Faculty Bibliography

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

Retraction of the bowels during abdominal surgery is generally facilitated by the use of a combination of various retractors along with surgical towels or sponges. The use of surgical towels and sponges may lead to retained foreign bodies or adhesions. In addition, these towels and sponges often require manipulation during long surgical procedures. The ideal way to avoid these problems in abdominal surgery is to develop a technique for retraction of the abdominal contents that eliminates the requirement for these foreign bodies. This article presents the results of a small trial for Lap Pak (Seguro Surgical, Columbia, MD), a disposable radio-opaque device that is made of silicone and retracts the bowels in a cephalad orientation without the need for towels or sponges.

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.

BACKGROUND: Measurement of prostate-specific antigen (PSA) in prostate cancer patients following radical prostatectomy (RP) has been hindered by the limit of quantification of available assays. Because radical prostatectomy removes the tissue responsible for PSA production, postsurgical PSA is typically undetectable with current assay methods. Evidence suggests, however, that more sensitive determination of PSA status following RP could improve assessment of patient prognosis and response to treatment and better target secondary therapy for those who may benefit most. We developed an investigational digital immunoassay with a limit of quantification 2 logs lower than current ultrasensitive third-generation PSA assays. METHODS: We developed reagents for a bead-based ELISA for use with high-density arrays of femtoliter-volume wells. Anti-PSA capture beads with immunocomplexes and associated enzyme labels were singulated within the wells of the arrays and interrogated for the presence of enzymatic product. We characterized analytical performance, compared its accuracy with a commercially available test, and analyzed longitudinal serum samples from a pilot study of 33 RP patients. RESULTS: The assay exhibited a functional sensitivity (20% interassay CV) <0.05 pg/mL, total imprecision <10% from 1 to 50 pg/mL, and excellent agreement with the comparator method. All RP samples were well within the assay measurement capability. PSA concentrations following surgery were found to be predictive of prostate cancer recurrence risk over 5 years. CONCLUSIONS: The robust 2-log improvement in limit of quantification relative to current ultrasensitive assays and the validated analytical performance of the assay allow for accurate assessment of PSA status after RP

Study Type - Harm (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Erythropoletin-stimulating agents (ESAs) have been widely prescribed for treating anaemia secondary to advanced maligancies with the objective of reducing the need for red blood cell transfusions and improving the quality of life. However, the risk/benefit of ESAs has recently been questioned and metaanalyses showing that these agents are associated with an increased risk of mortality when chronically administered to patients with advanced/metastatic cancers. In this study we examined the impact of short-term preoperative utilization of ESAs on biochemical recurrence - free survival rates after open radical retropubic prostatectomy (ORRP). OBJECTIVE: * To examine the impact of short-term preoperative utilization of erythropoietin-stimulating agents (ESAs) on biochemical recurrence (BCR)-free survival rates after open radical retropubic prostatectomy (ORRP) in light of the fact that the risk/benefit of ESAs has recently been questioned by the Food and Drug Administration (FDA) after reports showing a decreased survival. PATIENTS AND METHODS: * From 2000 to 2008, 1567 patients underwent ORRP and 97.5% of these signed informed consent to participate in the New York University Prospective and Longitudinal Outcomes Study. * Of the remaining 1528 patients, 1317 (86%) received preoperative ESA (group 1) and 211 (14%) did not (group 2). * Patients were also classified as having low-, intermediate- or high-risk disease based on D'Amico risk categories. * Kaplan-Meier survival curves and Cox's proportional hazard models were used to estimate BCR-free survival by ESA treatment. RESULTS: * A significant difference was observed for BCR-free survival between the low- and intermediate/high-risk groups. * There were no statistically significant differences between groups 1 and 2 for BCR-free survival in the entire study populations and within risk groups. * In addition, Cox regression models showed no statistically significant differences in BCR-free survival according to preoperative ESA administration in the entire cohort as well as among the low- and intermediate/high-risk groups. CONCLUSIONS: * The short-term use of ESAs as a preoperative blood management strategy for patients undergoing ORRP has no clinically relevant adverse effects on the biology of prostate cancer. * The present study supports the use of these agents before the procedure in patients undergoing surgery for localized disease

PURPOSE: The prevalence and mechanism of incontinence during sexual activity after radical prostatectomy has not been well described. We determined the prevalence and severity of incontinence during sexual activity with time and the relationship between incontinence during sexual activity and stress urinary incontinence in the absence of sexual activity. MATERIALS AND METHODS: A total of 1,459 men with prostate cancer underwent radical prostatectomy between October 2000 and December 2007, as performed by 1 surgeon. Patients completed UCLA-PCI preoperatively, and 3, 6, 12 and 24 months postoperatively. We analyzed the frequency distribution of incontinence during sexual activity and stress urinary incontinence with time. We also examined the relationship between incontinence during sexual activity and stress urinary incontinence by chi-square analysis. RESULTS: The percent of patients who reported any bother from incontinence during sexual activity was 44.4% at 3 months, which decreased to 36.1% at 24 months. The percent of patients reporting major bother from incontinence during sexual activity was 22.4% and 12.1% at 3 and 24 months, respectively. Bother from incontinence during sexual activity and from stress urinary incontinence were strongly associated at all times (p <0.001). More than half of the men with major bother due to incontinence during sexual activity also reported bother from stress urinary incontinence. However, more than 10% of those with no stress urinary incontinence problem reported major bother from incontinence during sexual activity. CONCLUSIONS: Incontinence during sexual activity is a persistent problem for some men after radical prostatectomy. Significant incontinence during sexual activity may occur in the absence of stress urinary incontinence during nonsexual activities. Effective management of this problem requires further investigation

BACKGROUND: Prostate-specific antigen (PSA) is the only independent predictor of biochemical recurrence (BCR) following radical prostatectomy (RP) subject to change over time. OBJECTIVE: To determine whether an ultrasensitive PSA measured at 3 yr following RP is a predictor of subsequent BCR. DESIGN, SETTING, AND PARTICIPANTS: There were 1197 consecutive men with clinically localized prostate cancer who underwent an open radical retropubic prostatectomy (ORRP) at a tertiary referral academic medical center. Exclusions included 107 men (8.9%) who developed a PSA level >/=0.2 ng/ml or underwent hormone therapy or radiation therapy (RT) within the first 3 r after surgery, 191 men (16%) who did not undergo a 3-yr ultrasensitive PSA assay, and 98 men (8.2%) who had PSA levels >/=0.1 and <0.2 at 3 yr. The remaining 801 men were stratified into two groups based on their ultrasensitive PSA level at 3 yr postoperatively: group 1, which consisted of patients whose PSA was </=0.04 (n=765), and group 2, which consisted of patients whose PSA was >0.04 and <0.10 (n=36). MEASUREMENTS: Delayed BCR was the primary end point and represented those men in this cohort who developed a PSA level >/=0.2 or underwent salvage RT for a persistently rising PSA level after 3 yr of follow-up. RESULTS AND LIMITATIONS: The 7-yr cumulative BCR-free survival rate for groups 1 and 2 was 0.957 (95% confidence interval [CI], 0.920-0.978) and 0.654 (95% CI, 0.318-0.855), respectively. In multivariable Cox proportional hazards models, ultrasensitive PSA level at 3 yr remained the only significant predictor of delayed BCR (likelihood ratio chi(2) for full model: 27.03; df=1; p < 0.001). A limitation of the study is that no uniform PSA assay was obtained. CONCLUSIONS: Our findings provide compelling evidence that an ultrasensitive PSA at 3 yr following RP provides useful insights into delayed BCR and is a source of reassurance for the overwhelming majority of men being followed for delayed recurrences