Current Status and Future Perspectives on the Etiology of Esophageal Adenocarcinoma

Esophageal adenocarcinoma is the most common type of esophageal cancer in most Western countries and is an important contributor to overall cancer mortality. Most cases of esophageal adenocarcinoma are believed to arise from Barrett’s esophagus. Esophageal adenocarcinoma occurs more frequently in white men over 50 years old, as well as in people with frequent symptoms of gastroesophageal reflux, in smokers and in people who are obese. Higher consumption of fruit and vegetables, use of non-steroidal anti-inflammatory drugs, and infection with Helicobacter pylori have all been shown to reduce the risk of esophageal adenocarcinoma. Here, we review the epidemiological evidence for the major risk factors of esophageal adenocarcinoma and also discuss perspectives for future research

Does risk of progression from Barrett’s esophagus to esophageal adenocarcinoma change based on the number of non-dysplastic endoscopies?

Funding: This study was funded in full by the National Institutes of Health, grant number (NIH P30DK056338‐16). The Northern Ireland Barrett’s register was funded by the UK Medical Research Council, Cancer Focus Northern Ireland (formerly the Ulster Cancer Foundation), NI HSC R&D Office, and Cancer Research UK. The Northern Ireland Cancer Registry is funded by the Public Health Agency.Peer reviewedPostprin

Evaluating the Revised American Society for Gastrointestinal Endoscopy Guidelines for Common Bile Duct Stone Diagnosis

Background/Aims The American Society for Gastrointestinal Endoscopy (ASGE) revised its guidelines for risk stratification of patients with suspected choledocholithiasis. This study aimed to assess the diagnostic performance of the revision and to compare it to the previous guidelines. Methods We conducted a retrospective cohort study of 267 patients with suspected choledocholithiasis. We identified high-risk patients according to the original and revised guidelines and examined the diagnostic accuracy of both guidelines. We measured the association between individual criteria and choledocholithiasis. Results Under the original guidelines, 165 (62%) patients met the criteria for high risk, of whom 79% had confirmed choledocholithiasis. The categorization had a sensitivity and specificity of 68% and 55%, respectively, for the detection of choledocholithiasis. Under the revised guidelines, 86 (32%) patients met the criteria for high risk, of whom 83% had choledocholithiasis. The revised categorization had a lower sensitivity and higher specificity of 37% and 80%, respectively. The positive predictive value of the high-risk categorization increased with the revision, reflecting a potential decrease in diagnostic endoscopic retrograde cholangiopancreatograpies (ERCPs). Stone visualized on imaging had the greatest specificity for choledocholithiasis. Gallstone pancreatitis was not associated with the risk for choledocholithiasis. Conclusions The 2019 revision of the ASGE guidelines decreases the utilization of ERCP as a diagnostic modality and offers an improved risk stratification tool

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

Background & Aims Risks for some cancers increase with height. We investigated the relationship between height and risk of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE). Methods We analyzed epidemiologic and genome-wide genomic data from individuals of European ancestry in the Barrett's 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. Results Height 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. Conclusions Height 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

A 5-year longitudinal study of schistosomiasis transmission in Shian village, the Anning River Valley, Sichuan Province, the Peoples' Republic of China

Background: Schistosoma japonicum is a major public health concern in the Peoples' Republic of China (PRC), with over one million people infected and another 50 million living in areas at risk of infection. Based on ecological, environmental, population genetic and molecular factors, schistosomiasis transmission in PRC can be categorised into four discrete ecosystems or transmission modes. It is predicted that the Three Gorges Dam (TGD) will impact upon the transmission of schistosomiasis in the PRC, with varying degree across the four transmission modes. We undertook longitudinal surveillance from 2002 to 2006 in sentinel villages both above and below the TGD across five provinces (Hunan, Jiangxi, Hubei, Anhui and Sichuan) to determine whether there was any impact of the TGD on schistosomiasis transmission during its construction. Here we present the results from a schistosomiasis-endemic village located above the dam in Sichuan Province. Results: Baseline results showed a human S. japonicum prevalence of 42.0% (95% CI: 36.6-47.5). At follow-up, results showed that the incidence of S. japonicum infection in the selected human cohort in Shian decreased by three quarters from 46% in 2003 to 11.3% in 2006. A significant (P < 0.01) downward trend was also evident in the yearly adjusted (for water contact) odds ratios. Over the four years of follow-up, the incidence of S. japonicum infection in bovines declined from 11.8% in the first year to zero in the final year of follow-up. Conclusions: The substantial decrease in human (75%) and bovine (100%) incidence observed in Shian village can probably be attributed to the annual human and bovine PZQ treatment of positives; as seen in drug (PZQ) intervention studies in other parts of PRC. If an increase in schistosome transmission had occurred as a result of the TGD, it would be of negligible size compared to the treatment induced decline seen here. It appears therefore that the construction of the TGD had virtually no impact on schistosomiasis transmission in Shian village over the period of study. Furthermore, contrary to previous reports from Sichuan downplaying the role of animals in human schistosome transmission, bovines may indeed play a role

Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett’s oesophagus and provides insights into clinical heterogeneity in reflux diagnosis

Objective: Gastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett's oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications. Design: We applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA). Results: We identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA. Conclusion: Our multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci

A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization.

Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible

Five-Year Longitudinal Assessment of the Downstream Impact on Schistosomiasis Transmission following Closure of the Three Gorges Dam

Schistosomiasis, caused by Schistosoma japonicum, is a significant parasitic disease and public health problem in China. How the parasite is transmitted there can be categorized into four distinct modes (modes I–IV) and it is predicted that the Three Gorges Dam, recently completed, will affect the way schistosomiasis is spread in these modes. We monitored transmission for a 5-year period (2002–2006) in eight villages, representative of the three modes (I–III) below the dam across four provinces (Hunan, Jiangxi, Hubei and Anhui) to determine whether there was any immediate impact of the dam on schistosomiasis spread. Human schistosomiasis incidence declined considerably within individual villages and each mode, and the yearly odds ratios (adjusted) for infection risk showed significant downward trends in all three modes over the follow-up period. The decreased human S. japonicum incidence recorded across transmission modes I–III was probably attributable to annual human and bovine praziquantel drug treatment. If an increase in schistosome transmission had occurred as a result of the dam, it would be of negligible size compared with this treatment-induced decline. There had thus been virtually no immediate impact of the TGD on schistosomiasis transmission downstream of the dam over the 5-year surveillance period