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This image is taken from Harraz et al (BJUI 2014) describing long-term renal outcomes for 2 different anastomotic techniques in a W-shaped (Hautmann) neobladder formation.
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Peyronie’s disease is a chronic and progressive disease characterised by fibrotic plaque of the tunica albuginea of the penis that can cause deformity, pain during erection and erectile dysfunction. Fibrosis is the hallmark of the pathology of Peyronie’s disease and is known to be driven by fibroblasts and myofibroblasts, which produce excessive amounts of extracellular matrix proteins and, hence, disturb the architecture of the tunica albuginea.
In this issue of BJUI, Kwon et al. [1] have shown that selective inhibition of histone deacetylase isoform 2 (HDAC-2) using a small hairpin silencing RNA elicits reversal of plaque development in vivo and prevention of collagen production and myofibroblast transformation in vitro. Histone deacetylases (HDACs) are a group of enzymes that remove acetyl groups from lysine amino acid in histones, causing histones to wrap around the DNA tightly and, ultimately, affecting gene transcription. In addition HDACs can de-acetylate cytosolic proteins and hence alter their function. Because of their direct effect on cell growth and death, HDACs have recently been attractive targets for anti-cancer drug development. Currently, there are > 100 clinical trials recruiting patients to investigate the clinical efficacy of HDAC inhibitors, most of which are non-selective HDAC inhibitors, bearing in mind that there are 11 isoforms of HDACs.
HDAC inhibitors have been suggested to have anti-fibrotic effects in the lung, liver, kidney and skin. They have been shown to reduce myofibroblast transformation and fibroblast activation, and counteract TGF-β actions and extracellular matrix production [2]. Although the exact mode of action of HDAC inhibitors in fibrosis is not clear, it has been suggested that HDAC inhibitors might repress the TGF-β pathway and interfere with phosphorylation and activation of STAT3, a key transcription factor in inflammatory pathways. Among all the isoforms of HDAC, HDAC-2 has been implicated in pathogenesis of fibrosis, firstly in kidney fibrosis [3] and later in Peyronie’s disease [4]. Currently available small-molecule HDAC inhibitors target more than one isoform of HDAC; to our knowledge isoform-selective small-molecule inhibitors are not available yet. Kwon et al. [1] have solved this problem using small hairpin silencing RNA to target HDAC-2 specifically. Although the clinical feasibility of such a silencing RNA approach remains to be tested, their study nevertheless gives an important indication for HDAC-2 as a possible target for fibrotic diseases, such as Peyronie’s. No doubt further research and development will be required to validate this target and develop small-molecule inhibitors selective for HDAC-2.
Selim Cellek* and David J. Ralph*†
*Centre for Biomedical Engineering, Cranfield University, Cranfield, and † University College London Hospital, London, UK
References
1 Kwon K-D, Choi MJ, Park J-M et al. Silencing histone deacetylase 2 using small hairpin RNA induces regression of fibrotic plaque in a rat model of Peyronie’s disease. BJU Int 2014; 114: 926–36
2 Pang M, Zhuang S. Histone deacetylase: a potential therapeutic target for fibrotic disorders. J Pharmacol Exp Ther 2010; 335: 266–72
3 Noh H, Oh EY, Seo JY et al. Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor-beta1-induced renal injury. Am J Physiol Renal Physiol 2009; 297: F729–39
4 Ryu JK, Kim WJ, Choi MJ et al. Inhibition of histone deacetylase 2 mitigates profibrotic TGF-β1 responses in fibroblasts derived from Peyronie’s plaque. Asian J Androl 2013; 15: 640–5
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These images are from an experimental paper by Knonenberg and Traxer (BJUI 2014)
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It has been another successful year for the BJUI. Our impact factor has gone up, the new design theme of ‘places’, featuring the location of the ‘Article of the Month’ on the front cover, has been well received and our web statistics have gone from strength to strength. Despite these successes, as a surgeon-scientist, I occasionally find that I am questioning myself, particularly where surgical science is concerned.
One such moment came recently while I was performing a live nerve-sparing robot-assisted radical cystectomy (RARC) during the European Association of Urology Robotic Urology Section (ERUS) 2014 meeting in Amsterdam. Open RC (ORC) is a morbid procedure and in cohort studies we thought that we had halved the complication rates with laparoscopy and lowered them even further with robotics. However, these results have not been replicated in randomised controlled trials. A letter in the NEJM comparing ORC and RARC showed no difference in outcomes, especially complication rates. Many feel that perhaps there was a difference in the experience of surgeons performing ORC and RARC, although the article itself mentions that this was not the case. Our own CORAL (randomised controlled trial of open, robotic and laparoscopic radical cystectomy) study comparing ORC, laparoscopic RC and RARC demonstrated no difference in 90-day complication rates, although all diversions were performed extracorporeally. In this issue of the BJUI, we present another randomised trial of ORC vs RARC showing no significant differences in health-related quality of life with scores returning to baseline after 3 months. We now await the results of the multicentre RAZOR (randomized open vs robotic cystectomy) study, which is expected to recruit fully this year. As I performed live, I could not help thinking about the negative results of these trials, which came up during my discussions with the audience. It is often good to question yourself rather than have blind faith without the scientific evidence.
Now for some positive news. It is becoming increasingly obvious that perhaps choline positron emission tomography (PET) will soon replace bone scans for detecting metastasis in prostate cancer. As tracer technology develops further, the death of traditional bone scanning in coming years seems imminent.
Finally, we have some exciting science for your reading pleasure. While the management of Peyronie’s disease has largely centred on various surgical techniques, there may be a new treatment for the plaque itself just over the horizon. The answer – ‘small hairpin RNA’; these can inhibit histone deacetylase 2 and induce plaque regression. Currently reported in a rat model, Phase I studies cannot be far away.
Prokar Dasgupta
King’s College London, Guy’s Hospital, London, UK
In this month’s issue of BJU International, Messer et al. [1] devise a prospective randomised trial to compare postoperative health-related quality of life (HRQoL) after robot-assisted (RARC) vs conventional open radical cystectomy (ORC). The investigators evaluated 40 patients over a follow-up period of 1 year and found no significant difference in HRQoL between surgical approaches. Moreover, they showed that the postoperative decrease in HRQoL returns to baseline within 3 months of surgery.
RC is one of the most challenging and potentially mutilating surgical interventions in the urological field and represents the standard-of-care treatment for patients with muscle-invasive bladder cancer. It is associated with a non-negligible risk of morbidity and mortality [2]. With the advent of new technologies, such as the Da Vinci surgical robot, carefully designed studies are needed to weigh the potential benefits of a novel approach against the increased costs associated with such tools. While RARC holds the promise of combining the benefits of a minimally invasive intervention with the precise robotic translation of the surgeon’s movements, these claims remain to be definitely proven in the clinical setting. As such, further elucidating the effect of surgical approach on perioperative outcomes after RC is essential for treatment planning, patient counselling and informed decision-making before surgery.
QoL is increasingly used as a quantitative measure of treatment success [3, 4]. These measures are gaining considerable traction in the USA, as reimbursements will soon be tied to patient satisfaction. While previous retrospective studies suggest that RARC has comparable perioperative oncological outcomes with potentially lower morbidity relative to ORC [5], there is a scarcity of high-quality evidence on HRQoL outcomes of RARC vs ORC. The difficulties of conducting randomised trials in the surgical setting are reflected by the relatively few participants in the Messer et al. [1] trial. Nonetheless, in their pilot study, the authors demonstrated the feasibility of a HRQoL trial in RC patients. Furthermore, they deliver initial evidence on the impact of surgical approach on HRQoL after RC.
From a clinical perspective, the authors contribute interesting findings to the ongoing debate. Their results suggest that the potential benefits of robot-assisted surgery on HRQoL may be limited in patients undergoing complex oncological surgery such as RC. Several hypotheses may be pertinent to their conclusions. For example, performing an open urinary diversion after RARC that can take as much time as the actual extirpative RC may mitigate any potential benefit of the minimally invasive approach. Furthermore, the study findings may be largely influenced by the surgical skills of the participating surgeons. Maybe the correct interpretation of their study findings is that there was no significant difference in HRQoL outcomes between ORC and RARC, at the institution where the trial was performed.
Nonetheless, the authors suitably demonstrate the feasibility of performing a randomised trial in this field and pave the way towards adequately powered, randomised multicentre trials that can provide further evidence on what impact RARC may have on perioperative outcomes and beyond.
Julian Hanske, Florian Roghmann, Joachim Noldus and Quoc-Dien Trinh*
Department of Urology, Marien Hospital, Ruhr-University Bochum, Herne, Germany, and *Division of Urologic Surgery and Center for Surgery and Public Health, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
References
1 Messer JC, Punnen S, Fitzgerald J, Svatek R, Parekh DJ. Health-related quality of life from a prospective randomised clinical trial of robot-assisted laparoscopic vs open radical cystectomy. BJU Int 2014; 114: 896–902
2 Roghmann F, Trinh QD, Braun K et al. Standardized assessment of complications in a contemporary series of European patients undergoing radical cystectomy. Int J Urol 2014; 21: 143–9
3 Cookson MS, Dutta SC, Chang SS, Clark T, Smith JA Jr, Wells N. Health related quality of life in patients treated with radical cystectomy and urinary diversion for urothelial carcinoma of the bladder: development and validation of a new disease specific questionnaire. J Urol 2003; 170: 1926–30
4 Loppenberg B, von Bodman C, Brock M, Roghmann F, Noldus J, Palisaar RJ. Effect of perioperative complications and functional outcomes on health-related quality of life after radical prostatectomy. Qual Life Res 2014. doi: 10.1007/s11136-014-0729-1
5 Kader AK, Richards KA, Krane LS, Pettus JA, Smith JJ, Hemal AK. Robot-assisted laparoscopic vs open radical cystectomy: comparison of complications and periopera
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November 2014 ushered in the third year of the international urology journal club (@iurojc) and also marked the 2500th follower of @iurojc.
This month’s article was published in European Urology (@Uroweb) on October 10, 2014, Sequential Combination of Mitomycin C Plus Bacillus Calmette-Guerin (BCG) Is More Effective but More Toxic Than BCG Alone in Patients with Non-Muscle-Invasive Bladder Cancer in Intermediate- and High-risk Patients: Final Outcome of CUETO 93009, a Randomized Prospective Trial.
The discussion was once again well attended by many of the Urology twitter gurus and leaders in the field of intravesical chemotherapy for non-muscle-invasive bladder cancer (NMIBC) (@davisbj, @JimCatto, @DrHWoo, @jimmontie, @uretericbud, @shomik_s, @UroDocAsh, etc).
Given the recent worldwide shortage of BCG, this article proved timely for discussion @iurojc. The authors from Spain conducted a prospective, randomized trial including 407 patients with intermediate- to high-risk NMIBC – 211 patients were allocated to receive mitomycin-C (MMC) and BCG, and 196 patients to receive BCG-alone. At 5 years, the disease free interval significantly improved with sequential MMC and BCG compared to BCG alone (HR 0.57, 95%CI 0.39-0.83, p=0.003), and reduced the relapse rate from 33.9% to 20.6%. However, sequential treatment lead to increased toxicity even after lowering the MMC dose to 10mg (p<0.001). The authors concluded that due to higher toxicity, sequential MMC and BCG therapy should only be given to patients with high likelihood of tumor recurrence (ie. recurrent T1 tumors).
The discussion started with the point being made that BCG strain may influence outcomes, with reference made to the @Uroweb article discussing the outcomes of NMIBC and BCG strain.
Subsequently, we were reminded that patients with recurrent T1 tumors are at high risk for disease progression and mortality, and that appropriately fit patients should be offered aggressive treatment (radical cystectomy).
@uretericbud also made the point that we aggressively treat T1 prostate and T1 kidney cancer, which have low cancer specific mortality, however cystectomy is the last resort for T1 bladder cancer (mortality >30%).
The reality of the worldwide BCG shortage was also highlighted during the discussion, ultimately affecting other ongoing MMC and BCG trials.
This month’s discussion concluded with a conversation regarding treatment options during the BCG shortage. The conclusion among the discussants was for MMC during the induction phase of treatment.
Overall, the consensus was that although the results of MMC and BCG in sequence are encouraging, appropriately fit patients may still benefit from radical cystectomy for recurrent T1 disease. With the worldwide shortage of BCG, perhaps this decision will be easier to make. Happy #movember everyone.
The winner of the Best Tweet prize is Vincent Misrai who will receive a complimentary registration to the USANZ Annual Scientific Meeting to be held in Adelaide, Australia in March 2015.
Thank you to the Urological Society of Australia and New Zealand (USANZ) for providing this generous prize. Thanks also to European Urology for enabling this paper to be open access for the November #urojc.
Zach Klaassen is a Resident in the Department of Surgery, Section of Urology Georgia Regents University – Medical College of Georgia Augusta, USA. @zklaassen_md
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These images are from an experimental paper by Long et al (BJUI 2014)
No such quiz/survey/pollIn the present issue of the BJUI Allott et al. [1] report results from a study where they used the Shared Equal Access Regional Cancer Hospital (SEARCH) database to explore the risk of biochemical recurrence (BCR) after radical prostatectomy (RP) among men who used statins after RP. They report improved BCR-free survival among statin users, especially among men with high-risk disease at baseline. The results provide some new insights into the current discussion on statins and prostate cancer outcomes.
Statins have recently shown promise as chemotherapeutic agents against prostate cancer. There is conflicting evidence on the effect on overall prostate cancer risk, but most studies able to evaluate the risk by tumour stage have reported lowered risk of advanced prostate cancer among statin users compared with the non-users [2], and lowered prostate cancer-specific mortality [3].
Taken together, these epidemiological findings suggest that statins may not strongly lower the risk of initiation of prostate cancer, but may be able to slow down the progression of the most dangerous form of the disease. In vitro studies support this by reporting growth inhibition and lower metastatic activity of prostate cancer cells after statin treatment [4].
Despite this, there has been recent controversy on statins’ effect on BCR of prostate cancer after radical treatment. A recent meta-analysis concluded that statin users may have a lower risk of BCR after external beam radiation therapy, but not after RP [5]. This could be due to statins acting as radiation sensitizers. Reports of improved BCR-free survival in statin users after brachytherapy would support this [6].
However, there are also differences in the characteristics of patients managed with RP or radiation therapy. Men undergoing RP have localised disease, which usually means low- to medium-grade tumours (Gleason ≤7), as high-grade disease (Gleason 8–10) progresses early and is more often locally advanced or already metastatic at diagnosis, leading to the choice of radiation therapy with neoadjuvant androgen deprivation instead of RP if curative treatment is still deemed possible.
This leads to the question whether the differing association between statins and BCR by treatment method is explained by patient selection, and whether statins are most effective against progression of high-grade disease. The study reported by Allott et al. [1] in this issue of the BJUI certainly suggests so. They report lowered risk of BCR among men who used statins after RP. They were able to study the effect of statin usage occurring after RP, not just usage at the time of RP. When the analysis was stratified by tumour characteristics, the improvement in relapse-free survival was strongest among men with high-risk disease (Gleason score ≥4 + 3; positive surgical margins).
The present study [1] supports the notion that statins could target a mechanism that is essential for progression of high-risk prostate cancer. This would be in concordance with the previously reported lowered risk of advanced prostate cancer and decreased prostate cancer mortality among statin users, as high-grade/high-risk cancer is the type progressing into advanced and fatal stages. On the other hand, if statins do not affect low-grade prostate cancer, this could explain why many RP series have not observed differences in biochemical relapses by statin use, as patients in these studies often have low-grade disease.
As always, statins’ benefits against prostate cancer are not really proven until verified in randomised clinical trials properly designed and powered to detect a difference in cancer endpoints. Designers of such trials should consider targeting the statin intervention to men with high-grade and/or high-risk prostate cancer for efficient study design.
Teemu J. Murtola*†
*School of Medicine, University of Tampere, and † Department of Urology, Tampere University Hospital, Tampere, Finland
References
1 Allott EH, Howard LE, Cooperberg MR et al. Postoperative statin use and risk of biochemical recurrence following radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. BJU Int 2014; 114: 661–6
2 Bansal D, Undela K, D’Cruz S, Schifano F. Statin use and risk of prostate cancer: a meta-analysis of observational studies. PLoS ONE 2012; 7:e46691
3 Yu O, Eberg M, Benayoun S et al. Use of statins and the risk of death in patients with prostate cancer. J Clin Oncol 2014; 32: 5–11
4 Brown M, Hart C, Tawadros T et al. The differential effects of statins on the metastatic behaviour of prostate cancer. Br J Cancer 2012; 106: 1689–96
5 Park HS, Schoenfeld JD, Mailhot RB et al. Statins and prostate cancer recurrence following radical prostatectomy or radiotherapy: a systematic review and meta-analysis. Ann Oncol 2013; 24: 1427–34
6 Moyad MA, Merrick GS, Butler WM et al. Statins, especially atorvastatin, may improve survival following brachytherapy for clinically localized prostate cancer. Urol Nurs 2006; 26: 298–303
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