Prognostic gene expression signature for high-grade serous ovarian cancer.

BACKGROUND: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC. PATIENTS AND METHODS: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies. RESULTS: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years. CONCLUSION: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.

Dairy and related nutrient intake and risk of uterine leiomyoma: a prospective cohort study.

STUDY QUESTION: Is there an association between consumption of dairy foods and related nutrients and risk of uterine leiomyoma? SUMMARY ANSWER: While dairy consumption was not consistently associated with uterine leiomyoma risk, intake of yogurt and calcium from foods may reduce risk of uterine leiomyoma. WHAT IS KNOWN ALREADY: Two studies have examined the association between dairy intake and uterine leiomyoma risk with inconsistent results. Dairy foods have been inversely associated with inflammation and tumorigenesis, suggesting that vitamins and minerals concentrated in these dietary sources may influence uterine leiomyoma risk. STUDY DESIGN, SIZE, DURATION: A prospective cohort study was carried out using data collected from 81 590 premenopausal women from 1991 to 2009 as part of the Nurses' Health Study II cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: Diet was assessed with a validated food frequency questionnaire every 4 years. Cases were restricted to self-reported ultrasound or hysterectomy-confirmation uterine leiomyoma. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE: Eight thousand one hundred and forty-two cases of ultrasound or hysterectomy-confirmed uterine leiomyoma were diagnosed over an 18-year period. When compared to participants who consumed two servings a week of total dairy foods, participants who consumed four or more servings had a borderline significant 8% reduced risk of uterine leiomyoma (HR = 0.92, 95% CI = 0.85, 1.00; ptrend = 0.19). When the association between specific dairy foods and uterine leiomyoma was examined, the relation between dairy-food intake and uterine leiomyoma appeared to be driven primarily by yogurt consumption (HR for 2+ servings/day = 0.76; 95% CI = 0.55, 1.04 compared to <=4 servings/week; ptrend = 0.03); however, there was a small number of cases in the 2+ servings/day group (n = 39). Of the nutrients examined, the association was strongest for calcium from foods (HR fifth quintile = 0.92, 95% CI = 0.86, 0.99; ptrend = 0.04). LIMITATIONS, REASONS FOR CAUTION: Some cases of uterine leiomyoma were likely misclassified, particularly those that were asymptomatic. It is possible that dairy product constituents reduce uterine leiomyoma symptomology rather than development, giving the appearance of a protective effect on leiomyoma development: no data on uterine leiomyoma symptomology were available. We did not have vitamin and mineral concentrations from actual blood levels. Similarly, there is the potential for misclassification of participants based on predicted 25(OH)D, and changes in vitamin D supplementation over time may have impacted prediction models for 25(OH)D. Further, some error in the self-reporting of dietary intake is expected. Given our prospective design, it is likely that these misclassifications were non-differential with respect to the outcome, likely biasing estimates toward the null. WIDER IMPLICATIONS OF THE FINDINGS: While no clear association between overall dairy consumption and uterine leiomyoma risk was observed, our findings suggest that intake of yogurt and calcium from foods may reduce risk of uterine leiomyoma. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by research grant HD081064 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The Nurses' Health Study II is supported by the Public Health Service grant UM1 CA176726 from the National Cancer Institute, NIH, U.S. Department of Health and Human Services. H.R.H. is supported by the National Cancer Institute, National Institutes of Health (K22 CA193860). There are no conflicts of interest to declare.

Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis.

Uterine leiomyomata (UL) are the most common neoplasms of the female reproductive tract and primary cause for hysterectomy, leading to considerable morbidity and high economic burden. Here we conduct a GWAS meta-analysis in 35,474 cases and 267,505 female controls of European ancestry, identifying eight novel genome-wide significant (P < 5 × 10-8) loci, in addition to confirming 21 previously reported loci, including multiple independent signals at 10 loci. Phenotypic stratification of UL by heavy menstrual bleeding in 3409 cases and 199,171 female controls reveals genome-wide significant associations at three of the 29 UL loci: 5p15.33 (TERT), 5q35.2 (FGFR4) and 11q22.3 (ATM). Four loci identified in the meta-analysis are also associated with endometriosis risk; an epidemiological meta-analysis across 402,868 women suggests at least a doubling of risk for UL diagnosis among those with a history of endometriosis. These findings increase our understanding of genetic contribution and biology underlying UL development, and suggest overlapping genetic origins with endometriosis.

Influence of anti-inflammatory diet and smoking on mortality and survival in men and women: two prospective cohort studies.

BACKGROUND: The associations between an anti-inflammatory diet and both all-cause and cause-specific mortality have been studied previously; however, the influence of an anti-inflammatory diet on survival time has not been investigated. Moreover, the potential modification of these associations by smoking status remains unclear. OBJECTIVE: The aims of this study were to examine the associations between an anti-inflammatory diet index (AIDI) and all-cause and cause-specific mortality, to determine the association between the AIDI and differences in survival time and to assess effect modification by smoking status. METHODS: The study population included 68 273 Swedish men and women (aged 45-83 years) at baseline. The anti-inflammatory potential of the diet was estimated using the validated AIDI, which includes 11 potential anti-inflammatory and five potential pro-inflammatory foods. Cox proportional hazards and Laplace regression were used to estimate hazard ratios and differences in survival time. RESULTS: During 16 years of follow-up (1 057 959 person-years), 16 088 deaths [5980 due to cardiovascular disease (CVD) and 5252 due to cancer] were recorded. Participants in the highest versus lowest quartile of the AIDI had lower risks of all-cause (18% reduction, 95% CI: 14-22%), CVD (20%, 95% CI: 14-26%) and cancer (13%, 95% CI: 5-20%) mortality. The strongest inverse associations between the highest and lowest quartiles of AIDI and risk of mortality were observed in current smokers: 31%, 36% and 22% lower risks of all-cause, CVD and cancer mortality, respectively. The difference in survival time between current smokers in the lowest AIDI quartile and never smokers in the highest quartile was 4.6 years. CONCLUSION: Adherence to a diet with high anti-inflammatory potential may reduce all-cause, CVD and cancer mortality and prolong survival time especially amongst smokers.

Fruit and vegetable consumption and risk of endometriosis.

STUDY QUESTION: Is there an association between intake of fruits and vegetables and risk of laparoscopically confirmed endometriosis? SUMMARY ANSWER: Higher intake of fruits, particularly citrus fruits, is associated with a lower risk of endometriosis. WHAT IS KNOWN ALREADY: Two case-control studies have examined the associations between fruit and vegetable intake and endometriosis risk with contrasting results. Diets rich in fruits and vegetables include higher levels of pro-vitamin A nutrients (alpha-carotene, beta-carotene, beta-cryptoxanthin) and women with endometriosis have been reported to have lower intake of vitamin A than women without endometriosis. STUDY DESIGN SIZE, DURATION: A prospective cohort study using data collected from 70 835 premenopausal women from 1991 to 2013 as part of the Nurses' Health Study II cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: Diet was assessed with a validated food frequency questionnaire (FFQ) every 4 years. Cases were restricted to laparoscopically confirmed endometriosis. Cox proportional hazards models were used to calculate rate ratios (RR) and 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE: During 840 012 person-years of follow-up, 2609 incident cases of laparoscopically confirmed endometriosis were reported (incidence rate = 311 per 100 000 person-years). We observed a non-linear inverse association between higher fruit consumption and risk of laparoscopically confirmed endometriosis (Psignificance of the curve = 0.005). This inverse association was particularly evident for citrus fruits. Women consuming ≥1 servings of citrus fruits/day had a 22% lower endometriosis risk (95% CI = 0.69-0.89; Ptrend = 0.004) compared to those consuming <1 serving/week. No association was observed between total vegetable intake and endometriosis risk. However, women consuming ≥1 servings/day cruciferous vegetables had a 13% higher risk of endometriosis (95% CI = 0.95-1.34; Ptrend = 0.03) compared to those consuming <1 serving/week. Of the nutrients examined, only beta-cryptoxanthin intake was significantly associated with lower endometriosis risk (RR fifth quintile = 0.88; 95% CI = 0.78-1.00; Ptrend = 0.02). LIMITATIONS REASONS FOR CAUTION: Some error in the self-reporting of dietary intake is expected, however, use of a validated FFQ and examining diet prospectively across multiple time points, make it unlikely that this non-differential misclassification strongly influenced the results. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that a higher intake of fruits, particularly citrus fruits, is associated with a lower risk of endometriosis, and beta-cryptoxanthin in these foods may partially explain this association. In contrast to what we hypothesized, consumption of some vegetables increased endometriosis risk which may indicate a role of gastrointestinal symptoms in both the presentation and exacerbation of endometriosis-related pain; however, it is not clear what components of these foods might underlie the observed associations. Future studies examining dietary patterns that consider different combinations of food intake may help clarify these associations. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by research grants HD4854, HD52473 and HD57210 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and grant P30 DK046200 from the National Institute of Diabetes and Digestive and Kidney Diseases. The Nurses' Health Study II is supported by the Public Health Service grant UM1 CA176726 from the National Cancer Institute, National Institutes of Health. HRH is supported by the National Cancer Institute, National Institutes of Health (K22 CA193860). No competing interests. TRIAL REGISTRATION NUMBER: n/a.

Long and irregular menstrual cycles, polycystic ovary syndrome, and ovarian cancer risk in a population-based case-control study.

Long and irregular menstrual cycles, a hallmark of polycystic ovary syndrome (PCOS), have been associated with higher androgen and lower sex hormone binding globulin levels and this altered hormonal environment may increase the risk of specific histologic subtypes of ovarian cancer. We investigated whether menstrual cycle characteristics and self-reported PCOS were associated with ovarian cancer risk among 2,041 women with epithelial ovarian cancer and 2,100 controls in the New England Case-Control Study (1992-2008). Menstrual cycle irregularity, menstrual cycle length, and PCOS were collected through in-person interview. Unconditional logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (95% CIs) for ovarian cancer risk overall, and polytomous logistic regression to evaluate whether risk differed between histologic subtypes. Overall, we observed no elevation in ovarian cancer risk for women who reported periods that were never regular or for those reporting a menstrual cycle length of >35 days with ORs of 0.87 (95% CI = 0.69-1.10) and 0.83 (95% CI = 0.44-1.54), respectively. We observed no overall association between self-reported PCOS and ovarian cancer (OR = 0.97; 95% CI = 0.61-1.56). However, we observed significant differences in the association with menstrual cycle irregularity and risk of ovarian cancer subtypes (pheterogeneity = 0.03) as well as by BMI and OC use (pinteraction < 0.01). Most notable, menstrual cycle irregularity was associated with a decreased risk of high grade serous tumors but an increased risk of serous borderline tumors among women who had never used OCs and those who were overweight. Future research in a large collaborative consortium may help clarify these associations.

Vitamin C intake and breast cancer mortality in a cohort of Swedish women.

BACKGROUND: Vitamin C may influence cancer progression through its antioxidant properties. However, the evidence from observational epidemiologic studies on vitamin C intake and survival following breast cancer diagnosis is not consistent, and the safety of vitamin C supplements following breast cancer diagnosis has not been extensively studied. METHODS: Using a food-frequency questionnaire we investigated whether vitamin C intake was associated with survival among 3405 women diagnosed with invasive breast cancer in the Swedish Mammography Cohort. RESULTS: From 1987-2010, there were 1055 total deaths with 416 deaths from breast cancer. Women in the highest quartile of pre-diagnosis vitamin C intake had an adjusted HR (95% CI) of breast cancer death of 0.75 (0.57-0.99) compared with those in the lowest quartile (Ptrend=0.03). There was a borderline significant association between vitamin C intake and total mortality (HR=0.84; 95% CI=0.71-1.00; Ptrend=0.08). Among 717 breast cancer cases for whom post-diagnosis supplement use was available, there was no association between vitamin C supplement use (≈1000 mg) and breast cancer-specific mortality (HR=1.06; 95% CI=0.52-2.17). CONCLUSION: Our findings suggest that dietary vitamin C intake before breast cancer diagnosis may be associated with breast cancer survival. In addition, post-diagnosis vitamin C supplementation at the level observed in our population was not associated with survival.

Parental smoking during pregnancy and risk of overweight and obesity in the daughter.

OBJECTIVE: Emerging evidence suggests that prenatal exposures may affect long-term health outcomes. In utero exposure to smoking is associated with an increased risk of overweight and obesity in children and adolescents. However, few studies have examined how prenatal exposure to parental smoking influences the risk of obesity during adulthood and whether these associations are independent of childhood and adolescent adiposity. The aim of the current study was to investigate whether prenatal exposure to parental smoking influences body size during adulthood and whether any association may be mediated by childhood and adolescent body size. METHODS: We investigated the association between parental smoking during pregnancy and the risk of being overweight and obese during adulthood and at age 18 and adiposity during childhood among 35 370 participants in the Nurses' Health Study II. Data on smoking during pregnancy and socioeconomic variables were provided by the mothers, and anthropometric data and adult risk factors were reported by participants. RESULTS: After adjustment for socioeconomic and behavioral variables, maternal smoking during pregnancy was associated with adiposity at ages 5-10, 18 and during adulthood. For age 18 overweight, the odd ratios, ORs (95% confidence intervals, CIs) for 1-14, 15-24 and 25+cigarettes per day were 1.13 (1.18-1.50), 1.40 (1.20-1.64) and 1.15 (0.79-1.69), and for obesity were 1.41 (1.14-1.75), 1.69 (1.31-2.18) and 2.36 (1.44-3.86). The corresponding ORs (95% CIs) for obesity during adulthood were 1.26 (1.16-1.37), 1.46 (1.30-1.63) and 1.43 (1.10-1.86). Risk of adiposity was not increased among daughters whose mothers stopped smoking during the first trimester (OR (95% CI) for overweight (1.03 (95% CI 0.90-1.17)) and for obesity (1.12 (95% CI 0.97-1.30)). Women whose fathers smoked during pregnancy were also at an increased risk of being overweight and obese during adulthood with covariate-adjusted ORs (95% CIs) for obesity of 1.19 (1.11-1.29) for 1-14 cigarettes per day, 1.27 (1.18-1.37) for 15-24 cigarettes per day and 1.40 (1.27-1.54) for 25+ cigarettes per day compared with fathers who did not smoke (Ptrend<0.0001). Paternal smoking during pregnancy was also associated with an increased risk of obesity at age 18 among those whose fathers smoked 15 or more cigarettes per day but was not associated with childhood body size. CONCLUSIONS: Maternal smoking during pregnancy was associated in a dose-response manner with overweight and obesity in the daughter across adolescence and adult life. Smoking cessation during the first trimester appears to mitigate this excess risk.Paternal smoking was also associated with the risk of being overweight and obese of the adult daughter and this association persisted after adjustment for maternal smoking.

Coffee and black tea consumption and breast cancer mortality in a cohort of Swedish women.

BACKGROUND: Coffee and black tea contain a mixture of compounds that have the potential to influence breast cancer risk and survival. However, epidemiologic data on the relation between coffee and black tea consumption and breast cancer survival are sparse. METHODS: We investigated the association between coffee and black tea consumption and survival among 3243 women with invasive breast cancer in the Swedish Mammography Cohort. Intake was estimated using a food frequency questionnaire. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs). RESULTS: From 1987 to 2010 there were 394 breast cancer-specific deaths and 973 total deaths. Coffee and black tea were not associated with breast cancer-specific or overall mortality. Women consuming 4+ cups of coffee per day had a covariate and clinical characteristics-adjusted HR (95% CI) of death from breast cancer of 1.14 (0.71-1.83; p(trend)=0.81) compared with those consuming <1 cup per day. Women consuming 2+ cups of black tea per day had a covariate and clinical characteristics-adjusted HR (95% CI) of death from breast cancer of 1.02 (0.67-1.55; p(trend)=0.94) compared with non-tea drinkers. Caffeine was also not associated with breast cancer-specific (HR for top to bottom quartile=1.06; 95% CI=0.79-1.44; p(trend)=0.71) or overall mortality. CONCLUSION: Our findings suggest that coffee, black tea, and caffeine consumption before breast cancer diagnosis do not influence breast cancer-specific and overall survival.

Alcohol intake and mortality among women with invasive breast cancer.

BACKGROUND: Alcohol intake has consistently been associated with increased breast cancer incidence in epidemiological studies. However, the relation between alcohol and survival after breast cancer diagnosis is less clear. METHODS: We investigated whether alcohol intake was associated with survival among 3146 women diagnosed with invasive breast cancer in the Swedish Mammography Cohort. Alcohol consumption was estimated using a food frequency questionnaire. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs). RESULTS: From 1987 to 2008 there were 385 breast cancer-specific deaths and 860 total deaths. No significant association was observed between alcohol intake and breast cancer-specific survival. Women who consumed 10 g per day (corresponding to approximately 0.75 to 1 drinks) or more of alcohol had an adjusted HR (95% CI) of breast cancer-specific death of 1.36 (0.82-2.26;p(trend)=0.47) compared with non-drinkers. A significant inverse association was observed between alcohol and non-breast cancer deaths. Those who consumed 3.4-9.9 g per day of alcohol had a 33% lower risk of death compared with non-drinkers (95% CI 0.50-0.90;p(trend)=0.04). CONCLUSION: Our findings suggest that alcohol intake up to approximately one small drink per day does not negatively impact breast cancer-specific survival and a half drink per day is associated with a decreased risk of mortality from other causes.

Etretinate as an effective adjunctive therapy for recalcitrant palmar/plantar hyperkeratosis in patients with erythrodermic cutaneous T cell lymphoma undergoing photopheresis.

BACKGROUND: Patients with erythrodermic cutaneous T cell lymphoma (CTCL) frequently have debilitating hyperkeratosis of the palms and soles that is refractory to therapy. OBJECTIVE: To evaluate the efficacy of etretinate as an adjunctive therapy for recalcitrant palmar and plantar hyperkeratosis in erythrodermic CTCL patients undergoing photopheresis. METHODS: Five patients with erythrodermic CTCL and recalcitrant palmar and plantar hyperkeratosis were given etretinate (0.8 mg/kg per day) while undergoing photopheresis therapy. RESULTS: There was a rapid and marked improvement of the hyperkeratosis in all patients. CONCLUSION: Etretinate is a safe and effective adjunctive treatment for recalcitrant palmar and plantar hyperkeratosis in erythrodermic CTCL patients undergoing photopheresis.