Effects of Preanalytical Sample Collection and Handling on Comprehensive Metabolite Measurements in Human Urine Biospecimens.

Epidemiology studies evaluate associations between the metabolome and disease risk. Urine is a common biospecimen used for such studies due to its wide availability and non-invasive collection. Evaluating the robustness of urinary metabolomic profiles under varying preanalytical conditions is thus of interest. Here we evaluate the impact of sample handling conditions on urine metabolome profiles relative to the gold standard condition (no preservative, no refrigeration storage, single freeze thaw). Conditions tested included the use of borate or chlorhexidine preservatives, various storage and freeze/thaw cycles. We demonstrate that sample handling conditions impact metabolite levels, with borate showing the largest impact with 125 of 1,048 altered metabolites (adjusted P < 0.05). When simulating a case-control study with expected inconsistencies in sample handling, we predicted the occurrence of false positive altered metabolites to be low (< 11). Predicted false positives increased substantially (³63) when cases were simulated to undergo alternate handling. Finally, we demonstrate that sample handling impacts on the urinary metabolome were markedly smaller than those in serum. While changes in urine metabolites incurred by sample handling are generally small, we recommend implementing consistent handling conditions and evaluating robustness of metabolite measurements for those showing significant associations with disease outcomes.

Association of Accelerometer-Measured Physical Activity Level With Risks of Hospitalization for 25 Common Health Conditions in UK Adults.

Importance: Higher physical activity levels are associated with lower risks of cancer, cardiovascular disease, and diabetes, but associations with many common and less severe health conditions are not known. These conditions impose large health care burdens and reduce quality of life. Objectives: To investigate the association between accelerometer-measured physical activity and the subsequent risk of hospitalization for 25 common reasons for hospitalization and to estimate the proportion of these hospitalizations that might have been prevented if participants had higher levels of physical activity. Design, Setting, and Participants: This prospective cohort study used data from a subset of 81 717 UK Biobank participants aged 42 to 78 years. Participants wore an accelerometer for 1 week (between June 1, 2013, and December 23, 2015) and were followed up over a median (IQR) of 6.8 (6.2-7.3) years; follow-up for the current study ended in 2021 (exact date varied by location). Exposures: Mean total and intensity-specific accelerometer-measured physical activity. Main Outcomes and Measures: Hospitalization for the most common health conditions. Cox proportional hazards regression analysis was used to estimate hazard ratios (HRs) and 95% CIs for mean accelerometer-measured physical activity (per 1-SD increment) and risks of hospitalization for 25 conditions. Population-attributable risks were used to estimate the proportion of hospitalizations for each condition that might be prevented if participants increased their moderate to vigorous physical activity (MVPA) by 20 minutes per day. Results: Among 81 717 participants, the mean (SD) age at accelerometer assessment was 61.5 (7.9) years; 56.4% were female, and 97.0% self-identified as White. Higher levels of accelerometer-measured physical activity were associated with lower risks of hospitalization for 9 conditions: gallbladder disease (HR per 1 SD, 0.74; 95% CI, 0.69-0.79), urinary tract infections (HR per 1 SD, 0.76; 95% CI, 0.69-0.84), diabetes (HR per 1 SD, 0.79; 95% CI, 0.74-0.84), venous thromboembolism (HR per 1 SD, 0.82; 95% CI, 0.75-0.90), pneumonia (HR per 1 SD, 0.83; 95% CI, 0.77-0.89), ischemic stroke (HR per 1 SD, 0.85; 95% CI, 0.76-0.95), iron deficiency anemia (HR per 1 SD, 0.91; 95% CI, 0.84-0.98), diverticular disease (HR per 1 SD, 0.94; 95% CI, 0.90-0.99), and colon polyps (HR per 1 SD, 0.96; 95% CI, 0.94-0.99). Positive associations were observed between overall physical activity and carpal tunnel syndrome (HR per 1 SD, 1.28; 95% CI, 1.18-1.40), osteoarthritis (HR per 1 SD, 1.15; 95% CI, 1.10-1.19), and inguinal hernia (HR per 1 SD, 1.13; 95% CI, 1.07-1.19), which were primarily induced by light physical activity. Increasing MVPA by 20 minutes per day was associated with reductions in hospitalization ranging from 3.8% (95% CI, 1.8%-5.7%) for colon polyps to 23.0% (95% CI, 17.1%-28.9%) for diabetes. Conclusions and Relevance: In this cohort study of UK Biobank participants, those with higher physical activity levels had lower risks of hospitalization across a broad range of health conditions. These findings suggest that aiming to increase MVPA by 20 minutes per day may be a useful nonpharmaceutical intervention to reduce health care burdens and improve quality of life.

Metabolomic Analysis of Renal Cell Carcinoma in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

Background: In the US in 2021, 76,080 kidney cancers are expected and >80% are renal cell carcinomas (RCCs). Along with excess fat, metabolic dysfunction is implicated in RCC etiology. To identify RCC-associated metabolites, we conducted a 1:1 matched case−control study nested within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Methods: We measured 522 serum metabolites in 267 cases/control pairs. Cases were followed for a median 7.1 years from blood draw to diagnosis. Using conditional logistic regression, we computed adjusted odds ratios (ORs) and 95% confidence intervals (CIs) comparing risk between 90th and 10th percentiles of log metabolite intensity, with the significance threshold at a false discovery rate <0.20. Results: Four metabolites were inversely associated with risk of RCC during follow-up­C38:4 PI, C34:0 PC, C14:0 SM, and C16:1 SM (ORs ranging from 0.33−0.44). Two were positively associated with RCC risk­C3-DC-CH3 carnitine and C5 carnitine (ORs = 2.84 and 2.83, respectively). These results were robust when further adjusted for metabolic risk factors (body mass index (BMI), physical activity, diabetes/hypertension history). Metabolites associated with RCC had weak correlations (|r| < 0.2) with risk factors of BMI, physical activity, smoking, alcohol, and diabetes/hypertension history. In mutually adjusted models, three metabolites (C38:4 PI, C14:0 SM, and C3-DC-CH3 carnitine) were independently associated with RCC risk. Conclusions: Serum concentrations of six metabolites were associated with RCC risk, and three of these had independent associations from the mutually adjusted model. These metabolites may point toward new biological pathways of relevance to this malignancy.

Association of Leisure Time Physical Activity Types and Risks of All-Cause, Cardiovascular, and Cancer Mortality Among Older Adults.

Importance: Higher amounts of physical activity are associated with increased longevity. However, whether different leisure time physical activity types are differentially associated with mortality risk is not established. Objectives: To examine whether participation in equivalent amounts of physical activity (7.5 to <15 metabolic equivalent of task [MET] hours per week) through different activity types is associated with mortality risk and to investigate the shape of the dose-response association. Design, Setting, and Participants: Participants in this cohort were respondents from the National Institutes of Health-AARP Diet and Health Study who completed the follow-up questionnaire between 2004 and 2005. This questionnaire collected data on weekly durations of different types of physical activities. Mortality was ascertained through December 31, 2019. Exposures: MET hours per week spent participating in the following activities: running, cycling, swimming, other aerobic exercise, racquet sports, golf, and walking for exercise. Main Outcomes and Measures: All-cause, cardiovascular, and cancer mortality. Separate multivariable-adjusted Cox proportional hazards regression models were fitted to estimate hazard ratios (HRs) and 95% CIs of mortality for each of the 7 types of leisure time physical activities, as well as the sum of these activities. Results: A total of 272 550 participants (157 415 men [58%]; mean [SD] age at baseline, 70.5 [5.4] years [range, 59-82 years]) provided information on types of leisure time activity, and 118 153 (43%) died during a mean (SD) follow-up of 12.4 (3.9) years. In comparison with those who did not participate in each activity, 7.5 to less than 15 MET hours per week of racquet sports (HR, 0.84; 95% CI, 0.75-0.93) and running (HR, 0.85; 95% CI, 0.78-0.92) were associated with the greatest relative risk reductions for all-cause mortality, followed by walking for exercise (HR, 0.91; 95% CI, 0.89-0.93), other aerobic activity (HR, 0.93; 95% CI, 0.90-0.95), golf (HR, 0.93; 95% CI, 0.90-0.97), swimming (HR, 0.95; 95% CI, 0.92-0.98), and cycling (HR, 0.97; 95% CI, 0.95-0.99). Each activity showed a curvilinear dose-response association with mortality risk; low MET hours per week of physical activity for any given activity type were associated with a large reduction in mortality risk, with diminishing returns for each increment in activity thereafter. Associations were similar for cardiovascular and cancer mortality. Conclusions and Relevance: This cohort study of older individuals found differences between different types of leisure time activities and mortality risk, but there were significant associations between participating in 7.5 to less than 15 MET hours per week of any activity and mortality risk.

COMETS Analytics: An Online Tool for Analyzing and Meta-Analyzing Metabolomics Data in Large Research Consortia.

Consortium-based research is crucial for producing reliable, high-quality findings, but existing tools for consortium studies have important drawbacks with respect to data protection, ease of deployment, and analytical rigor. To address these concerns, we developed COnsortium of METabolomics Studies (COMETS) Analytics to support and streamline consortium-based analyses of metabolomics and other -omics data. The application requires no specialized expertise and can be run locally to guarantee data protection or through a Web-based server for convenience and speed. Unlike other Web-based tools, COMETS Analytics enables standardized analyses to be run across all cohorts, using an algorithmic, reproducible approach to diagnose, document, and fix model issues. This eliminates the time-consuming and potentially error-prone step of manually customizing models by cohort, helping to accelerate consortium-based projects and enhancing analytical reproducibility. We demonstrated that the application scales well by performing 2 data analyses in 45 cohort studies that together comprised measurements of 4,647 metabolites in up to 134,742 participants. COMETS Analytics performed well in this test, as judged by the minimal errors that analysts had in preparing data inputs and the successful execution of all models attempted. As metabolomics gathers momentum among biomedical and epidemiologic researchers, COMETS Analytics may be a useful tool for facilitating large-scale consortium-based research.

Body Composition and Metabolomics in the Alberta Physical Activity and Breast Cancer Prevention Trial.

BACKGROUND: Obesity is correlated with many biomarkers, but the extent to which these correlate with underlying body composition is poorly understood. OBJECTIVES: Our objectives were to 1) describe/compare distinct contributions of fat/lean mass with BMI-metabolite correlations and 2) identify novel metabolite biomarkers of fat/lean mass. METHODS: The Alberta Physical Activity and Breast Cancer Prevention Trial was a 2-center randomized trial of healthy, inactive, postmenopausal women (n = 304). BMI (in kg/m2) was calculated using weight and height, whereas DXA estimated fat/lean mass. Ultra-performance liquid chromatography and mass spectrometry measured relative concentrations of serum metabolite concentrations. We estimated partial Pearson correlations between 1052 metabolites and BMI, adjusting for age, smoking, and site. Fat mass index (FMI; kg/m2) and lean mass index (LMI; kg/m2) correlations were estimated similarly, with mutual adjustment to evaluate independent effects. RESULTS: Using a Bonferroni-corrected α level <4.75 × 10-5,  we observed 53 BMI-correlated metabolites (|r| = 0.24-0.42). Of those, 21 were robustly correlated with FMI (|r| > 0.20), 25 modestly (0.10 ≤ |r| ≤ 0.20), and 7 virtually null (|r| < 0.10). Ten of 53 were more strongly correlated with LMI than with FMI. Examining non-BMI-correlated metabolites, 6 robustly correlated with FMI (|r| = 0.24-0.31) and 2 with LMI (r = 0.25-0.26). For these, correlations for fat and lean mass were in opposing directions compared with BMI-correlated metabolites, in which correlations were mostly in the same direction. CONCLUSIONS: Our results demonstrate how a thorough evaluation of the components of fat and lean mass, along with BMI, provides a more accurate assessment of the associations between body composition and metabolites than BMI alone. Such an assessment makes evident that some metabolites correlated with BMI predominantly reflect lean mass rather than fat, and some metabolites related to body composition are not correlated with BMI. Correctly characterizing these relations is important for an accurate understanding of how and why obesity is associated with disease.

Atypical Nodular Hidradenoma Versus Low-Grade Hidradenocarcinoma in a Young Female Patient: A Case Report and Review of Literature.

The objective of this study was to discuss an unusual postauricular mass in a pediatric patient. This mass had a broad differential including congenital anomaly, neoplasm, infection, and lymphovascular malformation. Atypical nodular hidradenoma is a rare adnexal tumor that is difficult to differentiate from hidradenocarcinoma. It is a rare entity, but especially rare in the pediatric population. This study aims to provide guidance on diagnosing hidradenoma and distinguishing it from hidradenocarcinoma through case presentation with a review of the literature. The patient in this report underwent wide location resection with close surveillance and has been disease-free during follow-up.

Physical Activity From Adolescence Through Midlife and Associations With Body Mass Index and Endometrial Cancer Risk.

Background: Physical activity is associated with lower risk for endometrial cancer, but the extent to which the association is mediated by body mass index (BMI) in midlife is unclear. This study describes the physical activity-endometrial cancer association and whether BMI mediates this relationship. Methods: Participants were 67 705 women in the National Institutes of Health-AARP Diet and Health Study (50-71 years) who recalled their physical activity patterns starting at age 15-18 years. We identified 5 long-term physical activity patterns between adolescence and cohort entry (ie, inactive, maintained low, maintained high, increasers, decreasers). We used Cox regression to assess the relationship between these patterns and midlife BMI and endometrial cancer, adjusting for covariates. Mediation analysis was used to estimate the proportion of the physical activity-endometrial cancer association that was mediated by midlife BMI. Results: During an average 12.4 years of follow-up 1468 endometrial cancers occurred. Compared with long-term inactive women, women who maintained high or increased activity levels had a 19% to 26% lower risk for endometrial cancer (maintained high activity: hazard ratio = 0.81, 95% confidence interval [CI] = 0.67 to 0.98; increasers: hazard ratio = 0.74, 95% CI = 0.61 to 0.91). They also had a 50% to 77% lower risk for obesity in midlife (eg, maintained high activity: odds ratio for a BMI of 30-39.9 kg/m2 = 0.50, 95% CI = 0.46 to 0.55; and maintained high activity, odds ratio for a BMI of ≥40 kg/m2 = 0.32, 95% CI = 0.26 to 0.39). BMI was a statistically significant mediator accounting for 55.5% to 62.7% of the physical activity-endometrial cancer associations observed. Conclusions: Both maintaining physical activity throughout adulthood and adopting activity later in adulthood can play a role in preventing obesity and lowering the risk for endometrial cancer.

Preanalytical Sample Handling Conditions and Their Effects on the Human Serum Metabolome in Epidemiologic Studies.

Many epidemiologic studies use metabolomics for discovery-based research. The degree to which sample handling may influence findings, however, is poorly understood. In 2016, serum samples from 13 volunteers from the US Department of Agriculture's Beltsville Human Nutrition Research Center were subjected to different clotting (30 minutes/120 minutes) and refrigeration (0 minutes/24 hours) conditions, as well as different numbers (0/1/4) and temperatures (ice/refrigerator/room temperature) of thaws. The median absolute percent difference (APD) between metabolite levels and correlations between levels across conditions were estimated for 628 metabolites. The potential for handling artifacts to induce false-positive associations was estimated using variable hypothetical scenarios in which 1%-100% of case samples had different handling than control samples. All handling conditions influenced metabolite levels. Across metabolites, the median APD when extending clotting time was 9.08%. When increasing the number of thaws from 0 to 4, the median APD was 10.05% for ice and 5.54% for room temperature. Metabolite levels were correlated highly across conditions (all r's ≥ 0.84), indicating that relative ranks were preserved. However, if handling varied even modestly by case status, our hypotheticals showed that results can be biased and can result in false-positive findings. Sample handling affects levels of metabolites, and special care should be taken to minimize effects. Shorter room-temperature thaws should be preferred over longer ice thaws, and handling should be meticulously matched by case status.

Dietary Polyunsaturated Fat Intake in Relation to Head and Neck, Esophageal, and Gastric Cancer Incidence in the National Institutes of Health-AARP Diet and Health Study.

Recent epidemiologic studies have examined the association of fish consumption with upper gastrointestinal cancer risk, but the associations with n-3 and n-6 polyunsaturated fatty acid (PUFA) subtypes remain unclear. Using the National Institutes of Health-AARP Diet and Health Study (United States, 1995-2011), we prospectively investigated the associations of PUFA subtypes, ratios, and fish with the incidence of head and neck cancer (HNC; n = 2,453), esophageal adenocarcinoma (EA; n = 855), esophageal squamous cell carcinoma (n = 267), and gastric cancer (cardia: n = 603; noncardia: n = 631) among 468,952 participants (median follow-up, 15.5 years). A food frequency questionnaire assessed diet. Multivariable-adjusted hazard ratios were estimated using Cox proportional hazards regression. A Benjamini-Hochberg (BH) procedure was used for false-discovery control. Long-chain n-3 PUFAs were associated with a 20% decreased HNC and EA risk (for HNC, quintile5 vs. 1 hazard ratio = 0.81, 95% confidence interval: 0.71, 0.92, and BH-adjusted Ptrend = 0.001; and for EA, quintile5 vs. 1 hazard ratio = 0.79, 95% confidence interval: 0.64, 0.98, and BH-adjusted Ptrend = 0.1). Similar associations were observed for nonfried fish but only for high intake. Further, the ratio of long-chain n-3:n-6 was associated with a decreased HNC and EA risk. No consistent associations were observed for gastric cancer. Our results indicate that dietary long-chain n-3 PUFA and nonfried fish intake are associated with lower HNC and EA risk.

Ketorolac usage in tonsillectomy and uvulopalatopharyngoplasty patients.

OBJECTIVE: Postoperative pain for tonsillectomy with or without adenoidectomy or uvulopalatopharyngoplasty (UPPP) can be severe. Ketorolac is a nonsteroidal anti-inflammatory drug that can be administered for analgesia in these patients. In the literature, ketorolac has been associated with an increased risk of hemorrhage after tonsillectomy with or without adenoidectomy. Many other surgical fields have successfully utilized this medicine for postoperative pain control without increased incidence of hemorrhage. The goal of this study was to analyze the effectiveness of ketorolac after tonsillectomy with or without adenoidectomy or UPPP in adults on postoperative hemorrhage rates. METHODS: Adult patients older than 18 years of age who underwent tonsillectomy with or without adenoidectomy and UPPP between 2013 and 2018 were assessed to determine hemorrhage rates. Hemorrhage rates were assessed based on patients presenting to the emergency department with complaint of hemorrhage. RESULTS: There was no significant difference between groups in the postoperative hemorrhage rates (P = .331) or the method of hemorrhage control. CONCLUSION: Ketorolac did not increase postoperative hemorrhage rates in patients posttonsillectomy with or without adenoidectomy or UPPP. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:876-879, 2020.

Identification of 102 Correlations between Serum Metabolites and Habitual Diet in a Metabolomics Study of the Prostate, Lung, Colorectal, and Ovarian Cancer Trial.

BACKGROUND: Metabolomics has proven useful for detecting objective biomarkers of diet that may help to improve dietary measurement. Studies to date, however, have focused on a relatively narrow set of lipid classes. OBJECTIVE: The aim of this study was to uncover candidate dietary biomarkers by identifying serum metabolites correlated with self-reported diet, particularly metabolites in underinvestigated lipid classes, e.g. triglycerides and plasmalogens. METHODS: We assessed dietary questionnaire data and serum metabolite correlations from 491 male and female participants aged 55-75 y in an exploratory cross-sectional study within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Self-reported intake was categorized into 50 foods, food groups, beverages, and supplements. We examined 522 identified metabolites using 2 metabolomics platforms (Broad Institute and Massachusetts General Hospital). Correlations were identified using partial Pearson's correlations adjusted for age, sex, BMI, smoking status, study site, and total energy intake [Bonferroni-corrected level of 0.05/(50 × 522) = 1.9 × 10-6]. We assessed prediction of dietary intake by multiple-metabolite linear models with the use of 10-fold crossvalidation least absolute shrinkage and selection operator (LASSO) regression. RESULTS: Eighteen foods, beverages, and supplements were correlated with ≥1 serum metabolite at the Bonferroni-corrected significance threshold, for a total of 102 correlations. Of these, only 5 have been reported previously, to our knowledge. Our strongest correlations were between citrus and proline betaine (r = 0.55), supplements and pantothenic acid (r = 0.46), and fish and C40:9 phosphatidylcholine (PC) (r = 0.35). The multivariate analysis similarly found reasonably large correlations between metabolite profiles and citrus (r = 0.59), supplements (r = 0.57), and fish (r = 0.44). CONCLUSIONS: Our study of PLCO participants identified many novel food-metabolite associations and replicated 5 previous associations. These candidate biomarkers of diet may help to complement measures of self-reported diet in nutritional epidemiology studies, though further validation work is still needed.

Fish/shellfish intake and the risk of head and neck cancer.

Fish intake and other dietary sources of omega-3 fatty acids have been shown to be associated with a reduced risk for some cancers. Although previous studies of head and neck cancer have reported associations with different dietary factors, including reduced risks for fruits and vegetables and putatively healthy dietary patterns, associations specific to fish intake are unclear. This study investigated the association between fish/shellfish intake and risk of squamous cell carcinoma of the head and neck (SCCHN) using data from the Carolina Head and Neck Cancer Epidemiology Study, a population-based case-control study conducted in 46 North Carolina counties with cases recruited from 2002 through 2006. Controls were frequency matched to the cases on age, sex, and race; the final sample size was 1039 cases and 1375 controls. Demographic, lifestyle, and dietary information were collected using an in-person interviewer-administered structured questionnaire. Multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated with unconditional logistic regression. Patients whose fish/shellfish intake was among the highest tertile had a 20% lower odds of SCCHN compared with those in the lowest tertile (OR: 0.80; 95% CI: 0.60-1.07) after adjustment for the matching and other factors (income, energy intake, fruit intake, cigarette smoking, and alcohol intake). The inverse association was more pronounced for oral cavity and oropharyngeal tumors, for African Americans, and for females, but CIs were wide. To further investigate this potential risk reduction strategy for SCCHN, future studies should consider examining specific fish/shellfish, cooking practices, and other omega-3 fatty acid sources.

Pre-diagnostic aspirin use and mortality after breast cancer.

BACKGROUND: Whether aspirin or other nonsteroidal anti-inflammation drug (NSAID) use is associated with mortality following breast cancer remains unclear. Consideration of use patterns and interaction with obesity may help to clarify the inconsistent results. METHODS: Pre-diagnosis NSAID use, weight, and height were assessed ~ 3 months after diagnosis through in-person interviews with a population-based cohort of 1,442 women with first primary breast cancer. Vital status was determined through the national death index after ~ 18 years of follow-up (N = 237/597 breast cancer-specific/all-cause deaths). We used Cox proportional hazards regression to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Multiplicative interaction by body mass index (BMI) was evaluated using the likelihood ratio test. RESULTS: Ever aspirin use was inversely associated with breast cancer-specific mortality (HR 0.87, 95% CI 0.59-1.29), but positively associated with all-cause mortality (HR 1.21, 95% CI 0.99-1.48); the CIs included the null values. The HRs, however, were more pronounced for the highest level of duration, frequency, regularity, and timing for all-cause, but not breast cancer-specific mortality. Interactions with BMI revealed no significant heterogeneity (pinteraction = 0.37 and pinteraction = 0.36, respectively). CONCLUSION: Pre-diagnosis aspirin use was not strongly associated with mortality following breast cancer. The all-cause mortality associations, however, were slightly stronger when we considered patterns of use.

A pooled analysis of dietary sugar/carbohydrate intake and esophageal and gastric cardia adenocarcinoma incidence and survival in the USA.

Background: During the past 40 years, esophageal/gastric cardia adenocarcinoma (EA/GCA) incidence increased in Westernized countries, but survival remained low. A parallel increase in sugar intake, which may facilitate carcinogenesis by promoting hyperglycaemia, led us to examine sugar/carbohydrate intake in association with EA/GCA incidence and survival. Methods: We pooled 500 EA cases, 529 GCA cases and 2027 controls from two US population-based case-control studies with cases followed for vital status. Dietary intake, assessed by study-specific food frequency questionnaires, was harmonized and pooled to estimate 12 measures of sugar/carbohydrate intake. Multivariable-adjusted odds ratios (ORs) and hazard ratios [95% confidence intervals (CIs)] were calculated using multinomial logistic regression and Cox proportional hazards regression, respectively. Results: EA incidence was increased by 51-58% in association with sucrose (ORQ5vs.Q1 = 1.51, 95% CI = 1.01-2.27), sweetened desserts/beverages (ORQ5vs.Q1 = 1.55, 95% CI = 1.06-2.27) and the dietary glycaemic index (ORQ5vs.Q1 = 1.58, 95% CI = 1.13-2.21). Body mass index (BMI) and gastro-esophageal reflux disease (GERD) modified these associations (Pmultiplicative-interaction ≤ 0.05). For associations with sucrose and sweetened desserts/beverages, respectively, the OR was elevated for BMI < 25 (ORQ4-5vs.Q1-3 = 1.79, 95% CI = 1.26-2.56 and ORQ4-5vs.Q1-3 = 1.45, 95% CI = 1.03-2.06), but not BMI ≥ 25 (ORQ4-5vs.Q1-3 = 1.05, 95% CI = 0.76-1.44 and ORQ4-5vs.Q1-3 = 0.85, 95% CI = 0.62-1.16). The EA-glycaemic index association was elevated for BMI ≥ 25 (ORQ4-5vs.Q1-3 = 1.38, 95% CI = 1.03-1.85), but not BMI < 25 (ORQ4-5vs.Q1-3 = 0.88, 95% CI = 0.62-1.24). The sucrose-EA association OR for GERD < weekly was 1.58 (95% CI = 1.16-2.14), but for GERD ≥ weekly was 1.01 (95% CI = 0.70-1.47). Sugar/carbohydrate measures were not associated with GCA incidence or EA/GCA survival. Conclusions: If confirmed, limiting intake of sucrose (e.g. table sugar), sweetened desserts/beverages, and foods that contribute to a high glycaemic index, may be plausible EA risk reduction strategies.

Dietary sugar/starches intake and Barrett's esophagus: a pooled analysis.

Barrett's esophagus (BE) is the key precursor lesion of esophageal adenocarcinoma, a lethal cancer that has increased rapidly in westernized countries over the past four decades. Dietary sugar intake has also been increasing over time, and may be associated with these tumors by promoting hyperinsulinemia. The study goal was to examine multiple measures of sugar/starches intake in association with BE. This pooled analysis included 472 BE cases and 492 controls from two similarly conducted case-control studies in the United States. Dietary intake data, collected by study-specific food frequency questionnaires, were harmonized across studies by linking with the University of Minnesota Nutrient Database, and pooled based on study-specific quartiles. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for age, sex, race, total energy intake, study indicator, body mass index, frequency of gastro-esophageal reflux, and fruit/vegetable intake. In both studies, intake of sucrose (cases vs. controls, g/day: 36.07 vs. 33.51; 36.80 vs. 35.06, respectively) and added sugar (46.15 vs. 41.01; 44.18 vs. 40.68, respectively) were higher in cases than controls. BE risk was increased 79% and 71%, respectively, for associations comparing the fourth to the first quartile of intake of sucrose (ORQ4vs.Q1 = 1.79, 95% CI = 1.07-3.02, P trend = 0.01) and added sugar (ORQ4vs.Q1 = 1.71, 95% CI = 1.05-2.80, P trend = 0.15). Intake of sweetened desserts/beverages was associated with 71% increase in BE risk (ORQ4vs.Q1 = 1.71, 95% CI = 1.07-2.73, P trend = 0.04). Limiting dietary intake of foods and beverages that are high in added sugar, especially refined table sugar, may reduce the risk of developing BE.

The Premenopausal Breast Cancer Collaboration: A Pooling Project of Studies Participating in the National Cancer Institute Cohort Consortium.

Breast cancer is a leading cancer diagnosis among premenopausal women around the world. Unlike rates in postmenopausal women, incidence rates of advanced breast cancer have increased in recent decades for premenopausal women. Progress in identifying contributors to breast cancer risk among premenopausal women has been constrained by the limited numbers of premenopausal breast cancer cases in individual studies and resulting low statistical power to subcategorize exposures or to study specific subtypes. The Premenopausal Breast Cancer Collaborative Group was established to facilitate cohort-based analyses of risk factors for premenopausal breast cancer by pooling individual-level data from studies participating in the United States National Cancer Institute Cohort Consortium. This article describes the Group, including the rationale for its initial aims related to pregnancy, obesity, and physical activity. We also describe the 20 cohort studies with data submitted to the Group by June 2016. The infrastructure developed for this work can be leveraged to support additional investigations. Cancer Epidemiol Biomarkers Prev; 26(9); 1360-9. ©2017 AACR.

Age-Specific Indicators of a Healthy Lifestyle and Postmenopausal Breast Cancer.

INTRODUCTION: Modifiable lifestyle factors have been consistently associated with breast cancer, and risk may vary by menopausal status. However, whether these associations vary according to age among postmenopausal women remains unresolved. METHODS: Using postmenopausal women from a population-based case-control study (990 cases and 1006 frequency-matched controls), we conducted multivariable-adjusted unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for lifestyle factors (lifetime alcohol intake, body mass index [BMI] in the year before diagnosis, lifetime recreational physical activity [RPA], and nonsteroidal anti-inflammatory drug use) in association with breast cancer stratified by age (<65 vs. 65+). We examined estrogen-related subgroups by (1) further stratifying by hormone replacement therapy (HRT) use and (2) restricting cases to estrogen receptor (ER)+/progesterone receptor (PR)+ cancers. RESULTS: Postmenopausal breast cancer incidence in women 65 years and older was positively associated with alcohol intake (OR = 1.79 for 15-30 g/day vs. nondrinkers, 95% CI: 1.03-3.12) and BMI (OR = 1.83 for BMI ≥30 vs. <25, 95% CI: 1.29-2.60), and inversely with RPA (OR = 0.69 for fourth quartile vs. inactive, 95% CI: 0.47-1.03). For postmenopausal women younger than 65, ORs were closer to the null. Tests for heterogeneity by age were significant at the p < 0.10 level for BMI and RPA, but not alcohol. Among older women, associations were stronger among never users of HRT and for those with ER+/PR+ cancers. The inverse associations with aspirin use did not differ by age. CONCLUSIONS: Interventions targeting modifiable lifestyle factors may reduce the burden of postmenopausal breast cancer among older women.