The metabolic potential of inflammatory and insulinaemic dietary patterns and risk of type 2 diabetes.

AIMS/HYPOTHESIS: Diets with higher inflammatory and insulinaemic potential have been associated with an increased risk of type 2 diabetes. However, it remains unknown whether plasma metabolomic profiles related to proinflammatory/hyperinsulinaemic diets and to inflammatory/insulin biomarkers are associated with type 2 diabetes risk. METHODS: We analysed 6840 participants from the Nurses' Health Study and Health Professionals Follow-up Study to identify the plasma metabolome related to empirical dietary inflammatory pattern (EDIP), empirical dietary index for hyperinsulinemia (EDIH), four circulating inflammatory biomarkers and C-peptide. Dietary intakes were assessed using validated food frequency questionnaires. Plasma metabolomic profiling was conducted by LC-MS/MS. Metabolomic signatures were derived using elastic net regression. Multivariable Cox regression was used to examine associations of the metabolomic profiles with type 2 diabetes risk. RESULTS: We identified 27 metabolites commonly associated with both EDIP and inflammatory biomarker z score and 21 commonly associated with both EDIH and C-peptide. Higher metabolomic dietary inflammatory potential (MDIP), reflecting higher metabolic potential of both an inflammatory dietary pattern and circulating inflammatory biomarkers, was associated with higher type 2 diabetes risk. The HR comparing highest vs lowest quartiles of MDIP was 3.26 (95% CI 2.39, 4.44). We observed a strong positive association with type 2 diabetes risk for the metabolomic signature associated with EDIP-only (HR 3.75; 95% CI 2.71, 5.17) or inflammatory biomarkers-only (HR 4.07; 95% CI 2.91, 5.69). In addition, higher metabolomic dietary index for hyperinsulinaemia (MDIH), reflecting higher metabolic potential of both an insulinaemic dietary pattern and circulating C-peptide, was associated with greater type 2 diabetes risk (HR 3.00; 95% CI 2.22, 4.06); further associations with type 2 diabetes were HR 2.79 (95% CI 2.07, 3.76) for EDIH-only signature and HR 3.89 (95% CI 2.82, 5.35) for C-peptide-only signature. The diet scores were significantly associated with risk, although adjustment for the corresponding metabolomic signature scores attenuated the associations with type 2 diabetes, these remained significant. CONCLUSIONS/INTERPRETATION: The metabolomic signatures reflecting proinflammatory or hyperinsulinaemic diets and related biomarkers were positively associated with type 2 diabetes risk, supporting that these dietary patterns may influence type 2 diabetes risk via the regulation of metabolism.

Healthy dietary patterns and risk of prostate cancer in men at high genetic risk.

Prostate cancer has high heritability. Healthy lifestyle has been associated with lower lethal prostate cancer risk among men at increased genetic susceptibility, but the role of healthy dietary patterns remains unknown. We prospectively followed 10,269 genotyped men in the Health Professionals Follow-up Study (1993-2019). Genetic risk was quantified using an established polygenic risk score (PRS). Five dietary patterns were investigated: healthy eating index, Mediterranean, diabetes risk-reducing, hyperinsulinemic and inflammatory diet. Overall and lethal prostate cancer rates (metastatic disease/prostate cancer-specific death) were analyzed using multivariable Cox proportional hazards models. During 26 years of follow-up, 2133 overall and 253 lethal prostate cancer events were documented. In the highest PRS quartile, higher adherence to a diabetes risk-reducing diet was associated with lower rates of overall (top vs. bottom quintile HR [95% CI], 0.74 [0.58-0.94]) and lethal prostate cancer (0.43 [0.21-0.88]). A low insulinemic diet was associated with similar lower rates (overall, 0.76 [0.60-0.95]; lethal, 0.46 [0.23-0.94]). Other dietary patterns showed weaker, but similar associations. In the highest PRS quartile, men with healthy lifestyles based on body weight, physical activity, and low insulinemic diet had a substantially lower rate (0.26 [0.13-0.49]) of lethal prostate cancer compared with men with unhealthy lifestyles, translating to a lifetime risk of 3.4% (95% CI, 2.3%-5.0%) among those with healthy lifestyles and 9.5% (5.3%-16.7%) among those with unhealthy lifestyles. Our findings indicate that lifestyle modifications lowering insulin resistance and chronic hyperinsulinemia could be relevant in preventing aggressive prostate cancer among men genetically predisposed to prostate cancer.

Identifying modifiable risk factors to prevent aggressive colorectal cancer.

It remains unclear if pre-diagnostic factors influence the developmental pathways of colorectal cancer (CRC) that could enhance tumor aggressiveness. This study used prospective data from 205,489 cancer-free US health professionals to investigate the associations of 31 known or putative risk factors with the risk of aggressive CRC. Tumor aggressiveness was characterized by three endpoints: aggressive CRC (cancer that causes death within 5 years of diagnosis), fatal CRC, and tumor stage at diagnosis. The data augmentation method was used to assess the difference in the associations between risk factors and endpoints. We documented 3201 CRC cases, of which 899 were aggressive. The protective associations of undergoing lower endoscopy (hazard ratios [HR] 0.43, 95% confidence interval (CI) 0.37, 0.49 for aggressive versus HR 0.61, 95% CI 0.56, 0.67 for non-aggressive) and regular use of aspirin (HR 0.70, 95% CI 0.61, 0.81 versus HR 0.84, 95% CI 0.77, 0.92) were stronger for aggressive than non-aggressive CRC (pHeterogeneity <0.05). Lower intake of whole grains or cereal fiber and greater dietary inflammatory potential were associated with a higher risk of aggressive but not non-aggressive CRC. The remaining risk factors showed comparable associations with aggressive CRC and non-aggressive CRC. Aggressive cases were more likely to have KRAS-mutated tumors but less likely to have distal or MSI-high tumors (p < .007). Similar results were observed for fatal CRC and advanced tumor stages at diagnosis. These findings provide initial evidence for the role of pre-diagnostic risk factors in the pathogenesis of aggressive CRC and suggest research priorities for preventive interventions.

An Improved Assessment Method to Estimate (Poly)phenol Intake in Adults with Chronic Pancreatitis.

BACKGROUND: Insights into (poly)phenol exposure represent a modifiable factor that may modulate inflammation in chronic pancreatitis (CP), yet intake is poorly characterized and methods for assessment are underdeveloped. AIMS: The aims are to develop and test a method for estimating (poly)phenol intake from a 90-day food frequency questionnaire (FFQ) using the Phenol-Explorer database and determine associations with dietary patterns in CP patients versus controls via analysis of previously collected cross-sectional data. METHODS: Fifty-two CP patients and 48 controls were recruited from an ambulatory clinic at a large, academic institution. To assess the feasibility of the proposed methodology for estimating dietary (poly)phenol exposure, a retrospective analysis of FFQ data was completed. Mann-Whitney U tests were used to compare (poly)phenol intake by group; Spearman correlations and multivariable-adjusted log-linear associations were used to compare (poly)phenol intakes with dietary scores within the sample. RESULTS: Estimation of (poly)phenol intake from FFQs was feasible and produced estimates within a range of intake previously reported. Total (poly)phenol intake was significantly lower in CP vs controls (463 vs. 567mg/1000kcal; p = 0.041). In adjusted analyses, higher total (poly)phenol intake was associated with higher HEI-2015 (r = 0.34, p < 0.001), aMED (r = 0.22, p = 0.007), EDIH (r = 0.29, p < 0.001), and EDIP scores (r = 0.35, p < 0.001), representing higher overall diet quality and lower insulinemic and anti-inflammatory dietary potentials, respectively. CONCLUSIONS: Using enhanced methods to derive total (poly)phenol intake from an FFQ is feasible. Those with CP have lower total (poly)phenol intake and less favorable dietary pattern indices, thus supporting future tailored dietary intervention studies in this population.

Developing and evaluating the construct validity of a dietary pattern predictive of plasma TMAO and choline.

BACKGROUND AND AIMS: The metabolism of choline (highly present in animal products) can produce trimethylamine N-oxide (TMAO), a metabolite with atherosclerotic effects; however, dietary fiber may suppress this metabolic pathway. This study aimed to develop a dietary pattern predictive of plasma TMAO and choline concentrations using reduced rank regression (RRR) and to evaluate its construct validity. METHODS AND RESULTS: Diet and plasma concentrations of choline (µmol/L) and TMAO (µmol/L) were assessed in 1724 post-menopausal women who participated in an ancillary study within the Women's Health Initiative Observational Study (1993-1998). The TMAO dietary pattern was developed using RRR in half of the sample (Training Sample) and applied to the other half of the sample (Validation Sample) to evaluate its construct validity. Energy-adjusted food groups were the predictor variables and plasma choline and TMAO, the response variables. ANCOVA and linear regression models were used to assess associations between each biomarker and the dietary pattern score. Discretionary fat, potatoes, red meat, and eggs were positively associated with the dietary pattern, while yogurt, fruits, added sugar, and starchy vegetables were inversely associated. Mean TMAO and choline concentrations significantly increased across increasing quartiles of the dietary pattern in the Training and Validation samples. Positive associations between the biomarkers and the TMAO dietary pattern were also observed in linear regression models (Validation Sample: TMAO, adjusted beta-coefficient = 0.037 (p-value = 0.0088); Choline, adjusted beta-coefficient = 0.011 (p-value = 0.0224). CONCLUSION: We established the TMAO dietary pattern, a dietary pattern reflecting the potential of the diet to contribute to plasma concentrations of TMAO and choline.

Long-Term Leisure-Time Physical Activity Intensity and All-Cause and Cause-Specific Mortality: A Prospective Cohort of US Adults.

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 <300 min/wk of long-term leisure-time MPA, additional leisure-time VPA was associated with lower mortality; however, among those who reported ≥300 min/wk of long-term leisure-time MPA, additional leisure-time VPA did not appear to be associated with lower mortality beyond MPA. 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.

Association between dietary inflammatory potential and mortality after cancer diagnosis in the Women's Health Initiative.

BACKGROUND: Chronic inflammation is implicated in cancer prognosis and can be modulated by diet. We examined associations between post-diagnosis dietary inflammatory potential and mortality outcomes among post-menopausal women diagnosed with cancer in the Women's Health Initiative (WHI). METHODS: Energy-adjusted dietary inflammatory index scores (E-DII) were calculated from dietary and supplemental intake data collected on the first food frequency questionnaire following the diagnosis of primary invasive cancer for 3434 women in the WHI. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for risk of death from any cause, cancer, cardiovascular disease (CVD) and other causes by post-diagnosis quartiles of E-DII. Subgroup analyses by cancer stage and grade were performed. RESULTS: There were 1156 deaths after a median 13 years of follow-up from the date of a cancer diagnosis. In the multivariable-adjusted analyses, a more anti-inflammatory diet plus supplements after cancer diagnosis was associated with lower all-cause mortality, cancer mortality, CVD mortality and mortality from other causes with HRsQ1vs.Q4 ranging from 0.47 to 0.68 (all P-trends < 0.05). Associations were stronger for cancers diagnosed at more distant stages or moderately differentiated grades. CONCLUSION: A more anti-inflammatory diet plus supplements after a cancer diagnosis may improve survival for post-menopausal cancer survivors.

Associations of dietary patterns with kidney cancer risk, kidney cancer-specific mortality and all-cause mortality among postmenopausal women.

BACKGROUND: The empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP) are novel measures of dietary quality associated with insulin hypersecretion or chronic inflammation, respectively, whereas the Healthy Eating Index (HEI-2015) measures adherence to the Dietary Guidelines for Americans (DGA). We evaluated associations of EDIH, EDIP and HEI-2015 on the risk of both kidney cancer development and mortality. METHODS: We calculated the dietary scores from baseline food frequency questionnaires among 115,830 participants aged 50-79 years in the Women's Health Initiative. Multivariable-adjusted Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) for kidney cancer risk, kidney cancer-specific mortality and all-cause mortality, per 1-standard deviation increment in dietary pattern scores. RESULTS: Higher EDIH was associated with greater risk of kidney cancer development [HR, 1.12; 95%CI, (1.01,1.23)], kidney cancer-specific death [1.22(0.99,1.48)], and all-cause mortality, [1.05(1.02,1.08)]. Higher HEI-2015 was associated with lower risk of kidney cancer development, [0.85(0.77, 0.94)], kidney cancer-specific death, [0.84(0.69,1.03)] and all-cause mortality, [0.97(0.95,1.00)]. However, EDIP was not significantly associated with outcomes. Associations did not differ by BMI categories. CONCLUSIONS: Low-insulinemic dietary patterns and higher quality diets, are worthy of testing in dietary pattern intervention trials for kidney cancer prevention and improved survivorship.

Proinflammatory Diet Is Associated With Increased Risk of Fecal Incontinence Among Older Women: Prospective Results From the Nurses' Health Study.

Fecal incontinence (FI) is a debilitating gastrointestinal disorder with a devastating impact on quality of life,1,2 particularly on older women, partly because of unique risk factors including parity and menopause.2,3 Therefore, identifying modifiable factors, such as diet, are crucial for developing effective prevention strategies for FI among those at risk. We previously found higher dietary fiber intake was associated with lower FI risk,4 providing the first population-based data to connect diet and FI prevention. However, prospective evidence on other dietary factors and FI risk has been limited. Dietary patterns may be associated with gut microbiome characteristics, which may influence inflammatory responses in the gastrointestinal tract5 and drive neurosensory disturbances.6 Moreover, chronic inflammation may drive reduced muscle mass and function,7 and pelvic floor dysfunction is an established FI risk factor.1,2 We hypothesized that a proinflammatory dietary pattern may be associated with increased FI risk and tested this hypothesis in the Nurses' Health Study.

Sugar-Sweetened and Artificially Sweetened Beverages and Risk of Liver Cancer and Chronic Liver Disease Mortality.

Importance: Approximately 65% of adults in the US consume sugar-sweetened beverages daily. Objective: To study the associations between intake of sugar-sweetened beverages, artificially sweetened beverages, and incidence of liver cancer and chronic liver disease mortality. Design, Setting, and Participants: A prospective cohort with 98 786 postmenopausal women aged 50 to 79 years enrolled in the Women's Health Initiative from 1993 to 1998 at 40 clinical centers in the US and were followed up to March 1, 2020. Exposures: Sugar-sweetened beverage intake was assessed based on a food frequency questionnaire administered at baseline and defined as the sum of regular soft drinks and fruit drinks (not including fruit juice); artificially sweetened beverage intake was measured at 3-year follow-up. Main Outcomes and Measures: The primary outcomes were (1) liver cancer incidence, and (2) mortality due to chronic liver disease, defined as death from nonalcoholic fatty liver disease, liver fibrosis, cirrhosis, alcoholic liver diseases, and chronic hepatitis. Cox proportional hazards regression models were used to estimate multivariable hazard ratios (HRs) and 95% CIs for liver cancer incidence and for chronic liver disease mortality, adjusting for potential confounders including demographics and lifestyle factors. Results: During a median follow-up of 20.9 years, 207 women developed liver cancer and 148 died from chronic liver disease. At baseline, 6.8% of women consumed 1 or more sugar-sweetened beverage servings per day, and 13.1% consumed 1 or more artificially sweetened beverage servings per day at 3-year follow-up. Compared with intake of 3 or fewer servings of sugar-sweetened beverages per month, those who consumed 1 or more servings per day had a significantly higher risk of liver cancer (18.0 vs 10.3 per 100 000 person-years [P value for trend = .02]; adjusted HR, 1.85 [95% CI, 1.16-2.96]; P = .01) and chronic liver disease mortality (17.7 vs 7.1 per 100 000 person-years [P value for trend <.001]; adjusted HR, 1.68 [95% CI, 1.03-2.75]; P = .04). Compared with intake of 3 or fewer artificially sweetened beverages per month, individuals who consumed 1 or more artificially sweetened beverages per day did not have significantly increased incidence of liver cancer (11.8 vs 10.2 per 100 000 person-years [P value for trend = .70]; adjusted HR, 1.17 [95% CI, 0.70-1.94]; P = .55) or chronic liver disease mortality (7.1 vs 5.3 per 100 000 person-years [P value for trend = .32]; adjusted HR, 0.95 [95% CI, 0.49-1.84]; P = .88). Conclusions and Relevance: In postmenopausal women, compared with consuming 3 or fewer servings of sugar-sweetened beverages per month, those who consumed 1 or more sugar-sweetened beverages per day had a higher incidence of liver cancer and death from chronic liver disease. Future studies should confirm these findings and identify the biological pathways of these associations.

Metabolic Dysregulation Explains the Diverse Impacts of Obesity in Males and Females with Gastrointestinal Cancers.

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.

Association of body mass index and inflammatory dietary pattern with breast cancer pathologic and genomic immunophenotype in the nurses' health study.

BACKGROUND: Breast tumor immune infiltration is clearly associated with improved treatment response and outcomes in breast cancer. However, modifiable patient factors associated with breast cancer immune infiltrates are poorly understood. The Nurses' Health Study (NHS) offers a unique cohort to study immune gene expression in tumor and adjacent normal breast tissue, immune cell-specific immunohistochemistry (IHC), and patient exposures. We evaluated the association of body mass index (BMI) change since age 18, physical activity, and the empirical dietary inflammatory pattern (EDIP) score, all implicated in systemic inflammation, with immune cell-specific expression scores. METHODS: This population-based, prospective observational study evaluated 882 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 IHC for four classic immune cell markers (CD8, CD4, CD20, and CD163). Four immune cell-specific scores were derived via lasso regression using 105 published immune expression signatures' association with IHC. In the remaining 620 patient evaluation cohort, we evaluated association of each immune cell-specific score as outcomes, with BMI change since age 18, physical activity, and 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. BMI change since age 18 was positively associated with CD4+ (ß = 0.16; p = 0.009), and CD163 novel immune scores (ß = 0.14; p = 0.04) in multivariable analyses. In other words, for each 10 unit (kg/m2) increase in BMI, the percentage of cells positive for CD4 and CD163 increased 1.6% and 1.4%, respectively. Neither physical activity nor EDIP was significantly associated with any immune cell-specific expression score in multivariable analyses. CONCLUSIONS: BMI change since age 18 was positively associated with novel CD4+ and CD163+ cell scores in breast cancer, supporting further study of the effect of modifiable factors like weight gain on the immune microenvironment.

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

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

Simple Sugar and Sugar-Sweetened Beverage Intake During Adolescence and Risk of Colorectal Cancer Precursors.

BACKGROUND & AIMS: Recent increasing trends in early-onset colorectal cancer (CRC) strongly supports that early-life diet is involved in CRC development. However, data are lacking on the relationship with high sugar intake during early life. METHODS: We prospectively investigated the association of adolescent simple sugar (fructose, glucose, added sugar, total sugar) and sugar-sweetened beverage (SSB) intake with CRC precursor risk in 33,106 participants of the Nurses' Health Study II who provided adolescent dietary information in 1998 and subsequently underwent lower gastrointestinal endoscopy between 1999 and 2015. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression for clustered data. RESULTS: During follow-up, 2909 conventional adenomas (758 high-risk) and 2355 serrated lesions were identified (mean age at diagnoses, 52.2 ± 4.3 years). High sugar and SSB intake during adolescence was positively associated with risk of adenoma, but not serrated lesions. Per each increment of 5% of calories from total fructose intake, multivariable ORs were 1.17 (95% CI, 1.05-1.31) for total and 1.30 (95% CI, 1.06-1.60) for high-risk adenoma. By subsite, ORs were 1.12 (95% CI, 0.96-1.30) for proximal, 1.24 (95% CI, 1.05-1.47) for distal, and 1.43 (95% CI, 1.10-1.86) for rectal adenoma. Per 1 serving/day increment in SSB intake, ORs were 1.11 (95% CI, 1.02-1.20) for total and 1.30 (95% CI, 1.08-1.55) for rectal adenoma. Contrary to adolescent intake, sugar and SSB intake during adulthood was not associated with adenoma risk. CONCLUSIONS: High intake of simple sugars and SSBs during adolescence was associated with increased risk of conventional adenoma, especially rectal adenoma.

Healthy lifestyle index and risk of pancreatic cancer in the Women's Health Initiative.

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 HRqt3rd 0.83, 95% CI 0.74-0.99; and HRqt4th 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 (HRqt4th 0.78, 95% CI 0.65-0.85 and HRqt4th 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/m2) 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.

Diet-Driven Inflammation and Insulinemia and Risk of Interval Breast Cancer.

Interval breast cancers (IBCs) emerge after a non-suspicious mammogram and before the patient's next scheduled screen. Risk factors associated with IBC have not been identified. This study evaluated if the empirical dietary inflammatory pattern (EDIP) or empirical dietary index for hyperinsulinemia (EDIH) scores are associated with IBC compared to screen-detected breast cancer. Data were from women 50-79 years-old in the Women's Health Initiative cohort who completed food frequency questionnaires at baseline (1993-98) and were followed through March 31, 2019 for breast cancer detection. Women were identified as having either IBC diagnosed within 1-year after their last negative screening mammogram (N = 317) or screen-detected breast cancer (N = 1,928). Multivariable-adjusted logistic regression analyses were used to estimate odds ratios for risk of IBC compared to screen-detected cancer in dietary index tertiles. No associations were observed between EDIP or EDIH and IBC. Odds ratios comparing the highest to the lowest dietary index tertile were 1.08; 95%CI, 0.78-1.48 for EDIP and 0.92; 95%CI, 0.67-1.27 for EDIH. The null associations persisted when stratified by BMI categories. Findings suggest that diet-driven inflammation or insulinemia may not be substantially associated with IBC risk among postmenopausal women. Future studies are warranted to identify modifiable factors for IBC prevention.

Dietary Inflammatory Potential and Risk of Crohn's Disease and Ulcerative Colitis.

BACKGROUND & AIMS: Inflammation is a potential mechanism through which diet modulates the onset of inflammatory bowel disease. We analyzed data from 3 large prospective cohorts to determine the effects of dietary inflammatory potential on the risk of developing Crohn's disease (CD) and ulcerative colitis (UC). METHODS: We collected data from 166,903 women and 41,931 men in the Nurses' Health Study (1984-2014), Nurses' Health Study II (1991-2015), and Health Professionals Follow-up Study (1986-2012). Empirical dietary inflammatory pattern (EDIP) scores were calculated based on the weighted sums of 18 food groups obtained via food frequency questionnaires. Self-reported CD and UC were confirmed by medical record review. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We documented 328 cases of CD and 428 cases of UC over 4,949,938 person-years of follow-up. The median age at IBD diagnosis was 55 years (range 29-85 years). Compared with participants in the lowest quartile of cumulative average EDIP score, those in the highest quartile (highest dietary inflammatory potential) had a 51% higher risk of CD (HR 1.51; 95% CI 1.10-2.07; Ptrend = .01). Compared with participants with persistently low EDIP scores (at 2 time points, separated by 8 years), those with a shift from a low to high inflammatory potential of diet or persistently consumed a proinflammatory diet had greater risk of CD (HR 2.05; 95% CI 1.10-3.79 and HR 1.77; 95% CI 1.10-2.84). In contrast, dietary inflammatory potential was not associated with the risk of developing UC (Ptrend = .62). CONCLUSIONS: In an analysis of 3 large prospective cohorts, we found dietary patterns with high inflammatory potential to be associated with increased risk of CD but not UC.

Association between weight cycling and risk of kidney cancer: a prospective cohort study and meta-analysis of observational studies.

PURPOSE: 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). METHODS: 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. RESULTS: 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). CONCLUSION: 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.

The relationship between inflammatory dietary pattern and incidence of periodontitis.

The long-term inflammatory impact of diet could potentially elevate the risk of periodontal disease through modification of systemic inflammation. The aim of the present study was to prospectively investigate the associations between a food-based, reduced rank regression (RRR)-derived, empirical dietary inflammatory pattern (EDIP) and incidence of periodontitis. The study population was composed of 34 940 men from the Health Professionals Follow-Up Study, who were free of periodontal disease and major illnesses at baseline (1986). Participants provided medical and dental history through mailed questionnaires every 2 years and dietary data through validated semi-quantitative FFQ every 4 years. We used Cox proportional hazard models to examine the associations between EDIP scores and validated self-reported incidence of periodontal disease over a 24-year follow-up period. No overall association between EDIP and the risk of periodontitis was observed; the hazard ratio comparing the highest EDIP quintile (most proinflammatory diet) with the lowest quintile was 0·99 (95 % CI 0·89, 1·10, P-value for trend = 0·97). A secondary analysis showed that among obese non-smokers (i.e. never and former smokers at baseline), the hazard ratio for periodontitis comparing the highest EDIP quintile with the lowest was 1·39 (95 % CI 0·98, 1·96, P-value for trend = 0·03). In conclusion, no overall association was detected between EDIP and incidence of self-reported periodontitis in the study population. From the subgroups evaluated, EDIP was significantly associated with increased risk of periodontitis only among non-smokers who were obese. Hence, this association must be interpreted with caution.

Physical activity and all-cause and cause-specific mortality: assessing the impact of reverse causation and measurement error in two large prospective cohorts.

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.