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Epithelial-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

BackgroundObservational studies have reported a modest association between obesity and risk of ovarian cancer; however, whether it is also associated with survival and whether this association varies for the different histologic subtypes are not clear. We undertook an international collaborative analysis to assess the association between body mass index (BMI), assessed shortly before diagnosis, progression-free survival (PFS), ovarian cancer-specific survival and overall survival (OS) among women with invasive ovarian cancer.MethodsWe used original data from 21 studies, which included 12 390 women with ovarian carcinoma. We combined study-specific adjusted hazard ratios (HRs) using random-effects models to estimate pooled HRs (pHR). We further explored associations by histologic subtype.ResultsOverall, 6715 (54%) deaths occurred during follow-up. A significant OS disadvantage was observed for women who were obese (BMI: 30-34.9, pHR: 1.10 (95% confidence intervals (CIs): 0.99-1.23); BMI: ⩾35, pHR: 1.12 (95% CI: 1.01-1.25)). Results were similar for PFS and ovarian cancer-specific survival. In analyses stratified by histologic subtype, associations were strongest for women with low-grade serous (pHR: 1.12 per 5 kg m(-2)) and endometrioid subtypes (pHR: 1.08 per 5 kg m(-2)), and more modest for the high-grade serous (pHR: 1.04 per 5 kg m(-2)) subtype, but only the association with high-grade serous cancers was significant.ConclusionsHigher BMI is associated with adverse survival among the majority of women with ovarian cancer.

We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n=675) and controls (n=1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs-PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616-were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with Pper-alleleor=0.5). However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (Pper-allele=0.03). Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04-1.24) p=0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus.

Low-moderate risk alleles that are relatively common in the population may explain a significant proportion of the excess familial risk of ovarian cancer (OC) not attributed to highly penetrant genes. In this study, we evaluated the risks of OC associated with common germline variants in five oncogenes (BRAF, ERBB2, KRAS, NMI and PIK3CA) known to be involved in OC development. Thirty-four tagging SNPs in these genes were genotyped in approximately 1800 invasive OC cases and 3000 controls from population-based studies in Denmark, the United Kingdom and the United States. We found no evidence of disease association for SNPs in BRAF, KRAS, ERBB2 and PIK3CA when OC was considered as a single disease phenotype; but after stratification by histological subtype, we found borderline evidence of association for SNPs in KRAS and BRAF with mucinous OC and in ERBB2 and PIK3CA with endometrioid OC. For NMI, we identified a SNP (rs11683487) that was associated with a decreased risk of OC (unadjusted P(dominant)=0.004). We then genotyped rs11683487 in another 1097 cases and 1792 controls from an additional three case-control studies from the United States. The combined odds ratio was 0.89 (95% confidence interval (CI): 0.80-0.99) and remained statistically significant (P(dominant)=0.032). We also identified two haplotypes in ERBB2 associated with an increased OC risk (P(global)=0.034) and a haplotype in BRAF that had a protective effect (P(global)=0.005). In conclusion, these data provide borderline evidence of association for common allelic variation in the NMI with risk of epithelial OC.

The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.

Background: Aspirin, nonaspirin nonsteroidal anti-inflammatory drugs (NA-NSAIDs) and acetaminophen all have biologic effects that might reduce the risk of ovarian cancer. However, epidemiologic data on this question are mixed.Methods: A population-based, case-control study in western Pennsylvania, eastern Ohio, and western New York State included 902 women with incident epithelial ovarian cancer who were diagnosed between February 2003 and November 2008 as well as 1802 matched controls. Regular use (at least 2 tablets per week for 6 months or more) of aspirin, NA-NSAIDs, and acetaminophen before the reference date (9 months before interview date) was assessed by in-person interview. We used logistic regression to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs).Results: The OR for aspirin use was 0.81 (95% CI = 0.63-1.03). Decreased risks were found among women who used aspirin continuously (0.71 [0.54-0.94]) or at a low-standardized daily dose (0.72 [0.53-0.97]), who used aspirin for the prevention of cardiovascular disease (0.72 [0.57-0.97]), who used aspirin more recently, or who used selective cyclooxygenase-2 inhibitors (0.60 [0.39-0.94]). No associations were observed among women using nonselective NA-NSAIDs or acetaminophen.Conclusions: Risk reductions of ovarian cancer were observed with use of aspirin or selective cyclooxygenase-2 inhibitors. However, the results should be interpreted with caution due to the inherent study limitations and biases. [ABSTRACT FROM AUTHOR]

Background: Among women with pelvic inflammatory disease (PID), we assessed the associations among antibodies to Chlamydia trachomatis elementary bodies (EB), antibodies to chlamydia heat shock protein (Chsp60), rates of pregnancy, and PID recurrence.Methods: Four hundred forty-three women with clinical signs and symptoms of mild to moderate PID enrolled in the PID Evaluation and Clinical Health Study were followed for a mean of 84 months for outcomes of time-to-pregnancy and time-to-PID recurrence. Antibodies to EB and Chsp60 were assessed in relation to these long-term sequelae of PID.Results: Rates of pregnancy were significantly lower (adj. hazard ratio 0.47, 95% confidence interval 0.28-0.79) and PID recurrence higher (adj. hazard ratio 2.48, 95% confidence interval 1.00-6.27) after adjusting for confounding factors among women whose antibody titers to chlamydia EB measured in the final year of follow-up were in the highest tertile.Conclusion: Among women with mild to moderate PID, antibodies to C. trachomatis were independently associated with reduced rates of pregnancy and elevated rates of recurrent PID. [ABSTRACT FROM AUTHOR]

Objective: Effectiveness differences between outpatient pelvic inflammatory disease (PID) treatment regimens are uncertain, but significant differences in cost exist.Goal: To examine the influence of antibiotic costs on PID therapy cost-effectiveness.Study Design: The authors used a Markov decision model to estimate the cost-effectiveness of recommended antibiotic regimens for PID and performed a value of information analysis to guide future research.Results: Antibiotic costs vary between USD 43 and USD188. Pairwise comparisons, assuming a hypothetical 1% relative risk reduction in PID complications with the more expensive regimen, showed economically reasonable cost-effectiveness ratios. Value of information and sample size considerations support further investigation to detect 10% PID complication rate differences between regimens with >or=USD 50 cost differences.Conclusions: Within the cost range of recommended regimens, use of more expensive antibiotics would be economically reasonable if relatively small decreases in PID complication rates exist. Further investigation of effectiveness differences between regimens is needed. [ABSTRACT FROM AUTHOR]

Women who deliver preterm are at increased risk for cardiovascular disease, but mechanisms are not understood. The authors considered that inflammation in women with spontaneous preterm birth (sPTB) might be related to their metabolic profile, such as lipids, and tested this in a nested case-control study from the Pregnancy Exposures and Preeclampsia Prevention Study (1997-2001). Cases were women with sPTB at 34-<37 weeks (n = 76) or < 34 weeks (n = 33). Controls were randomly selected women with term births (n = 228). Early pregnancy inflammation (C-reactive protein: > or = 8 microg/ml) and dyslipidemia (cholesterol: > 230 mg/dl or triglycerides: > 140 mg/dl) were evaluated in serum collected at < 21 weeks. Late pregnancy elevated C-reactive protein (> or = 12 microg/ml) was measured in a subset (n = 295). Polycotomous logistic regression was used to estimate the joint effects of C-reactive protein elevations and dyslipidemia on the risk of sPTB subtypes. After adjustment for race, body mass index, periconceptional vitamin use, and gestational age at sampling, early pregnancy inflammation (odds ratio = 2.9, 95% confidence interval (CI): 1.1, 7.2) and dyslipidemia (odds ratio = 2.0, 95% CI: 1.0, 4.2) were independently associated with sPTB at 34-<37 weeks. The presence of both conditions increased risk of sPTB at < 34 weeks 6.4-fold (95% CI: 1.7, 24.1). Half of the women with early pregnancy inflammation had elevated C-reactive protein late in gestation, and each was independently related to the risk of sPTB at < 34 weeks. The results indicate that some metabolic factors together with inflammation may be related to the risk of sPTB. [ABSTRACT FROM AUTHOR]

Context: Anecdotal reports suggest that the Health Insurance Portability and Accountability Act Privacy Rule (HIPAA Privacy Rule) may be affecting health research in the United States.Objective: To survey epidemiologists about their experiences with the HIPAA Privacy Rule.Design, Setting, and Participants: Thirteen societies of epidemiology distributed a national Web-based survey; 2805 respondents accessed the survey Web site and 1527 eligible professionals anonymously answered questions.Main Outcome Measures: Responses related influences such as research delays and added cost after Privacy Rule implementation, frequency and type of Privacy Rule-related institutional review board modifications, level of difficulty obtaining deidentified data and waivers, experiences with multisite studies, and perceived participant privacy benefits under the rule. Respondents ranked their perceptions of Privacy Rule influence on 5-point Likert scales.Results: A total of 875 (67.8%) respondents reported that the HIPAA Privacy Rule has made research more difficult at a level of 4 to 5 on a Likert scale, in which 5 indicates a great deal of added cost and time to study completion. A total of 684 (52.1%) of respondents identified a "most affected" protocol. Respondents indicated that the proportion of institutional review board applications in which the Privacy Rule had a negative influence on human subjects (participants) protection was significantly greater than the proportion in which it had a positive influence (P < .001).Conclusion: In this national survey of clinical scientists, only a quarter perceived that the rule has enhanced participants' confidentiality and privacy, whereas the HIPAA Privacy Rule was perceived to have a substantial, negative influence on the conduct of human subjects health research, often adding uncertainty, cost, and delay. [ABSTRACT FROM AUTHOR]

Vaginal complaints compel an evaluation of bacterial vaginosis (BV), however, many cases of BV are asymptomatic. We evaluated the sensitivity and specificity of vaginal symptoms in the diagnosis of BV and examined the utility of creating a BV screening tool using clinical, behavioural and demographic characteristics. A total of 1916 pregnant women were included in this analysis. In total, 757 women screened positive for BV and over one third of BV-positive women presented without any lower genital tract symptoms (39.4%). African American race, abnormal vaginal odour, and smoking were independently related to BV positivity. A BV screening tool including these three factors was fairly predictive of BV status with the area under the ROC curve equal to 0.669. This three-item prediction rule may be useful in identifying high- risk pregnant women in need of BV screening and, given the high specificity, accurately identify the group of BV-negative pregnant women. [ABSTRACT FROM AUTHOR]

The authors' objective was to determine the relation between periconceptional multivitamin use and the risk of small-for-gestational-age (SGA: <5th percentile; 5th-<10th percentiles) or preterm (<34 weeks; 34-<37 weeks) births. Women in the Pregnancy Exposures and Preeclampsia Prevention Study (1997-2001) reported at enrollment their regular multivitamin use in the past 6 months (n = 1,823). Women were classified as users or nonusers in multinomial logistic models. After adjustment for race, age, education, enrollment gestational age, and household density, periconceptional multivitamin use was associated with a reduced risk of preterm births (<34 weeks) (odds ratio (OR) = 0.29, 95% confidence interval (CI): 0.13, 0.64) and spontaneous preterm births (<34 weeks) (OR = 0.40, 95% CI: 0.16, 0.99). Risk of SGA (<5th percentile) was marginally lower (OR = 0.64, 95% CI: 0.40, 1.03) after adjustment for smoking, education, parity, enrollment gestational age, and body mass index. Prepregnancy body mass index modified this relation. Nonobese users had a reduction (OR = 0.54, 95% CI: 0.32, 0.91) in risk of SGA (<5th percentile); there was no effect among obese women. There was no effect of multivitamin use on risk of preterm births (34-<37 weeks) or SGA (5th-<10th percentiles). Sensitivity analysis for unmeasured confounding by folate intake supported these findings. Study results indicate lower rates of severe preterm births and extreme SGA in women who report periconceptional vitamin use, although these should be considered cautiously until replicated. [ABSTRACT FROM AUTHOR]

Chronic inflammation has been implicated in a variety of cancers. In this review, we consider associations between endometriosis and cancers both local (ovarian) and distant (breast). We review the epidemiological data linking endometriosis to ovarian and breast cancers. We then consider evidence for a role for sex steroid hormones and for inflammation in the aetiology of each of these cancers. Finally, we consider that endometriosis may promote alterations in sex steroid hormones and inflammatory mediators. A possible explanation for the association between endometriosis and these reproductive cancers may then be local and systemic enhancement of aberrant inflammatory and hormonal mediators. If this hypothesis is true, endometriosis may need to be considered as a risk factor for ovarian and breast cancers, triggering increasingly intensive surveillance. Moreover, treatments for endometriosis may require consideration of the impact on long-term cancer risk. [ABSTRACT FROM AUTHOR]

Controversy surrounds the association between bacterial vaginosis (BV) and pelvic inflammatory disease (PID). Women (N = 1,140) were ascertained at five US centers, enrolled (1999-2001), and followed up for a median of 3 years. Serial vaginal swabs were obtained for Gram's stain and cultures. PID was defined as 1) histologic endometritis or 2) pelvic pain and tenderness plus oral temperature >38.8 degrees C, leukorrhea or mucopus, erythrocyte sedimentation rate >15 mm/hour, white blood cell count >10,000, or gonococcal/chlamydial lower genital infection. Exploratory factor analysis identified two discrete clusters of genital microorganisms. The first correlated with BV by Gram's stain and consisted of the absence of hydrogen peroxide-producing lactobacillus, Gardnerella vaginalis, Mycoplasma hominis, anaerobic gram-negative rods, and, to a lesser degree, Ureaplasma urealyticum. The second, unrelated to BV by Gram's stain, consisted of Enterococcus species and Escherichia coli. Being in the highest tertile in terms of growth of BV-associated microorganisms increased PID risk (adjusted rate ratio = 2.03, 95% confidence interval: 1.16, 3.53). Carriage of non-BV-associated microorganisms did not increase PID risk. Women with heavy growth of BV-associated microorganisms and a new sexual partner appeared to be at particularly high risk (adjusted rate ratio = 8.77, 95% confidence interval: 1.11, 69.2). When identified by microbial culture, a combination of BV-related microorganisms significantly elevated the risk of acquiring PID. [ABSTRACT FROM AUTHOR]

Objective: To assess the effect of raloxifene compared with placebo on sexual function in older postmenopausal women undergoing therapy for the treatment of osteoporosis.Methods: A subset (12%) of English-speaking women in the United States and Canada participating in the Multiple Outcomes of Raloxifene Evaluation Trial were asked to complete a sexual function questionnaire at baseline and after 36 months of treatment. The Multiple Outcomes of Raloxifene Evaluation Trial is a multicenter, randomized, blinded, placebo-controlled clinical trial, in which 7,705 postmenopausal women with osteoporosis were randomly assigned to one of three groups: raloxifene hydrochloride 60 mg per day or 120 mg per day or placebo. In this substudy, 943 women completed the sexual function questionnaire at both visits. Because preliminary analyses showed no differences by raloxifene dose (n = 302 for 60 mg per day; n = 322 for 120 mg/day), the two groups were combined and compared with the placebo group (n = 319). For the given sample size, we had 80% power (alpha =.05, two-sided, ratio of raloxifene to placebo = 2:1) to detect a 10%-16% difference in the proportion of women experiencing no change in sexual function between placebo and treatment groups.Results: Overall, sexual function and changes in sexual function from baseline to study end between the raloxifene and placebo groups did not differ. In particular, there were no differences in sexual desire or frequency of sexual activity between the groups. Among sexually active women, there were no differences in enjoyment, satisfaction, orgasm, or reported sexual problems.Conclusion: Sexual function in older postmenopausal women with osteoporosis is not affected by treatment with raloxifene. [ABSTRACT FROM AUTHOR]