Esophageal cancer is a deadly disease that is becoming increasingly common in the United States. Barrett's esophagus (BE) is a pre-cancerous state that can develop into esophageal cancer, but is highly treatable. Progression of BE to esophageal cancer is still common due to missed diagnosis of Barrett's esophagus recurrence following treatment. Wide-Area Trans-Epithelial Sampling (WATS-3D) is a new technology that uses brush sampling to examine larger areas of the esophagus as compared to conventional biopsies. Preliminary studies show improved detection of cancerous changes in Barrett's esophagus surveillance. The investigators hope to see if the addition of WATS-3D increases the rate of detection of recurrent BE following treatment, which is of the utmost importance since it would allow for earlier re-treatment of disease and ultimately allow for prevention of progression to esophageal cancer.

Barrett's esophagus (BE) affects 5-15% of all patients with gastroesophageal reflux disease and approximately 1-2% of the entire population. The stepwise progression of BE from intestinal metaplasia (IM) to dysplasia can ultimately lead to esophageal adenocarcinoma (EAC). There are over 15,000 cases of EAC diagnosed in the United States each year. Regardless of stage of disease at time of diagnosis, the 5-year survival for EAC is an abysmal 19%. Endoscopic eradication therapy (EET) has been shown to be very effective in preventing progression of dysplastic BE to EAC with rates of complete eradication of intestinal metaplasia (CE-IM) > 90%. This is of paramount importance given the poor outcomes associated with the development of EAC.

Despite high success rates in achieving CE-IM, recent studies show that the recurrence of IM following CE-IM occurs with annual incidence of 8-10% and a 2-3% dysplasia rate per patient year of follow-up. The current paradigm of endoscopic surveillance following CE-IM focuses on random biopsies, which has raised concerns about sampling error and missed recurrence of IM and dysplasia leading to increased risk of interval development of EAC. New technologies, such as Wide-Area Trans-Epithelial Sampling (WATS-3D; CDx Diagnostics, Suffern, NY) have been studied to improve detection of dysplasia in BE. WATS-3D involves abrasive brush sampling of the esophagus that is then processed by a validated computer imaging system and subsequently reviewed by pathologist. Prior studies have shown increased dysplasia detection in routine BE surveillance with WATS-3D over standard biopsies, however there are no published data as to the additive value of WATS-3D for detection of recurrence of disease after endoscopic therapy.

Problem Statement:

Despite high success rates of successful eradication of BE with EET, recurrence rates are still high. Current Seattle Protocol biopsies for Post-EET surveillance is time-consuming, difficult to reproduce, and often misses IM recurrence putting patients at increased risk of developing EAC.

Hypothesis and Specific Aims:

The investigators hypothesize that the addition of WATS-3D to standard four-quadrant biopsies driven by HD-WLE and Narrow Band Imaging (NBI) will increase the rate of detection of recurrence of IM and dysplasia in patients who have undergone EET. To that end, increased recurrent IM detection will allow for proper choice of repeat EET and decreased progression to EAC. The specific aims:

1. To assess the additive diagnostic yield of WATS-3D sampling beyond that of standard biopsies for detection of IM or dysplasia (recurrence) in patients who have undergone EET for BE-related neoplasia.
2. To assess the difference in additive diagnostic yield of WATS-3D sampling beyond that of standard biopsies between CE-IM as defined by a single exam without IM vs. >1 exam
3. To assess the impact of order of tissue acquisition techniques on detection of recurrent IM or dysplasia (via randomization)

The proposed study will be a prospective multi-center design over 24 months. The participating centers will include Northwestern University, Washington University in St. Louis, University of Colorado and University of California, Los Angeles.

• A total of 200 patients will be in enrolled in this prospective study. All patients who have completed EET with at least one endoscopy with biopsies demonstrating no evidence of IM will be eligible for enrollment in the study. Enrollment will occur in the setting of outpatient clinic visit or in the endoscopy lab. The PI or study coordinator will meet with the patient and discuss the study, its objectives, and expectations and informed consent will be obtained.
• Enrolled subjects will have completed EET as per clinical standard of care within the framework of the following study design. Standard EET will be defined as resection of visible lesions and ablative therapy (either radio frequency ablation or cryo-therapy). Once complete eradication of intestinal metaplasia (CE-IM) is achieved as defined as no recurrence of BE endoscopically or on forceps biopsies for at least a single EGD, patients will then undergo post-EET surveillance.
• While adhering to standard post-EET surveillance endoscopy intervals, on a prospective basis, the investigators will add WATS-3D to the surveillance protocol. Each patient will be randomized to one of two groups. The first group will undergo biopsies with standard forceps first, followed by tissue sampling with WATS-3D. The second group will undergo tissue sampling with WATS-3D first, followed by biopsies with standard forceps. The forceps biopsies will then be examined by expert pathologists at each respective institution, while the WATS-3D samples will be evaluated at a central laboratory. Each surveillance endoscopy will follow current standard inspection with HD-WLE and NBI. Forceps biopsies will be obtained from: a) the gastric cardia, b) the new squamocolumnar junction, and c) targeted/neosquamous sampling of the original BE segment. WATS-3D brushing will be performed of the: a) squamocolumnar junction to include and visible islands and b) the neosquamous zone representative of the original BE segment. WATS-3D brushings will be taken in 5 cm esophageal segments of the neo-squamous mucosa.
• All physicians will participate in a training session (virtual) which will discuss the use of WATS-3D and ensure all sampling is standardized.
• Once a patient is randomized, all subsequent surveillance endoscopies will follow the same tissue sampling order. For instance, if a patient is assigned to the group that will undergo tissue sampling with WATS-3D first, followed by biopsies with standard forceps second, all surveillance endoscopies will follow sampling in this order. Patients will continue in the study for 2 consecutive endoscopies using this sampling protocol. All patients will be followed longitudinally for the duration of their endoscopy surveillance.
• The investigators will then compare the detection of IM and dysplastic cells obtained via Seattle Protocol biopsies to WATS-3D obtained samples.

Inclusion Criteria:

• All patients aged 18+ diagnosed with Barrett's esophagus with confirmed histologic dysplasia or intra-mucosal cancer undergoing surveillance after EET
• Patients who have achieved CE-IM on at least one surveillance endoscopy following EET
• All subjects must have given signed, informed consent prior to registration in the study

Exclusion Criteria:

• All patients who are unable or unwilling to give consent will not be included in the study
• All patients deemed to have refractory BE despite EET
• Patients who are pregnant, vulnerable populations such as prisoners, life expectancy < 1 year based on concurrent comorbidities, coagulopathy with INR > 1.5 that cannot be reversed, thrombocytopenia with platelets < 125,000 that cannot be corrected with blood products, unable to safely undergo elective endoscopy due to current comorbidities, and inability to pass standard endoscope will not be included in the study