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ObjectiveA history of periodontal disease and the presence of circulating antibodies to selected oral pathogens have been associated with increased risk of pancreatic cancer; however, direct relationships of oral microbes with pancreatic cancer have not been evaluated in prospective studies. We examine the relationship of oral microbiota with subsequent risk of pancreatic cancer in a large nested case–control study.DesignWe selected 361 incident adenocarcinoma of pancreas and 371 matched controls from two prospective cohort studies, the American Cancer Society Cancer Prevention Study II and the National Cancer Institute Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. From pre-diagnostic oral wash samples, we characterised the composition of the oral microbiota using bacterial 16S ribosomal RNA (16S rRNA) gene sequencing. The associations between oral microbiota and risk of pancreatic cancer, controlling for the random effect of cohorts and other covariates, were examined using traditional and L1-penalised least absolute shrinkage and selection operator logistic regression.ResultsCarriage of oral pathogens, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, were associated with higher risk of pancreatic cancer (adjusted OR for presence vs absence=1.60 and 95% CI 1.15 to 2.22; OR=2.20 and 95% CI 1.16 to 4.18, respectively). Phylum Fusobacteria and its genus Leptotrichia were associated with decreased pancreatic cancer risk (OR per per cent increase of relative abundance=0.94 and 95% CI 0.89 to 0.99; OR=0.87 and 95% CI 0.79 to 0.95, respectively). Risks related to these phylotypes remained after exclusion of cases that developed within 2 years of sample collection, reducing the likelihood of reverse causation in this prospective study.ConclusionsThis study provides supportive evidence that oral microbiota may play a role in the aetiology of pancreatic cancer.

The prevalence of excess body weight and the associated cancer burden have been rising over the past several decades globally. Between 1975 and 2016, the prevalence of excess body weight in adults-defined as a body mass index (BMI) ≥ 25 kg/m2-increased from nearly 21% in men and 24% in women to approximately 40% in both sexes. Notably, the prevalence of obesity (BMI ≥ 30 kg/m2) quadrupled in men, from 3% to 12%, and more than doubled in women, from 7% to 16%. This change, combined with population growth, resulted in a more than 6‐fold increase in the number of obese adults, from 100 to 671 million. The largest absolute increase in obesity occurred among men and boys in high‐income Western countries and among women and girls in Central Asia, the Middle East, and North Africa. The simultaneous rise in excess body weight in almost all countries is thought to be driven largely by changes in the global food system, which promotes energy‐dense, nutrient‐poor foods, alongside reduced opportunities for physical activity. In 2012, excess body weight accounted for approximately 3.9% of all cancers (544,300 cases) with proportion varying from less than 1% in low‐income countries to 7% or 8% in some high‐income Western countries and in Middle Eastern and Northern African countries. The attributable burden by sex was higher for women (368,500 cases) than for men (175,800 cases). Given the pandemic proportion of excess body weight in high‐income countries and the increasing prevalence in low‐ and middle‐income countries, the global cancer burden attributable to this condition is likely to increase in the future. There is emerging consensus on opportunities for obesity control through the multisectoral coordinated implementation of core policy actions to promote an environment conducive to a healthy diet and active living. The rapid increase in both the prevalence of excess body weight and the associated cancer burden highlights the need for a rejuvenated focus on identifying, implementing, and evaluating interventions to prevent and control excess body weight.

Oral microbiome dysbiosis is associated with oral disease and potentially with systemic diseases; however, the determinants of these microbial imbalances are largely unknown. In a study of 1204 US adults, we assessed the relationship of cigarette smoking with the oral microbiome. 16S rRNA gene sequencing was performed on DNA from oral wash samples, sequences were clustered into operational taxonomic units (OTUs) using QIIME and metagenomic content was inferred using PICRUSt. Overall oral microbiome composition differed between current and non-current (former and never) smokers ( P <0.001). Current smokers had lower relative abundance of the phylum Proteobacteria (4.6%) compared with never smokers (11.7%) (false discovery rate q =5.2 × 10 −7 ), with no difference between former and never smokers; the depletion of Proteobacteria in current smokers was also observed at class, genus and OTU levels. Taxa not belonging to Proteobacteria were also associated with smoking: the genera Capnocytophaga , Peptostreptococcus and Leptotrichia were depleted, while Atopobium and Streptococcus were enriched, in current compared with never smokers. Functional analysis from inferred metagenomes showed that bacterial genera depleted by smoking were related to carbohydrate and energy metabolism, and to xenobiotic metabolism. Our findings demonstrate that smoking alters the oral microbiome, potentially leading to shifts in functional pathways with implications for smoking-related diseases.

Diabetes is a major predictor of death from heart disease and stroke; its impact on nonvascular mortality, including specific cancers, is less understood. We examined the association of diabetes with cause-specific mortality, including deaths from specific cancers. A prospective cohort of 1,053,831 U.S. adults, without cancer at baseline, enrolled in the Cancer Prevention Study-II in 1982 and was followed for mortality until December 2008. At baseline, participants completed a self-administered questionnaire that included information on diabetes, smoking, physical activity, height, and weight. Multivariable-adjusted relative risks (RRs) (95% CI) were estimated using Cox proportional hazards regression. During 26 years of follow-up, 243,051 men and 222,109 women died. In multivariable models that controlled for age, BMI, and other variables, diabetes was associated with higher risk of all-cause mortality (women RR 1.90 [95% CI 1.87-1.93]; men 1.73 [1.70-1.75]). Among women, diabetes was associated with higher risk of death from cancers of the liver (1.40 [1.05-1.86]), pancreas (1.31 [1.14-1.51]), endometrium (1.33 [1.08-1.65]), colon (1.18 [1.04-1.33]), and breast (1.16 [1.03-1.29]). Among men, diabetes was associated with risk of death from cancers of the breast (4.20 [2.20-8.04]), liver (2.26 [1.89-2.70]), oral cavity and pharynx (1.44 [1.07-1.94]), pancreas (1.40 [1.23-1.59]), bladder (1.22 [1.01-1.47]), colon (1.15 [1.03-1.29]), and (inversely) prostate (0.88 [0.79-0.97]). Diabetes was also associated with higher risks of death involving the circulatory system, respiratory system, digestive system, genitourinary system, and external causes/accidental deaths. Diabetes is associated with higher risk of death for many diseases, including several specific forms of cancer.

Background Breast cancer incidence rates have not declined despite an improvement in risk prediction and the identification of modifiable risk factors, suggesting the need to identify novel risk factors and etiological pathways involved in this cancer. Metabolomics has emerged as a promising tool to find circulating metabolites associated with breast cancer risk. Methods Untargeted metabolomic analysis was done on prediagnostic plasma samples from a case–cohort study of 1695 incident breast cancer cases and a 1983 women subcohort drawn from Cancer Prevention Study 3. The associations of 868 named metabolites (per one standard deviation increase) with breast cancer were determined using Prentice-weighted Cox proportional hazards regression modeling. Results A total of 11 metabolites were associated with breast cancer at false discovery rate (FDR) < 0.05 with the majority having inverse association [ranging from RR = 0.85 (95% CI 0.80–0.92) to RR = 0.88 (95% CI 0.82–0.94)] and one having a positive association [RR = 1.14 (95% CI 1.06–1.23)]. An additional 50 metabolites were associated at FDR < 0.20 with inverse associations ranging from RR = 0.88 (95% CI 0.81–0.94) to RR = 0.91 (95% CI 0.85–0.98) and positive associations ranging from RR = 1.13 (95% CI 1.05–1.22) to RR = 1.11 (95% CI 1.02–1.20). Several of these associations validated the findings of previous metabolomic studies. These included findings that several progestogen and androgen steroids were associated with increased risk of breast cancer in postmenopausal women and four phospholipids, and the amino acids glutamine and asparagine were associated with decreased risk of this cancer in pre- and postmenopausal women. Several novel associations were also identified, including a positive association for syringol sulfate, a biomarker for smoked meat, and 3-methylcatechol sulfate and 3-hydroxypyridine glucuronide, which are metabolites of xenobiotics used for the production of pesticides and other products. Conclusions Our study validated previous metabolite findings and identified novel metabolites associated with breast cancer risk, demonstrating the utility of large metabolomic studies to provide new leads for understanding breast cancer etiology. Our novel findings suggest that consumption of smoked meats and exposure to catechol and pyridine should be investigated as potential risk factors for breast cancer.

To assess the independent effect of waist circumference on mortality across the entire body mass index (BMI) range and to estimate the loss in life expectancy related to a higher waist circumference. We pooled data from 11 prospective cohort studies with 650,386 white adults aged 20 to 83 years and enrolled from January 1, 1986, through December 31, 2000. We used proportional hazards regression to estimate hazard ratios (HRs) and 95% CIs for the association of waist circumference with mortality. During a median follow-up of 9 years (maximum, 21 years), 78,268 participants died. After accounting for age, study, BMI, smoking status, alcohol consumption, and physical activity, a strong positive linear association of waist circumference with all-cause mortality was observed for men (HR, 1.52 for waist circumferences of ≥110 vs <90 cm; 95% CI, 1.45-1.59; HR, 1.07 per 5-cm increment in waist circumference; 95% CI, 1.06-1.08) and women (HR, 1.80 for waist circumferences of ≥95 vs <70 cm; 95% CI, 1.70-1.89; HR, 1.09 per 5-cm increment in waist circumference; 95% CI, 1.08-1.09). The estimated decrease in life expectancy for highest vs lowest waist circumference was approximately 3 years for men and approximately 5 years for women. The HR per 5-cm increment in waist circumference was similar for both sexes at all BMI levels from 20 to 50 kg/m2, but it was higher at younger ages, higher for longer follow-up, and lower among male current smokers. The associations were stronger for heart and respiratory disease mortality than for cancer. In white adults, higher waist circumference was positively associated with higher mortality at all levels of BMI from 20 to 50 kg/m2. Waist circumference should be assessed in combination with BMI, even for those in the normal BMI range, as part of risk assessment for obesity-related premature mortality.

Background Dysbiosis of the oral microbiome can lead to local oral disease and potentially to cancers of the head, neck, and digestive tract. However, little is known regarding exogenous factors contributing to such microbial imbalance. Results We examined the impact of alcohol consumption on the oral microbiome in a cross-sectional study of 1044 US adults. Bacterial 16S rRNA genes from oral wash samples were amplified, sequenced, and assigned to bacterial taxa. We tested the association of alcohol drinking level (non-drinker, moderate drinker, or heavy drinker) and type (liquor, beer, or wine) with overall microbial composition and individual taxon abundance. The diversity of oral microbiota and overall bacterial profiles differed between heavy drinkers and non-drinkers (α-diversity richness p  = 0.0059 and β-diversity unweighted UniFrac p  = 0.0036), and abundance of commensal order Lactobacillales tends to be decreased with higher alcohol consumption (fold changes = 0.89 and 0.94 for heavy and moderate drinkers, p trend = 0.005 [ q  = 0.064]). Additionally, certain genera were enriched in subjects with higher alcohol consumption, including Actinomyces , Leptotrichia , Cardiobacterium , and Neisseria ; some of these genera contain oral pathogens, while Neisseria can synthesize the human carcinogen acetaldehyde from ethanol. Wine drinkers may differ from non-drinkers in microbial diversity and profiles (α-diversity richness p  = 0.048 and β-diversity unweighted UniFrac p  = 0.059) after controlling for drinking amount, while liquor and beer drinkers did not. All significant differences between drinkers and non-drinkers remained after exclusion of current smokers. Conclusions Our results, from a large human study of alcohol consumption and the oral microbiome, indicate that alcohol consumption, and heavy drinking in particular, may influence the oral microbiome composition. These findings may have implications for better understanding the potential role that oral bacteria play in alcohol-related diseases.

We developed an absolute risk model to identify individuals in the general population at elevated risk of pancreatic cancer. Using data on 3,349 cases and 3,654 controls from the PanScan Consortium, we developed a relative risk model for men and women of European ancestry based on non-genetic and genetic risk factors for pancreatic cancer. We estimated absolute risks based on these relative risks and population incidence rates. Our risk model included current smoking (multivariable adjusted odds ratio (OR) and 95% confidence interval: 2.20 [1.84-2.62]), heavy alcohol use (>3 drinks/day) (OR: 1.45 [1.19-1.76]), obesity (body mass index >30 kg/m(2)) (OR: 1.26 [1.09-1.45]), diabetes >3 years (nested case-control OR: 1.57 [1.13-2.18], case-control OR: 1.80 [1.40-2.32]), family history of pancreatic cancer (OR: 1.60 [1.20-2.12]), non-O ABO genotype (AO vs. OO genotype) (OR: 1.23 [1.10-1.37]) to (BB vs. OO genotype) (OR 1.58 [0.97-2.59]), rs3790844(chr1q32.1) (OR: 1.29 [1.19-1.40]), rs401681(5p15.33) (OR: 1.18 [1.10-1.26]) and rs9543325(13q22.1) (OR: 1.27 [1.18-1.36]). The areas under the ROC curve for risk models including only non-genetic factors, only genetic factors, and both non-genetic and genetic factors were 58%, 57% and 61%, respectively. We estimate that fewer than 3/1,000 U.S. non-Hispanic whites have more than a 5% predicted lifetime absolute risk. Although absolute risk modeling using established risk factors may help to identify a group of individuals at higher than average risk of pancreatic cancer, the immediate clinical utility of our model is limited. However, a risk model can increase awareness of the various risk factors for pancreatic cancer, including modifiable behaviors.

The authors of this Review discuss the mechanism of action of aspirin, current evidence concerning the main health outcomes affected by aspirin use, and the hypothesis that inhibition of platelet activation may mediate both the cardioprotective and cancer-preventive effects of low-dose aspirin. Clinical guidelines for prophylactic aspirin use currently only consider the cardiovascular benefits of aspirin, weighed against the potential harm from aspirin-induced bleeding. Daily aspirin use has been convincingly shown to reduce the risk of colorectal cancer and recurrence of adenomatous polyps, but in average-risk populations, these benefits alone do not outweigh harms from aspirin-induced bleeding. Recently published secondary analyses of cardiovascular trials provide the first randomized evidence that daily aspirin use may also reduce the incidence of all cancers combined, even at low doses (75–100 mg daily). This Review considers the general mechanism of action that defines aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) as a class, the specific advantages of aspirin over other NSAIDs for prophylactic use, the current evidence concerning the main health outcomes affected by aspirin use, and the hypothesis that inhibition of platelet activation may mediate both the cardioprotective and cancer-preventive effects of low-dose aspirin. It also considers how even a 10% reduction in overall cancer incidence beginning during the first 10 years of treatment could tip the balance of benefits and risks favourably in average-risk populations. Key Points Clinical guidelines for prophylactic aspirin use currently only consider the cardiovascular benefits of aspirin, weighed against the potential harm from aspirin-induced bleeding Daily aspirin use has been convincingly shown to reduce the risk of colorectal cancer but in average-risk populations this benefit alone does not outweigh harm from aspirin-induced bleeding Secondary analyses of cardiovascular trials showed that daily low-dose aspirin use may also reduce the incidence of all cancers combined, although uncertainty remains about the magnitude of the potential benefit. Even a 10% reduction in overall cancer incidence could substantially broaden the indications for prophylactic daily treatment with low-dose aspirin As daily treatment with low-dose aspirin was as effective as treatment with higher doses, inhibition of platelet activation may mediate both the cardioprotective and cancer preventive effects of low-dose aspirin