Search

Insulin resistance and hyperinsulinemia play important roles in the progression of multiple chronic disease and conditions. Diet modulates insulin response; however, evidence is limited regarding whether diets with higher insulinemic potential increase the risk of invasive breast cancer.We aimed to prospectively evaluate the association between a food-based empirical dietary index for hyperinsulinemia (EDIH) and the incidence of invasive breast cancer.We prospectively followed 76,686 women from the Nurses' Health Study (NHS; 1984-2016) and 93,287 women from the Nurses' Health Study II (NHSII; 1991-2017). Diet was assessed by food-frequency questionnaires every 4 y. The insulinemic potential of diet was evaluated using the previously established EDIH based on circulating C-peptide concentrations. Higher scores indicate higher insulinemic potential of the diet. Covariates included reproductive, hormonal, and anthropometric factors (height and BMI at age 18 y); race; socioeconomic status; total alcohol intake; total caloric intake; and physical activity.During 4,216,106 person-years of follow-up, we documented 10,602 breast cancer cases (6689 NHS, 3913 NHSII). In the pooled multivariable-adjusted analyses, women in the highest, compared with the lowest, EDIH quintile (Q) were at higher breast cancer risk (HRQ5 vs. Q1 = 1.15; 95% CI: 1.07, 1.24; P-trend 0.01). Although heterogeneity by estrogen receptor (ER) status was nonsignificant, the strongest association between EDIH and breast cancer was observed for ER-negative tumors (HRQ5 vs. Q1 = 1.21; 95% CI: 1.00, 1.46; P-trend = 0.02). Among tumor molecular subtypes, the strongest associations were observed for human epidermal growth factor receptor 2 (HER2)-enriched tumors (HRQ5 vs. Q1 = 1.62; 95% CI: 1.01, 2.61; P-trend = 0.02).A dietary pattern contributing to hyperinsulinemia and insulin resistance was associated with greater breast cancer risk, especially ER-negative and HER2-enriched tumors. Our findings suggest that dietary modifications to reduce insulinemic potential may reduce the risk of breast cancer.

Background: The 2018 physical activity guidelines for Americans recommend a minimum of 150 to 300 min/wk of moderate physical activity (MPA), 75 to 150 min/wk of vigorous physical activity (VPA), or an equivalent combination of both. However, it remains unclear whether higher levels of long-term VPA and MPA are, independently and jointly, associated with lower mortality. Methods: A total of 116 221 adults from 2 large prospective US cohorts (Nurses’ Health Study and Health Professionals Follow-up Study, 1988–2018) were analyzed. Detailed self-reported leisure-time physical activity was assessed with a validated questionnaire, repeated up to 15 times during the follow-up. Cox regression was used to estimate the hazard ratio and 95% CI of the association between long-term leisure-time physical activity intensity and all-cause and cause-specific mortality. Results: During 30 years of follow-up, we identified 47 596 deaths. In analyses mutually adjusted for MPA and VPA, hazard ratios comparing individuals meeting the long-term leisure-time VPA guideline (75–149 min/wk) versus no VPA were 0.81 (95% CI, 0.76–0.87) for all-cause mortality, 0.69 (95% CI, 0.60–0.78) for cardiovascular disease (CVD) mortality, and 0.85 (95% CI, 0.79–0.92) for non-CVD mortality. Meeting the long-term leisure-time MPA guideline (150–299 min/wk) was similarly associated with lower mortality: 19% to 25% lower risk of all-cause, CVD, and non-CVD mortality. Compared with those meeting the long-term leisure-time physical activity guidelines, participants who reported 2 to 4 times above the recommended minimum of long-term leisure-time VPA (150–299 min/wk) or MPA (300–599 min/wk) showed 2% to 4% and 3% to 13% lower mortality, respectively. Higher levels of either long-term leisure-time VPA (≥300 min/wk) or MPA (≥600 min/wk) did not clearly show further lower all-cause, CVD, and non-CVD mortality or harm. In joint analyses, for individuals who reported Conclusions: The nearly maximum association with lower mortality was achieved by performing ≈150 to 300 min/wk of long-term leisure-time VPA, 300 to 600 min/wk of long-term leisure-time MPA, or an equivalent combination of both.

The prevalence of obesity, defined as the body mass index (BMI) ≥ 30 kg/m2, has reached epidemic levels. Obesity is associated with an increased risk of various cancers, including gastrointestinal ones. Recent evidence has suggested that obesity disproportionately impacts males and females with cancer, resulting in varied transcriptional and metabolic dysregulation. This study aimed to elucidate the differences in the metabolic milieu of adenocarcinomas of the gastrointestinal (GI) tract both related and unrelated to sex in obesity. To demonstrate these obesity and sex-related effects, we utilized three primary data sources: serum metabolomics from obese and non-obese patients assessed via the Biocrates MxP Quant 500 mass spectrometry-based kit, the ORIEN tumor RNA-sequencing data for all adenocarcinoma cases to assess the impacts of obesity, and publicly available TCGA transcriptional analysis to assess GI cancers and sex-related differences in GI cancers specifically. We applied and integrated our unique transcriptional metabolic pipeline in combination with our metabolomics data to reveal how obesity and sex can dictate differential metabolism in patients. Differentially expressed genes (DEG) analysis of ORIEN obese adenocarcinoma as compared to normal-weight adenocarcinoma patients resulted in large-scale transcriptional reprogramming (4029 DEGs, adj. p < 0.05 and |logFC| > 0.58). Gene Set Enrichment and metabolic pipeline analysis showed genes enriched for pathways relating to immunity (inflammation, and CD40 signaling, among others) and metabolism. Specifically, we found alterations to steroid metabolism and tryptophan/kynurenine metabolism in obese patients, both of which are highly associated with disease severity and immune cell dysfunction. These findings were further confirmed using the TCGA colorectal adenocarcinoma (CRC) and esophageal adenocarcinoma (ESCA) data, which showed similar patterns of increased tryptophan catabolism for kynurenine production in obese patients. These patients further showed disparate alterations between males and females when comparing obese to non-obese patient populations. Alterations to immune and metabolic pathways were validated in six patients (two obese and four normal weight) via CD8+/CD4+ peripheral blood mononuclear cell RNA-sequencing and paired serum metabolomics, which showed differential kynurenine and lipid metabolism, which corresponded with altered T-cell transcriptome in obese populations. Overall, obesity is associated with differential transcriptional and metabolic programs in various disease sites. Further, these alterations, such as kynurenine and tryptophan metabolism, which impact both metabolism and immune phenotype, vary with sex and obesity together. This study warrants further in-depth investigation into obesity and sex-related alterations in cancers that may better define biomarkers of response to immunotherapy.

BACKGROUND & AIMS: Insulin and insulin-like growth factor (IGF)-1 signaling is a proposed mechanism linking dietary protein and major chronic diseases. However, it is unclear whether animal and plant proteins are associated with biomarkers of insulin and IGF axis. METHODS: We analyzed a total of 14,709 participants from Nurses’ Health Study and Health Professionals Follow-up Study who had provided a blood sample. Detailed dietary information was assessed using validated food frequency questionnaires. We assessed C-peptide, insulin, IGF-1, and IGF binding proteins (BP). Multivariable-adjusted linear regressions were used to examine associations of animal and plant protein intake with biomarkers after adjusting for confounders. RESULTS: The medians (5(th)-95(th) percentiles) of animal and plant protein intake (% of total energy) were 13% (8–19%) and 5% (4–7%), respectively. Compared to participants in the lowest quintile, those in the highest quintile of animal protein had 4.8% (95% CI: 1.9, 7.9; P-trend

Though studies have observed inverse associations between use of analgesics (aspirin, NSAIDs, and acetaminophen) and the risk of several cancers, the potential biological mechanisms underlying these associations are unclear. We investigated the relationship between analgesic use and serum concentrations of estrogens, androgens, and their metabolites among postmenopausal women to provide insights on whether analgesic use might influence endogenous hormone levels, which could in turn influence hormone-related cancer risk. The study included 1,860 postmenopausal women from two case–control studies nested within the Women's Health Initiative Observational Study. Analgesic use was reported at study baseline. Fifteen estrogens and estrogen metabolites and 12 androgens and androgen metabolites were quantified in baseline serum by LC/MS-MS. Linear regression with inverse probability weighting, stratified by menopausal hormone therapy (MHT) use, was used to estimate adjusted geometric mean concentrations of each hormone by analgesic use. Among women not currently using MHT (n = 951), low-dose aspirin (Prevention relevance:This study explores a potential pathway by which analgesic medications such as aspirin may prevent hormone-related cancers. The findings support a positive association between low-dose aspirin use and endogenous estrogens, indicating that further elucidation of the interplay between low-dose aspirin, estrogen concentrations, and cancer risk is needed.

Prostate cancer is common in countries with affluent dietary patterns and represents a heterogeneous collection of subtypes with varying behavior. Reductionist strategies focusing on individual nutrients or foods have not clearly defined risk factors. We have developed mechanisms-based dietary patterns focusing upon inflammation and chronic insulin hypersecretion, processes that are hypothesized to impact prostate carcinogenesis. In the Prostate, Lung, Colorectal, and Ovarian cancer cohort, we calculated the empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP) scores from food frequency questionnaire data among 3,517 men and women who provided a blood sample at enrollment. We used these scores in multivariable-adjusted linear regression to validate EDIH and EDIP against relevant circulating biomarkers. In a separate sample of 49,317 men, we used multivariable-adjusted Cox regression to evaluate associations of EDIH and EDIP with prostate cancer (total and subtypes) risk. Participants consuming the most hyperinsulinemic diets (EDIH quintile 5) had significantly higher concentrations of C-peptide, insulin, c-reactive protein, TNFα-R2, and lower adiponectin, than those in quintile 1. Similarly, participants consuming the most proinflammatory diets had significantly higher concentrations of IL6, TNFα-R2, C-peptide, insulin, and lower adiponectin. Men consuming hyperinsulinemic diets were at higher total prostate cancer risk: HRquintile5vs1, 1.11; 95% confidence interval (CI), 1.01–1.23; P trend = 0.03, especially high-grade cancer: HRquintile5vs1, 1.18; 95% CI, 1.02–1.37; P trend = 0.06. The EDIP was not associated with prostate cancer risk. In summary, EDIH and EDIP predicted concentrations of known insulinemic and inflammatory biomarkers, and EDIH further predicted risk of future prostate cancer. Interventions to reduce the adverse role of hyperinsulinemic diets may be a means of prostate cancer prevention.

supplemental table

Supplementary Figure from Analgesic Use and Circulating Estrogens, Androgens, and Their Metabolites in the Women's Health Initiative Observational Study

Supplementary tables

Branched-chain amino acids (BCAA) are essential amino acids, and emerging evidence suggests that BCAAs may mediate pathways related to cancer progression, possibly due to their involvement in insulin metabolism. We investigated the association between dietary intake of BCAAs with colorectal cancer risk in three prospective cohorts: the Nurses' Health Study I [(NHS), number of participants (n) at baseline = 77,017], NHS II (n = 92,984), and the Health Professionals Follow-up Study [(HPFS) n = 47,255]. Validated food frequency questionnaires were administered every 4 years and follow-up questionnaires on lifestyle biennially. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards regression models. Pooled HRs were obtained using random effect models. After up to 28 years of follow-up, 1,660 cases were observed in NHS, 306 in NHS II, and 1,343 in HPFS. In multivariable adjusted models, we observed a weak inverse association between BCAA intake and colorectal cancer [highest vs. lowest quintile, pooled HR including all three cohorts (95% CI): 0.89 (0.80–1.00), Ptrend = 0.06, HR per standard deviation (SD) increment 0.95 (0.92–0.99)]. However, after including dairy calcium to the models, BCAA intake was no longer associated with risk of colorectal cancer [HR 0.96 (0.85–1.08), Ptrend = 0.50, HR per SD increment 0.97 (0.93–1.01)]. We did not find evidence that higher dietary BCAA intake is associated with higher risk of colorectal cancer. As this is the first prospective study to examine the association between BCAA intake and colorectal cancer, our findings warrant investigation in other cohorts.

In January 2022, a group of experts came together to discuss current perspectives and future directions in nutritional immunology as part of a symposium organized by the Canadian Nutrition Society. Objectives included (1) creating an understanding of the complex interplay between diet and the immune system from infants through to older adults, (2) illustrating the role of micronutrients that are vital to the immune system, (3) learning about current research comparing the impact of various dietary patterns and novel approaches to reduce inflammation, autoimmune conditions, allergies, and infections, and (4) discussing select dietary recommendations aimed at improving disease-specific immune function. The aims of this review are to summarize the symposium and to identify key areas of research that require additional exploration to better understand the dynamic relationship between nutrition and immune function.

Background Diet modulates inflammation and insulin response and may be an important modifiable factor in the primary prevention of hepatocellular carcinoma (HCC) and chronic liver disease (CLD). We developed the empirical dietary inflammatory pattern (EDIP) and empirical dietary index for hyperinsulinemia (EDIH) scores to assess the inflammatory and insulinemic potentials of diet. We prospectively examined the associations of EDIP and EDIH at baseline with the following HCC risk and CLD mortality. Design We followed 485 931 individuals in the National Institutes of Health–American Association of Retired Persons Diet and Health Study since 1995. Cox proportional hazards regression was used to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (CIs). Results We confirmed 635 incident HCC cases and 993 CLD deaths. Participants in the highest compared with those in the lowest EDIP quartile had a 1.35 times higher risk of developing HCC (95% CI = 1.08 to 1.70, Ptrend = .0005) and a 1.70 times higher CLD mortality (95% CI = 1.41 to 2.04, Ptrend Conclusions Our findings suggest that inflammation and hyperinsulinemia are potential mechanisms linking diet to HCC development and CLD mortality.

PURPOSE: Lifestyle factors such as smoking, alcohol, body weight, physical activity, and diet quality have been associated with the risk of pancreatic cancer. However, studies of their combined association in women are limited. METHODS: Data on smoking habits, alcohol intake, diet composition, recreational physical activity, body weight, and waist circumference, obtained at recruitment for 136,945 postmenopausal women (aged 50–79 years) participating in the Women’s Health Initiative study, were categorized separately, with higher scores for each variable assigned to the categories representing healthier behaviors. The combined healthy lifestyle index (HLI) score, created by summing the scores for each risk factor, was grouped into quartiles. We used multivariable-adjusted Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for pancreatic cancer risk in association with the HLI. RESULTS: Over an average follow-up period of approximately 16.0 years, 1,119 incident cases of pancreatic cancer were ascertained. Compared to women in the lowest HLI quartile, those in the upper quartiles (qt) had a reduced risk of pancreatic cancer (multivariable-adjusted HRqt(3)(rd) 0.83, 95% CI 0.74–0.99; and HRqt(4)(th) 0.74, 95% CI 0.62–0.88, respectively, p trend = 0.001). Use of waist circumference instead of BMI in the HLI score yielded similar results. Among women who were either non-diabetic or non-smokers, high HLI was also associated with reduced risk HRqt(4)(th) 0.78, 95% CI 0.65–0.85 and HRqt(4)(th) 0.80, 95% CI 0.66–0.97, respectively). Stratification by BMI categories (18.5− < 25.0, 25.0− < 30.0 and > 30.0 kg/m(2)) showed similar results in all groups. CONCLUSIONS: Our findings suggest that in postmenopausal women, a healthy lifestyle is associated with reduced risk of pancreatic cancer.

Background: Insulin resistance and hyperinsulinemia play important roles in the progression of multiple chronic disease and conditions. Diet modulates insulin response; however, evidence is limited regarding whether diet with higher insulinemic potential is associated with invasive breast cancer risk.Objectives: We prospectively evaluated the association between adherence to a food-based empirical dietary index for hyperinsulinemia (EDIH) and the incidence of invasive breast cancer.Methods: We prospectively followed 76,595 women from the Nurses’ Health Study (NHS, 1984-2016) and 93,295 women from the Nurses’ Health Study II (NHSII, 1991-2017). Diet was assessed by food frequency questionnaires every 4 years. The insulinemic potential of diet was evaluated using the EDIH that was pre-defined based on circulating C-peptide concentrations. Higher scores indicate higher insulinemic potential, while lower scores indicate lower insulinemic potential.Results: During 4,215,162 person-years of follow-up, we documented 10,595 breast cancer cases (6,639 NHS; 3,914 NHSII). Being in the highest, compared with the lowest, EDIH quintile was associated with higher breast cancer risk (HRQ5vsQ1 1.18; 95% CI 1.10, 1.27; P-trend Citation Format: Andrea Romanos-Nanclares, Walter C. Willett, Bernard A. Rosner, Rulla M. Tamimi, Fred K. Tabung, Michelle D. Holmes, Wendy Y Chen, A. Heather Eliassen. Insulinemic potential of diet and risk of total and subtypes of breast cancer among US women [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-09-06.

OBJECTIVE To investigate the relationship between long-term weight training and mortality in male health professionals with and without type 2 diabetes. RESEARCH DESIGN AND METHODS We analyzed 31,140 men without type 2 diabetes and 2,588 with type 2 diabetes from the Health Professionals Follow-up Study (1992–2018). Information on weight training was repeatedly assessed using a biennial questionnaire. Cox regression was used to estimate hazard ratios (HRs) and 95% CIs. RESULTS During up to 26 years of follow-up, we documented 12,607 deaths (988 deaths among men with type 2 diabetes). Among participants without type 2 diabetes, 1–59 and 60–149 min/week of long-term weight training were associated with 14% (HR 0.86; 95% CI 0.82–0.89) and 8% (HR 0.92; 95% CI 0.85–0.99) lower mortality versus no weight training, respectively, after adjustment for aerobic activity. However, ≥150 min/week of weight training was not significantly associated with mortality (HR 1.05; 95% CI 0.91–1.20; overall P trend = 0.94; P quadratic < 0.001). Meeting the recommended aerobic physical activity guideline (≥150 min/week) and performing any weight training were associated with 20–34% lower mortality. Among participants with type 2 diabetes, a moderate level of pre-diagnosis weight training was associated with lower mortality, whereas post-diagnosis weight training showed no association. Performing both weight training and aerobic activity before and after diagnosis was associated with lower mortality. CONCLUSIONS A moderate level of long-term weight training was associated with lower mortality, independently of aerobic activity, among male health professionals with and without type 2 diabetes. Addition of weight training to aerobic activities may provide further benefit in mortality risk reduction. Studies are required to confirm our findings in diverse populations.

Previous attempts to identify low-carbohydrate diets (LCDs) in epidemiological studies relied on the LCD score, which is unable to identify ketogenic dieters. Ketogenic ratios of macronutrients are clinical equations proposed to predict ketogenic diets; however, their utility in epidemiological studies is unknown.To determine the number of participants consuming a ketogenic diet, compare ketogenic ratios to the LCD score, and evaluate their association with type 2 diabetes mellitus (T2DM).Secondary analysis of the Women's Health Initiative (WHI) with 17.9 ± 6.03 years of follow-up. Baseline food frequency questionnaires were used to calculate the ketogenic ratio as follows: (0.9*grams fat + 0.46*grams protein) divided by (0.1*grams fat + 0.58*grams protein + grams net carbohydrate), a value ≥1.5 is the minimum threshold for a ketogenic diet.125,982 postmenopausal women without diabetes (age 50-79 years) enrolled in the multicenter WHI observational study and clinical trials were included.Risk of self-reported incident T2DM.Cox proportional hazards models, adjusted for age, race, ethnicity, education, income, health insurance, relationship status, geographic region, WHI study component, female hormone use, smoking status, alcohol use, recreational physical activity, total energy intake, diet quality, body mass index, hyperlipidemia, and hypertension, were used to compare hazard ratios (HRs) and 95% confidence intervals (CIs) for T2DM between quintiles of the ketogenic ratio.18,775 incident cases of T2DM occurred. The median ketogenic ratio was 0.35 (interquartile range 0.28-0.42) and 15 individuals (0.01%) exceeded the threshold for a ketogenic diet. Higher ketogenic ratio quintiles were associated with increased risk of T2DM in a dose-dependent manner. Comparing extreme quintiles of the ketogenic ratio, the HR and 95% CI for diabetes was 1.24 (1.18-1.31; PIncreasing ketogenic ratio values are associated with increased risk of T2DM and align well with LCD scores; however, too few participants consumed a ketogenic diet to determine its association with T2DM.

Background Cardiometabolic diseases are prevalent in aging Americans. Although some studies have implicated greater intake of dairy products, it is not clear how dairy intake is related to biomarkers of cardiometabolic health. Objective Our aim was to test the hypothesis that associations of dairy foods with biomarkers of lipid metabolism, insulin-like growth factor signaling, and chronic inflammation may provide clues to understanding how dairy can influence cardiometabolic health. Design This was a cross-sectional study in the Women's Health Initiative using baseline food frequency questionnaire data to calculate dairy intake. Participants/setting Participants were 35,352 postmenopausal women aged 50 to 79 years at 40 clinical centers in the United States. Main outcome measures Baseline (1993-1998) concentrations of 20 circulating biomarkers were measured. Statistical analyses Multivariable-adjusted linear regression was used to estimate percent difference in biomarker concentrations per serving of total dairy and individual foods (milk, cheese, yogurt, butter, and low-fat varieties). Results Lower triglyceride concentrations were associated with greater intake of total dairy (–0.8% [95% CI –1.2% to –0.3%]), mainly driven by full-fat varieties. Individual dairy foods had specific associations with circulating lipid components. For example, greater total milk intake was associated with lower concentrations of total cholesterol (–0.4% [95% CI –0.7% to –0.2%]) and high-density lipoprotein cholesterol (–0.5% [95% CI –0.9% to –0.1%]), whereas greater butter intake was associated with higher total cholesterol (0.6% [95% CI 0.2% to 1.0%]) and high-density lipoprotein cholesterol (1.6% [95% CI 1.1% to 2.0%]) concentrations. In contrast, higher total yogurt intake was associated with lower total cholesterol (–1.1% [95% CI –2.0% to –0.2%]) and higher high-density lipoprotein cholesterol (1.8% [95% CI 0.5% to 3.1%]). Greater total dairy intake (regardless of fat content), total cheese, full-fat cheese, and yogurt were consistently associated with lower concentrations of glucose, insulin, and C-reactive protein. However, milk and butter were not associated with these biomarkers. Conclusions Higher dairy intake, except butter, was associated with a favorable profile of lipids, insulin response, and inflammatory biomarkers, regardless of fat content. Yet, specific dairy foods might influence these markers uniquely. Findings do not support a putative role of dairy in cardiometabolic diseases observed in some previous studies.

Background Although unopposed estrogen exposure is considered a major driver of endometrial carcinogenesis, chronic inflammation and insulin resistance and hyperinsulinemia are also major endometrial cancer risk factors. However, it is unclear whether diets with inflammatory or insulinemic potential are associated with risk of endometrial cancer. Methods We followed 48 330 women from the Nurses’ Health Study (1984-2016) and 85 426 women from the Nurses’ Health Study II (1989-2017). Using food frequency questionnaires, we calculated repeated measures of empirical dietary inflammatory pattern (EDIP) and empirical dietary index for hyperinsulinemia (EDIH) scores, which characterize the potential of the whole diet to modulate circulating biomarkers of inflammation or C-peptide, respectively. We used multivariable-adjusted Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for type I endometrial cancer risk. Results We documented 1462 type I endometrial cancer cases over 2 823 221 person-years of follow-up. In the pooled multivariable-adjusted analyses, women in the highest compared with lowest quintiles were at higher risk of type I endometrial cancer (EDIP HRQ5vsQ1 = 1.46, 95% CI = 1.24 to 1.73; Ptrend < .001; EDIH HRQ5vsQ1 = 1.58, 95% CI = 1.34 to 1.87; Ptrend < .001). Additional adjustment for body mass index attenuated the associations (EDIP HR = 1.03, 95% CI = 0.87 to 1.22; EDIH HR = 1.01, 95% CI = 0.85 to 1.21), and mediation analyses showed that body mass index may explain 60.4% (95% CI = 37.4% to 79.6%; P < .001) and 71.8% (95% CI = 41.0% to 90.4%; P < .001) of the association of endometrial cancer with EDIP and EDIH, respectively. Conclusions In this large cohort study, higher dietary inflammatory and insulinemic potential were each associated with increased endometrial cancer incidence, and this association may be almost entirely mediated by adiposity.

Purpose: Immune infiltration is associated with better treatment response and outcomes in breast cancer, yet data regarding the role of modifiable patient factors in immune infiltration are limited. Patients and Methods: This population-based, prospective observational study evaluated 882 Nurses’ Health Study (NHS) and NHSII participants diagnosed with invasive breast cancer with detailed exposure and gene expression data. Of these, 262 women (training cohort) had breast tumor immunohistochemistry (IHC) for four canonical immune cell markers: CD8, CD4, CD20, CD163. In this training cohort, 105 published immune cell-specific gene expression signatures were calculated, then lasso regression was used to derive four immune cell-specific scores based on association with IHC. In the remaining 620 patient testing cohort, we evaluated association of each immune-cell specific score as outcomes, with body mass index (BMI) change since age 18, physical activity, and the empirical dietary inflammatory pattern (EDIP) score as predictors, using multivariable-adjusted linear regression. Results: Among women with paired expression/IHC data from breast tumor tissue, we identified robust correlation between novel immune cell-specific expression scores and IHC (Spearman’s rho range 0.42-0.54; all p Citation Format: Daniel G. Stover, Adrienne Damicis, Yujing J. Heng, Katharine A. Collier, Elizabeth J. Adams, Kevin H. Kensler, Gabrielle M. Baker, Robert Wesolowski, Sagar Sardesai, Margaret Gatti-Mays, Bhuvaneswari Ramaswamy, A. Heather Eliassen, Susan E. Hankinson, Fred K. Tabung, Rulla M. Tamimi, Sarah Asad. Association of body mass index and inflammatory dietary pattern with breast cancer pathologic and genomic immunophenotype in the nurses’ health study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD9-11.

Fecal incontinence (FI) is a debilitating gastrointestinal disorder with a devastating impact on quality of life

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: Results of observational studies of the association between dietary fat and risk of invasive breast cancer have been inconsistent. In the Women's Health Initiative dietary modification (DM) randomized trial designed to lower fat intake, the intervention was not associated with a statistically significant reduction of overall breast cancer risk. However, the DM association with risk of ductal carcinoma in situ (DCIS) of the breast, a putative breast cancer precursor, has not been reported. Methods: A total of 48,835 postmenopausal women, ages 50–79 years at enrollment, with no breast cancer history and ≥32% of total energy intake from fat, were randomly assigned either to a dietary intervention (n = 19,541) designed to reduce total fat intake to 20% of energy and to increase vegetable, fruit, and grain consumption, or to a comparison group (n = 29,294). Cox proportional hazards models were used to estimate HRs and 95% confidence intervals for the association between the intervention and DCIS risk. Results: During 18.7 years (median) cumulative follow-up, including intervention (∼8.7 years) and post-intervention phases (∼13.0 years), 817 DCIS cases were ascertained. No evidence of an association between the DM intervention and DCIS risk was observed overall, or by trial phase (intervention and post-intervention). Similarly, no associations were found in subgroups defined by potential risk factors for DCIS. Conclusions: DM aiming to reduce fat intake was not associated with altered risk of DCIS. Impact: These results do not provide evidence of an association between dietary fat reduction and the risk of DCIS among postmenopausal women.

Weight cycling is common in populations. However, it is unclear whether frequency and magnitude of weight cycling is associated with kidney cancer risk, independent of body mass index (BMI). A prospective cohort study followed 85,562 participants from Health Professionals Follow-up Study and Nurses’ Health Study (1992–2014). At baseline, participants reported frequency and magnitude of intentional weight loss in the past 4 years. Cox proportional hazard model was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). We also conducted a meta-analysis of all available observational studies including our two cohorts. During 22 years of follow-up, we identified 441 kidney cancer cases. Compared with non-weight cyclers (no attempt of intentional weight loss), severe cyclers (≥ 3 times of intentional weight loss of ≥ 4.5 kg) were at increased kidney cancer risk after adjusting for BMI before weight cycling (pooled multivariable-adjusted HR, 1.78; 95% CI, 1.19, 2.66). Additional adjustment for attained BMI after weight cycling had minimal influence. There was a positive trend between weight cycling by frequency and magnitude and kidney cancer risk (P-trend = 0.01). Moreover, the observed positive association did not differ by subtypes of cyclers (e.g., adiposity status, weight-loss methods). In the meta-analysis, we found a strong positive association between weight cycling and kidney cancer risk (summary relative risk for weight cyclers vs. non-cyclers, 1.51; 95% CI, 1.16, 1.96; I2: 52.2%; 6 studies). Frequent substantial weight cycling was associated with increased risk of kidney cancer, independent of BMI. Our study suggests that weight cycling may be an important risk factor for kidney cancer.

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.

Interval breast cancer refers to cancer diagnosed after a negative screening mammogram and before the next scheduled screening mammogram. Interval breast cancer has worse prognosis than screening-detected cancer. Body mass index (BMI) influences the accuracy of mammography and overall postmenopausal breast cancer risk, yet how is obesity associated with postmenopausal interval breast cancer incidence is unclear. The current study included cancer-free postmenopausal women aged 50–79 years at enrollment in the Women’s Health Initiative who were diagnosed with breast cancer during follow-up. Analyses include 324 interval breast cancer cases diagnosed within one year after the participant’s last negative screening mammogram and 1969 screening-detected breast cancer patients. Obesity (BMI ≥ 30 kg/m2) was measured at baseline. Associations between obesity and incidence of interval cancer were determined by sequential logistic regression analyses. In multivariable-adjusted models, obesity was inversely associated with interval breast cancer risk [OR (95% CI) = 0.65 (0.46, 0.92)]. The inverse association persisted after excluding women diagnosed within 2 years [OR (95% CI) = 0.60 (0.42, 0.87)] or 4 years [OR (95% CI) = 0.56 (0.37, 0.86)] of enrollment, suggesting consistency of the association regardless of screening practices prior to trial entry. These findings warrant confirmation in studies with body composition measures.

Inflammation-related mechanisms may be important in the development of obstructive sleep apnea (OSA), and diet plays a crucial role in modulating inflammation. Current epidemiologic evidence for the associations between dietary patterns and OSA risk is limited to cross-sectional studies.We investigated prospectively the associations of overall diet quality and proinflammatory diet with OSA risk.We followed 145,801 participants in the Nurses' Health Study (NHS) (2002-2012), NHS II (1995-2013), and Health Professionals Follow-up Study (1996-2012). Alternative Healthy Eating Index 2010 (AHEI) and Empirical Dietary Inflammatory Pattern (EDIP) scores were calculated based on validated FFQs administered every 4 y. Cox models were used to estimate HRs and 95% CIs.We documented 8856 incident OSA cases during follow-up. In pooled analyses adjusted for potential confounders, higher diet quality (higher AHEI scores) was associated with lower OSA risk (HR comparing the highest with the lowest quintile of AHEI: 0.76; 95% CI: 0.71, 0.82; P-trend 0.001), and higher dietary inflammatory potential (higher EDIP scores) was associated with significantly increased risk (HR comparing the highest with the lowest quintile of EDIP: 1.94; 95% CI: 1.81, 2.08; P-trend 0.001). Additional adjustment for metabolic factors attenuated both associations. The association with AHEI score was no longer statistically significant (comparable HR: 0.98; 95% CI: 0.91, 1.05; P-trend = 0.54), whereas the association with EDIP score remained statistically significant (comparable HR: 1.31; 95% CI: 1.22, 1.41; P-trend 0.001).A healthier diet, particularly one with anti-inflammatory potential, was associated with lower OSA risk.

Background Hyperinsulinemia and inflammation are inter-related pathways that link diet with the risk of several chronic diseases. Evidence suggests that these pathways may also increase prostate cancer risk. Objective To determine whether hyperinsulinemic diet and inflammatory diet are associated with prostate cancer incidence and mortality. Design, setting, and participants We prospectively followed 41 209 men in the Health Professionals Follow-up Study (1986–2014). Scores for two validated dietary patterns were calculated from food frequency questionnaires at baseline and updated every 4 yr. Outcome measurements and statistical analysis Total, advanced, and lethal prostate cancer outcomes were assessed. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were determined for associations between two empirical hypothesis-oriented dietary patterns—empirical dietary index for hyperinsulinemia and empirical dietary inflammatory pattern—and prostate cancer risk estimated using Cox proportional hazard regression. Results and limitations During 28 yr of follow-up, 5929 incident cases of total prostate cancer, including 1019 advanced and 667 fatal, were documented. In multivariable-adjusted models, there was a 7% higher risk of advanced prostate cancer (HR: 1.07; 95% CI: 1.01–1.15) and a 9% higher risk of fatal prostate cancer (HR: 1.09; 95% CI: 1.00–1.18) per standard deviation (SD) increase in the hyperinsulinemic diet. When stratified by age, the hyperinsulinemic diet was associated with only earlier-onset aggressive prostate cancer (men under 65 yr), with per SD HRs of 1.20 (95% CI: 1.06–1.35) for advanced, 1.22 (1.04–1.42) for fatal, and 1.20 (1.04–1.38) for lethal. The inflammatory diet was not associated with prostate cancer risk in the overall study population, but was associated with earlier-onset lethal prostate cancer (per SD increase HR: 1.16; 95% CI: 1.00–1.35). Conclusions Hyperinsulinemia and inflammation may be potential mechanisms linking dietary patterns with the risk of aggressive prostate cancer, particularly earlier-onset disease. Patient summary Avoiding inflammatory and hyperinsulinemic dietary patterns may be beneficial for the prevention of clinically relevant prostate cancer, especially among younger men.

Background: Metabolic disturbance and inflammation may explain observed associations between higher body mass index (BMI) and increased risk of colorectal cancer (CRC); however, the underlying mechanisms are not fully understood. Objectives: We characterized individual plasma metabolites and metabolomic signatures of metabolic disturbance and inflammation and evaluated their association with prospective CRC risk within the Nurses’ Health Study and the Health Professionals Follow-up Study. Methods: Among 686 colorectal cancer cases and 686 age-matched controls, we used reduced rank regression of markers of metabolic disturbance (BMI, waist circumference, C-peptide, and adiponectin) or inflammation (BMI, C-reactive protein, interleukin-6, and tumor necrosis factor receptor superfamily member 1B) with cross-sectional measures of 353 plasma metabolites to develop a Y-score for metabolic disturbance and Y-score for inflammation among men and women separately. We then used elastic net regression to derive a signature of metabolites, and multiple linear regression to identify individual metabolites, associated with each Y-score. We evaluated the association of individual metabolites and the metabolomic signatures with odds of CRC using conditional logistic regression adjusted for other CRC risk factors. Results: The metabolomic signature of metabolic disturbance consisted of 41 metabolites selected via elastic net regression in men and 72 in women; the metabolomic signature of inflammation consisted of 68 metabolites in men and 119 in women. The metabolic disturbance metabolomic signatures captured, on average, 36% of variation in markers of metabolic disturbance in women and 35% in men; the inflammation signature captured 35% of variation in inflammatory markers in women and 26% in men. The metabolomic signature of metabolic disturbance was associated with increased odds of CRC (odds ratio (OR) comparing highest to lowest quartile = 1.63; 95% confidence interval (CI), 0.92, 2.91; Ptrend = 0.31) and the metabolomic signature of inflammation was associated with increased odds of CRC (OR = 2.01; 95% CI, 1.14, 3.57; Ptrend = 0.008) among men. Neither signature was associated with CRC among women. Of the metabolites associated with metabolic disturbance and inflammation, 13 metabolites were also associated with CRC: 4 metabolites classified as uremic toxins (2 purine nucleosides and 2 amino acid derivates); 3 sphingolipids; 3 glycerophospholipids; 2 sterols related to cholesterol homeostasis; and 3-ureidopropanoate, a uracil metabolism substrate. Conclusion: We identified plasma metabolomic signatures and individual metabolites associated with metabolic disturbance, inflammation, and CRC risk, highlighting pathways such as protein metabolism and lipid homeostasis that may relate adiposity-related metabolic disturbance and inflammation to CRC development. Citation Format: Alaina M. Bever, Dong Hang, Amit D. Joshi, Connor M. Geraghty, Dong Hoon Lee, Fred K. Tabung, Shuji Ogino, Jeffrey A. Meyerhardt, Andrew T. Chan, Edward L. Giovannucci, A. Heather Eliassen, Liming Liang, Meir J. Stampfer, Mingyang Song. Metabolomic signatures of metabolic disturbance and inflammation in relation to colorectal cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3006.

Rational manipulation of the gut microbiome by diet or other interventions is a promising approach to improving the efficacy and safety of cancer immunotherapy. However, linking lifestyle variables to specific microbial populations and the host immune response to cancer therapies is challenging due to their complexity. We established an experimental system to examine such complexity by linking a human dietary intervention and fecal biospecimens to mouse models to test the response to immunotherapy. Longitudinal human microbiome samples collected before and after a specific dietary or other intervention allow us to test the hypothesis that an intervention alters the response to immunotherapy via impact on the host microbiome. One set of samples was taken from the BEWELL study, which examined the impact of 2 × 80 mL black raspberry (BRB) drink boxes per day for 4 weeks in people at high risk for lung cancer. Participant samples were chosen based on enrichment of specific taxa. Pre- and post-BRB intervention samples were gavaged into mice. Mouse mc38 cells were injected subcutaneously and treated with anti-PD1 Ab or isotype control. Tumor size was monitored, and at the end of the study, tumor immune cell composition data were collected. Tumor growth over time was modeled using a linear mixed-effects model with tumor volume as the outcome variable and the predictor variables of time and treatment (PD1 vs. IgG) interacting with gavage and quadratic time to accommodate non-linear tumor growth and including random effects by mouse. For sample 68, enriched for Roseburia CAG 309, the interaction between time, gavage post-BRB, and Anti-PD1 treatment significantly affected tumor volume (p < 0.05) relative control. The same significant effect (p < 0.05) was also seen for sample 79, enriched for Lachnospira pectinoschiza, and samples 84 and 85, enriched for Blautia obeum. To determine the mechanism by which this might occur, we analyzed the tumor's immune cell composition. Post-BRB mice treated with Anti-PD1 showed a significant increase in tumor-infiltrating CD8+ immune cells relative control, as compared to mice gavaged with pre-BRB stool. Modeling results showed samples whose response was improved slightly after the BRB dietary intervention. These samples were associated with the enrichment of the taxon Roseburia CAG 309. A black-raspberry dietary intervention in humans modified the microbiomes of several participants in a way that is hypothesized to improve response to PD1 treatment. Future directions include supplementing individual microbes into pre-intervention gavages to confirm which taxa improve response. These results suggest that this modeling platform is an effective system for testing microbiome modification on tumor growth and assessing mechanisms by which this might occur and is extendable to other lifestyle-based interventions where pre- and post-intervention specimens are collected. Citation Format: Aaditya Pallerla, Bailey Conrad, Amna Bibi, Nyelia Williams, Caroline Wheeler, Rebecca Hoyd, Shankar Suman, Joseph Amann, Yangyang Liu, Marisa Bittoni, Shiqi Zhang, Madison Grogan, Alvin Anand, Najma Afrah, Carolyn Presley, Fred K. Tabung, Lang Li, Yael Vodovotz, Jiangjiang Zhu, David P. Carbone, Steven K. Clinton, Daniel Spakowicz. A causal modeling platform for testing lifestyle interventions on the microbiome and response to immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4435.

We evaluated associations of the Empirical Dietary Index for Hyperinsulinemia (EDIH), Empirical Dietary Inflammatory Pattern (EDIP) and Healthy Eating Index (HEI2015) and their metabolomics profiles with the risk of total and site-specific cancers. We used baseline food frequency questionnaires to calculate dietary scores among 112,468 postmenopausal women in the Women’s Health Initiative. We used multivariable-adjusted Cox regression to estimate hazard ratios (HR) and 95% confidence intervals for cancer risk estimation. Metabolomic profile scores were derived using elastic-net regression with leave-one-out cross validation. In over 17.8 years, 18,768 incident invasive cancers were adjudicated. Higher EDIH and EDIP scores were associated with greater total cancer risk, and higher HEI-2015 with lower risk: HRQ5vsQ1(95% CI): EDIH, 1.10 (1.04–1.15); EDIP, 1.08 (1.02–1.15); HEI-2015, 0.93 (0.89–0.98). The multivariable-adjusted incidence rate difference(Q5vsQ1) for total cancer was: +52 (EDIH), +41 (EDIP) and −49 (HEI-2015) per 100,000 person years. All three indices were associated with colorectal cancer, and EDIH and EDIP with endometrial and breast cancer risk. EDIH was further associated with luminal-B, ER-negative and triple negative breast cancer subtypes. Dietary patterns contributing to hyperinsulinemia and inflammation were associated with greater cancer risk, and higher overall dietary quality, with lower risk. The findings warrant the testing of these dietary patterns in clinical trials for cancer prevention among postmenopausal women.

Background: Dietary patterns promoting chronic inflammation, including the empirical dietary inflammatory pattern (EDIP), have been shown to strongly influence risk of weight gain, type 2 diabetes, cardiovascular disease, and colorectal cancer. However, it is unclear if this dietary pattern is associated with other tumors in which the mechanisms are not totally understood such as breast cancer. Methods: We prospectively followed 76,295 women from the Nurses’ Health Study (NHS, 1984-2016) and 91,078 women from the Nurses’ Health Study II (NHSII, 1991-2017). Diet was assessed by food frequency questionnaires (FFQs) every 4 years. The inflammatory potential of diet was evaluated using the previously established EDIP based on plasma C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor alpha receptor 2 (TNF-αR2). Higher scores indicate higher inflammatory potential of the diet. Results: During 4,153,676 person-years of follow-up, we documented 10,632 invasive breast cancer cases (6,807 NHS; 3,825 NHSII). In the pooled multivariable-adjusted analyses, women in the highest, compared with the lowest, EDIP quintile were at higher breast cancer risk (HRQ5vsQ1=1.12; 95% CI 1.05, 1.20; P-trend< 0.001). This association was attenuated after adjusting for weight change since age 18 y, although it remained significant (HRQ5vsQ1=1.07; 95% CI 1.00, 1.14; P-trend=0.01). In subtype analyses, we found evidence that the inflammatory potential of diet influenced breast cancer risk differentially by ER status (P-heterogeneity=0.038) and by molecular phenotype (P-heterogeneity=0.007), with the association between EDIP and breast cancer limited to ER-negative tumors (HRQ5vsQ1=1.31; 95% CI: 1.11, 1.55; P-trend=0.002; for ER-positive tumors, HR Q5vsQ1=1.03; 95% CI, 0.96, 1.12;P-trend=0.10) and basal-like tumors (HRQ5vsQ1=1.78; 95% CI: 1.19, 2.65; P-trend=0.004). Further adjustment for weight change since age 18 y did not materially alter the association for these subtypes. Conclusions: Dietary patterns with high potential to contribute to chronic systemic inflammation, based on higher EDIP scores, were associated with a modestly increased risk of breast cancer, which was more pronounced for ER-negative and basal-like breast tumors. Citation Format: Andrea Romanos-Nanclares, Walter C Willett, Bernard A Rosner, Daniel G Stover, Sarah Asad, Sagar Sardesai, Michelle D Holmes, Wendy Y Chen, Rulla M. Tamimi, Fred K Tabung, A Heather Eliassen. Proinflammatory Dietary Patterns and Risk of Total and Subtypes of Breast Cancer Among US Women [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-14.

ImportanceThe current Dietary Guidelines for Americans recommend multiple healthy eating patterns. However, few studies have examined the associations of adherence to different dietary patterns with long-term risk of total and cause-specific mortality.ObjectiveTo examine the associations of dietary scores for 4 healthy eating patterns with risk of total and cause-specific mortality.Design, Setting, and ParticipantsThis prospective cohort study included initially healthy women from the Nurses’ Health Study (NHS; 1984-2020) and men from the Health Professionals Follow-up Study (HPFS; 1986-2020).ExposuresHealthy Eating Index 2015 (HEI-2015), Alternate Mediterranean Diet (AMED) score, Healthful Plant-based Diet Index (HPDI), and Alternate Healthy Eating Index (AHEI).Main Outcomes and MeasuresThe main outcomes were total and cause-specific mortality overall and stratified by race and ethnicity and other potential risk factors.ResultsThe final study sample included 75 230 women from the NHS (mean [SD] baseline age, 50.2 [7.2] years) and 44 085 men from the HPFS (mean [SD] baseline age, 53.3 [9.6] years). During a total of 3 559 056 person-years of follow-up, 31 263 women and 22 900 men died. When comparing the highest with the lowest quintiles, the pooled multivariable-adjusted HRs of total mortality were 0.81 (95% CI, 0.79-0.84) for HEI-2015, 0.82 (95% CI, 0.79-0.84) for AMED score, 0.86 (95% CI, 0.83-0.89) for HPDI, and 0.80 (95% CI, 0.77-0.82) for AHEI (P Conclusions and RelevanceIn this cohort study of 2 large prospective cohorts with up to 36 years of follow-up, greater adherence to various healthy eating patterns was consistently associated with lower risk of total and cause-specific mortality. These findings support the recommendations of Dietary Guidelines for Americans that multiple healthy eating patterns can be adapted to individual food traditions and preferences.

Background: We prospectively examined the extent to which greater inflammatory and insulinemic potential of diet and lifestyle are associated with the risk of developing hepatocellular carcinoma (HCC) in two nationwide cohorts. Methods: Five kinds of pattern scores, including the empirical dietary inflammatory pattern (EDIP), empirical dietary index for hyperinsulinemia (EDIH) and insulin resistance (EDIR), empirical lifestyle pattern score for hyperinsulinemia (ELIH) and insulin resistance (ELIR) were calculated. Multivariable hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression. Results: After an average follow-up of 25.6 years among 119,316 participants, 142 incident HCC cases were documented. Higher adherence to EDIP (HR by comparing extreme tertiles: 2.03; 95% CI, 1.31–3.16; Ptrend = 0.001), EDIH (HR, 1.61; 95% CI, 1.06–2.43; Ptrend = 0.02), and EDIR (HR, 1.62; 95% CI: 1.08–2.42; Ptrend = 0.02) was associated with increased risk of HCC. Likewise, participants with higher scores of ELIH (HR, 1.89; 95% CI, 1.25–2.87; Ptrend = 0.001) and ELIR (HR, 2.05; 95% CI, 1.34–3.14, Ptrend = 0.0004) had higher risk of developing HCC. Additional adjustment for diabetes mellitus and/or body mass index attenuated the magnitude of the associations, indicating that diabetes and/or adiposity may partly mediate the association of these patterns with HCC risk. Conclusions: Our findings suggest that inflammation and insulin resistance/hyperinsulinemia are potential mechanisms linking dietary or lifestyle factors and HCC development. Impact: Inflammation and insulin resistance/hyperinsulinemia may partly mediate the association of diet and other lifestyles with HCC development, and interventions to reduce the adverse effect of pro-inflammatory and hyperinsulinemic diet and lifestyle may reduce HCC risk.

Most cohort studies have only a single physical activity (PA) measure and are thus susceptible to reverse causation and measurement error. Few studies have examined the impact of these potential biases on the association between PA and mortality. A total of 133,819 participants from Nurses' Health Study and Health Professionals Follow-up Study (1986-2014) reported PA through biennial questionnaires. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for PA and mortality using different analytic approaches comparing single (baseline, simple update = most recent) versus repeated (cumulative average) measures of PA and applying various lag times separating PA measurement and time at risk. Over 3.2 million person-years, we documented 47,273 deaths. The pooled multivariable-adjusted HR (95% CI) of all-cause mortality per 10 MET-hour/week was 0.95 (0.94-0.96) for baseline PA, 0.78 (0.77-0.79) for simple updated PA and 0.87 (0.86-0.88) for cumulative average PA in the range of 0-50 MET-hour/week. Simple updated PA showed the strongest inverse association, suggesting larger impact of reverse causation. Application of 2-year lag substantially reduced the apparent reverse causation (0.85 (0.84-0.86) for simple updated PA and 0.90 (0.89-0.91) for cumulative average PA), and 4-12-year lags had minimal additional effects. In the dose-response analysis, baseline or simple updated PA showed a J or U-shaped association with all-cause mortality while cumulative average PA showed an inverse association across a wide range of PA (0-150 MET-hour/week). Similar findings were observed for different specific mortality causes. In conclusion, PA measured at baseline or with short lag time was prone to bias. Cumulative average PA showed robust evidence that PA is inversely associated with mortality in a dose-response manner.