Citations

ABSTRACTEpithelial‐mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single‐nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome‐wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT‐related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive‐cancer patients and 23,447 controls. A P‐value <0.05 and a false discovery rate (FDR) <0.2 were considered statistically significant. In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (odds ratio (OR) = 1.16, 95% CI = 1.07–1.25, P = 0.0003, FDR = 0.19), whereas F8 rs7053448 (OR = 1.69, 95% CI = 1.27–2.24, P = 0.0003, FDR = 0.12), F8 rs7058826 (OR = 1.69, 95% CI = 1.27–2.24, P = 0.0003, FDR = 0.12), and CAPN13 rs1983383 (OR = 0.79, 95% CI = 0.69–0.90, P = 0.0005, FDR = 0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC.

AbstractBackgroundRib fractures are common after chest wall trauma. For patients with flail chest, surgical stabilization is a promising technique for reducing morbidity. Anatomical difficulties often lead to an inability to completely repair the flail chest; thus, the result is partial flail chest stabilization (PFS). We hypothesized that patients with PFS have outcomes similar to those undergoing complete flail chest stabilization (CFS).MethodsA prospectively collected database of all patients who underwent rib fracture stabilization procedures from August 2009 until February 2013 was reviewed. Abstracted data included procedural and complication data, extent of stabilization, and pulmonary function test results.ResultsOf 43 patients who underwent operative stabilization of flail chest, 23 (53 %) had CFS and 20 (47 %) underwent PFS. Anterior location of the fracture was the most common reason for PFS (45 %). Age, sex, operative time, pneumonia, intensive care unit and hospital length of stay, and narcotic use were the same in both groups. Total lung capacity was significantly improved in the CFS group at 3 months. No chest wall deformity was appreciated on follow‐up, and no patients underwent additional stabilization procedures following PFS.ConclusionDespite advances in surgical technique, not all fractures are amenable to repair. There was no difference in chest wall deformity, narcotic use, or clinically significant impairment in pulmonary function tests among patients who underwent PFS compared with CFS. Our data suggest that PFS is an acceptable strategy and that extending or creating additional incisions for CFS is unnecessary.

Abstract Background: CA125 is elevated in 80% of ovarian cancer cases and has proven utility in assessing response to therapy and prognosis. Unfortunately, CA125 is elevated in a variety of benign conditions and only in 50% of early stage ovarian cancers, resulting in a sensitivity and specificity unacceptable for population-based screening. Therefore, understanding factors that influence CA125 at presentation could provide important insights for interpreting CA125 values. Methods: Using pre-treatment CA125 and detailed epidemiologic data from 12 studies participating in the Ovarian Cancer Association Consortium (OCAC), we evaluated factors previously reported to influence CA125 levels, including age, race, oral contraceptive use, parity, tubal ligation, endometriosis, body mass index (BMI), personal history of breast cancer, or a family history of breast or ovarian cancer. We used linear regression to estimate the association between each variable and CA125 probit scores, which we used to standardize values between studies. Secondary analyses included adjustment for histologic subtype. We also estimated the associations within each study using log-transformed CA125 as the outcome and estimated summary measures using random effects meta-analyses. Results: Of the 4417 cases included in the analysis, 2918 (66%) were serous, 227 (5%) were mucinous, 484 (11%) were endometrioid, and 258 (6%) were clear cell carcinomas. Median CA125 values varied between studies with a high of 831 U/mL and a low of 271 U/mL. We observed no association between race, oral contraceptive use, tubal ligation, endometriosis, prior breast cancer, and family history of breast cancer and pre-treatment CA125. However, we observed increased pre-treatment CA125 levels with older age (&gt;70 vs. &lt; 50, p=0.03), parity (p=0.01), number of children (p=0.02), obesity (BMI&gt;30 vs. 21-25, p=0.03), and family history of ovarian cancer (p=0.05). Results were similar but attenuated when we calculated summary estimates of the association using meta-analysis of study specific estimates of the association with log-transformed CA125 rather than probit scores. Age and BMI remained predictive of pre-treatment CA125 values after adjustment for histologic subtype. Our data are limited by between site variability in CA125 assays; therefore, validation of these findings is needed with adjustment for type of assay used or in a study population in which all cases had pre-treatment CA125 values measured with the same assay. Conclusions: Despite these limitations, results from this analysis of over 4000 ovarian cancer cases suggest that age and body size may influence pre-treatment CA125 values. Citation Format: KL Terry, A Babic, BY Karlan, MT Goodman, D Lambrechts, F Heitz, K Matsuo, I McNeish, T Pejovic, S Kruger Kjaer, PM Webb, E Hogdall, EL Goode, DW Cramer, for the Ovarian Cancer Association Consortium. Epidemiologic predictors of pre-treatment CA125 in women with ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS13.

AbstractGenetic risk factors for cholangiocarcinoma (CCA) remain poorly understood. We assessed the effect of single‐nucleotide polymorphisms (SNPs) of genes modulating inflammation or carcinogenesis on CCA risk and survival. We conducted a case‐control, candidate gene association study of 370 CCA patients and 740 age‐, sex‐, and residential area‐matched healthy controls. Eighteen functional or putatively functional SNPs in nine genes were genotyped. The log‐additive genotype effects of SNPs on CCA risk and survival were determined using logistic regression and the log‐rank test, respectively. Initial analysis identified significant associations between SNP rs2143417 and rs689466 in cyclooxygenase 2 (COX‐2) and CCA risk, after adjusting for multiple comparisons (cutoff of P = 0.0028). However, these findings were not replicated in another independent cohort of 212 CCA cases and 424 matched controls. No significant association was found between any SNP and survival of CCA patients. Although COX‐2 has been shown to contribute to cholangiocarcinogenesis, the COX‐2 SNPs tested were not associated with risk of CCA. This study shows a lack of association between variants of genes related to inflammation and carcinogenesis and CCA risk and survival. Other factors than these genetic variants may play more important roles in CCA risk and survival.

On March 25 and 26, 2015, the National Heart, Lung, and Blood Institute sponsored a meeting on the State of the Science in Transfusion Medicine on the National Institutes of Health (NIH) campus in Bethesda, Maryland, which was attended by a diverse group of 330 registrants. The meeting's goal was to identify important research questions that could be answered in the next 5 to 10 years and which would have the potential to transform the clinical practice of transfusion medicine. These questions could be addressed by basic, translational, and/or clinical research studies and were focused on four areas: the three “classical” transfusion products (i.e., red blood cells, platelets, and plasma) and blood donor issues. Before the meeting, four working groups, one for each area, prepared five major questions for discussion along with a list of five to 10 additional questions for consideration. At the meeting itself, all of these questions, and others, were discussed in keynote lectures, small‐group breakout sessions, and large‐group sessions with open discourse involving all meeting attendees. In addition to the final lists of questions, provided herein, the meeting attendees identified multiple overarching, cross‐cutting themes that addressed issues common to all four areas; the latter are also provided. It is anticipated that addressing these scientific priorities, with careful attention to the overarching themes, will inform funding priorities developed by the NIH and provide a solid research platform for transforming the future practice of transfusion medicine.

Abstract Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P &lt; 0.05 and FDR &lt; 0.05). These results were replicated (P &lt; 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. Cancer Epidemiol Biomarkers Prev; 24(10); 1574–84. ©2015 AACR.

BACKGROUNDEfficacy trials have shown that antiviral therapy improves the outcomes of patients with chronic hepatitis B virus (HBV) infection. However, prospective data regarding the effect of antiviral therapy on the incidence of hepatocellular carcinoma (HCC), especially among patients without cirrhosis, are limited. The authors examined the impact of tenofovir disoproxil fumarate (TDF) on the incidence of HCC using a validated prediction model.METHODSThe incidence of HCC in patients treated with TDF was obtained in the pivotal TDF registration studies after 384 weeks of follow‐up. The predicted risk of HCC in individual patients was calculated using the Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B (REACH‐B) model, which estimates HCC incidence for up to 10 years based on age, sex, alanine aminotransferase level, hepatitis B e antigen status, and HBV‐DNA. Standardized incidence ratios (SIRs) were calculated comparing the observed and predicted numbers of HCC cases in the study cohort.RESULTSAmong 634 patients with evaluable baseline biopsies, 152 had cirrhosis (Ishak fibrosis score of 5 or 6) and 482 did not. During the 384 weeks of study, 14 cases of HCC were reported, with 4 occurring within the first year. The incidence of HCC was 0.37% per year in the study as a whole (0.28% among patients without cirrhosis and 0.65% among patients with cirrhosis). Among patients without cirrhosis, the observed incidence of HCC was significantly lower than predicted (SIR, 0.40; 95% confidence interval, 0.199‐0.795). The last HCC case in a patient with cirrhosis occurred around week 192 with an SIR of 0.51 (95% confidence interval, 0.231‐1.144) reported at week 384.CONCLUSIONSBased on the REACH‐B risk calculator, long‐term therapy with TDF was associated with a reduced incidence of HCC among patients without cirrhosis who met treatment criteria. Cancer 2015;121:3631–3638. © 2015 American Cancer Society.

Abstract Purpose: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. Experimental Design: We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis. Results: Five SNPs were significantly associated (P ≤ 1.0 × 10−5) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23), and rs6674079 (1q22), were located in long noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P ≤ 7.1 × 10−6). ENCODE ChIP-seq data at 1q22 for normal ovary show evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression and high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA ≤6 × 10−3). Conclusions: We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies. Clin Cancer Res; 21(23); 5264–76. ©2015 AACR.

This prospective, observational pilot study was conducted on an academic inpatient rehabilitation unit. Ninety-three persons with spinal cord dysfunction or severe neurological illness participated. All completed admission surveys; 46 completed surveys six months after discharge. The aims were to describe admission and post-discharge spirituality and associations between spirituality and rehabilitation outcomes. At admission, participants reported spirituality similar to that of other samples of medical patients. After discharge, frequency of private spiritual practices increased and spiritual and existential well-being decreased. No significant associations were detected between spirituality and rehabilitation outcomes. Findings suggest the importance of spirituality to the participants and future research with a larger sample and modifications to the methodology.