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Article of the Week: Silencing histone deacetylase 2 induces regression of fibrotic plaque in Peyronie’s disease

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Every week the Editor-in-Chief selects the 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.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Professor Ji-Kan Ryu discussing his paper. 

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

Silencing histone deacetylase 2 using small hairpin RNA induces regression of fibrotic plaque in a rat model of Peyronie’s disease

Ki-Dong Kwon, Min Ji Choi, Jin-Mi Park, Kang-Moon Song, Mi-Hye Kwon, Dulguun Batbold, Guo Nan Yin, Woo Jean Kim, Ji-Kan Ryu and Jun-Kyu Suh

National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon 400-711, Korea

Read the full article
OBJECTIVES

To examine the therapeutic effect of adenovirus encoding histone deacetylase 2 (HDAC2) small hairpin RNA (Ad-HDAC2 shRNA) in a rat model of Peyronie’s disease (PD) and to determine the mechanisms by which HDAC2 knockdown ameliorates fibrotic responses in primary fibroblasts derived from human PD plaque.

MATERIAL AND METHODS

Rats were distributed into four groups (n = 6 per group): age-matched controls without treatment; rats in which PD has been induced (PD rats) without treatment; PD rats receiving a single injection of control adenovirus encoding scrambled small hairpin RNA (Ad-shRNA) (day 15; 1 × 108 pfu/0.1 mL phosphate-buffered saline [PBS]); and PD rats receiving a single injection of Ad-HDAC2 shRNA (day 15; 1 × 108 pfu/0.1 mL PBS) into the lesion. PD-like plaque was induced by repeated intratunical injections of 100 μL each of human fibrin and thrombin solutions on days 0 and 5. On day 30, the penis was harvested for histological examination. Fibroblasts isolated from human PD plaque were pretreated with HDAC2 small interfering (si)RNA (100 pmoL) and then stimulated with transforming growth factor (TGF)-β1 (10 ng/mL) to determine hydroxyproline levels, procollagen mRNA, apoptosis and protein expression of poly(ADP-ribose) polymerase 1 (PARP1) and cyclin D1.

RESULTS

We observed that Ad-HDAC2 shRNA decreased inflammatory cell infiltration, reduced transnuclear expression of phospho-Smad3 and regressed fibrotic plaque of the tunica albuginea in PD rats in vivo. siRNA-mediated silencing of HDAC2 significantly decreased the TGF-β1-induced transdifferentiation of fibroblasts into myofibroblasts and collagen production, and induced apoptosis by downregulating the expression of PARP1, and decreased the expression of cyclin D1 (a positive cell-cycle regulator) in primary cultured fibroblasts derived from human PD plaque in vitro.

CONCLUSION

Specific inhibition of HDAC2 with RNA interference may represent a novel targeted therapy for PD.

Read more articles of the week

 

Editorial: Histone deacetylase inhibition: a new target for Peyronie’s disease?

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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.

Read the full article

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

 

Video: Inducing regression of fibrotic plaque in Peyronie’s disease by silencing histone deacetylase 2

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Silencing histone deacetylase 2 using small hairpin RNA induces regression of fibrotic plaque in a rat model of Peyronie’s disease

Ki-Dong Kwon, Min Ji Choi, Jin-Mi Park, Kang-Moon Song, Mi-Hye Kwon, Dulguun Batbold, Guo Nan Yin, Woo Jean Kim, Ji-Kan Ryu and Jun-Kyu Suh

National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon 400-711, Korea

Read the full article
OBJECTIVES

To examine the therapeutic effect of adenovirus encoding histone deacetylase 2 (HDAC2) small hairpin RNA (Ad-HDAC2 shRNA) in a rat model of Peyronie’s disease (PD) and to determine the mechanisms by which HDAC2 knockdown ameliorates fibrotic responses in primary fibroblasts derived from human PD plaque.

MATERIAL AND METHODS

Rats were distributed into four groups (n = 6 per group): age-matched controls without treatment; rats in which PD has been induced (PD rats) without treatment; PD rats receiving a single injection of control adenovirus encoding scrambled small hairpin RNA (Ad-shRNA) (day 15; 1 × 108 pfu/0.1 mL phosphate-buffered saline [PBS]); and PD rats receiving a single injection of Ad-HDAC2 shRNA (day 15; 1 × 108 pfu/0.1 mL PBS) into the lesion. PD-like plaque was induced by repeated intratunical injections of 100 μL each of human fibrin and thrombin solutions on days 0 and 5. On day 30, the penis was harvested for histological examination. Fibroblasts isolated from human PD plaque were pretreated with HDAC2 small interfering (si)RNA (100 pmoL) and then stimulated with transforming growth factor (TGF)-β1 (10 ng/mL) to determine hydroxyproline levels, procollagen mRNA, apoptosis and protein expression of poly(ADP-ribose) polymerase 1 (PARP1) and cyclin D1.

RESULTS

We observed that Ad-HDAC2 shRNA decreased inflammatory cell infiltration, reduced transnuclear expression of phospho-Smad3 and regressed fibrotic plaque of the tunica albuginea in PD rats in vivo. siRNA-mediated silencing of HDAC2 significantly decreased the TGF-β1-induced transdifferentiation of fibroblasts into myofibroblasts and collagen production, and induced apoptosis by downregulating the expression of PARP1, and decreased the expression of cyclin D1 (a positive cell-cycle regulator) in primary cultured fibroblasts derived from human PD plaque in vitro.

CONCLUSION

Specific inhibition of HDAC2 with RNA interference may represent a novel targeted therapy for PD.

Read more articles of the week

 

Article of the Month: Comparing health-related QoL outcomes for robotic cystectomy with those of traditional open radical cystectomy

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Every week the Editor-in-Chief selects the 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.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Dr. Dipen Parekh discussing his paper. 

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

Health-related quality of life from a prospective randomised clinical trial of robot-assisted laparoscopic vs open radical cystectomy

Jamie C. Messer, Sanoj Punnen*, John Fitzgerald, Robert Svatek and Dipen J. Parekh

Department of Urology, University of Texas Health Sciences Center at San Antonio, San Antonio, TX and *Department of Urology, Miller School of Medicine, University of Miami, Miami, FL, USA

Read the full article

Objective

To compare health-related quality-of-life (HRQoL) outcomes for robot-assisted laparoscopic radical cystectomy (RARC) with those of traditional open radical cystectomy (ORC) in a prospective randomised fashion.

Patients and Methods

This was a prospective randomised clinical trial evaluating the HRQoL for ORC vs RARC in consecutive patients from July 2009 to June 2011. We administered the Functional Assessment of Cancer Therapy–Vanderbilt Cystectomy Index questionnaire, validated to assess HRQoL, preoperatively and then at 3, 6, 9 and 12 months postoperatively. Scores for each domain and total scores were compared in terms of deviation from preoperative values for both the RARC and the ORC cohorts. Multivariate linear regression was used to assess the association between the type of radical cystectomy and HRQoL.

Results

At the time of the study, 47 patients had met the inclusion criteria, with 40 patients being randomised for analysis. The cohorts consisted of 20 patients undergoing ORC and 20 undergoing RARC, who were balanced with respect to baseline demographic and clinical features. Univariate analysis showed a return to baseline scores at 3 months postoperatively in all measured domains with no statistically significant difference among the various domains between the RARC and the ORC cohorts. Multivariate analysis showed no difference in HRQoL between the two approaches in any of the various domains, with the exception of a slightly higher physical well-being score in the RARC group at 6 months.

Conclusions

There were no significant differences in the HRQoL outcomes between ORC and RARC, with a return of quality of life scores to baseline scores 3 months after radical cystectomy in both cohorts.

Read more articles of the week

Editorial: Robotic and conventional open radical cystectomy lead to similar postoperative health-related quality of life

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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.

Read the full article

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

 

Video: Robot-assisted laparoscopic vs open radical cystectomy – health-related QoL from a prospective randomised clinical trial

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Health-related quality of life from a prospective randomised clinical trial of robot-assisted laparoscopic vs open radical cystectomy

Jamie C. Messer, Sanoj Punnen*, John Fitzgerald, Robert Svatek and Dipen J. Parekh

Department of Urology, University of Texas Health Sciences Center at San Antonio, San Antonio, TX and *Department of Urology, Miller School of Medicine, University of Miami, Miami, FL, USA

Read the full article

Objective

To compare health-related quality-of-life (HRQoL) outcomes for robot-assisted laparoscopic radical cystectomy (RARC) with those of traditional open radical cystectomy (ORC) in a prospective randomised fashion.

Patients and Methods

This was a prospective randomised clinical trial evaluating the HRQoL for ORC vs RARC in consecutive patients from July 2009 to June 2011. We administered the Functional Assessment of Cancer Therapy–Vanderbilt Cystectomy Index questionnaire, validated to assess HRQoL, preoperatively and then at 3, 6, 9 and 12 months postoperatively. Scores for each domain and total scores were compared in terms of deviation from preoperative values for both the RARC and the ORC cohorts. Multivariate linear regression was used to assess the association between the type of radical cystectomy and HRQoL.

Results

At the time of the study, 47 patients had met the inclusion criteria, with 40 patients being randomised for analysis. The cohorts consisted of 20 patients undergoing ORC and 20 undergoing RARC, who were balanced with respect to baseline demographic and clinical features. Univariate analysis showed a return to baseline scores at 3 months postoperatively in all measured domains with no statistically significant difference among the various domains between the RARC and the ORC cohorts. Multivariate analysis showed no difference in HRQoL between the two approaches in any of the various domains, with the exception of a slightly higher physical well-being score in the RARC group at 6 months.

Conclusions

There were no significant differences in the HRQoL outcomes between ORC and RARC, with a return of quality of life scores to baseline scores 3 months after radical cystectomy in both cohorts.

Read more articles of the week

Article of the Week: Early unclamping technique during RAPN can minimise warm ischaemia without increasing morbidity

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Every week the Editor-in-Chief selects the 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.

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

Early unclamping technique during robot-assisted laparoscopic partial nephrectomy can minimise warm ischaemia without increasing morbidity

Benoit Peyronnet, Hervé Baumert*, Romain Mathieu, Alexandra Masson-Lecomte†, Yohann Grassano‡, Mathieu Roumiguié§, Walid Massoud*, Vincent Abd El Fattah¶, Franck Bruyère**, Stéphane Droupy¶, Alexandre de la Taille†, Nicolas Doumerc§, Jean-Christophe Bernhard‡, Christophe Vaessen††, Morgan Rouprêt†† and Karim Bensalah

Departments of Urology, University of Rennes, Rennes, *Saint-Joseph Hospital, ††La Pitié Salpétrière Hospital, Paris, †Henri-Mondor Hospital, Créteil, ‡University of Bordeaux, Bordeaux, §University of Toulouse, Toulouse, ¶University of Nimes, Nimes, and **University of Tours, Tours, France

Read the full article

Objective

To compare perioperative outcomes of early unclamping (EUC) vs standard unclamping (SUC) during robot-assisted partial nephrectomy (RAPN), as early unclamping of the renal pedicle has been reported to decrease warm ischaemia time (WIT) during laparoscopic PN.

Patients and Methods

A retrospective multi-institutional study was conducted at eight French academic centres between 2009 and 2013. Patients who underwent RAPN for a renal mass were included in the study. Patients without vascular clamping or for whom the decision to perform a radical nephrectomy was taken before unclamping were excluded. Perioperative outcomes were compared using the chi-squared and Fisher’s exact tests for discrete variables and the Mann–Whitney test for continuous variables. Predictors of WIT and estimated blood loss (EBL) were assessed using multiple linear regression analysis.

Results

In all, there were 430 patients: 222 in the EUC group and 208 in the SUC group. Tumours were larger (35.8 vs 32.3 mm, P = 0.02) and more complex (R.E.N.A.L. nephrometry score 6.9 vs 6.1, P < 0.001) in the EUC group but surgeons were more experienced (>50 procedures 12.2% vs 1.4%, P < 0.001). The mean WIT was shorter (16.7 vs 22.3 min, P < 0.001) and EBL was higher (369.5 vs 240 mL, P = 0.001) in the EUC group with no significant difference in complications or transfusion rates. The results remained the same when analysing subgroups of complex renal tumours (R.E.N.A.L. nephrometry score ≥7) or RAPN performed by less experienced surgeons (<20 procedures). In multivariable analysis, EUC was predictive of decreased WIT (β –0.34; P < 0.001) but was not associated with EBL (β –0.09, P = 0.16).

Conclusions

EUC can reduce WIT during RAPN without increasing morbidity even for complex renal tumours or when being performed by less experienced surgeons.

Read more articles of the week

Article of the Week: Radical prostatectomy – postoperative statin use and risk of biochemical recurrence

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Every week the Editor-in-Chief selects the 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.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Emma Allott discussing her paper. 

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

Postoperative statin use and risk of biochemical recurrence following radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database

Emma H. Allott, PhD 1, 2, 3, Lauren E. Howard, BA 3, 4, Matthew R. Cooperberg, MD 5, Christopher J. Kane, MD 6, William J. Aronson, MD 7, 8, Martha K. Terris, MD 9, 10, Christopher L. Amling, MD 11 and Stephen J. Freedland, MD 1, 3, 12

1 Division of Urology, Department of Surgery, 4 Department of Biostatistics and Bioinformatics, 12 Department of Pathology, Duke University School of Medicine, 2 Cancer Prevention, Detection and Control Program, Duke Cancer Institute, 3 Division of Urology, Veterans Affairs Medical Center Durham, NC, 5 Department of Urology, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, 6 Urology Department, University of California San Diego Health System, San Diego, 7 Urology Section, Department of Surgery, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, 8 Department of Urology, UCLA School of Medicine, Los Angeles, CA, 9 Section of Urology, Veterans Affairs Medical Center, Augusta, 10 Department of Urology, Georgia Regents University, Augusta, GA, 11 Department of Urology, Oregon Health Sciences University, Portland, OR, USA

Read the full article
OBJECTIVE

To investigate the effect of statin use after radical prostatectomy (RP) on biochemical recurrence (BCR) in patients with prostate cancer who never received statins before RP.

PATIENTS AND METHODS

We conducted a retrospective analysis of 1146 RP patients within the Shared Equal Access Regional Cancer Hospital (SEARCH) database. Multivariable Cox proportional hazards analyses were used to examine differences in risk of BCR between post-RP statin users vs nonusers. To account for varying start dates and duration of statin use during follow-up, post-RP statin use was treated as a time-dependent variable. In a secondary analysis, models were stratified by race to examine the association of post-RP statin use with BCR among black and non-black men.

RESULTS

After adjusting for clinical and pathological characteristics, post-RP statin use was significantly associated with 36% reduced risk of BCR (hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.47–0.87; P = 0.004). Post-RP statin use remained associated with reduced risk of BCR after adjusting for preoperative serum cholesterol levels. In secondary analysis, after stratification by race, this protective association was significant in non-black (HR 0.49, 95% CI 0.32–0.75; P = 0.001) but not black men (HR 0.82, 95% CI 0.53–1.28; P = 0.384).

CONCLUSION

In this retrospective cohort of men undergoing RP, post-RP statin use was significantly associated with reduced risk of BCR. Whether the association between post-RP statin use and BCR differs by race requires further study. Given these findings, coupled with other studies suggesting that statins may reduce risk of advanced prostate cancer, randomised controlled trials are warranted to formally test the hypothesis that statins slow prostate cancer progression.

Read more articles of the week

Editorial: Statins and biochemical recurrence after radical prostatectomy – who benefits?

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In 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.

Read the full article

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

 

Video: Postoperative statin use and risk of biochemical recurrence following radical prostatectomy. Results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database.

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Postoperative statin use and risk of biochemical recurrence following radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database

Emma H. Allott, PhD 1, 2, 3, Lauren E. Howard, BA 3, 4, Matthew R. Cooperberg, MD 5, Christopher J. Kane, MD 6, William J. Aronson, MD 7, 8, Martha K. Terris, MD 9, 10, Christopher L. Amling, MD 11 and Stephen J. Freedland, MD 1, 3, 12

1 Division of Urology, Department of Surgery, 4 Department of Biostatistics and Bioinformatics, 12 Department of Pathology, Duke University School of Medicine, 2 Cancer Prevention, Detection and Control Program, Duke Cancer Institute, 3 Division of Urology, Veterans Affairs Medical Center Durham, NC, 5 Department of Urology, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, 6 Urology Department, University of California San Diego Health System, San Diego, 7 Urology Section, Department of Surgery, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, 8 Department of Urology, UCLA School of Medicine, Los Angeles, CA, 9 Section of Urology, Veterans Affairs Medical Center, Augusta, 10 Department of Urology, Georgia Regents University, Augusta, GA, 11 Department of Urology, Oregon Health Sciences University, Portland, OR, USA

Read the full article
OBJECTIVE

To investigate the effect of statin use after radical prostatectomy (RP) on biochemical recurrence (BCR) in patients with prostate cancer who never received statins before RP.

PATIENTS AND METHODS

We conducted a retrospective analysis of 1146 RP patients within the Shared Equal Access Regional Cancer Hospital (SEARCH) database. Multivariable Cox proportional hazards analyses were used to examine differences in risk of BCR between post-RP statin users vs nonusers. To account for varying start dates and duration of statin use during follow-up, post-RP statin use was treated as a time-dependent variable. In a secondary analysis, models were stratified by race to examine the association of post-RP statin use with BCR among black and non-black men.

RESULTS

After adjusting for clinical and pathological characteristics, post-RP statin use was significantly associated with 36% reduced risk of BCR (hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.47–0.87; P = 0.004). Post-RP statin use remained associated with reduced risk of BCR after adjusting for preoperative serum cholesterol levels. In secondary analysis, after stratification by race, this protective association was significant in non-black (HR 0.49, 95% CI 0.32–0.75; P = 0.001) but not black men (HR 0.82, 95% CI 0.53–1.28; P = 0.384).

CONCLUSION

In this retrospective cohort of men undergoing RP, post-RP statin use was significantly associated with reduced risk of BCR. Whether the association between post-RP statin use and BCR differs by race requires further study. Given these findings, coupled with other studies suggesting that statins may reduce risk of advanced prostate cancer, randomised controlled trials are warranted to formally test the hypothesis that statins slow prostate cancer progression.

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