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Funder: Funding details are provided in the Supplementary Material, Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally-efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, ���select and shrink for summary statistics��� (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestry; 7,669 women of East Asian ancestry; 1,072 women of African ancestry, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestry. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38(95%CI:1.28���1.48,AUC:0.588) per unit standard deviation, in women of European ancestry; 1.14(95%CI:1.08���1.19,AUC:0.538) in women of East Asian ancestry; 1.38(95%CI:1.21-1.58,AUC:0.593) in women of African ancestry; hazard ratios of 1.37(95%CI:1.30���1.44,AUC:0.592) in BRCA1 pathogenic variant carriers and 1.51(95%CI:1.36-1.67,AUC:0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

Prenatal diethylstilbestrol (DES) exposure is associated with increased risk of hormonally mediated cancers and other medical conditions. We evaluated the association between DES and risk of pancreatic cancer and pancreatic disorders, type 2 diabetes, and gallbladder disease, which may be involved with this malignancy. Our analyses used follow-up data from the US National Cancer Institute DES Combined Cohort Study. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for age, sex, cohort, body mass index, smoking, and alcohol for the association between prenatal DES exposure and type 2 diabetes, gallbladder disease (mainly cholelithiasis), pancreatic disorders (mainly pancreatitis), and pancreatic cancer among 5667 exposed and 3315 unexposed individuals followed from 1990 to 2017. Standardized incidence rate (SIR) ratios for pancreatic cancer were based on age-, race-, and calendar year-specific general population cancer incidence rates. In women and men combined, the hazards for total pancreatic disorders and pancreatitis were greater in the prenatally DES exposed than the unexposed (HR = 11, 95% CI 2.6–51 and HR = 7.0, 95% CI 1.5–33, respectively). DES was not associated overall with gallbladder disease (HR = 1.2, 95% CI 0.88–1.5) or diabetes (HR = 1.1, 95% CI 0.9–1.2). In women, but not in men, DES exposure was associated with increased risk of pancreatic cancer compared with the unexposed (HR: 4.1, 95% CI 0.84–20) or general population (SIR: 1.9, 95% CI 1.0–3.2). Prenatal DES exposure may increase the risk of pancreatic disorders, including pancreatitis in women and men. The data suggested elevated pancreatic cancer risk in DES-exposed women, but not in exposed men.

Endometriosis is a common gynecologic disease defined by the presence of endometrial-like tissue outside the uterine cavity. While its etiology is largely unknown, accumulating evidence suggests that inflammation plays a major role. Our objective was to investigate the association between peripheral blood leukocyte telomere length (LTL) and endometriosis using data from two large population-based studies, the New England Case-Control Study (NEC; n = 877) and the National Health and Nutrition Examination Survey (NHANES; n = 2268). NEC control participants were identified through a combination of random digit dialing, drivers’ license lists, and town resident lists. In NHANES, selection algorithms were used to identify a nationally representative sample. Blood samples and demographic, reproductive, and health-related information were available from both data sources. Endometriosis was defined as self-reported of physician-diagnosed endometriosis. LTL was measured using quantitative polymerase chain reaction. Multivariable logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for the association between LTL and endometriosis. Shorter LTL was associated with greater odds of history of endometriosis. In NEC, women with the shortest LTL tertile compared with the longest had a 2.5-fold greater odds of endometriosis (ORT3/T1 = 2.56, 95% CI = 1.16–5.63; p value, test for linear trend = 0.02). The association was stronger among women who usually experienced moderate or severe menstrual pain (OR T3/T1 = 3.50, 95% CI = 1.12–10.97). In NHANES, the data suggested a similar but attenuated association (ORT3/T1 = 1.29, 95% CI = 0.85–1.96). The observed associations in NEC suggest that shorter LTL may be associated with greater odds of endometriosis. A better understanding of how LTL influences endometriosis risk could elucidate novel disease pathophysiology.

Objective: To evaluate the associations between 10 well-established ovarian cancer risk factors and risk of ovarian cancer among women with vs. without endometriosis. Design: Pooled analysis of 9 case-control studies in the Ovarian Cancer Association Consortium. Setting: Population-based. Patient(s): We included 8,500 women with ovarian cancer, 13,592 control women. Intervention(s): Ten well-established ovarian cancer risk factors. Main Outcome Measure(s): Risk of ovarian cancer for women with and without endometriosis. Result(s): Most risk factor-ovarian cancer associations were similar when comparing women with and without endometriosis, and no interactions were statistically significant. However, body mass index (BMI) 25–2 was associated with increased ovarian cancer risk among women with endometriosis (odds ratio [OR] = 1.27, 95% confidence interval [CI] 1.00–1.60), but not associated with the risk among women without endometriosis (OR = 0.97; 95% CI, 0.91–1.05) when compared with BMI 18.5–2; an increased risk was observed for a BMI ≥30 kg/m2, although there was little difference comparing women with endometriosis (OR = 1.21; 95% CI, 0.94–1.57) to women without (OR = 1.13; 95% CI, 1.04–1.22) (P-interaction = .51). Genital talcum powder use and long-term menopausal estrogen-only therapy use showed increased ovarian cancer risk, but risk appeared greater for those with endometriosis vs. those without (genital talcum powder: OR = 1.38; 95% CI, 1.04–1.84 vs. OR = 1.12; 95% CI, 1.01–1.25, respectively; ≥10 years of estrogen-only therapy: OR = 1.88; 95% CI, 1.09–3.24 vs. OR = 1.42; 95% CI, 1.14–1.76, respectively); neither of these interactions were statistically significant (P-interaction = .65 and P-interaction = .96, respectively). Conclusion(s): The associations between ovarian cancer and most risk factors were similar among women with and without endometriosis. However, there was some suggestion of differences by endometriosis status for BMI, menopausal hormone therapy use, and genital talcum powder use, highlighting the complexity of ovarian cancer etiology.

Contains fulltext : 237689.pdf (Publisher’s version ) (Open Access) Familial, sequencing, and genome-wide association studies (GWASs) and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWASs) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through application of a pleiotropy-guided conditional/conjunction false discovery rate (FDR) approach in the setting of a TWASs. This identified 14 candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR < 0.05 that were >1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. The 22 genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk.

Background: Douching is associated with disorders involving genital tract inflammation and genital talc use with epithelial ovarian cancer (EOC), but their joint effects are infrequently considered. Methods: From 2,040 cases of EOC and 2,100 controls enrolled in eastern Massachusetts and New Hampshire, we used unconditional logistic regression to estimate risk for EOC associated with douching and/or talc use. In subsets of cases and controls, we also collected information about pelvic inflammatory disease (PID), ectopic pregnancy, and cervical neoplasia to estimate risk for these events from douching and/or talc use. Results: The adjusted OR and 95% confidence interval (CI) for all EOC was 0.94 (0.76–1.16) in women who douched but never used talc and 1.28 (1.09–1.51) in women who used talc but never douched. Compared with women who never regularly douched or used talc, ORs (95% CIs) were 0.83 (0.52–1.33) for women who both used talc and homemade douches and 1.53 (1.11–2.10) for women who both used talc and store-bought douches. Cases who both douched and used talc were more likely to have had PID compared with cases who had used neither [OR = 5.03 (95% CI, 1.61–15.7)]. Conclusions: Douching is not an independent risk factor for ovarian cancer, but the combination of talc use and store-bought douches may modestly increase the risk for EOC beyond that for talc use alone. Impact: The joint effect of talc use and douching, especially with commercial products, should be considered in evaluating risks associated with disorders involving genital tract inflammation or EOC.

INTRODUCTION: Fast food (FF) advertising is a potential risk factor for FF consumption among children, yet the impact of such advertising on children’s FF intake has not been assessed in a longitudinal, naturalistic study. Whether parents’ FF consumption mitigates advertising effects is also unknown. METHODS: One-year, longitudinal study among 624 preschool-age children, 3–5 years old, and one parent each recruited from New Hampshire, 2014–2015. Parents completed six online surveys every eight weeks and, at each, reported the number of times their children consumed FF in the past week. Each child’s advertisement exposure was determined by counting the brand-specific FF advertisements aired within the programs they viewed on children’s TV networks during the study. At baseline, parents reported the frequency of their own FF consumption. Data were analyzed in 2017–2018. RESULTS: Three FF brands targeted TV advertising to children during the study: McDonald’s, Wendy’s and Subway. Few children were exposed to child-targeted advertising for Wendy’s or Subway. Results from adjusted Poisson regression models focused on McDonald’s showed a differential effect of advertisement exposure on children’s McDonald’s intake in the past week (any or mean intake) by parental FF consumption (P

Background: Randomized trials using the biomarker cancer antigen (CA) 125, with or without pelvic ultrasound, have failed to show a clear benefit of general population screening for ovarian cancer. In part, this may be due to a lack of information about conditions, besides ovarian cancer, that can alter CA125 levels and affect specificity or sensitivity. We evaluated the association between common medical conditions and CA125 levels among women without ovarian cancer. Methods: We used data and specimens from 2,004 women without ovarian cancer who participated in the New England Case Control study between 1992 and 2008. Participants completed in-person interviews and donated blood samples at enrollment. We measured CA125 using the CA125II assay and calculated the association between medical conditions and log-transformed CA125 using linear regression. Results: The median age of participants was 53 years and 1,119 (56%) were postmenopausal. The average CA125 level was 14.5 units/mL for premenopausal and 11.7 for postmenopausal women. Among premenopausal women, CA125 was significantly lower for women with colon polyps (P = 0.06) and hysterectomy (P = 0.01) and significantly higher with endometriosis (P = 0.05). CA125 was also significantly higher in premenopausal women with coronary artery disease (CVD) (P < 0.01, n = 2 cases) but not among postmenopausal with CVD (n = 79). Furthermore, among postmenopausal women, CA125 was significantly lower for women with osteoporosis, hypercholesterolemia, and osteoarthritis (P = 0.03, 0.02, and 0.01 respectively) and higher for women with a history of inflammatory bowel disease (P = 0.04). Conclusions: Several chronic diseases are associated with CA125, which could influence the interpretation of CA125 in the context of ovarian cancer screening. Impact: Consideration of chronic medical conditions may be necessary to interpret CA125 values.

We report a meta-analysis of breast, prostate, ovarian, and endometrial cancer genome-wide association data (effective sample size: 237,483 cases/317,006 controls). This identified 465 independent lead variants (P−8) across 192 genomic regions. Four lead variants were >1Mb from previously identified risk loci for the four cancers and an additional 23 lead variant-cancer associations were novel for one of the cancers. Bayesian models supported pleiotropic effects involving at least two cancers at 222/465 lead variants in 118/192 regions. Gene-level association analysis identified 13 shared susceptibility genes (P−6) in 13 regions not previously implicated in any of the four cancers and not uncovered by our variant-level meta-analysis. Several lead variants had opposite effects across cancers, including a cluster of such variants in the TP53 pathway. Fifty-four lead variants were associated with blood cell traits and suggested genetic overlaps with clonal hematopoiesis. Our study highlights the remarkable pervasiveness of pleiotropy across hormone-related cancers, further illuminating their shared genetic and mechanistic origins at variant- and gene-level resolution.

Accumulating evidence suggests a relationship between endometrial cancer and epithelial ovarian cancer. For example, endometrial cancer and epithelial ovarian cancer share epidemiological risk factors and molecular features observed across histotypes are held in common (e.g. serous, endometrioid and clear cell). Independent genome-wide association studies (GWAS) for endometrial cancer and epithelial ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. Using GWAS summary statistics, we explored the shared genetic etiology between endometrial cancer and epithelial ovarian cancer. Genetic correlation analysis using LD Score regression revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10−5). To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e. inverse-variance meta-analysis, co-localization, and M-values), and performed analyses by stratified by subtype. We found seven loci associated with risk for both cancers (PBonferroni < 2.4 × 10−9). In addition, four novel regions at 7p22.2, 7q22.1, 9p12 and 11q13.3 were identified at a sub-genome wide threshold (P < 5 × 10−7). Integration with promoter-associated HiChIP chromatin loops from immortalized endometrium and epithelial ovarian cell lines, and expression quantitative trait loci (eQTL) data highlighted candidate target genes for further investigation.

Background Fast food is cross-sectionally associated with having overweight and obesity in young children. Objectives To examine whether fast food intake independently contributes to the development of overweight and obesity among preschool-age children. Methods Prospective cohort of 3- to 5-year-old children (n = 541) followed for 1 year. Children's height and weight were objectively measured at baseline and study end. Parents reported their child's fast food intake frequency in the past week from 11 chain fast food restaurants in six online follow-up surveys, completed approximately 8 weeks apart. Poisson regression with robust standard errors modelled the risk of a child increasing in weight status (ie, transitioning from a having a healthy weight to having overweight or from having overweight to having obesity) over the study period in relation to their average weekly fast food intake, adjusted for sociodemographics, child obesogenic behaviours, and parent weight status. Results At baseline, 18.1% of children had overweight and 9.8% had obesity; 8.1% of children transitioned to a greater weight status over the 1-year period. Mean fast food intake frequency among consumers was 2.1 (SD: 1.4) times per week. The risk of increasing in weight status increased linearly with each additional time fast food was consumed in an average week over the study year (RR: 1.38; 95% CI, 1.13-1.67; P Conclusions Greater fast food intake over 1 year was associated with increasing weight status during that time in this preschool-age cohort.

Statins are widely used to lower blood cholesterol and reduce risk for cardiovascular diseases, but attention has recently focused on a role in cancer prevention or therapy. Here we present data from a large case-control study addressing whether statin use can lower the risk for epithelial ovarian cancer (EOC). Between 1992 and 2008, data including medications used for at least 6 months were collected from 2,040 cases with EOC and 2,100 frequency-matched controls without the disease who participated in the New England Case Control study. We used unconditional logistic regression controlling for matching factors and potential confounders to examine the association between statin use and the risk for EOC. Overall, women who used statins had 32% lower risk of ovarian cancer compared to non-users (Odds ratio (OR) 0.68, 95% Confidence Interval (CI): 0.54-0.85), adjusting for the matching factors and other covariates. The reduced risk was most apparent in women taking a lipophilic statin who began use after age 49, and who had used them 2-4.9 years. Statin use was associated with lower risks for both serous and non-serous histologic subtypes with the strongest effect seen for mucinous and mixed epithelial subtypes. The association became apparent about a decade after the introduction of statins and did not appear to be confounded by indications for use of statins or medications used concomitantly. In this case-control study, statins were found to lower the risk for both serous and non-serous EOC and especially mucinous EOC.

Importance Diagnostic variation among pathologists interpreting cutaneous melanocytic lesions could lead to suboptimal care. Objective To estimate the potential association of second-opinion strategies in the histopathologic diagnosis of cutaneous melanocytic lesions with diagnostic accuracy and 1-year population-level costs in the US. Design, Setting, and Participants Decision analysis with 1-year time horizon including melanocytic lesion diagnoses available from US pathologists participating in the Melanoma Pathology Study (M-Path) and from the study panel of reference pathologists who classified cases using the MPATH-Dx classification tool. M-Path data collection occurred from July 2013 through March 2015; analyses for the present study were performed between April 2015 and January 2021. Exposures Various second-opinion strategies for interpretation of melanocytic cutaneous lesions. Main Outcomes and Measures Estimated accuracy of pathologists’ diagnoses, defined as concordance with the reference panel diagnoses, and 1-year postbiopsy medical costs under various second-opinion strategies. Expected percentage of concordant diagnoses, including percentages of overinterpretation and underinterpretation, and 1-year costs of medical care per 100 000 in the US population. Results Decision-analytic model parameters were based on diagnostic interpretations for 240 cases by 187 pathologists compared with reference panel diagnoses. Without second opinions, 83.2% of diagnoses in the US were estimated to be accurate—ie, concordant with the reference diagnosis; with overinterpretation (8.0%) or underinterpretation (8.8%), and 16 850 misclassified diagnoses per 100 000 biopsies. Accuracy increased under all second-opinion strategies. Accuracy (87.4% concordance with 3.6% overinterpretation and 9.1% underinterpretation) and cost (an increase of more than $10 million per 100 000 biopsies per year) were highest when second opinions were universal (eg, performed on all biopsies), relative to no second opinions. A selective second-opinion strategy based on pathologists’ desire or institutional requirements for a second opinion was most accurate (86.5% concordance; 4.4% overinterpretation; 9.1% underinterpretation) and would reduce costs by more than $1.9 million per 100 000 skin biopsies relative to no second opinions. Improvements in diagnostic accuracy with all second-opinion strategies were associated with reductions in overinterpretation but not underinterpretation. Conclusions and Relevance In this decision-analytic model, selective second-opinion strategies for interpretation of melanocytic skin lesions showed the potential to improve diagnostic accuracy and decrease costs relative to no second opinions or universal second opinions.

Background: Ovarian cancer is a deadly gynecologic cancer, accounting for approximately 14,000 deaths in the US annually. Lack of early detection modalities leads to advanced stage diagnosis with poorer prognosis. Cancer antigen 125 (CA125) is the most promising single biomarker for ovarian cancer screening. However, two large randomized screening trials comparing the combination of CA125 and transvaginal ultrasound to usual care did not show significant improvement in overall survival. Here, we examined whether using predicted personal CA125 cutpoints based on individual characteristics in postmenopausal women would improve discrimination of epithelial ovarian cancer cases from controls better than using a fixed cutpoint of 35 U/mL. Method: We first determined the effect estimates needed to calculate the predicted 90th and 95th percentile cutpoint of blood CA125 values for each individual using quantile regression model including validated predictors of CA125 (i.e. age, race, body-mass index, smoking status, parity, hysterectomy, age at last menstrual period, and duration of hormone therapy) using data on 28,998 women without ovarian cancer from Prostate Lung Colon and Ovarian Cancer Screening study (PLCO), European Prospective Investigation into Nutrition and Cancer (EPIC), Nurses' Health Studies (NHS/NHSII), and the New England Case Control Study. Then, we examined whether personalized cutpoints performed better than the fixed cutpoint of 35 U/mL in discriminating ovarian cancer cases from controls overall and by time between blood draw to clinical diagnosis using data on 581 incident ovarian cancer cases with CA125 measured up to 24 months prior to clinical diagnosis and 28,226 controls from PLCO, EPIC, and NHS/NHSII. Results: We observed that use of personalized CA125 cutpoints showed improved reclassification of ovarian cancer cases and controls compared to using the fixed cutpoint of 35 U/mL in blood CA125 measured 6 to 12 months prior to diagnosis with net reclassification improvement of 15% using the 90th percentile cutpoint and 12% using the 95th percentile cutpoint. The net reclassification improvement decreased as time between blood draw to clinical diagnosis increased. Conclusion: Our results suggest that redefining the upper limit of normal CA125 values using personalized cutpoints has the potential to modestly improve the performance of CA125 in ovarian cancer screening among average risk postmenopausal women. Citation Format: Naoko Sasamoto, Bernard A. Rosner, Renée T. Fortner, Britton Trabert, Allison F. Vitonis, Stephanie Nartey, Raina N. Fichorova, Linda J. Titus, Daniel W. Cramer, Nicolas Wentzensen, Shelley S. Tworoger, Rudolf Kaaks, Kathryn L. Terry. Personalized cutpoints of CA125 to improve early detection of ovarian cancer in postmenopausal women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 888.

Purpose: Prenatal exposure to diethylstilbestrol (DES), a prototype endocrine-disrupting chemical, is associated with risk for adverse reproductive outcomes and cancer in women. We investigated whether cardiovascular disease (CVD) risk might also be greater in women prenatally exposed to DES. Methods: DES-exposed (n = 3941) and -unexposed (n = 1705) women participating in the Combined DES Cohort Follow-up Study were followed prospectively from 1994 to 2013. Prenatal DES exposure (or lack of exposure) was documented in the birth record or physician’s note. Participants reported by questionnaire any “serious medical conditions requiring hospitalization, surgery or long-term treatment,” including coronary artery disease (CAD), myocardial infarction (MI), and stroke. We sought physician’s verification of self-reports and identified CVD deaths from the National Death Index. Hazard ratios (HRs) with 95% confidence intervals (CIs) from Cox proportional hazard regression models estimated associations between DES exposure and CVD incidence, adjusted for birth year, original cohort, and potential confounders. Results: In comparison of the exposed to the unexposed women, the HRs for reported conditions were 1.74 (95% CI, 1.03 to 2.93) for CAD, 2.20 (95% CI, 1.15 to 4.21) for MI, 1.01 (95% CI, 0.54 to 1.90) for stroke, and 1.31 (95% CI, 0.93 to 1.86) for the combined conditions (i.e., total CVD). The HRs were similar for verified outcomes (CAD, 1.72; MI, 2.67; stroke, 0.92; and total CVD, 1.25) and with additional adjustment for hypertension, diabetes, and high cholesterol (HRs: CAD, 1.67; MI, 2.04; stroke, 0.96; and total CVD, 1.24). Conclusions: These data demonstrate associations in women who have prenatal DES exposure with CAD and MI, but not with stroke, which appear to be independent of established CVD risk factors., Risks for CAD and MI were greater in women prenatally exposed to DES, a prototype endocrine disruptor, than in unexposed women.

Menstrual pain, a common gynecological condition, has been associated with increased risk of ovarian cancer in some, but not all studies. Furthermore, potential variations in the association between menstrual pain and ovarian cancer by histologic subtype have not been adequately evaluated due to lack of power. We assessed menstrual pain using either direct questions about having experienced menstrual pain, or indirect questions about menstrual pain as indication for use of hormones or medications. We used multivariate logistic regression to calculate the odds ratio (OR) for the association between severe menstrual pain and ovarian cancer, adjusting for potential confounders, and multinomial logistic regression to calculate odds ratios for specific histologic subtypes. We observed no association between ovarian cancer and menstrual pain assessed by indirect questions. Among studies using direct question, severe pain was associated with a small but significant increase in overall risk of ovarian cancer (OR=1.07, 95% CI: 1.01-1.13), after adjusting for endometriosis and other potential confounders. The association appeared to be more relevant for clear cell (OR=1.48, 95% CI: 1.10-1.99) and serous borderline (OR=1.31, 95% CI: 1.05-1.63) subtypes. In this large international pooled analysis of case-control studies, we observed a small increase in risk of ovarian cancer for women reporting severe menstrual pain. While we observed an increased ovarian cancer risk with severe menstrual pain, the possibility of recall bias and undiagnosed endometriosis cannot be excluded. Future validation in prospective studies with detailed information on endometriosis is needed. This article is protected by copyright. All rights reserved.

ObjectiveTo determine whether exposure to child-targeted fast-food (FF) television (TV) advertising is associated with children’s FF intake in a non-experimental setting.DesignCross-sectional survey conducted April–December 2013. Parents reported their pre-school child’s TV viewing time, channels watched and past-week FF consumption. Responses were combined with a list of FF commercials (ads) aired on children’s TV channels during the same period to calculate children’s exposure to child-targeted TV ads for the following chain FF restaurants: McDonald’s, Subway and Wendy’s (MSW).SettingPaediatric and Women, Infants, and Children (WIC) clinics in New Hampshire, USA.SubjectsParents (n 548) with a child of pre-school age.ResultsChildren’s mean age was 4·4 years; 43·2 % ate MSW in the past week. Among the 40·8 % exposed to MSW ads, 23·3 % had low, 34·2 % moderate and 42·5 % high exposure. McDonald’s accounted for over 70 % of children’s MSW ad exposure and consumption. Children’s MSW consumption was significantly associated with their ad exposure, but not overall TV viewing time. After adjusting for demographics, socio-economic status and other screen time, moderate MSW ad exposure was associated with a 31 % (95 % CI 1·12, 1·53) increase and high MSW ad exposure with a 26 % (95 % CI 1·13, 1·41) increase in the likelihood of consuming MSW in the past week. Further adjustment for parent FF consumption did not change the findings substantially.ConclusionsExposure to child-targeted FF TV advertising is positively associated with FF consumption among children of pre-school age, highlighting the vulnerability of young children to persuasive advertising and supporting recommendations to limit child-directed FF marketing.

SummaryBackground Melanoma incidence has increased in recent decades in the U.S.A. Uncertainty remains regarding how much of this increase is attributable to greater melanoma screening activities, potential detection bias and overdiagnosis. Objectives To use a cross-sectional ecological analysis to evaluate the relationship between skin biopsy and melanoma incidence rates over a more recent time period than prior reports. Methods Examination of the association of biopsy rates and melanoma incidence (invasive and in situ) in SEER-Medicare data (including 10 states) for 2002–2009. Results The skin biopsy rate increased by approximately 50% (6% per year) throughout this 8-year period, from 7012 biopsies per 100 000 persons in 2002 to 10 528 biopsies per 100 000 persons in 2009. The overall melanoma incidence rate increased approximately 4% (< 1% per year) over the same time period. The incidence of melanoma in situ increased approximately 10% (1% per year), while the incidence of invasive melanoma increased from 2002 to 2005 then decreased from 2006 to 2009. Regression models estimated that, on average, for every 1000 skin biopsies performed, an additional 5·2 (95% confidence interval 4·1–6·3) cases of melanoma in situ were diagnosed and 8·1 (95% confidence interval 6·7–9·5) cases of invasive melanoma were diagnosed. When considering individual states, some demonstrated a positive association between biopsy rate and invasive melanoma incidence, others an inverse association, and still others a more complex pattern. Conclusions Increased skin biopsies over time are associated with increased diagnosis of in situ melanoma, but the association with invasive melanoma is more complex.

It is not known whether patient age or tumor characteristics such as tumor regression or solar elastosis influence pathologists’ interpretation of melanocytic skin lesions. We undertook a study to determine the influence of these factors, and to explore pathologist characteristics associated with the direction of diagnosis. To meet our objective, we designed a cross-sectional survey study of pathologists’ clinical practices and perceptions. Pathologists were recruited from diverse practices in ten states in the U.S. We enrolled 207 pathologist participants whose practice included the interpretation of melanocytic skin lesions. Our findings indicated that the majority of pathologists (54.6%) were influenced toward a less severe diagnosis when patients were 70 years of age, or by the presence of tumor regression or solar elastosis (58.6%, 71.0%, 57.0%, respectively). Generally, pathologists with dermatopathology board certification and/or a high caseload of melanocytic skin lesions were more likely to be influenced, while those with more years’ experience interpreting MSL were less likely to be influenced. Our findings indicate that the interpretation of melanocytic skin lesions is influenced by patient age, tumor regression, and solar elastosis; such influence is associated with dermatopathology training and higher caseload, consistent with expertise and an appreciation of lesion complexity.

Breakfast cereals represent the most highly advertised packaged food on child-targeted television, and most ads are for cereals high in sugar. This study examined whether children's TV exposure to child-targeted, high-sugar breakfast cereal (SBC) ads was associated with their consumption of those SBC brands. Parents of 3- to 5-year-old children were recruited from pediatric and Women, Infants, and Children (WIC) clinics in Southern New Hampshire, USA, and completed a cross-sectional survey between April-December 2013. Parents reported their child's consumption of SBC brands; whether their child had watched any of 11 kids' channels in the past week; their child's TV viewing time; and socio-demographics. Children's exposure to child-targeted SBC TV ads was calculated by combining TV channel and viewing time with advertising data for SBC ads aired on kids' TV channels during the same timeframe. Five hundred forty-eight parents completed surveys; 52.7% had an annual household income of $50,000 or less. Children's mean age was 4.4 years, 51.6% were female, and 72.5% were non-Hispanic white. In the past week, 56.9% (N = 312) of children ate SBCs advertised on kids' channels. Overall, 40.6% of children were exposed to child-targeted SBC TV ads in the past week. In fully adjusted analyses, the number of SBC brands children consumed was positively associated with their exposure to child-targeted SBC ads. Children consumed 14% (RR = 1.14, 95% CI: 1.02, 1.27) more SBC brands for every 10 SBC ads seen in the past 7 days. Exposure to child-targeted SBC TV advertising is positively associated with SBC brand consumption among preschool-aged children. These findings support recommendations to limit the marketing of high-sugar foods to young children.

Background Prenatal exposure to diethylstilbestrol (DES), an endocrine-disrupting chemical, may be associated with depression in adulthood, but previous findings are inconsistent. Methods Women (3,888 DES exposed and 1,729 unexposed) and men (1,021 DES exposed and 1,042 unexposed) participating in the National Cancer Institute (NCI) DES Combined Cohort Follow-up Study were queried in 2011 for any history of depression diagnosis or treatment. Hazard ratios (HRs; 95% confidence intervals [CIs]) estimated the associations between prenatal DES exposure and depression risk. Results Depression was reported by 993 (26%) exposed and 405 (23%) unexposed women, and 177 (17%) exposed and 181 (17%) unexposed men. Compared with the unexposed, HRs for DES and depression were 1.1 (95% CI = 0.9, 1.2) in women and 1.0 (95% CI = 0.8, 1.2) in men. For medication-treated depression, the HRs (CIs) were 1.1 (0.9, 1.2) in women and 0.9 (0.7, 1.2) in men. In women, the HR (CI) for exposure to a low cumulative DES dose was 1.2 (1.0, 1.4), and for DES exposure before 8 weeks' gestation was 1.2 (1.0, 1.4). In men, the HR for low dose was 1.2 (95% CI = 0.9, 1.6) and there was no association with timing. In women, associations were uninfluenced by the presence of DES-related vaginal epithelial changes or a prior diagnosis of DES-related adverse outcomes. Conclusions Prenatal DES exposure was not associated overall with risk of depression in women or men. In women, exposure in early gestation or to a low cumulative dose may be weakly associated with an increased depression risk.

We assessed the associations of prenatal diethylstilbestrol (DES) exposure, a potent estrogen, with sexual orientation and gender identity in 3306 women and 1848 men who participated in a study of prenatal DES exposure. Odds ratios (OR) and 95% confidence intervals (CI) were derived from logistic regression models adjusted for birth year, study cohort, and education. Among women, the OR for DES in relation to reporting sexual orientation identity as nonheterosexual was 0.61 (95% CI 0.40–0.92) primarily due to a strong inverse association with a lesbian identity (OR 0.44, 95% CI 0.25–0.76). Among men, the OR for DES in relation to reporting a nonheterosexual sexual orientation identity was 1.4 (95% CI 0.82–2.4), and ORs were similar for having a gay identity (1.4, 95% CI 0.72–2.85) and bisexual identity (1.4, 95% CI 0.57–3.5). Only five individuals reported a gender identity not conforming to that assigned at birth, preventing meaningful analysis. Women who were prenatally exposed to DES were less likely to have a lesbian or bisexual orientation, while DES-exposed men were somewhat more likely to report being gay or bisexual, but estimates were imprecise.

Background Cancer Antigen 125 (CA125) is currently the best available ovarian cancer screening biomarker. However, CA125 has been limited by low sensitivity and specificity in part due to normal variation between individuals. Personal characteristics that influence CA125 could be used to improve its performance as screening biomarker. Methods We developed and validated linear and dichotomous (≥35 U/mL) circulating CA125 prediction models in postmenopausal women without ovarian cancer who participated in one of five large population-based studies: Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO, n = 26,981), European Prospective Investigation into Cancer and Nutrition (EPIC, n = 861), the Nurses’ Health Studies (NHS/NHSII, n = 81), and the New England Case Control Study (NEC, n = 923). The prediction models were developed using stepwise regression in PLCO and validated in EPIC, NHS/NHSII and NEC. Result The linear CA125 prediction model, which included age, race, body mass index (BMI), smoking status and duration, parity, hysterectomy, age at menopause, and duration of hormone therapy (HT), explained 5% of the total variance of CA125. The correlation between measured and predicted CA125 was comparable in PLCO testing dataset (r = 0.18) and external validation datasets (r = 0.14). The dichotomous CA125 prediction model included age, race, BMI, smoking status and duration, hysterectomy, time since menopause, and duration of HT with AUC of 0.64 in PLCO and 0.80 in validation dataset. Conclusions The linear prediction model explained a small portion of the total variability of CA125, suggesting the need to identify novel predictors of CA125. The dichotomous prediction model showed moderate discriminatory performance which validated well in independent dataset. Our dichotomous model could be valuable in identifying healthy women who may have elevated CA125 levels, which may contribute to reducing false positive tests using CA125 as screening biomarker.

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 2041 women with epithelial ovarian cancer and 2100 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

Supplemental Digital Content is available in the text., Background: Multiple studies of ovarian cancer and genital talc use have led only to consensus about possible carcinogenicity. Seeking greater clarity, we examined this association in 2,041 cases with epithelial ovarian cancer and 2,100 age- and-residence-matched controls. Methods: We defined genital talc use as regular application to the genital/rectal area directly, on sanitary napkins, tampons, or underwear. To estimate “talc-years,” we multiplied applications per year by years used. Unconditional logistic regression, Wald statistics, likelihood-ratio tests, and polytomous logistic regression were used to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI), trends, effect-modification, and heterogeneity by ovarian cancer histologic subtype. Results: Overall, genital talc use was associated with an OR (95% CI) of 1.33 (1.16, 1.52), with a trend for increasing risk by talc-years. Women who used talc were more likely to be older, heavier, asthma sufferers, and regular analgesic users—none of which was a confounder. Dose–responses were more apparent for premenopausal women, especially nonsmokers and those heavier or postmenopausal users of menopausal hormones (hormone therapy [HT]). Subtypes of ovarian cancer more likely to be associated with talc included invasive serous and endometrioid tumors and borderline serous and mucinous tumors. Premenopausal women and postmenopausal HT users with these subtypes who had accumulated >24 talc-years had ORs (95% CI) of 2.33 (1.32, 4.12) and 2.57 (1.51, 4.36), respectively. Conclusion: Risks for epithelial ovarian cancer from genital talc use vary by histologic subtype, menopausal status at diagnosis, HT use, weight, and smoking. These observations suggest that estrogen and/or prolactin may play a role via macrophage activity and inflammatory response to talc.

Fast food restaurants spend millions of dollars annually on child-targeted marketing, a substantial portion of which is allocated to toy premiums for kids' meals. The objectives of this study were to describe fast food toy premiums, and examine whether young children's knowledge of fast food toy premiums was associated with their fast food consumption. Parents of 3- to 5-year old children were recruited from pediatric and WIC clinics in Southern New Hampshire, and completed a cross-sectional survey between April 2013-March 2014. Parents reported whether their children usually knew what toys were being offered at fast food restaurants, and whether children had eaten at any of four restaurants that offer toy premiums with kids' meals (McDonald's, Burger King, Subway, Wendy's) during the 7 days preceding the survey. Seventy-one percent of eligible parents participated (N = 583); 48.4% did not receive any education beyond high school, and 27.1% of children were non-white. Half (49.7%) the children had eaten at one or more of the four fast food restaurants in the past week; one-third (33.9%) had eaten at McDonald's. The four restaurants released 49 unique toy premiums during the survey period; McDonald's released half of these. Even after controlling for parent fast food consumption and sociodemographics, children were 1.38 (95% CI = 1.04, 1.82) times more likely to have consumed McDonald's if they usually knew what toys were offered by fast food restaurants. We did not detect a relationship between children's toy knowledge and their intake of fast food from the other restaurants. In this community-based sample, young children's knowledge of fast food toys was associated with a greater frequency of eating at McDonald's, providing evidence in support of regulating child-directed marketing of unhealthy foods using toys.

Background: Combined oral contraceptive use is associated with a decreased risk of ovarian carcinoma (cancer). However, the relationship between progestin-only contraceptives and ovarian cancer risk is unclear. Two previous studies have suggested a protective effect whereas another reported a non-statistically significant increased risk of ovarian cancer. The current study examined the association between use of depot medroxyprogesterone acetate (DMPA), a progestin-only injectable contraceptive, and ovarian cancer risk, using data from seven case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Methods: A pooled analysis examining the relationship between DMPA use and ovarian cancer risk was conducted using 7,679 invasive ovarian cancer cases and 11,136 controls from six studies from the United States and one from Australia. Combined oral contraceptive use, parity, education level, age, and race/ethnicity were considered important a priori confounders and were included in all statistical models. OCAC study site was also included in all models. The impact of additional exposures, including a personal history of endometriosis, first-degree family history of ovarian cancer, tubal ligation, breastfeeding, body mass index, and menopausal hormonal therapy use on the association between DMPA use and ovarian cancer were considered. None of these variables was found to impact the DMPA use-ovarian cancer association by >10% and thus not included in the final models. Odds ratios (OR) and 95% confidence intervals (CI) were generated from logistic regression models. The association between duration of DMPA use, categorized as never use, Results: The frequency of DMPA use among controls ranged from 1.25% to 3.53% across the seven studies. DMPA use was more common in controls than in cases in all of the studies. Overall, ever use of DMPA was associated with a 26% decreased risk of ovarian cancer (95% CI 0.58-0.94), after taking into account combined oral contraceptive use, parity, education level, age, race/ethnicity, and OCAC study site. A significant trend with duration of use was observed in the two studies with these data (p=0.02). Conclusions: DMPA use appears to be associated with a decreased risk of ovarian cancer. The finding provides additional evidence that progestins may be protective for ovarian cancer. Further evaluation of the role of DMPA as a potential primary prevention strategy for ovarian cancer, especially in women for whom combined oral contraceptive use is contraindicated due to concerns about estrogen-induced thromboembolic events, is warranted. Citation Format: Minh Tung Phung, Penelope M. Webb, Jennifer Anne Doherty, Holly R. Harris, Pamela J. Thompson, Marc T. Goodman, Kirsten Moysich, Francesmary Modugno, Roberta B. Ness, Joellen M. Schildkraut, Andrew Berchuck, Daniel W. Cramer, Kathryn L. Terry, Linda Titus, Alice W. Lee, Malcolm C. Pike, Anna H. Wu, Celeste Leigh Pearce. Use of progestin-only injectable contraceptive is associated with reduced risk of ovarian cancer in the Ovarian Cancer Association Consortium [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B38.

Background: Endometriosis is a common gynecologic disorder that affects approximately 10% of women of reproductive age. It is also a well-established risk factor for ovarian cancer. Whether hormonal-related and other risk factors for ovarian cancer (e.g., parity, oral contraceptive use) are the same for women with and without endometriosis is currently unknown. Methods: We pooled questionnaire information from 10 population-based case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Data from 8,172 women with invasive epithelial ovarian cancer and 12,464 controls were included in our analysis. Associations of body mass index (BMI), parity, oral contraceptive use, breastfeeding, menopausal hormone therapy use, first-degree family history of ovarian cancer, tubal ligation, and hysterectomy with risk of ovarian cancer were stratified by history of endometriosis and analyzed using logistic regression. All models were conditioned on age, race/ethnicity, education, and OCAC study site. We fit an endometriosis interaction term for each risk factor to evaluate statistical interactions. Results: Among women with no history of endometriosis, those who had hysterectomies showed a 12% increased risk of ovarian cancer compared to those with intact uteri (OR=1.12, 95% CI 1.01-1.24); an increased risk was not observed among women with endometriosis (OR=0.74, 95% CI 0.53-1.05; p-interaction=0.009). Use of estrogen-progestin hormone therapy was associated with decreased risk ovarian cancer for women with histories of endometriosis (OR=0.69, 95% CI 0.47-1.02), but not for those without endometriosis (OR=0.96, 95% CI 0.87-1.07; p-interaction=0.02). We did not observe any significant statistical interactions for the other risk factors considered, and no interactions were significant after consideration of multiple comparisons. Conclusions: The associations of hysterectomy and menopausal estrogen-progestin hormone therapy use with risk of ovarian cancer seemed to differ by endometriosis status, suggesting interactions that may need to be considered in ovarian cancer risk profiling strategies. Future investigations into the biology underlying these interactions would be relevant. Citation Format: Aruna Muthukumar, Lilah Khoja, Penelope M. Webb, Harvey Risch, Jennifer Doherty, Holly Harris, Marc Goodman, Roberta Ness, Francesmary Modugno, Susanne K. Kjaer, Allan Jensen, Joellen Schildkraut, Andrew Berchuck, Kathryn L. Terry, Daniel Cramer, Linda J. Titus, Hoda Anton-Culver, Argyrios Ziogas, Anna H. Wu, Malcolm C. Pike, Celeste L. Pearce, Alice W. Lee. Are ovarian cancer risk factors different for women with endometriosis? [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B32.

IMPORTANCE: Breastfeeding has been associated with a reduced risk of epithelial ovarian cancer in multiple studies, but others showed no association. Whether risk reduction extends beyond that provided by pregnancy alone or differs by histotype is unclear. Furthermore, the observed associations between duration and timing of breastfeeding with ovarian cancer risk have been inconsistent. OBJECTIVE: To determine the association between breastfeeding (ie, ever/never, duration, timing) and ovarian cancer risk overall and by histotype. DESIGN, SETTING, AND PARTICIPANTS: A pooled analysis of parous women with ovarian cancer and controls from 13 case-control studies participating in the Ovarian Cancer Association Consortium was performed. Odds ratios (ORs) and 95% CIs of the overall association were calculated using multivariable logistic regression and polytomous logistic regression for histotype-specific associations. All data were collected from individual sites from November 1989 to December 2009, and analysis took place from September 2017 to July 2019. EXPOSURES: Data on breastfeeding history, including duration per child breastfed, age at first and last breastfeeding, and years since last breastfeeding were collected by questionnaire or interview and was harmonized across studies. MAIN OUTCOMES AND MEASURES: Diagnosis of epithelial ovarian cancer. RESULTS: A total of 9973 women with ovarian cancer (mean [SD] age, 57.4 [11.1] years) and 13 843 controls (mean [SD] age, 56.4 [11.7] years) were included. Breastfeeding was associated with a 24% lower risk of invasive ovarian cancer (odds ratio [OR], 0.76; 95% CI, 0.71-0.80). Independent of parity, ever having breastfed was associated with reduction in risk of all invasive ovarian cancers, particularly high-grade serous and endometrioid cancers. For a single breastfeeding episode, mean breastfeeding duration of 1 to 3 months was associated with 18% lower risk (OR, 0.82; 95% CI, 0.76-0.88), and breastfeeding for 12 or more months was associated with a 34% lower risk (OR, 0.66; 95% CI, 0.58-0.75). More recent breastfeeding was associated with a reduction in risk (OR, 0.56; 95% CI, 0.47-0.66 for

Background Animal studies suggest that prenatal exposure to diethylstilbestrol (DES) causes epigenetic alterations in primordial germ cells that affect the next generation, but human studies are sparse. Methods We assessed hormonally mediated outcomes in third generation women whose mothers were prenatally DES-exposed and unexposed. Results Compared to the unexposed, DES-exposed third generation women had an increased risk of irregular menses and amenorrhea; the respective prevalence ratios and 95% confidence intervals (CI) in follow-up data were 1.32 (95% CI: 1.10, 1.60) and 1.26 (95% CI: 1.06, 1.49); associations were more apparent in third generation women whose prenatally DES-exposed mothers were affected by vaginal epithelial changes. The follow-up data also indicated an association with preterm delivery (relative risk (RR): 1.54; 95% CI: 1.35, 1.75). Conclusion DES third generation women may have an increased risk of irregular menstrual cycles, amenorrhea, and preterm delivery, consistent with inter-generational effects of endocrine disrupting chemical exposure in humans.

Objectives The Melanocytic Pathology Study (MPath) reported variation in community pathologists’ interpretations of melanocytic skin lesions relative to reference diagnoses developed through consensus by a panel of three experts. Little is known about the impact of second (2nd) opinion strategies on false positives (FP- overdiagnosis relative to consensus diagnosis) or false negatives (FN-underdiagnosis relative to consensus diagnosis) in melanocytic lesion diagnosis, or on patient care costs incurred within one year of biopsy. Method Lesion severity was classified into five classes based on the nature of clinical follow-up care required. Relative to the reference diagnoses, community pathologists overcalled (FP) or undercalled (FN) as follows: Class I (FP: 7.8%), Class II (FN: 62.8%, FP: 12.5%), Class III (FN: 54.1%, FP: 5.5%), Class IV (FN: 48.1%, FP: 9.1%), Class V (FN: 27.9%). We assessed second opinion strategies on (1) concordance between community pathologists’ diagnoses and diagnoses rendered by the reference panel, and (2) patient care costs incurred during the first year following biopsy. Second opinion strategies assessed included: no 2nd opinion; 2nd opinion obtained for all lesions; 2nd opinion required for some lesions by institutional policyor based on pathologists’ preference. For each second opinion strategy, decision analysis was used to estimate the expected percent of concordant diagnoses, FN, and FP. Standardized care pathways were used to estimate care costs in the year following biopsy. Results Without a 2nd opinion, 83.2% of biopsies received a concordant diagnosis with 8.0% FP and 8.8% FN. Concordance increased under all 2nd opinion strategies and was highest (87.4%) with universally obtained 2nd opinions, resulting in 3.6% FP and 9.1% FN While the proportion of FN cases was fairly consistent across 2nd opinion strategies (range: 8.8% to 9.2%) the proportion FP cases ranged from 3.6% to 7.6%. Per 1 00 000 biopsies, the costs were estimated as $118.6 million with no 2nd opinions, and 127.6 million with 2nd opinions obtained for all lesions. Second opinion strategies based on institutional policy and/or pathologist preference reduced FP cases without appreciable change in FN cases, and led to lower costs in the year following diagnosis (approximately $117 million/100,000). Conclusions While 2nd opinion strategies did not appreciably alter the proportion of FN cases, they did result in fewer FP cases. If selectively implemented, 2nd opinion strategies have the potential to save resources and improve care in the year following biopsy. Such strategies could be mandated through regulatory channels.

Background: Prenatal diethylstilbestrol (DES) exposure is associated with adverse reproductive outcomes and cancer of the breast and vagina/cervix in adult women. DES effects on estrogen metabolism have been hypothesized, but reproductive hormone concentrations and metabolic pathways have not been comprehensively described. Methods: Blood samples were provided by 60 postmenopausal women (40 exposed and 20 unexposed) who were participants in the NCI Combined DES Cohort Study, had never used hormone supplements or been diagnosed with cancer, had responded to the most recent cohort study questionnaire, and lived within driving distance of Boston University Medical School (Boston, MA). Parent estrogens and their metabolites were measured by high-performance liquid chromatography–tandem mass spectrometry. Age-adjusted percent changes in geometric means and associated 95% confidence intervals (CIs) between the exposed and unexposed were calculated. Results: Concentrations of total estrogens (15.3%; CI, −4.1–38.5) and parent estrogens (27.1%; CI, −8.2–76.1) were slightly higher in the DES-exposed than unexposed. Ratios of path2:parent estrogens (−36.5%; CI, −53.0 to −14.3) and path2:path16 (−28.8%; CI, −47.3–3.7) were lower in the DES exposed. These associations persisted with adjustment for total estrogen, years since menopause, body mass index, parity, and recent alcohol intake. Conclusions: These preliminary data suggest that postmenopausal women who were prenatally DES exposed may have relatively less 2 than 16 pathway estrogen metabolism compared with unexposed women. Impact: Lower 2 pathway metabolism has been associated with increased postmenopausal breast cancer risk and could potentially offer a partial explanation for the modest increased risk observed for prenatally DES-exposed women. Cancer Epidemiol Biomarkers Prev; 27(10); 1208–13. ©2018 AACR.

Objectives The impact of malpractice concerns on pathologists' use of defensive medicine and interpretations of melanocytic skin lesions (MSLs) is unknown. Methods A total of 207 pathologists interpreting MSLs responded to a survey about past involvement in malpractice litigation, influence of malpractice concerns on diagnosis, and use of assurance behaviors (defensive medicine) to alleviate malpractice concerns. Assurance behaviors included requesting second opinions, additional slides, additional sampling, and ordering specialized tests. Results Of the pathologists, 27.5% reported that malpractice concerns influenced them toward a more severe MSL diagnosis. Nearly all (95.2%) pathologists reported practicing at least one assurance behavior due to malpractice concerns, and this practice was associated with being influenced toward a more severe MSL diagnosis (odds ratio, 2.72; 95% confidence interval, 1.41-5.26). Conclusions One of four US skin pathologists upgrade MSL diagnosis due to malpractice concerns, and nearly all practice assurance behaviors. Assurance behaviors are associated with rendering a more severe MSL diagnosis.

Introduction Child-directed TV advertising is believed to influence children's diets, yet prospective studies in naturalistic settings are absent. This study examined if child-directed TV advertisement exposure for ten brands of high-sugar breakfast cereals was associated with children's intake of those brands prospectively. Methods Observational study of 624 preschool-age children and their parents conducted in New Hampshire, 2014–2015. Over 1 year, parents completed a baseline and six online follow-up surveys, one every 8 weeks. Children's exposure to high-sugar breakfast cereal TV advertisements was based on the network-specific TV programs children watched in the 7 days prior to each follow-up assessment, and parents reported children's intake of each advertised high-sugar breakfast cereal brand during that same 7-day period. Data were analyzed in 2017–2018. Results In the fully adjusted Poisson regression model accounting for repeated measures and brand-specific effects, children with high-sugar breakfast cereal advertisement exposure in the past 7 days (i.e., recent exposure; RR=1.34, 95% CI=1.04, 1.72), at any assessment in the past (RR=1.23, 95% CI=1.06, 1.42), or recent and past exposure (RR=1.37, 95% CI=1.15, 1.63) combined had an increased risk of brand-specific high-sugar breakfast cereal intake. Absolute risk difference of children's high-sugar breakfast cereal intake because of high-sugar breakfast cereal TV advertisement exposure varied by brand. Conclusions This naturalistic study demonstrates that child-directed high-sugar breakfast cereal TV advertising was prospectively associated with brand-specific high-sugar breakfast cereal intake among preschoolers. Findings indicate that child-directed advertising influences begin earlier and last longer than previously demonstrated, highlighting limitations of current industry guidelines regarding the marketing of high-sugar foods to children under age 6 years.

BACKGROUND: Research examining the role of second opinions in pathology for diagnosis of melanocytic lesions is limited. OBJECTIVE: To assess current laboratory policies, clinical use of second opinions, and pathologists’ perceptions of second opinions for melanocytic lesions. MATERIALS AND METHODS: Cross-sectional data collected from 207 pathologists in 10 US states who diagnose melanocytic lesions. The web-based survey ascertained pathologists’ professional information, laboratory second opinion policy, use of second opinions, and perceptions of second opinion value for melanocytic lesions. RESULTS: Laboratory policies required second opinions for 31% of pathologists and most commonly required for melanoma in situ (26%) and invasive melanoma (30%). In practice, most pathologists reported requesting second opinions for melanocytic tumors of uncertain malignant potential (85%) and atypical Spitzoid lesions (88%). Most pathologists perceived that second opinions increased interpretive accuracy (78%) and protected them from malpractice lawsuits (62%). CONCLUSION: Use of second opinions in clinical practice is greater than that required by laboratory policies, especially for melanocytic tumors of uncertain malignant potential and atypical Spitzoid lesions. Quality of care in surgical interventions for atypical melanocytic proliferations critically depends on the accuracy of diagnosis in pathology reporting. Future research should examine the extent to which second opinions improve accuracy of melanocytic lesion diagnosis.

Concerns about breast cancer overdiagnosis have increased the need to understand how cancers detected through screening mammography differ from those first detected by a woman or her clinician. We investigated risk factor associations for invasive breast cancer by method of detection within a series of case-control studies (1992–2007) carried out in Wisconsin, Massachusetts, and New Hampshire (n = 15,648 invasive breast cancer patients and 17,602 controls aged 40–79 years). Approximately half of case women reported that their cancer had been detected by mammographic screening and half that they or their clinician had detected it. In polytomous logistic regression models, parity and age at first birth were more strongly associated with risk of mammography-detected breast cancer than with risk of woman/clinician-detected breast cancer (P ≤ 0.01; adjusted for mammography utilization). Among postmenopausal women, estrogen-progestin hormone use was predominantly associated with risk of woman/clinician-detected breast cancer (odds ratio (OR) = 1.49, 95% confidence interval (CI): 1.29, 1.72), whereas obesity was predominantly associated with risk of mammography-detected breast cancer (OR = 1.72, 95% CI: 1.54, 1.92). Among regularly screened premenopausal women, obesity was not associated with increased risk of mammography-detected breast cancer (OR = 0.99, 95% CI: 0.83, 1.18), but it was associated with reduced risk of woman/clinician-detected breast cancer (OR = 0.53, 95% CI: 0.43, 0.64). These findings indicate important differences in breast cancer risk factors according to method of detection.

Objective The aim of this study is to examine whether school food attenuates household income-related disparities in adolescents' frequency of fruit and vegetable intake (FVI). Method Telephone surveys were conducted between 2007 and 2008 with adolescent-parent dyads from Northern New England; participants were randomly assigned to be surveyed at different times throughout the year. The main analysis comprised 1542 adolescents who typically obtained breakfast/lunch at school at least once/week. FVI was measured using 7-day recall of the number of times adolescents consumed fruits and vegetables. Fully adjusted linear regression was used to compare FVI among adolescents who were surveyed while school was in session (currently exposed to school food) to those who were surveyed when school was not in session (currently unexposed to school food). Results Mean FVI was 8.0 (SD = 5.9) times/week. Among adolescents unexposed to school food, household income and FVI were strongly, positively associated. In contrast, among adolescents exposed to school food, FVI was similar across all income categories. We found a significant cross-over interaction between school food and household income in which consuming food at school was associated with higher FVI among adolescents from low-income households versus lower FVI among adolescents from high-income households. Conclusion School food may mitigate income disparities in adolescent FVI. The findings suggest that the school food environment positively influences FVI among low-income adolescents.

* Abbreviations: CCA — : clear cell adenocarcinoma DES — : diethylstilbestrol Although the basic tenet of medicine is “First, do no harm,” history is filled with good intentions that were at best unhelpful and at worst harmful. Because medicine seeks to cure afflictions, there is an overwhelming desire on the part of health providers and patients to administer treatment. In certain settings, treatment can be reasonable despite a risk of adverse consequences: for example, if the disease is cured or its morbidity abated and the treatment consequences are less disabling than the disease itself. In the absence of overt disease, the question of whether to apply an intervention is far more challenging. The safety of interventions must be weighed against the population’s level of risk, the morbidity and/or mortality associated with the disease, and the intervention’s efficacy (eg, BRCA1 mutation, mastectomy, reduced breast cancer risk). Interventions must meet an especially high standard of safety and efficacy … Address correspondence to Rebecca Troisi, ScD, Epidemiology and Biostatistics Program, Office of the Director, Division of Epidemiology and Genetics, National Cancer Institute, 9609/7E578, 9609 Medical Center Dr, Rockville, MD 20850. E-mail: troisir{at}mail.nih.gov

Background Little is known about how pathologists process differences between actual and perceived interpretations. Objective To compare perceived and actual diagnostic agreement before and after educational interventions. Methods Pathologists interpreted test sets of skin and/or breast specimens that included benign, atypical, in situ and invasive lesions. Interventions involved self-directed learning, one skin and one breast, that showed pathologists how their interpretations compared to a reference diagnoses. Prior to the educational intervention, participants estimated how their interpretations would compare to the reference diagnoses. After the intervention, participants estimated their overall agreement with the reference diagnoses. Perceived and actual agreements were compared. Results For pathologists interpreting skin, mean actual agreement was 52.4% and overall pre- and postinterventional mean perceived agreement was 72.9% vs 54.2%, an overestimated mean difference of 20.5% (95% confidence interval [CI] 17.2% to 24.0%) and 1.8% (95% CI -0.5% to 4.1%), respectively. For pathologists interpreting breast, mean actual agreement was 75.9% and overall pre- and postinterventional mean perceived agreement was 81.4% vs 76.9%, an overestimation of 5.5% (95% CI 3.0% to 8.0%) and 1.0% (95% CI 0.0% to 2.0%), respectively. Conclusions Pathologists interpreting breast tissue had improved comprehension of their performance after the intervention compared to pathologists interpreting skin lesions.

In the Diethylstilbestrol [DES] Combined Cohort Follow-up, the age- and calendar-year specific standardized incidence ratio [SIR] for clear cell adenocarcinoma [CCA] was 27.6 (95% confidence interval [CI] 7.51-70.6) for the exposed women. The SIR for breast cancer was 1.17 (95% CI 1.01-1.36) and the hazard ratio [HR] adjusted for birth year and cohort for comparison with the unexposed was 1.05 (95% CI 0.79-1.41). The SIR for pancreatic cancer was 2.43 (95% CI 1.21-4.34) and the adjusted HR for comparison with unexposed women was 7.16 (95% CI 0.84-61.5). There was little evidence of excess risk for other sites. There appeared to be a deficit in risk for endometrial cancer among the exposed (SIR 0.61; 95% CI 0.35-0.98), and an excess in the unexposed (SIR 1.55; 95% CI 0.95-2.40); the adjusted HR was 0.45 (95% CI 0.22-0.93) for the internal comparison. There was no overall excess cancer risk in exposed women compared with general population rates (1.06; 95% CI 0.95-1.17) or with unexposed participants (adjusted HR 1.03; 95% CI 0.84-1.25). These data do not support the suggestion that there is a diathesis of cancers in DES exposed female offspring The excess risk of breast and pancreatic cancers that we observed is concerning and warrants continued follow-up and mechanistic investigation. Environ. Mol. Mutagen. 60:395-403, 2019. Published 2017. This article is a US Government work and is in the public domain in the USA.

Objective To quantify the accuracy and reproducibility of pathologists’ diagnoses of melanocytic skin lesions. Design Observer accuracy and reproducibility study. Setting 10 US states. Participants Skin biopsy cases (n=240), grouped into sets of 36 or 48. Pathologists from 10 US states were randomized to independently interpret the same set on two occasions (phases 1 and 2), at least eight months apart. Main outcome measures Pathologists’ interpretations were condensed into five classes: I (eg, nevus or mild atypia); II (eg, moderate atypia); III (eg, severe atypia or melanoma in situ); IV (eg, pathologic stage T1a (pT1a) early invasive melanoma); and V (eg, ≥pT1b invasive melanoma). Reproducibility was assessed by intraobserver and interobserver concordance rates, and accuracy by concordance with three reference diagnoses. Results In phase 1, 187 pathologists completed 8976 independent case interpretations resulting in an average of 10 (SD 4) different diagnostic terms applied to each case. Among pathologists interpreting the same cases in both phases, when pathologists diagnosed a case as class I or class V during phase 1, they gave the same diagnosis in phase 2 for the majority of cases (class I 76.7%; class V 82.6%). However, the intraobserver reproducibility was lower for cases interpreted as class II (35.2%), class III (59.5%), and class IV (63.2%). Average interobserver concordance rates were lower, but with similar trends. Accuracy using a consensus diagnosis of experienced pathologists as reference varied by class: I, 92% (95% confidence interval 90% to 94%); II, 25% (22% to 28%); III, 40% (37% to 44%); IV, 43% (39% to 46%); and V, 72% (69% to 75%). It is estimated that at a population level, 82.8% (81.0% to 84.5%) of melanocytic skin biopsy diagnoses would have their diagnosis verified if reviewed by a consensus reference panel of experienced pathologists, with 8.0% (6.2% to 9.9%) of cases overinterpreted by the initial pathologist and 9.2% (8.8% to 9.6%) underinterpreted. Conclusion Diagnoses spanning moderately dysplastic nevi to early stage invasive melanoma were neither reproducible nor accurate in this large study of pathologists in the USA. Efforts to improve clinical practice should include using a standardized classification system, acknowledging uncertainty in pathology reports, and developing tools such as molecular markers to support pathologists’ visual assessments.

SummaryBackground Despite increasing melanoma incidence in the United States, little is known about the impact of primary melanoma diagnosis on healthcare utilization and changes in utilization over time. Objective To evaluate population-based temporal trends in healthcare utilization following primary melanoma diagnosis. Methods We conducted a before-after multiple time series study of Medicare beneficiaries ages ≥66 years with primary melanoma diagnoses between 2000 and 2009 using the Surveillance, Epidemiology, and End Results-Medicare database. The primary exposure was time from primary melanoma diagnosis at three to six months (+91 to +180 days) and six to 24 months (+91 to +720 days) post-diagnosis. Covariates include tumor-, patient-, and geographic-level characteristics and health care utilization during the six months prior to diagnosis (-91 to -180 days). Poisson regression was used to estimate population-based risk-adjusted utilization rates (per 1,000 person-years) for skin biopsies (based on biopsy days), benign skin excisions, internal medicine office visits, and dermatology office visits. Results The study population included 56,254 patients with first diagnoses of primary melanoma. Most patients were ≥75 years old (56.8%), male (62.1%), and staged with in situ melanoma (42.4%) or localized invasive melanoma (45.9%). From 2000 to 2009, risk-adjusted skin biopsy rates 24 months post-diagnosis increased from 358.3 to 541.3 per 1,000 person-years (P-value for trend

Purpose Cigarette smoking increases overall mortality, but it is not established whether smoking is associated with breast cancer prognosis. Methods We evaluated the association between smoking status before and after breast cancer diagnosis and mortality in the Collaborative Breast Cancer and Women’s Longevity Study, a population-based prospective observational study conducted in Wisconsin, New Hampshire, and Massachusetts. Participants included 20,691 women, ages 20 to 79 years, diagnosed with incident localized or regional invasive breast cancer between 1988 and 2008; a subset of 4,562 of these women were recontacted a median of 6 years after diagnosis. Hazard ratios (HRs) with 95% CIs were calculated according to smoking status for death as a result of breast cancer; cancers of the lung, pharynx, or intrathoracic organs; other cancer; respiratory disease; and cardiovascular disease. Results During a median of 12 years, 6,778 women died, including 2,894 who died as a result of breast cancer. Active smokers 1 year before breast cancer diagnosis were more likely than never smokers to die of breast cancer (HR, 1.25; 95% CI, 1.13 to 1.37), respiratory cancer (HR, 14.48; 95% CI, 9.89 to 21.21), other respiratory disease (HR, 6.02; 95% CI, 4.55 to 7.97), and cardiovascular disease (HR, 2.08; 95% CI, 1.80 to 2.41). The 10% of women who continued to smoke after diagnosis were more likely than never smokers to die of breast cancer (HR, 1.72; 95% CI, 1.13 to 2.60). When compared with women who continued to smoke after diagnosis, those who quit smoking after diagnosis had lower mortality from breast cancer (HR, 0.67; 95% CI, 0.38 to 1.19) and respiratory cancer (HR, 0.39; 95% CI, 0.16 to 0.95). Conclusion Smoking before or after diagnosis was associated with a higher mortality from breast cancer and several other causes.

Menstrual pain is associated with increased production of inflammatory molecules, such as prostaglandins. Inflammation is involved in pathogenesis of several cancers, including ovarian cancer. In this study, we examined the association between menstrual pain and risk of ovarian cancer.We conducted a case-control study with 2,028 cases of epithelial ovarian cancer and 2,091 age- and study center-matched controls. Women were asked to report the severity of menstrual pain during their twenties and thirties, when not using oral contraceptives or breastfeeding. We used an unconditional logistic regression to evaluate the association between menstrual pain and epithelial ovarian cancer risk overall, and polytomous logistic regression to evaluate whether the association differed across tumor subtypes.Risk of ovarian cancer was increased in women with moderate (OR 1.22, 95 % CI 1.05-1.42) and severe pain (OR 1.34, 95 % CI 1.09-1.65) compared to women with no or mild pain during menstrual period. The association differed by histologic subtypes, with significant associations for severe pain with endometrioid (OR 1.64, 95 % CI 1.15-2.34) and clear cell tumors (OR 1.91, 95 % CI 1.11-3.28).Our data suggest that moderate and severe pain during menstrual period are associated with increased risk of epithelial ovarian cancer. Due to high prevalence of menstrual pain in women of reproductive age, this observation warrants further studies.

Purpose: Genome wide association studies have identified common single nucleotide polymorphisms (SNPs) associated with breast cancer risk. Many of these SNPs have an unknown biologic significance. Hormonal risk factors may mediate the relationships between these loci and breast cancer risk. We explored the relation between breast cancer susceptibility loci and menstrual factors using data from two population-based studies. Methods: In the first dataset, composed of 1328 women ages 20–74 years without a breast cancer diagnosis who participated in an established population-based study conducted in three U.S. states, we used linear regression to assess the associations between 13 previously-identified breast cancer loci with age at menarche, age at natural menopause and the reproductive lifespan. The reproductive lifespan is defined as the time between age at menarche and age at natural menopause, excluding time for pregnancy, oral contraceptive use and lactation. A polygenic risk score created as the sum of the number of risk allele copies in the SNPs was also evaluated for an association with menstrual traits. Significant results were then evaluated in the second dataset comprised of 1353 women ages 43–86 years recruited as part of a cohort study based in Beaver Dam, WI. Results: Polygenic score and 13 loci were not associated with either age at menarche or reproductive lifespan. Two SNPs were associated with age at natural menopause; each increase in the number of copies of the minor allele (A) of rs17468277 (CASP8) was associated with a 1.12 year decrease in age at natural menopause (p = 0.02). The minor allele (G) of SNP rs10941679 (5p12) (p = 0.01) was associated with a 1.01 year increase in age at natural menopause, although these results were not replicated in the follow-up study (p = 0.14 and 0.98, respectively). Conclusions: We did not find evidence to support the hypothesis that breast cancer susceptibility loci are related to menstrual factors. The following are the 18 highest scoring abstracts of those submitted for presentation at the 37th Annual ASPO meeting held March 10–12, 2013, in Memphis, TN.

Previous studies have observed that tubal ligation and hysterectomy are associated with a decreased risk of ovarian cancer; however, little is known about whether these associations vary by surgical characteristics, individual characteristics or tumor histology. We used logistic regression to examine tubal ligation, simple hysterectomy and hysterectomy with unilateral oophorectomy in relation to risk of epithelial ovarian cancer in the New England Case-Control Study. Our primary analysis included 2,265 cases and 2,333 controls. Overall, tubal ligation was associated with a lower risk of epithelial ovarian cancer [odds ratio (OR) = 0.82, 95% confidence interval (CI): 0.68-0.97], especially for endometrioid tumors (OR = 0.45, 95% CI: 0.29-0.69). The inverse association between tubal ligation and ovarian cancer risk was stronger for women who had undergone the procedure at the time of last delivery (OR = 0.60, 95% CI: 0.42-0.84) rather than at a later time (OR = 0.93, 95% CI: 0.75-1.15). Overall, simple hysterectomy was not associated with ovarian cancer risk (OR: 1.09, 95% CI: 0.83-1.42), although it was associated with a nonsignificant decreased risk of ovarian cancer among women who underwent the procedure at age 45 or older (RR: 0.64, 95% CI: 0.40-1.02) or within the last 10 years (OR = 0.65, 95% CI: 0.38-1.13). Overall, women who had a hysterectomy with a unilateral oophorectomy had significantly lower risk of ovarian cancer (OR = 0.65, 95% CI: 0.45-0.94). In summary, tubal ligation and hysterectomy with unilateral oophorectomy were inversely associated with ovarian cancer risk in a large population-based case-control study. Additional research is necessary to understand the potential biologic mechanisms by which these procedures may reduce ovarian cancer risk.

We evaluated whether 13 single nucleotide polymorphisms (SNPs) identified in genome-wide association studies interact with one another and with reproductive and menstrual risk factors in association with breast cancer risk. DNA samples and information on parity, breastfeeding, age at menarche, age at first birth, and age at menopause were collected through structured interviews from 1,484 breast cancer cases and 1,307 controls who participated in a population-based case-control study conducted in three US states. A polygenic score was created as the sum of risk allele copies multiplied by the corresponding log odds estimate. Logistic regression was used to test the associations between SNPs, the score, reproductive and menstrual factors, and breast cancer risk. Nonlinearity of the score was assessed by the inclusion of a quadratic term for polygenic score. Interactions between the aforementioned variables were tested by including a cross-product term in models. We confirmed associations between rs13387042 (2q35), rs4973768 (SLC4A7), rs10941679 (5p12), rs2981582 (FGFR2), rs3817198 (LSP1), rs3803662 (TOX3), and rs6504950 (STXBP4) with breast cancer. Women in the score's highest quintile had 2.2-fold increased risk when compared to women in the lowest quintile (95 % confidence interval: 1.67-2.88). The quadratic polygenic score term was not significant in the model (p = 0.85), suggesting that the established breast cancer loci are not associated with increased risk more than the sum of risk alleles. Modifications of menstrual and reproductive risk factors associations with breast cancer risk by polygenic score were not observed. Our results suggest that the interactions between breast cancer susceptibility loci and reproductive factors are not strong contributors to breast cancer risk.

The 2010 Dietary Guidelines for Americans include reducing consumption of sugar-sweetened beverages. Among the many possible routes of access for youth, school vending machines provide ready availability of sugar-sweetened beverages. The purpose of this study was to determine variation in high school student access to sugar-sweetened beverages through vending machines by geographic location - urban, town or rural - and to offer an approach for analysing school vending machine content.Cross-sectional observational study.Between October 2007 and May 2008, trained coders recorded beverage vending machine content and machine-front advertising in 113 machines across 26 schools in New Hampshire and Vermont, USA.Compared with town schools, urban schools were significantly less likely to offer sugar-sweetened beverages (P = 0.002). Rural schools also offered more sugar-sweetened beverages than urban schools, but this difference was not significant. Advertisements for sugar-sweetened beverages were highly prevalent in town schools.High school students have ready access to sugar-sweetened beverages through their school vending machines. Town schools offer the highest risk of exposure; school vending machines located in towns offer up to twice as much access to sugar-sweetened beverages in both content and advertising compared with urban locations. Variation by geographic region suggests that healthier environments are possible and some schools can lead as inspirational role models.