MicroRNA Expression Profiles in Upper Tract Urothelial Carcinoma Differentiate Tumor Grade, Stage, and Survival: Implications for Clinical Decision-Making.

OBJECTIVE: To evaluate microRNA (miRNA) biomarkers for upper tract urothelial carcinoma (UTUC) to improve risk stratification. METHODS: miRNA was isolated from 157 radical nephroureterectomy specimens from 2 institutions. The relative expression of miRNA was examined for high grade vs low grade tumors as well as muscle invasive vs nonmuscle invasive tumors. Recurrence free survival (RFS) and overall survival (OS) were also stratified using relative expression of specific miRNA. RESULTS: The optimized model to identify high grade UTUC included miR-29b-2-5p, miR-18a-5p, miR-223-3p, and miR-199a-5p, generating a sensitivity of 83%, specificity of 85%, and generated a receiver operating characteristic (ROC) curve with area-under-the-curve of 0.86. Similarly, the model classifier for predicting ≥pT2 disease incorporated miR-10b-5p, miR-26a-5p-5p, miR-31-5p, and miR-146b-5p, producing a sensitivity of 64%, specificity of 96%, and area-under-the-curve of 0.90. RFS was best reflected by a combination of miR-10a-5p, miR-30c-5p, and miR-10b-5p, while OS was best predicted by miR-10a-5p, miR-199a-5p, miR-30c-5p, and miR-10b-5p. CONCLUSION: High-grade vs low-grade as well as muscle invasive vs nonmuscle invasive UTUC can be reliable distinguished with unique miRNA signatures. Furthermore, differential expression of UTUC miRNA produces robust classifiers for predicting RFS and OS that may help identify patients who would most benefit from adjuvant therapies.

Advances in the treatment of erectile dysfunction: what's new and upcoming?

Erectile dysfunction adversely affects up to 20% of all men and is the most commonly treated sexual disorder. The public health implications of this condition are significant and represent a challenge for our healthcare system. The physiological pathways responsible for erections have been extensively studied, and much advancement has been made since the introduction of phosphodiesterase 5 inhibitors. Newer agents, such as dopaminergic and melanocortin receptor agonists, which target central erectogenic pathways, are under investigation. Newer formulations and delivery methods of existing medications such as alprostadil will also be introduced in the near future. Furthermore, low-intensity shockwave lithotripsy and stem cell regenerative techniques are innovative approaches to the treatment of erectile dysfunction.

Outcomes for Management of Lichen Sclerosus Urethral Strictures by 3 Different Techniques.

OBJECTIVE: To evaluate the intermediate-term outcomes from a large, single institution series of patients with lichen sclerosus (LS) who underwent surgical management of their urethral strictures. MATERIALS AND METHODS: We retrospectively reviewed 79 patients who underwent surgical management of their LS urethral strictures from 2003 to 2014, comparing outcomes of patients undergoing a single-stage buccal mucosa graft (BMG) urethroplasty, 2-stage BMG urethroplasty, or perineal urethrostomy (PU). Demographic and surgical outcomes data were collected for all patients. RESULTS: Of the 79 patients, the mean follow-up was 32.4 months, mean age was 50.1 years, and the mean body mass index was 35.7, with morbid obesity (body mass index > 35) in 48% of the cohort. The mean stricture length was 9.6 cm (1.5-21 cm), with 62% of patients having a bulbopendulous stricture. Of the 37 patients who were planned for a 2-stage BMG urethroplasty, 9 (24%) patients had stricture recurrence or recurrent LS in the first-stage BMG. Single-stage BMG urethroplasty was performed in 20 patients with a mean stricture length of 9.47 cm (4-21 cm) and a success rate of 75%. Fourteen patients from the cohort received a PU as the primary treatment, with a success rate of 93%. CONCLUSION: Management of LS strictures continues to pose challenges to the reconstructive surgeon due to the high rate of stricture recurrence and often progression. Patients undergoing single-stage or 2-stage reconstruction often require revision and must be carefully observed for recurrent urethral stricture. PU offers the highest degree of success and should be considered for all patients.

Localization and proteomic characterization of cholesterol-rich membrane microdomains in the inner ear.

Biological membranes organize and compartmentalize cell signaling into discrete microdomains, a process that often involves stable, cholesterol-rich platforms that facilitate protein-protein interactions. Polarized cells with distinct apical and basolateral cell processes rely on such compartmentalization to maintain proper function. In the cochlea, a variety of highly polarized sensory and non-sensory cells are responsible for the early stages of sound processing in the ear, yet little is known about the mechanisms that traffic and organize signaling complexes within these cells. We sought to determine the prevalence, localization, and protein composition of cholesterol-rich lipid microdomains in the cochlea. Lipid raft components, including the scaffolding protein caveolin and the ganglioside GM1, were found in sensory, neural, and glial cells. Mass spectrometry of detergent-resistant membrane (DRM) fractions revealed over 600 putative raft proteins associated with subcellular localization, trafficking, and metabolism. Among the DRM constituents were several proteins involved in human forms of deafness including those involved in ion homeostasis, such as the potassium channel KCNQ1, the co-transporter SLC12A2, and gap junction proteins GJA1 and GJB6. The presence of caveolin in the cochlea and the abundance of proteins in cholesterol-rich DRM suggest that lipid microdomains play a significant role in cochlear physiology. BIOLOGICAL SIGNIFICANCE: Although mechanisms underlying cholesterol synthesis, homeostasis, and compartmentalization in the ear are poorly understood, there are several lines of evidence indicating that cholesterol is a key modulator of cochlear function. Depletion of cholesterol in mature sensory cells alters calcium signaling, changes excitability during development, and affects the biomechanical processes in outer hair cells that are responsible for hearing acuity. More recently, we have established that the cholesterol-modulator beta-cyclodextrin is capable of inducing significant and permanent hearing loss when delivered subcutaneously at high doses. We hypothesize that proteins involved in cochlear homeostasis and otopathology are partitioned into cholesterol-rich domains. The results of a large-scale proteomic analysis point to metabolic processes, scaffolding/trafficking, and ion homeostasis as particularly associated with cholesterol microdomains. These data offer insight into the proteins and protein families that may underlie cholesterol-mediated effects in sensory cell excitability and cyclodextrin ototoxicity.

Dedicated robotics team reduces pre-surgical preparation time.

CONTEXT: Robot-Assisted Laparoscopic Radical Prostatectomy (RALRP) requires significant preoperative setup time for the room, staff, and surgical platform. The utilization of a dedicated robotics operating room (OR) staff may facilitate efficiency and decrease costs. AIMS: We sought to determine the degree to which preoperative time decreased as experience was gained. MATERIALS AND METHODS: A total of 476 patients with a mean age of 60.2 years were evaluated (11/2006 to 1/2010). Data was assimilated through an institutional review board approved blinded, prospective database. Utilizing time from patient arrival in the OR to robot docking as preoperative preparation, our experience was evaluated. Age, body mass index (BMI), and American Society of Anesthesiologists risk scores (ASA) were compared. STATISTICAL ANALYSIS USED: Analysis of variance; Two-sample t-test for unequal variances. RESULTS: The first and last 100 cases were found to have similar age (P=0.27), BMI (P=0.11), and ASA (P=0.09). The average preoperative times were 66. 4 and 53.4 min, respectively (P<0.05). The second 100 patients treated were found to have a significantly shorter preoperative time when compared to the first 100 patients (P<0.05). When the first 100 cases were divided into cohorts of 10 cases the mean preoperative time for the first through fourth cohorts were 80.5, 69.3, 78.8, and 64.7 min, respectively. After treatment of our first 30 patients we found a significant drop in preoperative time. This persisted throughout the remainder of our experience. CONCLUSIONS: From the time of patient arrival a number of tasks are accomplished by the non-physician operating room staff during RALRP. The use of a consistent staff can decrease preoperative setup times and, therefore, the overall length of surgery.

Opioid utilization and health-care costs among patients with diabetic peripheral neuropathic pain treated with duloxetine vs. other therapies.

OBJECTIVE: This retrospective cohort study assessed subsequent opioid utilization and health-care costs among patients with diabetic peripheral neuropathic pain (DPNP) who initiated duloxetine vs. other standard of care (SOC) treatments. METHODS: Medical and pharmacy claims were analyzed for commercially-insured individuals aged 18-64. Two study cohorts were constructed from DPNP patients who initiated duloxetine or SOC medications (tricyclic antidepressants, venlafaxine, gabapentin, pregabalin) between March 1, 2005 and December 31, 2005. Initiation was defined as a prior 90-day period without access of the medication. The dispense date of the first initiation was denoted as the index date. Patients with opioids dispensed in the prior 90 days were excluded. Opioid utilization including total days, number of prescriptions filled, and morphine equivalent dosage was assessed for overall, long-acting, and short-acting opioids. Health-care costs and opioid use in the 12-month post-index period were examined via multivariate regression analyses. RESULTS: Four hundred and ninety-nine DPNP patients (272 duloxetine, 227 SOC) were identified. SOC patients had higher prevalence of comorbidities and pre-index health-care costs than duloxetine patients. Controlling for cross-cohort differences, duloxetine patients were significantly less likely to use any opioids than SOC patients. Also, duloxetine patients had 20 fewer adjusted opioid supply days (largely due to the use of short-acting opioids, P < 0.05) and significantly lower adjusted total costs ($8,088, P < 0.05) and diabetes-related costs ($3,092, P < 0.05) in the 12-month post-index period, with most of the cost differences from lower outpatient costs. CONCLUSIONS: DPNP patients who initiated duloxetine therapy were less likely to have subsequent opioid use and had lower health-care costs than SOC patients.