Diet Quality and Risk of Bladder Cancer in the Multiethnic Cohort Study.

This study analyzed the overall quality of the diet using predefined indices, including the Healthy Eating Index-2015 (HEI-2015), the Alternative Healthy Eating Index-2010 (AHEI-2010), the alternate Mediterranean Diet (aMED) score, the Dietary Approaches to Stop Hypertension (DASH) score, and the Dietary Inflammatory Index (DII®), to explore their association with the risk of bladder cancer in the Multiethnic Cohort Study. Data were taken from 186,979 African American, Japanese American, Latino, Native Hawaiian, and non-Hispanic White participants aged 45-75 years, with 1152 incident cases of invasive bladder cancer during a mean follow-up period of 19.2 ± 6.6 years. Cox models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) with comprehensive adjustment for smoking. Comparing the highest vs. lowest diet quality score quintile, HRs (95% CIs) in men was 1.08 (0.86-1.36) for HEI-2015, 1.05 (0.84-1.30) for AHEI-2010, 1.01 (0.80-1.27) for aMED, 1.13 (0.90-1.41) for DASH, and 0.96 (0.76-1.21) for DII®, whereas the corresponding HRs for women were 0.75 (0.53-1.07), 0.64 (0.45-0.92), 0.60 (0.40-0.88), 0.66 (0.46-0.95), and 0.63 (0.43-0.90) with all p values for trend <0.05. The inverse association found in women did not vary by smoking status or race and ethnicity. Our findings suggest that adopting high-quality diets may reduce the risk of invasive bladder cancer among women in a multiethnic population.

Plant-based dietary patterns and mortality from all causes, cardiovascular disease, and cancer: The Multiethnic Cohort Study.

BACKGROUND & AIMS: Plant-based dietary patterns have been associated with lower risk of cardiovascular disease (CVD), some cancers, and related mortality in U.S. POPULATIONS: However, the quality of plant foods has rarely been considered in the association between plant-based diets and mortality, especially in a population with various racial and ethnic backgrounds. We investigated whether the adherence to plant-based dietary patterns and the healthiness of plant foods are associated with mortality from all causes, CVD, and cancer and evaluated how the association varies by race and ethnicity. METHODS: A total of 144,729 African American, Japanese American, Latino, Native Hawaiian, and White men and women who participated in the Multiethnic Cohort Study (1993-2019) were included. Cox models were used to estimate HR and 95% CI of mortality from all causes, CVD, and cancer across quintiles of three plant-based diet scores: overall plant-based diet index (PDI), healthful plant-based diet index (hPDI), and unhealthful plant-based diet index (uPDI). RESULTS: Over an average 21 years of follow-up, we identified 65,087 deaths, including 18,663 from CVD and 16,171 from cancer. Comparing the highest versus lowest quintiles, greater scores of PDI and hPDI were associated with a lower risk of all-cause mortality in both men (HR = 0.85, 95% CI: 0.82-0.89 for PDI; HR = 0.88, 95% CI: 0.85-0.91 for hPDI; both P for trend <0.0001) and women (HR = 0.89, 95% CI: 0.86-0.93 for PDI; HR = 0.86, 95% CI: 0.83-0.89 for hPDI; both P for trend <0.0001). An increased risk of all-cause mortality with uPDI was observed only in women (HR = 1.11, 95% CI: 1.07-1.15, P for trend <0.0001; P for heterogeneity by sex = 0.019). A similar trend was shown for CVD mortality with a significant increase in risk with uPDI for both men and women. PDI was associated with a lower risk of cancer mortality in men (HR = 0.86, 95% CI: 0.80-0.92, P for trend <0.0001), while neither hPDI nor uPDI was associated in either sex. Compared with the other racial and ethnic groups within each sex, the association of uPDI with all-cause mortality was stronger in White men (P for heterogeneity by race and ethnicity = 0.009) and weaker in Latino women (P for heterogeneity = 0.002). CONCLUSION: A healthy plant-based dietary pattern emphasizing the quality of plant foods was associated with a lower risk of all-cause and CVD mortality in both men and women, although the magnitude of the associations varied across racial and ethnic groups.

Intake of Sugar and Food Sources of Sugar and Colorectal Cancer Risk in the Multiethnic Cohort Study.

BACKGROUND: The influence of sugar intake on the risk of colorectal cancer (CRC) remains controversial, and there is a need to investigate the heterogeneity of effects among racial and ethnic groups. OBJECTIVES: To examine the association of intake of simple sugars and their food sources with CRC risk according to race/ethnicity in a Multiethnic Cohort Study. METHODS: We analyzed data from 192,651 participants who participated in the Multiethnic Cohort Study comprising African-American, Japanese American, Latino, Native Hawaiian, and White older adults living in Hawaii and California with an average follow-up of 19 y. Intakes of total and specific types of sugars and sugary foods were estimated from a quantitative food frequency questionnaire completed by the participants in 1993-1996. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC risk according to quintiles (Q) of sugar and food intakes using Cox models adjusted for potential confounders. RESULTS: As of December 2017, 4403 incident CRC cases were identified. Among all participants, multivariable-adjusted CRC HRs for Q2, Q3, Q4, and Q5 compared with Q1 for total sugars were 1.03 (95% CI: 0.94, 1.13), 1.05 (95% CI: 0.96, 1.16), 1.12 (95% CI: 1.01, 1.24), and 1.13 (95% CI: 1.01, 1.27), respectively. A similar positive association was observed for total fructose, glucose, fructose, and maltose but not for added sugars and sugary foods. The increased risk appeared to be limited to colon cancer and to be strongest among younger participants (i.e., 45-54 y at baseline); an association with CRC was observed for sugar-sweetened beverages in the latter group. Among racial and ethnic groups, increased risk of CRC was most apparent in Latinos. CONCLUSIONS: In this diverse cohort, intakes of total sugar, total fructose, glucose, fructose, and maltose were associated with an increased risk of CRC, and the association was strongest for colon cancer, younger participants, and Latinos.

Reproductive Factors and Thyroid Cancer Risk: The Multiethnic Cohort Study.

Background: Women are three times more likely to be diagnosed with thyroid cancer than men, with incidence rates per 100,000 in the United States of 20.2 for women and 7.4 for men. Several reproductive and hormonal factors have been proposed as possible contributors to thyroid cancer risk, including age at menarche, parity, age at menopause, oral contraceptive use, surgical menopause, and menopausal hormone therapy. Our study aimed to investigate potential reproductive/hormonal factors in a multiethnic population. Methods: Risk factors for thyroid cancer were evaluated among female participants (n = 118,344) of the Multiethnic Cohort Study. The cohort was linked to Surveillance, Epidemiology, and End Results cancer incidence and statewide death certificate files in Hawaii and California, with 373 incident papillary thyroid cancer cases identified. Exposures investigated include age at menarche, parity, first pregnancy outcome, birth control use, and menopausal status and type. Multivariable Cox proportional hazards models were used to obtain relative risk (RR) of papillary thyroid cancer and their 95% confidence intervals (CI). Covariates included age, race and ethnicity, reproductive history, body size, smoking, and alcohol consumption. Results: We observed a statistically significant increased risk of papillary thyroid cancer for oophorectomy (adjusted RR 1.58, 95% CI: 1.26, 1.99), hysterectomy (adjusted RR 1.65, 95% CI: 1.33, 2.04), and surgical menopause (adjusted RR 1.55, 95% CI: 1.22, 1.97), and decreased risk for first live birth at ≤20 years of age versus nulliparity (adjusted RR 0.66, 95% CI: 0.46, 0.93). These associations did not vary by race and ethnicity (p het > 0.44). Conclusion: The reproductive risk factors for papillary thyroid cancer reported in the literature were largely confirmed in all racial and ethnic groups in our multiethnic population, which validates uniform obstetric and gynecological practice.

Differences in Neuropathology between Nitroglycerin-Induced Mouse Models of Episodic and Chronic Migraine.

Multiple animal models of migraine have been used to develop new therapies. Understanding the transition from episodic (EM) to chronic migraine (CM) is crucial. We established models mimicking EM and CM pain and assessed neuropathological differences. EM and CM models were induced with single NTG or multiple injections over 9 days. Mechanical hypersensitivity was assessed. Immunofluorescence utilized c-Fos, NeuN, and Iba1. Proinflammatory and anti-inflammatory markers were analyzed. Neuropeptides (CGRP, VIP, PACAP, and substance P) were assessed. Mechanical thresholds were similar. Notable neuropathological distinctions were observed in Sp5C and ACC. ACC showed increased c-Fos and NeuN expression in CM (p < 0.001) and unchanged in EM. Sp5C had higher c-Fos and NeuN expression in EM (p < 0.001). Iba1 was upregulated in Sp5C of EM and ACC of CM (p < 0.001). Proinflammatory markers were strongly expressed in Sp5C of EM and ACC of CM. CGRP expression was elevated in both regions and was higher in CM. VIP exhibited higher levels in the Sp5C of EM and ACC of CM, whereas PACAP and substance P were expressed in the Sp5C in both models. Despite similar thresholds, distinctive neuropathological differences in Sp5C and ACC between EM and CM models suggest a role in the EM to CM transformation.

Thyroid Cancer Survival in the Multiethnic Cohort Study.

OBJECTIVE: The US 5-year survival rate after thyroid cancer (TC) diagnosis is over 95%. Our aim was to investigate survival differences by sex and race and ethnicity in a multiethnic US population. DESIGN: In the Multiethnic Cohort (MEC) study, a total of 605 incident TC cases were identified by linkage to HI and CA statewide cancer registries. Cox models were performed to compare the risk of all-cause mortality among TC cases by sex and race and ethnicity, with adjustment for age, first course of treatment, baseline body mass index, smoking status, alcohol intake, and neighborhood socioeconomic status. Survival among cases was also compared to matched MEC controls with no thyroid cancer. RESULTS: After a mean follow-up of 10.1 years, 250 deaths occurred among TC cases, including 63 deaths attributed to thyroid cancer. The median survival was 14.7 years, and the 5-year age-adjusted overall survival was 84.4% for female cases and 68.7% for male cases (p < 0.0001, HR 2.28 (95% CI: 1.72, 3.01)). Age-adjusted survival was lower among African American, Native Hawaiian, and Filipino cases, compared to Japanese American cases, with Whites and Latinos being intermediate. Men and Filipinos were found to have excess mortality due to thyroid cancer compared to controls (adjusted HR 1.39, 95% CI: 1.11, 1.74; HR 1.62, 95% CI: 1.04, 2.53, respectively). CONCLUSIONS: Sex and racial and ethnic disparities in survival among TC cases were similar to those found in the general population. However, cases with TC had an excess risk of death among males and for Filipinos.

Avocado and Guacamole Consumption and Colorectal Cancer Risk: The Multiethnic Cohort Study.

Dietary fiber and phytonutrients can protect against colorectal cancer, yet their consumption is low in the US. Avocados are a potential source of these beneficial nutrients. Therefore, this study aimed to examine the relationship between avocados/guacamole consumption and colorectal cancer risk in the Multiethnic Cohort Study. We assessed avocados/guacamole consumption by using a food frequency questionnaire. We classified participants into three consumer groups: <1 serving/month, 1-3 servings/month, and ≥1 serving/week with one serving defined as ½ avocado or ½ cup. Colorectal cancer cases were ascertained through the Surveillance, Epidemiology and End Results Program cancer registries. Cox proportional hazards models of colorectal cancer were used to calculate hazard ratios and 95% confidence intervals across avocados/guacamole intake groups in each sex overall and by anatomic subsite (i.e., right colon, left colon, and rectum) and race and ethnicity. Of 192,651 eligible participants, 62.8% reported consuming <1 serving/month avocados/guacamole, 26.7% reported 1-3 servings/month, and 10.5% reported ≥1 serving/week. When adjusted for relevant covariates, there was no significant association with incident colorectal cancer overall, for subsites, or within racial and ethnic subgroups (all p for trend ≥ 0.06). In this large prospective cohort study, we did not find that consumption of avocados/guacamole was associated with colorectal cancer risk.

Racial and Ethnic Differences in the Population-Attributable Fractions of Alzheimer Disease and Related Dementias.

BACKGROUND AND OBJECTIVES: Previous studies estimated that modifiable risk factors explain up to 40% of the dementia cases in the United States and that this population-attributable fraction (PAF) differs by race and ethnicity-estimates of future impact based on the risk factor prevalence in contemporary surveys. The aim of this study was to determine the race-specific and ethnicity-specific PAF of late-onset Alzheimer disease and related dementias (ADRDs) based on the risk factor prevalence and associations observed on the same individuals within a prospective cohort. METHODS: Data were from Multiethnic Cohort Study participants (African American, Japanese American, Latino, Native Hawaiian, and White) enrolled in Medicare Fee-for-Service. We estimated the PAF based on the prevalence of risk factors at cohort baseline and their mutually adjusted association with subsequent ADRD incidence. Risk factors included low educational attainment and midlife exposures to low neighborhood socioeconomic status, unmarried status, history of hypertension, stroke, diabetes or heart disease, smoking, physical inactivity, short or long sleep duration, obesity, and low-quality diet, as well as APOE ε4 for a subset. RESULTS: Among 91,881 participants (mean age 59.3 at baseline, 55.0% female participants), 16,507 incident ADRD cases were identified from Medicare claims (1999-2016, mean follow-up 9.3 years). The PAF for nongenetic factors combined was similar in men (24.0% [95% CI 21.3-26.6]) and women (22.8% [20.3-25.2]) but varied across Japanese American (14.2% [11.1-17.2]), White (21.9% [19.0-24.7]), African American (27.8% [22.3-33.0]), Native Hawaiian (29.3% [21.0-36.7]), and Latino (33.3% [27.5-38.5]) groups. The combined PAF was attenuated when accounting for competing risk of death, in both men (10.4%) and women (13.9%) and across racial and ethnic groups (4.7%-25.5%). The combined PAF was also different by age at diagnosis and ADRD subtypes, higher for younger (65-74 years: 43.2%) than older (75-84 years: 32.4%; ≥85 years: 11.3%) diagnoses and higher for vascular or unspecified ADRD than for AD or Lewy body dementia. An additional PAF of 11.8% (9.9-13.6) was associated with APOE ε4, which together with nongenetic risk factors accounted for 30.6% (25.8-35.1) of ADRD. DISCUSSION: Known risk factors explained about a third of the ADRD cases but with unequal distributions across racial and ethnic groups.

Diet Quality and Body Mass Index Over 20 Years in the Multiethnic Cohort.

BACKGROUND: With increasing rates of overweight and obesity and disparities by ethnicity, it is important to understand the role of diet in ameliorating this health problem. OBJECTIVE: This study examined the relation of diet quality as measured by the Healthy Eating Index 2015 with body mass index (BMI; calculated as kg/m2) and obesity among participants of the Multiethnic Cohort (MEC) in cross-sectional analyses at 3 time points (T-1, T-2, and T-3) over 20 years. DESIGN: In a subset of 1,860 MEC participants, 3 cross-sectional analyses at cohort entry (1993 to 1996, T-1) and follow-ups in 2003 to 2008 (T-2) and 2013 to 2016 (T-3) were performed. PARTICIPANTS/SETTING: The cohort consists of African American, Native Hawaiian, Japanese American, Latino, and White adults in Hawaii and California; mean age was 48 years at T-1. MAIN OUTCOME MEASURE: BMI and weight status in relation to diet quality were measured. STATISTICAL ANALYSIS: Linear and multinomial logistic regressions were applied to analyze the relation of diet quality with BMI and obesity, while adjusting for known confounders. RESULTS: Healthy Eating Index 2015 increased by 6.1 and 5.1 units for men and women, respectively, from T-1 to T-3; the respective values for BMI were 1.5 and 2.4. Diet quality was inversely associated with BMI across time: BMI was lower by -0.47, -0.72, and -0.92 units for every 10-point increase in Healthy Eating Index 2015 scores at T-1, T-2, and T-3, respectively (P < .0001 for all). During the 20 years, the association was consistently high among Japanese American participants (-0.79, -0.87, and -1.02) and weakest in African American cohort members (-0.34, -0.37, and -0.40). Higher diet quality was related to lower odds of having obesity at all 3 time points; prevalence odds ratios were 0.72, 0.57, and 0.60. CONCLUSIONS: These findings suggest that consuming a high-quality diet is related to lower BMI and rates of overweight and obesity but with the strongest association at an older age. To understand the ethnic differences, investigations of dietary habits and behaviors and/or fat distribution patterns will be needed in the future.

No Association of Trichomonas vaginalis Seropositivity with Advanced Prostate Cancer Risk in the Multiethnic Cohort: A Nested Case-Control Study.

The potential involvement of a sexually transmitted agent has been suggested to contribute to the high number of prostate cancers in the United States and worldwide. We investigated the relationship of Trichomonas vaginalis seropositivity with prostate cancer risk in a nested case-control study within the Multiethnic Cohort in Hawaii and California using blood samples collected prior to cancer diagnoses. Incident cases of advanced prostate cancer (intermediate- to high-grade based on Gleason score ≥ 7 and/or disease spread outside the prostate) were matched to controls by age, ethnicity, and the date of blood collection. T. vaginalis serostatus was measured using an ELISA detecting IgG antibodies against a recombinant T. vaginalis α-actinin protein. Seropositivity to T. vaginalis was observed in 35 of 470 (7.4%) cases and 26 of 470 (5.5%) controls (unadjusted OR = 1.47, 95% CI 0.82-2.64; adjusted OR = 1.31, 95% CI 0.67-2.53). The association was similarly not significant when cases were confined to extraprostatic tumors having regional or distant spread (n = 121) regardless of grade (unadjusted OR = 1.37, 95% CI 0.63-3.01; adjusted OR = 1.20, 95% CI 0.46-3.11). The association of T. vaginalis with prostate cancer risk did not vary by aspirin use. Our findings do not support a role for T. vaginalis in the etiology of advanced prostate cancer.

CU06-1004 as a promising strategy to improve anti-cancer drug efficacy by preventing vascular leaky syndrome.

Background: Interleukin-2 (IL-2) is the first cancer therapeutic agent with an immunomodulatory function. Although it has been experimentally proven to be effective against metastatic renal cell carcinoma and metastatic melanoma, the clinical application of high-dose IL-2 (HDIL-2) has been limited because of its short half-life and severe side effects, such as vascular leakage syndrome (VLS) or capillary leaky syndrome (CLS). However, methods for overcoming this issue have not yet been identified. Methods: We discovered CU06-1004, an endothelial dysfunction blocker, through a previous study, and co-treated with IL-2 immunotherapy to confirm its inhibitory effect on HDIL-2-induced endothelial permeability. CU06-1004 was co-administered with HDIL-2 for 4 days in an in vivo mouse model. After drug injection, the mice were sacrificed, and Evans blue staining was performed. Results: In vitro, HDIL-2 treatment decreased HUVEC stability, which was rescued by co-treatment with CU06-1004. In our mouse model, co-administration of CU06-1004 and HDIL-2 prevented HDIL-2-induced vascular leakage by normalizing endothelial cells. Notably, the HDIL-2 and CU06-1004 combination therapy considerably reduced tumor growth in the B16F10 melanoma mouse model. Conclusion: Our data suggest that CU06-1004 acts as a potential anticancer drug candidate, not only by preventing HDIL-2-induced VLS but also by enhancing the anticancer effects of HDIL-2 immunotherapy.

Changes in Diet Quality over 10 Years and Subsequent Mortality from Cardiovascular Disease in the Multiethnic Cohort Study.

This study investigated how diet quality changes over a ten-year period, assessed using the following four diet quality indexes, the Healthy Eating Index-2015 (HEI-2015), Alternative Healthy Eating Index-2010 (AHEI-2010), alternate Mediterranean Diet (aMED), and Dietary Approaches to Stop Hypertension (DASH), were related to mortality from cardiovascular disease (CVD) in the Multiethnic Cohort Study. The analysis included 61,361 participants who completed both the 1993-1996 baseline survey and the 2003-2008 10-year follow-up surveys. Over the mean follow-up period of 13 years after the 10-year survey, 4174 deaths from CVD were identified. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using multivariable Cox models. Increases in diet quality scores were associated with a reduced risk of CVD mortality for all indexes: HRs per one SD increment of 0.94 to 0.99 (HR (95% CI), 0.96 (0.92-1.01) for HEI-2015, 0.96 (0.91-1.01) for AHEI-2010, 0.99 (0.94-1.04) for aMED, and 0.94 (0.89-0.99) for DASH) in men and 0.88 to 0.92 (0.88 (0.84-0.92) for HEI-2015, 0.90 (0.85-0.95) for AHEI-2010, 0.89 (0.84-0.95) for aMED, and 0.92 (0.87-0.96) for DASH) in women. The inverse association generally did not vary by race and ethnicity, age, body mass index, smoking, and hypertension in each sex. Our findings suggest that improving diet quality and maintaining a high-quality diet over time may help reduce the risk of CVD mortality and could also be beneficial for those at higher risk of CVD.

Healthful Plant-Based Dietary Pattern and Risk of Hepatocellular Carcinoma in a Multiethnic Population: A Cohort Study.

BACKGROUND: Plant-based dietary patterns assessed by a priori indices are associated with various health outcomes, but have rarely been examined in relation to liver cancer. OBJECTIVES: This study investigated the associations between plant-based diets and risk of hepatocellular carcinoma (HCC) and evaluated whether the associations vary by sex and race and ethnicity. METHODS: Data were from a total of 170,321 African American, Japanese American, Latino, Native Hawaiian, and White adults aged 45-75 y who completed a food frequency questionnaire in the Multiethnic Cohort Study. Cox models with adjustment for potential confounders were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for HCC according to 3 plant-based diet scores: overall plant-based diet index (PDI), healthful plant-based diet index (hPDI), and unhealthful plant-based diet index (uPDI). RESULTS: During a mean follow-up of 19.6 y, 722 incident HCC cases were identified. Multivariate-adjusted HR (95% CI) per 10-point increase was 0.82 (0.71-0.94) for PDI, 0.84 (0.74-0.96) for hPDI, and 1.08 (0.95-1.23) for uPDI. We found no significant differences by sex (all Pheterogeneity ≥ 0.53) or race and ethnicity (all Pheterogeneity ≥ 0.31). CONCLUSION: Greater adherence to plant-based diets rich in healthy plant foods and low in less healthy plant foods is associated with a reduced risk of HCC in a multiethnic population.

Long-term administration of CU06-1004 ameliorates cerebrovascular aging and BBB injury in aging mouse model.

BACKGROUND: Age-related changes in the cerebrovasculature, including blood-brain barrier (BBB) disruption and vascular dementia, are emerging as potential risks for many neurodegenerative diseases. Therefore, the endothelial cells that constitute the cerebrovasculature may play key roles in preventing brain injury. Our previous study showed that CU06-1004, an endothelial cell dysfunction blocker, prevented vascular leakage, enhanced vascular integrity in ischemic reperfusion injury, and promoted the normalization of tumor vasculature. Here, we evaluated the effects of CU06-1004 on age-related cerebrovascular functional decline in the aged mouse brain. RESULTS: In this study, we investigated the protective effects of CU06-1004 against oxidative stress-induced damage in human brain microvascular endothelial cells (HBMECs). HBMECs were treated with hydrogen peroxide (H2O2) to establish an oxidative stress-induced model of cellular injury. Compared with H2O2 treatment alone, pretreatment of HBMECs with CU06-1004 considerably reduced oxidative stress-induced cytotoxicity, reactive oxygen species generation, senescence-associated ß-galactosidase activity, senescence marker expression, and the expression levels of inflammatory proteins. Based on the observed cytoprotective effects of CU06-1004 in HBMECs, we examined whether CU06-1004 displayed protective effects against cerebrovascular aging in mice. Long-term administration of CU06-1004 alleviated age-associated cerebral microvascular rarefaction and cerebrovascular senescence in the aged mouse brain. CU06-1004 supplementation also reduced the extravasation of plasma IgG by improving BBB integrity in the aged mouse brain, associated with reductions in neuronal injury. A series of behavioral tests also revealed improved motor and cognitive functions in aged mice that received long-term CU06-1004 administration. CONCLUSIONS: These findings suggest that CU06-1004 may represent a promising therapeutic approach for delaying age-related cerebrovascular impairment and improving cognitive function in old age.

Diet quality and risk of gastric adenocarcinoma: The Multiethnic Cohort.

BACKGROUND: Certain dietary patterns (i.e., low intake of fruit/vegetables and high intake of salt and processed meats) have been associated with the risk of gastric cancer. However, it is unclear whether overall diet quality assessed by predefined indices that consider the complexity of dietary intake is associated with gastric cardia and distal adenocarcinoma. OBJECTIVES: To examine the association of a variety of diet indices with the risk of gastric cardia and distal adenocarcinoma and assess whether there are any subgroups that may benefit from better diets to reduce the risk of gastric adenocarcinoma. METHODS: Dietary indices of interest included the Alternative Healthy Index (AHEI)-2010, Healthy Eating Index (HEI)-2015, the Dietary Approach to Stop Hypertension, alternate Mediterranean diet (aMED), and the energy-adjusted Dietary Inflammatory Index. RESULTS: After an average follow-up time of 19.2 years, there were 836 incident cases of gastric distal adenocarcinoma and 207 cases of gastric cardia adenocarcinoma. We did not observe any significant associations between the dietary indices and gastric cancer for either anatomic site. Among former aspirin users, we observed an inverse association between aMED with distal cancer (HRQ5 vs. Q1: 0.64; 95% CI: 0.33, 1.23; P-trend = 0.03). Never smokers, who showed high-quality diet according to AHEI-2010, exhibited a 40% decreased risk of gastric distal cancer compared with those with the poorest-quality AHEI-2010 diet (HRQ5 vs. Q1: 0.60; 95% CI: 0.41, 0.88; P-trend = 0.08). CONCLUSIONS: In a multiethnic population, we did not observe overall significant associations between these dietary quality indices and risk of gastric cancer. However, among former aspirin users and never smokers, there could be a reduction of gastric distal adenocarcinoma risk with a higher adherence to a Mediterranean diet.

Predicting tolerability of high-dose fentanyl buccal tablets in cancer patients.

BACKGROUND & AIMS: Fentanyl buccal tablets (FBTs) are a rapid-onset opioid indicated for breakthrough cancer pain (BTcP) and FBT titration is needed to optimize BTcP management. We aimed to predict which patients could tolerate a high dose of FBT (400 µg or more at a time). METHODS: A retrospective analysis was performed to assess the final FBT dose. The final FBT doses were compared according to the clinical features. The prediction accuracy of patients tolerant of 400 µg or higher FBT was compared using the area under the receiver operating characteristic (ROC) curves. A risk scoring model based on the odds ratio (OR) was developed from the final multivariable model, and patients were assigned into two groups: low tolerance (0-1 point) and high tolerance (2-3 points). RESULTS: Among 131 patients, the most frequently effective dose of FBT was 200 µg (54%), followed by 100 µg (30%). The median value of morphine equivalent daily doses (MEDD) was 60 mg/day, and the most common daily use was 3-4 times/day. In multivariable analysis, male sex, younger age, and use of FBTs three or more times per day were independently associated with high-dose FBT. According to the risk scoring model, the patients with a final FBT of 400 µg or higher were significantly more in the high tolerance group (17%) compared to the low tolerance group (3%; p = 0.023). CONCLUSIONS: According to the dose relationship between the final FBT dose and the clinical features, three factors (sex, age, daily use of FBT) were independently associated with the final dose of FBT. Our risk score model could help predict tolerance to high-dose FBT and guide the titration plan for BTcP.

Mutations of TP53 and genes related to homologous recombination repair in breast cancer with germline BRCA1/2 mutations.

BACKGROUND: Germline mutations of breast cancer susceptibility gene BRCA1 and BRCA2 (gBRCA1/2) are associated with elevated risk of breast cancer in young women in Asia. BRCA1 and BRCA2 proteins contribute to genomic stability through homologous recombination (HR)-mediated double-strand DNA break repair in cooperation with other HR-related proteins. In this study, we analyzed the targeted sequencing data of Korean breast cancer patients with gBRCA1/2 mutations to investigate the alterations in HR-related genes and their clinical implications. MATERIALS AND METHODS: Data of the breast cancer patients with pathogenic gBRCA1/2 mutations and qualified targeted next-generation sequencing, SNUH FiRST cancer panel, were analyzed. Single nucleotide polymorphisms, small insertions, and deletions were analyzed with functional annotations using ANNOVAR. HR-related genes were defined as ABL1, ATM, ATR, BARD1, BRCA1, BRCA2, CDKN1A, CDKN2A, CHEK1, CHEK2, FANCA, FANCD2, FANCG, FANCI, FANCL, KDR, MUTYH, PALB2, POLE, POLQ, RAD50, RAD51, RAD51D, RAD54L, and TP53. Mismatch-repair genes were MLH1, MSH2, and MSH6. Clinical data were analyzed with cox proportional hazard models and survival analyses. RESULTS: Fifty-five Korean breast cancer patients with known gBRCA1/2 mutations and qualified targeted NGS data were analyzed. Ethnically distinct mutations in gBRCA1/2 genes were noted, with higher frequencies of Val1833Ser (14.8%), Glu1210Arg (11.1%), and Tyr130Ter (11.1%) in gBRCA1 and Arg2494Ter (25.0%) and Lys467Ter (14.3%) in gBRCA2. Considering subtypes, gBRCA1 mutations were associated with triple-negative breast cancers (TNBC), while gBRCA2 mutations were more likely hormone receptor-positive breast cancers. At least one missense mutation of HR-related genes was observed in 44 cases (80.0%). The most frequently co-mutated gene was TP53 (38.1%). In patients with gBRCA1/2 mutations, however, genetic variations of TP53 occurred in locations different from the known hotspots of those with sporadic breast cancers. The patients with both gBRCA1/2 and TP53 mutations were more likely to have TNBC, high Ki-67 values, and increased genetic mutations, especially of HR-related genes. Survival benefit was observed in the TP53 mutants of patients with gBRCA2 mutations, compared to those with TP53 wild types. CONCLUSION: Our study showed genetic heterogeneity of breast cancer patients with gBRCA1 and gBRCA2 mutations in the Korean populations. Further studies on precision medicine are needed for tailored treatments of patients with genetic diversity among different ethnic groups.

White Rice Consumption and Risk of Colorectal Cancer Among Japanese Americans: The Multiethnic Cohort Study.

BACKGROUND: White rice is a staple food for Japanese, a population at high risk for colorectal cancer (CRC). We investigated the association between white rice intake and CRC among Japanese Americans in the Multiethnic Cohort (MEC) study. METHODS: The MEC study is a prospective study established in Hawaii and California in 1993-1996. Usual dietary intake was assessed using a validated quantitative food frequency questionnaire at baseline. Cox proportional hazards models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for quartiles of intake and to perform trend tests across sex-specific quartiles with adjustment for relevant confounders. RESULTS: We identified 1,553 invasive CRC cases among 49,136 Japanese Americans (23,595 men and 25,541 women) during a mean follow-up of 19 years. White rice consumption was not associated with overall CRC incidence in men (Ptrend = 0.11) or women (Ptrend = 0.56). After excluding participants with a history of diabetes, the inverse associations were significant for CRC (Ptrend = 0.03, HR for quartile 4 [Q4] vs quartile 1 [Q1], 0.81; 95% CI, 0.64-1.03) and tumors of the distal colon (Ptrend = 0.006, HR for Q4 vs Q1, 0.66; 95% CI, 0.44-0.99) among men but not women. CONCLUSION: White rice consumption was not associated with an increased risk of overall CRC among Japanese Americans. An inverse association was observed with risk of CRC and distal colon cancer in men without a history of diabetes.

Modifying effects of race and ethnicity and APOE on the association of physical activity with risk of Alzheimer's disease and related dementias.

INTRODUCTION: We investigated whether the protective association of physical activity with risk of Alzheimer's disease and related dementias (ADRD) has genetic or behavioral variations. METHODS: In the Multiethnic Cohort, we analyzed moderate or vigorous physical activity (MVPA) reported at ages 45 to 75 among 88,047 participants in relation to 13,039 incident diagnoses of late-onset ADRD identified in Medicare claims (1999 to 2014), by five racial and ethnic groups, hours sitting, and in a subset (16%), apolipoprotein E (APOE) genotype. RESULTS: MVPA was inversely associated with ADRD (hazard ratio for ≥14 vs <2.5 hours/week: 0.83, 95% confidence interval [CI]: 0.76 to 0.90 in men; 0.88, 5% CI: 0.81 to 0.95 in women). The association was inverse in all racial and ethnic groups except Black participants (P-heterogeneity = 0.52), but stronger in individuals with lower levels of sitting duration or those who do not carry the APOE e4 risk allele. DISCUSSION: The different effects of physical activity by sitting duration and APOE genotype warrant further research.

Change in the inflammatory potential of diet over 10 years and subsequent mortality: the Multiethnic Cohort Study.

Dietary inflammatory potential assessed by the Dietary Inflammatory Index (DII®) has been associated with health outcomes. However, longitudinal changes in the DII in relation to health outcomes rarely have been studied. This study aimed to examine change in the DII score over 10 years and its association with subsequent mortality in the Multiethnic Cohort. The analysis included 56 263 African American, Japanese American, Latino, Native Hawaiian and White participants who completed baseline (45-75 years) and 10-year follow-up surveys, including a FFQ. Mean energy-adjusted DII (E-DII) decreased over 10 years in men (from -0·85 to -1·61) and women (from -1·80 to -2·47), reflecting changes towards a more anti-inflammatory diet. During an average follow-up of 13·0 years, 16 363 deaths were identified. In multivariable Cox models, compared with anti-inflammatory stable individuals, risk of all-cause mortality was increased with pro-inflammatory change in men (hazard ratio (HR) = 1·13, 95 % CI 1·03, 1·23) and women (HR = 1·22, 95 % CI 1·13, 1·32). Per one-point increase in E-DII score over time, HR was 1·02 (95 % CI 1·00, 1·03) for men and 1·06 (95 % CI 1·04, 1·07) for women (P for heterogeneity < 0·001). While no heterogeneity by race and ethnicity was observed for men, the increased risk per one-point increase among women was stronger in non-Whites than in Whites (P for heterogeneity = 0·004). Our findings suggest that a change towards a more pro-inflammatory diet is associated with an increased risk of mortality both in men and women, and that the association is stronger in women, especially non-White women, than in men.