Risk Of Esophageal Adenocarcinoma Research Articles

Biologically-targeted discovery-replication scan identifies G×G interaction in relation to risk of Barrett's esophagus and esophageal adenocarcinoma.

Inherited genetics represents an important contributor to risk of esophageal adenocarcinoma (EAC), and its precursor Barrett's esophagus (BE). Genome-wide association studies have identified ∼30 susceptibility variants for BE/EAC, yet genetic interactions remain unexamined. To address challenges in large-scale G×G scans, we combined knowledge-guided filtering and machine learning approaches, focusing on genes with (A) known/plausible links to BE/EAC pathogenesis (n=493) or (B) prior evidence of biological interactions (n=4,196). ∼75 x 106 SNP×SNP interactions were screened via hierarchical group lasso (glinternet) using BEACON GWAS data. The top ∼2000 interactions retained in each scan were prioritized using P values from single logistic models. Identical scans were repeated among males only (78%), with two independent GWAS datasets used for replication. In overall and male-specific primary replications, 11 of 187 and 20 of 191 interactions satisfied P<0.05, respectively. The strongest evidence for secondary replication was for rs17744726×rs3217992 among males, with consistent directionality across all cohorts (Pmeta=2.19×10-8); rs3217992 "T" was associated with reduced risk only in individuals homozygous for rs17744726 "G". Rs3217992 maps to the CDKN2B 3'UTR and reportedly disrupts microRNA-mediated repression. Rs17744726 maps to an intronic enhancer region in BLK. Through in-silico prioritization and experimental validation, we identified a nearby proxy variant (rs4841556) as a functional modulator of enhancer activity. Enhancer-gene mapping and eQTLs implicated BLK and FAM167A as targets. The first systematic G×G investigation in BE/EAC, this study uncovers differential risk associations for CDKN2B variation by BLK genotype, suggesting novel biological dependency between two risk loci encoding key mediators of tumor suppression and inflammation.

Association between sulfur microbial diet and the risk of esophageal cancer: a prospective cohort study in 101,752 American adults

BackgroundSulfur microbial diet (SMD) is a dietary pattern closely related to the intestinal load of sulfur-metabolizing microbes in humans. Diet and microbes may play an important role in the carcinogenesis of esophagus. However, epidemiological studies on SMD and esophageal cancer (EC) risk are scarce. Here, we evaluated this association based on a large American cohort.MethodsIn the cohort of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, a SMD score was calculated to evaluate participants’ compliance of SMD pattern, with higher scores presenting greater adherence. Cox hazards regression model was used to explore the association between the SMD score and the incidence of EC, esophageal squamous cell carcinoma (ESCC), and esophageal adenocarcinoma (EA). Subgroup analyses were conducted to figure out potential modifiers interacting with SMD on EC. Sensitivity analyses were used to testify the robustness of our main result.ResultsAmong 101,752 participants, 154 EC cases, consisted of 41 ESCC cases and 97 EA cases, were identified with mean follow-up of 8.9 years. In the fully adjusted model, the highest versus the lowest quartiles of the SMD score were found to be associated with an increased risk of EC and ESCC (EC: HRQ4 vs. Q1: 1.64; 95% CI: 1.05, 2.56; P = 0.016 for trend; ESCC: HRQ4 vs. Q1: 2.37; 95% CI: 1.02, 5.47; P = 0.031 for trend), while not significantly associated with increases risk of EA (HRQ4 vs. Q1: 1.41; P = 0.144 for trend). The main result remained through a series of sensitivity analyses. Subgroup analyses showed a stronger association between SMD and EC in participants with no regular consumption of aspirin (HRQ4 vs. Q1: 1.90; 95% CI: 1.04, 3.47) than in those using aspirin regularly (HRQ4 vs. Q1: 1.37; 95% CI: 0.71, 2.66) (P = 0.008 for interaction).ConclusionAdherence to the SMD pattern may be associated with increased risks of EC and ESCC, particularly for EC in individuals who do not regularly consume aspirin.

Exploring Dietary Factors and Esophageal Adenocarcinoma: Insights From Mendelian Randomization Study.

Esophageal adenocarcinoma and diet are not well understood to be associated. We conducted Mendelian randomization analysis using 18 dietary factors as exposures (primarily including fruit consumption, vegetable consumption, alcohol consumption, meat consumption, tea intake, fish intake, etc.), with esophageal adenocarcinoma as the outcome. The IVW method was the leading method used for detecting causal links. Cochran's Q test was utilized to assess heterogeneity, the intercept of the MR-Egger method was used to assess the presence of horizontal pleiotropy, and the existence of outliers was identified via the MR-Presso method. This study identified that both alcohol intake frequency (OR = 1.375, p = 0.0216) and coffee intake (OR = 2.680, p = 0.0304) were linked to a heightened risk of esophageal adenocarcinoma, while raw vegetable/salad consumption (OR = 0.117, p = 0.0258) and dried fruit intake (OR = 0.229, p = 0.00235) were associated with a decreased risk of esophageal adenocarcinoma. After FDR correction, only dried fruit intake (q = 0.0423) remained statistically significant. However, there was no evidence linking the other 14 dietary variables to esophageal adenocarcinoma. This study observed that alcohol consumption and coffee intake increase the risk of esophageal adenocarcinoma, while the intake of dried fruits rather than fresh fruits and raw vegetable intake rather than cooked vegetable intake reduce the risk of esophageal adenocarcinoma. Other dietary factors were not associated with the risk of esophageal adenocarcinoma.

Regulation of pro-apoptotic and anti-apoptotic factors in obesity-related esophageal adenocarcinoma

BackgroundObesity is a risk factor for esophageal adenocarcinoma (EAC). It was reported that obesity -associated inflammation correlates with insulin resistance and increased risk of EAC. The objective of the study is to investigate the role of obesity associated inflammatory mediators in the development of EAC.MethodsWe included 23 obese and nonobese patients with EAC or with or without Barrett’s esophagus (BE) after IRB approval. We collected 23 normal, 10 BE, and 19 EAC tissue samples from endoscopy or esophagectomy. The samples were analyzed for the expression levels of pro-apoptotic and anti-apoptotic factors, PKC-δ, cIAP2, FLIP, IGF-1, Akt, NF-kB and Ki67 by immunofluorescence and RT-PCR. We compared the expression levels between normal, BE, and EAC tissue using Students’ t-test between two groups.ResultsOur results showed decreased gene and protein expression of pro-apoptotic factors (bad, bak and bax) and increased expression of anti-apoptotic factors (bcl-2, Bcl-xL) in BE and EAC compared to normal tissues. There was increased gene and protein expression of PKC-δ, cIAP2, FLIP, NF-kB, IGF-1, Akt, and Ki67 in BE and EAC samples compared to normal esophagus. Further, an increased folds changes in mRNA expression of proapoptotic factors, antiapoptotic factors, PKC-δ, IGF-1, Akt, and Ki-67 was associated with obesity.ConclusionPatients with EAC had increased expression of cIAP2 and FLIP, and PKC-δ which is associated with inhibition of apoptosis and possible progression of esophageal adenocarcinoma.

Shifts in Serum Bile Acid Profiles Associated With Barrett's Esophagus and Stages of Progression to Esophageal Adenocarcinoma.

Reflux bile acids are believed to promote esophageal adenocarcinoma (EAC), but the role of systemic bile acids is unknown. This study aimed to assess associations between systemic bile acids and stages of Barrett's esophagus (BE) progression. Subjects with and without BE were enrolled in this multicenter cross-sectional study. Targeted serum bile acid profiling was performed, and a subset of subjects completed a validated food frequency questionnaire. RNA sequencing was performed on BE or gastric cardia tissue to assess bile acid associations with gene expression. A total of 141 subjects were enrolled with serum bile acids profiled (49 non-BE; 92 BE: 44 no dysplasia, 25 indefinite/low grade dysplasia, 23 high-grade dysplasia/EAC). Lower Healthy Eating Index score, older age, higher body mass index, and no proton pump inhibitor use were associated with increased levels of multiple bile acids. Global bile acid pools were distinct between non-BE and stages of BE neoplasia ( P = 0.004). Increasing cholic acid was associated with high-grade dysplasia/EAC compared with non-BE, even after adjusting for EAC risk factors (adjusted odds ratio 2.03, 95% confidence interval 1.11-3.71) as was the combination of unconjugated primary bile acids (adjusted odds ratio 1.81, 95% confidence interval 1.04-3.13). High cholic acid levels were associated with tissue gene expression changes including increased DNA replication and reduced lymphocyte differentiation genes. Alterations in serum bile acids are independently associated with advanced neoplasia in BE and may contribute to neoplastic progression. Future studies should explore associated gut microbiome changes, proneoplastic effects of bile acids, and whether these bile acids, particularly cholic acid, represent potential biomarkers or viable therapeutic targets for advanced neoplasia in BE.

764. PREDICTING AGE-SPECIFIC PREVALENCE OF BARRETT'S OESOPHAGUS IN AUSTRALIAN AND UNITED STATES

Abstract Background Barrett’s esophagus is the precursor to esophageal adenocarcinoma (EAC). EAC detected from endoscopic surveillance programs accounts for &amp;lt;10% of all EAC, suggesting a large number of patients with Barrett’s esophagus are likely unaccounted for. Several studies have estimated the observed prevalence of Barrett’s esophagus to be approximately 1%, but this may be an underestimate. The aim of this study is to use population incidence of EAC and rate of progression from Barrett’s esophagus from large cohort studies to estimate a realistic prevalence of Barrett’s esophagus. Methods A simple tree cohort model was created for progression to EAC from birth to death (100 years) for American and Australian population. Lifetime risk of esophageal cancer and adenocarcinoma were endpoints. This was then used to back-calculate age-specific and overall prevalence of Barrett’s esophagus using an optimisation algorithm. Results Lifetime risk of esophageal cancer and adenocarcinoma in US Whites is 0.56% and 0.36% respectively, while in Australian population is slightly higher at 0.81% and 0.61% (range 0.57% - 0.65%). Estimated overall prevalence of Barrett’s esophagus is ~3% (±0.3%) and ~5.4% (±0.6%) in US White and Australian populations, while in males is 5.3% (±0.6%) and 7.4% (±0.3%), respectively. Female cohorts were seen to have lower chance of developing esophageal cancer, adenocarcinoma, and Barrett’s esophagus. Conclusion Cohort studies of Barrett’s esophagus are likely to underestimate its prevalence of this silent disease. Computational models based on progression from Barrett’s esophagus to EAC accounting for undetected disease reveal higher estimates, which can help in future screening options.

787. THE CHALLENGE OF GASTRO-ESOPHAGEAL ONCOLOGICAL SURGERY AFTER BARIATRIC PROCEDURES: EXPERIENCE OF A REFERRAL HIGH-VOLUME UPPER GI SURGICAL CENTER

Abstract Background The effectiveness of bariatric surgery for weight loss in morbidly obese patients has been well established and it's becoming more common as many surgeons are trained to perform them safely, even in older patients. Obesity is associated with reflux and hormonal imbalances that increase the risk of Barrett's esophagus, esophageal adenocarcinoma and gastric cancer. Bariatric procedures alter gastric anatomy, vascularization and lymphatic drainage and render subsequent upper gastrointestinal surgery for malignancies a technical challenge, that will present more and more in the future. We present laparoscopic sleeve gastrectomy, gastric bypass and gastric banding conversion to oncological respective surgeries. Methods We retrospectively reviewed the medical records of our referral high-volume center for upper gastrointestinal surgery and identified patients who underwent upper gastrointestinal oncologic surgery from January 1998 to May 2024. We selected all patients who had previously undergone bariatric surgery (laparoscopic sleeve gastrectomy, laparoscopic gastric bypass, gastric banding, or other less common procedures). Three patients met our criteria, and we recorded: demographic characteristics, surgical technique, oncologic surgical outcome, postoperative complications, long-term complications, and oncologic follow-up. Results A hybrid IvorLewis esophagectomy was performed years after a sleeve gastrectomy for distal esophageal adenocarcinoma. The sleeve was used for gastric pull-up, adequately vascularized by the right gastroepiploic artery as demonstrated by intraoperative indocyanine green. A patient developed adenocarcinoma of the cardia after Roux-en-Y gastric bypass, infiltrating the gastric pouch, the gastric remnant and liver S2. After neoadjuvant chemotherapy, an open Ivor-Lewis esophagectomy was performed using the gastric remnant for a pull-up. In a third patient, a locally advanced adenocarcinoma of the stomach developed after gastric banding. After neoadjuvant chemotherapy, an open total gastrectomy with Roux-en-Y esophagojejunostomy was performed. Conclusion We report three cases of successful esophago-gastric oncological surgery in patients with altered anatomy and vascularization due to previous bariatric surgery, without major postoperative complications or mortality. Oncologic benchmarks for both esophageal and gastric surgery were met as a high lymph node yield and oncologic margins were maintained. Our heterogeneous series suggests that sleeve gastrectomy, gastric bypass, and gastric banding surgery can be successfully converted to resective surgeries after a metachronous neoplasia diagnosis in high-volume upper gastrointestinal centers. These and similar modified reconstructive techniques are likely to be used in the future as metabolic surgery and esophago-gastric cancer are increasing.

Association between four insulin resistance surrogates and the risk of esophageal cancer: a prospective cohort study using the UK Biobank

PurposeThis study explored the association between triglyceride-glucose (TyG), TyG index with body mass index (TyG-BMI), triglyceride/high-density lipoprotein cholesterol ratio (TG/HDL-C), metabolic score for insulin resistance (IR) (METS-IR) and the risk of esophageal cancer.MethodsA total of 388,900 participants from the United Kingdom Biobank from 2006 to 2010 were included. Fine-Gray models, restricted cubic spline (RCS), and receiver operating characteristic (ROC) curves were used to assess the association between the four IR surrogates and the risk of esophageal cancer, specifically, esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC).ResultsTen years after recruitment, 0.16% (95%CI 0.11–0.26%) had esophageal cancer and 4.17% (95%CI 3.86–4.46%) are deceased. For each standard deviation increase in the TyG index, TyG-BMI, TG/HDL-C, and METS-IR, the risk of EAC increased by Hazard ratios (HR)1.16, 1.37, 1.08, and 1.36, respectively (all P < 0.05), while the risk of ESCC decreased by HRs 0.80, 0.67, 0.77, and 0.65, respectively. RCS analysis indicated that most relationships were nonlinear (P < 0.05). ROC curves showed that METS-IR had a more robust diagnostic efficacy than TyG, TyG-BMI, and TG/HDL-C.ConclusionTyG index, TyG-BMI, TG/HDL-C, and METS-IR were closely associated with the risk of EAC and ESCC. Additionally, METS-IR surpassed the other three IR indices in predicting and diagnosing the risks of EAC and ESCC. The METS-IR is expected to become a more effective metric for identifying populations at early risk of esophageal cancer and for improving risk stratification.

Role of diet in the risks of esophageal adenocarcinoma and squamous cell carcinoma: an updated umbrella review.

This updated umbrella review aimed to evaluate the evidence regarding the associations between dietary factors and the risks of esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). The PubMed, Embase, Cochrane Library, and Web of Science databases were searched to identify relevant studies. The quality of the included meta-analyses was evaluated using A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2). For each association, the number of cases, random effects pooled effect size, 95% confidence intervals (CIs), heterogeneity, 95% prediction interval (PrI), small-study effect, and excess significance bias were recalculated to determine the evidence level. We identified 33 meta-analyses describing 58 dietary factors associated with ESCC and 29 meta-analyses describing 38 dietary factors associated with EAC. There was convincing evidence regarding the association of 2 dietary factors (areca nut and high alcohol) with the risk of ESCC. There was highly suggestive evidence regarding the association of only 1 dietary factor (healthy pattern) with the risk of ESCC. There was suggestive evidence regarding the association of 11 dietary factors with the risk of ESCC, including fruit, citrus fruit, vegetables, pickled vegetables, maté tea, moderate alcohol, hot beverages and foods, hot tea, salt, folate, and vitamin B6. There was convincing evidence regarding the association of one dietary factor (vitamin B6) with the risk of EAC. There was suggestive evidence regarding the association of 4 dietary factors with the risk of EAC, including processed meat, dietary fibre, carbohydrate, and vitamin B12. The convincing evidence regarding the associations between dietary factors and the risks of ESCC and EAC remained robust in sensitivity analyses. This umbrella review highlighted convincing evidence regarding the associations of areca nut and high alcohol with a higher risk of ESCC. Additionally, an association between vitamin B6 and a decreased risk of EAC was observed. Further research is needed to examine the dietary factors with weak evidence regarding their associations with ESCC and EAC.

The Aberrant Expression of Biomarkers and Risk Prediction for Neoplastic Changes in Barrett's Esophagus-Dysplasia.

Background: Barrett's esophagus (BE) is a pre-neoplastic condition associated with an increased risk of esophageal adenocarcinoma (EAC). The accurate diagnosis of BE and grading of dysplasia can help to optimize the management of patients with BE. However, BE may be missed and the accurate grading of dysplasia based on a routine histology has a considerable intra- and interobserver variability. Thus, well-defined biomarker testing remains indispensable. The aim of our study was to identify routinely applicable and relatively specific biomarkers for an accurate diagnosis of BE, as well as determining biomarkers to predict the risk of progression in BE-dysplasia. Methods: Retrospectively, we performed immunohistochemistry to test mucin 2(MUC2), trefoil factor 3 (TFF3), p53, p16, cyclin D1, Ki-67, beta-catenin, and minichromosome maintenance (MCM2) in biopsies. Prospectively, to identify chromosomal alterations, we conducted fluorescent in situ hybridization testing on fresh brush samples collected at the time of endoscopy surveillance. Results: We discovered that MUC2 and TFF3 are specific markers for the diagnosis of BE. Aberrant expression, including the loss and strong overexpression of p53, Ki-67, p16, beta-catenin, cyclin D1, and MCM2, was significantly associated with low-grade dysplasia (LGD), high-grade dysplasia (HGD), and EAC histology, with a relatively high risk of neoplastic changes. Furthermore, the aberrant expressions of p53 and p16 in BE-indefinite dysplasia (IND) progressor cohorts predicted the risk of progression. Conclusions: Assessing the biomarkers would be a suitable adjunct to accurate BE histology diagnoses and improve the accuracy of BE-dysplasia grading, thus reducing interobserver variability, particularly of LGD and risk prediction.

Helicobacter pylori infection does not influence the progression from gastroesophageal reflux disease to Barrett's esophagus to esophageal adenocarcinoma.

We conducted a meta-analysis evaluating the overall risk of esophageal adenocarcinoma (EAC) in individuals with Helicobacter pylori infection, and a network meta-analysis to assess the role of H. pylori infection in the progression from Barrett's esophagus (BE) to EAC. The MEDLINE, EMBASE and Cochrane databases were searched between 1988 and June 2023 for observational studies of H. pylori infection and the risk of EAC. Summary odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using the DerSimonian-Laird method. I2 statistics were calculated to examine heterogeneity. Thirteen studies were included in the meta-analysis and 3 additional studies were included in the network meta-analysis. For comparisons with controls, individuals with H. pylori infection were 46% less likely to develop EAC than individuals without H. pylori infection (OR, 0.54; 95% CI: 0.46, 0.64), with low heterogeneity between studies (I2=4.4%). The magnitude of the inverse association was stronger in the two large cohort studies (OR=0.31) than in the 11 case-control studies (OR=0.55). When comparing to controls, the network meta-analysis of 6 studies showed that H. pylori infection was associated with a lower risk of GERD (OR=0.68) or BE (OR=0.59) or EAC (OR=0.54); however, H. pylori infection was not associated with risk of EAC in patients with BE (OR=0.91; 95% CI: 0.68, 1.21). This meta-analysis provides the strongest evidence yet that H. pylori infection is inversely associated with EAC. H. pylori does not appear to be associated with BE progression to EAC.

Risk of Esophageal Adenocarcinoma After Bariatric Surgery: A Meta-Analysis of Retrospective Studies.

This study aims to systematically review and meta-analyze the evidence on the risk of esophageal adenocarcinoma (EAC) following metabolic and bariatric surgery (MBS). A systematic literature search was conducted on the China National Knowledge Infrastructure (CNKI), Wanfang, EMBASE, MEDLINE, Web of Science, The Cochrane Library, and PubMed databases. Meta-analysis utilized odds ratios (ORs) and 95% confidence intervals (CIs) to analyze the correlation between MBS and the risk of EAC. Meta-analysis was performed using STATA software (version 12.0). Fourteen studies involving patients with obesity undergoing bariatric surgery and control groups receiving conventional treatment were included. The meta-analysis indicated a reduction in the overall incidence of esophageal cancer after bariatric surgery (OR = 0.69, 95% CI: 0.51-0.95, P = 0.022). Subgroup analysis results demonstrated a decreased risk of EAC in European patients with obesity undergoing MBS treatment (OR: 0.60, 95% CI: 0.38-0.95, P = 0.028). In studies with a sample size greater than or equal to 100,000 patients, the risk of EAC in patients with obesity undergoing MBS was significantly lower than the non-surgery group (OR: 0.59, 95% CI: 0.42-0.83, P = 0.003). Articles published before 2020 and those published in 2020 or earlier showed a significant difference in the incidence of EAC between the surgery and non-surgery groups (OR: 0.57, 95% CI: 0.43-0.75, P < 0.001). The risk of EAC in patients with obesity with a follow-up time of less than 5years was statistically significant (OR: 0.46, 95% CI: 0.25-0.82, P = 0.009). Our meta-analysis results suggest a reduced risk of esophageal cancer in patients with obesity after bariatric surgery. CRD 42024505177.

Abstract 4850: Sex differences in cancer incidence: Prospective analyses in the UK Biobank

Abstract Background: Exploring the underlying sex differences in cancer incidence and the potential reasons for the differences may provide insights into cancer aetiology. We aimed to examine the differences in incidence of cancer between men and women in the UK Biobank and to assess the extent to which any disparities persisted after accounting of established risk factors for those cancers. Methods: Prospective analyses were performed in the UK Biobank to examine associations between sex and risk of 15 cancers (and 13 subtypes) common to both sexes using minimal and multivariable-adjusted Cox proportional hazards regression models. Results: Over an average of 10.5 (SD 2.2) years of follow-up, 46,081 incident cancers were identified in 470,771 individuals (aged 37 to 73 years at recruitment); 24,634 cancers (53.5%) diagnosed in women and 21,447 (46.5%) in men. While some differences in cancer risk between the sexes were attenuated in the comprehensively multivariable-adjusted models, men compared to women remained at greater risk of cancers at eight sites. Compared to women, men had higher risks of oesophageal adenocarcinoma (hazard ratio 5.45; 95% confidence interval, 4.17-7.12), gastric cardia (3.65; 2.48-5.38), bladder (3.47; 2.85-4.24), oral (2.06; 1.69-2.51), liver (1.91; 1.48-2.47), kidney (1.77; 1.51-2.09), rectum (1.7; 1.47-1.96), and leukaemia (1.43; 1.21-1.69); while women had higher risks of cancers of the breast, thyroid (0.36; 0.26-0.49), anus (0.41; 0.26-0.64), gallbladder (0.56; 0.31-0.99), and lung adenocarcinoma (0.72; 0.62-0.84). Conclusion: Further studies of unexplained sex differences may provide insights into cancer aetiology. Citation Format: Maira Khan, Keren Papier, Kirstin Pirie, Joshua Atkins, Tim Key, Ruth Travis. Sex differences in cancer incidence: Prospective analyses in the UK Biobank [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4850.

Risk of Esophageal Adenocarcinoma After Helicobacter pylori Eradication Treatment in a Population-Based Multinational Cohort Study

Helicobacter pylori infection is associated with a decreased risk of esophageal adenocarcinoma, and the decreasing prevalence of such infection might contribute to the increasing incidence of this tumor. We examined the hypothesis that eradication treatment of H pylori increases the risk of esophageal adenocarcinoma. This population-based multinational cohort, entitled "Nordic Helicobacter Pylori Eradication Project (NordHePEP)," included all adults (≥18 years) receiving H pylori eradication treatment from 1995-2018 in any of the 5 Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) with follow-up throughout 2019. Data came from national registers. We calculated standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) by dividing the cancer incidence in the exposed cohort by that of the entire Nordic background populations of the corresponding age, sex, calendar period, and country. Analyses were stratified by factors associated with esophageal adenocarcinoma (ie, education, comorbidity, gastroesophageal reflux, and certain medications). Among 661,987 participants who contributed 5,495,552 person-years after eradication treatment (median follow-up, 7.8 years; range, 1-24 years), 550 cases of esophageal adenocarcinoma developed. The overall SIR of esophageal adenocarcinoma was not increased (SIR= 0.89; 95% CI, 0.82-0.97). The SIR did not increase over time after eradication treatment, but rather decreased and was 0.73 (95% CI, 0.61-0.86) at 11-24 years after treatment. There were no major differences in the stratified analyses. The overall SIR of esophageal squamous cell carcinoma, calculated for comparison, showed no association (SIR= 0.99; 95% CI, 0.89-1.11). This absence on an increased risk of esophageal adenocarcinoma after eradication treatment of H pylori suggests eradication is safe from a cancer perspective.

Cholelithiasis and cholecystectomy increase the risk of gastroesophageal reflux disease and Barrett's esophagus.

Cholelithiasis or cholecystectomy may contribute to the development of gastroesophageal reflux disease (GERD), Barrett's esophagus (BE), and esophageal adenocarcinoma (EAC) through bile reflux; however, current observational studies yield inconsistent findings. We utilized a novel approach combining meta-analysis and Mendelian randomization (MR) analysis, to assess the association between them. The literature search was done using PubMed, Web of Science, and Embase databases, up to 3 November 2023. A meta-analysis of observational studies assessing the correlations between cholelithiasis or cholecystectomy, and the risk factors for GERD, BE, and EACwas conducted. In addition, the MR analysis was employed to assess the causative impact of genetic pre-disposition for cholelithiasis or cholecystectomy on these esophageal diseases. The results of the meta-analysis indicated that cholelithiasis was significantly linked to an elevated risk in the incidence of BE (RR, 1.77; 95% CI, 1.37-2.29; p < 0.001) and cholecystectomy was a risk factor for GERD (RR, 1.37; 95%CI, 1.09-1.72; p = 0.008). We observed significant genetic associations between cholelithiasis and both GERD (OR, 1.06; 95% CI, 1.02-1.10; p < 0.001) and BE (OR, 1.21; 95% CI, 1.11-1.32; p < 0.001), and a correlation between cholecystectomy and both GERD (OR, 1.04; 95% CI, 1.02-1.06; p < 0.001) and BE (OR, 1.13; 95% CI, 1.06-1.19; p < 0.001). After adjusting for common risk factors, such as smoking, alcohol consumption, and BMI in multivariate analysis, the risk of GERD and BE still persisted. Our study revealed that both cholelithiasis and cholecystectomy elevate the risk of GERD and BE. However, there is no observed increase in the risk of EAC, despite GERD and BE being the primary pathophysiological pathways leading to EAC. Therefore, patients with cholelithiasis and cholecystectomy should be vigilant regarding esophageal symptoms; however, invasive EAC cytology may not be necessary.

Ultra-processed foods, adiposity and risk of head and neck cancer and oesophageal adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition study: a mediation analysis

PurposeTo investigate the role of adiposity in the associations between ultra-processed food (UPF) consumption and head and neck cancer (HNC) and oesophageal adenocarcinoma (OAC) in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.MethodsOur study included 450,111 EPIC participants. We used Cox regressions to investigate the associations between the consumption of UPFs and HNC and OAC risk. A mediation analysis was performed to assess the role of body mass index (BMI) and waist-to-hip ratio (WHR) in these associations. In sensitivity analyses, we investigated accidental death as a negative control outcome.ResultsDuring a mean follow-up of 14.13 ± 3.98 years, 910 and 215 participants developed HNC and OAC, respectively. A 10% g/d higher consumption of UPFs was associated with an increased risk of HNC (hazard ratio [HR] = 1.23, 95% confidence interval [CI] 1.14–1.34) and OAC (HR = 1.24, 95% CI 1.05–1.47). WHR mediated 5% (95% CI 3–10%) of the association between the consumption of UPFs and HNC risk, while BMI and WHR, respectively, mediated 13% (95% CI 6–53%) and 15% (95% CI 8–72%) of the association between the consumption of UPFs and OAC risk. UPF consumption was positively associated with accidental death in the negative control analysis.ConclusionsWe reaffirmed that higher UPF consumption is associated with greater risk of HNC and OAC in EPIC. The proportion mediated via adiposity was small. Further research is required to investigate other mechanisms that may be at play (if there is indeed any causal effect of UPF consumption on these cancers).

Systematic Review and Meta-analysis of the Relationship Between Proton Pump Inhibitors and Esophageal Adenocarcinoma.

Esophageal adenocarcinoma (EAC) mortality continues to increase across the world. This meta-analysis was aimed to investigate the relationship between proton pump inhibitors (PPIs) and the risk of EAC. This meta-analysis was done as per the PRISMA checklist using relevant keywords. To this end, an extensive search was done on 29/6/2022 in EMBASE, Web of Science (ISI), PubMed, and Scopus. In this study, 95% confidence interval (CI) and standardized mean difference (SMD) were used to estimate the overall effect size. Analysis of the odds ratio (OR) for EAC was done using a random effects model. A total of 20 studies were included in the review. Compared to the group that received PPIs, the OR of EAC in the recipients of the PPIs group was obtained at 0.67 (95% CI = 0.39-1.29, P = 0.240). The meta-regression, including year, follow-up time, study design, sample size, quality of the study, study period, and geographical location, demonstrated no source of heterogeneity (P > 0.10). No significant relationship was found between PPIs use and the risk of EAC. Accordingly, PPIs do not have a protective or risk factor effect on EAC.

Barrett's Esophagus: Update on the Diagnosis and Treatment. Review

Barrett's esophagus (BE) is the condition in which a metaplastic columnar mucosa predisposed to neoplasia replaces the squamous mucosa of the distal esophagus. The current guidelines recommends that diagnosis requires the finding of intestinal metaplasia (IM) with goblet cells of at least 1 cm in length. BE affects approximately 1% of the general population and up to 14% of patients with gastroesophageal reflux disease (GERD). BE is a precursor of esophageal adenocarcinoma (EAC), which has increased in western countries. The main risk factors described for EAC associated with BE are male sex, age > 50 years, central obesity and tobacco use. Annual risk of EAC in patients with BE without dysplasia, low grade (LGD) and high-grade dysplasia is 0,1-0,3%, 0,5% y 5-8%, respectively. Treatment of non-dysplastic BE consists mainly of a healthy lifestyle change, chemoprevention with proton pump inhibitors and surveillance endoscopy every 3 to 5 years. It is recommended that from the presence of LGD patients are referred to an expert center for confirmation of the diagnosis, stage and thus define their management. In patients with BE and dysplasia or early-stage cancer, endoscopic therapy with resection and ablation is successful in about 90% of the patients. The main adverse event is esophageal stricture, which is managed endoscopically.

Development of Electronic Health Record-Based Machine Learning Models to Predict Barrett's Esophagus and Esophageal Adenocarcinoma Risk.

Screening for Barrett's esophagus (BE) is suggested in those with risk factors, but remains underutilized. BE/esophageal adenocarcinoma (EAC) risk prediction tools integrating multiple risk factors have been described. However, accuracy remains modest (area under the receiver-operating curve [AUROC] ≤0.7), and clinical implementation has been challenging. We aimed to develop machine learning (ML) BE/EAC risk prediction models from an electronic health record (EHR) database. The Clinical Data Analytics Platform, a deidentified EHR database of 6 million Mayo Clinic patients, was used to predict BE and EAC risk. BE and EAC cases and controls were identified using International Classification of Diseases codes and augmented curation (natural language processing) techniques applied to clinical, endoscopy, laboratory, and pathology notes. Cases were propensity score matched to 5 independent randomly selected control groups. An ensemble transformer-based ML model architecture was used to develop predictive models. We identified 8,476 BE cases, 1,539 EAC cases, and 252,276 controls. The BE ML transformer model had an overall sensitivity, specificity, and AUROC of 76%, 76%, and 0.84, respectively. The EAC ML transformer model had an overall sensitivity, specificity, and AUROC of 84%, 70%, and 0.84, respectively. Predictors of BE and EAC included conventional risk factors and additional novel factors, such as coronary artery disease, serum triglycerides, and electrolytes. ML models developed on an EHR database can predict incident BE and EAC risk with improved accuracy compared with conventional risk factor-based risk scores. Such a model may enable effective implementation of a minimally invasive screening technology.

Antireflux Surgery Versus Antireflux Medication and Risk of Esophageal Adenocarcinoma in Patients With Barrett’s Esophagus

Background and aimsAntireflux treatment is recommended to reduce esophageal adenocarcinoma in patients with Barrett’s esophagus. Antireflux surgery (fundoplication) counteracts gastroesophageal reflux of all types of carcinogenic gastric content, and reduces esophageal acid exposure to a greater extent than antireflux medication (proton pump inhibitors). We examined the hypothesis that antireflux surgery prevents esophageal adenocarcinoma to a larger degree than antireflux medication in patients with Barrett’s esophagus. MethodsThis multi-national and population-based cohort study included all patients with a diagnosis of Barrett’s esophagus in any of the national patient registries in Denmark (2012-2020), Finland (1987-1996 and 2010-2020), Norway (2008-2020), or Sweden (2006-2020). Patients who underwent antireflux surgery were compared with non-operated patients using antireflux medication. The risk of esophageal adenocarcinoma was calculated using multivariable Cox regression, providing hazard ratios (HR) with 95% confidence intervals (CI) adjusted for age, sex, country, calendar year, and comorbidity. ResultsThe cohort consisted of 33,939 patients with Barrett’s esophagus. Of these, 542 (1.6%) had undergone antireflux surgery. During up to 32 years of follow-up, the overall HR was not decreased in patients having undergone antireflux surgery compared to non-operated patients using antireflux medication but rather increased (adjusted HR 1.9, 95% CI 1.1-3.5). Additionally, HRs did not decrease with longer follow-up, but instead increased for each follow-up category, from 1.8 (95% CI 0.6-5.0) within 1-4 years of follow-up to 4.4 (95% CI 1.4-13.5) after 10-32 years of follow-up. ConclusionPatients with Barrett’s esophagus who undergo antireflux surgery do not seem to have a lower risk of esophageal adenocarcinoma than those using antireflux medication.