Faculty Bibliography

Epidemiologic and experimental data suggest that soy consumption may prevent prostate cancer and be beneficial for men with prostate cancer. Soy intake and risk of prostate cancer are inversely correlated; soy isoflavones inhibit growth of prostate cancer cells and reduce prostate carcinogenesis in animal models. We tested the hypothesis that soy consumption reduces biochemical recurrence after radical prostatectomy in a randomized controlled clinical trial with a soy protein supplement versus a casein-based placebo in men at increased risk for PSA failure in the first 2 years after radical prostatectomy. PSA was tested at 2-month intervals in year 1 and every 3 months in year 2. Eligibility criteria were: Gleason sum of >8, extra-capsular extension, seminal vesicle invasion, positive surgical margins, positive lymph nodes, and/or a preoperative PSA of >20 ng/ml. Biochemical recurrence was defined a priori as reaching a PSA value of alpha0.07 ng/ml, confirmed twice. A two-year PSA failure rate in eligible subjects of approximately 30% was expected, based on data from NYU and previous literature. With a planned sample size of 128 evaluable subjects per arm, the study had 80% power to detect a 50% reduction in PSA failure rate at a 2-sided significance level of 0.05. The soy protein isolate and placebo (generously provided by Solae LCC, St Louis, MO) were identical in composition, except for the protein source (19.2-19.8 g protein/day); the soy product provided daily 23.5 mg genistein and 40.9 mg total isoflavones (aglycone equivalents); the placebo was devoid of any soy-specific constituents. Accrual did not reach the intended level and 172 subjects were randomized and enrolled, of whom 142 were evaluable (completed two years on study or developed confirmed recurrence within two years). Soy protein consumption did not alter recurrence rate or time-to-recurrence (TTR). Of the 74 evaluable subjects in the soy arm 22 (30%) recurred as did 22 (32%) of the 68 subjects in the placebo arm recurred. The!

Study Type - Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? It is well recognized that RP is associated with short- and long-term SUI and erectile dysfunction. The incidence, clinical significance and treatment of UI during sexual activity is less well understood. The present study demonstrates the effectiveness of both an AUS and male sling to improve sexual QOL in men presenting with both SUI and UI during sexual activity. OBJECTIVE: * To determine the impact of anti-incontinence surgical procedures (artificial urinary sphincter [AUS] or male sling) on bother due to urinary incontinence (UI) during sexual activity after radical prostatectomy (RP). PATIENTS AND METHODS: * Between October 2000 and December 2007, 27 men in a large single-surgeon RP series underwent anti-incontinence surgery with an AUS or male sling. * In all, 16 of these 27 men completed a questionnaire retrospectively capturing bother attributable to UI during arousal and orgasm and the impact of the AUS/male sling on UI and sexual quality of life (QoL). RESULTS: * In all, 15 men were evaluable. Of these, 11 were sexually active; four and seven men underwent AUS and sling placement, respectively. * All 11 men had a marked improvement in stress UI symptoms, which was the primary indication for surgery. * All men undergoing AUS had an improvement in their sexual QoL, and most (three of four men) indicated marked improvement. * Slightly more than half of men undergoing the sling procedure reported marked improvement in sexual QoL. CONCLUSIONS: * Our study shows a beneficial effect of anti-incontinence surgery on UI during sexual activity. * Whether these surgical approaches would benefit men with significant bother due to UI limited to sexual activity warrants further investigation.

Although formation of urothelial carcinoma of the bladder (UCB) requires multiple steps and proceeds along divergent pathways, the underlying genetic and molecular determinants for each step and pathway remain undefined. By developing transgenic mice expressing single or combinatorial genetic alterations in urothelium, we demonstrated here that overcoming oncogene-induced compensatory tumor barriers was critical for urothelial tumor initiation. Constitutively active Ha-ras (Ras*) elicited urothelial hyperplasia that was persistent and did not progress to tumors over a 10 months period. This resistance to tumorigenesis coincided with increased expression of p53 and all pRb family proteins. Expression of a Simian virus 40 T antigen (SV40T), which disables p53 and pRb family proteins, in urothelial cells expressing Ras* triggered early-onset, rapidly-growing and high-grade papillary UCB that strongly resembled the human counterpart (pTaG3). Urothelial cells expressing both Ras* and SV40T had defective G(1)/S checkpoint, elevated Ras-GTPase and hyperactivated AKT-mTOR signaling. Inhibition of the AKT-mTOR pathway with rapamycin significantly reduced the size of high-grade papillary UCB but hyperactivated mitogen-activated protein kinase (MAPK). Inhibition of AKT-mTOR, MAPK and STAT3 altogether resulted in much greater tumor reduction and longer survival than did inhibition of AKT-mTOR pathway alone. Our studies provide the first experimental evidence delineating the combinatorial genetic events required for initiating high-grade papillary UCB, a poorly defined and highly challenging clinical entity. Furthermore, they suggest that targeted therapy using a single agent such as rapamycin may not be highly effective in controlling high-grade UCB and that combination therapy employing inhibitors against multiple targets are more likely to achieve desirable therapeutic outcomes.

PURPOSE OF REVIEW: alpha1-Adrenoceptor blockers are the most frequently prescribed medical therapy in the treatment of lower urinary tract symptom suggestive of benign prostatic hyperplasia (LUTS/BPH). The purpose of this review is to highlight the evolution of adrenoceptor blockers with emphasis on newly approved drugs. RECENT FINDINGS: Over the past years new formulations of several alpha1-adrenoceptor blockers were introduced to the market. Five long-acting alpha1-blockers are currently approved by the Food and Drug Administration for treatment of symptomatic LUTS/BPH: terazosin, doxazosin, tamsulosin, alfuzosin and silodosin. Silodosin is the only adrenoceptor blocker that exhibits true selectivity for the alpha1-adrenoceptor subtypes. This unique adrenoceptor selectivity profile likely accounts for the very favorable cardiovascular safety profile. SUMMARY: Tamsulosin, alfuzosin slow release and silodosin do not require dose titration. Alfuzosin, terazosin, doxazosin and silodosin have all been shown to be effective in relieving LUTS/BPH independent of prostate size. Low incidence of orthostatic hypotension has been reported for silodosin, but abnormal ejaculation is the most commonly reported adverse effect

BACKGROUND: During normal development in human and other placental mammals, the embryonic cloacal cavity separates along the axial longitudinal plane to give rise to the urethral system, ventrally, and the rectum, dorsally. Defects in cloacal development are very common and present clinically as a rectourethral fistula in about 1 in 5,000 live human births. Yet, the cellular mechanisms of cloacal septation remain poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: We previously detected Bone morphogenetic protein 7 (Bmp7) expression in the urorectal mesenchyme (URM), and have shown that loss of Bmp7 function results in the arrest of cloacal septation. Here, we present evidence that cloacal partitioning is driven by Bmp7 signaling in the cloacal endoderm. We performed TUNEL and immunofluorescent analysis on cloacal sections from Bmp7 null and control littermate embryos. We found that loss of Bmp7 results in a dramatic decrease in the endoderm survival and a delay in differentiation. We used immunological methods to show that Bmp7 functions by activating the c-Jun N-terminal kinase (JNK) pathway. We carried out confocal and 3D imaging analysis of mitotic chromosome bundles to show that during normal septation cells in the cloacal endoderm divide predominantly in the apical-basal direction. Loss of Bmp7/JNK signaling results in randomization of mitotic angles in the cloacal endoderm. We also conducted immunohistochemical analysis of human fetal sections to show that BMP/phospho-SMAD and JNK pathways function in the human cloacal region similar as in the mouse. CONCLUSION/SIGNIFICANCE: Our results strongly indicate that Bmp7/JNK signaling regulates remodeling of the cloacal endoderm resulting in a topological separation of the urinary and digestive systems. Our study points to the importance of Bmp and JNK signaling in cloacal development and rectourethral malformations

The most recent guidelines on prostate cancer screening from the American Urological Association (2009), the National Comprehensive Cancer Network (2011), and the European Association of Urology (2011), as well as treatment and advances in disease monitoring, have increased the androgen deprivation therapy (ADT) population and the duration of ADT usage as the first-line treatment for metastatic prostate cancer. According to the European Association of Urology, gonadotropin-releasing hormone (GnRH) agonists have become the leading therapeutic option for ADT because they avoid the physical and psychological discomforts associated with orchiectomy. However, GnRH agonists display several shortcomings, including testosterone (T) surge ("clinical flare") and microsurges. T surge delays the intended serologic endpoint of T suppression and may exacerbate clinical symptoms. Furthermore, ADT manifests an adverse-event spectrum that can impact quality of life with its attendant well-documented morbidities. Strategies to improve ADT tolerability include a holistic management approach, improved diet and exercise, and more specific monitoring to detect and prevent T depletion toxicities. Intermittent ADT, which allows hormonal recovery between treatment periods, has become increasingly utilized as a methodology for improving quality of life while not diminishing chronic ADT efficacy, and may also provide healthcare cost savings. This review assesses the present and potential future role of GnRH agonists in prostate cancer and explores strategies to minimize the adverse-event profile for patients receiving ADT.