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.

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.

An Analysis of Staging and Treatment Trends for Upper Tract Urothelial Carcinoma in the National Cancer Database.

BACKGROUND: The purpose of this study was to analyze contemporary trends for diagnosis and treatment of upper tract urothelial carcinoma (UTUC). PATIENTS AND METHODS: We identified all cases of UTUC in the National Cancer Database (NCDB) between 2004 and 2013. Data comprising tumor, patient, and facility factors were extracted. Treatment data for surgery and chemotherapy were also collected. Comparisons used χ2 testing. RESULTS: Over this 10-year period, the sex and age distribution of UTUC was stable at 60% male and median age of 72 years. Most tumors were < cT2 at diagnosis, with an upward trend over 10 years (66% to 72%; P < .001). However, presentation with clinical metastatic disease also rose, from 4.6% to 8.9% (P < .001). Primary tumor biopsy increased from 37% to 50%. Overall rate of nephroureterectomy decreased from 59.6% to 56.7% whereas endoscopic ablation increased from 9.8% to 11.5%. Ablation was much more common in < cT2 tumors than ≥ cT2 (18.3% vs. 3.7%) and for low-grade tumors than high-grade (22.6% vs. 5.9%). Neoadjuvant chemotherapy was significantly more used, but still at a low rate. CONCLUSION: Treatment of UTUC appears to be shifting toward conservative surgical management with tumor ablation, and increasing neoadjuvant chemotherapy use. More primary tumor biopsies are being performed, likely reflecting improved ureteroscopic instruments and training. The NCDB also reports an increase in metastatic disease, which must be interpreted cautiously and might be artifactual.

Short- and Long-term Complications and Outcomes of Radiation and Surgically Induced Rectourethral Fistula Repair With Buccal Mucosa Graft and Muscle Interposition Flap.

OBJECTIVE: To analyze and report 30-day, 90-day, and long-term complications and surgical outcomes over a 17-year period for anterior transperineal repair of rectourethral fistulas (RUFs) resulting from pelvic radiation and surgery. MATERIALS AND METHODS: We performed a retrospective review of patients undergoing RUF repair between January 1, 1998 and February 28, 2015, at a single institution. All RUF were repaired using an anterior transperineal approach with an interposition muscle flap and selective use of a buccal mucosa graft onlay. RESULTS: Ninety-eight patients underwent repair with an anterior transperineal approach and muscle interposition flap (49 non-radiation induced and 49 radiation or ablation induced). Thirty- and 90-day complication rates were 29% and 2%, respectively, for non-radiated RUF, and 29% and 24%, respectively, for radiated RUF. Urethral diverticula, urinary incontinence, urethral stricture, and bowel problems were delayed complications requiring surgery. At a median follow-up of 14.5 months (range 3-144), 98% (48 of 49) of non-radiated RUF were closed with 1 procedure, whereas 86% (42 of 49) of radiated RUF were closed with 1 procedure. Gastrointestinal tract continuity was restored in 94% (45 of 48) of non-radiated RUF and in 65% (30 of 46) of radiated RUF. CONCLUSION: Successful RUF closure is possible in 98% of non-radiated and in 86% of radiated or ablated patients with 1 procedure. Most radiation-induced RUF, regardless of size, can be successfully repaired with minimal short-term complications. Delayed complications may arise and require surgery, and thus continued surveillance is recommended.

Management of Radiation Anterior Prostato-symphyseal Fistulas With Interposition Rectus Abdominis Muscle Flap.

OBJECTIVE: To describe a novel, organ-sparing approach for reconstruction of radiation-induced anterior prostato-symphyseal fistulas (PSFs) at our institution over a consecutive 10-year period. MATERIALS AND METHODS: We performed a retrospective review of patients undergoing surgical reconstruction for anterior PSF between January 1, 2006 and October 31, 2015. Patient demographics as well as preoperative, operative, and postoperative data were reviewed, including etiology of fistula, surgical management, and outcomes. RESULTS: A total of 4 patients with anterior PSF underwent organ-sparing reconstruction. All fistulas were the result of previous pelvic radiation. All 4 patients presented with pubic osteomyelitis. Patients underwent pubic symphysis debridement, fistula closure, and placement of an interposition rectus abdominis muscle flap. At a median follow-up of 27 months, 100% of the patients undergoing repair with interposition rectus flap were closed with 1 procedure. CONCLUSION: Radiation-induced PSF can be successfully reconstructed with pubic symphysis debridement and fistula closure using an adjunct rectus abdominis interposition flap, avoiding prostatectomy and urinary diversion.

Rho-kinase inhibition attenuates calcium-induced contraction in ß-escin but not Triton X-100 permeabilized rabbit femoral artery.

K+-depolarization (KCl) of smooth muscle has long been known to cause Ca2+-dependent contraction, but only recently has this G protein-coupled receptor (GPCR)-independent stimulus been associated with rhoA kinase (ROCK)-dependent myosin light chain (MLC) phosphatase inhibition and Ca2+ sensitization. This study examined effects of ROCK inhibition on the concentration-response curves (CRCs) generated in femoral artery by incrementally adding increasing concentrations of KCl to intact tissues, and Ca2+ to tissues permeabilized with Triton X-100, ß-escin and α-toxin. For a comparison, tissue responses were assessed also in the presence of protein kinase C (PKC) and MLC kinase inhibition. The ROCK inhibitor H-1152 induced a strong concentration-dependent inhibition of a KCl CRC. A relatively low GF-109203X concentration (1 µM) sufficient to inhibit conventional PKC isotypes also inhibited the KCl CRC but did not affect the maximum tension. ROCK inhibitors had no effect on the Ca2+ CRC induced in Triton X-100 or α-toxin permeabilized tissues, but depressed the maximum contraction induced in ß-escin permeabilized tissue. GF-109203X at 1 µM depressed the maximum Ca2+-dependent contraction induced in α-toxin permeabilized tissue and had no effect on the Ca2+ CRC induced in Triton X-100 permeabilized tissue. The MLC kinase inhibitor wortmannin (1 µM) strongly depression the Ca2+ CRCs in tissues permeabilized with Triton X-100, α-toxin and ß-escin. H-1152 inhibited contractions induced by a single exposure to a submaximum [Ca2+] (pCa 6) in both rabbit and mouse femoral arteries. These data indicate that ß-escin permeabilized muscle preserves GPCR-independent, Ca2+- and ROCK-dependent, Ca2+ sensitization.