Protein Expression Profiles among Lichen Sclerosus Urethral Strictures-Can Urethroplasty Success be Predicted?

PURPOSE: Urethroplasty of lichen sclerosus strictures has a significantly higher failure rate than strictures due to other causes. We sought to determine predictors of urethroplasty failure in men with lichen sclerosus urethral stricture disease by evaluating protein expression profiles. MATERIALS AND METHODS: Urethral tissue was excised from patients with lichen sclerosus who were undergoing urethroplasty of urethral stricture disease at a single institution. A tissue microarray was created with cores from each sample. Immunohistochemistry was performed to compare protein expression related to inflammation, cell cycle disruption, oxidative stress, hormone receptor status and infection. Stricture recurrence was defined by the need for a subsequent unanticipated procedure for urethral stricture disease. RESULTS: We evaluated 50 men with lichen sclerosus urethral stricture disease, including 31 with successful reconstruction and 19 with recurrent stricture. Recurrent strictures expressed lower levels of several inflammatory markers and had a lower Ki-67 mitotic index and significantly higher vascular endothelial growth factor levels than nonrecurrent strictures. CONCLUSIONS: To our knowledge this is the first study to use tissue protein expression to identify risk factors for urethroplasty failure among men with lichen sclerosus urethral stricture disease. Our findings suggest that recurrent lichen sclerosus strictures demonstrate a suppressed inflammatory response, a decreased cell turnover rate, and poor oxygenation and nutrient delivery. Prospective studies are needed to clarify the role of these pathways in the pathophysiology of lichen sclerosus urethral stricture disease, determine whether preoperative biopsy can predict urethroplasty success, help counsel patients and develop future treatments.

Insights into the Pathophysiology of Urethral Stricture Disease due to Lichen Sclerosus: Comparison of Pathological Markers in Lichen Sclerosus Induced Strictures vs Nonlichen Sclerosus Induced Strictures.

PURPOSE: We evaluated the pathophysiology of lichen sclerosus and nonlichen sclerosus urethral stricture disease by comparing protein expression related to inflammation, cell cycle disruption, oxidative stress, hormone receptor status and infection. MATERIALS AND METHODS: Tissue samples were collected from the urethral strictures of 81 patients undergoing urethroplasty. Clinical and demographic data were obtained by chart review. After identifying areas pathognomonic for lichen sclerosus a tissue microarray was created with cores from each sample and immunohistochemistry was performed. RESULTS: Patients had similar baseline demographics and comorbidities. Of the 81 strictures 58 were and 23 were not due to lichen sclerosus. Lichen sclerosus strictures were significantly longer and showed higher levels of inflammation. The proportion of T cells which stained positive for CD8 was significantly higher in strictures due to lichen sclerosus (50% vs 13%, p = 0.004). CCL-4 was expressed significantly more in strictures due to lichen sclerosus (76% vs 42%, p = 0.01). Several other inflammatory markers were only found in strictures due to lichen sclerosus. Block-like p16, a surrogate for high risk human papillomavirus infection, and varicella zoster virus were found only in lichen sclerosus urethral stricture disease samples, although both were rare. Epstein-Barr virus RNA was found in significantly more lichen sclerosus samples (37% vs 10%, p = 0.024). CONCLUSIONS: To our knowledge this is the first study to evaluate protein expression in lichen sclerosus urethral stricture disease. These strictures demonstrate increased inflammation compared to nonlichen sclerosus urethral strictures. Markers of oxidative stress, cell cycle dysregulation and the androgen receptor do not appear to be uniquely associated with lichen sclerosus urethral stricture disease. Positive staining for several viruses in samples of lichen sclerosus urethral stricture disease suggests a possible infectious etiology.

Discovery of potent and selective 5-azaindazole inhibitors of leucine-rich repeat kinase 2 (LRRK2) - Part 1.

Parkinson's disease is a relatively common neurological disorder with incidence increasing with age. Present treatments merely alleviate the symptoms and do not alter the course of the disease, thus identification of disease modifying therapies represents a significant unmet medical need. Mutations in the LRRK2 gene are risk-factors for developing PD and it has been hypothesized that the increased kinase activity of certain LRRK2 mutants are responsible for the damage of the dopaminergic neurons, thus LRRK2 inhibitors offer the potential to target an underlying cause of the disease. In this communication, we describe hit-to-lead medicinal chemistry program on a novel series of 5-azaindazoles. Compound 1, obtained from high-throughput screening was optimized to a highly potent, selective series of molecules with promising DMPK properties. Introduction of heterocycles at the 3-position were found to significantly increase the potency and kinase selectivity, whilst changes to the 4-chlorobenzyl group improved the physicochemical properties. Our series was licensed to a major pharmaceutical company for further development.

Refractory Urethral Stricture Management: Indications for Alternative Grafts and Flaps.

PURPOSE OF REVIEW: Urethral strictures that are refractory to initial management present unique challenges to the reconstructive surgeon. Treatment trends have shifted as new tissue resources are becoming available. There is renewed interest in old methods as skill and technique have improved. We describe the scope of the surgical armamentarium available to develop creative approaches and successful outcomes. RECENT FINDINGS: We discuss techniques to maximize the availability of oral mucosa, harvest and use of rectal mucosa, and developments in tissue engineering. Evolving methods to assess success of repair are also described. Urethral reconstruction for refractory urethral strictures requires proficiency with multiple methods as these strictures often require combining techniques for successful treatment.

Applying the 15 Public Health Emergency Preparedness Capabilities to Support Large-Scale Tuberculosis Investigations in Complex Congregate Settings.

Public Health-Seattle and King County, a metropolitan health department in western Washington, experiences rates of tuberculosis (TB) that are 1.6 times higher than are state and national averages. The department's TB Control Program uses public health emergency management tools and capabilities sustained with Centers for Disease Control and Prevention grant funding to manage large-scale complex case investigations. We have described 3 contact investigations in large congregate settings that the TB Control Program conducted in 2015 and 2016. The program managed the investigations using public health emergency management tools, with support from the Preparedness Program. The 3 investigations encompassed medical evaluation of more than 1600 people, used more than 100 workers, identified nearly 30 individuals with latent TB infection, and prevented an estimated 3 cases of active disease. These incidents exemplify how investments in public health emergency preparedness can enhance health outcomes in traditional areas of public health.

Synthesis and structure-activity relationships of a novel series of pyrimidines as potent inhibitors of TBK1/IKKε kinases.

The design, synthesis and structure-activity relationships of a novel series of 2,4-diamino-5-cyclopropyl pyrimidines is described. Starting from BX795, originally reported to be a potent inhibitor of PDK1, we have developed compounds with improved selectivity and drug-like properties. These compounds have been evaluated in a range of cellular and in vivo assays, enabling us to probe the putative role of the TBK1/IKKε pathway in inflammatory diseases.

Using Preoperative Pelvic Floor Assessment to Predict Early Return of Continence after Robotic Radical Prostatectomy.

OBJECTIVE: To evaluate whether pre-operative pelvic floor physical therapy (PFPT) parameters may predict early return of urinary continence after RP. While long-term urinary continence is eventually achieved in most patients who undergo radical prostatectomy (RP), predicting when patients will become continent is challenging. Prior studies aiming to predict return of post-operative continence have not evaluated patient-specific pelvic floor strength parameters. METHODS: We reviewed a prospectively maintained database of patients undergoing RP who underwent pre-operative PFPT consultation and completed 3-month patient-reported quality of life evaluation. Trained therapists documented pelvic strength parameters. Urinary continence was defined as using 0 or 1 pad per day. We evaluated the association of PFPT parameters with urinary continence at 3 months, adjusting for other factors that could affect continence. RESULTS: 144 men met inclusion criteria. The majority of patients underwent nerve-sparing procedures and had intermediate- or high-risk prostate cancer. At 3 months, 90 of 144 (62.5%) were continent, while 54 of 144 (37.5%) were not. On multivariable analysis, prostate volume (OR 0.98, 95% CI 0.96-1.00) and pelvic floor endurance (OR 2.71, 95% CI 1.23-6.17) were significantly associated with being continent at 3 months. 56 of 76 (74%) men with good pelvic floor endurance were continent at 3 months, while only 34 of 68 (50%) men with poor endurance were continent (P = .006). CONCLUSION: Pre-operative assessment of pelvic floor endurance is an objective measure that may allow more accurate prediction of early continence after radical prostatectomy. Improved patient counseling could positively impact patient satisfaction and quality of life and reduce decision regret.

Perioperative complications and adverse sequelae of radical nephroureterectomy.

Radical nephroureterectomy (RNU) has long been considered the standard of care for treatment of upper tract urothelial carcinoma (UTUC). Despite providing oncologic control, RNU is associated with measurable morbidity and mortality. High quality data is lacking as a result of low disease incidence and very few randomized studies. In this article we will review preoperative nomograms that assist with patient counseling, summarize current knowledge about perioperative complications, and discuss adverse sequelae that may result after surgery.

Cost-effectiveness of Management Options for Small Renal Mass: A Systematic Review.

Costs of surgery for small renal masses (SRMs) are high. This study aimed to systematically review and evaluate the cost-effectiveness analyses of management options for SRMs. Six databases were searched from inception to August 2015. Inclusion criteria were full original research, full economic evaluation of management options for SRM, and written in English. Among 776 studies screened, 6 met the inclusion criteria. Ablation was cost-effective versus nephron-sparing surgery. Laparoscopic partial nephrectomy was cost-effective versus the open approach. Renal mass biopsy dominated immediate treatment in the United States, but not in Canada. According to the Consolidated Health Economic Evaluation Reporting Standards, all the studies had relatively good quality. Despite the observed evidence, future research is needed to fill in the knowledge gap. A few suggestions should be kept in mind such as conducting the cost-effectiveness analysis in a variety of countries.

Age, Body Mass Index, and Frequency of Sexual Activity are Independent Predictors of Testosterone Deficiency in Men With Erectile Dysfunction.

OBJECTIVES: To identify clinical predictors of testosterone deficiency (TD) in men with erectile dysfunction (ED), thereby identifying subgroups that are most likely to benefit from targeted testosterone screening. METHODS: Retrospective review was conducted on 498 men evaluated for ED between January 2013 and July 2014. Testing for TD by early morning serum measurement was offered to all eligible men. Patients with history of prostate cancer or testosterone replacement were excluded. Univariable linear regression was conducted to analyze 19 clinical variables for associations with serum total testosterone (TT), calculated free testosterone (cFT), and TD (T <300 ng/dL or cFT <6.5 ng/dL). Variables significant on univariable analysis were included in multiple regression models. RESULTS: A total of 225 men met inclusion criteria. Lower TT levels were associated with greater body mass index (BMI), less frequent sexual activity, and absence of clinical depression on multiple regression analysis. TT decreased by 49.5 ng/dL for each 5-point increase in BMI. BMI and age were the only independent predictors of cFT levels on multivariable analysis. Overall, 62 subjects (27.6%) met criteria for TD. Older age, greater BMI, and less frequent sexual activity were the only independent predictors of TD on multiple regression. We observed a 2.2-fold increase in the odds of TD for every 5-point increase in BMI, and a 1.8-fold increase for every 10 year increase in age. CONCLUSIONS: Men with ED and elevated BMI, advanced age, or infrequent sexual activity appear to be at high risk of TD, and such patients represent excellent potential candidates for targeted testosterone screening.

Is peri-operative urethral catheter drainage enough? The case for stentless pediatric robotic pyeloplasty.

BACKGROUND: The necessity for urinary diversion with trans-anastomotic ureteral stenting during pyeloplasty is currently under debate. Performing a stentless repair could eliminate stent-related morbidity, including: stent migration, urinary tract infection, flank pain, and bladder spasms. In addition, there would be no need for a second procedure and associated anesthesia required for stent removal. This study describes the outcomes of robotic-assisted laparoscopic pyeloplasty without use of a ureteral stent. MATERIALS AND METHODS: An IRB-approved prospective database of all pediatric patients undergoing robotic pyeloplasty from July 2012 to July 2014 at a single institution was reviewed. The 'bypass pyeloplasty' or Anderson-Hynes dismembered pyeloplasty (DP) technique was performed. In both groups, neither a ureteral stent nor an abdominal drainage catheter was utilized. Complications were recorded, including: postoperative pain, bladder spasms, fever, and urinary tract infections. Follow-up renal ultrasound was reviewed for hydronephrosis. RESULTS: Twenty-seven children (17 male, 10 female) with a mean age of 25 months (range 6-157 months) underwent robotic ureteral stentless pyeloplasty during the study time period. The bypass pyeloplasty technique was performed on 19 children (70%). Mean length of stay was 20.2 hours (range 11-46). No fever, urinary tract infections, or hematuria requiring intervention were experienced. Additionally, there were no reports of bladder spasms or pain requiring pharmacotherapy. The mean follow-up was 8 months (range 4-21). Pre-operative Society of Fetal Urology grading was 3.5 and 3.4 for the dismembered and bypass cohort, respectively, with improvements to 1.1 for both groups at 3 months. Postoperative renal ultrasound hydronephrosis resolved in eight children (29.6%), improved in 14 (51.9%), and was stable in five (18.5%). The overall success rate was 100%. DISCUSSION: This study was limited by its small cohort and short follow-up, which may not thoroughly describe the efficacy of the stentless repair as it has been shown that stricture and re-obstruction can occur several years after surgery. CONCLUSIONS: Robotic stentless pyeloplasty is a feasible alternative to conventional methods, with excellent success rates and minimal complications. Importantly, this technique circumvents the need for a second procedure and the associated risks of anesthesia.