Plasma Proteomic Signature Predicts Myeloid Neoplasm Risk.

PURPOSE: Clonal hematopoiesis (CH) is thought to be the origin of myeloid neoplasms (MN). Yet our understanding of the mechanisms driving CH progression to MN and clinical risk prediction of MN remains limited. The human proteome reflects complex interactions between genetic and epigenetic regulation of biological systems. We hypothesized that the plasma proteome might predict MN risk and inform our understanding of the mechanisms promoting MN development. EXPERIMENTAL DESIGN: We jointly characterized CH and plasma proteomic profiles of 46,237 individuals in the UK Biobank at baseline study entry. During 500,036 person-years of follow-up, 115 individuals developed MN. Cox proportional hazard regression was used to test for an association between plasma protein levels and MN risk. RESULTS: We identified 115 proteins associated with MN risk of which 30% (N=34) were also associated with CH. These were enriched for known regulators of the innate and adaptive immune system. Plasma proteomics improved the prediction of MN risk (AUC=0.85, p=5×10-9) beyond clinical factors and CH (AUC=0.80). In an independent group (N=381,485), we used inherited polygenic risk scores (PRS) for plasma protein levels to validate the relevance of these proteins to MN development. PRS analyses suggest that most MN-associated proteins we identified are not directly causally linked to MN risk, but rather represent downstream markers of pathways regulating the progression of CH to MN. CONCLUSIONS: These data highlight the role of immune cell regulation in the progression of CH to MN and the promise of leveraging multi-omic characterization of CH to improve MN risk stratification.

Alcohol Consumption Among Adults With a Cancer Diagnosis in the All of Us Research Program.

Importance: Alcohol consumption is associated with adverse oncologic and treatment outcomes among individuals with a diagnosis of cancer. As a key modifiable behavioral factor, alcohol consumption patterns among cancer survivors, especially during treatment, remain underexplored in the United States. Objective: To comprehensively characterize alcohol consumption patterns among US cancer survivors. Design, Setting, and Participants: This cross-sectional study used data from May 6, 2018, to January 1, 2022, from the National Institutes of Health All of Us Research Program, a diverse US cohort with electronic health record (EHR) linkage, and included 15 199 participants who reported a cancer diagnosis and 1839 patients among a subset with EHR data who underwent treatment within the past year of the baseline survey. Data analysis was performed from October 1, 2022, to January 31, 2023. Main Outcomes and Measures: Prevalence of current drinking and of risky drinking behaviors, including exceeding moderate drinking (>2 drinks on a typical drinking day), binge drinking (≥6 drinks on 1 occasion), and hazardous drinking (Alcohol Use Disorders Identification Test-Consumption [AUDIT-C] score ≥3 for women or ≥4 for men). Results: This study included 15 199 adults (mean [SD] age at baseline, 63.1 [13.0] years; 9508 women [62.6%]) with a cancer diagnosis. Overall, 11 815 cancer survivors (77.7%) were current drinkers. Among current drinkers, 1541 (13.0%) exceeded moderate drinking, 2812 (23.8%) reported binge drinking, and 4527 (38.3%) engaged in hazardous drinking. After multivariable adjustment, survivors who were younger than 65 years, men, or of Hispanic ethnicity or who received a diagnosis before 18 years of age or ever smoked were more likely to exceed moderate drinking (aged <50 years: odds ratio [OR], 2.90 [95% CI, 2.41-3.48]; aged 50-64 years: OR, 1.84 [95% CI, 1.58-2.15]; men: OR, 2.38 [95% CI, 2.09-2.72]; Hispanic ethnicity: OR, 1.31 [95% CI, 1.04-1.64]; aged <18 years at diagnosis: OR, 1.52 [95% CI, 1.04-2.24]; former smokers: OR, 2.46 [95% CI, 2.16-2.79]; current smokers: OR, 4.14 [95% CI, 3.40-5.04]) or binge drink (aged <50 years: OR, 4.46 [95% CI, 3.85-5.15]; aged 50-64 years: OR, 2.15 [95% CI, 1.90-2.43]; men: OR, 2.10 [95% CI, 1.89-2.34]; Hispanic ethnicity: OR, 1.31 [95% CI, 1.09-1.58]; aged <18 years at diagnosis: OR, 1.71 [95% CI, 1.24-2.35]; former smokers: OR, 1.69 [95% CI, 1.53-1.87]; current smokers: OR, 2.27 [95% CI, 1.91-2.71]). Survivors with cancer diagnosed before 18 years of age or who ever smoked were more likely to be hazardous drinkers (aged <18 years at diagnosis: OR, 1.52 [95% CI, 1.11-2.08]; former smokers: OR, 1.83 [95% CI, 1.68-1.99]; current smokers: OR, 2.13 [95% CI, 1.79-2.53]). Of 1839 survivors receiving treatment as captured in the EHR, 1405 (76.4%) were current drinkers, and among these, 170 (12.1%) exceeded moderate drinking, 329 (23.4%) reported binge drinking, and 540 (38.4%) engaged in hazardous drinking, with similar prevalence across different types of cancer treatment. Conclusions and Relevance: This cross-sectional study of a diverse US cohort suggests that alcohol consumption and risky drinking behaviors were common among cancer survivors, even among individuals receiving treatment. Given the adverse treatment and oncologic outcomes associated with alcohol consumption, additional research and implementation studies are critical in addressing this emerging concern among cancer survivors.

Red-flag signs and symptoms for earlier diagnosis of early-onset colorectal cancer.

BACKGROUND: Prompt detection of colorectal cancer (CRC) among individuals younger than age 50 years (early-onset CRC) is a clinical priority because of its alarming rise. METHODS: We conducted a matched case-control study of 5075 incident early-onset CRC among US commercial insurance beneficiaries (113 million adults aged 18-64 years) with 2 or more years of continuous enrollment (2006-2015) to identify red-flag signs and symptoms between 3 months to 2 years before the index date among 17 prespecified signs and symptoms. We assessed diagnostic intervals according to the presence of these signs and symptoms before and within 3 months of diagnosis. RESULTS: Between 3 months and 2 years before the index date, 4 red-flag signs and symptoms (abdominal pain, rectal bleeding, diarrhea, and iron deficiency anemia) were associated with an increased risk of early-onset CRC, with odds ratios (ORs) ranging from 1.34 to 5.13. Having 1, 2, or at least 3 of these signs and symptoms were associated with a 1.94-fold (95% confidence interval [CI] = 1.76 to 2.14), 3.59-fold (95% CI = 2.89 to 4.44), and 6.52-fold (95% CI = 3.78 to 11.23) risk (Ptrend < .001), respectively, with stronger associations for younger ages (Pinteraction < .001) and rectal cancer (Pheterogenity = .012). The number of different signs and symptoms was predictive of early-onset CRC beginning 18 months before diagnosis. Approximately 19.3% of patients had their first sign or symptom occur between 3 months and 2 years before diagnosis (median diagnostic interval = 8.7 months), and approximately 49.3% had the first sign or symptom within 3 months of diagnosis (median diagnostic interval = 0.53 month). CONCLUSIONS: Early recognition of red-flag signs and symptoms (abdominal pain, rectal bleeding, diarrhea, and iron-deficiency anemia) may improve early detection and timely diagnosis of early-onset CRC.

Sleep Behaviors, Genetic Predispositions, and Risk of Esophageal Cancer.

BACKGROUND: Risk factors contributing to more than 10-fold increase in esophageal cancer in the last 50 years remain underexplored. We aim to examine the associations of sleep behaviors with esophageal adenocarcinoma (EAC) and squamous cell carcinoma (ESCC). METHODS: We prospectively assessed the associations between sleep behaviors (chronotype, duration, daytime napping, daytime sleepiness, snoring, and insomnia) and EAC and ESCC risk in 393,114 participants in the UK Biobank (2006-2016). Participants with 0, 1, and ≥2 unhealthy behaviors, including sleep <6 or >9 h/d, daytime napping, and usual daytime sleepiness were classified as having a good, intermediate, and poor sleep. For EAC, we also examined interactions with polygenic risk score (PRS). Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: We documented 294 incident EAC and 95 ESCC. Sleep >9 h/d (HR, 2.05; 95% CI, 1.18-3.57) and sometimes daytime napping (HR, 1.36; 95% CI, 1.06-1.75) were individually associated with increased EAC risk. Compared with individuals with good sleep, those with intermediate sleep had a 47% (HR, 1.47; 95% CI, 1.13-1.91) increased EAC risk, and those with poor sleep showed an 87% (HR, 1.87; 95% CI, 1.24-2.82) higher risk (Ptrend < 0.001). The elevated risks for EAC were similar within strata of PRS (Pinteraction = 0.884). Evening chronotype was associated with elevated risk of ESCC diagnosed after 2 years of enrollment (HR, 2.79; 95% CI, 1.32-5.88). CONCLUSIONS: Unhealthy sleep behaviors were associated with an increased risk of EAC, independent of genetic risk. IMPACT: Sleep behaviors may serve as modifiable factors for the prevention of EAC.

Circulating markers of microbial translocation and host response to bacteria with risk of colorectal cancer: a prospective, nested case-control study in men.

BACKGROUND: Gut microbial dysbiosis contributes to colorectal cancer (CRC) pathogenesis, possibly mediated in part by increased intestinal permeability to endotoxin lipopolysaccharide (LPS), microbial translocation, and subsequent endotoxemia and inflammation. However, epidemiologic evidence linking circulating markers of microbial translocation with CRC risk is limited. METHODS: We conducted a prospective, nested case-control study of 261 incident CRC cases and 261 controls (matched on age and time of blood draw) among 18,159 men with pre-diagnostic blood specimens in the Health Professionals Follow-Up Study (1993-2009). We examined three complementary markers of microbial translocation and host response to bacteria, including LPS-binding protein (LBP), soluble CD14 (sCD14), and endotoxincore antibody (EndoCAb) immunoglobulin M (IgM), with subsequent risk of CRC. Unconditional logistic regressions were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). FINDINGS: Pre-diagnostic circulating levels of sCD14 were associated with a higher risk of incident CRC. Compared to men in the lowest quartile, the multivariable OR was 1.90 (95% CI, 1.13-3.22) for men in the highest quartile (OR per standard deviation [SD] increase, 1.28; 95%CI 1.06-1.53; Ptrend = 0.01). This positive association remained similar after adjusting for C-reactive protein, interleukin-6, and soluble tumor necrosis factor receptor-2, and within strata of putative CRC risk factors. We also observed a suggestive inverse association between EndoCAb IgM and risk of CRC (OR per SD increase, 0.84; 95%CI 0.69-1.02; Ptrend = 0.09). INTERPRETATION: Microbial translocation and host response to bacteria, as reflected by sCD14, is associated with risk of incident CRC in men. FUNDING: US National Institutes of Health.

Evaluation of Birth by Cesarean Delivery and Development of Early-Onset Colorectal Cancer.

Importance: The incidence of early-onset colorectal cancer (CRC), diagnosed younger than 50 years of age, has increased worldwide. Gut dysbiosis throughout the life course is hypothesized as a leading mechanism, yet epidemiologic data are limited. Objective: To prospectively examine the association between birth by cesarean delivery and early-onset CRC among offspring. Design, Setting, and Participants: In this population-based, nationwide case-control study in Sweden, adults diagnosed with CRC between 18 and 49 years of age from 1991 to 2017 were identified through the Epidemiology Strengthened by Histopathology Reports in Sweden (ESPRESSO) cohort. Up to 5 general population control individuals without CRC were matched with each case on age, sex, calendar year, and county of residence. Pathology-confirmed end points were linked with the Swedish Medical Birth Register and other national registers. Analyses were conducted from March 2022 through March 2023. Exposure: Birth by cesarean delivery. Main Outcomes and Measures: The primary outcome was development of early-onset CRC in the overall population and by sex. Results: We identified 564 case patients with incident early-onset CRC (mean [SD] age, 32.9 [6.2] years; 284 [50.4%] male) and 2180 matched controls (mean [SD] age, 32.7 [6.3] years; 1104 [50.6%] male). Compared with vaginal delivery, birth by cesarean delivery was not associated with early-onset CRC in the overall population (adjusted odds ratio [aOR], 1.28; 95% CI, 0.91-1.79) after multivariable adjustment for matching and maternal and pregnancy-related factors. A positive association was found for females (aOR, 1.62; 95% CI, 1.01-2.60), but there was no association for males (aOR, 1.05; 95% CI, 0.64-1.72). Conclusions and Relevance: In this nationwide, population-based case-control study, birth by cesarean delivery was not associated with early-onset CRC compared with birth by vaginal delivery in the overall population in Sweden. However, females born by cesarean delivery had greater odds of early-onset CRC compared with individuals born through vaginal delivery. This finding suggests that early-life gut dysbiosis may contribute to early-onset CRC in females.

Clonal Hematopoiesis and Risk of Incident Lung Cancer.

PURPOSE: To prospectively examine the association between clonal hematopoiesis (CH) and subsequent risk of lung cancer. METHODS: Among 200,629 UK Biobank (UKBB) participants with whole-exome sequencing, CH was identified in a nested case-control study of 832 incident lung cancer cases and 3,951 controls (2006-2019) matched on age and year at blood draw, sex, race, and smoking status. A similar nested case-control study (141 cases/652 controls) was conducted among 27,975 participants with whole-exome sequencing in the Mass General Brigham Biobank (MGBB, 2010-2021). In parallel, we compared CH frequency in published data from 5,003 patients with solid tumor (2,279 lung cancer) who had pretreatment blood sequencing performed through Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets. RESULTS: In UKBB, the presence of CH was associated with increased risk of lung cancer (cases: 12.5% v controls: 8.7%; multivariable-adjusted odds ratio [OR], 1.36; 95% CI, 1.06 to 1.74). The association remained robust after excluding participants with chronic obstructive pulmonary disease. No significant interactions with known risk factors, including polygenic risk score and C-reactive protein, were identified. In MGBB, we observed similar enrichment of CH in lung cancer (cases: 15.6% v controls: 12.7%). The meta-analyzed OR (95% CI) of UKBB and MGBB was 1.35 (1.08 to 1.68) for CH overall and 1.61 (1.19 to 2.18) for variant allele frequencies ≥ 10%. In Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets, CH with a variant allele frequency ≥ 10% was enriched in pretreatment lung cancer compared with other tumors after adjusting for age, sex, and smoking (OR for lung v breast cancer: 1.61; 95% CI, 1.03 to 2.53). CONCLUSION: Independent of known risk factors, CH is associated with increased risk of lung cancer.

Risk of nonalcoholic fatty liver disease and associations with gastrointestinal cancers.

Metabolic syndrome may contribute to the rising incidence of multiple gastrointestinal (GI) cancers in recent birth cohorts. However, other than hepatocellular carcinoma, the association between nonalcoholic fatty liver disease (NAFLD) and risk of non-liver GI cancers is unexplored. We prospectively examined the associations of NAFLD risk with GI cancers among 319,290 participants in the UK Biobank (2006-2019). Baseline risk for NAFLD was estimated using the Dallas Steatosis Index, a validated prediction tool. Multivariable Cox models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) according to NAFLD risk categories: low (<20%), intermediate (20%-49%), and high (≥50%). We also examined the associations by age of cancer diagnosis (earlier onset [<60] vs. ≥60). A total of 273 incident liver cancer and 4789 non-liver GI cancer cases were diagnosed. Compared with individuals at low risk for NAFLD, those at high risk had 2.41-fold risk of liver cancer (RR = 2.41, 95% CI: 1.73-3.35) and 23% increased risk of non-liver GI cancers (RR = 1.23, 95% CI: 1.14-1.32) (all ptrend < 0.001). Stronger associations were observed for men and individuals who were obese (all pinteraction < 0.05). NAFLD-associated elevated risk was stronger for earlier-onset cancers. For each 25% increase in NAFLD risk, the RRs for earlier-onset cancers were 1.32 (95% CI: 1.05-1.66) for esophageal cancer, 1.35 (95% CI: 1.06-1.72) for gastric cancer, 1.34 (95% CI: 1.09-1.65) for pancreatic cancer, and 1.10 (95% CI: 1.01-1.20) for colorectal cancer. Conclusion: NAFLD risk was associated with an increased risk of liver and most GI cancers, especially those of earlier onset.

Clinical and Genomic Characterization of Interval Colorectal Cancer in 3 Prospective Cohorts.

BACKGROUND & AIMS: Interval colorectal cancers (CRCs), cancers diagnosed after a screening/surveillance examination in which no cancer is detected, and before the date of next recommended examination, reflect an unprecedented challenge in CRC detection and prevention. To better understand this poorly characterized CRC variant, we examined the clinical and mutational characteristics of interval CRCs in comparison with screen detected CRCs. METHODS: We included 1175 CRCs documented in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial and 3661 CRCs in the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS). Multivariable Cox models were performed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of death risk. Whole exome sequencing was conducted in 147 PLCO cases and 796 NHS/HPFS cases. RESULTS: A total of 619 deaths (312 CRC-specific) and 2404 deaths (1904 CRC-specific) were confirmed during follow-up of PLCO and NHS/HPFS, respectively. Compared with screen detected CRCs, interval CRCs had a multivariate-adjusted HR (95% CI) of 1.47 (1.21-1.78) for CRC-specific mortality and 1.27 (1.09-1.47) for overall mortality (meta-analysis combining all 3 cohorts). However, we did not observe significant differences in mutational features between interval and screen detected CRCs (false discovery rate adjusted P > .05). CONCLUSION: Interval CRCs had a significantly increased risk of death compared with screen detected CRCs that were not explained by established clinical prognostic factors, including stage at diagnosis. The survival disadvantage of interval CRCs did not appear to be explained by differences in the genomic landscape of tumors characterized by whole exome sequencing.

Syndrome of inappropriate antidiuretic hormone secretion is associated with different proton pump inhibitor use: a pharmacovigilance study.

AIM: The objective of this study was to evaluate the reported associations between the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and a variety of proton pump inhibitors (PPI) through analysis of the reports extracted from the Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS: FAERS reports from January 2004 to March 2020 were used to conduct disproportionality and Bayesian analyses. The definition of SIADH relied on the preferred terms provided by the Medical Dictionary for Regulatory Activities. The time to onset, mortality, and hospitalization rates of PPI-related SIADH were also investigated. RESULTS: The study identified a total of 273 reports of PPI-associated SIADH, which appeared to influence more elderly than middle-aged patients (71.1% vs. 12.5%). Women were more affected than men (48.7% vs. 41.8%). Rabeprazole had a stronger SIADH association than other PPIs based on the highest reporting odds ratio (reporting odds ratio = 13.3, 95% confidence interval (CI) = 7.2, 24.9), proportional reporting ratio (proportional reporting ratio = 13.3, χ2 = 113.7), and empirical Bayes geometric mean (empirical Bayes geometric mean = 13.3, 95% CI = 7.9). The median time to SIADH onset was 22 (interquartile range 6-692) days after PPI administration. PPI-associated SIADH generally led to a 2.95% fatality rate and a 79.7% hospitalization rate. The highest hospitalization death rate occurred in esomeprazole (91.2%). CONCLUSION: According to our findings, more attention should be paid to SIADH within the first several months after the administration of PPIs. For women older than 65 years, dexlansoprazole may reduce the incidence of PPI-associated SIADH. Nonetheless, larger epidemiological studies are suggested to verify this conclusion.

Tooth count, untreated caries and mortality in US adults: a population-based cohort study.

BACKGROUND: The link between oral diseases and mortality remains under-explored. We aimed to evaluate the associations between tooth count, untreated caries and risk of all-cause and cause-specific mortality. METHODS: Data on 24 029 adults from the National Health and Nutrition Examination Survey 1988-94/1999-2010, with mortality linkage to the National Death Index to 31 December 2015, were analysed. Baseline total number of permanent teeth and any untreated caries were assessed by trained dental professionals. RESULTS: During up to 27 years of follow-up, 5270 deaths occurred. Fewer permanent teeth were associated with higher all-cause mortality, including heart disease and cancer mortality (all P <0.05 for trend) but not cerebrovascular disease mortality. For every 10 teeth missing, the multivariable-adjusted hazard ratios (HRs) were 1.13 (95% CI: 1.08 to 1.18) for all-cause, 1.16 (95% CI: 1.05, 1.29) for heart disease and 1.19 (95% CI: 1.09, 1.29) for cancer mortality. Untreated caries was associated with increased all-cause (HR: 1.26, 95% CI: 1.15, 1.39) and heart disease mortality (HR: 1.48, 95% CI: 1.17, 1.88) but not cerebrovascular disease/cancer mortality, after adjusting for tooth count, periodontitis and sociodemographic/lifestyle factors. Compared with those without untreated caries and with 25-28 teeth, individuals with untreated caries and 1-16 teeth had a 53% increased risk of all-cause mortality (HR: 1.53, 95% CI: 1.27, 1.85) and 96 % increased risk of heart disease mortality (HR: 1.96, 95% CI: 1.28, 3.01). CONCLUSIONS: In nationally representative cohorts, fewer permanent teeth and untreated caries were associated with all-cause and heart disease mortality. Fewer teeth were also associated with higher cancer mortality.

Total Vitamin D Intake and Risks of Early-Onset Colorectal Cancer and Precursors.

BACKGROUND & AIMS: Vitamin D has been implicated in colorectal cancer (CRC) pathogenesis, but it remains unknown whether total vitamin D intake is associated with early-onset CRC and precursors diagnosed before age 50. METHODS: We prospectively examined the association between total vitamin D intake and risks of early-onset CRC and precursors among women enrolled in the Nurses' Health Study II. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for early-onset CRC were estimated with Cox proportional hazards model. Multivariable-adjusted odds ratios (ORs) and 95% CIs for early-onset conventional adenoma and serrated polyp were estimated with logistic regression model. RESULTS: We documented 111 incident cases of early-onset CRC during 1,250,560 person-years of follow-up (1991 to 2015). Higher total vitamin D intake was significantly associated with a reduced risk of early-onset CRC (HR for ≥450 IU/day vs <300 IU/day, 0.49; 95% CI, 0.26-0.93; P for trend = .01). The HR per 400 IU/day increase was 0.46 (95% CI, 0.26-0.83). The inverse association was significant and appeared more evident for dietary sources of vitamin D (HR per 400 IU/day increase, 0.34; 95% CI, 0.15-0.79) than supplemental vitamin D (HR per 400 IU/day increase, 0.77; 95% CI, 0.37-1.62). For CRC precursors, the ORs per 400 IU/day increase were 0.76 (95% CI, 0.65-0.88) for conventional adenoma (n = 1,439) and 0.85 (95% CI, 0.75-0.97) for serrated polyp (n = 1,878). CONCLUSIONS: In a cohort of younger women, higher total vitamin D intake was associated with decreased risks of early-onset CRC and precursors.

Association of sedentary patterns with body fat distribution among US children and adolescents: a population-based study.

BACKGROUND/OBJECTIVES: Children and adolescents spend a substantial amount of time being sedentary. The impact of prolonged sedentary patterns on fat distribution has not been elucidated especially in the context of physical activity level. Our objective is to examine the independent and joint associations of prolonged sedentary patterns and physical activity level with fat distribution among children and adolescents. SUBJECTS/METHODS: This included US children (8-11 years) and adolescents (12-19 years) from the National Health and Nutrition Examination Survey 2003-2006. Sedentary patterns comprise accelerometer-measured average sedentary bout duration and self-reported time of sitting watching TV/videos. Fat distribution (trunk and total fat percentage) was determined via dual X-ray absorptiometry. RESULTS: Among 810 children and 2062 adolescents, average sedentary bout duration was associated with greater total and trunk fat percentages only among male children, after adjusting for moderate-to-vigorous physical activity (MVPA) level by accelerometer. Prolonged sitting watching TV/videos was associated with higher total and trunk fat percentages in male children and all adolescents, independent of levels of MVPA (all P for trend <0.05). Compared with ≤1 h/day, male children who spent ≥4 h/day sitting watching TV/videos had 4.43% higher trunk fat (95% CI, 1.69-7.17%), with similar associations for female (3.53%; 95% CI, 1.03-6.03%) and male adolescents (4.78%; 95% CI, 2.97-6.60%). About 13-17% children and adolescents spent <1 h on MVPA and ≥4 h sitting watching TV/videos per day. Compared with the most active group (MVPA ≥ 1 h/day and sitting watching TV/videos ≤1 h/day), trunk fat in this least active group was 6.21% higher in female children, 9.90% higher in male children, 6.84% higher in female adolescents, and 5.36% higher in male adolescents. CONCLUSIONS: Prolonged time spent on sitting watching TV/videos was associated with fat accumulation among children and adolescents, independent of physical activity level.

Metabolic syndrome, metabolic comorbid conditions and risk of early-onset colorectal cancer.

OBJECTIVE: Factors that lead to metabolic dysregulation are associated with increased risk of early-onset colorectal cancer (CRC diagnosed under age 50). However, the association between metabolic syndrome (MetS) and early-onset CRC remains unexamined. DESIGN: We conducted a nested case-control study among participants aged 18-64 in the IBM MarketScan Commercial Database (2006-2015). Incident CRC was identified using pathologist-coded International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, and controls were frequency matched. MetS was defined as presence of ≥3 conditions among obesity, hypertension, hyperlipidaemia and hyperglycaemia/type 2 diabetes, based on ICD-9-CM and use of medications. Multivariable logistic regressions were used to estimate ORs and 95% CIs. RESULTS: MetS was associated with increased risk of early-onset CRC (n=4673; multivariable adjusted OR 1.25; 95% CI 1.09 to 1.43), similar to CRC diagnosed at age 50-64 (n=14 928; OR 1.21; 95% CI 1.15 to 1.27). Compared with individuals without a metabolic comorbid condition, those with 1, 2 or ≥3 conditions had a 9% (1.09; 95% CI 1.00 to 1.17), 12% (1.12; 95% CI 1.01 to 1.24) and 31% (1.31; 95% CI 1.13 to 1.51) higher risk of early-onset CRC (ptrend <0.001). No associations were observed for one or two metabolic comorbid conditions and CRC diagnosed at age 50-64. These positive associations were driven by proximal (OR per condition 1.14; 95% CI 1.06 to 1.23) and distal colon cancer (OR 1.09; 95% CI 1.00 to 1.18), but not rectal cancer (OR 1.03; 95% CI 0.97 to 1.09). CONCLUSIONS: Metabolic dysregulation was associated with increased risk of early-onset CRC, driven by proximal and distal colon cancer, thus at least in part contribute to the rising incidence of early-onset CRC.

Glucosamine and Chondroitin Supplements and Risk of Colorectal Adenoma and Serrated Polyp.

BACKGROUND: Studies have shown an inverse association between use of glucosamine and chondroitin supplements and colorectal cancer risk. However, the association with the precursor lesion, colorectal adenoma and serrated polyp, has not been examined. METHODS: Analyses include 43,163 persons from the Nurses' Health Study (NHS), Health Professionals Follow-up Study (HPFS), and NHS2 who reported on glucosamine/chondroitin use in 2002 and who subsequently underwent ≥1 lower gastrointestinal endoscopy. By 2012, 5,715 conventional (2,016 high-risk) adenomas were detected, as were 4,954 serrated polyps. Multivariable logistic regression for clustered data was used to calculate OR and 95% confidence intervals (CI). RESULTS: Glucosamine/chondroitin use was inversely associated with high risk and any conventional adenoma in NHS and HPFS: in the pooled multivariable-adjusted model, glucosamine + chondroitin use at baseline was associated with a 26% (OR = 0.74; 95% CI, 0.60-0.90; P heterogeneity = 0.23) and a 10% (OR = 0.90; 95% CI, 0.81-0.99; P heterogeneity = 0.36) lower risk of high-risk adenoma and overall conventional adenoma, respectively. However, no association was observed in NHS2, a study of younger women (high-risk adenoma: OR = 1.09; 95% CI, 0.82-1.45; overall conventional adenoma: OR = 1.00; 95% CI, 0.86-1.17), and effect estimates pooled across all three studies were not significant (high-risk: OR = 0.83; 95% CI, 0.63-1.10; P heterogeneity = 0.03; overall conventional adenoma: OR = 0.93; 95% CI, 0.85-1.02; P heterogeneity = 0.31). No associations were observed for serrated polyps. CONCLUSIONS: Glucosamine/chondroitin use was associated with lower risks of high-risk and overall conventional adenoma in older adults; however, this association did not hold in younger women, or for serrated polyps. IMPACT: Our study suggests that glucosamine and chondroitin may act on early colorectal carcinogenesis in older adults.

Association of Hot Tea Consumption with Regional Adiposity Measured by Dual-Energy X-Ray Absorptiometry in NHANES 2003-2006.

OBJECTIVE: This study aimed to investigate the potential antiobesity benefits of hot tea consumption at the population level. METHODS: Using data from the National Health and Nutrition Examination Survey (NHANES) 2003-2006, the association between hot tea consumption and dual-energy x-ray-measured body fat was examined in a large representative sample of US adults (n = 5,681, 51.9% women). RESULTS: Compared with non-tea drinkers, men who consumed 0.25 to 1 cup per day of hot tea had 1.5% (95% CI: 0.4% to 2.6%) and 1.7% (95% CI: 0.4% to 3.0%) less total and trunk body fat, respectively. The associations were stronger among men 45 to 69 years old compared with younger men (20-44 years). For men who consumed 1 or more cups per day of hot tea, lower total (-1.2%, 95% CI: -2.3% to -0.2%) and trunk body fat (-1.3%, 95% CI: -2.6 to -0.1%) was observed among men 45 to 69 years old only. In women, those who drank 1 or more cups per day had 1.5% lower (95% CI: -2.7% to -0.3%) trunk body fat compared with non-tea drinkers. CONCLUSIONS: Consumption of hot tea might be considered as part of a healthy diet in order to support parameters associated with metabolic health and may be particularly important in older male age groups in supporting reduced central adiposity.

Milk intake and mammographic density in premenopausal women.

PURPOSE: Mammographic density is a strong risk factor for breast cancer. Although diet is associated with breast cancer risk, there are limited studies linking adult diet, including milk intake, with mammographic density. Here, we investigate the association of milk intake with mammographic density in premenopausal women. METHODS: We analyzed data from 375 cancer-free premenopausal women who had routine screening mammography at Washington University School of Medicine, St. Louis, Missouri in 2016. We used Volpara to measure volumetric percent density, dense volume, and non-dense volume. We collected information on recent milk intake (past 12 months), and categorized skim milk and low/reduced-fat milk intake into 4 groups: < 1/week, 1/week, 2-6 times/week, ≥ 1/day, while whole and soy milk intake were categorized into 2 groups: < 1/week, ≥ 1/week. We used multivariable linear regression model to evaluate the associations of milk intake and log-transformed volumetric percent density, dense volume, and non-dense volume. RESULTS: In multivariable analyses, volumetric percent density was 20% (p-value = 0.003) lower in the 1/week group, 14% (p-value = 0.047) lower in the 2-6/week group, and 12% (p-value = 0.144) lower in the ≥ 1/day group (p-trend = 0.011) compared with women who consumed low/reduced-fat milk < 1/week. Attenuated and non-significant associations were observed for low/reduced-fat milk intake and dense volume. There were no associations of whole, skim, and soy milk intake with volumetric percent density and dense volume. CONCLUSIONS: Recent low/reduced-fat milk intake was inversely associated with volumetric percent density in premenopausal women. Studies on childhood and adolescent milk intake and adult mammographic density in premenopausal women are needed.

Circulating Receptor Activator of Nuclear Factor-κB (RANK), RANK ligand (RANKL), and Mammographic Density in Premenopausal Women.

The receptor activator of nuclear factor-κB (RANK) pathway plays essential roles in breast development. Mammographic density is a strong risk factor for breast cancer, especially in premenopausal women. We, therefore, investigated the associations of circulating RANK and soluble RANK ligand (sRANKL) with mammographic density in premenopausal women. Mammographic density was measured as volumetric percent density in 365 cancer-free premenopausal women (mean age, 47.5 years) attending screening mammogram at the Washington University School of Medicine (St. Louis, MO). We used linear regression models adjusted for confounders, to compare the least-square means of volumetric percent density across tertiles of circulating RANK and sRANKL. Furthermore, because RANKL levels in mammary tissue are modulated by progesterone, we stratified analyses by progesterone levels. The mean volumetric percent density increased across tertiles of circulating RANK from 8.6% in tertile 1, to 8.8% in tertile 2, and 9.5% in tertile 3 (P trend = 0.02). For sRANKL, the mean volumetric percent density was 8.5% in tertile 1, 9.4% in tertile 2, and 9.0% in tertile 3 (P trend = 0.30). However, when restricted to women with higher progesterone levels, the mean volumetric percent density increased from 9.1% in sRANKL tertile 1 to 9.5% in tertile 2, and 10.1% in tertile 3 (P trend = 0.01). Circulating RANK was positively associated with volumetric percent density, while circulating sRANKL was positively associated with volumetric percent density among women with higher progesterone levels. These findings support the inhibition of RANKL signaling as a pathway to reduce mammographic density and possibly breast cancer incidence in high-risk women with dense breasts.

Sedentary Behaviors, TV Viewing Time, and Risk of Young-Onset Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) diagnosed before age 50 years, or young-onset CRC, is increasing globally with undefined etiology. A sedentary lifestyle is an emerging risk factor for CRC after age 50 years, but its role in young-onset CRC is unknown. METHODS: We prospectively evaluated sedentary behaviors, primarily time watching television (TV), and risk of young-onset CRC among 89 278 women in the Nurses' Health Study II ages 25-42 years at recruitment (1991-2011). We used Cox proportional hazards modelling to estimate relative risks (RR) and 95% confidence intervals (CIs). Statistical tests were two-sided. RESULTS: We documented 118 young-onset CRCs over 1 262 540 person-years. Sedentary TV viewing time was statistically significantly associated with increased risk of young-onset CRC, after adjusting for putative risk factors, including obesity and physical activity. Compared 7 hours, women with 7.1-14 hours per week of TV time had a multivariable relative risk (RR) of 1.12 (95% confidence interval [CI] = 0.72 to 1.75), further increased for greater than14 hours per week (RR = 1.69, 95% CI = 1.07 to 2.67, P trend = .03). This association was observed among participants without a CRC family history and was more pronounced for rectal cancer (RR for >14 vs <7 hours per week 2.44, 95% CI = 1.03 to 5.78, P trend = .04). Overweight or obese participants may be more susceptible. CONCLUSION: Independent of exercise and obesity, prolonged sedentary TV viewing time, a surrogate for a more inactive lifestyle, was associated with increased risk of young-onset CRC, particularly of the rectum. These findings provide further evidence on the importance of maintaining an active lifestyle.