Albuminuria-Related Genetic Biomarkers: Replication and Predictive Evaluation in Individuals with and without Diabetes from the UK Biobank.

Increased albuminuria indicates underlying glomerular pathology and is associated with worse renal disease outcomes, especially in diabetic kidney disease. Many single nucleotide polymorphisms (SNPs), associated with albuminuria, could be potentially useful to construct polygenic risk scores (PRSs) for kidney disease. We investigated the diagnostic accuracy of SNPs, previously associated with albuminuria-related traits, on albuminuria and renal injury in the UK Biobank population, with a particular interest in diabetes. Multivariable logistic regression was used to evaluate the influence of 91 SNPs on urine albumin-to-creatinine ratio (UACR)-related traits and kidney damage (any pathology indicating renal injury), stratifying by diabetes. Weighted PRSs for microalbuminuria and UACR from previous studies were used to calculate the area under the receiver operating characteristic curve (AUROC). CUBN-rs1801239 and DDR1-rs116772905 were associated with all the UACR-derived phenotypes, in both the overall and non-diabetic cohorts, but not with kidney damage. Several SNPs demonstrated different effects in individuals with diabetes compared to those without. SNPs did not improve the AUROC over currently used clinical variables. Many SNPs are associated with UACR or renal injury, suggesting a role in kidney dysfunction, dependent on the presence of diabetes in some cases. However, individual SNPs or PRSs did not improve the diagnostic accuracy for albuminuria or renal injury compared to standard clinical variables.

Identifying individuals at risk of esophageal adenocarcinoma: challenges, existing tools and future steps.

PURPOSE OF REVIEW: This review aims to discuss some of the clinical and epidemiological challenges of risk prediction models; summarize the evidence supporting existing models; and highlight the translational requirements. RECENT FINDINGS: A variety of risk prediction models exist to identify prevalent Barrett's esophagus or predict future esophageal adenocarcinoma. External validation studies have investigated performance of these models in a variety of settings. These models appear to be more predictive than use of symptoms alone, but the added complexity means that implementation challenges may require investigation. SUMMARY: Risk prediction models could be useful for identifying individuals at an increased risk of esophageal adenocarcinoma, which could assist screening decisions. However, risk prediction models must be implemented with care. Implementation science to assist the translation of existing models into practice may be an important next step.

Clinical Prediction Models for Pancreatic Cancer in General and At-Risk Populations: A Systematic Review.

INTRODUCTION: Identifying high-risk individuals using a risk prediction model could be a crucial first stage of screening pathways to improve the early detection of pancreatic cancer. A systematic review was conducted to critically evaluate the published primary literature on the development or validation of clinical risk prediction models for pancreatic cancer risk. METHODS: MEDLINE, Embase, and Web of Science were searched for relevant articles from the inception of each database up to November 2021. Study selection and data extraction were conducted by 2 independent reviewers. The Prediction model Risk Of Bias Assessment Tool (PROBAST) was applied to assess risk of bias. RESULTS: In total, 33 studies were included, describing 38 risk prediction models. Excluding studies with an overlapping population, this study consist of 15,848,100 participants, of which 58,313 were diagnosed with pancreatic cancer. Eight studies externally validated their model, and 13 performed internal validation. The studies described risk prediction models for pancreatic cancer in the general population (n = 14), patients with diabetes (n = 8), and individuals with gastrointestinal (and other) symptoms (symptoms included abdominal pain, unexplained weight loss, jaundice, and change in bowel habits and indigestion; n = 11). The commonly used clinical risk factors in the model were cigarette smoking (n = 27), age (n = 25), diabetes history (n = 22), chronic pancreatitis (n = 18), and body mass index (n = 14). In the 25 studies that assessed model performance, C-statistics ranged from 0.61 to 0.98. Of the 33 studies included, 6 were rated as being at a low risk of bias based on PROBAST. DISCUSSION: Many clinical risk prediction models for pancreatic cancer had been developed for different target populations. Although low risk-of-bias studies were identified, these require external validation and implementation studies to ensure that these will benefit clinical decision making.

The current and future incidence and mortality of gastric cancer in 185 countries, 2020-40: A population-based modelling study.

Background: To examine global patterns of gastric cancer in 2020 and the projected burden in 2040. Methods: Data on primary gastric cancer were extracted from the GLOBOCAN database for the year 2020. Age-standardized incidence and mortality rates were calculated by sex, country, world region and level of human development index (HDI) for 185 countries. The predicted burden of incidence and mortality in 2040 was calculated based on demographic projections. Findings: In total, ∼1.1 million new cases and 770,000 deaths of gastric cancer were estimated in 2020. Incidence rates were on average 2-fold higher in males than females (15.8 and 7.0 per 100,000, respectively) with variation across countries. Highest incidence rates were observed in Eastern Asia for both males and females (32.5 and 13.2, respectively); males residing in Japan (48.1), Mongolia (47.2) and Korea (39.7) had the highest rates in the world. Incidence was lowest in Africa with incidence rates < 5 per 100,000. Highest mortality rates were observed in Eastern Asia for both males (21.1) and females (8.8). A lower share of deaths was observed in very high HDI countries compared to medium and low HDI countries. The annual burden of gastric cancer is predicted to increase to ∼1.8 million new cases and ∼1.3 million deaths by 2040. Interpretation: These estimates of the global burden of gastric cancer pinpoint countries and regions of high incidence and mortality in need of cancer control initiatives. Primary prevention through eradication of H. pylori and behavioural changes such as reducing salt intake, smoking, obesity, and alcohol, remains key in stomach cancer control. Funding: No direct funding was received. All authors had access to the included study data and all authors agreed with the final decision to submit for publication.

Weight Change and Incident Distal Colorectal Adenoma Risk in the PLCO Cancer Screening Trial.

Background: Although obesity is a known risk factor, the impact of weight change on colorectal adenoma risk is less clear and could have important implications in disease prevention. We prospectively evaluated weight change in adulthood and incident colorectal adenoma. Methods: We assessed weight change during early-late (age 20 years to baseline, ie, ages 55-74 years), early-middle (20-50 years), and middle-late (50 years-baseline) adulthood using self-reported weight data in relation to incident distal adenoma in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (cases = 1053; controls = 16 576). For each period, we defined stable weight as greater than -0.5 kg to less than or equal to 1 kg/5 years, weight loss as less than or equal to -0.5 kg/5 years, and weight gain as greater than 1-2, greater than 2-3, or greater than 3 kg/5 years. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression; all tests were 2-sided. Results: Compared with stable weight, weight loss during early-late adulthood was associated with reduced adenoma risk (OR = 0.54, 95% CI = 0.34 to 0.86), particularly among those who were overweight or obese at age 20 years (OR = 0.39, 95% CI = 0.18 to 0.84). Results were similar for early-middle adulthood but less pronounced for middle-late adulthood. Weight gain greater than 3 kg/5 years during early-late adulthood was associated with increased risk (OR = 1.30, 95% CI = 1.07 to 1.58, P trend < .001). Findings appeared stronger among men (OR for >3 kg/5 years = 1.41, 95% CI = 1.11 to 1.80) than women (OR = 1.09, 95% CI = 0.79 to 1.50, P interaction = .21). Conclusions: Weight loss in adulthood was associated with reduced adenoma risk, particularly for those who were overweight or obese, whereas weight gain greater than 3 kg/5 years increased risk. Findings underscore the importance of healthy weight maintenance throughout adulthood in preventing colorectal adenoma.

The Role of Circulating Protein and Metabolite Biomarkers in the Development of Pancreatic Ductal Adenocarcinoma (PDAC): A Systematic Review and Meta-analysis.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, and this is attributed to it being diagnosed at an advanced stage. Understanding the pathways involved in initial development may improve early detection strategies. This systematic review assessed the association between circulating protein and metabolite biomarkers and PDAC development. METHODS: A literature search until August 2020 in MEDLINE, EMBASE, and Web of Science was performed. Studies were included if they assessed circulating blood, urine, or salivary biomarkers and their association with PDAC risk. Quality was assessed using the Newcastle-Ottawa scale for cohort studies. Random-effects meta-analyses were used to calculate pooled relative risk. RESULTS: A total of 65 studies were included. Higher levels of glucose were found to be positively associated with risk of developing PDAC [n = 4 studies; pooled relative risk (RR): 1.61; 95% CI: 1.16-2.22]. Additionally, an inverse association was seen with pyridoxal 5'-phosphate (PLP) levels (n = 4 studies; RR: 0.62; 95% CI: 0.44-0.87). Meta-analyses showed no association between levels of C-peptide, members of the insulin growth factor signaling pathway, C-reactive protein, adiponectin, 25-hydroxyvitamin D, and folate/homocysteine and PDAC risk. Four individual studies also reported a suggestive positive association of branched-chain amino acids with PDAC risk, but due to differences in measures reported, a meta-analysis could not be performed. CONCLUSIONS: Our pooled analysis demonstrates that higher serum glucose levels and lower levels of PLP are associated with risk of PDAC. IMPACT: Glucose and PLP levels are associated with PDAC risk. More prospective studies are required to identify biomarkers for early detection.

Does Risk of Progression from Barrett's Esophagus to Esophageal Adenocarcinoma Change Based on the Number of Non-dysplastic Endoscopies?

BACKGROUND: There is a large Barrett's esophagus patient population undergoing endoscopic surveillance. Methods to stratify patients into higher and lower risk groups may enable more varied surveillance intervals for patients with non-dysplastic Barrett's esophagus that could optimize use of endoscopy resources. OBJECTIVE: We aimed to assess whether risk of progression to esophageal adenocarcinoma differed in patients with multiple endoscopic biopsies negative for dysplasia. METHODS: We conducted a retrospective cohort study among individuals from the population-based Northern Ireland Barrett's register with a histologically confirmed diagnosis of non-dysplastic Barrett's esophagus (with intestinal metaplasia) between 1993 and 2010, who had at least one endoscopic biopsy conducted at least 12 months after diagnosis. We used Poisson regression to estimate incidence rate ratios (IRR) and 95% confidence intervals (CI) for the association between number of successive endoscopies showing non-dysplastic Barrett's esophagus and risk of esophageal adenocarcinoma alone, and combined with high-grade dysplasia, at the next endoscopy. RESULTS: We identified 1761 individuals who met our eligibility criteria. Subsequent risk of progression to esophageal adenocarcinoma was lower at the next endoscopy following two endoscopies showing non-dysplastic Barrett's esophagus (IRR 0.26, 95% CI 0.10-0.66) than following one endoscopy showing non-dysplastic Barrett's esophagus. Similar findings were apparent for risk of progression to esophageal adenocarcinoma or high-grade dysplasia (IRR 0.41, 95% CI 0.22-0.79). CONCLUSION: The lower risk of malignant progression in individuals with persistent non-dysplastic Barrett's esophagus over two consecutive endoscopic biopsies but not for longer term persistence does not support hypotheses of persistence being an indicator of less biologically aggressive lesions. Instead, the initial difference may be attributable to post-endoscopy cancers and support the necessity of adhering to robust quality standards for endoscopic procedures.

Circulating Sex Hormones Are Associated With Gastric and Colorectal Cancers but Not Esophageal Adenocarcinoma in the UK Biobank.

INTRODUCTION: Gastrointestinal cancers show an unexplained male predominance, but few prospective studies have investigated sex hormones and gastrointestinal cancer risk. This study aimed to determine the impact of circulating sex hormones on risk of esophageal, gastric, and colorectal cancers in men and women. METHODS: We included 219,425 men and 147,180 women from the UK Biobank. Sex hormones were quantified using chemiluminescent immunoassay. Gastrointestinal cancers were identified from cancer registry linkages. Sex hormone concentrations and risk of gastrointestinal cancers were investigated using Cox proportional hazards regression. RESULTS: During the 10 years of follow-up, 376 esophageal adenocarcinoma, 108 esophageal squamous cell carcinoma, and 333 gastric and 2,868 colorectal cancer cases were identified. Increased hazard ratios (HRs) were found for sex hormone-binding globulin (SHBG) and risk of gastric cancer in men (Q4 vs Q1 HR 1.43, 95% confidence interval [CI] 0.95-2.17, Ptrend = 0.01). Free testosterone was inversely associated with esophageal squamous cell carcinoma in women (Q4 vs Q1 HR 0.32, 95% CI 0.11-0.98, Ptrend = 0.05). For colorectal cancer, SHBG was associated with a reduced risk among men (Q4 vs Q1 HR 0.89, 95% CI 0.77-1.03, Ptrend = 0.04) and free testosterone concentrations was associated with a reduction in risk among women (Q4 vs Q1 HR 0.80, 95% CI 0.66-0.97, Ptrend = 0.01). No associations were found for esophageal adenocarcinoma. DISCUSSION: In this large prospective investigation of prediagnostic sex hormones and risk of gastrointestinal cancers, men with higher SHBG concentrations had higher gastric, yet lower colorectal, cancer risks, whereas women with higher free testosterone levels had a lower risk of esophageal squamous cell carcinoma and colorectal cancer.

The effectiveness and complexity of interventions targeting sedentary behaviour across the lifespan: a systematic review and meta-analysis.

BACKGROUND: Evidence suggests that sedentary behaviour (SB) is associated with poor health outcomes. SB at any age may have significant consequences for health and well-being and interventions targeting SB are accumulating. Therefore, the need to review the effects of multicomponent, complex interventions that incorporate effective strategies to reduce SB are essential. METHODS: A systematic review and meta-analysis were conducted investigating the impact of interventions targeting SB across the lifespan. Six databases were searched and two review authors independently screened studies for eligibility, completed data extraction and assessed the risk of bias and complexity of each of the included studies. RESULTS: A total of 77 adult studies (n=62, RCTs) and 84 studies (n=62, RCTs) in children were included. The findings demonstrated that interventions in adults when compared to active controls resulted in non-significant reductions in SB, although when compared to inactive controls significant reductions were found in both the short (MD -56.86; 95%CI -74.10, -39.63; n=4632; I2 83%) and medium-to-long term (MD -20.14; 95%CI -34.13, -6.16; n=4537; I2 65%). The findings demonstrated that interventions in children when compared to active controls may lead to relevant reductions in daily sedentary time in the short-term (MD -59.90; 95%CI -102.16, -17.65; n=267; I2 86%), while interventions in children when compared to inactive controls may lead to relevant reductions in the short-term (MD -25.86; 95%CI -40.77, -10.96; n=9480; I2 98%) and medium-to-long term (MD -14.02; 95%CI -19.49, -8.55; n=41,138; I2 98%). The assessment of complexity suggested that interventions may need to be suitably complex to address the challenges of a complex behaviour such as SB, but demonstrated that a higher complexity score is not necessarily associated with better outcomes in terms of sustained long-term changes. CONCLUSIONS: Interventions targeting reductions in SB have been shown to be successful, especially environmental interventions in both children and adults. More needs to be known about how best to optimise intervention effects. Future intervention studies should apply more rigorous methods to improve research quality, considering larger sample sizes, randomised controlled designs and valid and reliable measures of SB.

The association between erosive toothwear and gastro-oesophageal reflux-related symptoms and disease: A systematic review and meta-analysis.

OBJECTIVES: To conduct a systematic review and meta-analysis to explore the association between erosive toothwear and gastro-oesophageal reflux disease or symptoms (GERD/S). SOURCES: Electronic searches were performed in Scopus, Embase, and Web of Science databases for the identification of relevant studies, from 1980 until 2nd August 2019. STUDY SELECTION: The review protocol was registered on PROSPERO (CRD42018096959) and the review was conducted according to PRISMA guidelines. Observational studies which examined the association between erosive toothwear, and GERD/S were included and categorised according to the use of objective or subjective measures of GERD/S. Where possible, odds ratios (OR) and 95 % confidence intervals (CI) were derived and pooled in a meta-analysis. DATA: 27 studies were considered relevant for the qualitative synthesis and 19 studies were pooled. Significantly increased odds of erosive toothwear were observed in individuals with GERD/S. This trend was more strongly associated with objectively measured GERD/S (OR 4.13, 95 % CI 1.68-10.13), compared to subjectively measured GERD/S (OR 2.69, 95 % CI 1.13-6.38). Whilst heterogeneity was very high these trends remained in most sensitivity and subgroup analyses conducted. CONCLUSION: Individuals with GERD/S have a 2-4 fold increased odds ratio of also presenting with evidence of erosive toothwear compared with individuals who do not have GERD/S. CLINICAL SIGNIFICANCE: This review suggests the need for a multidisciplinary medical and dental approach to managing individuals who present with erosive toothwear or GERD/S. Timely referrals between oral health services and gastroenterology should be considered as part of effective diagnosis and management.

Fusobacterium nucleatum in the Colorectum and Its Association with Cancer Risk and Survival: A Systematic Review and Meta-analysis.

BACKGROUND: The gut microbiome, in particular Fusobacterium nucleatum, has been reported to play a role in colorectal cancer development and in patient prognosis. We aimed to perform a systematic review and meta-analysis of published studies to assess the prevalence of F. nucleatum in colorectal tumors and evaluate the association between F. nucleatum and colorectal cancer development and prognosis. METHODS: MEDLINE, EMBASE, and Web of Science databases were systematically searched for studies published until January 2019. Random effects meta-analyses were used to assess the prevalence of F. nucleatum in patients with colorectal cancer or tissues relative to controls and survival in F. nucleatum-positive versus -negative patients. RESULTS: Forty-five relevant articles were identified. Meta-analyses indicated higher odds of F. nucleatum being present in colorectal tissue samples from patients with colorectal cancer [n = 6 studies, pooled OR = 10.06; 95% confidence intervals (CI), 4.48-22.58] and individuals with colorectal polyps (n = 5 studies, pooled OR = 1.83; 95% CI, 1.07-3.16) compared with healthy controls. Similar results were apparent in fecal samples, and when comparing tumor with adjacent normal tissue. Meta-analyses indicated poorer survival in patients with colorectal cancer with high versus low F. nucleatum abundance (n = 5 studies, pooled HR = 1.87; 95% CI, 1.12-3.11). CONCLUSIONS: A consistent increase in the prevalence and/or abundance of F. nucleatum in colorectal cancer tissue and fecal samples compared with controls was apparent. High abundance of F. nucleatum in colorectal tumors was also associated with poorer overall survival. IMPACT: F. nucleatum could be useful as a diagnostic and prognostic marker for colorectal cancer or as a treatment target.

The association between self-reported poor oral health and gastrointestinal cancer risk in the UK Biobank: A large prospective cohort study.

Background: Controversy remains as to whether poor oral health is independently associated with gastrointestinal cancers, due to potential confounding by smoking, alcohol and poor nutrition. The aim of this study was to investigate the association between oral health conditions and gastrointestinal cancer risk. Methods: Data from the large, prospective UK Biobank cohort, which includes n = 475,766 participants, were analysed. Cox proportional hazard models were applied to estimate the relationship between gastrointestinal cancer risk and self-reported poor oral health (defined as painful gums, bleeding gums and/or having loose teeth), adjusting for confounders. Results: During an average six years of follow-up, n = 4069 gastrointestinal cancer cases were detected, of which 13% self-reported poor oral health. Overall, there was no association between self-reported poor oral health and risk of gastrointestinal cancer detected (hazard ratio 0.97, 95% confidence interval 0.88-1.07). In site-specific analysis, an increased risk of hepatobiliary cancers was observed in those with self-reported poor oral health (hazard ratio 1.32, 95% confidence interval 0.95-1.80), which was stronger for hepatocellular carcinoma (hazard ratio 1.75, 95% confidence interval 1.04-2.92). Conclusion: Overall there was no association between self-reported poor oral health and gastrointestinal cancer risk. However, there was a suggestion of an increased risk of hepatobiliary cancer, specifically hepatocellular carcinoma.

Fusobacterium nucleatum tumor DNA levels are associated with survival in colorectal cancer patients.

There is increasing evidence indicating a role for Fusobacterium nucleatum (F. nucleatum) in colorectal cancer (CRC) development and prognosis. This study evaluated F. nucleatum as a prognostic biomarker, by assessing its association with post-diagnosis survival from CRC. From September 2008 to April 2012 CRC patients (n = 190) were recruited from three hospitals within the Czech Republic. F. nucleatum DNA copies were measured in adjacent non-malignant and colorectal tumor tissues using quantitative real-time PCR. Cox Proportional Hazards (HR) models were applied to evaluate the association between F. nucleatum DNA and overall survival, adjusting for key confounders. Risk prediction modeling was conducted to evaluate the ability to predict survival based on F. nucleatum status. High, compared with low, levels of F. nucleatum in colorectal tumor tissues were associated with poorer overall survival (adjusted HR 1.68, 95% CI 1.02-2.77), which was slightly attenuated after additional adjustment for microsatellite instability status. However, inclusion of F. nucleatum in risk prediction models did not improve the ability to identify patients who died beyond known prognostic factors such as disease pathology staging. Although the increased presence of F. nucleatum was associated with poorer prognosis in CRC patients, this may have limited clinical relevance as a prognostic biomarker.

External validation of a model to determine risk of progression of Barrett's oesophagus to neoplasia.

BACKGROUND: A risk prediction model containing sex, smoking history, Barrett's oesophagus length and presence of low-grade dysplasia was found to identify individuals at a higher risk of progression to oesophageal adenocarcinoma or high-grade dysplasia. AIM: To externally validate the model predicting risk of progression from Barrett's oesophagus to neoplasia and assess the predictive utility of additional factors. METHODS: We conducted a retrospective cohort study among individuals from the population-based Northern Ireland Barrett's register with a histologically confirmed diagnosis of Barrett's oesophagus (with intestinal metaplasia) between 1993 and 2005. The association between a points based model and risk of progression to high-grade dysplasia or oesophageal adenocarcinoma until 2010 was assessed using Cox Proportional Hazards model. Model performance was assessed using area under the receiver operating characteristics curves (AUROC), sensitivity and specificity. RESULTS: We identified 1198 individuals with Barrett's oesophagus of whom 54 progressed. The model discriminated reasonably well between progressors and nonprogressors, with an AUROC of 0.70 (95% CI 0.63-0.78). When categorised into low, intermediate and high risk groups, the AUROC was 0.68 (95% CI 0.61-0.74). Compared to using data on dysplasia and segment length for risk stratification, the model resulted in a net reclassification improvement of 20.9%. CONCLUSIONS: This external validation provides further evidence that a model based on sex, smoking, Barrett's segment length and baseline low-grade dysplasia may help to risk stratify patients after an initial diagnosis of Barrett's oesophagus. The model also performed better than the use of low-grade dysplasia status alone for risk-stratification.

Information on Genetic Variants Does Not Increase Identification of Individuals at Risk of Esophageal Adenocarcinoma Compared to Clinical Risk Factors.

We previously developed a tool that identified individuals who later developed esophageal adenocarcinoma (based on age, sex, body mass index, smoking status, and prior esophageal conditions) with an area under the curve of 0.80. In this study, we collected data from 329,463 individuals in the UK Biobank cohort who were tested for genetic susceptibility to esophageal adenocarcinoma (a polygenic risk score based on 18 recognized genetic variants). We found that after inclusion of this genetic information, the area under the curve for identification of individuals who developed esophageal adenocarcinoma remained at 0.80. Testing for genetic variants associated with esophageal adenocarcinoma therefore seems unlikely to improve identification of individuals at risk of esophageal adenocarcinoma.

Physical activity, sedentary behaviour and risk of oesophago-gastric cancer: A prospective cohort study within UK Biobank.

BACKGROUND: Few observational studies have assessed the role of physical activity in oesophago-gastric cancer risk. OBJECTIVE: This prospective cohort study aimed to assess the association between physical activity and risk of oesophageal or gastric cancer. METHODS: A cohort of 359,033 adults aged 40-69 years were identified from the UK Biobank, which recruited participants between 2006 and 2010. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between self-reported levels of physical activity and screen-based sedentary behaviour and risk of oesophageal and gastric cancer were calculated using Cox proportional hazards models. RESULTS: During eight years of follow-up (mean = 5.5), 294 oesophageal cancer and 217 gastric cancer cases were identified. Physical activity and screen-based sedentary behaviour levels were not associated with overall oesophago-gastric cancer risk. However, when compared with low levels, high physical activity levels were associated with a significantly reduced risk of gastric non-cardia cancer (HR 0.58, 95% CI 0.37-0.95). Moderate physical activity levels were associated with a 38% reduced risk of oesophageal adenocarcinoma (HR 0.62, 95% CI 0.43-0.89), although no dose-response association was apparent. CONCLUSION: Moderate, rather than high, physical activity levels were associated with the strongest reductions in oesophageal adenocarcinoma risk in this large UK prospective cohort.

The association of lifetime alcohol use with mortality and cancer risk in older adults: A cohort study.

BACKGROUND: While current research is largely consistent as to the harms of heavy drinking in terms of both cancer incidence and mortality, there are disparate messages regarding the safety of light-moderate alcohol consumption, which may confuse public health messages. We aimed to evaluate the association between average lifetime alcohol intakes and risk of both cancer incidence and mortality. METHODS AND FINDINGS: We report a population-based cohort study using data from 99,654 adults (68.7% female), aged 55-74 years, participating in the U.S. Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Cox proportional hazards models assessed the risk of overall and cause-specific mortality, cancer incidence (excluding nonmelanoma skin cancer), and combined risk of cancer and death across categories of self-reported average lifetime alcohol intakes, with adjustment for potential confounders. During 836,740 person-years of follow-up (median 8.9 years), 9,599 deaths and 12,763 primary cancers occurred. Positive linear associations were observed between lifetime alcohol consumption and cancer-related mortality and total cancer incidence. J-shaped associations were observed between average lifetime alcohol consumption and overall mortality, cardiovascular-related mortality, and combined risk of death or cancer. In comparison to lifetime light alcohol drinkers (1-3 drinks per week), lifetime never or infrequent drinkers (<1 drink/week), as well as heavy (2-<3 drinks/day) and very heavy drinkers (3+ drinks/day) had increased overall mortality and combined risk of cancer or death. Corresponding hazard ratios (HRs) and 95% confidence intervals (CIs) for combined risk of cancer or death, respectively, were 1.09 (1.01-1.13) for never drinkers, 1.08 (1.03-1.13) for infrequent drinkers, 1.10 (1.02-1.18) for heavy drinkers, and 1.21 (1.13-1.30) for very heavy drinkers. This analysis is limited to older adults, and residual confounding by socioeconomic factors is possible. CONCLUSIONS: The study supports a J-shaped association between alcohol and mortality in older adults, which remains after adjustment for cancer risk. The results indicate that intakes below 1 drink per day were associated with the lowest risk of death. TRIAL REGISTRATION: NCT00339495 (ClinicalTrials.gov).

Model for Identifying Individuals at Risk for Esophageal Adenocarcinoma.

BACKGROUND & AIMS: The prognosis for most patients with esophageal adenocarcinoma (EAC) is poor because they present with advanced disease. Models developed to identify patients at risk for EAC and increase early detection have been developed based on data from case-control studies. We analyzed data from a prospective study to identify factors available to clinicians that identify individuals with a high absolute risk of EAC. METHODS: We collected data from 355,034 individuals (all older than 50 years) without a prior history of cancer enrolled in the UK Biobank prospective cohort study from 2006 through 2010; clinical data were collected through September 2014. We identified demographic, lifestyle, and medical factors, measured at baseline, that associated with development of EAC within 5 years using logistic regression analysis. We used these data to create a model to identify individuals at risk for EAC. Model performance was assessed using area under the receiver operating characteristics curve (AUROC), sensitivity, and specificity analyses. RESULTS: Within up to 5 years of follow up, 220 individuals developed EAC. Age, sex, smoking, body mass index, and history of esophageal conditions or treatments identified individuals who developed EAC (AUROC, 0.80; 95% CI, 0.77-0.82). We used these factors to develop a scoring system and identified a point cut off that 104,723 individuals (29.5%), including 170 of the 220 cases with EAC, were above. The scoring system identified individuals who developed EAC with 77.4% sensitivity and 70.5% specificity. The 5-year risk of EAC was 0.16% for individuals with scores above the threshold and 0.02% for individuals with scores below the threshold. CONCLUSION: We combined data on several well-established risk factors that are available to clinicians to develop a system to identify individuals with a higher absolute risk of EAC within 5 years. Studies are needed to evaluate the utility of these factors in a multi-stage, triaged, screening program.

Hormonal and reproductive factors and risk of upper gastrointestinal cancers in men: A prospective cohort study within the UK Biobank.

Incidence of upper gastrointestinal cancers of the oesophagus and stomach show a strong unexplained male predominance. Hormonal and reproductive factors have been associated with upper gastrointestinal cancers in women but there is little available data on men. To investigate this, we included 219,425 men enrolled in the UK Biobank in 2006-2010. Baseline assessments provided information on hormonal and reproductive factors (specifically hair baldness, number of children fathered, relative age at first facial hair and relative age voice broke) and incident oesophageal or gastric cancers were identified through linkage to U.K. cancer registries. Unadjusted and adjusted hazard ratios (HR) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. During 8 years of follow-up, 309 oesophageal 210 gastric cancers occurred. There was some evidence that male pattern baldness, was associated with gastric cancer risk (adjusted HR 1.35, 95% CI 0.97, 1.88), particularly for frontal male pattern baldness (adjusted HR 1.52, 95% CI 1.02, 2.28). There was little evidence of association between other hormonal and reproductive factors and risk of oesophageal or gastric cancer, overall or by histological subtype. In the first study of a range of male hormonal and reproductive factors and gastric cancer, there was a suggestion that male pattern baldness, often used as a proxy of sex hormone levels, may be associated with gastric cancer. Future prospective studies that directly test circulating sex steroid hormone levels in relation to upper gastrointestinal cancer risk are warranted.