Iyer, Prasad G.

Abstract Background Surveillance of nondysplastic Barrett’s esophagus (NDBE) is recommended to identify progression to dysplasia; however, the most cost-effective strategy remains unclear. Mutation of TP53 or aberrant expression of p53 have been associated with the development of dysplasia in BE. We sought to determine if surveillance intervals for BE could be stratified based on p53 expression. Methods A Markov model was developed for NDBE. Patients with NDBE underwent p53 immunohistochemistry (IHC) and those with abnormal p53 expression underwent surveillance endoscopy at 1 year, while patients with normal p53 expression underwent surveillance in 3 years. Patients with dysplasia underwent endoscopic therapy and surveillance. Results On base-case analysis, the strategy of stratifying surveillance based on abnormal p53 IHC was cost-effective relative to conventional surveillance and a natural history model, with an incremental cost-effectiveness ratio (ICER) of $8258 for p53 IHC-based surveillance. Both the conventional and p53-stratified surveillance strategies dominated the natural history model. On probabilistic sensitivity analysis, the p53 IHC strategy ($28 652; 16.78 quality-adjusted life years [QALYs]) was more cost-effective than conventional surveillance ($25 679; 16.17 QALYs) with a net monetary benefit of $306 873 compared with conventional surveillance ($297 642), with an ICER <$50 000 in 96% of iterations. The p53-stratification strategy was associated with a 14% reduction in the overall endoscopy burden and a 59% increase in dysplasia detection. Conclusion A surveillance strategy for BE based on abnormal p53 IHC is cost-effective relative to a conventional surveillance strategy and is likely to be associated with higher rates of dysplasia diagnosis.

INTRODUCTION: Preliminary data suggest that an encapsulated balloon (EsoCheck), coupled with a 2 methylated DNA biomarker panel (EsoGuard), detects Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) with high accuracy. The initial assay requires sample freezing upon collection. The purpose of this study was to assess a next-generation EsoCheck sampling device and EsoGuard assay in a much-enlarged multicenter study clinically enhanced by using a Clinical Laboratory Improvement Amendments of 1988-compliant assay and samples maintained at room temperature. METHODS: Cases with nondysplastic BE (NDBE), dysplastic BE (indefinite for dysplasia, low-grade dysplasia, high-grade dysplasia), EAC, junctional adenocarcinoma, plus endoscopy controls without esophageal intestinal metaplasia, were prospectively enrolled. Medical assistants at 6 institutions delivered the encapsulated balloon per orally with inflation in the stomach. The inflated balloon sampled the distal 5 cm of the esophagus and then was deflated and retracted into the capsule, preventing sample contamination. EsoGuard bisulfite sequencing assayed levels of methylated vimentin and methylated cyclin A1. RESULTS: A total of 243 evaluable patients—88 cases (median age 68 years, 78% men, 92% White) and 155 controls (median age 57 years, 41% men, 88% White)—underwent adequate EsoCheck sampling. The mean procedural time was approximately 3 minutes. Cases included 31 with NDBE, 16 with indefinite for dysplasia/low-grade dysplasia, 23 with high-grade dysplasia, and 18 with EAC/junctional adenocarcinoma. Thirty-seven NDBE and dysplastic BE cases (53%) were short-segment BE (<3 cm). Overall sensitivity was 85% (95% confidence interval 0.78–0.93) and specificity was 85% (95% confidence interval 0.79–0.90). Sensitivity for NDBE was 84%. EsoCheck/EsoGuard detected 100% of cancers (n = 18). DISCUSSION: EsoCheck/EsoGuard demonstrated high sensitivity and specificity in detecting BE and BE-related neoplasia.

Abstract Background Visceral fat represents a metabolically active entity linked to adverse metabolic sequelae of obesity. We aimed to determine if celiac artery mesenteric fat thickness can be reliably measured during endoscopic ultrasound (EUS), and if these measurements correlate with metabolic disease burden. Methods This was a retrospective analysis of patients who underwent celiac artery mesenteric fat measurement with endosonography (CAMEUS) measurement at a tertiary referral center, and a validation prospective trial of patients with obesity and nonalcoholic steatohepatitis who received paired EUS exams with CAMEUS measurement before and after six months of treatment with an intragastric balloon. Results CAMEUS was measured in 154 patients [56.5% females, mean age 56.5 ± 18.0 years, body mass index (BMI) 29.8 ± 8.0 kg/m2] and was estimated at 14.7 ± 6.5 mm. CAMEUS better correlated with the presence of non-alcoholic fatty liver disease (NAFLD) (R2 = 0.248, P &lt; 0.001) than BMI (R2 = 0.153, P &lt; 0.001), and significantly correlated with metabolic parameters and diseases. After six months of intragastric balloon placement, the prospective cohort experienced 11.7% total body weight loss, 1.3 points improvement in hemoglobin A1c (P = 0.001), and a 29.4% average decrease in CAMEUS (−6.4 ± 5.2 mm, P &lt; 0.001). CAMEUS correlated with improvements in weight (R2 = 0.368), aspartate aminotransferase to platelet ratio index (R2 = 0.138), and NAFLD activity score (R2 = 0.156) (all P &lt; 0.05). Conclusions CAMEUS is a novel measure that is significantly correlated with critical metabolic indices and can be easily captured during routine EUS to risk-stratify susceptible patients. This station could allow for EUS access to sampling and therapeutics of this metabolic region.

INTRODUCTION: Endoscopic eradication therapy (EET) combining endoscopic resection (ER) with endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) followed by ablation is the standard of care for the treatment of dysplastic Barrett's esophagus (BE). We have previously shown comparable rates of complete remission of intestinal metaplasia (CRIM) with both approaches. However, data comparing recurrence after CRIM are lacking. We compared rates of recurrence after CRIM with both techniques in a multicenter cohort. METHODS: Patients undergoing EET achieving CRIM at 3 academic institutions were included. Demographic and clinical data were abstracted. Outcomes included rates and predictors of any BE and dysplastic BE recurrence in the 2 groups. Cox-proportional hazards models and inverse probability treatment weighting (IPTW) analysis were used for analysis. RESULTS: A total of 621 patients (514 EMR and 107 ESD) achieving CRIM were included in the recurrence analysis. The incidence of any BE (15.7, 5.7 per 100 patient-years) and dysplastic BE recurrence (7.3, 5.3 per 100 patient-years) were comparable in the EMR and ESD groups, respectively. On multivariable analyses, the chances of BE recurrence were not influenced by ER technique (hazard ratio 0.87; 95% confidence interval 0.51–1.49; P = 0.62), which was also confirmed by IPTW analysis (ESD vs EMR: hazard ratio 0.98; 95% confidence interval 0.56–1.73; P = 0.94). BE length, lesion size, and history of cigarette smoking were independent predictors of BE recurrence. DISCUSSION: Patients with BE dysplasia/neoplasia achieving CRIM, initially treated with EMR/ablation, had comparable recurrence rates to ESD/ablation. Randomized trials are needed to confirm these outcomes between the 2 ER techniques.

Abstract Introduction: Barrett’s esophagus (BE) confers increased cancer risk. Endoscopic surveillance is recommended to distinguish non-dysplastic BE (NDBE), low grade dysplasia (LGD), high grade dysplasia (HGD), or adenocarcinoma (EAC) for endoscopic intervention. However, this paradigm is limited by sampling error, leading to missed/interval EAC. Herein, we aimed to classify these samples more accurately by performing whole genome methylation sequencing (WGMS) and utilizing multiple genomic features on endoscopic brush samples. Materials and methods: Endoscopic brush samples from patients with NDBE (n=18), HGD (18), EAC (18), and normal controls (18) were collected and underwent WGMS (discovery dataset). Sequence reads were processed through internal pipeline to extract CpG methylation and read level methylation ratio (alpha value). Copy number aberration (CNA) detection was performed using both CNVkit and ichorCNA. Differential methylated regions (DMRs) were identified through comparing EAC/HGD with NDBE and normal samples. Targeted methylation sequencing for selected DMRs and shallow WGMS were performed on EAC (41), HGD (26), LGD (23), NDBE (42), and normal controls (37) as validation. Ratio of the reads with alpha value&gt;0.6 for each DMR was used for further analysis. Detected CNA segments were summarized into chromosome arm loss or gain (aneuploidy score or AS representing the number of chromosome arms gained or lost in a sample) and trimmed median absolute deviation (tMAD). Classification models were developed using the discovery set and the best performing one was applied to the validation dataset. Results: Genome-wide DNA methylation largely segregated different groups of samples as diagnosed; however, some unexpected group crossings were observed. Top 200 DMRs were identified between EAC/HGD and NDBE and normal samples. CNA changes were widespread in EAC, very common in HGD but rare in NDBE (17/18 EACs,14/18 HGDs, 5/18 NDBEs with AS&gt;0). With tMAD &gt; 0.015, 16/18 EACs, 8/18 HGDs but none of 18 NDBEs passed the threshold. EAC or HGD samples without detectable CNAs had very low “tumor” fraction as determined by methylation-based cell type deconvolution or ichorCNA. Similar results were found in the validation dataset. A multi-omics (AS, tMAD, estimated tumor fraction, and DMR methylation) model could predict EAC, HGD, or NDBE with 0.81 accuracy through cross validation (10X) and 0.73 in the independent dataset. This increased to 0.98 and 0.90 in separating high risk EAC/HGD from NDBE, respectively. Conclusion: Multi-omics data obtained from single WGMS allow for a comprehensive analysis of BE samples with varying dysplasia levels. Using classification modeling, these characteristics can be effectively used to accurately identify and distinguish between EAC and HGD from NDBE, suggesting their utility as adjuncts to endoscopic surveillance biopsies. Citation Format: Zhifu Sun, Caroline L. Matchett, Seth W. Slettedahl, William R. Taylor, Panwen Wang, Calise Berger, Caryn E. Anderson, Melissa A. Passe, Ramona Lansing, Collin E. Chalmers, Patrick H. Foote, Jeanette E. Eckel Passow, Doug W. Mahoney, John B. Kisiel, Prasad G. Iyer. Multi-omics cancer risk assessment of Barrett’s esophagus with DNA methylation sequencing from endoscopic brush samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB249.

INTRODUCTION: A substantial proportion of patients with esophageal adenocarcinoma (EAC) do not report gastroesophageal reflux disease (GERD) symptoms. This study aimed to compare the risk factor profiles and cancer stage at presentation of patients with EAC with and without prior GERD. METHODS: In this retrospective cross-sectional study, patients with EAC were divided into 2 cohorts: (i) EAC with prior GERD: patients who reported typical GERD symptoms (heartburn or regurgitation) ≥1 year before cancer diagnosis and (ii) EAC without prior GERD: patients who did not report prior GERD symptoms or reported symptoms within 1 year of their cancer diagnosis. Baseline demographics, risk factors, and cancer stage at presentation were compared between the 2 cohorts. In addition, the distribution of patients based on numbers of BE/EAC–associated risk factors (1, 2, 3, 4, and 5 or more) was examined in the symptomatic and asymptomatic cohorts. RESULTS: Over 13 years, 388 patients with EAC with prior GERD and 245 patients with EAC without prior GERD were recruited. Both groups had similar baseline demographics and risk factors, but patients with EAC with prior GERD were more likely to have a history of BE. Asymptomatic patients had more advanced disease. Patients with 3 or more BE/EAC–related risk factors formed the largest proportion of patients in both the symptomatic and asymptomatic cohorts. DISCUSSION: Patients with EAC with and without prior GERD symptoms are phenotypically similar, suggesting that BE screening efforts to prevent or detect early EAC should not be restricted to just those with GERD.

INTRODUCTION: Endoscopic eradication therapy (EET) is standard of care for T1a esophageal adenocarcinoma (EAC). However, data on outcomes in high-risk T1a EAC are limited. We assessed and compared outcomes after EET of low-risk and high-risk T1a EAC, including intraluminal EAC recurrence, extraesophageal metastases, and overall survival. METHODS: Patients who underwent EET for T1a EAC at 3 referral Barrett's esophagus endotherapy units between 1996 and 2022 were included. Patients with submucosal invasion, positive deep margins, or metastases at initial diagnosis were excluded. High-risk T1a EAC was defined as T1a EAC with poor differentiation and/or lymphovascular invasion, with low-risk disease being defined without these features. All pathology was systematically assessed by expert gastrointestinal pathologists. Baseline and follow-up endoscopy and pathology data were abstracted. Time-to-event analyses were performed to compare outcomes between groups. RESULTS: One hundred eighty-eight patients with T1a EAC were included (high risk, n = 45; low risk, n = 143) with a median age of 70 years, and 84% were men. Groups were comparable for age, sex, Barrett's esophagus length, lesion size, and EET technique. Rates of delayed extraesophageal metastases (11.1% vs 1.4%) were significantly higher in the high-risk group ( P = 0.02). There was no significant difference in the rates of intraluminal EAC recurrence ( P = 0.79) and overall survival ( P = 0.73) between the 2 groups. DISCUSSION: Patients with high-risk T1a EAC undergoing successful EET had a substantially higher rate of extraesophageal metastases compared with those with low-risk T1a EAC on long-term follow-up. These data should be factored into discussions with patients while selecting treatment approaches. Additional prospective data in this area are critical.

INTRODUCTION: The coronavirus disease 19 (COVID-19) pandemic disrupted endoscopy practices, creating unprecedented decreases in cancer screening and surveillance services. We aimed to assess the impact of the pandemic on the proportion of patients diagnosed with Barrett's esophagus (BE) and BE-related dysplasia and adherence to established quality indicators. METHODS: Data from all esophagogastroduodenoscopies in the GI Quality Improvement Consortium, a national repository of matched endoscopy and pathology data, were analyzed from January 2018 to December 2022. Four cohorts were created based on procedure date and COVID-19 data: pre-pandemic (January 2018 to February 2020), pandemic-phase I (March 2020 to July 2020), pandemic-phase II (August 2020 to May 2021), and pandemic-phase III (June 2021 to December 2022). Observed and expected number of BE and BE-related dysplasia cases per month and adherence to the Seattle biopsy protocol and recommended surveillance intervals for nondysplastic BE (NDBE) were evaluated. RESULTS: Among 2,446,857 esophagogastroduodenoscopies performed during the study period, 104,124 (4.3%) had pathology-confirmed BE. The histologic distribution was 87.4% NDBE, 1.8% low-grade dysplasia, 2.4% indefinite for dysplasia, and 1.4% high-grade dysplasia. The number of monthly BE (−47.9% pandemic-phase I, −21.5% pandemic-phase II, and −19.0% pandemic-phase III) and BE-related dysplasia (high-grade dysplasia: 41.2%, −27.7%, and −19.0%; low-grade dysplasia: 49.1%, −35.3%, and −26.5%; any dysplasia: 46.7%, −32.3%, and −27.9%) diagnoses were significantly reduced during the pandemic phases compared with pre-pandemic data. Adherence rates to the Seattle protocol and recommended surveillance intervals for NDBE did not decline during the pandemic. DISCUSSION: There was a significant decline in the number of BE and BE-related dysplasia diagnoses during the COVID-19 pandemic, with an approximately 50% reduction in the number of cases of dysplasia diagnosed in the early pandemic. The absence of a compensatory increase in diagnoses in the pandemic-phase II and III periods may result in deleterious downstream effects on esophageal adenocarcinoma morbidity and mortality.