Mathew C. Raynor

Hrs Interacts with Sorting Nexin 1 and Regulates Degradation of Epidermal Growth Factor Receptor

Hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) is a mammalian homologue of yeast vacuolar protein sorting (Vps) protein Vps27p; however, the role of Hrs in lysosomal trafficking is unclear. Here, we report that Hrs interacts with sorting nexin 1 (SNX1), a recently identified mammalian homologue of yeast Vps5p that recognizes the lysosomal targeting code of epidermal growth factor receptor (EGFR) and participates in lysosomal trafficking of the receptor. Biochemical analyses demonstrate that Hrs and SNX1 are ubiquitous proteins that exist in both cytosolic and membrane-associated pools, and that the association of Hrs and SNX occurs on cellular membranes but not in the cytosol. Furthermore, endogenous SNX1 and Hrs form a ∼550-kDa complex that excludes EGFR. Immunofluorescence and subcellular fractionation studies show that Hrs and SNX1 colocalize on early endosomes. By using deletion analysis, we have mapped the binding domains of Hrs and SNX1 that mediate their association. Overexpression of Hrs or its SNX1-binding domain inhibits ligand-induced degradation of EGFR, but does not affect either constitutive or ligand-induced receptor-mediated endocytosis. These results suggest that Hrs may regulate lysosomal trafficking through its interaction with SNX1.

SNIP, a novel SNAP-25-interacting protein implicated in regulated exocytosis.

Synaptosome-associated protein of 25 kDa (SNAP-25) is a presynaptic membrane protein that has been clearly implicated in membrane fusion in both developing and mature neurons, although its mechanisms of action are unclear. We have now identified a novel SNAP-25-interacting protein named SNIP. SNIP is a hydrophilic, 145-kDa protein that comprises two predicted coiled-coil domains, two highly charged regions, and two proline-rich domains with multiple PPXY and PXXP motifs. SNIP is selectively expressed in brain where it co-distributes with SNAP-25 in most brain regions. Biochemical studies have revealed that SNIP is tightly associated with the brain cytoskeleton. Subcellular fractionation and immunofluorescence localization studies have demonstrated that SNIP co-localizes with SNAP-25 as well as the cortical actin cytoskeleton, suggesting that SNIP serves as a linker protein connecting SNAP-25 to the submembranous cytoskeleton. By using deletion analysis, we have mapped the binding domains of SNIP and SNAP-25, and we have demonstrated that the SNIP-SNAP-25 association is mediated via coiled-coil interactions. Moreover, we have shown that overexpression of SNIP or its SNAP-25-interacting domain inhibits Ca2+-dependent exocytosis from PC12 cells. These results indicate that SNIP is involved in regulation of neurosecretion, perhaps via its interaction with SNAP-25 and the cytoskeleton.

Multi-Institutional Analysis of Robotic Radical Cystectomy for Bladder Cancer: Perioperative Outcomes and Complications in 227 Patients

PURPOSE Recently, some surgeons have begun to describe single-institution case series with less invasive surgical approaches to bladder cancer such as laparoscopic or robotic-assisted techniques. We report on a multi-institutional, multi-surgeon experience with robotic radical cystectomy with regard to operative and pathologic outcomes and complications to evaluate the feasibility and reproducibility of this technique in a large cohort of patients. SUBJECTS AND METHODS Two hundred twenty-seven patients (178 males and 49 females) underwent a robotic cystectomy and urinary diversion at one of four institutions. Operative outcomes, pathological results, and complications of this combined case series are herein reported. RESULTS Mean age of this cohort was 67.1 years (range, 33-86 years) with a mean American Society of Anesthesiologists score of 2.7 (range, 2-4). One hundred sixty-eight patients (74%) underwent ileal conduit diversion, 58 (26%) underwent orthotopic ileal neobladder, and 1 patient (<1%) had no diversion (end-stage renal disease). The urinary diversion was performed extracorporeally in 97% cases, with 7 patients (3%) undergoing an intracorporeal diversion. Mean operating room time of all patients was 5.5 hours, and mean surgical blood loss was 256 mL. On surgical pathology, 120 (53%) patients had pT2 or less disease, 35 (15%) had pT3/T4 disease, and 46 (20%) had N+ disease. The mean number of lymph nodes removed was 18 (range, 3-52). There was a positive surgical margin in 5 cases--all with pT3-4 disease. Mean time to discharge was 5.5 days (median, 5 days), with 70% of patients discharged on postoperative day 5 or sooner. Sixty-eight patients (30%) experienced complications, with 7% having Clavien grade 3 or higher. On multivariate analysis, decreased age and increased American Society of Anesthesiologists score were predictors of higher Clavien complication score, with younger patients more likely to undergo neoadjuvant chemotherapy prior to surgery. CONCLUSION A multi-institutional experience with robotic radical cystectomy appears to demonstrate acceptable operative and pathologic outcomes, thus helping to validate the previously reported single-institution case series. Ultimately, oncologic follow-up of these patients will remain as the most important measure of therapeutic success.

Preoperatively Misclassified, Surgically Removed Benign Renal Masses: A Systematic Review of Surgical Series and United States Population Level Burden Estimate

PURPOSE A significant proportion of renal masses removed for suspected malignancy are histologically benign with the probability inversely proportional to lesion size. To our knowledge the number of preoperatively misclassified benign renal masses treated with nephrectomy is currently unknown. Given the increasing incidence and decreasing average size of renal cell carcinoma, this burden is likely increasing. We estimated the population level burden of surgically removed, preoperatively misclassified benign renal masses in the United States. MATERIALS AND METHODS We systematically reviewed the literature for studies of pathological findings of renal masses removed for suspected renal cell carcinoma based on preoperative imaging through July 1, 2014. We excluded studies that did not describe benign pathology and with masses not stratified by size, and in which pathology results were based on biopsy. SEER data were queried for the incidence of surgically removed renal cell carcinomas in 2000 to 2009. RESULTS A total of 19 studies of tumor pathology based on size met criteria for review. Pooled estimates of the proportion of benign histology in our primary analysis (American studies only and 1 cm increments) were 40.4%, 20.9%, 19.6%, 17.2%, 9.2% and 6.4% for tumors less than 1, 1 to less than 2, 2 to less than 3, 3 to less than 4, 4 to 7 and greater than 7, respectively. The estimated number of surgically resected benign renal masses in the United States from 2000 to 2009 increased by 82% from 3,098 to 5,624. CONCLUSIONS These estimates suggest that the population level burden of preoperatively misclassified benign renal masses is substantial and increasing rapidly, paralleling increases in surgically resected small renal cell carcinoma. This study illustrates an important and to our knowledge previously unstudied dimension of overtreatment that is not directly quantified in contemporary surveillance data.

Elimination of preoperative mechanical bowel preparation in patients undergoing cystectomy and urinary diversion

INTRODUCTION The utility of a preoperative mechanical bowel preparation prior to bowel surgery has recently been questioned. The purpose of this study is to compare the perioperative outcomes between patients undergoing cystectomy with urinary diversion with or without preoperative mechanical bowel preparation. METHODS Seventy patients underwent radical cystectomy and urinary diversion between May 2008 and August 2009 for bladder cancer. The first cohort of patients (n = 37) underwent cystectomy and diversion during the period May 2008-December 2008 and underwent a preoperative mechanical bowel preparation including a clear liquid diet, magnesium citrate solution, and an enema before surgery. The second cohort of patients underwent surgery during the period of January 2009-August 2009 (n=33). These patients were given a regular diet before surgery and did not undergo a mechanical bowel preparation except for the enema before surgery was performed to decrease rectal/colonic distention. Outcome measures included gastrointestinal and overall complications, and perioperative outcomes including recovery of bowel function. RESULTS There were no differences with regard to recovery of bowel function, time to discharge, or overall complication rates between the 2 groups. More specifically, the rate of GI complications was not different in prepped patients vs. nonprepped patients (22% vs. 15%; P = 0.494). There were no occurrences of bowel anastomotic leak, fistula, abscess, peritonitis, or surgical site infection in either group. One perioperative death occurred in the nonprepped group secondary to cardiovascular complications. CONCLUSIONS Preoperative mechanical bowel preparation prior to radical cystectomy with urinary diversion does not demonstrate any significant advantage in perioperative outcomes, including gastrointestinal complications. Further studies aimed at measuring patient satisfaction and larger randomized trials will be beneficial in evaluating the role of mechanical bowel preparation prior to urinary diversion.

Feasibility and Outcomes of Robotic-assisted Laparoscopic Radical Cystectomy for Bladder Cancer in Older Patients

OBJECTIVES To report our maturing experience with robotic radical cystectomy as applied to an older patient population with regard to perioperative measures and pathologic outcomes. A robotic approach to radical cystectomy for bladder cancer have recently been described, but its application in an older patient population, which is often the case in bladder cancer and cystectomy, has not yet been assessed. METHODS A total of 119 patients underwent robotic cystectomy and extracorporeal urinary diversion at our institution from January 2006 through October 2009 for clinically localized bladder cancer. Owing to the patient selection early in the present series, the first 20 cases were excluded. The clinical characteristics, operative outcomes, and pathologic results of the consecutive cases were categorized by age (younger, <70 years vs older, age ≥70 years). RESULTS The outcomes of the 61 younger and 38 older patients, including 7 patients >80 years old, were assessed. The younger versus older patients had a lower American Society of Anesthesiologists score (2.6 vs 3.0; P < .001), greater body mass index (28.2 vs 26.1; P = .008), and longer operating room time (4.8 vs 4.4 hours; P = .015). No differences were observed between the 2 groups in blood loss, time to discharge, or complication rate. Also, no significant differences were found in the surgical pathologic findings, including the organ-confined rate (62% vs 71%) and lymph node yield (19.5 vs 18.1). CONCLUSIONS Older patients do not appear to have any significant differences or compromises with regard to the perioperative and pathologic outcomes after robotic radical cystectomy. Thus, robotic radical cystectomy appears to be an appropriate surgical option for older patients.

Gender Differences in Compensation, Job Satisfaction and Other Practice Patterns in Urology

PURPOSE The proportion of women in urology has increased from less than 0.5% in 1981 to 10% today. Furthermore, 33% of students matching in urology are now female. In this analysis we characterize the female workforce in urology compared to that of men with regard to income, workload and job satisfaction. MATERIALS AND METHODS We collaborated with the American Urological Association to survey its domestic membership of practicing urologists regarding socioeconomic, workforce and quality of life issues. A total of 6,511 survey invitations were sent via e-mail. The survey consisted of 26 questions and took approximately 13 minutes to complete. Linear regression models were used to evaluate bivariable and multivariable associations with job satisfaction and compensation. RESULTS A total of 848 responses (660 or 90% male, 73 or 10% female) were collected for a total response rate of 13%. On bivariable analysis female urologists were younger (p <0.0001), more likely to be fellowship trained (p=0.002), worked in academics (p=0.008), were less likely to be self-employed and worked fewer hours (p=0.03) compared to male urologists. On multivariable analysis female gender was a significant predictor of lower compensation (p=0.001) when controlling for work hours, call frequency, age, practice setting and type, fellowship training and advance practice provider employment. Adjusted salaries among female urologists were

Cost Analysis of Robot-Assisted Laparoscopic Versus Hand-Assisted Laparoscopic Partial Nephrectomy

76,321 less than those of men. Gender was not a predictor of job satisfaction. CONCLUSIONS Female urologists are significantly less compensated compared to male urologists after adjusting for several factors likely contributing to compensation. There is no difference in job satisfaction between male and female urologists.

Peri- and postoperative outcomes of robot-assisted radical cystectomy (RARC).

PURPOSE To perform a cost comparison of three approaches to partial nephrectomy (PN): Open (OPN), hand-assisted laparoscopic (HALPN), and robot-assisted (RAPN). PATIENTS AND METHODS We retrospectively evaluated cost and clinical data from patients undergoing OPN, HALPN, and RAPN from 2007 to 2010 (n=89). Baseline demographic data, patient comorbidities, R.E.N.A.L. nephrometry score, and perioperative outcomes were assessed. Costs and subcosts from the operating room (OR) and hospital were evaluated using nonparametric statistical analyses. RESULTS Patient demographics and tumor characteristics were similar between HALPN and RAPN, while OPN patients had more comorbidities and more difficult-to-resect tumors. Thus, HALPN and RAPN were directly compared, while OPNs were excluded from the analysis. No difference was found in overall costs between HALPN and RAPN (

Single-Institution Experience with Robotic Partial Nephrectomy for Renal Masses Greater Than 4 cm

13,560 vs