Appendectomy and Long-term Colorectal Cancer Incidence, Overall and by Tumor Fusobacterium nucleatum Status.

OBJECTIVE: To test hypotheses that appendectomy history might lower long-term colorectal cancer risk and that the risk reduction might be strong for tumors enriched with Fusobacterium nucleatum, bacterial species implicated in colorectal carcinogenesis. BACKGROUND: The absence of the appendix, an immune system organ and a possible reservoir of certain pathogenic microbes, may affect the intestinal microbiome, thereby altering long-term colorectal cancer risk. METHODS: Utilizing databases of prospective cohort studies, namely the Nurses' Health Study and the Health Professionals Follow-up Study, we examined the association of appendectomy history with colorectal cancer incidence overall and subclassified by the amount of tumor tissue Fusobacterium nucleatum​​ (Fusobacterium animalis). We used an inverse probability weighted multivariable-adjusted duplication-method Cox proportional hazards regression model. RESULTS: During the follow-up of 139,406 participants (2,894,060 person-years), we documented 2811 incident colorectal cancer cases, of which 1065 cases provided tissue F. nucleatum analysis data. The multivariable-adjusted hazard ratio of appendectomy for overall colorectal cancer incidence was 0.92 (95% CI, 0.84-1.01). Appendectomy was associated with lower F. nucleatum-positive cancer incidence (multivariable-adjusted hazard ratio, 0.53; 95% CI, 0.33-0.85; P=0.0079), but not F. nucleatum-negative cancer incidence (multivariable-adjusted hazard ratio, 0.98; 95% CI, 0.83-1.14), suggesting a differential association by F. nucleatum status (Pheterogeneity=0.015). This differential association appeared to persist in various participant/patient strata including tumor location and microsatellite instability status. CONCLUSIONS: Appendectomy likely lowers the future long-term incidence of F. nucleatum-positive (but not F. nucleatum-negative) colorectal cancer. Our findings do not support the existing hypothesis that appendectomy may increase colorectal cancer risk.

Dietary Fiber Intake and Risk of Advanced and Aggressive Forms of Prostate Cancer: A Pooled Analysis of 15 Prospective Cohort Studies.

BACKGROUND: Evidence of an association between dietary fiber intake and risk of advanced and aggressive forms of prostate cancer (PC) and PC mortality is limited. OBJECTIVE: The aim of this study was to examine associations between intakes of dietary fiber overall and by food source and risk of advanced and aggressive forms of PC. DESIGN: The study design was a pooled analysis of the primary data from 15 cohorts in 3 continents. Baseline dietary fiber intake was assessed using a validated food frequency questionnaire or diet history in each study. PARTICIPANTS/SETTING: There were 842 149 men followed for up to 9 to 22 years between 1985 and 2009 across studies. MAIN OUTCOME MEASURES: The primary outcome measures were advanced (stage T4, N1, or M1 or PC mortality), advanced restricted (excluded men with missing stage and those with localized PC who died of PC), and high-grade PC (Gleason score ≥8 or poorly differentiated/undifferentiated) and PC mortality. STATISTICAL ANALYSIS PERFORMED: Study-specific multivariable hazard ratios (MVHR) were calculated using Cox proportional hazards regression and pooled using random effects models. RESULTS: Intake of dietary fiber overall, from fruits, and from vegetables was not associated with risk of advanced (n = 4863), advanced restricted (n = 2978), or high-grade PC (n = 9673) or PC mortality (n = 3097). Dietary fiber intake from grains was inversely associated with advanced PC (comparing the highest vs lowest quintile, MVHR 0.84; 95% CI 0.76-0.93), advanced restricted PC (MVHR 0.85; 95% CI 0.74-0.97), and PC mortality (MVHR 0.78; 95% CI 0.68-0.89); statistically significant trends were noted for each of these associations (P ≤ .03), and a null association was observed for high-grade PC for the same comparison (MVHR 1.00; 95% CI 0.93-1.07). The comparable results were 1.06 (95% CI 1.01-1.10; P value, test for trend = .002) for localized PC (n = 35,199) and 1.05 (95% CI 0.99-1.11; P value, test for trend = .04) for low/intermediate grade PC (n = 34 366). CONCLUSIONS: Weak nonsignificant associations were observed between total dietary fiber intake and risk of advanced forms of PC, high-grade PC, and PC mortality. High dietary fiber intake from grains was associated with a modestly lower risk of advanced forms of PC and PC mortality.

Multivitamin use after diagnosis and prostate cancer survival among men with nonmetastatic prostate cancer.

BACKGROUND: Multivitamin use is common among cancer patients. Whether post-diagnostic multivitamin supplementation is beneficial for prostate cancer survival is largely unknown, and some evidence even suggests potential harm. METHODS: We prospectively assessed post-diagnostic multivitamin use in relation to prostate cancer survival among 4756 men with nonmetastatic prostate cancer at diagnosis in the Health Professionals Follow-up Study (1986-2016). Cox regression models were used to evaluate the association between post-diagnostic multivitamin use and frequency and risk of lethal prostate cancer (distant metastases or prostate cancer-specific death) and all-cause mortality. RESULTS: We observed 438 lethal prostate cancer and 2609 deaths during a median follow-up of 11 years. Compared to non-users, post-diagnostic multivitamin use was not associated with risk of lethal prostate cancer (HR [95% CI], 0.98 [0.74-1.30]) or all-cause mortality (1.00 [0.88-1.12]), after adjustment for potential confounders. Similarly, null associations were observed across various categories of use frequency. Compared to non-users, men who used multivitamins regularly (6-9 tablets/week) after cancer diagnosis had similar risk of lethal prostate cancer (0.96 [0.72-1.28]) and all-cause mortality (0.99 [0.88-1.12]). CONCLUSIONS: We found no evidence that post-diagnostic multivitamin use among men with nonmetastatic prostate cancer was associated with better or worse survival in a well-nourished population.

Protein intake and its association with sleep quality: results from 3 prospective cohort studies.

BACKGROUND/OBJECTIVES: Sleep quality is a critical factor for daytime functioning and chronic disease risk. We investigated the association between intakes of total protein and protein subtypes and sleep quality in three U.S. cohorts. SUBJECTS/METHODS: In the Nurses' Health Study (NHS), NHS2, and Health Professionals Follow-up study (HPFS), dietary intake was assessed every 4 years using validated food frequency questionnaires. Sleep quality was measured once with the Pittsburgh Sleep Quality Index or adapted versions. With ordinal logistic regression, odds ratios (OR) and 95% confidence intervals (CI) were calculated to estimate the odds of having better sleep quality versus poorer sleep quality depending on protein intake (%Energy) based on the average of the prior two dietary questionnaires. RESULTS: In 32,212 women from NHS, 51,126 women from NHS2, and 14,796 men from HPFS, total protein intake was not associated with sleep quality. However, the intake of protein from vegetable sources showed no association or a positive association with sleep quality (OR for quartile 4 versus quartile 1 in NHS: 1.12, 1.04-1.20, P-trend < 0.001; NHS2: 1.01, 0.95-1.07, P-trend = 0.90; HPFS: 1.11, 0.99-1.23, P-trend = 0.05), whereas divergent results were observed for animal protein sources. Overall, intakes of processed red meat and poultry were associated with worse sleep quality, whereas no or positive associations were observed for dairy and fish protein. CONCLUSION: Our results suggest that plants as a source of protein may be associated with better sleep quality than animal sources of protein. Further studies are warranted to validate our findings.

Post-diagnostic multivitamin supplement use and colorectal cancer survival: A prospective cohort study.

BACKGROUND: Use of multivitamin supplements has been associated with lower incidence of colorectal cancer (CRC). However, its influence on CRC survival remains unknown. METHODS: Among 2424 patients with stage I-III CRC who provided detailed information about multivitamin supplements in the Nurses' Health Study and Health Professionals Follow-up Study, the authors calculated multivariable hazard ratios (HRs) of multivitamin supplements for all-cause and CRC-specific mortality according to post-diagnostic use and dose of multivitamin supplements. RESULTS: During a median follow-up of 11 years, the authors documented 1512 deaths, among which 343 were of CRC. Compared to non-users, post-diagnostic users of multivitamin supplements at a dose of 3-5 tablets/week had lower CRC-specific mortality (HR, 0.55; 95% confidence interval [CI], 0.36-0.83, p = .005), and post-diagnostic users at doses of 3-5 and 6-9 tablets/week had lower all-cause mortality (HR, 0.81; 95% CI, 0.67-0.99, p = .04; HR, 0.79; 95% CI, 0.70-0.88), p < .001). The dose-response analysis showed a curvilinear relationship for both CRC-specific (pnonlinearity < .001) and all-cause mortality (pnonlinearity = .004), with the maximum risk reduction observed at 3-5 tablets/week and no further reduction at higher doses. Compared to non-users in both pre- and post-diagnosis periods, new post-diagnostic users at dose of <10 tablets/week had a lower all-cause mortality (HR, 0.81; 95% CI, 0.71-0.94, p = .005), whereas new users at a dose of ≥10 tablets/week (HR, 1.58; 95% CI, 1.07-2.33) and discontinued users (HR, 1.35; 95% CI, 1.14-1.59) had a higher risk of mortality. CONCLUSIONS: Use of multivitamin supplements at a moderate dose after a diagnosis of nonmetastatic CRC is associated with lower CRC-specific and overall mortality, whereas a high dose (≥10 tablets/week) use is associated with higher CRC-specific mortality.

Pre-diagnostic circulating resistin concentrations and mortality among individuals with colorectal cancer: Results from the European Prospective Investigation into Cancer and Nutrition study.

Resistin is a protein involved in inflammation and angiogenesis processes and may play a role in the progression of colorectal cancer (CRC). However, it remains unclear whether resistin is associated with increased mortality after CRC diagnosis. We examined pre-diagnostic serum resistin concentrations in relation to CRC-specific and all-cause mortality among 1343 incident CRC cases from the European Prospective Investigation into Cancer and Nutrition cohort. For CRC-specific mortality as the primary outcome, hazard ratios (HRs) and 95% confidence intervals (95% CI) were estimated from competing risk analyses based on cause-specific Cox proportional hazards models and further in sensitivity analyses using Fine-Gray proportional subdistribution hazards models. For all-cause mortality as the secondary outcome, Cox proportional hazards models were used. Subgroup analyses were performed by sex, tumor subsite, tumor stage, body mass index and time to CRC diagnosis. Resistin was measured on a median of 4.8 years before CRC diagnosis. During a median follow-up of 8.2 years, 474 deaths from CRC and 147 deaths from other causes were observed. Resistin concentrations were not associated with CRC-specific mortality (HRQ4vsQ1 = 0.95, 95% CI: 0.73-1.23; Ptrend = .97; and HRper doubling of resistin concentration = 1.00; 95% CI: 0.84-1.19; P = .98) or all-cause mortality. Results from competing risk (sensitivity) analysis were similar. No associations were found in any subgroup analyses. These findings suggest no association between pre-diagnostic circulating resistin concentrations and CRC-specific or all-cause mortality among persons with CRC, and the potential insignificance of resistin in CRC progression.

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.

Being Breastfed in Infancy and Risk of Colorectal Cancer and Precursor Lesions.

BACKGROUND & AIMS: Emerging evidence implicates the importance of perinatal and early-life exposures in colorectal cancer (CRC) development. However, it remains unclear whether being breastfed in infancy is associated with CRC risk in adult life, particularly early adulthood. METHODS: We prospectively investigated the association between history of being breastfed and risk of CRC and its precursor lesions among 66,634 women 46-93 years of age from the Nurses' Health Study and 92,062 women 27-68 years of age from the Nurses' Health Study II. Cox regression and logistic regression for clustered data were used to estimate hazard ratios for CRC and odds ratios for CRC precursors, respectively. RESULTS: During 3.5 million person-years of follow-up, we identified 1490 incident cases of CRC in 2 cohorts. Having been breastfed was associated with a 23% (95% confidence interval [CI], 10% to 38%) increased risk of CRC. The risk of CRC increased with duration of being breastfed (Ptrend < .001). These findings were validated using breastfeeding information from the mothers of a subset of participants. Among younger participants from the Nurses' Health Study II, a significant association was observed between being breastfed and increased risk of high-risk adenomas under 50 years of age (odds ratio, 1.46; 95% CI, 1.16 to 1.83). Consistently, having been breastfed was associated with increased risk of CRC among participants ≤55 years of age (hazard ratio, 1.38; 95% CI, 1.06 to 1.80). CONCLUSIONS: Being breastfed in infancy was associated with increased risk of CRC in adulthood, including among younger adults. However, further research is needed to understand the underlying biological mechanisms, as this association does not establish causation.

Development and validation of a risk prediction model for post-polypectomy colorectal cancer in the USA: a prospective cohort study.

Background: Effective risk stratification tools for post-polypectomy colorectal cancer (PPCRC) are lacking. We aimed to develop an effective risk stratification tool for the prediction of PPCRC in three large population-based cohorts and to validate the tool in a clinical cohort. Methods: Leveraging the integrated endoscopic, histopathologic and epidemiologic data in three U.S population-based cohorts of health professional (the Nurses' Health Study (NHS) I, II and Health Professionals Follow-up Study (HPFS)), we developed a risk score to predict incident PPCRC among 26,741 patients with a polypectomy between 1986 and 2017. We validated the PPCRC score in the Mass General Brigham (MGB) Colonoscopy Cohort (Boston, Massachusetts, U.S) of 76,603 patients with a polypectomy between 2007 and 2018. In all four cohorts, we collected detailed data on patients' demographics, endoscopic history, polyp features, and lifestyle factors at polypectomy. The outcome, incidence of PPCRC, was assessed by biennial follow-up questionnaires in the NHS/HPFS cohorts, and through linkage to the Massachusetts Cancer Registry in the MGB cohort. In all four cohorts, individuals who were diagnosed with CRC or died before baseline or within six months after baseline were excluded. We used Cox regression to calculate the hazard ratio (HR), 95% confidence interval (CI) and assessed the discrimination using C-statistics and reclassification using the Net Reclassification Improvement (NRI). Findings: During a median follow-up of 12.8 years (interquartile range (IQR): 9.3, 16.7) and 5.1 years (IQR: 2.7, 7.8) in the NHS/HPFS and MGB cohorts, we documented 220 and 241 PPCRC cases, respectively. We identified a PPCRC risk score based on 11 predictors. In the validation cohort, the PPCRC risk score showed a strong association with PPCRC risk (HR for high vs. low, 3.55, 95% CI, 2.59-4.88) and demonstrated a C-statistic (95% CI) of 0.75 (0.70-0.79), and was discriminatory even within the low- and high-risk polyp groups (C-statistic, 0.73 and 0.71, respectively) defined by the current colonoscopy surveillance recommendations, leading to a NRI of 45% (95% CI, 36-54%) for patients with PPCRC. Interpretation: We developed and validated a risk stratification model for PPCRC that may be useful to guide tailored colonoscopy surveillance. Further work is needed to determine the optimal surveillance interval and test the added value of other predictors of PPCRC beyond those included in the current study, along with implementation studies. Funding: US National Institutes of Health, the American Cancer Society, the South-Eastern Norway Regional Health Authority, the Deutsche Forschungsgemeinschaft.

Different operationalizations of the 2018 WCRF/AICR cancer prevention recommendations and risk of cancer.

BACKGROUND: The standardized scoring system assessing adherence to the 2018 World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) cancer prevention recommendations assigns equal weight for each recommendation, thereby giving higher weight to dietary factors collectively (5 points) than adiposity (1 point) and physical activity (1 point). An alternative score assigning equal weights to the adiposity, physical activity, alcohol, and other dietary (composite) recommendations may better predict cancer associations. METHODS: We examined associations between standardized and alternative scores with cancer risk in two US prospective cohorts. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression. RESULTS: During 28 years of follow-up, 16,342 incident cancer cases in women and 8729 cases in men occurred. Individuals in the highest versus lowest quintile of the standardized score had a reduced overall cancer risk (women: HR = 0.89, 95% CI: 0.85, 0.94; men: HR = 0.87, 95% CI: 0.81, 0.94). Results were slightly stronger for the alternative score (women: HR = 0.83, 95% CI: 0.79, 0.87; men: HR = 0.81, 95% CI: 0.75, 0.86). Similar patterns were observed for obesity-related, alcohol-related, smoking-related, and digestive system cancers. CONCLUSIONS: Greater adherence to the WCRF/AICR cancer prevention recommendations was associated with lower cancer risk. A score assigning equal weights to the adiposity, physical activity, alcohol, and all remaining diet components yielded stronger associations than the standardized score.

Plasma total cholesterol concentration and risk of higher-grade prostate cancer: A nested case-control study and a dose-response meta-analysis.

Our previous publication found an increased risk of higher-grade (Gleason sum ≥7) prostate cancer for men with high total cholesterol concentration (≥200 mg/dl) in the Health Professionals Follow-up Study (HPFS). With additional 568 prostate cancer cases, we are now able to investigate this association in more detail. For the nested case-control study, we included 1260 men newly diagnosed with prostate cancer between 1993 and 2004, and 1328 controls. For the meta-analyses, 23 articles studied the relationship between total cholesterol level and prostate cancer incidence were included. Logistic regression models and dose-response meta-analysis were performed. An increased risk of higher-grade (Gleason sum ≥4 + 3) prostate cancer for high vs low quartile of total cholesterol level was observed in the HPFS (ORmultivariable = 1.56; 95% CI = 1.01-2.40). This finding was compatible with the association noted in the meta-analysis of highest vs lowest group of total cholesterol level, which suggested a moderately increased risk of higher-grade prostate cancer (Pooled RR =1.21; 95%CI: 1.11-1.32). Moreover, the dose-response meta-analysis indicated that an increased risk of higher-grade prostate cancer occurred primarily at total cholesterol levels ≥200 mg/dl, where the RR was 1.04 (95%CI: 1.01-1.08) per 20 mg/dl increase in total cholesterol level. However, total cholesterol concentration was not associated with the risk of prostate cancer overall either in the HPFS or in the meta-analysis. Our primary finding, as well as the result of the meta-analysis suggested a modest increased risk of higher-grade prostate cancer, at total cholesterol concentrations exceeding 200 mg/dl.

Dietary Inflammatory and Insulinemic Potentials, Plasma Metabolome and Risk of Colorectal Cancer.

The inflammatory and insulinemic potentials of diets have been associated with colorectal cancer risk. However, it is unknown whether the plasma metabolite profiles related to inflammatory diets, or to insulinemic diets, underlie this association. The aim of this study was to evaluate the association between metabolomic profile scores related to the food-based empirical dietary inflammatory patterns (EDIP), the empirical dietary index for hyperinsulinemia (EDIH), and plasma inflammation (CRP, IL-6, TNFα-R2, adiponectin) and insulin (C-peptide) biomarkers, and colorectal cancer risk. Elastic net regression was used to derive three metabolomic profile scores for each dietary pattern among 6840 participants from the Nurses' Health Study and Health Professionals Follow-up Study, and associations with CRC risk were examined using multivariable-adjusted logistic regression, in a case-control study of 524 matched pairs nested in both cohorts. Among 186 known metabolites, 27 were significantly associated with both the EDIP and inflammatory biomarkers, and 21 were significantly associated with both the EDIH and C-peptide. In men, odds ratios (ORs) of colorectal cancer, per 1 standard deviation (SD) increment in metabolomic score, were 1.91 (1.31-2.78) for the common EDIP and inflammatory-biomarker metabolome, 1.12 (0.78-1.60) for EDIP-only metabolome, and 1.65 (1.16-2.36) for the inflammatory-biomarkers-only metabolome. However, no association was found for EDIH-only, C-peptide-only, and the common metabolomic signatures in men. Moreover, the metabolomic signatures were not associated with colorectal cancer risk among women. Metabolomic profiles reflecting pro-inflammatory diets and inflammation biomarkers were associated with colorectal cancer risk in men, while no association was found in women. Larger studies are needed to confirm our findings.

Adherence to the World Cancer Research Fund/American Institute for Cancer Research cancer prevention recommendations throughout the life course and risk of colorectal cancer precursors.

BACKGROUND: Despite the increasing incidence in colorectal cancer (CRC) among the young population, the involvement of modifiable early-life exposures is understudied. METHODS: We prospectively investigated the association of lifestyle score, which measures adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations, in adolescence and adulthood with risk of CRC precursors in 34,509 women enrolled in the Nurses' Health Study II. Participants reported adolescent diet in 1998 and subsequently underwent at least one lower gastrointestinal endoscopy between 1999 and 2015. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression for clustered data. RESULTS: During follow-up (1998-2015), 3036 women had at least one adenoma, and 2660 had at least one serrated lesion. In multivariable analysis, per unit increase in adolescent WCRF/AICR lifestyle score was not associated with risk of total adenoma or serrated lesions, in contrast to adult WCRF/AICR lifestyle score (OR = 0.92, 95% CI: 0.87-0.97, Ptrend = 0.002 for total adenoma; and OR = 0.86, 95% CI: 0.81-0.92, Ptrend < 0.001 for total serrated lesions). CONCLUSION: Adherence to the 2018 WCRF/AICR recommendations during adulthood but not during adolescence was associated with a lower risk of CRC precursors.

Flavonoid intake and survival after diagnosis of colorectal cancer: a prospective study in 2 US cohorts.

BACKGROUND: Although experimental evidence supports anticancer effects of flavonoids, the influence of flavonoid intake on colorectal cancer (CRC) survival remains unknown. OBJECTIVES: This study aimed to assess the association of postdiagnostic flavonoid intake with mortality. METHODS: We prospectively assessed the association of postdiagnostic flavonoid intake with CRC-specific and all-cause mortality in 2552 patients diagnosed with stage I-III CRC in 2 cohort studies-the Nurses' Health Study and the Health Professionals Follow-up Study. We assessed the intake of total flavonoids and their subclasses using validated food frequency questionnaires. We used the inverse probability-weighted multivariable Cox proportional hazards regression model to calculate the hazard ratio (HR) of mortality after adjusting for prediagnostic flavonoid intake and other potential confounders. We performed spline analysis to evaluate dose-response relationships. RESULTS: The mean [standard deviation (SD)] age of patients at diagnosis was 68.7 (9.4) y. During 31,026 person-y of follow-up, we documented 1689 deaths, of which 327 were due to CRC. The total flavonoid intake was not associated with mortality, but a higher intake of flavan-3-ols was suggestively associated with lower CRC-specific and all-cause mortality, with multivariable HR (95% CI) per 1-SD increases of 0.83 (0.69-0.99; P = 0.04) and 0.91 (0.84-0.99; P = 0.02), respectively. The spline analysis showed a linear relationship between postdiagnostic flavan-3-ol intake and CRC-specific mortality (P = 0.01 for linearity). As the major contributor to flavan-3-ol intake, tea showed an inverse association with CRC-specific and all-cause mortality, with multivariable HRs per 1 cup/d of tea of 0.86 (0.75-0.99; P = 0.03) and 0.90 (0.85-0.95; P < 0.001), respectively. No beneficial associations were found for other flavonoid subclasses. CONCLUSIONS: Higher intake of flavan-3-ol after CRC diagnosis was associated with lower CRC-specific mortality. Small, readily achievable increases in the intake of flavan-3-ol-rich foods, such as tea, may help improve survival in patients with CRC.

Histopathology images predict multi-omics aberrations and prognoses in colorectal cancer patients.

Histopathologic assessment is indispensable for diagnosing colorectal cancer (CRC). However, manual evaluation of the diseased tissues under the microscope cannot reliably inform patient prognosis or genomic variations crucial for treatment selections. To address these challenges, we develop the Multi-omics Multi-cohort Assessment (MOMA) platform, an explainable machine learning approach, to systematically identify and interpret the relationship between patients' histologic patterns, multi-omics, and clinical profiles in three large patient cohorts (n = 1888). MOMA successfully predicts the overall survival, disease-free survival (log-rank test P-value<0.05), and copy number alterations of CRC patients. In addition, our approaches identify interpretable pathology patterns predictive of gene expression profiles, microsatellite instability status, and clinically actionable genetic alterations. We show that MOMA models are generalizable to multiple patient populations with different demographic compositions and pathology images collected from distinctive digitization methods. Our machine learning approaches provide clinically actionable predictions that could inform treatments for colorectal cancer patients.

Calcium Intake and Lung Cancer Risk: A Pooled Analysis of 12 Prospective Cohort Studies.

BACKGROUND: Previous studies on calcium intake and lung cancer risk reported inconsistent associations, possibly due to the differences in intake amounts and contributing sources of calcium and smoking prevalence. OBJECTIVES: We investigated the associations of lung cancer risk with intake of calcium from foods and/or supplements and major calcium-rich foods in 12 studies. METHODS: Data from 12 prospective cohort studies conducted in the United States, Europe, and Asia were pooled and harmonized. We applied the DRI to categorize calcium intake based on the recommendations and quintile distribution to categorize calcium-rich food intake. We ran multivariable Cox regression by each cohort and pooled risk estimates to compute overall HR (95% CI). RESULTS: Among 1,624,244 adult men and women, 21,513 incident lung cancer cases were ascertained during a mean follow-up of 9.9 y. Overall, the dietary calcium intake was not significantly associated with lung cancer risk; the HRs (95% CI) were 1.08 (0.98-1.18) for higher (>1.5 RDA) and 1.01 (0.95-1.07) for lower intake (<0.5 RDA) comparing with recommended intake (EAR to RDA). Milk and soy food intake were positively or inversely associated with lung cancer risk [HR (95% CI) = 1.07 (1.02-1.12) and 0.92 (0.84-1.00)], respectively. The positive association with milk intake was significant only in European and North American studies (P-interaction for region = 0.04). No significant association was observed for calcium supplements. CONCLUSIONS: In this largest prospective investigation, overall, calcium intake was not associated with risk of lung cancer, but milk intake was associated with a higher risk. Our findings underscore the importance of considering food sources of calcium in studies of calcium intake.

Simple Prediction Model for Colorectal Serrated Polyps: Development and External Validation Study in U.S. Prospective Cohorts.

Serrated polyps (SP) are precursors for colorectal cancer and contribute disproportionately to postcolonoscopy cancers. Leveraging three U.S. cohorts (43,974 women and 5,322 men), we developed prediction models for high-risk SPs (sized ≥10 mm or ≥3) among individuals undergoing their first colonoscopy screening. We then validated the model in the Partners Colonoscopy Cohort (51,203 women and 39,077 men). We evaluated discrimination and calibration using the C-statistic and Hosmer-Lemeshow test, respectively. The age and family history model generated a C-statistic [95% confidence interval (CI)] of 0.57 (0.56-0.58) in women and 0.58 (0.55-0.61) in men. Further inclusion of smoking, alcohol, and body mass index (the simple model) increased the C-statistic (95% CI) to 0.68 (0.67-0.69) in women and 0.68 (0.66-0.71) in men (all P < 0.001). Adding more predictors did not provide much incremental predictivity. In the validation cohort, moderate discrimination was observed in both women (0.60, 0.58-0.61) and men (0.60, 0.59-0.62). Notably, the simple model also yielded similar C-statistics for a composite endpoint of SPs and high-risk conventional adenomas (women, 0.62, 0.62-0.63; men, 0.63, 0.61-0.64). The model was adequately calibrated in both sets of cohorts. In summary, we developed and externally validated a simple prediction model based on five major risk factors for high-risk SPs that may be useful for healthy lifestyle recommendations and tailored colorectal cancer screening. PREVENTION RELEVANCE: On the basis of four prospective studies in the United States, we developed and externally validated a simple risk prediction model for high-risk SPs in the setting of colonoscopy screening. Our model showed moderate discriminatory accuracy and has potential utility for individualized risk assessment, healthy lifestyle recommendations, and tailored colorectal cancer prevention.

Fructose consumption from different food sources and cardiometabolic biomarkers: cross-sectional associations in US men and women.

BACKGROUND: Previous studies on the relationship between fructose intake and cardiometabolic biomarkers have yielded inconsistent results, and the metabolic effects of fructose are likely to vary across food sources such as fruit versus sugar-sweetened beverages (SSB). OBJECTIVES: We aimed to examine associations of fructose from 3 major sources (SSB, fruit juice, and fruit) with 14 insulinemic/glycemic, inflammatory, and lipid markers. METHODS: We utilized cross-sectional data from 6858 men in the Health Professionals Follow-up Study, 15,400 women in NHS, and 19,456 women in NHSII who were free of type 2 diabetes, CVDs, and cancer at blood draw. Fructose intake was assessed via a validated FFQ. Multivariable linear regression was used to estimate the percentage differences of biomarker concentrations according to fructose intake. RESULTS: We found a 20 g/d increase in total fructose intake was associated with 1.5%- 1.9% higher concentrations of proinflammatory markers plus 3.5% lower adiponectin, as well as 5.9% higher TG/HDL cholesterol ratio. Unfavorable profiles of most biomarkers were only associated with fructose from SSB and juice. In contrast, fruit fructose was associated with lower concentrations of C-peptide, CRP, IL-6, leptin, and total cholesterol. Substituting 20 g/d fruit fructose for SSB fructose was associated with 10.1% lower C-peptide, 2.7%-14.5% lower proinflammatory markers and 1.8%-5.2% lower blood lipids. CONCLUSIONS: Beverage fructose intake was associated with adverse profiles of multiple cardiometabolic biomarkers.

Post-diagnostic Zinc Supplement Use and Prostate Cancer Survival Among Men With Nonmetastatic Prostate Cancer.

PURPOSE: Biological and experimental evidence support restoration of normal zinc levels in malignant prostate cells as a promising prostate cancer treatment, yet the influence of zinc supplementation after diagnosis on prostate cancer survival in a human population is unknown. MATERIALS AND METHODS: We prospectively assessed post-diagnostic zinc supplementation in relation to prostate cancer survival among 5,788 men with nonmetastatic prostate cancer in the Health Professionals Follow-up Study (1986-2019). We used Cox regression models to estimate the multivariable hazard ratios and 95% confidence intervals of lethal prostate cancer (distant metastases or prostate cancer-specific death) and all-cause mortality according to post-diagnostic zinc supplement use and dosage. RESULTS: During a median follow-up of 11 years, we documented 527 lethal prostate cancer events and 3,198 all-cause deaths. Fifteen percent of men reported zinc supplement use post-diagnosis. Compared to nonusers, post-diagnostic zinc supplement use was associated suggestively with a lower risk of lethal prostate cancer (HR [95% CI], 0.82 [0.60-1.13]) and significantly with all-cause mortality (0.84 [0.74-0.96]). The inverse association was mostly observed among men who used post-diagnostic zinc supplements of 1-24 mg/d (lethal prostate cancer: 0.55 [0.32-0.96]; all-cause mortality: 0.77 [0.64-0.93]), while higher dosage did not show a lower risk. CONCLUSIONS: Post-diagnostic low-dose zinc supplement use among nonmetastatic prostate cancer patients was associated with lower risk of lethal prostate cancer and all-cause mortality. A potential benefit of low-dose post-diagnostic zinc supplement for prostate cancer survival merits further study.

Ultra-processed food consumption and risk of colorectal cancer precursors: results from 3 prospective cohorts.

BACKGROUND: Growing evidence indicates the adverse effect of ultra-processed food (UPF) consumption. However, it remains unknown whether UPF consumption influences the risk of colorectal cancer (CRC) precursors, namely conventional adenomas and serrated lesions. METHODS: We drew data from the Nurses' Health Study, Nurses' Health Study II, and Health Professionals Follow-up Study, comprising 142 052 participants who had undergone at least 1 lower gastrointestinal endoscopy during follow-up. To handle multiple records per participants, we used multivariable logistic regression for clustered data to calculate odds ratios (OR) and 95% confidence intervals (CIs) of colorectal polyps in relation to cumulative average consumption of UPFs. All statistical tests were 2-sided. RESULTS: We documented 11 644 patients with conventional adenomas and 10 478 with serrated lesions during 18-20 years of follow-up. Compared with participants in the lowest quintile of UPF consumption, those in the highest quintile had an increased risk of conventional adenomas (OR = 1.18, 95% CI = 1.11 to 1.26) and serrated lesions (OR = 1.20, 95% CI = 1.13 to 1.28). Similar results were found for high-risk polyps (ie, advanced adenomas and ≥10 mm serrated lesions; OR = 1.17, 95% CI = 1.07 to 1.28). These associations were slightly attenuated but remained statistically significant after further adjusting for body mass index, Western dietary pattern score, or individual dietary factors (fiber, folate, calcium, and vitamin D). The results remained essentially unchanged after excluding processed meat from total UPF intake. CONCLUSIONS: Higher consumption of UPFs is associated with an increased risk of CRC precursors. UPFs might be a modifiable target for early prevention of CRC.