P. Nyirády

Urinary Outflow Obstruction Increases Apoptosis and Deregulates Bcl-2 and Bax Expression in the Fetal Ovine Bladder

During organogenesis, net growth of tissues is determined by a balance between proliferation, hypertrophy, and apoptotic death. Human fetal bladder outflow obstruction is a major cause of end-stage renal failure in children and is associated with complex pathology in the kidney and lower urinary tract. Experimental manipulation of the fetal sheep urinary tract has proved informative in understanding the pathobiology of congenital obstructive uropathy. In this study we used an ovine model of fetal bladder outflow obstruction to examine effects on apoptotic cell death in the developing urinary bladder. While 30 days of obstruction in utero between 75 and 105 days gestation resulted in overall growth of the fetal bladder as assessed by weight, protein, and DNA measurements, we found that apoptosis, as assessed by in situ end-labeling, was up-regulated in fetal bladder detrusor muscle and lamina propria cells and that this was accompanied by a down-regulation of the anti-death protein Bcl-2 and an up-regulation of the pro-death protein Bax. Moreover, activated caspase-3, an effector of apoptotic death, was increased in obstructed bladders. This is the first study to define altered death in an experimental fetal model of bladder dysmorphogenesis. We speculate that enhanced apoptosis in detrusor smooth muscle cells is part of a remodeling response during compensatory hyperplasia and hypertrophy. Conversely, in the lamina propria, an imbalance between death and proliferation leads to a relative depletion of cells.

Effects of In Utero Bladder Outflow Obstruction on Fetal Sheep Detrusor Contractility, Compliance and Innervation

PURPOSE Congenital bladder outflow obstruction caused by posterior urethral valves is a common cause of end stage renal failure in boys. We hypothesized that fetal bladder outflow obstruction perturbs detrusor contractility and innervation and bladder storage volume-pressure relationships. MATERIALS AND METHODS Severe bladder outflow obstruction was induced in male fetal sheep by placing a urethral ring and urachal ligation midway through gestation at 75 days. Fetuses were examined 30 days after surgery, when urinary tract dilatation, enlarged bladders and histologically abnormal kidneys were documented. Isolated strips of bladder detrusor from sham operated and obstructed fetuses were subjected to electrical field stimulation, carbachol, KCl and alpha-beta methylene-adenosine triphosphate. Whole bladder storage characteristics were determined by filling cystometry and bladder innervation was investigated by immunohistochemistry and Western blot. RESULTS Tension-frequency contractility studies showed that obstructed fetal bladder strips were significantly hypocontractile versus sham operated controls in response to electrical field stimulation and the specific agonists carbachol, KCl and alpha-beta methylene-adenosine triphosphate. Hypocontractility was greater with nerve mediated stimulation than with carbachol, suggesting relative denervation. Reduced innervation was confirmed by S100 and protein gene product 9.5 immunohistochemistry and by measuring a significant reduction in protein gene product 9.5 protein expression using Western blot. Filling cystometry showed that obstructed fetal bladders appeared more compliant (Delta V/Delta P, where Delta V is the change in volume and Delta P is the change in pressure) with larger capacity, more flaccidity and yet retained stress relaxation. CONCLUSIONS In response to severe experimental fetal bladder outflow obstruction the bladder becomes large and hypocontractile, and has aberrant innervation.

Changes to the contractile function of ureter smooth muscle after partial infravesical obstruction in fetal sheep

To measure spontaneous contractile activity, and the responses to agonists using in vitro preparations of sheep ureter after a period of bladder outlet obstruction (BOO) initiated at mid‐gestation.

The Role of YKL-40 in Predicting Resistance to Docetaxel Chemotherapy in Prostate Cancer

Introduction: High baseline YKL-40 serum levels are associated with drug resistance in several solid tumours. However, their role in predicting docetaxel (DOC) resistance in prostate cancer (PCa) is unknown. Methods: Pre-treatment serum levels of YKL-40 and prostate-specific antigen (PSA) were analyzed in 109 castration-resistant prostate cancer patients who underwent DOC-therapy. Responsive patients were retreated by repeated series of DOC. Results were compared with the clinical parameters as well as overall (OS) and disease-specific survival (DSS). Results: YKL-40 but not PSA serum levels were significantly higher in patients with baseline resistance to DOC (p = 0.035). Higher YKL-40 and PSA levels were detected in patients with bone metastasis (p = 0.032; p = 0.010) and in those who were not pre-treated with radical prostatectomy (p = 0.011, p = 0.008). High YKL-40 levels were associated with shorter OS (p = 0.037) and DSS (p = 0.017) in patients who received DOC in the first-line setting. In multivariable analysis, ECOG performance status (p = 0.009), presence of any metastases (p = 0.016) and high PSA levels (p = 0.005) remained independent predictors for DSS. Conclusions: YKL-40 may help to identify patients with baseline resistance to DOC and therefore may help to optimize treatment decisions. In accordance, high pre-treatment YKL-40 serum levels were associated with shorter OS and DSS in patients who received DOC as first-line therapy.

PD49-06 THE ADHERENCE TO THE EAU GUIDELINES ON PENILE CANCER TREATMENT COULD INFLUENCE THE SURVIVAL: MULTICENTER, RETROSPECTIVE, EUROPEAN STUDY.

METHODS: Invasive penile cancer cases from 2010-2012 were identified from the NCDB. Pathologic tumor stage was recorded including spongiosal versus carvernosal involvement. Differences in demographic (age, race, comorbid status) and pathologic features (size of tumor, grade, nodal status, LVI, histology, and extranodal extension) between T2 and T3 tumors were compared using c and t-tests. Univariate and multivariate logistic regression was performed to determine the odds of positive lymph nodes (pN+) at inguinal lymph node dissection (ILND) relative to T-stage. RESULTS: There were 367 T2 and 507 T3 patients with penile cancer. The proportion of cases with pN+ disease was 15%, 32%, 46% and 58% for T1, T2, T3 and T4 cases, respectively. Compared to T2 tumors, T3 tumors were larger (mean size 5.8 cm vs. 4.3 cm), more often treated with radical penectomy (36% vs 17%), had higher positive surgical margin rates (12% vs 9%), more aggressive pathology (32% vs 27% poorly differentiated), and were more likely to have lymphovascular invasion (42% vs 31%) (all p < 0.05). In univariate analysis, compared to T1 tumors, T2 (OR 2.8, 95% CI 1.9-4.2) and T3 (OR 4.7, 95% CI 3.3-6.8) were both associated with an increased risk of positive lymph nodes. Although in multivariate analysis, both T2 (OR 2.0, 95% CI 1.2-3.3) and T3 (OR 2.3, 95% CI 1.4-3.6) remained significantly associated with risk of positive lymph nodes compared to T1 disease, there was no increase in risk between T2 and T3 disease (OR 1.1, 95% CI 0.7-1.8, p 1⁄4 0.56). CONCLUSIONS: The proposed new AJCC staging system for the penile cancer distinguishes spongiosal (T2) from cavernosal (T3) involvement and identifies significant differences in pathologic features of the tumors (grade, LVI and size). There does not appear to be a difference in positive lymph node status between the two grades when other clinical and pathological variables are considered. Further study is required to confirm these findings and the prognostic implications of the proposed new staging system.