Aaron P. Thrift

Incidence of Hepatocellular Carcinoma in All 50 United States, From 2000 Through 2012

BACKGROUND & AIMSnThe incidence and mortality of hepatocellular carcinoma (HCC) have been reported to be plateauing in the United States. The United States has large racial, ethnic, and regional variation; we collected data from all 50 states to better analyze changes in HCC incidence in the entire United States.nnnMETHODSnWe collected data from the US Cancer Statistics registry, which covers 97% of the population, and calculated adjusted incidence rates. We assessed annual trends among sociodemographic and geographic subgroups using joinpoint analysis.nnnRESULTSnHCC incidence increased from 4.4/100,000 in 2000 to 6.7/100,000 in 2012, increasing by 4.5% (95% confidence interval [CI], 4.3%-4.7%) annually between 2000 and 2009, but only by 0.7% annually (95% CI, -0.2% to 1.6%) from 2010 through 2012. The average annual percentage change (AAPC) between 2000 and 2012 was higher in men (increase, 3.7%) than in women (increase, 2.7%), and highest in 55- to 59-year-old individuals (AAPC, 8.9%; 95% CI, 7.1%-10.7%) and 60- to 64-year-old individuals (AAPC, 6.4%; 95% CI, 4.7%-8.2%). By 2012, rates in Hispanics surpassed those in Asians, and rates in Texas surpassed those in Hawaii (9.71/100,000 vs 9.68/100,000). Geographic variation within individual race and ethnic groups was observed, but rates werexa0highest in all major race and ethnic groups in Texas.nnnCONCLUSIONSnIn an analysis of the incidence of HCC in all 50 US states, we found the rate of increase in HCC to have slowed from 2010 through 2012. However, incidence is increasing in subgroups such as men ages 55 to 64 years old-especially those born in the peak era of hepatitis C virus infection and among whites/Caucasians. Rates in Hispanics have surpassed those in Asian Americans. We observed geographic differences, with Texas having the highest age-adjusted HCC rates nationwide.

Obesity and Risk of Esophageal Adenocarcinoma and Barrett’s Esophagus: A Mendelian Randomization Study

BACKGROUNDnData from observational studies suggest that body mass index (BMI) is causally related to esophageal adenocarcinoma (EAC) and its precursor, Barretts esophagus (BE). However, the relationships may be affected by bias and confounding.nnnMETHODSnWe used data from the Barretts and Esophageal Adenocarcinoma Genetic Susceptibility Study: 999 patients with EAC, 2061 patients with BE, and 2169 population controls. We applied the two-stage control function instrumental variable method of the Mendelian randomization approach to estimate the unbiased, unconfounded effect of BMI on risk of EAC and BE. This was performed using a genetic risk score, derived from 29 genetic variants shown to be associated with BMI, as an instrument for lifetime BMI. A higher score indicates propensity to obesity. All tests were two-sided.nnnRESULTSnThe genetic risk score was not associated with potential confounders, including gastroesophageal reflux symptoms and smoking. In the instrumental variable analyses (IV), EAC risk increased by 16% (IV-odds ratio [OR] = 1.16, 95% confidence interval [CI] = 1.01 to 1.33) and BE risk increased by 12% (IV-OR = 1.12, 95% CI = 1.00 to 1.25) per 1kg/m(2) increase in BMI. BMI was statistically significantly associated with EAC and BE in conventional epidemiologic analyses.nnnCONCLUSIONSnPeople with a high genetic propensity to obesity have higher risks of esophageal metaplasia and neoplasia than people with low genetic propensity. These analyses provide the strongest evidence to date that obesity is independently associated with BE and EAC, and is not due to confounding or bias inherent in conventional epidemiologic analyses.

The epidemic of oesophageal carcinoma: Where are we now?

Since the early 1970s, the incidence of oesophageal adenocarcinoma has increased dramatically in most Western populations. In contrast, the incidence of oesophageal squamous-cell carcinoma has decreased in these same populations. Epidemiological studies conducted over the past decade have provided great insights into the etiology of oesophageal cancer. These studies have identified gastro-oesophageal reflux disease, obesity and cigarette smoking as risk factors for oesophageal adenocarcinoma, while use of nonsteroidal anti-inflammatory drugs and infection with Helicobacter pylori are associated with reduced risk of oesophageal adenocarcinoma. For oesophageal squamous-cell carcinoma, alcohol and cigarette smoking are the two major risk factors underlying most cases. This review combines a synthesis of these studies with an analysis of data from the United States National Cancer Institutes Surveillance, Epidemiology, and End Results (SEER) program to discuss the change in incidence of oesophageal cancer and summarize current knowledge of risk factors.

A Multibiomarker Risk Score Helps Predict Risk for Barrett’s Esophagus

BACKGROUND & AIMSnRisk prediction models for Barretts esophagus (BE) have been developed using multiple demographic and clinical variables, but their predictive performance has been modest. Adding a multibiomarker risk score may improve discriminatory ability.nnnMETHODSnWe used data from 141 patients with definitive BE and 138 controls participating in a case-control study at the Michael E. DeBakey Veterans Affairs Medical Center (Houston, TX) (97% men, 65% of controls were white, and 89% of cases were white). We derived and compared 3 prediction models. Model 1 included only gastroesophageal reflux disease (GERD) frequency and duration; model 2 included GERD frequency and duration, age, sex, race, waist-to-hip ratio, and Helicobacter pylori status; and model 3 included the variables in model 2 as well as a multibiomarker risk score based on serum levels of interleukin (IL)12p70, IL6, IL8, IL10, and leptin. We assessed their predictive accuracy in terms of discrimination using the area under the receiver operating characteristic curve and calibration analyses.nnnRESULTSnThe multibiomarker risk score was associated significantly with risk for BE. Compared with persons with a score of 0, persons with a score of 3 or higher had a greater than 10-fold increased risk for BE (biomarker risk score, ≥3; odds ratio, 11.9; 95% confidence interval, 4.06-34.9; P trend < .001). Risk prediction using the multibiomarker score in conjunction with demographic and clinical features improved discrimination compared with using only GERD frequency and duration (area under the receiver operating characteristic curve, 0.85 vs 0.74; P = .01).nnnCONCLUSIONSnBased on data from a case-control study of predominantly white male veterans, a risk prediction model including a multibiomarker score, derived from serum levels of cytokines and leptin, as well as GERD frequency and duration, age, sex, race, waist-to-hip ratio, and H pylori infection, can identify persons in this population with BE more accurately than previous methods.

Alcohol and the Risk of Barrett's Esophagus: A Pooled Analysis from the International BEACON Consortium

OBJECTIVES:Results from studies examining the association between alcohol consumption and the risk of Barretts esophagus have been inconsistent. We assessed the risk of Barretts esophagus associated with total and beverage-specific alcohol consumption by pooling individual participant data from five case–control studies participating in the international Barretts and Esophageal Adenocarcinoma Consortium.METHODS:For analysis, there were 1,282 population-based controls, 1,418 controls with gastroesophageal reflux disease (GERD), and 1,169 patients with Barretts esophagus (cases). We estimated study-specific odds ratios (ORs) and 95% confidence intervals (95% CI) using multivariable logistic regression models adjusted for age, sex, body mass index (BMI), education, smoking status, and GERD symptoms. Summary risk estimates were obtained by random-effects models. We also examined potential effect modification by sex, BMI, GERD symptoms, and cigarette smoking.RESULTS:For comparisons with population-based controls, although there was a borderline statistically significant inverse association between any alcohol consumption and the risk of Barretts esophagus (any vs. none, summary OR=0.77, 95% CI=0.60–1.00), risk did not decrease in a dose-response manner (Ptrend=0.72). Among alcohol types, wine was associated with a moderately reduced risk of Barretts esophagus (any vs. none, OR=0.71, 95% CI=0.52–0.98); however, there was no consistent dose–response relationship (Ptrend=0.21). We found no association with alcohol consumption when cases were compared with GERD controls. Similar associations were observed across all strata of BMI, GERD symptoms, and cigarette smoking.CONCLUSIONS:Consistent with findings for esophageal adenocarcinoma, we found no evidence that alcohol consumption increases the risk of Barretts esophagus.

Mendelian randomization study of body mass index and colorectal cancer risk

Background: High body mass index (BMI) is consistently linked to increased risk of colorectal cancer for men, whereas the association is less clear for women. As risk estimates from observational studies may be biased and/or confounded, we conducted a Mendelian randomization study to estimate the causal association between BMI and colorectal cancer. Methods: We used data from 10,226 colorectal cancer cases and 10,286 controls of European ancestry. The Mendelian randomization analysis used a weighted genetic risk score, derived from 77 genome-wide association study–identified variants associated with higher BMI, as an instrumental variable (IV). We compared the IV odds ratio (IV-OR) with the OR obtained using a conventional covariate-adjusted analysis. Results: Individuals carrying greater numbers of BMI-increasing alleles had higher colorectal cancer risk [per weighted allele OR, 1.31; 95% confidence interval (CI), 1.10–1.57]. Our IV estimation results support the hypothesis that genetically influenced BMI is directly associated with risk for colorectal cancer (IV-OR per 5 kg/m2, 1.50; 95% CI, 1.13–2.01). In the sex-specific IV analyses higher BMI was associated with higher risk of colorectal cancer among women (IV-OR per 5 kg/m2, 1.82; 95% CI, 1.26–2.61). For men, genetically influenced BMI was not associated with colorectal cancer (IV-OR per 5 kg/m2, 1.18; 95% CI, 0.73–1.92). Conclusions: High BMI was associated with increased colorectal cancer risk for women. Whether abdominal obesity, rather than overall obesity, is a more important risk factor for men requires further investigation. Impact: Overall, conventional epidemiologic and Mendelian randomization studies suggest a strong association between obesity and the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(7); 1024–31. ©2015 AACR.

No significant effects of smoking or alcohol consumption on risk of Barrett's esophagus.

BackgroundSmoking, but not higher alcohol consumption, is associated with increased risk of esophageal adenocarcinoma (EAC) and progression from Barrett’s esophagus (BE) to EAC. However, it is still unclear whether smoking or alcohol is implicated in the development of BE.AimTo evaluate the associations between smoking, alcohol and the risk of BE.MethodsThe study included eligible patients scheduled for elective esophagogastroduodenoscopy (EGD) and a sample of patients eligible for screening colonoscopy recruited from primary care clinics. We compared 258 patients with definitive BE with two separate control groups: 453 patients from the primary care group (“colonoscopy controls”) and 1,145 patients from the elective EGD group (“endoscopy controls”) with no endoscopic or histopathologic BE. We calculated odds ratios (OR) and 95xa0% confidence intervals (95xa0% CI) using multivariable logistic regression models.ResultsSeventy-seven percent of BE cases, 75xa0% of colonoscopy controls and 72xa0% of endoscopy controls were ever smokers. Of these, approximately 45xa0% were current smokers. Overall, 91xa0% of study participants were ex or current alcohol drinkers, with the majority drinking beer. We found no association between various measure of smoking exposure (status, intensity, age at initiation, duration, pack-years and cessation) and risk of BE. Alcohol consumption was not associated with increased risk of BE. Conversely, moderate intake was associated with lower risk (14 to <28 drinks/week, OR 0.39, 95xa0% CI 0.15–1.00).ConclusionSmoking and alcohol were not strong or consistent risk factors for BE. The likely role of smoking in increasing risk of EAC is through promoting progression from BE to cancer.

Risk of Esophageal Adenocarcinoma Decreases With Height, Based on Consortium Analysis and Confirmed by Mendelian Randomization

BACKGROUND & AIMSnRisks for some cancers increase with height. We investigated the relationship between height and risk of esophageal adenocarcinoma (EAC) and its precursor, Barretts esophagus (BE).nnnMETHODSnWe analyzed epidemiologic and genome-wide genomic data from individuals of European ancestry in the Barretts and Esophageal Adenocarcinoma Consortium, from 999 cases of EAC, 2061 cases of BE, and 2168 population controls. Multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for associations between height and risks of EAC and BE. We performed a Mendelian randomization analysis to estimate an unconfounded effect of height on EAC and BE using a genetic risk score derived from 243 genetic variants associated with height as an instrumental variable.nnnRESULTSnHeight was associated inversely with EAC (per 10-cm increase in height: OR, 0.70; 95% CI, 0.62-0.79 for men and OR, 0.57; 95% CI 0.40-0.80 for women) and BE (per 10-cm increase in height: OR, 0.69; 95% CI, 0.62-0.77 for men and OR, 0.61; 95% CI, 0.48-0.77 for women). The risk estimates were consistent across strata of age, education level, smoking, gastroesophageal reflux symptoms, body mass index, and weight. Mendelian randomization analysis yielded results quantitatively similar to those from the conventional epidemiologic analysis.nnnCONCLUSIONSnHeight is associated inversely with risks of EAC and BE. Results from the Mendelian randomization study showed that the inverse association observed did not result from confounding factors. Mechanistic studies of the effect of height on EAC and BE are warranted; height could have utility in clinical risk stratification.

Mendelian randomization study of height and risk of colorectal cancer

BACKGROUNDnFor men and women, taller height is associated with increased risk of all cancers combined. For colorectal cancer (CRC), it is unclear whether the differential association of height by sex is real or is due to confounding or bias inherent in observational studies. We performed a Mendelian randomization study to examine the association between height and CRC risk.nnnMETHODSnTo minimize confounding and bias, we derived a weighted genetic risk score predicting height (using 696 genetic variants associated with height) in 10,226 CRC cases and 10,286 controls. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for associations between height, genetically predicted height and CRC.nnnRESULTSnUsing conventional methods, increased height (per 10-cm increment) was associated with increased CRC risk (OR = 1.08, 95% CI = 1.02-1.15). In sex-specific analyses, height was associated with CRC risk for women (OR = 1.15, 95% CI = 1.05-1.26), but not men (OR = 0.98, 95% CI = 0.92-1.05). Consistent with these results, carrying greater numbers of (weighted) height-increasing alleles (per 1-unit increase) was associated with higher CRC risk for women and men combined (OR = 1.07, 95% CI = 1.01-1.14) and for women (OR = 1.09, 95% CI =u2009 .01-1.19). There was weaker evidence of an association for men (OR = 1.05, 95% CI = 0.96-1.15).nnnCONCLUSIONnWe provide evidence for a causal association between height and CRC for women. The CRC-height association for men remains unclear and warrants further investigation in other large studies.

Risk factors and populations at risk: Selection of patients for screening for Barrett's oesophagus

Screening for Barretts oesophagus is an attractive notion due to the rising incidence of oesophageal adenocarcinoma, the relative ease of acquiring tissue from the oesophagus, and the availability of endoscopic therapy for early neoplastic lesions. If screening is recommended, the question remains: which patients should be screened? Endoscopy is frequently performed in patients with symptoms of gastro-oesophageal reflux disease, but the vast majority of patients diagnosed with oesophageal adenocarcinoma have never undergone a prior endoscopy. The efficiency of screening needs to be improved. A number of tools for predicting the presence of Barretts oesophagus or future risk of developing oesophageal adenocarcinoma are available. More research is needed to validate these tools and to identify the thresholds at which screening should be offered.