Flavonoid Intake and Plasma Sex Steroid Hormones, Prolactin, and Sex Hormone-Binding Globulin in Premenopausal Women

Background: Flavonoids potentially exert anti-cancer effects, as suggested by their chemical structures and supported by animal studies. In observational studies, however, the association between flavonoids and breast cancer, and potential underlying mechanisms, remain unclear. Objective: To examine the relationship between flavonoid intake and sex hormone levels using timed blood samples in follicular and luteal phases in the Nurses’ Health Study II among premenopausal women. Methods: Plasma concentrations of estrogens, androgens, progesterone, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), prolactin, and sex hormone-binding globulin (SHBG) were measured in samples collected between 1996 and 1999. Average flavonoid were calculated from semiquantitative food frequency questionnaires collected in 1995 and 1999. We used generalized linear models to calculate geometric mean hormone concentrations across categories of the intake of flavonoids and the subclasses. Results: Total flavonoid intake generally was not associated with the hormones of interest. The only significant association was with DHEAS (p-trend = 0.02), which was 11.1% (95% confidence interval (CI): −18.6%, −3.0%) lower comparing the highest vs. lowest quartile of flavonoid intake. In subclass analyses, the highest (vs. lowest) quartile of flavan-3-ol intake was associated with significantly lower DHEAS concentrations (−11.3% with 95% CI: −18.3%, −3.7%, p-trend = 0.01), and anthocyanin intake was associated with a significant inverse trend for DHEA (−18.0% with 95% CI: −27.9%, −6.7%, p-trend = 0.003). Conclusion: Flavonoid intake in this population had limited impact on most plasma sex hormones in premenopausal women. Anthocyanins and flavan-3-ols were associated with lower levels of DHEA and DHEAS

Magnesium intake, plasma C-peptide, and colorectal cancer incidence in US women: a 28-year follow-up study

Background: Laboratory studies suggest a possible role of magnesium intake in colorectal carcinogenesis but epidemiological evidence is inconclusive. Method: We tested magnesium–colorectal cancer hypothesis in the Nurses' Health Study, in which 85 924 women free of cancer in 1980 were followed until June 2008. Cox proportional hazards regression models were used to estimate multivariable relative risks (MV RRs, 95% confidence intervals). Results: In the age-adjusted model, magnesium intake was significantly inversely associated with colorectal cancer risk; the RRs from lowest to highest decile of total magnesium intake were 1.0 (ref), 0.93, 0.81, 0.72, 0.74, 0.77, 0.72, 0.75, 0.80, and 0.67 (Ptrend<0.001). However, in the MV model adjusted for known dietary and non-dietary risk factors for colorectal cancer, the association was significantly attenuated; the MV RRs were 1.0 (ref), 0.96, 0.85, 0.78, 0.82, 0.86, 0.84, 0.91, 1.02, and 0.93 (Ptrend=0.77). Similarly, magnesium intakes were significantly inversely associated with concentrations of plasma C-peptide in age-adjusted model (Ptrend=0.002) but not in multivariate-adjusted model (Ptrend=0.61). Results did not differ by subsite or modified by calcium intakes or body mass index. Conclusion: These prospective results do not support an independent association of magnesium intake with either colorectal cancer risk or plasma C-peptide levels in women

Cancer risk in Chinese diabetes patients: a retrospective cohort study based on management data

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

Pre-diagnostic circulating concentrations of fat-soluble vitamins and risk of glioma in three cohort studies

Few prospective studies have evaluated the relation between fat-soluble vitamins and glioma risk. Using three cohorts—UK Biobank (UKB), Nurses’ Health Study (NHS), and Health Professionals Follow-Up Study (HPFS), we investigated associations of pre-diagnostic concentrations of fat-soluble vitamins D, A, and E with incident glioma. In 346,785 participants (444 cases) in UKB, associations with vitamin D (25-hydroxyvitamin D [25(OH)D]) were evaluated by Cox proportional hazards regression. In NHS (52 cases, 104 controls) and HPFS (32 cases, 64 controls), associations with 25(OH)D, vitamin A (retinol), and vitamin E (α- and γ-tocopherol) were assessed using conditional logistic regression. Our results suggested plasma concentrations of 25(OH)D and retinol were not associated with glioma risk. Comparing the highest to lowest tertile, the multivariable hazard ratio (MVHR) for 25(OH)D was 0.87 (95% confidence interval [CI] 0.68–1.11) in UKB and the multivariable risk ratio (MVRR) was 0.97 (95% CI 0.51–1.85) in NHS and HPFS. In NHS and HPFS, the MVRR for the same comparison for retinol was 1.16 (95% CI 0.56–2.38). Nonsignificant associations were observed for α-tocopherol (MVRRtertile3vs1 = 0.61, 95% CI 0.29–1.32) and γ-tocopherol (MVRR tertile3vs1 = 1.30, 95% CI 0.63–2.69) that became stronger in 4-year lagged analyses. Further investigation is warranted on a potential association between α- and γ-tocopherol and glioma risk.publishedVersio

Healthy Dietary Patterns and Oxidative Stress as Measured by Fluorescent Oxidation Products in Nurses’ Health Study

Healthy diets may lower oxidative stress and risk of chronic diseases. However, no previous studies examined associations between diet and fluorescent oxidation products (FlOP), a global marker of oxidative stress. We evaluated associations between healthy eating patterns (Alternative Healthy Eating Index (AHEI), Dietary Approach to Stop Hypertension (DASH), and Alternate Mediterranean Diet (aMED)) and FlOP, measured at three excitation/emission wavelengths (FlOP_360, FlOP_320, FlOP_400) from 2021 blood samples collected from 1688 women within the Nurses’ Health Study. AHEI, DASH, and aMED scores were significantly positively associated with FlOP_360 and FlOP_320 concentrations (p-trend ≤ 0.04), but not associated with FlOP_400. Among specific food groups that contribute to these diet scores, significantly positive associations were observed with legumes and vegetables for FlOP_360, vegetables and fruits for FlOP_320, and legumes and alcohol for FlOP_400. Inverse associations were observed with nuts, sweets or desserts, and olive oil for FlOP_360, nuts for FlOP_320 and sweets or desserts for FlOP_400 (all p-trend ≤ 0.05). However, FlOP variation due to diet was small compared to overall FlOP variation. In conclusion, AHEI, DASH, and aMED scores were unexpectedly positively, but weakly, associated with FlOP_360 and FlOP_320. However, these findings should be interpreted cautiously as the determinants of FlOP concentrations are not fully understood

Expression of estrogen receptor, progesterone receptor, and Ki67 in normal breast tissue in relation to subsequent risk of breast cancer

Although expression of estrogen receptor (ER), progesterone receptor (PR), and cell proliferation marker Ki67 serve as predictive and prognostic factors in breast cancers, little is known about their roles in normal breast tissue. Here in a nested case–control study within the Nurses’ Health Studies (90 cases, 297 controls), we evaluated their expression levels in normal breast epithelium in relation to subsequent breast cancer risk among women with benign breast disease. Tissue microarrays were constructed using cores obtained from benign biopsies containing normal terminal duct lobular units and immunohistochemical stained for these markers. We found PR and Ki67 expression was non-significantly but positively associated with subsequent breast cancer risk, whereas ER expression was non-significantly inversely associated. After stratifying by lesion subtype, Ki67 was significantly associated with higher risk among women with proliferative lesions with atypical hyperplasia. However, given the small sample size, further studies are required to confirm these results

Calcium Intake and Risk of Colorectal Cancer According to Tumor-infiltrating T Cells

Calcium intake has been associated with a lower risk of colorectal cancer. Calcium signaling may enhance T-cell proliferation and differentiation, and contribute to T-cell–mediated antitumor immunity. In this prospective cohort study, we investigated the association between calcium intake and colorectal cancer risk according to tumor immunity status to provide additional insights into the role of calcium in colorectal carcinogenesis. The densities of tumor-infiltrating T-cell subsets [CD3+, CD8+, CD45RO (PTPRC)+, or FOXP3+ cell] were assessed using IHC and computer-assisted image analysis in 736 cancer cases that developed among 136,249 individuals in two cohorts. HRs and 95% confidence intervals (CI) were calculated using Cox proportional hazards regression. Total calcium intake was associated with a multivariable HR of 0.55 (comparing ≥1,200 vs. <600 mg/day; 95% CI, 0.36–0.84; Ptrend = 0.002) for CD8+ T-cell–low but not for CD8+ T-cell–high tumors (HR = 1.02; 95% CI, 0.67–1.55; Ptrend = 0.47). Similarly, the corresponding HRs (95% CIs) for calcium for low versus high T-cell–infiltrated tumors were 0.63 (0.42–0.94; Ptrend = 0.01) and 0.89 (0.58–1.35; Ptrend = 0.20) for CD3+; 0.58 (0.39–0.87; Ptrend = 0.006) and 1.04 (0.69–1.58; Ptrend = 0.54) for CD45RO+; and 0.56 (0.36–0.85; Ptrend = 0.006) and 1.10 (0.72–1.67; Ptrend = 0.47) for FOXP3+, although the differences by subtypes defined by T-cell density were not statistically significant. These potential differential associations generally appeared consistent regardless of sex, source of calcium intake, tumor location, and tumor microsatellite instability status. Our findings suggest a possible role of calcium in cancer immunoprevention via modulation of T-cell function

Partial substitution of red meat or processed meat with plant-based foods and the risk of colorectal cancer

Objectives: Shifting from animal-based to plant-based diets could reduce colorectal cancer (CRC) incidence. Currently, the impacts of these dietary shifts on CRC risk are ill-defined. Therefore, we examined partial substitutions of red or processed meat with whole grains, vegetables, fruits or a combination of these in relation to CRC risk in Finnish adults. Methods: We pooled five Finnish cohorts, resulting in 43 788 participants aged ≥ 25 years (79% men). Diet was assessed by validated food frequency questionnaires at study enrolment. We modelled partial substitutions of red (100 g/week) or processed meat (50 g/week) with corresponding amounts of plant-based foods. Cohort-specific hazard ratios (HR) for CRC were calculated using Cox proportional hazards models and pooled together using random-effects models. Adjustments included age, sex, energy intake and other relevant confounders. Results: During the median follow-up of 28.8 years, 1124 CRCs were diagnosed. We observed small risk reductions when red meat was substituted with vegetables (HR 0.97, 95% CI 0.95 − 0.99), fruits (0.97, 0.94 − 0.99), or whole grains, vegetables and fruits combined (0.97, 0.95 − 0.99). For processed meat, these substitutions yielded 1% risk reductions. Substituting red or processed meat with whole grains was associated with a decreased CRC risk only in participants with < median whole grain intake (0.92, 0.86 − 0.98; 0.96, 0.93 − 0.99, respectively; p interaction=0.001). Conclusions: Even small, easily implemented substitutions of red or processed meat with whole grains, vegetables or fruits could lower CRC risk in a population with high meat consumption. These findings broaden our insight into dietary modifications that could foster CRC primary prevention.Peer reviewe

Prediagnosis Leisure-Time Physical Activity and Lung Cancer Survival: A Pooled Analysis of 11 Cohorts

Background: Little is known about the association between physical activity before cancer diagnosis and survival among lung cancer patients. In this pooled analysis of 11 prospective cohorts, we investigated associations of prediagnosis leisuretime physical activity (LTPA) with all-cause and lung cancer–specific mortality among incident lung cancer patients. Methods: Using self-reported data on regular engagement in exercise and sports activities collected at study enrollment, we assessed metabolic equivalent hours (MET-h) of prediagnosis LTPA per week. According to the Physical Activity Guidelines for Americans, prediagnosis LTPA was classified into inactivity, less than 8.3 and at least 8.3 MET-h per week (the minimum recommended range). Cox regression was used to estimate hazard ratios (HRs) and 95% confidence interval (CIs) for all-cause and lung cancer–specific mortality after adjustment for major prognostic factors and lifetime smoking history. Results: Of 20 494 incident lung cancer patients, 16 864 died, including 13 596 deaths from lung cancer (overall 5-year relative survival rate ¼ 20.9%, 95% CI ¼ 20.3% to 21.5%). Compared with inactivity, prediagnosis LTPA of more than 8.3 MET-h per week was associated with a lower hazard of all-cause mortality (multivariable-adjusted HR ¼ 0.93, 95% CI ¼ 0.88 to 0.99), but not with lung cancer–specific mortality (multivariable-adjusted HR ¼ 0.99, 95% CI ¼ 0.95 to 1.04), among the overall population. Additive interaction was found by tumor stage (Pinteraction ¼ .008 for all-cause mortality and .003 for lung cancer–specific mortality). When restricted to localized cancer, prediagnosis LTPA of at least 8.3 MET-h per week linked to 20% lower mortality: multivariableadjusted HRs were 0.80 (95% CI¼ 0.67 to 0.97) for all-cause mortality and 0.80 (95% CI¼ 0.65 to 0.99) for lung cancer–specific mortality. Conclusions: Regular participation in LTPA that met or exceeded the minimum Physical Activity Guidelines was associated with reduced hazards of mortality among lung cancer patients, especially those with early stage cancer

Proceedings of the third international molecular pathological epidemiology (MPE) meeting

Molecular pathological epidemiology (MPE) is a transdisciplinary and relatively new scientific discipline that integrates theory, methods and resources from epidemiology, pathology, biostatistics, bioinformatics and computational biology. The underlying objective of MPE research is to better understand the etiology and progression of complex and heterogeneous human diseases with the goal of informing prevention and treatment efforts in population health and clinical medicine. Although MPE research has been commonly applied to investigating breast, lung, and colorectal cancers, its methodology can be used to study most diseases. Recent successes in MPE studies include: 1) the development of new statistical methods to address etiologic heterogeneity; 2) the enhancement of causal inference; 3) the identification of previously unknown exposure-subtype disease associations; and 4) better understanding of the role of lifestyle/behavioral factors on modifying prognosis according to disease subtype. Central challenges to MPE include the relative lack of transdisciplinary experts, educational programs, and forums to discuss issues related to the advancement of the field. To address these challenges, highlight recent successes in the field, and identify new opportunities, a series of MPE meetings have been held at the Dana-Farber Cancer Institute in Boston, MA. Herein, we share the proceedings of the Third International MPE Meeting, held in May 2016 and attended by 150 scientists from 17 countries. Special topics included integration of MPE with immunology and health disparity research. This meeting series will continue to provide an impetus to foster further transdisciplinary integration of divergent scientific fields