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Article of the Month: Progression and treatment of incident lower urinary tract symptoms (LUTS) among men in the California Men’s Health Study

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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.

This week we feature a video from Dr. Steven Jacobsen discussing his paper. 

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

Progression and treatment of incident lower urinary tract symptoms (LUTS) among men in the California Men’s Health Study

Lauren P. Wallner, Jeff M. Slezak*, Ronald K. Loo†, Virginia P. Quinn*, Stephen K. Van Den Eeden‡ and Steven J. Jacobsen*

Department of Medicine and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, *Department of Research and Evaluation, Kaiser Permanente Southern California, †Department of Urology, Southern California Permanente Medical Group, Pasadena, CA, and ‡Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA

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OBJECTIVES

To characterise the progression and treatment of lower urinary tract symptoms (LUTS) among men aged 45–69 years in the California Men’s Health Study.

PATIENTS AND METHODS

A total of 39 222 men, aged 45–69 years, enrolled in the Southern California Kaiser Permanente Health Plan were surveyed in 2002–2003 and again in 2006–2007. Those men who completed both surveys who did not have a diagnosis of benign prostatic hyperplasia (BPH) and were not on medication for LUTS at baseline were included in the study (N = 19 505). Among the men with no or mild symptoms at baseline, the incidence of moderate/severe LUTS (American Urological Association Symptom Index [AUASI] score ≥8) and odds of progression to severe LUTS (AUASI score ≥20) was estimated during 4 years of follow-up.

RESULTS

Of the 9640 men who reported no/mild LUTS at baseline, 3993 (41%) reported moderate/severe symptoms at follow-up and experienced a 4-point change in AUASI score on average. Of these men, 351 (8.8%) had received a pharmacological treatment, eight (0.2%) had undergone a minimally invasive or surgical procedure and 3634 (91.0%) had no treatment recorded. Men who progressed to severe symptoms (AUASI score ≥20; n = 165) were more likely to be on medication for BPH (odds ratio [OR] 8.09, 95% confidence interval [CI] 5.77–11.35), have a BPH diagnosis (OR 4.74, 95% CI 3.40–6.61) or have seen a urologist (OR 2.49, 95% CI 1.81–3.43) when compared with men who did not progress to severe symptoms (AUASI score <20).

CONCLUSION

These data show that the majority of men who experienced progression did not have pharmacological or surgical therapy for their symptoms and, therefore, may prove to be good candidates for a self-management plan.

Read more articles of the week

Video: Progression and treatment of incident lower urinary tract symptoms (LUTS) among men in the California Men’s Health Study

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Progression and treatment of incident lower urinary tract symptoms (LUTS) among men in the California Men’s Health Study

Lauren P. Wallner, Jeff M. Slezak*, Ronald K. Loo†, Virginia P. Quinn*, Stephen K. Van Den Eeden‡ and Steven J. Jacobsen*

Department of Medicine and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, *Department of Research and Evaluation, Kaiser Permanente Southern California, †Department of Urology, Southern California Permanente Medical Group, Pasadena, CA, and ‡Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA

Read the full article

OBJECTIVES

To characterise the progression and treatment of lower urinary tract symptoms (LUTS) among men aged 45–69 years in the California Men’s Health Study.

PATIENTS AND METHODS

A total of 39 222 men, aged 45–69 years, enrolled in the Southern California Kaiser Permanente Health Plan were surveyed in 2002–2003 and again in 2006–2007. Those men who completed both surveys who did not have a diagnosis of benign prostatic hyperplasia (BPH) and were not on medication for LUTS at baseline were included in the study (N = 19 505). Among the men with no or mild symptoms at baseline, the incidence of moderate/severe LUTS (American Urological Association Symptom Index [AUASI] score ≥8) and odds of progression to severe LUTS (AUASI score ≥20) was estimated during 4 years of follow-up.

RESULTS

Of the 9640 men who reported no/mild LUTS at baseline, 3993 (41%) reported moderate/severe symptoms at follow-up and experienced a 4-point change in AUASI score on average. Of these men, 351 (8.8%) had received a pharmacological treatment, eight (0.2%) had undergone a minimally invasive or surgical procedure and 3634 (91.0%) had no treatment recorded. Men who progressed to severe symptoms (AUASI score ≥20; n = 165) were more likely to be on medication for BPH (odds ratio [OR] 8.09, 95% confidence interval [CI] 5.77–11.35), have a BPH diagnosis (OR 4.74, 95% CI 3.40–6.61) or have seen a urologist (OR 2.49, 95% CI 1.81–3.43) when compared with men who did not progress to severe symptoms (AUASI score <20).

CONCLUSION

These data show that the majority of men who experienced progression did not have pharmacological or surgical therapy for their symptoms and, therefore, may prove to be good candidates for a self-management plan.

Read more articles of the week

Article of the Week: Spine Metastases in Prostate Cancer: Comparison of [99mTc]MDP Wholebody Bone Scintigraphy, [18F]Choline PET/CT, and [18F]NaF PET/CT

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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.

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

Spine metastases in prostate cancer: comparison of technetium-99m-MDP whole-body bone scintigraphy, [18F]choline positron emission tomography(PET)/computed tomography (CT) and [18F]NaF PET/CT

Mads H. Poulsen, Henrik Petersen*, Poul F. Høilund-Carlsen*, Jørn S. Jakobsen, Oke Gerke*, Jens Karstoft†, Signe I. Steffansen* and Steen Walter

Research Unit of Urology, Department of Urology, and Departments of *Nuclear Medicine and †Radiology, Odense University Hospital, Odense, Denmark

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OBJECTIVE

To compare the diagnostic accuracy of the following imaging techniques in the detection of spine metastases, using magnetic resonance imaging (MRI) as a reference: whole-body bone scintigraphy (WBS) with technetium-99m-MDP, [18F]-sodium fluoride (NaF) positron emission tomography (PET)/computed tomography (CT) and [18F]-fluoromethylcholine (FCH) PET/CT.

PATIENTS AND METHODS

The study entry criteria were biopsy-proven prostate cancer, a positive WBS consistent with bone metastases, and no history of androgen deprivation. Within 30 days of informed consent, trial scans were performed in random order. Scans were interpreted blindly for the purpose of a lesion-based analysis. The primary target variable was bone lesion (malignant/benign) and the ‘gold standard’ was MRI.

RESULTS

A total of 50 men were recruited between May 2009 and March 2012. Their mean age was 73 years, their median PSA level was 84 ng/mL, and the mean Gleason score of the tumours was 7.7. A total of 46 patients underwent all four scans, while four missed one PET/CT scan. A total of 526 bone lesions were found in the 50 men: 363 malignant and 163 non-malignant according to MRI. Sensitivity, specificity, positive and negative predictive values and accuracy were: WBS: 51, 82, 86, 43 and 61%; NaF-PET/CT: 93, 54, 82, 78 and 81%; and FCH-PET/CT: 85, 91, 95, 75 and 87%, respectively.

CONCLUSIONS

We found that FCH-PET/CT and NaF-PET/CT were superior to WBS with regard to detection of prostate cancer bone metastases within the spine. The present results call into question the use of WBS as the method of choice in patients with hormone-naïve prostate cancer.

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Editorial: Bone Metastases in Prostate Cancer: Which Scan?

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In this issue of BJUI, Poulsen et al. [1] present a prospective comparison of 18F-fluoride (NaF) and 18F-choline (FCH) positron emission tomography (PET)/CT with planar whole-body bone scintigraphy (WBS) using spinal MRI, including short tau inversion recovery (STIR), T1 and T2 sequences, as the reference standard in 50 hormone-naïve patients with confirmed bone metastases on WBS. They found that both PET/CT methods were significantly more sensitive and accurate than WBS and that FCH PET/CT was more specific than NaF PET/CT.

It has become increasingly recognised that planar WBS is no longer the most accurate method of assessing the skeleton for metastases and that novel imaging methods, including PET/CT, single-photon emission CT (SPECT)/CT and whole-body MRI offer advantages [2].

What is surprising in the presented results is that NaF PET/CT shows poor specificity (54%), a result that is discordant with previous literature [3, 4]. Compared with PET alone, using the CT component of hybrid PET/CT reduces false-positive interpretation of NaF uptake in benign lesions [3]. This raises the question as to whether the CT component of the PET/CT acquisition was used to full effect in the present study. The use of spinal MRI as a reference standard is also a possible limitation that is recognised by the authors, as this limits the comparison to only the spine, and MRI in itself is a method with known limitations. All patients had abnormal WBS for entry into the trial and whilst the PET methods were more sensitive on a lesion basis, a patient-based comparison was therefore not possible; however, the results imply that PET methods may identify metastatic disease in patients with normal WBS, as has been previously reported [3, 5].

Nevertheless, the authors should be congratulated in reporting valuable data from a prospective study where all imaging was performed in hormone-naïve patients, minimising confounding treatment-related effects, and within a small time window of 30 days; however, some questions remain. WBS is no longer state of the art for imaging the skeleton with radiolabelled bisphosphonates, such as 99mTc-methylene diphosphonate (MDP). Although NaF PET/CT has been shown to be superior to planar WBS augmented with SPECT [3], there have not been head-to-head comparisons with 99mTc-MDP SPECT/CT, where the potential advantages of the pharmacokinetics of NaF and the superior spatial resolution of PET compared with SPECT may not be as great. This may be particularly important given the difference in costs and availability of the two methods.

Despite the results from the present study, which show superiority of FCH PET/CT compared with NaF PET/CT with regard to specificity, taking the available literature as a whole, it remains unresolved as to what the best test for staging the skeleton in patients with high-risk prostate cancer should be at diagnosis. The different mechanisms of uptake of the PET tracers should be noted. NaF uptake reflects the local bone osteoblastic reaction to tumour within the bone marrow, whereas FCH uptake reflects metabolic activity within the tumour cells themselves. In prostate cancer, where the predominant effect is an increase in osteoblastic activity in the adjacent bone, the bone-specific tracers such as 99mTc-MDP and NaF have shown high sensitivity; however, direct imaging of tumour cell metabolism, such as increased choline kinase activity and cell membrane synthesis with FCH, may be advantageous in detecting metastases in the bone marrow before an osteoblastic reaction has occurred [6]. It is possible that both PET tracers may be required to provide optimum diagnostic accuracy and of course FCH PET/CT also provides valuable data on nodal and visceral metastatic disease. In patients with recurrent disease, better specificity has been reported with FCH [4], NaF possibly being limited by non-specific treatment-related effects such as osteoblastic flare. For similar reasons it may be that the more tumour-specific imaging methods, such as FCH PET/CT or diffusion-weighted MRI, may be better in assessing the treatment response of skeletal metastases. Questions therefore remain as to the best imaging test at different times in the management of patients with metastatic prostate cancer. 99mTc-MDP SPECT/CT deserves a full assessment, but perhaps the recent advent of PET/MRI and the potential synergies available from this hybrid technique may help resolve some of the remaining issues.

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Gary Cook*† and Vicky Goh*‡

*Division of Imaging Sciences and Biomedical Engineering, King’s College London, † Clinical PET Centre, and ‡ Department of Radiology, Guy’s and St Thomas’ Hospitals NHS Foundation Trust, London, UK

References

1 Poulsen MH, Petersen H, Høilund-Carlsen PF et al. Spine metastases in prostate cancer: comparison of [99mTc]MDP wholebody bone scintigraphy, [18F]choline PET/CT, and [18F]NaF PET/CT. BJU Int 2014; 114: 818–23

2 Fogelman I, Blake GM, Cook GJ. The isotope bone scan: we can do better. Eur J Nucl Med Mol Imaging 2013; 40: 1139–40

3 Even-Sapir E, Metser U, Mishani E et al. The detection of bone metastases in patients with high-risk prostate cancer: 99mTc-MDP Planar bone scintigraphy, single- and multi-field-of-view SPECT, 18F-fluoride PET, and 18F-fluoride PET/CT. J Nucl Med 2006; 47: 287–974

4 Langsteger W, Balogova S, Huchet V et al. Fluorocholine (18F) and sodium fluoride (18F) PET/CT in the detection of prostate cancer: prospective comparison of diagnostic performance determined by masked reading. Q J Nucl Med Mol Imaging 2011; 55: 448–57

5 Kjölhede H, Ahlgren G, Almquist H et al. Combined 18F-fluorocholine and 18F-fluoride positron emission tomography/computed tomography imaging for staging of high-risk prostate cancer. BJU Int 2012; 110: 1501–6

6 Beheshti M, Vali R, Waldenberger P et al. Detection of bone metastases in patients with prostate cancer by 18F fluorocholine and 18F fluoride PET-CT: a comparative study. Eur J Nucl Med Mol Imaging 2008; 35: 1766–74

 

Article of the Week: Perioperative and functional outcomes of elective RAPN for renal tumors with high surgical complexity

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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.

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

Perioperative and renal functional outcomes of elective robot-assisted partial nephrectomy for renal tumors with high surgical complexity

Alessandro Volpe*†, Diletta Garrou*‡, Daniele Amparore*‡, Geert De Naeyer*, Francesco Porpiglia‡, Vincenzo Ficarra*§ and Alexandre Mottrie*

*Division of Urology, O.L.V. Vattikuti Robotic Surgery Institute, Aalst, Belgium, †Division of Urology, University of Eastern Piedmont, Maggiore della Carità Hospital, Novara, ‡Division of Urology, University of Torino, San Luigi Hospital, Orbassano, and §Division of Urology, University of Udine, Udine, Italy

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OBJECTIVE

To evaluate the perioperative, postoperative and functional outcomes of robot-assisted partial nephrectomy (RAPN) for renal tumours with high surgical complexity at a large volume centre.

PATIENTS AND METHODS

Perioperative and functional outcomes of RAPNs for renal tumours with a Preoperative Aspects and Dimensions Used for an Anatomical (PADUA) score of ≥10 performed at our institution between September 2006 and December 2012 were collected in a prospectively maintained database and analysed. Surgical complications were graded according to the Clavien-Dindo classification. Serum creatinine and estimated glomerular filtration rate (eGFR) were assessed at the third postoperative day and 3–6 months after RAPN.

RESULTS

In all, 44 RAPNs for renal tumours with PADUA scores of ≥10 were included in the analysis; 23 tumours (52.3%) were cT1b. The median (interquartile range; range) operative time, estimated blood loss and warm ischaemia time (WIT) were 120 (94, 132; 60–230) min, 150 (80, 200; 25–1200) mL and 16 (13.8, 18; 5–35) min, respectively. Two intraoperative complications occurred (4.5%): one inferior vena caval injury and one bleed from the renal bed, which were both managed robotically. There were postoperative complications in 10 patients (22.7%), of whom four (9.1%) were high Clavien grade, including two bleeds that required percutaneous embolisation, one urinoma that resolved with ureteric stenting and one bowel occlusion managed with laparoscopic adhesiolysis. Two patients (4.5%) had positive surgical margins (PSMs) and were followed expectantly with no radiological recurrence at a mean follow-up of 23 months. The mean serum creatinine levels were significantly increased after surgery (121.1 vs 89.3 μmol/L; P = 0.001), but decreased over time, with no significant differences from the preoperative values at the 6-month follow-up (96.4 vs 89.3 μmol/L; P = 0.09). The same trend was seen for eGFR.

CONCLUSION

In experienced hands RAPN for renal tumours with a PADUA score of ≥10 is feasible with short WIT, acceptable major complication rate and good long-term renal functional outcomes. A slightly higher risk of PSMs can be expected due to the high surgical complexity of these lesions. The robotic technology allows a safe expansion of the indications of minimally invasive PN to anatomically very challenging renal lesions in referral centres.

Read more articles of the week

Editorial: Complex tumours, partial nephrectomy and functional outcomes

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In the paper by Volpe et al. [1], excellent renal functional outcomes are associated with partial nephrectomy in patients with high PADUA score cancers. The study is notable because it shows that, even in patients who are typically considered candidates for radical nephrectomy, partial nephrectomy can maintain excellent estimated GFR (eGFR) and outcomes; however, because we perform nephron-sparing procedures on patients who may also be candidates for radical nephrectomy, we must consider the varied nature of some of the data on partial nephrectomy.

The literature on renal ischaemia and functional outcomes is heterogeneous and highly debated [2]. There have been several contradictory studies and changes over time in the literature based on technology, surgeon, centre, measurement and, now, correlation with parenchyma-sparing.

A study conducted by the European Organisation for the Research and Treatment of Cancer (EORTC) compared radical nephrectomy (essentially an ischaemic time of infinity) and partial nephrectomy, reporting a 10-year overall survival benefit for patients treated with radical nephrectomy [3]. Nevertheless, this oft-criticized randomised trial also showed better eGFR in partial nephrectomy. The survival benefit reported in that study is countered by population-based studies suggesting that partial nephrectomy may still be a better option when feasible [4]. Unfortunately, these population-based studies may be considered to provide a lower level of evidence than a randomised study, and are also prone to several biases, the most notable being selection of both patients and centres. Surgeons may be more likely to perform nephron-sparing in patients in lower-risk groups. There are also other questions to consider. If a patient is more likely to be referred to a larger centre for partial nephrectomy, are they not also likely to be referred for their coronary artery bypass, aortic surgery, general medical care and even emergency care? Are these patients more likely to seek out second opinions for all of their medical care? Will this affect mortality? Are they more motivated and engaged in their own overall healthcare? These are just a few of the confounding factors that could influence outcomes and are difficult to control in population-based studies. Nevertheless, I am a firm believer in partial nephrectomy, and particularly in preserving renal function, as the better choice for the treatment of both straightforward and complex lesions. It will be difficult, however, to completely negate the implications of the EORTC trial.

Does reasonable ischaemic time affect eGFR outcome? The present study by Volpe et al. [1] would suggest that reasonable ischaemic times are completely acceptable. Several contradictory studies point out the benefits and risks of a limited or minimized clamp time for partial nephrectomy. Another separate paper by White et al. [5] is consistent with other studies that show that a clamped partial nephrectomy, even for high complexity masses, results in a minimal loss of renal function, if at all. Although there is also enthusiasm for a zero ischaemia technique, it is critical to point out that this may be surgeon-, patient-, technique- and institution-dependent. Ultimately, however, we are splitting hairs over a few points of eGFR. The real issue with long-term GFR outcomes in our patients is not only the impact of a few minutes of renal ischaemia, but also control of hypertension, diabetes and their role in medical renal disease. There is an absence of urological literature that controls for patients’ glycated haemoglobin levels or measures hypertension monthly and records the response to medical therapy. These critical pieces of information confound all eGFR and comparative measurements and make it difficult to compare published outcomes. Perhaps the best medical advice we can give patients is to diet, exercise and eat healthily for better overall health. In some sense, this advice may be far more important than the decision of partial vs radical nephrectomy for a complex mass.

What are the logical conclusions of these dilemmas? Clamped partial nephrectomy is possible in complex cases, and the procedure salvages eGFR. Further refinements are also interesting academically, including papers on parenchyma-sparing. Nevertheless, if we are serious about ‘healthy kidneys’, we might take a holistic approach and encourage our patients to pursue a healthier lifestyle so they can bolster lifelong preservation of renal function and general wellness. Would the effect be more profound than a few minutes of ischaemic time? I am betting it would.

Read the full article

Sam B. Bhayani 

Division of Urological Surgery, Washington University School of Medicine and Barnes-Jewish West County Hospital, St Louis, MO, USA

References

1 Volpe A, Garrou D, Amparore D et al. Perioperative and renal functional outcomes of elective robot-assisted partial nephrectomy for renal tumors with high surgical complexity. BJU Int 2014; 114: 903–9

2 Lane BR, Russo P, Uzzo RG et al. Comparison of cold and warm ischemia during partial nephrectomy in 660 solitary kidneys reveals predominant roles of nonmodifiable factors in determining ultimate renal function. J Urol 2011; 185: 421–7

3 Van Poppel H, Da Pozzo L, Albrecht W et al. A prospective, randomized EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. Eur Urol 2011; 59: 543–52

4 Sun M, Trinh Q-D, Bianchi M et al. A non-cancer related survival benefit is associated with partial nephrectomy. Eur Urol 2012; 61: 725–31

5 White MA, Georges-Pascal H, Autorino R et al. Outcomes of robotic partial nephrectomy for renal masses with nephrometry score of ≥ 7. Urology 2011; 77: 809–13

 

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.

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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

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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.

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