Role of α- and ß-adrenergic signaling in phenotypic targeting: significance in benign and malignant urologic disease.

The urinary tract is highly innervated by autonomic nerves which are essential in urinary tract development, the production of growth factors, and the control of homeostasis. These neural signals may become dysregulated in several genitourinary (GU) disease states, both benign and malignant. Accordingly, the autonomic nervous system is a therapeutic target for several genitourinary pathologies including cancer, voiding dysfunction, and obstructing nephrolithiasis. Adrenergic receptors (adrenoceptors) are G-Protein coupled-receptors that are distributed throughout the body. The major function of α1-adrenoceptors is signaling smooth muscle contractions through GPCR and intracellular calcium influx. Pharmacologic intervention of α-and ß-adrenoceptors is routinely and successfully implemented in the treatment of benign urologic illnesses, through the use of α-adrenoceptor antagonists. Furthermore, cell-based evidence recently established the antitumor effect of α1-adrenoceptor antagonists in prostate, bladder and renal tumors by reducing neovascularity and impairing growth within the tumor microenvironment via regulation of the phenotypic epithelial-mesenchymal transition (EMT). There has been a significant focus on repurposing the routinely used, Food and Drug Administration-approved α1-adrenoceptor antagonists to inhibit GU tumor growth and angiogenesis in patients with advanced prostate, bladder, and renal cancer. In this review we discuss the current evidence on (a) the signaling events of the autonomic nervous system mediated by its cognate α- and ß-adrenoceptors in regulating the phenotypic landscape (EMT) of genitourinary organs; and (b) the therapeutic significance of targeting this signaling pathway in benign and malignant urologic disease. Video abstract.

Urine Extracellular Vesicle GATA2 mRNA Discriminates Biopsy Result in Men with Suspicion of Prostate Cancer.

PURPOSE: Prostate specific antigen has limited performance in detecting prostate cancer. The transcription factor GATA2 is expressed in aggressive prostate cancer. We analyzed the predictive value of urine extracellular vesicle GATA2 mRNA alone and in combination with a multigene panel to improve detection of prostate cancer and high risk disease. MATERIALS AND METHODS: GATA2 mRNA was analyzed in matched extracellular vesicles isolated from urines before and after prostatectomy (16) and paired urine and tissue prostatectomy samples (19). Extracellular vesicle GATA2 mRNA performance to distinguish prostate cancer and high grade disease was tested in training (52) and validation (165) cohorts. The predictive value of a multigene score including GATA2, PCA3 and TMPRSS2-ERG (GAPT-E) was tested in both cohorts. RESULTS: Confirming its prostate origin, urine extracellular vesicle GATA2 mRNA levels decreased significantly after prostatectomy and correlated with prostate cancer tissue GATA2 mRNA levels. In the training and validation cohort GATA2 discriminated prostate cancer (AUC 0.74 and 0.66) and high grade disease (AUC 0.78 and 0.65), respectively. Notably, the GAPT-E score improved discrimination of prostate cancer (AUC 0.84 and 0.72) and high grade cancer (AUC 0.85 and 0.71) in both cohorts when compared with each biomarker alone and PT-E (PCA3 and TMPRSS2-ERG). A GAPT-E score for high grade prostate cancer would avoid 92.1% of unnecessary prostate biopsies, compared to 61.9% when a PT-E score is used. CONCLUSIONS: Urine extracellular vesicle GATA2 mRNA analysis improves the detection of high risk prostate cancer and may reduce the number of unnecessary biopsies.

Prostate biopsies: Available technique, approaches and diagnostic accuracy.

Despite advances in the diagnosis of prostate cancer over the past century, it remains a leading cause of cancer related death. A recent recommendation against screening has further complicated the diagnosis and management of this condition. It remains to be demonstrated if newer diagnostic modalities will have an impact on mortality rates. Most certainly, not all prostate cancers need to be diagnosed, and methods of accurately diagnosing those cancers that lead to death needs more work. In this review article, we describe the different techniques, approaches and diagnostic accuracies of the currently used biopsy methods.

Reliability of motor parameters for follow-up after local steroid injection in carpal tunnel syndrome.

BACKGROUND: Local steroid injection is one of the treatment modalities for carpal tunnel syndrome (CTS). Symptomatic and electrophysiological improvement has been previously documented. The electrophysiological parameter, which represents the most consistent change after local steroid injection, is not well-known. OBJECTIVE: The objective of this study was to evaluate the changes in electrophysiological parameters 1 month after local steroid injection and to determine the parameter that is able to depict improvement across the severity spectrum of CTS. MATERIALS AND METHODS: Forty-seven patients (27 with bilateral disease, 74 hands totally) were included. The electrophysiological parameters studied at baseline included sensory onset latency, sensory nerve action potential amplitude, sensory conduction velocity (CV), distal motor latency, compound muscle action potential amplitude and motor CV. All patients were injected with 40 mg triamcinalone at the wrist. After 1 month, symptomatic improvement from baseline was documented using visual analog score of 100. Electrophysiology was repeated. Paired t tests were done between baseline electrophysiology parameters and those obtained 1 month after steroid injection for significant improvement. Subgroup analyses were performed in hands with mild to moderate (Grade 3 or less by Bland's classification) and severe disease (Grades 4 and 5). RESULTS: All patients showed a symptomatic improvement. Distal motor latency showed most consistent improvement irrespective of the severity of CTS. In mild to moderate CTS (Grade 3 or less of the classification given by Bland) sensory parameters were recordable and showed significant improvement in addition to distal motor latency. In the subcategory of severe CTS (Grades 4 and 5 of Bland) where sensory parameters are not recordable distal motor latency and the motor CV showed a significant improvement. CONCLUSION: One month after local steroid injection among the electrophysiological parameters studied distal motor latencies showed most consistent and recordable improvement across the severity spectrum of CTS. This can be used as a single objective parameter to follow-up patients after a local steroid injection to document improvement or relapse. They can also be considered as objective parameter to follow-up patients after surgery.

Impact of statin use on biochemical recurrence in patients treated with radical prostatectomy.

BACKGROUND: The impact of statin use on biochemical recurrence (BCR) in patients treated with radical prostatectomy (RP) remains controversial. METHODS: We retrospectively evaluated 6842 patients who underwent RP for clinically localized prostate cancer (PC) between 2000 and 2011. Uni- and multivariable cox regression models addressed the association of statin use with BCR. RESULTS: Overall, 2275 (33.3%) patients used statins. Statin users were older and had a higher rate of positive surgical margins than patients not using statins (P-values 0.05). Within a median follow-up of 25 months (interquartile range: 8-42 months), 778 (11.4%) patients experienced BCR. Actuarial estimate 5-years BCR-free survival was 82%±1 for patients without statin use and 84±1% for patients using statins (P=0.05); statin use was not associated with BCR (hazard ratio: 0.88, 95% confidence interval: 0.76-1.03, P=0.10) after adjusting for the effects of standard clinicopathologic features. CONCLUSIONS: In PC patients undergoing RP, statin use was not independently associated with lower risk of BCR.

The trifecta outcome in 300 consecutive cases of robotic-assisted laparoscopic radical prostatectomy according to D'Amico risk criteria.

BACKGROUND: To analyze the trifecta outcome (continence, potency, and cancer control) in 300 cases of robotic-assisted laparoscopic radical prostatectomy (RARP). METHODS: A prospective assessment of outcomes in 300 consecutive patients that underwent a RARP performed by a single surgeon. Patients were grouped according to D'Amico risk criteria: Group I consisted of 'low-risk' cases (n = 64), Group II consisted of 'intermediate-risk' cases (n = 88), and Group III consisted of 'high-risk' cases (n = 148). Patients were evaluated for perioperative complications and the trifecta outcome. RESULTS: The operation time, blood loss, post-operative stay, duration of urethral catheterization, and perioperative complication rate were similar among all groups. The incidence of bilateral neurovascular bundle (NVB) preservation was significantly decreased with the increasing risk of cases (P < 0.001). The continence rates at the 1-week, 1-month, 3-month, 6-month, and 12-month follow-ups did not differ significantly between groups. The potency rates at the 12-month follow-up were not significantly different. The positive surgical margin and positive lymph node metastasis rate increased with the increasing risk of cases (P < 0.001). The biochemical recurrence rate (BCR, PSA >0.2 ng/mL) was 3.1, 11.36, and 19.59% in Groups I, II and III, respectively (P = 0.004). The trifecta outcome for RARP with bilateral NVB preservation showed no significant differences among groups. CONCLUSIONS: Undergoing a RARP is safe and feasible in high-risk prostate cancer patients. Compared to low-risk and intermediate-risk groups, the high-risk group had a significant higher incidence of positive surgical margin, positive lymph node metastasis, and BCR rate.

The impact of multiple biopsies on outcomes of nerve-sparing robotic-assisted radical prostatectomy.

Active surveillance of prostate cancer patients involves subjecting them to multiple prostate biopsies, and we sought to investigate the effects of this on functional outcomes after robotic-assisted radical prostatectomy (RARP). Between May 2009 and December 2009, 367 patients who consecutively underwent RARP by a single surgeon were divided into two groups, one that had single prostate biopsy and another multiple biopsies before RARP. The groups were matched for significant clinicopathologic preoperative variables, and only premorbidly potent low-risk cases that underwent nerve sparing were included. This left 50 and 23 patients for analysis in the single and multiple biopsy groups, respectively. The primary endpoint was potency and continence at 3 and 6 months after surgery. We found continence rates of 84% (83%) and 94% (96%) for single (multiple) biopsy groups at 3 and 6 months, respectively (P=0.88, P=0.77). Multiple biopsy patients had worse postoperative erectile function at 6 months (57% versus 80%, P=0.03). Men subject to multiple preoperative biopsies are more likely to become impotent postoperatively than those who undergo surgery after a single biopsy. This should be borne in mind when counseling men regarding repeat biopsy as part of an active surveillance strategy.

Learning curve for robotic assisted laparoscopic prostatectomy: a multi-institutional study of 3794 patients.

AIM: The aim of this study was to define the learning curve for positive surgical margin (PSM) rate and operative time (OT) for robotic assisted laparoscopic radical prostatectomy (RALP); while the learning curve appears shorter for surgical safety for RALP compared to other surgical modalities, this has not been well established for the above parameters. METHODS: We performed a retrospective cohort study of 3794 patients who underwent RALP between Jan 2003 and Sep 2009 by three surgeons (DL, PW, AKT) from three centers (UPenn, Karolinska, Cornell). Mean overall PSM rates and mean overall OT were calculated for all three surgeons at intervals of 50 RALPs per surgeon, and learning curves for these means were fit using a loess method. R version 2.71 was used for all statistical analysis. RESULTS: The learning curve for PSM rates for all patients demonstrated improvements continued with increasing surgeon experience, with over 1600 cases required to get a PSM rate <10%. When pT3 patients were evaluated, the learning curve started to plateau after 1000-1500 cases. Mean OT plateaued after 750 cases though with further surgical experience the OTs started to climb again. CONCLUSION: The learning curve for RALP is not as short as previously thought, and a large number of cases are needed to get PSM rates and OTs to a minimum. This suggests that RALP should be performed by high volume surgeons in order to optimize patient outcomes.

Nerve-sparing radical prostatectomy: current concepts in a robotic era.

Recovery of potency sufficient for penetrative intercourse at a year after surgery varies widely. Much of the progress achieved in the past two decades in improving potency outcomes after radical prostatectomy has resulted from an improved appreciation of the anatomic basis of the nerves responsible for erection. Recent studies suggest alternative and more complex course of nerves than previously described. Better appreciation of the variable and often invisible anatomical course of the cavernosal nerves continues to engender innovations in surgical technique to optimize their preservation. Exciting frontiers of research that include efforts in stem cell neural regeneration, development of specific fluorophores and biomarkers, and performing radical prostatectomy under hypothermic conditions may provide much-needed breakthroughs to improving potency outcomes following radical prostatectomy in this current age of improved life expectancy and heightened patient expectations.