Search

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

BACKGROUND: Observational studies suggest that blood concentrations of 25-hydroxyvitamin D [25(OH)D] are associated with morbidity, viral suppression, and mortality among adults living with HIV. OBJECTIVES: We evaluated the effect of cholecalciferol (vitamin D(3)) supplementation on the risk of HIV disease progression, HIV-1 viral suppression, comorbidities, weight change, and depression among HIV-infected individuals that were initiating antiretroviral therapy (ART) in Dar es Salaam, Tanzania. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of vitamin D(3) supplementation among 4000 HIV-infected adult men and nonpregnant women initiating ART with insufficient serum 25(OH)D concentrations (10% weight loss, incident wasting, and depression. RESULTS: During follow-up, 345 participants (17.2%) in the vitamin D(3) group and 371 participants (18.6%) in the placebo group experienced HIV disease progression or death and there was no difference in risk between groups (RR: 0.91; 95% CI: 0.79, 1.06). Vitamin D(3) supplementation did not affect the risk of an unsuppressed HIV-1 viral load (>1000 copies/mL) after 6 mo (RR: 1.10; 95% CI: 0.87, 1.41) and there was also no effect on change in BMI, risk of >10% weight loss, wasting, comorbidities, and depression (P values >0.05). CONCLUSIONS: Vitamin D supplementation did not affect the risk of HIV progression, viral suppression, common morbidities, weight-related indicators, or depression among adults initiating ART in Tanzania. This trial was registered at clinicaltrials.gov as NCT01798680.

Background Biological evidence indicates that smoking can influence macrophage functions and polarization, thereby promoting tumor evolution. We hypothesized that the association of smoking with colorectal cancer incidence might differ by macrophage infiltrates. Methods Using the Nurses’ Health Study and the Health Professionals Follow-up Study, we examined the association of smoking with incidence of colorectal cancer subclassified by macrophage counts. Multiplexed immunofluorescence (for CD68, CD86, IRF5, MAF, and MRC1 [CD206]) combined with digital image analysis and machine learning was used to identify overall, M1-polarized, and M2-polarized macrophages in tumor. We used inverse-probability–weighted multivariable Cox proportional hazards regression models to control for potential confounders and selection bias because of tissue data availability. All statistical tests were 2-sided. Results During follow-up of 131 144 participants (3 648 370 person-years), we documented 3092 incident colorectal cancer cases, including 871 cases with available macrophage data. The association of pack-years smoked with colorectal cancer incidence differed by stromal macrophage densities (Pheterogeneity = .003). Compared with never smoking, multivariable-adjusted hazard ratios (95% confidence interval) for tumors with low macrophage densities were 1.32 (0.97 to 1.79) for 1-19 pack-years, 1.31 (0.92 to 1.85) for 20-39 pack-years, and 1.74 (1.26 to 2.41) for 40 or more pack-years (Ptrend = .004). In contrast, pack-years smoked was not statistically significantly associated with the incidence of tumors having intermediate or high macrophage densities (Ptrend > .009, with an α level of .005). No statistically significant differential association was found for colorectal cancer subclassified by M1-like or M2-like macrophages. Conclusions The association of smoking with colorectal cancer incidence is stronger for tumors with lower stromal macrophage counts. Our findings suggest an interplay of smoking and macrophages in colorectal carcinogenesis.

BackgroundThe influence of type 2 diabetes mellitus (T2D) duration on cancer incidence remains poorly understood.MethodsWe prospectively followed for cancer incidence 113 429 women in the Nurses’ Health Study (1978-2014) and 45 604 men in the Health Professionals Follow-up Study (1988-2014) who were free of diabetes and cancer at baseline. Cancer incidences were ascertained by review of medical records.ResultsIn the multivariable-adjusted model incident, T2D was associated with higher risk of cancers in the colorectum, lung, pancreas, esophagus, liver, thyroid, breast, and endometrium. The pooled hazard ratios (HRs) ranged from 1.21 (95% confidence interval [CI] = 1.06 to 1.38) for colorectal cancer to 3.39 (95% CI = 2.24 to 5.12) for liver cancer. For both composite cancer outcomes and individual cancers, the elevated risks did not further increase after 8 years of T2D duration. The hazard ratio for total cancer was 1.28 (95% CI = 1.17 to 1.40) for T2D duration of 4.1-6.0 years, 1.37 (95% CI = 1.25 to 1.50) for 6.1-8.0 years, 1.21 (95% CI = 1.09 to 1.35) for 8.1-10.0 years, and 1.04 (95% CI = 0.95 to 1.14) after 15.0 years. In a cross-sectional analysis, a higher level of plasma C-peptide was found among participants with prevalent T2D of up to 8 years than those without T2D, whereas a higher level of HbA1c was found for those with prevalent T2D of up to 15 years.ConclusionsIncident T2D was associated with higher cancer risk, which peaked at approximately 8 years after diabetes diagnosis. Similar duration-dependent pattern was observed for plasma C-peptide. Our findings support a role of hyperinsulinemia in cancer development.

Background A low-carbohydrate diet may improve cancer survival, but relevant clinical evidence remains limited. Methods We followed 1542 stages I to III colorectal cancer (CRC) patients who completed a validated food frequency questionnaire between 6 months and 4 years after diagnosis. We calculated overall, animal-, and plant-rich, low-carbohydrate diet scores and examined their associations with CRC-specific and overall mortality using Cox proportional hazards regression after adjusting for potential predictors for cancer survival. We also assessed the intake and changes of macronutrients after diagnosis. Statistical tests were two-sided. Results Although no association was found for overall and animal-rich low-carbohydrate diet score, plant-rich, low-carbohydrate diet, which emphasizes plant sources of fat and protein with moderate consumption of animal products, was associated with lower CRC-specific mortality (hazard ratio [HR] comparing extreme quartiles = 0.37, 95% confidence interval [CI] = 0.25 to 0.57, Ptrend Conclusion Plant-rich, low-carbohydrate diet score was associated with lower mortality in patients with nonmetastatic CRC. Substituting plant fat and protein for carbohydrate, particularly that from refined starches and sugars, may improve patients’ survival.

Epidemiological evidence indicates that a family history of colorectal cancer (CRC) is associated with higher personal CRC risk (1–5). Beyond known familial CRC syndromes (including Lynch and polyposis syndromes), which together constitute less than 5% of CRC cases (6), the mechanisms underlying familial clustering of CRC remain largely unknown (7–9). Recent data by Goel et al. (10) suggest that one potential mechanism of familial clustering of CRC may be heritable predisposition to epigenomic instability and the development of tumors with hypomethylation in long interspersed nucleotide element 1 [LINE-1, which comprises approximately 17% of the human genome (11)]. Thus, we hypothesized that a family history of CRC might be associated with higher risk of CRC with low-level LINE-1 methylation. Because LINE-1 methylation-low CRC has been associated with aggressive tumor behavior (12–14), it is imperative to develop effective prevention strategies tailored to those who are susceptible to the development of this unfavorable cancer subtype. To test our hypothesis of possible familial clustering of LINE-1 methylation-low CRC, we utilized two US nationwide prospective cohort studies. We prospectively examined the relationship between a history of CRC in a first-degree relative and subsequent risk of developing CRC with varying degrees of LINE-1 methylation. We also examined the status of tumor microsatellite instability (MSI) and CpG island methylator phenotype (CIMP), both of which have been inversely associated with LINE-1 methylation level (15,16). In particular, we utilized tumor MSI status in our attempt to exclude the potential influence of Lynch syndrome (ie, heritable susceptibility to mismatch repair-deficient cancer, most likely to be MSI-high cancer). We aimed to support not only a possible link between the heritability of CRC and tumor epigenetic instability but also the possible presence of a previously unrecognized familial cancer trait. Akin to current MSI testing in CRC, tumor LINE-1 methylation level may potentially serve as a tumor biomarker for familial cancer risk assessment.

The association between black race and worse outcomes in operable breast cancer reported in previous studies has been attributed to a higher incidence of more aggressive triple-negative disease, disparities in care, and comorbidities. We evaluated associations between black race and outcomes, by tumor hormone receptor and HER2 expression, in patients who were treated with contemporary adjuvant therapy.The effect of black race on disease-free and overall survival was evaluated using Cox proportional hazards models adjusted for multiple covariates in a clinical trial population that was treated with anthracycline- and taxane-containing chemotherapy. Categorical variables were compared using the Fisher exact test. All P values are two-sided.Of 4817 eligible patients, 405 (8.4%) were black. Compared with nonblack patients, black patients had a higher rate of triple-negative disease (31.9% vs 17.2%; P.001) and a higher body mass index (median: 31.7 vs 27.4 kg/m(2); P.001). Black race was statistically significantly associated with worse disease-free survival (5-year disease-free survival, black vs nonblack: 76.7% vs 84.5%; hazard ratio of recurrence or death = 1.58, 95% confidence interval = 1.19 to 2.10, P = .0015) and overall survival (5-year overall survival, black vs nonblack: 87.6% vs 91.9%; hazard ratio of death = 1.49, 95% confidence interval = 1.05 to 2.12, P = .025) in patients with hormone receptor-positive HER2-negative disease but not in patients with triple-negative or HER2-positive disease. In a model that included black race, hormone receptor-positive HER2-negative disease vs other subtypes, and their interaction, the interaction term was statistically significant for disease-free survival (P = .027) but not for overall survival (P = .086).Factors other than disparities in care or aggressive disease contribute to increased recurrence in black women with hormone receptor-positive breast cancer.

This paper presents a robust method to conduct inference in finely stratified familial studies under proband-based sampling. We assume that the interest is in both the marginal effects of subject-specific covariates on a binary response and the familial aggregation of the response, as quantified by intrafamilial pairwise odds ratios. We adopt an estimating function for proband-based family studies originally developed by Zhao and others (1998) in the context of an unstratified design and treat the stratification effects as fixed nuisance parameters. Our method requires modeling only the first 2 joint moments of the observations and reduces by 2 orders of magnitude the bias induced by fitting the stratum-specific nuisance parameters. An analytical standard error estimator for the proposed estimator is also provided. The proposed approach is applied to a matched case–control familial study of sleep apnea. A simulation study confirms the usefulness of the approach.