exfoliated urine cells is associated with a bad prognosis. Indirectly, the present paper [3], supports the concept that the presence of TMPRSS:ERG regulates various cellular events leading to increased migration and proliferation of prostate cancer cells [6]. It is expected that further improvements in urinary molecular diagnostics based on the presence of TMPRSS:ERG will be achieved in the near future. However, clinicians should also be aware that, despite its high specificity, there are limitations of methodology used in this paper, in particular a large proportion of tumours may remain undetected and not all cancers exfoliate into the urine.

Read the full article

Zoran Culig

Experimental Urology, Department of Urology, Medical University of Innsbruck, Anichstrasse 35, Innsbruck, A-6020, Austria

References

1 Nguyen LT, Tretiakova MS, Silvis MR et al. ERG activates the YAP1 transcriptional program and induces the development of age-related prostate tumors. Cancer Cell 2015; 27: 797–808

2 Tomlins SA, Rhodes DR, Perner S et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 2005; 310: 644–8

3 Pal RP, Kockelbergh RC, Pringle JH et al. Immunocytochemical detection of ERG expression in exfoliated urinary cells identiﬁes with speciﬁcity patients with prostate cancer. BJU Int 2016; 117: 686–96

4 Leyten GH, Hessels D, Jannink SA et al. Prospective multicentre evaluation of PCA3 and TMPRSS2-ERG gene fusions as diagnostic and prognostic urinary biomarkers for prostate cancer. Eur Urol 2014; 65: 534–42

5 Tomlins SA, Day JR, Lonigro RJ et al. Urine TMPRSS2:ERG plus PCA3 for individualized prostate cancer risk assessment. Eur Urol 2015; [Epub ahead of print] DOI: 10.1016/j.eururo.2015.04.039

6 Washington MN, Weigel NL. 1(alpha),25-dihydroxyvitamin D3 inhibits growth of VCaP prostate cancer cells despite inducing the growth-promoting TMPRSS2:ERG gene fusion. Endocrinology 2010; 151: 1409–17

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

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