Association between occupational exposures and sarcoma incidence and mortality: systematic review and meta-analysis.

BACKGROUND: Sarcomas are a rare and heterogeneous group of tumors originating from mesenchymal or connective tissue. They represent less than 1% of all adult cancers. The etiology and epidemiology of sarcomas remain understudied and poorly understood. The main objective of our study was to systematically assess the association between various occupational exposures and risk of sarcomas. METHODS: We performed a systematic literature search using the PubMed, Scopus, EMBASE and Cochrane databases to identify relevant cohort and case-control studies. A meta-analysis method was applied on the incidence and mortality outcomes where the estimate with 95% confidence interval (CI) was obtained. RESULTS: We included a total of 50 publications in our systematic review and 35 in meta-analysis. For exposures to phenoxy herbicides and chlorophenols, the pooled odds ratio (OR) for sarcoma was 1.85 (95% CI: 1.22, 2.82), based on 16 studies with 2254 participants, while the pooled standardized mortality ratio was 40.93 (95% CI 2.19, 765.90), based on 4 cohort studies with 59,289 participants. For exposure to vinyl chloride monomers the pooled risk ratios for angiosarcoma of the liver and other STS were 19.23 (95% CI 2.03, 182.46) and 2.23 (95 CI 1.55, 3.22) respectively based on 3 cohort studies with 12,816 participants. Exposure to dioxins was associated with an increased STS mortality; the pooled standardized mortality ratio was 2.56 (95% CI 1.60, 4.10) based on 4 cohort studies with 30,797 participants. Finally, woodworking occupation was associated with an increased risk of STS with the pooled OR of 2.16 (95% CI 1.39, 3.36). CONCLUSIONS: Our findings suggest a positive association between higher exposure to dioxins and increased mortality from STS, between cumulative exposure to vinyl chloride monomers and increased mortality from angiosarcoma of the liver and STS, and between woodworking occupation and STS incidence. These findings were all statistically significant.

YAP activation protects urothelial cell carcinoma from treatment-induced DNA damage.

Current standard of care for muscle-invasive urothelial cell carcinoma (UCC) is surgery along with perioperative platinum-based chemotherapy. UCC is sensitive to cisplatin-based regimens, but acquired resistance eventually occurs, and a subset of tumors is intrinsically resistant. Thus, there is an unmet need for new therapeutic approaches to target chemotherapy-resistant UCC. Yes-associated protein (YAP) is a transcriptional co-activator that has been associated with bladder cancer progression and cisplatin resistance in ovarian cancer. In contrast, YAP has been shown to induce DNA damage associated apoptosis in non-small cell lung carcinoma. However, no data have been reported on the YAP role in UCC chemo-resistance. Thus, we have investigated the potential dichotomous role of YAP in UCC response to chemotherapy utilizing two patient-derived xenograft models recently established. Constitutive expression and activation of YAP inversely correlated with in vitro and in vivo cisplatin sensitivity. YAP overexpression protected while YAP knockdown sensitized UCC cells to chemotherapy and radiation effects via increased accumulation of DNA damage and apoptosis. Furthermore, pharmacological YAP inhibition with verteporfin inhibited tumor cell proliferation and restored sensitivity to cisplatin. In addition, nuclear YAP expression was associated with poor outcome in UCC patients who received perioperative chemotherapy. In conclusion, these results suggest that YAP activation exerts a protective role and represents a pharmacological target to enhance the anti-tumor effects of DNA damaging modalities in the treatment of UCC.

Identification of a new disease cluster of pemphigus vulgaris with autoimmune thyroid disease, rheumatoid arthritis and type I diabetes.

BACKGROUND: Pemphigus vulgaris (PV) is a potentially fatal autoimmune blistering skin disease. It is known that individuals with autoimmune diseases such as PV, as well as their family members, are at increased risk of developing other autoimmune diseases. However, it is unknown whether there are specific autoimmune diseases that cluster with PV. OBJECTIVES: To investigate the frequency of coexisting autoimmune diseases in patients with PV and their relatives, to determine the prevalence of specific autoimmune diseases in patients with PV vs. the general population and to identify statistically significant clinical clusters linking PV with other autoimmune disorders. METHODS: We performed a cross-sectional study and meta-analysis of patient data from our own patient database (n = 230), an anonymous online survey conducted by our laboratory (n = 171) and the International Pemphigus & Pemphigoid Foundation registry (n = 393). RESULTS: We found that the prevalences of autoimmune thyroid disease (AITD), rheumatoid arthritis and type 1 diabetes were significantly increased in patients with PV compared with the general population. These diseases were also among the most frequent in family members of patients with PV, in addition to systemic lupus erythematosus (SLE). Descriptive cluster analysis using basic principle components methods revealed that PV forms a distinct cluster with AITD, rheumatoid arthritis and type 1 diabetes, and another cluster with SLE, AITD and rheumatoid arthritis. CONCLUSIONS: PV belongs to an established autoimmune disease cluster that includes AITD, rheumatoid arthritis and type 1 diabetes. Our data suggest the possibility of common genetic elements across clinically distinct diseases that might underlie autoimmune susceptibility.

SU-E-T-16: Statistical Variability and Confidence Intervals for Planar Dose QA Pass Rates.

PURPOSE: The most common metric for comparing measured to calculated dose planes is a pass rate generated using percent difference, distance-to-agreement (DTA), or some combination of the two (e.g. gamma evaluation). The grid of analyzed points often corresponds to a dosimeter array with low areal-density of point detectors. This work examines the statistical uncertainty of planar dose comparison pass rates and proposes methods for establishing confidence intervals for pass rates obtained with low detector-density arrays. METHODS: Absolute dose planes were acquired via EPID for twenty intensity-modulated fields of varying complexity. Matching calculated dose planes were created via treatment planning system. Pass rates for each dose plane pair (centered to CAX) were calculated with various %/DTA composite analysis techniques. Software was designed to selectively sample the high-density EPID matrix to simulate many low-density measured grids, each representing a different alignment with respect to CAX. Simulations were repeated (100 positional iterations per field) using grids of varying detector-densities and both random and orthogonal point-detector orientation. For each simulation, pass rates were calculated with various composite analysis techniques. RESULTS: Repositioning simulated low-density grids leads to a distribution of possible pass rates for each measured/calculated dose plane pair, independent of whether the detector grid is random or uniform. Distributions can be predicted using a binomial distribution by which a confidence interval (function of sampling density and observed pass rate) is approximated for each pass rate. For example, 95% confidence intervals for IMRT pass rates (2%,2mm) average +/-5.3% and +/-3.8% with 1-detector/cm2 and 2-detector/cm2 grids, respectively. CONCLUSIONS: Pass rates for low-density array measurements are not absolute and should be reported with both a full description of calculation method and confidence intervals quantifying their uncertainty. Results extend to 3D detector arrays. The concept of fixed 'action levels' for pass rates must be reexamined for low-density array measurements.

Maintenance of strength gains while performing endurance training in oarswomen.

This study investigated the retention of strength gained after resistance training, while performing aerobic endurance training. Following a 10-week resistance training program (three times a week) that included maintenance aerobic endurance training (twice a week), 18 varsity oarswomen were matched on strength and randomly assigned to two groups: Group 1 performed maintenance resistance training once a week and Group 2 performed resistance training twice a week. Both groups performed endurance training four times a week during the 6-week maintenance resistance training program. There was a significant increase in strength (multiple-RM test) for three upper and three lower body exercises after the initial 10-week resistance training program. A further significant increase in two exercises (inclined leg press and knee flexion) were observed after 6 weeks of maintenance resistance training and endurance training in both groups. No further significant increases were observed in the four other exercises during maintenance strength training. These latter findings occurred at the same time that VO2max and ventilation threshold increased. These results suggest that strength gains can be maintained with resistance training once or twice a week while focusing on improving aerobic endurance performance without compromising the latter.