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While patients with Barrett's esophagus without dysplasia may benefit from endoscopic surveillance, those with low-grade dysplasia may be managed with either endoscopic surveillance or endoscopic eradication. Patients with Barrett's esophagus with high-grade dysplasia and/or intramucosal adenocarcinoma will generally require endoscopic eradication therapy. The management of Barrett's esophagus with dysplasia and early esophageal adenocarcinoma is predominantly endoscopic, with multiple effective methods available for the resection of raised neoplasia and ablation of flat neoplasia. High-dose proton-pump inhibitor therapy is advised during the treatment of Barrett's esophagus with dysplasia and early esophageal adenocarcinoma. After the endoscopic eradication of Barrett's esophagus and associated neoplasia, surveillance is required for the diagnosis and retreatment of recurrence or progression.

Purpose: Current endoscopy-based screening and surveillance programs have not been proven effective at decreasing esophageal adenocarcinoma (EAC) mortality, creating an unmet need for effective molecular tests for early detection of this highly lethal cancer. We conducted a genome-wide methylation screen to identify novel methylation markers that distinguish EAC and high-grade dysplasia (HGD) from normal squamous epithelium (SQ) or nondysplastic Barrett's esophagus (NDBE). Experimental Design: DNA methylation profiling of samples from SQ, NDBE, HGD, and EAC was performed using HM450 methylation arrays (Illumina) and reduced-representation bisulfate sequencing. Ultrasensitive methylation-specific droplet digital PCR and next-generation sequencing (NGS)-based bisulfite-sequencing assays were developed to detect the methylation level of candidate CpGs in independent esophageal biopsy and endoscopic brushing samples. Results: Five candidate methylation markers were significantly hypermethylated in HGD/EAC samples compared with SQ or NDBE (P < 0.01) in both esophageal biopsy and endoscopic brushing samples. In an independent set of brushing samples used to construct biomarker panels, a four-marker panel (model 1) demonstrated sensitivity of 85.0% and 90.8% for HGD and EACs respectively, with 84.2% and 97.9% specificity for NDBE and SQ respectively. In a validation set of brushing samples, the panel achieved sensitivity of 80% and 82.5% for HGD and EAC respectively, at specificity of 67.6% and 96.3% for NDBE and SQ samples. Conclusions: A novel DNA methylation marker panel differentiates HGD/EAC from SQ/NDBE. DNA-methylation–based molecular assays hold promise for the detection of HGD/EAC using esophageal brushing samples.

The relationship of age and date of birth (DOB) in the data

Background: Barrett's esophagus is often asymptomatic and only a small portion of Barrett's esophagus patients are currently diagnosed and under surveillance. Therefore, it is important to develop risk prediction models to identify high-risk individuals with Barrett's esophagus. Familial aggregation of Barrett's esophagus and esophageal adenocarcinoma, and the increased risk of esophageal adenocarcinoma for individuals with a family history, raise the necessity of including genetic factors in the prediction model. Methods to determine risk prediction models using both risk covariates and ascertained family data are not well developed.Methods: We developed a Barrett's Esophagus Translational Research Network (BETRNet) risk prediction model from 787 singly ascertained Barrett's esophagus pedigrees and 92 multiplex Barrett's esophagus pedigrees, fitting a multivariate logistic model that incorporates family history and clinical risk factors. The eight risk factors, age, sex, education level, parental status, smoking, heartburn frequency, regurgitation frequency, and use of acid suppressant, were included in the model. The prediction accuracy was evaluated on the training dataset and an independent validation dataset of 643 multiplex Barrett's esophagus pedigrees.Results: Our results indicate family information helps to predict Barrett's esophagus risk, and predicting in families improves both prediction calibration and discrimination accuracy.Conclusions: Our model can predict Barrett's esophagus risk for anyone with family members known to have, or not have, had Barrett's esophagus. It can predict risk for unrelated individuals without knowing any relatives' information.Impact: Our prediction model will shed light on effectively identifying high-risk individuals for Barrett's esophagus screening and surveillance, consequently allowing intervention at an early stage, and reducing mortality from esophageal adenocarcinoma. Cancer Epidemiol Biomarkers Prev; 25(5); 727–35. ©2016 AACR.

Supplementary Table 1. Missing rates for three risk factors by study site in BEAGESS Supplementary Table 2. Genome-wide significant single nucleotide polymorphisms (SNPs) selected for GxE analysis. Supplementary Table 3. Odds ratios (95% confidence intervals) for risk factors in the BEACON study according to the number of minor alleles (rs2687201 or rs10419226), using a combined BE/EA case group. Inverse probability weighting techniques were used to account for the missing risk factor data in the GXE interaction analysis. The weights were computed based on a logistic regression model fit to the indicator variable of the risk factor being observed, adjusting for case control status, region (Australia, Europe, North America), age, sex, SNP genotype, and four principal components. Supplementary Table 4. Odds ratios (95% confidence intervals) for risk factors in the BEACON study according to the number of minor alleles (rs2687201 or rs10419226), using a combined BE/EA case group. Supplementary Table 5. Thirteen imputed SNPs found to interact with GERD more significantly than rs2687201 in relation to risk of Barrett's esophagus (BE). Supplementary Table 6.1 Annotations for top SNPs identified in GxE analysis (ordered by interaction P value). Supplementary Table 6.2 Genotype-Tissue Expression (GTEx) eQTL analysis of top 14 SNPs identified.

Purpose:Current endoscopy-based screening and surveillance programs have not been proven effective at decreasing esophageal adenocarcinoma (EAC) mortality, creating an unmet need for effective molecular tests for early detection of this highly lethal cancer. We conducted a genome-wide methylation screen to identify novel methylation markers that distinguish EAC and high-grade dysplasia (HGD) from normal squamous epithelium (SQ) or nondysplastic Barrett's esophagus (NDBE).Experimental Design:DNA methylation profiling of samples from SQ, NDBE, HGD, and EAC was performed using HM450 methylation arrays (Illumina) and reduced-representation bisulfate sequencing. Ultrasensitive methylation-specific droplet digital PCR and next-generation sequencing (NGS)-based bisulfite-sequencing assays were developed to detect the methylation level of candidate CpGs in independent esophageal biopsy and endoscopic brushing samples.Results:Five candidate methylation markers were significantly hypermethylated in HGD/EAC samples compared with SQ or NDBE (P < 0.01) in both esophageal biopsy and endoscopic brushing samples. In an independent set of brushing samples used to construct biomarker panels, a four-marker panel (model 1) demonstrated sensitivity of 85.0% and 90.8% for HGD and EACs respectively, with 84.2% and 97.9% specificity for NDBE and SQ respectively. In a validation set of brushing samples, the panel achieved sensitivity of 80% and 82.5% for HGD and EAC respectively, at specificity of 67.6% and 96.3% for NDBE and SQ samples.Conclusions:A novel DNA methylation marker panel differentiates HGD/EAC from SQ/NDBE. DNA-methylation–based molecular assays hold promise for the detection of HGD/EAC using esophageal brushing samples.

Supplementary Methods of imputation of age and estimating the parameters of the prediction model. Supplementary Table S1 Missing rates on the 8 covariates in the training and validation datasets. Supplementary Table S2 Stepwise removal of covariates in the MLM model on the basis of LRT tests and AIC. Supplementary Table S3. Description of the eight predictor covariates. Supplementary Table S4 Number of informative pedigrees without missing covariate data.

Esophageal adenocarcinoma is a deadly cancer with increasing incidence in the United States, but mechanisms underlying pathogenesis are still mostly elusive. In addressing this question, we assessed gene fusion landscapes by comprehensive RNA sequencing (RNAseq) of 55 pretreatment esophageal adenocarcinoma and 49 nonmalignant biopsy tissues from patients undergoing endoscopy for Barrett's esophagus. In this cohort, we identified 21 novel candidate esophageal adenocarcinoma–associated fusions occurring in 3.33% to 11.67% of esophageal adenocarcinomas. Two candidate fusions were selected for validation by PCR and Sanger sequencing in an independent set of pretreatment esophageal adenocarcinoma (N = 115) and nonmalignant (N = 183) biopsy tissues. In particular, we observed RPS6KB1–VMP1 gene fusion as a recurrent event occurring in approximately 10% of esophageal adenocarcinoma cases. Notably, esophageal adenocarcinoma cases harboring RPS6KB1–VMP1 fusions exhibited significantly poorer overall survival as compared with fusion-negative cases. Mechanistic investigations established that the RPS6KB1–VMP1 transcript coded for a fusion protein, which significantly enhanced the growth rate of nondysplastic Barrett's esophagus cells. Compared with the wild-type VMP1 protein, which mediates normal cellular autophagy, RPS6KB1–VMP1 fusion exhibited aberrant subcellular localization and was relatively ineffective in triggering autophagy. Overall, our findings identified RPS6KB1–VMP1 as a genetic fusion that promotes esophageal adenocarcinoma by modulating autophagy-related processes, offering new insights into the molecular pathogenesis of esophageal adenocarcinomas. Cancer Res; 76(19); 5628–33. ©2016 AACR.

Supplementary Data from Novel DNA Methylation Biomarker Panel for Detection of Esophageal Adenocarcinoma and High-Grade Dysplasia

Association between 387 SNPs and risk of EA, BE, or EA/BE combined

Background: Several cancer-associated loci identified from genome-wide association studies (GWAS) have been associated with risks of multiple cancer sites, suggesting pleiotropic effects. We investigated whether GWAS-identified risk variants for other common cancers are associated with risk of esophageal adenocarcinoma (EA) or its precursor, Barrett's esophagus.Methods: We examined the associations between risks of EA and Barrett's esophagus and 387 SNPs that have been associated with risks of other cancers, by using genotype imputation data on 2,163 control participants and 3,885 (1,501 EA and 2,384 Barrett's esophagus) case patients from the Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study, and investigated effect modification by smoking history, body mass index (BMI), and reflux/heartburn.Results: After correcting for multiple testing, none of the tested 387 SNPs were statistically significantly associated with risk of EA or Barrett's esophagus. No evidence of effect modification by smoking, BMI, or reflux/heartburn was observed.Conclusions: Genetic risk variants for common cancers identified from GWAS appear not to be associated with risks of EA or Barrett's esophagus.Impact: To our knowledge, this is the first investigation of pleiotropic genetic associations with risks of EA and Barrett's esophagus. Cancer Epidemiol Biomarkers Prev; 24(11); 1801–3. ©2015 AACR.

Contains Supplementary Figures 1-3 as follows: Supplementary Figure 1: Full-length sequence and protein domains of RPS6KB1-VMP1 and OSBPL1A-LAMA3 fusion transcripts identified in EACs Supplementary Figure 2: Somatic copy-number aberrations in the RPS6KB1 and VMP1 genomic locus Supplementary Figure 3: NIH/3T3 transformation assay

Supplemental Figure S1: Assessment of precision of pyrosequencing assay for methylated B3GAT2 and ZNF793. Supplemental Figure S2: Correlation of pyrosequencing results with HM450 array beta values.Supplemental Figure S3: Methylation status of B3GAT2 cg16556906 in esophageal tissues and stomach tissues and AUC analysis. Supplemental Figure S4. Methylation status of B3GAT2 cg 'PS2' in esophageal and stomach tissues and AUC analysis. Supplemental Figure S5: Methylation status of ZNF793 CpGs in esophageal and gastric tissues and AUC analysis. Supplemental Figure S6. Results of pyrosequencing assays for methylated B3GAT2 cg PS2 (position 2) run on an independent validation set of tissue samples.

Background: Barrett's esophagus (BE) is a preneoplastic condition in which normal esophageal squamous epithelium (SQ) is replaced by specialized intestinal metaplasia. It is the presumed precursor for esophageal adenocarcinoma (EAC) as well as the strongest risk factor for this cancer. Unfortunately, many patients with BE go undiagnosed under the current BE screening guidelines. The development of noninvasive and accurate BE detection assays could potentially identify many of these undiagnosed BE patients.Methods: DNA methylation is a common epigenetic alteration in BE. Therefore, we conducted a genome-wide methylation screen to identify potential BE biomarkers. Samples from SQ (N = 12), stomach (N = 28), and BE (N = 29) were analyzed and methylation levels at over 485,000 CpG sites were compared. Pyrosequencing assays were used to validate the results and MethyLight assays were developed to detect the methylated alleles in endoscopic brushings.Results: We discovered two genes, B3GAT2 and ZNF793, that are aberrantly methylated in BE. Clinical validation studies confirmed B3GAT2 and ZNF793 methylation levels were significantly higher in BE samples (median = 32.5% and 33.1%, respectively) than in control tissues (median = 2.29% and 2.52%, respectively; P < 0.0001 for both genes). Furthermore, gene-specific MethyLight assays could accurately detect BE (P < 0.0001 for both) in endoscopic brushing samples.Conclusion: B3GAT2 and ZNF793 are hypermethylated in BE, and the methylation status of these genes can be used to detect BE in tissue samples.Impact: These findings support the development of methylated B3GAT2 and ZNF793 as biomarkers for noninvasive assays for the detection of BE. Cancer Epidemiol Biomarkers Prev; 24(12); 1890–7. ©2015 AACR.

Excel file containing Supplementary Tables 1-7 as follows: Supplementary Table 1 - Sample distribution in the discovery RNAseq cohort Supplementary Table 2 - Fusion transcripts detected in EACs in the discovery RNAseq cohort Supplementary Table 3 - Fusion transcripts detected in non-malignant samples in the discovery RNAseq cohort Supplementary Table 4 - Candidate fusion transcripts in EACs in the discovery RNAseq cohort Supplementary Table 5 - Sample distribution in the validation cohort Supplementary Table 6 - Candidate fusion frequencies in EACs in the discovery and validation cohorts Supplementary Table 7 - Candidate fusions found in both EAC and matched normal SQ tissues in the discovery cohort

Figure legends

Contains detailed experimental methods

Supplementary Figure from Novel DNA Methylation Biomarker Panel for Detection of Esophageal Adenocarcinoma and High-Grade Dysplasia

Supplemental Table S2: Methylation levels for B3GAT2 and ZNF793 from Human Methylation450 arrays.

Supplementary Figure S1. NIH Roadmap Epigenome Atlas characterization of genomic regions flanking rs2687201.

Background: Important risk factors for esophageal adenocarcinoma and its precursor, Barrett's esophagus, include gastroesophageal reflux disease, obesity, and cigarette smoking. Recently, genome-wide association studies have identified seven germline single-nucleotide polymorphisms (SNP) that are associated with risk of Barrett's esophagus and esophageal adenocarcinoma. Whether these genetic susceptibility loci modify previously identified exposure–disease associations is unclear.Methods: We analyzed exposure and genotype data from the BEACON Consortium discovery phase GWAS, which included 1,516 esophageal adenocarcinoma case patients, 2,416 Barrett's esophagus case patients, and 2,187 control participants. We examined the seven newly identified susceptibility SNPs for interactions with body mass index, smoking status, and report of weekly heartburn or reflux. Logistic regression models were used to estimate ORs for these risk factors stratified by SNP genotype, separately for Barrett's esophagus and esophageal adenocarcinoma.Results: The odds ratio for Barrett's esophagus associated with at least weekly heartburn or reflux varied significantly with the presence of at least one minor allele of rs2687201 (nominal P = 0.0005, FDR = 0.042). ORs (95% CIs) for weekly heartburn or reflux among participants with 0, 1, or 2 minor alleles of rs2687201 were 6.17 (4.91–7.56), 3.56 (2.85–4.44), and 3.97 (2.47–6.37), respectively. No statistically significant interactions were observed for smoking status and body mass index.Conclusion: Reflux symptoms are more strongly associated with Barrett's esophagus risk among persons homozygous for the major allele of rs2687201, which lies approximately 75 kb downstream of the transcription factor gene FOXP1.Impact: The novel gene–exposure interaction discovered in this study provides new insights into the etiology of esophageal adenocarcinoma. Cancer Epidemiol Biomarkers Prev; 24(11); 1739–47. ©2015 AACR.

Supplementary Table 3 from A Multicenter, Double-Blinded Validation Study of Methylation Biomarkers for Progression Prediction in Barrett's Esophagus

Supplementary Table 1 from A Multicenter, Double-Blinded Validation Study of Methylation Biomarkers for Progression Prediction in Barrett's Esophagus

Supplementary Table 4 from A Multicenter, Double-Blinded Validation Study of Methylation Biomarkers for Progression Prediction in Barrett's Esophagus

Supplementary Figure 2 from A Multicenter, Double-Blinded Validation Study of Methylation Biomarkers for Progression Prediction in Barrett's Esophagus

Supplementary Figure 1 from A Multicenter, Double-Blinded Validation Study of Methylation Biomarkers for Progression Prediction in Barrett's Esophagus

Supplementary Table 2 from A Multicenter, Double-Blinded Validation Study of Methylation Biomarkers for Progression Prediction in Barrett's Esophagus

BACKGROUND & AIMS: A non-endoscopic approach to Barrett’s esophagus (BE) surveillance after radiofrequency ablation (RFA) would offer a less invasive method for monitoring. We assessed the test characteristics and cost-effectiveness of the Cytosponge® in post-RFA patients. METHODS: We performed a multicenter study of dysplastic BE patients after at least one round of RFA. A positive Cytosponge® before endoscopy was defined as intestinal metaplasia (IM) on cytological assessment and/or TFF3 immunohistochemistry. Sensitivity, specificity, and receiver operator characteristic (ROC) curves were calculated. Multivariable regression was used to estimate the odds of a positive Cytosponge® in BE. A microsimulation cost-effectiveness model was performed to assess outcomes of various surveillance strategies: endoscopy-only, Cytosponge®-only, and alternating endoscopy/Cytosponge®. RESULTS: Of 234 patients, Cytosponge® adequately sampled the distal esophagus in 175 (75%). Of the 142 with both endoscopic and histologic data, 19 (13%) had residual/recurrent BE. For detecting any residual Barrett’s, Cytosponge® had a sensitivity of 74%, specificity of 85%, accuracy of 84%, and ROC curve showed an area under the curve of 0.74. The adjusted odds of a positive Cytosponge® in BE were 17.1 (95% CI: 5.2–55.9). Cytosponge®-only surveillance dominated all the surveillance strategies, being both less costly and more effective. Cytosponge®-only surveillance required

DESCRIPTION: The purpose of this best practice advice (BPA) article from the Clinical Practice Update Committee of the American Gastroenterological Association is to provide an update on advances and innovation regarding the screening and surveillance of Barrett’s esophagus. METHODS: The BPA statements presented here were developed from expert review of existing literature combined with discussion and expert opinion to provide practical advice. Formal rating of the quality of evidence or strength of BPAs was not the intent of this clinical practice update. This expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPUC and external peer review through standard procedures of Clinical Gastroenterology and Hepatology. BEST PRACTICE ADVICE 1: Screening with standard upper endoscopy may be considered in individuals with at least 3 established risk factors for Barrett’s esophagus (BE) and esophageal adenocarcinoma, including individuals who are male, non-Hispanic white, age >50 years, have a history of smoking, chronic gastroesophageal reflux disease, obesity, or a family history of BE or esophageal adenocarcinoma. BEST PRACTICE ADVICE 2: Nonendoscopic cell-collection devices may be considered as an option to screen for BE. BEST PRACTICE ADVICE 3: Screening and surveillance endoscopic examination should be performed using high-definition white light endoscopy and virtual chromoendoscopy, with endoscopists spending adequate time inspecting the Barrett’s segment. BEST PRACTICE ADVICE 4: Screening and surveillance exams should define the extent of BE using a standardized grading system documenting the circumferential and maximal extent of the columnar lined esophagus (Prague classification) with a clear description of landmarks and the location and characteristics of visible lesions (nodularity, ulceration), when present. BEST PRACTICE ADVICE 5: Advanced imaging technologies such as endomicroscopy may be used as adjunctive techniques to identify dysplasia. BEST PRACTICE ADVICE 6: Sampling during screening and surveillance exams should be performed using the Seattle biopsy protocol (4-quadrant biopsies every 1–2 cm and target biopsies from any visible lesion). BEST PRACTICE ADVICE 7: Wide-area transepithelial sampling may be used as an adjunctive technique to sample the suspected or established Barrett’s segment (in addition to the Seattle biopsy protocol). BEST PRACTICE ADVICE 8: Patients with erosive esophagitis should be biopsied when concern of dysplasia or malignancy exists. A repeat endoscopy should be performed after 8 weeks of twice a day proton pump inhibitor therapy. BEST PRACTICE ADVICE 9: Tissue systems pathology-based prediction assay may be utilized for risk stratification of patients with nondysplastic BE. BEST PRACTICE ADVICE 10: Risk stratification models may be utilized to selectively identify individuals at risk for Barrett’s associated neoplasia. BEST PRACTICE ADVICE 11: Given the significant interobserver variability among pathologists, the diagnosis of BE-related neoplasia should be confirmed by an expert pathology review. BEST PRACTICE ADVICE 12: Patients with BE-related neoplasia should be referred to endoscopists with expertise in advanced imaging, resection, and ablation. BEST PRACTICE ADVICE 13: All patients with BE should be placed on at least daily proton pump inhibitor therapy. BEST PRACTICE ADVICE 14: Patients with nondysplastic BE should undergo surveillance endoscopy in 3 to 5 years. BEST PRACTICE ADVICE 15: In patients undergoing surveillance after endoscopic eradication therapy, random biopsies should be taken of the esophagogastric junction, gastric cardia, and the distal 2 cm of the neosquamous epithelium as well as from all visible lesions, independent of the length of the original BE segment.

Background The comparative effectiveness of trimodality therapy vs definitive chemoradiation for treating locally advanced esophageal cancer in older adults is uncertain. Existing trials lack generalizability to older adults, a population with heightened frailty. We sought to emulate a hypothetical trial comparing these treatments using real-world data. Methods A cohort of adults aged 66-79 years diagnosed with locally advanced esophageal cancer between 2004 and 2017 was identified in the Surveillance Epidemiology and End Results–Medicare database. The clone-censor-weight method was leveraged to eliminate time-related biases when comparing outcomes between treatments. Outcomes included overall mortality, esophageal cancer–specific mortality, functional adverse events, and healthy days at home. Results A total of 1240 individuals with adenocarcinomas and 661 with squamous cell carcinomas were identified. For adenocarcinomas, the standardized 5-year risk of mortality was 73.4% for trimodality therapy and 83.8% for definitive chemoradiation (relative risk [RR] = 0.88, 95% confidence interval [CI] = 0.82 to 0.95). Trimodality therapy was associated with mortality risk reduction for squamous cell carcinomas (RR = 0.87, 95% CI = 0.70 to 1.01). The 1-year incidence of functional adverse events was higher in the trimodality group (adenocarcinomas RR = 1.40, 95% CI = 1.22 to 1.65; squamous cell carcinomas RR = 1.21, 95% CI = 1.00 to 1.49). Over 5 years, trimodality therapy was associated with 160 (95% CI = 67 to 229) and 177 (95% CI = 51 to 313) additional home days in individuals with adenocarcinomas and squamous cell carcinomas, respectively. Conclusions Compared with definitive chemoradiation, trimodality therapy was associated with reduced mortality but increased risk of function-related adverse events. Discussing these tradeoffs may help optimize care plans.

Gender disparities remain in the field of gastroenterology (GI) despite the decreasing gender gap in the medical field overall. We sought to examine primary and last female authorship as a marker of academic opportunity and advancement to assess the proportion of women publishing in GI over 20 years (1997–2017). In this observational study, we assessed the gender and nationality of primary and last authors of original research manuscripts in three GI journals (Gastroenterology, Gut, and American Journal of Gastroenterology) across a 20-year period in 5-year intervals (in 1997, 2002, 2007, and 2012). We used a validated gender-determining algorithm, genderize.io, to classify gender. Our primary outcome was the proportion of female primary and last authors, with secondary measures assessing trends in gender and nationality. Through the Genderize.io gender database, we were able to identify the gender for 3,673 (95.9%) of primary author names and 3,504 (95.4%) of last author names in the 3,615 manuscripts evaluated. Overall, there was a significant increase in female primary authors over time, from 18.1% in 1997 to 42.6% in 2017, a 6.0% increase per 5-year period (95% CI 4.8–7.2%). A similar trend was found for female last authors, however, at a slower rate, from 8.3% in 1997 to 24.7% in 2017, a 3.5% increase per 5 years (95% CI 2.5–4.4%). These trends were noted cumulatively, and in each journal individually. Manuscripts with a female last author were more likely to demonstrate a female primary author. Female authorship in high-impact gastroenterology journals has increased over time. Last authorship has lagged primary authorship in female representation and has increased more slowly over time. Interventions to reduce gender disparity in GI research should focus on the transition from first to last authorship.

The identification of hereditary cancer genes for esophageal adenocarcinoma (EAC) and its precursor, Barrett’s esophagus (BE), may prove critical for the development of novel prevention and treatment strategies. Specifically, efforts for detecting BE and EAC susceptibility genes have focused on families with three or more affected members, since these individuals have an earlier age onset compared to non-familial individuals. Given that the use of BE may overestimate the likelihood of disease heritability, we evaluated the age of diagnosis in kindreds with a restricted definition including only confirmed high-grade dysplasia (HGD) or EAC. The Familial Barrett’s Esophagus Consortium database was used to identify individuals with HGD and EAC. These individuals were subsequently split into three kindred groups: non-familial—a single affected family member, duplex—two affected family members, and multiplex—three or more affected family members. Age of cancer diagnosis and other risk factors were compared between individuals in these groups. The study included 441 non-familial, 46 duplex, and 13 multiplex individuals. There was a statistically significant difference for age of diagnosis for individuals in the multiplex families compared to the non-familial and duplex families (56.0 versus 64.3, 63.5; p = 0.049). There was no significant difference between demographic factors and other cancer risk factors between family types. The results of this study support a genetic basis for familial Barrett’s associated neoplasia and evaluation of the genetic susceptibility to this disease should continue to focus on families with multiple (three or more) affected members.

Endoscopic screening for Barrett’s esophagus (BE) is common, costly, and underperformed in at-risk people. A non-endoscopic cell collection device can be used to collect esophageal cells, enabling BE screening. This study assessed the acceptability and adequacy of a commercial non-endoscopic cell collection device in a US population. Six sites enrolled patients with confirmed BE or heartburn/regurgitation for ≥ 6 months. Patients underwent administration of the device, consisting of a sponge encapsulated in a capsule. The capsule dwelled in the stomach for 7.5 min and was retracted via an attached suture. An adequate sample was ≥ 1 columnar cell by H&E staining. Sample quality was rated using a 0–5 scale, with 0 = no columnar cells and 5 = plentiful groups. Trefoil Factor 3 (TFF3) staining was performed. Accuracy was assessed using esophagogastroduodenoscopy (EGD)/biopsy as the gold standard. Of 191 patients, 99.5% successfully swallowed the device. Overall sample adequacy was 91% (171/188), with 84% (158/188) high quality. The detachment rate was 2/190 (1%). Overall sensitivity, specificity, and accuracy of the assay with TFF3 staining were 76%, 77%, and 76%. Sensitivity, specificity, and accuracy for ≥ 3 cm BE were 86%, 77%, and 82%. Asked if willing to repeat the procedure, 93% would, and 65% indicated a preference for the device over EGD. This study demonstrated a high rate of sample adequacy and promising acceptability of this non-endoscopic sampling device in a US population. Diagnostic characteristics suggest that non-endoscopic assessment of BE deserves further development as an alternative to endoscopy.

Backgrounds & Aims Endoscopic management of gastroesophageal reflux disease (GERD) is being employed increasingly. The aim of this scoping review was to assess the volume of available evidence on the benefits of endoscopic and minimally invasive surgical therapies for GERD. METHODS criteria were used to perform an extensive literature search of data regarding the reported benefit of endoscopic therapies in GERD. Randomized controlled studies were utilized when available; however, data from observational studies were also reviewed. Results A formal review of evidence was performed in 22 studies. Inclusion and exclusion criteria and study duration were noted and tabulated. Assessment of outcomes was based on symptoms and objective criteria reported by investigators. Reported outcomes for the interventions were tabulated under the heading of subjective (symptom scores, quality of life metrics, and change in proton pump inhibitor use) and objective metrics (pH parameters, endoscopic signs, and lower esophageal sphincter pressure changes). Adverse events were noted and tabulated. The majority of studies showed symptomatic and objective improvement of GERD with the device therapies. Adverse events were minimal. However, normalization of acid exposure occurred in about 50% of patients and, for some modalities, long-term durability is uncertain. Conclusions This scoping review revealed that the endoluminal and minimally invasive surgical devices for GERD therapy are a promising alternative to proton pump inhibitor therapy. Their place in the treatment algorithm for GERD will be better defined when important clinical parameters, especially durability of effect, are better understood.

Introduction Ablation of Barrett's esophagus (BE) is the preferred approach for the treatment of neoplasia without visible lesions. Limited data on cryoballoon ablation (CBA) suggest its potential clinical utility. We evaluated the safety and efficacy of CBA in a multicenter study of patients with neoplastic BE. Methods In a prospective clinical trial, 11 academic and community centers recruited consecutive patients with BE of 1-6 cm length and low-grade dysplasia, high-grade dysplasia (HGD), or intramucosal adenocarcinoma (ImCA) confirmed by central pathology. Patients with symptomatic pre-existing strictures or visible BE lesions had dilation or endoscopic mucosal resection (EMR), respectively, before enrollment. A nitrous oxide cryoballoon focal ablation system was used to treat all visible columnar mucosa in up to 5 sessions. Study end points included complete eradication of all dysplasia (CE-D) and intestinal metaplasia (CE-IM) at 1 year. Results One hundred twenty patients with BE with ImCA (20%), HGD (56%), or low-grade dysplasia (23%) were enrolled. In the intention-to-treat analysis, the CE-D and CE-IM rates were 76% and 72%, respectively. In the per-protocol analysis (94 patients), the CE-D and CE-IM rates were 97% and 91%, respectively. Postablation pain was mild and short lived. Fifteen subjects (12.5%) developed strictures requiring dilation. One patient (0.8%) with HGD progressed to ImCA, which was successfully treated with EMR. Another patient (0.8%) developed gastrointestinal bleeding associated with clopidogrel use. One patient (0.8%) had buried BE with HGD in 1 biopsy, not confirmed by subsequent EMR. Discussion In patients with neoplastic BE, CBA was safe and effective. Head-to-head comparisons between CBA and other ablation modalities are warranted (clinicaltrials.gov registration NCT02514525).

OBJECTIVES The aim of this study was to evaluate penetration of antiretrovirals into compartments and efficacy of a dual, NRTI-sparing regimen in acute HIV infection (AHI). DESIGN Single-arm, open-label pilot study of participants with AHI initiating ritonavir-boosted darunavir 800 mg once daily and etravirine 400 mg once daily or 200 mg twice daily within 30 days of AHI diagnosis. METHODS Efficacy was defined as HIV RNA less than 200 copies/ml by week 24. Optional sub-studies included pharmacokinetics analysis from genital fluids (weeks 0-4, 12, 48), cerebrospinal fluid (CSF) (weeks 2-4, 24 and 48) and endoscopic biopsies (weeks 4-12 and 36-48). Neuropsychological performance was assessed at weeks 0, 24 and 48. RESULTS Fifteen AHI participants were enrolled. Twelve (80%) participants achieved HIV RNA less than 200 copies/ml by week 24. Among 12 participants retained through week 48, nine (75%) remained suppressed to less than 50 copies/ml. The median time from ART initiation to suppression less than 200 and less than 50 copies/ml was 59 and 86 days, respectively. The penetration ratios for etravirine and darunavir in gut associated lymphoid tissue were 19.2 and 3.05, respectively. Most AHI participants achieving viral suppression experienced neurocognitive improvement. Of the three participants without overall improvement in neurocognitive functioning as measured by impairment ratings (more than two tests below 1 SD), two had virologic failure. CONCLUSION NRTI-sparing ART started during AHI resulted in rapid viral suppression similar to NRTI-based regimens. More novel and compact two-drug treatments for AHI should be considered. Early institution of ART during AHI appears to improve overall neurocognitive function and may reduce the risk of subsequent neurocognitive impairment. CLINICALTRIALS.GOV:: NCT00855413.

The incidence of Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC) continues to rise, and risk stratification of patients with BE is needed. Impaired esophageal motility is associated with gastroesophageal reflux disease; however, whether esophageal dysmotility is a risk factor for dysplasia progression in BE is incompletely understood. This study aimed to characterize esophageal motility patterns in patients with BE and identify physiologic factors associated with dysplasia progression in BE. This multicenter retrospective study assessed data from adult patients with histologically confirmed BE who underwent high-resolution esophageal manometry from 1/2014 to 1/2018 at four tertiary care centers. Longitudinal data were collected when available among patients with non-dysplastic BE (NDBE) and separated as: no dysplastic progression or positive dysplastic progression. Multivariable logistic regression assessed for independent predictors of dysplasia progression. Among 193 patients, histology at index endoscopy identified 152 (79%) NDBE, 23 (12%) low-grade dysplasia, 14 (7%) high-grade dysplasia, and 4 (2%) EAC. Ninety-eight (51%) had abnormal esophageal motor function on manometry. Longitudinal data were available for 84 of 152 patients with initial NDBE. Twelve (14%) exhibited dysplastic progression to low-grade (6) or high-grade (6) dysplasia. Mean esophageal distal contractile integral was lower for patients that progressed [455 mmHg s cm (SD 515)] compared with patients who did not progress [987 mmHg s cm (SD 953); aOR 1.21 (95% CI 1.01, 1.44)]. In this retrospective study of 193 BE patients, the majority exhibited abnormal esophageal motor function. Reduced esophageal contractility was independently associated with dysplastic progression in BE. Characterizing esophageal physiology in BE may help to risk stratify patients.

Description: The purpose of this best practice advice article is to describe the role of Barrett's endoscopic therapy (BET) in patients with Barrett's esophagus (BE) with dysplasia and/or early cancer and appropriate follow-up of these patients. Methods: The best practice advice provided in this document is based on evidence and relevant publications reviewed by the committee. Best Practice Advice 1: In BE patients with confirmed low-grade dysplasia, a repeat examination with high-definition white-light endoscopy should be performed within 3–6 months to rule out the presence of a visible lesion, which should prompt endoscopic resection. Best Practice Advice 2: Both BET and continued surveillance are reasonable options for the management of BE patients with confirmed and persistent low-grade dysplasia. Best Practice Advice 3: BET is the preferred treatment for BE patients with high-grade dysplasia (HGD). Best Practice Advice 4: BET should be preferred over esophagectomy for BE patients with intramucosal esophageal adenocarcinoma (T1a). Best Practice Advice 5: BET is a reasonable alternative to esophagectomy in patients with submucosal esophageal adenocarcinoma (T1b) with low-risk features (

Background Question prompt lists (QPLs) are structured sets of disease-specific questions intended for patient use, encouraging patients to ask questions to facilitate their consultation with their physician. Aim The aim of this study was to develop a QPL specific to adults with gastroesophageal reflux disease (GERD), created by esophageal experts. Methods The QPL content (78 questions) was derived through a modified Delphi method consisting of 2 rounds. In round 1, 18 esophageal experts provided 5 answers to the prompt "What you wish your patients would ask" and "What questions do patients often not ask, that I wish they would ask?" In round 2, the experts rated each question on a 5-point Likert scale, and responses rated as "essential" or "important," determined by an a priori threshold of ≥4.0, were accepted for the QPL. Results Twelve esophageal experts participated. Of 143 questions from round 1, 110 (76.9%) were accepted for inclusion in the QPL, meeting a median value of ≥4.0, and, subsequently, it reduced to 78, minimizing redundancy. Median values ranged between 4.0 and 5.0, with the highest agreement median (5.0) for questions asking dosing and timing of proton pump inhibitor therapy, and surveillance in Barrett's. Questions were categorized into the following categories: "What does this illness mean," "lifestyle modifications," "general treatment," "treatment with proton pump inhibitors," "What I should expect for my future," and "Barrett's." The largest number of questions covered lifestyle modifications (21.8%), with the highest agreement median (5.0) for "How helpful are lifestyle modifications in GERD?" Conclusions A preliminary GERD-specific QPL, the first of its kind, was developed by esophageal experts. Modification after more patient consultation and feedback is planned in subsequent versions to create a GERD-QPL for eventual use in clinical gastroenterology.

Despite societal recommendations supporting Barrett's esophagus (BE) screening, it is unknown what proportion of eligible patients is screened in primary care. We assessed the proportion of BE screening- eligible patients evaluated in the primary care setting receiving upper esophagogastroduodenoscopy (EGD) and identified factors associated with undergoing EGD.This was a retrospective study of BE screening-eligible patients, as defined by the American College of Gastroenterology's BE guidelines, in a multipractice healthcare network consisting of 64 internal medicine practices and 94 family medicine (FM) practices. The proportion undergoing EGD, prevalence of BE and esophageal adenocarcinoma (EAC) in this group, and patient and provider factors associated with undergoing EGD were assessed. Multivariable logistic regression was performed to identify independent predictors of undergoing EGD.Of 1,127 screening-eligible patients, the mean age was 65.2 ± 8.6 years; 45% were obese; and 61% were smokers. Seventy-three percent were seeing FM; 94% were on proton pump inhibitors; and 44% took ≥1 gastroesophageal reflux disease (GERD) medication. Only 39% of patients (n = 436) had undergone EGD. The overall prevalence of BE or EAC was 9.9%. Of 39 (9%) referred for BE screening as the primary indication, BE/EAC prevalence was 35.1%. Factors associated with increased odds of having EGD were symptomatic GERD despite treatment (odds ratio [OR] 12.1, 95% confidence interval [CI] 9.1-16.3), being on ≥1 GERD medication (OR 1.4, 95% CI 1.0-1.9), and being an FM patient (OR 1.5, 95% CI 1.1-2.1).In this large, primary care population, only 39% of screening-eligible patients underwent EGD. Most of the examinations were triggered by refractory symptoms rather than screening referrals, highlighting a need for improved dissemination and implementation of BE screening.