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The role of diet on Coronavirus Disease 2019 (COVID-19) is emerging. We investigated the association between usual diet before the onset of the pandemic and risk and severity of subsequent SARS-CoV-2 infection.We included 42,935 participants aged 55-99 y in 2 ongoing cohort studies, the Nurses' Health Study II and Health Professionals Follow-up Study, who completed a series of COVID-19 surveys in 2020 and 2021. Using data from FFQs before COVID-19, we assessed diet quality using the Alternative Healthy Eating Index (AHEI)-2010, the alternative Mediterranean Diet (AMED) score, an Empirical Dietary Index for Hyperinsulinemia (EDIH), and an Empirical Dietary Inflammatory Pattern (EDIP). We calculated multivariable-adjusted ORs and 95% CIs for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and severity of COVID-19 after controlling for demographic, medical, and lifestyle factors.Among 19,754 participants tested for SARS-CoV-2, 1941 participants reported a positive result. Of these, 1327 reported symptoms needing assistance and another 109 were hospitalized. Healthier diets, represented by higher AHEI-2010 and AMED scores and lower EDIH and EDIP scores, were associated with lower likelihood of SARS-CoV-2 infection (quartile 4 compared with quartile 1: OR: 0.80; 95% CI: 0.69, 0.92 for AHEI-2010; OR: 0.78; 95% CI: 0.67, 0.92 for AMED; OR: 1.36; 95% CI: 1.16, 1.57 for EDIH; and OR: 1.13; 95% CI: 0.99, 1.30 for EDIP; all P-trend ≤ 0.01). In the analysis of COVID-19 severity, participants with healthier diet had lower likelihood of severe infection and were less likely to be hospitalized owing to COVID-19. However, associations were no longer significant after controlling for BMI and pre-existing medical conditions.Diet may be an important modifiable risk factor for SARS-CoV-2 infection, as well as for severity of COVID-19. This association is partially mediated by BMI and pre-existing medical conditions.

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Calcium intake has been associated with a lower risk of colorectal cancer. Calcium signaling may enhance T-cell proliferation and differentiation, and contribute to T-cell–mediated antitumor immunity. In this prospective cohort study, we investigated the association between calcium intake and colorectal cancer risk according to tumor immunity status to provide additional insights into the role of calcium in colorectal carcinogenesis. The densities of tumor-infiltrating T-cell subsets [CD3+, CD8+, CD45RO (PTPRC)+, or FOXP3+ cell] were assessed using IHC and computer-assisted image analysis in 736 cancer cases that developed among 136,249 individuals in two cohorts. HRs and 95% confidence intervals (CI) were calculated using Cox proportional hazards regression. Total calcium intake was associated with a multivariable HR of 0.55 (comparing ≥1,200 vs. Ptrend = 0.002) for CD8+ T-cell–low but not for CD8+ T-cell–high tumors (HR = 1.02; 95% CI, 0.67–1.55; Ptrend = 0.47). Similarly, the corresponding HRs (95% CIs) for calcium for low versus high T-cell–infiltrated tumors were 0.63 (0.42–0.94; Ptrend = 0.01) and 0.89 (0.58–1.35; Ptrend = 0.20) for CD3+; 0.58 (0.39–0.87; Ptrend = 0.006) and 1.04 (0.69–1.58; Ptrend = 0.54) for CD45RO+; and 0.56 (0.36–0.85; Ptrend = 0.006) and 1.10 (0.72–1.67; Ptrend = 0.47) for FOXP3+, although the differences by subtypes defined by T-cell density were not statistically significant. These potential differential associations generally appeared consistent regardless of sex, source of calcium intake, tumor location, and tumor microsatellite instability status. Our findings suggest a possible role of calcium in cancer immunoprevention via modulation of T-cell function.

Characteristics of the participating cohorts

Kaplan-Meier survival curves by prediagnostic dietary calcium intakes, stratified by stage, histologic type, and grade

This file contains Supplementary Tables 1-3. Supplementary Table 1 gives the distribution of prostate cancer cases by subtype included in the pooled Analyses of fruit, vegetable, and mature bean consumption and prostate cancer risk. Supplementary Table 2 gives the results of analyses using all main exposures modeled continuously. Supplementary Table 3 provides information on funding information for all cohort studies included in the pooled analysis.

Background: Lung cancer is the leading cause of cancer death. Little is known about whether prediagnostic nutritional factors may affect survival. We examined the associations of prediagnostic calcium intake from foods and/or supplements with lung cancer survival.Methods: The present analysis included 23,882 incident, primary lung cancer patients from 12 prospective cohort studies. Dietary calcium intake was assessed using food-frequency questionnaires at baseline in each cohort and standardized to caloric intake of 2,000 kcal/d for women and 2,500 kcal/d for men. Stratified, multivariable-adjusted Cox regression was applied to compute hazard ratios (HR) and 95% confidence intervals (CI).Results: The 5-year survival rates were 56%, 21%, and 5.7% for localized, regional, and distant stage lung cancer, respectively. Low prediagnostic dietary calcium intake (Conclusions: This large pooled analysis is the first, to our knowledge, to indicate that low prediagnostic dietary calcium intake may be associated with poorer survival among early-stage lung cancer patients.Impact: This multinational prospective study linked low calcium intake to lung cancer prognosis. Cancer Epidemiol Biomarkers Prev; 26(7); 1060–70. ©2017 AACR.

Background: Relationships between fruit, vegetable, and mature bean consumption and prostate cancer risk are unclear.Methods: We examined associations between fruit and vegetable groups, specific fruits and vegetables, and mature bean consumption and prostate cancer risk overall, by stage and grade, and for prostate cancer mortality in a pooled analysis of 15 prospective cohorts, including 52,680 total cases and 3,205 prostate cancer–related deaths among 842,149 men. Diet was measured by a food frequency questionnaire or similar instrument at baseline. We calculated study-specific relative risks using Cox proportional hazards regression, and then pooled these estimates using a random effects model.Results: We did not observe any statistically significant associations for advanced prostate cancer or prostate cancer mortality with any food group (including total fruits and vegetables, total fruits, total vegetables, fruit and vegetable juice, cruciferous vegetables, and tomato products), nor specific fruit and vegetables. In addition, we observed few statistically significant results for other prostate cancer outcomes. Pooled multivariable relative risks comparing the highest versus lowest quantiles across all fruit and vegetable exposures and prostate cancer outcomes ranged from 0.89 to 1.09. There was no evidence of effect modification for any association by age or body mass index.Conclusions: Results from this large, international, pooled analysis do not support a strong role of collective groupings of fruits, vegetables, or mature beans in prostate cancer.Impact: Further investigation of other dietary exposures, especially indicators of bioavailable nutrient intake or specific phytochemicals, should be considered for prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 26(8); 1276–87. ©2017 AACR.

Glioma is an aggressive neoplasm of the brain with poorly understood etiology. A limited number of pathogens have been examined as glioma risk factors, but data from prospective studies with infection status determined before disease are lacking. Herpesviruses comprise a large family of DNA viruses that infect humans and are linked to a range of chronic diseases. We conducted a prospective evaluation of the association between antibody to six human herpesviruses and glioma risk in the Janus Serum Bank (Janus) and the Cancer Prevention Study-II (CPS-II). In Janus and CPS-II, the risk for glioma was not related to seroprevalence of herpes simplex virus-1, varicella zoster virus, or human herpes viruses 6A or 6B. In Janus, seropositivity to either the Epstein Barr virus (EBV) EA[D] or VCAp18 antigen was associated with a lower risk of glioma (ORs: 0.55 [95% CI 0.32-0.94] and 0.57 [95% CI 0.38-0.85]). This inverse association was consistent by histologic subtype and was observed for gliomas diagnosed up to two decades following antibody measurement. In Janus, seropositivity to at least one of three examined cytomegalovirus (CMV) antigens (pp150, pp52, pp28) was associated with an increased risk of nonglioblastoma (OR: 2.08 [95% CI 1.07-4.03]). This association was limited to tumors diagnosed within 12 years of antibody measurement. In summary, we report evidence of an inverse association between exposure to EBV and glioma. We further report that CMV exposure may be related to a higher likelihood of the nonglioblastoma subtype.

Pancreatic cancer (PC) is the fourth leading cause of cancer mortality among women in the United States. Obesity is positively associated with PC risk. Current health recommendations focus on weight maintenance for healthy-weight individuals and weight loss for overweight/obese individuals; however, little research has assessed associations between PC risk and changes in weight throughout the life course. Using prospective cohort study data, we examined the relationship between baseline adulthood weight patterns self-reported between 1993 and 1998 and PC risk in 136,834 postmenopausal women with 873 incident PC cases through September 30, 2015, in the Women’s Health Initiative. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models, adjusting for age, smoking habits, heavy alcohol consumption, and body mass index. Compared with women with stable weight, no significant associations were found between steady weight gain (HR = 1.01, 95% CI: 0.83, 1.22), sustained weight loss (HR = 1.26, 95% CI: 0.85, 1.87), or weight cycling patterns (HR = 1.08, 95% CI: 0.89, 1.30) and PC. Results were similar when the outcome definition was restricted to pancreatic adenocarcinoma cases. Overall, we did not find evidence to suggest that weight changes in adulthood significantly impact PC risk among postmenopausal women.

Introduction: Ultra-processed foods (UPF) are associated with cardiovascular disease (CVD) in European populations. Evidence is limited from U.S. populations, for specific UPF subgroups, and in the diet quality context. Hypothesis: We hypothesized that U.S. women with higher UPF intake have higher CVD risk and evaluated this association by UPF subgroup and diet quality. Methods: Women from the Nurses' Health Study (NHS; n=75,639; 30-55y) and NHSII (n=90,770; 25-42y) with complete dietary intake data and without CVD/cancer at baseline were prospectively followed (1984-2014 and 1991-2015). Diet, demographics, lifestyle, and medical history were assessed every 2-4y using validated food frequency questionnaires and follow-up questionnaires. NOVA-classified UPF (% of energy) included ten subgroups: bread and cereals; sauces, spreads, and condiments; sweet snacks and desserts; savory snacks; sugar-sweetened beverages; animal-based products; ready-to-eat/heat dishes; yogurt and dairy desserts; hard liquors, and artificially sweetened beverages. The Alternative Healthy Eating Index (AHEI) measured diet quality. Primary outcomes were non-fatal myocardial infarction, fatal coronary heart disease (CHD), and non-fatal/fatal stroke. Multivariable-adjusted Cox regression estimated the associations of cumulatively-averaged UPF and subgroup intake quintiles with CVD risk. Each cohort was analyzed separately, and data were meta-analyzed (fixed effects models). Results: We identified 7,659 CVD cases (CHD=3,889; stroke=3,855) in NHS during 2,002,986 person-years of follow-up, and 1,588 CVD cases (CHD=807; stroke=786) in NHSII during 2,308,569 person-years. Pooled multivariable-adjusted hazard ratios [HRs (95%CIs)] of CVD, CHD, and stroke for the highest quintile of UPF intake ( vs. lowest) were 1.11 (1.04, 1.19; p-trend =0.002), 1.18 (1.08, 1.30; p-trend p-trend =0.37), respectively. Positive associations remained for participants with higher diet quality (AHEI above the sample median): CVD [HR=1.15 (1.05, 1.25; p-trend =0.009)] and CHD [HR=1.24 (1.09, 1.41; p-trend =0.007)]. Values of I 2 were non-significant. For UPF subgroups, intake for the highest quintile of sugar-sweetened beverages and animal-based products was significantly associated with higher risk of CVD, CHD, and stroke. Significant inverse associations were noted for bread and cereals and yogurt and dairy dessert with CVD, CHD, and stroke, for savory snacks with CHD, and for ready-to-eat/heat dishes with stroke. Conclusion: U.S. women with long-term higher total UPF intake had a higher CHD risk, even with a high-quality diet. Sugary drinks and animal-based products were predominant for CVD risk. Some UPF subgroups may contain beneficial components, warranting more nuanced food subgroup analyses. Replication is needed in racially/ethnically-diverse populations.

PURPOSE: The association between alcohol intake and glioma remains unclear. We evaluated the association between alcohol intake and incidence of glioma in three large, prospective cohort studies with repeated alcohol assessments. METHODS: We harnessed data from three studies with repeat alcohol assessment to compute hazard ratios (HR) and 95% confidence intervals (CI) for glioma by overall alcohol intake and intake from specific beverages using Cox proportional hazards regression, adjusted for age, cohort, body mass index, smoking status, and caloric intake. Analyses were conducted separately for glioma overall and for glioblastoma (GBM). RESULTS: We confirmed 554 incident glioma cases (362 GBM) among 237,505 participants with 6,216,378 person-years of follow up. Cumulative average alcohol intake was associated with reduced risk of glioma (HR=0.75, 95%CI:0.56–0.99 comparing >8–15 to ≤0.5 g/d; HR=0.71, 95%CI:0.53–0.96 comparing >15 g/d to ≤0.5 g/d). When stratified by sex, for the same comparisons, the HRs for men were 0.57 (95%CI:0.36–0.89) and 0.79 (0.53–1.16), and for women 0.90 (95%CI:0.62–1.30) and 0.62, 95%CI:0.39–0.97. Results were consistent when examining cumulative average, baseline, and recent intake, and with a 4 year lag. CONCLUSION: These results provide evidence against a positive association between alcohol intake and glioma risk. Alcohol intake was associated with reduced risk of glioma in both men and women.

BACKGROUND: Epidemiologic studies examining the relations between dairy product and calcium intakes and breast cancer have been inconclusive, especially for tumor subtypes. OBJECTIVE: To evaluate the associations between intakes of specific dairy products and calcium and risk of breast cancer overall and for subtypes defined by estrogen receptor (ER) status. METHOD: We pooled the individual-level data of over 1 million women who were followed for a maximum of 8–20 years across studies. Associations were evaluated for dairy product and calcium intakes and risk of incident invasive breast cancer overall (n = 37,861 cases) and by subtypes defined by ER status. Study-specific multivariable hazard ratios (HRs) were estimated and then combined using random-effects models. RESULTS: Overall, no clear association was observed between the consumption of specific dairy foods, dietary (from foods only) calcium, and total (from foods and supplements) calcium, and risk of overall breast cancer. Although each dairy product showed a null or very weak inverse association with risk of overall breast cancer (P, test for trend >0.05 for all), differences by ER status were suggested for yogurt and cottage/ricotta cheese with associations observed for ER-negative tumors only (pooled HR = 0.90, 95% CI: 0.83, 0.98 comparing ≥60 g/d with

Background: Patients with cancer are recommended to follow cancer prevention guidelines due to inadequate evidence for specific recommendations for cancer survivors. Methods: We examined whether diet and lifestyle scores measuring adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention guidelines were associated with colorectal cancer–specific and overall mortality among 1,491 patients with colorectal cancer in two prospective cohorts. Cox proportional hazards regression models were used to calculate the multivariable-adjusted HRs and 95% confidence intervals (CI). Results: During a median follow-up of 7.92 years, there were 641 deaths (179 colorectal cancer–specific deaths). Patients in the highest quartile of the post-diagnostic WCRF/AICR lifestyle score including diet, body mass index (BMI), and physical activity had a 24% lower risk (HR = 0.76, 95% CI: 0.49–1.18) of colorectal cancer–specific mortality and a 37% lower risk (HR = 0.63, 95% CI: 0.50–0.78) of overall mortality compared with the lowest quartile. When BMI was not included in the lifestyle score due to potential disease-related weight loss, stronger inverse associations were observed for both colorectal cancer–specific and overall mortality for the same comparison (colorectal cancer–specific: HR = 0.50, 95% CI: 0.32–0.79; overall: HR = 0.59, 95% CI: 0.47–0.75). The post-diagnostic WCRF/AICR diet score was not statistically significantly associated with either colorectal cancer–specific or overall mortality. Conclusions: Greater adherence to the WCRF/AICR cancer prevention recommendations was associated with improved survival in patients with colorectal cancer. Impact: This study provides support for patients with colorectal cancer to follow cancer prevention recommendations after diagnosis. Future studies on cancer survivors will continue to contribute to evidence-based diet and lifestyle recommendations for patients with cancer.

BACKGROUND: The influence of a high sugar diet on colorectal cancer (CRC) survival is unclear. METHODS: Among 1463 stage I–III CRC patients from the Nurses’ Health Study and Health Professionals Follow-up Study, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC-specific and all-cause mortality in relation to intake of post-diagnosis sugar-sweetened beverages (SSB), artificially sweetened beverages (ASB), fruit juice, fructose and other sugars. RESULTS: Over a median 8.0 years, 781 cases died (173 CRC-specific deaths). Multivariable-adjusted HRs for post-diagnosis intake and CRC-specific mortality were 1.21 (95% CI: 0.87–1.68) per 1 serving SSBs per day (serving/day) and 1.24 (95% CI: 0.95–1.63) per 20 grams fructose per day. Significant positive associations for CRC-specific mortality were primarily observed ≤5 years from diagnosis (HR per 1 serving/day of SSBs = 1.59, 95% CI: 1.06–2.38). Significant inverse associations were observed between ASBs and CRC-specific and all-cause mortality (HR for ≥5 versus

Background Folate may play a preventive role in the early stages of colorectal carcinogenesis, but long latencies may be needed to observe a reduction in colorectal cancer (CRC) incidence. In addition, concerns have been raised about the potential for cancer promotion with excessive folate intake, especially after the mandatory folic acid fortification in the United States in 1998. Objective We aimed to examine the association between folate intake in different chemical forms and CRC risk, especially in the postfortification era in the United States. Design We prospectively followed 86,320 women from the Nurses' Health Study (1980-2016). Folate intake was collected by validated food frequency questionnaires. CRC was self reported and confirmed by review of medical records. The association between the folate intake and CRC risk was assessed using Cox proportional hazards regression. Results We documented 1988 incident CRC cases during follow-up. Analyzing folate intake as a continuous variable, greater total folate intake 12-24 y before diagnosis was associated with lower risk of CRC (per increment of 400 dietary folate equivalents (DFE)/d, HR: 0.93, 95% CI: 0.85, 1.01 for 12-16 y; HR: 0.83, 95% CI: 0.75, 0.92 for 16-20 y; and HR: 0.87, 95% CI: 0.77, 0.99 for 20-24 y); and greater synthetic folic acid intake 16-24 y before diagnosis was also associated with a lower CRC risk (per increment of 400 DFE/d, HR: 0.91, 95% CI: 0.84, 0.99 for 16-20 y and HR: 0.91, 95% CI: 0.83-1.01 for 20-24 y). In the postfortification period (1998-2016), intake of total or specific forms of folate was not associated with CRC risk, even among multivitamin users. Conclusions Folate intake, both total and from synthetic forms, was associated with a lower risk of overall CRC after long latency periods. There was no evidence that high folate intake in the postfortification period was related to increased CRC risk in this US female population.

Background Although colorectal cancer (CRC) incidence in the USA is declining overall, its incidence is increasing among those younger than 50 years of age. The reasons underlying the increasing trend are largely unknown, although behavioral changes, such as unhealthy diet and lifestyle factors, may be partially responsible. Design A prospective cohort study included 94 217 women aged 26-45 years at baseline. Validated anthropometric measures and lifestyle information were self-reported biennially. Exposures were four recommendation-based dietary indices—the prime diet quality score and three plant-based dietary indices; and two mechanism-based indices—the empirical dietary and lifestyle index for hyperinsulinemia (EDIH and ELIH). We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for overall CRC and for early-onset (before age 50) and after age 50 CRC separately. Results We documented 332 cases of CRC during 24 years of follow-up (2 113 655 person-years), with an average age of 52 ± 7 years at diagnosis. Hyperinsulinemic dietary and lifestyle patterns were associated with a higher risk of CRC. Multivariable-adjusted HRs (95% CIs) comparing participants in the highest versus lowest quartile were: 1.67 for EDIH (95% CI: 1.15-2.44, P-trend = 0.01) and 1.51 for ELIH (95% CI: 1.10-2.08, P-trend = 0.01). Moreover, per 75% increment in rank, ELIH appeared to be a stronger risk factor for early-onset CRC (HR = 1.86, 95% CI: 1.12-3.07) than after age 50 CRC (HR = 1.20, 95% CI: 0.83-1.73, P-heterogeneity = 0.16). The four recommendation-based indices were not significantly associated with overall, early-onset, or after age 50 CRC risk (per 75% increment in rank, HRs ranged from 0.75 to 1.28). Conclusion Dietary and lifestyle patterns contributing to hyperinsulinemia were associated with greater CRC risk in younger women. Moreover, the hyperinsulinemic lifestyle showed a suggestively stronger positive association with early-onset CRC risk, compared with after age 50 CRC. Our findings suggest that dietary and lifestyle interventions to reduce insulinemic potential may be effective for CRC prevention among younger women.

Heavy alcohol consumption in mid-adulthood is an established risk factor of colorectal cancer (CRC). Alcohol use in early adulthood is common, but its association with subsequent CRC risk remains largely unknown. We prospectively investigated the association of average alcohol intake in early adulthood (age 18-22) with CRC risk later in life among 191,543 participants of the Nurses’ Health Study ([NHS], 1988-2014), NHSII (1989-2015) and Health Professionals Follow-Up Study (1988-2014). Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs), which were pooled using random effects models. We documented 2,624 CRC cases. High alcohol consumption in early adulthood (≥15 g/day) was associated with a higher CRC risk (multivariable HR 1.28, 95% CI 0.99 to 1.66, P(trend)=0.02; P(heterogeneity)=0.44), after adjusting for potential confounding factors in early adulthood. Among never/light smokers in early adulthood, the risk associated with high alcohol consumption in early adulthood was elevated (HR 1.53, 95% CI 1.04 to 2.24), compared with those who had

Associations between anthropometric factors and breast cancer (BC) risk have varied inconsistently by estrogen and/or progesterone receptor (ER/PR) status. Associations between prediagnostic anthropometric factors and risk of premenopausal and postmenopausal BC overall and ER/PR status subtypes were investigated in a pooled analysis of 20 prospective cohorts, including 36,297 BC cases among 1,061,915 women, using multivariable Cox regression analyses, controlling for reproductive factors, diet and other risk factors. We estimated dose–response relationships and tested for nonlinear associations using restricted cubic splines. Height showed positive, linear associations for premenopausal and postmenopausal BC risk (6–7% RR increase per 5 cm increment), with stronger associations for receptor-positive subtypes. Body mass index (BMI) at cohort baseline was strongly inversely associated with premenopausal BC risk, and strongly positively—and nonlinearly—associated with postmenopausal BC (especially among women who never used hormone replacement therapy). This was primarily observed for receptor-positive subtypes. Early adult BMI (at 18–20 years) showed inverse, linear associations for premenopausal and postmenopausal BC risk (21% and 11% RR decrease per 5 kg/m2, respectively) with stronger associations for receptor-negative subtypes. Adult weight gain since 18–20 years was positively associated with postmenopausal BC risk, stronger for receptor-positive subtypes, and among women who were leaner in early adulthood. Women heavier in early adulthood generally had reduced premenopausal BC risk, independent of later weight gain. Positive associations between height, baseline (adult) BMI, adult weight gain and postmenopausal BC risk were substantially stronger for hormone receptor-positive versus negative subtypes. Premenopausal BC risk was positively associated with height, but inversely with baseline BMI and weight gain (mostly in receptor-positive subtypes). Inverse associations with early adult BMI seemed stronger in receptor-negative subtypes of premenopausal and postmenopausal BC. Electronic supplementary material The online version of this article (10.1007/s10654-020-00688-3) contains supplementary material, which is available to authorized users.

Laboratory and animal research support a protective role for vitamin D in breast carcinogenesis, but epidemiologic studies have been inconclusive. To examine comprehensively the relationship of circulating 25-hydroxyvitamin D [25(OH)D] to subsequent breast cancer incidence, we harmonized and pooled participant-level data from 10 U.S. and 7 European prospective cohorts. Included were 10,484 invasive breast cancer cases and 12,953 matched controls. Median age (interdecile range) was 57 (42-68) years at blood collection and 63 (49-75) years at breast cancer diagnosis. Prediagnostic circulating 25(OH)D was either newly measured using a widely accepted immunoassay and laboratory or, if previously measured by the cohort, calibrated to this assay to permit using a common metric. Study-specific relative risks (RRs) for season-standardized 25(OH)D concentrations were estimated by conditional logistic regression and combined by random-effects models. Circulating 25(OH)D increased from a median of 22.6 nmol/L in consortium-wide decile 1 to 93.2 nmol/L in decile 10. Breast cancer risk in each decile was not statistically significantly different from risk in decile 5 in models adjusted for breast cancer risk factors, and no trend was apparent (P-trend = 0.64). Compared to women with sufficient 25(OH)D based on Institute of Medicine guidelines (50- 62.5 nmol/L), RRs were not statistically significantly different at either low concentrations ( 20 nmol/L, 3% of controls) or high concentrations (100- 125 nmol/L, 3% of controls; ≥ 125 nmol/L, 0.7% of controls). RR per 25 nmol/L increase in 25(OH)D was 0.99 [95% confidence intervaI (CI) 0.95-1.03]. Associations remained null across subgroups, including those defined by body mass index, physical activity, latitude, and season of blood collection. Although none of the associations by tumor characteristics reached statistical significance, suggestive inverse associations were seen for distant and triple negative tumors. Circulating 25(OH)D, comparably measured in 17 international cohorts and season-standardized, was not related to subsequent incidence of invasive breast cancer over a broad range in vitamin D status.

Participant level meta-analysis across multiple studies increases the sample size for pooled analyses, thereby improving precision in effect estimates and enabling subgroup analyses. For analyses involving biomarker measurements as an exposure of interest, investigators must first calibrate the data to address measurement variability arising from usage of different laboratories and/or assays. In practice, the calibration process involves reassaying a random subset of biospecimens from each study at a central laboratory and fitting models that relate the study-specific "local" and central laboratory measurements. Previous work in this area treats the calibration process from the perspective of measurement error techniques and imputes the estimated central laboratory value among individuals with only a local laboratory measurement. In this work, we propose a repeated measures method to calibrate biomarker measurements pooled from multiple studies with study-specific calibration subsets. We account for correlation between measurements made on the same person and between measurements made at the same laboratory. We demonstrate that the repeated measures approach provides valid inference, and compare it to existing calibration approaches grounded in measurement error techniques in an example describing the association between circulating vitamin D and stroke., Comment: 25 pages, 2 figures, 3 tables

PURPOSE: The association of dietary patterns with testosterone (T) and sex hormone binding globulin (SHBG) levels remains unclear. We investigated the associations of dietary patterns with T and SHBG levels to determine whether these associations vary by obesity status. METHODS: A cross-sectional analysis was conducted in 1376 middle-aged (≥ 40 years old) men of the Health Professionals Follow-up Study. Prudent (rich in whole grains and dietary fiber) and Western (rich in red meat and refined grains) diet scores were identified using principal component analysis. The Alternate Healthy Eating Index 2010 (AHEI-2010) score, a measure of overall diet quality, was defined based on foods and nutrients predictive of chronic disease risk. RESULTS: We identified a weak inverse association between AHEI-2010 and T levels (P(trend) = 0.07), but no associations with other dietary patterns. Null associations were observed between diet scores and SHBG. Obesity status appeared to modify the associations for the Prudent diet and AHEI-2010 with both T and SHBG (P(interaction) ≤ 0.05). T levels were lower (Q1 vs. Q4, 4.23 vs. 3.38) and SHBG higher (Q1 vs. Q4, 48.6 vs. 64.3) with adherence to a more prudent diet among obese men (P(trends) ≤ 0.05). CONCLUSION: We observed a weak inverse association between AHEI-2010 and T levels. Null associations were identified for SHBG. Obesity status seemed to modulate associations of T and SHBG levels with diet scores, especially the AHEI-2010 and prudent diets. However, this research question warrants further investigation in prospective studies.

Background: Higher total 25-hydroxyvitamin D [25(OH)D] levels are associated with improved survival among patients with colorectal cancer, but the relationships between circulating vitamin D binding protein (VDBP), and bioavailable or free 25(OH)D, and colorectal cancer survival remain unknown. Methods: We examined the associations between prediagnostic plasma levels of vitamin D–related markers and survival among 603 White participants diagnosed with colorectal cancer from two prospective U.S. cohorts. Plasma VDBP and total 25(OH)D were directly measured, while bioavailable and free 25(OH)D was calculated using a validated formula on the basis of total 25(OH)D, VDBP, and albumin levels. Cox proportional hazards regression was used to estimate HRs for overall and colorectal cancer–specific mortality, with adjustment for other prognostic markers and potential confounders. Results: Higher VDBP levels were associated with improved overall (Ptrend = 0.001) and colorectal cancer–specific survival (Ptrend = 0.02). Compared with patients in the lowest quartile, those in the highest quartile of VDBP had a multivariate HR of 0.58 [95% confidence interval (CI), 0.41–0.80] for overall mortality and 0.58 (95% CI, 0.37–0.91) for colorectal cancer–specific mortality. The results remained similar after further adjustment for total 25(OH)D levels. In contrast, neither bioavailable nor free 25(OH)D levels were associated with overall or colorectal cancer–specific mortality (all Ptrend > 0.15). Conclusions: Prediagnostic circulating concentrations of VDBP were positively associated with survival among patients with colorectal cancer. Impact: The clinical utility of VDBP as a prognostic marker warrants further exploration, as well as research into underlying mechanisms of action.

Background: Advanced prostate cancer etiology is poorly understood. Few studies have examined associations of anthropometric factors (e.g. early adulthood obesity) with advanced prostate cancer risk.Patients and methods: We carried out pooled analyses to examine associations between body fatness, height, and prostate cancer risk. Among 830 772 men, 51 734 incident prostate cancer cases were identified, including 4762 advanced (T4/N1/M1 or prostate cancer deaths) cases, 2915 advanced restricted (same as advanced, but excluding localized cancers that resulted in death) cases, 9489 high-grade cases, and 3027 prostate cancer deaths. Cox proportional hazards models were used to calculate study-specific hazard ratios (HR) and 95% confidence intervals (CI); results were pooled using random effects models.Results: No statistically significant associations were observed for body mass index (BMI) in early adulthood for advanced, advanced restricted, and high-grade prostate cancer, and prostate cancer mortality. Positive associations were shown for BMI at baseline with advanced prostate cancer (HR = 1.30, 95% CI = 0.95-1.78) and prostate cancer mortality (HR = 1.52, 95% CI = 1.12-2.07) comparing BMI >= 35.0 kg/m(2) with 21-22.9 kg/m(2). When considering early adulthood and baseline BMI together, a 27% higher prostate cancer mortality risk (95% CI = 9% to 49%) was observed for men with BMI = 30.0 kg/m(2) at baseline compared with BMI = 110 cm with = 1.00 with = 1.90 m withConclusion: Our findings suggest that height and total and central adiposity in mid-to-later adulthood, but not early adulthood adiposity, are associated with risk of advanced forms of prostate cancer. Thus, maintenance of healthy weight may help prevent advanced prostate cancer.

Background: Red and processed meat consumption has been consistently associated with increased risk of colorectal cancer (CRC), but the association for fish intake is unclear. Evidence using objective dietary assessment approaches to evaluate these associations is sparse. Objectives: We aim to investigate the plasma metabolite profiles related to red meat, poultry, and fish consumption and examine their associations with CRC risk. Methods: We measured plasma metabolites among 5269 participants from the Nurses’ Health Study (NHS), NHSII, and Health Professionals Follow-Up study (HPFS). We calculated partial Spearman correlations between each metabolite and self-reported intake of seven red meat, poultry, and fish groups. Metabolite profile scores correlated to self-reported dietary intakes were developed using elastic net regression. Associations between self-reported intakes, metabolite profile scores, and subsequent CRC risk were further evaluated using conditional logistic regression among 559 matched (1:1) case-control pairs in NHS/HPFS and replicated among 266 pairs in Women’s Health Study. Results: Plasma metabolites, especially highly unsaturated lipids, were differentially associated with red meat and fish groups. Metabolite profile scores for each food group were significantly correlated with the corresponding self-reported dietary intake. A higher dietary intake of processed red meat was associated with a higher risk of CRC (pooled OR per 1 SD, 1.15; 95% CI: 1.03, 1.29). In contrast, higher metabolite profile scores for all fish groups, not dietary intakes, were consistently associated with a lower CRC risk: the pooled OR per 1 SD was 0.86 (95% CI: 0.78, 0.96) for total fish, 0.86 (95% CI: 0.77, 0.96) for dark meat fish, and 0.87 (95% CI: 0.78, 0.97) for canned tuna fish. No significant associations were found for other food groups. Conclusions: Red meat and fish intake exhibited systematically different plasma metabolite profiles. Plasma metabolite profile of fish intake was inversely associated with CRC risk.

Background Although colorectal cancer (CRC) incidence is declining among adults aged ≥65 years, CRC incidence in younger adults has been rising. The protective role of calcium in colorectal carcinogenesis has been well established, but evidence is lacking on whether the association varies by age at diagnosis. We investigated the association between total calcium intake and risk of overall CRC and CRC before age 55 years. Methods In the Nurses’ Health Study II (1991–2015), 94 205 women aged 25–42 years at baseline were included in the analysis. Diet was assessed every 4 years through validated food frequency questionnaires. Multivariable-adjusted hazard ratios (HRs) and 95% CIs for CRC were estimated using the Cox proportional hazards model. Results We documented 349 incident CRC cases during 2 202 604 person-years of follow-up. Higher total calcium intake was associated with a reduced risk of CRC. Compared with those with Conclusions In a cohort of younger women, which reflects the birth cohorts, time periods and age ranges paralleling the recent rise in CRC, higher calcium intake was associated with a decreased risk of CRC.

Obesity is known to be associated with primary liver cancer (PLC), but the separate effects of excess abdominal and gluteofemoral size are unclear. Thus, we examined the association between waist and hip circumference with risk of PLC overall and by histologic type-hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The Liver Cancer Pooling Project is a consortium of prospective cohort studies that include data from 1,167,244 individuals (PLC n = 2,208, HCC n = 1,154, ICC n = 335). Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Waist circumference, per 5 cm increase, was associated with an 11% increased PLC risk (HR = 1.11, 95%CI: 1.09-1.14), including when adjusted for hip circumference (HR = 1.12, 95%CI: 1.08-1.17) and also when restricted to individuals in a normal body mass index (BMI) range (18.5 to

Background Excess body weight is an established cause of postmenopausal breast cancer, but it is unknown if weight loss reduces risk. Methods Associations between weight change and risk of breast cancer were examined among women aged 50 years and older in the Pooling Project of Prospective Studies of Diet and Cancer. In 10 cohorts, weight assessed on three surveys was used to examine weight change patterns over approximately 10 years (interval 1 median = 5.2 years; interval 2 median = 4.0 years). Sustained weight loss was defined as no less than 2 kg lost in interval 1 that was not regained in interval 2. Among 180 885 women, 6930 invasive breast cancers were identified during follow-up. Results Compared with women with stable weight (±2 kg), women with sustained weight loss had a lower risk of breast cancer. This risk reduction was linear and specific to women not using postmenopausal hormones (>2–4.5 kg lost: hazard ratio [HR] = 0.82, 95% confidence interval [CI] = 0.70 to 0.96; >4.5– Conclusions These results suggest that sustained weight loss, even modest amounts, is associated with lower breast cancer risk for women aged 50 years and older. Breast cancer prevention may be a strong weight-loss motivator for the two-thirds of American women who are overweight or obese.

BackgroundLittle is known about the association between physical activity before cancer diagnosis and survival among lung cancer patients. In this pooled analysis of 11 prospective cohorts, we investigated associations of prediagnosis leisure-time physical activity (LTPA) with all-cause and lung cancer–specific mortality among incident lung cancer patients.MethodsUsing self-reported data on regular engagement in exercise and sports activities collected at study enrollment, we assessed metabolic equivalent hours (MET-h) of prediagnosis LTPA per week. According to the Physical Activity Guidelines for Americans, prediagnosis LTPA was classified into inactivity, less than 8.3 and at least 8.3 MET-h per week (the minimum recommended range). Cox regression was used to estimate hazard ratios (HRs) and 95% confidence interval (CIs) for all-cause and lung cancer–specific mortality after adjustment for major prognostic factors and lifetime smoking history.ResultsOf 20 494 incident lung cancer patients, 16 864 died, including 13 596 deaths from lung cancer (overall 5-year relative survival rate = 20.9%, 95% CI = 20.3% to 21.5%). Compared with inactivity, prediagnosis LTPA of more than 8.3 MET-h per week was associated with a lower hazard of all-cause mortality (multivariable-adjusted HR = 0.93, 95% CI = 0.88 to 0.99), but not with lung cancer–specific mortality (multivariable-adjusted HR = 0.99, 95% CI = 0.95 to 1.04), among the overall population. Additive interaction was found by tumor stage (Pinteraction = .008 for all-cause mortality and .003 for lung cancer–specific mortality). When restricted to localized cancer, prediagnosis LTPA of at least 8.3 MET-h per week linked to 20% lower mortality: multivariable-adjusted HRs were 0.80 (95% CI = 0.67 to 0.97) for all-cause mortality and 0.80 (95% CI = 0.65 to 0.99) for lung cancer–specific mortality.ConclusionsRegular participation in LTPA that met or exceeded the minimum Physical Activity Guidelines was associated with reduced hazards of mortality among lung cancer patients, especially those with early stage cancer.

BACKGROUND Diet quality scores (DQSs) are frequently used to study diet-disease relationships but the validity of these scores derived from food frequency questionnaires (FFQs) has rarely been evaluated. OBJECTIVE To evaluate the validity and reproducibility of six commonly used DQSs derived from the FFQ, including the Alternate Healthy Eating Index-2010 (AHEI-2010), Dietary Approaches to Stop Hypertension (DASH) score, alternative Mediterranean Diet score (AMED), and three plant-based diet indices (overall, healthful, and unhealthful). DESIGN This analysis included 1,394 participants from the Men's (n = 652) and Women's (n = 742) Lifestyle Validation Studies. Participants completed a 152-item FFQ at the beginning of the study and one year later, and completed two weighed 7-day dietary records (7DDRs) and donated two blood samples six-month apart between FFQ assessments. The reproducibility of the FFQs was evaluated by rank intraclass correlation coefficients (ICC). The validity was assessed by comparing FFQ-derived DQSs to those from the average of two 7DDRs using Spearman rank correlation coefficients deattenuated for random measurement error in the 7DDRs (rs). Further, we calculated the correlations between DQSs and plasma biomarkers of diet including fatty acids, folate, carotenoids, retinol, and alpha-and gamma-tocopherol. RESULTS Six FFQ derived DQSs demonstrated moderate to high reproducibility (energy-adjusted ICCs = 0.61 to 0.84) and validity (energy-adjusted, deattenuated rs = 0.56 to 0.80) in both men and women. We consistently observed expected correlations between FFQ derived DQSs with plasma fatty acids, including long chain N-3 and trans fatty acids, most carotenoids, and gamma-tocopherol (rs>0.2). CONCLUSIONS Our study demonstrates the validity of the FFQ to evaluate overall diet quality using six commonly used DQSs. In addition, these DQSs have qualitatively demonstrated biological relevance as indicated by their correlations with circulating biomarkers.

Recent preclinical research strongly suggests that dietary sugars can enhance colorectal tumorigenesis by direct action, particularly in the proximal colon that unabsorbed fructose reaches.We aimed to examine long-term consumption of sugar-sweetened beverages (SSBs) and total fructose in relation to incidence and mortality of colorectal cancer (CRC) by anatomic subsite.We followed 121,111 participants from 2 prospective US cohort studies, the Nurses' Health Study (1984-2014) and Health Professionals Follow-Up Study (1986-2014), for incident CRC and related death. Cox proportional hazards regression was used to compute HRs and 95% CIs.During follow-up, we documented 2733 incident cases of CRC with a known anatomic location, of whom 901 died from CRC. Positive associations of SSB and total fructose intakes with cancer incidence and mortality were observed in the proximal colon but not in the distal colon or rectum (Pheterogeneity ≤ 0.03). SSB consumption was associated with a statistically significant increase in the incidence of proximal colon cancer (HR per 1-serving/d increment: 1.18; 95% CI: 1.03, 1.34; Ptrend = 0.02) and a more pronounced elevation in the mortality of proximal colon cancer (HR: 1.39; 95% CI: 1.13, 1.72; Ptrend = 0.002). Similarly, total fructose intake was associated with increased incidence and mortality of proximal colon cancer (HRs per 25-g/d increment: 1.18; 95% CI: 1.03, 1.35; and 1.42; 95% CI: 1.12, 1.79, respectively). Moreover, SSB and total fructose intakes during the most recent 10 y, rather than those from a more distant period, were associated with increased incidence of proximal colon cancer.SSB and total fructose consumption were associated with increased incidence and mortality of proximal colon cancer, particularly during later stages of tumorigenesis.

Background Several plant foods have been associated with a lower risk of colorectal cancer (CRC). However, not all plant foods are healthy, and little is known about the association between plant-based diets and specific molecular subtypes of CRC. We aimed to examine the association of healthy and unhealthy plant-based diets and the risk of CRC overall and by molecular subtypes. Methods We followed 76,386 women in the Nurses’ Health Study (1984-2014) and 47,387 men in the Health Professionals Follow-up Study (1986-2014) for up to 30 years. Plant-based diets were assessed using two indices derived from the food frequency questionnaires: a healthy plant-based diet index (hPDI) and an unhealthy plant-based diet index (uPDI). Colorectal tumor tissues were collected to measure the status of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and BRAF and KRAS mutations. Results During 3,143,205 person-years of follow-up, we documented 3077 incident CRC cases, including 1244 cases with available molecular marker data. A higher hPDI was associated with lower CRC incidence (hazard ratio [HR] comparing extreme quartiles=0.86, 95% CI: 0.77, 0.96; P-trend=0.04), whereas a higher uPDI was associated with higher CRC incidence (HR comparing extreme quartiles=1.16, 95% CI: 1.04, 1.29; P-trend=0.005). The association of hPDI significantly differed by KRAS status (P-heterogeneity=0.003) but not by other tumor markers. The hPDI was associated with lower incidence of KRAS-wildtype CRC (HR comparing extreme quartiles=0.74, 95% CI: 0.57, 0.96; P-trend=0.004) but not KRAS-mutant CRC (P-trend=0.22). Conclusions A plant-based diet rich in whole grains, fruits, and vegetables was associated with a lower incidence of CRC, especially KRAS-wildtype CRC, whereas a plant-based diet emphasizing unhealthy plant foods such as refined grains might be associated with higher CRC incidence. These data emphasize the importance of differentiating healthy and unhealthy plant foods when promoting plant-based diets for the primary prevention of CRC. The differential association of hPDI by KRAS status suggests the interplay of diet and specific tumor pathways.

BACKGROUND & AIMS: Vitamin D has been implicated in colorectal cancer (CRC) pathogenesis, but it remains unknown whether total vitamin D intake is associated with early-onset CRC and precursors diagnosed before age 50. METHODS: We prospectively examined the association between total vitamin D intake and risks of early-onset CRC and precursors among women enrolled in the Nurses’ Health Study II. Multivariable-adjusted hazard ratio (HR) and 95% confidence interval (CI) for early-onset CRC were estimated with Cox proportional hazards model. Multivariable-adjusted odds ratio (OR) and 95% CI for early-onset conventional adenoma and serrated polyp were estimated with logistic regression model. RESULTS: We documented 111 incident cases of early-onset CRC during 1,250,560 person-years of follow-up (1991 to 2015). Higher total vitamin D intake was significantly associated with a reduced risk of early-onset CRC (HR for ≥450 IU/day vs

Tea and coffee have antioxidant and neuroprotective effects. Observational studies suggest that tea and coffee intake may reduce cancer risk, but data on glioma risk are inconclusive. We evaluated the association between tea, coffee and caffeine intake and glioma risk in the female Nurses’ Health Study (NHS) and Nurses’ Health Study II (NHSII) and the male Health Professionals Follow-Up Study (HPFS). Cumulative intake was derived from validated quadrennial food frequency questionnaires. Glioma cases were confirmed by medical record review. Multivariable-adjusted hazard ratios of glioma by beverage intake category were estimated using Cox proportional hazards models. We documented 554 incident cases of glioma (256 in NHS, 87 in NHSII and 211 in HPFS). Compared to 2 cups/day, p-trend = 0.05), but not in women (HR = 0.74, 95% CI: 0.47–1.18 for >2 cups/day, p-trend = 0.11) or men (HR = 0.70, 95% CI: 0.30–1.60 for >2 cups/day, p-trend = 0.30) separately. Overall, we observed no significant associations between caffeinated, decaffeinated or total coffee intake and glioma risk. There were no material differences in the results with baseline values, 8-year lagged responses, or when limited to glioblastoma (n = 362). In three large prospective cohort studies, tea intake was borderline inversely associated with glioma risk. No significant associations were observed for coffee intake and glioma risk. These results merit further exploration in prospective studies.

Calcium intake has been associated with a lower risk of colorectal cancer. Calcium signaling may enhance T-cell proliferation and differentiation, and contribute to T-cell–mediated antitumor immunity. In this prospective cohort study, we investigated the association between calcium intake and colorectal cancer risk according to tumor immunity status to provide additional insights into the role of calcium in colorectal carcinogenesis. The densities of tumor-infiltrating T-cell subsets [CD3+, CD8+, CD45RO (PTPRC)+, or FOXP3+ cell] were assessed using IHC and computer-assisted image analysis in 736 cancer cases that developed among 136,249 individuals in two cohorts. HRs and 95% confidence intervals (CI) were calculated using Cox proportional hazards regression. Total calcium intake was associated with a multivariable HR of 0.55 (comparing ≥1,200 vs.

BACKGROUND AND PURPOSE: Caffeine is associated with a lower risk of some neurological diseases, but few prospective studies have investigated caffeine intake and risk of amyotrophic lateral sclerosis (ALS) mortality. We therefore determined associations between coffee, tea and caffeine intake, and risk of ALS mortality. METHODS: We conducted pooled analyses of eight international, prospective cohort studies, including 351 565 individuals (120 688 men and 230 877 women). We assessed coffee, tea and caffeine intake using validated food-frequency questionnaires administered at baseline. We used Cox regression to estimate study- and sex-specific risk ratios and 95% confidence intervals (CI) for ALS mortality, which were then pooled using a random-effects model. We conducted analyses using cohort-specific tertiles, absolute common cut-points and continuous measures of all exposures. RESULTS: During follow-up, 545 ALS deaths were documented. We did not observe statistically significant associations between coffee, tea or caffeine intake and risk of ALS mortality. The pooled multivariable risk ratio (MVRR) for ≥3 cups per day vs. >0 to

Background Many, but not all, epidemiologic studies suggest that waist and hip circumference, and waist-to-hip ratio [WHR] are positively associated with postmenopausal breast cancer. However, results are inconsistent for breast cancer subtypes, by strata of body mass index, or after adjustment for body mass index. We evaluated these associations in 10 prospective cohorts in the Pooling Project of Prospective Studies of Diet and Cancer. Methods These analyses included 256,214 postmenopausal women among whom 10,738 (N=1,346 estrogen receptor [ER]- and 6,587 ER+ tumors) were diagnosed with breast cancer during follow-up ranging up to 8-20 years. Study-specific, multivariable-adjusted hazard ratios [HR] were calculated for risk of breast cancer overall and by ER status using Cox proportional hazards regression analyses and controlled for age, race, education, height, reproductive factors, physical activity, smoking status, energy and alcohol intake, and family history of breast cancer. Pooled estimates were computed using random-effects models. Results The medians across studies ranged from 76.0-88.3 cm for waist circumference, 98.0-104.8 cm for hip circumference, and 0.77-0.84 for WHR. As expected, preliminary analyses showed stronger, positive associations for all three exposures for women who had never used hormone replacement therapy (HRT) compared to women who had used HRT (P for interaction 0.90 compared to 0.75-0.80 were 1.37 (95% CI 1.23-1.52) for overall breast cancer, 1.33 (95% CI 1.15-1.53) for ER+, and 1.29 (95% CI 0.94-1.77) for ER- breast cancer. The findings for ER+ and ER- tumors were significantly different for waist and hip circumference (P-value, test for common effects < 0.05). After additionally adjusting for body mass index, the associations for all three exposures were attenuated and only the associations for waist circumference and WHR for overall and ER+ breast cancer remained statistically significant. Similar positive associations were observed for waist circumference across strata of body mass index: the HRs (95% CI) for a 5 cm increment were 1.06 (1.03-1.09) for women with body mass index Conclusions In postmenopausal women who had not used HRT, higher waist circumference, hip circumference and WHR were associated with a modestly higher risk of breast cancer. Results were stronger for ER+ than ER- tumors for waist and hip circumference and did not vary by body mass index for all three exposures. Citation Format: Song R, Wang M, Smith-Warner SA, For the Pooling Project of Prospective Studies of Diet and Cancer Investigators. A pooled analysis of waist and hip circumference and postmenopausal breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-22-04.

Vitamin B supplementation can have side effects for human health, including cancer risk. We aimed to elucidate the role of vitamin B12 in lung cancer aetiology via direct measurements of pre‐diagnostic circulating vitamin B12 concentrations in a nested case‐control study, complemented with a Mendelian randomization (MR) approach in an independent case‐control sample. We used pre‐diagnostic biomarker data from 5,183 case‐control pairs nested within 20 prospective cohorts, and genetic data from 29,266 cases and 56,450 controls.Exposures included directly measured circulating vitamin B12 in pre‐diagnostic blood samples from the nested case‐control study, and 8 single nucleotide polymorphisms associated with vitamin B12 concentrations in the MR study.Our main outcome of interest was increased risk for lung cancer, overall and by histological subtype, per increase in circulating vitamin B12 concentrations.We found circulating vitamin B12 to be positively associated with overall lung cancer risk in a dose response fashion (odds ratio for a doubling in B12 [ORlog2B12] = 1.15, 95% confidence interval (95%CI) = 1.06‐1.25). The MR analysis based on 8 genetic variants also indicated that genetically determined higher vitamin B12 concentrations were positively associated with overall lung cancer risk (OR per 150 pmol/L standard deviation increase in B12 [ORSD]= 1.08, 95%CI= 1.00‐1.16).Considering the consistency of these two independent and complementary analyses, these findings support the hypothesis that high vitamin B12 status increases the risk of lung cancer.

Inflammation and hyperinsulinemia may drive associations between adiposity and colorectal cancer (CRC) risk, but few studies have examined this hypothesis using mediation analysis. We used inverse odds ratio weighting and logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) for estimated total effects (OR(TE)) of body mass index, waist circumference, and adult weight gain on CRC risk, and estimated effects operating through seven inflammatory and metabolic biomarkers (natural indirect effect; OR(NIE)) or through paths independent of these biomarkers (natural direct effect; OR(NDE)) among 209 CRC cases and 382 matched controls nested within the Health Professionals Follow-up Study, a prospective cohort of male health professionals. A one-interquartile range (IQR) increase in body mass index (3.6 kg/m(2)) was associated with an OR(TE) of 1.40 (95% CI: 1.13, 1.73), which decomposed into an OR(NIE) of 1.26 (95% CI: 0.97, 1.52) and an OR(NDE) of 1.11 (0.87, 1.42), with possibly stronger mediation by these biomarkers for adult weight gain (IQR = 10.4kg; OR(TE) = 1.32 [95% CI: 1.06, 1.64]; OR(NIE) = 1.47 [95% CI: 1.01, 1.81]; OR(NDE) = 0.89 [95% CI: 0.72, 1.11]), but no mediation for waist circumference. Mediation appeared to be stronger for the metabolic biomarkers than the inflammatory biomarkers. Inflammatory and metabolic mechanisms may mediate associations between both body mass index and adult weight gain with CRC risk.

Background: In the US, liver cancer incidence has been tripled since the 1980s. Beyond alcohol and coffee, the relationship between other dietary factors and liver cancer remains poorly understood. One objective of this study is to comprehensively evaluate the relationship between overall and specific botanical groups of fruit and vegetable intake with liver cancer risk. Although liver disease mortality is the 11th leading cause of death in the US, its relationship with diet remains unclear. We also aimed to evaluate the association between fruit and vegetable intake and liver disease mortality. Methods: The study was conducted in the US NIH-AARP Diet and Health Study with 470,653 participants aged 50-71 years in 1995-1996. Fruits (14 items plus fruit juice) and vegetables (23 items without white potatoes included) were estimated using a validated Food Frequency Questionnaire. Cox proportional hazards regression modeling was used to estimate the multivariable hazard ratios (HR) and 95% confidence intervals (95% CI) for liver cancer incidence and liver disease mortality. We adjusted a priori for potential confounders including age, sex, education, race, alcohol intake, body mass index, smoking, total energy intake, physical activity, diabetes, and aspirin use. Results: During a median follow-up of 15.5 years, 899 incident liver cancers and 934 chronic liver disease deaths occurred. Higher intake of total vegetables was associated with a lower risk of liver cancer (HRQuintile 5 vs Quintile 1=0.66, 95%CI=0.53-0.82, Ptrend Conclusions: Based on a large prospective US cohort study, higher intakes of total vegetables, and especially lettuce, cruciferous vegetables, legumes, and carrots, were associated with lower liver cancer incidence and liver disease mortality. Citation Format: Longgang Zhao, Lina Jin, Jessica L. Petrick, Fenglei Wang, Tang Li, Hongmei Zeng, Stephanie A. Smith-Warner, A. Heather Eliassen, Fang Fang Zhang, Peter T. Campbell, Edward Giovannucci, Linda M. Liao, Susan E. Steck, Katherine A. McGlynn, Xuehong Zhang. Fruit and vegetable consumption and risk of liver cancer and liver disease mortality: A prospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 730.

Pooling data from multiple studies improves estimation of exposure-disease associations through increased sample size. However, biomarker exposure measurements can vary substantially across laboratories and often require calibration to a reference assay prior to pooling. We develop two statistical methods for aggregating biomarker data from multiple studies: the full calibration method and the internalized method. The full calibration method calibrates all biomarker measurements regardless of the availability of reference laboratory measurements while the internalized method calibrates only non-reference laboratory measurements. We compare the performance of these two aggregation methods to two-stage methods. Furthermore, we compare the aggregated and two-stage methods when estimating the calibration curve from controls only or from a random sample of individuals from the study cohort. Our findings include the following: (1) Under random sampling for calibration, exposure effect estimates from the internalized method have a smaller mean squared error than those from the full calibration method. (2) Under the controls-only calibration design, the full calibration method yields effect estimates with the least bias. (3) The two-stage approaches produce average effect estimates that are similar to the full calibration method under a controls only calibration design and the internalized method under a random sample calibration design. We illustrate the methods in an application evaluating the relationship between circulating vitamin D levels and stroke risk in a pooling project of cohort studies.

The excess risk of cancer observed in patients with type 2 diabetes (T2DM) may have been influenced by detection bias. The aim of this study was to examine the real association by evaluating time-varying site-specific cancer risks in newly diagnosed T2DM patients. A total of 51,324 registered cancer-free individuals newly diagnosed with T2DM between 2004 and 2014 were linked with the Shanghai Cancer Registry and the Vital Statistics through September 2015. A total of 2920 primary, invasive cancer cases were identified during 325,354 person-years period. Within 1 year following diabetes onset, participants with T2DM had higher risks of total, lung and rectal cancer in men and total, liver, pancreas, thyroid, breast and uteri cancer in women. Thereafter the incidence for overall cancer decreased and then increased along with follow-up time, with the upward trend varying by cancer, suggesting potential detection bias. After the initial 1-year period, standardized incidence ratios (SIR) and 95% CIs for overall cancer were 0.80 (95% CI 0.76–0.85) in men and 0.93 (95% CI 0.88–0.99) in women, but a higher risk of breast and thyroid cancers were observed in women, with SIR and 95% CI being 1.13 (1.01, 1.28) and 1.37 (1.11, 1.63), respectively. Our results suggest that T2DM patients are at higher risk of certain cancers; this risk particularly increases shortly after diabetes diagnosis, which is likely to be due to detection bias caused by increased ascertainment. Prevention of female breast and thyroid cancers should be paid attention in Chinese individuals with T2DM.