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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

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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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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

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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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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

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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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Video: Evolution of SWL technique. A 25 year single centre experience of over 5000 patients

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Evolution of SWL technique. A 25 year single centre experience of over 5000 patients

Jitendra Jagtap, Shashikant Mishra, Amit Bhattu, Arvind Ganpule, Ravindra Sabnis and Mahesh Desai

Department of Urology, Muljibhai Patel Urological Hospital, Nadiad, India

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OBJECTIVE

To assess the impact of various treatment optimisation strategies in shockwave lithotripsy (SWL) used at a single centre over the last 25 years.

PATIENTS AND METHODS

In all, 5017 patients treated between 1989 and 2013 were reviewed and divided into groups A, B, C and D for the treatment periods of 1989–1994 (1561 patients), 1995–2000 (1741), 2001–2006 (1039) and 2007–2013 (676), respectively. The Sonolith 3000 (A and B) and Dornier compact delta lithotripters (C and D) were used. Refinements included frequent re-localisation, limiting maximum shocks and booster therapy in group B and Hounsfield unit estimation, power ramping and improved coupling in group D. Parameters reviewed were annual SWL utilisation, stone and treatment data, retreatment, auxiliary procedures, complications and stone-free rate (SFR).

RESULTS

The SFR with Dornier compact delta was significantly higher than that of the Sonolith 3000 (P < 0.001). The SFR improved significantly from 77.58%, 81.28%, 82.58% to 88.02% in groups A, B, C, and D, respectively (P < 0.001). There was a concomitant decrease in repeat SWL (re-treatment rate: A, 48.7%; B, 33.4%; C, 15.8%; and D, 10.1%; P < 0.001) and complication rates (A, 8%; B, 6.4%; C, 4.9%; and D, 1.6%; P < 0.001). This led to a rise in the efficiency quotient (EQ) in groups A–D from 50.41, 58.94, 68.78 to 77.06 (P < 0.001).The auxiliary procedure rates were similar in all groups (P = 0.62).

CONCLUSION

In conclusion, improvement in the EQ together with a concomitant decrease in complication rate can be achieved with optimum patient selection and use of various treatment optimising strategies.

 

Step-by-Step. Real time TRUS-guided free-hands technique for focal cryoablation of the prostate

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Real-time transrectal ultrasonography-guided hands-free technique for focal cryoablation of the prostate

Andre Luis de Castro Abreu, Duke Bahn*, Sameer Chopra, Scott Leslie, Toru Matsugasumi, Inderbir S. Gill and Osamu Ukimura

USC Institute of Urology, Catherine and Joseph Aresty Department of Urology, Center for Prostate Cancer Focal Therapy, Keck School of Medicine, University of Southern California, Los Angeles, and *Prostate Institute of America, Community Memorial Hospital, Ventura, CA, USA

How to Cite: de Castro Abreu, A. L., Bahn, D., Chopra, S., Leslie, S., Matsugasumi, T., Gill, I. S. and Ukimura, O. (2014), Real-time transrectal ultrasonography-guided hands-free technique for focal cryoablation of the prostate. BJU International, 114: 784–789. doi: 10.1111/bju.12795

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Objectives

To describe, step-by-step, our hands-free technique for focal cryoablation of prostate cancer.

Materials and Methods

After detailed discussion of its limitations and benefits, consent was obtained to perform focal cryoablation in patients with biopsy-proven unilateral low- to intermediate-risk prostate cancer. The procedure was performed transperineally, using a hands-free technique (without an external grid template) under real-time bi-plane transrectal ultrasonography (TRUS) guidance, using an argon/helium-gas-based third generation cryoablation system. Follow-up consisted of validated questionnaires, physical examination, PSA measures, multiparametric TRUS and/or magnetic resonance imaging (MRI) and mandatory biopsy.

Results

The important steps for achieving safety, satisfactory oncological and functional outcomes included: patient selection, including TRUS/MRI fusion target biopsy; thermocouple and cryoprobe placement with a hands-free technique, allowing delivery in unrestricted angulations according to the prostatic contour, the course of the neurovascular bundle and the rectal wall angle; and hands-free bi-plane TRUS probe manipulation to facilitate real-time monitoring of anatomical landmarks at the ideal angle of the image plane. To achieve a lethal temperature in the known cancer area, while preserving the urinary sphincter, neurovascular bundle, urethra and rectal wall, continuous intraoperative control of the thermocouple temperatures was necessary, as were real-time TRUS monitoring of ice-ball size, control of the energy delivered and the use of a warming urethral catheter.

Conclusion

We have described step-by-step the focal cryoablation of prostate cancer using a hands-free technique. This technique facilitates the effective delivery of cryoprobes and the intra-operative real-time quick manipulation of the TRUS probe.

 

Videos: Avoiding breaches of the histological boundaries of the prostate in open radical prostatectomy

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Assessing the extirpative quality of a radical prostatectomy technique: categorisation and mapping of technical errors

Christian Barré, Matthieu Thoulouzan*, Geneviève Aillet† and Jean-Michel Nguyen‡
Department of Urology, Jules Verne Clinic, Nantes, *Department of Urology, Rangueil University Hospital, Toulouse, †Institute of Histo-Pathology, and ‡Department of Epidemiology and Biostatistics, UMR 892, University Hospital, Nantes, France

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Objective

  • To examine the extirpative quality of an open radical prostatectomy (RP) technique by first categorising and mapping all intraprostatic incisions into benign tissue and then determining a cumulative technical error rate given by all intraprostatic incisions into benign and malignant tissue.

Patients and Methods

  • We performed a retrospective review of prospectively collected data relating to 1065 men with clinically localised prostate cancer who underwent open retropubic RP (70.6% nerve-sparing surgery [NSS]) by a single surgeon (January 2005 to December 2011).
  • We recorded all intraprostatic incisions: (i) iatrogenic positive surgical margins (PSMs), (ii) deep or superficial benign capsular incisions (BCIs), (iii) incisions into benign prostate glands at the prostate apex or bladder neck (benign glandular tissue incisions [BGTIs]), and determined incision location, length and nature (solitary/multiple).
  • We evaluated: (i) associations between benign incisions, NSS and PSMs, (ii) significant predictors for PSM risk by multivariate analysis, (iii) postoperative biochemical recurrence (BCR)-free survival (Kaplan–Meier method).

Results

  • Intraprostatic incision rates were 2.3% pT2 PSMs, 6.0% BCIs and 5.4% BGTIs. There were slight variations in rate over time and with NSS technique. Benign incisions were located as follows: 46.8% right posterolateral, 37.5% left posterolateral, and 15.7% bilateral for BCIs; 58.6% bladder neck and 41.4% apical for BGTIs.
  • The median (range) incision length, for solitary and multiple incisions respectively, was 4 (1–13) and 9 (2–25) mm for BCIs and 1 (1–5) and 2 (2–6) mm for BGTIs.
  • BCI rate, but not BGTI rate, was significantly associated with NSS (P = 0.004) and PSM (P = 0.005), and increased PSM risk 3.6-fold.
  • A PSM increased BCR risk two-fold (odds ratio 2.078, 95% confidence interval 1.383–3.122).
  • BCR-free survival decreased significantly even for short PSMs (<1 mm; P < 0.001).

Conclusions

  • Although the pT2 PSM rate was low (2.3%), the cumulative technical error rate (patients with at least one pT2 PSM, BCI or BGTI) was five-fold higher (12.5%).
  • Categorising and mapping intraprostatic incisions is a tool surgeons can use in self-audits to identify areas of potential improvement, reduce errors, and improve surgical skills.

 

Video: PROs in Prostate Brachytherapy

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Using Patient-Reported Outcomes to Assess and Improve Prostate Cancer Brachytherapy

James A. Talcott 1, 2, 10, 11, Judith Manola 3, Ronald C. Chen 4, Jack A. Clark 5, 6, Irving Kaplan 7, 8, Anthony V. D’Amico 8, 11 and Anthony L. Zietman 9, 11

1 Massachusetts General Hospital Cancer Center, Boston, MA, 2 Continuum Cancer Centers of New York, New York, NY, 3 Dana-Farber Cancer Institute, Boston, MA, 4 Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 5 Center for Health Quality, Outcomes, and Economic Research, Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA, 6 Boston University School of Public Health, 7 Beth Israel-Deaconess Medical Center, 8 Brigham and Women’s Hospital, 9 Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, 10 Albert Einstein School of Medicine, New York, NY, and 11 Harvard Medical School, Boston, MA, USA

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OBJECTIVE
  • To describe a successful quality improvement process that arose from unexpected differences in control groups’ short-term patient-reported outcomes (PROs) within a comparative effectiveness study of a prostate brachytherapy technique intended to reduce urinary morbidity.
PATIENTS AND METHODS
  • Patients planning prostate brachytherapy at one of three institutions were enrolled in a prospective cohort study.
  • Patients were surveyed using a validated instrument to assess treatment-related toxicity before treatment and at pre-specified intervals.
  • Unexpectedly, urinary PROs were worse in one of two standard brachytherapy technique control populations (US-BT1 and US-BT2). Therefore, we collaboratively reviewed treatment procedures, identified a discrepancy in technique, made a corrective modification, and evaluated the change.
RESULTS
  • The patient groups were demographically and clinically similar.
  • In the first preliminary analysis, US-BT2 patients reported significantly more short-term post-treatment urinary symptoms than US-BT1 patients.
  • The studies treating physicians reviewed the US-BT1 and US-BT2 treatment protocols and found that they differed in whether they used an indwelling urinary catheter.
  • After adopting the US-BT1 approach, short-term urinary morbidity in US-BT2 patients decreased significantly. Brachytherapy procedures were otherwise unchanged.
CONCLUSION
  • Many procedures in cancer treatments are not evaluated, resulting in practice variation and suboptimal outcomes. Patients, the primary medical consumers, provide little direct input in evaluations of their care.
  • We used PROs, a sensitive and valid measure of treatment-related toxicity, for quality assessment and quality improvement (QA/QI) of prostate brachytherapy. This serendipitous patient-centred QA/QI process may be a useful model for empirically evaluating complex cancer treatment procedures and for screening for substandard care.
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Video: Step-by-Step. Robotic assisted laparoscopic ureteral reimplantation – Extravesical approach

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Robot-assisted laparoscopic ureteric reimplantation: extravesical technique

Pankaj P. Dangle 1,*,Anup Shah 2 and Mohan S. Gundeti 3,4

1 Department of Surgery, Division of Urology, University of Chicago Medicine and Biological Sciences, Chicago, IL, USA

2 Pritzker School of Medicine, University of Chicago Medicine and Biological Sciences, Chicago, IL, USA

3 Center for Pediatric Robotic and Minimal Invasive Surgery, Department of Surgery, Division of Urology, University of Chicago Medicine and Biological Sciences, Chicago, IL, USA

4 Comer Children’s Hospital, Chicago, IL, USA

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Objectives

To describe our standardised approach to performing robot-assisted extravesical ureteric reimplantation.

Patients and Methods

A total of 29 children, with high grade (III–V) vesico-ureteric reflux (VUR) underwent robot-assisted extravesical ureteric reimplantation between September 2010 and September 2013. Follow-up renal ultrasonography was performed at 1 month and 3 months and a voiding cysto-urethrogram (VCUG) was obtained at 4 months to assess VUR resolution.

Results

The mean (range) patient age at the time of surgery was 5.38 (3.0–10.0) years. Postoperative VCUG showed complete resolution of VUR in 32/40 ureters (80%). Of the remaining refluxing ureters, downgrading of VUR on VCUG was shown in 7/8 ureters (87.5%). The mean (range) length of hospital stay was 1.8 (1–3) days.

Conclusions

In conclusion, robot-assisted extravesical ureteric reimplantation is technically feasible with acceptable resolution of VUR.

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Video: Effect of peri-operative aspirin medication in open or robot-assisted RP

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Open and robot-assisted radical retropubic prostatectomy in men receiving ongoing low-dose aspirin medication: revisiting an old paradigm?

Sami-Ramzi Leyh-Bannurah, Jens Hansen, Hendrik Isbarn, Thomas Steuber, Pierre Tennstedt, Uwe Michl, Thorsten Schlomm*, Alexander Haese, Hans Heinzer, Hartwig Huland, Markus Graefen and Lars Budäus

Martini Clinic, Prostate Cancer Center at University Hospital Hamburg-Eppendorf, and *Department of Urology, Section for Translational Prostate Cancer Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

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OBJECTIVE

• To assess blood loss, transfusion rates and 90-day complication rates in patients receiving ongoing 100 mg/day aspirin medication and undergoing open radical prostatectomy (RP) or robot-assisted RP (RARP).

PATIENTS AND METHODS

• Between February 2010 and August 2011, 2061 open RPs and 400 RARPs were performed. All patients received low-molecular-weight heparin for thrombembolism prophylaxis. Aspirin intake during surgery was recorded in 137 patients (5.5%).

• Descriptive statistics and multivariable analyses after propensity-score matching for balancing potential differences in patients with and without aspirin medication were used to assess the risk of blood loss above the median in patients undergoing open RP or RARP.

RESULTS

• The median blood loss in the open RP cohort with and without aspirin medication was 750 and 700 mL, respectively, and in the RARP cohort it was 200 and 150 mL, respectively. Within the same cohorts, transfusions were administered in 21 and 8% and 0 and 1% of patients, respectively.

• The 90-day complication rates in patients with ongoing aspirin medication were 5.8, 4.4, 7.3 and 0% for Clavien grades I, II, III and IV complications, respectively.

• In multivariable analyses and after propensity-score matching, prostate volume (odds ratio 1.03; 95% CI 1.02–1.04; P < 0.01) but not ongoing aspirin medication achieved independent predictor status for the risk of blood loss above the median.

CONCLUSIONS

• Major surgery such as open RP and RARP can be safely performed in patients with ongoing aspirin medication without greater blood loss.

• Higher 90-day complication rates were not detected in such patients.

• Differences in transfusion rates between the groups receiving and not receiving ongoing aspirin medication may be explained by a higher proportion of patients with coronary artery disease in the group receiving ongoing aspirin mediciation. This comorbidity may result in a higher peri-operative threshold for allogenic blood transfusion.

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Video: Prognostic value of neutrophil–lymphocyte ratio in patients with UTUC

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Validation of pretreatment neutrophil–lymphocyte ratio as a prognostic factor in a European cohort of patients with upper tract urothelial carcinoma

Orietta Dalpiaz, Georg C. Ehrlich, Sebastian Mannweiler*, Jessica M. Martín Hernández, Armin Gerger†, Tatjana Stojakovic‡, Karl Pummer, Richard Zigeuner, Martin Pichler† and Georg C. Hutterer

Department of Urology, *Institute of Pathology, †Division of Oncology, Department of Internal Medicine, and ‡Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria

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OBJECTIVE

• To investigate the potential prognostic significance of the neutrophil–lymphocyte ratio (NLR) in a large European cohort of patients with upper urinary tract urothelial cell carcinoma (UUT-UCC).

PATIENTS AND METHODS

• We retrospectively evaluated data from 202 consecutive patients with non-metastatic upper urinary tract urothelial cell carcinoma (UUT-UCC), who underwent surgery between 1990 and 2012 at a single tertiary academic centre.

• Patients’ cancer-specific survival (CSS) and overall survival (OS) were assessed using the Kaplan–Meier method.

• To evaluate the independent prognostic significance of the NLR, multivariate proportional Cox regression models were applied for both endpoints.

RESULTS

• A higher NLR was significantly associated with shorter CSS (P = 0.002, log-rank test), as well as with shorter OS (P < 0.001, log-rank test).

• Multivariate analysis identified a high NLR as an independent prognostic factor for patients’ CSS (hazard ratio 2.72, 95% CI 1.25–5.93, P = 0.012), and OS (hazard ratio 2.48, 95% CI 1.31–4.70, P = 0.005).

CONCLUSIONS

• In the present cohort, patients with a high preoperative NLR had higher cancer-specific and overall mortality after radical surgery for UUT-UCC, compared with those with a low preoperative NLR.

• This easily identifiable laboratory measure should be considered as an additional prognostic factor in UUT-UCC in future.

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