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.

Solid Renal Masses in Transplanted Allograft Kidneys: A Closer Look at the Epidemiology and Management.

The objective of this review is to explore the available literature on solid renal masses (SRMs) in transplant allograft kidneys to better understand the epidemiology and management of these tumors. A literature review using PubMed was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) methodology. Fifty-six relevant studies were identified from 1988 to 2015. A total of 174 SRMs in 163 patients were identified, with a mean tumor size of 2.75 cm (range 0.5-9.0 cm). Tumor histology was available for 164 (94.3%) tumors: clear cell renal cell carcinoma (RCC; 45.7%), papillary RCC (42.1%), chromophobe RCC (3%), and others (9.1%). Tumors were managed by partial nephrectomy (67.5%), radical nephrectomy (19.4%), percutaneous radiofrequency ablation (10.4%), and percutaneous cryoablation (2.4%). Of the 131 patients (80.3%) who underwent nephron-sparing interventions, 10 (7.6%) returned to dialysis and eight (6.1%) developed tumor recurrence over a mean follow-up of 2.85 years. Of the 110 patients (67.5%) who underwent partial nephrectomy, 3.6% developed a local recurrence during a mean follow-up of 3.12 years. The current management of SRMs in allograft kidneys mirrors management in the nontransplant population, with notable findings including an increased rate of papillary RCC and similar recurrence rates after partial nephrectomy in the transplant population despite complex surgical anatomy.

Synergism between metformin and statins in modifying the risk of biochemical recurrence following radical prostatectomy in men with diabetes.

BACKGROUND: To determine the effect of statins and metformin in combination on biochemical recurrence (BCR) among diabetic men undergoing radical prostatectomy (RP). METHODS: Diabetic men undergoing RP at our institution from January 1995 to March 2012 were retrospectively reviewed. Recipients of adjuvant radiation or hormonal therapy were excluded. Statin and/or metformin use was determined through review of electronic records. BCR-free survival was plotted using Kaplan-Meier analysis, and the effect of statins and metformin on BCR was assessed via a multivariate Cox proportional hazards model. RESULTS: Seven hundred and sixty-seven men met the inclusion criteria. Seventy-six (9.9%) were users of statins only, 56 (7.3%) were users of metformin only and 42 (5.5%) were dual users. Median follow-up time was 27 months. Dual users were less likely than nonusers or users of either medication alone to have a biopsy Gleason sum of 8-10 (P=0.033), and tended towards a lower rate of pathological T stage of pT3 or higher (P=0.064). Dual users had the highest 2-year and 5-year BCR-free survival, although this was not statistically significant (P=0.205). On multivariate regression, neither statin nor metformin use alone was significantly associated with BCR-free survival. However, their interaction led to a significantly lower BCR risk than would be expected from each medication's independent effects (hazard ratio=0.2; P=0.037). CONCLUSIONS: The combination of statins and metformin in men undergoing RP for prostate cancer (PCa) may be associated with a lower BCR risk than would be predicted based on the independent effects of both medications. A synergism between these two agents is biologically plausible based on our current understanding of their diverse molecular pathways of action. The results of future clinical trials involving the use of either medication in men with PCa should be carefully assessed for confirmatory evidence of such a relationship.

Prostate cancer disease characteristics for foreign-born South Asian men living in the United States.

INTRODUCTION: We report the largest known cohort of South Asian (SA) men treated by radical prostatectomy living in the United States. Our objective was to characterize this sub-population and compare them to our wider cohort of prostate cancer patients treated with radical prostatectomy in the United States. MATERIALS AND METHODS: All patients who underwent radical prostatectomy at two high-volume United States academic institutions at separate geographic locations between 1990 and 2011 were identified. Demographic data, pre-operative Prostate Specific Antigen (PSA), biopsy Gleason score, pathology Gleason score, pathology Stage, margin status, and node status were collected. In addition to SA men, African American (AA) men were identified and used for comparative analysis as a high-risk cohort. RESULTS: A total of 69 SA men were identified in Cohort 1 and 24 men were identified in Cohort 2. When comparing SA men against the entire cohort, no significant difference was found for age, year of surgery, biopsy Gleason score, or path Gleason score for either cohort. However, significant differences were found in pre-operative PSA (P = 0.01), pathologic stage (P<0.01), and positive node status (P = 0.04) for SA men in Cohort 1. Whereas in Cohort 2, SA men had a significantly higher proportion of positive surgical margins (P = 0.04). In all significant comparisons, characteristics were worse in SA men and similar to that of AA men. CONCLUSIONS: SA men have worse pathologic disease profiles when compared to the general population of men undergoing radical prostatectomy. SA men living in the United States have pathologic disease profiles that are comparable to AA men.

Autosomal dominant polycystic kidney disease and pain - a review of the disease from aetiology, evaluation, past surgical treatment options to current practice.

Autosomal Dominant Polycystic Kidney Disease (ADPKD), often referred to as "adult" polycystic kidney disease, is one of the commonest hereditary disorders. It affects approximately 4 to 6 million individuals worldwide. The disease progresses to end-stage renal disease and it accounts for 10-15% of patients requiring dialysis in the United States. A comprehensive Medline search for aetiology, evaluation, screening, cellular biology, and treatment was utilized to locate, extract, and synthesize relevant data with respect to this topic. Special attention was focused on urologic literature and surgical textbooks regarding operative treatment of pain associated with ADPKD. Now, patients with ADPKD have more treatment options. More specifically, several therapeutic alternatives are now available for the management of pain in these patients. A recent review of literature supports the performance of open or laparoscopic cyst decortication procedures for control of pain and infection without the worry of causing further renal impairment in those with preserved renal function.

Prospective evaluation of endorectal magnetic resonance imaging to detect tumor foci in men with prior negative prostastic biopsy: a pilot study.

PURPOSE: Prostate cancer foci have a characteristic appearance on endorectal magnetic resonance imaging (MRI) which might be useful for prostate cancer detection. In this pilot study the ability of endorectal MRI to detect prostate cancer foci prospectively in men at risk for a malignant prostatic neoplasm is assessed. MATERIALS AND METHODS: Endorectal MRI was performed in 33 consecutive men with 1 or more prior negative prostatic biopsies. All studies were read by 2 MRI dedicated study radiologists in consensus before and after receiving patient clinical data. Areas of interest on endorectal MRI were mapped as low, moderate or high suspicion for carcinoma on a prostate model. Directed needle biopsy cores of the prostate were obtained based on this model, and the histopathological findings were compared with MRI results. RESULTS: Carcinoma was detected in 7 of 33 men (21.2%) on post-MRI biopsy, including 1 of 18 (5.6%) with low, 1 of 8 (12.5%) with moderate and 5 of 7 (71.4%) with high suspicion MRI. The site of positive biopsy correlated correctly with the area of suspicion on MRI in 85.7% of cases. Overall, endorectal MRI had 40% positive predictive value (moderate or high suspicion), 94.4% negative predictive value (low suspicion) and 69.7% accuracy. On multivariate analysis positive endorectal MRI was associated with an 11.3-fold risk of positive biopsy. CONCLUSIONS: Endorectal MRI may effectively stratify patients with prior negative prostatic biopsy into low, moderate and high risk groups for a malignant prostatic neoplasm, and may improve our ability to identify prostatic tumor foci prospectively.

Pitfalls in the surgical management of cervical spine injuries.

Records of 69 cervical spine injury patients referred to the authors' institution over a 3-year period were reviewed. The senior author documented "definite" and "probable" pitfalls occurring in the pre-, intra-, and postoperative management. Diagnosis, traction, bracing, surgical timing, intraoperative technical errors, and incorrect surgical decisions were noted. Of the 69 patients, 39 (56%) suffered a pitfall of management. Twenty-seven patients (39%) accumulated 49 "definite" pitfalls between them and 12 patients (17%) suffered a total of 20 "probable" pitfalls. Of the 49 definite pitfalls, 7 (14%) were preoperative, 17 (34%) were those of surgical decision making, 21 (43%) were operative, and 4 (9%) postoperative. Diagnostic errors and incorrect bracing and traction led to neurological worsening. Intraoperatively, technical errors (30%), wrong timing of surgery (24%), and incorrect choice of operation (16%) were the common pitfalls. Postoperative pitfalls consisted of inappropriate bracing (17%). A Cervical Spine Research Society review (1989) rated complications of cervical spine surgery at 6.3% (63/992). In this study, a sizeable portion (56%) of cervical spine injury patients requiring surgery were at a risk of complications. Short of complications, there are areas of management where errors may have less well-documented undesirable effects or increase the potential for morbidity. An awareness of these pitfalls and increased use of non-operative treatment may eliminate up to 73% of the pitfalls and thereby decrease the morbidity associated with the management of cervical spine injuries.

Comparison of computerized tomography parameters of the thoracolumbar spine in normal control subjects and spinal cord injured patients.

The cross-sectional area and the sagittal and transverse diameters of the spinal canal at the thoracolumbar junction were measured using high resolution thin-section computerized tomography images in 15 control subjects and 28 patients with traumatic injury to the spinal cord at the thoracolumbar junction. No significant difference between the control and study groups was found with regard to any of the three measures taken. With the exception of the sagittal canal diameter for the first lumbar vertebra, all the mean values were higher for the spinal cord injured group. The ratio of the sagittal to transverse diameter was larger for the control group; however, this difference also was not significant. These findings suggest no significant differences in the dimensions and shape of the canal at the thoracolumbar region between the spinal cord injured and control groups. In contrast to the cervical spinal canal, there appears to be no correlation between the spinal cord injury and the dimensions of the thoracolumbar spinal canal.

Metastatic malignancy of the cervical spine. A nonoperative history.

Of 48 patients with spinal metastases treated at the Kenneth J. Norris Cancer Center at The University of Southern California Medical Center in Los Angeles, California between 1984 and 1987, 19 consecutive patients with cervical metastatic disease were identified and followed until death or remission. Prostate, breast, and lung neoplasms accounted for 57% of the cervical metastases. Associated nonspinal skeletal, extraskeletal, or multiple-level spinal metastases were seen in 95% of patients. Mean time from diagnosis of primary tumor to cervical metastasis was 29 months and mean survival after that was 14.7 months. Pain was the initial symptom in 89% of cases. No patient had neurologic deficit and three (16%) had slight radiographic collapse and deformity. Only one (5%) patient had documented instability. All patients had nonoperative treatment with radiotherapy, chemotherapy, or a combination. Irrespective, the pain recurred in all patients by 6 months. Nonoperative treatment may be appropriate in the absence of significant neurologic deficit or instability. The return of symptoms by 6 months warrants alternative modes of therapy.