Multistage study design from marker discovery to validation. Workflow overview of initial marker discovery using WGMS on DNA extracted from endoscopic brushing samples with cross-reference to an archival RRBS dataset from DNA extracted from independent tissue samples, and independent validation comparing paired endoscopic brushings and sponge-on-string samples. EAC, esophageal adenocarcinoma; EM-seq, enzymatic methyl sequencing; methyl-seq, methyl sequencing; WGBS, whole genome bisulfite sequencing.

Aberrant DNA methylation and copy-number alterations (CNA) drive Barrett's esophagus progression to esophageal adenocarcinoma; however, their combined utility for early detection is unclear. We aimed to identify and validate methylated DNA markers (MDM) and CNAs to distinguish esophageal adenocarcinoma/high-grade dysplasia (HGD) from nondysplastic Barrett's esophagus (NDBE). In this multiphase, multicenter study, we discovered and validated MDMs and quantified CNAs utilizing whole-genome methylation sequencing of esophageal brushings. DNA biomarkers identified from discovery were further validated in independent patients with paired esophageal brushing and swallowed capsule sponge samples. MDMs were filtered against a reduced representation bisulfite sequencing dataset obtained from independent tissue samples to advance only concordant candidates. CNA burden was quantified using ichorCNA-derived aneuploidy scores (AS). Two hundred MDMs discovered in HGD (N = 18) and esophageal adenocarcinoma (N = 18) versus NDBE brushing samples (N = 18) were tested in independent samples (N = 146). A 52-MDM panel achieved a cross-validated AUC of 0.88 [95% confidence interval (CI), 0.82-0.95]; the addition of AS improved discrimination of HGD/esophageal adenocarcinoma from NDBE to 0.91 (95% CI, 0.86-0.97) AUC. At 80% specificity, the combined model detected 93% of esophageal adenocarcinoma and 88% of HGD cases. In paired capsule sponge samples, a 58-MDM panel achieved a cross-validated AUC of 0.77 (95% CI, 0.66-0.88); a combined 58-MDM and AS model achieved AUC 0.80 (95% CI, 0.7-0.9). MDMs and AS discerned HGD/esophageal adenocarcinoma from normal esophagus/NDBE in endoscopic brushing and capsule sponge samples. This approach may improve Barrett's esophagus surveillance.Prevention Relevance: This study demonstrates that combining epigenetic and genomic biomarkers across minimally invasive sampling methods can accurately distinguish HGD/esophageal adenocarcinoma from nondysplastic Barrett's esophagus, offering promising, less invasive strategies to improve BE surveillance and enable endoscopic therapy for esophageal adenocarcinoma prevention and treatment.

Intraluminal duodenal diverticulum (IDD) is an exceedingly rare congenital anomaly of the foregut. This entity is most frequently discovered incidentally during esophagogastroduodenoscopy; however, patients have reported symptoms of gastrointestinal obstruction, bleeding, or pancreatitis. In this report, we discuss a case of an IDD that was diagnosed during routine upper endoscopy in an adult woman who was referred to the gastroenterology clinic because of unexplained changes in her bowel habits.

ROC curves for MDM performance in paired endoscopic brush and sponge samples. A, AUC analysis demonstrating discrimination of HGD/esophageal adenocarcinoma (EAC) from NDBE using the MDM panel, AS, and the combination in endoscopic brush samples. B, Corresponding AUC analysis showing marker performance in paired available (Table 1) sponge-on-string samples from the same patients.

INTRODUCTION: Ongoing surveillance after successful endoscopic eradication therapy for Barrett's esophagus (BE)-related neoplasia is essential to detect and manage recurrence. Despite established surveillance interval recommendations after complete eradication of intestinal metaplasia (CE-IM), patient compliance with repeat endoscopy is frequently suboptimal. Understanding patient drivers to adherence is essential to inform interventions that address the high rates of overdue surveillance and loss to follow-up. METHODS: Patients with BE-related neoplasia who achieved CE-IM were eligible for inclusion and classified as delayed or on-time for endoscopic surveillance. Patients were prospectively enrolled and participated in structured virtual interviews designed to explore barriers and facilitators to on-time care. A rapid qualitative analysis approach was applied, continuing until thematic saturation was reached. RESULTS: Thirty-nine patients were interviewed: 22 (56.4%) were delayed, and 17 (43.6%) were on-time for surveillance. Patients in the delayed group had longer mean BE segment lengths and a higher prevalence of tobacco use. Geographic distance from the treatment center was the most frequently cited barrier to follow-up (n = 17; 43.5%). Other common barriers were access limitations, financial concerns, misunderstanding of disease course, and test-related anxiety. DISCUSSION: Patient-related drivers of delay in postendoscopic eradication therapy surveillance are largely logistical, socioeconomical, and psychological in nature. Solutions to reduce the significant burden on the patient and achieve timely surveillance may include transitioning patients back to their local endoscopists after CE-IM or incorporating nonendoscopic surveillance methods through patient centered approaches.

Methylation and copy-number profiles in discovery and validation case and control sample sets. For methylation, each row is a marker from the filtered set of 52 MDMs and each column a patient sample. For copy number, each row is a chromosomal arm. Methylation marker levels measured in deciles above the 95th percentile value in NDBE are denoted by the increasing intensity of yellow to red color spectrum. Copy-number analysis shows amplifications (red) or deletions (blue) referent to neutral (white) as estimated by the AS method. NDBE referent to NE (gray, neutral by definition). EAC, esophageal adenocarcinoma.

AUC of the 52-MDM model in cytology brush validation data comparing NDBE vs. HGD/EAC, stratified by covariates.

Supplemental Table 1: Study adherence to the STARD (Standards for Reporting Diagnostic Accuracy Studies) 2015 checklist.

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.

Background and Aims: Endoscopic eradication therapy (EET) is guideline endorsed for management of early-stage (T1) esophageal adenocarcinoma (EAC). Patients with baseline high-grade dysplasia (HGD) and EAC are at highest risk of recurrence after successful EET, but limited data exist on long-term (>5 year) recurrence outcomes. Our aim was to assess the incidence and predictors of long-term recurrence in a multicenter cohort of patients with T1 EAC treated with EET. Methods: Patients with T1 EAC achieving successful endoscopic cancer eradication with a minimum of 5 years' clinical follow-up were included. The primary outcome was neoplastic recurrence, defined as dysplasia or EAC, and it was characterized as early (<2 years), intermediate (2-5 years), or late (>5 years). Predictors of recurrence were assessed by time to event analysis. Results: A total of 84 T1 EAC patients (75 T1a, 9 T1b) with a median 9.1 years (range, 5.1-18.3 years) of follow-up were included. The overall incidence of neoplastic recurrence was 2.0 per 100 person-years of follow-up. Seven recurrences (3 dysplasia, 4 EAC) occurred after 5 years of EAC remission. Overall, 88% of recurrences were treated successfully endoscopically. EAC recurrence-related mortality occurred in 3 patients at a median of 5.2 years from EAC remission. Complete eradication of intestinal metaplasia was independently associated with reduced recurrence (hazard ratio, .13). Conclusions: Following successful EET of T1 EAC, neoplastic recurrence occurred after 5 years in 8.3% of cases. Careful long-term surveillance should be continued in this patient population. Complete eradication of intestinal metaplasia should be the therapeutic end point for EET.