Neighborhood Obesogenic Environment and Risk of Prostate Cancer: The Multiethnic Cohort.

BACKGROUND: Obesity is associated with risk of aggressive prostate cancer. It is not known whether neighborhood obesogenic factors are independently associated with prostate cancer risk. METHODS: Neighborhood socioeconomic status (nSES) and four neighborhood obesogenic environment factors (urbanicity, mixed-land development, unhealthy food environment, and parks) were assessed for associations with prostate cancer risk among 41,563 African American, Japanese American, Latino, and White males in the Multiethnic Cohort (MEC) Study, California site. Multivariable Cox proportional hazards regression was used to estimate HRs and 95% confidence intervals (CI) for nonaggressive and aggressive prostate cancer, adjusting for individual-level sociodemographic, behavioral, and prostate cancer risk factors. Analyses were stratified by race, ethnicity, and, among Latino males, nativity. RESULTS: Males residing in low-SES, compared with high-SES, neighborhoods had lower risk of nonaggressive prostate cancer [lowest vs. highest quintile HR = 0.81; 95% confidence interval (CI) = 0.68-0.95, Ptrend 0.024], driven by a similar trend among foreign-born Latino males. Foreign-born Latino males in neighborhoods with low mixed-land development had increased risk of non-aggressive disease (lowest vs. highest quintile HR = 1.49; 95% CI = 1.07-2.09). For aggressive disease, the only association noted was between lower mixed-land development and lower risk among White males (Ptrend = 0.040). CONCLUSIONS: nSES and obesogenic environment factors were independently associated with prostate cancer risk; associations varied by race, ethnicity, nativity, and disease aggressiveness. IMPACT: Upstream structural and social determinants of health that contribute to neighborhood obesogenic characteristics likely impact prostate cancer risk differently across groups defined by race, ethnicity, and nativity and by disease aggressiveness.

Cancer Mortality Patterns by Birthplace and Generation Status of Mexican Latinos: The Multiethnic Cohort.

BACKGROUND: Latinos are the largest minority group in the United States. We assessed cancer mortality by birthplace and generation status of Mexican Latinos in the Multiethnic Cohort. METHODS: We included 26 751 Latinos of Mexican origin and 6093 non-Latino Whites aged 45-74 years at cohort entry (1993-1996) from the California Multiethnic Cohort component. The Mexican Latinos comprised 42% first-generation Mexico-born immigrants, 42% second-generation (28% US-born with both parents Mexico-born and 14% US-born with 1 parent US-born and 1 parent Mexico-born), and 16% third-generation or more who were US-born with both parents US-born. Multivariable Cox models were used to calculate covariate adjusted hazard ratios and 95% confidence intervals for overall and site-specific cancer mortality by birthplace and generation status. All statistical tests were 2-sided. RESULTS: Cancer death rate was highest among the US-born with 1 parent US-born and 1 parent Mexico-born (age-adjusted rate = 471.0 per 100 000 person-years) and US-born with both parents US-born (age-adjusted rate = 469.0 per 100 000 person-years) groups. The US-born with both parents Mexico-born group had a 30% (hazard ratio = 1.30, 95% confidence interval = 1.18 to 1.44) higher risk of cancer death than the first-generation Mexico-born immigrants group, showing US birthplace was associated with an elevated cancer mortality. For cancer-specific mortality, US birthplace was positively associated with colorectal, liver and lung, and ovarian cancer (P values ranged from .04 to .005). Among US-born Mexican Latinos, generation status was not statistically significantly associated with overall cancer or site-specific cancer mortality. CONCLUSIONS: Our findings suggest that US birthplace is a risk factor for cancer death in Mexican Americans. Identification of the contributing factors is important to curtail patterns of increasing cancer mortality in US-born Mexican Latinos.

The joint association of cardiometabolic health and weight on mortality in the multiethnic cohort.

Objective: While cardiometabolic abnormalities are associated with elevated risk of morbidity, they may not occur in all individuals with obesity. Less is known about associations with mortality, especially cancer mortality. This study examined associations between cardiometabolic-weight categories and mortality from cardiovascular disease (CVD), cancer, and all causes.Methods: Cox proportional hazards regressions of time to all-cause, CVD, and cancer mortalities were used to examine associations with cardiometabolic-weight status, in the Multiethnic Cohort (n=157,865). Cardiometabolic-weight status categories were: Metabolically Healthy Normal Weight, Metabolically Healthy Obese, Metabolically Healthy Overweight, Metabolically Unhealthy Normal Weight, Metabolically Unhealthy Obese, and Metabolically Unhealthy Overweight.Results: Higher mortality, especially for all-cause and CVD, was found for all metabolically unhealthy groups no matter the weight classification when compared to the Metabolically Healthy Normal Weight category across sex-ethnic groups. For all-cause mortality, a reduction in mortality was seen for males in the Metabolically Healthy Overweight category (HR: 0.88, 95% CI: 0.84, 0.93), especially for African American, Native Hawaiian, and Latino males. Mortality was elevated in the Metabolically Healthy Obese category for all-cause and CVD mortality in both sexes (HRrange: 1.08-1.93). Few associations were seen with cancer mortality.Conclusions: Past examinations of cardiometabolic-weight status and mortality have been hampered by a lack of diversity. In a racially/ethnically diverse population, metabolically unhealthy groups exhibited a substantially higher risk of death from all causes and CVD than metabolically healthy groups. A reduction in all-cause mortality was seen for some males classified as Metabolically Healthy Overweight; however, being classified as Metabolically Healthy Obese elevated mortality risk for males and females compared to Metabolically Healthy Normal Weight. Future research is needed to examine how sex-ethnic differences in body fat distribution and changes in weight over time influence associations between cardiometabolic-weight status and mortality.

Associations of the gut microbiome with hepatic adiposity in the Multiethnic Cohort Adiposity Phenotype Study.

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for liver cancer and prevalence varies by ethnicity. Along with genetic and lifestyle factors, the gut microbiome (GM) may contribute to NAFLD and its progression to advanced liver disease. Our cross-sectional analysis assessed the association of the GM with hepatic adiposity among African American, Japanese American, White, Latino, and Native Hawaiian participants in the Multiethnic Cohort. We used MRI to measure liver fat and determine nonalcoholic fatty liver disease (NAFLD) status (n = 511 cases) in 1,544 participants, aged 60-77 years, with 12-53% overall adiposity (BMI of 17.8-46.2 kg/m2). The GM was measured by 16S rRNA gene sequencing and, on a subset, by metagenomic sequencing. Alpha diversity was lower overall with NAFLD and in certain ethnicities (African Americans, Whites, and Latinos). In models regressing genus on NAFLD status, 62 of 149 genera (40%) exhibited a significant interaction between NAFLD and ethnicity stratified analysis found 69 genera significantly associated with NAFLD in at least one ethnic group. No single genus was significantly associated with NAFLD across all ethnicities. In contrast, the same bacterial metabolic pathways were over-represented in participants with NAFLD regardless of ethnicity. Imputed secondary bile acid and carbohydrate pathways were associated with NAFLD, the latter of which was corroborated by metagenomics, although different genera in different ethnicities were associated with these pathways. Overall, we found that NAFLD was associated with altered bacterial composition and metabolism, and that bacterial endotoxin, assessed by plasma lipopolysaccharide binding protein (LBP), may mediate liver fat-associated systemic inflammation in a manner that seems to vary by ethnicity.

Dairy foods, calcium, and risk of breast cancer overall and for subtypes defined by estrogen receptor status: a pooled analysis of 21 cohort studies.

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 <1 g/d of yogurt and 0.85, 95% CI: 0.76, 0.95 comparing ≥25 g/d with <1 g/d of cottage/ricotta cheese). Dietary calcium intake was only weakly associated with breast cancer risk (pooled HR = 0.98, 95% CI: 0.97, 0.99 per 350 mg/d). CONCLUSION: Our study shows that adult dairy or calcium consumption is unlikely to associate with a higher risk of breast cancer and that higher yogurt and cottage/ricotta cheese intakes were inversely associated with the risk of ER-negative breast cancer, a less hormonally dependent subtype with poor prognosis. Future studies on fermented dairy products, earlier life exposures, ER-negative breast cancer, and different racial/ethnic populations may further elucidate the relation.

Diabetes-Related Complications and Pancreatic Cancer Incidence in the Multiethnic Cohort.

BACKGROUND: People with diabetes are at an increased risk of developing pancreatic cancer. However, it is unclear whether diabetes-related complications are associated with risk of pancreatic cancer. METHODS: A nested matched case-control analysis was conducted among the fee-for-service Medicare participants of the prospective Multiethnic Cohort (n = ∼123 000). Between 2001 and 2014, 433 incident cases of pancreatic ductal adenocarcinoma were matched to 1728 controls by birth year, sex, race and ethnicity, and age at cohort entry. Participants were linked to data from the California and Hawaii cancer registries and Medicare claims. We used the diabetes complications severity index (DCSI) for the presence of 7 complications within 2 years prior to the diagnosis date of the index case. Multivariable conditional logistic regression was used to examine the association of DCSI with pancreatic cancer incidence. RESULTS: Diabetes was present among 45.4% of cases and 34.1% of controls. Cases had higher DCSI score compared with controls (score ≥4: 32.8% in cases; 21.2% in controls). The most prevalent diabetes-related complications for cases were cardiovascular disease (61.2%), nephropathy (31.2%), and cerebrovascular disease (21.7%). Individuals with diabetes (odds ratio [OR] = 1.48, 95% confidence interval [CI] = 1.14 to 1.91), nephropathy (OR = 1.75, 95% CI = 1.32 to 2.33), cardiovascular disease (OR = 1.88, 95% CI = 1.45 to 2.44), and metabolic complications (OR = 6.61, 95% CI = 2.49 to 17.50) were at increased risk of pancreatic cancer. For every 1-unit increase in DCSI score, participants had 18% greater risk of pancreatic cancer (OR = 1.18, 95% CI = 1.11 to 1.25). CONCLUSIONS: Participants with diabetes-related complications have an elevated risk of pancreatic cancer. Identifying diabetes-related complications may help identify high-risk groups who can be studied for development of early markers for this fatal cancer.

Hospital Characteristics and Breast Cancer Survival in the California Breast Cancer Survivorship Consortium.

INTRODUCTION: Racial/ethnic disparities in breast cancer survival are well documented, but the influence of health care institutions is unclear. We therefore examined the effect of hospital characteristics on survival. METHODS: Harmonized data pooled from 5 case-control and prospective cohort studies within the California Breast Cancer Survivorship Consortium were linked to the California Cancer Registry and the California Neighborhoods Data System. The study included 9,701 patients with breast cancer who were diagnosed between 1993 and 2007. First reporting hospitals were classified by hospital type-National Cancer Institute (NCI) -designated cancer center, American College of Surgeons (ACS) Cancer Program, other-and hospital composition of the neighborhood socioeconomic status and race/ethnicity of patients with cancer. Multivariable Cox proportional hazards models adjusted for clinical and patient-level prognostic factors were used to examine the influence of hospital characteristics on survival. RESULTS: Fewer than one half of women received their initial care at an NCI-designated cancer center (5%) or ACS program (38%) hospital. Receipt of initial care in ACS program hospitals varied by race/ethnicity-highest among non-Latina White patients (45%), and lowest among African Americans (21%). African-American women had superior breast cancer survival when receiving initial care in ACS hospitals versus other hospitals (non-ACS program and non-NCI-designated cancer center; hazard ratio, 0.67; 95% CI, 0.55 to 0.83). Other hospital characteristics were not associated with survival. CONCLUSION: African American women may benefit significantly from breast cancer care in ACS program hospitals; however, most did not receive initial care at such facilities. Future research should identify the aspects of ACS program hospitals that are associated with higher survival and evaluate strategies by which to enhance access to and use of high-quality hospitals, particularly among African American women.

Associations between reproductive factors and biliary tract cancers in women from the Biliary Tract Cancers Pooling Project.

BACKGROUND & AIMS: Gallbladder cancer (GBC) is known to have a female predominance while other biliary tract cancers (BTCs) have a male predominance. However, the role of female reproductive factors in BTC etiology remains unclear. METHODS: We pooled data from 19 studies of >1.5 million women participating in the Biliary Tract Cancers Pooling Project to examine the associations of parity, age at menarche, reproductive years, and age at menopause with BTC. Associations for age at menarche and reproductive years with BTC were analyzed separately for Asian and non-Asian women. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, stratified by study. RESULTS: During 21,681,798 person-years of follow-up, 875 cases of GBC, 379 of intrahepatic bile duct cancer (IHBDC), 450 of extrahepatic bile duct cancer (EHBDC), and 261 of ampulla of Vater cancer (AVC) occurred. High parity was associated with risk of GBC (HR ≥5 vs. 0 births 1.72; 95% CI 1.25-2.38). Age at menarche (HR per year increase 1.15; 95% CI 1.06-1.24) was associated with GBC risk in Asian women while reproductive years were associated with GBC risk (HR per 5 years 1.13; 95% CI 1.04-1.22) in non-Asian women. Later age at menarche was associated with IHBDC (HR 1.19; 95% CI 1.09-1.31) and EHBDC (HR 1.11; 95% CI 1.01-1.22) in Asian women only. CONCLUSION: We observed an increased risk of GBC with increasing parity. Among Asian women, older age at menarche was associated with increased risk for GBC, IHBDC, and EHBDC, while increasing reproductive years was associated with GBC in non-Asian women. These results suggest that sex hormones have distinct effects on cancers across the biliary tract that vary by geography. LAY SUMMARY: Our findings show that the risk of gallbladder cancer is increased among women who have given birth (especially women with 5 or more children). In women from Asian countries, later age at menarche increases the risk of gallbladder cancer, intrahepatic bile duct cancer and extrahepatic bile duct cancer. We did not see this same association in women from Western countries. Age at menopause was not associated with the risk of any biliary tract cancers.

Diet Quality and Breast Cancer Incidence in the Multiethnic Cohort.

This study investigated the relation of diet quality indexes (DQI) with breast cancer incidence among women from the Multiethnic Cohort (MEC). Participants completed a questionnaire with a validated food frequency questionnaire. Scores for Healthy Eating Index 2015 (HEI-2015), Alternate Healthy Eating Index 2010 (AHEI-2010), alternate Mediterranean diet score (aMED), and Dietary Approaches to Stop Hypertension (DASH) were divided into quintiles (Q1-Q5). Cox regression was applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for DQIs and breast cancer risk adjusted for known risk factors. The respective HRs for Q5 vs. Q1 were: 1.06 (95% CI, 0.98-1.14) for HEI-2015, 0.96 (95% CI, 0.90-1.04) for AHEI-2010, 1.01 (95% CI, 0.94-1.09) for aMED, and 0.95 (95% CI, 0.88-1.02) for DASH (ptrend > 0.05 for all). However, overweight and obesity were significantly associated with breast cancer incidence. Despite the null association for DQIs, diet quality may lower breast cancer risk through its positive influence on weight status.

Circulating Biomarker Score for Visceral Fat and Risks of Incident Colorectal and Postmenopausal Breast Cancer: The Multiethnic Cohort Adiposity Phenotype Study.

BACKGROUND: Visceral adipose tissue (VAT) may play a greater role than subcutaneous fat in increasing cancer risk but is poorly estimated in epidemiologic studies. METHODS: We developed a VAT prediction score by regression equations averaged across 100 least absolute shrinkage and selection operator models in a cross-sectional study of 1,801 older adults in the Multiethnic Cohort (MEC). The score was then used as proxy for VAT in case-control studies of postmenopausal breast (950 case-control pairs) and colorectal (831 case-control pairs) cancer in an independent sample in MEC. Abdominal MRI-derived VAT; circulating biomarkers of metabolic, hormonal, and inflammation dysfunctions; and ORs for incident cancer adjusted for BMI and other risk factors were assessed. RESULTS: The final score, composed of nine biomarkers, BMI, and height, explained 11% and 15% more of the variance in VAT than BMI alone in men and women, respectively. The area under the receiver operator curve for VAT >150 cm2 was 0.90 in men and 0.86 in women. The VAT score was associated with risk of breast cancer [OR (95% confidence interval [CI]) by increasing tertiles: 1.00, 1.09 (0.86-1.39), 1.48 (1.16-1.89); P trend = 0.002] but not with colorectal cancer (P = 0.84), although an association [1.00, 0.98 (0.68-1.39), 1.24 (0.88-1.76); P trend = 0.08] was suggested for this cancer after excluding cases that occurred within 7 years of blood draw (P heterogeneity = 0.06). CONCLUSIONS: The VAT score predicted risks of postmenopausal breast cancer and can be used for risk assessment in diverse populations. IMPACT: These findings provide specific evidence for a role of VAT in breast cancer.

Associations of plasma trimethylamine N-oxide, choline, carnitine, and betaine with inflammatory and cardiometabolic risk biomarkers and the fecal microbiome in the Multiethnic Cohort Adiposity Phenotype Study.

BACKGROUND: Trimethylamine N-oxide (TMAO), a compound derived from diet and metabolism by the gut microbiome, has been associated with several chronic diseases, although the mechanisms of action are not well understood and few human studies have investigated microbes involved in its production. OBJECTIVES: Our study aims were 1) to investigate associations of TMAO and its precursors (choline, carnitine, and betaine) with inflammatory and cardiometabolic risk biomarkers; and 2) to identify fecal microbiome profiles associated with TMAO. METHODS: We conducted a cross-sectional analysis using data collected from 1653 participants (826 men and 827 women, aged 60-77 y) in the Multiethnic Cohort Study. Plasma concentrations of TMAO and its precursors were measured by LC-tandem MS. We also analyzed fasting blood for markers of inflammation, glucose and insulin, cholesterol, and triglycerides (TGs), and further measured blood pressure. Fecal microbiome composition was evaluated by sequencing the 16S ribosomal RNA gene V1-V3 region. Associations of TMAO and its precursors with disease risk biomarkers were assessed by multivariable linear regression, whereas associations between TMAO and the fecal microbiome were assessed by permutational multivariate ANOVA and hurdle regression models using the negative binomial distribution. RESULTS: Median (IQR) concentration of plasma TMAO was 3.05 µmol/L (2.10-4.60 µmol/L). Higher concentrations of TMAO and carnitine, and lower concentrations of betaine, were associated with greater insulin resistance (all P < 0.02). Choline was associated with higher systolic blood pressure, TGs, lipopolysaccharide-binding protein, and lower HDL cholesterol (P ranging from <0.001 to 0.03), reflecting an adverse cardiometabolic risk profile. TMAO was associated with abundance of 13 genera (false discovery rate < 0.05), including Prevotella, Mitsuokella, Fusobacterium, Desulfovibrio, and bacteria belonging to the families Ruminococcaceae and Lachnospiraceae, as well as the methanogen Methanobrevibacter smithii. CONCLUSIONS: Plasma TMAO concentrations were associated with a number of trimethylamine-producing bacterial taxa, and, along with its precursors, may contribute to inflammatory and cardiometabolic risk pathways.

Association of change in the neighborhood obesogenic environment with colorectal cancer risk: The Multiethnic Cohort Study.

BACKGROUND: Neighborhood environment has been associated with health behaviors. Despite the evidence of the influence of neighborhood social and physical factors on cancer risk, no research has evaluated whether changes in the neighborhood obesogenic environment, either by physical moves to different neighborhoods or experiencing neighborhood redevelopment or neglect, affect cancer risk. METHODS: The association of change in neighborhood environment attributes (socioeconomic status, population density, restaurant and retail food environments, numbers of recreational facilities and businesses, commute patterns, traffic density, and street connectivity) with colorectal cancer (CRC) risk was examined among 95,472 Los Angeles, CA, Multiethnic Cohort participants, including 2295 invasive CRC cases diagnosed between 1993 and 2010 using Cox proportional hazards regression, adjusting for age, race/ethnicity, other risk factors including BMI and physical activity, and baseline levels of neighborhood attributes. Stratified analyses were conducted by racial/ethnic group and moving status. RESULTS: 40% of participants moved (changed physical residence) during follow-up. Across all races/ethnicities, upward change in population density was statistically significantly associated with higher CRC risk among male and female non-movers (HR: 1.35 and 1.41, respectively). The same association was also observed separately among female African American and Japanese American non-movers, male Latino non-movers, female African American and male White movers. Downward change in population density was significantly related to higher CRC risk among female non-movers (HR: 1.33). Downward change in traffic density was associated with lower CRC risk among male non-movers but with higher CRC risk among female movers (HR: 0.66 and 1.43, respectively). Downward changes in street connectivity or the number of recreational facilities were associated with higher CRC risk (HR: 1.34 and 1.54, respectively). Upward change in the number of recreational facilities was associated with lower CRC risk among female non-movers (HR: 0.70). Changes in the other neighborhood attributes did not exhibit significant associations with CRC risk within more than one racial/ethnic group. CONCLUSION: Changes over time in neighborhood attributes have an effect on the risk of colorectal cancer, which is separate from the baseline levels of the same attributes and individual-level risk factors, and differs between sexes, movers and non-movers and across racial/ethnic groups.

Diet Quality and Biomarker Profiles Related to Chronic Disease Prevention: The Multiethnic Cohort Study.

Objective: To understand how diet quality affects chronic disease etiology, the associations of 4 a priori diet quality indices with blood levels of lipid-soluble micronutrients and biomarkers of inflammation, lipid, and glucose metabolism were examined in 5 ethnic groups.Methods: In a cross-sectional design, the Adiposity Phenotype Study, a subset of the Multiethnic Cohort in Hawaii and Los Angeles, recruited participants of white, African American, Native Hawaiian, Japanese American, and Latino ancestry. A total of 896 men and 910 women completed a validated quantitative food frequency questionnaire and anthropometric measurements and donated a fasting blood sample. Using general linear models, covariate-adjusted mean levels of lipid-soluble micronutrients (total carotenes, lycopene, total tocopherols, total lutein, cryptoxanthins), biomarkers of inflammation (C-reactive protein [CRP], tumor necrosis factor-[Formula: see text]), adipokines (adiponectin, leptin), lipids (total cholesterol, high-density lipoprotein cholesterol [HDL-C], triglycerides), and glucose metabolism (glucose, insulin, homeostatic model assessment of insulin resistance [HOMA-IR]) were computed across tertiles of 4 a priori dietary indices Healthy Eating Index (HEI)-2010, Alternative HEI (AHEI)-2010, alternate Mediterranean Diet (aMED), Dietary Approaches to Stop Hypertension (DASH); trends were evaluated in models with diet quality scores as continuous variables.Results: With better diet quality, levels of carotenes, lutein, cryptoxanthin, adiponectin, and HDL-C were significantly higher (ptrend < 0.01), whereas levels of CRP, leptin, total cholesterol, triglycerides, glucose, insulin, and HOMA-IR were inversely associated (ptrend < 0.05) with diet quality. With the exception of cryptoxanthins and triglycerides, the associations were consistent across ethnic groups.Conclusions: These findings confirm the association between diet quality and nutrition-related biomarkers and support the idea that a high-quality diet positively influences biologic pathways involved in chronic disease etiology across different ethnic groups.

Association of serum γ-tocopherol levels with mortality: the Multiethnic Cohort Study.

BACKGROUND/OBJECTIVES: γ-Tocopherol has unique properties that protect against nitrogen oxide-mediated cellular damage. To elucidate the potential role of γ-tocopherol in the aging process, we examined the associations of serum γ-tocopherol levels with all-cause and cause-specific mortality. SUBJECTS/METHODS: Among participants in the biorepository subcohort of the Multiethnic Cohort Study, pre-cancer diagnostic serum γ-tocopherol levels were measured in a subset of 3904 men and 4461 women. Of these, 22.7% of men and 13.5% of women died during a mean follow-up time of 9.6 ± 2.6 years. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for mortality associated with γ-tocopherol were estimated by Cox proportional hazards regression. RESULTS: Positive associations of serum γ-tocopherol with all-cause, cancer, and cardiovascular disease mortality (CVD) (Ptrend < 0.05) were detected after adjusting for age, race/ethnicity, and serum cholesterol levels. The respective HRs (95% CIs) for the highest versus the lowest sex-specific γ-tocopherol quartile were 1.43 (1.17-1.74), 1.79 (1.22-2.64), and 1.52 (1.10-2.11) for men and 1.58 (1.25-2.00), 1.59 (1.05-2.41), and 1.59 (1.07-2.37) for women. Associations remained significant for all-cause mortality among women after further adjusting for smoking variables and history of cancer, CVD, diabetes, and hypertension at cohort entry (highest vs. lowest γ-tocopherol quartile: HR = 1.38; 95% CI = 1.08-1.75; Ptrend = 0.005). Overall, associations with all-cause mortality were consistent across race/ethnicity and were significant in three of ten sex-specific racial/ethnic groups in the fully adjusted models, with no interactions between ethnicity and γ-tocopherol. CONCLUSIONS: The positive association between γ-tocopherol and mortality suggests a potential physiological role for γ-tocopherol in response to pathological conditions.

Association of Imaging-Based Body Fat Distribution and Mammographic Density in the Multiethnic Cohort Adiposity Phenotype Study.

BACKGROUND: As the stronger association of obesity with postmenopausal breast cancer in Asian than white women may be due to body fat distribution, we examined the relation of adiposity measures with percent mammographic density (PMD), a strong predictor of breast cancer incidence. METHODS: A total of 938 women from five ethnic groups (69.1 ± 2.7 years) in the Adiposity Phenotype Study (APS) underwent DXA and MRI imaging. PMD was assessed in routine mammograms using a computer-assisted method. Spearman correlation coefficients were computed and general linear models were applied to estimate regression coefficients (ß) for PMD per 0.5 SD units of adiposity measures while adjusting for known confounders, including DXA total body fat. RESULTS: For 701 (75%) of the participants (69.1 ± 2.7 years), valid mammograms were obtained. Whereas total body fat, the trunk-to-periphery fat ratio (TPFR), visceral fat (VAT), and subcutaneous fat (SAT) were inversely correlated with PMD (P < 0.0001), the VAT/SAT ratio correlated positively (r spearman = 0.10; P = 0.01). In fully adjusted models, PMD remained inversely related to TPFR and SAT and disappeared for VAT, while it was strengthened for VAT/SAT (ß = 0.51; P = 0.009). This relation was stronger in Japanese Americans than other ethnic groups. CONCLUSIONS: This is the first study to show an association of a high VAT/SAT ratio with greater PMD, a marker of breast cancer risk after taking into account total body fat. IMPACT: The results indicate a link between the propensity to accumulate VAT and the amount of fat in the breast (1-PMD), which may influence the relation of obesity with breast cancer incidence.

Anthropometric Risk Factors for Cancers of the Biliary Tract in the Biliary Tract Cancers Pooling Project.

Biliary tract cancers are rare but highly fatal with poorly understood etiology. Identifying potentially modifiable risk factors for these cancers is essential for prevention. Here we estimated the relationship between adiposity and cancer across the biliary tract, including cancers of the gallbladder (GBC), intrahepatic bile ducts (IHBDC), extrahepatic bile ducts (EHBDC), and the ampulla of Vater (AVC). We pooled data from 27 prospective cohorts with over 2.7 million adults. Adiposity was measured using baseline body mass index (BMI), waist circumference, hip circumference, waist-to-hip, and waist-to-height ratios. HRs and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models adjusted for sex, education, race, smoking, and alcohol consumption with age as the time metric and the baseline hazard stratified by study. During 37,883,648 person-years of follow-up, 1,343 GBC cases, 1,194 EHBDC cases, 784 IHBDC cases, and 623 AVC cases occurred. For each 5 kg/m2 increase in BMI, there were risk increases for GBC (HR = 1.27; 95% CI, 1.19-1.36), IHBDC (HR = 1.32; 95% CI, 1.21-1.45), and EHBDC (HR = 1.13; 95% CI, 1.03-1.23), but not AVC (HR = 0.99; 95% CI, 0.88-1.11). Increasing waist circumference, hip circumference, waist-to-hip ratio, and waist-to-height ratio were associated with GBC and IHBDC but not EHBDC or AVC. These results indicate that adult adiposity is associated with an increased risk of biliary tract cancer, particularly GBC and IHBDC. Moreover, they provide evidence for recommending weight maintenance programs to reduce the risk of developing these cancers. SIGNIFICANCE: These findings identify a correlation between adiposity and biliary tract cancers, indicating that weight management programs may help minimize the risk of these diseases.

Smoking, Alcohol, and Biliary Tract Cancer Risk: A Pooling Project of 26 Prospective Studies.

BACKGROUND: Tobacco and alcohol are well-established risk factors for numerous cancers, yet their relationship to biliary tract cancers remains unclear. METHODS: We pooled data from 26 prospective studies to evaluate associations of cigarette smoking and alcohol consumption with biliary tract cancer risk. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with smoking and alcohol consumption were calculated. Random-effects meta-analysis produced summary estimates. All statistical tests were two-sided. RESULTS: Over a period of 38 369 156 person-years of follow-up, 1391 gallbladder, 758 intrahepatic bile duct, 1208 extrahepatic bile duct, and 623 ampulla of Vater cancer cases were identified. Ever, former, and current smoking were associated with increased extrahepatic bile duct and ampulla of Vater cancers risk (eg, current vs never smokers HR = 1.69, 95% CI = 1.34 to 2.13 and 2.22, 95% CI = 1.69 to 2.92, respectively), with dose-response effects for smoking pack-years, duration, and intensity (all Ptrend < .01). Current smoking and smoking intensity were also associated with intrahepatic bile duct cancer (eg, >40 cigarettes per day vs never smokers HR = 2.15, 95 % CI = 1.15 to 4.00; Ptrend = .001). No convincing association was observed between smoking and gallbladder cancer. Alcohol consumption was only associated with intrahepatic bile duct cancer, with increased risk for individuals consuming five or more vs zero drinks per day (HR = 2.35, 95%CI = 1.46 to 3.78; Ptrend = .04). There was evidence of statistical heterogeneity among several cancer sites, particularly between gallbladder cancer and the other biliary tract cancers. CONCLUSIONS: Smoking appears to increase the risk of developing all biliary tract cancers except gallbladder cancer. Alcohol may increase the risk of intrahepatic bile duct cancer. Findings highlight etiologic heterogeneity across the biliary tract.

Interethnic differences in pancreatic cancer incidence and risk factors: The Multiethnic Cohort.

While disparity in pancreatic cancer incidence between blacks and whites has been observed, few studies have examined disparity in other ethnic minorities. We evaluated variations in pancreatic cancer incidence and assessed the extent to which known risk factors account for differences in pancreatic cancer risk among African Americans, Native Hawaiians, Japanese Americans, Latino Americans, and European Americans in the Multiethnic Cohort Study. Risk factor data were obtained from the baseline questionnaire. Cox regression was used to estimate the relative risks (RRs) and 95% confidence intervals (CIs) for pancreatic cancer associated with risk factors and ethnicity. During an average 16.9-year follow-up, 1,532 incident pancreatic cancer cases were identified among 184,559 at-risk participants. Family history of pancreatic cancer (RR 1.97, 95% CI 1.50-2.58), diabetes (RR 1.32, 95% CI 1.14-1.54), body mass index ≥30 kg/m2 (RR 1.25, 95% CI 1.08-1.46), current smoking (<20 pack-years RR 1.43, 95% CI 1.19-1.73; ≥20 pack-years RR 1.76, 95% CI 1.46-2.12), and red meat intake (RR 1.17, 95% CI 1.00-1.36) were associated with pancreatic cancer. After adjustment for these risk factors, Native Hawaiians (RR 1.60, 95% CI 1.30-1.98), Japanese Americans (RR 1.33, 95% CI 1.15-1.54), and African Americans (RR 1.20, 95% CI 1.01-1.42), but not Latino Americans (RR 0.90, 95% CI 0.76-1.07), had a higher risk of pancreatic cancer compared to European Americans. Interethnic differences in pancreatic cancer risk are not fully explained by differences in the distribution of known risk factors. The greater risks in Native Hawaiians and Japanese Americans are new findings and elucidating the causes of these high rates may improve our understanding and prevention of pancreatic cancer.

Pancreatic Cancer Following Incident Diabetes in African Americans and Latinos: The Multiethnic Cohort.

Background: Diabetes has been proposed to be a risk factor for and a consequence of pancreatic cancer (PC). The relationship between recent-onset diabetes and PC is not well understood, and data in minorities are sparse. We examined the relationships between recent-onset diabetes and PC incidence in African Americans and Latinos in the Multiethnic Cohort. Methods: A total of 48 995 African Americans and Latinos without prior diabetes and cancer at baseline (1993-1996) were included in the study. Questionnaires, Medicare data, and California hospital discharge files were used to identify new diabetes diagnoses. Cox regressions were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer associated with diabetes and with diabetes duration. Results: A total of 15 833 (32.3%) participants developed diabetes between baseline and 2013. A total of 408 incident PC cases were identified during follow-up. Diabetes was associated with PC (HRage75 = 2.39, 95% CI = 1.91 to 2.98). Individuals with recent-onset diabetes (within three or fewer years of PC diagnosis) had a greater risk compared with those with long-term diabetes across all ages. The HRage75 for recent-onset diabetes was 4.08 (95% CI = 2.76 to 6.03) in Latinos and 3.38 (95% CI = 2.30 to 4.98) in African Americans. Conclusions: Diabetes was associated with a more than twofold higher risk of PC in African Americans and Latinos, but recent-onset diabetes was associated with a 2.3-fold greater increase in risk of PC than long-standing diabetes. Our findings support the hypothesis that recent-onset diabetes is a manifestation of PC and that long-standing diabetes is a risk factor for this malignancy.

Alcohol Intake and Colorectal Cancer Risk in the Multiethnic Cohort Study.

To investigate the association of alcohol intake with colorectal cancer risk according to race/ethnicity as well as sex, lifestyle-related factors, alcoholic beverage type, and anatomical subsite, we analyzed data from 190,698 black, Native Hawaiian, Japanese-American, Latino, and white persons in Hawaii and California in the Multiethnic Cohort Study, with 4,923 incident cases during a 16.7-year follow-up period (1993-2013). In multivariate Cox regression models, the hazard ratio was 1.16 (95% confidence interval (CI): 1.01, 1.34) for 15.0-29.9 g/day of alcohol and 1.28 (95% CI: 1.12, 1.45) for ≥30.0 g/day among men, and 1.06 (95% CI: 0.85, 1.32) and 1.15 (95% CI: 0.92, 1.43), respectively, among women, compared with nondrinkers (P for heterogeneity according to sex = 0.74). An increased risk was apparent among Native Hawaiians, Japanese Americans, Latinos, and white persons and among individuals with body mass index <25.0 (calculated as weight (kg)/height (m)2), never-users of nonsteroidal antiinflammatory drugs, and those with lower intake of dietary fiber and folate. Beer and wine, but not liquor, consumption was positively related to colorectal cancer risk. The association was stronger for rectum and left-colon tumors than for right-colon tumors. Our findings suggest that the positive association between alcohol and colorectal cancer varies according to race/ethnicity, lifestyle factors, alcoholic beverage type, and anatomical subsite of tumors.