Miguel Srougi

URINARY CONTINENCE AND PATHOLOGICAL OUTCOME AFTER BLADDER NECK PRESERVATION DURING RADICAL RETROPUBIC PROSTATECTOMY: A RANDOMIZED PROSPECTIVE TRIAL

PURPOSE Bladder neck preservation during radical prostatectomy has been advocated for improving urinary continence. We compared bladder neck preservation and resection in a randomized trial, looking at continence rates and surgical cancer control. MATERIALS AND METHODS Patients with stage T1c-T2c prostate cancer underwent radical retropubic prostatectomy with maximal preservation of the external urinary sphincter. Bladder neck preservation or resection was chosen by chance during surgery. Urinary continence (1 or no protective pad daily) was assessed by interview 2 days after catheter removal, and 2 and 6 months after surgery. The surgeon, pathologist and interviewer were the same throughout. Neither patient nor interviewer knew which procedure was done. Planned enrollment was 120. RESULTS Enrollment was stopped after 70 patients because surgical margins were positive only at the bladder neck in 10% of the preservation group but in none of the resection group (p = 0.08). Each group was assigned 35 patients but the bladder neck could not be preserved in 4 and 1 died, leaving 31 in the preservation group and 38 in the resection group. There were no statistically significant differences between groups in early or late urinary continence rates. Two days after catheter removal, and 2 and 6 months after surgery the respective rates were 79%, 87% and 95% with resection, and 67%, 87% and 97% with preservation. CONCLUSIONS In our opinion bladder neck preservation during radical retropubic prostatectomy does not improve urinary continence and might compromise cancer control. The external sphincter appears more important for continence after radical prostatectomy.

Salvage Radical Prostatectomy for Radiation-recurrent Prostate Cancer: A Multi-institutional Collaboration

BACKGROUND Oncologic outcomes in men with radiation-recurrent prostate cancer (PCa) treated with salvage radical prostatectomy (SRP) are poorly defined. OBJECTIVE To identify predictors of biochemical recurrence (BCR), metastasis, and death following SRP to help select patients who may benefit from SRP. DESIGN, SETTING, AND PARTICIPANTS This is a retrospective, international, multi-institutional cohort analysis. There was a median follow-up of 4.4 yr following SRP performed on 404 men with radiation-recurrent PCa from 1985 to 2009 in tertiary centers. INTERVENTION Open SRP. MEASUREMENTS BCR after SRP was defined as a serum prostate-specific antigen (PSA) ≥ 0.1 or ≥ 0.2 ng/ml (depending on the institution). Secondary end points included progression to metastasis and cancer-specific death. RESULTS AND LIMITATIONS Median age at SRP was 65 yr of age, and median pre-SRP PSA was 4.5 ng/ml. Following SRP, 195 patients experienced BCR, 64 developed metastases, and 40 died from PCa. At 10 yr after SRP, BCR-free survival, metastasis-free survival, and cancer-specific survival (CSS) probabilities were 37% (95% confidence interval [CI], 31-43), 77% (95% CI, 71-82), and 83% (95% CI, 76-88), respectively. On preoperative multivariable analysis, pre-SRP PSA and Gleason score at postradiation prostate biopsy predicted BCR (p = 0.022; global p < 0.001) and metastasis (p = 0.022; global p < 0.001). On postoperative multivariable analysis, pre-SRP PSA and pathologic Gleason score at SRP predicted BCR (p = 0.014; global p < 0.001) and metastasis (p < 0.001; global p < 0.001). Lymph node involvement (LNI) also predicted metastasis (p = 0.017). The main limitations of this study are its retrospective design and the follow-up period. CONCLUSIONS In a select group of patients who underwent SRP for radiation-recurrent PCa, freedom from clinical metastasis was observed in >75% of patients 10 yr after surgery. Patients with lower pre-SRP PSA levels and lower postradiation prostate biopsy Gleason score have the highest probability of cure from SRP.

Change in expression of miR-let7c, miR-100, and miR-218 from high grade localized prostate cancer to metastasis

OBJECTIVE MicroRNAs (miRNAs) are small noncoding regulatory RNAs (19-25 nucleotides) that play a major role in regulation of gene expression. They are responsible for the control of fundamental cellular processes that has been reported to be involved in human tumorigenesis. The characterization of miRNA profiles in human tumors is crucial for the understanding of carcinogenesis processes, finding of new tumor markers, and discovering of specific targets for the development of innovative therapies. The aim of this study is to find miRNAs involved in prostate cancer progression comparing the profile of miRNA expressed by localized high grade carcinoma and bone metastasis. MATERIAL AND METHODS Two groups of tumors where submitted to analyses. The first is characterized by 18 patients who underwent radical prostatectomy for treatment of localized high grade prostate carcinoma (PC) with mean Gleason score 8.6, all staged pT3. The second group is composed of 4 patients with metastatic, androgen-independent prostate carcinoma, and 2 PC cell lines. LNCaP derived from a metastatic PC to a lymph node, and another derived from an obstructive, androgen-independent PC (PcBRA1). Expression analysis of 14 miRNAs was carried out using quantitative RT-PCR. RESULTS miR-let7c, miR-100, and miR-218 were significantly overexpressed by all localized high GS, pT3 PC in comparison with metastatic carcinoma. (35.065 vs. 0.996 P<0.001), (55.550 vs. 8.314, P=0.010), and (33.549 vs. 2.748, P=0.001), respectively. CONCLUSION We hypothesize that miR-let7c, miR-100, and miR-218 may be involved in the process of metastasization of PC, and their role as controllers of the expression of RAS, c-myc, Laminin 5 β3, THAP2, SMARCA5, and BAZ2A should be matter of additional studies.

A Prospective Study Evaluating the Efficacy of the Artificial Sphincter AMS 800 for the Treatment of Postradical Prostatectomy Urinary Incontinence and the Correlation Between Preoperative Urodynamic and Surgical Outcomes

OBJECTIVES We have evaluated prospectively the long-term efficacy of the artificial urinary sphincter (AUS) AMS 800 for the treatment postradical prostatectomy urinary incontinence (PRPUI) patients. We also evaluated the correlation between preoperative urodynamic findings and surgical outcomes. METHODS From May 1997 to April 2003, 40 consecutive patients with PRPUI caused by intrinsic sphincter deficiency (ISD) were treated with the AMS 800. Mean age was 68.3 +/- 6.3 years. Continence status was evaluated on the basis of pad count, impact of urinary incontinence on the quality of life, complications, and surgical revisions. Preoperative urodynamic findings were correlated with surgical outcomes. RESULTS Follow-up ranged from 27 to 132 months (mean = 53.4 +/- 21.4 months). There was a significant reduction in pad count from 4.0 +/- 0.9 to 0.62 +/- 1.07 diapers per day (P <0.001) leading to continence in 90%. There was a significant reduction on the impact of incontinence decreasing from 5.0 +/- 0.7 to 1.4 +/- 0.93 (P <0.001) in a visual analogue scale (VAS). Surgical revision rate was 20%. Preoperative urodynamics was useful to identify sphincter deficiency. Except by a tendency of worse results in patients with reduced bladder compliance (RBC), other urodynamic parameters did not correlate with a worse surgical outcome. CONCLUSIONS The AMS 800 offers good long-term continence to most PRPUI patients. Preoperative findings like detrusor hyperactivity (DH), impaired detrusor contraction (IDC), low Valsalva leak point pressure, bladder outlet obstruction (BOO), and mild RBC were not associated with worse surgical outcomes.

Age-related increase of reactive oxygen species in neat semen in healthy fertile men.

OBJECTIVES The effects of advancing paternal age on the male reproductive system are well known, but its effects on fecundity remain controversial. Although oxidative stress is associated with poor semen quality and function, a relationship with advancing male age has not been established. The objective of this study was to analyze the relationship between male age and seminal reactive oxygen species (ROS) levels in men presenting for voluntary sterilization. METHODS We prospectively evaluated 98 fertile men who were candidates for vasectomy. These were divided into 2 age groups: less than 40 years (n = 78) and 40 or more years (n = 20). We used 46 infertile patients as positive controls. Standard semen analysis, seminal leukocyte count and ROS levels were measured in all samples. Fertile men with leukocytospermia were excluded. RESULTS The mean age of the men was 35.1 +/- 5.6 years. Men 40 years and older had significantly higher ROS levels compared with younger men (P <0.001). We observed a positive correlation between seminal ROS levels and age (r = 0.20; P = 0.040). In addition, ROS was negatively correlated with sperm concentration (r = -0.48; P <0.001) and motility (r = -0.21; P = 0.030). CONCLUSIONS Reactive oxygen species levels are significant higher in seminal ejaculates of healthy fertile men older than 40 years. ROS levels in whole ejaculate are significantly correlated to age among fertile men. Because ROS are clearly implicated in the pathogenesis of male infertility, these data suggest that delayed fatherhood may reduce the chances of pregnancy as men become progressively less fertile with age.

Quality of Life and Clinical Symptom Improvement Support Prostatic Artery Embolization for Patients with Acute Urinary Retention Caused by Benign Prostatic Hyperplasia

PURPOSE To show that prostatic artery embolization (PAE) improves quality of life (QoL) and lower urinary tract symptoms in patients with acute urinary retention caused by benign prostatic hyperplasia (BPH). MATERIALS AND METHODS This was a single-center prospective study of PAE in 11 patients with BPH managed with indwelling urinary catheters. International Prostate Symptom Score (IPSS), ultrasound, magnetic resonance (MR) imaging, QoL, and urodynamic tests were used to assess outcomes. Prostate size ranged from 30 to 90 g, and embolizations were performed with 300-500-μm Embosphere microspheres. RESULTS The rate of technical success (ie, bilateral PAE) was 75%, and the rate of clinical success (ie, catheter removal and symptom improvement) was 91% (10 of 11 patients). Postembolization syndrome manifested as mild pain in the perineum, retropubic area, and/or urethra. Ten of 11 patients urinated spontaneously after Foley catheter removal 4-25 days after PAE (mean, 12.1 d). No major complications were observed. Follow-up ranged from 19 to 48 months. In an asymptomatic patient, a discrete area of hypoperfusion suggesting small ischemia of the bladder was observed on 30-day MR imaging follow-up, but the bladder was normal on 90-day MR imaging. After 1 year, mean prostate volume reduction was greater than 30%, symptoms were mild (mean IPSS, 2.8 ± 2.1; P = .04), no erectile dysfunction was observed, and QoL improved significantly (mean, 0.4 ± 0.5; P = .001) using the paired t test. CONCLUSIONS Patients with severe symptoms and acute urinary retention caused by BPH can be treated safely by PAE, which improves clinical symptoms and QoL.

Abnormal Expression of MDM2 in Prostate Carcinoma

Mutation of p53 is rare in localized prostate carcinoma. The oncoprotein MDM2, whose gene has a response element for p53, promotes the degradation of p53 protein and inhibits its transcriptional activation of genes related to cell cycle arrest and apoptosis, constituting a negative feedback control. We studied p53 and MDM2 expression by immunohistochemistry and looked for mutations in p53 exons 5 to 8 by polymerase chain reaction-single strand conformational polymorphism in 118 patients submitted to radical prostatectomy for localized prostate cancer. In 28 cases, we studied cell proliferation by immunohistochemistry, using antibody for Ki-67, and apoptosis by the deoxynucleotidyl transferase mediated dUTP biotin nick end labeling technique. Although no p53 mutations were found, p53 protein was detected in 31.4% of the cases, and these cases had higher Gleason scores (P = .03) and more advanced tumor stages (P = .02). MDM2 was overexpressed in 40.7% of the cases, and these cases had greater tumor volumes (P = .001). Tumors that were positive for both p53 and MDM2 were larger (P = .003) and of more advanced stage (P = .03). Within the 28-case subset, the proliferative index was higher among MDM2-positive tumors (P = .046), and the apoptotic index was lower among p53-positive tumors (P = .01). We conclude that, although p53 mutation is a rare event in prostate carcinogenesis, the detection of p53 protein by immunohistochemistry is common and is associated with decreased apoptosis and increased histologic grade and tumor stage. We also conclude that the overexpression of MDM2 has a role in prostate carcinogenesis, being frequently detected and associated with increased cell proliferation and tumor volume. Finally, we propose that the MDM2-positive/p53-positive phenotype identifies prostate cancers with aggressive behavior.

MicroRNA expression profiles in the progression of prostate cancer—from high-grade prostate intraepithelial neoplasia to metastasis⁎

INTRODUCTION Models of the multistep process related to cancer progression have been designed for many cancers including prostate. The aim of this study is to propose a new model including a possible role for recently described micro RNAs in prostate cancer (CaP) progression. METHODS Sixty-three patients underwent radical prostatectomy to treat localized prostate carcinoma. The specimens of 15 patients were representative of high grade prostate intraepithelial neoplasia (HGPIN). Fourteen specimens represented localized favorable CaP, and 34 unfavorable, mostly non-organ-confined disease. Representing the advanced disease we studied 4 metastatic androgen-independent CaP and 2 cell lines. Micro RNAs were isolated using the mirVana miRNA Isolation kit and cDNA was obtained using the TaqMan miRNA Reverse Transcription kit to the miRNAs: hsa-miR-let7c, hsa-miR-15a, hsa-miR-16, hsa-miR-21, hsa-miR-25, hsa-miR-32, hsa-miR-100, hsa-miR-143, hsa-miR-145, hsa-miR-146a, hsa-miR-191, hsa-miR-199a, hsa-miR-206, and hsa-miR-218. Quantitative RT-PCR was carried out using the ABI 7500 Fast Real-Time PCR System and the TaqMan Universal PCR Master Mix. miRNA expression levels were measured by relative quantification, and fold expression changes were determined by the 2(-ΔΔCT) method. The small nucleolar RNA RNU43 was used as an endogenous control. RESULTS Except for miR-21 and miR-206, the expression levels of all miRNAs significantly changed during the progression of CaP. Interestingly, there was a significant global loss of miRNA expression between HGPIN and metastasis at 2 important steps. The first was related to the transition from HGPIN to invasive adenocarcinoma, and the second was related to the transition from localized to metastatic adenocarcinomas. CONCLUSION Through the analysis of 14 miRNAs in 4 groups of prostate lesions, which reproduced the progression of CaP, we showed that there is a global loss of miRNA expression at 2 distinct steps. The first related to the transition between HGPIN and localized invasive carcinoma, and the second associated with the transition from localized to metastatic CaP. The importance of our study is in the identification of possible miRNAs and miRNA-targeted genes involved in the progression of prostate carcinogenesis that may help the development of potential diagnostic or prognostic markers as well as the design of new target therapies.

miR-21 may acts as an oncomir by targeting RECK, a matrix metalloproteinase regulator, in prostate cancer

BackgroundPrognosis of prostate cancer (PCa) is based mainly in histological aspects together with PSA serum levels that not always reflect the real aggressive potential of the neoplasia. The micro RNA (miRNA) mir-21 has been shown to regulate invasiveness in cancer through translational repression of the Metaloproteinase (MMP) inhibitor RECK. Our aim is to investigate the levels of expression of RECK and miR-21 in PCa comparing with classical prognostic factors and disease outcome and also test if RECK is a target of miR-21 in in vitro study using PCa cell line.Materials and methodsTo determine if RECK is a target of miR-21 in prostate cancer we performed an in vitro assay with PCa cell line DU-145 transfected with pre-miR-21 and anti-miR-21. To determine miR-21 and RECK expression levels in PCa samples we performed quantitative real-time polymerase chain reaction (qRT-PCR).ResultsThe in vitro assays showed a decrease in expression levels of RECK after transfection with pre-miR-21, and an increase of MMP9 that is regulated by RECK compared to PCa cells treated with anti-miR-21. We defined three profiles to compare the prognostic factors. The first was characterized by miR-21 and RECK underexpression (N = 25) the second was characterized by miR-21 overexpression and RECK underexpression (N = 12), and the third was characterized by miR-21 underexpression and RECK overexpression (N = 16). From men who presented the second profile (miR-21 overexpression and RECK underexpression) 91.7% were staged pT3. For the other two groups 48.0%, and 46.7% of patients were staged pT3 (p = 0.025).ConclusionsOur results demonstrate RECK as a target of miR-21. We believe that miR-21 may be important in PCa progression through its regulation of RECK, a known regulator of tumor cell invasion.

Long-Term Effect of Early Postoperative Pelvic Floor Biofeedback on Continence in Men Undergoing Radical Prostatectomy: A Prospective, Randomized, Controlled Trial

PURPOSE The impact of pelvic floor muscle training on the recovery of urinary continence after radical prostatectomy is still controversial. We tested the effectiveness of biofeedback-pelvic floor muscle training in improving urinary incontinence in the 12 months following radical prostatectomy. MATERIALS AND METHODS A total of 73 patients who underwent radical prostatectomy were randomized to a treatment group (36) receiving biofeedback-pelvic floor muscle training once a week for 3 months as well as home exercises or a control group (37). Patients were evaluated 1, 3, 6 and 12 months postoperatively. Continence was defined as the use of 1 pad or less daily and incontinence severity was measured by the 24-hour pad test. Incontinence symptoms and quality of life were assessed with the International Continence Society male Short Form questionnaire and the Incontinence Impact Questionnaire. Pelvic floor muscle strength was evaluated with the Oxford score. RESULTS A total of 54 patients (26 pelvic floor muscle training and 28 controls) completed the trial. Duration of incontinence was shorter in the treatment group. At postoperative month 12, 25 (96.15%) patients in the treatment group and 21 (75.0%) in the control group were continent (p = 0.028). The absolute risk reduction was 21.2% (95% CI 3.45-38.81) and the relative risk of recovering continence was 1.28 (95% CI 1.02-1.69). The number needed to treat was 5 (95% CI 2.6-28.6). Overall there were significant changes in both groups in terms of incontinence symptoms, lower urinary tract symptoms, quality of life and pelvic floor muscle strength (p <0.0001). CONCLUSIONS Early biofeedback-pelvic floor muscle training not only hastens the recovery of urinary continence after radical prostatectomy but allows for significant improvements in the severity of incontinence, voiding symptoms and pelvic floor muscle strength 12 months postoperatively.