IgA transcytosis and antigen recognition govern ovarian cancer immunity.

Most ovarian cancers are infiltrated by prognostically relevant activated T cells1-3, yet exhibit low response rates to immune checkpoint inhibitors4. Memory B cell and plasma cell infiltrates have previously been associated with better outcomes in ovarian cancer5,6, but the nature and functional relevance of these responses are controversial. Here, using 3 independent cohorts that in total comprise 534 patients with high-grade serous ovarian cancer, we show that robust, protective humoral responses are dominated by the production of polyclonal IgA, which binds to polymeric IgA receptors that are universally expressed on ovarian cancer cells. Notably, tumour B-cell-derived IgA redirects myeloid cells against extracellular oncogenic drivers, which causes tumour cell death. In addition, IgA transcytosis through malignant epithelial cells elicits transcriptional changes that antagonize the RAS pathway and sensitize tumour cells to cytolytic killing by T cells, which also contributes to hindering malignant progression. Thus, tumour-antigen-specific and -antigen-independent IgA responses antagonize the growth of ovarian cancer by governing coordinated tumour cell, T cell and B cell responses. These findings provide a platform for identifying targets that are spontaneously recognized by intratumoural B-cell-derived antibodies, and suggest that immunotherapies that augment B cell responses may be more effective than approaches that focus on T cells, particularly for malignancies that are resistant to checkpoint inhibitors.

Associations between common contraceptive use and circulating inflammatory biomarkers.

Ovarian cancer incidence has declined in recent decades, due in part to oral contraceptive (OC) use and tubal ligation. However, intrauterine device (IUD) use has increasingly replaced OC use. As ovarian cancer is an inflammation-related disease, we examined the association of OC use, IUD use, and tubal ligation with plasma levels of C-reactive protein (CRP), interleukin 6 (IL-6), and soluble tumor necrosis factor α receptor 2 (sTNFR2), in the Nurses' Health Study (NHS) and NHSII. After adjusting for reproductive, hormonal, and lifestyle factors, and mutual adjustment for other methods of contraception, there were no differences in inflammatory markers between ever and never use of each method. However, CRP levels decreased from an average 30.4% (-53.6, 4.4) with every 5 years since initial IUD use (P-trend=0.03), while CRP increased an average 9.9% (95% CI: 5.7, 14.3) with every 5 years of use of OC (P-trend<0.0001) as well as differences by BMI and menopausal status. Our results suggest IUD use and tubal ligation are not associated with higher circulating inflammatory markers long term, although long duration of OC use may increase generalized inflammation, which may in part explain why its protective effect wanes over time.

The relationship of lifetime history of depression on the ovarian tumor immune microenvironment.

BACKGROUND: Depression is associated with a higher ovarian cancer risk. Prior work suggests that depression can lead to systemic immune suppression, which could potentially alter the anti-tumor immune response. METHODS: We evaluated the association of pre-diagnosis depression with features of the anti-tumor immune response, including T and B cells and immunoglobulins, among women with ovarian tumor tissue collected in three studies, the Nurses' Health Study (NHS; n = 237), NHSII (n = 137) and New England Case-Control Study (NECC; n = 215). Women reporting depressive symptoms above a clinically relevant cut-point, antidepressant use, or physician diagnosis of depression at any time prior to diagnosis of ovarian cancer were considered to have pre-diagnosis depression. Multiplex immunofluorescence was performed on tumor tissue microarrays to measure immune cell infiltration. In pooled analyses, we estimated odds ratios (OR) and 95% confidence intervals (CI) for the positivity of tumor immune cells using a beta-binomial model comparing those with and without depression. We used Bonferroni corrections to adjust for multiple comparisons. RESULTS: We observed no statistically significant association between depression status and any immune markers at the Bonferroni corrected p-value of 0.0045; however, several immune markers were significant at a nominal p-value of 0.05. Specifically, there were increased odds of having recently activated cytotoxic (CD3+CD8+CD69+) and exhausted-like T cells (CD3+Lag3+) in tumors of women with vs. without depression (OR = 1.36, 95 %CI = 1.09-1.69 and OR = 1.24, 95 %CI = 1.01-1.53, respectively). Associations were comparable when considering high grade serous tumors only (comparable ORs = 1.33, 95 %CI = 1.05-1.69 and OR = 1.25, 95 %CI = 0.99-1.58, respectively). There were decreased odds of having tumor infiltrating plasma cells (CD138+) in women with vs. without depression (OR = 0.54, 95 %CI = 0.33-0.90), which was similar among high grade serous carcinomas, although not statistically significant. Depression was also related to decreased odds of having naïve and memory B cells (CD20+: OR = 0.54, 95 %CI = 0.30-0.98) and increased odds of IgG (OR = 1.22, 95 %CI = 0.97-1.53) in high grade serous carcinomas. CONCLUSION: Our results provide suggestive evidence that depression may influence ovarian cancer outcomes through changes in the tumor immune microenvironment, including increasing T cell activation and exhaustion and reducing antibody-producing B cells. Further studies with clinical measures of depression and larger samples are needed to confirm these results.

Prospective Analyses of Sedentary Behavior in Relation to Risk of Ovarian Cancer.

We examined the association of sedentary behavior with risk of ovarian cancer overall, by tumor subtype, and by participant characteristics in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHS II). A total of 69,558 NHS participants (1992-2016) and 104,130 NHS II participants (1991-2015) who reported on time spent sitting at home, at work, and while watching television were included in the analysis, which included 884 histologically confirmed ovarian cancer cases. Multivariable-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for ovarian cancer by sitting time (no mutual adjustment for individual sitting types in primary analyses). We examined potential heterogeneity by tumor histological type (type I or II), body mass index (weight (kg)/height (m)2; < 25 or ≥25), and total physical activity (<15 or ≥15 metabolic equivalent of task-hours/week). We observed an increased risk of ovarian cancer for women who sat at work for 10-19 hours/week (HR = 1.25, 95% CI: 1.04, 1.51) and ≥20 hours/week (HR = 1.40, 95% CI: 1.14, 1.71) versus <5 hours/week. This association did not vary by body mass index, physical activity, or histotype (P for heterogeneity ≥ 0.43). No associations were observed for overall sitting, sitting while watching television, or other sitting at home. Longer sitting time at work was associated with elevated risk of ovarian cancer. Further investigations are required to confirm these findings and elucidate underlying mechanisms.

Pre-diagnosis and post-diagnosis dietary patterns and survival in women with ovarian cancer.

BACKGROUND: Evidence is limited on inflammation-related dietary patterns and mortality in ovarian cancer survivors. METHODS: We examined the associations between pre- and post-diagnosis dietary patterns, including change in diet from before to after diagnosis, and mortality among 1003 ovarian cancer survivors in two prospective cohort studies. Dietary pattern scores for empirical dietary inflammatory pattern (EDIP) and Alternative Healthy Eating Index (AHEI) were calculated based on food frequency questionnaires. We used Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for ovarian cancer-specific and all-cause mortality. RESULTS: Pre-diagnosis EDIP score and AHEI were not associated with mortality. Among non-high grade serous cases, a higher post-diagnosis EDIP score was associated with increased risk of all-cause mortality (HR5th vs 1st quintile = 1.95, 95% CI = 1.04-3.67, p-trend = 0.06). Compared to survivors consuming a low EDIP score diet before and after diagnosis, high post-diagnosis EDIP was associated with increased risk of ovarian cancer specific mortality (pre-to-post diagnosis low/high, HR = 1.38, 95% CI = 0.99-1.92; high/high HR = 1.58, 95% CI = 1.09-2.30) and all-cause mortality (low/high HR = 1.44, 95% CI = 1.06-1.95; high/high HR = 1.55, 95% CI = 1.10-2.19). CONCLUSION: Consuming a more inflammatory dietary pattern post-diagnosis was associated with increased mortality in ovarian cancer survivors, suggesting limiting the inflammatory potential of diet post-diagnosis could lead to enhanced survivorship.

Early life physical activity and risk of ovarian cancer in adulthood.

Emerging data suggest that exposures in early life may affect ovarian development and contribute to ovarian cancer risk. We evaluated the association between early life physical activity and risk of ovarian cancer in adulthood in two large prospective cohorts, the Nurses' Health Study (NHS) and NHSII. In total, analyses included 28 232 NHS participants (followed from 2004 to 2016) and 56 553 NHSII participants (followed from 1997 to 2017). Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of ovarian cancer overall and by early life body mass index (BMI). Neither physical activity at ages 12-13, 14-17 or 18-22 years nor average physical activity across these three periods was associated with ovarian cancer risk overall (≥78 vs <24 MET-h/wk, HRs = 1.34, 1.21, 1.08 and 1.24, respectively), or by categories of early life BMI (Pheterogeneity ≥ .44). No association was observed with the risk of high-grade serous or poorly differentiated tumors or postmenopausal ovarian cancer. Overall, early life physical activity was not clearly related to ovarian cancer risk during adulthood.

Prediagnosis and postdiagnosis leisure time physical activity and survival following diagnosis with ovarian cancer.

Little is known about the influence of prediagnosis and postdiagnosis physical activity on ovarian cancer survival. We investigated this association in two large cohorts, the Nurses' Health Study (NHS) and NHSII. Analyses included 1461 women with confirmed invasive, epithelial ovarian cancer and data on physical activity. Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for ovarian cancer-specific mortality. Ovarian cancer-specific mortality was not associated with physical activity reported 1-8 years before diagnosis overall (≥7.5 vs <1.5 MET-hours/week, HR = 0.96), for high-grade serous/ poorly differentiated tumors, or non-serous/ low-grade serous tumors (P-heterogeneity = .45). An inverse association was observed for activity 1-4 years after diagnosis (≥7.5 vs <1.5 MET-hours/week, HR = 0.67, 95%CI: 0.48-0.94), with similar results by histotype (P-heterogeneity = .53). Women who decreased their activity from ≥7.5 MET-hours/week 1-8 years before diagnosis to <7.5 MET-hours/week 1-4 years after diagnosis, compared to those with <7.5 MET-hours/week across periods, had a 49% increased risk of death (HR = 1.49, 95%CI: 1.07-2.08). Physical activity after, but not before, ovarian cancer diagnosis was associated with better prognosis.

Intrauterine device use and risk of ovarian cancer: Results from the New England Case-Control study and Nurses' Health Studies.

Results of studies assessing intrauterine device (IUD) use and ovarian cancer risk are inconsistent. We examined the association between IUD use, including duration, type and timing of use, and ovarian cancer risk using three population-based studies. Data from the New England Case-Control Study (NEC) and two prospective cohort studies, the Nurses' Health Studies (NHS/NHSII), were included in the analysis. Information on IUD use was collected by in-person interview in NEC and by biennial questionnaire in NHS/NHSII. We used unconditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) in NEC and Cox regression to calculate hazard ratios (HR) and 95% CI in NHS/NHSII. We used meta-analysis to combine the NEC and the pooled NHS/NHSII results. Overall, IUD use was not associated with epithelial ovarian cancer risk (OR = 0.96, 95% CI: 0.81-1.14 in NEC; HR = 0.89, 95% CI: 0.69-1.15 in NHS/NHSII; combined RR = 0.94, 95% CI: 0.81-1.08). Among IUD users, older age at first use was associated with increased ovarian cancer risk (P-trend = .03). We did not observe significant associations by IUD type or duration of use. In conclusion, IUD use was not associated with ovarian cancer risk in our study.

Antihypertensive medication use and ovarian cancer survival.

OBJECTIVE: Although experimental models suggest that use of beta-blockers, a common antihypertensive agent, may improve survival in ovarian cancer patients, results from clinical studies have been mixed. METHODS: We evaluated the associations of pre-diagnostic (n = 950) and post-diagnostic (n = 743) use of antihypertensive medications with survival among patients with invasive, epithelial ovarian cancer in the Nurses' Health Study (NHS; 1994-2016) and NHSII (2001-2017), with follow-up until 2018 and 2019, respectively. Cox proportional hazards models were used to estimate hazard ratios (HR) for ovarian cancer mortality according to antihypertensive medication use before and after diagnosis, considering multiple drug classes (beta-blockers, calcium-channel blockers, thiazide diuretics, angiotensin-converting enzyme [ACE] inhibitors). RESULTS: After adjusting for age, BMI, smoking status and tumor characteristics, pre-diagnostic use versus non-use of calcium-channel blockers was associated with higher ovarian cancer mortality (HR: 1.49; 95% CI: 1.13, 1.96), which was primarily due to polytherapy involving calcium-channel blockers (HR: 1.61; 95% CI: 1.15, 2.26). Pre-diagnostic use of beta-blockers, thiazide diuretics, or ACE inhibitors was not associated with ovarian cancer mortality. No association was observed for post-diagnostic antihypertensive medication use individually or in combination, except for lower mortality associated with polytherapy involving ACE inhibitors (HR: 0.53; 95% CI: 0.31, 0.91). CONCLUSION: Overall, we did not find clear relationships between antihypertensive medication use and ovarian cancer mortality. However, given the limitation of the data, we cannot determine whether the association may differ by type of beta-blockers. The reasons underlying the observed associations with pre-diagnostic calcium-channel blocker use and post-diagnostic ACE inhibitor use require further investigation.

"I think that a brief conversation from their provider can go a very long way": Patient and provider perspectives on barriers and facilitators of genetic testing after ovarian cancer.

OBJECTIVE: Identify predisposing, enabling, and reinforcing factors impacting genetic counseling/testing among ovarian cancer patients guided by Green and Kreuter's PRECEDE-PROCEED model. METHODS: Gynecologic oncology providers (N = 4), genetic counselors (N = 4), and ovarian cancer patients (N = 9) completed semi-structured qualitative interviews exploring participants' knowledge of and experiences with genetic counseling/testing. Interviews were audio recorded, transcribed verbatim, and analyzed using inductive content analysis by two independent raters. RESULTS: Thematic analysis identified predisposing, enabling, and reinforcing factors impacting referral for and uptake of genetic counseling/testing. Predisposing factors included participant's knowledge, beliefs, and attitudes related to genetic counseling/testing. Both patients and providers also cited that insurance coverage and out-of-pocket cost are major concerns for ovarian cancer patients considering genetic testing. Finally, both patients and providers emphasized that genetic counseling/testing would provide additional information to an ovarian cancer patient. While providers emphasized that genetic testing results were useful for informing a patient's personal treatment plan, patients emphasized that this knowledge would be beneficial for their family members. CONCLUSION: Barriers to genetic testing for ovarian cancer patients exist at multiple levels, including the patient (e.g., knowledge, attitudes), the provider (e.g., workload, availability of services), the institution (e.g., difficulty with referrals/scheduling), and the healthcare system (e.g., insurance/cost). Interventions aiming to increase genetic testing among ovarian cancer patients will likely need to target multiple levels of influence. Future quantitative studies are needed to replicate these results. This line of work will inform specific multilevel intervention strategies that are adaptable to different practice settings, ultimately improving guideline concordant care.

Prediagnosis and postdiagnosis smoking and survival following diagnosis with ovarian cancer.

Little is known about the influence of prediagnosis and postdiagnosis smoking and smoking cessation on ovarian cancer survival. We investigated this relationship in two prospective cohort studies, the Nurses' Health Study (NHS) and NHSII. Analyses included 1,279 women with confirmed invasive, Stage I-III epithelial ovarian cancer. We used Cox proportional hazards regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for ovarian cancer-specific mortality by smoking status, adjusting for age and year of diagnosis, tumor stage, histologic subtype, body mass index and nonsteroidal anti-inflammatory use (postdiagnosis models only). When examining prediagnosis smoking status (assessed a median of 12 months before diagnosis), risk of death was significantly increased for former smokers (HR = 1.19, 95% CI: 1.02-1.39), and suggestively for current smokers (HR = 1.21, 95% CI: 0.96-1.51) vs. never smokers. Longer smoking duration (≥20 years vs. never, HR = 1.23, 95% CI: 1.05-1.45) and higher pack-years (≥20 pack-years vs. never, HR = 1.28, 95% CI: 1.07-1.52) were also associated with worse outcome. With respect to postdiagnosis exposure, women who smoked ≥15 cigarettes per day after diagnosis (assessed a median of 11 months after diagnosis) had increased mortality compared to never smokers (HR = 2.34, 95% CI: 1.63-3.37). Those who continued smoking after diagnosis had 40% higher mortality (HR = 1.40, 95% CI: 1.05-1.87) compared to never smokers. Overall, our results suggest both prediagnosis and postdiagnosis smoking are associated with worse ovarian cancer outcomes.

Genome-Wide Association Study for Urinary and Fecal Incontinence in Women.

PURPOSE: Urinary incontinence and fecal incontinence are common disorders in women that negatively impact quality of life. In addition to known health and lifestyle risk factors, genetics may have a role in continence. Identification of genetic variants associated with urinary incontinence and fecal incontinence could result in a better understanding of etiologic pathways, and new interventions and treatments. MATERIALS AND METHODS: We previously generated genome-wide single nucleotide polymorphism data from Nurses' Health Studies participants. The participants provided longitudinal urinary incontinence and fecal incontinence information via questionnaires. Cases of urinary incontinence (6,120) had at least weekly urinary incontinence reported on a majority of questionnaires (3 or 4 across 12 to 16 years) while controls (4,811) consistently had little to no urinary incontinence reported. We classified cases of urinary incontinence in women into stress (1,809), urgency (1,942) and mixed (2,036) subtypes. Cases of fecal incontinence (4,247) had at least monthly fecal incontinence reported on a majority of questionnaires while controls (11,634) consistently had no fecal incontinence reported. We performed a genome-wide association study for each incontinence outcome. RESULTS: We identified 8 single nucleotide polymorphisms significantly associated (p <5×10-8) with urinary incontinence located in 2 loci, chromosomes 8q23.3 and 1p32.2. There were no genome-wide significant findings for the urinary incontinence subtype analyses. However, the significant associations for overall urinary incontinence were stronger for the urgency and mixed subtypes than for stress. While no single nucleotide polymorphism reached genome-wide significance for fecal incontinence, 4 single nucleotide polymorphisms had p <10-6. CONCLUSIONS: Few studies have collected genetic data and detailed urinary incontinence and fecal incontinence information. This genome-wide association study provides initial evidence of genetic associations for urinary incontinence and merits further research to replicate our findings and identify additional risk variants.

Patterns and predictors of genetic referral among ovarian cancer patients at a National Cancer Institute-Comprehensive Cancer Center.

Germline mutations (eg, BRCA1/2) have prognostic and treatment implications for ovarian cancer (OVCA) patients. Thus, national guidelines recommend genetic testing for OVCA patients. The present study examines patterns and predictors of genetics referral in OVCA patients. Electronic medical record data were abstracted retrospectively from 557 OVCA patients treated from 1 January 2001 to 31 December 2015. Logistic regression models identified sociodemographic characteristics, disease/treatment characteristics, family history data, provider characteristics, and survival data that predicted genetics referral. Overall, 27.5% of patients received referral. Eleven variables predicting referral were selected during stepwise regression: younger age, White race, not having private insurance, professional school education, year of OVCA diagnosis, platinum sensitivity, female gynecologic oncologist, chemotherapy administered by a gynecologic oncologist, clinical trial enrollment, longer overall survival, and family history of OVCA. Genetics referral among OVCA patients was similar to rates reported nationwide. Unique predictive factors will contribute to quality improvement and should be validated at a multi-institutional level to ensure guideline concordant care is provided to all OVCA patients. Future research should identify both patient-level and provider-level factors associated with genetics referral.

Predictors of survival trajectories among women with epithelial ovarian cancer.

OBJECTIVE: Although ovarian cancer is a deadly disease, approximately a third of women survive ≥9 years after diagnosis. The factors associated with achieving long-term survival are not well understood. In this study, data from the Surveillance, Epidemiology, and End Results (SEER) program were used to determine predictors of survival trajectories among women with epithelial ovarian cancer and across histotype (high-grade serous carcinoma (HGSC) and non-HGSC). METHODS: Data on 35,868 women diagnosed with epithelial ovarian cancer in 2004-2016 were extracted from SEER. Extended Cox proportional hazards regression was used to estimate overall and histotype-specific associations between patient and tumor characteristics and all-cause mortality within each survival time (t) interval (t < 3, 3 ≤ t < 6, 6 ≤ t < 9, and 9 ≤ t < 13 years). RESULTS: Age at diagnosis, marital status, race/ethnicity, stage, and surgery were more strongly associated with mortality in the short-term survival period, and these associations waned with increasing survival time. Exceptions to this pattern were age >70 years at diagnosis, where a high risk of mortality was observed in both the t < 3 and t ≥ 9 year time periods, and non-Hispanic Asian/Pacific Islanders, where a more pronounced inverse association with mortality was observed in t ≥ 9 years after diagnosis. Similar associations were observed for HGSC, although the waning effect was not apparent for most characteristics. Mortality associations for non-HGSC were more pronounced for stage and race/ethnicity, primarily for non-Hispanic Asian/Pacific Islanders. CONCLUSIONS: Most patient and tumor characteristics were more strongly associated with mortality in the years following diagnosis, but have declining impact with increasing survival time. Given this waning effect, it is critical to identify factors impacting risk of mortality as ovarian cancer patients advance through the survival trajectory.

Ovarian cancer risk factors by tumor aggressiveness: An analysis from the Ovarian Cancer Cohort Consortium.

Ovarian cancer risk factors differ by histotype; however, within subtype, there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in <1 year, n = 864), very aggressive (death in 1 to < 3 years, n = 1,390), moderately aggressive (death in 3 to < 5 years, n = 639), and less aggressive (lived 5+ years, n = 1,691). Using competing risks Cox proportional hazards regression, we assessed heterogeneity of associations by tumor aggressiveness for all cases and among serous and endometrioid/clear cell tumors. Associations between parity (phet = 0.01), family history of ovarian cancer (phet = 0.02), body mass index (BMI; phet ≤ 0.04) and smoking (phet < 0.01) and ovarian cancer risk differed by aggressiveness. A first/single pregnancy, relative to nulliparity, was inversely associated with highly aggressive disease (HR: 0.72; 95% CI [0.58-0.88]), no association was observed for subsequent pregnancies (per pregnancy, 0.97 [0.92-1.02]). In contrast, first and subsequent pregnancies were similarly associated with less aggressive disease (0.87 for both). Family history of ovarian cancer was only associated with risk of less aggressive disease (1.94 [1.47-2.55]). High BMI (≥35 vs. 20 to < 25 kg/m2 , 1.93 [1.46-2.56] and current smoking (vs. never, 1.30 [1.07-1.57]) were associated with increased risk of highly aggressive disease. Results were similar within histotypes. Ovarian cancer risk factors may be directly associated with subtypes defined by tumor aggressiveness, rather than through differential effects on histology. Studies to assess biological pathways are warranted.

Identification of Plasma Lipid Metabolites Associated with Nut Consumption in US Men and Women.

BACKGROUND: Intake of nuts has been inversely associated with risk of type 2 diabetes and cardiovascular disease, partly through inducing a healthy lipid profile. How nut intake may affect lipid metabolites remains unclear. OBJECTIVE: The aim of this study was to identify the plasma lipid metabolites associated with habitual nut consumption in US men and women. METHODS: We analyzed cross-sectional data from 1099 participants in the Nurses' Health Study (NHS), NHS II, and Health Professionals Follow-up Study. Metabolic profiling was conducted on plasma by LC-mass spectrometry. Nut intake was estimated from food-frequency questionnaires. We included 144 known lipid metabolites that had CVs ≤25%. Multivariate linear regression was used to assess the associations of nut consumption with individual plasma lipid metabolites. RESULTS: We identified 17 lipid metabolites that were significantly associated with nut intake, based on a 1 serving (28 g)/d increment in multivariate models [false discovery rate (FDR) P value <0.05]. Among these species, 8 were positively associated with nut intake [C24:0 sphingomyelin (SM), C36:3 phosphatidylcholine (PC) plasmalogen-A, C36:2 PC plasmalogen, C24:0 ceramide, C36:1 PC plasmalogen, C22:0 SM, C34:1 PC plasmalogen, and C36:2 phosphatidylethanolamine plasmalogen], with changes in relative metabolite level (expressed in number of SDs on the log scale) ranging from 0.36 to 0.46 for 1 serving/d of nuts. The other 9 metabolites were inversely associated with nut intake with changes in relative metabolite level ranging from -0.34 to -0.44. In stratified analysis, 3 metabolites were positively associated with both peanuts and peanut butter (C24:0 SM, C24:0 ceramide, and C22:0 SM), whereas 6 metabolites were inversely associated with other nuts (FDR P value <0.05). CONCLUSIONS: A panel of lipid metabolites was associated with intake of nuts, which may provide insight into biological mechanisms underlying associations between nuts and cardiometabolic health. Metabolites that were positively associated with intake of nuts may be helpful in identifying potential biomarkers of nut intake.

Body mass index throughout adulthood, physical activity, and risk of multiple myeloma: a prospective analysis in three large cohorts.

BACKGROUND: Obesity is the only known modifiable multiple myeloma (MM) risk factor. However, the influence of obesity in earlier or later adulthood and the role of other energy balance correlates in MM development are unclear. METHODS: We leveraged repeatedly updated data from the Nurses' Health Study, Health Professionals Follow-up Study, and Women's Health Study cohorts to further explore energy balance measures in MM etiology. Exposures derived from questionnaires included young adult body mass index (BMI), cumulative average BMI, BMI change since young adulthood, and cumulative average physical activity and walking. We assessed MM risk related to those variables with Cox proportional hazard models. RESULTS: We observed 575 incident MM cases in over five million person-years of follow-up across the cohorts. In pooled analyses, MM risk increased 17% per 5 kg/m2 increase in cumulative average BMI (95% confidence interval (CI): 1.05, 1.29) and 28% per 5 kg/m2 increase in young adult BMI (CI: 1.12, 1.47); adjustment for BMI change since young adulthood did not affect either association. BMI change since young adulthood and cumulative average physical activity and walking were not significantly associated with MM risk. CONCLUSIONS: These findings suggest that a high BMI in early and later adulthood are risk factors for MM.

Menopausal Hormone Therapy Is Associated With Increased Risk of Fecal Incontinence in Women After Menopause.

BACKGROUND & AIMS: Low estrogen levels can contribute to development of fecal incontinence (FI) in women after menopause by altering neuromuscular continence mechanisms. However, studies have produced conflicting results on the association between menopausal hormone therapy (MHT) and risk of FI. METHODS: We studied the association between MHT and risk of FI among 55,828 postmenopausal women (mean age, 73 years) who participated in the Nurses' Health Study, were enrolled since 2008, and with no report of FI. We defined incident FI as a report of at least 1 liquid or solid FI episode per month during 4 years of follow-up from self-administered, biennial questionnaires administered in 2010 and 2012. We used Cox proportional hazard models to calculate multivariate-adjusted hazard ratios and 95% confidence intervals (CIs) for FI risk in women receiving MHT, adjusting for potential confounding factors. RESULTS: During more than 185,000 person-years of follow-up, there were 6834 cases of incident FI. Compared with women who never used MHT, the multivariate hazard ratio for FI was 1.26 (95% CI, 1.18-1.34) for past users of MHT and 1.32 (95% CI, 1.20-1.45) for current users. The risk of FI increased with longer duration of MHT use (P trend ≤ .0001) and decreased with time since discontinuation. There was an increased risk of FI among women receiving MHT that contained a combination of estrogen and progestin (hazard ratio, 1.37; 95% CI, 1.10-1.70) compared with estrogen monotherapy. CONCLUSIONS: Current or past use of MHT was associated with a modestly increased risk of FI among postmenopausal women in the Nurses' Health Study. These results support a potential role for exogenous estrogens in the impairment of the fecal continence mechanism.

Surgical prevention strategies in ovarian cancer.

Given the current lack of effective screening for ovarian cancer, surgical removal of at-risk tissue is the most successful strategy to decrease risk of cancer development. However, the optimal timing of surgery and tissues to remove, as well as the appropriate patients to undergo preventive procedures are poorly understood. In this review, we first discuss the origin and precursors of ovarian epithelial carcinomas, focusing on high-grade serous carcinomas and endometriosis-associated carcinomas, which cause the majority of the mortality and incidence of ovarian cancer. In addition, we summarize the implications of current understanding of specific pathogenic origins for surgical prevention and remaining gaps in knowledge. Secondly, we review evidence from the epidemiologic literature on the associations of various surgical prevention strategies, including endometriosis excision, tubal procedures, and bilateral salpingo-oophorectomy, with risk of future ovarian cancer development, as well as the short- and long-term consequences of these strategies on women's health and quality and life. We conclude with recommendations for surgical prevention in women with high-risk genetic mutations and average-risk women, and a brief discussion of ongoing research that will help clarify optimal surgical approaches that balance risk-reduction with maintenance of women's quality of life.

A prospective study of the natural history of urinary incontinence in women.

BACKGROUND: Symptoms of urinary incontinence are commonly perceived to vary over time; yet, there is limited quantitative evidence regarding the natural history of urinary incontinence, especially over the long term. OBJECTIVE: We sought to delineate the course of urinary incontinence symptoms over time, using 2 large cohorts of middle-aged and older women, with data collected over 10 years. STUDY DESIGN: We studied 9376 women from the Nurses' Health Study, age 56-81 years at baseline, and 7491 women from the Nurses' Health Study II, age 39-56 years, with incident urinary incontinence in 2002 through 2003. Urinary incontinence severity was measured by the Sandvik severity index. We tracked persistence, progression, remission, and improvement of symptoms over 10 years. We also examined risk factors for urinary incontinence progression using logistic regression models. RESULTS: Among women age 39-56 years, 39% had slight, 45% had moderate, and 17% had severe urinary incontinence at onset. Among women age 56-81 years, 34% had slight, 45% had moderate, and 21% had severe urinary incontinence at onset. Across ages, most women reported persistence or progression of symptoms over follow-up; few (3-11%) reported remission. However, younger women and women with less severe urinary incontinence at onset were more likely to report remission or improvement of symptoms. We found that increasing age was associated with higher odds of progression only among older women (age 75-81 vs 56-60 years; odds ratio, 1.84; 95% confidence interval, 1.51-2.25). Among all women, higher body mass index was strongly associated with progression (younger women: odds ratio, 2.37; 95% confidence interval, 2.00-2.81; body mass index ≥30 vs <25 kg/m2; older women: odds ratio, 1.93; 95% confidence interval, 1.62-2.22). Additionally, greater physical activity was associated with lower odds of progression to severe urinary incontinence (younger women: odds ratio, 0.86; 95% confidence interval, 0.71-1.03; highest vs lowest quartile of activity; older women: odds ratio, 0.68; 95% confidence interval, 0.59-0.80). CONCLUSION: Most women with incident urinary incontinence continued to experience symptoms over 10 years; few had complete remission. Identification of risk factors for urinary incontinence progression, such as body mass index and physical activity, could be important for reducing symptoms over time.